Copper-Catalyzed Carbon-Heteroatom Bond Formations:
Asymmetric Hydroamination and Continuous-Flow Aromatic
Finkelstein Reaction
MASSACHUSETTS INSTITUTE OF TECHNOLOGYby
JUL
0 2 2019
Saki Ichikawa
LIBRARIES
B.S. Chemistry ARCHIVES
The University of Tokyo, 2014
SUBMITTED TO THE DEPARTMENT OF CHEMISTRY IN PARTIAL FULFILLMENT OF
THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY
AT THE
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
June 2019
C 2019 Massachusetts Institute of Technology. All rights reserved.
Signature redacted
Signature of Author: Department of Chemistry May 3, 2019Signature redacted
Certified by: Stephen L. Buchwald Camille Dreyfus Professor of Chemistry Associate Head, Department of Chemistry Thesis SupervisorSignature redacted
Accepted by:
Robert W. Field Haslam and Dewey Professor of Chemistry Chair, Departmental Committee on Graduate Students
This doctoral thesis has been examined by a committee of the Department of Chemistry as
follows:
Signature redacted
Professor Timothy F. Jamison:
Thesis Committee Chair
Professor Stephen L. Buchwald:
Signature redacted
Signature redacted
Thesis Supervisor
Professor Alexander T. Radosevich:
Copper-Catalyzed C arbon-Heteroatom Bond Formations:
Asymmetric Hydroamination and Continuous-Flow Aromatic
Finkelstein Reaction
by
Saki Ichikawa
Submitted to the Department of Chemistry on May 10th 2019
in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry
Abstract
The studies presented in this dissertation are regarding the development of new methods for copper-catalyzed carbon-heteroatom bond formations, including asymmetric hydroamination and continuous-flow aromatic Finkelstein reaction. The first part of this dissertation focuses on the development of copper-catalyzed asymmetric hydroamination reactions to access various classes of enantioenriched amines. This includes the development of a broadly applicable hydroamination protocol for the synthesis of enantioenriched N-arylamines (Chapter 1) and 1,2-diamines (Chapter 2). The second part of this dissertation describes the development of copper-catalyzed aromatic Finkelstein reaction under continuous-flow conditions (Chapter 3).
Part I.
Chapter 1. A Modified System for the Synthesis of Enantioenriched N-Arylamines through Copper-Catalyzed Hydroamination
Despite significant recent progress in copper-catalyzed enantioselective hydroamination chemistry, the synthesis of chiral N-arylamines, which are frequently found in natural products and pharmaceuticals, has not been realized. Initial experiments with N-arylhydroxylamine ester electrophiles were unsuccessful and instead, their reduction, in the presence of copper hydride (CuH) catalysts, was observed. We detail key modifications of our previously reported hydroamination protocols that led to broadly applicable conditions for the enantioselective net addition of secondary anilines across the double bond of styrenes, 1,1 -disubstituted alkenes, and terminal alkenes. NMR studies suggest that suppression of the undesired reduction pathway is the basis for the dramatic improvements in yield under this new protocol.
Chapter 2. Regio- and Enantioselective Synthesis of 1,2-Diamine Derivatives by Copper-Catalyzed Hydroamination
A highly regio- and enantioselective synthesis of 1,2-diamines using y-substituted allylic
pivalamides via copper-catalyzed hydroamination is reported. The N-pivaloyl group is essential, both in facilitating the hydrocupration step and in suppressing the unproductive fl-elimination from the alkylcopper intermediate. This synthetic approach enables an efficient construction of chiral, differentially protected, vicinal diamines under mild conditions with broad functional group tolerance.
Part II.
Chapter 3. Rapid and Efficient Copper-Catalyzed Finkelstein Reaction of (Hetero)Aromatics under Continuous-Flow Conditions
A general, rapid, and efficient method for the copper-catalyzed Finkelstein reaction of
(hetero)aromatics has been developed using continuous flow to generate a variety of aryl iodides. The described method can tolerate a broad range of functional groups, including N-H and O-H groups. Additionally, in lieu of isolation, the aryl iodide products in solution can be directly used in two distinct multistep continuous-flow processes (amidation or Mg-I exchange/nucleophilic addition) to demonstrate the flexibility of this method.
Thesis Supervisor: Stephen L. Buchwald Title: Camille Dreyfus Professor of Chemistry
Acknowledgements
My Ph.D. has been a quest to discover my own answer to this question: what makes a good
scientist? From research, discussions, and interactions with the people around me, I have learned to cultivate a growth mindset, untiring dedication, and a sense of optimism to bounce back from setbacks. Undoubtedly, the best asset I gained over the past years was to get to know these people, and I could not have gone through this journey without them. Thus, I would like to take this opportunity to thank them for their support, guidance, and friendship over the last years. First of all, I would like to express my sincerest gratitude to my research advisor, Prof. Stephen L. Buchwald, for his continuous encouragement and guidance throughout my Ph.D. During the toughest moments when I felt lost, you were by my side, reminding me what is important in life and giving me hope and the strength to carry on. At my individual meeting, there was once a time when you shared your story as a scientist and a PI. It was not solely about accomplishment and success; rather, it was about weakness and concerns you have in the course of your achievements. I was deeply impressed by your strength and adaptability to accept your own weakness, as well as your willingness to pass on everything you have learned, including negative aspects of it, to your students for their sake. I believe this is how a PI ought to be. Steve, you will forever be my best advisor, and it has been truly a privilege to be part of your group.
I would also like to thank my committee members, Profs. Timothy F. Jamison, Alexander T.
Radosevich, and Jeffrey F. Van Humbeck, for being helpful and informative during my time at MIT. Particularly, Prof. Timothy F. Jamison has been a wonderful thesis chair as well as the Department head of Chemistry. It has been always pleasant and helpful to have annual thesis chair meetings with you, and I am also grateful that I had the opportunity to serve the Department of Chemistry alongside you as a ChemREFS for the past years.
In the Buchwald group, I have been fortunate to have inspirational, supportive, and hard-working chemists as my colleagues. I would like to start with expressing my appreciation to Dr. Christine Nguyen who has kept our lab running and been willing to offer help to group members.
With respect to both current and former graduate students in the Buchwald group, my most sincere thanks go to my fellow classmates, Bryan Ingoglia, Drs. Jeffrey Yang and Anthony Rojas. Especially, Bryan has become one of my best friends in the lab, and working in the same bay of both the office and the lab has been tremendously fun. I miss Jeff and his sharp sense of humor (particularly, his conversations with Steve at group meetings), as well as Anthony who nicknamed me Saki-aki. I also would like to acknowledge the "fifth years", Drs. Nicholas Bruno, James Colombe, Philip Milner, Nootaree Niljianskul, Nathan Park, Ekaterina Vinogradova, and Rong Zhu, who helped me settle in the Buchwald group when I was a first-year graduate student, Dr. Pedro Arrechea and his professional pictures of beautiful birds, Dr. Paula Ruiz-Castillo and her hugs, Dr. Yang Yang and his vast knowledge of chemistry, as well as Dr. Yuxuan Ye and small chat with him in the lab. I would like to thank current graduate students in the group, Joey Dennis for his contributions to the group as a Safety Officer and a responsible co-worker (you always brightened up the atmosphere of our bay in the lab), Michael Gribble for his insightful conversations about chemistry and science in general (I still love your forth-year proposal), Richard Liu for his helpful feedbacks about my manuscripts (and sarcastic jokes at group
meetings that never fail to amuse me), Frieda Zhang for her fun conversations about a variety of topics from Japanese sweets to career plans after graduate school, Ryan King for letting me use some of his chemicals, Spencer Shinabery and his talent in grilling, Erica Tsai for her dedication to improve the departmental culture (it has been great to work with you as ChemREFS), Yujing Zhou for her tireless aspiration to be productive, Aaron Mallek for his group meeting presentations in a calm and well-projected voice, Sheng Feng for her dedication to experiments, Azin Saebi for her smiles, Jessica Xu for her impressive knowledge in computer science, as well as Corin Wagen for his pure passion toward chemistry. I also would like to wish good luck to the newest graduate students of the group, Elaine Reichert, Jacob Rodriguez, and Levi Knippel. I hope your time in this group will be fun and rewarding.
There are plenty of current and former post-docs from the Buchwald group to whom I would like to express my gratitude. In particular, I have been blessed with opportunities to collaborate with Drs. Mao Chen, Shaolin Zhu, and Xi-Jie Dai. Mao was one of the nicest people I have ever met, and I learnt a lot about continuous flow chemistry from him. Shaolin provided helpful suggestions when I was in the early stage of the aryl amine project, and he was a very educational mentor. Xi-Jie joined the 1,2-diamine project at the right time, providing tremendous help to me. I also would like to thank Dr. Koji Kubota for his warm encouragement, Dr. Liela Bayeh for fun conversations over lunch, Drs. Scott McCann and Andy Thomas for their thorough editing, Drs. Heemal Dhanjee, Sheng Guo, Alexander Schuppe, and Klaus Speck for their helpful suggestions after group meetings, Drs. Michael Pirnot and Mycah Uehling for helping me prepare for cumulative exams, Dr. Yiming Wang for his advice on my post-doc search, Drs. Haoxuan Wang, Boyoung Park, and Gary Zhang for being nice and caring co-workers. Additionally, I have had a lot of fun interacting with Drs. Erhad Ascic, Vasudev Bhonde, Thierry Leon, Aaron Sather, Hong Geun Lee, Jeffrey Bandar, Shi-Liang Shi, Dawen Niu, Sandra King, John Nguyen, Kurt Armbrust, Esben Olsen, Stefan Roesner, Tim Senter, Daniel Cohen, Stig Friis, Wenliang Huang, Joseph Macor, Xueqiang Wang, Yang Zhao, Oliver Engl, Kashif Khan, Nicholas White, Liang Zhang, Ivan Buslov, Gustavo Borrajo-Calleja, Kwangmin Shin, Chengxi
Li, Achim Link, Zhaohong Lu, and Jason Tao, during the time we overlapped.
As for graduate students outside of the Buchwald group, first and foremost, I would like to thank one of my best friends, Kelley Danahy. Kelley, being around you made everything so much better and enjoyable even during the toughest moments of our Ph.D. quest. We have been through a lot together, both ups and downs, and it was irreplaceable experience that we talked and shared almost everything that happened during our time in graduate school. I also have to give a shout out to my many friends who helped me learn how to relax, especially Jessica Weber (the Thanksgiving holidays with your family were so memorable), as well as Dr. Qifan Zhang (I still remember the time when we first chatted during visiting weekend), among others.
I would like to give a special thanks to the following people whose service to the Department of
Chemistry has helped facilitate the best research environment in the world: in the DCIF, Dr. Walt Massefski, Bruce Adams, John Grimes, and Dr. Mohanraja Kumar, for their continuous efforts to keep our NMR and HR-MS facilities running, as well as in the Chemistry Education Office, Dr. Jennifer Weisman (and of course her dog, Bunk), Rebecca Teixeira, Mitch Moise, and Jay Matthews, for their untiring support to facilitate all educational activities in the department.
I would not have been able to make it through the finish line if not for my family. Thus, I would
like to extend my sincere appreciations especially to my parents for their generous support. They have been willing to give me the freedom to explore my own career choices, and no matter how far they are physically, I still feel very close to them throughout this challenging period of my life. I am also grateful to my younger brother, Akito, and I could not have asked for a better sibling than him.
Finally, my utmost gratitude goes to Kenji Yasuda, a never-ending source of love, encouragement, and motivation. Thank you for being you, and for reminding me who I am.
Preface
Parts of this dissertation have been adapted from the following published articles co-written by the author.
[1] Chen, M.; Ichikawa, S.; Buchwald, S. L. "Rapid and Efficient Copper-Catalyzed
(Hetero)Aromatic Finkelstein Reaction under Continuous-Flow Conditions" Angew. Chem., Int. Ed. 2015, 54, 263-266.
[2] Ichikawa, S.; Zhu, S.; Buchwald, S. L. "A Modified System for the Synthesis of
Enantioenriched N-Arylamines through Copper-Catalyzed Hydroamination" Angew. Chem., Int. Ed. 2018, 57, 8714-8718.
Respective Contributions
This dissertation contains work that is the result of collaborative efforts between the author and other colleagues at MIT. The specific contributions are detailed below.
The work in Chapter 1 was a collaborative effort between Dr. Shaolin Zhu (Buchwald group,
MIT) and the author. Dr. Zhu is credited for the initial finding of the use of tBuOH and PPh3 for
the reaction optimization. Dr. Zhu and the author collaborated on the reaction optimization. The author conducted all of the experiments presented in Chapter 1.
The work in Chapter 2 was carried out in collaboration with Dr. Xi-Jie Dai (Buchwald group, MIT) and the author. Dr. Shaolin Zhu is credited with the initial exploration of the use of a N-protected allylic amine for the synthesis of 1,2-diamines. Dr. Dai and the author worked together on the exploration of the substrate scope for this method. The rest of the experiments in Chapter 2, which were the reaction optimization and a gram-scale reaction, was performed by the author. The work in Chapter 3 resulted from a collaborative effort between Dr. Mao Chen (Buchwald group, MIT) and the author. Dr. Chen initiated the project and is credited for idea, discovery, and optimization of this method under batch conditions. Dr. Chen and the author cooperatively worked on the optimization of this method under continuous-flow conditions, exploration of the substrate scope, and the initial assembling of the subsequent in-line step for a halogen exchange/amidation sequence. Dr. Chen was responsible for the multistep continuous-flow setup for a halogen exchange/Mg-I exchange/nucleophilic addition sequence.
Table of Contents
Part I. Copper-Catalyzed Asymmetric Hydroamination
Chapter 1. A Modified System for the Synthesis of Enantioenriched N-Arylamines through Copper-Catalyzed Hydroamination
1.1 Introduction 13
1.2 Results and Discussion 14
1.3 Mechanistic Investigations via 'H NMR spectroscopy 19
1.4 Conclusion 21
1.5 Experimental Section 22
1.5.1 General Information 22
1.5.2 Procedures for CuH-Catalyzed Hydroamination 23
1.5.3 Characterization Data for Hydroamination Products 24
1.5.4 Preparation of Hydroxylamine Esters 37
1.5.5 Mechanistic Experiments via 'H NMR spectroscopy 49
1.5.6 References for the Experimental Section 56
1.6 'H, 13C, and 19F NMR Spectra 57
1.7 Chiral HPLC Traces for Hydroamination Products 135
1.8 Bibliography 155
Chapter 2. Regio- and Enantioselective Synthesis of 1,2-Diamine Derivatives by Copper-Catalyzed Hydroamination
2.1 Introduction 160
2.2 Results and Discussion 162
2.3 Conclusion 165
2.4 Experimental Section 166
2.4.1 General Information 166
2.4.2 Procedures for CuH-Catalyzed Hydroamination 167
2.4.3 Characterization Data for Hydroamination Products 168
2.4.5 Preparation of Hydroxylamine Esters 180
2.4.6 References for the Experimental Section 185
2.5 'H, "C, and 9F NMR Spectra 186
2.6 GC and Chiral SFC Traces for Hydroamination Products 231
2.7 Bibliography 245
Part 11. Copper-Catalyzed Aromatic Finkelstein Reaction in Continuous-Flow
Chapter 3. Rapid and Efficient Copper-Catalyzed (Hetero)Aromatic Finkelstein Reaction under Continuous-Flow Conditions
3.1 Introduction 250
3.2 Results and Discussion 251
3.3 Conclusion 257
3.4 Experimental Section 258
3.4.1 General Information 258
3.4.2 Experimental Procedures 259
3.4.3 Characterization Data for Finkelstein Reaction Products 267
3.4.4 Preparation of Aryl Bromides 279
3.4.5 References for the Experimental Section 282
3.5 'H and 13C NMR Spectra 284
Part I. Copper-Catalyzed Asymmetric Hydroamination
Chapter 1. A Modified System for the Synthesis of Enantioenriched
N-Arylamines through Copper-Catalyzed Hydroamination
1.1 Introduction
Enantiomerically enriched N-arylamines are important synthetic targets in organic chemistry due to their prevalence in a variety of pharmaceuticals, agrochemicals, and functional
materials.J1 Consequently, their synthesis has been actively investigated over the past few
decades, leading to development of a number of useful approaches, including the addition of
nucleophiles to imines,[2] reductive amination,3
] and late transition metal-catalyzed
hydroamination. 41 In particular, the enantioselective hydroamination of alkenes and alkynes has
received considerable attention due to the conceptual simplicity of this method although the substrate scope is quite limited. While the overall process is thermodynamically feasible under
normal conditions,[5] the hydroamination of unactivated substrates is often hampered by
substantial kinetic demands, which makes the involvement of a catalyst indispensable.[6] In
addition, the use of a catalyst provides high levels of chemo-, regio-, and enantioselectivity of the reaction. Consequently, efficient, general, and selective catalysis for hydroamination has been a long-standing goal in synthetic chemistry.
The use of copper hydride (LCuH) catalysts has recently been demonstrated as a useful
means for the synthesis of chiral secondary and tertiary alkylamines. 71 In reactions using these
catalysts, an alkylcopper intermediate, generated by hydrocupration of an alkene, reacts with a N-alkylhydroxylamine ester to furnish the amine product. N-alkylhydroxylamine esters have previously been employed by several research groups as electrophilic nitrogen sources in
transition metal catalyzed processes. 1101 In contrast, to the best of our knowledge,
N-arylhydroxylamine esters have not been used in these transformations. The extension of the copper-catalyzed asymmetric hydroamination reaction to these electrophilic amine reagents would provide a versatile and flexible approach for the preparation of c-chiral arylamines.
Scheme 1. Initial result of the copper-catalyzed hydroamination of styrene ]a with N-arylhydroxylamine ester 2a.
(a) Reaction with N-arylhydroxylbenzoate under previous conditions
tBu
Ph/a 1a 3.0 mol% Cu(OAc)2 Bn 0 OMe
+ 3.3 mol% (S)-L1 N'
Bn (MeO)2MeSiH (3.0 equiv) Ph Me (S)-L1 = tBu 2
N 0 THF (2.0 M), 60 *C, 3 h 3a 0 P tBu
2a 17%, 41% ee OMe
(1.2 equiv) NEt2 (S)-DTBM-SEGPHOS tBu /2
(b) Possible mechanism and unproductive side reaction
Cu(OAc)2 catalyst L* generation [Si]-H [Sil-OR P L*CuH transmetallation hydrocupration [Si]-H Catalytic Asymmetric Hydroamination CuL* L*Cu-OR Ph Me Ill II unproductive reduction Ar I
Alkyl Alkyl L*CuH Alkyl
Ph Me Ar N,
V IV VI
1.2 Results and Discussion
In light of our previous studies,["] we began our investigation by exploring the reactivity of
N-arylhydroxylamine esters using styrene as the model substrate,
(S)-DTBM-SEGPHOS/Cu(OAc) 2 as the precatalyst and (MeO)2MeSiH 121 as the stoichiometric reductant.
We chose to employ the 4-diethylaminobenzoate ester of phenylbenzylhydroxylamine (2a) as the electrophilic amine source. In the case of aliphatic amines, reagents bearing this modified leaving group were found to possess better stability and enhanced reactivity relative to the
benzoate esters (Scheme la)."'e, I Under these conditions, a small amount of the desired
significant amount of N-benzylaniline was also formed by reductive cleavage of the N-O bond of 2a (Scheme ib).
Table 1. Reaction optimization.[a, b, c]
Bn + ',r X 2 (1.2 equiv) 3.0 mol % Cu(OAc)2 3.3 mol %(S)-L1, 6.0 mol % PR3
(MeO)2MeSiH (3.0 equiv)
additive THF (2.0 M), 60 -C, 3 h
Entry X PR3 Additive yield (%)[bl ee (%)[c]
1 OC(O)C6H4NEt2 PPh3 none 71 87
2 OC(O)C6H4NEt2 PPh3 IBuOH 97 91
3 OC(O)C6H4NEt2 none lBuOH 39 82
4 OC(O)C6H4NEt2 PCy3 SuOH 45 30
5 OC(O)C6H4NEt2 PCyPh2 tBuOH 81 80
6 OC(O)C6H4NEt2 P(2-anisyl)2Ph lBuOH 77 89
7 OC(O)C6H4NEt2 PPh3 iPrOH 48 92
8 OC(O)C6H4NEt2 PPh3 LiOtBu 76 87
9 OC(O)C6H4NEt2 PPh3 NaOtBu 19 89
10 OC(O)C6H4NEt2 PPh3 Mg(OBu)2 62 86
11 OAc PPh3 tBuOH 88 84
12 OPiv PPh3 tBuOH 88 84
13 OC(0)1,3-OMeC6H3 PPh3 BuOH 95 88
[a] Reaction conditions: 0.2 mmol la (1.0 equiv), 2a (1.2 equiv), Cu(OAc)2 (3.0 mol%),
(S)-DTBM-SEGPHOS (3.3 mol%), PR3 (6.0 mol%), additive (1.0 equiv), (MeO)2MeSiH (3.0 equiv)
in THF (0.1 mL) at 60 'C; see 1.5 Experimental Section for details. [b] The yield was determined by GC analysis using n-dodecane as the internal standard. [c] The enantioselectivity was determined by chiral HPLC analysis.
Ph la
a N' Bn
Ph Me 3a
Table 2. Scope of alkenes.[a b] R, R2 1a-1 I + 3 Bn 0 N, N 2a NEt2 (1.2 equiv) 3.0 mol % Cu(OAc)2 .3 mol % (R)-L1, 6.0 mol % PPh3
(MeO)2MeSiH (3.0 equiv)
IBuOH (1.0 equiv) THF (2.0 M), 60 *C, 3-6 h 0 Styrene derivatives N' Bn Ph Me 94% 99% eelb] (92% ee) 3a N'Bn Me 6 4%[b], 99% eelb] (72% GC yield, 86% ee) 3b KaN' Bn Me 79% CF3 85% ee 3c N-Bn 93% 90% ee 3e aN' Bn Ph OMe Me 77% 98% ee 3f (single diastereomer) U 1,1-Disubstituted alkenes Me Bn Me' Il Ph 84% 95% ee 3h 0 Terminal alkenes[c] Bn N Q 53% 3j Me Bn H: I Me N 70% 21:1 dr 31 with (R)-DTBM-SEGPHOS from (R)-limonene Bn 0 ~N 1z 50% 3k a N' Bn Me N 62% 95% ee 3g HMe Me Bn N 64% 1:29 dr 31' with (S)-DTBM-SEGPHOS from (R)-limonene Bn NN 52% 31
[a] Reaction conditions: 0.5 mmol alkene (1.0 equiv), 2a (1.2 equiv), Cu(OAc)2(3.0 mol%),
(R)-DTBM-SEGPHOS (3.3 mol%), PPh3 (6.0 mol%), tBuOH (1.0 equiv), (MeO)2MeSiH (3.0 equiv)
in THF (0.25 mL) at 60 *C; see 1.5 Experimental Section for details. [b] After recrystallization.
N' Bn R,,R2 3a-31 N Bn Ph"JK Me 86% 95% ee 3d
[c] ( )-DTBM-SEGPHOS was used. Both starting materials were fully converted after the reaction time.
To improve upon this result, we conducted an extensive evaluation of reaction conditions
and additives (Table 1). We found that the addition of a catalytic amount of PPh3 as a secondary
ligandl'31 led to a dramatic and unexpected enhancement in yield and enantioselectivity (71%
yield, 87% ee, entry 1). A non-chiral HCu-PPh3 species is presumably generated and does not
compete with the desired hydroamination catalyzed by the DTBM-SEGPHOS-bound copper species.[13] Further improvements were made by the addition of a stoichiometric amount of
tBuOH (1 equiv).1141 In this way, 3a was obtained in high yield and with a high level of
enantiomeric purity (97% yield, 91% ee, entry 2). The inclusion of both PPh3 and tBuOH were
necessary to achieve these results (entry 3). The use of other phosphines as additives resulted in considerably lower yields and/or enantioselectivities (entries 4-6), while the inclusion of other alcohols lowered the yield of 3a (entry 7). The presence of alkoxides, such as LiOtBu, were also investigated and were less effective compared to tBuOH (entries 8-10). A number of electrophilic amine reagents with different leaving groups also provided the desired product with slightly lower levels of enantioselectivity (entries 11-13).
With optimized conditions in hand, we sought to explore the substrate scope of this asymmetric hydroamination process. A variety of alkenes could be effectively transformed into the corresponding enantiomerically enriched amines in good to excellent yields (Table 2). Products from styrene (1a) as well as from styrenes bearing both electron-donating (1b) and electron-withdrawing ring substituents (1c) were competent coupling partners using this protocol. Further, the reaction could be applied to trans- (1d) and cis-fl-substituted styrenes (le), hindered /,J-disubstituted styrenes (If), and 1,1-disubstituted alkenes (1h). Both cis- and trans-#-substituted alkenes yielded the corresponding products in similar yields and in a stereoselective manner as we previously reported.!'"I Moreover, the reaction with 3-vinylpyridine provided 3g in an efficient manner. The catalyst system also achieved high levels of diastereoselectivity in the hydroamination of (R)-limonene (3i, 3i'). Terminal alkenes (Ij-11), which are relatively less reactive compared to styrene derivatives, were also competent substrates that gave the desired products in moderate yield under the reaction conditions. This protocol tolerated terminal alkenes containing a terminal epoxide (1k) and an indole (11).
Table 3. Scope of N-arylamine electrophiles.a. bI
R1k R 1 3.0 mol % Cu(OAc)2
+ 3.3 mol % (R)-L1, 6.0 mol % PPh3 N 3r
R3 (MeO)2MeSiH (3.0 equiv) R2
BuOH (1.0 equiv) R
N X THF (2.0 M), 60 *C, 3-6 h
Ar 2b-2j 4b-4j
(1.2 equiv) X = OC(O)C6H4NEt2 or OPiv
OMe M CF3 P CO2Me CI Me, F N 'Bn Me-KsN' Bn N Bn F3C Me Ph Phj-'Y Me Ph Me 77% 81% 78% 74% 96% ee 86% ee 93% ee 81% ee 4b 4c 4d 4e OMe S ,.-n-C 3H7 Br Me a. Me NN F3C N -I . N. Me N Ph ~Me MePh M PhN Me Ph Me Ph Me 75% 86% 83% 76% 68% 90% ee 91% ee 91% ee 83% ee 85% ee 4f 4g 4h 41 4j
[a] Reaction conditions: 0.5 mmol alkene (1.0 equiv), N-arylamine benzoate (1.2 equiv),
Cu(OAc)2 (3.0 mol%), (R)-DTBM-SEGPHOS (3.3 mol%), PPh3 (6.0 mol%), tBuOH (1.0 equiv),
(MeO)2MeSiH (3.0 equiv) in THF (0.25 mL) at 60 'C; see 1.5 Experimental Section for details.
[b] N-arylamine electrophiles bearing ortho-substituents on the aryl ring did not give products.
We also surveyed the scope of N-arylamine electrophiles (2b-2j) (Table 3). Electron-poor substituents on the aryl ring of the amine electrophile, including a trifluoromethyl group (2b), a fluorine (2c), and an ester (2d), were compatible with our protocol. Also, those containing an aryl chloride (2e) and bromide (2f) were suitable substrates for this process. Unfortunately, we were unable to prepare amine electrophiles in which the aryl group of the aniline had
electron-donating substituents, such as a methoxy group. 15'16] Substrates bearing heterocycles, including
a pyridine (2c) and a thiophene (2g) were successfully converted into the desired products. Additionally, using aryihydroxylamine esters with primary (2h) and cyclic secondary (2i) alkyl groups or an allyl group (2j) led to good results. Notably, an allylic C=C double bond in the
amine electrophile (2j) was left intact, suggesting that the hydrocupration of unactivated internal
alkenes is much more difficult than that of styrene derivatives.I l This also indicated that the
hydrocupration step proceeded in a highly chemoselectivity manner. We have also examined the reaction in the presence of a TIPS-protected propargyl substrate and 1-methyl-iH-imidazole. In the former case the reaction was well tolerated and the latter case, no product was formed (See
1.5 Experimental Section for details).
1.3 Mechanistic Investigations via 'H NMR Spectroscopy
Next, we were interested in ascertaining the origin of the beneficial effect of adding
tBuOH and PPh3 to the reaction mixture. We suspected that these additives attenuated the
unproductive reduction of the hydroxylamine ester reagent. Thus, N-arylhydroxylamine ester 2a
was treated with solutions of (MeO)2MeSiH and copper catalyst in THF-d8 either with or without
the presence of tBuOH/PPh3, and the consumption of 2a was monitored by 'H NMR
spectroscopy (Figure 2).'171 We found that if the amount of added PPh3 was kept constant, the
addition of tBuOH resulted in significantly slower consumption of 2a. The same trend was
observed comparing the presence and absence of PPh3, when the amount of added tBuOH was
kept constant. We speculate that the degradation pattern in the presence of tBuOH without PPh3
resulted from the fact that tBuOH was consumed before the reduction of 2a proceeded (see 1.5 Experimental Section for details). Taken together, this data suggests that both additives play an important role in suppressing the undesired reduction of the hydroxylamine ester, 2. With both additives, less than 10% of 2 was consumed over 1 hour. In comparison, when either additive was omitted, less than 10% of the 2 remained after 50 minutes.
Bn 0 NEt2 2a all a U U U U 0 Standard conditions 0 NSK THF-d8, 60 *C 5a A
+ with tBuOH, with PPh3
U w without tBuOH, wi
I with tBuOH, witho
*a -100 90 80 ~70 60 ccJ 50 o 440 o 30 20 10 0 th PPh3 ut PPh3 50 60 70
Figure 2. Relative rates of the reactions between LCuH and 2. Si* = Si(OMe)2Me. Standard
conditions: 0.4 mmol 2a (1.0 equiv), Cu(OAc)2 (5.0 mol%), (R)-DTBM-SEGPHOS (5.5 mol%),
PPh3 (10.0 mol%), tBuOH (1.0 equiv), (MeO)2MeSiH (3.0 equiv), and THF-d8 (0.53 mL) was
used. The progress of these reactions was monitored at 60 'C by 'H NMR spectroscopy.
Additionally, we monitored the CuH-catalyzed hydroamination of styrene using 2a in the
presence or absence of tBuOH/PPh3 via 'H NMR spectroscopy. We observed that the reaction
rate was also significantly enhanced by the addition of tBuOH/PPh3 (Figure 3), consistent with
the previously proposed' 4' 18] role of tBuOH and PPh3 in promoting turnover of the catalyst. It is
also possible that PPh3 prevents the coordination of amine electrophiles to LCuH, helping to
suppress its undesired reduction.
0 10 20 30 40
Bn 0 1.0 mol% Cu(OAc)
2
N I 1.1 mol% (R)-L1
(MeO)2MeSiH (3.0 equiv)
NEt2 THF-d8, 60 0C
(1.2 equiv) *additives: 2.0 mol% PPh
3 2a IBuOH (1.0 equiv) Bn ( 1 Me 3a vIw f la 100 90 80 o 70 60 0 5~ 50 E. 40 2-0 30 S20 0 4d10 I I I I I 0 10 20 30 40 50 Time [min]
-+- Amine electrophile 2a (with additives) -01- Product 3a (with additives) Amine electrophile 2a (without additives) ' Product 3a (without additives)
60
Figure 3. Reaction enhancement by the addition of tBuOH and PPh3.
1.4 Conclusion
In summary, we have developed a copper-catalyzed hydroamination of alkenes with arylamine O-benzoates for the preparation of enantioenriched tertiary arylamines. The use of
tBuOH, in conjunction with a catalytic amount of PPh3, was critical for enabling the use of
N-arylhydroxylamine esters as the electrophilic nitrogen source. This protocol has been successfully applied to the synthesis of a- and /-chiral arylamines with a variety of functional groups from a diverse range of alkene substrate classes.
-~
Gi
a-bdomh
1.5 Experimental Section 1.5.1 General Information General reagent information
All reactions were performed under an argon atmosphere using the indicated method in
the general procedures. Tetrahydrofuran (THF) was purchased from J.T. Baker in
CYCLE-TAINER@ solvent-delivery kegs and vigorously purged with argon for 2 h, followed by passage
under argon pressure through two packed columns of neutral alumina. Copper (II) acetate was purchased from Strem Chemicals Inc. and was used as received. DTBM-SEGPHOS was
purchased from Takasago and was used as received. Dimethoxymethylsilane ((MeO)2MeSiH,
moisture-sensitive) was purchased from Tokyo Chemical Industry Co. (TCI) and stored in a
nitrogen filled glove box at room temperature for long term storage. Caution:
Dimethoxy(methyl)silane (DMMS, CAS #16881-77-9) is listed by several vendors SDS or
MSDS as a H318, a category 1 Causes Serious Eye Damage. Other vendors list classified
DMMS as a H319, a category II Eye Irritant. DMMS should be handled in a well-ventilated fumehood using proper precaution as outlined for the handling of hazardous materials in "Prudent Practices in the Laboratorys'." At the end of the reaction either ammonium fluoride in methanol, aqueous sodium hydroxide (I M), or aqueous hydrochloric acid (I M) should be carefully added to the reaction mixture. This should be allowed to stir for at least 30 min or the time indicated in the detailed reaction procedure. All other solvents and commercial reagents were used as received from Sigma Aldrich, Alfa Aesar, Strem Chemicals Inc., Acros Organics,
TCI, Combi-Blocks, and Matrix Scientific. Flash Column Chromatography was performed using
silica gel purchased from Silicycle (SilicaFlash® F60, 40-63 mm). Organic solutions were concentrated in vacuo using a Buchi rotary evaporator.
General analytical information
All compounds were characterized by 'H NMR, "C NMR, and 19F NMR (when
applicable). New compounds were also characterized by IR spectroscopy, elementary analysis or high-resolution mass spectroscopy, optical rotation (if chiral and non-racemic), and melting point
analysis (if solids). 'H NMR, "C NMR, and 19F NMR spectra were recorded in CDCl3 or
CD2Cl2 on a Varian 300 MHz, Bruker 400 MHz, Varian 500 MHz, or Bruker 600 MHz
measured in reference to residual chloroform at 7.26 ppm or tetramethylsilane (TMS) at 0.00
ppm as the internal standard, multiplicity, coupling constant (Hz), and integration. Data for 13C
NMR are reported in terms of chemical shift in reference to deuterochloroform (77.16 ppm) and all were obtained with 'H decoupling. All IR spectra were recorded on a Thermo Scientific Nicolet iS5 spectrometer (iDS5 ATR, diamond) and are reported in terms of frequency of absorption (cm'). Melting points were measured using a Mel-Temp capillary melting point apparatus. Enantiomeric excess (ee) values were determined by high performance liquid chromatography (HPLC) analysis using a chiral stationary phase. Optical rotations were
measured on a Jasco P-1010 polarimeter with [a]D values reported in degrees. Elemental
analyses were performed by Atlantic Microlabs Inc., Norcross, GA. ESI-MS spectrometric data was recorded on a Bruker Daltonics APEXIV 4.7 Telsa FOURIER transform ico cyclotron resonance mass spectrometer (FT-ICR-MS). Yields and product ratios reported in Tables 2 and 3 of the manuscript reflect the average values from two independent runs.
1.5.2 Procedures for CuH-Catalyzed Hydroamination
General Procedure A for the Hydroamination ofAlkenes
R1 zR 2 3.0 mol % Cu(OAc)2
. 3.3 mol % (R)-L1, 6.0 mol % PPh3 R3
-~N
R3 (MeO)2MeSiH (3.0 equiv)
L.R2
IBuOH (1.0 equiv) R
X THF (2.0 M), 60 -C, 3-6 h
IAr
X = OC(O)C6H4NEt2 or OPiv
(1.2 equiv)
To a screw-cap oven-dried reaction tube (I) (Fisherbrand, 13 x 100 mm, 8 mL, catalog no. 1495935C) equipped with a stir bar was added the alkene (0.5 mmol, 1.0 equiv) and hydroxylamine ester (0.6 mmol, 1.2 equiv). Reaction tube I was then transferred into a nitrogen-filled glove box. In the glove box, a separate oven-dried reaction tube (II) equipped with a stir
bar was charged with Cu(OAc)2 (2.7 mg, 0.015 mmol, 3.0 mol %), (R)-DTBM-SEGPHOS (19.5
mg, 0.0165 mmol, 3.3 mol %), and PPh3(7.9 mg, 0.03 mmol, 6.0 mol %). THF (0.25 mL) was
added to reaction tube II via a syringe and the mixture was stirred at rt for 5 min until a homogenous blue solution formed, then dimethoxylmethylsilane (185 mL, 1.5 mmol, 3.0 equiv) was added by syringe. The resulting mixture was allowed to stir at rt for an additional 10 min, and the solution changed colors from blue to bright orange. To reaction tube I was added tBuOH
(37.1 mg, 0.5 mmol, 1.0 equiv) followed by the CuH catalyst solution from reaction tube II via
syringe. Reaction tube I was capped (Thermo Scientific 13 mm screw cap with TEF/SIL septa,
catalog no. C4015-66A), removed from the glove box, and placed in an oil bath preheated at 60 'C. After stirring for the time as indicated for each reaction, the reaction tube was removed from the oil bath and allowed to cool to rt. A saturated solution of NH4F in MeOH (5 mL) was
added and the mixture was stirred at rt for 30 min, followed by addition of a saturated aqueous
solution of Na2CO3 (10 mL) and EtOAc (20 mL). The phases were separated and the aqueous
layer was extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with a
saturated aqueous solution of Na2CO3 (2 x 10 mL) and then concentrated in vacuo. 'H NMR
analysis was used to determine the product yield by using 1,1,2,2-tetrachloroethane as an internal
standard (in CDC 3). The crude reaction mixture was purified by flash column chromatography.
1.5.3 Characterization Data for Hydroamination Products (S)-N-benzyl-N-(1-phenylethyl)aniline (3a)
PhN' Bn General Procedure A was followed using styrene (52.1 mg, 0.5 mmol, 1 equiv) and
4-(((benzyl(phenyl)amino)oxy)carbonyl)-NN-diethylaniline (224.7 mg, 0.6 mmol,
1.2 equiv). The reaction mixture was stirred for 3 h. The title product, 3a was
isolated as a white solid after purification by flash column chromatography
(pentanes/EtOAc/NEt3 = 99/0.5/0.5) and recrystallization induced by addition of hot hexanes/EtOAc solution. (Run 1: 139 mg, 0.485 mmol, 97% yield; Run 2: 129 mg, 0.449 mmol, 90% yield).
'H NMR (600 MHz, CDCl3) 8 7.36 (dd, J= 4.9, 2.3 Hz, 4H), 7.28 (td, J= 8.7, 8.1, 4.9 Hz, 5H),
7.24-7.14 (m, 2H), 6.87-6.66 (m, 3H), 5.31 (d, J= 7.0 Hz, 1 H), 4.66-4.34 (m, 2H), 1.63 (dd, J= 7.0, 1.9 Hz, 3H). 13C NMR (151 MHz, CDCI3) 5 149.2, 142.9, 140.1, 129.0, 128.5, 128.3, 126.9,
126.9, 126.5, 126.4, 117.2, 114.3, 57.2, 50.4, 18.7. m.p. 71 'C. IR (neat) 1596, 1502, 1494, 1451, 1383, 1252, 1027, 748, 728, 696. EA Calcd. for C21H2 1N: C, 87.76; H, 7.37. Found: C, 87.58; H,
7.36. Specific rotation [a]D2 4 = 104.4 (c
= 0.125 , CHC 3). HPLC analysis (OD-H, 1.0%
(S)-N-benzyl-N-(I-(4-methoxyphenyl)ethyl)aniline (3b)
Ph..N' Bn General Procedure A was followed using 4-methoxystyrene (67.1 mg, 0.5 Me mmol, 1 equiv) and
4-(((benzyl(phenyl)amino)oxy)carbonyl)-NN-MeOj diethylaniline (224.7 mg, 0.6 mmol, 1.2 equiv). The reaction mixture was stirred for 6 h. The title product was isolated as an off-white solid after
purification by flash column chromatography (pentanes/EtOAc/NEt3 = 99/0.5/0.5) and
recrystallization induced by addition of a hot hexanes/EtOAc solution (Run 1: 98 mg, 0.309
mmol, 62% yield; Run 2: 103 mg, 0.324 mmol, 65% yield).
'H NMR (600 MHz, CDC 3) 8 7.32-7.26 (m, 6H), 7.19 (dt, J= 8.9, 6.1 Hz, 2H), 6.88 (d, J= 8.8
Hz, 2H), 6.80 (d, J= 8.2 Hz, 2H), 6.73 (t, J= 7.3 Hz, IH), 5.28 (q, J= 7.0 Hz, 1H), 4.45 (q, J=
17.4 Hz, 2H), 3.82 (s, 3H), 1.60 (d, J= 7.0 Hz, 3H). 13C NMR (151 MHz, CDC 3) 5 158.5, 149.3,
140.2, 134.7, 129.0, 128.3, 128.1, 126.5, 126.4, 117.1, 114.4, 113.8, 56.6, 55.2, 50.1, 18.5. m.p.
86 'C. IR (neat) 1597, 1510, 1502, 1451, 1247, 1177, 1029, 747, 728, 694. EA Calcd. for C2 2H2 3NO: C, 83.24; H, 7.30. Found: C, 83.31; H, 7.29. Specific rotation [a]D
24 = -125.1 (c =
0.5, CHCI3). HPLC analysis (OD-H, 3.0% i-PrOH/hexanes, 0.8 mL/min) indicated 99% ee: tR
(major) = 9.0 min, tR (minor) = 7.6 min.
(S)-N-benzyl-N-(I -(3-(trifluoromethyl)phenyl)ethyl)aniline (3c)
PhN' Bn General Procedure A was followed using 3-(trifluoromethyl)styrene (86.1 mg,
0.5 mmol, I equiv) and
4-(((benzyl(phenyl)amino)oxy)carbonyl)-NN-Me diethylaniline (224.7 mg, 0.6 mmol, 1.2 equiv). The reaction mixture was stirred
for 6 h. The title product was isolated as a yellow oil after purification by flash
CF3
column chromatography (pentanes/EtOAc/NEt3 = 99/0.5/0.5) (Run 1: 144 mg,
0.405 mmol, 81% yield; Run 2: 137 mg, 0.385 mmol, 77% yield).
'H NMR (600 MHz, CDC 3) 8 7.54 (s, 1H), 7.48-7.37 (m, 2H), 7.33 (t, J= 7.8 Hz, 1 H), 7.18-7.16 (m, 4H), 7.14-7.06 (m, 3H), 6.82-6.61 (m, 3H), 5.20 (q, J= 6.9 Hz, 1 H), 4.58-4.24 (m, 2H),
1.54 (d, J= 7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) 6 148.9, 144.2, 139.7, 130.4, 129.2, 129.0,
128.5, 126.6, 126.6, 123.9, 123.9, 117.9 (d,J C-F= 6.0 Hz), 114.8 (d, JC-F = 10.6 Hz), 57.3, 50.5, 18.3. '"F NMR (471 MHz, CDC 3) 8 -63.0. IR (neat) 1502, 1327, 1162, 1120, 1073, 747, 727,
rotation [a]D2 4 = -23.7 (c = 0.5, CHCl
3). HPLC analysis (OD-H, 3.0% i-PrOH/hexanes, 0.8
mL/min) indicated 85% ee: tR (major) = 8.9 min, tR (minor) = 6.6 min.
(S)-N-benzyl-N-(1-phenylpropyl)aniline (3d)
PhN' Bn General Procedure A was followed using trans-fl-methylstyrene (59.1 mg, 0.5
Ph Me mmol, 1 equiv) and 4-(((benzyl(phenyl)amino)oxy)carbonyl)-NN-diethylaniline
(224.7 mg, 0.6 mmol, 1.2 equiv). The reaction mixture was stirred for 6 h. The title product was isolated as a white solid after purification via flash column chromatography
(pentanes/EtOAc/NEt3 = 99/0.5/0.5) (Run 1: 133 mg, 0.441 mmol, 88% yield; Run 2: 127 mg,
0.421 mmol, 84% yield).
'H NMR (600 MHz, CDCI3) 5 7.45-7.35 (m, 7H), 7.34-7.17 (m, 14H), 6.92 (d, J= 8.2 Hz, 2H), 6.79 (t, J= 7.2 Hz, I H), 5.05 (s, I H), 4.49 (d, J= 17.0 Hz, 2H), 4.37 (d, J= 17.0 Hz, 2H), 2.15
(pd, J= 7.0, 1.5 Hz, 4H), 1.13 (t, J= 7.3 Hz, 5H). 13C NMR (151 MHz, CDC 3) 5 149.5, 141.2,
139.8, 129.0, 128.4, 128.3, 127.9, 127.1, 126.8, 126.4, 117.5, 115.2, 64.8, 50.0, 25.1, 12.2. m.p.
65 'C. IR (neat) 1597, 1495, 1452, 1264, 1027, 735, 700, 667. HRMS-ESI (m/z) [M+H]t Calcd.
for C2 2H2 3N, 302.1826; found, 302.1898. Specific rotation [a]D2
4 = -126.9 (c
= 0.5, CHC 3).
HPLC analysis (OD-H, 1.0% i-PrOH/hexanes, 0.8 mL/min) indicated 95% ee: tR (major) = 8.2
min, tR (minor) = 7.1 min.
(S)-N-benzyl-N-phenyl-2,3-dihydro-1 H-inden- I-amine (3e)
Ph N-Bn General procedure A was followed using indene (58.1 mg, 0.5 mmol, 1 equiv) and 4-(((benzyl(phenyl)amino)oxy)carbonyl)-NN-diethylaniline (224.7 mg, 0.6 mmol, 1.2 equiv). The reaction mixture was stirred for 6 h. The title product was isolated as a slightly yellow oil after purification via flash column chromatography (pentanes/EtOAc/NEt3 = 99/0.5/0.5) (Run 1: 136 mg, 0.454 mmol, 91% yield;
Run 2: 142 mg, 0.474 mmol, 95% yield).
'H NMR (600 MHz, CDCI3) 6 7.43-7.26 (m, 1 1 H), 7.23 (t, J= 7.5 Hz, 1 H), 6.96 (d, J= 8.4 Hz,
2H), 6.83 (t, J= 7.4 Hz, 1 H), 5.77 (t, J= 8.3 Hz, 1 H), 4.45 (q, J= 17.6 Hz, 2H), 3.09-2.87 (m, 2H), 2.60-2.48 (m, I H), 2.20-2.05 (m, IH). 3C NMR (151 MHz, CDCI3) 6 150.0, 143.6, 143.0,
140.4, 129.2, 128.4, 127.7, 126.5, 126.4, 125.1, 124.5, 117.3, 114.1, 64.6, 50.9, 30.7, 30.2. IR (neat) 1595, 1501, 1451, 1388, 1247, 745, 728, 692. HRMS-ESI (m/z) [M+H]T Calcd. for
C2 2H21N, 300.1747; found, 300.1751. Specific rotation [a]D24 = -229.1(c = 0.5, CHCI3). HPLC
analysis (OD-H, 1.0% i-PrOH/hexanes, 0.8 mL/min) indicated 90% ee: tR (major) = 10.6 mm, tR
(minor) = 7.4 min.
N-benzyl-N-((1S)-3-methoxy-2-methyl-1-phenylpropyl)aniline (3f)
Ph N'Bn General procedure A was followed using
(E)-(3-methoxy-2-methylprop-1-en-1-yl)benzene (81.1 mg, 0.5 mmol, I equiv; prepared according to
Ph' Ph .'OMe literature s[221)and 4-(((benzyl(phenyl)amino)oxy)carbonyl)-NN-diethylaniline
Me
(224.7 mg, 0.6 mmol, 1.2 equiv). The reaction mixture was stirred for 6 h. The title product was isolated as a slightly yellow oil after purification via flash column
chromatography (pentanes/EtOAc/NEt3 = 99/0.5/0.5) (Run 1: 124 mg, 0.359 mmol, 72% yield;
Run 2: 142 mg, 0.411 mmol, 82% yield).
'H NMR (600 MHz, CDCl3) 8 7.37-7.28 (m, 5H), 7.24-7.19 (m, 4H), 7.17 (d, J= 7.1 Hz, I H), 7.12 (d, J= 7.6 Hz, 2H), 6.97 (d, J= 8.2 Hz, 2H), 6.81 (t, J= 7.3 Hz, 1 H), 5.03 (d, J= 10.9 Hz, 1 H), 4.47 (d, J= 16.5 Hz, 1 H), 4.22 (d, J= 16.4 Hz, 1 H), 3.74-3.62 (m, 2H), 3.39 (s, 3H), 2.84-2.65 (m, IH), 1.06 (d, J= 6.6 Hz, 3H). 13C NMR (151 MHz, CDCl3) 5 149.5, 139.1, 138.5,
128.8, 128.6, 128.2, 128.1, 127.2, 127.2, 126.3, 118.6, 117.7, 75.3, 67.7, 58.9, 49.1, 34.4, 15.8. IR (neat) 1597, 1495, 1451, 1105, 1077, 747, 727, 695. HRMS-ESI (m/z) [M+H]f Calcd. for
C2 4H27NO, 346.2165; found, 346.2151. Specific rotation [a]D2 4 = -127.8 (c = 0.5, CHC 3).
HPLC analysis (OD-H, 0.5% i-PrOH/hexanes, 0.8 mL/min) indicated 98% ee: tR (major) = 10.8
min, tR (minor) = 13.1 min.
(S)-N-benzyl-N-(1-(pyridin-3-yl)ethyl)aniline (3g)
Ph, N'Bn General procedure A was followed using 3-vinylpyridine (52.6 mg, 0.5 mmol, 1
Me equiv) and 4-(((benzyl(phenyl)amiino)oxy)carbonyl)-NN-diethylaniline (224.7
N mg, 0.6 mmol, 1.2 equiv). The reaction mixture was stirred for 6 h. The title
product was isolated as a yellow oil after purification via flash column
chromatography (pentanes/EtOAc/MeOH/NEt3 = 40/2/2/1) (Run 1: 89 mg, 0.309 mmol, 62%
yield; Run 2: 89 mg, 0.309 mmol, 62% yield).
'H NMR (600 MHz, CD2Cl2) 5 8.69 (d, J= 2.4 Hz, I H), 8.53 (dd, J= 4.8, 1.7 Hz, 1 H), 7.71 (d,
6.79 (t, J= 7.3 Hz, 1H), 5.37-5.33 (in, IH), 4.57 (d, J= 17.2 Hz, 1H), 4.47 (d, J= 17.2 Hz, I H),
1.69 (d, J = 7.0 Hz, 3H). "C NMR (151 MHz, CD2Cl2) 5 148.9, 148.8, 148.3, 139.8, 138.2, 134.6, 129.0, 128.4, 126.6, 126.5, 123.3, 117.9, 115.0, 55.9, 50.0, 17.8. IR (neat) 1595, 1502,
1494, 1253, 747, 728, 713, 693. HRMS-ESI (m/z) [M+H]+ Calcd. for C20H20N2, 289.1699;
found, 289.1692. Specific rotation [a]D24 = -86.4 (c =
0.5, CHCl3). HPLC analysis (OD-H,
10.0% i-PrOH/hexanes, 0.8 mL/min) indicated 95% ee: tR (major) = 18.8 min, R (minor) = 16.6
min.
(R)-N-benzyl-N-(2-(dimethyl(phenyl)silyl)propyl)aniline (3h)
Me Ph General procedure A was followed using
dimethyl(phenyl)(prop-1-en-2-I yl)silane (88.2 mg, 0.5 mmol, 1 equiv) and
4-Me, N Bn
Ph (((benzyl(phenyl)amino)oxy)carbonyl)-N,N-diethylaniline (224.7 mg, 0.6
mmol, 1.2 equiv). The reaction mixture was stirred for 6 h. The title product was isolated as a
slightly yellow oil after purification via flash column chromatography (pentanes/EtOAc/NEt3
99/0.5/0.5) (Run 1: 142 mg, 0.395 mmol, 79% yield; Run 2: 158 mg, 0.439 mmol, 88% yield).
'H NMR (600 MHz, CDCI3) 8 7.61-7.54 (in, 3H), 7.47-7.40 (in, 5H), 7.34-7.27 (in, 5H), 7.24 (d, J= 7.3 Hz, 2H), 7.22-7.07 (in, 7H), 6.66 (s, I H), 6.59 (d, J= 8.3 Hz, 4H), 4.62 (d, J= 17.1
Hz, 2H), 4.49 (d, J= 17.1 Hz, 2H), 3.71 (dd, J= 14.8, 3.8 Hz, 2H), 3.21 (dd, J= 14.8, 11.7 Hz,
2H), 1.68-1.64 (in, 2H), 1.08 (d, J= 7.2 Hz, 5H), 0.37 (d, J= 2.0 Hz, 1OH). 13C NMR (151
MHz, CDC 3) 5 148.5, 138.9, 137.6, 133.9, 129.2, 129.0, 128.5, 127.9, 126.6, 126.6, 115.9,
112.7, 55.3, 53.8, 19.4, 13.2, -4.6, -5.2. IR (neat) 1504, 1249, 831, 812, 773, 745, 727, 694. HRMS-ESI (m/z) [M+H]+ Calcd. for C24H29NSi, 360.2142; found, 360.2160. Specific rotation
[a]D2 4 = 3.5 (c = 0.5, CHCl3). HPLC analysis (OD-H, 10% i-PrOH/hexanes, 0.8 mL/min)
indicated 95% ee: tR (major) = 7.4 min, tR (minor) = 8.2 min.
N-benzyl-N-((S)-2-((R)-4-methyleyclohex-3-en-1-yl)propyl)aniline (3i)
Me Ph General procedure A was followed using (R)-limonene (68.1 mg, 0.5
H:
Bn mmol, 1 equiv) and 4-(((benzyl(phenyl)amino)oxy)carbonyl)-NN-Me diethylaniline (280.9 mg, 0.75 mmol, 1.5 equiv) The reaction mixture
was stirred for 24 h. The title product was isolated as a yellow oil after purification via flash
column chromatography (pentanes/EtOAc/NEt3= 99/0.5/0.5) (Run 1: 111 mg, 0.347 mmol, 69%
yield; Run 2: 112 mg, 0.351 mmol, 70% yield)
'H NMR (600 MHz, CDCI3) 6 7.46-7.35 (m, 3H), 7.32-7.24 (m, 5H), 6.83-6.70 (m, 3H), 5.53-5.43 (m, I H), 4.74-4.61 (m, 2H), 3.65 (dd, J= 14.7, 6.2 Hz, 1 H), 3.29 (dd, J= 14.7, 8.5 Hz, 1 H), 2.14-1.96 (m, 5H), 1.88-1.80 (m, 1H), 1.75 (s, 3H), 1.72-1.65 (m, 1H), 1.46-1.40 (m, IH), 1.02 (d, J= 6.9 Hz, 3H). 13C NMR (151 MHz, CDC 3) 5 148.9, 138.9, 134.1, 129.2, 128.6, 126.7, 126.7, 121.0, 116.1, 112.6, 55.9, 55.4, 36.4, 36.0, 30.8, 30.0, 24.8, 23.6, 14.2. IR (neat) 1596,
1504, 1451, 1353, 1233, 744, 727, 692. HRMS-ESI (m/z) [M+H]+ Calcd. for C23H29N,
320.2373; found, 320.2357. Specific rotation [a]D2 4
= 8.7 (c = 0.5, CHCl3). HPLC analysis (2 OD-H columns, hexanes, 0.5 mL/min) of the crude reaction mixture indicated 21:1 dr: tR (major) = 107.5 min, tR (minor) = 98.1 min.
N-benzyl-N-((R)-2-((R)-4-methylcyclohex-3-en-1-yl)propyl)aniline (3i')
H Me Ph General procedure A was followed using (R)-limonene (68.1 mg, 0.5
N'Bn mmol, 1 equiv) and
4-(((benzyl(phenyl)amino)oxy)carbonyl)-N,N-Me diethylaniline (280.9 mg, 0.75 mmol, 1.5 equiv). The reaction mixture
was stirred for 24 h. The title product was isolated as a yellow oil after purification via flash
column chromatography (pentanes/EtOAc/NEt3 = 99/0.5/0.5) (Run 1: 105 mg, 0.329 mmol, 66%
yield; Run 2: 99 mg, 0.3 10 mmol, 62% yield)
'H NMR (600 MHz, CDC 3) 6 7.43 (s, 1H), 7.38 (t, J= 7.5 Hz, 2H), 7.32-7.27 (m, 5H), 6.82-6.73 (m, 3H), 5.54-5.43 (m, I H), 4.77-4.61 (m, 2H), 3.66 (dd, J= 14.6, 5.3 Hz, 1 H), 3.26 (dd, J = 14.7, 9.1 Hz, IH), 2.18-2.09 (m, 2H), 2.08-2.01 (m, IH), 2.00-1.91 (m, IH), 1.84-1.77 (m,
1H), 1.75 (s, 3H), 1.69-1.62 (m, 1H), 1.54-1.46 (m, IH), 1.03 (d, J= 6.9 Hz, 3H). 13C NMR
(151 MHz, CDC 3) 6 148.8, 138.9, 134.1, 129.2, 128.6, 126.7, 126.7, 120.7, 116.01, 112.6, 56.2,
55.5, 36.7, 36.4, 31.0, 27.6, 27.2, 23.6, 14.2. IR (neat) 1596, 1504, 1494, 1451, 1353, 745, 727,
693. HRMS-ESI (m/z) [M+H]+ Calcd. for C23H29N, 320.2373; found, 320.2367. Specific rotation [a]D24 = 39.1 (c = 0.5, CHCl
3). HPLC analysis (2 OD-H columns, hexanes, 0.5
mL/min) of the crude reaction mixture indicated 1:29 dr: tR (major) = 94.4 min, tR (minor)
N-benzyl-N-(4-phenylbutyl)aniline (3j)
General procedure A was followed using 4-phenyl-I-butene (66.1 mg,
N'Ph 0.5 mmol, 1 equiv) and
4-(((benzyl(phenyl)amino)oxy)carbonyl)-NN-n diethylaniline (224.7 mg, 0.6 mmol, 1.2 equiv). The reaction mixture
was stirred for 24 h. The title product was isolated as a yellow oil after
purification via flash column chromatography (pentanes/EtOAc/NEt3 = 99/0.5/0.5) (Run 1: 80
mg, 0.254 mmol, 51% yield; Run 2: 87 mg, 0.276 mmol, 55% yield)
'H NMR (400 MHz, CDC 3) 6 7.24-7.05 (m, 12H), 6.66-6.49 (m, 3H), 4.43 (s, 2H), 3.32 (t, J
7.2 Hz, 2H), 2.55 (t, J= 7.2 Hz, 2H), 1.69-1.51 (m, 4H). 13C NMR (101 MHz, CDCl
3) 6 148.6,
142.3, 139.1, 129.3, 128.6, 128.4, 128.4, 126.8, 126.6, 125.9, 116.0, 112.1, 54.5, 51.2, 35.8, 29.1,
26.9. IR (neat) 1597, 1505, 1452, 1355, 1264,1028, 734, 695. HRMS-ESI (m/z) [M+H]+ Calcd. for C23H25N, 316.1983; found, 316.2055.
N-benzyl-N-(6-(oxiran-2-yl)hexyl)aniline (3k)
General procedure A was followed using 2-(hex-5-en-1-yl)oxirane
0
N'Ph (63.1 mg, 0.5 mmol, I equiv) and
4-Bn (((benzyl(phenyl)amino)oxy)carbonyl)-N,N-diethylaniline (224.7
mg, 0.6 mmol, 1.2 equiv). The reaction mixture was stirred for 6 h. The title product was isolated
as a yellow oil after purification via flash column chromatography (pentanes/EtOAc/NEt3 =
94.5/5/0.5) (Run 1: 77 mg, 0.249 mmol, 50% yield; Run 2: 76 mg, 0.246 mmol, 49% yield).
'H NMR (400 MHz, CDC3) 8 7.26-7.06 (m, 7H), 6.63-6.52 (m, 3H), 4.45 (s, 2H), 3.38-3.19 (m, 2H), 2.88-2.72 (m, IH), 2.65 (t, J= 4.5 Hz, IH), 2.36 (dd, J= 5.1, 2.7 Hz, 1H), 1.65-1.53
(m, 2H), 1.47-1.24 (m, 8H). 3C NMR (101 MHz, CDC
3) 6 148.6, 139.2, 129.3, 128.6, 126.8, 126.6, 116.0, 112.1, 54.5, 52.4, 51.3, 47.2, 32.5, 29.4, 27.2, 27.1, 26.1. IR (neat) 1597, 1504,
1451, 1354, 1194, 745, 728, 692. HRMS-ESI (m/z) [M+H]f Calcd. for C2 1H27NO, 310.2088;
N-(4-(IH-indol-1-yl)butyl)-N-benzylaniline (31)
Ph General procedure A was followed using 1-(but-3-en-1-yl)-IH-indole
(85.6 mg, 0.5 mmol, 1 equiv) and
4-N B n
(((benzyl(phenyl)amino)oxy)carbonyl)-N,N-diethylaniline (224.7 mg,
0.6 mmol, 1.2 equiv). The reaction mixture was stirred for 6 h. The
title product was isolated as a yellow oil after purification via flash column chromatography
(pentanes/EtOAc/NEt3 = 98/1.5/0.5) (Run 1: 84 mg, 0.237 mmol, 47% yield; Run 2: 100 mg,
0.281 mmol, 56% yield). 'H NMR (400 MHz, CDCl3) 5 7.54 (d, J= 7.8 Hz, 1 H), 7.24-7.15 (m, 3H), 7.15-7.04 (m, 6H), 7.01 (t, J= 7.4 Hz, IH), 6.94 (d, J= 3.1 Hz, 1H), 6.66-6.47 (m, 3H), 6.39 (d, J= 3.1 Hz, IH), 4.36 (s, 2H), 4.00 (t, J= 7.0 Hz, 2H), 3.26 (t, J= 7.5 Hz, 2H), 1.86-1.69 (m, 2H), 1.64-1.49 (m, 2H). "C NMR (101 MHz, CDCl3) 6 148.5, 138.9, 129.4, 128.7, 128.7, 127.8, 126.9, 126.6, 121.5, 121.1, 119.4, 116.4, 112.4, 109.4, 101.2, 54.6, 50.8, 46.3, 28.0, 24.9. IR (neat) 1596, 1505,
1463, 1451, 1355, 1315, 740, 693. HRMS-ESI (m/z) [M+H]+ Calcd. for C25H26N20, 355.1982;
found, 355.2053.
(R)-N-benzyl-N-(2-(dimethyl(phenyl)silyl)propyl)-3-(trifluoromethyl)aniline (4b)
< CF3 General procedure A was followed using
dimethyl(phenyl)(prop-1-en-Me 2-yI)silane (88.2 mg, 0.5 mmol, I equiv) and
4-(((benzyl(3-Mes . N, (trifluoromethyl)phenyl)amino)oxy)carbonyl)-NN-diethylaniline (265.5
MeS i NBn
Ph mg, 0.6 mmol, 1.2 equiv). The reaction mixture was stirred for 6 h. The
title product was isolated as a colorless oil after purification via flash column chromatography
(pentanes/EtOAc/NEt3 = 99/0.5/0.5) (Run 1: 162 mg, 0.379 mmol, 76% yield; Run 2: 165 mg,
0.386 mmol, 77% yield). IH NMR (600 MHz, CDC 3) 5 7.61-7.53 (m, 2H), 7.44-7.38 (m, 3H), 7.34-7.29 (m, 2H), 7.27-7.23 (m, 1 H), 7.20 (t, J= 8.1 Hz, 1 H), 7.15 (d, J= 7.5 Hz, 2H), 6.98-6.76 (m, 2H), 6.67 (dd, J= 8.4, 2.6 Hz, I H), 4.64 (d, J= 17.1 Hz, 1 H), 4.50 (d, J= 17.1 Hz, 1 H), 3.74 (dd, J= 14.9, 3.9 Hz, 1H), 3.23 (dd, J= 15.0, 11.7 Hz, 1H), 1.76-1.59 (m, IH), 1.08 (d, J= 7.3 Hz, 3H), 0.38 (d, J= 4.8 Hz, 6H). 13C NMR (101 MHz, CDC 3) 6 148.4, 138.0, 137.3, 133.8, 129.5, 129.3, 128.8 (d, J C-F= 5.1 Hz), 128.7, 128.6 (d, J C-F = 7.1 Hz), 128.0, 127.0, 126.6, 115.6, 112.3, 108.8, 55.5, 54.0, 19.3, 13.1, -4.5, -5.5. 19F NMR (471 MHz, CDC 3) 6 -63.1. IR (neat) 1319, 1162, 1117,
1066, 812, 775, 729, 695. HRMS-ESI (m/z) [M+H]* Calcd. for C25H28F3NSi, 428.2016; found,
428.2025. Specific rotation [a]D2 4 = -2.0 (c 0.5, CHC
3). HPLC analysis (OD-H, hexanes, 0.8
mL/min) indicated 96% ee: tR (major) = 18.1 min, tR (minor) = 21.5 min.
(S)-4-fluoro-N-((6-methoxypyridin-3-yl)methyl)-N-(1-phenylpropyl)aniline (4c)
OMe General procedure A was followed using trans-fl-methylstyrene (59.1 mg,
N 0.5 mmol, I equiv) and
N-(4-fluorophenyl)-N-((6-methoxypyridin-3-F ' yl)methyl)-0-pivaloylhydroxylamine (199.4 mg, 0.6 mmol, 1.2 equiv). The
reaction mixture was stirred for 6 h. The title product was isolated as a
N
Ph Me white solid after purification via flash column chromatography
(pentanes/EtOAc/NEt3 = 99/0.5/0.5) (Run 1: 138 mg, 0.394 mmol, 79%
yield; Run 2: 145 mg, 0.414 mmol, 83% yield).
' H NMR (600 MHz, CDC13) 6 7.98 (d, J= 2.4 Hz, 1 H), 7.41-7.32 (m, 3H), 7.32-7.28 (m, 3H), 6.94-6.88 (m, 2H), 6.86-6.79 (m, 2H), 6.62 (d, J= 8.5 Hz, I H), 4.63 (t, J= 7.3 Hz, 1 H), 4.20 (d, J= 15.7 Hz, IH), 4.01 (d, J = 15.6 Hz, IH), 2.09-1.96 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H). 3 C NMR (151 MHz, CDCl3) 6 163.2, 157.0 (d,J C-F 240.1 Hz), 145.8, 145.5 (d, JC-F 2.4 Hz), 140.5, 138.2, 128.3, 128.0, 127.3 (d, JC-F = 9.3 Hz), 120.3 (d, JC-F 7.8 Hz), 115.4, 115.3, 110.5, 67.5, 53.3, 48.1, 25.1, 11.9. '"F NMR (471 MHz, CDCI3) 6-125.2. IR (neat) 1505, 1490, 1280, 1228, 1025, 821, 735, 699. HRMS-ESI (m/z) [M+H] Calcd. for C22H23FN20, 351.1867;
found, 351.1856. Specific rotation [a]D24 = -74.7 (c = 0.5, CHC 3). HPLC analysis (OD-H,
1.0% i-PrOH/hexanes, 0.8 mL/min) indicated 86% ee: tR (major) = 13.8 min, tR (minor) = 12.1 min.
Methyl (S)-3-(benzyl(I -phenylethyl)amino)benzoate (4d)
CO2Me General Procedure A was followed using styrene (52.1 mg, 0.5 mmol, I equiv)
and methyl 3-(benzyl((4-(diethylamino)benzoyl)oxy)amino)benzoate (259.5 mg,
N'Bn 0.6 mmol, 1.2 equiv). The reaction mixture was stirred for 6 h. The title product
Ph)Me was isolated as a yellow solid after purification via flash column chromatography
(pentanes/EtOAc/NEt3 = 99/0.5/0.5) (Run 1: 136 mg, 0.394 mmol, 79% yield;
![Table 1. Reaction optimization.[a, b, c]](https://thumb-eu.123doks.com/thumbv2/123doknet/14494030.526449/15.917.148.739.187.769/table-reaction-optimization-a-b-c.webp)
![Table 2. Scope of alkenes.[a b] R, R2 1a-1 I + 3 Bn 0 N, 2a N NEt2 (1.2 equiv) 3.0 mol % Cu(OAc) 2 .3 mol % (R)-L1, 6.0 mol % PPh 3](https://thumb-eu.123doks.com/thumbv2/123doknet/14494030.526449/16.917.166.693.107.930/table-scope-alkenes-bn-net-equiv-oac-pph.webp)
