New approaches to the synthesis of aminoalkyl-o-carboranes

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New approaches to the synthesis of aminoalkyl-o-carboranes

Vincent Terrasson, José Giner Planas, Damien Prim, Clara Viñas, Francesc Teixidor

To cite this version:

Vincent Terrasson, José Giner Planas, Damien Prim, Clara Viñas, Francesc Teixidor. New approaches

to the synthesis of aminoalkyl-o-carboranes. EuroBoron, 2007, Bremen, Germany. �hal-02913338�

(2)

NH S

HN

NO₂ NO₂

TsNH S

S

HN N₃

N₃

NH OMe Ts

CF₃

Cl

NO₂ 78 %

81 %

98 % 90 %

99 %

87 %

New approaches to the synthesis of aminoalkyl-o-carboranes

aInstitut de Ciència de Materials de Barcelona (CSIC), Campus de la U.A.B, 08193 Bellaterra, Spain.

bInstitut Lavoisier UMR CNRS 8180, Université de Versailles-Saint Quentin en Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles, France

References

(1) J. F. Valliant, K. J. Guenther, A. S. King, P. Morel, P. Schaffer, O. O. Sogbein, K. A. Stephenson, Coord. Chem. Rev. 2002, 232, 173.

(2) See for example, D.-H. Kim, J. H. Won, S.-J. Kim, J. Ko, S. H. Kim, S. Cho, S. O. Kang, Organometallics 2001, 20, 1089.

(3) a) T. L. Heying, J. W. Ager, S. L. Clark, D. J. Mangold, H. L. Goldstein, M. Hillman, R. J. Polak, J. W. Szymanski, Inorg. Chem. 1963, 2, 1089. b) J. G. Wilson, A. K. M. Anisuzzaman, F. Alam, A. H. Soloway, Inorg.

Chem. 1992, 31, 1955. c) E. S. Alekseyeva, A. S. Batsanov, L. A. Boyd, M. A. Fox, T. G. Hibbert, J.A.K. Howard, J. A. H. MacBride, A. Mackinnon, K. Wade, Dalton Trans. 2003, 475.

(4) J.-D. Lee, Y.-J. Lee, H.-J. Jeong, J. S. Lee, C.-H. Lee, J. Ko, S. O. Kang, Organometallics 2003, 22, 445 and references there in.

(5) V. Terrasson, S. Marque, M. Georgy, J.-M. Campagne, D. Prim, Adv. Synth. Catal. 2006, 348, 2063.

(6) H. Nakamura, K. Aoyagi, Y. Yamamoto, J. Org. Chem. 1997, 62, 780.

V. Terrasson,â,bJ. G. Planas,âD. Prim,^bC. Viñas,âF. Teixidor â

Aminoalkyl-o-carboranes have attracted interest due to their potential use in boron neutron capture therapy (BNCT)¹and as ligands for transition metal catalysts.²The synthesis of aminoalkyl-o-carboranes is commonly carried out by the addition of terminal alkynes to activated boranes B₁₀H₁₂L₂.³However this methodology often gives low yields. Other approaches include the reaction of lithio-o-carborane with preformed amines.⁴It is therefore of interest to investigate new synthetic routes that produce aminoalkyl-o-carboranes in good yields and from other functional groups that allow the preparation of a variety of amines. In this sense, we have recently reported a synthesis of amines by Lewis acid-catalyzed direct amination of benzylic alcohols.⁵Thus, we are now interested in utilizing this organic synthetic procedure to introduce the o-carborane fragments, as part of several projects directed towards the preparation of new metal complexes and their application in catalysis and materials science.

1. Lewis acid-catalyzed amination of alcohols

⁵

2. Application to o -carboranylmethyl alcohols

OH

RNH2 +

5% L.A.

CH2Cl2

RT, 16h NH

1 R

+

Ph Ph

O Ph

Ph 2

Amines : Lewis Acids : Yield 1 (%) : Yield 2 (%) :

4-nitroaniline

NaAuCl4 91 0

FeCl₃ 90 5

BF₃.OEt₂ 86 10

Ts–NH₂

NaAuCl₄ 95 0

BF₃.OEt₂ 85 12

2,4-DNPH

NaAuCl4 68 28

BF₃.OEt₂ 13 82

TMS-N3

NaAuCl₄ 93 0

BF₃.OEt₂ 84 6

R¹ R² OH

R¹ Li

+ R²-CHO

THF -78 C, 1h

R¹ R² Yield (%) :

Me Phenyl 95

Me 2-Pyridinyl 87

Me Ferrocene 93

Ph 2-Furanyl 91

R¹ R² OH

+ ^{10 % L.A.}

CH₂Cl₂, 16h NH₂

O₂N

X

One simple and practical access to benzylic amines is the direct amination of the corresponding alcohols (easily available compounds) catalyzed by Lewis acids. In this way, it is avoided the necessary previous transformation of the hydroxyl function into a good leaving group that could then be displaced by an amine.

The reaction of diphenylmethanol with non-coordinating amines gives the desired amine products 1, but also the undesirable symmetrical ether 2, due to competition of the alcohol as a nucleophile (Scheme 1).

Scheme 1

The proportions of the resulting compounds depend on the nature of both the Lewis acid and the amine derivatives. Although nitroaniline gives similar yields of the amination products with Au(III), Fe(III) and BF3as catalysts (Table 1), for other amines, NaAuCl4seems to be the best catalyst in terms of reaction selectivity.

Table 1

Scheme 2

The reaction also gives good results replacing one or two phenyl groups in diphenylmethanol by thiophene units (Scheme 2), by substituting the phenyl group with electron donating (-OMe) or mild electron withdrawing functions (-CF₃).

Monobenzylic substrates also react under the same reaction conditions to give the amination product in good yields.

Table 2 Scheme 3

Scheme 4

In order to apply our strategy to o-carborane substituted benzylic alcohols, we have synthesized several new alcohols, following a previously described procedure (Scheme 3).⁶

Scheme 5 High yields of benzylic alcohols are

obtained by the reaction of o-

carboranyl lithium with

(hetero)aromatic aldehydes, either withπ-donor orπ-acceptor properties (Table 2).

Unfortunately, the reaction of these alcohols with nitroaniline in the presence of Lewis acid catalysts (Fe(III) or BF₃) does not lead to the amination product. In all cases, no reaction was observed at room temperature or refluxing conditions (Scheme 4).

The electron-withdrawing effect of the carborane seems to be strong enough to prevent the reaction, which is assumed to proceed through an S_N1-type mechanism, by destabilizing the benzylic cation intermediate.

Since the direct (catalyzed) amination of these alcohols did not work, we have changed our focus to conventional amination routes. For this, it is necessary to convert the hydroxyl group into a good leaving group such as tosylate in order to obtain the desired amines (Scheme 5).

Although the formation of the tosylate is observed (δ= 5.75 ppm in RMN¹H for the benzylic hydrogen instead of 5.10 ppm for the alcohol with R¹= Me and R²= Ph), the reaction proceeds very slowly converting only 20 % of the alcohol into the tosylate after 18 hours at reflux. Improvements of this strategy are in progress.

R¹ R² OH

R¹ R² OTs

TsCl NEt₃ CH2Cl2

NEt₃ CH2Cl2 HNR'R"

Amination??

We thank CICYT (Project MAT2006-05339), Generalitat de Catalunya (2005/SGR/00709), Spanish Government (RyC to J.G.P.), MENRT-France (grant to V.T.), CNRS and Université de Versailles-Saint Quentin en Yvelines for financial support.