Asymmetric synthesis of homoallylamines by nucleophilic addition of chirally modified allylboron reagent to N-borylimines

Article abstract of DOI:10.1055/s-1999-2996

One pot synthesis of enantioenriched homoallylamines from nitriles is described. Chirally modified allylboron reagents reacted with N-borylimines derived from partial reduction of nitriles with LiEt₃BH to afford enantioenriched homoallylamines

Full text of DOI:10.1055/s-1999-2996

LETTER
1987
Asymmetric Synthesis of Homoallylamines by Nucleophilic Addition of
Chirally Modified Allylboron Reagent to N-Borylimines
Shinichi Itsuno,* Ayako Yokoi, Shizue Kuroda
Department of Materials Science, Toyohashi University of Technology, Toyohashi 441-8580, Japan
Fax +81-532-44-6813; E-mail: itsuno@tutms.tut.ac.jp
Received 13 September 1999
chirally modified allylboron reagent was established to
prepare enantioenriched homoallylamine 3 as shown in
Scheme 1.
Abstract: One pot synthesis of enantioenriched homoallylamines
from nitriles is described. Chirally modified allylboron reagents re-
acted with N-borylimines derived from partial reduction of nitriles
with LiEt3BH to afford enantioenriched homoallylamines in up to
90% ee.
BEt3Li
H
Chirally modified
allylboron reagent
NH2
N
LiEt3BH
Key words: N-borylimine, homoallylamine, nitrile, LiEt3BH,
allylboration
R
CN
*
R
R
1
3
2
1a: R = Ph
1b: R = p-Tolyl
1c: R = o-Tolyl
1d: R = t-Bu
Enantioselective addition of chirally modified allylboron
reagents to imines has a high potential in the production
of optically active amines bearing a stereogenic center at
the a-position.1,2 In particular, N-masked imine deriva-
tives of ammonia including N-metalloimines are useful
substrates for this purpose. Over the last few years we
have been concerned with the development of the enanti-
oselective allylboration of N-masked imine species using
various chiral allylboron reagents.3 We have found that N-
metalloimines such as N-silylimines3 or N-alumino
imines4 are susceptible to allylboration with chiral allyl-
boron reagents to yield primary homoallylamines in high
chemical and optical yield. Although N-borylimines have
scarcely utilized in their alkylation or allylation to pro-
duce amines,5 they are another potential candidate as sub-
strate for the asymmetric allylboration. In this paper, we
have examined asymmetric allylboration of N-bo-
rylimines to lead to optically active primary homoally-
lamines.
B
B
4
5
i
iPrOCO
CO2 Pr
Ph
Me
O
NTs
O
O
B
B
6
7
Scheme 1
N-Borylimines can be prepared by partial reduction of ni-
trile with boranes5,6 or borohydrides.7 We initially exam-
ined partial reduction of benzonitrile with borane (BH3) or
diethylborane (Et2BH) followed by allylboration with tri-
allylborane. However, only a trace amount of the corre-
sponding homoallylamine was observed in the
complicated reaction mixture. Next, we have tested vari-
ous borohydrides as reducing agents of the nitrile and
found that the use of LiEt3BH (Super-Hydride®) afforded
the desired product primary homoallylamine in good yield
after allylboration. Generation of N-borylimine was easily
detected by TLC analysis. Hydrolysis of N-borylimine
yielded the corresponding aldehyde in quantitative yield,
which also proved the formation of the N-borylimine.
Without isolation, the resulting N-borylimines when treat-
ed with allylboron reagent afforded primary homoallyl-
amines after acidic hydrolysis. Thus, on the basis of the
above results the partial reduction of nitrile 1 with
LiEt3BH followed by asymmetric allylboration of 2 with
We chose chirally modified allylboron reagents 4-7
(Scheme 1) in this study, since these reagents are known
to be highly effective for asymmetric allylboration of
aldehydes8 and imines.3,9 The results of asymmetric al-
Synlett 1999, No. 12, 1987–1989 ISSN 0936-5214 © Thieme Stuttgart · New York

1988
S. Itsuno et al.
LETTER
lylboration of N-borylimine 2a derived from benzonitrile A typical experimental procedure is described for the
were shown in Table 1. Brown’s allylboron reagent 4 re- preparation of 2b and its asymmetric allylboration with 4.
vealed high enantioselectivity in the allylboration of 2a at To a solution of p-tolunitrile (5 mmol) in THF (5 ml) was
room temperature. Although the homoallylamine was ob- added dropwise a solution of LiEt3BH (1.0 M in THF, 5
tained even at –78 °C, almost no change of enantioselec- mmol) at 0 °C. The reaction mixture was stirred at room
tivity was observed at various temperatures of –78 °C to temperature for 1h to yield 2b10 which was used without
room temperature.
isolation. The THF solution of 2b obtained was then add-
ed to a solution of 4 prepared from (–)-DIP-Cl (1.92 g, 6
mmol) and allylmagnesium chloride (6 mmol). The reac-
tion mixture was then stirred for 5h at room temperature,
and quenched with 2M HCl. The aqueous layer was sepa-
rated, washed with ether, neutralized with NH4OH and ex-
tracted with ether. The combined extracts were dried over
MgSO4 and concentrated by rotary evaporator to yield a
colorless oil, which was purified by flash column chroma-
tography on silica gel to give the desired homoallylamine
in a 84% yield. Enantioselectivity (90% ee) was deter-
mined by HPLC using a chiral stationary phase [(Daicel
Chiralcel OD-H, hexane/isopropyl alcohol/diethylamine
(90:10:0.1)].
In Table 2 solvent effect on the enantioselectivity was in-
vestigated at room temperature in the allylboration of 2b
(entries 1-6). Of the solvents used in this reaction THF
gave the best result (90% ee). Enantioselectivity of this re-
action is insensitive to reaction temperature in the range of
room temperature to –78 °C. Slight decrease of the ee val-
ues was observed with lowering the temperature. Allyl-
boration of ortho substituted N-borylimine 2c showed
similar tendency. Under similar conditions pivalonitrile
also underwent the reaction sequence (reduction-allylbo-
ration) to afford the corresponding homoallylamine in fair
yield (entries 12, 13), although partial reduction of piva-
lonitrile to the N-borylimine with LiEt3BH required vigor-
ous reaction conditions (reflux for 3h) compared to other In summary, we have developed enantioselective allylbo-
aromatic nitriles (rt for 1h). In the case of this imine (2d), ration of N-borylimines with chirally modified allylboron
no reaction was observed at –78 °C even after 24h due to reagents. N-Borylimines are readily prepared from partial
its steric hindrance. Attempts to extend this chemistry to reduction of nitrile with LiEt3BH. Brown’s chiral allylbo-
include enolizable N-borylimines have not been success- rane 4 was found to be an excellent reagent in this reac-
ful probably due to the instability of these imines.
tion. Further investigations to develop other efficient
synthetic reactions using N-borylimines are in progress.
Acknowledgement
This study was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and Cul-
ture, Japan (Monbusho).
References and Notes
(1) For reactions of allyl organometallics with imines, see:
Kleinman, E. F.; Volkmann, R. A. in Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I.; Heathcock, C. H.; Eds.
Pergamon, Oxford, 1991, Vol. 2, Ch. 4.3.
(2) For a review on the asymmetric addition of nucleophile to the
C=N double bond, see: Enders, D.; Reinhold, U. Tetrahedron:
Asymmetry 1997, 8, 1895. Other recent examples, see:
Chataigner, I.; Zammattio, F.; Lebreton, J.; Villiéras, J. Synlett
1998, 275. Chen, G. –M.; Ramachandran, P. V.; Brown, H. C.
Angew. Chem. Int. Ed. 1999, 38, 825.
(3) Itsuno, S.; Watanabe, K.; Matsumoto, T.; Kuroda, S.; Yokoi,
A.; El-Shehawy, A. J. Chem. Soc., Perkin Trans. 1 1999,
2011. Itsuno, S.; Watanabe, K.; Ito, K.; El-Shehawy, A.;
Sarhan, A. A. Angew. Chem. Int. Ed. Engl. 1997, 36, 109.
Watanabe, K.; Ito, K.; Itsuno, S. Tetrahedron: Asymmetry
1995, 6, 1531.
(4) Watanabe, K.; Kuroda, S.; Yokoi, A.; Ito, K.; Itsuno, S. J.
Organomet. Chem. 1999, 581, 103.
(5) Itsuno, S.; Hachisuka, C.; Kitano, K. Tetrahedron Lett. 1992,
33, 627. Itsuno, S.; Yanaka, H.; Hachisuka, C.; Ito, K. J.
Chem. Soc., Perkin Trans. 1 1991, 1341. Itsuno, S.; Sasaki,
M.; Kuroda, S.; Ito, K. Tetrahedron: Asymmetry 1995, 6,
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(6) Brown, H. C.; Heim, P.; Yoon, N. M. J. Am. Chem. Soc. 1970,
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Synlett 1999, No. 12, 1987–1989 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Homoallylamines by Nucleophilic Addition
1989
(7) Itsuno, S.; Hachisuka, C.; Ushijima, Y.; Ito, K. Synth.
Commun. 1992, 22, 3229.
(10) IR spectra showed the absence of the C≡N group and
absorptions assigned to C=N stretching at 1660 cm-1. 1H NMR
showed the presence of a vinylic proton at 8.7 ppm. 11B NMR
showed a singlet at d –2.1.
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Article Identifier:
1437-2096,E;1999,0,12,1987,1989,ftx,en;Y18499ST.pdf
(9) Chen, G. –M.; Ramachandran, P. V.; Brown, H. C. Angew.
Chem. Int. Ed. 1999, 38, 825.
Synlett 1999, No. 12, 1987–1989 ISSN 0936-5214 © Thieme Stuttgart · New York