Enantioselective transfer aminoallylation: Synthesis of optically active homoallylic primary amines

Article abstract of DOI:10.1021/ja064106r

A camphorquinone-derived chiral homoallylic amine was found to react with various aldehydes via imine formation and asymmetric 2-azonia-Cope rearrangement to give optically active homoallylic primary amines. A practical level of enantioselectivity with hi

Full text of DOI:10.1021/ja064106r

Published on Web 08/04/2006
Enantioselective Transfer Aminoallylation: Synthesis of Optically Active
Homoallylic Primary Amines
Masaharu Sugiura, Chieko Mori, and Shuj Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received June 11, 2006; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Scheme 1. Transfer Aminoallylation
Homoallylic primary amines are of great value in organic
synthesis because the carbon-carbon double bonds of the allyl
groups are readily converted to a variety of functional groups and
desired substituents or protective groups can be introduced on the
free amine moieties. Addition of allylic nucleophiles to CdN
electrophiles is one of the most effective methods for construction
of homoallylic amines, and efficient enantioselective methods
including asymmetric catalysis have been reported.1 However, most
of those methods require deprotection of substituents on the nitrogen
to obtain primary amines, and direct routes to those compounds,
especially as optically active forms, have been limited. Istuno et
al.2 and Brown et al.3 reported allylboration of N-silylimines with
chiral allyboron reagents as a route to those compounds, and
although high enantioselectivities were obtained in these cases, only
non-enolizable imines were applicable.
We have recently reported R-aminoallylation of aldehydes with
ammonia and allylboronates for synthesis of homoallylic primary
amines4 and demonstrated an enantioselective version utilizing a
chiral allylboronate, although the selectivity was unsatisfactory. In
the course of our study into the allylation of hydroxyglycine,5 we
have found that â-branched allylglycines isomerized to the corre-
sponding linear isomers via imine formation with glyoxylic acid,
followed by 2-aza (or azonia)-Cope rearrangement. This type of
sigmatropic rearrangement was first reported in 1950,6 but has been
little utilized in organic synthesis due to the inherent problem of
the reversibility of the process. Overman and Kakimoto devised a
2-azonia-Cope rearrangement/Mannich reaction sequence to over-
come this problem.7 Although related transformations of homoal-
lylic alcohols via 2-oxonia-Cope rearrangement have been reported
and successfully utilized for the synthesis of optically active
homoallylic alcohols,8 an aza-analogue of this enantioselective
transformation has not yet been described. Herein we report, for
the first time, the highly enantioselective synthesis of homoallylic
primary amines via 2-azonia-Cope rearrangement.
Scheme 1 depicts the general concept. Under this resume,
optically active amine 1 reacts with aldehyde 2 to form imine 4,
which could then undergo 2-aza (or azonia, if the nitrogen is
protonated)-Cope rearrangement to 5. Finally, enantio-enriched
homoallylic primary amine 3 would be obtained after cleavage of
the CdN bond of 5. We term this sequence “transfer aminoally-
lation” because both the amino and the allyl groups of 1 are
incorporated in product 3. In addition, optically active amine 1 could
be prepared via aminoallylation of chiral carbonyl compounds with
ammonia, which we have reported previously.4
To examine the feasibility of this concept, we turned our attention
to ketone-derived homoallylic amines 1 (R1, R2 * H) because those
were expected to sterically bias the rearrangement from 4 to 5.
Considering accessibility by aminoallylation, an activated ketone,
(1R)-camphorquinone, was selected as a starting chiral ketone. We
were pleased to find that its aminoallylation with ammonia and
allylboronic acid pinacol ester4 proceeded smoothly to give R-ami-
noketone 1a in good yield with perfect diastereoselectivity (eq 1).
With 1a in hand, we then examined transfer aminoallylation of
glyoxylic acid monohydrate (2a) under several conditions, varying
solvents (CH2Cl2, CH3CN, EtOH, MeOH, and water) and temper-
ature (-40 °C to room temperature). It was found that high
enantioselectivities were obtained regardless of solvents. Of
particular note is that the reaction in ethanol at -40 °C provided
(S)-allylglycine with 93% ee after acidic work-up (Scheme 2). The
reaction proceeded much faster at room temperature albeit with
slightly lower selectivity.
Scheme 2. Transfer Aminoallylation of Glyoxylic Acid (2a) with 1a
An initial attempt to adapt 1a to the reaction with benzaldehyde
(2b) did not result in the formation of the desired product but,
instead, the corresponding imine 4b was obtained (Table 1, entry
1). Considering the superiority of glyoxylic acid as a substrate, acid
catalysts were anticipated to accelerate the rearrangement of 4b
via formation of the corresponding iminium ion. In fact, the reaction
proceeded well in the presence of a catalytic or stoichiometric
amount of an acid. Moreover, it was noted that excellent enanti-
oselectivities (up to 97% ee) were obtained even at 20-50 °C
(entries 2-5). Among the acids tested, a catalytic amount of
camphorsulfonic acid (CSA) was the best in terms of the yield and
the enantioselectivity (entries 4 and 5). In addition, use of
hydroxylamine was found to be important to release amine 3b in
high yield from the rearranged product.9
Transfer aminoallylation of various aldehydes was then inves-
tigated using CSA as a catalyst in DCE (Table 2). In all cases,
homoallylic primary amines were obtained with high enantiomeric
excesses over 95%. Electron-withdrawing aromatic aldehydes tend
to show higher reactivity than electron-donating ones (entries 1-6
and see also entry 5 of Table 1). In comparison with aromatic
aldehydes, reactions of aliphatic aldehydes, even though they are
9
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10.1021/ja064106r CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Transfer Aminoallylation of Benzaldehyde with 1aa
double bond. The geometries were assigned by NOESY experi-
ments.10 Only the major isomer of 5b showed a strong NOE
correlation between the bridgehead proton and the proton adjacent
to the nitrogen atom, proving the (E)-geometry of the CdN bond.
Formation of (S)-3b with high enantiomeric excess from both
isomers of 5b strongly supports that the rearrangement of 4b
proceeds via chair-like transition state TS to give (Z)-5b (Scheme
3) and that (E)-5b is generated through isomerization of (Z)-5b
under the acidic conditions.
entry
conditions
% yieldb
% eec
1
2
3
4
5
6
CH2Cl2, 20 °C, 1 d
0d
27
50
59
81
72
AcOH (1.0 equiv), CH2Cl2, 20 °C, 3 d
TFA (0.1 equiv), CH2Cl2, 20 °C, 3 d
CSA (0.1 equiv), CH2Cl2, 20 °C, 3 d
CSA (0.1 equiv), DCE, 50 °C, 1 d
TfOH (0.1 equiv), CH2Cl2, 20 °C, 2 d
97
95
97
97
87
In addition, the whole reaction process before quenching was
found to be reversible. When a geometrical mixture of 5b (E/Z )
89:11) was subjected to CSA (10 mol %) in CDCl3 at 50 °C,
1
formation of imine 4b was observed by H NMR analysis.10 The
a All reactions were quenched by treatment with HONH2‚AcOH (2.0
equiv) in MeOH at 50 °C for 3 h. b Isolated yield. c Determined by HPLC
analysis (CHIRALCEL OD-H). d Compound 4b was obtained.
reaction was allowed to equilibrate within 48 h with a ratio of 2b/
4b/(Z)-5b/(E)-5b ) 1:5:18:76, and almost the same ratio was
obtained starting from isolated imine 4b. As expected, the equi-
librium position is dependent on the aldehyde structure. For
example, the reaction of 2-thiophenecarboxaldehyde (2f) with 1a
in CDCl3 resulted in a ratio of 2f/4f/(Z)-5f/(E)-5f ) 4:35:18:43 at
50 °C after 48 h.10 The product ratio was much smaller than that
of the reaction with benzaldehyde.
In summary, we have demonstrated a direct, enantioselective
route to homoallylic primary amines based on asymmetric 2-azonia-
Cope rearrangement. Due to the high functional group tolerance
and practical level of enantioselectivity, application of this new
protocol to the synthesis of complex molecules would be possible.
Further studies including development of a catalytic, enantioselec-
tive method are now in progress.
Acknowledgment. This work was partially supported by
ERATO, Japan Science Technology Agency (JST), and a Grand-
in-Aid for Scientific Research from Japan Society of the Promotion
of Sciences (JSPS).
Supporting Information Available: Experimental details and
physical data (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org
Table 2. Transfer Aminoallylation of Various Aldehydesa
entry
R in 2
temp. (
°
C) % yieldb
% eec
1
2
3
4
5
6
7
8
9
p-NO2C6H4 (2c)
p-BrC6H4 (2d)
p-MeOC6H4 (2e)
2-thienyl (2f)
2-furanyl (2g)
3-pyridyl (2h)
PhCH2CH2 (2i)
PhCH2 (2j)
50
50
50
50
50
50
0
0
0
0
0
92
88
72
57
60
91
88
77
81
88
85
73
87
87
98
98
97
98
97
98
95
96
n-C7H15 (2k)
97d
93 (98)g
92 (97)g
95d
96
10 (S)-Me2CdCHC2H4CH(Me)CH2 (2l)e,f
11h 2le,f
12 cyclohexyl (2m)
13 BnOCH2CH2 (2n)
14 BnOCH2 (2o)
0
0
0
95
a All reactions were quenched by treatment with HONH2‚AcOH (2.0
equiv) in MeOH at 50 °C for 3 h. b Isolated yield. c Determined by HPLC
analysis. d Determined by HPLC analysis after benzoylation. e The enan-
tiomeric excess of 2l (purchased from Aldrich) was determined after its
transformation to the corresponding N′-benzoylhydrozone. f 95% ee (S).g The
values represent diastereomeric excesses (determined by 13C NMR analysis).
The converted values on the basis of % ee of 2l are in parentheses. h The
enantiomer of 1a was used.
References
(1) For a recent review: (a) Ding, H.; Friestad, G. K. Synthesis 2005, 2815.
For examples of asymmetric catalysis: (b) Kiyohara, H.; Nakamura, Y.;
Matsubara, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2006, 45, 1615 and
references therein.
(2) For a leading reference: Itsuno, S.; Watanabe, K.; Matsumoto, T.; Kuroda,
S.; Yokoi, A.; El-Shehawy, A. J. Chem. Soc., Perkin Trans. 1 1999, 2011.
(3) Chen, G.-M.; Ramachandran, P. V.; Brown, H. C. Angew. Chem., Int.
Ed. 1999, 38, 825.
Scheme 3. Isolation of the Rearranged Product 5b
(4) For aminoallylation with ammonia: (a) Sugiura, M.; Hirano, K.; Koba-
yashi, S. J. Am. Chem. Soc. 2004, 126, 7182. (b) Kobayashi, S.; Hirano,
K.; Sugiura, M. Chem. Commun. 2005, 104.
(5) Sugiura, M.; Mori, C.; Hirano. K.; Kobayashi, S. Can. J. Chem. 2005,
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(6) (a) Horowitz, R. M.; Geissman, T. A. J. Am. Chem. Soc. 1950, 72, 1518.
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(7) (a) Overman, L. E.; Kakimoto, M. J. Am. Chem. Soc. 1979, 101, 1310
and references therein. For a review: (b) Overman, L. E. Acc. Chem.
Res. 1992, 25, 352.
(8) For leading references: (a) Nokami, J.; Yoshizane, K.; Matsuura, H.;
Sumida, S. J. Am. Chem. Soc. 1998, 120, 6609. (b) Sumida, S.; Ohga,
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(9) For related transformations, see: (a) Bhalerao, U. Y.; Muralikrishna, C.;
Pandey, G. Synth. Commun. 1989, 19, 1303. (b) Lu, S.-S.; Uang, B.-J. J.
Chin. Chem. Soc. 1992, 39, 245. (1R)-camphorquinone was recovered as
3-oxime (88% recovery in entry 5 of Table 1). The oxime can be
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E. G. Synth. Commun. 1999, 29, 2831.
enolizable, were found to proceed smoothly at 0 °C (entries 7-14).
It is significant that the reaction tolerates various functional groups
including nitro, bromo, hetereocyclic, benzyloxy, and carboxyl
groups (entries 1-6, 13, 14, and see also Scheme 2) and that the
stereogenic carbon can be constructed independent of the chiral
aldehyde’s original configuration (entries 10 and 11).
To gain mechanistic insights, we attempted to isolate the
rearranged product 5b (Scheme 3). It was found that 5b was isolable
by silica gel chromatography and that two stereoisomers of 5b were
obtained in an 83:17 ratio. Both isomers were converted to (S)-3b
with 96% ee by treatment with hydroxylamine, indicating that the
two starting isomers were simply geometrical isomers of the CdN
(10) For details, see Supporting Information.
JA064106R
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