Magnesium-tartramide complex mediated asymmetric Strecker-type reaction of nitrones using cyanohydrin

Article abstract of DOI:10.1021/ol400898p

An asymmetric Strecker-type reaction of nitrones using acetone cyanohydrin as a source of HCN has been realized. A magnesium-tartramide complex, generated from (R,R)-2,3-dihydroxy-1,4-di(pyrrolidin-1-yl)-butane-1,4-dione and MeMgBr, promoted transcyanation from the bromomagnesium salt of the cyanohydrin, in the presence of a catalytic amount of DBU, to afford the corresponding optically active (S)-α-amino nitrile derivatives. The reaction was applicable to various nitrones giving high-to-excellent enantioselectivities.

Full text of DOI:10.1021/ol400898p

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
MagnesiumꢀTartramide Complex
Mediated Asymmetric Strecker-Type
Reaction of Nitrones Using Cyanohydrin
Takahiro Sakai, Takahiro Soeta, Kohei Endo, Shuhei Fujinami, and Yutaka Ukaji*
Division of Material Sciences, Graduate School of Natural Science and Technology,
Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan
ukaji@staff.kanazawa-u.ac.jp
Received April 2, 2013
ABSTRACT
An asymmetric Strecker-type reaction of nitrones using acetone cyanohydrin as a source of HCN has been realized. A magnesiumꢀtartramide
complex, generated from (R,R)-2,3-dihydroxy-1,4-di(pyrrolidin-1-yl)-butane-1,4-dione and MeMgBr, promoted transcyanation from the
bromomagnesium salt of the cyanohydrin, in the presence of a catalytic amount of DBU, to afford the corresponding optically active
(S)-R-amino nitrile derivatives. The reaction was applicable to various nitrones giving high-to-excellent enantioselectivities.
The asymmetric hydrocyanation of imino compounds,
known as the Strecker reaction, is an indispensable syn-
thetic procedure for producing optically active R-amino
nitriles,1,2 which are very important precursors of natural
and non-natural R-amino acids, 1,2-diamines, and inter-
mediates for several transformations.2a,3 For all these
reasons, the asymmetric Strecker reaction is attractive to
many organic chemists, and numerous variants have been
reported that use HCN or TMSCN as the cyanide source.
Due to their toxicity, volatility, and hazardous handling,
alternative cyanide sources are in high demand. Further-
more, the preparation of chiral auxiliaries for these reac-
tions is often difficult. In order to overcome the former
problem, alternative inexpensive cyanide sources have
been employed, such as n-Bu3SnCN,4 Et2AlCN,5 (EtO)2-
P(O)CN,6 EtOCOCN,2o,q,7 and CH3COCN.8 Among
such cyanide compounds, acetone cyanohydrin is a simple,
stable, easy to handle, and readily available cyanide source.9
(1) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27–45.
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r
10.1021/ol400898p
XXXX American Chemical Society

We have already developed a Strecker-type reaction of
nitrones using acetone cyanohydrin as a cyanide source by
treatment with n-BuMgCl.10,11 Among the imine analogues,
nitrone appears to be a promising candidate since it pos-
sesses an electronegative oxygen that can coordinate
strongly to metals.12,13
Table 1. Asymmetric Strecker-Type Reaction with 1a Promoted
by Bis(chloromagnesium)salt of Tartaric Acid Derivatives
We have previously investigated asymmetric nucleo-
philic addition reactions of nitrones based on the design
of a multinucleating reaction system utilizing tartaric acid
esters.14 Herein, we will describe an asymmetric Strecker-
type reaction with nitrones using acetone cyanohydrin
as a cyanide source mediated by a magnesiumꢀtartramide
complex.
entry
Y
solvent
t (h)
yield (%)
ee (%)a
1
Oi-Pr
THF
26
21
48
44
44
21
25
45
45
20
20
21
76
71
99
93
70
84
72
57
12
53
81
42
0
14
11
17
44
ꢀ3
0
2
NMe2
THF
3
NBn2
THF
4
NPh2
THF
5
pyrrolidinyl
piperidinyl
morpholinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
THF
6
THF
7
THF
8
DME
Et2O
toluene
CH2Cl2
MeCN
24
3
9
10
11
12
4
18
38
Figure 1. Original design of asymmetric Strecker-type reaction
utilizing tartaric acid derivative.
a Enantioselectivity was determined by HPLC analysis (Daicel
CHIRALPAK IA).
First, the asymmetric Strecker-type reaction of (Z)-
N-(benzylidene)benzylamine N-oxide (1a) was examined
with acetone cyanohydrin (2) based on our general design
of the multinucleating chiral reaction system as depicted in
Figure 1.14c,h Thus, a mixture of 2 and diisopropyl (R,R)-
tartrate was treated with 3.0 equiv of n-BuMgCl in THF
at 0 °C followed by the addition of 1a. The reaction gave
R-hydroxylamino nitrile 3a in 76% yield; however, no
chiral induction was observed (Table 1, entry 1). To
promote strong coordination of the carbonyl oxygen in
the tartaric acid moiety to magnesium metal and/or for
sterical bulkiness, the tartramide was employed instead
of the tartaric acid ester.15 By the use of N,N,N0,N0-
tetramethyl-(R,R)-tartramide, a slight enantiofacial differ-
entiation was realized (entry 2). Several tartramides were
then probed. Although tetrabenzyl- and tetraphenyltar-
tramides showed low levels of enantioselection (entries 3
and 4), an amide derived from pyrrolidine, 2,3-dihydroxy-
1,4-di(pyrrolidin-1-yl)-butane-1,4-dione (BTMTA),16 en-
hanced the enantioselectivity to 44% ee (entry 5). Amides
derived from piperidine and morpholine showed little
stereoselection (entries 6 and 7). Next, the effect of solvent
wasexaminedusing BTMTA. Among the ethereal solvents
examined, THF was better than DME and Et2O (entries 5,
8, and 9). Less polar solvents, toluene and CH2Cl2, showed
lower enantioselectivities (entries 10 and 11). While the
reaction in MeCN gave the product in slightly lower
(10) Sakai, T.; Soeta, T.; Inomata, K.; Ukaji, Y. Bull. Chem. Soc. Jpn.
2012, 85, 231–235.
(11) Transcyanation from cyanohydrin to carbonyl compounds pro-
moted by metallic reagents: (a) Mori, A.; Kinoshita, K.; Osaka, M.;
Inoue, S. Chem. Lett. 1990, 1171–1172. (b) Mori, A.; Inoue, S. Chem.
Lett. 1991, 145–148. (c) Ooi, T.; Miura, T.; Takaya, K.; Ichikawa, H.;
Maruoka, K. Tetrahedron 2001, 57, 867–873. (d) Watanabe, A.;
Matsumoto, K.; Shimada, Y.; Katsuki, T. Tetrahedron Lett. 2004, 45,
6229–6233. (e) Yanagisawa, A.; Matsumoto, T.; Kushihara, N.;
Yoshida, K. Adv. Synth. Catal. 2010, 352, 2918–2922.
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gies in Synthesis, in Nitrile Oxides, Nitrones, and Nitronates in Organic
Synthesis; Feuer, H., Ed.; John Wiley & Sons, Inc.: NJ, 2008, Chapter 2.
(13) Strecker-type reactions of nitrones: (a) Tsuge, O.; Urano, S.;
€
Iwasaki, T. Bull. Chem. Soc. Jpn. 1980, 53, 485–489. (b) Gossinger, E.
Monatsh. Chem. 1982, 113, 495–508. (c) Shatzmiller, S.; Shalom, E.;
Lidor, R.; Tartkovski, E. Justus Liebigs Ann. Chem. 1983, 906–912.
(d) Hosomi, A.; Shoji, H.; Sakurai, H. Chem. Lett. 1985, 1049–1052.
(e) Padwa, A.; Koehler, K. F. Chem. Commun. 1986, 789–790. (f)
Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28, 6469–6472. (g)
Merino, P.; Tejero, T.; Revuelta, J.; Romero, P.; Cicchi, S.; Mannucci,
V.; Brandi, A.; Goti, A. Tetrahedron: Asymmetry 2003, 14, 367–379.
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P.; Tejero, T. Org. Lett. 2003, 5, 4235–4238. (i) Merino, P.; Delso, I.;
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K. Bull. Chem. Soc. Jpn. 2000, 73, 447–452. (b) Ukaji, Y.; Yoshida, Y.;
Inomata, K. Tetrahedron: Asymmetry 2000, 11, 733–736. (c) Ukaji, Y.;
Inomata, K. Synlett 2003, 1075–1087. (d) Wei, W.; Kobayashi, M.;
Ukaji, Y.; Inomata, K. Chem. Lett. 2006, 35, 176–177. (e) Konishi, A.;
Wei, W.; Kobayashi, M.; Fujinami, S.; Ukaji, Y.; Inomata, K. Chem.
Lett. 2007, 36, 44–45. (f) Wei, W.; Hamamoto, Y.; Ukaji, Y.; Inomata,
K. Tetrahedron: Asymmetry 2008, 19, 476–481. (g) Wei, W.; Kobayashi,
M.; Ukaji, Y.; Inomata, K. Heterocycles 2009, 78, 717–724. (h) Ukaji,
Y.; Inomata, K. Chem. Rec. 2010, 10, 173–187.
(15) Asymmetric reactions using tatramides: (a) Ukaji, Y.; Soeta, T.
In Comprehensive Chirality; Carreira, E. M.; Yamamoto. H., Eds.; Elsevier:
Amsterdam, 2012; Section. 3.6.4. One of the most successful examples:
(b) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc.
1998, 120, 11943–11952.
(16) Suzuki, M.; Kimura, Y.; Terashima, S. Bull. Chem. Soc. Jpn.
1986, 59, 3559–3572. BTMTA is an abbreviation derived from an
alternative name, N,N,N0,N0-bis(tetramethylene)tartramide.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Reaction Conditions for Asymmetric Strecker-Type
Reaction to Nitrone 1a
Table 3. Asymmetric Strecker-Type Reaction of Nitrones 1
entry
R1
R2
Bn
t (h) yield (%) ee (%)a
entry
RMgX
base
t (h)
yield (%)
ee (%)a
1
Ph
Ph
Ph
Ph
a
b
c
d
e
f
22
21
21
21
21
21
23
41
41
4
80
47
6
89
72
63
96
90
96
96
85
96
79
97
73
90
87
93
1b
2b
3c
4c
5c
6c
7c
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
n-BuMgCl
MeMgBr
n-BuMgCl
ꢀ
39
21
21
45
45
45
22
15
nr
49
31
13
50
80
79
ꢀ
2
Me
3
Ph
TMEDA
Et3N
87
86
73
92
89
4
Ph2CH
58
72
75
63
89
73
95
94
97
87
90
88
5
4-(MeO)C6H4 Bn
DTBMPd
DBU
6
4-ClC6H4
4-BrC6H4
1-Nap
2-Nap
Me
Bn
7
Bn
g
h
i
DBU
8
Bn
9
Bn
a Enantioselectivities were determined by HPLC analysis (Daicel
CHIRALPAK IA). b To a mixture of (R,R)-BTMTA and 2 was added
n-BuMgCl at 0 °C. After 1 h, the nitrone 1a was added. c To a mixture of
(R,R)-BTMTA and 2 was added RMgX at 0 °C. After 1 h, base and 1a
were successively added. d 2,6-Di(tert-butyl)-4-methylpyridine.
10
11
12
13
14
15
Bn
j
Me
Ph2CH
Bn
k
l
2
c-Hex
c-Hex
t-Bu
6
Ph2CH
Bn
m
n
o
21
22
21
t-Bu
Ph2CH
38% ee (entry 12), the reaction did not proceed in much
polar solvents, DMF and DMSO.
a Enantioselectivities were determined by HPLC analysis (Daicel
CHIRALPAK IA).
In our previous work,10 gradual generation of the chloro-
magnesium salt of cyanohydrin by the use of 0.2 equiv of
n-BuMgCl made the reaction proceed smoothly. When the
transcyanationwasperformedwith2.2equivofn-BuMgCl,
enantioselectivity was improved, although the chemical
yield decreased (Table 2, entry 1). With only 2.0 equiv of
n-BuMgCl, transcyanation did not occur (entry 2). When
0.2 equiv of TMEDA was employed as an extra organic
base in addition to 2.0 equiv of n-BuMgCl, 3a was obtained
with enhanced chemical and optical yields (entry 3). The
reaction using other organic bases also gave 3a in good
enantioselectivities, though the chemical yields were not
enhanced (entries 4 and 5). DBU was the base of choice to
give 3a with 92% ee in moderate chemical yield (entry 6).
Finally, in order to examine the effect of the Lewis acidity
of the magnesium salt, MeMgBr instead of n-BuMgCl was
used. The chemical yield was enhanced up to 80% without
any remarkable decrease in enantioselectivity (entry 7).17
The influence of the substituents on the nitrogen atom
of the nitrones was investigated next, and N-benzyl nitrone
1a showed higher enantioselectivity than N-methyl and
N-phenyl nitrones 1b and 1c (Table 3, entries 1ꢀ3). Although
the addition reaction to a N-diphenylmethyl nitrone 1d was
sluggish, a cyanated product3d was obtained with excellent
enantioselectivity (entry 4). The asymmetric Strecker-type
reaction of various N-benzyl nitrones 1 was performed with
1.0 equiv of acetone cyanohydrin (2) utilizing 1.0 equiv of
(R,R)-BTMTA as a chiral auxiliary by the treatment of
2.0 equiv of MeMgBr and 0.2 equiv of DBU. In the case
of aromatic nitrones, most of the R-hydroxylamino nitrile
derivatives 3eꢀ3i were obtained in over 90% ee (entries
5ꢀ9). The Strecker-type reaction of aliphatic nitrones
proceeded faster than that of aromatic nitrones to give
the cyanated products with lower but still good enantio-
selectivities (entries 10, 12, and 14). In the case of aliphatic
nitrones, a diphenylmethyl substituent on the nitrogen
improved the stereoselection to afford the adducts in
high chemical yields with excellent enantioselectivities up
to 97% (entries 11, 13, and 15).
The absolute configuration of 3g was determined to be
S by X-ray crystallographic analysis of its single crystal
(Figure 2). The absolute configurations of other products
were tentatively determined to also be S.
The obtained product 3a (90% ee) was readily converted
to a diamine 4 by sequential reduction (Scheme 1). The
absolutestereochemistry of 4 wasconfirmedtobe alsoS by
comparisonof the specific rotation of the obtainedproduct
([R]25D þ57 (c 0.91, CCl4) [lit.18 (S)-isomer: [R]23D þ62 (c 1,
CCl4)]).19
(18) Hassan, N. A.; Bayer, E.; Jochims, J. C. J. Chem. Soc., Perkin
Trans. 1 1998, 3747–3757.
(19) (R)-Antipode 4 was reported to be used as a building block for
the exploration of drugs which could have anxiolytic or hypnotic
activities: Horwell, D. C.; Pritchard, M. C.; Richardson, R. S.; Roberts,
E.; Aranda, J. Eur. Pat. Appl. 1991, EP 405537 A1.
(17) When 0.1 and 0.4 equiv of DBU were used, the chemical yield
was decreased to 55% and 73%, respectively, with the same 89% ee.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. A Possible Reaction Pathway
Figure 2. X-ray structure of 3g (Flack parameter = 0.03).
Scheme 1. Conversion of 3a to a Diamine 4
method is very simple and avoids using dangerous cyanide
sources such as HCN and TMSCN. Furthermore, both
enantiomers of R-amino nitrile derivatives, which are versa-
tile synthetic intermediates, are readily synthesized because
both enantiomers of BTMTA are easily prepared from
commercially available (R,R)- and (S,S)-diethyl tartrates
in one step.16 Further studies on this reaction are in progress
in our laboratory.
Acknowledgment. The present work was financially sup-
ported in part by a Grant-in-Aid for Scientific Research (B)
(No. 24350022) from the Japan Society for the Promotion
of Science (JSPS) and an Adaptable and Seamless Techno-
logy Transfer Program through Target-driven R&D (No.
AS242Z02711Q) from the Japan Science and Technology
Agency (JST). This paper is dedicated to Professor Teruaki
Mukaiyama in celebration of the 40th anniversary of the
Mukaiyama aldol reaction.
Although the precise reaction mechanism is not yet clear,
one possible reaction pathway is shown in Scheme 2. When
2 and (R,R)-BTMTA are treated with 2 equiv of MeMgBr,
bromomagnesium salts 5 and 6 are formed. By the addition
of 0.2 equiv of DBU, deprotonation from 6 might occur to
furnish a tartramideꢀmagnesium atecomplex, to whichthe
nitrone 1 coordinates. The subsequent transcyanation pro-
ceeds from the re-face of the nitrone to afford the product
3 with a preference for the (S)-enantiomer. However, the
effect of amide substituents is still not well-elucidated.
In conclusion, the magnesiumꢀtartramide complex
mediated asymmetric Strecker-type reaction of nitrones
using acetone cyanohydrin has been developed. Various
types of nitrones were applicable to this reaction. The present
Supporting Information Available. Experimental pro-
cedures, spectroscopic and analytical data, and copies of
NMR spectra of the new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX