Dramatic lithium chloride effect on the reaction stereocontrol in Zn-mediated asymmetric cinnamylation: Highly practical synthesis of β-aryl homoallylic amines

Article abstract of DOI:10.1039/c0cc03230a

An extremely mild and practical approach for the preparation of enantiomerically enriched β-aryl substituted homoallylic amines bearing two adjacent stereogenic centers was realized by room temperature zinc-mediated highly stereoselective cinnamylation of

Full text of DOI:10.1039/c0cc03230a

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Dramatic lithium chloride effect on the reaction stereocontrol in
Zn-mediated asymmetric cinnamylation: highly practical synthesis
of b-aryl homoallylic aminesw
Min Liu,a An Shen,a Xing-Wen Sun,a Fei Deng,a Ming-Hua Xu*ab and Guo-Qiang Lin*a
Received 13th August 2010, Accepted 28th August 2010
DOI: 10.1039/c0cc03230a
An extremely mild and practical approach for the preparation of
enantiomerically enriched b-aryl substituted homoallylic amines
bearing two adjacent stereogenic centers was realized by room
temperature zinc-mediated highly stereoselective cinnamylation
of N-sulfinyl imines.
Homoallylic amines are important structural subunits and key
synthetic intermediates in the synthesis of many nitrogen-
containing natural products such as alkaloids. They have also
served as extremely versatile precursors to numerous organic
compounds. These important findings have stimulated the
effort to develop highly efficient synthetic strategies.1 Among
them, asymmetric allyl addition to imines for the synthesis of
optically active b-substituted homoallylic amines bearing two
adjacent stereogenic carbon centers is particularly interesting, as
the reaction creates two contiguous chiral centers in a single
operation. Despite the many methods developed,2 achieving
Scheme 1 Comparison profile of N-sulfinyl imine cinnamylation.
very high levels of control of the reaction stereoselectivity under
mild and practical conditions remains a challenging subject.
cinnamylation was examined, a range of b-aryl homoallylic
amines was also afforded in high yields and with very good
enantio-induction of the two new stereogenic centers in favor
of syn isomers at room temperature (Scheme 1a). With the
THF system, a reversal of stereofacial selectivity was again
achieved as we previously observed in the benzoyloxyallylation.
During the course of these studies, a report6 of diastereo-
selective addition of substituted allyliczinc chloride reagents to
N-tert-butanesulfinyl imines for asymmetric synthesis of
similar homoallylic amines drew our attention. In that work,
reactions of pre-prepared cinnamylzinc chloride with opposite
(S)-N-sulfinyl imines in THF at À78 1C resulted in the same
syn isomers but very surprisingly with entirely retained stereo-
chemistry at C-1 and C-2 positions (Scheme 1b). To explain
the observed results, the authors proposed a very unusual
Z-imine conformation in the six-membered chair transition
state model7 (Scheme 1b). These stereo outcomes contrasted
sharply with our findings from the in situ prepared, cinnamyl-
zinc bromide addition in THF, suggesting different reaction
transition states. However, it is unlikely that the allylic zinc
reagent difference between bromide and chloride will lead to
this transition state change.
During recent years we have been exploring the chemistry of
N-tert-butanesulfinyl imines3 for asymmetric synthesis of
various important chiral amines.4,5 In our previous studies,
we reported our successful development of simple approaches
for highly diastereoselective synthesis of chiral homoallylic
amines including densely functionalized b-amino-a-vinyl
alcohols by Zn or In-mediated allylation at room temperature.5
In spite of the extraordinary stereoselectivities, the use of
HMPA as a solvent in some cases5a,c is a disadvantage because
of its carcinogenic potential. In this context, we recently
discovered an effective new reaction system with great practic-
ability for room temperature zinc-mediated cinnamylation of
N-sulfinyl imines. Herein, we present our preliminary results,
which have led to the efficient synthesis of a series of enantio-
merically enriched b-aryl substituted homoallylic amines.
It has been described that the benzoyloxyallylation of
N-tert-butanesulfinyl imines can produce vinylic amino
alcohols with excellent diastereo- and enantioselectivity under
the conditions of a HMPA system.5c When the corresponding
a Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of
China. E-mail: xumh@mail.sioc.ac.cn, lingq@mail.sioc.ac.cn
b Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, 555 Zuchongzhi Road, Shanghai 201203,
To understand what led to the reaction stereochemical
differences, all reaction conditions, as well as experimental
details, were carefully compared and evaluated. In Reddy’s
work,6 cinnamylzinc chloride was pre-produced, following the
method of Knochel, by using a LiCl-mediated zinc insertion to
cinnamyl chlorides.8 It was found that an excess amount of
LiCl was used,9 and much of them after the reaction kept
People’s Republic of China
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data and copies of HPLC and NMR
spectra. CCDC 788747. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0cc03230a
c
8460 Chem. Commun., 2010, 46, 8460–8462
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remained in the subsequent cinnamylation system. Thus we
wondered whether the presence of LiCl10 is the origin of the
reversal of reaction stereocontrol.
1a and (E)-1-bromo-4-(3-bromoprop-1-enyl)benzene 2a in
DMF was carried out. As predicted, the addition gave the
major product (1R,2R)-syn-3a with 96% dr and 48% ee in
quantitative yield (entry 5). With LiCl as the additive, we were
very delighted to see a significant improvement of the reaction
enantioselectivity for the (1R,2R)-isomer (95% ee) while
maintaining high syn:anti diastereoselectivity (entries 6 and 8).
In particular, when 1 equiv. of LiCl was employed in DMF,
both of the observed diastereoselectivity (95 : 5 dr) and
enantioselectivity (95% ee) were comparable to those obtained
with the HMPA system (entry 8 vs. 2). It is noteworthy that a
small amount of H2O was also found to be important, as the
reaction in anhydrous DMF led to an obvious decrease of
yield and stereoselection (entry 7). This finding is similar as to
that we observed in the HMPA system.5a
To test this hypothesis, we began by investigating the stereo
outcome of the reaction of the above cinnamylation under
THF conditions using LiCl (2 equiv.) as an additive. The
reaction proceeded well at room temperature and afforded the
corresponding addition product with excellent syn:anti
diastereoselectivity (97 : 3) in 99% yield (Table 1, entry 3).
Although a moderate enantioselectivity (64%) was obtained,
not unexpectedly, the absolute configuration of the newly
generated stereocenters were (1R,2R), which was consistent
with those obtained from the HMPA system (entry 3 vs. 2).
This result clearly indicates that LiCl plays an important role
and its presence in the system could lead to a dramatic
opposite stereocontrolled reaction. In connection with our
previous work on Lewis base-mediated allylation,5a we thus
reasoned that the use of DMF as a solvent in combination
with LiCl as an additive might be a promising alternative to
HMPA conditions. Next, the reaction of (R)-N-sulfinyl imine
Having established a new environmentally benign reaction
system, we set out to explore the scope of cinnamylation of
N-tert-butanesulfinyl imines. As summarized in Table 2, a
series of (R)-N-sulfinyl imines bearing various R substituents
were examined in reactions with cinnamyl bromide 2a and 2b
in DMF in the presence of zinc (2 equiv.) and LiCl (1 equiv.) at
room temperature. To our delight, all reactions went smoothly
and afforded the cinnamylation products in good yields as well
as excellent syn stereoselectivities (95 : 5–99 : 1 dr, 95–99% ee).
In the cases of aromatic imines, the nature of aryl and
heteroaryl R groups did not seem to affect the reaction
diastereo- and enantioselectivity (entries 1–7). Remarkably,
N-sulfinyl imines of aliphatic aldehydes such as cinnamaldehyde,
3-phenylpropanal, and 3-methylbutanal also proved to be
Table 1 Cinnamylation to (R)-N-sulfinyl imine in different solvents
with/without LiCla
Additive
(equiv.)
Yield
(%)b syn : antic ee (%)d Config.
Entry Solvent
Table
2 Asymmetric cinnamylation to (R)-N-tert-butanesulfinyl
imines with DMF systema
1
2
3
4
5
6
7
8
THF
HMPA
THF
—
84
91
99
86
99
96
79
96
93 : 7
95 : 5
97 : 3
98 : 2
98 : 2
93 : 7
90 : 10
95 : 5
À87
96
64
69
48
95
92
95
(1S,2S)
(1R,2R)g
(1R,2R)
(1R,2R)
(1R,2R)
(1R,2R)
(1R,2R)
(1R,2R)
H2O (2)
LiCl (2)
LiCl (6)
—
LiCl (2)
LiCl (2)
LiCl (1)
THF
DMFe
DMFe
DMFf
DMFe
a
The reaction was performed with imine 1a (0.25 mmol), Zn/2a
b
(0.5 mmol), and additive in dry solvent (5 mL) at rt. Isolated
Entry
1
R
2
3
Yield (%)b syn : anti ee (%)e
c
yield. Diastereomeric ratio for the acetate derivative of product 3a
1
2
3
4
5
6
7
8
1a Ph
2a 3a 96
2a 3b 99
2a 3c 77
2a 3d 76
2a 3e 99
2a 3f 99
2a 3g 99
95 : 5
97 : 3
98 : 2
96 : 4
95 : 5
95 : 5
98 : 2d
99 : 1
98 : 2d
98 : 2d
97 : 3
98 : 2
95
96
99
97
97
95
98
97
96
95
99
97
after the removal of sulfinyl moiety; determined by LC-MS.
d
Enantiomeric excess for the acetate derivative of product 3 after
1b 4-BrC6H4
1c 4-CH3C6H4
1d 4-CH3OC6H4
1e 2,4-ClC6H3
1f b-Naphthyl
1g 2-Furanyl
1h (E)-PhCHQCH 2a 3h 96
1i PhCH2CH2 2a 3i 89
1j (CH3)2CHCH2 2a 3j 95
e
the removal of sulfinyl moiety, determined by chiral HPLC. Distilled
f
from activated Al2O3, containing B0.1% of H2O. Distilled from
CaH2. See Fig. 1 and ref. 11 for X-ray crystallographic details.
g
9
10
11
12
1a Ph
1a Ph
2b 3k 96
2bf 3k 92
a
The reaction was performed with imine 1 (0.25 mmol), Zn/2
(0.5 mmol), and LiCl (0.25 mmol) in DMF (5 mL, distilled from
b
activated Al2O3) at rt. Isolated yield. Diastereomeric ratio for the
c
acetate derivative of product 3 after the removal of sulfinyl moiety;
d
determined by LC-MS, unless otherwise noted. Determined by 1H
NMR of the crude acetate derivative of product 3 after the removal of
e
sulfinyl moiety. Enantiomeric excess for the acetate derivative of
product 3 after the removal of sulfinyl moiety, determined by chiral
f
HPLC. Pure Z isomer of 2b was used.
Fig. 1 X-ray crystal structure of (1R,2R)-3a.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8460–8462 8461

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Academy of Sciences (KJCX2-YW-H-07), the Shanghai
Municipal Committee of Science and Technology
(09JC1417300), and the Major State Basic Research
Development Program (2010CB833302).
Notes and references
1 For reviews, see: (a) Y. Yamamoto and N. Asao, Chem. Rev., 1993,
93, 2207; (b) D. Enders and U. Reinhold, Tetrahedron: Asymmetry,
1997, 8, 1895; (c) C. O. Puentes and V. Kouznetsov, J. Heterocycl.
Chem., 2002, 39, 595; (d) S. Kobayashi, M. Sugiura and C. Ogawa,
Adv. Synth. Catal., 2004, 346, 1023; (e) H. Ding and
G. K. Friestad, Synthesis, 2005, 2815; (f) V. V. Kouznetsov and
Scheme 2 Further reaction extension with DMF system.
L. Y. V. Mendez, Synthesis, 2008, 491.
´
2 For some recent examples, see: (a) R. Yanada, A. Kaieda and
Y. Takemoto, J. Org. Chem., 2001, 66, 7516; (b) H. Miyabe,
Y. Yamaoka, T. Naito and Y. Takemoto, J. Org. Chem., 2003,
68, 6745; (c) S. Kobayashi, C. Ogawa, H. Konishi and M. Sugiura,
J. Am. Chem. Soc., 2003, 125, 6610; (d) C.-L. K. Lee, H. Y.
Ling and T.-P. Loh, J. Org. Chem., 2004, 69, 7787;
(e) P. V. Ramachandran, T. E. Burghardt and L. Bland-Berry,
J. Org. Chem., 2005, 70, 7911; (f) K. L. Tan and E. N. Jacobsen,
Angew. Chem., Int. Ed., 2007, 46, 1315; (g) P. M. A. Rabbat,
S. C. Valdez and J. L. Leighton, Org. Lett., 2006, 8, 6119;
(h) J. D. Huber and J. L. Leighton, J. Am. Chem. Soc., 2007,
129, 14552; (i) D. Huber, N. R. Perl and J. L. Leighton, Angew.
Chem., Int. Ed., 2008, 47, 3037; (j) M. I. Feske, A. B. Santanilla
and J. L. Leighton, Org. Lett., 2010, 12, 688.
3 For recent reviews on the chemistry of N-tert-butanesulfinimines,
see: (a) C. H. Senanayake, D. Krishnamurthy, Z.-H. Lu, Z. Han
and E. Gallon, Aldrichimica Acta, 2005, 38, 93; (b) F. Ferreira,
C. Botuha, F. Chemla and A. Perez-Luna, Chem. Soc. Rev., 2009,
´
38, 1162; (c) M. T. Robak, M. A. Herbage and J. A. Ellman, Chem.
Rev., 2010, 110, 3600.
4 (a) Y.-W. Zhong, M.-H. Xu and G.-Q. Lin, Org. Lett., 2004, 6,
3953; (b) Y.-W. Zhong, K. Isumi, M.-H. Xu and G.-Q. Lin, Org.
Lett., 2004, 6, 4747; (c) Y.-W. Zhong, Y.-Z. Dong, K. Fang,
K. Isumi, M.-H. Xu and G.-Q. Lin, J. Am. Chem. Soc., 2005,
127, 11956; (d) R.-H. Liu, K. Fang, B. Wang, M.-H. Xu and
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(f) D.-M. Ji and M.-H. Xu, Chem. Commun., 2010, 46, 1550;
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5 (a) X.-W. Sun, M.-H. Xu and G.-Q. Lin, Org. Lett., 2006, 8, 4979;
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Eur. J., 2009, 15, 10217.
6 L. R. Reddy, B. Hu, M. Prashad and K. Prasad, Org. Lett., 2008,
10, 3109.
7 Generally, the trans geometry of aldimines is necessary, see:
(a) C. G. McCarty, in The Chemistry of the Carbon-Nitrogen
Double Bond, ed. S. Patai, Interscience, London, 1970, p. 363;
(b) Y. Yamamoto, S. Nishii, K. Maruyama, T. Komatsu and
W. Ito, J. Am. Chem. Soc., 1986, 108, 7776.
8 H. Ren, G. Dunet, P. Mayer and P. Knochel, J. Am. Chem. Soc.,
2007, 129, 5376.
9 See Supporting Information of ref. 6, page S3.
10 For an interesting example of the effect of LiCl on reaction
stereoselectivity change: J. H. Smitrovich, L. DiMichele,
C. X. Qu, G. N. Boice, T. D. Nelson, M. A. Huffman and
J. Murry, J. Org. Chem., 2004, 69, 1903.
11 CCDC 788747 contains the supplementary crystallographic data
for (1R,2R)-3a (C20H26BrNO2S).
12 For example, a-amino acid 7a could be readily acted as a key
intermediate for synthesis of a series of b-substituted biarylphenyl-
alanine amides, which are inhibitors of dipeptidyl peptidase IV
(DPP-4) for the treatment of type 2 diabetes, discovered by Merck
Research Laboratories. S. D. Edmondson, A. Mastracchio,
R. J. Mathvink, J. He and B. Harper, et al., J. Med. Chem.,
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excellent substrates, giving the corresponding syn-products
with 95–97% ee (entries 8–10). In addition, cinnamylation of
(R)-N-sulfinyl imine 1a with both (E) and (Z)-cinnamyl
bromide were examined, it was found that the same high levels
both of diastereoselectivity and enantioselectivity could be
obtained (entries 11 and 12). With the (E)-isomer, a slightly
better enantioselectivity was observed (entry 11).
Encouraged by the above success, we subsequently turned
our attention to further extend the reaction generality
(Scheme 2). As expected, treatment of N-sulfinyl imine 1a
with allyl bromide in DMF in the presence of zinc (2 equiv.)
and LiCl (2 equiv.) at room temperature resulted in the
formation of homoallylic amine 4 in 0.5 h in 99% yield with
98% de. 3-Bromopropenyl benzoate also reacted with 1a
smoothly to give benzoyloxyallylation product 5 in excellent
yield (96%) and stereoselectivity (99 : 1 dr, 97% ee).
Interestingly, when the similar cinnamylation was applied to
(S)-N-sulfinyl a-imino ester 6, the reaction proceeded with
high stereoselectivity (sole syn product, 95% ee) but only in
moderate yield (51%). After some experimentation we found
that the optimal conditions for this transformation did not
require LiCl, as depicted, all excellent yields (85–93%) and
stereoselectivities (>99 : 1 dr, 99% ee) could be achieved with
ease. Of note was the resulting optically pure b-vinyl-containing
a-amino acid derivatives 7a–c with two stereogenic centers,
which should be useful as a highly tunable chiral material.12
In summary, we have developed an extremely mild and
practical approach for the preparation of enantiomerically
enriched b-aryl substituted homoallylic amines bearing two
adjacent stereogenic centers, by room temperature zinc-
mediated highly stereoselective cinnamylation of N-sulfinyl
imines. Our finding of dramatic LiCl effect on the reaction
stereocontrol led to the discovery of a highly effective new
reaction system. The use of DMF as the solvent and LiCl as
the additive proved to be a promising alternative to the
unpleasant HMPA conditions. Moreover, the exceptionally
high levels of diastereo- and enantioselectivity in the cinna-
mylation of N-sulfinyl imino ester make it an attractive and
green method in the synthesis of structurally very important
b-vinyl-containing a-amino acids. Further studies concerning
the role of lithium chloride and synthetic applications of the
reaction in asymmetric synthesis are underway.
This work was generously supported by the National
Natural Science Foundation of China (20721003), the Chinese
c
8462 Chem. Commun., 2010, 46, 8460–8462
This journal is The Royal Society of Chemistry 2010