Dinuclear zinc-catalyzed enantioselective aza-henry reaction

Article abstract of DOI:10.1021/ol070618e

The dinuclear zinc catalyst 1a was found to catalyze the addition of nitroalkanes to carbamate-protected imines. This aza-Henry reaction proceeds with high enantioselectivity when various carbamate-protected imines are used. α,β-Unsaturated imines proved

Full text of DOI:10.1021/ol070618e

ORGANIC
LETTERS
2
007
Vol. 9, No. 10
023-2026
Dinuclear Zinc-Catalyzed
Enantioselective Aza-Henry Reaction
2
Barry M. Trost* and David W. Lupton
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-8080
bmtrost@stanford.edu
Received March 13, 2007
ABSTRACT
The dinuclear zinc catalyst 1a was found to catalyze the addition of nitroalkanes to carbamate-protected imines. This aza-Henry reaction
proceeds with high enantioselectivity when various carbamate-protected imines are used. -Unsaturated imines proved to be a particularly
useful class of substrate routinely giving the -nitro amine products in high enantiomeric excess.
r,â
r
The addition of nitroalkanes to imines, the aza-Henry (or
nitro-Mannich) reaction, is a powerful and efficient method
for the construction of carbon-carbon bonds. â-Nitro amines
formed in this way are readily converted into 1,2-diamines
catalyzed by 1a, we decided to investigate the enantioselec-
tive aza-Henry reaction. It was postulated that the dual Lewis
acid/Lewis basic functionality within 1a should facilitate both
formation of the nitronate anion and activation of the imine,
thus making it a useful catalyst for the aza-Henry reaction
1
under reductive conditions or oxidatively cleaved to afford
R-amino acids.2g In recent years, efforts have been directed
(eq 1). In the event, we have been able to develop an
4
toward the development of efficient enantioselective variants
enantioselective aza-Henry reaction catalyzed by 1a that
utilizes a range of tert-butyloxycarbonyl (Boc), methoxy-
carbonyl (Moc), and benzyloxycarbonyl (Cbz) protected
imines.
2
of this reaction. Although advances have been made since
2a
the pioneering work of Shibasaki, methods are often limited
regarding the imines that can be employed.
In light of our success developing direct enantioselective
Our optimization studies began by investigating imines
a and 2b as the electrophilic partner in the aza-Henry
aldol,3
a,b,e,f
Henry, Mannich, and alkynylation reactions
3c
3d,h
3g
5a
2
(
1) For a review, see: Lucet, D.; Le Gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 1017.
2) For selected references, see: (a) Yamada, K.; Harwood, S. J.; Gr o¨ ger,
(3) See: (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003.
(
(b) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367.
(c) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861. (d)
Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338. (e) Trost, B.
M.; Fettes, A.; Shireman, B. T. J. Am. Chem. Soc. 2004, 126, 2660. (f)
Trost, B. M.; Shin, S.; Sclafini, J. A. J. Am. Chem. Soc. 2005, 127, 8602.
(g) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc.
2006, 128, 8. (h) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J. Am.
Chem. Soc. 2006, 128, 2778. (i) Trost, B. M.; Hisaindee, S. Org. Lett. 2006,
8, 6003.
H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 3504. (b) Nishiwaki,
N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2001, 40, 2992. (c) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto,
Y. Org. Lett. 2004, 6, 625. (d) Nugent, B. M.; Yoder, R. A.; Johnston, J.
N. J. Am. Chem. Soc. 2004, 126, 3418. (e) Yoon, T. P.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2005, 44, 466. (f) Palomo, C.; Oiarbide, M.; Laso,
A.; Lopez, R. J. Am. Chem. Soc. 2005, 127, 17622. (g) Fini, F.; Sgarzani,
V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci, A. Angew. Chem.,
Int. Ed. 2005, 44, 7975. (h) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.;
Takemoto, Y. Chem.-Eur. J. 2006, 12, 466. (i) Palomo, C.; Oiarbide, M.;
Halder, R.; Laso, A.; Lopez, R. Angew. Chem., Int. Ed. 2006, 45, 117.
(4) For a discussion of dual activation with polynuclear catalysts, see:
Shibasaki, M.; Kanai, M.; Matsunaga, S. Aldrichimica Acta 2006, 39, 21.
And concerning the aza-Henry reaction, see: ref 2a.
1
0.1021/ol070618e CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/18/2007

5b
Moc-protected imines. Although switching from Boc to Cbz
decreased the yield and enantioselectivity (Table 2, entry 2),
Table 1. Selected Optimization Results for the Aza-Henry
Reaction
Table 2. Aza-Henry Reaction of Aryl and Alkyl Imines
catalyst temp
R2 [mol %] [°C] % yielda % eeb
entry
R1
catalyst temp
NO2Me % yielda/
solvent [equiv]
tBu
1
2
3
4
5
6
Ph
Ph
Ph
30
30
30
30
30
15
30
15
30
rt
rt
rt
rt
-20
-20
-20
rt
67
52
65
65
65
82
48
58
66
91
76
91
96
75
92
82
89
91
entry imine [mol %]
[°C]
% eeb
Bn
Me
Me
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2b
2b
2b
2b
2a
15
15
15
15
15
15
10
5
rt
rt
rt
rt
rt
THF
THF
toluene
THF
THF
10
10
10
2
2
2
2
2
2
57/53
55/45
34/4
72/74
63/77
82/92
61/85
47/75
67/91
c
p-MeC H
4
p-MeOC6H4
2-furan
2-thiophene
(CH3)3C-
6
t
Bu
t
Bu
c
t
7
Bu
-20 THF
-20 THF
-20 THF
8
9
Me
d
TBSOCH2(CH3)2C- Me
rt
a
Isolated yield. bHPLC Daicel OD-H, OJ-H, AD. Reacted for 38 h.
c
30
rt
THF
d
Reacted for 72 h.
a
Isolated yield. b HPLC Daicel AD. Catalyst 1b.
c
the Moc-protected imine gave results similar to those
obtained with Boc imine 2a (Table 2, entry 3). The reaction
showed sensitivity to electronics with p-tolualdehyde-derived
imine reacting with high enantioselectivity (Table 2, entry
reaction (Table 1). The use of Boc-protected imines as
substrates was desirable due to the possibility of multipoint
6
binding and its general utility as a protecting group for
7
nitrogen. To our satisfaction, when imine 2a was exposed
4
), while the more electron-rich p-anisaldehyde derivative
gave a significant decrease in the enantioselectivity (Table
, entry 5). As previously noted, heteroaromatic imines are
useful substrates for the aza-Henry reaction (Table 2, entry
). When the 2-thiophene-derived Boc imine was reacted
to catalyst 1a in the presence of nitromethane, the aza-Henry
product 3a was produced in 57% yield and 53% ee (Table
2
1, entry 1). Both yield and enantioselectivity were decreased
when nitromethane was used as solvent. We hypothesized
that this may be due to excess nitromethane binding to the
catalyst and inhibiting coordination of the imine. Indeed,
lowering the nitromethane loading from ten equivalents to
two resulted in an increase in ee and yield (Table 1, entry
6
with 15 mol % of 1a, only a modest yield of the expected
product was obtained. Increasing the catalyst loading allowed
the formation of the expected product in an acceptable yield
and ee (Table 1, entry 7).
4). Unfortunately, lowering the temperature to -20 °C
As noted, methyl carbamate protection of the imine does
not decrease the enantioselectivity or yield of the aza-Henry
reaction. This proved significant when the reactivity of
imines bearing R-tertiary centers was investigated. These
molecules, although difficult to prepare with Boc protection,
stopped the reaction; however, imine 2b reacted efficiently
at this temperature giving carbamate 3b in good yield and
high ee (Table 1, entry 6). Catalyst loading has an effect on
the enantioselectivity of the reaction (Table 1, entries 6-9).
This result suggests that modification of the catalyst by
8
could be prepared as the Moc analogues and, when subjected
3e
product occurs over the course of the reaction. The use of
additives that were able to increase catalyst turnover and
enantioselectivity in previous work3 was investigated;
however, these did not increase enantioselectivity or yield.
Although catalyst loading was high with imine 2a (Table 1,
entry 9), it was acceptable for imine 2b (Table 1, entry 6)
so it was decided to investigate the scope of this reaction,
with the hope that the conditions for the later substrate were
more typical for this reaction.
to the aza-Henry reaction conditions, provided the expected
products with good enantioselectivity (Table 2, entries 8 and
a,b
9
). Unfortunately, when imines derived from enolizable
aldehydes were used, significant isomerization to the enamine
occurred. This result, and the presence of an elegant route
to aza-Henry products derived from enolizable aldehydes,2
indicated that an exploration of this class of substrate would
not be worthwhile. Indeed, our subsequent studies demon-
strated that the utility of our reaction lay with substrates that
had until this stage been unexplored.
f
The sensitivity of catalyst 1a to the type of carbamate
group of the azomethine was investigated using Cbz- and
9
Imines derived from R,â-unsaturated aldehydes have
received little attention in the field of asymmetric catalysis
(5) For Boc imines, see: (a) Kanazawa, A. M.; Denis, J.-N.; Greene, A.
E. J. Org. Chem. 1994, 59, 1238. For Moc imines, see: (b) Vidal, J.;
Damestoy, S.; Guy, L.; Hannachi, J.; Aubry, A.; Collet, A. Chem.-Eur. J.
(8) Trost, B. M.; Jonasson, C. Angew. Chem., Int. Ed. 2003, 42, 2063.
(9) For other applications of R,â-unsaturated carbamate-protected imines,
see: (a) Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003. (b)
Matsunaga, S.; Yoshida, T.; Morimoto, H.; Kumagai, N.; Shibasaki, M. J.
Am. Chem. Soc. 2004, 126, 8777.
1
997, 3, 1691.
(
(
6) For an example of two-point binding with catalyst 1a, see: ref 3b.
7) For a review on nitrogen protection, see: Theodoridis, G. Tetrahedron
2
000, 56, 2339.
2024
Org. Lett., Vol. 9, No. 10, 2007

and are yet to be used as substrates in the aza-Henry reaction.
The potential of these substrates to provide interesting
materials for organic synthesis, along with the excellent
results observed with the alkynylation of R,â-unsaturated
aldehydes catalyzed by the bisprolinol ligand,3g made these
substrates worthy of investigation. Gratifyingly, when ex-
posed to 15 mol % of catalyst 1a, each R,â-unsaturated imine
gave the expected aza-Henry product in good yield and
gave an isolable aminal product,3h,12 while TBS-protected
nitroethanol provided the expected product with high enan-
tioselectivity (Table 4, entry 3).
Although attempts to detail the reaction mechanism have
not been undertaken, a useful cycle that explains the absolute
stereochemistry of the products can be proposed (Scheme
1). The initial step of this cycle involves deprotonation of
10
excellent enantioselectivity (Table 3). As was noted previ-
Scheme 1. Possible Mechanism for the Aza-Henry Reaction
Table 3. Aza-Henry Reaction of R,â-Unsaturated Imines
entry
R1
R2
R3
R4
% yielda
% eeb
1
2
3
4
5
Ph
Ph
H
H
H
H
Ph
H
H
H
H
H
H
CH3
Me
Bn
Me
Me
Me
Me
60
65
44
58
56
69
93
81
97
93
94
82
p-MeOC6H4
2-furan
Ph
c
c,d
6
Ph
a
b
c
d
Isolated yield. HPLC Diacel OD-H or AD. Room temperature. 30
mol % of 1a.
nitromethane by catalyst 1a13 to give the zinc nitronate
intermediate A. Binding of the imine in the orientation
indicated then gives structure B that can be attacked by the
nitronate to give intermediate C. Although this scenario is
consistent with the absolute stereochemistry of the product,
an alternate scenario in which the nitronate adds directly to
the unbound imine to give intermediate C is also plausible.
Association of nitromethane followed by proton transfer then
returns intermediate A, via a structure such as D.
In conclusion, we have been able to develop an enanti-
oselective aza-Henry reaction catalyzed by 1a that per-
forms well over a range of substrates. Aromatic sub-
strates gave high enantioselectivity; however, the use of 30
mol % of catalyst in some cases detracts from this method.
Gratifyingly, the hitherto unreported aza-Henry reaction of
R,â-unsaturated imines with nitromethane in the presence
of 15 mol % of 1a gave the expected products in consistently
high enantiomeric excess. These materials have great
potential in organic synthesis as the olefinic group can
undergo either reduction or oxidation to give a range of new
materials.
ously (Table 2, entry 2), the use of Cbz-protected imines
gave lower enantioselectivity (Table 3, entry 2). In the case
of Table 3, entries 3-5, the yields observed are, in part, due
to the instability of the starting materials that decompose
readily under non-inert conditions.
Higher-order nitroalkanes can serve as nitronate anion
sources in the aza-Henry reaction. When nitroethane was
reacted with either the furfural-derived Boc imine 2b or the
cinnamaldehyde-derived Moc imine, the diastereomeric
products formed with excellent ee and modest dr (Table 4,
Table 4. Aza-Henry Reaction Using Alternate Nitroalkanes
entry
1
R1
R2
R3
dra % yieldb % eec
2-furan
PhCHdCH Me Me
PhCHdCH Me CH2OTBS 2:1
tBu Me
3:1
3:1
65
52
61
98/92
99/99
94/92
d
2
e
Acknowledgment. We thank the National Science Foun-
dation and the National Institute of Health (GM 13598) for
their generous support of our programs. D.W.L. thanks the
American Australian Association for provision of a Sir
KeithMurdoch fellowship. Mass spectra were provided by
3
a
1
b
c
Ratio determined by H NMR. Isolated yield. HPLC Daicel OD-H
d
e
or AD. Room temperature. 96 h reaction time.
entries 1 and 2).11 Unfortunately, when 2-nitropropane was
used the reaction did not proceed. The use of nitroethanol
(
11) Absolute stereochemistry determined by [R]D correlation to known
1
compounds. For diastereoselectivity by H NMR correlation, see Supporting
Information.
(
10) Absolute stereochemistries of these new products were not deter-
(12) Trost, B. M.; Chung, C. K. J. Am. Chem. Soc. 2006, 128, 10358.
(13) For the X-ray crystallographic structure of a derivative of cata-
lyst 1a, see: Xiao, Y.; Wang, Z.; Ding, K. Chem.-Eur. J. 2005, 11,
3668.
mined by derivatization; however, by analogy to other aza-Henry products
obtained using this methodology, we have assigned the stereochemistry as
shown.
Org. Lett., Vol. 9, No. 10, 2007
2025

the Mass Spectrometry Regional Center of the University
of CaliforniasSan Francisco, supported by the NIH division
of research resources, and by the University of Illinois at
Urbana-Champaign Mass Spectrometry laboratories.
We thank Aldrich for a generous supply of the chiral li-
gand.
Supporting Information Available: Characterization
data, NMR spectra, and detailed experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL070618E
2026
Org. Lett., Vol. 9, No. 10, 2007