Application of the chiral bis(phosphine) monoxide ligand to catalytic enantioselective addition of dialkylzinc reagents to β-nitroalkenes

Article abstract of DOI:10.1021/ol062792t

(Chemical Equation Presented) Me-DuPHOS monoxide is shown to be a very effective ligand in the enantioselective copper-catalyzed addition of dialkylzinc reagents to β-nitroalkenes providing access to chiral nitroalkanes. The major advantages of this process are high yields, broad and complementary substrate scope, and high enantioselectivities. The effect of achiral dummy ligands as an additive has also been documented.

Full text of DOI:10.1021/ol062792t

ORGANIC
LETTERS
2
007
Vol. 9, No. 1
5-87
Application of the Chiral Bis(phosphine)
Monoxide Ligand to Catalytic
8
Enantioselective Addition of Dialkylzinc
Reagents to
â-Nitroalkenes
Alexandre C oˆ t e´ , Vincent N. G. Lindsay, and Andr e´ B. Charette*
D e´ partement de Chimie, UniVersit e´ de Montr e´ al, P.O. Box 6128, Station Downtown,
Montr e´ al, Qu e´ bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received November 16, 2006
ABSTRACT
Me-DuPHOS monoxide is shown to be a very effective ligand in the enantioselective copper-catalyzed addition of dialkylzinc reagents to
-nitroalkenes providing access to chiral nitroalkanes. The major advantages of this process are high yields, broad and complementary
â
substrate scope, and high enantioselectivities. The effect of achiral dummy ligands as an additive has also been documented.
The use of bis(phosphine) monoxides as hemilabile ligands
1
has found widespread applications in the field of catalysis.
Yet, their potential in asymmetric synthesis has long been
overlooked because so few cogent examples have been
2
reported. In addition to the previous work of Faller, we have
recently reported that the Me-DuPHOS monoxide (2a) could
be used to promote the catalytic addition of diorganozinc
reagents to imines.3
To determine the general scope of reactivity for this family
of ligands, we sought to further explore their synthetic utility.
To do so, we focused our efforts on the enantioselective
catalytic addition of diorganozinc reagents to â-nitroalkenes
and, more particularly, on the Cu‚2a complex, which, based
on our previous studies, has proven to be an excellent catalyst
4,5
Leâmann, F.; Seidelmann, O.; Wendisch, V. Tetrahedron: Asymmetry 2003,
14, 189-191. (f) Choi, H.; Hua, Z.; Ojima, I. Org. Lett. 2004, 6, 2689-
2691. (g) Mamprean, D. M.; Hoveyda, A. H. Org. Lett. 2004, 6, 2829-
2832. (h) Valleix, F.; Nagai, K.; Soeta, T.; Kuriyama, M.; Yamada, K.-i.;
Tomioka, K. Tetrahedron 2005, 61, 7420-7424. (i) Wu, J.; Mampreian,
D. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 4584-4585. (j)
Luchaco-Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192-
8193. (k) Sewald, N.; Wendisch, V. Tetrahedron: Asymmetry 1998, 9,
1341-1344. (l) Duursma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedron
2002, 58, 5773-5778. (m) Kang, J.; Lee, J. H.; Lim, D. S. Tetrahedron:
Asymmetry 2003, 14, 305-315.
(
1) Review on bis(phosphine) monoxide ligands: Grushin, V. V. Chem.
ReV. 2004, 104, 1629-1662.
2) Faller, J. W.; Grimmond, B. J.; D’Alliessi, D. G. J. Am. Chem. Soc.
001, 123, 2525-2529.
3) (a) C oˆ t e´ , A.; Boezio, A. A.; Charette, A. B. Angew. Chem., Int. Ed.
(
2
2
(
004, 43, 6525-6528. (b) Boezio, A. A.; Pytkowicz, J.; C oˆ t e´ , A.; Charette,
A. B. J. Am. Chem. Soc. 2003, 125, 14260-14261. (c) C oˆ t e´ , A.; Boezio,
A. A.; Charette, A. B. Proc. Natl. Acad. Sci. 2004, 101, 5405-5410.
(
4) (a) Sch a¨ fer, H.; Seebach, D. Tetrahedron 1995, 51, 2305-2324. (b)
Alexakis, A.; Benhaim, C. Org. Lett. 2000, 2, 2579-2581. (c) Rimkus, A.;
Sewald, N. Org. Lett. 2003, 5, 79-80. (d) Duursma, A.; Minnaard, A. J.;
Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 3700-3701. (e) Eilitz, U.;
(5) Addition of alkynylzinc reagents: Yamashita, M.; Yamada, K.-i.;
Tomioka, K. Org. Lett. 2005, 7, 2369-2371.
1
0.1021/ol062792t CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/15/2006

for this type of reaction. Considerable interest from the
scientific community has been drawn to the use of chiral
nitroalkanes as intermediates in synthetic reactions due to
or 2b. Although Me- and Et-DuPHOS-derived ligands
produced comparable selectivities, the higher reactivity of
the copper complex derived from 2a at -70 °C convinced
us to focus our attention on this particular ligand. We
6
the very versatile functionality of the nitro group. In this
communication, we report a valuable route to prepare chiral
â-nitroalkanes in high isolated yields by using bis(phosphine)
monoxide ligands.
observed that the use of (2a)
2
‚CuOTf, an air-stable complex,7
has in no way affected the effectiveness of the addition and
is preferable because no precomplexation step is required.
The nature of the solvent was also an important factor. In
We began our study by examining the behavior of ligand
2a using the same reaction conditions described in our
this case, toluene and Et O were found to be the solvents of
2
previous work on the addition of diorganozinc compounds
to imines (eq 1).
choice, whereas THF and CH Cl afforded lower yields and
2
2
3
b
selectivities. Because Et O has proven to give more repro-
2
ducible results than toluene under optimal temperature
conditions, i.e., -70 °C, it was used for the remainder of
our investigation.
As the data in Table 2 indicate, enantioselective catalytic
Despite disappointing preliminary results, a variety of
conditions were screened and the copper-ligand ratio was
identified as a critical factor for controlling the level of
enantioinduction (Table 1, entries 1-3). Similarly, when the
Table 2. Scope in the Optimized Conditions for the Conjugate
Addition
entry
R
yield (%)a
erb
Table 1. Optimization of the Bis(phosphine) Monoxide Ligand
and the Copper-Ligand Ratio
1
2
3
4
5
6
7
8
Ph
92 (5a)
93 (5b)
99 (5c)
92 (5d)
98 (5e)
95 (5f)
89 (5g)
90 (5h)
70 (5i)
91 (5j)
97.5:2.5
99:1
98:2
p-Cl-Ph
p-F-Ph
p-CF3-Ph
m-MeO-Ph
p-MeO-Ph
p-Me-Ph
2-furyl
97:3
97.5:2.5
94.5:5.5
97.5:2.5
91.5:8.5
99:1
entry
ligand
CuOTf (mol %)
yield (%)a
erb
1
2
3
4
5
6
7
8
9
0
1
2a
2a
2a
1
1
1
10
5
51
83
90
19
28
62
71
90
86
16
79
58.5:41.5
77:23
93.5:6.5
51:49
54.5:45.5
53.5:46.5
51:49
93.5:6.5
91:9
c
9
c-hexyl
n-heptyl
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0
10
97.5:2.5
a
b
Isolated yield. Enantiomeric ratios were determined by GC on chiral
c
c
stationary phases. Slow addition of the â-nitroalkene over 12 h.
d
3
2b
2c
2a
2a
addition using ligand 2a is effective for a wide variety of
â-nitrostyrenes. The high isolated yields obtained strongly
suggest that use of this ligand could significantly reduce the
extent of polymerization of nitroalkenes, a common problem
1
1
51.5:48.5
75:25
e
5
a
NMR yields using an internal standard. bEnantiomeric ratios were
c
8
determined by GC on chiral stationary phases. 5 mol % of the ligand was
used. 2.5 mol % of the ligand was used. The (2a)2‚CuOTf complex was
used.
found in these reactions. An analysis of substituents on
d
e
nitroalkenes indicates that their electronic properties also
influence enantioselectivities. It appears that the presence
of electron-donating groups, which are positioned to enrich
the double bond, lowers selectivities. Most notably, our
method tends to be complementary to the use of the
phosphoramidite ligand optimized by Ojima and to the
peptide phosphine ligand developed by Hoveyda.4g For
3
example, the p-CF -Ph derivative (Table 2, entry 4), which
reaction was carried out with Me-DuPHOS (1) or its bis-
oxidized form (3), very low enantioselectivities were obtained
4
f
(entries 4-6 and 7), indicating that the hemilabile nature of
the ligand is also a key element. We assumed that the active
catalyst was a chiral organocopper complex because poor
enantioselectivity was observed in the absence of copper salt
in the medium. Simple variations of the ligand were also
investigated, and a slightly lower selectivity was observed
with the bulky ligand 2c compared to those with ligand 2a
(
(
7) C oˆ t e´ , A.; Charette, A. B. J. Org. Chem. 2005, 70, 10864-10867.
8) (a) Lu, S.-F.; Du, D.-M.; Xu, J.; Zhang, S.-W. J. Am. Chem. Soc.
2006, 128, 7418-7419. (b) Watanabe, M.; Ikagawa, A.; Wang, H.; Murata,
K.; Ikariya, T. J. Am. Chem. Soc. 2004, 126, 11148-11149. (c) Ballini,
R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105,
9
33-971. (d) Jubert, C.; Knochel, P. J. Org. Chem. 1992, 57, 5431-5438.
(
6) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001. (b) Barrett, A. G. M.; Graboski, G. G. Chem. ReV. 1986, 86,
51-762.
(e) Denmark, S. E.; Hurd, A. R. Org. Lett. 1999, 1, 1311-1314. (f) Dadwal,
M.; Mohan, R.; Panda, D.; Mobin, S. M.; Namboothiri, I. N. N. Chem.
Commun. 2006, 338-340.
7
86
Org. Lett., Vol. 9, No. 1, 2007

is known to be a problematic substrate, can be obtained in
9
2% yield and in 97:3 er using 2a as the chiral ligand.
This method also allows for the addition to aliphatic
Table 3. Effect of Additives in the Conjugate Addition
nitroalkenes. This is synthetically valuable because the
resulting chiral nitroalkanes could not be synthesized easily
9
10
using reduction or arylation methods (Table 2, entries 9
and 10). However, in the case of the c-hexyl derivative, the
substrate had to be added slowly to circumvent the formation
entry
R
additive
none
PBu3
PPh3
pyridine
DABCO
CH3CONH2
CF3CONH2
PhCONH2
CH3CONHCH3
TolSO2NH2
t-BuCONH2
t-BuCONH2
t-BuCONH2
yield (%)a
erb
1
1
1
2
3
4
5
6
7
8
9
Ph
79
28
<5
76
31
98
94
96
95
88
90:10
92.5:7.5
n/a
of a substantial quantity of the polymerization product.
Zn,12 its stoichi-
Because of the lower reactivity of Me
ometry, the temperature of the reaction, and the reaction time
had to be increased (eq 2). The use of CH Cl as solvent
2
90:10
2
2
93.5:6.5
95.5:4.5
92.5:7.5
97.5:2.5
90:10
89:11
96.5:3.5
98:2
10
11
12
13
c
97 (90)
96 (91)
c
p-Cl-Ph
n-heptyl
c
76 (69)
97:3
also contributed to increased selectivity. High yields and
enantioselectivities were obtained using the conditions shown
in eq 2.
a NMR yield using an internal standard. bEnantiomeric ratios were
determined by GC on chiral stationary phases. Isolated yield in parentheses.
c
It was felt that the need for excess ligand (1:4 copper-
ligand ratio) in this reaction was necessary to favor a
1
3,14
monomeric or a slightly aggregated ethylcopper species.
level of enantiocontrol in the presence of pivalamide (Table
3, entries 11-13).
In light of this, the excess chiral ligand was substituted with
several achiral ligands that could potentially play the same
role (Table 3). Although the addition of strongly R-donor
ligands, such as phosphines or amines (entries 2-5), led to
a high degree of polymerization, the use of amides was
2
Zn to both aliphatic and
aromatic unsaturated â-nitroalkenes was effective with a high
In conclusion, a new application of bis(phosphine) mon-
oxides was disclosed demonstrating the tremendous potential
of this class of ligands in asymmetric catalysis. The (2a)2‚
CuOTf-catalyzed addition of diorganozinc to â-nitroalkenes
offers a complementary variation to previously reported
methods.
1
5
effective. Indeed, the addition of Et
(
(
9) Czekelius, C.; Carreira, E. M. Org. Lett. 2004, 6, 4575-4577.
10) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000,
Acknowledgment. This work was supported by NSERC
Canada), Merck Frosst Canada, Boehringer Ingelheim
(Canada), Ltd., and the Universit e´ de Montr e´ al. A.C. is
grateful to NSERC (ES D) and TD Bank Financial Group
for a postgraduate fellowship. V.N.G.L. is grateful to NSERC
(USRA) for an undergraduate fellowship.
(
1
22, 10716-10717.
(
11) No polymerization was observed with the n-heptyl derivative.
(12) Theoretical study: Haaland, A.; Green, J. C.; McGrady, G. S.;
Downs, A. J.; Gullo, E.; Lyall, M. J.; Timberlake, J.; Tutukin, A. V.; Volden,
H. V. Dalton Trans. 2003, 4356-4366.
(13) A 1:8 (CuOTf/2a) ratio has led to the same er; however, a lower
yield was observed.
14) (a) Gambarotta, S.; Stroiogo, S.; Floriani, C.; Chiesi-Villa, A.;
(
Supporting Information Available: Experimental pro-
cedures for the preparation of compounds and spectroscopic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
Guastini, C. Organometallics 1984, 3, 1444-1445. (b) Lappert, M. F.;
Pearce, R. J. Chem. Soc., Chem. Commun. 1973, 24-25. (c) Olmstead, M.
M.; Power, P. P. J. Am. Chem. Soc. 1990, 112, 8008-8014.
(
15) (a) Mikami, K.; Matsukawa, S. Nature 1997, 385, 613-615. (b)
Reetz, M. T.; Mehler, G. Tetrahedron Lett. 2003, 44, 4593-4596. (c) Pe n˜ a,
D.; Minnaard, A. J.; Boogers, J. A.; de Vries, A. H. M.; de Vries, J. G.;
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OL062792T
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