Iodomethylzinc phosphates: Powerful reagents for the cyclopropanation of alkenes

Article abstract of DOI:10.1021/ja0529687

A new family of zinc carbenoids derived from phosphoric acids was developed and used in the cyclopropanation of allylic alcohols and ethers and also of unfunctionalized olefins. The use of the chiral phosphoric acid of a 3,3′-disubstituted BINOL leads to efficient stereocontrol, affording the cyclopropanes of allylic and homoallylic ethers with complete conversions and up to 93% ee. A catalytic version of this reaction using 10 mol % of the chiral phosphate reagent is also disclosed. Copyright

Full text of DOI:10.1021/ja0529687

Published on Web 08/19/2005
Iodomethylzinc Phosphates: Powerful Reagents for the Cyclopropanation of
Alkenes
Marie-Christine Lacasse, Cyril Poulard, 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
Received May 6, 2005; E-mail: andre.charette@umontreal.ca
Since the first use of the Zn/Cu couple by Simmons and Smith
for the cyclopropanation of CdC, several new improved reagents
have been developed to increase the scope for the formation of the
1
cyclopropane unit. The reagent modification typically involves the
replacement of the iodide substituent of the Simmons-Smith
2
3
4
reagent (A) by either an ethyl (B) or halomethyl substituent (C).
Our group has been involved in the past few years in synthesizing,
characterizing, and studying newly developed organo(iodomethyl)-
zinc reagents that are still effective cyclopropanating reagents with
5,6
novel properties. Ultimately, the goal of this approach is to
introduce a chiral organic group (D) that will lead to high
enantioselectivities for the cyclopropanation of unfunctionalized
alkenes and use this reagent in catalytic amounts.7
Figure 1. ORTEP drawing of 2‚THF dimer.
Table 1. Cyclopropanation Using Achiral Phosphoric Acid 2
Since the electrophilicity of the iodomethylzinc species is
intimately related to the electron-withdrawing ability of the attached
group, we reasoned that the corresponding iodomethylzinc phos-
phate reagent should be sufficiently electrophilic to react with
alkenes in a (2+1) addition mode. To test this hypothesis,
commercially available diphenyl phosphate (1) was treated with 1
equiv of diethylzinc followed by 1 equiv of CH
Iodomethylzinc phosphate 2 was formed in quantitative yield within
0 min (NMR monitoring). Evaporation of the solution led to a
white solid that was stable for several weeks at 4 °C when protected
from oxygen and moisture.
2 2
I (eq 1).
a
1
6
Determined by H NMR using an internal standard. Isolated yield in
parentheses. b Only the allylic alcohol double bond reacted. Determined
by GC analysis using an internal standard.
c
The carbenoid was reactive enough so that alkenes bearing no
proximal basic groups could also be cyclopropanated (entries 4-5).
We then turned our efforts toward the design of a chiral zinc
phosphate reagent for the enantioselective cyclopropanation of
unfunctionalized alkenes. We envisioned that the use of a chiral
phosphoric acid derived from a 3,3′-disubstituted BINOL derivative
to efficiently project the chirality toward the carbenoid’s reactive
center would lead to efficient enantiodiscrimination. After consider-
The atom connectivity was unambiguously established by the
X-ray crystal structure of the THF complex (Figure 1), which
indicated that the reagent crystallized as a dimeric structure having
tetrahedral zinc centers. The bond lengths and angles are consistent
with those reported in the literature.8
9
able screening, chiral phosphoric acid 8 proved to be the best pre-
cursor for this transformation. Treatment of 8 with diethylzinc fol-
lowed by CH I and protected allylic alcohols led to good yields
2 2
The reactivity of 2 as a cyclopropanating agent was then tested
with representative substrates. Sequential treatment of diphenyl
phosphate with diethylzinc, diiodomethane, and an alkene led to
the cyclopropane in high yields (Table 1). Allylic alcohols and ether
reacted smoothly with 1.2 equiv of the reagent to generate the
corresponding cyclopropane in high yield (Table 1, entries 1-3).
It is quite remarkable that the cyclopropanation reaction of allylic
alcohols proceeded in such high yield, considering that the reagent
excess was only 20 mol %. Typically, at least 2 equiv of the
classical zinc carbenoids is necessary to get quantitative conversion
for this class of substrates.
of the cyclopropane (Table 2). Only 1.2 equiv of the chiral zinc
carbenoid that is formed in situ were enough to achieve high
conversions for the reaction of allylic ethers10 (Table 2). 1,2-
Dichloroethane (DCE) was the best solvent for this reaction,
allowing better reactivity and selectivity than dichloromethane. The
enantioselectivity is good, ranging from 85 to 91% ee for substrates
bearing methyl, benzyl, MOM, and nonbulky silyl protecting groups
(entries 1-5). Bulkier silyl protecting groups led to lower reaction
rates. The selectivity could be further improved by running the
reaction at -20 °C, although the reaction rate was lower (entry 6).
The cyclopropanation of a homoallylic benzyl ether led to complete
12440
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J. AM. CHEM. SOC. 2005, 127, 12440-12441
10.1021/ja0529687 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cyclopropanation with Chiral Phosphoric Acid 8
was sufficient and optimal to significantly decrease the rate of the
cyclopropanation between the alkene and the achiral reagent.
We then tested the reaction using 10 mol % of the chiral
phosphoric acid 8 (eq 2). Gratifyingly, 88% ee was observed when
allylic ether 9e was treated with 10 mol % of 8 and 90 mol % of
2 2
Zn(CH I) in the presence of DME. The cyclopropanation of the
more reactive olefin 13 required more DME to slow the background
reaction but it also lowered the rate of the asymmetric process. It
should be pointed out that in all the cases, it is possible to recover
the phosphoric acid reagent.13
entry
R
yield (%)a
ee (%)b
1
2
3
4
5
CH2OMe
(9a)
(9b)
(9c)
(9d)
(9e)
(9e)
(9f)
(9g)
>95 (73)
>95 (89)
95 (78)
91
90
85
90
87
92
93
CH2OBn
CH2OPMB
CH2OMOM
CH2OTES
CH2OTES
CH2CH2OBn
CH2OZnEt
75 (47)
c
>95 (79)
>95 (84)
>95 (85)
>95 (80)
d
c
6
7
8
e
39
a
1
Determined by H NMR using an internal standard. Isolated yield in
parentheses. Determined by HPLC on chiral stationary phase. c The
corresponding alcohol was obtained after deprotection with 1.0 M H3PO4
b
In conclusion, we have developed a new powerful family of zinc
carbenoids derived from phosphoric acids for the cyclopropanation
of alkenes. The reagents can be used in stoichiometric amounts or
in catalytic amounts if more complex phosphate reagents are used.
Further work is in progress to increase the scope of the reaction
and to develop better chiral discriminating reagents.
d
and NH4F at 40 °C. The reaction was performed at -20 °C for 48 h.
e
The opposite (S,S)-enantiomer was obtained.
Scheme 1. Catalytic Cycle for the Cyclopropanation Reaction
Acknowledgment. This work was supported by NSERC and
the Universit e´ de Montr e´ al. We are grateful to Vincent Lindsay
for the synthesis of 8.
Supporting Information Available: Experimental procedures and
characterization of new compounds including spectral data. X-ray
crystallographic file in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(
1) (a) Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness, C. M.
Org. React. 1973, 20, 1-131 (b) Charette, A. B.; Beauchemin, A. Org.
React. 2001, 58, 1-415. (c) Lebel, H.; Marcoux, J.-F.; Molinaro, C.;
Charette, A. B. Chem ReV. 2003, 103, 977-1050.
(
2) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323-5324.
3) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53-
(
58.
conversion and 93% ee (entry 7). This constitutes the highest
enantioselectivity ever reported for a homoallylic substrate in
enantioselective zinc-mediated reaction.11 However, the use of the
less reactive bis(homo)allylic benzyl ether as the substrate proved
to be detrimental to both conversions and ee.12 Finally, the prefor-
mation of a zinc alkoxide is detrimental to the enantioselectivities
(4) (a) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974-6981.
(b) Wittig, G.; Wingler, F. Chem. Ber. 1964, 97, 2146-2164.
(
5) (a) Charette, A. B.; Francoeur, S.; Martel, J.; Wilb, N. Angew. Chem. Int.
Ed. 2000, 39, 4539-4542. (b) Charette, A. B.; Beauchemin, A.; Francoeur,
S. J. Am. Chem. Soc. 2001, 123, 8139-8140. (c) Charette, A.; Beauchem-
in, A.; Francoeur, S.; B e´ langer-Gari e´ py, F.; Enright, G. D. Chem. Commun.
2002, 466-467.
6) Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 8621-8624.
7) For alternative approaches, see: (a) Long, J.; Yuan, Y.; Shi, Y. J. Am.
Chem. Soc. 2003, 125, 13632-13633. (b) Long, J.; Du, H.; Li, K.; Shi,
Y. Tetrahedron Lett. 2005, 46, 2737-2740. (c) Charette, A. B.; Juteau,
H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120, 11943-11952.
(
(
(
entry 8). This observation is quite significant since, unlike in pre-
10
viously developed systems from our laboratories and others, the
preformation of a zinc alkoxide is not required to obtain high con-
versions and enantioselectivities.
(
d) Kitajima, H.; Aoki, Y.; Ito, K.; Katsuki, T. Chem. Lett. 1995, 1113-
1114. (e) Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai,
N.; Kobayashi, S. Tetrahedron 1995, 51, 12013-12026. (f) Denmark, S.
E.; O’Connor, S. P. J. Org. Chem. 1997, 62, 584-594.
The main drawback of this reaction is the use of an expensive
chiral phosphoric acid in stoichiometric amounts. We thus explored
the possibility of regenerating the chiral iodomethylzinc species
from bis(iodomethyl)zinc through a Schlenk equilibration according
to Scheme 1. Unfortunately, only 68% ee was obtained if silyl ether
(8) (a) Denmark, S. E.; Edwards, J. P.; Wilson, S. R. J. Am. Chem. Soc. 1992,
1
14, 2592-2602. (b) Charette, A. B.; Marcoux, J.-F.; B e´ langer-Gari e´ py,
F. J. Am. Chem. Soc. 1996, 118, 6792-6793. (c) Charette, A. B.; Marcoux,
J.-F.; Molinaro, C.; Beauchemin, A.; Brochu, C.; Isabel, EÄ . J. Am. Chem.
Soc. 2000, 122, 4508-4509.
(
9) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356-5357.
9
2 2
e was treated with 10 mol % of 11 and 90 mol % of Zn(CH I) ,
(
10) The cyclopropanation of alkyl- or alkenyl-substituted allylic ethers in the
presence of 8 provided the corresponding cyclopropane in high conversions
but in e79% ee. However, we found that the level of enantioselection
was highly dependent upon the nature of the groups at 3 and 3′ and that
ligand screening is necessary. In the case of polyenes, high regiocontrol
was observed to favor the allylic ether double bond.
11) (a) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem.
Soc. 1998, 120, 11943-11952. (b) Charette, A. B.; Molinaro, C.; Brochu,
C. J. Am. Chem. Soc. 2001, 123, 12168-12175.
12) The cyclopropanation of benzyl (4E)-5-phenylpent-4-enyl ether in the
conditions reported in Table 2 led to 39% conversion and 50% ee.
13) See Supporting Information for details.
presumably because of the competing background reaction between
the substrate and the achiral reagent.
To minimize the background cyclopropanation that could arise
from pathway A, we envisioned that the addition of a Lewis basic
additive in less than stoichiometric amount (e90 mol %) that would
(
2 2 2
selectively complex Zn(CH I) or IZnCH I would not only decrease
(
the rate of the background cyclopropanation but also increase the
rate of the iodomethyl group exchange (pathway B). Several
additives were tested, and 0.5 equiv of 1,2-dimethoxyethane (DME)
(
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