Copper-mediated substitution reactions of alkylmagnesium reagents with allylic carbamates: (Z)-selective alkene synthesis [22]

Full text of DOI:10.1021/ja9820341

12998
J. Am. Chem. Soc. 1998, 120, 12998-12999
Copper-Mediated Substitution Reactions of
Alkylmagnesium Reagents with Allylic Carbamates:
(Z)-Selective Alkene Synthesis
Jacqueline H. Smitrovich and K. A. Woerpel*
Department of Chemistry, UniVersity of California
IrVine, California 92697-2025
and high (Z)-selectiVity (E:Z ) 6:94).16,17 This unexpected change
in alkene stereoselectivity must be a function of the change in
organometallic reagent, not an inherent selectivity of this substrate.
The reversal of selectivity observed with lithium versus
magnesium reagents is a general phenomenon with allylic
carbamate 1 as substrate. Upon changing only the metal in the
nucleophile, in all cases alkyllithium reagents showed (E)-
selectivity, whereas use of alkylmagnesium reagents resulted in
high (Z)-selectivity (eq 2, Table 1).17 Furthermore, γ:R-selectivity
ReceiVed June 11, 1998
Copper-mediated allylic substitution reactions represent im-
portant methods for the construction of alkenes.1,2 Both alkyl-
lithium and alkylmagnesium reagents have been used since the
initial report of these reactions with allylic acetates.3 The
regiochemistry of substitution with diorganocuprates is dependent
upon the level of substitution of the allylic substrate, with
substitution at the least hindered terminus predominating. Pro-
tocols have been developed, however, to effect clean γ-substitu-
tion (SN2′).4-6 Among these modifications, Gallina and Ciattini
reported a highly γ-selective substitution when allylic carbamates
were treated with lithium dialkylcuprates.7,8 As with other allylic
substitutions, these reactions afforded (E)-alkenes, but with syn
stereochemistry.9,10 We have discovered that replacement of
organolithium reagents in this transformation with organomag-
nesium reagents retained high γ-selectivity, but the reaction
occurred with complete reversal of alkene stereoselectivity,
providing (Z)-alkenes.11 When a readily available, enantiomeri-
cally pure allylic carbamate was used, a (Z)-alkene of high optical
purity was obtained. This methodology therefore provides access
to chiral, non-racemic (Z)-allylsilanes, for which few alternative
methods have been reported.12,13
(SN2′:SN2) is consistently high for both lithium and magnesium.
The drop in (Z)-selectivity with isopropylmagnesium chloride
demonstrates that there may be a limit to the size of the group
tolerated in the allylic position (entry 7). However, even with
this secondary nucleophile, the (Z)-isomer is still favored (E:Z )
13:87).
The presence of the vinylsilane moiety on the allylic carbamate
is not necessary for (Z)-selectivity, as demonstrated by the
substitution reaction of carbamate 4. Complexation of 4 with
copper(I) iodide followed by treatment with (dimethylphenylsilyl)-
methylmagnesium chloride afforded the (Z)-alkene 5 in high yield
with high selectivity (E:Z ) 9:91, eq 3).17 This ratio is comparable
Upon examining synthetic routes to allylsilane 2, we chose to
use the copper-mediated alkylation of allylic carbamates7,9 to favor
γ-substitution at the more hindered allylic terminus. Deprotonation
of carbamate 1, followed by complexation with CuI‚2LiCl, and
addition of (trimethylsilyl)methyllithium14 produced the (E)-
allylsilane with low selectivity (E:Z ) 71:29, eq 1).15 In contrast,
use of (trimethylsilyl)methylmagnesium chloride as the nucleo-
phile surprisingly afforded 2 in good yield, with high γ-selectivity
to that obtained with the corresponding vinylsilane 1 (E:Z ) 4:96,
entry 5, Table 1). Thus, the copper-mediated reactions of allylic
carbamates with organomagnesium reagents represent a general
synthesis of (Z)-olefins branched at the allylic position.
(1) Magid, R. M. Tetrahedron 1980, 36, 1901-1930.
(2) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-765.
(3) Rona, P.; To¨kes, L.; Tremble, J.; Crabbe´, P. J. Chem. Soc., Chem.
Commun. 1969, 43-44.
(4) Tanigawa, Y.; Kanamaru, H.; Sonoda, A.; Murahashi, S.-I. J. Am. Chem.
Soc. 1977, 99, 2361-2363.
The stereochemistry at the newly formed allylic center was
established by submission of optically active carbamate (R)-118
(5) Tseng, C. C.; Paisley, S. D.; Goering, H. L. J. Org. Chem. 1986, 51,
2884-2891.
(6) Ba¨ckvall, J.-E.; Selle´n, M.; Grant, B. J. Am. Chem. Soc. 1990, 112,
6615-6621.
(16) Representative Experimental Procedure. To a cooled (-78 °C) solution
of carbamate 1 (150 mg, 0.461 mmol) in 1.2 mL of THF was added dropwise
by syringe n-BuLi (1.30 M solution in hexanes, 355 mL, 0.461 mmol). After
5 min, the clear yellow-orange reaction mixture was added dropwise by cannula
to a cooled (-78 °C) solution of CuI‚2LiCl [prepared by stirring CuI (90 mg,
0.47 mmol) and LiCl (39 mg, 0.92 mmol) in 2.3 mL of THF at 22 °C for 10
min]. After 30 min, Me3SiCH2MgCl (0.69 M solution in THF, 670 mL, 0.46
mmol) was added dropwise by syringe, and the reaction mixture was allowed
to warm to 22 °C without removing the cold bath. After 16.5 h, 10 mL of 9:1
saturated aqueous NH4Cl/NH4OH and 20 mL of Et2O were added, and the
mixture was stirred for 30 min. The layers were separated, and the aqueous
layer was extracted with 3 × 20 mL of Et2O. The combined organic layers
were washed with 25 mL of brine, dried (MgSO4), filtered, and concentrated
in Vacuo. Purification by flash chromatography (pentane) afforded the product
(Z)-2 as a colorless oil (105 mg, 82%). The structure of the product was
(7) Gallina, C.; Ciattini, P. G. J. Am. Chem. Soc. 1979, 101, 1035-1036.
(8) Chiral carbamates have been used to induce high levels of asymmetry
at the newly formed allylic center: Denmark, S. E.; Marble, L. K. J. Org.
Chem. 1990, 55, 1984-1986.
(9) Goering, H. L.; Kantner, S. S.; Tseng, C. C. J. Org. Chem. 1983, 48,
715-721.
(10) Allylic derivatives typically undergo anti substitution via oxidative
addition of copper anti to the leaving group: Corey, E. J.; Boaz, N. W.
Tetrahedron Lett. 1984, 25, 3063-3066.
(11) Hoveyda has reported directed allylic substitution reactions, involving
π-allyl nickel intermediates, that form (Z)-alkenes: Didiuk, M. T.; Morken,
J. P.; Hoveyda, A. H. Tetrahedron 1998, 54, 1117-1130.
(12) Suginome, M.; Matsumoto, A.; Ito, Y. J. Am. Chem. Soc. 1996, 118,
3061-3062 and references cited therein.
1
determined using IR, H NMR, and 13C NMR spectroscopies, HR-MS, and
(13) Sarkar, T. K. Synthesis 1990, 969-983, 1101-1111.
(14) Silylmethyl groups have been used as nontransferable groups for
copper: Bertz, S. H.; Eriksson, M.; Miao, G.; Snyder, J. P. J. Am. Chem.
Soc. 1996, 118, 10906-10907.
(15) Although the use of Goering's conditions (MeLi and CuI) gave
comparable (Z)-selectivity, we found that using n-BuLi, lower temperatures,
and CuI‚2LiCl (a more soluble copper salt) resulted in more reproducible
results and increased yields.
elemental analysis. The details are provided as Supporting Information.
(17) Alkene geometries were assigned by analysis of 1H NMR coupling
constants, by comparison of spectral data to reported data, or by comparison
to reference materials. Details are provided as Supporting Information.
(18) (R)-1 was prepared from the corresponding alcohol, obtained in g94%
ee from Sharpless kinetic resolution (Kitano, Y.; Matsumoto, T.; Sato, F.
Tetrahedron 1988, 44, 4073-4086). Details are provided as Supporting
Information.
10.1021/ja9820341 CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/01/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 49, 1998 12999
(Z)-alkene by a similar syn oxidative addition24 would require
the higher energy conformer25 7b to lead to the major product
(eq 5). This analysis requires the reactivity of the reactant
conformation to be a function of the organometallic reagent. Since
the cause of this relationship between reactivity and nucleophile
is not obvious, a fundamentally different mechanism may be
operating.
An alternative model to explain the formation of (Z)-alkenes
with alkylmagnesium reagents relies on an anti carbometalation
followed by an anti elimination (eq 6). Since organomagnesium
Table 1. Effect of Nucleophile on (E:Z)-Selectivity (eq 2)
yieldb
(%)
entry product
R
M
E:Za
γ:Ra
1
3a
3b
3c
3d
Me
MgCl 38:62
72
72
90
69
68
78
71
93:7
94:6
95:5
99:1
99:1
>99:1
>99:1
2
Li
MgCl
Li
92:8
6:94
91:9
4:96
72:28
3c
4
i-Bu
5d
6
PhMe2SiCH2 MgCl
Li
i-Pr
7
MgCl 13:87
a Determined by GC analysis of the unpurified reaction mixture.
b Yields reported for purified material. c Enantiomerically enriched 1
was employed (see eq 4). d CuI was used, and the reaction was
performed at 0-22 °C.
to the copper-mediated reaction with isobutylmagnesium chloride
(eq 4). The resultant allylsilane 3b was reduced to the alkylsilane19
reagents are less reactive than organolithium reagents,26 formation
of the alkyl cuprate of 7a by transmetalation may be slow.
Carbometalation by the Grignard reagent anti to the carbamate
moiety of the copper complex, in its lower energy conformer 7a,
becomes an alternative pathway (eq 6).27 Anti-elimination28 from
the acyclic29 intermediate 8 would afford the observed (Z)-
alkene.30
In conclusion, we have demonstrated that the use of organo-
magnesium reagents in copper-mediated reactions of allylic
carbamates gives (Z)-alkenes, in a surprising reversal of stereo-
selectivity relative to their organolithium counterparts. This
method permits the synthesis of (Z)-allylsilanes in high yield, with
high selectivity, and with a high degree of enantiomeric purity.
The change in selectivity exhibited by alkylmagnesium reagents
is proposed to result from a change in the reaction pathway.
Further studies to elucidate the reaction mechanism and efforts
to extend the utility of this transformation are ongoing.
then oxidized20 to afford the known, volatile alcohol 6 ([R]D )
-11.9°, [R]D lit. ) -11.9°).21 Analysis of the carbamate obtained
from treatment of alcohol 6 with (R)-(R-methyl)benzylisocyanate
by capillary GC indicated a 94:6 ratio of diastereomers. Com-
parison to a reference compound22 indicated that the major
diastereomer is the (R,R)-isomer. Since the oxidation of the C-Si
bond occurs with retention of configuration,20,23 this data indicates
that the allylsilane 3b has predominately the (S)-configuration.
This experiment demonstrates that enantiomerically enriched (Z)-
alkenes, including (Z)-allylsilanes, may be prepared using this
methodology from readily available chiral, non-racemic allylic
carbamates.
The formation of (S)-3b from (R)-1 with high (Z)-selectivity
and optical purity (eq 4) provides some insight into the mechanism
of the copper-mediated substitution reactions with organomag-
nesium reagents. A pathway resembling the accepted mechanism
for the copper-mediated syn-substitution of allylic carbamates with
alkyllithium reagents9 would be subject to serious constraints.
Alkyllithium reagents are believed to provide (E)-alkenes by
oxidative addition of the cuprate syn to the carbamate moiety in
the lower energy conformation 7a followed by reductive elimina-
tion (eq 5).9 For the magnesium case, formation of the observed
Acknowledgment. This research was supported by a CAREER Award
from the National Science Foundation (CHE-9701622). J.H.S. thanks the
American Association of University Women for an American Fellowship.
K.A.W. thanks the American Cancer Society, the Research Corporation,
Glaxo-Wellcome, and the Camille and Henry Dreyfus Foundation for
awards to support research. We thank Professor William Evans (UCI),
Professor Larry Overman (UCI), and Professor Yoshihiko Ito (Kyoto
University) for helpful discussions. We are grateful to Professor Michinori
Suginome (Kyoto University) for experimental results regarding the
stereochemistry proof. Dr. John Greaves and Dr. John Mudd are
acknowledged for mass spectrometric data.
Supporting Information Available: Full experimental and analytical
details for all new compounds as well as detailed descriptions of the
stereochemistry proofs (33 pages, print/PDF). See any current masthead
page for ordering information and Web access instructions.
JA9820341
(24) Oxidative addition of copper anti to the carbamate moiety can be
excluded. Anti oxidative addition of copper into lower energy rotamer 7a
would lead to the minor (E)-allylsilane. Anti oxidative addition into higher
energy rotamer 7b would have afforded the (R)-enantiomer of 3b.
(25) To result in the observed (E:Z)-ratio of 4:96, the transition state
resembling the disfavored methyl in-plane conformation would need to be
favored by approximately 1.4 kcal/mol. For a discussion of allylic strain, see:
Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1860.
(26) Negishi, E.-i. Organometallics in Organic Synthesis; Wiley: New
York, 1980; Vol. 1, pp 54-57.
(27) Metal alkene complexes are more electrophilic than their corresponding
free alkenes. For a discussion of the theory behind this phenomenon, see:
Eisenstein, O.; Hoffmann, R. J. Am. Chem. Soc. 1981, 103, 4308-4320.
(28) Marek, I.; Alexakis, A.; Mangeney, P.; Normant, J. F. Bull. Soc. Chim.
Fr. 1992, 129, 171-190.
(19) Suginome, M.; Iwanami, T.; Matsumoto, A.; Ito, Y. Tetrahedron:
Asymmetry 1997, 8, 859-862.
(20) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044-
6046.
(21) Takenaka, M.; Takikawa, H.; Mori, K. Liebigs Ann. Chem. 1996,
1963-1964.
(22) The reference (R)-alcohol was prepared by asymmetric allylation
(Keck, G. E.; Krishnamurthy, D. Org. Synth. 1997, 75, 12-18). Details are
provided as supporting information.
(23) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics 1983,
2, 1694-1696.
(29) The acyclic form may be preferred because of repulsive interactions
between the CuI(-) and the carbamate moieties. We thank a reviewer for
this suggestion.
(30) The minor (E)-isomer of 3b appears to possess the (R)-stereochemistry
because of the relationship between (E:Z)-selectivity and optical purity (eq
4). This (E)-isomer of 3b may be formed from the organomagnesium reagent
by the mechanism accepted for alkyllithium reagents.