Copper-catalyzed hydride transfer from LiAlH4 for the formation of alkylidenecyclopropane derivatives

Article abstract of DOI:10.1039/b817710d

The copper-catalyzed addition of LiAlH₄ to cyclopropenylcarbinol leads to an easy and straightforward preparation of alkylidenecyclopropane derivative. The Royal Society of Chemistry.

Full text of DOI:10.1039/b817710d

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Copper-catalyzed hydride transfer from LiAlH4 for the formation
of alkylidenecyclopropane derivativesw
Samah Simaan and Ilan Marek*
Received (in Cambridge, UK) 8th October 2008, Accepted 17th November 2008
First published as an Advance Article on the web 5th December 2008
DOI: 10.1039/b817710d
The copper-catalyzed addition of LiAlH4 to cyclopropenyl-
carbinol leads to an easy and straightforward preparation of
alkylidenecyclopropane derivative.
Over the past few decades, racemic cyclopropene and alkyl-
idenecyclopropane (ACP) derivatives have been established as
powerful tools in synthetic chemistry. Indeed, on one hand,
cyclopropene derivatives can easily be transformed into more
complex molecules by hydro- or carbometallation reactions1
of the internal strained double bond2 whereas alkylidenecyclo-
propane derivatives have proved their usefulness by their
unique reactivity with transition-metal catalysts.3 These
Scheme 1
bromoethene in the presence of phase transfer catalyst, as
catalyzed transformations, also based on the release of the
described in Scheme 1, constantly led to very low yields of
high level of strain, can be performed either on the distal or
proximal bonds of the three-membered ring as well as on the
tribromocyclopropane 2 (R1 = H). Therefore, we thought to
develop an alternative strategy for the obtention of 4 (R1 = H)
exoalkylidene moiety.4 However, in the last few years, using
using our easily prepared precursor 3 (R1 = alkyl). In such
strain as design principle for asymmetric reaction led to a
case, the formal SN20 addition of a hydride to the cyclo-
propenylcarbinol 3 should be the relevant strategy for the
formation of the expected alkylidenecyclopropane derivative.
complete renaissance of the field.5 In this context, we have
recently reported the straightforward preparation of enantio-
merically pure cyclopropenylcarbinols 3 in excellent yields for
a kinetic resolution upon Sharpless epoxidation (Scheme 1).6
The copper (I)-catalyzed hydride transfer is known to be a mild
and often selective reducing agent, and among the most
extensively studied and routinely used is the phosphine-
Racemic 3 is easily prepared by a two step sequence: reaction
of substituted vinyl bromide derivatives 1 with bromoform in
the presence of cetrimide as phase-transfer catalyst,7 followed
stabilized hexameric complex [{CuH(PPh3)}6], commonly
referred to as Stryker’s reagent.8 It smoothly effects conjugate
by treatment of the resulting 1,1,2-tribromocyclopropanes 2
reductions of various a,b-unsaturated compounds.9 More
with n-BuLi and reaction with various aldehydes. Then,
starting from enantiomerically pure 3, the synthesis of alkyl-
recently, alternatives such as stannanes,10 boranes,11 and in
particular silanes12 have been developed as hydrogen equiva-
idenecyclopropanes 4 was readily achieved by a simple
combined copper-catalyzed carbomagnesiation followed by a
lents in CuH chemistry. Interestingly, since the initial report of
Whitesides that reported the preparation of copper hydride via
syn-b-elimination reaction in excellent yields and enantiomeric
excess.
treatment of i-Bu2AlH with CuBr,13 the use of HCu generated
from aluminium species has never been really developed.
Secondary allyl alcohol derivatives 3 led to alkylidenecyclo-
propanes 4 with a quaternary all-carbon stereocenter with a
complete transfer of chirality, regardless of the nature of the
We have recently reported that LiAlH4 could be success-
fully used to reduce cyclopropenylcarbinols 3 into the corres-
ponding anti-cyclopropylcarbinols 5 in excellent yield and
diastereoselectivity (Scheme 2, Path A).14
Although the regiochemistry of the hydroalumination reac-
alkylmagnesium halide. Moreover, in all these experiments,
the unique or major isomer detected had E-configuration.
To extend this methodology, and particularly if aiming to
tion leads to the carbon–aluminium bond in a g-position
prepare alkylidenecyclopropanes 4 possessing a tertiary stereo-
(as determined by treatment with D3O+ and exemplified in
center (R1 = H, R3 = alkyl, aryl), the more challenging
gaseous bromoethene 1 (R1 = H) has to be used to obtain 2.
the formation of the deuteriocyclopropane derivative 5), we
envisaged that the addition of a catalytic amount of copper(I)
salt to LiAlH4 should reverse the chemical outcome of the
Despite many attempts, the reaction of bromoform to
reaction via a postulated copper hydride species. Thus, a
The Mallat Family Laboratory of Organic Chemistry, Schulich
Faculty of Chemistry and the Lise Meitner-Minerva Center for
Computational Quantum Chemistry, Technion-Israel Institute of
Technology, Haifa, 32000, Israel. E-mail: chilanm@tx.technion.ac.il;
Fax: (+972)4 829 3709
w Electronic supplementary information (ESI) available: Experimental
details; characterization data and NMR spectra for compounds 6a–h.
See DOI: 10.1039/b817710d
Scheme 2
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Table 1 Formal SN20 addition of HCu on 3a–h
20 mol% of CuI and cyclopropenylcarbinol 3 at ꢁ50 1C and
slow warming to room temperature overnight gives the
expected alkylidenecyclopropanes 6 in very good yield as
described in Table 1.
Tertiary and secondary alcohol derivatives (Table 1, entries
1 to 4 and 5 to 9 respectively) led similarly to alkylidenecyclo-
propane derivatives via the formal SN20 reaction (the low yield
observed for 6c is most probably due to the volatile nature of
the final product, Table, entry 4). When commercially
available LiAlD4 was used as reducing agent, the alkylidene-
cyclopropane deuterated in the allylic position was obtained in
good yields with 495% deuterium incorporation (Table 1,
entries 2 and 8). Substituents on the double bond of the
cyclopropenyl ring (R1) can be either methyl or butyl.
Substituents R2 and R3 can be either alkyl, aryl or hydrogen
groups. When secondary alcohols are used (R2 = alkyl or
aryl, R3 = H, Table 1, entries 5 to 9), the fate of the
stereochemistry of the double bond is raised and in all the
tested experiments, we always found that the major isomer was
of (E)-configuration.
Yield
(%)a
Entry R1
R2
R3
Products
1
(3a)
CH3 C6H5
C6H5
6a
87
2
(3a)
CH3 C6H5
C6H5
6a(D) 85b
3
(3b)
C4H9 C6H5
C6H5
6b
6c
82
In conclusion, the addition of a catalytic amount of copper
salt such CuI to cyclopropenylcarbinol and LiAlH4 reverses
the chemical outcome of the reaction and a formal SN20
reaction proceeds without any trace of hydroalumination
reaction of the strained double bond. It is interesting to note
that the rarely used lithium aluminium hydride could be an
excellent source of copper hydride.
4
(3c)
CH3 C2H5
C2H5
40c
5
(3d)
CH3 C6H5
H
H
H
6d
6e
6f
60d
61e
68e
This research was supported by the German-Israeli Project
Cooperation (DIP-F. 6.2) and by the Israel Science Founda-
tion administrated by the Israel Academy of Sciences and
Humanities (grant N0 70/08). I.M. is holder of the Sir Michael
and Lady Sobell Academic Chair.
6
(3e)
C4H9 C6H5
7
(3f)
CH3 (CH2)2C6H5
Notes and references
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8
(3f)
CH3 (CH2)2C6H5
H
H
6f(D) 70b
9
(3g)
CH3 CH2C6H5
6g
6h
76d
10
(3h)
CH3 p-BrH4C6
H
83f,g
2 R. D. Bach and O. Dmitrenko, J. Am. Chem. Soc., 2004, 126,
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a
Yields of isolated pure products after purification by column
b
chromatography. LiAlD4 was used as reducing agent. Volatile
c
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d
e
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f
E/Z isomers in a 85 : 15 ratio. Isolated as E/Z isomers in a 90 : 10
g
ratio. ACP 6h was directly transformed into its corresponding
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294 | Chem. Commun., 2009, 292–294