Mechanism-Driven Elaboration of an Enantioselective Bromocyclopropanation Reaction of Allylic Alcohols

Article abstract of DOI:10.1002/anie.201506083

A stereoselective bromocyclopropanation of allylic alcohols using dibromomethylzinc bromide is described. Spectroscopic studies to monitor the formation of transient intermediates not only led to the development of a more-atom-economical halocyclopropanation reaction, but also highlighted the unique role of ether additives in the process. The desired bromo-substituted cyclopropanes were isolated in high yields and excellent diastereo- as well as enantioselectivities using readily available reagents.

Full text of DOI:10.1002/anie.201506083

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International Edition: DOI: 10.1002/anie.201506083
German Edition: DOI: 10.1002/ange.201506083
Carbenoids
Mechanism-Driven Elaboration of an Enantioselective
Bromocyclopropanation Reaction of Allylic Alcohols
Sylvain Taillemaud, Nicolas Diercxsens, Alexandre Gagnon, and AndrØ B. Charette*
Abstract: A stereoselective bromocyclopropanation of allylic
alcohols using dibromomethylzinc bromide is described.
Spectroscopic studies to monitor the formation of transient
intermediates not only led to the development of a more-atom-
economical halocyclopropanation reaction, but also high-
lighted the unique role of ether additives in the process. The
desired bromo-substituted cyclopropanes were isolated in high
yields and excellent diastereo- as well as enantioselectivities
using readily available reagents.
dibromomethyl(ethyl)zinc.[20] However, the reaction requires
the presence of oxygen to catalyze the reagent formation as
well as the mandatory use of the substrate as the solvent.
More recently, Walsh and co-workers reported an elegant
diastereoselective bromocyclopropanation of chiral allylic
alcohols, generated in situ by an enantioselective MIB-
catalyzed (MIB = (2S)-3-exo-(morpholino)isoborneol)
dialkylzinc 1,2-addition to a,b-unsaturated aldehydes
(Scheme 1).[21] In this work, (dibromomethyl)zinc 2,2,2-tri-
fluoroethoxide in excess (5 equiv) was the optimal cyclo-
propanating reagent.
A
s one of the most used carbocycles for the development of
new drugs,[1] the cyclopropane core is a key unit for the
pharmaceutical industry.[2] Yet, the synthesis of highly sub-
stituted cyclopropanes remains challenging, and new method-
ologies to access them are needed.[3]
Among the different cyclopropanation approaches, one of
the most straightforward methods involves the use of a-
substituted zinc carbenoids.[4,5] For example, it has been
shown that a-halocarbenoids can deliver enantiomerically
pure chloro-[6] and fluorocyclopropanes,[7] which are valuable
scaffolds present in numerous natural and synthetic bioactive
molecules.[8,9] Iodocyclopropanes can also be obtained by this
strategy, thus allowing further derivatization.[10] However, as
any iodinated compound, their stability to light and air causes
a major shelf-storage issue. In contrast, brominated com-
pounds provide a good compromise between stability and
reactivity,[11] and bromocyclopropanes are no exception. They
proved to be usable in lithium–halogen exchange reactions,[12]
Grignard-reagent formation,[13] elimination and formal sub-
stitution,[14] and even radical reactions.[15,16] Despite these
broad applications, few efficient methodologies currently
exist for the synthesis of enantioenriched bromocyclopro-
panes with good stereoselectivities. One of the earliest
methods involves the selective dehalogenation of dibromo-
cyclopropanes obtained by the reaction of dibromocarbene
with various alkenes.[17] While this is a popular strategy, the
dehalogenation process is rarely selective and a mixture of the
cis and trans bromocyclopropanes is usually observed.[18,19]
Miyano et al. reported the first Furukawa-type bromocyclo-
propanation of alkenes using what is presumed to be
Scheme 1. Simmons–Smith-type bromocyclopropanations.
Herein, we report a comprehensive spectroscopic study
and optimization of a dibromomethylzinc carbenoid forma-
tion from readily available reagents, which were employed in
a new enantio- and diastereoselective bromocyclopropana-
tion reaction of allylic alcohols. This method yields the
desired halogenated carbocycles in unprecedented high yields
and with excellent selectivities (Scheme 1).
The preparation of a-halozinc carbenoids (RZnCHIX)
typically requires a diiodohalomethane precursor.[6,10a] For
example, iodoform is used in the iodocyclopropanation and
chlorodiiodomethane leads to chlorocyclopropanes. How-
ever, in an attempt to utilize bromodiiodomethane to
generate bromocyclopropanes, we surprisingly found that
significant amounts of the undesired iodocyclopropane were
formed over the desired bromo-substituted product
(Scheme 2).[6]
[*] S. Taillemaud, N. Diercxsens, Prof. A. B. Charette
Department of Chemistry, University of Montreal
P.O. Box 6128 Stn Downtown, Montreal, Quebec, H3C 3J7 (Canada)
E-mail: andre.charette@umontreal.ca
Prof. A. Gagnon
Department of Chemistry, UniversitØ du QuØbec à MontrØal
P.O. Box 888, Stn Downtown, Montreal, Quebec, H3C 3P8 (Canada)
To rationalize these results, two possible scenarios were
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506083.
À
envisioned (Scheme 3): a) diethylzinc reacts with both the C
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material was recovered after 24 hours. However, we noted the
formation of a thick precipitate upon mixing diethylzinc and
bromoform, possibly indicating that the carbenoid was
formed but it either completely precipitated in dichloro-
methane or rapidly decomposed into zinc bromide. To
circumvent this issue, several coordinating additives were
tested to solubilize and stabilize the zinc carbenoid. In sharp
contrast, when 1.0 equivalent of dimethoxyethane (DME)
was employed as an additive,[24] the desired bromocyclopro-
pane was obtained in 66% yield after 24 hours. Unfortu-
nately, the level of stereocontrol was only moderate (15:1 d.r.,
67% ee) when using the ligand 2. Gratifyingly, a subsequent
screening of other coordinating solvents revealed that the
addition of 2.0 equivalents of Et2O per zinc atom was optimal,
thus yielding the desired bromocyclopropane in 71% yield,
with greater than 20:1 d.r. and 95% ee. Despite the fact that
the desired bromocyclopropane product was obtained with
high selectivity and yield, the minimization of the number of
equivalents of the reagents was addressed to make this
transformation more efficient. Under these reaction condi-
tions, more than 4.0 equivalents of the haloform were needed
for the reaction to proceed to completion.
Scheme 2. Initial attempt of bromocyclopropanation with CHBrI2.
Scheme 3. Halogen scrambling possibly taking place on the (bromo-
iodomethyl)zinc carbenoid.
À
I and C Br bonds leading to a mixture of the reagents A and
B, respectively (thus forming both ethyl iodide and ethyl
bromide as by-products); and/or b) the diethylzinc reacts
À
preferentially with the C I bond but a subsequent halogen
scrambling allows the formation of both the (diiodomethyl)-
zinc bromide A and (bromoiodomethyl)zinc iodide B.
To gain further insight into the reactive species generated
when diethylzinc is mixed with bromodiiodomethane, we
To improve the reaction efficiency, careful 1H NMR
monitoring of the reagent formation was undertaken.
1
monitored the formation of the reagent by H NMR spec-
1
troscopy. The first conclusion from this study is that iodo-
ethane was formed exclusively (> 99%) when diethylzinc was
mixed with bromodiiodomethane.[22] This result indicated the
Figure 1 illustrates the H NMR spectrum of a 2:1 mixture
À
strong preference for diethylzinc to react with the C I bond
of the haloform. These results are in agreement with the
previous observation made by Nishimura and Furukawa.[23]
When 1n HCl was added to this mixture, the signals
corresponding to both bromoiodomethane and diiodome-
thane were detected by NMR spectroscopy. This result can
only be obtained if there is a halogen scrambling between A
and B.
To suppress the undesired iodocyclopropanation, bromo-
form, which is known to react with diethylzinc towards the
formation of a reactive zinc carbenoid,[20] was used instead of
bromodiiodomethane. We hoped that by modifying Miyanoꢀs
reaction conditions, the requirement to introduce excess
alkene and oxygen/air would be by-passed. The first experi-
ment that was performed consisted of borrowing the pre-
viously optimized reaction conditions developed for the
enantioselective iodocyclopropanation, but applying them
to bromoform instead of iodoform (Scheme 4). Unfortu-
nately, under these reaction conditions, only the starting
Figure 1. 1H NMR spectrum of a 1:2:2 mixture of Et2Zn/CHBr3/Et2O in
CD2Cl2 (0.4m), À428C to RT, 10 min (0.1 equiv of triphenylmethane
relative to the amount of Et2Zn was added as the internal standard).
Zooms represent propene signals.
of CHBr3 and diethylzinc in the presence of 2.0 equivalents of
diethyl ether. The spectrum shows the presence of significant
amounts of residual bromoform given the signal at d =
6.90 ppm (0.65 equiv out of 2.0 equiv), the formation of
bromoethane from the signals at d = 3.43 and 1.65 ppm
(1.3 equiv instead of 2.0 equiv), and a new signal at d =
À
5.22 ppm, which was attributed to the carbenoid C H bond.
The formation of the latter was supported by the disappear-
À
ance of the C H signal upon adding water, which gave rise to
a new signal corresponding to dibromomethane. Intriguingly,
about 30% of the ethyl groups from the initial amount of
diethylzinc used cannot be accounted for. A close look at the
products indicated that propene was also formed in the
process. To gain further insight about the formation of the
1
reagent, its formation was monitored by H NMR spectros-
Scheme 4. Effects of coordinating ethers on the reactivity and selectiv-
ity.
copy. Aliquots taken after 10, 15, and 20 minutes indicated
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that, as expected, the amount of zinc carbenoid increased over
time. No formation of tetrabromoethylene or dibromome-
thane was observed, thus implying that the carbenoid was
stable. However the ratio EtBr/ZnCHBr2 decreased unex-
pectedly over time, thus indicating that EtBr was initially
formed much faster than “ZnCHBr2”. Furthermore, a close
look at the products formed in Figure 1 indicated that
significant amounts of propene were also formed in the
process. All these observations led to the conclusion that
a significant amount of bromoform was initially wasted to
form propene and zinc bromide by the 1,2-ethyl migration
depicted in Scheme 5. a-Alkylzinc carbenoids are known to
Figure 2. 1H NMR spectrum of a 1:1:1:2 mixture of Br2/Et2Zn/CHBr3/
Et2O in CD2Cl2 (0.4m), À428C to RT, 10 min (0.1 equiv of triphenyl-
methane—relative to the amount of Et2Zn—was added as the internal
standard).
starting material was observed after only four hours of
reaction time, thus giving the desired product in 88% yield
with high stereoselectivities (> 20:1 d.r., 95% ee).
With the optimal reaction conditions in hand, we next
examined the scope of the allylic alcohol component in this
new bromocyclopropanation reaction (Table 1). As illus-
trated, moderate to high yields, and excellent selectivities
were achieved for all the substrates tested. It was observed
that the presence of a methyl substituent on the aryl group of
the cinnamyl alcohol substrate had little effect on either the
yield or selectivity outcome of the reaction (entries 1–3).
However, when the phenyl moiety is replaced by a more
sterically demanding mesityl group, a marginal reduction in
yield was obtained (81%), however enantioselectivity was
slightly improved to 98% ee (entry 4). Importantly, both
electron-withdrawing and electron-donating substituents are
tolerated around the aryl ring, thus giving good yields and
excellent selectivity in all cases (entries 5 to 9). Entries 10 and
12 show that alkyl substituents are tolerated as well, with only
minor reductions of yields and still excellent stereoselectiv-
ities. As expected, a cis allylic alcohol is a more challenging
substrate as opposed to a trans-allylic alcohols. Nonetheless
a substrate of the former class still yields the desired
bromocyclopropane in acceptable yield and stereoselectivity
(54% yield, 5:1 d.r., 98% ee, entry 11). Exchange of the
aromatic group for a cyclohexane moiety still allows access to
the desired product with excellent stereoselectivity, although
in reduced yield (57% yield, > 20:1 d.r., 94% ee, entry 13).
This reduced yield is reasoned to be due to steric effects in
which the cyclohexane moiety inhibits approach of both the
chiral auxiliary and the carbenoid in the transition state.
Finally, entry 14 demonstrates that the newly developed
protocol is not only limited to disubstituted alkenes, as
trisubstituted alkenes are also viable substrates, thus giving
rise to high yields and stereoselectivity for the corresponding
bromocyclopropane under the optimized reaction conditions.
To avoid the use of bromine, it would also be possible to
exploit the Schlenk equilibrium between 1.0 equivalents of
zinc bromide and 1.0 equivalent of diethylzinc to yield
2.0 equivalents of ethylzinc bromide. Using this protocol,
the enantioselective bromocyclopropanation of cinnamyl
alcohol yielded the desired compound in nearly quantitative
Scheme 5. Proposed mechanism for the formation of the active
dibromomethylzinc reagent.
be unstable and undergo rapid decomposition to the alkene
by 1,2-alkyl shift. This decomposition pathway for the
Furukawa carbenoid has already been spectroscopically
established.[26] A subsequent Schlenk equilibration between
zinc bromide and diethylzinc generated ethylzinc bromide,
which could then react with the second equivalent of bromo-
form to generate the Simmons–Smith-type carbenoid
(Scheme 5).
The formation of propene was highlighted if 1.0 equiv-
alent of bromoform was slowly added to 1.0 equivalent of
diethylzinc. Under these reaction conditions, a large amount
1
(23%) of propene was detected by H NMR spectroscopy
along with less than 10% of the desired carbenoid signal.[27]
This experiment clearly shows the instability of the Furu-
kawa-type reagent and how fast the 1,2-ethyl migration is. On
this basis, it was envisioned that the generation of the reagent
using ethylzinc bromide instead of diethylzinc should lead to
a more efficient way to access the active cyclopropanating
reagent.
The simplest strategy for the formation of ethylzinc
bromide in CH2Cl2 is the reaction of 1.0 equivalent of Et2Zn
with 1.0 equivalent of bromine. The subsequent addition of
1.0 equivalent of CHBr3 should generate the desired Sim-
1
mons–Smith-type carbenoid. Gratifyingly, H NMR analysis
showed this procedure yielded the desired carbenoid in about
80% yield, without the need for a large excess of bromoform
(Figure 2). However, trace quantities of propene were still
observed by this protocol and attempts to completely
suppress it through reverse addition of reagents (ethylzinc
bromide added to bromoform) were unfruitful. Further fine-
tuning of the reaction conditions for the bromocyclopropa-
nation of cinnamyl alcohol revealed that using 2.6 equivalents
of Et2Zn, Br2, and CHBr3 were optimal. Full conversion of the
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Table 1: Scope of the monobromocyclopropanation reaction.
Table 1: (Continued)
Entry
Product
Yield [%]
92
d.r.[a]
ee [%]
6n
15[d]
>20:1
98
6a
Entry
1
Product
Yield [%]
88
d.r.[a]
ee [%]
[a] Determined by 1H NMR analysis of the crude mixture. [b] Determined
after benzylation of the alcohol. [c] Determined after benzoylation of the
alcohol. [d] Procedure: 1. ZnBr2 (1.3 equiv), Et2O (5.2 equiv); 2. Et2Zn
(1.3 equiv); 3. CHBr3 (2.6 equiv); 4. allylic alcohol, 2 (1.1 equiv); CH2Cl2,
À428C to RT, 4 h.
>20:1
95
6a
6b
2
3
4
5
6
7
8
85
88
81
83
66
74
80
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
94
96
98
95
96
94
96
yield and with excellent selectivities (entry 15). In addition,
the mesityl-substituted bromocyclopropane 6d furnished
single crystals suitable for X-Ray analysis, thus confirming
the absolute stereochemistry of the product.[28]
To illustrate the utility of bromocyclopropanes for late-
stage diversification, the compound 6i was engaged in
a Suzuki cross-coupling reaction using Buchwaldꢀs G3-
Xphos precatalyst 7 (Scheme 6).[29] This compound is an
6c
6d
6e
6 f
6g
6h
Scheme 6. Derivatization of the bromocyclopropane 6i and compar-
ison with the iodinated analogue. THF=tetrahydrofuran.
9
89
79
54
81
57
90
>20:1
>20:1
5:1
96
6i
6j
6k
6l
interesting example because of the presence of two function-
alization sites: the first one on the cyclopropane, the other on
the phenyl substituent. We were glad to obtain selective cross-
coupling on the arene, with the bromocyclopropane remain-
ing untouched. Conversely, the iodinated analogue 9 led to 10
in only 62%. After protection of the free alcohol (11), we
were able to perform the alkylation of the bromocyclopro-
pane by a lithium–halogen exchange followed by a quench
with methyl iodide (see 12) as a simple proof of concept.
In conclusion, we have described a protocol for the
efficient, enantioselective bromocyclopropanation of allylic
alcohols. In all cases, unprecedentedly high yields and
excellent stereoselectivities were obtained in a single step.
A comprehensive study of the nature and formation mech-
anism of the reactive carbenoid allowed the elaboration of the
fully optimized protocols and led to the development of more-
atom-economic reaction conditions than previously de-
10
11
12
13
14
95
98
>20:1
>20:1
>20:1
98[b]
94[c]
94
6m
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Acknowledgements
This work was supported by the Natural Science and
Engineering Research Council of Canada (NSERC), the
Canada Foundation for Innovation, the Canada Research
Chair Program, the FQRNT Centre in Green Chemistry and
Catalysis and UniversitØ de MontrØal. S.T. is grateful to
UniversitØ de MontrØal for postgraduate scholarships.
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Keywords: cyclopropanes · carbenoids · NMR spectroscopy ·
reaction mechanisms · zinc
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Received: July 2, 2015
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Revised: August 14, 2015
Published online: September 30, 2015
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