Journal of the American Chemical Society
Communication
We began our investigation by employing 1,3-dimesylate 1.
This substrate was designed to provide an alkylcyclopropane
with low volatility to facilitate isolation and analysis. We
Our next efforts focused on testing the impact of steric bulk
near the forming cyclopropane (Scheme 2b). For compounds
such as 11, standard reaction conditions employing rac-BINAP
23
evaluated a series of ligands in the presence of Ni(cod) and
as the ligand provided moderate yields. Fortunately, we
found that, for these more hindered substrates, using dppm as
the ligand and performing the reaction at 0 °C provided good
yields. A series of alkyl and aryl groups were well tolerated in
the β-position relative to the cyclopropane (10−12). For
example, the diol precursor for cyclopropane 12 was prepared
2
methylmagnesium iodide (MeMgI) in DCM/PhMe (Table 1).
Table 1. Ligand Evaluation of XEC Reaction of Unactivated
24
by a stereospecific Kumada ring-opening reaction. We were
also interested in the functional group compatibility of the
reaction. Compounds containing benzylic ethers (PMB), aryl
chlorides, alkyl ethers, and silyl protecting groups (TBS)
underwent smooth cyclopropane formation (13−15).
We next sought to confirm our hypothesis that aromatic
groups were not required for desired reactivity. To confirm
this, we successfully synthesized cyclopropanes containing only
a
Entry
Deviation from reaction conditions
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
none
BPhen
dppm
75
78
71
56
44
33
16
13
70
5
3
sp centers such as borneol derivative 16 and β-sitosterol
derivative 18. Acetonide 17 was formed smoothly from the
corresponding tetraol derivative, demonstrating tolerance to a
typical protecting group employed in polyketide synthesis.
These results confirm thatin contrast to our laboratory’s
previously published XC and XEC reactionsthis XEC
reaction does not require benzylic or allylic electrophiles to
PCy3
DPEPhos
SiMes·HBF4
Xantphos
no ligand
((R)-BINAP)NiCl2
PhMgBr
PhMgBr + Mg12
no Ni, no ligand
no MeMgl
5a,b,25
engage the nickel catalyst.
0
1
2
3
Based on these results, we concluded that arene coordina-
tion would no longer be critical for reactivity, but the reaction
could nonetheless provide a strategy for synthesis of
arylcyclopropanes. In our prior work, synthesis was restricted
to cyclopropanes bearing extended aromatic rings, due to
17
5
0
a
1
Yield determined by H NMR based on comparison to PhTMS as
internal standard.
5a,b,25
requirements to activate substrates for oxidative addition.
To thoroughly investigate the generality of this XEC reaction,
we evaluated simple benzylic substrates. Notably, under
standard conditions for preparation of the 1,3-dimesylates,
benzylic mesylates undergo substitution to afford the benzylic
The diphosphine ligands rac-BINAP and dppm, in addition to
the pyridyl ligand Bphen, produced the highest yields of
cyclopropane 2 (entries 1−3). Additionally, a 70% yield of the
desired cyclopropane was achieved utilizing bench-stable ((R)-
26
chlorides. Subjection of 1,3-chloromesylates to our standard
reaction conditions provided cyclopropanes bearing a range of
substituted aromatic substituents (Scheme 2c; 19−22).
The potential impact of this transformation would be
expanded if 1,3-diols could be employed as starting materials
for the reaction. We were encouraged that other XC and XEC
reactions that employ sulfonates generated in situ have been
BINAP)NiCl as the catalyst (entry 9). In general, across a
2
range of substrates, rac-BINAP and dppm provided robust
reaction yields, and so we selected these ligands for further
2
3
experiments.
Following the ligand evaluation, we next investigated the
importance of the Grignard reagent and nickel catalyst.
Modifying the Grignard reagent to phenylmagnesium bromide
almost completely shut down the reaction, with 5% of the
16,20a
reported.
A procedure was developed such that diol 23
was treated with MsCl and base, followed by addition to
catalyst and Grignard reagent. Cyclopropane 11 was formed in
good yield, similar to that observed when employing the
corresponding 1,3-dimesylate. Therefore, this method allows
direct conversion of a 1,3-diol to the corresponding cyclo-
desired cyclopropane observed (entry 10). Adding MgI to
2
PhMgBr reaction conditions provided a similar result (entry
1
1). A control reaction without nickel and ligand (MeMgI
only) produced a 5% yield of the desired cyclopropane (entry
2), while a control reaction in the absence of MeMgI
1
provided no conversion to the desired cyclopropane and only
recovered starting material (entry 13).
With optimized conditions in hand, we investigated the
tolerance of various substituted aromatic and heterocyclic
groups (Scheme 2a). Isolated yields are reported; however, for
certain substrates, volatility or polarity complicated isolation.
1
Therefore, yield determined by H NMR by comparison to an
internal standard is also reported. Heterocycles such as
thiophene, furan, and benzofuran were well tolerated under
the reaction conditions (3−5), as was the substituted
heterocycle 2-methoxypyridine (6). Electron-donating groups
were well tolerated in the synthesis of 2 and 7, as well as
In order to elucidate a potential reaction mechanism, our
first question was whether the mechanism involves oxidative
addition (OA) of an alkyl mesylate, or if alkyl iodides are
formed as intermediates in the reaction. A control experi-
ment demonstrated that, under the reaction conditions, in the
absence of a nickel catalyst, MeMgI converts 1,3-dimesylate 24
27
electron-withdrawing groups such as aryl CF and aryl fluoride
3
(8, 9).
B
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX