Copper-catalyzed cross-coupling of nonactivated secondary alkyl halides and tosylates with secondary alkyl grignard reagents

Article abstract of DOI:10.1021/ja304848n

Practical catalytic cross-coupling of secondary alkyl electrophiles with secondary alkyl nucleophiles under Cu catalysis has been realized. The use of TMEDA and LiOMe is critical for the success of the reaction. This cross-coupling reaction occurs via an S_N2 mechanism with inversion of configuration and therefore provides a general approach for the stereocontrolled formation of C-C bonds between two tertiary carbons from chiral secondary alcohols.

Full text of DOI:10.1021/ja304848n

Communication
pubs.acs.org/JACS
Copper-Catalyzed Cross-Coupling of Nonactivated Secondary Alkyl
Halides and Tosylates with Secondary Alkyl Grignard Reagents
Chu-Ting Yang,†,§ Zhen-Qi Zhang,†,§ Jun Liang,‡ Jing-Hui Liu,† Xiao-Yu Lu,‡ Huan-Huan Chen,‡
and Lei Liu*,†
†Tsinghua-Peking Center for Life Sciences, Department of Chemistry, Tsinghua University, Beijing 100084, China
‡Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
S
* Supporting Information
secondary alkyl sulfonates with primary Grignard reagents but
still not secondary or aromatic ones.13 Through NMR analysis it
ABSTRACT: Practical catalytic cross-coupling of secon-
dary alkyl electrophiles with secondary alkyl nucleophiles
under Cu catalysis has been realized. The use of TMEDA
and LiOMe is critical for the success of the reaction. This
cross-coupling reaction occurs via an SN2 mechanism with
inversion of configuration and therefore provides a general
approach for the stereocontrolled formation of C−C
bonds between two tertiary carbons from chiral secondary
alcohols.
was proposed that the active species of Burns’ catalyst consisted
of Cu ligated with LiBr in aggregated forms.13 This hypothesis
prompted us to examine the effect of other Li additives, which
led to the discovery of an easier-to-use yet more powerful
catalyst, namely, CuI/N,N,N′,N′-tetramethylethylenediamine
(TMEDA)/LiOMe. This catalyst expands the synthetic toolbox
for the construction of C−C bonds between two tertiary
carbons through transition-metal-catalyzed cross-coupling.
Moreover, because this Cu-catalyzed cross-coupling reaction
proceeds by an SN2 mechanism, it provides a general approach
for the stereocontrolled formation of C−C bonds from chiral
secondary alcohols.
Our study began with an examination of the cross-coupling
of 4-phenylbutan-2-yl tosylate (1a) with cyclohexylmagnesium
bromide (CyMgBr, 2a). We initially used CuI as the catalyst
and THF as the solvent. Hexamethylphosphoramide (HMPA)
was used as a cosolvent according to the previous work.13 We
also employed TMEDA as the additive because it may suppress
undesirable side reactions such as olefin formation via loss of
hydrogen halide.8,10 Unfortunately, the yield of the desired
product under these conditions was very low (Table 1, entry 1).
Addition of LiCl or LiBr did not significantly improve the
reaction (entries 2 and 3), but we were delighted to find that
LiI, LiOtBu, and LiOMe provided modest yields (entries 4−6).
Further optimization increased the yield to 85% at 0 °C (entry
7). Interestingly, HMPA is not essential for the reaction (entry
8), but the use of TMEDA is important (entry 9). Other
additives besides TMEDA, including PnBu3, N-methylpyrroli-
done (NMP), and PhCCCH3, could also promote the
reaction but gave lower yields (entries 10−12). On the other
hand, changing CuI to CuBr, Cu(I) thiophene-2-carboxylate
(CuTc), or Cu(OTf)2 dramatically reduced the yield (entries
13−15). A secondary alkyl bromide was also a good substrate
(entry 16), but the present conditions were not effective for the
coupling of an alkyl iodide, chloride, or mesylate (entries 17−
19). Finally, the reaction did not occur in the absence of
catalyst (entry 20). Pd and Ni salts did not promote the
reaction (entries 21 and 22), ruling out the involvement of Pd
or Ni contamination in the catalysis.
ince the pioneering studies of Kochi and Tamura,1 Suzuki,2
S
and Knochel,3 transition-metal-catalyzed C−C cross-
couplings of nonactivated alkyl electrophiles have emerged as
an important category of reactions.4 While many transition-
metal catalysts can now promote the coupling of primary alkyl
halides or pseudohalides, the number of examples involving
coupling of nonactivated secondary alkyl electrophiles is much
smaller.5 To solve this problem, Ni catalysts have been
intensively studied for the coupling of secondary alkyl
electrophiles,6 whereas some Pd,7 Fe,8 and Co9 catalysts have
also been examined for the same purpose. It is noteworthy that
most of the reported coupling reactions of secondary alkyl
electrophiles proceed by a radical mechanism.5,10 This
mechanism disfavors the use of secondary alkyl tosylates11
(which can be readily made from inexpensive secondary
alcohols), and therefore, alternative catalysts need to be
explored. Furthermore, most of the nucleophiles in the previous
coupling reactions of secondary alkyl electrophiles are either
aromatic or primary alkyl organometallic reagents.12 It remains
challenging to develop cross-coupling reactions of secondary alkyl
electrophiles with secondary alkyl nucleophiles. Such trans-
formations are desirable because they would increase the
flexibility in the synthesis of complex carbon skeletons.
Here we report the cross-coupling of nonactivated secondary
alkyl halides and pseudohalides with secondary alkyl Grignard
reagents under Cu catalysis. Our work was inspired by the
recent advances13−17 in Cu-catalyzed cross-coupling of alkyl
electrophiles to replace the classical stoichiometric alkylation
reactions of organocopper reagents. Previous studies by
Burns,13 Kambe,14 Cahiez,15 and others,16 including us,17
have shown that the coupling of primary alkyl halides can be
effectively promoted by different Cu catalysts. However, only a
special Cu catalyst (i.e., Burns’ catalyst “CuBr/LiSPh/LiBr/
THF”) was found to be able to induce the cross-coupling of
Received: May 25, 2012
Published: June 26, 2012
© 2012 American Chemical Society
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Communication
a
a
Table 1. Cross-Coupling between 1a and 2a
Table 2. Substrate Scope of the Coupling Reaction
a
Conditions: R−X (0.5 mmol), CyMgBr (1 M in THF, 1 mL),
catalyst (10 mol %), additive (20 mol %), Li salt (0.5 mmol), HMPA
b
c
(50 μL). GC yields after 24 h (averages of two runs). Isolated yield.
d
2 mol % catalyst was added. NiI2 was used in entry 22 because it is an
anhydrous salt. NiCl2 and NiBr2 as hydrated salts gave the same
negative results.
The above results show that CuI/TMEDA/LiOMe is a
competent catalyst for the cross-coupling of secondary alkyl
bromides and tosylates with secondary alkyl Grignard reagents.
In regard to the scope of this method (Table 2), secondary
alkyl electrophiles with different chain lengths and branching
can participate in the reaction. Both cyclic (3a−j, 3o) and
acyclic (3k−n) Grignard reagents are good substrates. The
same reaction conditions can also be used for coupling with
primary alkyl Grignard reagents (3p−r). More importantly, a
variety of synthetically useful functional groups, including CF3
(3d), ether (3e, 3g, 3h), N-Ts (3f, 3q), ester (3h), olefin (3j),
amide (3l), heterocycle (3n, 3r), and even an unprotected OH
group (3e) can be tolerated in the transformation. It is
interesting that an ester moiety (3h) can survive the reaction
conditions (surprisingly, we did not observe ester exchange
between LiOMe and the butyl ester in 3h). However, the
presence of a ketone group leads to a mixture of products (3i).
Further tests showed that the present catalyst may also be
used for coupling with tertiary alkyl Grignard reagents (Scheme
1). Such reactions are synthetically useful, as they allow the
a
Reactions were carried out at 0 °C for 24 h on a 0.5 mmol scale using
10 mol % CuI. For details, see the Supporting Information. Yields were
determined through isolation of the desired products. 3 equiv of
CyMgBr was used. Diastereomeric mixture.
b
c
Scheme 1. Coupling with a Tertiary Grignard Reagent
Scheme 2. Coupling with an Aryl Grignard Reagent
t
attachment of a Bu group to a primary or secondary carbon
atom. The reaction between 1c and 4 also represents the first
example of catalytic cross-coupling between a tertiary carbon
and a quaternary carbon from ordinary, nonactivated aliphatic
substrates.18 Moreover, although previous studies of Cu-
catalyzed cross-couplings have not shown any examples of
the arylation of a nonactivated secondary electrophile,13−17 our
experiments show that CuI/TMEDA/LiOMe is active enough
to promote the cross-coupling of secondary alkyl iodides with
aryl Grignard reagents (Scheme 2).
In regard to the chemoselectivity of the reaction, we found
that in the case of substrates with aryl and alkyl sites, the latter
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Communication
are much more reactive under the present conditions. Thus,
when 1d was treated with CyMgBr (Scheme 3), we observed
Kambe and co-workers previously showed that Cu-catalyzed
cross-coupling of Grignard reagents with primary alkyl halides
(with diastereometrically pure α,β-deuteriums) proceed via an
SN2 mechanism.14 Here, the possibility of coupling with
secondary alkyl halides allowed us to use chiral substrates to
examine the stereochemistry of the reaction. As shown in
Scheme 6, chiral tosylate 7b can be readily prepared from the
Scheme 3. Selectivity for Alkyl over Aryl Bromides
Scheme 6. Inversion of Configuration
only the desired alkyl−alkyl cross-coupling at the alkyl−Br
bond, whereas the aryl−alkyl cross-coupling at the aryl−Br
bond did not take place. The same chemoselectivity was also
observed for substrates with both alkyl−OTs and aryl−Br
bonds (Scheme 4). The tolerance of an aryl−Br bond in the
reaction allows for the design of sequential C−C and C−
heteroatom19 cross-couplings promoted by Cu catalysts.
corresponding chiral secondary alcohol. This tosylate under-
goes catalytic cross-coupling with CyMgBr to produce 8b in
70% yield. X-ray crystal analysis of 8b revealed that the reaction
occurs with inversion of configuration. This finding confirms
that the present cross-coupling reactions for secondary alkyl
halides also proceed by an SN2 mechanism. It should be noted
that the formation of 8b involves a cyclic secondary alkyl
tosylate. We also have evidence of inversion of configuration for
an acyclic secondary alkyl tosylate (Scheme 4).
Scheme 4. Site-Selective Sequential Cross-Couplings
(DMEDA = N,N′-Dimethylethylenediamine)
The importance of the above finding is that the present
cross-coupling reaction provides a practical approach for the
stereocontrolled formation of C−C bonds from chiral
secondary alcohols. As shown in Table 3, both acyclic and
cyclic chiral secondary alcohols can be easily converted to the
Table 3. Stereocontrolled Construction of C−C Bonds from
a
Chiral Secondary Alcohols
Additionally, although the present catalyst cannot promote
the cross-coupling of a secondary Grignard reagent with a
secondary alkyl chloride (Table 1, entry 18), it is active enough
to promote the alkyl−alkyl cross-coupling between a primary
alkyl chloride and a secondary Grignard reagent (Scheme 5).
Scheme 5. Cross-Coupling with Primary Alkyl Chlorides
Similar Cu-catalyzed cross-coupling reactions of alkyl chlorides
were accomplished previously by Kambe and co-workers, who
used 1-phenylpropyne as an additive.14 Interestingly, when a
primary chloride and a secondary tosylate were both present in
the substrate, only the tosylate underwent the cross-coupling.
Thus, a secondary tosylate is more reactive than a primary
chloride under the present reaction conditions. This observa-
tion is synthetically useful for the design of site-selective
sequential cross-coupling reactions.
a
Reactions were carried out at 0 °C for 24 h on a 0.5 mmol scale using
10 mol % CuI, 20 mol % TMEDA, 1 equiv of LiOMe, 0.5 mmol of R−
OTs, and 1.0 mmol of R3MgBr. For details, see the Supporting
Information. Isolated yields. Determined by chiral HPLC analysis.
b
c
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Journal of the American Chemical Society
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(5) Recent reviews: (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem.
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coupling reaction, the chiral tosylates can be alkylated with
either primary or secondary alkyl Grignard reagents in good
yields (65−79%). The enantioselectivities of these two-step
transformations were measured to be as high as 98−99% ee.
Because many methods are now available for the preparation of
chiral secondary alcohols, the present method expands the
toolbox for the construction of carbon skeletons with
stereocontrol. Nonetheless, it is worth mentioning that all of
the examples in Table 3 involved Grignard reagents possessing
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1
butylmagnesium bromide with chiral tosylate 7a. H NMR
analysis of the product (obtained in 43% isolated yield) showed
that this reaction produced two diastereoisomers in a 1:1 ratio
(see the Supporting Information). Thus, the chiral center in the
tosylate could not induce stereoselectivity at the chiral carbon
in the Grignard reagent. It would be interesting to examine
whether the use of chiral ligands can solve this problem.20
To summarize, we have developed a Cu-catalyzed cross-
coupling reaction of nonactivated secondary alkyl bromides and
tosylates with secondary alkyl Grignard reagents. This reaction
represents a rare example of transition-metal-catalyzed cross-
coupling between two tertiary alkyl carbons. The use of
TMEDA and LiOMe as additives is crucial. The reaction
tolerates a number of synthetically relevant functional groups,
including esters, amides, and aryl halides, and aromatic and
tertiary alkyl Grignard reagents are also good substrates.
Furthermore, primary alkyl chlorides can be used in the
reaction, but they are less reactive than secondary alkyl
tosylates. Finally, X-ray crystal analysis of the products revealed
that the reaction occurs via an SN2 mechanism with inversion of
configuration. Thus, the present cross-coupling reaction
provides a general approach for the stereocontrolled formation
of C−C bonds from chiral secondary alcohols.
Arellano, C.; Asensio, G.; Medio-Simon
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(11) Gonzal
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(12) In a recent study of Ni-catalyzed cross-coupling of alkyl halides
(see: Ren, P.; Vechorkin, O.; von Allmen, K.; Scopelliti, R.; Hu, X. L.
J. Am. Chem. Soc. 2011, 133, 7084 ), the authors reported an example
of the coupling of a secondary alkyl iodide with a secondary alkyl
Grignard reagent. The yield was only 7%.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, spectra, and crystallographic data (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Burns, D. H.; Miller, J. D.; Chan, H. K.; Delaney, M. O. J. Am.
Chem. Soc. 1997, 119, 2125.
(14) (a) Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem.
Soc. 2003, 125, 5646. (b) Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu,
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AUTHOR INFORMATION
■
Corresponding Author
lliu@mail.tsinghua.edu.cn
́ ́
(15) (a) Cahiez, G.; Chaboche, C.; Jezequel, M. Tetrahedron 2000,
56, 2733. (b) Cahiez, G.; Gager, O.; Buendia, J. Synlett 2010, 299.
(16) (a) Nakamura, E.; Arai, M.; Lipshutz, B. H. J. Org. Chem. 1991,
56, 5489. (b) Lipshutz, B. H. Acc. Chem. Res. 1997, 30, 277.
(c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248,
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(17) Yang, C.-T.; Zhang, Z.-Q.; Liu, Y.-C.; Liu, L. Angew. Chem., Int.
Ed. 2011, 50, 3904.
(18) Oshima and co-workers once reported a Cu(OTf)2-catalyzed
reaction between tertiary alkyl halides and cyclopentadienyl Grignard
reagents (see: Sai, M.; Someya, H.; Yorimitsu, H.; Oshima, K. Org.
Lett. 2008, 10, 2545 ). This particular reaction was proposed to involve
a special [Cp3Cu(II)]MgBr species.
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Author Contributions
§C.-T.Y. and Z.-Q.Z contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Our study was supported by the “973” Program of the Ministry
of Science and Technology (Grant 2011CB965300).
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