10.1002/anie.201704028
Angewandte Chemie International Edition
COMMUNICATION
efficiently trapped with methyl iodide to afford the sulfonyl nitrile
15j, a β, β-disubstituted nitrile. Standard sulfone-magnesium
exchange of 15j followed by methylation afforded the quaternary
nitrile 4q (82% yield).
CN
n O
CN
O
O
BuLi; Me
N
n
S
O
( )
20a
20b
20c
0)
(n=
15a
15d
4c
,
4k
,
53%
51%
(n=1)
(n=2)
(n=1)
(n=2)
N
O
O
O
O
Li
PhCHO
Ph
Ph
PhLi
S
CN
O
S
CN
Ph
O
S
Et3N,
(77%)
Li
N
N
O
CN
O
Me
n
14
18
19
21
MeI
(92%)
O
Figure 1. Lithiated nitrile alkylations of allylic ethers.
O
2-Pyridylsulfonylacetonitriles engage Bu3MgLi or BuLi in the
first sulfone-metal exchange. The sulfone-metal exchange offers
complementary advantages to existing routes to metalated
nitriles: substituted sulfones are readily prepared from
commercially available 2-pyridinesulfonylacetonitrile, alkylations
of 2-pyridinesulfonylacetonitrile only require K2CO3 or DBU
thereby avoiding the use of two equivalents of strong base, and
sulfonylnitriles are typically stable, crystalline solids. The sulfone-
metal exchange-alkylation is remarkably facile across a range of
cyclic and acylic substrates affording quaternary nitriles even
through alkylation with allylic ethers.
CN
Ph
S
CN
Bu
3MgLi
MeI
(82%)
N
Ph
Ph
15j
Ph
4q
Scheme 4. Conjugate Addition-Exchange Alkylation
Metalated nitriles are powerful nucleophiles capable of
challenging alkylations that fail with enolates.[24 The exceptional
nucleophilicity suggested that the sulfone-metal exchange might
allow the displacement of allylic ethers[25 thereby extending the
range of available electrophiles for carbon-carbon bond formation.
Exploratory experiments with the magnesiated or lithiated nitriles
derived from 15a and allyl methyl ether (20a, 10 equiv) afforded
the allyl nitrile 4c in low yield (Figure 1). Pairing BuLi for the
exchange with the glycol ether 20b afforded the allylated nitrile 4c
in 53% yield. 26 Although speculative, the successful allylation
may involve activation of the olefin through a lithium complex
21[27 which is consistent with the lack of allylation with the glycol
]
]
[
]
Acknowledgements
]
Financial support for this research from NSF (1639875) is
gratefully acknowledged. HRMS analysis conducted by Timothy
P. Wade and suggestions from Zhen Qiao are gratefully
acknowledged.
20c. Allylation of the seven-membered nitrile 15d with 20b gave
4k in 51% yield.
[ ]
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1
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[
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Publ. 2003, 55 pp., US 2003191121 A1 20031009. b) G. H.
15
Determined by monitoring a THF-d8 solution by H
Posner, C. Switzer J. Am. Chem. Soc. 1986, 108, 1239-1244. NMR which shows the rapid formation of butyl-2-
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9
K.-M. Roy, "Sulfones and Sulfoxides" in Ullmann's pyridylsulfone.
[
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Fine Chemicals Elvers, B., Ed. 2014, 3, 1169-1184.
16
The exchange with Bu3MgLi afforded butyl-2-
[
]
10
J.-Y. Lai, J. Yu, R. D. Hawkins, J. R. Falck. Tetrahedron pyridylsulfone in 93%. The metalated nitrile does not appear
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to deprotonate the sulfone (for a related example see:
[
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