Copper-catalyzed cyanomethylation of allylic alcohols with concomitant 1,2-aryl migration: Efficient synthesis of functionalized ketones containing an α-quaternary center

Article abstract of DOI:10.1002/anie.201411657

A copper-catalyzed alkylation of allylic alcohols by alkyl nitriles with concomitant 1,2-aryl migration was developed. Formation of the alkyl nitrile radical was followed by its intermolecular addition to alkenes and the migration of a vicinal aryl group with the concomitant generation of a carbonyl functionality to complete the domino sequence. Mechanistic studies suggested that 1,2-aryl migration proceeded through a radical pathway (neophyl rearrangement). The protocol provided an efficient route to functionalized ketones containing an α-quaternary center.

Full text of DOI:10.1002/anie.201411657

Angewandte
Chemie
DOI: 10.1002/anie.201411657
Synthetic Methods
Copper-Catalyzed Cyanomethylation of Allylic Alcohols with
Concomitant 1,2-Aryl Migration: Efficient Synthesis of Functionalized
Ketones Containing an a-Quaternary Center**
Ala Bunescu, Qian Wang, and Jieping Zhu*
Abstract: A copper-catalyzed alkylation of allylic alcohols by
alkyl nitriles with concomitant 1,2-aryl migration was devel-
oped. Formation of the alkyl nitrile radical was followed by its
intermolecular addition to alkenes and the migration of
a vicinal aryl group with the concomitant generation of
a carbonyl functionality to complete the domino sequence.
Mechanistic studies suggested that 1,2-aryl migration pro-
ceeded through a radical pathway (neophyl rearrangement).
The protocol provided an efficient route to functionalized
ketones containing an a-quaternary center.
Scheme 1. Copper-catalyzed coupling reaction between a,a-disubsti-
tuted allylic alcohols and alkyl nitriles with concomitant 1,2-aryl
migration. 1,10-Phen=1,10-phenanthroline, Tf=trifluoromethane-
sulfonyl.
alcohols into ketones,[13] examples of the generation of
homologated ketones with the creation of an a-quaternary
center are rare.[13h]
A
lkenes and nitriles are two of the most ubiquitous chemical
feedstocks and are essential in different domains of chemistry,
such as polymers,[1] agrochemicals, and pharmaceuticals.[2]
Therefore, many important chemical transformations of
these compounds have been developed.[3] Powerful synthetic
methodologies have been developed on the basis of the metal-
catalyzed oxidative vicinal difunctionalization of unactivated
alkenes;[4–7] however, examples of the copper-mediated/
catalyzed difunctionalization of alkenes with the generation
2-Methyl-3-phenylbut-3-en-2-ol (1a) and acetonitrile were
initially used as test substrates. When we applied our previously
developed alkylative lactonization conditions [Cu(OTf)2
(2.0 equiv), BiPy (1.0 equiv), DTBP (2.0 equiv), K3PO4
(2.0 equiv), H2O (11.0 equiv), air, 1408C, CH3CN (0.1m)],
ketone 2a was formed together with epoxide 3a in 61% yield
in a 1.9 :1 ratio. Although the usefulness of the formation of
epoxide 3a is evident,[14] we focused our attention on ketone 2
in this study. Conditions were systematically surveyed by
varying the copper salt, the ligand, the base, and the
temperature under an inert atmosphere.[15] The use of
sodium phosphate instead of potassium phosphate resulted
in a slight improvement in the ketone/epoxide ratio and the
overall yield (Table 1, entry 2 versus entry 1). A result with
important mechanistic implications was that the reaction took
place in the absence of DTBP, albeit with lower conversion
(Table 1, entry 3). On the other hand, only degradation was
observed in the absence of a base (Table 1, entry 4). The use
of 4,4’-dimethoxy-2,2’-bipyridine as the ligand provided
epoxide 3a as the major product, thus indicating the dramatic
effect of the ligand (Table 1, entries 5–8). Neither 2a nor 3a
was formed in the absence of Cu(OTf)2 and 1,10-Phen.
Reasoning that the methyl group has a low migratory
aptitude, we investigated the reaction between 2-methyl-1,1-
diphenylprop-2-en-1-ol (1b) and acetonitrile. Gratifyingly,
the desired ketone 2b was isolated in 84% yield under the
following conditions: Cu(OTf)2 (0.5 equiv), 1,10-Phen
(0.5 equiv), Na3PO4 (2.0 equiv), DTBP (2.0 + 2.0 equiv),
CH3CN (0.1m), 1408C (Table 1, entry 10). At a lower catalyst
loading (0.2 equiv), the reaction remained clean, but the
conversion was lower within the same reaction time (51% or
85% based on conversion; Table 1, entry 11).
of a C(sp ) C(sp ) bond remain scarce.[8] On the other hand,
although the formation of organometallic complexes (Ln, Rh,
3
3
À
À
Fe, Ru) by activation of the a-C H bond of acetonitrile has
been documented,[9] the synthetic use of nitriles is limited
mainly to their enolate form,[10] the formation of which
requires a strong base [pKa(MeCN) ꢀ 31.3, DMSO]. We
recently initiated a project aimed at the development of
methods for the direct coupling of unactivated alkenes with
alkyl nitriles and disclosed a copper-mediated/catalyzed oxy-
alkylation of unactivated alkenes with alkyl nitriles and
amides/acids as reaction partners for the synthesis of func-
tionalized phthalides, isochromanones, and g-lactones.[11,12]
We report herein a novel copper-catalyzed coupling reaction
of allylic alcohols with alkyl nitriles that leads to ketones with
the concomitant creation of an a-quaternary center
(Scheme 1). Although alkylation-induced 1,2-aryl migration
has recently been reported for the conversion of allylic
[*] Dr. A. Bunescu, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
We investigated the scope of the copper-catalyzed cou-
pling reaction of a,a-disubstituted allylic alcohols with alkyl
nitriles under the optimized conditions (Scheme 2). The
presence of electron-withdrawing groups (m-CF3, m-F, p-Cl)
[**] Financial support from the EPFL (Switzerland) and the Swiss
National Science Foundation (SNSF) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411657.
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Table 1: Arylalkylation of alkenes: Survey of reaction conditions.
Entry
1
Ligand
Base
2/3
Yield of 2+3 [%][b,c]
1
2
3
4
5
1a 1,10-Phen K3PO4
1a 1,10-Phen Na3PO4
1a 1,10-Phen Na3PO4
1.9 :1
2.3 :1
2.9 :1
–
(58)
(64)
(34)[d]
degradation
(35)
1a 1,10-Phen
–
1a 1,10-Phen CsOH·H2O 2.2 :1
6
7
8
1a Bpym
1a dtbpy
1a OMebpy
Na3PO4
Na3PO4
K3PO4
3.0 :1
1.8 :1
1:2.7
(38)
(41)
(70)
9
10
11
1b 1,10-Phen Na3PO4
1b 1,10-Phen Na3PO4
1b 1,10-Phen Na3PO4
only 2b
only 2b
only 2b
55
84[e,f]
51[e,g]
[a] Reactions were carried out on a 0.05 mmol scale in a sealed tube.
Standard conditions: Cu(OTf)2 (2.0 equiv), ligand (2.0 equiv), DTBP
(2.0 equiv), base (2.0 equiv), N2, 1408C, CH3CN (0.1m). [b] Yields in
parentheses were calculated from 1H NMR spectra by using CH2Br2 as an
internal standard. [c] The yield is given for a mixture of 2 and 3. [d] No
DTBP was used. The reaction reached 40% conversion according to
1H NMR spectroscopy. [e] DTBP was added in two portions (the second
portion after 2 h). [f] Cu(OTf)2 (0.5 equiv), 1,10-Phen (0.5 equiv).
[g] Cu(OTf)2 (0.2 equiv), 1,10-Phen (0.2 equiv), 85% based on conver-
sion (60%). Bpym=2,2’-bipyrimidine; dtbpy=4,4’-di-tert-butyl-2,2’-
bipyridine; OMebpy=4,4’-dimethoxy-2,2’-bipyridine; DTBP=di-tert-
butyl peroxide.
Scheme 2. Scope of the copper-catalyzed coupling reaction of allylic
alcohols with alkyl nitriles. [a] Reactions were carried out on
a 0.05 mmol scale in a sealed tube. Reaction conditions: Cu(OTf)2
(0.5 equiv), 1,10-Phen (0.5 equiv), DTBP (4.0 equiv, added in two
portions), Na3PO4 (2.0 equiv), RCH2CN (solvent, 0.1m), N2 atmos-
phere, 1408C.
on the a-aryl group was well-tolerated, and the desired a-
quaternary ketones 2c–e were formed in up to 88% yield.
Interestingly, the reaction of electron-rich 2-methyl-1,1-di-p-
tolylprop-2-en-1-ol with acetonitrile furnished migration
product 2 f in lower yield (48%). When two different
aromatic substituents were incorporated into tertiary alcohol
1, the electron-poor aryl group migrated in preference to the
electron-rich aryl group. In the case of 4-(1-hydroxy-2-
methyl-1-phenylallyl)benzonitrile (1j, R1 = Me, R2 = p-cya-
nophenyl, R3 = Ph), only one product, resulting from the
migration of the electron-poor para-cyano-substituted phenyl
group, was formed (product 2j, 76% yield). It is well-known
that electron-rich aryl groups have a high migratory aptitude
in Wagner–Meerwein-type rearrangements involving cationic
intermediates.[16] In contrast, electron-poor aryl groups
migrate preferentially in neophyl rearrangements involving
radical intermediates.[17] Therefore, our experimental results
indicated that the 1,2-aryl shift might occur via a radical
rather than a cationic intermediate. Only the aryl group
migrated when a-aryl-a-alkyl-substituted tertiary allylic alco-
hols were used, regardless of the nature of the alkyl group
(products 2k–r). Alkyl groups other than Me at the internal
position of the double bond were also well-tolerated (Et, nBu,
Ph), with the formation of the desired ketones in 71–80%
yield (products 2p–r). However, the reaction failed with
a monosubstituted olefin (R1 = H). Gratifyingly, other alkyl
nitriles, such as propionitrile and 3-methoxypropionitrile,
participated in this reaction to give the desired functionalized
ketones (products 2s,t) in up to 72% yield, albeit with low
diastereoselectivity (d.r. 1.3 :1). In none of these examples
was an epoxide isolated.
Mechanistically, ketone 2a could be generated by
a copper triflate catalyzed Meinwald rearrangement of
epoxide 3a.[18] However, a control experiment showed that
epoxide 3a was stable under our optimized reaction con-
ditions. On the other hand, 3a was converted into ketone 4a,
rather than ketone 2a, in 69% yield in the absence of a base
(Scheme 3). Preferential formation of a carbocation A
stabilized via phenonium ion B could explain the formation
of 4a. The same regioselectivity in the rearrangement of 5
(R = Ph) was observed to afford ketone 4b in 91% yield.
These results indicated that epoxide 3a was not the precursor
of ketone 2a and that these two compounds were formed
through two competitive processes.
Possible reaction pathways are depicted in Scheme 4.
Coordination of copper(II) triflate to the nitrile followed by
the deprotonation of complex C by sodium phosphate would
produce the organocopper species D.[19] Carbocupration of
1 by D[20] would lead to E, which could subsequently be
converted into epoxide 3 or undergo homolytic cleavage to
give radical F. Alternatively, the cyanomethyl radical G could
also be generated from D, and upon addition to 1 would
produce intermediate F. When both R2 and R3 are alkyl
substituents (1a, R2 = R3 = Me), F would be further oxidized
to carbocation H,[21] which upon alkyl migration would be
converted into ketone 2a. With aryl-substituted allylic
2
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Scheme 5. Trapping experiments with 2,2,6,6-tetramethylpiperidin-1-
oxyl (TEMPO). [a] Yield based on TEMPO.
when the reaction was quenched before the consumption of
TEMPO (after 1 h). On the other hand, compound 8 became
the major product (16% yield) when the same reaction was
performed in the absence of the copper salt and the ligand
(exp. 2). The results of these trapping experiments are in favor
of pathway b (Scheme 4) involving a cyanomethyl radical and
support the notion that the copper catalyst is responsible for
the generation of this radical under our reaction conditions.
In summary, we have developed a copper-catalyzed
oxidative coupling of allylic alcohols 1 with alkyl nitriles for
the synthesis of functionalized ketones 2. The reaction
involves the copper-catalyzed formation of alkyl nitrile
radicals, followed by their intermolecular addition to alkenes
and 1,2-aryl migration with the concurrent generation of
a carbonyl functionality. Electron-poor aryl groups under-
went the 1,2-shift in preference to electron-rich aryl groups in
accordance with the mechanism of the neophyl rearrange-
ment. The protocol provides an efficient route to function-
alized ketones containing an a-quaternary center.
Scheme 3. Cu(OTf)2-promoted rearrangement of epoxides 3a and 5.
Experimental Section
DTBP (2.0 equiv) was added to a mixture of an allylic alcohol 1,
Cu(OTf)2 (0.5 equiv), 1,10-Phen (0.5 equiv), and Na3PO4 (2.0 equiv)
in RCN (0.1m). The tube was sealed and the mixture stirred at 1408C
for 2 h, and then another portion of DTBP (2.0 equiv) was added, and
the mixture was stirred for an additional 2 h. The reaction mixture
was then partitioned between ethyl acetate and aqueous NH3 (25%).
The aqueous layer was extracted with ethyl acetate, and the combined
organic extracts were washed twice with aqueous HCl (2.0n),
aqueous NaOH (3.0n), and brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel to afford
ketone 2.
Scheme 4. Possible reaction pathways of the copper-catalyzed coupling
reaction of allylic alcohols with alkyl nitriles to give ketones 2.
alcohols, a neophyl rearrangement via a spiro[2,5]octadienyl
radical intermediate I might predominate in accord with the
experimental observations. The radical J resulting from the
1,2-aryl migration could be further oxidized to carbocation K
and therefore to ketone 2. Finally, the CuI species could be
oxidized to regenerate the CuII salt.[22–24] The fact that
a variable amount of 4-oxo-4-phenylbutanenitrile (6) was
produced when the reaction of 1a and acetonitrile was
performed in air was indicative of the presence of the radical
intermediate F.[25]
When the reaction of 1b was performed in MeCN in the
presence of TEMPO (2.0 equiv) under otherwise identical
conditions, 2-[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]aceto-
nitrile (7) and 1-methoxy-2,2,6,6-tetramethylpiperidine (8)
were obtained in yields of 14 and 7%, respectively (exp. 1,
Scheme 5). The formation of ketone 2b was not observed
Received: December 3, 2014
Published online: && &&, &&&&
Keywords: alkyl nitriles · allylic alcohols · copper triflate ·
.
ketones · neophyl rearrangement
[1] G. W. Coates, P. D. Hustad, S. Reinartz, Angew. Chem. Int. Ed.
2002, 41, 2236 – 2257; Angew. Chem. 2002, 114, 2340 – 2361.
[2] F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk, B. C. Shook, J.
Med. Chem. 2010, 53, 7902 – 7917; for a review on nitrile-
containing natural compounds, see: F. Fleming, Nat. Prod. Rep.
1999, 16, 597 – 606.
[3] Z. Rappoport, The Chemistry of the Cyano Group, Wiley,
London, 1970.
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.
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Communications
[4] a) D. M. Schultz, J. P. Wolfe, Synthesis 2012, 351 – 361; b) R. I.
McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011, 111, 2981 – 3019;
c) K. H. Jensen, M. S. Sigman, Org. Biomol. Chem. 2008, 6,
4083 – 4088; d) A. Minatti, K. MuÇiz, Chem. Soc. Rev. 2007, 36,
1142 – 1152.
[5] a) S. R. Chemler, P. H. Fuller, Chem. Soc. Rev. 2007, 36, 1153 –
1160; b) G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008,
108, 3054 – 3131; c) A. E. Wendlandt, A. M. Suess, S. S. Stahl,
Angew. Chem. Int. Ed. 2011, 50, 11062 – 11087; Angew. Chem.
2011, 123, 11256 – 11283; d) C. Zhang, C. Tang, N. Jiao, Chem.
Soc. Rev. 2012, 41, 3464 – 3484; e) Y. Shimizu, M. Kanai,
Tetrahedron Lett. 2014, 55, 3727 – 3737.
[6] For the copper-catalyzed difunctionalization of alkenes initiated
by aminocupration, see: a) T. P. Zabawa, D. Kasi, S. R. Chemler,
J. Am. Chem. Soc. 2005, 127, 11250 – 11251; b) W. Zeng, S. R.
Chemler, J. Am. Chem. Soc. 2007, 129, 12948 – 12949; c) P. H.
Fuller, J.-W. Kim, S. R. Chemler, J. Am. Chem. Soc. 2008, 130,
17638 – 17639; d) M. C. Paderes, S. R. Chemler, Eur. J. Org.
Chem. 2011, 3679 – 3684; e) T. W. Liwosz, S. R. Chemler, J. Am.
Chem. Soc. 2012, 134, 2020 – 2023; f) Y. Miller, L. Miao, A. S.
Hosseini, S. R. Chemler, J. Am. Chem. Soc. 2012, 134, 12149 –
12156.
[7] For the copper-catalyzed diamination of alkenes, see: a) B. Zhao,
X. Peng, S. Cui, Y. Shi, J. Am. Chem. Soc. 2010, 132, 11009 –
11011; b) B. Zhao, X. Peng, Y. Zhu, T. A. Ramirez, R. G.
Cornwall, Y. Shi, J. Am. Chem. Soc. 2011, 133, 20890 – 20900;
c) Y.-F. Wang, X. Zhu, S. Chiba, J. Am. Chem. Soc. 2012, 134,
3679 – 3682.
[8] For the copper-catalyzed trifluoromethylation of alkenes, see:
a) A. T. Parsons, S. L. Buchwald, Angew. Chem. Int. Ed. 2011, 50,
9120 – 9123; Angew. Chem. 2011, 123, 9286 – 9289; b) J. Xu, Y.
Fu, D.-F. Luo, Y.-Y. Jiang, B. Xiao, Z.-J. Liu, T.-J. Gong, L. Liu, J.
Am. Chem. Soc. 2011, 133, 15300 – 15303; c) X. Wang, Y. Ye, S.
Zhang, J. Feng, Y. Xu, Y. Zhang, J. Wang, J. Am. Chem. Soc.
2011, 133, 16410 – 16413; d) R. Zhu, S. L. Buchwald, J. Am.
Chem. Soc. 2012, 134, 12462 – 12465; e) L. Chu, F.-L. Qing, Org.
Lett. 2012, 14, 2106 – 2109; f) P. G. Janson, I. Ghoneim, N. O.
Ilchenko, K. Szabꢀ, Org. Lett. 2012, 14, 2882 – 2885; g) R. Zhu,
S. L. Buchwald, Angew. Chem. Int. Ed. 2013, 52, 12655 – 12658;
Angew. Chem. 2013, 125, 12887 – 12890; h) H. Egami, R.
Shimizu, S. Kawamura, M. Sodeoka, Angew. Chem. Int. Ed.
2013, 52, 4000 – 4003; Angew. Chem. 2013, 125, 4092 – 4095; i) H.
Egami, S. Kawamura, A. Miyazaki, M. Sodeoka, Angew. Chem.
Int. Ed. 2013, 52, 7841 – 7844; Angew. Chem. 2013, 125, 7995 –
7998; j) for a highlight, see: A. Studer, Angew. Chem. Int. Ed.
2012, 51, 8950 – 8958; Angew. Chem. 2012, 124, 9082 – 9090.
[9] a) S. D. Ittel, C. A. Tolman, A. D. English, J. P. Jesson, J. Am.
Chem. Soc. 1978, 100, 7577 – 7585; b) H. J. Heeres, A. Meetsma,
J. H. Teuben, Angew. Chem. Int. Ed. Engl. 1990, 29, 420 – 422;
Angew. Chem. 1990, 102, 449 – 450; c) D. Churchill, J. H. Shin, T.
Hascall, J. M. Hahn, B. M. Bridgewater, G. Parkin, Organo-
metallics 1999, 18, 2403 – 2406; d) M. E. Evans, T. Li, A. J. Vetter,
R. D. Rieth, W. D. Jones, J. Org. Chem. 2009, 74, 6907 – 6914.
[13] For recent examples of 1,2-aryl migration involving allylic
alcohols, see: a) X.-Q. Chu, H. Meng, Y. Zi, X.-P. Xu, S.-J. Ji,
Chem. Eur. J. 2014, 20, 17198 – 17206; b) Y. Li, B. Liu, H.-B. Li,
Q. Wang, J.-H. Li, Chem. Commun. 2015, 51, 1024 – 1026; c) Z.-
M. Chen, Z. Zhang, Y.-Q. Tu, M.-H. Xu, F.-M. Zhang, C.-C. Li,
S.-H. Wang, Chem. Commun. 2014, 50, 10805 – 10808; d) Z.-M.
Chen, W. Bai, S.-H. Wang, B.-M. Yang, Y.-Q. Tu, F.-M. Zhang,
Angew. Chem. Int. Ed. 2013, 52, 9781 – 9785; Angew. Chem.
2013, 125, 9963 – 9967; e) M. Salamone, M. Bietti, Synlett 2014,
25, 1803; f) X. Liu, F. Xiong, X. Huang, L. Xu, P. Li, X. Wu,
Angew. Chem. Int. Ed. 2013, 52, 6962 – 6966; Angew. Chem.
2013, 125, 7100 – 7104; g) X. Liu, X. Wu, Synlett 2013, 1882 –
1886; h) H. Egami, R. Shimizu, Y. Usui, M. Sodeoka, Chem.
Commun. 2013, 49, 7346 – 7348; i) H. Li, F.-M. Zhang, Y.-Q. Tu,
Q.-W. Zhang, Z.-M. Chen, Z.-H. Chen, J. Li, Chem. Sci. 2011, 2,
1839 – 1841; for an example of 1,4-migration, see: j) P. Gao, Y.-
W. Shen, R. Fang, X.-H. Hao, Z.-H. Qiu, F. Yang, X.-B. Yan, Q.
Wang, X.-J. Gong, X.-Y. Liu, Y.-M. Liang, Angew. Chem. Int. Ed.
2014, 53, 7629 – 7633; Angew. Chem. 2014, 126, 7759 – 7763.
[14] For examples, see: a) S. Hayashi, H. Yorimitsu, K. Oshima, J.
Am. Chem. Soc. 2009, 131, 2052 – 2053 and Ref. [8d].
[15] Copper salts: Cu(OTf)2, Cu(ClO4)2·6H2O, Cu(OAc)2, CuSO4,
CuBr, Cu(NO3)·3H2O; ligands: pyridine, 2,2’-bipyridine, 4,4’-
dimethoxy bipyridine, 2,2’-bipyrimidine, neocuproine, 1,10-phe-
nanthroline, 4,5-diazafluoren-9-one; bases: KOAc, LiOAc,
K3PO4, K2CO3, Na3PO4, Li3PO4, CsOPiv, CsOH·H2O.
[16] For reviews on pinacol/semipinacol rearrangements, see: a) K.-
D. Umland, S. F. Kirsch, Synlett 2013, 1471 – 1484; b) B. Wang, Y.
Tu, Acc. Chem. Res. 2011, 44, 1207 – 1222; c) T. J. Snape, Chem.
Soc. Rev. 2007, 36, 1823 – 1842.
[17] a) C. S. Aureliano Antunes, M. Bietti, G. Ercolani, O. Lanza-
lunga, M. Salamone, J. Org. Chem. 2005, 70, 3884 – 3891; b) for
a review, see: A. Studer, M. Bossart, Tetrahedron 2001, 57, 9649 –
9667.
[18] a) J. Meinwald, S. S. Labana, M. S. Chadha, J. Am. Chem. Soc.
1963, 85, 582 – 585; b) for a Cu(BF4)2-promoted Meinwald
rearrangement, see: M. W. C. Robinson, K. S. Pillinger, I.
Mabbett, D. A. Timms, A. E. Graham, Tetrahedron 2010, 66,
8377 – 8382.
[19] Copper preferentially undergoes C-metalation with alkyl
nitriles; see: a) M. Purzycki, W. Liu, G. Hilmersson, F. F.
Fleming, Chem. Commun. 2013, 49, 4700 – 4702; b) Y. Suto, R.
Tsuji, M. Kanai, M. Shibasaki, Org. Lett. 2005, 7, 3757 – 3760;
c) E. J. Corey, I. Kuwajima, Tetrahedron Lett. 1972, 13, 487 – 489.
[20] a) J. F. Normant, A. Alexakis, Synthesis 1981, 841 – 870; b) E.
Nakamura, M. isaka, S. Mstsuzawa, J. Am. Chem. Soc. 1988, 110,
1297 – 1298; c) L. Huang, H. Jiang, C. Qi, X. Liu, J. Am. Chem.
Soc. 2010, 132, 17652 – 17654; d) K. K. Toh, Y.-F. Wang, E. P. J.
Ng, S. Chiba, J. Am. Chem. Soc. 2011, 133, 13942 – 13945.
[21] C. L. Jenkins, J. K. Kochi, J. Am. Chem. Soc. 1972, 94, 843 – 855.
[22] Q. Xia, X. Liu, Y. Zhang, C. Chen, W. Chen, Org. Lett. 2013, 15,
3326 – 3329.
[23] For recent examples of DTBP-mediated transformations, see:
a) M.-B. Zhou, R.-J. Song, X.-H. Ouyang, Y. Liu, W.-T. Wei, G.-
B. Deng, J.-H. Li, Chem. Sci. 2013, 4, 2690 – 2694; b) S.-L. Zhou,
L.-N. Guo, H. Wang, X.-H. Duan, Chem. Eur. J. 2013, 19, 12970 –
12973; c) Z. Li, Y. Zhang, L. Zhang, Z.-Q. Liu, Org. Lett. 2014,
16, 382 – 385.
À
[10] For the catalytic C H functionalization of nitriles, see: a) N.
Kumagai, S. Matsunage, M. Shibasaki, J. Am. Chem. Soc. 2004,
126, 13632 – 13633; b) for a general review on metal-enolate
chemistry, see: F. Dꢁnꢂs, A. Pꢁrez-Luna, F. Chemla, Chem. Rev.
2010, 110, 2366 – 2447.
[11] A. Bunescu, Q. Wang, J. Zhu, Chem. Eur. J. 2014, 20, 14633 –
14636.
[12] For related studies, see: a) J. Li, Z. Wang, N. Wu, G. Gao, J. You,
Chem. Commun. 2014, 50, 15049 – 15051; b) J. Shen, D. Yang, Y.
Liu, S. Qin, J. Zhang, J. Sun, C. Liu, C. Liu, X. Zhao, C. Chu, R.
Liu, Org. Lett. 2014, 16, 350 – 353.
[24] a) G. E. Morris, D. Oakley, D. A. Pippard, D. J. H. Smith, J.
Chem. Soc. Chem. Commun. 1987, 411 – 412; b) R. T. Gephar-
t III, C. L. McMullin, N. G. Sapiezynski, E. S. Jang, M. J. B.
Aguila, T. R. Cundari, T. H. Warren, J. Am. Chem. Soc. 2012,
134, 17350 – 17353.
[25] C. Zhang, N. Jiao, J. Am. Chem. Soc. 2010, 132, 28 – 29.
4
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
A. Bunescu, Q. Wang,
J. Zhu*
&&& — &&&
Copper-Catalyzed Cyanomethylation of
Allylic Alcohols with Concomitant 1,2-Aryl
Migration: Efficient Synthesis of
Functionalized Ketones Containing an a-
Quaternary Center
A shift in gear: Ketones with an a-
copper-catalyzed formation of an alkyl
quaternary center were synthesized by the
title copper triflate catalyzed alkylation of
alkenes with non-activated alkyl nitriles
(see scheme; 1,10-Phen=1,10-phenan-
throline). The reaction involves the
nitrile radical, its addition to the alkene,
and the migration of a vicinal aryl group
with the concomitant generation of a car-
bonyl functionality.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!