Metalated nitriles: Organolithium, -magnesium? and -copper exchange of α-halonitriles

Article abstract of DOI:10.1021/jo047877r

(Chemical Equation Presented) α-Halonitriles react with alkyllithium, organomagnesium, and lithium dimethylcuprate reagents generating reactive, metalated nitriles. The rapid halogen-metal exchange with alkyllithium and Grignard reagents allows selective exchange in the presence of reactive carbonyl electrophiles, including aldehydes, providing a high-yielding alkylation protocol. Lithiated and magnesiated nitriles react with propargyl bromide by S_N2 displacement whereas organocopper nitriles react by S _N2′ displacement, correlating with the formation of a C-metalated nitrile.

Full text of DOI:10.1021/jo047877r

Metalated Nitriles: Organolithium, -magnesium, and -copper
Exchange of r-Halonitriles
Fraser F. Fleming,*,† Zhiyu Zhang,† Wang Liu,† and Paul Knochel*,‡
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530,
and Department Chemie, Ludwig-Maximilians-Universita¨t, Butenandtstrasse 5-13,
81377, Mu¨nchen, Germany
flemingf@duq.edu
Received November 30, 2004
R-Halonitriles react with alkyllithium, organomagnesium, and lithium dimethylcuprate reagents
generating reactive, metalated nitriles. The rapid halogen-metal exchange with alkyllithium and
Grignard reagents allows selective exchange in the presence of reactive carbonyl electrophiles,
including aldehydes, providing a high-yielding alkylation protocol. Lithiated and magnesiated
nitriles react with propargyl bromide by SN2 displacement whereas organocopper nitriles react by
SN2′ displacement, correlating with the formation of a C-metalated nitrile.
Introduction
putationally, deprotonating acetonitrile with lithium
amide leads directly to N-lithiated acetonitrile,7 which
correlates with numerous X-ray8 (1, 2) and solution9
structures (2, 3) of metalated nitriles (Figure 1). Remark-
ably, X-ray analyses8 consistently show metalated nitriles
as having partial double bond character for the C+CN
bond and only slight weakening of the CtN triple bond
(1.15-1.20 Å), relative to the CtN bond length of neutral
nitriles (1.14 Å)!10 Another characteristic feature of
R-Metalated nitriles are powerful nucleophiles, ideally
suited for sterically demanding alkylations.1 The excep-
tional nucleophilicity stems from the powerful inductive
stabilization2 of metalated nitriles that localizes negative
charge density on carbon to the virtual exclusion of
N-alkylation.3 Augmenting the nucleophilicity of meta-
lated nitriles is the extremely small steric demand of the
CN unit, with an A-value of only 0.2 kcal mol-1 4
.
Collectively, the exceptional nucleophilicity of metalated
nitriles,1 the facile installation of hindered centers,5 and
the conversion of nitriles into a range of functional
groups6 have resulted in the extensive use of metalated
nitriles in synthesis.
Metalated nitriles are typically synthesized by depro-
tonating the parent nitriles with metal amides.1 Com-
† Duquesne University.
‡ Ludwig-Maximilians-Universita¨t.
(1) (a) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1. (b)
Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org. React. 1984, 31, 1.
(2) Nitriles are powerful inductive stabilizing groups with weak
delocalizing effects: (a) Richard, J. P.; Williams, G.; Gao, J. J. Am.
Chem. Soc. 1999, 121, 715. (b) Bradamante, S.; Pagani, G. A. J. Chem.
Soc., Perkin Trans. 2 1986, 1035. (c) Dayal, S. K.; Ehrenson, S.; Taft,
R. W. J. Am. Chem. Soc. 1972, 94, 9113.
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Runsink, J.; Boche, G.; Marsch, M.; Ahlbrecht, H.; Sommer, H. Eur.
J. Org. Chem. 1998, 63. (b) Kawakami, Y.; Hisada, H.; Yamashita, Y.
Tetrahedron Lett. 1985, 26, 5835. (c) Watt, D. S. Synth. Commun. 1974,
4, 127. (d) Kruger, C. R.; Rochow, E. G. Angew. Chem., Int. Ed. 1963,
2, 617. (e) Prober, M. J. Am. Chem. Soc. 1956, 78, 2274.
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Organic Compounds; Wiley: New York, 1994; pp 696-7.
(5) Fleming, F. F.; Zhang, Z. Tetrahedron 2005, 61, 747.
FIGURE 1. Prototypical solution and X-ray structures of
metalated nitriles.
metalated nitriles is the persistent coordination of amide11
or amine ligands12 in X-ray and solution structures,
which feature in both N- and C-coordinated complexes
as gauged by the rapid equilibration between 3a and 3b
in Et2O at -100 °C.13
10.1021/jo047877r CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/22/2005
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J. Org. Chem. 2005, 70, 2200-2205

Metalated Nitriles
C-Metalated nitriles were experimentally inferred14
during pioneering deuterations of the chiral cyclopro-
panecarbonitrile 4.15 MeONa-MeOD deuteration pro-
ceeds with greater than 99.9% stereochemical retention
in generating 6a, presumably through the intermediacy
of the transient ion pair 5.16 In contrast, sequential
deprotonation-protonation with LDA causes complete
racemization (4 f 6b) of the putative9b,c intermediate
N-metalated nitrile 7 (Scheme 1).
with alkaline earth or transition metals.18 For example,
solution NMR of the magnesiated nitrile 819 and the
zincated nitrile 920 (Figure 2) imply metalation on carbon
in a trend that is maintained within numerous crystal
structures of transition metal complexes.18 Particu-
larly dramatic are the seminal heat-induced inter-
conversions of the crystalline ruthenium C- and N-
phenylsulfonylacetonitriles 10 and 11, in which the
preference for C- or N-coordination depends on the
phosphine ligand.21
SCHEME 1. Stereochemical Integrity of C- and
N-Metalated Nitriles
FIGURE 2. Solution and X-ray structures of C- and N-
metalated nitriles.
The absence of lithium as the counterion may facilitate
maintaining the stereochemical integrity since almost
all17 subsequent examples of C-metalated nitriles are
Selective formation of C- and N-metalated nitriles
offers the possibility for controlling regio- and stereo-
selective alkylations in previously undeveloped ways.
Precedent for divergent reactivity of C- and N-metalated
nitriles stems from metal-dependent cyclization22 and
carbonyl addition23 stereoselectivities, and metal-depend-
ent alkylation chemoselectivities.24 Efforts to harness
reactivity differences between C- and N-metalated ni-
triles stimulated a general route to metalated nitriles
having a variety of metal counterions, that, indeed,
exhibit reactivities which complement metal amide depro-
tonation-electrophilic alkylation of nitriles.25
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Carlier, P. R. Chirality 2003, 15, 340.
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Chem. 2000, 13, 347. The bond length is the mean of CN distance
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Int. Ed. 1989, 28, 1392.
(17) The only X-ray structure of a C-lithiated nitrile is for an N-
and C-lithiated cyclopropanecarbonitrile dimer: Boche, G.; Harms, K.;
Marsch, M. J. Am. Chem. Soc. 1988, 110, 6925.
(12) (a) Reference 8. (b) For stereoinduction with ephedrine ligands
see: Carlier, P. R.; Lam, W. W.-F.; Wan, N. C.; Williams, I. D. Angew.
Chem., Int. Ed. 1998, 37, 2252.
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Inorg. Chim. Acta 2000, 298, 239. (b) Ragaini, F.; Porta, F.; Fumagalli,
A.; Demartin, F. Organometallics 1991, 10, 3785. (c) Porta, F.; Ragaini,
F.; Cenini, S.; Demartin, F. Organometallics 1990, 9, 929. (d) Cowan,
R. L.; Trogler, W. J. Am. Chem. Soc. 1989, 111, 4750. (e) Del Pra, A.;
Forsellini, E.; Bombieri, G.; Michelin, R. A.; Ros, R. J. Chem. Soc.,
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126, 6798.
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2445.
(15) Subsequent approaches to chiral metalated nitriles have em-
ployed noncovalently linked chiral additives: (a) Suto, Y.; Kumagai,
N.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 3147.
(b) Reference 12b. (c) Kuwano, R.; Miyazaki, H.; Ito, Y. Chem. Commun.
1998, 71. (d) Soai, K.; Hirose, Y.; Sakata, S. Tetrahedron: Asymmetry
1992, 3, 677. (e) Soai, K.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1979,
52, 3371. For metalated nitriles containing chiral auxiliaries see: (f)
Enders, D.; Shilvock, J. P.; Raabe, G. J. Chem. Soc., Perkin Trans. I
1999, 1617. (g) Roux, M.-C.; Patel, S.; Me´rienne, C.; Morgant, G.;
Wartski, L. Bull. Chem. Soc. Fr. 1997, 134, 809. (h) Schrader, T. Chem.
Eur. J. 1997, 3, 1273. (i) Enders, D.; Kirchhoff, J.; Lausberg, V. Liebigs.
Ann. 1996, 1361. (j) Roux, M.-C.; Wartski, L.; Nierlich, M.; Lance, M.
Tetrahedron 1996, 52, 10083. (k) Enders, D.; Kirchhoff, J.; Mannes,
D.; Raabe, G. Synthesis 1995, 659. (l) Cativiela, C.; D´ıaz-de-Villegas,
M. D.; Ga´lvez, J. A.; Lapen˜a, Y. Tetrahedron 1995, 51, 5921. (m)
Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A. J. Org. Chem. 1994,
59, 2497. (n) Enders, D.; Mannes, D.; Raabe, G. Synlett 1992, 837. (o)
Enders, D.; Gerdes, P.; Kipphardt, H. Angew. Chem., Int. Ed. Engl.
1990, 29, 179. (p) Hanamoto, T.; Katsuki, T.; Yamaguchi, M. Tetra-
hedron Lett. 1986, 27, 2463. (q) Marco, J. L.; Royer, J.; Husson, H.-P.
Tetrahedron Lett. 1985, 26, 3567. (r) Enders, D.; Lotter, H.; Maigrot,
N.; Mazaleyrat, J.-P.; Welvart, Z. Nouv. J. Chem. 1984, 8, 747.
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2002, 58, 4787. (b) Thibonnet, J.; Knochel, P. Tetrahedron Lett. 2000,
41, 3319.
(20) (a) Orsini, F. Synthesis 1985, 500. See also: (b) Goasdoue, N.;
Gaudemar, M. J. Organomet. Chem. 1972, 39, 17.
(21) (a) Naota, T.; Tannna, A.; Murahashi, S.-I. Chem. Commun.
2001, 63. (b) Naota, T.; Tannna, A.; Murahashi, S.-I. J. Am. Chem.
Soc. 2000, 122, 2960. For an analogous interconversion of palladium
complexes see: Kujime, M.; Hikichi, S.; Akita, M. Organometallics
2001, 20, 4049.
(22) Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 2885.
(23) Trost, B. M.; Florez, J.; Jebaratnam, D. J. J. Am. Chem. Soc.
1987, 109, 613.
(24) (a) Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc. 2000,
122, 712. (b) Leung, C.-S.; Rowlands, M. G.; Jarman, M.; Foster, A.
B.; Griggs, L. J.; Wilman, D. E. V. J. Med. Chem. 1987, 30, 1550.
(25) For a preliminary communication see: Fleming, F. F.; Zhang,
Z.; Knochel, P. Org. Lett. 2004, 6, 501.
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Fleming et al.
TABLE 1. Halogen-Magnesium and -Lithium
Results and Discussion
Exchange-Alkylations of r-Halonitriles
Despite extensive halogen-metal exchange26 of func-
tionalized organometallics, only recently has halogen-
metal exchange been achieved with R-halonitriles.25,27
Historically, R-chloronitriles were serendipitously sub-
jected to chlorine-lithium exchange with BuLi,28 or
LDA,29 during the previously perplexing oxidative con-
version to ketones. Presumably the perceived difficulty30
in performing chlorine-metal exchange prevented the
reaction mechanism from being identified. The requisite
R-halonitriles are readily synthesized by brominating
(PBr3, Br2)31 or chlorinating (PCl5, pyridine)32 the parent
nitriles, through organomercury conjugate additions to
R-chloroacrylonitrile,33 and through Diels-Alder cyclo-
additions with R-chloroacrylonitrile.34
Exploratory reactions of bromonitrile 12a with i-
PrMgBr demonstrated the viability of accessing mag-
nesiated nitriles through bromine-magnesium exchange
(Scheme 2). Initial optimization was complicated by the
SCHEME 2. Prototypical Bromine-Magnesium
Exchange
competitive formation of a dimeric material (vide infra),
which led to dramatically reducing the time before
addition of the electrophile. Sequential addition of i-
PrMgBr to 12a followed, 1 min later, by the electrophile
causes rapid alkylation, implying a fast bromine-
magnesium exchange at -78 °C. A rapid exchange
correlates with the immediate color change that occurs
upon addition of the Grignard reagent, although the
yellow color may potentially be due to formation of the
bromate complex 13a.35 Fragmentation35 of the bromate
complex 13a generates i-PrBr and the magnesiated
nitrile 14a, which then reacts with the electrophile to
furnish the alkylated nitrile 15a.
a Isolated yields for sequential metalation-alkylation, procedure
A, and with an in situ metalation-alkylation, procedure B.
b Prepared by free radical bromination with NBS.39 c Contains 6%
of the hydroxynitrile resulting from deprotonation and carbonyl
addition.
(26) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003,
42, 4303.
(27) For related metal-halogen exchanges with R-iodoketones see:
(a) William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771. (b)
Aoki, Y.; Oshima, K.; Utimoto, K. Chem. Lett. 1995, 463.
(28) Banwell, M. G.; Clark, G. R.; Hockless, D. C. R.; Pallich, S. Aust.
J. Chem. 2001, 54, 691.
Diverse R-halonitriles efficiently alkylate an array of
electrophiles using the optimized exchange-electrophile
addition procedure (Table 1, column A). Bromine-
magnesium exchange generates magnesiated nitriles that
efficiently alkylate representative alkyl halide and car-
bonyl electrophiles (Table 1, entries 1-11), whereas the
corresponding chloronitriles react significantly less ef-
(29) Monti, S. A.; Chen, S.-C.; Yang, Y.-L.; Yuan, S.-S.; Bourgeois,
O. P. J. Org. Chem. 1978, 43, 4062.
(30) Clayden, J. In Organolithiums: Selectivity for Synthesis; Per-
gamon: Amsterdam, The Netherlands, 2002; Chapter 3.
(31) Stevens, C. L.; Coffield, T. H. J. Am. Chem. Soc. 1951, 73, 103.
(32) Freeman, P. K.; Balls, D. M.; Brown, D. J. J. Org. Chem. 1968,
33, 2211.
(33) (a) Russel, G. A.; Shi, B. Z. Synlett 1993, 701. (b) Giese, B.;
Gonza´lez-Go´mez, J.-A. Chem. Ber. 1986, 119, 1291. (c) Giese, B.;
Antonio, J.; Go´mez, G. Tetrahedron Lett. 1982, 23, 2765.
(34) For reviews see: (a) Reference 5. (b) Aggarwal, V. K.; Ali, A.;
Coogan, M. P. Tetrahedron 1999, 55, 293. (c) Ranganathan, S.;
Ranganathan, D.; Mehrota, A. K. Synthesis 1977, 289.
(35) (a) Hoffmann, R. W.; Bro¨nstrup, M.; Muller, M. Org. Lett. 2003,
5, 313. (b) Schulze, V.; Bro¨nstrup, M.; Bo¨hm, V. P. W.; Schwerdtfeger,
P.; Schimeczek, M.; Hoffmann, R. W. Angew. Chem., Int. Ed. 1998,
37, 824. (c) Reich, H. J.; Green, D. P.; Phillips, N. H.; Borst, J. P.; Reich,
I. L. Phosphorus, Sulfur, Silicon 1992, 67, 83.
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Metalated Nitriles
TABLE 2. Me2CuLi-Induced Exchange-Alkylations of
fectively. Chloronitriles exchange more slowly with i-
PrMgBr resulting in considerable dimerization between
the magnesiated nitrile and unreacted chloronitrile,
which is conveniently avoided by performing the ex-
change with BuLi (Table 1, entries 12-14). The efficient
lithium-chlorine exchange attests to the activation of the
carbon-chlorine bond by the nitrile since chlorine-metal
exchange is particularly difficult and seldom observed.30
The extremely rapid chlorine-lithium and bromine-
magnesium exchanges stimulated a more daring in situ
protocol where i-PrMgBr or BuLi is added to a solution
containing the halonitrile and the electrophile.36 Remark-
ably, the in situ protocol is successful even with particu-
larly electrophilic functionalities such as acyl cyanide and
aldehyde electrophiles. Comparing the exchange-alkyl-
ation and in situ alkylations reveals the latter to be the
method of choice, affording consistently a 20% higher
yield of alkylnitrile (Table 1, column B). Presumably the
increased yield of the in situ procedure is partly due to
rapid capture of the magnesiated nitrile with the elec-
trophile, which effectively circumvents prior single elec-
tron transfer between the magnesiated nitrile 14 and the
electrophilic halonitrile 12.37
r-Bromonitriles
Key regio- and chemoselectivity preferences of mag-
nesiated nitriles were probed with the in situ protocol.
Alkylations with cinnamyl and propargyl bromide occur
exclusively through SN2 alkylation, analogous to alkyl-
ations of lithiated nitriles obtained by metal amide depro-
tonation.1b Perhaps not surprisingly, iodine-magnesium
exchange is faster than the corresponding bromine-
magnesium exchange as gauged by the increased yield
for comparable exchange reactions of i-PrMgBr with
iodoacetonitrile and bromoacetonitrile (Table 1, entries
10 and 11). Even for the magnesium-bromine exchange
of bromoacetonitrile, only 6% of the hydroxynitrile arising
from deprotonation of bromoacetonitrile is obtained,
indicating that the metal-halogen exchange is faster
than the competitive deprotonation.38
proceed without any observable deprotonation, affording
high yields of the alkylated nitriles with allylic and
carbonyl electrophiles (Table 2, entries 5-8).
Key mechanistic insight was gleaned from copper-
halogen exchange reactions with the bromonitrile 12a
(Scheme 3). Me2CuLi-induced exchange of 12a generates
Dramatic advances in copper-halogen exchange40
stimulated developing an analogous copper-halogen
exchange with R-halonitiles.41 Optimization experiments
with bromonitrile 12b revealed that a facile copper-
bromine exchange with Me2CuLi is complete within 1.5
h at 0 °C. Subsequent addition of allylic electrophiles
generates alkylated nitriles (Table 2, entries 1-3), with
complete SN2′ displacement occurring for the alkylation
with propargyl bromide (Table 2, entry 4).42 Analogous
cuprate exchange-alkylations of the bromonitrile 12f
SCHEME 3. Organocopper Exchange of
Bromonitrile 12a
(36) For an excellent survey of halogen-metal exchange reactions
in the presence of electrophiles see: ref 30, pp 116 and 284-287.
(37) (a) Werry, J.; Stamm, H.; Sommer, A. Chem. Ber. 1990, 123,
1553. (b) Sˇindela´, K.; Holubek, J.; Sva´tek, E.; Schlanger, J.; Dlabacˇ,
A.; Valcha´rˇ, M.; Hurbantova´, M.; Protiva, M. Collect. Czech. Chem.
Commun. 1990, 55, 782. (c) Chauffaille, J.; Hebert, E.; Welvart, Z. J.
Chem. Soc., Perkin Trans. 2 1982, 1645. (d) Seux, R.; Morel, G.;
Foucaud, A. Tetrahedron 1975, 31, 1335.
the dimer 1643 (26%) and dimethylphenylacetonitrile (17,
42%), even when the exchange was performed with an
electrophile in situ at -78 °C. Presumably35 Me2CuLi
reacts with 12a to generate the bromate 13a that
(38) Only a trace of the iodo alcohol arising from the deprotonation
of 12c and addition of the resulting anion to cyclohexenone was
detected.
(39) Rouz-Schmitt, M.-C.; Petit, A.; Sevin, A.; Seyden-Penne, J.; Anh,
N. T. Tetrahedron 1990, 46, 1263.
(40) (a) Yang, X.; Rotter, T.; Piazza, C.; Knochel, P. Org. Lett. 2003,
5, 1229. (b) Piazza, C.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41,
3263.
(41) For a pioneering exchange of a sulfonyl ketone with Me2CuLi
see: Posner, G. H.; Switzer, C. J. Am. Chem. Soc. 1986, 108, 1239.
For a related exchange with a trifluorosulfonyl ester see: Petit, Y.;
Sanner, C.; Larcheveˆque, M. Tetrahedron Lett. 1990, 31, 2149.
(42) For excellent regioselectivity analyses see: (a) Yamanaka, M.;
Kato, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 6287. (b) Breit,
B.; Demel, P. In Modern Organocopper Chemistry; Krause, N., Ed.;
Wiley-VCH: Weinheim, Germany, 2002; pp 188-223.
(43) Obtained as a mixture of dl and meso isomers
J. Org. Chem, Vol. 70, No. 6, 2005 2203

Fleming et al.
fragments to the C-cuprated nitrile 18a.44 Reductive
elimination of 18a leads to 17 whereas competitive
alkylation of 18a with the electrophilic bromonitrile
12a, through single electron transfer, affords 16.37,39,45
Bromine-copper exchange of 12a with the less reactive
MeCu46 affords 16 (62%), but without the formation of
17 since collapse of the bromate 13a leads to an organo-
copper species and not a cuprate.47
SCHEME 5. Comparative Alkylations of N- and
C-Metalated Nitriles
Formation of dimethylphenylacetonitrile (17) by reduc-
tive elimination identifies C-cuprated nitriles as the key
intermediates resulting from Me2CuLi exchange. The
formation of C-cuprated nitrile 18b (Scheme 4) is con-
sistent with the SN2′ displacement of propargyl bromide
and difficult to rationalize if copper were coordinated to
nitrogen (19).48 Halogen-magnesium exchange of bromo-
nitrile 12b through an ate complex may initially lead to
the C-magnesiated nitrile 14b, although progression to
an N-metalated nitrile is equally conceivable. The am-
biguity is not resolved during alkylation with propargyl
bromide since N- and C-magnesiated nitriles are both
anticipated to react by SN2 alkylation,1b leaving the site
of magnesium coordination an open question (Scheme 4).
Conclusion
Halogen-metal exchange of R-halonitriles with organo-
metallics generates diverse metalated nitriles. Grignard
and alkyllithium reagents trigger the rapid metal-
halogen exchange of R-halonitriles whereas the exchange
with lithium dimethylcuprate is considerably slower. An
array of electrophiles efficiently intercept the intermedi-
ate metalated nitriles either through sequential addition
of the electrophile to the metalated nitrile or by perform-
ing the exchange in the presence of the electrophile. The
reactivities of organocopper- and halomagnesium-sub-
stituted nitriles imply C-metalated nitrile intermediates,
at least in the former instance, with complementary
regioselectivity preferences in comparable alkylations
with propargyl bromide. Synthetically, the organocopper-
substituted nitriles are efficiently accessed by sequential
deprotonation followed by the addition of MeCu. Col-
lectively the metal-halogen exchange allows tuning of
the metal coordination site with N- and C-metalated
nitriles exhibiting reactivity trends complementary to
those of metalated nitriles obtained through deprotona-
tion with metal amide bases.
SCHEME 4. Divergent SN2 and SN2′ Alkylations
with Propargyl Bromide
Lithiated nitriles are, almost without exception,17
N-coordinated.9b,c Alkylation of the, presumed, N-lithiated
nitrile 19b with propargyl bromide causes exclusive SN2
displacement (Scheme 5). The preference of the cuprate
18b for SN2′ alkylation (Scheme 4) stimulated an intrigu-
ing N f C transmetalation of the lithiated nitrile 19b
with MeCu. Sequential LDA deprotonation of 20 and
addition of MeCu generates the putative C-cuprated
nitrile 18b, which reacts with propargyl bromide to give
exclusively the SN2′ allenylnitrile 15l. Collectively, these
alkylations indicate a high propensity of copper for
coordination on carbon.
Experimental Section
General Nitrile Bromination Procedure. Neat bromine
and nitrile were sequentially added to ice-cooled PBr3. After
the addition, the ice bath was removed and the reaction was
heated at 60 °C. After 5 h the mixture was poured onto ice
and extracted with ether (3×), and then the crude extracts
were washed with NaHCO3 (3×) and water and then dried
(MgSO4). Concentration and purification of the crude product
by radial chromatography afforded analytically pure material.
General Alkylation Procedure A. A THF solution of
i-PrMgBr (1.05 equiv) was added to a -78 °C, THF solution
of the bromonitrile (1.0 equiv) and, after 1 min, neat electro-
phile (1.05 equiv) was added. After 2 h saturated, aqueous
NH4Cl solution was added, and the crude product was ex-
tracted with EtOAc, dried (MgSO4), concentrated, and purified
by radial chromatography to afford analytically pure material.
General in Situ Alkylation Procedure B. A THF solu-
tion of i-PrMgBr (1.05 equiv) was added to a -78 °C, THF
solution of the bromonitrile (1.0 equiv) and the electrophile
(1.05 equiv). After 2 h saturated, aqueous NH4Cl solution was
added, and the crude product was extracted with EtOAc, dried
(MgSO4), concentrated, and purified by radial chromatography
to afford analytically pure material.
(44) For the synthesis of C-cuprated nitriles see: (a) Kondo, J.; Ito,
Y.; Shinokubo, H.; Oshima, K. Angew. Chem., Int. Ed. 2004, 43, 106.
(b) Tsuda, T.; Nakatsuka, T.; Hirayama, T.; Saegusa, T. J. Chem. Soc.,
Chem. Commun. 1974, 557. (c) Corey, E. J.; Kuwajima, I. Tetrahedron
Lett. 1972, 487.
(45) Aryl- and R-aminomethyl cuprates couple in the presence of
electrophiles: (a) Dieter, R. K.; Li, S. J.; Chen, N. J. Org. Chem. 2004,
69, 2867. (b) Kronenburg, C. M. P.; Amijs, C. H. M.; Wijkens, P.;
Jastrzebski, J. T. B. H.; van Koten, G. Tetrahedron Lett. 2002, 43, 1113.
(c) Lipshutz, B. H.; Kayser, F.; Liu, Z.-P. Angew. Chem., Int. Ed. Engl.
1994, 33, 1842. (d) Lipshutz, B. H.; Siegmann, K.; Garcia, E. J. Am.
Chem. Soc. 1991, 113, 8161.
(46) MeCu does not cause bromine-copper exchange with 12b.
(47) The absence of 17 requires that no alkylation occurs between
the organocopper and organocuprate 18a, with the bromomethane
generated from fragmentation of the bromate 13a.
(48) Potentially, the transition state for reductive elimination could
arise from either an N- or C-cuprated nitrile ground state.
General Bromine-Copper Exchange Procedure. A
THF solution of the bromonitrile was added to a 0 °C, ether
solution of Me2CuLi [generated by adding methyllithium (2.2
equiv) to copper iodide (1.2 equiv)]. After 1 h, neat electrophile
(1.30 equiv) was added and, after a further 2 h at 0 °C,
2204 J. Org. Chem., Vol. 70, No. 6, 2005

Metalated Nitriles
saturated, aqueous NH4Cl solution was then added. The
mixture was stirred vigorously with exposure to air for 30 min,
and the crude product was then extracted with ethyl ether and
dried (MgSO4). Concentration of the crude product and puri-
fication by radial chromatography afforded analytically pure
material.
acknowledged as are insightful discussions with Dr.
Paul Carlier.
Supporting Information Available: Experimental pro-
cedures and 1H NMR and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support of this re-
search, and travel funds, from NSF is gratefully
JO047877R
J. Org. Chem, Vol. 70, No. 6, 2005 2205