Metalated nitrile and enolate chlorinations

Article abstract of DOI:10.1021/ol100897y

(Figure presented) Metalated nitriles and enolates rapidly and efficiently abstract chlorine from 2-chloro-2-fluoro-2-phenylacetonitrile to afford a diverse range of chloronitriles and chloroesters. The method provides the first general anionic chlorinati

Full text of DOI:10.1021/ol100897y

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2810-2813
Metalated Nitrile and Enolate
Chlorinations
Bhaskar Reddy Pitta and Fraser F. Fleming*
Department of Chemistry and Biochemistry, Duquesne UniVersity,
Pittsburgh, PennsylVania 15282-1530
flemingf@duq.edu
Received April 19, 2010
ABSTRACT
Metalated nitriles and enolates rapidly and efficiently abstract chlorine from 2-chloro-2-fluoro-2-phenylacetonitrile to afford a diverse range of
chloronitriles and chloroesters. The method provides the first general anionic chlorination of alkylnitriles, tolerates numerous functional groups,
and addresses the challenge of synthesizing r-chloronitriles under mild conditions.
R-Halonitriles are versatile synthetic precursors by virtue of
having two orthogonal functionalities substituting the same
carbon. The powerful inductive electron withdrawal1 of the
nitrile activates the C-X bond toward transition-metal
insertion in cross-coupling reactions2 (1 f 2). An analogous
activation facilitates the halogen-metal exchange, even with
chloronitriles, despite alkyl chlorides generally being unre-
active in this type of exchange (1 f 3, Scheme 1).3 The
electron-withdrawing halogen also activates the nitrile group
with the generally difficult nitrile hydrolysis4 proceeding
easily in a versatile hydrolysis-decarboxylation route to
ketones (1 f 4, Scheme 1).5 The synergistic effect of
geminal halogen and nitrile substitution also facilitates radical
reactions, with chloronitriles undergoing homolytic cleavage
and radical addition in the presence of an initiator and a
hydrogen atom donor (1 f 5, Scheme 1).6
Scheme 1. Representative Ractions of R-Halonitriles
(1) (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.
Historically, the two most prevalent routes to halonitriles
are through Diels-Alder cycloadditions with R-haloacry-
lonitriles7 and by free-radical halogenation of alkanenitriles.
Typically, these free-radical halogenations require rather
(2) Strotman, N. A.; Sommer, S.; Fu, G. C. Angew. Chem., Int. Ed.
2007, 46, 3556. For an electrochemical variation, see: Cannes, C.; Condon,
S.; Durandetti, M.; Perichon, J.; Nedelec, J.-Y. J. Org. Chem. 2000, 65,
4575.
(6) (a) Schule, A.; Liang, H.; Vors, J.-P.; Ciufolini, M. A. J. Org. Chem.
2009, 74, 1587. (b) Miura, K.; Fujisawa, N.; Saito, H.; Wang, D.; Hosomi,
A. Org. Lett. 2001, 3, 2591.
(3) Fleming, F. F.; Zhang, Z.; Liu, W.; Knochel, P. J. Org. Chem. 2005,
70, 2200.
(4) Eglin, J. L. Comments Inorg. Chem. 2002, 23, 23.
(5) Shiner, C. S.; Fisher, A. M.; Yacoby, F. Tetrahedron Lett. 1983,
24, 5687.
(7) For reviews see: (a) Aggarwal, V. K.; Ali, A.; Coogan, M. P.
Tetrahedron 1999, 55, 293. (b) Ranganathan, S.; Ranganathan, D.; Mehrota,
A. K. Synthesis 1977, 289.
10.1021/ol100897y  2010 American Chemical Society
Published on Web 05/18/2010

strong electrophilic halogen sources8 such as chlorine9 or
bromine,10 NBS,11 PCl5,12 or PBr5.13 Sporadic iodinations
of metalated nitriles14 demonstrate the viability of developing
a general electrophilic halogen source, although trapping with
molecular iodine lacks generality.15 In addition, iodonitriles
are thermally labile16 and have a limited reagent tolerance.
The current challenge in synthesizing halonitriles lies in
developing an efficient and reproducable halogenating agent
with functional group tolerance.
Table 1. Metalated Nitrile Chlorinations
Exploratory alkylations of metalated nitriles with 2-chloro-
2-fluoro-2-phenylacetonitrile (6)17 serendipitously revealed
this reagent to be an excellent chlorinating agent (Table 1).18
Optimizations with cyclohexanecarbonitrile (7a) revealed the
need to rapidly add a slight excess of 6 to the lithiated nitrile
to prevent dimerization (Table 1, entry 1).19 This simple
expedient minimizes the attack of the lithiated nitrile, derived
from 7, on the electrophilic chloronitrile 8, efficiently pro-
viding the chloronitrile in less than 5 min at -78 °C.
LDA-induced deprotonation and rapid addition of 6
efficiently halogenates a range of alkylnitriles (Table 1).
Cyclic and acyclic alkylnitriles (Table 1, entries 1-5) are
readily chlorinated as are several significantly more acidic20
arylacetonitriles (Table 1, entries 6-9). The chlorination
method is ideal for nitriles bearing functionality that would
otherwise react with radical-based halogenating agents: ni-
triles 7b, 7c, 7e, and 7i,21 containing alkene, alcohol, acetal,
and pyridine functionalities, respectively. The only limitation
lies in the substitution of the alkylnitriles which must be
tertiary.22
Encouraged by the effective chlorination of nitriles, the
analogous chlorination of enolates was explored. The at-
traction lies in expanding the limited number of electrophilic
halogenating agents available for intercepting ester enolates.23
Using the same deprotonation-chlorination protocol with a
(8) Halonitriles are also generated by halogenating cyanohydrins: (a)
Matveeva, E. D.; Podrugina, T. A.; Tishkovskaya, E. V.; Zefirov, N. S.
MendeleeV Commun. 2003, 260–262. (b) Gassman, P. G.; Guggenheim,
T. L. J. Org. Chem. 1982, 47, 3023.
(9) (a) Carpenter, W. R.; Armstrong, P. J. Org. Chem. 1964, 29, 2772.
(b) Rosenblatt, D. H.; Broome, G. H. J. Org. Chem. 1961, 26, 2116.
(10) Stevens, C. L.; Lenk, C. T. J. Org. Chem. 1954, 19, 538. (b)
Ginsburg, D.; Baizer, M. M. J. Am. Chem. Soc. 1949, 71, 2254.
(11) Couvreur, P.; Bruylants, A. J. Org. Chem. 1953, 18, 501.
(12) Freeman, P. K.; Balls, D. M.; Brown, D. J. J. Org. Chem. 1968,
33, 2211.
(13) Stevens, C. L.; Coffield, T. H. J. Am. Chem. Soc. 1951, 73, 103.
(14) (a) Della, E. W.; Knill, A. M.; Pigou, P. E. J. Org. Chem. 1993,
58, 2110. (b) Cambie, R. C.; Erson, A. D.; Gourdie, A. C.; Rutledge, P. S.;
Woodgate, P. D. J. Organomet. Chem. 1988, 348, 317.
(15) Sequential silylketenimine formation and iodination is currently the
most general route to iodonitriles but is limited to arylacetonitriles: Watt,
D. S. J. Org. Chem. 1974, 39, 2799.
a 14.3:1 ratio of diastereomers at the nitrile-bearing carbon. b 9:1 ratio
of diastereomers at the nitrile-bearing carbon.
series of ester enolates and 2-chloro-2-fluoro-2-phenylac-
etonitrile (6) readily provides the corresponding chloroesters
(Table 2, entries 1-7). Aliphatic, acyclic, and cyclic esters
are efficiently chlorinated as is the benzylic ester 9g (Table
2, entry 7). Alkenes are tolerated within the acyl skeleton
(Table 2, entries 1 and 4) and in the alkyl chain (Table 2,
entry 2). Analogous chlorinations of ketone and lactone
enolates smoothly afford the corresponding chloroketone and
(16) Mori, M.; Kubo, Y.; Ban, Y. Heterocycles 1990, 31, 433.
(17) Commercially available from SynQuest Fluorochemicals.
(18) In an extensive screening of halogenating agents no electrophilic
halogen source was as effective as 2-chloro-2-fluoro-2-phenylacetonitrile
(6).
(19) Li, X.; Jain, N.; Russell, R. K.; Ma, R.; Branum, S.; Xu, J.; Sui, Z.
Org. Process Res. DeV. 2006, 10, 354.
(20) Bordwell, F. G.; Branca, J. C.; Bares, J. E.; Filler, R. J. Org. Chem.
1988, 53, 780.
(21) Deutsch, H. M.; Shi, Q.; Gruszecka-Kowalik, E.; Schweri, M. M.
J. Med. Chem. 1996, 39, 1201.
(22) The conversion with secondary nitriles is low and considerable
dimerization is observed. A similar limitation exists for the iodination of
aldehyde enolates: Groenewegen, P.; Kallenberg, H.; van der Gen, A.
Tetrahedron Lett. 1979, 2817.
(23) (a) Arnold, R. T.; Kulenovic, S. T. J. Org. Chem. 1978, 43, 3687.
(b) Stotter, P. L.; Hill, K. A. J. Org. Chem. 1973, 38, 2576. (c) Rathke,
M. W.; Lindert, A. Tetrahedron Lett. 1971, 3995.
Org. Lett., Vol. 12, No. 12, 2010
2811

ronitrile (13)27 as the aromatic fragment is consistent with a
nucleophilic displacement on 6 releasing the carbenoid 1228
which subsequently dimerizes to fumaronitrile (13) (Scheme
2).29
Table 2. Chlorination of Ester and Ketone Enolates
Scheme 2. Metalated Nitrile Chlorination Mechanism
Prior halogen-magnesium exchange reactions, primarily
with bromonitriles, indicated that chloronitriles do not
undergo chlorine-magnesium exchange.3 Access to diverse
chloronitriles allowed a reinvestigation which revealed that
chloronitriles do exchange with i-PrMgCl, although at higher
temperatures than for the corresponding bromonitrile.30
Addition of 3 equiv of i-PrMgCl to 8a and warming to room
temperature effectively generates a nucleophilic magnesiated
Scheme 3. i-PrMgCl Exchange-Alkylation of Chloronitriles
chlorolactone (Table 2, entries 8 and 9, respectively), hinting
at the generality for chlorinating these carbonyl-containing
functionalities.
nitrile (Scheme 3). Intercepting the magnesiated nitrile with
3-phenylpropyl bromide affords the alkylated nitrile 14 in
Chlorofluoronitrile 6 functions as an excellent electrophilic
chlorine source,24 probably because of the powerful electron
withdrawal by the adjacent nitrile1 and fluorine groups.1c
Mechanistically, nucleophilic SN2-type attack24a,25 of the
metalated nitrile, or enolate, on 6 might generate the
chlorinated nitrile or carbonyl with simultaneous formation
of lithiated fluorophenylacetonitrile (12).26 Isolating fuma-
(26) Current mechanistic experiments do not exclude a single electron
transfer (SET) process. Small quantities of fluorophenylacetonitrile (i) are
occasionally isolated in the chlorinations which could be accounted for by
SET or SN2 mechanisms. (a) Jonczyk, A.; Kwast, A.; Makosza, M. J. Org.
Chem. 1979, 44, 1192.
(27) Spectrally indistinguishable to previously reported material: Yeh,
H.-C.; Wu, W.-C.; Wen, Y.-S.; Dai, D.-C.; Wang, J.-K.; Chen, C.-T. J.
Org. Chem. 2004, 69, 6455.
(28) Boche, G.; Lohrenz, J. C. W. Chem. ReV. 2001, 101, 697.
(29) (a) Maryanoff, C. A.; Sorgi, K. L.; Zientek, A. M. J. Org. Chem.
1994, 59, 237. (b) Makosza, M.; Serafin, B.; Gajos, I. Rocz. Chem. 1969,
43, 671.
(24) For related halogenating agents, see: (a) Plaumann, H. P.; Rodrigo,
R. Pol. J. Chem. 1979, 53, 201. (b) Hata, T. Bull. Chem. Soc. Jpn. 1964,
37, 547.
(30) The chloronitrile 8a requires room temperature, whereas the
corresponding bromonitrile exchanges with i-PrMgCl virtually instanta-
neously at - 78 °C.3
(25) Blay, G.; Cardona, L.; Garcia, B.; Lahoz, L.; Pedro, J. R.
Tetrahedron 1996, 52, 8611
.
2812
Org. Lett., Vol. 12, No. 12, 2010

70% yield. Essentially the same efficiency is realized by
adding i-PrMgCl to a solution containing the chloronitrile
and the electrophile.
Scheme 4. Reagent Tolerance of Chloronitriles
The analogous chlorine-magnesium exchange of the
arylacetonitrile 8f is significantly more facile. Activation of
the carbon-chlorine bond by the aromatic ring likely facili-
tates the exchange which proceeds at -78 °C.31 Sequentially
adding i-PrMgCl and methyl cyanoformate to 8f affords the
ester nitrile 15 in 85% yield (Scheme 3). Essentially the same
efficiency is achieved with an in situ procedure in which
i-PrMgCl is added to a -78 °C THF solution containing 8f
and methyl cyanoformate.
The potential of chloronitriles as synthetic intermediates
is illustrated in the synthesis and chlorine-magnesium
exchange of the functionalized chloronitrile 18 (Scheme 4).
Chlorination of the acetal-containing nitrile 16 efficiently
provides the chloronitrile 17. Subsequent acid-catalyzed
hydrolysis and Wittig olefination 17 f 18 proceed without
interference of the chloronitrile functionality. In fact R-chlo-
ronitriles readily tolerate acid,32 ozone,33 oxidants,34 hydride
reducing agents,35 and hydrogenation.36 The in situ chlorine-
magnesium exchange and alkylation of 18 with methyl
cyanoformate tolerates the enoate to efficiently generate the
ester nitrile 19. The selective formation of the magnesiated
nitrile from 18 represents one of the few examples of
selectively forming a metalated nitrile in the presence of an
enolizable carbonyl functionality.37
R-Chloronitriles are readily prepared by deprotonating
tertiary nitriles and rapidly adding the highly unusual
electrophilic chlorine source 2-chloro-2-fluoro-2-phenylac-
etonitrile (6). The method overcomes the long-standing
difficulty of preparing functionalized halonitriles that were
typically accessed under vigorous free radical conditions.
Ester, lactone, and ketone enolates react analogously, ef-
ficiently providing the corresponding R-chloro ester, R-chloro
lactone, and R-chloro ketone functionalities. The viability
of a chlorine-magnesium exchange with R-chloronitriles is
demonstrated, and their use as robust, latent metalated nitriles
is illustrated in the synthesis of a functionalized ester nitrile.
The high yields and the functional group tolerance make this
an ideal method for preparing chloronitriles.
(31) Stereoelectronic Effects; Kirby, A. J., Ed.; Oxford University Press:
Bath, UK, 1998.
(32) Jones, R. C. F.; Howard, K. J.; Nichols, J. R.; Snaith, J. S. J. Chem.
Soc., Perkin Trans. 1 1998, 2061.
(33) (a) Hofner, D.; Haslinger, E. Monatsh. Chem. 1998, 129, 393. (b)
Bienfait, B.; Coppe-Motte, G.; Merenyi, R.; Viehe, H. G.; Sicking, W.;
Sustmann, R. Tetrahedron 1991, 47, 8167.
Acknowledgment. Financial support from the National
Science Foundation (0808996 CHE, 0421252 HRMS, and
0614785 for NMR facilities) is gratefully acknowledged.
(34) (a) Carrupt, P. A.; Vogel, P. HelV. Chim. Acta 1989, 72, 1008. (b)
VerHaeghe, D. G.; Weber, G. S.; Pappalardo, P. A. Tetrahedron Lett. 1989,
30, 4041.
(35) Marshall, K. A.; Mapp, A. K.; Heathcock, C. H. J. Org. Chem.
1996, 61, 9135. (b) Clark, R. S. J.; Holmes, A. B.; Matassa, V. G. J. Chem.
Soc., Perkin Trans. 1 1990, 1389.
Supporting Information Available: Experimental pro-
(36) Yang, Y.-R.; Li, W.-D. Z. J. Org. Chem. 2005, 70, 8224. (b)
Foehlisch, B.; Bakr, D. A.; Fischer, P. J. Org. Chem. 2002, 67, 3682.
(37) For examples involving transition metals, see: (a) Recio, A.; Tunge,
J. A. Org. Lett. 2009, 11, 5630. (b) Goto, A.; Endo, K.; Ukai, Y.; Irle, S.;
Saito, S. Chem. Commun. 2008, 2212. (c) Kumagai, N.; Matsunaga, S.;
Shibasaki, M. Tetrahedron 2007, 63, 8598. (d) Fan, L.; Ozerov, O. V. Chem.
Commun. 2005, 4450.
1
cedures and H NMR and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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