Metalated Nitriles: Halogen - Metal Exchange with α-Halonitriles

Article abstract of DOI:10.1021/ol036202s

(Equation presented) α-Halonitriles react with organometallic reagents in a facile halogen-metal exchange. The halogen-metal exchange is extremely fast with Grignard and alkyllithium reagents, generating metalated nitriles in situ with aldehyde, ketone, a

Full text of DOI:10.1021/ol036202s

ORGANIC
LETTERS
2004
Vol. 6, No. 4
501-503
Metalated Nitriles: Halogen−Metal
Exchange with r-Halonitriles
,†
Fraser F. Fleming,* Zhiyu Zhang,† 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 10, 2003
ABSTRACT
r-Halonitriles react with organometallic reagents in a facile halogen−metal exchange. The halogen−metal exchange is extremely fast with
Grignard and alkyllithium reagents, generating metalated nitriles in situ with aldehyde, ketone, acid chloride, and acyl cyanide electrophiles.
Sequential halogen−metal exchange and methylation of conformationally constrained nitriles is highly stereoselective and consistent with a
retentive alkylation of a C-magnesiated nitrile.
R-Metalated nitriles are particularly versatile synthetic
intermediates.1 The versatility stems from the high carbon
nucleophilicity of metalated nitriles1 and the ease of convert-
ing the nitrile group into a plethora of functional derivatives.2
These synthetically valuable traits have led to metalated
nitriles being featured in numerous sterically demanding
alkylations.1
being favored by the hybridization of the cyclopropane ring
(Figure 1, 2).6 Conceptually, the metal coordination site in
metalated nitriles could potentially relay into reactivity
differences, as implied by intriguing stereoselectivity dif-
ferences exhibited by metalated nitriles generated in the
absence of amines.7
Metalated nitriles are typically generated by deprotonation
with metal amide bases.1b Seminal X-ray structures of
metalated nitriles,3 generated with excess amide bases,4 reveal
a preference for coordination of the metal with the nitrile
nitrogen that is consistent with solution NMR and IR
analyses5 (Figure 1, 1). Coordination of the metal at carbon
is only observed with lithiated cyclopropylnitriles where N-
and C-coordination exist, with the latter C-lithiated nitrile
Figure 1. X-ray structures of metalated nitriles.
† 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) Fatiadi, A. J. In The Chemistry of Triple-Bonded Functional Groups.
Supplement C; Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1983; pp
1157-1190.
(3) Boche, G. Angew. Chem., Int. Ed. 1989, 28, 277.
(4) Zarges, W.; Marsch, M.; Harms, K.; Boche, G. Angew. Chem., Int.
Ed. 1989, 28, 1392.
Historically, probing the reactivity of metalated nitriles
in the absence of amines has been complicated by the
difficulty in generating metalated nitriles without recourse
to metal amides for deprotonation. Density functional
(5) For leading references, see: (a) Corset, J.; Castella`-Ventura, M.;
Froment, F.; Strzalko, T.; Wartski, L. J. Org. Chem. 2003, 68, 3902. (b)
Carlier, P. R.; Lo, C. W.-S. J. Am. Chem. Soc. 2000, 122, 12819. (c) Carlier,
P. R.; Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 11602.
(6) (a) For a crystal structure, see: Boche, G.; Harms, K.; Marsch, M.
J. Am. Chem. Soc. 1988, 110, 6925. (b) For solution alkylations, see:
Walborsky, H. M.; Motes, J. M. J. Am. Chem. Soc. 1970, 92, 2445.
(7) Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 2885.
10.1021/ol036202s CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/28/2004

calculations8 reveal that deprotonation with lithium amide
bases leads directly to N-metalated nitriles, precluding their
use for kinetically accessing C-metalated nitriles. Alterna-
tively, the metal hydrides NaH and KH are generally
ineffective for deprotonating aliphatic nitriles,1b whereas
t-BuOK, while excellent for deprotonating nitriles,9 has the
complication of establishing rapid prototropic equilibria.10
A potentially general route for generating metalated
nitriles, without recourse to amide bases, is through halogen-
metal exchange.11 Halogen-metal exchange of related R-
iodoketones12 permits facile enolate formation, though the
analogous formation of metalated nitriles is unknown, despite
the opportunity for selectively generating elusive C-metalated
nitriles. The opportunity for accessing C-metalated nitriles,
with the added attraction of potentially generating metalated
nitriles in the presence of more acidic functionality, stimu-
lated the development of a halogen-metal exchange with
R-halonitriles.
Table 1. Halogen-Metal Exchange of R-Halonitriles
Diverse R-halonitriles are available by free-radical halo-
genation13 and from R-haloacrylonitriles by Diels-Alder
cycloaddition14 and organomercurial conjugate additions.15
Direct halogenation is particularly robust, providing R-bro-
16
monitriles with PBr3/Br2 and R-chloronitriles with PCl5/
pyridine17 (Scheme 1). Collectively, these halogenations
Scheme 1. Synthesis of R-Halonitriles
provide a range of R-halonitriles for probing the halogen-
metal exchange.
Halogen-metal exchange of R-halonitriles is extremely
rapid. Exploratory exchange reactions with 4a and i-PrMgBr
caused an immediate yellow coloration that correlated with
(8) Carlier, P. R. Chirality 2003, 15, 340.
(9) For recent examples, see: (a) Fleming, F. F.; Gudipati, V.; Steward,
O. W. J. Org. Chem. 2003, 68, 3943. (b) Bunlaksananusorn, T.; Rodriguez,
A. L.; Knochel, P. Chem. Commun. 2001, 745. (c) Makosza, M.; Judka,
M. Chem. Eur. J. 2002, 8, 4234.
a Isolated yields for sequential metalation-alkylation, column a, and with
an in situ metalation-alkylation, column b. b Prepared by free-radical
bromination with NBS.18
(10) Fleming, F. F.; Funk, L. A.; Altundas, R.; Sharief, V. J. Org. Chem.
2002, 67, 9414.
(11) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem.,
Int. Ed. 2000, 39, 4415.
the virtually instantaneous exchange at -78 °C. Intercepting
the metalated nitrile derived from 4a with allyl bromide
affords the corresponding quaternary nitrile 5a (Table 1, entry
1). The generality of the halogen-metal exchange was
probed with 4b and a range of electrophiles that affords a
variety of alkylated nitriles (Table 1, entries 2-6).
(12) (a) William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771.
(b) Aoki, Y.; Oshima, K.; Utimoto, K. Chem. Lett. 1995, 463.
(13) (a) Hartzler, H. D. In The Chemistry of the Cyano Group; Rappoport,
Z., Ed.; Wiley-Interscience: New York, 1970; Chapter 11, pp 671-716.
(b) For a novel photochemical conjugate addition-halogenation, see:
Mitani, M.; Kato, I.; Koyama, K. J. Am. Chem. Soc. 1983, 105, 6719.
(14) (a) Aggarwal, V. K.; Ali, A.; Coogan, M. P. Tetrahedron 1999, 55,
293. (b) Ranganathan, S.; Ranganathan, D.; Mehrota, A. K. Synthesis 1977,
289.
(15) (a) Russel, G. A.; Shi, B. Z. Synlett 1993, 701. (b) Giese, B.;
Gonza´lez-Go´mez, J.-A. Chem. Ber. 1986, 119, 1291.
(16) Stevens, C. L.; Coffield, T. H. J. Am. Chem. Soc. 1951, 73, 103.
(17) Freeman, P. K.; Balls, D. M. Brown, D. J. J. Org. Chem. 1968, 33,
2211.
The extremely rapid halogen-metal exchange suggested
performing the exchange with the electrophile in situ.19
(18) Rouz-Schmitt, M.-C.; Petit, A.; Sevin, A.; Seyden-Penne, J.; Anh,
N. T. Tetrahedron 1990, 46, 1263.
502
Org. Lett., Vol. 6, No. 4, 2004

Remarkably, the in situ electrophilic alkylation is successful
with acyl cyanide, acid chloride, ketone, and even aldehyde
electrophiles (Table 1, entries 3-6).20 In no instance was
prior addition of the organometallic to the electrophile
observed; in fact, the yield of reactions with in situ
electrophilic alkylation was consistently 20% higher (Table
1, column b). Significantly, the successful in situ metalation-
alkylation of iodoacetonitrile with i-PrMgBr indicates that
the metal halogen exchange is even faster than the potentially
competitive deprotonation (entry 7).21
Scheme 2. Stereoselective Alkylation
R-Chloronitriles are successfully metalated despite the
difficulty generally observed in chlorine-metal exchange
reactions.22 Metal-halogen exchange of chloronitriles is best
achieved with BuLi rather than i-PrMgBr, allowing sequen-
tial lithiation-alkylation (Table 1, entries 8 and 9). Formation
of lithiated nitriles from R-chloronitriles is particularly
significant since numerous R-chloronitriles are readily avail-
able from Diels-Alder cycloadditions.14
Mechanistically, halogen-metal exchange likely generates
a C-metalated nitrile.23 The configurational stability of the
putative C-metalated nitrile was probed through the in situ
methylation of a diastereomeric mixture24 of nitriles 4c
(Scheme 2). Formation of a single methylated nitrile 5h
indicates that the equilibration of the C-metalated nitriles is
rapid, relative to methylation, presumably through a con-
ducted tour mechanism.8 Exclusive25 formation of the equa-
torially oriented methyl group is consistent with formation
of an equatorial, C-magnesiated nitrile that alkylates methyl
iodide with retention of configuration.26
Grignard and alkyllithium reagents trigger the rapid
metal-halogen exchange of R-halonitriles. The resulting
metalated nitriles alkylate a variety of electrophiles that are
most efficiently intercepted in situ, preferentially allowing
halogen-metal exchange with i-PrMgBr or BuLi even in
the presence of reactive electrophiles. i-PrMgBr-induced
exchange and alkylation with diastereomeric bromonitriles
causes a rapid equilibration of the initial C-magnesiated
nitriles that converge to a single methylated nitrile upon
alkylation. Collectively, the metal-halogen exchange pro-
vides a general route to metalated nitriles for probing the
stereo- and regiochemical dependence in diverse metalated
nitrile alkylations.
(19) For an excellent survey of halogen-metal exchange reactions in
the presence of electrophiles, see: Clayden, J. In Organolithiums: SelectiVity
for Synthesis; Pergamon: Amsterdam, 2002; pp 116 and 284-287.
(20) Representative Procedure. A THF solution of i-PrMgBr (1.05
equiv) was added to a -78 °C THF (1 mmol) solution of 4b and the
electrophile (1.05 equiv). After 2 h, saturated, aqueous NH4Cl solution was
added, and the crude product was extracted with EtOAc, concentrated, and
purified by radial chromatography to afford analytically pure material by
Acknowledgment. Financial support of this research and
travel funds from NSF are gratefully acknowledged.
1
HRMS and H and 13C NMR.
(21) Only a trace of the iodo alcohol arising from the deprotonation of
4e and addition of the resulting anion to cyclohexenone was detected.
(22) Reference 19, Chapter 3.
(23) Halogen-metal exchange through an ate complex leads to C-
metalation, although progression to an N-metalated nitrile is conceivable:
(a) Hoffmann, R. W.; Bro¨nstrup, M.; Mu¨ller, 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.
Supporting Information Available: 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.
OL036202S
(25) 1H NMR analysis of the crude reaction mixture failed to identify
any of the independently prepared diastereomeric nitrile.
(24) A 2:1 ratio of diastereomers was employed.
(26) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. 2002, 41, 717.
Org. Lett., Vol. 6, No. 4, 2004
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