Alkenenitriles: Zn-Cu promoted conjugate additions of alkyl iodides in water

Article abstract of DOI:10.1021/ol060010q

A new silica-supported zinc-copper matrix dramatically promotes conjugate additions of alkyl iodides to alkenenitriles in water. Acyclic and cyclic nitriles react with functionalized alkyl iodides, overcoming the previous difficulty of performing conjugat

Full text of DOI:10.1021/ol060010q

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1557-1559
Alkenenitriles: Zn−Cu Promoted
Conjugate Additions of Alkyl Iodides in
Water
Fraser F. Fleming* and Subrahmanyam Gudipati
Department of Chemistry and Biochemistry, Duquesne UniVersity,
Pittsburgh, PennsylVania 15282-1530
flemingf@duq.edu
Received January 3, 2006
ABSTRACT
A new silica-supported zinc
cyclic nitriles react with functionalized alkyl iodides, overcoming the previous difficulty of performing conjugate additions to disubstituted
alkenenitriles with nonstabilized carbon nucleophiles. Conjugate additions with -chloroalkyl iodides generate cyclic nitriles primed for cyclization,
−copper matrix dramatically promotes conjugate additions of alkyl iodides to alkenenitriles in water. Acyclic and
ω
collectively providing one of the few annulation methods for cyclic alkenenitriles.
Conjugate additions to alkenenitriles are notoriously dif-
ficult.1 Organometallic conjugate additions are particularly
challenging because the powerful electron withdrawal of the
nitrile group2 polarizes the R-carbon more than the â-carbon,3
often redirecting nucleophilic attack to the nitrile group.1
Intramolecular conjugate additions with highly nucleophilic
organometallic reagents,4 particularly through temporary
chelation,5 overcome the recalcitrance of alkenenitriles
toward conjugate addition and simultaneously identify key
features required for intermolecular conjugate addition.
Currently, the most successful intermolecular conjugate
addition to alkenenitriles involves sonicating zerovalent zinc
with alkyl iodides in water-ethanol solutions (Scheme 1).6
Scheme 1. Zn-Cu Conjugate Additions to Alkenenitriles6
The reaction is remarkably tolerant of functionality in the
nitrile and the iodide,1 which likely reflects the intermediacy
of surface-adsorbed radicals as the reactive intermediates.7
The most pressing challenge for the Zn-Cu method lies in
overcoming the steric and electronic deactivation8 of ad-
ditional alkyl substitution which prevents conjugate addition
to substituted alkenenitriles.9
(1) Fleming, F. F.; Wang, Q. Chem. ReV. 2003, 103, 2035.
(2) (a) Richard, J. P.; Williams, G.; Gao, J. J. Am. Chem. Soc. 1999,
121, 715. (b) Bradamante, S.; Pagani, G. A. AdV. Carbanion Chem. 1996,
2, 189. (c) Bradamante, S.; Pagani, G. A. J. Chem. Soc., Perkin Trans. 2
1986, 1035. (d) Dayal, S. K.; Ehrenson, S.; Taft, R. W. J. Am. Chem. Soc.
1972, 94, 9113.
The difficulty of conjugate additions to increasingly
substituted alkenenitriles has prevented alkyl additions to
(6) (a) Dupuy, C.; Petrier, C.; Sarandeses, L. A.; Luche, J. L. Synth.
Commun. 1991, 21, 643. (b) Shono, T.; Nishiguchi, I.; Sasaki, M. J. Am.
Chem. Soc. 1978, 100, 4314.
(3) Reddy, G. S.; Mandell, L.; Goldstein, J. H. J. Am. Chem. Soc. 1961,
83, 3, 1300.
(4) (a) Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J.
Am. Chem. Soc. 1997, 119, 4353. (b) Fleming, F. F.; Hussain, Z.; Weaver,
D.; Norman, R. E. J. Org. Chem. 1997, 62, 1305. (c) Brattesani, D. N.;
Heathcock, C. H. J. Org. Chem. 1975, 40, 2165.
(5) (a) Fleming, F. F.; Zhang, Z.; Wang, Q.; Steward, O. W. Angew.
Chem., Int. Ed. 2004, 43, 1126. (b) Fleming, F. F.; Zhang, Z.; Wang, Q.;
Steward, O. W. J. Org. Chem. 2003, 68, 7646. (c) Fleming, F. F.; Gudipati,
V.; Steward, O. W. Tetrahedron 2003, 59, 5585.
(7) Sarandeses, L. A.; Mourin˜o, A.; Luche, J.-L. J. Chem. Soc., Chem.
Commun. 1992, 798.
(8) Zhao, M. M.; Qu, C.; Lynch, J. E. J. Org. Chem. 2005, 70, 6944.
(9) An exception is conjugate additions to alkenenitriles conjugated with
additional electron-withdrawing groups which are particularly facile: (a)
Fleming, F. F.; Pu, Y.; Tercek, F. J. Org. Chem. 1997, 62, 4883. (b)
Wallenfels, K.; Friedrich, K.; Reiser, J.; Ertel, W.; Thieme, H. K. Angew.
Chem., Int. Ed. 1976, 15, 261.
10.1021/ol060010q CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/15/2006

cyclic alkenenitriles, which necessarily have two-ring carbon
substituents.10 Conceptually, conjugate additions of ω-
chloroiodoalkanes to cyclic alkenenitriles are particularly
attractive because the resulting cyclic nitriles are readily
cyclized to ubiquitous ring systems.11 For example, nitrile 3
is selectively cyclized to the cis-decalin 4 in toluene or to
the trans-decalin 5 simply by judiciously employing THF
as the solvent (Scheme 2).12
iodobutane accompanied by significant formation of 1,8-
dichlorooctane, presumably formed by radical-radical cou-
pling. This suggested generating the surface radical over an
extended time period leading to seven sequential additions
of the iodide at 1 h intervals16 with two additional infusions
of zinc-copper matrix at 3 h intervals (Table 1, entry 2).
The 10-fold increase in yield is consistent with the continuous
formation of adsorbed radicals and the diminished efficiency
of 1-chloro-4-bromobutane as a radical precursor (Table 1,
entry 3).
Further optimization focused on improving the poor mass
recovery in these remarkably clean reactions. Suspecting that
the diminished mass balance is due to radical polymerization,
the zinc-copper matrix was adsorbed onto silica gel prior
to the introduction of nitrile 6c and 1-chloro-4-iodobutane.
The silica-supported zinc-copper matrix dramatically im-
proves the conjugate addition, providing the nitrile 7d in 64%
yield (Table 1, entry 4).
Scheme 2. Solvent-Selective Cyclizations to cis- and
trans-Decalins
The dramatic effect of the silica-supported zinc-copper
matrix is clearly evident from comparative conjugate addi-
tions with unmodified zinc-copper matrix (Table 2, compare
columns b and a, respectively). In all cases, the silica-
supported zinc-copper matrix is significantly more effective
in promoting the conjugate addition of alkyl iodides to
The unique cyclizations of cyclic nitriles stimulated
developing conjugate additions of ω-chloroiodoalkanes to
cyclic alkenenitriles. Exploratory forays with 1-chloro-4-
iodobutane, cyclohexenecarbonitrile (6c), and zinc-copper
matrix, under standard conditions,6a afforded the conjugate
addition product 7d in 4% yield (Table 1, entry 1). An
Table 2. Alkenenitrile Conjugate Additions with Zn-Cu and
Alkyliodides
Table 1. Conjugate Additions to Cyclohexenecarbonitrile (6c)
a Standard conditions for Zn-Cu promoted additions except with 3 equiv
of iodide with pure water as the solvent.6a b Using the general procedure
without silica gel.17 c Using the general procedure.17
intensive screening of solvent,6 temperature, stoichiometry,
ultrasonic irradiation,13 matrix,14 and additives15 identified
ambient water as the best medium. Closely monitoring the
reaction revealed a rapid initial consumption of 1-chloro-4-
(10) Fleming, F. F.; Zhang, Z. Tetrahedron 2005, 61, 747.
(11) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1.
(12) Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 2885.
(13) Ultrasonic irradiation was deleterious in contrast to reactions with
less highly substituted enones: Luche, J. L.; Allavena, C.; Petrier, C.; Dupuy,
C. Tetrahedron Lett. 1988, 29, 5373.
(14) (a) Takai, K.; Ueda, T.; Ikeda, N.; Ishiyama, T.; Matsushita, H.
Bull. Chem. Soc. Jpn. 2003, 76, 347. (b) Takai, K.; Ueda, T.; Ikeda, N.;
Moriwake, T. J. Org. Chem. 1996, 61, 7990.
(15) (a) Shukla, P.; Hsu, Y.-C.; Cheng, C.-H. J. Org. Chem. 2006, 71,
655. (b) Blanchard, P.; Da Silva, A. D.; El Kortbi, M. S.; Fourrey, J.-L.;
Machado, A. S.; Robert-Gero, M. J. Org. Chem. 1993, 58, 6517.
a Zinc-copper matrix in water. b Silica-supported zinc-copper matrix.
Org. Lett., Vol. 8, No. 8, 2006
1558

alkenenitriles.17 The effect is particularly pronounced with
the nitrile 6a (Table 2, entry 1) where the reduced steric
demand of the planar, acyclic alkenenitrile likely emanates
in a more facile radical polymerization. The silica-supported
zinc-copper matrix uniformly promotes conjugate additions
to acyclic and cyclic five- to seven-membered nitriles with
roughly equal efficacy. This represents the first general
method for the conjugate addition of nonstabilized alkyl
groups to disubstituted acyclic and cyclic alkenenitriles.
Mechanistically, the reaction likely involves the conjugate
addition of surface-generated radicals to alkenenitriles.7 The
unique efficacy of the modified matrix (Figure 1) in water
Selective reduction of the carbon-iodine bond enables
formation of cyclic chloroalkanenitriles ideally poised for
anionic cyclization. Deprotonating 7b with KHMDS readily
generates the cis-hydrindane 9b presumably via the N-
potassiated nitrile 8b (Scheme 2).11 The centrality of bio-
active trans-decalins stimulated a new cyclization of 7d via
the putative C-cuprated nitrile 8d (Scheme 3).22 Deproto-
Scheme 3. Hydrindane and Decalin Cyclizations of
ω-Halonitriles
nating 7d with LDA, transmetallating22 with methylcopper,
and warming the metalated nitrile to room temperature trigger
cyclization to the trans-decalin 9d. Exclusive23 formation
of trans-decalin 9d implies a distinctly different mechanism
from the cyclizations with amide bases and strongly suggests
an equatorially oriented Cu(III) intermediate as the reactive
species.24
Figure 1. Slica-supported zinc-copper matrix (left) and the
conventional matrix (right).
Depositing a mixture of zinc dust and copper iodide on
silica generates a highly efficient matrix for promoting the
conjugate addition of alkyl iodides to alkenenitriles in water.
The silica-supported zinc-copper matrix effectively permits
the conjugate addition of alkyl iodides to disubstituted
alkenenitriles and overcomes the long-standing difficulty of
conjugate addition to cyclic alkenenitriles. Chloroalkyl
iodides are excellent substrates for the conjugate addition,
generating functionalized nitriles that are readily cyclized
to hydrindane and decalin ring systems.
may stem from an increased concentration of the organic
reagents at the metal surface,18 localizing the intermediate
radical proximal to the alkenenitrile. In this scenario,
hydrogen bonding between the nitrile19 and the silica support
may position the â-carbon of the alkenenitrile in close
proximity to an alkyl radical adsorbed on an adjacent metal
surface. The resulting nitrile-stabilized radical must be rapidly
reduced20 because no cyclization21 onto the pendant olefin
occurs for nitrile 7g (Table 2, entry 7).
(16) The portionwise addition was significantly more effective than a
constant addition using a syringe pump.
Acknowledgment. Financial support from the National
Science Foundation (CHE 0515715) is gratefully acknowl-
edged.
(17) General Procedure: Water (192 equiv) was added to a stirred mixture
of Zn dust (3 equiv, 100 mesh) and powdered CuI (0.5 equiv). After 10
min, silica gel (27 equiv, 230-400 mesh) was added, followed by additional
water (192 equiv) and the alkenenitrile (1 equiv). After 15 min, the
alkyliodide (1 equiv) was added, followed by seven sequential additions of
the iodide (1 equiv) at 1 h intervals. Two additional infusions of Zn (3
equiv) and CuI (0.5 equiv) were added after 3 and 6 h with additional water
(192 equiv) added during the last addition. The resulting mixture was stirred
overnight and filtered through a glass fritted funnel, and then the crude
product was extracted with EtOAc, dried (Na2SO4), concentrated, and
purified by radial chromatography (1:20 EtOAc/hexanes) to afford analyti-
cally pure material.
(18) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275.
(19) Le Questel, J.-Y.; Berthelot, M.; Laurence, C. J. Phys. Org. Chem.
2000, 13, 347.
(20) Hydrogen-atom abstraction may occur from a zinc iodide-water
complex analogous to trialkylborane reductions in water: Spiegel, D. A.;
Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.; Wood, J. L. J. Am.
Chem. Soc. 2005, 127, 12513.
(21) Newcomb, M.; Horner, J. H.; Filipkowshi, M. A.; Ha, C.; Park,
S.-U. J. Am. Chem. Soc. 1995, 117, 3674.
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.
OL060010Q
(22) Fleming, F. F.; Zhang, Z.; Liu, W.; Knochel, P. J. Org. Chem. 2005,
70, 2200.
(23) No cis-decalin was observed, either in the crude reaction mixture
or after purification.
(24) Analogous Cu(III) species were verified as key intermediates during
coupling of lithium dimethyl cuprate with halobenzenes,a although the
lifetime of this intermediate may be short because a Cu(III) intermediate
was not detected by 13C NMR during the reaction of Me2CuLi with
1-bromocyclooctene.b (a) Spanenburg, W. J.; Snell, B. E.; Su, M.-C.
Microchem. J. 1993, 47, 79. (b) Yoshikai, N.; Nakamura, E. J. Am. Chem.
Soc. 2004, 126, 12264.
Org. Lett., Vol. 8, No. 8, 2006
1559