Alkenenitriles: Conjugate additions of alkyl iodides with a silica-supported zinc-copper matrix in water

Article abstract of DOI:10.1021/jo0711539

(Chemical Equation Presented) A new silica-supported zinc-copper matrix reagent promotes the conjugate addition of alkyl iodides to cyclic and acyclic alkenenitriles in water. X-ray diffraction and electron microscopy techniques suggest that the active co

Full text of DOI:10.1021/jo0711539

Alkenenitriles: Conjugate Additions of Alkyl Iodides with a
Silica-Supported Zinc-Copper Matrix in Water
Fraser F. Fleming,* Subrahmanyam Gudipati, and Jennifer A. Aitken†
Department of Chemistry and Biochemistry, Duquesne UniVersity, Pittsburgh, PennsylVania 15282-1530.
flemingf@duq.edu
ReceiVed May 31, 2007
A new silica-supported zinc-copper matrix reagent promotes the conjugate addition of alkyl iodides to
cyclic and acyclic alkenenitriles in water. X-ray diffraction and electron microscopy techniques suggest
that the active copper species generated from elemental zinc and copper(I) iodide is finely dispersed,
zerovalent copper. Alkyl iodides react with the silica-supported reagent to generate putative radicaloid
intermediates that efficiently add to alkenenitriles to provide â-substituted nitriles. Conjugate additions
to acyclic and cyclic 5-7-membered alkenenitriles are most effective for primary alkyliodides, although
secondary and tertiary alkyliodides are viable reaction partners. The strategy addresses the challenge of
performing conjugate additions to disubstituted alkenenitriles and demonstrates the beneficial role of the
silica-supported reagent.
Introduction
of the alkene more than the â-carbon.5 Comparable carbonyl
systems are polarized by resonance effects which are accen-
tuated by metal complexation to the carbonyl oxygen.6
Nitriles, in contrast, are relatively poor Lewis bases and
are not readily activated by Lewis acidic metal cations.7
Consequently, organometallic reagents tuned for conjugate
additions to unsaturated carbonyl compounds are often relatively
poor reagents for analogous additions to alkenenitriles. For
example, several organocopper8 and phenolic9 nucleophiles
simply do not react with many alkenenitriles, whereas
more nucleophilic reagents preferentially add to the nitrile
group.10
Conjugate addition reactions rank among the most important
carbon-carbon bond-forming reactions in organic synthesis.1
The centrality of conjugate addition reactions stems from the
efficient, stereoselective, installation of a new bond two or more
carbons removed from an electron-withdrawing group, with the
potential for subsequent R-alkylation.2 A measure of the maturity
of this transformation is gained from the diversity of organo-
metallic reagents capable of delivering carbon nucleophiles to
cyclic and acyclic electron-deficient alkenes.3
Despite dramatic advances in organometallic additions to
unsaturated carbonyl derivatives, the analogous conjugate
additions to alkenenitriles remain notoriously difficult.4
The paucity of conjugate additions to alkenenitriles stems
in part from the powerful inductive effect of the electron-
withdrawing nitrile group that polarizes the adjacent R-carbon
(5) Reddy, G. S.; Mandell, L.; Goldstein, J. H. J. Am. Chem. Soc. 1961,
83, 1300.
(6) Woodward, S. Chem. Soc. ReV. 2000, 29, 393.
(7) Gridnev, I. D.; Gridneva, N. A. Russ. Chem. ReV. 1995, 64,
1091.
(8) (a) House, H. O.; Umen, M. J. J. Org. Chem. 1973, 38, 3893. (b)
Totleben, M. J.; Curran, D. P.; Wipf, P. J. Org. Chem. 1992, 57, 1740,
footnote 17. (c) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.;
Maruyama, K. J. Org. Chem. 1982, 47, 119.
† Author for correspondence concerning X-ray and microscopy analyses
(aitkenj@duq.edu).
(1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: New York, 1992.
(9) Kawamine, K.; Takeuchi, R.; Miyashita, M.; Irie, H.; Shimamoto,
Ohfune, Y. Chem. Pharm. Bull. 1991, 39, 3170.
(2) Taylor, R. J. K. Synthesis 1992, 364.
(10) (a) Alexakis, A.; Berlan, J.; Besace, Y. Tetrahedron Lett. 1986, 27,
1047. (b) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. J. Org. Chem.
1984, 49, 3938. (c) Payne, G. B.; Deming, P. H.; Williams, P. H. J. Org.
Chem. 1961, 26, 659. (d) Robert, A; Fouchaud, A. Bull. Chim. Soc. Fr.
1969, 4528.
(3) Alexakis, A. The Conjugate Addition Reaction. In Transition Metals
for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; Vol. 1, pp 553-562.
(4) Fleming, F. F.; Wang, Q. Chem. ReV. 2003, 103, 2035.
10.1021/jo0711539 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/08/2007
J. Org. Chem. 2007, 72, 6961-6969
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Fleming et al.
Grignard reagents are sufficiently nucleophilic to overcome
the recalcitrance of alkenenitriles toward conjugate addition
provided that two aryl substituents are present on the R- and
â-carbons.4 Other highly nucleophilic organometallics engage
in conjugate additions to cyclic alkenenitriles devoid of aromatic
substituents in intramolecular additions provided that the
geometry of the alkenenitrile precludes attack on the CN unit.11
A related strategy is to temporarily tether nucleophilic organo-
metallics adjacent to an alkenenitrile through an alkoxide gen-
erated by addition to a ketone12 or deprotonation of an alcohol.13
For example, addition of a Grignard reagent to oxo-
nitrile 114 generates a halomagnesium alkoxide, through carbonyl
addition, which triggers a halogen-alkyl exchange15 with a
second Grignard to afford the alkyl magnesium alkoxide 2
(Scheme 1). Subsequent conjugate addition leads to the bis-mag-
nesiated nitrile 3 that rearranges to the C-magnesiated nitrile 4.
Intercepting 4 with electrophiles allows a formal inter-
molecular conjugate addition-alkylation through the entropi-
cally more favorable16 intramolecular delivery of the carbon
nucleophile.
Historically, the reagent combination of elemental zinc,
copper(I) iodide, and an alkyliodide18 provided a seminal
advance in conjugate additions to alkenenitriles.19 Intensive
optimization in related conjugate additions with enones identi-
fied two critical reaction parameters: the use of a mixed
alcohol-water solvent combination, and ultrasonic irradiation
(Scheme 2).20 Under optimal conditions, alkyl iodides and
bromides engage in conjugate addition reactions with mono-
substituted enoates, enamides, and alkenenitriles. Although the
precise mechanistic details remain uncertain, several key features
point to radical or radicaloid intermediates.21 An electron transfer
at the metal-iodide interface is thought to reduce the alkyl
iodide 6, possibly by electron transfer, to a surface-adsorbed
radical 7 (Scheme 2).19a Subsequent radical addition to an
electron-deficient olefin 8, such as acrylonitrile, generates a
stabilized radical 9 that is reduced and protonated to afford the
conjugate addition product 10.
SCHEME 2. Zn-CuI Conjugate Addition to Activated
Alkenes
SCHEME 1. Chelation-Controlled Conjugate Addition to a
Cyclic Alkenenitrile
The exceptional ability of the zinc-copper alkyliodide reagent
to trigger conjugate additions of alkyl iodides to acyclic
alkenenitriles provided an excellent lead for the more challeng-
ing conjugate additions to cyclic alkenenitriles. Extensive
optimization experiments have identified conditions for this
transformation and stimulated a series of material analyses that
provide new insight into the nature of the active species
previously referred to as a zinc-copper couple. Collectively,
this methodology addresses the long-standing difficulty of
conjugate additions to disubstituted alkenenitriles, demonstrates
the dramatic influence of performing the reaction in the presence
of silica gel, and provides key insight into the exact nature of
the reagent generated from elemental zinc and copper(I) iodide.
Intermolecular conjugate additions of organometallic reagents
to cyclic alkenenitriles remain a significant challenge. A few
organometallic reagents permit conjugate additions to acryloni-
trile, the most reactive alkenenitrile, although most organome-
tallic reagents are unable to react with substituted acrylonitriles.4
Presumably the combination of increased steric demand and
diminished electrophilicity prevents the conjugate addition,
explaining why very few methods are effective with cyclic
alkenenitriles which necessarily contain two substituents as part
of the ring.17
Results and Discussion
(11) (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.
(12) (a) Fleming, F. F.; Zhang, Z.; Wei, G.; Steward, O. W. Org. Lett.
2005, 7, 447. (b) Fleming, F. F.; Zhang, Z.; Wang, Q.; Steward, O. W.
Angew. Chem., Int. Ed. 2004, 43, 1126.
(13) (a) Fleming, F. F.; Zhang, Z.; Wang, Q.; Steward, O. W. J. Org.
Chem. 2003, 68, 7646. (b) Fleming, F. F.; Wang, Q.; Zhang, Z.; Steward,
O. W. J. Org. Chem. 2002, 67, 5953. (c) Fleming, F. F.; Gudipati, V.;
Steward, O. W. Tetrahedron 2003, 59, 5585. (d) Fleming, F. F.; Wang, Q.;
Steward, O. W. J. Org. Chem. 2003, 68, 4235. (e) Fleming, F. F.; Gudipati,
V.; Steward, O. W. Org. Lett. 2002, 4, 659. (f) Fleming, F. F.; Zhang, Z.;
Wang, Q.; Steward, O. W. Org. Lett. 2002, 4, 2493. (g) Fleming, F. F.;
Wang, Q.; Zhang, Z.; Steward, O. W. J. Org. Chem. 2002, 67, 5953.
(14) Fleming, F. F.; Zhang, Z.; Wei, G. Synthesis 2005, 3179.
(15) Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A. J. Am. Chem. Soc.
1990, 112, 9393.
Lead optimization forays engaged 1-chloro-4-iodobutane in
a conjugate addition with cyclohexenecarbonitrile (11a). The
(18) Dupuy, C.; Petrier, C.; Sarandeses, L. A.; Luche, J. L. Synth.
Commun. 1991, 21, 643.
(19) (a) Sua´rez, R. M.; Sestelo, J. P.; Sarandeses, L. A. Synlett 2002,
1435. (b) Blanchard, P.; DaSilva, A. D.; ElKortbi, M. S.; Fourrey, J.-L.;
Robert-Ge´ro, M. J. Org. Chem. 1993, 58, 6517. (c) Readman, S. K.;
Marsden, S. P.; Hodgson, A. Synlett 2000, 1628. (d) Tsunoi, S.; Ryu, I.;
Fukushima, H.; Tanaka, M.; Komatsu, M.; Sonoda, N. Synlett 1995, 1249.
(e) Sarandeses, L. A.; Mourino, A.; Luche, J.-L. J. Chem. Soc., Chem.
Commun. 1992, 798. (f) Blanchard, P.; El Kortbi, M. S.; Fourrey, J.-L.;
Robert-Gero, M. Tetrahedron Lett. 1992, 33, 3319.
(20) (a) Petrier, C.; Dupuy, C.; Luche, J. L. Tetrahedron Lett. 1986, 27,
3149. (b) Luche, J. L.; Allavena, C. Tetrahedron Lett. 1988, 29, 5369.
(21) Several cleverly designed conjugate additions to enones have trapped
the presumed intermediates by employing internal radical traps. The yields
of trapped product are typically in the range of 5-10% and in some cases
the radical is unable to be intercepted: (a) Sarandeses, L. A.; Mourino, A.;
Luche, J.-L. J. Chem. Soc., Chem. Commun. 1992, 798. (b) Luche, J. L.;
Allavena, C.; Petrier, C.; Dupuy, C. Tetrahedron Lett. 1988, 29, 5373.
(16) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of
Organic Compounds; Wiley: New York, 1994; pp 676-682.
(17) For a preliminary communication see: Fleming, F. F.; Gudipati, S.
Org. Lett. 2006, 8, 1557.
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Conjugate Addition of Alkyl Iodides to Alkenenitriles
TABLE 1. Optimizing Conjugate Additions to Cyclic Nitrile 11a
attraction of 11a as a prototype lies in the potential for
subsequent cyclization of the product 12a (eq 1).22
Under standard conditions,18 with elemental zinc and copper(I)
idodide, only a trace of the desired conjugate addition product
12a is observed. An intensive screening of solvent identified
pure water at ambient temperature as the best medium with
mixed organic-water combinations being significantly less
effective.23 Performing the reaction neat with grinding acceler-
ated the reaction but with poor mass recovery, presumably as a
result of alkenenitrile polymerization.24 Varying the reaction
temperature exerted a deleterious effect: higher temperatures
accelerate the reaction but lead to poor mass recovery, whereas
lowering the temperature to 0 °C causes the reaction to stall.
Ultrasonic irradiation,25 the use of copper alloys, different
copper(I) and -(II) salts,26 surfactants,27 Lewis acids,27a and metal
additives28 were similarly deleterious.
Closely monitoring the reaction revealed the rapid formation
of 1,8-dichlorooctane, presumably by radical dimerization. Slow
syringe pump delivery of the alkyliodide was probed as a means
of enhancing the lifetime of the surface generated radical,
although this proved less effective than the portion-wise addition
at varying time intervals. Eventually the most profitable
procedure was to simply add the alkyl iodide at 1 h intervals,
which provided the nitrile 12a in 4% yield (Table 1, entry 1).
After pursuing numerous addition combinations, a synthetically
viable procedure was identified in which 1 equiv of the iodide
was added every hour for 8 h (a total of 8 equiv including the
initial addition) with two additional infusions of Zn and CuI
added at 3 h intervals (Table 1, entry 2). Employing this addition
procedure with the corresponding bromide provides nitrile 12a
in a slightly lower yield, which correlates with the increased
bond strength of alkylbromides (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 finely dispersed zinc-copper matrix was absorbed onto silica
gel prior to the introduction of nitrile 11a and 1-chloro-4-
iodobutanesthe aim being to adsorb the radical onto a surface
proximal to the alkenenitrile. Experimentally the addition of
silica gel significantly increases the yield of the nitrile 12a
a Standard conditions for Zn-Cu promoted additions except with 3 equiv
of iodide and using pure water as the solvent. b Using the general procedure
without silica gel. c Using the general procedure with silicassee the
Experimental Section. d Using the general procedure with Zn-CuI additions
at 2, 4, 6, and 8 h intervals.
(Table 1, compare entries 2 and 5). Celite exhibits a similar
beneficial effect although the use of silica gel and the more
frequent addition of Zn, Cu(I)I, and silica gel affords the best
yield (Table 1, compare entries 6 and 7). In each case, depositing
the zinc-copper matrix onto silica gel or celite significantly
enhances the mass recovery of the crude product, which
essentially contains only 12a, dichlorooctane, and unreacted
1-chloro-4-iodobutane.
Comparative conjugate additions of alkylhalides to acyclic
and cyclic 5- through 7-membered alkenenitriles are consistently
more efficient with the silica-modified zinc-copper matrix than
with the conventional reagent (Table 2, columns b and a,
respectively.) Primary alkyliodides react selectively over alkyl-
chlorides and fluorides, providing access to modestly function-
alized, â-substituted, haloalkanenitriles (Table 2, entries 1-4
and 12-19). Although the efficiency with 1,3-dibromopropane
is modest, the reaction is remarkable in installing a bromopropyl
group without dimerization or reduction and protonation (Table
2, entry 12). The modest efficiency for the conjugate addition
with isopropyl iodide is surprising, because the addition of
structurally similar cyclohexyl iodide proceeds with the highest
yield of any alkylhalide (Table 2, compare entries 5 and 6).
The discrepancy may reflect solvation differences, because
iodoalkanes bearing polar hydroxyl or carbomethoxy groups
afford only traces of the conjugate addition products.
(22) Fleming, F. F.; Zhang, Z. Tetrahedron 2005, 61, 747.
(23) For a general overview see: (a) Li, C.-J. Chem. ReV. 2005, 105,
3095. (b) “Li, C.-J.; Chan, T.-H. Metal-Mediated Reactions. In Organic
Reactions in Aqueous Media; Wiley-Interscience: New York, 1997; Chapter
4.
(24) Makuska, R.; Bajoras, G.; Myagchenkov, V. A. Polym.-Plast.
Technol. Eng. 1991, 30, 575.
(25) Ultrasonic irradition 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.
(26) (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.
(27) (a) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209. (b)
“Lewis Acid Catalysis in Clean Solvents, Water, and Supercritical Carbon
Dioxide” Clean SolVents: AlternatiVe Media for Chemical Reactions and
Processing; ACS Symp. Ser.; American Chemical Society: Washington,
DC, 2002; No. 819, pp 151-165.
(28) (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.
Insight into the nature of the radical intermediate was probed
through conjugate additions to 11a with bromomethylcyclo-
propane and iodoalkanes containing alkene and alkyne functional
groups (Table 2, entries 9-11). Bromomethylcyclopropane (13)
reacts with nitrile 11a to afford alkenenitrile 12j, the formal
J. Org. Chem, Vol. 72, No. 18, 2007 6963

Fleming et al.
TABLE 2. Conjugate Addition of Alkylhalides to Alkenenitriles
a Column a: Zinc-copper matrix in water. Column b: Silica-supported zinc-copper matrix. b The yield with Celite-Zn-Cu is 77%. c Accompanied by
4% of the alkene derived by reduction of the triple bond. d Using the general procedure with Zn-CuI additions at 2, 4, 6, and 8 h intervals. e The yield with
Celite-Zn-Cu is 39%. f The yield with Celite-Zn-Cu is 67%.
product of butenyl addition (Scheme 3). Forming the ring-
opened product implies an initial reduction of cylcopropyl-
methylbromide to a cyclopropylmethyl-type radical 14 (n ) 1)
that rapidly fragments to the corresponding butenyl radical 15
(n ) 1).29 Subsequent addition of 15 (n ) 1) to alkenenitrile
11a affords the nitrile-stabilized radical 16 that is reduced and
protonated to afford 12j. The inability to detect any of the
hydrindane 17 arising from intramolecular addition of the nitrile-
stabilized radical onto the pendant alkene indicates that the
lifetime of the intermediate is very short30 or that interaction
(29) Newcomb, M. Tetrahedron 1993, 49, 1151.
6964 J. Org. Chem., Vol. 72, No. 18, 2007

Conjugate Addition of Alkyl Iodides to Alkenenitriles
SCHEME 3. Mechanistic Probes for the Zn-Cu(I)
Conjugate Addition
reactive metal surface in close proximity to an alkenenitrile
anchored in position by hydrogen bonding to the nitrile nitrogen
(19, Scheme 4).37 In this scenario, the aqueous solvent favors
localization of the two hydrophobic organic reagents at the metal
surface.38 Approach of the alkyliodide to the preorganized
complex 19 generates a radicaloid species ideally positioned
for addition to the adjacent alkenenitrile.
SCHEME 4. Silica-Supported Zn-CuI Conjugate Addition
with the zinc-copper matrix generates a radicaloid with
reactivity different from that of a free radical. Similarly, no
bicyclic nitriles were detected during the conjugate addition of
5-iodopentyne to alkenenitrile 11a (Table 2, entry 11) where
cyclization of the nitrile-stabilized radical could occur onto the
pendant alkyne. The inability to detect any hydrindane from
this reaction is significant, because 4% of an alkenenitrile
resulting from reduction of the triple bond was isolated from
the reaction.
6-Iodohex-1-ene adds smoothly to 11a to afford 12k (Table
2, entry 10) without any cyclopentylmethyl addition that could
potentially arise by cyclization of the first formed radical
(Scheme 3, 15 (n ) 3) f 14 (n ) 3) f 18).31 Formation of
radicaloid intermediates correlates with similar reactions that
are inhibited with radical traps20a and in which stereochemical
scrambling occurs with chiral secondary iodides.19a Radicaloid
intermediates are further implied from conjugate additions with
1,3-dibromopropane and 1-chloro-3-iodopropane (Table 2,
entries 12 and 13, respectively) where the formation of a true
organometallic would lead to reagent annihilation through rapid
cyclization to cyclopropane. Collectively, these mechanistic
probes implicate radicaloid intermediates with reactivities similar
to, but not identical with, those of the corresponding free
radical.32
Mechanistically the conjugate additions with and without
silica gel most plausibly occur by reduction of the alkyl halide
to generate a surface-adsorbed radical or radicaloid (Scheme
4). The reduction is analogous to that proposed for related
conjugate additions of alkylhalides to alkenenitriles with
elemental zinc,33 a zinc-FeCl3 combination,34 and a reagent
system composed of catalytic PbCl2 and elemental manganese.35
Silica gel is particularly abrasive36 and may facilitate maximum
surface exposure by grinding the zinc-copper matrix. Although
speculative, the silica gel might further function to provide a
Conversion of the resulting nitrile-stabilized radical 20 to the
neutral nitrile requires either reduction and protonation, or
hydrogen atom abstraction (Scheme 4). A one-electron reduction
of the nitrile-stabilized radical can be envisaged to generate a
zincated nitrile that will undergo protonation by the hydroxylic
solvent.39 An alternative process that might be considered is
hydrogen atom abstraction from a zinc iodide-water complex
since Lewis acid complexation of water by trialkylboranes
sufficiently lowers the O-H bond energy for water to act as a
hydrogen atom source in a related reduction.40
Materials Characterization. Complicating the mechanistic
details is the elusive identification of the exact reagent generated
from zinc dust and copper(I) iodide. Typically the resulting black
suspension is loosely referred to as a zinc-copper couple.41
Optimizing the ratio of zinc to copper(I) iodide demonstrates a
very narrow effective ratio for generating an active, black
reagent. The optimum ratio is 6 equiv of zinc to 1 equiv of
Cu(I)I with other ratios resulting in a significant loss of activity
or black materials devoid of any ability to react with alkylio-
dides.
Insight into the composition and morphological nature of the
reagent was provided by a series of materials characterization
analyses. Powder X-ray diffraction data (Figure 1) from samples
of the zinc-copper matrix exhibit diffraction patterns readily
indexed to three crystalline phases: Zn(OH)2,42 Zn metal,43 and
(30) Newcomb, M.; Horner, J. H.; Filipkowski, M. A.; Ha, C.; Park,
S.-U. J. Am. Chem. Soc. 1995, 117, 3674.
(31) The related addition to ethyl vinyl sulfone affords a 2:1 ratio of
cyclopentylmethyl and hexenyl addition: Zhao, M. M.; Qu, C.; Lynch, J.
E. J. Org. Chem. 2005, 70, 6944.
(32) Related radical probes with enones and enoates similarly imply
radicaloid intermediates and in one instance intramolecular cyclization onto
a pendant alkyne occurs in 10% yield.18
(33) Yamamoto, Y.; Nakano, S.; Maekawa, H.; Nishiguchi, I. Org. Lett.
2004, 6, 799.
(34) 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.
(35) (a) Takai, K.; Ueda, T.; Ikeda, N.; Moriwake, T. J. Org. Chem.
1996, 61, 7990. (b) Takai, K.; Ueda, T.; Ikeda, N.; Ishiyama, T.; Matsushita,
H. Bull. Chem. Soc. Jpn. 2003, 76, 347.
(37) Le Questel, J. Y.; Berthelot, M.; Laurence, C. J. Phys. Org. Chem.
2000, 13, 347.
(38) (a) Jung, Y.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129, 5492. (b)
Pirrung, M. C. Chem. Eur. J. 2006, 12, 1313. (c) Narayan, S.; Muldoon, J.;
Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2005, 44, 3275.
(39) Takai, K.; Ueda, T.; Ikeda, N.; Moriwake, T. J. Org. Chem. 1996,
61, 7990.
(40) Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.;
Wood, J. L. J. Am. Chem. Soc. 2005, 127, 12513.
(41) Unpublished X-ray analysis of the material indicated that the material
is not a copper hydride: ref 18, footnote 7.
(42) Stahl, R.; Jung, C.; Lutz, H. D.; Kockelmann, W.; Jacobs, H. Z.
Anorg. Allg. Chem. 1998, 624, 1130.
(36) After the reaction the octagonal stir bar is noticeably concave as a
result of the abrasive action of silica on the Teflon coating.
(43) Swanson, H. E.; Tatge, E. Natl. Bur. Stand. (U.S.) Circ. 1953, 359,
539.
J. Org. Chem, Vol. 72, No. 18, 2007 6965

Fleming et al.
Thermogravimetric analysis (TGA) provided some illumina-
tion into the nature of the elusive copper species. TGA analysis
drives off any absorbed water and allows metal oxidation which,
for the zinc-copper matrix in air, causes a 2.9% weight loss
upon heating to 1200 °C. Powder X-ray diffraction analysis of
the TGA residue provides an indirect, qualitative identification
of the composition of zinc and copper in the original matrix.
Diffraction peak indexing indicates the original material to be
oxidized primarily to ZnO accompanied by a lesser, but
significant quantity of CuO, and a very small amount of a brass,
Cu3Zn (Figure 3). Presumably heating the zinc-copper matrix
in air causes dehydration of zinc hydroxide to zinc oxide and
oxidation of the zerovalent copper species to copper oxide.
FIGURE 1. Powder X-ray diffraction patterns of the zinc-copper
matrix compared to calculated patterns for Zn(OH)2, Zn metal, and
CuI.45
CuI.44 Comparison of the intensities identifies the main com-
ponent as Zn(OH)2 accompanied by small amounts of residual
zinc metal and CuI. Significantly, the powder X-ray diffraction
pattern does not identify a major crystalline phase containing
copper. Essentially the same powder diffraction pattern is
obtained from the sample prepared in the presence of silica gel,
accompanied by additional peaks from the silica support.
An energy dispersive spectrum (Figure 2) shows that the
material consists of mainly zinc and copper with very little
iodine. Semiquantitative energy dispersive analysis focusing on
the zinc, copper, and iodine in these samples indicates the total
elemental composition is approximately 78% zinc, 19% copper,
and only 3% iodine (∼4:1 zinc to copper ratio). These data are
also supported by ICP analysis of the material, which identifies
zinc and copper in a ratio of approximately 5:1. Collectively
these data support the presence of a major copper-containing
component in the matrix that is not CuI. The inability to detect
the major copper component by powder X-ray diffraction,
combined with the EDS and ICP analyses, indicates that the
copper is present either in a noncrystalline form or has a very
small particle size, not readily detected in the presence of
strongly diffracting phases such as Zn(OH)2.
FIGURE 3. Powder X-ray diffraction pattern of the zinc-copper
matrix after TGA.47
Further insight into the elemental composition and particle
morphology was obtained from electron microscopy in com-
bination with Energy Dispersive Spectroscopy (EDS) for
identifying the composition of individual regions embedded
within the matrix (Figure 4). Electron micrographs collected
with a Field Emission Scanning Electron Microscope (FESEM)
reveal surprisingly similar morphology and particle sizes for
the zinc-copper matrix and the silica-supported zinc-copper
matrix (Figure 4 top and bottom, respectively). The particle sizes
lie between 50 and 500 nm, with most of the particles being
oval or round and fewer being more plate-like and irregular.
EDS analyses of more than 20 individual regions of the silica-
supported zinc-copper matrix identified two distinct composi-
tions: those containing only zinc, oxygen, and silicon and those
containing zinc, oxygen, copper, and silicon (in one individual
analysis EDS was focused on the region within the box in Figure
5 on the left and right, respectively). The analysis is consistent
with Zn(OH)2 as the major phase in the matrix accompanied
(44) Keen, D. A.; Hull, S. J. Phys.: Condens. Matter 1995, 7, 5793.
(45) Reference patterns were obtained from the powder diffraction file
(PDF): Zn(OH)2 reference code 01-089-0138; zinc metal reference code
01-087-0713, CuI reference code 01-083-1107.
(46) The Cu(K) peak appears because the sample is adhered to a double-
sided conductive carbon tape.
(47) Reference patterns were obtained from the powder diffraction file
(PDF): ZnO reference code 00-005-0664, CuO reference code 01-089-
5899, Cu3Zn reference code 03-065-6567.
FIGURE 2. Energy dispersive spectrum of the zinc-copper matrix.46
6966 J. Org. Chem., Vol. 72, No. 18, 2007

Conjugate Addition of Alkyl Iodides to Alkenenitriles
The material analyses consistently indicate that the reagent
derived from elemental zinc and copper(I) iodide is comprised
mainly of zinc hydroxide and a copper species that is most likely
finely dispersed zerovalent copper, possibly in the form of
nanoparticles. Powder diffraction and EDS data identify Zn-
(OH)2 as the main zinc component with only a trace of elemental
zinc. Stoichiometrically only half an equivalent of zinc is
required for the reduction of copper(I) iodide to copper zero
leaving the identity of the species undergoing oxidation by the
remaining zinc somewhat obscure. Experimentally the reaction
exhibits a precise requirement for zinc and copper in a 6:1 ratio,
which possibly controls the particle size of the copper. Devia-
tions from the 6:1 ratio afford a gray matrix tinged with a red
hue suggesting formation of a different particle size with
plasmon resonance different from that of the usual finely
dispersed copper. Fortunately, adsorbing the copper species
derived from a 6:1 ratio of elemental zinc and copper(I) iodide
onto silica gel reproducibly provides an excellent reagent for
the conjugate addition of alkyl iodides to alkenenitriles.
Metalated Nitrile Cyclizations. Conjugate additions of
chloroalkyliodides with the silica-supported zinc-copper matrix
affords chloroalkyl-substituted nitriles ideally poised for cy-
clization.49 An extensive series of metalated nitrile SNi cycliza-
tions demonstrates a profound sensitivity on solvent and metal
cation, which suggests that deprotonating alkylnitriles with
KHMDS in refluxing THF generate pyramidal, solvent-separated
ion pairs.50 In the case of nitrile 12n deprotonation with KHMDS
in refluxing THF affords the cis-hydrindane 22 exclusively
(Scheme 5).51 The stereoselectivity is consistent with cyclization
of a pyramidal potassiated nitrile via conformation 21b, which
avoids the torsional strain incurred in the tether for cyclization
through conformer 21a to the corresponding trans-hydrindane.
Similarly, cyclizing the analogous cyclohexanecarbonitrile 12c
under identical conditions affords the hydrindane 22, presumably
via the pyramidal potassiated nitrile 23.
FIGURE 4. SEM Images of the zinc-copper matrix (top) and the
silica-supported zinc-copper matrix (bottom).
SCHEME 5. Metalated Nitrile Cyclizations to
cis-Hydrindanes
FIGURE 5. Electron microscope images of regions containing Zn-
O-Si (left) and Zn-O-Cu-Si (right).
by a less abundant copper-containing phase comprised of
zerovalent copper. Unfortunately no particles were identified48
with copper alone, which is consistent with very small copper
particles intimately mixed with Zn(OH)2.
In contrast to generating nitrile carbanions with KHMDS in
refluxing THF, organocopper-substituted nitriles exhibit alky-
lation selectivities consistent with forming C-metalated nitriles.52
The metal-dependent structural differences suggested an intrigu-
ing strategy for controlling the ring junction stereoselectivity
simply by changing the metal cation. Attempts to redirect the
cyclization stereoselectivity by generating the cuprated nitrile
by sequential LDA deprotonation and transmetallation with
MeCu revealed a surprisingly low reactivity of the putative
C-cuprated nitrile 24 (Scheme 6). Refluxing 24 in THF fails to
generate any of the hydrindane 22! Cyclizing 24 requires the
addition of silver tetrafluoroborate to coax displacement of the
pendant electrophile, leading to the cis-hydrindane 22. Despite
the steric preference for orienting the small nitrile in the axial
orientation,53 no cyclization from conformer 24a is observed.
(48) Transmission electron miscroscopy coupled with EDS failed to locate
individual copper particles.
(49) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1.
(50) Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 2885.
(51) For a related cyclization to an angular nitrile-containing cis-
hydrindane see: Sato, M.; Suzuki, T.; Morisawa, H.; Fujita, S.; Inukai, N.;
Kaneko, C. Chem. Pharm. Bull. 1987, 35, 3647. The cis-hydrindane
stereochemistry was secured by hydrolysis to the corresponding amide and
spectral correlation with a previously characterized sample: Molander, G.
A.; Dowdy, E. D.; Schumann, H. J. Org. Chem. 1998, 63, 3386.
(52) Fleming, F. F.; Zhang, Z.; Liu, W.; Knochel, P. J. Org. Chem. 2005,
70, 2200.
(53) The A-value of a nitrile is only 0.2 kcal mol-1: Eliel, E. L.; Wilen,
S. H.; Mander, L. N. in Stereochemistry of Organic Compounds; Wiley:
New York, 1994; pp 696-7.
J. Org. Chem, Vol. 72, No. 18, 2007 6967

Fleming et al.
SCHEME 6. Cuprated Nitrile Cyclizations to
cis-Hydrindanes
identity remains elusive. Powder X-ray diffraction, SEM, EDS,
TGA, and ICP MS are consistent with the formation of an active
copper species that is likely a zerovalent copper, but in the
absence of definitive identification is best referred to as a zinc-
copper matrix.
Depositing the active copper species onto silica gel dramati-
cally facilitates the conjugate addition. Mechanistic probes are
consistent with reduction of the alkyliodide to a radicaloid or a
surface adsorbed radical that triggers conjugate addition to a
proximal alkenenitrile. The silica gel is proposed to anchor the
alkenenitrile in close proximity to the surface-adsorbed radi-
caloid through hydrogen bonding. Collectively, this methodol-
ogy addresses the long-standing difficulty of conjugate additions
to disubstituted alkenenitriles, demonstrates the dramatic influ-
ence of performing the reaction in the presence of silica gel,
and provides insight into the nature of the reagent generated
from elemental zinc and copper(I) iodide.
The cis-hydrindane 22 is the sole diastereomer detectable in
the crude reaction mixture, which implies preferential cyclization
through the more flexible conformation 24b with the axial
methyl copper. Relaxing the steric constraints by incorporating
an additional carbon in the tether is insufficient to redirect the
cyclization stereoselectivity since 12c cyclizes exclusively to
the cis-hydrindane 22 under identical conditions.
Experimental Section
Employing a C-cuprated nitrile in the corresponding decalin
cyclization with 12a successfully redirects the cyclization to
the trans-fused diastereomer 27 (Scheme 7). Sequential addition
of LDA and MeCu to 12a triggers cyclization to the trans-
decalin 27 as the exclusive diastereomer.54 For comparison,
cyclizing 12a with KHMDS in refluxing THF affords the trans-
decalin 27 and the corresponding cis-decalin in a 6.3:1 ratio.50
Exclusive formation of the trans-decalin 26 implies a distinctly
different mechanism from the analogous cyclization with
KHMDS and strongly suggests an equatorially oriented Cu-
(III) intermediate 26 as the reactive species.55
General Conjugate Addition 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) and additional water (192 equiv) were added in the
optimized procedure, followed by the alkenenitrile (1 equiv). (The
alkenenitrile was added directly in those reactions performed
without silica gel.) 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 was then vacuum filtered through a glass fritted
funnel. The crude product was then extracted with EtOAc, and the
combined extracts were dried (Na2SO4), concentrated, and purified
by radial chromatography (1:20 EtOAc/hexanes) to afford analyti-
cally pure material.
SCHEME 7. Cuprated Nitrile Cyclizations to trans-Decalin
Octahydro-1H-indene-3a-carbonitrile (22). (a) Cyclization of
12n: A THF solution (1 M, 0.40 mmol) of KHMDS was added to
a THF solution (10 mL) of 12n (55 mg, 0.30 mmol) and the mixture
was then heated to reflux. After 5 h the solution was cooled to rt,
saturated aqueous NH4Cl was added, and the organic phase was
separated, dried (Na2SO4), concentrated, and purified by radial
chromatography (1:20 EtOAc/hexanes) to afford 40 mg (91%) of
22 as an oil: IR (film) 2231 cm-1; 1H NMR (500 MHz, CDCl3) δ
Conclusion
The silica-supported zinc-copper matrix dramatically pro-
motes conjugate additions of alkylhalides to acyclic and cyclic
5-7-membered alkenenitriles. Detailed mechanistic probes
performed with primary alkyliodides are consistent with conver-
sion to a radicaloid species by the zinc-copper matrix derived
from elemental zinc and copper(I) iodide. Material characteriza-
tion strongly implies that the reagent loosely referred to as a
zinc-copper couple is actually finely dispersed, zerovalent
copper.
Detailed material analyses provide insight into the nature of
the zinc-copper matrix generated in the presence and absence
of silica gel. Powder X-ray diffraction does not support the
presence of coupled zinc and copper, but is silent on the exact
identity of the copper species. The absence of a diffracting
copper phase suggests either a noncrystalline form and/or small
particles of copper, possibly nanocrystals, although the exact
1.40-1.98 (m, 13H), 2.03-2.13 (m, 1H), 2.27-2.36 (m, 1H); 13
C
NMR (125 MHz, CDCl3) δ 20.9, 21.4, 22.7, 25.2, 27.4, 30.6, 36.6,
41.1, 44.0, 125.8; m/e 150 (M + H+); HRMS (EI) calcd for
C10H15N+ 149.1199, found 149.1189. (b) Cyclization of 12n via
an organocopper: A THF solution (1 M, 0.26 mmol) of LDA was
added to a -78 °C, THF solution (10 mL) of 12n (50 mg, 0.27
mmol). After 1 h, a THF solution (5 mL) of BuCu, made from a
hexanes solution (2.7M, 0.32 mmol) of BuLi and anhydrous CuI
(62 mg, 0.32 mmol), was added followed by solid AgBF4 (50 mg,
0.26 mmol). The reaction mixture was allowed to warm to rt and
after 16 h, saturated aqueous NH4Cl was added. The aqueous phase
was then separated and extracted with EtOAc. The organic extracts
were combined, dried (Na2SO4), concentrated, and then purified
by radial chromatography (1:20 EtOAc/hexanes) to afford 30 mg
(74%) of 22 as an oil. (c) Cyclization of 12c: A THF solution (1
M, 0.43 mmol) of KHMDS was added to a THF solution (10 mL)
of 12c (66 mg, 0.36 mmol) and the mixture was then heated to
reflux. After 5 h the solution was cooled to rt, saturated aqueous
NH4Cl was added, and the aqueous phase was then separated and
extracted with EtOAc. The organic extracts were combined, dried
(Na2SO4), concentrated, and then purified by radial chromatography
(1:20 EtOAc/hexanes) to afford 51.4 mg (97%) of 22. (d)
Cyclization of 12c via an organocopper: A THF solution (1 M,
(54) 1H NMR analysis of the crude reaction mixture failed to identify
any of the diastereomeric cis-decalin.
(55) 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 since a Cu(III) intermediate was
not detected by 13C NMR during the reaction of Me2CuLi with 1-bromocy-
clooctene.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.
6968 J. Org. Chem., Vol. 72, No. 18, 2007

Conjugate Addition of Alkyl Iodides to Alkenenitriles
0.26 mmol) of LDA was added to a -78 °C, THF solution (10
mL) of 22 (48 mg, 0.26 mmol). After 1 h, a THF solution (5 mL)
of MeCu, made from a hexanes solution (1.6 M, 0.31 mmol) of
MeLi and anhydrous CuI (59 mg, 0.31 mmol), was added, followed
by solid AgBF4 (60 mg, 0.31 mmol). The reaction mixture was
allowed to warm to rt and after 16 h, saturated aqueous NH4Cl
was added. The aqueous phase was then separated and extracted
with EtOAc. The organic extracts were combined, dried (Na2SO4),
concentrated, and then purified by radial chromatography (1:20
EtOAc/hexanes) to afford 26 mg (68%) of octahydro-1H-indene-
3a-carbonitrile as an oil. Basic hydrolysis of 22 (34.0 mg, 0.23
mmol) with excess NaOH in ethylene glycol at ∼240 °C for 6 h
afforded 7 mg (20%) of octahydro-1H-indene-3a-carboxamide (i)
as a white solid spectrally identical with previously characterized
material.51
hexanes solution (1.6 M, 0.75 mmol) of MeLi and anhydrous CuI
(143 mg, 0.75 mmol), was added. The reaction mixture was allowed
to warm to rt and after 16 h, saturated aqueous NH4Cl was added.
The aqueous phase was then separated and extracted with EtOAc.
The organic extracts were combined, dried (Na2SO4), concentrated,
and then purified by radial chromatography (1:20 EtOAc/hexanes)
to afford 73 mg (71%) of trans-decahydronaphthalene-4a-carbo-
nitrile spectroscopically identical with material previously isolated.50
Acknowledgment. Financial support from the National
Science Foundation (CHE 0515715, CHE 0421252 HRMS, and
DUE-0511444 powder X-ray diffractometer) is gratefully
acknowledged as is assistance from Dr. Mitchell Johnson.
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.
Decahydronaphthalene-4a-carbonitrile (27). A THF solution
(1 M, 0.26 mmol) of LDA was added to a -78 °C, THF solution
(15 mL) of 2-(4-chlorobutyl)cyclopentanecarbonitrile (125 mg, 0.62
mmol). After 1 h, a THF solution (5 mL) of MeCu, made from a
JO0711539
J. Org. Chem, Vol. 72, No. 18, 2007 6969