Surprising role of aryl halides in nickel-catalyzed reductive aldol reactions

Article abstract of DOI:10.1021/ol063028+

A new nickel-catalyzed method for the reductive aldol addition of acrylates and aldehydes has been developed. An unexpected requirement for an aryl iodide additive was found in the process, and the effect was shown to be linked to an initiation step.

Full text of DOI:10.1021/ol063028+

ORGANIC
LETTERS
2007
Vol. 9, No. 3
537-540
Surprising Role of Aryl Halides in
Nickel-Catalyzed Reductive Aldol
Reactions
Christa C. Chrovian and John Montgomery*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan 48109-1055
jmontg@umich.edu
Received December 14, 2006
ABSTRACT
A new nickel-catalyzed method for the reductive aldol addition of acrylates and aldehydes has been developed. An unexpected requirement
for an aryl iodide additive was found in the process, and the effect was shown to be linked to an initiation step.
Conjugate addition/aldol and reductive aldol sequences of
R,â-unsaturated carbonyls provide powerful strategies for the
synthesis of complex ketones and carboxylic acid derivatives.
Processes involving conjugate addition typically employ
organocuprates,1 organozincs,2 organoboranes,3 or organo-
zirconium reagents.4 In contrast, reductive aldol sequences
typically use reducing agents such as silane derivatives5 or
hydrogen gas6 as the terminal reductant.7,8 Alternatively, our
group recently disclosed a procedure for conjugate addition/
aldol addition involving aryl iodides directly while using
commercially available dimethylzinc as a promoter, thus
avoiding the requirement for prior synthesis of a metalated
nucleophile (Scheme 1; Table 1, entry 1).9 Since the
component that adds as a nucleophile (the aryl iodide) is
structurally distinct from the reducing agent (dimethylzinc),
the opportunity exists for addition of the aryl iodide and
organozinc to be competitive. Given the tremendous number
of products that are potentially accessible from the multi-
component character of the reaction, the development of
selective processes poses a significant challenge in chemo-
selectivity (Scheme 2). Additionally, the impact of each
reagent on the reactivity characteristics of the other reagents
can further complicate issues in chemoselectivity. Herein,
we describe the interdependence of the reactivity patterns
of the various components. Not only can tuning the structure
of the reducing agent completely change the course of the
reactions, but additives that are not incorporated into the
(1) (a) Chapdelaine, M. J.; Hulce, M. In Organic Reactions; Paquette,
L. A., Ed.; Wiley: New York, 1990; Vol. 38, p 225. (b) Lipshutz, B. H.;
Sengupta, S. In Organic Reactions; Paquette, L. A., Ed.; Wiley: New York,
1992; Vol. 41, p 135.
Scheme 1. Conjugate Addition/Aldol and Reductive Aldol
Products
(2) (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries,
A. H. M. Angew. Chem., Int. Ed. 1997, 36, 2620. (b) Arnold, L. A.; Naasz,
R.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2002, 67, 7244.
(3) (a) Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 2002,
124, 10984. (b) Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem.
Soc. 2003, 125, 1110.
(4) (a) Wipf, P.; Xu, W. J.; Smitrovich, J. H.; Lehmann, R.; Venanzi, L.
M. Tetrahedron 1994, 50, 1935. (b) Lipshutz, B. H.; Wood, M. R. J. Am.
Chem. Soc. 1993, 115, 12625. (c) Schwartz, J.; Loots, M. J.; Kosugi, H. J.
Am. Chem. Soc. 1980, 102, 1333.
10.1021/ol063028+ CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/12/2007

triethylborane as the reducing agent (Table 1). Whereas
dimethylzinc promoted addition of the aryl iodide component
to afford product 1 (Table 1, entry 1), diethylzinc and
triethylborane favored the reductive aldol pathway to give
product 2 (Table 1, entries 2 and 3). Preparatively useful
selectivity for product 2 was best obtained with triethyl-
borane, whereas diethylzinc afforded a 2:1 mixture of
products.
Given that the triethylborane-mediated variant provided a
high-yielding, syn-selective procedure for effecting the
reductive aldol reaction, we repeated the reaction in the
absence of phenyl iodide under otherwise identical condi-
tions. To our surprise, the coupling of tert-butyl acrylate,
benzaldehyde, and triethylborane with Ni(COD)2 afforded
none of the expected reductive aldol product 2, and starting
materials were cleanly recovered under conditions that
afforded high yields of 2 in the presence of phenyl iodide
(eq 1). As noted above (Table 1, entry 3), a small amount
Table 1. Impact of Reducing Agent Structurea
reducing
agent
% yield
(1:2)
(syn:anti)
(syn:anti)
entry
of 1
of 2
1
2
3
ZnMe2
ZnEt2
BEt3
88 (>98:2)
87 (67:33)
92 (5:95)
86:14
90:10
60:40
88:12
a Reaction conditions: tert-butyl acrylate (1.0 equiv), benzaldehyde (1.5
equiv), phenyl iodide (2.0 equiv), reducing agent (2.0 equiv), Ni(COD)2
(10 mol %), THF, 65 °C.
product structures can also have a profound impact on the
manner in which the other reagents combine.10 This study
provides the first examples of nickel-catalyzed reductive aldol
processes and illustrates a novel role of aryl iodides in
reaction initiation.
Scheme 2. Possible Reaction Products
(ca 5%) of the conjugate addition/aldol product 1 ac-
companied formation of the major product 2 in triethyl-
borane-mediated reductive aldol processes. When the aryl
iodide is used in excess, only trace amounts are consumed
in the course of the reaction. Quantities of aryl iodide as
low as 5-10 mol % are sufficient to promote the efficient
formation of 2.
To elucidate whether 1 and 2 are produced simultaneously
or sequentially in the triethylborane-mediated reaction, we
measured their production as the reaction progressed in an
experiment that employed a 1:1.2:1 stoichiometry of tert-
butyl acrylate, benzaldehyde, and phenyl iodide with 10 mol
% Ni(COD)2. After 1 min at rt, 4% conversion was noted,
with a 10:1 ratio of 1:2. As the reaction progressed, the
concentration of 1 remained relatively constant while 2
slowly accumulated, until the reaction was quenched after 7
h at 94% conversion with a 5:95 ratio of 1:2. Even though
a full equivalent of phenyl iodide was used, the burst of 1
noted during the first minute of the reaction corresponded
to the full amount of 1 generated during the reaction.
Compound 1 clearly results from an initiation event that
likely generates the active catalyst species responsible for
the formation of 2.
In initially exploring the impact of reducing agent structure
on the nickel-catalyzed conjugate addition/aldol addition
sequence involving aryl iodides, we compared Ni(COD)2-
catalyzed addition of tert-butyl acrylate, phenyl iodide, and
benzaldehyde employing dimethylzinc, diethylzinc, and
(5) (a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809. (b)
Matsuda, I.; Takahashi, K.; Sato, S. Tetrahedron Lett. 1990, 31, 5331. (c)
Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc. 1999, 121, 12202. (d) Taylor,
S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000, 122, 4528. (e)
Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001,
3, 1829. (f) Zhao, C.-X.; Bass, J.; Morken, J. P. Org. Lett. 2001, 3, 2839.
(g) Russell, A. E.; Fuller, N. O.; Taylor, S. J.; Aurriset, P.; Morken, J. P.
Org. Lett. 2004, 6, 2309. (h) Fuller, N. O.; Morken, J. P. Synlett 2005,
1459. (i) Lipshutz, B. H.; Chrisman, W.; Noson, K.; Papa, P.; Sclafani, J.
A.; Vivian, R. W.; Keith, J. M. Tetrahedron 2000, 56, 2779. (j) Nishiyama,
H.; Shiomi, T.; Tsuchiya, Y.; Matsuda, I. J. Am. Chem. Soc. 2005, 127,
6972. (k) Shibata, I.; Kato, H.; Ishida, T.; Yasuda, M.; Baba, A. Angew.
Chem., Int. Ed. 2004, 43, 711. (l) Miura, K.; Yamada, Y.; Tomita, M.;
Hosomi, A. Synlett 2004, 1985. (m) Lam, H. W.; Joensuu, P. M. Org. Lett.
2005, 7, 4225. (n) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O.
Angew. Chem., Int. Ed. 2006, 45, 1292. (o) Zhao, D.; Oisaki, K.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 1403. (p) Kiyooka, S.-i.;
Shimizu, A.; Torii, A. S. Tetrahedron Lett. 1998, 39, 5237.
To gain further insight into the requirements for the
initiating species, we examined several aromatic components
(7) (a) For a catalytic method involving dialkyl boranes, see: Lipshutz,
B. H.; Papa, P. Angew. Chem., Int. Ed. 2002, 41, 4580. (b) For a noncatalytic
method involving dialkyl boranes, see: Boldrini, G. P.; Bortolotti, M.;
Mancini, F.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Org. Chem.
1991, 56, 5820.
(8) For reducing agents other than silanes, boranes, and H2, see: (a)
Willis, M. C.; Woodward, R. L. J. Am. Chem. Soc. 2005, 127, 18012. (b)
Inoue, K.; Ishida, T.; Shibata, I.; Baba, A. AdV. Synth. Catal. 2002, 344,
283. (c) For a recent example of intramolecular diethylzinc-mediated
reductive aldols: Lam, H. W.; Joensuu, P. M.; Murray, G. J.; Fordyce, E.
A. F.; Prieto, O.; Luebbers, T. Org. Lett. 2006, 8, 3729.
(6) (a) Jang, H.-Y.; Krische, M. J. Acc. Chem. Res. 2004, 37, 653. (b)
Bocknack, B. M.; Wang, L.-C.; Krische, M. J. Proc. Natl. Acad. Sci. 2004,
101, 5421. (c) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem.
Soc. 2002, 124, 15156. (d) Huddleston, R. R.; Krische, M. J. Org. Lett.
2003, 5, 1143. (e) Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6, 691.
(9) Subburaj, K.; Montgomery, J. J. Am. Chem. Soc. 2003, 125, 11210.
(10) For an example of the interdependence of catalyst, ligand, and
reducing agent structure in a reductive aldol, see ref 5c.
538
Org. Lett., Vol. 9, No. 3, 2007

that could potentially participate in oxidative addition or
electron-transfer events (Table 2). An electron-rich aromatic
product 3 derived from ethyl conjugate addition followed
by aldol trapping (eq 2). Therefore, the reactivity of the
Table 2. Impact of Initiator Structurea
entry
additive
% yield of 2 (dr)
1
2
3
PhI
87 (88:12)
85 (88:12)
0
0
p-(MeO)C6H4I
2-iodo-m-xylene
PhBr
4
catalyst derived from Ni(COD)2 and phenyl iodide is clearly
different from other readily available sources of Ni(II). This
Ni(acac)2-catalyzed process may be useful, especially in
applications involving more complex alkylboranes derived
from hydroboration.11
5
6
7
8
9
10
PhOTf
0
10
0
C6H5CN
Ph2CdO
CH3I
CH3CH2I
HI
80 (86:14)
0
19
On the basis of the above analysis, we propose that the
aryl iodide plays a key role in the initiation step of the
triethylborane-mediated reductive aldol reaction. A possible
mechanistic sequence proceeds as follows (Scheme 3).
Oxidative addition of Ni(0) to the aryl iodide and coordina-
tion of acrylate 4 and triethylborane will afford intermediate
5. Reorganization of 5 to an ethyl(iodo)nickel species 6 and
boron enolate 7 may proceed by a migratory insertion,
transmetalation sequence. The role of triethylborane as a
Lewis acid to activate the enone and as a Lewis base (via a
bridging ethyl group) to activate the nickel center derives
from our prior computational study of enone/alkyne reductive
couplings, which described the nature of such interactions
with Ni(0) and dimethylzinc.12 Boron enolate 7 then under-
goes syn aldol addition with the aldehyde to provide product
1, which is thus solely derived from this required initiation
step. The resulting ethyl(iodo)nickel species 6 then com-
plexes with the acrylate and triethylborane concomitant with
loss of ethylene to generate nickel hydride 8.13 Reorganiza-
tion of 8 to boron enolate 9 is accompanied by the
regeneration of ethyl(iodo)nickel species 6.14 Syn aldol
addition of 9 with the aldehyde then provides compound 2,
which is the major product of the reaction. Species 6 is thus
a likely active catalyst for formation of the reductive aldol
product 2, and aldol product 1 is a byproduct of the initiation
step that generates active catalyst 6. While the proposed role
of the aryl iodide as an initiator that modifies the structure
of the active catalyst is novel, precedent involving a related
a Reaction conditions: tert-butyl acrylate (1.0 equiv), benzaldehyde (1.5
equiv), initiator (1.0 equiv), triethylborane (2.0 equiv), Ni(COD)2 (10 mol
%), THF, 65 °C.
iodide serves as an effective initiator for the reductive aldol
sequence (Table 2, entry 2), but a hindered aryl iodide does
not (Table 2, entry 3). Bromobenzene, phenyl triflate,
cyanobenzene, and benzophenone are completely ineffective
as reaction initiators (Table 2, entries 4-7). The only
nonaromatic initiator that exhibited effectiveness was methyl
iodide, which also allowed the reductive aldol reaction to
proceed efficiently in good yield (Table 2, entry 8). In
contrast, ethyl iodide was ineffective as an initiator, and HI-
promoted reactions proceeded in low yield (Table 2, entries
9 and 10).
Given the special role of organic iodides that lack steric
hindrance, we surmised that oxidative addition of nickel(0)
to the C-I bond was a critical step in reaction initiation.
This suggested that a Ni(II) precatalyst may potentially serve
as an effective catalyst source without aryl iodide initiators.
To probe this question, Ni(acac)2 was examined as a
precatalyst, and a third entirely distinct reaction pathway was
observed. Treatment of tert-butyl acrylate, benzaldehyde, and
triethylborane with 10 mol % Ni(acac)2 in THF, either in
the presence or the absence of phenyl iodide with no
appreciable change in rate, resulted in the production of
Scheme 3. Proposed Mechanism for Initiation and Addition Steps
Org. Lett., Vol. 9, No. 3, 2007
539

effect was noted in an elegant study from Cheng that
described an initiation effect of organic iodides in palladium-
catalyzed silaboration of allenes.15 In the Cheng work, a
proposal was made that the initiation step generates a boron-
containing byproduct, which then participates in the produc-
tive catalytic cycle, whereas our work proposes that catalyst
modification is responsible for the effect observed.
The scope of this reductive aldol process was then
examined (Table 3). Simple, monosubstituted acrylates were
the only Michael acceptors studied that underwent efficient
couplings. The scope of aldehydes, however, included a
number of structural variations. A variety of aromatic
aldehydes were examined, and electron-rich (Table 3, entry
2), heteroaromatic (Table 3, entry 3), electron-deficient
(Table 3, entry 4), and halogen-containing aromatic iodides
(Table 3, entry 5) were all tolerated. Consistent with our
observation that an aryl iodide initiator was required, only
entry 5 did not require the addition of phenyl iodide. The
reaction also tolerated unbranched aliphatic enolizable al-
dehydes (Table 3, entry 6), R-branched enolizable aldehydes
(Table 3, entry 7), and an R-benzyloxy aliphatic aldehyde
(Table 3, entry 8). Whereas good to excellent syn selectivity
was observed in all cases, diastereoselection with an R-alkoxy
aldehyde (Table 3, entry 8) was poor. In summary, three
Table 3. Scope of Nickel-Catalyzed Reductive Aldol
Reactionsa
entry
R
% yield of 2 (dr)
1
2
3
4
5
6
7
8
Ph
87 (88:12)
88 (87:13)
91 (88:12)
86 (90:10)
73 (89:11)
80 (86:14)
68 (96:4)
p-(MeO)C6H4
2-furyl
p-(NC)C6H4
m-(I)C6H4
(CH2)5CH3
(CH3CH2)2CH
BnO(CH3)CH
60 (45:45:5:5)b
a Reaction conditions: tert-butyl acrylate (1.0 equiv), aldehyde (1.5
equiv), phenyl iodide (1.0 equiv), triethylborane (2.0 equiv), Ni(COD)2 (10
mol %), THF, 65 °C. b The two major isomers are derived from a syn aldol
process.
distinct pathways (conjugate arylation/aldol, conjugate alkyl-
ation/aldol, or conjugate reduction/aldol) have been identified
for the nickel-catalyzed multicomponent addition of acrylates,
aldehydes, aryl iodides, and a reducing agent (organozinc
or organoborane). Each pathway may be selectively accessed
by careful choice of catalyst and reagent structure. Whereas
the impact of varying catalyst structure and reducing agent
structure is not surprising, the observation that aryl iodides
dramatically change the course of reactions even when they
are not incorporated into the product structure is of consider-
able conceptual interest. Evidence is presented that the role
of the aryl iodide is linked to an initiation step that alters
the catalyst structure, and we anticipate that this finding may
be useful in many contexts.
(11) 9-BBN derivatives derived from terminal olefins effectively proceed
in Ni(acac)2-catalyzed processes, but yields are modest and mixtures of
conjugate addition/aldol trapping and conjugate addition/protonation prod-
ucts are obtained. For examples of nickel-catalyzed conjugate additions of
alkenyl and aryl boranes, see: (a) Yoshida, K.; Ogasawara, M.; Hayashi,
T. J. Am. Chem. Soc. 2002, 124, 10984. (b) Yanagi, T.; Sasaki, H.; Suzuki,
A.; Miyaura, N. Synth. Commun. 1996, 26, 2503.
(12) (a) Hratchian, H.; Chowdhury, S. K.; Gutie´rrez-Garc´ıa, V. M.;
Schlegel, H. B.; Montgomery, J. Organometallics 2004, 23, 4636. For
examples of crystallographically characterized interactions of this type,
see: (b) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem. Soc.
2005, 127, 12810. (c) Kaschube, W.; Po¨rschke, K.-R.; Angermund, K.;
Kru¨ger, C.; Wilke, G. Chem. Ber. 1988, 121, 1921.
(13) For examples of other classes of nickel-catalyzed reductive couplings
employing triethylborane, see: (a) Kimura, M.; Ezoe, A.; Shibata, K.;
Tamaru, Y. J. Am. Chem. Soc. 1998, 120, 4033. (b) Huang, W.-S.; Chan,
J.; Jamison, T. F. Org. Lett. 2000, 26, 4221.
(14) Nickel enolate aldol reactions are also possible, although several
nickel complexes of chiral phosphines or N-heterocyclic carbenes participate
with no observable enantioselection.
Acknowledgment. Support for this work was provided
by the National Science Foundation (CHE-0553895).
Supporting Information Available: Experimental pro-
cedures and a copy of spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Yang, F.-Y.; Cheng, C.-H. J. Am. Chem. Soc. 2001, 123, 761.
(b) Chang, K.-J.; Rayabarapu, D. K.; Yang, F.-Y.; Cheng, C.-H. J. Am.
Chem. Soc. 2004, 127, 126.
OL063028+
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Org. Lett., Vol. 9, No. 3, 2007