Nickel-catalyzed reductive cyclization of organohalides

Article abstract of DOI:10.1021/ol200455n

A mild and convenient nickel-catalyzed method for free-radical cyclization of organohalides is described. The use of a NiCl₂DME/Pybox complex as the catalyst and zinc powder in methanol efficiently promotes the reductive cyclization of various

Full text of DOI:10.1021/ol200455n

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2050–2053
Nickel-Catalyzed Reductive
Cyclization of Organohalides
Hyejin Kim and Chulbom Lee*
Department of Chemistry, Seoul National University, Seoul 151-747, South Korea
chulbom@snu.ac.kr
Received February 19, 2011
ABSTRACT
A mild and convenient nickel-catalyzed method for free-radical cyclization of organohalides is described. The use of a NiCl2•DME/Pybox complex
as the catalyst and zinc powder in methanol efficiently promotes the reductive cyclization of various unsaturated alkyl halides to give carbo-, oxa-,
and azacycles as products in high yields.
Free radical cyclization of unsaturated organohalides is a
powerful method for ring construction that has found wide-
spread use in various domains of organic synthesis.1 This
process may be performed with a variety of radical media-
tors, among which stannane reagents have been most pop-
ular despite the toxicity and purification issues associated
with certain organotin species. Among the nonstannane-
based protocols,2 transition-metal-promoted radical reac-
tions represent an attractive approach due to the capability
of effecting catalysis,3 as exemplified by an array of atom
transfer radical addition (ATRA) reactions.4 However,
these processes, making use of the Kharasch mechanism,5
typically proceed with substrates activated by polyhalogen
substitution or an adjacent π-bond. Potentially more useful
catalyst systems applicable to simple alkyl halides are far
less common, and examples have been limited largely to
electrochemical settings6 or practiced in a narrow structural
context in the presence of a rather strong reductant.7 Given
the broadly established utility of the radical cyclization, the
development of an efficient catalyst that encompasses simple
halide substrates would be of high synthetic value, signifi-
cantly expanding the scope of the reaction. Herein, we
report a mild and convenient nickel-catalyzed method that
effects reductive radical cyclization of various alkyl halides
to give rise to carbo- and heterocyclic products in high yield.
Our initial investigations were focused on examining
the feasibility of metal catalysis for the cyclization of
(1) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; Vols. 1 and 2. (b) Giese, B. Radicals in
Organic Synthesis: Formation of CarbonÀCarbon Bonds; Pergamon:
Oxford, 1988. (c) Curran, D. P. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon: Oxford, 1991;
Vol. 4, pp 715À779.
(2) For reviews on alternate reagents to organotins, see: (a) Baguley,
P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072. (b) Studer, A.;
Amrein, S. Synthesis 2002, 835. (c) Walton, J. C.; Studer, A. Acc. Chem.
Res. 2005, 38, 794. (d) Studer, A.; Amrein, S. Angew. Chem., Int. Ed.
2000, 39, 3080. (e) Parsons, A. Chem. Br. 2002, 38, 42.
(3) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519.
(4) Matyjaszewski, K.; Xia, J. Chem. Rev. 2001, 101, 2921.
(5) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science 1945, 102, 128.
(6) For examples of nickel catalyses in electrochemical conditions,
see: (a) Ozaki, S.; Matsushita, H.; Ohmori, H. J. Chem. Soc., Chem.
Commun. 1992, 1120. (b) Ozaki, S.; Matsushita, H.; Ohmori, H. J. Chem.
Soc., Perkin Trans. 1 1993, 2339. (c) Ozaki, S.; Matsushita, H.; Emoto,
ꢀ ꢀ
M.; Ohmori, H. Chem. Pharm. Bull. 1995, 43, 32. (d) Nedelec, J.-Y.;
ꢀ
~
Perichon, J.; Troupel, M. Top. Cur. Chem. 1997, 185, 141. (e) Dunach,
E.; Esteves, A. P.; Freitas, A. M.; Medeiros, M. J.; Olivero, S. Tetra-
hedron Lett. 1999, 40, 8693. (f) Esteves, A. P.; Ferreira, E. C.; Medeiros,
M. J. Tetrahedron 2007, 63, 3006. For examples of cobalt catalyses using
vitamin B12, see: (g) Scheffold, R.; Rytz, G.; Walder, L. Vitamin B12 and
Related Co-Complexes as Catalyst in Organic Synthesis in Modern
Synthetic Methods; Scheffold, R., Ed.; J. Wiley: New York, 1983; Vol. 3,
p 355. (h) Scheffold, R.; Abrecht, S.; Orlinski, R.; Hans-Rudolf, R.;
Stamouli, P.; Tinembart, O.; Walder, L.; Weymuth, C. Pure Appl. Chem.
1987, 59, 363.
(7) For nickel-catalyzed radical reactions under nonelectroreductive
conditions for the synthesis of THF derivatives, see: (a) Vaupel, A.;
~
Knochel, P. J. Org. Chem. 1996, 61, 5743. (b) Phapale, V. B.; Bunuel, E.;
ꢀ
Garcıa-Iglesias, M.; Cardenas, D. J. Angew. Chem., Int. Ed. 2007, 46,
8790. For conjugate additions, see: (c) Molander, G. A.; Harris, C. R. J.
Org. Chem. 1997, 62, 7418. (d) Terao, J.; Nii, S.; Chowdhury, F. A.;
Nakamura, A.; Kambe, N. Adv. Synth. Catal. 2004, 346, 905. For a
samarium-catalyzed radical reaction, see: (e) Corey, E. J.; Zheng, G. Z.
Tetrahedron Lett. 1997, 38, 2045.
r
10.1021/ol200455n
Published on Web 03/18/2011
2011 American Chemical Society

(entry 2).9 Interestingly, the use of a multidentate nitrogen
ligand in lieu of pyridine completely suppressed β-hydrogen
elimination but led to significant dimerization to form 1f
(entries 3À5). While lowering catalyst loadings prevented
dimer formation (entries 6À9), promising results came from
solvent screening experiments in which a marked increase in
the yield of 1b was achieved using protic solvents (entries 6
and 7 vs entries 8 and 9). With methanol as the solvent and
the prototypal Pybox (R = H) as the ligand, the reaction
afforded the desired oxacycle 1b as a single diastereomer in
greater than 90% isolated yield (entry 10). It was also
noteworthy that the reaction could be completed in 2 h at
40 °C and rigorous exclusion of oxygen was unnecessary.
Table 2 illustrates the impact of additional reaction para-
meters on the course of the reductive cyclization of 1a.
Control experiments revealed all components of the catalyst
system (Ni/Pybox and Zn) to be indispensable to the reaction
(entries 2À4). Replacement of NiCl2•DME with other nickel
or palladium salts led to no or negligible reaction (entries
5À7). Similarly, the use of zinc as the reductant was also
found to be critical; the reaction was ineffective with Mn or
Et2Zn (entries 8 and 9). Finally, subjecting 1a to the Ni-
catalyzed conditions7a known to promote a radical cyclization
resulted in the formation of a complex mixture of products,
from which 1b was obtained only in 12% yield along with 1c
and 1d in 30% and 45% yield, respectively (entry 10).
Table 1. Transition-Metal-Catalyzed Reductive Cyclization of
β-Alkoxyacrylate 1aa
conversionb
entry
1
conditions
1b:1c:1d:1e:1f
3 mol % Pd(PPh3)4
95%
20:27:27:26:0
99%
3 equiv Zn, DMA, 40 °C, 4 h
15 mol % NiCl2•6H2O, 140 mol % pyridine
2
2.3 equiv Zn, THF, 60 °C, 24 h
20 mol % NiCl2•DME, 25 mol % bipy
6 equiv Zn, DMA, 25 °C, 30 h
19:31:36:14:0
99%
3
43:11:25:0:21
99%
4
20 mol % NiCl2•DME, 25 mol % terpy
6 equiv Zn, DMA, 25 °C, 22 h
33:8:22:0:37
99%
5
20 mol % NiCl2•DME, 25 mol % iPr-Pybox
6 equiv Zn, DMA, 25 °C, 46 h
53:23:10:0:14
91%
6
5 mol % NiCl2•DME, 6 mol % iPr-Pybox
3 equiv Zn, DMA, 25 °C, 24 h
33:30:37:0:0
99%
7
5 mol % NiCl2•DME, 6 mol % iPr-Pybox
3 equiv Zn, THF, 25 °C, 12 h
54:18:27:0:0
70%
Table 2. Effects of Reaction Parameters on the Efficiency of the
Reductive Cyclization of 1a
8
5 mol % NiCl2•DME, 6 mol % iPr-Pybox
3 equiv Zn, H2O, 25 °C, 35 h
87:13:0:0:0
99%
9
5 mol % NiCl2•DME, 6 mol % iPr-Pybox
3 equiv Zn, CH3OH, 25 °C, 4 h
91:9:0:0:0
99%
10
5 mol % NiCl2•DME, 6 mol % Pybox
3 equiv Zn, CH3OH, 25 °C, 20 h
93:6:0:0:0
a All reactions were carried out in 0.2 M concentration. b Conversion
and product ratios were determined by 1H NMR analysis of the crude
reaction mixtures.
entry
variation from “standard” conditions
none
yield (%)a
1
>90
<2
<2
nr
2
no NiCl2•DME
no Pybox
3
4
no Zn
5
NiCl2 instead of NiCl2•DME
Ni(acac)2 instead of NiCl2•DME
PdCl2(MeCN)2 instead of NiCl2•DME
Mn instead of Zn
nr
6
nr
7
<1
nr
8
9b
10c
Et2Zn instead of Zn
<2
12
β-alkoxyacrylate 1a, a transformation demonstrated for its
exceptional utility in the syntheses of numerous oxacyclic
natural products (Table 1).8 Thus, a series of catalysts were
tested for the reaction of 1a under reductive conditions.
While Pd(PPh3)4 did induce the cyclization of 1a to give
oxacycle 1b, there were generated substantial amounts of
byproducts presumably through simple reduction (1c), ring-
opening (1d), and β-hydrogen elimination (1e) (entry 1).
Similar mixtures of products were formed under the nickel
catalysis known to be capable of activating alkyl halides
Ni(acac)2/Et2Zn instead of NiCl2•DME/Zn
a Determined by 1H NMR. b THF solvent. c The reaction was carried
out in THF with 2 mol % Ni(acac)2 and 2 equiv of Et2Zn at À78 °C as
described in ref 7a.
With the established standard conditions, the scope of the
reaction was probed with an assortment of substrates. As
summarized in Table 3, a variety of unsaturated alkyl halides
underwent reductive cyclization under the nickel-catalyzed
conditions furnishing five- and six-membered oxa- (entries
1À7), carbo- (entries 8À10), and azacyclic (entries 11À13)
products in excellent yields. In most cases, simple reduction
products were formed in less than 5% yields. The reaction
(8) (a) Lee, E. Pure Appl. Chem. 2005, 77, 2073. (b) Lee, E.; Tae, J. S.;
Lee, C.; Park, C. M. Tetrahedron Lett. 1993, 34, 4831.
(9) Sustmann, R.; Hopp, P.; Holl, P. Tetrahedron Lett. 1989, 30, 689.
Org. Lett., Vol. 13, No. 8, 2011
2051

conditions were compatible with a broad range of functional
groups such as esters, ethers, sulfones, acetals, amides, and
sulfonamides. In general, iodo substrates were cyclized more
efficiently than bromides providing higher yields in shorter
reaction times (entries 1, 3, and 8 vs entries 2, 4, and 9),
whereas the corresponding chloride, tosylate, and mesylate
substrates did not react. Interestingly, secondary iodide 5a
reacted more rapidly than the primary iodide 1a (entry 5).
With respect to the unsaturation, both alkenes and alkynes of
varying electronic nature participated well in the reaction.
On the basis of the findings thus far garnered from our
studies, a free radical mechanism is proposed for the Ni-
catalyzed cyclization (Scheme 1). After reduction from the
Ni(II) precatalyst salt, the resulting Ni(0) complex brings
about homolysis of the CÀI bond of 1a to give the carbon-
centered radical 1g through a single electron transfer or direct
iodine abstraction process.10 While 1g enters on the course of
6-exo-trig addition and subsequent reduction to yield 1b, the
active Ni(0) species may be regenerated through reduction
mediated by zinc. This free radical mechanism, rather than a
two-electron pathway involving a carbonÀmetal σ-complex, is
more consistent with the enhanced reactivity of the secondary
halide substrate and the 2,5- and 2,6-cis-diastereoselectivity in
the formation of 1b and 3b.11
Table 3. Ni-Catalyzed Reductive Cyclization of Organohalidesa
Scheme 1. Proposed Mechanism for Ni-Catalyzed Cyclization
The radical mechanism operative in the present nickel
catalysis permits the cyclization reaction to be conducted in
combination with additional CÀC bond formation (eq 1).
Under the standard conditions in the presence of 10 equiv of
methyl acrylate, 12a was transformed into 12c in 81% yield via
tandem intra- and intermolecular addition, a result mirroring
that from the protocol using an organotin hydride.12 In sharp
contrast to alkyl halides, alkenyl substrates, however, dis-
played a differential mode of reactivity. As shown in eq 2,
only clean reduction took place in the reaction of a 3:1 (E/Z)
mixture of iodide 14a under the same conditions,13 suggesting
(10) (a) Elson, I. H.; Morrell, D. G.; Kochi, J. K. J. Organomet.
Chem. 1975, 84, C7. (b) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351. (c)
Kochi, J. K. Organometallic Mechanisms and Catalysis; Academic Press:
New York, 1978; Chapter 7, pp 138À183.
a All reactions were carried out in methanol (0.2 M) at 40 °C in the
presence of 5 mol % NiCl2•DME, 6 mol % Pybox, and 3 equiv of Zn
powder. b Isolated yields. c A 1:1 diastereomeric mixture was employed
as the reactant. d dr = 58:42. e dr = 52:48. f The simple deiodination
product was obtained in 10% yield.
(11) For discussion on the exclusive cis-stereoselectivity observed in
the radical cyclization of 1aÀ4a, see ref 8b.
(12) For a similar tandem radical addition reaction using tributyltin
hydride, see: Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303.
2052
Org. Lett., Vol. 13, No. 8, 2011

the existence of a mechanistic crossover. It is surmised that the
low valent nickel complex in this case did not prompt homo-
lytic cleavage of the CÀI bond, but instead formed a CÀNi σ-
bond via oxidative addition, possibly due to the instability of
the alkenyl radical in comparison with alkyl radicals. Then,
protonation of the CÀNi bond would generate the reductive
deiodination product 1e.14
halides with an effectiveness comparable or superior to
that of organotin hydride conditions without the necessity
ofslow addition. Inadditiontothe remarkableoperational
simplicity, the high functional group tolerance is also a
noteworthy feature of the present method. Current efforts
are aimed at exploring the full potential of the reaction,
including the expansion of the scope of both substrates and
reductantsandapplicationsincomplex moleculesynthesis.
Acknowledgment. This work was supported by the
BRL program of Korea Research Foundation. We thank
Seoul National University for startup research fund and
Korean Student Aids for a graduate fellowship to H.K.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have developed a mild and convenient
nickel-catalyzed method for radical cyclization. Using zinc
as the reductant in methanol, the Ni/Pybox catalyst effi-
ciently promotes reductive cyclization of various alkyl
(14) The reduction in an aprotic solvent required a longer reaction
time; the reaction of 14a (3:1 = E/Z) in DMA for 40 h resulted in the
formation of 1e in 67% yield with a 29% recovery of 14a as a 1:3 (E/Z)
mixture. No reaction occurred with (Z)-14a.
(13) The same reaction with a 1:14 (E/Z) mixture of 14a took 7 h to
give 1e in 92% yield.
Org. Lett., Vol. 13, No. 8, 2011
2053