Nickel-catalyzed synthesis of acrylamides from α-olefins and isocyanates

Article abstract of DOI:10.1021/ol063111x

(Chemical Equation Presented) The nickel(0)-catalyzed coupling of α-olefins and isocyanates proceeds in the presence of the N-heterocyclic carbene ligand IPr to provide α,β-unsaturated amides. Carbon-carbon bond formation occurs preferentially at the 2-po

Full text of DOI:10.1021/ol063111x

ORGANIC
LETTERS
2007
Vol. 9, No. 5
875-878
Nickel-Catalyzed Synthesis of
Acrylamides from
Isocyanates
r-Olefins and
Kristin D. Schleicher and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
tfj@mit.edu
Received December 22, 2006
ABSTRACT
The nickel(0)-catalyzed coupling of
-unsaturated amides. Carbon carbon bond formation occurs preferentially at the 2-position of the olefin. The N-tert-butyl amide products
can be converted to the corresponding primary amides under acidic conditions.
r-olefins and isocyanates proceeds in the presence of the N-heterocyclic carbene ligand IPr to provide
r
,
â
−
A major goal of organic chemistry is the elaboration of
molecular complexity from simple, inexpensive precursors.
Catalytic reactions that effect selective carbon-carbon bond
formation facilitate this aim with economy of operations1
and materials.2
with a greater variety of substitution patterns of the polymer
backbone and avoid the formation of byproducts such as
chloride salts.4
Several nickel(0)-mediated reactions of isocyanates have
been described in the literature. Much of the seminal
investigation in this area was done by Hoberg, who first
reported the stoichiometric5a and catalytic5c coupling reactions
of phenyl isocyanate and ethylene on nickel(0) with trialkyl-
phosphine ligands to give N-phenylacrylamide. Hoberg
proposed that the reaction proceeds via an azanickelacyclo-
pentanone intermediate, which then undergoes â-hydrogen
elimination (Scheme 1).
Methodology for the selective coupling of R-olefins and
isocyanates to provide acrylamides has potential applications
in the field of polymer science. Poly(N-alkylacrylamide)s
and poly(N-alkylmethacrylamide)s have been extensively
studied for their properties as temperature-sensitive aqueous
microgels.3 The monomers are commonly prepared by
reaction of (meth)acryloyl chloride with the corresponding
amine. By comparison, direct synthesis of these unsaturated
amides from alkenes and isocyanates would afford monomers
Other R-olefins react with phenyl isocyanate with nickel(0)
and phosphine ligands;5b,d-h the major product is the trans-
(4) Beak has also reported regioselective â′-lithiation and alkylation of
R,â-unsaturated amides: Beak, P.; Kempf, D. J.; Wilson, K. D. J. Am. Chem.
Soc. 1985, 107, 4745.
(1) (a) Wender, P. A.; Bi, F. C.; Gamber, G. G.; Gosselin, F.; Hubbard,
R. D.; Scanio, M. J. C.; Sun, R.; Williams, T. J.; Zhang, L. Pure Appl.
Chem. 2002, 74, 25. (b) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem.
Ind. (London) 1997, 765. (c) Wender, P. A.; Miller, B. L. In Organic
Synthesis: Theory and Applications; Huldicky, T., Ed.; JAI Press: Green-
wich, 1993; Vol. 2, p 27.
(5) (a) Hoberg, H.; Su¨mmermann, K.; Milchereit, A. Angew. Chem., Int.
Ed. Engl. 1985, 24, 325. (b) Hoberg, H.; Su¨mmermann, K.; Milchereit, A.
J. Organomet. Chem. 1985, 288, 237. (c) Hoberg, H.; Hernandez, E. J.
Chem. Soc., Chem. Commun. 1986, 544. (d) Hoberg, H.; Hernandez, E. J.
Organomet. Chem. 1986, 311, 307. (e) Hernandez, E.; Hoberg, H. J.
Organomet. Chem. 1987, 328, 403. (f) Hoberg, H.; Su¨mmermann, K.;
Hernandez, E.; Ruppin, C.; Guhl, D. (g) Hoberg, H. J. Organomet. Chem.
1988, 358, 507. (h) Hoberg, H.; Guhl, D. J. Organomet. Chem. 1990, 384,
C43.
(2) Trost, B. M. Science 1991, 254, 1471.
(3) (a) Liang, L.; Feng, X.; Liu, J.; Rieke, P. C.; Fryxell, G. E.
Macromolecules 1998, 31, 7845. (b) Pelton, R. AdV. Colloid Interface Sci.
2000, 85, 1. (c) Maeda, Y.; Nakamura, T.; Ikeda, I. Macromolecules 2001,
34, 1391.
10.1021/ol063111x CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/02/2007

In the presence of the NHC ligand IPr, excellent conver-
sions were obtained upon heating (Table 1, entry 2) or
extended reaction time (entry 1) in the nickel-catalyzed
coupling reaction. The NHC ligand gives products with the
opposite sense of regioselectivity compared to those obtained
when phosphine ligands are used (entries 7 and 8). The
observed selectivity for carbon-carbon bond formation at
the 2-position of the R-olefin may be attributed to a
preference for the substituent on the olefin to be oriented
away from the bulky NHC ligand (Figure 1).
Scheme 1. Hoberg’s Proposed Mechanism for the
Nickel-Catalyzed Coupling of Ethylene and Phenyl Isocyanate
disubstituted R,â-unsaturated amide. Formation of a 1,1-
disubstituted acrylamide is observed only in two cases as a
minor product, in 3% and 13% yield. In addition, isocyanates
have been shown to react on nickel(0) with electronically
activated alkenes,6 1,3-dienes,7 allenes,8 and aldehydes.9
Most recently, Louie has demonstrated that an NHC-
nickel(0) system efficiently catalyzes the cycloaddition of
diynes or alkynes and isocyanates to form pyridones.10a
Cycloadditions run with an excess of isocyanate lead to the
formation of pyrimidinediones.10b Free NHC ligands them-
selves are known to rapidly catalyze isocyanate trimerization
to urethanes as well as undergo reversible carboxylation in
the presence of carbon dioxide.11
Recent work in our laboratory has shown that N-hetero-
cyclic carbene (NHC) ligands can provide very high selectiv-
ity for reaction at the 2-position of an R-olefin in the nickel-
catalyzed coupling of aldehydes, R-olefins, and silyl triflates.12
Herein, we report the first example of a nickel(0)-catalyzed
reaction of an alkene and an isocyanate in which carbon-
carbon bond formation occurs selectively at the 2-position
of the R-olefin, yielding N-alkylated acrylamides (Table 1).
Figure 1. Model for observed regioselectivity in nickel-catalyzed
coupling of R-olefin and isocyanate.
A catalyst loading of 10 mol % with respect to the alkene
is optimal for yield, although a slightly higher turnover
number was noted with 5 mol % catalyst and ligand. Control
experiments run in the absence of either Ni(cod)2 or IPr
indicate that both species are necessary for catalysis.
The reaction proceeds smoothly in a variety of solvents
(Table 2). In the absence of solvent, the coupling of 1-octene
Table 2. Solvent Screen for Nickel-Catalyzed Coupling of
R-Olefin and Isocyanatea
Table 1. Optimization of Nickel-Catalyzed Coupling of
R-Olefin and Isocyanatea
entry
R
solvent
yieldb a (%)
yieldb b (%)
1
2
3
4
5
6
7
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Cy
toluene
THF
EtOAc
benzene
ether
71
67
69
64
69
72
37
17
15
15
19
18
18
8
Ni(cod)2 ligand
T
yieldc yieldc
entry ligandb (mol %) (mol %) time (°C) 1a (%) 1b (%)
1
IPr
10
10
5
10
10
5
4 d
rt
61
79
54
0
24
14
15
0
(neat)
(neat)
2d
3d
4
IPr
IPr
IAd
20 h 60
20 h 60
20 h 60
20 h 60
20 h 60
20 h 60
20 h 60
a Standard conditions (see the Supporting Information): Reactions were
run with 0.5 mmol of 1-octene, 1.0 mmol of tert-butyl isocyanate, 0.05
mmol of Ni(cod)2, and 0.05 mmol of IPr under Ar(g) in a sealed tube at 60
°C for 18-24 h. b Isolated yields.
10
10
10
10
10
10
10
10
10
10
5
6
7
8
I-t-Bu
PPh3
PCy2Ph
P(n-Bu)3
0
0
0
0
0
3
0
12
a Reactions were run with 0.5 mmol of 1-octene and 1.0 mmol of
cyclohexyl isocyanate in 2 mL of toluene under Ar(g) in a sealed tube.
b Abbreviations: IPr ) 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene;
IAd ) 1,3-bis(1-adamantyl)imidazol-2-ylidene; I-t-Bu ) 1,3-di-tert-butyl-
imidazol-2-ylidene. c Isolated yields. d Reactions carried out with 0.5 mL
of toluene.
and tert-butyl isocyanate occurs with good yield (entry 6);
however, with cyclohexyl isocyanate a diminished yield is
observed (entry 7), perhaps due to incomplete mixing
associated with the precipitation of solid cyclohexyl amide
products.
876
Org. Lett., Vol. 9, No. 5, 2007

the aromatic ring (entries 7 and 8). The catalytic reaction
appears to be selective for monosubstituted olefins (entries
9 and 10). In other experiments, 1,1-disubstituted, cis-, and
trans-olefins react poorly or not at all.13 Furthermore, esters
and trialkylsilyl-protected alcohols are well tolerated under
the reaction conditions. Hex-5-en-2-one reacts cleanly with
tert-butyl isocyanate, but with cyclohexyl isocyanate the yield
is substantially diminished (entries 13 and 14). Since the
hexenone differs from other linear aliphatic olefins we have
examined only at a position remote to the alkene, we
hypothesize that the enhanced selectivity may be due to
coordination of the carbonyl group to nickel at a selectivity-
determining step in the catalytic cycle.14
Table 3. Scope and Selectivity in Nickel-Catalyzed Coupling
of R-Olefins and Isocyanatesa
The scope of the reaction with respect to the isocyanate
appears to be limited to bulky, electron-rich alkyl isocyanates.
In the reactions of ethyl and benzyl isocyanate with 1-octene,
small amounts of coupling product can be isolated, but the
major products obtained are isocyanate oligomers. Slow or
portionwise addition of isocyanate does little to circumvent
this side reaction, and no improvement in yield is observed
when Ni(cod)2 and IPr are allowed to equilibrate in solution
for 6 h prior to reaction, as done by Louie.10a Phenyl
isocyanate, trichloromethyl isocyanate, and phenyl isocy-
anatoformate all gave no desired product under the reaction
conditions.
Table 4. Deprotection of R,â-Unsaturated Amides
a Standard conditions (see the Supporting Information): Reactions were
run with 0.5 mmol of 1-octene, 1.0 mmol of tert-butyl isocyanate, 0.05
mmol of Ni(cod)2, and 0.05 mmol of IPr in 0.5 mL of toluene under Ar(g)
in a sealed tube at 60 °C for 18-24 h. b Isolated yields. c Reaction was run
using 2 mL of toluene. d Isolated as a mixture of 8b and 8c, with relative
1
ratios determined by H NMR.
In recognition of the prevalence of primary amide motifs
in the natural world, we investigated the possibility of
forming such amides from our initial products. Deprotection
of N-tert-butyl amides requires strongly acidic conditions,
often coupled with heat;15 nevertheless, the reaction has been
successfully utilized in the contexts of natural product
synthesis16 and drug discovery.17 Still, it was unclear whether
1,1-disubstituted acrylamides would emerge unscathed from
the forcing conditions necessary to effect deprotection.
Gratifyingly, we were able to obtain the primary amides from
several of the coupling products after heating in neat
trifluoroacetic acid at reflux overnight (Table 4).
Table 3 illustrates the scope and selectivity of the reaction.
Reactions of aliphatic olefins with branching at the allylic
or homoallylic position proceed in high yields and with
excellent selectivity for carboxamidation at the 2-position
of the olefin. With allylbenzene, a third product is formed
in which the double bond has moved into conjugation with
(6) (a) Hernandez, E.; Hoberg, H. J. Organomet. Chem. 1986, 315, 245.
(b) Hoberg, H.; Hernandez, E.; Guhl, D. J. Organomet. Chem. 1988, 339,
213. (c) Hoberg, H.; Guhl, D. J. Organomet. Chem. 1989, 375, 245. (d)
Hoberg, H.; Nohlen, M. J. Organomet. Chem. 1990, 382, C6. (e) Hoberg,
H.; Guhl, D.; Betz, P. J. Organomet. Chem. 1990, 387, 233. Hoberg, H.;
Nohlen, M. J. Organomet. Chem. 1991, 412, 225.
(7) (a) Hoberg, H.; Hernanadez, E. Angew. Chem., Int. Ed. Engl. 1985,
24, 961. (b) Hernandez, E.; Hoberg, H. J. Organomet. Chem. 1987, 327,
429. (c) Hoberg, H.; Ba¨rhausen, D. J. Organomet. Chem. 1990, 397, C20.
(8) Hoberg, H.; Hernandez, E.; Su¨mmermann, K. J. Organomet. Chem.
1985, 295, C21.
(9) Hoberg, H.; Su¨mmermann, K. J. Organomet. Chem. 1984, 264, 379.
(10) (a) Duong, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004,
126, 11438. (b) Duong, H. A.; Louie, J. Tetrahedron 2006, 62, 7552.
Org. Lett., Vol. 9, No. 5, 2007
877

In summary, we have described a new preparation of
acrylamides via the nickel(0)-IPr-catalyzed reaction of simple
R-olefins and isocyanates. The NHC ligand gives products
with the opposite sense of regioselectivity compared to those
obtained using phosphine additives. Acid treatment converts
the N-tert-butyl products to free amides. In addition to more
conventional synthetic operations, compounds prepared by
this method may find application as novel monomers for
polymer synthesis.
Acknowledgment. This work was supported by the
NIGMS (GM-063755). We are grateful to Ms. Li Li for
obtaining mass spectrometric data for all compounds (MIT
Department of Chemistry Instrumentation Facility, which is
supported in part by the NSF (CHE-9809061 and DBI-
9729592) and the NIH (1S10RR13886-01)).
(11) (a) Duong, H. A.; Tekavec, T. N.; Arif, A. M.; Louie, J. Chem.
Commun. 2004, 1, 112. (b) Duong, H. A.; Cross, M. J.; Louie, J. Org. Lett.
2004, 6, 4679.
(12) Ho, C.-Y.; Jamison, T. F. Angew. Chem., Int. Ed. 2007, 46, 782.
(13) When reacted with cyclohexyl isocyanate, 10 mol % of Ni(cod)2,
and 10 mol % of IPr in toluene in a sealed tube at 60 °C for 18-24 h,
methylenecyclohexane and cyclohexene afforded coupling products in less
than 10% yield. No product was observed with trans-4-octene under
identical conditions.
(14) For related phenomena in coupling reactions of 1,6-enynes, see:
(a) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342. (b)
Moslin, R. M.; Jamison, T. F. Org. Lett. 2006, 8, 455. (c) Moslin, R. M.;
Miller, K. M.; Jamison, T. F. Tetrahedron 2006, 62, 7598.
(15) Lacey, R. N. J. Chem. Soc. 1960, 1633.
(16) Conover, L. H.; Butler, K.; Johnston, J. D.; Korst, J. J.; Woodward,
R. B. J. Am. Chem. Soc. 1962, 84, 3222.
Note Added after ASAP Publication. There was an error
in Scheme 1. The hash marks in two of the reaction arrows
were missing in the version published ASAP February 2,
2007; the corrected version was published ASAP February
5, 2007.
Supporting Information Available: Experimental pro-
cedures and characterization data for all numbered com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Huang, W.; Zhang, P.; Zuckett, J. F.; Wang, L.; Woolfrey, J.; Song,
Y.; Jia, Z. J.; Clizbe, L. A.; Su, T.; Tran, K.; Huang, B.; Wong, P.; Sinha,
U.; Park, G.; Reed, A.; Malinowski, J.; Hollenbach, S. J.; Scarborough, R.
M.; Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2003, 13, 561.
OL063111X
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Org. Lett., Vol. 9, No. 5, 2007