Nickel-catalyzed cycloadditive couplings of enynes and lsocyanates

Article abstract of DOI:10.1021/ol901703t

A mild and general route for preparing dienamides Is described. Nickel imidazolylldene complexes were used to mediate cycloadditlve coupling between enynes and isocyanates. Dienamides were prepared In excellent yields and with good E:Z selectivity. These

Full text of DOI:10.1021/ol901703t

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4168-4171
Nickel-Catalyzed Cycloadditive
Couplings of Enynes and Isocyanates
Brendan R. D’Souza and Janis Louie*
UniVersity of Utah, 315 S. 1400 E, Salt Lake City, Utah 84112
louie@chem.utah.edu
Received July 24, 2009
ABSTRACT
A mild and general route for preparing dienamides is described. Nickel imidazolylidene complexes were used to mediate cycloadditive coupling
between enynes and isocyanates. Dienamides were prepared in excellent yields and with good E:Z selectivity. These dienamides can be
further manipulated through oxidative cyclization methods. When a terminal enyne is employed, cyclization affords a lactam rather than a
dienamide.
A primary interest of our group is the development of
efficient cycloadditions that afford heterocycles and car-
bocycles.1-7 We have found that Ni/NHC complexes ef-
fectively catalyze the cycloaddition of diynes with CO2,2
isocyanates,3 carbonyls,4 and nitriles.5 These reactions afford
pyrones, pyridones, pyrimidinones, pyrans, and pyridines in
high yields. In addition, the same Ni/NHC system also
mediates the rearrangement of vinyl cyclopropanes6 and
cyclopropylen-ynes.7
The efficacy of our Ni/NHC-catalyzed cycloaddition
reactions that couple diynes/isocyanates3 and enynes/carbo-
nyls4 prompted us to investigate the Ni/NHC-catalyzed
cycloaddition of enynes and isocyanates. To date, only one
catalytic system, which utilizes Rh catalysts, effectively
cyclizes an olefin, an alkyne, and an isocyanate. This Rh
catalyst was used to couple an alkenyl-isocyanate with an
alkyne in the synthesis of Lasubine alkaloids.8 Herein, we
report our investigations involving the Ni-catalyzed reactions
between enynes and isocyanates to afford dienamides.
Despite the precedent that enynes and isocyanates were
both viable substrates indiVidually in the Ni-catalyzed
cycloaddition reaction, it was unclear whether they would
react with each other in a productive manner. However,
success in Ni-catalyzed reductive couplings between alkenes
and alkyl-substituted isocyanates9 suggested enynes and
isocyanates would be reactive under Ni-catalyzed cycload-
dition reaction conditions.
Our initial efforts revolved around evaluating a variety
of conditions that would yield an isolable product. As
shown in Table 1, a variety of phosphines and NHCs10
were evaluated as prospective ligands to determine the
potential reactivity between enyne (1a) and cyclohexyl
isocyanate (2a, eq 1). Attention was directed toward
minimizing alkyne cyclotrimerization, a known side
(1) (a) Zhang, K.; Chopade, P. R.; Louie, J. Tetrahedron Lett. 2008,
49, 4306. (b) Zuo, G.; Zhang, K.; Louie, J. Tetrahedron Lett. 2008, 49,
6797
.
(2) (a) Louie, J.; Gibby, J. E.; Farnworth, M. V.; Tekavec, T. N. J. Am.
Chem. Soc. 2002, 124, 15188. (b) Tekavec, T. N.; Arif, A. M.; Louie, J.
Tetrahedron 2004, 60, 7431
(3) (a) Duong, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004,
126, 11438. (b) Duong, H. A.; Louie, J. J. Organomet. Chem. 2005, 690,
5098. (c) Duong, H. A.; Louie, J. Tetrahedron 2006, 62, 7552
(4) (a) Tekavec, T. N.; Louie, J. Org. Lett. 2005, 7, 4037. (b) Tekavec,
T. N.; Louie, J. J. Org. Chem. 2008, 73, 2641
(5) (a) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J. J. Am.
Chem. Soc. 2005, 127, 5030. (b) Tekavec, T. N.; Zuo, G.; Simon, K.; Louie,
.
.
(8) (a) Yu, T. R.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782. (b) Yu,
T. R.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370. (c) Lee, E. E.; Rovis,
T. Org. Lett. 2008, 10, 1231.
.
(9) Scleicher, K. D.; Jamison, T. F. Org. Lett. 2007, 9, 875.
(10) IPr ) 1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene. SIPr )
1,3-bis(2,5-diisopropylphenyl)-4,5-dihydroimidazolin-2-ylidene. IMes ) 1,3-
bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene. ItBu ) 1,3-di-tert-butylimi-
dazol-2-ylidene.
J. J. Org. Chem. 2006, 71, 5834
(6) Zuo, G.; Louie, J. Angew. Chem., Int. Ed. 2004, 43, 2777
(7) Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005, 127, 5798
.
.
.
10.1021/ol901703t CCC: $40.75
Published on Web 08/25/2009
 2009 American Chemical Society

Table 1. Ni-Catalyzed Cycloaddition of Enyne 1 and CyNCO
(2a)a
Table 2. Dienamide Formation from Enyne 1 and Isocyanates
2a-2jc
entry
L
% conversion of 1b
% yield of 3b
1
2
3
4
5
6
7
8
none
P(n-Bu)3
PPh3
P(p-Tol)3
DPPF
BINAP
biphenP(t-Bu)2
ItBu
10
31
17
31
7
nd
ndc
nd
nd
nd
nd
nd
nd
nd
78
80
5
17
14
33
90
100
9
10
11
IMes
SIPr
IPr
a Reaction conditions: 10 mol % Ni(COD)2, 20 mol % L, 0.1 M 1a,
0.11 M 2a, toluene, room temperature, 17 h. b Determined by GC using
naphthalene as an internal standard. c nd ) not detectable by GC.
reaction.11 In general, poor conversions of enyne 1a were
observed when either monodentate or bidentate phosphines
were employed (entries 2-7). A slight increase in the
conversion was observed when the reaction was run with
bulky NHCs such as ItBu and IMes (entries 8 and 9).
However, in all cases (entries 2-9), no detectable coupling
product was observed. In contrast, when bulkier NHC
ligands such as SIPr and IPr were employed, a distinct
coupling product was isolated in good yields (entries 10
and 11). As expected, negligible coupling was observed
when Ni(COD)2 was used in the absence of an additional
donor ligand (entry 1).
Isolation of the major product revealed that cyclization
did indeed occur. Dienamide 3a, rather than a lactam product
that would arise from an additional carbon-nitrogen bond-
forming event (vide infra), was isolated in 70% yield.
The combination of Ni and IPr catalyzed the coupling
of enyne 1a with a variety of isocyanates (Table 2, eq 2).
Alkyl isocyanates reacted smoothly at room temperature
within 1-2 h. Furthermore, these reactions afforded
dienamides in excellent overall yields with good E:Z ratios
(entries 1-3). In contrast, aryl isocyanates reacted more
sluggishly and required slightly more forcing conditions.9
For example, the Ni-catalyzed coupling of enyne 1a and
phenyl isocyanate proceeded at 60 °C while no reaction
occurred at room temperature (entry 4). Nevertheless,
dienamide 3d was isolated in 89% yield. Aryl isocyanates
possessing both electron-donating groups as well as
electron-withdrawing groups were converted to their
respective dienamides in 71-80% yield. Aryl isocyanates
possessing electron-donating groups reacted faster than
a Determined by 1H NMR. b Isolated yields, average of 2 runs. c Reaction
conditions: 1 equiv of 1a 1 equiv of 2.
those possessing electron-withdrawing groups (entries
5-7). Sterically hindered aryl isocyanates such as 2h and
2i were also converted to their respective dienamides,
although under higher reaction temperatures, in excellent
yields of 71% and 80%, respectively (entries 8 and 9).
No reaction was observed when TMS-NCO was employed.
When either E or Z isomers of dienamide 3b were
resubjected to the nucleophilic IPr ligand, no isomerization
was observed. In addition, when the E-isomer of 3b was
resubjected to the reaction conditions, no isomerization to
the Z-dienamide was observed. However, when the Z-isomer
(11) (a) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901. (b) Tsuda,
T.; Morikawa, S.; Sumiya, R.; Saegusa, T. J. Org. Chem. 1988, 53, 3140.
Org. Lett., Vol. 11, No. 18, 2009
4169

of 3b was resubjected to the reaction conditions, a mixture
of E- and Z-products was obtained (eq 4). Thus, the
Z-dienamides are most likely the initial coupling product and
undergo a Ni(0)-mediated interconversion to the more stable
E-isomer over the course of the reaction.
Table 3. Substrate Scope Using Enynes 1b-1e and Isocyanates
2a and 2bg
A variety of enynes were also successfully converted
to their respective dienamide products (Table 3). A
significant increase in dienamide yield (3j and 3k) was
observed when enyne 1b was used as a coupling partner
in lieu of enyne 1a despite the similarity in the backbones
of these two substrates (Table 3, entries 1 and 2 versus
Table 2, entries 1 and 4, respectively). Enyne 1c afforded
a five-membered cyclic dienamide in good yield (entries
3 and 4). Dienamides having a bicyclic ring system with
a nitrogen atom on the bridgehead were also prepared in
good yields (entries 5 and 6). Somewhat surprisingly,
although enyne 1e, which possesses a bulky trimethylsilyl
group on the alkyne, has been used as a substrate in other
Ni-catalyzed cycloddition reactions,2b this enyne under-
goes cycloisomerization12 exclusively and does not afford
a dienamide product (entries 7).
Two possible mechanisms for dienamide formation are
depicted in Scheme 1.13 In pathway A, intramolecular
initial oxidiative coupling of the enyne and subsequent
insertion of the isocyanate leads to seven-membered
intermediate 5. Rather than undergoing C-N bond-
forming reductive elimination,14 ꢀ-hydride elimination
occurs resulting in 6. Facile reductive elimination from 6
would afford the Z-dienamide product. Alternatively,
nickelacycle 5 can arise from oxidative coupling of the
alkyne and the isocyanate to produce 7 prior to insertion
of the pendant olefin (pathway B, Scheme 1).12
a Determined by 1H NMR. b Isolated yields, average of 2 runs. c rt, 4 h.
d rt, 6 h. e 80 °C, 4 h. f 80 °C, 3 h. g Reaction conditions: 1 equiv of enyne,
1 equiv of isocyanate, 0.1 M toluene.
Interestingly, when enyne 1f was subjected to the coupling
conditions with either isocyanate 2a or 2b, dienamide
formation did not occur. Instead, a cyclic amide was formed
as the sole product, albeit in low yields (eq 5)
Lactams 10 and 11 likely arise from C-N bond-forming
reductive elimination from a seven-membered nickelacycle such
as 5b (Scheme 2). Insertion of the isocyanate into the Ni-Csp3
bond, rather than the Ni-Csp2 bond in 4, would lead to the
formation of 5b (mechanism A, Scheme 1). Alternatively,
nickelacycle 5b may arise from initial oxidative coupling
between the olefin of the enyne and the isocyante followed by
(12) Tekavac, T.; Louie, J. Tetrahedron 2008, 64, 6870.
(13) For an insightful discussion on the mechanism of the Rh catalyzed
couplings of alkenes, alkynes, and isocyanates, see ref 8.
4170
Org. Lett., Vol. 11, No. 18, 2009

Scheme 1
.
Possible Mechanisms for Dienamide Formation
Scheme 2. Possible Mechanism for Lactam Formation
the bromo-substituted iminoether 12 in 53% isolated yield.
Furthermore, when 3b was subjected to I2 in lieu of NBS,
higher yields were obtained of the halo-substituted imino-
ether; that is, the iodo-substituted iminoether 13 was obtained
in 90% isolated yield.
We have demonstrated that reductive coupling of enynes
and isocyanates can successfully take place using Ni(COD)2
and IPr ligand system to afford dienamides in good to
excellent yields. This catalyst system can be used to prepare
dienamides that contain five- or six-membered rings.
insertion of the pendant alkyne (mechanism B, Scheme 1).
Formation of 5b may be favored over 5a when the steric
interaction of the alkyne substituent and the ligand (i.e., IPr) is
small. In fact, we have observed this type of sterically driven
selectivity in other Ni-catalyzed cycloaddition chemistry.2b,4
Acknowledgment. We gratefully acknowledge the Cam-
ille and Henry Drefus Foundation and the NIGMS for support
of this research.
Supporting Information Available: 1H NMR, 13C NMR
and IR data for all compounds in PDF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901703T
Dienamides can be conveniently converted to iminoet-
(14) Koo, K.; Hillhouse, G. Organometallics 1995, 14, 4421.
hers.15 For example, the reaction of 3b with NBS afforded
(15) Wang, C.; Lu, J.; Mao, G.; Xi, Z. J. Org. Chem. 2005, 70, 5150.
Org. Lett., Vol. 11, No. 18, 2009
4171