Regioselective hydrocarbamoylation of 1-alkenes

Article abstract of DOI:10.1246/cl.2012.298

Nickel/Lewis acid cooperative catalysis derived from [Ni(cod)₂], AlEt₃, and N-heterocyclic carbene (NHC) effects highly regioselective hydrocarbamoylation of 1-alkenes. Variously substituted formamides and 1-alkenes can be employed to give a range of linear alkanamides regioselectively.

Full text of DOI:10.1246/cl.2012.298

doi:10.1246/cl.2012.298
298
Published on the web February 25, 2012
Regioselective Hydrocarbamoylation of 1-Alkenes
Yosuke Miyazaki,1 Yuuya Yamada,1 Yoshiaki Nakao,*1 and Tamejiro Hiyama*2
1Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510
2Research & Development Initiative, Chuo University, Bunkyo-ku, Tokyo 112-8551
(Received November 29, 2011; CL-111150; E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp)
Nickel/Lewis acid cooperative catalysis derived from
Table 1. Hydrocarbamoylation of 1-tridecenea
[Ni(cod)2] (5 mol %)
ligand (5–10 mol %)
LA (20 mol %)
solvent
[Ni(cod)2], AlEt3, and N-heterocyclic carbene (NHC) effects
highly regioselective hydrocarbamoylation of 1-alkenes. Vari-
ously substituted formamides and 1-alkenes can be employed to
give a range of linear alkanamides regioselectively.
O
O
+
Me2N
1a
H
10
Me2N
10
2a
3aa
R = 2,4,6-Me3–C6H2: IMes
2,6-i-Pr2–C6H3: IPr
t-Bu: ItBu
N
N
R
R
Preparation of amides under neutral conditions without the
need for toxic reagents and chemical wastes is still challenging
in synthetic organic chemistry,1 although a number of methods
for the synthesis of amides are available.2 Aminocarbonylation
of unsaturated C-C bonds would offer an alternative and waste-
free access to amides.3 Insertion of unsaturated compounds into
C-H bonds of formamides, namely, hydrocarbamoylation
reaction, would allow such transformations without the need
for toxic carbon monoxide. For example, ruthenium-catalyzed
hydrocarbamoylation reactions of alkenes have been reported,4
whereas we5 and others6 have recently developed the reaction
across alkynes,5,6 1,3-dienes,5 and norbornene6b catalyzed by
such transition metals as nickel,7 palladium, and rhodium. The
ruthenium-catalyzed reactions across alkenes, however, require
either harsh reaction conditions,4a,4b high-pressure carbon mon-
oxide,4a or a pyridyl group as a directing group.4c In addition,
regioselectivity of these ruthenium-catalyzed reactions is re-
portedly modest particularly with simple aliphatic 1-alkenes
such as 1-hexene, giving linear alkanamides contaminated with a
significant amount of branched amides as a minor component.4
The regioselective hydrocarbamoylation of alkenes can be
achieved via a radical pathway.8 However, the addition reaction
competes with alkylation of N-substituents. The hydrocarba-
moylation of 1-alkenes with high linear selectivity and broad
scope of substrates is highly desired as a novel transformation
potentially applicable to industrial production of bulk chemicals
without use of toxic carbon monoxide. Given the importance
of such “anti-Markovnikov” functionalization of 1-alkenes,9 we
report herein that nickel/Lewis acid catalysis effects exclusively
linear selective hydrocarbamoylation of 1-alkenes.
Our initial attempt to establish the regioselective hydro-
carbamoylation was commenced with the reaction of DMF (1a)
with 1-tridecene (2a) in the presence of [Ni(cod)2] (5 mol %)
various ligands, and 20 mol % of AlMe3 as a cocatalayst in
toluene at 130 °C (Table 1). Bulky phosphorus ligands such as
P(i-Pr)3 and P(t-Bu)3, which were effective for the intramolec-
ular hydrocarbamoylation of alkenes,5 gave the corresponding
linear alkanamide 3aa exclusively albeit in low yield (Entries 1
and 2). Encouraged by the observed excellent regioselectivity,
which was never achieved with the reported ruthenium catalysis
with such simple aliphatic 1-alkenes as 2a, we further explored
other ligands to improve the yield of 3aa and found that NHC
ligands were highly effective (Entries 3-6). Particularly, IAd
was found optimum to give 3aa in 62% yield after 2 h (Entry 6).
1-adamantyl: IAd
Temp
/°C
Yield of
3aa/%b
Entry Ligand
Solvent LA
toluene AlMe3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
P(i-Pr)3
P(t-Bu)3 toluene
130
130
130
130
130
130
130
130
130
130
130
100
100
100
8
15
36
19
44
62
58
48
46
2
19
81
92 (84)c
91
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
IMes
IPr
toluene
toluene
toluene
toluene
CPME
ItBu
IAd
IAd
IAd
IAd
IAd
IAd
IAd
IAd
IAd
dioxane AlMe3
THF
NMP
DMF
toluene
toluene
toluene
AlMe3
AlMe3
AlMe3
AlMe3
AlEt3
Al(oct)3
aThe reactions were carried out using 1a (0.50 mmol), 2a (0.75
mmol), n-C11H24 (internal standard, 125 ¯mol), [Ni(cod)2]
(5.0 mol %), ligand (10 mol % for phosphines and 5.0 mol %
for NHC), and Lewis acid (LA) (20 mol %) in a solvent
(0.50 mL). bDetermined by GC based on 1a as the limiting
c
reagent. Isolated yield on a 1.0 mmol scale run for 3 h.
With IAd as a ligand, we next examined solvents for the reaction
(Entries 7-11). Generally, nonpolar solvents were found to give
yields of 3aa better than with polar solvents, and, thus, the use
of 1a as a solvent was not effective (Entry 11). At this stage,
we noted the formation of a significant amount of insoluble
precipitates, which were tentatively ascribed to decomposition
of either of the metal catalysts. Because this could cause the
observed modest yields of 3aa, we simply lowered the reaction
temperature to 100 °C to find that the formation of the
precipitates was slowed and the yield of 3aa was improved
(Entry 12). Whereas the reaction run at lower temperature
slowed the reaction, the use of AlEt3 and Al(oct)3 instead of
AlMe3 showed improved homogeneity of the reaction mixture
without the formation of such precipitates, and the yield of 3aa
was further increased (Entries 13 and 14). Under the reaction
conditions thus optimized, alkanamide 3aa was isolated in 84%
yield from a reaction run on a 1.0 mmol-scale (Entry 13). Again,
Chem. Lett. 2012, 41, 298-300
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

299
Table 2. Hydrocarbamoylation of 1-alkenes catalyzed by Ni/
AlEt3
no trace amount of branched alkanamides was obtained under
the preparative reaction conditions.
[Ni(cod)2] (5 mol %)
IAd (5 mol %)
AlEt3 (20 mol %)
We next investigated the reaction of other formamides with
2a under the optimized reaction conditions (Table 2). Various N-
alkyl-substituted formamides gave the corresponding alkan-
amides in good yields (Entries 1-6), whereas the reaction of N-
aryl-substituted one (1h) was sluggish (Entry 8). Notably,
optically active formamide (R)- and (S)-1e gave enantiomeri-
cally pure alkanamide (R)- and (S)-3ea without any loss of
stereochemical information (Entries 4 and 5). Formamides
derived from primary amines did not give adducts at all under
these reaction conditions due presumably to the presence of
acidic hydrogen incompatible with the Lewis acid catalyst. The
hydrocarbamoylation of other 1-alkenes also proceeded to give
alkanamides having a range of functionalities including siloxy,
alkoxycarbonyl, internal double bond, and silyl groups (Entries
9-14). All the reactions showed exclusive linear selectivity
except for the reaction across styrene (2h), which gave a mixture
of linear and branched alkanamides (Entry 15). The formation of
a branched adduct in this particular case can be ascribed to the
contribution of a stable benzylnickel intermediate in a catalytic
cycle (vide infra).9,10 On the other hand, the addition across 1,1-
or 1,2-disubstituted alkenes was unsuccessful.
O
O
R1
R1
R3
+
N
R2
H
N
R2
R3
toluene, 100 °C
2 (1.5 mmol)
3
1 (1.0 mmol)
N
N
IAd
R1, R2 = Me, Me (1a); Et, Et (1b); Me, Bn (1c); Bn, Bn (1d);
1-phenylethyl, Bn (1e); –(CH2)5– (1f); –(CH2)2O(CH2)2– (1g); Me, Ph (1h)
R3 = C11H23 (2a); C6H13 (2b); (CH2)3OSiMe2t-Bu (2c); (CH2)3OPiv (2d);
cyclohex-3-en-1-yl (2e); t-Bu (2f); SiMe3 (2g); Ph (2h)
Product
O
Yield/%a
69
Entry
1
2
1
Time/h
12
1b 2a
Et2N
Bn
10
3ba
O
2
3
1c 2a
1d 2a
9
9
68
75
N
10
3ca
Me
O
Bn2N
10
10
3da
O
The reaction path is understood in terms of the catalytic cycle
shown in Scheme 1. Formamides coordinating to the Lewis acid
catalyst through their carbonyl oxygen would undergo the
oxidative addition of the C(sp2)-H bond to a nickel(0) species
to give nickel hydride B via the formation of ©2-formamide-
nickel intermediate A (Scheme 1).11 Alkenes coordinate to the
nickel center of B to form C, which undergoes migratory
insertion to give alkylnickel D. Reductive elimination followed
by ligand exchange reactions afford alkanamides and regenerate
A to complete the catalytic cycle. The exclusive formation of the
linear alkanamides results from regioselective migratory inser-
tion, which favors sterically less hindered primary alkylnickel D
rather than a secondary alkylnickel species. With vinylarenes, the
corresponding sec-alkylnickel species could be stabilized by the
aryl group10 to give branched adducts to some extent (Entry 15 of
Table 2). The reaction of 1d-d with 2g gave 3dg with 4% and
26% deuteration at the methylenes ¡ and ¢ to the carbonyl group
Bn
Ph
4
5
(R)-1eb 2a
(S)-1eb 2a
9
9
78b
81b
N
(R)- or (S)-3ea
O
6
1f
2a
9
65
N
10
3fa
O
7
1g 2a
1h 2a
1a 2b
6
9
6
53
13
81
N
10
O
3ga
O
8c
9
Me
N
10
3ha
Ph
O
Me2N
O
5
3ab
OSiMe2t-Bu
3
10c
11c
1a 2c
1a 2d
6
6
77
59
1
Me2N
(eq 1). The yield of 3dg-d was 47% as estimated by H NMR.
3ac
3ad
Unreacted 1d-d and 2g showed loss of deuterium and incorpo-
ration of deuterium, respectively. These results show that the
elemental steps except for the reductive elimination in the
proposed catalytic cycle are reversible. Partial incorporation of
deuterium at the ¢-position of the silyl group in 3dg and
recovered 2g can also be understood in terms of the reversible
hydronickelation process to give a sec-alkylnickel species, which
is reluctant to undergo the final reductive elimination. The use of
highly bulky carbene ligands would be crucial to promote the
reductive elimination from linear alkylnickel intermediate D.
In summary, we have developed regioselective hydrocarba-
moylation of alkenes by nickel/Lewis acid cooperative catal-
ysis.12 The exceptionally high regioselectivity achieved with the
present catalytic system would be highly useful as a method to
access variously functionalized amides as well as a novel
transformation of anti-Markovnikov selective functionalization
of alkenes. Further efforts will be paid to understand the
mechanism of the cooperative catalysis and its further applica-
tion to functionalization of unreactive bonds.13
O
O
3
t-Bu
Me2N
O
O
O
12d
13d
14
1a 2e
1d 2f
1d 2g
6
6
90
59
83
Me2N
3ae
O
Bn2N
Bn2N
t-Bu
3df
19
SiMe3
3dg
O
15
1d 2h
19
70e
Bn2N
Ph
3dh
b
c
aIsolated yields based on 1. >95% ee. Run with [Ni(cod)2]
d
(10 mol %), IAd (10 mol %), and AlEt3 (40 mol %). Run with
3.0 mmol of 2. 16% of a regioisomer was also obtained.
e
Chem. Lett. 2012, 41, 298-300
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

300
O
H
Al–
S. Chang, J. Am. Chem. Soc. 2005, 127, 16046. c) J. W.
Bode, R. M. Fox, K. D. Baucom, Angew. Chem., Int. Ed.
2006, 45, 1248. d) M. P. Cassidy, J. Raushel, V. V. Fokin,
Angew. Chem., Int. Ed. 2006, 45, 3154. e) W.-K. Chan,
C.-M. Ho, M.-K. Wong, C.-M. Che, J. Am. Chem. Soc. 2006,
128, 14796. f) C. Gunanathan, Y. Ben-David, D. Milstein,
Science 2007, 317, 790.
N+
Ni
3
L
A
1
2
a) R. C. Larock, Comprehensive Organic Transformations:
A Guide to Functional Group Preparations, 2nd ed., Wiley-
VCH, New York, 1999. b) C. L. Allen, J. M. J. Williams,
Chem. Soc. Rev. 2011, 40, 3405.
Modern Carbonylation Methods, ed. by L. Kollár, Wiley-
VCH, Weinheim, 2008.
a) Y. Tsuji, S. Yoshii, T. Ohsumi, T. Kondo, Y. Watanabe,
J. Organomet. Chem. 1987, 331, 379. b) T. Kondo, T.
Okada, T.-a. Mitsudo, Organometallics 1999, 18, 4123. c) S.
Ko, H. Han, S. Chang, Org. Lett. 2003, 5, 2687.
Y. Nakao, H. Idei, K. S. Kanyiva, T. Hiyama, J. Am. Chem.
Soc. 2009, 131, 5070.
a) Y. Kobayashi, H. Kamisaki, K. Yanada, R. Yanada, Y.
Takemoto, Tetrahedron Lett. 2005, 46, 7549. b) T. Fujihara,
Y. Katafuchi, T. Iwai, J. Terao, Y. Tsuji, J. Am. Chem. Soc.
2010, 132, 2094.
Al–
Al–
O
O
H
L
H
L = IAd
N+ Ni
N+ Ni
R2
Al = AlEt3
L
D
B
3
4
2
Al–
O
H
N+ Ni
L
5
6
R
C
Scheme 1. Plausible catalytic cycle.
O
7
For nickel-catalyzed arylation of formamides, see: J. Ju, M.
Jeong, J. Moon, H. M. Jung, S. Lee, Org. Lett. 2007, 9,
4615.
For a review, see: H.-H. Vogel, Synthesis 1970, 99.
M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew. Chem., Int.
Ed. 2004, 43, 3368.
[Ni(cod)2] (5 mol %)
IAd (5 mol %)
AlEt3 (20 mol %)
Bn2N
D
26% D
O
1d-d (0.30 mmol)
+
2g (0.45 mmol)
ð1Þ
Bn2N
SiMe3
8
9
C6D6, 100 °C, 3 h
4% D
3dg-d, 47% (NMR)
10 a) A. L. Casalnuovo, T. V. RajanBabu, T. A. Ayers, T. H.
Warren, J. Am. Chem. Soc. 1994, 116, 9869. b) Y. Nakao, N.
Kashihara, K. S. Kanyiva, T. Hiyama, Angew. Chem., Int.
Ed. 2010, 49, 4451.
recovered:
22% D
4% D
O
+
SiMe3
Bn2N
H/D
11 S. Ogoshi, H. Ikeda, H. Kurosawa, Angew. Chem., Int. Ed.
2007, 46, 4930.
3% D
2g, 48% (NMR)
40% D
1d, 41% (NMR)
12 For our previous reports on nickel/Lewis acid-catalyzed
functionalization of C-H bonds, see: a) Y. Nakao, K. S.
Kanyiva, T. Hiyama, J. Am. Chem. Soc. 2008, 130, 2448.
b) K. S. Kanyiva, F. Löbermann, Y. Nakao, T. Hiyama,
Tetrahedron Lett. 2009, 50, 3463. c) Y. Nakao, H. Idei, K. S.
Kanyiva, T. Hiyama, J. Am. Chem. Soc. 2009, 131, 15996.
d) Y. Nakao, Y. Yamada, N. Kashihara, T. Hiyama, J. Am.
Chem. Soc. 2010, 132, 13666.
This work has been supported financially by a Grant-in-Aid
for Scientific Research on Innovative Areas “Molecular Activa-
tion Directed toward Straightforward Synthesis” (to Y.N.,
No. 22105003) and Scientific Research (S) (to T.H.,
No. 21225005) from MEXT and JSPS, respectively.
References and Notes
13 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
1
For some exceptional examples, see: a) T. Naota, S.-I.
Murahashi, Synlett 1991, 693. b) S. H. Cho, E. J. Yoo, I. Bae,
Chem. Lett. 2012, 41, 298-300
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/