A serendipitous discovery: Nickel catalyst for the cycloaddition of diynes with unactivated nitriles

Article abstract of DOI:10.1002/anie.201104475

In the nick of time! The catalytic combination of [Ni(cod)₂] (cod=1,5-cyclooctadiene) and the ligand 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos) was used to access pyridines (see scheme). The reaction proceeds under ambient cond

Full text of DOI:10.1002/anie.201104475

Communications
DOI: 10.1002/anie.201104475
Heterocycles
A Serendipitous Discovery: Nickel Catalyst for the Cycloaddition of
Diynes with Unactivated Nitriles**
Puneet Kumar, Simon Prescher, and Janis Louie*
A variety of transition-metal complexes (i.e., Co, Ru, Rh, Ni,
and Fe) catalyze the cycloaddition of alkynes and nitriles to
form pyridines.[1–7] Most of the catalysts generate pyridines
through a mechanism that involves initial oxidative coupling
of the alkynes and then subsequent insertion of the nitrile
(i.e., formation of A, Scheme 1).[4d,8] In contrast, nickel-
ketenes.[11] In our efforts to expand this chemistry to
ketenimines, we serendipitously discovered that the combi-
nation of Ni0 and Xantphos (Xantphos = 4,5-bis(diphenyl-
phosphino)-9,9-dimethylxanthene) serves as a general cata-
lyst system for the cycloaddition of diynes and nitriles.
Furthermore, these cycloadditions proceed, in many cases,
more effectively than the current state-of-the-art catalytic
methods.
Upon investigating reaction conditions to promote the
cycloaddition between the diyne 1a and methyl 2-methyl-3-
(phenylimino)acrylate, we found that pyridine 1ket (rather
than the expected carbocycle) was obtained in moderate yield
when Xantphos was used as the ligand [Eq. (1), cod = 1,5-
Scheme 1. Transition-metal intermediates in the cycloaddition of
alkynes and nitriles.
mediated cycloadditions are thought to undergo hetero-
oxidative coupling between a single alkyne and the hetero-
atom-containing substrate, such as a nitrile, before insertion
of the second alkyne (i.e., formation of B, Scheme 1).[9] Thus,
a Ni/Ln-based system (especially where Ln = phosphine) that
provided pyridines remained absent, because of the difficulty
associated with forming the required azametallacyclopenta-
diene intermediate, until two notable solutions were devel-
oped. Takahashi et al. accessed the azametallacyclopenta-
diene intermediate stoichiometrically through transmetalla-
tion between [Ni(PPh3)2Cl2] and an azazirconacyclopenta-
diene complex.[9] Alternatively, catalytic pyridine formation
was achieved at 1008C between activated alkynes such as
benzyne with Ni/dppe (dppe = 1,2-bis(diphenylphosphino)-
ethane) as the catalyst.[10]
cyclooctadiene].[11–13] Surprised by this result, particularly in
light of previous difficulties associated with pyridine forma-
tion using Ni/PR3 catalysts (see above), we evaluated a variety
of monodentate and bidentate phosphines as potential ligands
in the nickel-catalyzed cycloaddition of diyne 1a and the
simple, unactivated benzonitrile 2a at 1008C (Table 1). As
expected, in most cases, little to no pyridine product was
observed despite good conversion of the diyne.[14] From the
pool of monodentate phosphines screened (entries 1–5), only
moderate catalytic activity was observed in reactions run with
PPh3 (q = 1458) and PCy3 (q = 1708). Even worse catalytic
activity was observed when the slightly larger monodentate
phosphine P(o-tol)3 (q = 1948) was used.[15]
We successfully developed an efficient nickel catalyst for
cycloaddition by replacing the phosphines with N-heterocylic
carbene (NHC) ligands.[6] Thus, enhancing the nucleophilicity
of the nickel center appeared to be the key for promoting
oxidative coupling of the alkyne and nitrile. Recently, we
reported a nickel-catalyzed cycloaddition of diynes and
[*] P. Kumar, S. Prescher, Prof. Dr. J. Louie
Department of Chemistry, University of Utah
315 South, 1400 East, Salt Lake City, UT 84112-0850 (USA)
E-mail: louie@chem.utah.edu
In general, bidentate phosphines did not fare any better.
Dppe (b = 858) was ineffective towards pyridine formation
(Table 1, entry 6). Although pyridine was observed when
bidentate ligands with larger bite angles such as binap (b =
928) or dppf (b = 968) were employed (entries 7 and 8), yields
were still marginal. Surprisingly, a dramatic increase in
pyridine formation occurred when Xantphos (b = 1118), a
bidentate ligand with a large bite angle, was evaluated
(entry 9).[15–16] Further optimization (entries 10–12) led to a
Homepage: http://www.chem.utah.edu/faculty/louie/index.html
[**] The NIGMS (5RO1GM076125) and the NSF (0911017) are
acknowledged for financial support. S.P. thanks the Technische
Universitꢀt Braunschweig and Deutscher Akademischer Austausch
Dienst (DAAD) for a fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104475.
10694
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Angew. Chem. Int. Ed. 2011, 50, 10694 –10698

Table 1: Ligand screening for nickel-catalyzed cycloaddition of a diyne
Table 2: Nickel-catalyzed cycloaddition of diynes and nitriles.[a,b]
and a nitrile.[a,b]
Entry Diyne
Nitrile
Product
Yield [%][c]
1
2
3
4
5
6
1a [X=
C(CO2Et)2)]
1a
2a (Ar=Ph) 3aa
98
87
Entry
Ligand (Ln)
Catalyst
loading
[mol%]
T
[8C]
Yield
[%][c]
2b (Ar=
2-MeC6H4)
2c (Ar=
4-OMeC6H4)
2d (Ar=
4-CF3C6H4)
2e (Ar=
3ab
3ac
3ad
3ae
3af
1
2
3
4
5
6
7
8
PCy3
PBu3
PPh3
P(o-tol)3
P(O-iPr)3
dppe
10
10
10
10
10
10
10
10
10
5
100
100
100
100
100
100
100
100
100
100
100
RT
27
–
23
11
–
–
21
7
1a
1a
1a
1a
90
99
>99
96
3,5-F2C6H3)
2 f (Ar=
dppf
rac-binap
Xantphos
Xantphos
Xantphos
Xantphos
2-naphtyl)
9
>99 (86)[d]
>99
10
11
12
3
3
>99
>99 (98)[d,e]
[a] For entries 1–5, 20 mol% Ln was used. For entries 6–9, 10 mol% Ln
was used. For entry 10, 5 mol% Ln was used. For entries 11–12, 3 mol%
Ln was used. [b] The reactions from entries 1–11 were analyzed after 24 h
and >99% diyne conversion was observed for all the entries.
[c] Analyzed by GC analysis using naphthalene as an internal standard.
[d] Yields of isolated products in parentheses. [e] The reaction was
complete in 3 h. binap=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl,
dppf=1,1’-bis(diphenylphosphino)ferrocene.
7
8
1b
1b [X=
C(CO2Me)2)]
1b
1b
1b
2a
2b
3ba
3bb
92 (86)[d]
85 (81)[d]
9
10
11
2c
2d
2e
3bc
3bd
3be
89 (64)[d]
98 (94)[d]
>99
system that provided pyridine 3aa in excellent yields under
mild reaction conditions (3 mol% Ni catalyst at RT for 3 h).
Thus, in contrast to our previous hypothesis,[6a] sterics may
play an equally or more important role than electronics in
12
1b
2g
3bg
>99[e]
promoting both the challenging oxidative coupling and
[15]
13
14
1b
1b
2h (R=Me) 3bh
94 (69)[d]
90 (72)[d]
À
reductive elimination of C N bond.
The reaction has a broad substrate scope and tolerates a
variety of functional groups (Table 2). Yields obtained using
the Ni/NHC catalyst system are provided in parentheses for
direct comparison.[6a] Diyne 1a reacted with benzonitrile 2a
to afford 3aa in excellent yields (entry 1). Electron-with-
drawing groups (4-CF3, 3,5-F2; entries 4 and 5) on the
arylnitrile afforded the cycloadduct in higher yields than
arylnitriles bearing electron-donating groups (2-Me, 4-OMe;
entries 2 and 3). 2-Napthylnitrile (2 f) also afforded the
pyridine product 3af in excellent yield (entry 6). Interestingly,
diyne 1b reacted with a variety of nitriles to provide 5,6-
membered fused-ring systems in higher yields than those
obtained with the Ni/SIPr catalyst system (entries 7–10, 13,
14). In addition, similar trends in the yields of the pyridine
products derived from diyne 1b were observed when the
electronics on the arylnitrile were modified (i.e., electron-
withdrawing substituents gave higher yields than substrates
bearing electron-donating substituents). However, these
effects were not as pronounced as they were with the original
Ni/NHC system (yields in parentheses; entry 9 versus
entry 10). Nitrile 2g bearing an activated olefin successfully
reacted with 1b to afford 3bg (entry 12) in excellent yield,
although an elevated temperature was required. Notably, no
2i (R=iPr)
3bi
15
16
17
1c
1d
1e
2a
2a
2a
3ca
3da
3ea
73 (78)[d]
80 (93)[d]
93
[a] Reaction conditions: 3 mol% [Ni(cod)2], 3 mol% Xantphos, diyne
(1 equiv, 0.1m), nitrile (1.5 equiv), toluene, RT, 3 h. [b] Nitriles were
neither distilled nor degassed. Nitriles were used as received. [c] Yields
of isolated products. [d] Yields reported for the Ni/NHC catalyst;
Ref. [6a]. [e] The reaction was run at 1008C. Ts=4-toluenesulfonyl.
product arising from incorporation of the olefin was
observed.[17] The challenging alkyl nitriles (2h and 2i) also
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Communications
afforded the desired pyridines in excellent yields (entries 13
Segphos catalyst (Table 3, entries 2 and 3 versus entry 6). The
[Ru] catalyst[4a] was found to be completely ineffective
towards pyridine product formation (entry 4). Although
excellent conversion of the diyne 1a was observed with the
Ni/SIPr catalyst, 3aa was produced in lower yields than with
the Ni/Xantphos system (entry 5 versus entry 6). Thus, lower
catalyst loadings, milder reaction conditions, and equimolar
substrate stoichiometry make Ni/Xantphos a more efficient
catalyst for coupling of diynes and unactivated nitriles.
We recently reported that Ni/NHC catalyzes the cyclo-
addition of diynes and cyanamides to access 2-aminopyri-
dines.[19] These cycloadditions possessed an expanded sub-
strate scope as terminal diynes were successfully converted
into pyridine products. However, SIPr was required as a
ligand rather than the standard IMes ligand employed for the
coupling of internal diynes and cyanamides. The Ni/Xantphos
system was evaluated and proved effective for the coupling of
particularly challenging substrates (Scheme 2). Specifically,
2,7-diynes (i.e., 1a and tetraethyl octa-1,7-diyne-4,4,5,5-
and 14). Similarly, sulfonamide diyne 1c and diyne ether 1d
reacted with benzonitrile 2a to yield products in good yields
(entries 15 and 16). The Thorpe–Ingold effect was not a
necessity of this reaction as diyne 1e reacted to afford the
cycloadduct 3ea in excellent yield (entry 17). It is important
to note that all nitriles evaluated were not purified prior to
use; instead, they were used as received from commercial
suppliers.
The efficacy of the Ni/Xantphos cycloaddition catalyst
system was compared to other, state-of-the-art transition-
metal catalysts based on Co, Ru, Rh, and Ni (Table 3,
entries 1–5 versus 6). Specifically, diyne 1a and benzonitrile
2a were subjected to a variety of catalytic conditions and
monitored for pyridine formation. Even after 24 hours in the
presence of a large excess of nitrile (20 equiv), full conversion
of the diyne was not reached with 5 mol% [Co] catalyst
(Table 3, entry 1). Also, the desired cycloadduct was formed
in only 70% yield.[18]
Table 3: Comparison of metal catalysts in the cycloaddition of diynes
and nitrile.
Entry [M]
(x mol%)
2a
T
t
1a
Yield
[%][a]
Scheme 2. Nickel-catalyzed cycloaddition of diynes and cyanamides.
[equiv] [8C] [h] Conv.
[%][a]
1
2
3
4
5
6
[Co][c] (5 mol%)
[Rh][d] (3 mol%)
[Rh][e] (3 mol%)
[Ru][f] (10 mol%)
20
RT 24
86
>99
32
70
>99
15
–
tetracarboxylate (1 f)) were successfully reacted with either
pyrrolidine-1-carbonitrile (2j), morpholine-4-carbonitrile
(2k), or N,N-diallylcyanamide (2l) to give 6,6-fused bicyclic
products (3aj, 3 fk, 3al). In addition, the same Ni/Xantphos
system could be used for both internal and terminal diynes.
Importantly, diallyl cyanamide, a cyanamide that is unreactive
with the Ni/IMes catalyst, gave 3al in good yield.
Treatment of the unsymmetrical diyne 1g with benzoni-
trile 2a led to the regioselective formation of the cycloadduct
3ga (Scheme 3). Despite the higher reactivity of terminal
diynes, the regioselectivity is governed by the insertion of a
less-sterically hindered alkyne (bearing H on the terminal
carbon atom) in the azametallacycle formed by initial
oxidative coupling of the internal alkyne (bearing Me on
the terminal carbon atom) and 2a. Analogous to the reaction
of the diyne 1g and 2a, N,N-dimethylcyanamide (2m) was
also regioselectively coupled with 1g to afford the 2-amino-
pyridine 3gm (Scheme 3).
1.5
1.5
1.5
60
RT
60
RT
RT
3
3
24
3
3
6[g]
[Ni/SIPr][h] (3 mol%) 1.5
[Ni/Xant][i] (3 mol%) 1.5
>99
>99
80
>99 (98)[b]
[a] Analyzed by GC using naphthalene as an internal standard. [b] Yield of
isolated product given within parentheses. [c] 5 mol% CoCl2, 6 mol%
dppe, excess Zn, diyne (1 equiv, 1m), nitrile (20 equiv), NMP, RT.
[d] 3 mol% [Rh(cod)]BF4, 3 mol% Segphos, diyne (1 equiv, 0.1m), nitrile
(1.5 equiv), 1,2-DCE, 608C. [e] Same conditions as in [d], but the reaction
was run at RT. [f] 10 mol% [Cp*Ru(cod)Cl], diyne (1 equiv, 0.1m), nitrile
(1.5 equiv), 1,2-DCE, 608C, 24 h. [g] Analyzed by NMR spectroscopy.
[h] 3 mol% [Ni(cod)2], 3 mol% SIPr, diyne (1 equiv, 0.1m), nitrile
(1.5 equiv), THF, RT. [i] 3 mol% [Ni(cod)2], 3 mol% Xantphos, diyne
(1 equiv, 0.1m), nitrile (1.5 equiv), toluene, RT. Cp*=C5Me5, 1,2-DCE =
1,2-dichloroethane, NMP=N-methylpyrrolidone, Segphos = (4,4’-bi-1,3-
benzodioxole)-5,5’-diylbis(diphenylphosphine), SIPr=N,N-bis(2,6-di-
isopropylphenyl)dihydroimidazol-2-ylidene, THF=tetrahydrofuran.
A Rh/binap catalyst[5a] developed by Tanaka et al. is
known for exhibiting excellent catalytic activity for activated
nitriles (an approach complementary to the Ru-catalyzed
cycloaddition developed independently by the groups of
Yamamoto and Saꢀ).[4] However, replacement of binap with
Segphos was required when simple nitriles, such as acetoni-
trile or benzonitrile, were employed. Although excellent yield
and conversion were observed at 608C, the reaction afforded
the pyridine in lower yield at room temperature with the Rh/
Scheme 3. Regioselectivity in the nickel-catalyzed cycloaddition of
diynes and nitriles.
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Angew. Chem. Int. Ed. 2011, 50, 10694 –10698

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The combination of high yields, mild reaction conditions,
and, importantly, efficient stoichiometry led us to investigate
the use of this system to rapidly click together a diyne with a
complex nitrile. Specifically, equimolar amounts of both the
diyne 1b and d-tocopherol-derived nitrile 2n were subjected
to the Ni/Xantphos catalyst at room temperature. After only
3 hours, pyridine 3bn was obtained in 94% yield [Eq. (2)].
Thus, excess nitrile is not required to obtain high yields of
potential pyridine bioconjugates.
In summary, we discovered a Ni/phosphine system that
promotes both oxidative coupling between an alkyne and a
À
nitrile as well as C N bond-forming reductive elimination.
The combination of catalytic amounts of Xantphos and Ni0
produced a variety of pyridines from unactivated nitriles and
diynes under mild and efficient reaction conditions. Studies
focused on understanding the mechanism of this reaction and
the application of this methodology toward the synthesis of
bioconjugates are ongoing.
[5] For [Rh]-catalyzed approaches to synthesizing pyridines through
a cycloaddition strategy, see: a) K. Tanaka, N. Suzuki, G.
Nishida, Eur. J. Org. Chem. 2006, 3917 – 3922; b) K. Tanaka, H.
Hara, G. Nishda, M. Hirano, Org. Lett. 2007, 9, 1907 – 1910; c) A.
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Org. Lett. 2009, 11, 2361 – 2364; f) Y. Komine, K. Tanaka, Org.
Lett. 2010, 12, 1312 – 1315.
Experimental Section
Representative procedure: In a nitrogen-filled glove box, diyne
(1 equiv, 0.1m) and nitrile (1.5 equiv) were added to an oven-dried
screw-cap vial equipped with a magnetic stir bar. In a separate vial
[Ni(cod)2] and Xantphos were weighed out (in 1:1 molar ratio) and
dissolved in toluene. The catalyst (3 mol%) solution was added to the
reaction mixture. The vial was sealed and brought out of the glove
box. The reaction was stirred at RT for 3 h. The resulting reaction
mixture was concentrated and purified by flash column chromate-
graphy on silica gel using first 15%, 30%, and finally 50% EtOAc/
hexanes.
[6] For [Ni]-catalyzed approaches to synthesizing pyridines through
a
cycloaddition strategy, see: a) M. M. McCormick, H. A.
Duong, G. Zuo, J. Louie, J. Am. Chem. Soc. 2005, 127, 5030 –
5031; b) T. N. Tekavec, G. Zuo, K. Simon, J. Louie, J. Org. Chem.
2006, 71, 5834 – 5836.
[7] For [Fe]-catalyzed approaches to synthesizing pyridines through
a cycloaddition strategy, see: a) B. R. DꢂSouza, T. K. Lane, J.
Louie, Org. Lett. 2011, 13, 2936 – 2939; b) C. Wang, X. Li, F. Wu,
B. Wan, Angew. Chem. 2011, 123, 7300 – 7304; Angew. Chem. Int.
Ed. 2011, 50, 7162 – 7166.
[8] For mechanistic discussions of Co-, Rh-, and Ru-catalyzed
cycloaddition reactions, see: a) G. Dazinger, M. Torres-Rodri-
gues, K. Kirchner, M. J. Calhorda, P. J. Costa, J. Organomet.
Chem. 2006, 691, 4434 – 4445; For studies involving [Ru], see:
b) Y. Yamamoto, T. Arakawa, R. Ogawa, K. Itoh, J. Am. Chem.
Soc. 2003, 125, 12143 – 12160. For studies involving [Co], see:
c) R. Diercks, B. E. Eaton, S. Gurtzgen, S. Jalisatgi, A. J.
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[9] For mechanistic discussion of Ni-catalyzed cycloaddition reac-
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J. N. Gitua, C. Kruger, Eur. J. Inorg. Chem. 2001, 77 – 88.
Received: June 28, 2011
Published online: September 20, 2011
Keywords: alkynes · cycloaddition · heterocycles · nickel ·
.
synthetic methods
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[16] At the suggestion of one of the reviewers, a similar bidentate
ligand, DPEphos was evaluated (3 mol% [Ni], 3 mol% DPE-
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and a 9% yield of pyridine was detected by GC analysis of the
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