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.
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 10694 –10698