Nickel-catalyzed [2+2+2] cycloaddition of diynes and cyanamides

Article abstract of DOI:10.1002/ejoc.201100428

A variety of bicyclic N,N-disubstituted 2-aminopyridines have been prepared from diynes and cyanamides by nickel-catalyzed [2+2+2] cycloaddition reactions. The reactions proceeded at room temperature with low catalyst loading to afford 2-aminopyridines in

Full text of DOI:10.1002/ejoc.201100428

FULL PAPER
DOI: 10.1002/ejoc.201100428
Nickel-Catalyzed [2+2+2] Cycloaddition of Diynes and Cyanamides
Ryan M. Stolley,[a] Michael T. Maczka,[a] and Janis Louie*[a]
Keywords: Nickel / Cycloaddition / Cyanamides / Alkynes / Carbenes
A variety of bicyclic N,N-disubstituted 2-aminopyridines
have been prepared from diynes and cyanamides by nickel-
catalyzed [2+2+2] cycloaddition reactions. The reactions pro-
ceeded at room temperature with low catalyst loading to af-
ford 2-aminopyridines in good to excellent yields. The
method is amenable to both internal and terminal diynes and
proceeds in a regioselective manner. A number of cyan-
amides with diverse functional group tolerance were used.
The intermolecular version employing 3-hexyne and N-
cyanopyrrolidine also afforded the desired N,N-disubstituted
2-aminopyridine in good yield.
in 47% yield.[37] Heller and co-workers used a chiral cobalt
catalyst to synthesize a variety of chiral 1-aryl-5,6,7,8-tetra-
hydroquinolines from aryl-substituted diynes and nitriles.
This system was also amenable to the cycloaddition of aryl-
substituted diynes and piperidine-1-carbonitrile as a single
example in an excellent yield.[38] Owing to our recent suc-
cess in the mild and efficient nickel-catalyzed [2+2+2] cyclo-
addition of alkynes and nitriles to generate pyridines,[39] we
believed that the use of cyanamides as coupling partners
would be a practical extension of this methodology. Herein
we report the nickel-catalyzed [2+2+2] cycloaddition of alk-
ynes and cyanamides at room temperature with low catalyst
loadings.
Introduction
2-Aminopyridines are attractive synthetic targets due to
their use in many fields of chemistry as organometallic li-
gands,[1–4] chromophores,[5–7] and intermediates in biolo-
gically active molecules.[8–14] A variety of methods for the
synthesis of 2-aminopyridines exist, namely the amination
of pyridines from sodium amide (the Chichibabin reac-
tion),[15,16] Buchwald–Hartwig amination reactions,[17–20]
the substitution of halopyridines,[21–24] multi-component
condensations,[25,26] hetero-Diels–Alder reactions,[27] and
Ullman-type aminations.[28,29] To complement existing
methods, an easily envisioned route is the [2+2+2] cycload-
dition of alkynes and cyanamides.
The metal-catalyzed [2+2+2] cycloaddition of alkynes
and nitriles using a variety transition metals has a rich and
extensive history and continues to be a highly studied
field.[30,31] Although studies of cycloadditions of alkynes
and nitriles are expansive, independent studies of analogous
cyanamides are few. The seminal work of Bönnemann et al.
demonstrated the cycloaddition of acetylene and cyanamide
using a unique (η6-boranato)cobalt catalyst at high tem-
perature and pressure.[32] Heller et al. accomplished a
[CpCo(cod)]-catalyzed cycloaddition of dimethylcyanamide
and acetylene as a single example, which afforded a moder-
ate 46% yield.[33] Maryanoff and co-workers performed a
more focused study demonstrating the effectiveness of the
cycloaddition of diynes with cyanamides using [CpCo-
(CO)2] as a catalyst.[34–36] More recently, Tanaka et al. de-
veloped a cationic [Rh(cod)]/BINAP cycloaddition catalyst
that facilitated the [2+2+2] cycloaddition of a malonate-
derived diyne and N-cyanomorpholine as a single example
Results and Discussion
Reaction Optimization
Diyne 1 and N-cyanopyrrolidine (2a) were chosen as
model substrates due to our familiarity and simplicity of 1
as well as the simplicity, ease of handling, and commercial
availability of 2a [Equation (1)]. Initial investigations fo-
cused on catalyst screening with [Ni(cod)2] (cod = 1,5-cyclo-
octadiene) as an Ni0 source in combination with a variety
of ligands: Phosphanes, phosphites, amines, and N-hetero-
cyclic carbenes (NHCs; Table 1). The resultant catalysts
were then added to a 1:1 solution of diyne 1 and 2a in
toluene. The reactions were stirred at room temperature for
3 h and analyzed by gas chromatography (GC). The prod-
uct 3 was detected with most of the ligands tested (En-
tries 1–5), which is significantly different to the results of
Ni-catalyzed cycloaddition reactions of simple nitriles for
which only select NHC ligands (i.e., no phosphanes) af-
forded appreciable amounts of pyridine products.[39] The
highest yields were obtained when either IMes or SIPr was
employed as the ligand. The effectiveness of the [Ni(cod)2]/
IMes catalyst is particularly surprising as this catalyst sys-
[a] Department of Chemistry, University of Utah,
315 South 1400 East, Salt Lake City, Utah 84112-0850, USA
Fax: +1-801-581-8433
E-mail: louie@chem.utah.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100428.
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R. M. Stolley, M. T. Maczka, J. Louie
FULL PAPER
tem typically produces significant amounts of a dimerized Table 2. Comparison of the reaction times for the reaction of 1 and
2a.[a]
diyne as a side-product.[35–39] Brief optimization showed
that increasing the concentration of the cyanamide retarded
the reaction and that a 1:1 diyne/cyanamide ratio was ideal.
In addition, catalyst loading could be reduced to 5 mol-%
[Ni(cod)2] and 10 mol-% IMes or SIPr without loss of yield.
Entry
Ligand
Time [min]
Conv. [%][b]
Yield [%][b]
1
2
3
4
SIPr
SIPr
SIPr
IMes
15
30
60
15
30
75
100
98
29
72
98
98
[a] Reaction conditions: 0.1 m diyne, 0.1 m cyanamide, 5 mol-%
[Ni(cod)2], 10 mol-% ligand, PhMe, room temp. [b] Determined by
GC relative to naphthalene as an internal standard.
Table 3. Solvent screening for cycloaddition of 1 and 2a.[a]
(1)
Entry
Solvent
Conv. [%][b]
Yield [%][b]
1
2
3
4
5
6
THF
Et2O
benzene
pentane
1,4-dioxane
toluene
95
100
33
100
100
100
67
86
4
98
95
98
Table 1. Ligand screening for the [2+2+2] cycloaddition reaction
between 1 and 2a.[a]
Entry
Ligand (mol-%)
Conv. [%][b]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
IPr (20)[c]
83
100
100
91
100
80
47
13
11
6
78
98
98
45
81
25
17
6
6
0
11
0
0
SIPr (20)[c]
[a] Reaction conditions: 0.1 m diyne, 0.1 m cyanamide, 5 mol-%
[Ni(cod)2], 10 mol-% IMes, room temp., 30 min. [b] Determined by
GC relative to naphthalene as an internal standard.
IMes (20)[c]
P(tBu)3 (20)
P(Cy)3 (20)
PPh3 (20)
DPPE (10)[c]
BINAP (10)[c]
DPPF (10)[c]
P(OPh)3 (20)
P(OiPr)3 (20)
TMEDA (20)[c]
[Ni(cod)2] (10)
Substrate Scope
With the optimized conditions in hand, we examined the
reactions of a range of diyne and cyanamide substrates with
varying electronic and steric properties (Table 4). In ad-
dition to the model cyanamide 2a, other dialkylcyanamides
readily underwent cyclization, affording excellent yields.
The yields appear to decrease with increasing steric bulk:
86
65
91
[a] Reaction conditions: 0.1 m diyne, 0.1 m cyanamide, 10 mol-%
[Ni(cod)2], PhMe, room temp., 3 h. [b] Determined by GC relative
to naphthalene as an internal standard. [c] SIPr = 1,3-bis(2,6-di- Me (4) Ͼ Et (5) Ͼ Pr (6; Entries 2–4). This is further high-
isopropylphenyl)-4,5-dihydroimidazolin-2-ylidine, IPr
=
1,3-
lighted by the complete inactivity of diisopropylcyanamide
(2e, see below) towards cycloaddition. The heterocyclic cy-
anamide N-cyanomorpholine (Entry 5) was an excellent
substrate, affording product 7 in 97% yield. In addition to
alkyl substituents, a variety of amine-protected cyanamides
were evaluated, these include methyl PMB cyanamide
bis(2,6-diisopropylphenyl)imidazol-2-ylidene, IMes = 1,3-bis(1,3,5-
trimethylphenyl)imidazol-2-ylidene, DPPE = 1,2-bis(diphenylphos-
phanyl)ethane, BINAP = rac-(1,1Ј-binaphthalene-2,2Ј-diyl)bis(di-
phenylphosphane), DPPF
= 1,1Ј-bis(diphenylphosphanyl)ferro-
cene, TMEDA = N,N,NЈ,NЈ-tetramethylethylenediamine.
Upon addition of a solution of [Ni(cod)2]/IMes to the (PMB = p-methoxybenzyl; 2g), dibenzylcyanamide (2h), as
reaction mixture, an instant and dramatic color change oc- well as carbonyl-protected cyanamides such as N-(tert-but-
curred, possibly an indication of a rapid reaction. As such, oxycarbonyl)-N-butylcyanamide (2i) and N-butyl-N-cyano-
the reaction times of the [Ni(cod)2]/IMes and [Ni(cod)2]/ acetamide (2j; Entries 6–9). Notable unreactive protected
SIPr systems were explored (Table 2). Two reaction mix- cyanamides are N-tosylated butylcyanamide (2k) and diall-
tures, both consisting of equimolar amounts of diyne 1 and ylcyanamide (2l; Figure 1). Note, N-tosylamines have been,
2a in toluene, were treated with either [Ni(cod)2]/IMes or for the most part, troublesome in many of our previous
[Ni(cod)2]/SIPr. Although the reactions with both SIPr and cycloaddition reactions.[39–43] It is unclear in this case
IMes as ligands each generated excellent yields of 2-amino- whether the steric bulk or the reactivity of the N-tosyl moi-
pyridine 3, we found that reactions run with IMes produced ety deactivates the catalyst. Diallylcyanamide was also em-
3 in only 15 min, whereas the analogous reaction run with ployed but was also found to deactivate the catalyst. Free
SIPr required 60 min to achieve the same yield (Entry 3 vs. amine is incompatible with our catalyst system as seen by
4).
the lack of reaction of free cyanamide and N-butylcyan-
A variety of solvents were screened for the [Ni(cod)2]/ amide. Cyanamides containing pendant functional groups
IMes-catalyzed cycloaddition of diyne 1 and cyanamide 2a [methyl 2-(N-butylcyanamido)acetate (2m), N-butyl-N-(3-
(Table 3). Excellent yields were obtained in pentane, 1,4- chloropropyl)cyanamide (2n), and N-butyl-N-(3-chloro-
dioxane, and toluene. Toluene was chosen for use in further ethyl)cyanamide (2o)] were also evaluated and gave mixed
cycloaddition reactions, because the yields were higher in results. Both chlorinated cyanamides 2n and 2o readily de-
toluene than in dioxane and also because many substrates activated the catalyst as no conversion was observed in
are only moderately soluble in pentane.
these reactions (Figure 1). Cyanamide 2m afforded amino-
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Nickel-Catalyzed Cycloaddition of Diynes and Cyanamides
pyridine 12 in 81% yield as a light-sensitive aminopyridine tries 12–14, respectively). Notably, diyne 20 readily reacted
that required purification by chromatography to be per- to afford an aminopyridine appended to a seven-membered
formed in a darkened room (Entry 10). Arylcyanamides are ring in 76% yield despite the lack of Thorpe–Ingold assist-
also good substrates with cyanamide 2p affording amino- ance in the substrate (Entry 15).
pyridine 13 in excellent yield (Entry 11). Various diynes
The regioselectivity of the reaction was investigated by
were subjected to the reaction conditions with model cyan- treating diyne 22 and cyanamide 2a under the optimized
amide 2a and afforded excellent yields. For example, reaction conditions; aminopyridine 23 was obtained as a
internal N-protected amines (14) and ethers (16) as well as single regioisomer in 76% yield [Equation (2)].[44] The struc-
linear diyne 18 all reacted well under our conditions (En- ture was assigned through complementary HMQC and
Table 4. Cycloaddition of cyanamides and internal diynes.[a]
[a] Reaction conditions: 0.1 m diyne, 0.1 m cyanamide, 5 mol-% [Ni(cod)2], 10 mol-% IMes, PhMe, room temp., 30 min. [b] Isolated yield,
average of at least two runs. [c] No reaction.
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Table 5. Cycloaddition reactions of the terminal malonate diyne.[a]
Figure 1. Examples of cyanamides that are incompatible with the
[Ni(cod)2]/NHC-catalyzed cycloaddition.
HMBC NMR experiments, with the regiochemistry being
determined by exclusive correlations between C-2 and pro-
tons located on C-4 and C-1.
[a] Reaction conditions: 0.1 m diyne, 0.1 m cyanamide, PhMe,
5 mol-% [Ni(cod)2], 10 mol-% SIPr, room temp., 60 min. [b] Iso-
lated yield, average of at least two runs. [c] No reaction.
Under these revised conditions, terminal diynes were
amenable to cycloaddition with most of the previously
tested cyanamides (Table 5). Alkyl substituents work well
with cyanamides 2a and 2f affording products 26 and 27 in
80 and 86% yields, respectively (Entries 1 and 2). Terminal
diynes were also compatible with N-Boc- (2i) and N-acyl-
protected (2j) cyanamides, with yields comparable to in-
ternal diynes (Entries 3 and 4). However, no reaction was
observed with diyne 25 and either PMB-protected cyan-
amide 2g or ester-functionalized cyanamide 2m (Entries 5
and 6). In addition to the alkylcyanamides, phenyl-substi-
tuted cyanamides (2p) are excellent substrates affording 32
in good yield (Entry 7).
(2)
We also investigated the synthesis of N,N-disubstituted 2-
aminopyridines by the cycloaddition of an untethered alk-
yne [Equation (3)]. Subjecting 3-hexyne (2 equiv.) and N-
cyanopyrrolidine (2a) to the optimized conditions described
above (5 mol-% of catalyst, room temp.) afforded 2-amino-
pyridine 24 in 86% yield.
In Situ Catalyst Generation
Previously, we developed a method that generates the
active Ni0/NHC catalyst in situ from air-stable, readily
available precursors.[45] The method employed [Ni(acac)2]
(3)
Terminal diynes, a challenging substrate for the parent as a nickel source, an appropriate NHC·HCl or HBF4 salt,
Ni-catalyzed nitrile cycloaddition reaction,[39] were also and nBuLi as a simultaneous reductant and base. We found
evaluated as potential substrates (Table 5). Initially, the this in situ method was also effective for the [2+2+2] cyclo-
[Ni(cod)2]/IMes-catalyzed reaction between diyne 25 and addition reactions of diynes and cyanamides. When diyne
cyanamide 2a only yielded trace amounts of the desired 1 and cyanamide 2a were treated with a stirred solution
product in an otherwise unidentifiable reaction mixture. of [Ni(acac)2], IMes·HCl, and nBuLi, aminopyridine 3 was
However, when IMes was substituted for SIPr, the reaction obtained in 80% yield. Furthermore, a variety of aminopyr-
was effective and generated aminopyridine 26 in 80% yield. idines were obtained in this fashion with yields comparable
Extended reaction times were required for the [Ni(cod)2]/ to the yields obtained in the initial substrate scope experi-
SIPr-catalyzed reactions. Interestingly, unlike internal di- ments (Table 6, Entries 1–5). In situ cycloaddition using ter-
ynes, the cycloaddition of terminal diynes and cyanamides minal diyne 25 and cyanamide 2a was also successful when
using [Ni(cod)2]/SIPr did not occur in 1,4-dioxane. The use IMes·HCl was replaced by SIPr·HBF4. Further cyanamides
of dioxane did lead to full conversion; however, no identifi- were tested with diyne 25 with mixed results. The reactions
able products were formed nor were any byproducts iso- with both cyanamides 2a and 2p went to completion and
lated from the complex reaction mixture. Thus, cycload- gave good yields, whereas the Boc (2i) and acyl (2j) cyan-
dition reactions using [Ni(cod)2]/SIPr were carried out ex- amides gave modest yields of 50 and 30% with 20 and 32%
clusively in toluene.
recovered starting material, respectively (Entries 6–9).
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Nickel-Catalyzed Cycloaddition of Diynes and Cyanamides
(1:1) (50 mL) and BrCN (1.4 g, 13.3 mmol, 0.6 equiv.) over 10 min.
The reaction mixture was stirred at ambient temperature for 3 h,
after which time hexane (10 mL) was added followed by an ad-
ditional 10 min of stirring. The mixture was then filtered through
a pad of Celite and washed with H2O (3ϫ50 mL) and brine
(2ϫ50 mL). The organic phase was then dried with anhydrous
Na2SO4 and concentrated to yield 1.35 g of 2d as a colorless oil;
Table 6. Yields from in situ generated Ni–carbene catalyst (rsm =
recovered starting material).[a]
1
yield 98%. H NMR (CDCl3): δ = 0.89 (t, J = 7.5 Hz, 3 H), 1.59
(dt, J1 = 5, J2 = 10 Hz, 2 H), 2.87 (t, J = 5 Hz, 2 H) ppm. 13C
NMR (CDCl ): δ = 10.92, 20.9, 53.1, 117.8 ppm. IR (neat): ν =
˜
3
2968, 2878, 2208, 1462, 1090 cm–1. HRMS (ESI): calcd. for
C7H15N2 [M + H]+ 127.1230; found 127.1230.
N-(tert-Butoxycarbonyl)-N-butylcyanamide (2i): N-Butylcyanamide
(740 mg, 7.6 mmol, 1 equiv.) in Et2O (5 mL) was added to a suspen-
sion of NaH (217 mg, 9.1 mmol, 1.2 equiv.) in THF (75 mL) at
0 °C. The mixture was warmed to room temperature, after which
Boc2O (1.9 mL, 8.3 mmol, 1.1 equiv.) was added. The reaction mix-
ture was stirred for 1 h, quenched with H2O (1 mL), and Et2O
(10 mL) was added. The crude reaction mixture was poured into
brine/water (1:1), extracted with Et2O (3ϫ15 mL), and concen-
trated. The residue was purified by column chromatography using
CH2Cl2 to afford 1.41 g of the title compound as a colorless oil;
[a] Isolated yields (average of at least two runs). [b] Reaction condi-
tions: 0.1 m diyne, 0.1 m cyanamide, PhMe, 5 mol-% [Ni(acac)2],
10 mol-% IMes·HCl, 25 mol-% nBuLi, room temp., 60 min. [c] Re-
action conditions: 0.1 m diyne, 0.1 m cyanamide, PhMe, 5 mol-%
[Ni(acac)2], 10 mol-% SIPr·HBF4, 25 mol-% nBuLi, room temp.,
60 min.
1
yield 95%. H NMR (CDCl3): δ = 0.94 (t, J = 7.5 Hz, 3 H), 1.38
(m, 2 H), 1.51 (s, 9 H), 1.66 (dt, 2 H), 3.46 (t, 2 H) ppm. 13C NMR
(CDCl3): δ = 13.7, 19.5, 27.9, 29.9, 47.6, 85.4, 109.8, 151.2 ppm.
IR (neat): ν = 2966, 2361, 2241, 1748, 1461, 1152 cm–1. HRMS
˜
(ESI): calcd. for C10H19N2O2 [M + H]+ 199.1441; found 199.1441.
Conclusions
N-Butyl-N-cyanoacetamide (2j): N-Butylcyanamide (770 mg,
7.9 mmol, 1 equiv.) in Et2O (5 mL) was added to a suspension of
NaH (230 mg, 9.4 mmol, 1.2 equiv.) in THF (25 mL) at 0 °C. The
mixture was warmed to room temperature, after which acetyl chlo-
ride (0.617 mL, 8.6 mmol, 1.1 equiv.) was added. The reaction mix-
ture was stirred for 1 h, quenched with H2O (1 mL), and Et2O was
added (10 mL). The crude reaction mixture was poured into brine/
water (1:1), extracted with Et2O (3ϫ15 mL), and concentrated.
The residue was purified by column chromatography using CH2Cl2
to afford 1.07 g of the title compound as a colorless volatile oil;
We have demonstrated that diynes undergo [2+2+2] cy-
cloaddition reactions with cyanamides in the presence of an
Ni–carbene catalyst to generate N,N-disubstituted 2-amino-
pyridines. The method is effective for the cycloaddition of
internal as well as terminal diynes with a variety of cyan-
amides, affording good to excellent yields. N,N-Disubsti-
tuted 2-aminopyridines were also obtained when using an
in situ generated Ni–carbene catalyst prepared from air-
stable, commercially available sources.
1
yield 98%. H NMR (CDCl3): δ = 0.93 (t, J = 7.5 Hz, 3 H), 1.35
(m, 2 H), 1.64 (dt, 2 H), 2.38 (s, 3 H), 3.54 (t, 2 H) ppm. 13C NMR
Experimental Section
(CDCl3): δ = 13.6, 19.6, 22.3, 29.7, 45.9, 111.1, 169.4 ppm. IR
(neat): ν = 2963, 2875, 2361, 2233, 1730, 1373, 1244 cm–1. HRMS
˜
General: Ligands 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine
(IPr), 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolin-2-ylid-
ine (SIPr), and 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidine
(IMes) were prepared according to literature procedures.[46,47] The
diynes dimethyl 2,2-bis(but-2-ynyl)malonate (1),[48] dimethyl 2,2-
bis(prop-2-yn-1-yl)malonate (25),[48] N,N-bis(but-2-ynyl)-p-toluene-
sulfonamide (14),[49] 1-(but-2-ynyloxy)but-2-yne (16),[50] and di-
methyl 2-(but-2-ynyl)-2-(4,4-dimethylpent-2-ynyl)malonate (22)[44]
were also prepared according to literature procedures. N-Butylcy-
anamide was also prepared by literature procedures.[51] The diynes
3,9-dodecadiyne (18) and 2,9-undecadiyne (20) were purchased
from GFS and Lancaster chemical companies, respectively, and dis-
tilled from CaH2 before use. Bis(1,5-cyclooctadiene)nickel(0),
[Ni(cod)2], was purchased from the Strem chemical company and
used without further purification. All other reagents were pur-
chased from commercial sources and used without further purifica-
tion. All liquid reagents were degassed prior to use by the freeze-
pump-thaw method. All reactions were preformed in a nitrogen-
filled glove box or under nitrogen using standard Schlenk tech-
niques unless otherwise noted.
(ESI): calcd. for C7H13N2O [M + H]+ 141.1022; found 141.1023.
N-Butyl-N-cyano-4-methylbenzenesulfonamide (2k): N-Butylcyan-
amide (1.21 g, 12.3 mmol, 1 equiv.) in Et2O (5 mL) was added to a
suspension of NaH (356 mg, 14.8 mmol, 1.2 equiv.) in THF
(50 mL) at 0 °C. The mixture was warmed to room temperature,
after which p-toluenesulfonyl chloride (2.9 g, 14.8 mmol, 1.2 equiv.)
in THF (5 mL) was added. The reaction mixture was stirred for
4 h, quenched with H2O (1 mL), and Et2O (10 mL) was added. The
crude reaction mixture was poured into brine/water (1:1), extracted
with Et2O (3ϫ15 mL), and concentrated. The residue was purified
by column chromatography using CH2Cl2 to afford 1.3 g of the
title compound as a viscous colorless oil; yield 97%. 1H NMR
(CDCl3): δ = 0.85 (t, J = 7.5 Hz, 3 H), 1.29 (m, 2 H), 1.59 (m, 2
H), 2.44 (s, 3 H), 3.33 (m, 2 H), 7.38 (d, 2 H), 7.78 (d, 2 H) ppm.
13C NMR (CDCl3): δ = 13.3, 19.1, 21.7, 29.6, 49.8, 108.5, 127.7,
130.4, 133.5, 146.5 ppm. IR (neat): ν = 2963, 2875, 2230, 1380,
˜
1173 cm–1. HRMS (ESI): calcd. for C12H17N2O2S [M + H]+
253.1005; found 253.1006.
Methyl 2-(N-Butylcyanamido)acetate (2m): N-Butylcyanamide
(1.01 g, 10.3 mmol, 1 equiv.) in Et2O (5 mL) was added to a suspen-
sion of NaH (295 mg, 12.3 mmol, 1.2 equiv.) in THF (50 mL) at
N,N-Dipropylcyanamide (2d): Dipropylamine (3 mL, 21.9 mmol,
1.0 equiv.) was added dropwise to a stirred solution of Et2O/THF
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R. M. Stolley, M. T. Maczka, J. Louie
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0 °C. The mixture was warmed to room temperature, after which
methyl 2-bromoacetate (1.0 mL, 11 mmol, 1.1 equiv.) was added.
The reaction mixture was stirred for 3 h, quenched with H2O
(1 mL), and Et2O (10 mL) was added. The crude reaction mixture
was poured into brine/water (1:1), extracted with Et2O (3ϫ15 mL),
and concentrated. The residue was purified by column chromatog-
raphy using CH2Cl2 to afford 1.53 g of the title compound as a
pale-yellow oil; yield 88%. 1H NMR (C6D6): δ = 0.59 (t, J =
7.5 Hz, 3 H), 0.98 (m, 2 H), 1.21 (dt, 2 H), 2.52 (t, 2 H), 3.19 (s, 2
H), 3.23 (s, 3 H) ppm. 13C NMR (C6D6): δ = 13.9, 20.1, 30.1, 52.1,
General Co-Cycloaddition Procedure for Terminally Substituted Di-
ynes (A): In a nitrogen-filled glove-box, [Ni(cod)2] (1 equiv.) and
IMes (2 equiv.) were diluted to 0.036 m in toluene or dioxane and
stirred for at least 4 h. A solution of diyne (100 mg) and cyanamide
(1 equiv.) in toluene or dioxane was placed in an oven-dried vial
equipped with a stirring bar. The [Ni(cod)2/IMes solution was
added to this stirred solution with a total reaction concentration
of 0.1 m in the diyne. The reaction mixture was stirred at ambient
temperature for 30 min, taken out of the glove-box, concentrated,
and then purified by flash column chromatography to afford the
aminopyridine product.
52.2, 52.6, 117.0, 168.9 ppm. IR (neat): ν = 2960, 2875, 2360, 2216,
˜
1752, 1217 cm–1. HRMS (ESI): calcd. for C8H15N2O2 [M + H]+
171.1128; found 171.1128.
General Co-Cycloaddition Procedure for Terminal Diynes (B): In a
nitrogen-filled glove box, [Ni(cod)2] (1 equiv.) and SIPr (2 equiv.)
were diluted to 0.036 m in toluene and stirred for at least 4 h. A
solution of diyne (100 mg) and cyanamide (1 equiv.) in toluene was
placed in an oven-dried vial equipped with a stirring bar. The
[Ni(cod)2]/SIPr solution was added to this stirred solution with a
total reaction concentration of 0.1 m in the diyne. The reaction mix-
ture was stirred at ambient temperature for 1 h, taken out of the
glove box, concentrated, and then purified by flash column
chromatography to afford the aminopyridine product.
N-Butyl-N-(3-chloropropyl)cyanamide (2n): N-Butylcyanamide
(805 mg, 8.2 mmol, 1 equiv.) in Et2O (5 mL) was added to a suspen-
sion of NaH (250 mg, 9.9 mmol, 1.2 equiv.) in THF (50 mL) at
0 °C. The mixture was warmed to room temperature, after which 1-
bromo-3-chloropropane (2.45 mL, 24.7 mmol, 3 equiv.) was added.
The mixture was heated to reflux and stirred overnight. The reac-
tion mixture was then quenched with H2O (1 mL), and Et2O
(10 mL) was added. The crude reaction mixture was poured into
brine/water (1:1), extracted with Et2O (3ϫ15 mL), and concen-
trated. The residue was purified by column chromatography using
CH2Cl2 to afford 1.3 g of the title compound as a colorless oil;
yield 91%. 1H NMR (C6D6): δ = 0.59 (t, J = 7.5 Hz, 3 H), 0.93
(m, 2 H), 1.15 (dt, 2 H), 1.48 (m, 2 H), 2.30 (t, J = 7.5 Hz, 2 H),
2.46 (t, J = 7.5 Hz, 2 H), 3.04 (t, J = 7.5 Hz, 2 H) ppm. 13C NMR
(CDCl3): δ = 13.99, 20.1, 30.1, 30.8, 41.9, 48.7, 51.9, 117.0 ppm.
In Situ Cycloaddition Procedure: In a nitrogen-filled glove box, [Ni-
(acac)2] (5.3 mg, 0.02 mmol) and either IMes·HCl (14.1 mg,
0.04 mmol) or SIPr·HBF4 (19.8 mg, 0.04 mmol) were suspended in
pentane (1.5 mL). To this was added a 2.5 m solution of nBuLi in
hexanes (45 mL, 0.103 mmol). The resultant suspension was stirred
at room temperature for 10 min. Concurrently, the appropriate di-
yne (0.41 mmol) and cyanamide (0.41 mmol) were placed in an
oven-dried vial equipped with a stirring bar and dissolved in tolu-
ene (3 mL). The catalyst solution was then added to the toluene
solution and the reaction mixture was stirred at room temperature
for 1 h. The reaction was quenched by the addition of MeOH
(5 drops). The reaction solution was then concentrated and purified
by column chromatography.
IR (neat): ν = 2961, 2874, 2361, 2208, 1459 cm–1. HRMS (ESI):
˜
calcd. for C8H16ClN2 [M + H]+ 175.0997; found 175.0997.
N-Butyl-N-(2-chloroethyl)cyanamide
(2o):
N-Butylcyanamide
(1.1 g, 11.2 mmol, 1.0 equiv.) in THF (5 mL) was added dropwise
to a stirring suspension of NaH (400 mg, 16.8 mmol, 1.5 equiv.) in
THF/DCE (1,2-dichloroethane) (1:1) (20 mL). The reaction mix-
ture was stirred at ambient temperature for 15 min, then heated at
reflux for 8 h. The mixture was cooled to room temperature,
quenched with MeOH (5 mL), and then poured into H2O
(100 mL). The suspension was extracted with CH2Cl2 (3ϫ15 mL).
The combined organic layers were dried with anhydrous Na2SO4,
concentrated, and purified by column chromatography eluting with
Dimethyl 1,4-Dimethyl-3-(pyrrolidin-1-yl)-5H-cyclopenta[c]pyridine-
6,6(7H)-dicarboxylate (3): General Procedure A was used with di-
yne 1 (100 mg, 0.42 mmol) and cyanamide 2a (42.7 mL, 0.42 mmol)
in toluene (3.6 mL). The remaining residue was purified by flash
column chromatography using hexanes/ethyl acetate (3:1) to afford
130.7 mg of the title compound as a white solid; yield 93%. M.p.
1
CH2Cl2 to afford 1.38 g of 2o as a pale-yellow oil; yield 77%. H
1
85–87 °C. H NMR (CDCl3): δ = 1.885 (m, 4 H), 2.162 (s, 3 H),
NMR (C6D6): δ = 0.68 (t, J = 7.5 Hz, 3 H), 0.97 (m, 2 H), 1.18
(dt, 2 H), 2.28 (t, J = 7.5 Hz, 2 H), 2.42 (t, J = 7.5 Hz, 3 H), 2.92
(t, J = 5 Hz, 2 H) ppm. 13C NMR (CDCl3): δ = 13.6, 19.5, 29.8,
2.30 (s, 3 H), 3.440 (m, 4 H), 3.475 (s, 2 H), 3.483 (s, 2 H), 3.763
(s, 6 H) ppm. 13C NMR (CDCl3): δ = 15.9, 21.9, 25.7, 38.7, 40.2,
50.3, 53.2, 60.0, 113.5, 124.7, 147.5, 150.3, 159.1, 172.4 ppm. IR
40.9, 51.7, 53.1, 116.8 ppm. IR (neat): ν = 2962, 2874, 2210, 1461,
˜
(neat): ν = 2955, 2870, 2211, 1738, 1600, 1430 cm–1. HRMS (ESI):
˜
1106 cm–1. HRMS (ESI): calcd. for C7H13N2 [M + H]+ 161.0840;
found 161.0841.
calcd. for C18H25N2O4 [M + H]+ 333.1809; found 333.1808.
Dimethyl 3-(Dimethylamino)-1,4-dimethyl-5H-cyclopenta[c]pyridine-
6,6(7H)-dicarboxylate (4): General Procedure A was used with di-
yne 1 (100 mg, 0.42 mmol) and cyanamide 2b (34.2 mL, 0.42 mmol)
in toluene (3.6 mL). The remaining residue was purified by flash
column chromatography using hexanes/ethyl acetate (3:1) to afford
129.5 mg of the title compound as a white solid; yield 99%. M.p.
N-Methyl-N-phenylcyanamide (2p): N-Methylaniline (1.7 mL,
15.6 mmol, 1 equiv.) was added to a solution of cyanogen bromide
(1 g, 9.4 mmol, 0.6 equiv.) in Et2O/THF (1:1) (25 mL) at room tem-
perature. The reaction mixture was then stirred overnight, after
which time hexane (5 mL) was added, and the mixture was stirred
for an additional 10 min. It was then filtered through a pad of
Celite, and the filtrate was washed with H2O (4ϫ25 mL) and brine
(2ϫ25 mL). The organic phase was dried with anhydrous Na2SO4,
and the solvent was removed under reduced pressure. The residue
was purified by column chromatography using ethyl acetate/hexane
(1:1) to afford 2.19 g of the title compound as a colorless solid:
yield 82%. M.p. 28–30 °C. 1H NMR (C6D6): δ = 2.21 (s, 3 H), 6.96
1
63–64 °C. H NMR (CDCl3): δ = 2.16 (s, 3 H), 2.34 (s, 3 H), 2.30
(s, 3 H), 2.78 (s, 6 H), 3.49 (s, 2 H), 3.50 (s, 2 H), 3.77 (s, 6 H)
ppm. 13C NMR (CDCl3): δ = 15.0, 21.8, 38.8, 40.1, 42.5, 53.3, 59.9,
117.2, 127.3, 147.9, 150.4, 172.3 ppm. IR (neat): ν = 2953, 2360,
˜
1735, 1588, 1442, 1277 cm–1. HRMS (ESI): calcd. for C16H23N2O4
[M + H]+ 307.1652; found 307.1652.
(m, 2 H), 6.76 (m, 1 H), 6.7 (m, 2 H) ppm. 13C NMR (C6D6): δ = Dimethyl 3-(Diethylamino)-1,4-dimethyl-5H-cyclopenta[c]pyridine-
36.2, 115.1, 123.3, 129.9, 141.4 ppm. IR (neat): ν = 2361, 2223,
6,6(7H)-dicarboxylate (5): General Procedure A was used with di-
yne 1 (100 mg, 0.42 mmol) and cyanamide 2c (42.7 mL, 0.42 mmol)
in toluene (3.6 mL). The remaining residue was purified by flash
˜
1600, 1114 cm–1. HRMS (ESI): calcd. for C8H9N2 [M + H]+
133.0760; found 133.0760.
3820
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3815–3824

Nickel-Catalyzed Cycloaddition of Diynes and Cyanamides
column chromatography using hexanes/ethyl acetate (3:1) to afford
135.8 mg of the title compound as a colorless oil; yield 93%. 1H
mide 2i (87.2 mg, 0.44 mmol) in toluene (3.6 mL). The remaining
residue was purified by flash column chromatography using hex-
NMR (CDCl3): δ = 1.01 (t, J = 8 Hz, 6 H), 2.11 (s, 3 H), 2.30 (s, anes/ethyl acetate (3:1) to afford 149.7 mg of the title compound as
1
3 H), 3.09 (m, 4 H), 3.48 (s, 2 H), 3.49 (s, 2 H), 3.74 (s, 6 H) ppm.
a colorless solid; yield 82%. M.p. 64–66 °C. H NMR (C6D5CD3,
60 °C): δ = 0.85 (t, J = 8 Hz, 3 H), 1.28 (m, 2 H), 1.38 (s, 9 H),
2.11 (s, 3 H), 2.21 (s, 3 H), 3.37 (s, 6 H), 3.45 (s, 2 H), 3.51 (s, 2
H), 3.88 (br. s, 2 H) ppm. 13C NMR (C6D5CD3, 60 °C): δ = 14.1,
14.8, 20.4, 21.5, 30.4, 38.6, 40.0, 51.4, 52.0, 52.7, 53.1, 59.8, 116.6,
13C NMR (CDCl3): δ = 13.4, 14.6, 21.7, 38.8, 40.1, 45.7, 53.0, 59.7,
119.3, 127.3, 147.8, 149.9, 160.3, 172.2 ppm. IR (neat): ν = 2967,
˜
2361, 1738, 1588, 1433, 1264 cm–1. HRMS (ESI): calcd. for
C18H27N2O4 [M + H]+ 335.1965; found 335.1968.
127.2, 147.4, 150.6, 159.1, 172.1, 172.7 ppm. IR (neat): ν = 2955,
˜
Dimethyl 3-(Dipropylamino)-1,4-dimethyl-5H-cyclopenta[c]pyridine-
6,6(7H)-dicarboxylate (6): General Procedure A was used with di-
yne 1 (100 mg, 0.42 mmol) and cyanamide 2d (53.5 mg, 0.42 mmol)
in toluene (3.6 mL). The remaining residue was purified by flash
column chromatography using hexanes/ethyl acetate (3:1) to afford
136.4 mg of the title compound as a colorless oil; yield 89%. 1H
NMR (CDCl3): δ = 0.839 (t, J = 8 Hz, 6 H), 1.24 (m, 4 H), 2.13
(s, 3 H), 2.32 (s, 3 H), 3.02 (m, 4 H), 3.49 (s, 2 H), 3.50 (s, 2 H),
3.77 (s, 6 H) ppm. 13C NMR (CDCl3): δ = 11.9, 14.7, 21.4, 21.9,
38.9, 40.2, 53.3, 53.9, 59.8, 119.2, 127.3, 147.9, 150.1, 160.8,
2361, 1738, 1595, 1434, 1271 cm–1. HRMS (ESI): calcd. for
C23H35N2O6 [M + H]+ 435.2490; found 435.2497.
Dimethyl 3-(N-Butylacetamido)-1,4-dimethyl-5H-cyclopenta[c]pyr-
idine-6,6(7H)-dicarboxylate (11): General Procedure A was used
with diyne 1 (100 mg, 0.42 mmol) and cyanamide 2j (63.1 mg,
0.45 mmol) in toluene (3.6 mL). The remaining residue was puri-
fied by flash column chromatography using 5% MeOH/CH2CH2
to afford 137.5 mg of the title compound as a colorless yellow vis-
cous oil; yield 87%. 1H NMR (C6D5CD3, 60 °C): δ = 0.81 (m, 3
H), 2.11 (br. s, 2 H), 1.59 (br. s, 2 H), 1.66 (s, 3 H), 1.87 (s, 3 H),
172.4 ppm. IR (neat): ν = 2956, 2872, 1739, 1589, 1433, 1267 cm–1.
˜
HRMS (ESI): calcd. for C20H31N2O4 [M + H]+ 363.2278; found
363.2279.
2.20 (s, 3 H), 3.35 (s, 6 H), 3.44 (s, 4 H), 4.03 (br. s, 1 H) ppm. 13
C
NMR (C6D5CD3, 60 °C): δ = 13.4, 13.9, 20.5, 21.4, 22.0, 30.4, 38.9,
39.9, 47.4, 52.7, 59.7, 123.9, 133.8, 137.4, 150.9, 151.5, 153.5, 168.9,
Dimethyl 1,4-Dimethyl-3-morpholino-5H-cyclopenta[c]pyridine-6,6-
(7H)-dicarboxylate (7): General Procedure A was used with diyne
1 (100 mg, 0.42 mmol) and cyanamide 2f (42.8 mL, 0.42 mmol) in
toluene (3.6 mL). The remaining residue was purified by flash col-
umn chromatography using hexanes/ethyl acetate (3:1) to afford
142.9 mg of the title compound as a white solid; yield 97%. M.p.
171.3 ppm. IR (neat): ν = 2955, 2361, 1738, 1595, 1434, 1271 cm–1.
˜
HRMS (ESI): calcd. for C20H29N2O5 [M + H]+ 377.2071; found
377.2072.
Dimethyl 3-[(Butyl)(2-methoxy-2-oxoethyl)amino]-1,4-dimethyl-5H-
cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (12): General Pro-
cedure A was used with diyne 1 (100 mg, 0.42 mmol) and cyana-
mide 2m (73 mg, 0.43 mmol) in toluene (3.6 mL). The remaining
residue was purified by flash column chromatography using hex-
anes/ethyl acetate (3:1) to afford 138.3 mg of the title compound as
a viscous colorless oil; yield 81%. (Note: The title compound is
light-sensitive, and chromatography was performed in a dimly lit
room. The green degradation products were not isolated.) 1H NMR
(CDCl3): δ = 0.87 (t, J = 7.5 Hz, 3 H), 1.27 (dt, J1 = 5, J2 = 10 Hz,
3 H), 1.55 (m, 2 H), 2.15 (s, 3 H), 2.23 (s, 3 H), 3.15 (m, 2 H), 3.45
(s, 2 H), 3.46 (s, 2 H), 3.65 (s, 3 H), 3.73 (s, 6 H), 3.91 (s, 2 H)
ppm. 13C NMR (CDCl3): δ = 14.1, 14.8, 20.4, 21.5, 30.4, 38.6, 40.0,
51.4, 52.0, 52.7, 53.1, 59.8, 116.6, 127.2, 147.4, 150.6, 159.1, 172.1,
1
82–83 °C. H NMR (CDCl3): δ = 2.16 (s, 3 H), 2.34 (s, 3 H), 3.08
(m, 4 H), 3.49 (s, 2 H), 3.51 (s, 2 H), 3.77 (s, 6 H), 3.84 (m, 4 H)
ppm. 13C NMR (CDCl3): δ = 14.5, 21.8, 38.8, 40.1, 50.8, 53.3, 59.9,
67.5, 117.9, 128.4, 148.6, 150.5, 160.3, 172.2 ppm. IR (neat): ν =
˜
2955, 2848, 2361, 1737, 1588, 1431, 1259 cm–1. HRMS (ESI): calcd.
for C18H25N2O5 [M + H]+ 349.1758; found 349.1757.
Dimethyl 3-[(4-Methoxybenzyl)(methyl)amino]-1,4-dimethyl-5H-cy-
clopenta[c]pyridine-6,6(7H)-dicarboxylate (8): General Procedure A
was used with diyne 1 (100 mg, 0.42 mmol) and cyanamide 2g
(74.6 mg, 0.42 mmol) in toluene (3.6 mL). The remaining residue
was purified by flash column chromatography using hexanes/ethyl
acetate (3:1) to afford 151.9 mg of the title compound as a viscous
172.7 ppm. IR (neat): ν = 2955, 2361, 1738, 1595, 1434, 1271 cm–1.
1
˜
colorless oil; yield 87%. H NMR (CDCl3): δ = 2.26 (s, 3 H), 2.41
HRMS (ESI): calcd. for C21H31N2O6 [M + H]+ 407.2177; found
407.2186.
(s, 3 H), 2.71 (s, 3 H), 3.57 (s, 2 H), 3.58 (s, 2 H), 3.82 (s, 6 H),
3.84 (s, 3 H), 6.92 (d, J = 8 Hz, 2 H), 7.37 (d, J = 8 Hz, 2 H) ppm.
13C NMR (CDCl3): δ = 14.7, 21.7, 38.7, 39.6, 40.0, 53.1, 55.3, 57.7,
59.8, 113.7, 117.8, 127.6, 129.3, 131.9, 148.0, 150.3, 172.1 ppm. IR
Dimethyl 1,4-Dimethyl-3-[(methyl)(phenyl)amino]-5H-cyclopenta-
[c]pyridine-6,6(7H)-dicarboxylate (13): General Procedure A was
used with diyne 1 (100 mg, 0.42 mmol) and cyanamide 2p (55.5 mg,
0.42 mmol) in toluene (3.0 mL). The remaining residue was puri-
fied by flash column chromatography using hexanes/ethyl acetate
(3:1) to afford 139 mg of the title compound as a colorless waxy
(neat): ν = 2953, 2838, 1737, 1588, 1512, 1436, 1246 cm–1. HRMS
˜
(ESI): calcd. for C23H29N2O5 [M + H]+ 413.2071; found 413.2069.
Dimethyl 3-(Dibenzylamino)-1,4-dimethyl-5H-cyclopenta[c]pyridine-
6,6(7H)-dicarboxylate (9): General Procedure A was used with di-
yne 1 (100 mg, 0.42 mmol) and cyanamide 2h (94.1 mg, 0.42 mmol)
in toluene (3.6 mL). The remaining residue was purified by flash
column chromatography using hexanes/ethyl acetate (3:1) to afford
170.8 mg of the title compound as a viscous colorless oil; yield
1
oil; yield 90%. H NMR (C6D5CD3): δ = 1.77 (s, 3 H), 2.29 (s, 3
H), 3.33 (s, 3 H), 3.34 (s, 6 H), 3.46 (s, 2 H), 3.53 (s, 2 H), 6.68 (d,
J = 10 Hz, 2 H), 6.74 (t, J = 7.5 Hz, 1 H), 7.03 (t, J = 7.5 Hz, 2
H) ppm. 13C NMR (CDCl3): δ = 14.5, 21.6, 38.9, 39.8, 39.8, 39.9,
52.4, 59.9, 117.9, 119.9, 120.9, 129.2, 129.9, 137.4, 149.8, 149.9,
1
88%. H NMR (CDCl3): δ = 2.30 (s, 3 H), 2.36 (s, 3 H), 3.55 (s, 2
150.7, 157.1, 171.6 ppm. IR (neat): ν = 2956, 1737, 1592, 1436,
˜
H), 3.55 (s, 2 H), 3.82 (s, 6 H), 4.31 (s, 3 H), 7.24 (m, 2 H), 7.32
(m, 4 H), 7.38 (m, 4 H) ppm. 13C NMR (CDCl3): δ = 14.6, 21.7,
38.8, 40.1, 53.2, 55.4, 59.8, 118.9, 126.8, 128.2, 128.3, 128.6, 139.9,
1265 cm–1. HRMS (ESI): calcd. for C21H25N2O4 [M + H]+
369.1809; found 369.1810.
148.2, 150.5, 159.9, 172.2 ppm. IR (neat): ν = 3029, 2952, 2360,
˜
4,7-Dimethyl-6-(pyrrolidin-1-yl)-2-tosyl-2,3-dihydro-1H-pyrrolo-
[3,4-c]pyridine (15): General Procedure A was used with diyne 14
(100 mg, 0.36 mmol) and cyanamide 2a (36.6 mL, 0.36 mmol) in
toluene (3.0 mL). The remaining residue was purified by flash col-
umn chromatography using hexanes/ethyl acetate (2:1) to afford
113.3 mg of the title compound as a white solid; yield 84%. M.p.
1737, 1591, 1434, 1267 cm–1. HRMS (ESI): calcd. for C28H31N2O4
[M + H]+ 459.2278; found 459.2282.
Dimethyl 3-[(tert-Butoxycarbonyl)(butyl)amino]-1,4-dimethyl-5H-
cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (10): General Pro-
cedure A was used with diyne 1 (100 mg, 0.42 mmol) and cyana-
Eur. J. Org. Chem. 2011, 3815–3824
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3821

R. M. Stolley, M. T. Maczka, J. Louie
FULL PAPER
1
110–112 °C (dec.). H NMR (CDCl3): δ = 1.88 (m, 4 H), 2.09 (s, 3 H), 1.31 (t, J = 7.5 Hz, 3 H), 1.91 (m, 4 H), 2.67 (m, 8 H), 3.45
H), 2.23 (s, 3 H), 2.42 (s, 3 H), 3.44 (m, 4 H), 4.50 (s, 4 H), 7.33
(m, 4 H) ppm. 13C NMR (CDCl3): δ = 13.5, 14.7, 15.58, 15.61,
(d, J = 9 Hz, 2 H), 7.79 (d, J = 9 Hz, 2 H) ppm. 13C NMR (CDCl3): 20.9, 21.1, 22.0, 25.7, 27.9, 50.8, 122.8, 126.5, 150.3, 155.3,
δ = 15.9, 21.7, 21.8, 25.8, 50.3, 52.6, 53.6, 111.4, 120.8, 127.7, 130.1,
157.5 ppm. IR (neat): ν = 2966, 2871, 1562, 1416 cm–1. HRMS
˜
134.1, 143.9, 146.5, 146.7, 159.2 ppm. IR (neat): ν = 2963, 2875,
(ESI): calcd. for C17H29N2 [M + H]+ 261.2325; found 261.2328.
˜
2230, 1380, 1173 cm–1. HRMS (ESI): calcd. for C20H26N3O2S [M
+ H]+ 372.1740; found 372.1749.
Dimethyl 3-(Pyrrolidin-1-yl)-5H-cyclopenta[c]pyridine-6,6(7H)-di-
carboxylate (26): General Procedure B was used with diyne 25
(100 mg, 0.48 mmol) and cyanamide 2a (48.4 mL, 0.48 mmol) in
toluene (4.1 mL). The remaining residue was purified by flash col-
umn chromatography using hexanes/ethyl acetate (3:1) to afford
116.8 mg of the title compound as a light-yellow solid; yield 80%.
4,7-Dimethyl-6-(pyrrolidin-1-yl)-1,3-dihydrofuro[3,4-c]pyridine (17):
General Procedure A was used with diyne 16 (103.4 mg,
0.85 mmol) and cyanamide 2a (85.3 mL, 0.85 mmol) in toluene
(7.2 mL). The remaining residue was purified by flash column
chromatography using hexanes/ethyl acetate (2:1) to afford
174.3 mg of the title compound as a colorless oil; yield 94%. 1H
NMR (CDCl3): δ = 1.91 (m, 4 H), 2.13 (s, 1 H), 2.27 (s, 3 H), 3.49
(m, 4 H), 4.99(s, 2 H), 5.02 (s, 2 H) ppm. 13C NMR (CDCl3): δ =
16.1, 21.9, 25.7, 50.2, 72.8, 73.2, 110.3, 123.7, 145.1, 149.9,
1
M.p. 98–99 °C. H NMR (CDCl3): δ = 1.95 (m, 4 H), 3.38 (m, 4
H), 3.45 (s, 4 H), 3.71 (s, 6 H), 6.20 (s, 1 H), 7.92 (s, 1 H) ppm.
13C NMR (CDCl3): δ = 25.6, 37.5, 40.5, 46.9, 53.1, 60.7, 101.8,
123.2, 143.1, 151.0, 157.0, 171.9 ppm. The melting point and spec-
tra match known values.[32]
159.1 ppm. IR (neat): ν = 2960, 2865, 2361, 1591, 1430.5, 1345,
˜
Dimethyl 3-Morpholino-5H-cyclopenta[c]pyridine-6,6(7H)-dicarb-
oxylate (27): General Procedure B was used with diyne 25 (100 mg,
0.48 mmol) and cyanamide 2f (48.5 mL, 0.48 mmol) in toluene
1060 cm–1. HRMS (ESI): calcd. for C13H19N2O [M
219.1492; found 219.1493.
+
H]+
1,4-Diethyl-3-(pyrrolidin-1-yl)-5,6,7,8-tetrahydroisoquinoline (19): (4.1 mL). The remaining residue was purified by flash column
General Procedure A was used with diyne 18 (107 mg, 0.66 mmol)
and cyanamide 2a (66.5 mL, 0.66 mmol) in toluene (5.2 mL). The
remaining residue was purified by flash column chromatography
using hexanes/ethyl acetate (3:1) to afford 156.6 mg of the title
compound as a colorless viscous oil; yield 92%. 1H NMR (CDCl3):
δ = 1.21 (t, J = 7.5 Hz, 3 H), 1.31 (t, J = 7.5 Hz, 3 H), 1.81 (m, 4
H), 1.95 (m, 4 H), 2.69 (m, 8 H), 3.47 (m, 4 H) ppm. 13C NMR
(CDCl3): δ = 12.3, 13.8, 20.5, 23.0, 23.1, 25.6, 25.8, 26.9, 27.6, 51.1,
chromatography using dichloromethane to afford 132.2 mg of the
title compound as a light-yellow wax; yield 86%. 1H NMR
(CDCl3): δ = 3.43 (m, 4 H), 3.49 (s, 4 H), 3.74 (s, 6 H), 3.79 (m, 4
H), 6.51 (s, 1 H), 8.01 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 37.6,
40.6, 46.3, 53.2, 60.7, 66.9, 102.8, 126.32, 143.1, 151.7, 159.5,
171.8 ppm. The spectra match known values.[32]
Dimethyl
3-[(tert-Butoxycarbonyl)(butyl)amino]-5H-cyclopenta-
[c]pyridine-6,6(7H)-dicarboxylate (28): General Procedure B was
used with diyne 25 (100 mg, 0.48 mmol) and cyanamide 2i (96 mg,
0.48 mmol) in toluene (4.1 mL). The remaining residue was puri-
fied by flash column chromatography using dichloromethane to af-
122.2, 123.1, 145.5, 155.4, 157.2 ppm. IR (neat): ν = 2931, 2866,
˜
2361, 1739, 1563, 1416 cm–1. HRMS (ESI): calcd. for C17H27N2 [M
+ H]+ 259.2169; found 259. 2170.
1,4-Dimethyl-3-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta- ford 160.7 mg of the title compound as a light-yellow viscous oil;
1
[c]pyridine (21): General Procedure A was used with diyne 20
(104 mg, 0.70 mmol) and cyanamide 2a (71 mL, 0.70 mmol) in tol-
uene (6 mL). The remaining residue was purified by flash column
chromatography using hexanes/ethyl acetate (3:1) to afford
130.3 mg of the title compound as a colorless viscous oil; yield
76%. 1H NMR (CDCl3): δ = 1.59 (m, 4 H), 1.81 (m, 2 H), 1.89
yield 82%. H NMR (CDCl3): δ = 0.86 (t, J = 7.5 Hz, 3 H), 1.27
(dt, J1 = 5, J2 = 10 Hz, 3 H), 1.48 (s, 9 H), 3.55 (s, 2 H), 3.56 (s, 2
H), 3.74 (s, 6 H), 3.86 (m, 2 H), 7.42 (s, 1 H), 8.17 (s, 1 H) ppm.
13C NMR (CDCl3): δ = 13.9, 20.2, 28.5, 31.2, 37.8, 40.4, 47.1, 53.3,
60.6, 80.8, 116.1, 132.3, 143.0, 150.9, 153.8, 154.6, 171.6 ppm. IR
(neat): ν = 2959, 1739, 1704, 1390, 1276, 1142 cm–1. HRMS (ESI):
˜
(m, 4 H), 2.17 (s, 3 H), 2.42 (s, 3 H), 2.75 (m, 4 H), 3.38 (m, 4 H) calcd. for C21H31N2O6[M + H]+ 407.2177; found 407.2189.
ppm. 13C NMR (CDCl3): δ = 15.7, 23.1, 25.5, 26.8, 27.6, 29.2, 30.1,
Dimethyl 3-(N-Butylacetamido)-5H-cyclopenta[c]pyridine-6,6(7H)-
32.2, 50.4, 116.1, 128.5, 148.9, 152.3, 158.2 ppm. IR (neat): ν =
˜
dicarboxylate (29): General Procedure B was used with diyne 25
(100 mg, 0.48 mmol) and cyanamide 2j (67 mg, 0.48 mmol) in tolu-
ene (4.1 mL). The remaining residue was purified by flash column
chromatography using dichloromethane to afford 155.5 mg of the
2920, 2853, 1570, 1420 cm–1. HRMS (ESI): calcd. for C16H25N2
[M + H]+ 245.2012; found 245.2014.
Dimethyl 4-tert-Butyl-1-methyl-3-(pyrrolidin-1-yl)-5H-cyclopenta-
[c]pyridine-6,6(7H)-dicarboxylate (23): General Procedure A was
used with diyne 22 (70 mg, 0.30 mmol) and cyanamide 2a
(31.0 mL, 0.30 mmol) in toluene (3.0 mL). The remaining residue
was purified by flash column chromatography using hexanes/ethyl
acetate (3:1) to afford 85.4 mg of the title compound as a colorless
1
title compound as a light-yellow viscous oil; yield 93%. H NMR
(CDCl3): δ = 0.84 (t, J = 7.5 Hz, 3 H), 1.27 (dt, J1 = 5, J2 = 10 Hz,
2 H), 1.47 (m, 2 H), 1.93 (br. s, 3 H), 3.61 (s, 4 H), 3.76 (br. s, 8
H), 7.04 (s, 1 H), 8.30 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 13.9,
20.2, 23.2, 30.5, 37.9, 40.4, 48.4, 53.4, 60.4, 117.7, 128.7, 135.1,
1
viscous oil; yield 76%. H NMR (CDCl3): δ = 1.34 (s, 9 H), 1.88
144.7, 152.5, 154.7, 170.2, 171.4 ppm. IR (neat): ν = 2955, 2361,
˜
(m, 4 H), 2.18 (s, 3 H), 3.42 (s, 2 H), 3.48 (m, 4 H), 3.68 (s, 2 H),
1738, 1595, 1434, 1271 cm–1. HRMS (ESI): calcd. for C18H25N2O5
3.75 (s, 6 H) ppm. 13C NMR (CDCl3): δ = 15.7, 25.7, 29.34, 29.55, [M + H]+ 349.1758; found 349.1760.
38.4, 39.2, 40.5, 50.2, 53.2, 60.5, 112.6, 122.3, 151.5, 157.2, 157.8,
Dimethyl 3-[(Methyl)(phenyl)amino]-5H-cyclopenta[c]pyridine-6,6-
172.3 ppm. IR (neat): ν = 2959, 1739, 1704, 1612, 1569, 1480, 1389,
˜
(7H)-dicarboxylate (32): General Procedure B was used with diyne
25 (100 mg, 0.48 mmol) and cyanamide 2p (63.5 mg, 0.48 mmol) in
toluene (4.1 mL). The remaining residue was purified by flash col-
umn chromatography using hexanes/ethyl acetate (1:2) to afford
135.5 mg of the title compound as a light-yellow viscous oil; yield
1275, 1141 cm–1. HRMS (ESI): calcd. for C21H31N2O4 [M + H]+
375.2278; found 375.2284.
2,3,4,5-Tetraethyl-6-(pyrrolidin-1-yl)pyridine (24): General Pro-
cedure A was used with 3-hexyne (75 mL, 0.66 mmol) and cyan-
amide 2a (33.3 mL, 0.33 mmol) in toluene (7.0 mL). The remaining
residue was purified by flash column chromatography using hex-
anes/ethyl acetate (3:1) to afford 74 mg of the title compound as a
waxy colorless oil; yield 86%. 1H NMR (CDCl3): δ = 1.17 (m, 9
1
83%. H NMR (CDCl3): δ = 3.36 (s, 3 H), 3.43 (s, 3 H), 3.48 (s, 3
H), 3.71 (s, 6 H), 6.41 (s, 1 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.21 (d,
J = 10 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2 H), 8.04 (s, 1 H) ppm. 13C
NMR (CDCl3): δ = 37.5, 38.9, 40.4, 53.2, 60.6, 104.8, 125.3, 125.7,
3822
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Nickel-Catalyzed Cycloaddition of Diynes and Cyanamides
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Acknowledgments
The authors thank the Ryan Looper group for the generous do-
nation of N-(4-methoxybenzyl)-N-methylcyanamide and general
advice. We gratefully acknowledge the National Science Founda-
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3823

R. M. Stolley, M. T. Maczka, J. Louie
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Published Online: May 24, 2011
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3815–3824