Iridium-Catalyzed [2+2+2] Cycloaddition of α,ω-Diynes with Cyanamides

Article abstract of DOI:10.1002/adsc.201500637

The complex [Ir(cod)Cl]₂/DPPF or rac-BINAP is an efficient catalyst for the [2+2+2] cycloaddition of α,ω-diynes with cyanamides. A wide range of cyanamides derived from secondary amines are good coupling partners for α,ω-diynes. The reaction of

Full text of DOI:10.1002/adsc.201500637

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DOI: 10.1002/adsc.201500637
Iridium-Catalyzed [2+2+2] Cycloaddition of a,w-Diynes with
Cyanamides
Toru Hashimoto,a Satoshi Ishii,a Reiko Yano,a Hiroki Miura,a,b Ken Sakata,c
and Ryo Takeuchia,*
a
Department of Chemistry and Biological Science, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara,
Kanagawa 252-5258, Japan
Fax: (+81)-42-759-6493; phone: (+81)-42-759-6231; e-mail: takeuchi@chem.aoyama.ac.jp
Present address: Department of Applied Chemistry, Faculty of Urban Environmental Sciences, Tokyo Metropolitan
b
University, 1-1 Minami-Osawa, Hachioji, Tokyo 192-0397, Japan
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
c
Received: July 2, 2015; Revised: August 26, 2015; Published online: November 25, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500637.
Abstract: The complex [Ir(cod)Cl]2/DPPF or rac- that cyanamide is more reactive than nitrile. This
BINAP is an efficient catalyst for the [2+2+2] cyclo- higher reactivity of cyanamide than nitrile was ana-
addition of a,w-diynes with cyanamides. A wide lyzed based on density functional theory (DFT) cal-
range of cyanamides derived from secondary amines culations at the B3LYP level.
are good coupling partners for a,w-diynes. The reac-
tion of unsymmetrical a,w-diynes possessing two dif-
ferent internal alkyne moieties with cyanamides is Keywords: 2-aminopyridines; cyanamides; cycloaddi-
regioselective. A competitive experiment showed tion; diynes; iridium
Introduction
functionalized nitriles. An interesting example is the
Ru-catalyzed reaction, in which the scope of nitriles is
Heterocyclic compounds constitute an important class limited. Only functionalized nitriles such as cyanofor-
of compounds in organic chemistry.[1] New synthetic mate, a-halonitrile and dicyanide can be used for the
methods for heterocyclic compounds have been ex- reaction.[5] Simple nitriles cannot be used for the Ru-
tensively studied. Transition metal-catalyzed cycload- catalyzed reaction. Cyanamide is an important nitrile
ditions provide a new and efficient route to complex in which an amino group directly connects to a nitrile
heterocyclic compounds that are not accessible by carbon.[9] Much attention has been paid to cyanamide
conventional reactions.[2] In particular, reactions in- as a substrate for a transition metal-catalyzed reac-
volving three p-components provide access to many tion.[10] With regard to [2+2+2] cycloaddition, the
complex heterocyclic compounds. Since the pioneer- first example of the reaction of alkyne with cyana-
ing work of Yamazaki and Wakatsuki,[3] the [2+2+2] mide (H2NCN) was reported by Bçnnemann in
cycloaddition of alkynes with nitriles has been studied 1984.[11] The reaction of cyanamide derived from a sec-
as an efficient and environmentally benign route to ondary amine with acetylene under photo-irradiation
pyridines, in contrast to the traditional route based on conditions was reported by Heller.[12] Maryanoff re-
a condensation reaction under strongly acidic or basic ported the CpCo(CO)2-catalyzed reaction of a,w-
conditions. Co,[4] Ru,[5] Rh,[6] Ni[7] and Fe[8] have all diynes with cyanamides (R2NCN).[13] A series of cyan-
been reported as catalysts for the [2+2+2] cycloaddi- amides (R2NCN) was examined by Maryanoff. Louie
tion of alkynes with nitriles. Much attention has been reported the Ni/NHC- and Fe-catalyzed reaction of
paid to the scope of nitriles. Nitriles in which a func- a,w-diynes with cyanamides.[14] Wan also reported the
tional group is directly connected to the nitrile carbon Fe-catalyzed reaction.[15] Only a single experiment has
are especially important, because [2+2+2] cycloaddi- been reported with an Rh catalyst.[6d] However, a new
tion with such nitriles gives functionalized pyridines. catalyst is still needed to expand the reaction scope
Despite its importance in pyridine synthesis, very few and improve the selectivity. 2-Aminopyridine is an at-
studies have examined [2+2+2] cycloaddition with tractive intermediate for the synthesis of biologically
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Toru Hashimoto et al.
active compounds.[16] The general method for the syn- a broader scope of nitriles, since both functionalized
thesis of 2-aminopyridines is the nucleophilic substitu- nitriles and unactivated nitriles can be used. Our pre-
tion of 2-halopyridines. A substitution reaction is vious study[19] showed that a- or b-aminonitrile was
useful for the construction of a simple 2-aminopyri- a good coupling partner for a,w-diynes. An amino
dine ring.[17] However, such a reaction is not suitable group did not inhibit the reaction despite its ability to
for the construction of a more complex multisubstitut- coordinate to the iridium center. This result prompted
ed 2-aminopyridine ring because of the need for fur- us to examine the cycloaddition with cyanamide in
ther synthetic elaboration to introduce other substitu- which an amino group is directly connected to a nitrile
ents into the pyridine ring. Further development of carbon. We report here the [2+2+2] cycloaddition of
the cycloaddition of alkynes with cyanamides has a,w-diynes with cyanamides.
been desired as an efficient and convergent method
for the construction of a multisubstituted 2-aminopyr-
idine ring in a single operation.
Results and Discussion
In the course of our study on iridium-catalyzed
carbon-carbon bond-forming reactions,[18] we found Screening of Ligands and Optimization of the
that [Ir(cod)Cl]2/BINAP was an efficient catalyst for Reaction Conditions
the [2+2+2] cycloaddition of a,w-diynes with ni-
triles.[19] One of the advantages of [Ir(cod)Cl]2 catalyst Diyne 1a reacted with cyanamide 2a to give 2-amino-
over other transition metals, especially Cp- or Cp*-co- pyridine 3aa. The phosphine ligand had a profound
ordinated transition metals, is that we can alter the effect on the reaction. The screening of phosphine li-
catalytic activity and selectivity by choosing appropri- gands was performed in the reaction of diyne 1a with
ate phosphines. The iridium-catalyzed reaction has 1.2 equiv. of cyanamide 2a in the presence of
Table 1. Reaction of diyne 1a with cyanamide 2a.[a]
Entry
Ligand
Conditions
Yield of 3aa [%][b]
1
none
PPh3
DPPE
DPPP
benzene, reflux, 24 h
benzene, reflux, 24 h
benzene, reflux, 13 h
benzene, reflux, 24 h
benzene, reflux, 24 h
benzene, reflux, 24 h
benzene, reflux, 1 h
benzene, reflux, 1 h
benzene, reflux, 24 h
benzene, reflux, 24 h
benzene, reflux, 24 h
dioxane, 808C, 1 h
DCE, 808C, 1 h
0
0
76
0
2
2[c]
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17[f]
18
DPPB
DPPPen[d]
DPPF
0
>99
97
98
80
66
93
96
>99
84
80
0
rac-BINAP
F-DPPE[e]
BIPHEP
DPPBenzene
DPPF
DPPF
DPPF
DPPF
rac-BINAP
DPPF
THF, reflux, 1 h
benzene, 508C, 24 h
benzene, 508C, 24 h
benzene, r.t., 24 h
benzene, r.t., 24 h
rac-BINAP
5
[a]
A mixture of diyne 1a (1 mmol), cyanamide 2a (1.2 mmol), [Ir(cod)Cl]2 (0.005 mmol), ligand (0.01 mmol) and solvent
(2.5 mL) was stirred.
Isolated yield based on the amount of 1a.
PPh3 (0.02 mmol).
1,5-Bis(diphenylphosphino)pentane.
1,2-Bis[di(pentafluorophenyl)phosphino]ethane.
2a (3 mmol), [Ir(cod)Cl]2 (0.01 mmol), DPPF (0.02 mmol), benzene (5 mL).
[b]
[c]
[d]
[e]
[f]
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Iridium-Catalyzed [2+2+2] Cycloaddition of a,w-Diynes with Cyanamides
Table 2. Reaction of diyne 1a with cyanamide 2.[a]
0.5 mol% [Ir(cod)Cl]2 in refluxing benzene at a ratio
of P/Ir=2. The results are summarized in Table 1.
[Ir(cod)Cl]2 without any ligand and [Ir(cod)Cl]2 with
PPh3 did not give 3aa (entries 1 and 2). A bidentate
phosphine ligand was effective. DPPE gave 3aa in
76% yield (entry 3). DPPP, DPPB and DPPPen were
inferior to DPPE (entries 4–6). DPPF gave the best
result, and product 3aa was obtained in quantitative
yield (entry 7). rac-BINAP and F-DPPE were as ef-
fective as DPPF (entries 8 and 9). BIPHEP gave 3aa
in 80% yield (entry 10). DPPBenzene was less effec-
tive than BIPHEP (entry 11). DPPF, rac-BINAP and
F-DPPE were selected as promising ligands. The
effect of the solvent was examined at 808C (en-
tries 12–14). Benzene gave 3aa in a slightly higher
yield than DCE and dioxane (entries 12 and 13). The
reaction under refluxing THF gave 3aa in quantitative
yield (entry 14). The effect of temperature on the re-
action was examined by using DPPF and rac-BINAP
as a ligand. A decrease in the reaction temperature
from 808C to 508C decreased the yield of 3aa (en-
tries 15 and 16). The reaction at room temperature
did not give 3aa (entries 17 and 18). The reaction
temperature needed to be above 508C to obtain 3aa
in high yield. Notably, our Ir catalyst requires
0.5 mol% catalyst loading.
Scope of Cyanamides 2
We subjected various cyanamides 2b–j to the reaction
of 1a under the optimized conditions as noted above.
Diyne 1a reacted with various cyanamides 2b–i to
give 3ab–ai. The results are summarized in Table 2.
Cyanamides derived from secondary amines are good
coupling partners with diyne 1a. The reactions of 1a
with 2b and 2c gave 3ab and 3ac in respective yields
of 91% and 97% (entries 1 and 2). Similarly, cyan-
amides derived from acyclic secondary amines
smoothly underwent cycloaddition with 1a. Products
3ad and 3ae were obtained in respective yields of
93% and 92% (entries 3 and 4). Cyanamide 2f, de-
rived from an aromatic secondary amine, gave a good
result, and product 3af was obtained in quantitative
yield (entry 5). An increase in the steric bulk of the
cyanamide decreased the yield of the product. The re-
actions with 2g and 2h gave slightly lower yields com-
pared to those with 2b–f (entries 6 and 7). The reac-
tion of 1a with diisopropylcyanamide (2i), which is
a more hindered cyanamide than 2a–h, gave 3ai in
31% yield (entry 8). In contrast, cyanamide derived
[a]
A
mixture of diyne 1a (1 mmol), cyanamide
2
(1.2 mmol), [Ir(cod)Cl]2 (0.01 mmol), ligand (0.02 mmol)
and benzene (2.5 mL) was stirred under refluxing ben-
zene for 1 h.
Isolated yield based on the amount of 1a.
For 24 h.
For 15 h.
2i (2.5 mmol).
[b]
[c]
[d]
[e]
[f]
[Ir(cod)Cl]2 (0.02 mmol), rac-BINAP (0.04 mmol), reflux-
ing xylene (2.5 mL) for 24 h.
from a primary amine such as n-hexylamine did not Scope of Diynes 1
react with diyne 1a, and the corresponding product
was not obtained. Cyanamide 2j bearing an acetyl We examined the reactions of various diynes 1b–m
group could be used for the reaction, and product 3aj with cyanamide 2a. The results are summarized in
was obtained in 79% yield under more forcing condi- Table 3. The tether structure of the diyne had a con-
tions (entry 9).
siderable effect on the reaction. Diyne 1b derived
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Table 3. Reaction of diyne 1 with cyanamide 2a.[a]
[a]
A mixture of diyne 1 (1 mmol), cyanamide 2a (1.2 mmol), [Ir(cod)Cl]2 (0.01 mmol), DPPF (0.02 mmol) and solvent
(2.5 mL) was stirred.
Isolated yield based on the amount of 1.
Diyne 1c (0.5 mmol), cyanamide 2a (0.6 mmol), [Ir(cod)Cl]2 (0.005 mmol), DPPF (0.01 mmol) and benzene (2.5 mL).
Cyanamide 2a (5 mmol), rac-BINAP (0.02 mmol).
Diyne 1 (0.5 mmol), cyanamide 2a (0.6 mmol), [Ir(cod)Cl]2 (0.01 mmol), rac-BINAP (0.02 mmol) and solvent (2.5 mL).
[Ir(cod)Cl]2 (0.02 mmol), rac-BINAP (0.04 mmol) and solvent (5 mL).
rac-BINAP (0.02 mmol).
[b]
[c]
[d]
[e]
[f]
[g]
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Iridium-Catalyzed [2+2+2] Cycloaddition of a,w-Diynes with Cyanamides
from acetylacetone and diyne 1c derived from benzyl went completely regioselective cycloaddition to give
acetate reacted with 2a to give 3ba and 3ca in nearly a single product.[19] The regioselectivity could be rea-
quantitative yields (entries 1 and 2). Similarly, diyne sonably explained by the electronic effect of a sub-
1d derived from methone underwent cycloaddition stituent on an alkyne carbon. The regioselectivity of
with 2a to give 3da in 97% yield (entry 3). These the reactions of unsymmetrical internal diynes with
three diynes 1b–d gave products in a yield that was cyanamides has been examined.[14b,c,15] Further im-
comparable to that with diyne 1a derived from malo- provements to achieve a completely regioselective re-
nate. As mentioned above, two carbonyl groups at the action have been desired. We examined the regiose-
5-position gave a good result. Two hydroxymethyl lectivity of the reaction with cyanamide. We subjected
groups at the 5-position of 2,7-nonadiyne decreased unsymmetrical diynes 1n–q to the reaction with cyan-
the yield. The reaction of 1e with 2a gave 3ea in 50% amides 2a and 2d under the optimized conditions
yield (entry 4). Heteroatom-tethered diynes were ex- (Table 4). The structure of the products was deter-
amined. The reaction of 1f with 2a gave 3fa in 79% mined on the basis of 2D-NMR analysis (see the Sup-
yield (entry 5). The reaction of ether-tethered diyne porting Information, pp S27, S29, S31, S33, S35, S37,
1g gave a lower yield than that with tosylamide-teth- S39, S41, S43, S45, S47). Phenyl-substituted diyne 1n
ered diyne 1f (entry 6). The reaction provides an underwent cycloaddition in the presence of DPPF
atom-economical route to biologically important pyri- ligand with 2a to give a 70:30 mixture of 4na and 5na
dine-based fused heterocycles.[20] Diyne 1h with no in 86% yield (entry 1). The regioselectivity was im-
substituents at the 5-position underwent the reaction proved by the use of rac-BINAP instead of DPPF.
with 2a to give 3ha in 59% yield (entry 7), which is The reaction of 1n with 2a in the presence of rac-
lower than the yield with diynes 1a–d. This result BINAP ligand gave 4na in 94% yield as a single prod-
clearly showed that the Thorpe–Ingold effect is im- uct in which a Ph group was substituted at the a-posi-
portant for the reaction with cyanamide. With these tion (entry 2). The reaction of 1n with 2d gave 4nd in
three diynes 1f–h, rac-BINAP was better than DPPF 96% yield as a single product with the same regiose-
(entries 5–7). Various bicyclic pyridines with five- lectivity (entry 3). The reaction of 2-pyridyl-substitut-
membered rings were formed by the reaction. We ed diyne 1o was also regioselective and gave 2,2’-bi-
tried to form bicyclic pyridine with a six-membered pyridine derivatives. Products 4oa and 4od were ob-
ring. Diyne 1i with no substituents at the 5- and 6-po- tained as a single product in respective yields of 93%
sitions gave no product because of the lack of and 95% (entries 4 and 5). This reaction provides
a Thorpe–Ingold effect[21] (entry 8). The substituents a new route to functionalized 2,2’-bipyridines, which
at the 5- and 6-positions were essential for cyclization is expected to have various applications. TMS-substi-
to give a bicyclic pyridine with a six-membered ring. tuted diyne 1p underwent cycloaddition with 2a to
Diyne 1j smoothly underwent cycloaddition with 2a give 5pa in 90% yield as a single product in which the
to give 3ja in 92% yield (entry 9). Cyclization is effec- TMS group was substituted at the b-position
tive for the formation of a six-membered ring. Termi- (entry 6). The reaction of 1p with 2d gave 5pd in 95%
nal diyne 1k could be used for the reaction. The reac- yield with the same regioselectivity (entry 7). Notably,
tion of 1k with 2a gave 3ka in 73% yield under more both reactions exclusively gave the more hindered
forcing reaction conditions than those for 1a product. The regioselectivity of the reaction of 1p was
(entry 10). With a terminal diyne, pyridine formation opposite that of 1n–o. Ethyl-substituted diyne 1q un-
competed with the self-dimerization or self-trimeriza- derwent cycloaddition with 2a to give a 67:33 mixture
tion of 1k. Ethyl-substituted diyne 1l reacted with 2a of 4qa and 5qa in 94% yield (entry 8). The reaction of
to give 3la in 92% yield (entry 11). The reaction of 1l 1q with 2d gave a similar product distribution
gave a yield comparable to that of 1a. Phenyl-substi- (entry 9).
tuted diyne 1m reacted with 2a to give 3ma in 90%
The key intermediate in the cycloaddition is irida-
yield (entry 12). rac-BINAP was better than DPPF cyclopentadiene[22] which is formed by the oxidative
for the reaction of 1m. More-hindered diynes 1l–m cyclization of a,w-diyne to iridium diphosphine spe-
than 1a could be used for the reaction.
cies. The reaction of iridacyclopentadiene with cyan-
amide gives the 2-aminopyridine product. The regio-
selectivity of the reaction of an unsymmetrical diyne
is determined when iridacyclopentadiene reacts with
the carbon-nitrogen triple bond in cyanamide. In our
previous paper,[19] we showed that the regioselectivity
Regioselective [2+2+2] Cycloaddition of
Unsymmetrical Diynes 1n–q
In cycloaddition with nitriles, one of the advantages of the reaction with nitriles was controlled by an elec-
of an iridium catalyst over other transition metal cata- tronic effect. Specifically, the more electron-deficient
lysts is that the reaction is highly regioselective. We a-carbon preferentially reacts with the more electron-
previously reported that unsymmetrical diynes pos- rich nitrile nitrogen.
sessing two different internal alkyne moieties under-
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Table 4. Regioselective [2+2+2] cycloaddition of diynes 1n–q with 2a and 2d.[a]
Entry
Diyne 1
Cyanamide 2
Ligand
Product
Yield [%][b]
Ratio 4/5
1
2
3
1n: R=Ph, E=CO2Me
1n: R=Ph, E=CO2Me
1n: R=Ph, E=CO2Me
1o: R=2-Py, E=CO2Me
1o: R=2-Py, E=CO2Me
1p: R=Me3Si, E=CO2Me
1p: R=Me3Si, E=CO2Me
1q: R=Et, E=CO2Et
1q: R=Et, E=CO2Et
2a
2a
2d
2a
2d
2a
2d
2a
2d
DPPF
4na, 5na
4na
4nd
4oa
4od
5pa
5pd
4qa, 5qa
4qd, 5qd
86
94
96
93
95
90
95
94
94
70/30
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
rac-BINAP
>99/1
>99/1
>99/1
>99/1
1/>99
1/>99
67/33
4[c]
5[c]
6[d]
7[d]
8[e]
9[f]
73/27
[a]
A mixture of diyne 1 (1 mmol), cyanamide 2a or 2d (1.2 mmol), [Ir(cod)Cl]2 (0.01 mmol), ligand (0.02 mmol) and ben-
zene (2.5 mL) was stirred under refluxing for 24 h.
Isolated yield based on the amount of 1.
[b]
[c]
[d]
[e]
[f]
For 1 h.
[Ir(cod)Cl]2 (0.02 mmol), rac-BINAP (0.04 mmol) and benzene (5 mL).
Diyne 1q (0.95 mmol), cyanamide 2d (1.23 mmol).
Diyne 1q (1.05 mmol), cyanamide 2d (1.37 mmol).
With diynes 1n and 1o, a phenyl group or 2-pyridyl
group is substituted at the a-carbon in iridacyclopen-
tadienes 6n or 6o. The Hammett constant shows that
a phenyl group and a 2-pyridyl group are more elec-
tron-withdrawing than
a
methyl group.[23] Thus,
a phenyl- or 2-pyridyl-substituted a-carbon is more
electron-deficient than a methyl-substituted a-carbon.
Consequently, a phenyl- or 2-pyridyl-substituted a-
carbon reacts with an electron-rich nitrile nitrogen to
give 4na, 4nd, 4oa and 4od (Scheme 1).
With diyne 1p, a trimethylsilyl group is substituted
at the a-carbon in iridacyclopentadiene 6p. Based on
the Hammett constant, a trimethylsilyl group is more
electron-donating than a methyl group.[23] The elec-
tron-donating property of a trimethylsilyl group
makes a trimethylsilyl-substituted a-carbon more
electron-rich than a methyl-substituted a-carbon.
Consequently, a trimethylsilyl-substituted a-carbon
reacts with a more electron-deficient nitrile carbon to
give 5pa and 5pd. The steric effect of a trimethylsilyl
group should lead to the formation of the less-hin-
dered product 4pa and 4pd. However, the absence of
the less-hindered product shows that the steric effect
does not determine the regioselectivity. Why doesn’t
the steric effect of a trimethylsilyl group determine
the regioselectivity? The DFT calculation for the re-
action mechanism in our previous paper showed con-
secutive bond formation between iridacyclopenta-
Scheme 1. Regioselective reaction of iridacyclopentadienes
diene and nitrile (Scheme 2).[19] Nitrile coordinates to 6n–q with cyanamide 2.
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Iridium-Catalyzed [2+2+2] Cycloaddition of a,w-Diynes with Cyanamides
Scheme 2. Reaction of a-trimethylsilyl-substituted iridacyclopentadiene with nitrile.
the iridacyclopentadiene plane in an end-on mode. Competitive Reaction of Cyanamide 2a and
This end-on coordination delivers nitrile perpendicu- Benzonitrile
lar to the iridacyclopentadiene plane in intermediate
À
7. C C bond formation via a transition state trans- To compare the reactivity of cyanamide to that of ni-
forms an sp-hybridized nitrile carbon into an sp2-hy- trile, we performed a competitive experiment. The re-
bridized imine carbon. The substituent on the nitrile sults are shown in Scheme 3. The reaction of 1 mmol
carbon bends away from the newly formed C=N of diyne 1a with an equal amount of a mixture of 2a
bond. In intermediates 7 and 8, the distance between and benzonitrile under the optimized conditions in
the TMS group and R group seems to be too large to Table 1 gave 0.89 mmol of 3a and 0.05 mmol of 9.
allow for their effective steric interaction (Scheme 2). Similarly, the reaction of 1 mmol of diyne 1a with an
Thus, regioselection toward two a-carbons is only in- equal amount of a mixture of 2a and 2-cyanopyridine
fluenced by an electronic effect. With diyne 1q, gave 0.71 mmol of 3a and 0.21 mmol of 10. In both re-
a methyl group and an ethyl group are substituted at actions, the product derived from cyanamide 2a was
the a-carbon in iridacyclopentadiene 6q. These predominant. Based on these results, the order of the
groups are electronically similar, but sterically differ- relative reactivities proved to be cyanamide 2a>2-cy-
ent. To avoid steric repulsion between the Et group anopyridine>benzonitirile.
and the R2N group, the less hindered Me-substituted
a-carbon reacts with a nitrile carbon predominantly.
The steric effect determines the regioselection in this
case.
Scheme 3. Competitive reaction of cyanamide 2a and benzonitrile or 2-cyanopyridine.
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Toru Hashimoto et al.
Theoretical Calculations for the Difference in
Reactivity between Cyanamide and Nitrile
The energy diagrams and optimized structures are
shown in Figure 1 and Figure 2, respectively. The end-
on coordination of Me2NCN to iridacyclopentadiene I
To explain why cyanamide is more reactive than ni- gives complex II. The relative Gibbs free energy at
trile, we examined DFT calculations for the reaction 298 K (DG298 K) of II is 4.5 kcalmolÀ1.[28] The first
mechanism. In our previous study, we examined the bond formation between the cyanamide carbon and
reaction mechanism of the model reaction system for the C-5 atom gives the azairidabicyclo[3.2.0]hepta-
iridium-catalyzed cycloaddition with nitriles by using triene complex III through transition state TSI.[29] The
DFT calculations, and proposed a reaction pathway relative free energies of TSI and III are 20.4 and
where the iridacyclopentadiene generated by oxida- 9.5 kcalmolÀ1, respectively, and the barrier height of
tive cyclization of a,w-diyne reacts with nitrile to give TSI from II is 15.9 kcalmolÀ1. Subsequent bond for-
the iridium pyridine complex via an azairidabicy- mation between the cyanamide nitrogen and the C-2
clo[3.2.0]heptatriene complex.[19] Based on the results, atom gives h4-pyridine Ir complex IV via TSII. The
we further carried out B3LYP DFT calculations[24,25] relative free energy of TSII is 16.5 kcalmolÀ1, and the
(LANL2DZ[26] for Ir atom and 6-31G*[27] for other barrier height of TSII from III is 7.0 kcalmolÀ1, which
atoms) to examine the reaction pathway from the iri- is smaller than that of TSI.
dacyclopentadiene to the h4-complex in the model re-
In the case of MeCN, the examined reaction path-
action [Eq (1)], and discuss the difference in the reac- way corresponds to II’!TSI’!III’!TSII’!IV’, as
tivity between Me2NCN and MeCN.
shown in Figure 1. The initial end-on complex II, in
which the s-lone pair orbital at the nitrogen plays an
important role, has almost the same free energy
(4.5 kcalmolÀ1) as the complex II’ (4.2 kcalmolÀ1). On
the other hand, the relative free energy of TSI
(20.4 kcalmolÀ1) is slightly lower than that of TSI’
(21.8 kcalmolÀ1). Moreover, the relative energy of
TSII (16.5 kcalmolÀ1) is much lower than the energy
of TSII’ (22.2 kcalmolÀ1). These results show that the
Figure 1. Relative Gibbs free energy (DG298 K) diagram (kcalmolÀ1) for the model reaction pathways. Relative energies (DE)
are in parentheses.
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Iridium-Catalyzed [2+2+2] Cycloaddition of a,w-Diynes with Cyanamides
Figure 2. Optimized structures of stationary points for the model reaction pathways. Bond lengths are in angstroms.
reaction of I with Me2NCN is preferred to that with
MeCN.
The orbital energy diagrams near frontier orbitals
of MeCN and Me2NCN are shown in Figure 5. The
At the first bond-formation step via TSI’ for the re- orbital energies of HO and (HO-1) MOs in Me2NCN
action of MeCN, electron delocalization from the p are higher than those of the corresponding two degen-
occupied orbital (HOMO) in MeCN to the LUMO, erate p orbitals in MeCN. This suggests that the p-nu-
which is localized at the Ir atom in iridacyclopenta- cleophilicity of the cyano group in Me2NCN is stron-
À
diene, strengthens the Ir N bond (Figure 3a), while ger than that in MeCN. Thus, the electron delocaliza-
electron delocalization from the HOMO of iridacyclo- tion from Me2NCN to iridacyclopentadiene (Fig-
pentadiene to the p* unoccupied orbital (LUMO) in ure 3a, and Figure 4b, c) is enhanced. As a result, the
À
MeCN is responsible for C C bond formation (Fig- relative energies of TSI and TSII are lower than
ure 3b).
those of TSI’ and TSII’. This difference is responsible
In the subsequent step via TSII’, electron delocali- for the higher reactivity of cyanamide than nitrile.
zation from iridacyclopentadiene to MeCN (Fig-
À
ure 4a) participates not only in C C bond formation
but also in N C bond formation. On the other hand,
À
both electron delocalization from the p orbital in
MeCN to the LUMO in iridacyclopentadiene (Fig-
ure 4b) and delocalization from the other p orbital in
MeCN to the (LU+9)MO in iridacyclopentadiene
À
(Figure 4c) contribute to N C bond formation.
Figure 3. Orbital interactions between iridacyclopentadiene
and MeCN at TSI’.
Figure 4. Orbital interactions between iridacyclopentadiene
and MeCN at TSII’.
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Toru Hashimoto et al.
Experimental Section
General Methods and Materials
1H and 13C NMR spectra were measured on JEOL JNM-
ECP 500A, JEOL ECS-400 and JEOL ECX 500II spectrom-
eters using TMS as an internal standard. Samples were dis-
solved in CDCl3. GC analyses were performed on a Shimad-
zu GC-14B or a Shimadzu GC-2014 using 3.2 mm”2 m glass
columns packed with 5% OV-17 on 60/80 mesh Chromosorb
WAW-DMCS. The products were purified by column chro-
matography on 63–210 mesh silica gel (Kanto Kagaku;
Silica Gel 60N). High-resolution mass spectra were obtained
with a JEOL Mstation JMS-700. All reagents and solvents
were dried and purified before use by the usual procedures.
[Ir(cod)Cl]2 was prepared as described previously.[30] Diynes
1a–d,[19] 1e,[31] 1f,[19] 1g and 1h,[32] 1j,[19] 1k,[33] 1l,[19] 1m,[34]
1n,[19] 1o and 1p,[35] and 1q[36] were prepared as described in
the literature. Diyne 1i was purchased. Cyanamides 2b,[14c]
2c,[14b] 2d,[14c] 2f,[14c] 2h,[37] and 2i[15] were prepared as de-
scribed in the literature. Cyanamide 2a was purchased.
Procedure for the Preparation of Cyanamides
CAUTION: cyanogen bromide is toxic, handle in a ventila-
tion hood. Care should be taken during both the set-up and
work-up of cyanation reactions.
Figure 5. Orbital energy diagrams of MeCN and Me2NCN at
the B3LYP/6-31G* level.
n-Hexylmethylcyanamide
(2e):
N-Methylhexylamine
(1.030 g, 8.94 mmol) was added to a solution of cyanogen
bromide (552 mg, 5.21 mmol) dissolved in dry Et2O/THF
(1:1) (16 mL) at 08C. The solution was then stirred for 3 h.
Solids were then filtered off through a pad of celite, and the
filtrate was washed with H2O. The organic phase was dried
with MgSO4, and the solvent was removed under reduced
pressure. Column chromatography of the residue gave 2e
(hexane/AcOEt=4/1; yield: 409 mg (2.92 mmol, 65%);
yellow oil; Rf =0.55 (hexane/AcOEt=7/3); IR (Zn/Se-ATR,
neat): n=2956, 2929, 2860, 2210, 1465, 1379, 1313, 1258,
1209, 1167, 1107, 1061, 894, 784, 730, 638, 609, 598,
Conclusions
We have developed a new and efficient catalyst for
the cycloaddition of alkynes with cyanamides. Our
catalyst system offers considerable advantages com-
pared to previously reported catalyst systems. (i) The
experimental procedure is more convenient than any
previously reported. Pre-treatment of the catalyst
system is not necessary. The procedure simply re-
quires mixing of [Ir(cod)Cl]2 and an appropriate di-
561 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d=0.90 (t, J=
phosphine ligand in solvent before the addition of 7.0 Hz, 3H), 1.28–1.39 (m, 6H), 1.59–1.67 (m, 2H), 2.85 (s,
3H), 2.96 (t, J=7.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz):
d=13.9, 22.4, 26.0, 27.1, 31.3, 38.7, 52.9, 118.6; HR-MS (EI)
m/z=140.1314 [M]+, calcd. for C8H16N2: 140.1313.
Cyclohexylmethylcyanamide (2g): The title compound
was prepared according to the procedure for the preparation
of 2e using N-methylcyclohexylamine (558 mg, 4.93 mmol)
and cyanogen bromide (318 mg, 3.00 mmol). Column chro-
matography of the residue gave 2g (CH2Cl2); yield: 312 mg
(2.26 mmol, 92%); colorless oil; Rf =0.48 (hexane/AcOEt=
7/3); IR (Zn/Se-ATR, neat): n=3006, 2935, 2858, 2208,
substrates. In the case of the Ni catalyst,[14c] air-sensi-
tive Ni(cod)2 and free NHC in DCE must be stirred
for at least 4 h before the reaction. In the case of the
Fe catalyst, an Fe(II) salt must be reduced to a low-
valent Fe catalyst species by Zn before the reac-
tion.[14b,15] (ii) The catalytic activity can be altered at
will through the use of various commercially available
phosphines. (iii) Electronically different unsymmetri-
cal diynes undergo highly regioselective cycloaddition.
The regioselectivity can be explained by electronic ef- 1747, 1451, 1384, 1347, 1269, 1236, 1217, 1169, 1130, 1052,
992, 924, 892, 822, 752, 664 cmÀ1 1H NMR (CDCl3,
;
fects.
Cyanamide is a good substrate for the iridium-cata-
500 MHz): d=1.15–1.20 (m, 1H), 1.23–1.32 (m, 2H), 1.34–
1.42 (m, 2H), 1.63–1.66 (m, 1H), 1.82–1.86 (m, 2H), 1.96–
1.99 (m, 2H), 2.70 (tt, J=4.0 and 10.5 Hz, 1H), 2.85 (s, 3H);
13C NMR (CDCl3, 125 MHz): d=24.8, 25.1, 30.3, 36.8, 59.9,
117.6; HR-MS (EI) m/z=138.1157 [M]+, calcd. for C8H14N2:
138.1157.
N-Cyano-N-n-hexylacetamide (2j): n-Hexylamine (2.50 g,
24.70 mmol) in dry Et2O (30 mL) was added to a solution of
cyanogen bromide (1.570 g, 14.82 mmol) dissolved in dry
Et2O (50 mL) at 08C. The solution was stirred for 1 h. Solids
lyzed [2+2+2] cycloaddition of a,w-diynes. The reac-
tion is an atom-economical route to 2-aminopyridines.
The results described here should lead to new oppor-
tunities for the application of organoiridium chemis-
try in cycloaddition. Further theoretical studies will
be needed to explore the substrate scope and mecha-
nistic considerations.
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Iridium-Catalyzed [2+2+2] Cycloaddition of a,w-Diynes with Cyanamides
were then filtered off through a pad of celite, and the filtrate
was washed with H2O. The organic phase was dried with
MgSO4, and the solvent was removed under reduced pres-
sure. n-Hexylcyanamide was obtained; yield: 1.220 g
(9.67 mmol, 78%). This compound was used without further
purification. n-Hexylcyanamide (976 mg, 7.73 mmol) in
Et2O (5 mL) was added to a suspension of NaH (385 mg,
60 wt% in paraffin oil, 9.63 mmol) in THF (25 mL) at 08C.
The mixture was warmed to room temperature, after which
acetyl chloride (717 mg, 9.13 mmol) was added. The reaction
mixture was stirred for 1 h, and quenched with H2O (1 mL).
The crude reaction mixture was extracted with Et2O (3”
15 mL), and concentrated. Column chromatography of the
residue gave 2j (hexane/AcOEt=9/1); yield: 1.164 g
(6.92 mmol, 90% yield); colorless oil; Rf =0.58 (hexane/
AcOEt=4/1). IR (Zn/Se-ATR, neat): n=2956, 2931, 2861,
2232, 1727, 1462, 1371, 1348, 1244, 1180, 1139, 1037, 1001,
and filled with argon. Benzene (1 mL) was added to the
flask. To the flask were added a benzene (1.5 mL) solution
of cyanamide 2a (112 mg, 1.0 mmol) and 2-cyanopyridine
(104 mg, 1.0 mmol). Diyne 1a (236.2 mg, 1.0 mmol) was
added to the reaction mixture. The mixture was stirred
under reflux for 1 h. The progress of the reaction was moni-
tored by GLC. After the reaction was complete, the solvent
was evaporated under vacuum. Column chromatography of
the residue gave a mixture of 3aa and 10[19] (AcOEt); yield:
341 mg. The molar ratio of 3aa/10 was determined to be
72:28 by NMR.
Dimethyl
1,4-dimethyl-3-morpholino-5H-cyclopenta[c]-
pyridine-6,6(7H)-dicarboxylate (3aa): The title compound
was obtained as a pale yellow oil; yield: 348 mg (>99%,
1.0 mmol scale); mp 93.5–95.08C; Rf =0.48 (hexane/
AcOEt=11/9); IR (Zn/Se-ATR, neat): n=2962, 2909, 2862,
2840, 1730, 1587, 1434, 1420, 1364, 1256, 1196, 1160, 1109,
1
889, 811, 763, 727, 682, 630, 609, 586 cmÀ1; H NMR (CDCl3,
1062, 1034, 925, 850, 799, 610 cmÀ1
;
1H NMR (CDCl3,
500 MHz): d=0.90 (t, J=6.5 Hz, 3H), 1.30–1.36 (m, 6H),
1.65–1.71 (m, 2H), 2.40 (s, 3H), 3.55 (t, J=7.0 Hz, 2H);
13C NMR (CDCl3, 125 MHz): d=13.9, 22.2, 22.4, 25.8, 27.5,
31.1, 46.1, 110.9, 169.3; HR-MS (EI): m/z=169.1339 [M+
H]+, calcd. for C9H17N2O: 169.1341.
500 MHz): d=2.15 (s, 3H), 2.34 (s, 3H), 3.07 (dd, J=4.5 Hz,
J=4.5 Hz, 4H), 3.49 (s, 2H), 3.51 (s, 2H), 3.77 (s, 6H), 3.83
(dd, J=4.5 Hz, J=4.5 Hz, 4H); 13C NMR (CDCl3,
125 MHz): d=14.3, 21.5, 38.5, 39.8, 50.5, 53.1, 59.6, 67.2,
117.7, 128.1, 148.3, 150.3, 160.0, 171.9; HRMS (EI+): m/z=
348.1685 [M]+, calcd. for C18H24N2O5: 348.1685.
Dimethyl
1,4-dimethyl-3-(pyrrolidin-1-yl)-5H-cyclopen-
Typical Procedure for the [2+2+2] Cycloaddition of
Diyne (1) with Cyanamide (2)
ta[c]pyridine-6,6(7H)-dicarboxylate (3ab): The title com-
pound was obtained as a white solid; yield: 303 mg (91%,
1.0 mmol scale); mp 104.5–106.08C; Rf =0.40 (hexane/
AcOEt=4/1); IR (Zn/Se-ATR, neat): n=2960, 2921, 2878,
2850, 1731, 1597, 1579, 1426, 1270, 1157, 1113, 943, 866, 756,
A flask was charged with [Ir(cod)Cl]2 (3.4 mg, 0.005 mmol)
and DPPF (5.5 mg, 0.01 mmol). The flask was evacuated
and filled with argon. To the flask were added benzene
(2.5 mL) and cyanamide (2a) (134 mg, 1.2 mmol). Diyne 1a
(236.2 mg, 1.0 mmol) was added to the reaction mixture.
The mixture was stirred under reflux for 1 h. The progress
of the reaction was monitored by GLC. After the reaction
was complete, the solvent was evaporated under vacuum.
Column chromatography of the residue gave 3aa (n-hexane/
AcOEt=7/3); yield: 348 mg (1.0 mmol, >99%).
706, 607 cmÀ1 1H NMR (CDCl3, 270 MHz): d=1.85–1.90
;
(m, 4H), 2.15 (s, 3H), 2.29 (s, 3H), 3.41–3.47 (m, 8H), 3.75
(s, 6H); 13C NMR (CDCl3, 67.8 MHz): d=15.7, 21.6, 25.4,
38.4, 39.9, 50.1, 53.0, 59.7, 113.3, 124.4, 147.2, 150.0, 158.8,
172.1; HR-MS (FAB): m/z=333.1808 [M+H]+, calcd. for
C18H25N2O4: 333.1814; found .
Dimethyl
1,4-dimethyl-3-(piperidin-1-yl)-5H-cyclopen-
ta[c]pyridine-6,6(7H)-dicarboxylate (3ac): The title com-
pound was obtained as a brown oil; yield: 336 mg (97%,
1.0 mmol scale); Rf =0.58 (hexane/AcOEt=7/3); IR (Zn/Se-
ATR, neat): n=2931, 2849, 1735, 1584, 1432, 1370, 1265,
Competitive Experiment for the [2+2+2] Cyclo-
addition of Diyne (1a) with Cyanamide (2a) and
Benzonitrile
1
1253, 1222, 1199, 1162, 1114, 1061, 857, 754 cmÀ1; H NMR
A flask was charged with [Ir(cod)Cl]2 (6.7 mg, 0.01 mmol)
and DPPF (11.0 mg, 0.02 mmol). The flask was evacuated
and filled with argon. Benzene (1 mL) was added to the
flask. To the flask were added a benzene (1.5 mL) solution
of cyanamide 2a (112 mg, 1.0 mmol) and benzonitrile
(103 mg, 1.0 mmol). Diyne 1a (236.2 mg, 1.0 mmol) was
added to the reaction mixture. The mixture was stirred
under reflux for 1 h. The progress of the reaction was moni-
tored by GLC. After the reaction was complete, the solvent
was evaporated under vacuum. Column chromatography of
the residue gave a mixture of 3aa and 9[19] (AcOEt); yield:
325 mg. The molar ratio of 3aa/9 was determined to be 96:4
by NMR.
(CDCl3, 270 MHz): d=1.54–1.72 (m, 6H), 2.14 (s, 3H), 2.33
(s, 3H), 2.98–3.02 (m, 4H), 3.48 (s, 2H), 3.50 (s, 2H), 3.76
(s, 6H); 13C NMR (CDCl3, 67.8 MHz): d=14.2, 21.5, 24.5,
26.3, 38.5, 39.8, 51.4, 53.0, 59.6, 117.9, 127.3, 147.9, 149.9,
161.4, 171.9; HR-MS (FAB): m/z=347.1958 [M+H]+, calcd.
for C19H27N2O4: 347.1971.
Dimethyl
3-(diethylamino)-1,4-dimethyl-5H-cyclopen-
ta[c]pyridine-6,6(7H)-dicarboxylate (3ad): The title com-
pound was obtained as a pale brown oil; yield: 312 mg
(93%, 1.0 mmol scale); Rf =0.40 (hexane/AcOEt=4/1); IR
(Zn/Se-ATR, neat): n=2965, 2931, 2869, 1736, 1585, 1433,
1259, 1163, 1095, 1059, 964, 952, 863, 804, 687, 601,
591 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d=1.03 (t, J=
6.9 Hz, 6H), 2.12 (s, 3H), 2.32 (s, 3H), 3.11 (q, J=7.0 Hz,
4H), 3.50 (d, J=7.5 Hz, 4H), 3.77 (s, 6H); 13C NMR
(CDCl3, 125 MHz): d=13.3, 14.5, 21.6, 38.6, 40.0, 45.6, 53.0,
59.6, 119.2, 127.1, 147.7, 149.8, 160.2, 172.1; HR-MS (FAB):
m/z=335.1971 [M+H]+, calcd. for C18H27N2O4: 335.1971.
Dimethyl 3-[hexyl(methyl)amino]-1,4-dimethyl-3-morpho-
lino-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ae):
Competitive Experiment for the [2+2+2] Cyclo-
addition of Diyne (1a) with Cyanamide (2a) and 2-
Cyanopyridine
A flask was charged with [Ir(cod)Cl]2 (6.7 mg, 0.01 mmol)
and DPPF (11.0 mg, 0.02 mmol). The flask was evacuated
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Toru Hashimoto et al.
The title compound was obtained as a yellow oil; yield;
346 mg (92%, 1.0 mmol scale); Rf =0.43 (hexane/AcOEt=4/
1); IR (Zn/Se-ATR, neat): n=2952, 2927, 2857, 1737, 1585,
1433, 1261, 1198, 1162, 1103, 1057, 965, 862, 768, 686, 645,
125.6, 129.4, 148.3, 149.1, 159.0, 172.1; HR-MS (FAB): m/z=
363.2301 [M+H]+, calcd. for C20H31N2O4: 363.2284.
Dimethyl 3-(N-hexylacetamido)-1,4-dimethyl-5,7-dihydro-
6H-cyclopenta[c]pyridine-6,6-dicarboxylate (3aj): The title
compound was obtained as a red oil; yield: 319 mg; (79%,
1 mmol scale); Rf =0.40 (AcOEt); IR (Zn/Se-ATR, neat):
n=2954, 2928, 2857, 1736, 1661, 1586, 1434, 1395, 1265,
1232, 1199, 1165, 1131, 1092, 1062, 1027, 952, 859, 828, 762,
601 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d=0.87 (t, J=
6.5 Hz, 3H), 1.27–1.30 (m, 2H), 1.52–1.58 (m, 6H), 2.13 (s,
3H), 2.32 (s, 3H), 2.74 (s, 3H), 3.00 (dd, J=7.5 Hz, J=
7.5 Hz, 2H), 3.48 (s, 2H), 3.50 (s, 2H), 3.76 (s, 6H);
13C NMR (CDCl3, 125 MHz): d=14.0, 14.6, 21.6, 22.6, 26.8,
27.9, 31.7, 38.6, 39.6, 39.9, 53.0, 54.5, 59.6, 117.6, 126.9, 147.7,
150.0, 161.5, 172.1; HR-MS (FAB): m/z=377.2423 [M+H]+,
calcd. for C21H33N2O4: 377.2440.
728, 691, 631, 617, 555 cmÀ1
;
1H NMR (CDCl3, 558C,
500 MHz): d=0.85 (t, J=7.0 Hz, 3H), 1.25–1.31 (m, 4H),
1.52–1.54 (m, 2H), 1.72 (s, 3H), 2.12 (s, 3H), 2.41 (s, 3H),
3.44 (br, 1H), 3.57 (s, 2H), 3.60 (s, 2H), 3.76–3.86 (m, 7H);
13C NMR (CDCl3, 558C, 125 MHz): d=13.6, 13.8, 21.4, 22.1,
22.3, 27.4, 29.2, 38.9, 40.0, 47.7, 53.0, 59.6, 123.7, 133.7, 150.9,
151.3, 152.8, 169.8, 171.4; HR-MS (EI): m/z=404.2302 [M]+,
calcd. for C22H32N2O5: 404.2311.
Dimethyl 3-[methyl(phenyl)amino]-1,4-dimethyl-3-mor-
pholino-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate
(3af): The title compound was obtained as a pale yellow oil;
yield: 366 mg (99%, 1.0 mmol scale); Rf =0.54 (hexane/
AcOEt=3/2); IR (Zn/Se-ATR, neat): n=3006, 2953, 2919,
1734, 1590, 1498, 1434, 1264, 1164, 1105, 1064, 1036, 749,
6,6-Diacetyl-1,4-dimethyl-3-morpholino-6,7-dihydro-5H-
cyclopenta[c]pyridine (3ba): The title compound was ob-
tained as a brown solid; yield; 306 mg; (97%, 1.0 mmol
scale); mp 131.3–132.88C; Rf =0.45 (hexane/AcOEt=9/11);
IR (Zn/Se-ATR, neat): n=2963, 2944, 2893, 2849, 2822,
1697, 1589, 1422, 1361, 1258, 1205, 1162, 1134, 1113, 1034,
1
695 cmÀ1; H NMR (CDCl3, 270 MHz): d=1.88 (s, 3H), 2.40
(s. 3H), 3.34 (s, 3H), 3.53 (s, 2H), 3.59 (s, 2H), 3.78 (s, 6H),
6.59–6.64 (m, 2H), 6.73–6.80 (m, 1H), 7.13–7.20 (m, 2H);
13C NMR (CDCl3, 67.8 MHz): d=14.3, 21.6, 38.7, 38.8, 39.9,
53.1, 59.5, 115.5, 118.5, 122.1, 128.8, 130.5, 148.5, 150.1,
150.9, 156.4, 171.8; HR-MS (EI): m/z=368.1748 [M]+, calcd.
for C21H24N2O4: 368.1736.
924, 851, 700, 587, 569 cmÀ1 1H NMR (CDCl3, 270 MHz):
;
d=2.17 (s, 3H), 2.19 (s, 6H), 2.35 (s, 3H), 3.05–3.08 (m,
4H), 3.39 (d, J=6.3 Hz, 4H), 3.81–3.84 (m, 4H); 13C NMR
(CDCl3, 125 MHz): d=14.3, 21.6, 26.4, 35.4, 36.5, 50.5, 67.2,
74.3, 117.8, 127.8, 148.5, 150.1, 160.0, 201.4; HR-MS (FAB):
m/z=317.1859 [M+H]+, calcd. for C18H25N2O3: 317.1865.
Methyl 1,4-dimethyl-3-morpholino-6-phenyl-6,7-dihydro-
5H-cyclopenta[c]pyridine-6-carboxylate (3ca): The title
compound was obtained as a brown oil; yield: 182 mg (99%,
0.5 mmol scale); Rf =0.50 (hexane/AcOEt=3/2); IR (Zn/Se-
ATR, neat): n=2981, 2955, 2897, 2844, 1726, 1598, 1585,
1417, 1263, 1249, 1210, 1165, 1114, 1036, 967, 930, 867, 728,
Dimethyl
3-[cyclohexyl(methyl)amino]-1,4-dimethyl-3-
morpholino-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate
(3ag): The title compound was obtained as a white solid;
yield: 317 mg; (85%, 1.0 mmol scale); mp 88.0–91.08C; Rf =
0.53 (hexane/AcOEt=3/1); IR (Zn/Se-ATR, neat): n=2947,
2849, 1735, 1599, 1581, 1450, 1432, 1268, 1245, 1157, 1051,
866, 795, 767, 694, 648, 609 cmÀ1
;
1H NMR (CDCl3,
400 MHz): d=1.04–1.15 (m, 1H), 1.17–1.28 (m, 2H), 1.43–
1.53 (m, 2H), 1.58–1.62 (m, 1H), 1.73–1.79 (m, 4H), 2.12 (s,
3H), 2.31 (s, 3H), 2.69 (s, 3H), 3.02 (tt, J=3.2 and 11.6 Hz,
1H), 3.49 (s, 2H), 3.50 (s, 2H), 3.77 (s, 6H); 13C NMR
(CDCl3, 100 MHz): d=14.7, 21.7, 26.05, 26.07, 29.9, 32.9,
38.6, 40.0, 53.0, 59.6, 60.6, 118.0, 126.7, 147.5, 149.9, 161.6,
172.1; HR-MS (EI): m/z=374.2210 [M]+, calcd. for
C21H30N2O4: 374.2206.
1
698, 638, 607 cmÀ1; H NMR (CDCl3, 270 MHz): d=2.19 (s,
3H), 2.39 (s, 3H), 3.07–3.29 (m, 6H), 3.62 (s, 3H), 3.82–3.95
(m, 6H), 7.23–7.39 (m, 5H); 13C NMR (CDCl3, 125 MHz):
d=14.4, 21.6, 40.5, 41.9, 50.6, 52.7, 58.9, 67.2, 117.7, 126.4,
127.1, 128.6, 129.2, 142.6, 148.1, 151.4, 159.8, 175.6; HR-MS
(FAB): m/z=367.2038 [M+H]+, calcd. for C22H27N2O3:
367.2022.
Dimethyl 3-(dibenzylamino)-1,4-dimethyl-3-morpholino-
5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3ah): The
title compound was obtained as a brown oil; yield: 377 mg;
(82%, 1.0 mmol scale); Rf =0.55 (hexane/AcOEt=7/3); IR
(Zn/Se-ATR, neat): n=3028, 2952, 2915, 1734, 1587, 1494,
1,4,5’,5’-Tetramethyl-3-morpholino-5H-2,3,6,7-tetrahydro-
cyclopenta[c]pyridine-6-spiro-2’-cyclohexan-1’,3’-dione
(3da): The title compound was obtained as a white solid;
yield: 346 mg (97%, 1.0 mmol scale); mp 206.2–208.08C;
Rf =0.40 (hexane/AcOEt=1/1); IR (Zn/Se-ATR, neat): n=
2952, 2913, 2886, 2843, 1730, 1696, 1589, 1421, 1323, 1254,
1
1433, 1255, 1197, 1163, 1061, 949, 736, 698 cmÀ1; H NMR
(CDCl3, 270 MHz): d=2.24 (s, 3H), 2.29 (s, 3H), 3.48 (s,
4H), 3.75 (s, 6H), 4.24 (s, 4H), 7.15–7.33 (m, 10H);
13C NMR (CDCl3, 67.8 MHz): d=14.3, 21.4, 38.6, 39.9, 53.0,
55.2, 59.5, 118.8, 126.5, 128.0, 128.1, 128.4, 139.6, 148.0,
150.2, 159.7, 172.0; HR-MS (EI): m/z=458.2213 [M]+, calcd,
for C28H30N2O4: 458.2206.
1115, 1064, 1032, 1020, 930, 852, 804, 610 cmÀ1 1H NMR
;
(CDCl3, 270 MHz): d=0.97 (s, 3H), 1.12 (s, 3H), 2.16 (s,
3H), 2.29 (s, 3H), 2.62 (d, J=14.0 Hz, 2H), 2.82 (d, J=
14.3 Hz, 2H), 3.06 (q, J=4.6 Hz, 4H), 3.30 (s, 2H), 3.36 (s,
2H), 3.83 (q, J=4.3 Hz, 4H); 13C NMR (CDCl3, 125 MHz):
d=14.2, 21.6. 27.4, 29.2, 30.5, 35.3, 39.1, 50.6, 51.3, 67.2,
70.5, 117.8, 126.8, 148.1, 151.1, 160.2, 206.3; HR-MS (FAB):
m/z=357.2184 [M+H]+, calcd. for C21H29N2O3: 357.2178.
(1,4-Dimethyl-3-morpholino-6,7-dihydro-5H-cyclopen-
Dimethyl 3-(diisopropylamino)-1,4-dimethyl-3-morpholi-
no-5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate
(3ai):
The title compound was obtained as a white solid; yield:
113 mg (31%, 1.0 mmol scale): mp 81.1–82.58C; Rf =0.55
(hexane/AcOEt=3/1); IR (Zn/Se-ATR, neat): n=2975,
2958, 2920, 2871, 2845, 1747, 1733, 1585, 1434, 1377, 1302,
ta[c]pyridine-6,6-diyl)dimethanol (3ea): The title compound
was obtained as a pale orange solid; yield: 140 mg (50%,
0.95 mmol scale); mp 146.5–149.78C; Rf =0.15 (AcOEt); IR
(Zn/Se-ATR, neat): n=3407, 3276, 3203, 2951, 2924, 2865,
2846, 1656, 1581, 1420, 1362, 1252, 1108, 1031, 927, 847, 731,
1
1253, 1175, 1058, 959, 849, 816, 671 cmÀ1; H NMR (CDCl3,
270 MHz): d=0.99 (d, J=6.5 Hz, 12H), 2.18 (s, 3H), 2.33 (s,
3H), 3.49–3.58 (m, 6H), 3.77 (s, 6H); 13C NMR (CDCl3,
67.8 MHz): d=14.8, 21.2, 21.8, 38.9, 40.2, 49.4, 53.0, 59.5,
683 cmÀ1 1H NMR (CDCl3, 270 MHz): d=1.58 (br, 2H),
;
3912
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3901 – 3916

FULL PAPERS
Iridium-Catalyzed [2+2+2] Cycloaddition of a,w-Diynes with Cyanamides
2.13 (s, 3H), 2.32 (s, 3H), 2.72 (s, 2H), 2.76 (s, 2H), 3.06–
3.10 (m, 4H), 3.76–3.77 (m, 4H), 3.82–3.86 (m, 4H);
13C NMR (CDCl3, 125 MHz): d=14.3, 21.5, 36.4, 37.7, 48.5,
50.6, 67.3, 69.5, 118.5, 129.8, 149.0, 152.2, 159.7; HR-MS
(EI): m/z=292.1786 [M]+, calcd. for C16H24N2O3: 292.1787.
4,7-Dimethyl-6-morpholino-2-tosyl-2,3-dihydro-1H-pyrro-
lo[3,4-c]pyridine (3fa): The title compound was obtained as
a pale orange solid; yield: 306 mg (79%, 1.0 mmol scale):
mp 166.0–169.08C; Rf =0.50 (hexane/AcOEt=1/1); IR (Zn/
Se-ATR, neat): n=2948, 2911, 2847, 2812, 1608, 1596, 1423,
1341, 1260, 1150, 1116, 1100, 1035, 930, 834, 817, 714, 664,
1H NMR (CDCl3, 270 MHz): d=3.43–3.46 (m, 4H), 3.50 (s,
4H), 3.75 (s, 6H), 3.79–3.83 (m, 4H), 6.53 (s, 1H), 8.02 (s,
1H); 13C NMR (CDCl3, 67.8 MHz): d=37.3, 40.3, 46.0, 53.0,
60.5, 66.7, 102.6, 126.1, 142.9, 151.5, 159.2, 171.6; HR-MS
(EI): m/z=320.1367 [M]+, calcd. for C16H20N2O5: 320.1372.
Dimethyl 1,4-diethyl-3-morpholino-5H-cyclopenta[c]pyri-
dine-6,6(7H)-dicarboxylate (3la): The title compound was
obtained as a brown oil; yield: 375 mg (92%, 1.08 mmol
scale); Rf =0.55 (hexane/AcOEt=3/2); IR (Zn/Se-ATR,
neat): n=2960, 2848, 1735, 1583, 1421, 1362, 1248, 1201,
1
1164, 1116, 1066, 966, 912, 853, 755, 665, 609 cmÀ1; H NMR
1
589, 571 cmÀ1; H NMR (CDCl3, 270 MHz): d=2.09 (s, 3H),
(CDCl3, 270 MHz): d=1.18 (t, J=7.6 Hz, 3H), 1.23 (t, J=
7.6 Hz, 3H), 2.62 (q, J=7.6 Hz, 4H), 3.07 (q, J=4.6 Hz,
4H), 3.50 (s, 2H), 3.52 (s, 2H), 3.76 (s, 6H), 3.83 (q, J=
4.6 Hz, 4H); 13C NMR (CDCl3, 125 MHz): d=12.4, 13.5,
21.3, 28.3, 37.9, 39.3, 51.7, 53.0, 60.1, 67.3, 124.9, 128.4, 150.0,
153.4, 160.0, 171.8; HR-MS (FAB): m/z=377.2089 [M+H]+,
calcd. for C20H29N2O5: 377.2076.
2.28 (s, 3H), 2.42 (s, 3H), 3.04–3.07 (m, 4H), 3.80–3.83 (m,
4H), 4.50–4.52 (m, 4H), 7.32–7.35 (m, 2H), 7.77–7.80 (m,
2H); 13C NMR (CDCl3, 67.8 MHz): d=14.2, 21.5 (2C), 50.4,
52.2, 53.2, 67.0, 116.2, 124.5, 127.5, 129.9, 133.6, 143.8, 146.5,
147.4, 160.5; HR-MS (FAB): m/z=387.1606 [M]+, calcd. for
C20H25N3O3S: 387.1617.
4,7-Dimethyl-6-morpholino-1,3-dihydrofuro[3,4-c]pyridine
(3ga): The title compound was obtained as a pale orange
solid; yield: 71 mg (59%, 0.51 mmol scale); mp 105.0–
108.08C; Rf =0.53 (hexane/AcOEt=1/1); IR (Zn/Se-ATR,
neat): n=2973, 2905, 2845, 2817, 1595, 1455, 1420, 1389,
1365, 1304, 1262, 1137, 1110, 1061, 1029, 931, 922, 901, 847,
Dimethyl 3-morpholino-1,4-diphenyl-5,7-dihydro-6H-cy-
clopenta[c]pyridine-6,6-dicarboxylate (3ma): The title com-
pound was obtained as a pale orange solid; yield: 423 mg
(90%, 1.0 mmol scale): mp 144.5–146.78C; Rf =0.50
(hexane/AcOEt=3/1); IR (Zn/Se-ATR, neat): n=2955,
2911, 2847, 1754, 1735, 1589, 1575, 1560, 1494, 1415, 1396,
1366, 1255, 1239, 1194, 1171, 1115, 1065, 993, 897, 851, 775,
1
767, 687, 593 cmÀ1; H NMR (CDCl3, 270 MHz): d=2.13 (s,
3H), 2.32 (s, 3H), 3.09–3.12 (m, 4H), 3.83–3.86 (m, 4H),
5.00 (s 2H), 5.04 (s, 2H); 13C NMR (CDCl3, 67.8 MHz): d=
14.3, 21.6, 50.4, 67.0, 72.4, 72.8, 114.8, 127.3, 145.8, 149.8,
160.2; HR-MS (EI): m/z=234.1370 [M]+, calcd. for
C13H18N2O2: 234.1368.
1,4-Dimethyl-3-morpholino-6,7-dihydro-5H-cyclopenta[c]-
pyridine (3ha): The title compound was obtained as an
orange solid; yield: 73 mg (59%, 0.53 mmol scale); mp 41.2–
44.58C; Rf =0.50 (hexane/AcOEt=3/1); IR (Zn/Se-ATR,
neat): n=2956, 2918, 2852, 2832, 1584, 1421, 1363, 1301,
700 cmÀ1 1H NMR (CDCl3, 500 MHz): d=3.07–3.09 (m,
;
4H), 3.41 (s, 2H), 3.54–3.56 (m, 4H), 3.69 (s, 6H), 3.81 (s,
2H), 7.31–7.35 (m, 1H), 7.38–7.49 (m, 7H), 7.83–7.85 (m,
2H); 13C NMR (CDCl3, 125 MHz): d=40.0, 40.2, 49.5, 53.0,
60.4, 66.8, 122.5, 126.2, 127.4, 128.2, 128.3, 128.4, 128.7,
129.0, 137.5, 139.7, 149.6, 151.7, 158.4, 171.6; HR-MS (EI):
m/z=472.2004 [M]+, calcd. for C28H28N2O5: 472.1998.
Dimethyl 4-methyl-3-morpholino-1-phenyl-5H-cyclopen-
ta[c]pyridine-6,6(7H)-dicarboxylate (4na): The title com-
pound was obtained as a white solid; yield: 384 mg (94%,
1.0 mmol scale); mp 166.2–168.58C; Rf =0.48 (hexane/
AcOEt=11/9); IR (Zn/Se-ATR, neat): n=2965, 2891, 2849,
1731, 1595, 1560, 1415, 1362, 1254, 1212, 1164, 1115, 1072,
1259, 1114, 1068, 1035, 1014, 923, 849, 686, 584 cmÀ1
;
1H NMR (CDCl3, 270 MHz): d=2.07 (quint, J=7.3 Hz,
1H), 2.15 (s, 3H), 2.34 (s, 3H), 2.76–2.84 (m, 4H), 3.06–3.09
(m, 4H), 3.82–3.86 (m, 4H); 13C NMR (CDCl3, 67.8 MHz):
d=14.3, 21.7, 24.5, 30.5, 31.9, 50.7, 67.3, 117.9, 120.4, 126.0,
132.2, 148.2, 154.5, 159.4; HR-MS (EI): m/z=232.1569 [M]+,
calcd. for C14H20N2O: 232.1576.
1
1037, 944, 900, 851, 784, 758, 703, 693, 635 cmÀ1; H NMR
(CDCl3, 270 MHz): d=2.24 (s, 3H), 3.18–3.19 (m, 4H), 3.53
(s, 2H), 3.74 (s, 6H), 3.80 (s, 2H), 3.85–3.87 (m, 4H), 7.34–
7.38 (m, 1H), 7.43–7.46 (m, 2H), 7.79–7.81 (m, 2H);
13C NMR (CDCl3, 125 MHz): d=14.5, 39.4, 40.2, 50.5, 53.1,
60.1, 67.2, 119.2, 127.1, 128.0, 128.2, 139.8, 148.2, 151.9,
160.2, 171.7; HR-MS (FAB): m/z=411.1933 [M+H]+, calcd.
for C23H27N2O5: 411.1920.
Tetraethyl
1,4-dimethyl-3-morpholino-isoquinoline-
6,6,7,7(5H,8H)-tetracarboxylate (3ja): The title compound
was obtained as a brown oil; yield: 493 mg (92%, 1.0 mmol
scale); Rf =0.53 (hexane/AcOEt=1/1); IR (Zn/Se-ATR,
neat): n=2981, 2958, 2908, 2849, 1730, 1572, 1427, 1365,
1262, 1239, 1199, 1116, 1037, 925, 864, 749, 736, 697,
Dimethyl 1-methyl-3-morpholino-4-phenyl-5H-cyclopen-
ta[c]pyridine-6,6(7H)-dicarboxylate (5na): The title com-
pound was obtained as a white solid; yield: 107 mg (26%,
1 mmol scale); mp 135.0–137.88C; Rf =0.48 (hexane/
AcOEt=3/2); IR (Zn/Se-ATR, neat): n=3057, 2990, 2951,
2910, 2854, 2838, 1754, 1724, 1577, 1436, 1417, 1369, 1274,
1254, 1195, 1163, 1150, 1114, 1068, 1048, 1033, 1020, 956,
580 cmÀ1 1H NMR (CDCl3, 270 MHz): d=1.20–1.26 (m,
;
12H), 2.15 (s, 3H), 2.37 (s, 3H), 3.03–3.07 (m. 4H), 3.32–
3.34 (m, 4H), 3.82–3.85 (m, 4H), 4.14–4.23 (m, 8H);
13C NMR (CDCl3, 125 MHz): d=13.5, 13.7, 22.1, 31.7, 32.9,
50.7, 53.4, 56.8, 57.0, 61.8, 61.9, 67.2, 119.3, 121.1, 142.0,
151.1, 158.6, 169.77, 169.82; HR-MS (EI): m/z=534.2584
[M]+, calcd. for C27H38N2O9: 534.2577.
926, 901, 853, 787, 756, 707, 692, 676, 644, 617, 573 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d=2.39 (s, 3H), 2.98–3.00 (m,
4H), 3.38 (s, 2H), 3.50–3.52 (m, 6H), 3.72 (s, 6H), 7.27–7.32
(m, 1H), 7.40–7.41 (m, 4H); 13C NMR (CDCl3, 125 MHz):
d=21.8, 38.3, 40.4, 49.6, 53.0, 59.8, 66.8, 121.2, 127.06,
127.12, 128.6, 129.0, 137.8, 149.9, 150.0, 158.3, 171.8; HR-MS
(EI): m/z=410.1838 [M]+, calcd. for C23H26N2O5: 410.1842.
Dimethyl 3-diethylamino-4-methyl-1-phenyl-5H-cyclopen-
ta[c]pyridine-6,6(7H)-dicarboxylate (4nd): The title com-
Dimethyl
pyridine-6,6(7H)-dicarboxylate (3ka): The title compound
was obtained as white solid; yield: 234 mg; (73%,
1,4-dimethyl-3-morpholino-5H-cyclopenta[c]-
a
1.0 mmol scale); mp 146.0–147.08C; Rf =0.45 (hexane/
AcOEt=9/1); IR (Zn/Se-ATR, neat): n=2964, 2900, 2845,
2816, 1730, 1619, 1560, 1486, 1415, 1277, 1241, 1200, 1154,
1116, 1069, 1046, 966, 934, 883, 835, 761, 651, 595 cmÀ1
;
Adv. Synth. Catal. 2015, 357, 3901 – 3916
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3913

FULL PAPERS
Toru Hashimoto et al.
pound was obtained as a yellow oil; yield: 380 mg (96%,
1.0 mmol scale); Rf =0.45 (hexane/AcOEt=7/3); IR (Zn/Se-
ATR, neat): n=2960, 2918, 2851, 1731, 1597, 1561, 1416,
1374, 1252, 1203, 1170, 1065, 1026, 965, 876, 756, 694, 627,
37.5, 42.3, 47.4, 53.0, 59.7, 121.8, 128.5, 152.0, 157.5, 167.1,
172.0; HR-MS (EI): m/z=392.2131 [M]+, calcd. for
C20H32N2O4Si: 392.2131.
Diethyl 1-ethyl-4-methyl-3-morpholino-5,7-dihydro-6H-cy-
clopenta[c]pyridine-6,6-dicarboxylate (4qa): The title com-
pound was obtained as a colorless oil; yield: 236 mg (64%,
0.95 mmol scale); Rf =0.54 (hexane/AcOEt=7/3); IR (Zn/
Se-ATR, neat): n=2963, 2913, 2849, 1731, 1584, 1447, 1422,
1407, 1384, 1363, 1248, 1205, 1185, 1159, 1132, 1117, 1066,
565 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d=1.11 (t, J=
7.0 Hz, 6H), 2.21 (s, 3H), 3.21 (q, J=7.0 Hz, 4H), 3.53 (s,
2H), 3.74 (s. 6H), 3.80 (s, 2H), 7.32–7.35 (m, 1H), 7.42–7.45
(m, 2H), 7.79–7.81 (m, 2H); 13C NMR (CDCl3, 125 MHz):
d=13.4, 14.8, 39.6, 40.2, 45.4, 53.0, 60.0, 120.3, 125.9, 127.7,
128.1, 128.3, 140.3, 147.6, 151.4, 160.4, 171.9; HR-MS (EI):
m/z=396.2041 [M]+, calcd. for C23H28N2O4: 396.2049.
1
1054, 1032, 939, 924, 859, 732, 666 cmÀ1; H NMR (CDCl3,
500 MHz): d=1.22 (t, J=8.0 Hz, 3H), 1.27 (t, J=6.5 Hz,
6H), 2.15 (s, 3H), 2.62 (q, J=8.0 Hz, 2H), 3.09–3.10 (m,
4H), 3.47 (s, 2H), 3.51 (s, 2H), 3.82–3.84 (m, 4H), 4.22 (q,
J=8.0 Hz, 4H); 13C NMR (CDCl3, 125 MHz): d=12.5, 14.0,
14.3, 28.3, 38.0, 39.6, 50.6, 59.9, 61.8, 67.2, 117.4, 127.4, 150.5,
153.0, 159.9, 171.5; HR-MS (EI): m/z=390.2154 [M]+, calcd.
for C21H30N2O5: 390.2155.
Dimethyl 4-methyl-3-morpholino-1-pyridyl-5H-cyclopen-
ta[c]pyridine-6,6(7H)-dicarboxylate (4oa): The title com-
pound was obtained as a white solid; yield: 381 mg (93%,
1.0 mmol scale); mp 206.0–208.08C; Rf =0.50 (hexane/
AcOEt=1/1); IR (Zn/Se-ATR, neat): n=2968, 2954, 2890,
2843, 1730, 1583, 1556, 1423, 1413, 1362, 1278, 1254, 1196,
1162, 1117, 1100, 1076, 1050, 1037, 943, 925, 904, 851, 801,
Diethyl 4-ethyl-1-methyl-3-morpholino-5,7-dihydro-6H-cy-
clopenta[c]pyridine-6,6-dicarboxylate (5qa): The title com-
pound was obtained as a white solid; yield: 114 mg (30%,
0.95 mmol scale); mp 82.2–83.48C; Rf =0.47 (hexane/
AcOEt=7/3); IR (Zn/Se-ATR, neat): n=2966, 2905, 2855,
2818, 1753, 1725, 1583, 1468, 1422, 1381, 1364, 1296, 1272,
1248, 1228, 1201, 1188, 1162, 1130, 1119, 1098, 1070, 1048,
760, 745, 706, 672, 645, 618, 558 cmÀ1 1H NMR (CDCl3,
;
500 MHz): d=2.25 (s, 3H), 3.19 (m, 4H), 3.52 (s, 2H), 3.76
(s, 6H), 3.88 (m, 4H), 4.15 (s, 2H), 7.19–7.22 (m, 1H), 7.74–
7.77 (m, 1H), 8.33–8.34 (m, 1H), 8.64–8.65 (m, 1H);
13C NMR (CDCl3, 125 MHz): d=14.6, 39.3, 41.4, 50.6, 53.0,
59.8, 67.1, 120.8, 122.2, 122.3, 129.4, 136.1, 146.0, 148.4,
152.6, 158.0, 159.5, 172.3; HR-MS (EI): m/z=411.1799 [M]+,
calcd. for C22H25N3O5: 411.1794.
1031, 1014, 955, 925, 861, 771, 736, 680, 615, 577 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d=1.17 (t, J=7.5 Hz, 3H),
1.27 (t, J=7.0 Hz, 6H), 2.34 (s, 3H), 2.62 (q, J=7.5 Hz,
2H), 3.03–3.05 (m, 4H), 3.48 (s, 2H), 3.51 (s, 2H), 3.82–3.84
(m, 4H), 4.22 (q, J=7.0 Hz, 4H); 13C NMR (CDCl3,
125 MHz): d=13.6, 14.0, 21.3, 21.6, 38.2, 39.3, 51.7, 60.1,
61.8, 67.3, 125.2, 129.5, 148.7, 150.1, 160.1, 171.4; HR-MS
(EI): m/z=390.2154 [M]+, calcd. for C21H30N2O5: 390.2155.
Dimethyl 3-diethylamino-4-methyl-1-pyridyl-5H-cyclopen-
ta[c]pyridine-6,6(7H)-dicarboxylate (4od): The title com-
pound was obtained as a white solid; yield: 377 mg (95%,
1.0 mmol scale); mp 96.5–98.08C; Rf =0.58 (hexane/
AcOEt=7/3); IR (Zn/Se-ATR, neat): n=2999, 2952, 2871,
2836, 1732, 1583, 1462, 1417, 1340, 1246, 1205, 1166, 1069,
853, 797, 742, 690, 662, 561 cmÀ1
;
1H NMR (CDCl3,
500 MHz): d=1.11 (t, J=7.0 Hz, 6H), 2.23 (s, 3H), 3.22 (q,
J=7.0 Hz, 4H), 3.53 (s, 2H), 3.76 (s, 6H), 4.15 (s, 2H),
7.17–7.20 (m, 1H), 7.72–7.76 (m, 1H), 8.31–8.32 (m, 1H),
8.63–8.65 (m, 1H); 13C NMR (CDCl3, 125 MHz): d=13.2,
14.9, 39.4, 41.5, 45.4, 52.9, 59.8, 121.8, 122.1, 122.2, 128.2,
136.0, 145.4, 148.3, 152.2, 158.5, 159.6, 172.4; HR-MS (EI):
m/z=397.1998 [M]+, calcd. for C22H27N3O4: 397.2002.
Diethyl
3-(diethylamino)-1-ethyl-4-methyl-5,7-dihydro-
6H-cyclopenta[c]pyridine-6,6-dicarboxylate (4qd): The title
compound was obtained as a pale yellow oil; yield: 271 mg
(68%, 1.05 mmol scale); Rf =0.48 (hexane/AcOEt=17/3);
IR (Zn/Se-ATR, neat): n=2970, 2933, 2871, 1732, 1597,
1583, 1448, 1422, 1367, 1337, 1251, 1209, 1181, 1159, 1098,
1054, 1012, 861, 802 cmÀ1; H NMR (CDCl3, 500 MHz): d=
1
Dimethyl 1-methyl-3-morpholino-4-(trimethylsilyl)-5H-cy-
clopenta[c]pyridine-6,6(7H)-dicarboxylate (5pa): The title
compound was obtained as a brown oil; yield: 365 mg (90%,
1.0 mmol scale); Rf =0.53 (hexane/AcOEt=11/9); IR (Zn/
Se-ATR, neat): n=2953, 2916, 2851, 1736, 1572, 1434, 1402,
1377, 1360, 1255, 1201, 1165, 1115, 1071, 920, 904, 839, 754,
1.04 (t, J=7.0 Hz, 6H), 1.21 (t, J=7.5 Hz, 3H), 1.27 (t, J=
7.0 Hz, 6H), 2.13 (s, 3H), 2.61 (q, J=7.5 Hz, 2H), 3.12 (q,
J=7.0 Hz, 4H), 3.47 (s, 2H), 3.51 (s, 2H), 4.22 (q, J=
7.0 Hz, 4H); 13C NMR (CDCl3, 125 MHz): d=12.7, 13.2,
14.0, 14.5, 28.3, 38.1, 39.8, 45.6, 59.8, 61.8, 118.8, 126.4, 150.1,
152.4, 160.1, 171.7; HR-MS (EI): m/z=376.2357 [M]+, calcd.
for C21H32N2O4: 376.2362.
1
693, 644 cmÀ1; H NMR (CDCl3, 500 MHz): d=0.35 (s, 9H),
2.38 (s, 3H), 2.95 (s, 4H), 3.47 (s, 2H), 3.61 (s, 2H), 3.77 (s,
6H), 3.81–3.83 (m. 4H); 13C NMR (CDCl3, 125 MHz): d=
1.9, 21.9, 37.7, 42.5, 52.7, 53.1, 59.4, 66.8, 122.6, 130.9, 153.5,
157.6, 168.1, 171.9; HRMS (FAB): m/z=407.1989 [M+H]+,
calcd. for C20H31N2O5Si: 407.2002.
Diethyl
3-(diethylamino)-4-ethyl-1-methyl-5,7-dihydro-
6H-cyclopenta[c]pyridine-6,6-dicarboxylate (5qd): The title
compound was obtained as a colorless oil; yield: 102 mg
(26%, 1.05 mmol scale); Rf =0.40 (hexane/AcOEt=17/3);
IR (Zn/Se-ATR, neat): n=2972, 2933, 2871, 1732, 1585,
1443, 1423, 1367, 1333, 1252, 1206, 1182, 1159, 1098, 1064,
Dimethyl
3-(diethylamino)-1-methyl-4-(trimethylsilyl)-
5H-cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (5pd): The
title compound was obtained as an yellow oil; yield: 372 mg
(95%, 1.0 mmol scale); Rf =0.50 (hexane/AcOEt=7/3); IR
(Zn/Se-ATR, neat): n=2954, 2895, 2870, 1738, 1571, 1556,
1434, 1402, 1371, 1358, 1251, 1201, 1163, 1071, 1051, 888,
1
860, 597, 582 cmÀ1; H NMR (CDCl3, 500 MHz): d=1.01 (t,
J=6.5 Hz, 6H), 1.12 (t, J=7.5 Hz, 3H), 1.27 (t, J=7.5 Hz,
6H), 2.33 (s, 3H), 2.61 (q, J=7.5 Hz, 2H), 3.06 (q, J=
6.5 Hz, 4H), 3.48 (s, 2H), 3.52 (s, 2H), 4.22 (q, J=7.5 Hz,
4H); 13C NMR (CDCl3, 125 MHz): d=13.4 (2C), 14.0, 21.4,
21.6, 38.4, 39.4, 47.1, 60.0, 61.8, 127.1, 128.8, 148.3, 149.6,
160.1, 171.6; HR-MS (EI): m/z=376.2357 [M]+, calcd. for
C21H32N2O4: 376.2362.
839, 756, 688, 642, 604, 578 cmÀ1
;
1H NMR (CDCl3,
500 MHz): d=0.34 (s, 9H), 0.95 (t, J=7.5 Hz, 6H), 2.34 (s,
3H), 3.05 (q, J=7.5 Hz, 4H), 3.45 (s, 2H), 3.58 (s, 2H), 3.76
(s, 6H); 13C NMR (CDCl3, 125 MHz): d=1.7, 12.1, 21.9,
3914
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FULL PAPERS
Iridium-Catalyzed [2+2+2] Cycloaddition of a,w-Diynes with Cyanamides
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This research was supported by Grant-in-Aid for Scientific
Research (C) from the Japan Society for the Promotion of
Science (25410119) and the Ministry of Education, Culture,
Sports, Science, and Technology of Japan. We thank Mr. Yuta
Ito and Mr. Yoshiya Sekiguchi for experimental assistance.
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Adv. Synth. Catal. 2015, 357, 3901 – 3916