Iron-catalyzed cycloaddition reaction of diynes and cyanamides at room temperature

Article abstract of DOI:10.1021/jo400057t

An iron-catalyzed [2 + 2 + 2] cycloaddition reaction of diynes and cyanamides at room temperature is reported. Highly substituted 2-aminopyridines were obtained in good to excellent yields with high regioselectivity. Insights toward the reaction process w

Full text of DOI:10.1021/jo400057t

Article
pubs.acs.org/joc
Iron-Catalyzed Cycloaddition Reaction of Diynes and Cyanamides
at Room Temperature
Chunxiang Wang, Dongping Wang, Fen Xu, Bin Pan, and Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
S
* Supporting Information
ABSTRACT: An iron-catalyzed [2 + 2 + 2] cycloaddition
reaction of diynes and cyanamides at room temperature is
reported. Highly substituted 2-aminopyridines were obtained
in good to excellent yields with high regioselectivity. Insights
toward the reaction process were investigated through in situ
IR spectra and control experiments. In this iron-catalyzed cycloaddition reaction, the active iron species was generated only in the
presence of both alkynes and nitriles. The lower reaction temperature, broad substrates scope, and inversed regioselectivity make
it a complementary method to the previously developed iron catalytic system.
reactivity. Preliminary results indicated that the formation of
benzene byproducts7 was strongly inhibited in the presence of
nitriles, but a certain amount of nitrile and relatively long reaction
time were necessary in our system. Independently, Louie and co-
workers reported an iron-catalyzed cycloaddition reaction of
alkynenitriles and alkynes using a similar strategy (eq 2).8a Later,
they applied the catalyst system to the reaction of diynes and
cyanamides with slight modification by increasing the metal/
ligand ratio from 1:1.3 to 1:2 (eq 3).8b Reactions of diynes with
unactivated nitriles under Louie’s system afforded only trace
amount of pyridine products.8b In contrast, cyanamides were
good substrates for the formation of 2-aminopyridines where
only 5 mol % catalyst and 1.2 equiv of cyanamide were required
to afford the desired products in good yields.
Synthesis of 2-aminopyridines from [2 + 2 + 2] cycloaddition
of alkynes and cyanamides has been reported as a part or a
single example in most previous works, including the cobalt,9
rhodium,10 nickel,3m and titanium11 catalytic systems and a
photocatalytic system.12 In contrast, systematic studies on the
formation of 2-aminopyridines via cycloaddition reaction of
alkynes with cyanamides have rarely been reported.8b,13
Maryanoff and co-workers described the cycloaddition of
diynes with cyanamides using CpCo(CO)2 as a catalyst at
high temperature (ca. 100 °C).13a More recently, Louie and co-
workers developed a Ni/NHC-catalyzed system for the
formation of 2-aminopyridines at room temperature13b and
later reported a Fe/bis(aldimino)pyridine (L2) catalytic sys-
tem.8b The 2-aminopyridine products were obtained in moderate
to excellent yields in both cases. However, in the case of Ni,
air-sensitive Ni(COD)2 must be stored at −20 °C and can be
easily decomposed. In the case of Fe, high reaction temperature
was generally required, and benzene14 was selected as solvent.
Therefore, a milder and more environmentally benign method is
desired.
INTRODUCTION
■
Transition-metal-catalyzed [2 + 2 + 2] cycloaddition reaction of
two molecular of alkynes and one molecular of nitrile is one of
the most powerful methods to construct pyridine cores.1 Com-
pared with other traditional methods,2 the cycloaddition reaction
is extremely atom-efficient and can generate two C−C bonds and
one C−N bond simultaneously in a single step. Simple modifica-
tion on the substituents of the alkyne or nitrile moieties makes it
possible to synthesize multisubstituted pyridines. However,
despite numerous studies in this field,3,4 only a few examples
based on the iron catalysis have been reported.5
Iron is generally regarded as a cheap, benign, relatively non-
toxic, and abundant metal compared with other late transition
metals. Many transformations can be effectively promoted by
iron catalysis.6 Recently, we have reported a simple and efficient
iron catalyst for the cycloaddition reaction of diynes and un-
activated nitriles at room temperature (eq 1).4a The appropriate
ligand as well as the metal/ligand ratio plays a crucial role on the
Received: January 10, 2013
Published: February 1, 2013
© 2013 American Chemical Society
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In the course of our study on the metal-catalyzed cycloaddition
reactions,4 we found that FeI2/dppp/Zn is an efficient catalyst
for the cycloaddition of diynes and unactivated nitriles to give
pyridines.4a In view of the fact that the use of cyanamides instead
of unactivated nitriles as coupling partners can show higher
reactivity in the cycloaddition reaction, herein we report the
iron-catalyzed [2 + 2 + 2] cycloaddition reaction of diynes
and cyanamides at room temperature to afford 2-aminopyridines.
The high reactivity of this catalyst allows the synthesis of
2-aminopyridines at ambient temperature with lower catalyst
loading or without requiring a large excess of cyanamide. The use
of commercial available iron salt and ligand makes this method
more elegant.
in the previous nickel system,13b also gave the desired products
(entries 6 and 7), albeit a lower yield of product 3g was observed
under 5 mol % catalyst. In addition to dialkylcyanamides, methyl-
phenyl (2h) and dibenzyl (2i) substituted cyanamides were
evaluated to produce 2-aminopyridines in excellent yields
(entries 8 and 9). The reactions of various diynes with model
cyanamide 2a were also tested and afforded good to excellent
yields. Diynes without a tertiary center on the tether chain
furnished the corresponding 2-aminopyridines with good yields
(entries 11 and 12); however, only trace amount of product 3l
was obtained in the presence of 5 mol % catalyst. In addition, the
challenging terminal diyne 1e gave 2-aminopyridine 3m in good
yield (entry 13). It is worth noting that the difficult substrate
phenyl-substituted diyne (1f), which showed no reactivity in the
previous iron system,8b was compatible with our catalytic system
to give 2-aminopyridine 3n in excellent yield (entry 14). Never-
theless, in accordance with previous work,8b TMS substituted
diyne (1g) was completely unreactive (entry 15).
RESULTS AND DISCUSSION
■
Initially, diyne 1a and cyanamide 2a were selected as the model
substrates to screen reaction conditions. We were delighted to
find that 2-aminopyridine 3a was obtained in 99% yield (Table 1,
To further evaluate the reactivity of our catalytic system,
unsymmetrical diynes were subjected to the cycloaddition reac-
tion with 2 equiv of cyanamide 2a (entries 16−18). Moderate to
good yields were obtained in these cases. Nevertheless, slightly
different from our previous results,4a the 2-aminopyridine prod-
uct was not produced as a single regioisomer. For example, the
reaction of Me, H substituted diyne 1h and cyanamide 2a
afforded 2-aminopyridine 3p as the major product in 67% yield
with a 94:6 ratio of 3p:3p′ (entry 16). This result may ascribe
to the inherent electronic structure of cyanamides. A similar
regioselectivity was observed in the reaction with NTs-based
Ph, Me substituted diyne 1j. (Note: malonate backbone Ph,
Me substituted diyne provided a similar product ratio in 94%
combined yield, but the two regioisomers failed to be separated
due to the same polarity.) Interestingly, a bulkier TMS, Me
substituted diyne 1i gave the product as a single regioisomer
(entry 17). In consistency with our previous observations,4a the
larger alkyne substituent of the major product was placed ortho
to the nitrile substituent. As demonstrated by the reaction of
diyne 1j and cyanamide 2a under different catalytic systems in
Louie’s report,8b the contrast in regioselectivity between our
system and their system showed an interesting example of ligand-
dependent regioselectivity. Unfortunately, the reason is still
unknown and will be a topic of further investigation.
In our previous work, we have shown that the intermolecular
reaction of phenylacetylene and CH3CN successfully took place
to afford two regioisomers in a 66% combined yield with a 10:1
ratio, and no unwanted side products were detected.4a Following
this avenue, the complete intermolecular [2 + 2 + 2] cyclo-
addition of monoyne 1k and cyanamide 2a was conducted under
our system (eq 4) and Louie’s system (eq 5), respectively.
Different products (3s and 3t) were obtained in comparable
yields (70% versus 62%). This result suggested that these two
iron-based systems may provide a complementary method to
exclusively synthesize 2-amino-3,6-diaryl pyridines or 2-amino-
4,6-diaryl pyridines from the same starting materials.
a
Table 1. Screening Reaction Conditions
b
b
entry
x
2a (equiv)
conv (%)
yield (%)
1
2
3
10
5
10
5
100
100
86
99
99
83
97
99
5
2
c
4
5
2
100
100
5
10
2
a
0.25 mmol 1a, x mol % FeI2, 2x mol % dppp, 2x mol % Zn, 1 mL
THF, rt, 24 h [dppp = 1,3-bis(diphenylphosphino)propane]. Deter-
mined by GC. Naphthalene was used as internal standard. 36 h.
b
c
entry 1) at room temperature using our previous developed
catalytic system (10 mol % FeI2, 20 mol % dppp, and 20 mol %
Zn in THF). Reducing the catalyst loading and nitrile amount
by half, the reaction took place smoothly without any loss of
yield (entry 2). Further decreasing the nitrile amount to 2 equiv
led to a lower but acceptable yield (83%, entry 3). This result
suggested that an excess amount of nitrile was required to achieve
satisfactory yield; however, this problem can be fixed by
prolonging the reaction time to 36 h (97%, entry 4) or using
higher catalyst loading (99%, entry 5). Considering that changing
additive senquence by slow addition of diyne into cyanamide
does not essentially alter the reactivity of catalyst, we tested the
scope of the reaction under the following conditions with-
out using the inconvenient syringe pump technique: 5 mol %
catalyst, 5 equiv of cyanamide or 10 mol % catalyst, 2 equiv of
cyanamide at room temperature for 24 h.
Reactions of various diynes and cyanamides to give 2-amino-
pyridine derivatives were examined under the optimized reaction
conditions above. The results are summarized in Table 2.
Dialkylcyanamides 2a−2f reacted efficiently with malonate
backbone diyne 1a to afford products in good to excellent yields
(entries 1−6). Notably, cycloaddition of diethyl cyanamide 2e,
which was a problematic substrate in the previous iron system,8b
successfully provided the product 3e in good yield (entry 5).
Specifically, the substrates diisopropylcyanamide 2f and
diallylcyanamide 2g, completely unreactive toward cycloaddition
Regarding the mechanism, early studies indicate that Louie’s
system follows the mechanism of cobalt-catalyzed pyridine for-
mation via a ferracyclopentadiene intermediate 4, whereas our
system follows the mechanism of nickel-catalyzed pyridine for-
mation via an azaferracyclopentadiene intermediate 5, as shown
in Scheme 1.8b However, the real reaction process is completely
a black box in these catalytic systems.4a,8 To gain insight into
the mechanism, we monitored the reaction of 1a and 2a (2 equiv)
by using in situ IR spectra (Figure 1). Disappointedly, no intermediate
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a
Table 2. Iron-Catalyzed Cycloaddition of Diynes and Cyanamides
a
b
c
0.5 mmol diyne, 2 mL THF, rt, 24 h, with protocol A or protocol B. Isolated yields. Protocol A: 5 mol % FeI2, 10 mol % dppp, 10 mol % Zn dust,
d
e
f
5 equiv of cyanamide. Protocol B: 10 mol % FeI2, 20 mol % dppp, 20 mol % Zn dust, 2 equiv of cyanamide. Ts = p-toluenesulfonyl. Cycloaddition
of diyne 1a with cyanamide 2f or 2i also reacted efficiently; however, the products were difficult to purify because of the similar polarity as the
g
h
i
starting materials. TMS = trimethylsilyl. Isolated yield of the major product. Product ratio (major/minor) determined by 1H NMR or GC before
separation.
reaction in the first few hours; this phenomenon promoted us to gain
more detailed information about the reaction process.
Control experiments on the catalyst preparation were
conducted. The model reaction of 1a and 2a (2 equiv) was
tested in the presence of 10 mol % catalyst with different
pretreatments. The standard catalyst was first stirred for 12 h and
filtrated. Subsequently, diyne 1a and cyanamide 2a were added
into the resulting solution (eq 6). To our surprise, no pyridine
product was formed. Similarly, when diyne 1a (eq 7) or
cyanamide 2a (eq 8) was separately added with catalyst before
filtration, the same result was observed. In contrast, when diyne
1a was divided into two portions (eq 9), 10 mol % of 1a was
was caught in our system during the reaction process. Instead, typical
bands associated with C−O−C bond stretching vibration (1212
cm−1) on diyne 1a and C−N bond stretching vibration (1271 cm−1)
added first with cyanamide 2a and stirred for 8 h. After filtration,
the rest 90 mol % of 1a was added, and we were pleased to find
on 2-aminopyridine 3a were observed (Figure 1, left). After careful
that product 3a was obtained in 18% yield. From these results, we
hypothesized that the reduction process occurred only in the
presence of both diyne and nitrile (Scheme 2). The direct
reduction of precatalyst 6 to generate active species 8 by zinc dust
was not operative, which did not agree with the previous
assumption (Scheme 1).8b This result showed the first example
investigation of this spectra, we found that almost no consumption of
diyne 1a was detected in the first 5 h (Figure 1, right, red line), and a
new peak at 1271 cm−1 was gradually accumulated at very low speed
(Figure 1, right, blue line). In the next 9 h, the peak at 1212 cm−1
decreased rapidly, and the peak at 1271 cm−1 was simultaneously
formed. It seems that an induction period is required to initialize the
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Scheme 1. Proposed Mechanism under Different Systems
Figure 1. In situ IR spectra.
been neglected for a long period of time in the previous studies of
in situ generated catalysts.
Considering that ZnI2 in situ generated from the reduction
process is not only a spectator, we added 20 mol % of ZnI2 into
the reaction solution performed in eq 9 and surprisingly found
that the yield of pyridine product was improved to 61% (eq 10,
versus eq 9, 18%). This result indicated that ZnI2 might act as a
Lewis acid by activating the alkyne or nitrile moieties,15 thus
allowing the generation of active low-valent iron species to be
much easier. This assumption was further supported by the reac-
tion of 1d and 2a under 5 mol % catalyst. After adding 10 mol %
of ZnI2, 2-aminopyridine 3l was obtained in 49% yield (eq 11).
Encouraged by this result, we proceeded to evaluate the
reactivity in the presence of 5 mol % catalyst and 1.2 equiv of
cyanamide with 10 mol % ZnI2 as additive, as shown in Table 3.
For those reactive cyanamides (e.g., 2a and 2b), the addition of
ZnI2 failed to show any beneficial effect on the product yield
of substrate-participated active species generation in the metal-
catalyzed [2 + 2 + 2] cycloaddition reactions, which may have
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Although these data showed an important step forward,
the modified mechanism is still far from its mature state. For
example, the coordination mode of the substrates in intermediate
7 (Scheme 2), the role of ZnI2, and the real reduction process are
still unclear at this time and must await further study. Future
work based on these points is currently underway.
Scheme 2. Modified Mechanism
CONCLUSIONS
■
In summary, we presented an efficient iron catalyst for the
[2 + 2 + 2] cycloaddition reaction of alkynes and cyanamides to
form 2-aminopyridines at room temperature with good to
excellent yields. The regioselectivity as well as the broad
substrates scope makes it a complementary method to the
previous developed systems. Importantly, the presence of
both alkynes and nitriles is the key to the generation of active
iron species. Interestingly, the reactivity of the catalyst can
be improved by adding a small amount of Lewis acid ZnI2. We
are currently expending this method to other cycloaddition
reactions.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were carried out under an
atmosphere of argon using standard Schlenk techniques or in an argon-
filled glovebox unless otherwise noted. Column chromatography was
carried out on silica gel (300−400 mesh) using a forced flow of eluent at
0.3−0.5 bar pressure. For TLC, silica gel GF254 was used and visualized
by fluorescence quenching under UV light. THF was dried according to
the standard procedure and was distilled prior to use. FeI2 (99.99%
purity) was purchased from Sigma Aldrich. Diynes were prepared
according to literature procedures.10,16 Cyanamides were also prepared
according to literature procedures.13b Liquid cyanamides were degassed
using three sequential freeze−pump−thaw cycles.
Table 3. Cycloaddition with 1.2 equiv of Cyanamide under
a
5 mol % Catalyst
1H NMR, 13C NMR, and 19F NMR spectra were recorded at 400, 100,
and 377 MHz respectively. The chemical shifts for H NMR were
1
recorded in ppm downfield from tetramethylsilane (TMS) with the
solvent resonance as the internal standard (7.26 ppm for CDCl3 or
2.05 ppm for CD3COCD3). The chemical shifts for 13C NMR were
recorded in ppm downfield using the central peak of CDCl3 (77.16 ppm)
or CD3COCD3 (29.84 ppm) as the internal standard. Coupling constants
(J) are reported in hertz and refer to apparent peak multiplications.
The abbreviations s, d, t, q, and m stand for singlet, doublet, triplet,
quartet, and multiplet, respectively. All 13C NMR spectra were proton
decoupled. In situ IR spectra were recorded with a diamond probe head.
Gas chromatography was performed using the following conditions:
initial oven temperature, 150 °C, held for 3 min; temperature ramp rate
10 °C/min; final temperature, 180 °C, held for 4 min; temperature ramp
rate 50 °C/min; final temperature, 280 °C, held for 8 min; detector
temperature, 280 °C.
General Procedure for the Cycloaddition. General Procedure A.
FeI2 (5 mol %, 7.8 mg, 0.025 mmol) and dppp (10 mol %, 21.2 mg,
0.05 mmol) were weighed in the glovebox and placed in a dried
Schlenk tube. Subsequenly, 2 mL distilled THF was added. The
resulting mixture was stirred at room temperature for 30 min to afford
an orange-yellow clear solution, at which time Zn dust (10 mol %,
3.3 mg, 0.05 mmol) was added. After an additional 30 min of stirring,
diyne (0.5 mmol) was added followed by cyanamide (2.5 mmol,
5 equiv), and the mixture was stirred for 24 h until most of the starting
diyne was consumed. The solvent was evaporated, and the crude
product was directly purified by silica gel flash column chromatog-
raphy to give the desired product.
yield
b
lit. yield
d
bc
,
entry diyne cyanamide product yield (%)
(%)
(%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
2a
2b
2c
2d
2e
2h
2a
2a
3a
3b
3c
3d
3e
3h
3j
91
88
16
6
84
81
79
88
51
82
82
73
97
90
95
e
67
9
35
70
tr
94
52
3k
a
Reaction conditions: 0.5 mmol diyne, 5 mol % FeI2, 10 mol % dppp,
10 mol % ZnI2, 10 mol % Zn, 1.2 equiv of cyanamide, 2 mL THF, rt,
24 h. Isolated yields. Without adding 10 mol % ZnI2 as additive.
b
c
d
Yield reported in ref 8b: 5 mol % catalyst, 1.2 equiv of cyanamide,
e
70 °C. 10 mol % catalyst.
(Table 3, entries 1, 2, and 7). On the contrary, slight decrease
on the yield was observed, although 100% of diyne conversion
was detected in these cases. This may ascribe to the diyne
dimerization resulting from the activation of alkyne moieties by
ZnI2. For less reactive cyanamides (e.g., 2c, 2d, 2e, and 2h) or
diyne (e.g., 1c), the product yields were greatly improved after
adding catalytic amount of ZnI2 (Table 3, entries 3, 4, 5, 6, and 8).
It seems that the catalytic amount of ZnI2 acts as a double-edged
sword in this cycloaddition reaction, improving the product yield
while promoting the diyne dimerization. It is noteworthy that
the yields obtained under the modified catalyst were comparable with
the results of the previous iron catalytic system,8b but without using
syringe pump technique or requiring high reaction temperature.
General Procedure B. Procedure for the reaction with 10 mol %
catalyst and 2 equiv cyanamide was similar to the above method except
for the amount of each reactant: diyne (0.5 mmol), FeI2 (10 mol %,
15.6 mg, 0.05 mmol), dppp (20 mol %, 42.4 mg, 0.1 mmol), Zn dust
(20 mol %, 6.5 mg, 0.10 mmol), cyanamide (1 mol, 2 equiv).
General Procedure C. FeI2 (5 mol %, 7.8 mg, 0.025 mmol) and dppp
(10 mol %, 21.2 mg, 0.05 mmol) were weighed in the glovebox and
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placed in a dried Schlenk tube. Subsequenly, 2 mL distilled THF was
added. The resulting mixture was stirred at room temperature for
30 min to afford an orange-yellow clear solution, at which time ZnI2
(10 mol %, 16.0 mg, 0.05 mmol) and Zn dust (10 mol %, 3.3 mg,
0.05 mmol) were added. After an additional 30 min of stirring, diyne
(0.5 mmol) was added followed by cyanamide (0.6 mmol, 1.2 equiv),
and the mixture was stirred for 24 h until most of the starting diyne was
consumed. The solvent was evaporated, and the crude product was
directly purified by silica gel flash column chromatography to give the
desired product.
(petroleum ether/ethyl acetate = 5/1); 1H NMR (400 MHz, CDCl3) δ
1.88 (s, 3H), 2.40 (s, 3H), 3.35 (s, 3H), 3.54 (s, 2H), 3.59 (s, 2H), 3.79
(s, 6H), 6.62 (d, J = 8 Hz, 2H), 6.77 (t, J = 8 Hz, 1H), 7.17 (t, J = 8 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 172.0, 156.6, 151.1, 150.3, 148.7,
130.7, 129.0, 122.3, 118.7, 115.7, 59.7, 53.3, 40.0, 38.94, 38.88, 21.8,
14.5.
N,N-Dibenzyl-4,7-dimethyl-2-tosyl-2,3-dihydro-1H-pyrrolo[3,4-c]-
pyridin-6-amine (3i). White solid: 244 mg, 98% yield (procedure A) or
224 mg, 90% yield (procedure B); mp 159−160 °C; Rf = 0.3 (petroleum
1
ether/ethyl acetate = 10/1); H NMR (400 MHz, CDCl3) δ 2.18 (s,
Dimethyl 3-(Dimethylamino)-1,4-dimethyl-5H-cyclopenta[c]-
pyridine-6,6(7H)-dicarboxylate (3a).8b White solid: 141 mg, 92%
yield (procedure A) or 135 mg, 88% yield (procedure B); Rf = 0.3
(petroleum ether/ethyl acetate = 5/1); 1H NMR (400 MHz, CDCl3) δ
2.14 (s, 3H), 2.31 (s, 3H), 2.76 (s, 6H), 3.47 (s, 2H), 3.48 (s, 2H), 3.74
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 172.1, 161.4, 150.2, 147.8,
127.1, 117.1, 59.8, 53.1, 42.4, 40.0, 38.6, 21.7, 14.9.
Dimethyl 1,4-Dimethyl-3-(pyrrolidin-1-yl)-5H-cyclopenta[c]-
pyridine-6,6(7H)-dicarboxylate (3b).8b White solid: 136 mg, 82%
yield (procedure A) or 141 mg, 85% yield (procedure B); Rf = 0.3
(petroleum ether/ethyl acetate = 5/1); 1H NMR (400 MHz, CDCl3) δ
1.87 (s, 4H), 2.15 (s, 3H), 2.29 (s, 3H), 3.43 (s, 4H), 3.47 (s, 4H), 3.75
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 172.3, 159.0, 150.2, 147.4,
124.6, 113.4, 59.9, 53.1, 50.3, 40.1, 38.6, 25.6, 21.8, 15.8.
Dimethyl 1,4-Dimethyl-3-(piperidin-1-yl)-5H-cyclopenta[c]-
pyridine-6,6(7H)-dicarboxylate (3c).8b Colorless oil: 149 mg, 86%
yield (procedure A) or 166 mg, 96% yield (procedure B); Rf = 0.3
(petroleum ether/ethyl acetate = 5/1); 1H NMR (400 MHz, CDCl3) δ
1.55 (s, 2H), 1.65 (s, 4H), 2.12 (s, 3H), 2.31 (s, 3H), 2.98 (s, 4H), 3.46
(s, 2H), 3.48 (s, 2H), 3.73 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
172.0, 161.6, 150.0, 148.0, 127.4, 118.0, 59.7, 53.1, 51.5, 39.9, 38.6, 26.4,
24.7, 21.7, 14.3.
3H), 2.22 (s, 3H), 2.40 (s, 3H), 4.25 (s, 4H), 4.48 (s, 4H), 7.18 (t, J = 8
Hz, 2H), 7.23−7.33 (m, 10 H), 7.78 (d, J = 8 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 160.3, 147.2, 146.8, 143.9, 139.4, 133.9, 130.0, 128.4,
128.2, 127.7, 126.8, 124.6, 117.3, 55.3, 53.4, 52.5, 21.6, 21.5, 14.5;
HRMS (ESI, m/z) calcd for C30H31N3O2SNa [M + Na]+ 520.2035,
found 520.2017.
N,N,4,7-Tetramethyl-2-tosyl-2,3-dihydro-1H-pyrrolo[3,4-c]-
pyridin-6-amine (3j). White solid: 166 mg, 96% yield (procedure A) or
164 mg, 95% yield (procedure B); mp 155−156 °C; Rf = 0.3 (petroleum
ether/ethyl acetate = 4/1); 1H NMR (400 MHz, CDCl3) δ 2.08 (s, 3H),
2.26 (s, 3H), 2.40 (s, 3H), 2.76 (s, 6H), 4.48 (s, 2H), 4.50 (s, 2H), 7.32
(d, J = 8 Hz, 2H), 7.77 (d, J = 8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 161.8, 146.9, 146.6, 143.9, 133.9, 130.0, 127.6, 123.4, 115.3, 53.3,
52.5, 42.2, 21.6, 14.9; HRMS (ESI, m/z) calcd for C18H23N3O2SNa
[M + Na]+ 368.1409, found 368.1412.
N,N,4,7-Tetramethyl-1,3-dihydrofuro[3,4-c]pyridin-6-amine (3k).
White solid: 78 mg, 81% yield (procedure A) or 75 mg, 78% yield
(procedure B); mp 66−67 °C; Rf = 0.3 (petroleum ether/ethyl acetate =
20/1); 1H NMR (400 MHz, CDCl3) δ 2.12 (s, 3H), 2.30 (s, 3H), 2.81
(s, 6H), 4.99 (s, 2H), 5.03 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 161.7, 149.9, 145.5, 126.4, 114.2, 73.1, 72.7, 42.3, 21.9, 15.1; HRMS
(ESI, m/z) calcd for C11H16N2ONa [M + Na]+ 215.1160, found
215.1161.
Dimethyl 1,4-Dimethyl-3-morpholino-5H-cyclopenta[c]pyridine-
6,6(7H)-dicarboxylate (3d).8b White solid: 136 mg, 78% yield (proce-
dure A) or 165 mg, 95% yield (procedure B); Rf = 0.3 (petroleum ether/
N,N,1,4-Tetramethyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-
amine (3l). Colorless oil: trace (procedure A) or 71 mg, 75% yield
1
ethyl acetate = 5/1); H NMR (400 MHz, CDCl3) δ 2.13 (s, 3H),
1
(procedure B); Rf = 0.3 (petroleum ether/ethyl acetate = 20/1); H
2.31 (s, 3H), 3.05 (t, J = 4 Hz, 4H), 3.47 (s, 2H), 3.49 (s, 2H), 3.74 (s,
6H), 3.80 (t, J = 4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 172.0,
160.1, 150.4, 148.4, 128.2, 117.8, 67.3, 59.8, 53.2, 50.7, 39.9, 38.6,
21.7, 14.4.
Dimethyl 3-(Diethylamino)-1,4-dimethyl-5H-cyclopenta[c]-
pyridine-6,6(7H)-dicarboxylate (3e).8b Colorless oil: 131 mg, 76%
yield (procedure A) or 143 mg, 83% yield (procedure B); Rf = 0.3
(petroleum ether/ethyl acetate = 5/1); 1H NMR (400 MHz, CDCl3) δ
1.03 (s, 6H), 2.12 (s, 3H), 2.32 (s, 3H), 3.11 (t, J = 4 Hz, 4H), 3.50
(s, 4H), 3.77 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 172.2,
160.4, 150.0, 147.9, 127.3, 119.3, 59.7, 53.2, 45.7, 40.1, 38.8, 21.8,
14.6, 13.4.
N,N-Diisopropyl-4,7-dimethyl-2-tosyl-2,3-dihydro-1H-pyrrolo-
[3,4-c]pyridin-6-amine (3f). White solid: 167 mg, 83% yield (pro-
cedure A) or 183 mg, 91% yield (procedure B); mp 97−98 °C; Rf = 0.3
(petroleum ether/ethyl acetate = 10/1); 1H NMR (400 MHz, CDCl3) δ
0.97 (d, J = 8 Hz, 12H), 2.10 (s, 3H), 2.27 (s, 3H), 2.41 (s, 3H), 3.51 (m,
2H), 4.49 (s, 2H), 4.54 (s, 2H), 7.31 (s, J = 8 Hz, 2H), 7.79 (s, J = 8 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 160.0, 147.5, 145.7, 143.9, 134.1,
130.0, 127.7, 126.1, 124.0, 53.5, 52.7, 49.6, 21.8, 21.7, 21.3, 14.9; HRMS
(ESI, m/z) calcd for C22H31N3O2SNa [M + Na]+ 424.2035, found
424.2040.
NMR (400 MHz, CDCl3) δ 2.07 (m, 2H), 2.17 (s, 3H), 2.35 (s, 3H),
2.79−2.81 (m, 10 H); 13C NMR (100 MHz, CDCl3) δ 160.8, 154.6,
147.8, 131.5, 117.5, 42.6, 32.1, 30.6, 24.7, 21.9, 14.9; HRMS (ESI, m/z)
calcd for C12H19N2 [M + H]+ 191.1548, found 191.1552.
Dimethyl 3-(Dimethylamino)-5H-cyclopenta[c]pyridine-6,6(7H)-
dicarboxylate (3m). White solid: 97 mg, 70% yield (procedure A) or
102 mg, 73% yield (procedure B); mp 101−102 °C; Rf = 0.3 (petroleum
ether/ethyl acetate = 5/1); 1H NMR (400 MHz, CDCl3) δ 3.03 (s, 6H),
3.47 (s, 4H), 3.73 (s, 6H), 6.38 (s, 1H), 7.97 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 171.9, 159.2, 151.2, 142.9, 123.7, 101.3, 60.7, 53.1, 40.5,
38.6, 37.5; HRMS (ESI, m/z) calcd for C14H18N2O4Na [M + Na]+
301.1164, found 301.1160.
Dimethyl 3-(Dimethylamino)-1,4-diphenyl-5H-cyclopenta[c]-
pyridine-6,6(7H)-dicarboxylate (3n). White solid: 202 mg, 94% yield
(procedure A) or 211 mg, 98% yield (procedure B); mp 142−143 °C; Rf
1
= 0.3 (petroleum ether/ethyl acetate = 20/1); H NMR (400 MHz,
CD3COCD3) δ 2.67 (s, 6H), 3.38 (s, 2H), 3.65 (s, 6H), 3.80 (s, 2H),
7.35−7.52 (m, 8H), 7.91 (d, J = 8 Hz, 2H); 13C NMR (100 MHz,
CD3COCD3) δ 172.0, 159.8, 152.8, 149.7, 141.0, 139.4, 129.9, 129.5,
129.2, 129.0, 128.9, 127.9, 125.5, 122.0, 61.2, 53.2, 41.7, 40.7, 40.5;
HRMS (ESI, m/z) calcd for C26H27O4N2 [M + H]+ 431.1965, found
431.1966.
Dimethyl 3-(Diallylamino)-1,4-dimethyl-5H-cyclopenta[c]-
pyridine-6,6(7H)-dicarboxylate (3g). Colorless oil: 72 mg, 40% yield
(procedure A) or 134 mg, 75% yield (procedure B); Rf = 0.3 (petroleum
Dimethyl 3-(Dimethylamino)-4-methyl-5H-cyclopenta[c]-
pyridine-6,6(7H)-dicarboxylate (3p).3m
1
ether/ethyl acetate = 20/1); H NMR (400 MHz, CDCl3) δ 2.14 (s,
3H), 2.31 (s, 3H), 3.48 (s, 2H), 3.49 (s, 2H), 3.76 (s, 6H), 5.07 (d, J = 1.6
Hz, 1H), 5.10 (d, J = 1.6 Hz, 1H), 5.16 (d, J = 1.6 Hz, 1H), 5.20 (d, J =
1.6 Hz, 1H), 5.48−5.93 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 172.2,
160.0, 150.3, 147.8, 136.2, 127.4, 117.9, 116.5, 59.8, 53.7, 40.1, 38.7,
21.8, 14.7; HRMS (ESI, m/z) calcd for C20H26N2O4Na [M + Na]+
381.1790, found 381.1806.
Dimethyl 1,4-Dimethyl-3-(methyl(phenyl)amino)-5H-cyclopenta-
[c]pyridine-6,6(7H)-dicarboxylate (3h).8b Yellowish oil: 168 mg, 91%
yield (procedure A) or 182 mg, 99% yield (procedure B); Rf = 0.2
Colorless oil: 98 mg, 67% yield (procedure B); Rf = 0.3 (petroleum
ether/ethyl acetate = 10/1); H NMR (400 MHz, CDCl3) δ 2.14 (s,
3H), 2.73 (s, 6H), 3.43 (s, 2H), 3.51 (s, 2H), 3.70 (s, 6H), 7.90 (s, 1H);
1
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Article
13C NMR (100 MHz, CDCl3) δ 171.8, 161.7, 150.5, 139.6, 129.3, 119.9,
4,6-Bis(4-fluorophenyl)-N,N-dimethylpyridin-2-amine (3t).
60.2, 53.0, 42.3, 39.6, 38.1, 15.0; HMBC (400 MHz, CDCl3) H1 (7.90
ppm) couples with C7 (129.3 ppm), H2 (2.73 ppm) couples with C4
(161.7 ppm), H3 (2.14 ppm) couples with C4 (161.7 ppm), C5 (119.9
ppm) and C6 (150.5 ppm); HRMS (ESI, m/z) calcd for C15H20N2O4Na
[M + Na]+ 315.1321, found 315.1327.
Dimethyl 3-(Dimethylamino)-1-methyl-4-(trimethylsilyl)-5H-
cyclopenta[c]pyridine-6,6(7H)-dicarboxylate (3q).
Compound 3t was prepared using the modified procedure of Louie’s
system8b with 2a (407.0 μL, 5 mmol), FeBr2 (10.8 mg, 0.05 mmol), L2
(37.0 mg, 0.10 mmol), and zinc (6.5 mg, 0.10 mmol) in 2 mL benzene.
1k (117 μL, 1 mmol) was then added into the solution. The reaction was
stirred at 70 °C for 24 h, after which time the product was isolated via
silica gel flash chromatography (eluent, petroleum ether/ethyl acetate =
400/1). White solid: 96 mg, 62% yield; mp 128−129 °C; Rf = 0.5
(petroleum ether/ethyl acetate = 20/1); 1H NMR (400 MHz,
CD3COCD3) δ 3.20 (s, 6H), 6.76 (s, 1H), 7.23 (dt, J = 4, 8 Hz, 4H),
7.35 (s, 1H), 7.83 (dt, J = 4, 8 Hz, 2H), 8.23 (dt, J = 4, 8 Hz, 2H); 13C
NMR (100 MHz, CD3COCD3) δ 165.2 (JC−F = 9 Hz), 162.8 (JC−F = 10
Hz), 160.5, 155.0, 150.2, 137.3 (JC−F = 3 Hz), 137.0 (JC−F = 4 Hz), 129.9
Colorless oil: 108 mg, 59% yield (procedure B); Rf = 0.3 (petroleum
ether/ethyl acetate = 10/1); H NMR (400 MHz, CDCl3) δ 0.32 (s,
1
9H), 2.35 (s, 3H), 2.62 (s, 6H), 3.44 (s, 2H), 3.58 (s, 2H), 3.75 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 172.1, 169.2, 157.8, 152.7, 129.3, 120.9,
59.8, 53.1, 44.9, 42.5, 37.7, 22.0, 1.6; HMBC (400 MHz, CDCl3) H1
(2.62 ppm) couples with C4 (169.2 ppm), H2 (0.32 ppm) couples
with C4 (169.2 ppm); HRMS (ESI, m/z) calcd for C18H28N2O4NaSi
[M + Na]+ 387.1716, found 387.1723.
N,N,4-Trimethyl-7-phenyl-2-tosyl-2,3-dihydro-1H-pyrrolo[3,4-c]-
pyridin-6-amine (3r).
(JC−F = 8 Hz), 129.6 (JC−F = 8 Hz), 116.4 (JC−F = 22 Hz), 115.8 (JC−F
=
21 Hz), 106.9, 102.9, 38.2; HMBC (400 MHz, CD3COCD3) H1 (3.20
ppm) couples with C2 (160.5 ppm), H3 (6.76 ppm) couples with C2
(160.5 ppm) and C4 (137.7 ppm), H5 (7.35 ppm) couples with C4
(137.7 ppm); 19F NMR (377 MHz, CD3COCD3) δ −115.7, −116.0;
HRMS (ESI, m/z) calcd for C19H17F2N2 [M + H]+ 311.1354, found
311.1336.
Procedure for in Situ IR Spectra. Under the protection of nitrogen
gas, to a Schlenk tube were added FeI2 (10 mol %), dppp (20 mol %),
Zn (20 mol %), diyne 1a (1 equiv), and cyanamide 2a (2 equiv) suc-
cessively. Reactions were carried out with [cat.] = 0.06 M, [1a] = 0.6 M,
[2a] = 1.2 M with continuous stirring at room temperature. The reaction
was monitored by in situ IR.
White solid: 145 mg, 71% yield (procedure B); mp 194−195 °C; Rf = 0.3
(petroleum ether/ethyl acetate = 10/1); 1H NMR (400 MHz, CDCl3) δ
2.31 (s, 3H), 2.40 (s, 3H), 2.61 (s, 6H), 4.34 (s, 2H), 4.52 (s, 2H), 7.22−
7.39 (m, 7H), 7.70 (d, J = 4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
159.1, 148.6, 146.5, 143.8, 138.1, 133.7, 129.9, 128.9, 128.5, 127.6, 127.2,
121.3, 117.5, 53.7, 52.2, 41.3, 29.8, 21.9, 21.6; HMBC (400 MHz,
CDCl3) H8 (2.31 ppm) couples with C6 (121.3 ppm) and C7 (148.6
ppm), H1 (2.61 ppm) couples with C2 (159.1 ppm); HRMS (ESI, m/z)
calcd for C23H26N3O2S [M + H]+ 408.1740, found 408.1722.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 19F NMR spectra, HMBC and HRMS spectra. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: bswan@dicp.ac.cn.
3,6-Bis(4-fluorophenyl)-N,N-dimethylpyridin-2-amine (3s).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Basic Research Program
of China (2010CB833300) and the National Natural Science
Foundation of China (21172218) is gratefully acknowledged.
We also thank Prof. Jie Xu, Dr. Zhongtian Du, and Miss Junxia
Liu (DNL 0601, DICP) for the support of in situ IR spectra,
as well as our referees for valuable suggestions on revising the
manuscript.
Pale yellow solid: 109 mg, 70% yield (procedure B); mp 116−117 °C;
Rf = 0.5 (petroleum ether/ethyl acetate = 20/1); 1H NMR (400 MHz,
CD3COCD3) δ 2.77 (s, 6H), 7.23 (dt, J = 4, 8 Hz, 4H), 7.44 (d, J = 8 Hz,
1H), 7.56 (d, J = 8 Hz, 1H), 7.60 (t, J = 4 Hz, 2H), 7.22 (t, J = 8 Hz, 2H);
13C NMR (100 MHz, CD3COCD3) δ 164.6 (JC−F = 147 Hz), 162.2
REFERENCES
■
(JC−F = 145 Hz), 160.2, 152.7, 141.4, 137.7 (JC−F = 3 Hz), 136.6 (JC−F
=
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