Microwave-assisted, rhodium(III)-catalyzed N-annulation reactions of aryl and α,β-unsaturated ketones with alkynes

Article abstract of DOI:10.1002/chem.201302699

New Rh^III-catalyzed, one-pot N-annulation reactions of aryl and α,β-unsaturated ketones with alkynes in the presence of ammonium acetate have been developed. Under microwave irradiation conditions, the processes lead to rapid formation of the respective isoquinoline and pyridine derivatives with efficiencies that are strongly dependent on the steric nature of the aryl ring and enone substituents. By employing this protocol, a variety of isoquinoline and pyridine derivatives were prepared in high yields. In addition, a new one-pot approach to the synthesis of pyridines, involving four-component reactions of ketones, formaldehyde, NH₄OAc, and alkynes, has been uncovered. This process takes place through a route involving initial aldol condensation of the ketone with formaldehyde to generate a branched α,β-unsaturated ketone that then undergoes Rh ^III-catalyzed N-annulation with NH₄OAc and the alkyne. Ring road: One-pot N-annulation reactions of aryl and α,β-unsaturated ketones with alkynes in the presence of NH₄OAc under microwave (MW) irradiation conditions have been developed (see scheme). These processes lead to the rapid formation of the respective isoquinoline and pyridine derivatives. In addition, an approach for the synthesis of pyridines that involves four-component reactions is presented. Copyright

Full text of DOI:10.1002/chem.201302699

DOI: 10.1002/chem.201302699
Full Paper
&
CÀH Activation
Microwave-Assisted, Rhodium(III)-Catalyzed N-Annulation
Reactions of Aryl and a,b-Unsaturated Ketones with Alkynes
Hyejeong Lee, Yong-Kyun Sim, Jung-Woo Park, and Chul-Ho Jun*[a]
Dedicated to Professor Teruaki Mukaiyama in celebration of the 40th anniversary of the Mukaiyama aldol reaction
Abstract: New RhIII-catalyzed, one-pot N-annulation reac-
tions of aryl and a,b-unsaturated ketones with alkynes in the
presence of ammonium acetate have been developed.
Under microwave irradiation conditions, the processes lead
to rapid formation of the respective isoquinoline and pyri-
dine derivatives with efficiencies that are strongly depen-
dent on the steric nature of the aryl ring and enone sub-
stituents. By employing this protocol, a variety of isoquino-
line and pyridine derivatives were prepared in high yields. In
addition, a new one-pot approach to the synthesis of pyri-
dines, involving four-component reactions of ketones, form-
aldehyde, NH4OAc, and alkynes, has been uncovered. This
process takes place through a route involving initial aldol
condensation of the ketone with formaldehyde to generate
a branched a,b-unsaturated ketone that then undergoes
RhIII-catalyzed N-annulation with NH4OAc and the alkyne.
Introduction
lowed by cyclization of the resulting ortho-alkenyl-aryl keti-
mines.[7]
The development of new methods for the synthesis of N-heter-
The results of several studies have demonstrated that micro-
ocyclic compounds, which utilize transition-metal-catalyzed CÀ wave irradiation serves as a good alternative to conventional
H bond activation processes, is an important goal of synthetic
organic chemists because processes of this type are typically
highly chemoselective and atom-economic.[1] Particular interest
in this area has focused on the synthesis of isoquinolines and
pyridines owing to their biological properties and, consequent-
ly, their use in the pharmaceutical industry. Current synthetic
protocols devised for the preparation of these nitrogen hetero-
heating to enhance the rates of chemical reactions.[8] In spite
of the existing controversy about the origin of the effect,[9] mi-
crowave irradiation has become the accepted format for affect-
ing specific types of organic reactions, such as by-product-free
condensation processes. Because one of the steps in the new
process we have developed involves a condensation reaction
between a ketone and ammonia to give an imine, we have uti-
cycles utilize chelation-assisted, transition-metal-promoted CÀ lized microwave irradiation instead of conventional heating to
H bond activation of a variety of different starting materials, in-
cluding imines,[2] oximes,[3] and azides,[4] followed by ensuing
N-annulation reactions. However, many of the previously devel-
oped N-annulation reactions possess several disadvantageous
features, including the use of unstable preinstalled imine func-
tionality and the limited availability of a,b-unsaturated imine
reactants.[2,3] To overcome these problems, we recently devel-
oped two new methods for the synthesis of pyridines that uti-
lize RhIII/CuII-catalyzed reaction of an allylamine and alkyne,[5]
and between a,b-enones, alkynes, and NH4OAc.[6] The strategy
used to design these reactions relied on observations made in
our previous studies, which led to the development of
a method for the synthesis of isoquinolines through sequential
RhI-catalyzed ortho-alkenylation reactions of aryl ketimines fol-
promote the new N-annulation reaction developed in the cur-
rent study.
Herein, we describe the results of an investigation that has
resulted in the development of a new one-pot method for the
facile synthesis of isoquinolines and pyridines. In this process,
which involves RhIII-catalyzed C–H activation and N-annulation
steps, aryl and a,b-unsaturated ketones react with alkynes and
NH4OAc under microwave irradiation conditions to generate
the respective isoquinolines and pyridines. In addition, this
strategy has been applied in devising a new one-pot, four-
component method for N-annulation reactions between alkyl
ketones, formaldehyde, alkynes, and NH4OAc.
Results and Discussion
The protocol for carrying out the RhIII-catalyzed, microwave-as-
sisted, one-pot, three-component annulation reaction, leading
to the generation of isoquinolines, was investigated by using
4-methoxyacetophenone (1a) as the aryl ketone substrate. To
determine the effect of microwaves as a heat source, we car-
ried out comparison studies of N-annulation reactions under
conventional heating and microwave irradiation. When the N-
[a] H. Lee, Y.-K. Sim, Dr. J.-W. Park, Prof. Dr. C.-H. Jun
Department of Chemistry, Yonsei University
50 Yonsei-ro, Seodaemun-gu, Seoul 120-749 (Korea)
Fax: (+82)2-3147-2644
E-mail: junch@yonsei.ac.kr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201302699.
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annulation reaction of 1a was performed with 4-octyne (2a,
2 equiv) and ammonium acetate (3, 2 equiv) in the presence of
[Cp*RhCl2]2 (4, Cp*=pentamethylcyclopentadienyl, 2.5 mol%
[Rh]) and Cu(OAc)2·H2O (5, 2.0 equiv) under microwave irradia-
tion conditions (1008C, 10 min), isoquinoline 6a was isolated
in 76% yield (80% yield determined by GC analysis), whereas
the same reaction under conventional thermal heating condi-
tions did not give any product (Scheme 1). This result indicates
that the N-annulation proceeds in a much more facile manner
under microwave irradiation than conventional heating.
in the presence of 4 (5 mol% [Rh]) and 5 (2 equiv) at 1508C
under microwave irradiation conditions produces the corre-
sponding isoquinoline 6a in 93% yield of isolated product
(Table 2, entry 1). In addition, N-annulation reactions using
both alkyl (2b) and aryl (2c) substituted alkynes take place to
form the respective isoquinolines 6b (94%) and 6c (92%;
Table 2, entries 2 and 3). Interestingly, reaction of the unsym-
metric and sterically biased alkyne, 4,4-dimethylpent-2-yne
(2d), generates isoquinoline 6d, in which the bulky tert-butyl
group is positioned at C3 exclusively with a 41% yield of iso-
lated product (Table 2, entry 4). Other aryl ketones, such as
acetophenone (1b), 4-trifluoromethyl acetophenone (1c), hex-
anophenone
(1d),
benzophenone
(1e),
cyclohexyl-
(phenyl)methanone (1 f), and 3,4-dihydronaphthalen-1(2H)-one
(1g), also participate in N-annulation reactions that produce
the corresponding isoquinoline derivatives isolated in 90–97%
yields (Table 2, entries 5–10).
To gain information about factors controlling the regioselec-
tivity of the N-annulation process, studies were carried out
with aryl ketones that contain meta-aryl ring substituents. Sub-
strates of this type are interesting because they possess two
different ortho-CÀH bonds that can be activated in the initial
carbometalation step of the reaction. Interestingly, N-annula-
tion reaction of 3-methylacetophenone (1h) with 4-octyne
(2a) and NH4OAc was observed to form 1,7-dimethyl-3,4-dipro-
pylisoquinoline (6k) exclusively (91% yield of isolated product,
Table 2, entry 11), which demonstrates that only the C6 ortho-
CÀH bond of the aryl group is activated in this reaction. Thus,
it appears that the regiochemical course of this process is
guided by the steric influence of meta substituents. Moreover,
reaction of N-(3-acetylphenyl)acetamide (1i) with 2a exclusive-
ly forms the isoquinoline regioisomer 6l (88% yield of isolated
product, Table 2, entry 12). Likewise, 3-aminoacetophenone
(1j) reacts with 2a under these conditions to generate a mix-
ture of N-(1-methyl-3,4-dipropylisoquinolin-7-yl)acetamide (6l)
and 1-methyl-3,4-dipropylisoquinolin-7-amine (6m; Table 2,
entry 13), both being produced through activation of the less
sterically hindered aryl ketone C6 CÀH bond. In this process, it
is likely that acetamide 6l is formed by acetylation of 6m by
NH4OAc (3). The same regiochemical driving force operates in
the reaction of 3-hydroxyacetophenone (1k) with 2a, which
results in formation of the single isoquinoline regioisomer 6n
(Table 2, entry 14). However, reaction of 3-methoxyacetophe-
none (1l) with 2a was observed to yield a mixture of re-
gioisomers, 6o and 6p in a 46:48 ratio (Table 2, entry 15). In
this case, formation of 6p is a consequence of the activating
effect of the C3 methoxy group, which competes with its steric
effect. The results of further studies show that heteroaromatic
ketones also serve as substrates for the new N-annulation reac-
tion. For example, 1-(thiophen-2-yl)ethanone (1m) and 1-
(furan-2-yl)ethanone (1n) react with 2a in the presence of 3, 4
(5 mol% [Rh]), and 5 (2 equiv) under microwave irradiation
conditions (1508C) to generate the corresponding pyridines
6q and 6r in high yields (Table 2, entries 16 and 17).
Scheme 1. Comparison between MW and conventional heating for synthesis
of 6a.
Next, the reactions were carried out with various amines to
find a suitable reagent for the nitrogen source under more in-
tense reaction conditions (5 mol% 4, 1308C; Table 1). For ex-
ample, the reaction of 1a, 2a, and NH3 in the presence of 4
(5 mol% [Rh]) and 5 (2.0 equiv based on 1a) under microwave
Table 1. Nitrogen sources for the N-annulation reaction of aryl ketone 1a
with alkyne 2a.
Entry
Nitrogen source
Yield [%][a]
1
2
3
4
5
6
7
8
NH3 (7.0m solution in MeOH)
NH2OH·HCl
97
0
30
1
90
17
2
H2NÀNH2·xH2O
PhNHÀNH2
NH4OAc (3)
NH4Cl
NH4NO3
NH4Cl+NaOAc
14
[a] Yields of isolated products.
irradiation conditions was observed to form 6a in 97% yield of
isolated product (Table 1, entry 1). The results of studies prob-
ing the use of other nitrogen sources for this process, such as
NH4OAc, NH2OH,[6] PhNHNH2, NH2NH2, NH4NO3, and NH4Cl
(Table 1, entries 2–8), showed that NH4OAc (3) is ideal because
it promotes efficient reactions (90%) and is an easily handled
solid.
The scope of the N-annulation reaction was investigated
with various aryl ketones, alkynes, and ammonium acetate as
the nitrogen source (Table 2). The results of this effort demon-
strated that reaction of 1a with 4-octyne (2a) and NH4OAc (3)
Using the protocol described above, an investigation of N-
annulation reactions of nonaromatic a,b-unsaturated ketones
was carried out. The results of this effort demonstrate that,
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Table 2. Substrate scope for the N-annulation reaction of aryl ketone 1, alkyne 2, and NH4OAc (3).
Entry Aryl ketone 1
Alkyne 2
(R3 and R4)
Product 6
Yield
[%][a]
Entry Aryl ketone Alkyne 2 Product 6
Yield
[%][a]
1
(R3 and
R4)
93
(>99)
1
10
11
2a
2a
93 (>99)
94
(>99)
2
3
1a
1a
91 (>99)
92
(>99)
12
2a
88 (>99)
6l/6m
50:27
4
1a
41 (46) 13
2a
5
6
2a
2a
95 (98) 14
2a
2c
66
6o/6p
46:48
93 (97) 15
92
(>99)
7
8
9
2a
2a
2a
16
2a
2a
94 (>99)
90
(>99)
17
71 (78)
97
(>99)
[a] Yield of isolated product. Yields determined by GC analysis are given in parentheses.
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under the conditions developed for reactions of aryl ketones,
a variety of a,b-unsaturated ketones (7) react efficiently with
alkynes (2) to generate substituted pyridines (Table 3). For ex-
ample, the vinyl ketones oct-1-en-3-one (7a), 1-cyclohexyl-
Table 5. Effects of b substituents (R3) in 7 on the N-annulation reaction.
Table 3. Effects of carbonyl substituents (R1) in 7 on the N-annulation re-
action.
(2a) in the presence of 3, 4 (5 mol% [Rh]), and 5 (2 equiv) at
1508C under microwave irradiation conditions forms pyridine
8i in only 42% yield of isolated product. Finally, a,b-unsaturat-
ed ketones bearing n-propyl (7j) and tert-butyl (7k) groups at
the b position do not serve as substrates for this process. The
results suggest that the efficiency of the N-annulation reaction
is strongly dependent on steric effects associated with the
presence of b substituents on the a,b-enone in the following
order: H>Me>n-C3H7 ꢀt-C4H9.
Cy=cyclohexyl.
prop-2-en-1-one (7b), and 1,1-diphenylbut-3-en-2-one (7c)
participate in N-annulation reactions with 4-octyne that pro-
duce the respective pyridines 8a–c, which were isolated in
high yields (50–89%). In addition, vinyl ketones containing n-
C3H7 (7d) and n-C5H11 (7e) a substituents also undergo reac-
tions with alkyne 2a in the presence of the same catalytic
system to form the corresponding pyridines 8d and 8e in high
yields of isolated products (91% for 8d and 89% for 8e,
Table 4). However, a,b-unsaturated ketones with long alkyl
The N-annulation reaction is thought to proceed in the fol-
lowing sequence (Figure 1). First, imine 9 is generated by con-
densation of a,b-enone 7 with ammonia. Activation of the NÀ
H bond in imine 9 by RhIII gives iminorhodium(III) intermediate
10. Then, RhIII-promoted b-CÀH bond activation in the inter-
mediate 10 and subsequent coordination of alkyne 2a affords
rhodacyclic complex A. Carbometalation of alkyne in A gives
rise to seven-membered rhodacycle B. Reductive elimination of
B results in the formation of pyridine 8 and RhI. Catalytically
active RhIII complex is regenerated by CuII-promoted oxidation
of the resulting RhI intermediate with 5. In this process, it is
Table 4. Effects of a substituents (R2) in 7 on the N-annulation reaction.
chains, such as n-C8H17 (7 f) and n-C10H21 (7g), at the a position
undergo much less efficient annulation reactions that form the
corresponding pyridine 8 f and 8g, which were isolated in low
yields (42% for 8 f and 30% for 8g).
The b substituents have a pronounced effect on the N-annu-
lation process (Table 5). Thus, in contrast to the reaction of the
simple vinyl ketone 7h with 2a that produces pyridine 8h in
76% yield of isolated product, the corresponding reaction of
the b-methyl-substituted substrate 7i with the same alkyne
Figure 1. Proposed mechanism of the N-annulation reaction and origin of
the steric effect of b substituent R on rhodacycle B.
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likely that bulky b substituents R, such as n-propyl and tert-
butyl, retard the N-annulation reaction by causing steric inter-
ference in the alkyne carbometalation step transforming inter-
mediate A to B (Figure 1).
1-Acylcycloalkenes are potentially interesting substrates for
the N-annulation reaction because the process would lead to
the generation of polycyclic pyridine derivatives (Scheme 2). To
A notable issue arises in N-annulation reactions of ketones
that possess both aryl a,b-unsaturated moieties, in which two
CÀH bond cleavage sites exist. In these substrates, isoquino-
lines and pyridines can be generated by activation of the re-
spective ortho-CÀH and vinyl CÀH bonds. To probe this issue,
reaction of the aryl a,b-unsaturated ketone 11 a with dipheny-
lacetylene (2c) was performed using 3, 4 (5 mol% [Rh]), and 5
(2 equiv) and microwave irradiation conditions (1508C). This
process generates a mixture of isoquinoline 6s and pyridine
8n in a 63:37 ratio and 83% combined yield of isolated prod-
ucts (Scheme 4a). This result suggests that the ortho sp2 CÀH
bond is more reactive than the vinylic sp2 CÀH bond toward
rhodium(III)-catalyzed CÀH bond activation.
Scheme 2. N-Annulation reactions of cyclic a,b-enones a) 7l and b) 7m with
2a and 3.
explore this possibility, reaction of 1-(cyclohex-1-en-1-yl)etha-
none 7l with 2a was performed under the optimized condi-
tions described above. This reaction was found to produce the
tetrahydroisoquinoline derivative 8l along with the unexpect-
ed isoquinoline 6e in a ratio of 77:23 (Scheme 2a). To confirm
that 6e is produced in this process by dehydrogenative oxida-
tion, a mixture of 8l and the copper catalyst 5 (2 equiv) was
heated at 1508C for 30 min under microwave irradiation condi-
tions. The observation that this reaction generates 6e (40%)
shows that Cu(OAc)2 promotes dehydrogenation of the tetra-
hydroisoquinoline ring system (Scheme 3). In contrast to that
Scheme 4. Chemoselectivity of N-annulation reactions of aryl a,b-enones 11
with 2c and 3.
Based on the finding that the bulky b substituents present
in a,b-enones retard the N-annulation reaction, we explored
the reaction of an aryl a,b-enone, such as chalcone 11 b, that
contains a b substituent. Reaction of this substance under the
standard conditions was found to result in exclusive formation
of isoquinoline 6t (86% yield of isolated product), thus dem-
onstrating again that the b-phenyl substituent suppresses the
pyridine forming process (Scheme 4b). In contrast, N-annula-
tion reaction of aryl a,b-enone 11 c, which bears an o-methoxy
aryl substituent, leads to production of pyridine 8o (84%)
without competitive formation of an isoquinoline derivative
(Scheme 4c). This phenomenon is a likely consequence of the
difficulty associated with the Rh-promoted aromatic CÀH bond
activation step required to form the isoquinoline moiety
caused by steric hindrance between the o-methoxy group and
n-butyl group in the key intermediate 12.
Scheme 3. Dehydrogenative of 8l by 5.
of 7l, the N-annulation reaction of 1-(cyclopent-1-en-1-yl)etha-
none (7m) with 2a is not efficient. It is likely that the b-CÀH
bond in 7m is not readily accessible to the metal center, a re-
quirement for CÀH bond activation. However, when a greater
amount of the Rh catalyst is used, 7m reacts to form the bicy-
clic pyridine derivative 8m in moderate yield (e.g., 5 mol%:
9%; 10 mol%: 58%, Scheme 2b). Finally, 1-acylcycloalkenes
containing larger ring systems, such as 1-acetylcycloheptene
and 1-acetylcyclooctene, do not undergo the N-annulation re-
action.
Branched a,b-unsaturated ketones, which serve as substrates
for the three-component N-annulation reaction, can be gener-
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ated by aldol reactions of alkyl ketones with formaldehyde.
Owing to this feature, we anticipated that the overall process
involving a,b-unsaturated ketone formation and N-annulation
could be carried out in a one-pot manner. The feasibility of
this new, four-component N-annulation reaction was explored.
The results show that reaction of 2-cycloheptenone (13a) with
a mixture of paraformaldehyde (14a, 1.5 equiv HCHO), 2a, and
3 in the presence of the catalyst mixture containing 4 (5 mol%
[Rh]) and 5 (2 equiv), under microwave irradiation conditions
(1508C), leads to formation of pyridine 8p isolated in 76%
yield (Table 6, entry 1).[10] In addition, reaction of the linear
The use of cycloalkanones as substrates in this one-pot,
four-component N-annulation reaction is interesting because
the processes would produce fused pyridines directly. To deter-
mine if this process is successful, cyclohexanone (13d) was
subjected to reaction with alkyne 2a. This process forms tetra-
hydroquinoline 8t in 48% yield of isolated product (Table 7). In
Table 7. Four-component N-annulation reactions of alkyne 2a with cyclo-
alkanones 13.
Table 6. RhIII-catalyzed, four-component N-annulation reaction between
ketone 13, aldehyde 14, alkyne 2a, and NH4OAc (3).
Entry Ketone (13)
RÀCHO (14) Pyridine (8)
Yield [%][a]
(CH2O)n
(14a)
1
76
addition we observed that medium-ring-sized cycloalkanones,
such as cycloheptanone (13e), cyclooctanone (13 f), and cyclo-
decanone (13g), also undergo reaction with 2a to afford the
corresponding pyridines 8u, 8v, and 8w, which were isolated
in moderate yields (41–61%). However, cyclopentanone (13c)
does not serve as a substrate for this process, a likely conse-
quence of the unfavorable generation of the conformation of
the a-methylene ketimine rhodium intermediate required for
CÀH bond activation.
2
14a
50
CH3ÀCHO
(14b)
3
4
13a
13a
10
n-C3H7ÀCHO
(14c)
–
Conclusion
[a] Yield of isolated product.
The investigation described herein has led to the development
of a new, microwave-promoted, one-pot N-annulation reaction
of aryl and a,b-unsaturated ketones with ammonium acetate
and alkynes that produces the respective isoquinoline and pyr-
idine derivatives. The efficiencies of the N-annulation reactions,
which are generally high, are lessened by the steric effects of
aryl ring and enone substituents. By using this protocol, a varie-
ty of isoquinoline and pyridine derivatives were synthesized in
high yields. Importantly, the studies have also led to the devel-
opment of a new one-pot, four-component N-annulation reac-
tion between ketones, formaldehyde, NH4OAc, and alkynes
that generates pyridine derivatives through a pathway initiated
by aldol condensation of the ketones with formaldehyde to
produce a-methylene ketones.
ketone 5-nonanone (13b) with 14a/2a/3 affords the corre-
sponding pyridine 8q, which was isolated in 50% yield
(Table 6, entry 2).
Studies were conducted to determine if other aldehydes,
such as acetaldehyde (14b) and butyraldehyde (14c), would
participate in this four-component N-annulation reaction. The
results show that reaction of 13a with alkyne 2a, NH4OAc (3),
and 14b gives the corresponding pyridine 8r in only 10%
yield of isolated product (Table 6, entry 3), and that 14c does
not undergo the process (Table 6, entry 4). These observations
are consistent with the N-annulation reactivities of a,b-enones
that contain b substituents (see above).
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6-Methoxy-1-methyl-3,4-dipentylisoquinoline
(6b):
1H NMR
Experimental Section
(400 MHz, CDCl3): d=7.91 (d, J=8.8 Hz, 1H), 7.10 (d, J=2.0 Hz,
1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 3.87 (s, 3H), 2.87–2.78 (m, 7H),
1.70–1.53 (m, 4H), 1.45–1.30 (m, 8H), 0.88–0.82 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=160.4, 155.2, 152.7, 137.5, 128.2,
125.7, 121.9, 117.4, 102.3, 55.5, 35.9, 32.6, 32.5, 30.7, 30.3, 28.1,
22.9, 22.8, 22.6, 14.4, 14.3 ppm; IR (CH2Cl2): n˜ =3003, 2963, 2920,
2856, 1620, 1573, 1464, 1413, 1271, 1129, 1156 cmÀ1; HRMS (ESI):
m/z calcd for C21H32NO+ [M+H]+: 314.2478; found: 314.2478.
General
Flash column chromatography was performed using Merck 230–
400 mesh silica gel and column chromatography was monitored
by analytical thin-layer chromatography carried out on 0.25 Merck
silica gel plates (60F-254) with UV light as a visualizing agent, p-
anisaldehyde, ninhydrin, and KMnO4 solution as staining solutions,
and heat as developing agent. Microwave experiments were per-
formed in a CEM Discover instrument with appropriate internal IR
temperature control and 10 mL Pyrex vials. The reaction tempera-
ture, pressure, and microwave power were monitored by comput-
er, and a 10 mL thick walled Pyrex vessel with Teflon septa with
a crimp top was used as reaction vessel. Gas chromatographic
analyses were performed on an Agilent 7890A instrument with
flame ionization detector and an Agilent HP-5 capillary column.
Mass chromatography analyses were performed on an Agilent
5975C instrument and an Agilent HP-5MS column. IR spectra were
recorded using a Bruker Vertex 70 FTIR spectrometer. 1H and
13C NMR spectra were recorded on Bruker Advance II/DPX 400
6-Methoxy-1-methyl-3,4-diphenylisoquinoline
(6c): 1H NMR
(400 MHz, CDCl3): d=8.04 (d, J=9.2 Hz, 1H), 7.30–7.27 (m, 5H),
7.17–7.12 (m, 6H), 6.91 (d, J=2.6 Hz, 1H), 3.64 (s, 3H), 2.98 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=160.7, 157.1, 150.2, 141.3,
138.2, 138.0, 131.4, 130.4, 128.4, 127.7, 127.6, 127.2, 121.8, 118.8,
104.6 ppm.
3-(tert-Butyl)-6-methoxy-1,4-dimethylisoquinoline (6d): 1H NMR
(400 MHz, CDCl3): d=7.95 (d, J=9.2 Hz, 1H), 7.19 (d, J=2.0 Hz,
1H), 7.12 (dd, J=9.2, 2.4 Hz, 1H), 3.94 (s, 1H), 2.84 (s, 3H), 2.70 (s,
3H), 1.53 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=160.1, 158.1,
153.1, 139.3, 127.8, 121.3, 120.9, 117.8, 101.9, 55.5, 38.6, 31.2, 22.8,
16.5 ppm; IR (CH2Cl2): n˜ =3049, 2954, 2871, 1620, 1579, 1505, 1413,
1362, 1272, 1230, 1045 cmÀ1; HRMS (ESI): m/z calcd for C16H22NO+
[M+H]+: 244.1696; found: 244.1696.
(400 MHz H, 100 MHz 13C) spectrometers with chemical shifts re-
ported relative to residual deuterated solvent peaks. H NMR spec-
1
1
1
tra were referenced to CDCl3 (for H, d=7.26 ppm) as internal stan-
dard, and are reported as chemical shift multiplicity: br=broad,
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet.
13C NMR spectra were referenced to the residual CDCl3 (for 13C, d=
77.26 ppm) as internal standard. High-resolution mass spectra were
provided by YCRF Yonsei University. Most commercially available
reagent-grade chemicals (1a–h, 1j–n, 2a–d, 3, 5, 7a, 7l,m, 11 b,
13a–g, and 14a–c) were purchased from Aldrich Chemical Compa-
ny, TCI, and Burdick and Jackson, and used as received without fur-
ther purification unless otherwise stated. Toluene (purchased from
Duksan Chemical) was distilled from sodium/benzophenone under
a nitrogen atmosphere prior to use. Complex [Cp*RhCl2]2 (4)[11] was
prepared according to the literature procedure and stored in a re-
frigerator under a N2 atmosphere.
1
1-Methyl-3,4-dipropylisoquinoline (6e): H NMR (400 MHz, CDCl3):
d=8.06 (d, J=8.0 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.64 (t, J=
7.2 Hz, 1H), 7.47 (t, J=7.2 Hz, 1H), 2.99–2.91 (m, 7H), 1.83–1.76 (m,
2H), 1.71–1.62 (m, 2H), 1.10–1.03 ppm (m, 6H); 13C NMR (100 MHz,
CDCl3): d=155.8, 151.4, 135.6, 129.8, 126.7, 126.3, 125.6, 123.7,
37.1, 29.9, 24.3, 24.0, 21.9, 14.7, 14.5 ppm.
1-Methyl-3,4-dipropyl-6-(trifluoromethyl)isoquinoline
(6 f):
1H NMR (400 MHz, CDCl3): d=8.24 (s, 1H), 8.18 (d, J=8.8 Hz, 1H),
7.66 (dd, J=8.8, 1.6 Hz, 1H), 3.01 (t, J=8.0 Hz, 2H), 2.95–2.91 (m,
5H), 1.85–1.75 (m, 2H), 1.72–1.63 (m, 2H), 1.10 (t, J=7.2 Hz, 3H),
1.05 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=156.0,
153.6, 134.9, 131.6, 131.3, 131.0, 130.7, 127.6, 127.1, 125.7, 123.0,
121.6, 121.5, 121.5, 121.4, 121.2, 121.1, 121.1, 121.1, 37.7, 29.9, 24.6,
23.9, 22.7, 14.7, 14.6 ppm; IR (CH2Cl2): n˜ =2962, 2933, 2874, 1573,
1446, 1338, 1307, 1160, 1130, 1090, 822 cmÀ1; HRMS (ESI): m/z
calcd for C17H21F3N+ [M+H]+: 296.1621; found: 296.1621.
Typical procedure for the three component N-annulation re-
action (Tables 2–5)
1
6-Pentyl-2,3-dipropylpyridine (6g): H NMR (400 MHz, CDCl3): d=
8.10 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.61 (t, J=8.0 Hz,
1H), 7.46 (t, J=7.6 Hz, 1H), 3.24 (t, J=7.6 Hz, 2H), 2.99–2.90 (m,
4H), 1.87–1.75 (m, 4H), 1.72–1.62 (m, 2H), 1.49–1.33 (m, 4H), 1.10–
1.02 (m, 6H), 0.90 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=159.7, 151.8, 136.0, 129.4, 126.2, 126.0, 125.5, 125.3,
123.9, 37.5, 35.7, 32.3, 30.1, 30.0, 24.3, 23.9, 22.8, 14.8, 14.5,
14.3 ppm; IR (CH2Cl2): n˜ =3071, 2958, 2930, 2871, 1697, 1566, 1461,
1338, 1257, 1088, 759 cmÀ1; HRMS (ESI): m/z calcd for C20H30N+
[M+H]+: 284.2373; found: 284.2373.
[Cp*RhCl2]2 (4, 3.1 mg, 0.005 mmol), Cu(OAc)2·H2O (5, 79.9 mg,
0.40 mmol), and NH4OAc (3, 30.8 mg, 0.40 mmol) were added to
a
MeOH solution (0.1 mL) of 4-methoxyacetophenone (1a,
30.0 mg, 0.20 mmol) and 4-octyne (2a, 44.1 mg, 0.40 mmol) in
10 mL Pyrex tube. After capping the reaction vessel with Teflon
septa, the reaction mixture was stirred at 1508C for 10 min to
ensure homogeneous conditions under microwave irradiation.
After cooling to room temperature, the reaction mixture was fil-
tered through a celite pad. The reaction progress was monitored
by GC-MS. All volatiles were removed in vacuo, and the resulting
crude mixture was subject to flash column chromatography (n-
hexane/ethyl acetate 20:1) to afford 6-methoxy-1-methyl-3,4-dipro-
pylisoquinoline (6a, 48.0 mg, 0.187 mmol) in 93% yield.
1
1-Phenyl-3,4-dipropylisoquinoline (6h): H NMR (400 MHz, CDCl3):
d=8.00 (d, J=7.6 Hz, 2H), 7.65–7.59 (m, 3H), 7.48–7.35 (m, 4H),
3.07–3.00 (m, 4H), 1.89–1.83 (m, 2H), 1.76–1.70 (m, 2H), 1.14–
1.03 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=158.3, 152.4,
140.3, 136.3, 130.2, 129.6, 128.4, 128.3, 128.2, 127.3, 125.5, 125.4,
123.5, 37.6, 30.1, 24.3, 23.8, 14.9, 14.5 ppm.
1-Cyclohexyl-3,4-dipropylisoquinoline (6i): 1H NMR (400 MHz,
CDCl3): d=8.16 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.57 (t,
J=7.2 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 3.50–3.45 (m, 1H), 2.97–2.88
(m, 4H), 1.94–1.77 (m, 9H), 1.70–1.61 (m, 2H), 1.55–1.46 (m, 2H),
1.42–1.35 (m, 1H), 1.08 (t, J=7.2 Hz, 3H), 1.01 ppm (t, J=7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=162.4, 151.7, 135.9, 129.0,
125.5, 125.2, 125.0, 124.8, 124.0, 41.6, 37.4, 32.8, 30.1, 27.2, 26.6,
6-Methoxy-1-methyl-3,4-dipropylisoquinoline
(6a):
1H NMR
(400 MHz, CDCl3): d=7.99 (d, J=9.2 Hz, 1H), 7.18 (d, J=2.4 Hz,
1H), 7.13 (dd, J=9.2, 2.4 Hz, 1H), 3.95 (s, 1H), 2.95–2.86 (m, 7H),
1.80–1.65 (m, 4H), 1.11–1.02 ppm (m, 6H); 13C NMR (100 MHz,
CDCl3): d=160.5, 155.2, 152.4, 137.6, 128.2, 125.7, 121.9, 117.4,
102.5, 55.5, 37.7, 30.2, 24.1, 23.9, 22.3, 14.9, 14.6 ppm; IR (CH2Cl2):
n˜ =2958, 2931, 2871, 1715, 1620, 1463, 1414, 1221, 1029, 837 cmÀ1
;
HRMS (ESI): m/z calcd for C17H24NO+ [M+H]+: 258.1852; found:
258.1852.
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24.3, 23.3, 14.9, 14.5 ppm; IR (CH2Cl2): n˜ =3071, 2957, 2928, 2870,
2853, 1565, 1450, 1336, 1263, 1088, 985 cmÀ1; HRMS (ESI): m/z
calcd for C21H30N+ [M+H]+: 296.2373; found: 296.2361.
(m, 2H), 1.05–1.01 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=
153.3, 149.6, 145.6, 133.3, 130.5, 126.9, 122.7, 36.8, 32.0, 24.5, 24.3,
23.6, 14.7, 14.6 ppm.
2,3-Dipropyl-8,9-dihydro-7H-benzo[de]quinolone (6j): 1H NMR
(400 MHz, CDCl3): d=7.75 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H),
7.21 (d, J=6.8 Hz, 1H), 3.20 (t, J=6.0 Hz, 2H), 3.07 (t, J=6.0 Hz,
2H), 2.97–2.88 (m, 4H), 2.19–2.12 (m, 2H), 1.83–1.73 (m, 2H), 1.71–
1.62 (m, 2H), 1.10–1.03 ppm (m, 6H); 13C NMR (100 MHz, CDCl3):
d=157.3, 151.8, 139.2, 135.9, 129.6, 126.2, 123.9, 123.7, 121.1, 37.7,
34.7, 31.0, 30.2, 24.3, 24.1, 23.6, 14.8, 14.6 ppm; IR (CH2Cl2): n˜ =
7-Methyl-4,5-dipropylfuro[2,3-c]pyridine (6r): 1H NMR (400 MHz,
CDCl3): d=7.65 (d, J=2.0 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 2.84–2.77
(m, 4H), 2.70 (s, 3H), 1.77–1.60 (m, 4H), 1.03–0.98 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=151.8, 149.5, 147.1, 139.5, 134.1,
125.7, 105.5, 36.7, 31.8, 24.4, 24.3, 18.6, 14.5 ppm.
1-(Hex-1-en-2-yl)-3,4-diphenylisoquinoline
(6s):
1H NMR
(400 MHz, CDCl3): d=8.4 (d, J=7.8 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H),
7.40–7.33 (m, 5H), 7.28–7.26 (m, 2H), 7.21–7.16 (m, 3H), 5.64 (s,
1H), 5.32 (s, 1H), 2.80 (t, J=7.4 Hz, 2H), 1.65–1.53 (m, 2H), 1.49–
1.42 (m, 2H), 0.93 ppm (t, J=7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=161.9, 149.3, 148.1, 141.2, 137.9, 137.1, 131.6, 130.7,
130.6, 130.1, 129.5, 128.5, 127.7, 127.4, 127.2, 126.5, 126.1, 125.6,
117.2, 37.1, 30.3, 22.8, 14.3 ppm; IR (CH2Cl2): n˜ =3058, 3027, 2956,
2869, 2858, 1542, 1501, 1445, 1378, 766, 698 cmÀ1; HRMS (ESI): m/z
calcd for C27H26N+ [M+H]+: 364.2060; found: 364.2045.
3,4-Diphenyl-1-styrylisoquinoline (6t): 1H NMR (400 MHz, CDCl3):
d=8.43 (d, J=8.0 Hz, 1H), 8.16–8.06 (m, 2H), 7.72–7.68 (m, 2H),
7.61–7.54 (m, 2H), 7.48–7.46 (m, 2H), 7.42–7.30 (m, 6H), 7.26–
7.19 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=153.7, 150.1,
141.4, 138.0, 137.4, 137.0, 136.3, 131.6, 130.8, 130.1, 130.0, 129.0,
128.7, 128.5, 127.8, 127.7, 127.5, 127.3, 126.9, 126.5, 125.6, 124.5,
123.2 ppm.
2957, 2870, 2835, 1609, 1571, 1390, 1330, 1255, 1091, 791 cmÀ1
;
HRMS (ESI): m/z calcd for C18H24N+ [M+H]+: 254.1903; found:
254.1901.
1,7-Dimethyl-3,4-dipropylisoquinoline (6k): 1H NMR (400 MHz,
CDCl3): d=7.85–7.82 (m, 2H), 7.46 (d, J=8.4 Hz, 1H), 2.95 (t, J=
8.0 Hz, 2H), 2.90–2.87 (m, 5H), 2.52 (s, 3H), 1.83–1.73 (m, 2H),
1.70–1.61 (m, 2H), 1.09–1.02 ppm (m, 6H); 13C NMR (100 MHz,
CDCl3): d=155.1, 151.0, 135.0, 133.8, 131.7, 126.4, 126.2, 125.2,
123.7, 37.6, 30.0, 24.5, 24.0, 22.6, 21.9, 14.8, 14.6 ppm.
N-(1-Methyl-3,4-dipropylisoquinolin-7-yl)acetamide (6l): M.p.
1
140–1448C; H NMR (400 MHz, CDCl3): d=8.3 (s, 1H), 7.90 (d, J=
8.8 Hz, 1H), 7.72 (d, J=6.8 Hz, 2H), 2.96–2.85 (m, 7H), 2.24 (s, 3H),
1.81–1.72 (m, 2H), 1.69–1.59 (m, 2H), 1.09–1.01 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=168.8, 155.4, 151.2, 135.2, 132.8,
126.6, 126.4, 124.9, 123.6, 115.1, 37.5, 30.0, 24.9, 24.5, 24.1, 22.6,
14.8, 14.6 ppm; IR (CH2Cl2): n˜ =2958, 2929, 2870, 1723, 1669, 1624,
1583, 1550, 1320, 1276, 875, 829 cmÀ1; HRMS (ESI): m/z calcd for
C18H25N2O+ [M+H]+: 285.1961; found: 285.1956.
1
1-Cyclohexylprop-2-en-1-one (7b): H NMR (400 MHz, CDCl3): d=
6.43 (dd, J=17.6, 10.4 Hz, 1H), 6.25 (d, J=17.2 Hz, 1H), 5.75 (d, J=
10.4 Hz, 1H), 2.65–2.58 (m, 1H), 1.85–1.68 (m, 5H), 1.42–1.26 ppm
(m, 5H); 13C NMR (100 MHz, CDCl3): d=203.8, 135.2, 128.0, 48.4,
28.8, 26.1, 25.9 ppm.
1,1-Diphenylbut-3-en-2-one (7c): 1H NMR (400 MHz, CDCl3): d=
7.34–7.21 (m, 10H), 6.47 (dd, J=17.2, 10.0 Hz, 1H), 6.34 (dd, J=
17.6, 1.6 Hz, 1H), 5.73 (dd, J=10.0, 1.2 Hz, 1H), 5.33 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=197.8, 138.4, 135.6, 129.4, 129.2,
128.9, 127.5, 62.5 ppm; IR (CH2Cl2): n˜ =3085, 3061, 3029, 1716,
1657, 1598, 1494, 1449, 1317, 1278, 747, 701 cmÀ1; HRMS (ESI): m/z
calcd for C16H14ONa+ [M+Na]+: 245.0937; found: 245.0932.
1-Methyl-3,4-dipropylisoquinolin-7-amine (6m): M.p. 185–1918C;
1H NMR (400 MHz, CDCl3): d=7.79 (d, J=8.8 Hz, 1H), 7.17 (d, J=
2.0 Hz, 1H), 7.10 (dd, J=9.2, 2.4 Hz, 1H), 3.92 (s, 2H), 2.93–2.89 (m,
2H), 2.86–2.82 (m, 2H), 2.79 (s, 3H), 1.80–1.71 (m, 2H), 1.69–1.59
(m, 2H), 1.09–1.01 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=
153.6, 148.8, 143.7, 129.8, 127.6, 126.4, 125.3, 121.6, 107.0, 37.4,
30.1, 24.6, 24.2, 22.6, 14.9, 14.6 ppm; IR (CH2Cl2): n˜ =3341, 3183,
2958, 2929, 2869, 1641, 1624, 1566, 1511, 1414, 1242, 856,
830 cmÀ1; HRMS (ESI): m/z calcd for C16H23N2 [M+H]+: 243.1856;
+
found: 243.1847.
4-Methylene-1-phenylheptan-3-one (7d): 1H NMR (400 MHz,
CDCl3): d=7.30–7.17 (m, 5H), 5.96 (s, 1H), 5.69 (s, 1H), 3.02–2.91
(m, 4H), 2.25 (t, J=7.6 Hz, 2H), 1.47–1.37 (m, 2H), 0.90 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=201.3, 141.6, 128.7,
128.6, 126.3, 124.0, 39.8, 33.1, 30.6, 21.8, 14.0 ppm; IR (CH2Cl2): n˜ =
1-Methyl-3,4-dipropylisoquinolin-7-ol (6n): M.p. 175–1818C;
1H NMR (400 MHz, CD2Cl2): d=12.68 (s, 1H), 7.71 (d, J=9.2 Hz, 1H),
7.34 (d, J=9.2 Hz, 1H), 2.92–2.82 (m, 4H), 2.71 (s, 3H), 1.73–1.68
(m, 2H), 1.58–1.53 (m, 2H), 1.04–0.96 ppm (m, 6H); 13C NMR
(100 MHz, CD2Cl2): d=157.7, 153.5, 144.6, 131.0, 130.1, 128.1, 126.1,
125.9, 108.2, 34.7, 30.1, 24.8, 24.6, 19.4, 14.8, 14.5 ppm; IR (CH2Cl2):
n˜ =3355, 2958, 2924, 2852, 1670, 1585, 1451, 1361, 1289, 884, 787,
686 cmÀ1; HRMS (ESI): m/z calcd for C16H22NO+ [M+H]+: 244.1696;
found: 244.1696.
3028, 2960, 2872, 1718, 1678, 1603, 1453, 1273, 1069, 936 cmÀ1
;
HRMS (ESI): m/z calcd for C14H19O+ [M+H]+: 203.1430; found:
203.1422.
4-Methylene-1-phenylnonan-3-one (7e): 1H NMR (400 MHz,
CDCl3): d=7.29–7.16 (m, 5H), 5.95 (s, 1H), 5.69 (s, 1H), 3.02–2.90 (t,
J=7.2 Hz, 6H), 1.42–1.25 (m, 6H), 0.88 ppm (t, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=201.2, 149.3, 141.6, 128.7, 128.6,
126.3, 123.8, 39.8, 31.8, 31.1, 30.6, 28.4, 22.7, 14.2 ppm; IR (CH2Cl2):
7-Methoxy-1-methyl-3,4-diphenylisoquinoline
(6o):
1H NMR
(400 MHz, CDCl3): d=7.58 (d, J=9.2 Hz, 1H), 7.38–7.30 (m, 6H),
7.25–7.14 (m, 6H), 7.97 (s, 3H), 3.03 ppm (m, 3H); 13C NMR
(100 MHz, CDCl3): d=158.1, 156.2, 148.0, 141.3, 138.0, 131.6, 130.5,
129.4, 128.4, 128.2, 127.8, 127.5, 127.3, 126.9, 122.4, 103.7, 55.7,
23.1 ppm.
3063, 3028, 2956, 2858, 1711, 1678, 1454, 1410, 1077, 932 cmÀ1
;
HRMS (EI+): m/z calcd for C16H22O+ [M]+: 230.1671; found:
230.1675.
1H NMR
4-Methylene-1-phenyldodecanonan-3-one
(7 f):
1H NMR
5-Methoxy-1-methyl-3,4-diphenylisoquinoline
(6p):
(400 MHz, CDCl3): d=7.79 (d, J=8.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H),
7.23–7.21 (m, 2H), 7.16–7.09 (m, 8H), 6.95 (d, J=7.6 Hz, 1H), 3.40
(s, 3H), 3.04 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=157.3,
157.1, 151.4, 141.9, 141.7, 130.6, 130.5, 128.2, 128.0, 127.7, 127.5,
127.3, 126.7, 125.9, 118.3, 110.3, 55.8, 23.6 ppm.
(400 MHz, CDCl3): d=7.30–7.26 (m, 2H), 7.21–7.17 (m, 3H), 5.96 (s,
1H), 5.70 (s,1H), 3.03–2.99 (m, 2H), 2.95–2.91 (m, 2H), 2.26 (t, J=
7.1 Hz, 2H), 1.40–1.36 (m, 2H), 1.32–1.24 (m, 5H), 0.88 ppm (t, J=
6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=201.3, 149.3, 141.6,
128.7, 128.6, 126.3, 123.8, 39.9, 32.1, 31.2, 30.7, 29.7, 29.6, 29.5,
28.7, 22.9, 14.3 ppm; IR (CH2Cl2): n˜ =3086, 3062, 3027, 2954, 2926,
2854, 1679, 1495, 1454, 1265, 748, 699 cmÀ1; HRMS (ESI): m/z calcd
for C19H28ONa+ [M+Na]+: 295.2032; found: 295.2019.
7-Methyl-4,5-dipropylthieno[2,3-c]pyridine
(6q):
1H NMR
(400 MHz, CDCl3): d=7.58 (d, J=5.2 Hz, 1H), 7.38 (d, J=5.2 Hz,
1H), 2.91–2.84 (m, 4H), 2.74 (s, 3H), 1.81–1.73 (m, 2H), 1.71–1.61
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4-Methylene-1-phenyltetradecanonan-3-one
(7g):
1H NMR
132.5, 128.7, 128.5, 126.0, 36.8, 36.5, 36.2, 34.2, 34.1, 24.2, 24.1,
23.4, 14.5, 14.3 ppm; IR (CH2Cl2): n˜ =2959, 2930, 2871, 1732, 1453,
1266, 1110, 748, 708 cmÀ1; HRMS (ESI): m/z calcd for C22H32N+
[M+H]+: 310.2529; found: 310.2514.
(400 MHz, CDCl3): d=7.29–7.19 (m, 5H), 5.95 (s, 1H), 5.69 (s, 1H),
3.02–2.91 (m, 4H), 2.26 (t, J=6.8 Hz, 2H), 1.30–1.26 (m, 18H),
0.88 ppm (t, J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=201.2,
149.3, 141.6, 128.7, 128.6, 126.3, 123.8, 39.9, 32.1, 31.1, 30.6, 29.8,
29.7, 29.6, 29.6, 28.7, 22.9, 14.3 ppm; IR (CH2Cl2): n˜ =3063, 3028,
2925, 2854, 1711, 1681, 1496, 1455, 1282, 1077 cmÀ1; HRMS (EI+):
m/z calcd for C21H32O+ [M]+: 300.2453; found: 300.2456.
3-Pentyl-2-phenethyl-5,6-dipropylpyridine
(8e):
1H NMR
(400 MHz, CDCl3): d=7.28–7.15 (m, 5H), 7.13 (s, 1H), 3.07–2.98 (m,
2H), 2.74 (t, J=8.8 Hz, 2H), 2.54 (t, J=7.6 Hz, 2H), 2.46 (t, J=
8.0 Hz, 2H), 1.76–1.69 (m, 2H), 1.65–1.55 (m, 2H), 1.53–1.45 (m,
2H), 1.35–1.26 (m, 6H), 1.03–0.96 (m, 6H), 0.89 ppm (t, J=6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=156.9, 155.6, 142.6, 138.1,
132.8, 132.7, 128.7, 128.5, 126.0, 36.6, 36.4, 36.2, 34.1, 32.0, 32.0,
30.7, 24.2, 23.5, 22.7, 14.5, 14.3, 14.3 ppm; IR (CH2Cl2): n˜ =3027,
2958, 2870, 1712, 1452, 1237, 1075, 749 cmÀ1; HRMS (ESI): m/z
calcd for C24H36N+ [M+H]+: 338.2842; found: 338.2842.
1
5-Phenylpent-1-en-3-one (7h): H NMR (400 MHz, CDCl3): d=7.30–
7.26 (m, 3H), 7.21–7.17 (m, 3H), 6.36 (dd, J=17.6, 10.4 Hz, 1H),
5.83 (dd, J=10.4, 0.8 Hz, 1H), 2.97–2.90 ppm (m, 4H); 13C NMR
(100 MHz, CDCl3): d=199.9, 141.3, 136.7, 128.6, 128.5, 128.4, 126.3,
41.4, 30.0 ppm.
1-Phenylhex-4-en-3-one (7i): 1H NMR (400 MHz, CDCl3): d=7.30–
7.24 (m, 2H), 7.22–7.15 (m, 3H), 6.88–6.82 (m, 1H), 6.13 (dd, J=
1.56, 15.8 Hz, 1H), 2.96–2.92 (m, 2H), 2.88–2.84 (m, 2H), 1.89 ppm
(dd, J=1.56, 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=199.5,
143.0, 141.5, 132.1, 128.6, 128.5, 126.2, 41.7, 30.2, 18.5 ppm.
1-Phenyloct-4-en-3-one (7j): 1H NMR (400 MHz, CDCl3): d=7.28–
7.18 (m, 5H), 6.84–6.76 (m, 1H), 2.94–2.83 (m, 4H), 2.19–2.13 (m,
2H), 1.51–1.44 (m, 2H), 0.97 ppm (t, J=7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=199.6, 147.6, 141.4, 130.6, 128.6, 128.5, 126.2,
41.7, 34.6, 30.2, 21.5, 13.8 ppm.
6,6-Dimethyl-1-phenylhept-4-en-3-one (7k): 1H NMR (400 MHz,
CDCl3): d=7.29–7.26 (m, 2H), 7.21–7.18 (m, 3H), 6.79 (d, J=
16.0 Hz, 1H), 6.00 (d, J=16.0 Hz, 1H), 2.96–2.85 (m, 4H), 1.06 ppm
(s, 9H); 13C NMR (100 MHz, CDCl3): d=200.3, 157.4, 141.5, 128.7,
128.6, 126.2, 125.6, 42.0, 33.9, 30.3, 28.9 ppm; IR (CH2Cl2): n˜ =3062,
2961, 2905, 2867, 1696, 1673, 1495, 1454, 1364, 1296, 983 cmÀ1
HRMS (ESI): m/z calcd for C15H20ONa+ [M+Na]+: 239.1406; found:
1
3-Octyl-2-phenethyl-5,6-dipropylpyridine (8 f): H NMR (400 MHz,
CDCl3): d=7.28–7.11 (m, 5H), 3.09–3.00 (m, 4H), 2.73 (t, J=7.7 Hz,
2H), 2.54 (t, J=7.6 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H), 1.78–1.69 (m,
2H), 1.65–1.55 (m, 2H), 1.50–1.46 (m, 2H), 1.35–1.23 (m, 5H), 1.03–
0.96 (m, 6H), 0.88 ppm (t, J=6.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=157.0, 155.7, 142.8, 138.0, 132.7, 132.7, 132.7, 128.8,
128.5, 126.0, 36.8, 36.6, 36.2, 34.2, 32.1, 32.0, 31.0, 29.9, 29.7, 29.5,
24.2, 23.5, 22.9, 14.5, 14.3 ppm; IR (CH2Cl2): n˜ =3026, 2957, 2926,
2856, 1591, 1576, 1494, 1452, 748, 698 cmÀ1; HRMS (ESI): m/z calcd
for C27H42N+ [M+H]+: 380.3312; found: 380.3296.
1
3-Decyl-2-phenethyl-5,6-dipropylpyridine (8g): H NMR (400 MHz,
CDCl3): d=7.28–7.17 (m, 5H), 7.11 (s, 1H), 3.01 (br s, 4H), 2.72 (t,
J=7.6 Hz, 2H), 2.53 (t, J=7.4 Hz, 2H), 2.45 (t, J=7.5 Hz, 2H), 1.75–
1.70 (m, 2H), 1.68–1.57 (m, 2H), 1.48 (m, 2H), 1.30–1.21 (m, 14H),
1.02–0.95 (m, 6H), 0.87 ppm (t, J=6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=157.0, 155.7, 142.7, 138.0, 132.7, 132.6, 128.8, 128.7,
128.6, 128.5, 126.0, 36.8, 36.6, 36.2, 34.1, 32.1, 32.0, 31.8, 31.0, 29.8,
29.7, 29.6, 24.2, 23.5, 22.93, 22.91, 14.5, 14.4 ppm.
;
239.1406.
1
6-Pentyl-2,3-dipropylpyridine (8a): H NMR (400 MHz, CDCl3): d=
1
6-Phenethyl-2,3-dipropylpyridine (8h): H NMR (400 MHz, CDCl3):
7.30 (d, J=7.7 Hz, 1H), 6.88 (d, J=7.7 Hz, 1H), 2.75–2.68 (m, 4H),
2.54 (t, J=7.6 Hz, 2H), 1.74–1.54 (m, 6H), 1.34–1.31 (m, 4H), 0.98
(q, J=7.2 Hz, 6H), 0.86 ppm (t, J=7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=159.6, 159.4, 137.2, 132.2, 120.0, 38.4, 37.3, 34.2, 31.9,
30.2, 24.2, 23.6, 22.8, 14.5, 14.3, 14.3 ppm; IR (CH2Cl2): n˜ =2958,
2929, 2871, 1737, 1591, 1571, 1463, 1377, 1242, 829 cmÀ1; HRMS
(ESI): m/z calcd for C16H28N+ [M+H]+: 234.2216; found: 234.2208.
d=7.31–7.24 (m, 3H), 7.20–7.15 (m, 3H), 6.84 (d, J=7.8 Hz, 2H),
3.09–3.01 (m, 4H), 2.78 (t, J=7.8 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H),
1.79–1.69 (m, 2H), 1.65–1.56 (m, 2H), 1.05–0.97 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=159.7, 158.0, 142.1, 137.4, 132.7,
128.7, 128.5, 126.0, 120.4, 39.8, 37.1, 36.4, 34.1, 29.9, 24.1, 23.5,
14.5, 14.3 ppm; IR (CH2Cl2): n˜ =3084, 3061, 3027, 2959, 2929, 2870,
1716, 1590, 1573, 1495, 1455, 749, 698 cmÀ1; HRMS (ESI): m/z calcd
for C19H26N+ [M+H]+: 268.2060; found: 268.2047.
1
6-Cyclohexyl-2,3-dipropylpyridine (8b): H NMR (400 MHz, CDCl3):
d=7.32 (d, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 2.73 (t, J=
8.0 Hz, 2H), 2.67–2.63 (m, 1H), 2.54 (t, J=7.6 Hz, 2H), 1.96–1.94 (m,
2H), 1.83–1.82 (m, 2H), 1.74–1.67 (m, 4H), 1.64–1.55 (m, 2H), 1.49–
1.36 (m, 4H), 1.01–0.96 ppm (m, 6H); 13C NMR (100 MHz, CDCl3):
d=163.5, 159.3, 137.2, 132.3, 117.6, 46.4, 37.3, 34.2, 33.4, 26.9, 26.5,
24.1, 23.4, 14.5, 14.4 ppm; IR (CH2Cl2): n˜ =3054, 2958, 2927, 2853,
1589, 1570, 1459, 1400, 1377, 1132, 830, 740 cmÀ1; HRMS (ESI): m/z
calcd for C17H28N+ [M+H]+: 246.2216; found: 246.2211.
4-Methyl-6-phenethyl-2,3-dipropylpyridine
(8i):
1H NMR
(400 MHz, CDCl3): d=7.28–7.24 (m, 3H), 7.21–7.15 (m, 2H), 6.73 (s,
1H), 3.04–2.98 (m, 4H), 2.77 (t, J=8.0 Hz, 2H), 2.57 (t, J=8.4 Hz,
2H), 2.25 (s, 3H), 1.78–1.68 (m, 2H), 1.55–1.45 (m, 2H), 1.04–
1.00 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=157.2, 153.6,
139.3, 132.4, 130.0, 128.8, 128.6, 128.0, 126.3, 37.6, 35.1, 31.3, 24.0,
23.7, 22.7, 15.8, 14.8, 14.7 ppm; IR (CH2Cl2): n˜ =3061, 3027, 2959,
2930, 2871, 1714, 1603, 1565, 1494, 1453, 727, 698 cmÀ1; HRMS
(ESI): m/z calcd for C20H27N+ [M+H]+: 282.2216; found: 282.2201.
1
6-Benzhydryl-2,3-dipropylpyridine (8c): H NMR (400 MHz, CDCl3):
d=7.31–7.25 (m, 6H), 7.20–7.17 (m, 5H), 6.81 (d, J=7.6 Hz, 1H),
5.62 (s, 1H), 2.74 (t, J=7.6 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 1.72–
1.66 (m, 2H), 1.64–1.56 (m, 2H), 0.99–0.92 ppm (m, 6H); 13C NMR
(100 MHz, CDCl3): d=159.9, 159.5, 143.8, 137.1, 133.0, 130.3, 129.7,
128.5, 128.4, 126.4, 121.2, 59.3, 37.1, 34.2, 24.0, 23.0, 14.4,
14.4 ppm; IR (CH2Cl2): n˜ =3060, 3026, 2960, 2930, 2870, 1586, 1571,
1494, 1452, 1078, 1031, 748, 699 cmÀ1; HRMS (ESI): m/z calcd for
C24H28N+ [M+H]+: 330.2216; found: 330.2204.
2-Phenethyl-3,5,6-tripropylpyridine (8d): 1H NMR (400 MHz,
CDCl3): d=7.28–7.17 (m, 5H), 7.16 (s, 1H), 3.08–3.00 (m, 4H), 2.77
(t, J=7.6 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H),
1.79–1.69 (m, 2H), 1.65–1.48 (m, 4H), 1.03–0.91 ppm (m, 9H);
13C NMR (100 MHz, CDCl3): d=157.0, 155.7, 142.7, 138.0, 132.6,
1-Methyl-3,4-dipropyl-5,6,7,8-tetrahydroisoquinoline
(8l):
1H NMR (400 MHz, CDCl3): d=2.70–2.67 (m, 4H), 2.58 (t, J=8.4 Hz,
2H), 2.51 (t, J=8.4 Hz, 2H), 2.37 (s, 3H), 1.77–1.65 (m, 6H), 1.49–
1.44 (m, 2H), 1.03–0.98 ppm (m, 6H); 13C NMR (100 MHz, CDCl3):
d=155.8, 153.5, 144.2, 131.1, 128.3, 37.4, 30.3, 26.7, 24.1, 23.5, 22.8,
22.7, 22.2, 14.9, 14.7 ppm.
1-Methyl-3,4-dipropyl-6,7-dihydro-5H-cyclopenta[c]pyridine
1
(8m): H NMR (400 MHz, CDCl3): d=2.85 (q, J=8.0 Hz, 4H), 2.71 (t,
J=8.0 Hz, 2H), 2.53 (t, J=8.0 Hz, 2H), 2.40 (s, 3H), 2.10–2.03 (m,
2H), 1.73–1.67 (m, 2H), 1.52–1.46 (m, 2H), 1.02–0.97 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=157.4, 152.8, 150.3, 135.5, 129.2,
37.0, 32.0, 31.9, 31.1, 24.6, 24.3, 23.7, 22.0, 14.7, 14.6 ppm; IR
Chem. Eur. J. 2014, 20, 323 – 333
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Full Paper
(CH2Cl2): n˜ =2959, 2932, 2870, 1712, 1584, 1459, 1431, 1234,
1091 cmÀ1; HRMS (ESI): m/z calcd for C15H24N+ [M+H]+: 218.1903;
found: 218.1901.
1.43 (m, 2H), 1.05–1.00 ppm (m, 6H); 13C NMR (100 MHz, CDCl3):
d=157.7, 157.3, 143.3, 132.9, 131.6, 129.1, 126.9, 38.1, 36.9, 31.2,
31.2, 28.8, 24.0, 23.8, 15.7, 14.8, 14.7 ppm; IR (CH2Cl2): n˜ =3022,
2958, 2927, 2870, 1702, 1554, 1454, 1415, 1377, 1091, 804,
722 cmÀ1; HRMS (ESI): m/z calcd for C17H26N+ [M+H]+: 244.2060;
found: 244.2052.
2,3-Dipropyl-5,6,7,8-tetrahydroquinoline (8t): 1H NMR (400 MHz,
CDCl3): d=7.08 (s, 1H), 2.86 (t, J=6.0 Hz, 2H), 2.70 (t, J=8.0 Hz,
4H), 2.52 (t, J=7.6 Hz, 2H), 1.88–1.84 (m, 2H), 1.80–1.74 (m, 2H),
1.70–1.63 (m, 2H), 1.63–1.56 (m, 2H), 1.02–0.96 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=157.3, 154.0, 137.8, 132.4, 129.4,
37.2, 34.1, 32.3, 28.6, 24.3, 23.9, 23.6, 23.1, 14.6, 14.4 ppm; IR
(CH2Cl2): n˜ =2958, 2932, 2870, 1737, 1690, 1563, 1450, 1188,
927 cmÀ1; HRMS (ESI): m/z calcd for C15H24N+ [M+H]+: 218.1903;
found: 218.1903.
3-Butyl-2,5,6-triphenylpyridine (8n): 1H NMR (400 MHz, CDCl3):
d=7.62–7.60 (m, 3H), 7.48–7.38 (m, 5H), 7.32–7.20 (m, 6H), 2.74 (t,
J=7.7 Hz, 2H), 1.62–1.55 (m, 2H), 1.37–1.29 (m, 2H), 0.86 ppm (t,
J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=157.5, 154.2, 140.2,
134.7, 134.4, 130.3, 129.9, 129.5, 128.5, 128.3, 128.1, 128.0, 127.8,
127.7, 127.3, 33.5, 32.0, 22.8, 14.1 ppm; IR (CH2Cl2): n˜ =3059, 3028,
2956, 2928, 2859, 1551, 1495, 1446, 1426, 1378, 766, 699 cmÀ1
;
HRMS (ESI): m/z calcd for C27H26N+ [M+H]+: 364.2060; found:
364.2045.
3-Butyl-2-(2-methoxyphenyl)-5,6-diphenylpyridine (8o): M.p.
133–1378C; 1H NMR (400 MHz, CDCl3): d=7.60 (s, 1H), 7.39–7.35
(m, 4H), 7.28–7.22 (m, 5H), 7.19–7.17 (m, 3H), 7.06 (t, J=7.6 Hz,
1H), 6.97 (d, J=8.4 Hz, 1H), 3.80 (s, 3H), 2.56–2.52 (m, 2H), 1.55–
1.47 (m, 2H), 1.29–1.20 (m, 2H), 0.80 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=157.0, 155.6, 154.2, 140.6, 140.5,
139.0, 135.9, 134.7, 131.5, 130.4, 130.2, 129.9, 129.6, 128.4, 127.9,
127.5, 127.2, 121.0, 111.0, 55.7, 32.7, 31.7, 22.8, 14.1 ppm; IR
(CH2Cl2): n˜ =2956, 2928, 2858, 2835, 1600, 1580, 1491, 1459, 1424,
1025, 752, 699 cmÀ1; HRMS (ESI): m/z calcd for C28H28NO+ [M+H]+:
394.2165; found: 394.2167.
2,3-Dipropyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (8u):
1H NMR (400 MHz, CDCl3): d=7.09 (s, 1H), 2.97 (t, J=5.6 Hz, 2H),
2.71–2.67 (m, 4H), 2.52 (t, J=7.6 Hz, 2H), 1.85–1.81 (m, 2H), 1.74–
1.54 (m, 8H), 1.01–0.96 ppm (m, 6H); 13C NMR (100 MHz, CDCl3):
d=160.0, 156.3, 137.8, 135.2, 132.3, 39.2, 36.9, 35.1, 34.0, 32.8, 28.4,
27.0, 24.3, 23.7, 14.6, 14.4 ppm; IR (CH2Cl2): n˜ =2958, 2924, 2870,
1703, 1562, 1454, 1338, 1164, 960 cmÀ1; HRMS (ESI): m/z calcd for
C16H26N+ [M+H]+: 232.2060; found: 232.2056.
2,3-Dipropyl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine
(8v):
1H NMR (400 MHz, CDCl3): d=7.09 (s, 1H), 2.90 (t, J=6.4 Hz, 2H),
2.74–2.68 (m, 4H), 2.54 (t, J=7.6 Hz, 2H), 1.76–1.57 (m, 8H), 1.36–
1.35 (m, 4H), 1.00–0.95 ppm (m, 6H); 13C NMR (100 MHz, CDCl3):
d=157.7, 157.5, 137.7, 133.2, 132.7, 37.1, 34.4, 34.1, 32.5, 31.7, 31.0,
26.3, 26.2, 24.2, 23.9, 14.5, 14.3 ppm; IR (CH2Cl2): n˜ =2957, 2927,
2869, 1561, 1451, 1360, 1171, 1088, 919 cmÀ1; HRMS (ESI): m/z
calcd for C17H28N+ [M+H]+: 246.2216; found: 246.2206.
Typical procedure for the four-component N-annulation re-
action (Table 6)
A 10 mL Pyrex tube was charged with 2-cycloheptenone (13a,
22.0 mg, 0.20 mmol), 4-octyne (2a, 44.1 mg, 0.40 mmol), parafor-
maldehyde (14a, 9.0 mg, 0.30 mmol), [Cp*RhCl2]2 (4, 3.1 mg,
0.005 mmol), Cu(OAc)2·H2O (5, 80.0 mg, 0.40 mmol), NH4OAc (3,
30.8 mg, 0.40 mmol), and MeOH (0.1 mL), and the reaction vessel
was capped with Teflon septa. The reaction was performed with in-
ternal magnetic stirring for 10 min to ensure homogeneous condi-
tions at 1508C under microwave irradiation. After cooling to room
temperature, the reaction mixture was filtered through a celite
pad. The reaction progress was monitored by GC-MS. Then, all vol-
atiles were removed in vacuo and the resulting crude mixture was
subject to flash column chromatography (n-hexane/ethyl acetate
20:1) to give 2,3-dipropyl-6,7-dihydro-5H-cyclohepta[b]pyridine
(8p, 34.8 mg, 0.152 mmol) in 76% yield.
2,3-Dipropyl-6,7-dihydro-5H-cyclohepta[b]pyridine (8p): 1H NMR
(400 MHz, CDCl3): d=7.15 (s, 1H), 6.25 (dt, J=12.3, 1.9 Hz, 1H),
5.93–5.89 (m, 1H), 3.04 (t, J=5.2 Hz, 2H), 2.72–2.68 (m, 2H), 2.53 (t,
J=7.7 Hz, 2H), 2.46 (m, 2H), 2.00–1.94 (m, 2H), 1.74–1.64 (m, 2H),
1.64–1.54 (m, 2H), 1.01–0.95 ppm (m, 6H); 13C NMR (100 MHz,
CDCl3): d=157.5, 157.0, 139.4, 133.2, 132.6, 128.9, 127.5, 38.8, 36.9,
33.9, 32.8, 25.1, 24.2, 23.6, 14.6, 14.3 ppm; IR (CH2Cl2): n˜ =2959,
2929, 2870, 1736, 1551, 1452, 1246, 1065, 921 cmÀ1; HRMS (ESI): m/
z calcd for C16H24N+ [M+H]+: 230.1903; found: 230.1895.
2,3-Dipropyl-5,6,7,8,9,10,11,12-octahydrocyclodeca[b]pyridine
1
(8w): H NMR (400 MHz, CDCl3): d=7.14 (s, 1H), 2.92 (t, J=6.0 Hz,
2H), 2.78 (t, J=6.8 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 2.54 (t, J=
7.6 Hz, 2H), 1.95–1.89 (m, 2H), 1.80–1.75 (m, 2H), 1.74–1.66 (m,
2H), 1.65–1.55 (m, 2H), 1.49–1.46 (m, 4H), 1.14–1.07 (m, 4H), 0.99–
0.95 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=157.3, 156.6,
137.4, 132.4, 132.3, 36.8, 34.1, 31.1, 29.4, 28.7, 28.6, 26.8, 26.5, 24.2,
23.5, 21.1, 20.7, 14.3, 14.3 ppm; IR (CH2Cl2): n˜2996, 2928, 2869,
1706, 1595, 1555, 1447, 838, 705 cmÀ1; HRMS (ESI): m/z calcd for
C19H32N+ [M+H]+: 274.2529; found: 274.2517.
2-Methylene-1-phenylhexan-1-one (11a): 1H NMR (400 MHz,
CDCl3): d=7.74 (d, J=8.8 Hz, 2H), 7.55–7.48 (m, 3H), 5.80 (s, 1H),
5.56 (s, 1H), 2.47 (t, J=10.8 Hz, 2H), 1.50–1.42 (m, 6H), 0.92 ppm (t,
J=11.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=201.2, 149.3, 141.6,
128.7, 128.6, 126.3, 123.8, 39.8, 31.8, 31.1, 30.6, 28.4, 22.7,
14.2 ppm.
1-(2-Methoxyphenyl)-2-methylenehexan-1-one (11c): 1H NMR
(400 MHz, CDCl3): d=7.36 (t, J=1.6 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H),
6.97–6.90 (m, 2H), 5.80 (s, 1H), 5.59 (s, 1H), 3.75 (s, 3H), 2.44 (t, J=
7.2 Hz, 2H), 1.54–1.46 (m, 2H), 1.43–1.36 (m, 2H), 0.94 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=198.8, 157.2, 150.0,
131.4, 129.7, 129.2, 127.8, 120.4, 111.6, 55.8, 30.6, 30.5, 22.6,
14.2 ppm.
2-Butyl-3,5,6-tripropylpyridine (8q): 1H NMR (400 MHz, CDCl3):
d=7.11 (s, 1H), 2.71 (q, J=8.0 Hz, 4H), 2.52 (t, J=7.6 Hz, 4H),
1.72–1.54 (m, 8H), 1.46–1.36 (m, 2H), 1.00–0.92 ppm (m, 12H);
13C NMR (100 MHz, CDCl3): d=157.1, 156.9, 137.9, 132.2, 132.2,
36.9, 34.7, 34.2, 32.6, 24.3, 23.6, 23.2, 14.5, 14.4, 14.4 ppm; IR
(CH2Cl2): n˜ =2959, 2931, 2871, 1688, 1451, 1339, 1091, 921 cmÀ1
HRMS (ESI): m/z calcd for C18H32N+ [M+H]+: 262.2529; found:
;
Acknowledgements
262.2519.
4-Methyl-2,3-dipropyl-6,7-dihydro-5H-cyclohepta[b]pyridine (8r):
1H NMR (400 MHz, CDCl3): d=6.53 (d, J=11.6 Hz, 1H), 6.16–6.10
(m, 1H), 2.83 (t, J=6.4 Hz, 2H), 2.74–2.70 (m, 2H), 2.61–2.57 (m,
2H), 2.26–2.17 (m, 5H), 2.14–2.08 (m, 2H), 1.75–1.65 (m, 2H), 1.54–
This study was supported by the Mid-career Research Program
(Grant 2011-0016830) through NRF grant funded by the Minis-
try of Education, Science, and Technology.
Chem. Eur. J. 2014, 20, 323 – 333
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Full Paper
[4] Y.-F. Wang, K. K. Toh, J.-Y. Lee, S. Chiba, Angew. Chem. 2011, 123, 6049–
6053; Angew. Chem. Int. Ed. 2011, 50, 5927–5931.
[5] D.-S. Kim, J.-W. Park, C.-H. Jun, Chem. Commun. 2012, 48, 11334–11336.
[6] Y.-K. Sim, H. Lee, J.-W. Park, D.-S. Kim, C.-H. Jun, Chem. Commun. 2012,
48, 11787–11789.
Keywords: alkynes
heterocycles · ketones
·
annulation
·
CÀH activation
·
[1] a) G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651–3678; b) T. W.
Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147–1169; c) D. A. Colby,
R. G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110, 624–655; d) X. Chen,
K. M. Eagle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2009, 121, 5196–5217;
Angew. Chem. Int. Ed. 2009, 48, 5094–5115; e) K. Godula, D. Sames, Sci-
ence 2006, 312, 67–72; f) F. Kakiuchi, N. Chatani, Adv. Synth. Catal.
2003, 345, 1077–1101.
[2] a) T. Fukutani, N. Umeda, K. Hirano, T. Satoh, M. Miura, Chem. Commun.
2009, 5141–5143; b) N. Guimond, K. Fagnou, J. Am. Chem. Soc. 2009,
131, 12050–12051; c) X. Wei, M. Zhao, Z. Du, X. Li, Org. Lett. 2011, 13,
4636–4639; for references to the preparation of pyridines from imines,
see: d) D. A. Colby, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2008,
130, 3645–3651; e) K. Parthasarathy, M. Jeganmohan, C.-H. Cheng, Org.
Lett. 2008, 10, 325–328; f) T. K. Hyster, T. Rovis, Chem. Commun. 2011,
47, 11846–11847; g) P. C. Too, T. Noji, Y. J. Lim, X. Li, S. Chiba, Synlett
2011, 2789–2794; h) R. M. Martin, R. G. Bergman, J. A. Ellman, J. Org.
Chem. 2012, 77, 2501–2507.
[7] S.-G. Lim, J. H. Lee, C. W. Moon, J.-B. Hong, C.-H. Jun, Org. Lett. 2003, 5,
2759–2761.
[8] a) S. Caddick, R. Fitzmaurice, Tetrahedron 2009, 65, 3325–3355, and ref-
erences therein; for reviews on microwave-assisted reactions by transi-
tion-metal catalysts, see: b) P. Appukkuttan, E. Van der Eycken, Eur. J.
Org. Chem. 2008, 1133–1155; c) P. Nilsson, K. Olofsson, M. Larhed, Top.
Curr. Chem. 2006, 266, 103–144; d) M. Larhed, C. Moberg, A. Hallberg,
Acc. Chem. Res. 2002, 35, 717–727.
[9] a) N. Kuhnert, Angew. Chem. 2002, 114, 1943–1946; Angew. Chem. Int.
Ed. 2002, 41, 1863–1866; b) C. O. Kappe, Angew. Chem. 2004, 116,
6408–6443; Angew. Chem. Int. Ed. 2004, 43, 6250–6284; c) C. O. Kappe,
B. Pieber, D. Dallinger, Angew. Chem. 2013, 125, 1124–1130; Angew.
Chem. Int. Ed. 2013, 52, 1088–1094; d) G. B. Dudley, A. E. Stiegman,
M. R. Rosana, Angew. Chem. 2013, 125, 8074–8079; Angew. Chem. Int.
Ed. 2013, 52, 7918–7923; e) C. O. Kappe, Angew. Chem. 2013, 125,
8080–8084; Angew. Chem. Int. Ed. 2013, 52, 7924–7928.
[10] In this reaction, the use of 1.5 equivalents of 14a is optimal.
[11] J. W. Kang, K. Moseley, P. M. Maitlis, J. Am. Chem. Soc. 1969, 91, 5970–
5977.
[3] a) P. C. Too, Y.-F. Wang, S. Chiba, Org. Lett. 2010, 12, 5688–5691; b) P. C.
Too, S. H. Chua, S. H. Wong, S. Chiba, J. Org. Chem. 2011, 76, 6159–
6168; c) X. Zhang, D. Chen, M. Zhao, J. Zhao, A. Jia, X. Li, Adv. Synth.
Catal. 2011, 353, 719–723; d) K. Parthasarathy, C.-H. Cheng, J. Org.
Chem. 2009, 74, 9359–9364; e) L. Zheng, J. Ju, Y. Bin, R. Hua, J. Org.
Chem. 2012, 77, 5794–5800.
Received: July 11, 2013
Published online on November 25, 2013
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