C(sp3)-H dehydrogenation and C(sp2)-H alkoxy carbonylation of inactivated cyclic amines towards functionalized N-heterocycles

Article abstract of DOI:10.1039/c6cc10227a

A novel and efficient synthesis of tetrahydropyridine (THP)-, dihydropyrrole (DHP)-, or tetrahydroazepine (THA)-3-carboxylates via cascade reactions of inactivated cyclic amines with CO and alcohols is presented. To our knowledge, this should be the first

Full text of DOI:10.1039/c6cc10227a

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3
2
C(sp )-H Dehydrogenation and C(sp )-H Alkoxy Carbonylation of
Inactivated Cyclic Amines towards Functionalized N-Heterocycles
Received 00th January 20xx,
Accepted 00th January 20xx
Yan He*, Fang Wang, Xinying Zhang, and Xuesen Fan*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel and efficient synthesis of tetrahydropyridine (THP)-, synthesis as it avoids multi-step pre-activation of starting materials
5
dihydropyrrole (DHP)-, or tetrahydroazepine (THA)-3-carboxylates and minimizes production of by-products. Following this trend,
3
via cascade reactions of inactivated cyclic amines with CO and direct C(sp )–H bond functionalization of saturated cyclic amines
alcohols is presented. To our knowledge, this should be the first provides a promising approach toward various heterocycles. For
example in which functionalized N-heterocycles were prepared instance, Liang’s study found that platinum could promote the
3
2
6
directly from Pd-catalyzed C(sp )-H dehydrogenation and C(sp )-H dehydrogenation of piperidine to give an enamine intermediate,
carbonylation of saturated cyclic amines. Moreover, the DHP-3- which then reacted with nitroolefins to afford functionalized THPs
7a
carboxylates thus obtained could readily undergo an oxidative (Scheme 1, 1). Kanai found that similar transformation could be
7b
aromatization to give pyrrole-3-carboxylates by using O2 as a realized under the promotion of Fe(III)/butyl peroxide (TBP). In
green oxidant. Notable features of the methods developed herein addition, Bruneau reported a Ru-catalyzed cascade N- and C(3)-
include simple substrates, high efficiency and excellent atom- dialkylation of cyclic amines with alcohols involving a hydrogen
7c
economy, mild reaction conditions, and broad substrate scope.
autotransfer process. Following this study, the same group also
developed a selective C(3)-alkylation of saturated cyclic amines by
7d
Tetrahydropyridine (THP) and its derivatives are highly valuable
in synthetic and medicinal chemistry since they are the essential
structural motifs of numerous natural products, therapeutic agents
and functional materials. Among them, THP-3-carboxylates are
well known for their diverse biological activities such as anti-
using aldehyde as the alkylation reagent (Scheme 1, 2). Inspired
7
by these elegant pioneering studies, we have devised and
established an unprecedented synthesis of THP-3-carboxylates
1-2
3
through a C(sp )-H dehydrogenation of piperidine followed by a
2
8
C(sp )-H alkoxy carbonylation of the in situ formed cyclic enamine
intermediate (Scheme 1, 3). Herein, we wish to report our detailed
results in this regard.
bacterial, antitubercular, M muscarinic receptor antagonizing, and
5
3-4
α-glucosidase inhibiting. Due to their importance, several elegant
methods for the preparation of THP-3-carboxylates have been
developed, which include the reaction of N-benzyl γ-chloropropyl
4a
amines with conjugated alkynoates, phosphine-promoted [3+3]
4b
annulation of aziridines with allenoates, four-component reaction
of primary amines with β-dicarbonyl compounds, α,β-unsaturated
4c-4d
4e-4h
aldehydes and alcohols,
etc.
While these literature methods
are generally reliable, regio-selective, efficient and atom-economy
synthesis of THP-3-carboxylates from simple substrates under mild
conditions still remains as a challenging topic in the synthetic
chemistry arena.
Scheme 1. Different synthetic approaches toward THP derivatives
Our study was initiated by treating 1-benzylpiperidine (1a) with
In recent years, transition metal-catalyzed inert C–H bond
functionalization has emerged as an attractive strategy in organic CO (1 atm) and ethanol (2a) in the presence of Pd(OAc)
and
2
o
Cu(OAc) in CH CN at 80 C under air for 12 h, from which ethyl 1-
2
3
benzyl-1,4,5,6-tetrahydropyridine-3-carboxylate (3a) was obtained
in 48% yield (Table 1, entry 1). Next, different Pd catalysts were
tried, and PdCl was found to be more effective than Pd(PPh ) Cl ,
School of Chemistry and Chemical Engineering, School of Environment,
Collaborative Innovation Centre of Henan Province for Green Manufacturing of Fine
Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of
Education, Henan Normal University, Xinxiang, Henan 453007, China.
E-mail: heyan@htu.cn; xuesen.fan@htu.cn
2
3 2
2
Pd (dba) , and Pd(OAc) (entries 1-4). In the absence of Pd catalyst,
2
3
2
the formation of 3a was not observed (entry 5). Following studies
†
Electronic Supplementary Information (ESI) available: Experimental procedures,
on the effect of different oxidants such as CuCl CuBr , CuO, and O
2,
2
2
Mechanism studies, characterisation data and NMR spectra. See DOI: 10.1039/
x0xx00000x.
showed that they were much less effective than Cu(OAc)
2
(entries
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Journal Name
a
a,b
Table 1. Optimization studies on the formation of 3a
Table 2. Substrate scope for the synthesis of 3
View Article Online
DOI: 10.1039/C6CC10227A
b
Entry
Catalyst
Pd(OAc)
PdCl
PdCl (PPh
Pd
Oxidant (equiv) Additive Solvent
T (C) Yield (%)
1
2
3
4
5
6
7
8
9
2
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
(1)
(1)
(1)
(1)
(1)
-
-
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
48
55
2
3a, 75%
3e, 79%
3b, 75%
3c, 77%
3d, 85%
2
3
)
2
-
trace
35
2
(dba)
-
3
-
-
-
-
3f, 70%
3j, 55%
3n, 80%
3g, 78%
3k, 65%
3h, 82%
3l, 56%
3p, 76%
PdCl
PdCl
2
2
2
2
2
2
2
2
CuCl
CuBr
2
(1)
(1)
trace
trace
trace
trace
76
2
-
3
i, 84%
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
CuO (1)
-
O
2
-
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
(1)
(1)
(1)
(1)
KI
KBr
KCl
3
m, 70%
3o, 50%
62
53
I
2
70
PdCl
2
Cu(OAc)
2
(0.2)/O
2
2
2
2
2
2
KI
KI
KI
KI
KI
KI
75
3
t, 73%
3
3
q, 70%
u, 82%
3r, 66%
3v, 72%
3s, 78%
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
(0.2)/O
(0.2)/O
(0.2)/O
(0.2)/O
(0.2)/O
toluene
DCE
40
58
dioxane
65
3w, 60%
3x, 54%
CH
CH
3
CN
CN
62
a
3
70
Reaction conditions: 1 (0.5 mmol), CO/O
2
(5:1, balloon), 2 (5 mmol), PdCl
2
o
a
(0.05 mmol), Cu(OAc)
atm), 12 h. Isolated yield.
2
(0.1 mmol), KI (0.5 mmol), CH
3
CN (5 mL), 80 C, O
2
(1
Reaction conditions: 1a (0.3 mmol), CO (balloon), 2a (3 mmol), catalyst (0.03
b
b
mmol), additive (0.3 mmol), solvent (3 mL), air, 12 h. Isolated yield.
6
-9 vs 2). Gratifyingly, the yield of 3a improved to 76% by using KI as
reaction of piperidines, we were then curious about whether this
new protocol could be extended from piperidines to pyrrolidines. If
successful, it would provide a novel synthetic approach toward
functionalized dihydropyrroles (DHPs), which are frequently found
9
an additive (entry 10). Next, we were delighted to find that a
combination of 0.2 equiv of Cu(OAc) with O (1 atm) as the oxidant
afforded 3a in a yield of 75% (entry 14). Next, various solvents
including toluene, DCE, and 1,4-dioxane were tried, and they were
found less favorable than CH CN (entries 15-17 vs 14). Finally,
2
2
1
0-11
in natural products and pharmaceutical-related compounds.
While a number of elegant methods for the synthesis of DHPs have
3
o
1
2,13
temperatures lower or higher than 80 C resulted in decreased
efficiency (entries 18-19).
been established,
the synthesis of DHP-3-carboxylates directly
from pyrrolidine has not been realized before. Thus, we continued
our study by treating 1-benzylpyrrolidine (4a) with CO and 2a under
the optimized reaction conditions for the preparation of 3a (Table 1,
entry 14), and the desired ethyl 1-benzyl-4,5-dihydro-1H-pyrrole-3-
carboxylate (5a) was obtained in 38% yield. Meanwhile, 1-benzyl
pyrrole was obtained along with 5a in a yield of 42%. This result
indicated that in addition to taking part into the desired alkoxy
carbonylation, the in situ formed DHP intermediate also underwent
an oxidative aromatization to give the pyrrole product under the
reaction conditions. To suppress the formation of 1-benzylpyrrole,
different reaction conditions were then screened. After some trials
and errors, we found that the yield of 5a could be improved to 68%
With the optimized reaction conditions in hands (Table 1, entry
14), a range of piperidines (1) were tried to probe the generality of
this synthetic method. First, 1-benzylpiperidines with different
substituents attached on the phenyl ring of the benzyl unit
underwent this cascade reaction smoothly to afford 3a-3f in good
yields (Table 2). Various functional groups, from the electron-
donating methoxy to the electron-withdrawing fluoro, chloro or
cyano were well tolerated. Second, 1 with 2-phenylethyl, ethyl,
octyl, or cyclopentyl unit also took part in this reaction smoothly
affording 3g-3j in moderate to good yields. Moreover, a range of 1-
aryl substituted piperidines worked well to give 3k-3p in 50-80%
yields. The electronic nature of the 1-aryl unit affected the yield of 3
in that substrates with electron-donating groups on the aryl ring
were more favourable than those with an electron-withdrawing
group (3n, 3p vs 3o). In addition to the good tolerance of different
N-substituents, this reaction was also amenable to substrates
bearing a methyl group on the o- or p-position of the piperidine ring,
and afforded 3q-3u in 66-82% yields. Interestingly, the functiona-
lization of o-methylpiperidines took place regioselectively on the
less steric hindered side (3q-3s), and the formation of other regio-
by increasing the amount of Cu(OAc) from 0.2 to 1 equiv and using
2
air instead of O as the co-oxidant. Next, a series of pyrrolidines (4)
2
were tried to study the substrate generality, and all of them took
part in this reaction to afford the corresponding DHP-3-carboxylates
(
5) in moderate to good yields (Table 3). Notably, the N-substituent
in 4 could be either an alkyl or aryl unit bearing different functional
groups. When it was extended to 1-benzyl-2-methylpyrrolidine (4k),
DHP-3-carboxylate 5k was obtained along with ethyl (E)-2-(1-
benzylpyrrolidin-2-ylidene)acetate (5k'), an exo-cyclic enamino
7e
1
4
isomers was not observed. Finally, a number of alcohols (2) were
tested, and they gave 3v-3x in moderate yields.
ester, in 25% and 52% yield, respectively. When 2-methyl-1-(2-
methylbenzyl)pyrrolidine (4l) was used, 5l and 5l' were obtained in
yields of 20% and 44%, respectively.
After establishing a new synthesis of THP-3-carboxylates from the
2
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Table 3. Substrate scope for the synthesis of 5
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a,b
View Article Online
DOI: 10.1039/C6CC10227A
5b, 63%
5f, 45%
5c, 60%
5g, 50%
5d, 76%
5
a, 68%
Scheme 3. Plausible pathway leading to the formation of 3a
5
e, 61%
5h, 52%
5k', 52%
5
i, 44%
5j, 60%
5k, 25%
5
l, 20%
5l', 44%
a
2
Reaction conditions: 4 (0.5 mmol), CO (balloon), 2a (5 mmol), PdCl (0.05
b
o
mmol), Cu(OAc)
Isolated yield.
2 3
(0.5 mmol), KI (0.5 mmol), CH CN (5 mL), 80 C, air, 12 h.
Moreover, the established protocol for the dehydrogenation and
carbonylation of saturated cyclic amines could also be extended to
azepanes (6). Thus, 1-(o-tolyl)azepane (6a) was treated with CO and
2a under the optimized conditions for the synthesis of 3a (Table 1,
entry 14), and the desired THA-3-carboxylate 7a was obtained in 60%
yield (Scheme 2, 1). Similarly, 7b was successfully synthesized in 51%
yield from 1-(4-bromophenyl)azepane (6b) (Scheme 2, 2).
Scheme 4. Control Experiments
a,b
Table 4. Substrate scope for the synthesis of 8
Scheme 2. Synthesis of 7a and 7b
8a, 92%
8b, 90%
8f, 82%
8c, 88%
8
d, 91%
7
,8
Based on the above results and previous reports , a pathway to
account for the formation of 3a is proposed in Scheme 3. Initially,
8
e, 85%
1
a is dehydrogenated under the promotion of Pd/Cu to give an
a
o
Reaction conditions: 5 (0.2 mmol), under O
2
(ballon), DMSO (2 mL), 80 C, 12
b
iminium intermediate A. Subsequent β-hydrogen elimination occurs
with A to produce an enamine intermediate B. Next, palladation of
h, sealed tube. Isolated yield.
B affords intermediate C, which then undergoes an alkoxy further verify the effect of Cu(OAc)
and KI, more control
2
0
carbonylation with CO and 2a to produce 3a and generate the Pd
experiments were carried out. First, the reaction of 1a with 2a and
II
II
species. The Pd species could be regenerated by Cu in the CO was carried out under standard reaction conditions but in the
presence of O2.
absence of Cu(OAc) . Under this circumstance, the yield of 3a
As the proposed enamine intermediate B could not be isolated decreased to 11% (Scheme 4, 4). This result told that Cu(OAc) is
2
2
from the reaction of 1a with CO and 2a, it was prepared from 1- indispensible as an catalyst for the efficient formation of 3a when
benzylpiperidin-2-one based on a literature procedure (see SI). oxygen is used as the oxidant. Second, the reaction of 1a with 2a
Then, it was subjected to the standard reaction conditions. From and CO was run in the absence of KI (Scheme 4, 5), and the yield of
this reaction, 3a was obtained in a yield of 85% (Scheme 4, 1).
3a decreased to 53%, indicating that the presence of KI is beneficial
In other two control experiments, the reaction of 1a with CO and to the formation of 3a. Based on a literature report, KI might be
9
2
a was carried out in the presence of 1 or 2 equiv of Cu(OAc) under able to improve the activity of the catalyst.
2
N , and 3a was obtained in yields of 35% and 79%, respectively
2
Finally, to showcase the synthetic value of the DHP-3-carboxy-
lates (5) obtained above and develop an alternative approach
(
Scheme 4, 2 and 3). These results together with those included in
Table 1 indicate that the efficient formation of 3a needs at least 2
toward the synthetically and pharmaceutically significant pyrrole-3-
equiv of Cu(OAc) in the absence of O or air as the co-oxidant. To
15-17
2
2
carboxylates,
several DHP-3-carboxylates (5) were treated with
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Hopkinson, F. Glorius and J. Wencel-Delord, Chem. Soc.VRieewvA.,rt2ic0le1O6,nl4in5e,
900.
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carboxylates 8a-8f were obtained in high efficiency (Table 4).
2
DOI: 10.1039/C6CC10227A
[
[
In summary, we have developed a novel and efficient
synthesis of THP-, DHP- or THA-3-carboxylates via the one-pot
cascade reactions of piperidines, pyrrolidines or azepanes with
CO and alcohols. Mechanistically, the formation of the target
products involves firstly a dehydrogenation of saturated cyclic
amines followed by an alkoxy carbonylation of the in situ
formed cyclic enamine intermediates. In addition, the DHP-3-
carboxylates thus obtained could readily undergo an oxidative
aromatization to give the corresponding pyrrole-3-carboxy-
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This work was financially supported by the National Natural
Science Foundation of China (NSFC) (grant number 21572047),
Program for Innovative Research Team in Science and Technology in
Universities of Henan Province (15IRTSTHN 003), and Program for
Science and Technology Innovation Talents in Universities of Henan
Province (15HASTIT005).
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