Synthesis of α-Formylated N-Heterocycles and Their 1,1-Diacetates from Inactivated Cyclic Amines Involving an Oxidative Ring Contraction

Article abstract of DOI:10.1021/acs.orglett.7b04029

A novel synthesis of pyrrolidine-2-carbaldehydes or tetrahydropyridine-2-carbaldehydes from the cascade reactions of N-arylpiperidines or N-arylazepanes is presented. Mechanistically, the formation of the title compounds involves an unprecedented oxidative ring contraction of inactivated cyclic amines via Cu(OAc)₂/KI/O₂-promoted oxidative cleavage and reformation of the C-N bond. Interestingly, when PhI(OAc)₂ was used in place of KI, 1,1-diacetates of the corresponding aldehydes were directly obtained with good efficiency. To the best of our knowledge, this is the first example of regioselective C(sp³)-H bond functionalization and C(sp³)-N bond activation of saturated cyclic amines using copper salt and oxygen.

Full text of DOI:10.1021/acs.orglett.7b04029

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of α‑Formylated N‑Heterocycles and Their 1,1-Diacetates
from Inactivated Cyclic Amines Involving an Oxidative Ring
Contraction
Fang Wang, Yan He,* Miaomiao Tian, Xinying Zhang, and Xuesen Fan*
School of Environment, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for
Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Henan
Normal University, Xinxiang, Henan 453007, China
*
S Supporting Information
ABSTRACT: A novel synthesis of pyrrolidine-2-carbalde-
hydes or tetrahydropyridine-2-carbaldehydes from the cascade
reactions of N-arylpiperidines or N-arylazepanes is presented.
Mechanistically, the formation of the title compounds involves
an unprecedented oxidative ring contraction of inactivated
cyclic amines via Cu(OAc) /KI/O -promoted oxidative
2
2
cleavage and reformation of the C−N bond. Interestingly,
when PhI(OAc) was used in place of KI, 1,1-diacetates of the corresponding aldehydes were directly obtained with good
2
3
3
efficiency. To the best of our knowledge, this is the first example of regioselective C(sp )−H bond functionalization and C(sp )−
N bond activation of saturated cyclic amines using copper salt and oxygen.
3
n recent years, C(sp )−H bond activation has attracted much
resulting mixture. Instead, 1-phenylpyrrolidine-2-carbaldehyde
2a) was obtained in 25% yield (Scheme 2; Table 1, entry 1).
I
attention owing to its elimination of substrate(s) preactivation
and minimization of byproduct(s) production. In particular, the
C(sp )−H bond functionalization of inactivated cyclic amines
turns out to be a highly promising strategy for the synthesis of
heterocyclic derivatives bearing diverse functional groups. In
this regard, we have recently disclosed a new synthesis of
tetrahydropyridine-3-carboxylate via oxidative dehydrogenation
of N-substituted piperidine followed by an alkoxy carbonylation
of the in situ formed cyclic enamine intermediate with CO and
alcohol under the promotion of a combination of PdCl /
Cu(OAc) /KI/O (Scheme 1, (1)). In continuation of our
(
3
Scheme 2. Unexpected Formation of 2a from 1a
1
,2
Notwithstanding the proposed enamine (I) was not obtained,
it occurred to us that the unexpected formation of 2a was much
more interesting because (1) while α-formyl pyrrole derivatives
are well-known for their unique functional property and rich
2
3
2
2
4
,5
Scheme 1. Transformations of Inactivated Cyclic Amines via
C(sp )−H Bond Functionalization
reactivity,
efficient and sustainable methods for their
3
6−9
preparation are currently still highly limited
and (2) the
formation of 2a from 1a indicated that a mechanistically
interesting and synthetically promising ring contraction of 1a
through an oxidative C−N bond cleavage and reformation had
taken place. Notably, while transition-metal-catalyzed cleavage of
the C−N single bond in inactivated amines has evolved as a mild
and convenient nitrogen and carbon source for organic
10,11
synthesis,
oxidative ring contraction of inactivated saturated
cyclic amines to afford α-formylated N-heterocycles has not been
reported previously.
interest in this aspect, we have serendipitously found a novel
Aiming to develop this promising transformation into an
efficient and reliable synthetic approach to hydrogenated α-
formylpyrrole derivatives, various parameters were screened.
First, to verify the role played by PdCl and Cu(OAc) in the
synthesis of α-formylated pyrrolidine through Cu(OAc) /KI/
2
O -promoted oxidative ring contraction of N-substituted
2
piperidine (Scheme 1, (2)). Herein we report our detailed study.
The initial attempt of our study was to obtain the proposed
2
2
3
formation of 2a, the reaction was carried out in the presence of
enamine intermediate as shown in Scheme 1. For this purpose,
1
-phenylpiperidine (1a) was treated with PdCl , Cu(OAc) , and
2 2
KI under O in CH CN at 80 °C. To our surprise, the expected 1-
phenyl-1,2,3,4-tetrahydropyridine (I) was not isolated from the
Received: December 27, 2017
2
3
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b04029
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
,
a b
Table 1. Optimization Studies
Scheme 3. Substrate Scope for the Synthesis of 2
b
entry
oxidant (equiv)
additive
solvent
yield (%)
c
1
Cu(OAc) (0.2)/O
KI
KI
KI
KI
KI
KI
KI
I2
CH CN
25
28
2
2
3
2
3
4
5
6
7
8
9
Cu(OAc) (0.2)/O
CH CN
2
2
3
PdCl (0.1)/O
CH CN
trace
2
2
3
O2
CH CN
3
Cu(OAc) (0.5)/O
CH CN
36
58
2
2
3
Cu(OAc) (1)/O
CH CN
2
2
2
2
2
2
3
Cu(OAc) (2)/O
CH CN
59
2
3
Cu(OAc) (1)/O
CH CN
56
2
3
Cu(OAc) (1)/O
CH CN
trace
15
2
3
10
11
12
13
14
15
16
17
18
Cu(OAc) (1)/N
KI
KI
KI
KI
KI
KI
KI
KI
KI
CH CN
2
3
CuO (1)/O2
CuCl (1)/O
CH CN
3
CH CN
trace
trace
17
2
2
2
3
CuBr (1)/O
CH CN
2
3
a
Cu(OAc) (1)/O
DCE
Reaction conditions: 1 (0.5 mmol), Cu(OAc) (0.5 mmol), KI (0.5
2
b
2
2
2
2
2
Cu(OAc) (1)/O
dioxane
DMF
23
mmol), CH
yield.
CN (5 mL), 80 °C, O (1 atm, balloon), 12 h. Isolated
3 2
2
Cu(OAc) (1)/O
trace
27
2
Cu(OAc) (1)/O
DMSO
2
low yield of 21%. However, 1-(2-nitrophenyl)-, 1-pentyl-, or 1-
benzylpiperidine remained almost intact under the conditions,
and the desired products (2p, 2q, and 2r) were not obtained.
Cu(OAc) ·H O (1)/O
CH CN
51
2
2
2
3
a
Reaction conditions: 1a (0.5 mmol), additive (0.5 mmol), solvent (5
2d
b
c
mL), 80 °C, O (1 atm, balloon), 12 h. Isolated yield. PdCl (0.05
mmol).
2
2
Having established a novel synthesis of pyrrolidine-2-
carbaldehydes (2) from the reaction of N-arylpiperidines (1),
we were interested in extending the substrate scope from
piperidine (1) to azepane (3), from which piperidine-2-
carbaldehydes were expected to be formed. To date, α-
formylated pyridines and their hydrogenated derivatives have
been widely used in the synthesis of metal complexes with
relevance in medicinal and coordination chemistry. Moreover,
they are also versatile intermediates in the synthesis of
imidazo[1,5-a]pyridines, tetrahedral metal organic cages, and
Cu(OAc) but in the absence of PdCl . Under these circum-
stances, the yield of 2a increased from 25% to 28% compared
with that using a combination of PdCl and Cu(OAc) (Table 1,
entry 2 vs 1). When the reaction was carried out in the presence
of PdCl but in the absence of Cu(OAc) , 2a was formed only in
a trace amount (entry 3). In the absence of PdCl and Cu(OAc) ,
the formation of 2a was not observed (entry 4). These results
indicate that using Cu(OAc) alone is more beneficial than using
a combination of PdCl with Cu(OAc) or using PdCl alone in
promoting this reaction. Further screening found that increasing
the amount of Cu(OAc) from 0.2 equiv to 0.5, 1, or 2 equiv
improved the yield of 3a significantly (entries 5−7). With 1 equiv
of Cu(OAc) , KI was replaced by I as the additive, but no better
result was obtained (entry 8). Without an additive, however, 2a
was formed only in a trace amount (entry 9). When the reaction
was carried out under nitrogen atmosphere, the yield of 2a was
2
2
2
2
2
2
2
2
12
2
indolizines, etc. Notwithstanding their importance, efficient
2
2
2
preparations of piperidine-2-carbaldehydes have only been
13
sporadically reported. To develop a novel and facile synthetic
2
protocol to hydrogenated α-formylpyridines, 1-phenylazepane
(
3a) was subjected to the optimized reaction conditions for the
2
2
formation of 2a (Table 1, entry 6). Surprisingly, the desired 1-
phenylpiperidine-2-carbaldehyde (4a) was obtained only in a
trace amount. Meanwhile, 1-phenyl-1,4,5,6-tetrahydropyridine-
2
-carbaldehyde (5a) was isolated in 18% yield (Scheme 4). Based
low (entry 10), indicating that the presence of O is essential for
2
the efficient formation of 2a. Following studies on the effect of
different copper salts showed that CuO, CuCl , and CuBr were
Scheme 4. Formation of 5a under Different Conditions
2
2
less effective than Cu(OAc) in promoting this reaction (entries
2
1
1−13 vs 6). DCE, 1,4-dioxane, DMF, and DMSO were found to
be less favorable than CH CN as the solvent (entries 14−17 vs
3
6
). When Cu(OAc) was replaced by Cu(OAc) ·H O, 2a was
2 2 2
obtained in a slightly lower yield (entry 18).
With the optimized reaction conditions in hand, a range of N-
substituted piperidines (1) were tried as substrates, and the
results are included in Scheme 3. First, 1-phenylpiperidines with
different substituents attached on the phenyl ring reacted
smoothly to afford 2a−m in moderate yields. Various functional
groups, from methyl to fluoro, chloro, bromo, or nitro, were well
tolerated. In another respect, this reaction was also amenable to
substrate bearing a methyl group on the ortho-position of the
piperidine ring, namely 2-methyl-1-phenylpiperidine, and
afforded the corresponding products 2n and 2n′. It was also
observed that 1-(2-methoxyphenyl)piperidine afforded 2o in a
on this observation, we treated 3a with reduced amounts of
Cu(OAc) or at lower reaction temperature with the aim of
2
improving the selectivity for the formation of 4a. However, under
these conditions, the transformation of 3a was very sluggish, and
neither 4a nor 5a could be obtained in an efficient manner. Next,
we moved our focus from 4a to 5a and continued our study in
searching for suitable conditions for the efficient formation of 5a.
After some investigation, we were pleased to find that the yield of
5a could be improved to 50% by treating 3a with 3 equiv of
B
DOI: 10.1021/acs.orglett.7b04029
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
,
a b
Cu(OAc) and 1 equiv of KI under O in CH CN at 80 °C for 12
Scheme 7. Substrate Scope for the Synthesis of 6 and 7
2
2
3
h (Scheme 4).
Next, a range of 1-arylazepanes (3) were subjected to the
optimized reaction conditions to explore the scope of this novel
transformation. It turned out that 3 with various functional
groups attached on the 1-aryl unit gave the corresponding α-
formyl tetrahydropyridines (5a−j, Scheme 5) in moderate yields.
Different substituents on the aryl group such as halides, methyl,
ethyl, and methoxy were tolerated under the reaction conditions.
,
ab
Scheme 5. Substrate Scope for the Synthesis of 5
a
Conditions: 1 or 3 (0.5 mmol), Cu(OAc) (0.5 mmol), PhI(OAc)
2
2
b
(0.5 mmol), CH CN (5 mL), 80 °C, O (1 atm), 12 h. Isolated yield.
3
2
Scheme 8. Miscellaneous Transformations
a
Reaction conditions: 3 (0.5 mmol), Cu(OAc) (1.5 mmol), KI (0.5
2
b
mmol), CH CN (5 mL), 80 °C, O (1 atm), 12 h. Isolated yield.
3
2
During our study on optimizing the reaction conditions for the
14,15
formation of 2a from 1a, we observed that when PhI(OAc)2
was used in place of KI as an additive, the reaction did not afford
a. Instead, (1-phenylpyrrolidin-2-yl)methylene diacetate (6a)
2
was obtained in a yield of 64% (Scheme 6). This finding is highly
gave 5a or 7a in yield of 80% and 78%, respectively, indicating
that 4a might be a key intermediate in the formation of 5a and 7a
from 3a (Scheme 8).
Scheme 6. Unexpected Formation of 6a
On the basis of the above observations and previous
10,11
reports,
a plausible pathway accounting for the formation
of 2a is proposed in Scheme 9. Initially, dehydrogenation of 1a
Scheme 9. Proposed Pathway for the Formation of 2a
attractive as the protection of aldehydes is a frequently used
strategy in organic synthesis to prevent undesired side reactions,
and among various versions of aldehyde protection, 1,1-
diacetates (acylals) have the advantage of being stable under a
range of conditions. Moreover, 1,1-diacetates could be used as
16
precursors in the synthesis of various functional molecules.
Therefore, the direct formation of 6a from 1a is of potential
applicability in accomplishing related synthetic missions. Thus,
the substrate scope of the 1,1-diacetate formation was studied. It
turned out that in addition to 1a, other 1-arylpiperidines with
different substituents on the 1-aryl unit were also suitable for this
reaction to give 6b−f in moderate yields (Scheme 7).
Interestingly, when 3a was subjected to similar conditions, it
gave (1-phenylpiperidin-2-yl)methylene diacetate (7a), the 1,1-
diacetate of 4a rather than that of 5a. Several other N-substituted
azepanes gave the corresponding products 7b−f in moderate
yields (Scheme 7), thus resulting in a direct and convenient
approach to related aldehyde equivalents from simple starting
materials.
under the promotion of Cu(II)/O forms iminium ion A. Under
2
the reaction conditions, A is further oxidized to give complex B
with the cleavage of the C−N bond and the formation of the
formyl unit. Intermediate B is then tautomerized into an enol
intermediate C. Complexation of Cu(II) with the enol unit in C
affords intermediate D. Finally, reductive elimination occurs in D
to give 2a through the C−N bond reformation. Notably, in this
cascade process, copper salt should have played a dual rule as
both the co-oxidant and the coupling catalyst.
Finally, it is worth noting that when 1-phenylpyrrolidine (8)
was subjected to the optimized conditions, the formation of 1-
phenylazetidine-2-carbaldehyde (9) was not observed. Instead,
the formation of several pyrrole derivatives (including 10, 11,
and 12) was observed based on GC−MS and/or NMR analysis
(Scheme 10).
As mentioned above, aldehyde 4a could not be obtained
effectively from the reaction of 3a as it mainly afforded 5a under
the promotion of Cu(OAc) /KI/O (Scheme 4). To solve this
2
2
problem, 7a was treated with dilute sulfuric acid obtaining 4a in
6% yield (Scheme 8). Moreover, 4b and 4c could also be
8
In summary, we have developed a novel synthesis of α-
formylated N-heterocycles and their 1,1-diacetates through the
cascade reactions of inactivated cyclic amines featuring an
obtained under similar conditions. In addition, when 4a was
treated with Cu(OAc) /KI/O or Cu(OAc) /PhI(OAc) /O , it
2
2
2
2
2
C
DOI: 10.1021/acs.orglett.7b04029
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
5) Wood, J. M.; Furkert, D. P.; Brimble, M. A. Org. Biomol. Chem.
Scheme 10. Transformation of 1-Phenylpyrrolidine (8)
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(
oxidative ring contraction. Compared with previous reports, this
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mechanism are currently underway in our laboratory.
(
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ASSOCIATED CONTENT
Supporting Information
■
*
S
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b04029.
2
Commun. 2012, 48, 10295. (d) Ronson, T. K.; Zarra, S.; Black, S. P.;
Nitschke, J. R. Chem. Commun. 2013, 49, 2476. (e) Chow, M. J.; Licona,
C.; Wong, D. Y. Q.; Pastorin, G.; Gaiddon, C.; Ang, W. H. J. Med. Chem.
Experimental procedure, characterization data, and NMR
spectra for all products (PDF)
2
014, 57, 6043. (f) Sadowski, B.; Klajn, J.; Gryko, D. T. Org. Biomol.
Chem. 2016, 14, 7804. (g) Capomolla, S. S.; Lim, N.-K.; Zhang, H. Org.
Lett. 2015, 17, 3564.
(13) Basarab, G. S.; Galullo, V.; DeGrace, N.; Hauck, S.; Joubran, C.;
Wesolowski, S. S. Org. Lett. 2014, 16, 6456.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: heyan@htu.cn.
E-mail: xuesen.fan@htu.cn.
ORCID
(14) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(b) Narayan, R.; Manna, S.; Antonchick, A. P. Synlett 2015, 26, 1785.
(c) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328.
(d) Zhang, X.; Cong, Y.; Lin, G.; Guo, X.; Cao, Y.; Lei, K.; Du, Y. Youji
Xinying Zhang: 0000-0002-3416-4623
Xuesen Fan: 0000-0002-2040-6919
Notes
Huaxue 2016, 36, 2513.
15) (a) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133,
996. (b) Huang, J.; He, Y.; Wang, Y.; Zhu, Q. Chem. - Eur. J. 2012, 18,
(
5
The authors declare no competing financial interest.
13964. (c) Shang, S.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Angew.
Chem., Int. Ed. 2014, 53, 6216. (d) Zhang, N.; Cheng, R.; Zhang-
Negrerie, D.; Du, Y.; Zhao, K. J. Org. Chem. 2014, 79, 10581. (e) Zhang,
B.; Zhang, X.; Hu, B.; Sun, D.; Wang, S.; Zhang-Negrerie, D.; Du, Y. Org.
Lett. 2017, 19, 902. (f) Maiti, S.; Achar, T. K.; Mal, P. Org. Lett. 2017, 19,
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (NSFC) (Grant Nos. 21702050 and 21572047), Program
for Innovative Research Team in Science and Technology in
Universities of Henan Province (15IRTSTHN003), Program for
Science and Technology Innovation Talents in Universities of
Henan Province (15HASTIT005), and Plan for Scientific
Innovation Talents of Henan Province (184200510012) for
financial support.
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M.; Seidi, F. ACS Catal. 2012, 2, 1259. (b) Shirini, F.; Mamaghani, M.;
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DOI: 10.1021/acs.orglett.7b04029
Org. Lett. XXXX, XXX, XXX−XXX