An N-Heterocyclic Carbene-Catalyzed Oxidative γ-Aminoalkylation of Saturated Carboxylic Acids through in Situ Activation Strategy: Access to δ-Lactam

Article abstract of DOI:10.1021/acs.orglett.5b03223

An N-Heterocyclic Carbene (NHC)-catalyzed oxidative formal [4 + 2] annulation of acylhydrazones with saturated carboxylic acids bearing γ-H to assemble δ-lactams featuring a chiral carbon stereogenic center was developed through an in situ activation stra

Full text of DOI:10.1021/acs.orglett.5b03223

Letter
pubs.acs.org/OrgLett
An N‑Heterocyclic Carbene-Catalyzed Oxidative γ‑Aminoalkylation of
Saturated Carboxylic Acids through in Situ Activation Strategy:
Access to δ‑Lactam
Yonglei Que, Yuanwei Xie, Tuanjie Li, Chenxia Yu, Shujiang Tu, and Changsheng Yao*
Jangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, School of Chemistry and Chemical Engineering,
Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R. China
S
* Supporting Information
ABSTRACT: An N-Heterocyclic Carbene (NHC)-catalyzed oxidative formal [4 + 2] annulation of acylhydrazones with
saturated carboxylic acids bearing γ-H to assemble δ-lactams featuring a chiral carbon stereogenic center was developed through
an in situ activation strategy. The ready availability of the starting materials, excellent enantioselectivity, facile assembly, high
yields, and potential biological significance of the final products make this protocol an attractive alternative for the construction of
the pyridinone scaffold.
exquisite conversion of α,β-unsaturated acyl chlorides into I.7
arbonyl compounds, such as esters, ketones, and
Caldehydes, are versatile building blocks that have been Later, the Chi group reported efficient oxidative generation of I
from enal.8 Our prior study demonstrated that the debromi-
employed widely for the production of pharmaceuticals and
nation and deprotonation of the Breslow intermediate derived
from NHC and 2-bromo-2-enal bearing γ-H could deliver I
readily.9 More recently, Chi et al. and our group disclosed the
successful formation of I via the reaction of NHC and the α,β-
unsaturated carboxylic esters under basic conditions (Scheme
1).10 The reaction of these NHC-bounded vinyl enolates as
novel synthones with activated double bonds could provide
new access to highly functionalized molecular scaffolds.
Carboxylic acids are not only readily available but also more
stable compared with the α-functionalized aldehydes and enals
used previously in NHC-catalyzed reactions. Besides, they are
less liable to enolize than ketone and activated esters, which
may avoid the occurrence of the side reaction including aldol
condensation, Michael addition, and Claisen condensation.
These noticeable advantages make the carboxylic acids ideal
starting materials for organic synthesis, and considerable
attention has been focused on their organocatalytic trans-
formations.11 In 2014, Scheidt and co-workers devised an
NHC-catalyzed shortcut to enolates from the acyl imidazoles
materials. Thus, plenty of effort has been devoted to the
efficient transformations of these kinds of compounds. The
introduction of a functional unit at the α-position of carbonyl
compounds could be achieved easily using enolates as key
intermediates.1 However, the direct installation of a functional
group at nonreactive sp3 hybridized carbon atoms remote from
the carbonyl group is a long-term challenge for organic
chemists. Recent reports disclosed the transition-metal-
catalyzed direct remote C−H functionalization with the
assistance of auxiliary groups or directing groups.2 In addition,
organocatalytic remote activation of C(sp3)−H has also
progressed.3 Even so, the convenient and straightforward
introduction of a functional group at the remote nonreactive
site, e.g. the γ-position of readily available saturated carboxylic
acids are still worthy of further research.
N-heterocyclic carbenes (NHCs) have shown excellent
catalytic activity for several “umpolung” reactions,4 such as
a1−d1 polarity inversion of the aldehyde to involve benzoin
condensation and Stetter reaction5 and a3−d3 umpolung of enal
(homoenolate).6 Thus, much exertion has been directed toward
the formation and reactivity of NHC-bounded intermediates,
e.g., an NHC-bounded vinyl enolate (I). Ye et al. proposed an
Received: November 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03223
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We started by using saturated acid 1a and hydrazone 2a as
model substrates to optimize the reaction conditions, and the
results are reported in Table 1. Under the basic reaction
Scheme 1. Generation of NHC-Bounded Vinyl Enolate (I)
Table 1. Optimization of the Reaction Conditions
a
b
entry
4
precat.
solvent
base
yield (%)
ee (%)
1
4a
4a
4b
4c
4d
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
DME
DCM
THF
THF
THF
THF
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
−
70
−
98
generated in situ from the carboxylic acid and carbon-
yldiimidazole (CDI), which provided an easy means for the
direct functionalization of the α-carbon of carboxylic acids.12
Later, Ye et al. presented the mild conversion of mixed
anhydrides of α,β-unsaturated carboxylic acids into α,β-
unsaturated acyl azoliums.13 More recently, our group
proposed the direct formation of homoenolates from carboxylic
acids via the in situ activation strategy presented by peptide
coupling reagents.14 We envisaged that the above-mentioned
homoenolates could be transformed into vinyl enolate I via
oxidation and deprotonation if they possessed γ-H. The
subsequent reaction of these key intermediates with polar
double bond could pave a new avenue to a six-membered ring
from readily available carboxylic acids (Scheme 2).
To continue our work on NHC-catalyzed cascade synthesis
of heterocycles,8b,9,10b,14,15 herein we shall report our
preliminary study of the NHC-promoted oxidative asymmetric
formal [4 + 2] synthesis of δ-lactams with biological interest
and great synthetic potential in the presence of peptide
coupling reagents through an in situ activation strategy.16
2
B
B
B
B
A
C
D
E
3
−
−
99
−
−
99
4
34
trace
trace
82
−
5
6
7
8
−
99
−
99
99
−
−
−
−
99
9
44
10
11
12
13
14
15
16
F
−
C
C
C
C
C
C
C
C
16
63
trace
−
−
−
DABCO
Et3N
c
17
Cs2CO3
Cs2CO3
80
d
18
73
98
a
b
c
Yield of the isolated product. Determined by HPLC. Reactions
were run at 15 °C. Reactions were run at 35 °C.
d
conditions, no formation of the desired product 3a was
observed in the absence of the NHC catalyst (Table 1, entry 1).
Several acid activating reagents such as 2-(7-aza-1H-benzo-
triazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
(HATU), carbonyldiimidazole (CDI), and dicyclohexylcarbo-
diimide (DCC) were screened. We were pleased to find that
the desired product 3a was obtained in good yield with 98% ee
during the preliminary screening when HATU was employed as
an activator (Table 1, entry 2). CDI was not effective for the
annulation, and DCC/HOBt could give a 21% yield with 98%
ee. Then we explored the influence of oxidants (Table 1, entries
2−5). The oxidant 4a could deliver better results compared
with other ones. Subsequently, the effect of chiral catalysts was
studied (Table 1, entries 6−10). The chiral catalyst C indicated
good catalytic ability in 82% yield with 99% ee (Table 1, entry
7). The catalyst E could also catalyze the reaction to give 3a
with similar ee but a lower yield (Table 1, entry 9). The solvent
optimization revealed that THF was superior to others (Table
1, entries 11−13). Besides, other organic and inorganic bases
were examined and the product 3a was not observed (Table 1,
Scheme 2. Our Proposal for the Oxidative Generation of
Vinyl Enolate from Saturated Carboxylic Acids through the
in Situ Activation Strategy
B
DOI: 10.1021/acs.orglett.5b03223
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Organic Letters
Letter
entries 14−16). After temperature screening, 25 °C was
optimal in view of yields and enantioselectivity (Table 1,
entries 17−18).
With the optimized reaction conditions in hand, the scope of
saturated acids and hydrazones was examined (Table 2). It was
Scheme 3. A Putative Reaction Mechanism for the Oxidative
Formal [4 + 2] Synthesis of δ-Lactams
Table 2. Scope of Substrates
a
b
entry
R1
R2
3
yield (%)
ee (%)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
82
83
90
93
86
95
77
81
90
85
62
84
94
88
86
72
99
99
99
99
99
99
98
99
99
99
99
99
99
98
99
99
2
4-BrC6H4
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-t-BuC6H4
4-NO2C6H4
3-BrC6H4
3-MeC6H4
2-MeC6H4
Thien-2-yl
Ph
3
4
5
6
7
3g
3h
3i
i.e., Breslow intermediate V, which was similar to the reported
NHC-catalyzed reactions of esters of carboxylic acids.17 The
subsequent oxidation of V delivered α,β-unsaturated acyl
azolium VI, which was converted into NHC-bounded vinyl
enolate I via deprotonation. The successive formal [4 + 2]
reaction of I with acylhydrazones yielded the δ-lactams finally,
which was akin to the known results.10a
8
9
10
11
12
13
14
15
16
3j
3k
3l
4-BrC6H4
2-Naphthyl
2-Naphthyl
4-MeC6H4
Thien-2-yl
Ph
3m
3n
3o
3p
3-MeC6H4
Ph
To shed some light on the reaction mechanism, a few control
experiments were carried out, which gave experimental
evidence for our proposed reaction mechanism (Scheme 4;
Ph
a
b
Yield of the isolated product. Determined by HPLC.
Scheme 4. Some Control Experiments for Validating the
Reaction Mechanism
found that both electron-withdrawing groups (4-Br, 4-Cl, 4-F)
and electron-donating groups (4-MeO, 4-t-Bu) on the aromatic
ring of hydrazones were well tolerated and gave the desired
products (3b−3f). To our delight, the hydrazones with an
aromatic ring having a strong electron-withdrawing group (4-
NO2) could also give a good yield with 98% ee (3g). The
hydrazones bearing a meta-substituted phenyl ring (3-BrC6H4
and 3-MeC6H4) also worked well (3h−3i). Notably, the
challenging ortho-substituted substrate (2-MeC6H4) was
compatible successfully (3j). Interestingly, the oxidative
annulation through in situ activation of saturated carboxylic
acids could also be applied to heterocyclic hydrazone (3k).
These results highlighted the broad application scope of
hydrazones for the assembly of the scaffolds of δ-lactam
through an in situ activation strategy. The scope of saturated
acids also was tested for the reaction, and the results showed
that the reactions turned out to be tolerant of various β-arylated
saturated acids (3l−3p). Unfortunately, the β-dialkylated
saturated aliphatic acids were not suitable for the reaction
conditions, which may be attributed to the lack of conjugate
effect of the alkyl group.
The HPLC analysis data and optical rotation of δ-lactam
product 3b were consistent with those reported in the
literature;10a thus, the absolute configuration of the final
products can be determined by comparison.
A plausible reaction pathway for this NHC-catalyzed
oxidative annulation through in situ activation is illustrated in
Scheme 3. The reaction of NHC with esters 5 generated in situ
from saturated carboxylic acids and HATU gave the acyl
azolium II, which was transformed into enolate III upon
deprotonation. Its following β-sp3-H shift gave homoenolate IV,
for details, please see the Supporting Information, SI). The
oxidation of saturated carboxylic acids (or their esters) into
their α,β-unsaturated counterparts was not achieved, and the
key intermediate, 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 3-
phenylbutanoate (5), could be isolated successfully via stepwise
reaction. Besides, intermediate 5 could react with 2 to give the
desired cycloadduct catalyzed by NHC presented by oxidants.
These results demonstrated that 5 should be a crucial
intermediate for this oxidative formal [4 + 2] annulation, and
the oxidation of Breslow intermediate V was decisive.10a
To explore the generality of this approach, isatin and 2,2,2-
trifluoro-1-phenylethanone containing an activated carbonyl
group were subjected to this protocol, and the expected δ-
lactones were obtained in good yields with moderate
enantioselectivity (Scheme 5), which highlighted the wide
substrate scope of our strategy.
In conclusion, an NHC-catalyzed oxidative γ-aminoalkylation
of saturated carboxylic acids possessing γ-H was realized
through an in situ activation strategy. This organocatalytic
cascade process afforded a new approach to δ-lactams (or δ-
C
DOI: 10.1021/acs.orglett.5b03223
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 5. Oxidative Formal [4 + 2] Synthesis of δ-Lactones
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lactones) with ready availability of the starting materials,
excellent enantioselectivity, high yields, convergent assembly,
and mild reaction conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03223.
Experimental details, copies of 1H and 13C NMR spectra
for all products (PDF)
(9) (a) Yao, C.; Xiao, Z.; Liu, R.; Li, T.; Jiao, W.; Yu, C. Chem. - Eur.
J. 2013, 19, 456. (b) Xiao, Z.; Yu, C.; Li, T.; Wang, X.; Yao, C. Org.
Lett. 2014, 16, 3632. (c) Xie, Y.; Que, Y.; Li, T.; Zhu, L.; Yu, C.; Yao,
C. Org. Biomol. Chem. 2015, 13, 1829.
AUTHOR INFORMATION
Corresponding Author
■
(10) (a) Xu, J.; Jin, Z.; Chi, Y. R. Org. Lett. 2013, 15, 5028. (b) Que,
Y.; Li, T.; Yu, C.; Wang, X.-S.; Yao, C. J. Org. Chem. 2015, 80, 3289.
(11) For reviews of organocatalytic transformations of carboxylic
acids, please see: (a) Morrill, L. C.; Smith, A. D. Chem. Soc. Rev. 2014,
43, 6214. For selected examples, please see: (b) Morrill, L. C.;
Douglas, J.; Lebl, T.; Slawin, A. M. Z.; Fox, D. J.; Smith, A. D. Chem.
Sci. 2013, 4, 4146. (c) Stark, D. G.; Morrill, L. C.; Yeh, P.-P.; Slawin, A.
M. Z.; O'Riordan, T. J. C.; Smith, A. D. Angew. Chem., Int. Ed. 2013,
52, 11642. (d) Stark, D. G.; O’ Riordan, T. J. C.; Smith, A. D. Org. Lett.
2014, 16, 6496. (e) Smith, S. R.; Douglas, J.; Prevet, H.; Shapland, P.;
Slawin, A. M. Z.; Smith, A. D. J. Org. Chem. 2014, 79, 1626.
(12) Lee, A.; Younai, A.; Price, C. K.; Izquierdo, J.; Mishra, R. K.;
Scheidt, K. A. J. Am. Chem. Soc. 2014, 136, 10589.
*E-mail: csyao@jsnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from National Natural
Science Foundation of China (Nos. 21372101 and 21242014),
a Project Funded by the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions, Graduate
Research and Innovation Projects in Jiangsu Normal University
(2014YYB025).
(13) Chen, X.-Y.; Gao, Z.-H.; Song, C.-Y.; Zhang, C.-L.; Wang, Z.-X.;
Ye, S. Angew. Chem., Int. Ed. 2014, 53, 11611.
(14) Xie, Y.; Yu, C.; Li, T.; Tu, S.; Yao, C. Chem. - Eur. J. 2015, 21,
5355.
(15) Yao, C.; Wang, D.; Lu, J.; Li, T.; Jiao, W.; Yu, C. Chem. - Eur. J.
2012, 18, 1914.
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DOI: 10.1021/acs.orglett.5b03223
Org. Lett. XXXX, XXX, XXX−XXX