Hydride transfer initiated ring expansion of pyrrolidines toward highly functionalized tetrahydro-1-benzazepines

Article abstract of DOI:10.1039/c8cc08238c

A novel hydride transfer initiated ring expansion of 4-pyrrolidinyl isatins to synthesize tetrahydro-1-benzazepines has been developed. This methodology represents an atom- and step-economical protocol to assemble seven-membered polycyclic amines from pyr

Full text of DOI:10.1039/c8cc08238c

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Hydride transfer initiated ring expansion of
pyrrolidines toward highly functionalized
tetrahydro-1-benzazepines†
Cite this: Chem. Commun., 2018,
54, 13833
Received 15th October 2018,
Accepted 14th November 2018
a
Shuai Wang,‡a Xiao-De An,‡a Shuai-Shuai Li,
Xicheng Liu,c Qing Liud and
ab
Jian Xiao
*
DOI: 10.1039/c8cc08238c
rsc.li/chemcomm
A novel hydride transfer initiated ring expansion of 4-pyrrolidinyl
isatins to synthesize tetrahydro-1-benzazepines has been developed.
This methodology represents an atom- and step-economical protocol
to assemble seven-membered polycyclic amines from pyrrolidine
derivatives in one step.
Highly functionalized seven-membered nitrogen-containing hetero-
cycles are privileged motifs in a wide range of natural products1
and pharmaceutically important agents.2 Among these families,
1-benzazepine derivatives are conspicuous members due to
their extensive application in many medicinal molecules, such
as tolvaptan (vasopressin receptor antagonist),2e zilpaterol (beef
improvement agent),2f benazepril (angiotensin-converting-
enzyme inhibitor),2g fedovapagon (antidiuretic),2h and mianserin
and mirtazapine (antidepressants)2i (Fig. 1). Therefore, the
Fig. 1 Representative pharmaceuticals containing 1-benzazepine skeletons.
development of synthetic methodologies to access structurally engineered starting materials decrease the efficiency and practicality
diverse 1-benzazepine derivatives is of great significance. However, of these synthetic methods. As a consequence, the exploration of
this issue remains a daunting challenge in organic synthesis new efficient methodologies to construct 1-benzazepine derivatives
because of the unfavorable transannular interactions, entropic is still in great demand.
penalties and angle strains.3 Recently, a couple of protocols
The ring expansion of cyclic compounds provides one of the
have been reported to assemble 1-benzazepine analogues, such most powerful tools to construct seven-membered azacycles.
as Mannich-type reaction,4a,b Friedel–Crafts-type annulation,4c–e During the past few years, several ring expansion approaches
[1,5]-hydride shift/7-endo cyclization4f,g and oxidative cross- have been developed, with three-,6 four-7 and six-membered8
coupling reaction.4h Nevertheless, these direct annulation strategies heterocycles as starting materials (Scheme 1a). Meanwhile, so
commonly rely on linear synthetic precursors, suffering from far, ring expansion starting from five-membered pyrrolidines to
slow cyclization kinetics.5 Furthermore, the necessity of highly access tetrahydro-1-benzazepines has never been realized,
despite the fact that pyrrolidines are widely present in plenty
a Shandong Province Key Laboratory of Applied Mycology, College of Chemistry and
Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109,
China. E-mail: chemjianxiao@163.com
of natural alkaloids and drugs.9 To the best of our knowledge, the
ring expansion of pyrrolidines still poses formidable challenges
since these transformations are thermodynamically unfavourable
processes.10 Remarkably, although the ring expansion of five-
membered pyrrolidines has enabled the straightforward
construction of six-, eight- and nine-membered rings,11 there
is no report dealing with the synthesis of seven-membered
tetrahydro-1-benzazepines. To address these challenges and as
our continuing interest in establishing one-step assembly of
molecular complexity,12 herein, we report the first ring expansion
of a five-membered nitrogen-containing ring to a seven-membered
b College of Marine Science and Engineering, Qingdao Agricultural University,
Qingdao 266109, China
c College of Chemistry and Chemical Engineering, Qufu Normal University,
Qufu 273165, China
d College of Chemical and Environmental Engineering, Shandong
University of Science and Technology, Qingdao 266590, China
† Electronic supplementary information (ESI) available. CCDC 1829218. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8cc08238c
‡ These authors contributed equally.
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Fig. 2 The X-ray crystal structure of 3a.
and 100 1C were the optimal reaction conditions (Table 1, entries
10–17). Notably, the reaction under a N2 atmosphere only gave the
desired product in less than 8% yield (Table 1, entry 18), implying
the importance of molecular oxygen in this transformation.
However, the following experiment under an O2 atmosphere
provided 3a in 38% yield, which suggested that the avoidance
of the oxidation of phenols was vital for this reaction (Table 1,
entry 19). Consequently, the best reaction conditions were
selected as indicated in entry 10.
Scheme 1 Ring expansion strategies toward seven-membered azacycles.
heterocycles, providing an efficient synthesis of highly functio-
nalized tetrahydro-1-benzazepines from pyrrolidines (Scheme 1b).
The initial attempt began with the reaction between 1-benzyl-
4-pyrrolidinyl isatin 1a and p-cresol 2a in DCE at 120 1C with
methanesulfonic acid (MsOH) as a catalyst. Surprisingly, the
ring expansion product 3a was isolated in 13% yield (Table 1,
entry 1). The structure of 3a was unambiguously confirmed by
X-ray crystallographic analysis (Fig. 2). Other Brønsted acids such
as trifluoromethanesulfonic acid (TfOH), bis(trifluoromethane-
sulfonyl)amide (Tf2NH) and (À)-10-camphorsulfonic acid ((À)-CSA)
led to inferior results (Table 1, entries 2–4). Subsequently, various
Lewis acids were examined and it was found that Sc(OTf)3 showed
the best efficiency, delivering 3a in 40% yield (Table 1, entries 5–9).
Further screening the solvents and temperature indicated that DCE
With the optimized reaction conditions in hand, the scope
of this ring expansion methodology was evaluated over a wide
array of substrates (Scheme 2). At the outset, we sought to
investigate the substrate scope with respect to the isatins. As
shown in Scheme 2, a variety of alkyl and aryl substituents were
installed on the N-atoms of the isatins to evaluate the general
applicability of this transformation (3a–g). Remarkably, the
isatins bearing the benzyl (3a–b), phenyl (3c), cyclopropyl (3f)
and allyl (3g) groups were totally tolerable, delivering the
corresponding tetrahydro-1-benzazepines in decent yields. It
is worth mentioning that the strained cyclopropane and alkene
moieties were also compatible with this system. Notably,
N-methyl isatin exhibited the best efficiency and delivered the
desired ring expansion product 3d in 69% yield. More intriguingly,
the successful assembly of the cyclohexane-fused polycyclic amine
product 3h from octahydro-isoindole implied the potential
application of this approach in building complex polycyclic
compounds. Subsequently, the scope of the phenol derivatives
was examined (3i–q). As expected, the reactions of hydroqui-
none, 4-benzyloxyphenol and 4-isopropylphenol with 1-benzyl-4-
pyrrolidinyl isatin 1a proceeded well, giving rise to the corres-
ponding products 3i–k in acceptable yields. Notably, when
2,6-diisopropylphenol was used as a reaction candidate, the
reaction occurred at the para-position of the hydroxyl group,
yielding different products 3l–p in 43–74% yields. Finally, it was
found that o-cresol could also engage in this transformation,
affording 3q in acceptable yield. However, for phenol and other
substituted phenols, the yields were low. Further examination of
other nucleophiles such as p-xylene, aniline and indole met with
failure (see the ESI†).
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Solvent
T (1C)
Yieldb (%)
1
2
3
4
5
6
7
8
MsOH
TfOH
Tf2NH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
DCM
CHCl3
MeCN
THF
120
120
120
120
120
120
120
120
120
100
80
100
100
100
100
100
100
100
100
13
10
n.r
n.r.
Trace
40
25
30
38
59
50
30
26
18
n.r.
n.r.
n.r.
o8
38
(À)-CSA
ZnCl2
Sc(OTf)3
Sm(OTf)3
Y(OTf)3
Gd(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
9
10
11
12
13
14
15
16
17
18c
19d
HFIP
DCE
DCE
In order to shed light on the mechanism of the transformation,
some control experiments were performed (Scheme 3). Protection
a
Reaction conditions: a solution of 1a (0.1 mmol), catalyst (0.02 mmol), of p-cresol 2a with a methyl group totally suppressed this reaction
and phenol 2a (0.3 mmol) in the indicated solvent (2.0 mL) was stirred
(Scheme 3, I), indicating the importance of the free OH group.
b
When the 5-position was occupied by a methyl group in
The reaction was performed under an O2 atmosphere. n.r. = no reaction. substrate 1a, no desired product was observed (Scheme 3, II).
under an air atmosphere for 4 days. Isolated yield after column
c
chromatography. The reaction was performed under a N2 atmosphere.
d
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Scheme 4 Proposed reaction mechanism.
(Scheme 3, IV).13 Reduction of 1a afforded the alcohol inter-
mediate, which could be fully oxidized to 1a under the standard
conditions in 10 minutes (Scheme 3, V).
On the basis of the above experiments and literature pre-
cedents, a plausible reaction mechanism of this transformation
is proposed as shown in Scheme 4. Activated by Sc(OTf)3,
1-benzyl-4-pyrrolidinyl isatin 1a undergoes [1,5]-hydride transfer
to furnish intermediate B.13,14 The subsequent intermolecular
Mannich-type reaction delivers intermediate C, which is easily
oxidized to isatin derivative D by air. Then intermediate D
engages in the key ring-opening step via transition state E
catalyzed by Sc(OTf)3 to give ortho-quinone methide (o-QM)
intermediate F.15 The following intramolecular nucleophilic
addition toward o-QM generates the desired product 3a as the
final ring expansion product. In the whole process, the Sc(OTf)3
catalyst plays the key role in initiating the [1,5]-hydride transfer
as well as the ring-opening processes.
In summary, a novel hydride transfer induced ring expansion of
4-pyrrolidinyl isatins has been developed to synthesize tetrahydro-1-
benzazepines in one step, which represents the first example of ring
expansion from a pyrrolidine ring to a seven-membered azacycles.
A range of substituted phenols and 4-pyrrolidinyl isatins were
tolerated to afford the highly functionalized tetrahydro-1-
benzazepine derivatives in decent yields. This methodology
provides an efficient protocol to one-step assembly of seven-
membered polycyclic amines via ring expansion of readily
available pyrrolidine derivatives. We believe that this report
will not only offer a distinctive protocol for ring-expansion of
five-membered azacycles, but also find wide application in the
construction of biologically significant tetrahydro-1-benzazepine
derivatives.
Scheme 2 The scope of tetrahydro-1-benzazepines. Reaction conditions:
a solution of 1 (0.1 mmol), Sc(OTf)3 (0.02 mmol), and phenol 2 (0.3 mmol) in
DCE (2.0 mL) was stirred at 100 1C under an air atmosphere for 4 days. The
yields are for the isolated products.
Intriguingly, the replacement of 1a with 1-phenylpyrrolidine
also impeded this reaction (Scheme 3, III), implying that the
1, 2-dicarbonyl moiety of the isatin was indispensable. For
the 1-phenylpyrrolidine substrate with an acetyl group on the
2-position of the phenyl ring, the cascade [1,5]-hydride transfer/
cyclization occurred with the oxygen anion as a nucleophile
We are grateful for financial support from the NSFC
(21702117, 21878167) and the Natural Science Foundation of
Shandong Province (JQ201604, ZR2017BB005) as well as the Key
Research and Development Program of Shandong Province
(2017GSF218073). We thank Prof Liu-Zhu Gong (University of
Science and Technology of China) for valuable suggestions. We
also thank Prof Da-Wen Niu (Sichuan University) for HRMS
analysis.
Conflicts of interest
Scheme 3 Control experiments.
There are no conflicts to declare.
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13836 | Chem. Commun., 2018, 54, 13833--13836
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