Mild, Metal-Free Oxidative Ring-Expansion Approach for the Synthesis of Benzo[ b]azepines

Article abstract of DOI:10.1021/acs.orglett.9b01433

Benzo[b]azepines are important structural motifs for the pharmaceutical industry. However, their syntheses are usually lengthy, involving several steps, transition-metal catalysts, and/or harsh conditions. A novel, general, mild, and metal-free oxidative ring expansion tandem reaction of hydroquinolines with TMSCHN₂ as a versatile soft nucleophile to gain access to these valuable compounds in a simple and straightforward manner is presented.

Full text of DOI:10.1021/acs.orglett.9b01433

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Mild, Metal-Free Oxidative Ring-Expansion Approach for the
Synthesis of Benzo[b]azepines
̃
Sebastian Stockerl, Tobias Danelzik, Dariusz G. Piekarski, and Olga García Mancheno*
Organic Chemistry Institute, University of Mu
̈
nster, D-48149 Mu
̈
nster, Germany
S
* Supporting Information
ABSTRACT: Benzo[b]azepines are important structural motifs
for the pharmaceutical industry. However, their syntheses are
usually lengthy, involving several steps, transition-metal
catalysts, and/or harsh conditions. A novel, general, mild, and
metal-free oxidative ring expansion tandem reaction of hydro-
quinolines with TMSCHN2 as a versatile soft nucleophile to
gain access to these valuable compounds in a simple and
straightforward manner is presented.
enzannulated medium-size N-heterocycles are key struc-
Scheme 1. Synthetic Approaches to Benzo[b]azepines
B
tural motifs in numerous natural products, pharmaceut-
icals, and agrochemicals.1 In particular, 7-membered hetero-
cycles such as benzo[b]azepines represent an important class
of compounds, because of their broad bioactivity (Figure 1).
Figure 1. Selected examples of bioactive derivatives.
For example, the benzo[b]azepines mianserin2 and tolvaptan3
are used as an antidepressant and a diuretic drug, respectively.
In addition, epinastine2 and benzazepinediones4 are employed
as antiallergic and anticancer agents, whereas tetrahydronaph-
thoazepines show antiparasitic activity.5
mention that the reported to date ring expansion reactions to
give rise to benzo[b]azepines that rely on the use of hazardous
diazomethane (or its Li/Mg salts) and preisolated quinolinium
ions, which dramatically limit their synthetic application.8
Alternatively, more convenient diazoacetates have been
employed in an oxidative, two-step approach with tetrahy-
droiso-quinolines toward benzo[d]azepines. However, this
method requires transition metals to induce the last ring-
expansion step.9
Because of these limitations, our group lately focused on the
development of more-convenient methods for the ring
expansion of benzo-fused heterocycles. Subsequently, oxidative
C−H functionalization10 of xanthenes, acridanes, and tetrahy-
To gain access to this class of 7-membered heterocyclic
compounds, several synthetic strategies have been developed.
However, their classical synthesis often requires a multistep
ring-closing reaction,6 including intramolecular aminations,6a
rearrangements,6b,c transition-metal-based catalysts, and harsh
conditions (Scheme 1A).6d−g Besides these methods, the ring
expansion reaction represents a different appealing approach.7
Consequently, although they are reliant on elaborated
precursors, various methods have been reported to gain
benzo[b]azepines (Scheme 1B), including the thermal ring
expansion of dihydroquinolines with azides7a,b or indoles with
activated acetylenes,7d as well as gold-catalyzed7c and hydride-
transfer7e-initiated reactions. In this context, although diazo-
methane derivatives arose as ideal reagents, it is noteworthy to
Received: April 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01433
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Organic Letters
Letter
droisoquinolines with TMSCHN2, followed by rearrangement,
successfully gave access to the corresponding 7-membered
heterocycles.11 Even though these approaches overcame some
of the previously mentioned limitations, they still require either
a transition-metal catalyst or high temperatures. Therefore, a
simple, mild, and efficient metal-free synthetic approach for the
construction of 7-membered heterocycles is still in high
demand. Based on this criterion, we herein describe a general
methodology for the straightforward synthesis of benzo[b]-
azepines by a novel, mild and metal-free oxidative C−H bond
functionalization/ring expansion tandem reaction from readily
available dihydroquinolines (see Scheme 1C).
equivalents of the oxidant showed great influence on the
reaction outcome (Table 1, entries 8 and 9). Thus, 2a was
delightfully obtained in a high yield of 73% by employing just
1.0 equiv of Ph3C+ClO4− (Table 1, entry 8), while the use of a
1.5 equiv of oxidant led to a notable decrease in yield (43%;
see Table 1, entry 9). Also, an excess of the TMSCHN2
reagent was crucial, since the use of 1.2 equiv instead of 2.4
equiv led to a low product yield (28%; see Table 1, entry 10).14
Under the optimized conditions (Table 1, entry 8), the
scope of the reaction was investigated (see Table 2). A variety
a b
,
Table 2. Substrate Scope with Dihydroquinolines 1
We started our screening with N-methylcarboxylate
dihydroquinoline (1a)12,13 as a model substrate for the
optimization of the reaction conditions of the metal-free ring
expansion with TMSCHN2 (Table 1; see the Supporting
Information (SI) for a complete screening).
a
Table 1. Optimization of the Reaction Conditions with 1a
b
c
entry
oxidant (equiv)
solvent
temperature (°C) yield (%)
d
Ph3C+ClO4 (1.1)
DCM
DCM
DCM
DCM
DCM
MeCN
MeCN
MeCN
MeCN
MeCN
rt
0
42 (45)
41
33
22
45
51
48
73
−
1
2
3
4
5
6
7
8
9
Ph3C+ClO4 (1.1)
−
Ph3C+ClO4 (1.1)
50
rt
rt
rt
rt
rt
rt
rt
−
Ph3C+BF4 (1.1)
−
T+ClO4 (1.1)
−
Ph3C+ClO4 (1.1)
−
T+ClO4 (1.1)
−
Ph3C+ClO4 (1.0)
−
Ph3C+ClO4 (1.5)
43
28
−
e
Ph3C+ClO4 (1.1)
−
10
a
1a (0.1 mmol, 1.0 equiv) and oxidant were stirred in appropriate
solvent (0.1 M) for 30 min at room temperature (rt); TMSCHN2
(2.0 M in Et2O, 2.4 equiv) was added dropwise and the reaction
b
mixture was stirred for 1 h at the appropriate temperature. T+
=
c
d
2,2,6,6-tetramethyl-1-oxopiperidinium. Isolated yield. The yield of
the 16-h reaction is shown in brackets. 1.2 equiv of TMSCHN2.
e
a
1 (0.1 mmol, 1.0 equiv) and Ph3C+ClO4− (1.0 equiv) were stirred in
MeCN (0.1 M) for 30 min at rt; TMSCHN2 (2.0 M in Et2O, 2.4
equiv) was added dropwise and the reaction mixture was stirred for 1
Initially, triphenylmethyl (trityl) perchlorate (Ph3C+ClO4 )
−
b
h at rt. Isolated yield. cInseparable 3:1 mixture of 8-/6-Me
was used as a mild, hydride abstractor-type oxidant, providing
the desired benzazepine 2a in a promising 42% yield in the
reaction with an excess of TMSCHN2 (2.4 equiv) at room
temperature (rt) in dichloromethane (DCM) for 1 h (Table 1,
entry 1). A prolonged reaction time of 16 h was tested, giving
2a in a similar moderate yield of 45% (Table 1, entry 1).
Therefore, a reaction time of 1 h was chosen for the following
studies. Increasing or decreasing the temperature to 50 °C or 0
°C lead to a decrease of the yield (Table 1, entries 2 and 3).
Various mild trityl and 2,2,6,6-tetramethylpiperidinyloxyl
(TEMPO) oxoammonium salt-based oxidants were next
screened (Table 1, entries 4 and 5), showing the superiority
of the perchlorate versus the trifluoroborate salts, as well as a
benzo[b]azepines, from the reaction with commercially available 1e
as a 3:1 7-/5-Me isomeric mixture.
of carbamoyl N-protecting groups on the dihydroquinoline
were first tested. While the ethylcarbamate provided 2b in an
inferior yield of 32%, Cbz- and Troc-protected dihydroquino-
lines 1c and 1d could be efficiently employed in the reaction,
leading to the products in a synthetically acceptable yield of
50%−60%.
Next, different substituted N-methoxycarbamoyl dihydro-
quinoline derivatives 1 were explored. Substitution in almost
all positions of the dihydroquinoline core were well-tolerated,
except for the C2-position, which hampered both the oxidation
and the nucleophilic attack of the TMSCHN2 reagent.15 Thus,
the 3- to 7-methyl-substituted benzazepines 2e and 2f/2h and
2i were obtained in excellent yields (92%−97%), whereas the
reaction of 2-substituted methyl dihydroquinoline 1g only led
to recovery of the starting material, along with decomposition
slightly enhanced yield when using T+ClO4 , with respect to
−
Ph3C+ClO4− in DCM (45% vs 42%). To our delight, a solvent
screening showed a significant increase of the yield of the ring-
expansion reaction with both perchlorate salts when using
acetonitrile (MeCN) as the solvent (Table 1, entries 6 and 7),
in which Ph3C+ClO4− provided the best results. Moreover, the
B
DOI: 10.1021/acs.orglett.9b01433
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Letter
products. Further derivatives carrying other electron-donating
groups, such as the methoxy group (1l, 1n, and 1v; 52%, 86%,
and 83%), electron-rich arene substituents (1k and 1o; 83%
and 86%), alkynylic (1u; 84%), and alkylic (1t; 75%) provided
the corresponding benzo[b]azepines 2 in good yields. When
bromo- and chloro-containing derivatives were employed, the
benzazepines 2j, 2m, 2q, and 2r were formed in excellent
yields of 81%−95%. Deactivating electron-withdrawing groups
such as a carboxylic ester, nitro or trifluoromethyl groups were
also tolerated in the ring-expansion reaction, providing 2p, 2s,
and 2x in moderate to good yields (54%, 66% and 72% yield,
respectively). In addition, the benzo-fused phenantridine
derivative 1w was converted almost completely, giving 2w in
an excellent 97% yield.
Scheme 3. Scale-Up Reaction and Derivatization of 2
The extension of this ring-expansion method to other N-
and O-heterocycles was performed next (see Scheme 2). The
Scheme 2. Ring Expansion of Further N- and O-
Heterocycles
Similarly, the reaction of methyl-substituted benzazepines 2h
and 2i led to the corresponding endoperoxides 11h and 11i in
moderate yields (52% and 60%, respectively). A further
synthetic application of the developed methodology was
demonstrated by the synthesis of the tolvaptan-like arginine
vasopressin (AVP) receptor agonist 12 (see Scheme 3,
bottom).18 The hydrogenation of 2a using Pd/C and
deprotection with trimethylsilyl iodide (TMSI) provided the
intermediate 14. The final condensation of 14 and the acyl
chloride, derived from the appropriate benzoic acid 15,
afforded the desired AVP receptor agonist 12 in 47%.
Considering the mechanism of the one-pot C−H function-
alization/ring expansion reaction, two possible pathways for
the ring expansion step could be envisioned (see Scheme 4,
top). Thus, after hydride abstraction and nucleophilic attack of
the diazomethane on the iminium ion intermediate I, the
formed diazo compound II undergoes nitrogen release upon
nucleophilic attack of the olefinic carbon in 3-position or the N
atom, leading to the cyclopropane cationic intermediate III or
the aziridinium IV, respectively. Subsequent rearrangement
and ring expansion results in the formation of the 7-membered
cationic intermediate V or VI, respectively. Finally, release of
TMS+ as the leaving group leads to the formation of
benzazepine 2a. In order to gain some insight into the
mechanism of the ring-expansion reaction, both experimental
and computational studies were performed. In order to rule
out one of the possible pathways for the ring expansion step,
the reaction of 1a with TMSCDN2 (∼50% D; see the SI) was
performed (Scheme 4, middle). In the case of a high selective
reaction, either the 2- or 3-substituted benzazepine should be
formed. The ring expansion resulted in the sole formation of
the 3-deuterated product 2a-3D in 32% yield, which is
produced from the C-pathway. Moreover, the quantum
chemistry calculations19 at the density functional theory
(DFT) level of theory20 with TMSCHN2 as model nucleophile
revealed that both pathways might be possible (Scheme 4,
bottom), although it shows that the C-pathway is thermody-
namically and kinetically more favored (lower barrier (TS2)
and more stable than the key intermediate (III)) (see the SI
for details). Nonetheless, the product obtained via the N-
pathway may be also potentially formed because (i) the
expansion of dihydroisoquinoline 3 and the more challenging
expansion of dihydropyridines such as 4-phenyl dihydropyr-
idine 5 was also possible under our standard conditions,
leading to the corresponding azepines 4 and 6 in yields of 40%
and 58%, respectively. To our delight, we were also able to
apply the optimized conditions in the ring-expansion reaction
of 5- to 6-membered heterocycles. Accordingly, the double N-
protected benzimidazole 7 reacted smoothly, giving quinoxa-
line 8 in 84% yield. Finally, the analogous oxygen-containing
heterocycle 2H-chromene (9) was able to ring-expand to the
corresponding benzoxepine 10;16 however, a stronger oxidant
such as a TEMPO oxoammonium salt was required. In this
case, the use of LiClO4 as an additive provided the best results,
leading to the product in a good yield of 65% (see the SI for
the reoptimization study).
In addition, the derivatization of the obtained benzo[b]-
azepines was explored (see Scheme 3). To our delight, the
ring-expansion reaction could be easily scaled up from 0.1 to
1.0 and 6.0 mmol with only slight detriment of the yield (2a,
58 and 57% vs 73%; see Scheme 3). Several endoperoxides 11,
which are valuable precursors for the synthesis of d-fused
benzo[b]azepines with antitumor activity,17 were then
prepared (Scheme 3, top). The Schenck-ene reaction of 2a
using rose bengal as a photosensitizer in order to generate
singlet oxygen provided 11a in an excellent yield of 91%.
C
DOI: 10.1021/acs.orglett.9b01433
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Letter
Scheme 4. Mechanistic Considerations
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: olga.garcia@uni-muenster.de.
ORCID
Olga García Mancheno: 0000-0002-7578-5418
̃
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The Deutsche Forschungsgemeinschaft (DFG) is gratefully
acknowledged for generous support.
■
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i.e., the migration of TMS (TS5) leading to the intermediate
VI.21
In conclusion, we have developed a mild, metal-free method
for the synthesis of benzo[b]azepines via a simple and practical
one-pot oxidative C−H functionalization/ring expansion
approach using TMSCHN2 as versatile nucleophile bearing
two potential leaving groups (N2 and TMS+). This method
could also be extended to other type of N- and O-heterocycles,
as well as applied for the synthesis of interesting synthetic
intermediates and bioactive molecules, such as a tolvaptan-like
AVP receptor agonist. Moreover, quantum chemistry calcu-
lations revealed that two competitive mechanisms for the ring-
expansion step are possible, which access energetically similar
intermediates (V and VI) from which the same main product
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ASSOCIATED CONTENT
* Supporting Information
■
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glett.9b01433.
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Experimental procedures, characterization data, and
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(13) The reaction of the preformed N-Troc, N-Boc, or N-CO2Me
salts with TMSCHN2 did not lead to the desired benzazepine
products.
(14) An excess of TMSCHN2 only provided a small amount of
secondary cyclopropanation byproducts that could only be detected
via MS (<5%; see the SI).
(15) No example of 8-substituted substrates 1 is presented since
they could not be obtained using the standard method (see the SI).
(16) For an alternative method, see: Courant, T.; Pasco, M.;
Lecourt, T. Org. Lett. 2018, 20, 2757−2761.
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(21) The electronically dissimilar tert-butyl diazoacetate seems to
favor the N-pathway (see the SI), but it might imply a divergent
mechanism.
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