Unified Synthesis of Azepines by Visible-Light-Mediated Dearomative Ring Expansion of Aromatic N-Ylides

Article abstract of DOI:10.1021/acs.orglett.0c04050

Herein, we report a unified approach to azepines by dearomative photochemical rearrangement of aromatic N-ylides. Deprotonation of quaternary aromatic salts with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or N,N,N′,N'-tetramethylquanidine (TMG) under visible light irradiation provides mono- and polycyclic azepines in yields up to 98%. This ring-expansion presents a new mode of access to functionalized azepines from N-heteroarenes using two straightforward steps and simple starting materials.

Full text of DOI:10.1021/acs.orglett.0c04050

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Letter
Unified Synthesis of Azepines by Visible-Light-Mediated
Dearomative Ring Expansion of Aromatic N‑Ylides
Matthew J. Mailloux, Gabrielle S. Fleming,‡ Shruti S. Kumta,‡ and Aaron B. Beeler*
Cite This: Org. Lett. 2021, 23, 525−529
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ABSTRACT: Herein, we report a unified approach to azepines by
dearomative photochemical rearrangement of aromatic N-ylides. De-
protonation of quaternary aromatic salts with 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) or N,N,N′,N’-tetramethylquanidine (TMG) under
visible light irradiation provides mono- and polycyclic azepines in yields
up to 98%. This ring-expansion presents a new mode of access to
functionalized azepines from N-heteroarenes using two straightforward
steps and simple starting materials.
Scheme 1. Previous Applications of α-Diazoacetate
Decomposition, and Our Approaches to an aza-Buchner
Ring Expansion
zepines are seven-membered nitrogen heterocycles found
broadly in both pharmaceuticals1 and natural products2 as
A
core skeletal components and as functional appendages. They
are among the top 100 most common heterocycles employed
in drug discovery.1 Current methods of synthesizing
monocyclic azepines include aza-Prins cyclizations,3 ring
closing metathesis,4 [4 + 3]5 and [5 + 2]6 cycloadditions,
and condensation/reduction sequences.7 These methods can
have limitations in scope and utility, require multistep
syntheses of precursors, or use expensive transition metal
catalysts. Our interest in the synthesis of cycloheptatrienes8 via
the Buchner ring expansion led to the pursuit of an aza variant
to access azepines directly from pyridines, which we believed
would be a valued addition to the field of dearomatization.9−11
We identified a report in which N-acylated isoquinolines and
quinolines were ring expanded to benzazepines using copper-
(II) triflate and ethyl diazoacetate;12 in another example,
dihydroquinoline N-methylcarboxylates were ring expanded to
benzazepines using TMS-diazomethane and an oxidant.13
However, to the best of our knowledge, there is no reported
method for the general dearomative ring expansion of pyridine
derivatives. There are many methods to synthesize densely
functionalized pyridine derivatives by both traditional ring-
forming methods14 and emergent C−H functionalization
strategies;15 a general method of pyridine ring expansion
would enable modification of pre-existing libraries and
facilitate modular de novo synthesis of azepines. Furthermore,
access to the fully unsaturated azepine ring would also permit
downstream manipulation of the imine and olefins.
Previously, we used flow chemistry to develop an improved
protocol for the rhodium(II)-mediated intermolecular Buchner
ring expansion (Scheme 1).8 At the outset of this investigation,
we were aware that dimeric rhodium(II) tetracarboxylate
catalysts form stable complexes with pyridine,16 so a different
reaction paradigm was necessary. Thus, our initial approach to
Received: December 7, 2020
Published: January 4, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04050
© 2021 American Chemical Society
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an aza-Buchner ring expansion focused on the photolysis of
aryl diazoacetates (Scheme 1). In recent work, the Davies lab
described the blue light photolysis of aryl diazoacetates in O−
H, N−H, and C−H insertions and cyclopropanations, all of
which proceed through a donor−acceptor carbene intermedi-
ate.17 The Koenigs lab followed with cyclopropanation of alkyl-
substituted arenes18a and cyclooctatetraenes18b by a similar
method. Aryl diazoacetate photolysis offered access to carbenes
without the use of transition metal catalysts. Trapping carbenes
with pyridine would produce pyridinium ylides,19 which have
seen significant use in [3 + 2] cycloadditions along with
isoquinolinium and quinolinium ylides.20 Inspired by work
from Streith et al. involving N-iminopyridinium ylides,21 we
reasoned that pyridinium methylides could rearrange to
provide azepines via a bicyclic aza-norcaradiene (aza-NCD).
Streith et al. postulated that N-iminopyridinium ylides are
photochemically excited by UV light to give singlet diradicals
by an n to π* transition.22 The excited species then undergoes
α-recombination to form a bicyclic intermediate, and 6π
electrocyclic ring opening to give the 1,2-diazepine product.
Following this principle, we set out to generate pyridinium
methylides via photolysis of aryl diazoacetates and identify
conditions for their ring expansion to give azepines.
carbene byproducts. However, we did observe ethyl phenyl-
glyoxylate 6 which we presume could arise from benzylic
aerobic oxidation of 5. We reasoned that conducting the
reaction in a flow photoreactor would improve photon flux and
minimize aerobic oxidation,25 so we investigated the ring
expansion of pyridinium salt 5 using a flow photoreactor
constructed in-house. Conducting the reaction in flow
increased the yield of 2 to 91%.
With promising results from our initial experiments, we
optimized the reaction conditions in flow (Table 1). The ring
Table 1. Optimization of Reaction Conditions for Ring
a
Expansion of 5
variable
solvent
entry
solvent
base (equiv)
yield (2)
1
2
3
4
5
6
7
8
MeOH
CHCl3
MeCN
1,2-DCE
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
1,2-DCE
DCM
DCM
DCM
DCM
DBU (5)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
2,6-lutidine (5)
TEA (5)
DIPEA (5)
TMP (5)
TMG (5)
TBD (2.5)
DBU (1)
0
81
81, 79
b
87
91
n.r.
0
In our initial experiments we were pleased to find that blue-
light photolysis of ethyl phenyldiazoacetate 1 in the presence
of excess pyridine afforded the desired product 2 in low yields
as a single regioisomer (Scheme 2a).
base
0
9
<5
56
93
43
Scheme 2. Generation of Azepine (2) by Diazo Photolysis
(a) and Pyridinium Salt Deprotonation (b)
10
11
12
c
concentration
temperature
13
14
15
16
17
18
19
DBU (5)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
28
d
89
e
11
f
no light
no base
residence time
O2
0
n.r.
g
80
h
19
a
Experiments carried out on 35−50 μmol scale. Yields were
determined by quantitative NMR using an internal standard.
Abbreviations: TMP = 2,2,6,6-tetramethylpiperidine, n.r. = no
b
c
d
reaction. MeCN (0.5% water). 0.10 M with respect to 5. 0 °C.
e
f
g
h
50 °C. 24 h in the dark. 4 h residence time. Batch trial under O2
(1 atm).
expansion proceeded smoothly in polar aprotic solvents
including dichloromethane, 1,2-dichloroethane (1,2-DCE),
chloroform, and acetonitrile. We observed the best results
with 5 equiv of strong, non-nucleophilic guanidine and
amidine bases including N,N,N′,N′-tetramethylguanidine
(TMG), DBU, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD). Weaker bases provided either little or no conversion
to the desired product. A trial at 0.1 M pyridinium bromide 5
decreased the yield, presumably by accelerating intermolecular
interactions leading to polymerization. The reaction yield was
unchanged when cooled to 0 °C, but decreased significantly at
50 °C. When 5 was treated with excess DBU for 24 h in the
dark, we observed no formation of azepine 2. With blue light
irradiation in the absence of base for 24 h, the starting material
was recovered quantitatively. Lastly, under an oxygen
atmosphere in batch, 6 and 2 were obtained in yields of 57%
and 19%, respectively. We arrived at optimized reaction
However, this method required a large (10 equiv) excess of
pyridine and was burdened by known carbene byproducts
diazine23 3 and 2,3-diphenylmaleate24 4. To avoid competitive
side reactions and determine the photochemical dependency of
the ylide rearrangement, we synthesized pyridinium bromide
salt 5 (Scheme 2b) and irradiated it with blue light in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Grat-
ifyingly, we observed improved yields of 2 compared to the
diazo photolysis method; furthermore, we did not observe the
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conditions which utilize 5.0 equiv of DBU in DCM, 1,2-DCE,
or MeCN with a residence time of 2 h in a 440 nm flow
photoreactor.
With optimized conditions for 5, we investigated the scope
of the reaction with a variety of pyridinium salts (Scheme 3a),
which we synthesized by SN2 displacement. In substrates 7, 2,
8, and 9, ester/nitrile substitution had little impact on the yield
of the azepine. The addition of halogens on the phenyl ring
also had no significant effect (10, 11). Monosubstituted
azepine 12a was synthesized using 1.05 equiv of TMG at −20
°C. With careful workup, we were able to characterize 12a by
1H NMR. However, the product was not stable to silica gel
chromatography and quickly decomposed. The instability and
1H NMR spectrum of 12a paralleled observations from
Steglich’s synthesis of unsubstituted 2H-azepine.26 Under
modified conditions, we submitted 12a directly to NaBH4
reduction in methanol giving 12b quantitatively, which was
stable in solution. Curiously, the addition of electron-donating
groups at the 4-position (13, 14) provided no observable
azepine product; in both cases, the pyridine fragment was
obtained with high recovery (>85%). We hypothesize that the
4-amino groups significantly destabilize the ylide intermediate
by electron donation, promoting its decomposition. Lastly, a
substrate with a phenyl ketone (15) gave no observable
azepine. Next, we investigated the regioselectivity of the ring
expansion using 3-substituted pyridinium salts (Scheme 3b).
With 3-chloro and 3-methoxy derivatives (16, 17), we
observed poor regioselectivity (2:1 r.r.) at 20 °C; the
regioselectivity was improved to 5:1 by cooling the reaction
to −20 °C. With 3-methyl and 3-N-Boc amino substrates (18,
19) we saw improved regioselectivity (10:1, 15:1, respec-
tively). Similarly, a salt bearing an acetal (20) provided the
highest regioselectivity, with no minor regioisomer detectable
Scheme 3. Scope and Regioselectivity of Pyridinium Salts
Yielding Monocyclic Azepines (Reported Yields Are after
Isolation)
1
by H NMR (>19:1 r.r.). Based on these observations, we
hypothesize that the regioselectivity is guided mostly by steric
constraint imparted by the R group, since groups with varied
electronic contributions provided the same major regioisomer.
With good substrate tolerance for monocyclic azepines, we
sought to ring expand isoquinolines, quinolines, and
phenanthridines to provide polycyclic azepines (Scheme 4a).
Using an isoquinolinium salt (21), we optimized the reaction
conditions for the formation of 31. By adding 21 dropwise to 5
equiv of DBU, we isolated α-imino ester 31 as the sole azepine
product in moderate yields (34%). We hypothesize 41 is the
initial product, which isomerizes to 31 via proton transfer or
1,5-hydride shift (Scheme 4b). Other isoquinolinium salts
(22−25) gave analogous 1H-benzo[c]azepines (32−35) in
good yields, and the reaction operated smoothly despite
modification at each major region of the molecule. Similarly,
quinolinium salts 26 and 27 gave 3H-benzo[c]azepines 36 and
37. Lastly, phenanthridinium salts 28−30 gave 5H-dibenzo-
[c,e]azepines 38−40 in improved yields compared to the
isoquinolines and quinolines. We found that employing a tert-
butyl ester (32, 37, 39) as the electron-withdrawing group
provided slightly improved yields in all three substrate types.
We suspect that the added steric constraint of the large ester
slows intermolecular interactions leading to decomposition.
After establishing generality of our ring expansion method,
we carried out experiments to inform a plausible mechanism
(Scheme 5). To determine whether an electron-withdrawing
group was necessary, we synthesized 1,1-diphenylpyridinium
salt 42 and subjected it to the previously optimized conditions
and observed pyridine and benzophenone (44) as the sole
products. After failing to observe 43, we conducted a batch
experiment with thoroughly degassed solvent, a range of LED
wavelengths, and with gradual increase of temperature from
−40 to 20 °C. Despite our efforts to achieve an oxygen-free
environment, we obtained only pyridine and 44.
a
b
c
We reasoned that reaction intermediates leading to azepine
43 could decompose by extrusion of pyridine affording a triplet
diphenylcarbene,27 or by oxidation of the ylide intermediate.
Oxygen quenching experiments in batch showed diminished
100 μmol scale. 1 mmol scale. 1.05 equiv of TMG was used at −20
d
°C. 1.05 equiv of TMG at −20 °C, then NaBH4 in MeOH.
Regioselectivity was determined by analysis of the crude H NMR
spectrum. For clarity, the major regioisomer is shown.
1
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Scheme 4. Scope of Polycyclic Salts Yielding
Benzo[c]azepines and Dibenzo[c,e]azepines (Reported
Yields Are after Isolation)
Scheme 5. Mechanistic Experiments and Plausible
Mechanism of the Ring Expansion of Pyridinium Ylides
a
1H NMR spectra were recorded at 1, 6, 12, and 24 h.
singlet excited state giving aza-NCD intermediates that rapidly
undergo 6π-electrocyclic ring opening, affording azepine
products (Scheme 5). Further rearrangement of polycyclic
products 31−40 gives α-imino ester/nitrile isomers, which are
useful functional groups themselves.31 In contrast to the
regioisomers seen in 16−20, the single regioisomers obtained
in substrates 31−40 suggest that polycyclic N-ylides undergo
regiospecific aziridine formation which is likely due to radical
stabilization from the fused benzene ring.
a
b
5 equiv of DBU. 1.05 equiv of TMG.
In summary, we have developed a simple method for the
dearomative ring expansion of aromatic N-heterocycles to
azepines. So far, we have demonstrated generality for pyridines,
isoquinolines, quinoline, and phenanthridine and have
provided preliminary mechanistic studies that strongly suggest
photochemical excitation of the ylide followed by diradical
recombination 6π-electrocyclic ring opening. This mild
demaromative ring expansion will enable the synthesis of
diverse azepines from readily available starting materials.
yields of azepine 2 and increased yields of glyoxylate 6,
suggesting the presence of a radical intermediate. Similarly, two
trials run with radical scavengers28 (2,2,6,6-tetramethylpiperin-
1-yl)oxyl (TEMPO) and 9-azabicyclo[3.3.1]nonane N-oxyl
(ABNO) gave greatly diminished yields of the azepine, with
ABNO nearly stopping product formation altogether. To
determine reversibility, we irradiated azepines 2 and 31 with
blue LEDs and monitored them by 1H NMR and observed no
decomposition within 24 h. Based on these observations, the
electrocyclic opening of the postulated aza-NCD is irreversible
under the reaction conditions. We propose that analogously to
pyridine N-oxides29 and N-iminopyridinium ylides,30 pyridi-
nium methylides undergo radical recombination from the
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AUTHOR INFORMATION
Corresponding Author
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(13) Stockerl, S.; Danelzik, T.; Piekarski, D. G.; Mancheno, O. G.
̃
Org. Lett. 2019, 21, 4535−4539.
Aaron B. Beeler − Department of Chemistry, Boston
University, Boston, Massachusetts 02215, United States;
orcid.org/0000-0002-2447-0651; Email: beelera@
bu.edu
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Matthew J. Mailloux − Department of Chemistry, Boston
University, Boston, Massachusetts 02215, United States
Gabrielle S. Fleming − Department of Chemistry, Boston
University, Boston, Massachusetts 02215, United States
Shruti S. Kumta − Department of Chemistry, Boston
University, Boston, Massachusetts 02215, United States
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Author Contributions
‡G.S.F. and S.S.K. contributed equally.
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Notes
The authors declare no competing financial interest.
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The authors gratefully acknowledge Dr. Norman Lee (Boston
University) for high-resoluation mass spectrometry data and
colleagues of the Beeler Research Group (Boston University)
for insightful discussion. NMR (CHE-0619339) and MS
(CHE-0443618) facilities at Boston University are supported
by the NSF.
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