A Photochemical Two-Step Formal [5+2] Cycloaddition: A Condensation-Ring-Expansion Approach to Substituted Azepanes

Article abstract of DOI:10.1055/s-0036-1589049

Seven-membered nitrogen-containing heterocycles are considerably underrepresented in the literature compared to their five- and six-membered analogues. Herein, we report a relatively understudied photochemical rearrangement of N -vinylpyrrolidinones to azepin-4-ones in good yields. This transformation allows for the conversion of readily available pyrrolidinones and aldehydes to densely functionalized azepane derivatives in a facile two-step procedure.

Full text of DOI:10.1055/s-0036-1589049

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
S. M. Thullen et al.
Letter
Synlett
A Photochemical Two-Step Formal [5+2] Cycloaddition: A Conden-
sation–Ring-Expansion Approach to Substituted Azepanes
Scott M. Thullena,b
David M. Rubushb,c
Tomislav Rovis*a,b
O
R2
O
O
1. – H2O
R2
+
NH
0
0
0
0
0-
0
0
1
6-
2
8
7
8-
6
6
9
R1
H
R1
2. hν
O
NH
a Department of Chemistry, Columbia University, New York,
NY 10027, USA
via:
24 Examples
40–92% Yield
tr2504@columbia.edu
R2
N
b Department of Chemistry, Colorado State University, Fort
Collins, CO 80523, USA
R1
c Current Address: Department of Chemistry, Benedictine
University, Lisle, IL 60532, USA
Dedicated to our friend and colleague Victor Snieckus on the
occasion of his 80th birthday.
Received: 08.03.2017
Accepted after revision: 10.05.2017
Published online: 29.06.2017
a.
R
N
R
N
R
N
R
N
DOI: 10.1055/s-0036-1589049; Art ID: st-2017-b0169-l
Abstract Seven-membered nitrogen-containing heterocycles are con-
siderably underrepresented in the literature compared to their five- and
six-membered analogues. Herein, we report a relatively understudied
photochemical rearrangement of N-vinylpyrrolidinones to azepin-4-
ones in good yields. This transformation allows for the conversion of
readily available pyrrolidinones and aldehydes to densely functionalized
azepane derivatives in a facile two-step procedure.
Appearance in
FDA-approved drugs:
39%
59%
5%
Patents describing
their synthesis:
26232
35809
901
78
b.
R
O
R
H
N
R
Key words azepane, photochemistry, photo-Fries rearrangement,
heterocycles, [5+2] cycloaddition
N
N
R
R
O
O
O
Seven-membered nitrogen-containing rings present an
intriguing challenge compared to their five- and six-mem-
bered analogues. Although they occur with less frequency
than these other ‘common’ rings, their appearance in mole-
cules of biological interest provides significant motivation
to construct these frameworks efficiently and effectively.1
Additionally, five- and six-membered heterocycles have
been heavily explored, while substantially less work has
been done on the construction of seven-membered (and
larger) nitrogen-containing rings (Figure 1).2
This is particularly evident when considering the inci-
dence of seven- and eight-membered rings in pharmaceuti-
cals approved by the FDA3 compared to their coverage in the
patent literature (Figure 1).4
While cyclization strategies dominate azepane and azo-
cane synthesis, we felt that two component-coupling ap-
proaches were fundamentally more powerful and consid-
ered various disconnections. A [5+2] approach proved allur-
ing since the two-atom unit may be an alkene or surrogate,
trivially accessed and abundant, while the five-atom unit is
pyrrolidinone. Such a union could be realized by condensa-
Figure 1 a. Prevalence of saturated nitrogen-containing heterocycles
in FDA-approved pharmaceuticals (%)3 and in patents detailing their
construction;4 b. A conceptualized approach at a formal [5+2] union to
form azepanes.
Booker-Milburn (ref. 6):
Buhr (ref. 5):
O
O
O
R1
R2
O
N
R1
hν
hν
N
3
N
NH
R2
O
O
This work:
O
R2
O
O
1. condensation
R2
NH
R1
+
H
R1
2. hν
NH
O
via:
R2
N
R1
Scheme 1 Comparison between this work and prior art
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
S. M. Thullen et al.
Letter
Synlett
tion of pyrrolidinone with aldehydes followed by a photo-
chemical Fries-like rearrangement to form the azepinone.
This reaction was first described in the patent literature
(Scheme 1);5 subsequent studies by Booker-Milburn6,
Mazzocchi7, and others8 have shown similar photochemical
[5+2]-ring-expansion chemistry with the maleimide and
phthalimide frameworks, respectively. Stimulated by the
conviction that this photo-Fries-like chemistry9 could be a
powerful reaction for the synthesis of azepanes, we sought
to develop the method.
The N-vinylpyrrolidinones are readily accessible
through the condensation of a desired aldehyde and pyrro-
lidinone (Scheme 2). Unlike the chemistry of the maleimid-
es, this method allows for the facile and diverse structural
modification and functionalization around the azepane
motif. Additionally, the resultant vinylogous amide moiety
formed during the reaction is an exemplary functional
group for further manipulation.10
The photochemical rearrangement tolerates a broad
range of substitution on the enamine (Scheme 3) including
simple alkyl groups (4c–e) as well as aryl (4f), and electron-
rich and electron-poor benzyl substituents (4m–o). Di-
enamine-substituted pyrrolidinone 3l participates in the
reaction, although in diminished yield. A stereocenter pres-
ent on the alkene substituent remains intact over the
course of the reaction (4j). Unfortunately, efforts to create
quaternary centers α to the ketone as well as substrates
which included carbonyl moieties other than the reactive
amide showed no conversion under the irradiative condi-
tions.14
O
R
O
hν (254 nm)
0.02 M
N
R
O
THF, 45 °C, time
NH
3
4
Me
Me
NH
Me
Me
O
O
O
H
Me
Me
O
O
AcOH
O
R2
R2
NH
N
NH
4b
NH
NH
R1
H
R1
PhMe, 110 °C
4c
4d
60% 60 h
4e
85% 60 h
1
2
3
90% 48 h
77% 48 h
23 examples
45–96% yield
OTBS
O
O
O
O
CF3
Ph
C5H11
4
Scheme 2 Formation of N-vinylpyrrolidinones
NH
4i
90% 48 h
NH
NH
NH
4g
4f
4h
Our investigation into the photochemical11 [5+2] cyclo-
addition began with optimization of the reaction condi-
tions on 3a, using the conditions reported in the patent lit-
erature5 as a starting point (Table 1, entry 1). The use of THF
as solvent increases the yield of the reaction to 48% over 24
hours (Table 1, entry 8). Dilution of the reaction to 0.02 M
further increases the yield, presumably due to disfavored
competitive polymerization12 and dimerization13 pathways.
62% 72 h
82% 60 h
64% 48 h
Me
O
O
O
O
Me
O
Me
Me
NH
NH
4k
85% 48 h
NH
4j
4l
40% 48 h
Me
58%, 99% ee 48 h*
R1
O
S
O
R2
Table 1 Optimization Conditions
NH
4p
40% 48 h
NH
O
O
R1, R2
=
H, H
H, OMe
H, CF3
= 92% 48 h (4a)
= 74% 48 h (4m)
= 72% 48 h (4n)
hν (254 nm)
concentration
Bn
*>99% ee 3 used as
starting material.
N
Bn
solvent, 45 °C, time
OMe, OMe = 74% 48 h (4o)
NH
3a
4a
Scheme 3 Scope of alkene substituent
Entry
Solvent
Concentration (M) Time (h)
Yield (%)
Functionalization at any of the positions on the pyrro-
lidinone ring is also possible (Scheme 4). Interestingly, het-
eroatoms are often tolerated, even in the case of unprotect-
ed alcohols. Pre-existing stereocenters on the pyrrolidinone
ring do not racemize in the rearrangement chemistry with
the exception of stereocenters α to the amide. It is pre-
sumed that this is due to the Norrish Type I cleavage of the
C–C bond that does not lead to any productive pathways
and recombines, scrambling the stereocenter.
1
2
3
4
5
6
7
8
MeOH
MeCN
THF
0.2
0.2
0.2
0.2
0.5
1.0
0.1
0.02
24
24
24
48
48
48
48
48
40
22
48
75
67
55
81
92
THF
THF
THF
THF
THF
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
S. M. Thullen et al.
Letter
Synlett
then either recombine to reform the starting material or
combine with the carbon β to the nitrogen to generate
imine V. Tautomerization of V gives the observed product.
Investigation of a similar maleimide system by Booker-
Milburn and coworkers6c suggests that the reactive biradi-
cal intermediate proceeds through an excited singlet state
as opposed to an excited triplet state. When directly irradi-
ated, they solely observed the [5+2] cycloaddition product
whereas when they irradiated the maleimide in the pres-
ence of the triplet sensitizer benzophenone, they solely ob-
served the [2+2] cycloaddition between the alkene and ma-
leimide backbone.16 In our system, addition of oxygen or
catalytic benzophenone as triplet quenchers did not inter-
fere with the outcome of the reaction, supporting the likeli-
hood of a singlet pathway.
O
O
Bn
hν (254 nm)
0.02 M
N
Bn
R
THF, 45 °C, 48 h
R
NH
5
6
O
O
O
Bn
Bn
Bn
F
NH
NH
NH
HO
TBSO
6a
6b
6c
65%, 6% ee*
O
67%, >99% ee*
63%, >99% ee*
O
O
Bn
Bn
Bn
NH
NH
NH
Ph
TBSO
Global reduction:
6d
6e
6f
O
HO
Bn
Bn
89%, >99% ee*
51%, >99% ee*
Bn
75%, >99% ee*
NaBH4
O
O
AcOH, 0 °C
NH
4a
NH
Bn
7
NH
99%
4:1 dr
N
Hydrogenation:
H
6g
6h
O
O
Bn
Bn
82%
73%
Pd/C
H2
*>99% ee 5 used as starting material.
CH2Cl2
NTs
NTs
Scheme 4 Scope of pyrrolidinone substituent
8
9
99%
Wolff–Kishner:
The transformation also allows us to access larger rings
(6h). A further increase in ring size leads to difficulty in pu-
rification due to competitive polymerization, despite dilut-
ing the samples to 0.001 M.
O
1. TsNHNH2
TsOH
C5H11
C5H11
2. catecholborane,
then KOAc
NCbz
10
NCbz
11
76%
*
O
II
Norrish-type I
cleavage
O
O
Scheme 6 Derivatization reactions
IV
III
N
R
N
N
R
R
The cyclic vinylogous amide moiety formed in this
transformation is easily manipulated to a variety of useful
functional handles (Scheme 6). Georg10 and others17 have
extensively studied the modification of the six-membered
vinylogous amide analogues; however, the comparable re-
activity with seven-membered azepin-4-ones is relatively
rare.18 We found that these scaffolds easily convert into oth-
er useful seven-membered heterocycles. Global reduction
of the vinylogous amide, as well as semireduction by hydro-
genation to the ketone each proceed uneventfully; a Wolff–
Kishner protocol results in deoxygenation with alkene mi-
gration to deliver 11.
O
R
V
excitation
recombination
N
tautomerization
O
VI
R
O
I
N
R
NH
Scheme 5 Potential reaction mechanism15
In conclusion, we have developed a formal two-step
[5+2] cycloaddition to form azepinones exploiting a rela-
tively understudied photochemical rearrangement.19,20 This
facile approach allows for the construction of synthetically
useful functionalized azepin-4-ones in good yields from
A potential mechanism for this reactivity, as argued by
Shizuka and coworkers15, involves the Norrish-type I (α)
homolytic cleavage of the amide bond after irradiation with
254 nm light (Scheme 5). The resultant biradical III can
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
S. M. Thullen et al.
Letter
Synlett
readily available aldehydes and pyrrolidinones. Modifica-
tion of these substrates allows for the access to a diverse set
of substituted azepane derivatives.
(12) (a) Haaf, F.; Sanner, A.; Straub, F. Polym. J. 1985, 17, 143.
(b) Güven, O.; Șen, M. Polymer 1991, 32, 2491. (c) Yamago, S.
Chem. Rev. 2009, 109, 5051.
(13) Song, F.; Snook, J. H.; Foxman, B. M.; Snider, B. B. Tetrahedron
1998, 54, 13035.
(14) Compounds that do not show reactivity in the photochemical
rearrangement chemistry are listed in the Supporting Informa-
tion. Generally speaking, other carbonyl moieties or other UV-
reactive moieties seem to be detrimental to the reaction.
(15) Shizuka, H.; Ogiwara, T.; Morita, T. Bull. Chem. Soc. Jpn. 1977, 50,
2067.
Funding Information
We thank NIGMS for support (GM80442)
N
G
I
M
S
G(
M
8
0
4
4
2)
Supporting Information
(16) Specifically (from ref. 6c) see Scheme 7.
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589049.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
O
O
benzophenone
hν (350 nm)
O
Cl
Cl
Cl
Cl
hν (350 nm)
Cl
Cl
N
N
References and Notes
MeCN
"T1"
MeCN
"S1"
N
O
O
O
(1) (a) Riley, D. L.; van Otterlo, W. A. L. Heterocycles in Natural
Product Synthesis 2011, 537. (b) Greger, H. Planta Med. 2006, 72,
99.
(2) (a) Rousseau, G.; Homsi, F. Chem. Soc. Rev. 1997, 26, 453.
(b) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 87.
(3) (a) Vitaku, E.; Smith, B. R.; Njardarson, J. T. J. Med. Chem. 2014,
57, 10257. (b) Smith, B. R.; Eastman, C. M.; Njardarson, J. T.
J. Med. Chem. 2014, 57, 9764. (c) Ilardi, E. A.; Vitaku, E.;
Njardarson, J. T. J. Med. Chem. 2014, 57, 2832.
66%
44%
Scheme 7
(17) For select approaches to derivatize six-membered ring vinylo-
gous amides, see: (a) Hickmott, P. W. Tetrahedron 1982, 38,
1975. (b) Comins, D. L.; Zeller, E. Tetrahedron Lett. 1991, 32,
5889. (c) Sěbesta, R.; Pizzuti, M. G.; Boersma, A. J.; Minnaard, A.
J.; Feringa, B. L. Chem. Commun. 2005, 13, 1711. (d) Seki, H.;
Georg, G. I. J. Am. Chem. Soc. 2010, 132, 15512. (e) Brimouille, R.;
Bach, T. Science 2013, 342, 840.
(4) Based on Scifinder search of patents containing synthesis of
‘pyrrolidines’, ‘piperidines’, ‘azepanes’, and ‘azocanes’.
(5) Buhr, G. DE 2013761, 1970.
(6) (a) Booker-Milburn, K. I.; Anson, C. E.; Clissold, C.; Costin, N. J.;
Dainty, R. F.; Murray, M.; Patel, D.; Sharpe, A. Eur. J. Org. Chem.
2001, 1473. (b) Booker-Milburn, K. I.; Dudin, L. F.; Anson, C. E.;
Guile, S. D. Org. Lett. 2001, 3, 3005. (c) Roscini, C.; Cubbage, K. L.;
Berry, M.; Orr-Ewing, A. J.; Booker-Milburn, K. I. Angew. Chem.
Int. Ed. 2009, 48, 8716. (d) Cubbage, K. L.; Orr-Ewing, A. J.;
Booker-Milburn, K. I. Angew. Chem. Int. Ed. 2009, 48, 2514.
(e) Lainchbury, M. D.; Medley, M. I.; Taylor, P. M.; Hirst, P.;
Dohle, W.; Booker-Milburn, K. I. J. Org. Chem. 2008, 73, 6497.
(7) (a) Mazzocchi, P. H.; Bowen, M. J.; Narain, N. K. J. Am. Chem. Soc.
1977, 99, 7063. (b) Mazzocchi, P. H.; Minamikawa, S.; Bowen, M.
J. J. Org. Chem. 1978, 43, 3079. (c) Mazzocchi, P. H.; Wilson, P.;
Khachik, F.; Klinger, L.; Minamikawa, S. J. Org. Chem. 1983, 48,
2981.
(18) (a) Granger, B. A.; Jewett, I. T.; Butler, J. D.; Hua, B.; Knezevic, C.
E.; Parkinson, E. I.; Hergenrother, P. J.; Martin, S. F. J. Am. Chem.
Soc. 2013, 135, 12984. (b) Granger, B. A.; Jewett, I. T.; Butler, J.
D.; Martin, S. F. Tetrahedron 2014, 70, 4094. (c) Sakya, S. M.;
Flick, A. C.; Coe, J. W.; Gray, D. L.; Liang, S.; Ferri, F.; Van Den
Berg, M.; Pouwer, K. Tetrahedron Lett. 2012, 53, 723.
(19) General Procedure
An N-vinyl pyrrolidinone was charged in a quartz reaction
vessel, under an argon atmosphere, and degassed THF was
added (0.01 M) via cannula. The quartz reaction vessel was irra-
diated in a Rayonet reactor (internal temp. ca. 45 °C) using 254
nm mercury arc lamps until completion. The reaction was then
passed through a short silica plug and concentrated in vacuo.
The crude product was purified using flash chromatography on
silica gel (EtOAc–hexanes or MeOH–CH2Cl2).
(8) Sato, Y.; Nakai, H.; Mizoguchi, T.; Hatanaka, Y.; Kanaoka, Y.
J. Am. Chem. Soc. 1976, 98, 2349.
(20) Representative Product 3-Benzyl-1,5,6,7-tetrahydro-4H-
azepin-4-one (4a)
(9) For the seminal work on amide photo-Fries chemistry, see:
(a) Izzo, P. T.; Kende, A. S. Tetrahedron Lett. 1966, 5731. (b) Yang,
N. C.; Lenz, G. R. Tetrahedron Lett. 1967, 4897. (c) Hoffmann, R.
W.; Eicken, K. R. Tetrahedron Lett. 1968, 1759. (d) Hoffmann, R.
W.; Eicken, K. R. Chem. Ber. 1969, 102, 2987.
Compound 4a was obtained using general procedure from vinyl
lactam 3a. White solid; 92% yield. 1H NMR (400 MHz, CDCl3):
δ = 7.31–7.08 (m, 5 H), 6.76 (d, J = 7.3 Hz, 1 H), 5.61 (s, 1 H), 3.53
(s, 2 H), 3.46–3.36 (m, 2 H), 2.78–2.68 (m, 2 H), 1.99 (m, 2 H). 13
C
(10) For a recent review on the reactivity of cyclic vinylogous amides
as well as other applicable references, see: Seki, H.; Georg, G. I.
Synlett 2014, 25, 2536.
(11) For recent reviews on photochemistry in organic synthesis, see:
(a) Tanoury, G. J. Synthesis 2016, 48, 2009. (b) Hoffmann, N.
Chem. Rev. 2008, 108, 1052.
NMR (101 MHz, CDCl3): δ = 198.76, 142.55, 128.61, 128.17,
125.60, 109.74, 47.18, 42.62, 37.00, 22.94. IR (ATR): 3278, 3075,
2929, 1617, 1544, 1405, 1367, 1325, 1234, 1159, 1108, 1066
cm–1. Rf = 0.15 (85:15 EtOAc–hexanes). LRMS (ESI+APCI): m/z
[M + H]+ calcd for [C13H16NO]+: 202.28; found: 202.4.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D