Direct access to tetrahydro[1,2]diazepinones from α,β-epoxy-N- aziridinylimines via anionic rearrangement

Article abstract of DOI:10.1021/ol400070j

A novel one-step synthetic approach to tetrahydro[1,2]diazepinones via base-promoted rearrangement of α,β-epoxy-N-aziridinylimines, derived from α,β-epoxyketones and N-aminoaziridines, has been developed.

Full text of DOI:10.1021/ol400070j

ORGANIC
LETTERS
2013
Vol. 15, No. 4
914–916
Direct Access to
Tetrahydro[1,2]diazepinones from
r,β-Epoxy‑N‑aziridinylimines via Anionic
Rearrangement
Fufang Wu,†,‡,§,^ Min Dong, ,^ Fang Fang,‡ Yingxia Sang,‡ Yun Li,§ Bin Cheng,‡,§
Lihe Zhang,*, and Hongbin Zhai*,§
Department of Chemistry, University of Science and Technology of China, Hefei 230026,
China, State Key Laboratory of Natural and Biomimetic Drugs,
School of Pharmaceutical Sciences, Peking University, 38 College Road, Beijing 100083,
China, State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China, and CAS Key Laboratory of Synthetic Chemistry of Natural
Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
zhaih@lzu.edu.cn, zdszlh@bjmu.edu.cn
Received January 10, 2013
ABSTRACT
A novel one-step synthetic approach to tetrahydro[1,2]diazepinones via base-promoted rearrangement of r,β-epoxy-N-aziridinylimines,
derived from R,β-epoxyketones and N-aminoaziridines, has been developed.
Aziridinylimines (1a) have emerged as a class of attrac-
tive and versatile chemical entities in modern organic
synthesis. For instance, these compounds have been em-
ployed as the precursors of many reactive intermediates
such as diazoalkanes, carbenes, and carbocations.1 In
addition, N-aziridinylimines have been used in a catalytic
Shapiro reaction2 and to produce geminal methylene
radicals3aÀe and trimethylenemethane (TMM) biradical
intermediates,3f to effect further radical cyclizations. The
TMM biradical chemistry resulted in facile construction
of triquinanes and was applied to an elegant total synthesis
of hirsutene.3f In addition, the conversion of R,β-epoxy-N-
aziridinylimines (1b) into carbonyl compounds, alkynes,
and nitrogen through fragmentation of diazo intermedi-
ates was discovered by Eschenmoser4 and, almost simul-
taneously, by Tanabe.5 Furthermore, anionic cyclization
† University of Science and Technology of China.
‡ Shanghai Institute of Organic Chemistry.
(4) (a) Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta
1967, 50, 708. (b) Schreiber, J.; Felix, D.; Eschenmoser, A.; Winter, M.;
Gautschi, F.; Schulte-Elte, K. H.; Sundt, E.; Ohloff, G.; Kalvoda, J.;
Kaufmann, H.; Wieland, P.; Anner, G. Helv. Chim. Acta 1967, 50,
2101.
(5) Tosylhydrazones were used instead. See: Tanabe, M.; Crowe,
D. F.; Dehn, R. I.; Detre, G. Tetrahedron Lett. 1967, 8, 3739.
(6) (a) Leone, C. L.; Chamberlin, A. R. Tetrahedron Lett. 1991,
32, 1691. (b) Kim, S.; Cho, C. M.; Yoon, J.-Y. J. Org. Chem. 1996,
61, 6018. (c) Kim, S.; Oh, D. H.; Yoon, J.-Y.; Cheong, J. H. J. Am.
Chem. Soc. 1999, 121, 5330. (d) Hwang, J.; Hong, Y.-T.; Kim, S.
Adv. Synth. Catal. 2005, 347, 1513. (e) Kim, S.; Hwang, J. Synlett
2010, 1511.
§ Lanzhou University.
Peking University.
^ These authors contributed equally to this work.
(1) Kirmse, W. Eur. J. Org. Chem. 1998, 201.
(2) Maruoka, K.; Oishi, M.; Yamamoto, H. J. Am. Chem. Soc. 1996,
118, 2289.
(3) (a) Kim, S.; Kee, I. S.; Lee, S. J. Am. Chem. Soc. 1991, 113, 9882.
(b) Kim, S.; Kee, I. S. Tetrahedron Lett. 1993, 34, 4213. (c) Lee,
H.-Y.; Kim, D.-I.; Kim, S. Chem. Commun. 1996, 1539. (d) Kim, S.;
Cheong, J. H. Synlett 1997, 947. (e) Kim, S.; Cheong, J. H.; Yoo, J.
Synlett 1998, 981. (f) Lee, H.-Y.; Kim, Y. J. Am. Chem. Soc. 2003, 125,
10156.
r
10.1021/ol400070j
Published on Web 02/04/2013
2013 American Chemical Society

of N-aziridinylimines can be used to construct consecutive
carbonÀcarbon bonds.6
Table 1. Effect of the Base on the Rearrangement
entry
base
time (min)
yielda (%)
Epoxyaziridinylimine 2awas synthesized bydehydrative
condensation7 of the corresponding R,β-epoxyketone8 and
1-amino-2-phenylaziridine.9 During the course of our in-
vestigations related to the Shapiro reaction, we discovered
that, upon treatment with 1.5 equiv of MeLi, n-BuLi, or
lithium diisopropylamide (LDA) at À78 ꢀC, 2a underwent
an unprecedented rearrangement to afford 3a in a good
to excellent yield (entries 6À8, Table 1). Compound 3a
features a novel and potentially biologically significant10
1,5,6,7-tetrahydro[1,2]diazepin-4-one core structure. n-BuLi
and LDA seemed to be slightly better than MeLi as the
base since they led to higher yields of the product. Neither
anionic addition to the hydrazone moiety nor Shairo-
type reaction took place under the reaction condi-
tions. Note that the structural resemblance of 3a to
benzodiazepine11 (A, Table 1) might endow the novel
heterocyclic molecule 3a with attractive pharma-
cological properties. Benzodiazepine derivatives are
widely used as anticonvulsant, antianxiety, hypnotic,
and anti-inflammatory agents.12 Some benzodiaze-
pines have been applied in photography as dyes for
acrylic fibers.9 In addition, pyrrolodiazepines are
known as a family of substances with pronounced
analgesic, anxiolytic, sedative, antiepileptic, anti-
bacterial, and antifungal activities.13 In contrast to
the above-mentioned bases, employment of K2CO3,
t-BuOK, LHMDS, or KHMDS resulted in no rear-
rangement reaction at all (entries 1À4, Table 1). In the
case of NaOMe (entry 5) as the base, the starting
material was completely consumed, while no isolable
products were formed.
1
2
3
4
5
6
7
8
K2CO3
t-BuOK
LHMDS
KHMDS
NaOMe
MeLi
40
40
40
40
20
20
20
20
NR
NR
NR
NR
complex
86
n-BuLi
LDA
96
94
a Isolated yield.
Table 2. Base-Promoted Rearrangement of 2
entry
R1
R2
methoda reactant/product yieldd (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
Bb
2a/3a
2a/3a
2b/3b
2b/3b
2c/3c
2c/3c
2d/3d
2d/3d
2e/3ac
2e/3e
2f/3f
96
94
93
98
86
94
81
96
57
98
91
92
75
91
73
81
p-MeC6H4 Ph
p-MeC6H4 Ph
p-MeOC6H4 Ph
p-MeOC6H4 Ph
p-PhC6H4 Ph
p-PhC6H4 Ph
p-BrC6H4 Ph
10 p-BrC6H4 Ph
11 Ph
12 Ph
13 Ph
14 Ph
15 t-Bu
16 t-Bu
p-ClC6H4
p-ClC6H4
p-MeC6H4
p-MeC6H4
Ph
In order to explore the scope of the current method,
epoxyaziridinylimines with various substituents attached
to the benzene ring adjacent to the imino group (2bÀe)
or to that connected to the aziridine moiety (2f, g) were
2f/3f
2g/3g
2g/3g
2h/3h
2h/3h
Ph
(7) Stevens, R. V.; Chang, J. H.; Lapalme, R.; Schow, S.; Schlageter,
M. G.; Shapiro, R.; Weller, H. N. J. Am. Chem. Soc. 1983, 105, 7719.
(8) House, H. O.; Reif, D. J.; Wasson, R. L. J. Am. Chem. Soc. 1957,
79, 2490.
a Method A: base = n-BuLi. Method B: base = LDA. b LDA (2 equiv),
40 min. c n-BuLi (2 equiv). d Isolated yield.
t
screened (Table 2). In addition, 2h features a bulky Bu
(9) Felix, D.; Muller, R. K.; Horn, U.; Joos, R.; Schreiber, J.;
Eschenmoser, A. Helv. Chim. Acta 1972, 55, 1276.
(10) (a) Kim, H. S.; Jeong, G.; Lee, H. C.; Kim, J. H.; Park, Y. T.;
group adjacent to the imino carbon. All substrates were
treated with n-BuLi (method A) and LDA (method B),
respectively. As for method A, regular addition has to be
adopted; otherwise, the desired rearrangement products
cannot be obtained at all. In contrast, the addition order is
not significant for methodB. Ingeneral, the rearrangement
reaction takes place smoothly to afford the corresponding
diazepinones 3 under the reaction conditions. However,
for the brominated reactant 2e, both debromination and
Okamoto, Y.; Kajiwara, S.; Kurasawa, Y. J. Heterocycl. Chem. 2000,
€
37, 1277. (b) Ghavtadze, N.; Frohlich, R.; Wurthwein, E.-U. Eur. J. Org.
€
Chem. 2009, 1228.
(11) Sherrill, R. G.; Berman, J. M.; Birkemo, L.; Croom, D. K.;
Dezube, M.; Ervin, G. N.; Grizzle, M. K.; James, M. K.; Johnson, M. F.;
Queen, K. L.; Rimele, T. J.; Vanmiddlesworth, F.; Sugg, E. E. Bioorg.
Med. Chem. Lett. 2001, 11, 1145.
(12) Yadav, J. S.; Reddy, B. V. S.; Eshwaraiah, B.; Anuradha, K.
Green Chem. 2002, 4, 592.
(13) Stroganova, T. A.; Butin, A. V.; Vasilin, V. K.; Nevolina, T. A.;
Krapivin, G. D. Synlett 2007, 1106.
Org. Lett., Vol. 15, No. 4, 2013
915

rearrangement occurred and 3a was formed in 57% yield
when n-BuLi was used in the reaction (entry 9). In the case
of 2h, anexcess amount of LDA (2 equiv) and a longer time
(40 min) were necessary for the reaction to reach comple-
tion (entry 16). If n-BuLi was used as the base instead, 2h
behaved similar to other substrates although the yield of
the product dropped to 73% (entry 15). It was noted that
LDA gave higher yields of the products than n-BuLi for
all substrates except the parent epoxyaziridinylimine 2a,
where method B proved superior duetothe milder reaction
conditions. The structure of 3e was confirmed by X-ray
crystallographic analysis (Figure 1).
Furthermore, treatment of 1,2-disubstituted epoxide 4a
(Scheme 2) with n-BuLi afforded allylic alcohol 8 (36%) in
addition to the seven-membered cyclic ketone 7a (40%).
The formation of 8 arises from addition of n-butyl anion
followed by fragmentation involving loss of styrene and
nitrogen gas. However, when LDA was used instead of
n-BuLi as the base, neither 7a nor 8 could be generated
from the same substrate.
Scheme 2. Rearrangement of 4a
Figure 1. X-ray structure of 3e.
A plausible mechanism for the present transformation is
proposed in Scheme 1. Epoxyaziridinylimine 4 is deproto-
nated to produce anion 5,14 which undergoes a rearrange-
ment via a six-membered chairlike transition state (forming
The reactivity of 4 (Scheme 1) seems to be dependent
upon the nature of the R substituent. With R = H, only
cyclic ketone 7 is produced. When R = Me, the deproto-
nation/rearrangement process (Scheme 1) is dramatically
retarded due to steric hindrance, allowing the formation of
allylic alcohol 8 via tandem nucleophilic addition/frag-
mentation (Scheme 2).
Scheme 1. Proposed Mechanism
In summary, we have developed a novel one-step syn-
thetic approach to tetrahydro[1,2]diazepinones, featuring
base-promoted rearrangement of R,β-epoxy-N-aziridiny-
limines. The seven-membered heterocyclic ketones thus
generated may have potential pharmaceutical applications
that deserve further exploration.
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program: 2010CB833200),
NSFC (21172100; 21272105, 21290183), Program for
Changjiang Scholars and Innovative Research Team in
University (PCSIRT: IRT1138), and “111” Program of
MOE for financial support.
enolate 6) followed by protonation, leading to the genera-
tion of ketone 7.
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Supporting Information Available. Experimental pro-
cedures, analytical data, and copies of 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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