Intramolecular Schmidt Reaction of Vinyl Azides with Cyclic Ketones

Article abstract of DOI:10.1021/acs.orglett.8b00395

Cyclic ketones tethered with a vinyl azide group undergo a Schmidt-hydrolysis sequence to give secondary lactams bearing a ketone side chain. Secondary lactams are obtained in a regioselective manner that is not possible in a conventional Schimdt reaction. In addition to the well-documented C-2 nucleophilicity, the N nucleophilicity of vinyl azide disclosed in this work opens a new direction for reaction invention involving vinyl azides.

Full text of DOI:10.1021/acs.orglett.8b00395

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Intramolecular Schmidt Reaction of Vinyl Azides with Cyclic Ketones
Peng Chen, Chu-Han Sun, Yu Wang, Ying Xue, Chen Chen, Mei-Hua Shen,* and Hua-Dong Xu*
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Pharmaceutical Engineering & Life Science,
Changzhou University, Changzhou 213164, P. R. China
S
* Supporting Information
ABSTRACT: Cyclic ketones tethered with a vinyl azide group
undergo a Schmidt-hydrolysis sequence to give secondary
lactams bearing a ketone side chain. Secondary lactams are
obtained in a regioselective manner that is not possible in a
conventional Schimdt reaction. In addition to the well-
documented C-2 nucleophilicity, the N nucleophilicity of
vinyl azide disclosed in this work opens a new direction for
reaction invention involving vinyl azides.
chmidt reactions1 of cyclic ketones are an extremely
practical and efficient method for the preparation of both
synthetically and biologically important lactams, especially for
δ- and ε-lactams.1d However, the problematic regioselectivity
issue for unsymmetrical ketones deteriorates their synthetic
potential (Scheme 1, eq 1).2 An intramolecular Schmidt
hydrolysis would afford secondary amide D (Scheme 2, path a).
S
This chemistry had been discovered by the Moore12 and
Scheme 2. Vinyl Azide Acting as C-Nucleophile and N-
Nucleophile
Scheme 1. Comparison of Conventional Schmidt Reactions
with Schmidt Reaction of Vinyl Azide
Hassner groups,13 and advanced by the groups of Chiba,11c,d
and Jiao.14 We were curious whether the vinyl azide, just like
alkyl azide15 in a Schimdt reaction, could serve as a N-
nucleophile that could attack an activated carbonyl group by
the internal nitrogen atom to form diazonium cation E and
then N-vinyl amide F, as operated in a conventional Schmidt
reaction (Scheme 2, path b). To the best of our knowledge, this
reactivity is not well documented for vinyl azide.
At the outset, phenyl vinyl azide was subject to reaction with
benzocyclohexan-1-one in the presence of 20 mol % fluoroboric
acid (48% HBF4 aqueous solution) in acetonitrile at rt; N-
phenylacetamide was obtained (71%) with full recovery of the
cyclic ketone (Scheme 3). These outcomes indicated that no
intermolecular Schmidt reaction occurred; instead, protona-
tion/1,2-migration sequence took place (Scheme 2, path a).
reaction has been developed to solve this issue,3 but this
strategy is not viable for the synthesis of secondary lactams
because only bicyclic tertiary lactams would be obtained
through this method (Scheme 1, eq 2). Herein, we report an
intramolecular Schmidt reaction that can complementarily
deliver secondary lactams with a ketone side chain through the
reaction of vinyl azides with cyclic ketones (Scheme 1, eq 3).
In the course of our studies on azirine, we became interested
in the chemistry of vinyl azide.4 Attributed to its diverse
reactivities, this unique functional group has been used as
versatile synthons for various transformations.5 It can be used
as azirine precursor,6 nitrene progenitor,7 radical receptor,8
(formal) 1,3-dipole,9 1,3-dipolephile10 and latent nitrilium
ions,11 etc. Electrophilic attack on or protonation of vinyl
azide A at C2 would give diazonium cation B, which could
undergo 1,2-migration to generate nitrilium ions C; subsequent
Received: February 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00395
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The use of HBF4 (20 mol %) in MeCN (Table 1, entry 7)
were adopted as the standard conditions for further studies and,
in order to explore the substrate scope, a diversity of vinyl
azides 6b−t were made and submitted to these conditions
(Table 2). Vinyl azide 6b with an additional α-carboxylate
group reacted smoothly to give cyclic amide 7b with a normally
difficult amide-substituted quaternary carbon center. Vinyl
azides 6c−e, derived from benzofused cyclohexanones, were
also feasible for this reaction, albeit giving corresponding
cycloheptamides 7c−e in lower yields. One carbon elongation
of the tether between the groups of cyclic ketone and vinyl
azide results in 6f, which was converted to lactam 7f in 56%
yield under the standard conditions. Installation of a
carboxylate group at the α-position improves the reaction
dramatically, as demonstrated by 81% 7g from 6g. Three
methylene linked vinyl azide 6h was also converted to the
Schmidt lactam 7h in 64% yield with 32% 8h. Similarly, a high
yield of 85% of 7i was also obtained with substrate 6i.
Fluorination on the aryl ring does not affect the reaction
significantly, as lactams 7j (79%) and 7k (74%) were obtained
in good yields. Interestingly, though benzo-fused cyclo-
hexanone 6l reacted equally as well as cyclopentanone
analogous 6h did (70% 7l), 6m could not provide better
yield as 6i did (40% 7m vs 85% 7i). The use of an electron-
releasing methoxyl group showed a beneficial effect on the
reaction, and lactam 7n was collected in 82% yield.
Incorporation of a NTs moiety in the linker led to a messy
reaction, and only 36% of Schmidt product 7o was isolated
even after 20 h. Pleasingly, with propylene as the tether,
nonbenzo-fused cyclic ketones 6p−t are all excellent substrates
for this HBF4-promoted Schmidt reaction, and related lactams
were produced in high yields up to 87%.
Scheme 3. Acid-Promoted Hydrolysis of Phenyl Vinyl Azide
in the Presence of Benzocyclohexan-1-one
It was envisioned that the kinetically favored intramolecular
process might help to facilitate the Schmidt pathway to
outcompete path a. Thus, vinyl azide 6a with a dihydroinde-
none group in proximity was chosen for this purpose, and
conditions for a conventional Schmidt reaction were evaluated
with it (Table 1). To our delight, with 20 mol % Lewis acid
Table 1. Condition Optimization for Intramoleclar Schmidt
a
Reaction of Vinyl Azide
When non-benzofused cyclic compounds 9a−i with a one-
carbon linker between the carbonyl group and the vinyl azide
moiety were treated with the standard conditions, only
diketones 10a−i were collected without any detection of the
corresponding lactams, indicating that the vinyl azide hydrolysis
outcompetes other pathways. The presence of an alkene group
in 9e may cause additional side reactions leading to a decrease
in the yield of 10e. In the case of 9j, a tertiary amine group in
the molecule necessitates 1.2 equiv of HBF4 to achieve a
complete conversion. Interestingly, a mixture of unidentified
products was formed for the reaction of vinyl azide 9k.
a
6a (50 mg, 1.0 equiv), solvent (3 mL), catalyst (20 mol %) at 15 °C
b
c
for 10−15 h. Isolated yield. 21% revovery of 6a.
According to Hassner’s report,13 a brief mechanism to
accommodate the formation of these two types of products is
summarized in Scheme 4. Protonation of vinyl azides 6/9 at C2
results in intermediate III, subsequent hydrolysis affords
diketones 8/10 via IV (Scheme 4, route B); meanwhile, attack
of the proton activated carbonyl group by the azide group
delivered cyclic intermediate I, which is transformed to lactam
II through Schmidt rearrangement and is further hydrolyzed to
open up the ring giving 7 (route A). Our studies show that
vinyl azides 9a−j bypassed route A, probably due to the
unfavorable formation of intermediate I possessing a fused 5-
membered ring (m = 0) and/or subsequent formation of
strained β-lactam II (m = 0). Benzofusion improves the
reactivity of carbonyl group toward protonation and, therefore,
could render route A preferred for 6a−e. As for 6p−t, the
formation of flexible 7-membered cyclic intermediates I (m =
2) would assist it in adopting a conformation with perfect
orbital alignment for subsequent nitrogen extrusion-alkyl group
migration event to give energetically favorable six-membered
bicyclic intermediates II (m = 2). Collectively, these benefits
BF3·Et2O, the desired reaction did occur at 15 °C to give a
Schmidt-type product lactam 7a in 65% yield, but with 30%
starting material kept intact (entry 1). TiCl4 shows higher
catalytic ability, albeit resulted in a more complex reaction
mixture (entry 2). Bronsted acid CF3CO2H was less efficient
than TiCl4 as only partial conversion of 6a was observed after
15 h in MeCN (entry 3). Treatment with 20 mol % TfOH led
to a mixture of 21% 6a, 34% 7a, and a diketone 8a in 31% yield,
a product derived from vinyl azide hydrolysis (entry 4).
Interestingly, full conversion was achieved with MsOH as
catalyst to give 48% 7a and 37% 8a (entry 5), but sulfamic acid
was totally ineffective (entry 6). Complete reaction was
achieved with 20 mol % HBF4 (48% aqueous solution) to
yield 7a in 84% isolated yield with 12% 8a (entry 7).
Chlorinated solvents DCE and DCM afforded deteriorated
selectivity (entries 8 and 9). When performed in nonpolar
solvents toluene and methyl tert-butyl ether (MTBE), the
reaction gave diketone 8a favorably (entries 10 and 11), while
in CF3CH2OH, a complex mixture was obtained from which 7a
was isolated in 68% yield (entry 12).
B
DOI: 10.1021/acs.orglett.8b00395
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Intramolecular Schmidt Reaction of Vinyl Azides with Cyclic Ketone and Hydrolysis of Vinyl Azides
a
b
c
d
6 (50 mg, 1.0 equiv), MeCN (3 mL), HBF4 (20 mol %) at 15 °C for 10−15 h. isolated yield. 12% 8a was collected. Inseparable mixture, NMR
e
f
g
h
i
yield. 32% 8h was collected. 20 h. 22% 8s was collected. 1.2 equiv of HBF4 was used. Mixture of unidentified products was obtained (4 times of
repetition).
must make the transformations through route A be fast enough
to outcompete corresponding vinyl azide hydrolysis (Scheme 4,
route B). The divergent chemoselectivity shown between 6 and
9 and the exclusive formation of lactams 7 without their
regioisomers 7′ rules out an alternative pathway in which HN3
generated by route B reacts with the cyclic ketone
intermolecularly. It is worth noting that, for many substrates
other than 6a, 6h, and 6s in Table 2, their hydrolytic products
of type 8 have also been observed but were difficult to collect in
pure form by silica gel column chromatography.
To gain more information for this reaction, acyclic substrate
11 was prepared and submitted to the standard conditions.
Unlike its cyclic congener 6c, the reaction of 11 produced
diketone 14 in 56% yield and the intramolecular Schmidt
product 12 in only 12% yield, along with 8% inseparable amide
13 (Scheme 5). This might be attributed to the reduced
flexibility in cyclic ketone that favors an intramolecular process.
In summary, we have developed a novel intramolecular
Schmidt-hydrolysis sequence that affords secondary lactams
with a ketone side chain in exclusive regioselectivity that is
impossible for conventional Schimdt reactions and, therefore,
C
DOI: 10.1021/acs.orglett.8b00395
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Mechanistic Explanation for the Formation of 7
and 8/10
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ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: shenmh@cczu.edu.cn.
*E-mail: hdxu@cczu.edu.cn.
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ORCID
Hua-Dong Xu: 0000-0002-4510-3754
Notes
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Chem., Int. Ed. 2013, 52, 7850.
The authors declare no competing financial interest.
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̈
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC 21402014 and 21672027), QingLan Project of Jiangsu
Province (2016), and Six-Talent-Peaks Program of Jiangsu
(2016) for financial support.
D
DOI: 10.1021/acs.orglett.8b00395
Org. Lett. XXXX, XXX, XXX−XXX