An intramolecular Schmidt reaction of δ-azido N-acylbenzotriazoles

Article abstract of DOI:10.1021/acs.orglett.1c00200

A Lewis acid promoted intramolecular Schmidt reaction of N-acylbenzotriazoles with alkyl azides was designed and realized. The benzotriazole was not only employed as an efficient activator for initiating the Schmidt rearrangement but also used as a powerful terminator for the subsequent nucleophilic trapping of the isocyanate ion and/or N-acyliminium ion from the rearrangement. Thirteen δ-azido N-acylbenzotriazoles were investigated, and the conversion afforded the desired benzotriazole-1carboxamides and lactams with good to excellent yields.

Full text of DOI:10.1021/acs.orglett.1c00200

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Letter
An Intramolecular Schmidt Reaction of δ‑Azido
N‑Acylbenzotriazoles
Chun-Fang Liu,‡ Zhi-Qi Cao,‡ Shao-Lei Ding, Jing Zhu, and Peiming Gu*
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ABSTRACT: A Lewis acid promoted intramolecular Schmidt reaction of N-acylbenzotriazoles with alkyl azides was designed and
realized. The benzotriazole was not only employed as an efficient activator for initiating the Schmidt rearrangement but also used as
a powerful terminator for the subsequent nucleophilic trapping of the isocyanate ion and/or N-acyliminium ion from the
rearrangement. Thirteen δ-azido N-acylbenzotriazoles were investigated, and the conversion afforded the desired benzotriazole-1-
carboxamides and lactams with good to excellent yields.
he classic Schmidt reaction of HN3 with aldehydes,
ketones, and carboxylic acids is a powerful approach for
alkyl azides with carboxylic acid derivatives to be feasible, two
major issues might be addressed: (1) a good leaving group
should be attached to the carbonyl group for better initiating
the rearrangement and (2) a suitable nucleophile is required
for efficiently capturing the isocyanate ion or N-acyliminium
ion from the Schmidt reaction.
T
accessing to the nitrogen-containing molecules,1 and in the
past three decades, efforts in replacement of the highly toxic
HN3 with other nitrogen reactants have made great
success,1c,2,3 resulting in more efficient aza-ring formation.
The less reactive alkyl azides were systematically demonstrated
The benzotriazole is regarded as an excellent leaving group
in synthetic chemistry, and it has been extensively applied in
many organic transformations.11 Therefore, 1-acylbenzotria-
zole,12 also a type of amide, could be a potential electrophile
for the intramolecular Schmidt reaction of alkyl azides. It was
envisioned that nucleophilic attack of azide onto the 1-
acylbenzotriazole would take place when the δ-azido N-
acylbenzotriazole 1 was activated by an acid promoter
(Scheme 2), and an acyl N-diazonium ion intermediate I
would be generated with releasing a benzotriazole anion. Then
the isocyanate ion II and N-acyliminium ion III would be
produced from the rearrangement of intermediate I, where the
competitive 1,2-shift of two β-carbons to the electron-deficient
nitrogen atom with loss of nitrogen gas would proceed. Finally,
both the isocyanate ion II and N-acyliminium ion III would be
in situ intermolecularly captured by the strongly nucleophilic
benzotriazole anion, and the benzotriazole type carbamide 2
and lactam 3 would be furnished as the ultimate products.
as successful azides in reaction with ketones and aldehydes by
4
́
Aube’s group, and then the electrophiles were expanded to
the carbenium ions derived from alkenes5 or alcohols5a,6 or
expoxides7 or alkynes;8 however, the carboxylic acids were
unreactive with the alkyl azides. We have realized the Schmidt
reaction of alkyl azides with the carboxylic acids via an in situ
activation strategy for the carboxylic acids,9 where isocyanate
ion and N-acyliminium ion salts were proposed as the initial
products. The two ions could be terminated by an additional
nucleophile to produce electroneutral products (Scheme 1),
but only the major ion could be captured by the preinstalled
intramolecular nucleophile, and trapping the minor ion should
fail as the potential product is the unfavored bridged lactam.
Intermolecular capture of the two rearrangement ions with
excessive doses of nucleophiles could be a reasonable choice,
though it gave only poor results.10 In seeking to explore the
more efficient activation strategies for the carboxylic acids and
new electrophiles for the Schmidt reaction, we report here an
intramolecular reaction of the alkyl azides with the N-
acylbenzotriazoles.
Received: January 19, 2021
Published: January 25, 2021
Investigation of the amide as an electrophile for the Schmidt
reaction of alkyl azides would be desirable, although the amide
presents a challenge as it is generally a less reactive substrate,
mainly due to the p−π conjugation in the amide group.
According to our previous research, for the Schmidt reaction of
https://dx.doi.org/10.1021/acs.orglett.1c00200
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1147−1151
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Scheme 1. Schmidt Reaction of Alkyl Azides with
Carboxylic Acid Derivatives
Table 1. Schmidt Reaction of the δ-Azido N-
a
Acylbenzotriazole 1a
b
entry
acid
conditions
results (yield, %)
c
1
2
3
4
5
6
7
8
9
10
11
12
SnCl4
TiCl4
reflux, DCM, 24 h
reflux, DCM, 24 h
reflux, DCM, 24 h
reflux, DCM, 24 h
reflux, DCM, 24 h
rt, 24 h
reflux, DCE, 2.5 h
reflux, DCE, 3.5 h
reflux, DCE, 4 h
reflux, DCE, 120 h
reflux, DCE, 120 h
reflux, DCE, 4 h
dec
2a (10), 3a (20)
c
Et2AlCl2
BF3·OEt2
TfOH
dec
2a (17), 3a (20)
complex, 3a (8)
d
c
TFA
dec
BF3·OEt2
BF3·OEt2
BF3·OEt2
SnCl4
TiCl4
BF3·OEt2
2a (45), 3a (45)
2a (45), 3a (34)
2a (34), 3a (38)
complex, 3a (25)
complex, 3a (18)
2a (45), 3a (43)
e
f
a
Reaction of the δ-azido N-acylbenzotriazole 1a (73 mg, 0.30 mmol)
with the acid promoter (0.90 mmol) in the mentioned solvent (1.5
b
c
mL). Isolated yield. Hydrolysis of the N-acylbenzotriazole was
d
e
observed. TFA (1.5 mL) as the reaction solvent. Reaction promoted
with 0.60 mmol of BF3·OEt2. Reaction with 1.0 mmol of 1a.
f
desired carbamide 2a and lactam 3a were obtained in a
combined yield of 90% with a ratio of 1/1 in 2.5 h (entry 7,
Table 1). The carbamide 2a was further characterized by X-ray
single-crystal diffraction. Then the attempt to reduce the acid
promoter (2.0 equiv) encountered a failure, and the combined
yield of the desired products was reduced to 79% (entry 8,
Table 1). It should be noted that a longer reaction time would
count against the yield, and benzotriazole was significantly
produced (entry 9, Table 1). Then the carbamide 2a and
lactam 3a were isolated and subjected to BF3·OEt2 at refluxing
dichloroethane for 3 h, and the carbamide 2a was completely
decomposed to benzotriazole, while only trace benzotriazole
was observed with that of lactam 3a. Further, SnCl4 and TiCl4
were re-examined for the Schmidt reaction of 1a in refluxing
dichloroethane; however both reactions failed to give positive
results, and the substrate was consumed after 120 h, affording
the lactam 3a with poor yields from the very complex reaction
mixtures (entries 10 and 11, Table 1).
Scheme 2. Proposed Process for the Schmidt Reaction of
Alkyl Azides with N-Acylbenzotriazoles
The potential migratory groups in the rearrangement of 1a
were two methylene carbons, and the above results indicated
that the shift process had poor regioselectivities. Then an alkyl
or an aryl group was assembled at the α-carbon of the carbonyl
group, and the δ-azido N-acylbenzotriazoles 1b−1f were
prepared for exploration. With the optimized reaction
conditions in hand (entry 7, Table 1), substrates 1b−1f were
all converted to the desired carbamides and lactams with
excellent combined yields (Scheme 3). Reaction of azide 1b for
25 min afforded the benzotriazole-1-carboxamide 2b with 79%
yield and the lactam 3b with 11% yield, and it was observed
that 68% of 2c and 22% of 3c were obtained from the reaction
of substrate 1c, suggesting steric hindrance might slightly affect
the migration process. It seemed that a shift of the benzylic
methine carbon was more preferred, where the reaction of
acylbenzotriazoles 1d gave a carbamide 2d with 93% yield and
the lactam 3d with only 6% yield. However, the substrate 1e
attached with a chlorine at the para position of the aryl ring in
the benzylic substrate led to slightly decreased regioselectivitiy,
The δ-azido N-acylbenzotriazole 1a13 was prepared for
testing the above hypothesis, and several acids (3.0 equiv)
were applied to promote the reaction in the refluxing
dichloromethane (Table 1). Among the acid promoters, BF3·
OEt2 was found to be a promising one, and the carbamide 2a
with a yield of 17% and the lactam 3a with a yield of 20% were
isolated after 24 h, where 30% of 1a could be recovered. To
consume all of the substrate, the reaction temperature was
increased, and the conversion was carried out in refluxing
dichloroethane. As expected, both of the rearrangement ions
were well captured with the benzotriazole anion, and the
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Generally, migration of the aryl group was favored over the
alkyl group in the Schmidt reaction (Scheme 5). To enhance
Scheme 3. Schmidt Reaction of the 2-Substituted δ-Azido
N-Acylbenzotriazoles 1b−1f
Scheme 5. Schmidt Reaction of δ-Azido N-
Acylbenzotriazole 1i−1m
a
Reaction of the δ-azido N-acylbenzotriazole 1 (0.30 mmol) with
BF3·OEt2 (0.90 mmol) in the refluxing dichloroethane (1.5 mL).
b
Reaction of 1f (100 mg, 0.30 mmol) with BF3·OEt2 (47 mg, 42 μL,
0.33 mmol) in refluxing dichloroethane (1.5 mL).
where the carbamide 2e was obtained in 74% and lactam 3e
was isolated in 16% yield. The δ-azido N-acylbenzotriazole 1f
was converted into the carbamide 2f in 63% yield with the
above reaction conditions; meanwhile, trace 3f could be
observed and obvious decomposition of the products occurred
with this case. Then the substrate 1f was treated with less BF3·
OEt2 (1.1 equiv) for 5.7 h in the refluxing dichloroethane, and
fortunately, the yield of carbamide 2f was improved to 89%.
With these types of substrates, the carbamides 2 from
migration of the methine carbon (C2) were all obtained as
the dominant products, and the lactams 3 from migration of
the methylene carbon (C4) were isolated as the minor
products.
The δ-azido N-acylbenzotriazole 1g, in the form of 1a
attached by an ethyl group at the C4 position, had two
different types of β-carbons for the potential migration.
Compound 1g as treated with BF3·OEt2 for 25 min, and the
carbamide 2g from migration of a methylene carbon (C2) was
observed with 16% yield as a minor product and the lactam 3g
from the competitive migration of a methine carbon (C4) was
isolated with 77% yield (Scheme 4). Interestingly, treatment of
the migration of C4, five more substrates 1i−1m were
prepared for investigation. BF3·OEt2 was not a good promoter
for the reaction of these substrates, where only 12% of 2-
oxoindole 3i could be isolated from the BF3·OEt2-promoted
reaction of 1i. It should be noted that the benzotriazole type
product was unstable under the acidic conditions, and the low
yield could be owing to the decomposition of 3i. Fortunately,
further evaluation revealed that SnCl4 and TfOH could give
better results for the reaction of azide 1i, and only migration of
the aryl group was observed, affording 3i from the N-
acyliminium ion as the sole product with 87% and 90% yields,
respectively. Further, the structure of oxoindole 3i was
confirmed unambiguously by X-ray diffraction single-crystal
structural analysis. Then SnCl4 was employed as the acid
promoter for this type of substrate. 2-Oxoindoles 3j and 3k
were produced with 81% and 82% yields from the substrates 1j
and 1k, and again the competitive shift of the benzylic methine
carbon was entirely restricted. TfOH was not reliable when it
was employed for the reaction of the δ-azido N-acylbenzo-
triazole 1k, where the desired 3k was isolated in only 46% yield
from the complex reaction mixture. Azides 1l and 1m with a
methyl benzotriazole unit were also converted into the desired
oxoindoles 3l and 3m with SnCl4 in both good yields.
Scheme 4. Schmidt Reaction of 4-Substituted δ-Azido N-
Acylbenzotriazoles 1g and 1h
Finally, a mixture of 1j and 1l was treated with SnCl4 at 60
°C for 6 h in dichloroethane (Scheme 6), and the oxoindoles
3i, 3j, 3l, and 3m were obtained in a combined yield of 67%,
1
where the ratio of the four oxoindoles was determined by H
NMR as about 1:1:1:1. Formation of oxoindoles 3i and 3m
from the cross experiment supported the proposed reaction
process, where the benzotriazole anion was released at the
rearrangement stage and the N-acyliminium ion was
intermolecularly captured by the benzotriazole anion in
termination stage.
The Bt group could be removed from the rearrangement
product, and two experiments were carried out on the
carbamide 2d (Scheme 7). Treatment of 2d with TiCl4 gave
lactam 5d in 56% yield, where an intramolecular Friedel−
Crafts-type acylation occurred. The carbamide 2d could also
be reduced by sodium borohydride, furnishing a formamide 6d
in 81% yield.
1g with SnCl4 (2.0 equiv) at 60 °C in dichloroethane for 3 h
afforded 2g (30%) and 3g (68%) with a higher combined yield
of 98%. It indicated that the migratory aptitudes of the two β-
carbons could be slightly influenced by the acid promoters, as
more 2g was obtained with the SnCl4-promoted reaction when
compared with that of BF3·OEt2-promoted reaction. When the
4-phenyl δ-azido N-acylbenzotriazole 1h was treated with BF3·
OEt2, only the lactam 3h could be observed and isolated in
90% yield from the reaction mixture, indicating that migration
of C-4 significantly increased when the phenyl ring was
attached at the shifting group.
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orcid.org/0000-0002-2812-4019; Email: gupm@
nxu.edu.cn
Scheme 6. Cross Reaction of 1j and 1l
Authors
Chun-Fang Liu − College of Chemistry & Chemical
Engineering, Ningxia Engineering and Research Center for
Natural Medicines, Ningxia University, Yinchuan 750021,
China
Zhi-Qi Cao − College of Chemistry & Chemical Engineering,
Ningxia Engineering and Research Center for Natural
Medicines, Ningxia University, Yinchuan 750021, China
Shao-Lei Ding − College of Chemistry & Chemical
Engineering, Ningxia Engineering and Research Center for
Natural Medicines, Ningxia University, Yinchuan 750021,
China
Jing Zhu − College of Chemistry & Chemical Engineering,
Ningxia Engineering and Research Center for Natural
Medicines, Ningxia University, Yinchuan 750021, China
Scheme 7. Conversion of Carbamide 2d
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00200
Author Contributions
‡C.-F.L. and Z.Q.C. contributed equally.
Notes
The authors declare no competing financial interest.
In summary, the benzotriazole-activated intramolecular
Schmidt reaction of the ω-azido carboxylic acids was designed,
and it proceeded efficiently. Generally, the initial products
from the rearrangement reaction, isocyanate ion, and/or N-
acyliminium ion were produced in the presence of acid
promoter, and then they were rapidly captured by the
benzotriazole anion. Thirteen ω-Azido N-acylbenzotriazoles
were successfully converted into the corresponding carbamides
2 and/or lactams 3 in good to excellent combined yields, and
the ratio of the products reflected the competitive 1,2-
migration of two β-carbons to the nitrogen atom.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No 22061035 and 21662027) and the
Program for Leading Talents of Ningxia Province
(KJT2015002).
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AUTHOR INFORMATION
Corresponding Author
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Peiming Gu − College of Chemistry & Chemical Engineering,
Ningxia Engineering and Research Center for Natural
Medicines, Ningxia University, Yinchuan 750021, China;
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