Intramolecular schmidt reaction of Acyl chlorides with alkyl azides: Capture of N-acyliminium ion intermediates with aromatic rings

Article abstract of DOI:10.1021/ol501058a

Intramolecular Schmidt reaction of acyl chlorides with alkyl azides through N-acyliminium ion intermediates is designed and realized. The intramolecular capture of the intermediates with aromatic rings affords several nitrogen-containing tricyclic skeleto

Full text of DOI:10.1021/ol501058a

Letter
pubs.acs.org/OrgLett
Intramolecular Schmidt Reaction of Acyl Chlorides with Alkyl Azides:
Capture of N‑Acyliminium Ion Intermediates with Aromatic rings
Xiao-Jing Li, Jin-Bao Qiao, Jian Sun, Xue-Qiang Li, and Peiming Gu*
Key Laboratory of Energy Sources & Engineering, State Key Laboratory Cultivation Base of Natural Gas Conversion and Department
of Chemistry, Ningxia University, Yinchuan 750021, China
S
* Supporting Information
ABSTRACT: Intramolecular Schmidt reaction of acyl chlor-
ides with alkyl azides through N-acyliminium ion intermediates
is designed and realized. The intramolecular capture of the
intermediates with aromatic rings affords several nitrogen-
containing tricyclic skeletons. The important feature of the
domino process is the efficiency in bond reorganization and
ring formation.
Scheme 2. Schmidt Reaction of Acyl Chloride through
Isocyanate Ion Intermediate
he Schmidt reaction of electrophiles with hydrazoic acid
(HN3) was extensively explored in early studies. In the
1
T
1990s, the replacement of HN3 with alkyl azides was proven
very successful in the Schmidt reaction of aldehydes,2−4
ketones5 and carbocations.6 Inspired by the strategy, an
intramolecular Schmidt reaction of ω-azido acyl chlorides
(formed from ω- azido carboxylic acids with oxalyl chloride)
through isocyanate ion intermediates was reported with our
effort (Scheme 1).7 In this paper, we present a new type of
intramolecular Schmidt reaction of the designed ω-azido acyl
chlorides featured with N-acyliminium ion intermediates.
In the previous paper, 1,2-migration of the methine carbon
next to the carbonyl group of the aminodiazonium ion
intermediate I (Scheme 2) resulted in an isocyanate ion
Scheme 1. Schmidt Reaction of Carboxylic Acids or Acyl
Chlorides
intermediate with loss of nitrogen gas, which was captured by
an aromatic ring to afford the benzo fused lactam. But if the 1,2-
migration of the methylene carbon on the right took place, the
N-acyliminium ion intermediate would be produced.
The migration aptitude of the substituted carbon increased
with the size of the substituent, which was observed in the
reaction of ketones with hydroxyalkyl azides.8 Thus, if the N-
acyliminium ion intermediate was desired, the sensitive
approach would be to increase the tendency of migration of
bond b and limit the migration of bond a in the aminodiazonium
ion intermediate I. We envisioned that if the benzyl group
(Scheme 2) was transferred from the left carbon to the right
carbon, then the substrate would be a new ω-azido acyl
chloride (Scheme 3). Migration of the methine group would be
preferred over the methylene group; as a result, formation of
the N-acyliminium ion III would take place, and meanwhile, the
competitive generation of isocyanate ion intermediate would be
strongly limited. Another advantage of this strategy is that the
Received: April 11, 2014
Published: May 13, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 3. Designed Schmidt Reaction of Acyl Chloride
through N-Acyliminium Ion Intermediate
Table 1. Intramolecular Reaction of Alkyl Azides with Acyl
Chlorides
a
benzyl group would be in the suitable position, which would
offer an aromatic ring for the subsequent intramolecular
capture of the N-acyliminium ion.
To test our proposal, the ω-azido carboxylic acid 1a was
prepared. Several acids were examined as the promoters, but no
desired lactam 2a was afforded. The poor reactivity of the
Schmidt reaction of carboxylic acid with alkyl azide was
demonstrated convincingly as before.7 Treatment of the azido
carboxylic acid 1a with (COCl)2 followed by the addition of
SnCl4 succeeded in formation of the lactam 2a9 in 75% yield
(Table 1, entry 1). The lactam could also be delivered in 67%
yield by exposure of the azido carboxylic acid 1a with (COCl)2
followed by TiCl4.
To our delight, the successful conversion of carboxylic acid
1a to lactam 2a indicated the reaction proceeded with the
following three stages: (1) the in situ generation of the ω-azido
acyl chloride was achieved by treatment of carboxylic acid with
oxalyl chloride; (2) the attack of the azido group upon the
carbonyl group of acyl chloride initiated the rearrangement of
the aminodiazonium ion intermediate, resulting in N-
acyliminium ion III; and (3) the intramolecular Pictet−
Spengler cylization10 of the N-acyliminium ion with the
aromatic ring spontaneously furnished the fused polycyclic
oxobenzoindolizidine. The wonderful efficiency of the con-
version was embodied in the combination of acyl chlorination,
Schmidt reaction of the acyl chloride, and Pictet−Spengler
cyclization. During the process, two new rings were
constructed, one bond was broken, and three new bonds
were formed.
a
Treatment of azido acid 1 with (COCl)2 in DCM for 1 h at room
We then explored the scope of azido carboxylic acids, and a
series of ω-azido carboxylic acids 1b−j were submitted to the
acidic conditions. Not surprisingly, all of them were converted
to the desired lactams. Introduction of methoxyl group on the
aromatic ring slightly decreased the yield in the presence of
SnCl4 (Table 1, entry 3). But if TfOH was applied, the yield of
lactam 2b was increased to 68% (Table 1, entry 4). The methyl
group had similar effects on the conversion with that of
methoxyl group (Table 1, entries 5 and 6). The electron-
withdrawing groups on the aromatic ring exhibited good
flexibility for this conversion (Table 1, entries 7−9). Only one
lactam 2f was obtained from the reaction of the 2-naphthyl
analogue azide 1f, which indicated the cyclization took place at
the more reactive α-position of naphthyl ring (Table 1, entries
10 and 11). When the meta-substituted aromatic rings were
used, mixtures of regioisomers were obtained from the Pictet−
temperature followed by acid promoter (4 equiv) in refluxing DCM
for the time mentioned in the table. Isolated yield. Refluxing period
of the reaction.
b
c
Spengler cyclization. SnCl4, TiCl4, and TfOH were examined
for the azides 1g and 1h. The first two promoters ensured the
efficiency of the conversion of azides 1g and 1h but with poor
regioselectivities, while TfOH gave the corresponding lactams
in slightly better regioselectivities with poor yields (Table 1,
entries 12−17). The SnCl4-promoted reaction of the azido acid
1i afforded benzoquinolizidine 2i in 34% yield, whereas the
TiCl4 conditions gave lactam in 57% yield (Table 1, entries 18
and 19).
The benzopyrroloazepine 2j was obtained in 71% yield when
the ω-azido carboxylic acid 1j was allowed to react with SnCl4
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Letter
(Table 1, entry 20). Finally, the structure of lactam 2j was
confirmed unambiguously by X-ray crystallographic analysis
(Figure 1).
REFERENCES
■
(1) For two recently selected reviews on Schmidt reaction of
carboxylic acids with HN3, see: (a) Wrobleski, A.; Coombs, T. C.;
́ ́
Huh, C. W.; Li, S.-W.; Aube, J. Org. React. 2012, 78, 1−320. (b) Aube,
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Eds.; Wiley: Weinheim, 2010; pp 191−237.
(2) For the Schmidt reaction of aldehydes with alkyl azides, see:
(a) Lee, H.-L.; Aube,
(b) Milligan, G. L.; Mossman, C. J.; Aube,
1995, 117, 10449−10459.
(3) For the modified intermolecular Schmidt reaction of aldehydes
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Chem. Soc. 1955, 77, 951−954.
(4) For the modified intermolecular Schmidt reaction of aldehydes
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X.-Y.; Yi, M.; Li, X.-Q.; Xue, P.; Li, R. Org. Lett. 2013, 15, 1124−1127.
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Figure 1. X-ray structure of lactam 2j.
(6) For the Schmidt reaction of carbocations with alkyl azides, see:
(a) Pearson, W. H.; Schkeryantz, J. M. Tetrahedron Lett. 1992, 33,
5291−5294. (b) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.;
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10194. (c) Reddy, P. G.; Varghese, B.; Baskaran, S. Org. Lett. 2003, 5,
583−585.
The above experiments suggested the formation of N-
acyliminium ions in the process, which were derived from the
aminodiazonium ion species. Given the wide application of N-
acyliminium ion in construction of carbon−carbon and
carbon−heteroatom bonds,11 the Schmidt reaction of acyl
chlorides with alkyl azides through N-acyliminium ion
intermediates would be of high potential importance in
synthetic chemistry.
In conclusion, we have designed and realized the Schmidt
reaction of acyl chlorides with alkyl azides through N-
acyliminium ion intermediates. An efficient one-pot, three-
step protocol combining acyl chlorination, intramolecular
Schmidt reaction of the acyl chloride, and Pictet−Spengler
cyclization of the N-acyliminium ion intermediate are achieved
to afford several different types of nitrogen-containing tricyclic
skeletons in good yield.
(7) Gu, P.; Kang, X.-Y.; Sun, J.; Wang, B.-J.; Yi, M.; Li, X.-Q.; Xue, P.;
Li, R. Org. Lett. 2012, 14, 5796−5799.
(8) Smith, B. T.; Gracias, V.; Aube,
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G. H. Synlett 1999, 441−443.
(10) For a selected review on the Pictet−Spengler reaction, see: Cox,
E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797−1842.
(11) For a selected review on the cyclizations of N-acyliminium ions,
see: Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431−1628.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data and copies of
NMR spectra for all new compounds and X-ray crystallographic
data for compound 2j. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gupm@nxu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21262024), the Program for New
Century Excellent Talents in University (NCET-13-0874), and
the Scientific Research Foundation for Returned Scholars
(Ministry of Education of China). We thank Mr. Yong-Liang
Shao at Lanzhou University for X-ray analysis.
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