Intramolecular Schmidt reaction of acyl chlorides with alkyl azides: Rapid access to fused polycyclic nitrogen-containing heterocycles via a multistep one-pot transformation

Article abstract of DOI:10.1021/ol302890a

The first intramolecular Schmidt reaction of acyl chlorides with alkyl azides has been developed. In this one-pot conversion, an ω-azido hydrocinnamic acid is converted to a tricyclic lactam. The most important feature of the process is the efficiency in bond formation (one bond broken and three new bonds created) and ring construction (two new rings formed).

Full text of DOI:10.1021/ol302890a

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5796–5799
Intramolecular Schmidt Reaction of Acyl
Chlorides with Alkyl Azides: Rapid Access
to Fused Polycyclic Nitrogen-Containing
Heterocycles via a Multistep One-Pot
Transformation
Peiming Gu,* Xiao-Yan Kang, Jian Sun, Bao-Juan Wang, Ming Yi, Xue-Qiang Li,
Ping Xue, and Rui Li
Key Laboratory of Energy Sources & Engineering, State Key Laboratory Cultivation
Base of Natural Gas Conversion and Department of Chemistry, Ningxia University,
Yinchuan 750021, China
gupm@nxu.edu.cn
Received October 19, 2012
ABSTRACT
The first intramolecular Schmidt reaction of acyl chlorides with alkyl azides has been developed. In this one-pot conversion, an ω-azido
hydrocinnamic acid is converted to a tricyclic lactam. The most important feature of the process is the efficiency in bond formation (one bond
broken and three new bonds created) and ring construction (two new rings formed).
The Schmidt reaction of carboxylic acids with hydrazoic
acid (HN3) in the presence of acid catalysts was reported to
afford amines,1 which were one-carbon shorter homo-
Scheme 1. Schmidt Reaction of Carboxylic Acid with HN3
logues of the substrates (Scheme 1). The replacement of
HN3 with an alkyl azide for the analogous conversion of
2
3
ꢀ
ketones or carbocations was realized by Aube and by
Pearson in the early 1990s. Since then, the intramolecular
Schmidt reaction has proven to be a powerful strategy for
the synthesis of natural and non-natural products.4 How-
ever no successful conversion of carboxylic acids or their
derivatives with alkyl azides has been reported. In this
paper, we describe the first efficient intramolecular reac-
tion of alkyl azides with acyl chlorides to give fused
polycyclic nitrogen-containing heterocycles.
The isocyanate intermediate in the classical Schmidt
reaction of carboxylic acid with HN3 was hydrolyzed by
water, with subsequent release of carbon dioxide. We
envisioned that an isocyanate ion would be formed if the
alkylazideswere reactedwitha carboxylicacid(Scheme2).
To increase the atom efficiency of this conversion, the
intramolecular capture of the promised intermediate was
(1) For selected reviews on the Schmidt reaction of carboxylic acids
with HN3, see: (a) Wolff, H. Org. React. 1946, 3, 307–336. (b)
Koldobskii, G. I.; Ostrovskii, V. A.; Gidaspov, B. V. Russ. Chem. Rev.
1978, 47, 1084–1094. (c) Shioiri, T. Comp. Org. Synth. 1991, 6, 795–828.
(d) Wrobleski, A.; Coombs, T. C.; Huh, C. W.; Li, S.-W.; Aube, J. Org.
React. 2012, 78, 1–320.
ꢀ
ꢀ
(2) (a) Aube, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965–
ꢀ
8966. (b) Milligan, G. L.; Mossman, C. J.; Aube, J. J. Am. Chem. Soc.
1995, 117, 10449–10459.
(3) (a) Pearson, W. H.; Schkeryantz, J. M. Tetrahedron Lett. 1992, 33,
5291–5294. (b) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.;
Fang, W.; Blickensdorf, J. D. J. Am. Chem. Soc. 1993, 115, 10183–
10194.
ꢀ
(4) For a selected review, see: Aube, J. In Organic Azides: Synthesis
and Applications; Brase, S., Banert, K., Eds.; Wiley: Weinheim, 2009;
pp 191ꢀ237.
r
10.1021/ol302890a
Published on Web 10/26/2012
2012 American Chemical Society

designed. The azido carboxylic acid or its derivative 1 was
selected for this attempt. The process would be initiated by
the intramolecular nucleophilic attack of the azido group
upon the carbonyl group of acid or its derivative, which
would result in forming the aminodiazonium ion inter-
mediate I under acidic conditions. The 1,2-migration of the
CꢀC bond attaching to the carbonyl group to the nitrogen
atom would give the isocyanate ion II, which would be
captured by the aromatic ring5 to afford lactam 2. The
aromatic ring was selected for nucleophilic addition due to
the potential synthetic application of the product, which is
a prominent substructure in many alkaloids.
Table 1. Intramolecular Reaction of Alkyl Azides with Acyl
Chloridesa
Scheme 2. Design of Intramolecular Schmidt Reaction of Car-
boxylic Acid Derivatives with Alkyl Azides
To test our proposal, the azido acid 1a was prepared by
hydrolysis of the corresponding ester.6 Treatment of 1a
with SnCl4 (4.0 equiv) for 17 h in refluxing DCM failed to
give any of the desired lactam2a. To ourdelight, activation
ofthe azido acid with(COCl)2 (3.5 equiv) inthe presenceof
a catalytic amount of DMF followed by the addition of
SnCl4 gave the lactam 2a in 85% yield (entry 1, Table 1).7
We reasoned that the acyl chloride formed in situ was more
reactive than the carboxylic acid 1a during the nuclephilic
attack of the azido group.
a Treatment of azido acid 1 with (COCl)2 in the presence or absence
of DMF in DCM for 1 h at room temperature followed by SnCl4
(4 equiv) in refluxing DCM for the time mentioned in the table. b Isolated
yield. c Refluxing period of the reaction.
the corresponding lactams. The structures of 2b and 2j
were confirmed by X-ray crystallographic analysis.
Noteworthy features of the conversion include the fol-
lowing: (1) elegant efficiency of the process has been
demonstrated in bond formation (three new bonds
created) and ring construction (two new rings); (2) the
reaction proceeds through a three-step sequence, acyl-
chlorination of the carboxylic acid, Schmidt rearrange-
ment of the acyl chloride with the alkyl azide, and electro-
philic addition of the isocyanate ion to the aromatic ring;
(3) the overall yields of this conversion are good, even for
the preparation of lactam 2k, with the average yield of the
three steps being 74% from the overall 40% yield (entry 11);
(4) the steric effect of ortho substituents is minimal (entries
8 and 9); (5) electron-withdrawing or -donating groups on
the aromatic ring exhibit comparable reactivity in the
preparation of benzoindolizidine units (entries 1ꢀ10); (6)
an electron-withdrawing group gives a better result in the
synthesis of benzoquinuolizidine units (entries 11 and 12);
(7) the meta-substituted aromatic rings result in lactams in
the mixture of regioisomers (entries 6, 7) while the
2-naphthyl analogue affords only one lactam, 2j (entry 10).
The azido aromatic ketones 5f and 5f0 (Scheme 3) were
separated as minor products from the reaction mixture, from
the competitive intramolecular FriedelꢀCrafts acylation
After the successful conversion of 1a to the lactam 2a, a
series of azido acids 1bꢀ1l were all smoothly converted to
(5) Previous conversion of 4-phenylbutyric acid with HN3 in the
presence of sulfinic acid afforded cyclic amide, which was different in
form from the products in this paper; see: Datta, S. K.; Grundmann, C.;
Bhattacharyya, N. K. J. Chem. Soc. (C) 1970, 2058.
ꢀ
(6) Lee, H.-L.; Aube, J. Tetrahedron 2007, 63, 9007–9015.
(7) Known compound; for selected papers, see: (a) Newcomb, M.;
Esker, J. L. Tetrahedron Lett. 1991, 32, 1035–1038. (b) Esker, J. L.;
Newcomb, M. J. Org. Chem. 1993, 58, 4933–4940. (c) Orito, K.;
Miyazawa, M.; Nakamura, T.; Horibata, A.; Ushito, H.; Nagasaki,
H; Yuguchi, M.; Yamashita, S.; Yamazaki, T.; Tokuda, M. J. Org.
Chem. 2006, 71, 5951–5958. (d) Bertrand, M. B.; Neukom, J. D.; Wolfe,
J. P. J. Org. Chem. 2008, 73, 8851–8860. (e) Brenzovich, W. E., Jr.;
Benitez, D.; Lackner, A. D.; Shunatona, H. P.; Tkatchouk, E.;
Goddard, W. A., III; Toste, F. D. Angew. Chem., Int. Ed. 2010, 49,
5519–5522. (f) Mai, D. N.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132,
12157–12159.
Org. Lett., Vol. 14, No. 22, 2012
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from the Schmidt reaction of the acyl chlorides with the
alkyl azides.
Scheme 3. A Possible Process of Acyl-Chlorination/Friedelꢀ
Crafts Acylation/Schmidt Reaction to Address Lactam from
Azido Acid
Scheme 4. Attempt to Convert the Azido Aromatic Ketones to
Lactams
by the acyl chloride of the aromatic ring. These ketones
raised the possibility that the lactams 2 are the product of
a domino process of intramolecular FriedelꢀCrafts acy-
lation/intramolecular Schmidt reaction.8 However, azido
aromatic ketones had been proven to be less reactive than
their analogue of azido aliphic ketones.2b The aromatic
ketone 5f was therefore submitted to the reaction condi-
tions but failed to give the lactam 2f (Scheme 4). Further-
more, we had prepared the azido ketones 5a and 5c (see
Supporting Information for details), which were possible
intermediates toward the lactams 2a and 2c by the
competing mechanism. Treatment of 5a with SnCl4 in
the presence or absence of (COCl)2 with a catalytic
amount of DMF for 4 h gave only a trace of lactam 2c.
The ketone 5c was exposed to the reaction conditions for
an even longer time (17 vs 4 h) and still failed to give the
lactam 2c in reasonable yield. It should be noted that the
two competing processes (Schemes 2 and 3) are both
initiated from the acyl chloride. Once the acyl chloride
was formed, the competition between the intramolecular
nucleophilic attack of the azide upon the acyl chloride
(the first process) with FriedelꢀCrafts acylation (the
second process) would take place. If FriedelꢀCrafts
acylation were faster, the aromatic ketone would be
formed and should have survived, as the Schmidt reaction
of the aromatic ketone is clearly not favored. We con-
clude that the polycyclic lactams were mainly delivered
The successful conversion of azido acyl chlorides offers a
reliable method to address benzo fused lactams, which are
difficult to obtain from the Schmidt reaction of aromatic
ketones. It should be noted that the lactams in Table 1
represented benzoindolizidine and benzoquinuolizidine
units, which widely exist in phenanthropiperidine alka-
loids9 and Amaryllidaceae alkaloids.10
In conclusion, we have established a practical procedure
for the construction of fused polycyclic nitrogen-contain-
ing heterocycles. The three-step combination of acyl chlo-
rination, Schmidt reaction of the acyl chloride, and elec-
trophilic addition of the isocyanate ion onto the aromatic
ring in one pot gives the polycyclic lactams in good yield.
The most important feature of the process is the efficiency
in bond formation and ring construction. The competitive
mechanism of the conversion through a domino process of
intramolecular FriedelꢀCrafts acylation/intramolecular
Schmidt reaction was excluded by further experiments.
Currently, extensive applications of this methodology in
the total synthesis of natural products are underway in our
laboratory.
Acknowledgment. This work was supported by the The
National Natural Science Foundation of China (No.
21262024), the Key Project of Chinese Ministry of Educa-
tion (211193), the 100 Talents Program of Ningxia, the
Natural Science Foundation of Ningxia (NZ1043 and
NZ1165), the National Basic Research Program 973 of
China (No. 2010CB534916), and the “211” Project in
(8) For domino processes involving an intramolecular Schmidt reac-
ꢀ
tion of ketones, see: (a) Golden, J. E.; Aube, J. Angew. Chem., Int. Ed.
ꢀ
2002, 41, 4316–4318. (b) Zeng, Y.; Reddy, D. S.; Hirt, E.; Aube, J. Org.
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Lett. 2004, 6, 4993–4995. (c) Zeng, Y.; Aube, J. J. Am. Chem. Soc. 2005,
127, 15712–15713. (d) Gu, P.; Zhao, Y.-M.; Tu, Y. Q.; Ma, Y.; Zhang, F.
Org. Lett. 2006, 8, 5271–5273. (e) Frankowski, K. J.; Golden, J. E.; Zeng,
Y.; Lei, Y.; Aube, J. J. Am. Chem. Soc. 2008, 130, 6018–6024. (f) Zhao,
Y.-M.; Gu, P.; Tu, Y.-Q.; Fan, C.-A.; Zhang, Q. Org. Lett. 2008, 10,
1763–1766. (g) Huh, C. W.; Somal, G. K.; Katz, C. E.; Pei, H.; Zeng, Y.;
(9) Reviews: (a) Li, Z.; Jin, Z.; Huang, R. Synthesis 2001, 16, 2365–
2378. (b) Gellert, E. J. Nat. Prod. 1982, 45, 50–73. (c) Bick, I. R. C.;
Sinchai, W. The Alkaloids 1982, 19, 193–220. (d) Govindachari, T. R.;
Viswanathan, N. Heterocycles 1978, 11, 587–613.
(10) For reviews on Amaryllidaceae alkaloids, see: (a) Jin, Z. Nat.
Prod. Rep. 2009, 26, 363–381 and previous reviews in this series. (b)
Hoshino, O. The Alkaloids 1998, 51, 323–424. (c) Martin, S. F. The
Alkaloids 1988, 30, 251–376.
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Douglas, J. T.; Aube, J. J. Org. Chem. 2009, 74, 7618–7626. (h) Meyer,
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A. M.; Katz, C. E.; Li, S.-W.; Velde, D. V.; Aube, J. Org. Lett. 2010, 12,
1244–1247. (i) Chen, Z.-H.; Tu, Y.-Q.; Zhang, S.-Y.; Zhang, F.-M. Org.
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Lett. 2011, 13, 724–727. (j) Huh, C. W.; Schroeder, C.; Singh, G.; Aube,
J. J. Org. Chem. 2011, 76, 3160–3165.
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Org. Lett., Vol. 14, No. 22, 2012

Ningxia University (ndzr09-1), and we gratefully thank
Prof. Douglass F. Taber at the University of Delaware for
the modification of our manuscript.
spectra for all new compounds and X-ray crystallo-
graphic data for compounds 2b and 2j. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data and copies of NMR
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5799