Intramolecular Schmidt reaction of acyl chlorides with alkyl azides: Preparation of pyrrolizine by intramolecular capture of intermediates with alkenes or alkynes

Article abstract of DOI:10.1039/c4cc07166b

The preparation of substituted pyrrolizines through the Schmidt reaction of acyl chlorides with alkyl azides has been realized. Intramolecular capture of the isocyanate ion and N-acyliminium ion intermediates from the Schmidt process with alkene or alkyne

Full text of DOI:10.1039/c4cc07166b

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: B. Wang, P. Xue
and P. Gu, Chem. Commun., 2014, DOI: 10.1039/C4CC07166B.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

View Article Online
DOI: 10.1039/C4CC07166B
Page 1 of 3
ChemComm
Journal Name
RSCPublishing
COMMUNICATION
Intramolecular Schmidt Reaction of Acyl Chlorides
with Alkyl Azides: Preparation of Pyrrolizine by
Intramolecular Capture of Intermediates with Alkene
or Alkyne
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Bao-Juan Wang, Ping Xue, Peiming Gu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
(Scheme 1). The substrate 1a was prepared from the commercially
available ethyl 5-bromopentanoate 3. Alkylation of 3 with cinnamyl
bromide 4a afforded the ω-bromo ester 5a in 70% yield. Azidation of
the bromide 5a with NaN3 delivered the corresponding ω-azido ester
6a in 82% yield. Then it was successfully saponified with aqueous
LiOH to the desired ω-azido carboxylic acid 1a in 82% yield. The
conversion of 1a to lactam 2a was achieved by treatment of 1a with
Preparation of substituted pyrrolizines through the Schmidt
reaction of acyl chlorides with alkyl azides has been realized.
The intramolecular capture of the isocyanate ion and
N-
acyliminium ion intermediates from the Schmidt process with
alkene or alkyne was achieved, and the efficiency of the
conversion was demonstrated in ring construction and bond
formation.
o
(COCl)2 followed by TfOH at 50 C for 4 h, and the pyrrolizine 2a
was obtained in 46% yield. The lactam 2a had been used as an
advanced intermediate in the total synthesis of pyrrolam A.4 TiCl4 and
SnCl4 had been also examined, but no better results were obtained
with the ω-azido carboxylic acid 1a. The structure of pyrrolizidine 2a
was confirmed unambiguously by X-ray analysis (Figure 1).5
The Schmidt reaction of alkyl azides with electrophiles can provide
the nitrogen-containing heterocycles,1,2 and the conversion has been
extensively applied in the total synthesis of alkaloids. Very recently,
the intramolecular reaction of alkyl azides with acyl chlorides was
reported with our efforts.2a,2b Two different intermediates, isocyanate
ion2a and N-acyliminium ion2b, could be addressed from the designed
ω-azido acyl chlorides (formed in situ from the ω-azido carboxylic
acid with oxalyl chloride). The termination of the rearrangement was
realized by the capture of the isocyanate ion and N-acyliminium ion
with aromatic rings, affording a range of benzo fused lactams. In this
paper, we describe the intramolecular capture of the above two
intermediates with alkenes or alkynes to afford several substituted
pyrrolizines.
Scheme 1. Synthesis of Pyrrolizidine 2.
Br
O
O
N3
O
O
a
b
Br
O
O
R1
R1
R2
R2
5a 70%
5b 39%
5c 78%
6a 82%
6b 92%
6c 88%
R2
3
R1
Br
4a: R1 = C6H5, R2 = H
Pyrrolizidine and its derivatives possess a bicyclic nitrogen-
containing ring system, which generally have potent biological
properties. A range of synthetic methods toward them have been
developed, and the general strategy is to construct one ring by another
one.3 The formation of two rings in one-pot operation is exceedingly
rare. The Schmidt reaction of acyl chlorides with alkyl azides had
demonstrated the efficiency in formation of multiple-ring systems,
however only aromatic rings were used for capture of the
intermediates in the previous research. It was supposed that the alkene
or alkyne in the suitable position of the ω-azido acyl chloride could
also proceed the intramolecular nucleophilic attack upon the
intermediate from the Schmidt reaction, which might provide a
possibility to efficiently address the bicyclic skeleton of the
pyrrolizidine.
4b: R1 = p-Br-C6H4, R2 = H
4c: R1 = Me, R2 = Me
c
O
N3
d or e
HO
O
O
- H+
R2
R1
R1
R2
C
N
N
R1
R2
2a 46%
2b 46%
2c 66%
1a 82%
1b 81%
1c 83%
Reagents and conditions: (a) LDA, then 4, 70% for 5a, 39% for 5b
and 78% for 5c; (b) NaN3, 82% for 6a, 92% for 6b and 88% for 6c;
(c) LiOH, 82% for 1a, 81% for 1b and 83% for 1c; (d) (COCl)2, then
TfOH, 46% for 2a, 46% for 2b;(e) (COCl)2, then SnCl4, then DBU,
66% for 2c.
Initially, this proposal was tested with the ω-azido carboxylic acid
1a through the capture of isocyanate ion intermediate with alkene
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 1

View Article Online
DOI: 10.1039/C4CC07166B
ChemComm
Page 2 of 3
COMMUNICATION
Journal Name
intramolecular nucleophilic capture of the isocyanate ion with alkyne
and the intermolecular addition of chloride ion to the alkenyl cation
might be taken through a concerted process. TfOH had been examined
for this substrate, but complex mixture was obtained, and trace ketone
from hydration of alkyne was observed.
Scheme 2. Preparation of Pyrrolizidines 13a and 13b.
EtO2C
EtO2C
Ph
c
EtO2C
EtO2C
Ph
EtO2C
EtO2C
EtO2C
a
b
Cl
EtO2C
Cl
N3
8
11
10
7
Ph
d
Br
9
Figure 1. X-ray structure of lactam 2.
O
O
N3
HO
O
The analogy ω-azido carboxylic acid 1b with bromo attachment at
the para-position of the phenyl group was also prepared and
successfully converted to lactam 2b in 46% yield (Scheme 1). The
substrate with a methoxy group at the aromatic ring of 1a was
Ph
Ph
Cl
Cl
e
N
N
+
Ph
12
13a
13b
obtained through the above strategy, but the Schmidt reaction failed Reagents and conditions: (a) NaH, 1-chloro-3-iodopropane; (b) NaH,
with TfOH, SnCl4 and TiCl4 (not shown in Scheme 1), and only some 9, 59% for two steps; (c) NaN3, 91%; (d) LiOH, then AcOH, 62%; (e)
insoluble solid was observed with this case. It should be noted that the (COCl)2, then SnCl4, 60% for 13a and 7% for 13b.
insoluble phenomenon was also encountered with the reaction of 2a
and 2b, and the crude mixtures of the above two conversions were
nearly pure by NMR determination, but lactams 1a and 1b were
obtained with only 46% yield. We thought that it might be due to the
polymerization of the aryl alkene. Then a new ω-azido carboxylic acid
1c with the alkene unit substituted with two methyl groups was
prepared and examined (Scheme 1). Treatment of 1c with (COCl)2
followed by SnCl4 could proceed the Schmidt reaction and the
following intermediate capture, though the reaction afforded mixture
of lactams (I, II and 2c, Figure 2). Fortunately, the more stable α,β-
unsaturated lactam 2c was obtained while the mixture was treated with
DBU, and the overall yield (66%) was much better than that of 1a and
1b. TfOH had been used for 1c, but it gave a very complex mixture.
Figure 3. X-ray structure of lactam 13a.
O
O
O
Two chiral ω-azido carboxylic acids 16a and 16b were prepared
and converted to the corresponding pyrrolizidines (Scheme 3).
Alkylation of known azide 1411 with 1-bromopent-2-yne afforded
azide 15a in 57% yield. And it should be noted here that only one
diastereomer could be observed and separated from the conversion.
Then the removal of chiral auxiliary of 15a with H2O2 under the basic
conditions produced the desired chiral carboxylic acid 16a in 56%
yield. Treatment of 16a with (COCl)2 followed by SnCl4 afforded
allene 18a as unseparated mixture of diastereomers (dr ratio, 1:1) in
60% yield. The entire α-H elimination of the alkenyl cation
intermediate was observed in this case. The analogy carboxylic acid
16b was prepared by the similar procedure, and the domino
conversion was also proven to be successful. The allene 18b (from α-
H elimination) was obtained in 47% yield, and it was accompanied
with chloride 17b (11%, from addition of chloride ion).
Me
Cl
Me
Me
Me
N
N
N
Me
I
II
2c
Figure 2. Primary products of Schmidt reaction of 1c.
To our delight, the above reaction, featured by the capture of
isocyanate ion intermediate with alkene, was fortunately realized. The
process was very challenging due to the following potential reactions:
(1) the intramolecular reaction of the azido group with the alkene (the
Schmidt reaction of alkene),6 (2) the Friedel–Crafts addition of acyl
chloride to alkene.7 For the latter competitive reaction, formation of
enone would take place, and the enone was reported to be more
difficult to proceed the Schmidt reaction with the alkyl azide.8
Scheme 3. Preparation of Pyrrolizidines 17 and 18.
After the successful capture of isocyanate ion with alkene was
achieved, the alkyne analogy was prepared to see if the Click
chemistry9 could be avoided and the similar conversion could be
addressed (Scheme 2). Alkylation of diethyl malonate 7 with 1-
chloro-3-iodopropane afforded chloride 8, which was further treated
with bromide 9 to give chloride 10 in 59% yield for two steps.
Azidation of 10 with NaN3 afforded azide 11 in 91% yield.
Decarboxylation of 11 with LiOH followed by AcOH produced the
ω-azido carboxylic acid 12 in 62% yield. The SnCl4 promoted
rearrangement of the ω-azido acyl chloride formed from 12 in situ
gave two lactams 13a (60% yield) and 13b (7% yield). These two
diastereomers could be separated by careful column chromatography.
The E-configuration of the C-C double bond in the major lactam 13a
was confirmed by X-ray analysis (Figure 3).10 It indicated that the
O
N3
a
O
R
O
N3
O
N3
HO
O
N
O
b
N
O
14
15a R = Me 57%
15b R = H 58%
16a R = Me 56%
16b R = H 51%
Ph
Ph
R
c
O
H
O
O
H
H
R
ii
R
R
N
H
N
H
N
+
C
Cl
i
Cl-
H
18a R = Me 60%
18b R = H 47%
17a R = Me 0%
17b R = H 11%
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C4CC07166B
Page 3 of 3
Journal Name
ChemComm
COMMUNICATION
Reagents and conditions: (a) NaHMDS, 1-bromopent-2-yne, 57%
for 15a; NaHMDS, 1-bromobut-2-yne, 58% for 15b; (b) H2O2, LiOH,
56% for 16a; H2O2, LiOH, 51% for 16b; (c) (COCl)2, then SnCl4, 60%
for 18a; (COCl)2, then SnCl4, 11% for 17b and 47% for 18b.
1
2
For two recently selected reviews, see: (a) A. Wrobleski, T. C. Coombs,
C. W. Huh, S.-W. Li, J. Aubé, Org. React. 2012, 78, 1-320. (b) J.
Aubé, In Organic Azides: Synthesis and Applications; S. Bräse, K.
Banert, Eds.; Wiley: Weinheim, 2009; pp 191-237.
The exploration of N-acyliminium ion intermediate from the
Schmidt reaction of acyl chloride with alkyl azide was outlined in
Scheme 4, which was designed to be captured by an alkyne. Treatment
of diethyl malonate 7 with NaH followed by 3-bromopropionitrile
yielded nitrile 19 in 70% yield. Further alkylation of 19 with 1-
bromobut-2-yne produced the alkyne 20, which was further
For the Schmidt reaction of acyl chlorides, see: a) P. Gu, X.-Y. Kang,
J. Sun, B.-J. Wang, M. Yi, X.-Q. Li, P. Xue, R. Li, Org. Lett. 2012,
14, 5796-5799. b) X.-J. Li, J.-B. Qiao, J. Sun, X.-Q. Li, P. Gu, Org.
Lett. 2014, 16, 2865-2867. For other research on the Schmidt reaction
in our group, see: (c) P. Gu, J. Sun, X.-Y. Kang, M. Yi, X.-Q. Li, P.
Xue, R. Li, Org. Lett. 2013, 15, 1124-1127. (d) M. Yi, P. Gu, X.-Y.
Kang, J. Sun, R. Li, X.-Q. Li, Tetrahedron Lett. 2014, 55, 105–107.
Reviews on the preparation of pyrrolizines, see: (a) D. Robins, J. Nat.
Prod. Rep. 1995, 12, 413-418 and references therein. (b) W. M. Dai,
Y. Nagao, Heterocycles 1990, 30, 1231-1261.
o
decarboxylated with LiCl at 140 C to afford ester 21. Reduction of
21 to alcohol 22 was realized in the presence of KBH4 and LiCl, and
the yield was 82%. The azide 23 was obtained from 22 in 99% yield
through tosylation and azidation. The cyano group of 23 was
hydrolyzed in the aqueous NaOH in 83% yield. Treatment of the ω-
azido carboxylic acid 24 with (COCl)2 followed by SnCl4 furnished
lactam 25 in 35% yield. The intermolecular attack of the resulting
alkenyl cation with the chloride ion was found, and the competitive
elimination process was excluded.
3
4
5
6
Y. Aoyagi, T. Manabe, A. Ohta, T. Kurihara, G.-L. Pang, T. Yuhara,
Tetrahedron 1996, 52, 869–876.
Scheme 4. Preparation of Pyrrolizidine 25.
The crystal structures of lactam 2a has been deposited at the
Cambridge Crystallographic Data Centre (CCDC 1021200).
Schmidt reaction of alkene with alkyl azide, see: (a) W. H. Pearson, R.
Walavalkar, J. M. Schkeryantz, W.-K. Fang, J. D. Blickensdorf, J.
Am. Chem. Soc. 1993, 115, 10183–10194. (b) W. H. Pearson, D. A.
Hutta, W.-K. Fang, J. Org. Chem. 2000, 65, 8326–8332.
CO2Et
EtO2C
CO2Et
CN
EtO2C
CO2Et
CN
EtO2C
a
b
c
EtO2C
CN
CN
20
21
7
19
7
8
Acylation of alkenes, see: J. K. Groves, Chem. Soc. Rev. 1972, 1, 73-
d
97.
N3
HO
O
N3
HO
O
Reaction of enone with alkyl azide, see: (a) A. G. Schultz, R.
Ravichandran, J. Org. Chem. 1980, 45, 5008–5009. (b) A. G. Schultz,
W. G. McMahon, J. Org. Chem. 1984, 49, 1676–1678. (c) C. K. Sha,
S. L. Ouyang, D. Y. Hsieh, T. H. Hseu, J. Chem. Soc., Chem.
Commun. 1984, 492–494. (d) C. K. Sha, J. J. Yuang, S. L. Ouyang,
Heterocycles 1984, 566. (e) C. K. Sha, S. L. Ouyang, D. Y. Hsieh, R.
C. Chang, S. C. Chang, J. Org. Chem. 1986, 51, 1490–1494. (f) A. G.
CN
g
f
e
N
Cl
23
25
22
24
Reagents and conditions: (a) NaH, 3-bromopropionitrile, 70%; (b)
NaH, 1-bromobut-2-yne, 90%; (c) LiCl, 140 oC, 66%; (d) KBH4, LiCl,
82%; (e) TsCl, then NaN3, 99%; (f) 15% NaOH, 83%; (g) (COCl)2,
then SnCl4, 35%.
Schultz, Adv. Cycloaddit. 1988,
1, 53. (g) G. A. Molander, M.
Hiersemann, Tetrahedron Lett. 1997, 38, 4347–4350. (h) G. A.
Molander, T. B. Christopher, Tetrahedron Lett. 2002, 43, 5385–5388.
Conclusions
(i) D. S. Reddy, W. R. Judd, J. Aube, Org. Lett. 2003, 5, 3899–3902.
(j) J. M. Mahoney, C. R. Smith, J. N. Johnston, J. Am. Chem. Soc.
2005, 127, 1354–1355. (k) Y.-M. Zhao, P. Gu, Y.-Q. Tu, H.-J. Zhang,
Q.-W. Zhang, C.-A. Fan, J. Org. Chem. 2010, 75, 5289–5295.
Selected reviews on the click chemistry, see: (a) M. Meldal, C.W.
Tornøe, Chem. Rev. 2008, 108, 2952-3015. (b) J. E. Moses, A. D.
Moorhouse, Chem. Soc. Rev. 2007, 36, 1249-1262. (c) J.-F. Lutz,
Angew. Chem. Int. Ed. Engl. 2007, 46, 1018-1025. (d) M. V. Gil, M.
J. Arévalo, Ó. López, Synthesis 2007, 1589-1620. (e) V.D. Bock, H.
Hiemstra, J.H. van Maarseveen, Eur. J. Org. Chem. 2006, 51-68.
In summary, the intramolecular capture of both the intermediates
from the Schmidt reaction of acyl chloride with alkyl azide,
isocyanate ion and N-acyliminium ion, has been successfully achieved.
The one-pot conversion combining the chloridization, the Schmidt
reaction, and the intramolecular capture of intermediates with alkene
or alkyne demonstrated a very useful methodology toward the
preparation of substituted pyrrolizines. These results would strongly
encourage us to apply this strategy to the synthesis of some suitable
natural alkaloids.
9
This work was supported by the National Natural Science
Foundation of China (No. 21262024), the Program for New Century 10 The crystal structures of lactam 13a has been deposited at the
Excellent Talents in University (NCET-13-0874), and the Scientific
Research Foundation for Returned Scholars (Ministry of Education of
China).
Cambridge Crystallographic Data Centre (CCDC 1021204).
11 15, known compound, see: M. Nahrwold, C. Weiß, T. Bogner, F.
Mertink, J. Conradi, B. Sammet, R. Palmisano, S. R. Gracia, T.
Preuße, N. Sewald, J. Med. Chem. 2013, 56, 1853-1864.
Notes and references
Key Laboratory of Energy Sources & Engineering, State Key Laboratory
Cultivation Base of Natural Gas Conversion and Department of Chemistry,
Ningxia University, Yinchuan 750021, China. E-mail: gupm@nxu.edu.cn.
†
Electronic Supplementary Information (ESI) available: [Experimental
procedures and spectroscopic data and copies of NMR spectra for all new
compounds]. See DOI: 10.1039/c000000x/
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3