A new synthetic methodology for the pyrrolidine ring

Article abstract of DOI:10.1055/s-0029-1219547

An unprecedented synthesis of pyrrolidine rings has been accomplished by the reaction of azidoacetyl derivatives with maleate and fumarate esters. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219547

LETTER
931
A New Synthetic Methodology for the Pyrrolidine Ring
S
ynthetic Methodo
a
logy for th
l
e
Pyrro
i
lidine
R
l
ing a Belei,a Elena Bicu,a Peter G. Jones,b M. Lucian Birsa*a
a
Department of Organic Chemistry, ‘Al. I. Cuza’ University of Iasi, 11 Carol I, 700506 Iasi, Romania
Fax +40(232)201313; E-mail: lbirsa@uaic.ro
Institute of Inorganic and Analytical Chemistry, Technical University of Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
b
Received 7 December 2009
thesis.17,18 The reaction of 10-(azidoacetyl)-10H-
phenothiazine (1a, Scheme 1) with an equimolecular
amount of dimethyl maleate in boiling toluene provided a
mixture of two compounds that were separated by column
chromatography (silica gel, EtOAc–hexane = 1:1). The
minor compound (14% isolated yield) was easily identi-
fied as enamine derivative 3a by mass spectrometry and
NMR analysis.19 The Z-stereochemistry around the dou-
ble bond was indicated by the chemical shift of the amine
hydrogen (d = 8.47 ppm), implying an intramolecular hy-
drogen bond with the oxygen atom of the ester group. The
structure of the major compound (45% isolated yield) 2a
was unambiguously proved by X-ray analysis
(Figure 1).20 This is consistent with the NMR spectrum,
which unexpectedly indicated four different methyl ester
groups.21 In view of the above results we performed the
same reaction using two equivalents of methyl maleate.
Regardless of the azide/maleate ratio, the reaction output
Abstract: An unprecedented synthesis of pyrrolidine rings has
been accomplished by the reaction of azidoacetyl derivatives with
maleate and fumarate esters.
Key words: azides, enamines, pyrrolidine, phenothiazine
Phenothiazines, which are inexpensive and widely avail-
able, belong to an important class of tricyclic nitrogen–
sulfur heterocycles; they possess a broad spectrum of
pharmacological activities including psychotropic, immu-
nopotentiating, antimicrobial, antifungal, antiprolifera-
tive, and antitumor activities, and stimulation of the
penetration of anticancer agents through the blood–brain
barrier.1–9 One important modification of the parent phe-
nothiazine structure is the introduction of a substituent at
the thiazine nitrogen atom. This includes the azide moiety,
a grouping that leads to energy-rich and flexible interme-
diates and has enjoyed considerable interest since its dis-
covery in 1864.10–13 In spite of their explosive properties,
organic azides are valuable intermediates in organic syn-
thesis.14 Thus they are used in the synthesis of anilines and
N-alkyl-substituted anilines,15 as precursors for nitrenes
and as dipoles in cycloadditions.16
Following our interest in the synthesis of new phenothia-
zine derivatives with various substituents in search of
better medicinal agents, we have investigated the cycload-
dition reactions of 10-(azidoacetyl)-10H-phenothiazine
with various olefinic dipolarophiles. We wish to report
here an unprecedented interaction of azidoacetyl deriva-
tives 1 as C-nucleophiles with maleate and fumarate es-
ters, leading to pyrrolidine derivatives. Highly substituted
pyrrolidines are found in pharmaceuticals and natural al-
kaloids and are privileged building blocks in organic syn-
Figure 1 Molecular structure of pyrrolidine 2a; the ellipsoids repre-
sent 50% probability levels
CO2Me
CO2Me
CO2Me
O
CO2Me
N3
R
H
toluene, reflux
O
HN
+
+
N
CO2Me
H
48 h, 70–72%
R
O
CO2Me
CO2Me
MeO2C
R
1a,b
2a,b
3a,b
a R = 10H-phenothiazinyl
b R = Ph
Scheme 1
SYNLETT 2010, No. 6, pp 0931–0933
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x.
x
x.
2
0
1
0
Advanced online publication: 23.02.2010
DOI: 10.1055/s-0029-1219547; Art ID: D35409ST
© Georg Thieme Verlag Stuttgart · New York

932
D. Belei et al.
LETTER
was unchanged, with an improved yield for pyrrolidine though no experimental evidence in support of a detailed
derivative (58%) when two equivalents of dimethyl male- mechanism for the conversion of azides into pyrrolidines
ate were used.
has been obtained, based on the above facts we can as-
sume that a 1,3-dipolar cycloaddition between the ylide 6
and dimethyl maleate closes the pyrrolidine ring through
an exo-TS (Scheme 3). The configuration of the azome-
thine ylide is controlled by favorable interactions between
the acidic hydrogen atom and the two flanking carbonyl
groups. The formation of intermediate 6 can be explained
by an initial cycloaddition reaction of azide with maleate
that provides the corresponding 4,5-dihydro-1,2,3-tria-
zole. Thermal decomposition of the triazole followed by a
1,2-prototropic shift is a reasonable pathway for the for-
mation of azomethine ylide, which leads to the observed
stereochemical outcome.
These studies were extended by the treatment of phenacyl
azide 1b with dimethyl maleate in toluene. After 48 hours
reflux two products were detected in the reaction mixture,
the pyrrolidine derivative 2b (60%) and enamine 3b
(12%).
Again, the major product was pyrrolidine 2b with a ratio
of the two products of 4:1. These results are in contrast to
those obtained from the reaction of azide 1a with N-phe-
nyl maleimide (Scheme 2). Thus, heating an equimolecu-
lar mixture of 10-(azidoacetyl)-10H-phenothiazine and N-
phenyl maleimide in toluene for 48 hours produced a mix-
ture of enamine 4 and aziridine 5 in a 3:1 ratio and 70%
total isolated yield.
O
O
H
N
1,2-H shift
N
CO2Me
CO2Me
CO2Me
CO2Me
R
R
Ph
O
Ph
N
6 +
O
O
O
N
N3
O
O
Ph
N
MeO2C
CO2Me
O
+
HN
N
CO2Me
toluene
reflux, 48 h
O
O
1 +
R
CO2Me
R
R
H
N
O
R
R = 10H-phenothiazinyl
1a
4
5
CO2Me
CO2Me
CO2Me
MeO2C
Scheme 3
Scheme 2
Several facts support the above suppositions. The reaction
of azides 1a,b with dimethyl fumarate, under conditions
described for dimethyl maleate, led to the same mixture of
reaction products with an identical distribution and yields.
A comparison of the NMR spectra with those of 2a,b re-
vealed small shifts for several signals. Most likely, the di-
polar cycloaddition of azomethine ylide 6 with dimethyl
fumarate leads to an isomeric pyrrolidine where the two
esters groups are trans to each other.
The formation of enamines in both sequences and an azir-
idine in the latter can be explained by a Michael-type ad-
dition of nucleophilic N1 atom to the olefinic double
bond. A simultaneous or subsequent elimination of mo-
lecular nitrogen opens the way for the aziridine ring clo-
sure or for a 1,2-hydride shift to the nitrogen atom. The
latter process, which leads to the enamines, appears to be
favored. The formation of a nitrene compound before the
Michael-type interaction of azide with the olefinic dipo-
larophiles was ruled out by heating the azide 1a alone in
toluene. Regardless of the concentration (10–3 or 1 M), af-
ter 48 hours reflux the azide was recovered in quantitative
yields.
In conclusion, we have disclosed an unprecedented syn-
thesis of the pyrrolidine ring from organic azides and
maleate and fumarate esters. This reaction can serve for
the synthesis of various substituted pyrrolidines since the
positions 2 and 5 can be easily functionalized. The scope
and limitations of this new synthetic methodology are un-
der investigation.
From the mechanistic point of view the unexpected for-
mation of pyrrolidine derivatives 2 can be explained
through the enamines as intermediates or via a sequence
involving dipolar cycloaddition. The first alternative was
ruled out by subjecting the pure enamines 3a,b and dime-
thyl maleate to the same reaction conditions. After 48
hours reflux the stating materials were recovered in quan-
titative yields.
Acknowledgment
Part of this work has been supported by the Romanian PN II
(UEFISCSU-IDEI 2643) program.
References and Notes
A literature survey on azide chemistry revealed no direct
transformation to a pyrrolidine ring or a related system.
Further inspection of the X-ray structure shows that the
two ester groups on the pyrrolidine are cis related. Al-
(1) Mietzsch, F. Angew. Chem. 1954, 66, 363.
(2) Ionescu, M.; Mantsch, H. Adv. Heterocycl. Chem. 1967, 8,
83.
(3) Bodea, C.; Silberg, I. Adv. Heterocycl. Chem. 1968, 9, 321.
Synlett 2010, No. 6, 931–933 © Thieme Stuttgart · New York

LETTER
Synthetic Methodology for the Pyrrolidine Ring
933
(4) Valzelli, L.; Garattini, S. In Principles of
Psychopharmacology; Clark, W. G., Ed.; Academic Press:
New York, 1970, 255.
(5) Okafor, C. O. Heterocycles 1977, 7, 391.
(6) Eckstein, Z.; Urbanski, T. Adv. Heterocycl. Chem. 1978, 23,
1.
(100 MHz, CDCl3, TMS): d = 46.9 (t), 50.9 (q), 52.6 (q),
90.4 (d), 120.9 (s), 126.9 (d), 127.1 (d), 127.3 (d), 128.1 (d),
133.2 (s), 137.6 (s), 164.1 (s), 168.6 (s), 170.0 (s). MS (EI):
m/z (%) = 398 (12)[M+], 331 (12), 199 (100). Anal. Calcd
for C20H18N2O5S: C, 60.29; H, 4.55; N, 7.03. Found: C,
60.57; H, 4.61; N, 7.28.
(7) Szabo, J. Chem. Heterocycl. Compd. (Engl. Transl.) 1979,
15, 291.
(20) (a) Crystal Structure Determination of 2a
Crystal Data
(8) Albery, W. J.; Foulds, A. W.; Hall, K. J.; Hillman, A. R.;
Edgell, R. G.; Orchard, A. F. Nature (London) 1979, 282,
793.
Monoclinic, space group P21/c, a = 8.9732 (3), b = 21.1876
(7), c = 13.1662 (4) Å, b = 94.560 (4)°, Z = 4, T = 100 K.
Data Collection
(9) Motohashi, N. In Bioactive Molecules 4: Phenothiazines
and 1,4-Benzothiazines, Chemical and Biomedical Aspects;
Gupta, R. R., Ed.; Elsevier: Amsterdam, 1988, 705.
(10) Grieß, P. Philos. Trans. R. Soc. London 1864, 13, 377.
(11) Grieß, P. Justus Liebigs Ann. Chem. 1865, 135, 131.
(12) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
(13) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem. Int. Ed. 2005, 44, 5188.
(14) Chemistry of Halides, Pseudo-Halides and Azides, Part 1
and 2; Patai, S., Ed.; Wiley: Chichester, 1995.
(15) Kumar, H. M. S.; Reddy, B. V. S.; Anjaneyulu, S.; Yadav, J.
S. Tetrahedron Lett. 1999, 40, 8305.
A crystal ca. 0.3 × 0.25 × 0.2 mm3 was used to record 64269
intensities on a Oxford Diffraction Xcalibur E
diffractometer using MoKa radiation (l = 0.71073 Å).
Structure Refinement
The structure was refined anisotropically on F2 (program
SHELXL-97)20b to wR2 = 0.0854, R1 = 0.0346 for 351
parameters and 7192 unique reflexions. Data have been
deposited in Cambridge under the number CCDC-756944.
(b) Sheldrick, G. M. Acta Crystallogr., Sect. A.: Fundam.
Crystallogr. 2008, 64, 112.
(21) Analytical Data of Pyrrolidine 2a
Yield 1.57 g, 58%; Rf = 0.25; mp 192–193 °C. IR (ATR):
3342, 1734, 1723, 1675, 1432, 1342, 1297, 1031, 771, 755
cm–1. 1H NMR (400 MHz, CDCl3, TMS): d = 2.75 (s, 2 H,
CH2), 3.23 (s, 1 H, NH), 3.54 (s, 3 H, CH3), 3.62 (s, 3 H,
CH3), 3.66 (m, 1 H, CH), 3.69 (s, 3 H, CH3), 3.75 (m, 1 H,
CH), 3.79 (s, 3 H, CH3), 4.70 (m, 1 H, CH), 7.20–7.70 (m, 8
H, 8 × CHar). 13C NMR (100 MHz, CDCl3, TMS): d = 40.2
(t), 51.4 (q), 51.9 (q), 52.1 (q), 52.2 (q), 53.0 (d), 59.0 (d),
69.3 (s), 126.3 (d), 126.9 (d), 127.0 (d), 127.3 (d), 127.4 (d),
127.8 (d), 128.1 (d), 133.5 (s), 133.4 (d), 138.0 (s), 138.2 (s),
170.3 (s), 170.4 (s), 170.6 (s), 171.1 (s), 173.1 (s). MS (EI):
m/z (%) = 542 (5)[M+], 483 (3), 451 (3), 316 (16), 284 (12),
224 (18), 199 (100). Anal. Calcd for C26H26N2O9S: C, 57.56;
H, 4.83; N, 5.16. Found: C, 57.79; H, 4.99; N, 5.47.
(16) Huisgen, R.; Knorr, R.; Möbius, L.; Szeimies, G. Chem. Ber.
1965, 98, 4014.
(17) Pyne, S. G.; Davis, A. S.; Gates, N. J.; Nicole, J.; Hartley, J.
P.; Lindsay, K. B.; Machan, T.; Tang, M. Synlett 2004, 2670.
(18) Harwood, L. M.; Vickers, R. J. In Synthetic Applications of
1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products; Padwa, A.; Pearson, W., Eds.; Wiley
and Sons: New York, 2002.
(19) Analytical Data of Enamine 3a
Yield 0.28 g, 14%; Rf = 0.47; mp 163–164 °C. IR (ATR):
2941, 1743, 1676, 1602, 1443, 1335, 1220, 1116, 754 cm–1.
1H NMR (400 MHz, CDCl3, TMS): d = 3.66 (s, 3 H, CH3),
3.77 (s, 3 H, CH3), 4.39 (br s, 2 H, CH2), 5.40 (s, 1 H, CH),
7.23–7.54 (m, 8 H, 8 × CHar), 8.47 (s, 1 H, NH). 13C NMR
Synlett 2010, No. 6, 931–933 © Thieme Stuttgart · New York