An anionic condensation and fragmentation approach to substituted 3-pyrrolines

Article abstract of DOI:10.1016/S0040-4039(02)02191-3

We have identified an anionic condensation and fragmentation sequence from the coupling of 7-azabicyclo[2.2.1]heptenones with aldehydes. This reaction leads to the stereoselective formation of disubstituted 3-pyrrolines as are present in a wide array of bioactive molecules.

Full text of DOI:10.1016/S0040-4039(02)02191-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8913–8915
An anionic condensation and fragmentation approach to
substituted 3-pyrrolines
G. Mahika Weeresakare,b Qing Xua,† and Jon D. Rainierb,*
aDepartment of Chemistry, The University of Arizona, Tucson, AZ 85721, USA
bDepartment of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA
Received 5 September 2002; accepted 30 September 2002
Abstract—We have identified an anionic condensation and fragmentation sequence from the coupling of 7-azabicy-
clo[2.2.1]heptenones with aldehydes. This reaction leads to the stereoselective formation of disubstituted 3-pyrrolines as are
present in a wide array of bioactive molecules. © 2002 Elsevier Science Ltd. All rights reserved.
Their presence in a variety of biologically active targets
have made substituted pyrroles and pyrrolines popular
targets for chemical synthesis.1 Our interest in these
agents came shortly after our discovery that oxabicy-
clo[2.2.1]heptenones undergo a condensation and frag-
mentation sequence resulting in the formation of
dihydrofurans when subjected to aldehydes and anionic
conditions (Eq. (1)).2
able to access potentially important 3-pyrrolines includ-
ing pyrroline containing natural products.3 Described
herein is the realization of this goal through the anionic
coupling of 7-azabicyclo[2.2.1]heptenone 8 with substi-
tuted aldehydes.
In order to examine the aforementioned anionic cou-
pling chemistry, we required ready access to 7-azabicy-
clo[2.2.1]heptenones and turned to pyrrole Diels–Alder
chemistry.4 In an analogous fashion to our approach to
the chemical synthesis of 1, Boc pyrrole 3 was con-
densed with bromo-propynoate 45 to give 7-azabicy-
clo[2.2.1]heptadiene 6.6 Hydrolysis of the vinyl bromide
then provided coupling precursor 8. In an effort to
avoid the use of 4,7 we also carried out the cycloaddi-
tion between 3 and alkynyl sulphone 58 to generate 7.
Hydrolysis of the vinyl sulphone was accomplished on
large scale by sequentially exposing 7 to Et2NH/NEt3,
KOt-Bu,9 and acid to give 8 in 74% yield (Scheme 1).
(1)
By applying the reaction outlined in Eq. (1) to the
analogous nitrogen containing system (i.e. 7-azabicy-
clo[2.2.1]heptenones), we reasoned that we would be
Scheme 1. Synthesis of azabicyclo[2.2.1]heptenone 8.
* Corresponding author.
† Current Address: Department of Chemistry, Oregon State University, Corvallis, OR 97331-4003, USA.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02191-3

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G. M. Weeresakare et al. / Tetrahedron Letters 43 (2002) 8913–8915
With 7-azabicyclo[2.2.1]heptenone 8 in hand, we exam-
ined its anionic condensation chemistry with aldehydes.
Our efforts commenced with the anionic condensation
of 8 with benzaldehyde in the presence of NaH (Table
1, entry 1). This resulted in the generation of 3-pyrro-
line 9 in 76% yield as a 2.5:1, E:Z mixture of olefin
isomers.13 By way of comparison, the anionic coupling
of the corresponding 7-oxabicyclo[2.2.1]heptenone gave
the dihydrofuran analogous to 9 in 57% yield.10 We
were pleased to find that other aryl substituted alde-
hydes were also amenable to this transformation. That
is, when subjected to 8 and NaH, furfural and anisalde-
hyde gave 3-pyrrolines 10 and 11 in 87 and 70% yields,
respectively (entries 2 and 3). The reaction was not
limited to aryl aldehydes; the coupling of 8 with
propanal and isobutyraldehyde gave 12 and 13, respec-
tively (entries 4 and 5). Interestingly, the major olefin
isomer was reversed in these latter two reactions.11
Ethyl glyoxylate was also utilized in the coupling reac-
tion with 8 to give 1413 in 83% yield as a 4:1, Z:E
mixture of olefin isomers (entry 6). The transformation
of 8 into the corresponding pyrroline appears to be
somewhat sensitive to steric inhibition; attempted con-
densation of 8 with pivaldehyde did not give the
expected pyrroline but instead resulted in the formation
of alkylated 7-azabicyclo[2.2.1]heptenone upon quench-
ing the anion of 8 with MeI (entry 7).
Scheme 2. Working hypothesis for the condensation of azabi-
cyclo[2.2.1]heptenones with aldehydes.
clo[2.2.1]heptene ring systems. Our current efforts are
focused on further evaluating the scope of this reaction
as well as its use in the synthesis of pyrroline containing
natural products.
Acknowledgements
We are grateful to the National Science Foundation
(CHE-9983715) for support of this work. Support of
the NMR facility in the Department of Chemistry at
the University of Arizona by the National Science
Foundation under Grant No. 9729350 is also gratefully
acknowledged. We are indebted to Dr. Neil Jacobsen
and Dr. Arpad Somagyi for help with NMR and mass
spectra experiments, respectively.
Our current working hypothesis for the azabicy-
clo[2.2.1]heptenone to pyrroline transformation is out-
References
lined in Scheme
2
for the condensation with
benzaldehyde. We believe that the initial aldolate
undergoes a cyclization reaction onto the pendant
ketone to give oxetane intermediate 15. Anionic frag-
mentation relieves the ring strain present in 15 and
leads to the corresponding 3-pyrroline 16.12
1. Selected recent examples of pyrroline synthesis: (a) Her-
couet, A.; Neu, A.; Peyronel, J. F.; Carboni, B. Synlett.
2002, 829; (b) Green, M. P.; Prodger, J. C.; Sherlock, A.
E.; Hayes, C. J. Org. Lett. 2001, 3, 3377; (c) Dieter, R.
K.; Yu, H. Org. Lett. 2001, 3, 3855; (c) Breuil-
Desvergnes, V.; Compain, P.; Vate`le, J.-M.; Gore´, J.
Tetrahedron Lett. 1999, 40, 5009; (d) Ishii, K.; Ohno, H.;
Takemoto, Y.; Ibuka, T. Synlett. 1999, 228; (e) Schu-
macher, K. K.; Jiang, J.; Joullie´, M. M.; Tetrahedron:
Asymmetry 1998, 9, 47; (f) Ojima, I.; Zhu, J. W.; Vidal,
E. S.; Kass, D. F. J. Am. Chem. Soc. 1998, 120, 6690; (g)
Balasubramanian, T.; Hassner, A. Tetrahedron Lett.
1996, 37, 5755; (h) Burley, I.; Hewson, A. T. Tetrahedron
Lett. 1994, 35, 7099.
To conclude, we have identified a novel anion mediated
condensation and fragmentation reaction of azabicy-
Table 1. Azabicyclo[2.2.1]heptenone–aldehyde condensa-
tions
2. (a) Rainier, J. D.; Xu, Q. Org. Lett. 1999, 1, 27; (b) Xu,
Q.; Weeresakare, M.; Rainier, J. D. Tetrahedron 2001, 57,
8029.
3. For reviews of pyrroline containing natural products see:
(a) Mauger, A. B. J. Nat. Prod. 1996, 59, 1205; (b) Daly,
J. W. J. Nat. Prod. 1998, 61, 162.
4. For
a
review on the synthesis of 7-azabicy-
Entry
R
Pyrroline
Yield (%)
E:Z
clo[2.2.1]heptenes which includes Diels–Alder approaches
see: Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179.
5. (a) Heaton, C. D.; Noller, C. R. J. Am. Chem. Soc. 1949,
71, 2948; (b) Chamberlain, P.; Rooney, A. E. Tetrahedron
Lett. 1979, 20, 383; (c) Leroy, J. Tetrahedron Lett. 1992,
33, 2969.
6. Zhang, C.; Trudell, M. L. J. Org. Chem. 1996, 61, 7189.
7. WARNING: Bromoalkyne 4 is a known lachrymator. In
addition, the use of 4 has led to painful skin rashes in
spite of the use of protective gear and a well ventilated,
high flow fume hood.
1
2
3
4
5
6
7
Ph
9
10
11
12
13
14
–
76
87
70
84
60
83
2.5:1a
2:1a
2-Furyl
p-OMePh
Et
i-Pr
CO2Et
t-Bu
4:1a
1:4a
1:18a
1:4b
c
–
a From 1H NMR integration of the vinyl signals.
b From 1H NMR integration of the methyl ester signals.
c Product was methylated 8.

G. M. Weeresakare et al. / Tetrahedron Letters 43 (2002) 8913–8915
8915
8. Shen, M.; Schultz, A. G. Tetrahedron Lett. 1981, 22,
3347.
MHz, CDCl3) l 7.49–7.27 (m, 6H), 6.04 (s, 0.7H), 5.96–
5.88 (m, 1.3H), 5.72 (s, 0.3H), 5.70 (s, 0.7H), 5.12 (s,
0.7H), 5.03 (s, 0.3H), 4.32–4.25 (m, 1H), 4.12–4.07 (m,
1H), 3.75 (s, 3H), 1.44–1.35 (m, 3H), 1.27 (s, 7.8 H), 1.25
(s, 1.2H); 13C NMR (125 MHz, CDCl3) l 169.7, 169.1,
167.1, 154.4, 153.7, 138.4, 137.3, 134.9, 134.6, 133.4,
132.7, 131.0, 130.7, 129.4, 129.4, 128.4, 128.3,128.1,
127.5, 126.9, 125.5, 124.8, 80.6, 80.2, 66.9, 66.8, 62.9,
62.7, 62.7, 60.6, 52.0, 51.8, 28.1, 14.0; IR (CCl4) 2974,
9. While the KOt-Bu step was not needed on small scale
(0.07 mmol), the yield of 8 was much lower (10–25%) on
larger scale when the KOt-Bu step was omitted. Pre-
sumably, KOt-Bu serves to eliminate the sulphone from
the amino sulphone intermediate that was generated from
the reaction of 7 with NEt3 and HNEt2.
10. When exposed to the condensation reaction with alde-
hydes, oxabicyclo[2.2.1]heptenones having substitution at
the bridgehead gave much higher yields of dihydrofurans
than those lacking substitution. See Ref. 2.
1797, 1729, 1400 cm−1
; HRMS (FAB) calcd for
C22H28NO7 (MH+) 402.1917, found 402.1915. 14: (E-iso-
1
mer): H NMR (500 MHz, CDCl3) l 6.38–6.36 (m, 1H),
6.25 (s, 1H), 5.93–5.82 (m, 2H), 5.08–5.07 (m, 0.66H),
5.00 (s, 0.33H), 4.27–4.09 (m, 4H), 3.70 (s, 2H), 3.69 (m,
1H), 1.39 (s, 6H), 1.37 (s, 3H), 1.29–1.21 (m, 6H); 13C
NMR (125 MHz, CDCl3) l 169.4, 169.0, 166.0, 165.2,
154.1, 149.6, 149.1, 130.8, 130.4, 130.0, 125.2, 125.1,
123.2, 123.1, 80.8, 80.6, 66.8, 66.7, 63.0, 62.8, 61.6, 61.4,
60.9, 52.1, 52.0, 28.1, 28.0, 14.1, 14.0, 14.0, 13.9; IR
(CCl4) 2981, 1709, 1387, 1178,1060 cm−1; HRMS (FAB)
calcd for C19H28NO8 (MH+) 398.1815, found 398.1803.
14 (Z-isomer): 1H NMR (500 MHz, CDCl3) l 6.72 (d,
J=0.7 Hz, 0.6H), 6.53 (s, 0.4H), 6.01–5.96 (m, 1H),
5.84–5.79 (m, 1H), 5.31 (s, 0.4H), 5.24 (s, 0.6H), 5.14 (dd,
J=4.8, 2.4 Hz, 0.6H), 5.08 (d, J=2.4 Hz, 0.4H), 4.32–
4.28 (m, 2H), 4.24–4.17 (m, 2H), 3.79 (s, 1.8 H), 3.78 (s,
1.2H), 1.46 (s, 5H), 1.45 (s, 4H), 1.32–1.26 (m, 6H); 13C
NMR (125 MHz, CDCl3) l 170.0, 170.0,166.3, 165.8,
165.4, 153.2, 144.9, 144.6, 130.8, 124.6, 124.5, 123.8,
122.4, 81.3, 81.1, 66.9, 66.5, 66.4, 66.3, 61.5, 60.8, 60.8,
52.4, 52.3, 28.1, 28.1, 14.0, 13.9; IR (CCl4) 2999,
1710,1385 cm−1; HRMS (FAB) calcd for C19H28O8N
(MH+) 398.1815, found 398.1805.
11. The olefin geometry was determined spectroscopically
from the presence (Z-isomer) or lack (E-isomer) of NOEs
between the exocyclic vinyl hydrogen and the ethyl ester
hydrogens.
12. As indirect evidence of this mechanism, we have found
that 1 undergoes a two-carbon ring expansion reaction
when exposed to unsaturated ketones and esters. See Ref.
2b and: Rainier, J. D.; Xu, Q. Org. Lett. 1999, 1, 1161.
13. Representative characterization data: 9 (Z-isomer): 1H
NMR (500 MHz, CDCl3) l 7.41–7.26 (m, 6H), 6.09 (m,
0.3H), 6.04 (m, 0.7H), 5.84 (m, 0.7H), 5.79 (m, 0.3H),
5.36 (d, J=1.6 H, 0.7 Hz), 5.18 (d, J=2.4 Hz, 0.7H), 5.12
(d, J=2.3 Hz, 0.3H), 4.16 (q, J=7.1 Hz, 2H), 3.80 (s,
2H), 3.79 (s, 1H), 1.46 (s, 3H), 1.45 (s, 6H), 1.14–1.10 (m,
3H); 13C NMR (125 MHz, CDCl3) l 170.5, 170.2, 168.1,
168.0, 153.6, 152.9, 136.0, 135.5, 132.8, 132.7, 132.5,
131.5, 128.7, 128.4, 128.3, 128.0, 128.0, 127.9, 127.8,
123.5, 123.4, 80.8, 80.7, 67.4, 67.2, 67.0, 66.5, 60.7, 52.4,
52.2, 28.3, 28.2, 13.7; IR (CCl4) 2957, 2369, 1721, 1387
cm−1
;
HRMS (FAB) calcd for C22H28NO7 (MH+)
402.1917, found 402.1917. 9 (E-isomer): 1H NMR (500