A novel entry into 1-methyl- and 1-aryl-octahydropyrrolo[3,4-b]pyrroles and their N-1-C-2 fused derivatives: Stereoselective synthesis via an intramolecular azomethine ylide cycloaddition reaction

Article abstract of DOI:10.1016/j.tetlet.2005.08.077

Synthesis of some novel pyrrolo[3,4-b]pyrrole derivatives has been accomplished in good yields by the intramolecular azomethine ylide cycloaddition reaction of a strategically situated unactivated alkenyl aldehyde with various secondary amino acids. A cis

Full text of DOI:10.1016/j.tetlet.2005.08.077

Tetrahedron
Letters
Tetrahedron Letters 46(2005) 7197–7200
A novel entry into 1-methyl- and
1
-aryl-octahydropyrrolo[3,4-b]pyrroles and their N-1–C-2 fused
derivatives: stereoselective synthesis via an intramolecular
azomethine ylide cycloaddition reaction
Mahalingam Poornachandran and Raghavachary Raghunathan*
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Received 17 June 2005; revised 12 August 2005; accepted 17 August 2005
Available online 6September 2005
Abstract—Synthesis of some novel pyrrolo[3,4-b]pyrrole derivatives has been accomplished in good yields by the intramolecular
azomethine ylide cycloaddition reaction of a strategically situated unactivated alkenyl aldehyde with various secondary amino acids.
A cis fused cycloadduct was formed in all cases.
ꢀ
2005 Published by Elsevier Ltd.
The synthesis of polysubstituted and fused pyrrolidines,
pyrrolizidines, indazolidines, pyranoquinolines and pyr-
rolo b-carboline ring systems has received synthetic
chemistsÕ attention over the years since these hetero-
cycles form the structural subunits of biologically
heterocycles6,7 since it is capable of annulating a proline
moiety with high regio- and stereocontrol to even unac-
tivated internal olefins, which do not react intermolecu-
larly. This powerful methodology has been extensively
applied for the synthesis of complex molecules including
8
1
important alkaloids and pharmaceutically important
heterocycles with removable and fixed chiral auxilia-
2
9–11
compounds. Specifically, pyrrolo[3,4-b]pyrrole and its
ries.
Though the intramolecular cycloaddition of
3
derivatives are used as adenosine kinase inhibitors
azomethine ylides generated by the decarboxylative con-
densation of amino acids with strategically positioned
alkenyl aldehydes and alkynyl aldehydes has been stud-
ied in several systems, to the best of our knowledge there
has been no report on the cycloaddition of a simple N-
tethered alkenyl aldehyde with acyclic or cyclic amino
acids resulting in the formation of pyrrolo[3,4-b]pyr-
roles. Hence, herein we report our synthetic approach
for the convergent synthesis of 1-methyl, 1-aryl-octahy-
dro-5-tosylpyrrolo[3,4-b]pyrrole and its N-1–C-2 fused
analogues.
and serve as prime intermediates in the synthesis of
4
-quinolone carboxylic acid and uracil-based antibacte-
rials, which selectively inhibit DNA polymerase III C
4
and type II bacterial topoisomerase.
The wide range of bioactivities of these systems
prompted us to devise a synthetic route to these hetero-
cycles. In considering possible synthetic schemes, we
decided that a [3+2] cycloaddition reaction would af-
ford the most concise approach. A review of inter- and
intramolecular versions of azomethine ylide cycloaddi-
tion revealed the versatility of intramolecular [3+2]
The requisite olefinic aldehyde 5 was synthesized in four
steps in excellent yield. Tosylation of allylamine 1 under
standard reaction conditions gave sulfonamide 2 which
was treated with ethyl bromo-/chloroacetate to afford
N-allyl-N-(ethoxycarbonylmethyl)toluene-4-sulfonamide
5
cycloaddition for the synthesis of complex molecules.
The intramolecular [3+2] mode of cycloaddition has re-
sulted in elegant syntheses of stereochemically defined
3
in 85% yield. Reduction of the ester with LAH gave
alcohol 4. The oxidation of 4 to 5 with routine oxidizing
agents like PCC, PDC, active MnO and Cr O under
Keywords: Azomethine ylide; Intramolecular; Cycloaddition; Pyrrolo-
pyrrole; Stereoselective.
2
2
3
*
Corresponding author. Tel.: +91 44 24746655; fax: +91 44
2352494; e-mail: ragharaghunathan@yahoo.com
different reaction conditions did not give the expected
results. However, the oxidation could be accomplished
2
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.08.077

7198
M. Poornachandran, R. Raghunathan / Tetrahedron Letters 46 (2005) 7197–7200
(
i)
(ii)
Ts
N
H
H
H N
Ts
2
N
H
O
HN CH COOH
2
Ts
N
1
2
N
R
O
3
Ts
N
toluene
reflux
(
iii)
CHO
(
iv) Ts
N
Ts
N
5
OH
R
CHO
8a-e
5
4
8
a R=H; 8b R=Me; 8c R=OMe;
9a-e
Scheme 1. Reagents and conditions: (i) TBAF, 10% NaOH/benzene,
tosyl chloride, 0 ꢁC–rt; 8 h, 90%; (ii) ethyl bromo-/chloroacetate,
8d R=Cl; 8e R=Br
Scheme 3.
K
2
CO
3 4
/acetone, 5 h, 85%; (iii) LiAlH /THF, 65 ꢁC, 4 h, 90%; (iv)
iodoxybenzoic acid, DMSO, 4 h, 94%.
with the stereochemistry observed for conventional
1
0,17
successfully with iodoxybenzoic acid (IBX) in DMSO to
yield the key aldehyde 5, N-allyl-N-(2-oxo-ethyl)toluene-
azomethine ylide cycloaddition in similar systems.
The stereochemistry of a representative bicyclic com-
1
8
1
4
-sulfonamide in excellent yield. Though a synthetic
pound 9e, was determined on the basis of H NMR-
COSY experiments. The coupling constant between H-
3a and H-6a was 2.4 Hz, which is consistent only with
a cis ring fusion. The stereochemistry of the cycloadduct
9e, was further unambiguously corroborated by an X-
pathway for the aldehyde 5 was reported in the litera-
1
2
ture, the present reaction protocol is advantageous
since it gives the key aldehyde in excellent overall yield
(
Scheme 1).
1
9
ray crystallographic analysis (Fig. 1).
With aldehydes 5 in hand, the cycloaddition reactions
were carried out with the formation of unstabilized
azomethine ylides generated by decarboxylative conden-
In order to extend the scope of this reaction to the syn-
thesis of N-1–C-2 fused derivatives of pyrrolo[3,4-b]-
pyrroles, the alkenyl aldehyde 5 was reacted with
proline 10a and thiaproline 10b to afford the tricyclic
1
3–16
sation with various secondary amino acids.
Con-
densation of 5 with sarcosine 6 in refluxing toluene
under Dean–Stark reaction conditions, generated the
azomethine ylide which cyclized to yield the cis adduct,
1
-methyl-octahydro-5-tosylpyrrolo[3-4-b]pyrrole, 7 as a
brownish oil in 78% yield in 3 h (Scheme 2) (Table 1, en-
try 1).
The same reaction was carried out with various N-aryl
glycines 8a–e to obtain cis fused cycloadducts 9a–e in
good yields (Scheme 3) (Table 1, entries 2–6). Among
the solvents used, toluene was found to be the best.
The assignment of cis stereochemistry to the ring junc-
tions of all cycloadducts was initially made by analogy
H
Figure 1. X-ray crystal structure of compound 9e.
HN CH2 COOH
CH3
toluene
reflux
Ts
N
Ts N
CHO
N
CH3
H
7
5
6
H
X
toluene
Ts
N
Ts N
COOH reflux
Scheme 2.
CHO
5
N
H
N
X
H
1
0a,b
11a,b
Table 1. Intramolecular azomethine cycloadditions of compound 5
with secondary amino acids
1
1
0a, X= CH2
0b X= S
Entry
Amino acid
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
6
3
4
3
2.5
2
3.5
4
5
3
3.5
7
78
76
79
81
80
79
83
74
68
65
Scheme 4.
8a
8b
8c
9a
9b
9c
H
8d
8e
9d
9e
NH
toluene Ts
reflux
N
Ts
N
N
10a
10b
12
14
11a
11b
13
15
CHO
H
COOH
5
12
13
10
Scheme 5.

M. Poornachandran, R. Raghunathan / Tetrahedron Letters 46 (2005) 7197–7200
7199
H
COOH
Ts
N
toluene
reflux
Ts
N
N
CHO
NH
H
N
H
N
H
5
14
15
Scheme 6.
compounds 11a,b in good yields (Scheme 4) (Table 1,
entries 7 and 8).
Eur. J. Pharmacol. 2000, 398, 73–81; (c) Sternsfeld, F.;
Guibin, A. R.; Jelly, R. A.; Matassa, V. G.; Reeve, A. J.;
Hunt, P. A.; Beer, M. S.; Heald, A.; Stanton, J. A.; Sohal,
B.; Watt, A. P.; Street, L. J. J. Med. Chem. 1999, 42, 677–
690.
. Bauser, M.; Delapierre, G.; Hauswald, M.; Flessner, T.;
DÕUrso, D.; Hermann, A.; Beyreuther, B.; De Vry, J.;
Spreyer, P.; Reissmuller, E.; Meier, H. Bioorg. Med.
Chem. Lett. 2004, 14, 1997–2000.
Pyrido[3,4-b]indoles have been proved to be depressants
2
0
of the central nervous system and potent antiulcer
3
2
1
agents. In anticipation of enhancing bioactivity, we
have synthesized pyrrolo[3,4-b]pyrroles 13, 15 fused with
tetrahydroisoquinoline and tetrahydropyridoindole
units by the reaction of 5 with 1,2,3,4-tetrahydro iso-
quinoline-2-carboxylic acid 12 and 1,2,3,4-tetrahydro-
b-carboline-3-carboxylic acid 14 (Schemes 5 and 6)
4. Petersen, U.; Schenke, T.; Krebs, A.; Grohe, K.; Scherie-
wer, M.; Haller, I.; Mezger, K. G.; Endermann, R.; Zeiler,
H. J. U.S. Patent, 5,416,096, 1996; Chem. Abstr. 1996, 124,
2
89280c.
(
Table 1, entries 9 and 10). In all cases, the cycloaddition
5
. For some recent examples, see: (a) Vedejs, E.; Piotrowski,
D. W.; Tucci, F. C. J. Org. Chem. 2000, 65, 5498–5505; (b)
Pandey, G.; Sahoo, A. K.; Bagul, T. D. Org. Lett. 2000, 2,
took place in a cis fashion on the basis of 2D NMR
experiments, where the coupling constants of hydrogen
atoms on the ring junctions corresponded closely to
those of 9e.
2
299–2301; (c) Vedejs, E.; Klapers, A.; Naidu, B. N.;
Piotrowski, D. W.; Tucci, F. C. J. Am. Chem. Soc. 2000,
22, 5401–5402; (d) Coldham, I.; Crapnell, K. M.;
1
In conclusion, we have accomplished the synthesis of
some novel pyrrolo[3,4-b]pyrrole derivatives of biologi-
cal interest with high stereoselectivity by tandem ylide
generation followed by intramolecular trapping by an
N-tethered alkenyl group. Further work is in progress
for the screening of the biological activities of the syn-
thesized molecules and the synthesis of bis-pyrrolo[3,4-
b]pyrrole derivatives.
Moseley, J. D.; Rabot, R. J. Chem. Soc., Perkin Trans. 1
2001, 1758–1763; (e) Novikov, M. S.; Khlebnikov, A. F.;
Besidina, O. V.; Kastikov, R. R. Tetrahedron Lett. 2001,
42, 533–535.
6
. (a) Padwa, A. Angew. Chem., Int. Ed. Engl. 1976, 15, 123–
1
80; (b) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977,
1
6, 10–23.
7
8
. Jacobi, P. A.; Martinelli, M. J.; Polane, S. J. Am. Chem.
Soc. 1984, 106, 5594–5598.
. (a) Confalone, P. N.; Huie, E. M. J. Org. Chem. 1983, 48,
2
994–2997; (b) Confalone, P. N.; Huie, E. M. J. Am.
Acknowledgements
Chem. Soc. 1984, 106, 7175–7178; (c) Mahmud, H.;
Lovely, C. J.; Dias, H. V. R. Tetrahedron 2001, 57,
4095–4105; (d) Smith, R.; Livinghouse, T. J. Org. Chem.
1983, 48, 1554–1555; (e) DeShong, P.; Kell, D. A.; Sidler,
D. R. J. Org. Chem. 1985, 50, 2309–2315.
. Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani, T. J. Chem.
Soc., Perkin Trans. 1 2001, 452–456, and references cited
therein.
P.C. thanks the Department of Science and Technology
DST), New Delhi, India, for financial support. Profes-
sor V. T. Ramakrishnan is gratefully acknowledged
for useful discussions. The authors thank SAIF, IIT,
Chennai, for spectral data.
(
9
1
1
0. Russel, M. G. N.; Beer, M. S.; Stanton, J. A.; Sohal, B.;
Mortishire Smith, R. J.; Castro, J. L. Bioorg. Med. Chem.
Lett. 1999, 9, 2491–2496.
1. Pedrosa, R.; Andr e´ s, C.; Heras, L.; Nieto, J. Org. Lett.
2002, 4, 2513–2516, and references cited therein.
References and notes
1
. (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In
Alkaloids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Pergamon Press: New York, 1999; Vol. 13, pp
12. Suritami, T.; Shinokubo, H.; Oshima, K. Org. Lett. 2001,
3, 2709–2711.
1
–161; (b) Daly, J. W. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1998; Vol. 50, pp 141–
69; (c) Howard, A. S.; Michael, J. P. In The Alkaloids;
13. (a) Grigg, R.; Surendrakumar, S.; Thianpatanagul, S.;
Vipond, D. J. Chem. Soc., Chem. Commun. 1987, 47–49;
(b) Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. J. Chem.
Soc., Chem. Commun. 1987, 49–51; (c) Grigg, R.; Idle, J.;
McMeekin, P.; Surendrakumar, S.; Vipond, D. J. Chem.
Soc., Perkin. Trans. 1 1988, 2703–2713.
14. For examples, of intramolecular 1,3-dipolar cycloaddi-
tions of azomethine ylides generated by the decarboxyl-
ation, see: (a) Grigg, R.; Savic, V.; Thronton-Pett, M.
Tetrahedron 1997, 53, 10633–10642; (b) Harling, J. D.;
Orlek, B. S. Tetrahedron 1998, 54, 14905–14912; (c)
Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron Lett.
1999, 40, 3339–3342; (d) Snider, B. B.; Ahn, Y.; OÕHare, S.
M. Org. Lett. 2001, 3, 4217–4220.
1
Brossi, A., Ed.; Academic Press: New York, 1986; Vol. 28,
p 183; (d) Wrobel, J. T. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1985; Vol. 26, p 327; (e)
Takahata, A.; Momose, T. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, 1993; Vol. 44, p 189;
(
f) Robins, D. J. Nat. Prod. Rep. 1995, 12, 413–418; (g)
Liddell, J. R. Nat. Prod. Rep. 1996, 13, 187–193; (h)
Michael, J. P. Nat. Prod. Rep. 1995, 12, 535–552.
. (a) Patvardhan, S. P.; Joshi, K. S.; Vadlamudi, R. V. S. V.;
Desphande, S. G. Ind. J. Pharm. Sci. 1998, 60, 384–387;
2
(
b) Gupta, P.; Butler, P.; Shepperson, N. B.; McHarg, A.

7200
M. Poornachandran, R. Raghunathan / Tetrahedron Letters 46 (2005) 7197–7200
1
1
5. Nyerges, M.; Bal a´ zs, L.; K a´ das, I.; Bitter, I.; K o¨ vesdhi, I.;
T o¨ ke, L. Tetrahedron 1995, 51, 6783–6788.
6. (a) Manikandan, S.; Raghunathan, R. Synth. Commun.
The residue was then subjected to column chromatogra-
phy (silica gel, 100–200 mesh) with hexane–ethyl acetate
(8:2) to obtain the cycloadduct 9e, 1-(4-bromophenyl)-
octahydro-5-pyrrolo[3,4-b]pyrrole.
2002, 32, 3587–3594; (b) Amalraj, A.; Raghunathan, R.
Tetrahedron 2001, 57, 10293–10298; (c) Subramaiyan, G.;
Raghunathan, R.; Nethaji, M. Tetrahedron 2002, 58,
White powder, 79% (0.33 g); mp: 210 ꢁC IR (KBr): 1338,
À1
1
1161 cm ; H NMR (CDCl3, 400 MHz) (d): 1.81–1.86(m,
1H); 2.03–2.08 (m, 1H); 2.35 (s, 3H); 2.85–2.89 (m, 1H);
3.06–3.14 (m, 4H); 3.20–3.29 (m, 2H); 3.92–3.96 (dt, 1H,
9075–9079.
1
7. (a) Armstrong, P.; Grigg, R.; Jordan, M. W.; Malone, J.
F. Tetrahedron 1985, 41, 3547–3558; (b) Grigg, R.; Duffy,
L. M.; Dorrity, M. J.; Malone, J. F.; Rajviroongit, S.;
Thornton-Pett, M. Tetrahedron 1990, 46, 2213–2230.
8. All new compounds were characterized by spectroscopic
data. A typical experimental procedure for the synthesis
and characterization of cycloadduct 9e: A mixture of
J = 2.4, J = 6.8 Hz); 6.21–6.24 (d, 2H, J = 9.1 Hz); 7.18–
1 2
13
7.22 (m, 4H); 7.55–7.57 (m, 2H). C NMR (CDCl3,
100 MHz): d 21.54, 29.54, 42.36, 48.30, 52.42, 53.10, 62.57,
+
1
108.90, 114.14, 127.84. m/z, M 421.60 (25%). Anal.
Calcd for
19 21 2 2
C H N O SBr; C, 54.16; H, 5.02; N,
6.64. Found: C, 54.28; H, 5.12; N, 6.54. The spectral data
of all other cycloadducts were consistent with their
structures.
2.0 mmol of N-allyl-N-(2-oxo-ethyl)toluene-4-sulfonamide
5, 3.0 mmol of N-(p-bromo)phenyl glycine 8e in 30 mL of
dry toluene was refluxed under Dean–Stark conditions till
the completion of the reaction (3.5 h). The reaction
mixture was then concentrated under reduced pressure.
The concentrate was then extracted with dichloromethane
19. Selvanayagam, S.; Velmurugan, D.; Ravikumar, K.;
Poornachandran, M.; Raghunathan, R. Acta Crystallogr.
2005, E61, 2493–2495.
20. Saxena, A. K.; Jain, P. C.; Anand, N. J. Med. Chem. 1973,
16, 560–564.
(
2 · 20 mL) and water (2 · 20 mL). The organic layer was
washed with brine solution (2 · 20 mL), dried over anhy-
21. Tripathi, R. C.; Patnaik, G. K.; Saxena, A. K. Indian J.
Chem. 1989, 28B, 333–337.
drous sodium sulfate and concentrated in vacuum.