An alternative route to pyrrolotriazoles and other N-bridgehead heterocycles

Article abstract of DOI:10.1055/s-2006-947324

1,2-Diaza-1,3-butadienes bearing a Boc moiety at N-1 react with acetonitrile derivatives to afford 1-Boc-protected 1,2-diaminopyrroles that represent, by flexible condensation-deprotection or deprotection-condensation steps, a flexible entry to different

Full text of DOI:10.1055/s-2006-947324

1734
LETTER
An Alternative Route to Pyrrolotriazoles and other N-Bridgehead
Heterocycles
S
ynthesis of Pyrro
r
lotriazol
a
es zio A. Attanasi, Lucia De Crescentini, Paolino Filippone,* Fabio Mantellini, Francesca R. Perrulli,
Stefania Santeusanio*
Istituto di Chimica Organica della Facoltà di Scienze Matematiche, Fisiche e Naturali, Università degli Studi di Urbino ‘Carlo Bo’,
Via Sasso 75, 61029 Urbino, Italy
Fax +39(0722)303441; E-mail: santeusanio@uniurb.it
Received 26 February 2006
R2
H
Abstract: 1,2-Diaza-1,3-butadienes bearing a Boc moiety at N-1
R1O2C
N
H
R1O2C
N
Boc
react with acetonitrile derivatives to afford 1-Boc-protected 1,2-di-
aminopyrroles that represent, by flexible condensation–deprotec-
tion or deprotection–condensation steps, a flexible entry to different
N-bridgehead heterocycles.
N
1a,b
N
+
NH
R2
Boc
N
Key words: 1,2-diaza-1,3-butadienes, protecting groups, nitriles,
pyrroles, fused-ring systems
3a–e
2a–e
1,2-Diaza-1,3-butadienes1a–d represent an important class
of powerful intermediates in organic synthesis as Michael
acceptor reagents owing to the presence of the conjugated
heterodiene system.1e–i Among them of particular interest
are tert-butyl (3-alkoxy-1-methyl-3-oxoprop-1-enyl)di-
azenecarboxylate derivatives 1a,b (Scheme 1) that direct-
ly introduce the Boc group into a variety of heterocycles
bearing an amino function and/or nitrogen heteroatom.2
The Boc group is still one of the most widely used in syn-
thetic organic chemistry when it is required to protect
amino function due to its easy removal.3
R2
R1O2C
R1O2C
R2
H
NH2
NH
N
N
NH
NH
Boc
Boc
5a–e
4a–e
5a R1 = Et; R2 = CN
5b R1 = Et; R2 = PiperidineCO
5c R1 = Et; R2 = 4-NO2C6H4
5d R1 = Et; R2 = 2,4-Cl2C6H3
5e R1 = Me; R2 = 4-ClC6H4NHCO
Scheme 1
The nucleophilic attack of the activated methylene group
of acetonitrile derivatives 2a–e at the aza–ene system of
1a,b affords hydrazone 1,4-adducts 3a–e. By means of
intramolecular ring closure on the nitrile function we
achieved 1-Boc-protected 1,2-diaminopyrrole derivatives
5a–e (Scheme 1).4,5
The same conditions applied to 5e5b afforded a new ap-
proach to pyrrolo[2,3-d]pyrimidin-4-one derivatives9
9a,b10 by means of intramolecular ring closure owing to
the amidic NH on the iminoether function of 7e,f10 and
successive Boc removal. In this case the preliminary
deprotection of the 1-amino function to produce 1,2-di-
aminopyrrole derivative 1010 and subsequent conden-
sation with orthoesters 6a,b represents a convenient
means of obtaining pyrrolo[1,2-b][1,2,4]triazole deriva-
tives 8e,f10 (Scheme 2, Table 1).
We considered of interest their use as building blocks in a
synthetic pathway to afford different N-bridgehead
heterocycles useful as intermediates in drug discovery,
agrochemicals, photographic materials and dyes.6 A liter-
ature survey shows that the synthesis of pyrrolo[1,2-
b][1,2,4]triazole derivatives involves cyclocondensation
reaction of appropriately functionalised triazole deriva-
tives to form the fused pyrrole ring.7 Herein we propose an
alternative route to this heterocyclic pattern via 1-Boc-
protected 1,2-diaminopyrroles.
In order to widen the scope of this approach towards dif-
ferent N-bridgehead heterocycles, we explored the one-
pot reaction between pyrrole derivatives 5a–d5b and meth-
yl pyruvate under acidic heterogeneous catalysis with
Amberlyst 15H to achieve pyrrolo[1,2-b][1,2,4]triazin-3-
one11 derivatives 11a–d12 in 65–82% yields (Scheme 3).
Pyrrole derivatives 5a,b reacted with orthoesters 6a,b un-
der solvent-free conditions to produce pyrrolo[1,2-
b][1,2,4]triazole derivatives 8a–d8 through iminoether in-
termediates 7a–d8 (Scheme 2, Table 1). The reaction can
be performed more conveniently in a one-pot procedure
without the isolation of 7.
With the aim of affording derivatives bearing the pyrrolo-
triazine skeleton with a different position of the carbonyl
group in respect to 11a,b or various degrees of saturation,
we planned the selective alkylation at the 1-amino func-
tion of 5a with ethyl 2-bromoacetate (12a) or phenacyl
bromide (12b) to obtain 13a,b13 in good yields (80–83%,
Scheme 4). We found that for 13a both thermal Boc
SYNLETT 2006, No. 11, pp 1734–1738
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-947324; Art ID: D06306ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Pyrrolotriazoles
1735
Table 1 Synthesis of Pyrrolo[1,2-b][1,2,4]triazoles 8a–f and Pyrrolo[2,3-d]pyrimidin-4-ones 9a,b
Pyrrole 5
Orthoester 6
Product 7
Product 8
Product 9
R1
R2
R3
R4
Yield
(%)a
Yield
(%)a
Yield
(%)a
5a
5b
5e
Et
CN
6a
6b
H
Et
7a (5a + 6a)
7b (5a + 6b)
7c (5b + 6a)
7d (5b + 6b)
7e (5e + 6a)
7f (5e + 6b)
80
85
68
79
78
68
8a
58
61
55
58
60
86
9a (5e + 6a)
9b (5e + 6b)
90
94
Et
PiperidineCO
4-ClC6H4NHCO
Me
Me
8b
Me
8c
8d
8e (10 + 6a)
8f (10 + 6b)
a Yield of pure isolated products.
R2
5a
R1O2C
R2
R1O2C
R3C(OR4)3
6a,b
R1
NaOH
THF, r.t.
H
12a R1 = OEt
12b R1 = Ph
Br
i
N
5a,b
N
N
N
O
solvent-free
100 °C
OR4
N
R3
NH
EtO2C
CN
R3
Boc
8a–d
7a–d
13a,b 80–83%
NH2
N
Cl
N
R1 = OEt
R1 = Ph
Boc
O
R3C(OR4)3
R1
R1O2C
O
6a,b
N
i
5e
7e,f
i or ii
R3
solvent-free
100 °C
N
N
iii
9a,b
NH2
Cl
EtO2C
CN
EtO2C
CN
iv
Cl
N
N
NH
O
N
R3C(OR4)3
ii
O
R1O2C
NH
N
R1
HN
Boc
O
NH
R1O2C
6a,b
ii
15 73%
14 80–81%
H
EtO2C
CN
NH2
N
N
NH2
10
N
R3
N
N
8e,f
HN
R1
Scheme 2 Reagents and conditions: i) 180 °C; ii) Amberlyst 15H,
16 80%
refluxing dioxane, 4 h.
EtO2C
CN
O
N
EtO2C
R2
N
N
O
R1
O
N
N
5a–d
17 78%
Amberlyst 15H
dioxane, ∆
HN
Scheme 4 Reagents and conditions: i) 180 °C; ii) Amberlyst 15H,
refluxing dioxane; iii) Amberlyst 15H, refluxing THF; iv) TFA,
CH2Cl2, 0 °C.
11a–d
O
11a R2 = CN, 79%
11b R2 = PiperidineCO, 68%
11c R2 = 4-NO2C6H4, 65%
11d R2 = 2,4-Cl2C6H3, 82%
reaction conditions, 13b can give rise to different pyr-
role[1,2-b][1,2,4]triazine derivatives 15,13 16,13 and 1713
in good yields (Scheme 4). In particular, derivative 17 is
thus obtained as the sole regioisomer by a different reac-
tion pathway and in a more satisfactory yield than previ-
ously reported.5a
Scheme 3
removal and treatment with Amberlyst 15H in refluxing
dioxane led to pyrrole[1,2-b][1,2,4]triazin-2-one deriva-
tive 1412 in comparable yields (80–81%). By varying the
Synlett 2006, No. 11, 1734–1738 © Thieme Stuttgart · New York

1736
O. A. Attanasi et al.
LETTER
Analytical data of 5e: white powder from Et2O; mp 215–
In summary, we report herein an improved and flexible
condensation–deprotection or deprotection–condensation
sequence of 1-Boc-protected 1,2-diamminopyrroles with
orthoesters and different carbonyl compounds for the
synthesis of target N-bridgehead heterocycles such as
pyrrolotriazole and pyrrolotriazine derivatives that repre-
sent the core of compounds of potential usefulness in
medicinal14 and technological fields.15
217 °C (dec.). IR (nujol): 3349, 3264, 1724, 1689, 1680,
1649, 1614, 1593 cm–1. 1H NMR (400 MHz, DMSO-d6):
d = 1.47 (s, 9 H, t-BuO), 2.24 (s, 3 H, CH3), 3.84 (s, 3 H,
OCH3), 6.69 (s, 2 H, NH2) 7.34 (d, J = 7.6 Hz, 2 H, Ar), 7.64
(d, J = 7.6 Hz, 2 H, Ar), 10.14 (s, 1 H, NH), 11.73 (s, 1 H,
NH). 13C NMR (100 MHz, DMSO-d6): d = 11.33, 27.85,
52.04, 81.14, 88.97, 103.45, 120.08, 125.46, 128.39, 133.62,
138.41, 148.12, 153.61, 163.29, 167.80. Anal. Calcd for
C19H23N4O5Cl: C, 53.97; H, 5.48; N, 13.25. Found: C, 53.59;
H, 5.37; N, 13.45.
Acknowledgment
(6) (a) Pearson, W. H.; Bergmeier, S. C.; Chytra, J. A. Synthesis
1990, 156. (b) Ito, T. JP 07048376, 1995.
This work was supported by financial assistance from the M.I.U.R.-
Roma (PRIN 2004), and the Università degli Studi di Urbino ‘Carlo
Bo’.
(7) (a) Becker, H. G. O.; Steinleitner, H. D.; Timpe, H. J.
Synthesis 1973, 414. (b) Suzuki, M.; Mikoshiba, H.;
Takahashi, O.; Shimada, Y.; Matsuoka, K.; Yamazaki, S.;
Yamakawa, K.; Sato, K. EP 518238, 1992. (c) Yamazaki,
S.; Shimada, Y.; Matsuoka, M. JP 05255333, 1993.
(d) Maeda, H. JP 2000044563, 2000.
References and Notes
(1) (a) Attanasi, O. A.; Filippone, P. Synlett 1997, 1128.
(b) Boeckman, R. K.; Reed, J.; Ge, P. Org. Lett. 2001, 3,
3651. (c) Avalos, M.; Babiano, R.; Cintas, P.; Clemente, F.
R.; Gordillo, R.; Jiménez, J. L.; Palacios, J. C. J. Org. Chem.
2002, 67, 2241. (d) Palacios, F.; Aparicio, D.; de los Santos,
J. M. Tetrahedron 1999, 55, 13767. (e) Palacios, F.;
Aparicio, D.; Lopez, Y.; de los Santos, J. M. Tetrahedron
2005, 61, 2815. (f) Palacios, F.; Aparicio, D.; de los Santos,
J. M.; Ignacio, R.; Lopez, Y. Arkivoc 2005, (vi), 153.
(g) Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Mantellini, F.; Santeusanio, S. Arkivoc 2002, (xi), 274; and
the references cited therein. (h) Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Filippone, P.; Lillini, S.;
Mantellini, F.; Santeusanio, S. Synlett 2005, 1474.
(i) Attanasi, O. A.; Baccolini, G.; Boga, C.; De Crescentini,
L.; Filippone, P.; Mantellini, F. J. Org. Chem. 2005, 70,
4033.
(8) Procedure for the Preparation of Derivatives 7b and 8b.
Pyrrole derivative 5a (308 mg, 1 mmol) and 6b (4 mL) were
heated at 100 °C in an oil bath under magnetic stirring for 5
h. Then, 6b was removed under reduced pressure and the
residue was heated at 180 °C in an oil bath for 30 min. The
resulting dark residue was treated with THF and Et2O to
afford 8b as a light grey powder that was recrystallised as a
white powder from hot EtOH. Analytical data of 8b: mp
221–222 °C. IR (nujol): 3203, 3176, 2220, 1673, 1620, 1562
cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.29 (t, J = 6.8
Hz, 3 H, OCH2CH3), 2.42 (s, 3 H, CH3), 2.53 (s, 3 H, CH3),
4.23 (q, J = 6.8 Hz, 2 H, OCH2CH3), 13.43 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 10.31, 11.99, 14.21,
59.78, 59.89, 111.88, 115.71, 120.37, 137.98, 153.76,
163.11. MS: m/z (%) = 232 (28) [M+], 203 (100), 187 (20),
159 (9). Anal. Calcd for C11H12N4O2: C, 56.89; H, 5.21; N,
24.12. Found: C, 56.72; H, 5.26; N, 24.43.
(2) (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone,
P.; Mantellini, F.; Santeusanio, S. Synlett 2004, 549.
(b) Attanasi, O. A.; Carvoli, G.; Filippone, P.; Perrulli, F. R.;
Santeusanio, S.; Serri, A. M. Synlett 2004, 1643.
Derivative 7b was isolated in a separate experiment by
stopping the reaction after heating at 100 °C for 5 h and
removing 6b under reduced pressure. The oily residue was
treated with Et2O–light PE to obtain 7b as a beige powder.
Analytical data of 7b: mp 160 °C (dec.). IR (nujol): 3260,
2220, 1734, 1677, 1658, 1552 cm–1. 1H NMR (400 MHz,
DMSO-d6): d = 1.28 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.41 (s,
9 H, t-BuO), 1.99 (s, 3 H, CH3), 2.30 (s, 3 H, CH3), 3.78 (s,
3 H, OCH3), 4.23 (q, J = 7.2 Hz, 2 H, OCH2CH3), 10.32 (br
s, 1 H, NH). 13C NMR (100 MHz, DMSO-d6): d = 10.12,
13.99, 17.17, 27.60, 54.25, 59.84, 77.64, 81.28, 106.86,
115.23, 134.89, 146.04, 154.31, 162.36, 168.42. MS:
m/z (%) = 364 (38) [M+], 308 (100), 264 (88), 235 (63), 192
(58). Anal. Calcd for C17H24N4O5: C, 56.03; H, 6.64; N,
15.38. Found: C, 55.87; H, 6.68; N, 15.18.
(c) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone,
P.; Mantellini, F.; Santeusanio, S. J. Org. Chem. 2002, 67,
8178. (d) Attanasi, O. A.; Filippone, P.; Perrulli, F. R.;
Santeusanio, S. Eur. J. Org. Chem. 2002, 2323.
(e) Attanasi, O. A.; Filippone, P.; Guidi, B.; Mantellini, F.;
Santeusanio, S. Synthesis 2001, 1837.
(3) (a) Agami, C.; Couty, F. Tetrahedron 2002, 58, 2701.
(b) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley: New York, 1999.
(4) (a) Attanasi, O. A.; Foresti, E.; McKillop, A.; Santeusanio,
S.; Serra-Zanetti, F. J. Chem. Soc., Perkin Trans. 1 1990,
1669. (b) Attanasi, O. A.; De Crescentini, L.; Liao, Z.;
McKillop, A.; Santeusanio, S.; Serra-Zanetti, F. J. Chem.
Soc., Perkin Trans. 1 1992, 1009.
(5) (a) Attanasi, O. A.; De Crescentini, L.; Foresti, E.; Gatti, G.;
Giorgi, R.; Perrulli, F. R.; Santeusanio, S. J. Chem. Soc.,
Perkin Trans. 1 1997, 1829. (b) Prepared as reported in ref.
5a. Analytical data of 5d: white powder from Et2O; mp 186–
188 °C (dec.). IR (nujol): 3439, 3353, 3241, 1751, 1666,
1620, 1563 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 0.94
(t, J = 7.2 Hz, 3 H, OCH2CH3), 1.47 (s, 9 H, t-BuO), 2.26 (s,
3 H, CH3), 3.90 (q, J = 7.2 Hz, 2 H, OCH2CH3), 4.28 (s, 2 H,
NH2), 7.20–7.35 (m, 2 H, Ar), 7.52 (s, 1 H, Ar), 9.89 (br s, 1
H, NH). 13C NMR (100 MHz, DMSO-d6): d = 9.99, 13.69,
27.83, 58.37, 80.66, 95.85, 106.82, 126.45, 127.94, 128.03,
129.53, 130.68, 133.81, 134.07, 135.27, 154.21, 164.39.
Anal. Calcd for C19H23N3O4Cl2: C, 53.28; H, 5.41; N, 9.81.
Found: C, 53.44; H, 5.29; N, 9.70.
(9) Yamasaki, T.; Nakamura, H.; Okamoto, Y.; Okawara, T.;
Furukawa, M. J. Chem. Soc., Perkin Trans. 1 1992, 1287.
(10) Analytical data of 7f: white powder from Et2O–cyclohexane,
mp 167 °C (dec.). IR (nujol): 3211, 3178, 1746, 1664, 1645,
1616, 1556 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.40
(s, 9 H, t-BuO), 1.84 (s, 3 H, CH3), 2.28 (s, 3 H, CH3), 3.66
(s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 7.30 (d, J = 8.8 Hz, 2
H, Ar), 7.63 (d, J = 8.8 Hz, 2 H, Ar), 10.10 (s, 1 H, NH),
10.35 (s, 1 H, NH). 13C NMR (100 MHz, DMSO-d6):
d = 10.57, 17.27, 27.71, 51.16, 53.59, 80.74, 102.78, 105.67,
120.60, 126.11, 128.39, 133.43, 138.73, 139.92, 154.50,
162.40, 165.36, 167.74. MS: m/z (%) = 478 (13) [M+], 296
(100), 252 (21), 220 (19). Anal. Calcd for C22H27N4O6Cl: C,
55.17; H, 5.68; N, 11.70. Found: C, 55.03; H, 5.72; N, 11.65.
Analytical data of 8f: white powder from EtOAc–cyclo-
hexane, mp 235–239 °C (dec.). IR (nujol): 3393, 3075,
Synlett 2006, No. 11, 1734–1738 © Thieme Stuttgart · New York

LETTER
1670, 1635, 1588, 1555 cm–1. 1H NMR (400 MHz, DMSO-
Synthesis of Pyrrolotriazoles
1737
H, 2 OCH2CH3), 1.29 and 1.38 (2 s, 9 H, t-BuO), 2.24 and
2.27 (2 s, 3 H, CH3), 4.11–4.20 (m, 4 H, OCH2CH3), 4.40–
4.60 (m, 2 H, CH2), 6.49 (s, 2 H, NH2). 13C NMR (100 MHz,
DMSO-d6): d = 9.95, 14.09, 27.44, 51.51, 52.77, 59.54,
61.46, 65.52, 82.57, 83.07, 105.92, 116.40, 131.40, 148.09,
151.69, 152.06, 162.76, 169.62, 169.86. MS: m/z (%) = 394
(15)[M+], 338 (100), 293 (18), 265 (26), 192 (88). Anal.
Calcd for C18H26N4O6: C, 54.81; H, 6.64; N, 14.20. Found:
C, 54.67; H, 6.38; N, 14.34.
Analytical data of 14: white powder from hot EtOH, mp
246–250 °C (dec.). IR (nujol): 3250, 3114, 2218, 1699,
1612, 1567 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.26
(t, J = 6.5 Hz, 3 H, OCH2CH3), 2.35 (s, 3 H, CH3), 3.70 (d,
J = 8.0 Hz, 2 H, CH2), 4.20 (q, J = 6.5 Hz, 2 H, OCH2CH3),
6.79 (t, J = 8.0 Hz, 1 H, NH), 11.68 (s, 1 H, NH). 13C NMR
(100 MHz, DMSO-d6): d = 9.93, 14.06, 49.28, 59.66, 71.57,
106.63, 114.08, 132.04, 136.00, 162.57, 165.62. MS:
m/z (%) = 248 (87) [M+], 219 (61), 203 (27), 164 (100).
Anal. Calcd for C11H12N4O3: C, 53.22; H, 4.87; N, 22.57.
Found: C, 53.34; H, 4.96; N, 22.37.
d6): d = 2.41 (s, 3 H, CH3), 2.54 (s, 3 H, CH3), 3.87 (s, 3 H,
OCH3), 7.36 (d, J = 8.0 Hz, 2 H, Ar), 7.68 (d, J = 8.0 Hz, 2
H, Ar) 11.81 (s, 1 H, NH), 12.95 (br s, 1 H, NH). 13C NMR
(100 MHz, DMSO-d6): d = 11.48, 11.83, 52.07, 89.38,
107.69, 120.12, 121.85, 125.93, 128.76, 138.61, 154.38,
160.89, 168.71. MS: m/z (%) = 346 (25) [M+], 220 (71), 188
(74), 169 (100). Anal. Calcd for C16H15N4O3Cl: C, 55.42; H,
4.36; N, 16.16. Found: C, 55.46; H, 4.14; N, 16.01.
Analytical data of 9b: beige powder from hot EtOAc, mp
228–229 °C (dec.). IR (nujol): 3326, 3270, 3217, 3054,
1692, 1681, 1615, 1563, 1532 cm–1. 1H NMR (400 MHz,
DMSO-d6): d = 2.11 (s, 3 H, CH3), 2.52 (s, 3 H, CH3), 3.66
(s, 3 H, OCH3), 5.87 (s, 2 H, NH2), 7.39 (d, J = 8.4 Hz, 2 H,
Ar), 7.61 (d, J = 8.4 Hz, 2 H, Ar). 13C NMR (100 MHz,
DMSO-d6): d = 10.60, 23.90, 50.76, 100.23, 102.91, 129.45,
130.64, 133.28, 137.48, 139.98, 145.97, 153.79, 156.49,
164.40. MS: m/z (%) = 346 (20) [M+], 314 (58), 299 (40),
271 (13), 152 (100), 111 (70). Anal. Calcd for
C16H15N4O3Cl: C, 55.42; H, 4.36; N, 16.16. Found: C, 55.27;
H, 4.12; N, 16.22.
Preparation of Derivative 13b.
Analytical data of 10: beige powder from dioxane, mp 221–
222 °C (dec.). IR (nujol): 3464, 3344, 3195, 1661, 1641,
1594, 1546 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 2.42
(s, 3 H, CH3), 3.83 (s, 3 H, OCH3), 5.53 (s, 2 H, NH2), 6.48
(s, 2 H, NH2), 7.33 (d, J = 8.5 Hz, 2 H, Ar), 7.63 (d, J = 8.5
Hz, 2 H, Ar), 11.93 (s, 1 H, NH). 13C NMR (100 MHz,
DMSO-d6): d = 12.11, 51.83, 89.12, 101.66, 119.91, 125.24,
128.49, 135.22, 138.69, 148.59, 163.49, 168.18. MS:
m/z (%) = 322 (4) [M+], 290 (13), 196 (12), 168 (28), 153
(56), 127 (100). Anal. Calcd for C14H15N4O3Cl: C, 52.10; H,
4.68; N, 17.36. Found: C, 52.26; H, 4.82; N, 17.09.
(11) Dickinson, C. L.; Middleton, W. J.; Engelhardt, V. A. J. Org.
Chem. 1962, 27, 2470.
Pyrrole derivative 5a (308 mg, 1 mmol) and NaOH (50 mg,
1.25 mmol) were suspended in THF (4 mL) and
magnetically stirred for 10 min at r.t. Then, 12b (229 mg,
1.15 mmol) was added to the reaction mixture and the
stirring was maintained for 24 h. The reaction work-up was
the same as for 13a. The crude was recrystallised from
EtOAc–light PE to obtain 13b as a white powder.
Analytical data of 13b: mp 157 °C (dec.). IR (nujol): 3327,
3243, 3194, 2220, 1726, 1703, 1693, 1650, 1592 cm–1. 1H
NMR (400 MHz, DMSO-d6): d = 1.26 (t, J = 6.8 Hz, 3 H,
OCH2CH3), 1.30 and 1.33 (2 s, 9 H, t-BuO), 2.32 and 2.35 (2
s, 3 H, CH3), 4.19 (q, J = 6.8 Hz, 2 H, OCH2CH3), 5.13 and
5.15 (2 overlapped d, J = 18.4 Hz, 1 H, COCHaCHb), 5.51
(d, J = 18.4 Hz, 1 H, COCHaCHb), 6.60 and 6.63 (2 s, 2 H,
NH2), 7.60 (t, J = 7.6 Hz, 2 H, Ar), 7.72 (t, J = 7.6 Hz, 1 H,
Ar), 8.04 (d, J = 7.6 Hz, 2 H, Ar). 13C NMR (100 MHz,
DMSO-d6): d = 10.70, 14.70, 14.81, 28.13, 28.29, 57.25,
58.29, 60.25, 66.14, 83.09, 83.51, 106.58, 117.15, 128.92,
129.65, 132.09, 134.99, 149.08, 152.64, 152.92, 163.49,
196.03, 196.62. MS: m/z (%) = 426 (7) [M+], 370 (60), 352
(62), 192 (50), 164 (100). Anal. Calcd for C22H26N4O5: C,
61.96; H 6.15; N, 13.14. Found: C, 61.72; H, 6.24; N, 13.26.
Preparation of Derivative 15.
Compound 13b (426 mg, 1 mmol) was refluxed in THF (5
mL) in the presence of Amberlyst 15H (400 mg) for 12 h.
The resin was removed by filtration, THF was evaporated
under reduced pressure and treated with Et2O to obtain a
yellow residue. The crude was recrystallised from MeOH to
furnish 15 as light orange crystals.
Analytical data of 15: mp 137–139 °C (dec.). IR (nujol):
3070, 2227, 1751, 1707, 1539 cm–1. 1H NMR (400 MHz,
DMSO-d6): d = 1.20–1.33 (m, 12 H, OCH2CH3 and t-BuO),
2.45 (2 s, 3 H, CH3), 4.28 (q, J = 7.2 Hz, 2 H, OCH2CH3),
4.40 (d, J = 17.2 Hz, 1 H, CHaCHb), 5.62 (d, J = 17.2 Hz, 1
H, CHaCHb), 6.60 and 6.63 (2 s, 2 H, NH2), 7.56–7.65 (m, 3
H, Ar), 8.09 (d, J = 8.4 Hz, 2 H, Ar). 13C NMR (100 MHz,
DMSO-d6): d = 11.20, 14.71, 27.91, 47.32, 60.93, 85.91,
85.98, 109.81, 114.53, 127.98, 129.84, 133.42, 134.86,
135.89, 138.57, 154.98, 162.85, 164.22. MS: m/z (%) = 408
(11) [M+], 352 (100), 323 (19), 307 (13). Anal. Calcd for
C22H24N4O4: C, 64.69; H, 5.92; N, 13.71. Found: C, 64.71;
H, 5.92; N, 13.69.
(12) Representative Procedure for the Preparation of
Derivative 11d.
Pyrrole derivative 5d (428 mg, 1 mmol) and methyl pyruvate
(135 mg, 1.323 mmol) were refluxed in dioxane (4 mL) in
the presence of Amberlyst 15H (400 mg) for 2 h. Then the
resin was removed by filtration and the solvent evaporated
under reduced pressure. The residue, treated with Et2O, gave
derivative 11d as a yellow powder.
Analytical data of 11d: mp 226–229 °C. IR (nujol): 3129,
3077, 1706, 1679, 1578 cm–1. 1H NMR (400 MHz, DMSO-
d6): d = 0.96 (t, J = 7.2 Hz, 3 H, OCH2CH3), 2.27 (s, 3 H,
CH3), 2.60 (s, 3 H, CH3), 3.97 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 7.29 (d, J = 8.4 Hz, 1 H, Ar), 7.38 (d, J = 8.4 Hz,
1 H, Ar), 7.60 (s, 1 H, Ar), 12.19 (s, 1 H, NH). 13C NMR (100
MHz, DMSO-d6): d = 9.64, 13.61, 17.39, 59.19, 95.53,
110.21, 123.49, 126.36, 126.53, 128.06, 130.84, 132.16,
134.38, 135.70, 150.23, 151.82, 164.02. MS: m/z (%) = 379
(75) [M+], 350 (100), 344 (58), 316 (91). Anal. Calcd for
C17H15N3O3Cl2: C, 53.70; H, 3.98; N, 11.05. Found: C,
53.58; H, 3.72; N, 11.18.
(13) Preparation of Derivative 13a.
Pyrrole derivative 5a (308 mg, 1 mmol) and NaOH (100 mg,
2.5 mmol) were suspended in THF (4 mL) and magnetically
stirred for 10 min at r.t. Then 12a (334 mg, 2 mmol) was
added to the reaction mixture and the stirring was continued
for 30 min; THF was removed under reduced pressure and
the residue was dissolved in EtOAc and washed with H2O in
a separatory funnel. The organic phase was dried over
Na2SO4 and evaporated under reduced pressure; the solid
residue was recrystallised from hot EtOAc to give 13a as a
white powder.
Preparation of Derivative 16.
Compound 13b (426 mg, 1 mmol) was dissolved at 0 °C in
a mixture of CH2Cl2–TFA (1:1, 8 mL) and maintained at the
same temperature for 2.75 h. Then the solvent was removed
under reduced pressure and the residue was treated with
Analytical data of 13a: mp 155–157 °C (dec.). IR (nujol):
3347, 3321, 3244, 3205, 2214, 1742, 1724, 1699, 1652, 1590
cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.15–1.26 (m, 6
Synlett 2006, No. 11, 1734–1738 © Thieme Stuttgart · New York

1738
O. A. Attanasi et al.
LETTER
Et2O to obtain a yellow powder that was recrystallised from
CHCl3–light PE to give pure derivative 16.
Preparation of Derivative 17.
Compound 13b (426 mg, 1 mmol) was refluxed in dioxane
(5 mL) in the presence of Amberlyst 15H (400 mg) for 8 h.
The resin was removed by filtration and dioxane was
evaporated under reduced pressure. The residue, treated with
Et2O, furnished pure derivative 17 as red-orange crystals in
a 78% yield, with analytical data as previously reported.
(14) Hunt, J. T.; Mitt, T.; Borzillen, R.; Gullo-Brown, J.;
Fargnoli, J.; Fink, B.; Han, W.-C.; Mortillo, S.; Vite, G.;
Wautlet, B.; Wong, T.; Yu, C.; Zheng, X.; Bhide, R. J. Med.
Chem. 2004, 47, 4054.
Analytical data of 16: mp 202–203 °C (dec.). IR (nujol):
3258, 2215, 1682, 1550 cm–1. 1H NMR (400 MHz, DMSO-
d6): d = 1.30 (t, J = 6.8 Hz, 3 H, OCH2CH3), 2.45 (s, 3 H,
CH3), 4.25 (q, J = 6.8 Hz, 2 H, OCH2CH3), 4.31 (d, J = 8.8
Hz, 2 H, CH2), 6.37 (t, J = 8.8 Hz, 1 H, NH), 7.50–7.60 (m,
3 H, Ar), 8.07 (d, J = 8.4 Hz, 2 H, Ar). 13C NMR (100 MHz,
DMSO-d6): d = 9.91, 14.12, 43.91, 59.89, 84.49, 108.47,
114.60, 127.18, 128.90, 131.99, 133.81, 134.86, 139.16,
162.85. MS: m/z (%) = 308 (82) [M+], 277 (100), 250 (42).
Anal. Calcd for C17H16N4O4: C, 66.22; H, 5.23; N, 18.17.
Found: C, 66.18; H, 5.26; N, 18.19.
(15) Takahashi, O.; Soejima, S. JP 11024217, 1999.
Synlett 2006, No. 11, 1734–1738 © Thieme Stuttgart · New York