One-pot synthesis of new fused 4,5-bridged l,2,5-triazepine-3,6-diones, l,2,5-triazepine-3,7-diones heterocycles by Petasis reaction

Article abstract of DOI:10.1021/cc900092x

The one pot synthesis of a new fused l,2,5-triazepine-3,6-diones, l,2,5-triazepine-3,7-diones heterocyles has been described via Petasis reactions. These heterocycles might be suitable for elaboration into larger peptides at amino termini. The scope and limitations of this method have been examined.

Full text of DOI:10.1021/cc900092x

J. Comb. Chem. 2010, 12, 75–83
75
One-Pot Synthesis of New Fused 4,5-Bridged
1,2,5-Triazepine-3,6-diones, 1,2,5-Triazepine-3,7-diones Heterocycles
by Petasis Reaction
Subhasish Neogi, Amrita Roy, and Dinabandhu Naskar*
Syngene International Ltd, Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road,
Bangalore 560 099, India
ReceiVed June 24, 2009
The one pot synthesis of a new fused 1,2,5-triazepine-3,6-diones, 1,2,5-triazepine-3,7-diones heterocyles
has been described via Petasis reactions. These heterocycles might be suitable for elaboration into larger
peptides at amino termini. The scope and limitations of this method have been examined.
Introduction
and regulating both the activation and breakdown of peptide
hormones.12 Proline is unique among proteogenic amino
acids in possessing a secondary amino group. Acyl prolines
possess no amide hydrogen atoms and, therefore, the energies
of the cis- and trans-isomeric forms are similar.13 In nature,
the Xaa- Pro peptide (Xaa ) any proteinogenic amino acid)
bond can exist in both stable conformations, structure I and
II, and both forms occur in proteins as in ribonuclease,14
and in bioactive peptides, such as bradykinin.15a
It was reported that some proline-containing bioactive
peptides including angiotensin and thyroliberin are believed
to bind to their receptor with the Pro residue fixed in the
cis-form.15b
With the recent emergence of combinatorial chemistry and
high speed parallel synthesis in the lead discovery arena,
the multicomponent reaction (MCR) has witnessed a resur-
gence of interest.1 Easily automated one-pot reactions, such
as Ugi,2 Passerini,3 Petasis4 reactions are powerful tools for
producing diverse arrays of compounds, often in one step
and high yield. The Petasis Boronic Acid-Mannich reaction
which provides a powerful and convenient method for the
preparation of R-amino acids4 is also quite useful for the
synthesis of combinatorial libraries. In earlier studies, it was
shown that hydrazine can participate in the Petasis Boronic
Acid-Mannich reaction to afford various R-hydrazinocar-
boxylic acids.5 Because of our interests in the synthesis of
combinatorial libraries of heterocycles for drug discovery,6,7
we have investigated further the scope and limitations of
using substituted hydrazines in the Petasis Boronic Acid-
Mannich reaction. Within this context, we wished to apply
the strategy more broadly to the preparation of heterocycles,
that is, drug like chemical collections, for high throughput
biological screening. Herein, we report a practical method
for the synthesis of 4,5-bridged 1,2,5-triazepine-3,6-diones,
1,2,5-triazepine 3,7-diones heterocyles via multicomponent
condensation reactions in one pot. However, there is no
literature report available for the synthesis of 1,2,5-triazepine-
3,6-diones 2, 6 and 1,2,5-triazepine-3,7-diones 4 via Petasis
reaction.
Robinson et. al reported the synthesis of dipeptide cis-
Gly-Pro (III)16 which is expected to mimic VI turn.
Curran et. al reported the synthesis of bicyclic dipeptides
having constrained cis-proline amides (IV).17
Gani et al. reported the synthesis of new fused 1,2,5-
triazepine-1,5-dione heterocycles (V and VI)18a,b which is
expected to mimic structural features of cis-peptidyl proli-
namides which might be used as reverse turn mimetic in the
design of biologically active molecules that need to emulate
features of the common ꢀ-turn motifs (e.g., type I, II, IV).
ꢀ-Turns are not only important structural features in
protein secondary structures but are implicated in the receptor
bound conformations of many bioactive peptides.15a,18-20
Work on the synthesis of systems designed to mimic the
various types of ꢀ-turns include indole derivatives,21 R-alky-
lated aspartic and glutamic acids,22 azanorbornane deriva-
tives,23 and acetylenes.24,25
It is also well-known that benzodiazepine diones (com-
pound VII) constitute an important class of bioactive
compounds. Members of this class have been identified as
platelet aggregation inhibiting mimics of the argentine-
glycine-aspartic acid (RGD) peptide sequence, as anticon-
vulsant agents, as anxiolytic agents, and as antitumor
compounds.26
Unlike the other 19 common amino acids, which pre-
dominantly assume trans-amide conformations when incor-
porated into peptides and proteins, proline amides display
an equal tendency to assume both the cis- (I) and trans-
amide (II) conformation.8 Because only proline amides
possess this conformational flexibility, it has been speculated
that cis-trans proline isomerization plays many important
biochemical roles, including controlling the rate of protein
folding,9 triggering receptor-mediated transmembrane signal-
ing,10 providing a recognition element in peptide antigens,11
Because of a lack of a general synthetic method may have
precluded a comprehensive biological evaluation of this
* To whom correspondence should be addressed. E-mail: dinabandhu.
naskar@syngeneintl.com, dbn70@yahoo.com.
10.1021/cc900092x  2010 American Chemical Society
Published on Web 12/02/2009

76 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Neogi et al.
afforded 45% yield of the desired product after purification.
When R1 ) substituted phenyl and Bn and R2 ) substituted
aryl (2h-2m), these reactions proceeded in moderate yields
affording 39-54% of the corresponding 4,5-bridged 1,2,5-
triazepine-3,6-diones after purification by HPLC. As ex-
pected, the product consisted of a 50:50 mixture of racemic
diastereomers (liquid chromatography mass spectroscopy,
LCMS). In the example 2a, the racemic diastereomers (1:1)
were separated by preparative HPLC and characterized by
LCMS, 1H NMR, 13C NMR, and high resolution mass
spectrometry (HRMS) [2a(A) and 2a(B)]. In the example
2m also, the racemic diastereomers (1:1) were separated by
1
preparative HPLC and characterized by LCMS, H NMR,
13C NMR, and CHN [2 m(A) and 2 m(B)]. It is noteworthy
that the reactions proceed through the Petasis, coupling, de-
Boc, and cyclization in one pot without purification until
the final product (2) is isolated. (Table 1; Figure 3).
In Table 2; when R1 ) Bn, and R2 ) naphthyl, aryl (4a-
4b), these reactions proceeded in moderate yields ranging
from 34-48% of the corresponding 4,5-bridged 1,2,5-
triazepine-3,7-diones after purification by HPLC. When R1
) cyclohexyl, and R2 ) aryl, (4c-4d), these reactions
proceeded in 32% yields of the desired product after
purification. As expected, the product consisted of a 50:50
mixture of racemic diastereomers (LCMS). In the example
4a, the racemic diastereomers (1:1) were separated by
interesting structural class of compounds for these new fused
1,2,5-triazepine-3,6-diones, 1,2,5-triazepine-3,7-diones de-
rivatives, herein, we report an efficient synthesis of 4,5-
bridged 1,2,5-triazepine-3,6-diones, and 4,5-bridged 1,2,5-
triazepine-3,7-dionesderivativesviamulticomponentcondensation
reactions in one pot (Tables 1, 2, and 3).
1
preparative HPLC and characterized by LCMS, H NMR,
13C NMR, and HRMS/CHN [4a(A) and 4a(B)]. Similar to
the above reaction, the reactions proceed through the Petasis,
coupling, de-Boc, and cyclization in one pot without
purification until the final product (4) is isolated (Table 2;
Figure 3).
Result and Discussion
In Table 3; when R1 ) Bn, and R2 ) aryl (6a-6e), these
reactions proceeded in poor yields in one pot ranging from
25%-35% of the corresponding 4,5-bridged 1,2,5-triazepine-
3,6-diones after purification by HPLC. The reactions proceed
through the Petasis, coupling, de-Boc, and cyclization in one
pot without purification until the final product (6) is isolated
(Table 3; Figure 3).
A variety of N-1-Boc-N-2-(alkyl)-hydrazines5 (Figure 1)
were subjected to Petasis three component condensation
reaction in the presence of glyoxylic acid monohydrate and
a variety of boronic acids (Figure 2) in dichloromethane
(DCM) for 24 h, coupling with L-proline methyl ester
hydrochloride in the presence of HBTU/DIEA, Boc depro-
tection using 4 M HCl in 1,4-dioaxne and upon evaporation
of the crude reaction mixture which was then cyclized in
presence of toluene/HOAc/reflux overnight (Table 1).
Similarly, L-proline methylesterhydrochloride was sub-
jected to Petasis, coupling with a variety of N-1-Boc-N-2-
(alkyl)-hydrazines, de-Boc and cyclization conditions (Table
2).
Also, N-1-Boc-N-2-benzyl hydrazine was subjected to
Petasis, coupling with pipecolic acid methyl ester hydro-
chloride, de-Boc and cyclization conditions (Table 3).
In Table 1; when R1 ) Bn and R2 ) aryl (2a-2c), these
reactions proceeded in moderate yields affording 42-50%
of the corresponding 4,5-bridged 1,2,5-triazepine-3,6-diones
after purification by high-performance liquid chromatography
(HPLC). It is also interesting that when R2 ) heterocyclic
(2d), the reaction afforded 36% yield of the desired product
after purification. When R1 ) cyclohexyl and R2 ) aryl (2e-
2f), these reactions proceeded in moderate yields affording
43-48% of the corresponding 4,5-bridged 1,2,5-triazepine-
3,6-diones after purification by HPLC. It is to be noted that
when R1 ) CH2CO2Me, and R2 ) naphthyl (2g), this reaction
Conclusion
In summary, we have demonstrated that an efficient
synthesis of 4,5-bridged 1,2,5-triazepine-3,6-diones, and 4,5-
bridged 1,2,5-triazepine-3,7-diones heterocycles have been
developed from N-1-Boc-N-2-(alkyl/phenyl substituted)-
hydrazines utilizing multicomponent condensation reactions
in one pot. All these compounds are having two/three points
of diversity, and these heterocycles might be further suitable
for elaboration into larger peptides at amino termini. To the
best of our knowledge these compounds have not been
synthesized previously.
Experimental Section
General Procedure for the Synthesis of 4,5-Bridged
1,2,5-Triazepine-3,6-diones 2 (Table 1). To a stirred
mixture of glyoxylic acid monohydrate (184 mg, 2 mmol)
in DCM (5 mL) was added N-1-Boc-N-2-(benzyl)-hydrazine
(446 mg, 2 mmol) followed by p-methoxyphenyl boronic
acid (304 mg, 2 mmol). The resulting mixture was stirred at

Fused 4,5-Bridged 1,2,5-Triazepine-3,6-diones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 77
Table 1. Synthesis of 4,5-Bridged 1,2,5-Triazepine-3,6-diones
a All yields refer to pure, isolated products; the reactions proceed through the Petasis, coupling, de-Boc, and cyclization in one pot without
purification until the final product (2) is isolated. All compounds have been characterized by LC-MS, 1H NMR, 13C NMR, and HRMS.
ambient temperature for 24 h, and to this solution were added
L-proline methyl ester hydrochloride (331 mg, 2 mmol),
HBTU (759 mg, 2 mmol), DIEA (774 mg, 6 mmol); the
reaction mixture was stirred at ambient temperature for 4 h,
and after this time, the solvent was removed and dried under
reduced pressure. To this reaction mixture was added 4.0 M
HCl (4 mL) in dioxane. The resulting mixture was stirred at
ambient temperature for 3 h. The solvent was evaporated
and dried under reduced pressure. To a solution of this
reaction mixture in toluene (20 mL) was added HOAc (0.20
mL) and refluxed for overnight. The solvent was removed
and the crude product was purified by HPLC to afford 310
mg (42%) of 2a as a white solid. The diastereomers (A and
B) have been separated by preparative HPLC; [Polaris C18
column (250 × 500 mm, 10 µm particle size), mobile phase
0.1% aqueous TFA/CH3CN linear gradient over 55 min, 6.0
mL/min]; analytical HPLC: Polaris C18 column (4.6 × 250
mm, 3 µm particle size), mobile phase 0.1% aqueous
phosphoric acid/CH3CN linear gradient over 30 min, 1 mL/
min, one peak detected by ELS and UV at 220 nm, tR )
5.64 (A) and another peak detected by ELS and UV at 220
nm, tR ) 7.66 (B).
2a(A). White solid, m.p (Met-TempII): 108°-109 °C
(uncorrected); [R]D -30.90 (c ) 0.488, CHCl3, at 20 °C);
1H NMR (CDCl3, 300 MHz): δ ) 1.86-2.14 (m, 3H), 2.63
(m, 1H), 3.42 (m, 1H), 3.53 (d, J ) 14.1 Hz, 1H), 3.75 (m,
1H), 3.84 (s, 3H), 3.98 (d, J ) 14.4 Hz, 1H), 4.56 (s, 1H),
5.46 (m, 1H), 6.80 (br. s, 1H), 6.99 (d, J ) 8.7 Hz, 2H),
7.21 (m, 2H), 7.34 (m, 3H), 7.53 (d, J ) 9 Hz, 2H); 13C
NMR (CDCl3, 75 MHz): 22.88, 29.23, 48.55, 55.73, 57.32,
75.96, 115.11, 128.45, 129.17, 129.83, 130.19, 131.39,
135.36, 160.38, 169.79, 172.57; LCMS (ELSD): 366.1

78 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Table 2. Synthesis of 4,5-Bridged 1,2,5-Triazepine-3,7-diones
Neogi et al.
a All yields refer to pure, isolated products; the reactions proceed through the Petasis, coupling, de-Boc, and cyclization in one pot without
purification until the final product (4) is isolated. All compounds have been characterized by LC-MS, 1H NMR, 13C NMR, and HRMS.
Table 3. Synthesis of 4,5-Bridged 1,2,5-Triazepine-3,6-diones
a All yields refer to pure, isolated products; the reactions proceed through the Petasis, coupling, de-Boc, and cyclization in one pot without
purification until the final product (6) is isolated. All compounds have been characterized by LC-MS, 1H NMR, and 13C NMR.
Figure 1. Diversity reagents 1.
(M+H+); HRMS: 366.180917 [Calcd for C21H24N3O3
5.14 (m, 1H), 6.13 (br. s, 1H), 6.96 (d, J ) 9 Hz, 2H), 7.04
(d, J ) 9 Hz, 2H), 7.29-7.39 (m, 5H); 13C NMR (CDCl3,
75 MHz): 22.80, 27.83, 48.95, 55.72, 58.60, 58.97, 70.91,
114.65, 124.34, 128.62, 129.29, 129.32, 131.07, 132.97,
160.20, 169.09, 171.49; LCMS (ELSD): 366.1 (M+H+);
HRMS: 366.180545 [Calcd for C21H24N3O3 366.181767
(M+H)+].
366.181767 (M+H)+].
2a(B). White solid, m.p (Met-TempII): 179°-180 °C
(uncorrected); [R]D -29.959 (c ) 0.484, CHCl3, at 20 °C);
1H NMR (CDCl3, 300 MHz): δ ) 1.92-2.2 (m, 3H), 2.64
(m, 1H), 3.67 (m, 1H), 3.72 (d, J ) 13.2 Hz, 1H), 3.77 (m,
1H), 3.85 (s, 3H), 3.93 (d, J ) 12.9 Hz, 1H), 4.79 (s, 1H),

Fused 4,5-Bridged 1,2,5-Triazepine-3,6-diones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 79
Figure 2. Diversity reagents 1A.
Figure 3. New fused 4,5-bridged 1,2,5-triazepine-3,6-diones, 1,2,5-triazepine-3,7-diones heterocycles.
2b. White Solid; m.p (Met-Temp): 178°-179 °C (uncor-
7.30-7.38 (m, 3H); 13C NMR (CDCl3, 75 MHz): 22.89,
1
rected); H NMR (CDCl3, 300 MHz): δ ) 1.87-1.93 (m,
27.78, 49.02, 56.34, 56.46, 57.32, 57.44, 112.18, 117.61,
120.91, 121.22, 125.13, 128.43, 128.94, 129.09, 135.50,
149.92, 169.73, 172.85; LCMS (ESI): 396.1 (M+H+);
HRMS: 396.1921 [Calculated for C22H26N3O4 396.1923
(M+H)+].
3H), 2.52 (s, 3H), 2.55 (m, 1H), 3.44 (m, 1H), 3.54 (d, J )
14.1 Hz, 1H), 3.73 (m, 1H), 3.99 (d, J ) 14.1 Hz, 1H), 4.57
(s, 1H), 5.45-5.48 (m, 1H), 6.63 (br. s, 1H), 7.19-7.22 (m,
2H), 7.3-7.35 (m, 5H); 7.53 (d, J ) 8.4 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): 15.98, 22.88, 26.9, 48.53, 57.3, 57.46,
76.13, 127.47, 128.52, 129.04, 129.19, 134.76, 135.09,
140.05, 169.2, 172.5; LCMS (ELSD): 381.9 (M+H+);
HRMS: 382.1581 [Calculated for C21H24N3O2S 382.1589
(M+H)+].
2d. White Solid; m.p (Met-Temp): 223°-224 °C (uncor-
1
rected); H NMR (CDCl3, 300 MHz): δ ) 1.88-1.96 (m,
2H), 2.1-2.17 (m, 1H), 2.61 (m, 1H), 3.40-3.44 (m, 1H),
3.67-3.78 (m, 2H), 4.22 (d, J ) 14.1 Hz, 1H), 5.06 (s, 1H),
5.44-5.48 (m, 1H), 6.88 (br. s, 1H), 7.29-7.41 (m, 7H),
7.60 (s, 1H), 7.80-7.87 (m, 2H); 13C NMR (CDCl3, 75
MHz): 22.89, 26.80, 48.58, 57.24, 57.66, 72.72, 122.85,
125.06, 125.23, 125.42, 125.58, 128.90, 129.01, 129.33,
134.77, 139.47, 140.13, 140.73, 168.5, 172.8; LCMS (ELSD):
392.1 (M+H+); HRMS: 392.148332 [Calculated for
C22H22N3O2S 392.148874 (M+H)+].
2c. White Solid; m.p (Met-Temp): 85°- 86 °C (uncor-
1
rected); H NMR (CDCl3, 300 MHz): δ ) 1.88-1.96 (m,
2H), 2.09-2.16 (m, 1H), 2.64 (m, 1H), 3.46 (m, 1H), 3.53
(d, J ) 14.1 Hz, 1H), 3.77 (m, 1H), 3.93 (s, 3H), 3.96 (s,
3H), 4.02 (d, J ) 14.1 Hz, 1H), 4.56 (s, 1H), 5.43-5.48 (m,
1H), 6.94-6.96 (m, 1H), 7.08 (s, 1H), 7.17-7.23 (m, 3H);

80 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
2e. White Solid; m.p (Met-Temp): 185°- 186 °C (uncor-
Neogi et al.
3.76-3.81 (m, 1H), 3.92-3.97 (m, 1H), 4.93-4.97 (m, 1H),
5.16 (s, 1H), 6.44 (s, 1H), 6.53-6.55 (d, J ) 7.56, 1H),
6.61-6.63 (d, J ) 7.6, 1H), 6.86-6.88 (d, J ) 8.24, 1H),
7.10-7.15 (m, 2H), 7.22-7.28 (m, 3H); 13C NMR (CDCl3,
100 MHz): 19.16, 22.38, 27.81, 48.69, 55.20, 58.34, 71.87,
114.22, 114.88, 119.75, 121.33, 125.22, 126.72, 129.85,
130.09, 132.10, 134.76, 145.43, 159.69, 168.60, 172.36;
LCMS (UV): 366.2 (M+H+). Anal. Calcd for C21H23N3O3:
C, 69.02; H, 6.34; N, 11.50. Found: C, 69.14; H, 6.40; N,
11.55.
1
rected); H NMR (CDCl3, 300 MHz): δ ) 0.72 (m, 2H),
1.20-1.23 (m, 3H), 1.62-1.66 (m, 4H), 1.84-2.04 (m, 3H),
2.13-2.41 (m, 4H), 2.68 (m, 1H), 3.39-3.43 (m, 1H),
3.75-3.79 (m, 1H), 4.39 (s, 1H), 5.45-5.5 (m, 1H), 6.65
(br. s, 1H), 7.3-7.46 (m, 5H), 13C NMR (CDCl3, 75 MHz):
22.91, 25.93, 26.03, 26.74, 26.91, 31.34, 31.43, 34.94, 46.09,
48.42, 57.14, 60.37, 126, 128.66, 129.07, 129.36, 129.59,
138.32, 169.68, 172.73; LCMS (ESI): 342.2 (M+H+);
HRMS: 342.2172 [Calculated for C20H28N3O2 342.2182
(M+H)+].
2k. White solid; m.p (Met-Temp): 189°-190 °C (uncor-
rected); H NMR (CDCl3, 400 MHz): δ ) 1.82-1.85 (m,
1
2f. White Solid; m.p (Met-Temp): 90°-91 °C (uncor-
1
rected); H NMR (CDCl3, 300 MHz): δ ) 0.66-0.78 (m,
1H), 1.99-2.11 (m, 2H), 2.45 (s, 3H), 2.54-2.58 (m, 1H),
3.71-3.75 (m, 1H), 3.81-3.84 (m, 1H), 4.43-4.47 (m, 1H),
5.91 (s, 1H), 6.93 (s, 1H), 6.97-7.02 (m, 3H), 7.06-7.08
(d, J )8.32, 2H), 7.19-7.21 (d, J ) 8.32, 2H), 7.33-7.35
(m, 2H); 13C NMR (CDCl3, 100 MHz): 17.94, 24.59, 30.36,
50.99, 60.02, 68.68, 115.11, 123.54, 129.16, 131.34, 132.38,
134.05, 141.79, 148.42, 170.31, 175.06; LCMS (UV): 368.2
(M+H+). Anal. Calcd for C20H21N3O2S: C, 65.37; H, 5.76;
N, 11.44. Found: C, 65.32; H, 5.81; N, 11.38.
2H), 1.05-1.23 (m, 3H),1.45-1.50 (m, 2H), 1.57-1.66 (m,
2H), 1.83-1.99 (m, 3H), 2.12-2.23 (m, 2H), 2.36-2.44 (m,
2H), 2.65-2.71 (m, 1H), 3.37-3.45 (m, 1H), 3.71-3.79 (m,
1H), 3.83 (s, 3H), 4.34 (s, 1H), 5.42-5.47 (m, 1H), 6.45
(br. s, 1H), 6.91 (d, J ) 8.7 Hz, 2H), 7.35 (d, J ) 8.7 Hz,
2H); 13C NMR (CDCl3,75 MHz): 22.91, 25.71, 25.95, 26.75,
26.92, 31.37, 31.48, 34.95, 48.42, 55.67, 57.15, 55.98, 60.35,
114.77, 129.74, 130.40, 133.21, 160.15, 169.96, 172.73:
LCMS (ELSD): 372.1 (M+H+); HRMS: 372.228179 [Cal-
culated for C21H30N3O3 372.228717 (M+H)+].
2l. White solid; m.p (Met-Temp): 69°-70 °C (uncor-
rected); H NMR (CDCl3, 400 MHz): δ ) 1.84-1.87 (m,
1
2g. White Solid; m.p (Met-Temp): 181°-182 °C (uncor-
1H), 2.01-2.12 (m, 2H), 2.58-2.63 (m, 1H), 3.73-3.75 (m,
1H), 3.80 (s, 3H), 3.81-3.87 (m, 1H), 4.49-4.53 (m, 1H),
5.99 (s, 1H), 6.84 (s, 1H), 6.85-6.87 (m, 3H), 6.98-7.08
(m, 5H), 7.35-7.39 (m, 2H); 13C NMR (CDCl3, 100 MHz):
22.16, 27.96, 48.57, 55.31, 57.67, 66.22, 112.71, 114.43,
121.03, 127.03, 129.74, 129.94, 146.08, 159.69, 168.31,
172.70; LCMS (UV): 352.2 (M+H+). Anal. Calcd for
C20H21N3O3: C, 68.36; H, 6.02; N, 11.96. Found: C, 68.23;
H, 6.09; N, 11.88.
2m(A). White solid; m.p (Met-Temp): 85°-87 °C (uncor-
rected); [R]D -18.52 (c ) 0.866, CH2Cl2, at 20 °C); 1HNMR
(CDCl3, 400 MHz): δ ) 1.85-1.94 (m, 2H), 2.07-2.12 (m,
1H), 2.56-2.61 (m, 1H), 3.39-3.44 (m, 1H), 3.49-3.52 (m,
1H), 3.70-3.74 (m, 1H), 3.87 (s, 3H), 3.91-3.95 (m, 1H),
4.54 (s, 1H), 5.38-5.42 (m, 1H), 6.98-7.03 (m, 1H), 7.09
(s, 1H), 7.15-7.17 (d, J ) 7.64, 2H), 7.26-7.32 (m, 5H);
13C NMR (CDCl3, 100 MHz): 22.44, 26.46, 48.26, 56.30,
56.92, 57.08, 75.17, 113.90, 124.83, 128.23, 128.77, 128.87,
130.18, 134.49, 148.19, 148.30, 151.42, 153.88, 168.86,
172.14; LCMS (UV): 384.2 (M+H+). Anal. Calcd for
C21H22FN3O3: C, 65.78; H, 5.78; N, 10.96. Found: C, 65.69;
H, 5.75; N, 10.83.
1
rected); H NMR (CDCl3, 300 MHz): δ ) 1.85-2.37 (m,
3H), 2.6-2.8 (m, 1H), 3.31(s, 3H), 3.55-3.61 (m, 1H),
3.79-3.91 (m, 3H), 5.25-5.45 (m, 1H), 5.75-5.98 (m, 1H),
7.01 (br s., 1H), 7.15 (m, 1H), 7.48-7.58 (m, 3H), 7.89-7.94
(m, 3H); 13C NMR (CDCl3, 75 MHz): 22.85, 27.87, 49.33,
52.25, 56.71, 58.68, 67.03, 122.61, 125.7, 126.25, 127.27,
127.81, 129.64, 129.85, 129.99, 132.79, 134.47, 169.80,
172.41; LCMS (ELSD): 368.1 (M+H+); HRMS: 368.1604
[Calculated for C20H22N3O4 368.1610 (M+H)+].
2h. White solid; m.p (Met-Temp): 73°-74 °C (uncor-
rected); H NMR (CDCl3, 400 MHz): δ ) 1.75 (m, 1H),
1
1.99-2.08 (m, 2H), 2.55-2.60 (m, 1H), 3.70-3.74 (m, 1H),
3.75 (s, 3H), 3.82 (s, 3H), 3.87-3.94 (m, 1H), 4.39-4.44
(m, 1H), 5.87 (s, 1H), 6.63 (s, 1H), 6.67-6.69 (d, J )8.2,
1H), 6.79-6.81 (d, J )8.28, 1H), 6.96-7.03 (m, 4H),
7.33-7.37 (m, 2H); 13C NMR (CDCl3, 100 MHz): 22.07,
27.87, 48.71, 55.77, 57.83, 66.42, 111.19, 111.54, 112.76,
120.92, 121.17, 126.79, 129.92, 145.88, 149.12, 149.27,
168.89, 172.55; LCMS (UV): 382.1 (M+H+). Anal. Calcd
For C21H23N3O4: C, 66.13; H, 6.08; N, 11.02. Found: C,
66.22; H, 6.12; N, 11.11.
2i. White solid; m.p (Met-Temp): 95°-96 °C (uncor-
2m(B). White solid; m.p (Met-Temp): 80°-82 °C (uncor-
rected); [R]D -49.25 (c ) 0.944, CHCl3, at 20 °C); 1HNMR
(CDCl3, 400 MHz): δ ) 1.89-1.93 (m, 1H), 1.99-2.02 (m,
1H), 2.08-2.13 (m, 1H), 2.53-2.58 (m, 1H), 3.66-3.77 (m,
3H), 3.88 (s, 3H), 3.90-3.91 (m, 1H), 4.78 (s, 1H),
5.08-5.12 (m, 1H), 6.74 (s, 1H), 6.78-6.86 (m, 2H),
6.97-7.01 (m, 1H), 7.27-7.37 (m, 5H); 13C NMR (CDCl3,
100 MHz): 22.38, 27.37, 48.59, 56.30, 58.14, 58.48, 70.10,
113.90, 117.54, 124.89, 125.88, 128.32, 128.91, 128.95,
135.07, 147.90, 148.01, 150.91, 153.38, 168.07, 171.03; LCMS
(UV): 384.2 (M+H+). Anal. Calcd for C21H22FN3O3: C, 65.78;
H, 5.78; N, 10.96. Found: C, 65.74; H, 5.81; N, 10.99.
General Procedure for the Synthesis of 4,5-Bridged
1,2,5-Triazepine-3,7-diones 4 (Table 2). To a stirred
1
rected); H NMR (CDCl3, 400 MHz): δ ) 1.86 (m, 1H),
2.02-2.11 (m, 2H), 2.57 (m, 1H), 3.70-3.75 (m, 1H),
3.81-3.84 (m, 1H), 4.47-4.51 (m, 1H), 5.81 (s, 1H), 5.95
(s, 2H), 6.57-6.59 (m, 2H), 6.74-6.76 (d, J ) 8.44, 1H),
6.93-6.96 (m, 2H), 7.03-7.08 (m, 3H); 13C NMR (CDCl3,
100 MHz): 22.09, 27.82, 48.69, 57.80, 67.20, 101.33, 108.62,
108.74, 114.31, 116.35, 116.58, 122.16, 127.90, 142.11,
147.91, 148.10, 156.44, 158.84, 168.28, 172.50; LCMS
(UV): 384.2 (M+H+). Anal. Calcd for C20H18FN3O4: C,
62.66; H, 4.73; N, 10.96. Found: C, 62.73; H, 4.81; N, 10.89.
2j. White solid; m.p (Met-Temp): 78°-79 °C (uncor-
1
rected); H NMR (CDCl3, 400 MHz): δ ) 1.93 (m, 1H),
2.06-2.13 (m, 2H), 2.39 (s, 3H), 2.61 (m, 1H), 3.69 (s, 3H),

Fused 4,5-Bridged 1,2,5-Triazepine-3,6-diones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 81
mixture of glyoxylic acid monohydrate (184 mg, 2 mmol)
in DCM (5 mL) was added L-proline methyl esterhydro-
chloride (331 mg, 2 mmol) followed by p-methoxyphenyl
boronic acid (304 mg, 2 mmol). The resulting mixture was
stirred at ambient temperature for 24 h, and to this solution
were added N-1-Boc-N-2-(benzyl)-hydrazine (446 mg, 2
mmol), HBTU (759 mg, 2 mmol), and DIEA (774 mg, 6
mmol). The reaction mixture was stirred at ambient tem-
perature for 4 h, and after this time, the solvent was removed
and dried under reduced pressure. To this reaction mixture
was added 4.0 M HCl (4 mL) in dioxane. The resulting
mixture was stirred at ambient temperature for 4 h. The
solvent was evaporated and dried under reduced pressure.
To a solution of this reaction mixture in toluene (20 mL)
was added HOAc (0.20 mL) and refluxed for overnight. The
solvent was removed, and the crude product was purified
by HPLC to afford 251 mg (34%) of 4b as a white solid.
4a(A). White solid; m.p (Met-Temp): 210°-211 °C
(uncorrected); [R]D +84.607 (c ) 0.890, CHCl3, at 20 °C);
1H NMR (CDCl3, 300 MHz): δ ) 1.78-2.14 (m, 3H),
2.36-2.41 (m, 1H), 2.91-2.99 (m, 1H), 3.18-3.24 (m, 1H),
3.41-3.45 (m, 1H), 4.58-4.72 (m, 2H), 5.65 (s, 1H), 6.62
(br s, 1H), 7.10-7.13 (m, 2H), 7.20-7.29 (m, 3H), 7.46-7.64
(m, 3H), 7.82 (d, J ) 7.82 Hz, 2H), 7.91 (d, J ) 9.3 Hz,
1H), 8.46 (d, J ) 8.46 Hz, 1H); 13C NMR(CDCl3, 75 MHz):
22.40, 23.06, 52.39, 52.44, 59.97, 61.47, 121.22, 125.46,
125.78, 126.51, 127.32, 128.78, 128.93, 129.13, 129.37,
129.44, 130.11, 131.31, 133.51; 133.71, 168.23, 169.82;
LCMS (ELSD): 386 (M+H+); HRMS: 386.185503 [Calcu-
lated for C24H24N3O2 386.186852 (M+H)+].
25.61, 26.07, 30.59, 31.04, 35.39, 52.94, 55.48, 60.15, 66.29,
116.59, 128.59, 129.29, 129.74, 133.71, 160.70; 167.39,
168.92; LCMS (ELSD): 342.2 (M+H+);HRMS: 342.2167
[Calculated for C20H28N3O2 342.2182 (M+H)+].
4d. White Solid; m.p (Met-Temp): 89°-90 °C (uncor-
rected); 1H NMR(CDCl3, 300 MHz):δ ) 0.93-1.22 (m, 5H),
1.7-1.74 (m, 6H), 1.85-2.21 (m, 3H), 2.45 (m, 1H), 2.60
(m, 1H), 3.1(m, 1H), 3.21(m, 1H), 3.83 (s, 3H), 3.84 (m,1H),
4.61 (m, 1H), 4.72 (m, 1H), 6.95 (d, J ) 9 Hz, 2H), 7.43 (d,
J ) 8.4 Hz, 2H), 8.4 (br. s, 1H); 13CNMR(CDCl3, 75 MHz):
22.91, 23.76, 25.89, 26.03, 26.48, 30.98, 31.44, 35.81, 53.32,
55.7, 55.9, 60.42, 66.04, 114.43, 125.84, 131.44, 160.74,
167.84, 169.16; LCMS (ELSD): 372.1 (M+H+); HRMS:
372.229450 [Calculated for C21H30N3O3 372.228717
(M+H)+].
General Procedure for the Synthesis of 4,5-Bridged
1,2,5-Triazepine-3,6-diones 6 (Table 3). To a stirred
mixture of glyoxylic acid monohydrate (184 mg, 2 mmol)
in DCM (5 mL) was added N-1-Boc-N-2-(benzyl)- hydrazine
(446 mg, 2 mmol), followed by p-methoxyphenyl boronic
acid (304 mg, 2 mmol). The resulting mixture was stirred at
ambient temperature for 24 h, and to this solution were added
pipecolic acid methyl ester hydrochloride (359 mg, 2 mmol),
HATU (761 mg, 2 mmol), and DIEA (774 mg, 6 mmol).
The reaction mixture was stirred at ambient temperature for
4 h, and after this time, the solvent was removed and dried
under reduced pressure. To this reaction mixture was added
4.0 M HCl (6 mL) in dioxane. The resulting mixture was
stirred at ambient temperature for 4 h. The solvent was
evaporated and dried under reduced pressure. To a solution
of this reaction mixture in toluene (20 mL) was added HOAc
(0.20 mL) and refluxed for overnight. The solvent was
removed and the crude product was purified by HPLC to
afford 197 mg (26%) of 6a as a white solid.
4a(B). White solid; m.p (Met-Temp): 215°-216 °C
(uncorrected) [R]D +93.171 (c ) 0.946, CHCl3, at 20 °C);
1H NMR (CDCl3, 400 MHz): δ ) 1.77-2.14 (m, 3H),
2.31-2.36 (m, 1H), 2.91-2.93 (m, 1H), 3.16-3.18 (m, 1H),
3.37-3.40 (m, 1H), 4.54-4.57 (m, 1H), 4.66-4.70 (m, 1H),
5.62 (s, 1H), 6.66 (br s, 1H), 7.10-7.11 (m, 2H), 7.19-7.27
(m, 3H), 7.44-7.61 (m, 3H), 7.77-7.83 (m, 2H), 7.88-7.90
6a. White solid; m.p (Met-Temp): 220°-221 °C (uncor-
1
rected); H NMR (CDCl3, 400 MHz): δ ) 1.64-1.75 (m,
3H), 1.82-1.90 (m, 2H), 2.01-2.05 (m, 1H), 2.26-2.29 (m,
1H), 3.20-3.24 (m, 1H), 3.81 (s, 3H), 3.86-3.87 (m, 1H),
3.94 (m, 1H), 4.23 (m, 1H), 4.83 (m, 1H), 6.47 (br. s, 1H),
6.92 (d, J ) 8.68 Hz, 2H), 7.23-7.27 (m, 2H), 7.30-7.36
(m, 5H); 13C NMR(CDCl3, 100 MHz): 22.75, 24.58, 26.75,
44.02, 55.32, 58.32, 73.98, 74.03, 114.51, 128.18, 128.26,
128.87, 128.91, 129.02, 130.28, 159.89, 170.01, 172.06;
LCMS (UV): 380.5 (M+H+). Anal. Calcd forC22H25N3O3:
C, 69.64; H, 6.64; N, 11.07. Found: C, 69.73; H, 6.69, N,
11.19.
(d, J ) 7.92 Hz, 1H), 8.43-8.45 (d, J ) 8.48 Hz, 1H); 13
C
NMR(CDCl3, 100 MHz): 22.94, 24.42, 52.97, 54.03, 58.55,
68.23, 123.55, 124.51, 125.44, 125.66, 126.54, 128.41,
128.43, 128.48, 128.77, 128.87, 129.18, 130.85, 132.61,
133.75; 133.80, 169.84, 171.62; LCMS (ELSD): 386.2
(M+H+); Anal. Calcd for C24H23N3O2: C, 74.78; H, 6.01;
N, 10.90. Found: C, 74.69; H, 6.05; N, 10.92.
4b. White solid, m.p (Met-TempII): 64°-65 °C (uncor-
1
rected); H NMR (CDCl3, 300 MHz): δ ) 2.02 (m, 3H),
2.55 (m, 2H), 3.10 (m, 1H), 3.86 (s, 3H), 4.66 (m, 2H), 4.78
(m, 1H), 5.02 (d, J ) 14.1 Hz, 1H), 6.99 (d, J ) 7.5 Hz,
2H), 7.49 (m, 5H), 7.52 (d, J ) 7.2 Hz, 2H), 8.21 (br. s,
1H); 13C NMR (CDCl3, 75 MHz): 22.35, 23.26, 52.18, 52.95,
55.29, 59.92, 65.45, 114.08, 125.04, 128.76, 129.13, 129.37;
131.08, 133.51, 160.41, 166.95, 168.31; LCMS (ELSD): 366
(M+H+); HRMS: 366.181249 [Calcd for C21H24N3O3
366.181767 (M+H)+].
6b. White solid; m.p (Met-Temp): 167°-168 °C (uncor-
1
rected); H NMR (CDCl3, 400 MHz): δ ) 1.70-1.76 (m,
3H), 1.82-1.84 (m, 2H), 1.87-1.91 (m, 1H), 2.29 (m, 1H),
3.22 (m, 1H), 3.85-3.88 (m, 1H), 3.96-3.99 (m, 1H),
4.23-4.25 (m, 1H), 4.89-4.92 (m, 1H), 6.53 (br. s, 1H),
7.3-7.43 (m, 10H); 13C NMR(CDCl3, 100 MHz): 22.53,
24.42, 26.65, 43.81, 58.41, 62.01, 74.65, 128.20, 128.76,
128.79, 128.93, 128.96, 129.03, 134.47, 134.85, 169.73,
172.18; LCMS (UV): 350.2 (M+H+). Anal. Calcd for
C21H23N3O2: C, 72.18; H, 6.63; N, 12.03. Found: C, 72.15;
H, 6.7, N, 12.11.
1
4c. Liquid; H NMR (CDCl3, 300 MHz):δ ) 0.96-1.28
(m, 5H), 1.65-1.77 (m, 6H), 1.95-2.14 (m, 3H), 2.45 (m,
1H), 2.61 (m, 1H), 3.06 (m, 1H), 3.27 (m, 1H), 3.87 (m,
1H), 4.68 (s, 1H), 4.75 (m, 1H), 7.43-7.51 (m, 5H), 8.45
(br. s, 1H); 13C NMR(CDCl3, 75 MHz): 22.56, 23.31, 25.48,
6c. White solid; m.p: (Met-Temp): 61°-62 °C (uncor-
1
rected); H NMR (CDCl3, 400 MHz): δ ) 1.68-1.77 (m,

82 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Neogi et al.
Tetrahedron Lett. 2001, 42, 2545. (e) Koolmeister, T.;
Sodergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5965.
(f) Koolmeister, T.; Sodergren, M.; Scobie, M. Tetrahedron
Lett. 2002, 43, 5969. (g) Thompson, K. A.; Hall, D. G. Chem
Commun. 2000, 2379.
3H), 1.85-1.89 (m, 1H), 2.03-2.05 (m, 1H), 2.24 (m, 1H),
3.26-3.28 (m, 1H), 3.81-3.88 (m, 1H), 3.96-3.99 (m, 1H),
4.17 (m, 1H), 4.67-4.78 (m, 1H), 4.86 (s, 1H), 5.98 (s, 2H),
6.68-6.85 (m, 3H), 7.17 (m, 1H), 7.27-7.39 (m, 5H); 13C
NMR (CDCl3, 100 MHz): 22.35, 24.31, 26.47, 43.86, 58.19,
61.88, 74.27, 101.35, 108.42, 108.69, 122.78, 128.20, 128.26,
128.37, 128.67, 134.74, 148.09, 148.25, 169.96,172.30;
LCMS (UV): 394.2 (M+H+). Anal. Calcd for C22H23N3O4:
C, 67.16; H, 5.89; N, 10.68. Found: C, 67.22; H, 5.85; N,
10.59.
(5) Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetrahedron
Lett. 2002, 43, 6845.
(6) The Petasis Boronic Acid-Mannich reaction has also been
applied to the synthesis of heterocyclicsystems:(a) Batey,
R. A.; MacKay, D. B.; Santhakumar, V. J. J. Am. Chem. Soc.
1999, 121, 5075. (b) Petasis, N. A.; Patel, Z. D. Tetrahedron
Lett. 2000, 41, 9607. (c) Wang, Q.; Finn, M. G. Org. Lett.
2000, 2, 4063. (d) Berree, F.; Debache, A.; Marsac, Y.;
Carboni, B. Tetrahedron Lett. 2001, 42, 3591, and references
cited therein. (e) Smith III, A. B.; Minbiole, K. P.; Verhoest,
P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942. (f)
Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem.
Soc. 2001, 123, 12426.
(7) (a) Klopfenstein, S. R.; Chen, J. J.; Golebiowski, A.; Li, M.;
Peng, S. X.; Shao, X. Tetrahedron Lett. 2000, 41, 4835. (b)
Golebiowski, A.; Klopfenstein, S. R.; Chen, J. J.; Shao, X.
Tetrahedron Lett. 2000, 41, 4841. (c) Schlienger, N.; Bryce,
M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023. (d)
Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(e) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem.sEur. J. 2000, 6, 3321. (f) Grdner, B.; Nakanishi, H.;
Kahn, M. Tetrahedron 1993, 49, 3433. (g) Naskar, D.; Roy,
A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003,
44, 8865. (h) Naskar, D.; Roy, A.; Seibel, W. L.; Portlock,
D. E. Tetrahedron Lett. 2003, 44, 5819. (i) Naskar, D.; Roy,
A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003,
44, 8861. (j) Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B.
Tetrahedron Lett. 2008, 49, 6762. (k) Portlock, D. E.;
Ostaszewski, R.; Naskar, D.; West, L. Tetrahedron Lett. 2003,
44, 603. (l) Portlock, D. E.; Naskar, D.; West, L.; Ostaszewski,
R.; Chen, J. J. Tetrahedron Lett. 2003, 44, 5121. (m) Naskar,
D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett.
2003, 44, 6297.
(8) Grathwohl, C; Wuthrich, K. Biopolymers 1981, 20, 2623.
(9) (a) Brandts, J. F.; Halvorson, H. R.; Brennan, M. Biochemistry
1975, 14, 953. (b) Borden, K. L.; Richards, F. M. Biochemistry
1990, 29, 3071. (c) Texter, F. L.; Spencer, D. B.; Rosenstein,
R.; Matthews, C. R. Biochemistry 1992, 31, 5687. (d)
Shalongo, W.; Jagannadham, M. N.; Heid, P.; Stellwegen, E.
Biochemistry 1992, 31, 11390. (e) Lang, K.; Schmid, F. X. J.
Mol. Biol. 1990, 212, 185. (f) Kiefhaber, T.; Kohler, H. H.;
Schmid, F. X. J. Mol. Biol. 1992, 224, 217. (g) Kiefhaber,
T.; Kohler, H. H.; Schmid, F. X. J. Mol. Biol. 1992, 224,
231.
(10) (a) Brandl, C. J.; Deber, C. M. Proc. Natl. Acad. Sci. U.S.A.
1986, 83, 917. (b) Williams, K. A.; Deber, C. M. Biochemistry
1991, 30, 8919. (c) Vogel, H.; Nilsson, L.; Rigler, R.; Meder,
S.; Boheim, G.; Beck, W.; Kurth, H. H.; Jung, G. Eur.
J. Biochem. 1993, 212, 305. (d) Wess, J.; Nanavati, S.; Vogel,
Z.; Maggio, R. EMBO J. 1993, 12, 331. (e) Suchyna, T. M.;
Xu, L. X.; Gao, F.; Fourtner, C. R.; Nicholson, B. J. Nature
1993, 365, 847.
6d. White solid; m.p: (Met-Temp): 80°-81 °C (uncor-
rected); H NMR (CDCl3, 400 MHz): δ ) 1.69-1.75 (m,
1
3H), 1.85-1.89 (m, 1H), 2.02-2.03 (m, 1H), 2.23-2.25 (m,
1H), 3.23-3.26 (m, 1H), 3.82-3.91 (m, 4H), 3.95-3.99 (m,
1H), 4.17-4.19 (m, 1H), 4.65-4.67 (m, 1H), 4.80 (s, 1H),
6.91-6.95 (m, 1H), 6.98-7.02 (m, 1H), 7.08-7.11 (m, 1H),
7.27-7.39 (m, 6H); 13C NMR (CDCl3, 100 MHz): 22.35,
24.32, 26.41, 43.97, 56.18, 58.23, 61.84, 73.73, 113.62,
116.42, 116.61, 125.07, 126.95, 128.32, 128.85, 128.95,
134.63, 148.04, 148.15, 151.10, 153.57, 169.65, 172.27;
LCMS (UV): 398.2 (M+H+). Anal. Calcd for C22H24FN3O3:
C, 66.48; H, 6.09; N, 10.57. Found: C, 66.59; H, 6.15; N,
10.55.
6e. White solid; m.p (Met-Temp): 60°-61 °C (uncor-
1
rected); H NMR (CDCl3, 400 MHz): δ ) 1.61-1.74 (m,
3H), 2.04-2.06 (m, 1H), 2.46 (s, 3H), 2.49-2.55 (m, 2H),
3.68-3.3.70 (s, 1H), 3.77-3.80 (m, 4H), 3.96-4.02 (m, 2H),
4.61-4.62 (m, 1H), 5.19 (s, 1H), 6.72-6.78 (m, 3H),
6.93-6.95 (m, 1H), 7.22-7.33 (m, 5H); 13C NMR (CDCl3,
100 MHz): 20.05, 24.39, 24.54, 31.73, 42.42, 53.99, 55.19,
59.07, 62.46, 111.86, 116.55, 127.85, 128.45, 128.54, 128.70,
128.89, 136.85, 139.30, 159.24, 163.39, 165.86, 170.85,
173.18; LCMS (UV): 394.2 (M+H+). Anal. Calcd for
C23H27N3O3: C, 70.21; H, 6.92; N, 10.68. Found: C, 70.30;
H, 6.89; N, 10.66.
Acknowledgment. The authors thank Dr. Ashis Baran
Mandal and gratefully acknowledge Dr. Goutam Das, COO,
Syngene International Ltd. for his invaluable support.
Supporting Information Available. Detailed experimen-
tal procedure and compound characterization. This material
is available free of charge via the Internet at http://
pubs.acs.org.
References and Notes
(1) For two recent excellent reviews, see: (a) Weber, L.; Illgen,
K.; Almstetter, M. Synlett 1999, 3, 366. (b) Dax, S. L.;
McNally, J. J.; Youngman, M. A. Curr. Med. Chem. 1999, 6,
255.
(2) (a) Ugi, I. Angew, Chem., Int. Ed. Engl. 1962, 1, 8. (b) Ugi,
I.; Steinbruckner, C. Chem Ber. 1961, 94, 734. (c) Ugi, I.;
Domling, A.; Horl, W. EndeaVor 1994, 18, 115. (d) Domling,
A. Comb. Chem. High Throughput Screening 1998, 1, 1.
(3) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b) Gokel,
G.; Ludke, G.; Ugi, I. In Isonitrile Chemistry; Ugi, I., Ed.;
Academic Press: New York, 1971; p 145.
(11) Richards, N. G. J.; Hinds, M. G.; Brennard, D. M.; Glennie,
M. J.; Welsh, J. M.; Robinson, J. A. Biochem. Pharmacol.
1990, 40, 119.
(12) (a) Yaron, A.; Naider, F. Crit. ReV. Biochem. Mol. Biol. 1993,
28, 31. (b) London, R. E.; Stewart, J. M.; Cann, J. R. Biochem.
Pharmacol. 1990, 40, 41. (c) Yaron, A. Biopolymers 1987,
26, S215.
(13) Blair, W. S.; Semler, B. L. Curr.Opin. Cell Biol. 1991, 3,
1039.
(14) Fischer, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 1415.
(15) (a) London, R. E.; Stewart, J. M.; Williams, R.; Cann, J. R.;
Matwiyoff, N. A. J. Am. Chem. Soc. 1979, 1, 245501. (b)
Liakopoulou-Kyriakides; Galardy, R. E. Biochem. 1979, 18,
1952.
(4) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445. (b) Petasis, N. A.; Goodman, A.; Zavialov, I. A.
Tetrahedron 1997, 53, 16463. (c) Hansen, T. K.; Schlienger,
N.; Hansen, B. S.; Andersen, P. H.; Bryce, M. R. Tetrahedron
1999, 40, 3651. (d) Jiang, B.; Yang, C.-G.; Gu, X.-H.

Fused 4,5-Bridged 1,2,5-Triazepine-3,6-diones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 83
(16) Gramberg, D.; Robinson, J. A. Tetrahedron Lett. 1994, 35,
861.
(22) Obercht, D.; Bohdal, U.; Daly, J.; Lehmann, C.; Schonholzer,
P.; Muller, K. Tetrahedron 1995, 51, 10883.
(17) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36,
(23) Horwell, D. C.; Taylor, D.; Williams, H. M. G. Bioorg. Med.
Chem. Lett. 1997, 7, 31.
191.
(18) (a) Lenman, M. M.; Ingham, S. L.; Gani, D. Chem. Commun
1996, 85. (b) Lenman, M. M.; Lewis, A.; Gani, D. J. Chem
Soc., Perkin Trans1 1997, 2297.
(24) Hartzoulakis, B.; Rutherford, T. J.; Ryan, M. D.; Gani, D.
Tetrahedron Lett. 1996, 37, 6911.
(25) Kemp, D. S.; Li, Z. Q. Tetrahedron Lett. 1995, 36, 4175.
(26) (a) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996,
61, 8935, and reference therein. (b) Hulme, C.; Peng, J.; Tang,
S.-Y.; Burns, C. J.; Morize, I.; Labaudiniere, R J. Org. Chem.
1998, 63, 8021, and reference therein.
(19) Rose, G. D.; Gierasch, L. M.; Smith, J. A. AdV. Protein Chem.
1985, 37, 1.
(20) Nowick, J. S.; Smith, E. M.; Pairish, M. Chem. Soc. ReV. 1996,
401.
(21) De La Figuera, N.; Alkorta, I.; Garcia-Lopez, M. T.; Herranz,
R.; Gonzalez-Muniz, R. Tetrahedron Lett. 1995, 51, 7841.
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