Ceric ammonium nitrate (CAN) promoted efficient synthesis of 1,5-benzodiazepine derivatives

Article abstract of DOI:10.1055/s-2006-939066

Ceric ammonium nitrate was found to be an efficient reagent for the preparation of 1,5-benzodiazepine derivatives of a wide range of substituted o-phenylenediamines and electronically divergent ketones in moderate to excellent isolated yields (60-98%) und

Full text of DOI:10.1055/s-2006-939066

LETTER
1009
Ceric Ammonium Nitrate (CAN) Promoted Efficient Synthesis of
1
1
,5-Benzodiazepine Derivatives
S
R
ynthesis of 1,5-
a
enzodiaze
v
pine
D
eriva
t
i
ive
s
Varala, Ramu Enugala, Sreelatha Nuvula, Srinivas R. Adapa*
Indian Institute of Chemical Technology, Hyderabad – 500 007, India
Fax +91(40)27160921; E-mail: rvarala_iict@yahoo.co.in
Received 17 January 2006
there is scope to explore efficient methods for the synthe-
sis of 1,5-benzodiazepines using a milder, non-hazardous
and inexpensive reagent.
Abstract: Ceric ammonium nitrate was found to be an efficient
reagent for the preparation of 1,5-benzodiazepine derivatives of a
wide range of substituted o-phenylenediamines and electronically
divergent ketones in moderate to excellent isolated yields (60–98%)
under mild conditions using methanol as solvent at ambient temper-
ature.
In continuation of our interest in developing novel
synthetic methodologies, particularly carbon–carbon,
8
carbon–heteratom bond formations, and being interested
Key words: 1,5-benzodiazepines, ceric ammonium nitrate, o-phen-
ylenediamines
in the use of lanthanide salts as environmentally friendly
reagents for organic synthesis, we undertook a study of
the utility of several lanthanide salts as catalysts for the
synthesis of 1,5-benzodiazepines. Among the various lan-
thanide salts such as TbCl , Sm(NO ) , ErCl , Pr(NO ) ,
Due to their accessibility, easy functionalization and
potential pharmacological properties, 1,5-benzodiazepine
derivatives have received significant attention and repre-
sent a ‘privileged scaffold’ found in compounds active
against a variety of target types including peptide hor-
3
3 3
3
3 3
YbCl , CAN (ceric ammonium nitrate), Tb(NO ) ,
3
3 3
La(NO ) , YCl and LaCl studied for this reaction, CAN
3
3
3
3
was found to be the most effective catalyst in terms of
conversion and reaction rates. CAN has emerged as
powerful single electron transfer reagent in many carbon–
2
a
mones (such as CCK), interleukin converting enzymes
2
b
2c
(
ICE) and potassium blockers (I ). More recently, the
9
k
carbon bond-forming reactions. However, to the best of
area of biological interest of 1,5-benzodiazepines has
our knowledge, there are no earlier reports on the prepara-
3a
been extended to various diseases such as cancer, viral
infection (non-nucleoside inhibitors of HIV-1 reverse
10
tion of 1,5-benzodiazepines using CAN to date.
At first, we evaluated the feasibility of o-phenylenedi-
amine (o-PD) (1 mmol) and acetophenone (2.2 mmol)
using CAN (10 mol%, Scheme 1) at ambient temperature
in acetonitrile as solvent to afford the corresponding 1,5-
benzidiazepine in 45% yield in four hours.
3
b
3c,d
transcriptase),
and cardiovascular disorders.
In
addition, 1,5-benzodiazepines show antidepressive,
antifungal, antibacterial, antifeedant, antiinflammatory,
4
analgesic and anticonvulsant activities. Derivatives are
5
also used as dyes for acrylic fibre in photography.
Moreover, 1,5-benzodiazepines are valuable synthons
used for the preparation of other fused ring compounds
such as triazolo-, oxadiazolo-, oxazino-, or furano-benzo-
R2
CAN
(10 mol%)
H
N
O
R3
R3
R
NH2
R3
R
R2
+
NH2
6
R1
MeOH, r.t.
R1
diazepines.
N
R2
1
1
Despite their importance from a pharmacological,
industrial and synthetic point of view, comparatively few
methods for their preparation are reported in the literature,
a great number of which have appeared only very recently
R, R = H; R = Me, R = H;
1
1
(27 examples)
R = Cl, R = H; R = NO2, R = H;
1
1
R, R = Me; R = Cl, R = Cl;
1
R = COPh, R = H
7
a
7b
employing BF ·OEt , NaBH , polyphosphoric acid or Scheme 1
3
2
4
7
c
7d
7e
SiO2,
MgO/POCl3,
Yb(OTf)3,
Al O /P O or
2 3 2 5
7
f,g
AcOH under microwave conditions, Amberlyst-15 in
ionic liquid, CeCl ·7H O/NaI supported on silica gel,
1-butyl-3-methylimidazolium bromide
[bmim]Br), Sc(OTf) as catalysts or as stoichiometric
Encouraged by this result, we studied different reaction
parameters. The reaction was performed in different sol-
vents such as MeCN, MeCN–H O, CHCl , MeOH, and
7
h
7i
3
2
7
j
and InBr3,
(
2
3
7
k
7l
3
H O. Methanol (89%) and chloroform (80%) were found
2
reagents. However, many of these methods have draw-
to be the best solvents in terms of yields and reaction time.
The reaction was also conducted in solvent-free condi-
tions but the yields were poorer compared to the yields ob-
tained in methanol as solvent. Next, the optimization of
ceric ammonium nitrate was tested, wherein it was found
that 10 mol% of CAN is sufficient to promote reaction.
No reaction was observed when o-phenylenediamine was
reacted with acetophenone under similar conditions in the
7
a,b
backs such as low yields of the products, high temper-
7
c
7d
atures, drastic reaction conditions, long reaction
7
c
7e,i,j,l
times, and relatively expensive reagents.
Therefore,
SYNLETT 2006, No. 7, pp 1009–1014
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939066; Art ID: D01706ST
©
Georg Thieme Verlag Stuttgart · New York

1
010
R. Varala et al.
LETTER
absence of the CAN even after stirring for 2 days, thus 4,5-Dichloro o-phenylenediamine (diamine F) reacted
highlighting the role of the CAN as a promoter. Any ex- rapidly with acetophenone giving a yield of 92% in 3.5
cess of CAN beyond this loading did not show any further hours. Likewise, 4,5-dimethyl o-phenylenediamine (di-
increase in conversion and yield. Use of less than the re- amine E) reacted faster than the simple and 4-benzoyl
quired catalyst loading resulted in poor yields. The opti- derivatives (see Table 1); whereas 4-methyl o-phenylene-
mum yields of the product were obtained when a 1:2.2 diamine (diamine B) reacted sluggishly. The order of
ratio of o-phenylenediamine to ketone was used.
reactivity of various substituted o-phenylenediamines
with acetophenone is as follows: F > A > E > G > B. The
benzodiazepines were the only products obtained and the
rest of the material was essentially starting material. The
scope and generality of the present procedure was extend-
ed to various aliphatic ketones as well (Table 1). The
reaction of o-phenylenediamine with acetone when per-
formed under similar conditions gave high yields of 2,3-
dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine (entry
Having established the optimized reaction conditions, we
then successfully synthesized a wide variety of biological-
ly relevant 1,5-benzodiazepines using CAN (10 mol%) in
methanol at room temperature, and the results from this
study are shown in Table 1. In all cases, the reactions were
clean and complete within 2.5–6.5 hours. Water was add-
ed to the reaction mixture and the pure product was isolat-
ed by extracting with diethyl ether and after usual workup
and purification by silica gel column chromatography.
Electronically divergent acetophenones were employed as
novel substrates for the synthesis of corresponding 1,5-
benzodiazepines in good to excellent yields (Table 1). 4-
Methoxy acetophenone gave a moderate yield of 66% in
1
5a, Table 1). It is noteworthy that, in the reaction with an
unsymmetrical ketone such as 2-butanone, the ring clo-
sure occurred selectively giving a single product in 2.5
hours (92%, entry 16, Table 1). 3-Pentanone also reacted
well to furnish the desired product in 88% yield (entry 17,
Table 1). Cyclic ketones such as cyclopentanone and
cyclohexanone (entries 18 and 19, Table 1) also reacted
efficiently to afford the corresponding fused ring benzo-
diazepines in excellent yields. To demonstrate the scope
of this methodology, the reaction was performed with o-
phenylenediamine and acetophenone on a 20-mmol scale
6
.5 hours (entry 3). Entries 4 and 5 (Table 1), on reacting
with o-phenylenediamine resulted corresponding product
in 5 hours and 4.5 hours in good yields (85%, 80%, re-
spectively). Acetophenones containing halo substituents,
except bromo substituent, reacted rapidly (entry 6,
Table 1). The order of the reactivity of the substituted
acetophenones towards o-phenylenediamine in terms of
yields and time is as follows: fluoro > chloro > iodo ~
methyl > hydroxy > nitro > bromo > methoxy. In a similar
fashion, substituted o-phenylenediamines also reacted
well with substituted acetophenones and gave the corre-
sponding 1,5-benzodiazepines in good yields (entries 7–
(
entry 1, Table 1) using CAN. The reaction was complete
in 3.5 hours affording the corresponding product in 85%
yield, thus confirming the possibility of being scaled up,
if desired. The mechanism of the reaction probably
involves an intramolecular imine–enamine cyclization
promoted by CAN, as already reported by Jung and co-
workers when using polyphosphoric acid or SiO2.7
c
1
4). For diamines C and D, the reaction did not give the
expected products with acetophenone even after stirring
for 12 hours under the present experimental conditions.
Table 1 CAN-Promoted Synthesis of 1,5-Benzodiazepines
Entry
Diamine
Ketone
Benzodiazepine
Time (h)
Yields (%)a,b
O
H
N
A
89/85c,7i
1
3.5
N
O
Me
H
N
Me
A
877i
2
4.0
N
Me
Synlett 2006, No. 7, 1009–1014 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,5-Benzodiazepine Derivatives
1011
Table 1 CAN-Promoted Synthesis of 1,5-Benzodiazepines (continued)
Entry
Diamine
Ketone
Benzodiazepine
Time (h)
Yields (%)a,b
OMe
H
N
O
A
3
6.5
66
N
MeO
OMe
OH
H
N
O
4
5
6
A
A
A
5.0
85
HO
O2N
X
N
OH
NO2
H
N
O
4.5
80
N
NO2
X
H
N
O
X = F
X = Cl
X = Br
X = I
3.5
4.0
6.0
4.5
95
92
74
88
N
X
H
O
N
Me
7
8
B
E
6.0
4.5
657k
N
H
N
O
Me
Me
857g
N
Me
H
N
O
Me
Me
9
E
4.5
76
Me
N
Me
Synlett 2006, No. 7, 1009–1014 © Thieme Stuttgart · New York

1
012
R. Varala et al.
LETTER
Table 1 CAN-Promoted Synthesis of 1,5-Benzodiazepines (continued)
Entry
Diamine
Ketone
Benzodiazepine
Time (h)
Yields (%)a,b
H
O
N
Cl
F
1
0
3.5
92
90
78
Cl
N
Me
H
O
N
Cl
F
1
1
1
1
2
3
4.0
Cl
N
Me
Me
Cl
H
O
Cl
Cl
N
F
6.0
Cl
N
Cl
NO2
H
N
O
Cl
Cl
F
4.5
60
N
O2N
NO2
H
N
O
PhOC
1
1
4
5
G
5
807h
N
A
B
C
D
E
F
7j
3
4
2
3
.0
.5
.5
.0
90
H
N
7j
82
O
7j
88
7j
92
7j
N
3.0
.5
87
X
3
95
H
N
1
1
6
7
A
A
2.5
3.0
927j
O
N
H
N
887h
O
N
Synlett 2006, No. 7, 1009–1014 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,5-Benzodiazepine Derivatives
1013
Table 1 CAN-Promoted Synthesis of 1,5-Benzodiazepines (continued)
Entry
Diamine
Ketone
Benzodiazepine
Time (h)
3.0
Yields (%)a,b
O
H
N
A
957e
1
1
8
9
N
H
N
O
A
987e
3.5
N
NH2
Me
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
Cl
O2N
Me
Me
Cl
PhOC
Diamine:
NH2
NH2
NH2
NH2 Cl
A
B
C
D
E
F
G
a
Yields refer to the isolated pure products after column chromatography.
b
c
All novel compounds were characterized by H NMR and/or 13C NMR, IR and mass spectra.
1
Reaction on 20-mmol scale.
In conclusion, we have developed a practical procedure
for the synthesis of 2,3-dihydro-1H-1,5-benzodiazepines
at ambient temperature using ceric ammonium nitrate in
methanol. The advantages of the present protocol are
mild, short reaction times, study of wide range of elec-
tronically divergent substrates, easy work up, low toxi-
city, inexpensive, and ready availability of the catalyst,
that make the procedure an attractive alternative to the ex-
isting methods for the synthesis of 1,5-benzodiazepines.
Pentassuglia, G.; Polinelli, S.; Tarzia, G.; Ursini, A.; Van
Amsterdam, F. T. M. Arch. Pharm. 1997, 330, 353.
4) (a) Schutz, H. Benzodiazepines; Springer: Heidelberg,
(
1982. (b) Landquist, J. K. In Comprehensive Heterocyclic
Chemistry, Vol. 1; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon: Oxford, 1984, 166–170. (c) Randall, L. O.;
Kappel, B. Benzodiazepines; Garattini, S.; Mussini, E.;
Randall, L. O., Eds.; Raven Press: New York, 1973, 27.
(5) Haris, R. C.; Straley, J. M. US Patent 1537757, 1968; Chem.
Abstr. 1970, 73, 100054w.
(
6) (a) Essaber, M.; Baouid, A.; Hasnaoui, A.; Benharref, A.;
Lavergne, J.-P. Synth. Commun. 1998, 28, 4097. (b) El-
Sayed, A. M. E. l.; Abdel-Ghany, H.; El-Saghier, A. M. M.
Synth. Commun. 1999, 29, 3561. (c) Xu, J. X.; Wu, H. T.;
Jin, S. Chin. J. Chem. 1999, 17, 84. (d) Zhang, X. Y.; Xu, J.
X.; Jin, S. Chin. J. Chem. 1999, 17, 404. (e) Reddy, K. V.
V.; Rao, P. S.; Ashok, D. Synth. Commun. 2000, 30, 1825.
7) (a) Herbert, J. A. L.; Suschitzky, H. J. Chem. Soc., Perkin
Trans. 1 1974, 2657. (b) Morales, H. R.; Ulbarela, B. A.;
Contreras, R. Heterocycles 1986, 24, 135. (c) Jung, D. I.;
Choi, T. W.; Kim, Y. Y.; Kim, I. S.; Park, Y. M.; Lee, Y. G.;
Jung, D. H. Synth. Commun. 1999, 29, 1941.
Acknowledgment
V.R. thanks Council of Scientific Industrial Research (CSIR, India)
for award of fellowship.
(
References and Notes
(
(
1) IICT communication no: 050809.
2) (a) Werner, W.; Baumgart, J.; Burckhardt, G.; Fleck, W. F.;
Geller, K.; Gutsche, W.; Hanschmann, H.; Messerschmidt,
A.; Roemer, W. Biophys. Chem. 1990, 35, 271. (b) Herpin,
T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.;
Labaudinière, R. F. J. Comb. Chem. 2000, 5, 513.
(
2
d) Balakrishna, M. S.; Kaboudin, B. Tetrahedron Lett.
001, 42, 1127. (e) Curini, M.; Epifano, F.; Marcotullio, M.
C.; Rosati, O. Tetrahedron Lett. 2001, 42, 3193.
(
(
f) Kaboudin, B.; Navaee, K. Heterocycles 2001, 55, 1443.
g) Pozarentzi, M.; Stephanatou, J. S.; Tsoleridis, C. A.
(c) Claremon, D. A.; Liverton, N.; Selnick, H. G.; Smith, G.
R. PCT Int. Appl. WO 9640653, 1996.
Tetrahedron Lett. 2002, 43, 1755. (h) Yadav, J. S.; Reddy,
B. V. S.; Eshwaraiah, B.; Anuradha, K. Green Chem. 2002,
(
3) (a) Atwal, K. S.; Bergey, J. L.; Hedberg, A.; Moreland, S. J.
Med. Chem. 1987, 30, 635. (b) Merluzzi, V.; Hargrave, K.
D.; Labadia, M.; Grozinger, K.; Skoog, M.; Wu, J. C.; Shih,
C.-K.; Eckner, K.; Hattox, S.; Adams, J.; Rosenthal, A. S.;
Faanes, R.; Eckner, R. J.; Koup, R. A.; Sullivan, J. L.
Science 1990, 250, 1411. (c) Di Braccio, M.; Grossi, G.;
Roma, G.; Vargiu, L.; Mura, M.; Marongiu, M. E. Eur. J.
Med. Chem. 2001, 36, 935. (d) Tranquillini, M. E.; Cassara,
P. G.; Corsi, M.; Curotto, G.; Donati, D.; Finizia, G.;
4
, 592. (i) Sabitha, G.; Reddy, G. S. K. K.; Reddy, K. B.;
Reddy, N. M.; Yadav, J. S. Adv. Synth. Catal. 2004, 346,
21. (j) Yadav, J. S.; Reddy, B. V. S.; Kumar, S. P.; Nagaiah,
9
K. Synthesis 2005, 480. (k) Jarikote, D. V.; Siddiqui, S. A.;
Rajagopal, R.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V.
Tetrahedron Lett. 2003, 44, 1835. (l) De, S. K.; Gibbs, R. A.
Tetrahedron Lett. 2005, 46, 1811.
Synlett 2006, No. 7, 1009–1014 © Thieme Stuttgart · New York

1
014
(
R. Varala et al.
LETTER
8) (a) Varala, R.; Ramu, E.; Alam, M. M.; Adapa, S. R. Synlett
004, 1747. (b) Varala, R.; Ramu, E.; Alam, M. M.; Adapa,
J = 13.38 Hz, 1 H), 3.52 (br s, NH), 6.98 (m, 1 H), 7.00 (m,
6 H), 7.22 (m, 1 H), 7.47 (m, 4 H). C NMR (75 MHz,
1
3
2
S. R. Chem. Lett. 2004, 33, 1614. (c) Varala, R.; Ramu, E.;
Adapa, S. R. Bull. Chem. Soc. Jpn. 2006, 79, 140.
CDCl ): d = 30.02, 42.92, 73.37, 121.29, 122.16, 123.53,
3
123.38, 126.78, 127.57, 127.75, 129.58, 137.23, 138.80,
(
(
d) Varala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 720.
e) Alam, M. M.; Varala, R.; Adapa, S. R. Tetrahedron Lett.
144.65, 146.95, 148.40, 154.05, 163.82. MS (EI): m/z =
402 [M ].
+
2
003, 5115. (f) Varala, R.; Alam, M. M.; Adapa, S. R.
Compound 6 (X = F): pale-yellow crystalline solid, mp 104–
–
1
Synlett 2003, 67. (g) Varala, R.; Ramu, E.; Adapa, S. R.
Tetrahedron Lett. 2006, 47, 877. (h) Alam, M. M.; Varala,
R.; Ramu, E.; Adapa, S. R. Lett. Org. Chem. 2006, 3, 187.
9) For recent reports, see: (a) Nair, V.; Balagopal, L.; Rajan,
R.; Mathew, J. Acc. Chem. Res. 2004, 37, 21. (b) Kuttan,
A.; Nowshudin, S.; Rao, M. N. A. Tetrahedron Lett. 2004,
105 °C. IR (KBr): 3271, 1651, 1603, 1231 cm .
1
H NMR (300 MHz, CDCl ): d = 1.75 (s, 3 H), 2.87 (d,
3
J = 13.60 Hz, 1 H), 3.04 (d, J = 12.84 Hz, 1 H), 3.30 (br s,
(
NH), 6.75–6.79 (m, 1 H), 6.82–6.92 (m, 4 H), 7.00–7.05 (m,
1
3
2 H), 7.19–7.25 (m, 1 H), 7.48–7.62 (m, 4 H). C NMR (75
MHz, CDCl ): d = 29.72, 42.94, 73.38, 114.70, 114.79,
3
45, 2663. (c) Comin, M. J.; Elhalem, E.; Rodriguez, J. B.
114.97, 115.06, 126.22, 127.0, 128.50, 129.20, 135.46,
137.44, 140.36, 143.2, 160.23, 162.22, 165.26, 165.53,
Tetrahedron 2004, 60, 11851. (d) Nair, V.; Suja, T. D.;
Mohanan, K. Tetrahedron Lett. 2005, 46, 3217. (e)Fujioka,
H.; Ohba, Y.; Hirose, H.; Murai, K.; Kita, Y. Org. Lett. 2005,
+
163.50. MS (EI): m/z = 348 [M ].
Compound 9: pale-yellow crystalline solid; mp 102–103 °C.
–
1 1
7, 3303.
IR (KBr): 3325, 1636, 1594 cm . H NMR (200 MHz,
(
10) Representative Procedure.
CDCl ): d = 1.72 (s, 3 H), 2.26–2.36 (s, 6 H), 2.45 (s, 3 H),
3
A mixture of o-phenylenediamine (1.0 mmol), ketone (2.2
mmol) and CAN (0.055 g, 10 mol%) in MeOH (2 mL) was
stirred at r.t. for the time specified in Table 1. After the
2.58 (s, 3 H), 2.91 (d, J = 12.84 Hz, 1 H), 3.03 (d, J = 13.60
Hz, 1 H), 3.29 (br s, NH), 6.56 (s, 1 H), 7.02–7.07 (m, 1 H),
7.24–7.28 (m, 4 H), 7.47–7.53 (m, 2 H), 7.83–7.87 (d, 2 H).
1
3
reaction was over, the reaction mixture was diluted with H O
C NMR (75 MHz, CDCl ): d = 19.12, 21.10, 29.88, 43.06,
2
3
and extracted with Et O (3 × 10 mL). The combined organic
72.88, 122.34, 125.24, 127.05, 128.44, 128.76, 128.94,
129.58, 129.60, 134.58, 136.56, 137.26, 137.96, 139.68,
2
layers were dried over Na SO , concentrated in vacuo and
2
4
+
purified by column chromatography on silica gel with
EtOAc and n-hexane (2:8) as eluent to afford the
corresponding pure 1,5-benzodiazapine. Previously reported
materials were characterized by comparison of their NMR
and mass spectra with those of authentic samples. All novel
compounds gave satisfactory spectroscopic data in
accordance to their proposed structures.
166.76. MS (EI): m/z = 368 [M ].
Compound 10: yellow crystalline solid, mp 158–160 °C. IR
–
1 1
(KBr): 3304, 1638, 1603, 761 cm . H NMR (300 MHz,
CDCl ): d = 1.75 (s, 3 H), 2.93 (d, J = 13.60 Hz, 1 H), 3.12
3
(d, J = 12.84 Hz, 1 H), 3.49 (br s, NH), 6.88 (s, 1 H), 7.13–
1
3
7.30 (m, 5 H), 7.36 (s, 1 H), 7.50–7.53 (m, 5 H). C NMR
(75 MHz, CDCl ): d = 29.97, 43.23, 72.97, 121.90, 124.14,
3
Spectral Data for Selected Compounds:
125.33, 127.30, 128.35, 128.76, 130.13, 137.84, 139.26,
+
Compound 2: pale yellow crystalline solid, mp 98–99 °C. IR
146.83, 168.81. MS (EI): m/z = 381 [M ].
–
1 1
(
KBr): 3318, 1630, 1598 cm . H NMR (200 MHz, CDCl ):
Compound 11: pale-yellow solid, mp 179–180 °C. IR (KBr):
3
–
1 1
d = 1.72 (s, 3 H), 2.26 (s, 3 H), 2.32 (s, 3 H), 2.98 (d,
J = 13.38 Hz, 1 H), 3.05 (d, J = 13.38 Hz, 1 H), 3.43 (br s,
NH), 6.76 (m, 1 H), 7.01 (m, 6 H), 7.23 (m, 1 H), 7.49 (m,
3434, 1636, 1597, 817 cm . H NMR (300 MHz, CDCl ):
3
d = 1.75 (s, 3 H), 2.34 (s, 3 H), 2.37 (s, 3 H), 2.95 (d,
J = 13.60 Hz, 1 H), 3.09 (d, J = 13.60 Hz, 1 H), 3.50 (br s,
NH), 6.88 (s, 1 H), 7.05–7.09 (t, 3 H), 7.28 (s, 1 H), 7.38–
4
4
1
1
H). 13C NMR (75 MHz, CDCl ): d = 20.75, 21.16, 29.85,
3
+
2.97, 73.06, 121.28, 121.38, 125.18, 126.03, 127.15,
28.50, 128.67, 128.92, 129.22, 136.45, 137.0, 138.18,
7.44 (t, 3 H), 7.50–7.53 (d, 2 H). MS (EI): m/z = 409 [M ].
Compound 12: pale-yellow crystalline solid, mp 199–
+
7i
–1 1
39.76, 140.32, 144.98, 166.82. MS (EI): m/z = 340 [M ].
200 °C. IR (KBr): 3325, 1630, 1594 cm . H NMR (300
Compound 3: yellowish solid, mp 114–116 °C. IR (neat):
MHz, CDCl ): d = 1.77 (s, 3 H), 2.88 (d, J = 13.60 Hz, 1 H),
3
–
1 1
3
325, 1135, 1640, 1594 cm . H NMR (200 MHz, CDCl ):
3.11 (d, J = 13.60 Hz, 1 H), 3.48 (br s, NH), 6.92 (s, 1 H),
3
d = 1.71 (s, 3 H), 2.85 (d, J = 12.84 Hz, 1 H), 2.98 (d,
J = 13.60 Hz, 1 H), 3.73 (s, 3 H), 3.77 (s, 3 H), 6.65–6.78
7.21–7.25 (m, 4 H), 7.38 (s, 1 H), 7.45–7.51 (m, 4 H). MS
(FAB): m/z = 451 [M + 1].
+
(
(
m, 4 H), 6.95–7.02 (m, 2 H), 7.18–7.25 (m, 2 H), 7.42–7.55
m, 4 H). MS (EI): m/z = 372 [M ].
Compound 13: reddish crystalline solid, mp 218–220 °C. IR
+
–1 1
(KBr): 3387, 1640, 1585 cm . H NMR (300 MHz, CDCl ):
3
Compound 4: yellow crystalline solid, mp 219–220 °C. IR
d = 1.74 (s, 3 H), 2.69 (d, J = 9.82 Hz, 1 H), 2.82 (d,
J = 11.33 Hz, 1 H), 2.93 (br s, NH), 6.92 (s, 1 H), 7.21–7.25
(m, 4 H), 7.38 (s, 1 H), 7.45–7.51 (m, 4 H). MS (FAB):
–
1 1
(
KBr): 3339, 1636, 1599 cm . H NMR (200 MHz, CDCl ):
3
d = 1.65 (s, 3 H), 2.77 (d, J = 12.63 Hz, 1 H), 2.89 (d,
J = 7.43 Hz, 1 H), 4.18 (br s, NH), 6.57–6.64 (m, 4 H), 6.81–
+
m/z = 472 [M + 1].
Compound 15 (R = R = Cl): reddish crystalline solid, mp
1
7
.00 (m, 1 H), 7.10–7.18 (m, 1 H), 7.28–7.55 (m, 4 H).
+
–1 1
MS (EI): m/z = 344 [M ].
92–94 °C. IR (KBr): 3325, 1636, 1590 cm . H NMR (200
Compound 5: red crystalline solid, mp 156–158 °C. IR
MHz, CDCl ): d = 1.35 (s, 6 H), 2.26 (s, 2 H), 2.34 (s, 1 H),
3
–
1
1
+
(
KBr): 3325, 1642, 1597 cm . H NMR (300 MHz, CDCl ):
6.78 (s, 1 H), 7.18 (s, 1 H). MS (EI): m/z = 257 [M ].
3
d = 1.83 (s, 3 H), 2.96 (d, J = 13.38 Hz, 1 H ), 3.27 (d,
Synlett 2006, No. 7, 1009–1014 © Thieme Stuttgart · New York