A facile intramolecular azido/amido reductive cyclization approach: synthesis of pyrrolobenzodiazepines and their dimers

Article abstract of DOI:10.1016/j.tetlet.2008.01.004

A new synthetic pathway has been developed for the preparation of imine-containing pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) and their dimers. Selective reduction of aromatic azides as well as aliphatic amides in a single step leading to an intramolecular

Full text of DOI:10.1016/j.tetlet.2008.01.004

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1465–1468
A facile intramolecular azido/amido reductive cyclization approach:
synthesis of pyrrolobenzodiazepines and their dimers
a,
a
b
a
*
Ahmed Kamal , N. Shankaraiah , N. Markandeya , K. Laxma Reddy ,
Ch. Sanjeeva Reddy b
a Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Department of Chemistry, Kakatiya University, Warangal 506 009, AP, India
Received 31 October 2007; revised 20 December 2007; accepted 2 January 2008
Available online 8 January 2008
Abstract
A new synthetic pathway has been developed for the preparation of imine-containing pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) and
their dimers. Selective reduction of aromatic azides as well as aliphatic amides in a single step leading to an intramolecular reductive
cyclization process by employing LiAlH4 or LiBH4 provides the cyclized imines.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Pyrrolo[2,1-c][1,4]benzodiazepines; Intramolecular reductive cyclization; Azides; Amides; LiAlH4; LiBH4
Recently, there has been growing interest in developing
and discovering small nitrogen-containing heterocyclic
compounds capable of binding to DNA in a highly
sequence-selective manner.1 The pyrrolo[2,1-c][1,4]benzo-
diazepines (PBDs) are a family of tricyclic, low molecular
weight, naturally occurring DNA-interactive antitumour
antibiotics isolated from various Streptomyces species.
Well-known examples include anthramycin, chicamycin
A, abbeymycin, DC-81 dimers and SJG-136 (Fig. 1). These
compounds exert their cytotoxic potency by covalently
binding between the electrophilic C11-position of the
PBD B-ring and the C2-amino group of a guanine base
in the minor groove of DNA2 in a sequence specific fashion
preferentially with Pu–G–Pu motifs.2a In recent develop-
ments, viable synthetic routes3 have allowed many ana-
logues of PBD monomers to be explored, including the
joining of two DC-81 units together through their C8-posi-
tions using alkane spacers to create a new family of PBD
dimers.4,5 These bisfunctional-alkylating agents are capable
of cross-linking DNA and one of the C86-linked dimers,
DSB-120 (n = 1), is a remarkably efficient interstrand
DNA cross-linker, being approximately 300- and 50-fold
more efficient than the clinically used cross-linking agents,
melphalan and cisplatin, respectively. DSB-120 is highly
cytotoxic in a number of murine and human cell lines with
IC50 values as low as 0.5 nM. Another PBD dimer, SJG-
136 shows markedly superior in vitro cytotoxic potency
and interstrand DNA cross-linking reactivity and is pres-
ently under clinical evaluation.7 Recently, a number of effi-
cient solid-supported8 as well as solid-phase9 combinatorial
synthetic approaches have been developed in this labora-
tory for the preparation of different types of PBDs.
There has been considerable effort from a number of
research groups towards developing new synthetic routes
for the preparation of the PBD ring system.10 However,
due to the difficulties associated with the synthesis of sub-
stantial quantities of these compounds, little has been
achieved in structure–activity relationship (SAR) aspects.11
Kaneko and co-workers12 have developed a method for the
reduction of PBD dilactams to the carbinolamine through
iminothioether reduction using aluminium amalgam
(Al–Hg). Similarly, Thurston and co-workers13 developed
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189.
E-mail addresses: ahmedkamal@iict.res.in, ahmedkamal@iictnet.org
(A. Kamal).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.004

1466
A. Kamal et al. / Tetrahedron Letters 49 (2008) 1465–1468
OH
10
N
H
OCH3
H
9
A
6
11
N
HO
N
H3C
H
H
8
1
2
B 11a
N
C
N
7
NH2
H3CO
N
5
4
OH
N
OH
3
O
O
O
O
Anthramycin
Chicamycin
Abbeymycin
N
O
O
n
H
H
N
N
OCH3 H3CO
O
O
n = 1 (DSB-120)
N
N
O
O
H
H
N
N
OCH3 H3CO
SJG-136
Fig. 1.
O
O
a deprotective-cyclization method employing HgCl2 and
CaCO3, which has been employed quite successfully for
the preparation of a variety of PBDs. However, some of
these reported synthetic pathways involve a large number
of steps, and expensive and hazardous reagents such as
SnCl2, HgCl2 and thiols. In spite of the advantages of tin
and mercury in synthetic organic chemistry, the presence
of traces of these in the final products has proved to be dis-
advantageous towards most of the cell lines screened.
Recently, some new methods for the synthesis of PBDs
have also been developed in this laboratory, for example,
bismuth triflate deprotective-cyclization14 and azido-reduc-
tive cyclizations.15 In continuation of these efforts, a versa-
tile and inexpensive strategy has been developed for the
reduction of aromatic azides and aliphatic amides in one-
step leading to intramolecular reductive cyclization as a
convenient route for the preparation of imine-containing
PBDs.
Synthesis of substituted 2-azidobenzoic acids 1a–h has
been accomplished by using an established procedure,16
which involves the reduction of commercially available 2-
nitrobenzoic acids with SnCl2ꢀ2H2O followed by azidation
with NaNO2, HCl (aq), NaN3 and NaOAc to afford the
starting materials. These were then treated with oxalyl
chloride and coupled to 2(S)-proline hydrochloride or
2(S),4(R)-hydroxy L-proline hydrochloride in the presence
CH3
R3
R3
O
R3
O
R2
R1
R2
R1
N
R2
R1
N3
O
N3
N3
COOH
CH3
R4
i,ii
iii
OH
N
N
R4
O
O
1a-h
2a-l
3a-l
iv
R3
R2
R1
N
H
N
R4
O
4a-l
Scheme 1. Reagents and conditions: (i) (COCl)2, 1–3 drops DMF, CH2Cl2, 0 °C–rt, 2 h; (ii) Et3N, L-proline hydrochloride or hydroxy L-proline
hydrochloride, THF/H2O, 0 °C–rt, 2 h, 75–80%; (iii) N,O-dimethylhydroxylamine hydrochloride, EDCI, NMM, CH2Cl2, ꢁ15 °C, 1 h, 80–85%; (iv)
LiAlH4, dry THF, ꢁ15 to ꢁ20 °C, 40–50 min or LiBH4 dry THF 0 °C–rt, 120–140 min, 50–68%.

A. Kamal et al. / Tetrahedron Letters 49 (2008) 1465–1468
1467
Table 1
HO
N3
O
Synthesis of pyrrolo[2,1-c][1,4]benzodiazepine analogues 4a–l through
intramolecular (azido/amido) reductive cyclization employing LiAlH4 or
LiBH4
OCH3
H3CO
5
Product R1
R2
R3
R4 LiAlH4 Time LiBH4 Time EIMS
(min)/yielda
(%)
(min)/yielda
(%)
i
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
Me
Cl
OMe
H
Br
OMe OMe
OMe OBn
H
H
OMe OMe
OMe OBn
H
H
H
H
H
H
H
H
H
H
OBn
Br
H
H
H
H
H
H
H
H
H
H
H
40/65
45/60
40/62
45/68
45/60
40/65
50/58
45/58
120/55
125/50
130/60
120/65
125/52
120/60
135/58
140/62
130/58
135/56
130/50
140/68
200
214
235
230
306
358
260
336
216
230
276
352
N3
O
O
O
N3
O
n
H3CO
OCH3
OCH3 H3CO
6a-c; n = 1-3
ii, iii, iv
H
Me
OH 45/52
OH 40/56
OH 50/52
OH 50/58
4j
H
H
H
N3
N3
HOOC
O
O
COOH
4k
4l
n
N
N
OCH3 H3CO
a
Isolated yields.
O
O
7a-c; n = 1-3
v
of Et3N to give amides 2a–l in excellent yields. The carbox-
ylic acid groups of 2a–l were protected with N,O-di-
methylhydroxylamine hydrochloride in the presence of
NMM (N-methylmorpholine) and EDCI (1-ethyl-3-(3-
dimethylamino-propyl)carbodiimide) to afford the azido-
benzoyl pyrrolidine Weinreb amides 3a–l17 in good
yields. In this approach, apart from novelty and high
yields, other significant advantages are simple work-up
and ease of purification. The azide as well as amide func-
tionalities were reduced with LiAlH4 or LiBH4 to provide
the cyclized target compounds 4a–l18 as illustrated in
Scheme 1 and Table 1. This deprotective-cyclization has
been investigated under different conditions by varying
the temperature and time. However, prolonged reaction
times and higher temperatures led to a minor amount of
the secondary amine form of the PBD being obtained
(10–15%).
Further, this approach has also been extended towards
the preparation of PBD dimers 9a–c. The required precur-
sor, methyl 2-azido-4-hydroxy-5-methoxybenzoate (5) was
prepared by a reported method.19 Upon dimerization with
different alkane spacers in the presence of K2CO3 followed
by hydrolysis with LiOH (2 N), the acid groups were trea-
ted with oxalyl chloride, and then coupled with 2(S)-pro-
line hydrochloride in the presence of Et3N to afford
dimeric acids 7a–c. The acid groups were then protected
with N,O-dimethylhydroxylamine hydrochloride followed
by reductive cyclization to give the target dimers 9a–c as
shown in Scheme 2.
CH3
H3C
O
N
O
N
O
N
O
N
N3
N3
O
O
H3C
CH3
n
OCH3 H3CO
O
O
8a-c; n = 1-3
vi
N
N
O
O
H
H
n
N
N
H3CO
OCH3
O
O
9a; n = 1 (DSB-120)
9b; n = 2
9c; n = 3
Scheme 2. Reagents and conditions: (i) K2CO3, dibromoalkane, dry
DMF, rt, 12 h, 85%; (ii) LiOH (2 N) THF/MeOH/H2O (3:1:1), rt, 4 h,
85–88%; (iii) (COCl)2, 1–3 drops DMF, CH2Cl2, 0 °C–rt, 2 h; (iv) Et3N,
L-proline hydrochloride, THF/H2O, 0 °C–rt, 2 h, 75%; (v) N,O-di-
methylhydroxylamine hydrochloride, EDCI, NMM, CH2Cl2, ꢁ15 °C,
1 h, 85%; (vi) LiAlH4, dry THF, ꢁ15 to ꢁ20 °C, 40–50 min or LiBH4 dry
THF 0 °C–rt, 120–140 min, 50–68%.
Acknowledgement
The authors N.S., N.M.K. and K.L.R. are grateful to
CSIR, New Delhi for the award of Research Fellowships.
In conclusion, a new versatile method has been devel-
oped for the synthesis of PBD monomers and their dimers.
In this method we have utilized an intramolecular reductive
cyclization approach for simultaneous reduction of azido
and amido functionalities by employing LiAlH4 or LiBH4.
This new synthetic pathway is highly amenable for the gen-
eration of libraries of pyrrolo[2,1-c][1,4]benzodiazepines
and their dimers with diversity in both the A- and C-rings.
References and notes
1. (a) Trauger, J. W.; Baird, E. E.; Dervan, P. B. J. Am. Chem. Soc.
1998, 120, 3534–3535; (b) White, S.; Szewczyk, J. W.; Turner, J. M.;
Baird, E. E.; Dervan, P. B. Nature 1998, 391, 468–471; (c) Kielkopf,
C. L.; White, S.; Szewczyk, J. W.; Turner, J. M.; Baird, E. E.; Dervan,
P. B.; Rees, D. C. Science 1998, 282, 111–115; (d) Dervan, P. B.
FASEB 1997, 11, 2546; (e) Turner, J. M.; Baird, E. E.; Dervan, P. B.
J. Am. Chem. Soc. 1997, 119, 7636–7644; (f) Wemmer, D. E.; Dervan,

1468
A. Kamal et al. / Tetrahedron Letters 49 (2008) 1465–1468
P. B. Curr. Opin. Struct. Biol. 1997, 7, 355–361; (g) Gottesfeld, J. M.;
evaporated under vacuum to give 3a (Scheme 1) in good yield.
Compounds 3a–l and 8a–c were synthesized in the same manner.
Neely, L.; Trauger, J. W.; Baird, E. E.; Dervan, P. B. Nature 1997,
387, 202–205; (h) Szewczyk, J. W.; Baird, E. E.; Dervan, P. B. Angew.
Chem., Int. Ed. 1996, 35, 1487–1489.
1
Compound 3a (FT-IR): cmꢁ1 2128; 1636; 1486; 1449; 1420; 1296; H
NMR (300 MHz, CDCl3): d 7.35–7.45 (m, 2H); 7.11–7.21 (m, 2H);
5.03–5.10 (m, 1H); 3.91 (s, 3H); 3.40–3.50 (m, 1H); 3.30–3.39 (m, 1H);
3.25 (s, 3H); 2.22–2.34 (m, 1H); 1.82–2.12 (m, 3H); ESI-MS: m/z 326
(M++Na); HRMS calcd for C14H17N5O3 (M+) 303.1949, found
303.1919. Compound 3e: (FT-IR): cmꢁ1 2963; 2125; 1670; 1636; 1578;
1456; 1423; 1385; 1310; 1265; 1H NMR (300 MHz, CDCl3): d 7.30–
7.42 (m, 5H); 7.06 (t, 1H, J = 7.55 Hz); 6.90–6.94 (m, 2H); 5.15 (s,
2H); 5.03–5.07 (m, 1H); 3.90 (s, 3H); 3.31–3.44 (m, 2H); 3.24 (s, 3H);
2.24–2.31 (m, 1H); 1.84–2.09 (m, 3H); LC-MSD: m/z 432 (M++Na);
HRMS calcd for C21H23N5O4 (M+) 409.2739, found 409.2742.
Compound 8a: (FT-IR): cmꢁ1 2114; 1631; 1514; 1460; 1430; 1385;
1248; 1210; 1H NMR (300 MHz, CDCl3): d 6.88 (s, 2H); 6.69 (s, 2H);
5.05–5.09 (m, 2H); 4.21–4.28 (m, 4H); 3.88 (s, 6H); 3.83 (s, 6H); 3.36–
3.50 (m, 4H); 3.25 (s, 6H); 2.24–2.44 (m, 4H); 1.83–2.10 (m, 4H); 1.68–
1.73 (m, 2H); ESI-MS: m/z 739 (M++H); 761 (M++Na); HRMS
calcd for C33H42N10O10 (M+) 738.4472, found 738.4450.
2. (a) Thurston, D. E. In Molecular Aspects of Anticancer Drug–DNA
Interactions; Neidle, S., Waring, M. J., Eds.; Macmillan Press Ltd:
Basingstoke, Hants, UK, 1993; Vol. 1, pp 54–88; (b) Remers, W. A. In
The Chemistry of Antitumor Antibiotics; Wiley-Interscience: New
York, 1988; Vol. 2; pp 28–92; (c) Hurley, L. H.; Thurston, D. E.
Pharm. Res. 1984, 2, 52–59.
3. Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433–465.
4. Bose, D. S.; Thompson, A. S.; Ching, J. S.; Hartley, J. A.; Berardini,
M. D.; Jenkins, T. C.; Neidle, S.; Hurley, L. H.; Thurston, D. E. J.
Am. Chem. Soc. 1992, 114, 4939–4941.
5. Thurston, D. E.; Bose, D. S.; Thompson, A. S.; Howard, P. W.;
Leoni, A.; Croker, S. J.; Jenkins, T. C.; Neidle, S.; Hartley, J. A.;
Hurley, L. H. J. Org. Chem. 1996, 61, 8141–8147.
6. (a) Bose, D. S.; Thompson, A. S.; Ching, J. A.; Hartley, J. A.;
Berardini, M. D.; Jenkins, T. C.; Neidle, S.; Hurley, L. H.; Thurston,
D. E. J. Am. Chem. Soc. 1992, 114, 4939–4941; (b) Bose, D. S.;
Thompson, A. S.; Smellie, M.; Berardini, M. D.; Hartley, J. A.;
Jenkins, T. C.; Neidle, S.; Thurston, D. E. J. Chem. Soc., Chem.
Commun. 1992, 1518–1520.
7. (a) Gregson, S. J.; Howard, P. W.; Hartley, J. A.; Brooks, A. A.;
Adams, L. J.; Jenkins, T. C.; Kelland, L. R.; Thurston, D. E. J. Med.
Chem. 2001, 44, 737–748; (b) Gregson, S. J.; Howard, P. W.; Gullick,
D. R.; Hamaguchi, A.; Corcoran, K. E.; Brooks, N. A.; Hartley, J.
A.; Jenkins, T. C.; Patel, S.; Guille, M. J.; Thurston, D. E. J. Med.
Chem. 2004, 47, 1161–1174.
8. (a) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N. Synlett
2004, 2533–2536; (b) Kamal, A.; Devaiah, V.; Reddy, K. L.;
Shankaraiah, N. Adv. Synth. Catal. 2006, 348, 249–254.
9. (a) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.; Reddy,
D. R. S. Mini-Rev. Med. Chem. 2006, 6, 53–68; (b) Kamal, A.; Reddy,
K. L.; Devaiah, V.; Shankaraiah, N.; Reddy, G. S. K.; Raghavan, S.
J. Comb. Chem. 2007, 9, 29–42; (c) Kamal, A.; Shankaraiah, N.;
Devaiah, V.; Reddy, K. L. Tetrahedron Lett. 2006, 47, 6553–6556; (d)
Kamal, A.; Shankaraiah, N.; Reddy, K. L.; Devaiah, V. Tetrahedron
Lett. 2006, 47, 4253–4257; (e) Kamal, A.; Reddy, K. L.; Devaiah, V.;
Shankaraiah, N. Synlett 2004, 1841–1843.
10. Kamal, A.; Rao, M. V.; Reddy, B. S. N. Khim. Geterotsikl. (Chem.
Heterocycl. Compd.) 1998, 1588–1604.
11. Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh, G.; Reddy, G. S. K.
Curr. Med. Chem.—Anti-Cancer Agents 2002, 2, 215–254.
12. Kaneko, T.; Wong, H.; Doyle, T. W.; Rose, W. C.; Bradner, W. T. J.
Med. Chem. 1985, 28, 388–392.
13. (a) Langley, D. R.; Thurston, D. E. J. Org. Chem. 1987, 52, 91–97; (b)
Courtney, S. M.; Thurston, D. E. Tetrahedron Lett. 1993, 34, 5327–
5328; (c) Bose, D. S.; Jones, G. B.; Thurston, D. E. Tetrahedron 1992,
48, 751–758.
14. Kamal, A.; Reddy, P. S. M. M.; Reddy, D. R. Tetrahedron Lett. 2003,
44, 2857–2860.
15. (a) Kamal, A.; Ramana, A. V.; Reddy, K. S.; Ramana, K. V.; Babu,
A. H.; Prasad, B. R. Tetrahedron Lett. 2004, 45, 8187–8190; (b)
Kamal, A.; Reddy, K. S.; Prasad, B. R.; Babu, A. H.; Ramana, A. V.
Tetrahedron Lett. 2004, 45, 6517–6521.
16. Budyka, M. F.; Biktimirova, N. V.; Gavrishova, T. N. Chem.
Heterocycl. Compd. 2007, 43, 454–459.
17. Typical procedure for the synthesis of compound 3a: The azidobenzoyl
proline acid (2a, 276 mg, 1 mmol) was dissolved in anhydrous CH2Cl2
(10 mL) and cooled to ꢁ15 °C followed by the addition of N,O-
dimethylhydroxylamine hydrochloride (107 mg, 1.1 mmol) and
NMM (0.08 mL, 1.1 mmol). Then EDCI (210 mg, 1.1 mmol) was
added portionwise as a solid over 30 min. The reaction mixture was
stirred at the same temperature for 1 h and then ice-cold HCl (1 M,
5 mL) was added. The reaction mixture was extracted with CH2Cl2
(3 ꢂ 30 mL), the combined organic layer was washed with aqueous
NaHCO3 (3 ꢂ 30 mL) solution, dried over anhydrous Na2SO4, and
18. Typical procedure (LiAlH4) for compound 4a: To azide 3a (200 mg,
0.66 mmol) in dry THF (15 mL) was added LiAlH4 (52 mg,
1.45 mmol) portionwise over 5 min at ꢁ15 to ꢁ20 °C and the reaction
stirred at the same temperature for 40 min. This was then quenched
with ethyl acetate, then ice-cold water was added and the reaction
mixture filtered through a sintered funnel. The combined layers were
extracted with ethyl acetate (3 ꢂ 30 mL), the organic layers dried over
anhydrous Na2SO4 and evaporated under vacuum to give product 4a.
This was purified by column chromatography (silica gel 100–200
mesh) using ethyl acetate/hexane (9:1) as eluent. Procedure for LiBH4:
Compound 3a (200 mg, 0.66 mmol) in dry THF (15 mL) was treated
with LiBH4 (42 mg, 2.00 mmol) at 0 °C and the reaction stirred at
room temperature for 130 min. Quenching with ice-cold water,
filtration through a sintered funnel, extraction with ethyl acetate
(3 ꢂ 30 mL), and purification by column chromatography gave 4a.
Both procedures were also applied for the preparation of PBD dimers
by utilizing varying amounts (2 equiv) of pyrrolobenzodiazepine
followed by purification by column chromatography (silica gel 100–
200 mesh) using CHCl3/MeOH (95:5) as eluent to produce 9a–c as
shown in Scheme 2. Compound 4a: 1H NMR (200 MHz, CDCl3): d
8.05 (d, 1H, J = 7.43 Hz); 7.79 (d, 1H, J = 4.46 Hz); 7.53 (t, 1H,
J = 6.69 Hz); 7.28–7.38 (m, 2H); 3.36–3.94 (m, 3H); 2.26–2.38, (m,
26
2H); 2.02–2.16 (m, 2H); MS (EI): m/z 200 [M+]; ½aꢃD +343 (c 0.4,
CHCl3); HRMS calcd for C12H12N2O (M+) 200.1506, found
200.1513. Compound 4e: 1H NMR (200 MHz, CDCl3): d 7.64 (d,
1H, J = 6.68 Hz); 7.28–7.38 (m, 6H); 6.89–7.03 (m, 2H); 5.03–5.15 (m,
2H); 3.67–3.95 (m, 2H); 2.54–2.62 (m, 1H); 1.61–2.13 (m, 3H); LC-
26
MSD: m/z 337 (m+CH3O)+; ½aꢃD +298 (c 0.4, CHCl3); HRMS calcd
for C19H18N2O2 (M+) 306.2297, found 306.2301. Compound 9a: 1H
NMR (200 MHz, CDCl3): d 7.57 (d, 2H, J = 2.34 Hz); 7.50 (s, 2H);
7.10 (s, 2H); 4.16–4.35 (m, 4H) 3.96 (s, 6H); 3.40–3.87 (m, 6H); 2.05–
2.48 (m, 10H); 13C NMR (50 MHz, CDCl3): d 24.8, 28.6; 29.0; 31.8;
33.9; 46.5; 56.1; 65.3; 105.5; 108.0; 113.5; 148.1; 158.1; 160.3; 177.0;
FABMS: m/z 533 (M++H); HRMS calcd for C29H32N4O6 (M+)
532.3587, found 532.3522. Compound 9b: 1H NMR (200 MHz,
CDCl3): d 7.68 (d, 2H, J = 4.68 Hz); 7.50 (s, 2H); 6.82 (s, 2H); 4.10–
4.20 (m, 4H) 3.93 (s, 6H); 3.51–3.84 (m, 4H); 2.27–2.38 (m, 4H); 2.06–
2.10 (m, 10H); 13C NMR (50 MHz, CDCl3): d 164.6; 162.4; 150.6;
147.8; 140.6; 120.3; 111.6; 110.7; 65.4; 56.1; 53.7; 46.7; 29.6; 25.7; 24.2;
FABMS: m/z 547 (M++H); HRMS calcd for C30H34N4O6 (M+)
546.3710, found 546.3737. Compound 9c: 1H NMR (200 MHz,
CDCl3): d 7.67 (d, 2H, J = 4.68 Hz); 7.50 (s, 2H); 6.80 (s, 2H); 4.04–
4.23 (m, 4H) 3.93 (s, 6H); 3.44–3.84 (m, 6H); 2.27–2.37 (m, 4H); 1.92–
2.11 (m, 8H); 1.66 (m, 2H); 13C NMR (50 MHz, CDCl3): d 164.7;
162.4; 150.8; 147.8; 140.6; 120.1; 111.5; 110.4; 68.5; 56.2; 53.7; 46.7;
29.7; 28.6; 24.2; 22.5; FABMS: m/z 561 (M++H); HRMS calcd for
C31H36N4O6 (M+) 560.3833, found 560.3812.
19. Kamal, A.; Shankaraiah, N.; Devaiah, V.; Reddy, K. L. Tetrahedron
Lett. 2006, 47, 9025–9028.