An efficient selective reduction of aromatic azides to amines employing BF3·OEt2/NaI: Synthesis of pyrrolobenzodiazepines

Article abstract of DOI:10.1055/s-2008-1072742

A selective and facile method for the reduction of aromatic azides to amines by employing borontrifluoride diethyl etherate and sodium iodide. This methodology has been applied towards the preparation of biologically important imine-containing pyrrolobenzodiazepines and their dilactams through intramolecular reductive-cyclization process. In this protocol the reagent systems are amenable for the generation of solution-phase combinatorial synthesis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072742

LETTER
1297
An Efficient Selective Reduction of Aromatic Azides to Amines Employing
BF3·OEt2/NaI: Synthesis of Pyrrolobenzodiazepines
S
ynthesis of Pyrro
h
lobenzodiaze
m
pines ed Kamal,*a N. Shankaraiah,a N. Markandeya,b Ch. Sanjeeva Reddy*b
a
Chemical Biology, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)927193189; E-mail: ahmedkamal@iict.res.in
b
Department of Chemistry, Kakatiya University, Warangal 506009, A.P., India
Fax +91(870)2439600; E-mail: chsrkue@yahoo.in
Received 20 November 2007
Table 1 Selective Reduction of Aromatic Azides 1a–j to Amines
2a–j by Employing BF3·OEt2 and NaI
Abstract: A selective and facile method for the reduction of aro-
matic azides to amines by employing borontrifluoride diethyl ether-
ate and sodium iodide. This methodology has been applied towards
the preparation of biologically important imine-containing pyr-
rolobenzodiazepines and their dilactams through intramolecular re-
ductive–cyclization process. In this protocol the reagent systems are
amenable for the generation of solution-phase combinatorial syn-
thesis.
R1
NH2
R1
N3
BF3⋅OEt2, NaI (50 mol%)
MeCN, 10–40 min, r.t.
R2
R3
R2
R3
1a–j
2a–j
Entry R1
R2
R3
Time
(min)
Yield EIMS
(%)a,b
Key words: pyrrolo[2,1-c][1,4]benzodiazepines, boron trifluoride
diethyl etherate, sodium iodide, intramoleculor reductive–cycliza-
tion
2a
2b
2c
2d
2e
2f
H
H
COOH
30
40
35
40
35
10
15
25
20
30
85
80
92
86
88
90
96
84
94
96
137
151
171
183
273
165
185
197
211
287
H
Me
COOH
In recent years, azides1 have attracted much attention as
key intermediates for the synthesis of a large number of
organic compounds such as nucleosides, carbohydrates,2
and nitrogen-containing heterocycles3 – such as pyr-
rolobenzodiazepines, quinolines, lactams, and cyclic imi-
des. The conversion of aromatic azides into amines has
been a desirable strategy in various synthetic sequences
and for this purpose a variety of reagents has been report-
ed in the literature.4a–h However, in terms of their practical
applicability, selectivity, commercial availability, and re-
action conditions, most of these methods have certain dis-
advantages, prompting considerable demand for the
development of novel, more efficient, mild, and selective
methodologies.5
H
Cl
COOH
OH
OMe
OMe
Me
COOH
OBn
H
COOH
COOMe
COOMe
COOMe
COOMe
COOMe
2g
2h
2i
H
Cl
OH
OMe
OBn
OMe
OMe
OMe
2j
a Isolated yields.
b Compounds characterized by 1H NMR, IR, and EIMS.
Recently, we have reported6 a versatile method for the re-
duction of aromatic azides to amines in solution as well as
on solid phase employing BF3·OEt2 and EtSH in anhy-
drous CH2Cl2. This new methodology is applicable for the
synthesis of naturally occurring DC-81 and also for resin
cleavage. Ethanethiol used in this methodology is a re-
agent of highly volatile nature, malodorous, and requiring
safety precautions for carrying out the reaction. In this
connection, we herein report a mild, efficient, and selec-
tive method for the reduction of aromatic azides 1a–j to
their corresponding amines 2a–j by employing boron tri-
fluoride diethyl etherate and sodium iodide in acetonitrile
at room temperature to give excellent yields as shown in
Table 1.
This method is an efficient and convenient alternative to
the aza-Wittig route by employing TPP or Bu3P as it does
not require any anhydrous conditions and furthermore,
this reagent system is inexpensive. In continuation of
these efforts, this methodology has been applied for the
synthesis of pyrrolo[2,1-c][1,4]benzodiazepines (PBD)
through an intramolecular azido-reductive cyclization ap-
proach. Pyrrolo[2,1-c][1,4]benzodiazepines are a family
of naturally occurring antitumor antibiotics that usually
interact with DNA covalently in a sequence-selective
manner preferentially at Pu-G-Pu motifs.7 The develop-
ment of viable synthetic pathways8 has allowed many an-
alogues of PBD monomers to be explored. The substituted
azidobenzoyl prolinaldehydes9 3a–f have been reduced
with BF3·OEt2 and NaI to afford the reductive-cyclized
products 4a–f in good yields, which are illustrated in
Table 2. However, in our previous studies9 employing
BF3·OEt2 and EtSH for the reduction of azido to amino
functionality, an additional cyclization step is necessary to
SYNLETT 2008, No. 9, pp 1297–1300
x
x.
x
x.
2
0
0
8
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072742; Art ID: D37407ST
© Georg Thieme Verlag Stuttgart · New York

1298
A. Kamal et al.
LETTER
Table 2 Synthesis of Pyrrolo[2,1-c][1,4]benzodiazepines 4a–h via Azido-Reductive Cyclization Approach by Employing BF3·OEt2 and NaI
R1
R2
R1
R2
N3
N
CHO
BF3⋅OEt2, NaI (50 mol%)
H
MeCN, 60–80 min, r.t.
N
N
R3
R3
O
O
3a–h
4a–h
Entry
4a
R1
H
R2
R3
Time (min)
Yield (%)a,b
EIMS
200
214
336
260
216
230
352
276
H
H
60
65
70
68
75
80
80
80
92
90
90
88
75
78
82
80
4b
4c
H
Me
H
OBn
OMe
OMe
H
H
4d
4e
OMe
H
H
OH
OH
OH
OH
4f
H
Me
4g
OBn
OMe
OMe
OMe
4h
a Isolated yields.
b Compounds characterized by 1H NMR, IR, and EIMS.
obtain this product as the aldehyde intermediate is protect- diones. Some of these dilactams have been reported to
ed by the ethanethiol, which is present in the reaction me- possess significant in vivo antitumor activity in the P388
dium. In contrast the present methodology using BF3·OEt2 rat model.10 This tricyclic ring system has been used for a
and NaI results in the reduction of azide to amine followed number of pharmaceutical applications, including as a
by cyclization in a single step.
template for design and assembly of peptidomimetic
agents,11 anxiolytic drugs,12 anticonvulsants,13 and herbi-
cides.14 Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones
This reagent system has also been employed towards the
preparation of pyrrolo[2,1-c][1,4]benzodiazepine-5,11-
Table 3 An Efficient Synthesis of Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones 6a–j via Azido-Reductive Cyclization Approach by Em-
ploying BF3·OEt2 and NaI19,20
O
H
R1
R2
R1
R2
N3
N
COOMe
H
BF3⋅OEt2, NaI (50 mol%)
N
MeCN, 60–80 min, r.t.
N
R3
R3
O
O
5a–j
6a–j
Entry
6a
6b
6c
R1
R2
R3
H
H
H
H
H
Time (min)
Yield (%)a,b
EIMS
216
230
250
276
352
232
246
266
292
368
H
H
60
60
65
68
70
68
75
75
72
80
90
96
95
90
96
95
85
86
78
85
H
Me
Cl
H
6d
6e
OMe
OBn
H
OMe
OMe
H
6f
OH
OH
OH
OH
OH
6g
6h
6i
H
Me
Cl
H
OMe
OBn
OMe
OMe
6j
a Isolated yields.
b Compounds characterized by 1H NMR, IR, and EIMS.
Synlett 2008, No. 9, 1297–1300 © Thieme Stuttgart · New York

LETTER
Synthesis of Pyrrolobenzodiazepines
1299
(12) Wright, W. B.; Brabander, H. J.; Greenblatt, E. N.; Day, I.
P.; Hardy, R. A. J. Med. Chem. 1978, 21, 1087.
(13) Di Martino, G.; Massa, S.; Corelli, F.; Pantaleoni, G.; Fanini,
D.; Palumbo, G. Eur. J. Med. Chem. 1983, 18, 347.
(14) Karp, G. M.; Manfredi, M. C.; Guaciaro, M. A.; Ortlip, C.
L.; Marc, P.; Szamosi, I. T. J. Agric. Food Chem. 1997, 45,
493.
(15) (a) Kaneko, T.; Wong, H.; Doyle, T. W. J. Antibiotics 1984,
37, 300. (b) Kamal, A.; Reddy, B. S. P.; Reddy, B. S. N.
Tetrahedron Lett. 1996, 37, 2281. (c) Jones, G. B.; Davey,
C. L.; Jenkins, T. C.; Kamal, A.; Kneale, G.; Neidle, S.;
Webster, G. D.; Thurston, D. E. Anti-Cancer Drug Des.
1990, 5, 249. (d) Kaneko, T.; Wong, H.; Doyle, T. W.
Tetrahedron Lett. 1983, 24, 5165.
have been employed as intermediates in the synthesis of
naturally occurring and synthetically modified PBD imi-
nes such as tomaymycin and chicamycin.15 They are also
useful precursors for the PBD cyclic secondary amines16
which can be converted into PBD imines by mild oxida-
tion.17 Their importance as intermediates for a wide range
of biologically active compounds, such as psychomotor
depressant activity18a–c and sedative activity18d has been
extensively investigated. The substrates 5a–j have been
converted into its lactams 6a–j in the presence of
BF3·OEt2 and NaI by intramolecular azido-reductive cy-
clization process to give excellent yields as shown in
Table 3.
(16) Kamal, A.; Howard, P. W.; Reddy, B. S. N.; Reddy, B. S. P.;
Thurston, D. E. Tetrahedron 1997, 53, 3223.
In summary, we have demonstrated an efficient, mild,
cost-effective, and ecofriendly protocol for the reduction
of azido functionality. Additionally, this method has been
successfully applied to the efficient synthesis of pharma-
cologically important nitrogen-containing heterocycles,
such as pyrrolobenzodiazepine analogues through the in-
tramolecular azido-reductive cyclization process employ-
ing this reagent system.
(17) (a) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433.
(b) Kamal, A.; Rao, M. V.; Reddy, B. S. N. Khim.
Geterotsikl. Soedin. (Chem. Heterocycl. Compd.) 1998,
1588. (c) Kamal, A.; Rao, N. V. Chem. Commun. 1996, 385.
(18) (a) Carbateas, P. M. US 3,732,212, 1973; Chem. Abstr.
1973, 79, P42570x. (b) Carbateas, P. M. US 3,763,183,
1973; Chem. Abstr. 1973, 79, P146567t. (c) Carbateas, P.
M. US 3,860,600, 1975; Chem. Abstr. 1975, 83, P58892x.
(d) Reddy, B. S. P. PhD Thesis; Osmania University: India,
1995.
(19) General Procedure for Azido Reductions
Acknowledgment
The substituted aromatic azides were dissolved in MeCN (15
mL), BF3·OEt2 (2.0 equiv), NaI (50 mol%) was added and
then solvent stirred at r.t. for 10–80 min to afford reductively
cyclized products. The reaction mixture was quenched with
aq Na2S2O3 followed by neutralization with aq NaHCO3
soln. The mixture was extracted with EtOAc (3 × 35 mL)
and the combined organic extracts dried over anhyd Na2SO4.
The solvent was evaporated under vacuum and the residue
purified by column chromatography through SiO2 (60–120
mesh) eluting with EtOAc–hexane (yields as shown in
Tables 1–3).
The authors N.S. and N.M.K. are grateful to CSIR, New Delhi, for
the award of Research Fellowships.
References and Notes
(1) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
(2) Smith, S. C.; Heathcock, C. H. J. Org. Chem. 1992, 57,
6379.
(3) McDonald, F. E.; Danishefsky, S. J. J. Org. Chem. 1992, 57,
7001.
(4) (a) Ito, M.; Koyakumaru, K.; Takaya, T. H. Synthesis 1995,
376. (b) Rao, H. S. P.; Siva, P. Synth. Commun. 1994, 24,
549. (c) Alverez, S. G.; Fisher, G. B.; Singavam, B.
Tetrahedron Lett. 1995, 36, 2567. (d) Molina, P.; Diaz, I.;
Tarraga, A. Tetrahedron 1995, 51, 5617. (e) Ramesha, A.
R.; Bhat, S.; Chandrasekaran, S. J. Org. Chem. 1995, 60,
7682. (f) Capperucci, A.; Degl’Innocenti, A.; Funicello, M.;
Mauriello, G.; Scafato, P.; Spagnolo, P. J. Org. Chem. 1995,
60, 2254. (g) Kamal, A.; Reddy, B. S. P.; Reddy, B. S. N.
Tetrahedron Lett. 1996, 37, 6803. (h) Huang, Y.; Zhang, Y.;
Wang, Y. Tetrahedron Lett. 1997, 38, 1065.
(20) Selected Data
Compound 2h: 1H NMR (200 MHz, CDCl3): d = 7.35–7.45
(m, 5 H), 7.22 (s, 1 H), 6.15 (s, 1 H), 5.47–5.90 (br s, 2 H),
5.20 (s, 2 H), 3.84 (s, 3 H), 3.83 (s, 3 H). MS (EI): m/z = 287
[M+].
Compound 4a: 1H NMR (200 MHz, CDCl3): d = 8.05 (d,
J = 7.43 Hz, 1 H), 7.79 (d, J = 4.46 Hz, 1 H), 7.53 (t, J = 6.69
Hz, 1 H), 7.28–7.38 (m, 2 H), 3.36–3.94 (m, 3 H), 2.26–2.38,
(m, 2 H), 2.02–2.16 (m, 2 H). MS (EI): m/z = 200 [M+].
[a]D26 +343 (c 0.4, CHCl3).
Compound 4b: 1H NMR (400 MHz, CDCl3): d = 8.00–8.05
(m, 1 H), 7.00–7.80 (m, 1 H), 7.40–7.60 (m, 1 H), 7.20–7.30
(m, 1 H), 3.40–3.90 (m, 3 H), 1.90–2.50 (m, 7 H). MS (EI):
m/z = 214 [M+].
(5) Molander, G. A. Chem. Rev. 1992, 92, 29.
(6) (a) Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh, G.; Reddy,
G. S. K. Curr. Med. Chem.: Anti-Cancer Agents 2002, 2,
215. (b) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah,
N.; Reddy, D. R. Mini-Rev. Med. Chem. 2006, 6, 53.
(c) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.;
Rao, M. V. Mini-Rev. Med. Chem. 2006, 6, 71.
(7) Thurston, D. E. In Molecular Aspects of Anticancer Drug-
DNA Interactions, Vol. 1; Neidle, S.; Waring, M. J., Eds.;
The Macmillan Press Ltd: London, 1993, 54.
Compound 4e: 1H NMR (200 MHz, DMSO-d6): d = 7.84 (d,
1 H, J = 7.32), 7.12–7.26 (m, 1 H), 6.95 (d, 1 H, J = 5.01
Hz), 6.70–7.80 (m, 2 H), 4.92 (d, 1 H, J = 4.81 Hz), 4.17–
4.26 (m, 1 H), 4.02 (m, 1 H), 3.50–3.75 (m, 2 H), 1.95–2.10
(m, 1 H), 1.70–1.80 (m, 1 H). 13C NMR (50 MHz, DMSO-
d6): d = 166.5, 150.2, 144.6, 133.5, 131.7, 131.4, 128.6,
125.2, 71.0, 56.6, 52.0, 39.5. MS (EI): m/z 216 [M+]. HRMS:
m/z calcd for C12H12N2O2: 216.2358; found: 216.2361.
Compound 6a: 1H NMR (200 MHz, CDCl3): d = 9.22 (br s,
1 H), 7.96–8.08 (d, 1 H, J = 8.03 Hz), 7.42–7.58 (t, 1 H,
J = 8.03, 7.03 Hz), 7.21–7.28 (m, 1 H), 7.03–7.07 (d, 1 H,
J = 8.03 Hz), 4.05–4.09 (d, 1 H, J = 6.57 Hz), 3.75–3.86 (m,
1 H), 3.51–3.65 (m, 1 H), 2.71–2.82 (m, 1 H), 1.85–2.15 (m,
3 H). MS (EI): m/z = 216 [M+]. HRMS: m/z calcd for
C12H12N2O2: 216.2358; found: 216.2363.
(8) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433.
(9) Kamal, A.; Shankaraiah, N.; Reddy, K. L.; Devaiah, V.
Tetrahedron Lett. 2006, 47, 4253.
(10) Kneko, T.; Wong, H.; Doyle, T. W.; Rose, W. C.; Brander,
W. T. J. Med. Chem. 1985, 28, 388.
(11) Blackburn, B. K.; Lee, A.; Baier, M.; Kohl, B.; Olivero, A.
G.; Matamoros, R.; Robarge, K. D.; McDowell, R. S. J. Med.
Chem. 1997, 40, 717.
Synlett 2008, No. 9, 1297–1300 © Thieme Stuttgart · New York

1300
A. Kamal et al.
LETTER
Compound 6f: 1H NMR (200 MHz, DMSO-d6): d = 7.84 (d,
1 H, J = 7.3 Hz), 7.12–7.26 (m, 1 H), 6.95 (d, 1 H, J = 5.0
Hz), 6.70–6.80 (m, 2 H), 4.92 (d, 1 H, J = 4.8 Hz), 4.17–4.26
(m, 1 H), 4.02–4.10 (m, 1 H), 3.50–3.75 (m, 2 H), 1.95–2.10
(m, 1 H). 13C NMR (50 MHz, DMSO-d6): d = 166.5, 150.2,
144.6, 133.5, 131.7, 131.4, 128.6, 125.2, 71.0, 56.6, 52.0,
39.5. MS (EI): m/z = 232 [M+]. HRMS: m/z calcd for
C12H12N2O3: 232.2352; found: 232.2358.
Compound 6j: 1H NMR (200 MHz, CDCl3): d = 10.10 (s, 1
H), 7.26–7.40 (m, 6 H), 6.49 (s, 1 H), 5.10 (s, 2 H), 3.98–4.01
(d, 1 H, J = 6.44 Hz), 3.91 (s, 3 H), 3.65–3.75 (m, 1 H), 3.42–
3.50 (m, 2 H), 2.65–2.75 (m, 1 H), 1.90–2.00 (m, 2 H). 13
C
NMR (50 MHz, DMSO-d6): d = 171.2, 166.5, 152.2, 146.6,
137.2, 131.4, 129.5, 128.6, 118.3, 113.4, 106.8, 71.0, 68.5,
56.6, 54.0, 35.8. MS (EI): m/z = 368 [M+]. HRMS: m/z calcd
for C20H20N2O5: 368.3824; found: 368.3831.
Synlett 2008, No. 9, 1297–1300 © Thieme Stuttgart · New York