Copper-catalyzed synthesis of indole-fused benzodiazepines

Article abstract of DOI:10.1002/adsc.201100388

The copper-catalyzed synthesis of indole-fused benzodiazepine via a cascade reaction between 3-halo-1H-indole-2-carbaldehydes and substituted 1,2-phenylenediamines is reported. Reactions with N-Boc-protected indole-aldehydes are found to be more efficient

Full text of DOI:10.1002/adsc.201100388

UPDATE
DOI: 10.1002/adsc.201100388
Copper-Catalyzed Synthesis of Indole-Fused Benzodiazepines[1]
Subhasish Biswasa and Sanjay Batraa,*
a
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, PO Box 173, Lucknow – 226 001,
India
Fax : (+91)-522-262-3405 or (+91)-522-262-3938; phone: (+91)-522-262-141-118, extension 4234 or 4368;
e-mail: batra_san@yahoo.co.uk or s_batra@cdri.res.in
Received: May 16, 2011; Revised: July 5, 2011; Published online: October 10, 2011
Abstract: The copper-catalyzed synthesis of indole-
fused benzodiazepine via a cascade reaction be-
tween 3-halo-1H-indole-2-carbaldehydes and substi-
tuted 1,2-phenylenediamines is reported. Reactions
with N-Boc-protected indole-aldehydes are found
ciated biological activities[7] have kept the interest of
synthetic and medicinal chemists alive for formulating
newer approaches towards their synthesis.
The study required 3-iodo-1H-indole-2-carbalde-
hyde as the starting material which was prepared via
iodination of the indole-2-carbaldehyde with I2/
KOH.[8] Initially, 3-iodo-1H-indole-2-carbaldehyde
and 1,2-phenylenediamine were used as the model
substrates to optimize the reaction conditions includ-
ing catalysts, ligands, bases and solvents. As shown in
Table 1, five copper catalysts (0.1 equiv.) were tested
with 20 mol% of l-proline as ligand, 2 equiv. of
K3PO4 (relative to amount of 3-iodo-1H-indole-2-car-
baldehyde) as the base and DMSO as the solvent at
908C (entries 1–5), and Cu2O provided the highest
to be more efficient to afford indole
ACHTUNGTRENNUNG[1,5]benzodiazepines.
ACHTUNGTRENN[UNG 3,2-b]-
Keywords: benzodiazepines; cascade reactions;
copper; coupling; indoles; indolo
diazepines
ACHUTGTNREN[UNG 3,2-b]AHCTUNGTRENN[GUN 1,5]benzo-
Copper-catalyzed cascade reactions have been suc- yield (entry 3). Other ligands, N,N-dimethylethylene-
cessfully applied for the synthesis of a variety N-het- diamine, N,N-tetramethylethylenediamine, rac-1,2-di-
erocyclic compounds.[2] Recently, we reported an effi- aminocyclohexane, were screened and l-proline was
cient method for preparing pyrazole-fused benzodia- found to be most suited (compare entries 3, 6–8).
zepines via copper-catalyzed reaction between 4-iodo- Next the effect of other bases, K2CO3 and Cs2CO3
pyrazole-3-carbaldehydes
and
1,2-phenylenedia- was evaluated, and K3PO4 showed the best activity
mines.[3] The approach is of considerable importance (compare entries 3, 9, 10). The effect of solvents was
as it provides one-pot access to heterofused benzodia- also investigated, and DMSO was the optimal solvent
zepines from easily available starting materials. In our (compare entries 3, 11-13). The reaction failed in the
endeavors to develop novel pathways to annulated in- absence of a copper source (entry 14) whereas pro-
doles,[4] we envisioned that our method could also be duced lower yields of product in the absence of ligand
applied to 3-iodo-1H-indole-2-carbaldehydes for (entry 15).
achieving the synthesis of indole-fused benzodiaze-
pines. An isolated report[5] in the literature discloses 3-iodo-1H-indole-2-carbaldehyde with several 1,2-
the preparation of indole[3,2-b][1,5]benzodiazepine phenylenediamines was investigated under the opti-
The scope of copper-catalyzed domino reactions of
A
ACHTUNGTRENNUNG
via an initial Cu2O-mediated Ullman reaction be- mized conditions (using 10 mol% of Cu2O as the cata-
tween 3-aminoindoles and 2-chloroaniline followed by lyst, 20 mol% of l-proline, 2 equiv. of K3PO4 as the
acylation and subsequent cyclization with POCl3. This base, and DMSO as the solvent at 908C). As shown
approach invariably produced C-6 substituted indole- in Table 2 (entries 1–3), most of the substrates exam-
ACHTUNGTRENNUNG[3,2-b]ACHTUNGTRENNUNG[1,5]benzodiazepines. We wish to provide an ined provided the products in satisfactory yields. As
update on the use of our methodology for successfully compared to unsubstituted 1,2-phenylenediamine, the
preparing the indole-fused benzodiazepine. The study diamine bearing a methyl group (electron-donating
highlights the influence of substitutions on NH of the group) yielded the corresponding product in better
indole to enhance the efficiency of the cascade cycli- yields (entry 1) whereas the diamine containing a
zation.
halide (electron-withdrawing group) on the phenyl
Indole-annulated medium rings are an important ring furnished the products in relatively lower yields
class of compounds that are well represented both in (entries 2 and 3). To introduce the substrate diversity
nature and throughout chemical synthesis.[6] The asso- with respect to indole, in the first stage the NH was
Adv. Synth. Catal. 2011, 353, 2861 – 2867
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Subhasish Biswas and Sanjay Batra
UPDATE
Table 1. Results of the study for optimizing the reaction[a] of
3-iodo-1H-indole-2-carbaldehyde with 1,2-phenylenedi-
ACHTUNGTRENNUNGamine.
afford the required materials in excellent yields. and
the results of their reactions with several 1,2-pheny-
AHCTUNGTREGlNNNU enediamines are illustrated in Table 3. It was satisfy-
ing to note that all substrates reacted smoothly to
afford the required products in excellent yields.
Inspired by the success of the methodology with 3-
iodo-1H-indole-2-carbaldehyde we considered it ap-
propriate to test its suitability with 3-bromo-1H-
indole-2-carbaldehyde. Although we anticipated the
formation of similar products, the exercise was ex-
pected to expand the substrate base for the protocol.
As
a consequence 3-bromo-1H-indole-2-carbalde-
hydes[10] and their N-benzyl- or N-Boc-protected ana-
logues were prepared and subjected to reactions with
either 1,2-phenylenediamine or 3,4-diaminotoluene
under similar conditions. The results of this study are
presented in Table 4. Expectedly all substrates reacted
smoothly to afford the corresponding products. As
evident from Table 4, the reaction time for the bromo
derivatives and the isolated yields of the products
were comparable with those of the iodo derivatives.
Like the iodo derivatives, the Boc-substituted 3-
bromo-1H-indole-2-carbaldehydes were found to be
better starting materials for the protocol and they too
afforded the N-deprotected products.
Entry Catalyst
Ligand Base
Solvent Yield [%][b]
1
CuI
A
A
A
A
A
B
C
D
A
A
A
A
A
–
K3PO4 DMSO 50
K3PO4 DMSO 47
2
3
4
CuBr
Cu2O
CuSO4
K3PO4 DMSO 68
K3PO4 DMSO 22
K3PO4 DMSO <10
K3PO4 DMSO 55
K3PO4 DMSO 58
K3PO4 DMSO 53
K2CO3 DMSO 15
Cs2CO3 DMSO 30
5
CuACHTUNGTRENNUNG(OAc)2
6
7
8
9
10
11
12
13
14
15
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
–
K3PO4 DMF
K3PO4 toluene 47
K3PO4 dioxane 25
56
In summary, we have demonstrated that the
copper-catalyzed cascade sequence provides
a
K3PO4 DMSO
–
Cu2O
–
K3PO4 DMSO 38
straightforward access to indole-fused benzodiaze-
pines and hence expands the scope of our strategy for
assembling heterofused benzodiazepines. This work
reflects that compared to the unprotected 3-halo-1H-
indole-2-carbaldehydes, the N-Boc-3-halo-1H-indole-
2-carbaldehydes are preferable substrates for obtain-
ing indole-fused benzodiazepines.
[a]
Reaction conditions: under nitrogen atmosphere, 3-iodo-
1H-indole-2-carbaldehyde (0.74 mmol), 1,2-phenylenedi-
ACHTUNGTRENNUNGamine (0.74 mmol), Cu salt (0.074 mmol), ligand
(0.15 mmol), base (1.48 mmol), solvent (2 mL), tempera-
ture (908C), reaction time (11 h).
Isolated yields.
[b]
protected with benzyl and butoxycarbonyl (Boc)
groups and the corresponding substrates were subject-
ed to reaction with different 1,2-phenylenediamines
(Table 2, entries 4–11). It was discovered that the re-
actions of N-benzyl-3-iodo-1H-indole-2-carbaldehyde
were completed in 15–16 h and the yields were com-
parable to those of the unprotected indole derivatives
(Table 2, entries 4–7). On the other hand we were de-
lighted to discover that the reactions of N-Boc-3-
iodo-1H-indole-2-carbaldehyde with different 1,2-phe-
Experimental Section
General Procedure for Indole-Fused Benzodiazepines
as Exemplified for the Synthesis of 5,12-Dihydro-
indoloACTHNURTGENN[UG 3,2-b]AHCUTNGTREN[NUGN 1,5]benzodiazepine
To a solution of 3-iodo-1H-indole-2-carbaldehyde (200 mg,
0.74 mmol) in DMSO (2 mL), 1,2-phenylenediamine (0.08 g,
0.74 mmol), K3PO4 (315 mg, 1.48 mmol), Cu2O (14 mg,
0.074 mmol) and l-proline (17 mg, 0.15 mmol) were added
and the reaction mixture was heated at 908C for 11 h under
nylenediamines were relatively efficient to afford the a nitrogen atmosphere. Thereafter, water (50 mL) and ethyl
acetate (25 mL) were added and the reaction mass was
passed through a Celite bed and the layers were separated.
The aqueous layer was further extracted with ethyl acetate
(2ꢁ20 mL) and the collected organic layer was washed with
brine, dried over anhydrous Na2SO4 and concentrated under
vacuum. Column chromatography of the crude product over
products in excellent yields in less time (Table 2, en-
tries 8–11). More importantly, the Boc group was
cleaved during the reaction to afford the N-deprotect-
ed indole analogues. The presence of a base in the re-
action medium may be responsible for such a depro-
tection.[4]
Next, reactions of the indoles carrying variations in
the phenyl unit were investigated. The required com-
pounds were prepared following the reported proce-
silica gel furnished the pure 5,12-dihydroindolo
ACHTUNGTRENNUNG[3,2-b]-
AHCTUNGTRENNUNG
yield: 117 mg (68%).
5,12-Dihydroindolo
[3,2-b]
E
(Table 2,
dure.[9] Essentially the NH was protected as Boc to entry 8): Solid; mp >2508C; Rf =0.52 (EtOAc/hexanes,
2862
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Copper-Catalyzed Synthesis of Indole-Fused Benzodiazepines
Table 2. Scope of reaction with different unsubstituted and N-substituted indole derivatives.
Entry
1
1
2
3
Time
11 h
Yield [%][b]
70
2
12 h
66
3
4
12 h
15 h
62
69
5
6
7
15 h
16 h
16 h
70
64
62
8
9
8 h
8 h
83
85
Adv. Synth. Catal. 2011, 353, 2861 – 2867
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Subhasish Biswas and Sanjay Batra
UPDATE
Table 2. (Continued)
Entry
1
2
3
Time
8.5 h
Yield [%][b]
10
76
11
8.5 h
73
[a]
Reaction conditions: under nitrogen atmosphere,
1
(0.55 mmol), 2 (0.55 mmol), Cu2O (0.055 mmol), l-proline
(0.11 mmol), K3PO4 (1.6 mmol), DMSO (2 mL), temperature (908C).
Isolated yields.
[b]
20:80, v/v); IR (KBr): nmax =3345 (NH) cmÀ1
;
1H NMR
5-Benzyl-5,12-dihydroindoloACTHUGNTRENNU[G 3,2-b]ACHTUNGERTN[NUNG 1,5]benzodiazepine
(300 MHz, DMSO-d6): d=7.04 (t, 1H, J=7.3 Hz, ArH),
7.15–7.23 (m, 4H, ArH), 7.46 (d, 1H, J=8.0 Hz, ArH), 7.62
(s, 2H, ArH), 7.65 (s, 1H, =CH), 11.93 (brs, 1H, NH), 12.93
(brs, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d=101.7,
112.0, 119.8, 120.9, 122.3, 122.9, 127.9, 128.7, 137.3, 146.2;
ESI-MS: m/z=234 [M+H]+; ESI-HR-MS: m/z=234.1071,
calcd. for C15H11N3 [MH]+: 234.1069.
(Table 2, entry 4): White solid; mp >2508C; Rf =0.63
(EtOAc/hexanes, 20:80, v/v); IR (KBr): nmax =3332 (NH)
cmÀ1
;
1H NMR (300 MHz, DMSO-d6): d=6.34 (s, 2H,
CH2Ph), 7.10 (s, 3H, ArH), 7.20 (s, 6H, ArH). 7.37 (s, 1H,
ArH), 7.47 (d, 1H, J=7.3 Hz, ArH), 7.54 (d, 1H, J=6.6 Hz,
ArH), 7.68 (s, 1H, ArH), 7.70 (s, 1H, =CH), 12.99 (brs, 1H,
NH); 13C NMR (50 MHz, DMSO-d6): d=47.3, 104.3, 111.1,
119.0, 120.4, 121.1, 123.0, 123.3, 126.6, 126.9, 127.1, 128.4,
129.1, 138.3, 138.8, 143.6, 145.8; ESI-MS: m/z=324 [M+
H]+; ESI-HR-MS: m/z=324.1425, calcd. for C22H17N3
[MH]+: 324.1422.
10-Methyl-5,12-dihydroindoloACHTNUTRGENN[UG 3,2-b]ACHUTNTGREN[NUGN 1,5]benzodiazepine
(Table 2, entries 1 and 9): White solid; mp >2508C; Rf =
0.54 (EtOAc/hexanes, 20:80, v/v); IR (KBr): nmax =3352
1
(NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=2.45 (s, 3H,
CH3), 7.03 (t, 1H, J=7.4 Hz, ArH), 7.16 (s, 2H, ArH), 7.33
(s, 1H, ArH), 7.44 (s, 1H, ArH), 7.46 (s, 1H, ArH), 7.54 (d,
1H, J=8.2 Hz, ArH), 7.63 (d, 1H, J=7.9 Hz, =CH), 11.96
(brs, 1H, NH), 12.83 (brs, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d=21.4, 101.3, 110.9, 111.9, 118.0,
119.6, 120.7, 122.6, 127.9, 128.8, 137.1; ESI-MS: m/z=248
[M+H]+; ESI-HR-MS: m/z=248.1220, calcd. for C16H13N3
[MH]+: 248.1217.
5-Benzyl-10-methyl-5,12-dihydroindoloACTHUGNRTENNU[G 3,2-b]ACHTGNUTREN[NGNU 1,5]benzo-
diazepine (Table 2, entry 5): White solid; mp >2508C; Rf =
0.67 (EtOAc/hexanes, 20:80, v/v); IR (KBr): nmax =3338
1
(NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=2.44 (s, 3H,
CH3), 6.33 (s, 2H, CH2Ph), 7.09 (d, 3H, J=6.5 Hz, ArH),
7.14–7.21 (m, 4H, ArH), 7.32 (s, 1H, ArH), 7.34 (s, 1H,
ArH), 7.40–7.54 (m, 3H, ArH), 7.68 (d, 1H, J=7.6 Hz, =
CH), 12.88 (brs, 1H, NH); 13C NMR (75 MHz, DMSO-d6):
d=21.4, 47.2, 104.0, 110.6, 110.8, 111.0, 118.6, 118.8, 120.3,
121.0, 123.1, 123.3, 124.4, 126.6, 126.9, 127.1, 128.4, 129.3,
138.8, 143.9, 145.3; ESI-MS: m/z=338 [M+H]+; ESI-HR-
MS: m/z=338.1577, calcd. for C23H19N3 [MH]+: 338.1579.
10-Chloro-5,12-dihydroindoloACHTNUTRGENN[UG 3,2-b]ACHUTNTGREN[NUGN 1,5]benzodiazepine
(Table 2, entries 2 and 10): Brown solid; mp >2508C; Rf =
0.48 (EtOAc/hexanes, 20:80, v/v); IR (KBr): nmax =3355
1
(NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=7.05 (t, 1H,
J=7.3 Hz, ArH), 7.16–7.25 (m, 3H, ArH), 7.47 (d, 1H, J=
8.0 Hz, ArH), 7.59, (s, 1H, ArH), 7.63 (s, 2H, ArH and=
CH), 11.99 (brs, 1H, NH), 13.12 (brs, 1H, NH); 13C NMR
(75 MHz, DMSO-d6): d=102.3, 112.1, 119.8, 120.9, 122.4,
123.1, 126.5, 127.8, 128.1, 137.4, 147.5; ESI-MS: m/z=268
5-Benzyl-10-chloro-5,12-dihydroindoloACTHUGNRTENNU[G 3,2-b]ACHTGNUTREN[NGNU 1,5]benzo-
diazepine (Table 2, entry 6): Brown solid; mp >2508C; Rf =
0.61 (EtOAc/hexanes, 20:80, v/v); IR (KBr): nmax =3342
1
(NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=6.31 (s, 2H,
CH2Ph), 7.09 (t, 3H, J=6.9 Hz, ArH), 7.17–7.23 (m, 5H,
ArH), 7.40 (s, 1H, ArH), 7.48–7.56 (m, 2H, ArH), 7.65–7.72
(m, 2H, ArH and =CH), 12.19 (brs, 1H, NH); 13C NMR
(75 MHz, DMSO-d6): d=47.4, 104.9, 111.1, 113.8, 120.5,
121.3, 123.5, 126.4, 126.6, 126.9, 127.0, 128.1, 128.4, 128.6,
130.5, 138.4, 138.7, 139.9, 144.2; ESI-MS: m/z=358 [M+
H]+; ESI-HR-MS: m/z=358.1036, calcd. for C22H16ClN3
[MH]+: 358.1033.
[M+H]+;
calcd.
C15H10ClN3 [MH]+: 268.0563.
9,10-Dichloro-5,12-dihydroindoloACTUHGTNREN[NUNG 3,2-b]ACHTNUGTREN[NGNU 1,5]benzo-
ESI-HR-MS:
m/z=268.0567,
for
diazepine (Table 2, entries 3 and 11): Brown solid; mp
>2508C; Rf =0.46 (EtOAc/hexanes, 20:80, v/v); IR (KBr):
1
nmax =3358 (NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=
7.06 (t, 1H, J=10.4 Hz, ArH), 7.16–7.25 (m, 2H, ArH), 7.47
(d, 1H, J=12.3 Hz, ArH), 7.65, (d, 1H, J=10.7 Hz, ArH),
7.85 (s, 2H, ArH and=CH), 12.04 (brs, 1H, NH), 13.36
(brs, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d=104.5,
113.2, 121.5, 122.2, 124.9, 125.9, 126.0, 127.9, 128.7, 134.9,
138.3, 149.4; ESI-MS: m/z=302 [M+H]+; ESI-HR-MS: m/
z=302.0176, calcd. for C15H9Cl2N3 [MH]+: 302.0173.
5-Benzyl-9,10-dichloro-5,12-dihydroindoloACTHUNTGRNENUG[3,2-b]CAHTUNGTRENN[UGN 1,5]-
benzodiazepine (Table 2, entry 7): Brown solid; mp
>2508C; Rf =0.58 (EtOAc/hexanes, 20:80, v/v); IR (KBr):
1
nmax =3347 (NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=
6.29 (s, 2H, CH2Ph), 7.09 (t, 2H, J=8.0 Hz, ArH), 7.16 (d,
1H, J=7.1 Hz, ArH), 7.19–7.23 (m, 4H, ArH), 7.44 (s, 1H,
2864
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Copper-Catalyzed Synthesis of Indole-Fused Benzodiazepines
Table 3. Scope of reaction[a] with different N-Boc-indole derivatives.
Entry
1
1
2
3
Yield [%][b]
80
2
3
4
5
84
78
75
83
82
6
[a]
Reaction conditions: under nitrogen atmosphere,
1 (0.69 mmol), 2 (0.69 mmol), Cu2O (0.069 mmol), l-proline
(0.14 mmol), K3PO4 (1.4 mmol), DMSO (2 mL), temperature (908C), reaction time (8 h).
Isolated yields
[b]
ArH), 7.50 (d, 1H, J=8.7 Hz, ArH), 7.71–7.76 (m, 2H,
ArH), 7.96 (brs, 1H, =CH), 13.36 (brs, 1H, NH); 13C NMR
(75 MHz, DMSO-d6): d=47.7, 105.9, 111.6, 112.8, 121.1,
124.3, 126.9, 127.0, 127.3, 127.4, 128.4, 128.5, 128.9, 139.0,
139.1, 148.7, 150.6, 154.8; ESI-MS: m/z=393 [M+H]+; ESI-
HR-MS: m/z=393.2808, calcd. for C22H15Cl2N3 [MH]+:
393.2806.
1H, NH); 13C NMR (75 MHz, DMSO-d6): d=101.6, 105.0,
105.3, 111.3, 112.9, 118.5, 121.8, 128.1, 130.4, 133.9, 143.6,
145.7, 155.7, 158.8; ESI-MS: m/z=252 [M+H]+; ESI-HR-
MS: m/z=252.1012, calcd. for C15H10FN3 [MH]+: 252.1015.
2-Fluoro-10-methyl-5,12-dihydroindoloACTHNUGTRENNU[G 3,2-b]ACHUTTGNREN[NUNG 1,5]benzo-
diazepine (Table 3, entry 2): White solid; mp >2508C; Rf =
0.59 (EtOAc/hexanes, 20:80, v/v); IR (KBr): nmax =3359
2-Fluoro-5,12-dihydroindoloACHTNUTRGENN[UG 3,2-b]ACHUTNTGREN[NUGN 1,5]benzodiazepine
1
(NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=2.44 (s, 3H,
(Table 3, entry 1): White solid; mp >2508C; Rf =0.55
(EtOAc/hexanes, 20:80, v/v); IR (KBr): nmax =3356 (NH)
CH3), 7.01 (t, 2H, J=8.7 Hz, ArH), 7.16 (s, 1H, ArH), 7.34–
7.53 (m, 4H, 3ꢁArH and =CH), 12.05 (s, 1H, NH), 12.84 (s,
1H, NH); 13C NMR (50 MHz, DMSO-d6): d=21.3, 101.3,
101.4, 104.9, 105.3, 111.2, 112.8, 113.0, 123.4, 128.0, 128.1,
130.6, 133.9, 155.7, 158.8; ESI-MS: m/z=265 [M+H]+; ESI-
1
cmÀ1; H NMR (300 MHz, DMSO-d6): d=7.02 (t, 1H, J=
7.4 Hz, ArH), 7.21 (d, 3H, J=10.6 Hz, ArH), 7.42 (s, 1H,
ArH), 7.46 (s, 1H, ArH), 7.54 (d, 1H, J=6.7 Hz, ArH), 7.67
(d, 1H, J=6.9 Hz, =CH), 12.09 (brs, 1H, NH), 13.01 (brs,
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Subhasish Biswas and Sanjay Batra
Table 4. Scope of reaction[a] with different unsubstituted and N-substituted 3-bromoindole derivatives.
UPDATE
Entry
1
1
2
3
Time
8 h
Yield [%][b]
65
2
3
8 h
69
62
10 h
4
10 h
67
5
6
7
8 h
8 h
9 h
9 h
80
84
79
83
8
[a]
Reaction conditions: under nitrogen atmosphere,
4
(0.74 mmol), 2 (0.74 mmol), Cu2O (0.074 mmol), l-proline
(0.15 mmol), K3PO4 (1.48 mmol), DMSO (2 mL), temperature (908C).
Isolated yields.
[b]
1
HR-MS: m/z=265.1019, calcd. for C16H12FN3 [MH]+:
265.1015.
10-Chloro-2-fluoro-5,12-dihydroindolo
diazepine (Table 3, entry 3): Brown solid; mp >2508C; Rf =
0.54 (EtOAc/hexanes, 20:80, v/v); IR (KBr): nmax =3347
(NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=7.04 (t, 1H,
J=7.5 Hz, ArH), 7.22 (d, 1H, J=7.1 Hz, ArH), 7.26 (s, 1H,
ArH), 7.42 (s, 1H, ArH), 7.45 (s, 1H, ArH), 7.61 (d, 1H, J=
8.5 Hz, ArH) 7.65 (s, 1H, =CH), 12.12 (brs, 1H, NH), 13.23
(brs, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d=102.3,
ACHUTNGRENU[NG 3,2-b]AHCTUNGTRENN[GUN 1,5]benzo-
2866
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Adv. Synth. Catal. 2011, 353, 2861 – 2867

Copper-Catalyzed Synthesis of Indole-Fused Benzodiazepines
105.2, 105.5, 111.5, 111.8, 113.2, 122.6, 126.7, 128.1, 129.9,
134.1, 147.2, 155.9; ESI-MS: m/z=286 [M+H]+; ESI-HR-
MS: m/z=286.0467, calcd. for C15H9ClFN3 [MH]+: 286.0469.
[3] M. Nayak, S. Batra, Adv. Synth. Catal. 2010, 352, 3431–
3437.
[4] S. Biswas, V. Singh, S. Batra, Tetrahedron 2010, 66,
7781–7786.
9,10-Dichloro-2-fluoro-5,12-dihydroindoloACTHUNTGRNENUG[3,2-b]CAHTUNGTRENN[UGN 1,5]-
benzodiazepine (Table 3, entry 4): Brown solid; mp
>2508C; Rf =0.51 (EtOAc/hexanes, 20:80, v/v);IR (KBr):
[5] S. Hiremath, D. M. Hiremath, M. G. Purohit, Indian J.
Chem. B 1984, 23, 930–933.
1
nmax =3344 (NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=
[6] Selected citations a) M. Alvarez, J. A. Joule, Alkaloids;
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1227; g) V. A. Peshkov, S. V. Hove, P. A. Donets, O. P.
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X. Y. Chen, L. H. Sun, S. Ye, J. Org. Chem. 2010, 75,
6973–6976; i) B. M. Trost, M. Osipov, G. Dong, J. Am.
Chem. Soc. 2010, 132, 15800–15807; j) J. Maruyama, H.
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dron 2009, 65, 1327–1335; k) Y. Ohta, H. Chiba, S.
Oishi, N. Fujii, H. Ohno, Org. Lett. 2008, 10, 3535–
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[7] Only a few citations a) S. Xiao, X. X. Shi, Tetrahedron:
Asymmetry 2010, 21, 226–231; b) A. Putey, F. Popo-
wycz, Q.-T. Do, P. Bernard, S. K. Talapatra, F. Koziel-
ski, C. M. Galmarini, B. Joseph, J. Med. Chem. 2009,
52, 5916–5925; c) W. S. Phutdhawong, W. Ruensamran,
W. Phutdhawong T. Taechowisan, Bioorg. Med. Chem.
Lett. 2009, 19, 5753–5756; d) L. Keller, S. Beaumont, J.-
M. Liu, S. Thoret, J. S. Bignon, J. Wdzieczak-Bakala, P.
Dauban, R. H. Dodd, J. Med. Chem. 2008, 51, 3414–
3421; e) G. A. Elmegeed, W. K. B. Khalil, A. A. Raouf,
M. M. Abdelhalim, Eur. J. Med. Chem. 2008, 43, 763–
770; f) A. Brancale, R. Silvestri, Med. Res. Rev. 2007,
27, 209–238.
7.05 (dt, 1H, J=9.5 Hz 2.5 Hz, ArH), 7.26 (s, 1H, ArH),
7.43–7.47 (m, 2H, ArH), 7.86 (s, 2H, ArH and =CH), 12.17
(brs, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d=102.9,
103.0, 105.3, 105.6, 111.7, 112.0, 113.1, 113.3, 124.7, 127.9,
129.4, 134.3, 148.3, 155.9, 159.0; ESI-MS: m/z=320 [M+
H]+; ESI-HR-MS: m/z=320.0139, calcd. for C15H8Cl2FN3
[MH]+: 320.0136.
2-Bromo-10-methyl-5,12-dihydroindoloACHTNUGRTNENUG[3,2-b]HCATUNGTRNEN[UGN 1,5]-
benzodiazepine (Table 3, entry 5): White solid; mp >2508C;
Rf =0.56 (EtOAc/hexanes, 20:80, v/v); IR (KBr): nmax =3352
1
(NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=2.44 (s, 3H,
CH3), 7.06 (s, 1H, ArH), 7.15 (s, 1H, ArH), 7.25- 7.33 (m,
1H, ArH), 7.39–7.46 (m, 2H, ArH), 7.54 (d, 1H, J=6.4 Hz,
ArH), 7.85 (s, 1H, =CH), 12.18 (brs, 1H, NH), 12.92 (brs,
1H, NH); 13C NMR (75 MHz, DMSO-d6): d=21.3, 100.8,
112.1, 113.8, 122.9, 123.8, 125.2, 129.7, 130.2, 135.8, 145.3;
ESI-MS:
m/z=326.0217, calcd. for C16H12BrN3 [MH]+: 326.0215.
2-Methoxy-10-methyl-5,12-dihydroindolo[3,2-b][1,5]-
m/z=326
[M+H]+;
ESI-HR-MS:
A
ACHTUNGTRENNUNG
benzodiazepine (Table 3, entry 6): White solid; mp >2508C;
Rf =0.58 (EtOAc/hexanes, 20:80, v/v); IR (KBr): nmax =3348
1
(NH) cmÀ1; H NMR (300 MHz, DMSO-d6): d=2.44 (s, 3H,
CH3), 3.78 (s, 3H, OCH3), 6.80 (dd, 1H, J=8.9 Hz 2.3 Hz,
ArH), 7.08 (s, 1H, ArH), 7.11 (s, 1H, ArH), 7.31 (s, 1H,
ArH), 7.34 (s, 1H, ArH), 7.43 (s, 1H, ArH), 7.52 (d, 1H, J=
8.1 Hz, =CH), 11.76 (brs, 1H, NH), 12.72 (brs, 1H, NH);
13C NMR (75 MHz, DMSO-d6): d=21.3, 55.3, 101.1, 101.8,
112.6, 113.4, 128.2, 129.1, 132.4, 145.9, 153.8; ESI-MS: m/z=
278 [M+H]+; ESI-HR-MS: m/z=278.1218, calcd. for
C17H15N3O [MH]+: 278.1215.
Acknowledgements
One of the authors gratefully acknowledges the financial help
in the form of fellowship from CSIR, New Delhi. Authors ac-
knowledge the SAIF Division for providing the spectroscopic
and analytical data.
[8] T. Choshi, T. Sada, H. Fujimoto, C. Nagayama, E.
Sugino, S. Hibino, J. Org. Chem. 1997, 62, 2535–2543.
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Commun. 2009, 7581–7583.
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WO2008/37783A1, 2008; Chem. Abs. 2008, 148,
403204; b) Z. Wang, R. Vince, Bioorg. Med. Chem.
2008, 16, 3587–3595.
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Adv. Synth. Catal. 2011, 353, 2861 – 2867
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2867