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Synlett 2018; 29(09): 1176-1180
DOI: 10.1055/s-0037-1609347
letter
© Georg Thieme Verlag Stuttgart · New York

Facile Access to 1,5-Benzodiazepines via Amine-Promoted (4+3) Annulations of δ-Acetoxy Allenoates with o-Diaminobenzenes under Mild Conditions

Yi-Fan Wang
a   Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, P. R. of China   Email: tongxf@ecust.edu.cn
,
Cheng-Yu He
b   Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: tianping@sioc.ac.cn
,
Longlei Hou
a   Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, P. R. of China   Email: tongxf@ecust.edu.cn
,
Ping Tian  *
b   Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: tianping@sioc.ac.cn
c   Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, P. R. of China   Email: tianping@shutcm.edu.cn
,
Guo-Qiang Lin
b   Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: tianping@sioc.ac.cn
c   Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, P. R. of China   Email: tianping@shutcm.edu.cn
,
Xiaofeng Tong*
a   Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, P. R. of China   Email: tongxf@ecust.edu.cn
› Author Affiliations

Financial support was generously provided by the 973 Program (2015CB856600), NSFC (21472042, 21772016, 21572251, 21572253), and the Collaborative Innovation Center of Chemical Science and Engineering (Tianjin).
Further Information

Publication History

Received: 20 January 2018

Accepted after revision: 20 February 2018

Publication Date:
23 March 2018 (online)

 
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Abstract

An amine-promoted (4+3) annulation of δ-acetoxy allenoate with o-diaminobenzene is reported, providing a facile access to 1,5-benzodiazepine. This method features wide reaction scope, mild conditions, and readily available starting materials. The cascade reaction involves aza-Michael addition of o-diaminobenzene to allenoate, elimination of acetate group, and subsequent 1,6-aza-Michael addition.


#

Key words

1,5-benzodiazepine - annulation - allenoate - diamino­benzene - catalyst-free

Nitrogen-containing heterocycles always receive much attention in both of organic synthesis and pharmaceutical communities. In this context, benzodiazepine derivatives possess a unique seven-membered heterocycles, which exhibit a wide range of biological activities,[1] such as anti­biotic,[2] anticancer,[3] and antiviral (HIV) activities.[4] Moreover, benzodiazepines are useful starting materials for the construction of other heterocycles, such as triazole and oxadiazole.[5] Indeed, benzodiazepine skeleton has been recognized as the privileged medicinal structure, which was initially coined by Merck scientists and becomes a well-­accepted and popular concept.[6]

Therefore, a lot of efficient methods have been developed for the preparation of benzodiazepine derivatives. Among these contributions, the condensation reactions of o-diaminobenzenes with α,β-unsaturated carbonyl compounds or 1,3-dicarbonyl compounds represent two straightforward strategies and may be the most common methods (Scheme [1, a]).[7] However, these two methods suffer from the requirement of acid catalyst and relatively higher reaction temperature. While the three-component reaction between o-diaminobenzene, aromatic aldehyde, and methyl acetoacetate has also emerged as a powerful method for the construction of benzodiazepine derivative, alkyl aldehydes are not tolerated, thus severely limiting the reaction scope (Scheme [1, b]).[8] To complement the above-mentioned limitations, we herein report a new strategy toward 1,5-benzodiazepine synthesis via the (3+4) annulation of δ-acetoxy allenoate with o-diaminobenzene (Scheme [1, c]). This method features mild reaction conditions, simple experimental operation as well as wide substrate scope.

Zoom Image
Scheme 1 Synthesis of benzodiazepine on the base of o-diamino­benzene

Recently, our group has demonstrated that δ-acetoxy allenoate 1 is a highly active 3C-atom component, which readily undergoes (3+n) annulations with various 1,n-bisnucleophiles (n = 2, 3) under the Lewis base catalysis.[9] Thus, we envisioned that, in view of its 1,4-bisnucleophilicity, o-diaminobenzene 2 might also be a suitable four-atom component for the (3+4) annulation with allenoate 1. To verify this hypothesis, the reaction of allenoate 1a and o-diaminobenzene 2a was conducted with the assistance of DABCO (20 mol%) and K2CO3 (1.2 equiv) in toluene at room temperature. To our delight, the desired (3+4) annulation product 3aa was isolated in 73% yield (Table [1], entry 1). The structural assignment was initially supported by NMR and HRMS, and later corroborated by X-ray crystallography of product 3ga (Figure [1]).[10]

Table 1 Reaction Optimization of Allenoate 1a and o-Diaminobenzene 2a a

Entry

Catalyst (20 mol%)

Additives (1.2 equiv)

Yield of 3aa (%)b

1

DABCO

K2CO3

73

2

PPh3

K2CO3

60

3

DMAP

K2CO3

13

4

–

K2CO3

76

5

–

Na2CO3

63

6

–

NaHCO3

46

7

–

Et3N

85

8

–

DIPEA

93

a Reaction conditions: To a solution of 2a (0.2 mmol) and base additives (0.24 mmol) in toluene (2 mL) was slowly added the solution of 1a (0.24 mmol) in toluene (2 mL) at room temperature.

b Yield of isolated product after column chromatography.

Zoom Image
Figure 1 The x-ray structure of 3ga

Our previous works have pointed out that the reactivity of allenoate 1 strongly depends on the nature of the employed catalyst. Thus, catalysts PPh3 and DMAP were then tested with the hope that something different would be ­disclosed.[9] However, these two catalysts under the otherwise identical conditions still gave 3aa, albeit in inferior yields (Table [1], entries 2 and 3). These results led us to realize that the (3+4) annulation toward product 3aa might not involve the Lewis base catalyst. Indeed, a slightly higher yield of 3aa (76%) was obtained when none of them was used (Table [1], entry 4). On the basis of these results, base additive was further screened, which rapidly disclosed that organic base DIPEA was the best one, affording product 3aa in as high as 93% isolated yield (Table [1], entries 5–8).

After establishing the optimal reaction conditions, we turned our attention to exploring the substrate scope with respective to allenoate partner by reacting with 2a.[11] As shown in Scheme [2], the (3+4) annulation smoothly ­occurred under these mild conditions and 1,5-benzodiazepine derivatives were generally obtained in good to excellent yields. A wide range of aryl groups at δ-position of ­allenoate 1, including 4-MeOC6H4, 4-MeC6H4, 4-i-PrC6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-CNC6H4, 2-BrC6H4, 3-BrC6H4, 3-MeC6H4, were well tolerated. Significantly, these cases with either electron-rich or electron-poor phenyl groups all afforded good yields (3aa–ha). For the case of 1i with a 2-BrC6H4 substitution, the (3+4) annulation could also take place smoothly to deliver product 3ia in 81% yield, indicating that the steric hindrance had little effect on the reaction efficiency. The reaction was further extended to allenoate with furan or thiophene substitution, affording products 3la and 3ma in 34% and 87% yields, respectively. Allenoates 1n with a 1-naphthyl substituent and 1o with a styryl group were also suitable substrates, and the corresponding products 3na and 3oa were obtained in good yields. Notably, the reactions of allenoates 1p and 1q bearing an alkyl group also worked well. In addition, the simplest allenoate 1r was also examined. Unfortunately, product 3ra was isolated only in 45% yield, which might attribute to its higher reactivity to produce some unidentified side products.

Zoom Image
Scheme 2 The reaction scope with respective to allenoate 1

We then moved on to investigate the substrate scope of o-diaminobenzene (Scheme [3]).[11] It was found that diamino­benzenes 2b–e with either electron-donating or electron-withdrawn groups were compatible with this (3+4) annulation, giving products 3ab–ae in 34–71% yields. Naphthalene-2,3-diamine 2f also reacted well with allenoate 1a to deliver product 3af in 51% yield.

Zoom Image
Scheme 3 Substrate scope with respective to o-diaminobenzene

According to these results and our previous works, we proposed a plausible mechanism for the observed catalyst-free (3+4) annulation (Scheme [4]). Due to the intramolecular H-bond interaction, the NH group of o-diaminobenzene seems to be readily deprotonated, thus promoting the ­Michael addition with allenoate 1.[12] As a result, intermediate A is formed, which undergoes elimination of acetate group to afford diene intermediate B. The fact that intermediate B could not be detected for all of the cases might imply that B would be able to undergo rapid intramolecular 1,6-addition to give enolate C. Finally, product 3 was resulted in via a deprotonation process, thus furnishing a (3+4) annulation.

Zoom Image
Scheme 4 A plausible mechanism

In summary, we have developed a new strategy toward 1,5-benzodiazepine synthesis via (3+4) annulations between δ-acetoxy allenoates with o-diaminobenzenes. The (3+4) annulation might proceed via a sequence including aza-Michael addition of diaminobenzene to allenoate, elimination of acetate group, and subsequent 1,6-addition. This method features readily available starting material, mild reaction conditions, high reaction efficiency, as well as wide substrate scope.


#

Acknowledgment

Undergraduate students from SIOC, SHUTCM, and ECUST are ­acknowledged for their helpful contribution. Authors thank Jie Sun (SIOC) for X-ray crystallographic analysis and all the reviewers for their constructive remarks.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0037-1609347.
  • Supporting Information

  • References and Notes

  • 2 Knabe J. Büch HP. Bender S. Arch. Pharm. 1995; 328: 59
    CrossrefPubMedSearch in Google Scholar
  • 3 Atwal KS. Bergey JL. Hedberg A. Moreland S. J. Med. Chem. 1987; 30: 635
    CrossrefPubMedSearch in Google Scholar
  • 4 Di Braccio M. Grossi G. Roma G. Vargiu L. Mura M. Marongiu ME. Eur. J. Med. Chem. 2001; 36: 935
    CrossrefPubMedSearch in Google Scholar
  • 10 CCDC 1816325 contains the supplementary crystallographic data for 3ga. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 11 Acetoxy Allenoates 1 and o-Diaminobenzenes 2 To a 10 mL vial were added o-diaminobenzene 2 (0.2 mmol, 1.0 equiv), DIPEA (0.24 mmol, 1.2 equiv), and toluene (2 mL), followed by the slow addition of a solution of δ-acetoxy allenoate 1 (0.24 mmol,1.2 equiv) in toluene (2 mL). The solution was stirred for 12 h at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate (30:1 to 15:1 v/v) as the eluent to give the corresponding annulations product 3. Ethyl (Z)-2-{4-(4-Isopropylphenyl)-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-ylidene}acetate (3da) Yellow solid, 86% yield; mp 70–72 °C. 1H NMR (400 MHz, CDCl3): δ = 10.26 (s, 1 H), 7.26 (d, J = 8.2 Hz, 2 H), 7.20 (d, J = 8.2 Hz, 2 H), 6.99–6.93 (m, 2 H), 6.92–6.85 (m, 1 H), 6.76–6.72 (m, 1 H), 4.79 (dd, J = 9.6, 3.8 Hz, 1 H), 4.64 (s, 1 H), 4.23–4.06 (m, 2 H), 3.66 (br s, 1 H),2.90 (hept, J = 6.9 Hz, 1 H), 2.72 (dd, J = 13.8, 9.6 Hz, 1 H), 2.49 (ddd, J = 13.8, 3.8, 1.3 Hz, 1 H), 1.34–1.17 (m, 9 H). 13C NMR (100 MHz, CDCl3): δ = 170.28, 158.84, 148.67, 142.39, 137.83, 129.65, 126.80, 125.98, 124.91, 122.48, 121.35, 120.70, 83.95, 64.84, 58.79, 40.39, 33.76, 23.94, 23.91, 14.53. IR (KBr): 3853, 3336, 2960, 2929, 2870, 1734, 1654, 1616, 1560, 1540, 1507, 1480, 1437, 1364, 1286, 1266, 1246, 1157, 1117, 1095, 1051, 829 cm–1. HRMS (ESI): m/z calcd for C22H27N2O2 +: 351.2067; found: 351.2067 [M + H]+. Ethyl (Z)-2-{4-(4-Cyanophenyl)-1,3,4,5-tetrahydro-2H-benzo[b]­[1,4]diazepin-2-ylidene}acetate (3ha) Yellow solid, 72% yield; mp 60–62 °C. 1H NMR (400 MHz, CDCl3): δ = 10.16 (s, 1 H), 7.66–7.60 (m, 2 H), 7.55–7.50 (m, 2 H), 7.03–6.92 (m, 3 H), 6.83–6.79 (m, 1 H), 5.00–4.92 (m, 1 H), 4.43 (s, 1 H), 4.21–4.04 (m, 2 H), 3.73 (s, 1 H), 2.73 (dd, J = 13.8, 4.7 Hz, 1 H), 2.49 (dd, J = 13.9, 7.0 Hz, 1 H), 1.26 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 169.98, 157.03, 149.30, 137.66, 132.43, 130.48, 127.12, 125.09, 122.49, 122.38, 120.97, 118.63, 111.61, 85.04, 64.57, 58.93, 39.37, 14.44. IR (neat): 3629, 3567, 3343, 3057, 2980, 2931, 2228, 1734, 1653, 1616, 1559, 1541, 1501, 1437, 1405, 1364, 1284, 1267, 1233, 1159, 1118, 1095, 1048, 833 cm–1. HRMS (ESI): m/z calcd for C20H20N3O2 +: 334.1550; found: 334.1550 [M + H]+. Ethyl (Z)-2-{4-Methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]dia­zepin-2-ylidene}acetate (3pa) Yellow liquid, 82% yield. 1H NMR (400 MHz, CDCl3): δ = 10.13 (s, 1 H), 6.91–6.75 (m, 3 H), 6.71–6.64 (m, 1 H), 4.61 (s, 1 H), 4.08 (q, J = 7.1 Hz, 2 H), 3.88–3.76 (m, 1 H), 3.17 (br s, 1 H), 2.40 (dd, J = 13.8, 4.4 Hz, 1 H), 2.15 (dd, J = 13.8, 7.0 Hz, 1 H), 1.26–1.17 (m, 6 H).13C NMR (100 MHz, CDCl3): δ = 170.11, 159.16, 137.87, 130.34, 124.67, 122.27, 121.67, 120.90, 84.25, 58.79, 55.83, 39.31, 23.40, 14.54. IR (neat): 3347, 2973, 2927, 1648, 1616, 1588, 1498, 1447, 1364, 1307, 1274, 1232, 1159, 1115, 1095, 1044, 916, 784 cm–1. HRMS (ESI): m/z calcd for C14H19N2O2 +: 247.1441; found: 247.1440 [M + H]+. Ethyl (Z)-2-{4-Benzyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]dia­zepin-2-ylidene}acetate (3qa) Yellow solid, 85% yield; mp 106–108 °C. 1H NMR (400 MHz, CDCl3): δ = 10.13 (s, 1 H),7.31–7.12 (m, 5 H), 6.89–6.75 (m, 3 H), 6.63–6.56 (m, 1 H), 4.64 (s, 1 H),4.16–4.00 (m, 2 H),3.94–3.82 (m, 1 H), 3.23 (br s, 1 H), 2.82–2.67 (m, 2 H), 2.42 (dd, J = 13.7, 4.7 Hz, 1 H), 2.23 (dd, J = 13.8, 7.2 Hz, 1 H), 1.21 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.08, 158.92, 137.89, 137.57, 130.94, 129.27, 128.74, 126.70, 124.69, 122.15, 121.95, 121.33, 84.32, 62.01, 58.80, 43.31, 37.26, 14.52. IR (neat): 3386, 1618, 1588, 1505, 1404, 1365, 1332, 1285, 1262, 1225, 1158, 1123, 1095, 1065, 1039, 1004, 790 cm–1. HRMS (ESI): m/z calcd for C20H23N2O2 +: 323.1754; found: 323.1757 [M + H]+. Ethyl (Z)-2-{1,3,4,5-Tetrahydro-2H-benzo[b][1,4]diazepin-2-ylidene}acetate (3ra) Yellow solid, 45% yield; mp 56–58 °C. 1H NMR (400 MHz, CDCl3): δ = 10.22 (s, 1 H), 6.88–6.79 (m, 2 H), 6.76–6.70 (m, 1 H), 6.67–6.59 (m, 1 H), 4.61 (s, 1 H), 4.08 (q, J = 7.1 Hz, 2 H), 3.60–3.52 (m, 2 H), 3.13 (br s, 1 H), 2.49–2.41 (m, 2 H), 1.21 (t, J = 7.1 Hz, 3 H).13C NMR (100 MHz, CDCl3): δ = 170.34, 160.98, 138.16, 128.87, 124.60, 122.64, 120.60, 119.79, 83.32, 58.81, 48.70, 33.76, 14.55. IR (neat): 3386, 1618, 1588, 1505, 1404, 1365, 1332, 1285, 1262, 1225, 1158, 1123, 1095, 1065, 1039, 1004, 790 cm–1. HRMS (ESI): m/z calcd for C13H17N2O2 +: 233.1285; found: 233.1284 [M + H]+. Ethyl (Z)-2-{7,8-Dimethyl-4-phenyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-ylidene}acetate (3ab) Yellow solid, 70% yield; mp 100–102 °C. 1H NMR (400 MHz, CDCl3): δ = 10.18 (s, 1 H), 7.41–7.22 (m, 5 H), 6.76 (s, 1 H), 6.55 (s, 1 H), 4.80 (dd, J = 9.2, 4.0 Hz, 1 H), 4.58 (s, 1 H), 4.23–4.05 (m, 2 H), 3.56 (br s, 1 H), 2.67 (dd, J = 13.7, 9.2 Hz, 1 H), 2.50 (ddd, J = 13.7, 4.0, 1.1 Hz, 1 H), 2.17 (s, 6 H), 1.27 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.29, 158.92, 145.05, 135.43, 133.22, 129.69, 128.73, 127.83, 127.41, 126.05, 123.53, 121.90, 83.54, 65.16, 58.73, 40.37, 19.10, 18.74, 14.55. IR (KBr): 3376, 3276, 3064, 2973, 2906, 2888, 2859, 1654, 1609, 1513, 1482, 1451, 1428, 1365, 1310, 1281, 1242, 1199, 1160, 1129, 1094, 1048, 988, 950, 897 cm–1. HRMS (ESI): m/z calcd for C21H25N2O2 +: 337.1911; found: 337.1910 [M + H]+. Ethyl (Z)-2-{7,8-Dibromo-4-phenyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-ylidene}acetate (3ae) Yellow solid, 34% yield; mp 60–62 °C. 1H NMR (400 MHz, CDCl3): δ = 10.17 (s, 1 H), 7.35–7.16 (m, 5 H), 7.13 (s, 1 H), 6.94 (s, 1 H), 4.72 (dd, J = 9.1, 3.6 Hz, 1 H), 4.57 (s, 1 H), 4.16–3.99 (m, 2 H), 3.69 (br s, 1 H), 2.62 (dd, J = 14.0, 9.1 Hz, 1 H), 2.48 (dd, J = 14.0, 3.7 Hz, 1 H), 1.20 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.23, 157.97, 143.54, 137.84, 131.84, 130.32, 128.03, 125.10, 122.55, 122.08, 121.74, 121.01, 84.72, 64.57, 58.98, 39.93, 14.61. IR (neat): 3420, 3132, 1717, 1653, 1617, 1559, 1540, 1507, 1490, 1457, 1404, 1300, 1239, 1160, 1066, 1010, 700 cm–1. HRMS (ESI): m/z calcd for C19H19 Br2N2O2 +: 464.9808; found: 464.9806 [M + H]+. Ethyl (Z)-2-{4-Phenyl-1,3,4,5-tetrahydro-2H-naphtho[2,3-b][1,4]diazepin-2-ylidene}acetate (3af) Yellow solid, 51% yield; mp 65–67 °C. 1H NMR (400 MHz, CDCl3): δ = 10.43 (s, 1 H), 7.71–7.59 (m, 2 H), 7.45–7.23 (m, 8 H), 7.16 (s, 1 H), 4.85 (dd, J = 9.1, 4.6 Hz, 1 H), 4.67 (s, 1 H), 4.25–4.11 (m, 2 H), 3.96 (s, 1 H), 2.70 (dd, J = 13.8, 9.1 Hz, 1 H), 2.60 (dd, J = 13.8, 4.6 Hz, 1 H), 1.30 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.24, 158.02, 144.63, 137.89, 132.05, 131.81, 129.99, 128.83, 128.00, 126.73, 126.15, 125.77, 125.25, 124.32, 119.10, 116.58, 85.17, 64.80, 59.00, 39.54, 14.54. IR (KBr): 3629, 3619, 3600, 3587, 3567, 3546, 3528, 3503, 3355, 3056, 2977, 2926, 1734, 1717, 1684, 1654, 1616, 1576, 1559, 1541, 1522, 1507, 1490, 1474, 1457, 1437, 1364, 1286, 1248, 1185, 1156, 1096, 1047, 872, 788 cm–1. HRMS (ESI). m/z calcd for C23H23N2O2 +: 359.1754; found: 359.1753 [M + H]+.

  • References and Notes

  • 2 Knabe J. Büch HP. Bender S. Arch. Pharm. 1995; 328: 59
    CrossrefPubMedSearch in Google Scholar
  • 3 Atwal KS. Bergey JL. Hedberg A. Moreland S. J. Med. Chem. 1987; 30: 635
    CrossrefPubMedSearch in Google Scholar
  • 4 Di Braccio M. Grossi G. Roma G. Vargiu L. Mura M. Marongiu ME. Eur. J. Med. Chem. 2001; 36: 935
    CrossrefPubMedSearch in Google Scholar
  • 10 CCDC 1816325 contains the supplementary crystallographic data for 3ga. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 11 Acetoxy Allenoates 1 and o-Diaminobenzenes 2 To a 10 mL vial were added o-diaminobenzene 2 (0.2 mmol, 1.0 equiv), DIPEA (0.24 mmol, 1.2 equiv), and toluene (2 mL), followed by the slow addition of a solution of δ-acetoxy allenoate 1 (0.24 mmol,1.2 equiv) in toluene (2 mL). The solution was stirred for 12 h at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate (30:1 to 15:1 v/v) as the eluent to give the corresponding annulations product 3. Ethyl (Z)-2-{4-(4-Isopropylphenyl)-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-ylidene}acetate (3da) Yellow solid, 86% yield; mp 70–72 °C. 1H NMR (400 MHz, CDCl3): δ = 10.26 (s, 1 H), 7.26 (d, J = 8.2 Hz, 2 H), 7.20 (d, J = 8.2 Hz, 2 H), 6.99–6.93 (m, 2 H), 6.92–6.85 (m, 1 H), 6.76–6.72 (m, 1 H), 4.79 (dd, J = 9.6, 3.8 Hz, 1 H), 4.64 (s, 1 H), 4.23–4.06 (m, 2 H), 3.66 (br s, 1 H),2.90 (hept, J = 6.9 Hz, 1 H), 2.72 (dd, J = 13.8, 9.6 Hz, 1 H), 2.49 (ddd, J = 13.8, 3.8, 1.3 Hz, 1 H), 1.34–1.17 (m, 9 H). 13C NMR (100 MHz, CDCl3): δ = 170.28, 158.84, 148.67, 142.39, 137.83, 129.65, 126.80, 125.98, 124.91, 122.48, 121.35, 120.70, 83.95, 64.84, 58.79, 40.39, 33.76, 23.94, 23.91, 14.53. IR (KBr): 3853, 3336, 2960, 2929, 2870, 1734, 1654, 1616, 1560, 1540, 1507, 1480, 1437, 1364, 1286, 1266, 1246, 1157, 1117, 1095, 1051, 829 cm–1. HRMS (ESI): m/z calcd for C22H27N2O2 +: 351.2067; found: 351.2067 [M + H]+. Ethyl (Z)-2-{4-(4-Cyanophenyl)-1,3,4,5-tetrahydro-2H-benzo[b]­[1,4]diazepin-2-ylidene}acetate (3ha) Yellow solid, 72% yield; mp 60–62 °C. 1H NMR (400 MHz, CDCl3): δ = 10.16 (s, 1 H), 7.66–7.60 (m, 2 H), 7.55–7.50 (m, 2 H), 7.03–6.92 (m, 3 H), 6.83–6.79 (m, 1 H), 5.00–4.92 (m, 1 H), 4.43 (s, 1 H), 4.21–4.04 (m, 2 H), 3.73 (s, 1 H), 2.73 (dd, J = 13.8, 4.7 Hz, 1 H), 2.49 (dd, J = 13.9, 7.0 Hz, 1 H), 1.26 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 169.98, 157.03, 149.30, 137.66, 132.43, 130.48, 127.12, 125.09, 122.49, 122.38, 120.97, 118.63, 111.61, 85.04, 64.57, 58.93, 39.37, 14.44. IR (neat): 3629, 3567, 3343, 3057, 2980, 2931, 2228, 1734, 1653, 1616, 1559, 1541, 1501, 1437, 1405, 1364, 1284, 1267, 1233, 1159, 1118, 1095, 1048, 833 cm–1. HRMS (ESI): m/z calcd for C20H20N3O2 +: 334.1550; found: 334.1550 [M + H]+. Ethyl (Z)-2-{4-Methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]dia­zepin-2-ylidene}acetate (3pa) Yellow liquid, 82% yield. 1H NMR (400 MHz, CDCl3): δ = 10.13 (s, 1 H), 6.91–6.75 (m, 3 H), 6.71–6.64 (m, 1 H), 4.61 (s, 1 H), 4.08 (q, J = 7.1 Hz, 2 H), 3.88–3.76 (m, 1 H), 3.17 (br s, 1 H), 2.40 (dd, J = 13.8, 4.4 Hz, 1 H), 2.15 (dd, J = 13.8, 7.0 Hz, 1 H), 1.26–1.17 (m, 6 H).13C NMR (100 MHz, CDCl3): δ = 170.11, 159.16, 137.87, 130.34, 124.67, 122.27, 121.67, 120.90, 84.25, 58.79, 55.83, 39.31, 23.40, 14.54. IR (neat): 3347, 2973, 2927, 1648, 1616, 1588, 1498, 1447, 1364, 1307, 1274, 1232, 1159, 1115, 1095, 1044, 916, 784 cm–1. HRMS (ESI): m/z calcd for C14H19N2O2 +: 247.1441; found: 247.1440 [M + H]+. Ethyl (Z)-2-{4-Benzyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]dia­zepin-2-ylidene}acetate (3qa) Yellow solid, 85% yield; mp 106–108 °C. 1H NMR (400 MHz, CDCl3): δ = 10.13 (s, 1 H),7.31–7.12 (m, 5 H), 6.89–6.75 (m, 3 H), 6.63–6.56 (m, 1 H), 4.64 (s, 1 H),4.16–4.00 (m, 2 H),3.94–3.82 (m, 1 H), 3.23 (br s, 1 H), 2.82–2.67 (m, 2 H), 2.42 (dd, J = 13.7, 4.7 Hz, 1 H), 2.23 (dd, J = 13.8, 7.2 Hz, 1 H), 1.21 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.08, 158.92, 137.89, 137.57, 130.94, 129.27, 128.74, 126.70, 124.69, 122.15, 121.95, 121.33, 84.32, 62.01, 58.80, 43.31, 37.26, 14.52. IR (neat): 3386, 1618, 1588, 1505, 1404, 1365, 1332, 1285, 1262, 1225, 1158, 1123, 1095, 1065, 1039, 1004, 790 cm–1. HRMS (ESI): m/z calcd for C20H23N2O2 +: 323.1754; found: 323.1757 [M + H]+. Ethyl (Z)-2-{1,3,4,5-Tetrahydro-2H-benzo[b][1,4]diazepin-2-ylidene}acetate (3ra) Yellow solid, 45% yield; mp 56–58 °C. 1H NMR (400 MHz, CDCl3): δ = 10.22 (s, 1 H), 6.88–6.79 (m, 2 H), 6.76–6.70 (m, 1 H), 6.67–6.59 (m, 1 H), 4.61 (s, 1 H), 4.08 (q, J = 7.1 Hz, 2 H), 3.60–3.52 (m, 2 H), 3.13 (br s, 1 H), 2.49–2.41 (m, 2 H), 1.21 (t, J = 7.1 Hz, 3 H).13C NMR (100 MHz, CDCl3): δ = 170.34, 160.98, 138.16, 128.87, 124.60, 122.64, 120.60, 119.79, 83.32, 58.81, 48.70, 33.76, 14.55. IR (neat): 3386, 1618, 1588, 1505, 1404, 1365, 1332, 1285, 1262, 1225, 1158, 1123, 1095, 1065, 1039, 1004, 790 cm–1. HRMS (ESI): m/z calcd for C13H17N2O2 +: 233.1285; found: 233.1284 [M + H]+. Ethyl (Z)-2-{7,8-Dimethyl-4-phenyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-ylidene}acetate (3ab) Yellow solid, 70% yield; mp 100–102 °C. 1H NMR (400 MHz, CDCl3): δ = 10.18 (s, 1 H), 7.41–7.22 (m, 5 H), 6.76 (s, 1 H), 6.55 (s, 1 H), 4.80 (dd, J = 9.2, 4.0 Hz, 1 H), 4.58 (s, 1 H), 4.23–4.05 (m, 2 H), 3.56 (br s, 1 H), 2.67 (dd, J = 13.7, 9.2 Hz, 1 H), 2.50 (ddd, J = 13.7, 4.0, 1.1 Hz, 1 H), 2.17 (s, 6 H), 1.27 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.29, 158.92, 145.05, 135.43, 133.22, 129.69, 128.73, 127.83, 127.41, 126.05, 123.53, 121.90, 83.54, 65.16, 58.73, 40.37, 19.10, 18.74, 14.55. IR (KBr): 3376, 3276, 3064, 2973, 2906, 2888, 2859, 1654, 1609, 1513, 1482, 1451, 1428, 1365, 1310, 1281, 1242, 1199, 1160, 1129, 1094, 1048, 988, 950, 897 cm–1. HRMS (ESI): m/z calcd for C21H25N2O2 +: 337.1911; found: 337.1910 [M + H]+. Ethyl (Z)-2-{7,8-Dibromo-4-phenyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-ylidene}acetate (3ae) Yellow solid, 34% yield; mp 60–62 °C. 1H NMR (400 MHz, CDCl3): δ = 10.17 (s, 1 H), 7.35–7.16 (m, 5 H), 7.13 (s, 1 H), 6.94 (s, 1 H), 4.72 (dd, J = 9.1, 3.6 Hz, 1 H), 4.57 (s, 1 H), 4.16–3.99 (m, 2 H), 3.69 (br s, 1 H), 2.62 (dd, J = 14.0, 9.1 Hz, 1 H), 2.48 (dd, J = 14.0, 3.7 Hz, 1 H), 1.20 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.23, 157.97, 143.54, 137.84, 131.84, 130.32, 128.03, 125.10, 122.55, 122.08, 121.74, 121.01, 84.72, 64.57, 58.98, 39.93, 14.61. IR (neat): 3420, 3132, 1717, 1653, 1617, 1559, 1540, 1507, 1490, 1457, 1404, 1300, 1239, 1160, 1066, 1010, 700 cm–1. HRMS (ESI): m/z calcd for C19H19 Br2N2O2 +: 464.9808; found: 464.9806 [M + H]+. Ethyl (Z)-2-{4-Phenyl-1,3,4,5-tetrahydro-2H-naphtho[2,3-b][1,4]diazepin-2-ylidene}acetate (3af) Yellow solid, 51% yield; mp 65–67 °C. 1H NMR (400 MHz, CDCl3): δ = 10.43 (s, 1 H), 7.71–7.59 (m, 2 H), 7.45–7.23 (m, 8 H), 7.16 (s, 1 H), 4.85 (dd, J = 9.1, 4.6 Hz, 1 H), 4.67 (s, 1 H), 4.25–4.11 (m, 2 H), 3.96 (s, 1 H), 2.70 (dd, J = 13.8, 9.1 Hz, 1 H), 2.60 (dd, J = 13.8, 4.6 Hz, 1 H), 1.30 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.24, 158.02, 144.63, 137.89, 132.05, 131.81, 129.99, 128.83, 128.00, 126.73, 126.15, 125.77, 125.25, 124.32, 119.10, 116.58, 85.17, 64.80, 59.00, 39.54, 14.54. IR (KBr): 3629, 3619, 3600, 3587, 3567, 3546, 3528, 3503, 3355, 3056, 2977, 2926, 1734, 1717, 1684, 1654, 1616, 1576, 1559, 1541, 1522, 1507, 1490, 1474, 1457, 1437, 1364, 1286, 1248, 1185, 1156, 1096, 1047, 872, 788 cm–1. HRMS (ESI). m/z calcd for C23H23N2O2 +: 359.1754; found: 359.1753 [M + H]+.

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Scheme 1 Synthesis of benzodiazepine on the base of o-diamino­benzene
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Figure 1 The x-ray structure of 3ga
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Scheme 2 The reaction scope with respective to allenoate 1
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Scheme 3 Substrate scope with respective to o-diaminobenzene
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Scheme 4 A plausible mechanism