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Synthesis Of 1,5-Benzodiazepine DerivativesJung Dai-Il a , Choi Tae-wonchoi a , Kim Yun-Younga , Kim In-Shik a , Park You-Mi a , Lee Yong-Gyun a &Jung Doo-Hee aa Department of Chemistry College of NaturalSciences, Dong-A University 840, Hadan-Dong, Saha-Gu, Pusan, Korea, 604-714Published online: 17 Sep 2007.

To cite this article: Jung Dai-Il , Choi Tae-wonchoi , Kim Yun-Young , Kim In-Shik , Park You-Mi , Lee Yong-Gyun & Jung Doo-Hee (1999): Synthesis Of 1,5-Benzodiazepine Derivatives, Synthetic Communications: An International Journal forRapid Communication of Synthetic Organic Chemistry, 29:11, 1941-1951

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SYNTHETIC COMMUNICATIONS, 29( 1 l), 1941-1951 (1999)

SYNTHESIS OF 1,s-BENZODIAZEPINE DERIVATIVES.

Dai-11, J u n i - Tae-Won, Choi - Yun-Young, Kim - In-Shik, Kim *

You-Mi, Park - Yong-Gyun, Lee * Doo-Hee, Jung

Department of Chemistry College of Natural Sciences, Dong-A University 840, Hadan-Dong, Saha-Gu, Pusan, Korea 604-7 14

Abstract : 2,4,4-Trimethyl-3H-S-hydr~.1,5-benzodiazepine was obtained by the reaction of o-phenylenediamine and acetonedicarboxylic acid (or acetone) in various methods (Method 1, 2, 3). When 0-phenylenediamine was heated with acetophenone in the presence of PPA (or SO), 2,4-diphenyl4methyl-3H-5-hydrc+1,5-benzodiazepine 5 was isolated (Method 4).

The benzodiazepines have various therapeutic applications, many being

are anticonvulsants and used for inducing sleep. Diazepam and nitrazepam

flurazepam is both an antianxiety agent and a potent hypnotic',2.

In addition to the 1 ,4-benzodiazepines, 5-aryl-l,5-benzodiazepines with

the general fomular 1 have also recently been used. They possess a

activity spectrum similar to the 5-aryl- 1,4-benz~diazepines~.

Author to whom correspondence should be addressed.

Copyright 0 1999 by Marcel Dekker, Inc.

1941

www.dekker.com

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1942 JUNG ET AL.

Merchant et a1 showed4 that the reaction of o-phenylenediamine with

acrylic acid in the presence of polyphosphoric acid (PPA) gave

benzodiazepinone 2 and pyridobenzodiazepinone 3. Recently Kalyanam et a1

reported the correct structure of pyridobenzodiazepinone 3 formed in the

reaction of o-phenylenediamine with acrylic acid catalyzed by PPASS6.

However the reaction of o-phenylenediamine with acrylic acid in the

presence of acetonedicarboxylic acid instead of PPA as catalyst only resulted

in the formation of 2,4,4-trimethyl-3H-5-hydro-1,5-benzodiazepine. In view of

this interesting result, we report the synthesis of 1,s-benzodiazepine

derivatives by using various reagents instead of PPA.

When o-phenylenediamine was treated with acrylic acid in the presence

of acetonedicarboxylic acid at room temperature for 3hrs, a yellow

crystalline solid, 4 was isolated (86%) (Method 1). It's structure was

assigned on the basis of NMR which showed a singlet at 6 1.33 and 6 2.36

for two methyl protons and one methyl protons respectively. C3-Methylene

protons show at 62.22, and N5 proton appears at 6 2.97. MS displayed a

protonated molecular ion at m/. 188 corresponding to the molecular formular

CIZHI~NZ. From these observations, this product was proposed to have the

structure of 2,4,4-trimethyl-3H-5-hydro- 1,5-benzodiazepine 4. Similar results

were obtained when PPA (isolated yield, 94%), or SiOz (isolated yield,

93%) were added to the reaction mixture.

Treatment of o-phenylenediamine with acetonedicarboxylic acid at room

temperature in the presence of PPA (or SiOz, or HC1) afforded 4 in

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1,5-BENZODIAZEPINE DERIVATIVES 1943

excellent yield (Method 2). Also, treatment of o-phenylenediamine with

acetone at room temperature in the presence of PPA (or SiOz, or

CHFCHCOOH, or CH2=CHCOOH and PPA, or CHz=CHCOOH and Si02)

afforded 4 in excellent yield (Method 3). As shown in method 1 (B)

and method 3 (D; c, d, e), these results indicate that the reactant is not

CHz=CHCOOH but acetonedicarboxylic acid (or acetone) because the product

is 2,4,4-trimethyl-3H-5-hydro-l,5-benzodiazepine 4 (Scheme 1).

A possible mechanism for the formation of 1,5-benzodiazepine is shown

Figure 1. Amine of o-phenylenediamine attacks carbonyl group of ketone,

giving the intermediate diimine A. A 1,3 shift of the hydrogen attached

methyl group then occurs to afford an isomeric enamine B which cyclizes to

produce seven-membered ring (Figure I ) .

C

1,5-Benzodiazepines

Figure 1. Possible mechanism for the formation of 1J-benzodiazepines.

However, the reaction of o-phenylenediamine with 2-ketoglutaric acid in

the presence of CHz=CHCOOH and PPA (or CHFCHCOOH and SiOz) did

not occur. When o-phenylenediamine was heated with acetophenone in the

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a a. CHz=CHCOOH Isolated Yield = 88 %

c. CH~=CHCOOH, SiOz Idated ~ ~ ~ 9 3 % b. CHz=CHCOOH. PPA Isdated Yield=w%

4

a. cnci3. PPA IdEted Yield = 91 % b. cnC13. Si02 Isolated Yield 5 89 % C. CHCIs. HCI Iddated Ysld=97%

4

'a. PPA b. SiO2 C. CHz=CHCOOH d. CHz=CHCOOH. PPA e. CH~=CHCOOH, sioz

Isolated Yield = 96 % Isolated Yiald = 95 % Isolated Yiald = 88 % lnolated Yidd = 93 % Isolatsd Yidd = 90 %

+ o=c aNHz 'CH3 D NHZ

E 40-45" C

5 'a. PPA b. Si02

ladated Yicld = 48 % Isolated Yield = 42 %

Scheme 1.

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1,5-BENZODJAZEPINE DERIVATIVES 1945

presence of PPA (or SiOz) at 4O-5O0C, a yellow crystalline solid, 2,4-di-

phenyl-4-methyl-3H-5-hydro-1,5-benzodiazepine 5 was isolated.

EXPERIMENTAL SECTION

Melting points were determined on an electrothermal capillary melting

point apparatus and uncorrected. TLC was performed on glass plates coated

with silicon oxide (silica gel 60F254) and compounds were visualized using a

uv lamp. Proton nuclear magnetic resonance and I3C NMR spectra were

obtained with Bruker AC 200 (200MHz) and Varian Gemini (200MHz)

spectrometers. Mass spectra were measured with HP 589011 GC/Mass (70eV,

EI). The organic solvents and chemicals were obtained from commercial

products and purified by the appropriate methods before use.

Reaction of o-phenylenediamine with acrylic acid in the presence of

PPA(Method 1-A-a) : o-Phenylenediamine (5.4 g, 5 x lo-* mol) and acrylic

acid (8.6 g, 12 x lo-' mol) were added to PPA (1.5 g) previously heated to

100°C. The reaction mixture was refluxed for further 3hrs, cooled to room

temperature and decomposed with ice and water. The aqueous solution was

extracted with chloroform. The chloroform extract washed with water (30

mL), then with 5% NaHC03 (100 mL) and again with water (30 mL). The

organic layer was dried (Na2S04), filtered and concentrated. The residue was

chromatographed on a silica gel (n-hexane : ethyl acetate : CHzCh = 2 : 1

: 1, v/v/v) to yield benzodiazepinone z4 (4.13 g, 51%) as a white crystalline

solid.: mp 146-147°C; IR (KBr) 3400 (s , N-H), 3100 (aromatic C-H), 2900

(aliphatic C-H), 1675 (C=O), 730 (=CH, aromatic OOP) a i l ; 'H NMR

(CDCl3) 6 2.7 (t, CH2, 2H), 3.68 (t, CH2, 2H), 3.85 ( s , NH, lH), 6.6-7.0

(m, ph, 4H), 8.11 (s, NH, 1H); I3C NMR (CDC13) 6 173.26, 138.73,

126.29, 125.20, 122.11, 120.40, 119.75, 45.39, 36.24; Mass (70eV), mlz (rel.

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1946 JUNG ET AL.

Int, %) 162 ( l lS) , 145 (5.8), 133 (3.8), 119 (loo), 107 (21.2), 92 ( l lS) ,

80 (6.7), 65 (11.5)

Reaction of o-phenylenediarnine with acrylic acid in the presence of SiOz

(Method I-A-b) : A mixture of o-phenylenediamine (5.4 g, 5 x mol) and

acrylic acid (8.6 g, 12x lo-' mol) added Si02 (1.5 x lo-' g) was stirred and

reflwed. Heating was continued for further 3hrs, the dark brown solution

cooled to room temperature, diluted with chloroform and filtered of Si02.

The filtered solution was washed with water and neutralized with NaHC03

(100 mL). The organic layer was dried (MgS04) and concentrated. The

residue was chromatographed on a silica gel (n-hexane : ethyl acetate :

CHIC12 = 2 : 1 : 1, v/v/v) to yield benzodiazepinone 2 (4.2 g, 52%) as a

white crystalline solid.

Reaction of o-phenylenediamine with acetonedicarboxylic acid in the

presence of acrylic acid (Method I-B-a) : o-Phenylenediamine (5.4 g, 5 x

lo-* mol) and acetonedicarboxylic acid (14.6 g, 10 x 10-2mol) added acrylic

acid (8.6 g, 1 2 x lo-' mol) was stirred. The reaction mixture was stirred at

room temperature for 3hrs, diluted with water and neutralized with aq.

NaOH. It was extracted with chloroform (3 x 100 mL), the extract washed

with water and dried (NazS04). Removal of chloroform gave

2,4,4-trimethyl-3H-5-hydro-1,5-benzodiazepine 47 a yellow solid (8.08 g,

86%) which crystallized from n-hexane.: m.p 147-148°C; IR (KBr) 3275 (s,

N-H), 3070 (aromatic, C-H), 2930 (aliphatic, C-H), 1660 (s, C=H); 'H NMR

(CDCl3) 6 1.35 ( s , CH3, 6H), 2.25 ( s , CH2, 2H), 2.35 ( s , CH3, 3H), 3.01

(s, NH, lH), 6.8-7.2 (m, ph, 4H); 13C NMR (CDCL) 6 172.37, 140.75,

137.85, 126.77, 125.44, 122.04, 121.69, 68.38, 45.02, 30.43, 29.83; Mass (70

eV), ndz (rel. Int, %) : 188 (35.6), 173 (loo), 158 (0.38), 132 (61.5), 117

(5.Q 92 (115), 77 (7.7), 65 (11.5). Anal. Culcd for C I ~ H M N ~ : C, 76.59; H,

8.51; N, 14.89. Found: C, 76.30; H, 8.63; N, 14.80.

Reaction of o-phenylenediamine with acetonedicarboxylic acid in the

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1.5-BENZODIAZEPINE DERIVATIVES 1947

presence of acrylic acid and PPA (Method I-B-6) : o-Phenylenediamine

(5.4 g, 5 x lo-’ mol) and acetonedicarboxylic acid (14.6 g, l o x 10’ mol)

were added to a mixture of acrylic acid (8.6 g, 12 x 10’ mol) and PPA

(1.52 g). The reaction mixture was stirred at room temperature for 3hrs,

diluted with water and neutralized with aq. NaOH. The aqueous solution

was extracted with chloroform (3 x 100 mL). The chloroform extract washed

with water and was dried (MgS04). The chloroform was removed under

aspirator pressure and the remaining sticky oil was separated by flash

column chromatography on a silica gel (n-hexane : ethyl acetate = 5 : 1,

v/v) to yield 2,4,4-trimethyl-3H-5-hydro-1,5-benzodiazepine 4 (8.83 g, 94%)

as a yellow solid.

Reaction of o-phenylenediamine with acetonedicarboxylic acid in the

presence of acrylic acid and SiOz (Method 1-B-c) : A mixture of

o-phenylenediamine (5.4 g, 5 x 10” mol) and acetonedicarboxylic acid (14.6

g, l o x lo-’ mol) added acrylic acid (8.6g, 12x 10.’ mol) and Si02 ( 1 . 5 ~

lo-’ g) was stirred at room temperature for 3hrs. The reaction mixture was

diluted with water and chloroform, then filtered off Si02. After the filterate

was separated, the chloroform extract washed with water and was dried

(MgS04). The chloroform was removed under aspirator pressure and the

remaining sticky oil was separated by flash column chromatography on a

silica gel (n-hexane : ethyl acetate = 5 : 1, v/v) to yield 2,4,4-trimethyl-3H-

5-hydro-l,5-benzodiazepine 4 (8.73 g, 93%) as a yellow solid.

Reaction of o-phenylenediamine with acetonedicarboxylic acid in the

presence of PPA (Method 2-C-a) : A solution of o-phenylenediamine (5.4 g,

5 X lo‘* mol) and acetonedicarboxylic acid (14.6 g, 10 x lo-’ mol) in chloro-

form (15 mL) added PPA (1.5 g) was stirred. The reaction mixture was

stirred at room temperature for 3hrs, diluted with water and neutralized with

5% NaHCO3 (50 A). It was extracted with chloroform (3x70 mL), the

extract washed with water and dried (NazSO4). The organic layer was

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1948 JUNG ET AL.

filtered and concentrated. The residue was chromatographed on a silica gel

(n-hexane : ethyl acetate = 5 : 1, v/v) to yield 2,4,4-trimethyl-3H-5-hydro-

1,5-benzodiazepine 4 (8.53 g, 91%) as a yellow solid.

Reaction of o-phenylenediamine with acetonedicarboxylic acid in the

presence of SiOt (Method 2-C-b) : A solution of o-phenylenediamine (5.4 g,

5 x mol) and acetonedicarboxylic acid (14.6 g, 10 x lo-’ mol) in

chloroform (15 mL) added SiO2 (0.15 g) was stirred at room temperature

for 3hrs. The reaction mixture was diluted with water and neutralized with

5% NaHCO3 (30 mL), then filtered off Si02. The aqueous solution was

extracted with chloroform (3 x 70 mL). The chloroform extract washed with

water (30 mL) and dried (MgS04). The organic layer was concentrated.

Removal of chloroform gave 2,4,4-trimethyl-3H-5-hydro-l,5-benzodiazepine 4

as a yellow solid (8.36 g, 89%) which crystallized from n-hexane.

Reaction of o-phenylenediamine with acetonedicarboxylic acid in the

presence of HCl (Method 2-C-c) : A solution of o-phenylenediamine (5.4 g,

5 x 10’ mol) and acetonedicarboxylic acid (14.6 g, 10 X loe2 mol) in

chloroform (15 mL) added 10% HCl (2 mL) was stirred. The reaction

mixture was stirred at room temperature for 8hrs. The mixture was extracted

with 10% aq. NaHCO3. The residue was chromatographed on a silica gel

(n-hexane : ethyl acetate = 5 : 1, v/v) to yield 2,4,4-trimethyl-3H-5-hydro-

1,5-benzodiazepine 4 (9.1 1 g, 97%) as a yellow solid.

Reaction of 0-phenylenediamine with acetone in the presence of PPA

(Method 3-D-a) : A solution of o-phenylenediamine (5.4 g, 5 x 10” mol)

and acetone (20 g, 3 X lo-’ mol) added PPA (0.16 g) was stirred at room

temperature for 3hrs. The reaction mixture was stirred with water and

neutralized with 5% NaHC03 (50 mL). It was extracted with chloroform (3

xlOOnL), the extract washed with water and dried (MgSO4). The organic

layer was concentrated. Removal of chloroform gave 2,4,4-trimethyl-3H-

5-hydro-l,5-benzodiazepine 4 as a yellow solid (9.02 g, 96%) which

crystallized from n-hexane.

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1,5-BENZODIAZEPINE DERIVATIVES 1949

Reaction of o-phenylenediamine with acetone in the presence of SiOz

(Method 3-D-b) : In a solution of o-phenylenediamine (5.4 g, 5 X l o 2 mol)

and acetone (20 g, 3 x 10' mol), catalyst quantity 0.15g of Si02 was added

and stirred at room temperature for 3hrs. The reaction mixture was diluted

with water and neutralized with 10% HC1 (30 mL). The aqueous solution

was extracted with chloroform (3 x 100 mL). The chloroform extract washed

with water and was dried (MgS04). The chloroform was removed under

aspirator pressure. Removal of chloroform gave 2,4,4-trimethyl-3H-5-hydro-

1,5-benzodiazepine 4 as a yellow solid (8.90 g, 95%) which crystallized

from n-hexane.

Reaction of o-phenylenediamine with acetone in the presence of acrylic

acid (Method 3-D-c) : A solution of o-phenylenediamine (5.4 g, 5 x lom2

mol) and acetone (20g, 3 x lo-' mol) added acrylic acid (5 mL) was stirred

at room temperature for 3hrs. The reaction mixture was diluted with water

and neutralized with 5% NaHCO3 (50 mL). It was extracted with chloroform

(3x100 mL), the extract washed with water and dried (MgS04). The

organic layer was concentrated. Removal of chloroform gave 2,4,4-trimethyl-

3H-5-hydro-1,S-benzodiazepine 4 as a yellow solid (8.26 g, 88%) which

crystallized from n-Hexane.

Reaction of o-phenylenediamine with acetone in the presence of acrylic

acid and PPA (Method 3-D-d) : o-Phenylenediamine (5.4 g, 5~ lo-* mol)

and acetone (20 g, 3 X 10'mol) were added to a mixture of acrylic acid ( 5

mL) and PPA (1.5 g). The reaction mixture was stirred at room temperature

for 3hrs, diluted with water and neutralized with aq. NaOH. The aqueous

solution was extracted with chloroform (3 x 100 mL). The chloroform extract

washed with water and was dried (MgS04). The chloroform was removed

under aspirator pressure and the remaining sticky oil was separated by flash

column chromatography on a silica gel (n-hexane : ethyl acetate = 5 : 1,

v/v) to yield 2,4,4-trimethyl-3H-5-hydro-1,5-benzodiazepine 4 (8.738, 93%) as

a yellow solid.

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1950 JUNG ET AL.

Reaction of o-phenylenediamine with acetone in the presence of acrylic

acid and Si02 (Method 3-D-e) : A solution of o-phenylenediamine (5.4 g, 5

x 10' mol) and acetone (20 g, 3 x lo-' mol) added acrylic acid (5 A) and

SiOz (0.15 g) was stirred at room temperature for 3hrs. The reaction mixture

was diluted with water and neutralized with 5% NaHC03 (30 mL), then

filtered off SiOz. The aqueous solution was extracted with chloroform. The

chloroform extract washed with water (30 mL) and dried (MgS04). The

organic layer was concentrated under aspirator pressure. Removal of

chloroform gave 2,4,4-trimethyl-3H-5-hydro- 1,5-benzodiazepine 4 as a yellow

solid (8.45 g, 90%), which crystallized from n-Hexane.

Reaction of o-phenylenediamine with acetophenone in the presence of PPA

(Method 4-E-a) : A solution of o-phenylenediamine (2.7 g, 2.5 x mol)

and acetophenone (8.67 g, 7 x 10-I mol) added PPA (0.63g) was stirred at

4O-5O0C for 5hrs. The reaction mixture was diluted with water and

neutralized with 5% NaHC03 (50 mL). It was extracted with chloroform (3

x 100 A), the extract washed with water and dried (MgS04). The

chloroform was removed under aspirator pressure arid the remaining sticky

oil was separated by flash column chromatography on a silica gel (n-hexane

: ethyl acetate = 8 : 1, v/v) to yield 2,4-diphenyl-4-methy1-3H-5-hydro-l,5-

benzodiazepine 5' (3.57g, 46%) as a yellow crystalline solid.: mp 151-152OC;

'H NMR (CDCh) 6 1.75 ( s , CH3, 3H), 2.93 and 3.10 (d, CHI, 2H, J =

0.17 Hz) or 2.99 and 3.16 (d, CH2, 2H, J = 0.17 Hz) 3.15 (s, NH, lH),

6.80-7.62 (m, phenyl, 14H); Mass (70eV), m/z (rel. Int, %) 312 (9.6), 310

(14.4), 295 (100). Anal, Calcd for CIZHI~NI : C, 84.60; H, 6.41; N, 8.97.

Found: C , 83.89; H, 6.83; N, 8.51.

Reaction of o-phenylenediamine with acetophenone in the presence of SiOz

(Method 4-E-b) : In a solution of o-phenylenediamine (2.70 g, 2.5 x lo-'

mol) and acetophenone (8.67 g, 7 x lo-' mol), catalyst quantity 0.08 g of

Si02 was added and stirred. The reaction mixture was stirred at 40-5O'C for

5hrs. The mixture was extracted with 10% aq. NaHCO3. The organic layer

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1,s-BENZODIAZEPINE DERIVATIVES 195 1

was dried (MgSO& filtered and concentrated. The residue was chromato-

graphed on silica gel (n-hexane : ethyl acetate = 8 : 1, v/v) to yield 2,4-di-

phenyl-4-methyl-3H-5-hydro- 1,5-benzodiazepine 5 (3.28 g, 42%) as a yellow

crystalline solid.

ACKNOWLEDGEMENT

This work was partially supported by the Korean Ministry of Education

(BSRI-97-3446) and office of Research of Dong-A University (1998).

REFERENCES

1. Randall, L. 0. and Kappell, B. "The Benzodiazepines", ed. Garattini, S.

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2. Kyburz, E. "Medicinal Chemistry Advaces", ed. F. G. de las Heras

and Vega, S.; Pergamon, Oxford, 1981; pp. 355.

3. Roth, H. J., Eger, K. and Troschutz, R. "Drug Synthesis,

Pharmaceutical Chemisty", Ellis Honvood Limited : England, 1988.

4. Merchant, J. R., Chotia, D. S., Indian J. Chem., 1975, 8, 814.

5. Patar, S., Bentov, M., Reichmann, M. E., J. Am. Chem. SOC., 1952, 74,

845.

6. Kalyanarn, N., Manjunatha, S. G., Indian J. Chem., 1991, 9, 892.

7. Morales, H. R., Bulbarela, A. Contreras, R., Heterocycles, 1986, 24, 1,

135-139.

8. Herbert, John A. L., Suschitzky, H., J. Chem. SOC., Perkin Trans. I

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(Received in the USA 09 November 1998)

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