Benzodiazepine Synthesis

Molly Eckman
CHEM 213 Section 2
TA: Luke Swider
4/30/15

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Introduction
Benzodiazepines are a type of heterocycle formed from the combination of a benzene ring and a
seven-atom ring. Although they have some use as dyes in the photography industry,1 benzodiazepines
are a clinically important class of molecules whose pharmacological utility has led them to be used for
treatment of diseases such as anxiety and epilepsy.2 They are particularly useful in the treatment of
anxiety disorders. Benzodiazepines work in conjunction with GABA is the primary inhibitory neuron in
the brain. By binding to an allosteric site on the GABA receptors of the postsynaptic neuron,
benzodiazepines increase the binding affinity of the receptor for GABA and therefore its depressant
effects.3 1,5-benzodiazepines are unique in that they retain the sedative and anticonvulsant effects of 1,4benzodiazepines while reducing negative side effects.4
Due to their medicinal utility, several synthetic methods for 1,5-benzodiazepines have been
developed. These methods generally use o-phenylenediamines in condensation reactions,5 reactions with
ketones,6 or in the presence of PPA and heat.7 While some methods, such as surface-mediated reactions,
have higher selectivity and yields,1 this experiment utilizes a simple one-pot reaction to synthesize 2,3dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine from acetone and 1,2 diaminobenzene. In this reaction,
sulfamic acid catalyzes a condensation between 1,2-diaminobenzene and acetone (Scheme 1).

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Scheme 1: Condensation of acetone and 1,2-diamino benzene to produce 1,5-benzodiazepine.

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Sulfamic acid forms hydrogen bonds with a nitrogen-bound carbon of the diaminobenzene and
the carbonyl of an acetone molecule. This promotes the nucleophilic attack of nitrogen to the carbonyl
carbon. The negatively charged oxygen then deprotonates the nitrogen, creating a strong leaving group
that is removed when the oxygen of the sulfamic acid attacks the remaining hydrogen of the nitrogen.
This process is repeated with the remaining amine group and a second molecule of acetone.
Isomerization and subsequent proton transfer produce the final product of 2,3-dihydro-2,2,4-trimethyl1H-1,5-benzodiazepine.
The purpose of this experiment is to synthesize a 1,5-benzodiazepine from acetone and 1,2diaminobenzene via the condensation reaction outlined above (Figure 1). Melting point analysis, IR, 1H
NMR, and

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C NMR were used to characterize the product and determine the purity. This reaction

illustrates the importance of this condensation mechanism in the synthesis of benzodiazepines such as
the 1,5-benzodiazepines used for the treatment anxiety and convulsive disorders.

Figure 1: Synthesis of 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine.

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Experimental
2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine. 1,2-diaminobenzene (0.553 g, 5 mmol), acetone
(0.8 mL, 11 mmol), and sulfamic acid (0.05 g) were combined and stirred at room temperature for 2
hours. The reaction mixture was partitioned in ethyl acetate (5 mL) and water (35 mL). The aqueous
layer was extracted with ethyl acetate (2 x 20 mL). The organic layer was dried over sodium sulfate and
the solvent evaporated using a stream of nitrogen. Product was recrystallized in 1:2 ethyl acetate in
hexanes to yield yellow crystals (154 mg, 163.8%). mp 121-124oC; 1H NMR (400 MHz CDCl3): (ppm)
1.3406 (s, 6H), 2.2212 (s, 2H), 2.3639 (s, 3H), 2.9720 (s, 1H), 6.7319 (t, 1H), 6.9862 (t, 2H), 7.1230 (t,
1H); 13C NMR (15 MHz, CDCl3) (ppm): 29.7937, 30.4080, 44.9852, 68.4132, 121.6989, 122.0535,
122.4373, 126.7183, 137.8268, 140.7073, 172.4559; IR (ATR) max (cm-1) 3289.1, 2922.1, 2847.6,
2355.5, 2630.0, 1560.2, 1452.5, 1425.5.

Results and Discussion

In this experiment, 1,5-benzodiazepine 3 was synthesized from the sulfamic acid-catalyzed
condensation of 1,2-diaminobenzene 1 and acetone 2. An aqueous workup was used to quench the
reaction and remove starting material. Recrystallization was used to purify the product and produced
pale yellow crystals in a 163.8% yield. The melting point was measured to be 121-124 oC, which is
lower than the expected value of 137-139oC.8 Both the impossibly high yield and the low melting point
indicate high levels of impurities. Despite the low level of purity, NMR and IR data confirm the
synthesis of the 1,5-benzodiazepine.
The IR spectrum (Figure 1, Supplemental Data) indicates the formation of the desired
heterocycle as well as the presence of impurities. The aromatic carbon-hydrogen as well as the nitrogenhydrogen stretch appear as a combined peak at 3289.1 cm-1, while the aliphatic carbon-hydrogen stretch

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appears at 2922.1 cm-1. In the fingerprint region, alkene carbon-carbon bonds appear as peaks around
1560.2 cm-1; the scissor bend and umbrella bend occur around 1452.5 and 1376.7 cm -1 respectively.
Most notable is the peak at 2355.5 cm -1, which corresponds to the primary amine found in the starting
material. The spectra clearly lacks a peak around 1700 cm -1 which would indicate the presence of the
carbonyl of the acetone starting material.
The 1H NMR spectrum (Figure 2, Supplemental Data) supports the claim that 2,3-dihydro-2,2,4trimethyl-1H-1,5-benzodiazepine was synthesized. The singlet at 2.2212 ppm with an integration of 2
corresponds to the methylene bridge hydrogens. This group is exclusively found in the product
benzodiazepine. The singlet at 1.3406 ppm with an integration of 6 indicates the presence of the geminal
methyl groups. While these groups are also present on the acetone starting material, the loss of the
carbonyl has shifted their signal upfield. In addition, the singlet at 2.3639 ppm with an integration of 2
corresponds to methyl adjacent to the imine. Without benzodiazepine synthesis, this methyl would have
been chemically indistinguishable from the other methyl groups. The broad singlet at 2.9720 ppm with
an integration of 0.779 is characteristic of the hydrogen bound to the nitrogen. The four aromatic
hydrogens appear as peaks between 7.2708 and 6.7210 ppm. The hydrogens opposite the nitrogens are
chemically similar enough to appear as one peak at 6.9862 ppm, causing the higher integration value of
1.867. The other aromatic hydrogens appear as peaks at 7.1294 and 6.7382 ppm, with the hydrogen
nearest to the imine group further downfield due to increased deshielding. The coupling pattern is
characteristic of ortho-substituted benzene rings. The lack of any extraneous peaks indicates high levels
of purity.
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C NMR data (Figure 3, Supplemental Data) also confirms the synthesis of the 1,5-

benzodiazepine. The most obvious evidence is the number of chemically distinct carbons. The spectrum,
discounting the triplet at 76.9858 ppm caused by the CDCl 3 solvent, shows 11 distinct carbons.
Conversely, the 1,2-diaminobenzene and acetone starting materials have a total of 5 distinct carbons.

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The methyl carbons appear as two distinct peaks at 30.4080 and 29.7937 ppm; in the starting material
these peaks would be identical. The secondary carbon, found exclusively in the product, appears as the
peak at 44.9852 ppm while the quaternary carbon produces a peak at 68.4132 ppm. The four nonsubstituted aromatic carbons are shown through the peaks between 126.7183 and 121.6989 ppm. In the
original 1,2-diaminobenzene, only two peaks would appear in this range. The substituted aromatic
carbons appear further upfield at 140.7073 ppm and 137.8268 ppm. Like the other aromatic carbons,
only one peak would appear in this range in the spectrum of the starting benzene. Finally, the imine
carbon appears at 172.4559 ppm. While this peak could be confused with the carbonyl carbon of the
starting acetone, it is not shifted far enough downfield. Like the 1H NMR, the lack of any extraneous
peaks indicates high levels of purity.
Overall, it is difficult to assess the purity of the product and therefore the overall success of the
reaction. The absurdly high yield, depressed melting point, and extraneous IR peaks indicate that
significant amounts of impurities are present. However, 1H NMR and 13C NMR data, both generally
more specific and sensitive than the other methods of analysis, indicate high levels of purity. Due to the
inconclusive nature of this data, this experiment should be repeated. Column chromatography may be
used instead of recrystallization to purify the product, as it is possible that starting material may have cocrystallized with the desired product. In the future, other synthesis methods may be used in order to
identify the best overall method.

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References
(1)

Balakrishna, M. .; Kaboudin, B. Tetrahedron Lett. 2001, 42 (6), 11271129.

(2)

Beyer, K.-H. Nachrichten aus Chemie, Tech. und Lab. 2010, 31 (1), 2425.

(3)

Ticku, M. K. Neuropharmacology 1983, 22 (12), 14591470.

(4)

Chapman, A. G.; Horton, R. W.; Meldrum, B. S. Epilepsia 1978, 19 (3), 293299.

(5)

Ried, W.; Stahlhofen, P. Chem. Ber. 1957, 90 (5), 815824.

(6)

Ried, W.; Torinus, E. Chem. Ber. 1959, 92 (11), 29022916.

(7)

Dai-Il, J.; Tae-wonchoi, C.; Yun-Young, K.; In-Shik, K.; You-Mi, P.; Yong-Gyun, L.; Doo-Hee, J.
Synth. Commun. 1999, 29 (11), 19411951.

(8)

2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine. MSDS No. S411337

www.sigmaaldrich.com/ (accessed Apr 30, 2015).

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Supplemental Information
Figure 1. 60 MHz 1H NMR of 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine.
Figure 2. 400 MHz 1H NMR of 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine.
Figure 3. 100 MHz 13C NMR of 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine.
Figure 4. IR of 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine.