Reaction of β-lapachone with 1,2-diamines: Facile synthesis of novel tetracyclic pyrazines

Article abstract of DOI:10.1080/00397910600978507

The reactions of β-lapachone (1) with 1,2-diaminoethane (2) and 1,2-diaminopropane (4) gave the tetracyclic pyrazine derivatives (3) and mixtures of (5) and (6), respectively, while reaction with o-phenylene diamine (7) gave the quinoxaline derivative (8). The structure of pyrazine derivative (3) is confirmed by single-crystal X-ray diffraction study. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600978507

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Reaction of β‐Lapachone with 1,2‐Diamines:
Facile Synthesis of Novel Tetracyclic
Pyrazines
Pahup Singh a , Anshu Dandia a , Kavita Natani a , Venu Sharma a , Raju
Ratnani b , A. L. Bingham c , M. B. Hursthouse c , M. E. Light c & J. E. Drake
d
a Department of Chemistry , University of Rajasthan , Jaipur, India
b Department of Pure and Applied Chemistry , M.D.S. University , Ajmer,
India
c Department of Chemistry , University of Southampton , Highfield,
Southampton, United Kingdom
d Department of Chemistry and Biochemistry , University of Windsor ,
Windsor, Ontario, Canada
Published online: 25 Jul 2007.
To cite this article: Pahup Singh , Anshu Dandia , Kavita Natani , Venu Sharma , Raju Ratnani , A. L.
Bingham , M. B. Hursthouse , M. E. Light & J. E. Drake (2007) Reaction of β‐Lapachone with 1,2‐Diamines:
Facile Synthesis of Novel Tetracyclic Pyrazines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:1, 113-118, DOI: 10.1080/00397910600978507
To link to this article: http://dx.doi.org/10.1080/00397910600978507
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Synthetic Communicationsw, 37: 113–118, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600978507
Reaction of b-Lapachone with
1,2-Diamines: Facile Synthesis
of Novel Tetracyclic Pyrazines
Pahup Singh, Anshu Dandia, Kavita Natani, and
Venu Sharma
Department of Chemistry, University of Rajasthan, Jaipur, India
Raju Ratnani
Department of Pure and Applied Chemistry, M.D.S. University,
Ajmer, India
A. L. Bingham, M. B. Hursthouse, and M. E. Light
Department of Chemistry, University of Southampton, Highfield,
Southampton, United Kingdom
J. E. Drake
Department of Chemistry and Biochemistry, University of Windsor,
Windsor, Ontario, Canada
Abstract: The reactions of b-lapachone (1) with 1,2-diaminoethane (2) and 1,2-diami-
nopropane (4) gave the tetracyclic pyrazine derivatives (3) and mixtures of (5) and (6),
respectively, while reaction with o-phenylene diamine (7) gave the quinoxaline deriva-
tive (8). The structure of pyrazine derivative (3) is confirmed by single-crystal X-ray
diffraction study.
Keywords: b-lapachone, 1,2-diamines, carbonyl reactivity, regioisomer
Received May 10, 2006
Address correspondence to Pahup Singh, Department of Chemistry, University of
Rajasthan, Jaipur 302004, India. E-mail: pahupsingh@yahoo.co.uk
113

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P. Singh et al.
1. INTRODUCTION
A number of prenyl naphthoquinone congeners such as lapachol, deoxylapachol,
a- and b-lapachones, dehydro-a-lapachone, and dehydroiso-b-lapachone have
been isolated from the woods of various Bignoniaceae[1–5] Malvaceae,[6] and
Verbenaceae[7] plants. b-Lapachone (1), a 1,2-naphthoquinone, is obtained in
low yield naturally and was synthesized from lapachol through cyclization of
the isoprenyl side chain of lapachol under microwave irradiation.[8]
We report the reactions of b-lapachone with different 1,2-diamines using
conventional heating and microwave irradiation.
2. RESULTS AND DISCUSSION
The reaction of b-lapachone (1) with 1,2-diaminoethane (2) at room tempera-
ture gave the corresponding tetracyclic pyrazine derivative 3 (Scheme 1). This
observation is in contrast to what Di Chenna et al. observed.[9] We have not
found the formation of a monoarylimine-o-quinone derivative.
We extended our studies to the reaction of b-lapachone with 1,2-diamino-
propane. Similar results involving the formation of the pyrazine derivatives
(5 and 6) were noticed (Scheme 2).
The reaction of o-phenylene diamine (7) with (1) gave the quinoxaline
derivative 8 (Scheme 3).
The structure of 3, involving facile dehydrogenative cyclocondensation
even under mild conditions, was confirmed by single-crystal X-ray diffraction
(Fig. 1).
3. EXPERIMENTAL
Melting points were determined in soft-glass capillaries in an electrothermal
melting-point apparatus and are uncorrected. Qualitative and quantitative
thin-layer chromatography (TLC) was conducted on TLC aluminium sheets,
1
Kieselgel 60F254 (E. Merck). H NMR and 13C NMR spectra were recorded
on a Bruker DRX 300 instrument using CDCl3 as solvent. Mass spectra
(EIMS) were generated on a Jeol D-300 spectrometer. All compounds were
homogeneous on TLC plates in various solvent systems.
Scheme 1.

Novel Tetracyclic Pyrazines
115
Scheme 2.
3.1. Reaction of b-Lapachone with 1,2-Diaminoethane (1)
b-Lapachone (61 mg, 0.25 mmol) and 1,2-diaminoethane (2 mL) were stirred
at room temperature for 24 h until completion of the reaction (TLC).
Petroleumether (60–808C, 10 mL) was added to the reaction mixture.
Crude product is separated by filtration and purified by preparative TLC
(benzene, Rf 0.29). Yield (54.9 mg, 90%).
3.2. 5,6-Dihydro-7,7-dimethyl-7H-pyrano[30,20:4]naphtha[1,2-b]-
pyrazine (3)
Physical properties: yellow needles, mp 77–808C; (found: C, 77.03; N, 10.57;
C17H16N2O requires C, 77.27; N, 10.60%); dH (300 MHz; CDCl3; Me4Si) 1.50
(6H, s, 2Me), 2.04 (2H, t, J 7.0, -CH2-), 3.24 (2H, t, J 7.0, -CH2-), 7.73 (2H, m,
2Ar-H), 8.33 (1H, m, 1Ar-H), 8.76 (2H, m, N-CH55CH-N), 9.14 (1H, br d,
1 ꢀ Ar-H); dC (300 MHz; CDCl3; Me4Si) 18.26 (C7-CH3), 26.80 (C7-CH3),
32.39 (C5 and C6), 75.37 (C7), 110–130 (aromatic-C), 138.19 (-C55N of
C4a), 139.99 (C3), 143.93(C2), 150.43 (C8a); MS (m/z, rel. int. %) 264
Scheme 3.

116
P. Singh et al.
Figure 1. ORTEP plot of the asymmetric unit of C17H16N2O. The nonhydrogen
atoms are drawn with 50% probability ellipsoids.
[M]þ (C17H16N2O) (55), 249 [M-Me]þ (15), 235 [249-CH2]þ (10), 221 [235-
CH2]þ (100), 209 (60), 188, 127; X-ray analysis: the C(3)–C(4) bond length
˚
(1.362 A) was found to be very close to the aromatic C-C bond length.
3.3. Reaction of b-Lapachone with 1,2-Diaminopropane (2)
1,2-Diaminopropane (2 mL) was added to b-lapachone (61 mg, 0.25 mmol),
and the mixture was stirred at room temperature. The progress of the
reaction was examined on TLC plate, which after 5 min indicated the
formation of two products in a ratio of 1:3. These two products were
separated by preparative TLC and characterized as regioisomers 5 and 6
(benzene, Rf 0.48, 0.36 respectively) on the basis of spectral studies. Yield:
14.33 mg, 23.5% of 5; 43 mg, 70.5% of 6.
The reaction was also carried out under microwaves, where it was
completed in 15 s. However, under MW irradiation, the reaction showed
the formation of the two products, 5 and 6, in a 2:3 ratio, indicating
the enhanced yield of regioisomer 5. To check the possibility of conversion
of 6 to 5, the reaction mixture was further irradiated for a longer period of
10 min, but no change was found in the product ratio. Yield: 23.42 mg,
38.4% of 5; 35.13 mg, 57.6% of 6.

Novel Tetracyclic Pyrazines
117
3.4. 5,6-Dihydro-2,7,7-trimethyl-7H-pyrano[30,20:4] naphtha [1,2-
b]-pyrazine (5)
Physical properties: pale yellow needles, mp 75–788C; found: C, 77.44; N,
10.04; C18H18N2O requires C, 77.69; N, 10.07%; dH (300 MHz; CDCl3;
Me4Si) 1.49 (6H, s, 2Me), 2.03 (2H, t, J 7.0, -CH2-), 2.76 (3H, br s, N55C-
CH3), 3.21 (2H, t, J 7.0, CH2-), 7.71 (2H, m, 2Ar-H), 8.32 (1H, m, 1Ar-H),
8.60 (1H, br s, N-CH55C-N), 9.07 (1H, m, 1Ar-H).
3.5. 5,6-Dihydro-3,7,7-trimethyl-7H-pyrano[30,20:4] naphtha [1,2-
b]-pyrazine (6)
Physical properties: bright yellow needles, mp 70–728C; found: C, 77.93;
N, 10.07; C18H18N2O requires C, 77.69; N, 10.05%; dH (300 MHz;
CDCl3; Me4Si) 1.49 (6H, s, 2Me), 2.02 (2H, t, J 7.0, -CH2-), 2.79 (3H, br s,
N55C-CH3), 3.22 (2H, t, J 7.0, -CH2-), 7.71 (2H, m, 2Ar-H), 8.32 (1H, m,
1Ar-H), 8.69 (1H, br s, N-C55CH-N), 9.16 (1H, m, 1Ar-H).
3.6. Reaction of b-Lapachone with o-Phenylene Diamine (3)
The analogous reaction of b-lapachone (61 mg, 0.25 mmol) with o-phenylene
diamine (21 mg, 0.25 mmol) in ethyl alcohol (15 mL) was carried out at room
temperature. The reaction was examined on a TLC plate, which indicated
product 8 with minor impurities. This compound was purified by preparative
TLC (benzene Rf 0.76). Yield: 56.12 mg, 92%.
3.7. 7,8-Dihydro-9,9-dimethyl-9H-pyrano[30,20:4] naphtha [1,2-b]-
quinoxaline (8)
Physical properties: bright yellow needles, mp 113–1158C; found: C, 80.51; N,
8.93; C21H18N2O requires C, 80.25; N, 8.91%. dH (300 MHz; CDCl3; Me4Si)
1.53 (6H, s, 2Me), 2.07 (2H, t, J 7.0, -CH2-), 3.35 (2H, t, J ¼ 7.0, -CH2-), 7.80
(3H, m, 3Ar-H), 8.30 (1H, m, 1Ar-H), 9.33 (1H, m, 1Ar-H); dC (300 MHz;
CDCl3; Me4Si) 18.33 (C9-CH3), 26.86 (C9-CH3), 32.52 (C7 & C8), 76.03
(C9), 109–130 (aromatic-C), 140.79 (-C55N of C14b), 142.59 (-C55N of
C6a), 144.55 (C10a); MS (m/z, rel. int. %) 314 [M]þ (C21H18N2O) (75), 299
[M-Me]þ (15), 285 [299-CH2]þ (10), 271 [285-CH2]þ, 229 (20).
4. CONCLUSION
We have developed a facile method for quantitative synthesis of a novel
tetracyclic ring system involving the formation of the pyrazine ring in the

118
P. Singh et al.
absence of any solvent/catalyst by reaction of b-lapachone with various
amines at room temperature.
ACKNOWLEDGMENT
Authors (P. S. and A. D.) are thankful to UGC for financial support. M. B. H.
thanks the U.K. Engineering and Physical Sciences Council for support of the
X-ray facilities at Southampton University. J. E. D. thanks the University of
Windsor for financial support.
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