A new route to 2-substituted perimidines based on nitrile oxide chemistry

Article abstract of DOI:10.1016/j.tetlet.2009.04.118

A new route to perimidines has been developed which involves reaction of a nitrile oxide with 1,8-diaminonaphthalene. Benzonitrile oxide, generated by dehydrochlorination of benzohydroximoyl chloride, and 1,8-diaminonaphthalene afforded 2-phenylperimidine

Full text of DOI:10.1016/j.tetlet.2009.04.118

Tetrahedron Letters 50 (2009) 4104–4106
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new route to 2-substituted perimidines based on nitrile oxide chemistry
*
Iain A. S. Smellie, Andreas Fromm, R. Michael Paton
EaStCHEM, School of Chemistry, The University of Edinburgh, King’s Buildings, West Mains Road, Edinburgh EH9 3JJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route to perimidines has been developed which involves reaction of a nitrile oxide with 1,8-dia-
minonaphthalene. Benzonitrile oxide, generated by dehydrochlorination of benzohydroximoyl chloride,
and 1,8-diaminonaphthalene afforded 2-phenylperimidine. 2-Pyranosylperimidines were prepared by
the same approach from pyranosyl hydroximoyl chlorides.
Received 14 March 2009
Revised 9 April 2009
Accepted 28 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
C-Glycosides
Nitrile oxides
Perimidines
Glycals
It has previously been shown10–12 that the reactions of nitrile
oxides with 1,2-diaminobenzene can be used to prepare 2-substi-
tuted benzimidazoles. In view of the peri-arrangement of the two
amino groups in DAN, we reasoned that DAN and nitrile oxides
should react similarly, and thus provide a new synthetic approach
to 2-substituted perimidines. To test this hypothesis we attempted
to prepare the known 2-phenylperimidine (1, R = Ph)1,13 by reac-
tion of DAN with benzonitrile oxide (5, R = Ph). As nitrile oxides
are prone to dimerise to furoxans (1,2,5-oxadiazole N-oxides),14
the benzonitrile oxide was generated in situ by dehydrochlorina-
tion of benzohydroximoyl chloride (6, R = Ph). A solution of
PhCCl@NOH (1.3 mmol) and DAN (2.5 mmol) in dry EtOH was
heated at reflux for 5 h. After cooling and addition of CH2Cl2, the
reaction mixture was worked up by washing with aq K2CO3 and
then with 4% aq CuSO4, followed by chromatography; washing
with aq CuSO4 was found to be an effective means of removing
excess DAN. The product was identified as 2-phenylperimidine (1
R = Ph, 68%) by comparison of its physical and spectroscopic prop-
erties with those reported in the literature.13,15 The reaction is
believed to involve initial dehydrochlorination of the hydroximoyl
chloride by DAN acting as a base to generate the nitrile oxide 5,
then nucleophilic addition of one of the amino groups of a second
molecule of DAN to the nitrile oxide to form the mono-amidoxime
7, followed by cyclisation with loss of hydroxylamine, as illustrated
in Scheme 1.
Perimidines (1H-benzo[d,e]quinazolines) (1) are unusual among
azines in that the lone pair of a pyrrole-like nitrogen participates in
the
p-system of the molecule, and there is a transfer of electron
density from the heterocycle to the naphthalene ring.1 These peri-
naphtho-fusedpyrimidinesthereforehavethecharacteristicsofboth
p
-deficient and p
-excessive systems.2 They have long been used in
dyestuffs1 and in the manufacture of polyester fibres,1 and more
recently as a source of a novel carbene ligand.3 Their biological activ-
ity has also attracted attention, for example, their potential to act as
anti-fungal, anti-microbial, anti-ulcer and anti-tumour agents.1,4,5
Most synthetic routes1 to 2-substituted perimidines are based on
the reactions of 1,8-diaminonaphthalene (2, DAN) with various car-
bonyl compounds. Carboxylic acids,6,7 acyl halides and anhydrides
afford the mono-amide derivatives 3, and these undergo acid-cata-
lysed cyclisation to 1. The corresponding reaction with aldehydes af-
fords 2,3-dihydroperimidines 4, which are readily dehydrogenated
to 1.8,9 Althougha wide range of 2-alkyl, aryl and heterocycle-substi-
tuted perimidines have been prepared by these approaches, there
have been no examples bearing carbohydrate groups so far.
R
R
R
O
NH2
N
NH
NH2 NH2
HN
HN
NH
Having established that 2-phenylperimidine could be prepared
by reaction of DAN with benzonitrile oxide, the same approach was
investigated using pyranosyl nitrile oxides as a route to 2-pyrano-
sylperimidines. We have previously described a method for the
synthesis of pyranosyl hydroximoyl chlorides and shown that they
are an efficient source of pyranosyl nitrile oxides.16,17 The same
1
2
3
4
* Corresponding author. Tel: +44 31 650 4714; fax: +44 31 650 4743.
E-mail address: R.M.Paton@ed.ac.uk (R. M. Paton).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.118

I. A. S. Smellie et al. / Tetrahedron Letters 50 (2009) 4104–4106
4105
R
R
NOH
NH2
HN
N
NH
R
DAN
- NH2OH
DAN
- HCl
NOH
R
N O
Cl
6
5
7
1
Scheme 1.
method was therefore used in the present work. In a typical exper-
iment, a solution of -xylose-derived hydroximoyl chloride 6a
reflux, compound 9b was the major product (Table 1, entries 3 and
4). -Galactopyranosyl-perimidine 8d (69%) was prepared similarly
from DAN and 6d (Table 1, entry 7). The corresponding reaction at
room temperature in the -mannose series also yielded the expected
mannopyranosyl-perimidine 8c (55%), but in ethanol at reflux the
proportion of the glycal-perimidine increased to 9b:8c = 8.5:1
(Table 1, entries 5 and 6), consistent with the more favourable
arrangement for the elimination of AcOH.
D
D
(0.6 mmol) and DAN (1.5 mmol) in dry EtOH was heated at reflux
for 5 h. Work-up of the reaction mixture as described above for 1
(R = Ph) afforded two products (Table 1, entry 1). The more polar
product (silica/Et2O, Rf = 0.27) was identified from its spectroscopic
D
properties18 as the target
D-xylopyranosyl-perimidine 8a (16%). In
the 1H and 13C NMR spectra there were, in addition to the expected
peaks associated with the tri-O-acetylxylopyranosyl substituent,
characteristic signals for the carbons and hydrogens of the perimi-
dine moiety;9 in particular the dC values for C-2 (154.0 ppm), C-3a
(145.8), C-9a (139.4) and C-9b (123.6). The less polar product
(Rf = 0.35) was assigned the corresponding glycal structure 9a
(43%).19 In contrast to 8a, in this case only two acetate groups were
detected in the NMR spectra [dH 2.12, 2.10 (Me); dC 171.0, 170.9
(C@O) and 22.3, 22.2 (Me)] and, in addition to the perimidine sig-
AcO
AcO
AcO
AcO
O
O
X
X
AcO
OAc
AcO
8b
9b
HN
N
X =
13
nals, there were distinctive C peaks for the glycal carbons C-10
AcO
AcO
AcO
AcO
O
O
and C-20 at 149.2 and 99.9 ppm, respectively. In order to minimise
the formation of the glycal the reaction was repeated under less
forcing conditions (room temperature, 15 h). Under these condi-
tions the major product was the target pyranosyl-perimidine 8a
(60%) with only traces of 9a being detected (Table 1, entry 2).
The formation of 9a is attributed to facile base-catalysed elimina-
tion of acetic acid at C-10/C-20 of the xylopyranosyl ring yielding
the glycal in which the alkene unit is conjugated to the perimidine.
X
X
AcO
OAc
AcO
OAc
8c
8d
In conclusion, a new and efficient route to 2-substituted
perimidines has been established, based on the cyclocondensation
of 1,8-diaminonaphthalene with nitrile oxides. This approach is
particularly suited for the synthesis of 2-pyranosyl-perimidines
from pyranosyl nitrile oxides, which can readily be generated from
the corresponding hydroximoyl chlorides.
O
O
HN
N
AcO
AcO
CCl=NOH
AcO
AcO
OAc
OAc
Acknowledgement
6a
8a
We thank the EPSRC for financial support.
O
HN
AcO
AcO
References and notes
N
1. For reviews of perimidine chemistry see: (a) Pozharskii, A. F.; Dalnikovskaya, V.
V. Russ. Chem. Rev. 1981, 50, 816–835; (b) Liu, K. C. Zhonghua Yaoxue Zazhi
1988, 40, 203–216; (c) Claramunt, R. M.; Dotor, J.; Elguero, J. Ann. Quim. 1995,
91, 151–183; (d) Undheim, K.; Benneche, C. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
Oxford, 1996; Vol. 6, Chapter 2.
2. Woodgate, P. D.; Herbert, J. M.; Denny, W. A. Heterocycles 1987, 26, 1029–1036.
3. Bazinet, P.; Yap, G. P. A.; Richeson, D. S. J. Am. Chem. Soc. 2003, 125, 13314–
13315.
9a
Similar results were obtained with the reaction of hydroximoyl
chlorides 6b–d prepared from -glucose, -mannose and -galact-
ose, respectively (Table 1). DAN and -glucose-derived hydroximoyl
D
D
D
D
chloride6b, at roomtemperatureaffordedthepyranosyl-perimidine
8b20 (65%), together with traces of the glycal 9b, and in EtOH at
4. Herbert, J. M.; Woodgate, P. D.; Denny, W. A. J. Med. Chem. 1987, 30, 2081–2086.
5. Bu, X.; Deady, L. W.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 2001,
44, 2004–2014.
Table 1
6. Mobinikhaledi, A.; Amrollahi, M. A.; Foroughifar, N.; Jirandehi, H. F. Asian J.
Chem. 2005, 17, 2411–2414.
7. Mobinikhaledi, A.; Foroughifar, N.; Goli, R. Phosphorus, Sulfur Silicon Relat. Elem.
2005, 180, 2549–2554.
8. Maquestiau, A.; Berte, L.; Mayence, A.; Vanden Eynde, J. J. Synth. Commun. 1991,
21, 2171–2180.
9. Llamas-Saiz, A. L.; Foces-Foces, C.; Sanz, D.; Claramunt, R. M.; Dotor, J.; Elguero,
J.; Catalan, J.; del Valle, J. C. J. Chem. Soc., Perkin Trans. 2 1995, 1389–1398.
10. Sasaki, T.; Yoshioka, T.; Suzuki, Y. Bull. Chem. Soc. Jpn. 1969, 42, 3335–3338.
11. Risitano, F.; Grassi, G.; Foti, F.; Caruso, F. J. Chem. Res. (S) 1983, 52.
12. Abdelhamid, A. O.; Parkanyi, C.; Rashid, S. M. K.; Lloyd, W. D. J. Heterocycl.
Chem. 1988, 25, 403–405.
Formation of perimidines 8 and 9
Entry
RCCl@NOH
Conditionsa
Pyranosyl-perimidine
Glycal-perimidineb
1
2
3
4
5
6
7
D-Xyl (6a)
D-Xyl (6a)
D-Glc (6b)
D-Glc (6b)
D-Man (6c)
D-Man (6c)
D-Gal (6d)
A
B
A
B
A
B
B
8a (16%)
8a (60%)
8b (16%)
8b (65%)
8c (4%)
9a (43%)
9a (trace)
9b (34%)
9b (trace)
9b (34%)
9b (trace)
—
8c (55%)
8d (69%)
a
A: 5 h, reflux; B: 15 h, room temperature.
2-(2-Deoxy-1-enopyranosyl)perimidines.
13. Sierra, M. A.; Mancheno, M. J.; Del Amo, J. C.; Fernandez, I. Chem. Eur. J. 2003, 9,
4943–4953.
b

4106
I. A. S. Smellie et al. / Tetrahedron Letters 50 (2009) 4104–4106
14. Paton, R. M. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 4, Chapter 5.
15. Orange crystals (68%); mp 187–188 °C (lit13 187–188 °C); dH (360 MHz, CDCl3);
6.65 (2H, br s, 9-H, 4-H), 7.14–7.26 (4H, m, ArH), 7.47–7.55 (3H, m, ArH), 7.85–
7.90 (2H, m, ArH); dC (93 MHz, CDCl3); 120.9, 122.9, 127.2, 129.4, 129.9, 132.2,
135.01, 136.4 (C-6a), 153.7 (C-2); m/z (EI) 244 (M+); HRMS (EI) found: M++1
244.10036, C17H12N2 requires: M++H 244.10005.
(COCH3), 66.8 (C-50), 69.8, 71.2, 73.6, 78.8 (C-10–C-40), 104.1 (C-9), 115.0 (C-4),
119.2 (C-7), 121.1 (C-6), 123.6 (C-9b), 129.5 (C-8), 130.3 (C-5), 136.6 (C-6a),
139.4 (C-9a), 145.8 (C-3a), 154.0 (C-2), 170.7, 171.1, 171.2 (COCH3); m/z (FAB)
427 (M+ +1); HRMS (FAB) found: M++1 427.15109, C22H22N2O7 requires: M++H
427.15053.
19. 2-(30,40-Di-O-acetyl-
solid (43%); mp 148–149 °C;
D
-threo-pento-1-enopyranosyl)perimidine
(9a).Orange
½ ꢀ ꢁ113 (c 0.15, CHCl3); dH (360 MHz,
a 2D0
16. Baker, K. W. J.; Gibb, A.; March, A. R.; Parsons, S.; Paton, R. M. Tetrahedron Lett.
2001, 42, 4065–4068.
CD3SOCD3); 2.10, 2.12 (6H, s, COCH3) 4.14 (1H, m, 50a-H), 4.48 (1H, m, 50b-
H), 5.04 (1H, m, 30-H), 5.12 (1H, m, 40-H), 6.02 (1H, d, J = 5.1 Hz, 20-H), 6.58 (1H,
dd, J = 0.9, 7.2 Hz, 9-H), 6.60 (1H, dd, J = 1.1, 7.5 Hz, 4-H), 7.47–7.51 (4H, m, H-
5, H-6, H-7, H-8), 10.49 (1H, br s, NH); dC (93 MHz, CD3S(O)CD3); 22.2, 22.3
(COCH3), 64.5, 66.2, 67.6 (C-30–C-50), 99.9 (C-20), 104.7 (C-9), 115.2 (C-4), 119.5
(C-7), 121.0 (C-6), 123.8 (C-9b), 129.5 (C-8), 130.4 (C-5), 136.6 (C-6a), 139.2 (C-
9a), 145.9 (C-3a), 149.2 (C-10), 150.1 (C-2), 170.9, 171.0 (COCH3); m/z (FAB) 367
(M+ +1); HRMS (FAB) found: M++1 367.12985, C20H18N2O5 requires: M++H
367.12940.
17. Baker, K. W. J.; March, A. R.; Parsons, S.; Paton, R. M.; Stewart, G. W. Tetrahedron
2002, 58, 8505–8513.
18. 2-(20,30,40-Tri-O-acetyl-
D-xylopyranosyl)perimidine (8a).Yellow/green solid
(60%); mp 169–170 °C; ½a D20
ꢁ40 (c 0.2, CHCl3); dH (360 MHz, CD3SOCD3);
ꢀ
1.93, 2.03, 2.05 (9H, s, COCH3), 3.67 (1H, dd, J = 10.9, 11.0 Hz, 50a-H), 4.10 (1H,
dd, J = 5.5, 11.0 Hz, 50e-H), 4.24 (1H, d, J = 9.7 Hz, 10-H), 5.02 (1H, m, 40-H), 5.24
(1H, dd, J = 9.6, 9.7 Hz, 20-H), 5.41 (1H, dd, J = 9.5, 9.6 Hz, 30-H), 6.42 (1H, dd,
J = 0.9, 7.2 Hz, 9-H), 6.54 (1H, dd, J = 1.1, 7.5 Hz, 4-H), 6.99–7.17 (4H, m, H-5, H-
6, H-7, H-8), 10.48 (1H, br s, NH); dC (93 MHz, CD3SOCD3); 21.8, 21.9, 22.0
20. The structure of compound 8b has been confirmed by X-ray crystallography
(Moggach, S. unpublished observations).