Investigation of the reaction of o-aminonitriles with ketones: A new modification of Friedl?nder reaction and structures of its products

Article abstract of DOI:10.1055/s-2007-1000841

A new modification of the Friedl?nder reaction is described and the new byproduct obtained from the reaction of o-aminonitriles and ketones was found to be 2,3-dihydroquinazolin-4(1H)-one. The mechanism probably involved the formation of an intermediate o

Full text of DOI:10.1055/s-2007-1000841

LETTER
233
Investigation of the Reaction of o-Aminonitriles with Ketones: A New
Modification of Friedländer Reaction and Structures of Its Products
R
eactiono
i
f
o
-A
m
a
inonitriles
r
w
ith Ke
o
tones ng Li,* Lijun Zhang, Daxin Shi, Qing Li, Dong Wang, Chunxia Wang, Qi Zhang, Ling Zhang, Yanqiu Fan
School of Chemical Engineering and Environment, Beijing Institute of Technology, 100081 Beijing, P. R. of China
Fax +86(10)68913293; E-mail: jrli@bit.edu.cn
Received 22 September 2007
of 1 with cyclohexanone in DMF in the presence of anhy-
drous ZnCl2 under reflux gave two different compounds.
One was the expected quinoline 2 (tacrine analogues) ob-
tained from the normal Friedländer condensation, and the
Abstract: A new modification of the Friedländer reaction is de-
scribed and the new byproduct obtained from the reaction of o-ami-
nonitriles and ketones was found to be 2,3-dihydroquinazolin-
4(1H)-one. The mechanism probably involved the formation of an
intermediate oxazine, via the Pinner reaction and its transformation other was the ‘unexpected’ spiro compound 4 obtained
into new products via the Dimroth rearrangement.
from the new annulation. Compounds 2 gave satisfactory
analytical and spectroscopic data in agreement with their
postulated structures.11 As for the new conversion prod-
ucts, their structures were assigned to be spiropyrimidino-
ne derivatives 4, not oxazines 3. High resolution mass
spectrometry of 4a suggested an elemental composition of
C26H23N3O4 for its molecular ion and its IR spectrum
showed two strong bands in the range of 3186–3239 cm–1
due to NH absorptions, and one strong band at 1659 cm–1
due to C=O absorption. In the 13C NMR spectrum, the sig-
nals of two quaternary carbons, C2 and C4, resonated at
d = 165.5 and 67.1 ppm, respectively. And their chemical
shifts were coincident with those of similar compounds in
the literature (Figure 1).12
Key words: Friedländer reactions, cyclizations, spiro compounds,
rearrangements, molecular recognition
Aromatic o-aminonitriles are versatile synthons1 for the
synthesis of quinolines,2 pyrimidines,3 quinazolines,4
quinazolinones,5 quinazolinediones,6 and other fused ni-
trogen-containing heterocycles. The classical Friedländer
annulation involving the cyclocondensation of an o-ami-
nobenzonitrile with a carbonyl compound possessing a re-
active a-methylene group is a straightforward method for
the synthesis of quinoline skeleton compounds.7
Tacrine (9-amino-1,2,3,4-tetrahydroacridine, commer-
cially named THA),8 which is currently one of the major
approved drugs for treatment of mild to moderate Alz-
heimer’s disease, is obtained by Friedländer-type cyclocon-
densation of o-aminobenzonitrile with cyclohexanone.
Because of the serious toxicity of THA, a large number of
its derivatives and analogues have been synthesized
through this kind of reaction.9 Recently, during our syn-
thetic study of THA derivatives, a new conversion was
found that proceeded along with the normal Friedländer
annulation. The structure of the new product, which was
obtained from the reaction of o-aminonitriles and cyclo-
hexanone under refluxing in the presence of anhydrous
ZnCl2, was assigned as spiropyrimidinones (Scheme 1).
Ar
OH
CN
CN
CHO
Ar
cat.
CN
+
+
O
NH2
1
Ar
O
NH2
N
O
2a, 47.2%
2b, 50.4%
1a,b
ZnCl2, DMF
reflux
Ar
NH
A subsequent study of the reaction of aromatic o-ami-
nobenzonitriles with ketones in our laboratory gave simi-
lar results. Thus, additional experiments based on both the
mechanism of this new conversion and the structures of
products were carried out. Herein, we report the results of
our findings.
O
a: Ar = 3-NO2C6H4
b: Ar = 4-NO2C6H4
O
N
H
3a,b
Ar
O
O
3-Amino-1-phenyl-1H-benzo[f]chromene-2-arbonitriles
1, the starting materials for this work, were conveniently
synthesized from a three-component reaction using com-
mercial b-napathanol, aldehyde and malononitrile using a
standard methodology reported by Sakurai.10 Cyclization
NH
N
H
4a, 30.2%
4b, 27.6%
Scheme 1 Reaction of o-aminonitriles with cyclohexanone
SYNLETT 2008, No. 2, pp 0233–0236
x
x.
x
x.
2
0
0
7
Advanced online publication: 11.12.2007
DOI: 10.1055/s-2007-1000841; Art ID: W17507ST
© Georg Thieme Verlag Stuttgart · New York

234
J. Li et al.
LETTER
162 ppm
163 ppm
O
O
Cl
Cl
NH
NH
N
H
N
H
Ph
68 ppm
66 ppm
164 ppm
O
Cl
Ph
N
N
H
63 ppm
Figure 1 13C NMR spectroscopic data of known compounds
To unambiguously confirm the structure of compound 4a,
yellow single crystals of 4a were grown from a solution of
tetrahydrofuran by slow evaporation at room temperature
and its X-ray diffraction data were collected.13 The molec-
ular structure of 4a (Figure 2) further confirmed the spiro-
pyrimidinone structure. Two molecules of 4a were linked
by two N(2)–H(2)…O(6) and N(5)–H(5) …O(2) hydro-
gen bonds, together with two tetrahydrofuran molecules
to form a triclinic crystal structure. A similar structure was
also found for compound 4b (Figure 3).13
Figure 3 Crystal structure of compound 4b
Encouraged by these results, we then reinvestigated the
reaction of aromatic o-aminonitriles 5 with various ke-
tones 6. The results are summarized in Table 1. As shown
in Table 1, all the data suggested a high generality of the
new conversion. Various ketones reacted with substituted
o-aminobenzonitriles in the presence of ZnCl2 to give two
heterocycles: a quinoline built up through the normal
Friedländer reaction, and a quinazolinone produced via
Table 1 Reaction of o-Aminobenzonitriles with Ketonesa
NH2
R4
R3
R1
R2
N
7
R3
R1
R2
CN
ZnCl2
reflux
O
+
O
R4
NH2
R1
R2
NH
R3
R4
5
6
N
H
8
Entry R1 R2
R3, R4
R3, R4 = (CH2)4
Time Yield(%)bYield (%)b
(h)
of 7
of 8
Figure 2 Crystal structure of compound 4a
a
b
c
H
H
H
Cl
1.5 17
69
NO2 R3, R4 = (CH2)3
1
1
15
12
71
In addition, a confirmation study was carried out to further
confirm our assignments of the new conversion products.
Hence, compounds 8 were independently synthesized via
the reaction of o-aminobenzamide and ketone 6 in the
presence of the catalyst p-TsOH (Scheme 2). They exhib-
ited the same spectroscopic data as the products prepared
from the Friedländer reaction.
NO2 R3 = Me
R4 = Et
75
d
e
f
H
NO2 R3 = Me
R4 = Me2CH
1
trace
76
70
65
66
Cl
Cl
Cl
H
H
H
R3 = Me
R4 = Et
1.5 trace
1.5 trace
R3 = Me
O
O
R4
R4 = Me2CH
R2
R1
R2
R1
NH
NH2
p-TsOH
R4
O
g
R3 = Me, R4 = 4- 1.5 trace
MeOC6H4
+
R3
R3
N
H
NH2
a All reactions were carried out using 5 (6 mmol), 6 (4 mL), ZnCl2 (6
mmol), and DMF (8 mL).
6
8
b Isolated yield.
Scheme 2 Synthesis of compounds 8
Synlett 2008, No. 2, 233–236 © Thieme Stuttgart · New York

LETTER
Reaction of o-Aminonitriles with Ketones
235
R1
R2
CN
CN
R1
R2
R1
R1
R3
CN
N
R4
R3
A
OH
R3
O
+
R4
– H2O
NH2
N
H
R4
I
Pinner
B
NH
NH2
NH
R1
R2
R1
R2
R1
C
N
R4
O
O
R4
R4
N
H
R3
N
O
R3
R2
R3
II
NH2
R1
R2
R1
R2
R4
R3
NH
R3
R4
N
H
N
III
IV
Scheme 3 Proposed mechanism
the new conversion route. The results also showed that o-
aminobenzonitriles 5 having strong electron-withdrawing
substituents on the aromatic ring were cyclized with ke-
tones to give the corresponding quinolines 7 in lower
yields but quinazolinones 8 in better yields than other o-
aminobenzonitriles. This probably suggests that electron-
withdrawing groups on the aromatic ring facilitate the
new conversion. In addition, different ketones could be
employed but had not much influence on the yield of
product 8.
References and Notes
(1) (a) Taylor, E. C.; McKillop, A. The Chemistry of Cyclic
Enaminonitriles and o-Aminonitrile; Wiley: New York,
1970. (b) Erian, A. W. Chem. Rev. 1993, 93, 1991.
(2) (a) Varala, R.; Enugala, R.; Adapa, S. R. Synthesis 2006,
3825. (b) Cheng, C. C.; Yan, S. J. Org. React. (N. Y.) 1982,
28, 37. (c) Madrid, P. B.; Sherrill, J.; Lion, A. P.; Weisman,
J. L.; DeRisi, J. L.; Guy, R. K. Bioorg. Med. Chem. Lett.
2005, 15, 1015.
(3) Abd El-Wahab, A. H. F. Acta Pharm. 2002, 54, 269.
(4) (a) Rosowsky, A.; Chen, H. J. Org. Chem. 2001, 66, 7522.
(b) Mohareb, R. M.; Al-Omran, F. A. Monatsh. Chem..
2002, 133, 1443. (c) Wiklund, P.; Bergman, J. Org. Biomol.
Chem. 2003, 1, 467.
(5) (a) Roth, G. A.; Tai, J. J. J. Heterocycl. Chem. 1996, 33,
2051. (b) Grubs, G. S.; Zhi, L.; Jones, T. K.; Marschke, K.
B.; Tegley, C. M. PCT Int. Appl., WO0066560, 2000.
(6) (a) Mizuno, T.; Okamoto, N.; Ho, T.; Miyata, T. Heteroat.
Chem. 2000, 11, 428. (b) Mizuno, T. Kagaku to Kogyo
2002, 76, 431; Chem. Abstr. 2002, 138, 256866j.
On the basis of these observations, a possible mechanism
was proposed (Scheme 3). The formation of pyridine ring
compound IV takes place via normal Friedländer reaction
(A), while the new modification may proceed via a differ-
ent route (B) after the key intermediate I is formed by ad-
dition of the amino group of the o-aminonitrile onto the
carbonyl of the cyclohexanone. The hydroxyl group of in-
termediate I then attacks the nitrile group (i.e. Pinner
reaction14) to afford a benzoxazine II, which subsequently
rearranges to give the new conversion product III (Dim-
roth rearrangement15). We called this new conversion as
the PDF pathway.16
(c) Yoshida, T. Jpn. Patent, JP200491403, 2004.
(d) Mizuno, T.; Iwai, T.; Ishino, Y. Tetrahedron Lett. 2004,
45, 7073. (e) Nourry, A.; Legoupy, S.; Huet, F. Tetrahedron
Lett. 2007, 48, 6014.
(7) (a) Zhichkin, P.; Beer, C. M. C.; Rennells, W. M.; Fairfax,
D. J. Synlett 2006, 379. (b) Ryabukhin, S. V.; Volochnyuk,
D. M.; Plaskon, A. S.; Naumchik, V. S.; Tolmachev, A. A.
Synthesis 2007, 1214. (c) Antoniow, S.; Witt, D. Synthesis
2007, 363. (d) Yadav, J. S.; Reddy, B. V. S.; Premalatha, K.
Synlett 2004, 963. (e) Palimkar, S. S.; Siddiqui, S. A.;
Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. J. Org. Chem.
2003, 68, 9371. (f) Patteux, C.; Levacher, V.; Dupas, G.
Org. Lett. 2003, 5, 3061. (g) Dormer, P. G.; Eng, K. K.;
Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider, P.
J.; Sager, J. W.; Volante, R. P. J. Org. Chem. 2003, 68, 467.
(h) Gladiali, S.; Chelucci, G.; Mudadu, M. S.; Gastaut, M.
A.; Thunmet, P. R. J. Org. Chem. 2001, 66, 400. (i) Boger,
D. L.; Chen, J.-H. J. Org. Chem. 1995, 60, 7369. (j)Riesgo,
E. C.; Jin, X.; Thummel, R. P. J. Org. Chem. 1996, 61, 3017.
In summary, a new modification of Friedländer annula-
tion for the cyclization of o-aminonitriles with ketones in
the presence of ZnCl2 was described, and the structures of
the conversion products were confirmed as quinazolinone
derivatives. Further studies to extend the scope of this new
conversion and to fully understand its mechanism are in
progress.
Acknowledgment
This work was supported by the grant of Beijing Institute of Tech-
nology. We are grateful for analytical help of the Beijing University
Analysis Center and Institute of Chemistry, Chinese Academy of
Sciences.
Synlett 2008, No. 2, 233–236 © Thieme Stuttgart · New York

236
J. Li et al.
LETTER
11H-naphtho[1¢,2¢:5,6]pyrano[2,3-d]pyrimidin-11
(10H)-one (4a): yellow solid; mp 275–278 °C. IR (KBr):
3187, 2937, 1659, 1630, 1527, 1349, 1227 cm–1. 1H NMR
(400 MHz, DMSO-d6): d = 1.22 (m, 1 H, CH2), 1.38 (m, 4 H,
CH2), 1.66 (m, 4 H, CH2), 1.76 (m, 1 H, CH2), 5.76 (s, 1 H,
CH), 7.23 (s, 1 H, NH), 7.43–7.52 (m, J = 7.8 Hz, 4 H, ArH),
7.58 (s, 1 H, NH), 7.63 (d, J = 7.8 Hz, 1 H, ArH), 7.96 (m,
(8) (a) Grigis, N. S.; Pederson, E. B. Synthesis 1985, 547.
(b) Schredl, M.; Hornung, O.; Regen, F.; Albrecht, N.;
Danker-Hopfe, H.; Heuser, I. Pharmacopsych. 2006, 6.
(c) Engger, S. A.; Levy, R.; Sahakian, B. J. Lancet 1991,
337, 989. (d) Summers, W. K.; Majovski, L. V.; Marsh, G.
M. N. New Engl. J. Med. 1996, 315, 1241. (e) Proctor, G.
R.; Harvey, A. L. Curr. Med. Chem. 2000, 7, 295. (f) Li, J.
R.; Zhou, X. W.; Cheng, P.; Guo, Y. J. J. Beijing Inst.
Technol. 2002, 11, 375.
(9) (a) Carlier, P. R.; Han, Y. F.; Chow, E. S. H.; Li, C. P. L.;
Wang, H.; Lieu, T. X.; Wong, H. S.; Pang, Y. P. Bioorg.
Med. Chem. 1999, 7, 351. (b) Camps, P.; Formosa, X.;
Muňoz-Torrero, D. M.; Petrignet, J.; Badia, A.; Clos, M. V.
J. Med. Chem. 2005, 48, 1701. (c) Hu, M. K.; Wu, L. J.;
Hsiao, G.; Yen, M. H. J. Med. Chem. 2002, 45, 2277.
(d) Haviv, H. R.; Wong, D. M.; G reenblatt, H. M.; Carlier,
P. R.; Han, Y. F.; Pang, Y. P.; Silman, I.; Sussman, J. L.
J. Am. Chem. Soc. 2005, 127, 11029.
J = 1.8, 7.8 Hz, 4 H, ArH), 8.12 (t, J = 1.8 Hz, 1 H, ArH). 13
NMR (100 MHz, DMSO-d6): d = 20.7, 21.1, 24.7, 34.3,
36.0, 36.3, 67.1, 81.6, 116.9, 117.0, 121.1, 121.9, 123.3,
125.0, 127.4, 128.6, 129.6, 129.9, 130.6, 130.8, 134.1,
147.6, 147.7, 148.8, 154.8, 165.5. MS (ESI): m/z = 442.3
C
[M + H+]. Anal. Calcd for C26H23N3O4: C, 70.73; H, 5.25; N,
9.52. Found: C, 70.45; H, 5.22; N, 9.61.
6-Chloro-2,2-pentamethylene-1,2-dihydroquinazolin-4
(3H)-one (8a): light yellow solid; mp 232–233 °C. IR (KBr):
3358, 3173, 2934, 2855, 1643, 1612, 1493, 825 cm–1. 1H
NMR (DMSO-d6): d = 1.23–1.73 (m, 10 H, CH2), 6.63 (dd,
J = 2.0, 8.0 Hz, 1 H, ArH), 6.86 (d, J = 2.0 Hz, 1 H, ArH),
6.90 (s, 1 H, NH), 7.54 (d, J = 8.0 Hz, 1 H, ArH), 8.05 (s, 1
H, NH). MS (ESI): m/z (%) = 264.2 (100) [M + H]+. Anal.
Calcd for C13H15ClN2O (252.1): C, 62.28; H, 6.03; N, 14.14.
Found: C, 62.19; H, 5.92; N, 14.11.
(10) (a) Sakurai, A.; Midorikawa, N. Bull. Chem. Soc. Jpn. 1967,
40, 1680. (b) Sakurai, A.; Midorikawa, N. Bull. Chem. Soc.
Jpn. 1968, 41, 430. (c) Shi, D. Q.; Zhang, S.; Zhuang, Q. Y.;
Wang, X. S.; Tu, S. J.; Hu, H. Chin. J. Org. Chem. 2003, 23,
1419.
(11) Typical Procedure for Preparation of Products 2 and 4:
o-Aminonitrile 1 (1.5 mmol), cyclohexanone (1.7 mmol),
anhyd zinc chloride (1.6 mmol) and DMF (10 mL) were
added into a 50-mL flask. The reaction mixture was refluxed
for 2 h (monitored by TLC). Then the mixture was diluted
with H2O and titrated to pH 12–13 by 20% NaOH. After
filtration, the solid was dissolved in THF, the organic phase
obtained was combined with the extracted component of
filtrate (using EtOAc) and evaporated in vacuo, and then
chromatographed (Merck, 200–300 mesh, EtOAc–PE, 1:2)
to afford product 2 and 4.
2,2-Butamethylene-6-nitro-1,2-dihydroquinazolin-4
(3H)-one (8b): mp 281–283 °C. IR (KBr): 3319, 3180,
2912, 1672, 1619, 1534, 1310 cm–1. 1H NMR (DMSO-d6): d
= 1.67–1.88 (m, 8 H, C4H8), 6.82 (d, J = 8.0 Hz, 1 H, ArH),
8.10 (dd, J = 2.4, 8.0 Hz, 1 H, ArH), 8.30 (s, 1 H, NH), 8.42
(d, J = 2.4 Hz, 1 H, ArH), 8.56 (s, 1 H, NH). 13C NMR
(DMSO-d6): d = 21.90 (2 × C), 40.15 (2 × C), 77.32, 112.31,
114.14, 124.11, 128.62, 136.68, 151.63, 161.21. MS (ESI):
m/z (%) = 248.2 (100) [M + H]+. Anal. Calcd for
C12H13N3O3: C, 58.29; H, 5.30; N, 16.99. Found: C, 58.33;
H, 5.31; N, 17.08.
Selected data for compounds 2, 4 and 8:
(12) (a) Su, W. K.; Yang, B. B. J. Chem. Res. 2002, 604.
(b) Cai, G. P.; Xu, X. L.; Li, Z. F.; Weber, W. P.; Lu, P. J.
Heterocycl. Chem. 2002, 39, 1271. (c) Yoo, C. L.; Fettinger,
J. C.; Kurth, M. J. J. Org. Chem. 2005, 70, 6941.
(13) CCDC 660416 (4a) and CCDC 667600(4b) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://
14-(3-Nitrophenyl)-9,10,11,12-tetrahydro-14H-
naphtho[1¢,2¢:5,6]pyrano[2,3-b]quinolin-13-amine (2a):
yellow solid; mp 287–289 °C. IR (KBr): 3450, 3364, 2935,
1640, 1607, 1573, 1523, 1445, 1348, 1232 cm–1. 1H NMR:
(400 MHz, CDCl3): d = 1.80–1.86 (m, 4 H, CH2), 2.28–2.42
(m, 2 H, CH2), 2.82 (m, 2 H, CH2), 4.42 (s, 2 H, NH2), 5.76
(s, 1 H, CH), 7.34–7.40 (q, J = 8.0 Hz, 2 H, ArH), 7.46–7.51
(m, J = 8.0 Hz, 2 H, ArH), 7.72 (d, J = 7.9 Hz, 1 H, ArH),
7.79 (t, J = 7.9 Hz, 2 H, ArH), 7.98 (m, J = 2.0, 8.0 Hz, 2 H,
ArH), 8.38 (t, J = 2.0 Hz, 1 H, ArH). 13C NMR (100 MHz,
CDCl3): d = 22.3, 22.4, 22.9, 32.4, 37.9, 99.3, 113.2, 114.9,
118.5, 121.8, 122.1 (2 × C), 124.3, 127.1, 128.9, 129.8,
129.9, 130.5, 130.8, 134.3, 145.6, 148.0, 149.0, 150.3,
154.5, 154.8. MS (ESI): m/z = 424.3 [M + H+]. Anal. Calcd
for C26H21N3O3: C, 73.74; H, 5.00; N, 9.92. Found: C, 73.60;
H, 5.05; N, 9.75.
www.ccdc.cam.ac.uk/data_request/cif.
(14) (a) Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1877, 10,
1899. (b) Siskos, A. P.; Hill, A. M. Tetrahedron Lett. 2003,
44, 789.
(15) Rozhkov, V. Y.; Batog, L. V.; Shevtsova, E. K.; Struchkova,
M. I. Mendeleev Commun. 2004, 76.
(16) This new conversion is abbreviated as PDF conversion,
which means a new conversion from Pinner to Dimroth
rearrangement in the Friedländer reaction.
8,9,12-Trihydro-9,9-pentamethylene-12-(3-nitrophenyl)-
Synlett 2008, No. 2, 233–236 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.