Novel synthesis of α-arylnaphthalenes from diphenylacetaldehydes and 1,1-diphenylacetones

Article abstract of DOI:10.1016/j.tetlet.2006.03.054

A two-step synthesis of 1-amino-4-arylnaphthalene-2-carbonitriles from diphenylacetaldehydes and 1,1-diphenylacetones involves condensation of the carbonyl compounds with malonodinitrile and cyclization of the aryl-ylidenemalonodinitriles obtained in conc

Full text of DOI:10.1016/j.tetlet.2006.03.054

Tetrahedron Letters 47 (2006) 3435–3438
Novel synthesis of a-arylnaphthalenes from
diphenylacetaldehydes and 1,1-diphenylacetones
*
´
Bartłomiej Kozik, Jarosław Wilamowski, Maciej Gora and Janusz J. Sepioł
Department of Organic Chemistry, Jagiellonian University, Ingardena 3, PL-30-060 Krako´w, Poland
Received 12 February 2006; revised 3 March 2006; accepted 9 March 2006
Available online 30 March 2006
Abstract—A two-step synthesis of 1-amino-4-arylnaphthalene-2-carbonitriles from diphenylacetaldehydes and 1,1-diphenylacetones
involves condensation of the carbonyl compounds with malonodinitrile and cyclization of the aryl-ylidenemalonodinitriles obtained
in concentrated sulfuric acid. The benzannulation reaction is accompanied with a quasi-aromatic rearrangement. Some of synthe-
sized aminonitriles reveal considerable biological activity against phytopathogenic fungi.
Ó 2006 Elsevier Ltd. All rights reserved.
R2
1-Arylnaphthalenes have attracted considerable atten-
tion due to their physical and chemical properties. As
an important class of biaryls, arylnaphthalenes consti-
tute building blocks in a variety of natural products
and biologically active compounds.1 They are also use-
ful for the synthesis of advanced materials such us con-
ducting polymers,2 chiral ligands3 and liquid crystals.4
Arylnaphthalenes also have the ability to form atropo-
isomers, especially in such cases where two naphthyl
moieties of a chiral compound are connected at their a
positions.5 By far the most efficient methods for the
preparation of arylnaphthalenes are based on various
cross-coupling reactions such as Ullmann, Stille, Suzuki
or Grignard reagents.1,6 Other approaches for the syn-
thesis of arylnaphthalenes include benzannulation reac-
tions.7 In the present letter we report an efficient
synthesis of 1-amino-4-phenyl(aryl)naphthalene-2-car-
bonitriles of the general formula 2 or 3 either from
2,2-diphenylethanals or from 1,1-diphenylpropan-2-
ones (Scheme 1).
B
R1
R
path "a"
R1
A
path "a"
R
CN
A
NH2
A
2
R2
H+
R1
B
NC
path "b"
CN
1
R2
R
path "b"
B
R, R1, R2 = H, CH3
CN
NH2
3
Scheme 1.
alkanones, 2-cycloalkylidenecycloalkanones and other
unsaturated ketones.8 Under strongly acidic conditions,
via a series of protonation–deprotonation processes, the
dinitriles obtained from these carbonyl compounds are
transformed into six-carbon unsaturated cyclic imi-
nes.8c,f In the final stage, the imines unobtrusively tauto-
merize to the aromatic, vicinal aminonitriles. The newly
formed benzene ring possesses a two-carbon unit
derived from the malonodinitrile moiety of the starting
ylidenemalonodinitrile, and is usually annulated to
another aromatic unit such as a benzene or naphthalene.
Unhindered tautomerization of the intermediate imino-
nitrile appears to be essential for the successful outcome
There is a variety of aldehydes and ketones, which on
condensation with malonodinitrile, afford ylidenemalono-
dinitriles having a structure suitable for cyclization to
isomeric, aromatic aminonitriles. These varieties include
1-arylalkan-2-ones, 1,3-diarylpropan-2-ones, 2-arylalka-
nals, 2-arylcycloalkanones, 2-(1-cycloalken-1-yl)cyclo-
Keywords: 1-Arylnaphthalenes; Aromatic aminonitriles; Rearrange-
ment; Cyclization; Fungistatic activity.
*
Corresponding author. Tel.: +48 6083 80373; fax: +48 1263 40515;
e-mail: sepiol@chemia.uj.edu.pl
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.054

3436
B. Kozik et al. / Tetrahedron Letters 47 (2006) 3435–3438
of the reaction. The transformation of the dinitriles 1
into aminonitriles 2 or 3 involves hybridization changes
of some carbon atoms of the assembled benzene ring.
Thus, the reported method could be of use in syntheses
of axially chiral a-arylnaphthalenes from appropriate
dinitriles having the general formula 1. Chirality
exchange from sp3 central chirality to axial chirality
has been of great interest in studies of asymmetric
reactions.9
Therefore, aldehyde 4b was condensed with malono-
dinitrile using the standard method (Table 1).13
Methyl-substituted aldehyde 4b was prepared by oxida-
tion of 4-methylstilbene with perbenzoic acid, followed
by rearrangement of the resulting oxirane using bis-
muth(III) perchlorate oxide hydrate (BiOClO4ÆxH2O)
as a catalyst.14 Similarly, pinacol rearrangement of
1,2-bis(4-methylphenyl)ethane-1,2-diol in glacial acetic
acid, catalyzed by sulfuric acid, gave dimethyl derivative
4c in good yield.15
The above mentioned criteria are met by 2,2-diphenyl-
ethanal (4a), its derivatives 4b and 4c, 1,1-diphenyl-
propan-2-one (4d) and also by the ketones 4e and 4f,
which are all precursors of 5a–f (Scheme 2 and Table
1). Surprisingly, a survey of chemical literature revealed
that with the exception of 5a, no report had been pub-
lished on the preparation of aryl-alkylidenemalonodi-
nitriles from 4b–f.10 Similarly, cyclization reactions of
alkylidenemalonodinitriles 1 to aromatic aminonitriles
of the type 2 or 3 appear to be unexplored to date.
The present studies might thus be useful for the exploi-
tation of compounds related to 1 in the syntheses of a
limited variety of carbocyclic, aromatic aminonitriles.
To investigate the scope of the synthesis of 1-amino-4-
arylnaphthalene-2-carbonitriles 6 we required different
1,1-diarylalkan-2-ones. Ketone 4e was obtained from
phenylacetone according to the published procedure.16
Preparation of diarylpropanone 4f was based on pinacol
rearrangement15 of 1,1-diarylpropane-1,2-diol.17 Con-
densation of ketones 4d–f with malonodinitrile gave
the dinitriles 5d–f in moderate yields (Table 1).13
Cyclization of 5a and 5d in concentrated sulfuric acid
occurred in a straightforward manner to give amino-
nitriles 6a and 6d, respectively, in high yields.18 The
pathways of ring closure of ylidenemalonodinitriles
5b–c and 5e–f in concentrated sulfuric acid were more
complex in comparison with the straightforward cycliza-
tion of dinitriles 5a and 5d. Our studies were also aimed
at establishing the preference of the attack of the pro-
tonated nitrile group on the substituted or unsubstituted
benzene ring—as outlined in Scheme 1. Cyclization of
5b and 5e might occur along path ‘a’ or path ‘b’ to give
vicinal aminonitriles of the general structure 2 or 3, with
the new aromatic ring being annulated to the benzene
system ‘A’ or ‘B’ (Scheme 1).
The reported condensation of aldehyde 4a with malono-
dinitrile had been catalyzed by potassium fluoride and
gave 5a in moderate yield, along with its isomer.10 In
a search for a better procedure for synthesizing 5a we
condensed 4a with malonodinitrile in boiling benzene
in the presence of NH4OAc/AcOH as a catalyst and
with continuous removal of water. Difficulties in isola-
tion of the dinitrile 5a from the reaction mixture
prompted us to design a more effective method. Thus,
condensation of 4a with malonodinitrile in anhydrous
ethanol with piperidine as a catalyst furnished 5a
in 78% yield.11,12a However, using the same method, di-
nitrile 5c was obtained in lower yield.12b
In our earlier communications we reported that some
aryl-alkylidenemalonodinitriles undergo cyclization in
strong acids via an unusual pathway.8l,m The pathway
appears to involve the ipso electrophilic attack of the
activated nitrile group and the formation of a spiro-
benzenium- or spiroarenium cation connected to a five-
carbon carbocyclic, unsaturated ring, arising from the
ylidenemalonodinitrile moiety. The crucial rearrange-
ment of the spiroarenium cation leads to stable, vicinal
aminonitriles. In the present investigations the dinitriles
5b, 5c, 5e and 5f had the structure suitable for the elec-
trophilic ipso attack of the nitrile group at the para posi-
tion with respect to the methyl group on the phenyl
substituent. All the above mentioned dinitriles under-
went cyclization and a rearrangement. The electrophilic
R2
R2
R2
ii
i
R
R
R1
R
O
R1
R1
NC
CN
CN
NH2
6
4
5
Scheme 2. Reagents and conditions: (i) CH2(CN)2, piperidine, EtOH,
5 min (4a,c) or CH2(CN)2, piperidine–AcOH/NH4OAc, C6H6, 5–17 h
(4b,d–f); (ii) concd H2SO4, ꢀ15 °C!ꢀ5 °C, 1 h.
Table 1. Synthesis of dinitriles 5, and cyclization of 5 to aminonitriles 6
Compound
R
R1
R2
4!5 (yield, %)
5a, mp (°C)
5!6 (yield, %)
6a, mp (°C)
4a–6a
4b–6b
4c–6c
4d–6d
4e–6e
4f–6f
H
H
H
CH3
CH3
CH3
H
H
H
CH3
H
H
78
41
36
27
45
45
110–11110
95–97b
110–112b
100–101b
oilb
90
79
60
90
71
77
116–117b
172–174b
182.5–183.5b
169–171c
117–119b
169.5–170b
CH3
CH3
H
CH3
CH3
CH3
oilb
a The structures of all compounds were in agreement with their IR and NMR spectra.
b The results of elemental analysis for new compounds were in agreement with the calculated values.
c The IR and 1H NMR data were in agreement with the values in Ref. 22. However, the mp of 6d is not given in this reference.

B. Kozik et al. / Tetrahedron Letters 47 (2006) 3435–3438
3437
Acknowledgement
The support of this research by the Jagiellonian Univer-
sity within project No. DS 74 is gratefully acknowledged.
H+
+
CN
NC
CN
HN
References and notes
5e
5e'
´
1. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359–1469.
1,2-alkyl
shift
H
2. (a) Yamamoto, T.; Maruyama, T.; Zhou, Z.; Ito, T.;
Fukada, T.; Yoneda, Y.; Begum, F.; Ikeda, T.; Sasaki, S.;
Takezoe, H.; Fukada, A.; Kubota, K. J. Am. Chem. Soc.
1994, 116, 4832–4845; (b) Papillon, J.; Schulz, E.; Gelinas,
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3. (a) Noyori, R. Chem. Soc. Rev. 1989, 18, 187–208; (b)
Narasaka, K. Synthesis 1991, 1–11.
4. (a) Piao, G.; Akagi, K.; Shirakawa, H.; Kyotani, M. Curr.
Appl. Phys. 2001, 1, 121–123; (b) Akagi, K.; Piao, G.;
Kaneko, S.; Higuchi, I.; Shirakawa, H.; Kyotani, M.
Synth. Met. 1999, 102, 1406–1409.
+
+
CN
CN
HN
5e''
NH
5e'''
4'
3'
2'
5'
6'
1'
5
8
4
3
6
7
2
-H+
CN
1
NH2
6e
5. (a) Cammidge, A. N.; Crepy, K. V. L. Tetrahedron 2004,
60, 4377–4386; (b) Hattori, T.; Takeda, A.; Yamabe, O.;
Miyano, S. Tetrahedron 2002, 58, 233–238, and references
cited therein.
Scheme 3.
6. Stanforth, S. P. Tetrahedron 1998, 54, 263–303.
7. (a) Lee, K. Y.; Kim, S. C.; Kim, J. N. Tetrahedron Lett.
2006, 47, 977–980; (b) Nishii, Y.; Yoshida, T.; Asano, H.;
Wakasugi, K.; Morita, J.-i.; Aso, Y.; Yoshida, E.;
Motoyoshiya, J.; Aoyama, H.; Tanabe, Y. J. Org. Chem.
2005, 70, 2667–2678, and references cited therein.
8. For leading review articles and publications on this
subject, see e.g.: (a) Taylor, E. C.; McKillop, A. In The
Advances in Organic Chemistry; Taylor, E. C., Ed.; The
Chemistry of Cyclic Enaminonitriles and o-Aminonitriles;
Interscience: New York, 1970; Vol. 5, pp 79–308; (b)
Bamfield, P.; Gordon, P. F. Chem. Soc. Rev. 1984, 13,
441–488; (c) Campaigne, E.; Schneller, S. W. Synthesis
1976, 705–716; (d) Fatiadi, A. J. Synthesis 1978, 165–204,
and 241–282; (e) Freeman, F. Chem. Rev. 1980, 80, 329–
350; (f) Campaigne, E.; Maulding, D. R.; Roelofs, W. L. J.
Org. Chem. 1964, 29, 1543–1549; (g) Sepiol, J.; Kawalek,
B.; Mirek, J. Synthesis 1977, 701–704; (h) Sepiol, J.;
Mirek, J.; Soulen, R. L. Pol. J. Chem. 1978, 52, 1389–
1394; (i) Sepioł, J. Synthesis 1983, 559–563; (j) Gorecki, T.;
Sepiol, J. J. Synlett 1994, 533–534; (k) Wilamowski, J.;
Osman, D.; Machaj, A.; Kawałek, B.; Sepioł, J. J. J.
Prakt. Chem. 1995, 337, 234–236; (l) Sepiol, J. J.;
Wilamowski, J. Tetrahedron Lett. 2001, 42, 5287–5289;
(m) Sepiol, J. J.; Gora, M.; Luczynski, M. K. Synlett 2001,
attack and cyclization at the methyl substituted benzene
ring in 5b and 5e predominated (Scheme 3). NMR stud-
ies allowed for unambiguous assignment of the struc-
tures of the aminonitriles.19 The position of the methyl
group at C-6 of naphthalene 6e was established through
2D NMR experiments. The mechanism of the quasi-aro-
matic rearrangement is presented in Scheme 3.
The electrophilic ipso attack of the active nitrile function
of 5e leads to the spirobenzenium cation 5e0. The alkyl
shift (5e00) gives 5e000, which after losing the proton tauto-
merizes to 6e. Recently published results of a similar
quasi-aromatic rearrangement seem to involve allylic-
type carbocations in the alkyl-shift stage.8l,m The
rearrangements discussed here appear to be the first
example of cyclization involving the benzylic-type carbo-
cation. The stability of this carbocation may have
contributed to the relatively high yield of 6e.
The synthetic approach presented in this letter involves
the synthesis of a-arylnaphthalenes through a one-stage
construction of the naphthalene system. This approach
might potentially be employed in the synthesis of some
chiral a-arylnaphthalenes equipped with versatile amino
and nitrile functions.
´
1383–1386; (n) Krasodomski, W.; Łuczynski, M. K.;
Wilamowski, J.; Sepioł, J. J. Tetrahedron 2003, 59, 5677–
5683.
9. Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am.
Chem. Soc. 2004, 126, 5358–5359.
Furthermore, according to our earlier studies, 1-amino-
naphthalene-2-carbonitriles possessing short alkyl
groups at the ‘4’ position are highly active against some
phytopathogenic fungi such as Fusarium culmorum,
Alternaria brassicicola, Botrytis cinerea and others.20
In connection with these studies, we presumed that
the aminonitriles having phenyl or aryl groups at the
‘4’ position might also exhibit fungicidal activity. Preli-
minary tests of aminonitriles 6a–f revealed their diverse
biological activity against some phytopathogenic
fungi. Aminonitrile 6a showed considerable fungistatic
activity.21
10. Zimerman, H. C.; Armesto, D.; Amezua, M.; Gannet, T.
J. Am. Chem. Soc. 1979, 101, 6367–6383.
11. Aldehyde 4a and ketone 4d are commercially available
from Fluka Chemie AG and Aldrich-Chemical Co Ltd,
respectively.
12. (a) Preparation of 3,3-diphenyl-1-propene-1,1-dicarbo-
nitrile (5a): a solution of diphenylacetaldehyde (4a)
(1.14 g, 5.8 mmol), malonodinitrile (0.38 g, 5.8 mmol),
piperidine (40 lL) and anhydrous ethanol (5 mL) were
heated to reflux for 5 min and then slowly cooled in an ice-
bath. The resulting colourless precipitated solid was
washed with a small amount of chilled ethanol. Dinitrile
4a was obtained as small white crystals; 1.11 g (78%); mp

3438
B. Kozik et al. / Tetrahedron Letters 47 (2006) 3435–3438
110–111 °C (Ref. 10; mp 107.5–113 °C); (b) dinitrile 5c
19. Spectroscopic data of 6e:1H NMR (CDCl3, 500 MHz) d
2.27 (s, 3H, C3–CH3), 2.35 (s, 3H, C6–CH3), 5.08 (br s,
2H, NH2), 7.07 (s, 1H, C5–H), 7.17–7.20 (m, 2H, C20–H,
C60–H), 7.28 (dd, J = 8.5 Hz and J = 1.6 Hz, 1H, C7–H),
7.41–7.45 (m, 1H, C40–H), 7.47–7.51 (m, 2H, C30–H, C50–
H), 7.70 (d, J = 8.5 Hz, 1H, C8–H); 13C NMR (CDCl3,
125 MHz) d 19.49 (C3–CH3), 21.89 (C6–CH3), 91.29 (C-
2), 118.40 (CN), 118.44, 120.85 (C-8), 126.48 (C-5), 127.19
(2C; C-7, C-40), 128.56 (2C; C-30, C-50), 128.93, 130.73
(2C; C-20, C-60), 132.53 (C-3), 135.49, 138.90, 139.10,
147.87 (C-1); IR (KBr) 3457, 3372, 3254 (NH2), 3054,
3023, 2920, 2851, 2199 (CN), 1652 (NH2), 1623, 1574,
1506, 1440, 1369, 1257, 1159, 1071, 815, 776, 722,
695 cmꢀ1. Anal. Calcd for C19H16N2: C, 83.79; H, 5.92;
N, 10.29%. Found: C, 83.85; H, 5.97; N, 10.18. The
HMBC spectrum of 6e revealed correlation through three
bonds between C-1 (d 147.87 ppm) and the proton bonded
to the C-8 carbon atom (Scheme 3). The resonance of this
proton appeared at d 7.70 as a doublet with a coupling
constant of 8.5 Hz. This doublet arose through coupling
(J = 8.5 Hz) with the neighbouring proton connected to
C-7 (d 7.28 ppm). This proton was also coupled over four
bonds to the proton at C-5 (J = 1.6 Hz). The signal of the
proton at C-5 appeared as a broad singlet at d 7.07 and
had an unclear multiplet structure. All acquired data
indicate the location of the methyl group at the ‘6’ position
of 6e.
was synthesized in the same manner as 5a, and was
isolated by column chromatography (SiO2/CCl4) followed
by recrystallization from petroleum ether (bp 60–90 °C).
13. General procedure for the preparation of diarylalkylide-
nemalonodinitriles 5b,d-f: a solution of the carbonyl
compound 4b,d–f (14 mmol), malonodinitrile (1.0 g,
15 mmol), glacial acetic acid (0.7 g, 12 mmol), ammonium
acetate (0.5 g, 6.5 mmol), piperidine (0.4 g, 5 mmol) and
benzene (30 mL) were heated for 10–17 h (4b: 5 h) with
continuous water separation. The reaction mixture was
washed with water, dried over anhydrous magnesium
sulfate and the solvent was evaporated. The crude
products were purified by vacuum distillation (5e: 141–
144 °C/1 mmHg) or by column chromatography (5b:
SiO2/CCl4; 5d: SiO2/toluene; 5f: flash chromatography
SiO2/toluene and then SiO2/petroleum ether (bp 60–
90 °C)–ethyl acetate, 25:1).
14. Anderson, A. M.; Blazek, J. M.; Garg, P.; Payne, B. J.;
Mohan, R. S. Tetrahedron Lett. 2000, 41, 1527–1530.
15. Amedio, J. C., Jr.; Bernard, P. J.; Fountain, M.; Van
Wagenen, G., Jr. Synth. Commun. 1998, 28, 3895–3906.
16. Cragoe, E. J., Jr.; Pietruszkiewicz, A. M.; Robb, C. M. J.
Org. Chem. 1958, 23, 971–980.
17. (a) Stoermer, R. Ber. Dtsch. Chem. Ges. 1906, 39, 2288–
2306; (b) Hatch, M. J.; Cram, D. J. J. Am. Chem. Soc.
1953, 75, 38–44.
18. General procedure for the preparation of aminonitriles
6a–f: the ylidenemalonodinitriles 5a–f (150 mg) were
dissolved in chilled concentrated sulfuric acid (5 mL).
After stirring at ꢀ5 to ꢀ15 °C (ice + NaCl bath) for 1 h,
the resulting brown solution was poured onto crushed ice.
The obtained suspension was neutralized with aq NaOH,
extracted with chloroform, dried over anhydrous magne-
sium sulfate and the solvent was removed under reduced
pressure. Crude aminonitriles were purified by column
chromatography (6c,e,f: SiO2/toluene) or by vacuum
sublimation (6a,b,d). An analytical sample of 1-amino-
3,6-dimethyl-4-phenylnaphthalene-2-carbonitrile (6e) was
obtained as small beige crystals through recrystallization
from cyclohexane.
20. Wilamowski, J.; Kulig, E.; Sepiol, J. J.; Burgiel, Z. J. Pest
Manage. Sci. 2001, 57, 625–632.
21. A comparison of the fungistatic activity of 1-amino-4-
phenylnaphthalene-2-carbonitrile (6a) and a commercial
fungicide—captan (data in brackets) against four phyto-
pathogenic fungi: Fusarium culmorum: 93 (743); Alternaria
brassicicola 30 (11); Botrytis cinerea 11 (18); Penicillium
expansum 20 (45). The data were recorded for the EC50 level
of activity and are expressed as mg/dm3 concentrations.
22. (a) Kobayashi, K.; Uneda, T.; Takada, K.; Tanaka, H.;
Kitamura, T.; Morikawa, O.; Konishi, H. Chem. Lett.
1996, 25–26; (b) Kobayashi, K.; Uneda, T.; Takada, K.;
Tanaka, H.; Kitamura, T.; Morikawa, O.; Konishi, H.
J. Org. Chem. 1997, 62, 664–668.