Improved Syntheses of 3,5-Diaryl-Substituted Phenols

Full text of DOI:10.1021/jo9711403

J . Org. Chem. 1997, 62, 8215-8217
8215
Notes
NaOH in refluxing ethanol afforded 3,5-diaryl-substitut-
ed phenols 6a -g in 52-94% yield (Scheme 1). Acetone
derivative 2 was readily prepared in 59% yield by
reacting bromoacetone with benzotriazole in the presence
of triethylamine in hot (65-70 °C) toluene. Significantly,
we prepared the 3-(ortho-substituted-aryl)phenol 6g in
52% yield. This type of ortho-substituted 3,5-diarylphe-
nol was previously unknown and specifically could not
be prepared by the method of Eichinger et al.3 Our
method thus allows access to a wider variety of phenols.
Constants and NMR characteristics of phenols 6a -g are
shown in Tables 1 and 2.
Im p r oved Syn th eses of
3,5-Dia r yl-Su bstitu ted P h en ols
Alan R. Katritzky,* Sergei A. Belyakov, and
Scott A. Henderson
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Peter J . Steel
Department of Chemistry, University of Canterbury,
Christchurch, New Zealand
Received J une 23, 1997
In tr od u ction
Our suggested reaction mechanism for the formation
of 6a -g involves intermediate Michael adducts 3a -g
which undergo aldol-like condensation and dehydration
to give the corresponding cyclohexenones 4a -g. Loss of
benzotriazole under the action of excess base leads to
cyclohexadienones 5a -g, which readily rearrange into
3,5-diarylphenols 6a -g.
Although much less familiar than their alkyl-substi-
tuted analogues, aryl-substituted phenols have recently
shown interesting potential for the preparation of “mo-
lecular harpoons”.1 Previous procedures for the synthe-
ses of arylated phenols2,3 are mostly of academic interest
rather than solid preparative methods. Synthetic routes
based on assembling the phenol backbone from “aliphatic
building blocks” seem to be of most promise, generally
involving intermediate aryl-substituted cyclohex-2-enones
or 6-(ethoxycarbonyl)cyclohex-2-enones from the reaction
of chalcones with carbonyl compounds carrying CH2C(O)
or CH2C(O)CH2 fragments.2 Aromatization of aryl-
substituted cyclohexenones into phenols often requires
strong conditions (treatment with Pd/C in refluxing
diphenyl ether,4 or refluxing cymene,5 etc.). Even milder
aromatization methods, e.g., oxidation by bromine,6,7 did
not guarantee improved yields or better isolation proce-
dures. Tandem Michael addition/aldol condensation of
1-(2-oxopropyl)pyridinium chloride with chalcones forms
cyclohexenones, which aromatize by the elimination of
pyridinium chloride to give 3,5-diaryl-substituted phe-
nols.3,8 With the exception of 3-(4-nitrophenyl)-5-phe-
nylphenol (82%), yields of 3,5-diarylphenols were poor to
moderate (34-62%) via this method.
Neither phase-transfer conditions nor milder base
(piperidine), in the reaction of chalcones 1b and 1e with
benzotriazolylacetone 2, afforded the expected phenols:
instead the reaction stopped at the stage of the cyclo-
hexenones 4b and 4e, respectively (Scheme 2), which
1
were isolated by column chromatography. The H NMR
spectra of ketones 4b and 4e each show the expected
signals: an upfield doublet for two C(4) protons, a doublet
of triplets for the proton of the C(5) atom, and a wide (J
) 13-14 Hz) doublet at ca. 5.9-6.5 ppm corresponding
to the C(6) proton adjacent to the benzotriazole moiety.
The signals typical for the benzotriazole aromatic protons
were also present. The benzotriazole moiety is present
as the benzotriazol-1-yl isomer in compound 4b, whereas
it appears as the benzotriazol-2-yl isomer in compound
4e, as follows from their NMR spectra. The 13C and APT
NMR spectra also confirmed the suggested structure of
ketones 4b and 4e: they contain three upfield signals
(higher than 70 ppm), one secondary and two tertiary
for C(4), C(5), and C(6), respectively.
Our recent successful preparations of pyridine deriva-
tives from 2-(benzotriazol-1-yl)acetamide and 2-(benzo-
triazol-1-yl)acetonitrile demonstrated the efficiency of
benzotriazole as an uncharged leaving species leading to
easier heteroaromatization of the intermediates.9 We
have now utilized this property to develop a simple and
efficient preparation of 3,5-diaryl-substituted phenols.
Treatment of cyclohexenones 4b and 4e with NaOH
in refluxing ethanol led to the loss of benzotriazole and
formation of the corresponding phenols 6b and 6e in high
yields (Scheme 2). The melting points and GC/MS data
of the phenols prepared in this way were consistent with
those of 6b and 6e obtained according to Scheme 1. This
result supports the proposed reaction mechanism and
also demonstrates that the loss of benzotriazole moiety
occurs under the action of a strong base.
Resu lts a n d Discu ssion
Reactions of 1-(benzotriazol-1-yl)propan-2-one (2) with
1,3-diarylprop-2-enones 1a -g in the presence of excess
The structure of 4b was confirmed by X-ray crystal-
lography. As shown in Figure 1, this compound crystal-
lizes with the cyclohexenone ring disordered over two,
approximately equally populated, half-chair conforma-
tions. This disorder also results in some high thermal
displacement parameters for certain atoms. The crystal-
lographic analysis also determines the relative stereo-
chemistry of the substituents, with the C-5 and C-6 aryl
groups being trans. Whereas the p-tolyl and benzotria-
zolyl ring are approximately orthogonal to the cyclohex-
enone plane (angles between mean planes being 72.5(3)
and 92.4(3), respectively), the conjugated p-anisyl ring
is more coplanar with the cyclohexenone ring (angle
(1) Naka, K.; Sadownik, A.; Regen, S. L. J . Am. Chem. Soc. 1993,
115, 2278.
(2) Dimroth, K. In Topics in Current Chemistry, 129: Photochemistry
and Organic Synthesis; Boschke, F. L., Ed.; Springer-Verlag: Berlin-
Heidelberg, 1985; p 99.
(3) Eichinger, K.; Nussbaumer, P.; Balkan, S.; Schulz, G. Synthesis
1987, 1061.
(4) Downes, A. M.; Gill, N. S.; Lions, F. J . Am. Chem. Soc. 1950,
72, 3464.
(5) Zimmerman, H. E.; Schuster, D. I. J . Am. Chem. Soc. 1962, 84,
4527.
(6) Sexsmith, D. R.; Rassweiler, J . H. J . Org. Chem. 1960, 25, 1229.
(7) Yates, P.; Hyre, J . E. J . Org. Chem. 1962, 27, 4101.
(8) The analogous use of onium salts in the formation of cyclohex-
enone skeleton was earlier employed by Zimmerman and Schuster.5
(9) Katritzky, A. R.; Belyakov, S. A.; Sorochinsky, A. E.; Henderson,
S. A.; Chen, J . J . Org. Chem. 1997, 62, 6210.
S0022-3263(97)01140-7 CCC: $14.00 © 1997 American Chemical Society

8216 J . Org. Chem., Vol. 62, No. 23, 1997
Notes
Sch em e 1
Exp er im en ta l Section
Gen er a l. See refs 10 and 11. 1,3-Diarylprop-2-enones 1b,f,g
were prepared according to general literature procedure,12 and
1a ,c-e were commercially available. 1H NMR spectra of
phenols 6a -c,e-g and of cyclohexenone 4b were recorded in
CDCl3, and compounds 6d and 4e in the mixture CDCl3:DMSO-
d6 (3:1 v/v), at 300 MHz. 13C NMR spectra were recorded at 75
MHz in the same solvents.
1-(Ben zotr ia zol-1-yl)p r op a n -2-on e (2). A solution of ben-
zotriazole (5.43 g, 46 mmol), bromoacetone (6.25 g, 46 mmol),
and triethylamine (7.0 mL, 50 mmol) in toluene (100 mL) was
stirred at 65-70 °C for 1 h. The precipitate was filtered, washed
with toluene, dispersed in water (100 mL), stirred for 5 min,
and filtered. The crude product was suspended in 10% NaOH
solution, stirred for 5 min, filtered, washed with water, and air-
dried to give ketone 2 (4.27 g, 53%). The analytical sample was
prepared by recrystallization from toluene. Plates, mp 56-57
°C; 1H NMR δ 2.21 (s, 3H), 5.44 (s, 2H), 7.40-7.45 (m, 2H), 7.48-
7.50 (m, 1H), 8.07 (d, J ) 8.8 Hz, 1H); 13C NMR δ 27.0, 56.7,
109.0, 120.1, 124.1, 127.9, 133.3, 145.9, 199.8. Anal. Calcd for
C9H9N3O: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.51; H, 5.23;
N, 23.95.
3-(4-Meth oxyph en yl)-5-(4-m eth ylph en yl)-6-(ben zotr iazol-
1-yl)cycloh ex-2-en on e (4b). To a mixture of chalcone 1b (0.38
g, 1.5 mmol), ketone 2 (0.26 g, 1.5 mmol), CH2Cl2 (20 mL), and
water (5 mL) was added a solution of tetrabutylammonium
chloride (0.03 g, 0.15 mmol) in 50% NaOH (0.48 g, 6.0 mmol),
and the resulting mixture was vigorously stirred at reflux for 8
h. The reaction mixture was diluted with CH2Cl2 (30 mL) and
washed with water (50 mL), and the organic layer was sepa-
rated, dried over anhyd Na2SO4, and evaporated. The resulting
crude product was recrystallized from MeOH/dioxane to give 4b
(0.52 g, 84%) as yellowish crystals. The analytical sample was
obtained after column chromatography of the recrystallized
product (silica gel, eluent CHCl3). Needles, mp 263-264 °C; 1H
NMR δ 2.18 (s, 3H), 3.35 (d, J ) 8.0 Hz, 2 H), 3.87 (s, 3H), 4.34
(dt, J 1 ) 8.1 Hz, J 2 ) 15.9 Hz, 1H), 5.92 (d, J ) 13.4 Hz, 1H),
6.72 (s, 1H), 6.94 (d, J ) 7.8 Hz, 2H), 6.96 (d, J ) 8.9 Hz, 2H),
7.07 (d, J ) 8.0 Hz, 2H), 7.25-7.32 (m, 1H), 7.37-7.43 (m, 2H),
7.61 (d, J ) 8.8 Hz, 2H), 7.96 (d, J ) 8.5 Hz, 1H);13C NMR δ
20.9, 36.8, 45.9, 55.4, 67.6, 109.6, 114.4, 120.1, 121.8, 123.5,
126.9, 127.2, 128.0, 129.2, 129.4, 133.2, 135.7, 137.4, 145.8, 158.5,
161.9, 191.1. Anal. Calcd for C26H23N3O2: C, 76.26; H, 5.66;
N, 10.26. Found: C, 76.41; H, 5.69; N, 10.32.
Cr ysta l Da ta of th e Cycloh exen on e 4b. Solu tion a n d
Refin em en t: C26H23N3O2, Mr ) 409.5, monoclinic, space group
P21/n, a ) 6.391(3), b ) 13.103(3), c ) 26.253(6) Å, â ) 96.84(2)°,
V ) 2183(1) Å,3 T ) -120 °C, F(000) ) 864, Z ) 4, Dc ) 1.25
g‚cm-3, µ(Mo KR) ) 0.80 cm-1. Data were collected using the
ω-2θ scan technique with a Nicolet P4 four-circle diffractometer
to a 2θmax of 50°. The structure was solved by direct methods
and refined on F2 by full-matrix least-squares procedures. Non-
hydrogen atoms were made anisotropic and hydrogen atoms
were included in calculated positions. In the final least-squares
cycles 302 parameters were adjusted; the final R index was 0.049
for data with I > 2σ(I) and wR 0.115 for all 3845 data.13
3,5-Bis(4-ch lor op h en yl)-6-(ben zotr ia zol-2-yl)cycloh ex-2-
en on e (4e). A mixture of chalcone 1e (0.41 g, 1.5 mmol), ketone
2 (0.26 g, 1.5 mmol), and piperidine (10 drops) in EtOH (30 mL)
was refluxed with stirring for 8 h. On cooling, the mixture was
acidified with HCl (10%, 10 mL) and diluted with CH2Cl2 (50
mL). The organic layer was separated, washed with water (30
mL), and dried over anhyd Na2SO4, and the solvent was
evaporated. The resulting solid was purified by column chro-
matography (silica gel, eluent CHCl3). After evaporation of the
solvent from the fractions with Rf 0.19-0.21 (silica gel TLC
plates, eluent - CHCl3) the product was triturated with MeOH
and filtered to give 4e (0.254 g, 39%) as white plates, mp 273-
274 °C; 1H NMR δ 3.24-3.34 (m, 2H), 4.51 (ddd, J 1 ) 6.0 Hz, J 2
) 13.5 Hz, 1H), 6.02 (d, J ) 13.5 Hz, 1H), 6.68 (s, 1H), 7.15 (d,
Ta ble 1. P r ep a r a tion of 3,5-Dia r yl-su bstitu ted P h en ols 6
phenol yield
mp
(°C)
lit mp
(°C)
solvent for
recrystallization
molecular
formula
6
(%)
a
b
c
d
75 93-94
72 77-79
93-94a
hexanes
-
exanes
MeOH
C18H14
C20H18O2
C18H13ClO
C18H13NO3
O
b
-
91 115-116 110-112c
d
76 168-169
(dec)
94 154-155 156-157c
-
e
hexanes/
pet. ether
hexanes
C18H12Cl2O
e
f
g
82 83-85
52 oil
-
C22H15NO3
C18H12Cl2Of
a
b
Literature mp, ref 6. MS found: 290.1264 [M+]; calcd:
290.1307 [M+]. c Literature mp, ref 3. Anal. Calcd N, 4.81;
Found: N, 5.13. e Anal. Calcd N, 4.10; Found: N, 4.08. f MS found:
314.0253 [M+]; calcd: 314.0265 [M+].
d
between mean planes ) 29.6(3)). There are no unusually
short intermolecular interactions, with the crystal pack-
ing being controlled by stacking interactions between aryl
rings of adjacent molecules.
In summary, we found that [3 + 3] annulation reaction
of 1-(benzotriazol-1-yl)propan-2-one (2) with 1,3-diaryl-
prop-2-enones 1a -g under basic conditions leads to
benzotriazole-substituted cyclohex-2-enones 4 by means
of tandem Michael reaction/intramolecular aldol-type
condensation. Intermediates 4 under the action of strong
base rapidly lose benzotriazole in situ, thus promoting
formation of cyclohexadienones 5 which easily rearrange
into phenols 6. This reaction sequence was successfully
used for the preparation of a series of 3,5-diaryl-
substituted phenols in high yields and is suggested as a
new and effective synthetic route to this class of substi-
tuted phenols. Compared to a previous method,3 our
methodology gives access to the 3-(ortho-substituted-
aryl)phenols of type 6g, which could not be prepared by
the previous procedure.
(10) Katritzky, A. R.; Li, J . J . Org. Chem. 1996, 61, 1624.
(11) Katritzky, A. R.; Wu, H.; Xie, L. J . Org. Chem. 1996, 61, 4035.
(12) Szmant, H. H.; Basso, A. J . J . Am. Chem. Soc. 1952, 74, 4397.
(13) The authors have deposited atomic coordinates for this struc-
ture with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.

Notes
J . Org. Chem., Vol. 62, No. 23, 1997 8217
Ta ble 2. NMR Da ta of 3,5-Dia r yl-Su bstitu ted P h en ols 6
phenol
6
1H NMR δ (ppm),
J (Hz)
13C NMR
δ (ppm)
a
b
5.68 (br s, 1H), 7.06 (s, 2H), 7.33-7.47 (m, 7H), 7.61 (d, J ) 7.5, 4H)
2.32 (s, 3H), 3.74 (s, 3H), 5.30 (br s, 1H), 6.86 (d, J ) 8.5, 2H), 7.00 (s,
1H), 7.01 (s, 1H), 7.13 (d, J ) 7.9, 2H), 7.28 (s, 1H), 7.40-7.46 (m, 4H)
6.55 (br s, 1H), 7.01 (s, 1H), 7.08 (s, 1H), 7.25-7.48 (m, 8H), 7.51
(d, J ) 6.9, 2H)
7.12 (s, 1H), 7.17 (s, 1H), 7.32 (s, 1H), 7.34 (t, J ) 7.2, 1H), 7.46 (t, J )
7.1, 2H), 7.63 (d, J ) 7.4, 2H), 7.81 (d, J ) 8.8, 2H), 8.28
(d, J ) 8.8, 2H), 9.45 (br s, 1H)
6.60 (br s, 1H), 6.96 (s, 2H), 7.15 (s, 1H), 7.25 (d, J ) 8.5, 4H), 7.32
(d, J ) 8.5, 4H)
5.60 (br s, 1H), 7.03 (s, 1H), 7.18 (s, 1H),7.25 (s, 1H), 7.42-7.60 (m, 5H),
7.93 (d, J ) 7.7, 2H), 7.87 (d, J ) 9.6, 2H), 8.17 (d, J ) 8.0, 1H),
8.47 (s, 1H)
113.1, 118.9, 127.2, 127.6, 128.8, 140.7, 143.4, 156.2
21.0, 55.2, 112.5, 112.6, 114.1, 117.8, 126.9, 128.1, 129.4,
133.4, 137.1, 138.0, 142.7, 143.0, 156.6, 159.1
113.0, 113.5, 118.3, 127.1, 127.5,128.3, 128.7, 128.8, 133.5,
139.1, 140.6, 141.9, 143.4, 156.6
c
d
112.7, 114.0, 123.1, 126.2, 126.8,127.0, 128.0, 139.5, 139.8,
142.4,146.2, 146.8, 157.7
e
f
113.4, 118.1, 128.2, 128.8, 133.7, 138.8, 142.1, 156.6
113.0, 117.3, 121.5, 122.0, 122.3, 125.3, 125.7, 125.9, 126.3,
126.8, 128.1, 128.4, 129.7, 131.4, 133.1, 133.8, 139.1,
140.2, 142.3, 143.3, 148.7, 156.1
g
5.62 (br s, 1H), 6.87 (s, 1H), 7.10 (s, 1H), 7.18 (s, 1H), 7.24-7.32 (m, 2H),
7.36 (d, J ) 7.1, 1H) 7.39-7.47 (m, 2H), 7.49 (s, 1H), 7.58 (d, J ) 7.8, 2H)
113.7, 115.3, 120.9, 127.2, 127.7, 128.8, 129.8, 132.0, 133.2,
133.9, 138.7, 140.1, 140.4, 142.9, 155.8
Anal. Calcd for C24H17Cl2N3O: C, 66.37; H, 3.95. Found: C,
66.00; H, 3.75.
Sch em e 2
Gen er a l P r oced u r e for th e P r ep a r a tion of 3,5-Disu b-
stitu ted P h en ols 6a -g. To a solution of NaOH (0.22 g, 5.44
mmol) in EtOH (10 mL) were added 1,3-diarylprop-2-enone
1a -g (1.36 mmol) and ketone 2 (0.24 g, 1.36 mmol) at rt, and
the mixture was refluxed for 1 h. The yellow-brownish solution
was acidified (HCl concentrated) to pH 3-4, and water (30 mL)
and CH2Cl2 (50 mL) were added. The organic layer was
separated, washed with Na2CO3 (10% solution, 20 mL) and water
(2 × 30 mL), separated, and dried over anhyd Na2SO4. After
evaporation of the solvent, the crude product obtained was
purified by column chromatography (silica gel; eluent - CHCl3).
The appropriate fraction was collected, and the solvent was
removed in vacuo to give the desired phenol 6a -g. The yields
and characteristics of the phenols are given in Tables 1 and 2.
Gen er a l P r oced u r e for th e P r ep a r a tion of P h en ols 6b,e
fr om Cycloh exen on es 4b,e. A mixture of cyclohexenone 4b
or 4e (0.60 mmol) and NaOH (47 mg, 1.20 mmol) in EtOH (15
mL) was refluxed for 15 min (4b) or 1 h (4e). On cooling, the
mixture was poured into water (50 mL) and stirred for 10 min,
and the precipitate was filtered, washed with water (3 × 10 mL)
and ligroine (3 × 20 mL), and air-dried to give 6b and 6e,
respectively.
3-(4-Meth oxyp h en yl)-5-(4-m eth ylp h en yl)p h en ol (6b): Mi-
crocrystals, mp 80-82 °C (the sample prepared directly from
1b and 2 by the general procedure above had mp 77-79 °C,
Table 1). GC/MS data of the samples prepared by both methods
were identical.
3,5-Bis(4-ch lor oph en yl)ph en ol (6e): Microcrystals, mp 160-
161 °C (the sample prepared directly from 1e and 2 by the
general procedure above had mp 156-157 °C, Table 1). GC/
MS data of the samples prepared by both methods were
identical.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and HRMS spectra for compounds 6b and 6g and X-ray data
for compound 4b (11 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
F igu r e 1. Perspective view of the X-ray crystal structure of
4b.
J ) 8.4 Hz, 2H), 7.28 (d, J ) 8.3 Hz, 2H), 7.31-7.34 (m, 2H),
7.44 (d, J ) 8.5 Hz, 2H), 7.57 (d, J ) 8.6 Hz, 2H), 7.75-7.80 (m,
2H); 13C NMR δ 36.3, 45.7, 73.5, 117.9, 123.4, 126.2, 127.4, 128.4,
128.6, 129.0, 133.0, 135.2, 136.8, 137.0, 143.9, 157.4, 190.7.
J O9711403