An easy access to unsymmetric trisubstituted methane derivatives (TRSMs)

Article abstract of DOI:10.1016/j.tetlet.2005.03.001

A new series of unsymmetric trisubstituted methane derivatives (TRSMs) has been synthesized through Friedel-Crafts alkylation of aromatic nucleophiles using acid-sensitive heteroaryl carbinols.

Full text of DOI:10.1016/j.tetlet.2005.03.001

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3097–3102
An easy access to unsymmetric trisubstituted methane
derivatives (TRSMs)q
Sajal Kumar Das, Shagufta and Gautam Panda*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226001, UP, India
Received 19 November 2004; revised 22 February 2005; accepted 1 March 2005
Available online 16 March 2005
Abstract—A new series of unsymmetric trisubstituted methane derivatives (TRSMs) has been synthesized through Friedel–Crafts
alkylation of aromatic nucleophiles using acid-sensitive heteroaryl carbinols.
Ó 2005 Elsevier Ltd. All rights reserved.
Trisubstituted methane derivatives (TRSMs) represent
an important class of biologically active molecules.
to block various functional moieties. These applications
are well documented and have been the subject of a
number of reviews.11
Substituted triarylmethanes (TRAMs),
a class of
TRSMs is of considerable interest as dyes, photochromic
agents and materials for theoretical studies.1 Examples
of TRSMs include the potent and selective non-steroidal
aromatase inhibitors2 (NSAIs) letrozole3 1 (Ciba Geigy)
and vorozole4 2 (Janssen). Recently, the antiproliferative
activity of the nonimidazole part of clotrimazole
analogues such as 3 was also reported,5 Figure 1.
Recently, we reported a new series of substituted triar-
ylmethane derivatives (TRAMs) having antitubercular
activity.12 In continuation of our earlier work, we
became interested in synthesizing some hetero-
aryldiarylmethane derivatives where one of the aryl
rings is replaced by a heterocycle. Two well-established
methods are known for the synthesis of TRAMs.13
One is the Bayer condensation in which an aromatic
or heterocyclic aldehyde is condensed with another aro-
matic or heterocyclic ring. A second method involved
Friedel–Crafts alkylation of aromatic compounds using
diaryl carbinols as alkylating agents. Surprisingly, to the
best of our knowledge, the synthesis of unsymmetric tri-
arylmethanes is less developed. One method involves
displacement of a benzotriazole moiety in (benzo-
triazol-1-yl)-diarylmethanes either by an electron rich
arene or by [4-(N,N-dimethylamino)phenyl]magnesium
bromide.1 Furthermore, the synthesis of hetero-
aryldiarylmethanes is not well established using acid cat-
alyzed Friedel–Crafts alkylation chemistry. This could
be due to the fact that the heterocyclic ring of heteroaryl
carbinols, especially acid sensitive rings, for example,
furan and pyridine, are easily attacked by the protic or
Lewis acid catalysts used in Friedel–Crafts alkylation
reactions. Isomerization of 2-furylcarbinols to cyclopen-
tenones in the presence of acids has also been de-
scribed.14 Another disadvantage is that the synthesis of
unsymmetric heteroaryldiarylmethanes is not possible
using the Bayer condensation as it leads to symmetric
heteroaryldiaryl or aryldiheteroarylmethanes. Thus, we
TRAMs have also served as suitable building blocks for
generating dendrimers.6 Dendrimers with appropriate
peripheral functionalities have been used in bioconjuga-
tion,7 cross-linking,8 mass spectrometry,9 fluorescence10
and optics.10 Triphenylmethyl (trityl) derivatives, are
widely used as protecting groups in organic synthesis
N
N
N
N
N
N
R
N
N
Cl
N
NC
CN
Cl
1
2
vorozole
letrozole
clotrimazole, R= imidazole
3, R= H
Figure 1.
Keywords: TRAMs; FC reaction.
q CDRI Communication No. 6652.
*
Corresponding author. Tel.: +91 5222364635; fax: +91
5222223938; e-mail addresses: bapi.rm@yahoo.com; gautam_
panda@lycos.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.001

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S. Kumar Das et al. / Tetrahedron Letters 46 (2005) 3097–3102
have undertaken the synthesis of unsymmetric hetero-
aryldiarylmethanes, a class of trisubstituted methanes
(TRSMs) by way of a Friedel–Crafts alkylation strategy
using thienyl, pyridyl and (5-methyl)-furyl carbinols.
when thiophenol and 3-thiocresol were used as the
nucleophiles. This is possibly due to the higher nucleo-
philicity of sulfur than the carbon atoms of the benzene
ring. We did not isolate any O-alkylated product when
phenol was used as the nucleophile.
4-Methoxyphenyl magnesium bromide 4 was reacted
with thiophene-2-carbaldehyde 5, pyridine-3-carbalde-
hyde 6 and 5-methylfurfural 7 at room temperature to
furnish the carbinols 8, 9 and 10, respectively (Table 1).
It is important to mention that the carbinol 10 was not
stable and got decomposed at room temperature. The
isolation of the carbinol 10 was achieved through column
chromatography (basic alumina) and was stored at 0 °C.
We next used carbinol 9 as the alkylating agent in the Fri-
edel–Crafts (FC) reaction. During FC alkylation using
protic or Lewis acids, the N atom of the pyridine ring
is protonated or complexed with metals and thus the het-
erocycle separates out from the reaction mixture giving
no FC alkylated product. Under our reaction conditions,
treatment of carbinol 9 with various aromatic nucleo-
philes in the presence of anhydrous AlCl3 furnished het-
eroaryldiarylmethane derivatives 17–23.15 As indicated in
Table 2, nucleophilic attack occurred through the sulfur
of thiophenol and 3-thiocresol onto the carbinol carbon
atom of 9 giving rise to 21 and 22, respectively.
To begin with, carbinol 8 was used as a building block
for the synthesis of various unsymmetric hetero-
aryldiarylmethane derivatives. Towards this objective,
8 was treated with the various nucleophiles such as phe-
nol, anisole, N,N-dimethylaniline, N-ethylaniline, thio-
phenol and 3-thiocresol in the presence of concd
H2SO4 to furnish TRSMs 11, 12, 13, 14, 15 and 16 as
the arylated products.15 Nucleophilic attack of phenol oc-
curred through the o- and p-carbon atoms of the benz-
ene ring to give 11b as the major product and 11a as
the minor one. The singlet methine proton appeared at
After the successful demonstration of the FC reaction
with thiophenes and pyridines, we wanted to explore
our synthetic strategy with acid sensitive furans. Furyl
carbinols are well known for their isomerization to
cyclopentenones in the presence of protic and Lewis
acids.14 However, treatment of furyl carbinol 10 with
N,N-dimethylaniline, N-ethylaniline, thiophenol, 2-thio-
cresol and 3-thiocresol in the presence of anhydrous
AlCl3 gave the corresponding alkylated products 24,
25, 26, 27 and 28, respectively, in good yields and purity.15
1
d 5.55 ppm in the H NMR of 11b whereas the same
proton appeared at d 5.86 ppm in 11a due to the
increased ÀI effect of the o-hydroxyl in 11a than the
p-hydroxyl in 11b, Table 2. We did not isolate any
o-substituted product in the cases of anisole and N,N-
dimethylaniline. However, reaction with N-ethylaniline,
contrary to our expectation, furnished 13 through attack
of the p-carbon of the N-ethylaniline. It was interesting
to note that nucleophilic attack occurred through sulfur
In conclusion, we have developed a very short and easy
synthetic route for the preparation of unsymmetric
trisubstituted methane derivatives. A new series of
TRSMs 15, 16, 21, 22, 26, 27 and 28 containing a
Table 1. Synthesis of carbinols 8, 9 and 10
Entry
Grignard reagent
RCHO
Carbinol
Conditions and yield
rt, THF, 1 h, 68%
MeO
MgBr
OH
S
CHO
CHO
1
S
5
OMe
8
4
(yellow oil)
MeO
MgBr
OH
2
rt, THF, 2 h, 68%
N
6
N
OMe
4
9
pale yellow solid,
m.p. 105oC
MeO
MgBr
OH
O
CHO
3
rt, THF, 1 h, 65%
O
7
OMe
4
10
yellow oil

S. Kumar Das et al. / Tetrahedron Letters 46 (2005) 3097–3102
3099
Table 2. Synthesis of unsymmetric methane derivatives 11–28 from the carbinols 8, 9 and 10
H3CO
H3CO
H3CO
Aromatic Nucleophiles
X
Y
X
R
Y
or
R1
or
R
R
OH
R1
8, R= 2-Thienyl,
9, R= 3-Pyridyl,
10, R= (5-Methyl)-2-furyl
X = OH, OCH3, NHC2H5, N(CH3)2, NH2, Y = SH
R1= H, 2-CH3, 3-CH3
Entry
Carbinol
(1 equiv)
Nucleophile
(1.5 equiv)
Producta
Reaction conditionsb,c
Yieldd
MeO
OH
S
1
8
Phenol
Benzene, concd H2SO4, 60 °C, 2 h
11a (10%)
11b (60%)
ortho-OH, 11a, brown semi-solid
para-OH, 11b, brown semi-solid
MeO
OMe
2
8
Anisole
Benzene, concd H2SO4, 60 °C, 2 h
63%
S
12, pale yellow solid, m.p. 90oC
MeO
NHC2H5
3
8
N-Ethylaniline
Benzene, concd H2SO4, 60 °C, 45 min
76%
S
13, black semi-solid
MeO
N
4
5
8
8
N,N-Dimethylaniline
Benzene, concd H2SO4, 60 °C, 45 min
73%
80%
S
14, black semi-solid
MeO
S
Thiophenol
Benzene, concd H2SO4, 60 °C, 30 min
S
15, white solid, m.p. 76oC
MeO
S
6
8
3-Thiocresol
Benzene, concd H2SO4, 60 °C, 30 min
70%
S
16, yellow oil
MeO
OH
7
9
Phenol
Benzene, anhyd AlCl3, 70 °C, 2 h
17a (5%)
17b (55%)
N
ortho-OH, 17a, colourless semi-solid
para-OH, 17b, colourless semi-solid
MeO
OMe
8
9
Anisole
Benzene, anhyd AlCl3, 70 °C, 2 h
67%
N
18, light yellow semi-solid
(continued on next page)

3100
S. Kumar Das et al. / Tetrahedron Letters 46 (2005) 3097–3102
Table 2 (continued)
Entry
Carbinol
(1 equiv)
Nucleophile
(1.5 equiv)
Producta
Reaction conditionsb,c
Yieldd
MeO
NHC2H5
9
9
N-Ethylaniline
Benzene, anhyd AlCl3, 70 °C, 1 h
65%
N
19, light yellow semi-solid
MeO
N
10
11
9
9
N,N-dimethylaniline
Benzene, anhyd AlCl3, 70 °C, 45 min
70%
72%
N
20, light yellow semi-solid
MeO
S
Thiophenol
Benzene, anhyd AlCl3, 70 °C, 30 min
N
21, light yellow solid, m.p. 84oC
MeO
S
12
13
9
9
3-Thiocresol
Benzene, anhyd AlCl3, 70 °C, 30 min
64%
50%
N
22, yellow semi-solid
MeO
NH2
Aniline
Benzene, anhyd AlCl3, 70 °C, 2 h
N
23, brown semi-solid
MeO NHC2H5
14
15
16
10
10
10
N-Ethylaniline
N,N-Dimethylaniline
Thiophenol
Benzene, anhyd AlCl3, rt, 30 min
Benzene, anhyd AlCl3, rt, 45 min
Benzene, anhyd AlCl3, rt, 30 min
63%
61%
60%
O
24, pale yellow oil
MeO
N
O
25, yellow oil
MeO
S
O
26, light yellow semi-solid
MeO
S
17
18
10
10
3-Thiocresol
2-Thiocresol
Benzene, anhyd AlCl3, rt, 30 min
Benzene, anhyd AlCl3, rt, 30 min
78%
75%
O
27, yellow oil
MeO
S
O
28, yellow oil
a Although all the Friedel–Crafts alkylated products were unsymmetric except for 12 and 18, they were isolated as racemic mixtures.
b Concd H2SO4 was used in catalytic amounts.
c One equivalent of anhydrous AlCl3 was used.
d Isolated yield after silica gel column chromatography.

S. Kumar Das et al. / Tetrahedron Letters 46 (2005) 3097–3102
3101
3555; (c) Piancatelli, G.; Scettri, A.; David, G.; DÕAuria,
M. Tetrahedron 1978, 34, 2775, and references therein.
15. Friedel–Crafts Alkylation: (i) To a solution of carbinol 8
{0.18 g, 0.818 mmol (1 equiv)} and nucleophile (1.5 equiv)
in dry benzene (10 mL) was added a catalytic amount of
H2SO4 and the mixture was refluxed at 60 °C until
completion of the reaction. Extraction with ethyl acetate
and column chromatography of the crude product over
silica gel (ethyl acetate/hexane) furnished compounds 11a–
b, 12, 13, 14, 15 and 16.
thioether group has been synthesized in only two steps,
that is, the Grignard reaction and Friedel–Crafts alkyl-
ation. These thioethers cannot be synthesized using pre-
viously reported methodology.1 We have shown that
carbinols containing acid-sensitive heterocycles can be
used as alkylating agents in FC reactions.
Acknowledgements
(ii) To a solution of carbinol 9 {0.18 g, 0.83 mmol
(1 equiv)} and nucleophile (1.5 equiv) in dry benzene
(15 mL), anhydrous AlCl3 (1.0 equiv) was added and the
mixture was refluxed at 70 °C. After usual work-up,
column chromatography over silica gel (ethyl acetate/
hexane) furnished 17a–b, 18, 19, 20, 21, 22 and 23. (iii) To
a solution of carbinol 10 {0.18 g, 0.82 mmol (1 equiv)} and
nucleophile (1.5 equiv) in dry benzene (15 mL), anhydrous
AlCl3 (1.0 equiv) was added and the mixture was stirred at
rt. After usual work-up, column chromatography over
silica gel (ethyl acetate/hexane) furnished 24, 25, 26, 27
and 28.
Shagufta and S.K.D. thank CSIR for providing
fellowships.
References and notes
1. (a) Terrier, M.; Boubaker, T.; Xiao, L.; Farrell, P. G. J.
Org. Chem. 1992, 57, 3924; (b) Muthyala, R.; Katritzky,
A. R.; Lan, X. Dyes Pigments 1994, 25, 303; (c) Aldag, R.
Photochromism Based on Dissociation Processes. In
Photochromism: Molecules and Systems; Durr, H.,
Bouas-Laurent, H., Eds.; Elsevier: London, 1990; and
references cited therein.
Selected Spectral Data: 2-[(4-Methoxyphenyl)phenylsulfan-
ylmethyl]thiophene 15: IR (KBr): 1603, 1511, 1352, 1251,
1
1177, 695 cmÀ1, H NMR (200 MHz, CDCl3): d 7.33 (d,
2H, J = 6.8 Hz), 7.31–7.29 (m, 2H), 7.18–7.14 (m, 4H),
6.86 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 5.64 (s,
1H), 3.75 (s, 3H); 13C NMR (50 MHz, CDCl3): d 159.4,
146.3, 135.9, 133.6, 131.9, 129.7, 129.2, 127.5, 127.0, 126.4,
125.6, 114.3, 55.6, 53.0; MS (FAB): 312 (M+), Anal.
C18H16OS2; calcd: C, 69.19; H, 5.16. Found: C, 69.29; H,
5.25.
2. Recanatini, M.; Cavalli, A.; Valenti, P. Med. Res. Rev.
2002, 22, 282.
3. Bhatnagar, A. S.; Hausler, A.; Schieweck, K.; Lang, M.;
Bowman, R. J. Steroid Biochem. Mol. Biol. 1990, 37,
1021.
4. Vanden Bossche, H.; Willemsens, G.; Roels, I.; Bellens,
D.; Moereels, H.; Coene, M. C.; Le Jeune, L.; Lauwers,
W.; Janssen, P. A. Biochem. Pharmacol. 1990, 40, 1707.
5. Al-Qawasmeh, R. A.; Lee, Y.; Cao, M. Y.; Gu, X.;
Vassilakos, A.; Wright, J. A.; Young, A. Bioorg. Med.
Chem. Lett. 2004, 14, 347.
6. Baker, L. A.; Sun, L.; Crooks, R. M. Bull. Korean Chem.
Soc. 2002, 23, 647.
7. Koster, H.; Beck, S.; Coull, J. M.; Dunne, T.; Gildea, B.
D.; Kissinger, C.; OÕKeeffe, T. Nucleic Acids Symp. Ser.
1991, 24, 318.
8. (a) Kwiatkowski, M.; Chattopadhyaya, J. B. Nucleic Acids
Symp. Ser. 1984, 14, 299; (b) Ramage, R.; Wahl, F. O.
Tetrahedron Lett. 1993, 34, 7133; (c) Letsinger, R. L.;
Finnan, J. L. J. Am. Chem. Soc. 1975, 97, 7197.
9. (a) Shchepinov, M. S.; Chalk, R.; Southern, E. M.
Tetrahedron 2000, 56, 2713; (b) Chattopadhyaya, J. B.;
Reese, C. B. J. Chem. Soc., Chem. Commun. 1978, 639.
10. (a) Breslow, R.; Kaplan, L.; LaFollette, D. J. Am. Chem.
Soc. 1968, 90, 4056; (b) Fisher, E. F.; Caruthers, M. H.
Nucleic Acids Res. 1983, 11, 1589; (c) Fourrey, J. L.;
Varenne, J.; Blonski, C.; Dousset, P.; Shire, D. Tetrahe-
dron Lett. 1987, 28, 5157; (d) Meier, H.; Kim, S. Eur. J.
Org. Chem. 2001, 1163; (e) Noack, A.; Hartmann, H.
Chem. Lett. 2002, 644; (f) Brasselet, S.; Cherioux, F.;
Audebert, P.; Zyss, J. Chem. Mater. 1999, 11, 1915.
11. (a) Shchepinov, M. S.; Korshun, V. A. Chem. Soc. Rev.
2003, 32, 170; (b) Dinger, M. B.; Scott, M. J. J. Chem.
Soc., Perkin Trans. 1 2000, 1741, and references therein.
12. Panda, G.; Shagufta; Mishra, J. K.; Chaturvedi, V.;
Srivastava, A. K.; Srivastava, R.; Srivastava, B. S. Bioorg.
Med. Chem. 2004, 12, 5269.
4-[(4-Methoxyphenyl)pyridin-3-ylmethyl]phenol 17b: IR
(KBr): 3428, 1611, 1510, 1458, 1249, 757 cmÀ1
,
1H
NMR (200 MHz, CDCl3): d 8.43 (d, 1H, J = 7.0 Hz),
8.37 (s, 1H), 7.44 (d, 1H, J = 7.8 Hz), 7.26 (m, 1H), 6.98
(d, 2H, J = 8.6 Hz), 6.87 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H,
J = 8.6 Hz), 6.75 (d, 2H, J = 8.6 Hz), 5.41 (s, 1H), 3.76 (s,
3H), 13C NMR (50 MHz, CDCl3): d 158.7, 156.3, 150.1,
146.8, 141.5, 138.0, 135.4, 134.1, 130.5, 124.0, 116.1, 114.3,
55.6, 53.1; MS (FAB): 292 (M++H), Anal. C19H17NO2;
calcd: C, 78.33; H, 5.88; N, 4.81. Found: C, 78.43; H, 5.90;
N, 4.83.
{4-[(4-Methoxyphenyl)pyridin-3-ylmethyl]phenyl} dimeth-
ylamine 20: IR (neat): 1612, 1515, 1249, 757 cmÀ1 1H
,
NMR (200 MHz, CDCl3): d 8.33 (m, 2H), 7.67 (d, 1H,
J = 7.8 Hz), 7.27 (m, 1H), 6.91 (d, 2H, J = 8.6 Hz), 6.84 (d,
2H, J = 8.6 Hz), 6.71 (d, 2H, J = 8.6 Hz), 6.55 (d, 2H,
J = 8.6 Hz), 5.30 (s, 1H), 3.64 (s, 3H), 2.79 (s, 6H), 13C
NMR (50 MHz, CDCl3): d 158.5, 151.2, 149.7, 147.8, 140.9,
137.0, 136.1, 131.3, 130.5, 130.2, 123.5, 114.2, 113.0, 55.6,
53.1, 41.0, 30.1 MS (FAB): 318 (M+), Anal. C21H22N2O:
Calcd: C, 79.21; H, 6.96; N, 8.80. Found: C, 79.25; H, 6.99;
N, 8.90.
{4-[(4-Methoxyphenyl)-(5-methyl-furan-2-yl)methyl]phen-
yl}dimethylamine 25: IR (neat): 2951, 1612, 1516, 1448,
1349, 1220, 1033, 759 cmÀ1, 1H NMR (200 MHz, CDCl3):
d 7.07 (d, 2H, J = 8.6 Hz), 7.01 (d, 2H, J = 8.6 Hz), 6.79 (d,
2H, J = 8.8 Hz), 6.64 (d, 2H, J = 8.8 Hz), 5.83 (d, 1H,
J = 2.0 Hz), 5.71 (d, 1H, J = 2.0 Hz), 5.24 (s, 1H), 3.72 (s,
3H), 2.87 (s, 6H), 2.21 (s, 3H); 13C NMR (50 MHz, CDCl3):
d 158.6, 156.5, 151.5, 149.8, 135.5, 131.0, 130.1, 129.7,
114.1, 113.1, 109.0, 106.3, 55.6, 49.7, 41.1, 14.1; MS (FAB):
321 (M+), Anal. C21H23NO2: Calcd: C, 78.47; H, 7.21; N,
4.36. Found: C, 78.50; H, 7.25; N, 4.40.
13. (a) Casiraghi, G.; Casnati, G.; Cornia, M. Tetrahedron
Lett. 1973, 679; (b) Pindur, U.; Flo, C. J. Heterocycl.
Chem. 1989, 26, 1563; (c) Ungnade, H. E.; Crandall, E. W.
J. Am. Chem. Soc. 1949, 71, 2209; (d) Snyder, H. R.;
Konecky, M. S. J. Am. Chem. Soc. 1958, 80, 4388.
14. (a) DÕAuria, M. Heterocycles 2000, 52, 185; (b) Piancatelli,
G.; Scettri, A.; Barbadoro, S. Tetrahedron Lett. 1976,
2-[(4-Methoxyphenyl)phenylsulfanylmethyl]-5-methylfu-
ran 26: IR (neat): 1602, 1510, 1352, 1250, 760 cmÀ1 1H
,
NMR (200 MHz, CDCl3): d 7.32 (d, 2H, J = 6.8 Hz), 7.32–
7.16 (m, 5H), 6.82 (d, 2H, J = 8.8 Hz), 6.01 (d, 1H,

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S. Kumar Das et al. / Tetrahedron Letters 46 (2005) 3097–3102
J = 3.0 Hz), 5.84 (d, 1H, J = 3.0 Hz), 5.35 (s, 1H), 3.77 (s,
3H), 2.25 (s, 3H); 13C NMR (50 MHz, CDCl3): d 159.4,
152.4, 152.1, 135.7, 132.5, 131.7, 129.9, 129.0, 127.6, 114.3,
109.5, 106.7, 55.6, 51.3, 14.0; MS (FAB): 201 (M+ÀSC6H5),
Anal. C19H18O2S: Calcd: C, 73.52; H, 5.84. Found: C,
73.40; H, 5.90.