An efficient organocatalyzed multicomponent synthesis of diarylmethanes via Mannich type Friedel-Crafts reaction

Article abstract of DOI:10.1016/j.tetlet.2009.09.155

We have developed an efficient organocatalyzed, multicomponent synthesis of diarylmethane derivatives from tertiary aromatic amines, formaldehyde and 2-naphthols via Mannich type Friedel-Crafts reaction. Several organocatalysts such as (-)-chinchonidine, l-proline, l-thiaproline, and l-pipecolonic acid have been screened for the reaction but the best results were obtained with l-proline. In this Mannich type Friedel-Crafts alkylation, tertiary aromatic amines react with formaldehyde-proline adduct to generate 1-(4-(dimethylamino)benzyl)pyrrolidinium-2-carboxylate intermediate, which undergoes nucleophilic addition to give substituted diarylmethanes in excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.09.155

Tetrahedron Letters 50 (2009) 7024–7027
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Tetrahedron Letters
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An efficient organocatalyzed multicomponent synthesis of diarylmethanes via
Mannich type Friedel–Crafts reaction
*
Atul Kumar , Mukesh Kumar, Maneesh Kumar Gupta
Medicinal and Process Chemistry Division, Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2009
Revised 25 September 2009
Accepted 28 September 2009
Available online 1 October 2009
We have developed an efficient organocatalyzed, multicomponent synthesis of diarylmethane derivatives
from tertiary aromatic amines, formaldehyde and 2-naphthols via Mannich type Friedel–Crafts reaction.
Several organocatalysts such as (À)-chinchonidine,
L
-proline,
L
-thiaproline, and
L-pipecolonic acid have
been screened for the reaction but the best results were obtained with
L
-proline. In this Mannich type
Friedel–Crafts alkylation, tertiary aromatic amines react with formaldehyde–proline adduct to generate
1-(4-(dimethylamino)benzyl)pyrrolidinium-2-carboxylate intermediate, which undergoes nucleophilic
addition to give substituted diarylmethanes in excellent yields.
Keywords:
Organocatalyst
Friedel–Crafts reaction
Diarylmethane derivatives
Multicomponent reaction
Ó 2009 Elsevier Ltd. All rights reserved.
Multicomponent reactions (MCRs) are involved in some of the
most interesting and challenging transformation in organic synthe-
sis. MCRs have been receiving much attention1 because of their
efficiency and diversity of products, which is now considered as
important tools in the modern drug discovery process.2 Besides,
these MCRs have been effectively used in the total synthesis of
complex natural products.3 Many studies for the improvement
and application of already known classical MCRs, such as the Man-
nich reaction,4Ugi reaction,5 and Biginelli reaction6 have been re-
ported. However, the development of new MCRs is still an
important issue in the field of medicinal and organic chemistry.
Organocatalysts have exhibited immense promise in the syn-
thesis of multicomponent reactions.7 The catalytic property of
small organic molecules like cinchona alkaloids and amino acids
are well known.8 However much attention has been focused on
toward the development of organocatalyzed multicomponent reac-
tions,17 we wish to report here a new organocatalyzed Mannich type
three-componentFriedel–Crafts reactionof tertiary aromaticamine,
formaldehyde, and 2-naphthol. In this Mannich type Friedel–Crafts
alkylation, tertiary aromatic amines react with formaldehyde–pro-
line adduct to generate 1-(4-(dimethylamino)benzyl)pyrrolidini-
um-2-carboxylate intermediate, which undergoes nucleophilic
addition reaction with 2-naphthol to afford substituted diaryl meth-
ane derivatives 4a in high yields (Scheme 1).
Diaryl and triaryl methane derivatives are important constitu-
ents of dyes and have shown a wide range of biological activities.18
Katritzky et al. reported the synthesis of diaryl methane deriva-
tives from benzotrizole analogues of N,N-dialkylanilines and naph-
thol in moderate yields. The procedure involves multi-step
synthesis and drastic conditions such as the use of hydrochloric
acid.19 Recently, Rong et al. reported a homocoupling of p-xylene
to afford biarylmethane as major product using Pd(OAc)2/CF3COOH
(TFA)/K2S2O8 catalytic system along with biaryls as minor product.20
We have developed an organocatalyzed three-component syn-
thesis of diarylmethane derivatives from tertiary aromatic amines,
formaldehyde, and 2-naphthols in high yields.
L-proline, an inexpensive, and efficient catalyst. L-Proline has been
found to be very effective in enamine-based direct catalytic asym-
metric aldol,9 Mannich,10 Diels–Alder,11 and Knoevenagel type of
reactions.12
Friedel–Crafts alkylation is one of the most powerful C–C bond
forming reaction in organic synthesis.13 Friedel–Crafts reactions
are especially given by electron-rich arenes. Naphthols have been
showntobe gooddonorsinFriedel–Craftsalkylation andthenucleus
has interesting biological activity as well as catalytic properties.14,15
Micheal-type Friedel–Crafts reaction of 2-naphthols with activated
Initial efforts were focused on the search of an efficient catalyst
for the three-component coupling of 2-naphthol, formaldehyde,
and N,N-dimethylaniline. It was observed that when the acid cata-
lysts such as acetic acid, p-toluene sulfonic acid (PTSA), or boric
acid were used, it led to the formation of 5 as major products
and 4a (diarylmethane derivatives) as a minor product in a low
yield (Table 1).
species such as iminium ions,16
a
,b-unsaturated olefins,15a and
aza-dicarboxylate14b are well known. In continuation of our efforts
We then screened a number of organocatalysts such as (À)-
* Corresponding author. Tel.: +91 522 2612411; fax: +91 522 26233405.
E-mail address: dratulsax@gmail.com (A. Kumar).
chinchonidine, L-proline, L-thiaproline, and L-pipecolonic acid for
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.155

A. Kumar et al. / Tetrahedron Letters 50 (2009) 7024–7027
7025
R1
N
R2
R1
R3
R1
N
R3
1a
OH
R1
N
R2
OH
Proline
R2
HCHO
2
N
+
R2
3a
4a
5
Scheme 1. Synthesis of diarylmethane derivatives via Mannich type Friedel–Crafts reaction.
Table 1
boxylate, which on reaction with 2-naphthol gives diarylmethanes
4a as a major product and small amounts of 5 (Fig. 1).
Screening of catalysts for coupling of 2-naphthol, formaldehyde, and N,N-
dimethylanilinea
Decreasing the amount of
crease in the yield of 4a, and 5 were formed in reasonable amounts.
Increasing the amount of -proline (30 mol %), no significant in-
crease in the yield of 4a was observed.
Thus, 20 mol % of -proline was found to be the optimum for
L-proline (10 mol %) resulted in a de-
Entry Catalyst
Catalyst (mol %) Yields 4ab (%) Yields 5b (%)
L
1
2
3
4
Acetic acid
PTSA
20
20
20
20
Trace
Trace
Trace
40
90
88
85
25
Boric acid
(À)-
L
efficient synthesis of 4a. The optimization data is summarized in
Table 1.
We further studied the effect of solvent on L-proline-catalyzed
coupling reaction of 2-naphthol, formaldehyde, and N,N-dimethyl-
Chinchonidine
5
6
7
8
9
L
L
L
L
L
-Pipecolonic acid
-Thiaproline
-Proline
-Proline
-proline
20
20
20
10
30
65
65
85
55
85
10
15
Trace
<5
Trace
aniline (Table 2). In aprotic solvents such as dichloromethane and
a
Reaction
conditions:
N,N-dimethylaniline
(1.0 mmol),
formaldehyde
(1.0 mmol), 2-naphthol (1.0 mmol), EtOH, rt, 12 h stirr.
b
Table 2
Isolated yield.
Solvent effect on L-proline catalyzed the three-component reaction of N,N-dimeth-
ylaniline, formaldehyde, and 2-naphthola
Entry
Solvents
Time (h)
Yield of 4ab (%)
the efficient synthesis of 4a. All these organocatalysts showed bet-
ter selectivity for 4a in comparison to 5. -Proline was found to be
L
1
2
3
4
5
6c
Dichloromethane
Tetrahydrofuran
Acetonitrile
Methanol
Ethanol
Ethanol
12
12
12
12
12
5
35
28
72
84
85
45
the best catalyst for the synthesis of diarylmethane derivatives
(4a). In the presence of acid catalysts bis compound 5 was obtained
as a major product, which probably formed by the reaction of aza
quinone methide intermediate with N,N-dimethylaniline and 2-
naphthol was unable to compete with dialkylaniline. Whereas in
the case of organocatalyst (proline) reacts with formaldehyde to
form an adduct, which reacts with dialkylaniline to generate an
intermediate 1-(4-(dimethylamino)benzyl) pyrrolidinium-2-car-
a
Reaction conditions: N,N-dimethylaniline (1 mmol), formaldehyde (1 mmol), 2-
naphthol (1 mmol),
L-proline (20 mol %), rt, stirr.
b
Isolated yield.
Reflex.
c
Acid catalysed Mechanism
R
R1
N
R
R
N
N
R
N
R1
R
N
R1
R1
R1
+
CH2O
(Aza quinone methide)
Major
Organocatalysed mechanism
H2C
O
HN
OH
HOOC
H2C
N
N
HN
N
H
COOH
HOOC
A
COO
OH
N
N
N
B
4a
Major
C
(1-(4-(dimethylamino)benzyl)pyrrolidinium-2-carboxylate)
Figure 1. Possible mechanism of reaction.

7026
A. Kumar et al. / Tetrahedron Letters 50 (2009) 7024–7027
Table 3
Table 3 (continued)
Proline catalyzed three-component Mannich type Friedel–Crafts coupling of tertiary
S.No.
11
R1/R2
R3
H
Product
Yieldb (%)
aromatic amines, formaldehyde, and 2-naphthola
S.No.
1
R1/R2
R3
H
Product
Yieldb (%)
N
CH3
80
N
OH
4k
CH3
80
OH
OH
4a
HO
N
N
N
12
13
14
C2H5
CH3
CH3
H
80
82
81
2
C2H5
H
78
OH
4l
HO
HO
4b
N
m-CH3
3
4
5
6
CH3
CH3
CH3
CH3
m-CH3
o-CH3
H
81
80
76
80
OH
OH
OH
OH
4m
4c
4d
N
N
o-CH3
OH
4n
HO
N
a
Reaction conditions: N,N-dialkylaniline (1.0 mmol), formaldehyde (1.0 mmol),
2-naphthol (1.0 mmol), EtOH, rt, 12 h stirr.
b
Isolated yields.
4e
N
tetrahydrofuran, poor yield of 4a was obtained with significant for-
mation of 5. However, acetonitrile gave moderate yield of 4a.
Whereas in protic solvents such as methanol and ethanol, 4a was
obtained in higher yields. Stirring the reaction mixture in ethanol
for 12 h was found to be the optimal condition. Upon heating,
the reaction mixture gave a complex mixture and 4a was obtained
in 45% yield.
H
HO
OH
4f
In order to generalize the reaction we carried out the organocat-
alyzed three-component reaction of substituted tertiary aromatic
amines, 2-naphthols, and formaldehyde21 (Table 3).
In conclusion, we have developed an efficient organocatalyzed
multicomponent Mannich type Friedel–Crafts reaction of tertiary
aromatic amines, formaldehyde, and 2-naphthol for the synthesis
of diarylmethane derivatives. Further development of this Mannich
type Friedel–Crafts reaction and its application to the synthesis of
bioactive compounds are in progress.
N
7
8
9
C2H5
CH3
CH3
H
80
82
80
HO
HO
OH
OH
4g
N
m-CH3
4h
Acknowledgments
N
Mukesh Kumar and Maneesh Kumar Gupta are thankful to
CSIR–UGC, New Delhi, for the award of SRF.
o-CH3
HO
OH
4i
References and notes
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´
L.; Riva, R. Org. React. 2005, 65, 1–140; (c) Ramon, D. J.; Yus, M. Angew. Chem.
N
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Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913–2916.
10
CH3
H
74
OH
4j
HO
12

A. Kumar et al. / Tetrahedron Letters 50 (2009) 7024–7027
4. For reviews, see: (a) Marques, M. M. B. Angew. Chem. 2006, 118, 356–360. (1 mmol), formaldehyde (1 mmol),
7027
L
-proline (20 mol %), and 5 ml ethanol were
´
Angew. Chem., Int. Ed. 2006, 45, 348–352; (b) Cordova, A. Acc. Chem. Res. 2004,
37, 102–112.
taken. The reaction mixture was then stirred at room temperature for an
appropriate time and the progress of the reaction was monitored by TLC. After
completion of the reaction, the solvent was removed and the residue was
extracted with ethyl acetate. Evaporation of the solvent gave a crude product
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Angew. Chem., Int. Ed. 2000, 39, 168–3210; For recent studies, see: (b)
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which
was
purified
by
column
chromatography
(silica
gel,
ethylacetate:hexane). Analytical data for few representative compounds. 1-
(4-(Dimethylamino)-2-methylbenzyl)naphthalen-2-ol
(4c)
brown
solid;
mp = 138–140 °C, 1H NMR (200 MHz, CDCl3): d 2.46 (s, 3H, CH3), 2.88 (s, 6H,
N(CH3)2), 4.27 (s, 2H, CH2), 5.17 (s, 1H, OH), 6.36 (d, 1H, ArH, J = 2.6 Hz), 6.56 (d,
1H, ArH, J = 8.4 Hz), 6.67 (d, 1H, ArH, J = 2.5 Hz), 7.11 (d, 1H, ArH, J = 8.8 Hz),
7.30–7.47 (m, 2H, ArH), 7.75 (d, 1H, ArH, J = 8.8 Hz), 7.80 (d, 2H, ArH J = 8.1 Hz)
ppm; 13C NMR (200 MHz, CDCl3): d 20.83, 28.16, 41.25, 111.31, 115.58, 117.98,
118.60, 123.55, 123.75, 125.52, 126.96, 128.63, 128.76, 128.92, 129.85, 134.24,
6. Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904–1905; Hongming, Li.;
Wang, B.; Deng, Li. J. Am. Chem. Soc. 2006, 128, 732–733.
7. For reviews, see: (a) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879–888; (b) Kappe,
C. O. QSAR Comb. Sci. 2003, 22, 630–645; For recent research, see: (c) Nilsson, B.
L.; Overman, L. E. J. Org. Chem. 2006, 71, 7706–7714; (d) Cohen, F.; Overman, L.
E. J. Am. Chem. Soc. 2006, 128, 2604–2608; (e) Suzuki, I.; Suzumura, Y.; Takeda,
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Amimour, M.; Belfaitah, A.; Rhouati, S.; Carboni, B. Tetrahedron Lett. 2006, 47,
5697–5699; (g) Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005, 127, 16386–
16387.
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9. (a) Bogevig, A.; Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 1790–1793; (b) Janey, J. M.; Hsiano, Y.;
Armstrong, J. D., III J. Org. Chem. 2006, 71, 390–392.
10. (a) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig, A.; Jorgensen, K. A. J.
Am. Chem. Soc. 2002, 124, 827–833; (b) Kotrusz, P.; Toma, S. Molecules 2006,
11, 197–205. For recent reviews, see: (a) Domling, A. Chem. Rev. 2006, 106, 17–
89. (b) Banfi, L.; Riva, R. Org. React. 2005, 65, 1–140. (c) Ramón, D. J.; Yus, M.
Angew. Chem. 2005, 117, 1628–1661; Angew. Chem., Int. Ed. 2005, 44, 1602–
1634. (d) Zhu, J. Eur. J. Org. Chem. 2003, 1133–1144.
137.59, 149.91, 152.24. IR (KBr): cmax 3779, 2921, 2364, 1611, 1439, 1271, 804,
747, 687 cmÀ1. ESIMS: m/z 292 (M+H), Anal. Calcd for C20H21NO: C, 82.44; H,
7.26; N, 4.18. Found: C, 82.36; H, 7.16; N, 4.12. 1-(4-(Dimethylamino)-2-
methylbenzyl)naphthalene-2,7-diol (4h) brown solid, mp = 157–160 °C 1H NMR
(200 MHz, CDCl3): d 2.47 (s, 3H, CH3), 3.21 (s, 6H, N(CH3)2), 4.09 (s, 2H, CH2),
6.27 (d, 2H, ArH, J = 2.5 Hz), 6.34–6.59 (m, 1H, ArH), 6.79–7.02 (m, 3H, ArH),
7.47–7.69 (m, 2H, ArH), 8.89 (s, 1H, OH), 9.06 (s, 1H, OH) ppm; 13C NMR
(300 MHz, CDCl3 + DMSO-d6): d 25.23, 31.74, 43.97, 110.24, 115.32, 119.54,
119.70, 119.89, 120.71, 128.11, 132.07, 132.23, 132.68, 134.61, 140.59, 141.17,
153.61, 158.25, 160.55. IR (KBr): cmax 3778, 3325, 2957, 2364, 1626, 1504,
1319, 819, 773, 688 cmÀ1 ESIMS: m/z 308 (M+H). Anal. Calcd for C20H21NO2: C,
78.15; H, 6.89; N, 4.56. Found: C, 78.10; H, 6.81; N, 4.46. 1-((2-
(Dimethylamino)naphthalen-1yl)methyl)naphthalen-2-ol (4e) solid, mp = 196–
198 °C 1H NMR (200 MHz, CDCl3 + DMSO-d6): d 2.79 (s, 6H, N(CH3)2), 4.80 (s,
2H, CH2), 6.58 (d, 1H, ArH, J = 7.7 Hz), 6.75 (d, 1H, ArH, J = 7.7 Hz), 7.24–7.32
(m, 3H, ArH), 7.51–7.80 (m, 6H, ArH), 8.29–8.41 (m, 2H, ArH), 8.51 (s, 1H, OH)
ppm; 13C NMR (300 MHZ, CDCl3 + DMSO-d6): d 27.09, 45.41, 114.20, 116.99,
118.64, 122.72, 123.56, 124.48, 124.67, 124.79, 125.34, 126.32, 126.63, 128.41,
128.76, 128.88, 131.07, 133.37, 134.35, 149.20, 153.60. IR (KBr): cmax 3774,
2955, 2367, 1587, 1438, 1275, 1149, 809, 755, 682 cmÀ1. ESIMS: m/z 328
(M+H). Anal. Calcd for C23H21NO: C, 84.37; H, 6.46; N, 4.28. Found: C, 84.317;
H, 6.38; N, 4.22. 1-(4-(Dimethylamino)benzyl)naphthalen-2-ol (4a) brown solid,
mp = 127–130 °C 1H NMR (300 MHz, CDCl3): d (s, 6H, (NCH3)2), 4.37 (s, 2H,
CH2), 5.82 (s, 1H, OH), 6.65 (d, 2H, ArH, J = 8.5 Hz), 7.09–7.18 (m, 3H, ArH),
7.29–7.46 (m, 2H, ArH), 7.67 (d, 1H, ArH, J = 8.7 Hz), 7.77 (d, 1H, ArH,
J = 8.0 Hz), 7.95 (d, J = 8.5 Hz, 1H, ArH) ppm; 13C NMR (200 MHz, CDCl3): d
30.17, 41.29, 113.83, 118.49, 123.52, 123.76, 126.97, 128.70, 128.91, 129.25,
130.61, 134.11, 142.24, 151.81. IR (KBr): cmax 3772, 2920, 2366, 1619, 1440,
1265, 806, 745, 684 cmÀ1. ESIMS: m/z 278 (M+H). Anal. Calcd for C19H19NO: C,
82.28; H, 6.90; N, 5.05. Found: C, 82.22; H, 6.82; N, 4.97. 1-(4-
(Diethylamino)benzyl)naphthalene-2,7-diol (4g) brown solid, mp = 130–134 °C
1H NMR (300 MHz, CDCl3): d 0.95 (t, 6H, CH2CH3, J = 6.9 Hz), 3.12 (q, 4H, NCH2,
J = 6.9 Hz), 4.13 (s, 2H, CH2), 6.44 (d, 2H, ArH, J = 5.4 Hz), 6.76 (d, 1H, ArH,
J = 1.8 Hz), 6.79 (d, 1H, ArH, J = 1.9 Hz), 6.88–7.12 (m, 3H, ArH), 7.36 (d, 1H,
ArH, J = 8.7 Hz), 7.44 (d, 1H, ArH, J = 8.7 Hz), 8.15 (s, 1H, OH), 8.61 (s, 1H, OH)
ppm; 13C NMR (300 MHz, CDCl3): d 12.44, 29.57, 44.66, 105.82, 112.70, 114.93,
115.25, 117.34, 123.84, 127.42, 129.16, 129.81, 135.48, 140.54, 141.19, 152.65,
11. Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
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13. (a) Olah, G. A. In Friedel–Crafts and Related Reaction; Wiley: New York, 1963; (b)
Olah, G. A. In Friedel–Crafts Chemistry; Wiley: New York, 1973.
14. For limited examples of naphthols in asymmetric Friedel–Craft reaction, see:
(a) Erker, G.; van der Zeijden, A. A. H. Angew. Chem., Int. Ed. 1990, 29, 512; (b)
Brandes, S.; Bella, M.; Kjaersgaard, A.; Jorgensen, K. A. Angew. Chem., Int. Ed.
2006, 45, 1147.
15. For limited examples of naphthols in Michael-type Friedel–Crafts reaction in a
racemic form, see: (a) Kidwai, M.; Saxena, S.; Khan, M. K. R.; Thukral, S. S.
Bioorg. Med. Chem. Lett. 2005, 15, 4295; (b) Aoki, S.; Amamoto, C.; Oyamada, J.;
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K.; Itabashi, K. Nippon Kagaku Kaishi 1989, 244.
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17. (a) Kumar, A.; Maurya, R. A. Tetrahedron Lett. 2008, 49, 5471–5474; (b) Kumar,
A.; Maurya, R. A. Tetrahedron 2008, 64, 3471–3482; (c) Kumar, A.; Maurya, R. A.
Tetrahedron Lett. 2007, 48, 3887–3890.
18. Washburn, W. N. J. Med. Chem. 2009, 52, 1785–1794.
19. Katritzky, A. R.; Lan, X.; Lam, J. N. J. Org. Chem. 1991, 56, 4397–4403.
20. Rong, Y.; Ruoshi, Li.; Wenjun, Lu. Organometallics 2007, 26, 4376–4378.
21. General procedure for the synthesis of compound 4: In a round-bottom flask
equipped with a magnetic stirrer, b-naphthol (1 mmol), N,N-dimethylaniline
155.37. IR (KBr): c .
max 3780, 2950, 2356, 1625, 1430, 1260, 805, 744, 687 cmÀ1
ESIMS: m/z 322 (M+H). Anal. Calcd for C21H23NO2: C, 78.47; H, 7.21; N, 4.36.
Found: C, 78.22; H, 7.12; N, 3.89.