Dual-reagent catalysis within Ir-Sn domain: Highly selective alkylation of arenes and heteroarenes with aromatic aldehydes

Article abstract of DOI:10.1021/jo062633n

(Chemical Equation Presented) Reactions of arenes and heteroarenes with aromatic aldehydes proceeded smoothly in the presence of a catalytic combination of [Ir(COD)Cl]₂-SnCl₄ to afford the corresponding triarylmethane derivatives (TRAMs) in high yields. This 100% TRAM selective transformation is clean and eliminates the use of acid systems.

Full text of DOI:10.1021/jo062633n

CHART 1. Representative Bioactive TRAMs and Analogues
Dual-Reagent Catalysis within Ir-Sn Domain:
Highly Selective Alkylation of Arenes and
Heteroarenes with Aromatic Aldehydes
Susmita Podder, Joyanta Choudhury, Ujjal Kanti Roy,
and Sujit Roy*
Organometallics & Catalysis Laboratory, Department of
Chemistry, Indian Institute of Technology,
Kharagpur 721302, India
sroy@chem.iitkgp.ernet.in
ReceiVed December 22, 2006
for carbon-carbon bond formation3 led us to recently propose
a dual-reagent catalyst system comprised of Ir(I) and Sn(IV)
for the FCA of arenes using alcohols.4 Herein we demonstrate
the further utility of the reagent combination for the bisarylation
of aldehydes leading to highly selective formation of triaryl-
methanes (TRAMs).
Motifs bearing triarylmethane (TRAM) and their heterocyclic
variants constitute an integral part of a number of bioactive
compounds, prodrugs, pharmaceuticals, and dyes (Chart 1).5
They are also well exploited as building blocks for dendrimers,
and NLOs.6 Routes to TRAMs, via Lewis acid (LA) catalyzed
alkylation of arenes with aldehyde as alkylating agent, are often
restricted by the formation of a multitude of products, a high
(even stoichiometric) amount of catalyst loading, and at times
drastic reaction conditions.7 While LA-catalyzed reductive
alkylations of arenes with aldehydes do not suffer from the said
process limitations, they afford exclusively the corresponding
diarylmethanes.8 Two most recent reports on TRAM-selective
transformations using catalytic BF3:H2O or AuCl3/3AgOTf are
Reactions of arenes and heteroarenes with aromatic aldehydes
proceeded smoothly in the presence of a catalytic combina-
tion of [Ir(COD)Cl]2-SnCl4 to afford the corresponding
triarylmethane derivatives (TRAMs) in high yields. This
100% TRAM selective transformation is clean and eliminates
the use of acid systems.
Even after 125 years since its discovery, Friedel-Crafts
alkylation (FCA) remains a fundamental tool for the construction
of various organic architectures of pharmaceutical and industrial
relevance.1 Within the FCA domain, there has been multiprong
development in the area of alkylation of arenes and heteroarenes.
Tuning a FCA catalyst to deliver high turnover frequency (TOF),
substrate and alkylating agent selectivity, and envirotolerability
continues to be an important exercise. Toward this pursuit, the
evolution/resurgence of d- and f-block metal catalysts (either
simple salts or designer complexes) is quite breathtaking.2 Our
continuing success in developing an efficient bimetallic pathway
(3) (a) Sinha, P.; Roy, S. Organometallics 2004, 23, 67. (b) Banerjee,
M.; Roy, S. Org. Lett. 2004, 6, 2137. (c) Banerjee, M.; Roy, S. J. Mol.
Catal. A: Chem. 2006, 246, 231.
(4) Choudhury, J.; Podder, S.; Roy, S. J. Am. Chem. Soc. 2005, 127,
6162.
(5) (a) Wulff, H.; Miller, M. J.; Ha¨nsel, W.; Grissmer, S.; Cahalan,
M. D.; Chandy, K. G. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 8151. (b)
McNaughton-Smith, G. A.; Rigdon G. C.; Stocker, J. W. Icagen, Inc.,
U.S.A., PCT Int. Appl. WO-2000050026, 2000 [CAN 133, 187954]. (c)
Lacroix, R.; Poupelin, J. P.; Lacroix, J.; Reynouard, F.; Combescot, C. Ann.
Pharm. Fr. 1979, 37, 131. (d) Poupelin, J. P.; Saint-Ruf, G.; Foussard-
Blanpin, O.; Narcisse, G.; Uchida-Ernouf, G.; Lacroix, R. Eur. J. Med.
Chem. 1978, 13, 67. (e) Manzoni, C.; Lovati, M. R.; Bonelli, A.; Galli, G.;
Sirtori, C. R. Eur. J. Pharmacol. 1990, 190, 39. (f) Finer, J. T.; Chabala
J. C.; Lewis, E. Cytokinetics, Inc., U.S.A., PCT Int. Appl. WO-2002056880,
2005, [CAN 137, 124985]. (g) Mibu, N.; Yokomizo, K.; Uyeda, M.; Sumoto,
K. Chem. Pharm. Bull. 2003, 51, 1325. (h) Oclarit, J. M.; Ohta, S.;
Kamimura, K.; Yamaoka, Y.; Shimizu, T.; Ikegami, S. Nat. Prod. Lett.
1994, 4, 309.
(6) (a) Shagufta, S. K. D.; Panda, G. Tetrahedron Lett. 2005, 46, 3097
and references cited therein. (b) Sanguinet, L.; Twieg, R. J.; Wiggers, G.;
Mao, G.; Singer, K. D.; Petschek, R. G. Tetrahedron Lett. 2005, 46, 5121.
(c) Baker, L. A.; Sun, L.; Crooks, R. M. Bull. Korean Chem. Soc. 2002,
23, 647.
(7) Selected references: (a) Roberts, R. M.; EI-Khawaga, A. M.; Sweeney
K. M.; EI-Zohry, M. F. J. Org. Soc. 1987, 52, 1591 and references cited
therein. (b) Mibu, N.; Yokomizo, K.; Uyeda, M.; Sumoto, K. Chem. Pharm.
Bull. 2003, 51, 1325.
(1) (a) Olah, G. A. Friedel Crafts and Related Reactions; Wiley-
Interscience: New York, 1964; Vol. II, Part I. (b) Olah, G. A. A Life of
Magic Chemistry. Autobiographical reflections of a Nobel Prize winner;
Wiley-Interscience: New York, 2001. (c) Roberts, R. M.; Khalaf, A. A.
Friedel-Crafts Alkylation Chemistry. A Century of DiscoVery; Marcel
Dekker: New York, 1984.
(2) For an overview: (a) Lewis Acids in Organic Synthesis; Yamamoto,
H., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Vols. 1 and 2. (b)
Kobayashi, S. In Stimulating Concepts in Chemistry; Vo¨gtle, F., Stoddart,
J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, Germany, 2000; pp
3-12. (c) Corma, A.; Garcia, H. Chem. ReV. 2003, 103, 4307. (d) Bandini,
M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550.
(e) Fu¨rstner, A.; Voigtla¨nder, D.; Schrader, W.; Giebel, D.; Reetz, M. T.
Org. Lett. 2001, 3, 417. (f) Dyker, G.; Hildebrandt, D.; Liu, J.; Merz, K.
Angew. Chem., Int. Ed. 2003, 42, 4399. (g) Mertins, K.; Jovel, I.; Kischel,
J.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 238. (h) Iovel, I.;
Mertins, K.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2005,
44, 3913.
(8) (a) Hashimoto, Y.; Hirata, K.; Kagoshima, H.; Kihara, N.; Hasegawa,
M.; Saigo, K. Tetrahedron 1993, 49, 5969. (b) Tsuchimoto, T.; Tobita, K.;
Hiyama, T.; Fukuzawa, S-I. J. Org. Soc. 1997, 62, 6997. (c) Miyai, T.;
Oniishi, Y.; Baba, A. Tetrahedron 1999, 55, 1017.
10.1021/jo062633n CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/20/2007
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J. Org. Chem. 2007, 72, 3100-3103

TABLE 2. Bisarylation of 4-Nitrobenzaldehyde with Anisole in the
SCHEME 1. Synthesis of TRAM 3: Model Studies with
Aldehyde 1 and Arene 2
Presence of Catalytic Ir-LA Combinationa
entry
Lewis acid partner
yield of 3 (%)b
1
2
3
4
5
6
7
8
AlCl3
InCl3
TiCl4
BF3.Et2O
CdCl2
Sc(OTf)3
SnCl2
5(5)
4(4)
11(11)
3(3)
0
2(2)
13(13)
<1(<1)
ZnCl2
TABLE 1. Bisarylation of 4-Nitrobenzaldehyde with Anisole in the
a Reaction conditions: aldehyde (1 mmol), anisole (3 mmol), [Ir-
(COD)Cl]2 (0.01 mmol, 1%), Lewis acid (0.04 mmol, 4%), 90 °C, 1.5 h.
b Yields in parentheses are in the absence of [Ir(COD)Cl]2
Presence of Catalytic Tm-Sn Combinationa
entry
Tm partner
yield of 3 (%)
1
2b
3c
4
5
6
7
8
9
Nil
11
77
<1
12
25
34
10
17
9
[Ir(COD)Cl]2
[Ir(COD)Cl]2
IrCl3
CHART 2. Synthesis of Bioactive TRAMs [24-26] with
Catalytic Ir-Sn Combination
IrCl(CO)(PPh3)2
RhCl(CO)(PPh3)2
RhCl(PPh3)3
[Rh(COD)Cl]2
CoCl(PPh3)3
NiCl2(PPh3)2
PdCl2(PPh3)2
PtCl2(PPh3)2
10
11
12
10
10
12
a Reaction conditions: aldehyde (1 mmol), anisole (3 mmol), Tm
complex (0.01 mmol, 1%), SnCl4 (0.04 mmol, 4%), 90 °C, 1.5 h.
b Additionally 12% of another isomer (4-nitrophenyl)(2-methoxyphenyl)(4-
methoxyphenyl)methane 3′ was obtained. c Without SnCl4.
(1 mol %) and AgOTf (3 mol %) catalysts, but in both cases
there was no conversion, and starting materials were isolated
back satisfactorily.
noteworthy.9 However, in our hand, the latter failed in a model
reaction (see discussion later).
With the reliable bimetallic combination of catalytic [Ir-
(COD)Cl]2/SnCl4, we next explored the bisarylation of aldehyde
1 with various arenes and heteroarenes for the synthesis of
corresponding TRAMs. The results represented in Table 3 show
that all the reactions gave selective formation of triarylmethane
derivatives. Electron-rich arenes and heteroarenes such as
anisole, 1,2-dimethoxybenzene, 1,3,5-trimethoxybenzene, 1-meth-
oxynaphthalene, thiophenol, 2,5-dimethylfuran, thiophene, and
4-methylphenol gave the corresponding TRAMs in moderate
to good yields (entries 1-4 and 6-9). The reaction of
1,4-dimethoxybenzene was comparatively slower and workup
after 12 h led to the isolation of desired product 7 in 37% yield
along with ∼52% of unreacted aldehyde (entry 5). Reaction of
phenol afforded the corresponding TRAMs 13 and 13′ in 56%
and 35% yields, respectively (entry 11). Incorporation of
electrowithdrawing substituent as in 4-chlorophenol caused
lowering in the yield of TRAM (entry 10).
For model studies we had chosen the bisarylation of 4-ni-
trobenzaldehyde (1) with anisole (2) for the synthesis of the
desired TRAM (4-nitrophenyl)bis(4-methoxyphenyl)methane (3)
(Scheme 1). Initial catalyst screening included a combination
of a low-valent late transition metal organometallic complex
(1 mol %) with SnCl4 (4 mol %). Among these, IrI and RhI
were promising Tm partners to SnCl4 (Table 1, entries 2, 5,
and 6). Unsurpassed catalytic efficiency was observed in the
case of [Ir(COD)Cl]2 as the partner, which afforded 3 in 77%
yield after 1.5 h (entry 2). Most gratifyingly, the reaction is
highly selective toward triarylmethane, and no diarylmethane
or other realkylation products were formed. Note that individu-
ally either [Ir(COD)Cl]2 or SnCl4 was poorly active, and even
a simple combination of IrCl3 and SnCl4 was also ineffective
(entries 1, 3, and 4). The above results prompted us to test
whether LAs, other than SnCl4, can be used as a partner to
iridium. The model reaction was, therefore, executed with a dual
combination of [Ir(COD)Cl]2 (1 mol %) and a Lewis acid (4
mol %) representing each of the four groups in Olah’s seminal
paper.10 Surprisingly, all of the LAs inclusive of AlCl3, InCl3,
TiCl4, BF3.Et2O, CdCl2, Sc(OTf)3, SnCl2, and ZnCl2 were
ineffective (Table 2). Finally, the model reaction was tested with
reported AuCl3 (1 mol %), as well as a combination of AuCl3
Henceforth we have tested the generality of the present
reaction with anisole varying the aldehyde partner (Table 4).
Reactions were facile with aromatic or heteroaromatic aldehydes
having an electron-withdrawing substituent on the aromatic ring
(entries 1-5 and 8). For terephthaldehyde having two aldehyde
moieties in the same substrate, anisole was used in excess (10
equiv with respect to aldehyde) and the desired product 15 was
obtained in 71% yield (entry 2). Noteworthy is the fact that the
reaction can tolerate other carbonyl groups such as keto, ester,
and carboxylic acid in the alkylating agent, which is indicative
of aldehyde selectivity (entries 3-5), and the corresponding
TRAMs 16-18 were obtained in excellent yields. Facile reaction
of 5-nitrofurfural afforded TRAM 21 in 88% yield (entry 8).
In contrast to the above results, reactions of benzaldehyde and
4-methylbenzaldehyde led to a decrease in product yield (entries
6 and 7), possibly due to the decrease in electrophilicity at the
aldehydic carbon atom. In our hand, 4-methoxybenzaldehyde
(9) (a) BF3:H2O as catalyst: Prakash, G. K. S.; Paknia, F.; Mathew T.;
Olah, G. A. Abstracts of Papers; 230th National Meeting of the American
Chemical Society, Washington, DC, Aug 28-Sept 1, 2005; American
Chemical Society: Washington, DC, 2005. (b) Prakash, G. K. S.; Shah, E;
Panja, C.; Mathew, T.; Shakhmin, A.; Olah, G. A. Abstracts of Papers;
232nd National Meeting of the American Chemical Society, San Francisco,
CA, Sept. 10-14, 2006; American Chemical Society: Washington, DC,
2006. (c) AuCl3/3AgOTf as catalyst: Nair, V.; Abhilash, K. G.; Vidya, N.
Org. Lett. 2005, 7, 5857.
(10) Olah, G. A.; Kobayashi, S.; Tashiro, M. J. Am. Chem. Soc. 1972,
94, 7443.
J. Org. Chem, Vol. 72, No. 8, 2007 3101

TABLE 3. Bisarylation of 4-Nitrobenzaldehyde (RCHO) with Various Arenes (Ar-H) Leading to Product TRAM (RCHAr2)a
a Reaction conditions: aldehyde 1 (1 mmol), arene (3 mmol), [Ir(COD)Cl]2 (0.01 mmol), SnCl4 (0.04 mmol), 90 °C. b Plus 12% of (4-nitrophenyl)(2-
methoxy phenyl)(4-methoxyphenyl)methane 3′. c Plus 35% of (4-nitrophenyl)(2-hydroxyphenyl)(4-hydroxyphenyl)methane 13′.
SCHEME 2. Control Experiments on the Intermediacy of Secondary Alcohol
failed to give the desired TRAM. While the reactions of aromatic
and heteroaromatic aldehydes having electron-withdrawing
substituent on the aromatic ring are generally facile, those of
aliphatic aldehydes are comparatively low yielding. For example,
with p-formaldehyde a mixture of regioisomer was obtained in
66% overall yield (entry 9). Due to its low boiling point, the
reaction of propanal was performed at 50 °C and the desired
product 23 was isolated in 30% yield (entry 10).
SCHEME 3. Reaction of Secondary Alcohol with
Heteroarene
While further scope and limitation of the bisarylation of
aldehyde using the bimetallic Ir-Sn catalyst combination is
under study, Chart 2 shows the synthesis of three bioactive
TRAMs 24-26 varying the aldehyde and arene motifs. In each
case, exclusive TRAM selectivity was noticed and no byproduct
was formed.
Even though we are far away from realizing the exact
mechanism for the present dual-reagent catalysis, the following
experimental results may be noted.
heterobimetallic complex [Ir2(COD)2(SnCl3)2(Cl)2(µ-Cl)2] (27)
having IrIII-SnIV motif.4 With 27 as catalyst (1 mol %), the
model reaction of 4-nitrobenzaldehyde (1) with anisole (2) at
90 °C afforded the desired TRAM (4-nitrophenyl)bis(4-meth-
oxy-phenyl)methane (3) in 40% yield after 1.5 h, indicating a
distinct heterobimetallic reactivity. Several attempts were made
to isolate the active catalyst, which is equal in turn-over
frequency to that of the combination of [Ir(COD)Cl]2/4SnCl4
in the TRAM forming reaction. This endeavor remained
unsuccessful until now.
(1) Reaction of [IrCl(COD)]2 in dichloromethane with SnCl4
in benzene under ambient condition led to the isolation of a
3102 J. Org. Chem., Vol. 72, No. 8, 2007

TABLE 4. Bisarylation of Different Aldehydes (R1CHO) with
dimethylfuran affording the corresponding TRAM product 29
in very high yield (99%) in just 10 min (Scheme 3).
Anisole (Ar1-H) Leading to Product TRAM (R1CHAr1 )a
2
(3) While studies are underway in our laboratory to under-
stand the detailed mechanism, an electrophilic aromatic substitu-
tion pathway is indicated by the formation of regioisomers in a
few cases (Table 3, entries 1 and 11, and Table 4, entry 9).
One may also note that in a number of cases bisarylation was
100% regioselective giving rise to a single product.
(4) Plausible complexation/interaction of the carbonyl func-
tionality at the tin center is indicated by preliminary in situ FT-
IR and 13C NMR experiments.11
In summary, we have developed a facile protocol using a
dual reagent catalysis concept for the bisarylation of aldehydes
that is 100% TRAM selective. While the exact nature of the
active catalyst from the dual combination of [Ir(COD)Cl]2/
4SnCl4 remains to be established, control experiments suggested
the plausible involvement of a heterobimetallic Ir-Sn core in
the present catalysis.
Experimental Section
Bisarylation of 4-Nitrobenzaldehyde with Anisole. A 10-mL
Schlenk flask equipped with a magnetic bar was charged with [Ir-
(COD)Cl]2 (0.01 mmol), SnCl4 (0.04 mmol), and anisole (3 mmol).
The flask was degassed with argon and placed into a constant
temperature bath at 90 °C. After the mixture was stirred vigorously
for 5 min, 4-nitrobenzaldehyde (1 mmol) was added to it, and the
reaction was allowed to continue at 90 °C (TLC monitoring;
petroleum ether 60-80 °C/ethylacetate (9:1)). After completion of
the reaction, the mixture was quenched with aqueous NH4F solution
and extracted with diethyl ether. The combined extract was washed
with water and brine and dried over MgSO4, and the solvent was
removed under reduced pressure. Purification by silica gel column
chromatography (60/120 mesh, petroleum ether 60-80 °C/ethyl-
acetate (97:3)) afforded triarylmethane 3 (269 mg, 77%, Rf 0.30
petroleum ether 60-80 °C/EtOAc (9:1)), along with another
regioisomer 3′ (42 mg, 12%, Rf 0.37 petroleum ether 60-80 °C/
EtOAc (9:1)).
Spectral data for 3: 1H NMR (200 MHz, CDCl3, 25 °C) δ 3.79
(s, 6H; 2 OCH3), 5.53 (s, 1H; CH), 6.84 (d, 3J(H,H) ) 8.7 Hz, 4H;
CH aromatic), 6.99 (d, 3J(H,H) ) 8.7 Hz, 4H; CH aromatic), 7.26
3
3
(d, J(H,H) ) 8.6 Hz, 2H; CH aromatic), 8.13 (d, J(H,H) ) 8.6
Hz, 2H; CH aromatic); 13C NMR (54.6 MHz, CDCl3, 25 °C) δ
54.9, 55.2, 113.9, 123.4, 130.0, 130.1, 134.7, 146.3, 152.3, 158.3;
HRMS calcd for C21H19NO4 + H+ 350.1392, found 350.1384. Anal.
(C21H19NO4) Calcd: C, 72.18; H, 5.48; N, 4.01. Found: C, 72.29;
H, 5.50; N, 4.03.
Spectral data for isomer 3′: 1H NMR (200 MHz, CDCl3,
25 °C) δ 3.71 (3H, s, OCH3), 3.79 (3H, s, OCH3), 5.91 (1H, s,
CH), 6.77-7.00 (8H, m, CH aromatic), 7.23 (2H, d, J ) 8.8 Hz,
CH aromatic), 8.11 (2H, d, J ) 8.8 Hz, CH aromatic); 13C NMR
(54.6 MHz, CDCl3, 25 °C) δ 48.9, 55.1, 55.4, 110.7, 113.8, 120.4,
123.3, 128.1, 129.8, 129.9, 130.3, 131.3, 134.1, 146.3, 152.3, 156.8,
158.2. HRMS: calcd for C21H19NO4 + H+ 350.1392, found
350.1375.Anal. (C21H19NO4) Calcd: C, 72.18; H, 5.48; N, 4.01.
Found: C, 72.31, H, 5.60, N, 4.09.
a Reaction conditions: anisole (3 mmol), aldehyde (1 mmol), [Ir-
(COD)Cl]2 (0.01 mmol), SnCl4 (0.04 mmol), 90 °C. b Aldehyde:arene 1:10.
c Plus 29% of (2-methoxyphenyl)(4-methoxyphenyl)methane 22′. d At
50 °C.
(2) The reaction of 4-nitrobenzaldehyde (1 mmol) with a
mixture of two arenes, namely 1,3,5-trimethoxybenzene (1
mmol) and 4-methylphenol (1 mmol), in the presence of
catalytic Ir-Sn afforded the cross-coupled TRAM product 28
in 37% yield besides self-coupled products (Scheme 2). TRAM
28 can only arise via the possible intermediacy of secondary
alcohol as an intermediate. Indeed under the mediation of Ir-
Sn as catalyst, diphenylcarbinol reacted spontaneously with 2,5-
Acknowledgment. Financial support from DST (to S.R.),
CSIR (to S.P.), and UGC (to J.C. and U.K.R.) is acknowledged
(11) For 4-methylbenzaldehyde, the shifts in the carbonyl frequency (∆ν,
cm-1) after the addition of SnCl4, complex 27, and [Ir(COD)Cl]2/4SnCl4
are 111, 102, and 110, respectively. The corresponding shifts in 13C NMR
signal of -CHO (∆δ, ppm) are 6.62, 0.52, and 0.79, respectively. Similar
behavior was also observed (in FT-IR) with Tm-SnCl4 combinations where
Ir(CO)Cl(PPh3)2 and Rh(CO)Cl(PPh3)2 are the Tm partners. See the
Supporting Information.
Supporting Information Available: Additional experimental
details and spectral and analytical data for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO062633N
J. Org. Chem, Vol. 72, No. 8, 2007 3103