I2-DMSO catalyzed synthesis of 1,2,2-triarylethanones via dual C-H activation of aryl methyl ketones

Article abstract of DOI:10.1016/j.tetlet.2014.01.137

An I₂-DMSO promoted domino protocol was developed for the synthesis of 1,2,2-triarylethanones from readily available aromatic methyl ketones and methoxybenzenes. The 1,2,2-triarylethanones are important precursors for the synthesis of Tamoxifen

Full text of DOI:10.1016/j.tetlet.2014.01.137

Accepted Manuscript
I2-DMSO catalyzed synthesis of 1,2,2-triarylethanones via dual C-H activation
of aryl methyl ketones
M. Raghavender Reddy, N. Nageswara Rao, K. Ramakrishna, H.M. Meshram
PII:
S0040-4039(14)00193-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.137
TETL 44170
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 December 2013
27 January 2014
28 January 2014
Please cite this article as: Raghavender Reddy, M., Nageswara Rao, N., Ramakrishna, K., Meshram, H.M., I2-DMSO
catalyzed synthesis of 1,2,2-triarylethanones via dual C-H activation of aryl methyl ketones, Tetrahedron Letters
(2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.01.137
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I2-DMSO catalyzed synthesis of 1,2,2-triaryl
ethanones via dual C-H activation
of aryl methyl ketones
M. Raghavender Reddy, N. Nageswara Rao, K. Ramakrishna, H. M. Meshram*
Ar2
O
OMe
R1
R2
O
I2/DMSO
R1
Ar2
CH3
950C, 2-4 h
MeO
OMe
R2 R1
R2
R1, R2 = H, OMe
Ar2 = 4-NO2C6H5-, 4-BrC6H5-, 4-ClC6H5-, C6H5-, 4-PhC6H5-,
4-HOC6H5, 5-MeC4H2S, 5-ClC4H2S, 8-OMe-C10H6-

Tetrahedron Letters
1
I2-DMSO catalyzed synthesis of 1,2,2-triarylethanones via dual C-H activation of
aryl methyl ketones
M. Raghavender Reddy, N. Nageswara Rao, K. Ramakrishna, H. M. Meshram*
Medicinal Chemistry and Pharmacology Division,
CSIR-Indian Institute of Chemical Technology,
Hyderabad–500 007, India. hmmeshram@yahoo.com.
Abstract— An I2-DMSO promoted domino protocol developed for the synthesis of 1,2,2-triarylethanones from readily
available aromatic methyl ketones and methoxybenzenes. The 1,2,2-triarylethanones are important precursors for the
synthesis of Tamoxifen and Droloxifene. The use of mild reaction conditions, high yield, and single step synthesis are the
advantages of the present protocol.
Keywords: Acetophenone, Iodine, DMSO, Kornblum oxidation, 1,2,2-triarylethanones and Friedel-Crafts reaction
Ar2
O
The 1,2,2-triarylethanones have attracted considerable
attention, mainly because of the interesting properties
associated with it. These compounds are structural analogs of
the widely employed drug intermediates like Tamoxifen (A)
and droloxifene (B) which are widely used as adjuvant in the
chemotherapy of the estrogen receptor breast cancer.1
Tamoxifen is the first drug of choice used in the therapy of
hormone-dependent breast cancer and also reduces the risk of
both recurrence and contralateral breast cancer due to
medicinal importance of these compounds. In view of this
many of the methods were reported for the synthesis 1,2,2-
triarylethanones2, which involves the use of palladium-based
catalysts3 and SeO2-BF3.OEt2.4 Recently, An-Xin Wu and
coworkers developed useful protocols for the synthesis of
1,2,2-triarylethanones via C-H oxidation of aryl methyl
ketones.5 On the basis of the previous literature survey, we
found that a wide range of acetophenones could easily be
transformed into α-iodo acetophenone6 in the presence of
I2/DMSO, and α-iodo acetophenone was easily transformed to
α-ketoaldehyde in the media of DMSO via Kornblum
oxidation.7 The α-ketoaldehyde is an excellent electrophilic
agent which further reacted with different nucleophiles to
yield regioselective products by Friedel-Crafts reaction. So it
is highly desirable to develop simple efficient catalytic and
eco-friendly approach for the synthesis of triarylethanones via
C-H activation of acetophenones.
OMe
R1
R2
O
I2/DMSO
R1
Ar2
CH3
950C, 2-4 h
MeO
OMe
R2 R1
R2
R1, R2 = H, OMe
Ar2 = 4-NO2C6H5-, 4-BrC6H5-, 4-ClC6H5-, C6H5-, 4-PhC6H5-,
4-HOC6H5, 5-MeC4H2S, 5-ClC4H2S, 8-OMe-C10H6-
Scheme 1: Synthesis of 1,2,2-triarylethanones from
methoxybenzenes and aryl methyl ketones
Our initial investigations focused on the diarylation of
acetophenone with 1,2,4-trimethoxybenzene and the results
are summarized in Table 1.
Table 1: Screening studies of the reaction of 1c and 2d with
various conditionsa
MeO
O
OMe
OMe
OMe
O
MeO
Catalyst
Solvent
OMe
MeO
OMe
OMe
Yield (%)b
NRc
Entry
Temperature (0C) Time (h)
Catalyst Solvent
-
-
-
6
6
1
2
3
4
5
6
7
100
100
95
NR
DMSO
DMSO
10
NIS
12
O
O
N
N
10
DMSO
DMSO
-
NaI
KI
I2
95
95
12
12
12
12
12
2
OH
20
A. Tamoxifen
B. Droloxifene
NR
NR
NR
95
Dioxane
I2
100
Recently, iodine has received considerable attention in
organic and pharmaceutical syntheses due to its inexpensive,
non-toxic, and environmentally friendly nature..8 In view of
this iodine has been used as an efficient catalyst for several
chemical transformations.9
I2
100
100
8
9
DMF
70
I2
DMSO
10
2
I2
DMSO
95
80
DMSO
80
2
11
I2
75
a methoxybenzene (2 equiv.), Acetophenone (1 equiv.), DMSO (2 equiv.)
and Iodine (1.3 equiv.) at 950C, b Isolated yield. c No reaction.
Herein, we wish to report an efficient and regio-selective
domino strategy for the synthesis of triarylethanones via
bisarylation of acetophenone catalyzed by I2-DMSO (Scheme
1).

2
Tetrahedron Letters
The use of catalysts such as NIS, NaI and KI resulted in lower
yields (Table 1, entry 3-5). The solvents dioxane and DMF
were not suitable for the reaction (Table 1, entry 2, and entry
7-8). No significant amount of product was observed in the
absence of iodine or DMSO (Table 1, entry 1-2 and entry 6).
Remarkably, among the amounts of catalyst (I2) and oxidant
(DMSO) screened (Table 1, entries 9–11), the combined
amounts of 1.3 equiv I2 and 2 equiv DMSO turned out to be
the best (Table 1, entry 10).
other activated arenes (Table 2, entries 15-19). The 1,3,5-
trimethoxybenzene showed slight steric and electronic effects
that are responsible for the lower yield and longer reaction
time (Table 2, entries 8-14).
Subsequently, a series of aryl methyl ketone derivatives and
methoxybenzenes were examined. The substrates bearing
electron donating group on the phenyl ring of acetophenone
(Table 2, entry 5, entry 13 and entry 19) and 8-methoxy-2-
naphthyl acetophenone (Table 2, entry 14) also afforded the
products in high yields (80-85%). When the substrates
bearing electron-withdrawing groups such as nitro group was
examined the corresponding product was obtained with a
comparatively lower yield in 65–70% (Table 2, entry 1 and
entry 8). Acetophenones bearing halogen substituents were
well tolerated and gave good yield of the products (Table 2,
entry 2, entry 9-10 and entry 15-16). The heterocyclic
acetophenones like 5-methyl-2-thienyl-methyl ketone and 5-
chloro-2-thienyl-methyl ketones (Table 2, entry 6 and entry 7)
also gave good yield. Furthermore, 4-phenyl acetophenone
also reacted with methoxybenzenes to give promising results
(Table 2, entry 4, entry 12, and entry 18). All the products
were characterized by IR, Mass and NMR spectral data.11
Table 2: Scope of synthesis of 1,2,2-triarylethanonesa
O
O
Ar1
I2, DMSO
Ar2
Ar1
H
Ar2
900C, 2-4 h
Ar1
Ar2
Ar1
Entry
1
Product
Time (h)
5
Yield (%)b
65
MeO
OMe
2a
O2N
3a
1a
3b
3c
3d
2
3
2c
Br
5
4
5
65
70
2d
2e
65
4
Ph
2f
3e
3f
5
6
3
4
75
65
HO
S
S
2h
3g
2i
A series of control experiments were conducted to prove the
mechanism of the reaction (Scheme 2). Acetophenone was
heated with I2 at 95 0C for 30 min. and α-iodoacetophenenone
(A) was obtained in 80% yield (Scheme 2i). The α-
iodoacetophenenone (A) could be converted into
7
4
65
Cl
MeO
OMe
2a
O2N
1b
3h
3i
70
70
8
9
5
5
OMe
2b
Cl
phenylglyoxal (B) or hydrated hemiacetal (C) in
a
3j
5
10
2c
70
quantitative conversion in DMSO at 95 0C (Scheme 2i).
Moreover, α-iodoacetophenenone (A) (1.0 mmol) also treated
with 1a (2.0 mmol) and I2 (1.2 mmol) at 95 0C in DMSO, and
the product 3q was afforded in 85% yield (Scheme 2ii).7 The
reaction of hydrated hemiacetal (C) (1 mmol) with 1a (2
mmol) also proceeded smoothly and gave an excellent yield
(90%) of product (Scheme 2iii), whereas the same reaction in
the absence of I2 gave low yields of product (Scheme 2iv).
These results indicated that I2 plays an important role and α-
iodoacetophenenone (A) and phenylglyoxal (B) are the key
intermediates in this protocol.
Br
11
2d
3k
3l
2
4
2
75
70
2e
12
Ph
2f
80
3m
3n
13
14
HO
MeO
3
80
75
2j
OMe
MeO
1c
3o
2.5
15
16
17
18
2b
Cl
OMe
3p
2.5
75
2c
Br
2d
3q
3r
80
75
2
3
O
O
O
O
I
OH
OH
O
DMSO, 95 0
95% conversion
C
I2
(i)
2e
H
C
Ph
B
2c
A 80% Yield
MeO
O
OMe
3s
2f
2
19
85
O
OMe
HO
I
I2
DMSO, 95 0
a acetophenone (1 mmol), methoxybenzene (2 mmol), Iodine 1.3 (mmol) and DMSO (2 mmol)
at 95 0C. b yield refers to pure products after column chromatography
(ii)
OMe
3q
C
OMe
90% yield
1a
A
MeO
The optimized reaction conditions10 were used as a basis for
the study of the domino reaction with other activated arenes.
The results are summarized in Table 2. 1,3-
dimethoxybenzene (Table 2, Entry 1-7) with various
acetophenones afforded a lower yield and required a longer
reaction time as compared to 1,3,5- or 1,2,4-
trimethoxybenzene (Table 2, Entries 8–19). This indicates
that highly activated benzenes are the best substrates for these
reactions. 1,2,4-Trimethoxybenzene was the most effective
arene for Friedel–Crafts alkylation reaction in relation to the
OMe
MeO
OMe
O
OMe
O
OH
OH
I2/DMSO
95 0
(iii)
OMe
3q
C
OMe
C
1a
90% yield
MeO
OMe
MeO
OMe
O
OMe
O
OH
OH
DMSO
95 0
(iv)
OMe
3q
C
OMe
C
1a
40% yield
MeO
OMe

Tetrahedron Letters
Scheme 2: Control experiments to prove the mechanism
Initially acetophenone was converted to
3
Yang, Y.; Wu, Y.- D.; Deng, C.; Cao, L. -P.; Meng, X.-G.;
Wu, A.-X. Org. Lett. 2010, 12, 1856; (e) Yin, G.; Zhou,
B.; Meng, X.; Wu, A. –X.; Pan, Y. Org. Lett. 2006, 8,
2245.
α-
iodoacetophenenone (A), which on Kornblum oxidation
phenylglyoxal (B) was formed in the presence of I2-DMSO.
Subsequent, regioselective double nucleophilic addition of
1,2,4-trimethoxybenzene with phenylglyoxal gave 1-phenyl-
2,2-bis(2,4,5-trimethoxyphenyl)ethanone. (Scheme 3)
6. (a) Yadav, J. S.; Reddy, B. V. S.; Singh, A. P.; Basak, A.
K. Tetrahedron Lett. 2008, 49, 5880; (b) Moorthy, J. M.;
Senapati, K.; Singhal, N. Tetrahedron Lett. 2009, 50,
2493; (c) Yin, G.; Gao, N.; She, N.; Hu, S.; Wu, A.; Pan,
Y. Synthesis 2007, 3113; (d) Zhu, Y. –P.; Lian, M.; Jia, F.
-C.; Liu, M. -C.; Yuan, J. -J.; Gao, Q. -H.; Wu, A. -X.
Chem. Commun., 2012, 48, 9086; (e) Gao, M.; Yin, G.;
Wang, Z.; Wu, Y.; Guo, C.; Pan, Y.; Wu, A. –X.
Tetrahedron 2009, 65, 6047.
7. (a) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones,
W. J.; Larson, H. O.; Levand, O.; Weaver, W. M. J. Am.
Chem. Soc. 1957, 79, 6562; (b) Kornblum, N.; Jones, W.
J.; Anderson, G. J. J. Am. Chem. Soc. 1959, 81, 4113.
8. (a) Togo, H.; Iida, S. Synlett 2006, 14, 2159; (b)
Jaratjaroonphong, J.; Sathalalai, S.; Techasauvapak, P.;
Reutrakul, V. Tetrahedron Lett. 2009, 50, 6012.
O
I2
O
O
O
O
I
I2
CHO
DMSO
I2
H
OMe
DMSO
Oxidation
A
B
MeO
OMe
MeO
O
OMe
OMe
MeO
O
OMe
OMe
OMe
OMe
MeO
MeO
OMe
OMe
Scheme 3: Plausible mechanism of the reaction
9. (a) Jereb, M.; Vrazic, D. Org. Biomol. Chem. 2013, 11,
1978; (b) Jaratjaroonphong, J.; Krajangsri, S.; Vichai
Reutrakul, V. Tetrahedron Lett. 2012, 53, 2476; (c) Chu,
C. –M.; Huang, W. –J.; Liu, J. –T.; Yao, C. -F.
Tetrahedron Lett. 2007, 48, 6881.
In conclusion, we have developed a highly efficient method
for the synthesis of 1,2,2-triarylethanones via dual C-H
activation of acetophenone and subsequent reaction with
electron rich arenes. The main advantages of present protocol
include the use of inexpensive catalyst and lower reaction
time.
10.General procedure: Iodine (1.3 mmol) was added slowly
to a solution of acetophenone (1.0 mmol) in dry DMSO (2
mmol) at room temperature under a dry nitrogen
0
atmosphere, which is then heated to 95 C for 30 min.
Subsequently, 1,2,4-trimetoxy benzene (2.0 mmol) was
Acknowledgments
0
added and heated at 95 C for stipulated amount of time.
After completion of the reaction, hypo solution was added
and extracted with ethyl acetate. The organic layer was
separated, washed with brine solution, dried over
anhydrous Na2SO4, and concentrated under reduced
pressure. After removal of the organics a low melting
solid remained. The solid was further purified by column
chromatography (hexane/ethyl acetate, 20:1) to obtain
1,2,2-triarylethanones (80% yield) as a white solid. (See
supporting information file for characterization data of 1H
13C NMR, mass spectra of 3(a-s)).
M. R. R., N. N. R and K R . thank CSIR-UGC for the
award of fellowship, and Dr. A. Kamal, outstanding scientist
and Head of MCP Division for his support and
encouragement.
The authors thank CSIR, New delhi for financial support
as part of XII five year plan program under the title ACT
CSC-0301
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