O-benzyl trichloroacetimidates having electron-withdrawing substituents in acid-catalyzed diarylmethane synthesis

Article abstract of DOI:10.1055/s-2006-944217

Reaction of O-benzyl trichloroacetimidates having electron-withdrawing substituents with arenes in the presence of catalytic amounts of TMSOTf gave the corresponding diarylmethanes in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944217

LETTER
1729
O-Benzyl Trichloroacetimidates Having Electron-Withdrawing Substituents
in Acid-Catalyzed Diarylmethane Synthesis
A
cid-Cata
i
lyzed
D
a
iarylmetha
n
ne Synthesisjun Zhang, Richard R. Schmidt*
Fachbereich Chemie, Universität Konstanz, Fach M 725, 78457, Konstanz, Germany
Fax +49(7531)883135; E-mail: Richard.Schmidt@uni-konstanz.de
Received 16 March 2006
NuH, X+
Y
Y
H
O
NH
CCl3
H
Nu
Abstract: Reaction of O-benzyl trichloroacetimidates having
electron-withdrawing substituents with arenes in the presence of
catalytic amounts of TMSOTf gave the corresponding diaryl-
methanes in good to excellent yields.
R
R
CCl3—CONH2
X+ = catalyst
Y = –OR, NR1R2 (R1 = acyl, R2 = alkyl)
–CH=CH2, –CH=CH–OR, –Ar,
Key words: O-benzyl trichloroacetimidates, arenes, diaryl-
methanes, catalysis
Scheme 1
Diarylmethane derivatives are fundamental building
blocks in organic synthesis and their preparation is an im-
portant industrial goal. They are important precursors for
preparing dyes and medicines,1–6 and they are also fre-
quently used as subunits in supramolecular structures
such as macrocycles, catenanes, and rotaxanes.7 Classi-
cally, diarylmethanes are prepared by the Friedel–Crafts
alkylation using benzylic halides, alcohols or aryl alde-
hydes.8 The standard conditions for the Friedel–Crafts
alkylation employ an alkyl halide and a Lewis acid pro-
moter such as aluminium(III) chloride. These conditions,
however, produce hydrogen halide, which induces side
reactions resulting in the production of by-products, and
disposal of the aluminium hydroxide, formed by usual
work-up, causes additional problems. There is, therefore,
a substantial interest to develop methods requiring mild
reaction conditions and catalytic amounts of the promot-
ers. Herein, we wish to report a convenient and efficient
synthesis of diarylmethanes by alkylation of arenes with
O-benzyl trichloroacetimidates in the presence of catalyt-
ic amounts of TMSOTf. In order to examine the scope of
this reaction, only O-benzyl trichloroacetimidates having
electron-withdrawing substituents were investigated.
reactions.13–16 As one of the extensions of this reaction
principle, we envisioned that even O-benzyl trichloro-
acetimidates having electron-withdrawing substituents
could be suitable alkylating agents for various nucleo-
philes if acid-catalyzed activation is still available.
Particularly suitable C-nucleophiles could be aromatic
compounds thus providing variously substituted diaryl-
methanes (Scheme 2).
The conversion of substituted benzyl alcohols to trichlo-
roacetimidates 2a–g25 is shown in Table 1. The starting
alcohols 1 are commercially available (1a–f) or prepared
according to published procedures (1g).17 These alcohols
were then transformed into the corresponding trichloro-
acetimidates using trichloroacetonitrile (10 equiv) and
DBU (0.01 equiv) in dry CH2Cl2. The reactions were al-
lowed to proceed at room temperature for 2–4 hours. TLC
showed that all the starting alcohols were converted to the
trichloroacetimidates during this period, except for the re-
action with 3,5-dinitrobenzyl alcohol (1f), which did go to
completion only after 12 hours. The reaction mixtures
were then concentrated under reduced pressure and the
trichloroacetimidates were purified by silica gel column
The transformation of O,O- and N,O-hemiacetals into O-
trichloroacetimidoyl derivatives and their acid-catalyzed
activation has proven to be a highly attractive and
powerful alternative to the classical glycosylation meth-
ods. It is currently one of the most frequently applied
strategies for glycoside bond formation (Scheme 1,
Y = OR, NR1R2).9–12 Other systems supporting carbonium
ion generation such as benzyl, allyl, oxyallyl, cyclo-
propylmethyl and cyclobutyl (Scheme 1, Y = –CH=CH2,
–CH=CH–OR, cyclopropyl, etc.) can also be transformed
into the corresponding trichloroacetimidate (TCAI) and
then employed in these valuable acid-catalyzed alkylation
CCl3
CCl3
NH
TMSOTf
CH2Cl2
O
O
+
NTMS
H
–
OTf
R
H
R
Donor
R'
Acceptor
H2N
CCl3
O
R
R'
SYNLETT 2006, No. 11, pp 1729–1733
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
Scheme 2
DOI: 10.1055/s-2006-944217; Art ID: G09506ST
© Georg Thieme Verlag Stuttgart · New York

1730
J. Zhang, R. R. Schmidt
LETTER
Table 1 Preparation of O-Benzyl Trichloroacetimidates 2a–g
CCl3
R
R
O
NCCCl3, DBU
CH2Cl2, r.t.
NH
OH
1
2
Reactant
Product
2a18
2b
R
Reaction time (h) Yield (%)a
Purification solvent (T/P + Et3N)b
1:4 + 0.5%
1a
1b
1c
1d
1e
1f
4-NO2
3.5
3.0
92
86
90
84
80
68
4-COOMe
4-CN
1:5 + 0.5%
2c
3.0
1:4 + 0.5%
2d19
2e
4-Br
2.0
1:5 + 0.5%
2-Br
2.5
1:5 + 0.5%
2f
3,5-di-NO2
12.0
1:3 + 0.5%
O
1g17
2g
4.0
95
1:5 + 0.5%
4
B
O
a Yields refer to pure isolated product.
b T: toluene; P: petroleum ether.
chromatography, using 10–20% toluene in petroleum 6a–d were obtained,25 except for entry 12, in which only
ether containing 0.5% of triethylamine. If desired, excess monoalkylated product 5f was isolated with higher yield
trichloroacetonitrile can be readily recovered. In most cas- than that of entry 6 (Table 2, method B, entries 8–12). The
es, yields in the transformations from alcohols to trichlo- regioselectivity in these displacement reactions is con-
roacetimidates were very high (85–95%), except the yield trolled both by the electron densities at different positions
of 68% for compound 2f.
and by the steric hindrance in compound 3, thus leading to
the 4-monoalkylated or 4,6-dialkylated products, rather
than to those alkylated at the sterically hindered 2-position
or electron-poor 5-position. The alkylation reaction was
further studied by reacting the trichloroacetimidates with
nonactivated benzene as nucleophile under similar condi-
tions. When equivalent amounts of benzene were used in
the reactions, only low yields (10–30%) of diaryl-
methanes 7 were obtained. This problem was solved
with excess amounts of benzene [of trichloroacetimidate
(1 mmol):benzene (1 mL)]; the results are outlined in
Table 2 (method C, entries 13–18).25 Compounds 7a–e
have been previously prepared.20–24 Compounds 5g and
7g are of value in Suzuki cross-coupling reactions.
Trichloroacetimidates 2a–g were then employed for the
alkylation studies with 1,3-dimethoxybenzene (3,
Table 2, Method A). With an electron-withdrawing group
at the aromatic ring, O-benzyl trichloroacetimidates 2a–g
are less prone to form the carbonium ions and hence the
alkylation reaction is less favored. However, we found
that the reaction between the trichloroacetimidates 2a–g
and compound 3 proceeded successfully though slowly
(12–24 h) in the presence of catalytic amounts of
TMSOTf under a nitrogen atmosphere and at room tem-
perature, giving the diarylmethanes (5a–g) in good yields
(Table 2, entries 1–7).25 It is noteworthy that, with 2.5
equivalents of trichloroacetimidate, dialkylated products
Table 2 Alkylation Reactions with Benzyl Trichloroacetimidates
Entry
TCAI
Method
Reaction time (h) Product
Yield (%)a
Purification solvent (P/T/E)b
Method A: molar ratio of 2:3 = 1:1
TMSOTf (0.2 equiv)
OCNHCCl3
+
R
CH2Cl2
OMe
OMe
MeO
MeO
2
R
3
5
1
2a
A
18
74
5:1:1
OMe
NO2
MeO
5a
Synlett 2006, No. 11, 1729–1733 © Thieme Stuttgart · New York

LETTER
Acid-Catalyzed Diarylmethane Synthesis
1731
Table 2 Alkylation Reactions with Benzyl Trichloroacetimidates (continued)
Entry
TCAI
Method
Reaction time (h) Product
Yield (%)a
81
Purification solvent (P/T/E)b
5:1:1
2
2b
A
12
OMe
COOMe
MeO
5b
3
4
2c
A
A
12
76
70
5:1:1
8:1:1
OMe
OMe
CN
Br
MeO
5c
2d
12
MeO
5d
Br
5
6
2e
2f
A
A
15
64
63
8:1:1
4:1:1
OMe
OMe
MeO
5e
NO2
24
MeO
NO2
5f
O
B
OMe
MeO
7
2g
A
10
77
6:1:1
O
5g
Method B: molar ratio of 2:3 = 2.5:1
TMSOTf (0.2 equiv)
OCNHCCl3
R
+
2
CH2Cl2
OMe
MeO
MeO
OMe
R
R
6
3
NO2
NO2
8
2a
B
18
68
3:1:1
OMe
MeO
6a
CO2Me
CO2Me
9
2b
B
12
76
3:1:1
OMe
MeO
6b
Synlett 2006, No. 11, 1729–1733 © Thieme Stuttgart · New York

1732
J. Zhang, R. R. Schmidt
LETTER
Table 2 Alkylation Reactions with Benzyl Trichloroacetimidates (continued)
Entry
10
TCAI
Method
Reaction time (h) Product
Yield (%)a
Purification solvent (P/T/E)b
CN
CN
2c
B
12
79
3:1:1
MeO
6c
OMe
Br
Br
11
12
2d
B
B
18
73
72
4:1:1
4:1:1
OMe
OMe
MeO
6d
NO2
2f
24
MeO
NO2
5f
Method C: compound 2, 1 mmol; benzene (6), 1 mL
TMSOTf (0.2 equiv)
CH2Cl2
OCNHCCl3
+
2
6
7
R
R
13
2a
2b
2c
2d
C
24
38
78
75
77
6:1:1
6:1:1
6:1:1
8:1:1
NO2
7a20
7b21
7c22
7d23
14
15
16
C
C
C
15
15
15
COOMe
CN
Br
Br
17
18
2e
2g
C
C
15
15
65
81
8:1:1
8:1:1
7e24
O
B
O
7g
a Yields refer to pure isolated product. In the case of method A and B, yields are based on 1,3-dimethoxybenzene; in the case of method C, yields
are based on the corresponding trichloroacetimidates.
b P: petroleum ether; T: toluene; E: ethyl acetate.
Synlett 2006, No. 11, 1729–1733 © Thieme Stuttgart · New York

LETTER
Acid-Catalyzed Diarylmethane Synthesis
1733
(19) Alterman, M.; Andersson, H. O.; Garg, N.; Ahlsen, G.;
Loevgren, S.; Classon, B.; Danielson, U. H.; Kvarnstroem,
I.; Vrang, L.; Unge, T.; Samuelsson, B.; Hallberg, A. J. Med.
Chem. 1999, 42, 3835.
(20) Darbeau, R. W.; White, E. H.; Song, F.; Darbeau, N. R.;
Chou, J. J. Org. Chem. 1999, 64, 5966.
(21) Dohle, W.; Lindsay, D. M.; Knochel, P. Org. Lett. 2001, 3,
2871.
(22) Arnold, D. R.; Du, X.; Chen, J. Can. J. Chem. 1995, 73, 307.
(23) Hicks, L. D.; Han, J. K.; Fry, A. J. Tetrahedron Lett. 2000,
41, 7817.
In summary, we have demonstrated a mild and efficient
method for the synthesis of diarylmethane derivatives
from the corresponding O-benzyl trichloroacetimidates as
alkylating agents and aromatic compounds as nucleo-
philes. Even with electron-withdrawing substituents, only
catalytic amounts of TMSOTf were required as promoter;
the method has the advantage of simple work-up, conve-
nient isolation of the products, and very good yields. The
protocol avoids the accumulation of environmental
harmful material and it is a useful addition to the existing
synthetic strategies.
(24) Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron Lett. 1998, 39,
6291.
(25) All compounds gave satisfactory analytical data. Described
below are representative procedures and spectral data for
compound 2c, 5c, 6c, and 7c.
Acknowledgement
General Procedure for the Preparation of
Trichloroacetimidates.
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. The support from the
Alexander von Humboldt-Foundation for J.Z. is highly appreciated.
To a stirred solution of 4-hydroxymethylbenzonitrile (1c,
2.67 g, 20 mmol) in dry CH2Cl2 (20 mL) and trichloroaceto-
nitrile (20 mL, 200 mmol) was added DBU (0.03 mL, 0.2
mmol) at r.t. under nitrogen and stirred for 3 h. The reaction
mixture was concentrated under reduced pressure and the
crude residue was purified by column chromatography
(toluene–PE = 1:8, +0.5% Et3N) to give 2c as a white
powder (5.02 g, 90%). 1H NMR (250 MHz, CDCl3): d = 8.47
(br, 1 H, NH), 7.68 (d, 2 H, J = 8.0 Hz), 7.54 (d, 2 H, J = 8.0
Hz), 5.39 (s, 2 H, CH2). Anal. Calcd for C10H7Cl3N2O
(275.96): C, 43.28; H, 2.54; N, 10.09. Found: C, 43.24; H,
2.75; N, 10.20.
General Procedure for the Alkylation Reactions.
To a solution of trichloroacetimidate 2c (1.40 g, 5 mmol) in
dry CH2Cl2 (20 mL) was added the corresponding acceptors
(method A: 5 mmol of 1,3-dimethoxybenzene; method B:
2 mmol of 1,3-dimethoxybenzene; method C: 5 mL of
benzene). The mixture was stirred under the protection of N2
and then TMSOTf (180 mL, 0.5 mmol) was added. After
completion of the reaction (TLC), the mixture was
neutralized with Et3N, concentrated in vacuo, and the
residue was purified by flash chromatography.
References and Notes
(1) Zollinger, H. Color Chemistry; VCH: Weinheim, 1987.
(2) Katritzky, A. R.; Lan, X.; Lam, J. N. J. Org. Chem. 1991, 56,
4397.
(3) Boyd, R. E.; Rasmussen, C. R.; Press, J. B.; Raffa, R. B.;
Codd, E. E.; Connelly, C. D.; Li, Q. S.; Martinez, R. P.;
Lewis, M. A.; Almond, H. R.; Reitz, A. B. J. Med. Chem.
2001, 44, 863.
(4) Hsin, L. W.; Dersch, C. M.; Baumann, M. H.; Stafford, D.;
Glowa, G. R.; Rothman, R. B.; Jacobon, A. E.; Rice, K. C. J.
Med. Chem. 2002, 45, 1321.
(5) Novak, T. J.; Kramer, D. N.; Klapper, H.; Dassch, L. W. J.
Org. Chem. 1991, 41, 870.
(6) Katritzky, A. R.; Lan, X.; Lam, J. N. Synthesis 1990, 341.
(7) Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303.
(8) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S. J.
Org. Chem. 1997, 62, 6997; and references therein.
(9) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212;
Angew. Chem. 1986, 98, 213.
(10) Roussel, F.; Takhi, M.; Schmidt, R. R. J. Org. Chem. 2001,
66, 8540.
(11) Abdel-Rahman, A. A.-H.; Jonke, S.; El Ashry, E. S. H.;
Schmidt, R. R. Angew. Chem. Int. Ed. 2002, 41, 2972;
Angew. Chem. 2002, 114, 3100.
(12) El-Nezhawy, A. O. H.; El-Diwani, H. I.; Schmidt, R. R. Eur.
J. Org. Chem. 2002, 4137.
(13) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun.
1981, 1240.
(14) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc.,
Perkin. Trans. 1 1985, 2247.
(15) Abdel-Rahman, A. A.-H.; Winterfeld, G. A.; Takhi, M.;
Schmidt, R. R. Eur. J. Org. Chem. 2002, 713.
(16) Ali, I. A. I.; El Ashry, E. S. H.; Schmidt, R. R. Tetrahedron
2004, 60, 4773.
(17) Filippis, A.; Morin, C.; Thimon, C. Synth. Commun. 2002,
32, 2669.
(18) Clegg, W.; Pogue, H. J.; Lowe, M. P.; Butterfield, I. M.;
Jackson, R. F. W. Acta Crystallogr., Sect. C: Cryst. Struct.
Commun. 1995, 51, 741.
Compound 5c: yield 0.96 g, 76%. 1H NMR (250 MHz,
CDCl3): d = 7.52 (d, 2 H, J = 8.3 Hz), 7.26 (d, 2 H, J = 8.3
Hz), 6.98 (d, 1 H, J = 8.3 Hz), 6.45–6.41 (m, 2 H), 3.93 (s, 2
H, CH2), 3.80 (s, 3 H, OCH3), 3.76 (s, 3H, OCH3). 13C NMR
(62.5 MHz, CDCl3): d = 159.95, 158.20, 147.41, 131.99,
130.69, 129.37, 104.20, 98.74, 96.08, 55.30, 35.70. Anal.
Calcd for C16H15NO2 (253.11): C, 75.87; H, 5.97; N, 5.53.
Found: C, 75.62; H, 5.75; N, 5.50.
Compound 6c: yield 0.73 g, 79%. 1H NMR (250 MHz,
CDCl3): d = 7.53 (d, 4 H, J = 8.4 Hz), 7.26 (d, 4 H, J = 8.4
Hz), 6.83 (s, 1 H), 6.46 (s, 1 H), 3.91 (s, 4 H, 2 × CH2), 3.79
(s, 6 H, 2 × OCH3). 13C NMR (62.5 MHz, CDCl3): d =
157.20, 147.29, 132.09, 132.03, 129.28, 119.59, 109.55,
96.10, 95.49, 55.57, 35.66. Anal. Calcd for C16H15NO2
(368.15): C, 78.24; H, 5.47; N, 7.60. Found: C, 78.25; H,
5.73; N, 7.60.
Compound 7c: yield 0.72 g, 75%. 1H NMR (250 MHz,
CDCl3): d = 7.50 (d, 2 H, J = 8.4 Hz), 7.36–7.16 (m, 7 H),
4.06 (s, 2 H); practically identical to the published data.22
Synlett 2006, No. 11, 1729–1733 © Thieme Stuttgart · New York