Reductive coupling of aromatic aldehydes and acetophenone induced by TiCl4-Al/CH2(COOEt)2

Article abstract of DOI:10.14233/ajchem.2013.14890

Induced by TiCl₄-Al/CH₂(COOEt)₂ in CH ₂Cl₂, some aromatic aldehydes and acetophenone can afford the corresponding 1,2-diols in 13-91 % yields with good dl- diastereoselectivities within 45-60 min at room temperature.

Full text of DOI:10.14233/ajchem.2013.14890

Asian Journal of Chemistry; Vol. 25, No. 14 (2013), 7993-7996
http://dx.doi.org/10.14233/ajchem.2013.14890
Reductive Coupling of Aromatic Aldehydes and Acetophenone Induced by TiCl4-Al/CH2(COOEt)2
*
CHANG-YING SONG , SHU-XIANG WANG, WEN-HAO CHU, JI-TAI LI, ZHENG ZHOU, HONG-YU LI and ZI-QING CAO
Key Laboratory of Analytical Science and Technology, Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and
Environmental Science, Hebei University, Baoding 071002, Hebei Province, P. R. China
*Corresponding author: E-mail: scy@hbu.edu.cn
(Received: 3 December 2012;
Accepted: 29 July 2013)
AJC-13857
Induced by TiCl4-Al/CH2(COOEt)2 in CH2Cl2, some aromatic aldehydes and acetophenone can afford the corresponding 1,2-diols in
13-91 % yields with good dl-diastereoselectivities within 45-60 min at room temperature.
Key Words: Aromatic aldehydes, Pinacol coupling, Pinacol, Low valent titanium, Esters.
Cp2TiPh, five aromatic aldehydes gave desired pinacol in 54-
96 % yields within 1-4 h. Kulinkovich et al.15, reported the
titanium(III) isopropoxide prepared by the reaction of
titanium(IV) isopropoxide with one equivalent of the Grignard
reagent transformed the aldehydes and the aromatic ketones
into the corresponding pinacols in good yields.
INTRODUCTION
Pinacol coupling reaction of carbonyl compounds is an
important organic reaction to form both the new C-C bond
and pinacols1,2, which has ofen been employed in total synthesis
of many natural products3,4. The chiral pinacols are also the
prominent auxiliaries in many asymmetric synthesis5-7. In parti-
cular, pinacol coupling has been employed as a key step in the
construction of HIV-protease inhibitors8. Recent efforts have
focused on the development of new reagents and reaction
systems to improve the reactivity of the reagents and diastereo-
selectivity of the products.
However, in spite of their potential utility, some of the
reported methods suffer from drawbacks such as longer
reaction time, expensive catalysts and harsh terms. Esters can
coordinate with TiCl4, so we wish to report the results on the
reductive coupling of aromatic aldehydes mediated by low
valent titanium using esters as ligands.
Since the first report by Mukayama9 of pinacol coupling
reactions mediated with a titanium reagent in 1973, low valent
titanium has attracted increasing attention. Clerici and Porta10
reported pinacol coupling of aromatic aldehydes and ketones
promoted by aqueous titanium trichloride in basic media, the
reaction was completed in a few minutes, but the method has
some limitations with respect to some aromatic aldehydes and
ketones and the diastereoslectivities of the pinacols are poor.
Schwartz and Barden11 reported the stereoselective pinacol
coupling in aqueous media in 1996, the 1,2-diols with good
yields and high diastereoselectivities were obtained. Gansäuer
et al.12 reported the titanocene-catalyzed pinacol coupling of
aromatic aldehydes proceeding in good yields and with high
diastereoselectivity under reagent control. Enders and Ullrich13
reported asymmetric pinacol coupling of aromatic aldehydes
under homogeneous conditions with TiCl2 in the presence of
enantiopure amines or hydrazines afforded 1,2-diols in mode-
rate to excellent yields with good dl-diastereoselectivities.
Itoh et al.14 reported diastereoselective pinacol coupling of
aldehydes promoted by monomeric titanocene(III) complex
EXPERIMENTAL
Liquid aldehydes were distilled prior to use. IR spectra
were recorded on a Bio-Rad FTS-40 spectrometer (KBr). MS
were determined on a VG-7070E spectrometer (EI, 70 eV).
1H NMR spectra were measured on a Bruker AVANCE 400
(400 MHz) spectrometer using TMS as the internal standard
and CDCl3 as a solvent.
General procedure: A 50 mL two neck round bottom
flask was charged with CH2Cl2 (5 mL), CH2(COOEt)2 (3
mmol), TiCl4 (2 mmol) under a nitrogen atmosphere. The two
neck round flask was put into ultrasonic bath and then Al
powder (4 mmol) was added. The reaction mixture was
irratiated and turned into dark green immediately. After 5 min,
the mixture was removed from ultrasonic bath. Then the
desired aldehyde (1, 1 mmol) in 1 mL CH2Cl2 was added and
the mixture was stirred at room temperature for a period as
indicated in Table-2 (the reaction was followed by TLC). After
the completion of the reaction, the resulting suspension was
quenched with 10 mL of 10 % K2CO3 and extracted with ethyl

7994 Song et al.
Asian J. Chem.
OH OH
acetate (3 mL × 15 mL ). The combined organic layers were
washed with saturated aqueous NaHCO3 solution and brine,
dried over anhydrous magnesium sulphate for 12 h and filtered.
Ethyl acetate was evaporated under reduced pressure to give
the crude product, which was separated by column chromato-
graphy on silica (200-300 mesh), eluted with petroleum ether
or a mixture of petroleum ether and diethyl ether. The authen-
TiCl4-Al-Ester
Ph
H
Ph
C
H
C
H
Ph
O
Scheme-I
OH OH
R1
R2
TiCl4-Al/CH2(COOEt)2
R1
C
C
R1
1
ticity of the product was established by their H NMR, MS
and IR spectral data.
O
R2 R2
2a: 1H NMR: δ 2.52 (2H, s, OH, meso), 3.18 (2H, s, OH,
dl), 4.68 (2H, s, CH, dl), 4.82 (2H, s, CH, meso), 7.11-7.32
(20H, m, Ph-H). m/z (%): 214 (1), 180 (7.6), 167 (12.5), 149
(6.0), 107 (93.8), 79 (100), 77 (73.8). IR (KBr, νmax, cm-1):
3480-3200.
2b: 1H NMR: δ 3.03 (2H, s, OH, meso), 3.07 (2H, s, OH,
dl), 5.42 (2H, d, CH, dl), 5.67 (2H, d, CH, meso), 7.14-7.28
(16H, m, Ph-H). m/z (%): 282 (1), 165 (47), 141 (89), 113
(13), 107 (14), 77 (100), 51 (38). IR (KBr, νmax, cm-1): 3500-
3100.
2c: 1H NMR: δ 2.80 (2H, s, OH, meso), 3.37 (2H, s, OH,
dl), 4.66 (2H, s, CH, dl), 4.85 (2H, s, CH, meso), 6.96-7.34
(16H, m, Ph-H). m/z (%): 263 (1.2), 251 (1.6), 178 (4.6), 165
(4.6), 141 (100), 113 (23.8), 77 (71.0). IR (KBr, νmax, cm-1):
3318-3260.
2d: 1H NMR: 2.96 (2H, s, OH, dl), 4.63 (2H, s, CH, dl),
7.02-7.28 (8H, m, Ph-H). m/z (%): 276 (14), 249 (32), 155
(100), 111 (8). IR (KBr, νmax, cm-1): 3420-3380.
2e: 1H NMR: δ 3.02 (2H, s, OH, meso), 3.06 (2H, s, OH,
dl), 5.31 (2H, s, CH, dl), 5.60 (2H, s, CH, meso), 7.22-7.68
(12H, m, Ph-H). m/z (%): 352 (1), 305 (1.4), 233 (10), 175
(100), 145 (10), 111 (25), 77 (15). IR (KBr, νmax, cm-1): 3400-
3320.
1
2
Scheme-II
dibutyl (o-)phthalate (Entry 7), diethyl camphorate (Entry 8),
diethyl malonate (Entry 9) and ethyl acetoacetate (Entry 10)
as ligands under stirring at room temperature within 40-50
min, 1,2-diphenyl-1,2-ethanediol was obtained with 90-93 %
yields.
However, the structure of esters had obvious effect on the
diastereoselectivity of 1,2-diphenyl-1,2-ethanediol. When the
ligand was single ester, the dl/meso of 1,2-diphenyl-1,2-
ethanediol was low. For example, when ethyl acetate , isopentyl
acetate and ethyl acetoacetate were used as ligands, the dl/
meso of 1,2-diphenyl-1,2-ethanediol was 68/32, 66/34 and 65/
35, respectively. For the double ester, using diethyl oxalate,
diethyl butanedioate, diethyl o-phthalate, dibutyl o-phthalate,
diethyl camphorate as ligands, the dl/meso of 1,2-diphenyl-
1,2-ethanediol was 76/24, 77/23, 82/18, 83/17 and 70/30,
respectively. Using diethyl malonate as ligand, the dl/meso of
1,2-diphenyl-1,2-ethanediol was 97.4/2.6. When diethyl
(trans)-butenedioate was used as ligand, the dl/meso of 1,2-
diphenyl-1,2-ethanediol was 16/84.
From the results above, using CH2(COOEt)2 as ligand,
the 1,2-diphenyl-1,2-ethanediol could be obtained in high yield
and good dl-diastereoselectivity. So we did a series of experi-
ments on the pinacol coupling of aromatic aldehydes and
ketones using CH2(COOEt)2 as ligand. The results are listed
in Table-2.
2f: 1H NMR: δ 2.32 (6H, s, CH3, dl), 4.69 (2H, s, CH, dl),
7.04-7.09 (16H, m, Ph-H). m/z (%): 242 (1.2), 195 (6), 121
(100), 107 (12), 77 (13). IR (KBr, νmax, cm-1): 3450-3280 cm-1.
2g: 1H NMR: δ 3.75 (6H, s, CH3O, dl), 3.79 (6H, s, CH3O,
meso), 5.13 (2H, s, CH, dl), 5.34 (2H, s, CH, meso) 6.85-7.25
(16H, m, Ph-H) ppm. Anal. calcd. (%) for C16H18O4: C 70.06,
H 6.61; found (%) C 70.02, H 6.63. IR (KBr, νmax, cm-1): 3640-
3130 cm-1.
The coupling of some aromatic aldehydes mediated by
TiCl4-Al using CH2(COOEt)2 as ligand was carried out in good
yields. For example, using the present system under stirring at
room temperature for 45 and 60 min, 2a and 2d were obtained
with 90 and 91 % yields, respectively. Whereas 2a and 2d
were prepared in 50 and 71 % yields, respectively with TiCl4-
Al in Et2O under stirring for 38 and 29 h16.
1
2h: H NMR: δ 4.59 (2H, s, CH, dl), 4.67 (2H, s, CH,
meso), 5.96 (4H, s, CH2, dl ), 6.06 (4H, s, CH2, meso ), 6.56-
6.81 (12H, m, Ph-H). m/z (%): 302 (1), 284 (2.5), 268 (5.0),
255 (11.8), 151 (100), 123 (32), 93 (77.1), 65 (39.0). IR (KBr,
νmax, cm-1): 3600-3100 cm-1.
1
As shown in Table-2, benzaldehyde and the aromatic
aldehydes with electron-withdrawing substituents in the
benzene ring (1a-1e) had high reactivity in the present system.
Under stirring at room temperature, 1a-1e afforded 2a-2e in
86-91 % yields within 45-60 min. In contrast, the aromatic
aldehydes with electron-donating substituents in the benzene
ring (1f-1i) showed lower reactivity. Compounds of 2g and
2h were obtained with 38 and 28 % yields within 1 h under
stirring at room temperature When 1g was as substrate, trace
amount of 2 g was obtained.
2j: H NMR: δ 1.51 (6H, s, CH3, dl), 1.59 (6H, s, CH3,
meso), 2.30 (2H, s, OH, meso), 2.60 (2H, s, OH, dl), 7.20-
7.26 (20H, m, Ph-H) ppm. m/z (%): 225 (4), 206 (4), 181
(32), 165 (9), 121 (100), 105 (12), 77 (11), 43 (80). IR (KBr,
νmax, cm-1): 3600-3100 cm-1.
RESULTS AND DISCUSSION
The effect of different esters on the benzaldehyde were
investigated (Table-1). As shown in Table-1, the coupling of
benzaldehyde mediated by TiCl4-Al using different esters as
ligands was carried out in good yields for a short time. For
example, using ethyl acetate (Entry 1), diethyl oxalate (Entry 3),
diethyl butanedioate (Entry 5), diethyl (o-)phthalate (Entry 6),
On the other hand, when the substrate were C6H5COCH3
(1j) and 4-ClC6H5COCH3 (1k), the yields of the corresponding
1,2-diols were 13 and 0 %, respectively. The results showed
that aromatic ketones had little reactivity induced by this system.

Vol. 25, No. 14 (2013)
Reductive Coupling of Aromatic Aldehydes and Acetophenone Induced by TiCl4-Al/CH2(COOEt)2 7995
TABLE-1
EFFECT OF THE STRUCTURE OF ESTER ON PINACOLIZATION OF BENZALDEHYDE
Entry
Ester
Temperature (oC)
Time (min)
Isolated yield (%)
dl/meso*
68/32
1
2
3
CH3COOEt
26
26
25
40
50
45
91
65
93
CH3COOCH2CH2CH(CH3)2
66/34
EtOOC-COOEt
COOEt
76/24
4
5
25
27
50
45
67
91
16/84
77/23
EtOOC
COOEt
COOEt
COOEt
6
7
28
26
40
45
92
90
82/18
83/17
COOEt
COOBu-n
COOBu-n
8
28
50
90
70/30
COOEt
COOEt
O
OEt
9
25
26
45
45
90
91
97.4/2.6
65/35
OEt
O
O
O
10
OEt
*Ratio of dl- and meso- isomer is determined by 1H NMR..
TABLE-2
PINACOLIZATION OF AROMATIC ALDEHYDES AND KETONES MEDIATED BY TiCl4-Al/CH2(COOEt)2
Entry
Substrate
C6H5CHO
Temperature (ºC)
Time (min)
Yield (%)
dl/meso*
97.4/2.6
80/20
98.7/1.3
dl only
68/32
dl only
67/33
80/20
–
a
b
c
d
e
f
25
22
21
21
22
20
22
21
21
22
22
45
50
60
60
60
60
60
60
60
60
60
90
86
2-ClC6H4CHO
3-ClC6H4CHO
4-ClC6H4CHO
2,4-Cl2C6H3CHO
4-CH3C6H4CHO
2-CH3OC6H4CHO
3,4-(OCH2O)C6H3CHO
4-CH3OC6H4CHO
PhCOCH3
90
91
87
73
g
h
i
38
28
Trace
13
j
77/23
–
k
PhCOPh
0
Improved diastereoselectivity has been observed in the
present system. When 4-ClC6H4CHO (1d) and 4-CH3C6H4CHO
(1f) are substrates, the dl/meso of the corresponding 1,2-diols
were 75/25 and 74/26, respectively in Itoh's report8, whereas
in the present system, 2d and 2f are both dl-only.
some aromatic aldehydes by using TiCl4-Al/CH2(COOEt)2 in
CH2Cl2 under stirring at room temperature. The main advantage
of the present procedure is the milder reaction conditions,
inexpensive catalyst and operational simplicity.
ACKNOWLEDGEMENTS
In addition, the position of substituents in the benzene
ring has some effects on the dl/meso in the system. The coupling
of the aromatic aldehydes with meta- or para-position substi-
tuents in the benzene ring has high diastereoselectivities,
whereas the coupling of aromatic aldehydes with ortho-position
substituents in the benzene ring showed low diastereo-
slectivities. For example, the dl/meso of 2c, 2d and 2f were
98.7/1.3, dl-only and dl-only. However, using 2-ClC6H4CHO
(1b), 2,4-Cl2C6H3CHO (1e) and 2-CH3OC6H4CHO (1g) as
substrates, the dl/meso of the corresponding 1,2-diols were
80/20, 68/32 and 67/33, respectively.
This work was supported by grants from Education
Department of Hebei province (Project Z2012041), College
students' innovative entrepreneurial training plan (Project
2012068) and Open Fund of Laboratory of Key Laboratory
of Analytical Science and Technology of Hebei Province
(Project 09265631D-6).
REFERENCES
1. G.M. Robertson, In eds.: B.M. Trost and I. Fleming, Comprehensive
Organic Synthesis, Pergamon: Oxford, p. 563 (1991).
2. J.E. McMurry, Chem. Rev., 89, 1513 (1989).
In summary, we have found an efficient and convenient
method for the preparation of diastereoslective pinacols from
3. E.J. Corey, R.L. Danheiser, S. Chandrasekaran, P. Siret, G.E. Keck and
J. Gras, J. Am. Chem. Soc., 100, 8031 (1978).

7996 Song et al.
Asian J. Chem.
4. C.S. Swindell, W. Fan and P.G. Klimko, Tetrahedron Lett., 35, 4959
(1994).
10. A. Clerici and O. Porta, Tetrahedron Lett., 23, 3517 (1982).
11. M.C. Barden and J. Schwartz, J. Am. Chem. Soc., 118, 5484 (1996).
12. A. Gansäuer, M. Moschioni and D. Bauer, Eur. J. Org. Chem., 1923
(1998).
5. J.K. Whitesell, Chem. Rev., 89, 1581 (1989).
6. C.A. Ray, T.W. Wallace and R.A. Ward, Tetrahedron Lett., 41, 3501
(2000).
13. D. Enders and E.C. Ullrich, Tetrahedron: Asymm., 11, 3861 (2000).
14. Y. Yamamoto, R. Hattori, T. Miwa, Y.I. Nakagai, T. Kubota, C.
Yamamoto, Y. Okamoto and K. Itoh, J. Org. Chem., 66, 3865 (2001).
15. E.A. Matiushenkov, N.A. Sokolov and O.G. Kulinkovich, Synlett, 77
(2004).
7. M.B. Andrus, B.B.A. Somasekhar, E.L. Meredith and N.K. Dalley,
Org. Lett., 2, 2035 (2000).
8. (a) B. Kammermeier, G. Beck, D. Jacobi and H. Jendralla, Angew. Chem.,
106, 719 (1994); (b) M.T. Reetz and N. Griebenow, Liebigs Ann., 335
(1996).
16. Y.L. Hu, Z.Y. Du, J.X. Wang, Y.S. Xi and S.J. Gu, Synth. Commun.,
28, 3305 (1998).
9. T. Mukaiyama, T. Sato and J. Hanna, Chem. Lett., 1041 (1973).