A convenient and selective synthesis of unsymmetrical benzoins via the cyanide ion catalyzed cleavage of benzils

Article abstract of DOI:10.1016/j.tet.2004.03.016

The cyanide ion-catalyzed cleavage of benzils is used for the generation of various 'masked' acyl intermediates. The reaction of these intermediates with various aldehydes furnishes the corresponding esters of unsymmetrical benzoins in very good yields. A variety of unsymmetrical benzoin derivatives are synthesized in this way, including ferrocene derivatives. The hydrolysis of benzoin esters and their subsequent oxidation affords the corresponding unsymmetrical benzoins and benzils in high yield.

Full text of DOI:10.1016/j.tet.2004.03.016

Tetrahedron 60 (2004) 3803–3811
A convenient and selective synthesis of unsymmetrical benzoins
via the cyanide ion catalyzed cleavage of benzils
¨
Ayhan S. Demir and Omer Reis
*
Department of Chemistry, Middle East Technical University, Inonu Bulvari, 06531 Ankara, Turkey
Received 18 November 2003; revised 10 February 2004; accepted 4 March 2004
Abstract—The cyanide ion-catalyzed cleavage of benzils is used for the generation of various ‘masked’ acyl intermediates. The reaction of
these intermediates with various aldehydes furnishes the corresponding esters of unsymmetrical benzoins in very good yields. A variety of
unsymmetrical benzoin derivatives are synthesized in this way, including ferrocene derivatives. The hydrolysis of benzoin esters and their
subsequent oxidation affords the corresponding unsymmetrical benzoins and benzils in high yield.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Grignard reagents can be added to OTMS cyanohydrins to
form the isomeric benzoin via a common intermediate.4,5
These methods have certain drawbacks such as use of air
sensitive reagents and protection–deprotection steps.
Recently, an excellent method was disclosed in which
acylsilanes produce 1c in the cyanide ion-catalyzed
reaction. This intermediate reacts with aldehydes to afford
the corresponding silyl protected benzoins in high yields.6
However, the synthesis of acylsilanes are generally
accomplished via the corresponding dithianes that also
requires the use of air sensitive reagents and some laborious
protection–deprotection steps.7 Although C–C forming
enzymes8 have been shown to provide unsymmetrical
benzoins in enantiomerically pure form, its applicability is
limited to the use of only a few aldehydes; and enzymes
mediating this reaction are not readily available.8d Some
other methods have also been reported to provide less stable
unsymmetrical benzoins, but the versatility of the reaction is
limited by low yields (30–50%) and side products.9
The cyanide ion-catalyzed condensation of aromatic
aldehydes to the corresponding benzoins has great synthetic
utility. According to a well documented classical benzoin
condensation mechanism, cyanide ion catalyzed generation
of acyl anion equivalent 1a ion is the key step in this
transformation.1 Many improvements have been made for
the symmetrical benzoin condensation utilizing thiazolium
and triazolium salts,2 but synthesis of unsymmetrical
benzoins, under traditional conditions, have problems
associated with the formation of four possible benzoins,
two of them being isomeric.3 Thus, the synthesis of a
specific isomer, especially the more energetic one, is
accomplished by condensation of an acceptor aldehyde
with an acyl anion equivalent of type 1 (Figure 1).
In 1923, Dakin and Harington showed that the cyanide ion
catalyzes the cleavage of benzil to benzaldehyde and the
ester of benzoic acid.10 Later, the mechanism and kinetics of
the reaction were investigated by Kwart and Baevsky,
demonstrating the intermediacy of 1d.11 Trisler and Frye
showed that 1d, in aprotic solvent DMSO where it is highly
nucleophilic, reacts with another molecule of benzil present
in the reaction solution to form trans-a,a0-stilbendiol
dibenzoate.12 This work showed that 1d is a potent
nucleophile and can react with an electrophile in the medium.
Later, Kuebrich and Schowen used benzil and cyanide in
DMF to generate the intermediate 1d and examined its
reaction with benzaldehyde and furfural.13Although 1d
could be generated efficiently under aprotic conditions,
utilizing it to unsymmetrical benzoins has only been
Figure 1.
Common approaches employ LDA deprotonation of the
TMS ether of an aromatic cyanohydrin to form 1b or the
BuLi deprotonation of dithianes to form 1e, which can
subsequently be reacted with the acceptor aldehydes to
obtain the desired benzoins. Alternatively, aromatic
Keywords: Benzoin; Benzil; Unsymmetrical; Photolabile.
*
Corresponding author. Tel.: þ90-312-2103242; fax: þ90-312-2101280;
e-mail address: asdemir@metu.edu.tr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.016

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A. S. Demir, O. Reis / Tetrahedron 60 (2004) 3803–3811
3804
exemplified with furfural and not well developed and
understood as discussed below; otherwise it would be quite
useful for benzoin synthesis in both free and protected form.
Herein we report our investigation focused on under-
standing the nature of 1d and its derivatives together with its
possible utilization for the synthesis of unsymmetrical
benzoins.
the thermodynamically more stable isomer under typical
basic hydrolysis conditions, the correct structural assign-
ment of the initial structures gains prime importance.
Reported 1H NMR shift values for a series of mono
substituted benzoins show that two ortho-protons of benzoyl
moiety resonate at around d 7.9.9 For the compounds listed
in Table 1, we observed two doublets at around d 7.9 and 8.1
that respectively originate from the benzoyl moiety of the
benzoin and ester part. However, ferrocenecarboxaldehyde
afforded the isomeric products 4h and 4l instead of the
expected compounds 6 and 7 (Scheme 2). This observation
was based on the lack of two ortho-protons of benzoyl
moiety in benzoin portion of the molecule supported by 2D
NMR analysis. All other products have 2D NMR spectra in
agreement with the structures depicted in Table 1. The
difference in reactivity can be attributed to the electron-rich
nature of the ferrocenyl group. Although aldehyde 3e has
two electron-donating groups, methoxy substituent on the
meta- position has a s-value with a positive sign and yields
the expected product. For a better understanding, 3,4,5-
trimethoxybenzaldehyde 9 was reacted in a similar manner
and two isomeric products were isolated in a 1:2 ratio (in
favor of isomeric product) just after the completion of the
reaction. Changing the p-methoxy group with an acetoxy
group resulted in the formation of the desired isomer 4f. As
mentioned previously, Kuebrich et al. reported the same
reaction with electron-rich furfural.13 Although they
reported the formation of 10 according to the mechanism
in Scheme 1, their NMR data strongly resembles that of 11
lacking the two ortho-benzoyl protons. This supports the
idea that electron-rich aldehydes have a propensity to yield
isomeric products but it is not clear whether this is a
problem of product stability or a different mechanism is
operative.
2. Results and discussion
For the synthesis of unsymmetrical benzoins, a solution of
benzil 2a and a potentially competent electrophile, 2-
trifluoromethylbenzaldehyde 3a, in DMF was treated with
KCN. Product 4a was obtained as expected, in agreement
with the mechanisms proposed by Kuebrich et al., as shown
in Scheme 1. According to this procedure, various
aldehydes were reacted in order to understand the scope
of the reaction and the effect of the electronic nature of the
substituents. We have also shown that 2-naphthil 2b can be
used instead of 2a (entries 9–12). Protected unsymmetrical
benzoins, including interesting ferrocenyl derivatives, were
obtained in very good to excellent yields as summarized in
Table 1.
Some derivatives of benzoins are very useful photolabile
protecting group of carboxylic acids. Upon irradiation at
,350 nm they release the acid moiety. The best photosen-
sitive benzoin developed so far can be obtained from 4e
after hydrolysis,5 and a recent report showed that 4e itself
releases the benzoate moiety almost quantitatively.4c Thus,
the present method may allow the rapid synthesis of
derivatives of 4, which can then be tested for photolability,
such as 4f.14 Recently reported synthesis of unprotected
form of 4e in 56% yield (overall 35% yield starting from
benzaldehyde) by a dithiane method4d compared to 71% of
this method (for hydrolysis, see below) is very promising in
terms of yield and operational simplicity.
Products 4a-l are in protected form and their hydrolysis can
afford the corresponding unsymmetrical benzoins or benzils
upon oxidation. Hydrolysis of the products to the corre-
sponding benzoins 12 was carried out in a basic medium
similar to previously reported procedure (Scheme 3).16
While isomerization was not a problem with most
derivatives, the 2-methyl derivative 4d afforded an isomeric
mixture, and 2-Br derivative 4c exhibited a small amount of
isomerization and the product was obtained in a 9:1 ratio.
Particular attention to the structural integrity was required,
because it was demonstrated by Corrie et al. that carbonyl
derivatives of unsymmetrical benzoins may scramble to
form isomeric compounds.15 Taking into account the fact
that some unsymmetrical benzoins may also isomerize to
Scheme 1.

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A. S. Demir, O. Reis / Tetrahedron 60 (2004) 3803–3811
3805
Table 1. Yields and structures of unsymmetrical benzoin derivatives
Benzil 2 Ar1 Aldehyde 3 Ar2
Entry
Product 4
Yield (%)a
1
2a Ph
3a 2-CF3Ph
4a
4b
4c
4d
98
99
95
93
2
3
4
2a Ph
2a Ph
2a Ph
3b 2-FPh
3c 2-BrPh
3d 2-MePh
5
6
2a Ph
3e 3,5-(OMe)2Ph
4e
4f
83
85
2a Ph
3f 3,5-(OMe)2-4-OAcPh
7
2a Ph
3g 2-pyridyl
3h ferrocenyl
3i 2-naphthyl
4g
4h
4i
78
89
77
8
2a Ph
9b
2b 2-naphthyl
10b
2b 2-naphthyl
2b 2-naphthyl
3j Ph
4j
79
73
11b
3k 1-Br-2-naphthyl
4k
12b
2b 2-naphthyl
3h ferrocenyl
4l
74
a
Isolated yields.
R: 2-naphthoyl.
b

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A. S. Demir, O. Reis / Tetrahedron 60 (2004) 3803–3811
3806
Scheme 2.
Other o-substituted a-diketones were effectively converted
into the corresponding benzoins.
An0 interesting feature of the reaction was observed with
2,2 -bipyridil 2h. When the reaction was carried out in the
presence of 2-methylbenzaldehyde at 35 8C, the reaction
was very slow and only small amounts of product were
observed after 5 days. Increasing the temperature resulted in
the formation of side products. When 2-fluorobenzaldehyde
was used instead of 2-methylbenzaldehyde (Table 2, entry
6), the yield was 65% after 72 h, even though the reaction
was not complete. Increasing the temperature also increased
the amounts of side products. Changing 2-fluorobenz-
aldehyde with the more electronegative 2-trifluoromethyl-
benzaldehyde furnished the product 4r in 77% yield in 24 h.
This behavior of the reaction can be attributed to the rate of
formation of intermediate 13 from 2,20-bipyridil and the rate
of its reaction with the aldehyde. Although the cyanide
attack should have been favored by the presence of pyridyl
moiety, it disfavors the cleavage of the central C–C bond
formation and retards the transfer of this group onto oxygen,
which results in the slow formation of 13. The increase in
the reaction rate upon the use of an aldehyde substituted
with a more electronegative group can be explained on the
basis of the increased stability of the intermediate 13
which can rearrange back to the starting material and only
reacts with an appreciable rate when the aldehyde is very
reactive.
Scheme 3.
Hydrolysis of already isomeric 4h furnished 12a. Oxidation
was a problem during hydrolysis if the oxygen in the
medium was not removed before the reaction, as reported
previously.16 Isomerization possibly occurs via an endiol
intermediate like 8 and the yellow color that developed
during the reaction was attributed to this intermediate. This
intermediate is expected to be easily oxidized during
hydrolysis if air is not excluded from the medium. In the
hydrolysis of 4e to the corresponding benzoin 12d, 4:1
mixture of isomers was obtained under standard conditions.
When the same reaction was carried out at lower pH values,
a 10:1 mixture of isomers was obtained with prolonged
reaction times (6–8 h) in 94% overall yield.
In order to obtain further insights into the scope of the
reaction, a series of electronically diverse ortho-substituted
symmetric a-diketones were reacted with selected alde-
hydes as depicted earlier in Scheme 1. ortho-Position was
selected in order to asses the effect of the steric hindrance
adjacent to the reacting center. The results are summarized
in Table 2. Amongst these a-diketones, o-methoxy was
unreactive under the reaction conditions. Increasing the
temperature did not affect the transformation. This stability
of the diketone 2c can be attributed to the strong electron-
donating nature of –OMe, which disfavors cyanide
addition. Although this type of group eases the shift of the
carbonyl group, Kwart and Baevsky described the failure of
an electron-donating group to significantly accelerate the
cleavage if the resonance stabilization of the positive charge
on the migrating carbonyl was the only important feature.
According to the mechanism of cyanide ion cleavage of
benzil proposed by Kwart and Baevsky, the phenyl ring
having a substituent with a more positive s-value ends up as
aldehyde, while the other phenyl ring ends up in the ester or
acid part through the decomposition of intermediate 14 that
can be trapped with an aldehyde, thus forming disubstituted
unsymmetrical benzoins. In fact, when compound 15 was

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3807
Table 2. Yields of disubstituted benzoin derivatives
Entry
1
Benzil 2 Ar1
2c 2-OMePh
Aldehyde 3 Ar2
Product 4
Yielda (%)
—
2d
No reaction
2
3
4
2d 2-MePh
2e 2-BrPh
2f 2-ClPh
2g 2-FPh
2h
2d
2d
2d
4m
4n
4o
73
69
82
72
5
4p
6
2h 2-pyridyl
2b
4q
65
7
2h 2-pyridyl
2a
4r
77
a
Isolated yields.
treated with KCN in the presence of aldehyde 3d
(Scheme 4), we isolated the product 16 where electron
rich ferrocene ring occupied the ester part. The hydrolysis of
16 furnished only ferrocene carboxylic acid and correspond-
ing 2-methylbenzil in accordance with the proposed
structure. Similarly, reaction of 17 with 3h and subsequent
hydrolysis of the crude product afforded 18 in 69% yield in
accordance with these predictions. According to these
results, the reaction of unsymmetrical benzils is promising
and requires further investigation to find out if this approach
is a generally applicable; a subject already under investi-
gation. It is worth mentioning that a comparable result was
obtained in an unoptimized reaction between 2a and 3d in
refluxing MeCN as solvent.
3. Conclusion
In conclusion, we have shown that the cyanide ion-
catalyzed cleavage of aromatic a-diketones can be used
for the generation of various ‘masked’ acyl intermediates of
type 1d. These intermediates may be reacted with various
aromatic aldehydes to form the corresponding esters of
unsymmetrical benzoins in high yields. A variety of
different benzoin derivatives can be synthesized in this
way. In addition, benzoate ester products may be used as
photoprotective groups. This method does not require the
handling of air sensitive reagents and protecting groups. It
gave either better or at least comparable results for the
synthesis of certain unsymmetrical benzoins such as the

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A. S. Demir, O. Reis / Tetrahedron 60 (2004) 3803–3811
3808
Scheme 4.
photolabile protecting group 12d. Thus, this method
generally offers the simplest approach for certain benzoins.
(12), 149 (32), 139 (82), 109 (22), 86 (24), 69 (74); 1H NMR
(CDCl3) d 7.38 (1H, s), 7.44–7.48 (1H, m), 7.51–7.54 (1H,
m), 7.72 (1H, d, J¼8 Hz), 7.78 (1H, d, J¼8.6 Hz), 7.97 (1H,
d, J¼8.6 Hz), 8.2 (1H, d, J¼8.5 Hz); 13C NMR (CDCl3) d
41.3, 119.9, 127.2, 128.2, 128.5, 128.8, 129.2, 131.6, 135.0,
138.4. Anal. Calcd for C11H7Br3: C, 34.87; H 1.86 found C,
34.95; H, 1.85.
4. Experimental
4.1. General
To a solution of 1-bromo-2-dibromomethyl naphthalene
(1.89 g, 5 mmol) in 200 ml EtOH, a solution of AgNO3
(1.7 g, 10 mmol) in 50 ml water was added and resulting
solution was refluxed. After 75 min green precipitate was
filtered by suction from hot solution. White crystals
appeared upon concentration under reduced pressure and
crystals were washed with cold EtOH:H2O (4:1) to obtain
1-bromo-2-naphthaldehyde (3k) quantitatively. Analytical
data were in agreement with published values.18
NMR spectra were recorded on a Bruker DPX 400.
Chemical shifts d are reported in ppm relative to CHCl3
(1H: d¼7.26) and CDCl3 (13C: d¼77.0) as an internal
standard; coupling constnats are reported in Hz. Column
chromatography was conducted on silica gel 60 (mesh size
40–63 mm). TLC was carried out on aluminum sheets
precoated with silica gel 60F254 (Merck), and the spots were
visualized with UV light (l¼254 nm). MS: ThermoQuest
Finnigan multi Mass (EI, 70 eV). Melting points were
measured on a capillary tube apparatus and are uncorrected.
All aldehydes 3a-j were purchased and used as obtained.
3k was prepared from 1-bromo-2-methyl-naphthalene (see
below). Benzils 2c-g (2h commercially available) were
synthesized by the oxidation of the corresponding benzoins,
prepared by classical benzoin condensation and structure of
benzils was confirmed by comparison of the analytical data
with published values; 2c (mp17a 128–129 8C), 2d (mp17b
92 8C), 2e (mp17c 128–130 8C), 2f (mp17d 134–135 8C), 2g
(mp17e 95.5–96.6 8C) and 15 (mp17f 85.5–86 8C) DMF was
4.2. General procedure for the synthesis of protected
benzoins
To a solution of 5 mmol diketone and 5 mmol of aromatic
aldehyde in 3 ml DMF was added 0.2 equiv. of KCN (the
course of reaction generally was not affected by the amount
and source of DMF). The reaction was monitored by TLC.
After completion of reaction, the mixture was directly
subjected to chromatography through to a pad of silica to
remove DMF and side products and eluted with 1:7
EtOAc:hexane. Evaporation of the solvent with rotary
evaporator followed by high vacuum furnished the desired
product. For some reactions, the product was pure enough
for most purposes. Otherwise, products were purified with a
second column chromatography with 1:7 EtOAc:hexane as
eluent or crystallized from a mixture of EtOAc:Hexane.
˚
distilled under vacuum and stored over 4 A molecular-
sieves.
4.1.1. 1-Bromo-2-naphthaldehyde (3k). To a solution of
1-bromo-2-methyl-naphthalene (3.58 ml, 23 mmol) and
NBS (12 g, 67 mmol) in CCl4 (250 ml), benzoyl peroxide
(0.75 g, 3 mmol) was added in multiple portions and the
resulting solution was heated under reflux for 7 h. The
reaction mixture was filtered and evaporated under reduced
pressure to obtain waxy brownish solid. Crystallization
from hot ethanol gave 5.86 g yellowish crystals of 1-bromo-
2-dibromomethyl naphthalene in 85% yield: mp 82.5–
83.5 8C; MS(EI), m/z 378–380 (Mþ, 18), 299 (100), 219
4.2.1. 1-(2-Trifluoromethylphenyl)-2-oxo-2-phenylethyl
benzoate (4a). Colorless viscous oil (1.82 g), 1H NMR
(CDCl3) d 7.32–7.38 (4H, m), 7.41–7.53 (6H, m), 7.72
(1H, d, J¼7.6 Hz), 7.86 (2H, d, J¼8.2 Hz), 7.98 (2H, d,
J¼8.2 Hz); 13C NMR (CDCl3) d 73.1 (1.5 Hz long range

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A. S. Demir, O. Reis / Tetrahedron 60 (2004) 3803–3811
3809
coupling is observable), 127.0 (q, J¼5.5 Hz), 127.1 (q,
J¼273 Hz), 129.7 (q, J¼30 Hz), 128.7, 129.10, 129.17,
129.8, 130.6, 131.2, 132.7, 132.8, 133.6, 133.9, 135.0,
165.4, 193.2. Anal. Calcd for C22H15F3O3: C, 68.75; H 3.93
found C, 68.88; H, 4.07.
4.2.8. 1-Phenyl-2-oxo-2-ferrocenylethyl benzoate (4h).
Red solid (1.89 g), mp 146.5–147 8C; MS(EI), m/z 423
(Mþ, 100), 213 (100), 185 (46), 153 (26), 129 (34), 105 (60),
77 (36); 1H NMR (CDCl3) d 4.1 (5H, s), 4.34 (1H, s), 4.41
(1H, s), 4.58 (1H, s), 4.82 (1H,m), 6.58 (1H, s), 7.19–7.37
(5H, m), 7.46–7.51 (3H, m), 8.06 (2H, d, J¼7.4 Hz); 13C
NMR (CDCl3) d 70.0, 70.1, 72.5, 72.6, 76.4, 79.2, 128.6,
129.1, 129.3, 129.5, 130.1, 130.4, 133.4, 135.6, 165.9,
197.7. Anal. Calcd for C25H20FeO3: C, 70.77; H, 4.75 found
C, 70.62; H, 4.78; HRMS Calcd: 424.0761, found:
424.0762.
4.2.2. 1-(2-Fluorophenyl)-2-oxo-2-phenylethyl benzoate
(4b). White solid (1.66 g), mp 102–103 8C; 1H NMR
(CDCl3) d 7.03–7.11 (2H, m), 7.25–7.31 (1H, m), 7.34–
7.38 (5H, m), 7.44–7.54 (3H, m), 7.93 (2H, m), 8.03 (2H,
m); 13C NMR (CDCl3) d 70.7, 116.4 (d, J¼22 Hz), 121.8 (d,
J¼13 Hz), 125.2 (d, J¼2.7 Hz), 128.7, 128.9, 129.12, 129.7,
130.4, 130.5 (d, J¼1.9 Hz), 131.7 (d, J¼8.2 Hz), 133.6,
134.0, 134.7, 160.5 (d, J¼250 Hz), 165.9, 192.8. Anal.
Calcd for C21H15FO3: C, 75.44; H 4.52 found C, 75.45; H,
4.61.
4.2.9. 2-(2-Naphthyl)-2-oxo-1-(2-naphthyl)ethyl 2-
naphthoate (4i). White solid (1.79 g), mp 150–151 8C;
1H NMR (CDCl3) d 7.3–7.43 (6H, m), 7.61–7.79 (9H, m),
7.94–7.96 (1H, m), 7.56–8.05 (2H, m), 8.50 (1H, s), 8.60
(1H, s); 13C NMR (CDCl3) d 78.5, 124.8, 125.9, 126.1,
126.8, 126.9, 127.0, 127.2, 128.11, 128.17, 128.5, 128.6,
128.7, 128.9, 129.2, 129.5, 129.9, 130.1, 131.17, 131.91,
132.1, 132.6, 132.8, 132.9, 133.8, 134.0, 136.0, 136.1,
166.3, 193.6. Anal. Calcd for C33H22O3: C, 84.96; H, 4.75
found C, 84.91; H, 4.88.
4.2.3. 1-(2-Bromophenyl)-2-oxo-2-phenylethyl benzoate
(4c). White solid (1.88 g), mp 110–111 8C; MS(EI), m/z
394–396 (Mþ, ,2), 289 (32), 183–185 (100), 155–157
(35), 105 (100), 77 (100); 1H NMR (CDCl3) d 7.17 (1H, m),
7,25 (1H, m), 7,34–7,48 (8H, m), 7,92 (2H, d, J¼7.3 Hz),
8.02 (2H, d, J¼7.2 Hz); 13C NMR (CDCl3) d 76.8, 125.1,
128.5, 128.7, 129.10, 129.17, 129.7, 130.4, 131.0, 131.3,
133.6, 133.90, 133.98, 134.2, 134.9, 165.7, 193.3. Anal.
Calcd for C21H15BrO3: C, 63.81; H 3.83 found C, 63.84; H,
3.83.
4.2.10. 2-(2-Naphthyl)-2-oxo-1-phenylethyl 2-naphtho-
ate (4j). White solid (1.66 g), mp 169–171 8C (decompose);
1H NMR (CDCl3) d 7.21 (1H, s), 7.28–7.38 (3H, m), 7.43–
7.50 (4H, m), 7.57–7.59 (2H, m), 7.72–7.80 (4H, m), 7.84–
7.88 (2H, m), 7.94–7.97 (1H, m), 8.04–8.07 (1H, m), 8.49
(1H, s), 8.62 (1H, s); 13C NMR (CDCl3) d 78.3, 124.7,
125.9, 126.9, 127.10, 127.18, 128.12, 128.14, 128.5, 128.6,
128.94, 128.98, 129.1, 129.5, 129.6, 129.8, 130.1, 131.0,
132.0, 132.6, 132.8, 132.9, 134.5, 136.0, 136.1, 166.3,
193.6. Anal. Calcd for C29H20O3: C, 83.63; H, 4.84 found C,
83.37; H, 4.74.
4.2.4. 1-(2-Methylphenyl)-2-oxo-2-phenylethyl benzoate
(4d). White solid (1.54 g), mp 133–134 8C; 1H NMR
(CDCl3) d 2.57 (3H, s, Me), 7.19–7.23 (1H, m), 7.27–7.29
(2H, m), 7.38–7.47 (5H, m), 7.52–7.59 (2H), 7.90 (2H, d,
J¼7.4 Hz), 8.13 (2H, d, J¼7.3 Hz); 13C NMR (CDCl3) d
19.9, 75.8, 127.1, 128.7, 129.0, 129.8, 129.9, 130.4, 131.6,
132.8, 133.5, 133.6, 135.5, 137.5, 166.1, 194.1. Anal. Calcd
for C22H18O3: C, 79.98; H, 5.49 found C, 79.82; H, 5.45.
4.2.11. 2-(2-Naphthyl)-2-oxo-1-(1-bromo-2-naphthyl)-
ethyl 2-naphthoate (4k). White solid (1.99 g), mp 153.5–
154 8C; 1H NMR (CDCl3) d 7.39–7.55 (6H, m), 7.61 (1H, d,
J¼8.6 Hz), 7.70–7.98 (8H, m), 7.99–8.06 (3H(2HþCH),
m), 8.33 (1H, d, J¼8.5 Hz), 8.62 (1H, s), 8.64 (1H, s); 13C
NMR (CDCl3) d 78.4, 124.5, 125.8, 126.1, 126.4, 126.9,
127.0, 127.2, 128.10, 128.14, 128.19, 128.4, 128.61, 128.66,
128.7, 128.8, 129.0, 129.1, 129.2, 129.8, 130.2, 131.3,
132.1, 132.2, 132.7, 132.8, 132.9, 135.1, 136.1, 136.3,
166.3, 194.0. Anal. Calcd for C33H21BrO3: C, 72.67; H 3.88
found C, 72.41; H, 3.93.
4.2.5. 1-(3,5-Dimethoxyphenyl)-2-oxo-2-phenylethyl
1
benzoate (4e). White solid (1.56 g), mp 136–137 8C; H
NMR (CDCl3) d 3.70 (6H, s), 6.37 (1H, t, J¼2 Hz), 6.63
(2H, d, J¼2 Hz), 6.91 (1H, s), 7.31–7.39 (4H, m), 7.44–
7.52 (2H, m), 7.93 (2H, d, J¼7.4 Hz), 8.05 (2H, d,
J¼7.5 Hz); 13C NMR (CDCl3) d 55.8, 78.3, 101.5, 107.1,
128.8, 129.1, 129.2, 129.8, 130.4, 133.8, 133.9, 135.1,
136.1, 161.6, 166.3, 193.9. Anal. Calcd for C23H20O5: C,
73.39; H 5.36 found C, 73.27; H, 5.48.
4.2.6. 1-(3,5-Dimethoxy-4-acetoxyphenyl)-2-oxo-2-
phenylethyl benzoate (4f). White solid (1.85 g), mp
141.5–142 8C; 1H NMR (CDCl3) d 2.24 (3H, s), 3.75
(6H, s), 6.70 (2H, s), 6.91 (1H, s), 7.92 (2H, d, J¼8.4 Hz),
8.04 (2H, 8.3); 13C NMR (CDCl3) d 20.7, 56.5, 77.9, 105.7,
128.7, 129.0, 129.1, 129.7, 129.9, 130.4, 132.1, 133.6,
133.8, 135.2, 153.0, 166.0, 168.2, 193.5. Anal. Calcd for
C25H22O7: C, 69.12; H, 5.10 found C, 69.28; H, 5.15.
4.2.12. 2-(Ferrocenyl)-2-oxo-1-(1-bromo-2-naphthyl)-
ethyl 2-naphthoate (4l). Red solid (1.94 g), mp decompose
.190 8C; H NMR (CDCl3) d 4.13 (5H, s), 4.33 (1H, s),
1
4.41 (1H, s), 4.63 (1H, s), 4.88 (1H, s), 6.83 (1H, s), 7.35–
7.51 (4H, m), 7.62–7.64 (1H, m), 7.77–7.88 (6H, m), 7.97
(1H, br s), 8.06–8.09 (1H, m), 8.63 (1H, s); 13C NMR
(CDCl3) d 70.0, 70.2, 70.65, 72.5, 72.6, 76.5, 79.5, 125.9,
126.3, 126.8, 126.9, 127.1, 127.3, 128.12, 128.18, 128.4,
128.5, 128.6, 129.1, 129.3, 129.8, 132.0, 132.92, 132.96,
133.6, 133.9, 136.1, 166.1, 197.7. Anal. Calcd for
C33H24FeO3: C, 75.58; H, 4.61 found C, 75.30; H, 4.79.
HRMS Calcd: 524.1074, found: 524.1066.
4.2.7. 1-(2-Pyridyl)-2-oxo-2-phenylethyl benzoate (4g).
1
White solid (1.24 g), mp 125–126 8C; H NMR (CDCl3) d
7.16–7.2 (1H, m), 7.35–7.39 (4H, m), 7.44–7.55 (2H, m),
7.89 1H, d, J¼7.8 Hz), 7.64–7.69 (1H, m), 8.05 (2H, d,
J¼8.4 Hz), 8.1 (2H, d, J¼8.5 Hz), 8.52 (1H, d, J¼4.2 Hz).
Anal. Calcd for C20H15NO3: C, 75.70; H, 4.76; N, 4.41
found C, 75.44; H, 5.08; N, 4.35.
4.2.13. 2-(2-Methylphenyl)-1-ferrocenyl-2-oxoethyl 2-
methylbenzoate (4m). Red solid (1.65 g), mp 101–
102 8C; MS(EI), m/z 452 (Mþ, 50), 213 (100), 185 (28),

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A. S. Demir, O. Reis / Tetrahedron 60 (2004) 3803–3811
3810
119 (48), 91 (46); 1H NMR (CDCl3) d 2.61 (3H, s, Me), 2.68
(3H, s, Me), 4.30 (5H, s), 4.40 (2H, s), 4.50 (1H, s), 4.94
(1H, s), 7.01 (1H, s), 7.2–7.32 (5H, m), 7.36–7.43 (2H, m),
8.06 (1H, m); 13C NMR (CDCl3) d 19.9, 22.1, 69.8, 69.9,
70.6, 72.3, 72.6, 76.5, 76.6, 126.0, 127.0, 129.6, 130.1,
131.4, 131.5, 131.8, 132.3, 134.1, 137.3, 140.8, 167.1,
198.1. Anal. Calcd for C27H24FeO3: C, 71.69; H, 5.35 found
C, 71,51; H, 5,16. HRMS Calcd: 452.1075, found:
452.1076.
131.29, 135.8, 135.9, 146.4, 148.0, 149.0, 150.0, 163.0,
192.7. Anal. Calcd for C20H13F3N2O3: C, 62.18; H, 3.39; N,
7.25 found C, 61.71; H, 3.62; N, 7.15.
4.2.19. 1-(2-Methylphenyl)-2-oxo-2-phenylethyl ferro-
cenecarboxylate (16). Red solid (1.60 g, 73%), MS(EI),
m/z 438 (Mþz, 5), 230 (82), 213 (100), 185 (23), 166 (28),
129 (37), 104 (32), 76 (44); 1H NMR (CDCl3) d 2.48 (3H, s),
4.24 (5H, s), 4.33 (2H, s), 4.78 (1H, s), 4.82 (1H, s), 7.10–
7.25 (4H, m), 7.28–7.5 (4H, m), 7.86 (2H, m); 13C NMR
(CDCl3) d 20.0, 70.8, 71.1, 71.20, 71.26, 72.0, 72.1, 75.4,
127.7, 129.73, 129.79, 130.4, 130.6, 132.39, 133.9, 134.2,
136.7, 138.3, 172.3, 195.8. Anal. Calcd for C26H22FeO3: C,
71.07; 5.01 found C, 71.36; H, 5.17.
4.2.14. 2-(2-Bromophenyl)-1-(2-methylphenyl)-2-
oxoethyl 2-bromobenzoate (4n). White solid (1.68 g), mp
115–116 8C; 1H NMR (CDCl3) d 7.19–7.27 (3H, m), 7.3–
7.5 (5H, m), 7.56–7.60 (2H, m), 7.68 (1H, d, J¼7.5 Hz),
7.83 (1H, d, J¼7.5 Hz), 8.04 (1H, d, J¼6.3 Hz); 13C NMR
(CDCl3) d 21.0, 78.6, 122.7, 125.1, 126.0, 127.4, 128.2,
129.2, 130.7, 131.1, 131.5, 132.02, 132.1, 132.4, 133.1,
133.2, 133.8, 134.7, 135.7, 139.0, 165.1, 196.2. Anal. Calcd
for C22H16Br2O3: C, 54.13; H, 3.30 found C, 54.44; H, 3.68.
4.3. General procedure for the hydrolysis of protected
benzoins
Benzoins were obtained according to following procedure.
Compound 12d was isolated in 85% yield and data was in
agreement with the published values.13
4.2.15. 2-(2-Chlorophenyl)-1-(2-methylphenyl)-2-
oxoethyl 2-chlorobenzoate (4o). White solid (1.64 g), mp
1
95 8C; H NMR (CDCl3) d 2.27 (3H, s, Me), 7.04–7.39
4.3.1. 2-Hydroxy-2-ferrocenyl-1-phenylethan-1-one
(12a). 0.5 g (1.18 mmol) 3h was dissolved in 50 ml
MeCN and argon was bubbled through the solution for
15 min to remove the oxygen from medium. While refluxing
the solution, 0.06 g NaOH in 20 ml of water was added
dropwise in 15 min. Resulting solution was refluxed for an
additional 30 min and concentrated under reduced pressure
to get slurry, which was then extracted with EtOAc. Organic
phase was dried over MgSO4 and concentrated to obtain
brownish-red solid 12a with 87% yield. During reaction or
work up some contamination of the product with 15 might
occur. This oxidation product can easily be separated by
flash column chromatography. Red solid (0.32 g), mp
107 8C; MS(EI), m/z 318 (Mþz, 100), 213 (92), 185 (55),
(10H, m), 7.49–7.52 (1H, m), 7.73 (1H, d, J¼1.9 Hz), 7.96
(1H, dd, J¼7.6, 1.2 Hz); 13C NMR (CDCl3) d 20.9, 76.2,
126.0, 126.8, 127.6, 129.0, 129.5, 130.4, 130.5, 130.9,
131.50, 131.52, 132.0, 132.1, 132.4, 133.1, 134.6, 134.8,
135.7, 139.0, 164.7, 196.1. Anal. Calcd for C22H16Cl2O3: C,
66.18; H, 4.04 found C, 66.07; H, 4.25.
4.2.16. 2-(2-Fluorophenyl)-1-(2-methylphenyl)-2-
oxoethyl 2-fluorobenzoate (4p). White solid (1.32 g), mp
94 8C; 1H NMR (CDCl3) d 2.45 (3H, s, Me), 6.92–6.97 (1H,
m), 7.04–7.27 (8H, m), 7.43–7.54 (2H, m), 7.72–7.74 (1H,
m), 7.96–7.99 (1H, m); 13C NMR (CDCl3) d 20.8, 72.8,
116.2 (d, J¼22 Hz), 117.4 (d, J¼22 Hz), 118.4 (d,
J¼9.5 Hz), 121.1 (d, J¼14.1 Hz), 124.2 (d, J¼3.6 Hz),
125.0 (J¼3.6 Hz), 125.9, 128.7, 130.1, 130.2, 131.4 (d,
J¼8.3 Hz), 131.9, 132.0, 132.9, 135.1 (d, J¼9 Hz), 135.6,
160.4 (d, J¼248 Hz), 162.7 (d, J¼260 Hz), 163.5 (d,
J¼3.7 Hz), 195.8. Anal. Calcd for C22H16F2O3: C, 72.13;
H, 4.40 found C, 71.99; H, 4.58.
1
129 (52), 121 (16), 105 (16), 77 (24); H NMR (CDCl3) d
4.09 (5H, s), 4.47 (1H, s), 4.54 (2H, s, 1H exchangeable with
D2O), 4.66 (1H, s), 4.86 (1H, s), 5.47 (1H, s), 7.38 (5H, m);
13C NMR (CDCl3) d 68.9, 69.2, 69.4, 71.6, 71.7, 76.2,
126.8, 127.2, 127.7, 139.8, 202.3. Anal. Calcd For
C18H16FeO2: C, 67,52; H, 5.03 found C, 67.62; H, 5.02.
4.2.17. 2-(2-Pyridyl)-1-(2-fluorophenyl)-2-oxoethyl 2-
1
pyridoate (4q). White solid (1.09 g), mp 121–122 8C; H
4.3.2. 2-(2-Trifluoromethylphenyl)-2-hydroxy-1-phenyl-
ethan-1-one (12b). Hydrolysis was carried out as for 3h
except that the reaction was carried out at RT. Reaction was
monitored by TLC and after all of the starting material has
been consumed, mixture was worked up as above; 94%
NMR (CDCl3) d 6.94–7.04 (2H, m), 7.12–7.25 (1H, m),
7.31–7.45 (3H, m), 7.65–7.76 (2H, m), 7.85 (1H, s), 7.98
(1H, d, J¼7.8 Hz), 8.09 (1H, d, J¼7.7 Hz), 7.86 (1H, d,
J¼4.4 Hz), 8.70 (1H, s); 13C NMR (CDCl3) d 74.8, 118.5 (d,
J¼21 Hz), 123.8 (d, J¼14 Hz), 125.2, 126.8 (d, J¼3.6 Hz),
128.0, 129.5, 130.0, 133.0 (d, J¼2.7 Hz), 133.5 (d,
J¼8.3 Hz), 139.3, 139.4, 149.9, 151.4, 152.5, 153.6, 163.3
(d, J¼250 Hz), 166.8, 195.6. Anal. Calcd for C19H13FN2O3:
C, 67.85; H, 3.90; N, 8.33 found C, 67.95; H, 4.01; N, 8.17.
1
yield, white solid (0.22 g), mp 82 8C; H NMR (CDCl3) d
4.23 (1H, br s), 6.12 (1H, s), 6.98 (1H, d, d¼6.4), 7.12–7.35
(4H, m), 7.4–7.43 (1H, m), 7.68 (1H, m), 7.76 (2H, d,
J¼7.4 Hz); 13C NMR (CDCl3) d 72.1, 124.6 (q, J¼272 Hz),
127.0 (q, J¼5.5 Hz), 129.02, 129.08 (q, J¼30 Hz), 129.1,
129.4, 129.5, 133.0, 133.5, 134.3, 137.9, 198. Anal. Calcd
for C15H11F3O2: C, 64.29; H 3.96 found C, 64.45; H, 4.13.
4.2.18. 2-(2-Pyridyl)-1-(2-trifluoromethylphenyl)-2-
oxoethyl 2-pyridoate (4r). White solid (1.49 g), mp 113–
114.58C; 1H NMR (CDCl3) d 7.3–7.34 (1H, m), 7.34–7.47
(4H, m), 7.69–7.75 (3H, m), 7.93 (1H, s), 8.0–8.06 (2H, m),
8.47 (1H, d, J¼4 Hz), 8.68 (1H, d, J¼3 Hz); 13C NMR
(CDCl3) d 73.3 (1.7 Hz long range coupling is observable),
123.0 (q, J¼272 Hz), 121.8, 124.5, 125.9 (q, J¼5.5 Hz),
126.0, 126.5, 128.1, 128.7 (q, J¼30 Hz), 129.3, 131.11,
4.3.3. 2-(2-Fluorophenyl)-2-hydroxy-1-phenylethan-1-
1
one (12c). 95% yield, white solid (0.26 g), mp 87 8C; H
NMR (CDCl3) d 4.44 (br s, 1H), 6.13 (s, 1H), 6.90–7.00
(2H, m), 7.08–7.19 (2H, m), 7.29–7.33 (2H, m), 7.41–7.45
(1H, m), 7.84 (2H, m); 13C NMR (CDCl3) d 69.6, 116.4 (d,
J¼22 Hz), 125.1 (d, J¼3.4 Hz), 127.0 (d, J¼14.1 Hz),
129.0, 129.1, 129.5 (d, J¼3.6 Hz), 130.7 (d, J¼8.5 Hz),

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A. S. Demir, O. Reis / Tetrahedron 60 (2004) 3803–3811
3811
3. (a) Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1930, 52, 220.
(b) Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1930, 52, 4107.
(c) Semerano, G. Gazz. Chim. Ital. 1941, 71, 447. (d) Merz,
K. W.; Plauth, D. Chem. Ber. 1957, 90, 1744.
133.5, 134.3. 160.4 (d, J¼246 Hz), 198.4. Anal. Calcd for
C14H11FO2: C, 73.03; H 4.82 found C, 73.09; H, 4.91.
4.3.4. 2-(2-Fluorophenyl)-2-hydroxy-1-ferrocenylethan-
1-one (18). 69% yield from 25 (two steps), mp 126.5–
4. (a) Corrie, J. E. T. Tetrahedron 1998, 54, 5407, and references
there in. (b) Stowell, M. H. B.; Rock, R. S.; Rees, D. C.; Chan,
S. I. Tetrahedron Lett. 1996, 37, 307. (c) Lee, H. B.;
Balasubramanian, S. J. Org. Chem. 1999, 64, 3454.
1
127.5 8C; H NMR (CDCl3) 4.01 (5H, s), 4.4 (1H, s), 4.48
(2H, m, 1H from OH), 4.63 (1H, s), 4.82 (1H, s), 5.73 (1H,
d, d¼5.9), 7.02–7.08 (2H, m), 7.17–7.24 (2H, m), 7.29 (1H,
m); 13C NMR (CDCl3) d 70.1, 70.5, 73.1, 73.2, 73.3, 74.5,
116.2 (d, J¼22 Hz), 125.0 (d, J¼3.3 Hz), 128.1, 129.4 (d,
J¼3.7 Hz), 130.5 (d, J¼8.3 Hz), 160.5 (d, J¼245 Hz),
202.6. Anal. Calcd for C18H15FFeO2: C, 63.89; H 4.47
found C, 63.64; H, 4.24; HRMS Calcd: 338.0405, found:
338.0396.
´
(d) Aurelien, B.; Bochet, C. G. J. Org. Chem. 2002, 67, 5567.
5. (a) Corrie, J. E. T.; Trentham, D. R. J. Chem. Soc., Perkin
Trans. 1 1992, 2409. (b) Pirrung, M. C.; Shuey, S. W. J. Org.
Chem. 1994, 59, 3890. (c) Pirrung, M. C.; Bradley, J. C. J. Org.
Chem. 1995, 60, 1116. (d) Rock, R. S.; Chan, S. I. J. Am.
Chem. Soc. 1998, 120, 10766. (e) Cameron, J. F.; Willson,
´
C. G.; Frechet, J. M. J. J. Chem. Soc., Perkin Trans. 1 1997,
2429.
4.4. General procedure for the oxidation of benzoins
6. Linghu, X.; Jonhson, J. S. Angew. Chem., Int. Ed. 2003, 42,
2534.
12a was oxidized according to a known procedure17 with
81% yield to obtain 15. All analytical results were in
agreement with published data.17f,19
´
7. Patrocınio, A. F.; Moran, P. J. S. J. Organomet. Chem. 2000,
603, 220.
8. (a) Demir, A. S.; Dunnwald, T.; Iding, H.; Pohl, M.; Muller,
M. Tetrahedron: Asymmetry 1999, 10, 4769. (b) Demir, A. S.;
Pohl, M.; Janzen, E.; Muller, M. J. Chem. Soc., Perkin Trans. 1
2001, 633. (c) Demir, A. S.; Sesenoglu, O.; Eren, E.; Hosrik,
B.; Pohl, M.; Janzen, E.; Kolter, D.; Feldmann, R.;
Dunkelmann, P.; Muller, M. Adv. Synth. Catal. 2002, 344,
96. (d) Dunkelmann, P.; Kolter-jung, D.; Nitsche, A.; Demir,
A. S.; Siegert, P.; Lingen, B.; Baumann, M.; Pohl, M.; Muller,
M. J. Am. Chem. Soc. 2002, 124, 12084.
4.4.1. 1-(2-Fluorophenyl)-2-phenylethane-1,2-dione (17).
(87% yield); yellowish-white solid; MS(EI), m/z 228 (Mþ,
4), 123 (44), 105 (100), 95 (24), 77 (59); 1H NMR (CDCl3) d
7.02–7.07 (1H, m), 7.25–7.29 (1H, m), 7.42–7.46 (2H, m),
7.53–7.59 (2H, m), 7.89 (2H, m), 7.95–7.99 (1H, m); 13C
NMR (CDCl3)
d
116.9 (d, J¼21.6 Hz), 122.9 (d,
J¼10.8 Hz), 125.2 (d, J¼3.4 Hz), 129.2, 130.2, 131.2,
132.5, 134.7, 136.83 (d, J¼8.7 Hz), 163.2 (d, J¼257 Hz),
191.7, 192.7. Anal. Calcd for C14H9FO2: C, 73.68; H, 3.97
found C, 73.71; H, 4.19.
9. Clerici, A.; Porta, O. J. Org. Chem. 1993, 58, 2889.
10. Dakin, H. D.; Harington, C. R. J. Biol. Chem. 1923, 55, 487.
11. Kwart, H.; Baevsky, M. M. J. Am. Chem. Soc. 1958, 80, 580.
12. Trisler, J. C.; Frye, J. L. J. Org. Chem. 1965, 30, 306.
13. Kuebrich, J. P.; Schowen, R. L. J. Am. Chem. Soc. 1971, 93,
1220.
Acknowledgements
Financial support from Middle East Technical University
(BAP-2003), the Scientific and Technical Research Council
of Turkey (TUBITAK), Turkish Academy of Science
14. Properties of 7f as photolabile protecting group is under
investigation and results will be published in due course.
15. Papageorgiou, G.; Corrie, J. E. T. Tetrahedron 1997, 53, 3917.
16. Rozwadowska, M. D. Tetrahedron 1985, 41, 3135.
17. (a) Leonard, N. J.; Rapala, R. T.; Herzog, H. L.; Blout, E. R.
J. Am. Chem. Soc. 1949, 71, 2997. (b) Griffin, G. W.;
Manmade, A. J. Org. Chem. 1972, 37, 2589. (c) Christy, M. E.;
Colton, C. D.; Mackay, M.; Staas, W. H.; Wong, J. B.;
Engelhardt, E. L. J. Med. Chem. 1977, 20, 421. (d) McKillop,
A.; Swann, B. P.; Ford, M. E.; Taylor, E. C. J. Am. Chem. Soc.
1973, 95, 3641. (e) D’Agostino, V. F.; Dunn, M. J.; Ehrlich,
A. E.; Becker, E. I. J. Org. Chem. 1958, 23, 1539. (f) Rausch,
M. D.; Siegel, A. J. Org. Chem. 1968, 33, 4545.
¨
(TUBA) and Turkish State Planning Organization (DPT)
is gratefully acknowledged.
References and notes
1. (a) Lapworth, A. J. J. Chem. Soc. 1903, 83, 995. (b) Kuebrich,
J. P.; Schowen, R. L.; Wang, M.; Lupes, M. E. J. Am. Chem.
Soc. 1971, 93, 1214.
2. (a) White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124.
(b) Teles, J. H.; Melder, J. P.; Ebel, K.; Schneider, R.; Harder,
W.; Brode, S.; Enders, D.; Breuer, K.; Raabe, G. Helv. Chim.
Acta 1996, 79, 61. (c) Enders, D.; Breuer, K.; Teles, J. H. Helv.
Chim. Acta 1996, 79, 1217. (d) For a highly enantioselective
symmetrical benzoin condensation, see: Enders, D.; Kallfass,
U. Angew. Chem., Int. Ed. 2002, 41, 1743.
18. Trost, B. M.; Liu, G. J. Org. Chem. 1981, 46, 4617.
19. Glidewell, C.; Ahmed, S. Z.; Gottfried, M.; Lightfoot, P.;
Royles, B. J. L.; Scott, J. P.; Wonnemann, J. J. Organomet.
Chem. 1997, 530, 177.