Photogeneration of amines from α-keto carbamates: Design and preparation of photoactive compounds

Article abstract of DOI:10.1039/a602018f

The design and synthesis of substituted desyl (2-oxo-1,2-diphenylethyl) groups has been investigated to create new photolabile protecting groups. The photoreactivity of these chromophores stems from the diverse photochemistry of the desyl group. Several chromophore designs have been explored in which the substitution pattern of the parent desyl chromophore was varied systematically. The required benzoin chromophores are prepared by a variety of synthetic routes, depending on the structure of the benzoin chromophore desired. Symmetrical benzoins are readily available via the benzoin condensation. Unsymmetrical benzoins including 2,2-disubstituted α-hydroxy ketones are generally prepared via trimethylsilyl (TMS) masked cyanohydrins. On reaction with a Grignard reagent, the TMS masked cyanohydrin functions as an α-hydroxycarbonyl equivalent to form α-hydroxy ketones. Alternatively, lithiation of a TMS masked cyanohydrin generates a benzoyl anion equivalent which reacts with aldehydes and ketones to generate substituted benzoins. These desyl chromophores have significant potential as new photolabile protecting moieties for a variety of functional groups and are used to mask primary and secondary amines as photosensitive α-keto carbamates. The substituted benzoin carbamates are readily prepared from the appropriate benzoin by reaction with isocyanates or by activation as a mixed carbonate followed by reaction with the free amine. These α-keto carbamates are interesting for two main reasons. First, the facile synthesis of these materials indicates the ease of introduction of the desyl based photolabile group. Second, these α-keto carbamates may be used for rapid evaluation of novel photoactive desyl based chromophores.

Full text of DOI:10.1039/a602018f

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Photogeneration of amines from á-keto carbamates: design and
preparation of photoactive compounds
James F. Cameron,*,†,a C. Grant Willson‡,a and Jean M. J. Fréchet §,b
a
IBM Research Division, Almaden Research Center, 650 Harry Road, San Jose,
California 95120-6099, USA
b Department of Chemistry, Baker Laboratory, Cornell University, Ithaca,
New York 14853-1301, USA
The design and synthesis of substituted desyl (2-oxo-1,2-diphenylethyl) groups has been investigated to
create new photolabile protecting groups. The photoreactivity of these chromophores stems from the
diverse photochemistry of the desyl group. Several chromophore designs have been explored in which the
substitution pattern of the parent desyl chromophore was varied systematically. The required benzoin
chromophores are prepared by a variety of synthetic routes, depending on the structure of the benzoin
chromophore desired. Symmetrical benzoins are readily available via the benzoin condensation.
U nsymmetrical benzoins including 2,2-disubstituted á-hydroxy ketones are generally prepared via
trimethylsilyl (TM S) masked cyanohydrins. On reaction with a G rignard reagent, the TM S masked
cyanohydrin functions as an á-hydroxycarbonyl equivalent to form á-hydroxy ketones. Alternatively,
lithiation of a TM S masked cyanohydrin generates a benzoyl anion equivalent which reacts with
aldehydes and ketones to generate substituted benzoins. These desyl chromophores have significant
potential as new photolabile protecting moieties for a variety of functional groups and are used to mask
primary and secondary amines as photosensitive á-keto carbamates. The substituted benzoin carbamates
are readily prepared from the appropriate benzoin by reaction with isocyanates or by activation as a mixed
carbonate followed by reaction with the free amine. These á-keto carbamates are interesting for two main
reasons. F irst, the facile synthesis of these materials indicates the ease of introduction of the desyl based
photolabile group. Second, these á-keto carbamates may be used for rapid evaluation of novel photoactive
desyl based chromophores.
desyl (2-oxo-1,2-diphenylethyl) chromophores.8 We now
Introduction
describe the full details of the design concepts and synthetic
principles used in creating new improved chromophores for
photolabile protecting groups. Emphasis is placed on chromo-
phore design with a view to creating new, practical photolabile
amino protecting groups. The desyl chromophore and its sub-
stituted analogues offer significant advantages over current
photolabile protecting groups. The literature describing the
photochemistry of the desyl chromophore suggests that in
comparison with o-nitrobenzyl photochemistry, the 3Ј,5Ј-
dimethoxybenzoin chromophore will exhibit: (1) increased
stability of photo by-products; (2) improved photoefficiency
and (3) enhanced rate of photorelease.
First, the parent desyl chromophore is well known to under-
go photocleavage via classical photochemical pathways such as
α-cleavage (Norrish Type I). In contrast, m-methoxy substi-
tution causes photocyclization to become the major photo-
cleavage pathway.9,10 The photolysis of 3Ј,5Ј-dimethoxybenzoin
acetate¶ affords 5,7-dimethoxy-2-phenylbenzo[b]furan and
acetic acid as the major products (Scheme 1). In comparison,
o-nitrobenzyl photochemistry is complicated by the formation
of photochemically active o-nitroso carbonyl by-products. Sec-
ond, 3Ј,5Ј-dimethoxybenzoin esters have been developed as
photolabile carboxy protecting groups10–12 and shown to liber-
ate the free acid quantitatively, with a quantum yield of 0.64 at
365 nm.10 In contrast, the photoefficiency for photocleavage of
simple o-nitrobenzyl esters is typically 0.10. The unique mode
of photoreactivity offered by substituted benzoins has been
applied to the caged release of phosphate esters13–15 and
inorganic phosphate16 (Scheme 1). In these applications, 3Ј,5Ј-
dimethoxybenzoin phosphate was found to cyclize with a photo-
efficiency of 78%, which is more than double that of related
The application of photolabile protecting groups in synthetic
organic chemistry has received considerable attention due to
the mild, neutral conditions which can be used to effect depro-
tection. Indeed, photolabile protecting groups have been
developed for most common functional groups.1 For instance,
several photolabile groups based on the well known o-nitro-
benzyl photorearrangement have been used to mask such
diverse functional groups as alcohols, amines, carboxylic acids
and carbonyl compounds. Traditionally used in classical
synthetic organic applications, photolabile groups are now
frequently used in advanced technologies. For example, in light-
flash physiology, caged nucleoside triphosphates,2 photolabile
calcium chelators3 and photoactive precursors of neuro-
transmitters4 all rely on efficient photodeprotection strategies
for their success.
Recently, we developed a new strategy for the photorelease
of reactive organic bases by masking amines and diamines as
photoactive carbamates.5–7 Under the action of light, these
neutral carbamates decompose to liberate free amines. How-
ever, we found that some commonly used photolabile amino
protecting groups, e.g. the 3,5-dimethoxy-α,α-dimethylbenzyl-
oxycarbonyl and o-nitrobenzyloxycarbonyl moieties, undergo
somewhat complex photochemistry and suffer from deleterious
side reactions upon prolonged photolysis.
We recently published a preliminary report on the utility of
new photolabile amino protecting groups based on substituted
† Present Address: Shipley Company, 455 Forest Street, Marlborough,
MA 01752, USA.
‡ Present Address: Departments of Chemical Engineering and
Chemistry, University of Texas, Austin, TX 78712, USA.
§ Present Address: Department of Chemistry, University of California
Berkeley, CA 94720, USA.
¶ IUPAC name: 1-(3,5-dimethoxyphenyl)-2-oxo-2-phenylethyl acetate.
J. Chem. Soc., Perkin Trans. 1, 1997
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X
OH
C
CH
C
O
C
O
R2
R1
R2
R1
R3
Where X = OAc, OP(O)(OEt)2, OP(O)O22–, OCONR3R4
R1, R2 = H; R1 = H, R2 = 3,5-(OMe)2
R3 = H: Refluxing PhCH3
R3 = aryl, alkyl: Sn(O2CC7H15) in PhH
N
C O
R3 = H, R4 = C6H11; R3, R4 = -(CH2)5-
OCONHC6H11
hν
C
C
O
R2
R1
R3
R2
+
HX + Others
R1
O
Where : 1 R1 = R2 = H, R3 = H
2 R1 = R2 = 3,5-OMe, R3 = H
3 R1 = R2 = 3-OMe, R3 = H
In the case of X = OCONR3R4, HX
rapidly loses CO2 to give HNR3R4
4 R1 = R2 = 3,4-OCH2O, R3 = H
5 R1 = R2 = 4-OMe, R3 = H
Scheme 1
6 R1 = H, R2 = 3,5-OMe, R3 = H
7 R1 = H, R2 = 3,4-OCH2O, R3 = H
8 R1 = 4-OMe, R2 = 3,5-OMe, R3 = H
9 R1 = 4-SMe, R2 = 3,5-OMe, R3 = H
10 R1 = 4-OMe, R2 = H, R3 = H
unsubstituted benzoin phosphates.17 Third, the photorelease of
phosphate from desyl phosphates proceeds at least 1000 times
faster and up to 1.24 times as efficiently as o-nitrobenzyl
derived phosphate esters.14,17
11 R1 = 3,4-C4H4 (2-Naphth), R2 = 3,5-OMe, R3 = H
12 R1 = H, R2 = 3,5-OMe, R3 = Ph
13 R1 = H, R2 = 3,5-OMe, R3 = Me
14 R1 = H, R2 = 3,5-OMe, R3 = 3,5-diOMePh
15 R1 = 3,5-OMe, R2 = H, R3 = Ph
Results and discussion
General design considerations
The substituted benzoin chromophore may be envisioned as a
light sensitive protecting group for a variety of common func-
tional groups. For instance, we initially reported on the utility
of 3Ј,5Ј-dimethoxybenzoinyl|| carbamates as photoprecursors
of both primary and secondary amines8 (Scheme 1). More
recently, we have further developed these materials as novel
amine base progenitors for use in polymer imaging and coating
chemistry.18 Independent of our investigation, Pirrung and co-
workers have also developed the photolabile 3Ј,5Ј-dimethoxy-
benzoinyloxycarbonyl group specifically for the protection of
secondary amines.19 The same group have also extended the
scope of the 3Ј,5Ј-dimethoxybenzoinyl chromophore to allow
for protection of both alcohols20,21 and thiols.20
In this paper, emphasis is placed on developing desyl based α-
keto carbamates as masked amines because these materials may
offer significant advantages over current photolabile amino
protecting groups. There were two main reasons for interest in
these α-keto carbamates. First, the synthesis of these materials
illustrates the relative ease with which desyl based photolabile
protecting groups may be introduced. In general, α-keto car-
bamates are synthetically accessible; substituted benzoin car-
bamates may be synthesized via the appropriate benzoin by
reaction with isocyanates or by activation as a mixed carbonate
followed by reaction with the free amine. Second, these photo-
sensitive α-keto carbamates may be used for rapid evaluation of
novel desyl based chromophores. The diverse array of photoac-
tive α-keto carbamates prepared herein provided a materials
base for our investigation of chromophore structure–photo-
sensitivity relationships during photoliberation of amino
groups.22 The utility of α-keto carbamates derived from
alkoxy substituted desyl chromophores has recently been
described.8,18,22
OCONHC6H11
Me CH
C
OMe
O
16
Scheme 2
(Scheme 2). Previously, we had found methyllithium to be an
excellent catalyst for the addition of a diverse array of alcohols
to isocyanates.5,6 Accordingly, the methyllithium catalysed add-
ition was investigated first. Under these conditions, the addition
of benzoin to cyclohexyl isocyanate afforded benzoin N-cyclo-
hexylcarbamate 1 in only 21% yield. Under the anionic reaction
conditions, the major reaction pathway involved a combination
of cyclization and dehydration. Intramolecular cyclization of
benzoin N-cyclohexylcarbamate 1 to give 3-cyclohexyl-4-
hydroxy-4,5-diphenyloxazolidin-2-one 17 was followed by sub-
sequent dehydration to give 3-cyclohexyl-4,5-diphenyl-2,3-
dihydrooxazol-2-one 20 as the major product.
Cyclization of α-keto carbamates to oxazolidin-2-ones fol-
lowed by elimination of water is known to proceed in the pres-
ence of base.23 In order to minimize the cyclization–elimination
reaction, we developed mild, neutral conditions for the prepar-
ation of desyl carbamates. We found that simply heating a solu-
tion of the benzoin and isocyanate in toluene gave the required
desyl carbamate. Under these conditions, the yield of benzoin
N-cyclohexylcarbamate 1 was 77%. The direct addition of a
benzoin to an isocyanate was commonly accompanied by some
minor oxidation of the benzoin to the corresponding benzil
e.g. 1,2-diphenylethanedione (vide infra). The efficiency of
the direct addition was largely unaffected by amine catalysts,
such as 4-dimethylaminopyridine (DMAP) and 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU). Stannous 2-ethylhexanoate,
which is a well known catalyst for urethane formation,24 failed
to take the reaction to completion.
Design and synthesis
Preparation of unsubstituted á-keto carbamates. Simple,
unsubstituted α-keto carbamates may be prepared by reacting
an α-hydroxy ketone with an isocyanate. For example, benzoin
N-cyclohexylcarbamate 1 was prepared by the reaction of ben-
zoin with cyclohexyl isocyanate under a variety of conditions
Preparation of aryl substituted á-keto carbamates. Photo-
labile amino protecting groups based on symmetrical benzoins.—
Since symmetrical benzoins are more accessible than their
unsymmetrical counterparts, the first generation of new photo-
sensitive protecting groups was based on symmetrical benzoins.
|| IUPAC name: 1-(3,5-dimethoxyphenyl)-2-oxo-2-phenylethyl.
2430
J. Chem. Soc., Perkin Trans. 1, 1997

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bis(3-methoxyphenyl)oxazolidin-2-one 18. A trace amount of
O
O
1,2-bis(3-methoxyphenyl)ethanedione was also isolated from
the direct addition of this benzoin to cyclohexyl isocyanate.
Sheehan et al.10 reported that the photosensitivity of piperoin
O
N
O
N
OH
R1
[1,2-bis(1,3-benzodioxol-5-yl)-2-hydroxyethanone]
derived
R2
esters is close to that of esters derived from the less readily
available unsymmetrical benzoins. With this in mind, com-
mercially available piperoin was derivatized with cyclohexyl
isocyanate to give cyclohexylcarbamate 4 (Scheme 2).
All the carbamates prepared so far are synthesized by the
direct addition of an isocyanate with the requisite benzoin.
While this strategy allows for the facile synthesis of masked
primary amines, it is somewhat restricted by the availability of
the requisite isocyanates. If substituted desyl chromophores are
to find widespread use as light sensitive amino protecting
groups then a general strategy which allows for the masking of
free amines is required. This is illustrated by the masking of
piperidine as piperoinyl carbamate 26 (Scheme 4). Piperoin was
R2
R1
Where : 20 R1 = R2 = H
21 R1 = H, R2 = 3,4-OCH2O
Where : 17 R1 = R2 = H
18 R1 = R2 = 3-OMe
19 R1 = H, R2 = 3,4-OCH2O
OTMS
CN
OMe
OMe
OH
O
O
CH
C
O
23
22
OH
CH
C
O
O
R2
R1
O
N
O
C
1) O2N
O
Cl
Me
2)
HN
OMe
24
OCO N
CH
Because of the pronounced activating effect of meta methoxy
substitution on the photocyclization of benzoin esters,10,15 we
chose to investigate the 3,3Ј,5,5Ј-tetramethoxybenzoin chromo-
phore as a photolabile amino protecting group. Despite a liter-
ature report that this benzoin 25 was unavailable by benzoin
condensation,25 we succeeded in preparing this material in 31%
yield by reaction of 3,5-dimethoxybenzaldehyde in DMF in the
presence of potassium cyanide and tetra-n-butylammonium
iodide26 (Scheme 3). Subsequent reaction with cyclohexyl iso-
C
R2
R1
O
Where : 26 R1 = R2 = 3,4-OCH2O
27 R1 = H, R2 = 3,5-OMe
Scheme 4
converted to piperidinocarbamate 26 via its p-nitrophenyl
mixed carbonate followed by treatment with piperidine. A trace
of 1,2-bis(1,3-benzodioxol-5-yl)ethanedione was isolated from
the preparation of piperidinocarbamate 26. The protection of a
secondary amine as an α-keto carbamate is particularly attract-
ive as it does not suffer from any competing cyclization reac-
tions of the sort observed during masking of primary amines
via direct addition to an isocyanate. This competing cyclization
reaction may severely limit the utility of photosensitive α-keto
carbamates derived from primary amines.
To further clarify the nature of the meta activating effect on
the photochemistry of benzoin carbamates, carbamate 5, con-
taining a 4,4Ј-dimethoxy substituted benzoin chromophore,
was synthesized. In contrast to the 3Ј,5Ј-dimethoxybenzoin
chromophore, the α-(4-methoxyphenyl)-4-methoxyphenacyl
chromophore as in 5 is known to photocleave by a variety of
mechanisms of which cyclization is a minor pathway.9 Carb-
amate 5 was prepared by reaction of anisoin [2-hydroxy-1,2-
bis(4-methoxyphenyl)ethanone] with cyclohexyl isocyanate in
refluxing toluene (Scheme 2).
Photolabile amino protecting groups based on unsymmetrical
benzoins.—An efficient synthesis of unsymmetrical benzoins
was required to enable the synthesis of a variety of carba-
mates derived from unsymmetrical benzoins. Because 3Ј,5Ј-
dimethoxybenzoin 28 is known to be an efficient chromophore
for photocyclization, several synthetic strategies towards this
particular unsymmetrical benzoin were investigated. The
diverse chemistry offered by masked cyanohydrins is particu-
larly well suited to the synthesis of unsymmetrical benzoins.
This chemistry offers two complementary approaches to the
problem of preparing unsymmetrical benzoins such as 28.
MeO
MeO
OMe
OH
CH
KCN/Bun4N I
DMF
CHO
C
O
MeO
MeO
OMe
25
Scheme 3
cyanate in refluxing toluene gave the cyclohexylamine photo-
precursor 2 in 77% yield (Scheme 2). This material is the
masked amine equivalent of the highly photosensitive 3,3Ј,5,5Ј-
tetramethoxybenzoinyl acetate and phosphate esters reported
by Corrie and Trentham.17 Interestingly, the direct addition of
benzoin 25 to cyclohexyl isocyanate was accompanied by a
trace of 1,2-bis(3,5-dimethoxyphenyl)ethanedione.
The cyclohexylcarbamate of 3,3Ј-dimethoxybenzoin 3 was
attractive because it would allow comparison of the effect of
two versus four meta activating groups in the chromophore.
3,3Ј-Dimethoxybenzoin 27 reacted with cyclohexyl isocyanate to
give the requisite carbamate 3 in 49% yield (Scheme 2). The
addition of this particular benzoin to cyclohexyl isocyanate was
plagued by cyclization of the carbamate to 3-cyclohexyl-4-
hydroxy-4,5-bis(3-methoxyphenyl)oxazolidin-2-one 18. In this
case, the 4-hydroxyoxazolidin-2-one 18 was isolated in two crys-
tal crops each of which proved to be a different stereoisomer as
indicated by H and 13C NMR spectroscopy. The crude gum
1
isolated from the reaction itself was indeed the desired
cyclohexylcarbamate 3, as indicated by 1H NMR spectroscopy.
However, cyclization tended to occur during subsequent
chromatographic operations and crystallization only succeeded
in separating stereoisomers of 3-cyclohexyl-4-hydroxy-4,5-
J. Chem. Soc., Perkin Trans. 1, 1997
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First, one can use a trimethylsilyl (TMS) masked cyanohydrin
as an electrophilic α-hydroxycarbonyl synthon in reaction with
a Grignard reagent.28 Second, TMS masked cyanohydrins offer
the prospect of umpolung; deprotonation of a TMS masked
cyanohydrin gives a nucleophilic benzoyl anion synthetic
equivalent which reacts with electrophiles.29
For future evaluation of the meta activating effect of meth-
oxy groups on the photocyclization, we proposed to prepare the
cyclohexylcarbamate of the isomeric 3,5-dimethoxybenzoin.
Interestingly, on attempting to isolate the isomeric 3,5-
dimethoxybenzoin from the analogous reaction of α-(3,5-
dimethoxyphenyl)-α-(trimethylsiloxy)acetonitrile anion with
benzaldehyde, only 3Ј,5Ј-dimethoxybenzoin 28 was isolated in
50% yield. Corrie and Trentham 17 have recently reported the
synthesis of 3,5-dimethoxybenzoin 22 in 65% yield by this
same strategy. In their case, the TMS moiety was removed
under acidic conditions, rather than by fluoride mediated
hydrolysis. Thus, it seems that fluoride anion may be sufficiently
basic as to effect isomerization of some unsymmetrical
benzoins, as well as retro addition (vide infra).
Using the first approach, 3Ј,5Ј-dimethoxybenzoin 28 was
prepared from 3,5-dimethoxybenzaldehyde (Scheme 5). Con-
OTMS
OTMS
R1
R2
CN
CN
A carbamate 7, derived from an unsymmetrical benzoin 29,
containing the 1,3-methylenedioxy substituent, was also pre-
pared in the usual way (Scheme 2). The addition of the benzoin
to cyclohexyl isocyanate proved troublesome because the crude
carbamate readily undergoes intramolecular cyclization during
purification similar to that observed for 3,3Ј-dimethoxybenzoin
N-cyclohexylcarbamate 3. Some of the desired carbamate was
separable by chromatography, but the majority of the column
fractions consisted of a mixture of the desired carbamate 7
(cyclohexyl CH, m, δH 3.50), 5-(1,3-benzodioxol-5-yl)-3-cyclo-
hexyl-4-hydroxy-4-phenyloxazolidin-2-one 19 (cyclohexyl CH,
m, δH 2.87) and 5-(1,3-benzodioxol-5-yl)-3-cyclohexyl-4-phenyl-
2,3-dihydrooxazol-2-one 21 (cyclohexyl CH, m, δH 3.29). The
required benzoin 29 was prepared in two steps involving
conversion of piperonal to α-(1,3-benzodioxol-5-yl)-α-(tri-
methylsiloxy)acetonitrile 23 followed by reaction with phenyl-
magnesium bromide (Scheme 5).
For some applications with inherently light sensitive sub-
strates e.g. tryptophan and pyrimidines, efficient red shifted
photolabile protecting groups would be of significant value.
Accordingly, we investigated extending the UV absorption of
these benzoinyl based carbamates. The general approach was to
modify the benzoyl chromophore while retaining the photo-
cyclization efficiency offered by the 3Ј,5Ј-dimethoxyphenyl
moiety. In an attempt to extend the n–π* transition of these
novel benzoin carbamates to longer wavelength, a variety of
bathochromic substituted analogues of 3Ј,5Ј-dimethoxy-
benzoin N-cyclohexylcarbamate were prepared.
One strategy used was to modify the 3Ј,5Ј-dimethoxybenzoin
chromophore by incorporating a 4-methoxy substituent into
the 1-phenyl ring. Through this modification, the new chromo-
phore may be considered as the α-(3,5-dimethoxyphenyl)-4-
methoxyphenacyl moiety and as such may be expected to be
similar to the known photolabile 4-methoxyphenacyl group
and its α substituted analogues. The 4-methoxyphenacyl and
the α-methylphenacyl group have been widely used as both car-
boxy32 and amino 33 photolabile protecting groups. Thus, the
new chromophore should possess the combined photosensitiv-
ity of the 3Ј,5Ј-dimethoxybenzoin chromophore and the known
photolability of α-substituted 4-methoxyphenacyl protecting
groups. The required benzoin 30 was prepared from α-(4-
methoxyphenyl)-α-(trimethylsiloxy)acetonitrile22 by lithiation
and subsequent reaction of the carbanion with 3,5-dimethoxy-
benzaldehyde. Fluoride ion mediated hydrolysis gave the
desired benzoin 30 (Scheme 5). With this benzoin in hand, con-
version to the masked cyclohexylamine 8 was accomplished
by reaction with cyclohexyl isocyanate in refluxing toluene
(Scheme 2).22
1) LDA
MgBr
1)
R1
2) H3O+
2)
CHO
R2
3) Bun4N+F–
OH
CH
C
O
R1
R2
Where : 28 R1 = H, R2 = 3,5-OMe; Grignard/umpolung
29 R1 = H, R2 = 3,4-OCH2O; Grignard
30 R1 = 4-OMe, R2 = 3,5-OMe; umpolung
31 R1 = 4-SMe, R2 = 3,5-OMe; umpolung
32 R1 = 3,4-C4H4 (2-Naphth), R2 = 3,5-OMe; umpolung
Scheme 5
version of the aldehyde to α-(3,5-dimethoxyphenyl)-α-(tri-
methylsiloxy)acetonitrile was achieved by zinc iodide catalysed
reaction with trimethylsilyl cyanide.30 Subsequent reaction with
phenylmagnesium bromide, followed by acid mediated
hydrolysis of the intermediate imine, gave the desired 3Ј,5Ј-
dimethoxybenzoin 28. In contrast, the original procedure of
Sheehan et al.,10 in which 3,5-dimethoxybenzaldehyde cyano-
hydrin is reacted with a large excess of phenylmagnesium brom-
ide, failed to provide any of the desired benzoin. This failure
illustrates the need for protection of the hydroxy group during
the Grignard reaction.
Second, the umpolung approach, in which α-phenyl-α-
(trimethylsiloxy)acetonitrile was used as a benzoyl anion
equivalent, was also used to prepare 3Ј,5Ј-dimethoxybenzoin
28. Lithiation of α-phenyl-α-(trimethylsiloxy)acetonitrile, fol-
lowed by reaction with 3,5-dimethoxybenzaldehyde gave the
corresponding TMS masked benzoin. Subsequent hydrolysis
using tetra-n-butylammonium fluoride gave 3Ј,5Ј-dimethoxy-
benzoin 28 (Scheme 5).
With 3Ј,5Ј-dimethoxybenzoin readily available,** carbamates
containing the 3Ј,5Ј-dimethoxybenzoin chromophore were
readily prepared. First, 3Ј,5Ј-dimethoxybenzoin N-cyclohexyl-
carbamate 6 was prepared from 3Ј,5Ј-dimethoxybenzoin 28 and
cyclohexyl isocyanate (Scheme 2). This material is the masked
amine equivalent of the highly photosensitive 3Ј,5Ј-dimethoxy-
benzoin acetate reported by Sheehan et al.10 Again, the direct
addition of the benzoin to cyclohexyl isocyanate formed a trace
of the corresponding benzil. In this case, 1-(3,5-dimethoxy-
phenyl)-2-phenylethanedione was isolated in a trace amount. A
piperidine photoprecursor 27 containing the 3Ј,5Ј-dimethoxy-
benzoin chromophore was also prepared (Scheme 4). This
photosensitive carbamate was prepared in a similar fashion to
piperoin piperidinocarbamate 26.
Using a strategy similar to that described above, a 4-methyl-
thio substituent was incorporated into the 1-phenyl moiety. In
the case of α-keto sulfonates, such a structural modification
greatly increases the absorption maxima above 300 nm.34
Because of such improved absorption characteristics, these
materials function as efficient red shifted photoacid generators.
By analogy, cyclohexylcarbamate 9 containing the 4-methylthio
modified chromophore may be expected to be an efficient
** During preparation of this manuscript, a report on the use of classical
dithiane umpolung synthons for the synthesis of unsymmetrical alkoxy
substituted benzoins appeared.31 In contrast to the initial report by
Lee,12 this latter work found the Corey–Seebach dithiane addition to be
an effective route for the synthesis of unsymmerical benzoins including
3Ј,5Ј-dimethoxybenzoin.
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source of cyclohexylamine beyond 300 nm. The substituted
benzoinyl chromophore in carbamate 9 may also be viewed as a
thiomethyl substituted analogue of the light sensitive phenacyl
chromophore. The additional photolability of the phenacyl
chromophore in 9 may be expected to increase further the
photosensitivity of the protecting group. In this regard, carb-
amate 9 is similar to carbamate 8. Carbamate 9 was prepared
from benzoin 31 by reaction with cyclohexyl isocyanate in
refluxing toluene (Scheme 2). The required benzoin 31 was
prepared from the masked TMS cyanohydrin of 4-methyl-
thiobenzaldehyde by lithiation and reaction with 3,5-dimethoxy-
benzaldehyde. Subsequent fluoride assisted desilylation gave
benzoin 31 (Scheme 5).
Following modification of the 3Ј,5Ј-dimethoxybenzoin
chromophore to photoactive substituted phenacyl groups it
seemed appropriate to evaluate carbamates containing simple
substituted phenacyl groups for comparison. Hence, two other
cyclohexyl carbamates containing basic phenacyl chromo-
phores were prepared (Scheme 2). Firstly, cyclohexyl carbamate
16 incorporating the parent α-methyl-4-methoxyphenacyl pho-
tolabile moiety was prepared from 2-hydroxy-1-(4-methoxy-
phenyl)propanone.35 In this reaction, a trace of the correspond-
ing 2,3-dihydrooxazol-2-one 24 was also isolated. A similar
addition reaction with 4-methoxybenzoin proceeded smoothly
to give the corresponding cyclohexylcarbamate 10. This carba-
mate contains the α-phenyl-4-methoxyphenacyl photolabile
group. 4-Methoxybenzoin was prepared by the benzoin rever-
sion synthesis from benzoin and 4-methoxybenzaldehyde.36
Introduction of a 4-nitro substituent on the 1-phenyl moiety
by reaction of α-(4-nitrophenyl)-α-(trimethylsiloxy)acetonitrile
with 3,5-dimethoxybenzaldehyde was also investigated. In this
case, attempted formation of the carbanion with LDA at
Ϫ78 ЊC resulted in a complex mixture. Hunig and Wehner 29
reported a similar difficulty on attempted alkylation of α-(4-
nitrophenyl)-α-(trimethylsiloxy)acetonitrile.
In another approach, the 1-phenyl substituent was replaced
by a 1-(2-naphthyl) substituent as in carbamate 11. The
required benzoin 32 was prepared by reaction of the carbanion
of α-(2-naphthyl)-α-(trimethylsiloxy)acetonitrile with 3,5-di-
methoxybenzaldehyde in the usual way (Scheme 5). Addition
of substituted benzoin 32 to cyclohexyl isocyanate gave the
requisite carbamate 11 (Scheme 2). A trace amount of the
corresponding benzil, 1-(3,5-dimethoxyphenyl)-2-(2-naphthyl)-
ethanedione, was formed during the addition. Table 1 and Table
2 summarize the analytical data on α-hydroxy ketones and α-
keto carbamates, respectively.
Preparation of 2,2-disubstituted á-keto carbamates. Previous
experience in improving the photoefficiency of the o-nitro-
benzyl photorearrangement 6 suggested that we apply similar
design principles to improve the photosensitivity of substituted
benzoin chromophores. One of the most successful structural
modifications made during studies of the o-nitrobenzyl photo-
rearrangement was α-substitution at the benzylic carbon
atom.37 The increased photoefficiency offered by this structural
change is believed to stem from increased stabilization of the
intermediate benzylic radical species. Since a benzylic radical
may be an intermediate in the photocyclization of the desyl
masking group, application of this strategy towards improved
photosensitivity appeared promising. Accordingly, a variety of
2,2-disubstituted α-hydroxy ketones were prepared as poten-
tially improved chromophores for amine photogeneration via
benzoin photocyclization. The first carbamate 12, containing a
2,2-disubstituted α-hydroxy keto chromophore was prepared by
reaction of α-hydroxy ketone 33 with cyclohexyl isocyanate
in the presence of a catalytic amount of stannous 2-ethyl-
hexanoate (Scheme 2). This tin() salt was reported to be a
useful catalyst for the preparation of tertiary carbamates24 and
proved to be the catalyst of choice for reaction of our α-keto
substituted tertiary alcohols with isocyanates. The requisite α-
hydroxy ketone 33 was prepared by reaction of benzil and 3,5-
MeO
MeO
MeO
MeO
OH
C
1) Mg, THF, heat
C
Cl
2) PhCOCOPh
3) NH4Cl–
O
33
Scheme 6
dimethoxyphenylmagnesium chloride (Scheme 6). The prepar-
ation of the necessary Grignard reagent required somewhat
forcing conditions; near complete reaction was achieved by
heating a solution of 1-chloro-3,5-dimethoxybenzene and
magnesium turnings in THF at reflux overnight.
In carbamate 12, an α-phenyl group has been incorporated
into the 3Ј,5Ј-dimethoxybenzoin chromophore. This substi-
tution pattern may suffer from steric interference in the benzoin
photocyclization. Accordingly, it seemed appropriate to pre-
pare the α-methyl derivative in which the potentially favourable
2,2-disubstitution pattern is retained but steric congestion is
reduced. The required α-hydroxy ketone 35 was prepared by
lithiation of α-phenyl-α-(trimethylsiloxy)acetonitrile followed
by reaction with 3,5-dimethoxyacetophenone (Scheme 7). In
MeO
OTMS
OTMS
1) LDA
C
C
O
MeO
2)
CN
Me
COCH3
MeO
MeO
34
Dil HCl / p-Dioxane
MeO
MeO
OH
C
C
Me
O
35
Scheme 7
this case, the TMS masked benzoin 34 was isolated and ultim-
ately deprotected by acidolysis. The resulting α-hydroxy ketone
35 was converted to the cyclohexylcarbamate 13, via the tin()
catalysed carbamoylation reaction described above (Scheme 2).
The 3,5-dimethoxy substitution pattern has been shown to
play a particularly important role in the photocyclization of
substituted benzoins when substitution is on the benzylic aro-
matic ring.8–21 In the case of the o-nitrobenzyl photorearrange-
ment, substitution by an additional o-nitro group is reported to
cause a near fivefold increase in photoefficiency, relative to the
mono o-nitrobenzyl chromophore.6,37 It may be possible to
combine these two observations to further improve the photo-
sensitivity of the benzoin photocyclization by incorporating
both features into a single chromophore. Cyclohexylcarbamate
14, incorporating two 3,5-dimethoxyphenyl substituents
adjacent to the hydroxy substituted carbon, was prepared
from α-hydroxy ketone 38, by the stannous 2-ethylhexanoate
catalysed addition to cyclohexyl isocyanate (Scheme 2).22
The chromophore based on 2,2-bis(3,5-dimethoxyphenyl)-2-
hydroxy-1-phenylethanone 38 warrants a special mention as it
does not contain a chiral centre. By using this group, facile
protection of optically active substrates may be envisioned
without undesired formation of diastereoisomers. This feature
may render α-hydroxy ketone 38 particularly useful as a photo-
removable group in protection schemes involving optically
active substrates e.g. peptides, phosphotriesters. The TMS
masked hydroxy ketone 37 was prepared from α-phenyl-α-
J. Chem. Soc., Perkin Trans. 1, 1997
2433

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OTMS
C–Li+
CN
O
MeO
MeO
MeO
MeO
OTMS
MeO
OMe
1) Mg, THF, heat
Cl
C
C
Dimethoxyethane
MeO
2)
O
CN
OMe
OMe
36
MeO
MeO
OMe
3) HCl
Bun4N+F–
4) 30% H2SO4 / PhCH3
37
Dil HCl / p-Dioxane
MeO
MeO
OH
C
C
O
MeO
OMe
38
Scheme 8
(trimethylsiloxy)acetonitrile, by reaction with 3,3Ј,5,5Ј-tetra-
methoxybenzophenone 36.22 Interestingly, fluoride ion medi-
ated hydrolysis of the TMS masked intermediate 37 resulted in
recovery of the substituted ketone 36 while acidolysis provided
the desired α-hydroxy ketone 38 (Scheme 8). The efficient
recovery of starting benzophenone from the fluoride mediated
hydrolysis implies that fluoride is sufficiently basic so as to
cause reversion of the TMS masked benzoin back to the start-
ing benzophenone 36. This is in contrast to the reaction of
TMS masked cyanohydrins and aldehydes in which fluoride
mediated hydrolysis of the crude TMS masked benzoin prod-
ucts proceeds smoothly while acidolysis suffers from significant
side reactions. 3,3Ј,5,5Ј-Tetramethoxybenzophenone 36 was
prepared by reaction of 3,5-dimethoxybenzonitrile with 3,5-
dimethoxyphenylmagnesium chloride (Scheme 8). On acidic
work-up, the ketimine intermediate was isolated as the corre-
sponding hydrochloride salt and hydrolysed to the free ketone
36 using 30% sulfuric acid in refluxing toluene.22
OMe
OMe
MeO
MeO
OTMS
OTMS
1) LDA
2) PhCOPh
C
C
O
CN
39
Dil HCl / p-Dioxane
OMe
OH
C
C
O
OMe
40
To further gauge the importance of double 3,5-dimethoxy
substitution adjacent to the hydroxy substituted carbon as in
14, a carbamate in which the substitution pattern is reversed
should provide the required contrast in photoreactivity. For this
purpose cyclohexylcarbamate 15 was prepared. This particular
carbamate 15 was conveniently prepared via the usual tin()
catalysed reaction (Scheme 2). The required α-hydroxy ketone
40 was prepared by lithiation of α-(3,5-dimethoxyphenyl)-α-
(trimethylsiloxy)acetonitrile followed by reaction with benzo-
phenone (Scheme 9). The TMS masked benzoin 39 was isolated
and deprotected by acidolysis to give 40 in 81% yield.
Since a significant amount of α-hydroxy ketone 40 was
readily available, several other methods of masking amines as
tertiary carbamates were investigated. Initially, the conditions
used to prepare other benzoin carbamates were investigated.
However, heating a solution of the α-hydroxy ketone 40 with
cyclohexyl isocyanate failed to give any of the desired carb-
amate 15. The cuprous chloride catalysed addition of tertiary
alcohols to isocyanates was also investigated.38 In the case of α-
hydroxy ketone 40, smooth addition to cyclohexyl isocyanate
took place initially but as the reaction progressed a complex,
multicomponent mixture resulted. The reaction of tertiary
alcohols with carbamoyl chlorides is reported to give the
corresponding tertiary carbamates directly.39 However, in the
case of α-hydroxy ketone 40, DMAP catalysed reaction with
N,NЈ-diethylcarbamoyl chloride failed. The synthesis of
tertiary carbamates can also be realized by activation of the
tertiary alcohol as a mixed carbonate followed by reaction with
an amine. In the case of α-hydroxy ketone 40, attempted acti-
Scheme 9
vation by derivatization to the p-nitrophenyl mixed carbonate
afforded only recovered starting material. Table 1 and Table 2
summarize the analytical data on 2,2-disubstituted α-hydroxy
ketones and α-keto carbamates, respectively.
Conclusions
The synthesis of a variety of substituted benzoin chromophores
was investigated. These chromophores hold significant poten-
tial as new photolabile protecting groups for a variety of func-
tional groups. For instance, masking of amino groups with
these chromophores gave photoactive α-keto carbamates. The
required benzoin chromophores were prepared by a variety of
synthetic routes, depending on the structure of the benzoin
chromophore desired. The benzoin condensation was used to
prepare symmetrical benzoins. The synthetic versatility of TMS
masked cyanohydrins was particularly useful in preparing
unsymmetrical benzoins. In their reaction with a Grignard
reagent, TMS masked cyanohydrins function as α-hydroxy car-
bonyl equivalents to form α-hydroxy ketones. Alternatively,
lithiation of a TMS masked cyanohydrin generates a benzoyl
anion equivalent which reacts with aldehydes and ketones to
generate benzoins and 2,2-disubstituted α-hydroxy ketones
respectively. These chromophores were used to mask primary
and secondary amines. Masking of primary amines was
achieved by the direct addition of the substituted benzoin to an
2434
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
Table 1 Analytical data on α-hydroxy ketones
Elemental analysis (%)
Yield (%)
mp (ЊC)
Comp.
δH (ppm)d
δC (ppm)
ν/cmϪ1
Calc.
Found
29
40
4.39 [1 H, br s, OH (D2O exch.)],
5.87 (1 H, s, 2-CH), 5.91 and 5.93
(each 1 H, ABq, Jgem 1.2, OCH2O),
6.73–6.78 [2 H, m, Ar(2) 4,7-H],
6.85 [1 H, dd, Jo 8.0, Jm 1.6, Ar(2)
6-H], 7.44 [2 H, m approximates
to t, Ar(1) 3,5-H], 7.56 [1 H, m
approximates to t, Ar(1) 4-H], 7.92 [2
H, m approximates to d, Ar(1) 2,6-H]
2.47 (3 H, s, SCH3), 3.74 [6 H, s,
75.71 (d), 101.15 (t), 107.70 (d), 108.69
(d), 121.75 (d), 128.58 (d), 129.03 (d),
132.76 (s), 133.32 (s), 133.81 (d),
147.76 (s), 148.13 (s), 198.66 (s)
3458, 1681,
1502, 1488,
1443, 1247,
1099, 1039,
975, 695
C15H12O4
(256.25)
C, 70.3
H, 4.7
127–129a
C, 70.5
H, 4.8
31
32
62
112–113
14.42 (q), 55.25 (q), 75.85 (d), 100.25
3370, 1678,
1670, 1608,
1596, 1591,
1206, 1162,
1156, 1088
C17H18O4S
(318.47)
C, 64.1
H, 5.7
Ar(2) 3,5-OCH3], 4.58 [1 H, d, J 6.1, (d), 105.69 (d), 124.70 (d), 129.34 (d),
OH (D2O exch.)], 5.80 (1 H, d, J 6.1, 141.22 (s), 147.36 (s), 161.15 (s),
C, 64.3
H, 5.8
S, 9.7
2-CH), 6.36 [1 H, t, Jm 2.1, Ar(2)
4-H], 6.47 [2 H, d, Jm 2.1, Ar(2)
2,6-H], 7.21 and 7.84 [each 2 H,
ABq, Jo 7.8, Ar(1) 3,5-H and 2,6-H
respectively]
3.74 (6 H, s, 3,5-OCH3), 4.62 [1 H,
br d, J 5.2, OH (D2O exch.)], 6.02
(1 H, br d, J 5.2, 2-CH), 6.35 [1 H,
197.37 (s)c
S, 10.0
b
55.25 (q), 76.13 (d), 100.32 (d), 105.74
(d), 124.13 (d), 126.88 (d), 127.68 (d),
128.50 (d), 128.93 (d), 129.65 (d),
3454, 1677,
1608, 1596,
1466, 1430,
1283, 1205,
1158, 1065
C20H18O4
(322.34)
C, 74.5
H, 5.6
C, 74.3
H, 5.4
t, Jm 2.2, Ar(2) 4-H], 6.55 [2 H, d, Jm 130.68 (s), 131.20 (s), 132.12 (s),
2.2, Ar(2) 2,6-H], 7.50–7.65 [2 H, m, 135.75 (s), 141.12 (s), 161.17 (s),
Ar(1) 6,7-H], 7.81–8.03 [4 H, m,
Ar(1) 3,4,5,8-H], 8.49 [1 H, br s,
Ar(1) 1-H]
198.55 (s)
33
35
46
3.71 [6 H, s, Ar(2) 3,5-OCH3], 4.96
[1 H, s, OH (D2O exch.)], 6.42 [1 H,
t, Jm 2.2, Ar(2) 4-H], 6.59 [2 H, d,
55.23 (q), 84.91 (s), 100.02 (d), 106.51
(d), 128.04 (d), 128.11 (d), 128.19 (d),
128.26 (d), 130.67 (d), 132.86 (d),
3429, 1674,
1611, 1597,
1426, 1235,
1205, 1158,
1068, 703
C22H20O4
(348.38)
C, 75.8
H, 5.8
111.5–113
C, 75.95
H, 5.7
Jm 2.2, Ar(2) 2,6-H], 7.29–7.51 [8 H, 135.18 (s), 141.68 (s), 143.79 (s),
m, Ph(2) 2,6-H and Ph(1) 3,4,5-H],
7.72 [2 H, m approximates to d, Jo
6.7, Ph(1) 2,6-H]
2.12 (3 H, s, CH3), 3.76 [6 H, s,
Ar(2) 3,5-OCH3], 4.70 [1 H, s, OH
(slow D2O exch.)], 6.41 [1 H, t, Jm
160.55 (s), 200.48 (s)
99
Oil
26.17 (q), 55.25 (q), 78.99 (s), 99.69
(d), 104.05 (d), 128.18 (d), 130.02 (d),
132.91 (d), 133.41 (s), 144.78 (s),
3462, 1679,
1607, 1597,
1458, 1427,
1206, 1157,
1063, 1047
C17H18O4
(286.31)
C, 71.3
H, 6.3
C, 71.2
H, 6.3
2.2, Ar(2) 4-H], 6.61 [2 H, d, Jm 2.2, 161.10 (s), 201.48 (s)
Ar(2) 2,6-H], 7.31 [2 H, m
approximates to t, Ar(1) 3,5-H],
7.46 [1 H, m approximates to t,
Ar(1) 4-H], 7.75 [2 H, m
approximates to d, Ar(1) 2,6-H]
40
81
93–94
3.63 [6 H, s, Ar(1) 3,5-OCH3], 5.08
[1 H, s, OH (D2O exch.)], 6.56 [1 H,
t, Jm 2.3, Ar(1) 4-H], 6.85 [2 H, d,
Jm 2.3, Ar(1) 2,6-H], 7.29–7.48
[10 H, m, both Ar(2) 2,2-diPh]
55.28 (q), 84.88 (s), 105.88 (d), 108.38
3446, 1679,
1607, 1597,
1458, 1427,
1206, 1157,
1063, 1047
C22H20O4
(348.38)
C, 75.8
H, 5.8
(d), 128.08 (d), 128.16 (d), 128.28 (d),
136.87 (s), 144.74 (s), 160.10 (s),
200.39 (s)
C, 75.8
H, 5.8
a Lit.,40 120 ЊC, 112 ЊC. b Yield and mp not determined. c The carbon resonance unaccounted for is (are) assumed to be coincident with other carbon
1
resonances. Although the 13C NMR data alone are not definitive, the diverse array of analytical data including H NMR, infrared and elemental
results, strongly support the proposed identity of this compound especially when considered together with the 13C NMR data. d In the assignments in
Tables 1 and 2, Ar(1) refers to the phenyl group with the R1 substituent and Ar(2) refers to the phenyl group with the R2 substituent.
isocyanate. Derivatization of these photosensitive benzoins
generally proceeded smoothly in refluxing toluene but in some
cases was complicated by intramolecular cyclization of the α-
keto carbamate functionality to give substituted oxazolidin-2-
one heterocycles. In contrast, carbamoylation of 2,2-disubsti-
tuted α-hydroxy ketones required tin() catalysis for efficient
reaction. Protection of secondary amines was readily achieved
by activation of the benzoin as a mixed p-nitrophenyl carbonate
followed by reaction with the free amine.
Bruker AF250 spectrometer using tetramethylsilane as internal
standard. J Values are quoted in Hz. Microanalyses were per-
formed by Desert Analytics, Tucson, AZ. Piperoin was
obtained from ICN Biomedicals. Table 1 and Table 2 summar-
ize the analytical data on α-hydroxy ketones and α-keto carb-
amates, respectively. Ether refers to diethyl ether.
Benzoin synthesis
1,2-Bis(3,5-dimethoxyphenyl)-2-hydroxyethanone 25. To a
solution of 3,5-dimethoxybenzaldehyde (6.64 g, 40 mmol) in
DMF (25 cm3) at room temperature under nitrogen was added
tetra-n-butylammonium iodide (1.26 g, 3.4 mmol) followed by
potassium cyanide (0.52 g, 8 mmol) and the resulting solution
stirred at room temperature for 18 h. The reaction mixture was
poured into water (150 cm3) and the product extracted into
dichloromethane (3 × 50 cm3). The combined organic extracts
were washed with brine (2 × 25 cm3) and dried (MgSO4).
Removal of the solvent in vacuo gave a yellow oil (11.16 g)
which solidified on cooling. Recrystallization (CH2Cl2–EtOH)
allowed isolation of the crude benzoin as an off-white solid
Experimental
General procedures
Melting points and boiling points are uncorrected; melting
points were recorded on a Gallenkamp melting point instru-
ment. Unless stated otherwise, infrared spectra were obtained
as KBr disks using
a Nicolet FT-IR/44 spectrometer.
Ultraviolet–visible spectra were measured in acetonitrile solu-
tion using a Hewlett-Packard 8450 Diode Array Spectro-
photometer. NMR spectra were recorded in CDCl3 on a
J. Chem. Soc., Perkin Trans. 1, 1997
2435

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Table 2 Analytical data on α-keto carbamates
λmax/nm
Elemental analysis (%)
Yield (%)
mp (ЊC)
(ε/dm3
Comp.
δH (ppm)q
δC (ppm)
ν/cmϪ1
molϪ1 cmϪ1
)
Calc.
Found
1a
21/77
87–88
1.05–2.15 [10 H, m, cyclohexyl 24.63 (t), 25.33 (t), 33.10 (t),
3342, 2934,
246 (13 120),
325 (296)
C21H23NO3
(337.40)
C, 74.75
H, 6.9
(CH2)5], 3.47 (1 H, m,
50.06 (d), 77.15 (d), 128.48 (d), 1706, 1678,
cyclohexyl CH), 4.68 and
5.00 (total 1 H, each br d,
NH), 6.87 (1 H, s, 2-CH),
7.14–7.55 [8 H, m, Ar(1)
3,4,5-H and Ar(2) 2,3,4,5,6-H],
7.96 [2 H, m approximates to
d, Jo 8.1 Ar(1) 2,6-H]
128.53 (d), 128.71 (d), 128.93
(d), 129.04 (d), 133.24 (d),
133.97 (s), 134.73 (s), 154.60
(s), 194.98 (s)
1531, 1449,
1251, 1229,
1059, 697
C, 74.9
H, 7.0
N, 4.2
N, 4.15
2b
77
116–118
1.05–2.15 [10 H, m,
24.61 (t), 25.32 (t), 33.06 (t),
50.04 (d), 55.31 (q), 55.42 (q),
77.26 (d), 101.11 (d), 105.86
(d), 106.38 (d), 106.45 (d),
135.94 (s), 136.40 (s), 154.46
(s), 160.60 (s), 161.04 (s),
3406, 3326,
2933, 1694,
1598, 1429,
1232, 1214,
1159, 1054
202 (20 770),
267 (6421),
320 (2256)
C25H31NO7
(457.51)
C, 65.6
H, 6.8
cyclohexyl (CH2)5], 3.48 (1 H,
m, cyclohexyl CH), 3.76 and
3.78 (each 6 H, each s, 3,3Ј,
5,5Ј-OCH3), 4.62 and 4.92
(total 1 H, each br d, NH),
C, 65.6
H, 6.8
N, 2.95
N, 3.1
6.41 [1 H, t, Jm 2.2, Ar(2) 4-H], 194.34 (s)
6.57–6.61 [3 H, m, Ar(1) 4-H
and Ar(2) 2,6-H], 6.68 (1 H, s,
2-CH), 7.10 [2 H, d, Jm 2.0,
Ar(1) 2,6-H]
3c
49
1.05–2.05 [10 H, m, cyclohexyl 24.62 (t), 25.32 (t), 33.10 (t),
3360, 1727,
1673, 1610,
1593, 1591,
1525, 1226,
1204, 1160
218 (26 523),
252 (7597),
282 (2763),
309 (2260)
C23H27NO5
(397.46)
C, 69.5
H, 6.85
N, 3.5
Gum
(CH2)5], 3.49 (1 H, m,
50.05 (d), 55.18 (q), 55.29 (q),
77.16 (d), 112.77 (d), 113.67
(d), 120.03 (d), 120.86 (d),
121.34 (d), 129.45 (d), 129.97
(d), 135.32 (s), 135.93 (s),
154.54 (s), 159.60 (s), 159.86
(s), 194.63 (s)
cyclohexyl CH), 3.77 and
3.80 (each 3 H, each s, 3,3Ј-
OCH3), 4.63 and 4.95 (total
1 H, each br d, NH), 6.79 (1
H, s, 2-CH), 6.87 [1 H, dd, Jo
8.0, Jm 1.8, Ar(1) 4-H], 6.99
[1 H, br t, Ar(2) 2-H], 7.02–
7.08 [2 H, m, Ar(2) 4,6-CH],
7.28 [2 H, overlapping t, Jo 8.0,
Ar(1) and Ar(2) 5,5Ј-H], 7.48
[1 H, br t, Ar(1) H-2], 7.56
[1 H, dt, Jo 8.0, Jm 1.8, Ar(1)
6-H]
C, 69.8
H, 7.0
N, 3.3
4d
27
148–149
1.05–2.15 [10 H, m, cyclohexyl 24.62 (t), 25.33 (t), 33.10 (t),
3426, 2934,
230 (21 959),
278 (8839),
296 (8858),
312 (9401)
C23H23NO7
(425.47)
C, 64.9
H, 5.45
N, 3.3
(CH2)5], 3.49 (1 H, m,
50.03 (d), 76.77 (d), 101.25 (t), 1712, 1678,
cyclohexyl CH), 4.59 and
4.95 (total 1 H, each br d,
101.74 (t), 107.89 (d), 108.46
(d), 108.56 (d), 108.63 (d),
1505, 1492,
1447, 1253,
1222, 1039
C, 64.6
H, 5.4
N, 3.4
NH), 5.88 and 5.90 (each 1 H, 122.69 (d), 125.11 (d), 127.85
ABq, Jgem 1.2, OCH2O), 5.96
(2 H, s, OCH2O), 6.67 (1 H,
s, 2-CH), 6.78 [2 H, m, Jo 8.2,
Ar(1) and Ar(2), 7,7Ј-H], 6.92
[2 H, m, Ar(2) 4,6-H], 7.42
[1 H, s, Ar(1) 4-H], 7.57 [1 H,
d, Jo 8.1, Ar(1) 6-H]
(s), 129.24 (s), 148.01 (s),
148.22 (s), 151.88 (s), 154.57
(s), 192.75 (s)r
5 e
46
1.05–2.15 [10 H, m, cyclohexyl 24.64 (t), 25.34 (t), 33.11 (t),
3330, 1710,
1686, 1600,
1513, 1308,
1265, 1250,
1233, 1169
219 (17 355),
274 (16 666),
325 (770)
C23H27NO5
(397.46)
C, 69.75
H, 6.9
119–121
(CH2)5], 3.50 (1 H, m,
49.98 (d), 55.12 (q), 55.29 (q),
76.45 (d), 113.66 (d), 114.32
(d), 126.47 (s), 127.58 (s),
129.98 (d), 131.01 (d), 154.73
(s), 160.01 (s), 163.46 (s),
cyclohexyl CH), 3.75 and
3.80 (each 3 H, each s, 4,4Ј-
OCH3), 4.65 and 4.99 (total
1 H, each br d, NH), 6.80
C, 69.5
H, 6.85
N, 3.5
N, 3.5
(1 H, s, 2-CH), 6.85 [4 H, d, Jo 193.29 (s)
8.8, 3,3Ј,5,5Ј-H], 7.38 [2 H, d,
Jo 8.8, Ar(2) 2,6-H], 7.94 [2 H,
d, Jo 8.8, Ar(1) 2,6-H]
1.05–2.15 [10 H, m, cyclohexyl 24.62 (t), 25.33 (t), 33.11 (t),
6f
59
3428, 3371,
2935, 1712,
1698, 1680,
1610, 1597,
1205, 1158
243 (16 633),
280 (2994)
C23H27NO5
(397.46)
C, 69.75
H, 6.9
149–151
(CH2)5], 3.46 (1 H, m,
50.06 (d), 55.30 (q), 77.16 (d),
101.07 (d), 106.43 (d), 128.46
(d), 128.69 (d), 133.26 (d),
134.72 (s), 135.91 (s), 154.51
cyclohexyl CH), 3.75 (3 H,
s, 3Ј,5Ј-OCH3), 4.62 and 4.95
(total 1 H, each br d, NH),
C, 69.5
H, 6.8
N, 3.6
N, 3.5
6.41 [1 H, t, Jm 2.2, Ar(2) 4-H], (s), 161.03 (s), 194.77 (s)
6.61 [2 H, d, Jm 2.2, Ar(2)
2,6-H], 6.75 (1 H, s, 2-CH),
7.40 [2 H, m approximates to
t, Ar(1) 3,5-H], 7.52 [1 H, m
approximates to t, Ar(1) 4-H],
7.96 [2 H, m approximates to
d, Ar(1) 2,6-H]
2436
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
Table 2 (Continued )
λmax/nm
Elemental analysis (%)
Yield (%)
mp (ЊC)
(ε/dm3
Comp.
δH (ppm)q
δC (ppm)
ν/cmϪ1
molϪ1 cmϪ1
)
Calc.
Found
7g
19
124–126
1.05–2.25 [10 H, m, cyclohexyl 24.63 (t), 25.33 (t), 33.11 (t),
3363, 1705,
241 (15 418),
288 (4964)
C22H23NO5
(381.41)
C, 69.3
H, 6.1
(CH2)5], 3.50 (1 H, m,
50.05 (d), 76.77 (d), 101.27 (t), 1682, 1502,
cyclohexyl CH), 4.52 and
108.59 (d), 108.72 (d), 122.84
1490, 1447,
1250, 1235,
1061, 1041
C, 69.1
H, 6.1
N, 3.7
4.92 (total 1 H, each br d, NH), (d), 127.49 (d), 128.48 (d),
5.93 and 5.95 (each 1 H, ABq, 128.67 (d), 133.25 (s), 134.66
N, 3.7
Jgem 1.2, OCH2O), 6.73–6.79
and 6.91–6.97 [each 2 H, each
m, Ar(2) 4,6,7-H and 2-CH],
7.37 [2 H, m approximates to
t, Ar(1) 3,5-H], 7.48 [1 H, m
approximates to t, Ar(1) 4-H],
7.94 [2 H, m approximates to
d, Ar(1) 2,6-H]
(s), 148.04 (s), 148.27 (s),
154.57 (s), 194.77 (s)
9 h
10i
11j
92
152–154
1.05–2.05 [10 H, m, cyclohexyl 14.52 (q), 24.62 (t), 25.33 (t),
3365, 1727,
1673, 1610,
1593, 1591,
1525, 1226,
1204, 1160
312 (20 991)
C24H29NO5S
(443.54)
C, 65.0
H, 6.6
N, 3.2
S, 7.2
(CH2)5], 2.48 (3 H, s, SCH3),
3.46 (1 H, m, cyclohexyl CH),
4.54 and 4.93 (total 1 H, each
33.10 (t), 50.04 (d), 55.29 (q),
76.45 (d), 100.98 (d), 106.40
(d), 124.76 (d), 129.07 (d),
C, 64.7
H, 6.6
N, 3.1
S, 7.5
br d, NH), 6.40 [1 H, t, Jm 2.2, 130.76 (s), 136.15 (s), 146.37
Ar(2) 4-H], 6.59 [2 H, d, Jm
2.2, Ar(2) 2,6-H], 6.71 (1 H, s,
2-CH), 7.19 and 7.87 [each
2 H, ABq, Jo 8.6, Ar(1) 3,5-H
and 2,6-H respectively]
(s), 154.50 (s), 161.02 (s),
193.56 (s)
52
87–90
1.05–2.15 [10 H, m, cyclohexyl 24.63 (t), 25.34 (t), 33.13 (t),
(CH2)5], 3.50 (1 H, m,
3348, 1712,
1687, 1601,
1512, 1261,
1252, 1232,
1172, 1062
280 (16 757)
C22H25NO4
(367.43)
C, 71.9
H, 6.9
50.03 (d), 55.31 (q), 76.83 (d),
113.71 (d), 127.59 (s), 128.47
(d), 128.87 (d), 131.07 (d),
134.51 (s), 154.62 (s), 163.55
(s), 193.23 (s)r
cyclohexyl CH), 3.81 (3 H, s,
4-OCH3), 4.62 and 4.97 (total
1 H, each br d, NH), 6.85 (1
H, s, 2-CH), 6.87 [2 H, d, Jo
8.8, Ar(1) 3,5-H], 7.33 [3 H,
m, Ar(2) 3,4,5-H], 7.47 [2 H,
m, Ar(2) 2,6-H], 7.95 [2 H, d,
Jo 8.8, Ar(1) 2,6-H]
C, 71.7
H, 6.9
N, 3.9
N, 3.8
70
1.05–2.15 [10 H, m, cyclohexyl 24.62 (t), 25.33 (t), 33.12 (t),
3426, 3380,
1725, 1711,
1692, 1675,
1610, 1598,
1253, 1158
204 (59 671),
245 (41 242),
251 (47 901),
284 (10 503),
292 (9464),
334 (2022)
C27H28NO5
(446.50)
C, 72.6
H, 6.3
160–161
(CH2)5], 3.52 (1 H, m,
50.08 (d), 55.29 (q), 77.16 (d),
101.02 (d), 106.46 (d), 124.19
(d), 126.65 (d), 127.60 (d),
128.37 (d), 128.53 (d), 129.59
cyclohexyl CH), 3.74 (6 H,
s, 3,5-OCH3), 4.55 and 4.97
(total 1 H, each br d, NH),
C, 72.6
H, 6.6
N, 3.15
N, 3.1
6.40 [1 H, t, Jm 2.2, Ar(2) 4-H], (d), 130.57 (d), 132.08 (s),
6.66 [2 H, d, Jm 2.2, Ar(2)
2,6-H], 6.93 (1 H, s, 2-CH),
7.46–7.65 [2 H, m, Ar(1)
6,7-H], 7.80–8.05 [4 H, m,
Ar(1) 3,4,5,8-H], 8.49 [1 H,
br s, Ar(1) 1-H]
132.24 (s), 135.54 (s), 136.06
(s), 154.59 (s), 161.04 (s),
194.77 (s)
12k
94
0.74–2.10 [10 H, m, cyclohexyl 24.48 (t), 25.23 (t), 32.66 (t),
3350, 2933,
1726, 1711,
1608, 1588,
1510, 1316,
1200, 1161
244 (15 234),
278 (2934)
C29H31NO5
(473.55)
C, 73.55
H, 6.6
173–174.5 (CH2)5], 3.19 (1 H, m,
cyclohexyl CH), 3.75 [6 H, s,
Ar(2) 3,5-OCH3], 4.38 and
4.82 (total 1 H, each br d,
NH), 6.38 [1 H, t, Jm 2.2,
Ar(2) 4-H], 6.78 [2 H, d, Jm
2.2, Ar(2) 2,6-H], 7.26–7.46
[6 H, m, Ar(1) and ArЈ(2)
3,4,5-H], 7.58 [2 H, m
49.62 (d), 55.25 (q), 87.70 (s),
99.25 (d), 105.31 (d), 127.53
(d), 127.56 (d), 127.69 (d),
127.77 (d), 128.98 (d), 131.32
(d), 136.86 (s), 140.17 (s),
142.39 (s), 153.03 (s), 160.43
(s), 195.30 (s)
C, 73.6
H, 6.55
N, 2.9
N, 3.0
approximates to d, ArЈ(2)
2,6-H], 7.81 [2 H, m,
approximates to d, Ar(1)
2,6-H]
0.65–2.10 [10 H, m, cyclohexyl 24.59 (t), 25.25 (t), 27.14 (q),
13l
66
3376, 3267,
2936, 1712,
86.16 (s), 99.03 (d), 102.62 (d), 1694, 1601,
228 (12 783),
242 (12 532),
278 (3082)
C24H29NO5
(411.48)
C, 70.05
H, 7.1
114–116
(CH2)5], 1.96 (3 H, s, 3-CH3),
3.22 (1 H, m, cyclohexyl CH),
3.77 [6 H, s, Ar(2) 3,5-OCH3],
4.48 and 4.75 (total 1 H, each
32.80 (t), 49.56 (d), 55.30 (q),
C, 70.1
H, 7.05
N, 3.4
127.73 (d), 128.96 (d), 131.61
(d), 135.46 (s), 143.06 (s),
1451, 1208,
1158, 1048
N, 3.4
br d, NH), 6.38 [1 H, t, Jm 2.2, 153.10 (s), 160.99 (s), 196.97 (s)
Ar(2) 4-H], 6.66 [2 H, d, Jm 2.2,
Ar(2) 2,6-H], 7.27 [2 H, m
approximates to t, Ar(1) 3,5-H],
7.36 [1 H, m approximates to t,
Ar(1) 4-H], 7.76 [2 H, m
approximates to d, Ar(1) 2,6-H]
J. Chem. Soc., Perkin Trans. 1, 1997
2437

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Table 2 (Continued)
λmax/nm
Elemental analysis (%)
Yield (%)
mp (ЊC)
(ε/dm3
Comp.
δH (ppm)q
δC (ppm)
ν/cmϪ1
molϪ1 cmϪ1
)
Calc.
Found
15m
81
171–173
0.86–2.10 [10 H, m, cyclohexyl 24.46 (t), 25.26 (t), 32.73 (t),
3427, 2935,
1715, 1689,
1596, 1451,
1295, 1206,
1157, 1045
264 (7373),
318 (2061)
C29H31NO5
(473.55)
C, 73.55
H, 6.6
(CH2)5], 3.25 (1 H, m,
cyclohexyl CH), 3.72 [6 H, s,
Ar(1) 3,5-OCH3], 4.40 and
49.69 (d), 55.28 (q), 88.24 (s),
104.07 (d), 106.96 (d), 127.31
(d), 127.64 (d), 127.94 (d),
C, 73.6
H, 6.55
N, 3.0
4.89 (total 1 H, each br d, NH), 138.23 (s), 140.30 (s), 153.24
6.50 [1 H, t, Jm 2.2, Ar(1) 4-H], (s), 159.92 (s), 194.58 (s)
7.02 [2 H, d, Jm 2.2, Ar(1)
N, 3.0
2,6-H], 7.29 [6 H, m, Ar(2)
3,3Ј,4,4Ј,5,5Ј-H], 7.54 [4 H,
m approximates to d, Ar(2)
2,2Ј-6,6Ј-H]
16n
73
1.05–2.15 [10 H, m, cyclohexyl 17.42 (q), 24.63 (t), 25.32 (t),
3325, 2937,
1711, 1686,
1603, 1537,
1263, 1237,
1144, 1089
217 (11 591),
272 (16 797)
C17H23NO4
(305.36)
C, 66.9
H, 7.6
117–118
(CH2)5], 1.46 (3 H, d, J 6.9,
3-CH3), 3.47 (1 H, m,
33.10 (t), 49.90 (d), 55.36 (q),
70.64 (d), 113.78 (d), 127.35
(s), 130.74 (d), 154.68 (s),
163.64 (s), 196.35 (s)
C, 66.8
H, 7.6
N, 4.6
cyclohexyl CH), 3.86 (3 H, s,
4-OCH3), 4.62 and 4.89 (total
1 H, each br d, NH), 5.92 (1 H,
q, J 6.9, 2-CH), 6.93 and 7.95
[each 2 H, ABq, Jo 8.8, Ar(1)
3,5-H and 2,6-H respectively]
1.59 [6 H, br s, piperidino
3,4,5 (CH2)], 3.44 [4 H, m,
piperidino 2,6 (CH2)], 5.93
and 5.95 (each 1 H, ABq, Jgem
1.2, OCH2O), 6.00 (2 H, s,
OCH2O), 6.60 (1 H, s, 2-CH),
6.78 [2 H, overlapping d, Jo
8.2, Ar(1) and Ar(2) 7,7Ј-H],
6.90–7.00 [2 H, m, Ar(2)
N, 4.6
26o
43
147–149
24.21 (t), 25.62 (t), 45.04 (t),
77.03 (d), 101.23 (t), 101.72
(t), 107.89 (d), 108.42 (d),
108.54 (d), 122.55 (d), 125.06
(d), 128.04 (s), 129.34 (s),
147.98 (s), 148.13 (s), 151.83
(s), 154.47 (s), 192.82 (s)r
1692 (sh),
1678, 1504,
1490, 1468,
1444, 1251,
1237, 1037,
931
230 (21 536),
278 (8964),
296 (8848),
312 (9702)
C22H21NO7
(411.40)
C, 64.2
H, 5.15
N, 3.4
C, 64.3
H, 5.2
N, 3.4
4,6-H], 7.43 [1 H, d, Jm 1.8,
Ar(1) 4-H], 7.59 [1 H, dd, Jo
8.2, Jm 1.8, Ar(1) 6-H]
27p
38
1.59 [6 H, br s, piperidino
24.21 (t), 25.63 (t), 45.04 (t),
55.28 (q), 77.70 (d), 100.59
(d), 106.42 (d), 128.43 (d),
128.70 (d), 133.15 (d), 134.83
(s), 136.19 (s), 154.40 (s),
160.93 (s), 194.81 (s)
1697, 1680
1612, 1595
1433, 1266
1234, 1164
1156, 1063
243 (14 511),
280 (2854)
C22H24NO5
(382.42)
C, 68.9
H, 6.6
N, 3.65
124–124.5 3,4,5 (CH2)3], 3.50 [4 H, br d,
piperidino 2,6 (CH2)], 3.75
[6 H, s, Ar(2) 3,5-OCH3], 6.41
[1 H, t, Jm 2.2, Ar(2) 4-H],
6.62 [2 H, d, Jm 2.2, Ar(2)
2,6-H], 6.73 (1 H, s, 2-CH),
7.40 [2 H, m approximates to
t, Ar(1) 3,5-H], 7.51 [1 H, m
approximates to t, Ar(1) 4-H],
7.97 [2 H, m approximates to
d, Ar(1) 2,6-H]
C, 68.7
H, 6.45
N, 3.5
a Purified by flash chromatography (10% EtOAc–90% hexane) followed by recrystallization from CH2Cl2–hexane. b Purified by flash chromatography
(25% EtOAc–75% hexane) followed by recrystallization from CH2Cl2–hexane. c Purified by successive flash chromatography (20% EtOAc–80%
hexane). d Purified by flash chromatography (CH2Cl2) followed by recrystallization from CH2Cl2–hexane. e Purified by trituration with CH2Cl2
followed by recrystallization from CH2Cl2–hexane. f Purified by flash chromatography (CH2Cl2) followed by recrystallization from CH2Cl2–hexane.
g Purified by flash chromatography (10% EtOAc–90% hexane) followed by recrystallization from EtOAc–hexane. h Purified by trituration with cold
toluene followed by recrystallization from CH2Cl2–hexane. i Purified by flash chromatography (20% EtOAc–80% hexane) followed by recrystalliza-
tion from CH2Cl2–hexane. j Purified by flash chromatography (CH2Cl2) followed by recrystallization from EtOAc–hexane. k Purified by flash chroma-
tography (15% EtOAc–85% hexane) followed by recrystallization from EtOAc–hexane. l Purified by flash chromatography (15% EtOAc–85% hexane)
followed by recrystallization from PhH–hexane. m Purified by flash chromatography (15% EtOAc–85% hexane) followed by recrystallization from
EtOAc–hexane. n Purified by flash chromatography (20% EtOAc–80% hexane) followed by recrystallization from EtOAc–hexane. o Purified by flash
chromatography (20% EtOAc–80% hexane) followed by recrystallization from EtOAc–hexane. p Purified by trituration with ether followed by
recrystallization from Et2O. q 1H NMR of these cyclohexyl carbamates routinely showed two broad resonances for the carbamate NH proton and no
apparent duplication of any other resonances. This effect is likely due to the presence of anti and syn rotamers as a result of rotational isomerism
about the amide like bond.41 Typically, the minor carbamate syn rotamer is often difficult to detect at room temperature since the resonances typically
blend into the baseline (a hidden partner).41 The fact that only the NH resonance was clearly duplicated suggest that all the other resonances in the
hidden partner are sufficiently broadened and blend in to the baseline. r See Table 1, footnote c.
(4.47 g). Further recrystallization from EtOH gave benzoin 25 as
a white solid (4.18 g, 31%); mp 102–103 ЊC (lit.,17 102–103 ЊC).
one portion. The resulting solution was then stirred at 95 ЊC
overnight. Vacuum distillation of the red oil afforded the TMS
masked cyanohydrin 23 as a pale yellow oil (21.60 g, 87%); bp
90–95 ЊC (0.5 mmHg); νmax/cmϪ1 2242, 1506, 1490, 1447, 1235,
1103, 1085, 1041, 938, 875; δH 0.24 [9 H, s, OSi(CH3)3], 5.41 (1
H, s, CH), 6.01 (2 H, s, OCH2O), 6.82 (1 H, d, Jo 8.0, 7-H), 6.93
(1 H, dd, Jo 8.0, Jm 1.8, 6-H), 6.98 (1 H, d, Jm 1.8, 4-H); δC
Ϫ0.47 (q), 63.22 (d), 101.29 (t), 106.76 (d), 108.13 (d), 118.95
(s), 120.02 (d), 130.00 (s), 148.02 (s), 148.28 (s).
Representative synthesis of benzoins using á-aryl-á-(trimethyl-
siloxy)acetonitrile as an electrophilic á-hydroxycarbonyl
synthon: preparation of 2-(1,3-benzodioxol-5-yl)-2-hydroxy-1-
phenylethanone 29
(a)
á-(1,3-Benzodioxol-5-yl)-á-(trimethylsiloxy)acetonitrile
23. To a mixture of piperonal (15.01 g, 0.1 mol) and anhydrous
zinc iodide (59 mg, 0.2 mmol) under nitrogen at room tem-
perature was added trimethylsilyl cyanide (10.91 g, 0.11 mol) in
(b) 2-(1,3-Benzodioxol-5-yl)-2-hydroxy-1-phenylethanone 29.
To an ice cooled solution of phenylmagnesium bromide (3 mol
2438
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
dmϪ3 in Et2O; 13.2 cm3, 39.4 mmol) in anhydrous tetrahydro-
furan (40 cm3) under nitrogen was added a solution of α-(1,3-
benzodioxol-5-yl)-α-(trimethylsiloxy)acetonitrile 23 (8.94 g,
35.9 mmol) in anhydrous tetrahydrofuran (40 cm3). The result-
ing solution was stirred at 0 ЊC for 2 h, then quenched by pour-
ing into a mixture of ice (350 g) and concentrated sulfuric acid
(20 cm3) and stirring for 1 h. The tetrahydrofuran was removed
in vacuo and the residue extracted with ether (3 × 100 cm3). The
combined ether extracts were washed with 10% hydrochloric
acid (2 × 50 cm3) and brine (1 × 50 cm3), dried (MgSO4) and
concentrated under reduced pressure. The residue was taken up
in a mixture of methanol (100 cm3) and 10% hydrochloric acid
(35 cm3) and the resulting solution stirred at room temperature
for 60 h. During this time, a significant amount of solid precipi-
tated. The reaction mixture was cooled to 0 ЊC and the solid
collected by filtration. The white solid (4.53 g) was identified as
the desired benzoin albeit in a crude form. Recrystallization
from methanol furnished benzoin 29 as a white crystalline solid
(3.63 g, 40%). See Table 1 for analytical data.
tetrahydrofuran (2 × 10 cm3). Based on the weight of these resi-
dues (0.65 g), the Grignard solution was assumed to contain
0.122 mol of 3,5-dimethoxyphenylmagnesium chloride. This
Grignard reagent was added dropwise to a solution of benzil
(25.65 g, 0.122 mol) in dry tetrahydrofuran (200 cm3). The solu-
tion was brought to reflux and stirred at reflux for 16 h. After
cooling, the reaction was quenched with saturated aqueous
ammonium chloride (100 cm3) and the tetrahydrofuran re-
moved in vacuo. The residue was extracted with ether (3 × 100
cm3) and the combined ether extracts were washed with water
(2 × 75 cm3) and brine (1 × 75 cm3) and dried (MgSO4).
Removal of the solvent under reduced pressure gave a dark
brown viscous oil (45.71 g) which failed to crystallize. The crude
product was purified in a batch mode by flash chromatography
using 10% EtOAc–90% hexane as eluent. In this way, a total of
5.92 g of benzil was recovered from the early fractions of each
column. The later fractions from each column were combined
to give the crude product as a colourless oil (18.94 g) which
crystallized on trituration with ethanol. Recrystallization from
ethanol gave benzoin 33 as a white crystalline solid (15.14
g, 46% based on recovered starting benzil). See Table 1 for
analytical data.
Representative synthesis of benzoins using á-aryl-á-(trimethyl-
siloxy)acetonitrile as a benzoyl anion synthon: preparation of
2-(3,5-dimethoxyphenyl)-2-hydroxy-1-(4-methylthiophenyl)-
ethanone 31
2-(3,5-Dimethoxyphenyl)-2-hydroxy-1-phenylpropanone 35
2-(3,5-Dimethoxyphenyl)-2-trimethylsiloxy-1-phenylpropan-
one 34 was prepared from α-phenyl-α-(trimethylsiloxy)-
acetonitrile30 (5.93 g, 28.9 mmol) and 3,5-dimethoxyaceto-
phenone (5.2 g, 28.9 mmol) in the same manner as described for
31. The TMS masked benzoin 34 was isolated as an orange oil
(10.82 g); νmax(liquid film)/cmϪ1 1685, 1607, 1597, 1425, 1253,
1207, 1157, 1066, 1012, 843; δH 0.00 [9 H, s, OSi(CH3)3], 1.74 (3
H, s, CH3), 3.72 [6 H, s, Ar(2) 3,5-OCH3], 6.30 [1 H, t, Jm 2.2,
Ar(2) 4-H], 6.62 [2 H, d, Jm 2.2, Ar(2) 2,6-H], 7.23 [2 H, t, Jo 7.8,
Ar(1) 3,5-H], 7.34 [1 H, t, Jo 7.8, Ar(1) 4-H], 7.90 [2 H, d, Jo 7.8,
Ar(1) 2,6-H]; δC 1.60 (q), 29.83 (q), 55.14 (q), 83.35 (s), 98.41
(d), 102.48 (d), 127.57 (d), 130.70 (d), 132.19 (d), 134.63 (s),
147.55 (s), 160.82 (s), 200.42 (s).
The TMS ether 34 was dissolved in a mixture of 1,4-dioxane
(60 cm3), methanol (40 cm3) and 10% hydrochloric acid (50 cm3)
and the resulting solution stirred at room temperature for 2 h.
After concentration under reduced pressure, the residue was
partitioned between ether (200 cm3) and water (50 cm3) and the
organic layer washed with water (2 × 35 cm3) and brine (1 × 35
cm3) and dried (MgSO4). Removal of the solvent in vacuo gave
the crude benzoin as an orange oil (9.64 g) which failed to
crystallize. The oil was purified by flash chromatography
using 15% EtOAc–85% hexane to afford the desired benzoin
35 as a colourless oil (8.2 g, 99%). See Table 1 for analytical
data.
To a solution of dry, distilled diisopropylamine (7.7 cm3, 55
mmol) in anhydrous 1,2-dimethoxyethane (50 cm3) at Ϫ78 ЊC
under nitrogen was added a solution of n-butyllithium in hex-
anes (1.6 mol dmϪ3; 31.3 cm3, 50 mmol). The solution was
stirred at Ϫ78 ЊC for 1 h, then treated dropwise with a solu-
tion of α-(4-methylthiophenyl)-α-(trimethylsiloxy)acetonitrile42
(12.57 g, 50 mmol) in dry 1,2-dimethoxyethane (50 cm3). After
1 h at Ϫ78 ЊC, a solution of 3,5-dimethoxybenzaldehyde (9.14
g, 55 mmol) in dry 1,2-dimethoxyethane (50 cm3) was added
and the reaction allowed to slowly warm up to 0 ЊC over 4 h.
Once at 0 ЊC, saturated aqueous ammonium chloride (75 cm3)
was added and the mixture stirred for 5 min. Ether (150 cm3)
was added and the layers separated. The organic layer was
washed with saturated aqueous ammonium chloride (1 × 50
cm3), dried (MgSO4) and concentrated in vacuo to give an
orange oil (21.30 g). The oil was taken up in tetrahydrofuran
(75 cm3) and a solution of tetra-n-butylammonium fluoride in
tetrahydrofuran (1 mol dmϪ3; 55 cm3, 55 mmol) added. The
resulting solution was stirred at room temperature under nitro-
gen for 4 h, concentrated in vacuo and the residue partitioned
between ether (200 cm3) and water (50 cm3). The layers were
separated and the organic layer washed with water (2 × 50 cm3)
and brine (1 × 50 cm3). After drying (MgSO4), removal of the
solvent in vacuo gave a yellow oil (18.73 g) which on trituration
with a little methanol gave a solid which was recrystallized from
methanol to give benzoin 31 as a white crystalline solid (9.79 g,
62%). See Table 1 for analytical data.
1-(3,5-Dimethoxyphenyl)-2-hydroxy-2,2-diphenylethanone 40
1-(3,5-Dimethoxyphenyl)-2-trimethylsiloxy-2,2-diphenylethan-
one 39 was prepared from α-(3,5-dimethoxyphenyl)-α-
(trimethylsiloxy)acetonitrile17 (6.63 g, 25 mmol) and benzo-
phenone (4.78 g, 26.3 mmol) in a manner similar to that
described for 34. The TMS masked benzoin 39 was isolated as
an orange oil (11.19 g); νmax(liquid film)/cmϪ1 1685, 1593, 1424,
1252, 1206, 1157, 1075, 1067, 890, 700; δH Ϫ0.20 [9 H, s,
OSi(CH3)3], 3.75 (6 H, s, 3,5-OCH3), 6.55 [1 H, t, Jm 2.2, Ar(1)
4-H], 7.17 [2 H, d, Jm 2.2, Ar(1) 2,6-H], 7.25–7.50 [10 H, m,
both Ar(2) 2,2-diPh]; δC 1.29 (q), 55.29 (q), 88.61 (s), 104.89 (d),
108.06 (d), 127.69 (d), 127.88 (d), 128.26 (d), 138.18 (s), 142.95
(s), 159.75 (s), 201.03 (s). This material was contaminated by a
trace amount of the starting benzophenone.
Acidolysis of the crude TMS masked benzoin 39 was per-
formed as described for 35 and gave the crude benzoin as an
orange oil (10.07 g) which crystallized on standing. Subse-
quent recrystallization from methanol gave benzoin 40 as a
white crystalline solid (7.02 g, 81%). See Table 1 for analytical
data.
2-(3,5-Dimethoxyphenyl)-2-hydroxy-1-(2-naphthyl)ethanone 32
The title compound 32 was prepared from α-(2-naphthyl)-α-
(trimethylsiloxy)acetonitrile43 (11.42 g, 44.7 mmol) in the
same manner as described for 31. See Table 1 for analytical
data.
2-(3,5-Dimethoxyphenyl)-2-hydroxy-1,2-diphenylethanone 33
To a suspension of clean, dry magnesium turnings (3.62 g,
0.149 mol) in dry tetrahydrofuran (20 cm3) at room temperature
was added a few drops of a solution of 1-chloro-3,5-
dimethoxybenzene (23.38 g, 0.135 mol) in dry tetrahydrofuran
(100 cm3). No visible reaction took place even on adding a few
drops of 1,2-dibromoethane. The suspension was then brought
to reflux whereupon the addition of a few drops of 1,2-
dibromoethane caused a vigorous reaction. The remainder of
the aryl chloride solution was added dropwise over 30 min and
the solution heated at reflux overnight. After cooling, the mag-
nesium residues were filtered off under nitrogen and rinsed with
J. Chem. Soc., Perkin Trans. 1, 1997
2439

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Carbamate synthesis
Cyclohexylcarbamate of 1,2-bis(3,5-dimethoxyphenyl)-2-
Preparation of the cyclohexylcarbamate of 2-hydroxy-1,2-
diphenylethanone 1†† via methyllithium catalysed reaction. To a
solution of 2-hydroxy-1,2-diphenylethanone (5.31 g, 25 mmol)
in anhydrous tetrahydrofuran (80 cm3) at room temperature
was added methyllithium (1.4 mol dmϪ3 in Et2O; 1.8 cm3, 2.5
mmol). After stirring for 1 h, a solution of cyclohexyl isocyan-
ate (4.9 cm3, 4.77 g, 26.3 mmol) in dry tetrahydrofuran (20 cm3)
was added and the resulting solution heated at reflux for 14 h.
After cooling, the tetrahydrofuran was removed in vacuo
and the residue taken up in dichloromethane (200 cm3) and
washed with water (3 × 25 cm3) and brine (1 × 25 cm3). After
drying (MgSO4), removal of the solvent under reduced pressure
gave a pale yellow solid (7.17 g). Flash chromatography (10%
EtOAc–90% hexane) allowed isolation of the following three
fractions. First, a yellow gum (50 mg) was isolated and identi-
fied as 1,2-diphenylethanedione44 by spectroscopy and elem-
ental analysis. Next, a white solid (2.82 g) was isolated and
recrystallized from Et2O–hexane. In this way, 3-cyclohexyl-4,5-
diphenyl-2,3-dihydrooxazol-2-one 20 was isolated as a white
crystalline solid (2.04 g); mp 161–163 ЊC [Found: C, 79.1;
H, 6.6; N, 4.3. Calc. for C21H21NO2 (319.39): C, 79.0; H, 6.6;
N, 4.4%]; λmax/nm 292 (ε/dm3 molϪ1 cmϪ1 14 590); νmax/cmϪ1
2939, 1747, 1367, 1354, 1347, 991, 750, 704, 694, 668; δH 1.05–
2.27 [10 H, m, cyclohexyl (CH2)5], 3.23–3.39 (1 H, m, cyclohexyl
CH), 7.11–7.21 (5 H, m, 5 ArH), 7.35–7.43 (2 H, m, 2 ArH),
7.48–7.58 (3 H, m, 3 ArH); δC 24.66 (t), 25.63 (t), 29.62 (t), 54.31
(d), 123.55 (s), 124.05 (d), 127.25 (d), 127.61 (s), 127.90 (s),
128.27 (d), 129.41 (d), 129.98 (d), 130.66 (d), 133.94 (s), 155.85
(s).
hydroxyethanone 2
A solution of 1,2-bis(3,5-dimethoxyphenyl)-2-hydroxyethan-
one 25 (1.5 g, 4.5 mmol) was treated with cyclohexyl isocyanate
(0.6 cm3, 0.62 g, 5 mmol) in refluxing toluene (80 cm3) in a
manner similar to that described for 1. Work-up and purific-
ation gave carbamate 2 as a fluffy white solid (1.58 g, 77%). See
Table 2 for analytical data. Flash chromatography also gave a
yellow solid (0.1 g) which was recrystallized from ethyl acetate–
hexane to give light yellow crystals (57 mg). This material was
identified as 1,2-bis(3,5-dimethoxyphenyl)ethanedione17 by
spectroscopic and elemental analysis.
Cyclohexylcarbamate of 2-hydroxy-1,2-bis(3-methoxyphenyl)-
ethanone 3
2-Hydroxy-1,2-bis(3-methoxyphenyl)ethanone27 (3.64 g, 13.4
mmol) was treated with cyclohexyl isocyanate (1.9 cm3, 1.84 g,
14.7 mmol) in refluxing toluene (75 cm3) in a similar manner to
that described for 1. The usual work-up gave a yellow oil (6.32
g) which on flash chromatography (20% EtOAc–80% hexane)
gave the following fractions. First, a colourless oil (0.12 g) was
isolated and recrystallized from ethanol to give a light yellow
crystalline solid (34 mg). This material was identified as 1,2-
bis(3-methoxyphenyl)ethanedione45 by spectroscopic and
elemental analysis. Next, a mixture enriched in the desired
carbamate was isolated as a white foam (2.02 g). Trituration
with EtOAc–hexane gave a stereoisomer of 3-cyclohexyl-4-
hydroxy-4,5-bis(3-methoxyphenyl)oxazolidin-2-one 18 as
a
white crystalline solid (0.61 g); mp 151–154 ЊC [Found: C,
69.65; H, 6.8; N, 3.45. Calc. for C23H27NO5 (397.46): C, 69.5; H,
6.85; N, 3.5%]; λmax/nm 276 (ε/dm3 molϪ1 cmϪ1 3612), 283
(3331); νmax/cmϪ1 3295, 1739, 1604, 1495, 1461, 1453, 1429,
1369, 1265, 1036; δH 0.95–2.45 [10 H, m, cyclohexyl (CH2)5],
2.94 (1 H, m, cyclohexyl CH), 3.61 and 3.63 (each 3 H, each s,
3,3Ј-OCH3), 4.46 [1 H, s, OH (D2O exch.)], 5.47 (1 H, s, Ox
5-CH), 6.45 (1 H, m, 1 ArH), 6.56–6.71 (4 H, m, 4 ArH), 6.79 (1
H, br d, J 7.3, 1 ArH), 6.94–7.08 (2 H, m, 2 ArH); δC 25.00 (t),
25.82 (t), 26.01 (t), 29.91 (t), 30.95 (t), 53.72 (d), 55.02 (q),
55.07 (q), 87.44 (d), 95.21 (s), 110.75 (d), 112.43 (d), 113.99 (d),
114.47 (d), 117.92 (d), 119.59 (d), 128.54 (d), 128.67 (d), 136.67
(s), 138.49 (s), 156.76 (s), 158.92 (s).‡‡
Concentration of the mother liquor gave the desired carba-
mate 3 as a white gum (1.23 g). Besides the homogeneous
materials described above, flash chromatography also generated
a number of mixed fractions which were combined and concen-
trated to give a white foam (2.95 g). This material was rechro-
matographed as above to afford additional 1,2-bis(3-methoxy-
phenyl)ethanedione (50 mg),45 along with a mixture greatly
enriched in the desired carbamate as a white gum (2.33 g). In
the case of the latter mixture, trituration with aqueous ethanol
led to crystallization of another stereoisomer of 3-cyclohexyl-4-
Last, a white foam (2.67 g) was isolated. This material
proved to be
a mixture of 3-cyclohexyl-4-hydroxy-4,5-
diphenyloxazolidin-2-one 17 and the desired carbamate 1. Trit-
uration with EtOAc–hexane allowed crystallization of the
oxazolidin-2-one 17 as a cream coloured solid (0.4 g). This
material was purified by recrystallization from EtOAc–hexane
to give the oxazolidin-2-one 17 as a white solid (69 mg); mp 185–
188 ЊC [Found: C, 74.4; H, 7.0; N, 4.2. Calc. for C21H23NO3
(337.40): C, 74.7; H, 6.9; N, 4.15%]; λmax/nm 251 (ε/dm3 molϪ1
cmϪ1 519), 257 (588), 261 (478), 263 (475), 267 (328), 284 (102);
νmax/cmϪ1 3417, 3262, 2933, 1712, 1450, 1360, 1350, 1101, 703,
695; δH 0.95–2.24 [10 H, m, cyclohexyl (CH2)5], 2.23 [1 H, s, OH
(D2O exch.)], 2.82–2.94 (1 H, m, cyclohexyl CH), 5.53 (1 H, s,
5-CH), 7.12–7.17 (2 H, m, 2 ArH), 7.36–7.58 (8 H, m, 8 ArH);
δC 24.90 (t), 25.78 (t), 25.99 (t), 29.86 (t), 30.69 (t), 53.85 (d),
85.98 (d), 92.17 (s), 125.98 (d), 126.60 (d), 128.65 (d), 128.72 (s),
128.79 (d), 128.94 (d), 129.19 (d), 131.99 (s), 155.85 (s).
The mother liquor, rich in the desired carbamate, was con-
centrated and the residue crystallized from CH2Cl2–hexane to
afford the desired carbamate 1 as a white solid (1.78 g, 21%).
See Table 2 for analytical data.
hydroxy-4,5-bis(3-methoxyphenyl)oxazolidin-2-one 18 as
a
Representative procedure for the non-catalysed synthesis of
cyclohexylcarbamates: preparation of the cyclohexylcarbamate
of 2-hydroxy-1,2-diphenylethanone 1
white crystalline solid (0.27 g); mp 173–175 ЊC [Found: C, 69.5;
H, 6.95; N, 3.5. Calc. for C23H27NO5 (397.46): C, 69.5; H, 6.85;
N, 3.5%]; λmax/nm 275 (ε/dm3 molϪ1 cmϪ1 4367), 281 (4094); νmax
/
To a solution of benzoin (9.02 g, 42.5 mmol) in toluene (100
cm3) at room temperature under nitrogen was added cyclohexyl
isocyanate (6 cm3, 5.85 g, 46.7 mmol) and the resulting solution
heated at reflux for 48 h. After cooling, the reaction mixture was
diluted with ether (100 cm3) and washed with water (2 × 75 cm3)
and brine (1 × 50 cm3) and dried (MgSO4). Removal of the
solvent in vacuo gave the crude product as a yellow solid (12.10
g). Flash chromatography (10% EtOAc–90% hexane) followed
by recrystallization from CH2Cl2–hexane gave the desired
carbamate 1 as a white solid (11.10 g, 77%). This material had
spectroscopic data identical to an authentic sample prepared
above (see Table 2).
cmϪ1 3316, 2929, 1708, 1608, 1357, 1287, 1271, 1259, 1047, 753;
δH 0.95–2.22 [10 H, m, cyclohexyl (CH2)5], 2.42 [1 H, s, OH
(D2O exch.)], 2.90 (1 H, m, cyclohexyl CH), 3.77 and 3.85 (each
3 H, each s, 3,3Ј-OCH3), 5.49 (1 H, s, CH), 6.66–6.74 (2 H, m, 2
ArH), 6.88–7.00 (2 H, m, 2 ArH), 7.07–7.15 (2 H, m, 2 ArH),
7.24–7.43 (2 H, m, 2 ArH); δC 24.92 (t), 25.78 (t), 26.02 (t), 29.91
(t), 30.66 (t), 53.89 (d), 55.21 (q), 55.28 (q), 85.85 (d), 92.11 (s),
111.25 (d), 112.37 (d), 114.40 (d), 114.93 (d), 118.10 (d), 118.91
(d), 129.72 (d), 129.93 (d), 133.56 (s), 141.20 (s), 155.77 (s),
159.75 (s), 159.89 (s).
Concentration of the mother liquor afforded more of car-
bamate 3 as a white gum (1.38 g). The gum resisted all attempts
†† IUPAC name: 2-oxo-1,2-diphenylethyl N-cyclohexylcarbamate. The
other carbamates can be named similarly.
‡‡ See Table 1, footnote c.
2440
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
at crystallization. As outlined above, attempted crystallization
would lead to cyclization to form stereoisomers of oxazolidin-
2-one 18. Overall 2.61 g of carbamate 3 was isolated, this cor-
responds to a 49% yield. See Table 2 for analytical data.
(1.36 g, 5 mmol) was converted to the corresponding piper-
idinocarbamate 27 via the p-nitrophenyl mixed carbonate
method described for 26. Work-up followed by purification gave
carbamate 27 as a white solid (0.72 g, 38%). See Table 2 for
analytical data.
Cyclohexylcarbamate of 1,2-bis(1,3-benzodioxol-5-yl)-2-
hydroxyethanone 4
Cyclohexylcarbamate of 2-(1,3-benzodioxol-5-yl)-2-hydroxy-1-
phenylethanone 7
1,2-Bis(1,3-benzodioxol-5-yl)-2-hydroxyethanone (2.25 g, 7.5
mmol) was treated with cyclohexyl isocyanate (1.1 cm3, 1.05 g,
8.3 mmol) in refluxing toluene (50 cm3) in a manner similar to
that described for 1. Work-up and purification gave carbamate
4 as a white solid (0.85 g, 27%). See Table 2 for analytical data.
2-(1,3-Benzodioxol-5-yl)-2-hydroxy-1-phenylethanone 29 (1.44
g, 5.6 mmol) was treated with cyclohexyl isocyanate (0.8 cm3,
0.74 g, 5.9 mmol) in refluxing toluene (60 cm3) in a similar
manner to that described for 1. Work-up and purification gave
carbamate 7 as a white powder (0.41 g, 19%). See Table 2 for
analytical data. The mixed fractions from the column (1.21 g)
consisted of the desired carbamate 7 (cyclohexyl CH, m, δH
3.50), the corresponding 4-hydroxyoxazolidin-2-one 19 (cyclo-
hexyl CH, m, δH 2.87) and 2,3-dihydrooxazol-2-one 21 (cyclo-
hexyl CH, m, δH 3.29).
Representative procedure for the synthesis of piperidino-
carbamates: preparation of the piperidinocarbamate of 1,2-
bis(1,3-benzodioxol-5-yl)-2-hydroxyethanone 26
To
a solution of 1,2-bis(1,3-benzodioxol-5-yl)-2-hydroxy-
ethanone (3 g, 10 mmol) and p-nitrophenyl chloroformate (2.02
g, 10 mmol) in dichloromethane (25 cm3) at 0–5 ЊC under nitro-
gen was added a solution of triethylamine (2.13 g, 21 mmol) in
dichloromethane (10 cm3). The resulting solution was stirred at
room temperature for 6 h at which point TLC indicated com-
plete consumption of the starting benzoin. A solution of
piperidine (0.9 g, 10.5 mmol) in dichloromethane (25 cm3) was
added and the mixture stirred at room temperature for 48 h. At
this point, TLC indicated that a trace of mixed carbonate
remained. To complete the reaction, the mixture was heated at
reflux for 4 h. After cooling, the reaction mixture was washed
with water (1 × 20 cm3), NaOH (0.5 ; 2 × 20 cm3), water
(1 × 20 cm3), 2.5% hydrochloric acid (1 × 20 cm3) and brine
(1 × 20 cm3). After drying (MgSO4), removal of the solvent
under reduced pressure gave an orange–brown foam (3.85 g).
After purification, carbamate 26 was isolated as pale yellow
platelets (1.7 g, 43%). See Table 2 for analytical data. Flash
chromatography also gave a yellow solid (0.17 g) which was
recrystallized from ethyl acetate–hexane to give light yellow
crystals (88 mg). This material was identified as 1,2-bis(1,3-
benzodioxol-5-yl)ethanedione46 by spectroscopy and elemental
analysis.
Cyclohexylcarbamate of 2-(3,5-dimethoxyphenyl)-2-hydroxy-1-
(4-methylthiophenyl)ethanone 9
2-(3,5-Dimethoxyphenyl)-2-hydroxy-1-(4-methylthiophenyl)-
ethanone 31 (2.39 g, 7.5 mmol) was treated with cyclohexyl
isocyanate (1.1 cm3, 1.03 g, 8.3 mmol) in refluxing toluene (50
cm3) in a manner similar to that described for 1. Work-up and
purification gave carbamate 9 as a white solid (3.06 g, 92%). See
Table 2 for analytical data.
Cyclohexylcarbamate of 2-hydroxy-1-(4-methoxyphenyl)-
propanone 16
2-Hydroxy-1-(4-methoxyphenyl)propanone35 (2.7 g, 15 mmol)
was treated with cyclohexyl isocyanate (2.1 cm3, 2.07 g, 16.5
mmol) in refluxing toluene (50 cm3) in a manner similar to that
described for 1. Work-up and purification gave carbamate 16 as
a white solid (3.32 g, 73%). See Table 2 for analytical data.
Flash chromatography also allowed isolation of a minor, less
polar, fraction which was recrystallized from aqueous etha-
nol to afford 3-cyclohexyl-4-(4-methoxyphenyl)-5-methyl-2,3-
dihydrooxazol-2-one 24 as a white crystalline solid (0.14 g); mp
114–115 ЊC [Found: C, 70.95; H, 7.35; N, 5.0. Calc. for
C17H21NO3 (287.35): C, 71.05; H, 7.4; N, 4.9%]; λmax/nm 280 (ε/
dm3 molϪ1 cmϪ1 21 203); νmax/cmϪ1 2933, 1747, 1513, 1364,
1348, 1295, 1252, 1237, 1180, 758; δH 1.10–2.27 [10 H, m, cyclo-
hexyl (CH2)5], 2.25 (3 H, s, CH3), 3.52–3.74 (1 H, m, cyclohexyl
CH), 3.83 (3 H, s, 4-OCH3), 6.92 and 7.39 [each 2 H, ABq, Jo
8.5, 2,6-H and 3,5-H respectively]; δC 9.76 (q), 24.90 (t), 25.86
(t), 30.08 (t), 54.14 (d), 55.19 (q), 114.01 (d), 117.23 (s), 121.03
(s), 126.83 (d), 133.99 (s), 154.21 (s), 158.87 (s).
Cyclohexylcarbamate of 2-hydroxy-1,2-bis(4-methoxyphenyl)-
ethanone 5
2-Hydroxy-1,2-bis(4-methoxyphenyl)ethanone (4.05 g, 15
mmol) was treated with cyclohexyl isocyanate (2.1 cm3, 2.07 g,
16.5 mmol) in refluxing toluene (75 cm3) in a similar manner to
that described for 1. Work-up followed by purification gave
carbamate 5 as large white crystals (2.75 g, 46%). See Table 2
for analytical data.
Cyclohexylcarbamate of 2-(3,5-dimethoxyphenyl)-2-hydroxy-1-
phenylethanone 6
Cyclohexylcarbamate of 2-hydroxy-1-(4-methoxyphenyl)-2-
phenylethanone 10
2-(3,5-Dimethoxyphenyl)-2-hydroxy-1-phenylethanone17
28
2-Hydroxy-1-(4-methoxyphenyl)-2-phenylethanone36 (1.75 g,
7.2 mmol) was treated with cyclohexyl isocyanate (1 cm3, 0.99 g,
8 mmol) in refluxing toluene (25 cm3) in a similar manner to
that described for 1. Work-up and purification gave carbamate
10 as a fine white powder (1.37 g, 52%). See Table 2 for ana-
lytical data.
(1.49 g, 5.5 mmol) was treated with cyclohexyl isocyanate (0.8
cm3, 0.75 g, 6 mmol) in refluxing toluene (50 cm3) in a manner
similar to that described for 1. Work-up followed by purifi-
cation gave carbamate 6 as a white crystalline solid (1.28 g,
59%). See Table 2 for analytical data. Flash chromatography
also afforded a colourless oil (40 mg) which was recrystallized
from ethyl acetate–hexane to give 1-(3,5-dimethoxyphenyl)-2-
phenylethanedione as light yellow crystals (20 mg) [Found: C,
71.2; H, 5.2. Calc. for C16H14O4 (270.27): C, 71.1; H, 5.2%]; δH
3.83 (6 H, s, 3,5-OCH3), 6.74 [1 H, t, Jm 2.2, Ar(2) 4-H], 7.10 [2
H, d, Jm 2.2, Ar(2) 2,6-H], 7.51 [2 H, m approximates to t, Ar(1)
3,5-H], 7.65 [1 H, m approximates to t, Ar(1) 4-H], 7.96 [2 H, m
approximates to d, Ar(1) 2,6-H]; δC 55.56 (q), 107.27 (d), 107.44
(d), 128.89 (d), 129.78 (d), 132.84 (s), 134.59 (s), 134.77 (d),
161.02 (s), 194.31 (s), 194.35 (s).
Cyclohexylcarbamate of 2-(3,5-dimethoxyphenyl)-2-hydroxy-1-
(2-naphthyl)ethanone 11
2-(3,5-Dimethoxyphenyl)-2-hydroxy-1-(2-naphthyl)ethanone
32 (0.34 g, 1.2 mmol) was treated with cyclohexyl isocyanate
(0.2 cm3, 0.17 g, 1.4 mmol) in refluxing toluene (25 cm3) in a
manner similar to that described for 1. Work-up and purifi-
cation gave carbamate 11 as a fine white powder (0.38 g, 70%).
See Table 2 for analytical data. Flash chromatography also gave
a yellow solid (50 mg) which was recrystallized from ethyl
acetate–hexane to give 1-(3,5-dimethoxyphenyl)-2-(2-naphthyl)-
ethanedione as a pale yellow crystalline solid (38 mg) [Found:
C, 74.7; H, 5.05. Calc. for C20H16O4 (320.33): C, 75.0; H, 5.0%];
Piperidinocarbamate of 2-(3,5-dimethoxyphenyl)-2-hydroxy-1-
phenylethanone 27
2-(3,5-Dimethoxyphenyl)-2-hydroxy-1-phenylethanone17
28
J. Chem. Soc., Perkin Trans. 1, 1997
2441

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9 J. C. Sheehan and R. M. Wilson, J. Am. Chem. Soc., 1964, 86, 5277.
10 J. C. Sheehan, R. M. Wilson and A. W. Oxford, J. Am. Chem. Soc.,
1971, 93, 7222.
δH 3.83 (6 H, s, 3,5-OCH3), 6.75 [1 H, t, Jm 2.2, Ar(2) 4-H], 7.15
[2 H, d, Jm 2.2, Ar(2) 2,6-H], 7.55–7.67 [2 H, m, Ar(1) 6,7-H],
7.88–7.98 [3 H, m, Ar(1) 4,5,8-H], 8.09 [1 H, dd, Jo 8.6, Jm 1.7,
Ar(1) 3-H], 8.39 [1 H, d, Jm 1.7, Ar(1) 1-H]; δC 55.58 (q), 107.36
(d), 107.47 (d), 123.55 (d), 127.08 (d), 127.85 (d), 129.06 (d),
129.44 (d), 129.82 (d), 130.19 (s), 132.22 (s), 133.41 (d), 134.74
(s), 136.28 (s), 161.05 (s), 194.33 (s), 194.38 (s).
11 G. L. Eian and J. F. Trend, USP 4 369 244/1983 (Chem. Abstr., 1982,
96, 190735w); USP 4 980 096/1990 (Chem. Abstr., 1982, 96,
182850q).
12 R. A. Lee, USP 4 469 774/1984 (Chem. Abstr., 1984, 101, 201566s).
13 R. S. Givens and B. Matuszewski, J. Am. Chem. Soc., 1984, 106,
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P. S. Athey, B. Matuszewski, L. W. Kueper, III, J. Y. Xue and
T. Fister, J. Am. Chem. Soc., 1992, 114, 8708.
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Representative procedure for the catalysed preparation of cyclo-
hexylcarbamates: preparation of the cyclohexylcarbamate of 2-
(3,5-dimethoxyphenyl)-2-hydroxy-1,2-diphenylethanone 12
To
a solution of 2-(3,5-dimethoxyphenyl)-2-hydroxy-1,2-
diphenylethanone 33 (1.74 g, 5 mmol) in benzene (50 cm3) at
room temperature under nitrogen was added stannous 2-
ethylhexanoate (0.1 g) followed by cyclohexyl isocyanate (0.7
cm3, 0.69 g, 5.5 mmol). After stirring for 24 h, the reaction
mixture was purified to give carbamate 12 as a fluffy white solid
(2.23 g, 94%). See Table 2 for analytical data.
18 J. F. Cameron, C. G. Willson and J. M. J. Fréchet, Polym. Mater. Sci.
Eng., 1995, 74, 284; 323; 437.
19 M. C. Pirrung and C.-Y. Huang, Tetrahedron Lett., 1995, 36, 5883.
20 M. C. Pirrung and J. C. Bradley, J. Org. Chem., 1995, 60, 1116.
21 M. C. Pirrung and J. C. Bradley, J. Org. Chem., 1995, 60, 6270.
22 J. F. Cameron, C. G. Willson and J. M. J. Fréchet, J. Am. Chem. Soc.,
1996, 118, 12925.
23 R. Gompper, Chem. Ber., 1956, 89, 1748; M. F. Saettone, J. Org.
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Chem. Soc., 1972, 94, 6562.
Cyclohexylcarbamate of 2-(3,5-dimethoxyphenyl)-2-hydroxy-1-
phenylpropanone 13
The cyclohexylcarbamate of 2-(3,5-dimethoxyphenyl)-2-
hydroxy-1-phenylpropanone 13 was prepared in a manner simi-
lar to that described for 12. After purification, carbamate 13
was isolated as white platelets (2.79 g, 66%). See Table 2 for
analytical data.
24 T. Francis and M. P. Thorne, Can. J. Chem., 1976, 54, 24.
25 J. L. Hartwell and S. R. L. Kornberg, J. Am. Chem. Soc., 1945, 67,
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26 G. H. Hakimelahi, C. B. Boyce and H. S. Kasmei, Helv. Chim. Acta,
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27 A. Schonberg and W. Malchow, Chem. Ber., 1922, 55, 3746.
28 L. R. Krepski, S. R. Heilmann and J. K. Rasmussen, Tetrahedron
Lett., 1983, 24, 1983.
29 S. Hunig and G. Wehner, Chem. Ber., 1979, 112, 2062; Synthesis,
1975, 391.
30 D. A. Evans, L. K. Truesdale and G. L. Carrol, J. Chem. Soc., Chem.
Commun., 1973, 55.
Cyclohexylcarbamate of 1-(3,5-dimethoxyphenyl)-2-hydroxy-
2,2-diphenylethanone 15
The cyclohexylcarbamate of 1-(3,5-dimethoxyphenyl)-2-
hydroxy-2,2-diphenylethanone 15 was prepared in a similar
manner to that described for 12. After purification, carbamate
15 was isolated as a white solid (1.48 g, 81%). See Table 2 for
analytical data.
31 M. H. B. Stowell, R. S. Rock, D. C. Rees and S. I. Chan, Tetrahedron
Lett., 1996, 37, 307.
32 J. C. Sheehan and K. Umezawa, J. Org. Chem., 1973, 38, 3771.
33 G. Church, J. M. Ferland and J. Gauthier, Tetrahedron Lett., 1989,
30, 1901.
Acknowledgements
Partial support of this work at Cornell University by the Office
of Naval Research is acknowledged with thanks.
34 G. Berner, G. Rist, R. Kirchmayr and W. Rutsch, Radcure Europe
’85, Society of Manufacturing Engineers, Dearborn, MI, 1985, 446.
35 I. Elphimoff-Felkin and M. Verrier, Bull. Soc. Chim. Fr., 1967, 1047.
36 J. S. Buck and W. S. Ide, J. Am. Chem. Soc., 1930, 52, 220.
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ORGN 237.
Paper 6/02018F
Received 26th February 1997
Accepted 2nd April 1997
2442
J. Chem. Soc., Perkin Trans. 1, 1997