Organocatalytic selective benzoylation of alcohols with trichloromethyl phenyl ketone: Inverse selectivity in benzoylation of alcohols containing phenol or aromatic amine functionality

Article abstract of DOI:10.1016/j.tet.2012.08.051

Trichloromethyl phenyl ketone benzoylates primary and secondary aliphatic alcoholic groups in compounds also containing a phenolic group in the presence of 2-10 mol % of PMDETA organocatalyst at room temperature in high yields and excellent selectivity. It also shows the potential to selectively benzoylate primary alcoholic groups of aminoarylalkanols and primary-secondary diols as well as primary amino group of alkyl amines in the presence of aryl amines under similar conditions. A rationale for the selectivity and efficiency of the reaction has been provided.

Full text of DOI:10.1016/j.tet.2012.08.051

Tetrahedron 68 (2012) 9068e9075
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalytic selective benzoylation of alcohols with trichloromethyl phenyl
ketone: inverse selectivity in benzoylation of alcohols containing phenol or
aromatic amine functionality
*
Ram N. Ram , Vineet Kumar Soni, Dharmendra Kumar Gupta
Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi 110016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 June 2012
Received in revised form 14 August 2012
Accepted 17 August 2012
Available online 23 August 2012
Trichloromethyl phenyl ketone benzoylates primary and secondary aliphatic alcoholic groups in com-
pounds also containing a phenolic group in the presence of 2e10 mol % of PMDETA organocatalyst at
room temperature in high yields and excellent selectivity. It also shows the potential to selectively
benzoylate primary alcoholic groups of aminoarylalkanols and primary-secondary diols as well as pri-
mary amino group of alkyl amines in the presence of aryl amines under similar conditions. A rationale for
the selectivity and efficiency of the reaction has been provided.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Selective O-benzoylation
Inverse selectivity
Phenolic alcohols
Aminobenzyl alcohols
PMDETA-catalyzed
Organocatalyst
Trichloromethyl phenyl ketone
1. Introduction
Therefore, several catalytic methods have been reported for
selective benzoylation of a hydroxy group. Most of these reports,
Benzoylation of alcoholic groups is a common occurrence in
chemistry. Some familiar applications of this reaction are in the
synthesis of natural1 and synthetic2 benzoate esters, protection of
alcoholic groups in multi-step synthesis,3 modification of physical
and spectroscopic properties of compounds in analysis and
structure determination,4 and molecular recognition.5 Benzoyla-
tion invokes special consideration for selective protection of a hy-
droxy group owing to the better hydrolytic/nucleophilic stability
of the benzoate and its lower susceptibility to rearrange by mi-
gration to another neighboring hydroxy or nucleophilic group
than acetate and most other aliphatic ester protecting groups.3a,6
Usually benzoylation of the hydroxy group is performed with
benzoyl chloride or benzoic anhydride in the presence of a stoi-
chiometric amount or more of a base resulting in the formation of
a considerable amount of undesired chemical waste. Moreover,
due to the high reactivity of these benzoylating agents, selectivity
between different types of hydroxy groups is generally not satis-
factory. Benzoyl chloride is also lachrymatory and is inconvenient
to handle and store.
however, focus on selective acetylation and deal with direct se-
lectivity exploiting the higher nucleophilicity of a hydroxy group
conferred by steric or electronic effects, for example, selective
benzoylation of a primary alcoholic group in the presence of a ste-
rically more hindered secondary alcoholic group.7 Accordingly,
more nucleophilic phenolate anions derived from phenolic alcohols
in mildly basic media7a,8 and amino groups in amino alcohols7a,8d,9
could be selectively benzoylated. However, the inverse selectivity,
that is, selective benzoylation of an alcoholic group in the presence
of a phenolic or an amino group is scarcely reported. It has been
realized for a long time that this type of inverse selectivity could be
observed under acidic conditions due to the suppressed ionization
of the phenolic group or protonation of the amino group.7a Thus,
phenolic alcohols could be benzoylated at the alcoholic group by
the classical acid-catalyzed Fischer esterification with benzoic acid
usually with complete selectivity. Selective O-acylation of aliphatic
amino alcohols is a recognized problem and requires even more
strongly acidic conditions for complete protonation of the amino
group or prior hydrochloride salt formation, yet seldom yields
satisfactory results.7a,10 The acidity is further compounded by the
liberated HCl from the acylating agent acyl chloride. While these
acidic acylations may be acceptable for the preparation of simple
starting materials, they are of little use in multi-step synthesis
* Corresponding author. Tel.: þ91 11 26591508; fax: þ91 11 26582037; e-mail
address: rnram@chemistry.iitd.ernet.in (R.N. Ram).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.051

R.N. Ram et al. / Tetrahedron 68 (2012) 9068e9075
9069
involving molecules containing acid sensitive protecting or other
groups. The problem is arguably more severe for alcohols con-
taining an amino group linked to an aromatic ring due to not so
favorable acidebase equilibria. Nevertheless, a few milder Lewis
acid-catalyzed methods have been reported for selective benzoy-
lation of an alcoholic group in the presence of a phenolic group,
such as Bz2O/Sc(OTf)3,8c Bz2O/Bi(OTf)3,11 vinyl benzoate/
(ClBu2Sn)2O,12 and PhCOCl/LiClO4.13 However, exceptions are also
known and the selectivity appears to depend on the nature of the
Lewis acid catalyst.14 Recently, Oshima and co-workers15 benzoy-
lated aliphatic amino alcohols at the alcoholic group by a tetranu-
clear zinc cluster Zn4(OCOCF3)6O-catalyzed transesterfication with
PhCO2Me with remarkable chemo-selectivity without any detect-
able mono-benzoylation at the amino group and with the forma-
tion of only 7e18% of ester amide dibenzoylated products.
However, metal catalysis in general is less desirable than the
greener organocatalysis.16 Incidentally, a few rather non-classical
benzoylating agents were found to benzoylate the alcoholic
groups of phenolic alcohols8d,9b,17 under neutral conditions or, cu-
riously, on catalysis with a tertiary base with varying degree of
selectivity. The primary hydroxy groups of the nucleosides deoxy-
adenosine and deoxyguanosine were also benzoylated selectively
in the presence of the amino groups of the base moieties.18,19
Phenolic alcohols may also be mono-acylated at the alcoholic
group by Mitsunobu reaction with aromatic acids.20 However,
a common problem with the non-classical benzoylating agents,
besides lower degree of selectivity, is that they are not commer-
cially available, need to be freshly prepared from the very benzoyl
chloride8d,9b,18 or benzoic acid19 at the time of use and also that
these as well as Mitsunobu reaction leave considerable amount of
organic material after the reaction to be separated from the ben-
zoylated product. Remarkably, selective O-benzoylation of 3-
amino-5-bromobenzyl alcohol has been reported to occur with
benzoic anhydride in the presence of threefold excess of Et3N and
DMAP catalyst in CH2Cl2 in 83% yield.21 However, it raises the en-
vironmental concern as mentioned earlier. Lipase-catalyzed che-
moselective benzoylation of the alcoholic groups of a few phenolic
alcohols with vinyl benzoate2d and that of adenosine with O-ben-
zoylacetoxime22 has also been reported. However, the scope of the
lipase-catalyzed reactions might be limited, as the efficiency and
selectivity of lipase-catalyzed acylations are known to depend on
the source of the lipase as well as on the structure of the acylating
agent and substrate.6a,b,22,23 Further, most of these reported
methods for benzoylation with inverse selectivity also have one or
more of the following limitations: less than excellent selectivi-
ty,8c,17 more so in the case of secondary alcohols,8d,11 and
yields,8d,10b,13,20b anhydrous reaction conditions,8c,d,9b,18,19,22 inert
atmosphere,15,22 relatively high temperatures,8d,9b,10c,11,12,20a
expensive,8c toxic12 or large amounts10c,13 of catalyst, potential
risk to acid-sensitive groups,8b,c,12,13,24 such as TBDMS, use of excess
reagent and its removal,2d,8c,11,12,18,19,22 etc. Besides, all these
methods use significant amount of a solvent. Indeed realizing
O-benzoylation with inverse selectivity under mild and green
conditions is not a trivial task and requires ingenuity, enzyme’s
dexterity, or serendipity, or protectionedeprotection methodology
as the last resort,7a,10b,25 or in the case of phenolic alcohols,
dibenzoylation followed by selective debenzoylation of the aryl
ester.26
a benzoylating agent for alcohols in the presence of a catalytic
amount of Et3N at 25 ꢀC has been briefly reported.31 This is an at-
tractive method for benzoylation owing to formation of the neutral,
volatile, and easily removable by-product chloroform. However, the
method has not received much attention probably due to its little
known selectivity profile. Some years back, we observed that
chloral could be used for selective formylation of alcoholic group in
phenolic alcohols by stirring at room temperature in acetone in the
presence of K2CO3.32 However, this reaction failed in the case of o-
and p-hydroxybenzyl alcohols furnishing mixtures of unidentifi-
able products, presumably through base-promoted elimination in
the formylated products to quinone methides under the reaction
conditions.33 It was envisaged that the selective acylation might be
successful under mildly basic conditions at lower temperatures and
by changing the formylation to benzoylation. Accordingly, we now
wish to report successful selective benzoylation of phenolic alco-
hols with commercially available (SigmaeAldrichCPR, etc.) or easily
prepared34 trichloromethyl phenyl ketone at ambient tempera-
tures catalyzed by a small amount (2 mol %) of an organocatalyst
N,N,N0,N00,N00-pentamethyldiethylenetriamine (PMDETA), which
also displays a wide range of selectivity, including inverse selec-
tivity in benzoylation of alcohols containing an aromatic amine
functionality.
2. Results and discussion
Several base catalysts (NaOR,27b,28a,b,d,i,29b,30a,b,d,f,g NaH,28f,30c
K2CO3,27c,28c,i KOH,28g NaHCO3,29a Et3N,27c,28e,i,29c,31 DMAP28h,30e
)
have been reported for haloform cleavage of trichloromethyl
ketones in different solvents (MeOH, MeOH/CH2Cl2, MeOH/THF,
THF, DMF, MeCN, CHCl3, toluene) at temperatures ranging from 0 ꢀC
to room temperatures to heating in a sealed tube28e and reaction
times varying from few minutes to several hours. Different reported
reaction temperatures and/or times for the same catalyst such as
Et3N28e,i,29c,31 and DMAP28h,30e have added to the confusion in se-
lection of a suitable catalyst for investigating selective benzoylation
with trichloromethyl phenyl ketone. Therefore, it was considered
necessary to first identify a suitable catalyst, which functioned ef-
ficiently under mild conditions in benzoylation with tri-
chloromethyl phenyl ketone. Accordingly, the reported and some
new commercially available organic bases were evaluated for the
catalysis. Inorganic bases, such as alkoxide and K2CO3 were not
considered due to their high basicity or our earlier experience.32
Thus, a mixture of trichloromethyl phenyl ketone 1, methanol,
and the organic base catalyst (1:1.2:0.02 mol ratio) was stirred at
room temperature (20e25 ꢀC) until the reaction was completed as
indicated by TLC monitoring. The product methyl benzoate was
isolated by flash column chromatography. The results are shown in
Table 1. It was observed that of all the tertiary bases examined,
Table 1
Base-catalyzed benzoylation of methanol with trichloromethyl phenyl ketone 1 in
the presence of different catalystsa
catalyst
+
PhCOCCl3
1
MeOH
PhCOOMe
Entry no. Catalyst
Catalyst (mol %) Time
PhCOOMe yield (%)
1
2
3
4
5
6
7
Et3N
DBU
2
2
2
2
2
6 h
2.5 h
3 h
90
90
92
89
A trichloroacetyl group has been used as an ester or amide group
equivalent through haloform cleavage with an alcohol or amine in
the presence of a base.27 The reaction has been found to be useful
for introducing an ester or amide group on reactive heteroaromatic
rings28 or in other sensitive molecules such as enol ethers and
enamines29 by electrophilic trichloroacetylation followed by halo-
form cleavage and has also been used during total synthe-
ses.28feh,29a,c,30 The possibility of trichloromethyl phenyl ketone as
DMAP
TMEDA
PMDETA
6 h
10 min 95
24 h
6 h
2,20-Bipyridine
120
No reaction
No reaction
2,20-Bipyridineb 120
a
Reactions were performed with
1 (2 mmol) and methanol (2.4 mmol) at
20e25 ꢀC without a solvent.
b
In THF (5 mL) and MeOH (1 mL) at reflux temperature.

9070
R.N. Ram et al. / Tetrahedron 68 (2012) 9068e9075
Table 3
PMDETA was the most efficient. The reaction was complete even
with 2 mol % of the catalyst in 10 min at room temperature
affording methyl benzoate in 95% isolated yield. The formation of
chloroform was detected by 1H NMR spectroscopy. Therefore, this
catalyst was used for further investigation. Next, the reaction of 1
was performed with 1 equiv of several other alcohols using 2 mol %
of PMDETA as catalyst at room temperature (20e25 ꢀC) without
any solvent. Inert atmosphere or dry conditions were not necessary.
The benzoates were isolated by flash column chromatography. The
results are shown in Table 2. The reaction was found to be quite
general for benzoylation of primary alcohols. Though the reaction
time was considerably increased (2.5e18 h) in the case of higher
PMDETA-catalyzed selective benzoylation of benzyl alcohol and its derivatives in the
presence of phenols/aniline with trichloromethyl phenyl ketone 1a
OH
OCOPh
PhCOCCl3
1
X
X
+
+
PMDETA
R
R
3
R
2
R
2
(2-5 mol%)
Entry no.
R
X
Time (h)
Isolated
yield of 3 (%)
Recovered phenol/
aniline 2 (%)
1
2
3
4
5
6
H
OH
OH
OH
OH
OH
NH2
6
6
4
6
36
2
95
93
94
92
91
91
90
91
Me
OMe
Cl
NO2
H
Table 2
PMDETA-catalyzed benzoylation of different alcohols with trichloromethyl phenyl
66
89 (17)b
72
ketone 1a
92 (14)c
a
Entry no.
Alcohol
Time (h)
Benzoate yield (%)
Reactions were performed with alcohol, phenol and 1 (2 mmol each) and
PMDETA (0.1 mmol, 5 mol %) at 20e25 ꢀC without a solvent. Acetonitrile (1 mL) was
1
2
3
4
5
6
7
8
Ethanol
Propanol
Allyl alcohol
Benzyl alcohol
n-Butanol
1-Octanol
1-Nonanol
Geraniol
2.5
12
10
8
12
14
15
8
95
94
92
96
92
92
94
91
90
93
96
96
96
91
92
used as solvent where the alcohol or phenol was solid (entries 2, 4, and 5).
b
Yield of recovered alcohol in parenthesis. Trichloromethyl phenyl ketone 1 was
also recovered in 15% yield.
c
With 1.2 equiv of 1 and 2 mol % of PMDETA. Yield of benzanilide in parenthesis.
as determined by 1H NMR of the crude mixture, thus showing
considerable preference for benzoylation of alcoholic group in the
presence of aromatic amino group. Separation by column chro-
matography afforded these products in 92 and 14% isolated yields,
respectively, along with 72% of the unreacted aniline. It is note-
worthy that Zucco and co-workers35 observed selective N-ben-
zoylation of ethanol amine by the same reagent. In view of their
report and our observation, it was expected that 1 may also ben-
zoylate alkyl amines selectively in the presence of aryl amines. The
selectivity was actually more satisfying than anticipated because
the reaction of a mixture of benzyl amine and aniline with 1 equiv
of 1 in the presence 2 mol % of PMDETA furnished N-benzylben-
zamide in 95% isolated yield as the only benzoylated product along
with the recovered aniline (89%) (Scheme 1). The competition ex-
periment with a 1:1 mixture of cyclohexanol and phenol showed
that secondary alcohols can also be selectively benzoylated in the
presence of phenols under similar conditions with higher amount
of the catalyst (10 mol %) and longer reaction time.
9
2-Chloroethanolb
trans-Hex-2-en-1-ol
But-2-yn-1-ol
Pent-2-yn-1-ol
Cinnamyl alcohol
2,3-Epoxycinnamyl alcohol
m-(tert-Butyldimethylsilyloxy)
benzyl alcohol
p-Acetoxybenzyl alcohol
2-Propanolc
16
12
6
10
11
12
13
14
15
6
10
12
12
16
17
18
19
20
18
48
48
24
24
93
82
89
Cyclohexanolc
tert-Butyl alcohold
Phenold
No reaction
No reaction
a
Reactions were performed with 1, alcohol/phenol (2 mmol each), and PMDETA
(0.04 mmol, 2 mol %) at 20e25 ꢀC without a solvent.
b
With 5 mol % of PMDETA.
With 10 mol % of PMDETA.
With 50 mol % of PMDETA and alcohol/phenol as solvent (5 mL) under reflux or
c
d
heating at 60 ꢀC, respectively.
primary alcohols, the yields of the benzoates were consistently
high. Functional groups like carbonecarbon double and triple
bonds, epoxide, TBDMS ether, and aryl acetate ester were not dis-
turbed. Secondary alcohols, such as 2-propanol and cyclohexanol
(entries 17 and 18) were found to be less reactive and required
higher amount of the catalyst (10 mol %) and longer reaction time
(48 h) for the reaction to complete. tert-Butyl alcohol and phenol
reacted not at all even when 50 mol % of the catalyst was used and
the reaction mixture was heated in excess (5 mL) of the hydroxy
compound to reflux or at 60 ꢀC, respectively, for 24 h.
The resistance of phenol to benzoylation strongly suggested that
aliphatic alcohols may be selectively benzoylated in the presence of
phenols. Therefore, a few competition experiments were per-
formed on mixtures of aliphatic alcohols and phenols with 1 equiv
of 1 as shown in Table 3. It was observed that even with 2.5-fold
excess (5 mol %) of the catalyst, the alcohols were exclusively
benzoylated. No aryl benzoates were detected in the reaction
mixture and the phenols were recovered unchanged. Benzoylation
of a mixture of benzyl alcohol and aniline (1:1 mol ratio) with 1
under similar conditions also occurred with inverse selectivity.
However, it required 1.2 equiv of 1 for complete disappearance of
benzyl alcohol due to formation of a small amount of benzanilide
along with the major product benzyl benzoate. The reaction was
complete in much shorter time (2 h) with only 2 mol % of PMDETA
to afford a mixture of benzyl benzoate and benzanilide in 5:1 ratio
NH2
NHCOPh
+
1/ PMDETA
NH2
OH
NH2
(2 mol%)
+
20-25 °C,
30 min
95%
89%
OH
OCOPh
88%
OH
1/ PMDETA
(10 mol%)
+
+
20-25 °C, 48 h
89%
Scheme 1. Some other competition experiments.
These results were supplemented by highly efficient selective
benzoylation of several phenolic alcohols and m- and p-amino-
benzyl alcohols with 1 in the presence of 2 mol % of PMDETA (Table
4). As expected, phenolic alcohols were selectively benzoylated at
the alcoholic group. The selectivity was almost perfect. No aryl
esters or alkyl aryl diesters were detected in the reaction mixture
by 1H NMR spectroscopy. The phenolic diol given at entry 12 in
Table 4 yielded the dibenzoate 4l exclusively even with 2 equiv of 1,
showing strong preference for benzoylation of the alcoholic group.
The sensitive o- and p-hydroxybenzylic primary and secondary
alcohols (Table 4, entries 2, 3, 5, and 6) were selectively benzoylated
at the benzylic alcoholic group in high yields. However, m- and

R.N. Ram et al. / Tetrahedron 68 (2012) 9068e9075
9071
Table 4
PMDETA-catalyzed selective benzoylation of phenolic alcohols and aminobenzyl alcohols with trichloromethyl phenyl ketone 1a
Entry no.
Phenolic/amino alcohol
Time (h)
Product(s) (4, 5)
Yield (%)
OH
OCOPh
1
16
95
4a
OH
OH
OH
OH
OCOPh
2
3
4
14
92
87
86
4b
OH
OH
HO
OCOPh
4c
14
HO
OH
OH
OCOPh
48b
4d
OH
OH
OH
OCOPh
OH
5
6
7
8
9
72b
60b
12
84
86
92
91
93
4e
OH
HO
OCOPh
4f
HO
OH
OCOPh
4g
MeO
OH
MeO
OH
OH
OMe
OCOPh
12
4h
OMe
OH
OH
OH
OCOPh
12
4i
HO
HO
OH
OCOPh
OCOPh
OCOPh
10
11
12
12
94
91
4j
HO
HO
OH
4k
HO
HO
HO
OH
PhOCO
12
13
30
92c
OH
OH
OH 4l
OCOPh
5'a
OCOPh
2
2
+
78 (14)d
76 (13)d
5a
NHCOPh
NH2
NH2
OH
OCOPh
5b
OCOPh
5'b
14
+
H2N
H2N
PhOCHN
a
Reactions were performed with phenolic alcohol or aminobenzyl alcohol and 1 (2 mmol each) and PMDETA (0.04 mmol, 2 mol %) in acetonitrile (1 mL) at 20e25 ꢀC.
With 10 mol % of PMDETA.
With 4 mmol (2 equiv) of 1 and 0.04 mmol (2 mol %) of PMDETA in ethyl acetate (5 mL).
Yield of O,N-dibenzoylated product in parenthesis. The reaction was performed with 1.2 equiv of 1.
b
c
d
p-aminobenzyl alcohols (Table 4, entries 13 and 14) yielded O-
mentioned earlier.19,21 The dibenzoylated products were obtained
in 14% and 13% yields, respectively. Though the selectivity in the
case of aminobenzyl alcohols is lower, it may be considered ap-
preciable in view of the difficulty level of the task and in the ab-
sence of a greener and better known method.
benzoylated and N,O-dibenzoylated products in 5:1 ratio in each
case as determined by 1H NMR spectra of the crude reaction mix-
ture. No N-mono-benzoylation was detected. Chemical separation
by washing with dil HCl afforded the major O-benzoylated products
in 78% and 76% yields, respectively, comparable to that obtained
from the reported methods but having other limitations as
The lower reactivity of secondary alcohols (Table 2, entries 17
and 18) prompted us to briefly evaluate the reaction for selective

9072
R.N. Ram et al. / Tetrahedron 68 (2012) 9068e9075
benzoylation of primary alcoholic group in the presence of a sec-
ondary one. Thus, treatment of 1-phenylethane-1,2-diol with
1 equiv of 1 in acetonitrile in the presence of 2 mol % of PMDETA at
20e25 ꢀC for 14 h led to mono-benzoylation at the primary hy-
droxy group exclusively in 92% yield.
toluenediisocyanate catalyzed by several tertiary bases.36 In this
reaction, the higher efficiency of PMDETA catalyst was rationalized
in terms of its multipoint activating interaction through all the
three nitrogen atoms with the reactants along the reaction path-
way. It is likely that in the present case also PMDETA is playing
a similar role. Thus, the high efficiency of PMDETA catalyst in the
present benzoylation reactions might be attributed to involvement
of probably a halogen bond-assisted assembly of the reactants and
the catalyst during the reaction as indicated in Scheme 2, providing
the benefits of an intramolecular reaction. A trichloromethyl group
is expected to be a good halogen bond donor particularly to the
basic nitrogen atoms due to synergistic electron withdrawing effect
of the three chlorine atoms.37 The role of halogen bonding in solid
state is well known and there is a growing realization that it may
assume considerable significance in condensed media as well.37
All the products were identified by IR, 1H NMR, 13C NMR spec-
troscopy and comparison with the reported data available in the
literature. The structures of the new compounds were also sup-
ported by HRMS.
Regarding the mechanism of the reaction, a few observations
are worth mentioning. (i) Benzoylation of m-hydroxybenzyl alcohol
with 1 in the presence of 2 mol % of any of the catalysts Et3N,
TMEDA or DMAP did not proceed to completion in any case even
after 48 h. However, 1H NMR spectra of the reaction mixtures at
different stages of the reaction revealed formation of the alkyl ester
exclusively as the product. No aryl ester or alkyl aryl diester could
be detected. Thus, the observed selectivity was not due to the
catalyst, but was an inherent property of the benzoylating
reagentesubstrate system. (ii) Nome and co-workers27d studied
EtNH2-catalyzed haloform cleavage of 1 with alcohols and sug-
gested a mechanism involving initial reversible formation of
hemiacetal tetrahedral intermediate followed by its slow cleavage
to the benzoate ester product in the rate determining step, which
was assisted by deprotonation of the hydroxy group of the hemi-
acetal intermediate with EtNH2. In the absence of the catalyst, the
reaction did not proceed beyond the tetrahedral intermediate
stage. The hemiacetal could not be isolated due to its reversibility to
the starting materials. In view of these observations, it appears that
the interplay of the steric hindrance of the bulky CCl3 group and its
relatively poorer nucleofugality, the nucleophilicity and steric
environment of the attacking nucleophile, and the reversibility of
the tetrahedral intermediate could be the reason for the selectivity
observed in the present investigation. Thus, the formation of the
tetrahedral intermediate by attack through a phenolic group or
phenolate ion could arguably be highly reversible due to consid-
erably higher nucleofugality of the phenolate ion than that of the
trichloromethyl anion. This might not be the case when the alco-
holic group acted as the nucleophile due to the higher basicity and
lower nucleofugality of the alkoxide, thus leading to the formation
of the alkyl benzoate through the haloform cleavage in the forward
direction. Though Yamada and co-workers8d suggested that higher
nucleophilicity of the alcoholic group than phenolic group under
neutral conditions was the reason for selective benzoylation of the
alcoholic group of phenolic alcohols with twisted amides, this
might not be the reason for the selectivity observed in the present
case because the reaction conditions would not be considered to be
neutral. The primary hydroxy group in aminobenzyl alcohols and 1-
phenylethane-1,2-diol is sterically less hindered thus getting pref-
erentially engaged in the formation of the tetrahedral intermediate.
However, due to considerably higher nucleophilicity of the amino
group than the hydroxy group in the aminobenzyl alcohols, ben-
zoylation at the more hindered amino group could not be com-
pletely suppressed. The amino group of benzyl amine has the
double advantage of being more nucleophilic and less hindered
than that of aniline, thus getting benzoylated with overwhelming
preference over the amino group of aniline.
OR
O
H
Cl
Ph
Ph
Cl
O
Cl
O
H
Cl
R
proton shifts
Cl
Cl
NMe2
NMe2
Me2N
Me2N
N
N
Me
Me
Scheme 2. Halogen bond-assisted catalysis by PMDETA.
3. Conclusion
In the presence of a small amount of an inexpensive organo-
catalyst PMDETA, trichloromethyl phenyl ketone benzoylates al-
cohols selectively. The reaction displays a wide range of selectivity.
Primary as well as secondary alcoholic groups of phenolic alcohols
are almost chemospecifically benzoylated in high yields. Selective
mono-benzoylation of primary alcoholic group in amino-
arylalkanols and primary-secondary diols may also be realized.
Primary alkyl amines may be selectively benzoylated in the pres-
ence of primary aryl amines with excellent selectivity. The reaction
occurs under mild conditions not requiring anhydrous conditions
or inert atmosphere. Several sensitive groups, such as carbon-
ecarbon double and triple bonds, epoxide, TBDMS ether, and aryl
acetate ester are not disturbed. Only stoichiometric amount of the
alcohol is enough for the reaction to proceed with adequate rate at
ambient temperatures. The reaction occurs under solvent free
conditions in the case of liquid alcohols and only a minimal amount
of a solvent just enough to allow stirring is required in the case of
solid substrates. The work up procedure is simple due to the for-
mation of the neutral volatile by-product chloroform. It comple-
ments effectively and rather supersedes the reported acid-
catalyzed methods for benzoylation with inverse selectivity in
some respects. The present green reaction is therefore a useful
versatile method for selective benzoylation of alcohols. In-
volvement of a halogen bond-assisted assembly of the substrate,
reagent, and catalyst has been proposed as the possible reason for
the high efficiency of the reaction.
4. Experimental section
4.1. General remarks
The observed order of efficiency of the base catalysts (Table 1) is
PMDETA (pKa 9.1)>DBU (pKa 12)>DMAP (pKa 9.7)>TMEDA (pKa
8.97), Et3N (pKa 10.8), which is not in order of their base strength,
contrary to the expectation on the basis of rate determining base-
promoted cleavage of the tetrahedral intermediate. However, if
the number of basic sites present in the catalyst and the basicity of
the catalyst both are considered in that order of importance, the
observed order of catalyst efficiency could be rationalized. A similar
observation has been made earlier during a study on kinetics of
polyurethane formation in reaction of diethyleneglycol with 2,4-
IR spectra were recorded on NICOLET 6700 FT-IR spectrometer
by taking solid samples as KBr pellets and liquids as thin films on
KBr discs. NMR spectra were recorded on Bruker Spectrospin DPX
300 MHz FT NMR spectrometer in CDCl3 with TMS as internal
standard. DEPT spectra were routinely recorded to identify differ-
ent types of carbons. High-resolution mass spectra were recorded
on a Bruker, micrOTOF-QII mass spectrometer using electron spray

R.N. Ram et al. / Tetrahedron 68 (2012) 9068e9075
9073
ionization (ESI) in positive ion mode. Melting points were de-
termined on a Melt-Temp apparatus by taking the samples in
a glass capillary sealed at one end and are uncorrected. The prog-
ress of the reaction was monitored by TLC using a glass plate coated
with a TLC grade silica gel. Iodine was used for visualizing the spots.
Rf values were determined by performing thin layer chromatogra-
phy on Merck DC-Alufolien silica gel 60WF254s thin aluminum
precoated plates using 30% (v/v) EtOAc in n-hexane as the de-
veloping solvent. Column chromatography was performed using
flash column chromatography techniques. Silica gel (60e120 mesh)
was used as the stationary phase and n-hexane, n-hexane/ethyl
acetate mixtures (9e7:1e3 v/v) and chloroform were used as the
mobile phase. Trichloromethyl phenyl ketone34 was prepared by
the reported method. PMDETA was purchased from SigmaeAldrich
and was used as received.
and filtered. Evaporation of the solvent under reduced pressure
afforded aniline (0.166 g, 89% yield).
4.5. PMDETA-catalyzed selective benzoylation of phenolic
alcohols with trichloromethyl phenyl ketone (1)
General procedure: Trichloromethyl phenyl ketone (0.447 g,
2 mmol), phenolic alcohol (2 mmol), and PMDETA (0.007 g,
0.04 mmol; 0.035 g, 0.2 mmol in case of entries 4e6) were taken in
a 25 mL round bottom flask. To this heterogeneous mixture, ace-
tonitrile (1 mL) was added, the flask was stoppered and the
resulting viscous solution was stirred at room temperature
(20e25 ꢀC) on a magnetic stirrer. The progress of the reaction was
monitored by TLC. After the completion of the reaction (12e60 h),
the crude reaction mixture was purified by flash column chroma-
tography using n-hexane/EtOAc (7:3 v/v) as the solvent for elution
to provide the phenolic alkyl benzoates 4aek in 84e95% yields. The
products 4a,26b 4b,38 4c,20a 4i,12 4j,39 4k,40 and 5b41 are known in
the literature.
4.2. PMDETA-catalyzed benzoylation of alcohols with tri-
chloromethyl phenyl ketone (1)
General procedure: In
a 25 mL round bottom flask, tri-
chloromethyl phenyl ketone (0.447 g, 2 mmol), alcohol (2 mmol;
0.077 g, 2.4 mmol in the case of methanol), and PMDETA (0.007 g,
0.04 mmol; 0.035 g, 0.2 mmol in case of secondary alcohols) were
taken without any solvent. The flask was stoppered and the mixture
was stirred at room temperature (20e25 ꢀC) on a magnetic stirrer.
The progress of the reaction was monitored by TLC. After the
completion of the reaction (10 min to 48 h), the crude reaction
mixture was purified by flash column chromatography using
n-hexane or ethyl acetate (5e10% v/v) in n-hexane as the solvent
for elution to furnish the benzoate esters (Table 2) in 82e96% yield.
4.5.1. 1-(3-Hydroxyphenyl)ethyl benzoate (4d). Colorless flakes, mp
62 ꢀC (n-hexane/CHCl3), 0.416 g, 86% yield; Rf 0.52 (n-hexane/
EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.08 (d, J¼7.2 Hz, 2H, AreH),
7.56 (t, J¼7.5 Hz, 1H, AreH), 7.44 (t, J¼7.5 Hz, 2H, AreH), 7.23 (t,
J¼7.8 Hz, 1H, AreH), 7.0 (d, J¼7.5 Hz, 1H, AreH), 6.92 (s, 1H, AreH),
6.76 (dd, J¼8.1 and 1.5 Hz, 1H, AreH), 6.08 (q, J¼6.6 Hz, 1H, ArCH),
5.09 (s, 1H, ArOH), 1.65 (d, J¼6.6 Hz, 3H, CH3) ppm; dC (75.5 MHz,
CDCl3): 166.3, 156.0, 143.4, 133.1, 130.2, 129.8, 129.6, 128.4, 118.0,
114.9, 113.0, 73.0, 22.3 ppm; IR (neat): nmax 3405 (br m), 1695(s),
1596(m), 1454(m), 1317(m), 1277(s), 1120(m), 1064(m), 865(m)
cmꢂ1; HRMS m/z calcd for [C15H14O3þNa]þ: 265.0835, found:
265.0834.
4.3. Competition experiments: PMDETA-catalyzed selective
benzoylation of benzyl alcohols in the presence of phenols/
aniline with trichloromethyl phenyl ketone (1)
4.5.2. 1-(2-Hydroxyphenyl)ethyl benzoate (4e). White needles, mp
101 ꢀC (n-hexane/EtOAc); 0.406 g, 84% yield; Rf 0.54 (n-hexane/
EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.05 (d, J¼7.5 Hz, 2H, AreH),
7.63 (s, 1H, ArOH), 7.57 (t, J¼7.5 Hz, 1H, AreH), 7.41e7.46 (m, 3H,
AreH), 7.24 (t, J¼7.5 Hz, 1H, AreH), 6.94e6.98 (m, 2H, AreH), 6.29
(q, J¼6.6 Hz, 1H, ArCH), 1.78 (d, J¼6.6 Hz, 3H, CH3) ppm; dC
(75.5 MHz, CDCl3): 167.8, 154.4, 133.4, 130.1, 129.8, 129.5, 128.4,
127.0, 126.6, 120.9, 118.0, 68.5, 19.9 ppm; IR (KBr): nmax 3358(br s),
1693(s), 1602(m), 1451(m), 1289(s), 1123(m), 1052(m), 749(m),
710(m) cmꢂ1; HRMS m/z calcd for [C15H14O3þNa]þ: 265.0835,
found: 265.0836.
General procedure: In a 25 mL round bottom flask were placed
benzyl alcohol or substituted benzyl alcohol (2 mmol), the corre-
sponding phenol or aniline (2 mmol), trichloromethyl phenyl ke-
tone (0.447 g, 2 mmol; 0.536 g, 2.4 mmol in the case of aniline), and
PMDETA (0.017 g, 0.1 mmol; 0.007 g, 0.04 mmol in case of aniline).
Acetonitrile (1 mL) was additionally taken in the case of any solid
reactant for smooth stirring. The flask was stoppered and the re-
action mixture was stirred at room temperature (20e25 ꢀC) on
a magnetic stirrer. The progress of the reaction was monitored by
TLC. After the completion of the reaction (2e36 h), the crude re-
action mixture was purified by flash column chromatography using
n-hexane/EtOAc (9:1 v/v) as the solvent for elution to obtain benzyl
benzoates 3 in 66e95% yield. Further elution with chloroform
afforded recovered phenols 2 (89e91%) or aniline (72%).
4.5.3. 1-(4-Hydroxyphenyl)ethyl benzoate (4f). Colorless flakes, mp
65 ꢀC (n-hexane/CHCl3), 0.415 g, 86% yield; Rf 0.48 (n-hexane/
EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.06 (d, J¼7.2 Hz, 2H, AreH),
7.54 (t, J¼7.2 Hz, 1H, AreH), 7.42 (t, J¼7.2 Hz, 2H, AreH), 7.30 (d,
J¼8.4 Hz, 2H, AreH), 6.80 (d, J¼8.4 Hz, 2H, AreH), 6.07 (q, J¼6.6 Hz,
1H, ArCH), 5.94 (s, 1H, ArOH), 1.64 (d, J¼6.6 Hz, 3H, CH3) ppm; dC
(75.5 MHz, CDCl3): 166.3, 155.5, 133.5, 133.0, 130.4, 129.6, 128.3,
127.7, 115.3, 73.0, 22.2 ppm; IR (neat): nmax 3399(br m), 1693(s),
1609(m), 1517(s), 1450(m), 1328(m), 1275(s), 1174(m), 1119(m),
4.4. Competition experiment: PMDETA-catalyzed selective
benzoylation of benzyl amine in the presence of aniline with
trichloromethyl phenyl ketone (1)
A solution of benzyl amine (0.214 g, 2 mmol), aniline (0.186 g,
2 mmol), trichloromethyl phenyl ketone (0.447 g, 2 mmol), and
PMDETA (0.007 g, 0.04 mmol) in acetonitrile (1 mL) was stirred in
a stoppered flask at room temperature (20e25 ꢀC) on a magnetic
stirrer. The progress of the reaction was monitored by TLC. After the
completion of the reaction (30 min), the crude reaction mixture
was diluted with 50 mL of EtOAc and washed with 1 N HCl
(4ꢁ30 mL). The organic layer was dried (anhyd Na2SO4), filtered,
and evaporated under reduced pressure to yield N-benzylbenza-
mide (0.401 g, 95% yield). The aqueous washings were combined
and basified with excess saturated Na2CO3 solution. The basified
solution was extracted with EtOAc (50 mL), dried (anhyd Na2SO4),
1060(m), 832(m), 713(m) cmꢂ1
;
HRMS m/z calcd for
[C15H14O3þNa]þ: 265.0835, found: 265.0837.
4.5.4. 4-Hydroxy-3-methoxybenzyl benzoate (4g). Colorless liquid,
0.475 g, 92% yield; Rf 0.49 (n-hexane/EtOAc, 7:3 v/v); dH (300 MHz,
CDCl3): 8.06 (d, J¼7.5 Hz, 2H, AreH), 7.55 (t, J¼7.5 Hz, 1H, AreH),
7.42 (t, J¼7.5 Hz, 2H, AreH), 6.91e7.0 (m, 3H, AreH), 5.69 (s, 1H,
ArOH), 5.28 (s, 2H, ArCH2), 3.90 (s, 3H, OCH3) ppm; dC (75.5 MHz,
CDCl3): 166.5, 146.5, 145.8, 132.9, 130.1, 129.6, 128.3, 127.8, 122.0,
114.4, 111.3, 66.9, 55.9 ppm; IR (neat): nmax 3432(br m), 1714(s),
1606(m), 1517(s), 1458(s), 1374(m), 1273(s), 1159(s), 1114(m),

9074
R.N. Ram et al. / Tetrahedron 68 (2012) 9068e9075
1031(m), 714(m) cmꢂ1; HRMS m/z calcd for [C15H14O4þNa]þ:
3343(m), 1710(s), 1634(m), 1594(m), 1495(m), 1454(m), 1281(s),
1122(m), 1072(m), 774(m), 711(s), 684(m) cmꢂ1; HRMS m/z calcd
for [C14H13NO2þNa]þ: 250.0838, found: 250.0839.
281.0784, found: 281.0784.
4.5.5. 2-Hydroxy-3-methoxybenzyl benzoate (4h). Colorless liquid,
0.470 g, 91% yield; Rf 0.41 (n-hexane/EtOAc, 7:3 v/v); 1H NMR
(300 MHz, CDCl3): dH 8.07 (d, J¼7.5 Hz, 2H, AreH), 7.53 (t, J¼7.5 Hz,
1H, AreH), 7.40 (t, J¼7.5 Hz, 2H, AreH), 7.01 (t, J¼7.8 Hz, 1H, AreH),
6.85 (d, J¼5.1 Hz, 2H, AreH), 6.22 (s, 1H, ArOH), 5.44 (s, 2H, ArCH2),
3.87 (s, 3H, OCH3) ppm; dC (75.5 MHz, CDCl3): 166.8, 146.7, 144.2,
132.9, 130.1, 129.7, 128.2, 122.1, 121.8, 119.5, 110.9, 61.9, 56.0 ppm; IR
(neat): nmax 3368(br s), 3062(m), 3015(m), 2964(m), 2935(m),
2838(m), 1704(s), 1606(m), 1489(s), 1444(s), 1375(m), 1350(m),
4.6.2. 3-Benzamidobenzyl benzoate (50a). White needles, mp 82 ꢀC
(n-hexane/CHCl3); 0.092 g, 14% yield; Rf 0.39 (n-hexane/EtOAc, 7:3
v/v); dH (300 MHz, CDCl3): 8.07 (d, J¼7.8 Hz, 2H, AreH), 8.06 (s, 1H,
ArNH), 7.86 (d, J¼7.2 Hz, 2H, AreH), 7.73 (s, 1H, AreH), 7.67 (d,
J¼7.8 Hz, 1H, AreH), 7.34e7.57 (m, 7H, AreH), 7.23 (t, J¼7.5 Hz, 1H,
AreH), 5.34 (s, 2H, ArCH2) ppm; dC (75.5 MHz, CDCl3): 166.4, 165.9,
138.2,137.0,134.8,133.1,131.9,129.9,129.7,129.3, 128.7,128.4,127.0,
124.1, 120.1, 119.8, 66.4 ppm; IR (KBr): nmax 3348(m), 1719(s),
1664(s), 1609(m), 1538(s), 1489(m), 1450(m), 1368(m), 1317(m),
1280(s), 1179(m), 1109(m), 1079(s), 926(m), 781(m), 709(s) cmꢂ1
;
HRMS m/z calcd for [C15H14O4þNa]þ: 281.0784, found: 281.0780.
1276(s), 1114(m),
713(s) cmꢂ1
;
HRMS
m/z
calcd
for
[C21H17NO3þNa]þ: 354.1101, found: 354.1092.
4.5.6. p-Hydroxycinnamyl benzoate (4k).40 White needles, mp
77 ꢀC (n-hexane/EtOAc); 0.463 g, 92% yield; Rf 0.51 (n-hexane/
EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.08 (d, J¼7.5 Hz, 2H, AreH),
7.57 (t, J¼7.5 Hz, 1H, AreH), 7.45 (t, J¼7.5 Hz, 2H, AreH), 7.30 (d,
8.7 Hz, 2H, AreH), 6.8 (d, 8.7 Hz, 2H, AreH), 6.68 (d, 15.9 Hz, 1H,
ArCH]CH), 6.26 (td, 15.9, 6.6 Hz, 1H, ArCH]CH), 6.21 (s, 1H, ArOH),
4.96 (d, 6.6 Hz, 2H, ]CHCH2) ppm; dC (75.5 MHz, CDCl3): 166.6,
155.7, 134.1, 133.0, 130.2, 129.6, 129.0, 128.4, 128.1, 120.8, 115.5,
65.9 ppm; IR (KBr): nmax 3369(br s), 1704(s), 1606(m), 1513(m),
1321(m), 1272(s), 1226(s), 1173(m), 1120(m), 968(m), 933(m),
4.6.3. 4-Aminobenzyl benzoate (5b).41 Colorless flakes, mp 45 ꢀC
(n-hexane/EtOAc); 0.344 g, 76% yield; Rf 0.37 (n-hexane/EtOAc, 7:3
v/v); dH (300 MHz, CDCl3): 8.04 (d, J¼7.5 Hz, 2H, AreH), 7.50 (t,
J¼7.5 Hz, 1H, AreH), 7.38 (t, J¼7.5 Hz, 2H, AreH), 7.23 (d, J¼8.4 Hz,
2H, AreH), 6.64 (d, J¼8.4 Hz, 2H, AreH), 5.22 (s, 2H, ArCH2), 3.73 (s,
2H, ArNH2) ppm; dC (75.5 MHz, CDCl3): 166.5, 146.6, 132.7, 130.2,
130.0, 129.5, 128.2, 125.5, 114.8, 66.8 ppm; IR (KBr): nmax 3443(w,
sh), 3375(m), 1710(s), 1618(m), 1520(m), 1318(m), 1272(s), 1177(m),
1110(m), 822(m), 713(m) cmꢂ1
.
851(m), 710(m) cmꢂ1
.
4.6.4. 4-Benzamidobenzyl benzoate (50b). White needles, mp 86 ꢀC
(n-hexane/CHCl3); 0.086 g, 13% yield; Rf 0.41 (n-hexane-EtOAc, 7:3
v/v); dH (300 MHz, CDCl3): 8.06 (d, J¼7.8 Hz, 2H, AreH), 8.05 (s, 1H,
ArNH), 7.86 (d, J¼7.2 Hz, 2H, AreH), 7.67 (d, J¼8.4 Hz, 2H, AreH),
7.40e7.58 (m, 8H, AreH), 5.33 (s, 2H, ArCH2) ppm; dC (75.5 MHz,
CDCl3): 166.5, 165.8, 138, 134.7, 133.0, 132.0, 131.9, 130.0, 129.6,
129.2, 128.7, 128.3, 127.0, 120.3, 66.3 ppm; IR (KBr): nmax 3342(m),
1719(s), 1653(s), 1600(m), 1518(s), 1409(m), 1316(m), 1279(s),
4.5.7. (3-Benzoyloxymethyl-2-hydroxy-5-methyl)benzyl benzoate (4l).
Colorless liquid, 0.692 g, 92%; Rf 0.54 (n-hexane/EtOAc, 7:3 v/v); dH
(300 MHz, CDCl3): 8.56 (s, 1H, ArOH), 8.06 (d, J¼7.5 Hz, 4H, AreH),
7.53 (t, J¼7.5 Hz, 2H, AreH), 7.40 (t, J¼7.5 Hz, 4H, AreH), 7.20 (s, 2H,
AreH), 5.39 (s, 4H, ArCH2), 2.28 (s, 3H, CH3) ppm; dC (75.5 MHz,
CDCl3): 167.8, 151.9, 133.2, 132.6, 129.8, 129.6, 129.4, 128.3,
123.2, 63.1, 20.3 ppm; IR (neat): nmax 3267(br m), 1718(s),
1688(s), 1487(m), 1454(m), 1376(m), 1275(s), 1111(s), 713(s) cmꢂ1
;
1114(m), 826(m), 711(m) cmꢂ1
;
HRMS m/z calcd for
HRMS m/z calcd for [C23H20O5þNa]þ: 399.1203, found: 399.1191.
[C21H17NO3þNa]þ: 354.1101, found: 354.1102.
4.6. PMDETA-catalyzed selective benzoylation of 3- and 4-
aminobenzyl alcohols with trichloromethyl phenyl ketone (1)
4.7. PMDETA-catalyzed selective mono-benzoylation of 1-
phenylethane-1,2-diol with trichloromethyl phenyl ketone (1)
General procedure: In
a 25 mL round bottom flask, tri-
To
a mixture of trichloromethyl phenyl ketone (0.447 g,
chloromethyl phenyl ketone (0.536 g, 2.4 mmol), 3- or 4-
aminobenzyl alcohol (2 mmol), and PMDETA (0.007 g, 0.04 mmol)
were taken. To this heterogeneous mixture, acetonitrile (1 mL) was
added and the solution was stirred at room temperature (20e25 ꢀC)
on a magnetic stirrer. The progress of the reaction was monitored
by TLC. After the completion of the reaction (2 h), the crude re-
action mixture was diluted with 50 mL of Et2O/EtOAc (1:1 v/v)
mixture and washed with 1 N HCl (4ꢁ30 mL). The organic layer was
dried (anhyd Na2SO4), filtered, and evaporated under reduced
pressure to yield m- or p- benzimidobenzyl benzoate in 14 or 13%
yield, respectively. The aqueous washings were combined and ba-
sified with excess saturated Na2CO3 solution. The basified solution
was extracted with EtOAc (50 mL), the organic layer was washed
with brine (30 mL), dried (anhyd Na2SO4), and filtered. Evaporation
of the solvent under reduced pressure afforded pure 3- or 4-
aminobenzyl benzoate in 78 or 76% yield, respectively.
2 mmol), 1-phenylethane-1,2-diol (0.276 g, 2 mmol), and PMDETA
(0.007 g, 0.04 mmol) was added acetonitrile (1 mL) and the viscous
solution was stirred in a stoppered 25 mL flask at room tempera-
ture (20e25 ꢀC) on a magnetic stirrer. The progress of the reaction
was monitored by TLC. After the completion of the reaction (14 h),
the crude reaction mixture was purified by flash column chroma-
tography using n-hexane/EtOAc (9:1 v/v) as the solvent for elution
to furnish 2-hydroxy-2-phenylethyl benzoate42 (0.446 g, 92%).
Acknowledgements
We are thankful to the University Grant Commission, New Delhi
and the Council of Scientific Research, New Delhi for research fel-
lowships to V.K.S. and D.K.G., respectively.
References and notes
4.6.1. 3-Aminobenzyl benzoate (5a). Colorless flakes, mp 46 ꢀC
(n-hexane/EtOAc); 0.354 g, 78% yield; Rf 0.38 (n-hexane/EtOAc, 7:3
v/v); dH (300 MHz, CDCl3): 8.09 (d, J¼7.5 Hz, 2H, AreH), 7.56 (t,
J¼7.5 Hz, 1H, AreH), 7.44 (t, J¼7.5 Hz, 2H, AreH), 7.17 (t, J¼7.2 Hz,
1H, AreH), 6.84 (d, J¼7.5 Hz, 1H, AreH), 6.77(s, 1H, AreH), 6.67 (d,
J¼7.5 Hz, 1H, Are), 5.28 (s, 2H, ArCH2), 3.72 (s, 2H, ArNH2) ppm; dC
(75.5 MHz, CDCl3): 166.3, 146.6, 137.0, 132.9, 130.0, 129.5, 129.4,
128.2, 117.9, 114.7, 114.4, 66.6 ppm; IR (KBr): nmax 3426(m),
1. (a) Santos, V. A. F. F. M.; Regasini, L. O.; Nogueira, C. R.; Passerini, G. D.; Mar-
tinez, I.; Bolzani, V. S.; Graminha, M. A. S.; Cicarelli, R. M. B.; Furlan, M. J. Nat.
Prod. 2012, 75, 991e995; (b) Harrar, K.; Reiser, O. Chem. Commun. 2012,
3457e3459; (c) Ramesh, P.; Meshram, H. M. Tetrahedron Lett. 2011, 52,
2443e2445; (d) Ogawa, Y.; Oku, H.; Iwaoka, E.; Iinuma, M.; Ishiguro, K. J. Nat.
Prod. 2006, 69, 1215e1217; (e) Guenard, D.; Gueritte-Voegelein, F.; Potier, P. Acc.
Chem. Res. 1993, 26, 160e167; (f) Schlessinger, R. H.; Lopes, A. J. Org. Chem. 1981,
46, 5252e5253.
ꢀ
ꢀ
2. (a) Manach, C. L.; Baron, A.; Guillot, R.; Vauzeilles, B.; Beau, J.-M. Tetrahedron
ꢀ
ꢀ
Lett. 2011, 52, 1462e1465; (b) Rodríguez-Perez, T.; Fernandez, S.; Martínez-

R.N. Ram et al. / Tetrahedron 68 (2012) 9068e9075
9075
ꢀ
Montero, S.; Gonzalez-García, T.; Sanghvi, Y. S.; Gotor, V.; Ferrero, M. Eur. J. Org.
19. N,N-Bis(2-oxo-oxazolidin-3-yl)phosphorodiamidic chloride/PhCOOH/pyridine:
Liguori, A.; Perri, E.; Sindona, G.; Uccella, N. Tetrahedron 1988, 44, 229e234.
20. (a) 5,50-Dimethyl-3,30-azoisoxazole/PPh3 Iranpoor, N.; Firouzabadi, H.; Khalili,
D. Org. Biomol. Chem. 2010, 8, 4436e4443; (b) DIAD/PPh3 Appendino, G.;
Minassi, A.; Daddario, N.; Bianchi, F.; Tron, G. C. Org. Lett. 2002, 4, 3839e3841.
21. Reuter, R.; Wegner, H. A. Chem.dEur. J. 2011, 17, 2987e2995.
22. Moris, F.; Gotor, V. J. Org. Chem. 1993, 58, 653e660.
23. (a) Batovska, D. I.; Tsubota, S.; Kato, Y.; Asano, Y.; Ubukata, M. Tetrahedron:
Asymmetry 2004, 15, 3551e3559 and references cited therein; (b) Pedrocchi-
Fantoni, G.; Servi, S. J. Chem. Soc., Perkin Trans. 1 1992, 1029e1033.
24. Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A. J. Org. Chem. 1998, 63,
2342e2347.
25. Shashidhar, M. S.; Bhatt, M. V. J. Chem. Soc., Chem. Commun. 1987, 654e656.
26. (a) Chakraborti, A. K.; Sharma, L.; Nayak, M. K. J. Org. Chem. 2002, 67,
2541e2547; (b) Bell, K. H. Aust. J. Chem. 1987, 40, 1723e1725.
27. (a) Menezes, F. G.; Gallardo, H.; Zucco, C. Quim. Nova 2010, 33, 2233e2244
(Review); (b) Morimoto, H.; Wiedemann, S. H.; Yamaguchi, A.; Harada, S.; Chen,
Z.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2006, 45, 3146e3150 and
references cited therein; (c) Silvestri, R.; Artico, M.; La Regina, G.; De Martino,
G.; La Colla, M.; Loddo, R.; La Colla, P. IL Farmaco 2004, 59, 201e210; (d) Uieara,
M.; Zucco, C.; Zanette, D.; Rezende, M. C.; Nome, F. J. Chem. Soc., Perkin Trans. 2
1987, 175e179.
28. (a) Tshibaka, T.; Roche, I. U.; Dufresne, S.; Lubell, W. D.; Skene, W. G. J. Org.
Chem. 2009, 74, 9497e9500; (b) Schmuck, C.; Bickert, V.; Merschky, M.; Geiger,
L.; Rupprecht, D.; Dudaczek, J.; Wich, P.; Rehm, T.; Machon, U. Eur. J. Org. Chem.
2008, 324e329; (c) Smith, J. A.; Ng, S.; White, J. Org. Biomol. Chem. 2006, 4,
2477e2482; (d) Jaramillo, D.; Liu, Q.; Aldrich-Wright, J.; Tor, Y. J. Org. Chem.
2004, 69, 8151e8153; (e) Zanatta, N.; Faoro, D.; Silva, S. C.; Bonacorso, H. G.;
Martins, M. A. P. Tetrahedron Lett. 2004, 45, 5689e5691; (f) Heckel, A.; Dervan,
P. B. Chem.dEur. J. 2003, 9, 3353e3366; (g) Fedouloff, M.; Hossner, F.; Voyle, M.;
Ranson, J.; Powles, J.; Riley, G.; Sanger, G. Bioorg. Med. Chem. 2001, 9,
2119e2128; (h) Huang, L.; Quada, J. C., Jr.; Lown, J. W. Bioconjugate Chem. 1995,
6, 21e33; (i) Harbuc, J. W.; Rapoport, H. J. Org. Chem. 1972, 37, 3618e3622.
29. (a) Xu, Z.; Li, Y.; Xiang, Q.; Pei, Z.; Liu, X.; Lu, B.; Chen, L.; Wang, G.; Pang, J.; Lin,
Y. J. Med. Chem. 2010, 53, 4642e4653; (b) Bennasar, M. L.; Roca, T.; Monerris,
M.; Juan, C.; Bosch, J. Tetrahedron 2002, 58, 8099e8106; (c) Trost, B. M.; Bal-
kovec, J. M.; Mao, M. K.-T. J. Am. Chem. Soc. 1986, 108, 4974e4983.
30. (a) Ondrus, A. E.; Kaniskan, H. U.; Movassaghi, M. Tetrahedron 2010, 66,
4784e4795; (b) Patel, J.; Pelloux-Leon, N.; Minassian, F.; Vallee, Y. J. Org. Chem.
2005, 70, 9081e9084; (c) Lanter, J. C.; Chen, H.; Zhang, X.; Sui, Z. Org. Lett. 2005,
7, 5905e5907; (d) Bennasar, M. L.; Roca, T.; Zulaica, E.; Monerris, M. Tetrahe-
dron 2004, 60, 6785e6789; (e) Kumar, R.; Lown, J. W. Org. Biomol. Chem. 2003,
1, 3327e3342; (f) Bennasar, M. L.; Zulaica, E.; Alonso, Y.; Bosch, J. Tetrahedron:
Asymmetry 2003, 14, 469e479; (g) Yamamoto, T.; Ujihara, H.; Watanabe, S.;
Harada, M.; Matsuda, H.; Hagiwara, T. Tetrahedron 2003, 59, 517e524.
31. Hess, S. C.; Nome, F.; Zucco, C.; Rezende, M. C. Synth. Commun. 1989, 19,
3037e3045.
Chem. 2010, 1736e1744; (c) Takahashi, M.; Morimoto, H.; Suzuki, Y.; Odagi, T.;
Yamashita, M.; Kawai, H. Tetrahedron 2004, 60, 11771e11781; (d) De la Goutte,
J. T.; Khan, J. A.; Vulfson, E. N. Biotechnol. Bioeng. 2001, 75, 93e99; (e) Mathe, C.;
Imbach, J.-L.; Gosselin, G. Carbohydr. Res. 2000, 323, 226e229.
3. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
John Wiley & Sons, Inc.: New York, NY, 1999; p 173; (b) Hachiya, I.; Sugiura, Y.;
Araki, H.; Inaoka, O.; Shimizu, M.; Akita, M.; Hamaguchi, T. Tetrahedron:
Asymmetry 2007, 18, 915e918; (c) Moss, R. A.; Jiang, W. Tetrahedron Lett. 1999,
40, 2867e2870; (d) Tadanier, J.; Lee, C.-M.; Whittern, D.; Wideburg, N. Carbo-
hydr. Res. 1990, 201, 185e207; (e) Mulzer, J.; Brand, C. Tetrahedron 1986, 42,
5961e5968; (f) Marx, M. H.; Wiley, R. A. Tetrahedron Lett. 1985, 26, 1379e1380.
4. (a) Kanamaru, S.; Honma, M.; Murakami, T.; Tsushima, T.; Kudo, S.; Tanaka, K.;
Nihei, K. I.; Nehira, T.; Hashimoto, M. Chirality 2012, 24, 137e146; (b) Kwang-
Hyok, S.; Ui-Nam, P.; Sarkar, C.; Bhadra, R. Clin. Chim. Acta 2005, 354, 41e47.
5. Fung, Y.-S.; Yan, S.-C.; Wong, M.-K. Org. Biomol. Chem. 2012, 10, 3122e3130.
6. (a) Santaniello, E.; Ciuffreda, P.; Casati, S.; Alessandrini, L.; Repetto, A. J. Mol.
Catal. B: Enzym. 2006, 40, 81e85; (b) Ciuffreda, P.; Casati, S.; Santaniello, E.
Tetrahedron Lett. 2003, 44, 3663e3665; (c) Ciuffreda, P.; Alessandrini, L.; Ter-
raneo, G.; Santaniello, E. Tetrahedron: Asymmetry 2003, 14, 3197e3201.
7. (a) Nahmany, M.; Melman, A. Org. Biomol. Chem. 2004, 2, 1563e1572 (Review);
(b) Twibanire, J. K.; Grindley, T. B. Org. Lett. 2011, 13, 2988e2991; (c) Wakita, N.;
Hara, S. Tetrahedron 2010, 66, 7939e7945; (d) Caddick, S.; McCarroll, A. J.;
Sandham, D. A. Tetrahedron 2001, 57, 6305e6310; (e) Iwasaki, F.; Maki, T.;
Onomura, O.; Nakashima, W.; Matsumura, Y. J. Org. Chem. 2000, 65, 996e1002;
(f) Morcuende, A.; Valverde, S.; Herradon, B. Synlett 1994, 89e91.
8. (a) PhCOCl/NEt3: Jessen, H. J.; Schulz, T.; Balzarini, J.; Meier, C. Angew. Chem., Int.
Ed. 2008, 47, 8719e8722; (b) Bz2O/VO(OTf)2 and acid anhydride/DMAP/pyri-
dine: Chen, C.-T.; Kuo, J.-H.; Li, C.-H.; Barhate, N. B.; Hon, S.-W.; Li, T.-W.; Chao,
S.-D.; Liu, C.-C.; Li, Y.-C.; Chang, L.-H.; Lin, J.-S.; Liu, C.-J.; Chou, Y.-C. Org. Lett.
2001, 23, 3729e3732; (c) Bz2O/Sc(OTf)3 and Bz2O/DMAP/Et3N: Ishihara, K.;
Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1996, 61, 4560e4567; (d)
Twisted amides 1-benzoyl-4,4-dimethyl (and 4-isopropyl)thiazolidine-2-
thione: Yamada, S.; Sugaki, T.; Matsuzaki, K. J. Org. Chem. 1996, 61,
5932e5938; (e) Aroyl chloride/DMAP/Et3N: Takahashi, M.; Ogiku, T.; Okarnura,
K.; Da-te, T.; Ohrnizu, H.; Kondoa, K.; lwasaki, T. J. Chem. Soc., Perkin Trans. 1
1993, 1473e1479.
9. (a) NHC/PhCO2Me: Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7,
2453e2456; (b) 1-(2,5-Dichlorophenyl)-2,2-bis(methylsulfanyl)vinyl benzoate/
BuLi: Degani, I.; Dughera, S.; Fochi, R.; Serra, E. Synthesis 1999, 7, 1200e1208;
(c) 4-Acyloxy-3-ethoxy-6-methylpyrimidine: Botta, M.; De Angelis, F.; Nicoletti,
R.; Pani, A.; Marongiu, H. E.; La Colla, P. Tetrahedron Lett. 1988, 29, 2741e2744;
(d) PhCOCN: Murahashi, S. I.; Naota, T.; Nakajima, N. Tetrahedron Lett. 1985, 26,
925e928; (e) C6F5COPh/pyridine or DMF: Igolen, J.; Morin, C. J. Org. Chem. 1980,
45, 4802e4804; (f) Dialkyl acylphosphonates: Sekine, M.; Satoh, M.; Yamagata,
H.; Hata, T. J. Org. Chem. 1980, 45, 4162e4167.
10. (a) Wu, C.; Long, X.; Li, S.; Fu, X. Tetrahedron: Asymmetry 2012, 23, 315e328; (b)
Kristensen, T. E.; Hansen, F. K.; Hansen, T. Eur. J. Org. Chem. 2009, 387e395; (c)
Sharghi, H.; Sarvari, M. H. Tetrahedron 2003, 59, 3627e3633; (d) Sharghi, H.;
Sarvari, M. H. J. Org. Chem. 2003, 68, 4096e4099.
32. Ram, R. N.; Meher, N. K. Tetrahedron 2002, 58, 2997e3001.
33. (a) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367e5405
(Review); (b) Rodriguez, R.; Adlington, R. M.; Moses, J. E.; Cowley, A.; Baldwin,
J. E. Org. Biomol. Chem. 2005, 3, 3488e3495.
11. Mohammapoor-Baltrok, I.; Aliyan, H.; Khosropour, A. R. Tetrahedron 2001, 57,
5851e5854.
34. (a) Aggarwal, V. K.; Mereu, A. J. Org. Chem. 2000, 65, 7211e7212; (b) Gallina, C.;
Giordano, C. Synthesis 1989, 466e468.
35. Rebelo, R. A.; Rezende, M. C.; Nome, F.; Zucco, C. Synth. Commun. 1987, 17,
1741e1748.
12. Orita, A.; Sakamoto, K.; Hamada, Y.; Mltsutome, A.; Otera, J. Tetrahedron 1999,
55, 2899e2910.
13. Bandgar, B. P.; Kamble, V. T.; Sadavarte, V. S.; Uppalla, L. S. Synlett 2002,
735e738.
14. Chandra, K. L.; Saravanan, P.; Singh, R. K.; Singh, V. K. Tetrahedron 2002, 58,
1369e1374.
36. Maris, R. V.; Tamano, Y.; Yoshimura, H.; Gay, K. M. J. Cellular Plastics 2005, 41,
305e322.
ꢀ
37. Erdelyi, M. Chem. Soc. Rev. 2012, 41, 3547e3557.
15. Ohshima, T.; Iwasaki, T.; Maegawa, Y.; Yoshiyama, A.; Mashima, K. J. Am. Chem.
38. Lebrasseur, N. J. Org. Chem. 2007, 72, 6280e6283.
39. Athikomkulchai, A.; Prawat, H.; Thasana, N.; Ruangrungsi, N.; Ruchirawat, S.
Chem. Pharm. Bull. 2006, 54, 262e264.
40. Popravko, S. A.; Sokolov, I. V.; Torgov, I. V. Khim. Prir. Soedin. 1984, 152e160.
41. Sattigeri, J. A.; Sethi, S.; Kishore, K. PCT Int. Appl. WO 2007054790 A1 20070518,
2007.
Soc. 2008, 130, 2944e2945.
16. (a) MacMillan, D. W. C. Nature 2008, 455, 304e308; (b) Renzi, P.; Bella, M. Chem.
Commun. 2012, 6881e6896.
17. Dialkyl benzoylphosphonate/DBU: Sekine, M.; Kume, A.; Hata, T. Tetrahedron
Lett. 1981, 22, 3617e3620.
18. N-Benzoyltetrazole/Et3N: Stawinski, J.; Hozumi, T.; Narang, S. A. J. Chem. Soc.,
Chem. Commun. 1976, 243e244.
42. Lee, D.; Williamson, C. L.; Chan, L.; Taylor, M. S. J. Am. Chem. Soc. 2012, 134,
8260e8267.