Activation of Benzyl Aryl Carbonates: The Role of Cation-π Interactions

Article abstract of DOI:10.1021/acs.joc.6b00441

Benzyl aryl carbonates can react with a nucleophile to yield an activated electrophile and an aryloxide anion. Previously, we had utilized this in the synthesis of α-nitro esters from nitroalkanes. To further understand the process of activation of these carbonates by nucleophiles, we have performed kinetic studies on the hydrolysis of carbonates using nucleophiles. Rate constants for the hydrolysis were obtained under pseudo-first-order conditions with DABCO as the nucleophile. A comparison of rate constant for hydrolysis of isobutyl phenyl carbonate with benzyl phenyl carbonate shows that the presence of benzyl group results in a 16-fold acceleration of hydrolysis rate. This indicates that the transition state for activation of carbonate is stabilized by cation-π interactions. A comparison of the rate constant for various aromatic rings indicates that electron-donating substituents on the benzyl groups accelerate the rate of hydrolysis. Studies were also carried out with DMAP as nucleophile and the results are presented. Our studies show that stable carbonates can be activated using nucleophiles. Activated acyl groups generated from acid anhydrides have been used in several enantioselective reactions. Our studies show that carbonates can be stable alternatives to acid anhydrides.

Full text of DOI:10.1021/acs.joc.6b00441

Article
pubs.acs.org/joc
Activation of Benzyl Aryl Carbonates: The Role of Cation−π
Interactions
Golipalli Ramana Reddy,† Anusha S. Avadhani,† and Sridhar Rajaram*,‡
†New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bangalore 560064, India
‡International Centre for Materials Science, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bangalore
560064, India
S
* Supporting Information
ABSTRACT: Benzyl aryl carbonates can react with a
nucleophile to yield an activated electrophile and an aryloxide
anion. Previously, we had utilized this in the synthesis of α-
nitro esters from nitroalkanes. To further understand the
process of activation of these carbonates by nucleophiles, we
have performed kinetic studies on the hydrolysis of carbonates
using nucleophiles. Rate constants for the hydrolysis were
obtained under pseudo-first-order conditions with DABCO as
the nucleophile. A comparison of rate constant for hydrolysis of isobutyl phenyl carbonate with benzyl phenyl carbonate shows
that the presence of benzyl group results in a 16-fold acceleration of hydrolysis rate. This indicates that the transition state for
activation of carbonate is stabilized by cation−π interactions. A comparison of the rate constant for various aromatic rings
indicates that electron-donating substituents on the benzyl groups accelerate the rate of hydrolysis. Studies were also carried out
with DMAP as nucleophile and the results are presented. Our studies show that stable carbonates can be activated using
nucleophiles. Activated acyl groups generated from acid anhydrides have been used in several enantioselective reactions. Our
studies show that carbonates can be stable alternatives to acid anhydrides.
phenoxide. Deprotonation of a nitroalkane by the phenoxide
generates a nitronate anion. Reaction of nitronate anion with
the activated electrophile through oxygen atom is rendered
reversible by DABCO, while attack through carbon leads to the
formation of an α-nitro ester.2−4
INTRODUCTION
■
The Strecker reaction is one of the most versatile methods for
the synthesis of α-amino acids.1 Although the utility of this
method is well established, the toxicity of cyanide is a major
concern with this reaction. In an attempt to develop a more
benign reaction, we reported on the use of carbonate as a
carboxyl group synthon in the synthesis of α-nitro esters
(Scheme 1).2
The nucleophilic activation of carbonates generates an
activated acyl group. Smith and co-workers have shown that
nucleophilic activation of carbonates can be used for an O- to
C-carboxyl transfer.5 Initial reports focused on the use of a N-
Heterocyclic carbene as nucleophile. Later, an enantioselective
version was reported using a chiral isothiourea.6 Recently, Lou
and co-workers have shown that carbonates can be used to trap
the product of reaction between glycine imine esters and aryl
aldehydes.7 The aldol products are difficult to isolate as the
reactions are reversible.8 Trapping the hydroxyl group with
carbonate facilitates isolation of aldol products, which are then
readily converted to β-hydroxy-α-amino acids. The generation
of an activated acyl group from a stable carbonate under mild
conditions is likely to be useful in similar applications. To
understand this fundamental step, we have studied the
hydrolysis of various carbonates in the presence of nucleophiles
(Figure 1). Our studies indicate a likely role for cation−π
interactions in the activation of carbonates. Cation−π
interactions have been shown to play a key role in stabilizing
protein structures9 and in stabilizing transition states of
In this method, benzyl phenyl carbonate is activated with
DABCO to transiently generate an activated electrophile and
Scheme 1. Synthesis of α-Nitro Esters Using Carbonates as
Carboxyl-Group Equivalents
Received: February 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00441
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The Journal of Organic Chemistry
Article
Figure 1. Structure of carbonates used in this study.
enzymatic10 as well as nonenzymatic reactions.11 Additionally,
cation−π interactions have also been invoked as key factors in
enhancing the enantioselectivity of several organo-catalyzed
reactions.12 Herein, we report kinetic studies on the activation
of carbonates that support our hypothesis.
Table 2. Evaluating the Effect of Benzene Ring Substitution
in the Synthesis of α-Nitro Esters
RESULTS AND DISCUSSION
■
a
entry
carbonate
product
time
% yield
As mentioned earlier, we had developed a synthesis of α-nitro
esters using benzyl phenyl carbonate as the source of carboxyl
group. To further extend the scope of our reaction, we explored
combinations of several solvents and carbonates. In this
context, a reaction was performed with t-butyl phenyl carbonate
(1b), 2-phenyl nitroethane, and DABCO using EtOAc as the
solvent. Under these conditions, we failed to observe any
product formation and the starting materials were recovered in
good yield (Table 1). To test whether this was due to steric
1
2
3
4
1a
1d
1e
1f
4a
4d
4e
4f
5 h
5 h
3 h
1 h
77
74
70
48
a
Reactions were quenched after complete consumption of starting
materials.
and characterize these side-products. However, the faster
reaction with carbonate 1f indicated a possible role for
cation−π interactions in the activation of carbonates. To
quantify the increase in reaction rate with variation in benzyl
group, we wanted to evaluate the rate constant for consumption
of carbonate. However, the variable yields observed for
formation of α-nitro esters precluded the possibility of using
this reaction for a kinetic study. Therefore, we decided to study
the activation of carbonates using a model reaction that would
potentially go through a similar transition state. For this
purpose, we chose the DABCO mediated hydrolysis of
carbonates as our model reaction. The reaction of DABCO
with a benzyl aryl carbonate generates an activated acyl group.
In the case of α-nitro ester formation, the activated acyl group
reacts with nitronate anion, while in our model reaction it is
expected to react with water. Decompostion of the resulting
benzyl hydrogen carbonate will yield the corresponding alcohol.
DMSO was chosen as the solvent for this study as it was used
as an additive in the synthesis of α-nitro esters.2
To examine the role of benzyl group, we synthesized various
carbonates (Figure 1) and studied the kinetics of their
hydrolysis under pseudo-first-order conditions in the presence
of DABCO as a nucleophile. An 80:20 mixture of DMSO-d6
and D2O was used as solvent and the initial concentration of
carbonate was 0.03 M. Reactions were performed in an NMR
tube, which was immersed in an oil bath maintained at 40 °C.
The percentage of carbonate remaining at various time points
(Ct) was measured by comparing its integration with an
internal standard. Rate constants were obtained by plotting
ln(100/Ct) vs time (see Supporting Information) and the
results are summarized in Table 3. Reactions were performed in
Table 1. Formation of α-Nitro Esters with Various
Carbonates
%
% nitro alkane
recovered
% carbonate
recovered
entry carbonate yield
1
2
3
1b
1c
1a
0
85
86
0
>95
>95
0
0
64
crowding, the less hindered isobutyl phenyl carbonate (1c) was
evaluated under the same conditions. Here again, we could not
obtain any product and the starting materials were recovered.
When benzyl phenyl carbonate was used under the same
conditions, the product was obtained in 64% yield. These
experiments indicated a key role for the benzyl group in
activation of the carbonate.
In order to clarify the role of benzyl groups in this reaction,
we evaluated carbonates 1d, 1e, and 1f in the synthesis of α-
nitro esters and the results are summarized in Table 2 (yields
are unoptimized). All the reactions were monitored by TLC
and quenched after complete consumption of starting materials.
In the reaction with carbonate 1f, the nitroalkane was
consumed at a much faster rate than in the reaction with 1a.
Although the reaction was faster, the yield was lower possibly
due to formation of side products.3 We were unable to isolate
B
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triplicate and average rate constants are reported (see
Supporting Information for standard deviations).
systems is 0.1 kcal/mol.13b On the basis of these studies, we
expected the transition state for hydrolysis of 4-methylbenzyl
phenyl carbonate (1g) to be ∼0.1 to 0.5 kcal/mol more stable
than the transition state for hydrolysis of 1a. Corresponding to
this, we expected the hydrolysis of 1g to be faster than the
hydrolysis of 1a. Consistent with our hypothesis, the rate
constant for hydrolysis of 4-methylbenzyl phenyl carbonate
(1g) was higher (k = 2.3 × 10−3/min) than the rate constant
for hydrolysis of carbonate 1a (k = 1.4 × 10−3/min). This
shows that the transition state for hydrolysis of carbonate 1g, is
0.3 kcal/mol more stable than the transition state for hydrolysis
of 1a. With respect to hydrolysis of isobutyl phenyl carbonate
1c, a 26-fold rate acceleration was observed. We then studied
the hydrolysis of other carbonates shown in Figure 1. The 4-
bromobenzyl phenyl carbonate (1e) hydrolyzed at the same
rate as benzyl phenyl carbonate (k = 1.5 × 10−3/min), while the
hydrolysis of naphthalenemethyl phenyl carbonates (1d and
1h) were faster. Interestingly, the positional isomers showed
different rates of hydrolysis, with carbonate 1h hydrolyzing
faster (relative rate ≈ 34) than carbonate 1d (relative rate ≈
23). The observed rate accelerations are consistent with greater
stabilization of cation by extended π-systems.14 Hydrolysis of
carbonate 1f was ∼51 times faster than the hydrolysis of
carbonate 1c. The hydrolysis of 3,4-dimethoxy benzyl phenyl
carbonate 1i is slightly slower than the hydrolysis of carbonate
1f with a relative rate of ∼44. We attribute this to unfavorable
steric interactions between the nucleophile and a meta
substituent on the benzene ring. Consistent with this, the
hydrolysis of 3-methoxy benzyl phenyl carbonate 1j (relative
rate ≈ 14) was slower than the hydrolysis of the 4-methoxy
substituted carbonate 1f. To probe the effect of an electron
withdrawing group on the aromatic system, we studied the
hydrolysis of the 4-CF3 substituted carbonate 1k. Electron-
withdrawing groups on the benzene ring are expected to
diminish cation−π interactions and indeed carbonate 1k
hydrolyzed at a slower rate than carbonate 1a. For systemati-
cally analyzing the effect of substituents on the proposed
transition state, we used Hammett plots.15 In this study, we
used carbonates 1a, 1e, 1f, 1g, and 1k as the substituents on
these carbonates have well-defined σ values. The logarithm of
relative rate with respect to 1a was plotted against various σ
Table 3. Rate Constants for Hydrolysis of Carbonates with
DABCO as the Nucleophile
a
entry
carbonate
rate constant k (min−1
)
relative rate
1
2
1c
1a
1d
1e
1f
8.8 × 10−5
1.4 × 10−3
2.0 × 10−3
1.5 × 10−3
4.5 × 10−3
2.3 × 10−3
2.9 × 10−3
3.9 × 10−3
1.2 × 10−3
9.3 × 10−4
1
16
23
17
51
26
33
44
14
11
3
4
5
6
1g
1h
1i
7
8
9
1j
10
1k
a
Reactions were performed in an NMR tube immersed in an oil bath
maintained at 40 °C. For monitoring the reactions, the NMR tube was
immersed in an ice bath for a few minutes followed by recording of
spectra at 25 °C. All reactions were repeated thrice and the average k is
reported. For standard deviations see Supporting Information.
We began our studies on hydrolysis of unsubstituted
carbonate 1a. The hydrolysis reached 92% conversion over
1900 min. A plot of ln(100/Ct) vs time gave an excellent linear
fit and a rate constant of k = 1.4 × 10−3/min was obtained.
Under similar conditions, the rate constant for hydrolysis of
isobutyl phenyl carbonate 1c was found to be 8.8 × 10−5/min.
The 16-fold acceleration in the presence of benzyl group can be
rationalized by the hypothetical mechanism shown in Scheme
2. We hypothesize that the observed rate acceleration is due to
Scheme 2. Hypothetical Reaction Pathway for the Hydrolysis
of Carbonate, with the Nucleophilic Attack of DABCO on
a
the Carbonate as the Rate Determining Step
15
−
parameters. Correlation with σp and σp values gave the best
fits. (R2 = 0.85 and 0.88 respectively. see Supporting
Information). The corresponding ρ values were −1.84 and
−1.66 respectively. The low values for ρ are possibly due to
shielding of the cation from the aromatic system by solvent
molecules.16 Cation−π interactions are known to depend on
the distance of the cationic group from the benzyl ring.17 To
test this, we synthesized the phenethyl carbonate 1l and studied
the hydrolysis under our standard conditions. The reaction was
very slow and only ∼13% of the carbonate was consumed in
720 min. The reduction of hydrolysis rate in this case is
attributable to the increased distance between the aromatic ring
and the cationic center.
a
A plausible transition state that involves cation−π interaction is
shown.
In order to test the generality of the cation−π induced rate
acceleration, we decided to study the hydrolysis of carbonates
using DMAP as the nucleophile. Previous work from the Mayr
group has shown that DABCO is a better nucleophile than
DMAP.18 On the basis of our proposed transition state for the
attack of nucleophile (Scheme 2), we expected the hydrolysis to
be slower with the less nucleophilic DMAP. Indeed, to get
appreciable rates of hydrolysis, the reactions had to be carried
out at 60 °C. When we plotted ln(100/Ct) vs time (see
stabilization of the transition state by cation−π interactions
between the acyl-ammonium cation and the benzene ring. The
stabilization of the transition state is expected to be sensitive to
the substitution pattern of the aromatic ring. Theoretical
calculations have shown that in gas phase, toluene binds
tetramethylammonium ion more strongly than benzene by 0.5
kcal/mol.13a On the other hand, thermochemical measurements
have shown that the difference in binding energy between these
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Supporting Information), we did not obtain straight lines. The
reactions appeared to be faster at initial time points and settled
down to a slower rate as the reaction progressed. Therefore, we
were unable to compare rate constants. A qualitative idea about
cation−π interaction could be obtained by comparing the time
taken for the reaction to reach ∼90% completion. The results
are summarized in Table 4. As expected, 4-methoxybenzyl
hydrolysis were observed. Nucleophilic activation leads to
generation of a strong base along with an activated acyl group.
Together, this can be a useful tool for exploring new reactivity
patterns. Typically, activated acyl groups are generated from the
much more reactive acid anhydrides, whereas in our approach
this can be generated from stable and easy-to-purify carbonates.
Further work in our group will focus on developing novel
transformations using this system.
Table 4. Hydrolysis of Carbonates with DMAP as the
a
Nucleophile
EXPERIMENTAL SECTION
■
All glassware was dried overnight in an oven at 120 °C prior to use.
Reactions were carried out under argon atmosphere using standard
Schlenk techniques and were monitored by thin layer chromatography
(TLC) using silica gel TLC plates. Flash column chromatography was
performed using silica gel of mesh size 230−400. Grease-free solvents
for flash column chromatography were obtained by distillation. Unless
otherwise noted, all chemicals obtained from commercial sources were
used without further purification. Infrared spectra were recorded using
b
time (approximately 90% completion)
entry
carbonate
run 1
run 2
1
2
3
4
5
1a
1d
1f
39 h (90%)
20 h (89%)
6.5 h (92%)
19 h (90%)
5 h (92%)
41 h (90%)
20 h (89%)
6.2 h (89%)
21 h (91%)
5 h (90%)
1
an FT-IR Spectrometer. H and 13C NMRs were recorded on a 400
MHz Fourier Transform NMR spectrometer. Chemical shifts are
reported in parts per million (ppm) with respect to the residual
1h
1i
1
solvent peak. For H NMRs recorded in CDCl3, the residual solvent
peak at 7.27 ppm was used for calibration. For {1H} 13C NMRs
recorded in CDCl3, the residual solvent peak at 77.16 ppm was used
for calibration. For 1H NMRs recorded in DMSO-d6, the residual
solvent peak at 2.50 ppm was used for calibration. For {1H} 13C
NMRs recorded in DMSO-d6, the residual solvent peak at 39.5 ppm
was used for calibration. 13C NMRs were recorded at 100 MHz using
proton decoupling. HRMS were recorded using Q-TOF mass analyzer.
Melting points were measured using melting point apparatus.
General Procedure for the Synthesis of Carbonates. Two
general procedures were adapted from literature.2
a
Time taken for the reactions to reach ∼90% completion are given.
Reactions were performed at 60 °C and monitored as mentioned in
b
Table 3.
phenyl carbonate (1f) hydrolyzed ∼6 times faster than the
unsubstituted carbonate 1a. In contrast to the reaction with
DABCO, the dimethoxy substituted carbonate (1i) also
hydrolyzed at the same rate as the 4-methoxy substituted
carbonate (1f). Similarly, a significant acceleration is seen in the
hydrolysis of the naphthalenemethyl phenyl carbonates (1h,
1d). Here, the positional isomers are hydrolyzed at a similar
rate. On the basis of the above results, it is clear that the
cation−π interactions play an important role in activating
benzyl phenyl carbonates. Activated acyl groups have been used
in many reactions including kinetic resolution of alcohols and
enantioselective O- to C-carboxyl transfer.5,6 In kinetic
resolutions of secondary alcohols, an anhydride is typically
used as a source of activated acyl group.12c,d Benzyl carbonates
are more stable than acid anhydrides and are also easily
purified. Therefore, these reagents could potentially replace
acid anhydrides as acyl donors. Cation−π interactions appear to
be important in stabilizing the transition state for nucleophilic
attack of these carbonates. Varying the substituents on the
aromatic ring of the benzyl group can tune this interaction and
facilitate rapid activation of these stable carbonates.
Method A. A round bottomed flask was charged with phenol (1
equiv), dichloromethane (DCM), and pyridine (1.26 equiv). The flask
was immersed in an ice bath and benzyl chloroformate (1.3 equiv) was
added dropwise. The reaction mixture was allowed to warm up to
room temperature and stirred overnight. The reaction mixture was
transferred to a separatory funnel and diluted with DCM. The organic
layer was washed successively with deionized water, 5% NaOH, 1 M
HCl, and brine. The organic layer was dried over Na2SO4 and
concentrated. The material obtained was purified by flash column
chromatography.
Method B. A round bottomed flask was charged with the required
benzyl alcohol (1 equiv), DCM, and pyridine (1.26 equiv). The flask
was immersed in an ice bath and phenyl chloroformate (1.3 equiv) was
added dropwise. The reaction mixture was allowed to warm up to
room temperature and stirred overnight. The reaction mixture was
transferred to a separatory funnel and diluted with DCM. The organic
layer was washed successively with deionized water, 5% NaOH, 1 M
HCl and brine. The organic layer was dried over Na2SO4 and
concentrated. The material obtained was purified by flash column
chromatography.
CONCLUSIONS
■
Benzyl phenyl carbonate (1a). Method A was employed with
the following quantities: phenol (4.68 g, 49.7 mmol), benzyl
chloroformate (2.93 M solution in toluene, 22 mL (64.7 mmol),
pyridine (5 mL, 62.5 mmol), and DCM (50 mL).
We have studied the hydrolysis of benzyl aryl carbonates
mediated by nucleophiles. Rate constants for reactions
mediated by DABCO were obtained under pseudo-first-order
conditions. Comparison of the rate constant for hydrolysis of
isobutyl phenyl carbonate with various substituted benzyl
carbonates showed that cation−π interactions play an
important role in hydrolysis. Importantly, 4-methoxybenzyl
phenyl carbonate hydrolyzed at a faster rate than naphthale-
nemethyl phenyl carbonate. This indicates that a 4-methox-
ybenzyl group might stabilize an ammonium cation better than
a naphthalenemethyl group. When hydrolyses were performed
with DMAP, we were unable to get good straight line fits for
our data. Therefore, rates of hydrolysis were compared in a
qualitative manner and trends similar to DABCO mediated
Column Chromatography. Approximately 150 mL of silica was
packed into a column using 20% DCM in hexanes as the solvent. The
material obtained from workup was loaded on the column after
dissolution in a minimum amount of this solvent. Approximately 500
mL of 20% DCM in hexanes was eluted followed by elution with 1200
mL of 25% DCM in hexanes. The eluted solvent was collected in 25
mL fractions. Fractions 21−63 contained product. These fractions
were concentrated and dried under high vacuum to give 6.46 g of
1
product (yield: 57%). The H NMR of the product was in agreement
with the literature.19
tert-Butyl phenyl carbonate (1b). Method B was employed with
the following quantities: tert-butyl alcohol (3.4 mL, 35.55 mmol),
D
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phenyl chloroformate (5.8 mL, 46.2 mmol), pyridine (3.7 mL, 45.9
mmol), and DCM (35 mL).
MHz, DMSO-d6) δ 152.9, 150.7, 134.5, 131.5, 130.5, 129.6, 126.2,
121.8, 121.2, 68.9; IR (film): 1759, 1492, 1201, 1012, 772, 496 cm−1;
+
HRMS (ESI) m/z (M + Na)+ Calcd for C14H11BrNaO3 328.9789,
Column Chromatography. Approximately 130 mL of silica was
packed into a column using 2% ethyl acetate (EtOAc) in hexanes as
the solvent. The material obtained from workup was adsorbed on silica
and loaded on the column. Approximately 800 mL of 2% EtOAc in
hexanes was eluted. The eluted solvent was collected in 25 mL
fractions. Fractions 6−27 contained product. These fractions were
concentrated and dried under high vacuum to give 4.1 g of product
(yield: 88%). The 1H NMR data of the product was in agreement with
the literature.20
2-Methylpropyl phenyl carbonate (1c). Method A was
modified by replacing benzyl chloroformate with isobutylchlorofor-
mate and the following quantities were used: isobutyl chloroformate (3
mL, 23.1 mmol), phenol (3.24 g, 34.4 mmol), pyridine (3.5 mL, 43.4
mmol), and DCM (35 mL).
Column Chromatography. Approximately 100 mL of silica was
packed into a column using 25% DCM in hexanes as the solvent. The
material obtained from work up was loaded on the column after
dissolution in a minimum amount of this solvent. Approximately 1000
mL of 25% DCM in hexanes was eluted. The eluted solvent was
collected in 25 mL fractions. Fractions 4−29 contained product. These
fractions were concentrated and dried under high vacuum to give 3.1 g
of product (yield: 69%).
found 328.9787.
4-Methoxybenzyl phenyl carbonate (1f). Method B was
employed with the following quantities: 4-methoxybenzyl alcohol (4
g, 28.95 mmol), phenyl chloroformate (4.7 mL, 37.46 mmol), pyridine
(3 mL, 37.2 mmol), and DCM (30 mL).
Column Chromatography. Approximately 110 mL of silica was
packed into a column using 0.7% EtOAc in hexanes as the solvent. The
material obtained from workup was loaded on the column after
dissolution in a minimum amount of this solvent. Approximately 1100
mL of 0.7% EtOAc in hexanes was eluted followed by elution with 400
mL of 30% DCM in hexanes. The eluted solvent was collected in 25
mL fractions. Fractions 33−53 contained pure product. These
fractions were concentrated and dried under high vacuum to give
5.07 g of product (yield: 68%). The 1H NMR data of the product was
in agreement with the literature.19
4-Methylbenzyl phenyl carbonate (1g). Method B was
employed with the following quantities: 4-methylbenzyl alcohol (2 g,
16.37 mmol), phenyl chloroformate (2.7 mL, 21.5 mmol), pyridine
(1.6 mL, 19.9 mmol), and DCM (16 mL).
Column Chromatography. Approximately 110 mL of silica was
packed into a column using 1% EtOAc in hexanes as the solvent. The
material obtained from workup was adsorbed on silica and loaded on
the column. Approximately 1100 mL of 1% EtOAc in hexanes was
eluted followed by elution with 500 mL of 15% EtOAc in hexanes. The
eluted solvent was collected in 25 mL fractions. Fractions 3−20
contained product. These fractions were concentrated and dried under
Characterization. Colorless liquid; Rf 0.36 in 10% EtOAc in
1
hexanes; H NMR (400 MHz, CDCl3) δ 7.42−7.37 (m, 2H), 7.27−
7.17 (m, 3H), 4.05 (d, J = 6.7 Hz, 2H), 2.07 (m, 1H), 1.06 (d, J = 6.7
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 154.0, 151.3, 129.6, 126.1,
121.2, 74.9, 28.0, 19.0; IR (film):1758, 1237, 1204, 768 cm−1; HRMS
+
(ESI): m/z (M + Na)+ Calcd for C11H14NaO3 217.0841, found
1
high vacuum to give 2.88 g of product (yield: 73%). The H NMR,
217.0832.
data of the product was in agreement with the literature.21
Naphthalen-2-ylmethyl phenyl carbonate (1d). Method B was
employed with the following quantities: naphthalene-2-ylmethanol (4
g, 25.32 mmol), phenyl chloroformate (4.8 mL, 38.26 mmol), pyridine
(2.7 mL, 33.5 mmol), and DCM (25 mL).
Naphthalen-1-ylmethyl phenyl carbonate (1h). Method B was
employed with the following quantities: naphthalene-1-ylmethanol
(1.73 g, 10.9 mmol), phenyl chloroformate (1.7 mL, 13.5 mmol),
pyridine (1 mL, 12.4 mmol), and DCM (10 mL).
Column Chromatography. Approximately 110 mL of silica was
packed into a column using 1.1% EtOAc in hexanes as the solvent. The
material obtained from workup was adsorbed on silica and loaded on
the column. Approximately 1600 mL of 1.1% EtOAc in hexanes was
eluted. The eluted solvent was collected in 25 mL fractions. Fractions
34−62 contained product. These fractions were concentrated and
dried under high vacuum to give 2.03 g of product (yield: 29%).
Characterization. Pale brown crystalline solid; mp = 45−46 °C; Rf
0.2 in 2.5% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ 8.13 (d,
J = 8.5 Hz, 1H), 7.93−7.90 (m, 2H), 7.65−7.54 (m, 3H), 7.49 (dd, J =
7.1, 8.2 Hz, 1H), 7.41−7.36 (m, 2H), 7.25−7.17 (m, 3H), 5.76 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 153.8, 151.3, 133.9, 131.0,
130.5, 130.0, 129.6, 128.9, 128.2, 127.0, 126.22, 126.17, 125.4, 123.6,
121.2, 68.7; IR (film):1763, 1244, 1212, 976, 772 cm−1; HRMS (ESI)
Column Chromatography. Approximately 90 mL of silica was
packed into a column using 1% EtOAc in hexanes as the solvent. The
material obtained from workup was adsorbed on silica and loaded on
the column. Approximately 1400 mL of 1% EtOAc in hexanes was
eluted. The eluted solvent was collected in 25 mL fractions. Fractions
26−44 contained product. These fractions were concentrated and
dried under high vacuum to give 1.79 g of product (yield: 59%).
Characterization. Crystalline white solid; mp = 43−44 °C; Rf 0.4 in
5% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.2
Hz, 1H), 7.93−7.90 (m, 2H), 7.65−7.54 (m, 3H), 7.49 (dd, J = 7.6,
8.2 Hz, 1H), 7.41−7.37 (m, 2H), 7.25−7.18 (m, 3H), 5.76 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 153.7, 151.2, 133.8, 131.6, 130.3,
129.8, 129.5, 128.8, 128.1, 126.8, 126.1, 126.0, 125.3, 123.5, 121.0,
68.6; IR (film): 1757, 1246, 1206, 1068, 974, 771, 686 cm−1; HRMS
+
m/z (M + Na)+ Calcd for C18H14NaO3 301.0841, found 301.0838.
+
(ESI) m/z (M + Na)+ Calcd for C18H14NaO3 301.0841, found
4-Bromobenzyl phenyl carbonate (1e). Method B was
employed with the following quantities: 4-bromobenzyl alcohol
(3.41 g, 18.22 mmol), phenyl chloroformate (3.5 mL, 27.8 mmol),
pyridine (2 mL, 24.8 mmol), and DCM (20 mL).
301.0835.
3,4-Dimethoxybenzyl phenyl carbonate (1i). Method B was
employed with the following quantities: 3,4-dimethoxybenzyl alcohol
(3.068 g, 18.24 mmol), phenyl chloroformate (3.5 mL, 27.9 mmol),
pyridine (1.9 mL, 23.6 mmol), and DCM (18 mL).
Column Chromatography. Approximately 100 mL of silica was
packed into a column using 8% EtOAc in hexanes as the solvent. The
material obtained from workup was adsorbed on silica and loaded on
the column. Approximately 900 mL of 8% EtOAc in hexanes was
eluted followed by elution with 300 mL of 15% EtOAc in hexanes and
200 mL of 20% EtOAc in hexanes. The eluted solvent was collected in
25 mL fractions. Fractions 25−49 contained product. These fractions
were concentrated and dried under high vacuum to give 4.18 g of
product (yield: 80%).
Column Chromatography. Approximately 110 mL of silica was
packed into a column using 25% DCM in hexanes as the solvent. The
material obtained from workup was loaded on the column after
dissolution in a minimum amount of this solvent. Approximately 1300
mL of 25% DCM in hexanes was eluted and collected in 25 mL
fractions. Fractions 8−53 contained product. The fractions were
concentrated. However, the isolated compound contained diphenyl
carbonate. This mixture was purified by column chromatography,
using 110 mL silica. Approximately 1200 mL of 0.77% EtOAc in
hexanes was eluted followed by 300 mL of DCM and 25 mL fractions
were collected. Fractions 45−61 contained pure compound. These
fractions were concentrated and dried under high vacuum to give 2.6 g
of product (yield: 46%).
Characterization. Crystalline white solid; mp = 47−48 °C; Rf 0.16
1
in 20% EtOAc in hexanes; H NMR (400 MHz, CDCl3) δ 7.41−7.36
(m, 2H), 7.27−7.17 (m, 3H), 7.04−6.98 (m, 2H), 6.89−6.87 (m, 1H),
5.22 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 153.8, 151.3, 149.7, 149.2, 129.6, 127.4, 126.2, 121.9, 121.2, 112.1,
Characterization. Pale yellow liquid; Rf 0.13 in 30% DCM in
hexanes; 1H NMR (400 MHz, DMSO-d6) δ 7.63−7.61 (m, 2H),
7.46−7.41 (m, 4H), 7.31−7.23 (m, 3H), 5.25 (s, 2H); 13C NMR (100
E
DOI: 10.1021/acs.joc.6b00441
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The Journal of Organic Chemistry
Article
111.2, 70.7, 56.1; IR (film): 1739, 1247, 1023, 748, 705 cm−1. Anal.
Calcd for C16H16O5: C, 66.66; H, 5.59. Found: C, 66.88; H, 5.62.
3-Methoxybenzyl phenyl carbonate (1j). Method B was
employed with the following quantities: 3-methoxybenzyl alcohol
(960 μL, 7.72 mmol), phenyl chloroformate (1.2 mL, 9.6 mmol),
pyridine (800 μL, 9.93 mmol), and DCM (8 mL).
Column Chromatography. Approximately 80 mL of silica was
packed into a column using 3% EtOAc in hexanes as the solvent. The
material obtained from workup was adsorbed on silica and loaded on
the column. Approximately 600 mL of 3% EtOAc in hexanes was
eluted followed by elution with 400 mL of 8% EtOAc in hexanes. The
eluted solvent was collected in 25 mL fractions. Fractions 14−25
contained product. These fractions were concentrated and dried under
high vacuum to give 1.39 g of product (yield: 70%).
formed. The suspension was transferred to a separatory funnel
containing 15 mL of 1 M KHSO4. The aqueous layer was extracted
with diethyl ether (3 × 20 mL). The combined ether layers were dried
over Na2SO4, concentrated, and purified by flash column chromatog-
raphy.
Benzyl 2-nitro-3-phenylpropanoate (4a). The general proce-
dure was employed with the following quantities: 2-phenylnitro ethane
(100 mg, 0.66 mmol), 1a (455 mg, 2.0 mmol), DABCO (150 mg, 1.33
mmol), and DMSO (140 μL, 2.0 mmol). Time: 5 h.
Column Chromatography. Approximately 50 mL of silica was
packed into a column using 25% DCM in hexanes as the solvent. The
material obtained from workup was loaded on the column after
dissolution in a minimum amount of this solvent. Approximately 800
mL of 25% DCM in hexanes was eluted followed by elution with 400
mL of 40% DCM in hexanes. The eluted solvent was collected in 12
mL fractions. Fractions 58−67 contained product, diphenyl carbonate
and phenyl benzyl carbonate. Fractions 68−71 contained pure
product. Fractions 58−67 were concentrated and purified by column
chromatography. Approximately 40 mL of silica was packed into a
column using 3% EtOAc in hexanes as the solvent. The mixed
fractions from the first column was adsorbed on silica and loaded on
the column. Approximately 450 mL of 3% EtOAc in hexanes was
eluted followed by elution with 100 mL of 50% DCM in hexanes. The
eluted solvent was collected in 12 mL fractions. Fractions 36−38
contained product. The fractions containing pure product from
column I and column II were concentrated and dried under high
vacuum to give 149 mg of product (yield: 78%). The 1H NMR, data of
the product was in agreement with the literature.2
Characterization. White viscous liquid; Rf 0.16 in 5% EtOAc in
1
hexanes; H NMR (400 MHz, CDCl3) δ 7.42−7.37 (m, 2H), 7.34−
7.30 (m, 1H), 7.25−7.18 (m, 3H), 7.04−6.91 (m, 3H), 5.26 (s, 2H),
3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.0, 153.8, 151.3,
136.4, 129.9, 129.6, 126.2, 121.2, 120.8, 114.6, 113.9, 70.3, 55.4; IR
(film): 1755, 1590, 1205, 1039, 685, 504 cm−1; HRMS (ESI) m/z (M
+
+ Na)+ Calcd for C15H14NaO4 281.0790; Found: 281.0790.
4-Trifluoromethylbenzyl phenyl carbonate (1k). Method B
was employed with the following quantities: 4-trifluoromethylalcohol
(650 mg, 3.69 mmol), phenyl chloroformate (700 μL, 5.1 mmol),
pyridine (420 μL, 5.21 mmol), and DCM (6 mL)
Column Chromatography. Approximately 96 mL of silica was
packed into a column using 2% EtOAc in hexanes as the solvent. The
material obtained from workup was adsorbed on silica and loaded on
the column. Approximately 1400 mL of 2% EtOAc in hexanes was
eluted. The eluted solvent was collected in 25 mL fractions. Fractions
39−56 contained product. These fractions were concentrated and
dried under high vacuum to give 611 mg of product (yield: 56%).
Characterization. Crystalline white solid; mp = 62−64 °C; Rf 0.16
in 2% EtOAc in hexanes; 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J
= 8.2 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.47−7.42 (m, 2H), 7.32−
7.25 (m, 3H), 5.38 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 154.1,
152.0, 141.1, 130.9, 129.8, 127.5, 126.7 (q, J = 3.6 Hz), 124.0, 122.4,
70.0; IR (film): 1750, 1275, 1105, 1066, 715 cm−1; HRMS (ESI) m/z
(M + Na)+ Calcd for C15H11F3O3Na+ 319.0558; Found: 319.0557.
Phenyl-2-phenylethyl carbonate (1l). Method B was employed
with the following quantities: 2-phenylethanol (4 mL, 33.3 mmol),
phenyl chloroformate (5.4 mL, 43.04 mmol), pyridine (3.4 mL, 42.2
mmol), and DCM (30 mL).
Column Chromatography. Approximately 110 mL of silica was
packed into a column using 0.7% EtOAc in hexanes as the solvent. The
material obtained from workup was adsorbed on silica and loaded on
the column. Approximately 1100 mL of 0.7% EtOAc in hexanes was
eluted followed by elution of 1100 mL of 30% DCM in hexanes. The
eluted solvent was collected in 25 mL fractions. Fractions 45−84
contained product. These fractions were concentrated and dried under
high vacuum to give 6.63 g of product (yield: 82%).
Naphthalen-2-ylmethyl 2-nitro-3-phenylpropanoate (4d).
The general procedure was employed with the following quantities:
2-phenylnitro ethane (75 mg, 0.5 mmol), 1d (415 mg, 1.5 mmol),
DABCO (112 mg, 1 mmol), and DMSO (110 μL, 1.5 mmol). Time: 5
h.
Column Chromatography. Approximately 45 mL of silica was
packed into a column using 3% EtOAc in hexanes as the solvent. The
material obtained from workup was adsorbed on silica and loaded on
the column. Approximately 700 mL of 3% EtOAc in hexanes was
eluted. The eluted solvent was collected in 25 mL fractions. Fractions
15−22 contained product. These fractions were concentrated and
dried under high vacuum to give 135 mg of product. The obtained
product contained 7.5 mol % of bis(naphthalene-2-ylmehtyl)
1
carbonate as impurity. Yield: 74% (based on H NMR).
Characterization. Brown viscous liquid; Rf 0.23 in 5% EtOAc in
1
hexanes; H NMR (400 MHz, CDCl3) δ 7.92−7.86 (m, 3H), 7.59−
7.43 (m, 5H), 7.26−7.24 (m, 3H), 7.15−7.12 (m, 2H), 5.70 (s, 2H),
5.37 (dd, J = 6.2, 9.1 Hz, 1H), 3.56 (dd, J = 9.1, 14.4 Hz, 1H), 3.46
(dd, J = 6.2, 14.4 Hz, 1H) ; 13C NMR (100 MHz, CDCl3) δ 164.2,
133.93, 133.90, 131.7, 130.2, 129.8, 129.1, 129.0, 128.96, 128.3, 127.9,
127.1, 126.3, 125.3, 123.3, 89.1, 67.2, 36.4; IR (film): 1747, 1562,
1202, 1170, 859, 777, 701 cm−1; HRMS (ESI) m/z (M-H)− Calcd for
−
C20H16NO4 , 334.1084, found, 334.1081.
Characterization. Amorphous white solid; mp = 79−80 °C ;Rf 0.16
in 2.5% EtOAc in hexanes; 1H NMR (400 MHz, CDCl3) δ 7.41−7.33
(m, 4H), 7.29−7.28 (m, 2H), 7.26−7.23 (m, 2H), 7.17−7.14 (m, 2H),
4.47 (t, J = 7.1 Hz, 2H), 3.07(t, J = 7.1 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 153.6, 151.1, 137.0, 129.5, 129.0, 128.6, 126.8, 126.0, 121.1,
69.0, 35.1 ; IR (film):1751, 1486, 1262, 969, 757, 704, 501 cm−1;
4-Bromobenzyl 2-nitro-3-phenylpropanoate (4e). The gen-
eral procedure was employed with the following quantities: 2-
phenylnitro ethane (75 mg, 0.5 mmol), 1e (456 mg, 1.5 mmol),
DABCO (112 mg, 1 mmol), and DMSO (110 μL, 1.5 mmol). Time: 3
h.
Column Chromatography. Approximately 45 mL of silica was
packed into a column using 25% toluene in hexanes as the solvent.
The material obtained from workup was adsorbed on silica and loaded
on the column. Approximately 1300 mL of 25% toluene in hexanes
was eluted. The eluted solvent was collected in 25 mL fractions.
Fractions 35−49 contained product. These fractions were concen-
trated and dried under high vacuum to give 127 mg of product (yield:
70%).
+
HRMS (ESI) m/z (M + Na)+ Calcd for C15H14NaO3 265.0840,
found 265.0835.
General Procedure for the Synthesis of Nitroesters. A thick-
walled glass tube with a Teflon screw cap was charged with
phenylnitroethane (1equiv) and aryl phenyl carbonate (3 equiv).
The tube was flushed with argon and dimethyl sulfoxide (3 equiv) was
added followed by 1,4-diazabicyclo [2.2.2] octane (DABCO) (2
equiv). The tube was capped and immersed in an oil bath at 60 °C.
The reaction mixture was stirred at this temperature and the progress
of the reaction was monitored by TLC.
Characterization. Brown viscous liquid; Rf. 0.16 in 50% DCM in
1
hexanes; H NMR (400 MHz, CDCl3) δ 7.52−7.48 (m, 2H), 7.33−
7.28 (m, 3H), 7.19−7.13 (m, 4H), 5.37 (dd, J = 6.3, 9.1 Hz, 1H), 5.17
(s, 2H), 3.57 (dd, J = 9.1, 14.5 Hz, 1H), 3.48 (dd, J = 6.3, 14.5 Hz,
1H) ; 13C NMR (100 MHz, CDCl3) δ 164.0, 133.9, 133.3, 132.1,
130.2, 129.2, 129.0, 128.0, 123.2, 89.1, 67.9, 36.4; IR (film): 1747,
Workup Procedure. After completion of reaction by TLC, the
reaction mixture was cooled to 0 °C and quenched with 1 M KHSO4.
This was further stirred at room temperature until a suspension was
F
DOI: 10.1021/acs.joc.6b00441
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The Journal of Organic Chemistry
Article
1562, 1489, 1198, 1174, 802, 697 cm−1; HRMS (ESI) m/z (M-H)−
Calcd for C16H13BrNO4 , 362.0033, found 362.0028.
4-Methoxybenzyl 2-nitro-3-phenylpropanoate (4f). The
general procedure was employed with the following quantities: 2-
phenylnitro ethane (75 mg, 0.5 mmol), 1f (384 mg, 1.5 mmol),
DABCO (112 mg, 1 mmol), and DMSO (110 μL, 1.5 mmol). Time: 1
h.
Tetrahedron 2009, 65, 1219−1234. (c) Doyle, A. G.; Jacobsen, E. N.
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Column Chromatography. Approximately 45 mL of silica was
packed into a column using 60% toluene in hexanes as the solvent.
The material obtained from workup was adsorbed on silica and loaded
on the column. Approximately 400 mL of 60% toluene in hexanes was
eluted followed by the elution of 400 mL of 70% toluene in hexanes.
The eluted solvent was collected in 25 mL fractions. Fractions 16−22
contained product. These fractions were concentrated and dried under
high vacuum to give 82 mg of product. The obtained product contains
7.5 mol % of bis(4-methoxybenzyl) carbonate as impurity. Yield: 48%
1
(based on H NMR).
Characterization. Brown viscous liquid; Rf. 0.16 in 30% DCM in
1
hexanes; H NMR (400 MHz, CDCl3) δ 7.31−7.27 (m, 3H), 7.25−
7.15 (m, 4H), 6.89−6.87 (m, 2H), 5.34 (dd, J = 6.0, 9.2 Hz, 1H), 5.17
(s, 2H), 3.81 (s, 3H), 3.54 (dd, J = 9.4, 14.5 Hz, 1H), 3.45 (dd, J = 6.0,
14.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 164.1, 160.3, 134.1,
130.6, 129.1, 129.0, 127.9, 126.4, 114.3, 89.3, 68.7, 55.5, 36.4; IR
(film): 1747, 1614, 1558, 1513, 1250, 1174, 1028, 826, 701 cm−1;
(5) (a) Gould, E.; Walden, D. M.; Kasten, K.; Johnston, R. C.; Wu, J.;
Slawin, A. M. Z.; Mustard, T. J. L.; Johnston, B.; Davies, T.; Cheong,
P. H. − Y.; Smith, A. D. Chem. Sci. 2014, 5, 3651−3658. (b) Campbell,
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−
HRMS (ESI) m/z (M-H)− Calcd for C17H16NO5 , 314.1034, found
314.1024.
Hydrolysis of Carbonates with DABCO. A 1 mL volumetric flask
was charged with 1 mg of naphthalene (as an internal standard) and
0.03 mmol (1 equiv) of carbonate. To this 600 μL of DMSO-d6 was
added. Carbonate and naphthalene were dissolved in the solvent
followed by the addition of 200 μL of D2O. To this, 5.1 equiv ( 7%)
of DABCO was added and the solution was made up to the mark using
DMSO. The solution was immediately transferred to a clean NMR
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1
tube and H NMR spectra were recorded at regular intervals.
Note: For hydrolysis of carbonate 1c, the ASCII files of NMR were
exported to origin and integration of peaks was performed in origin.
Hydrolysis of Carbonates with DMAP. A 1 mL volumetric flask
was charged with 1 mg of naphthalene (as an internal standard)22 and
0.03 mmol (1 equiv) of carbonate. To this 600 μL of DMSO-d6 was
added. Carbonate and naphthalene were dissolved in the solvent
followed by the addition of 200 μL of D2O. To this, 5 equiv ( 2%) of
DMAP was added and the solution was made up to the mark using
DMSO. The solution was immediately transferred to a clean NMR
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tube and H NMR spectra were recorded at regular intervals.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00441.
■
S
Kinetic plots, Hammett plots and NMR spectra. (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: rajaram@jncasr.ac.in.
■
́
(10) (a) Faraldos, J. A.; Antonczak, A. K.; Gonzalez, V.; Fullerton, R.;
Tippmann, E. M.; Allemann, R. K. J. Am. Chem. Soc. 2011, 133,
13906−13909. (b) Abe, I.; Prestwich, G. D. Proc. Natl. Acad. Sci. U. S.
A. 1995, 92, 9274−9278. (c) Kagan, R. M.; Clarke, S. Arch. Biochem.
Biophys. 1994, 310, 417−427. (d) Shi, Z.; Buntel, C. J.; Griffin, J. H.
Proc. Natl. Acad. Sci. U. S. A. 1994, 91, 7370−7374. (e) Poralla, K.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank JNCASR and DST for funding. We
gratefully acknowledge Ms. D. Mukherjee and Ms. P. Kalra
for help with the initial experiments. We thank Prof. H.
Chakrapani and Prof. E. Prabhakaran for helpful discussions.
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DOI: 10.1021/acs.joc.6b00441
J. Org. Chem. XXXX, XXX, XXX−XXX