Zinc Triflate Catalyzed C-Benzylation: Chemo- and Regioselective Route to Amido Substituted Diaryl and Arylheteroarylmethanes

Article abstract of DOI:10.1021/acs.joc.5b01646

An unprecedented zinc triflate catalyzed selective C-benzylation of anilides and heteroaryl amides with benzyl chlorides having electron-donating group at para-position is reported. The protocol offers moderate to high yield of para-amido substituted diaryl and arylheteroarylmethanes, uses cheap and easily available benzyl chlorides as the benzylating agent, catalytic amount of zinc triflate, and takes place under ambient conditions. Aminodiarylmethane derivatives can be obtained by hydrolysis of the corresponding amides. The methodology has also been applied for preparing dimethoxydiarylmethanes in good yields, which are the key precursors for synthesis of phenolic natural products.

Full text of DOI:10.1021/acs.joc.5b01646

Article
pubs.acs.org/joc
Zinc Triflate Catalyzed C‑Benzylation: Chemo- and Regioselective
Route to Amido Substituted Diaryl and Arylheteroarylmethanes
Mahesh Subhashrao Deshmukh,† Ananya Srivastava,‡ Biswajit Das,† and Nidhi Jain*,‡
†Daiichi Sankyo India Pharma Pvt. Ltd., Sector-18, Gurgaon, Haryana 122015, India
‡Department of Chemistry, Indian Institute of Technology, New Delhi 110016, India
S
* Supporting Information
ABSTRACT: An unprecedented zinc triflate catalyzed
selective C-benzylation of anilides and heteroaryl amides
with benzyl chlorides having electron-donating group at para-
position is reported. The protocol offers moderate to high
yield of para-amido substituted diaryl and arylheteroaryl-
methanes, uses cheap and easily available benzyl chlorides as the benzylating agent, catalytic amount of zinc triflate, and takes
place under ambient conditions. Aminodiarylmethane derivatives can be obtained by hydrolysis of the corresponding amides.
The methodology has also been applied for preparing dimethoxydiarylmethanes in good yields, which are the key precursors for
synthesis of phenolic natural products.
N-benzylation, anilides are often used as substrates since they
are less nucleophilic than amines. However, even they yield N-
benzylated product when subjected to base promoted
benzylation with benzyl halides.11 Under acid mediated
conditions employing benzyl alcohols as benzylating agents,
acids such as pTSA12 furnish a mixture of 5-benzylated and
5,N-dibenzylated oxindoles (Figure 2), while with others like
INTRODUCTION
■
Diarylmethanes are important constituents of agrochemicals,
natural products, supramolecular structures, fine and bulk
chemicals.1,2 They are key precursors for the synthesis of
fluorenyl-based electroactive and photoactive oligomers and
polymers.3 Specifically, amido, amino, and methoxy substituted
diaryl- and arylheteroaryl-methane motifs are an integral part of
a number of biologically potent compounds.4 As shown in
Figure 1, they exhibit diverse activities such as prostacyclin
Figure 1. Biologically important substituted diarylmethanes.
receptor antagonist for pain and inflammation, for treatment of
arteriosclerosis and hypercholesterolemia, and nonsteroidal
nuclear receptor inhibitors.5 Therefore, the development of
mild, efficient and economical methods for their synthesis is an
important goal for organic chemists.
Figure 2. Literature procedures for C/N-benzylation of anilides vs our
approach.
The classical approaches toward amine substituted diaryl-
methane synthesis involve addition reaction of aromatic amines
with styrene,6 reduction of diarylketones having an amine
group7 or transition metal assisted cross coupling reactions of
aromatic bromides having an amine group with benzylzinc
reagents.8 An ancient approach uses cheaply available 4,4′-
diaminodiphenylmethane, and involves its selective mono-
acetylation followed by diazotization.9 The diazonium salt is
then replaced by hydroxy group, and alkylated to yield the 4-
amido-4′-methoxydiarylmethanes. While the above methods
suffer from harsh reaction conditions, employing direct
benzylation strategy between aryl amines and benzyl halides
also fails, and instead of producing amine substituted
diarylmethanes, yields the N-benzylated product.10 To prevent
Al-grafted MCM-41, a complex mixture of both N-benzylated
and ortho- and para- C-benzylated products is obtained.12b
Apparently, with the current methods available, it is almost
impossible to perform para-selective C-benzylation of anilides.
As an attempt to lift this limitation, herein, we demonstrate an
exclusive C-benzylation of anilides and heteroaryl amides with
benzyl chlorides using zinc triflate as the catalyst under ambient
conditions. This is the first report showing the use of benzyl
halides as C-benzylating agents under acidic conditions.
Received: July 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01646
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a
RESULTS AND DISCUSSION
Table 1. Optimization Table for C-Benzylation of Anilide
■
The benzylation was discovered accidently during our
endeavors of carrying out copper triflate mediated meta-
selective amidation of pivaloylanilide (1a) using 4-methoxy
benzyl azidoester (2a′) in dioxane at 50 °C (Scheme 1). While
b
catalyst
(equiv)
temp °C
% yield
entry
X
solvent
(time, h) (dibenzylated)
Scheme 1. Cu(OTf)2 Catalyzed Reaction of Pivaloylanilide
with Azido Ester
1
2
3
4
N3CO2 AlCl3, (0.2)
N3CO2 AlCl3, (1.2)
DCE
60 (24)
60 (16)
80 (16)
80 (16)
0
DCE
25
0
Cl
AlCl3, (1.2)
DCE
N3CO2 Cu(OTf)2,
(0.2)
Dioxane
34
5
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cu(OTf)2,
(0.2)
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
CH3CN
THF
80 (16)
80 (16)
80 (16)
80 (16)
80 (16)
RT (16)
RT (16)
RT (24)
RT (24)
RT (24)
RT (24)
RT (24)
RT (24)
RT (24)
RT (24)
RT (24)
RT (24)
RT (24)
RT (24)
28
6
Yb(OTf)3,
(0.2)
57 (26)
44 (40)
48 (37)
53 (32)
69 (5)
65 (5)
84 (5), 0
0
7
Sc(OTf)3,
(0.2)
8
Zn(OTf)2,
(0.2)
9
In(OTf)3,
(0.2)
10
11
12
13
14
15
16
17
18
19
Zn(OTf)2,
(0.2)
we did not get the desired product, an unexpected product was
isolated in 30% yield, and the reaction did not go to completion
even after stirring for 24 h. The spectroscopic characterization
showed the product to be N-[4-(4-methoxybenzyl)phenyl]-2,2-
dimethylpropanamide (3a). Intrigued by this observation, we
checked if there were any previous reports on C-benzylation of
anilides using copper catalyst. Since no precedence to a similar
work was found, and realizing its potential in making molecules
with diaryl methane motif, we decided to explore the reaction
in further details.
Zn(OTf)2,
(0.1)
c
Zn(OTf)2,
(0.1)
N3CO2 Zn(OTf)2,
(0.1)
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Zn(OTf)2,
(0.1)
48 (5)
48 (2)
49 (13)
0
Zn(OTf)2,
(0.1)
Extensive optimization studies were taken up with 1a as the
substrate, and variations in the catalyst, solvent, time and
temperature were done (Table 1). First, to ascertain the role of
copper triflate as a Lewis acid, reaction between 1a and 2a′ was
carried out using the conventional Lewis acid aluminum
trichloride (0.2 equiv) in dichloroethane at 60 °C (entry 1).
The reaction was found to fail completely, and 3a was not seen
even after stirring for 24 h. However, on increasing the catalyst
loading from 0.2 equiv to 1.2 equiv (entry 2), the desired
product was obtained, albeit in low yield (25%). Further, on
changing the benzylating agent from azidoester to 4-
methoxybenzyl chloride (2a), no product was obtained even
at elevated temperatures (80 °C, entry 3). With Cu(OTf)2 as
the catalyst, however, the reaction between 1a and 2a yielded
3a in 28% yield (entry 4). These preliminary experiments
confirmed the potential of Cu(OTf)2 over AlCl3 as a catalyst in
promoting C-benzylation with benzyl chlorides. Motivated by
the results, we next explored several other Lewis acids such as
Yb(OTf)3, Sc(OTf)3, Zn(OTf)2, and In(OTf)3 in dioxane at 80
°C (entry 6−9). With these Lewis acid catalysts, the yield of 3a
was found to increase (44−57%); however, formation of
substantial amount of dibenzylated product was also seen (26−
40%). Since Zn(OTf)2 happened to be the cheapest of all the
triflates examined, it was selected for further studies. Bringing
down the reaction temperature from 80 °C to ambient
conditions resulted in an increase in the yield of monobenzy-
lated product 3a to 69%, and drastically reduced the
dibenzylated product formation (entry 10). Pleased with this
finding, we next monitored the reaction by lowering the
catalytic loading to 10 mol %. Although, this resulted in a slight
drop in the yield of 3a (entry 11), increasing the reaction time
up to 24 h helped in escalating the yield of 3a up to 84% (entry
12). Applying identical reaction conditions on 2a′ in place of 2a
Zn(OTf)2
, (0.1)
DCM
Zn(OTf)2,
(0.1)
DMF
Zn(OTf)2,
(0.1)
DMSO
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
0
Zn(OTf)2,
(0.1)
14 (31)
5
d
20
Zn(OTf)2,
(0.1)
e
21
Zn(OTf)2,
(0.1)
0
f
22
Zn(OTf)2,
(0.1)
64 (15)
63 (14)
g
23
Zn(OTf)2,
(0.1)
24
25
Cl
pTSA (0.2)
pTSA (0.2)
pTSA (0.05)
pTSA (0.2)
Dioxane
Dioxane
CH3NO2
CH3NO2
RT (18)
90 (18)
90 (18)
90 (18)
0
Cl
0
h
26
OH
OH
33
40
h
27
a
1a (1.0 equiv), benzylating reagent (1.2 equiv) and catalyst in solvent.
HPLC yield of 3a. benzyl chloride was used in place of 4-methoxy
benzyl chloride (2a). K3PO4 (1.1 equiv) was used as base. Et3N (1
equiv) was used as base. Acetic acid (2.0 equiv) was used as additive.
Trifluoroacetic acid (2.0 equiv) was used as additive. 1a (1.0 equiv),
4-methoxybenzyl alcohol (1.0 equiv), pTSA in nitromethane.
b
c
d
e
f
g
h
did not give any product (entry 13). Next, to assess the
necessity of methoxy group in this reaction, reaction with
unsubstituted benzyl chloride was carried out. As expected, no
product was seen in this case (entry 12). Screening of solvents
such as acetonitrile, THF, DCM, DMF, DMSO and toluene
was done, and all were found to be inferior to 1,4-dioxane
(entry 14−19). In fact, the reaction was completely inhibited
with coordinating solvents like DMF and DMSO (entries 17
B
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and 18). Addition of bases such as K3PO4 and Et3N was
detrimental to the reaction, and did not yield any product
(entries 20 and 21), which is reasonable since they tend to
quench the acid catalysis by coordinating with zinc ion.
Addition of acids such as acetic acid and TFA, dropped the
yield of 3a due to significant formation of disubstituted
products (entries 22 and 23). Replacing Zn(OTf)2 with pTSA
as the acid catalyst, however, failed to yield the desired product
(entries 24 and 25). The literature conditions12 employing 4-
methoxybenzyl alcohol and pTSA as the catalyst, when applied
to 1a as the substrate, yielded the desired product 3a in only
33% yield along with unreacted 1a (entry 26). The yield did
not improve much on increasing the catalyst loading from 5
mol % to 20 mol % (entry 27), demonstrating the higher
efficiency of Zn(OTf)2 over pTSA in catalyzing the reaction.
The optimized conditions for obtaining the monosubstituted
product were found to be with methoxy substituted benzyl
chloride, and 10 mol % Zn(OTf)2 at room temperature for 24
h. To explore the versatility of this method, the substrate scope
was tested by using various amides and benzylating agents
(Table 2). Under the optimized reaction condition, changing
the amide from N-pivaloyl (1a) to N-acetyl (1b) resulted in a
drop in the yield of diarylmethane amide from 76% (3a) to
53% (3b). However, with carbamate in place of amide, as in
ethyl phenyl carbamate (1c), the highest yield of benzylated
product (3c, 84%) was isolated. With ortho-methyl and ethyl
derivatives of pivaloylamide, products 3d and 3e were isolated
in similar yields as with the unsubstituted counterpart 3a.
Presence of electron withdrawing ester group at ortho-
position to the amide resulted in slightly lower yield of the
corresponding diarylmethane derivative (3f). In fact, with very
strong electron withdrawing substituent like nitro, no trace of
the desired product 3g was seen even on heating the contents
at 100 °C for 24 h, suggesting that highly electron deficient
arenes are not suitable for this reaction. In general, it was found
that ethyl phenyl carbamate gave higher product yields (3c, 3h,
3i) compared to those obtained from the corresponding
pivaloyl amide (3a, 3f, 3j) as the starting substrate, again
indicative of electron rich arenes to facilitate the reaction. After
evaluating the effect of ortho-substituent on reaction yield, we
shifted our focus toward the meta-position, which is closest to
the reaction center. Lower yields were obtained with
substituents at the meta-position (3j, 3k) compared to those
occupying ortho-position (3d, 3f). While the effect was less
pronounced with small substituents like methyl (3d and 3j),
the disparity increased with bulkier ester group (3f and 3k).
The significant drop in reaction yield is governed both by the
steric and electronic effects of ester group, which not only
reduces the electron density at para-position of anilide but also
makes the approach of incoming electrophile difficult. The
reaction of 1a with 4-trifluoromethoxybenzyl chloride (2e) was
attempted but failed to yield the desired product 3s, suggesting
the inability of trifluoromethoxy group in assisting the
departure of chloride, thus inhibiting the formation of the
reactive intermediate species discussed later.
Table 2. Substrate Scope with Anilide Derivatives and
Benzyl Chlorides
a
During optimization studies it became clear that para-
methoxy group on benzyl chloride was necessary for facilitating
the reaction (Table 1, entry 3). Going further, reactivity pattern
with respect to other substituents on benzyl chloride was
examined. Reaction was found to work well with other para-
substituted benzylating reagents such as 4-methylsulfanylbenzyl
chloride (2b), 3-fluoro-4-methoxybenzyl chloride (2c) and 5-
chloro-6-(chloromethyl)-1,3-benzodioxole (2d), and gave the
a
1 (1.0 equiv), 2 (1.2 equiv), and Zn(OTf)2 (10 mol %) in 1,4-
dioxane (2.0 mL) were stirred at room temperature for 24 h. % Yields
are isolated yields. Reaction was performed at 100 °C for 24 h.
b
C
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a
desired products (3l-3r) in moderate yields. The lower product
yield of 3l (64%) compared to 3a (76%) is due to weaker
electron donation ability of sulfur compared to oxygen.
Interestingly, a comparable yield of 3m was obtained, even
on introduction of electron withdrawing fluoro substituent
ortho- to the methoxy. Further, the yield of the product, 3n
obtained with 2d was found comparable to that of 3l obtained
with 2b. This might be due to compensation of steric and
electron withdrawing effect of chloro substituent by additional
alkoxy subtituent at meta-position in 2d.
Table 4. C-Benzylation of Anisole Derivatives
The reaction was extended to heterocyclic substrates (4)
such as 2-oxoindole, benzoxazolone, and benzothiazolone as
well (Table 3). A C-5 alkylation of oxoindole, and a C-6
a
Table 3. Substrate Scope with Heterocyclic Derivatives
a
6 (1.0 equiv), 2 (1.2 equiv), and Zn(OTf)2 (10 mol %) in 1,4-
dioxane (2.0 mL) were stirred at room temperature for 24 h. % Yields
b
are isolated yields. 4-Methoxybenzyl chloride (4.0 equiv) was used.
presence of Zn(OTf)2 (10 mol %) at room temperature yielded
dimethoxydiarylmethane (7a) in 71% yield. With ortho-chloro
and ortho-bromo substituted anisole derivatives, slightly lower
yield of products (7b, 7c) were obtained. On increasing the
amount of 2a to 4 equiv, dibenzylation took place at ortho- and
para-positions of anisole and 7d was obtained in 59% yield.
The ability to control mono- and dibenzylation adds to the
synthetic utility of this protocol which has been illustrated by
demethylation of 7d to yield the naturally occurring 2,4-bis(4-
hydroxybenzyl)phenol. The methodology provides a facile
access to these molecules, as the earlier reports on their
synthesis involve either the use of benzyl alcohols with
phosphorus pentoxide on solid supports giving low ortho-para
selectivity, or base promoted reaction of 4-methoxybenzyl
halides in excess anisole,14 or transition metal catalyzed cross
couplings using benzylborane, aryltrialkoxysilane and aryl-
lithium as coupling partners.15 This natural product has
recently been reported to be an inhibitor of heat shock
transcription factor 1, and also enhances the effectiveness of
conventional anticancer agents such as cisplatin and placlitax-
el.16
To understand the mechanism of reaction, control experi-
ments were carried out. Addition of TEMPO (1 equiv) to the
reaction of 1a and 2a did not quench the reaction, and the
desired product 3a was isolated suggesting that the reaction did
not follow a free radical path. It was evident that the electron
donating para-substituent in benzyl chloride played a crucial
role in this reaction, as no product was formed in its absence
(entry 12, Table 1), or its replacement with poor electron
donor like trifluoromethoxy group. Based on these exper-
imental findings and literature information, two reaction
pathways could be postulated as shown in Scheme 2. In one
probable scenario, 2a gets converted to reactive intermediate,
methyl (4-methylidenecyclohexa-2,5-dien-1-ylidene) oxonium
(8),17 which undergoes electrophilic aromatic substitution
reaction with anilide 1a at the para-position and yields 3a.
Alternatively, it gets converted to 4-methoxybenzyl triflate (8′),
a
4 (1.0 equiv), 2 (1.2 equiv), and Zn(OTf)2 (10 mol %) in 1,4-
dioxane (2.0 mL) were stirred at 40 °C for 24 h. % Yields are isolated
yields.
alkylation in case of benzoxazolone and benzothiazolone took
place to yield the substituted aryl-heteroarylmethanes (5a−5f)
in moderate yields, with an optimal reaction temperature of 40
°C. The only preceding report on a one-step C-5 alkylation of
oxindole employed benzyl alcohol and pTSA at 90 °C yielding
a mixture of 5a and N-benzylated 5a.12 Hence the above result,
furnishing an exclusive C-5 alkylation in one step under acid
catalysis is a useful method. Benzylation of 1,3-dimethyluracil
gave 5-(4-methoxybenzyl)-1,3-dimethylpyrimidine-2,4-
(1H,3H)-dione (5g) in 72% yield. These 5-benzyl uracil
derivatives are biologically important as antiviral agents, and for
inhibiting the mammalian enzyme uridine phosphorylase
responsible for degradation of floxuridine, a known anticancer
drug.13
As shown in Table 4, the reaction conditions were further
explored to test if benzylation of anisole and its derivatives
could as well be mediated by Zn(OTf)2. We were delighted to
find that the reaction of anisole (6a) with 2a (1.2 equiv) in the
D
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Scheme 2. Plausible Mechanism
CONCLUSIONS
■
Through this work, we demonstrate a facile and versatile
method for para-selective C-benzylation of anilides mediated
by Zn(OTf)2 under ambient conditions. The protocol is quite
robust, uses catalytic amount of inexpensive Zn(OTf)2, easily
available methoxysubstituted benzyl chlorides as benzylating
agents, and provides moderate to high yield of amido
substituted diaryl and arylheteroaryl methane derivatives. The
reaction conditions are favorable for regioselective mono- and
dibenzylation of arylmethyl ethers as well. Benzyltriflate
generated in situ is believed to be the reactive intermediate
for effecting mild benzylation. The strategy offers significant
synthetic utility, as hydrolysis of the amide provides an easy
access to para-substituted aminodiarylmethane derivatives.
EXPERIMENTAL SECTION
■
1
General Experimental Details. H NMR and 13C NMR spectra
were recorded on 400 MHz spectrometer. Chemical shifts (δ) are
reported in parts per million downfield from TMS as an internal
standard or residual solvent. All organic solvents and reagents were
used as received from commercial sources. The starting materials such
as substituted 2,2-dimethyl-N-phenylpropanamides,18 and N-phenyl-
acetamide19 were prepared using the literature reported procedures
whereas substituted ethyl phenyl carbamates were synthesized using
modified procedure (mentioned below). The reported yields are the
actual isolated yields of pure materials. Flash chromatography was
performed on prepacked silica gel columns. Achiral HPLC analysis was
performed on HPLC system using C18 HPLC column (5.0 μm, 4.6
mm × 250 mm) and acetonitrile and formic acid (0.1% v/v in water)
as gradient eluting solvent system.
Representative Procedure for Preparation of Ethyl Phenyl
Carbamate (1c). Ethyl chloroformate (61 μL, 6.45 mmol) was slowly
added to a stirred solution of aniline (500 mg, 5.38 mmol) and
triethylamine (1.1 mL, 8.07 mmol) in dry DCM (20 mL) at 0 °C. The
resulting reaction mixture was stirred at 10 °C for 2 h. After
completion of reaction, it was diluted with DCM (80 mL) and washed
with water (50 mL), 6N aq. HCl (50 mL) and brine (50 mL). The
organic layer was dried over anhydrous Na2SO4 and the solvent was
removed under a vacuum to get crude product contaminated with
N,N′-diphenyl urea. It was then stirred in hexanes (50 mL) and
filtered. The filtrate was concentrated under reduced pressure to get
the pure title product. The ester and methyl substituted carbamates
(1h and 1i) were prepared following above-mentioned procedure.
Representative Procedure for Preparation of Amido Substituted
Diarylmethanes (3a−3s). 2a (46 μL, 0.339 mmol) was added to a
which thereafter undergoes para-benzylation to yield 3a. To
identify the active intermediate, time-dependent UV−vis
analysis of the reaction mixture was performed (Supporting
Information). Addition of Zn(OTf)2 to 2a in dioxane showed
appearance of a new peak at 292 nm indicating the formation of
a new species, believed to be either 8 or 8′. In order to confirm
the reactive species, a time-dependent 1H NMR study was done
(Figure 3). 1H NMR of 2a in CD3CN showed peaks at 7.4−6.9,
4.6, and 3.8 δ corresponding to aromatic, benzylic and methoxy
protons, respectively. Addition of Zn(OTf)2 (10 mol %) to
above solution showed appearance of additional peaks in all the
three regions suggesting formation of multiple species after 10
min. The benzylic region showed two new signals at 4.54 and
4.95 δ corresponding to protons of 4-methoxybenzyl alcohol
and the more deshielded 4-methoxybenzyl triflate, respectively.
On addition of 1a to this solution, the 1H NMR recorded after
1 min showed a decrease in the intensity of peak at 4.95 δ
suggesting that 4-methoxybenzyl triflate which was generated as
the reactive species during the reaction was getting consumed
on addition of 1a. Increasing the reaction time to 10 min
resulted in further decrease in the intensity of the peak at 4.95 δ
due to its conversion to the product 3a. Based on these
observations, we believe that the reaction goes via formation of
8′ as the active intermediate.
Figure 3. Time dependent overlay of 1H NMR spectra of reaction of 1a, 2a and Zn(OTf)2 in CD3CN. 4-Methoxybenzyl chloride and 4-
methoxybenzyl alcohol have been included for comparison.
E
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stirred solution of 1a (50 mg, 0.282 mmol) and Zn(OTf)2 (10 mg,
0.028 mmol) in dry 1,4-dioxane (2.0 mL) at room temperature. The
resulting reaction mixture was stirred at same temperature for 24 h.
After completion of reaction, it was diluted with EtOAc (50 mL) and
washed with saturated aqueous NaHCO3 solution (25 mL) and brine
(25 mL). Organic layer was dried over anhydrous Na2SO4 and the
solvent was removed under a vacuum to get crude compound, which
was purified by column chromatography using EtOAc:hexanes as
eluting medium.
7.17 (br. s., 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H),
6.97 (s, 1H), 6.81 (d, J = 8.8 Hz, 2H), 3.85 (s, 2H), 3.78 (s, 3H), 2.20
(s, 3H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 176.4,
157.9, 138.2, 133.8, 133.3, 130.8, 129.8, 129.0, 127.2, 123.0, 113.9,
55.3, 40.5, 39.7, 27.7, 17.7. HRMS-ESI exact mass calcd. for
+
C20H25NNaO2 [M + Na]+ requires m/z 334.1777, found m/z
334.1778.
N-[2-Ethyl-4-(4-methoxybenzyl)phenyl]-2,2-dimethylpropana-
1
mide (3e). Light yellow liquid; 73% yield (58 mg); H NMR (400
Representative Procedure for Preparation of Aryl-heteroaryl-
methanes (5a−5g). 2a (61 μL, 0.451 mmol) was added to a stirred
solution of 1,3-dihydro-2H-indol-2-one (50 mg, 0.376 mmol) and
Zn(OTf)2 (10 mg, 0.038 mmol) in dry 1,4-dioxane (2.0 mL) at room
temperature. The resulting reaction mixture was stirred at 40 °C for 24
h. After completion of reaction, it was diluted with EtOAc (50 mL)
and washed with saturated aqueous NaHCO3 solution (25 mL) and
brine (25 mL). Organic layer was dried over anhydrous Na2SO4 and
the solvent was removed under a vacuum to get crude compound,
which was purified by column chromatography using EtOAc:hexanes
as eluting medium.
Representative Procedure for Preparation of 4,4′-Dimethoxy-
diarylmethanes (7a−7c). 2a (75 μL, 0.556 mmol) was added to a
stirred solution of anisole (51 μL, 0.463 mmol) and Zn(OTf)2 (17 mg,
0.046 mmol) in dry 1,4-dioxane (2.0 mL) at room temperature. The
resulting reaction mixture was stirred at room temperature for 24 h. It
was then diluted with EtOAc (50 mL) and washed with saturated
aqueous NaHCO3 solution (25 mL) and brine. Organic layer was
dried over anhydrous Na2SO4 and the solvent was removed under a
vacuum to get crude compound, which was purified by column
chromatography using EtOAc:hexanes as eluting medium.
MHz, CDCl3) δ (ppm) 7.74 (d, J = 8.0 Hz, 1H), 7.23 (br. s., 1H), 7.08
(d, J = 8.4 Hz, 2H), 7.03−7.01 (m, 1H), 6.99 (d, J = 1.6 Hz, 1H), 6.81
(d, J = 8.8 Hz, 2H), 3.87 (s, 2H), 3.78 (s, 3H), 2.54 (q, J = 7.6 Hz,
2H), 1.32 (s, 9H), 1.21 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 176.5, 157.9, 138.4, 134.8, 133.3, 133.2, 129.8, 129.0,
127.2, 123.6, 113.9, 55.3, 40.6, 39.7, 27.7, 24.5, 14.0. HRMS-ESI exact
+
mass calcd. for C21H27NNaO2 [M + Na]+ requires m/z 348.1931,
found m/z 348.1934.
Ethyl 2-[(2,2-dimethylpropanoyl)amino]-5-(4-methoxybenzyl)-
benzoate (3f). White solid; 68% yield (50 mg); 1H NMR (400
MHz, CDCl3) δ (ppm) 11.27 (br. s., 1H), 8.68 (d, J = 8.5 Hz, 1H),
7.87 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 2.4, 8.7 Hz, 1H), 7.07 (d, J = 8.8
Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.37 (q, J = 7.0 Hz, 2H), 3.90 (s,
2H), 3.78 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 177.8, 168.4, 158.1, 140.2, 135.3, 135.1,
132.9, 130.8, 129.7, 120.6, 115.4, 113.9, 61.3, 55.3, 40.3, 40.2, 27.6,
+
14.2. HRMS-ESI exact mass calcd. For C22H27NNaO4 [M + Na]+
requires m/z 392.1835, found m/z 392.1832.
N-[4-(4-Methoxybenzyl)-2-nitrophenyl]-2,2-dimethylpropana-
mide (3g). Compound was not formed even in traces, and could not
be characterized.
Procedure for Preparation of 1-Methoxy-2,4-bis(4-
methoxybenzyl)benzene (7d). 2a (75 μL, 3.704 mmol) was added
to a stirred solution of anisole (101 μL, 0.926 mmol) and Zn(OTf)2
(34 mg, 0.093 mmol) in dry 1,4-dioxane (3.0 mL) at room
temperature. The resulting reaction mixture was stirred at room
temperature for 24 h. After completion of reaction, it was diluted with
EtOAc (50 mL) and washed with saturated aqueous NaHCO3 solution
(25 mL) and brine (25 mL). Organic layer was dried over anhydrous
Na2SO4 and the solvent was removed under a vacuum to get crude
compound, which was purified by column chromatography using
EtOAc:hexanes as eluting medium.
Characterization Data. N-[4-(4-Methoxybenzyl)phenyl]-2,2-di-
methylpropanamide (3a). White solid; 76% yield (64 mg); melting
point 129 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.43 (d, J = 8.5
Hz, 2H), 7.28 (br. s., 1H), 7.12 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.7 Hz,
2H), 6.81 (d, J = 8.7 Hz, 2H), 3.88 (s, 2H), 3.77 (s, 4H), 1.30 (s, 9H);
13C NMR (100 MHz, CDCl3) δ (ppm) 176.5, 157.9, 137.5, 136.0,
Ethyl 2-[(ethoxycarbonyl)amino]-5-(4-methoxybenzyl)benzoate
(3h). Colorless liquid; 75% yield (57 mg); 1H NMR (400 MHz,
CDCl3) δ (ppm) 10.40 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 7.84 (d, J =
2.3 Hz, 1H), 7.33 (dd, J = 2.3, 8.6 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H),
6.83 (d, J = 8.7 Hz, 2H), 4.36 (q, J = 7.2 Hz, 2H), 4.21 (q, J = 7.2 Hz,
2H), 3.89 (s, 2H), 3.78 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H), 1.31 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 168.1, 158.1,
153.8, 140.1, 135.0, 134.5, 132.9, 130.8, 129.7, 119.1, 114.8, 114.0,
61.3, 61.1, 55.3, 40.1, 14.5, 14.2. HRMS-ESI exact mass calcd. for
+
C20H23NNaO5 [M + Na]+ requires m/z 380.1459, found m/z
380.1468.
Ethyl [4-(4-methoxybenzyl)-3-methylphenyl]carbamate (3i). Col-
1
orless liquid; 71% yield (59 mg); H NMR (400 MHz, CDCl3) δ
(ppm) 7.19 (s, 1H), 7.13 (dd, J = 2.5, 8.3 Hz, 1H), 7.01 (d, J = 8.3 Hz,
3H), 6.80 (d, J = 8.6 Hz, 2H), 6.50 (br. s., 1H), 4.21 (q, J = 7.1 Hz,
2H), 3.86 (s, 2H), 3.77 (s, 3H), 2.20 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 157.9, 153.7, 137.4, 136.1,
134.6, 132.5, 130.4, 129.6, 120.7, 116.4, 113.8, 61.1, 55.2, 37.9, 19.7,
133.3, 129.8, 129.3, 120.1, 113.9, 55.3, 40.4, 39.5, 27.6. HRMS-ESI
+
exact mass calcd. for C19H23NNaO2 [M + Na]+ requires m/z
+
14.6. HRMS-ESI exact mass calcd. for C18H21NNaO3 [M + Na]+
320.1629, found m/z 320.1621.
requires m/z 322.1424, found m/z 322.1414.
N-[4-(4-Methoxybenzyl)phenyl]acetamide (3b). White solid; 53%
yield (50 mg); melting point 116 °C; 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.39 (d, J = 8.4 Hz, 2H), 7.29 (br. s., 1H), 7.12−6.06 (m, 4H),
6.83−6.80 (d, J = 8.8 Hz, 2H), 3.88 (s, 2H), 3.78 (s, 3H), 2.14 (s, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 167.2, 156.9, 136.6, 134.8,
132.2, 128.8, 128.3, 119.1, 112.9, 54.2, 39.4, 23.5. HRMS-ESI exact
N-[4-(4-Methoxybenzyl)-3-methylphenyl]-2,2-dimethylpropana-
mide (3j). White solid; 65% yield (53 mg); melting point 109 °C; 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.39 (d, J = 2.8 Hz, 1H), 7.29−
7.24 (m, 1H), 7.04 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.80
(d, J = 8.5 Hz, 2H), 3.88 (s, 2H), 3.77 (s, 3H), 2.20 (s, 3H), 1.31 (s,
9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 176.5, 157.8, 137.4,
136.3, 135.3, 132.5, 130.3, 129.5, 121.8, 117.5, 113.8, 55.3, 39.6, 38.0,
+
mass calcd. for C16H17NNaO2 [M + Na]+ requires m/z 278.1151,
found m/z 278.1153.
+
27.7, 19.7. HRMS-ESI exact mass calcd. for C20H26NO2 [M + H]+
Ethyl [4-(4-methoxybenzyl)phenyl]carbamate (3c). Orange solid;
84% yield (72 mg); melting point 72 °C; 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.28 (d, J = 8.0 Hz, 2H), 7.09 (t, J = 8.4 Hz, 4H),
6.82 (d, J = 8.4 Hz, 2H), 6.56 (br. s., 1H), 4.21 (q, J = 7.2 Hz, 2H),
3.87 (s, 2H), 3.78 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 158.0, 153.7, 136.7, 135.9, 133.3, 129.8, 129.4,
118.9, 113.9, 61.2, 55.3, 40.3, 14.6. HRMS-ESI exact mass calcd. for
requires m/z 312.1958, found m/z 312.1958.
Methyl 5-[(2,2-dimethylpropanoyl)amino]-2-(4-methoxybenzyl)-
benzoate (3k). White solid; 58% yield (44 mg); melting point 119 °C;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.98 (d, J = 2.5 Hz, 1H), 7.70
(dd, J = 2.5, 8.3 Hz, 1H), 7.35 (br. s., 1H), 7.17 (d, J = 8.5 Hz, 1H),
7.04 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 4.26 (s, 2H), 3.82
(s, 3H), 3.77 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 176.7, 167.6, 157.8, 138.5, 136.2, 133.1, 132.1, 130.2, 129.8,
123.5, 121.9, 113.7, 55.2, 52.1, 39.6, 38.2, 27.6. HRMS-ESI exact mass
+
C17H19NNaO3 [M + Na]+ requires m/z 308.1262, found m/z
308.1257.
N-[4-(4-Methoxybenzyl)-2-methylphenyl]-2,2-dimethylpropana-
+
calcd. for C21H25NNaO4 [M + Na]+ requires m/z 378.1683, found
mide (3d). Light yellow solid; 72% yield (59 mg); melting point 104
1
°C; H NMR (400 MHz, CDCl3) δ (ppm) 7.73 (d, J = 8.0 Hz, 1H),
m/z 378.1675.
F
DOI: 10.1021/acs.joc.5b01646
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2,2-Dimethyl-N-{4-[4-(methylsulfanyl)benzyl]phenyl}-
5-(4-Methoxybenzyl)-1,3-dihydro-2H-indol-2-one (5a). White
solid; 64% yield (61 mg); melting point 167 °C; 1H NMR (400
MHz, DMSO-d6) δ (ppm) 10.25 (s, 1H), 7.11 (d, J = 8.8 Hz, 2H),
7.03−6.96 (m, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 7.8 Hz, 1H),
3.79 (s, 2H), 3.70 (s, 3H), 3.40 (s, 2H); 13C NMR (100 MHz,
DMSO) δ (ppm) 176.8, 158.0, 142.1, 135.1, 134.2, 130.0, 127.9, 126.
5, 125.1, 114.3, 109.3, 55.5, 40.4, 36.2. HRMS-ESI exact mass calcd. for
propanamide (3l). White solid; 64% yield (57 mg); melting point 120
1
°C; H NMR (400 MHz, CDCl3) δ (ppm) 7.44 (d, J = 8.4 Hz, 2H),
7.28 (br. s., 1H), 7.18 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H),
7.10−7.06 (d, J = 8.4 Hz, 2H), 3.90 (s, 2H), 2.45 (s, 3H), 1.30 (s, 9H);
13C NMR (100 MHz, CDCl3) δ (ppm) 176.5, 138.3, 136.9, 136.2,
135.7, 129.4, 129.4, 127.2, 120.2, 40.7, 39.6, 27.6, 16.3. HRMS-ESI
exact mass calcd. for C19H23NNaOS+ [M + Na]+ requires m/z
336.1388, found m/z 336.1392.
N-[4-(3-Fluoro-4-methoxybenzyl)phenyl]-2,2-dimethylpropana-
mide (3m). White solid; 74% yield (66 mg); melting point 125 °C; 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.45 (d, J = 8.5 Hz, 2H), 7.28 (bs,
1H), 7.12 (d, J = 8.5 Hz, 2H), 6.88−6.84 (m, 3H), 3.86 (d, J = 1.0 Hz,
2H), 3.85 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 176.5, 151.2, 146.0, 145.9, 136.7, 136.3, 134.4, 134.3, 129.3,
124.3, 124.2, 120.2, 116.6, 116.4, 113.5, 113.5, 56.4, 40.3, 39.6, 27.6.
HRMS-ESI exact mass calcd. for C19H22FNNaO2+ [M + Na]+ requires
m/z 338.1529, found m/z 338.1527.
+
C16H15NO2 [M + H]+ requires m/z 254.1176, found m/z 254.1177.
6-(4-Methoxybenzyl)-1,3-benzoxazol-2(3H)-one (5b). White solid;
74% yield (70 mg); melting point 159 °C; 1H NMR (400 MHz,
DMSO-d6) δ (ppm) 11.49 (br. s., 1H), 7.17−7.10 (m, 3H), 6.98 (d, J
= 1.0 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.87 (s, 2H), 3.71 (s, 3H); 13C
NMR (100 MHz, DMSO) δ (ppm) 157.5, 154.4, 143.4, 135.9, 133.2,
129.5, 128.2, 123.7, 113.8, 109.5, 109.4, 54.9. HRMS-ESI exact mass
+
calcd. for C15H13NNaO3 [M + Na]+ requires m/z 278.0787, found
m/z 278.0787.
6-(4-Methoxybenzyl)-1,3-benzothiazol-2(3H)-one (5c). White
solid; 72% yield (65 mg); melting point 173 °C; 1H NMR (400
MHz, DMSO-d6) δ (ppm) 11.78 (br. s., 1H), 7.39 (d, J = 1.8 Hz, 1H),
7.16−7.08 (m, 3H), 7.04−7.00 (m, 1H), 6.84 (d, J = 8.5 Hz, 2H), 3.85
(s, 2H), 3.70 (s, 3H); 13C NMR (100 MHz, DMSO) δ (ppm) 170.4,
158.1, 136.9, 134.9, 133.7, 130.1, 127.3, 123.9, 122.9, 114.3, 111.9,
55.5. HRMS-ESI exact mass calcd. for C15H13NNaO2S+ [M + Na]+
requires m/z 294.0543, found m/z 294.0549.
N-{4-[(6-Chloro-1,3-benzodioxol-5-yl)methyl]phenyl}-2,2-dime-
thylpropanamide (3n). White solid; 70% yield (68 mg); melting point
1
144 °C; H NMR (400 MHz, CDCl3) δ (ppm) 7.45 (d, J = 8.5 Hz,
2H), 7.28 (br. s., 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.84 (s, 1H), 6.58 (s,
1H), 5.93 (s, 2H), 3.95 (s, 2H), 1.31 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 176.5, 146.7, 146.7, 136.3, 135.6, 131.7, 129.3, 125.5,
120.1, 110.3, 109.8, 101.6, 39.6, 38.4, 27.6. HRMS-ESI exact mass
calcd. for C19H20ClNNaO3+ [M + Na]+ requires m/z 368.1030, found
m/z 368.1023.
5-[(6-Chloro-1,3-benzodioxol-5-yl)methyl]-1,3-dihydro-2H-indol-
2-one (5d). Brown solid; 55% yield (62 mg); melting point 230 °C;
1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.30 (s, 1H), 7.05 (s, 1H),
N-{4-[(6-Chloro-1,3-benzodioxol-5-yl)methyl]-2-ethylphenyl}-2,2-
dimethylpropanamide (3o). White solid; 75% yield (68 mg); melting
point 134 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.77 (d, J = 8.6
Hz, 1H), 7.25 (br. s., 1H), 7.04−6.99 (m, 2H), 6.84 (s, 1H), 6.58 (s,
1H), 5.93 (s, 2H), 3.94 (s, 2H), 2.56 (q, J = 7.6 Hz, 2H), 1.33 (s, 9H),
1.22 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 176.5,
146.7, 146.6, 136.5, 134.8, 133.5, 131.8, 129.0, 127.2, 125.4, 123.5,
110.3, 109.8, 101.6, 39.7, 38.5, 27.7, 24.5, 14.0. HRMS-ESI exact mass
calcd. for C21H24ClNNaO3+ [M + Na]+ requires m/z 396.1333, found
m/z 396.1336.
7.03−6.97 (m, 2H), 6.92 (s, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.04 (s,
2H), 3.88 (s, 2H), 3.42 (s, 2H); 13C NMR (100 MHz, DMSO) δ
(ppm) 176.3, 146.6, 146.5, 141.9, 132.5, 131.9, 127.4, 126.0, 124.4,
124.2, 110.5, 109.4, 108.8, 101.8, 37.7, 35.7. HRMS-ESI exact mass
calcd. for C16H12ClNNaO3+ [M + Na]+ requires m/z 324.0410, found
m/z 324.0398.
6-[(6-Chloro-1,3-benzodioxol-5-yl)methyl]-1,3-benzoxazol-2(3H)-
1
one (5e). White solid; 59% yield (66 mg); melting point 196 °C; H
NMR (400 MHz, DMSO-d6) δ (ppm) 11.54 (bs, 1H), 7.13 (d, J = 1.3
Hz, 1H), 7.06 (s, 1H), 7.02−6.95 (m, 3H), 6.04 (s, 2H), 3.96 (s, 2H);
13C NMR (100 MHz, DMSO) δ (ppm) 154.4, 146.6, 143.4, 133.7,
131.4, 128.5, 124.2, 123.6, 110.5, 109.5, 109.4, 101.8, 37.8. HRMS-ESI
Ethyl 5-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-2-[(2,2-
dimethylpropanoyl)amino] benzoate (3p). Colorless liquid; 67%
1
yield (56 mg); H NMR (400 MHz, CDCl3) δ (ppm) 11.29 (br. s.,
+
exact mass calcd. for C15H10ClNNaO4 [M + Na]+ requires m/z
1H), 8.69 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.33 (dd, J =
2.4, 8.7 Hz, 1H), 6.85 (s, 1H), 6.56 (s, 1H), 5.94 (s, 2H), 4.38 (q, J =
7.2 Hz, 2H), 3.97 (s, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.34 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 177.8, 168.3, 146.8, 140.4, 135.0,
133.5, 131.3, 130.9, 125.5, 120.6, 115.4, 110.2, 109.9, 101.7, 61.4, 40.3,
326.0191, found m/z 326.0190.
6-[(6-Chloro-1,3-benzodioxol-5-yl)methyl]-1,3-benzothiazol-
2(3H)-one (5f). White solid; 59% yield (62 mg); melting point 234 °C;
1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.81 (br s, 1H), 7.38 (d, J
= 1.8 Hz, 1H), 7.14−7.08 (m, 1H), 7.07−7.00 (m, 2H), 6.96 (s, 1H),
6.04 (s, 2H), 3.94 (s, 2H); 13C NMR (100 MHz, DMSO) δ (ppm)
170.4, 147.2, 147.1, 135.1, 134.8, 131.8, 127.2, 124.8, 123.9, 122.8,
111.9, 111.1, 110.0, 102.3, 38.2. For C15H11ClNO3S+ [M + H]+
requires m/z 320.0145, found m/z 320.0142.
+
38.3, 27.6, 14.2. HRMS-ESI exact mass calcd. for C22H24ClNNaO5
[M + Na]+ requires m/z 440.1246, found m/z 440.1235.
N-{4-[(6-Chloro-1,3-benzodioxol-5-yl)methyl]-3-methylphenyl}-
2,2-dimethylpropanamide (3q). White solid; 65% yield (61 mg);
melting point 129 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.44 (d,
J = 2.8 Hz, 1H), 7.29−7.24 (m, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.86 (s,
1H), 6.34 (s, 1H), 5.91 (s, 2H), 3.91 (s, 2H), 2.20 (s, 3H), 1.31 (s,
9H); 13C NMR (100 MHz, CDCl3) δ (ppm) 176.5, 146.8, 146.5,
137.6, 136.6, 133.6, 131.1, 130.1, 125.5, 121.9, 117.6, 109.7, 109.7,
101.6, 39.6, 36.0, 27.6, 19.6. HRMS-ESI exact mass calcd. for
5-(4-Methoxybenzyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
(5g). White solid; 72% yield (67 mg); melting point 80 °C; 1H NMR
(400 MHz, CDCl3) δ (ppm) 7.15 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6
Hz, 2H), 6.69 (s, 1H), 3.79 (s, 3H), 3.60 (s, 2H), 3.36 (s, 3H), 3.31 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 162.5, 157.3, 150.7,
138.7, 129.2, 129.1, 113.2, 113.1, 54.2, 35.9, 31.3, 27.0. HRMS-ESI
+
C20H22ClNNaO3 [M + Na]+ requires m/z 382.1179, found m/z
+
exact mass calcd. for C14H16N2O3 [M + H]+ requires m/z 261.1234,
382.1180.
found m/z 261.1235.
Methyl 2-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-5-[(2,2-
dimethylpropanoyl)amino]benzoate (3r). White solid; 60% yield
(51 mg); melting point 97 °C; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.06 (d, J = 2.5 Hz, 1H), 7.71 (dd, J = 2.5, 8.5 Hz, 1H), 7.39 (d, J = 1.3
Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.85 (s, 1H), 6.40 (s, 1H), 5.92 (s,
2H), 4.32 (s, 2H), 3.84 (s, 3H), 1.32 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 176.7, 167.4, 146.7, 146.5, 136.6, 136.5, 131.7, 131.7,
130.2, 125.5, 123.7, 122.0, 110.0, 109.7, 101.6, 52.1, 39.6, 36.6, 27.7.
HRMS-ESI exact mass calcd. for C21H21ClNO5+ [M + H]+ requires m/
z 404.1259, found m/z 404.1272.
1,1′-Methanediylbis(4-methoxybenzene) (7a). White solid; 71%
1
yield (75 mg); melting point 53 °C; H NMR (400 MHz, CDCl3) δ
(ppm) 7.09 (d, J = 8.6 Hz, 4H), 6.82 (d, J = 8.8 Hz, 4H), 3.86 (s, 2H),
3.78 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 157.9, 133.7,
+
129.7, 113.9, 55.3, 40.1. HRMS-ESI exact mass calcd. for C15H16NaO2
[M + Na]+ requires m/z 251.1042, found m/z 251.1042.
2-Chloro-1-methoxy-4-(4-methoxybenzyl)benzene (7b). White
1
solid; 57% yield (53 mg); H NMR (400 MHz, CDCl3) δ (ppm)
7.17 (d, J = 2.3 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.01 (dd, J = 2.3, 8.3
Hz, 1H), 6.85−6.81 (m, 3H), 3.86 (s, 3H), 3.83 (s, 2H), 3.78 (s, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 158.1, 153.3, 134.9, 132.9,
130.5, 129.8, 127.9, 122.3, 114.0, 112.1, 56.2, 55.3, 39.9. HRMS-ESI
2,2-dimethyl-N-{4-[4-(trifluoromethoxy)benzyl]phenyl}-
propanamide (3s). Compound was not formed even in traces, and
could not be characterized.
G
DOI: 10.1021/acs.joc.5b01646
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
exact mass calcd. for C15H15ClO2+ [M]+ requires m/z 262.0755, found
m/z 262.0760.
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2-Bromo-1-methoxy-4-(4-methoxybenzyl)benzene (7c). Colorless
liquid; 62% yield (51 mg); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.35
(d, J = 2.3 Hz, 1H), 7.10−7.03 (m, 3H), 6.85−6.78 (m, 3H), 3.86 (s,
3H), 3.83 (s, 2H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 157.0, 153.1, 134.3, 132.5, 131.8, 128.7, 127.6, 112.9, 110.9,
110.5, 55.24, 54.2, 38.7. HRMS-ESI exact mass calcd. for
+
C15H15BrNaO2 [M + Na]+ requires m/z 329.0148, found m/z
329.0147.
1-Methoxy-2,4-bis(4-methoxybenzyl)benzene (7d). Colorless
1
liquid; 59% yield (190 mg); H NMR (400 MHz, CDCl3) δ (ppm)
7.10 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.95 (dd, J = 2.4, 8.2
Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.82−6.78 (m, 4H), 6.76 (d, J = 8.3
Hz, 1H), 3.86 (s, 2H), 3.81 (s, 2H), 3.79−3.74 (m, 9H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 157.8, 157.7, 155.7, 133.8, 133.4, 133.2,
130.8, 129.9, 129.8, 129.7, 127.4, 113.8, 113.7, 110.5, 55.5, 55.3, 55.2,
+
40.1, 35.0. HRMS-ESI exact mass calcd. for C23H24NaO3 [M + Na]+
requires m/z 371.1616, found m/z 371.1617.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01646.
Copies of 1H and 13C NMR spectra for all the
synthesized compounds, and UV−vis data. (PDF)
AUTHOR INFORMATION
Corresponding Author
*njain@chemistry.iitd.ac.in
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank DST-FIST for funding the ESI-HRMS
facility at IIT Delhi. MSD thanks Daiichi Sankyo India Pharma
Pvt. Ltd. for the funds and research facilities. AS thanks CSIR,
New Delhi for providing the graduate fellowship. We thank Dr.
P.C. Ravikumar, IIT Mandi for providing the HR-MS data of
compounds 7b and 7c.
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DOI: 10.1021/acs.joc.5b01646
J. Org. Chem. XXXX, XXX, XXX−XXX