Ir(III)-catalyzed aromatic C-H bond functionalization via metal carbene migratory insertion

Article abstract of DOI:10.1021/jo5023102

Ir(III)-catalyzed coupling of aromatic C-H bonds with diazomalonates has been achieved successfully via a metal carbene migratory insertion process. With different types of carbamoyl directing groups, a wide range of arenes, including heteroarenes, can be used as substrates in this Ir(III)-catalyzed C-H functionalization reaction. Mono- and bisfunctionalized products can be obtained selectively simply by changing the number of equivalents of the diazo substrate. Moreover, when diazomalonates bearing one or two tert-butyl groups are used as the substrates, the C-H bond functionalization is followed by decarboxyation, leading to products with a -CH₂CO₂Me or -CH₂CO₂H moiety at the position ortho to the directing group. This reaction demonstrates that direct C-H activation and the metal carbene migratory insertion can be merged into one catalytic cycle with an Ir(III) complex as the catalyst.

Full text of DOI:10.1021/jo5023102

Article
pubs.acs.org/joc
Ir(III)-Catalyzed Aromatic C−H Bond Functionalization via Metal
Carbene Migratory Insertion
Ying Xia,† Zhen Liu,† Sheng Feng,† Yan Zhang,† and Jianbo Wang*,†,‡
†Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of the Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
‡State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Ir(III)-catalyzed coupling of aromatic C−H
bonds with diazomalonates has been achieved successfully via a
metal carbene migratory insertion process. With different types
of carbamoyl directing groups, a wide range of arenes,
including heteroarenes, can be used as substrates in this
Ir(III)-catalyzed C−H functionalization reaction. Mono- and
bisfunctionalized products can be obtained selectively simply
by changing the number of equivalents of the diazo substrate.
Moreover, when diazomalonates bearing one or two tert-butyl
groups are used as the substrates, the C−H bond
functionalization is followed by decarboxyation, leading to
products with a −CH2CO2Me or −CH2CO2H moiety at the position ortho to the directing group. This reaction demonstrates
that direct C−H activation and the metal carbene migratory insertion can be merged into one catalytic cycle with an Ir(III)
complex as the catalyst.
In 2011, we reported an example of this type of aromatic
C(sp2)−H bond insertion in the Cu-catalyzed C−H bond
functionalization of 1,3-azoles with N-tosylhydrazones (Scheme
2a).5 In this transformation, the copper carbene precursor of
INTRODUCTION
■
Transition-metal-catalyzed C−H functionalization with metal
carbene species, namely, C−H bond insertion of the metal
carbene, is a unique and practical method in organic synthesis.1
In classic Rh(II) carbene C(sp3)−H bond insertion reactions,
the Rh(II) carbene species is first formed from a carbene
precursor, most commonly an α-diazocarbonyl compound.
This is followed by a concerted direct C−H insertion
mechanism, while the corresponding aromatic C(sp2)−H
bond insertion is proposed as an electrophilic aromatic
substitution.2 In both cases, electron-rich C−H bonds show
higher reactivity toward the electron-deficient metal carbene
than electron-poor ones. Recently, a new approach toward
C(sp2)−H functionalization has appeared that is proposed to
involve a different reaction mode of the metal carbene.3 The
transformation consists of C−H bond metalation followed by
metal carbene formation and migratory insertion (Scheme 1).4
Scheme 2. Aromatic C(sp2)−H Bond Functionalization with
N-Tosylhydrazones or Diazo Compounds
Scheme 1. Formal Aromatic C(sp2)−H Bond Insertion
Received: October 8, 2014
© XXXX American Chemical Society
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a
Table 1. Optimization Experiments with the Ir(III)-Catalyzed Reaction of 1a and 2a
b
c
entry
additive (mol %)
AgOAc (8)
solvent
t (h)
T (°C)
yield (%)
0
3a:3a′
−
−
1
2
DCE
24
24
24
24
24
24
24
24
24
24
12
10
70
70
70
70
70
70
70
90
110
90
90
90
d
AgSbF6 (8)
DCE
<1
3
AgNTf2 (8)
DCE
<10
23
0.6:1
15:1
−
4
AgNTf2 (8)/AgOAc (4)
AgNTf2(8)/AgOAc(4)
AgNTf2 (8)/AgOAc (4)
AgNTf2 (8)/AgOAc (4)
AgNTf2 (8)/AgOAc (4)
AgNTf2 (8)/AgOAc (4)
AgNTf2 (8)/AgOAc (4)
AgNTf2 (8)/AgOAc (4)
AgNTf2 (8)/AgOAc (4)
DCE
d
5
MeCN
MeOH
dioxane
DCE
<1
d
6
<1
−
−
d
7
<1
8
38
30
8:1
5:1
4:1
>30:1
>30:1
9
DCE
e
10
11
12
DCE
25
f
DCE
86
g
DCE
88
a
The reactions carried out with 1a (0.20 mmol) and 2a (0.24 mmol) in the presence of 2 mol % Ir(III) catalyst in 1.0 mL of solvent for the indicated
b
c
d
times. Yields refer to products isolated by column chromatography. The ratio was estimated by GC−MS analysis of the reaction mixture. Only a
e
f
trace amount of the product was detected by GC−MS analysis of the reaction mixture. 1a:2a = 1:2. 2a was dissolved in 0.6 mL of DCE and added
g
via peristaltic pump for 10 h. 2a was dissolved in 0.6 mL of DCE and added via syringe pump for 5 h.
the diazo substrate is generated in situ from the N-
tosylhydrazone through a Bamford−Stevens reaction.6 Hirano
and Miura later expanded the substrate scope by replacing
Cu(I) with Ni(II) and Co(II) catalysts in similar trans-
formations.7 In 2012, significant progress was made by Yu and
co-workers, who demonstrated that non-heteroarenes bearing a
directing group could react with diazo compounds to give an
ortho-C−H alkylated product under catalysis of a Rh(III)
complex.8,9 Subsequently, the groups of Rovis,10 Glorius,11 Li,12
Cui,13 Wang,14 Yi,15 and Chang16 as well as our group17 have
demonstrated the successful exploration of diazo compounds as
cross-coupling partners in Rh(III)-catalyzed ortho-C−H bond
functionalization with a directing group (Scheme 2b). Very
recently, an asymmetric catalytic version of such a reaction was
achieved by Cramer’s group using a chiral Rh(III) complex.18
Although significant progress has been made in this type of
aromatic C(sp2)−H bond functionalization, it is still in its
infancy compared with the traditional C−H insertion of Rh(II)
carbene species. New catalysts and versatile reaction types still
wait to be explored. In this context, we have noticed that
iridium complexes have attracted significant attention in the
area of direct C−H functionalizations because of their excellent
performance in C−H bond activation.19−21 For example,
Chang and co-workers reported a series of Ir(III)-catalyzed
direct C−H bond amination reactions in which organoazides
are the most common amino sources.22 Very recently, the
direct C−H alkynylation of arenes was achieved by Li and co-
workers using an Ir(III) catalyst, which gives complementary
results compared with a Rh(III) catalyst.23 Inspired by these
accomplishments and also in connection to our own interest in
cross-coupling reactions involving carbene species,24 we have
conceived that Ir(III)-catalyzed direct C−H bond functional-
ization of arenes with diazo compounds may be feasible. Herein
we report the first chelation-assisted Ir(III)-catalyzed ortho-C−
H functionalization of aromatic C−H bonds with diazomalo-
nates.25 This reaction shows a broad scope of aromatic C−H
bonds with easy control of the mono- and bis-C−H
functionalization (Scheme 2c). Moreover, the directing groups
reported in this study, namely, alkyl carbamoyl groups, are
different from those previously reported for Rh(III)-catalyzed
reactions.10−18 Mechanistically, an Ir(III) carbene migratory
insertion process is proposed as the key step involved in this
transformation.
RESULTS AND DISCUSSION
■
Optimization of the Reaction Conditions. At the outset
of this investigation, N-tert-butylbenzamide (1a) and dimethyl
diazomalonate (2a) were used as the substrates to optimize the
reaction conditions (Table 1). The dimeric
(pentamethylcyclopentadienyl)iridium complex [Ir(III)-
Cp*Cl2]2, which is the most widely used Ir(III) catalyst
precursor in direct C−H functionalization reactions,22,23 was
employed as the catalyst in this reaction. A series of Ag(I)
additives, which are required for the formation of a cationic
Ir(III) species by chloride abstraction, were first investigated
under reaction conditions of 70 °C in DCE for 24 h. However,
none or only a trace amount of the expected ortho-
functionalized product 3a was observed by GC−MS analysis
when AgOAc or AgSbF6 was used as an additive (entries 1 and
2). The strongly cationic AgNTf2 was more efficient than the
other Ag(I) additives, but the bisfunctionalized product 3a′ was
also formed in significant amount (entry 3). When AgOAc was
added together with AgNTf2 as a coadditive,22e both the yield
B
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and the ratio of mono- to bisfunctionalized product were
improved, and 3a was isolated in 23% yield (entry 4). The
effect of the solvent was then screened, and it was found that no
solvent was superior to the non-coordinative solvent DCE
(entries 5−7). High reaction temperature could facilitate the
transformation; however, the selectivity for the monofunction-
alized product over the bisfunctionalized product declined
(entries 8 and 9). Increasing the amount of the diazo substrate
2a did not improve the yield or the selectivity (entry 10). This
experiment indicates that low concentration of the diazo
substrate may be beneficial for the reaction. Indeed, both the
yield and the selectivity improved when the diazo substrate was
added slowly (entries 11 and 12). With slow addition of the
diazo substrate over 5 h, the product 3a was isolated in 88%
yield with excellent monoalkylation selectivity (entry 12).26
Substrate Scope. Having established the optimized
reaction conditions, we then explored the scope of this reaction
system. A series of substituted aryl amides were first
investigated. The reaction with diazomalonates proceeded
smoothly to afford the ortho-alkylated products in 49−99%
yield (Scheme 3). The structure of 3a was confirmed
unambiguously by X-ray crystallography. The electronic
properties of the substituents on benzamides showed little
influence on this transformation. Benzamides bearing either
electron-donating (3b and 3c) or electron-withdrawing (3d−i)
substituents at the para position afforded the corresponding
products in excellent yields. The meta- and ortho-substituted
benzamides gave almost quantitative yields in this reaction (3j−
m). For the meta-substituted benzamide 1j, only one product
was observed, and the C−H functionalization occurred
regioselectively at the sterically more accessible position
(3j).22a Some multisubstituted benzamides were also subjected
to this reaction and afforded the corresponding C−H bond-
functionalized products in excellent yields (3n and 3o). It is
noteworthy that this reaction fully tolerates halogen sub-
stituents, providing the possibility for further transformation via
cross-coupling reactions (3f−h, 3n, and 3o). Naphthamides
were also suitable substrates for this reaction, and the C−H-
alkylated products were obtained in good yields (3p and 3q).
Moderate regioselectivity was observed when 2-naphthamide
(2p) was used as the substrate, and again the C−H
functionalization took place at sterically less hindered site.
The structure of the 3-alkylated major product (3p) was
confirmed through X-ray crystallography. Additionally, this
Ir(III)-catalyzed C−H functionalization also tolerated hetero-
aryl amides, as furan- and thiophene-derived amides were also
converted to the corresponding products in moderate to good
yields (3r−u).
Scheme 3. Scope of the Benzamides in the Ir(III)-Catalyzed
C−H Functionalization
a
Some other diazomalonate esters were also explored to react
with benzamide 1a, all of which afforded results comparable to
those for dimethyl diazomalonate 2a (3v−x). It is again
worthwhile to mention that all of these examples gave excellent
monoalkylation selectivity under the current reaction con-
ditions, and none or only a trace amount of the bisalkylated
products could be detected by GC−MS analysis of the reaction
mixture.
a
The reaction conditions are described in entry 12 of Table 1.
b
c
Isolated yields with column chromatography. The regioselectivity
d
was determined by 1H NMR spectroscopy. This product was isolated
as an isomeric mixture (2.5:1), as a result of the hindered rotation of
the amide C−N bond.
We next explored the scope of the directing group on the
aromatic substrate of this reaction (Scheme 4). The N
substituent on the benzamide can be varied from a tert-butyl
group to cyclohexyl, isopropyl, propyl, and adamantyl groups,
although the less sterically hindered propyl group led to only a
moderate yield (5a−d). An interesting observation is that the
NH moiety is not essential to this transformation, as the
reaction still works well with N,N-disubstituted benzamides
(5e−g). Again, the steric hindrance of the directing group has
an influence on this reaction to some extent (5e−g). Apart
from benzamides, simple aryl ketones were also suitable
substrates for this Ir(III)-catalyzed C−H functionalization
reaction, although the corresponding products were obtained
in diminished yields (5h−j). It should be noted that the
C
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Scheme 4. Scope of the Directing Group in Ir(III)-Catalyzed
C−H Functionalization
Scheme 5. Ir(III)-Catalyzed Reaction of Benzamide 1a and
Diazomalonate 2e: C−H Alkylation/C−C Bond Cleavage
Sequence
a
Scheme 6. Scope of the Ir(III)-Catalyzed C−H Alkylation/
a
C−C Bond Cleavage Sequence
a
The reaction conditions are described in entry 12 of Table 1.
Isolated yields with column chromatography.
b
bulkiness of the directing group is essential to this C−H
functionalization, as the simplest substrates, N-methylbenza-
mide and acetophenone, did not afford the desired products,
and the starting materials largely remained. To our delight, this
Ir(III)-catalyzed reaction system could be expanded to N-
pivaloyl-protected aniline in good yield (5k). Finally, an
analogue of benzamide 1a enlarged by one carbon between
the arene moiety and the directing moiety, was less effective in
this reaction, indicating that the size of the iridacycle formed in
the C−H activation step has a significant influence on the
efficiency of this transformation (5l).
When 1-tert-butyl 3-methyl 2-diazomalonate (2e) was
employed as the carbene precursor to react with benzamide
1a under the optimized reaction conditions, the anticipated
product 3y was not observed. Instead, monoester product 6a
was obtained in 86% isolated yield. We speculate that the
formation of 6a occurs because the tert-butyl ester moiety is
liable to hydrolysis under the acidic conditions. Thus, the
normal coupling product 3y is generated first and then
undergoes hydrolysis with the assistance of a Lewis acidic
Ir(III) or Ag(I) complex. The metal malonate is formed with
the release of tert-butyl cation, which gives isobutene. Finally, a
decarboxylation process occurs, leading to the observed
product 6a (Scheme 5). From the viewpoint of synthesis, this
Ir(III)-catalyzed C−H alkylation/C−C bond cleavage sequence
affords a method for ortho-C−H functionalization with a
CH2CO2Me moiety.12,15 Notably, this transformation also
shows excellent monoalkylation selectivity.
a
The reaction conditions are described in entry 12 of Table 1.
b
c
Isolated yields with column chromatography. The regioselectivity
1
was determined by H NMR spectroscopy.
This Ir(III)-catalyzed C−H alkylation/C−C bond cleavage
sequence was then investigated by testing a wide range of
arenes (Scheme 6). Similar to the reaction of dimethyl
diazomalonate 2a, this reaction also shows a wide substrate
scope with high efficiency and excellent monoalkylation
selectivity. Benzamides bearing different types of substituents
worked well in this reaction (6b−j). The structure of product
6c was confirmed unambiguously by X-ray crystallography.
Compared with the reaction with 2a, the reaction of 2-
naphthamide afforded a better regioselective C−H alkylation
D
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(6k), and the reaction of 1-naphthamide showed a similar result
(6l). Notably, this reaction can also be applied to the
functionalization of heteroarenes, affording the corresponding
products in moderate to excellent yields (6m−p). Other
directing groups were also explored under the same reaction
conditions, and results comparable to those for the reactions
with 2a were obtained (6q−t).
the reaction conditions, suggesting the possibility to achieve
double C−H bond functionalization in a single operation. This
was indeed the case. When 2.4 equiv of dimethyl 2-
diazomalonate 2a was used to react with benzamide 1a under
reaction conditions otherwise identical to those described in
entry 12 of Table 1, the bisalkylated product 8a was obtained
cleanly in 92% isolated yield (Scheme 8, 8a). The substrates
Subsequently, we proceeded to investigate this Ir(III)-
catalyzed reaction with di-tert-butyl diazomalonate (2f), which
bears two CO2tBu moieties, as the carbene precursor.
Interestingly, under the identical conditions, one of the two
CO2tBu moieties vanished in the reaction but the other one
was only hydrolyzed, affording a free carboxylic acid moiety
(Scheme 7, 7a). To the best of our knowledge, direct
Scheme 8. Scope of the Ir(III)-Catalyzed Double C−H
a
Alkylation Reaction with Diazo Compound 2a
Scheme 7. Scope of the Ir(III)-Catalyzed C−H Alkylation/
a
C−C/C−O Bond Cleavage Sequence
a
The reaction conditions are described in entry 12 of Table 1, except
b
that the amount of diazo compound 2a was 0.48 mmol. Isolated
yields with column chromatography.
with an electron-donating or electron-withdrawing group at the
para position or with methoxy at the meta position were all
tolerated well under the reaction conditions, affording the
bisalkylated products in good to excellent yields (Scheme 8,
8b−d). Therefore, the selectivity for mono- or bisfunctionalized
products could be controlled by varying the number of
equivalents of the diazo compound used for the reaction.
Similarly, 1-tert-butyl 3-methyl 2-diazomalonate 2e was also
suitable substrate for this Ir(III)-catalyzed bisalkylation
reaction, and a series of aryl amides were smoothly converted
to the bisfunctionalized products with a CH2CO2Me moiety
(Scheme 9). Benzamides bearing various substituents showed
high efficiency in this transformation, affording the correspond-
ing products in 82−93% yield (9a−f). 2-Naphthamide could
a
The reaction conditions are described in entry 12 of Table 1.
Isolated yields with column chromatography.
b
Scheme 9. Scope of the Ir(III)-Catalyzed Double C−H
a
transition-metal-catalyzed C−H functionalization with a
CH2CO2H moiety has not been reported previously. The
efficiency of this transformation was then tested using a number
of aryl amides, and the corresponding aryl acetic acids were
obtained in 42−99% yield (Scheme 7). Benzamides containing
electron-donating or electron-withdrawing substituents all
reacted smoothly to afford the C−H-functionalized product
with a CH2CO2H moiety (7b−h). Naphthamides were
converted to the corresponding products with high efficiency
and excellent regioselectivity (7i−j). The C−H-functionalized
product in the reaction of 2-naphthamide was not observed in
the 1H NMR analysis, demonstrating that the regioselectivity is
higher than that of the corresponding reaction of diazomalo-
nate 2a or 2e. Heteroaryl amides were also suitable substrates
for this transformation, although diminished yields were
obtained for the furan-containing heterocycles (7k−n). It
should be noted again that this type of reaction also shows
excellent monoalkylation selectivity.
Alkylation Reaction with Diazo Compound 2e
a
As shown by the results reported above, the selectivity for
mono- versus bisfunctionalization is excellent under the current
reaction conditions. However, the bisfunctionalized product
was observed in GC−MS analysis during the optimization of
The reaction conditions are described in entry 12 of Table 1, except
b
that the amount of diazo compound 2e was 0.48 mmol. Isolated
yields with column chromatography. The monoalkylated product 6k
c
was isolated in 47% yield.
E
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1
not be fully transformed to the corresponding bisalkylated
product, which was isolated in only 51% yield under the same
conditions. The monoalkylated product 6k was also isolated in
47% yield. This result might be attributable to the steric effect,
which hindered the second alkylation process (9g).
Mechanistic Studies. Preliminary mechanistic studies were
then carried out in order to gain insights into the mechanism of
this Ir(III)-catalyzed C−H alkylation (Scheme 10).27 First,
2a was consumed completely in all cases. H NMR analysis of
the product mixture gave an average 3a:3a-d4 ratio of 3.0. It is
noteworthy that the deuterium cleaved from 1a-d5 was not
incorporated into the malonate moiety of the products,
indicating fast H/D exchange with the rather acidic position.
Interestingly, the deuterium was partially merged into the
amide NH moiety, and the deuterated ratio increased to some
extent as the reaction time was prolonged. Another observation
is that H/D scrambling did not occur, which indicates that the
C−H functionalization is rather faster than the ortho-H/D
exchange. Meanwhile, two separate reactions of 1a or 1a-d5
under the standard conditions were conducted. The reactions
were stopped within 20 min to keep a low conversion (less than
10%). The observed reaction rates of 1a and 1a-d5 were almost
the same (kH/kD = 1.1). These results suggest that the cleavage
of the C−H bond is not involved in the rate-limiting step. The
results are in accordance with the aforementioned argument
that the reaction may involve an electrophilic C−H metalation
pathway. Moreover, the difference of these two KIE values
indicates that the rate-limiting step should occur before the
cleavage of the C−H bond,28 and presumably the electrophilic
metalation is involved in the rate-limiting step.
Scheme 10. Experiments for Mechanistic Studies
Then the reaction of benzamide 1a-d5 with diazo compound
2a was carried out with an additional 5 equiv of H2O under the
standard conditions. The target product was isolated in 76%
yield, indicating that water has a marginal effect on the Ir(III)-
catalyzed C−H alkylation. Besides, the ortho-D was retained in
a considerable ratio even in the presence of a large excess
amount of H source (10 equiv), again suggesting that the C−H
alkylation is faster than the ortho-H/D exchange (Scheme 10c).
These results indicate that this Ir(III)-catalyzed C−H activation
is largely irreversible on the time scale of the reaction, which is
in accordance with the previous reports.22
Since Ir(III) complexes also catalyze traditional carbene
transfer reactions with diazo compounds,25 some control
experiments with traditional carbene acceptors were then
carried out in order to gain further insights into the reaction
(Scheme 11). When 3 equiv of cyclohexene was added to the
standard reaction mixture, cyclopropanation or allylic C−H
insertion of the cyclohexene was not observed. Interestingly,
the formation of 3a was completely inhibited, and 1a and 2a
were recovered in 92% and 48% yield, respectively. This is
probably due to the weaker electrophilic nature of the iridium
center upon ligation to the alkene (Scheme 11a). When
cyclohexene was treated with 2a in the absence of 1a under the
standard conditions, the cyclopropanation or allylic C−H
insertion also did not occur (Scheme 11b).
Similar experiments were then performed by replacing
cyclohexene with anisole. In contrast to the experiment with
cyclohexene, the C−H alkylation was not affected by the added
anisole, and 3a was obtained in 85% yield. In this reaction, the
C−H insertion product of the reaction of the electron-rich
anisole with diazo compound 2a was not observed (Scheme
11c), and the same result was obtained in the absence of 1a
(Scheme 11d). Notably, the experiments also indicated that the
diazo compound was consumed slowly in the absence of arene
substrate, suggesting that this reaction is largely different from
the traditional metal carbene reactions, in which the metal
catalyst and the arene substrate interact antecedent to metal
carbene formation. Moreover, the directing group was found to
be essential for the electrophilic C−H activation, as the simple
electron-rich arene anisole did not undergo C−H functionaliza-
tion under the same conditions.
amide competition experiments were performed to study the
electronic preference of the reaction. Thus, equimolar mixtures
of unsubstituted amide 1a and para-substituted benzamides 1b,
1c, 1e, and 1f were subjected to the competition reaction. The
results from these experiments show a significant electronic
effect on the reaction. The ratios of the observed products for
substituted benzamides to the product for unsubstituted amide
1a were 2.0, 1.7, 0.50, 0.11 for OMe, Me, Cl, and NO2
substituents, respectively (Scheme 10a). We can thus conclude
that this Ir(III)-catalyzed C−H functionalization is more
favorable for benzamides bearing an electron-donating
substituent, indicating that an electrophilic C−H activation is
involved in the reaction mechanism of this reaction.8
Next, an intermolecular competition experiment using
equimolar amounts of 1a and 1a-d5 was carried out (Scheme
10b). Three runs of this reaction for 5, 10, and 20 min afforded
similar results, in which the small amount of diazo compound
F
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Scheme 11. Control Experiments with Traditional Carbene
Acceptors
Scheme 12. Proposed Reaction Mechanism
aromatic C(sp2)−H bond insertions, C−H functionalization
with a CH2CO2Me or CH2CO2H moiety can be achieved
through in situ de-esterification. Additionally, the mono- and
bisfunctionalized reaction modes can be readily controlled by
varying the amount of diazomalonate used in the reaction.
From a mechanistic point of view, this catalytic reaction
demonstrates that the well-developed C−H activation process
by the Ir(III) complex can be successfully incorporated with the
Ir(III) carbene migratory insertion process to achieve highly
efficient aromatic C−H bond alkylation. This may open up new
possibilities to further develop novel Ir(III)-catalyzed C−H
bond transformations.
On the basis of these experimental observations and
literature precedents,19−23 a mechanism for the present
Ir(III)-catalyzed C−H alkylation reaction is proposed as
shown in Scheme 12. First, the active cationic Ir(III) species
A is generated with the assistance of the Ag salts.22e This
electrophilic Ir(III) species coordinates to the carbonyl oxygen
of the amide to generate iridium complex B.22i At this point, an
intramolecular electrophilic metalation may occur to form
intermediate C, from which HOAc is eliminated to produce
iridacyclic intermediate D. The metalation step might be the
rate-limiting step according to the above experimental
observations. The iridacyclic complex D reacts with the diazo
compound to form a cyclic Ir(III) carbene species with the
extrusion of N2.29 Subsequent migratory insertion of Ir(III)
carbene species E takes place, leading to the formation of
intermediate F, similar to the Rh(III)-catalyzed C−H
functionalization.8−18 Finally, protonation of E produces the
desired alkylated product with regeneration of the active Ir(III)
catalyst.
EXPERIMENTAL SECTION
■
General Methods. All of the solvents were distilled under a
nitrogen atmosphere prior to use. Dioxane was dried over Na with
benzophenone ketyl intermediate as the indicator. MeCN, MeOH, and
DCE were dried over CaH2. Aryl amides were prepared according to
the literature procedure,22a and unless otherwise specified, the catalysts
were used directly as received from commercial sources without
further purification. For chromatography, 200−300 mesh silica gel
1
(Qingdao, China) was employed. Chemical shifts for H NMR (400
MHz) and 13C NMR (100 MHz) spectra are reported relative to
tetramethylsilane (TMS). IR spectra are reported in wavenumbers
(cm−1). For HRMS measurements, the mass analyzer was FT-ICR.
General Procedure for Ir(III)-Catalyzed Monoalkylation.
Under atmospheric conditions, arene 1 or 4 (0.2 mmol), [IrCp*Cl2]2
(3.2 mg, 0.004 mmol, 2 mol %), AgNTf2 (6.2 mg, 0.016 mmol, 8 mol
%), and AgOAc (1.3 mg, 0.008 mmol, 4 mol %) were successively
added to a 10 mL Schlenk tube. The reaction tube was degassed three
times with nitrogen gas, and dry DCE (1.0 mL) was added using a
syringe. It should be noted that the arene in a liquid form was added to
the reaction tube by syringe after addition of the solvent. The reaction
tube was immersed in a 90 °C oil bath with stirring, and then diazo
compound 2 (0.24 mmol dissolved in 0.6 mL of DCE) was added via
peristaltic pump for 5 h. After another 5 h of stirring, the reaction
mixture was cooled to room temperature and filtered through a short
plug of silica gel (petroleum ether (PE):ethyl acetate (EA) = 1:1, 15
mL). The solvent was then removed in vacuo to leave a crude mixture,
CONCLUSION
■
In summary, we have developed a versatile Ir(III)-catalyzed
aromatic ortho-C−H alkylation reaction with diazomalonates.
This methodology shows the advantages of high efficiency,
excellent compatibility of a series of functional groups, and
good regioselectivity. In addition to the formal carbene
G
dx.doi.org/10.1021/jo5023102 | J. Org. Chem. XXXX, XXX, XXX−XXX

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which was purified by silica gel column chromatography to afford pure
product 3a−x, 5a−l, 6a−t, or 7a−n. For products 3a−x, 5a−l, and
6a−t, PE:EA = 5:1 to 3:1 was generally used as the solvent for column
chromatography. For acid products 7a−n, the reaction mixture was
filtered through a short plug of Celite (PE:EA = 1:1, 15 mL) after the
reaction was finished, and CH2Cl2:MeOH = 75:1 was used as the
solvent for column chromatography.
General Procedure for Ir(III)-Catalyzed Bisalkylation. Under
atmospheric conditions, arene 1 (0.2 mmol), [IrCp*Cl2]2 (3.2 mg,
0.004 mmol, 2 mol %), AgNTf2 (6.2 mg, 0.016 mmol, 8 mol %), and
AgOAc (1.3 mg, 0.008 mmol, 4 mol %) were successively added to a
10 mL Schlenk tube. The reaction tube was degassed three times with
nitrogen gas, and dry DCE (1.0 mL) was added using a syringe. The
reaction tube was immersed in a 90 °C oil bath with stirring, and then
diazo compound 2a or 2e (0.48 mmol dissolved in 0.6 mL of DCE)
was added via peristaltic pump for 5 h. After another 5 h of stirring, the
reaction mixture was cooled to room temperature and filtered through
a short plug of silica gel (PE:EA = 1:1, 15 mL). The solvent was then
removed in vacuo to leave a crude mixture, which was purified by silica
gel column chromatography to afford pure product 8a−d or 9a−g
using PE:EA = 5:1 to 3:1 as the solvent.
(ESI, m/z) calcd for C16H21ClNO5 [M + H]+ 342.1103, found
342.1112, calcd for C16H20ClNNaO5 [M + Na]+ 364.0922, found
364.0924; IR (film) 733, 1150, 1219, 1531, 1650, 1739, 2962, 3305
cm−1.
Dimethyl 2-(5-Bromo-2-(tert-butylcarbamoyl)phenyl)malonate
1
(3g). Yield 82% (63 mg); white solid, mp 110−111 °C; H NMR
(400 MHz, CDCl3) δ 7.65 (d, J = 1.7 Hz, 1H), 7.48 (dd, J = 1.7, 8.2
Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 6.00 (s, 1H), 5.32 (s, 1H), 3.78 (s,
6H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.3, 167.5,
136.8, 132.8, 132.3, 131.4, 128.8, 124.0, 53.3, 53.0, 52.2, 28.6; HRMS
(ESI, m/z) calcd for C16H2179BrNO5 [M + H]+ 386.0598, found
386.0606; IR (film) 733, 1150, 1218, 1530, 1650, 1738, 2959, 3311
cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)-5-iodophenyl)malonate
1
(3h). Yield 87% (75 mg); white solid, mp 122−124 °C; H NMR
(400 MHz, CDCl3) δ 7.83 (d, J = 1.4 Hz, 1H), 7.68 (dd, J = 1.4, 8.1
Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.03 (s, 1H), 5.28 (s, 1H), 3.78 (s,
6H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.3, 167.6,
138.6, 137.3, 137.3, 132.1, 128.8, 95.9, 53.2, 53.0, 52.1, 28.5; HRMS
(ESI, m/z) calcd for C16H21INO5 [M + H]+ 434.0459, found
434.0465; IR (film) 731, 910, 1150, 1217, 1652, 1737, 2917, 3317
cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)phenyl)malonate (3a). Yield
1
Dimethyl 2-(4-(tert-Butylcarbamoyl)-[1,1′-biphenyl]-3-yl)-
malonate (3i). Yield 84% (64 mg); white solid, mp 112−113 °C;
1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.58−7.40 (m, 4H),
7.46−7.42 (m, 2H), 7.38−7.35 (m, 1H), 6.07 (s, 1H), 5.46 (s, 1H),
3.78 (s, 6H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.8,
168.2, 142.8, 139.8, 136.6, 130.8, 128.8, 128.6, 127.9, 127.8, 127.2,
126.8, 53.6, 52.9, 52.0, 28.6; HRMS (ESI, m/z) calcd for C22H26NO5
[M + H]+ 384.1806, found 384.1812; IR (film) 732, 1148, 1217, 1305,
1652, 1736, 2957, 3378 cm−1.
88% (54 mg); white solid, mp 113−115 °C; H NMR (400 MHz,
CDCl3) δ 7.50−7.48 (m, 1H), 7.44−7.40 (m, 2H), 7.36−7.32 (m,
1H), 5.98 (s, 1H), 5.38 (s, 1H), 3.76 (s, 6H), 1.45 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 168.8, 168.4, 137.9, 130.4, 129.9, 129.7, 128.2,
127.2, 53.6, 52.8, 52.0, 28.6; HRMS (ESI, m/z) calcd for C16H22NO5
[M + H]+ 308.1492, found 308.1495; IR (film) 735, 1148, 1220, 1528,
1655, 1737, 2917, 3388 cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)-5-methylphenyl)malonate
(3b). Yield 83% (53 mg); white solid, mp 84−85 °C; 1H NMR
(400 MHz, CDCl3) δ 7.33 (d, J = 7.8 Hz, 1H), 7.28 (s, 1H), 7.14 (d, J
= 7.6 Hz, 1H), 5.97 (s, 1H), 5.40 (s, 1H), 3.76 (s, 6H), 2.36 (s, 3H),
1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.0, 168.4, 140.1,
135.0, 130.3, 130.2, 128.9, 127.2, 53.4, 52.8, 51.8, 28.6, 21.3; HRMS
(ESI, m/z) calcd for C17H24NO5 [M + H]+ 322.1649, found 322.1652;
IR (film) 732, 1148, 1237, 1308, 1654, 1737, 2964, 3386 cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)-5-methoxyphenyl)malonate
(3c). Yield 83% (56 mg); white solid, mp 127−128 °C; 1H NMR (400
MHz, CDCl3) δ 7.39 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H),
6.84 (dd, J = 2.4, 8.5 Hz, 1H), 5.93 (s, 1H), 5.48 (s, 1H), 3.82 (s, 3H),
3.77 (s, 6H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.8,
168.3, 160.5, 132.4, 130.3, 128.8, 115.4, 113.4, 55.4, 53.5, 52.8, 51.8,
28.7; HRMS (ESI, m/z) calcd for C17H24NO6 [M + H]+ 338.1598,
found 338.1602; IR (film) 680, 1147, 1242, 1549, 1622, 1746, 2955,
3296 cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)-4-methylphenyl)malonate
1
(3j). Yield 99% (64 mg); white solid, mp 127−130 °C; H NMR
(400 MHz, CDCl3) δ 7.37 (d, J = 7.9 Hz, 1H), 7.27−7.22 (m, 2H),
5.99 (s, 1H), 5.30 (s, 1H), 3.76 (s, 6H), 2.35 (s, 3H), 1.44 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 169.0, 168.5, 138.2, 137.8, 130.6, 129.6,
127.9, 127.2, 53.3, 52.8, 51.9, 28.6, 20.9; HRMS (ESI, m/z) calcd for
C17H24NO5 [M + H]+ 322.1649, found 322.1655; IR (film) 734, 1029,
1254, 1541, 1630, 1750, 2926, 3288 cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)-3-methylphenyl)malonate
1
(3k). Yield 99% (64 mg); white solid, mp 128−131 °C; H NMR
(400 MHz, CDCl3) δ 7.33 (d, J = 7.7 Hz, 1H), 7.29−7.25 (m, 1H),
7.17 (d, J = 7.4 Hz, 1H), 5.72 (s, 1H), 4.89 (s, 1H), 3.75 (s, 6H), 2.36
(s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.6, 168.0,
138.7, 134.7, 130.2, 128.7, 126.2, 54.0, 52.8, 52.0, 28.6, 19.2; HRMS
(ESI, m/z) calcd for C17H24NO5 [M + H]+ 322.1649, found 322.1647;
IR (film) 732, 910, 1135, 1248, 1628, 1737, 2917, 3256 cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)-3-methoxyphenyl)malonate
Dimethyl 2-(2-(tert-Butylcarbamoyl)-5-(trifluoromethyl)phenyl)-
malonate (3d). Yield 93% (70 mg); white solid, mp 123−125 °C;
1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.62−7.55 (m, 2H), 6.08
1
(3l). Yield 99% (67 mg); white solid, mp 93−95 °C; H NMR (400
(s, 1H), 5.34 (s, 1H), 3.79 (s, 6H), 1.45 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 168.1, 167.1, 141.2, 131.8 (q, J = 32.9 Hz), 131.2, 127.8,
126.9 (q, J = 3.7 Hz), 125.2 (q, J = 3.5 Hz), 123.4 (q, J = 272.6 Hz),
53.5, 53.1, 52.4, 28.5; HRMS (ESI, m/z) calcd for C17H21F3NO5 [M +
H]+ 376.1366, found 376.1371; IR (film) 688, 1151, 1222, 1331, 1639,
1736, 2917, 3301 cm−1.
MHz, CDCl3) δ 7.33 (t, J = 8.1 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.90
(d, J = 8.3 Hz, 1H), 5.79 (s, 1H), 5.05 (s, 1H), 3.83 (s, 3H), 3.75 (s,
6H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.6, 165.7,
156.0, 131.4, 130.0, 128.0, 121.2, 111.0, 55.9, 53.7, 52.8, 51.9, 28.7;
HRMS (ESI, m/z) calcd for C17H24NO6 [M + H]+ 338.1598, found
338.1605; IR (film) 732, 1148, 1264, 1471, 1660, 1737, 2958, 3373
cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)-5-nitrophenyl)malonate
1
Dimethyl 2-(2-(tert-Butylcarbamoyl)-3-fluorophenyl)malonate
(3e). Yield 84% (59 mg); yellow solid, mp 117−119 °C; H NMR
1
(3m). Yield 99% (64 mg); white solid, mp 150−153 °C; H NMR
(400 MHz, CDCl3) δ 8.40 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 2.0, 8.4
Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 5.33 (s, 1H), 3.81 (s,
6H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 167.8, 166.4,
148.2, 143.5, 132.2, 128.4, 125.2, 123.2, 53.4, 53.3, 52.6, 28.5; HRMS
(ESI, m/z) calcd for C16H21N2O7 [M + H]+ 353.1343, found
353.1353; IR (film) 734, 1150, 1221, 1350, 1656, 1739, 2958, 3311
cm−1.
(400 MHz, CDCl3) δ 7.39−7.28 (m, 2H), 7.08 (t, J = 8.7 Hz, 1H),
5.88 (s, 1H), 5.16 (s, 1H), 3.77 (s, 6H), 1.45 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 168.3, 163.0, 158.9 (d, J = 247.1 Hz), 132.6 (d, J = 3.4
Hz), 130.6 (d, J = 8.8 Hz), 126.2 (d, J = 18.5 Hz), 125.1 (d, J = 3.3
Hz), 115.7 (d, J = 22.5 Hz), 53.4, 52.9, 52.3, 28.6; HRMS (ESI, m/z)
calcd for C16H21FNO5 [M + H]+ 326.1398, found 326.1400; IR (film)
736, 1146, 1244, 1552, 1640, 1734, 2925, 3269 cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)-5-chlorophenyl)malonate
1
(3f). Yield 97% (66 mg); white solid, mp 102−104 °C; H NMR
Dimethyl 2-(5-Bromo-2-(tert-butylcarbamoyl)-4-methylphenyl)-
malonate (3n). Yield 94% (75 mg); white solid, mp 138−140 °C;
1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.31 (s, 1H), 6.04 (s,
(400 MHz, CDCl3) δ 7.50 (d, J = 1.9 Hz, 1H), 7.38 (d, J = 8.2 Hz,
1H), 7.31 (dd, J = 1.9, 8.2 Hz, 1H), 6.03 (s, 1H), 5.34 (s, 1H), 3.78 (s,
6H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.2, 167.4,
136.2, 135.8, 132.2, 129.9, 128.6, 128.4, 53.3, 53.0, 52.1, 28.5; HRMS
1H), 5.26 (s, 1H), 3.78 (s, 6H), 2.39 (s, 3H), 1.43 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 168.5, 167.6, 138.4, 137.0, 133.5, 129.4, 129.2,
H
dx.doi.org/10.1021/jo5023102 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
126.4, 53.0, 53.0, 52.1, 28.6, 22.5; HRMS (ESI, m/z) calcd for
C17H2379BrNO5 [M + H]+ 400.0754, found 400.0762; IR (film) 733,
1024, 1219, 1435, 1651, 1739, 2955, 3314 cm−1.
Dimethyl 2-(3-Bromo-2-(tert-butylcarbamoyl)-4-methylphenyl)-
malonate (3o). Yield 96% (77 mg); white solid, mp 179−180 °C;
1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.0 Hz, 1H), 7.26 (d, J =
8.0 Hz, 1H), 5.61 (s, 1H), 4.87 (s, 1H), 3.76 (s, 6H), 2.41 (s, 3H),
1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.3, 166.3, 140.2,
139.0, 130.9, 128.6, 127.8, 121.9, 53.9, 53.0, 52.4, 28.5, 23.2; HRMS
(ESI, m/z) calcd for C17H2379BrNO5 [M + H]+ 400.0754, found
400.0760; IR (film) 731, 1140, 1203, 1434, 1634, 1738, 2951, 3248
cm−1.
336.1810; IR (film) 739, 1031, 1218, 1526, 1658, 1732, 2977, 3374
cm−1.
Diisopropyl 2-(2-(tert-Butylcarbamoyl)phenyl)malonate (3w).
Yield 99% (72 mg) (2.5:1 for the amide bond); white solid, mp
1
71−73 °C; H NMR (400 MHz, CDCl3) δ 7.55−7.51 (m, 1.19H),
7.44−7.38 (m, 1.82H), 7.35−7.31 (m, 0.84H), 6.03 (s, 0.74H), 5.93
(s, 0.19H), 5.24 (s, 0.70H), 5.11−5.05 (m, 2.09H), 4.82 (s, 0.33H),
1.45 (s, 9H), 1.28−1.24 (m, 12H); 13C NMR (100 MHz, CDCl3) δ
168.5, 168.0, (167.0), (139.2), 138.2, 130.5, (129.8), 129.6, 129.5,
(128.8), (128.8), 128.0, 127.3, 69.4, (54.6), (54.2), 51.9, 28.6, (28.4),
21.5; HRMS (ESI, m/z) calcd for C20H30NO5 [M + H]+ 364.2118,
found 364.2129; IR (film) 738, 1101, 1180, 1220, 1660, 1729, 2982,
3361 cm−1.
Dimethyl 2-(3-(tert-Butylcarbamoyl)naphthalen-2-yl)malonate
(3p). C1:C3 = 1:7, total yield 86% (61 mg). Data for the major
1-Benzyl 3-Methyl 2-(2-(tert-Butylcarbamoyl)phenyl)malonate
(3x). Yield 85% (65 mg); colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.48−7.30 (m, 9H), 5.93 (s, 1H), 5.43 (s, 1H), 5.19 (AB
quart, J = 4.7 Hz, 2H), 3.72 (s, 3H), 1.40 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 168.7, 168.4, 168.2, 137.8, 135.2, 130.3, 129.8, 129.7,
128.4, 128.2, 128.1, 128.0, 127.1, 67.4, 53.8, 52.7, 51.9, 28.5; HRMS
(ESI, m/z) calcd for C22H26NO5 [M + H]+ 384.1806, found 384.1809;
IR (film) 736, 1145, 1217, 1307, 1657, 1735, 2964, 3378 cm−1.
Dimethyl 2-(2-(Cyclohexylcarbamoyl)phenyl)malonate (5a).
1
product (C3-alkylated): white solid, mp 129−131 °C; H NMR (400
MHz, CDCl3) δ 7.92 (s, 2H), 7.84−7.82 (m, 2H), 7.55−7.50 (m, 2H),
6.06 (s, 1H), 5.57 (s, 1H), 3.79 (s, 6H), 1.48 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 169.1, 168.7, 135.3, 133.4, 132.1, 129.3, 128.1, 127.8,
127.7, 127.4, 127.1, 127.0, 53.7, 52.8, 52.0, 28.7; HRMS (ESI, m/z)
calcd for C20H24NO5 [M + H]+ 358.1649, found 358.1655; IR (film)
757, 1147, 1220, 1529, 1653, 1736, 2954, 3310 cm−1.
Dimethyl 2-(1-(tert-Butylcarbamoyl)naphthalen-2-yl)malonate
1
1
(3q). Yield 76% (54 mg); white solid, mp 165−168 °C; H NMR
Yield 83% (55 mg); white solid, mp 137−139 °C; H NMR (400
(400 MHz, CDCl3) δ 7.97−7.95 (m, 1H), 7.88−7.83 (m, 2H), 7.62
(d, J = 8.7 Hz, 1H), 7.56−7.50 (m, 2H), 5.93 (s, 1H), 5.10 (s, 1H),
3.77 (s, 6H), 1.54 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 167.6,
136.5, 132.9, 129.8, 129.2, 128.0, 127.2, 126.8, 126.3, 125.6, 125.3,
54.2, 53.0, 52.4, 28.7; HRMS (ESI, m/z) calcd for C20H24NO5 [M +
H]+ 358.1649, found 358.1653; IR (film) 758, 1138, 1215, 1434, 1655,
1736, 2955, 3363 cm−1.
MHz, CDCl3) δ 7.52−7.42 (m, 3H), 7.38−7.34 (m, 1H), 6.10 (d, J =
6.8 Hz, 1H), 5.35 (s, 1H), 3.98−3.90 (m, 1H), 3.76 (s, 6H), 2.00 (br,
1H), 1.76−1.73 (m, 2H), 1.66−1.63 (m, 1H), 1.46−1.37 (m, 2H),
1.27−1.18 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 168.8, 167.9,
136.9, 130.7, 130.2, 129.9, 128.2, 127.3, 53.8, 52.8, 48.7, 32.9, 25.4,
24.8; HRMS (ESI, m/z) calcd for C18H24NO5 [M + H]+ 334.1649,
found 334.1642; IR (film) 731, 910, 1149, 1258, 1636, 1751, 2933,
3370 cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)benzo[b]thiophen-3-yl)-
malonate (3r). Yield 95% (69 mg); white solid, mp 126−127 °C;
1H NMR (400 MHz, CDCl3) δ 7.83−7.78 (m, 2H), 7.42−7.40 (m,
Dimethyl 2-(2-(Isopropylcarbamoyl)phenyl)malonate (5b). Yield
1
84% (49 mg); white solid, mp 151−153 °C; H NMR (400 MHz,
2H), 7.24 (s, 1H), 5.78 (s, 1H), 3.78 (s, 6H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 168.4, 161.6, 138.7, 138.6, 138.3, 126.0, 125.7,
124.9, 123.0, 122.6, 53.1, 52.4, 50.2, 28.5; HRMS (ESI, m/z) calcd for
C18H22NO5S [M + H]+ 364.1213, found 364.1208; IR (film) 728,
1157, 1297, 1541, 1653, 1746, 2958, 3307 cm−1.
CDCl3) δ 7.51−7.42 (m, 3H), 7.37−7.33 (m, 1H), 6.12 (d, J = 6.8 Hz,
1H), 5.36 (s, 1H), 4.26−4.18 (m, 1H), 3.76 (s, 6H), 1.23 (d, J = 6.6
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 168.8, 167.9, 136.7, 130.8,
130.2, 129.8, 128.2, 127.3, 53.8, 52.8, 41.9, 22.5; HRMS (ESI, m/z)
calcd for C15H20NO5 [M + H]+ 294.1336, found 294.1333; IR (film)
706, 1147, 1260, 1546, 1629, 1749, 2955, 3266 cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)benzofuran-3-yl)malonate
1
(3s). Yield 49% (34 mg); white solid, mp 164−167 °C; H NMR
Dimethyl 2-(2-(Propylcarbamoyl)phenyl)malonate (5c). Yield
1
(400 MHz, CDCl3) δ 7.74 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.3 Hz,
1H), 7.42−7.38 (m, 1H), 7.30−7.27 (m, 1H), 6.59 (s, 1H), 6.43 (s,
1H), 3.76 (s, 6H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
168.1, 158.8, 153.1, 144.4, 127.3, 127.0, 123.7, 123.0, 116.9, 111.4,
52.8, 51.8, 47.6, 28.9; HRMS (ESI, m/z) calcd for C18H22NO6 [M +
H]+ 348.1442, found 348.1444; IR (film) 751, 1030, 1154, 1276, 1637,
1741, 2922, 3331 cm−1.
55% (32 mg); white solid, mp 98−100 °C; H NMR (400 MHz,
CDCl3) δ 7.51−7.42 (m, 3H), 7.38−7.34 (m, 1H), 6.34 (br, 1H), 5.37
(s, 1H), 3.76 (s, 6H), 3.37 (q, J = 6.8 Hz, 2H), 1.66−1.51 (m, 2H),
0.98 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 168.7,
136.6, 130.9, 130.3, 130.0, 128.3, 127.4, 53.9, 52.8, 41.6, 22.7, 11.3;
HRMS (ESI, m/z) calcd for C15H20NO5 [M + H]+ 294.1336, found
294.1335; IR (film) 741, 1148, 1261, 1435, 1640, 1736, 2961, 3302
cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)thiophen-3-yl)malonate (3t).
Yield 69% (43 mg); white solid, mp 84−85 °C; 1H NMR (400 MHz,
CDCl3) δ 7.30 (d, J = 5.1 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 6.30 (s,
1H), 5.70 (s, 1H), 3.77 (s, 6H), 1.44 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 168.4, 161.5, 136.0, 133.6, 130.0, 125.9, 52.9, 52.2, 51.0,
28.7; HRMS (ESI, m/z) calcd for C14H20NO5S [M + H]+ 314.1057,
found 314.1056; IR (film) 742, 1152, 1214, 1543, 1648, 1736, 2954,
3367 cm−1.
Dimethyl 2-(2-(Adamantan-1-ylcarbamoyl)phenyl)malonate
1
(5d). Yield 90% (69 mg); white solid, mp 144−145 °C; H NMR
(400 MHz, CDCl3) δ 7.51−7.49 (m, 1H), 7.45−7.39 (m, 2H), 7.36−
7.32 (m, 1H), 5.83 (s, 1H), 5.39 (s, 1H), 3.76 (s, 6H), 2.11 (s, 9H),
1.72 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 168.8, 168.1, 138.0,
130.2, 129.8, 129.7, 128.2, 127.2, 53.5, 52.8, 52.7, 41.4, 36.2, 29.4;
HRMS (ESI, m/z) calcd for C22H28NO5 [M + H]+ 386.1962, found
386.1960; IR (film) 729, 1148, 1306, 1524, 1652, 1736, 2907, 3365
cm−1.
Dimethyl 2-(2-(tert-Butylcarbamoyl)furan-3-yl)malonate (3u).
1
Yield 52% (31 mg); white solid, mp 164−166 °C; H NMR (400
MHz, CDCl3) δ 7.34 (d, J = 1.7 Hz, 1H), 6.69 (d, J = 1.7 Hz, 1H),
6.24 (s, 1H), 5.94 (s, 1H), 3.76 (s, 6H), 1.44 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 168.2, 158.2, 143.8, 142.0, 122.0, 113.7, 52.8, 51.5,
47.9, 28.9; HRMS (ESI, m/z) calcd for C14H20NO6 [M + H]+
298.1285, found 298.1282; IR (film) 761, 1151, 1276, 1543, 1638,
1756, 2931, 3357 cm−1.
Diethyl 2-(2-(tert-Butylcarbamoyl)phenyl)malonate (3v). Yield
84% (56 mg); white solid, mp 47−48 °C; 1H NMR (400 MHz,
CDCl3) δ 7.52−7.50 (m, 1H), 7.44−7.39 (m, 2H), 7.36−7.32 (m,
1H), 6.00 (s, 1H), 5.32 (s, 1H), 4.30−4.16 (m, 4H), 1.45 (s, 9H), 1.27
(t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 168.5, 168.4,
138.0, 130.4, 129.8, 129.6, 128.1, 127.2, 61.8, 54.0, 51.9, 28.6, 14.0;
HRMS (ESI, m/z) calcd for C18H26NO5 [M + H]+ 336.1806, found
Dimethyl 2-(2-(Diisopropylcarbamoyl)phenyl)malonate (5e).
Yield 96% (64 mg); white solid, mp 94−96 °C; 1H NMR (400
MHz, CDCl3) δ 7.56 (d, J = 7.6 Hz, 1H), 7.41−7.36 (m, 1H), 7.35−
7.31 (m, 1H), 7.17 (d, J = 7.4 Hz, 1H), 4.92 (s, 1H), 3.75 (s, 3H), 3.74
(s, 3H), 3.72−3.67 (m, 1H), 3.56−3.45 (m, 1H), 1.57 (t, J = 7.6 Hz,
6H), 1.12 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 169.2, 168.8, 168.2, 138.6, 129.8, 129.4, 128.6,
128.0, 124.8, 53.7, 52.9, 52.8, 50.9, 45.9, 20.6, 20.5, 20.5, 20.3; HRMS
(ESI, m/z) calcd for C18H26NO5 [M + H]+ 336.1806, found 336.1802;
IR (film) 731, 1032, 1147, 1341, 1436, 1626, 1738, 2936 cm−1.
Dimethyl 2-(2-(Dimethylcarbamoyl)phenyl)malonate (5f). Yield
45% (64 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.60−7.58
(m, 1H), 7.44−7.40 (m, 1H), 7.38−7.34 (m, 1H), 7.24−7.22 (m, 1H),
I
dx.doi.org/10.1021/jo5023102 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4.88 (s, 1H), 3.75 (s, 6H), 3.12 (s, 3H), 2.84 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 170.2, 168.4, 136.8, 129.8, 129.2, 128.1, 126.2, 53.8,
52.9, 39.0, 34.8; HRMS (ESI, m/z) calcd for C14H18NO5 [M + H]+
280.1180, found 280.1177; IR (film) 731, 915, 1195, 1266, 1436, 1629,
1737, 2919 cm−1.
Dimethyl 2-(2-(Morpholine-4-carbonyl)phenyl)malonate (5g).
Yield 75% (48 mg); white solid, mp 99−100 °C; 1H NMR (400
MHz, CDCl3) δ 7.60 (d, J = 7.8 Hz, 1H), 7.45−7.42 (m, 1H), 7.39−
7.35 (m, 1H), 7.22 (d, J = 7.5 Hz, 1H), 4.94 (s, 1H), 3.94−3.57 (m,
12H), 3.26 (br, 2H); 13C NMR (100 MHz, CDCl3) δ 168.8, 135.8,
130.1, 129.8, 129.5, 128.1, 126.1, 66.8, 66.7, 53.6, 52.9, 47.7, 42.1;
HRMS (ESI, m/z) calcd for C16H20NO6 [M + H]+ 322.1285, found
322.1280; IR (film) 731, 1019, 1114, 1280, 1432, 1632, 1736, 2954
cm−1.
Dimethyl 2-(2-Pivaloylphenyl)malonate (5h). Yield 55% (32 mg);
colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 1H),
7.45−7.41 (m, 1H), 7.37−7.31 (m, 2H), 4.63 (s, 1H), 3.75 (s, 6H),
1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 213.1, 168.4, 140.6,
130.3, 129.7, 129.4, 127.1, 125.2, 54.1, 52.9, 45.0, 27.6; HRMS (ESI,
m/z) calcd for C16H21O5 [M + H]+ 293.1384, found 293.1380; IR
(film) 746, 965, 1147, 1276, 1435, 1682, 1739, 2956 cm−1.
Dimethyl 2-(2-Isobutyrylphenyl)malonate (5i). Yield 61% (34
mg); yellow solid, mp 51−54 °C; 1H NMR (400 MHz, CDCl3) δ 7.72
(d, J = 7.6 Hz, 1H), 7.54−7.48 (m, 2H), 7.45−7.41 (m, 1H), 5.25 (s,
1H), 3.77 (s, 6H), 3.50−3.40 (m, 1H), 1.18 (d, J = 6.9 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 207.9, 168.9, 137.5, 132.5, 131.6, 130.5,
128.2, 128.0, 54.2, 52.7, 38.0, 18.6; HRMS (ESI, m/z) calcd for
C15H19O5 [M + H]+ 279.1227, found 279.1224, calcd for C15H18NaO5
[M + Na]+ 301.1046, found 301.1045; IR (film) 732, 979, 1148, 1228,
1435, 1682, 1738, 2923 cm−1.
280.1543, found 280.1545; IR (film) 727, 1163, 1250, 1497, 1648,
1737, 2960, 3338 cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)-5-nitrophenyl)acetate (6c).
Yield 87% (51 mg); white solid, mp 86−88 °C; 1H NMR (400
MHz, CDCl3) δ 8.13 (dd, J = 2.1, 8.4 Hz, 1H), 8.09 (d, J = 2.1 Hz,
1H), 7.61 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 3.94 (s, 2H), 3.75 (s, 3H),
1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.5, 166.9, 148.0,
143.8, 133.4, 128.7, 125.9, 122.5, 52.4, 52.3, 38.4, 28.5; HRMS (ESI,
m/z) calcd for C14H19N2O5 [M + H]+ 295.1288, found 295.1292; IR
(film) 734, 1220, 1348, 1525, 1648, 1739, 2966, 3303 cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)-5-(trifluoromethyl)phenyl)-
1
acetate (6d). Yield 84% (53 mg); white solid, mp 75−77 °C; H
NMR (400 MHz, CDCl3) δ 7.57 (s, 2H), 7.48 (s, 1H), 6.27 (s, 1H),
3.91 (s, 2H), 3.73 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 171.9, 167.7, 141.5, 132.4, 131.7 (q, J = 32.6 Hz), 128.2, 127.8 (q, J =
3.7 Hz), 124.5 (q, J = 3.7 Hz), 123.5 (q, J = 272.6 Hz), 52.3, 52.1, 38.5,
28.6; HRMS (ESI, m/z) calcd for C15H19F3NO3 [M + H]+ 318.1312,
found 318.1313; IR (film) 842, 1127, 1218, 1330, 1538, 1647, 1741,
3313 cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)-5-chlorophenyl)acetate (6e).
Yield 83% (47 mg); white solid, mp 73−75 °C; 1H NMR (400 MHz,
CDCl3) δ 7.40 (d, J = 8.2 Hz, 1H), 7.26 (dd, J = 2.0, 8.2 Hz, 1H), 7.21
(d, J = 2.0 Hz, 1H), 6.27 (s, 1H), 3.83 (s, 2H), 3.72 (s, 3H), 1.43 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 172.0, 167.9, 136.5, 135.4,
133.4, 130.8, 129.0, 127.6, 52.2, 51.9, 38.4, 28.6; HRMS (ESI, m/z)
calcd for C14H19ClNO3 [M + H]+ 284.1048, found 284.1048; IR
(film) 830, 1167, 1220, 1538, 1645, 1739, 2965, 3303 cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)-5-iodophenyl)acetate (6f).
1
Yield 88% (66 mg); colorless oil; H NMR (400 MHz, CDCl3) δ
7.63 (dd, J = 1.4, 8.1 Hz, 1H), 7.58 (d, J = 1.4 Hz, 1H), 7.18 (d, J = 8.1
Hz, 1H), 6.26 (s, 1H), 3.79 (s, 2H), 3.72 (s, 3H), 1.42 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 172.0, 168.0, 139.6, 137.6, 136.5, 133.5,
129.1, 95.7, 52.2, 51.9, 38.1, 28.6; HRMS (ESI, m/z) calcd for
C14H19INO3 [M + H]+ 376.0404, found 376.0403; IR (film) 882,
1167, 1219, 1533, 1644, 1738, 2968, 3320 cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)-4-methylphenyl)acetate (6g).
Yield 93% (49 mg); white solid, mp 69−70 °C; 1H NMR (400 MHz,
CDCl3) δ 7.27 (s, 1H), 7.12 (AB quart, J = 7.8 Hz, 2H), 6.28 (s, 1H),
3.80 (s, 2H), 3.70 (s, 3H), 2.34 (s, 3H), 1.44 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 172.8, 169.0, 138.0, 137.2, 130.7, 130.4, 128.2, 128.2,
52.0, 51.6, 38.2, 28.6, 20.9; HRMS (ESI, m/z) calcd for C15H22NO3
[M + H]+ 264.1594, found 264.1596; IR (film) 822, 1163, 1221, 1530,
1651, 1739, 2969, 3321 cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)-3-methoxyphenyl)acetate
(6h). Yield 95% (53 mg); white solid, mp 92−93 °C; 1H NMR
(400 MHz, CDCl3) δ 7.28−7.24 (m, 1H), 6.85−6.81 (m, 2H), 5.97 (s,
1H), 3.83 (s, 3H), 3.73 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 172.3, 166.4, 156.3, 132.6, 129.8, 128.1, 122.7,
110.2, 55.9, 52.0, 51.7, 38.3, 28.7; HRMS (ESI, m/z) calcd for
C15H22NO4 [M + H]+ 280.1543, found 280.1546; IR (film) 764, 1078,
1263, 1470, 1660, 1736, 2962, 3376 cm−1.
Dimethyl 2-(2-Benzoylphenyl)malonate (5j). Yield 34% (21 mg);
1
yellow oil; H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H),
7.62−7.56 (m, 3H), 7.48−7.40 (m, 4H), 5.14 (s, 1H), 3.73 (s, 6H),
3.50−3.40 (m, 1H), 1.18 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 197.5, 168.6, 138.1, 137.5, 133.2, 132.4, 131.1, 130.4, 130.3,
130.0, 128.4, 127.4, 54.0, 52.8; HRMS (ESI, m/z) calcd for C18H17O5
[M + H]+ 313.1070, found 313.1067; IR (film) 717, 1022, 1151, 1257,
1435, 1662, 1739, 2925 cm−1.
Dimethyl 2-(2-Pivalamidophenyl)malonate (5k). Yield 70% (43
mg); white solid, mp 79−81 °C; 1H NMR (400 MHz, CDCl3) δ 9.03
(s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.38−7.34 (m, 1H), 7.22−7.20 (m,
1H), 7.15−7.11 (m, 1H), 4.66 (s, 1H), 3.74 (s, 6H), 1.30 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 177.2, 169.4, 137.0, 131.5, 129.2, 126.5,
125.7, 125.2, 56.8, 53.1, 39.5, 27.4; HRMS (ESI, m/z) calcd for
C16H22NO5 [M + H]+ 308.1492, found 308.1490; IR (film) 749, 1155,
1300, 1441, 1680, 1726, 2958, 3353 cm−1.
Dimethyl 2-(2-(2-(tert-Butylamino)-2-oxoethyl)phenyl)malonate
1
(5l). Yield 56% (36 mg); white solid, mp 87−89 °C; H NMR (400
MHz, CDCl3) δ 7.48−7.46 (m, 1H), 7.35−7.27 (m, 3H), 5.34 (s, 1H),
4.90 (s, 1H), 3.76 (s, 6H), 3.54 (s, 2H), 1.24 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 169.2, 168.6, 134.2, 131.8, 130.9, 130.2, 128.9, 128.0,
53.8, 52.9, 51.2, 42.5, 28.4; HRMS (ESI, m/z) calcd for C17H24NO5
[M + H]+ 322.1649, found 322.1642; IR (film) 735, 1148, 1224, 1434,
1651, 1737, 2958, 3321 cm−1.
Methyl 2-(5-Bromo-2-(tert-butylcarbamoyl)-4-methylphenyl)-
1
acetate (6i). Yield 86% (59 mg); white solid, mp 97−99 °C; H
NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.32 (s, 1H), 6.30 (s, 1H),
3.78 (s, 2H), 3.72 (s, 3H), 2.38 (s, 3H), 1.43 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 172.3, 168.0, 137.3, 137.2, 134.4, 130.4, 129.8, 126.0,
52.2, 51.8, 37.8, 28.6, 22.3; HRMS (ESI, m/z) calcd for
C15H2179BrNO3 [M + H]+ 342.0699, found 342.0698; IR (film) 733,
1165, 1220, 1553, 1644, 1739, 2969, 3327 cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)phenyl)acetate (6a). Yield 86%
(43 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.46−7.44 (m,
1H), 7.36−7.27 (m, 2H), 7.22−7.20 (m, 1H), 6.26 (s, 1H), 3.86 (s,
2H), 3.70 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
172.5, 168.9, 138.1, 131.4, 130.8, 129.7, 127.5, 127.4, 52.0, 51.7, 38.6,
28.6; HRMS (ESI, m/z) calcd for C14H20NO3 [M + H]+ 250.1438,
found 250.1440; IR (film) 732, 1165, 1220, 1530, 1655, 1738, 2965,
3336 cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)-5-methoxyphenyl)acetate
(6b). Yield 84% (47 mg); white solid, mp 64−65 °C; 1H NMR
(400 MHz, CDCl3) δ 7.42 (d, J = 8.5 Hz, 1H), 6.80 (dd, J = 2.5, 8.5
Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H), 6.23 (s, 1H), 3.86 (s, 2H), 3.80 (s,
3H), 3.71 (s, 3H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
172.4, 168.7, 160.4, 133.5, 130.6, 129.3, 116.4, 112.4, 55.2, 52.1, 51.6,
38.9, 28.7; HRMS (ESI, m/z) calcd for C15H22NO4 [M + H]+
Methyl 2-(3-Bromo-2-(tert-butylcarbamoyl)-4-methylphenyl)-
1
acetate (6j). Yield 92% (63 mg); white solid, mp 111−114 °C; H
NMR (400 MHz, CDCl3) δ 7.18 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 7.8
Hz, 1H), 5.81 (s, 1H), 3.71 (s, 3H), 3.68 (s, 2H), 2.39 (s, 3H), 1.44 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 172.1, 166.9, 140.4, 137.9,
130.7, 129.6, 129.0, 122.2, 52.1, 52.1, 38.2, 28.5, 23.1; HRMS (ESI, m/
z) calcd for C15H2179BrNO3 [M + H]+ 342.0699, found 342.0700; IR
(film) 731, 1170, 1221, 1529, 1655, 1737, 2964, 3307 cm−1.
Methyl 2-(3-(tert-Butylcarbamoyl)naphthalen-2-yl)acetate (6k).
C3:C1 > 15:1, total yield 93% (56 mg); white solid, mp 139−140 °C;
1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.84−7.76 (m, 2H), 7.66
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The Journal of Organic Chemistry
Article
(s, 1H), 7.50−7.47 (m, 2H), 6.19 (s, 1H), 4.06 (s, 2H), 3.71 (s, 3H),
1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.6, 169.2, 135.9,
133.6, 131.9, 130.2, 129.2, 127.9, 127.4, 127.2, 127.1, 126.5, 52.0, 51.8,
38.8, 28.6; HRMS (ESI, m/z) calcd for C18H22NO3 [M + H]+
300.1594, found 300.1596; IR (film) 759, 1165, 1253, 1536, 1659,
1713, 2969, 3310 cm−1.
7.21 (dd, J = 1.3, 7.5 Hz, 1H), 6.09 (s, 1H), 3.87 (s, 2H), 3.72 (s, 3H),
2.10 (s, 9H), 1.71 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 172.5,
168.6, 138.2, 131.4, 130.8, 129.7, 127.6, 127.4, 52.5, 52.1, 41.4, 38.6,
36.3, 29.4; HRMS (ESI, m/z) calcd for C20H26NO3 [M + H]+
328.1907, found 328.1909; IR (film) 729, 1162, 1306, 1527, 1649,
1738, 2906, 3362 cm−1.
Methyl 2-(1-(tert-Butylcarbamoyl)naphthalen-2-yl)acetate (6l).
Methyl 2-(2-(Diisopropylcarbamoyl)phenyl)acetate (6t). Yield
1
1
Yield 84% (50 mg); yellow solid, mp 99−101 °C; H NMR (400
90% (50 mg); colorless oil; H NMR (400 MHz, CDCl3) δ 7.32−
MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.82−7.78 (m, 2H), 7.55−
7.46 (m, 2H), 7.30 (d, J = 8.4 Hz, 1H), 6.28 (s, 1H), 3.90 (br, 2H),
3.72 (s, 3H), 1.52 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.4,
168.2, 136.1, 132.5, 130.2, 129.1, 127.9, 127.3, 127.0, 126.2, 125.2,
52.2, 52.1, 38.8, 28.7; HRMS (ESI, m/z) calcd for C18H22NO3 [M +
H]+ 300.1594, found 300.1597; IR (film) 732, 1163, 1221, 1526, 1656,
1735, 2968, 3349 cm−1.
7.24 (m, 3H), 7.15 (d, J = 7.2 Hz, 1H), 3.86−3.73 (m, 2H), 3.68 (s,
3H), 3.53−3.47 (m, 2H), 1.56 (d, J = 6.8 Hz, 6H), 1.13−1.09 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 171.8, 169.8, 138.4, 130.8,
130.7, 128.4, 126.9, 125.0, 51.9, 50.8, 45.8, 37.7, 20.7, 20.6, 20.5, 20.4;
HRMS (ESI, m/z) calcd for C16H24NO3 [M + H]+ 278.1757, found
278.1755; IR (film) 731, 1162, 1213, 1338, 1436, 1628, 1739, 2966
cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)benzo[b]thiophen-3-yl)acetate
2-(2-tert-Butylcarbamoyl)phenyl)acetic Acid (7a). Yield 86% (40
mg); yellow solid, mp 146−148 °C; H NMR (400 MHz, CDCl3) δ
1
1
(6m). Yield 95% (58 mg); white solid, mp 111−113 °C; H NMR
(400 MHz, CDCl3) δ 7.82−7.79 (m, 2H), 7.43−7.38 (m, 2H), 7.32
(br, 1H), 4.12 (s, 2H), 3.74 (s, 3H), 1.50 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 171.7, 162.1, 139.2, 138.8, 138.2, 127.2, 126.0, 124.7,
122.7, 122.6, 52.6, 52.3, 33.0, 28.8; HRMS (ESI, m/z) calcd for
C16H20NO3S [M + H]+ 306.1158, found 306.1159; IR (film) 757,
1219, 1298, 1541, 1652, 1719, 2966, 3321 cm−1.
13.47 (br, 1H), 7.46−7.39 (m, 3H), 7.32−7.28 (m, 1H), 6.37 (br,
1H), 3.68 (s, 2H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
171.7, 171.1, 135.3, 133.1, 131.6, 131.4, 127.7, 127.4, 53.0, 42.0, 28.5;
HRMS (ESI, m/z) calcd for C13H18NO3 [M + H]+ 236.1281, found
236.1280; IR (film) 731, 1219, 1454, 1556, 1590, 1731, 2972, 3290
cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)benzofuran-3-yl)acetate (6n).
Yield 57% (33 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.57
(d, J = 7.8 Hz, 1H), 747−7.38 (m, 2H), 7.30−7.26 (m, 1H), 6.56 (s,
1H), 4.28 (s, 2H), 3.71 (s, 3H), 1.49 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.9, 159.1, 153.0, 144.34, 128.7, 126.9, 123.4, 121.0,
117.8, 111.5, 52.1, 51.6, 29.4, 28.9; HRMS (ESI, m/z) calcd for
C16H20NO4 [M + H]+ 290.1387, found 290.1388; IR (film) 748, 1165,
1449, 1517, 1663, 1741, 2968, 3434 cm−1.
2-(2-(tert-Butylcarbamoyl)-5-methylphenyl)acetic Acid (7b).
Yield 86% (43 mg); yellow oil; 1H NMR (400 MHz, CDCl3) δ
13.96 (br, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.21 (s, 1H), 7.10 (d, J = 7.8
Hz, 1H), 6.31 (br, 1H), 3.65 (s, 2H), 2.34 (s, 3H), 1.48 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 171.8, 171.2, 142.0, 133.2, 132.3, 128.3,
127.4, 52.9, 42.0, 28.5, 21.1; HRMS (ESI, m/z) calcd for C14H20NO3
[M + H]+ 250.1438, found 250.1439; IR (film) 732, 911, 1220, 1455,
1595, 1731, 2972, 3309 cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)thiophen-3-yl)acetate (6o).
Yield 96% (49 mg); white solid, mp 56−58 °C; 1H NMR (400
MHz, CDCl3) δ 7.29 (d, J = 5.0 Hz, 1H), 6.92 (d, J = 5.0 Hz, 1H),
6.85 (br, 1H), 3.90 (s, 2H), 3.73 (s, 3H), 1.45 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 172.0, 161.8, 136.9, 133.6, 130.3, 126.7, 52.4, 52.0,
34.8, 28.8; HRMS (ESI, m/z) calcd for C12H18NO3S [M + H]+
256.1002, found 256.1004; IR (film) 720, 1219, 1299, 1545, 1649,
1736, 2964, 3313 cm−1.
Methyl 2-(2-(tert-Butylcarbamoyl)furan-3-yl)acetate (6p). Yield
66% (32 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J
= 1.7 Hz, 1H), 6.50 (d, J = 1.7 Hz, 1H), 6.23 (br, 1H), 4.02 (s, 2H),
3.71 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.5,
158.7, 143.5, 141.9, 122.9, 114.5, 51.9, 51.3, 30.7, 29.0; HRMS (ESI,
m/z) calcd for C12H18NO4 [M + H]+ 240.1230, found 240.1230, calcd
for C12H17NNaO4 [M + Na]+ 262.1050, found 262.1055; IR (film)
748, 852, 1171, 1525, 1658, 1741, 2921, 3439 cm−1.
2-(2-(tert-Butylcarbamoyl)-5-methoxyphenyl)acetic Acid (7c).
Yield 99% (53 mg); yellow solid, mp 116−118 °C; H NMR (400
1
MHz, CDCl3) δ 13.07 (br, 1H), 7.38 (d, J = 8.6 Hz, 1H), 6.92 (d, J =
2.5 Hz, 1H), 6.81 (dd, J = 2.5, 8.6 Hz, 1H), 6.09 (br, 1H), 3.82 (s,
3H), 3.69 (s, 3H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
171.0, 161.8, 135.7, 129.0, 127.3, 116.4, 113.7, 113.6, 55.5, 52.9, 42.5,
28.6; HRMS (ESI, m/z) calcd for C14H20NO4 [M + H]+ 266.1387,
found 266.1385; IR (film) 732, 1251, 1456, 1548, 1603, 1731, 2972,
3307 cm−1.
2-(2-(tert-Butylcarbamoyl)-5-(trifluoromethyl)phenyl)acetic Acid
1
(7d). Yield 84% (51 mg); yellow solid, mp 132−135 °C; H NMR
(400 MHz, CDCl3) δ 10.83 (br, 1H), 7.59−7.52 (m, 3H), 6.63 (s,
1H), 3.74 (s, 2H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
171.9, 169.5, 139.2, 133.6, 132.8 (q, J = 33.0 Hz), 128.2, 128.1 (q, J =
3.6 Hz), 124.6 (q, J = 3.5 Hz), 123.2 (q, J = 272.7 Hz), 53.2, 41.0,
28.4; HRMS (ESI, m/z) calcd for C14H17F3NO3 [M + H]+ 304.1155,
found 304.1158; IR (film) 669, 730, 907, 1136, 1332, 1550, 1605,
1732 cm−1.
Methyl 2-(2-(Cyclohexylcarbamoyl)phenyl)acetate (6q). Yield
1
76% (42 mg); white solid, mp 135−136 °C; H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 7.4 Hz, 1H), 7.38−7.27 (m, 2H), 7.24 (d, J = 7.4
Hz, 1H), 6.45 (d, J = 5.2 Hz, 1H), 3.95−3.93 (m, 1H), 3.85 (s, 2H),
3.71 (s, 3H), 2.02−1.99 (m, 2H), 1.76−1.62 (m, 3H), 1.46−1.37 (m,
2H), 1.26−1.18 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 172.7,
168.3, 137.3, 131.6, 130.9, 129.9, 127.8, 127.5, 52.2, 48.6, 38.7, 32.9,
25.5, 24.8; HRMS (ESI, m/z) calcd for C16H22NO3 [M + H]+
276.1594, found 276.1594, calcd for C16H21NNaO3 [M + Na]+
298.1414, found 298.1421; IR (film) 732, 909, 1247, 1541, 1628,
1730, 2933, 3284 cm−1.
2-(2-(tert-Butylcarbamoyl)-5-nitrophenyl)acetic Acid (7e). Yield
1
95% (53 mg); brown solid, mp 140−143 °C; H NMR (400 MHz,
CDCl3) δ 9.74 (br, 1H), 8.16 (d, J = 2.1 Hz, 1H), 8.10 (dd, J = 2.1, 8.4
Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.54 (br, 1H), 3.83 (s, 2H), 1.48 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 172.0, 168.4, 148.6, 141.9,
134.4, 128.8, 126.1, 122.6, 53.3, 40.5, 28.4; HRMS (ESI, m/z) calcd for
C13H17N2O5 [M + H]+ 281.1132, found 281.1137; IR (film) 733, 913,
1222, 1349, 1522, 1655, 2963, 3300 cm−1.
2-(2-(tert-Butylcarbamoyl)-5-chlorophenyl)acetic Acid (7f). Yield
1
Methyl 2-(2-(Isopropylcarbamoyl)phenyl)acetate (6r). Yield 83%
96% (52 mg); brown solid, mp 158−161 °C; H NMR (400 MHz,
1
(39 mg); white solid, mp 81−83 °C; H NMR (400 MHz, CDCl3) δ
CDCl3) δ 12.83 (br, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.36 (s, 1H), 7.26
(d, J = 8.3 Hz, 1H), 6.48 (s, 1H), 3.66 (s, 2H), 1.48 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 171.4, 170.0, 137.2, 134.8, 133.9, 131.4, 128.9,
127.8, 53.1, 41.4, 28.4; HRMS (ESI, m/z) calcd for C13H17ClNO3 [M
+ H]+ 270.0892, found 270.0893; IR (film) 731, 907, 1220, 1458,
1584, 1721, 2928, 3252 cm−1.
7.45 (d, J = 7.4 Hz, 1H), 7.38−7.28 (m, 2H), 7.23 (d, J = 7.4 Hz, 1H),
6.43 (s, 1H), 4.28−4.19 (m, 1H), 3.85 (s, 2H), 3.70 (s, 3H), 1.23 (d, J
= 6.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.6, 168.4, 137.2,
131.6, 131.0, 130.0, 127.7, 127.4, 52.1, 41.8, 38.6, 22.6; HRMS (ESI,
m/z) calcd for C13H18NO3 [M + H]+ 236.1281, found 236.1284, calcd
for C13H17NNaO3 [M + Na]+ 258.1101, found 258.1101; IR (film)
731, 1170, 1259, 1533, 1638, 1736, 2970, 3292 cm−1.
2-(2-(tert-Butylcarbamoyl)-5-iodophenyl)acetic Acid (7g). Yield
1
93% (67 mg); gray solid, mp 125−129 °C; H NMR (400 MHz,
Methyl 2-(2-(Adamantan-1-ylcarbamoyl)phenyl)acetate (6s).
Yield 75% (49 mg); white solid, mp 90−91 °C; 1H NMR (400
MHz, CDCl3) δ 7.46 (dd, J = 1.3, 7.5 Hz, 1H), 7.36−7.28 (m, 2H),
CDCl3) δ 12.07 (br, 1H), 7.72 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.18
(d, J = 8.1 Hz, 1H), 6.56 (s, 1H), 3.61 (s, 2H), 1.47 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 171.6, 170.1, 140.1, 136.7, 134.9, 134.7, 129.0,
K
dx.doi.org/10.1021/jo5023102 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
97.7, 53.1, 41.1, 28.4; HRMS (ESI, m/z) calcd for C13H17INO3 [M +
H]+ 362.0248, found 362.0252; IR (film) 733, 894, 1218, 1455, 1580,
1727, 2966, 3291 cm−1.
135−136 °C; H NMR (400 MHz, CDCl3) δ 7.08 (s, 2H), 5.91 (s,
1H), 4.94 (s, 2H), 3.81 (s, 3H), 3.76 (s, 12H), 1.43 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 168.5, 166.8, 159.5, 132.0, 130.8, 114.7, 55.4,
53.8, 52.9, 52.2, 28.4; HRMS (ESI, m/z) calcd for C22H30NO10 [M +
H]+ 468.1864, found 468.1862; IR (film) 732, 1147, 1309, 1436, 1660,
1737, 2953, 3368 cm−1.
2-(2-(tert-Butylcarbamoyl)-3-methoxyphenyl)acetic Acid (7h).
1
Yield 99% (53 mg); yellow oil; H NMR (400 MHz, CDCl3) δ 7.33
(t, J = 8.0 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H),
6.45 (s, 1H), 3.87 (s, 3H), 3.63 (s, 2H), 1.48 (s, 9H), acid proton was
not found; 13C NMR (100 MHz, CDCl3) δ 171.6, 168.0, 156.4, 135.0,
131.5, 124.5, 123.6, 110.6, 56.1, 52.8, 42.1, 28.6; HRMS (ESI, m/z)
calcd for C14H20NO4 [M + H]+ 266.1387, found 266.1388; IR (film)
733, 911, 1081, 1264, 1470, 1596, 1730, 2974 cm−1.
Tetramethyl 2,2′-(2-(tert-Butylcarbamoyl)-5-chloro-1,3-
phenylene)dimalonate (8c). Yield 78% (74 mg); white solid, mp
1
141−143 °C; H NMR (400 MHz, CDCl3) δ 7.56 (s, 2H), 5.94 (s,
1H), 4.89 (s, 2H), 3.78 (s, 12H), 1.43 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 168.2, 165.9, 137.5, 135.1, 131.1, 129.4, 53.6, 53.1, 52.5,
28.4; HRMS (ESI, m/z) calcd for C21H27ClNO9 [M + H]+ 472.1369,
found 472.1370; IR (film) 734, 1020, 1145, 1223, 1658, 1737, 2957,
3350 cm−1.
2-(3-(tert-Butylcarbamoyl)naphthalen-2-yl)acetic Acid (7i). Yield
1
90% (52 mg); yellow solid, mp 168−171 °C; H NMR (400 MHz,
CDCl3) δ 13.76 (br, 1H), 7.92 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.77
(s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.54−7.45 (m, 2H), 6.55 (s, 1H),
3.78 (s, 2H), 1.53 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.0,
171.3, 134.1, 133.2, 131.5, 130.7, 129.1, 128.1, 127.9, 127.8, 127.5,
127.0, 53.1, 41.8, 28.5; HRMS (ESI, m/z) calcd for C17H20NO3 [M +
H]+ 286.1438, found 286.1442; IR (film) 733, 1166, 1218, 1449, 1527,
1611, 1739, 2969 cm−1.
Tetramethyl 2,2′-(2-(tert-Butylcarbamoyl)-4-methoxy-1,3-
phenylene)dimalonate (8d). Yield 78% (73 mg); white solid, mp
163−165 °C; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.7 Hz, 1H),
6.97 (d, J = 8.7 Hz, 1H), 6.01 (s, 1H), 4.90 (s, 1H), 4.87 (s, 1H), 3.81
(s, 3H), 3.76−1.73 (m, 12H), 1.40 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 168.9, 168.4, 168.3, 166.5, 157.5, 140.3, 130.6, 121.4, 119.4,
112.2, 56.1, 53.1, 52.8, 52.5, 52.3, 51.2, 28.3; HRMS (ESI, m/z) calcd
for C22H30NO10 [M + H]+ 468.1864, found 468.1861; IR (film) 731,
912, 1150, 1263, 1662, 1737, 2955, 3356 cm−1.
2-(1-(tert-Butylcarbamoyl)naphthalen-2-yl)acetic Acid (7j). Yield
81% (43 mg); yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J =
8.4 Hz, 1H), 7.83−7.78 (m, 2H), 7.56−7.47 (m, 2H), 7.34 (d, J = 8.4
Hz, 1H), 6.29 (s, 1H), 3.73 (s, 2H), 1.52 (s, 9H), acid proton was not
found; 13C NMR (100 MHz, CDCl3) δ 172.9, 169.7, 134.2, 132.6,
130.0, 129.8, 129.0, 128.3, 127.4, 126.4, 124.5, 53.0, 40.9, 28.6; HRMS
(ESI, m/z) calcd for C17H20NO3 [M + H]+ 286.1438, found 286.1445;
IR (film) 733, 1220, 1366, 1534, 1611, 1723, 2956, 3316 cm−1.
2-(2-(tert-Butylcarbamoyl)benzo[b]thiophen-3-yl)acetic Acid
Dimethyl 2,2′-(2-(tert-Butylcarbamoyl)-1,3-phenylene)diacetate
(9a). Yield 90% (58 mg); white solid, mp 62−64 °C; 1H NMR
(400 MHz, CDCl3) δ 7.30−7.26 (m, 1H), 7.19−7.17 (m, 2H), 6.27 (s,
1H), 3.71 (s, 10H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
172.1, 167.8, 139.1, 130.9, 129.4, 128.9, 52.0, 51.8, 38.4, 28.4; HRMS
(ESI, m/z) calcd for C17H24NO5 [M + H]+ 322.1649, found 322.1647;
IR (film) 779, 1019, 1162, 1526, 1661, 1736, 2953, 3352 cm−1.
Dimethyl 2,2′-(2-(tert-Butylcarbamoyl)-5-methyl-1,3-phenylene)-
1
(7k). Yield 84% (49 mg); yellow solid, mp 129−132 °C; H NMR
(400 MHz, CDCl3) δ 10.89 (br, 1H), 7.99−7.97 (m, 1H), 7.79−7.77
(m, 1H), 7.48−7.44 (m, 2H), 6.42 (s, 1H), 4.04 (s, 2H), 1.50 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 170.4, 164.3, 139.1, 138.2, 132.6,
132.3, 127.3, 125.6, 123.6, 122.5, 53.4, 35.6, 28.6; HRMS (ESI, m/z)
calcd for C15H18NO3S [M + H]+ 292.1002, found 292.1005, calcd for
C15H17NNaO3S [M + Na]+ 314.0821, found 314.0828; IR (film) 729,
909, 1218, 1305, 1547, 1596, 1716, 2972 cm−1.
1
diacetate (9b). Yield 85% (57 mg); white solid, mp 95−97 °C; H
NMR (400 MHz, CDCl3) δ 6.98 (s, 2H), 6.26 (s, 1H), 3.71 (s, 6H),
3.68 (s, 4H), 2.31 (s, 3H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 172.3, 168.1, 138.8, 136.5, 130.8, 130.1, 52.0, 51.8, 38.4, 28.4, 21.0;
HRMS (ESI, m/z) calcd for C18H26NO5 [M + H]+ 336.1806, found
336.1802; IR (film) 860, 1164, 1222, 1528, 1659, 1736, 2956, 3361
cm−1.
2-(2-(tert-Butylcarbamoyl)benzofuran-3-yl)acetic Acid (7l). Yield
Dimethyl 2,2′-(2-(tert-Butylcarbamoyl)-5-methoxy-1,3-
1
62% (34 mg); yellow oil; H NMR (400 MHz, CDCl3) δ 12.78 (br,
phenylene)diacetate (9c). Yield 91% (64 mg); white solid, mp
1
1H), 7.73 (d, J = 7.8 Hz, 1H), 7.50−7.46 (m, 2H), 7.36−7.27 (m,
1H), 6.72 (s, 1H), 4.04 (s, 2H), 1.53 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.6, 160.8, 153.4, 143.64, 128.0, 128.0, 124.0, 121.0,
119.2, 111.7, 52.8, 31.9, 28.7; HRMS (ESI, m/z) calcd for C15H18NO4
[M + H]+ 276.1230, found 276.1236; IR (film) 732, 1221, 1366, 1453,
1555, 1724, 2965, 3258 cm−1.
115−117 °C; H NMR (400 MHz, CDCl3) δ 6.70 (s, 2H), 6.27 (s,
1H), 3.78 (s, 3H), 3.71 (s, 6H), 3.69 (s, 4H), 1.41 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 172.1, 167.9, 159.4, 132.6, 132.1, 114.8, 55.2,
52.1, 51.7, 38.7, 28.4; HRMS (ESI, m/z) calcd for C18H26NO6 [M +
H]+ 352.1755, found 352.1749; IR (film) 734, 1167, 1320, 1525, 1655,
1731, 2966, 3376 cm−1.
2-(2-(tert-Butylcarbamoyl)thiophen-3-yl)acetic Acid (7m). Yield
Dimethyl 2,2′-(2-(tert-Butylcarbamoyl)-5-(trifluoromethyl)-1,3-
1
81% (39 mg); brown solid, mp 134−137 °C; H NMR (400 MHz,
phenylene)diacetate (9d). Yield 82% (64 mg); white solid, mp
1
CDCl3) δ 12.57 (br, 1H), 7.35 (d, J = 5.0 Hz, 1H), 7.05 (d, J = 5.0 Hz,
1H), 6.18 (s, 1H), 3.86 (s, 2H), 1.48 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 171.1, 164.0, 138.1, 132.1, 131.6, 127.5, 53.2, 37.8, 28.6;
HRMS (ESI, m/z) calcd for C11H16NO3S [M + H]+ 242.0845, found
242.0850; IR (film) 732, 909, 1216, 1366, 1422, 1548, 1723, 2970
cm−1.
108−110 °C; H NMR (400 MHz, CDCl3) δ 7.45 (s, 2H), 6.28 (s,
1H), 3.77 (s, 4H), 3.74 (s, 6H), 1.42 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 171.5, 166.7, 142.3, 132.1, 131.1 (q, J = 32.7 Hz), 126.4 (q, J
= 3.7 Hz), 123.4 (q, J = 272.6 Hz), 52.3, 38.4, 28.4; HRMS (ESI, m/z)
calcd for C18H23F3NO5 [M + H]+ 390.1523, found 390.1526; IR (film)
734, 906, 1156, 1222, 1630, 1739, 2960, 3255 cm−1.
2-(2-(tert-Butylcarbamoyl)furan-3-yl)acetic Acid (7n). Yield 42%
(20 mg); brown oil; H NMR (400 MHz, CDCl3) δ 12.91 (br, 1H),
Dimethyl 2,2′-(2-(tert-Butylcarbamoyl)-5-iodo-1,3-phenylene)-
diacetate (9e). Yield 82% (73 mg); white solid, mp 112−115 °C;
1H NMR (400 MHz, CDCl3) δ 7.54 (s, 2H), 6.28 (s, 1H), 3.72 (s,
1
7.39 (d, J = 1.0 Hz, 1H), 6.50 (d, J = 1.0 Hz, 1H), 6.41 (br, 1H), 3.77
(s, 2H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.1, 160.3,
143.4, 143.0, 124.3, 115.4, 52.5, 34.0, 28.8; HRMS (ESI, m/z) calcd for
C11H16NO4 [M + H]+ 226.1074, found 226.1072; IR (film) 767, 1188,
1406, 1533, 1611, 1655, 1735, 2970 cm−1.
6H), 3.65 (s, 4H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
171.6, 167.0, 138.7, 138.2, 132.8, 94.5, 52.2, 52.0, 38.0, 28.4; HRMS
(ESI, m/z) calcd for C17H23INO [M + H]+ 448.0615, found
5
448.0651; calcd for C17H22INNaO5 [M + Na]+ 470.0435, found
470.0442; IR (film) 701, 744, 1228, 1566, 1677, 2925 cm−1.
Dimethyl 2,2′-(2-(tert-Butylcarbamoyl)-4-methoxy-1,3-
phenylene)diacetate (9f). Yield 93% (65 mg); white solid, mp 69−
71 °C; 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.5 Hz, 1H), 6.83
(d, J = 8.7 Hz, 1H), 6.20 (s, 1H), 3.80 (s, 3H), 3.71−3.70 (m, 10H),
1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.5, 172.4, 167.8,
156.8, 140.4, 130.5, 122.5, 119.8, 110.8, 55.7, 52.0, 51.8, 37.7, 32.8,
28.5; HRMS (ESI, m/z) calcd for C18H26NO6 [M + H]+ 352.1755,
found 352.1748; IR (film) 731, 1072, 1160, 1268, 1662, 1736, 2956,
3396 cm−1.
Tetramethyl 2,2′-(2-(tert-Butylcarbamoyl)-1,3-phenylene)-
dimalonate (8a). Yield 92% (80 mg); yellow solid, mp 119−121
1
°C; H NMR (400 MHz, CDCl3) δ 7.56−7.54 (m, 2H), 7.44−7.40
(m, 1H), 5.91 (s, 1H), 4.93 (s, 2H), 3.76 (s, 12H), 1.44 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 168.7, 168.0, 166.8, 139.1, 129.4, 129.2,
53.9, 53.0, 52.4, 28.4; HRMS (ESI, m/z) calcd for C21H28NO9 [M +
H]+ 438.1759, found 438.1764; IR (film) 731, 1147, 1201, 1311, 1663,
−1
1736, 2959, 3362 cm
.
Tetramethyl 2,2′-(2-(tert-Butylcarbamoyl)-5-methoxy-1,3-
phenylene)dimalonate (8b). Yield 90% (84 mg); white solid, mp
L
dx.doi.org/10.1021/jo5023102 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Dimethyl 2,2′-(2-(tert-Butylcarbamoyl)naphthalene-1,3-diyl)-
diacetate (9g). Yield 51% (38 mg) [the monoalkylated product
(6k) was isolated in 47% yield (28 mg)], white solid, mp 147−149 °C;
1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 1H), 7.80 (d, J =
7.4 Hz, 1H), 7.70 (s, 1H), 7.55−7.47 (m, 2H), 6.41 (s, 1H), 4.19−3.97
(m, 4H), 3.73−3.72 (m, 6H), 1.45 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 172.2, 172.1, 168.4, 137.8, 133.3, 131.2, 129.8, 128.5, 128.1,
127.0, 126.8, 126.6, 123.7, 52.3, 52.0, 52.0, 38.7, 35.6, 28.5; HRMS
(ESI, m/z) calcd for C21H26NO5 [M + H]+ 372.1806, found 372.1809;
IR (film) 730, 1163, 1220, 1525, 1659, 1736, 2955, 3370 cm−1.
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5444−5452.
ASSOCIATED CONTENT
■
(13) (a) Cui, S.; Zhang, Y.; Wang, D.; Wu, Q. Chem. Sci. 2013, 4,
3912−3916. (b) Zhang, Y.; Zheng, J.; Cui, S. J. Org. Chem. 2014, 79,
6490−6500.
S
* Supporting Information
Experiments for mechanistic studies, copies of H and 13C
1
NMR spectra, and X-ray crystallographic data (CIF) for
products 3a, 3p, and 6c. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Liang, Y.; Yu, K.; Li, B.; Xu, S.; Song, H.; Wang, B. Chem.
Commun. 2014, 50, 6130−6133.
(15) Shi, J.; Yan, Y.; Li, Q.; Xu, H. E.; Yi, W. Chem. Commun. 2014,
50, 6483−6486.
(16) Jeong, J.; Patel, P.; Hwang, H.; Chang, S. Org. Lett. 2014, 16,
4598−4601.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangjb@pku.edu.cn.
(17) Hu, F.; Xia, Y.; Ye, F.; Liu, Z.; Ma, C.; Zhang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2014, 53, 1364−1367.
(18) Ye, B.; Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 7896−7899.
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Chem. Soc. 1982, 104, 352−354. (b) Bergman, R. G. Science 1984, 223,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Basic Research
Program of China (973 Program, 2015CB856600) and the
National Natural Science Foundation of China (21272010 and
21332002).
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The Journal of Organic Chemistry
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