Rh(III)-catalyzed annulation of BOC-protected benzamides with diazo compounds: Approach to isocoumarins

Article abstract of DOI:10.3390/molecules24050937

A mild rhodium-catalyzed annulation of Boc-protected benzamides with diazo compounds via C?C/C?O bond formation has been explored. In the presence of [Cp*RhCl₂]₂, AgSbF₆ and Cs₂CO₃, Boc-protected benzamides can be effectively annulated to yield isocoumarins in 0.5–2 h.

Full text of DOI:10.3390/molecules24050937

molecules
Article
Rh(III)-Catalyzed Annulation of Boc-Protected
Benzamides with Diazo Compounds: Approach
to Isocoumarins
Guangyu Dong 1,2,3, Chunpu Li 1 and Hong Liu 1,2,3,
*
1
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, China; 18115120903@163.com (G.D.); lcp1681993@163.com (C.L.)
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China
School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210,China
Correspondence: hliu@simm.ac.cn; Tel.: +86-21-50807042
2
3
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 2 February 2019; Accepted: 22 February 2019; Published: 7 March 2019
Abstract: A mild rhodium-catalyzed annulation of Boc-protected benzamides with diazo compounds
via C
−
C/C O bond formation has been explored. In the presence of [Cp*RhCl2]2, AgSbF6 and
−
Cs2CO3, Boc-protected benzamides can be effectively annulated to yield isocoumarins in 0.5–2 h.
Keywords: rhodium; annulation; Boc-protected benzamides
1. Introduction
Isocoumarins are valuable structural subunits because of their wide presence in numerous natural
and synthetic compounds that exhibit potent biological activities (Figure 1) [1–4]. Some approaches to
synthesize isocoumarins have been developed. Of the reported methods, the transition metal mediated
coupling reaction facilitated by preactived C-X or C-M reagents has been recognized as a way to
furnish the isocoumarin ring [
5–
9]. Additionally, oxidative annulations of the carboxylic acid with
alkynes could also be viewed as an alternate strategy [10
–
16]. No doubt these methods are useful
and practical, but the application of these reactions is somehow limited due to its requirements of a
stoichiometric amount of oxidants and unkind temperatures. Consequently, it is highly desirable to
develop more efficient methodologies for the synthesis of isocoumarins.
OH
O
OH
O
O
O
N
O
O
O
COOH
O
Autofluorescence isocoumarin
GABA receptor ligand
NM-3
antiangiogenic agent
185322
inhibitor of microtubule assembly
Figure 1. Bioactive isocoumarins derivatives.
Rhodium-catalyzed C-H activation/cyclization has recently been pursued for constructing diverse
heterocyclic systems [17 20]. Within rhodium catalysis, amide has attracted attention because of their
particularly stable functionality. In this context, diazo compounds, as versatile partners of amides for
C-H activation or cyclization, are widely applied in the organic process [21 27]. Prior contributions
in this area include Rh(III)-catalyzed cyclization of benzamides and diazo compounds to construct
isoindolinones via C-C/C-N bond formation reported by groups of Rovis, Yu and Cramer [28 30].
–
–
–
Molecules 2019, 24, 937; doi:10.3390/molecules24050937
www.mdpi.com/journal/molecules

Molecules 2019, 24, 937
2 of 19
Besides, Rh(III) or Ir(III) catalysts were found to be effective for the synthsis of isoquinolinones,
which is followed by the C-H coupling of N-methoxybenzamides with diazo compounds [31 32].
,
Despite significant progress, most of the reported studies are limited to bear N-heterocycles along
with the formation of a C-C/C-N bond. In sharp contrast, few examples of Rh(III)-catalyzed C-C/C-O
bond formation related to C-H cyclization of aromatics with diazo compounds are developed.
Notably, C-C/C-O bond formation via Rh(III)-catalyzed C-H activation/cyclization of aromatics
with diazo compounds has been achieved in 2015(Scheme 1, eqn (1)) [33]. In 2016, Rh(III)-catalyzed
C-H annulation of N-tosylacrylamides and diazo compounds via C-C or C-N cleavages has been
reported (Scheme 1, eqn (2)) [34]. Recently, A simple Rh(III)-catalyzed C-H activation that uses cyclic
2-diazo-1,3-diketones as starting materials has been developed (Scheme 1, eqn (3)) [35]. Though
these methods are of high synthetic value, restricted substrate scope and high temperature or long
reaction time may preclude their widespread application. Thus, it is necessary to develop more
methods to construct a C-C/C-O bond by C-H annulation. Given that the directing group (DG)
is pivotal in the construction of various heterocycles, we thus focus on finding DGs which could
offer a tool to form diverse molecules in the means of breaking the C-N bond. In response to this
unmet need, we show herein that N-tert-butoxycarbonyl (N-Boc) benzamides together with diazo
compounds, allows delivery of corresponding isocoumarins under Rh(III) catalysis via C-C/C-O
bond formation (Scheme 1, (4)). In this protocol, the Boc-protected benzamides could serve as good
substrates and the reaction proceeds with concomitant removal of NHBoc auxiliary to afford the
corresponding isocoumarins with high efficacy in short time (0.5–2 h). In this work, the tert-butyl
formylcarbamate group formally served as an oxidizing DG using the C-N bond as an internal oxidant.
Meanwhile, tert-butyl formylcarbamate group is an important structural motif of many biologically
active compounds. Our work may provide a method to enable the late-stage diversification of
functional molecules with tert-butyl formylcarbamate groups.
Scheme 1. Rh(III)-catalyzed C-H activation of benzamides derivatives: (1) N-alkyl-substituted
benzamides-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation;
(2)
Acylsulfonamide-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation; (3) Primary
benzamides-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation; (4) N-Boc
benzamides-assisted annulation via Rh(III)-catalyzed C-C/C-O bond formation.

Molecules 2019, 24, 937
3 of 19
2. Results and Discussion
2.1. Optimization of Reaction Conditions for Synthesis of Ethyl 3-Methyl-1-oxo-1H-Isochromene-4-Carboxylate
3aa
We initiated our investigation by evaluating the feasibility of the combination of N-Boc
benzamides 1a or other N-substituted benzamides 1a1
–1a5 and ethyl diazoacetoacetate 2a. As shown in
Table 1, amide derivatives 1a1 1a5 failed to undergo the annulation (Table 1, entries 1–5), while N-Boc
–
benzamides could be utilized. Therefore N-Boc benzamides 1a was opted to be used for optimization
with ethyl diazoacetoacetate 2a. We hypothesize that the electron-withdrawing capability of the Boc
group makes the C-N bond easy to break. Several additives were further screened (Table 1, entries
7–10). When Ag2O and AgOAc were added to the reaction, no evidence of 3aa was observed, while
3aa was obtained in 33% yield with AgSbF6. We then turned our attention to screen solvents and
acetonitrile was found to give the higher yield (47%; Table 1, entry 11). However, the explored efficiency
was deficient, so the kind of bases was further explored (Table 1, entries 13–15). To our delight, we
found that Cs2CO3 accompanied by AgSbF6 could obtain the highest yield (80%; Table 1, entry 14).
Based on this model, we then explored catalyst species Co, Ru, Ir (Table 1, entries 16–18). [Cp*RhCl2]2
was chosen to be employed as catalysts for this annulation according to the obtained yields listed on
Table 1. Interestingly, product 3aa was obtained in a slightly lower yield when the reaction was carried
out under N2 atmosphere (Table 1, entry 19). Next, an attempt to lower the reaction temperature to
25 ◦C resulted in a decreased yield (Table 1, entry 20). Notably, there was no obvious change in yield,
whether the reaction dealt with higher temperature or longer reaction time (Table 1, entries 21 and 23).
Hence the optimized conditions of Rh(III)-Catalyzed annulation of Boc-protected benzamides with
diazo compounds were as follows: 5 mmol% [Cp*RhCl2]2 as catalyst, 2.0 equiv Cs2CO3 and 15 mmol%
AgSbF6 as the additives. The reaction performed best at 60 ◦C for 0.5 h under air with acetonitrile as
the solvent.
Table 1. Optimization of reaction conditions a.
Entry
R1
R2
Base
Addtive
Solvent
3aa Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 b
17 c
18 d
H
Me
Boc
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Acetyl
Boc
Boc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Na2CO3
Cs2CO3
Na2Opiv
NaOAc
NaOAc
NaOAc
-
-
-
-
-
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
nr
nr
nr
nr
trace
19
nr
nr
23
33
47
trace
67
80
30
nr
14
16
CO2Me
i
CO2 pr
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Ag2O
AgOAc
Cu(OAc)2
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
-
DCE
CH3CN
MeOH
CH3CN
CH3CN
CH3CN
DCE
-
-
DCE
DCE

Molecules 2019, 24, 937
4 of 19
Table 1. Cont.
Entry
R1
R2
Base
Addtive
Solvent
3aa Yield (%)
19 e
20 f
21 g
22 h
23 i
a
H
H
H
H
H
Boc
Boc
Boc
Boc
Boc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
78
54
79
65
78
Unless otherwise specified, all the reactions were carried out with 0.1 mmol of 1a, 1a1–1a5 and 0.12 mmol of 2a,
5 mol% of Rh-cat, 2.0 equiv Cs2CO3 and 15 mol% AgSbF6 under air atmosphere at 60 ◦C for 0.5 h. All listed yields
are isolated ones. b Cp*Co(CO)I2 instead of [Cp*RhCl2]2. c [(p-cymene)RuCl2]2 instead of [Cp*RhCl2]2. d [Cp*IrCl2]2
e
f
instead of [Cp*RhCl2]2. The reaction was carried out under N2 atmosphere. The reaction was carried out at room
temperature for 1 h under air. The reaction was carried out at 80 ◦C for 0.5 h under air. The reaction was carried
g
h
out at 60 ◦C for 5 min under air. The reaction was carried out at 60 ◦C for 6 h under air.
i
2.2. Substrate Scope for the Boc-Protected Benzamides
With the optimized conditions in hand, we embarked on the investigation of the substrate scope
of Boc-protected benzamides to test the generality of this C-H activation/annulation reaction (Table 2).
It was found that a variety of amides could successfully cyclize to give the desired products in
moderate to good yields. Electron-donating groups such as methyl, tert-butyl and methoxy group at
the para-position of the benzene ring gave 3ba
In contrast, electron-withdrawing groups such as CF3 and nitro group afforded 3ka and 3la in 22%
and trace yields. Halogen substituents (F, Cl, Br and I) provided 3ga 3ja in 48–72% yields, indicating
, 3ea and 3fa in 87%, 79% and 81% yields, respectively.
–
that the products of this reaction were compatible in transition-metal-catalyzed coupling reactions.
In particular, we were pleased to obtain the single crystal X-ray of 3ga (see Supporting Information (SI),
CCDC: 1891024). Presumably owing to the steric effect, meta-phenzyl-substituted benzamide provided
3pa in 60% yield, while para- and ortho-phenzyl-substituted benzamides provided 3ba and 3ra in 87%
and 65% yields. Notably, 1-naphthamide gave the desired product 3ua in 51% yield. In regard to the
heteroaromatic amides such as thiophene, delivered the desired products 3va in 68% yields.
Table 2. Scope of Boc-protected benzamides derivatives a.
3ba b, 87%
3aa, 80%
3ca, 68%
3da, 61%
O
O
MeO
CO2Et
3fa b, 81%
3ea, 79%
3ga, 72%
3ga

Molecules 2019, 24, 937
5 of 19
Table 2. Cont.
3ha, 48%
3la, trace
3pa, 60%
3ia, 61%
3ma, 69%
3qa, 48%
3ua, 51%
3ja, 51%
3na, 75%
3ra, 65%
3va, 68%
3ka c, 22%
3oa, 61%
3sa, 53%
3ta, 82%
a
Unless otherwise specified, 0.1 mmol of 1, 0.12 mmol of 2a, 5 mol% of Rh-cat, 2.0 equiv Cs2CO3 and 15 mol%
AgSbF6 under air atmosphere at 60 ◦C for 0.5 h. All listed yields are isolated ones. The reaction was performed at
b
60 ◦C for 2 h. The reaction was performed at 80 ◦C for 2 h.
c
2.3. Substrate Scope for the Diazo Compounds
After the examination of benzamides, diazo coupling partners were also investigated, and the
results are described in Table 3. When the R2 with phenyl groups were used, the 3ab−3ae were given
in 51 79% yields. R2 with a cyclopropyl and a cyclohexyl group gave 3af and 3ag in moderate yield.
−
When R2 with branched alkyl groups such as an isopropyl and an ethyl group were used, the 3ai and
3aj were given in 45% and 61% yields. When R3 with a methyl, a tert-butyl, an n-propyl or a benzyl
group was used, the 3ak–3ao were given in 25–70% yields.

Molecules 2019, 24, 937
6 of 19
Table 3. Scope of Diazo Compounds a.
3ac b, 69%
3ad b, 61%
3ah, 77%
3al, 50%
3ae b, 51%
3ab, 79%
3af, 68%
3ag, 61%
3ai, 45%
3aj, 61%
3ak, 53%
3ao, 63%
3am c, 25%
3an, 70%
a
Unless otherwise specified, 0.1 mmol of 1, 0.12 mmol of 2a, 5 mol% of Rh-cat, 2.0 equiv Cs2CO3 and 15 mol%
AgSbF6 under air atmosphere at 60 ◦C for 0.5 h. All listed yields are isolated ones. The reaction was performed at
b
60 ◦C for 2 h. The reaction was performed at 80 ◦C for 2 h.
c
2.4. Gram-Scale Preparation and Derivatization of the Annulation Product
In addition, 60% yield was obtained for the gram-scale synthesis of 3aa, thus offering a practical
access to highly functionalized isocoumarins (Scheme 2a). The applications of the isocoumarins have
been demonstrated in several derivatization reactions. Formation of the desired
4 was achieved by
reaction with ammonium acetate. In order to be more similar to the structures of Figure 1, removal of
carboxylic esters at 4-position has been carried out to give 5 in 75% yield.

Molecules 2019, 24, 937
7 of 19
a) Gram-scale preparation
O
O
[Cp*RhCl2]2 (5 mol%)
AgSbF6 (15 mol%)
Cs2CO3 (2 equiv.)
N2
2a
Boc
O
N
O
H
H
O
O
CH3CN, 60 oC, 0.5h
CO2Et
1a
3aa
0.62g (60 %)
1g
b) Derivatization of a o annulation product
O
O
O
O
NH4OAc, AcOH
80 oC, reflux
HCl
NH
O
110 oC, refiux
CO2Et
4, 55%
CO2Et
3aa
5, 75%
Scheme 2. Gram-scale reaction (a) and derivatization (b) of the annulation product.
2.5. Mechanism
To obtain a more mechanistic insight, further experiments were carried out (Scheme 3). When
p-methoxy-Boc-benzamide 1f was run in competition with the p-trifluoromethyl-Boc-benzamide 1k, the
reaction favors the electron-donating substituent of the benzamide, suggesting that electrophilic-type
benzamide were inherently less reactive (Scheme 3a). To gain further insights, the kinetic-isotope
effect (KIE) was studied in parallel and competition experiments (Scheme 3b,c). Experiments with
the same amounts of 1a and deuterium-labeled benzamide 1a
of 1.44 was obtained (Scheme 3b). Furthermore, separate reactions of 1a or 1a
gave the corresponding products 3aa and 3aa 4, respectively, displaying the similar KIE value of
1.24 (Scheme 3c). These results suggested that C H cleavage is likely involved in the rate-limiting
–
d5 were conducted, and a kH/kD value
–
d5 together with 2a
–d
−
step. Moreover, when 1a was treated with diethyl 2-diazomalonate, corresponding products was not
observed under the standard reaction conditions, indicating that the final lactonization of ketone is
significant in the transformation (Scheme 3d).
Based on the preliminary mechanistic experiments and literature precedents, a plausible
mechanistic pathway is proposed in Scheme 4. Firstly, the catalytically active Rhodium species
formed from [Cp*RhCl2]2, then the C-H metalation takes place to afford five-membered cyclometalated
Rhodium species
via a Rh(III)-catalyzed C(sp2)-H bond cleavage. After insertion of the diazo
compounds, Rh(III)-carbene species C can be formed with extrusion of N2. Subsequently, the species
A is
B
C
undergoes a migratory insertion of carbene into the Rh-C bond, provided six-membered species
. Then, complex D could undergo protonation to give intermediate , which can tautomerize to
. Finally, lactonization of intermediate could afford the desired isocoumarin product
and the active catalyst A.
D
E
intermediate
F
F
3

Molecules 2019, 24, 937
8 of 19
Scheme 3. Mechanistic Studies: (a) Intermoleculalr competition:benzamides; (
b) Competition
experiment; ( ) Parallel experiment; (
c
d) Verify the role of the final lactonization of ketone experiment.
Scheme 4. Plausible reaction mechanism.

Molecules 2019, 24, 937
9 of 19
3. Materials and Methods
3.1. Chemistry
Reagents and Solvents: Rh catalysts and additives were commercially available. PE refers to
◦
petroleum ether (b.p. 60–90 C), EA refers to ethyl acetate. Acetonitrile was used to the HPLC
grade. All commercially available reagents and reactants were used without purification unless
otherwise noted.
Chromatography: Flash column chromatography was carried out using commercially available
200–300 mesh under pressure unless otherwise indicated. Gradient flash chromatography was
conducted eluting with PE/EA, they are listed as volume/volume ratios.
Data Collection: Nuclear magnetic resonance (NMR) spectra were run on 500 MHz instrument.
Chemical shifts were reported in parts per million (ppm,
δ) downfield from tetramethylsilane. Data
are reported as follows: chemical shift in ppm ( ), multiplicity (s = singlet, d = doublet, t = triplet,
δ
q = quartet, m = multiplet), coupling constant (Hz) and integration. Low- and high-resolution mass
spectra (LRMS and HRMS) were measured on spectrometer.
3.2. Experimental Part Method
3.2.1. General Procedure for the Synthesis of Isocoumarins and α-Pyrones
To a mixture of [Cp*RhCl2]2 (3 mg, 0.0049 mmol, 5 mol%) and AgSbF6 (5 mg, 0.015 mmol,
15 mol%) in acetonitrile (2 mL) was added tert-butyl benzoylcarbamate
1
(0.1 mmol), diazo compounds
◦
2
(0.12 mmol), Cs2CO3(65 mg, 0.2 mmol, 2 equiv). The reaction mixture was stirred at 60 C for 0.5–2 h
and the progress was monitored using TLC detection. After completion of present reaction, the solvent
was evaporated under reduced pressure and the residue passed through flash column chromatography
on silica gel to afford the desired products 3.
3.2.2. Procedure for the Synthesis of Diazo Substrates
Diazo substrates were synthesized from the corresponding ketonic esters or 1,3 di-ketones as
shown in Scheme S1. 2a–2o was synthesized according to the literatures [36].
To a solution of ketonic ester or 1,3-di-ketone (5 mmol) in CH3CN, 6 mmol TsN3 was added.
Then the reaction mixture was cooled to 0 ◦C and a solution of DBU (6 mmol) in 10 mL CH3CN was
added dropwise. Next, the reaction temperature was raised to room temperature. After stirring for
3 h, the residue was extracted with EA for 3 times. The combined organic layers were washed with
water and brine sequentially, dried over Na2SO4, filtered and concentrated. The crude product was
purified by flash chromatography on silica gel (PE: EA = 100:1) to afford the corresponding product in
50–90% yields.
3.2.3. Procedure for the Synthesis of Benzoylcarbamate Derivatives [37]
To a solution of benzamide (4.1 mmol) in dichloromethane (10.0 mL) was slowly added oxalyl
chloride (630 mg, 0.43 mL 4.94 mmol) at 0 ◦C. The reaction mixture was warmed to 50 ◦C and stirred
for 1 h. After cooling to 0 ◦C, a solution of the corresponding alcohol in dichloromethane was added,
which was stirred at that temperature for 2 h. The reaction mixture was quenched by the addition
of sat. aq. NaHCO3 and then extracted with dichloromethane. The combined organic layer was
washed with brine and dried over Na2SO4. The volatiles were evaporated and the resulting crude
product was purified by silica gel chromatography (eluent: dichloromethane to dichloromethane/ethyl
acetate = 9/1) to give white powder. 1a
,
1b and 1f were synthesized according to the literatures [37–39].
1
tert-Butyl (4-ethylbenzoyl)carbamate (1c). White solid. H NMR (500 MHz, DMSO-d6)
δ
10.54 (s, 1H), 7.78
(d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 2.66 (q, J = 7.6 Hz, 2H), 1.47 (s, 9H), 1.19 (t, J = 7.6 Hz, 3H).

Molecules 2019, 24, 937
10 of 19
13C NMR (126 MHz, DMSO-d6)
δ
165.7, 150.4, 148.6, 130.9, 128.4, 127.6, 80.6, 28.0, 27.7, 15.1. HRMS
(ESI) calcd for [C14H19NO3+Na] 272.1365, found 272.1253.
1
tert-Butyl (4-isopropylbenzoyl)carbamate (1d). White solid. H NMR (500 MHz, DMSO-d6)
1H), 7.79 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 2.95 (dt, J = 13.8, 6.9 Hz, 1H), 1.47 (s, 9H), 1.22 (s,
3H), 1.21 (s, 3H). 13C NMR (126 MHz, DMSO)
165.7, 153.1, 150.4, 131.1, 128.4, 126.2, 80.6, 33.3, 27.7,
δ 10.54 (s,
δ
23.5. HRMS (ESI) calcd for [C15H21NO3+Na] 286.1521, found 286.1417.
tert-Butyl (4-(tert-butyl)benzoyl)carbamate (1e). White solid. 1H NMR (600 MHz, DMSO-d6)
δ
10.57 (s, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 1.47 (s, 9H), 1.30 (s, 9H). 13C NMR
(126 MHz, DMSO-d6)
δ 165.7, 155.3, 150.4, 130.7, 128.2, 125.1, 80.6, 34.7, 30.8, 27.7. HRMS (ESI) calcd
for [C18H23NO3-H]− 276.1678, found 276.1603.
1
tert-Butyl (4-fluorobenzoyl)carbamate (1h). White solid. H NMR (500 MHz, DMSO-d6)
δ 10.67 (s, 1H),
7.92 (dd, J = 8.9, 5.5 Hz, 2H), 7.31 (t, J = 8.8 Hz, 2H), 1.48 (s, 9H). 13C NMR (126 MHz, DMSO-d6)
δ
165.9, 165.4, 163.9, 150.8, 131.6 (d, J = 9.3 Hz), 130.5 (d, J = 2.6 Hz), 115.8, 115.6, 81.2, 28.2. HRMS (ESI)
calcd for [C12H14FNO3+Na] 262.0958, found 262.0848.
1
tert-Butyl (4-chlorobenzoyl)carbamate (1g). White solid. H NMR (500 MHz, CD3OD) δ 10.76 (s, 1H),
7.77 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H), 1.47 (s, 8H). 13C NMR (126 MHz, DMSO-d6)
δ 165.4,
150.61, 137.5, 132.6, 130.5, 128.6, 81.1, 28.0. HRMS (ESI) calcd for [C12H14ClNO3+Na] 278.0662, found
278.0561.
1
tert-Butyl (4-bromobenzoyl)carbamate (1i). White solid. H NMR (400 MHz, CD3OD)
δ
10.76 (s, 1H),
165.2,
7.78 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 1.47 (s, 9H). 13C NMR (126 MHz, DMSO-d6)
δ
150.2, 132.7, 131.2, 130.3, 126.1, 80.8, 27.7. HRMS (ESI) calcd for [C12H14BrNO3+Na] 278.0662, found
278.0561.
1
tert-Butyl (4-iodobenzoyl)carbamate (1j). White solid. H NMR (500 MHz, DMSO-d6)
δ
10.72 (s, 1H),
7.89–7.84 (m, 2H), 7.64–7.59 (m, 2H), 1.47 (s, 9H). 13C NMR (126 MHz, DMSO-d6)
δ 165.5, 150.3, 137.1,
132.9, 130.1, 100.4, 80.8, 27.7. HRMS (ESI) calcd for [C12H14INO3+Na] 370.0018, found 369.9917.
1
tert-Butyl (4-(trifluoromethyl)benzoyl)carbamate (1k). White solid. H NMR (500 MHz, DMSO-d6)
δ 10.93
(s, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 1.50 (s, 9H). 13C NMR (126 MHz, DMSO-d6)
δ
165.3, 150.2, 137.5, 129.1, 125.2 (d, J = 3.6 Hz), 122.7, 81.0, 27.7. HRMS (ESI) calcd for [C13H14F3NO3+Na]
312.0926, found 312.0814.
1
tert-Butyl (4-nitrobenzoyl)carbamate (1l). White solid. H NMR (500 MHz, DMSO-d6)
δ
11.04 (s, 1H), 8.32
165.5, 150.5,
(d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H), 1.50 (s, 9H). 13C NMR (126 MHz, DMSO-d6)
δ
149.8, 139.7, 130.1, 123.7, 81.6, 28.1. HRMS (ESI) calcd for [C12H11N2O5+Na] 289.0903, found 289.0801.
1
tert-Butyl (4-(benzyloxy)benzoyl)carbamate (1m). White solid. H NMR (500 MHz, DMSO-d6)
δ
10.47 (s,
1H), 7.85 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H),
7.08 (d, J = 8.7 Hz, 2H), 5.19 (s, 2H), 1.47 (s, 9H). 13C NMR (126 MHz, DMSO-d6)
δ
165.1, 161.6, 150.5,
136.5, 130.40, 128.4, 127.9, 127.7, 125.7, 114.3, 80.5, 69.4, 27.7. HRMS (ESI) calcd for [C19H21NO4+Na]
350.1471, found 350.1353.
tert-Butyl (4-(dimethylamino)benzoyl)carbamate (1n). White solid. 1H NMR (500 MHz, DMSO-d6)
11.66 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 9.1 Hz, 2H), 3.03 (s, 6H), 1.51 (s, 9H). 13C NMR
(126 MHz, DMSO-d6) 165.5, 164.1, 160.4, 153.6, 130.6, 128.9, 116.1, 110.7, 83.3, 27.5. HRMS (ESI) calcd
for [C14H20N2O3+Na] 287.1474, found 287.1353.
δ
δ
1
tert-Butyl [1,10-biphenyl]-4-carbonylcarbamate (1o). White solid. H NMR (500 MHz, DMSO-d6)
(s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.76 (dd, J = 25.2, 7.9 Hz, 4H), 7.50 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.3 Hz,
1H), 1.49 (s, 9H). 13C NMR (126 MHz, DMSO-d6)
166.2, 150.9, 144.3, 139.4, 132.8, 129.5, 128.8, 127.4,
126.9, 81.2, 28.3. HRMS (ESI) calcd for [C18H19NO3+Na] 320.1365, found 320.1262.
δ 10.70
δ

Molecules 2019, 24, 937
11 of 19
tert-Butyl (3-methylbenzoyl)carbamate (1p). White solid. 1H NMR (500 MHz, DMSO-d6)
δ
10.61 (s,
1H), 7.71–7.60 (m, 2H), 7.37 (dt, J = 15.0, 7.4 Hz, 2H), 2.36 (s, 3H), 1.47 (s, 9H). 13C NMR (126 MHz,
DMSO-d6)
δ 166.1, 150.4, 137.6, 133.5, 132.9, 128.7, 128.2, 125.4, 80.7, 27.8, 20.80. HRMS (ESI) calcd for
[C13H17NO3-H]− 234.1208, found 234.1132.
1
tert-Butyl (3-chlorobenzoyl)carbamate (1q). White solid. H NMR (500 MHz, DMSO-d6)
δ 10.76 (s, 1H),
7.89 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 1.47 (s, 9H). 13
C
NMR (126 MHz, DMSO-d6) δ 164.74, 150.16, 135.54, 133.04, 132.06, 130.24, 127.96, 126.94, 80.92, 27.71.
HRMS (ESI) calcd for [C12H14ClNO3-H]− 254.0662, found 254.0587.
1
tert-Butyl (2-methylbenzoyl)carbamate (1r). White solid. H NMR (500 MHz, DMSO-d6)
δ
10.66 (s, 1H),
7.38–7.30 (m, 2H), 7.27–7.19 (m, 2H), 2.30 (s, 3H), 1.39 (s, 9H). 13C NMR (126 MHz, DMSO-d6)
δ 169.6,
150.8, 136.4, 135.5, 130.8, 130.4, 127.6, 125.9, 81.16, 28.1, 19.6. HRMS (ESI) calcd for [C13H17NO3-H]−
234.1208, found 234.1131.
1
tert-Butyl (2-chlorobenzoyl)carbamate (1s). White solid. H NMR (500 MHz, DMSO-d6)
7.50–7.42 (m, 3H), 7.41–7.36 (m, 1H), 1.35 (s, 9H). 13C NMR (126 MHz, DMSO-d6)
δ
10.92 (s, 1H),
167.1, 150.1,
δ
136.3, 131.02, 129.2, 128.4, 127.1, 81.2, 27.5. HRMS (ESI) calcd for [C12H14ClNO3-H]− 254.0662, found
254.0583.
1
tert-Butyl (3,4-dimethylbenzoyl)carbamate (1t). White solid. H NMR (500 MHz, CDCl3)
δ
7.93 (s, 1H),
7.59 (d, J = 1.1 Hz, 1H), 7.51 (dd, J = 7.9, 1.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 2.30 (s, 6H), 1.53 (s, 9H).
13C NMR (126 MHz, CDCl3)
δ 165.3, 149.8, 142.4, 137.5, 130.9, 130.1, 128.9, 124.9, 82.7, 28.2, 20.1, 19.9.
HRMS (ESI) calcd for [C14H19NO3-H]− 248.1365, found 248.1287.
1
tert-Butyl 2-naphthoylcarbamate (1u). White solid. H NMR (500 MHz, DMSO-d6)
δ 10.83 (s, 1H), 8.55 (s,
1H), 8.09 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.91 (dd, J = 8.6, 1.8 Hz, 1H), 7.73–7.60 (m, 2H),
1.53 (s, 9H). 13C NMR (126 MHz, DMSO-d6)
δ
165.8, 150.1, 134.3, 131.5, 130.4, 128.8, 127.9, 127.6, 127.3,
126.5, 124.2, 80.4. HRMS (ESI) calcd for [C16H17NO3 + Na] 294.1208, found 294.1104.
1
tert-Butyl thiophene-2-carbonylcarbamate (1v). White solid. H NMR (500 MHz, DMSO-d6)
δ 10.72 (s,
1H), 8.06 (d, J = 3.5 Hz, 1H), 7.92 (d, J = 4.7 Hz, 1H), 7.23–7.09 (m, 1H), 1.48 (s, 9H). 13C NMR (126 MHz,
DMSO-d6)
δ
159.8, 150.0, 138.6, 133.8, 131.0, 128.3, 80.9, 27.8. HRMS (ESI) calcd for [C10H13NO3S-H]−
226.0616, found 226.0539.
1a1–1a5 were synthesized according to the literatures [40–43].
3.2.4. Characterization of the Products
1
Ethyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3aa). Colorless oil. H NMR (500 MHz, DMSO-d6)
δ
8.17 (dd, J = 7.9, 0.8 Hz, 1H), 7.93–7.81 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 4.41 (q,
J = 7.1 Hz, 2H), 2.39 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 165.9, 161.3, 157.8,
135.2, 134.8, 129.8, 128.3, 124.2, 119.7, 110.4, 61.8, 19.4, 14.3. HRMS (ESI) calcd for [C13H12O4 + H]+
233.0736, found 233.0808.
1
Ethyl 3,6-dimethyl-1-oxo-1H-isochromene-4-carboxylate (3ba). White solid. H NMR (500 MHz, CDCl3)
δ
8.13 (d, J = 8.1 Hz, 1H), 7.50 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 2.41
(s, 3H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 165.9, 161.3, 157.5, 146.3, 134.7, 129.7,
129.5, 124.1, 117.1, 110.2, 61.7, 22.3, 19.3, 14.3. HRMS (ESI) calcd for [C14H14O4 + H]+ 247.0892, found
247.0960.
1
Ethyl 6-ethyl-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ca). White solid. H NMR (500 MHz, CDCl3)
δ
8.18 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.75 (q, J = 7.6 Hz,
2H), 2.43 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ
166.1,
161.4, 157.7, 152.5, 134.9, 129.9, 128.4, 123.1, 117.4, 110.4, 61.7, 29.6, 19.4, 15.1, 14.4. HRMS (ESI) calcd
for [C15H16O4 + H]+ 261.1049, found 261.1125.

Molecules 2019, 24, 937
12 of 19
1
Ethyl 6-isopropyl-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3da). White solid. H NMR (500 MHz,
CDCl3) 8.20 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 4.45 (q, J = 7.1 Hz,
2H), 3.01 (dt, J = 13.8, 6.9 Hz, 1H), 2.44 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.29 (s, 3H), 1.27 (s, 3H). 13
δ
C
NMR (126 MHz, CDCl3) δ 166.12, 161.37, 157.74, 156.99, 134.93, 129.96, 127.08, 121.84, 117.55, 110.48,
34.91, 23.66, 19.39, 14.39. HRMS (ESI) calcd for [C16H18O4 + H]+ 275.1205, found 275.1284.
1
Ethyl 6-(tert-butyl)-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ea). White solid. H NMR (500 MHz,
CDCl3)
δ
8.19 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 8.4, 1.7 Hz, 1H), 4.45 (q, J = 7.1 Hz,
166.2, 161.3, 159.2,
2H), 2.44 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.35 (s, 9H). 13C NMR (126 MHz, CDCl3)
δ
157.8, 134.6, 129.5, 126.1, 120.6, 117.1, 110.6, 61.6, 35.7, 31.1, 19.4, 14.4. HRMS (ESI) calcd for [C17H20O4
+ H]+ 289.1362, found 289.1437.
1
Ethyl 6-methoxy-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3fa). White solid. H NMR (500 MHz,
D2O)
δ
8.18 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.8, 2.4 Hz, 1H), 4.43 (q, J = 7.2 Hz,
166.0, 165.0, 161.0,
2H), 3.89 (s, 3H), 2.44 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, D2O)
δ
158.9, 137.0, 132.0, 116.3, 112.6, 110.0, 107.0, 61.7, 55.73, 19.7, 14.4. HRMS (ESI) calcd for [C14H14O5 +
H]+ 263.0841, found 263.0911.
Ethyl 6-chloro-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ga). White solid. 1H NMR (500 MHz,
CDCl3) δ 8.22 (dd, J = 8.5, 0.4 Hz, 1H), 7.86 (d, J = 1.4 Hz, 1H), 7.48 (dd, J = 8.5, 1.2 Hz, 1H), 4.48 (q, J
= 7.1 Hz, 2H), 2.50 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 164.6, 159.7, 159.0,
141.4, 135.4, 130.6, 128.0, 123.5, 117.1, 108.6, 61.2, 19.0, 13.6. HRMS (ESI) calcd for [C13H11ClO4 + H]+
267.0346, found 267.0415.
Ethyl 6-fluoro-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ha). White solid. 1H NMR (500 MHz,
CDCl3)
δ
8.29 (dd, J = 8.4, 6.2 Hz, 1H), 7.54 (d, J = 10.5 Hz, 1H), 7.23–7.13 (m, 1H), 4.44 (q, J = 7.1 Hz,
168.0, 166.2, 165.5, 160.3, 160.1,
2H), 2.48 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ
137.5, 133.1, 116.4, 116.0, 110.8, 109.6 (d, J = 2.6 Hz), 61.9, 19.8, 14.4. HRMS (ESI) calcd for [C13H11FNO3
- H]− 249.0641, found 249.0562.
Ethyl 6-bromo-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ia). White solid. 1H NMR (500 MHz, CDCl3)
δ
8.12 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.62 (dd, J = 8.5, 1.8 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H),
2.48 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 165.1, 160.3, 159.5, 135.9, 131.5, 131.0,
130.8, 127.1, 118.0, 109.0, 61.7, 19.5, 14.1. HRMS (ESI) calcd for [C13H12BrO4 + H]+ 310.9841, found
310.9917.
1
Ethyl 6-iodo-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ja). White solid. H NMR (500 MHz, CDCl3)
δ
8.20 (s, 1H), 7.93 (dd, J = 8.3, 2.0 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 4.48–4.41 (m, 2H), 2.46 (s, 3H), 1.43
(dd, J = 7.4, 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 165.3, 160.8, 159.5, 137.4, 135.8, 133.4, 130.8,
118.7, 109.0, 104.1, 62.0, 19.7, 14.3. HRMS (ESI) calcd for [C13H12IO4 + H]+ 358.9702, found 358.9773.
1
Ethyl 3-methyl-1-oxo-6-(trifluoromethyl)-1H-isochromene-4-carboxylate (3ka). White solid. H NMR (500
MHz, CDCl3)
δ
8.40 (d, J = 8.3 Hz, 1H), 8.17 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.52
165.2, 160.3, 160.1, 136.7, 136.4, 135.3,
(s, 3H), 1.44 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ
130.7, 124.5 (d, J = 3.3 Hz), 122.2–121.4 (m), 109.7, 62.1, 19.8, 14.3. HRMS (ESI) calcd for [C14H11F3O4 +
H]+ 301.0609, found 301.0676.
Ethyl 3-methyl-6-nitro-1-oxo-1H-isochromene-4-carboxylate (3la). White solid. HRMS (ESI) calcd for
[C13H11NO6 - H]− 276.0586, found 276.0518.
1
Ethyl 6-(benzyloxy)-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ma). White solid. H NMR (500 MHz,
CDCl3)
2.4 Hz, 1H), 5.18 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz,
CDCl3) 166.2, 164.4, 161.2, 159.1, 137.3, 136.1, 132.3, 129.1, 128.7, 127.9, 117.1, 113.1, 110.3, 108.3, 70.7,
61.9, 19.9, 14.6. HRMS (ESI) calcd for [C20H18IO5 + H]+ 339.1154, found 339.1230.
δ 8.22 (d, J = 8.8 Hz, 1H), 7.49–7.39 (m, 4H), 7.36 (dd, J = 16.5, 4.7 Hz, 2H), 7.12 (dd, J = 8.8,
δ

Molecules 2019, 24, 937
13 of 19
Ethyl 6-(dimethylamino)-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3na). White solid. 1H NMR
(500 MHz, CDCl3) 8.06 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 9.9 Hz, 2H), 4.42 (q, J = 6.8 Hz, 2H), 3.08 (s, 6H),
δ
2.39 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 166.5, 161.6, 158.1, 154.5, 136.3, 131.5,
112.7, 110.2, 107.5, 103.9, 61.4, 40.2, 19.5, 14.4. HRMS (ESI) calcd for [C15H17NO4 + H]+ 276.1158, found
276.1230.
Ethyl 3-methyl-1-oxo-6-phenyl-1H-isochromene-4-carboxylate (3oa). White solid. 1H NMR (500 MHz,
CDCl3)
δ 8.37–8.31 (m, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.73 (dd, J = 8.2, 1.7 Hz, 1H), 7.64 (dd, J = 7.9,
0.9 Hz, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.44 (t,
J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 166.0, 161.3, 158.3, 148.0, 139.7, 135.2, 130.4, 129.2, 128.8,
127.6, 127.3, 122.6, 118.3, 110.4, 61.8, 19.5, 14.4. HRMS (ESI) calcd for [C19H16O4 + H]+ 309.1049, found
309.1120.
1
Ethyl 3,7-dimethyl-1-oxo-1H-isochromene-4-carboxylate (3pa). White solid. H NMR (500 MHz, CDCl3)
δ
8.06 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.53 (dd, J = 8.3, 1.5 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 2.44 (s, 3H),
2.43 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 166.0, 161.5, 157.0, 138.5, 136.4, 132.2,
129.4, 124.1, 119.5, 110.2, 61.7, 21.2, 19.3, 14.3. HRMS (ESI) calcd for [C14H14O4 + H]+ 247.0892, found
247.0961.
Ethyl 7-chloro-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3qa). White solid. 1H NMR (500 MHz,
CDCl3) δ 8.25 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.47 (s,
3H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 165.4, 160.0, 158.5, 135.3, 134.1, 133.1, 129.0,
126.0, 120.8, 109.6, 61.8, 19.4, 14.2. HRMS (ESI) calcd for [C13H11ClO4 + H]+ 267.0346, found 267.0422.
1
Ethyl 3,5-dimethyl-1-oxo-1H-isochromene-4-carboxylate (3ra). White solid. H NMR (500 MHz, CDCl3)
δ
7.59–7.53 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.80 (s, 3H),
2.38 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 166.4, 160.6, 156.6, 143.81, 136.2,
134.3, 131.2, 121.9, 118.1, 110.9, 61.7, 23.6, 19.0, 14.3. HRMS (ESI) calcd for [C14H14O4 + H]+ 247.0892,
found 247.0960.
Ethyl 8-chloro-3-methyl-1-oxo-1H-isochromene-4-carboxylate (3sa). White solid. 1H NMR (500 MHz,
CDCl3)
δ 7.63–7.56 (m, 2H), 7.53 (d, J = 7.6 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.42 (t, J = 7.2
Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ 165.8, 158.0, 157.7, 137.7, 137.3, 134.8, 131.2, 122.9, 116.8, 110.3,
62.0, 19.2, 14.3. HRMS (ESI) calcd for [C13H11ClO4 + H]+ 267.0346, found 267.0425.
1
Ethyl 3,6,7-trimethyl-1-oxo-1H-isochromene-4-carboxylate (3ta). White solid. H NMR (500 MHz, CDCl3)
δ
8.02 (s, 1H), 7.51 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H), 1.42 (t, J = 7.2 Hz,
3H). 13C NMR (126 MHz, CDCl3)
δ 166.0, 161.4, 156.8, 145.4, 137.6, 132.6, 129.8, 124.6, 117.3, 110.0, 61.5,
20.7, 19.6, 19.2, 14.2. HRMS (ESI) calcd for [C15H16O4 + H]+ 261.1049, found 261.1116.
Ethyl 3-methyl-1-oxo-1H-benzo[g]isochromene-4-carboxylate (3ua). White solid. 1H NMR (500 MHz,
CDCl3)
7.62–7.55 (m, 1H), 4.58–4.50 (m, 2H), 2.52–2.49 (m, 3H), 1.53–1.47 (m, 3H). 13C NMR (126 MHz, CDCl3)
166.3, 161.6, 156.1, 136.6, 132.2, 132.1, 129.8, 129.7, 129.6, 129.2, 128.5, 127.2, 123.1, 110.3, 61.8, 19.4,
14.4. HRMS (ESI) calcd for [C17H14O4 + H]+ 283.0892, found 283.0966.
δ 8.97–8.93 (m, 1H), 8.26–8.21 (m, 1H), 8.07–8.02 (m, 1H), 7.98–7.92 (m, 1H), 7.71–7.62 (m, 1H),
δ
1
Ethyl 5-methyl-7-oxo-7H-thieno [2,3-c]pyran-4-carboxylate (3vq). White solid. H NMR (500 MHz, CDCl3)
7.87 (d, J = 5.2 Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.45 (t, J = 7.1 Hz,
3H). 13C NMR (126 MHz, CDCl3)
165.0, 164.5, 157.2, 145.4, 136.7, 126.3, 122.4, 108.3, 61.7, 20.2, 14.4.
HRMS (ESI) calcd for [C11H10O4S + H]+ 283.0300, found 239.0371.
δ
δ
1
Ethyl 1-oxo-3-phenyl-1H-isochromene-4-carboxylate (3ab). White solid. H NMR (500 MHz, CDCl3)
δ
8.37 (dd, J = 8.0, 0.8 Hz, 1H), 7.82–7.77 (m, 1H), 7.75 (dd, J = 8.1, 0.7 Hz, 1H), 7.65 (dd, J = 8.0, 1.6 Hz,
2H), 7.61–7.55 (m, 1H), 7.50–7.43 (m, 3H), 4.20 (q, J = 7.2 Hz, 2H), 1.05 (t, J = 7.1 Hz, 3H). 13C NMR

Molecules 2019, 24, 937
14 of 19
(126 MHz, CDCl3)
δ
166.3, 161.1, 155.4, 135.3, 134.7, 132.6, 130.5, 129.9, 128.8, 128.5, 128.1, 124.1, 119.8,
110.9, 61.9, 13.5. HRMS (ESI) calcd for [C18H14O4 + H]+ 295.0892, found 295.0961.
Ethyl 3-(4-methoxyphenyl)-1-oxo-1H-isochromene-4-carboxylate (3ac). white solid.1H NMR (500 MHz,
CDCl3)
δ 8.34 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H),
7.55 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.12 (t, J = 7.1 Hz,
3H). 13C NMR (126 MHz, CDCl3)
δ 166.6, 161.4, 161.2, 155.1, 135.2, 134.9, 129.8, 128.4, 124.8, 123.9,
119.5, 113.9, 109.9, 61.9, 55.4, 13.7. HRMS (ESI) calcd for [C19H16O5 + H]+ 325.0998, found 325.1069.
Ethyl 3-(4-chlorophenyl)-1-oxo-1H-isochromene-4-carboxylate (3ad). White solid. 1H NMR (500 MHz,
CDCl3)
δ
8.36 (dd, J = 7.9, 0.9 Hz, 1H), 7.82–7.77 (m, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.62–7.56 (m, 3H),
166.0,
7.47–7.41 (m, 2H), 4.23 (q, J = 7.2 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3)
δ
160.8, 153.9, 136.7, 135.3, 134.4, 130.9, 129.9, 129.4, 129.0, 128.7, 124.1, 119.7, 111.2, 62.0, 13.6. HRMS
(ESI) calcd for [C18H13ClO4 + H]+ 329.0502, found 329.0575.
1
Ethyl 3-(naphthalen-2-yl)-1-oxo-1H-isochromene-4-carboxylate (3ae). Colorless oil. H NMR (500 MHz,
CDCl3)
δ 8.39 (dd, J = 7.9, 0.7 Hz, 1H), 8.20 (s, 1H), 7.95–7.86 (m, 3H), 7.84–7.75 (m, 2H), 7.71 (dd, J = 8.6,
1.7 Hz, 1H), 7.63–7.51 (m, 3H), 4.21 (q, J = 7.1 Hz, 2H), 0.99 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz,
CDCl3)
δ 166.5, 161.2, 155.3, 135.4, 134.9, 134.1, 132.8, 129.9, 128.9, 128.7, 128.3, 127.8, 127.0, 124.8, 124.3,
119.9, 111.3, 62.1, 13.7. HRMS (ESI) calcd for [C22H16O4 + H]+ 345.1049, found 345.1111.
1
Ethyl 3-cyclopropyl-1-oxo-1H-isochromene-4-carboxylate (3af). Colorless oil. H NMR (500 MHz, CDCl3)
δ
8.25 (ddd, J = 8.0, 1.4, 0.7 Hz, 2H), 7.76–7.65 (m, 4H), 7.47 (ddd, J = 8.4, 6.8, 1.6 Hz, 2H), 4.49 (q,
J = 7.2 Hz, 4H), 2.31 (tt, J = 8.3, 5.0 Hz, 2H), 1.45 (t, J = 7.1 Hz, 6H), 1.33–1.22 (m, 5H), 1.09–0.97 (m, 4H).
13C NMR (126 MHz, CDCl3)
166.2, 160.8, 160.3, 135.1, 129.7, 127.6, 123.6, 119.1, 109.4, 61.7, 14.3, 12.5,
8.5. HRMS (ESI) calcd for [C15H14O4 + H]+ 259.0892, found 259.0957.
δ
1
Ethyl 3-cyclohexyl-1-oxo-1H-isochromene-4-carboxylate (3ag). Colorless oil. H NMR (500 MHz, CDCl3)
8.34–8.28 (m, 1H), 7.77–7.72 (m, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.52 (dd, J = 11.2, 4.0 Hz, 1H), 4.47
(q, J = 7.1 Hz, 2H), 2.79 (tt, J = 11.8, 3.2 Hz, 1H), 1.87 (d, J = 10.2 Hz, 4H), 1.84–1.71 (m, 3H), 1.45 (t,
J = 7.1 Hz, 3H), 1.32 (dd, J = 15.5, 5.9 Hz, 3H). 13C NMR (126 MHz, CDCl3)
166.4, 163.1, 161.8, 135.3,
δ
δ
135.1, 130.0, 128.4, 124.2, 120.0, 109.6, 62.1, 42.1, 30.3, 26.3, 25.8, 14.6. HRMS (ESI) calcd for [C18H20O4 +
H]+ 301.1362, found 301.1433.
1
7,8,9,10-tetrahydrocyclohepta[c]isochromene-5,11-dione (3ah). White solid. H NMR (500 MHz, CD3OD)
δ
8.20 (s, 1H), 8.07 (s, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.53 (d, J = 6.5 Hz, 1H), 2.96 (s, 2H), 2.81 (d, J = 3.1 Hz,
2H), 1.94 (d, J = 2.5 Hz, 4H). 13C NMR (126 MHz, CD3OD)
δ 204.4, 165.5, 162.6, 136.2, 135.9, 130.2,
129.2, 125.7, 120.8, 117.3, 43.7, 33.1, 24.2, 23.4. HRMS (ESI) calcd for [C14H12O3 + H]+ 227.0786, found
227.0708.
1
Ethyl 3-isopropyl-1-oxo-1H-isochromene-4-carboxylate (3ai). Colorless oil. H NMR (500 MHz, CDCl3)
δ
8.28 (dd, J = 7.9, 1.0 Hz, 1H), 7.74–7.69 (m, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.52–7.47 (m, 1H), 4.44 (q,
J = 7.2 Hz, 2H), 3.13 (dt, J = 13.7, 6.8 Hz, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.32 (s, 3H), 1.31 (s, 3H). 13C NMR
(126 MHz, CDCl3) 166.1, 163.2, 161.5, 135.1, 134.8, 129.8, 128.3, 124.0, 119.8, 109.2, 61.9, 31.7, 20.2, 14.3.
HRMS (ESI) calcd for [C15H16O4 + H]+ 261.1049, found 261.1123.
δ
1
Ethyl 3-ethyl-1-oxo-1H-isochromene-4-carboxylate (3aj). Colorless oil. H NMR (500 MHz, CDCl3) δ 8.29
(d, J = 7.8 Hz, 1H), 7.76–7.68 (m, 2H), 7.53–7.48 (m, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.71 (q, J = 7.5 Hz, 2H),
1.42 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.9, 161.6, 135.1, 134.8,
129.8, 128.3, 124.2, 119.7, 109.8, 61.8, 26.4, 14.3, 12.3. HRMS (ESI) calcd for [C14H14O4 + H]+ 247.0892,
found 247.0964.
1
tert-Butyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ak). White solid. H NMR (500 MHz, CDCl3)
δ
8.30 (d, J = 8.0 Hz, 1H), 7.81–7.69 (m, 2H), 7.52 (t, J = 7.2 Hz, 1H), 2.45 (s, 3H), 1.65 (s, 9H). 13C NMR

Molecules 2019, 24, 937
15 of 19
(126 MHz, CDCl3)
δ
165.1, 161.5, 156.3, 135.1, 135.0, 129.8, 128.1, 123.9, 119.7, 111.8, 83.2, 28.3, 19.1.
HRMS (ESI) calcd for [C15H16O4 + H]+ 261.1049, found 261.1114.
1
Benzyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3al). White solid. H NMR (500 MHz, CDCl3)
δ
8.27 (d, J = 8.0 Hz, 1H), 7.70 (ddd, J = 11.6, 9.6, 4.7 Hz, 2H), 7.52–7.43 (m, 3H), 7.43–7.34 (m, 3H), 5.42
(s, 2H), 2.40 (s, 3H). 13C NMR (126 MHz, CDCl3)
δ 165.7, 161.1, 158.0, 135.1, 134.6, 129.7, 128.9, 128.6,
128.2, 124.1, 119.5, 109.99, 67.6, 19.4. HRMS (ESI) calcd for [C18H14O4 + H]+ 295.0892, found 295.0962.
1
Allyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3am). Colorless oil. H NMR (500 MHz, CDCl3)
δ
8.27 (dd, J = 27.2, 8.0 Hz, 1H), 7.80–7.70 (m, 2H), 7.51 (t, J = 7.5 Hz, 1H), 6.05 (ddt, J = 16.5, 10.4, 6.0 Hz,
1H), 5.45 (dd, J = 17.2, 1.3 Hz, 1H), 5.35 (dd, J = 10.4, 0.9 Hz, 1H), 4.88 (d, J = 6.0 Hz, 2H), 2.46 (s, 3H).
13C NMR (126 MHz, CDCl3)
δ 165.6, 161.2, 158.1, 135.2, 134.6, 131.3, 129.7, 128.3, 124.2, 119.8, 119.5,
110.0, 66.4, 19.4. HRMS (ESI) calcd for [C14H12O4 + H]+ 245.0736, found 245.0811.
1
Methyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3an). Colorless oil. H NMR (500 MHz, CDCl3)
δ
8.31–8.25 (m, 1H), 7.73 (qd, J = 8.4, 4.0 Hz, 2H), 3.97 (s, 3H), 2.45 (s, 3H). 13C NMR (126 MHz, CDCl3)
δ
166.3, 161.1, 158.1, 135.1, 134.5, 129.7, 128.2, 124.2, 119.5, 110.0, 52.4, 19.4. HRMS (ESI) calcd for
[C12H10O4 + H]+ 219.0579, found 219.0648.
1
Propyl 3-methyl-1-oxo-1H-isochromene-4-carboxylate (3ao). Colorless oil. H NMR (500 MHz, CDCl3)
8.31–8.26 (m, 1H), 7.74 (qd, J = 8.3, 4.0 Hz, 2H), 7.51 (ddd, J = 8.2, 6.7, 1.8 Hz, 1H), 4.35 (t, J = 6.7 Hz,
2H), 2.46 (s, 3H), 1.87–[44]1.75 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, CDCl3)
166.1,
δ
δ
161.4, 157.8, 135.2, 134.8, 129.8, 128.3, 124.3, 119.7, 110.5, 67.5, 22.1, 19.5, 10.7. HRMS (ESI) calcd for
[C14H14O4 + H]+ 247.0892, found 247.0964.
3.2.5. Derivatization Experiments
Ethyl 3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (
4
) [45]. A mixture of the product 3aa (323 mg)
◦
and ammonium acetate (250 mg) in 0.5 mL of acetic acid is stirred at 80 C overnight, and then cooled
and poured into water. The solid is collected by filtration, washed with water and dried to yield the
1
title compound [44]. White solid. H NMR (400 MHz, CDCl3) δ 11.74 (s, 1H), 8.42 (dd, J = 8.0, 1.0 Hz,
1H), 7.94 (d, J = 8.3 Hz, 1H), 7.74–7.65 (m, 1H), 7.48 (t, J = 7.2 Hz, 1H), 4.46 (d, J = 7.1 Hz, 2H), 2.59 (s,
3H), 1.44 (t, J = 7.1 Hz, 3H). 13C NMR (126MHz, CDCl3)
δ 167.2, 141.2, 135.9, 133.4, 127.4, 126.5, 124.5,
109.5, 61.4, 19.1, 14.5. HRMS (ESI) calcd for [C13H13NO3 + H]+ 232.0895, found 232.0970.
3-methyl-1H-isochromen-1-one (5) [46]. To a 100 mL rd-bottom flask was charged with conc. HCl
(3.51 mL, 96 mmol) and heated to 110 ◦C. 3aa (232 mg, 1 mmol) was then added portionwise and the
mixture was allowed to stir at reflux for 22 h. The resulting white solid and yellow solution was cooled
to room temperature and the solid was collected by vacuum filtration. The solid was further dried
using a mechanical vacuum pump (10−3 torr), and then heated over a hot water bath at 50–60 ◦C for
1
1 h to give isocoumarin
CDCl3)
1H), 6.19 (s, 1H), 2.21 (d, J = 0.6 Hz, 3H). 13C NMR (126 MHz, CDCl3)
5
as an off-white solid (120 mg, 75%) [47]. White solid. H NMR (400 MHz,
δ
8.16 (d, J = 8.0 Hz, 1H), 7.61 (td, J = 7.7, 1.3 Hz, 1H), 7.42–7.33 (m, 1H), 7.27 (d, J = 8.0 Hz,
163.1, 154.7, 137.8, 134.8, 129.6,
127.6, 124.9, 120.0, 103.6, 19.7. HRMS (ESI) calcd for [C10H8O2 + H]+ 161.0524, found 161.0593.
δ
3.2.6. Compete Experiments and Mechanistic Studies
1a–d
5. Benzoic acid-d5 (10 mmol) in SOCl2 (10 mL) was refluxed at 85 ◦C. After 30 min, the mixture
turned clear. The reaction was stopped, and the reaction solution was concentrated to give the acyl
chloride. A solution of acyl chloride prepared above in anhydrous dichloromethane (10 mL) was
injected dropwise to an aqueous ammonia solution (con. 20 mL) in an ice bath. After stirring for 30 min,
the precipitate was collected by suction filtration, washed with water and n-hexane, and dried under
reduced pressure at 50 ◦C. Recrystallization from ethyl acetate afforded the compounds benzamide
1
following general Procedure for the synthesis of benzoylcarbamate derivatives. H NMR (500 MHz,

Molecules 2019, 24, 937
16 of 19
DMSO-d6)
δ
10.65 (s, 1H), 1.47 (s, 10H). 13C NMR (126 MHz, DMSO-d6)
δ
166.47, 150.87, 133.82, 132.31,
128.35, 81.17, 28.20. HRMS (ESI) calcd for [C12H10D5NO3 + Na]+ 249.1366, found 249.1256.
Scheme 3b: To a mixture of [Cp*RhCl2]2 (3 mg, 0.0049 mmol, 5 mol%) and AgSbF6 (5 mg, 0.015 mmol,
15 mol%) in acetonitrile (2 mL) was added 1a (22.1 mg, 0.6 mmol), 1a-d5(22.6 mg, 0.1mmol) and ethyl
2-diazo-3-oxobutanoate 2a (18.7 mg, 0.12 mmol), Cs2CO3(65 mg, 0.2 mmol, 2 equiv). The reaction
mixture was stirred at 60 ◦C for 1 min and the progress was monitored using TLC detection. After
completion of the present reaction, the solvent was evaporated under reduced pressure and the residue
passed through flash column chromatography on silica gel to afford the mixture of products 3a and
3a–d4 with 17.0 mg (74% yield).
Scheme 3c: To a mixture of [Cp*RhCl2]2 (3 mg, 0.0049 mmol, 5 mol%) and AgSbF6 (5 mg, 0.015 mmol,
15 mol%) in acetonitrile (2 mL) was added 1a (22.1 mg, 0.6 mmol) or 1a–d5 (22.6 mg, 0.1mmol) and
ethyl 2-diazo-3-oxobutanoate 2a (18.7 mg, 0.12 mmol), Cs2CO3(65 mg, 0.2 mmol, 2 equiv). The reaction
mixture was stirred at 60 ◦C for 1 min and the progress was monitored using TLC detection. After
completion of the present reaction, the solvent was evaporated under reduced pressure and the residue
passed through flash column chromatography on silica gel to afford the mixture of products 3aa
(17.0 mg, 74%) or 3aa–d4 (14.1 mg, 59.7%).
Scheme 3d: To a mixture of [Cp*RhCl2]2 (3 mg, 0.0049 mmol, 5 mol%) and AgSbF6 (5 mg, 0.015 mmol,
15 mol%) in acetonitrile (2 mL) was added 1a (22 mg, 0.1 mmol) and diethyl 2-diazomalonate (22 mg,
0.12 mmol), Cs2CO3 (65 mg, 0.2 mmol, 2 equiv). The reaction mixture was stirred at 80 ◦C and the
progress was monitored using TLC detection.
4. Conclusions
In conclusion, we have successfully developed a Rhodium-catalyzed C-H activation/annulation
of diazo compounds with Boc-protected benzamidesubstrates for efficient synthesis of isocoumarins.
The tert-butyl formylcarbamate group formally served as an oxidizing DG using the C-N bond as an
internal oxidant. In this strategy, the novel Boc-amide groups as removable directing groups enable
the benzamides to construct C-C/C-O bonds to provide isocoumarins. Moreover, this reaction features
broad substrate scopes and good tolerance. We believe the mild procedure will be of importance to
medicinal chemists.
Supplementary Materials: The following are available online. 1. X-ray single crystal structure of compound 3ga;
2. 1H and 13C NMR Spectra of benzamides; 3. 1H and 13C NMR Spectra of Products; 4. 1H Spectra of Compete
experiments; 5. MS Spectra of benzamides; 6. MS Spectra of Products.
Author Contributions: Experiments and investigation, G.D.; formal analysis and data curation, G.D. and C.L.;
writing—original draft preparation, G.D.; writing—review and editing, C.L. and H.L.
Funding: We gratefully acknowledge financial support from the National Natural Science Foundation of China
(81620108027, 21632008, and 21672231), the Major Project of Chinese National Programs for Fundamental Research
and Development (2015CB910304).
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Saeed, A. Isocoumarins, miraculous natural products blessed with diverse pharmacological activities. Eur. J.
Med. Chem. 2016, 116, 290–317. [CrossRef] [PubMed]
2.
Agata, N.; Nogi, H.; Bamberg, M.; Milhollen, M.; Pu, M.; Weitman, S.; Kharbanda, S.; Kufe, D. The
angiogenesis inhibitor NM-3 is active against human NSCLC xenografts alone and in combination with
docetaxel. Cancer Chemoth. Pharm. 2005, 56, 610–614. [CrossRef] [PubMed]
3.
Kawano, T.; Agata, N.; Kharbanda, S.; Avigan, D.; Kufe, D. A novel isocoumarin derivative induces mitotic
phase arrest and apoptosis of human multiple myeloma cells. Cancer Chemoth. Pharm. 2007, 59, 329–335.
[CrossRef] [PubMed]

Molecules 2019, 24, 937
17 of 19
4.
Ozoe, Y.; Kuriyama, T.; Tachibana, Y.; Harimaya, K.; Takahashi, N.; Yaguchi, T.; Suzuki, E.; Imamura, K.-i.;
Oyama, K. Isocoumarin Derivative as a Novel GABA Receptor Ligand from Neosartorya quadricincta.
J. Pest. Sci. 2004, 29, 328–331. [CrossRef]
5.
6.
Larock, R.C.; Doty, M.J.; Han, X. Synthesis of Isocoumarins and
Annulation of Internal Alkynes. J. Org. Chem. 1999, 64, 8770–8779. [CrossRef] [PubMed]
Rayabarapu, D.K.; Shukla, P.; Cheng, C.-H. Cyclization of Oxa-Bicyclic Alkenes with -Iodo-(Z)-propenoates
α-Pyrones via Palladium-Catalyzed
β
and o-Iodobenzoate Catalyzed by Nickel Complexes: A Simple Efficient Route to Annulated Coumarins.
Org. Lett. 2003, 5, 4903–4906. [CrossRef] [PubMed]
7.
8.
Cherry, K.; Parrain, J.-L.; Thibonnet, J.; Duchêne, A.; Abarbri, M. Synthesis of Isocoumarins and α-Pyrones
via Tandem Stille Reaction/Heterocyclization. J. Org. Chem. 2005, 70, 6669–6675. [CrossRef] [PubMed]
Luo, J.; Lu, Y.; Liu, S.; Liu, J.; Deng, G.J. Efficient One-Pot Synthesis of Dibenzopyranones via a
Decarboxylative Cross-Coupling and Lactonization Sequence. Adv. Synth. Catal. 2011, 353, 2604–2608.
[CrossRef]
9.
Panda, N.; Mishra, P.; Mattan, I. Synthesis of Isocoumarins via Silver(I)-Mediated Annulation of Enol Esters.
J. Org. Chem. 2016, 81, 1047–1056. [CrossRef] [PubMed]
10. Ueura, K.; Satoh, T.; Miura, M. An Efficient Waste-Free Oxidative Coupling via Regioselective C H Bond
−
Cleavage: Rh/Cu-Catalyzed Reaction of Benzoic Acids with Alkynes and Acrylates under Air. Org. Lett.
2007, 9, 1407–1409. [CrossRef] [PubMed]
11. Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. Synthesis of Functionalized
α-Pyrone and Butenolide
Derivatives by Rhodium-Catalyzed Oxidative Coupling of Substituted Acrylic Acids with Alkynes and
Alkenes. J. Org. Chem. 2009, 74, 6295–6298. [CrossRef] [PubMed]
12. Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K. Versatile Synthesis of Isocoumarins and α-Pyrones
by Ruthenium-Catalyzed Oxidative C-H/O–H Bond Cleavages. Org. Lett. 2012, 14, 930–933. [CrossRef]
[PubMed]
13. Frasco, D.A.; Lilly, C.P.; Boyle, P.D.; Ison, E.A. Cp*IrIII-Catalyzed Oxidative Coupling of Benzoic Acids with
Alkynes. ACS Catal. 2013, 3, 2421–2429. [CrossRef]
14. Warratz, S.; Kornhaass, C.; Cajaraville, A.; Niepotter, B.; Stalke, D.; Ackermann, L. Ruthenium(II)-catalyzed
C-H activation/alkyne annulation by weak coordination with O2 as the sole oxidant. Angew Chem. Int.
Ed. Engl. 2015, 54, 5513–5517. [CrossRef] [PubMed]
15. Liu, X.-G.; Gao, H.; Zhang, S.-S.; Li, Q.; Wang, H. N–O Bond as External Oxidant in Group 9
Cp*M(III)-Catalyzed Oxidative C-H Coupling Reactions. ACS Catal. 2017, 7, 5078–5086. [CrossRef]
16. Qiu, Y.; Tian, C.; Massignan, L.; Rogge, T.; Ackermann, L. Electrooxidative Ruthenium-Catalyzed C-H/O-H
Annulation by Weak O-Coordination. Angew Chem. Int. Ed. Engl. 2018, 57, 5818–5822. [CrossRef] [PubMed]
17. Colby, D.A.; Bergman, R.G.; Ellman, J.A. Rhodium-Catalyzed C C Bond Formation via Heteroatom-Directed
−
C−H Bond Activation. Chem. Rev. 2010, 110, 624–655. [CrossRef] [PubMed]
18. Wencel-Delord, J.; Dröge, T.; Liu, F.; Glorius, F. Towards mild metal-catalyzed C-H bond activation.
Chem. Soc. Rev. 2011, 40, 4740–4761. [CrossRef] [PubMed]
19. Song, G.; Wang, F.; Li, X. C-C, C-O and C-N bond formation via rhodium(iii)-catalyzed oxidative C-H
activation. Chem. Soc. Rev. 2012, 41, 3651–3678. [CrossRef] [PubMed]
20. Peneau, A.; Guillou, C.; Chabaud, L. Recent Advances in [Cp*MIII] (M = Co, Rh, Ir)-Catalyzed Intramolecular
Annulation Through C-H Activation. Eur. J. Org. Chem. 2018, 2018, 5777–5794. [CrossRef]
21. Adams, J.; Spero, D.M. Rhodium (II) catalyzed reactions of diazo-carbonyl compounds. Tetrahedron. 1991, 47,
1765–1808. [CrossRef]
22. Padwa, A.; Austin, D.J. Ligand Effects on the Chemoselectivity of Transition Metal Catalyzed Reactions of
α-Diazo Carbonyl Compounds. Angew Chem. Int. Ed. Engl. 1994, 33, 1797–1815. [CrossRef]
23. Ye, T.; McKervey, M.A. Organic Synthesis with .alpha.-Diazo Carbonyl Compounds. Chem. Rev. 1994, 94,
1091–1160. [CrossRef]
24. Maas, G. Ruthenium-catalysed carbenoid cyclopropanation reactions with diazo compounds. Chem. Soc. Rev.
2004, 33, 183–190. [CrossRef] [PubMed]
25. Zhang, Y.; Wang, J. Recent development of reactions with
α-diazocarbonyl compounds as nucleophiles.
Chem. Commun. (Camb). 2009, 5350–5361. [CrossRef] [PubMed]
26. Zhang, Y.; Wang, J. Recent Developments in Pd-Catalyzed Reactions of Diazo Compounds. Eur. J. Org. Chem.
2011, 2011, 1015–1026. [CrossRef]

Molecules 2019, 24, 937
18 of 19
27. Xiao, Q.; Zhang, Y.; Wang, J. Diazo Compounds and N-Tosylhydrazones: Novel Cross-Coupling Partners in
Transition-Metal-Catalyzed Reactions. Acc. Chem. Res. 2013, 46, 236–247. [CrossRef] [PubMed]
28. Hyster, T.K.; Ruhl, K.E.; Rovis, T. A Coupling of Benzamides and Donor/Acceptor Diazo Compounds To
Form γ-Lactams via Rh(III)-Catalyzed C-H Activation. J. Am. Chem. Soc. 2013, 135, 5364–5367. [CrossRef]
[PubMed]
29. Lam, H.-W.; Man, K.-Y.; Chan, W.-W.; Zhou, Z.; Yu, W.-Y. Rhodium(iii)-catalyzed formal oxidative [4 + 1]
cycloaddition of benzohydroxamic acids and
Org. Biomol. Chem. 2014, 12, 4112–4116. [CrossRef] [PubMed]
30. Ye, B.; Cramer, N. Asymmetric Synthesis
α-diazoesters. A facile synthesis of functionalized benzolactams.
of
Isoindolones
by
Chiral
Cyclopentadienyl-Rhodium(III)-Catalyzed C–H Functionalizations. Angew Chem. Int. Ed. 2014, 53,
7896–7899. [CrossRef] [PubMed]
31. Shi, L.; Yu, K.; Wang, B. Regioselective synthesis of multisubstituted isoquinolones and pyridones via
Rh(iii)-catalyzed annulation reactions. Chem. Commun. (Camb). 2015, 51, 17277–17280. [CrossRef] [PubMed]
32. Phatake, R.S.; Patel, P.; Ramana, C.V. Ir(III)-Catalyzed Carbenoid Functionalization of Benzamides: Synthesis
of N-Methoxyisoquinolinediones and N-Methoxyisoquinolinones. Org. Lett. 2016, 18, 2828–2831. [CrossRef]
[PubMed]
33. Li, X.G.; Sun, M.; Liu, K.; Jin, Q.; Liu, P.N. Rh(iii)-catalyzed C-H activation/cyclization of benzamides and
diazo compounds to form isocoumarins and
[CrossRef] [PubMed]
α-pyrones. Chem. Commun. (Camb). 2015, 51, 2380–2383.
34. Wu, J.; Wang, D.; Wan, Y.; Ma, C. Rhodium-catalyzed tunable oxidative cyclization toward the selective
synthesis of α-pyrones and furans. Chem. Commun. (Camb). 2016, 52, 1661–1664. [CrossRef] [PubMed]
35. He, X.; Han, G.; Zuo, Y.; Shang, Y. Rh(III)-catalyzed C-H activation of primary benzamides and tandem
cyclization with cyclic 2-diazo-1,3-diketones for the synthesis of isocoumarins. Tetrahedron. 2018, 74,
7082–7088. [CrossRef]
36. Sun, P.; Gao, S.; Yang, C.; Guo, S.; Lin, A.; Yao, H. Controllable Rh(III)-Catalyzed Annulation between
Salicylaldehydes and Diazo Compounds: Divergent Synthesis of Chromones and Benzofurans. Org. Lett.
2016, 18, 6464–6467. [CrossRef] [PubMed]
37. Kanbayashi, N.; Takenaka, K.; Okamura, T.A.; Onitsuka, K. Asymmetric auto-tandem catalysis with a
planar-chiral ruthenium complex: sequential allylic amidation and atom-transfer radical cyclization. Angew
Chem. Int. Ed. Engl. 2013, 52, 4897–4901. [CrossRef] [PubMed]
38. Evans, V.; Mahon, M.F.; Webster, R.L. A mild, copper-catalysed amide deprotection strategy: use of tert-butyl
as a protecting group. Tetrahedron. 2014, 70, 7593–7597. [CrossRef]
39. Tanaka, K.-I.; Yoshifuji, S.; Nitta, Y. A New Method for the Synthesis of Amides from Amines: Ruthenium
Tetroxide Oxidation of N-Protected Alkylamines. Chem. Pharm. Bull. 1988, 36, 3125–3129. [CrossRef]
40. Meng, G.; Lei, P.; Szostak, M. A General Method for Two-Step Transamidation of Secondary Amides Using
Commercially Available, Air- and Moisture-Stable Palladium/NHC (N-Heterocyclic Carbene) Complexes.
Org. Lett. 2017, 19, 2158–2161. [CrossRef] [PubMed]
41. Xu, L.; Zhang, S.; Trudell, M.L. Novel chromium(VI) catalyzed oxidation of N-alkylamides to imides with
periodic acid. Chem. Commun. (Camb). 2004, 1668–1669. [CrossRef] [PubMed]
42. Meng, G.; Shi, S.; Lalancette, R.; Szostak, R.; Szostak, M. Reversible Twisting of Primary Amides via Ground
State N-C(O) Destabilization: Highly Twisted Rotationally Inverted Acyclic Amides. J. Am. Chem. Soc. 2018
,
140, 727–734. [CrossRef] [PubMed]
43. Yin, H.; de Almeida, A.M.; de Almeida, M.V.; Lindhardt, A.T.; Skrydstrup, T. Synthesis of acyl carbamates
via four component Pd-catalyzed carbonylative coupling of aryl halides, potassium cyanate, and alcohols.
Org. Lett. 2015, 17, 1248–1251. [CrossRef] [PubMed]
44. Furber, M.; Alcaraz, L.; Luckhurst, C.; Bahl, A.; Beaton, H.; Bowers, K.; Collington, J.; Denton, R.; Donald, D.;
Kinchin, E.; et al. Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H1 antagonists.
Part II: Optimising in vivo clearance. Bioorg. Med. Chem. Lett. 2012, 22, 7707–7710. [CrossRef] [PubMed]
45. Wu, Y.; Sun, P.; Zhang, K.; Yang, T.; Yao, H.; Lin, A. Rh(III)-Catalyzed Redox-Neutral Annulation of Primary
Benzamides with Diazo Compounds: Approach to Isoquinolinones. J. Org. Chem. 2016, 81, 2166–2173.
[CrossRef] [PubMed]

Molecules 2019, 24, 937
19 of 19
46. Perveen, S.; Zhao, Z.; Zhang, G.; Liu, J.; Anwar, M.; Fang, X. Enantioselective Synthesis of
1,2-Dihydronaphthalenes via Oxidative N-Heterocyclic Carbene Catalysis. Org. Lett. 2017, 19, 2470–2473.
[CrossRef] [PubMed]
47. Weerasinghe, M.S.; Karlson, S.T.; Lu, Y.; Wheeler, K.A. Crystal Photodimerization Reactions of Spatially
Engineered Isocoumarin Assemblies. Cryst. Growth Des. 2016, 16, 1781–1785. [CrossRef]
Sample Availability: Not available.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).