Rh-catalyzed intramolecular aromatic C-H insertion of α-diazo β-ketoesters: Synthesis of 4-carbonyl chroman derivatives

Article abstract of DOI:10.1016/j.tet.2014.03.093

A Rh-catalyzed intramolecular aromatic C-H insertion of α-diazo β-ketoesters was developed. This protocol offers a practical strategy for the synthesis of 4-carbonyl chroman derivatives with high yield and is compatible with a wide variety of substituents

Full text of DOI:10.1016/j.tet.2014.03.093

Tetrahedron 70 (2014) 3400e3406
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rh-catalyzed intramolecular aromatic CeH insertion of
a-diazo
b-ketoesters: synthesis of 4-carbonyl chroman derivatives
*
*
Xiaolin Zhang, Mei Lei, Yi-Nan Zhang , Li-Hong Hu
Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Rh-catalyzed intramolecular aromatic CeH insertion of
a-diazo b-ketoesters was developed. This
Received 25 December 2013
Received in revised form 21 March 2014
Accepted 28 March 2014
protocol offers a practical strategy for the synthesis of 4-carbonyl chroman derivatives with high yield
and is compatible with a wide variety of substituents. Synthetic applications of the 4-carbonyl chroman
were also demonstrated.
Available online 3 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
CeH insertion
Diazo compounds
Synthetic methods
Heterocycles
1. Introduction
a number of elaborative heterocycles. For example, Padwa and Sa
first introduced the method in 1999.10 As a part of our synthetic
As one of the most prevalent polycyclic heterocycle in natural
products benzopyran derivatives, especially displayed in numerous
kinds of flavonoids, are widely distributed in plant secondary me-
tabolites, fulfilling a series of significant functions.1,2 The benzo-
pyran derivatives are also found to be responsible for observed
biological activities in medicinal chemistry. For example, as one of
the benzopyran sub-category, several privileged structures of 4-
carbonyl chroman have been extensively studied, such as
deguelin,3 stachyoidin,4 and brazilide A5 (Fig. 1). The major syn-
thetic efforts to this 4-carbonyl chroman category previously fo-
cused on Robinsen cyclization,6 BucherereBergs reaction,7 and
Favorskii type rearrangement.8 Until very recently, Nicolaou and
co-workers proposed an organo-SOMO catalytic enantioselective
intramolecular FriedeleCrafts arylation to carry out the structure
with electronic-rich analogs.9 However, lengthy procedures, poor
yields, and access to limited substitution patterns make these
methodologies unsuitable for high-throughput synthesis and
library generation.
method development toward exquisite heterocycles in the context
of diazo precursors, we recently described a tunable aromatic CeH
insertion and Wolff rearrangement of
a-diazo-b-ketoesters to
The aromatic CeH insertion is a valuable and powerful synthetic
approach for the efficient construction of structurally unique
frameworks and the wide adaptability of this robust method have
been proved to tolerate diverse functional groups, allowing to reach
* Corresponding authors. Tel./fax: þ86 21 20231965; e-mail addresses: ynzhang@
sibs.ac.cn (Y.-N. Zhang), lhhu@simm.ac.cn (L.-H. Hu).
Fig. 1. Representative 4-carbonyl chroman derivatives.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.093

X. Zhang et al. / Tetrahedron 70 (2014) 3400e3406
3401
multiple nitrogen-containing heterocycles (Scheme 1).11 Here we
wish to expand this method to oxygen (sulfur)-containing struc-
tures, which is capable of producing a range of 4-carbonyl chro-
mans exactly.
Table 1
Condition screening of CeH insertiona
Entry
Catalyst
Solvent
T (ꢀC)/t (h)
Yieldb (%)
1
2
3
4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Ag2O
CH2Cl2
CHCl3
DCE
25/2
25/2
25/2
25/2
25/2
25/2
25/4
25/2
25/2
25/2
100/3
100/3
62
0
10
90
87
87
67
0
0
0
0
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCM
DCM
DCM
Tol
5c
6d
7e
8
9
CuI
Scheme 1. Intramolecular aromatic CeH insertion to heterocycles.
10
11
12
Nonef
Ag2O
Nonef
Tol
2. Results and discussion
a
Reactions were carried out with 0.2 mmol 1a and 0.5 mol % catalyst unless
specified at room temperature with stirring.
To test our rational design, we prepared
a-diazo-b-ketoesters
b
Isolated yield.
Catalyst loading (0.1 mol %).
Catalyst loading (0.1 mol %).
Catalyst loading (0.05 mol %).
precursors 1aeu in three steps, which were started from the nu-
cleophilic substitution of bromoacetate to phenoxyacetate, followed
by Claisen condensation12 and Regitz diazo transfer13 (Scheme 2).
To our delight, initial survey of the aromatic CeH insertion between
1a and Rh2(OAc)4 in dichloromethane gave the desired product in
moderate yield, suggesting the rhodium catalyst allowed the
intramolecular reaction under the neutral conditions, albeit to
a limited extent (Table 1, entry 1). According to our previous
c
d
e
f
No catalyst was added.
position probably due to the combine effect of the electron density
and hindrance effect (Table 2, entry 11). However, the insertion
could not happen to sp3 CeH bond when employing the substrate
that has both sp2 ortho-positions blocked (entry 17, Table 2). Com-
paring with the aromatic CeH insertion containing nitrogen atom,
the oxygen substrates showed better yields and broader tolerance
to sensitive functional groups, suggesting it would be a sufficiently
mild platform to build 4-carbonyl chroman-based natural products.
research,11 Du Bois’ catalyst bis[rhodium( a0 0-tetramethyl-1,3-
a,a, ,a
benzenedipropionic acid)] that possess two chelating bis-
carboxylate ligand can enhance the yield of cyclization with sul-
fonamide substrate, thus we found the treatment of Rh2(esp)2 to 1a
also remarkably improved the yield, even lower the loading amount
to 0.1 mol % (Table 1, entries 4e7). Further screen of solvents and
transition metal catalysts revealed dichloromethane and Rh2(esp)2
were the best solvent and catalyst for this catalytic system (Table 1,
entries 2 and 3, 8e10). However, substrate 1a could not undergo
Wolff rearrangement reaction either with Ag2O or under self-
thermal initiation condition, as its tertiary amine counterpart did
(Table 1, entries 11 and 12). We reasoned that the less nucleophilic
oxygen was unable to attack the Wolff ketene intermediate so that it
cannot transfer to the subsequent carboxylacrylate.
Table 2
The reaction scope of the CeH insertion to form 4-carbonyl chromana
Entry
R
Yieldb (%)
1
2
3
4
5
6
7
8
H
4-Cl
4-I
4-F
90 (2a)
86 (2b)
82 (2c)
81 (2d)
97 (2e)
92 (2f)
90 (2g)
85 (2h)
83 (2i)
95 (2j)
96 (2k)
93 (2l)
88 (2m)
91 (2n)
94 (2o)
91 (2p)
0c
4-OMe
4-tBu
4-Ph
2-Cl
2-I
9
10
11
12
13
14
15
16
17
2-OMe
3-OMe
2-Me
2,3-DiMe
3,4-DiMe
3,4-[1,3]Dioxole
1-Naphthal
2,6-DiMe
Scheme 2. Preparation of
a-diazo-b-ketoesters 1aeu (a) K2CO3, bromoacetate, KI,
DMF, 50 ꢀC, 16 h; (b) LiHDMS, EtOAc, THF, ꢁ78 ꢀC, 2 h; (c) TsN3, TEA, CH3CN, room
temperature, 2 h.
Next we investigated the scope of this aromatic CeH insertion to
construct 4-carbonyl chroman analogs under the optimized con-
ditions. Firstly, we found that the electron properties of the aro-
matic ring did not affect the reaction: both electron-donating and
electron-withdrawing groups on the phenyl rings worked well
(Table 2, entries 1e6). Subsequently, regarding to the positions of
substitution, the reaction can tolerate not only ortho- and meta-
substitutions but also the di-substitution and poly-aromatic ring
system, such as naphthalene and biphenyl (Table 2, entries 7e16). It
was also worth to note that the CeH insertion exclusively occurred
at the para-position of methoxyl substitution instead of ortho-
a
Reactions were carried out with 0.2 mmol 1a and 0.5 mol % catalyst unless
specified at room temperature with stirring.
b
Isolated yield.
All starting materials left.
c
We then explored the reaction scope of the ester group and the
possibility to other heterocyclic scaffolds (Fig. 2). For a variety of
ester substituents, the reaction afforded chroman ring in
high yields comparable to the ethyl ester. However, the

3402
X. Zhang et al. / Tetrahedron 70 (2014) 3400e3406
seven-membered ring precursor 1t produced only a trace amount
of benzooxepane (LCeMS detected, but too low to isolate). Addi-
tionally, in our attempt to include the sulfur substrate in the cata-
lytic system, we found that the rhodium catalyst lose its activity
instantly after treating with the first drops of thioether substrate
1u. The reason can probably be ascribed to the displacement of
acetate ligand to thioether one that was commonly occurred on
rhodium and other transition metal complexes.14
3. Conclusions
In summary, we have developed a direct aromatic CeH insertion
for efficient construction of 4-carbonyl chromans that are privilege
in many biologically active compounds. Starting from the simple
materials, high yields were obtained with different substitution
patterns on the aromatic ring. And the following synthetic con-
version indicates the potential application of the CeH insertion
product as a versatile and straightforward building block. We are
exploring the total synthesis of the related 4-carbonyl chroman
natural products by using this method.
4. Experimental section
4.1. General
All reagents were purchased from commercial suppliers unless
otherwise stated. Dichloromethane was distilled from CaH2 under
argon. THF was distilled from Na/benzophenone under argon. All
moisture-sensitive reactions were carried out in oven-dried glass-
ware under argon atmosphere. 1H NMR spectra were recorded on
a Bruker AVIII-400 spectrometer. 13C NMR spectra were obtained by
using the same NMR spectrometers. The following abbreviations
are used for the multiplicities: s: singlet, d: doublet, t: triplet, q:
quartet, m: multiplet, br: broad, br s: broad singlet for proton
spectra. Chemical shifts are reported in parts per million with the
solvent signals as reference, coupling constants (J) are reported in
Hertz (Hz). MS (ESI) was run on a Bruker Esquire 3000 plus spec-
trometer in MeOH. HRMS (ESI) were determined on a Micromass
Q-Tof Global mass spectrometer. Flash column chromatography
was performed using silica gel (200e300 mesh). Visualization was
achieved under a UV lamp (254 nm and 365 nm).
Fig. 2. Further scope of the CeH insertion reaction.a aReactions were carried out with
0.2 mmol 1a and 0.5 mol % catalyst at room temperature with stirring. bIsolated yield.
To demonstrate the reliability and practicability of this CeH in-
sertion method, we also commented on the synthetic trans-
formations of the 1-carbonyl chroman product. The CeH insertion
product 2a was readily converted into the chroman-3-one 3 through
the decarboxylation at high temperature. The ketoester motif of 2a
can also be served as the building block of various heterocycles, such
as the cytosine derivative 4. And the successive reduction of the
ketoester with sodium borohydride delivered the trans/cis mixture
of alcohol 5 in a 5:1 ratio, which was demonstrated by the 2D NMR
analysis. All the transformations proceeded in good yields under
non-optimized conditions (Scheme 3).
4.2. General procedure for preparing starting material 1aeu
To a solution of b-ketoester (2.0 mmol) in acetonitrile (10 mL)
were added p-methylbenzenesulfonyl azide (0.414 g, 2.1 mmol) and
triethylamine (0.5 mL, 3.6 mmol). The resulting orange slurry was
stirred for 2 h at room temperature. After evaporating all the vol-
atiles, the residue was purified by flash column chromatography
eluting with the mixture of petroleum ether and ethyl acetate
(20:1).
4.2.1. Ethyl 2-diazo-3-oxo-4-phenoxybutanoate (1a). Yellow solid;
isolated yield 81% (402 mg). Rf 0.33 (PE/EtOAc, 6:1); mp 52e53 ꢀC;
1H NMR (400 MHz, CDCl3):
d 7.26e7.31 (m, 2H), 6.92e6.99 (m, 3H),
5.14 (s, 2H), 4.32 (q, J¼7.0 Hz, 2H), 1.35 (t, J¼7.0 Hz, 3H) ppm. The
date of the compound is identical with the described date of the
reference.15
4.2.2. Ethyl 4-(4-chlorophenoxy)-2-diazo-3-oxobutanoate
(1b). Colorless solid; isolated yield 80% (451 mg). Rf 0.31 (PE/
EtOAc, 6:1); mp 68e68.5 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.21e7.25
(m, 2H), 6.83e6.87 (m, 2H), 5.12 (s, 2H), 4.34 (q, J¼7.1 Hz, 2H), 1.36
(t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 186.80, 161.28,
156.78,129.53,126.68,116.32, 71.42, 62.11,14.49 ppm; MS (ESI): m/z
346 [MþNaþCH3CN]þ; HRMS (ESI): m/z [MþH]þ calcd for
C12H12ClN2O4 283.0480, found 283.0483.
4.2.3. Ethyl 2-diazo-4-(4-iodophenoxy)-3-oxobutanoate (1c). Light
yellow solid; isolated yield 83% (620 mg). Rf 0.35 (PE/EtOAc, 6:1);
mp 68e68.5 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.53e7.57 (m, 2H),
6.68e6.71 (m, 2H), 5.11 (s, 2H), 4.33 (q, J¼7.8 Hz, 2H), 1.35 (t,
J¼7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 186.71, 161.27, 158.04,
138.41, 117.32, 84.03, 71.12, 62.12, 14.49 ppm; MS (ESI): m/z 397
Scheme 3. Synthetic transformations of 2a.

X. Zhang et al. / Tetrahedron 70 (2014) 3400e3406
3403
[MþNa]þ; HRMS (ESI) m/z [MþH]þ calcd for C12H12IN2O4 374.9836,
MS (ESI): m/z 301 [MþNa]þ; HRMS (ESI): m/z [MþH]þ calcd for
found 374.9828.
C13H15N2O5 279.0975, found 279.0972.
4.2.4. Ethyl 2-diazo-4-(4-fluorophenoxy)-3-oxobutanoate
(1d). Colorless solid; isolated yield 78% (415 mg). Rf 0.37 (PE/
EtOAc, 6:1); mp 68.9e69.3 ꢀC; 1H NMR (400 MHz, CDCl3):
4.2.11. Ethyl 2-diazo-4-(3-methoxyphenoxy)-3-oxobutanoate
(1k). Yellow solid; isolated yield 82% (456 mg). Rf 0.31 (PE/EtOAc,
5:1); mp 59.0e59.4 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.17 (t,
d
6.93e6.98 (m, 2H), 6.85e6.88 (m, 2H), 5.10 (s, 2H), 4.33 (q,
J¼8.0 Hz, 1H), 6.47e6.58 (m, 3H), 5.12 (s, 2H), 4.33 (q, J¼7.1 Hz, 2H),
J¼8.0 Hz, 2H), 1.35 (t, J¼8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
3.78 (s, 3H), 1.35 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
187.10, 161.28, 157.83 (d, 1JCeF¼239.2 Hz), 154.28 (d, 4JCeF¼4.0 Hz),
d 187.00, 161.29, 160.95, 159.32, 130.03, 107.42, 106.73, 101.65, 76.90,
2
3
116.19 (d, JCeF¼23.1 Hz), 116.01 (d, JCeF¼8.2 Hz), 75.42, 71.92,
62.07, 14.47 ppm; MS (ESI): m/z 330 [MþNaþCH3CN]þ; HRMS (ESI):
m/z [MþH]þ calcd for C12H12FN2O4 267.0776, found 267.0772.
71.18, 62.03, 55.44, 14.48 ppm; MS (ESI): m/z 342
[MþNaþCH3CN]þ; HRMS (ESI): m/z [MþH]þ calcd for C13H15N2O5
279.0975, found 279.0980.
4.2.5. Ethyl 2-diazo-4-(4-methoxyphenoxy)-3-oxobutanoate
4.2.12. Ethyl 2-diazo-3-oxo-4-(o-tolyloxy)butanoate(1l). Light yel-
low solid; isolated yield 82% (430 mg). Rf 0.45 (PE/EtOAc, 6:1); mp
(1e). Colorless solid; isolated yield 76% (422 mg). Rf 0.32 (PE/
EtOAc, 5:1); mp 73.1e74.0 ꢀC; 1H NMR (400 MHz, CDCl3):
d
6.89 (d,
77.0e77.7 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.16 (d, J¼7.7 Hz, 1H),
J¼8.5 Hz, 2H), 6.82 (d, J¼8.5 Hz, 2H), 5.09 (s, 2H), 4.33 (q, J¼7.2 Hz,
7.11 (t, J¼8.0, 8.0 Hz,1H), 6.89 (t, J¼8.0, 7.7 Hz,1H), 6.70 (d, J¼8.0 Hz,
1H), 5.16 (s, 2H), 4.34 (q, J¼8.0 Hz, 2H), 2.31 (s, 3H), 1.35 (t, J¼8.0 Hz,
2H), 3.76 (s, 3H), 1.35 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
187.50, 161.33, 154.56, 152.33, 116.17, 114.76, 75.37, 72.21, 62.01,
3H); 13C NMR (100 MHz, CDCl3):
d 187.40, 161.34, 156.35, 131.11,
55.83, 14.49 ppm; MS (ESI): m/z 342 [MþNaþCH3CN]þ; HRMS
127.41, 126.77, 121.43, 111.65, 71.53, 62.01, 16.39, 14.48 ppm; MS
(ESI): m/z [MþH]þ calcd for C13H15N2O5 279.0975, found 279.0972.
(ESI): m/z 326 [MþNaþCH3CN]þ; HRMS (ESI): m/z [MþH]þ calcd for
C13H15N2O4 263.1026, found 263.1021.
4.2.6. Ethyl 4-(4-(tert-butyl)phenoxy)-2-diazo-3-oxobutanoate
(1f). Yellow solid; isolated yield 87% (529 mg). Rf 0.41 (PE/EtOAc,
4.2.13. Ethyl2-diazo-4-(2,3-dimethylphenoxy)-3-oxobutanoate
6:1); mp 67.1e67.4 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.27e7.31 (m,
(1m). Yellow solid; isolated yield 85% (469 mg). Rf 0.35 (PE/EtOAc,
2H), 6.84e6.88 (m, 2H), 5.12 (s, 2H), 4.34 (q, J¼7.1 Hz, 2H), 1.36 (t,
7:1); mp 71.0e71.4 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.0 (t, J¼8.0,
J¼7.1 Hz, 3H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
187.38,
8.0 Hz, 1H), 6.80 (d, J¼8.0 Hz,1H), 6.59 (d, J¼8.0 Hz,1H), 5.14 (s, 2H),
161.34, 155.87, 144.39, 126.42, 114.41, 71.38, 62.01, 34.24, 31.62,
14.48 ppm; MS (ESI): m/z 368 [MþNaþCH3CN]þ; HRMS (ESI): m/z
[MþH]þ calcd for C16H21N2O4 305.1496, found 305.1491.
4.33 (q, J¼8.0 Hz, 2H), 2.27 (s, 3H), 2.23 (s, 3H),1.35 (t, J¼8.0 Hz, 3H);
13C NMR (100 MHz, CDCl3):
d 187.51, 161.34, 156.14, 138.41, 125.90,
125.78, 123.30, 109.61, 71.85, 61.98, 20.22, 14.47, 11.89 ppm; MS
(ESI): m/z 340 [MþNaþCH3CN]þ; HRMS (ESI): m/z [MþH]þ calcd for
4.2.7. Ethyl 4-([1,10-biphenyl]-4-yloxy)-2-diazo-3-oxobutanoate
(1g). Light yellow solid; isolated yield 84% (544 mg). Rf 0.35 (PE/
EtOAc, 5:1); mp 110.1e110.6 ꢀC; 1H NMR (400 MHz, CDCl3):
C14H17N2O4 277.1183, found 277.1188.
4.2.14. Ethyl 2-diazo-4-(3,4-dimethylphenoxy)-3-oxobutanoate
d
7.50e7.55 (m, 4H), 7.41 (t, J¼8.0 Hz, 2H), 7.31 (t, J¼6.0 Hz, 1H), 7.00
(d, J¼8.0 Hz, 2H), 5.19 (s, 2H), 4.35 (q, J¼8.0 Hz, 2H),1.37 (t, J¼8.0 Hz,
3H); 13C NMR (100 MHz, CDCl3):
187.07, 161.29, 157.60, 140.75,
(1n). Yellow solid; isolated yield 84% (464 mg). Rf 0.32 (PE/EtOAc,
7:1); mp 72.0e72.3 ꢀC; 1H NMR (400 MHz, CDCl3):
d 7.02 (d,
d
J¼12.0 Hz, 1H), 6.75 (d, J¼4.0 Hz, 1H), 6.65 (dd, J¼12.0, 4.0 Hz, 1H),
134.76, 128.80, 128.80, 128.30, 126.88, 126.87, 115.15, 71.22, 62.04,
14.45 ppm; MS (ESI): m/z 388 [MþNaþCH3CN]þ; HRMS (ESI): m/z
[MþH]þ calcd for C18H17N2O4 325.1183, found 325.1187.
5.10 (s, 2H), 4.34 (q, J¼8.0 Hz, 2H), 2.22 (s, 3H), 2.18 (s, 3H), 1.36 (t,
J¼8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 187.41, 161.37, 156.23,
137.96, 130.42, 129.74, 116.53, 111.79, 71.39, 62.00, 20.18, 18.97,
14.48 ppm; MS (ESI): m/z 340 [MþNaþCH3CN]þ; HRMS (ESI): m/z
[MþH]þ calcd for C14H17N2O4 277.1183, found 277.1189.
4.2.8. Ethyl 4-(2-chlorophenoxy)-2-diazo-3-oxobutanoate
(1h). Colorless solid; isolated yield 87% (490 mg). Rf 0.34 (PE/
EtOAc, 5:1); mp 82.1e82.7 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.37 (d,
4.2.15. Ethyl 4-(benzo[d][1,3]dioxol-5-yloxy)-2-diazo-3-
oxobutanoate (1o). Light yellow solid; isolated yield 88%
(514 mg). Rf 0.30 (PE/EtOAc, 5:1); mp 93.1e93.5 ꢀC; 1H NMR
J¼8.0 Hz, 1H), 7.16 (t, J¼8.0 Hz, 1H), 6.92 (t, J¼8.0 Hz, 1H), 6.81 (d,
J¼8.0 Hz, 1H), 5.21 (s, 2H), 4.32 (q, J¼8.0 Hz, 2H), 1.34 (t, J¼8.0 Hz,
3H); 13C NMR (100 MHz, CDCl3):
d
186.47, 161.25, 153.80, 130.65,
(400 MHz, CDCl3):
d
6.68 (d, J¼8.5 Hz, 1H), 6.54 (d, J¼2.5 Hz, 1H),
127.68, 123.34, 122.50, 114.23, 75.43, 71.99, 62.08, 14.43 ppm; MS
6.33 (dd, J¼8.5, 2.5 Hz, 1H), 5.91 (s, 2H), 5.06 (s, 2H), 4.32 (q,
(ESI) m/z: 346 [MþNaþCH3CN]þ; HRMS (ESI): m/z [MþH]þ calcd for
J¼8.5 Hz, 2H), 1.35 (t, J¼8.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
C
12H12ClN2O4 283.0480, found 283.0482.
d 187.23, 161.26, 153.65, 148.38, 142.45, 107.99, 106.39, 101.39, 98.77,
76.91, 72.29, 62.01, 14.46 ppm; MS (ESI): m/z 315 [MþNa]þ; HRMS
4.2.9. Ethyl 2-diazo-4-(2-iodophenoxy)-3-oxobutanoate (1i). Light
yellow solid; isolated yield 85% (636 mg). Rf 0.32 (PE/EtOAc, 6:1);
(ESI): m/z [MþH]þ calcd for C13H13N2O6 293.0768, found 293.0763.
mp 84.0e84.5 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.79 (dd, J¼7.7,
4.2.16. Ethyl 2-diazo-4-(naphthalen-1-yloxy)-3-oxobutanoate
1.5 Hz, 1H), 7.25 (td, J¼8.2, 1.5 Hz, 1H), 6.66e6.78 (m, 2H), 5.20 (s,
(1p). Purple solid; isolated yield 83% (494 mg). Rf 0.32 (PE/EtOAc,
2H), 4.33 (q, J¼7.1 Hz, 2H), 1.35 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz,
5:1); mp 131.1e131.7 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.38e8.42 (m,
CDCl3):
d
186.21,161.13,156.86, 139.72,129.39,123.42,112.72, 86.52,
1H), 7.78e7.82 (m, 1H), 7.45e7.52 (m, 3H), 7.34 (t, J¼8.8 Hz, 1H),
75.38, 72.06, 62.02, 14.47 ppm; MS (ESI): m/z 397 [MþNa]þ; HRMS
6.73 (d, J¼8.0 Hz, 1H), 5.33 (s, 2H), 4.35 (q, J¼8.0 Hz, 2H), 1.36 (t,
(ESI): m/z [MþH]þ calcd for C12H12IN2O4 374.9836, found 374.9830.
J¼8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 186.88, 161.38, 153.99,
134.74, 127.51, 126.69, 125.80, 125.64, 125.59, 122.41, 121.40, 105.57,
71.57, 62.07,14.50 ppm; MS (ESI): m/z 362 [MþNaþCH3CN]þ; HRMS
(ESI): m/z [MþH]þ calcd for C16H15N2O4 299.1026, found 299.1022.
4.2.10. Ethyl 2-diazo-4-(2-methoxyphenoxy)-3-oxobutanoate
(1j). Yellow solid; isolated yield 87% (484 mg). Rf 0.30 (PE/EtOAc,
5:1); mp 92.2e92.7 ꢀC; 1H NMR (400 MHz, CDCl3):
d
6.78e6.97 (m,
4H), 5.19 (s, 2H), 4.31 (q, J¼8.0 Hz, 2H), 3.87 (s, 3H), 1.33 (t, J¼8.0 Hz,
3H); 13C NMR (100 MHz, CDCl3):
187.05, 161.31, 149.63, 147.47,
122.35, 120.72, 114.42, 112.13, 75.23, 72.17, 61.93, 55.96, 14.41 ppm;
4.2.17. Ethyl 2-diazo-4-(2,6-dimethylphenoxy)-3-oxobutanoate
d
(1q). Colorless solid; isolated yield 82% (452 mg). Rf 0.35 (PE/
EtOAc, 6:1); mp 72e72.5 ꢀC; 1H NMR (400 MHz, CDCl3):
d 6.91e7.00

3404
X. Zhang et al. / Tetrahedron 70 (2014) 3400e3406
(m, 3H), 4.92 (s, 2H), 4.27 (q, J¼8.0 Hz, 2H), 2.28 (s, 6H), 1.31 (t,
10:1); mp 103.0e103.4 ꢀC. 1H NMR (400 MHz, CDCl3):
d 13.07 (s,
J¼8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
187.31, 161.24, 155.59,
1H), 7.77 (d, J¼2.4 Hz, 1H), 7.01 (dd, J¼8.5, 2.4 Hz, 1H), 6.82 (d,
130.86, 129.00, 124.42, 75.14, 74.90, 61.79, 16.37, 14.44 ppm; MS
J¼8.5 Hz, 1H), 4.64 (s, 2H), 4.44 (q, J¼7.1 Hz, 2H), 1.45 (t, J¼7.1 Hz,
(ESI): m/z 340 [MþNaþCH3CN]þ; HRMS (ESI): m/z [MþH]þ calcd for
3H); 13C NMR (100 MHz, CDCl3):
d 170.60, 170.05, 149.81, 127.31,
C
14H17N2O4 277.1183, found 277.1185.
126.16, 125.68, 121.57, 117.56, 96.65, 66.09, 61.95, 14.32 ppm; MS
(ESI): m/z 253 [MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ calcd for
4.2.18. Isopropyl 2-diazo-3-oxo-4-phenoxybutanoate (1r). Yellow
solid; isolated yield 75% (393 mg). Rf 0.36 (PE/EtOAc, 6:1); mp
C12H12ClO4 255.0419, found 255.0420.
72.3e72.5 ꢀC. 1H NMR (400 MHz, CDCl3):
d
7.28 (t, J¼8.0 Hz, 2H),
4.3.3. Ethyl 3-hydroxy-6-iodo-2H-chromene-4-carboxylate
6.97 (t, J¼8.0 Hz, 1H), 6.93 (d, J¼8.0 Hz, 2H), 5.15e5.23 (m, 1H), 5.14
(2c). Colorless solid; isolated yield 82% (142 mg). Rf 0.60 (PE/
(s, 2H), 1.34 (d, J¼4.0 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d
187.22,
EtOAc, 10:1); mp 78.2e78.5 ꢀC. 1H NMR (400 MHz, CDCl3):
d 13.03
160.91, 158.11, 129.62, 121.70, 114.94, 75.67, 71.21, 70.21, 22.09 ppm;
MS (ESI): m/z 326 [MþNaþCH3CN]þ; HRMS (ESI): m/z [MþH]þ
calcd for C13H15N2O4 263.1026, found 263.1031.
(s, 1H), 8.10 (d, J¼2.1 Hz, 1H), 7.33 (dd, J¼8.4, 2.1 Hz, 1H), 6.65 (d,
J¼8.4 Hz, 1H), 4.64 (s, 2H), 4.43 (q, J¼7.1 Hz, 2H), 1.45 (t, J¼7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3):
d 170.54, 169.75, 151.14, 135.18,
134.52, 122.50, 118.57, 96.33, 85.14, 66.00, 61.96, 14.25 ppm; MS
(ESI) m/z 345 [MꢁH]ꢁ; HRMS (ESI) m/z [MþH]þ calcd for C12H12IO4
346.9775, found 346.9779.
4.2.19. tert-Butyl 2-diazo-3-oxo-4-phenoxybutanoate (1s). Yellow
solid; isolated yield 71% (392 mg). Rf 0.39 (PE/EtOAc, 6:1); mp
78.1e78.6 ꢀC. 1H NMR (400 MHz, CDCl3):
d
7.28 (t, J¼8.0 Hz, 2H),
6.97 (t, J¼8.0 Hz, 1H), 6.93 (d, J¼8.0 Hz, 2H), 5.11 (s, 2H), 1.55 (s, 9H);
13C NMR (100 MHz, CDCl3):
187.42, 160.52, 158.15, 129.61, 121.67,
4.3.4. Ethyl 6-fluoro-3-hydroxy-2H-chromene-4-carboxylate
(2d). Colorless solid; isolated yield 81% (96 mg). Rf 0.62 (PE/EtOAc,
d
114.99, 84.10, 76.26, 71.23, 28.45 ppm; MS (ESI): m/z 340
[MþNaþCH3CN]þ; HRMS (ESI): m/z [MþH]þ calcd for C14H17N2O4
277.1183, found 277.1180.
10:1); mp 75.1e75.5 ꢀC. 1H NMR (400 MHz, CDCl3):
d 13.08 (s, 1H),
7.49e7.53 (m,1H), 6.81e6.85 (m,1H), 6.72e6.77 (m,1H), 4.62 (s, 2H),
4.44 (q, J¼7.1 Hz, 2H), 1.45 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz,
1
CDCl3):
d
170.66, 170.44, 158.14 (d, JCeF¼237.0 Hz), 147.18 (d,
4.2.20. Ethyl 2-diazo-3-oxo-5-phenoxypentanoate (1t). Yellow
solid; isolated yield 84% (440 mg). Rf 0.41 (PE/EtOAc, 6:1); mp
4JCeF¼1.5 Hz),121.41 (d, 3JCeF¼9.5 Hz),117.06 (d, 3JCeF¼8.9 Hz),112.67
(d, 2JCeF¼13.7 Hz), 112.47 (d, 2JCeF¼10.3 Hz), 96.89 (d, 4JCeF¼1.0 Hz),
66.19, 61.89,14.35 ppm; MS (ESI): m/z 237 [MꢁH]ꢁ; HRMS (ESI): m/z
[MþH]þ calcd for C12H12FO4 239.0714 found 239.0717.
68.1e68.5 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.23e7.33 (m, 2H),
6.86e6.99 (m, 3H), 4.32e4.37 (m, 4H), 3.39 (t, J¼7.0 Hz, 2H), 1.37 (t,
J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 190.15, 161.38, 158.74,
129.54, 121.02, 114.76, 76.91, 62.84, 61.71, 40.02, 14.48 ppm; MS
4.3.5. Ethyl 3-hydroxy-6-methoxy-2H-chromene-4-carboxylate
(ESI): m/z 326 [MþNaþCH3CN]þ; HRMS (ESI): m/z [MþH]þ calcd for
(2e). Gray solid; isolated yield 97% (121 mg). Rf 0.45 (PE/EtOAc,
C
13H15N2O4 263.1026, found 263.1028.
10:1); mp 58.2e59.1 ꢀC. 1H NMR (400 MHz, CDCl3):
d 13.02 (s, 1H),
7.39 (d, J¼4.0 Hz, 1H), 6.83 (d, J¼8.0 Hz, 1H), 6.61 (dd, J¼8.0, 4.0 Hz,
4.2.21. Ethyl 2-diazo-3-oxo-4-(p-tolylthio)butanoate (1u). Light
yellow liquid; isolated yield 94% (520 mg); Rf 0.33 (PE/EtOAc, 10:1).
1H), 4.59 (s, 2H), 4.42 (q, J¼6.0 Hz, 2H), 3.78 (s, 3H),1.44 (t, J¼6.0 Hz,
3H); 13C NMR (100 MHz, CDCl3):
d 170.92, 170.41, 154.78, 145.34,
1H NMR (400 MHz, CDCl3):
d
7.32 (dd, J¼1.6, 6.4 Hz, 2H), 7.09 (d,
120.98, 116.73, 111.80, 111.32, 97.24, 66.29, 61.64, 55.73, 14.37 ppm;
J¼8.0 Hz, 2H), 4.30 (q, J¼6.4 Hz, 2H), 4.08 (s, 2H), 2.31 (s, 3H),1.33 (t,
MS (ESI): m/z 249 [MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ calcd for
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
187.17, 161.06, 137.28,
C13H15O5 251.0914, found 251.0915.
131.10, 130.91, 129.76, 61.69, 42.14, 21.06, 14.28 ppm; MS (ESI): m/z
279 [MþH]þ; HRMS (ESI): m/z [MþH]þ calcd for C13H15N2O3S
279.0803, found 279.0800.
4.3.6. Ethyl 6-(tert-butyl)-3-hydroxy-2H-chromene-4-carboxylate
(2f). Yellow solid; isolated yield 92% (127 mg). Rf 0.61 (PE/EtOAc,
10:1); mp 59.2e59.7 ꢀC. 1H NMR (400 MHz, CDCl3):
d 12.93 (s, 1H),
4.3. General procedure for the Rh2(esp)2-catalyzed aromatic
CeH insertion
7.87 (d, J¼2.4 Hz, 1H), 7.10 (dd, J¼8.4, 2.4 Hz, 1H), 6.84 (d, J¼8.4 Hz,
1H), 4.63 (s, 2H), 4.41 (q, J¼7.2 Hz, 2H), 1.46 (t, J¼7.2 Hz, 3H), 1.31 (s,
9H); 13C NMR (100 MHz, CDCl3):
d 171.11, 169.37, 149.50, 128.30,
A solution of
a
-diazo-
b
-ketoester (0.5 mmol) in CH2Cl2 (5 mL) is
125.83, 123.58, 121.66, 119.70, 97.34, 65.99, 61.57, 16.10, 14.37 ppm;
added via syringe pump at a rate of 5e10 mL/h to a stirred solution
of Rh2(esp)2 (2 mg, 0.5 mol %) in anhydrous CH2Cl2 (5 mL) at room
temperature under a nitrogen atmosphere. The reaction mixture
was continued stirring for another hour upon the completion of
addition. After evaporating all the volatiles, the residue was puri-
fied by flash column chromatography eluting with the mixture of
petroleum ether and ethyl acetate (50:1).
MS (ESI): m/z 275 [MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ calcd for
C16H21O4 277.1434, found 277.1438.
4.3.7. Ethyl 3-hydroxy-6-phenyl-2H-chromene-4-carboxylate
(2g). Colorless solid; isolated yield 90% (133 mg). Rf 0.45 (PE/
EtOAc, 10:1); mp 69.0e69.4 ꢀC. 1H NMR (400 MHz, CDCl3):
d 13.04
(s, 1H), 8.09 (d, J¼2.1 Hz, 1H), 7.56e7.58 (m, 2H), 7.45 (t, J¼7.6 Hz,
2H), 7.31e7.36 (m, 2H), 6.99 (d, J¼8.3 Hz, 1H), 4.70 (s, 2H), 4.45 (q,
J¼7.1 Hz, 2H), 1.47 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
4.3.1. Ethyl 3-hydroxy-2H-chromene-4-carboxylate (2a). Light yel-
low solid; isolated yield 90% (100 mg). Rf 0.55 (PE/EtOAc, 10:1); mp
d
170.92, 169.59, 150.93, 141.37, 135.32, 128.86, 126.90, 126.86,
57.6e57.9 ꢀC. 1H NMR (400 MHz, CDCl3)
d
12.97 (s, 1H), 7.78 (dd,
125.26, 124.76, 120.25, 116.71, 97.15, 66.14, 61.70, 14.36 ppm; MS
(ESI): m/z 295 [MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ calcd for C18H17O4
297.1121, found 297.1123.
J¼7.9, 1.6 Hz, 1H), 7.07 (dt, J¼7.9, 1.6 Hz, 1H), 6.98 (dt, J¼7.9, 1.4 Hz,
1H), 6.91 (dd, J¼7.9, 1.4 Hz, 1H), 4.65 (s, 2H), 4.43 (q, J¼7.1 Hz, 2H),
1.44 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 171.01, 169.45,
151.40, 126.60, 125.85, 122.34, 120.12, 116.50, 97.20, 66.07, 61.65,
14.39 ppm; HRMS (ESI): m/z [MþH]þ calcd for C12H13O4 221.0808,
found 221.0805.
4.3.8. Ethyl 8-chloro-3-hydroxy-2H-chromene-4-carboxylate
(2h). Colorless solid; isolated yield 85% (108 mg). Rf 0.54 (PE/
EtOAc, 10:1); mp 73.3e73.6 ꢀC. 1H NMR (400 MHz, CDCl3):
d 13.05
(s, 1H), 7.69 (d, J¼8.0 Hz, 1H), 7.13 (d, J¼8.0 Hz, 1H), 6.90 (t, J¼8.0 Hz,
4.3.2. Ethyl 6-chloro-3-hydroxy-2H-chromene-4-carboxylate
(2b). Yellow solid; isolated yield 86% (109 mg). Rf 0.51 (PE/EtOAc,
1H), 4.74 (s, 2H), 4.43 (q, J¼7.1 Hz, 2H), 1.43 (t, J¼7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 170.70, 169.55, 147.05, 127.30, 124.25,

X. Zhang et al. / Tetrahedron 70 (2014) 3400e3406
3405
122.53, 121.78, 121.72, 96.97, 66.34, 61.88, 14.35 ppm; MS (ESI): m/z
253 [MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ calcd for C12H12ClO4
255.0419, found 255.0420.
Rf 0.52 (PE/EtOAc, 10:1); mp 79.0e79.5 ꢀC. 1H NMR (400 MHz,
CDCl3): d 12.80 (s, 1H), 7.29 (s, 1H), 6.49 (s, 1H), 5.91 (s, 2H), 4.56 (s,
2H), 4.41 (q, J¼8.0 Hz, 2H), 1.42 (t, J¼8.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3):
d 170.71, 168.14, 146.51, 145.45, 142.72, 112.88,
4.3.9. Ethyl 3-hydroxy-8-iodo-2H-chromene-4-carboxylate
105.87, 101.25, 99.00, 97.35, 66.41, 61.65, 14.39 ppm; MS (ESI): m/z
263 [MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ calcd for C13H13O6 265.0707,
found 265.0710.
(2i). Colorless solid; isolated yield 83% (143 mg). Rf 0.43 (PE/
EtOAc, 10:1); mp 82.1e82.7 ꢀC. 1H NMR (400 MHz, CDCl3):
d 13.03
(s, 1H), 7.75 (dd, J¼7.9, 1.4 Hz, 1H), 7.51 (dd, J¼7.9, 1.4 Hz,1H), 6.73 (t,
J¼7.9 Hz, 1H), 4.73 (s, 2H), 4.42 (q, J¼7.1 Hz, 2H), 1.43 (t, J¼7.1 Hz,
4.3.16. Ethyl 3-hydroxy-2H-benzo[h]chromene-4-carboxylate
3H); 13C NMR (100 MHz, CDCl3):
d
170.62, 169.58, 150.38, 136.18,
(2p). Light yellow solid; isolated yield 91% (123 mg). Rf 0.55 (PE/
126.02, 123.94, 120.82, 96.92, 84.33, 66.54, 61.87, 14.36 ppm; MS
EtOAc, 10:1); mp 69.1e69.6 ꢀC. 1H NMR (400 MHz, CDCl3):
d 12.98
(ESI): m/z 344.9 [MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ calcd for
(s, 1H), 8.13e8.16 (m, 1H), 7.94 (d, J¼8.8 Hz, 1H), 7.75e7.77 (m, 1H),
C
12H12IO4 346.9775, found 346.9778.
7.40e7.49 (m, 3H), 4.83 (s, 2H), 4.46 (q, J¼7.2 Hz, 2H), 1.46 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 170.94, 168.93, 146.21,
4.3.10. Ethyl 3-hydroxy-8-methoxy-2H-chromene-4-carboxylate
132.63, 127.44, 125.94, 125.77, 124.70, 123.88, 121.76, 121.38, 115.05,
97.63, 66.49, 61.67, 14.42 ppm; MS (ESI): m/z 269 [MꢁH]ꢁ; HRMS
(ESI): m/z [MþH]þ calcd for C16H15O4 271.0965, found 271.0969.
(2j). Light yellow solid; isolated yield 95% (118 mg). Rf 0.46 (PE/
EtOAc,10:1); mp 77.3e77.6 ꢀC. 1H NMR (400 MHz, CDCl3):
d 13.01 (s,
1H), 7.41 (d, J¼8.1 Hz, 1H), 6.93 (t, J¼8.1 Hz, 1H), 6.75 (d, J¼8.1 Hz,
1H), 4.70 (s, 2H), 4.41 (q, J¼7.1 Hz, 2H), 3.87 (s, 3H), 1.42 (t, J¼7.1 Hz,
4.3.17. Isopropyl 3-hydroxy-2H-chromene-4-carboxylate
3H); 13C NMR (100 MHz, CDCl3):
d
170.92, 169.59, 148.33, 140.28,
(2r). Colorless solid; isolated yield 82% (96 mg). Rf 0.6 (PE/EtOAc,
121.93, 121.13, 118.13, 109.67, 97.15, 66.30, 61.64, 56.13, 14.33 ppm;
10:1); mp 65.1e65.8 ꢀC. 1H NMR (400 MHz, CDCl3):
d 13.03 (s, 1H),
MS (ESI): m/z 249 [MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ calcd for
7.78 (dd, J¼7.9, 1.6 Hz,1H), 7.07 (dt, J¼7.9, 1.6 Hz, 1H), 6.98 (dt, J¼7.9,
C
13H15O5 251.0914, found 251.0910.
1.4 Hz, 1H), 6.90 (dd, J¼7.9, 1.4 Hz, 1H), 5.26e5.35 (m, 1H), 4.64 (s,
2H), 1.41 (d, J¼6.3 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d 170.58,
4.3.11. Ethyl 3-hydroxy-7-methoxy-2H-chromene-4-carboxylate
169.40, 151.37, 126.50, 125.82, 122.32, 120.29, 116.48, 97.32, 69.76,
66.08, 22.09 ppm; MS (ESI): m/z 235 [MþH]þ; HRMS (ESI): m/z
[MþH]þ calcd for C13H15O4 235.0965, found 235.0961.
(2k). Colorless solid; isolated yield 96% (120 mg). Rf 0.47 (PE/
EtOAc, 10:1); mp 56.1e56.6 ꢀC. 1H NMR (400 MHz, CDCl3):
d 12.76
(s, 1H), 7.69 (d, J¼8.0 Hz, 1H), 6.56 (dd, J¼8.0, 4.0 Hz, 1H), 6.49 ( d,
J¼4.0 Hz, 1H), 4.63 (s, 2H), 4.41 (q, J¼8.0 Hz, 2H), 3.78 (s, 3H), 1.43 (t,
4.3.18. tert-Butyl 3-hydroxy-2H-chromene-4-carboxylate
J¼8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
170.92, 167.38, 158.52,
(2s). Colorless solid: isolated yield 85% (105 mg). Rf 0.62 (PE/
152.59, 126.49, 112.73, 108.07, 102.41, 97.10, 66.19, 61.54, 55.49,
14.39 ppm; MS (ESI): m/z 249 [MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ
calcd for C13H15O5 251.0914, found 251.0916.
EtOAc,10:1); mp 81.2e81.4 ꢀC. 1H NMR (400 MHz, CDCl3):
d 13.19 (s,
1H), 7.77 (d, J¼7.9 Hz, 1H), 7.06 (t, J¼7.9 Hz, 1H), 6.96 (t, J¼7.9 Hz,
1H), 6.90 (d, J¼7.9 Hz, 1H), 4.62 (s, 2H), 1.63 (s, 9H); 13C NMR
(100 MHz, CDCl3):
d 170.58, 169.11, 151.44, 126.35, 125.82, 122.19,
4.3.12. Ethyl 3-hydroxy-8-methyl-2H-chromene-4-carboxylate
120.59, 116.44, 97.99, 83.75, 66.12, 28.52 ppm; MS (ESI): m/z 247
[MꢁH]-; HRMS (ESI): m/z [MþH]þ calcd for C14H17O4 249.1121,
found 249.1119.
(2l). Colorless solid; isolated yield 93% (108 mg). Rf 0.6 (PE/EtOAc,
10:1); mp 71.2e71.7 ꢀC. 1H NMR (400 MHz, CDCl3):
d 12.95 (s, 1H),
7.62 (d, J¼7.8 Hz, 1H), 6.96 (d, J¼7.8 Hz, 1H), 6.89 (t, J¼7.8 Hz, 1H),
4.65 (s, 2H), 4.42 (q, J¼7.1 Hz, 2H), 2.22 (s, 3H), 1.43 (t, J¼7.1 Hz, 3H);
4.4. Preparation of compounds 3e5
13C NMR (100 MHz, CDCl3):
d 171.11, 169.37, 149.50, 128.30, 125.83,
123.58, 121.66, 119.70, 97.34, 65.99, 61.57, 16.10, 14.37 ppm; MS
(ESI): m/z 233 [MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ calcd for C13H15O4
235.0965, found 235.0969.
4.4.1. chroman-3-one (3). The mixture of 2a (44 mg, 0.2 mmol) and
Ph2O (400 mg) was heated to 210 ꢀC under argon for 30 min. After
cooling to the room temperature, the residue was purified on silica
gel (PE/EtOAc, 30:1) to get the product as a colorless oil (25 mg,
4.3.13. Ethyl 3-hydroxy-7,8-dimethyl-2H-chromene-4-carboxylate
84%). 1H NMR (400 MHz, CDCl3):
d 7.26e7.22 (m, 1H), 7.14e7.12 (m,
(2m). Colorless solid; isolated yield 88% (109 mg). Rf 0.6 (PE/
1H), 7.06 (d, J¼7.6 Hz, 2H), 4.41 (s, 2H), 3.62 (s, 2H); 13C NMR
EtOAc, 10:1); mp 57.2e57.8 ꢀC. 1H NMR (400 MHz, CDCl3):
d
12.82
(100 MHz, CDCl3): d 207.74, 154.65, 129.08, 128.58, 123.45, 121.63,
(s,1H), 7.51 (d, J¼8.0 Hz,1H), 6.80 (d, J¼8.0 Hz,1H), 4.62 (s, 2H), 4.41
117.80, 73.08, 41.03 ppm. The date of the compound is identical
(q, J¼8.0 Hz, 2H), 2.25 (s, 3H), 2.15 (s, 3H), 1.42 (t, J¼8.0 Hz, 3H); 13
C
with the described date of the reference.16
NMR (100 MHz, CDCl3):
d 171.12, 168.79, 149.42, 135.64, 124.47,
123.20, 122.73, 117.41, 97.50, 66.10, 61.48, 19.89, 14.37, 11.90 ppm;
4.4.2. 3-Amino-4,5-dihydro-1H-chromeno[3,4-d]pyrimidin-1-one
(4). The sodium metal (10 mg, 0.4 mmol) was added to absolute
EtOH (400 mL) at room temperature and stirred for 30 min until the
MS (ESI) m/z 247 [MꢁH]ꢁ; HRMS (ESI) m/z [MþH]þ calcd for
C
14H17O4 249.1121, found 249.1125.
solid was dissolved. Guanidine hydrochloride (28.5 mg, 0.3 mmol)
and 2a (44 mg, 0.2 mmol) were added to the solution and raise the
temperature to 80 ꢀC with stirring overnight. Saturated aqueous
NH4Cl solution (1 mL) was added to neutralize the reaction. The
resulting mixture was extracted with EtOAc (10 mLꢂ2), washed
with brine, dried over Na2SO4, and concentrated. The residue was
purified on silica gel (CH2Cl2/MeOH, 30:1) to get the product as
4.3.14. Ethyl 3-hydroxy-6,7-dimethyl-2H-chromene-4-carboxylate
(2n). Colorless solid; isolated yield 91% (113 mg). Rf 0.63 (PE/
EtOAc, 10:1); mp 68.2e68.6 ꢀC. 1H NMR (400 MHz, CDCl3):
d 12.82
(s, 1H), 7.54 (s, 1H), 6.70 (s, 1H), 4.59 (s, 2H), 4.42 (q, J¼7.1 Hz, 2H),
2.21 (s, 3H), 2.20 (s, 3H), 1.44 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3):
d 170.98, 168.82, 149.39, 135.04, 130.09, 126.82, 117.43,
117.32, 97.13, 66.18, 61.53,19.65,19.62,14.35 ppm; MS (ESI): m/z 247
[MꢁH]ꢁ; HRMS (ESI): m/z [MþH]þ calcd for C14H17O4 249.1121,
found 249.1125.
a colorless solid (37 mg, 86%). 1H NMR (400 MHz, DMSO-d6):
d 11.80
(s, 1H), 8.38 (dd, J¼1.6, 7.6 Hz, 1H), 7.05e7.02 (m, 1H), 6.94e6.90 (m,
1H), 6.84e6.82 (m, 2H), 4.75 (s, 2H), 3.17 (d, J¼5.6 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6):
d 159.47, 158.96, 155.29, 151.39, 126.31,
4.3.15. Ethyl 7-hydroxy-6H-[1,3]dioxolo[4,5-g]chromene-8-
carboxylate (2o). Light yellow solid; isolated yield 94% (124 mg).
124.72, 121.48, 120.70, 115.55, 101.70, 67.92 ppm; HRMS (ESI): m/z
[MþH]þ calcd for C11H10N3O2 216.0773, found 216.0767.

3406
X. Zhang et al. / Tetrahedron 70 (2014) 3400e3406
4.4.3. trans-Ethyl 3-hydroxychroman-4-carboxylate (5). To a solu-
tion of 2a (66 mg, 0.3 mmol) in methanol (1 mL) was added sodium
borohydride (35 mg, 0.9 mmol) at 0 ꢀC. After stirring for 30 min, the
reaction was stopped by the addition of water (1 mL). The resulting
mixture was extracted with EtOAc (10 mLꢂ2), washed with brine,
dried over Na2SO4, and concentrated. The residue was purified on
silica gel (PE/EtOAc, 5:1) to get the product as a colorless oil (60 mg,
90%). The crude proton NMR showed a 5:1 ratio of a trans/cis
mixture. The trans-product was demonstrated by the HSQC/HMBC
assignment and further cross peaks identification of NOESY (see
this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.03.093.
References and notes
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Supplementary data). 1H NMR (400 MHz, CDCl3):
d 7.22e7.18 (m,
2H), 6.93e6.87 (m, 2H), 4.34e4.28 (m, 1H), 4.22 (q, J¼7.2 Hz, 2H),
4.15e4.13 (m, 1H), 4.03 (d, J¼4.4 Hz, 1H), 3.28 (d, J¼7.2 Hz, 1H), 1.32
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 172.39, 153.73,
130.29, 129.05, 121.02, 117.12, 117.00, 67.40, 64.22, 61.65, 46.13,
14.26 ppm; HRMS (ESI): m/z [MþH]þ calcd for C12H15O4 223.0970,
found 223.0960.
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This work was supported by the National Natural Science
Foundation of China (grant 81273397), the Chinese National Sci-
ence & Technology Major Project ‘Key New Drug Creation and
Manufacturing Program’ (grants 2013ZX09508104, 2012ZX09103-
101-018, 2014ZX09301-306-03), the Science Foundation of
Shanghai (grant 12XD1405700), and Basic and Advanced Technol-
ogy Research Project in Henan Province (grant 122300410004).
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Supplementary data
These data include all the NMR data of compounds 1aeu, 2aer,
and 3e5 described in this article. Supplementary data related to