Three-Component Ring-Opening Reactions of Cyclic Ethers, α-Diazo Esters, and Weak Nucleophiles under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.joc.8b02091

A protocol for three-component reactions of cyclic ethers, α-diazo esters, and weak nitrogen, oxygen, carbon, and sulfur nucleophiles (pK_a = 2.2-14.8) to afford a variety of structurally complex α-oxyalkylated esters is reported. These reactions involve intermolecular activation of the cyclic ether (present in excess) by the α-diazo ester to form an oxonium ylide under metal-free conditions, followed by ring opening by the nucleophile.

Full text of DOI:10.1021/acs.joc.8b02091

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Article
Three-Component Ring-Opening Reactions of Cyclic Ethers, #-
Diazo Esters, and Weak Nucleophiles under Metal-Free Conditions
Lin Lu, Chuwei Chen, Huanfeng Jiang, and Biaolin Yin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02091 • Publication Date (Web): 07 Nov 2018
Downloaded from http://pubs.acs.org on November 8, 2018
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Three-Component Ring-Opening Reactions of Cyclic Ethers, α-Diazo
Esters, and Weak Nucleophiles under Metal-Free Conditions
Lin Lu, Chuwei Chen, Huanfeng Jiang and Biaolin Yin*
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Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry
and Chemical Engineering, South China University of Technology, Guangzhou, P. R. China, 510640.
Abstract: A protocol for three-component reactions of cyclic ethers, α-diazo esters, and weak nitrogen,
oxygen, carbon, and sulfur nucleophiles (pKa = 2.2–14.8) to afford a variety of structurally complex
α-oxyalkylated esters is reported. These reactions involve intermolecular activation of the cyclic ether
(present in excess) by the α-diazo ester to form an oxonium ylide under metal-free conditions, followed
by ring opening by the nucleophile.
Introduction
Multicomponent reactions (MCRs) involve three or more components and provide access to
products that contain the elements of all the starting materials. These simple, efficient,
atom-economical reactions are capable of generating structurally complex molecules in a single pot.1
For example, MCRs involving α-diazo esters have been widely used in the synthesis of a variety of
esters.2 However, most of the reported α-diazo ester-based MCRs require a transition-metal catalyst
(e.g., Rh,3 Ir,4 Ru,5 Pd,6 Cu,7 or Fe8) to trap the carbene generated by release of nitrogen from the diazo
group. The development of novel methods for metal-free α-diazo ester-based MCRs is highly desirable.
Cyclic ethers, such as THF, 1,4-dioxane, and THP, are readily available compounds that can be
efficiently transformed into other useful molecules and thus have attracted much attention from
synthetic chemists. Among the most widely used reactions of cyclic ethers are ring-opening or
ring-expansion reactions that rely on the nucleophilicity of the O atom and afford acyclic ethers or
larger-ring cyclic ethers. Ring-opening reactions of cyclic ethers are usually mediated by a strong
Lewis or Brønsted acid that facilitates the formation of an oxonium ion intermediate (Scheme 1, eq 1).9
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Ring-opening reactions of cyclic ethers can also be promoted by a pendant α-diazo ester moiety, by
means of a mechanism involving the generation of an oxonium ylide with a weakened C–O bond,
which is then cleaved by intermolecular attack of a nucleophile (Scheme 1, eq 2). This transformation
has been widely used in the construction of oxa-polycyclic compounds.10
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Most of the previously reported instances of such transformations have involved two components:
a nucleophile (HNu) and a molecule that contains the ether and diazo functionalities. The presence of
the two functionalities in one molecule guarantees prior formation of the oxonium ylide and suppresses
intermolecular insertion of HNu into the carbene formed in situ from the diazo group.11 However, the
development of three-component reactions of diazo esters, cyclic ethers, and nucleophiles would
increase the diversity of the ring-opening reactions of cyclic ethers and might serve as a route to acyclic
ethers, and thus would be highly desirable. Oku once reported a photolysis three-component reaction of
diazo esters, cyclic ethers under metal-free condition, but the narrow substrate scope and low yields of
products limited its application.12 We envisioned that, on one hand, the use of an excess of the cyclic
ether would accelerate coordination between the carbene and the ether, thus allowing the reaction to
proceed efficiently under metal-free conditions, on the other hand, the use of a suitable base would
make the nucleophiles more reactive thus suppressing the decomposition of coordinated carbenes and
improving the efficiency of the reaction. As part of our ongoing work on the transformation of furan
derivatives to value-added products,13 we herein report a protocol for α-diazo ester-based
three-component reactions involving ring opening of cyclic ethers under metal-free conditions (Scheme
1, eq 3).
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Scheme 1. Ring-Opening Reactions of Cyclic Ethers
Results and Discussion
Development of this protocol required us to address the formidable challenges posed by the
following possible side reactions: ring-opening polymerization,14 HNu insertion, ring expansion,15 and
an addition-elimination pathway (Scheme 2, reactions a–d, respectively). Thus, the success of our
strategy would depend on the identification of HNu species with appropriate nucleophilicity.
Scheme 2. Potential Challenges of Three-Component Reactions of α-Diazo Esters, THF, and HNu
Results and Discussion
To test the feasibility of our strategy and to optimize the reaction conditions, we used ethyl
2-(2-bromophenyl)-2-diazoacetate (2a), 4,N-dimethyl-benzenesulfonamide (1a, pKa = 11.7)16 and
excess THF (1 mL, which served as both solvent and reactant) as the model substrates (Table 1). When
K2CO3 was used as a base, reaction at 80 °C provided ring-opening product 3a in 99% yield (entry 1).
Decreasing the amount of THF to 5–20 equiv and using toluene (1 mL) as the solvent lowered the yield
(entries 2–5) and resulted in the formation of unidentified by-products. However, 25 or 30 equiv of
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THF in toluene gave a 99% yield of 3a (entries 6 and 7). Product 3a also formed in the absence of
K2CO3, albeit in a lower yield (76%, entry 8). Screening of other bases demonstrated that Cs2CO3,
DBU, K3PO4, KOH, and NaOH gave lower yields than K2CO3 (entries 9–13), as did Na2CO3, Et3N,
and KOAc (entries 14–16). Thus, we concluded that the optimal conditions involved the use of K2CO3
and excess THF at a reaction temperature of 80 °C (entry 1).
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Table 1. Optimization of Reaction Conditionsa
O
Br N2
O
OEt
TsN
OEt
(1 mL)
TsNH
Me
+
O
Br
Me
O
base, 80 oC, 12 h
2a (0.4 mmol)
1a (0.2 mmol)
3a
entry
yield of 3a (%)b
base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
99
27
1
2c
3d
4e
5f
6g
7h
8
60
70
84
99
99
76
Cs2CO3
K3PO4
DBU
49
9
50
10
11
12
13
14
15
73
KOH
trace
trace
90
NaOH
Na2CO3
Et3N
94
16
98
KOAc
b
aReaction conditions, unless otherwise noted: 1a (0.2 mmol), 2a (0.4 mmol), base (2 equiv), THF (1 mL), 80 °C, 12 h. Yields
c
were determined by 1H NMR with 4-nitrotoluene as an internal standard. THF (5 equiv), toluene (1 mL). dTHF (10 equiv),
e
f
g
h
toluene (1 mL). THF (15 equiv), toluene (1 mL). THF (20 equiv), toluene (1 mL). THF (25 equiv), toluene (1 mL). THF (30
equiv), toluene (1 mL).
With the optimized conditions in hand, we surveyed the generality of the protocol by carrying out
reactions of diazoacetate 2a with sulfonamide nucleophiles 1 bearing a variety of R groups (Table 2).
When R was H, Me, i-Pr, or cyclohexyl, products 3a–3d were formed in excellent yields (entries 1–4).
However, if R was t-Bu or ethoxycarbonylmethyl, a complicated product mixture was obtained, and the
products 3e and 3f were obtained in only moderate yields (entries 5 and 6). The relatively low yield of
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3e might have been due to the steric bulk of the t-Bu group, but the reason for the low yield of 3f
remains unclear. When R was phenyl or phenyl substituted with a 2, 6-dimethyl, 4-Br, 4-OMe, or 4-CF3
group, the corresponding ring-opening products (3g–3k) were produced in good to excellent yields
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(entries 7–11). Substrates with heterocyclic
R groups (i.e., pyrimidin-2-yl, thiazol-2-yl,
benzo[d]thiazol-2-yl, and pyridin-2-yl) also smoothly underwent the desired reaction, yielding 3l–3o in
63–78% yields (entries 12–15).
Table 2. Reactions of Various Sulfonamidesa
O
O
Br
N
2
O
O
TsN
R
OEt
(1 mL)
OEt
TsN
or
OEt
TsNH
R
O
Br
+
Br
K CO (2 equiv)
2
3
O
o
2
80 C, 12 h
1 (0.2 mmol)
2a (0.4 mmol)
3
entry
3 (% yield)b
3a (99)
3b (89)
3c (94)
3d (98)
3e (56)
3f (60)
3g (90)
3h (90)
3i (90)
R
Me
H
1
2c
3
i-Pr
cyclohexyl
t-Bu
4
5
ethoxycarbonylmethyl
Ph
6
7
2,6-di-Me-C6H3
4-Br-C6H4
8
9
4-OMe-C6H4
4-CF3-C6H4
3j (78)
3k (85)
3l (78)
10
11
12
13
14
15
pyrimidin-2-yl
thiazol-2-yl
3m (66)
3n (63)
3o (76)
benzo[d]thiazol-2-yl
pyridin-2-yl
aReaction conditions, unless otherwise noted: 1 (0.2 mmol), 2a (0.4 mmol), K2CO3 (2 equiv), THF (1 mL), 80 °C, 12 h. bIsolated
yields are reported. cThe amount of 2a was 0.8 mmol.
Next, reactions between 2a and N and O nucleophiles with various pKa values were examined
under the standard conditions (Table 3). The pKa of the nucleophile clearly influenced the reaction
outcome. N-Methyl-methanesulfonamide (pKa = 11.8) afforded product 3p in an excellent yield (95%,
entry 1). The nucleophile o-benzoic acid sulfimide, which has a low pKa (2.2), afforded a complex
product mixture, and the yield of 3q was very low (27%, entry 2). In contrast, phthalimide (pKa = 9.8),
which has steric bulk comparable to that of o-benzoic acid sulfimide, provided 3r in 95% yield (entry
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3). Other N-nucleophiles, including 2,2,2-trifluoro-N-phenyl-acetamide, 3H-benzooxazol-2-one, and
imidazole (pKa = 8.3–12.9), provided the corresponding products (3s–3u) in moderate to excellent
yields (entries 4–6). However, the organic bases aniline and benzyl amine, which have pKa values
of >20, did not afford 3v and 3w, respectively (entries 7 and 8). Both of the two reaction mixtures were
very complicated. The O-nucleophiles p-cresol, β-naphthol, benzoic acid, and 3,3-dimethylbutyric acid
(pKa = 4.2–10.9) were suitable substrates for this transformation, giving 3x–3aa in excellent yields
(entries 9–12). In contrast, benzyl alcohol, with a pKa of 15.4, failed to afford 3ab (entry 13), with the
formation of a major by-product of ethyl 2-(2-bromophenyl)acetate (20% yield). But thiobenzyl
alcohol (pKa = 9.4) gave desired product 3ac in 75% yield (entry 14). Notably, the C-nucleophiles
5-nitro-1H-indole (pKa = 14.8) and 3-oxo-3-phenyl-propionic acid ethyl ester (pKa = 9.1) gave products
3ad and 3ae in 82% (entry 15) and 70% yields (entry 16, dr = 5:1), respectively. However, an indole
with a high pKa (17.0) was not a suitable nucleophile (entry 17), and product 3af was not detected with
the recovery of indole almost quantitatively. These results suggest that nucleophiles with pKa values in
the range of 2.2–14.8 were suitable substrates for this transformation.
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Table 3. Reactions of Other Nucleophilesa
O
Br N2
O
(1 mL)
OEt
Nu
OEt
O
HNu
+
K2CO3 (2 equiv), 80 oC, 12 h
Br
O
1
2a
3
pKa
entry NuH
3 (% yield)b
O
O
S
O
O
O
S
Me
N
OEt
Me
N
Me
H
1
11.8
2.2
Me
Br
O
3P (95%)
O
O
O
O
O
O
S
N
OEt
S
N
H
2
3
Br
O
O
3q (27%)
O
O
O
O
N
OEt
N
H
9.8
Br
O
O
3r (95%)
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O
CF3CO
O
N
OEt
COCF3
4
5
6
7
8
9
9.5
8.3
Ph
Br
Ph
N
H
3s (63%)
O
O
O
O
N
OEt
O
N
H
O
Br
3t (70%)
O
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O
H
N
OEt
N
N
12.9
>20
>20
10.9
Br
N
3u (96%)
O
Ph
O
N
OEt
H
N
H
Ph
H
Br
3v (ND)
O
Bn
O
N
H
OEt
H
N
Bn
H
Br
3w (ND)
Me
O
O
O
OEt
Me
O H
Br
3x (98%)
O
O
O
OEt
10
9.9
Br
3y (98%)
O
O
PhCOO
OEt
11
12
13
PhCOO-H
4.2
5.0
Br
3z (96%)
O
O
O
O
OEt
Br
3aa (96%)
O
Bn
O
O
OEt
Bn-O-H
Bn-S-H
15.4
Br
3ab (ND)
O
Bn
O
S
OEt
14
15
16
9.4
14.8
9.1
Br
3ac (75%)
O
O2N
O N
2
O
N
OEt
Br
N
H
3ad (82%)
O
O
O
O
O
Ph
EtO
OEt
Ph
OEt
Br
O
H
3ae (70%, dr = 5:1)
O
O
N
OEt
17
17
N
Br
H
3af (ND)
aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), K2CO3 (2 equiv), THF (1 mL), 80 °C. bIsolated yields are reported.
Next, we evaluated various cyclic ethers in reactions involving 1a as the nucleophile 2a as the
diazo ester (Table 4). Like THF, tetrahydropyran, 1,4-dioxane, and tetrahydrofuran-d8 underwent the
ring-opening reaction, providing products 3ag-3ai in good to excellent yields (75-96%). However,
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when oxetane or 12-crown-4 was used as the substrates, the α-diazo ester decomposed without forming
the desired product (3aj or 3ak, respectively), and the by-product ethyl 2-(2-bromophenyl)acetate was
isolated in 18% and 21%, respectively. To our disappointment, chain ether, like diethyl ether and
methyl tertiary butyl ether, was not suit able for this reaction, probably because of the larger steric
hindrance.
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Table 4. Reactions of Various Cyclic Ethersa
O
Br N2
O
(1 mL)
OEt
OEt
O
TsMeN
Ts NHMe
+
Br
K2CO3 (2 equiv)
80 oC, 12 h
O
1a
2a
3
O
O
O
D
D D D
Me
N
Me
O
O
N
O
O
Ts
OEt
O
Ts
Ts
OEt
Ts
N
OEt
Br
Me
Br
Br
D
D D
D
3ag, 75%b
3ah, 86%b
3ai, 96%b
O
O
Me
N
O
Ts
OEt
N
OEt
4
Br
Me Br
3aj, ND
3ak, ND
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), K2CO3 (2 equiv), solvent (1 mL), 80 °C. bIsolated yields are reported.
Finally, we turned our attention to the reactions of nucleophile 1a and THF with α-diazo esters 2
bearing various R1 and R2 groups (Table 5). When R2 was Et and R1 was a phenyl group, a 2-naphthyl
group, or a phenyl group substituted with 4-Me, 4-F, 4-Br, or 2-Me, the corresponding products were
obtained in good to excellent yields (entries 1–5). Notably, When R1 was 4-phenyl-C6H4, a moderate
yield of 3aq was obtained (entry 6), whereas the 2-phenyl-C6H4-substituted substrate afforded only a
trace amount of 3ar (entry 7). We speculate that the 2-phenyl substituent on the steric bulk of the
phenyl group hindered coordination of THF or attack of nucleophile 1a. 2-Naphthyl of R1 gave the 3as
in 80% yield. When R1 was acetyl, corresponding product 3at was not detected; 1a was recovered, and
the α-diazo ester decomposed (entry 9). When R1 was 2-Br-Ph, R2 could be Me, i-Pr, or t-Bu, and
products 3au–3aw were obtained in excellent yields (entries 10–12).
Table 5. Reactions of Various α-Diazo Estersa
O
N
(1 mL)
2
2
O
O
OR
2
1
Ts NHMe
+
MeN
OR
R
o
1
K CO (2 equiv), 80 C, 12 h
3
2
3
Ts
R
1a
2
O
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R2
Et
entry
1
R1
3 (% yield)b
3al (88)
C6H5
5
6
7
8
2
3
4-Me-C6H4
4-F-C6H4
Et
3am (78)
3an (72)
3ao (70)
3ap (93)
3aq (50)
3ar (trace)
3as (80)
3at (ND)
3au (92)
3av (98)
3aw (98)
Et
4
4-Br-C6H4
2-Me-C6H4
4-pheny-C6H4
2-pheny-C6H4
2-naphthyl
Acetyl
Et
5
Et
9
6
Et
10
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7
Et
8
Et
9
Et
10
11
12
2-Br-C6H4
2-Br-C6H4
2-Br-C6H4
Me
i-Pr
t-Bu
aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), K2CO3 (2 equiv), THF (1 mL), 80 °C. bIsolated yields are reported.
Scheme 3. Modification of Two Pharmaceutical Compounds
Because these α-diazo ester-based MCRs proceeded under mild conditions and resulted
exclusively in carbon-heteroatom bond formation, we investigated the use of this protocol for
modification of two pharmaceutical compounds (Scheme 3). Specifically, treatment of celecoxib with
2a in 1,4-dioxane under the standard conditions afforded a 50% yield of N,N-dioxyalkylated product
3ax. Similarly, the reaction of 2a with thalidomide in 1,4-dioxane gave oxyalkylated product 3ay in
98% yield.
Conclusion
In summary, we have developed a simple, practical protocol for three-component reactions of
α-diazo esters, cyclic ethers, and relatively weak nitrogen, oxygen, carbon, and sulfur nucleophiles; the
reactions involved ring opening of the cyclic ethers and offered access to a variety of structurally
complex α-oxyalkylated esters. Nucleophiles with pKa values in the range of 2.2–14.8 were suitable
substrates. We believe that the mild metal-free conditions, the generality of the protocol, and the
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diversity of the products that can be obtained will make this protocol useful in organic synthesis and for
the modification of pharmaceutical compounds in drug-delivery research. The strategy of using an
excess of the cyclic ether to guarantee the intermolecular formation of an oxonium ylide intermediate
prior to attack of the nucleophile can be expected to facilitate the design of new α-diazo ester-based
MCRs under metal-free conditions.
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Experimental Section
General Information. All reactions were carried out in 25 mL Schlenck tubes under N2
atmosphere. TLC was performed with commercially prepared 100–400 mesh silica gel plates (GF254),
which were visualized at 254 nm. Unless otherwise noted, all reagents were reagent grade and were
used as supplied. NMR spectra were recorded in CDCl3 on a 400 MHz spectrometer. Chemical shifts
are reported in parts per million (δ) relative to TMS (0.00 ppm). IR spectra were obtained with an
infrared Fourier spectrometer; samples were analyzed either as potassium bromide pellets or as liquid
films between two potassium bromide pellets. High-resolution mass spectra (ESI) were obtained with a
LCMS-IT-TOF mass spectrometer.
General Procedure for 1: To a solution of the appropriate aniline (10mmol,) in pyridine (50 mL)
was added p-toluenesulfonyl chloride (2.10 g, 11mmol) at 0 °C. After being stirred at 25 °C for 2~3
hours, pyridine was removed by rotary evaporator and the reaction mixture was poured into water. The
product was extracted with CH2Cl2 (three times), dried over MgSO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography with petroleum ether /ethyl acetate (5/1) as
the eluent to give corresponding product.17
N, 4-dimethylbenzenesulfonamide (1a). White solid (1.84 g, 99%); 1H NMR (400 MHz, CDCl3) δ
7.79 – 7.71 (m, 2H), 7.37 – 7.28 (m, 2H), 4.50 (s, 1H), 2.64 (d, J = 5.4 Hz, 3H), 2.43 (s, 3H).The
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N-isopropyl-4-methylbenzenesulfonamide (1c). White solid (2.12 g, 99%); H NMR (400 MHz,
CDCl3) δ 7.82 – 7.72 (m, 2H), 7.33 – 7.27 (m, 2H), 4.70 (s, 1H), 3.55 – 3.31 (m, 1H), 2.42 (s, 3H), 1.07
(d, J = 6.5 Hz, 6H). The spectroscopic data is in agreement with the reported literature.17b
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N-cyclohexyl-4-methylbenzenesulfonamide (1d). White solid (2.51 g, 99%); H NMR (400 MHz,
CDCl3) δ 7.84 – 7.65 (m, 2H), 7.32 – 7.27 (m, 2H), 4.71 (d, J = 7.4 Hz, 1H), 3.20 – 3.02 (m, 1H), 2.42
(s, 3H), 1.79 – 1.69 (m, 2H), 1.67 – 1.57 (m, 2H), 1.55 – 1.43 (m, 1H), 1.31 – 1.01 (m, 5H). The
spectroscopic data is in agreement with the reported literature.17b
1
N-(tert-butyl)-4-methylbenzenesulfonamide (1e). White solid (2.26 g, 99%); H NMR (400 MHz,
CDCl3) δ 7.86 – 7.72 (m, 2H), 7.32 – 7.20 (m, 2H), 5.12 (s, 1H), 2.41 (s, 3H), 1.21 (s, 9H). The
spectroscopic data is in agreement with the reported literature.17b
Ethyl tosylglycinate (1f). White solid (2.06 g, 80%); 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.66 (m,
2H), 7.36 – 7.28 (m, 2H), 5.23 (s, 1H), 4.20 – 3.98 (m, 2H), 3.77 (d, J = 5.5 Hz, 2H), 2.42 (s, 3H), 1.18
(t, J = 7.8 Hz, 3H). The spectroscopic data is in agreement with the reported literature.17f
1
4-Methyl-N-phenylbenzenesulfonamide (1g). White solid (2.45 g, 99%); H NMR (400 MHz,
CDCl3) δ 7.77 – 7.64 (m, 2H), 7.46 (s, 1H), 7.24 – 7.14 (m, 4H), 7.14 – 7.02 (m, 3H), 2.33 (s, 3H). The
spectroscopic data is in agreement with the reported literature.17a
1
N-(2,6-dimethylphenyl)-4-methylbenzenesulfonamide (1h). White solid (2.64 g, 96%); H NMR
(400 MHz, CDCl3) δ 7.66 – 7.51 (m, 2H), 7.30 – 7.19 (m, 2H), 7.11 – 7.05 (m, 1H), 7.03 – 6.96 (m,
2H), 6.24 (s, 1H), 2.42 (s, 3H), 2.04 (s, 6H). The spectroscopic data is in agreement with the reported
literature.17a
1
N-(4-bromophenyl)-4-methylbenzenesulfonamide (1i). White solid (2.98 g, 99%); H NMR (400
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MHz, CDCl3) δ 7.72 – 7.63 (m, 2H), 7.40 (s, 1H), 7.35 – 7.28 (m, 2H), 7.25 – 7.19 (m, 2H), 7.03 –
6.93 (m, 2H), 2.37 (s, 3H). The spectroscopic data is in agreement with the reported literature.17a
N-(4-methoxyphenyl)-4-methylbenzenesulfonamide (1j). White solid (2.38 g, 86%); 1H NMR (400
MHz, CDCl3) δ 7.72 – 7.51 (m, 2H), 7.25 – 7.14 (m, 2H), 7.07 – 6.86 (m, 3H), 6.81 – 6.63 (m, 2H),
3.73 (s, 3H), 2.37 (s, 3H). The spectroscopic data is in agreement with the reported literature.17a
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4-Methyl-N-(4-(trifluoromethyl)phenyl)benzenesulfonamide (1k). White solid (2.52 g, 80%); H
NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.83 – 7.73 (m, 2H), 7.49 – 7.40 (m, 2H), 7.28 – 7.17 (m, 4H),
2.36 (s, 3H). The spectroscopic data is in agreement with the reported literature.17a
1
4-Methyl-N-(pyrimidin-2-yl)benzenesulfonamide (1l). Brown solid (1.89 g, 76%); H NMR (400
MHz, DMSO) δ 11.73 (s, 1H), 8.55 – 8.44 (m, 2H), 7.93 – 7.83 (m, 2H), 7.43 – 7.30 (m, 2H), 7.04 (t, J
= 4.9 Hz, 1H), 2.35 (s, 3H). The spectroscopic data is in agreement with the reported literature.17d
1
4-Methyl-N-(thiazol-2-yl)benzenesulfonamide (1m). Brown solid (2.03 g, 80%); H NMR (400
MHz, DMSO) δ 12.68 (s, 1H), 7.75 – 7.62 (m, 2H), 7.38 – 7.28 (m, 2H), 7.23 (d, J = 4.6 Hz, 1H), 6.81
(d, J = 4.5 Hz, 1H), 2.34 (s, 3H). The spectroscopic data is in agreement with the reported literature.17e
N-(Benzo[d]thiazol-2-yl)-4-methylbenzenesulfonamide (1n). Brown solid (2.28 g, 75%); 1H NMR
(400 MHz, DMSO) δ 13.16 (s, 1H), 7.82 – 7.71 (m, 3H), 7.41 – 7.32 (m, 3H), 7.32 – 7.27 (m, 1H),
7.27 – 7.19 (m, 1H), 2.34 (s, 3H). The spectroscopic data is in agreement with the reported literature.17d
4-Methyl-N-(pyridin-2-yl)benzenesulfonamide (1o). Gray solid (1.73 g, 70%); 1H NMR (400 MHz,
DMSO) δ 8.01 (d, J = 4.5 Hz, 1H), 7.80 – 7.73 (m, 2H), 7.73 – 7.65 (m, 1H), 7.38 – 7.26 (m, 2H), 7.14
(d, J = 8.6 Hz, 1H), 6.90 – 6.79 (m, 1H), 2.33 (s, 3H). The spectroscopic data is in agreement with the
reported literature.17d
General
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1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) (2.28 g, 15 mmol) in anhydrous CH3CN (20 mL) was
added dropwise to a solution of ethyl phenyl acetate (10 mmol) and p-toluenesulfonyl azide (TsN3)
(2.37 g, 12 mmol) in anhydrous CH3CN (30 mL). Then the reaction mixture was stirred at room
temperature for 15 h. After water (20 mL) was added, the resulting mixture was extracted with ethyl
acetate (3 ×40 mL). The combined organic layer was washed with brine (20 mL) and dried over
anhydrous MgSO4. After removal of the solvent under reduced pressure, the residue was purified by
silica gel column chromatography with petroleum ether/ethyl acetate (30/1) as the eluent to give
corresponding product.18
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Ethyl 2-(2-bromophenyl)-2-diazoacetate (2a). Orange oil (2.4 g, 91%); H NMR (400 MHz,
CDCl3) δ 7.61 (d, J = 8.1 Hz, 1H), 7.52 (dd, J = 7.8, 1.4 Hz, 1H), 7.39 – 7.34 (m, 1H), 7.20 (td, J = 7.7,
1.5 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). The spectroscopic data is in agreement
with the reported literature.18a
Ethyl 2-diazo-2-phenylacetate (2b). Orange oil (1.69 g, 89%); 1H NMR (400 MHz, CDCl3) δ 7.48
(d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.9 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.33 (t, J
= 7.1 Hz, 3H). The spectroscopic data is in agreement with the reported literature.18c
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Ethyl 2-diazo-2-(p-tolyl)acetate (2c). Orange oil (1.88 g, 92%); H NMR (400 MHz, CDCl3) δ
7.36 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.33 (s, 3H), 1.33 (t, J = 7.1
Hz, 3H). The spectroscopic data is in agreement with the reported literature.18c
1
Ethyl 2-diazo-2-(4-fluorophenyl)acetate (2d). Orange oil (1.83 g, 88%); H NMR (400 MHz,
CDCl3) δ 7.49 – 7.38 (m, 2H), 7.13 – 7.02 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).
The spectroscopic data is in agreement with the reported literature.18a
1
Ethyl 2-(4-bromophenyl)-2-diazoacetate (2e). Orange solid (2.30 g, 86%); H NMR (400 MHz,
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CDCl3) δ 7.49 – 7.38 (m, 2H), 7.13 – 7.02 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).
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Ethyl 2-diazo-2-(o-tolyl)acetate (2f). Orange oil (1.83 g, 90%); H NMR (400 MHz, CDCl3) δ
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7.49 – 7.38 (m, 2H), 7.13 – 7.02 (m, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). The
spectroscopic data is in agreement with the reported literature.18c
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Ethyl 2-([1,1'-biphenyl]-4-yl)-2-diazoacetate (2g). Orange solid (2.39 g, 90%); H NMR (400
MHz, CDCl3) δ 7.67 – 7.51 (m, 6H), 7.43 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 4.34 (q, J = 7.1
Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). The spectroscopic data is in agreement with the reported literature.18c
2-(Diazo(ethoxy)methyl)-1,1'-biphenyl (2h). Orange oil (2.40 g, 90%); 1H NMR (400 MHz, CDCl3)
δ 7.63 – 7.56 (m, 1H), 7.42 – 7.26 (m, 8H), 4.19 (q, J = 6.8 Hz, 2H), 1.20 (t, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 166.1, 140.8, 140.3, 130.91 130.6, 128.79, 128.3, 128.3, 127.8, 127.3, 123.3, 60.9,
14.4. IR: 2983, 2097, 1702, 1171, 755 cm-1. HRMS (ESI-TOF) m/z calcd for C16H14N2NaO2 [M+Na]+:
267.1134; found: 267.1133.
Ethyl 2-diazo-2-(naphthalen-2-yl)acetate (2i). Orange solid (2.16 g, 90%);1H NMR (400 MHz,
CDCl3) δ 8.01 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.49
– 7.38 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). The spectroscopic data is in
agreement with the reported literature.18c
Ethyl 2-diazo-3-oxobutanoate (2j). Orange oil (1.34 g, 86%); 1H NMR (400 MHz, CDCl3) δ 4.31
(q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). The spectroscopic data is in agreement with
the reported literature.18d
1
Methyl 2-(2-bromophenyl)-2-diazoacetate (2k). Orange oil (2.27 g, 90%); H NMR (400 MHz,
CDCl3) δ 7.61 (dd, J = 8.1, 1.1 Hz, 1H), 7.51 (dd, J = 7.8, 1.6 Hz, 1H), 7.36 (td, J = 7.7, 1.3 Hz, 1H),
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7.20 (td, J = 7.8, 1.7 Hz, 1H), 3.83 (s, 3H). The spectroscopic data is in agreement with the reported
literature.18b
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Isopropyl 2-(2-bromophenyl)-2-diazoacetate (2l). Orange oil (2.54 g, 90%);1H NMR (400 MHz,
CDCl3) δ 7.61 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.7 Hz,
1H), 5.17 (dt, J = 12.5, 6.2 Hz, 1H), 1.31 (d, J = 6.3 Hz, 6H). The spectroscopic data is in agreement
with the reported literature.18b
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Tert-butyl 2-(2-bromophenyl)-2-diazoacetate (2m). Orange oil (2.90 g, 86%) 1H NMR (400 MHz,
CDCl3) δ 7.59 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.17 (t, J = 7.4 Hz,
1H), 1.52 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 172.3, 164.8, 133.4, 132.9, 129.8, 127.6, 82.2, 28.4.
IR: 2979, 2094, 1697, 1149, 756cm-1. HRMS (ESI-TOF) m/z calcd for C22H28BrNNaO5S [M+Na]+ :
319.0058; found: 319.0050.
General Procedure for 3: To an oven-dried 25 mL Schlenk tube equipped with a stir bar were
added K2CO3 (0.4 mmol), nucleophiles 1 (0.2 mmol), and THF (0.5 mL), and then α-Diazo esters 2 and
o
THF (0.5 mL) were added under N2. The mixture was stirred at 80 C for 12 h. The corresponding
reaction mixture was filtered through a pad of celite, washed with EtOAc and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether
/ethyl acetate (10/1 to 5/1) as the eluent to give corresponding product.
Procedure of the gram-scale synthesis of 3a: To an oven-dried 250 mL Schlenk tube equipped
with a stir bar were added K2CO3 (1.5 g, 10.8 mmol), N, 4-dimethylbenzenesulfonamide (1.0 g, 5.4
mmol), and THF (15.0 mL), and then ethyl 2-(2-bromophenyl)-2-diazoacetate (2.90 g, 10.8 mmol) and
o
THF (10.0 mL) were added under N2. The mixture was stirred at 80 C for 12 h. The corresponding
reaction mixture was filtered through a pad of celite, washed with EtOAc and concentrated under
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reduced pressure. The residue was purified by silica gel column chromatography with petroleum
ether/ethyl acetate (5/1) as the eluent to give corresponding product 3a in 99% yield (2.65 g).
Ethyl 2-(2-bromophenyl)-2-(4-((N, 4-dimethylphenyl)sulfonamido)butoxy)acetate (3a). Colorless
oil (98.6 mg, 99%); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H),
7.49 (d, J = 7.6 Hz, 1H), 7.35 – 7.26 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 5.30 (s, 1H), 4.30 – 4.06 (m, 2H),
3.69 – 3.58 (m, 1H), 3.57 – 3.44 (m, 1H), 2.99 (t, J = 6.3 Hz, 2H), 2.68 (s, 3H), 2.41 (s, 3H), 1.75 –
1.56 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.3, 143.2, 136.5, 134.4, 132.9,
130.1, 129.7, 128.8, 127.8, 127.4, 124.0, 79.6 (CH), 69.5 (CH2), 61.3 (CH2), 49.7 (CH2), 34.6 (CH3),
26.5 (CH2), 24.2 (CH3), 21.5 (CH3), 14.1. IR: 3065, 2636, 1747, 1597, 1467, 751cm-1.HRMS (ESI-TOF)
m/z calcd for C22H29BrNO5S [M+H]+ : 498.0950; found: 498.0945.
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Diethyl 2,2'-(((tosylazanediyl)bis(butane-4,1-diyl))bis(oxy))bis(2-(2-bromophenyl)acetate) (3b).
Colorless oil (141.7 mg, 89%); 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.62 (m, 2H), 7.59 – 7.54 (m, 2H),
7.50 – 7.44 (m, 2H), 7.35 – 7.29 (m, 2H), 7.27 – 7.23 (m, 2H), 7.22 – 7.15 (m, 2H), 5.27 (s, 2H), 4.26 –
4.10 (m, 4H), 3.63 – 3.53 (m, 2H), 3.51 – 3.37 (m, 2H), 3.10 (s, 4H), 2.40 (s, 3H), 1.60 (s, 8H), 1.22 (t,
J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 170.3, 142.9, 136.9, 136.5, 132.87, 130.0, 129.6, 128.8,
127.8, 127.1, 123.9, 79.6 (CH), 69.7 (CH2), 61.3 (CH2), 48.0 (CH2), 26.7 (CH2), 25.4 (CH2), 21.5
(CH3), 14.1 (CH3). IR: 3058, 2939, 1747, 1597, 1469, 1338, 748cm-1. HRMS (ESI-TOF) m/z calcd for
C35H44Br2NO8S [M+H]+ : 796.1154; found: 796.1135.
Ethyl 2-(2-bromophenyl)-2-(4-((N-isopropyl-4-methylphenyl)sulfonamido)butoxy)acetate (3c).
Colorless oil (98.9 mg, 94%); 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.64 (m, 2H), 7.59 – 7.54 (m, 1H),
7.53 – 7.48 (m, 1H), 7.36 – 7.29 (m, 1H), 7.28 – 7.23 (m, 2H), 7.22 – 7.15 (m, 1H), 5.30 (s, 1H), 4.28 –
4.12 (m, 2H), 4.10 – 3.98 (m, 1H), 3.68 – 3.59 (m, 1H), 3.56 – 3.46 (m, 1H), 3.17 – 2.98 (m, 2H), 2.40
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(s, 3H), 1.83 – 1.73 (m, 2H), 1.71 – 1.61 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H), 1.02 (d, J = 6.8 Hz, 6H). 13C
NMR (100 MHz, CDCl3) δ 170.2, 142.78, 138.3, 136.5, 132.8, 129.99, 129.5, 128.9, 127.8, 127.0,
123.9, 79.7, 69.9, 61.3, 49.4, 42.7, 28.7, 27.1, 21.5, 21.1, 14.1. IR: 3061, 2978, 1747, 1597.65, 1468,
1336, 751cm-1. HRMS (ESI-TOF) m/z calcd for C24H33BrNO5S [M+H]+ : 526.1263; found: 526.1254.
Ethyl 2-(2-bromophenyl)-2-(4-((N-cyclohexyl-4-methylphenyl)sulfonamido)butoxy)acetate (3d).
Colorless oil (110.9 mg, 98%); 1H NMR (400 MHz, CDCl3) δ 7.73 – 7.64 (m, 2H), 7.59 – 7.54 (m, 1H),
7.53 – 7.48 (m, 1H), 7.36 – 7.29 (m, 1H), 7.27 – 7.22 (m, 2H), 7.22 – 7.15 (m, 1H), 5.30 (s, 1H), 4.30 –
4.06 (m, 2H), 3.69 – 3.53 (m, 2H), 3.53 – 3.44 (m, 1H), 3.20 – 3.07 (m, 2H), 2.40 (s, 3H), 1.80 – 1.62
(m, 6H), 1.61 – 1.48 (m, 3H), 1.38 – 1.18 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 170.3, 142.7, 138.8,
136.5, 132.8, 130.0, 129.5, 128.9, 127.8, 126.9, 123.9, 79.7, 69.9, 61.3, 57.9, 43.6, 31.7, 31.7, 28.7,
27.0, 26.1, 25.3, 21.5, 14.1. IR: 3066, 2934, 1747, 1598, 1468, 1335, 753cm-1. HRMS (ESI-TOF) m/z
calcd for C27H37BrNO5S [M+H]+ : 566.1576; found: 566.1566.
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Ethyl 2-(2-bromophenyl)-2-(4-((N-(tert-butyl)-4-methylphenyl)sulfonamido)butoxy)acetate (3e).
Colorless oil (62.9 mg, 56%); 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.66 (m, 2H), 7.61 – 7.56 (m, 1H),
7.55 – 7.51 (m, 1H), 7.37 – 7.30 (m, 1H), 7.27 – 7.22 (m, 2H), 7.23 – 7.17 (m, 1H), 5.32 (s, 1H), 4.29 –
4.14 (m, 2H), 3.72 – 3.60 (m, 1H), 3.58 – 3.45 (m, 1H), 3.46 – 3.33 (m, 2H), 2.41 (s, 3H), 1.94 – 1.79
(m, 2H), 1.72 – 1.61 (m, 2H), 1.29 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
170.3, 142.4, 141.5, 136.6, 132.89, 130.0, 129.4, 128.9, 127.8, 126.9, 123.9, 79.7, 70.0, 61.3, 58.9, 46.3,
29.8, 29.4, 27.1, 21.4, 14.1. IR: 3033, 2980, 1747, 1598, 1471, 1320, 752cm-1. HRMS (ESI-TOF) m/z
calcd for C25H34BrNNaO5S [M+Na]+ : 562.1239; found: 562.1232.
Ethyl2-(2-bromophenyl)-2-(4-((N-(2-ethoxy-2-oxoethyl)-4-methylphenyl)sulfonamido)butoxy)acet
ate (3f). Colorless oil (68.4 mg, 60%); 1H NMR (400 MHz, CDCl3) δ 7.76 – 7.67 (m, 2H), 7.61 – 7.54
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(m, 1H), 7.51 – 7.44 (m, 1H), 7.36 – 7.31 (m, 1H), 7.30 – 7.25 (m, 2H), 7.23 – 7.16 (m, 1H), 5.28 (s,
1H), 4.25 – 4.13 (m, 2H), 4.11 – 3.99 (m, 4H), 3.64 – 3.55 (m, 1H), 3.54 – 3.40 (m, 1H), 3.36 – 3.18
(m, 2H), 2.42 (s, 3H), 1.72 – 1.55 (m, 4H), 1.26 – 1.15 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 170.2,
169.0, 143, 136.8, 136.5, 132.9, 130.0, 129.5, 128.8, 127.8, 127.4, 124.0, 79.6 (CH), 69.5 (CH2), 61.3
(CH2), 61.2 (CH2), 48.0 (CH2), 47.9 (CH2), 26.5 (CH2), 24.6 (CH2), 21.5 (CH3), 14.1 (CH3), 14.0 (CH3).
IR: 3036, 2936, 1747, 1597, 1468, 1341, 754cm-1. HRMS (ESI-TOF) m/z calcd for C25H33BrNO7S
[M+H]+ : 570.1161; found: 570.1153.
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Ethyl
2-(2-bromophenyl)-2-(4-((4-methyl-N-phenylphenyl)sulfonamido)butoxy)acetate
(3g).
Colorless oil (100.8 mg, 90%); 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.50 (m, 1H), 7.49 – 7.40 (m, 3H),
7.32 – 7.24 (m, 4H), 7.24 – 7.19 (m, 2H), 7.19 – 7.12 (m, 1H), 7.07 – 6.95 (m, 2H), 5.25 (s, 1H), 4.25 –
4.05 (m, 2H), 3.64 – 3.50 (m, 3H), 3.48 – 3.36 (m, 1H), 2.40 (s, 3H), 1.73 – 1.60 (m, 2H), 1.56 – 1.45
(m, 2H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.2, 143.3, 139.1, 136.5, 135.3,
132.8, 129.9, 129.3, 128.9, 128.9, 128.8, 127.8, 127.8, 127.7, 123.9, 79.6, 69.5, 61.3, 50.1, 26.4, 24.8,
21.6, 14.1. IR: 3028, 2937, 1746, 1595, 1492, 1347, 753cm-1. HRMS (ESI-TOF) m/z calcd for
C27H31BrNO5S [M+H]+ : 560.1106; found: 560.1100.
Ethyl2-(2-bromophenyl)-2-(4-((N-(2,6-dimethylphenyl)-4-methylphenyl)sulfonamido)butoxy)aceta
te (3h). Colorless oil (105.8 mg, 90%);1H NMR (400 MHz, CDCl3) δ 7.68 – 7.61 (m, 2H), 7.54 (d, J =
8.0 Hz, 1H), 7.45 – 7.38 (m, 1H), 7.28 – 7.21 (m, 3H), 7.19 – 7.13 (m, 1H), 7.13 – 7.07 (m, 1H), 7.05 –
6.98 (m, 2H), 5.24 (s, 1H), 4.24 – 4.07 (m, 2H), 3.62 – 3.53 (m, 1H), 3.53 – 3.45 (m, 2H), 3.45 – 3.36
(m, 1H), 2.40 (s, 3H), 2.10 – 1.97 (m, 6H), 1.71 – 1.49 (m, 4H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 170.1, 143.1, 139.2, 139.1, 138.2, 136.9, 136.4, 132.8, 130.0, 129.6, 129.0, 129.0,
128.8, 128.1, 127.8, 127.4, 123.9, 79.7 (CH), 69.8 (CH2), 61.3 (CH2), 51.1 (CH2), 27.0 (CH2), 26.2
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(CH2), 21.6 (CH3), 19.2 (CH3), 19.2 (CH3), 14.1 (CH3). IR: 3063, 2928, 1746, 1596, 1469, 1343,
740cm-1.HRMS (ESI-TOF) m/z calcd for C29H35BrNO5S [M+H]+: 588.1419; found: 588.1406.
Ethyl 2-(2-bromophenyl)-2-(4-((N-(4-bromophenyl)-4-methylphenyl)sulfonamido)butoxy)acetate
(3i). Colorless oil (114.8 mg, 90%); 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.51 (m, 1H), 7.46 – 7.36 (m,
5H), 7.32 – 7.27 (m, 1H), 7.26 – 7.21 (m, 2H), 7.21 – 7.14 (m, 1H), 6.94 – 6.86 (m, 2H), 5.24 (s, 1H),
4.23 – 4.10 (m, 2H), 3.61 – 3.55 (m, 1H), 3.55 – 3.48 (m, 2H), 3.47 – 3.39 (m, 1H), 2.41 (s, 3H), 1.71 –
1.60 (m, 2H), 1.58 – 1.47 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.2, 143.6,
138.2, 136.5, 134.9, 132.9, 132.2, 130.3, 130.0, 129.5, 128.8, 127.8, 127.7, 123.9, 121.6, 79.6, 69.4,
61.3, 49.9, 26.3, 24.8, 21.6, 14.1. IR: 3058, 2936, 1746, 1596, 1485, 1349, 751cm-1. HRMS (ESI-TOF)
m/z calcd for C27H30Br2NO5S [M+H]+ : 638.0211; found: 638.0203.
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Ethyl2-(2-bromophenyl)-2-(4-((N-(4-methoxyphenyl)-4-methylphenyl)sulfonamido)butoxy)acetate
(3j). Colorless oil (92.0 mg, 78%); 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.53 (m, 1H), 7.50 – 7.43 (m,
3H), 7.34 – 7.27 (m, 1H), 7.27 – 7.22 (m, 2H), 7.18 (td, J = 7.7, 1.6 Hz, 1H), 6.96 – 6.89 (m, 2H), 6.82
– 6.77 (m, 2H), 5.26 (s, 1H), 4.26 – 4.07 (m, 2H), 3.79 (s, 3H), 3.63 – 3.55 (m, 1H), 3.55 – 3.49 (m,
2H), 3.49 – 3.41 (m, 1H), 2.42 (s, 3H), 1.75 – 1.63 (m, 2H), 1.59 – 1.43 (m, 2H), 1.22 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 170.2, 159.0, 143.2, 136.5, 135.4, 132.8, 131.5, 130.0, 129.9,
129.4, 128.9, 127.8, 127.7, 123.9, 114.2, 79.6, 69.5, 61.3, 55.4, 50.3, 26.4, 24.8, 21.5, 14.1. IR: 3066,
2937, 1746, 1613.40, 1469, 1326, 748cm-1. HRMS (ESI-TOF) m/z calcd for C28H33BrNO6S [M+H]+ :
590.1212; found: 590.1212.
Ethyl2-(2-bromophenyl)-2-(4-((4-methyl-N-(4-(trifluoromethyl)phenyl)phenyl)sulfonamido)butoxy
)acetate (3k). Colorless oil (106.8 mg, 85%); 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.2 Hz, 3H),
7.46 – 7.38 (m, 3H), 7.31 – 7.22 (m, 3H), 7.21 – 7.14 (m, 3H), 5.28 – 5.18 (m, 1H), 4.21 – 4.08 (m,
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2H), 3.65 – 3.52 (m, 3H), 3.47 – 3.35 (m, 1H), 2.41 (s, 3H), 1.72 – 1.61 (m, 2H), 1.58 – 1.46 (m, 2H),
1.19 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.3, 143.8, 142.6, 136.5, 134.9, 132.9, 130.1,
129.6, 128.8, 128.8, 127.8, 127.7, 126.2, 126.1, 126.1, 126.1, 124.0, 79.7, 69.4, 61.4, 49.8, 26.4, 24.8,
21.6, 14.1. 19F NMR (376 MHz, CDCl3) δ -62.47. IR: 3058, 2934, 1746, 1603, 1467, 1345, 753cm-1.
HRMS (ESI-TOF) m/z calcd for C28H30BrF3NO5S [M+H]+ : 628.0980; found: 628.0987.
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Ethyl 2-(2-bromophenyl)-2-(4-((4-methyl-N-(pyrimidin-2-yl)phenyl)sulfonamido)butoxy)acetate
(3l). Colorless oil (87.7 mg, 78%); 1H NMR (400 MHz, CDCl3) δ 8.50 – 8.31 (m, 2H), 8.01 – 7.88 (m,
2H), 7.62 – 7.48 (m, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.26 – 7.21 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 6.82 (t,
J = 4.8 Hz, 1H), 5.33 (s, 1H), 4.33 – 4.08 (m, 4H), 3.74 – 3.62 (m, 1H), 3.61 – 3.47 (m, 1H), 2.38 (s,
3H), 2.04 – 1.88 (m, 2H), 1.82 – 1.67 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
170.3, 158.2, 157.4, 143.5, 137.9, 136.6, 132.8, 130.0, 128.9, 128.9, 128.6, 127.8, 123.9, 115.3, 79.7,
70.0, 61.3, 47.0, 26.9, 26.3, 21.6, 14.1. IR: 3055, 2955, 1746, 1580, 1412, 1355, 735cm-1. HRMS
(ESI-TOF) m/z calcd for C25H29BrN3O5S [M+H]+ : 562.1011; found: 562.1008.
Ethyl 2-(2-bromophenyl)-2-(4-((4-methyl-N-(thiazol-2-yl)phenyl)sulfonamido)butoxy)acetate (3m).
Colorless oil (74.8 mg, 66%); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0
Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 3.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz,
2H), 7.18 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 3.5 Hz, 1H), 5.28 (s, 1H), 4.26 – 4.08 (m, 2H), 3.98 – 3.83 (m,
2H), 3.70 – 3.55 (m, 1H), 3.53 – 3.40 (m, 1H), 2.38 (s, 3H), 1.80 – 1.67 (m, 4H), 1.21 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 170.3, 161.0, 144.5, 138.7, 136.5, 135.0, 132.8, 130.0, 129.8,
128.9, 127.8, 127.3, 123.9, 116.3, 79.7, 69.6, 61.3, 49.8, 26.6, 25.0, 21.6, 14.1. IR: 3057, 2944, 1745,
1596, 1459, 1358, 739cm-1. HRMS (ESI-TOF) m/z calcd for C24H28BrN2O5S2 [M+H]+ : 567.0623;
found: 567.0623.
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Ethyl2-(4-((N-(benzo[d]thiazol-2-yl)-4-methylphenyl)sulfonamido)butoxy)-2-(2-bromophenyl)acet
ate (3n). Colorless oil (77.7 mg, 63%); 1H NMR (400 MHz, CDCl3) δ 7.79 – 7.67 (m, 4H), 7.57 – 7.47
(m, 2H), 7.37 (t, J = 3.6 Hz, 1H), 7.30 – 7.21 (m, 4H), 7.16 (t, J = 3.6 Hz, 1H), 5.30 (s, 1H), 4.25 –
4.12 (m, 2H), 4.12 – 4.05 (m, 2H), 3.70 – 3.60 (m, 1H), 3.57 – 3.45 (m, 1H), 2.36 (s, 3H), 1.97 – 1.85
(m, 2H), 1.82 – 1.68 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.3, 159.9,
149.6, 144.9, 136.5, 135.3, 133.4, 132.8, 130.0, 128.9, 127.8, 127.2, 126.0, 124.3, 123.9, 121.6, 120.8,
79.7, 69.7, 61.3, 49.8, 26.7, 25.2, 21.6, 14.1. IR: 3057, 2984, 1745, 1596, 1494, 1362, 739cm-1. HRMS
(ESI-TOF) m/z calcd for C28H30BrN2O5S2 [M+H]+ : 617.0780; found: 617.0776.
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Ethyl 2-(2-bromophenyl)-2-(4-((4-methyl-N-(pyridin-2-yl)phenyl)sulfonamido)butoxy)acetate (3o).
Colorless oil (85.3 mg, 76%); 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 4.8 Hz, 1H), 7.74 – 7.66 (m,
1H), 7.61 – 7.51 (m, 2H), 7.50 – 7.40 (m, 3H), 7.33 – 7.25 (m, 1H), 7.23 – 7.10 (m, 4H), 5.25 (s, 1H),
4.30 – 4.04 (m, 2H), 3.89 – 3.69 (m, 2H), 3.64 – 3.50 (m, 1H), 3.49 – 3.37 (m, 1H), 2.37 (s, 3H), 1.73 –
1.62 (m, 2H), 1.61 – 1.49 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.3, 152.4,
148.2, 143.5, 137.7, 136.5, 135.4, 132.8, 130.0, 129.5, 128.8, 127.8, 127.5, 123.9, 123.5, 121.7, 79.6,
69.6, 61.3, 47.5, 26.6, 25.0, 21.6, 14.1. IR: 3066, 2939, 1746, 1588, 1467, 1349, 749cm-1. HRMS
(ESI-TOF) m/z calcd for C26H30BrN2O5S [M+H]+ : 561.1059; found: 561.1055.
Ethyl 2-(2-bromophenyl)-2-(4-(N-methylmethylsulfonamido)butoxy)acetate (3p). Colorless oil
(80.2 mg, 95%); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.33
(t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 5.30 (s, 1H), 4.28 – 4.13 (m, 2H), 3.70 – 3.58 (m, 1H),
3.58 – 3.43 (m, 1H), 3.22 – 3.07 (m, 2H), 2.82 (s, 3H), 2.77 (s, 3H), 1.78 – 1.59 (m, 4H), 1.23 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.3, 136.4, 132.9, 130.1, 128.8, 127.8, 124.0, 79.7, 69.6,
61.4, 49.6, 35.3, 34.5, 26.5, 24.5, 14.1. IR: 3056, 2935, 1745, 1468, 1331, 1149, 750cm-1. HRMS
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(ESI-TOF) m/z calcd for C16H25BrNO5S [M+H]+: 422.0637; found: 422.0634.
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Ethyl 2-(2-bromophenyl)-2-(4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)butoxy)acetate (3q).
Colorless oil (26.8 mg, 27%); 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.2 Hz, 1H), 7.95 – 7.90 (m,
1H), 7.90 – 7.80 (m, 2H), 7.61 – 7.50 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.24 – 7.15 (m, 1H), 5.33 (s,
1H), 4.31 – 4.09 (m, 2H), 3.91 – 3.78 (m, 2H), 3.72 – 3.63 (m, 1H), 3.59 – 3.50 (m, 1H), 2.04 – 1.90
(m, 2H), 1.85 – 1.72 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.2, 159.0,
137.7, 136.5, 134.7, 134.3, 132.8, 130.0, 128.9, 127.9, 127.4, 125.1, 124.0, 120.9, 79.7, 69.4, 61.4, 39.1,
26.9, 25.2, 14.1. IR: 3058, 2923, 1730, 1554, 1467, 1335, 749cm-1. HRMS (ESI-TOF) m/z calcd for
C21H23BrNO6S [M+H]+ : 496.0429; found: 496.0420.
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Ethyl 2-(2-bromophenyl)-2-(4-(1,3-dioxoisoindolin-2-yl)butoxy)acetate (3r). Colorless oil (87.4
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mg, 95%); H NMR (400 MHz, CDCl3) δ 7.91 – 7.77 (m, 2H), 7.74 – 7.65 (m, 2H), 7.58 – 7.47 (m,
2H), 7.36 – 7.30 (m, 1H), 7.23 – 7.11 (m, 1H), 5.30 (s, 1H), 4.26 – 4.09 (m, 2H), 3.78 – 3.68 (m, 2H),
3.68 – 3.60 (m, 1H), 3.56 – 3.47 (m, 1H), 1.86 – 1.75 (m, 2H), 1.74 – 1.63 (m, 2H), 1.22 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 170.2, 168.4, 136.5, 133.9, 132.8, 132.1, 130.0, 128.9, 127.8,
123.9, 123.2, 79.7, 69.6, 61.3, 37.7, 27.0, 25.3, 14.1. IR: 3057, 2940, 1746, 1712, 1468, 1397, 1335,
721cm-1. HRMS (ESI-TOF) m/z calcd for C22H23BrNO5 [M+H]+ : 460.0760; found: 460.0756.
Ethyl 2-(2-bromophenyl)-2-(4-(2,2,2-trifluoro-N-phenylacetamido)butoxy)acetate (3s). Colorless
oil (63.3 mg, 63%); 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.46 – 7.38 (m, 4H), 7.33 –
7.27 (m, 1H), 7.24 – 7.15 (m, 3H), 5.27 (s, 1H), 4.24 – 4.10 (m, 2H), 3.81 – 3.71 (m, 2H), 3.67 – 3.57
(m, 1H), 3.52 – 3.40 (m, 1H), 1.71 – 1.62 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 170.2, 138.9, 136.4, 132.9, 130.1, 129.4, 129.0, 128.8, 128.4, 127.8, 124.0, 69.5, 61.4, 51.4,
26.7, 23.6, 14.1. 19F NMR (376 MHz, CDCl3) δ -67.09. IR: 3058, 2940, 1746, 1694, 1595, 1495, 1205,
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751cm-1. HRMS (ESI-TOF) m/z calcd for C22H24BrF3NO4 [M+H]+ : 502.0841; found: 502.0833.
Ethyl 2-(2-bromophenyl)-2-(4-(2-oxobenzo[d]oxazol-3(2H)-yl)butoxy)acetate (3t). Colorless oil
(62.7 mg, 70%); 1HNMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H), 7.52 – 7.45 (m, 1H), 7.34 (t, J
= 7.6 Hz, 1H), 7.24 – 7.06 (m, 4H), 7.01 (d, J = 7.6 Hz, 1H), 5.32 (s, 1H), 4.29 – 4.11 (m, 2H), 3.89 (t,
J = 7.2 Hz, 2H), 3.77 – 3.65 (m, 1H), 3.61 – 3.50 (m, 1H), 1.99 – 1.86 (m, 2H), 1.80 – 1.66 (m, 2H),
1.23 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.3, 154.6, 142.7, 136.4, 132.9, 131.2, 130.1,
128.8, 127.9, 124.1, 123.8, 122.3, 110.0, 108.5, 79.7, 69.5, 61.4, 42.0, 26.7, 24.7, 14.1. IR: 3055, 2958,
1776, 1486, 1394, 1255, 753cm-1. HRMS (ESI-TOF) m/z calcd for C21H23BrNO5 [M+H]+ : 448.0760;
found: 448.0759.
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Ethyl 2-(2-bromophenyl)-2-(4-(3a,7a-dihydro-1H-benzo[d]imidazol-1-yl)butoxy)acetate (3u).
Colorless oil (83.1 mg, 96 %); 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.84 – 7.75 (m, 1H), 7.58 (d,
J = 8.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.36 – 7.23 (m, 3H), 7.20 (t, J = 7.6 Hz,
1H), 5.31 (s, 1H), 4.34 – 4.10 (m, 4H), 3.71 – 3.59 (m, 1H), 3.56 – 3.42 (m, 1H), 2.08 – 1.89 (m, 2H),
1.77 – 1.50 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.3, 143.8, 143.1, 136.3,
133.8, 133.0, 130.2, 128.8, 127.9, 124.1, 122.8, 122.0, 120.3, 109.8, 79.8, 69.6, 61.5, 44.7, 27.0, 26.6,
14.1. IR: 3056, 2936, 1744, 1614, 1495, 1367, 745cm-1. HRMS (ESI-TOF) m/z calcd for C21H24BrN2O3
[M+H]+ : 433.0947; found: 433.0948.
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Ethyl 2-(2-bromophenyl)-2-(4-(p-tolyloxy)butoxy)acetate (3x). Colorless oil (82.5 mg, 98%); H
NMR (400 MHz, CDCl3) δ 7.60 – 7.48 (m, 2H), 7.34 – 7.26 (m, 1H), 7.20 – 7.13 (m, 1H), 7.09 – 6.98
(m, 2H), 6.81 – 6.70 (m, 2H), 5.32 (s, 1H), 4.26 – 4.09 (m, 2H), 4.02 – 3.87 (m, 2H), 3.73 – 3.62 (m,
1H), 3.60 – 3.47 (m, 1H), 2.26 (s, 3H), 1.93 – 1.74 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 170.4, 156.9, 136.6, 132.9, 130.05, 129.9, 129.7, 128.9, 127.9, 124.0, 114.4, 79.7, 69.9,
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67.6, 61.4, 26.3, 26.1, 20.5, 14.1. IR: 3058, 2940, 1747, 1613, 1471, 1243.33, 750cm-1. HRMS
(ESI-TOF) m/z calcd for C21H26BrO4 [M+H]+ : 421.1014; found: 421.1014.
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Ethyl 2-(2-bromophenyl)-2-(4-(naphthalen-2-yloxy)butoxy)acetate (3y). Colorless oil (89.6 mg,
98%); 1H NMR (400 MHz, CDCl3) δ 7.84 – 7.72 (m, 3H), 7.61 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 7.6 Hz,
1H), 7.40 – 7.33 (m, 2H), 7.26 – 7.12 (m, 3H), 5.41 (s, 1H), 4.31 – 4.19 (m, 2H), 4.18 – 4.07 (m, 2H),
3.82 – 3.71 (m, 1H), 3.69 – 3.58 (m, 1H), 2.08 – 1.86 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 170.4, 157.0, 136.6, 134.7, 132.9, 130.1, 129.4, 128.9, 127.9, 127.7, 126.8, 126.4,
124.0, 123.5, 119.1, 106.6, 79.7, 69.9, 67.6, 61.4, 26.4, 26.1, 14.2. IR: 3055, 2985, 1745, 1600, 1441,
1265, 744cm-1. HRMS (ESI-TOF) m/z calcd for C24H26BrO4 [M+H]+ : 457.1014; found: 457.1014.
4-(1-(2-Bromophenyl)-2-ethoxy-2-oxoethoxy)butylbenzoate (3z). Colorless oil (83.5 mg, 96%); 1H
NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.8 Hz, 2H), 7.61 – 7.48 (m, 3H), 7.46 – 7.36 (m, 2H), 7.36 –
7.29 (m, 1H), 7.22 – 7.14 (m, 1H), 5.33 (s, 1H), 4.34 (t, J = 6.2 Hz, 2H), 4.25 – 4.11 (m, 2H), 3.72 –
3.61 (m, 1H), 3.60 – 3.51 (m, 1H), 1.92 – 1.78 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 170.3, 166.6, 136.5, 132.9, 132.9, 130.4, 130.1, 129.6, 128.9, 128.3, 127.8, 124.0, 79.7, 69.7,
64.7, 61.4, 26.3, 25.5, 14.1. IR: 3055, 2956, 1747, 1719, 1470, 1275, 1108, 751cm-1. HRMS (ESI-TOF)
m/z calcd for C21H24BrO5 [M+H]+ : 435.0807; found: 435.0806.
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4-(1-(2Bromophenyl)-2-ethoxy-2-oxoethoxy)butyl 3,3-dimethylbutanoate (3aa). Colorless oil (82.4
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mg, 96%); H NMR (400 MHz, CDCl3) δ 7.59 – 7.54 (m, 1H), 7.53 – 7.48 (m, 1H), 7.36 – 7.30 (m,
1H), 7.22 – 7.15 (m, 1H), 5.31 (s, 1H), 4.25 – 4.12 (m, 2H), 4.11 – 4.04 (m, 2H), 3.68 – 3.58 (m, 1H),
3.55 – 3.45 (m, 1H), 2.18 (s, 2H), 1.79 – 1.64 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H), 1.01 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ 172.4, 170.2, 136.5, 132.9, 130.0, 128.8, 127.8, 124.0, 79.7 (CH), 69.7 (CH2),
63.7 (CH2), 61.3 (CH2), 48.0 (CH2), 30.7 (Cq), 29.7 (CH3), 26.3 (CH2), 25.4 (CH2), 14.1 (CH3). IR:
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3056, 2958, 1734, 1470, 1442, 1325, 751cm-1. HRMS (ESI-TOF) m/z calcd for C20H30BrO5 [M+H]+ :
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429.1277; found: 429.1277.
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Ethyl 2-(4-(benzylthio)butoxy)-2-(2-bromophenyl)acetate (3ac). Colorless oil (65.6 mg, 75%); H
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NMR (400 MHz, CDCl3) δ 7.62 – 7.57 (m, 1H), 7.56 – 7.51 (m, 1H), 7.38 – 7.30 (m, 5H), 7.28 – 7.17
(m, 2H), 5.32 (s, 1H), 4.27 – 4.15 (m, 2H), 3.71 (s, 2H), 3.66 – 3.56 (m, 1H), 3.53 – 3.43 (m, 1H), 2.51
– 2.38 (m, 2H), 1.81 – 1.61 (m, 4H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.3,
138.6, 136.6, 132.9, 130.0, 128.9, 128.5, 127.8, 126.9, 124.0, 79.6, 69.7, 61.3, 36.2, 31.0, 28.7, 25.8,
14.1. IR: 3062, 2937, 1747, 1494, 1470, 1369, 751cm-1. HRMS (ESI-TOF) m/z calcd for C21H26BrO3S
[M+H]+ : 437.0786; found: 437.0791.
Ethyl
2-(2-bromophenyl)-2-(4-(5-nitro-3a,7a-dihydro-1H-indol-1-yl)butoxy)acetate
(3ad).
Colorless oil (81.8 mg, 82%); 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.0 Hz, 1H), 8.12 – 8.03 (m,
1H), 7.60 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.41 – 7.33 (m, 2H), 7.30 – 7.26 (m, 1H), 7.26 –
7.18 (m, 1H), 6.67 (d, J = 3.2 Hz, 1H), 5.32 (s, 1H), 4.29 – 4.14 (m, 4H), 3.71 – 3.62 (m, 1H), 3.59 –
3.48 (m, 1H), 2.07 – 1.93 (m, 2H), 1.73 – 1.59 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 170.3, 141.4, 138.9, 136.3, 133.0, 131.2, 130.2, 128.8, 127.9, 127.7, 124.1, 118.2, 117.1,
109.4, 103.9, 79.7, 69.6, 61.5, 46.6, 27.3, 26.7, 14.1. IR: 3056, 2927, 1744, 1577, 1475, 1332, 744cm-1.
HRMS (ESI-TOF) m/z calcd for C22H23BrN2NaO5 [M+Na]+ : 499.0665; found: 499.0662.
Ethyl 2-benzoyl-6-(1-(2-bromophenyl)-2-ethoxy-2-oxoethoxy)hexanoate (3ae). Colorless oil (70.7
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mg, 70%); H NMR (400 MHz, CDCl3) δ 7.63 – 7.47 (m, 4H), 7.46 – 7.35 (m, 3H), 7.34 – 7.28 (m,
1H), 7.24 – 7.10 (m, 1H), 5.54 (s, 0.9H), 5.32 (s, 1H), 5.23 (s, 0.1H), 4.28 – 4.11 (m, 4H), 4.07 – 3.92
(m, 2H), 3.73 – 3.61 (m, 1H), 3.60 – 3.43 (m, 1H), 1.95 – 1.76 (m, 4H), 1.31 (t, J = 7.1 Hz, 2.5H), 1.23
(t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 0.5H). 13C NMR (100 MHz, CDCl3) δ 170.3, 167.8, 165.3,
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136.5, 135.2, 132.8, 130.2, 130.0, 128.9, 128.8, 128.6, 127.8, 127.6, 127.4, 124.0, 100.7, 79.6, 72.6,
69.8, 61.3, 59.7, 26.8, 26.1, 14.4, 14.1. IR: 3055, 2985, 1745, 1623, 1470, 1266, 742 cm-1. HRMS
(ESI-TOF) m/z calcd for C25H30BrO6 [M+H]+ : 505.1226; found: 505.1224.
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Ethyl (R)-2-(2-bromophenyl)-2-((5-((N,4-dimethylphenyl)sulfonamido)pentyl)oxy)acetate (3ag).
Colorless oil (76.8 mg, 75%); 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.61 (m, 2H), 7.56 (d, J = 8.0 Hz,
1H), 7.51 (d, J = 7.7 Hz, 1H), 7.36 – 7.27 (m, 3H), 7.22 – 7.15 (m, 1H), 5.29 (s, 1H), 4.28 – 4.05 (m,
2H), 3.65 – 3.53 (m, 1H), 3.51 – 3.37 (m, 1H), 3.03 – 2.90 (m, 2H), 2.68 (s, 3H), 2.42 (s, 3H), 1.71 –
1.59 (m, 2H), 1.59 – 1.48 (m, 2H), 1.46 – 1.35 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 170.4, 143.2, 136.6, 134.6, 132.9, 130.1, 129.7, 128.9, 127.9, 127.5, 124.0, 79.7 (CH), 70.1
(CH2), 61.4 (CH2), 50.0 (CH2), 34.7 (CH3), 29.2 (CH2), 27.4 (CH2), 23.1 (CH2), 21.6 (CH3), 14.1 (CH3).
IR: 3059, 2938, 1747, 1597, 1467, 1340, 744cm-1. HRMS (ESI-TOF) m/z calcd for C23H31BrNO5S
[M+H]+ : 512.1106; found: 512.1103.
Ethyl2-(2-bromophenyl)-2-(2-(2-((N,4-dimethylphenyl)sulfonamido)ethoxy)ethoxy)acetate (3ah).
Colorless oil (88.4 mg, 86%); 1H NMR (400 MHz, CDCl3) δ 7.73 – 7.62 (m, 2H), 7.58 – 7.53 (m, 1H),
7.53 – 7.47 (m, 1H), 7.35 – 7.25 (m, 3H), 7.22 – 7.13 (m, 1H), 5.38 (s, 1H), 4.29 – 4.02 (m, 2H), 3.82 –
3.68 (m, 1H), 3.67 – 3.52 (m, 5H), 3.28 – 3.13 (m, 2H), 2.81 (s, 3H), 2.42 (s, 3H), 1.21 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 170.1, 143.3, 136.3, 134.7, 132.9, 130.1, 129.7, 128.92, 127.8,
127.4, 123.9, 79.9 (CH), 70.3 (CH2), 70.2 (CH2), 69.4 (CH2), 61.4 (CH2), 49.8 (CH2), 36.4 (CH3), 21.5
(CH3), 14.1 (CH3). IR: 3056, 2924, 1746, 1597, 1467, 1339, 752cm-1. HRMS (ESI-TOF) m/z calcd for
C22H29BrNO6S [M+H]+ : 514.0899; found: 514.0895.
Ethyl2-(2-bromophenyl)-2-(4-((N,4-dimethylphenyl)sulfonamido)butoxy-1,1,2,2,3,3,4,4-d8)acetate
(3ai). Colorless oil (97.2 mg, 96%); 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.61 (m, 2H), 7.56 (d, J = 8.0
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Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.36 – 7.26 (m, 3H), 7.23 – 7.14 (m, 1H), 5.29 (s, 1H), 4.30 – 4.03
(m, 2H), 2.68 (s, 3H), 2.41 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.3,
143.2, 136.5, 134.6, 132.9, 130.0, 129.6, 128.9, 127.8, 127.4, 124.0, 79.6, 61.3, 34.5, 21.5, 14.1. IR:
3085, 2981, 2086, 1746, 1597, 1468, 1342, 753cm-1. HRMS (ESI-TOF) m/z calcd for C22H21D8BrNO5S
[M+H]+ : 506.1453; found: 506.1448.
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Ethyl 2-(4-((N,4-dimethylphenyl)sulfonamido)butoxy)-2-phenylacetate (3al). Colorless oil (73.9
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mg, 88%); H NMR (400 MHz, CDCl3) δ 7.69 – 7.59 (m, 2H), 7.47 – 7.40 (m, 2H), 7.38 – 7.25 (m,
5H), 4.84 (s, 1H), 4.34 – 4.01 (m, 2H), 3.63 – 3.54 (m, 1H), 3.52 – 3.42 (m, 1H), 3.09 – 2.91 (m, 2H),
2.68 (s, 3H), 2.41 (s, 3H), 1.74 – 1.56 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
171.0, 143.2, 136.8, 134.6, 129.6, 128.5, 127.4, 127.1, 81.1, 69.1, 61.1, 49.8, 34.6, 26.5, 24.2, 21.49,
14.1. IR: 3058, 2936, 1746, 1598, 1455, 1340, 737cm-1. HRMS (ESI-TOF) m/z calcd for C22H30NO5S
[M+H]+ : 420.1845; found: 420.1843.
Ethyl 2-(4-((N,4-dimethylphenyl)sulfonamido)butoxy)-2-(p-tolyl)acetate (3am). Colorless oil (67.7
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mg, 78%); H NMR (400 MHz, CDCl3) δ 7.74 – 7.60 (m, 2H), 7.36 – 7.28 (m, 4H), 7.22 – 7.06 (m,
2H), 4.82 (s, 1H), 4.29 – 4.03 (m, 2H), 3.64 – 3.53 (m, 1H), 3.52 – 3.42 (m, 1H), 3.13 – 2.87 (m, 2H),
2.70 (s, 3H), 2.43 (s, 3H), 2.36 (s, 3H), 1.77 – 1.56 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 171.1, 143.2, 138.4, 134.5, 133.8, 129.6, 129.3, 127.4, 127.1, 80.9, 68.9, 61.1, 49.8,
34.6, 26.5, 24.3, 21.5, 21.2, 14.1. IR: 3065, 2926, 1747, 1598, 1459, 1340, 739cm-1. HRMS (ESI-TOF)
m/z calcd for C23H30NO5S [M+H]+ : 434.2001; found: 434.2001.
Ethyl 2-(4-((N,4-dimethylphenyl)sulfonamido)butoxy)-2-(4-fluorophenyl)acetate (3an). Colorless
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oil (63.1 mg, 72%); H NMR (400 MHz, CDCl3) δ 7.68 – 7.60 (m, 2H), 7.47 – 7.37 (m, 2H), 7.34 –
7.25 (m, 2H), 7.08 – 6.98 (m, 2H), 4.82 (s, 1H), 4.26 – 4.05 (m, 2H), 3.64 – 3.54 (m, 1H), 3.52 – 3.43
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(m, 1H), 3.06 – 2.93 (m, 2H), 2.69 (s, 3H), 2.42 (s, 3H), 1.77 – 1.58 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 170.8, 162.8 (d, J = 247.1 Hz), 143.2, 134.5, 132.6 (d, J = 3.3Hz),
129.6, 128.9 (d, J = 8.3 Hz), 127.4, 115.5 (d, J = 21.6 Hz), 80.3, 69.1, 61.2, 49.7, 34.6, 26.4, 24.2, 21.5,
14.1. IR: 3057, 2937, 1747, 1509, 1460.99, 1340, 740cm-1. HRMS (ESI-TOF) m/z calcd for
C22H29FNO5S [M+H]+ : 438.1750; found: 438.1750.
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Ethyl 2-(4-bromophenyl)-2-(4-((N,4-dimethylphenyl)sulfonamido)butoxy)acetate (3ao). Colorless
1
oil (69.7 mg, 70%); H NMR (400 MHz, CDCl3) δ 7.68 – 7.62 (m, 2H), 7.62 – 7.58 (m, 1H), 7.48 –
7.43 (m, 1H), 7.40 – 7.35 (m, 1H), 7.33 – 7.28 (m, 2H), 7.25 – 7.19 (m, 1H), 4.80 (s, 1H), 4.27 – 4.06
(m, 2H), 3.64 – 3.54 (m, 1H), 3.52 – 3.43 (m, 1H), 3.07 – 2.91 (m, 2H), 2.69 (s, 3H), 2.42 (s, 3H), 1.72
– 1.62 (m, 4H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.4, 143.2, 139.0, 134.5,
131.7, 130.1, 130.1, 129.7, 127.4, 125.7, 122.6, 80.3, 69.3, 61.4, 49.7, 34.6, 26.4, 24.1, 21.5, 14.1. IR:
3056, 2926, 1747, 1571, 1470, 1161, 739cm-1. HRMS (ESI-TOF) m/z calcd for C22H29BrNO5S [M+H]+ :
498.0950; found: 498.0949.
Ethyl 2-(4-((N,4-dimethylphenyl)sulfonamido)butoxy)-2-(o-tolyl)acetate (3ap). Colorless oil (80.7
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mg, 93%); H NMR (400 MHz, CDCl3) δ 7.70 – 7.55 (m, 2H), 7.46 – 7.36 (m, 1H), 7.33 – 7.24 (m,
2H), 7.24 – 7.10 (m, 3H), 5.05 (s, 1H), 4.27 – 4.02 (m, 2H), 3.65 – 3.52 (m, 1H), 3.51 – 3.35 (m, 1H),
3.10 – 2.89 (m, 2H), 2.68 (s, 3H), 2.46 – 2.33 (m, 6H), 1.77 – 1.54 (m, 4H), 1.20 (t, J = 7.1 Hz, 3H).13C
NMR (100 MHz, CDCl3) δ 171.2, 143.2, 136.5, 135.2, 134.6, 130.6, 129.6, 128.4, 127.4, 127.4, 126.20,
78.24, 69.1, 61.0, 49.8, 34.6, 26.5, 24.3, 21.5, 19.4, 14.1. IR: 3065, 2931, 1747, 1599, 1462, 1341,
741cm-1. HRMS (ESI-TOF) m/z calcd for C23H32NO5S [M+H]+ : 434.2001; found: 434.1999.
Ethyl
2-([1,1'-biphenyl]-4-yl)-2-(4-((N,4-dimethylphenyl)sulfonamido)butoxy)acetate
(3aq).
Colorless oil (49.6 mg, 50%); 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.62 (m, 2H), 7.61 – 7.55 (m, 4H),
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7.54 – 7.49 (m, 2H), 7.46 – 7.39 (m, 2H), 7.38 – 7.31 (m, 1H), 7.30 – 7.24 (m, 2H), 4.89 (s, 1H), 4.33 –
4.07 (m, 2H), 3.68 – 3.57 (m, 1H), 3.56 – 3.45 (m, 1H), 3.11 – 2.92 (m, 2H), 2.69 (s, 3H), 2.39 (s, 3H),
1.81 – 1.60 (m, 4H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.0, 143.2, 141.5, 140.6,
135.8, 134.5, 129.6, 128.8, 127.6, 127.5, 127.4, 127.3, 127.1, 80.9, 69.1, 61.3, 49.8, 34.6, 26.5, 24.3,
21.5, 14.12. IR: 3056, 2935, 1746, 1599, 1488, 1340, 760cm-1. HRMS (ESI-TOF) m/z calcd for
C28H34NO5S [M+H]+ : 496.2158; found: 496.2152.
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Ethyl 2-(4-((N,4-dimethylphenyl)sulfonamido)butoxy)-2-(naphthalen-2-yl)acetate (3as). Colorless
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oil (78.7 mg, 80%); H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.88 – 7.79 (m, 3H), 7.65 – 7.59 (m,
2H), 7.59 – 7.53 (m, 1H), 7.52 – 7.44 (m, 2H), 7.28 – 7.21 (m, 2H), 5.01 (s, 1H), 4.31 – 4.03 (m, 2H),
3.70 – 3.58 (m, 1H), 3.56 – 3.43 (m, 1H), 3.06 – 2.91 (m, 2H), 2.67 (s, 3H), 2.38 (s, 3H), 1.81 – 1.56
(m, 4H), 1.20 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.0, 143.2, 134.5, 134.2, 133.4,
133.2, 129.6, 128.4, 128.2, 127.7, 127.4, 126.7, 126.4, 126.3, 124.6, 81.2, 69.1, 61.3, 49.8, 34.6, 26.5,
24.3, 21.5, 14.1. IR: 3059, 2936, 1746, 1599, 1460, 1338, 750cm-1. HRMS (ESI-TOF) m/z calcd for
C26H31NNaO5S [M+Na]+ : 492.1821; found: 492.1812.
Methyl
2-(2-bromophenyl)-2-(4-((N,4-dimethylphenyl)sulfonamido)butoxy)acetate
(3au).
Colorless oil (89.6 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.60 (m, 2H), 7.59 – 7.54 (m, 1H),
7.52 – 7.45 (m, 1H), 7.36 – 7.26 (m, 3H), 7.23 – 7.16 (m, 1H), 5.32 (s, 1H), 3.72 (s, 3H), 3.69 – 3.58
(m, 1H), 3.56 – 3.43 (m, 1H), 3.06 – 2.91 (m, 2H), 2.68 (s, 3H), 2.41 (s, 3H), 1.76 – 1.57 (m, 4H). 13C
NMR (100 MHz, CDCl3) δ 170.7, 143.2, 136.4, 134.5, 132.9, 130.1, 129.6, 128.9, 127.9, 127.4, 124.0,
79.6, 69.5, 52.3, 49.7, 34.6, 26.5, 24.2, 21.5. IR: 3056, 2957, 1747, 1590, 1437, 1351, 750cm-1. HRMS
(ESI-TOF) m/z calcd for C21H27BrNO5S [M+H]+ : 484.0793; found: 484.0786.
Isopropyl
2-(2-bromophenyl)-2-(4-((N,4-dimethylphenyl)sulfonamido)butoxy)acetate
(3av).
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