A Sequential One-Pot Synthesis of Functionalized Esters and Thioesters through a Ring-Opening Acylation of Cyclic Ethers and Thioethers

Article abstract of DOI:10.1002/ejoc.201801225

A one-pot protocol for the synthesis of functionalized esters and thioesters is reported from cyclic ethers/thioethers and carboxylic acids via acyloxyphosphonium salts as key intermediates. The reaction of styrene oxide with acyloxyphosphonium salts gave complete regioselectivity and good yields of the resulting functionalized ester, whereas cyclohexene oxide gave moderate yields. Styrene episulfide, on the other hand, gave good yields with moderate regioselectivity whereas cyclohexene sulfide gave quantitative yields of the corresponding thioesters. We have also shown an alternate procedure for the ring opening of THF to form 4-bromo butyl esters. All these reactions were carried out in the absence of a catalyst, showing the synthetic versatility of our method.

Full text of DOI:10.1002/ejoc.201801225

A Journal of
Accepted Article
Title: A sequential one-pot synthesis of functionalized esters and
thioesters via ring opening-acylation of cyclic ethers and
thioethers
Authors: Gopinath Purushothaman and Chandrasekaran Srinivasan
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10.1002/ejoc.201801225
European Journal of Organic Chemistry
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A sequential one-pot synthesis of functionalized esters and
thioesters via ring opening-acylation of cyclic ethers and
thioethers
Purushothaman Gopinatha,b,* and Srinivasan Chandrasekarana,*
Abstract: A one-pot protocol for the synthesis of functionalized esters
and thioesters are reported from cyclic ethers/thioethers and
carboxylic acids via acyloxyphosphonium salts as key intermediates.
The reaction of styrene oxide with acyloxyphosphonium salts gave
complete regioselectivity and good yields of the resulting
functionalized ester, whereas cyclohexene oxide gave moderate
yields. Styrene episulfide on the other hand gave good yields with
moderate regioselectivty whereas cyclohexene sulfide gave
quantitative yield of the corresponding thioesters. We have also
shown an alternate procedure for the ring opening of THF to form 4-
bromo butyl esters. All these reactions were carried out in the absence
of catalyst, showing the synthetic versatility of our method.
acids (2) using PPh3 and NBS (or NCS) are versatile
intermediates in organic synthesis as they give direct access to
acyl halides,[11] acyl azides,[12] esters,[13] thioesters,[14] and
amides[15] (Scheme 1). Our group has already demonstrated the
use of this salt for the generation of thiocarboxylate ions using
benzyltriethylammonium tetrathiomolybdate[14a,b,c,16] for the
formation of thioesters,[14a,b] Michael addition, epoxide and
aziridine ring opening[14c] etc. Since these salts have an unutilized
bromide ions, we worked out a synthetic strategy to use them for
the ring opening of epoxides or thiiranes followed by acylation of
the resulting alkoxide/thiolate in the same pot.
Introduction
Main Ring opening of cyclic ethers and thioethers has great
synthetic potential in organic synthesis as it gives direct access to
bifunctionalised molecules.[1] Of particular importance are
haloesters[2] which are used as key intermediates in the synthesis
of many biologically useful molecules. [3] In contrast to halohydrins,
Scheme 1. Previous reports on the applications of acyloxyphosphonium salts.
haloesters are generally difficult to synthesize in a single step. Results and Discussion
One viable route for their synthesis is the ring opening of cyclic
ethers with acid halides. Although, acylative cleavage of cyclic
ethers with acid halides is known, in general they require catalysts
such as Lewis acids,[4] lanthanide salts,[5] palladium/platinum
complexes,[6,7] SmI2[8] etc. or high pressures[9] with the exception
of acyl iodides.[10] Some of the issues associated with the existing
methods are as follows: (a) Lewis acids were used in
stoichiometric amount and are either air sensitive (BCl3),[4d] or
longer reaction times (ZnCl2, FeCl3)[4a,b] with lower regioselectivity.
(b) Lanthanide salts are hygroscopic and hence difficult to handle,
whereas palladium, platinum & SmI2 catalysts are expensive.
We first investigated the opening of an epoxide (cyclic ether) with
acyloxyphosphonium intermediates, 1. Accordingly, benzoic acid,
triphenyl phosphine, NBS & styrene oxide were stirred together in
dichloromethane for 7h. Interestingly, the expected bromo
substituted ester, 4a was obtained regioselectively in 65% yield
with ring opening at the benzylic carbon. Next, we screened
different solvents for optimizing the reaction conditions and
observed a maximum yield of 65% with dichloromethane (CH2Cl2)
and chloroform (CHCl3). With acetone and acetonitrile as solvents
the yield was poor and with DMF & hexane the reaction didn’t
proceed even after stirring for 24 h. On the other hand with
benzene as solvent, a moderate yield of the corresponding
functionalized bromoester was obtained. Hence dichloromethane
was chosen as the solvent for further studies (Table 1).
All these reactions also suffer from the additional limitation of
using an acid halide, which in general are difficult to synthesize &
handle (especially acyl iodides). It also involves an additional step
for their synthesis from the corresponding carboxylic acids.
Acyloxyphosphonium salts, 1 synthesized in situ from carboxylic
Encouraged by the optimized results, we extended the protocol to
other carboxylic acids and in all the cases the ring opening
occurred regioselectively at the benzylic position, showing the
synthetic utility of the method (Table 2). We envisage the
following mechanism, wherein styrene oxide, 3 first reacts with
acyloxyphosphonium salt, 1 to form oxonium intermediate, A,
which is followed by ring opening with bromide ion to form the
[a]
[b]
Prof. S. Chandrasekaran, and Dr. P. Gopinath, Department of
Organic Chemistry, Indian Institute of Science, Bangalore 560012,
India. Email: scn@iisc.ac.in; gopi@iisertirupati.ac.in
Dr. P. Gopinath, Department of Chemistry, Indian Institute of
Science Education and Research (IISER) Tirupati, Tirupati 517507,
India. E-mail: gopi@iisertirupati.ac.in
corresponding bromoesters,
4 (Scheme 2). The correct
http://www.iisertirupati.ac.in/people/faculty/gopi.php
Supporting information for this article is given via a link at the end of
the document.
regioisomer was identified using 1H NMR and was further
confirmed by single crystal X-ray analysis of compound 4e (fig 1).
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Table 1. Screening of solvents for the ring opening of styrene oxide [a]
Scheme 2. Proposed mechanism for the formation of bromoesters
Solvent
Time (h)
Yield (%)
CH2Cl2
CHCl3
7
7
65
65
CH3CN
Acetone
DMF
Hexane
Benzene
24
24
24
24
7
10
15
No Reaction
No
55
[a] Reaction was carried out with benzoic acid (1 mmol), PPh3 (1.1 mmol),
NBS (1.1 mmol) & styrene oxide (1.1 mmol) in the corresponding solvent
(3 mL).
Fig 1. ORTEP diagram of compound 4e
Table 2. Reaction of styrene oxide with various carboxylic acids.[a]
To demonstrate the generality of this methodology, the protocol
was extended to other epoxides as well. With cyclohexene oxide,
we obtained the corresponding trans-bromo subsituted ester, 6.
The yields were only moderate due to the formation of side
product from dehydrohalogenation (Table 3).
Table 3. Reaction of cyclohexene oxide with various carboxylic acids.[a]
[a] Reaction was carried out with various carboxylic acids (1 mmol), PPh3 (1.1
mmol), NBS (1.1 mmol) & cyclohexene oxide (1.1 mmol) in dichloromethane (3
mL) as solvent
We then attempted the ring opening of tetrahydrofuran (THF, a
cyclic ether) under similar conditions to show the synthetic
versatility of our protocol. Again, the reaction is believed to
proceed via an oxonium intermediate, 7 (which activates the THF
ring for facile opening by bromide ion). With benzoic acid as
substrate we obtained the corresponding bromo substituted ester,
8a in 85% yield. (Scheme 3).
[a] Reaction was carried out with various carboxylic acids (1 mmol), PPh3 (1.1
mmol), NBS (1.1 mmol) & Styrene oxide (1.1 mmol) in dichloromethane (3 mL)
as solvent.
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10.1002/ejoc.201801225
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source instead of Br2 without any additional catalysts. The
reaction with benzoic acid as substrate gave 85% yield of the
corresponding bromo substituted ester, which is superior to the
reactions reported with catalysts (60-65%). We extended the
protocol to other carboxylic acids to demonstrate the generality of
the method and the results are summarized in Table 4. In all the
cases, the final bromo substituted esters (8a-k) were obtained in
good to excellent yields (60-85%).
Finally, we attempted the ring opening of thiiranes using the same
protocol. Although ring opening of epoxides to bromo substituted
esters are documented, the corresponding reaction with thiiranes
to form bromo substituted thioesters was less studied.[17] Since
thioesters are important synthetic intermediates in organic
synthesis particularly in peptide coupling,[18] acyl transfer,[19] as
protecting group for thiols,[20] and as key intermediates in various
biological process,[21] we adapted the same protocol for the
synthesis of bromo substituted thioesters from thiiranes.
Scheme 3. Proposed mechanism for THF ring opening.
Table 4. Reaction of THF with various carboxylic acids.[a]
Accordingly styrene episulphide 9,[22] PPh3, and NBS were treated
with various carboxylic acids, to afford the corresponding bromo
substituted thioesters in good yields but with
a lower
regioselectivity. We speculate that since the benzylic position of
styrene episulfide is less reactive than styrene oxide, moderate
regioselectivity was observed. The results of this study are
summarized in Table 5.
Table 5. Reaction of styrene episulfide with various carboxylic acids.[a
]
[a] Reaction was carried out with various carboxylic acids (1 mmol), PPh3 (1.1
mmol), NBS (1.1 mmol), & styrene episulfide (1.1 mmol) in dichloromethane (3
mL) as solvent. b Based on 1H NMR.
In order to further improve the selectivity we studied the effect of
Lewis acid on the regioisomeric ratio using p-methoxy benzoic
acid, as the starting material. With 20 mol % of lithium perchlorate
there was no change in the ratio of regioisomers but with 1 equiv
of lithium perchlorate the ratio increased to 4:1 from 2:1 albeit with
lower yield (50%). With 2 equiv of lithium perchlorate both the ratio
and yield decreased to 3:1 and 40% respectively and with
BF3.OEt2 (1equiv) as Lewis acid the ratio increased to 7:1 while
the yield dropping down to 25% (Table 6). We presume that Lewis
acids increase the reactivity of benzylic carbon by coordination to
the sulfur atom of styrene episulfide (and polarize the C-S bond),
[a] Reaction was carried out with various carboxylic acids (1 mmol), PPh3 (1.1
mmol), & NBS (1.1 mmol), in THF (3 mL) as solvent.
Although similar types of reactions were reported with THF using
zinc bromide[4f] and allyl samarium bromide[4e] as catalyst in
dichloromethane as solvent, herein we report an alternate method
for their synthesis without any catalyst. In the present protocol,
THF was used as solvent and NBS was used as the bromide
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resulting in increased reigioselectivity but the yields dropped due
to the formation of complex side products.
oxide and cyclohexene sulfide gave the corresponding bromo
esters and thioesters exclusively with trans geometry. Ring
opening of thiiranes was very facile and gave quantitative yield of
the corresponding bromo substituted thioesters.
Table 6. Effect of Lewis acids on the regioisomeric ratio of ring opening of
styrene episulfide.[a]
Experimental Section
General Procedures. All reactions were carried out in oven-dried
apparatus using dry solvents under anhydrous conditions, unless
otherwise noted. Reaction mixtures were stirred magnetically unless
otherwise stated. Commercial grade solvents were distilled and dried
according to literature procedures (“Purification of laboratory chemicals”,
3rd Ed., D. D. Perrin, W. L. F. Armarego, Pergamon Press, Oxford, 1988).
Analytical TLC was performed on commercial plates coated with silica gel
GF254 (0.25 mm). Silica gel (230 - 400 mesh) was used for column
chromatography. Melting points determined are uncorrected. Yields refer
to chromatographically and spectroscopically (1H NMR) homogeneous
materials, unless otherwise stated. NMR spectra were recorded on 300 or
400 MHz instruments and calibrated using residual undeuterated solvent
as an internal reference. The following abbreviations explain the
multiplicity s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br
= broad. IR spectra were recorded on a FT-IR spectrometer. High-
resolution mass spectra (HR-MS) were recorded on a Micromass Q-TOF
mass spectrometer.
Catalysts
Regioisomeric ratio
Yield (%)
10d : 11d
No catalyst
2 : 1
2 : 1
4 : 1
3 : 1
7 : 1
60
55
50
40
25
LiClO4 (0.2equiv)
LiClO4 (1.0equiv)
LiClO4 (2.0equiv)
BF3.OEt2 (1.0equiv)
[a] Reaction was carried out with various carboxylic acids (1 mmol), PPh3 (1.1
mmol), NBS (1.1 mmol), styrene episulfide (1.1 mmol) & corresponding Lewis
acids in dichloromethane (3mL) as solvent.
Later we extended the same protocol for ring opening of
cyclohexene sulfide and the corresponding trans-bromo
substituted thioesters were obtained in almost quantitative yields.
The reactions were generally fast and completed within 10 mins
(Table 7).
General procedure for the formation of 1,2 bromoesters: N-
bromosuccinimide (0.195g, 1.1 mmol) was added to a well stirred solution
of the corresponding acid (1 mmol) and PPh3 (0.288g, 1.1 mmol) in CH2Cl2
(3mL). After 2 minutes the corresponding epoxide (1.1 mmol) was added
to it. Completion of the reaction was monitored through TLC. The crude
mixture was then purified by column chromatography. Compounds 4a, 6a
4g,[23] 4k,[24] 6a,[25] 6d,[23] & 6e[26] are reported are reported.
Table 7. Reaction of cyclohexene sulfide with various carboxylic acids.[a]
2-bromo-2-phenylethyl 4-chlorobenzoate (4b): Yield: 62% (210.5 mg); IR
(Neat) 1724, 1267, 1092 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.92 (d, J =
8.7 Hz, 2H), 7.48 – 7.33 (m, 7H), 5.25 (t, J = 7.2 Hz, 1H), 4.78 (m, 2H); 13
C
NMR (75 MHz, CDCl3): δ 165.0, 139.8, 137.9, 131.0, 129.1, 128.9, 128.8,
127.9, 127.8, 68.0, 49.8; HR - MS m/z: calcd for C15H12BrClO2Na+
[M+Na+]: 360.9607; found: 360.9600.
2-bromo-2-phenylethyl 4-methylbenzoate (4c): Yield: 76% (242.6 mg); IR
(Neat): 1720, 1269, 1105 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.87 (d, J =
8.1 Hz, 2H), 7.48 – 7.45 (m, 2H), 7.39 – 7.25 (m, 3H), 7.21 (d, J = 7.5 Hz,
2H), 5.26 (t, J = 7.5 Hz, 1H), 4.77 (m, 2H), 2.39 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 165.9, 144.0, 138.1, 129.7, 129.1, 128.9, 128.8, 127.8, 126.8,
67.7, 50.1, 12.6; HR - MS m/z: calcd for C16H15BrO2Na+ [M+Na+]:
341.0153; found: 341.0143.
[a] Reaction was carried out with various carboxylic acids (1 mmol), PPh3 (1.1
mmol), NBS (1.1 mmol), cyclohexene oxide (1.1 mmol) in dichloromethane
(3mL) as solvent
2-bromo-2-phenylethyl 3-methoxybenzoate (4d): Yield: 60% (201.1 mg);
IR (Neat): 1724, 2919, 1274 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.59 –
7.07 (m, 9H), 5.25 (t, J = 7.5 Hz, 1H), 4.78 (m, 2H), 3.80 (s, 3H); 13C NMR
(75 MHz, CDCl3): δ 165.7, 159.5, 138.1, 130.8, 129.4, 129.0, 128.8, 127.8,
122.1, 119.8, 114.1, 67.9, 55.3, 49.9; HR
- MS m/z: calcd for
Conclusions
C16H15BrO3Na+ [M+Na+]: 357.0102; found: 357.0084.
In conclusion, a variety of bromo substituted esters and thioesters
have been synthesized using acyloxyphosphonium salt as a
common intermediate, thereby showing the synthetic utility of this
protocol. The reactions were generally regioselective, especially
styrene oxide, which showed complete regioselectivity with the
ring opening occurring at the benzylic position. Both cyclohexene
2-bromo-2-phenylethyl 4-nitrobenzoate (4e): yellow solid; Yield: 60%
(210.1 mg); m. p: 95 ˚C; IR (Neat): 1730, 1528, 1268 cm-1; 1H NMR (300
MHz, CDCl3): δ 8.26 (d, J = 9.0 Hz, 2H), 8.14 (d, J = 9.0 Hz, 2H), 7.49 –
7.34 (m, 5H), 5.28 (t, J = 7.5 Hz, 1H), 4.83 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 163.9, 150.6, 137.6, 134.8, 130.8, 129.2, 128.9, 127.7, 123.5,
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68.5, 49.5; Anal. Calcd for C15H12BrNO4: C, 51.45; H, 3.45; N,4.00; Found:
C, 51.32; H, 3.42; N, 4.09.
4-bromobutyl 3-nitrobenzoate (8e): Yield: 77% (232.7 mg); IR (Neat): 1725,
1533, 1350 cm-1; 1H NMR (300 MHz, CDCl3, 25°C): δ 8.55 (t, J = 1.8 Hz,
1H), 8.45 – 8.36 (m, 2H), 7.68 ( t, 8.1 Hz, 1H), 4.43 (t, J = 6.0 Hz, 2H), 3.50
(t, J = 6.3 Hz, 2H), 2.11 – 1.95 (m, 4H); 13C NMR (75 MHz, CDCl3, 25°C):
δ 164.4, 148.2, 135.2, 131.9, 129.6, 127.4, 124.5, 64.9, 32.9, 29.2, 27.3;
HR - MS m/z: calcd for C11H12BrNO4Na+ [M+Na+]: 323.9847; found:
323.9846.
2-bromo-2-phenylethyl 2-phenylacetate (4f): Yield: 78% (249.0 mg); IR
(Neat): 1740, 1142cm-1; 1H NMR (300 MHz, CDCl3): δ 7.26 (m, 10H), 5.09
(t, J = 7.2 Hz, 1H), 4.58 (m, 2H), 3.59 (s, 2H); 13C NMR (75 MHz, CDCl3):
δ 170.7, 137.9, 133.4, 129.2, 128.8, 128.7,128.5, 127.7, 127.1, 67.6, 49.6,
41.0; HR - MS m/z: calcd for C16H15BrO2Na+ [M+Na+]: 341.0153; found:
341.0182.
4-bromobutyl 3,5-dinitrobenzoate (8f): Yield: 85% (295.0 mg); IR (Neat):
1731, 1544, 1346, 1282 cm-1; 1H NMR (300 MHz, CDCl3, 25°C): δ 9.24 (t,
J = 2.1 Hz, 1H), 9.16 (d, J = 2.1 Hz, 2H), 4.15 (t, J= 6 Hz, 2H), 3.1 (t, J =
5.9 Hz, 2H), 2.05 (m, 4H); 13C NMR (75 MHz, CDCl3, 25°C): δ 162.4, 148.6,
133.8, 129.4, 122.4, 66.0, 32.7, 29.0, 27.2; Anal. Calcd for C11H11BrN2O6:
C, 38.06; H, 3.19; N,8.07; Found: C, 37.81; H, 3.29; N, 8.24.
2-bromo-2-phenylethyl 2-oxo-2-phenylacetate (4h): Yield: 80% (266.5
mg); IR (Neat): 1744, 1689, 1194, 1173 cm-1; 1H NMR (300 MHz, CDCl3):
δ7.81 – 7.77 (m, 2H), 7.65 – 7.60 (m, 1H), 7.49 – 7.36 (m, 7H), 5.24 (t, J
= 7.5 Hz, 1H), 4.89 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 185.6, 162.9,
137.3, 135.0, 132.0, 130.0, 129.3, 129.0, 128.9, 127.9, 68.2, 48.7; HR -
MS m/z: calcd for C16H13BrO3Na+ [M+Na+]: 354.9946; found: 354.9926.
General procedure for the formation of 1,2 bromothioesters: N-
bromosuccinimide (0.195g, 1.1 mmol) was added to a well stirred solution
of the corresponding acid (1 mmol) and PPh3 (0.288g, 1.1 mmol) in CH2Cl2
(3mL). After 2 minutes the corresponding thiirane (1.1 mmol) was added
to it. Completion of the reaction was monitored through TLC. The crude
mixture was then purified by column chromatography. Regioisomers 10 &
11 were inseparable.
2-bromo-2-phenylethyl 4-methoxybenzoate (4i): Yield: 75% (251.4 mg); IR
(Neat): 1715, 1605, 1258 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.94 (d, J =
6.9 Hz, 2H), 7.48 – 7.32 (m, 5H), 6.89 (d, J = 6.9 Hz, 2H), 5.26 (t, J = 7.2
Hz, 1H), 4.76 (m, 2H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 165.6,
163.6, 138.1, 131.7, 128.9, 128.8, 127.8, 121.8, 113.6, 67.6, 55.4, 50.2;
HR - MS m/z: calcd for C16H15BrO3Na+ [M+Na+]: 357.0102; found:
357.0105.
2-bromo-2-phenylethyl benzothioate (10a)
& 2-bromo-1-phenylethyl
benzothioate (11a): (80 : 20). Yield: 80% (257.0 mg); IR (Neat) 1666, 1582,
1208, 903 cm-1; 1H NMR (300 MHz, CDCl3, 25°C): δ 7.94 - 7.89 (m, 2H),
7.57 – 7.52 (m, 1H), 7.45 – 7.30 (m, 10H), 5.12 (dd, J1 = 7.2 Hz, J2 = 9.0
Hz, 1H), 5.06 (dd, J1 = 4.8 Hz, J2 = 9.9 Hz, 0.23H), 4.03 – 3.93 (m, 1.3H),
3.85 – 3.77 (m, 1.3H); 13C NMR (75 MHz, CDCl3, 25°C): 190.4, 140.1,
136.5, 133.7, 128.7, 128.6, 128.3, 128.1, 127.8, 127.6, 127.3, 51.8, 48.8,
37.5, 34.7; Anal. Calcd for C15H13BrOS: C, 56.08; H, 4.08; S, 9.98 Found:
C, 55.78; H, 4.11; S, 10.40.
2-bromo-2-phenylethyl 2-(4-nitrophenyl)acetate (4j): Yield: 63% (229.4
mg); IR (Neat) 1740, 1519, 1347 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.10
(d, J = 8.7 Hz, 2H), 7.32 – 7.30 (m, 7H), 5.08 (t, J = 7.5 Hz, 1H), 4.60 (m,
2H), 3.69 (s, 2H); 13C NMR (75 MHz, CDCl3): δ 169.3, 147.1, 140.6, 137.6,
130.2, 129.0, 128.8, 127.7, 123.6, 67.7, 49.2, 40.7; Anal. Calcd for
C16H14BrNO4: C, 52.77; H, 3.87; N,3.850; Found: C, 52.97; H, 4.23; N, 3.90.
trans-2-bromocyclohexyl 4-methylbenzoate (6b): Yield: 48% (142.6 mg);
IR (Neat) 1722, 1271, 1100 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.96 (d, J
= 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 5.11 (dt, J1 = 4.2 Hz, J2 = 9.0 Hz,
1H), 4.15 (dt, J1 = 4.2 Hz, J2 = 10.2 Hz, 1H), 2.42 (s, 3H), 2.40 (m, 1H),
2.27 (m, 1H), 1.89 (m, 3H), 1.49 (m, 3H); 13C NMR (75 MHz, CDCl3): δ
165.7, 143.7, 129.7, 129.1, 127.5, 76.1, 52.7, 35.5, 31.1, 25.4, 23.3, 21.7;
HR - MS m/z: calcd for C14H17BrO2Na+ [M+Na+]: 319.0307; found:
319.0307.
2-bromo-2-phenylethyl 4-methylbenzothioate (10b)
&
2-bromo-1-
phenylethyl 4-methylbenzothioate (11b): (67 : 33). Yield: 75% (251.4 mg);
IR (Neat) 1661, 1605, 1207, 1175 cm-1; 1H NMR (300 MHz, CDCl3, 25°C):
δ 7.82 - 7.79 (m, 1H), 7.70 – 7.64 (m, 1H), 7.55 – 7.31 (m, 5H), 7.25 – 7.20
(m, 2H), 5.12 (dd, J1 = 6.9 Hz, J2 = 8.1 Hz, 0.6H), 5.05 (dd, J1 = 5.1 Hz, J2
= 10.2 Hz, 0.35H), 4.02 – 3.94 (m, 1H), 3.85 – 3.76 (m, 1H) 2.34 (s, 3H);
13C NMR (75 MHz, CDCl3, 25°C): 190.0, 144.6, 144.2, 132.1, 129.3, 128.8,
128.2, 128.1, 127.6, 127.4, 51.8, 48.6, 37.5, 34.8, 21.6; Anal. Calcd for
C16H15BrOS: C, 57.32; H, 4.51; S, 9.56 Found: C, 57.61; H, 4.62; S, 9.73.
trans-2-bromocyclohexyl 3-nitrobenzoate (6c): Yield: 40% (131.3 mg); IR
(Neat) 1719, 1265 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.88 (t, J = 1.5 Hz,
1H), 8.46 – 8.39 (m, 2H), 7.68 (t, J = 7.8 Hz, 1H), 5.17 (m, 1H), 4.16 (m,
1H), 2.37 (m, 2H), 1.91 (m, 4H), 1.48 (m, 2H); 13C NMR (75 MHz, CDCl3):
δ 163.5, 148.5, 135.5, 131.9, 129.6, 127.5, 124.7, 77.7, 52.5, 35.8, 31.5,
25.7, 23.5; HR - MS m/z: calcd for C13H14BrNO4Na+ [M+Na+]: 350.0002;
found: 350.0003.
2-bromo-2-phenylethyl 2-phenylethanethioate (10c)
&
2-bromo-1-
phenylethyl 2-phenylethanethioate (11c): (85 : 15). Yield: 70% (234.7 mg);
IR (Neat) 1668, 1494, 1021 cm-1; 1H NMR (400 MHz, CDCl3, 25°C): δ 7.40
- 7.19 (m, 12H), 4.97 (dd, J1 = 6.8 Hz, J2 = 8.8 Hz, 1H), 4.81 (dd, J1 = 4.8
Hz, J2 = 10.0 Hz, 0.18H), 3.83 – 3.73 (m, 3.2H), 3.68 (dd, J1 = 4.0 Hz, J2 =
6.0 Hz, 0.4H), 3.62 (dd, J1 = 8.8 Hz, J2 = 13.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3, 25°C): 195.9, 139.8, 133.1, 129.6, 129.4, 129.3, 128.8, 128.7,
128.6, 128.5, 128.4, 128.3, 128.0, 127.5, 126.6, 51.5, 50.3, 50.2, 48.9,
47.7, 34.6; Anal. Calcd for C16H15BrOS: C, 57.32; H, 4.51; S, 9.56 Found:
C, 57.70; H, 4.72; S, 9.68.
General procedure for the formation of 1,4 bromoesters: To a well
stirred solution of carboxylic acid (1 mmol) and PPh3 (0.288g, 1.1 mmol)
in THF (3mL) was added N-bromosuccinimide (0.195g, 1.1mmol).
Completion of the reaction was monitored through TLC. The crude mixture
was then purified by column chromatography. Compounds 8a, 6a 8b,4f
8c,4f 8g,4f 8h,[27] 8i,4f 8j,[28]
&
8k[29] are reported.
2-bromo-2-phenylethyl 4-methoxybenzothioate (10d)
&
2-bromo-1-
phenylethyl 4-methoxybenzothioate (11d): (67 : 33). Yield: 60% (210.7
1
mg); IR (Neat) 1658, 1603, 1509, 1257 cm-1; H NMR (300 MHz, CDCl3,
4-bromobutyl 3-methoxybenzoate (8d): Yield: 85% (244.1 mg); IR (Neat):
1718, 1600, 1587, 1280 cm-1; 1H NMR (300 MHz, CDCl3, 25°C): δ 7.65 –
7.55 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 7.12 – 7.09 (m, 1H), 4.35 (t, J = 6.0
Hz, 2H), 3.85 (s, 3H), 3.48 (t, J = 6.5 Hz, 2H), 1.99 (m, 4H); 13C NMR (75
MHz, CDCl3, 25°C): δ 166.3, 159.5, 131.4, 129.3, 121.8, 119.3, 114.0, 64.0,
55.4, 33.1, 29.3, 27.3; HR - MS m/z: calcd for C12H15BrO3Na+ [M+Na+]:
309.0102; found: 309.0102.
25°C): δ 7.93 - 7.88 (m, 2H), 7.45 – 7.26 (m, 5H), 6.93 – 6.89 (m, 2H), 5.12
(dd, J1 = 6.9 Hz, J2 = 8.7 Hz, 0.67H), 5.04 (dd, J1 = 5.1 Hz, J2 = 10.2 Hz,
0.33H), 4.02 – 3.94 (m, 1.H), 3.86 (d, 3H) 3.83 – 3.76 (m, 1H); 13C NMR
(100 MHz, CDCl3, 25°C): 188.8, 188.3, 164.0, 163.9, 140.1, 138.0, 132.2,
132.1, 129.5, 129.2, 128.7, 128.2, 128.0, 127.5, 113.8, 113.7, 55.4, 52.0,
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10.1002/ejoc.201801225
European Journal of Organic Chemistry
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48.5, 37.3, 34.9; Anal. Calcd for C16H15BrO2S: C, 54.71; H, 4.30; S, 9.11
Found: C, 54.98; H, 4.46; S, 9.25.
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trans-2-bromocyclohexyl benzothioate (13a): Yield: 99% (296.2 mg); IR
(Neat): 1663, 1445, 1204 cm-1; 1H NMR (300 MHz, CDCl3, 25°C): δ 7.98 –
7.60 (m, 2H), 7.60 – 7.55 (m, 1H), 7.48 – 7.42 (m, 2H), 4.34 (dt, J1 = 3.6
Hz, J2 = 6.9 Hz, 1H), 4.14 – 4.08 (m, 1H), 2.47 – 2.27 (m, 2H), 2.04 – 1.94
(m, 1H), 1.89 – 1.43 (m,5H); 13C NMR (75 MHz, CDCl3, 25°C): δ 190.2,
136.9, 133.4, 128.6, 127.3, 54.5, 48.5, 34.4, 30.2, 24.1, 23.5; HR - MS m/z:
calcd for C13H15BrOSNa+ [M+Na+]: 320.9923; found: 320.9908.
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trans-2-bromocyclohexyl 4-methylbenzothioate (13b): Yield: 99% (310
mg); IR (Neat): 1661, 1607, 1446, 1206, 1175 cm-1; 1H NMR (400 MHz,
CDCl3, 25°C): δ 7.86 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 4.37 –
4.33 (m, 1H), 4.13 – 4.08 (m, 1H), 2.44 – 2.39 (m, 4H), 2.34 – 2.28 (m, 1H),
2.01 – 1.96 (m, 1H), 1.84 – 1.81 (m, 1H), 1.71 – 1.62 (m, 3H), 1.50 – 1.48
(m, 1H); 13C NMR (100 MHz, CDCl3, 25°C): δ 189.9, 144.4, 134.3, 129.3,
127.4, 54.6, 48.1, 34.3, 30.0, 24.0, 23.3, 21.7; HR - MS m/z: calcd for
C14H17BrOSNa+ [M+Na+]: 335.0081; found: 335.0093.
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trans-2-bromocyclohexyl 4-nitrobenzothioate (13c): Yield: 87% (299.5
mg); IR (Neat): 1660, 1605, 1525, 1350 cm-1; 1H NMR (300 MHz, CDCl3,
25°C): δ 8.31 (d, J = 8.7 Hz, 2H), 8.12 (d, J = 8.7 Hz, 2H), 4.30 (dt, J1 = 3.6
Hz, J2 = 7.5 Hz, 1H), 4.16 – 4.10 (m, 1H), 2.47 – 2.30 (m, 2H), 2.07 – 1.96
(m, 1H), 1.89 – 1.46 (m, 5H); 13C NMR (75 MHz, CDCl3, 25°C): δ 188.8,
150.6, 141.4, 128.3, 123.8, 53.7, 49.5, 35.0, 30.6, 24.2, 23.6; Anal. Calcd
for C13H14BrNO3S: C, 45.36; H, 4.10; S, 9.32; N, 4.07 Found: C, 45.74; H,
4.30; S, 9.74; N, 4.23.
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trans-2-bromocyclohexyl 2-phenylethanethioate (13d): Yield: 96% (300.7
mg); IR (Neat): 1692, 1495, 1445, 1188, 999, 980 cm-1; 1H NMR (300 MHz,
CDCl3, 25°C): δ 7.36 – 7.25 (m, 5H), 4.20 – 4.17 (m, 1H), 3.89 – 3.82 (m,
3H), 2.31 – 2.17 (m, 2H), 1.96 – 1.71 (m, 2H), 1.59 – 1.38 (m, 4H); 13C
NMR (75 MHz, CDCl3, 25°C): δ 195.5, 133.3, 129.5, 128.6, 127.4, 54.3,
50.5, 48.6, 34.4, 30.0, 24.0, 23.4, 21.7; HR - MS m/z: calcd for
C14H17BrOSNa+ [M+Na+]: 335.0081; found: 335.0071.
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trans-2-bromocyclohexyl) (E)-3-phenylprop-2-enethioate (13e): Yield:
86% (279.7 mg); IR (Neat): 1672, 1654, 1615, 1447, 1039 cm-1; 1H NMR
(300 MHz, CDCl3, 25°C): δ 7.62 (d, J = 15.9 Hz, 1H), 7.55 – 7.51 (m, 2H),
7.40 – 7.38 (m, 3H), 6.68 (d, J = 15.9 Hz, 1H), 4.29 (dt, J1 = 3.4 Hz, J2 =
6.9 Hz, 1H), 4.06 – 4.00 (m, 1H), 2.43 – 2.24 (m, 2H), 2.02 – 1.92 (m, 1H),
1.87 – 1.74 (m, 1H), 1.70– 1.58 (m, 3H), 1.52 – 1.44 (m, 1H); 13C NMR (75
MHz, CDCl3, 25°C): δ 188.0, 140.9, 134.0, 130.6, 128.9, 128.4, 124.6, 54.5,
48.3, 34.5, 30.2, 24.1, 23.5; Anal. Calcd for C15H17BrOS: C, 55.39; H, 5.27;
S, 9.86 Found: C, 55.80; H, 4.90; S, 9.32.
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Keywords: acylation • multicomponent reactions • synthetic
methods • functionalized esters • Thioesters
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Entry for the Table of Contents (Please choose one layout)
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Multicomponent reaction*
Purushothaman Gopinatha,b,* Srinivasan
Chandrasekarana
Page No. – Page No.
A sequential one-pot synthesis of
functionalized esters and thioesters
via ring opening-acylation of cyclic
ethers and thioethers.
Functionalized esters and thioesters were synthesized from carboxylic acids and
cyclic ethers/thioethers via acyloxyphosphonium salts as key intermediates. The
resulting esters were obtained in high yields and with complete regioselectivity (for
styrene oxide). On the other hand thioesters were obtained in good yields but with
moderate regioselectivity (for styrene episulfide).
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