A facile and efficient method for synthesis of β-iodocarboxylates from terminal epoxides

Article abstract of DOI:10.1016/j.tetlet.2019.151353

A facile and efficient method has been developed for synthesis of β-iodocarboxylates in the presences of Ph₃P/I₂. Starting from epoxides, a series of β-iodocarboxylate compounds can be directly obtained in toluene media with excellent yields. Moreover, the method was successfully applied for the late-stage modification of natural products, such as isosteviol and vincamine derivatives, achieving the corresponding β-iodocarboxylates in good yields.

Full text of DOI:10.1016/j.tetlet.2019.151353

Journal Pre-proofs
A facile and efficient method for synthesis of β-iodocarboxylates from terminal
epoxides
Ye-Fu Zhu, Bo-Le Wei, Wen-Qiong Wang, Li-Jiang Xuan
PII:
S0040-4039(19)31144-X
https://doi.org/10.1016/j.tetlet.2019.151353
TETL 151353
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 August 2019
17 October 2019
1 November 2019
Please cite this article as: Zhu, Y-F., Wei, B-L., Wang, W-Q., Xuan, L-J., A facile and efficient method for synthesis
of β-iodocarboxylates from terminal epoxides, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.151353
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will
undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing
this version to give early visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.

A facile and efficient method for synthesis of
β-iodocarboxylates from terminal epoxides
Ye-Fu Zhua,b, Bo-Le Weia,b, Wen-Qiong Wanga and Li-Jiang Xuana,*
Affiliation
aState Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 501 Haike Road, Zhangjiang
Hi-Tech Park, Shanghai 201203, PR China.
bUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road,
Beijing 100049, PR China.
*Corresponding to: Li-Jiang Xuan; Tel: +86-21-20231968, Fax:
+86-21-20231968, E-mail address: ljxuan@simm.ac.cn.

Abstract
A facile and efficient method has been developed for synthesis of
β-iodocarboxylates in the presences of Ph3P/I2. Starting from epoxides, a series of
β-iodocarboxylate compounds can be directly obtained in toluene media with
excellent yields. Moreover, the method was successfully applied for the late-stage
modification of natural products, such as isosteviol and vincamine derivatives,
achieving the corresponding β-iodocarboxylates in good yields.
Key words: epoxides, Ph3P, I2, β-iodocarboxylates
Introduction
Epoxides are a class of compounds of growing importance, which have extensive
application in many fields, such as medicine [1], pesticides [2], food [3], dyestuff [4]
and plastic [3b, 5]. They are used as versatile building blocks in organic synthesis due
to their advantages of easy preparation, scale-up feasibility and tolerance to a broad
range of conditions[6]. Thus, a wide spectrum of reactions using epoxides have been
well-established, such as ring opening reaction [7], cycloaddition reaction [8],
polymerzation reaction [9], oxidation reaction and reduction reaction [10].
The synthetic significance of epoxides stems largely from their facile and
stereospecific nucleophilic ring opening to furnish valuable 1, 2-difunctional
compounds (Scheme 1) [11]. These versatile synthetic building blocks include but are
not limited to 1,2-diols [12], β-amino alcohols [7b, 11c, 13], β-alkoxy alcohols [12,
14], β-acetoxy alcohols [12, 14f, 15], β-halohydrins [16] and halohydrin esters [17].
Although numerous synthesis of chlorocarboxylates [18] and bromocarboxylate
[17] esters have been reported by the nucleophilic ring opening of epoxdides, little
work was focused on the selective ring opening to afford corresponding
β-iodocarboxylates. The only example directly from epoxides, as far as we know, is
the preparation of acyliodine, a dangerous and inconvenient reagent with low yield
[19]. Considering the great importance of β-iodocarboxylates for the synthesis of

lipids [20] and biologically active compounds [21], a prompt method to this building
block is extremely needed. Inspired by previous work [17,18b], we herein report an
immediate epoxide ring opening reaction promoted by Ph3P/I2 with good yields and
high selectivity.
HO
R1
O R
HO
R1
OH
O
O
HO
R1
NH2
HO
R1
O
R1
O
HO
R1
X
O
X
R
R1
Scheme 1. Common strategies for the synthesis of difunctional products from epoxides.
Triphenylphosphine (Ph3P) has been used as a versatile reagent in a number of
functional group transformations due to its inexpensiveness, affordability, and
reactivity. Considering the special properties of Ph3P-I2 intermediate, we assumed that
phosphorous atom may have an important influence on this ring opening reaction. To
validate the feasibility of this hypothesis, we have initially investigated the ring
opening reaction by using compound 1 and iodine as the substrate, Ph3P as ligand,
formic acid as carbon resource. After stirring for 15 min at 80 °C in CHCl3, the
expected product 1a was obtained in 78% yield (Table 1, entry 1). This result clearly
indicated that the synthetic route of iodo-formate was reasonable and feasible. In an
attempt to improve the yield of 1a, the model reaction was carried out under various
conditions (Table 1).
Preliminary experiments suggested that solvent effect had a significant impact on
the yield of 1a. Hence, various solvents were applied to the ring opening reaction.
According to the results, toluene gave the best isolated yield at 82% (Table 1, entries
1-9). Further adjustment of temperature exhibited dramatic drop in the yields with
decrease of heat (Table 1, entries 3, 9-11). After the investigation of the other factors,
including the amount of Ph3P, iodine and formic acid (see ESI), the optimal

conditions were finally established as heating the epoxide with slightly extra amount
of Ph3P, I2, and formic acid (105 mol%) in toluene for 15 min.
Table 1. Optimization of the reaction conditionsa
O
O
O
Ph3P (1.2 equiv.)
O
I
2 (1.2 equiv.)
O
I
O
+
Solvent
Temperature
15min
HO
H
Cl
Cl
1b
Formic acid
1a
Entry
Solvent
Temp (°C)
Yield[c] (%)
1
2
CHCl3
THF
80
80
80
80
80
80
80
80
60
40
20
78
ND[d]
98(82)
91
3
Toluene
4
1,4-dioxane
Acetone
CH3CN
DMF
5
34
6
93
7
87
8
DCM
Tol
95
9
94
10
11
Tol
71
Tol
52
[a] Reaction conditions: Epoxides 1 (1 mmol), Ph3P (1.2 mmol), I2 (1.2 mmol), formic acid (4 mmol),
toluene (2 mL), all reactions were carried out with solvent (2 mL) in a 35 mL sealed tube (total volume
50 mL) for 15 min. [b] Substituted epoxide 1 were made by epichlorohydrin (meso), K2CO3 and
4-chlorophenol. [c] Yields were determined by LC-MS, the number in parentheses refers to the yield of
isolated 1a. [d] Not detected.
Table 2. Reactions of substituted epoxides with formic acid.
O
O
O
Standard conditions[a]
O
Cl
O
OH
O
I
R
R
R
K2CO3
Acetone
Reflux
overnight
Epoxides
1-13
1a - 13a
Entry
Epoxides[b](R)
Products
Yield[c](%)
1(4-Cl)
2(4-H)
1
2
1a
2a
82
81
85
80
80
86
85
80
78
81
82
3(4-NO2)
4(4-OMe)
5(4-tBu)
6(2-Cl)
3
3a
4
4a
5
5a
6
6a
7(2-Me)
8(3,4-OMe)
9(3-OMe)
10(2-iPr)
11(4-Ph)
7
7a
8
8a
9
9a
10
11
10a
11a
12
12
12a
75
O
O

O
O
13
13
13a
77
[a] Standard conditions: Epoxides (1 mmol), Ph3P (1.05 mmol), I2 (1.05 mmol), formic acid (1.05 mmol),
toluene (2 mL), 80 °C, 15min. [b] Substituted epoxides in this table were made by epichlorohydrin
(meso), K2CO3 and the corresponding phenol. [c] Isolated yields.
We next studied the scope of this ring opening reaction by using a series of
differently substituted epoxides under the selected conditions [22]. As shown in Table
2, ortho, meta and para substituted aromatics were chosen to further explore the steric
hindrance and electronic effects. The desired products 1a-10a were obtained in good
yields ranging from 78% to 86%, which indicated that these factors have low
influence on the reaction. Naphthol and biphenyl derivatives were further used to
extend the scope of the reaction, with yields of 75% - 82% (Table 2, entries 11-13).
Table 3. Reactions of different carbonxylic acids with 1.
O
O
R
I
O
Ph3P (1.05equiv.)
O
I
2 (1.05equiv.)
O
O
+
Toluene
80 °C
HO
R
Cl
Cl
15-40min
Acid
1a-1k
1
O
O
O
O
O
O
O
I
O
I
O
I
Cl
Cl
Cl
1a
1b
1c
(75%)
(86%)
(82%)
O
O
O
I
O
O
O
O
O
I
I
O
Cl
Cl
Cl
1d
1e
1f
(75%)
(73%)
(74%)
O
O
O
O
O
O
O
O
O
I
I
I
Cl
Cl
Cl
1g
1hb
1ib
(74%)
(80%)
(78%)
H
H
H
O
O
O
O
O
I
O
Cl
I
Cl
1jb
1kb (72%)
(83%)
[a] Reaction conditions: Epoxides 1 (1 mmol), Ph3P (1.05 mmol), I2 (1.05 mmol), corresponding acid
(1.05 mmol), toluene (2 mL) in sealed tube, 80 °C, 15min. [b] The reaction proceeded for 40min. [c]
Isolated yields.

To further broaden the scope of the reaction, serials of carboxylic acids were also
examined as the resource of acyl groups. Both aromatic and aliphatic acids proceeded
smoothly to give the corresponding products in good to excellent yields (72% - 86%,
Table 3). Even, to our delight, the steric pivalic acid and 1-adamantanecarboxylic acid
also produced the β-iodocarboxylates 1g and 1k with 74% and 72% yields,
respectively. Since the concept of late-stage diversification, especially on natural
products, by predictable and efficient transformations is absolutely crucial for
fine-tuning the biological activity [23], we therefore examined the robustness of this
transformation on certain natural products. With extended reaction time, the epoxide
ring opening reaction was successfully implemented on isosteviol and vincamine
though with moderate yields (Scheme 2). The tolerance to several sensitive functional
groups has indicated its potential application in the late-stage diversification of natural
products and medicinal substrates and some drug molecules that containing
carboxylic acid can be also applied in this reaction for prodrug modification.
Scheme 2. Reactions of 1 with natural products.
O
O
O
Ph3P (1.05equiv.)
O
H
I
2 (1.05equiv.)
O
O
+
Toluene
80 °C
4h
Cl
H
O
O
HO
I
Cl
l
1
1l
(46%)
H
N
H
N
N
Ph3P (1.05equiv.)
O
Cl
O
N
O
I
2 (1.05equiv.)
O
+
O
Toluene
80 °C
6h
O
Cl
OH
I
m
1m
(55%)
1
To reveal the stereoselectivity and mechanism of this ring opening reaction, two
parallel reactions were carried out under the optimal conditions (Scheme 3).

Scheme 3. Reaction substrate expansion and mechanism speculation.
JHa-Hb = 9.4 Hz
Hb
Ph3P (1.05 equiv.)
I
Hb
O
I2 (1.05 equiv.)
O
Ha
Ph
+
Toluene
80 °C
O
Ha
HO
O
30 min
14a
14
I
Ph3P (1.05 equiv.)
O
O
OH
LAH
THF
H
O
I2 (1.05 equiv.)
+
Toluene
80 °C
30 min
ice bath
10 min
HO
O
16
15
15a
(R)-2-phenyloxirane
(S)-1-phenylethanol
Ph3P (1.05 equiv.)
O
I2 (1.05 equiv.)
I
O
Toluene
80 °C
30 min
+
HO
O
O
O
17
17a
O
I2
Ph
P
I
Ph
Ph
HCOOH
Ph
O
Ph
O
Ph
Ph
15
Ph
P
I
I
P
I
H
P
Ph
Ph
I
Ph
O
Ph
Ph
O
I
- H
a
c
b
O
Ph
Ph
Ph
Ph
Ph
Ph
O
Ph
O
Ph
O
P
O
Ph
P
Ph
O
P
P
+
Ph
O
O
I
O
Ph
I
O
O
Ph
O
Ph
H
H
Ph
Ph
I
I
d
e
f
g
To be specific, 14a, prepared from cyclohexene oxide (14), was determined as trans
formation according to the coupling constant (J) between Ha and Hb and the yield of
this reaction is 52%. On the other hand, 15a, prepared from (R)-2-phenyloxirane
(65% yield), was reduced by LAH to resolve (S)-1-phenylethanol (16), the absolute
configuration of which was confirmed by optical rotational activity spectrum
according to the comparison with authentic substrates in database [24]. What’s more,
we used compound 17 as the epoxide to get the desired product 17a with 62% yield.
These results indicated the chiral center of alcohol that attached to the acyl group
maintained and the iodine nucleophilic attack happened on the other side of epoxides.
Based on these observations, a plausible mechanism for the formation of
β-iodoformate is proposed in Scheme 3. An initial reaction between Ph3P and iodine
provides triphenylphosphonium iodide as reactive species. Nucleophilic displacement
of these intermediates by the formic acid could afford b. Withdrawal of hydroiodic

acid leads to the generation of intermediate c, which next forms complex pair d
between the electron-deficient phorsphorus atom and the electron-rich oxygen atom.
The facial attack by iodine anion followed by trans-esterification finally delivers
β-iodocarboxylate (g) and triphenylphosphine oxide.
Conclusions
In conclusion, we have developed a straightforward and efficient procedure for the
synthesis of β-iodocarboxylates from the corresponding epoxides and acids via a ring
opening process with good to excellent yields. The procedures were successfully
applied in natural products isosteviol and vincamine diversificaiton to obtain
corresponding products. The mild conditions, short reaction time, and generality of
substrates would distinguish current transformation from the known synthesis of
halohydrin esters.
Conflict of interest
All of the authors have no conflicts of interest to declare.
Acknowledgements
We gratefully acknowledge grants from the State Key Laboratory of Drug Research
(SIMM1601ZZ-03), the National Natural Science Foundation of China (No.
81602995 and 21702219) and the Drug Innovation Major Project of China (Grant Nos.
2018ZX09735001-002-005).
References
[1]
(a) S. K. Das, Asian. J. Org. Chem. 6 (2017) 243-256;
(b) E. A. Larin, Y. M. Atroshchenko, ARKIVOC (2016) 217-226.
(a) P. Xiao, T. Mori, I. Kamei, R. Kondo, FEMS Microbiol. Lett. 314 (2011)
140-146;
[2]

(b) H. Glatt, R. Jung, F. Oesch, Mutat. Res. 111 (1983) 99-118.
(a) K. Lee, A. M. Herian, T. Richardson, J. Food. Protect. 47 (1984) 340-342;
(b) M. R. Philo, A. P. Damant, L. Castle, Food Addit. Contam. 14 (1997)
75-82;
[3]
[4]
(c) J. M. do Carmo, A. A. da Silva, J. Morgan, Y. X. Wang, S. Munusamy, J.
E. Hall, Nutr. Metab. Cardiovasc. Dis. 22 (2012) 598-604.
(a) J. E. Klee, W. H. Meyer, Polym. Bull. 31 (1993) 659-664;
(b) D. Ross, L. E. Locascio, Anal. Chem. 75 (2003) 1218-1220.
A. S. Wronski, T. V. Parry, J. Mater. Sci. 17 (1982) 2047-2055.
(a) R. E. Parker, N. S. Isaacs, Chem. Rev. 59 (1959) 737-799;
(b) J. G. Smith, Synthesis-Stuttgart 8 (1984) 629-656;
(c) A. P. S. S. Murphree, ARKIVOC (2005) 6-33;
[5]
[6]
(d) H. Lin, J. Y. Liu, H. B. Wang, A. A. Q. Ahmed, Z. L. Wu, J. Mol. Catal.
B-Enzym 72 (2011) 77-89.
[7]
[8]
[9]
(a) I. Paterson, D. J. Berrisford, Angew. Chem. Int. Ed. 31 (1992) 1179-1180;
(b) D. M. Hodgson, A. R. Gibbs, G. P. Lee, Tetrahedron 52 (1996)
14361-14384;
(c) J. A. Ciaccio, M. Smrtka, W. A. Maio, D. Rucando, Tetrahedron Lett. 45
(2004) 7201-7204.
(a) M. Tu, R. J. Davis, J. Catal. 199 (2001) 85-91;
(b) A. Decortes, A. M. Castilla, A. W. Kleij, Angew. Chem. Int. Ed. Engl. 49
(2010) 9822-9837;
(c) F. Castro-Gomez, G. Salassa, A. W. Kleij, C. Bo, Chemistry (Easton) 19
(2013) 6289-6298.
(a) T. Sakai, N. Kihara, T. Endo, Macromolecules 28 (1995) 4701-4706;
(b) R. M. Thomas, P. C. Widger, S. M. Ahmed, R. C. Jeske, W. Hirahata, E.
B. Lobkovsky, G. W. Coates, J. Am. Chem. Soc. 132 (2010) 16520-16525;
(c) D. J. Darensbourg, A. D. Yeung, Polym. Chem. 5 (2014) 3949-3962.
[10] (a) E. L. Eliel, M. N. Rerick, J. Am. Chem. Soc. 82 (1960) 1362-1367;

(b) T. V. Rajanbabu, W. A. Nugent, M. S. Beattie, J. Am. Chem. Soc. 112
(1990) 6408-6409.
[11] (a) E. N. Jacobsen, Acc. Chem. Res. 33 (2000) 421-431;
(b) H. Sharghi, M. A. Nasseri, K. Niknam, J. Org. Chem. 66 (2001)
7287-7293;
(c) T. Ollevier, G. Lavie-Compin, Tetrahedron Lett. 45 (2004) 49-52;
(d) Y. Sarazin, J.-F. Carpentier, Chem. Rev. 115 (2015) 3564-3614.
[12] M. Moghadam, S. Tangestaninejad, V. Mirkhani, I. Mohammadpoor-Baltork,
S. A. Taghavi, Catal. Commun. 8 (2007) 2087-2095.
[13] (a) R. A. Slater, W. Howson, G. T. Swayne, E. M. Taylor, D. R. Reavill, J.
Med. Chem. 31 (1988) 345-351;
(b) A. N. Boa, S. Clark, P. R. Hirst, R. Westwood, Tetrahedron Lett. 44
(2003) 9299-9302;
(c) K. Kopka, S. Wagner, B. Riemann, M. P. Law, C. Puke, S. K. Luthra, V.
W. Pike, T. Wichter, W. Schmitz, O. Schober, Bioorg. Med. Chem. 11 (2003)
3513-3527;
(d) A. K. Chakraborti, S. Rudrawar, A. Kondaskar, Org. Biomol. Chem. 2
(2004) 1277-1280;
(e) G. Huerta, G. Contreras‐Ordoñez, C. Alvarez‐Toledano, V. Santes, E.
Gómez, R. A. Toscano, Synth. Commun. 35 (2004) 2393-2406;
(f) F. Carree, R. Gil, J. Collin, Org. Lett. 7 (2005) 1023-1026;
(g) R. I. Kureshy, S. Singh, N. H. Khan, S. H. R. Abdi, S. Agrawal, R. V.
Jasra, Tetrahedron-Asym. 17 (2006) 1638-1643;
(h) K. Tanaka, S. Oda, M. Shiro, Chem. Commun. 44 (2008) 820-822;
(i) G. Moura-Letts, J. Lizza, Synthesis 49 (2016), 1231-1242;
(j) F. A. Saddique, A. F. Zahoor, S. Faiz, S. A. R. Naqvi, M. Usman, M.
Ahmad, Synth. Commun. 46 (2016) 831-868.
[14] (a) M. Lautens, K. Fagnou, M. Taylor, Org. Lett. 2 (2000), 1677-1679;
(b) J. Barluenga, H. Vazquez-Villa, A. Ballesteros, J. M. Gonzalez, Org. Lett.
4 (2002), 2817-2819;

(c) V. Mirkhani, S. Tangestaninejad, B. Yadollahi, L. Alipanah, Tetrahedron
59 (2003) 8213-8218;
(d) M. Moghadam, S. Tangestaninejad, V. Mirkhani, R. Shaibani, Tetrahedron
60 (2004), 6105-6111;
(e) R. V. Yarapathi, S. M. Reddy, S. Tammishetti, React. Funct. Polym. 64
(2005) 157-161;
(f) H. Firouzabadi, N. Iranpoor, A. A. Jafari, S. Makarem, J. Mol. Catal.
A-Chem. 250 (2006) 237-242.
[15] G. Salvador, T. Mercedes, O. Natalia, W. Richard, P. Margarita, Eur. J. Org.
Chem. 2004 (2010) 2160-2165.
[16] (a) G. Palumbo, C. Ferreri, R. Caputo, Tetrahedron Lett. 24 (1983),
1307-1310;
(b) R. Caputo, C. Ferreri, S. Noviello, G. Palumbo, Synthesis 17 (1986)
499-501.
[17] (a) N. Iranpoor, H. Firouzabadi, M. Chitsazi, A. Ali Jafari, Tetrahedron 58
(2002) 7037-7042;
(b) N. Iranpoor, H. Firouzabadi, A. Jamalian, Tetrahedron 62 (2006)
1823-1827.
[18] (a) N. Azizi, B. Mirmashhori, M. R. Saidi, Catal. Commun. 8 (2007)
2198-2203;
(b) L. P. Nielsen, C. P. Stevenson, D. G. Blackmond, E. N. Jacobsen, J. Am.
Chem. Soc. 126 (2004) 1360-1362.
[19] K. Nakano, S. Kodama, Y. Permana, K. Nozaki, Chem. Commun. 41 (2009)
6970-6972.
[20] (a) J. D. Schmitt, A. B. Nixon, A. Emilsson, L. W. Daniel, R. L. Wykle,
Chem. Phys. Lipids. 62 (1992) 263-268;
(b) J. R. Williams, J. C. Boehm, Steroids 60 (1995) 699-708.
[21] (a) K. G. Watson, Y. M. Fung, M. Gredley, G. J. Bird, W. R. Jackson, H.
Gountzos, B. R. Matthews, J. Chem. Soc. Chem. Commun. 15 (1990)
1018-1019;

(b) P. J. Walsh, Y. L. Bennani, K. B. Sharpless, Tetrahedron Lett. 34 (1993)
5545-5548;
(c) M. Kapoor, N. Anand, K. Ahmad, S. Koul, S. S. Chimni, S. C. Taneja, G.
N. Qazi, Tetrahedron Asymmetry 16 (2005) 717-725.
[22] (a) J. L. Wright, T. F. Gregory, T. G. Heffner, R. G. MacKenzie, T. A.
Pugsley, S. V. Meulen, L. D. Wise, Bioorg. Med. Chem. Lett. 7 (1997)
1377-1380;
(b) R. W. Marquis, A. M. Lago, J. F. Callahan, R. E. L. Trout, M. Gowen, E.
G. DelMar, B. C. Van Wagenen, S. Logan, S. Shimizu, J. Fox, E. F. Nemeth,
Z. Yang, T. Roethke, B. R. Smith, K. W. Ward, J. Lee, R. M. Keenan, P.
Bhatnagar, J. Med. Chem. 52 (2009) 3982-3993.
[23] J. Wencel-Delord, F. Glorius, Nat. Chem. 5 (2013) 369-375.
[24] (a) C. Holec, K. Neufeld, J. Pietruszka, Adv. Synth. Catal. 358 (2016)
1810-1819;
(b) V. Bodai, L. Nagy-Gyor, R. Ouml; Rkenyi, Z. Molnar, S. Kohari, B.
Erdelyi, Z. Nagymate, C. Romsics, C. Paizs, L. Poppe, G. Hornyanszky, J.
Mol. Catal. B-Enzym. 134 (2016) 206-214;
(c) A. Kišić, M. Stephan, B. Mohar, Adv. Synth. Catal. 357 (2015) 2540-2546.





We developed a facile and efficient method for the synthesis of β-iodocarboxylates.
The reaction was proceeded in the presence of Ph3P and I2.
-iodocarboxylate compounds are directly obtained with excellent yields.
This method was applied successfully for the late-stage modification of natural products.