An efficient synthesis of α-isothiocyanato-α,β-unsaturated esters from morita-baylis-hillman adducts

Full text of DOI:10.1002/bkcs.10705

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DOI: 10.1002/bkcs.10705
BULLETIN OF THE
K. H. Kim et al.
KOREAN CHEMICAL SOCIETY
An Efficient Synthesis of α-Isothiocyanato-α,β-unsaturated Esters from
Morita–Baylis–Hillman Adducts
*
Ko Hoon Kim, Su Yeon Kim, Junseong Lee, and Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju
500-757, Korea. *E-mail: kimjn@chonnam.ac.kr
Received October 12, 2015, Accepted December 11, 2015, Published online March 14, 2016
Keywords: α-Isothiocyanato-α,β-unsaturated esters, Morita–Baylis–Hillman adducts, 1,4,2-Oxathiazole,
Isothiocyanates
Isothiocyanates (ITCs) have been used extensively in
organic synthesis, particularly for the synthesis of various
heterocyclic compounds.1a,b Numerous ITCs including phe-
nethyl ITC (PEITC) and sulforaphane showed interesting
biological activities such as antitumor activity.1c–f Among
ITCs, α-isothiocyanato-α,β-unsaturated ester derivatives,
including paulomycins A and B and their analogues, have
been known as antibiotics.2 In addition, α-isothiocyanato-
α,β-unsaturated esters have been used for the synthesis of
many heterocyclic compounds such as 1,3-oxazolidine-2-
thione,3a 2-alkylthio-4H-imidazol-4-ones,3b,c carbolines,3d
pyrimido[4,5-b]indoles,3d and poly-substituted pyridines.3e
In the early 1990s, we reported an efficient synthesis of
ITCs from primary nitroalkanes in a one-pot procedure
(Eq. (1) in Scheme 1).4 Dehydration of primary nitroalkane
by Mukaiyama procedure5 generates the corresponding
nitrile oxide, and the following [3 + 2] cycloaddition to
C S double bond of thiourea afforded 5,5-diamino-1,4,2-
oxathiazole intermediate.4,6 The 1,4,2-oxathiazole was read-
ily converted to ITC at room temperature in short time
(<5 min.).4,6,7
prepared from MBH acetate 1 and NaNO2,9 as shown in
Eq. (2). The synthesis of 3 has been reported by sequential
Knoevenagel condensation of aldehyde and methyl azidoa-
cetate to form the azide derivative, a subsequent Staudinger
reaction with PPh3 to form iminophosphorane, and the aza-
Wittig reaction with carbon disulfide (Eq. (3) in Scheme
1).3,10 However, the yields of α-isothiocyanato-α,-
β-unsaturated esters were low to moderate in most cases
(49–78%).3a,3c,10a
The required primary nitroalkanes 2a–2j were prepared
from MBH acetates and sodium nitrite according to the
reported method.9 The reaction of 2a in the presence of p-
chlorophenylisocyanate (2.0 equiv), thiourea (1.1 equiv),
and a catalytic amount of Et3N (5 mol%) in benzene
(reflux) for 2 h afforded 3a in good yield (83%). Similarly,
the reactions of 2-naphthyl, 5-methyl-2-thienyl, 2-furyl, and
4-nitrophenyl derivatives 2b–2e afforded the corresponding
α-isothiocyanato-α,β-unsaturated esters 3b–3e in good
yields (80–93%). The alkyl derivative 3f and styryl deriva-
tive 3g were also synthesized in good yields (73 and 75%,
respectively). In addition, ethyl ester 3h and acetyl deriva-
tives 3i and 3j were synthesized in good yields
(67–82%).11 The structure of 3g was confirmed unequivo-
cally by its crystal structure,12 as also shown in Table 1.
In summary, a facile one-pot synthetic procedure of
α-isothiocyanato-α,β-unsaturated esters has been developed
Morita–Baylis–Hillman (MBH) adducts have been
used for the synthesis of various cyclic and acyclic com-
pounds.8 During our continuous studies with MBH adducts,
we reasoned out that α-isothiocyanato-α,β-unsaturated ester
3 could be synthesized from primary nitroalkane 2,
4-ClC6H4NCO
Et3N, thiourea
N
O
- urea
R
(1)
(2)
(3)
R
C N O
R
R N C S
R
R
NO2
NH2
NH2
benzene, reflux
(Ref. 4)
S
COOMe
OAc
COOMe
NO2
NaNO2
R
This Work
COOMe
N
C
S
4-ClC6H4NCO
Et3N, thiourea
benzene, reflux
MBH acetate 1
N3
2
3
COOMe
CS2
(Ref. 3a)
PPh3
COOMe
R-CHO
R
R
COOMe
N
N3
PPh3
Scheme 1. Synthetic rationale of α-isothiocyanato-α,β-unsaturated esters.
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Table 1. Synthesis of α-isothiocyanato-α,β-unsaturated esters.
COOMe
OAc
COOMe
NO 2
R
Conditionsa
Conditionsb
R
COOMe
N
C
S
R
3
MBH acetate 1
2
X-ray structure of 3g
COOMe
COOMe
COOMe
COOEt
COOMe
COOMe
S
O
Me
N
C
S
N
C
S
N
N
C
S
N
O2N
C
S
C
S
3c (93%)
3d (87%)
3e (80%)
3a (83%)
3b (85%)
COOMe
COOMe
COMe
COMe
Ph
N
C
S
N
C
S
N
C
S
N
N
C
S
Cl
C
S
3f (73%)
3g (75%)
3h (82%)
3i (68%)
3j (67%)
aPrimary nitroalkanes 2a-2j were prepared from MBH acetates according to the reported method9 (NaNO2, DMF, room temperature)
in moderate to good yields (53-84%).
bConditions: 2a-2j (1.0 mmol), 4-ClC6H4NCO (2.0 equiv.), thiourea (1.1 equiv.), Et3N (5 mol%), benzene, reflux, 2 h.
starting from primary nitroalkanes that prepared from MBH
adducts. The yields of products were higher than the
reported one using expensive methyl azidoacetate. Further
studies on the scope of reaction and biological activity of
the ITCs are currently underway.
129.92, 131.44, 131.92, 132.99, 134.21, 144.26, 163.48;
ESIMS m/z 270 [M++H]. Anal. Calcd for C15H11NO2S: C,
66.89; H, 4.12; N, 5.20. Found: C, 66.71; H, 4.01; N, 5.26.
ꢀ
Compound 3c. 93%; pale yellow solid, mp 92–93 C;
1
IR (KBr) 2032, 1718, 1597, 1434, 1260 cm−1; H NMR
(CDCl3, 600 MHz) δ 2.56 (d, J = 0.6 Hz, 3H), 3.90 (s,
3H), 6.77–6.78 (m, 1H), 7.22 (dd, J = 3.6 and 0.6 Hz, 1H),
7.42 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ 15.83, 53.14,
115.19, 126.16, 126.21, 134.22, 134.45, 144.50, 147.25,
163.38; ESIMS m/z 240 [M++H]. Anal. Calcd for
C10H9NO2S2: C, 50.19; H, 3.79; N, 5.85. Found: C,
50.30; H, 3.94; N, 5.82.
Experimental
Typical Procedure for the Synthesis of 3a. A stirred mix-
ture of 2a (221 mg, 1.0 mmol), 4-chlorophenylisocyanate
(306 mg, 2.0 mmol), thiourea (84 mg, 1.1 mmol), and
Et3N (5 mg, 0.05 mmol) in benzene (4.0 mL) was heated
to reflux for 2 h. After the usual aqueous extractive workup
and column chromatographic purification process (hexanes/
Et2O, 10:1) 3a was isolated as a white solid, 182 mg
(83%). Other compounds were synthesized similarly, and
the spectroscopic data of 3a–3j are as follows.
ꢀ
Compound 3d. 87%; white solid, mp 65–66 C; IR
1
(KBr) 2018, 1726, 1619, 1471, 1435, 1274 cm−1; H NMR
(CDCl3, 600 MHz) δ 3.90 (s, 3H), 6.57 (dd, J = 3.6 and
1.8 Hz, 1H), 7.11 (d, J = 3.6 Hz, 1H), 7.25 (s, 1H), 7.58
(d, J = 1.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 53.28,
112.90, 116.04, 116.67, 120.21, 142.59, 145.44, 149.05,
163.01; ESIMS m/z 210 [M++H]. Anal. Calcd for
C9H7NO3S: C, 51.67; H, 3.37; N, 6.69. Found: C,
51.85; H, 3.20; N, 6.56.
Compound 3a.3e 83%; white solid, mp 52–53 C; IR
ꢀ
(KBr) 2014, 1728, 1622, 1435, 1259 cm−1; 1H NMR
(CDCl3, 300 MHz) δ 3.87 (s, 3H), 7.22 (s, 1H), 7.34–7.41
(m, 3H), 7.72–7.76 (m, 2H); 13C NMR (CDCl3, 125 MHz)
δ 53.41, 119.32, 128.88, 130.19, 130.82, 131.81, 132.35,
144.16, 163.39; ESIMS m/z 220 [M++H]. Anal. Calcd for
C11H9NO2S: C, 60.26; H, 4.14; N, 6.39. Found: C,
60.50; H, 4.27; N, 6.28.
ꢀ
Compound 3e. 80%; white solid, mp 133–134 C; IR
(KBr) 2027, 1724, 1515, 1347, 1274 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 3.98 (s, 3H), 7.28 (s, 1H), 7.98 (d,
J = 9.0 Hz, 2H), 8.29 (d, J = 9.0 Hz, 2H); 13C NMR
(CDCl3, 125 MHz) δ 53.79, 123.34, 123.99, 127.77,
130.65, 138.39, 146.63, 148.10, 162.68; ESIMS m/z
265 [M++H]. Anal. Calcd for C11H8N2O4S: C, 50.00; H,
3.05; N, 10.60. Found: C, 50.23; H, 3.18; N, 10.43.
ꢀ
Compound 3b. 85%; white solid, mp 100–101 C; IR
(KBr) 2039, 1721, 1617, 1428, 1248 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 3.96 (s, 3H), 7.44 (s, 1H), 7.51–7.57
(m, 2H), 7.84–7.90 (m, 3H), 7.97 (dd, J = 8.0 and 1.5 Hz,
1H), 8.23 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 53.44,
119.29, 126.07, 126.78, 127.74, 127.82, 128.56, 128.91,
Compound 3f. 73%; colorless oil; IR (film) 2032, 1735,
1637, 1437, 1260 cm−1; 1H NMR (CDCl3, 500 MHz) δ
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S. R. Rajski, ChemBioChem 2008, 9, 729; (d) X. Wu,
Q.-h. Zhou, K. Xu, Acta Pharmacol. Sin. 2009, 30, 501;
(e) A. T. Dinkova-Kostova, R. V. Kostov, Trends Mol. Med.
2012, 18, 337; (f ) S. S. Hecht, Drug Metab. Rev. 2000,
32, 395.
0.91 (t, J = 7.0 Hz, 3H), 1.31–1.36 (m, 4H), 1.44–1.50 (m,
2H), 2.34 (q, J = 7.5 Hz, 2H), 3.86 (s, 3H), 6.65 (t,
J = 7.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 13.90,
22.35, 27.79, 28.77, 31.37, 53.02, 122.95, 139.66, 142.58,
162.40; ESIMS m/z 214 [M++H]. Anal. Calcd for
C10H15NO2S: C, 56.31; H, 7.09; N, 6.57. Found: C,
56.20; H, 7.22; N, 6.54.
2. For biological activity of α-isothiocyanato-α,β-unsaturated
esters, such as Paulomycins A and B, see:(a) P. F. Wiley,
S. A. Mizsak, L. Baczynskyj, A. D. Argoudelis,
D. J. Duchamp, W. Watt, J. Org. Chem. 1986, 51, 2493;
(b) A. D. Argoudelis, L. Baczynskyj, S. A. Mizsak,
F. B. Shilliday, P. A. Spinelli, J. DeZwaan, J. Antibiot. 1987,
XL, 419.
3. For synthetic usefulness of α-isothiocyanato-α,β-unsaturated
esters, see:(a) K. Kobayashi, K. Ezaki, H. Hashimoto, Helv.
Chim. Acta 2013, 96, 431; (b) Y. Sun, L.-P. Gao,
M.-W. Ding, Synth. Commun. 2006, 36, 1185;
(c) F.-L. Yang, Z.-J. Liu, X.-B. Huang, M.-W. Ding,
J. Heterocycl. Chem. 2004, 41, 77; (d) P. Molina,
P. M. Fresneda, J. Chem. Soc., Perkin Trans. 1 1988, 1819;
(e) J. Barluenga, M. Ferrero, E. Pelaez-Arango, F. Lopez-
Ortiz, F. Palacios, J. Chem. Soc., Chem. Commun. 1994, 865.
4. J. N. Kim, J. H. Song, E. K. Ryu, Synth. Commun. 1994,
24, 1101.
Compound 3g. 75%; pale yellow solid, mp
ꢀ
110–111 C; IR (KBr) 2064, 1719, 1606, 1427,
1
1277 cm−1; H NMR (CDCl3, 600 MHz) δ 3.89 (s, 3H),
6.95–7.00 (m, 1H), 7.14–7.20 (m, 2H), 7.33–7.40 (m, 3H),
7.51–7.53 (m, 2H); 13C NMR (CDCl3, 150 MHz) δ 53.12,
119.97, 122.17, 127.64, 128.91, 129.75, 134.11, 135.65,
142.03, 143.71, 162.96; ESIMS m/z 246 [M++H]. Anal.
Calcd for C13H11NO2S: C, 63.65; H, 4.52; N, 5.71.
Found: C, 63.71; H, 4.77; N, 5.56.
Compound 3h.3a,b 82%; colorless oil; IR (film) 2015,
1724, 1623, 1259 cm−1; 1H NMR (CDCl3, 500 MHz) δ
1.42 (t, J = 7.5 Hz, 3H), 4.40 (q, J = 7.5 Hz, 2H), 7.29 (s,
1H), 7.41–7.47 (m, 3H), 7.81–7.84 (m, 2H); 13C NMR
(CDCl3, 125 MHz) δ 14.26, 62.86, 119.59, 128.85, 130.17,
130.73, 131.42, 132.41, 144.46, 162.86; ESIMS m/z
234 [M++H]. Anal. Calcd for C12H11NO2S: C, 61.78; H,
4.75; N, 6.00. Found: C, 61.95; H, 4.59; N, 6.12.
5. T. Mukaiyama, T. Hoshino, J. Am. Chem. Soc. 1960,
82, 5339.
6. For synthesis of isothiocyanates from nitrile oxides, see:
(a) J. N. Kim, E. K. Ryu, Tetrahedron Lett. 1993, 34, 8283;
(b) J. N. Kim, K. S. Jung, H. J. Lee, J. S. Son, Tetrahedron
Lett. 1997, 38, 1597; (c) K. S. Jung, H. J. Lee, H. N. Song,
J. N. Kim, Synth. Commun. 1998, 28, 1879.
7. For the formation and fragmentation of 1,4,2-oxathiazoles,
see:(a) R. J. O’Reilly, L. Radom, Org. Lett. 2009, 11, 1325;
(b) Y. W. Lim, R. J. Hewitt, B. A. Burkett, Eur. J. Org.
Chem. 2015, 4840; (c) B. A. Burkett, P. Fu, R. J. Hewitt,
S. L. Ng, J. D. W. Toh, Eur. J. Org. Chem. 2014, 1053;
(d) R. J. Hewitt, M. J. H. Ong, Y. W. Lim, B. A. Burkett,
Eur. J. Org. Chem. 2015, 6687.
8. For general reviews on MBH reaction, see: (a) D. Basavaiah,
A. J. Rao, T. Satyanarayana, Chem. Rev. 2003, 103, 811;
(b) D. Basavaiah, B. S. Reddy, S. S. Badsara, Chem. Rev.
2010, 110, 5447; (c) V. Singh, S. Batra, Tetrahedron 2008,
64, 4511; (d) J. N. Kim, K. Y. Lee, Curr. Org. Chem. 2002,
6, 627; (e) K. Y. Lee, S. Gowrisankar, J. N. Kim, Bull.
Korean Chem. Soc. 2005, 26, 1481; (f ) S. Gowrisankar,
H. S. Lee, S. H. Kim, K. Y. Lee, J. N. Kim, Tetrahedron
2009, 65, 8769; (g) M. Shi, F.-J. Wang, M.-X. Zhao, Y. Wei,
The Chemistry of the Morita–Baylis–Hillman Reaction, RSC
Publishing, Cambridge, 2011.
9. For synthesis of primary nitroalkanes of MBH adducts, see:
(a) W. P. Hong, K.-J. Lee, Synthesis 2005, 33; (b) S.-H. Ji,
W. P. Hong, S. H. Ko, K.-J. Lee, J. Heterocycl. Chem. 2006,
43, 799; (c) S.-R. Sheng, S.-Y. Lin, Q. Wang, X.-L. Liu,
M. Lin, Synth. Commun. 2007, 37, 1011; (d) H. J. Kim,
E. M. Jeong, K.-J. Lee, J. Heterocycl. Chem. 2011, 48, 965;
(e) S. U. Dighe, S. Mukhopadhyay, S. Kolle, S. Kanojiya,
S. Batra, Angew. Chem. Int. Ed. 2015, 54, 10926.
ꢀ
Compound 3i. 68%; pale yellow solid, mp 72–73 C;
1
IR (KBr) 2053, 1667, 1447, 1244 cm−1; H NMR (CDCl3,
600 MHz) δ 2.53 (s, 3H), 7.11 (s, 1H), 7.43–7.47 (m, 3H),
7.85–7.86 (m, 2H); 13C NMR (CDCl3, 150 MHz) δ 25.44,
128.59, 128.93, 130.31, 131.04, 131.72, 132.34, 146.94,
191.48; ESIMS m/z 204 [M++H]. Anal. Calcd for
C11H9NOS: C, 65.00; H, 4.46; N, 6.89. Found: C,
65.29; H, 4.28; N, 6.96.
ꢀ
Compound 3j. 67%; white solid, mp 90–91 C; IR
(KBr) 1987, 1686, 1490, 1275 cm−1; 1H NMR (CDCl3,
500 MHz) δ 2.53 (s, 3H), 7.05 (s, 1H), 7.43 (d,
J = 8.5 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H); 13C NMR
(CDCl3, 125 MHz) δ 25.44, 129.19, 129.25, 129.98,
130.87, 131.45, 136.90, 147.74, 191.27; ESIMS m/z
238 [M++H], 240 [M++H + 2]. Anal. Calcd for
C11H8ClNOS: C, 55.58; H, 3.39; N, 5.89. Found: C,
55.83; H, 3.48; N, 5.81.
Acknowledgments. This work was supported by the
National Research Foundation of Korea (NRF) grant
funded by the Korea government (MSIP) (NRF-
2015R1A4A1041036). Spectroscopic data were obtained
from the Korea Basic Science Institute, Gwangju branch.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
References
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P. M. Fresneda, M. V. Vinader, M. C. Foces-Foces,
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1. For
general
reviews
on
isothiocyanates,
see:
(a) A. K. Mukerjee, R. Ashare, Chem. Rev. 1991, 91, 1;
(b) K. G. Bedane, G. S. Singh, Arkivoc 2015, vi, 206;
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Bull. Korean Chem. Soc. 2016, Vol. 37, 592–595
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11. An introduction of nitro group at the primary position of
MBH acetate derived from acrylonitrile failed, unfortunately.
To the best of our knowledge, there is no report on the syn-
thesis of primary nitro compound of MBH adduct of
acrylonitrile.
crystal dimensions 0.12 × 0.21 × 0.10 mm3, Monoclinic,
space group P21/n, a = 5.7385(3) Å, b = 15.0987(9) Å,
c = 14.3355(8) Å, α = 90ꢀ, β = 90.759(4)o, γ = 90ꢀ,
V = 1241.97 Å3, Z = 4, Dcalcd = 1.312 mg/m3, F000 = 512.0,
MoK (λ = 0.71073 Å), R1 = 0.0481, wR2 = 0.1514, GOF =
1.062 (I > 2 (I)). The X-ray data have been deposited in
CCDC with number 1424661.
12. Crystal data of compound 3g: solvent of crystal growth (hex-
ane + CH2Cl2); empirical formula C13H11NO2S, Fw = 245.3,
Bull. Korean Chem. Soc. 2016, Vol. 37, 592–595
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