Facile reaction of thiols and amines with alkyl 4-hydroxy-2-alkynoates in water under neutral conditions and ultrasound irradiation

Article abstract of DOI:10.1016/j.tetlet.2009.02.106

This Letter describes an alternative protocol for the Michael addition of thiols to 4-hydroxy-2-alkynoates. The reaction proceeds at room temperature in water under ultrasound irradiation. With amines instead of thiols a sequential conjugate addition/lact

Full text of DOI:10.1016/j.tetlet.2009.02.106

Tetrahedron Letters 50 (2009) 2060–2064
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile reaction of thiols and amines with alkyl 4-hydroxy-2-alkynoates in water
under neutral conditions and ultrasound irradiation
*
Antonio Arcadi , Maria Alfonsi, Fabio Marinelli
Department of Chemistry, Chemical Engineering and Materials-University of L’Aquila-Via Vetoio, 67010 L’Aquila, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes an alternative protocol for the Michael addition of thiols to 4-hydroxy-2-alkynoates.
The reaction proceeds at room temperature in water under ultrasound irradiation. With amines instead
of thiols a sequential conjugate addition/lactonization reaction leads to important 4-amino-furan-2-one
derivatives.
Received 18 December 2008
Revised 10 February 2009
Accepted 13 February 2009
Available online 21 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aqueous medium
Ultrasound irradiation
Hetero-Michael reaction
Thiols
Amines
4-Hydroxy-2-alkynoates
Environmental concerns demand clean reaction processes by
moving away from highly volatile and harmful organic solvents.1
Water has attracted increasing attention over the last years in re-
sponse to calls for sustainable chemistry.2 In addition to its abun-
dance and for economical and safety reasons, water has unique
physical and chemical properties, and by utilizing these it would
be possible to realize reactivity and selectivity that cannot be at-
tained in organic solvents.3 Then, the potential benefits of using
aqueous medium for organic transformations including pericyclic
reactions, free-radical reactions, aldol reactions, Michael additions,
and organometallic reactions have been investigated.4 Work-up
and purification can be carried out by simple phase separation
techniques. However, organic solvents are still used instead of
water because most organic substrates are not soluble in water,
and as a result, water cannot function as a reaction medium. Con-
sequently, either organic co-solvents and/or substrate modifica-
tions are almost always employed in preparative reactions
performed in water to improve the solubility of substrates.5 A pos-
sible alternative could be represented by the development of or-
ganic microenvironments in the aqueous phase6 through the use
of surface-active reagents.7 The same objective can be achieved
by using MW heating.8 Ultrasound is in many instances a comple-
mentary technique9 to microwave for driving efficiently chemical
reactions in water.10
As part of our ongoing research devoted to the development of
green organic chemistry using water as the reaction medium,11 we
report an alternative procedure for the Michael-type addition of
thiols or amines to 4-hydroxy-2-alkynoates12 in water under neu-
tral conditions and ultrasound irradiation (Scheme 1).
Sonochemistry shares with sustainable chemistry the search for
milder and faster procedures in organic synthesis and can be read-
ily adapted for scale-up.13 Even if the Michael addition of amines
and thiols to a,b-unsaturated ketones in water under neutral con-
ditions was widely investigated,14 to the best of our knowledge
there is only a report of Michael addition of thiols or amines to
dimethylacetylene dicarboxylate (DMAD) in water.15
a
,b-Unsatu-
rated ynoates are expected to be poorer Michael acceptors rela-
tively to DMAD and
,b-unsaturated ynones.16
a
We chose the addition of 2-naphthylthiol 2a to 4-hydroxy-4-p-
tolyl-but-2-ynoic acid ethyl ester17 1a as the model system. The 4-
hydroxy-2-alkynoates 1a was added to a vessel flask containing
3 mL of water, immersed in a water bath (rt) and sonicated for
5 min. Afterwards the 2-naphthylthiol 2a was added to the reac-
tion mixture which was irradiated with ultrasound till completion
O
R1
R2
O
OR3
OR3
Nu
R1
Nu
R1
R2
+
+
O
NuH
O
OH
R2
OH
1
2
3
4
Nu = ArS, RS, ArNH, RNH, R2N
* Corresponding author. Tel.: +39 0862 433774; fax: +39 0862 433753.
E-mail address: arcadi@univaq.it (A. Arcadi).
Scheme 1. Michael-type addition of thiols and amines to 4-hydroxy-2-alkynoates 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.106

A. Arcadi et al. / Tetrahedron Letters 50 (2009) 2060–2064
2061
O
H
H2O
O
S
a)
+
OCH2CH
3
H
OCH2CH3
SH
OH
rt, 2.5 h
H3C
OH
H3C
3a (90%)
1a
2a
CH3CN
b)
c)
3a (31%)
3a (91%)
1a + 2a
1a + 2a
80°C, 8 h
CH3CN
80°C, 3.5 h
NaHCO3
Scheme 2. Addition of 2-naphthylthiol 2a to 4-hydroxy-4-p-tolyl-but-2-ynoic acid ethyl ester 1a.
of the reaction. Interestingly only the formation of the only Z iso-
mer 3a in 90% yield was observed (Scheme 2a). By contrast, it
was reported14 that in the addition of 2a to DMAD in water, the
E isomer was the major product and the E/Z ratio was 0.67. Analo-
gously, sulfur nucleophile addition reactions to b-(2-aminophe-
16). b-Amino-a,b-unsaturated esters 5 are typical push–pull ethyl-
enes, which can undergo Z to E isomerization.21
4-Aminofuranones are very interesting heterocyclic derivatives,
since they are useful precursors for the preparation of tetronic
acids,22 whose biological activity is well known.23 Moreover, sev-
eral molecules incorporating the 4-amino-5H-furan-2-one core
have shown interesting pharmacological activity.24 It has been pre-
viously reported that the formation of enamine 5 was an energet-
ically favored process in CH2Cl2, but the lactonization required
acidic conditions and thermal activation (HCl, 2PrOH, reflux).25
Very likely, the sequential lactonization reaction observed un-
der our milder reaction conditions is a consequence of the role
played by water as a Brønsted acid catalyst both in Michael addi-
tion and in the transesterification step. The application of ultra-
sound irradiation significantly increased the reaction rate and
yield compared to the traditional stirring (Table 1, entries 10 and
11). In order to show the general applicability of the method, the
sequential amination/lactonization reaction of 4-hydroxy-2-
alkynoates in water under ultrasound irradiation was studied by
using structurally diverse amines. While when primary amines
were used as nucleophiles only the corresponding 4-amino-
2(5H)-furanones were isolated as products, with the secondary ali-
phatic piperidine 2j the lack of selectivity was observed due the
competitive formation of the amide derivatives 6 (Scheme 5).26
In summary, this Letter describes an efficient protocol for the
highly regioselective Michael addition of thiols to 4-hydroxy-2-
alkynoates in water under ultrasound irradiation. It is noteworthy
that the present reactions proceeded without the addition of any
acid or base. Significant rate acceleration is observed in water com-
nyl)-a,b-ynones proceeded with high E stereoselectivity and the
stereochemical outcome resulted in the subsequent cyclization
reaction.18 In our case the formation of the E isomer can be ruled
out because the formation of the corresponding 4-substituted-
5H-furan-2-one derivative 4 has not been observed.
To investigate the advantageous role of water as a solvent for
this method, comparative reaction was carried out in CH3CN. We
failed to obtain 3a in satisfactory yield under neutral conditions
by reacting 1a with 2a in CH3CN at 80 °C (Scheme 2b). Accordingly
to the results observed on the synthesis of b-keto-1,3-dithianes
from conjugated ynones,16 the Michael addition of 2a to 1a in
CH3CN at 80 °C proceeded in similar yield than in water at rt only
under basic conditions (Scheme 2c).
The plausible role of water in promoting the reaction can be
rationalized by the hydrogen bond formation between water
and the carbonyl of the 4-hydroxy-2-alkynoate which increases
the electrophilic character of the b-carbon of the a,b-unstaturated
ynoate. Simultaneously, activation of the thiol can take place in
dependence on its hydrogen bond formation capability. The
hydrogen in water works as a Brønsted acid. Also, the oxygen
in water may coordinate with the hydrogen of thiol, and as a re-
sult, functions as a Brønsted base. This dual activation mode19 by
water may be important in promoting Michael addition reactions
more efficiently and under milder neutral conditions than in
CH3CN.
The scope of the reaction was investigated using a range of thi-
ols 2a–d and 4-hydroxy-2-alkynoates 1a–c (Table 1, entries 1–9).20
The nucleophilic addition to 4-hydroxy-2-alkynoates of aryl thiols
proceeded stereoselectively to give exclusively the (Z)-4-hydroxy-
3-arylsulfanyl-2-alkenoates 3a–f in 63–90% yields. A worsening of
the stereoselectivity of the addition reaction was observed with al-
kyl thiols 2e–f (Table 1, entries 7–9): the 4-alkylsulfanyl-5H-furan-
2-ones 4a–b were isolated as minor products.
Interestingly, the procedure can be extended to other alkyno-
ates. The Z isomer was still the major product in the reaction of
2a with the ethyl propiolate. The E isomer was isolated in 5% yield
together with the product of a double conjugate addition of 2a to
ethyl propiolate (5% yield) (Scheme 3). The stereochemistry of
the Z and E isomers was assigned on the basis of the coupling con-
stants (10.0 Hz vs 15.0 Hz).
H2O
O
SH
O
+
S
H
O
OEt
rt, 2 h
H
(67%)
2a
Scheme 3. Addition of 2-naphthylthiol 2a to ethyl propiolate.
R4
O
OR3
R1
R2
R4
OH
N
N
R1
R2
R4
R
R
O
N
+
+
O
OR3
R1
O
H
OH
R2
R
A conjugate addition/cyclization domino reaction leading to the
4-substituted-5H-furan-2-one derivatives 4 was prevalent when
nitrogen nucleophiles were used instead of thiols as reagents un-
der the same reaction conditions (Scheme 4; Table 1, entries 10–
1
2g-i
5
4c-f
Scheme 4. Conjugate addition/cyclization reaction of 4-hydroxy-2-alkynoates 1
with amines 2g–i.

2062
A. Arcadi et al. / Tetrahedron Letters 50 (2009) 2060–2064
Table 1
Reaction of thiolsa and aminesa 2 with 4-hydroxy-2-alkynoates 1
Entry
4-Hydroxy-2-alkynoates 1
NuH 2
Time (h)
Product 3 (yield%)b
Product 4 (yield%)b
H
O
SH
1
1a
2a
2.5
3a (90)
O
H3C
S
H
OEt
O
OH
OH
CH3
OH
O
2
3
4
5
6
1b
2a
1.5
2.5
2
3b (63)
H3C
O
OEt
S
O
H3C
H3C
OH
O
1c
2a
3c (67)
O
OEt
OH
S
S
O
O
OH
SH
O
1c
1c
1c
2b
3d (63)
3e (70)
3f (67)
OH
Cl
SH
2c
1.5
O
S
Cl
O
O
OH
SH
2d
1.5
O
S
H3C
OH
H CO
3
SH
H CO
3
O
O
S
7
1b
1b
1c
2e
2.5
1
3g (59)
4a (13)
S
O
H3C
H3C
H3C
H3C
O
OCH3
OH
8c
9
2e
3g (59)
4a (21)
O
S
O
S
O
O
2f
24
3h (52)
4b (10)
O
SH
O
O
OH
H
N
10
1b
1b
2g
3
3
4c (90)
O
H3C
H3C
NH2
O
11d
2g
4c (69)

A. Arcadi et al. / Tetrahedron Letters 50 (2009) 2060–2064
2063
Table 1 (continued)
Entry
4-Hydroxy-2-alkynoates 1
NuH 2
Time (h)
Product 3 (yield%)b
Product 4 (yield%)b
H
N
12
13
1b
2h
2
4d (91)
O
H3C
O
NH2
H3C
H
N
CH3
O
2h
19
4e (66)
O
H3C
O
OEt
OH
H
N
14
15
1b
1b
1c
2i
5
3
2
4f (60)
O
H3C
O
NH2
H3C
N
2j
4g (43)
O
O
N
H
H3C
H3C
O
O
N
16
2j
4h (50)
a
Reactions were carried out in water at rt under ultrasound irradiation using the following molar ratios: [1]:[2] = [1]:[1.1].
Yield refers to single run and is for pure isolated products.
Reaction was carried out in water at rt under ultrasound irradiation using the following conditions: [1]:[2e]:[NaHCO3] = [1]:[1.1]:[1.1].
Reaction was carried out in water at rt without ultrasound irradiation.
b
c
d
4. Perchyonok, V. T.; Lykakis, I. N.; Tuck, K. L. Green Chem. 2008, 10, 153–163;
Mlynarski, J.; Paradowska, J. Chem. Soc. Rev. 2008, 37, 1502–1511; Li, C.-J.; Chen,
L. Chem. Soc. Rev. 2006, 35, 68–82; Liu, S.; Xiao, J. J. Mol. Catal. A: Chem. 2007,
270, 1–43.
5. Grieco, P. A. Organic Synthesis in Water; Blackie: London, 1988.
6. Khan, M. N. Micellar Catalysis; CRC Press: Boca Raton, USA, 2006; Vilotijevic, I.;
Jamison, T. F. Science 2007, 317, 1189–1192.
H
N
R1
R2
R1
R2
N
O
N
O
O
+
+
OR3
R1
O
OH
R2
OH
2j
4g-h
1
6
7. Vasuki, G.; Kumaravel, K. Tetrahedron Lett. 2008, 49, 5636–5638.
8. Polshettiwar, V.; Varma, R. S. Chem. Soc. Rev. 2008, 37, 1546–1557.
9. Cravotto, G.; Cintas, P. Chem. Soc. Rev. 2006, 35, 180–196.
10. Leite, A. C. L.; de Moreira, D. R.; Coelho, L. C. D.; de Menezes, F. D.; Brondani, D.
C. Tetrahedron Lett. 2008, 49, 1538–1541.
H3C
O
N
O
N
H3C
OH
OH
11. Arcadi, A.; Cerichelli, G.; Chiarini, M.; Vico, R.; Zorzan, D. Eur. J. Org. Chem. 2004,
3404–3407; Arcadi, A.; Cerichelli, G.; Chiarini, M.; Correa, M.; Zorzan, D. Eur. J.
Org. Chem. 2003, 4080–4086.
6a (16%)
6b (13%)
12. Xiao, W.-J.; Alper, H. J. Org. Chem. 1992, 62, 3422–3423; Jones, E. R. H.; Whiting,
M. C. J. Chem. Soc. 1949, 1423–1430.
Scheme 5. Reaction of 4-hydroxy-2-alkynoates 1 with piperidine 2j.
13. Mason, T.; Lorimer, J. Applied Sonochemistry: Uses of Power Ultrasound in
Chemistry and Processing; Wiley-VCH, 2002.
pared to organic solvents. With amines instead of thiols a sequen-
tial conjugate addition/lactonization reaction leads to important 4-
amino-furan-2-one derivatives. Ultrasound irradiation shows sig-
nificant advantages compared to the traditional stirring.
14. Sharma, G.; Kumar, R.; Chakraborti, A. K. Tetrahedron Lett. 2008, 49, 4269–
4271; Yadav, J. S.; Swamy, T.; Suba Reddy, B. V.; Krishna Rao, D. J. Mol. Catal. A:
Chem. 2007, 274, 116–119; Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett.
2006, 11, 2433–2436; Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Adv. Synth.
Catal. 2005, 347, 655–661.
15. Ziyaey-Halimehjani, A.; Saidi, M. R. Tetrahedron Lett. 2008, 49, 1244–1248.
16. Xu, C.; Bartley, J. K.; Enache, D. I.; Knight, D. W.; Lunn, M. M.; Lok, M.;
Hutchings, G. J. Tetrahedron Lett. 2008, 49, 2454–2456; Gaunt, M. J.; Sneddon,
H. F.; Hewitt, P. R.; Orsini, P.; Hook, D. F.; Ley, S. V. Org. Biomol. Chem. 2003, 1,
15–16.
Acknowledgment
This work was supported by the University of L’Aquila (Italy).
17. Alfonsi, M.; Arcadi, A.; Chiarini, M.; Marinelli, F. J. Org. Chem. 2007, 72, 9510–
9517.
18. Arcadi, A.; Marinelli, F.; Rossi, E. Tetrahedron 1999, 55, 13233–13250.
19. Shirakawa, S.; Shimuzu, S. Synlett 2007, 3160–3164.
References and notes
1. Adams, D. J.; Dyson, P. J.; Taverner, S. J. Chemistry in Alternative Reaction Media;
Wiley-Interscience: Cambridge, 2004; Nelson, W. M. Green Solvents for
Chemistry, Perspective and Practice; Oxford University Press: New York, 2003;
Wei, W.; Keh, C. C. K.; Li, C.-J. Clean Technol. Environ. Policy 2005, 7, 62–69.
2. Herrerias, C. I.; Yao, X. Q.; Li, Z. P.; Li, C. J. Chem. Rev. 2007, 107, 2546–2562;
Hailes, H. C. Org. Process Res. Dev. 2007, 11, 114–120; Lindsstrom, U. M. Chem.
Rev. 2002, 102, 2751–2772.
3. Shapiro, N.; Vigalok, A. A. Angew. Chem., Int. Ed. 2008, 47, 2849–2852; Narayan,
S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2005, 44, 3275–3279; Ribe, S.; Wipf, P. Chem. Commun. 2001, 299–307.
20. General procedure: Alkyl 4-hydroxy-2-alkynoate 1 (0.5 mmol) was added to a
vessel flask containing 3 mL of water, immersed in water bath (rt) and
sonicated for 5 min in a Falc Ultrasonic Model instrument. Afterwards the thiol
or amine 2 (0.55 mmol) was added to the reaction mixture. Upon completion
of the reaction (monitoring by TLC or GC-MS), the mixture was extracted with
water (50 mL) and ethyl acetate (3 Â 50 mL). The combined organic layers
were dried (Na2SO4) and evaporated. The residue was purified by
chromatography (hexane/ethyl acetate mixture) to give 3 or 4.
21. Rossi, E.; Abbiati, G.; Canevari, V.; Nava, D.; Arcadi, A. Tetrahedron 2004, 60,
11391–11398.

2064
A. Arcadi et al. / Tetrahedron Letters 50 (2009) 2060–2064
22. Greenhhill, J. W.; Ramli, M.; Tomassini, T. J. Chem. Soc., Perkin Trans. 1 1975,
588–591.
23. Mack, R. A.; Baer, J. E.; Radov, L. A.; Elzer, P. H.; Georgiev, V. S. Eur. J. Med. Chim.
Ther. 1989, 24, 61–64.
25. Tejedor, D.; Santos-Expòsito, A.; García-Tellado, F. Synlett 2006, 1607–1609.
26. Gabriele, B.; Salerno, G.; Plastina, P.; Costa, M.; Crespini, A. Adv. Synth. Catal.
2004, 346, 351–358; Mal’kina, A. G.; Skvortsov, Y. M.; Gritsa, A. I.;
Gromkova, R. A.; Trofimov, B. A. J. Org. Chem. USSR (Engl. Transl.) 1989, 25,
1677–1679.
24. Hamman, M. T. Curr. Pharm. Des. 2003, 9, 879–889.