Alkyne-enol ether cross-metathesis in the presence of CuSO4: Direct formation of 3-substituted crotonaldehydes in aqueous medium

Article abstract of DOI:10.1021/jo900205x

An efficient synthesis of 3-substituted crotonaldehydes via alkyne-enol ether cross-metathesis in the presence of CuSO₄ and in aqueous medium was developed. Crotonaldehydes were obtained in good yields from terminal aryl-alkynes as well as from

Full text of DOI:10.1021/jo900205x

Alkyne-Enol Ether Cross-Metathesis in the
Presence of CuSO4: Direct Formation of
3-Substituted Crotonaldehydes in Aqueous
Medium
Daniele Castagnolo, Lorenzo Botta, and Maurizio Botta*
Dipartimento Farmaco Chimico Tecnologico, UniVersita`
degli Studi di Siena, Via A. de Gasperi 2, 53100 Siena, Italy
FIGURE 1. Grubbs’ catalyst and crotyl systems.
botta@unisi.it
Consequently, due to their versatility and use in organic
synthesis, attempts in the development of new syntheses of
crotonaldehydes and crotyl-related compounds are of high
interest. Herein a rapid and efficient synthesis of 3-aryl/alkyl-
crotonaldehydes through an enyne cross-metathesis reaction in
aqueous medium and in the presence of copper was reported.
Enyne metathesis constitutes an important and largely used
method for 1,3-diene synthesis.6 The most synthetically useful
version of catalytic enyne metathesis is the intermolecular (cross)
reaction which involves the addition of an alkene across the
triple bond of an alkyne producing conjugated dienes with a
high degree of regiocontrol. The synthetic appeal of cross-
metathesis is that it offers direct and catalytic access to
conjugated dienes, which have broad utility in synthesis. In the
course of our work on the synthesis of enantiopure antifungal
agents via enyne cross-metathesis,7 we were attracted by the
possibility of performing metathetic reactions in water since it
offers several advantages such safety, economics, and environ-
mental compatibility. Despite the fact that the aqueous olefin
metathesis has been documented,8 only a few studies on alkene-
alkyne metathesis reactions carried out in aqueous medium have
been reported so far.9 During our metathetic studies in water,
we were surprised to find that reaction of alkyne 3a with
ethylvinyl ether (EVE) in the presence of Grubbs’ second
generation catalyst 2 (Figure 1) in 1:1 tert-butanol/water led to
the expected diene 4a together with a small amount of the side
compound 3-phenyl-crotonaldehyde 5a (Scheme 1 and Table
ReceiVed February 02, 2009
An efficient synthesis of 3-substituted crotonaldehydes via
alkyne-enol ether cross-metathesis in the presence of CuSO4
and in aqueous medium was developed. Crotonaldehydes
were obtained in good yields from terminal aryl-alkynes as
well as from terminal alkyl-alkynes. All of the reactions were
carried out under microwave irradiation and were completed
in a few minutes. Water was used as the cosolvent, making
this approach safer, economic, and desiderable from an
enviromental point of view.
Crotonaldehydes, and more generally R,ꢀ-unsaturated car-
bonyl compounds, are versatile organic molecules that may be
used in synthetic applications such as carbonyl addition,
conjugate addition, and as a prochiral dienophile.1 Commercially
available crotonaldehyde 1 is often employed in the synthesis
of tocopherol (vitamin E), the food preservative sorbic acid,
and the solvent 3-methylbutanol as well as many natural
products.2 Moreover, crotonaldehyde and crotyl structural motifs
are also present in many natural compounds such as polyketides,
retinoids, and carotenoids (Figure 1).3 Surprisingly, a few direct
approaches for the synthesis of crotonaldehydes are known, and
they generally require several steps.4,5
(6) For review, see: (a) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104,
1317–1382. (b) Mori, M. J. Mol. Catal. A 2004, 213, 73–79. (c) Mori, M. In
Enyne Metathesis in Top. Organomet. Chem.; Furstner, A., Ed.; Springer: Berlin
Heidelberg, 1998; Vol. 1, p 133. (d) Mori, M. In Enyne Metathesis in Handbook
of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vol.
2, p 176.
(1) For reviews, see: (a) Jung, M. E. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon Elsevier: Oxford,
1991; Vol. 4, p 1. (b) LeeV. J. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon Elsevier: Oxford, 1991;
Vol. 4, pp 69 and 139. (c) Kozlowski, J. A. In ComprehensiVe Organic Synthesis;
Trost, B., Fleming, I. M., Semmelhack, M. F., Eds.; Pergamon Elsevier: Oxford,
1991; Vol. 4, p 169. (d) Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R.
Tetrahedron 1996, 52, 8001. (e) Ciganek, E. Org. React. 1997, 51, 201. (f)
Basavaiah, D.; Jaganmohan Rao, A.; Satyanarayana, T. Chem. ReV. 2003, 103,
811.
(2) (a) Smith, A. B., III; Simov, V. Org. Lett. 2006, 8, 3315–3318. (b) Hong,
B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett. 2006, 8, 2217–2220. (c)
Fettes, A.; Carreira, E. M. J. Org. Chem. 2003, 68, 9274–9283.
(3) Krinsky, N. I. Pure Appl. Chem. 1994, 66, 1003–1010.
(7) (a) Castagnolo, D.; Giorgi, G.; Spinosa, R.; Corelli, F.; Botta, M. Eur. J.
Org. Chem. 2007, 3676–3686. (b) Castagnolo, D.; Renzulli, M. L.; Galletti, E.;
Corelli, F.; Botta, M. Tetrahedron: Asymmetry 2005, 16, 2893–2896. (c) Giessert,
A. J.; Snyder, L.; Markham, J.; Diver, S. T. Org. Lett. 2003, 5, 1793–1796.
(8) (a) Lipshutz, B. H.; Aguinaldo, G. T.; Ghorai, S.; Voigtritter, K. Org.
Lett. 2008, 10, 1325–1328. (b) Gallivan, J. P.; Jordan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 2005, 46, 2577–2580. (c) Kirkland, T. A.; Lynn, D. M.; Grubbs,
R. H. J. Org. Chem. 1998, 63, 9904–9909. (d) Hong, S. H.; Grubbs, R. H. J. Am.
Chem. Soc. 2006, 128, 3508–3509. (e) Binder, J. B.; Blank, J. J.; Raines, R. T.
Org. Lett. 2007, 9, 4885–4888. (f) Polshettiwar, V.; Varma, R. S. J. Org. Chem.
2008, 73, 7417–7419.
(9) (a) Gułajski, Ł.; Michrowska, A.; Naroznik, J.; Kaczmarska, Z.; Rupnicki,
L.; Grela, K. ChemSusChem 2008, 1, 103–109. (b) Binder, J. B.; Guzei, I. A.;
Raines, R. T. AdV. Synth. Catal. 2007, 349, 395. (c) Gułajski, Ł.; Sledz, P.;
Lupa, A.; Grela, K. Green Chem. 2008, 10, 271. (d) Michrowska, A.; Gułajski,
Ł.; Kaczmarska, Z.; Mennecke, K.; Kirschning, A.; Grela, K. Green Chem. 2006,
8, 685.
(4) Fischer, R.; Weitz, H. U.S. Patent 4284796.
(5) Hibst, H.; Storck, S.; Demuth, D.; Stichert, W.; Klein, J.; Schunk, S.;
Sundermann, A. U.S. Patent 7071363.
3172 J. Org. Chem. 2009, 74, 3172–3174
10.1021/jo900205x CCC: $40.75 2009 American Chemical Society
Published on Web 03/18/2009

TABLE 2. Conversions and Yields of 5
SCHEME 1. Enyne Cross-Metathesis in the Presence of
CuSO4
TABLE 1. Optimization of the Copper-Mediated Enyne
Cross-Metathesis
CuSO4 dienes E/Z 4a aldehyde E/Z 5a
(equiv)
entry
solventa
toluene
(conv %)b
(conv %)b
1
2
3
4
5
6
>95
>95
83
ND
ND
17
toluene
2
H2O/tBuOH 1:1
H2O/tBuOH 1:1
H2O/tBuOH 1:1
H2O/tBuOH 1:1
0.5
1.0
2.0
traces
traces
traces
85
88
>90
a All of the reactions were carried out at 80 °C under microwave
b
1
irradiation. Conversion was calculated by H NMR.
SCHEME 2. Synthesis of Crotonaldehydes 5a-k
1, entry 3).10 On the other hand, the standard metathetic reaction7
of 3a with EVE in toluene led only to 4a and no traces of
aldehyde 5a were detected (entry 1).
Since the enol ether 4a can be considered as the protected
equivalent of aldehyde 5a, the formation of this latter compound
could be explained through the hydrolysis of the enol ether 4a
itself. Hence, on the basis of literature data on the cleavage of
acetals,11 it was reasoned that performing the same reaction in
aqueous medium and in the presence of the weak acidic salt
CuSO4 could lead to the complete conversion of 4a into 5a.
Experiments using different solvents and amounts of CuSO4
were performed, and results are shown in Table 1. When 2.0
equiv of CuSO4 was used (entry 6), the highest conversion of
4a into 5a was achieved. The use of catalytic or stoichiometric
amount of CuSO4 (entries 4 and 5) led to slightly lower
conversion values. Finally, when 3a and EVE were reacted in
the presence of 2 equiv of CuSO4 in toluene (entry 2), no traces
of aldehydes 5a were detected and only dienes 4a were
obtained.12 In all of the cases, reactions were carried out under
microwave irradiation and were completed in 30 min (3 runs
× 10 min).7a,b Hence, in order to generalize these results, a
series of alkynes 3a-k were reacted with EVE in a mixture of
1:1 H2O/tBuOH and in the presence of CuSO4 (Scheme 2).
Results are summarized in Table 2. In all of the cases, aldehydes
5a-k were obtained as a 2/1 mixture of E/Z isomers that were
separated by chromatography on silica gel.
a All of the reactions were performed at 80 °C with 2 equiv of CuSO4
under microwave irradiation for 3 × 10 min. b Conversion of alkynes
into dienes and aldehydes was calculated by 1H NMR. c Isolated yields
are reported. d Isolated yields of E isomers after equilibration of the E/Z
mixture with I2 were reported.
1
1-3). Only traces of dienes 4a-c were detected by H NMR
analysis. Reaction of aromatic alkyne 3d led to desired
aldehydes 5d in low yields (entry 4), maybe due to the electron-
withdrawing effect of the p-methoxy moiety on the naphthyl
ring, which makes alkyne 3d less reactive toward metathesis
reaction. However, as shown by conversion values in Table 2,
only a small amount of dienes 4d was detected from the reaction
mixture. When propargylic alcohols 3e-g were reacted with
EVE, the desired compounds 5e-g were obtained together with
dienes 4e-g in an almost 2:1 ratio (entries 5-7). Attempts to
obtain full conversion of these alkynes into aldehydes was
unsuccessful. However, dienes 4e-g could be recycled and
converted into desired aldehydes 5e-g (in a 2:1 E/Z ratio) in
45% yield after treatment with CuSO4 (2 equiv) in 1:1 H2O/
tBuOH. The lower yields of aldehydes 5e-g compared to those
of 5a-c could be due to the steric hindrance of substituents on
the propargylic alcohols, which makes these substrates less
reactive. This latter hypothesis was confirmed by the behavior
of the less hindered alkyl-alkynes 3h,i, which were converted
into 5h,i in good yields (entries 8 and 9). Only a small amount
of the dienes 4h,i was detected. On the other hand, when the
bulky triisopropylsilylacetylene 3j was subjected to the copper-
mediated enyne cross-metathesis, only traces of the dienes 4j
were detected by HPLC-MS analysis and no aldehydes 5j were
formed (entry 10). This result confirms the poor reactivity of
bulky alkynes toward the enyne cross-metathesis reaction.
Finally, alkyne 3k was reacted with EVE, affording aldehyde
When the aromatic alkynes 3a-c were reacted with EVE,
the desired aldehydes 5a-c were obtained in good yields (entries
(10) Compounds 4a and 5a were always isolated as a 2/1 mixture of
E/Zisomers.
(11) (a) Caballero, G. M.; Gros, E. G. Synth. Commun. 1995, 25, 395–404.
(b) Tokunaga, M.; Aoyama, H.; Kiyosu, J.; Shirogane, Y.; Iwasawa, T.; Obora,
Y.; Tsuji, Y. J. Organomet. Chem. 2007, 692, 472. (c) Aoyama, H.; Tokunaga,
M.; Hiraiwa, S.; Shirogane, Y.; Obora, Y.; Tsuji, Y. Org. Lett. 2004, 6, 509.
(12) Experiments in the presence of different acids (namely, 0.1 N HCl, 60
mol % of TsOH, 100 mol % of BF3 · Et2O, 80 mol % of Cu(OTf)2) were
attempted. In all of the cases, conversion values were lower. When 150 mol %
of Cu(OTf)2 was used, a coversion value (<90%) comparable to that achieved
in the presence of CuSO4 was obtained.
J. Org. Chem. Vol. 74, No. 8, 2009 3173

SCHEME 3. Isomerization of (Z)-5k to (E)-5k
thermodynamically stable compounds. The structure of the E/Z
isomers was assigned by NOESY experiments.
In summary, an efficient and rapid synthesis of 3-substituted
crotonaldehydes 5 in aqueous medium has been developed. In
this work, we have discovered that 3-substituted crotonaldehydes
5 could be synthesized directly from aryl/alkyl-alkynes through
an alkyne-enol ether cross-metathesis reaction when water was
used as cosolvent. The presence of CuSO4 proved to be
fundamental for achieving high conversion of alkynes 3 into
desired aldehydes 5. All of the reactions were carried out in
aqueous medium, making this approach an easy and green
method for the transformation of terminal alkynes into crotyl
systems.
SCHEME 4. Proposed Mechanism of Formation of
Crotonaldehydes 5
Experimental Section
Synthesis of Crotonaldehydes (E)-5a and (Z)-5a. Alkyne 3a
(1.0 mmol), ethylvinyl ether (9.0 mmol), CuSO4 (2.0 mmol), and
Grubbs’ catalyst (0.1 mmol) were suspended in a 1:1 mixture of
water and tert-BuOH (2.0 mL each) in a 10 mL glass vial equipped
with a small magnetic stirring bar. The mixture was heated at 80 °C
under microwave irradiation for 3 × 10 min, using an irradiation
power of 300 W. The mixture was then poured into a solution of
NH4Cl (20 mL), NH4OH (0.5 mL), and Et2O (10 mL), stirred for
an additional 10 min, and then extracted with Et2O (2 × 10 mL).
The combined organic phases were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (SiO2)
using 1:4 Et2O/hexanes as the eluent to yield the crotonaldehydes
(E)-5a and (Z)-5a as single isomers, as tan oils.
5k in good yield (entry 11). Surprisingly, only (E)-5k aldehyde
was isolated, and no traces of (Z)-5k were detected. The
compounds (E/Z)-5k are dienes due to the conjugation of the
formed crotyl system with the cyclohexene double bond.
It is documented that (Z)-dienes could be converted into the
corresponding (E)-dienes by simple heating in toluene.13 As a
consequence, it has been hypothesized that in the course of the
copper-mediated metathetic reaction a Z to E equilibration of
“diene (Z)-5k” could occur, leading to the formation of the
thermodynamically stable (E)-5k as the only reaction product,
as illustrated in Scheme 3. The high yield of 5k could also
confirm this assumption.
In all of the other cases, aldehydes 5a-i were obtained in a
2:1 E/Z isomeric ratio as observed by 1H NMR. This result might
be explained by assuming that the reaction proceeds first through
the formation of dienes 4a-i in a 2:1 ratio7 via ruthenium-
catalyzed metathesis followed by CuSO4-mediated hydrolysis
and subsequent keto-enolic equilibration to afford crotonalde-
hydes 5a-i, as proposed in Scheme 4.
(E)-5a: Yield 36%; Rf ) 0.38 Et2O/hexanes 1:4; 1H NMR (400
MHz, CDCl3) δ 10.11 (d, J ) 7.7 Hz, 1H), 7.48-7.47 (m, 2H),
7.35-7.31 (m, 3H), 6.33 (d, J ) 7.7 Hz, 1H), 2.50 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 191.3, 157.6, 140.5, 130.1, 128.7,
128.4, 127.2, 126.3, 126.2, 16.4 ppm; IR (CHCl3) ν 1660 cm-1
;
MS (ESI) m/z ) 147.1 [M + H], 169.0 [M + Na+]. Anal. Calcd
for C10H10O: C, 82.16; H, 6.89. Found: C, 82.20; H, 7.03.
(Z)-5a: Yield 18%; Rf ) 0.47 Et2O/hexanes 1:4; 1H NMR (400
MHz, CDCl3) δ 9.41 (d, J ) 8.0 Hz, 1H), 7.34-7.24 (m, 5H),
6.07 (d, J ) 8.0 Hz, 1H), 2.25 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 193.4, 162.1, 138.4, 129.2, 129.1, 128.4, 128.3, 26.4 ppm;
IR (CHCl3) ν 1660 cm-1; MS (ESI) m/z ) 147.1 [M + H], 169.0
[M + Na+]. Anal. Calcd for C10H10O: C, 82.16; H, 6.89. Found:
C, 82.19; H, 6.98.
Finally E/Z aldehyde isomers were equilibrated through
reaction with I2.14,15 Treatment of pure Z aldehydes 5a-i with
a catalytic amount of I2 in DCM (Scheme 2) led in all cases
after 7 h to the formation in quantitative yields of the E isomer
as the only product, confirming that E isomers are the
Acknowledgment. We are grateful to Italian Ministero
dell’Istruzione, dell’Universita` e della Ricerca (PRIN Anno 2006
prot.-2006030948_002).
Supporting Information Available: General methods, char-
acterization data, and 1H NMR and 13C NMR spectra of
aldehydes 5a-k are reported. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) Barluenga, J. Synthesis 1997, 968–974.
(14) (a) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. (b) Vedejs,
E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1. (c) Saltiel, J.; Ganapathy, S.;
Werking, C. J. Phys. Chem. 1987, 91, 2755.
(15) Hanessian, S.; Botta, M. Tetrahedron Lett. 1987, 28, 1151–1154.
JO900205X
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