A one-pot synthesis of α-formyl-α-allylacetates via nucleophilic catalysis

Article abstract of DOI:10.1016/j.tetlet.2011.10.035

A step-economical one-pot nucleophilic catalysis/thermal Claisen-rearrangement protocol for the direct synthesis of α-formyl- α-allylacetates from allylic alcohols and activated alkynes has been developed. The product α-formyl-α-allylacetates were further reacted in situ to give either protected enol ethers or β-hydroxy-4-pentenoates.

Full text of DOI:10.1016/j.tetlet.2011.10.035

Tetrahedron Letters 52 (2011) 6785–6787
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A one-pot synthesis of
a-formyl-
a-allylacetates via nucleophilic catalysis
⇑
William Chung, Petra Lindovska, Jason E. Camp
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A step-economical one-pot nucleophilic catalysis/thermal Claisen-rearrangement protocol for the direct
Received 30 August 2011
Revised 27 September 2011
Accepted 7 October 2011
Available online 14 October 2011
synthesis of
product -formyl-
hydroxy-4-pentenoates.
a
-formyl-
a-allylacetates from allylic alcohols and activated alkynes has been developed. The
a
a-allylacetates were further reacted in situ to give either protected enol ethers or b-
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Claisen-rearrangement
Nucleophilic catalysis
Step-economical
One-pot
DABCO
R3
a
-Formyl-a-allylacetates are found in a number of biologically
active natural products1 and are important intermediates in the syn-
thesis of peptide inhibitors,2 as well as biologically active uracils3
and pyrimidines.4 These compounds are challenging substrates to
synthesize via conventional enolate chemistry due to their propen-
sity to undergo dimerization reactions and multiple allylations.5,6
R
OH R3
+
R2
[3,3]-
O
CO2R4
R1
R
DABCO
Claisen
O
H
R1
thermal
R1 CO2R4
R
R2
CO2R4
R1
1
2
3
4
The most common method for
is via formylation of a
a-formyl-a-allylacetate formation
c
,d-unsaturated ester,2 which itself must be
Scheme 1. Proposed one-pot synthesis of a-formyl-a-allylacetates.
synthesized. Thus, a more step-economical method to these impor-
tant compounds from commercial starting materials would be
highly beneficial. A one-pot synthesis would be an ideal approach
as it minimizes the transfer of material and avoids the purification
work of Inanaga et al.,13 a number of researchers have employed
a nucleophilic catalysis approach, notably the use of trialkyl phos-
phines,14 DMAP,15 and N-methylmorpholine,16 for the formation of
allyl vinyl ethers from allylic alcohols and activated alkynes. In our
previous work on the one-pot nucleophilic catalysis / thermal rear-
rangement approach towards the synthesis of highly substituted
pyrroles from oximes and activated alkynes, it was found that
DABCO17 was the best catalyst for processes that required heat-
ing.18 Thus, the reaction of both primary and secondary allyl alco-
hols 1 with ethyl propiolate (2a) in CH2Cl2 at rt in the presence of
10 mol % DABCO gave the desired allyl vinyl ethers 3 in moderate
to good yields (Scheme 2).19 The only exception was triene 3g,
which was produced in a yield that was too low to be synthetically
useful in a one-pot process. All of the vinyl ethers 3 were isolated
as the E-isomer as determined by their JHH coupling constants.
The second phase of this work was directed towards the thermal
rearrangement of allyl vinyl ethers 3 to a-formyl-a-allylacetates 4.
The temperature at which the thermal Claisen rearrangement of
allyl vinyl ethers will proceed is highly dependent on the nature of
the substituent on the alkene moiety.10 Substrates that contained
electron-withdrawing groups required higher temperatures.20,21
steps.7,8
a
-Formyl-
ophilic addition/Claisen-rearrangement process (Scheme 1).9,10 This
efficient method for the synthesis of -formyl- -allylacetateswould
a-allylacetates can be formed in a one-pot nucle-
a
a
be step-economical and limit the overall productioncosts in termsof
time, expense and waste. Thus, addition of allyl alcohols 1 to acti-
vated ynones 2, promoted by a nucleophilic catalyst (DABCO), would
result in the formation of allyl vinyl ethers 3. Subsequent thermal
Claisen rearrangement of dienes 3 would give
tates 4. Herein, we report a novel one-pot procedure based on this
approach for the synthesis of -formyl- -allylacetates as well as
a-formyl-a-allylace-
a
a
their subsequent in situ derivatization to either protected enol
ethers or b-hydroxy-4-pentenoates.
3
The formation of allyl vinyl ethers11,12 from the addition of allyl
alcohols to activated alkynes was initially investigated. Impor-
tantly, the conditions need to be viable under the subsequent ther-
mal rearrangement conditions (vide infra). Building on the initial
⇑
Corresponding author. Tel.: +44 115 846 8464.
E-mail address: jason.camp@nottingham.ac.uk (J.E. Camp).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.035

6786
W. Chung et al. / Tetrahedron Letters 52 (2011) 6785–6787
CO2Et 2a
R
R
OTBS
R3
R
OH
R1
R
DABCO (10 mol%)
TBS-Cl, Et3N
DMAP, 0.5 h
CO2Et
O
R1
CO2Et
DABCO (10 mol%)
R
CO2Et
CH2Cl2, rt, 0.5 h
R
OH
R2
5
1
3
4
R1
toluene, rt, 0.5 h;
150 °C, 15 h
R2
R
OBoc
R3
CO2Et
Boc2O, Et3N
DMAP, 0.5 h
CO2Et
CO2Et
O
O
1
R1
CO2Et
3b, 94%
3a, 44%
6
TBS
TBS
TBS
CO2Et
O
O
O
O
O
CO2Et
CO2Et
5c, 81%
CO2Et
3c, 97%
3d, 92%
5e, 86%
5a, 38%
CO2Et
Ph
O
CO2Et
O
Boc
Boc
O
O
3f, 57%
3e, 60%
CO2Et
CO2Et
CO2Et
O
6c, 60%
6e, 67%
3g, 8%
Scheme 2. Synthesis of allyl vinyl ethers 3 via nucleophilic catalysis.
Scheme 4. Synthesis of enol ethers 5 and 6.
Having demonstrated the feasibility of the one-pot synthesis of
protected -formyl- -allylacetates, the synthesis of a series of
reduced b-hydroxy-4-pentenoate derivatives 7 was also investi-
gated.24 This one-pot process involved an initial 1,4-addition fol-
lowed by a thermal Claisen rearrangement and in situ reduction of
a
a
Therefore, we wanted to establish the minimum temperature for the
rearrangement of allyl vinyl ethers 3 to aldehydes 4. Thus, heating a
solution of allyl vinyl ether 3c to 150 °C in either an oil bath or in a
microwave oven led to quantitative and 39% conversion to
a-for-
the
a-formyl-a-allylacetate. Thus, subjection of allyl alcohols 1
myl-a-allylacetate 4c, respectively (Scheme 3). While the thermal
rearrangement was clean by 1H NMR analysis, attempts to purify
the microwave derived material by column chromatography (1:9
EtOAc/petrol with 1% Et3N) resulted in complete degradation. In
and ethyl propiolate (2a) to the standard conditions followed by sol-
vent exchange and reduction with NaBH4 gave b-hydroxy-4-pente-
noates 7 in moderate to good yields (Scheme 5).25 The products of
both primary 7a,c,f,h,i and secondary alcohols 7e,j were amenable
to this process. Cyclic alcohols 1i,j were also subjected to the
three-step process to give alcohols 7i,j in moderate yields. b-Hydro-
xy-4-pentenoates 7c,f,i,j were formed as inseparable mixtures of
diastereomers due to facile epimerization prior to reduction.
solution,
keto-enol tautomers.
Having demonstrated the feasibility of both of the proposed
steps independently, a one-pot synthesis of -formyl- -allylace-
tates from allyl alcohols and ethyl propiolate was investigated.
As the purification of -formyl- -allylacetates 4 proved to be prob-
a-formyl-a-allylacetates 4c existed as a 1:1 mixture of
a
a
a
a
lematic (vide supra), the product aldehydes were converted into
enol ethers. Thus, the reaction of allyl alcohols 1 with ethyl propi-
CO2Et
DABCO (10 mol%)
R2
R
OH
R2
OH
R
NaBH4, THF
°C - rt, 1 h
olate (2a) gave a-formyl-a-allylacetates 4 (Scheme 4). Addition of
4
TBS-Cl22 or Boc2O23 to the reaction mixture resulted in the forma-
tion of enol ethers 5 or 6, respectively. Several features of the one-
pot method are noteworthy. It was found that a 0.5 h mixing of the
reagents at room temperature prior to increasing the temperature
R1
toluene, rt, 0.5 h;
150 °C, 15 h
0
R1
CO2Et
1
7
to 150 °C was necessary in order to form the a-formyl-a-allylace-
OH
OH
OH
tate. This method proved to be very expedient for both primary
and secondary alcohols. Additionally, slightly better yields were
obtained using the TBS-protocol. For example, subjection of 1e
and 2a to the optimized conditions gave either enol ether 5e or
6e depending on the trapping agent that was employed. All of
the enol ethers 5 and 6 were isolated as a single geometric isomer,
though the configuration of the isomer was not determined.
CO2Et
7a, 43%
CO2Et
CO2Et
7c, 81%
5:4a
7e, 89%
OH
OH
Ph
OH
CO2Et
OH
CO2Et
CO2Et
CO2Et
O
toluene, 150 °C
CO2Et
O
thermal, 15 h, 100%
OR
microwave, 1 h, 39%
7f, 33%
7h, 81%
7i, 46%
7j, 46%
3:2a
1:1a
3:2a
CO2Et
3c
4c
Scheme 5. One-pot synthesis of b-hydroxy-4-pentenoates 7. aRatio of two insep-
arable diastereoisomers.
Scheme 3. Thermal vs. microwave rearrangement of allyl vinyl ether 3c.

W. Chung et al. / Tetrahedron Letters 52 (2011) 6785–6787
6787
12. For recent examples of vinyl enol ether formation, see: (a) Suda, M. Chem. Lett.
1981, 967–970; (b) Maeda, K.; Shinokubo, H.; Oshima, K.; Utimoto, K. J. Org.
Chem. 1996, 61, 2262–2263; (c) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C.
A. J. Am. Chem. Soc. 2010, 132, 1202–1203.
13. Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241–244.
14. Donadel, O. J.; Martín, T.; Martín, V. S.; Padrón, J. M. Bioorg. Med. Chem. Lett.
2007, 17, 18–21.
15. Sabitha, G.; Reddy, D. V.; Rao, A. S.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 4195–
4198.
16. Clark, J. S.; Hayes, S. T.; Blake, A. J.; Gobbi, L. Tetrahedron Lett. 2007, 48, 2501–
2503.
CO2Me
O
DABCO (10 mol%)
+
OH
CO2Me
toluene, rt, 0.5 h;
150 °C, 15 h, 21%
5:4 mixture
CO2Me
CO2Me
1c
2b
8
Scheme 6. Synthesis of dimethyl 2-(but-3-en-2-yl)-3-oxosuccinate (8).
17. For the use of DABCO as a nucleophilic catalyst for the synthesis of allyl vinyl
ethers, see: Tellam, J. P.; Kociok-Köhn, G.; Carbery, D. R. Org. Lett. 2008, 10,
5199–5202.
18. Ngwerume, S.; Camp, J. E. J. Org. Chem. 2010, 75, 6271–6274.
19. Typical procedure for the synthesis of allyl vinyl ether 3: To a stirred solution of
geraniol (1d, 0.48 mL, 2.64 mmol) and DABCO (27 mg, 0.24 mmol) in dry
CH2Cl2 (10 mL) at rt was added ethyl propiolate (2a, 0.25 mL, 2.40 mmol)
dropwise over 10 min and the resultant mixture was stirred for 0.5 h at rt. The
solvent was removed under reduced pressure and the residue was purified by
flash column chromatography on silica gel (15:1 petrol/EtOAc) to give ethyl 3-
Additionally, this method was extended to the synthesis of di-
methyl 2-(but-3-en-2-yl)-3-oxosuccinate (8) via the reaction of
(E)-2-buten-1-ol (1c) with dimethyl acetylenedicarboxylate (2b)
using the standard protocol. Diester 8 was isolated in moderate
yield as a 5:4 mixture of diastereomers (Scheme 6).26
In conclusion, we have developed a simple one-pot approach to
the synthesis of a-formyl-a-allylacetates as well as their protected
{[(E)-3,7-dimethylocta-2,6-dien-1-yl]oxy}acrylate (3d, 0.64 g, 92%) as
a
enol ether or b-hydroxy-4-pentenoate derivatives based on a novel
nucleophilic catalysis/thermal rearrangement protocol.
colourless oil.
20. For the thermal rearrangement of b-alloxyacrylates, see: (a) Croxall, W. J.; Van
Hook, J. O. J. Am. Chem. Soc. 1950, 72, 803–808; (b) Croxall, W. J.; Van Hook, J. O.
U.S. Patent 2540071, 1951; Chem. Abstr. 1951, 45, 32837.; (c) Gravey, D. S.;
May, P. D.; Nadzan, A. M. J. Org. Chem. 1990, 55, 936–940.
Acknowledgments
21. For the rearrangement of related allylic acetates, see: (a) Bourgeois, D.; Craig,
D.; King, N. P.; Mountford, D. M. Angew. Chem., Int. Ed. 2005, 44, 618–621; (b)
Camp, J. E.; Craig, D. Tetrahedron Lett. 2009, 50, 3503–3508.
We thank the School of Chemistry at the University of Notting-
ham and Vertex Pharmaceuticals Ltd for supporting the research as
well as the University of Nottingham’s Chemistry Class of 1960
Alumni (summer fellowship for P.L.).
22. Typical procedure for the synthesis of TBS-enol ethers 5: To a stirred solution of
(E)-2-buten-1-ol (1c, 0.19 mL, 2.2 mmol) and DABCO (22 mg, 0.2 mmol) in dry
toluene (2 mL) at rt was added ethyl propiolate (2a, 0.20 mL, 2.0 mmol)
dropwise over 10 min and the resultant solution was stirred for 0.5 h at rt. The
mixture was heated to 150 °C for 15 h, cooled to rt and DMAP (25 mg,
0.2 mmol), Et3N (0.34 mL, 2.4 mmol) and TBS-Cl (332 mg, 2.2 mmol) were
added. The mixture was stirred for 3 h at rt. H2O (20 mL) was added and the
mixture was extracted with Et2O (3 Â 20 mL). The combined organic extracts
were washed with brine (20 mL) and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure to give ethyl 2-{[(tert-
butyldimethylsilyl)oxy]methylene}-3-methylpent-4-enoate (5c, 460 mg, 81%)
as a brown oil.
23. Typical procedure for the synthesis of Boc-enol ethers 6: To a stirred solution of 2-
buten-1-ol (1c, 0.19 mL, 2.2 mmol) and DABCO (22 mg, 0.2 mmol) in dry
toluene (2 mL) at rt was added ethyl propiolate (2a, 0.20 mL, 2.0 mmol)
dropwise over 10 min and the resultant solution was stirred for 0.5 h at rt. The
mixture was heated to 150 °C for 15 h, cooled to rt and DMAP (24 mg,
0.2 mmol), Et3N (0.28 mL, 2.0 mmol) and Boc2O (0.87 g, 4.0 mmol) were added.
The mixture was stirred for 3 h at rt. H2O (20 mL) was added and the mixture
was extracted with Et2O (3 Â 20 mL). The combined organic extracts were
washed with brine (20 mL) and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure to give ethyl 2-{[(tert-butoxy-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.035.
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