Synthesis of Allenyl Esters by Horner-Wadsworth-Emmons Reactions of Ketenes Mediated by Isopropylmagnesium Bromide

Article abstract of DOI:10.1055/s-0034-1378803

The synthesis of conjugated allenyl esters (tri-substituted allenes) was achieved by magnesium(II)-mediated Horner-Wadsworth-Emmons reaction of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate with disubstituted ketenes. In addition, a novel access to α-fluorinated allenyl carboxamides (tetrasubstituted allenes) is presented.

Full text of DOI:10.1055/s-0034-1378803

SYNLETT
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2
1
4
1
4
3
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-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2135–2138
letter
2135
S. Sano et al.
Letter
Synlett
Synthesis of Allenyl Esters by Horner–Wadsworth–Emmons Reac-
tions of Ketenes Mediated by Isopropylmagnesium Bromide
Shigeki Sano*
1) i-PrMgBr
O
P
Tomoya Matsumoto
Teppei Yano
Ph
H
CF3CH2O
CF3CH2O
Ph
2)
98% yield
•
CO2Me
•
O
Me
CO2Me
Munehisa Toguchi
Michiyasu Nakao
Me
or
CON(OMe)Me
or
O
Ph
F
THF
0 °C
20 examples
EtO
EtO
Graduate School of Pharmaceutical Sciences, Tokushima
University, Sho-machi, Tokushima 770-8505, Japan
ssano@tokushima-u.ac.jp
100% yield
•
P
Me
CON(OMe)Me
F
Received: 03.06.2015
Accepted after revision: 17.06.2015
Published online: 10.08.2015
situ from 2-phenylpropionyl chloride (5a) and triethyl-
amine,9g,j as shown in Table 1. Phosphonoacetate 1 is a typi-
cal Z-selective HWE reagent due to the electron-withdraw-
ing effect of the two trifluoroethoxy groups on its phospho-
rus atom. As expected, the desired conjugated allenyl ester
6a (tri-substituted allene) was obtained by the HWE reac-
tion of 1 in good to excellent yields by using bases such as
n-BuLi, NaH, and i-PrMgBr (entries 1–3). Among these, i-
DOI: 10.1055/s-0034-1378803; Art ID: st-2015-u0413-l
Abstract The synthesis of conjugated allenyl esters (tri-substituted al-
lenes) was achieved by magnesium(II)-mediated Horner–Wadsworth–
Emmons reaction of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate
with disubstituted ketenes. In addition, a novel access to α-fluorinated
allenyl carboxamides (tetrasubstituted allenes) is presented.
Key words Horner–Wadsworth–Emmons reaction, allenes, ketenes,
Grignard reagents, fluorine
Table 1 HWE Reactions of Phosphonoacetates 1–4 with Phenyl Methyl
Ketene Prepared In Situ from 2-Phenylpropionyl Chloride (5a)
Since the first synthesis of glutinic acid (allene-1,3-di-
carboxylic acid) in 1887,1 allenes have attracted consider-
able attention as chemical curiosities.2 Furthermore, allene
derivatives have recently been established as versatile
building blocks in organic synthesis, including asymmetric
synthesis.3 Allenic structures are also found in natural
products and pharmaceutical agents.4 We have already es-
tablished a characteristic method of synthesizing conjugat-
ed allenyl esters from diethyl α-alkynyl-α-methoxy
malonates through a cascade reaction,5 and suggested the
possibility of developing novel inhibitors of cysteine prote-
ase based on several biomimetic reactions by using conju-
gated allenyl compounds and their precursors.6 On the oth-
er hand, the Horner–Wadsworth–Emmons (HWE) reaction
of phosphonoacetates with aldehydes (or ketones) is one of
the most useful methods of synthesizing α,β-unsaturated
esters.7 There are, however, only a limited number of re-
ports concerning the HWE reaction of ketene for the prepa-
ration of allenyl esters.8,9 We now describe a facile one-pot
synthesis of allenyl esters (tri- or tetra-substituted allenes)
by HWE reactions of ketenes using i-PrMgBr as base.
Et3N (2 equiv)
Ph
COCl
base
Me
5a
O
P
Ph
H
(1.1 equiv)
(2 equiv)
R1O
R2O
CO2R3
•
Me
CO2R3
THF
THF
1–4
6a,a'
0 °C, 1 h
0 °C, 1 h
1: R1 = R2 = CF3CH2, R3 = Me
2: R1 = R2 = Ph, R3 = Et
6a: R3 = Me
6a': R3 = Et
3: R1 = CF3CH2, R2 = Me, R3 = Me
4: R1 = R2 = R3 = Me
Entry
HWE reagent
Base
Yield (%)a
1
1
1
1
2
3
4
n-BuLi
68 (6a)
5 (6a)
2
NaH
3
i-PrMgBr
i-PrMgBr
i-PrMgBr
i-PrMgBr
98 (6a)
96 (6a′)
81 (6a)
72 (6a)
4
5
We first investigated HWE reactions of methyl bis(2,2,2-
trifluoroethyl)phosphonoacetate (Still–Gennari reagent,
1)10,11 with a di-substituted ketene, which was prepared in
6
a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2135–2138

2136
S. Sano et al.
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PrMgBr afforded allenyl ester 6a in almost quantitative
yield (98%).12,13 We have reported the use of stereoselective
HWE reactions for the preparation of α,β-unsaturated es-
ters by using i-PrMgBr.14 Thus, HWE reagents 2–4 were in-
vestigated in the HWE reaction mediated by i-PrMgBr for
the preparation of conjugated allenyl esters 6a and 6a′
(entries 4–6). As a result, Z-selective HWE reagent 2 (Ando
reagent)15,16 also furnished 6a′ in excellent yield (96%). It
appears that increasing the Z-selectivity of HWE reagents in
the reaction with aldehydes and ketones tends to increase
the chemical yield of allenyl ester 6a (entries 3, 5, and 6).
To explore the substrate scope of the HWE reaction, a
range of ketenes generated in situ from the corresponding
acyl chlorides 5a–h were subjected to reaction with HWE
reagent 1 as shown in Table 2. In all cases investigated, HWE
reactions of di-substituted ketenes derived from acyl chlo-
rides 5b–e proceeded smoothly to afford 90–100% yields of
the desired allenyl esters 6b–e (tri-substituted allenes)
(entries 1–4). On the other hand, the HWE reaction of
mono-substituted ketenes derived from acyl chlorides 5f–h
resulted in the formation of allenyl esters 6f–h (di-substi-
tuted allenes) in low yields (entries 5–7). It is interesting to
note that a similar HWE reaction of ketenes derived from
5f–h with α-methylated Still–Gennari reagent (7)17 afforded
the corresponding allenyl esters 8f–h (tri-substituted al-
lenes) in higher yields than those of 6f–h (entries 8–10).
The HWE reaction of 7 with phenyl methyl ketene derived
from acyl chloride 5a furnished allenyl ester 8a (tetra-sub-
stituted allene) in 89% yield (entry 11).
We next investigated the use of ethyl 2-fluoro-2-dieth-
ylphosphonoacetate (9)18,19 in place of 1 as the HWE re-
agent to obtain a fluorinated allenyl ester. There are very
few examples of the synthesis of α-fluorinated allenyl es-
ters.20 As a result, the desired product 12a (tetra-substitut-
ed allene) was obtained in moderate yield (Table 3, entry 1).
However, the HWE reaction of phosphonoacetic acid 10 us-
ing 2.1 equivalent of i-PrMgBr did not proceed (entry 2).
Nevertheless, the HWE reaction of Weinreb amide 1121
with di-substituted ketenes derived from acyl chlorides 5a–
c afforded fluorinated allenyl carboxamides 14a–c (tetra-
substituted allenes) in 71–100% yields (entries 3–8).22 Un-
fortunately, poor yields of fluorinated allenyl carboxamides
Table 3 HWE Reactions of α-Fluorophosphonoacetates 9–11 with
Ketenes Prepared In Situ from Acid Chlorides 5a–c and 5f–h
Et3N (2 equiv)
R1
COCl
5a–c,f–h
i-PrMgBr
R2
R1
R2
F
O
P
O
(1.1 equiv)
(2 equiv)
Table 2 HWE Reactions of Phosphonoacetates 1 and 7 with Ketenes
Prepared In Situ from Acid Chlorides 5a–h
EtO
EtO
•
X
COX
THF
THF
F
0 °C, 1 h
0 °C, 1 h
Et3N (2 equiv)
12–14
9–11
R1
COCl
9: X = OEt, 10: X = OH, 11: X = N(OMe)Me
5a–h
R2
i-PrMgBr
R1
R2
R
O
P
(1.1 equiv) (2 equiv)
Entry
HWE reagent
R1
Ph
R2
Me
Yield (%)a
CF3CH2O
CF3CH2O
•
CO2Me
1
2c
3
9 (X = OEt)
ca. 57 (12a)b
0 (13a)
CO2Me
THF
THF
R
10 (X = OH)
Ph
Me
Me
Me
Me
Et
0 °C, 1 h
0 °C, 1 h
1 R = H
7 R = Me
6b–h R = H
8a,f–h R = Me
11 [X = N(OMe)Me]
11 [X = N(OMe)Me]
11 [X = N(OMe)Me]
11 [X = N(OMe)Me]
11 [X = N(OMe)Me]
11 [X = N(OMe)Me]
11 [X = N(OMe)Me]
11 [X = N(OMe)Me]
11 [X = N(OMe)Me]
11 [X = N(OMe)Me]
Ph
71 (14a)
90 (14a)
100 (14a)
71 (14b)
94 (14b)
92 (14c)
0 (14f)f
4d
5e
6
Ph
Entry
HWE reagent
R1
R2
Yield (%)a
Ph
Ph
1
2
1 (R = H)
1 (R = H)
1 (R = H)
1 (R = H)
1 (R = H)
1 (R = H)
1 (R = H)
7 (R = Me)
7 (R = Me)
7 (R = Me)
7 (R = Me)
Ph
Et
Ph
Me
Me
H
100 (6b)
100 (6c)
90 (6d)
97 (6e)
29 (6f)
38 (6g)
22 (6h)
40 (8f)
69 (8g)
65 (8h)
89 (8a)
7e
8
Ph
Et
Ph
Ph
Ph
H
3
4-O2NC6H4
4-MeOC6H4
Ph
9
Ph
4
10
11e
12
Bn
H
0 (14g)g
5
Bn
H
ca. 14 (14g)b,h
0 (14h)i
6
Bn
H
n-C6H13
H
7
n-C6H13
Ph
H
a Isolated yield.
8
H
b Containing small amounts of impurities.
c i-PrMgBr (2.1 equiv) was used.
9
Bn
H
d Reaction mixture was stirred for 3 h.
e Reaction mixture was stirred for 18 h.
f HWE reagent 11 was recovered (ca. 54%).
g HWE reagent 11 was recovered (ca. 40%).
h HWE reagent 11 was recovered (ca. 20%).
i HWE reagent 11 was not recovered.
10
11b
n-C6H13
Ph
H
Me
a Isolated yield.
b Reaction mixture was stirred for 3 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2135–2138

2137
S. Sano et al.
Letter
Synlett
14f–h (tri-substituted allenes) were obtained in the HWE
reaction of Weinreb amide 11 with mono-substituted
ketenes derived from acyl chlorides 5f–h (entries 9–12).
In conclusion, we have developed a facile method of
synthesizing conjugated allenyl esters 6 and 8 through the
magnesium(II)-mediated HWE reaction of 1 and 7 with di-
substituted ketenes, which were prepared in situ from the
corresponding acid chlorides. For the first time, α-fluorinat-
ed allenyl carboxamides 14 have also been prepared by us-
ing the magnesium(II)-mediated HWE reaction of 11 with
di-substituted ketenes. We believe that the proposed meth-
od of synthesizing conjugated allenyl carboxylic acid deriv-
atives is a valuable addition to the chemistry of allenes.
Watanabe, T.; Tanaka, K. Tetrahedron: Asymmetry 2001, 12, 669.
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Y.; Sun, X.-L.; Jing, Q.; Tang, Y. Chem. Commun. 2006, 2980. (i) Li,
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Acknowledgment
This work was supported in part by a JSPS KAKENHI Grant (Number
2359007) and by a Grant for the Regional Innovation Cluster Program
(Global Type) promoted by MEXT.
(10) DeHoff, B.; Roy, M.-N. Methyl bis(2,2,2-trifluoroethoxy)phos-
phinylacetate, In e-EROS Encyclopedia of Reagents for Organic
Synthesis; Wiley: New York, 2012.
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Supporting Information
Supporting information for this article is available online at
(12) Typical Procedure: To a solution of methyl bis(2,2,2-trifluoro-
ethyl)phosphonoacetate (1; 40 μL, 0.188 mmol) in anhydrous
THF (1.9 mL) was added i-PrMgBr (0.77 mol/L in THF, 269 μL,
0.207 mmol), and the solution was stirred at 0 °C for 1 h under
argon. After adding triethylamine (53 μL, 0.377 mmol) and 2-
phenylpropionyl chloride (5a; 56 μL, 0.377 mmol), the mixture
was stirred at 0 °C for 1 h under argon. The reaction mixture
was treated with sat. aq NH4Cl (2 mL) and then extracted with
CHCl3 (3 × 20 mL). The extract was dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The oily residue was puri-
fied by silica gel column chromatography (n-hexane–EtOAc,
12.5:1 to 11:1) to afford allenyl ester 6a (34.7 mg, 98%).
(13) Data for 6a: Pale-yellow oil; IR (neat): 2951, 1948, 1722, 1495,
1437, 1392, 1263, 1209, 1151 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 2.21 (d, J = 2.9 Hz, 3 H), 3.75 (s, 3 H), 5.90 (q, J = 2.9 Hz, 1 H),
7.27–7.28 (m, 1 H), 7.33–7.40 (m, 4 H). 13C NMR (125 MHz,
CDCl3): δ = 16.2, 52.1, 89.5, 105.5, 126.2, 127.9, 128.6, 134.3,
166.1, 214.0. MS (ESI): m/z [M + Na]+ calcd for C12H12NaO2:
211.0735; found: 211.0732. Anal. Calcd for C12H12O2: C, 76.57;
H, 6.43. Found: C, 76.27; H, 6.54.
(14) (a) Sano, S.; Ando, T.; Yokoyama, K.; Nagao, Y. Synlett 1998, 777.
(b) Sano, S.; Teranishi, R.; Nagao, Y. Tetrahedron Lett. 2002, 43,
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93. (d) Sano, S.; Takemoto, Y.; Nagao, Y. Tetrahedron Lett. 2003,
44, 8853. (e) Sano, S.; Matsumoto, T.; Nanataki, H.; Tempaku, S.;
Nakao, M. Tetrahedron Lett. 2014, 55, 6248.
(15) Roy, M.-N. Ethyl 2-(diphenoxyphosphinyl)acetate, In e-EROS
Encyclopedia of Reagents for Organic Synthesis; Wiley: New York,
2013.
http://dx.doi.org/10.1055/s-0034-1378803.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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3
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6
1
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4
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C
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.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2135–2138