An efficient DABCO-catalyzed Ireland-Claisen rearrangement of allylic acrylates

Article abstract of DOI:10.1055/s-2007-967985

A novel DABCO-catalyzed Ireland-Claisen [3,3]-rearrangement of allylic acrylates to give α-methylene-γ,δ-unsaturated carboxylic acids in the presence of an excess of TMSCl and DBU in refluxing acetonitrile was developed. The protocol provides an easy entry to α-methylene-γ, δ-unsaturated carboxylic acids from allylic alcohols in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-967985

288
LETTER
An Efficient DABCO-Catalyzed Ireland–Claisen Rearrangement of Allylic
Acrylates
D
ABCO-Catalyze
u
d Ireland–Cla
n
ise
n
Rearran
x
gement of
A
i
llylic
A
a
crylates Li,a Quanrui Wang,*a Andreas Goeke,b,c Georg Fráter*c
a
Department of Chemistry, Fudan University, 200433 Shanghai, P. R. of China
Fax +86(21)65641740; E-mail: qrwang@fudan.edu.cn
b
c
Shanghai Givaudan Ltd., Fragrances, 201203 Shanghai, P. R. of China
Givaudan Schweiz AG, Fragrance Research, Überlandstrabe 138, 8600 Dübendorf, Switzerland
Fax +41(44)8242926; E-mail: georg.frater@givaudan.com
Received 17 October 2006
biologically interesting compounds. Recent examples in-
clude the herbertane sesquiterpenes,4 (–)-dactylolide,5
Pro-Pro E-alkene dipeptide isostere,6 anticancer agent
roseophilin7 and 1,22-dihydroxynitianes.8
Abstract: A novel DABCO-catalyzed Ireland–Claisen [3,3]-rear-
rangement of allylic acrylates to give a-methylene-g,d-unsaturated
carboxylic acids in the presence of an excess of TMSCl and DBU
in refluxing acetonitrile was developed. The protocol provides an
easy entry to a-methylene-g,d-unsaturated carboxylic acids from
allylic alcohols in good yields.
By far the most frequently employed method for the ste-
reoselective generation of either Z- or E-configured ester
enolates has been the deprotonation using a strong base.
Several other strategies have also been developed,3 such
as conjugate additions of organometallic nucleophiles to
allyl acrylates and trapping the enolate intermediates as
silylketene acetals,3c and dimerization of allyl acrylates to
the dimeric silylketene acetals via electrochemical reduc-
tion.9 All of these require stoichiometric quantities of
reagents.
Key words: DABCO, allylic acrylates, Ireland–Claisen rearrange-
ment, a-methylene-g,d-unsaturated carboxylic acids
The thermal sigmatropic rearrangement of allyl vinyl
ethers, referred to as the Claisen rearrangement,1 provides
an excellent route to g,d-unsaturated carbonyl compounds
from allylic alcohols. Among numerous variants, the Ire-
land–Claisen rearrangement of allylic esters has attracted
much attention since its discovery in 1972 by Ireland and
Mueller.2,3 Generally, the allylic ester is first deprotonated
with a strong base like LDA to give the corresponding
enolate. In order to avoid the possible aldol side reactions
under these basic conditions, the enolates are usually
transformed to silylketene acetals in the presence of a
silylating agent prior to the rearrangement.3 The sub-
sequent Ireland–Claisen rearrangement proceeds to pro-
vide, after hydrolysis of the silyl ester, a g,d-unsaturated
carboxylic acid (Scheme 1).
In 1993, Inanaga reported the first example of a tricyclo-
hexylphosphine-catalyzed Ireland–Claisen rearrange-
ment.10 This provided an efficient entry to a-methylene-
g,d-unsaturated carboxylic acids. Thomas and Smith suc-
cessfully utilized this method as a key step in an approach
to a synthesis of galbonolide B.11
Herein, we report the use of 1,4-diaza-bicyclo[2.2.2]oc-
tane (DABCO) as a nucleophilic catalyst in the Ireland-
type [3,3]-rearrangement of a range of allylic acrylates.
Being a moderately hindered weak base yet a nucleophile,
DABCO has well been applied for catalyzing the Baylis–
Hillman reaction12,13 and N-methylation of indoles with
dimethyl carbonate.14 This novel method for effecting the
Claisen rearrangement is of interest considering the fact
that trialkylphosphines are generally very expensive and
the use of them is often found to be rather inconvenient
due to their propensity to oxidation.
R2
R2
R2
R3
R1
R5
R3
R1
R5
R3
R1
R5
R4
1.
1. LiNR2
2. TMSCl
2. H3O+
O
O
O
R4
R4
O
OH
OTMS
Scheme 1
R1
R2
+
HO
R1
R2
2a–j
1. THF, r.t.
2. H3O+
CH2
CH2=CHCOCl
In contrast to the classical Claisen rearrangement, the es-
ter Ireland–Claisen rearrangement can be induced under
much milder conditions, often at below ambient tempera-
tures, thus allowing the reaction to convert acid-sensitive
and thermally unstable molecules.3 In fact, the Ireland–
Claisen rearrangement has been frequently exploited as a
key step in synthesis of many naturally occurring and/or
CHMgBr
O
80–95%
Et3N
65–95%
1a–j
1. DABCO, TMSCl, DBU
2. aq HCl
CO2H
O
R1
R2
R1
O
75–90%
R2
3a–j
4a–j
Scheme 2
SYNLETT 2007, No. 2, pp 0288–0292
0
1.
0
2.
2
0
0
7
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-967985; Art ID: W21506ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
DABCO-Catalyzed Ireland–Claisen Rearrangement of Allylic Acrylates
289
The synthetic sequence is depicted in Scheme 2. The As shown in Table 1, the diastereoselective rearrange-
allylic alcohols 2 required for the generation of esters 3 ment delivered products with exclusive E-configuration
were readily obtained from the Grignard addition reaction in the case of secondary allyl esters (Table 1, entries 1–3),
of vinylmagnesium bromide to the corresponding alde- or, in the case of tertiary esters, preferentially E-config-
hydes or ketones 1 in THF, except for linalool (2g), which ured acids (Table 1, entries 4, 6, 7). The predominance of
was commercially available. The synthesis of the corre- E-products can be accounted for by a plausible chair-
sponding acrylates 3 was accomplished by the reaction of shaped transition state with the more sterically demanding
acryloyl chloride with the alcohols 2 in the presence of group adopting the pseudo-equatorial position (see be-
catalytic amounts of triethylamine in moderate to high low).18
yields.17
Worthy of note is that in the reaction of vinyl- and phenyl-
The rearrangement of esters 3 were carried out with substituted allyl esters 3i and 3j migration of the a-meth-
DABCO as the catalyst under conditions comparable to yleno double bond to the aliphatic chain occurred under
those described by Inanaga.10 Thus, 3a was treated with our conditions, affording the fully conjugated carboxylic
DABCO (0.2 equiv), trimethylsilyl chloride (TMSCl, 3.0 acids 4i and 4j, respectively (Table 1, entries 9, 10).
equiv), and DBU (2.0 equiv) in acetonitrile under reflux.
The reaction was monitored by TLC and the rearrange-
To further test the applicability of the protocol, we exam-
ined the molecular transformation of 3k, which was easily
ment was complete after seven hours. Acidic work-up
prepared from 4-hydroxy-3,5,5-trimethylcyclohex-2-
furnished the a-methylene-4-octenoic acid (4a) in 84%
enone. It can be envisaged that in the presence of large
quantities of trimethylsilyl chloride 3k would give the si-
lyloxy diene 5 (Figure 1) with concurrent formation of the
required structure for Ireland–Claisen rearrangement. In-
isolated yield.15 We found also that the addition of
DABCO was indispensable for the reaction, even though
DBU is a comparable nucleophile.16
Several other organic bases, such as Et3N, i-Pr2NEt and deed, the rearranged product 4k was formed after 24 hours
DMAP as well as PPh3 were also examined to promote the by employing 0.3 equivalents of DABCO, 10.0 equiva-
rearrangement. However, under a variety of different lents of TMSCl and 3.0 equivalents DBU. Apparently, the
conditions, no or unacceptable yields of the desired prod- initial rearrangement product isomerized under the
ucts were obtained. This might be due to the decrease of reaction conditions. However, the reaction proceeded to
nucleophilicity in comparison with DABCO.
provide a low (15%) yield of the product with 85% con-
version. Most of the substrate had suffered decomposition
as indicated by the isolation of the starting alcohol in 55%
yield (Table 1, entry 11). Instead of DABCO, tricyclohex-
ylphosphine was found to be more active, leading to the
formation of 4k in 75% yield (Table 1, entry 12).
This result encouraged us to explore the generality of our
method. A range of allylic esters were then subjected to
the Ireland–Claisen rearrangement according to our pro-
tocol, including the esters derived from secondary and ter-
tiary allylic alcohols carrying aliphatic, olefinic and
aromatic substituents. In general, all of the reactions test-
ed worked well and the unsaturated carboxylic acid prod-
ucts were obtained in high yields after 7–15 hours. The
results are summarized in Table 1. The configurations of
compounds 4 were unambiguously determined either
through data comparison with the literature reports or via
analysis of 1H NMR, 13C NMR, and 2D NMR spectra.17
O
O
OTMS
5
Figure 1
Table 1 DABCO-Catalyzed Ireland–Claisen Rearrangement of Allylic Acrylatesa
Entry
Substrate
Time (h)
Product
Yield (%)b,c
E:Z ratiod
O
COOH
84b
>99:1
O
1
7
4a
4b
3a
3b
O
COOH
80b
>99:1
O
2
7
Synlett 2007, No. 2, 288–292 © Thieme Stuttgart · New York

290
Y. Li et al.
LETTER
Table 1 DABCO-Catalyzed Ireland–Claisen Rearrangement of Allylic Acrylatesa (continued)
Entry
3
Substrate
Time (h)
7.5
Product
Yield (%)b,c
E:Z ratiod
O
COOH
O
86b
>99:1
4c
3c
O
O
O
COOH
COOH
O
O
O
4
5
12
10
75b
53:47
4d
3d
3e
82b
4e
4f
COOH
6
7
8
13
15
12
81b
79b
85b
80:20
61:38
3f
O
O
COOH
O
O
3g
4g
HOOC
4h
3h
3i
O
O
HOOC
Ph
O
9
8
88c
90c
>99:1
>99:1
Ph
4i
HOOC
O
O
10
8.5
4j
3j
11e
12f
12
12
15b
75b
HOOC
O
O
O
3k
3k
4k
4k
a The reaction was carried out in MeCN under reflux, using DABCO (0.2 equiv), TMSCl (3.0 equiv), and DBU (2.0 equiv).
b Isolated yield by chromatography.
c Isolated yield by recrystallization.
d The trans/cis ratio by GC.
e DABCO (0.3 equiv), TMSCl (10.0 equiv), and DBU (3.0 equiv) were used. Conversion reached 85%. 4-Hydroxy-3,5,5-trimethylcyclohex-2-
enone was isolated in 55% yield.
f PCy3 (0.2 equiv), TMSCl (10.0 equiv), and DBU (2.5 equiv) were used. Conversion reached 100%. 4-Hydroxy-3,5,5-trimethylcyclohex-2-
enone was isolated in 5% yield.
Synlett 2007, No. 2, 288–292 © Thieme Stuttgart · New York

LETTER
DABCO-Catalyzed Ireland–Claisen Rearrangement of Allylic Acrylates
291
OTMS
Acknowledgment
OH
H3O+
2
Y.L. and Q.W. are grateful to the Givaudan Schweiz AG for finan-
cial support under the Discovery-Project (No. 04174). The diligent
assistance of Mr. Yongjun Wang (Spring 2006) and Mr. Ruiyao
Wang (Spring 2005) as undergraduate research participants is much
appreciated.
O
R
2
O
R
R1
R1
IV
O
4
DBU-H+
DBU
NR3 OTMS
N
R1
R2
O
N
DABCO
R3N
3
References and Notes
2
O
R
O
H
R1
(1) For an excellent review on the thermal, aliphatic Claisen
rearrangement, see: Ziegler, F. E. Chem. Rev. 1988, 88,
1423.
(2) (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94,
5897. (b) Ireland, R. E.; Mueller, R. H.; Willard, A. F. J. Am.
Chem. Soc. 1976, 98, 2868. (c) Ireland, R. E.; Wipf, P.;
Armstrong, J. D. J. Org. Chem. 1991, 56, 650. (d) Gilbert,
J. C.; Yin, J.; Fakhreddine, F. H.; Karpinski, M. L.
Tetrahedron 2004, 60, 51.
R1
R2
III
O
[3,3]-rearrangement
OTMS
I
R3N
O
TMSCl
R1
II
R2
Scheme 3 Reaction mechanism for the DABCO-catalyzed rearran-
(3) For excellent recent reviews, see: (a) Martin-Castro, A. M.
Chem. Rev. 2004, 104, 2939. (b) Chai, Y.-H.; Hong, S.-p.;
Lindsay, H. A.; McFarland, C.; McIntosh, C. Tetrahedron
2002, 58, 2905. For sequential 1,4-addition–Claisen
rearrangement, see: (c) Aoki, Y.; Kuwajima, I. Tetrahedron
Lett. 1990, 31, 7457. (d) Takai, K.; Ueda, T.; Kaihara, H.;
Sunami, Y.; Moriwake, T. J. Org. Chem. 1996, 61, 8728.
(4) Srikrishna, A.; Lakshmi, B. V. Tetrahedron Lett. 2005, 46,
4879.
(5) Louis, I.; Hungerford, L. N.; Humphries, E. J.; McLeod, M.
D. Org. Lett. 2006, 8, 1117.
(6) Bandur, N. G.; Harms, K.; Koert, U. Synlett 2005, 773.
(7) Viseux, E. M. E.; Parsons, P. J.; Pavey, J. B. J.; Carter, C.
M.; Pinto, I. Synlett 2003, 1856.
gement of allylic acrylates
Like the trialkylphosphine as the catalyst,10 the following
mechanistic rationale for the DABCO-catalyzed Ireland–
Claisen rearrangement of allylic acrylates was proposed
(Scheme 3). In this reaction, DABCO functions as a nu-
cleophile to first react with allyl acrylates and to generate
the zwitterions I, which are intercepted by TMSCl to give
intermediate ammonium allyl silyl ketene acetals II. In
refluxing acetonitrile, II undergo [3,3]-sigmatropic
rearrangement resulting in the formation of the silyl ester
ammonium salt III. A chair conformation would be
preferred for the cyclic transition state with the larger
substituent R1 in the less-hindered pseudoequatorial posi-
tion. In the presence of the strongly hindered DBU, suc-
cessive deprotonation of III occurs to regenerate DABCO
as the catalyst and to furnish the silyl a-methylene-g,d-un-
saturated carboxylates IV. Final hydrolytic desilylation of
IV provides the a-methylene-g,d-unsaturated carboxylic
acids 4.
(8) Wilson, M. S.; Woo, J. C. S.; Dake, G. R. J. Org. Chem.
2006, 71, 4237.
(9) Troll, T.; Wiedemann, J. Tetrahedron Lett. 1992, 33, 3847.
(10) Hanamoto, T.; Baba, Y.; Inanaga, J. J. Org. Chem. 1993, 58,
299.
(11) Smith, P. M.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1
1998, 3541.
(12) (a) Ciganek, E. Org. React. 1997, 51, 201. (b) Basavaiah,
D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811.
(13) The unexpected superiority of DABCO over more basic
tertiary amine catalysts in the Baylis–Hillman reaction
between acrylamide and aldehydes has been reported. See:
Faltin, C.; Fleming, E. M.; Connon, S. J. J. Org. Chem. 2004,
69, 6496.
In summary, we have established a novel, DABCO-
catalyzed Ireland–Claisen rearrangement leading to a-
methylene-g,d-unsaturated carboxylic acids. The protocol
accepts a wide range of allylic acrylates with good to high
yields. The products feature densely functionalized
compounds enabling easy further transformation. For
example, they can be employed as precursors for the con-
structions of a-methylene-g-butyrolactones,10,19 a family
that has created considerable attention over the years since
this kind of ring is a ubiquitous subunit in a wide variety
of biologically active natural products.20 Our protocol is
especially attractive since the reaction conditions are
mild, and all of the reagents are inexpensive and oxygen-
insensitive, hence without the necessity for rigorous sol-
vent purification and degassing associated with the use of
trialkylphosphines. We are currently investigating the
scope and limitations of this DABCO-catalyzed process
with respect to other unsaturated allylic esters as sub-
strates. Promising results have been achieved and will be
reported in the near future.
(14) Shieh, W.; Dell, S.; Bach, A.; Repič, O.; Blacklock, T. J. J.
Org. Chem. 2003, 68, 1854.
(15) General Procedure of the Rearrangement.
A reaction flask was charged with the allylic acrylate 3 (32.4
mmol), DABCO (0.73 g, 6.5 mmol), TMSCl (10.58 g, 97.4
mmol), DBU (9.90 g, 65.0 mmol) and MeCN (75 mL). The
mixture was heated under reflux and the reaction was
monitored by GC or TLC until the reaction was complete
(reaction time as specified in Table 1). Then, the volatiles
were removed under reduced pressure. The residue was
suspended in Et2O (100 mL) and stirred with 3 N HCl (40
mL) for a couple of minutes. The organic layer was
separated, and washed sequentially with brine and H2O,
dried over anhyd MgSO4 and concentrated in vacuo. The
residue was purified by column chromatography or
subjected to bulb-to-bulb distillation or recrystallization
from EtOH to afford the pure compounds 4a–h as a colorless
oil and 4i–j as a white solid (Table 1).
(16) Ghosh, N. Synlett 2004, 574.
Synlett 2007, No. 2, 288–292 © Thieme Stuttgart · New York

292
Y. Li et al.
LETTER
(17) All new compounds have been isolated in pure form and
characterized by spectral data (NMR, IR and MS).
(s), 126.8 (t), 117.6 (d), 36.8 (d), 29.4 (t), 21.4 (2q), 13.3 (q).
IR (KBr,): ca. 3000, 1695, 1630, 1434, 1284, 1156, 952
cm–1. MS (EI): m/z = 168 [M]+, 125 [M – C3H7]+.
Compound 4j: 1H NMR (300 MHz, CDCl3): d = 7.34 (d,
J = 11.4 Hz, 1 H), 6.55 (dd, J = 14.7, 10.5 Hz, 1 H), 6.39
(dd, J = 14.7, 11.4 Hz, 1 H), 6.22 (dd, J = 14.1, 10.5 Hz, 1
H), 5.96 (dq, J = 14.1, 6.8 Hz, 1 H), 1.95 (s, 3 H), 1.85 (d,
J = 6.8 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 173.7 (s),
141.0 (2 d), 135.0 (d), 131.6 (d), 125.2 (d), 125.0 (s), 18.6
(q), 12.3 (q). IR: (KBr): ca. 3000, 1678, 1601, 1427, 1316,
1268, 987, 929 cm–1. MS (EI): m/z = 152 [M]+, 107 [M –
CO2H]+.
Selected Data for Compounds 4.
Compound 4c: 1H NMR (300 MHz, CDCl3): d = 12.23 (br,
1 H), 6.33 (s, 1 H), 5.67 (br s, 1 H), 5.52 (dd, J = 15.5, 6.1
Hz, 1 H), 5.42 (dt, J = 15.5, 6.1 Hz, 1 H), 2.99 (d, J = 6.1 Hz,
2 H), 2.30 (dsept, J = 6.1, 6.8 Hz, 1 H), 1.00 (2 d, J = 6.8 Hz,
6 H). 13C NMR (75 MHz, CDCl3): d = 173.0 (s), 140.5 (d),
139.5 (s), 127.3 (t), 123.0 (d), 34.1 (t), 31.1 (d), 22.4 (2q). IR
(KBr): ca. 3000, 1698, 1436, 1289, 1158, 952 cm–1. MS (EI):
m/z = 154 [M]+, 111 [M – C3H7]+.
Compound 4e: 1H NMR (300 MHz, CDCl3): d = ca. 11.1 (br,
1 H), 6.32 (s, 1 H), 5.68 (s, 1 H), 5.15 (t, J = 7.2 Hz, 1 H),
3.03 (d, J = 7.2 Hz, 2 H), 2.08 (br q, J = 7.5 Hz, 2 H), 2.07
(q, J = 7.5 Hz, 2 H), 1.03 (t, J = 7.5 Hz, 3 H), 0.97 (t, J = 7.5
Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 173.1 (s), 145.6
(s), 139.5 (s), 126.9 (t), 118.2 (d), 29.2 (2 t), 23.2 (t), 12.1 (q),
12.8 (q). IR (KBr): ca. 3000, 1698, 1629, 1434, 1283, 1155,
954 cm–1. MS (EI): m/z = 168 [M]+, 139 [M – C2H5]+.
Compound 4f (major trans-isomer): 1H NMR (300 MHz,
CDCl3): d = ca. 11.0 (br, 1 H), 6.31 (s, 1 H), 5.65 (s, 1 H),
5.23 (t, J = 7.2 Hz, 1 H), 3.01 (d, J = 7.2 Hz, 2 H), 2.30 (sept,
J = 6.8 Hz, 1 H), 1.60 (s, 3 H), 1.03 (2 d, J = 6.8 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 173.1 (s), 144.1 (s), 139.1
Compound 4k: 1H NMR (400 MHz, CDCl3): d = 6.47 (s, 1
H), 5.92 (s, 1 H), 5.75 (s, 1 H), 3.19 (s, 2 H), 2.24 (s, 2 H),
2.22 (s, 2 H), 1.05 (s, 6 H). 13C NMR (100 MHz, CDCl3):
d = 28.3 (2 q), 33.7 (s), 39.6 (t), 43.8 (t), 51.0 (t), 125.8 (d),
130.3 (t), 136.0 (s), 161.1 (s), 171.1 (s), 200.6 (s). IR: (KBr):
ca. 3000, 2929, 1720, 1667, 1372, 1160, 982 cm–1. MS (EI):
m/z = 208 [M]+, 163 [M – CO2H]+.
(18) For a computational study on boat or chair preferences in the
Ireland–Claisen rearrangements of cylohexenyl silyl ketene
acetals, see: Khaledy, M. M.; Kalani, M. Y. S.; Khuong, K.
S.; Houk, K. N. J. Org. Chem. 2003, 68, 572.
(19) For a review on this topic, see: Hoffmann, H. M. R.; Rabe, J.
Angew. Chem., Int. Ed. Engl. 1985, 24, 94.
(20) Cateni, F.; Zilic, J.; Zacchigna, M.; Bonivento, P.; Frausin,
F.; Scarcia, V. Eur. J. Med. Chem. 2006, 41, 192; and
references cited therein.
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