Stereoselective synthesis of substituted dienes by the double ortho ester Claisen rearrangement

Article abstract of DOI:10.1016/j.tetlet.2004.12.015

This letter shows the highly stereoselective synthesis of substituted (E)-1,3-dienes from substituted propargylic diols via the double ortho ester Claisen rearrangement. The cyclohexyl-substituted diene undergoes thermal Diels-Alder cycloaddition with maleic anhydride to produce the corresponding bicyclic diester in highly stereoselective manner.

Full text of DOI:10.1016/j.tetlet.2004.12.015

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 779–782
Stereoselective synthesis of substituted dienes by the double
ortho ester Claisen rearrangement
Suk-pyo Hong, Sung-jun Yoon and Byung-chan Yu*
Department of Chemistry, Mokwon University, Daejon, 302-729, Republic of Korea
Received 6 November 2004; revised 2 December 2004; accepted 6 December 2004
Available online 18 December 2004
Abstract—This letter shows the highly stereoselective synthesis of substituted (E)-1,3-dienes from substituted propargylic diols via
the double ortho ester Claisen rearrangement. The cyclohexyl-substituted diene undergoes thermal Diels–Alder cycloaddition with
maleic anhydride to produce the corresponding bicyclic diester in highly stereoselective manner.
Ó 2004 Elsevier Ltd. All rights reserved.
1
The ortho ester Claisen rearrangement has been known
as one of the major methodologies in organic synthesis
because the methodology provides efficiency in conver-
sion and predictable stereochemistry in carbon–carbon
ester Claisen rearrangement of unsubstituted proparg-
6
ylic diol has been reported, to the best of our knowledge,
the stereoselectivity of the double Claisen rearrangement
of substituted propargylic diols has not been utilized as
a synthetic methodology for the stereodefined dienes in
an efficient manner. We here report the efficient and con-
cise syntheses of the substituted dienes employing the
novel double ortho ester Claisen rearrangement. The
substituted propargylic diols were prepared in moderate
to good yields by the direct addition of lithiated dianion
of propargylic alcohol (Scheme 1), or anion of THP pro-
2
bond formations. The general condition is that treat-
3
4
ment of an allylic or a propargylic alcohol with an
ortho ester in the presence of a catalytic amount of pro-
pionic acid gives rise to the corresponding olefinic ester
or allenic ester upon heating within the range of 80–
60 °C. The conversion is efficient due to the vinyl ether
of the Claisen precursor could be generated in situ
affording the corresponding ester in a good yield. The
ortho ester Claisen rearrangement of allenols providing
1
7
tected propargylic alcohol to the corresponding alde-
hydes at À78 °C.
5
the 1,3-dienes has also been reported. However, the
yields of the resulting dienes are generally low or moder-
ate. The stereoselectivity varies from low to high up to
The propargylic diols were treated with an excess tri-
ethylorthoacetate in the presence of a catalytic amount
of propionic acid. The mixtures were heated at 130 °C
for 3 to 24 h to afford the corresponding dienes in a
highly stereoselective manner. The isolated yields and
stereoselectivities are recorded in Table 1. The optimum
yields were observed when the rearrangement proceeded
without a high boiling solvent, such as toluene or xylene.
9
5:5.
We have been interested in the stereoselective synthesis
of 1,3-dienes by employing the double ortho ester Clai-
sen rearrangement of the propargylic diol with various
substituents. Although an example of the double ortho
R
CH C(OEt)
2
x n-BuLi
3
3
EtO2C
EtO C
H
o
CH CH CO H
2
3
2
2
HO
-78 C,RCHO
OH
HO
R
Scheme 1.
Keywords: The double ortho ester Claisen rearrangement; Substituted propargylic diols; (E)-1,3-dienes; Diels–Alder cycloaddition.
*
Corresponding author. Tel.: +82 042 829 7565; fax: +82 042 822 7560; e-mail: chanyu@mokwon.ac.kr
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.015

780
S. Hong et al. / Tetrahedron Letters 46 (2005) 779–782
a
Table 1. The double ortho ester Claisen rearrangement of the substituted propargylic diols
R
CH C(OEt)3
EtO C
2
3
EtO C
CH CH CO H
2
HO
OH
3
2
2
R
d
b
Entry
1
Substrate
Reaction time (h)
20
Product
Yield (%)
E/Z ratio
EtO C
2
72
99:1
EtO C
2
HO
OH
OH
1
2
4
EtO C
2
c
2
19
EtO C
56
91:9
2
HO
3
EtO C
2
(
CH ) CH
2 5 3
EtO C
3
4
10
24
2
84
58
83:17
95:5
HO
OH
(
CH ) CH
2 5
3
5
6
8
EtO C
2
(CH ) CH=CH
2 3 2
EtO C
2
HO
OH
(
CH ) CH=CH
2
2
3
7
EtO C
2
EtO C
5
6
9
2
72
63
97:3
HO
OH
OH
9
10
12
EtO C
2
EtO C
17
2
>99:1
HO
1
1
1
EtO C
2
EtO C
2
7
17
82
96:4
HO
HO
OH
3
14
EtO C
2
(
CH ) OTBS
2
4
c
EtO C
8
9
15
17
2
76
66
83:17
OH
(
CH ) OTBS
2
4
1
1
5
7
16
18
EtO C
2
Ph
c
EtO
C
90:10
2
HO
OH
Ph
EtO C
Cl
2
EtO C
2
c
1
1
0
1
13
10
70
22
78:22
2
0
HO
HO
OH
OH
1
2
9
1
Cl
EtO C
2
EtO C
2
c
79:21
22
a
b
c
Reaction conditions: 1 equiv of the propargylic diols, 5–7 equiv of triethylortho acetate, a catalytic amount of propionic acid at 120–130 °C.
E/Z ratios were determined by capillary GC analysis.
1
E/Z ratios were determined by H NMR analysis.
d
Isolated yields.

S. Hong et al. / Tetrahedron Letters 46 (2005) 779–782
781
Propionic acid was used within 10 mol% of the diols.
During the reaction we were able to observe the interme-
diate allenol according to TLC analysis.
HO
CH C(OEt)3
3
HO
OH
O
CH CH CO H
3
2
2
OEt
1
3
26
The rearrangement of methyl-substituted propargylic
diol 1 gave the corresponding (E)-diene diethylester 2
in 72% yield with a 99:1 E/Z ratio according to capillary
1
GC and H NMR analysis. Chain elongation from ethyl
EtO
2
EtO C
O
to pentyl causes slightly decreasing selectivity, as shown
in entries 2 and 3. In the case of the rearrangement of
propargylic diol with pentenyl group bearing a terminal
olefin, an increase of stereoselectivity to 95:5 was ob-
served. An attempt to effect the novel double Claisen-
intramolecular Diels–Alder reaction with the terminal
olefinic diol in one pot has not been successful, but re-
sulted in decomposition after several attempts, probably
due to the presence of propionic acid during the Diels–
Alder reaction at a high temperature.
EtO2C
O
OEt
2
7
14
OEt
OEt
O
O
O
O
EtO H
4(E)
EtO H
H
H
As expected, an increase of the bulkiness of the substitu-
ent by employing isopropyl, tert-butyl and cyclohexyl
groups also gave great stereoselectivities of the dienes
H
H
1
2
7-chair
10, 12 and 14, respectively, as shown in entries 5, 6
and 7. Use of 4-(t-butyldimethylsilyloxy)butyl substitu-
ent caused a decreasing selectivity to 83:17 ratio accord-
ing to H NMR analysis. Although the stereoselectivity
H
O
1
H
of the rearrangement in entry 8 is not as great as in the
case of entry 1, this resulting diene is considered to be
attractive because the protected alcohol functionality
of diene 16 could be utilized to manipulate further chain
elongation, such as the incorporation of a dienophile to
effect the intramolecular Diels–Alder cycloaddition
afterward. The reaction of the diols bearing a phenyl
substituent gave the diene 18 with a selectivity of 90:10
in 66% yield. However, the presence of a para-substi-
tuted electron-withdrawing group leads to decreasing
selectivity, down to 78:22 as shown in entry 10. When
the benzyl group was substituted, the selectivity de-
creased to 79:21 as shown in entry 11, with a low yield.
The low yield might be caused from the elimination of
the starting benzyl-substituted propargylic diol. In the
case of the furan-substituted propargylic diol 23, we ob-
tained only the first Claisen adduct (an allenol) 24 in a
low yield (Scheme 2).
EtO H
O
EtO
2
7-boat
Scheme 3. Proposed mechanism of the double ortho ester Claisen
rearrangement of the cyclohexyl substituted propargylic diol 13.
O
O
O
O
H
H
o
240 C
EtO C
EtO C
2
2
+
EtO C
EtO C
2
2
O
O
14
Scheme 4.
28
29
The mechanism of the double ortho ester Claisen rear-
rangement of cyclohexyl substituted propargylic alcohol
as an exemplary reaction could be postulated as follows
the chair transition state is disposed as equatorial posi-
tion resulting the (E)-diene products exclusively.
(
2
Scheme 3): The diols would be converted to the allenol
6 which undergoes the second rearrangement to give
To demonstrate the novel Diels–Alder cycloaddition
with the diene the corresponding diene 14 was subjected
to thermal Diels–Alder cycloaddition reaction with
maleic anhydride to afford the bicyclic diester 29 in
78% yield with the selectivity of ca. >99:1(endo:exo)
the corresponding diene 14. The high stereoselectivity
probably comes from a chair transition state of the sec-
ond Claisen rearrangement which should be more stable
than the boat transition state of 27. The substituent in
8
,9
(Scheme 4).
In conclusion, we were able to synthesize the stereode-
fined 1,3-dienes starting from propargylic alcohol in a
two step sequence involving the double ortho ester Cla-
isen rearrangement in a high stereoselective manner. The
substituted dienes could be useful precursors for the
Diels–Alder reactions. Currently, we are investigating
the use of the dienes as key intermediates toward synthe-
sis of biologically interesting natural products.
EtO C
2
HO
O
EtO C
2
CH C(OEt)
3
O
OH
3
O
HO
O
OEt
2
3
2
4
25
Scheme 2.

782
S. Hong et al. / Tetrahedron Letters 46 (2005) 779–782
residue was chromatographed on silica gel. Elution with
Acknowledgments
8
3
0% ether in hexanes gave 5.5 g (91%) of the diol: IR (neat)
À1
1
305, 2924, 2242, 1450, 1006 cm ; H NMR (200 MHz,
) d 4.31 (2H, s, –CH OH), 4.19 (1H, d, J = 6.1 Hz,
methine), 1.81–1.17 (13H, m, –OH and cyclohexyl Hs) ppm.
This work has been supported by the Mokwon Univer-
sity Fund of 2004. We thank Sung-Kon Ryu of KRICT
for the assistance of NMR spectra.
CDCl
3
2
13
C NMR (125 MHz, CDCl
3.8, 28.5, 28.1, 26.2, 25.8 ppm; EI+ mass spectrum m/z
(%): 137 (M-CH OH, 9), 121 (8), 108 (9), 95 (11), 91 (9), 86
12), 83 (68), 68 (100), 55 (85).
3
) 85.5, 83.7, 77.4, 66.8, 50.5,
4
References and notes
2
(
3
-Cyclohexylmethylene-4-methylenehexanedioic acid diethyl
1
2
. Johnson, W. S.; Werthmann, L.; Bartlett, W. R.; Brockson,
T. J.; Li, T. T.; Faulkner, D. J.; Peterson, M. R. J. Am.
Chem. Soc. 1970, 92, 741.
. For review articles on the Claisen rearrangement: (a)
Ziegler, F. E. Chem. Rev. 1988, 88, 1423; (b) Lutz, R.
Chem. Rev. 1984, 84, 206; (c) Ziegler, F. E. Acc. Chem. Res.
ester (14). The mixture of 500 mg (3.0 mmol) of the
propargylic diol, 2.7 mL (15 mmol) of triethylorthoacetate
and 11 mg (0.15 mmol) of propionic acid was stirred for
1
7 h at 130 °C. The mixture was chromatographed on silica
gel. Elution with 10% ether in hexanes gave 750 mg (82%)
of the diene 14. The stereoselectivity of the ester was
observed to be 96:4 (E:Z) according to the analysis of gas
chromatography: IR (neat) 3085, 2925, 1738, 1631, 1447,
1
977, 10, 227; (d) Bennett, G. B. Synthesis 1977, 589.
. (a) Stork, G.; Raucher, S. J. Am. Chem. Soc. 1976, 98, 1583;
b) Daub, G. W.; Edwards, J. P.; Okada, C. R.; Allen, J.
3
(
À1
1
1
366, 1034, 979, 900 cm ; H NMR (200 MHz, CDCl
3
) d
W.; Maxey, C. T.; Wells, M. S.; Goldstein, A. S.; Dibley,
M. J.; Wang, C. J.; Ostercamp, D. P.; Chung, S.; Cunn-
ingham, P. S.; Berliner, M. A. J. Org. Chem. 1997, 62, 1976,
and references therein.
5
.23 (1H, d, J = 9.8 Hz, vinyl H), 5.14 and 4.97 (2H, d and
d, J = 1.6 Hz, terminal olefinic Hs), 4.10 (4H, q, J = 7.3 Hz,
OCH CH ), 3.16 and 3.08 (4H, s and s, methylenes), 2.30
–
2
3
(
1H, m, methine of cyclohexyl group), 1.80–1.40 (10H,
m, cyclohexyl Hs), 1.23 (6H, t, J = 7.3 Hz, –OCH CH
ppm; C NMR (125 Hz, CDCl ) 171.1, 170.5, 139.7, 138.3,
4
5
. (a) Handerson, M. A.; Heathcock, C. H. J. Org. Chem.
1
1
988, 53, 4736; (b) Ha, J. D.; Cha, J. K. J. Am. Chem. Soc.
999, 121, 10012.
2
3
)
1
3
3
1
1
2
(
5
31.2, 117.6, 60.4, 60.1, 42.0, 41.3, 37.7, 33.1, 25.8, 25.4,
3.9 ppm; EI+ mass spectrum m/z (%): 308 (M, 7), 263 (62),
34 (66), 220 (44), 205 (6), 188 (47), 175 (40), 161 (58), 147
100), 133 (27), 119 (40), 105 (58), 91 (57), 79 (36), 67 (27),
5 (32).
Rel-(3aR,7R,7aS)-(7-Cyclohexyl-6-ethoxycarbonyl methyl-
,3-dioxo-1,3,3a,4,7,7a-hexahydroisobenzofuran-5-yl) acetic
. (a) Bertrand, M.; Viala, J. Tetrahedron Lett. 1978, 19, 2575;
b) Egert, E.; Schumidt, D.; Gonschorreck, C.; Hoppe, D.
(
Tetrahedron Lett. 1987, 28, 789; (c) Behrens, U.; Wolff, D.;
Hoppe, D. Synthesis 1991, 644.
. Ishino, Y.; Nishiguchi, I.; Kim, K.; Hirashima, T. Synthesis
6
7
1982, 740.
1
. The diols 3, 7 and 17 were prepared by the following steps:
acid ethyl ester (29). The mixture of 300 mg (1.0 mmol) of
the diene, 470 mg (4.8 mmol) of maleic anhydride was
stirred for 5 h at 240 °C. Water was added. The aqueous
layer was separated and extracted with ether three times.
) n-BuLi, -78 oC, RCHO
R
1
H
THPO
2) PPTS, EtOH
HO
OH
The extracts were washed with brine, dried over MgSO
4
8
9
. For other examples of the endo Diels–Alder adducts using
maleic anhydride as dienophile, see: Stereoselective Synthe-
sis; Helmchen, G., Ed.; Georg Thieme: Stuttgart: New
York, 1996; Vol. 5, p 2802.
. The representative procedure of the cyclohexyl propargylic
diol, the following double ortho ester Claisen rearrange-
ment and the Diels–Alder cycloaddition reaction:
and concentrated under reduce pressure. The residue was
chromatographed on silica gel. Elution with 50% ether in
hexanes gave 310 mg (78%) of the ester (endo:exo = 99:1):
IR (neat) 2928, 1851, 1778, 1731, 1447, 1368, 1244, 1159,
À1
1
1030 cm
J = 7.2 Hz, –OCH
Hs), 3.33 and 2.91 (2H, AB, JAB = 15.5 Hz, –CH
3.75 and 3.05 (2H, AB, JAB = 16.8 Hz, –CH CO
(2H, m, allylic methylene), 2.54 (1H, d, J = 8.4 Hz, allylic
methylene), 1.90–1.14 (17H, m, cyclohexyl Hs, –OCH CH
) 174.5, 174.1, 170.2,
;
H NMR (200 MHz, CDCl
CH ), 3.44–3.41(2H, m, angular methine
CO Et),
Et), 2.61
3
) d 4.10 (4H, q,
2
3
2
2
1-Cyclohexylbut-2-yne-1,4-diol (13) To a solution 2.0 g
2
2
(
36 mmol) of the propargylic alcohol in 20 mL of THF
was added 30 mL (75 mmol) of 2.5 M solution n-BuLi in
hexanes dropwise at À78 °C. The solution was stirred for
2
)
3
1
3
ppm; C NMR (125 MHz, CDCl
3
1
h and then added 4.3 mL (36 mmol) of freshly distilled
170.1, 132.2, 128.9, 61.1, 61.0, 60.9, 48.0, 42.0, 40.2, 40.1,
39.9, 31.2, 31.2, 28.9, 26.4, 26.2, 26.1, 14.1, 13.9; EI+ mass
spectrum, m/z (%): 406 (M , 12), 361 (25), 333 (100), 304
cyclohexanealdehyde in a portion. The mixture was allowed
to warm to room temperature. Water was added. The
organic layer was separated and extracted with ether three
times. The extracts were washed with brine, dried over
MgSO4 and concentrated under reduced pressure. The
+
(6), 287 (55), 277 (11), 259 (87), 221 (7), 205 (65), 177 (71),
165 (25), 149 (30), 132 (18), 121 (22), 105 (93), 93 (17), 83
(40), 67 (13).