Studies of ring-closing mode of 4-hydroxy-2-vinylidenebutanoates: 5-exo-trig versus 5-endo-dig

Article abstract of DOI:10.1016/j.tetlet.2007.01.037

The ring-closing mode of benzyl 4-hydroxy-2-vinylidenebutanoates (5-exo-trig vs 5-endo-dig) could precisely be controlled in a highly selective manner by the proper choice of conditions (solvent and base).

Full text of DOI:10.1016/j.tetlet.2007.01.037

Tetrahedron Letters 48 (2007) 1735–1738
Studies of ring-closing mode of 4-hydroxy-2-vinylidene-
butanoates: 5-exo-trig versus 5-endo-dig
Shinji Kitagaki, Daisuke Shibata and Chisato Mukai*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology,
Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
Received 18 December 2006; revised 5 January 2007; accepted 9 January 2007
Available online 12 January 2007
Abstract—The ring-closing mode of benzyl 4-hydroxy-2-vinylidenebutanoates (5-exo-trig vs 5-endo-dig) could precisely be con-
trolled in a highly selective manner by the proper choice of conditions (solvent and base).
Ó 2007 Elsevier Ltd. All rights reserved.
The ring-closing mode, exo- versus endo-manner, some-
times becomes the central issue in the synthesis of target
cyclic compounds. The ring-closing mode might be
properly predicted on the basis of Baldwin’s rule1a that
is widely recognized as a reliable empirical rule. As a
typical example (Scheme 1), the exclusive formation of
a-methoxymethyl-c-lactone 3, via the reaction of the
intermediate of 2 with the liberated methoxide anion,
was observed when the a,b-unsaturated ester 1 was
exposed to basic conditions.1b This result could be
regarded as the so-called ‘5-exo-trig’ mode (route a),
which is a favored pathway based on Baldwin’s rule.1a
An alternative ‘5-endo-trig’ mode (a disfavored path-
way) leading to compound 4 could not be detected
(route b).1b
SO2Ph
SO2Ph
t-BuOK, t-BuOH, rt
n=1~4
n
n
OH
•
O
5
6
Scheme 2. Ring-closing reaction of phenylsulfonylallenes 5.
the five- to eight-membered oxacycles 6 (Scheme 2). In
this Letter, we have investigated the ring-closing reac-
tion of 1-(2-hydroxyalkyl)-1-(benzyloxycarbonyl)allene
derivatives under basic conditions to determine if the
terminal alkoxide species, generated in situ in the reac-
tion vessel, would preferentially attack the carbonyl
functionality through the 5-exo-trig mode or the central
carbon atom of the allene moiety through the 5-endo-dig
mode,5 both of which are the favored processes accord-
ing to Baldwin’s rule.1
During our studies2 on the ring-closing reaction of phen-
ylsulfonylallenes, we found that 1-(x-hydroxyalkyl)-1-
(phenylsulfonyl)allene derivatives 5 easily underwent
the endo-dig mode2a–e ring-closing reaction3,4 to produce
For the initial evaluation, the optimized conditions2 for
the endo-dig mode ring-closing reaction of phenyl-
sulfonylallenes 5 was examined for that of benzyl
4-hydroxy-2-vinylidenebutanoate 7.6 However, treat-
ment of 7 with t-BuOK (1 equiv) in t-BuOH (0.1 M
solution)à at room temperature for 5 min predominantly
produced the exo-trig mode product 8§ in a 65% yield
along with a small amount of the endo-dig mode product
a
O
O
O
O
a
b
OMe
OMe
O
O
OH
O
OMe
b
3
2
1
4
Scheme 1. 5-exo-Trig versus 5-endo-trig.
It took a prolonged time to completely consume the starting material
upon exposure to a catalytic amount of t-BuOK.
Keywords: Allenes; Ring-closing mode; Solvent effect; Baldwin’s rule.
à When the reaction ran in THF in the presence of t-BuOK, 8 was
obtained in a 33% yield as the only isolatable product.
*
Corresponding author. Tel.: +81 76 234 4411; fax: +81 76 234
4410; e-mail: cmukai@kenroku.kanazawa-u.ac.jp
§ The stereochemistry was determined to be (E) by an NOE analysis.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.037

1736
S. Kitagaki et al. / Tetrahedron Letters 48 (2007) 1735–1738
Table 1. Ring-closing reaction of primary alcohol
5-exo-trig mode product 8 in a highly selective manner
(entries 1–5), whereas the almost exclusive formation
of the 5-endo-dig mode product 9 was achieved when
treated with tertiary amine bases (entries 12–16). If the
tertiary amines, such as DBU, DBN, and DABCO,
attack first at the sp-hybridized carbon center of com-
pound 7, the corresponding benzyl 3-trialkylammo-
nium-2-(2-hydroxyethyl)-2-butenoate species 70 must
be formed in situ (Scheme 3).8 The transformation of
thus formed a,b-unsaturated ester intermediates into
compound 9 should involve the 5-endo-trig mode ring-
closing process of 700, which is, however, believed to be
the disfavored pathway on the basis of Baldwin’s rule.
Thus, it might be reasonable to describe that the ring-
closing reaction of compound 7 leading to 9 would pro-
ceed via the 5-endo-dig mode by the direct attack of the
terminal alkoxide group at the sp-hybridized carbon
center. In addition, the complementary production of
compounds 8 and 9 could be realized by simply chang-
ing the solvent upon exposure of 7 to Cs2CO3. The order
of solvent possessing a higher dielectric constant is as
follows: DMSO (46.45) > DMF (36.71) > MeCN
(35.94) > CH2Cl2 (8.93) > THF (7.58).9 On the basis of
the dielectric constant, these five solvents can be clearly
divided into two groups; one consists of DMSO, DMF,
and MeCN, and the other, CH2Cl2 and THF. The for-
mer group predominantly afforded the 5-endo-dig prod-
uct 9, whereas the latter group exclusively produced the
5-exo-trig product 8. Although a full mechanistic discus-
sion for the ring-closing reaction of compound 7 is pre-
mature at this point, the dielectric constant of the
solvent might govern the preferred conformation10 of
compound 7 and/or the transition state of the ring-clos-
ing process as long as Cs2CO3 was used as a base.
O
O
O
O
base
rt
OCH2Ph
OCH2Ph
+
OH
•
O
OR
7
8: R = CH2Ph
8': R = CH3
9
Entry Base (equiv)
Solvent Time
Yield
Yield
of 8 (%) of 9 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
t-BuOK (1.0)
t-BuONa (1.0) t-BuOH
t-BuOLi (1.0)
t-BuOH
5 min 65
5 min 47
6
8
a
t-BuOH 12 h
55
45b
34b
49
55
12
6
—
—
—
—
—
41
45
45
54
53
64
72
70
49
65
MeOK (2.0)
MeOLi (2.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
K2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
DBU (1.5)
DBU (1.5)
DBU (1.5)
DBN (1.5)
DABCO (3.0) DMSO 24 h
TBAF (1.5) DMSO 5 min
MeOH
MeOH
THF
2 h
6 h
24 h
a
a
CH2Cl2 24 h
DMF
DMF
MeCN
DMSO
THF
DMF
DMSO 30 min
DMSO 1 h
4 h
8 h
4 h
2 h
10
6
c
2 h
—
c
30 min
—
c
—
—
—
—
c
c
c
a A trace amount of 9 was detected by TLC.
b (E)-2-(1-Methoxyethylidene)-c-lactone (80) was obtained instead of 8.
c A trace amount of 8 was detected by TLC.
9 (6%) (Table 1, entry 1). t-BuONa and t-BuOLi gave
similar results, but with lower yields (entries 2 and 3).
Changing the alkoxide/alcohol system from t-BuOK/t-
BuOH to MeOK/MeOH or MeOLi/MeOH resulted in
the exclusive formation of (E)-2-(1-methoxyethylid-
ene)-c-lactone (80)– in rather low yields (45% and 34%
yield, respectively) (entries 4 and 5). Cs2CO3 in THF
or CH2Cl2 again exclusively afforded the exo-trig mode
product 8 (entries 6 and 7). In contrast to these results,
the endo-dig mode product 9 unexpectedly became the
major product (41%) when 7 was exposed to Cs2CO3
(1 equiv) in DMF at room temperature for 4 h (entry
8). K2CO3 was found to use instead of Cs2CO3 for the
preferential formation of the endo-dig mode product 9
(entry 9). Both MeCN and DMSO could also be used
as a suitable solvent for the selective production of 9 (en-
tries 10 and 11). Furthermore, tertiary amines, such as
DBU, DBN (1,5-diazabicyclo[4.3.0]non-5-ene), and
DABCO, were shown to be suitable bases for the highly
selective formation of the endo-dig mode product 9 (en-
tries 12–16). In particular, the best result (72%) was ob-
tained when 7 was treated with DBU (1.5 equiv)k in
DMSO at room temperature for 30 min (entry 14).
TBAF behaved like the tertiary amines, but with a much
faster consumption of the starting material (entry 17).7
There are several points that deserve to be mentioned.
An alkoxide/alcohol system consistently produced the
Secondary and tertiary alcohols 10, 11 were used for the
ring-closing reaction under the typical four conditions
(entries 1, 6, 11, and 14 in Table 1). These results are
summarized in Table 2. All reactions proceeded in a
highly selective manner to afford the 5-exo-trig mode
products 12, 14 or the 5-endo-dig mode products 13,
15 depending on the reaction conditions, although the
chemical yields of dimethyl derivatives 14, 15 are consis-
tently lower than those of products 8, 9 derived from the
primary alcohol 7. Thus, it became obvious that the
ring-closing mode (5-exo-trig vs 5-endo-dig) could be
controlled in a highly selective manner by the proper
choice of the reaction conditions,11 regardless of the
bulkiness of the nucleophilic alcohol moiety of the start-
ing allenes.
O
O
R3N
OCH2Ph
OCH2Ph
7
-
-
HO
R3N
O
+
+
R3N
7'
7"
R3N = DBU, DBN, DABCO
5-endo-trig
– Compound 8 could not be detected in the reaction mixture.
k 1 equiv of DBU could mediate the ring-closing reaction, but it took a
prolonged time to completely consume the starting material.
9
R3N
+
Scheme 3.

S. Kitagaki et al. / Tetrahedron Letters 48 (2007) 1735–1738
Table 2. Ring-closing reaction of secondary and tertiary alcohols
1737
R
O
O
O
O
R
R
O
OCH2Ph
OCH2Ph
base
rt
+
OH
•
OCH2Ph
10: R = H
11: R = Me
13: R = H
15: R = Me
12: R = H
14: R = Me
Entry
Substrate
Base (equiv)
Solvent
Time
exo-Prod (%)
endo-Prod (%)
a
1
2
3
4
5
6
7
8
10
10
10
10
11
11
11
11
t-BuOK (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
DBU (1.5)
t-BuOK (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
DBU (1.5)
t-BuOH
THF
DMSO
DMSO
t-BuOH
THF
5 min
24 h
4 h
30 min
5 min
24 h
12 (61)
12 (44)
—
—
a
b
—
—
13 (52)
13 (70)
b
c
14 (51)
14 (38)
—
c
—
d
DMSO
DMSO
3 h
30 min
—
—
15 (46)
15 (65)
d
a A trace amount of 13 was detected by TLC.
b A trace amount of 12 was detected by TLC.
c A trace amount of 15 was detected by TLC.
d A trace amount of 14 was detected by TLC.
Newly developed endo-dig mode ring-closing procedure
could nicely be applied to the synthesis of chiral
dihydrofuran 18 (Scheme 4). The methyl ester congener
of 18 has been shown to be a key synthetic intermediate
for the first total synthesis of (ꢀ)-xyloketal A.12 The
known propargyl alcohol 16,13 derived from methyl
(S)-3-hydroxy-2-methylpropionate, was treated with
benzyl chloroformate to give the corresponding carbon-
ate, conversion of which into allene 17 was achieved by
the successive Pd(OAc)2-mediated rearrangement14
under 10 atm CO at 40 °C and conventional depro-
tection reaction. Treatment of 17 with TBAF in DMSO
at room temperature exclusively furnished the 5-
endo-dig mode product 18 in a 53% yield.
ration of the larger-membered oxacycles as well as to the
synthesis of natural products are currently underway.
Acknowledgment
This work was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Cul-
ture, Sports, Science, and Technology, Japan, for which
we are thankful.
References and notes
1. (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
734–736; (b) Baldwin, J. E.; Cutting, J.; Dupont, W.;
Kruse, L.; Silberman, L.; Thomas, R. C. J. Chem. Soc.,
Chem. Commun. 1976, 736–738.
In conclusion, we have described that the ring-closing
mode (5-exo-trig vs 5-endo-dig) of benzyl 4-hydroxy-2-
vinylidenebutanoates could precisely be controlled in a
highly selective manner by the proper choice of condi-
tions (solvent and base). The endo-dig mode ring-closing
protocol of allenes was extended to the synthesis of a
key intermediate for the synthesis of (ꢀ)-xyloketal A.
Further studies on the reaction mechanism of this
ring-closing reaction, and application of it to the prepa-
2. (a) Mukai, C.; Yamashita, H.; Hanaoka, M. Org. Lett.
2001, 3, 3385–3387; (b) Mukai, C.; Ukon, R.; Kuroda, N.
Tetrahedron Lett. 2003, 44, 1583–1586; (c) Mukai, C.;
Kobayashi, M.; Kubota, S.; Takahashi, Y.; Kitagaki, S. J.
Org. Chem. 2004, 69, 2128–2136; (d) Mukai, C.; Ohta, M.;
Yamashita, H.; Kitagaki, S. J. Org. Chem. 2004, 69, 6867–
6873; (e) Mukai, C.; Kuroda, N.; Ukon, R.; Itoh, R. J.
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8, 1843–1845.
1. ClCO2CH2Ph, pyridine
O
CH2Cl2, 0 °C, 1 h
OCH2Ph
3. Parsons reported an exo-mode ring-closing reaction of
allenyl sulfoxide derivatives, see: (a) Pairaudeau, G.;
Parsons, P. J.; Underwood, J. M. J. Chem. Soc., Chem.
Commun. 1987, 1718–1720; (b) Gray, M.; Parsons, P. J.;
Neary, A. P. Synlett 1992, 597–598; (c) Gray, M.; Parsons,
P. J.; Neary, A. P. Synlett 1993, 281–282; (d) Parsons, P.
J.; Stefinovic, M. Synlett 1993, 931–932; (e) Edwards, N.;
Macritchie, J. A.; Parsons, P. J.; Drew, M. G. B.; Jahans,
A. W. Tetrahedron 1997, 53, 12651–12660.
4. Dai described an exo-mode cyclization of the allenyl
sulfone derivatives resulting in the formation of five-
membered oxacycles: Dai, W.-M.; Lee, M. Y. H. Tetra-
hedron 1998, 54, 12497–12512.
2. Pd(OAc)2 (5 mol%), PPh3
PhCH2OH, CO (10 atm)
40 °C, 12 h
OTBDPS
OH
•
OH
16
17 (51%)
3. TBAF, AcOH, THF
0 °C, 1 h
O
TBAF, DMSO
rt, 30 min
OCH2Ph
O
18 (53%)
Scheme 4. Synthesis of dihydrofuran 18.

1738
S. Kitagaki et al. / Tetrahedron Letters 48 (2007) 1735–1738
5. For example of 5-endo-dig mode cyclization of allenyl
mura, T.; Shinokubo, H.; Ohshima, K.; Omoto, K.;
Fujimoto, H. J. Am. Chem. Soc. 2000, 122, 11041–
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esters under basic conditions, see: Nagao, Y.; Kim, K.;
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6. Benzyl ester derivative 7 was chosen as the starting
material because it seemed to be easily handled and
monitored than the corresponding methyl ester.
11. The ring-closing reaction of benzyl 2-methylenebutanoate
A (benzyl ester congener of compound 1 in Scheme 1) was
examined under the several aforementioned basic condi-
tions as control experiments. In these cases, the corre-
7. Another condition (NaH in THF at 0 °C) afforded 8 in a
41% yield along with 9 in 7% yield. In addition, no
reaction occurred when Et3N (excess) in THF at room
temperature was used.
sponding a-benzyloxymethyl-c-lactone
B
(benzyloxy
congener of 3 in Scheme 1) was consistently obtained as
the only isolatable product in the range of 55–78% yield
regardless of the conditions.
8. Shi recently reported the intermolecular reaction of ethyl
2,3-butadienoate with salicyl N-tosylimine in the presence
of a catalytic amount of DABCO resulting in the
formation of the chromene derivatives (Shi, Y.-L.; Shi,
M. Org. Lett. 2005, 7, 3057–3060). The plausible mech-
anism of this reaction was proposed as follows. The initial
Michael-type addition of DABCO at the sp-hybridized
carbon center of ethyl 2,3-butadienoate would lead to the
production of the ethyl 3-trialkylammonium-2-butenoate
species, which would subsequently be captured by salicyl
N-tosylimine to give the chromene derivatives.
O
O
O
O
base
rt
OCH2Ph
OCH2Ph
+
OH
O
OCH2Ph
A
Base
B
C
Solvent
t-BuOH
THF
DMSO
DMSO
Yield
t
-BuOK
78%
67%
55%
62%
0%
0%
0%
0%
Cs2CO3
Cs2CO3
DBU
9. Riddick, J. A.; Bunger, W. B.; Sakano, T. K. Organic
Solvents: Physical Properties and Methods of Purification;
John Wiley & Sons: New York, 1986.
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1429.
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Chem. 2002, 67, 5517–5526.
14. Tsuji, J.; Sugiura, T.; Minami, I. Tetrahedron Lett. 1986,
27, 731–734.
10. Ohshima and co-workers demonstrated that the dielectric
constant of the solvent significantly affects the preferred
conformation of allyl a-iodoacetate during their studies on
its radical cyclization with Et3B: Yorimitsu, H.; Naka-