Twisted amides as selective acylating agents for hydroxyl groups under neutral conditions: Models for activated peptides during enzymatic acyl transfer reaction

Article abstract of DOI:10.1021/jo9522015

The highly twisted amide 2 served as a selective acylating agent for diols under neutral conditions. The reaction of primary-secondary diols with 2 led to the corresponding primary alkyl monopivalates. For diols containing alcoholic and phenolic hydroxyl groups, alcoholic hydroxyl groups were selectively acylated under neutral conditions, whereas, the opposite selectivity was observed under basic conditions, similar to the cases using acyl halides or acid anhydrides. Although 1 and 3 were unreactive to alcohols, 5-10 having substituent groups at C-4 were reactive to alcohols to give the corresponding acetates or benzoates.

Full text of DOI:10.1021/jo9522015

5932
J . Org. Chem. 1996, 61, 5932-5938
Tw isted Am id es a s Selective Acyla tin g Agen ts for Hyd r oxyl
Gr ou p s u n d er Neu tr a l Con d ition s: Mod els for Activa ted P ep tid es
d u r in g En zym a tic Acyl Tr a n sfer Rea ction
Shinji Yamada,*,† Takayuki Sugaki,‡ and Kazuhiro Matsuzaki‡
Department of Chemistry, Faculty of Science, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112,
J apan, and Department of Materials Science, Faculty of Science, Kanagawa University, Hiratsuka,
Kanagawa 259-12, J apan
Received December 12, 1995X
The highly twisted amide 2 served as a selective acylating agent for diols under neutral conditions.
The reaction of primary-secondary diols with 2 led to the corresponding primary alkyl monopiv-
alates. For diols containing alcoholic and phenolic hydroxyl groups, alcoholic hydroxyl groups were
selectively acylated under neutral conditions, whereas, the opposite selectivity was observed under
basic conditions, similar to the cases using acyl halides or acid anhydrides. Although 1 and 3
were unreactive to alcohols, 5-10 having substituent groups at C-4 were reactive to alcohols to
give the corresponding acetates or benzoates.
In tr od u ction
by 13C NMR, IR, UV spectroscopic analysis and X-ray
analysis.9 Therefore, this compound is considered to be
a transition state model for activated peptide during the
enzymatic acyl transfer reaction.10 Here we describe the
selective acylation of diols using twisted amides as
acylating agents under neutral conditions.
It has been documented that amides are much less
reactive toward nucleophiles than esters, and the hy-
drolysis of amides proceeds only under severe conditions.1
Such properties of amides have been explained by means
of the resonance of the nitrogen lone pair electron with
the carbonyl group.2 Nevertheless, enzymatically, the
hydrolysis of amides readily proceeds under very mild
conditions.3 Although the exact mechanism of the enzyme-
catalyzed hydrolysis of peptides has not yet been eluci-
dated, it seems an attractive hypothesis that the C (O)-N
bond of the peptides is twisted in the transition state4
and the subsequent loss of resonance energy activates
the carbonyl groups for hydrolysis. Recently, it has also
been proposed that the orthogonal R-keto amide moiety
of R-thrombin inhibitor cyclotheonamide B might function
as an electrophilic mimic of the ArgX scissile amide bond
of thrombin substrates.5
Resu lts a n d Discu ssion 11
Compounds 1-312 were readily prepared from the
reaction of commercially available 1,3-thiazolidine-2-
thione with corresponding acid chlorides in the presence
of triethylamine. Similarly, 3-pivaloyloxazolidone (4),7
which has a structure analogous to 2, and amides 5-10
were also prepared by the acylation of the corresponding
1,3-oxazolidinone and 4-alkyl-1,3-thiazolidine-2-thiones,
respectively.
In the course of our research on the selective acylation
of hydroxyl groups using active amides,6 we have found
that 3-pivaloyl-1,3-thiazolidine-2-thione (2)6-8 has a high
reactivity although it has the bukiest acyl group among
them, furthermore, the high reactivity was ascribed to
its highly twisted amide linkage, which was confirmed
† Ochanomizu University.
‡ Kanagawa University.
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) For an example, see: Green, T. W.; Wuts, G. M. Protective Groups
in Organic Chemistry, 2nd ed.; J ohn Wiley & Sons, Inc.; New York,
1991.
(2) Pauling, L. The Nature of the Chemical Bond; Cornell University
Press: Ithaca, NY, 1960. Robin, M. B.; Bovey, F. A.; Basch, H. In The
Chemistry of Amides; Zabicky, J .,Ed.; Wiley-Interscience: London,
1970; pp 1-72.
To examine the reactivity of 1-4 under neutral condi-
tions, the acylations of hexanol were studied. A mixture
of hexanol and 1.1 equiv of 1 - 4 in toluene was heated
at 80 °C for 18 h. Among the reagents 1-4, 2 was the
most reactive to quantitatively give hexyl pivalate,
(3) For an example, see: Wong, C.-H.; Whitesides, G. M. Enzymes
in Synthetic Organic Chemistry; Elsevier Science Ltd.: Oxford, 1994.
(4) (a) Lumry, R. The Enzymes; Boyer, P. D.; Lardy, H.; Myrback,
K., Eds.; Academic Press: New York, 1959; p 157. (b) J encks, P. W.
Current Aspects of Biochemical Energetics; Kaplan, N. O.; Kennedy,
E. P., Eds.; Academic Press: New York, 1966; p 273. (c) J encks, W. P.
Catalysis in Chemistry and Enzymology; McGraw-Hill: New York,
1969; p 282. (d) Lipscomb, W. N. Tetrahedron 1974, 30, 1725. (e) Walsh,
C. Enzymatic Reaction Mechanisms; Freeman and Company: New
York, 1979; Chapter 2, pp 24-48. (f) Fersht, A. Enzyme Structure and
Mechanism, 2nd ed.; Freeman: New York, 1984; pp 331-344.
(5) Hagihara, M.; Schreiber, S. L. J . Am. Chem. Soc. 1992, 114, 6570.
(6) Yamada, S. J . Org. Chem. 1992, 57, 1591.
(9) Yamada, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1083.
(10) Brown and his co-workers have studied the hydrolysis of bicyclic
distorted amides as models for activated peptide NsCdO units
produced during enzyme-catalyzed hydrolysis, see: Somayaji, V.;
Brown, R. S. J . Org. Chem. 1986, 51, 2676. Wang, P. Q.; Bennet, A.
J .; Brown, R. S.; Santarsiero, B. D. J . Am. Chem. Soc. 1991, 113, 5757.
(11) For a preliminary communication, see: ref 7.
(12) Compound 1: Chung-shi, L.; Yuen-hwa, Y.; Yao, L.; Yong-jun,
L.; Ai-hsueh, L.; Chi-yi, H. Tetrahedron Lett., 1981, 22, 3467. Com-
pound 2: see refs 6 and 8. Compound 3: Izawa, T.; Mukaiyama, T.
Bull. Chem. Soc. J pn. 1979, 53, 555.
(7) Yamada, S. Tetrahedron Lett. 1992, 33, 2171.
(8) Improved method for the synthesis of 2 was described in
Experimental Section.
S0022-3263(95)02201-8 CCC: $12.00 © 1996 American Chemical Society

Twisted Amides as Selective Acylating Agents
J . Org. Chem., Vol. 61, No. 17, 1996 5933
Ta ble 1. Acyla tion of Hexa n ol w ith
3-Acyl-1,3-th ia zolid in e-2-th ion es u n d er Neu tr a l
Con d ition s
shows these results and those for the reactions with
pivaloyl chloride or pivalic anhydride to compare them
with the selectivities.
The pivaloylation of 1,4-pentanediol (12) with 2 gave
monoesters6 in 84% yield with a small amount of the
diester and the recovery of the diol (entry 1). The ratio
of the primary to secondary pivalates was 27:1. On the
other hand, the ratios in the reactions with pivaloyl
chloride and pivalic anhydride were 3:1 and 8:1, respec-
tively (entries 2 and 3). Similarly, diols 13-15 were also
selectively acylated with 2 to give the corresponding
primary alkyl pivalates6 (entries 4-8). In particular,
extremely high selectivity was observed in the case of
1,4-octanediol (14) (entry 6). Although the acylations of
alcohols using the 3-acyl-1,3-thiazolidine-2-thiones have
been performed by activation with a base15 or Lewis acids
such as AgClO416 or CsF,17 the acylations with the twisted
amide 2 proceed even under neutral conditions because
the amide has a torsional strain around C (O)-N bond,
which reduces the activation energy for the acylation
step. Compound 16 is in 1:2 equilibrium of a ring-opened
alcohol 16a having a primary hydroxyl group and an
acetal 16b having a secondary hydroxyl group in CDCl3.
The acylation of 16 with 2 in toluene at 80 °C for 24 h
gave a 92:8 mixture of [(2-pivaloyloxy)methyl]benzalde-
hyde (17) and dimerized compound 18 (Scheme 1). On
the other hand, employing pivaloyl chloride, the dimer
18 was produced as a major product. The dimer may be
generated from the addition of ring-opened alcohol 16a
to an oxonium intermediate which is produced by dehy-
dration from the acetal 16b. Trost and Flygare have
reported that similar chemoselective acylation of â-keto
diols with the amide 2, where the primary alkyl pivalates
were selectively produced, during the synthesis of (-)-
reagent
product
yield/%a
recovery/%
1
2
3
4
11a
11b
11c
11b
2
97
1
98
3
99
99
1
a
Determined by GLC analysis.
although it has the bulkiest acyl group (Table 1). On the
other hand, the other amides were unreactive under
these reaction conditions. Since it has been known that
distorted amides are more readily hydrolyzed than the
planar ones,13,14 the high reactivity of 2 should be
attributed to its highly twisted amide structure. Thus,
the carbonyl group of 2 is more electrophilic than those
of 1 and 3 because of the loss of amide resonance. The
quite low reactivity of 4, whose structure is analogous to
that of 2, may be ascribed to the difference in the leaving
property between the oxazolidinone and thiazolidine-2-
thione groups.
In order to explore the selectivity of 2 for the acylation
of hydroxyl groups under neutral conditions, the diols
containing primary and secondary hydroxyl groups were
employed for the model substrates. A mixture of a diol
and 1.1 equiv of 2 in toluene was stirred at 65-80 °C for
22-65 h, and the yields and products ratios were
determined by GLC and 1H NMR analyses. Table 2
Ta ble 2. Selective P iva loyla tion of Diols Con ta in in g P r im a r y a n d Secon d a r y Hyd r oxyl Gr ou p s

5934 J . Org. Chem., Vol. 61, No. 17, 1996
Yamada et al.
Ta ble 3. Selective P iva loyla tion of Diols Con ta in in g Alcoh olic a n d P h en olic Hyd r oxyl Gr ou p s
Sch em e 1
of a variety of diols having phenolic and alcoholic hy-
droxyl groups. A mixture of the diols and 2 in toluene
were heated at 60-80 °C for 20-60 h under neutral
conditions. Table 3 shows the results and those of the
reactions with pivaloyl chloride for the comparison. The
alcoholic primary hydroxyl groups of 19-23 were acyl-
ated to yield alkyl esters exclusively (entries 1, 4, 7, 9,
and 11). In contrast, the reactions with pivaloyl chloride
selectively gave aryl pivalates (entries 3, 6, 8, 10, and
12). When the reactions with 2 were carried out in the
(13) Blackburn, G. M.; Plackett, J . D. J . Chem. Soc. Perkin 2, 1972,
1366. Idem. ibid. 1973, 981.
(14) Bennet, A. J .; Wang, Q-P. Slebocka-Tilk, H.; Somayaji, V.;
Brown, R. S.; Santarsiero, B. D. J . Am. Chem. Soc. 1990, 112, 6383.
(15) Nagao, Y.; Ikeda, T.; Inoue, T.; Yagi, M.; Shiro, M.; Fujita, E.
J . Org. Chem. 1985, 50, 4072.
(16) Plusquellec, D.; Roulleau, F.; Bertho, F.; Lefeuvre, M.; Brown,
E. Tetrahedron 1986, 42, 2457.
(17) Yamada, M.; Yahiro, S.; Yamano, T.; Nakatani. Y.; Ourisson,
G. Bull. Soc. Chim. Fr. 1990, 127, 824.
(18) Trost, B. M.; Flygare, J . A. Tetrahedron Lett. 1994, 35, 4059.
(19) Trost, B. M.; Flygare, J . A. J . Org. Chem. 1994, 59, 1078.
calyculin A18 and rosefurane,19 although the diols undergo
cyclization and dehydration to give furans in the acyla-
tion with acid chlorides even in the presence of pyridine.
We then investigated the selectivity for the acylation

Twisted Amides as Selective Acylating Agents
J . Org. Chem., Vol. 61, No. 17, 1996 5935
presence of triethylamine, the selectivity was reversed
to give aryl pivalates similar to the reactions used
pivaloyl chloride (entries 2 and 5). Even in the cases of
24 and 25, which have secondary hydroxyl groups, the
alcoholic hydroxyl groups were still predominantly acyl-
ated (entries 13 and 15). As can be seen from these
results, the chemoselectivity of 2 for hydroxyl groups is
on the order of primary > secondary > phenolic OH. Such
selectivity is attributable to the difference in the nucleo-
philicities between the phenolic and alcoholic hydroxyl
groups. Thus, the nucleophilicity of the phenolic hy-
droxyl group is less than that of the alcoholic one under
neutral conditions, whereas, under basic conditions, the
nucleophilicity of the latter is less than that of the former
because the phenolate is more easily produced in basic
media. In the case of 4-(hydroxyethyl)aniline (26), the
amino group is selectively acylated to give an amide 27
in 69% yield together with 20% of a diacyl compound 28
(Scheme 2). The result is almost in agreement with that
reported for the aminolysis of 3-hexadecanoylthiazoli-
dine-2-thione with 26.20
Sch em e 2
We then turned our attention to selective acetylation
and benzoylation. As described in Table 1, the reactivi-
ties of compound 1 and 3 to hexanol are quite lower than
that of 2. The low reactivity is ascribed to their planar
C (O)-N geometry, which enables amide resonance and
lowers the carbonyl reactivity. If alkyl substituents are
introduced at C-4, the C (O)-N bond may rotate because
of the steric repulsion between the acyl and the substitu-
ent groups. On the basis of this expectation, we made
amides 5-10 and investigated their structures and
reactivities.
F igu r e 1. Projection of the amide groups of 1, 2 and 5 down
the C-N bonds and the C (O)-N twist angle τ.
Sch em e 3
Figure 1 shows the projections of the amide groups of
1,2 and 521 down the C-N bonds and the values of the C
(O)-N twist angles τ.9,22 Comparing the projection of 5
with those of 1 and 2, the C (O)-N bond of 5 is more
twisted than that of 1, though less than that of 2.
Therefore, it is clear that the introduction of a gem-
dimethyl group at C-4 is effective for twisting the C
(O)-N bond.
To elucidate the reactivity and selectivity of 5-10, the
acetylation and benzoylation of 19 and 22 were studied.
The results are listed in Table 4. Reactions of 22 with
5-7 gave 3-hydroxy-4-methoxybenzyl acetate (29a )23 as
a major product with a small amount of 3-acetoxy-4-
methoxybenzyl alcohol (29b)23 and the diacetate24 (entries
1-3). Since the reaction with 1 was very slow under the
same reaction conditions, the introduction of a substitu-
ent group at C-4 is effective for accelerating the reactions.
Benzoylations of 22 with 8 and 9 yielded 30a 25 in high
selectivity similar to the corresponding acetylations
(entries 5 and 6). It is interesting to note that when 10
was employed for the benzoylation, the phenolic hydroxyl
group was selectively acylated to give 30b as a major
product (entry 7) similar to the case used benzoyl chloride
(entry 8). Details about the differce in the selectivity
between 10 and the others are not clear, but following
mechanistic sequence may be possible as shown in
Scheme 3: generation of acyl cation by heterolysis of the
C (O)-N bond, deprotonation of the phenolic hydroxyl
group by the thiazolidine-2-thione anion, and the reaction
of acyl cation with the phenoxide ion.
(20) Nagao, Y.; Seno, K.; Kawabata, K.; Miyasaka, T.; Takao, S.;
Fujita, E. Tetrahedron Lett. 1980, 21, 841.
(21) Yamada, S. J . Org. Chem. 1996, 61, 941.
(22) Winkler, F. K.; Dunitz, J . D. J . Mol. Biol. 1971, 59, 169.
(23) Quick, J .; Crelling, J . K. J . Org. Chem. 1978, 43, 155.
(24) Ruderman, B. J . Chem. Soc. India, 1945, 64, 204.
(25) Yamato, M.; Hashigaki, K.; Honda, E.; Sato, K.; Koyama, T.,
Chem. Pharm. Bull. 1977, 25, 695.

5936 J . Org. Chem., Vol. 61, No. 17, 1996
Yamada et al.
Ta ble 4. Selective Acetyla tion a n d Ben zoyla tion of Diols Con ta in in g Alcoh olic a n d P h en olic Hyd r oxyl Gr ou p s
filtration, and the filtrate was recrystallized from hexane-ether
to yield 4.5 g of pure pale yellow plates in 88% yield.
Su m m a r y
We have described selective acylations of hydroxyl
groups using twisted amides under neutral conditions.
The reaction of primary-secondary diols with 2 led to
the corresponding primary monopivalates. For diols
containing alcoholic and phenolic hydroxyl groups, the
alcoholic hydroxyl groups were selectively acylated.
Since the selectivity was completely opposite to that of
the acyl halides or acid anhydrides, the present method
is complimentary to the general ones. Another merit of
the present method is that it will be applied to the
compounds which are labile to acids or bases, because
the reaction can be conducted under neutral conditions.
The present results indicate that it is possible to control
the electrophilicity of an amide carbonyl by controlling
the C (O)-N twist angle. Since it is postulated that the
C (O)-N bond of peptide substrates are twisted and are
activated during enzyme-catalyzed hydrolysis, the present
twisted amides are considered to be models for the
activated peptides.
P r ep a r a tion of 3-Acetyl-4-isop r op yl-1,3-th ia zolid in e-
2-th ion e (6). To a solution of 4-isopropyl-1,3-thiazolidine-2-
thione26 (500 mg, 3.1 mmol) and triethylamine (0.7 mL) in dry
CH2Cl2 (15 mL) was added dropwise acetyl chloride (290 mg,
3.7 mL) at 0 °C. The solution was stirred for 8 h at room
temperature. The solution was washed with water and dried
over anhydrous MgSO4. After concentration in vacuo the
residue was subjected to column chromatography (Florisil)
using a 5:1 mixture of hexane-ethyl acetate as an eluent
solvent to give 589 mg of an oily amide 6 in 93% yield: IR
(neat) 2964, 1698, 1368, 1276, 1210, 1074 cm-1; 1H NMR (400
MHz) δ 0.98 (d, J ) 6.84 Hz, 3 H), 1.06 (d, J ) 6.84 Hz, 3 H),
2.38 (dt, J ) 6.3, 6.8 Hz, 1 H), 2.78 (s, 3 H), 3.03 (d, J ) 11.2
Hz, 1 H), 3.51 (dd, J ) 8.3, 11.2 Hz, 1 H), 5.15 (t, J ) 6.8, 8.3
Hz, 1 H); 13C NMR (400 MHz) δ 17.7, 19.0, 26.9, 30.4, 30.7,
71.2, 170.6, 203.2; MS m/z 203 (M+, 79), 161 (17), 118 (100),
69 (24); HRMS calcd for C8H13NOS2 203.0439, found 203.0411.
P r ep a r a tion of 3-Acetyl-4-ter t-bu tyl-1,3-th ia zolid in e-
2-th ion e (7). Concentrated sulfuric acid (7.5 g) was added
dropwise to a round bottom flask containing tert-leucinol (3.0
g, 25.6 mmol) at 0 °C and the mixture was vigorously stirred
for 2 h. Then, potassium O-ethyl dithiocarbonate in CH2Cl2
(6.1 g, 38.4 mmol), 2 N NaOH (100 mL), and ethanol (30 mL)
were added to the reaction mixture, and the solution was
heated at 80 °C for 2 h. After cooling to room temperature,
the solution was acidified with 2 N HCl and extracted with
three 50 mL portions of CHCl3. The combined extracts were
washed with water and dried over anhydrous MgSO4. Evapo-
ration of the solvent gave crude mixture of compounds, which
was subjected to column chromatography (silica gel) to give
two crystalline compounds. The less polar fraction was 4-tert-
butyl-1,3-thiazolidine-2-thione (31)(3.2 g): mp 143-144 °C; IR
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. Silica gel chro-
matography was carried out using Wakogel C-200 or Florisil
(100-200 mesh). GLC was carried out using a 5% SE-30 or
10% DC-550 column (2 m x 3 mm). Infrared spectra were
obtained as neat films between NaCl plates or as KBr pellets.
1H NMR spectra were recorded at 270 and 400 MHz in CDCl3,
and the chemical shifts were reported relative to internal
SiMe4. 13C NMR spectra were recorded at 100.4 MHz as 0.5
M solution in CDCl3, and the chemical shifts were reported
relative to internal SiMe4. High- and low-resolution mass
spectra were recorded at an ionizing voltage of 70 eV by
electron impact.
1
(KBr) 3154, 2957, 1506, 1293, 1042, 967, 663 cm-1; H NMR
(270 MHz) δ 1.02 (s, 9 H), 3.42 (m, 2 H), 4.04 (t, J ) 8.79 Hz,
1 H), 7.28 (br s, 1 H); 13C NMR (400 MHz) δ 25.9, 34.4, 34.6,
73.6, 201.5; MS m/z 175 (M+, 51), 132 (36), 118 (69), 73 (100);
HRMS calcd for C7H13NS2 175.0490, found 175.0466. The
polar fraction was 4-tert-butyl-1,3-oxazolidine-2-thione (32)(0.8
g): mp 153-156 °C; IR (KBr) 3183, 2962, 1534, 1285, 1183
cm-1; 1H NMR (270 MHz) δ 0.94 (s, 9 H), 3.78 (dd, J ) 9.4, 6.2
Hz, 1 H), 4.47 (dd, J ) 9.4, 6.2 Hz, 1 H); MS m/z 159 (M+,
P r ep a r a t ion of 3-P iva loyl-1,3-t h ia zolid in e-2-t h ion e6
(2). To a solution of 1,3-thiazolidine-2-thione (3.0 g, 25.2
mmol) and triethylamine (5.0 g, 50 mmol) in CH2Cl2 (60 mL)
was added dropwise pivaloyl chloride (3.62 g, 30.2 mmol) at 0
°C. The solution was stirred for 2 h at 0 °C. The reaction
mixture was washed with water, dried over anhydrous MgSO4,
and concentrated to give a solid. This was dissolved in
hexane-ether, the insoluble precipitate was removed by
(26) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. J . Org. Chem. 1986, 51, 2391.

Twisted Amides as Selective Acylating Agents
J . Org. Chem., Vol. 61, No. 17, 1996 5937
100), 131 (30); HRMS calcd for C7H13NOS 159.0718, found
159.0737. To a solution of 4-tert-butyl-1,3-thiazolidine-2-thione
(300 mg, 1,7 mmol) and triethylamine (1.0 mL) in dry CH2Cl2
(15 mL) was added dropwise acetyl chloride (175 mg, 2,2 mmol)
at 0 °C, and the solution was stirred for 2 h at room
temperature. The reaction mixture was washed with water,
dried over anhydrous MgSO4, and concentrated to give an
yellow oil. This was subjected to column chromatography
(Florisil) to give amide 7 (350 mg, 94%): IR (neat) 2965, 1699,
1369, 1272, 1193, 1085, 1033 cm-1; 1H NMR (400 MHz) δ 1.04
(s, 9 H), 2.78 (s, 3 H), 3.10 (d, J ) 12.7Hz, 1 H), 3.53 (dd, J )
8.3, 12.7 Hz, 1 H), 5.31 (d, J ) 8.3, 1 H); 13C NMR (400 MHz)
δ 26.7, 26.8, 30.4, 38.0, 72.0, 170.3, 205.3; MS m/z 217 (M+,
68), 161 (15), 118 (100), 55 (38); HRMS calcd for C9H15NOS2
217.0595, found 217.0549.
room temperature for overnight. The reaction mixture was
washed with water and dried over anhydrous MgSO4. Evapo-
ration of the solvent to give crude compounds, which was
separated by preparative TLC using a 3:1 mixture of hexane
and ethyl acetate as an eluent solvent to yield esters.
1-(P iva loyloxy)octa n -4-ol (14a ): IR (neat) 3447, 2959,
1
1731, 1481, 1286, 1162 cm-1; H NMR (400 MHz) δ 0.91 (t, J
) 7.1 Hz, 3 H), 1.20 (s, 9 H), 3.63 (br s, 1 H), 4.09 (t, J ) 6.6
Hz, 2 H); MS m/z 231 (M+ + 1, 1), 213 (1), 171 (3), 144 (8), 103
(60), 85 (38), 71 (100), 57 (98); HRMS calcd for C13H27O3 (M+
+ 1) 231.1960, found 231.1955.
2-[(P iva loyloxy)m eth yl]ben za ld eh yd e (17): IR (neat)
1
1731, 1677, 1580, 1321, 1290, 1142, 911, 741 cm-1; H NMR
(270 MHz) δ 1.25 (s, 9 H), 5.54 (s, 2 H), 7.51-7.89 (m, 4 H),
10.21 (s, 1 H); MS m/z 220 (M+, 1), 205 (1), 151 (23), 135 (67),
118 (40), 105 (31), 77 (36), 57 (100); HRMS calcd for C13H16O3
220.1100, found 220.1067.
P r epar ation of 3-Ben zoyl-4,4-dim eth yl-1,3-th iazolidin e-
2-th ion e (8). To a solution of 4,4-dimethyl-1,3-thiazolidine-
2-thione (2.0 g, 13.6 mmol) and triethylamine (3.0 mL) in 30
mL of dry CH2Cl2 was added dropwise benzoyl chloride (2.3 g,
16 mmol) at 0 °C. The solution was stirred for 20 h at room
temperature. The reaction mixture was washed with water,
dried over anhydrous MgSO4, and concentrated to give a yellow
solid. This was recrystallized from ether to give pure amide
8 (2.8 g, 82%): mp 154-156 °C; IR (KBr) 1693, 1322, 1272,
1164, 998, 705 cm-1; 1H NMR (270 MHz) δ 1.72 (s, 6 H), 3.42
(s, 2 H), 7.43 (t, J ) 7.3 Hz, 2 H), 7.56 (t, J ) 7.3 Hz, 1 H),
7.78 (d, J ) 7.3 Hz, 2 H); 13C NMR (400 MHz) δ 25.1, 25.2,
45.5, 73.7, 128.7, 129.8, 133.4, 134.3, 172.7, 200.8; MS m/z 251
1,3-Dih yd r oisoben zofu r a n yl 2-for m ylben zyl eth er (18):
IR (neat) 3055, 2890, 2750, 1695, 1602, 1465, 1370, 1192, 1076,
1003, 755 cm-1; 1H NMR (270 MHz) δ 5.06-5.41 (m, 4 H), 6.41
(d, J ) 2.0 Hz, 1 H), 7.28-7.87 (m, 8 H), 10.27 (s, 1 H); MS
m/z 135 (9), 118 (100), 105 (11), 89 (82); HRMS calcd for
C8H7O2 (M+ - dihydrobenzofuranyl group) 135.0446, found
135.0425.
2-[2-(P iva loyloxy)eth yl]p h en ol (19a ): IR (neat) 3418,
1
1704, 1481, 1458, 1292 1233, 1170, 753 cm-1; H NMR (400
(M+, 14), 106 (6), 105 (100), 77 (40); HRMS calcd for C12H13
NOS2 251.0439, found 251.0457.
-
MHz) δ 1.19 (s, 9 H), 2.95 (t, J ) 7.32 Hz, 2 H), 4.28 (t, J )
7.32 Hz, 2 H), 6.84 (t, J ) 7.6 Hz, 2 H), 7.14 (t, J ) 7.6 Hz,
2H); MS m/z 222 (M+, 8), 138 (4), 120 (100), 107 (11), 55 (45);
HRMS calcd for C13H18O3 222.1256, found 222.1275.
P r ep a r a tion of 3-Ben zoyl-4-isop r op yl-1,3-th ia zolid in e-
2-th ion e (9). To a solution of 4-isopropyl-1,3-thiazolidine-2-
thione (1.0 g, 6.2 mmol) and triethylamine (1.7 mL) in dry
CH2Cl2 (50 mL) was added dropwise benzoyl chloride (1.05 g,
7.4 mmol) at 0 °C. The solution was stirred for 20 h at room
temperature. The reaction mixture was washed with water,
dried over anhydrous MgSO4, and concentrated in vacuo to
give a yellow solid. This was recrystallized from hexane-ether
to give pure amide 9 (1.42 g, 86%): mp 88-90 °C; IR (KBr)
1691, 1275, 1215, 1190, 1149, 1122, 1028, 973, 728, 692, 664
cm-1; 1H NMR (400 MHz) δ 1.05 (d, J ) 6.8 Hz, 6 H), 2.53 (dt,
J ) 4.4, 6.8 Hz, 1 H), 3.38 (dd, J ) 7.8, 11.2 Hz, 1 H), 3.48
(dd, J ) 7.8, 11.2 Hz, 1 H), 4.94 (dt, J ) 4.9, 7.8 Hz, 1 H), 7.42
(t, J ) 7.3 Hz, 2 H), 7.54 (t, J ) 7.3 Hz, 1 H), 7.90 (d, J ) 7.3
Hz, 2 H); 13C NMR (400 MHz, CDCl3) δ 16.3, 19.2, 29.5, 30.7,
73.1, 128.5, 129.9, 133.0, 133.9, 171.7, 203.0; MS m/z 265 (M+,
17), 194 (2), 105 (100), 77 (38); HRMS calcd for C13H15NOS2
265.0595, found 265.0637.
2-(2-Hydr oxyeth yl)ph en yl pivalate (19b): IR (neat) 3398,
2974, 1750, 1481, 1280, 1261, 1174, 1121, 1044, 750 cm-1; 1H
NMR (270 MHz) δ 1.38 (s, 9 H), 2.79 (t, J ) 6.4 Hz, 2 H), 3.81
(t, J ) 6.4 Hz, 2 H), 6.82 (d, J ) 8.1 Hz, 1 H), 7.01 (d, J ) 7.8
Hz, 1 H), 7.15-7.30 (m, 2 H); MS m/z 222 (M+, 0.5), 138 (8),
120 (100), 107 (25), 55 (82); HRMS calcd for C13H18O3 222.1256,
found 222.1232.
4-[2-(P iva loyloxy)eth yl]p h en ol (20a ): IR (neat) 3403,
2973, 1704, 1517, 1292, 1225, 1169 cm-1; 1H NMR (270 MHz)
δ 1.16 (s, 9 H), 2.86 (t, J ) 6.8 Hz, 2 H), 4.23 (t, J ) 6.8 HZ,
2 H), 5.02 (br s, 1 H), 6.75 (d, J ) 8.8 Hz, 2 H), 7.08 (d, J ) 8.8
Hz, 2 H); MS m/z 222 (M+, 2), 138 (5), 120 (100), 107 (18);
HRMS calcd for C13H18O3 222.1256, found 222.1259.
4-(2-Hyd r oxyeth yl)p h en yl p iva la te (20b): mp 46-48 °C;
P r ep a r a tion of 3-Ben zoyl-4-ter t-bu tyl-1,3-th ia zolid in e-
2-th ion e (10). To a solution of 4-tert-butyl-1,3-thiazolidine-
2-thione (330, 1.89 mg) and triethylamine (0.5 mL) in dry
CH2Cl2 (15 mL) was added dropwise benzoyl chloride (320 mg,
2.26 mmol) at 0 °C. The solution was stirred for 5 h at room
temperature. The reaction mixture was washed with water,
dried over anhydrous MgSO4, and concentrated to give a
yellow solid. This was recrystallized from hexane-ether to
give pure amide 10 (460 mg, 87%): mp 110-112 °C; IR (KBr)
IR (CHCl3) 3380, 2975, 1751, 1508, 1199, 1167, 1123, 1048
1
cm-1; H NMR (400 MHz) δ 1.35 (s, 9 H), 2.86 (t, J ) 6.6 Hz,
2 H), 3.85 (t, J ) 6.6 Hz, 2 H), 6.99 (d, J ) 8.4 Hz, 2 H), 7.24
(d, J ) 8.4 Hz, 2 H); MS m/z 222 (M+, 28), 138 (63), 107 (100),
55 (80); HRMS calcd for C13H18O3 222.1256, found 222.1240.
2-[4-(P iva loyloxy)bu tyl]p h en ol (21a ): IR (neat) 3422,
1
2960, 1703, 1457, 1293, 1173, 753 cm-1; H NMR (270 MHz)
δ 1.20 (s, 9 H), 1.64-1.76 (m, 4 H), 2.65 (t, J ) 7.3 Hz, 2 H),
4.12 (t, J ) 6.1 Hz, 2 H), 5.04 (s, 1 H), 6.76 (d, J ) 8.1 Hz, 1
H), 6.86 (t, J ) 7.6 Hz, 1 H), 7.05-7.11 (m, 2 H); MS m/z 250
(M+, 37), 166 (13), 148 (100), 133 (8), 120 (20), 107 (44); HRMS
calcd for C15H22O3 250.1569, found 250.1589.
1703, 1365, 1319, 1265, 1221, 1141, 802, 692, 667 cm-1 1H
;
NMR (400 MHz) δ 1.10 (s, 1 H), 3.30 (dd, J ) 2.4, 11.7 Hz, 1
H), 3.73 (dd, J ) 9.3, 11.7 Hz, 1 H), 5.15 (dd, J ) 2.4, 9.3 Hz,
1 H), 7.41 (t, J ) 7.3 Hz, 2 H), 7.54 (t, J ) 7.3 Hz, 1 H), 7.80
(d, J ) 7.3 Hz, 2 H); 13C NMR (400 MHz) δ 26.8, 31.3, 37.9,
75.0, 128.2, 130.3, 132.9, 133.8, 171.8, 203.1; MS m/z 279 (M+,
21), 105 (100), 77 (16); HRMS calcd for C14H17NOS2 279.0751,
found 279.0724.
Gen er a l P r oced u r e for th e Selective Acyla tion of
Diols w ith Tw isted Am id es 2, 5-10. A mixture of a diol
(0.3 mmol) and an amide (0.33 mmol) in dry toluene (5 mL)
was stirred at 60-80 °C or refluxing temperature for 18-90
h. The reaction mixture was concentrated and separated by
preparative TLC using a 3:1 mixture of hexane and ethyl
acetate as an eluent solvent to yield esters.
2-(4-Hydr oxybu tyl)ph en yl pivalate (21b): IR (neat) 3395,
1
2937, 1749, 1480, 1122 cm-1; H NMR (270 MHz) δ 1.38 (s, 9
H), 1.58-1.67 (m, 4 H), 2.54 (t, J ) 7.3 Hz, 2 H), 3.63 (t, J )
5.7 Hz, 2 H), 6.96 (dd, J ) 1.7, 7.8 Hz, 1 H), 7.11-7.26 (m, 3
H); MS m/z 250 (M+, 64), 166 (15), 148 (100), 133 (11), 120
(18), 107 (52); HRMS calcd for C15H22O3 250.1569, found
250.1593.
3-Hyd r oxy-4-m eth oxyben zyl p iva la te (22a ): IR (neat)
3448, 2972, 1725, 1515, 1280, 1159, 1131, 1032 cm-1; 1H NMR
(270 MHz) δ 1.21 (s, 9 H), 3.89 (s, 3 H), 5.00 (s, 2 H), 5.18 (br
s, 1 H), 6.82 (d, J ) 0.7 Hz, 2 H), 6.92 (s, 1 H); MS m/z 238
(M+, 24), 154 (7), 137 (100), 122 (14), 57 (54); HRMS calcd for
Gen er a l P r oced u r e for th e Acyla tion of Diols w ith
Acyl Ha lid es. To a mixture of a diol (0.3 mmol) and
triethylamine (0.6 mmol) in CH2Cl2 (5 mL) was added dropwise
acyl chloride (0.33 mmol) at 0 °C. The solution was stirred at
C
13H18O4 238.1205, found 238.1196.

5938 J . Org. Chem., Vol. 61, No. 17, 1996
Yamada et al.
4-Meth oxy-3-(pivaloyloxy)ben zyl alcoh ol (22b): IR (neat)
3420, 2974, 1753, 1514, 1269, 1125, 1030 cm-1; 1H NMR (270
MHz) δ 1.36 (s, 9 H), 3.80 (s, 3 H), 4.58 (s, 2 H), 6.92 (d, J )
8.3 Hz, 1 H), 7.02 (d, J ) 2.0 Hz, 1 H), 7.15 (dd, J ) 2.2, 8.3
Hz, 1 H); MS m/z 238 (M+, 4), 154 (21), 137 (4), 57 (100); HRMS
calcd for C13H18O4 238.1205, found 238.1180.
3-(P iva loyloxy)estr a n -17â-ol (25b): mp 183-185 °C; IR
(KBr) 3554, 1742, 1483, 1149, 1130 cm-1; 1H NMR (270 MHz)
δ 0.78 (s, 3 H), 1.27 (s, 9 H), 3.73 (t, J ) 8.5 Hz, 1 H), 6.76 (br
s, 1 H), 6.81 (dd, J ) 2.4, 8.3 Hz, 1 H), 7.27 (d, J ) 8.3 Hz, 1
H); MS m/z 356 (M+, 25), 341 (8), 272 (27), 86 (76), 69 (100);
HRMS calcd for C23H32O3 356.2351, found 356.2323.
4-Hyd r oxy-3-m eth oxyben zyl p iva la te (23a ): IR (neat)
3520, 2970, 1725, 1515, 1280, 1157, 1131 cm-1; 1H NMR (270
MHz) δ 1.21 (s, 9 H), 3.89 (s, 3 H), 5.03 (s, 2 H), 6.85 (d, J )
5.9 Hz, 1 H), 6.86 (d, J ) 5.9 Hz, 1 H), 6.88 (s, 1 H); MS m/z
238 (M+, 54), 137 (77), 119 (100); HRMS calcd for C13H18O4
238.1205, found 238.1176.
3-Meth oxy-4-(pivaloyloxy)ben zyl alcoh ol (23b): IR (neat)
3469, 2973, 1754, 1513, 1269, 1126, 1030 cm-1; 1H NMR (270
MHz) δ 1.37 (s, 9 H), 3.81 (s, 3 H), 4.66 (s, 2 H), 6.88 (d, J )
8.1 Hz, 1 H), 6.90 (d, J ) 8.1 Hz, 1 H), 6.97 (s, 1 H); MS m/z
238 (M+, 71), 154 (100); HRMS calcd for C13H18O4 238.1205,
found 238.1221.
4-(2-Hyd r oxyeth yl)tr im eth ylp r op ion a n ilid e (27): mp
112.5-114.5 °C; IR (KBr) 3440, 3320, 1659, 1608, 1538, 1413,
1326, 1245, 1163, 1069, 1021, 818, 602 cm-1 1H NMR (400
;
MHz) δ 1.31 (s, 9 H), 2.82 (t, J ) 6.6 Hz, 2 H), 3.81 (t, J ) 6.6
Hz, 2 H), 7.16 (d, J ) 8.5 Hz, 2 H), 7.45 (d, J ) 8.5 Hz, 2 H);
MS m/z 221 (M+, 10), 190 (11), 106 (40), 57 (100); HRMS calcd
for C13H19NO2 221.1416, found 221.1431.
4-[2-(P iva loyloxy)eth yl]tr im eth ylp r op ion a n ilid e (28):
mp 151-152 °C; IR (KBr) 3448, 1726, 1659, 1604, 1526, 1163
cm-1; 1H NMR (400 MHz) δ 1.16 (s, 9 H), 1.31 (s, 9 H), 2.89 (d,
J ) 6.8 Hz, 2 H), 4.23 (d, J ) 6.8 Hz, 2 H), 7.17 (d, J ) 8.5 Hz,
2 H), 7.46 (d, J ) 8.5 Hz, 2 H); MS m/z 305 (M+, 2), 262 (1),
2-[3-(P iva loyloxy)bu tyl]p h en ol (24a ): IR (neat) 3447,
1
2977, 1699, 1457, 1184, 752 cm-1; H NMR (270 MHz) δ 1.22
203 (22), 119 (17), 106 (8), 57 (100); HRMS calcd for C18H27
NO3 305.1991, found 305.1973.
-
(s, 9 H), 1.24 (d, J ) 6.4 Hz, 3 H), 1.79-1.94 (m, 4 H), 2.65 (m,
2 H), 4.93 (m, 1 H), 5.35 (s, 1 H), 6.75 (d, J ) 7.3 Hz, 1 H),
6.85 (t, J ) 7.3 Hz, 1 H), 7.07 (t, J ) 7.3 Hz, 2 H); MS m/z 250
(M+, 65), 233 (3), 148 (100), 133 (30), 119 (11), 107 (44); HRMS
calcd for C15H22O3 250.1569, found 250.1523.
4-Meth oxy-3-(ben zoyloxy)ben zyl alcoh ol (30b): IR (KBr)
3444, 2974, 1735, 1511, 1268, 1022 cm-1; 1H NMR (270 MHz)
δ 3.82 (s, 3 H), 4.65 (s, 2 H), 6.99 (d, J ) 8.3 Hz, 1 H), 7.19 (d,
J ) 2.1 Hz, 1 H), 7.24 (dd, J ) 8.3, 2.1 Hz, 1 H), 7.51 (t, J )
8 Hz, 2 H), 7.63 (t, J ) 8 Hz, 1 H), 8.21 (dd, J ) 8, 1 Hz, 2 H)
; MS m/z 258 (M+, 23), 136 (5), 105 (100); HRMS calcd for
C15H14O4 258.0892, found 258.0874.
2-(3-Hydr oxybu tyl)ph en yl pivalate (24b): IR (neat) 3395,
2969, 1749, 1123 cm-1; 1H NMR (270 MHz) δ 1.20 (d, J ) 6.4
Hz, 3 H), 1.38 (s, 9 H), 1.44-1.76 (m, 2 H), 2.45-2.62 (m, 2
H), 3.54-3.68 (m, 1 H), 6.96 (dd, J ) 2.0, 8.1 Hz, 1 H), 7.12-
7.27 (m, 3 H); MS m/z 250 (M+, 25), 233 (5), 217 (4), 148 (100),
133 (20), 107 (24); HRMS calcd for C15H22O3 250.1569, found
250.1535.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 6-10, 14a , 17, 18, 19a -25a , 19b-25b, 27, 28, 30b,
31, and 32 (27 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
17â-(P iva loyloxy)estr a n -3-ol (25a ): mp 232-234 °C; IR
1
(KBr) 3464, 1713, 1501, 1303, 1187, 608 cm-1; H NMR (400
MHz) δ 0.84 (s, 3 H), 1.21 (s, 9 H), 4.66 (br t, J ) 8.0 Hz, 1 H),
6.57 (d, J ) 2.4, 1 H), 6.63 (dd, J ) 2.4, 8.3 Hz, 1 H), 7.14 (d,
J ) 8.3 Hz, 1 H); MS m/z 356 (M+, 17), 341 (5), 120 (35), 81
(64), 69 (100); HRMS calcd for C23H32O3 356.2351, found
356.2359.
J O9522015