Benzoyl methyl phosphate as an efficient reagent for the selective monobenzoylation of N-Bz-FTY720

Article abstract of DOI:10.1039/c4ra02401j

A novel and efficient method for the selective monobenzoylation of N-Bz-FTY720 with benzoyl methyl phosphate (BMP) promoted by Zn(OAc)₂ and Cs₂CO₃ was developed. Benzoyl methyl phosphate plays an important role as a biomimetic acylating agent for the monobenzoylation of 1,3-diols.

Full text of DOI:10.1039/c4ra02401j

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Benzoyl methyl phosphate as an efficient reagent
for the selective monobenzoylation of N-Bz-
FTY720†
Cite this: RSC Adv., 2014, 4, 23131
*
*
Hidemasa Hikawa, Maiko Hamada, Yuusaku Yokoyama and Isao Azumaya
Received 21st March 2014
Accepted 12th May 2014
A novel and efficient method for the selective monobenzoylation of N-Bz-FTY720 with benzoyl methyl
phosphate (BMP) promoted by Zn(OAc)2 and Cs2CO3 was developed. Benzoyl methyl phosphate plays
an important role as a biomimetic acylating agent for the monobenzoylation of 1,3-diols.
DOI: 10.1039/c4ra02401j
www.rsc.org/advances
unprotected monosaccharides and natural products has been
developed.5 Muramatsu and co-workers reported an efficient
Introduction
method for selective monobenzoylation of 1,2- and 1,3-diols in
water catalyzed by Me2SnCl2.5a Interestingly, a biomimetic
approach was utilized for the reaction of acyl phosphate
monoesters with diols in the presence of lanthanum salts in
water, producing esters through chelation-directed selectivity
by Kluger and co-workers.2
Acyl adenylates are mixed carboxylic-phosphoric anhydrides
that are potentially useful as biomimetic and efficient reagents
for acylation reactions.1,2 The mechanism of reactions with acyl
phosphates has been reported by Jencks.1 Kluger and co-
workers reported that the direct monoacylation of diols by
benzoyl phosphates in water was a good biomimetic model
for the enzymatic aminoacylation of tRNA by aminoacyl
adenylates.2h This is a promising progress for the potential use
of benzoyl methyl phosphates 2 in organic synthesis. Further-
more, in biological systems, the syntheses of the compounds
essential for life are accomplished efficiently and cleanly via
enzymatic catalysis. Therefore, development of a synthetic
pathway similar to a biosynthetic one is the attractive and much
attention, yet most challenging, research goals for a synthetic
chemist.3
We have been developing atom economical and environ-
mentally benign reactions with green processes, such as
unprotected syntheses, benzylic C–H activations, cascade reac-
tions and chemoselective reactions in aqueous media.4
Recently, we reported a novel and efficient method for the
environmentally benign, catalyst- and auxiliary-free synthesis of
2-phenylbenzimidazoles in water.4a Benzoyl methyl phosphates
play important roles as biomimetic acylating agents for the one-
pot tandem approach without additional catalysts.
FTY720 (Fingolimod) is the rst of a novel class of sphin-
gosine 1-phosphate (S1P) receptor modulators (Fig. 1),6 and is
rapidly monophosphorylated in vivo to form FTY720-phosphate,
which is an agonist for four sphingosine-1-phosphate (S1P)
receptors (S1P1,3,4,5). Therefore, complementary agonists for
each S1P receptor should be valuable tools to ascertain the
mechanism of immunosuppressive action of FTY720, and
provide further information to researchers. Indeed, Takeda and
co-workers reported a method for selective and direct phos-
phorylation of various 1,3-diols using silver(I) oxide.7 Further-
more, FTY720 has a propan-1,3-diol moiety, and protection of
one of the hydroxyl groups is needed for the preparation of
FTY720-phosphate. Kiuchi and co-workers reported asymmetric
synthesis of FTY720-phosphate using the lipase-catalyzed acyl-
ation as the key step.8 While enzymatic acylation of N-protected
FTY720 has been reported, to the best of our knowledge, the
nonenzymatic monobenzoylation has not been described
before.9 Additionally, investigation for the reaction of FTY720
analogs using BMP 2 as a biomimetic acylating reagent will
provide new insight into the phosphorylation mechanism of
sphingosine kinase.
Herein, we report the development of a novel and efficient
method for selective monobenzoylation of N-Bz-FTY720.
Notably, benzoyl methyl phosphate 2 plays an important role as
a biomimetic acylating agent. In general, selective protection of
hydroxyl groups of polyols is very important in organic
synthesis. Therefore, catalytic regioselective acylation of
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba
274-8510, Japan. E-mail: hidemasa.hikawa@phar.toho-u.ac.jp; yokoyama@phar.
toho-u.ac.jp
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all compounds. See DOI: 10.1039/c4ra02401j
Fig. 1 FTY720 and FTY720-phosphate.
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Table 2 Effect of saltsa
Results and discussion
First, we heated a mixture of N-Bz-FTY720 1, benzoyl methyl
phosphate 2 (1.1 equiv.) and Zn(OAc)2 (5 equiv.) in THF at 40 ꢀC
for 24 h. Desired monobenzoylated 3 was obtained in 34% yield
along with dibenzoylated 4, acetoxy 5 and recovery of SM 1
(entry 1, Table 1). When 1 was heated at 80 ꢀC for 24 h, the
reaction afforded desired 3 in only 25% yield along with 4 in
12% yield and 5 in 16% yield (entry 2). Unfortunately, water
suppressed the reaction (entry 3).
Conv.b (%)
BMP 2
(equiv.) Mono 3 Di 4 OAc 5
Entry Salt (equiv.)
6
SM 1
Thus, we investigated the effects of various salts as catalysts
to improve the reactivity and selectivity of the mono-
benzoylation (Table 2). When a mixture of diol 1 and BMP 2 (5
equiv.) was stirred in the presence of Zn(OAc)2 (5 equiv.) in THF
at 40 ꢀC for 4 h, desired 3 was obtained in 36% yield along with 4
and 5 (entry 1). ZnTAc24 was also an effective salt, giving desired
3 in 32% yield (entry 2).10 In contrast, ZnCl2 or Zn(OTf)2 resulted
in no reaction (entries 3 and 4). To compare Zn(OAc)2 with other
efficient salts, we tested the reaction using CuCl2 or Cu(OTf)2.
Interestingly, the N-benzoyl group of 1 was activated by copper
salts to give cyclized 6 (entry 5, 35%; entry 6, 48%). Cu(OAc)2 was
ineffective for monobenzylation (entry 7). The use of only 1
equiv. of Zn(OAc)2 or BMP 2 resulted in slightly lower yields
(entries 8 and 9). The reaction in the presence of a catalytic
amount of Zn(OAc)2 (0.2 equiv.) afforded desired 3 in 15% yield
(aer 15 h) and in 26% yield (aer 24 h), suggesting that the
active Zn(II) species did not regenerate (entry 10). The reaction
did not proceed in the absence of Zn(OAc)2 (entry 11). Thus, diol
1 is less nucleophilic.
1
2
3
4
5
6
7
8
9
10
Zn(OAc)2 (5)
ZnTAc24 (5)
ZnCl2 (5)
Zn(OTf)2 (5)
CuCl2 (5)
Cu(OTf)2 (5)
Cu(OAc)2 (5)
Zn(OAc)2 (1)
Zn(OAc)2 (5)
Zn(OAc)2 (0.2)
5
5
5
5
5
5
5
5
1
5
36
32
2
6
0
0
10
0
0
0
0
0
45
68
98
No reaction
2
16
10
0
0
0
1
0
0
0
0
0
0
0
0
35 63
48 27
0
0
0
0
90
71
72
85
28
28
15c
(26)d
11e
None
1
No reaction
a
Reaction conditions: diol 1, BMP 2 (1 or 5 equiv.), salt (0.2–5 equiv.),
solvent (0.05 M), 40 ꢀC, 4 h. b HPLC area%. c 15 h. d 24 h. e 8 h.
Table 3 Effect of solventsa
Next, we investigated the effect of solvents on the selective
monobenzylation (Table 3). When using DMF, the reaction also
proceeded to give desired 3 in 36% yield (entry 1). In contrast,
CH2Cl2, hexane, or alcohols such as EtOH or tBuOH resulted in
low yields (entries 2–5). Interestingly, when using pyridine,
Conv.b (%)
Table 1 The reaction of N-Bz-FTY720 1 with BMP 2a
Entry
Solv.
Mono 3
Di 4
OAc 5
SM 1
1
2
3
4
5
6
DMF
36
18
5
0
4
0
55
82
CH2Cl2
Hexane
EtOH
tBuOH
Py
No reaction
15
27
14
1
0
0
0
2
22
84
71
61
a
Reaction conditions: diol 1, BMP 2 (1 equiv.), Zn(OAc)2 (5 equiv.),
solvent (0.05 M), 40 ꢀC, 4 h. b HPLC area%.
Yield (%)
Entry
Solv.
T (ꢀC)
Mono 3
Di 4
OAc 5
SM 1
1
2
3
THF
THF
THF–H2O
40
80
40
34
25
3
12
5
16
38
0
desired 3 was obtained in 14% yield along with byproduct 5 in
22% yield (entry 6).
No reaction
A low concentration of SM 1 (0.005 M) did not afford
byproducts 4 and 5 (entry 1, Table 4). In contrast, the byproduct
increased at a higher concentration of SM 1 (entries 2–4).
Next, we investigated the effect of base on the selective
monobenzylation (Table 5). The use of inorganic bases such as
NaHCO3, Na2CO3 and K3PO4, or an organic base, Et3N, resulted
in 38–48% yields (entries 1–4). Interestingly, Cs2CO3 enhanced
a
Reaction conditions: diol 1, BMP 2 (5 equiv.), Zn(OAc)2 (1 equiv.), THF
(0.05 M), 40–80 ꢀC, 24 h.
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Table 4 Effect of concentration
Conv.a (%)
Scheme 1 The reaction in the absence of BMP 2.
Entry
Conc. of SM 1 (M)
Mono 3
Di 4
OAc 5
SM 1
1
2
3
4
0.005
0.01
0.05
0.1
33
35
37
36
0
2
6
5
0
0
10
12
67
63
46
46
on Clarke's proposal. Clarke and Arnold reported that the
mechanism of the lanthanide(III) salt catalyzed mono-acylation
of diols proceeds via chelation of the diol and acid anhydride to
the lanthanide salt, followed by an intramolecular acyl trans-
fer.11 Diol 1 is less nucleophilic, since in the absence of Zn(OAc)2
the reaction of 1 with BMP 2 did not proceed (see Table 2, entry
10). First, diol 1 was reacted with BMP 2 in the presence of
Zn(OAc)2 to form intermediate 7 in which both a diol and BMP 2
coordinated to the Zn(II) salt. Next, in the presence of base,
deprotonation of the hydroxyl group proceeded smoothly due to
the increased acidity of 7, followed by formation of alkoxide 8.
Indeed, the use of Cs2CO3 enhanced the reaction (see Table 5).
Next, intramolecular nucleophilic attack from the alkoxide into
the activated acyl group, which was a bisbidentate chelate of
Zn(II), gave desired 3 along with regenerated Zn(II). Kluger and
co-workers reported that Mg2+ scavenges the methyl phosphate
byproduct to establish the La3+ catalyst.2c Indeed, in the pres-
ence of Cs2CO3 as a base, Zn(OAc)2-catalyzed monobenzoylation
occurred to give the desired 3 in 57% yield (entry 10 in Table 2
vs. entry 8 in Table 5). Furthermore, as shown in Scheme 2B,
a
HPLC area%.
Table 5 Effect of basea
Conv.b (%)
Entry
Base
Solv.
T/t (ꢀC/h)
Mono 3
Di 4
SM 1
1
2
3
4
5
6
7
8c
NaHCO3
Na2CO3
K3PO4
THF
THF
THF
THF
THF
THF
DMF
DMF
40/4
40/4
40/4
40/4
40/4
40/96
40/2
40/24
38
40
42
48
53
60
66
57
0
0
4
6
6
62
60
54
46
41
25
20
37
Et3N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
11
14
6
a
Reaction conditions: diol 1, BMP 2 (5 equiv.), Zn(OAc)2 (5 equiv.),
b
c
solvent (0.005 M), 40 ꢀC, 3 h. HPLC area%. Used 0.2 equiv. of
Zn(OAc)2, 24 h.
the reaction to give desired 3 in 53% yield (entry 5). Further-
more, aer 96 h, desired 3 was obtained in 60% yield (entry 6).
The use of DMF enhanced the reaction to give desired 3 in 66%
yield (entry 7). Notably, in the presence of a catalytic amount of
Zn(OAc)2 (0.2 equiv.), the reaction proceeded smoothly to give
desired 3 in 57% yield (entry 8).
To gain insight into the reaction mechanism, we carried out
the reaction in the absence of BMP 2 (Scheme 1). BMP 2 played
an important role in the production of acetylated 5, since the
reaction did not afford 5 in its absence.
On the basis of our results and literature reports, the
following mechanism can be suggested. A mechanism for the
selective monobenzoylation reaction of 1,3-diol to form a
coordinated intermediate is shown in Scheme 2A and is based Scheme 2 Plausible mechanism.
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BMP 2 reacts with acetoxy anion (AcOꢁ) to form anhydride 9.
Nucleophilic attack on the acetyl group affords byproduct 5.
When using pyridine as a solvent, desired 3 was obtained in
14% yield along with byproduct 5 in 22% yield (see entry 6 in
Table 3). BMP 2 might react with pyridine to form a 1-ben-
zoylpyridinium intermediate, which then reacts with AcOꢁ to
form mixed anhydride 9. Phosphorylation of diol 1 with BMP 2
did not occur in our catalytic system, suggesting that Zn(II)
could activate the benzoyl group along with the ion pair of Zn(II)
cation and phosphate anion to give desired 3 and stable
Procedure for the preparation of N-(1-hydroxy-2-
(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)benzamide 1
To a solution of (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-
diol hydrochloride) (3.4 g, 10 mmol) and triethylamine (2.9 mL,
21 mmol) in CH2Cl2 (50 mL) and THF (10 mL) was added
benzoyl chloride (1.27 mL, 11 mmol). The mixture was stirred at
room temperature for 1 day. The reaction mixture was ltered to
remove a precipitate. Water (20 mL) was added to the ltrate,
which was extracted with CHCl3 (50 mL ꢂ 3). The organic layer
was washed with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was puried by ash column chromatog-
raphy (silica gel, hexanes–EtOAc) to give 1 as a white solid
(2.77 g, 68%).
2ꢁ
MeOPO4 (Scheme 2C, le). Nucleophilic attack on the acetyl
group of anhydride 9 is favored due to steric interactions
between the phenyl ring of the benzoyl group and the hydroxyl
group (Scheme 2C, right).
N-(1-Hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-
benzamide 1. White solid, mp 81–83 C; IR (KBr) (cmꢁ1) 3241,
ꢀ
1630; 1H NMR (400 MHz, CDCl3); d 7.60 (dt, J ¼ 7.2 Hz, 1.5 Hz,
2H), 7.49 (tt, J ¼ 7.2 Hz, 1.5 Hz, 1H), 7.39 (tt, J ¼ 7.6 Hz, 7.6 Hz,
2H), 7.13 (d, J ¼ 8.2 Hz, 2H), 7.09 (d, J ¼ 8.2 Hz, 2H), 6.62 (brs,
1H), 4.00 (dd, J ¼ 11.8 Hz, 5.6 Hz, 2H), 3.88 (t, J ¼ 6.7 Hz, 2H),
3.72 (dd, J ¼ 11.3 Hz, 6.7 Hz, 2H), 2.72–2.68 (m, 2H), 2.55 (t, J ¼
7.7 Hz, 2H), 2.12–2.08 (m, 2H), 1.60–1.53 (m, 2H), 1.32–1.22 (m,
10H), 0.87 (t, J ¼ 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3); d 14.1,
22.7, 29.3, 29.4, 29.5, 31.5, 31.9, 34.8, 35.5, 61.7, 66.1, 126.9,
128.2, 128.6, 128.8, 131.8, 134.4, 138.5, 141.0, 168.5; MS (EI): m/z
(%) 411 (M+, 20), 105 (100); HRMS-EI: m/z (M+) calcd for
Conclusions
In summary, we have for the rst time achieved the Zn(OAc)2-
promoted monobenzoylation reaction of FTY720 with benzoyl
methyl phosphate (BMP). Notably, benzoyl methyl phosphate
plays an important role as an acylating reagent.12 The develop-
ment of this efficient biomimetic pathway promises to generate
further innovative organic reactions. We are currently investi-
gating the scope of various 1,2- and 1,3-diols, which are highly
functionalized bioactive compounds, and new reactions using
benzoyl methyl phosphates.
C
26H37NO3 411.2773, found 411.2772.
Procedure for monobenzoylation of diol 1 with BMP 2
Experimental
Procedure for preparation of benzoyl methyl phosphates 2
A mixture of benzoyl methyl phosphate 2 (298 mg, 1.25 mmol)
and 1 (102 mg, 0.25 mmol) in DMF (10 mL) was stirred at 40 ꢀC
A mixture of trimethylphosphate (11.5 mL, 0.1 mol) and NaI for 24 h. Aer being poured into water, the mixture was
(15.5 g, 0.1 mol) in acetone (130 mL) was stirred at room extracted with EtOAc (20 mL ꢂ 3). The organic layer was
temperature for 3 days, leading to crystallization of the product, concentrated in vacuo. The residue was puried by ash column
sodium dimethyl phosphate (13.8 g, 94%).
chromatography (silica gel, hexanes–EtOAc) to give 3 (65 mg,
Sodium dimethyl phosphate (1.0 g, 6.9 mmol) and N,N- 50%) as colorless oil.
dimethylaminopyridine (41 mg, 0.3 mmol) were suspended in
2-Benzamido-2-(hydroxymethyl)-4-(4-octylphenyl)butyl
dry tetrahydrofuran (15 mL), then benzoyl chloride (0.8 mL, benzoate 3. Colourless oil; IR (KBr) (cmꢁ1) 3382, 2926, 2854,
6.4 mmol) was added under argon. The mixture was stirred at 1722, 1649; 1H NMR (400 MHz, CDCl3); d 8.06–8.03 (m, 2H),
room temperature for 3 h. The reaction mixture was ltered to 8.69–8.67 (m, 2H), 7.60 (tt, J ¼ 7.2 Hz, 1.5 Hz, 1H), 7.53–7.40 (m,
remove sodium chloride. Water (20 mL) was added to the 5H), 7.13 (d, J ¼ 8.2 Hz, 2H), 7.07 (d, J ¼ 8.2 Hz, 2H), 6.71 (brs,
ltrate, which was extracted with CHCl3 (30 mL ꢂ 3). The 1H), 4.79 (d, J ¼ 11.3 Hz, 1H), 4.59 (d, J ¼ 11.3 Hz, 1H), 4.00–3.90
organic layer was washed with brine, dried over MgSO4 and (m, 2H), 2.79 (ddd, J ¼ 13.3 Hz, 11.3 Hz, 5.6 Hz, 1H), 2.68 (ddd, J
concentrated in vacuo. The residue was puried by ash column ¼ 13.3 Hz, 11.3 Hz, 5.6 Hz, 1H), 2.54 (t, J ¼ 7.7 Hz, 2H), 2.44
chromatography (silica gel, hexanes–EtOAc) to give the benzoyl (ddd, J ¼ 14.3 Hz, 11.3 Hz, 5.6 Hz, 1H), 2.19 (ddd, J ¼ 14.3 Hz,
dimethyl phosphate as a colorless oil (1.3 g, 87%).
11.3 Hz, 5.6 Hz, 1H), 1.53 (m, 2H), 1.35–1.23 (m, 10H), 0.87 (t, J
The mixture of benzoyl dimethyl phosphate (1.3 g, 5.5 mmol) ¼ 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3); d 14.1, 22.7, 29.3,
and NaI (0.83 g, 5.5 mmol) in acetone (30 mL) was stirred at 29.4, 29.5, 31.5, 31.9, 34.5, 35.5, 61.5, 65.6, 66.2, 126.9, 128.2,
room temperature for 3 days, leading to crystallization of the 128.6, 128.7, 129.4, 129.8, 131.8, 133.6, 134.4, 138.4, 140.9,
product, the sodium salt of benzoyl methyl phosphate 2 (1.2 g, 167.2, 168.3; MS (EI): m/z (%) 515 (M+, 13), 159 (100); HRMS-EI:
93%).
Benzoyl methyl phosphate 2.2f White solid. dp 189–191 ꢀC; IR
m/z (M+) calcd for C33H41NO4 515.3036, found 515.3036.
2-Benzamido-2-(4-octylphenethyl)propane-1,3-diyl dibenzoate
(KBr) (cmꢁ1) 2953, 1711, 1271; 1H NMR (400 MHz, D2O); d 7.98 4. Colourless oil; IR (KBr) (cmꢁ1) 3412, 2925, 2854, 1722, 1651;
(d, J ¼ 9.6 Hz, 2H), 7.61 (t, J ¼ 8.3 Hz, 1H), 7.45 (t, J ¼ 7.7 Hz, 1H NMR (400 MHz, CDCl3); d 8.02–7.99 (m, 4H), 7.74–7.67 (m,
2H), 3.63 (d, J ¼ 11.4 Hz, 3H); 13C NMR (100 MHz, DMSO-d6); d 2H), 7.57–7.49 (m, 3H), 7.46–7.38 (m, 6H), 7.14 (d, J ¼ 8.2 Hz,
151.2, 143.8, 135.0, 130.1, 129.8, 128.9, 126.4, 122.5, 121.7, 2H), 7.08 (d, J ¼ 8.2 Hz, 2H), 6.92 (brs, 1H), 4.90 (d, J ¼ 11.8 Hz,
118.8, 111.3; MS (FAB); m/z 239 [M + H]+.
2H), 4.82 (d, J ¼ 11.8 Hz, 2H), 2.81–2.76 (m, 2H), 2.56–2.52 (m,
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4H), 1.54 (m, 2H), 1.35–1.23 (m, 10H), 0.87 (t, J ¼ 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3); d 14.1, 22.7, 29.3, 29.4, 29.5, 29.6,
31.5, 31.9, 34.3, 35.6, 59.6, 65.9, 126.9, 128.3, 128.5, 128.6, 128.7,
129.5, 129.7, 131.6, 133.4, 134.6, 138.3, 140.9, 166.7, 167.3; MS
(EI): m/z (%) 619 (M+, 5), 159 (100); HRMS-EI: m/z (M+) calcd for
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C
40H45NO5 619.3298, found 619.3297.
2-Benzamido-2-(hydroxymethyl)-4-(4-octylphenyl)butyl acetate
5. Colourless oil; 1H NMR (400 MHz, CDCl3); d 7.66 (dt, J ¼ 7.2
Hz, 1.5 Hz, 2H), 7.51 (tt, J ¼ 7.2 Hz, 1.5 Hz, 1H), 7.46–7.40 (m,
2H), 7.14–7.06 (m, 4H), 6.59 (brs, 1H), 4.58–4.52 (m, 2H), 4.30 (d,
J ¼ 11.8 Hz, 1H), 3.90 (dd, J ¼ 12.4 Hz, 7.2 Hz, 1H), 3.85 (dd, J ¼
12.4 Hz, 6.1 Hz, 1H), 2.73 (ddd, J ¼ 13.3 Hz, 11.3 Hz, 5.6 Hz, 1H),
2.62 (ddd, J ¼ 13.3 Hz, 10.7 Hz, 5.6 Hz, 1H), 2.54 (t, J ¼ 7.7 Hz,
2H), 2.31 (ddd, J ¼ 14.3 Hz, 11.3 Hz, 5.6 Hz, 1H), 2.08 (ddd, J ¼
14.3 Hz, 11.3 Hz, 5.6 Hz, 1H), 1.60–1.53 (m, 2H), 1.35–1.22 (m,
10H), 0.87 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3); d 14.1,
20.9, 22.7, 29.3, 29.3, 29.4, 29.5, 31.5, 31.9, 34.5, 35.5, 61.2, 65.6,
65.9, 126.9, 128.2, 128.6, 128.7, 131.8, 134.3, 138.4, 140.9, 168.3,
171.6; MS (EI): m/z (%) 453 (M+, 16), 159 (100); HRMS-EI: m/z
(M+) calcd for C28H39NO4 453.2879, found 453.2879.
{4-(4-Octylphenethyl)-2-phenyl-4,5-dihydrooxazol-4-yl}methanol
6. Colourless oil; IR (KBr) (cmꢁ1) 2923, 2853, 1648; 1H NMR (400
MHz, CDCl3); d 7.96 (dt, J ¼ 7.2 Hz, 1.5 Hz, 2H), 7.50 (tt, J ¼ 7.2
Hz, 1.5 Hz, 1H), 7.45–7.40 (m, 2H), 7.08 (brs, 4H), 4.42 (d, J ¼ 8.2
Hz, 2H), 4.28 (d, J ¼ 8.7 Hz, 1H), 3.83 (dd, J ¼ 11.3 Hz, 3.6 Hz,
1H), 3.55 (dd, J ¼ 11.3 Hz, 8.7 Hz, 1H), 2.65–2.52 (m, 4H), 2.01
(ddd, J ¼ 14.3 Hz, 11.3 Hz, 5.6 Hz, 1H), 1.89–1.81 (m, 2H), 1.60–
1.53 (m, 2H), 1.35–1.22 (m, 10H), 0.87 (t, J ¼ 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3); d 14.1, 22.7, 29.3, 29.4, 29.5, 31.6, 31.9,
35.5, 38.2, 67.7, 72.6, 75.0, 76.7, 77.0, 77.2, 77.3, 128.1, 128.4,
128.4, 128.5, 128.6, 131.6, 138.8, 140.6; MS (EI): m/z (%) 393 (M+,
30), 177 (100); HRMS-EI: m/z (M+) calcd for C26H35NO2 393.2668,
found 393.2667.
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Chem. Pharm. Bull., 2012, 60, 1395–1398; (b) M. Hamada,
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9 Mono-benzylation of 2-substituted serinols has been
reported. M. S. Hong, T. W. Kim, B. Jung and S. H. Kang,
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11 P. A. Clarke, P. L. Arnold, M. A. Smith, L. S. Natrajan,
C. Wilson and C. Chan, Chem. Commun., 2003, 2588–
2589.
10 ZnTAC24,
a
mixture of Zn-cluster [Zn4(OCOCF3)6O]
developed by Mashima and Ohshima group and its
triuoroacetic acid adduct, catalyzes a wide variety of 12 Benzoyl chloride resulted in low yield (mono 3: 37%) along
condensation reactions such as oxazoline syntheses and
transesterications. (a) T. Ohshima and K. Mashima, J.
with recovery of SM 1 (60%) [reaction conditions: BzCl
(1.05 equiv.), Et3N (1.05 equiv.), THF, rt, 24 h].
23136 | RSC Adv., 2014, 4, 23131–23136
This journal is © The Royal Society of Chemistry 2014