A new and more efficient synthesis of methylene acetals

Article abstract of DOI:10.1055/s-0029-1216992

A new and efficient synthesis of benzyl chlorides and methylene acetals by use of 2,4-dichloro-6-methoxy[l,3,5]triazine (MeOTCT) and dimethyl sulfoxide has been developed. Chlorides are the major products for benzyl alcohols, while methylene acetals are the major products for secondary alcohols. This procedure provides the highest yields so far for methylene acetals of steroids. A plausible mechanism is proposed on the basis of the experiments. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216992

3828
PAPER
A New and More Efficient Synthesis of Methylene Acetals
S
ynthesis of Methy
u
lene
A
cetalsobiao Chu,a Yanqiao Zhang,a Chunbao Li,*a Yuqing Zhangb
a
Department of Chemistry, College of Science, Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27403475; E-mail: lichunbao@tju.edu.cn
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. of China
b
Received 18 June 2009; revised 16 July 2009
yl sulfoxide (5.0 equiv) was used partially because of its
ability to dissolve the substrates.
Abstract: A new and efficient synthesis of benzyl chlorides and
methylene acetals by use of 2,4-dichloro-6-methoxy[1,3,5]triazine
(MeOTCT) and dimethyl sulfoxide has been developed. Chlorides
are the major products for benzyl alcohols, while methylene acetals
are the major products for secondary alcohols. This procedure pro-
vides the highest yields so far for methylene acetals of steroids. A
plausible mechanism is proposed on the basis of the experiments.
When benzyl alcohols (Table 1, entries 1–4) were treated
with MeOTCT/dimethyl sulfoxide, the corresponding
benzyl chlorides were obtained in excellent yields. No
methylene acetals were detectable. This compared favor-
ably to our previous procedure where TCT/dimethyl sulf-
oxide was used to chlorinate benzyl alcohols, in term of
reaction scale and operation, although this reaction had to
be performed at a higher temperature, which is harsher
than the previous method.9
Key words: 2,4-dichloro-6-methoxy[1,3,5]triazine, dimethyl sulf-
oxide, alcohols, benzyl chlorides, methylene acetals
Methylene acetals of alcohols are useful compounds.1 The
formation of methylene acetals is also one of the most use-
ful and versatile reactions in protective organic chemis-
try.2 Various regents such as formaldehyde,3 sodium
hydride/dibromo- or dichloromethane,4 or dimethyl sulf-
oxide/phosphoryl chloride,5 dimethyl sulfoxide/N-bromo-
succinimide, or dimethyl sulfoxide/bromine systems6
have been reported previously to give methylene acetals
from alcohols. Many of the methods, however, suffer
from limitations such as longer reaction times or lower
yields.
When aliphatic alcohols (Table 1, entries 6–8) were sub-
jected to the above reaction conditions, both chlorides and
methylene acetals were obtained. We were delighted to
find that secondary alcohols (Table 1, entries 9–17) were
exclusively converted into methylene acetals. No chlo-
rides were detectable. When cholesterol was subjected to
the above procedure, the methylene acetal of cholesterol
directly precipitated from the reaction mixture in 80%
1
yield and pure enough by H NMR analysis so that no
chromatographic purification was needed. In the litera-
ture,10 the yields of the acetals were all below 30%, far be-
low ours. Diosgenin possesses an acid-labile ketal
functional group, which was transformed into its methyl-
ene acetal in 82% yield in short reaction time (3 h). Estra-
diol possesses two hydroxy groups. The chemoselectivity
is excellent and only the aliphatic hydroxy group formed
acetal in 72% yield (Table 1, entry 11). d-17,17¢-Methyl-
Recently, we have reported an improved method which
employed dimethyl sulfoxide activated by 2,4-dichloro-6-
methoxy[1,3,5]triazine (MeOTCT) as a source of methyl-
ene to convert amides into bisamides.7 2,4,6-Trichloro-
1,3,5-triazine (TCT) and derivates have been reported as
efficient reagents in a number of processes involving
functional-group transformations.8 These cost-effective
reagents are amenable to large-scale processes. Therefore,
we became interested in synthesis of methylene acetals by
the reaction of alcohols with MeOTCT-activated dimeth-
yl sulfoxide.
enedioxybis[3-methoxyestra-1,3,5(10)-triene]
shows
mild estrogenic and antilipemic activity, and was synthe-
sized in 29.4% yield (Scheme 1) starting from the methyl
ether of estradiol in the literature.11 Similarly, 2-formyl-
estradiol (Table 1, entry 12) was converted into methyl-
Table 1 summarizes reactions of alcohols with dimethyl ene acetal in high yield (76%). This procedure is also
sulfoxide activated by MeOTCT. The reactions were per- efficient in forming intramolecular acetals. Diols
formed using MeOTCT and dimethyl sulfoxide in various (Table 1, entries 13–16) were all transformed into their
solvents, such as toluene, acetonitrile, chloroform, and methylene acetals in fair to good yields within a few
dimethyl sulfoxide. The best results were obtained with hours. Although the trityl group is acid-labile, the methyl-
toluene. The optimized procedure consisted of the addi- ene acetal of the inositol derivate (Table 1, entry 16) was
tion of alcohol (1 equiv) to the solution of MeOTCT (1.2 obtained in 63% yield. The methylene acetal ring of the
equiv) and dimethyl sulfoxide (5 equiv) in anhydrous tol- product is highly strained, which was not accessible from
uene (8 mL) at 80 °C. Decreasing the amount of MeOTCT the reaction of the inositol diol (Table 1, entry 16) with
or lowering the reaction temperature caused longer reac- formaldehyde, diiodomethane, dibromomethane, or di-
tion times and lower yields. An excess amount of dimeth- azomethane.12
SYNTHESIS 2009, No. 22, pp 3828–3832
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x.
x
x
.
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Advanced online publication: 08.09.2009
DOI: 10.1055/s-0029-1216992; Art ID: F12109SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Methylene Acetals
3829
Table 1 Preparation of Benzyl Chlorides and Methylene Acetals
R1
R1
R1
R1
MeOTCT, DMSO
toluene, 80 °C
+
R2
O
O
R2
R2
Cl
R2
OH
Entry Substrate
Chloride
Methylene acetal
Time Yield of Yield of
(h) chloridea acetala
(%)
(%)
1
2
3
3
90
Cl
OH
OH
86
OH
Cl
O
O
3
2.5 91
Cl
4
3
4
94
88
Cl
NO2
OH
NO2
5
OH
Cl
6
7
4
4
25
35
46
52
OH
Cl
O
O
O
O
O
O
O
OH
Cl
O
O
8
4
32
50
80
O
Cl
OH
9b
2.5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
HO
O
O
10
3
82
O
O
O
O
H
O
H
H
O
H
H
H
H
H
H
H
H
H
HO
HO
H
O
O
11
12
13
6
72
76
48
OH
O
O
H
H
H
H
H
H
H
H
H
H
OH
HO
5
OH
O
O
H
H
H
H
H
CHO
OH
OHC
HO
OHC
HO
H
H
H
4.5
OH
O
O
OH
Synthesis 2009, No. 22, 3828–3832 © Thieme Stuttgart · New York

3830
G. Chu et al.
PAPER
Table 1 Preparation of Benzyl Chlorides and Methylene Acetals (continued)
R1
R1
R1
R1
MeOTCT, DMSO
toluene, 80 °C
+
R2
O
O
R2
R2
Cl
R2
OH
Entry Substrate
Chloride
Methylene acetal
Time Yield of Yield of
(h) chloridea acetala
(%)
(%)
14
6
52
O
HO
O
O
O
HO
BnO
OBn
BnO
OBn
OMe
OMe
15
4.5
65
O
O
O
O
N
OH
OH
N
O
O
16
17
5
8
63
65
O
O
O
O
O
O
TrO
TrO
OH
OH
O
O
O
O
OH
a Isolated yields.
b DMSO as solvent instead of toluene.
On the basis of the above experiments and our previous alcohols and methylene acetals from secondary alcohols
research,7,9
plausible mechanism is proposed using dimethyl sulfoxide activated by MeOTCT. This rep-
a
(Scheme 2). The adduct of MeOTCT and dimethyl sulf- resents the synthesis of steroidal methylene acetals in the
oxide reacts with the alcohol to form a dimethyl alkoxy- highest yields so far. The procedure reported herein is op-
sulfonium salt (I), which reacts in two pathways. A erationally simple, and requires inexpensive and commer-
dimethyl(arylmethyl)sulfonium salt is active enough to cially available reagents. A plausible mechanism of the
yield the corresponding chloride (VI), and the major path- reaction is proposed and supported by the experiments.
way of the reaction is SN2 for less hindered benzylic alco-
hols (Table 1, entries 1 and 2). In contrast, a primary
All the chemicals were obtained from commercial sources or pre-
aliphatic sulfonium salt is not active enough for complete
chloride substitution, and decomposes to regenerate the
alcohol and the sulfonium ion (II). The sulfonium salt (I)
formed by the secondary alcohols (Table 1, entries 9–17)
and dimethyl sulfoxide gives no corresponding chloride
due to its lower activity and steric effects. Similar to the
Pummerer rearrangement, thioether III is formed by the
addition of the alcohol to intermediate II. Thioether III is
a good nucleophile and capable of substituting the chlo-
ride of 4-chloro-6-methoxy-1,3,5-triazin-2-ol (CMTO) to
generate sulfonium salt IV. The alcohol substitutes sulfo-
nium IV to form methylene acetal V.
pared according to standard methods. All the chemicals and sol-
vents used in reactions were dried by standard procedures prior to
use. IR spectra were recorded on a Bio-Rad Excalibur FTS3000
1
spectrometer. The H NMR (500 MHz) and 13C NMR (125 MHz)
spectra were recorded on a Varian Oxford 500 spectrometer. Chem-
ical shifts are reported relative to TMS (1H) or CDCl3 (13C). Mass
spectra (ESI) were obtained on a Finnigan LCQ Advantage MAX
spectrometer. Elemental analyses for C, H, and N were performed
on a Yanaco CHNCORNER MF-3 elemental analyzer, and the
analytical results were within 0.4% of the theoretical values.
Benzyl Chloride (Table 1, Entry 1); Typical Procedure for the
Chlorination of Benzyl Alcohols
The procedure for the chlorination of benzyl alcohol (Table 1, entry
1) is representative for all benzyl alcohols in Table 1. Benzyl alco-
hol (500 mg, 4.63 mmol) was added to the soln of MeOTCT (994
In conclusion, we have developed a new and more effi-
cient method to synthesize benzyl chlorides from benzyl
O
O
OH
ref. 9
29.4%
MeO
OMe
MeO
Scheme 1
Synthesis 2009, No. 22, 3828–3832 © Thieme Stuttgart · New York

PAPER
Synthesis of Methylene Acetals
3831
R1
OMe
OMe
R1
O
+
S
HO
–
R2
+
S
N
N
N
– Cl–
O
N
N
N
+
OMe
S
+
R2
Cl
Cl
O
Cl
N
N
N
MeOTCT
I
OH
Cl
CMTO
+
O
Cl
R1
R1
O
S
Cl–
+
S
OH
R2
OMe
R2
R1
R1
VI
R1
R1
N
N
R1
R2
R2
– HCl
R1
Cl
+
S
R2
O
O
R2
CMTO
+
N
HO
S
O
HO
R2
– H+
R2
O
S
V
III
II
IV
Scheme 2
mg, 5.56 mmol) and anhyd DMSO (1.86 g, 23.2 mmol) in anhyd
toluene (8 mL). The mixture was stirred at 80 °C and monitored by
TLC until completion (6 h). Then it was neutralized with sat. aq
NaHCO3 (20 mL), and the mixture was extracted with CH2Cl2
(3 × 20 mL). The extract was washed with H2O (5 × 5 mL), and
dried over anhyd Na2SO4. The solvent was concentrated in vacuo to
give crude product, which was then filtered through a silica gel pad
with PE to afford benzyl chloride; yield: 525 mg (90%).
13C NMR (125 MHz, CDCl3): d = 141.0, 121.7, 109.5, 91.3, 181.0,
67.1, 62.3, 56.7, 50.3, 41.8, 40.5, 40.0, 39.7, 37.4, 37.1, 32.3, 32.1,
31.7, 31.6, 30.5, 29.9, 29.1, 29.0, 21.1, 19.6, 17.4, 16.5, 14.8.
ESI-MS: m/z (%) = 842.4 (100) [M + H]+.
Anal. Calcd for C55H84O6: C, 78.52; H, 10.06. Found: C, 78.48; H,
10.12.
17,17¢-Methylenedioxybis[estra-1,3,5(10)-triene] (Table 1,
Entry 11)
Bis(octyloxy)methane (Table 1, Entry 6); Typical Procedure for
the Preparation of Methylene Acetals from Aliphatic Alcohols
The procedure for the reaction of MeOTCT-activated DMSO and
octan-1-ol (Table 1, entry 6) is representative for all aliphatic alco-
hols in Table 1. Octan-1-ol (500 mg, 3.85 mmol) was added to the
soln of MeOTCT (826 mg, 4.62 mmol) and anhyd DMSO (1.50 g,
19.2 mmol) in anhyd toluene (8 mL). The mixture was stirred at 80
°C and monitored by TLC until completion (4 h). Then it was neu-
tralized with sat. aq NaHCO3 (20 mL), and extracted with CH2Cl2
(3 × 20 mL). The extract was washed with H2O (5 × 5 mL), and
dried over anhyd Na2SO4. The solvent was concentrated in vacuo to
give crude product, which was further purified by column chroma-
tography (silica gel, (PE–Et2O, 6:1) to afford 1-chlorooctane; yield:
141 mg (25%) and bis(octyloxy)methane; yield: 242 mg (46%).
[The reactions of diols (Table 1, entries 13–16) with activated
DMSO need a double dosage of DMSO and MeOTCT.]
Yield: 72%.
IR (KBr): 3373, 2926, 2867, 1610, 1499, 1248, 1160, 1054, 1019
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.16 (d, J = 8.4, 2 H), 6.64–6.57
(m, 4 H), 4.76 (s, 2 H), 3.71 (t, J = 8.4 Hz, 2 H), 2.84–2.88 (m, 6 H),
3.71 (t, J = 8.4, 2 H), 2.89 (m, 4 H), 2.30–1.22 (m, 28 H).
13C NMR (125 MHz, CDCl3): d = 155.1, 138.0, 131.5, 126.4, 115.6,
113.1, 93.9, 86.0, 50.1, 44.1, 43.2, 38.9, 37.7, 32.7, 29.8, 28.2, 27.0,
23.3, 12.0.
ESI-MS: m/z (%) = 556.5 (45) [M]+, 579.2 (100) [M + Na]+.
Anal. Calcd for C37H48O4: C, 79.82; H, 8.69. Found: C, 79.88; H,
8.72.
2,2¢-Diformyl-17,17¢-methylenedioxybis[estra-1,3,5(10)-triene]
(Table 1, Entry 12)
Yield: 76%.
3,3¢-Methylenedioxybischolesterol (Table 1, Entry 9)
Cholesterol (500 mg, 1.34 mmol) was added to the soln of
MeOTCT (288 mg, 1.61 mmol) in anhyd DMSO (8 mL). The mix-
ture was stirred at 80 °C, and solid appeared 2.5 h later. Then the
mixture was added to aq NaHCO3 (20 mL). After filtration, washing
with H2O, and drying with anhyd Na2SO4, pure product was ob-
tained; yield: 428 mg (80%).
IR (KBr): 3320, 2932, 2852, 1653, 1527, 1486, 1466, 1056, 1043
cm–1.
1H NMR (500 MHz, CDCl3): d = 10.78 (s, 2 H), 9.81 (s, 2 H), 7.43
(s, 2 H), 6.70 (s, 2 H), 4.76 (s, 2 H), 3.71 (t, J = 8.4 Hz, 2 H), 2.89
(m, 4 H), 2.35–1.14 (m, 32 H).
13C NMR (125 MHz, CDCl3): d = 196.3, 159.5, 148.3, 133.0, 130.8,
119.2, 117.2, 94.2, 86.0, 50.2, 43.7, 43.2, 38.5, 37.5, 32.2, 29.9,
28.3, 26.9, 23.3, 12.1.
3,3¢-Methylenedioxybisdiosgenin (Table 1, Entry 10)
Yield: 82%.
IR (KBr): 2980, 2933, 2816, 1455, 1376, 1152, 1096, 1038, 1006,
981, 899 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.35 (d, J = 4.4 Hz, 2 H), 4.79 (s,
2 H), 4.41 (q, J = 7.5 Hz, 2 H), 3.46 (dd, J = 5.7, 9.4 Hz, 4 H), 3.38
(m, 2 H), 2.35 (dd, J = 3.1, 13.1 Hz, 2 H), 2.23 (t, J = 12.2 Hz, 2 H),
1.99 (m, 4 H), 1.90–0.98 (m, 64 H).
ESI-MS: m/z (%) = 636.5 (38) [M + Na]+, 1249.2 (100) [2 M +
Na]+.
Anal. Calcd for C39H48O6: C, 76.44; H, 7.90. Found: C, 76.48; H,
7.95.
2-[(1,3-Dioxolan-4-yl)methyl]isoindoline-1,3-dione (Table 1,
entry 15)
Yield: 65%.
Synthesis 2009, No. 22, 3828–3832 © Thieme Stuttgart · New York

3832
G. Chu et al.
PAPER
IR (KBr): 3315, 2932, 2852, 1653, 1527, 1486, 1466, 1056, 1043,
715 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.87 (dd, J = 3.0, 5.4 Hz, 2 H),
7.74 (dd, J = 3.0, 5.4 Hz, 2 H), 5.09 (s, 1 H), 4.88 (s, 1 H), 4.42 (m,
1 H), 3.95 (m, 2 H), 3.77 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 168.5, 134.3, 132.2, 123.7, 95.4,
73.4, 68.0, 40.0.
References
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ESI-MS: m/z (%) = 489.6 (100) [2 M + Na]+.
Anal. Calcd for C12H11NO4: C, 61.80; H, 4.75; N, 6.01. Found: C,
61.74; H, 4.78; N, 5.97.
4-Trityl-2,6-methylenedioxy-myo-inositol 1,3,5-Orthoformate
(Table 1, Entry 16)
Yield: 63%.
(7) Wang, Q.; Sun, L.; Jiang, Y.; Li, C. Beilstein J. Org. Chem.
2008, 4, 51; DOI: 10.3762/bjoc.4.51.
IR (KBr): 3060, 2942, 2882, 1489, 1448, 1179, 1167, 1137, 1109,
1086, 1041, 1006, 965, 926, 701 cm–1.
(8) (a) Blotny, G. Tetrahedron 2006, 62, 9507. (b) Das, B.;
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Catal. Commun. 2007, 8, 1595.
1H NMR (500 MHz, CDCl3): d = 7.58 (d, J = 7.5 Hz, 6 H), 7.33 (t,
J = 7.4 Hz, 6 H), 7.27 (t, J = 7.2 Hz, 3 H), 5.55 (s, 1 H), 5.02 (d,
J = 5.8 Hz, 1 H), 4.71 (t, J = 4.6 Hz, 1 H), 4.57 (t, J = 4.8 Hz, 2 H),
4.43 (d, J = 5.9 Hz, 2 H), 3.61 (s, 2 H).
13C NMR (125 MHz, CDCl3): d = 144.5, 129.3, 129.2, 128.2, 128.1,
127.6, 102.4, 88.0, 84.6, 71.5, 66.4, 63.3, 61.9.
(9) Sun, L.; Pei, G.; Niu, H.; Wang, Q.; Li, C. Synthesis 2008,
3919.
ESI-MS: m/z (%) = 912.6 (100) [2M + Na]+.
(10) (a) Suzuki, K.; Inanaga, J.; Yamaguchi, M. Chem. Lett.
1979, 1277. (b) Herz, J. E.; Lucero, J.; Santoyo, Y.; Waight,
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Anal. Calcd for C27H24O6: C, 72.96; H, 5.44. Found: C, 72.88; H,
5.48.
Acknowledgment
(11) Wendt, G. R.; Ledig, K. W. US Patent 3267120, 1964;
We thank the NSFC for financial support.
Chem. Abstr. 1966, 65, 13794f.
(12) Shao, M.; Chu, G.; Li, C. unpublished results.
Synthesis 2009, No. 22, 3828–3832 © Thieme Stuttgart · New York