Synthesis of dithioacetals and oxathioacetals with chiral auxiliaries

Article abstract of DOI:10.1081/SCC-200025627

One-pot synthesis of dithioacetals as well as an efficient method for oxathioacetal is reported. Additionally, some chiral auxiliaries were used to synthesize enantiomerically pure dithioacetals and oxathioacetals.

Full text of DOI:10.1081/SCC-200025627

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Synthesis of Dithioacetals and
Oxathioacetals with Chiral
Auxiliaries
Javid H. Zaidi a , Fazal Naeem a , Khalid M. Khan b
, Rashid Iqbal a & Zia‐Ullah b
a Department of Chemistry , Quaid‐i‐Azam
University , Islamabad, 45320, Pakistan
b H.E.J. Research Institute of Chemistry,
International Center for Chemical Sciences ,
University of Karachi , Karachi, Pakistan
Published online: 10 Jan 2011.
To cite this article: Javid H. Zaidi , Fazal Naeem , Khalid M. Khan , Rashid
Iqbal & Zia‐Ullah (2004) Synthesis of Dithioacetals and Oxathioacetals with
Chiral Auxiliaries, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:14, 2641-2653, DOI: 10.1081/
SCC-200025627
To link to this article: http://dx.doi.org/10.1081/SCC-200025627
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 14, pp. 2641–2653, 2004
Synthesis of Dithioacetals and
Oxathioacetals with Chiral Auxiliaries
1
2
Javid H. Zaidi,1, Fazal Naeem, Khalid M. Khan,
*
Rashid Iqbal,1 and Zia-Ullah2
1Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan
2H.E.J. Research Institute of Chemistry, International Center for
Chemical Sciences, University of Karachi, Karachi, Pakistan
ABSTRACT
One-pot synthesis of dithioacetals as well as an efficient method for
oxathioacetal is reported. Additionally, some chiral auxiliaries were
used to synthesize enantiomerically pure dithioacetals and oxathioacetals.
Key Words: Dithioacetals; Oxathioacetals; Chiral auxiliaries.
INTRODUCTION
We report herein one-pot reaction for the synthesis of dithioacetals as well
as an efficient and high-yield method for the preparation of oxathioacetals.
*
Correspondence: Javid H. Zaidi, Department of Chemistry, Quaid-i-Azam University,
Islamabad 45320, Pakistan; E-mail: javid_zaidi@yahoo.com.
2641
DOI: 10.1080/SCC-200025627
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2642
Zaidi et al.
These methods are also efficiently used for the synthesis of chiral dithioacetals
and oxathioacetals. Though various methods for the synthesis of dithioacetals
and oxathioacetals are documented in the literature,[1] however, they often
vary in protocols and yields require optimization.[2–6] The use of dithioacetals
as chemical equivalent of formyl anion synthon is very common in organic
synthesis. 1,3-Dithiane,[7] for example, is commercially available and can
be readily metalated. Metalation of oxathioacetals is also known in the litera-
ture.[8] Thus, dithioacetals and oxathioacetals with tagged chiral auxiliaries
can be used for asymmetric induction via metallation followed by alkylation.
RESULTS AND DISCUSSION
In this article, we describe a general one-pot synthesis of dithioacetals,
using commercially available, inexpensive reagents and simple reaction con-
ditions, e.g., the synthesis of bis(phenylthio)methane (1) involves refluxing a
mixture of thiophenol, formalin, anhydrous calcium chloride and catalytic
amount of concentrated hydrochloric acid and then allowed the reaction
mixture to stand overnight at room temperature. This method is economical
and fairly convenient than the one reported by Corey and Seebach.[5] This
method can also be extended to synthesize C-alkyl or -aryl substituted dithio-
acetals. Compounds 4 and 5 were synthesized in high yields using acetal-
dehyde and benzaldehyde instead of formalin, respectively (Sch. 1). Chiral
dithioacetal 9 was synthesized by employing the same method from chiral
camphorthiol 8, which was prepared by reducing thiocamphor 7, obtained
by reacting naturally occurring (þ)-camphor 6 with phosphorous pentasulfide
(Sch. 2).[9]
Scheme 1.

Synthesis of Dithioacetals and Oxathioacetals
2643
Scheme 2.
An efficient and general method has also been developed to synthesize
oxathioacetals. In this method, 1 equiv. of a thiol was allowed to react with
5 equiv. of diisopropylethylamine and alkoxymethylchloride in refluxing
chloroform for 8 hr under nitrogen. Alkoxymethylchloride was prepared
starting from the corresponding alcohol using the previously described
method.[10,11] This methodology was carried out to prepare chiral oxathioacetals
as given in Sch. 3. An advantage of this methodology is that both the alcohol and
the thiol components of the oxathioacetals can be varied at will using a chiral
alcohol, such as (2)-menthol, and/or a thiol, such as N-protected methyl ester
of L-cysteine (Sch. 4). Similarly, the chloromethyl methyl sulfide can also be
used to access corresponding dithioacetals 20 and 21 as shown in Sch. 5.
Ethyl vinyl ether can also be used for the synthesis of oxathioacetals
under mild conditions. The thiol protected L-cysteine also afforded the corres-
ponding oxathioacetal by this method in quantitative yield. 1H NMR spectrum
of the product indicated that it is (1 : 1) diastereoisomeric mixture, which
resulted from the generation of a new chiral center. This method can also
be viewed as a protection strategy of a mercaptan by an ethoxyethyl group,
which can also be removed under mild conditions without any detectable race-
mization. The ethoxyethyl group can be a useful protecting group for L-
cysteine in peptide synthesis (Sch. 6).
CONCLUSION
We developed a general methodology for convenient synthesis of dithio-
acetals as well as oxathioacetals and this strategy has been extended for the

2644
Zaidi et al.
Scheme 3.
high yield synthesis of some chiral dithioacetals and oxathioacetals. The
studies related to chiral inductions proceeding from metallation protocols of
these mono- and di-thioacetals as well as the use of ethyl vinyl ether appeared
as a new method for the protection of thiol functionality with particular
importance in L-cysteine.
EXPERIMENTAL
Chloroform and methylene chloride were dried by refluxing over P2O5
followed by distillation. Thin layer chromatography (TLC) was performed
on precoated silica gel plates (0.25 mm, Merck). Column chromatography
was performed on Merck silica gel having mesh size (0.063–0.200 mm,
Merck). Melting points were reported for all crystalline products and are
1
uncorrected. H NMR spectra were recorded at 300 MHz on GE QE 300
and 400 spectrometer (Oxford magnet). EIMS spectroscopic analysis was per-
formed on a VG-70SE mass spectrometer. Optical rotations were measured on
a JASCO DIP-370 digital polarimeter.

Synthesis of Dithioacetals and Oxathioacetals
2645
Scheme 4.
Synthesis of Dithioacetals 1, 2, and 3
Thiol 23 mL (224 mmol) was taken in a round bottom flask (100 mL),
4.4 g (40 mmol) of anhydrous CaCl2, and 100 mL of conc. HCl were added,
subsequently. The flask was fitted with double surface condenser and cooled
to 08C in ice bath. Formalin (37% aqueous solution) (4.3 mL) was added drop-
wise into the reaction flask. After complete addition of formalin the reaction
mixture was refluxed vigorously for 5–10 min and was allowed to stand at
room temperature over night. The reaction mixture was diluted with distilled
water (ca. 20 mL) and extracted with ether (20 mL ꢀ 3). Combined organic
layer was washed with brine and dried over MgSO4. Solvent was removed
under reduced pressure and the residue was column chromatographed on
silica gel using 3% ethylacetate in n-hexane as an eluent to afford the product.
bis(Phenylthio)methane (1). White solid m.p. 398C (Lit.[5] m.p 39.5–
40.58C); 1H NMR (300 MHz, CDCl3): d 7.94–7.74 (m, 10H), 4.85 (s, 2H); 13
C
NMR (75 MHz, CDCl3): d 135.8 (C-1/C-10), 129.9 (C-2, C-6/C-20, C-60),
129.1 (C-3, C-5/C-30, C-50), 124.7 (C-4/C-40), 124.7 (CH), 34.6 (CH2);
Scheme 5.

2646
Zaidi et al.
Scheme 6.
EIMS (m/z, %rel. abund.): 232 (Mþ, 20), 123 (100); Anal. Calcd. for
C13H12S2: C, 67.20; H, 5.21. Found: C, 67.22; H, 5.26.
bis(Ethylthio)methane (2). Colorless oil; 1H NMR (300 MHz, CDCl3):
d 3.69 (s, 2H), 2.65 (q, J ¼ 7.4 Hz, 4H), 1.26 (t, J ¼ 7.4 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d 33.7 (CH2), 25.8 (2CH2), 12.8 (CH3); EIMS (m/z,
%rel. abund.): 136.9 (Mþ, 8), 121 (13), 106 (22), 74 (39), 42 (100), 32
(18); Anal. Calcd. for C5H12S2: C, 44.07; H, 8.88. Found: C, 44.10; H, 8.86.
bis(t-Butylthio)methane (3). Colorless oil; 1H NMR (300MHz, CDCl3):
d 3.68 (s, 2H), 1.36 (s, 18H); 13C NMR (75 MHz, CDCl3): d 43.8 (C-1/C-10),
31.38 (6CH3), 27.8 (SCH2); EIMS (m/z, %rel. abund.): 192 (Mþ, 100), 103
(67); Anal. Calcd. for C9H20S2: C, 56.19; H, 10.48. Found: C, 56.29; H, 10.42.
1,1-bis(Phenylthio)ethane (4) and
bis(Phenylthio)phenylmethane (5)
These compounds were prepared by the same procedure as described for
compounds 1, 2, and 3 by using acetaldehyde and benzaldehyde, respectively,
instead of formalin.
Compound 4. 1H NMR (300 MHz, CDCl3): d 7.49–7.29 (m, 10H), 4.53
(q, J ¼ 6.9 Hz, 1H), 1.61 (d, J ¼ 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3):

Synthesis of Dithioacetals and Oxathioacetals
2647
d 132.3 (C-1/C-10), 129.6 (C-3, C-5/C-30, C-50), 128.9 (C-2, 6/C-20, C-60),
126.7 (C-4/C-400), 50.8 (CH), 21.6 (CH3); EIMS (m/z, %rel. abund.): 246
(Mþ, 6), 169 (54), 231 (29); Anal. Calcd. for C14H14S2: C, 68.24; H, 5.73.
Found: C, 68.20; H, 5.75.
1
Compound 5. Pale yellow solid m.p. 518C (lit.[6] 52–538C); H NMR
(300 MHz, CDCl3): d 7.41–7.35 (m, 6H), 7.38–7.21 (m, 9H), 5.42 (s, 1H);
13C NMR (75 MHz, CDCl3): d 133.8 (C-100, arom.), 132.5 (C-1/C-10), 128.6
(C-2, C-6/C-20, C-60), 128.0 (C-200/C-600), 128.6 (CH), 128.6 (CH), 127.4
(C-C-300/C-500), 126.5 (C-4/C-40), 125.4 (C-400); EIMS (m/z, %rel. abund.):
308 (Mþ, 9), 231 (69), 154 (76), 77 (100), 78 (31); Anal. Calcd. for
C19H16S2: C, 73.98; H, 5.23. Found: C, 73.90; H, 5.28.
Preparation of Chiral Thiocamphor (7)
(þ)-Camphor (6) (15.2 g, 99.8 mmol) was dissolved in dried and distilled
pyridine (100 mL) and the solution was set to gentle reflux with stirring.
Phosphorouspentasulfide (12 g, 27 mmol) was added in portions to the
above solution. The reddish orange suspension was left refluxing with stirring
for 12 hr. Pyridine (80 mL) was then removed by distillation. Cold residue was
diluted with petroleum ether (40–608C) (150 mL) and was washed with 2 N
hydrochloric acid (50 mL ꢀ 3), distilled water, brine, and dried (MgSO4).
Solvent was evaporated under reduced pressure to afford orange-red solid
(13.5 g, 80% yield) which was pure enough (TLC analysis) and was used in
the next step without purification. Small quantity of this product was passed
through a silica gel column using n-hexane as an eluent for spectral analysis
and measurement of optical rotation.
Compound 7. M.p. 1378C (Aldrich Catalog Handbook of Chemicals, 1994;
136–1388C); [a]2D5 ¼ 22.3 (c ¼ 0.1 CHCl3). IR (CHCl3): y 2960, 1450, 1410,
1390, 1360, 1300, 1260, 1210, 1130, 1090 cm21; 1H NMR (300 MHz, CDCl3):
d 2.81–2.74 (m, 1H), 2.40 (d, J ¼ 21 Hz, 1H), 2.16 (t, J ¼ 4.4 Hz, 1H), 2.05–
1.94 (m, 1H), 1.79–1.71 (m, 1H), 1.41–1.22 (m, 2H), 1.09 (s, 3H), 1.03
(s, 3H), 0.78 (s, 3H); 13C NMR (75 MHz, CDCl3): d 267.0 (C-2), 69.3 (C-1),
55.5 (C-3), 48.9 (C-4), 145.1 (C-5), 33.9 (C-6), 26.2 (C-5), 21.7 (C-8), 19.8
(C-9), 13.1 (C-10); EIMS (m/z, %rel. abund.): 168 (Mþ, 100), 153, 125, 113,
93, 85, 79, 69; HRMS for C10H16S (after recrystallization): 168.1864, found:
168.1802; Anal. Calcd. for C10H16S: C, 71.36; H, 9.58. Found: C, 71.40; H, 9.56.
Preparation of Chiral Camphorthiol (8)
Thiocamphor crude (6 g, 35.7 mmol) was dissolved in 1,2-dimetho-
xyethane (25 mL) and stirred at room temperature. Sodium borohydride

2648
Zaidi et al.
(340 mg, 8.93 mmol) was added to above solution and stirred at room tempera-
ture over night. The reaction mixture was quenched with distilled water along
with a few drops of 0.1 N solution of hydrochloric acid. The reaction mixture
was extracted with ether (50 mL ꢀ 2). Combined organic layer was washed
with distilled water, brine, and dried over MgSO4. Solvents were evaporated
under reduced pressure and the residue was chromatographed on silica gel
column using n-hexane as an eluent to afford white crystalline solid (5.6 g,
92% yield).
Compound 8. M.p. 2208C, [a]2D5 ¼ þ 5.9 (c ¼ 0.6 CHCl3); IR (CHCl3):
1
y 2950, 2890, 2720, 2590, 1500, 1390, 1110 cm21. H NMR (300 MHz,
CDCl3); d 2.94–2.84 (m, 1H), 2.02–1.94 (m, 2H), 1.73–1.60 (m, 3H),
1.28–1.11 (m, 2H), 1.02 (s, 3H), 0.89 (s, 3H), 0.805 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 48.8 (C), 46.3 (C), 42.9 (CH), 44.2 (CH), 35.2 (CH2),
31.6 (CH2), 27.5 (CH2), 20.8 (CH3), 18.7 (CH3), 13.7 (CH3); EIMS (m/z,
%rel. abund.): 170 (Mþ, 15%), 155, 137, 121, 107, 93 (100), 81; exact mass
calcd. for C10H18S: 170.2022, found: 170.1997; Anal. Calcd. for C10H18S:
C, 70.52; H, 10.65. Found: C, 70.46; H, 10.68.
Chiral bis(Thiocamphor)methane (9)
This compound was prepared by using the method described for the prep-
aration of compounds 1, 2, and 3 to afford compound 9 as white crystalline
solid.
1
Compound 9. M.p. 1688C; IR (CHCl3): y 2945, 1640, 1260 cm21. H
NMR (300 MHz, CDCl3): d 3.15 (s, 2H), 2.94–2.89 (m, 2H), 1.93–1.82
(m, 3H), 1.70–1.63 (m, 5H), 1.27–1.13 (m, 4H), 0.98 (s, 6H), 0.95 (s, 6H),
0.94–0.84 (m, 2H), 0.82 (s, 6H); 13C NMR (75 MHz, CDCl3): d 52.2 (C-1/
C-10), 49.4 (C-2/C-20), 45.3 (C-7/C-70), 42.9 (C-4/40), 35.5 (C-3/30), 33.6
(CH2), 33.0 (C-7/70), 28.0 (C-8/80), 23.4 (2CH3), 21.1 (2CH3), 13.6
(2CH3); EIMS (m/z, %rel. abund.): 352 (Mþ, 15); Anal. Calcd. for
C21H36S2: C, 71.52; H, 10.29. Found: C, 71.50; H, 10.30.
Synthesis of Oxathioacetals
Thiol (1 mmol) was dissolved in dried and distilled chloroform (10 mL)
under static nitrogen atmosphere. It was set to gentle reflux with stirring.
Diisopropylethylamine (5 mmol) and alkoxymethylchloride (5 mmol) are
added into the refluxing solution subsequently. The reaction mixture was
allowed to reflux for 8 hr. Reaction mixture was cooled, diluted with chloro-
form (ca. 10 mL) and was washed with distilled water, brine, and dried

Synthesis of Dithioacetals and Oxathioacetals
2649
(MgSO4). Solvent was removed under reduced pressure and residue was
purified on a silica gel column.
1
Methoxymethylphenylsulfide (10). Colorless oil; H NMR (300 MHz,
CDCl3): d 7.49–7.44 (m, 2H), 7.31–7.17 (m, 3H), 4.95 (s, 2H), 3.42
(s, 3H); 13C NMR (100 MHz, CDCl3): d 137.1 (C-3/C-5), 134.2 (C-1),
129.0 (C-4), 123.3 (C-2/C-6), 75.6 (CH2), 56.0 (CH3); EIMS (m/z, %rel.
abund.): 154 (Mþ, 42), 123 (59), 109 (19), 77 (100), 51 (14). Anal. Calcd.
for C8H10OS: C, 71.52; H, 10.29. Found: C, 71.49; H, 10.28.
n-Butoxymethylphenylsulphide (11). Colorlessoil; 1H NMR (300 MHz,
CDCl3): d 7.51–7.47 (m, 2H), 7.32–7.18 (m, 3H), 5.0 (s, 2H), 3.62 (t,
J ¼ 6.5 Hz, 2H), 1.62–1.55 (m, 2H), 1.43–1.35 (m, 2H), 0.93 (t, J ¼ 7.3 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 137.2 (C-3/C-5), 137.0 (C-1), 129.1 (C-
4), 123.2 (C-2/C-6), 75.4 (SCH2), 72.0 (OC-10), 29.2 (C-20), 18.1 (C-30), 12.9
(C-40); EIMS (m/z, %rel. abund.): 196 (Mþ, 29), 181 (22), 139 (53), 123 (62),
77 (100), 62 (49); Anal. Calcd. for C11H16OS: C, 67.30; H, 8.22. Found: C,
67.31; H, 8.21.
Preparation of Acetal of (2)-Menthol (13).
(2)-Menthol (12) (39.32 g, 25 mmol) was placed in a round bottom flask
and anhydrous CaCl2 (5.6 g, 50 mmol), concentrated hydrochloric acid
(140 mL) were added subsequently. The reaction flask fitted with a reflux con-
denser, was cooled in an ice bath. Formalin (37 % aqueous solution, 10 mL)
was added dropwise into the flask. After complete addition of formalin the
reaction mixture was vigorously refluxed for 5–10 min and was allowed to
stand at room temperature for 8 hr. The reaction mixture was diluted with
water (50 mL) and was extracted with ether (50 mL ꢀ 3). Combined organic
layer was washed with water, brine, and dried (MgSO4). The solvent was
removed under reduced pressure and residue was chromatographed on a
silica gel column using 3% ethylacetate in n-hexane as an eluent to afford
white crystalline product 13.
Compound 13. M.p. 588C [a]2D5 ¼ 2 6.4 (c ¼ 0.2 CHCl3); H NMR
1
(300 MHz, CDCl3): d 4.75 (s, 2H), 3.25–3.16 (m, 2H), 2.18–2.06 (m, 4H),
1.61–0.75 (m, 14H), 0.852 (d, J ¼ 7 Hz, 6H), 0.841 (d, J ¼ 7 Hz, 6H),
0.706 (d, J ¼ 7 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 95.29 (OCH2), 79.1
(C-1/C-10), 48.6 (C-2/C-20), 42.4 (C-6/C-60), 34.4 (C-4/C-40), 31.6 (2C),
25.3 (C-5/C-50), 23.1 (CH3), 21.2 (2CH3), 16.1 (2CH3); EIMS (m/z, %rel.
abund.): 324 (Mþ, 31), 309 (13), 294 (18), 266 (7), 238 (22), 186 (56), 170
(19), 156 (100), 140 (68); Anal. Calcd. for C21H40O2: C, 77.72; H, 12.42.
Found: C, 77.60; H, 12.54.

2650
Zaidi et al.
Preparation of Menthoxymethylchloride (14).
Compound 13 (16.2 g, 50 mmol) and anhydrous methanol (200 mL) were
stirred at room temperature under static nitrogen atmosphere. Freshly distilled
acetyl chloride (3.5 mL, 0.048 mol) was then added dropwise with a syringe.
The reaction mixture was allowed to stir at room temperature for 36 hr. After
36 hr the compound 14 was ready to be used without any workup.
Menthoxymethyl Phenylsulfide (15), Alkoxymethylthioacetals
of N-Protected Methyl Ester of L-Cysteine 17, 18, and 19
These compounds were synthesized by the method described for the
preparation of compounds 10 and 11.
Menthoxymethyl Phenylsulfide (15). Colorless oil; [a]2D5 ¼ 2 9.2
1
(c ¼ 1.2 CHCl3); H NMR (300 MHz, CDCl3): d 7.46 (d, J ¼ 8 Hz, 2H),
7.31–7.28 (m, 2H), 7.24–7.19 (m, 1H), 5.16 (d, J ¼ 11.7 Hz, 1H), 6.02
(d, J ¼ 11.7 Hz, 1H), 3.49–3.41 (m, 1H), 2.15–2.06 (m, 3H), 1.67–1.58
(m, 3H), 0.997–0.947 (m, 3H), 0.906 (d, J ¼ 6.5 Hz, 3H), 0.834
(d, J ¼ 7 Hz, 3H), 0.688 (d, J ¼ 7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
130.1 (C-3/C-5), 129.2 (C-1), 128.7 (C-4), 126.1 (C-2/C-6), 72.7 (OCH2),
68.3 (C), 48.2 (C), 39.9 (C), 34.4 (CH2), 31.4 (CH2), 25.1 (C), 23.0 (CH2),
22.3 (CH3), 21.1 (CH3), 15.8 (CH3); EIMS (m/z, %rel. abund.): 278 (Mþ,
26), 264 (35), 222 (34), 140 (8), 124 (6), 110 (72), 77 (100), 64 (41), 51
(14); C17H26OS: 278 (Mþ, 26), 264 (35), 222 (34), 140 (18), 124 (6), 110
(72), 77 (100), 64 (41), 51 (14); Anal. Calcd. for C17H26OS: C, 73.33; H,
9.41. Found: C, 73.20; H, 9.54.
Methoxymethylthioacetal of N-Protected Methyl Ester of L-Cysteine
1
(17). Colorless oil; [a]2D5 ¼ þ1.34 (c ¼ 0.752 CHCl3); H NMR (300 MHz,
CDCl3): d 7.35–7.24 (m, 5H), 6.15 (bd, J ¼ 8 Hz, 1H), 5.11 (s, 2H), 4.65–
4.51 (m, 3H), 3.74 (s, 3H), 3.31 (s, 3H), 3.14 (dd, J ¼ 14.4, J ¼ 5.3 Hz,
1H), 3.0 (dd, J ¼ 14.4, J ¼ 5.3 Hz, 1H); 13C NMR (75 MHz, CDCl3): d
169.3 (CO), 166.2 (CONH), 132.6 (C-1, arom.), 130.8 (C-4), 128.9 (C-2/C-
6), 127.0 (C-3/C-5), 58.5 (OCH3), 57.0 (CH), 50.8 (CH3), 32.6 (CH2S);
EIMS (m/z, %rel. abund.): 269 (Mþ, 34), 238 (17), 206 (48), 77 (56), 77
(100); Anal. Calcd. for C12H15NO4S: C, 53.52; H, 5.61; N, 5.20. Found: C,
53.40; H, 5.67; N, 5.26.
n-Butoxymethlythioacetal of N-Protected Methyl Ester of L-Cysteine
(18). Colorless oil; [a]D25 ¼ þ1.3 (c ¼ 1.0 CHCl3); 1H NMR (400 MHz,
CDCl3): d 7.34–7.24 (m, 5H), 6.35 (bd, J ¼ 8.5 Hz, 1H), 5.1 (s, 2H), 4.67–
4.53 (m, 3H), 3.73 (s, 3H), 3.67–3.55 (m, 1H), 3.38–3.31 (m, 1H), 3.2 (dd,
J ¼ 14.4, J ¼ 5.3 Hz, 1H), 2.95 (dd, J ¼ 14.4, J ¼ 5.3 Hz, 1H), 1.60–1.56

Synthesis of Dithioacetals and Oxathioacetals
2651
(m, 2H), 1.41–1.23 (m, 2H), 0.84 (t, J ¼ 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 169.3 (CO), 166.7 (CONH), 132.8 (C-1, arom.), 130.9 (C-4,
arom.), 129.0 (C-3/C-5), 127.1 (C-2/C-6), 72.7 (OCH2), 56.3 (CH), 50.6
(OCH3), 34.4 (CH2S), 31.6 (CH2), 20.4 (CH2), 14.1 (CH3). EIMS (m/z,
%rel. abund.): 311 (Mþ, 9), 280 (46), 254 (13), 252 (23), 238 (22), 206
(32); Anal. Calcd. for C20H29NO4S: C, 63.30; H, 7.70; N, 3.69. Found: C,
63.33; H, 7.67; N, 3.68.
Menthoxymethylthioacetal of N-Protected Methyl Ester of L-Cysteine
(19). White crystalline solid, m.p. 1078C; [a]2D5 ¼ 22.4 (c ¼ 0.6 CHCl3);
1H NMR (300 MHz, CDCl3): d 7.34–7.24 (m, 5H), 6.13 (bd, J ¼ 8.1 Hz,
1H), 5.1 (s, 2H), 4.68–4.60 (m, 3H), 3.73 (s, 3H), 3.33–3.24 (m, 1H), 3.13
(dd, J ¼ 14, J ¼ 5.5 Hz, 1H), 3.0 (dd, J ¼ 14, J ¼ 5.5 Hz, 1H), 2.14–2.04
(m, 2H), 1.64–1.55 (m, 2H), 1.25–0.817 (m, 5H), 0.88 (d, J ¼ 7.1 Hz, 6H),
0.74 (d, J ¼ 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 169.1 (CO),
167.0 (CONH), 132.8 (C-1, arom.), 130.6 (C-4, arom.), 129.0 (C-2/C-6),
126.9 (C-3/C-5), 75.9 [C-100, 56.8 (CH), 50.4 (OCH3), 48.2 (CH, C-20),
36.0 (CH2), 34.7 (CH, C-5), 34.0 (CH2S), 33.8 (CH2), 28.0 (CH(CH3)2)],
26.7 (CH2), 20.6 (CH3), 18.0 (CH3), 17.0 (CH3); EIMS (m/z, %rel. abund.):
393 (Mþ, 23), 334 (27), 316 (48), 288 (68), 267 (29), 77 (100); Anal.
Calcd. for C21H31NO4S: C, 64.09; H, 7.94; N, 3.56. Found C, 64.15; H,
7.88; N, 3.49.
Preparation of Dithioacetals: Reaction of Thiols
with Chloromethyl Methylsulfide
The thiol (1 mmol) was dissolved in anhydrous chloroform (10 mL) and
was stirred under static nitrogen atmosphere. Diisopropylethylamine (5mmol)
was added to the above solution and was set to gentle reflux. Chloromethyl
methylsulfide (5 mmol) was slowly added into the reaction mixture and was
refluxed for 8 hr. Reaction was allowed to cool to room temperature and was
diluted with chloroform (10 mL). Organic layer was washed with distilled
water, brine, and dried over MgSO4. Solvent was removed under reduced press-
ure and the residue was purified by silica gel column chromatography.
Thiomethylthiophenylmethane (20). Colorless oil; 1H NMR (400 MHz,
CDCl3): d 7.45–7.40 (m, 5H), 4.1 (s, 2H), 2.16, (s, 3H); 13C NMR (100 MHz,
CDCl3): d 134.2 (C-3/C-5), 130.4 (C-2/C-6), 139.6 (C-3/C-5), 124.6 (C-4),
40.0 (CH2), 18.1 (CH3); EIMS (m/z, %rel. abund.): 170 (Mþ, 29), 155 (51),
123 (79), 109 (81), 77 (100), 64 (31), 51 (16); Anal. Calcd. for C8H10S2:
C, 56.42; H, 5.92. Found: C, 56.50; H, 5.88.
Thiomethylthiocamphormethane(21). Colorlessoil;1HNMR(CDCl3);
d 3.60 (s, 2H), 2.94–2.84 (m, 1H), 2.15 (s, 3H), 1.95–1.57 (m, 3H), 1.26–1.12

2652
Zaidi et al.
(m, 2H), 0.98 (s, 3H), 0.95 (s, 3H), 0.90–0.88 (m, 2H), 0.82 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 50.7 (C-2), 49.6 (C-1), 45.3 (C-7), 44.0 (C-5), 36.9
(SCH2), 35.0 (C-6), 33.0 (C-3), 26.6 (C-4), 21.4 (CH3), 19.4 (CH3), 14.2
(SCH3), 12.6 (CH3); EIMS (m/z, %rel. abund.): 230 (Mþ, 16), 216 (43),
184 (58), 170 (66), 138 (100), 123 (12), 93 (44), 79 (24), 65 (8); exact mass
calcd. for C12H22S2 230.274, found 230.264; Anal. Calcd. for C12H22S2: C,
62.55; H, 9.62. Found: C, 62.66; H, 9.57.
Preparation of Ethoxyethylthioacetals
Thiol (1 mmol) was stirred in methylene chloride (20 mL), to this solution
few crystals of pyridinium p-toluenesulfonate (PPTS) were added. Ethyl vinyl
ether (1.5 mmol) was added slowly into the reaction flask and was stirred at
room temperature for 1 hr. Reaction was quenched with saturated aqueous
solution of sodium bicarbonate. Organic layer was separated, washed with dis-
tilled water, brine, and dried (MgSO4). Solvent was removed under reduced
pressure and the residue was chromatographed to afford the pure compound.
Ethoxyethylthiobenzene (22). Colorless oil; 1H NMR (400 MHz,
CDCl3): d 7.47–7.44 (m, 2H), 7.25–7.23 (m, 3H), 4.8 (q, J ¼ 6.5 Hz, 1H),
4.01–3.93 (m, 1H), 3.50–3.42 (m, 2H), 1.48 (d, J ¼ 6.5 Hz, 3H) 1.2
(t, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 134.1 (C-1, arom.),
128.8 (C-3/C-50), 127.3 (C-2/C-6), 125.6 (C-4), 69.4 (CH2O), 65.3
(OCH2), 34.0 (SCH2), 14.2 (CH3); EIMS (m/z, %rel. abund.): 182 (Mþ, 7),
137 (49), 78 (13), 77 (100), 51 (31); Anal. Calcd. for C10H14O4S: C, 65.89;
H, 7.74. Found: C, 65.93; H, 7.70.
Ethoxyethylthioacetal of N-Protected Methyl Ester of L-Cysteine
(23). Colorless oil; 1H NMR (400 MHz, CDCl3): d 7.32–7.23 (m, 5H),
6.34, 6.05 (brd, J ¼ 8 Hz, 1H), 5.1 (s, 2H), 4.66–4.54 (m, 2H), 3.76–3.30
(m, 5H), 3.11–2.9 (m, 2H), 1.5 and 1.46 (d, J ¼ 6.4 Hz, 3H), 1.2–1.13
(m, 3H); integration of –NH proton at d 6.34 and 6.05 and methyl protons
at d 1.5 and 1.46 showed that it was about 1 : 1 mixture of diastreoisomers.
Deprotection of Ethoxyethyl Group in Compound (23)
Ethoxyethylthioacetal of N-protected methyl ester of L-cysteine (23)
(100 mg) was dissolved in methanol (10 mL) and few crystals of PPTS were
added to this solution and was refluxed gently for 2 hr. After workup and puri-
fication by silica gel column chromatography N-protected methyl ester of L-
cysteine was obtained and no detectable change in its optical rotation was
observed.

Synthesis of Dithioacetals and Oxathioacetals
ACKNOWLEDGMENTS
2653
We are grateful to Paul Harrington for getting the Spectra of the com-
pounds. We are also thankful to Mr. Sarfraz Naseem Bhatti for his help.
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Received February 17, 2004