Sequential one-pot addition of excess aryl-grignard reagents and electrophiles to O-alkyl thioformates

Article abstract of DOI:10.1002/chem.201301573

The sequential addition of aromatic Grignard reagents to O-alkyl thioformates proceeded to completion within 30s to give aryl benzylic sulfanes in good yields. This reaction may begin with the nucleophilic attack of the Grignard reagent onto the carbon atom of the O-alkyl thioformates, followed by the elimination of ROMgBr to generate aromatic thioaldehydes, which then react with a second molecule of the Grignard reagent at the sulfur atom to form arylsulfanyl benzylic Grignard reagents. To confirm the generation of aromatic thioaldehydes, the reaction between O-alkyl thioformates and phenyl Grignard reagent was carried out in the presence of cyclopentadiene. As a result, hetero-Diels-Alder adducts of the thioaldehyde and the diene were formed. The treatment of a mixture of the thioformate and phenyl Grignard reagent with iodine gave 1,2-bis(phenylsulfanyl)-1,2-diphenyl ethane as a product, which indicated the formation of arylsulfanyl benzylic Grignard reagents in the reaction mixture. When electrophiles were added to the Grignard reagents that were generated insitu, four-component coupling products, that is, O-alkyl thioformates, two molecules of Grignard reagents, and electrophiles, were obtained in moderate-to-good yields. The use of silyl chloride or allylic bromides gave the adducts within 5min, whereas the reaction with benzylic halides required more than 30min. The addition to carbonyl compounds was complete within 1min and the use of lithium bromide as an additive enhanced the yields of the four-component coupling products. Finally, oxiranes and imines also participated in the coupling reaction. Into the melting pot: The addition of excess aryl Grignard reagents and electrophiles to O-alkyl thioformates gives aryl sulfanes through four-component coupling reactions (see scheme). These reactions may involve the formation of aromatic thioaldehydes and aryl-benzylic Grignard reagents as intermediates. For addition to carbonyl compounds, the use of lithium halides as an additive enhanced the efficiency of the reaction. Copyright

Full text of DOI:10.1002/chem.201301573

DOI: 10.1002/chem.201301573
Sequential One-Pot Addition of Excess Aryl-Grignard Reagents and
Electrophiles to O-Alkyl Thioformates
Toshiaki Murai,*[a, b] Kenta Morikawa,[a] and Toshifumi Maruyama[a]
Abstract: The sequential addition of ar-
omatic Grignard reagents to O-alkyl
thioformates proceeded to completion
within 30 s to give aryl benzylic sul-
fanes in good yields. This reaction may
begin with the nucleophilic attack of
the Grignard reagent onto the carbon
atom of the O-alkyl thioformates, fol-
lowed by the elimination of ROMgBr
to generate aromatic thioaldehydes,
which then react with a second mole-
cule of the Grignard reagent at the
sulfur atom to form arylsulfanyl ben-
zylic Grignard reagents. To confirm the
generation of aromatic thioaldehydes,
the reaction between O-alkyl thiofor-
mates and phenyl Grignard reagent
was carried out in the presence of cy-
clopentadiene. As result, hetero-
philes were added to the Grignard re-
agents that were generated in situ,
four-component coupling products, that
is, O-alkyl thioformates, two molecules
of Grignard reagents, and electrophiles,
were obtained in moderate-to-good
yields. The use of silyl chloride or allyl-
ic bromides gave the adducts within
5 min, whereas the reaction with ben-
zylic halides required more than
30 min. The addition to carbonyl com-
pounds was complete within 1 min and
the use of lithium bromide as an addi-
tive enhanced the yields of the four-
component coupling products. Finally,
oxiranes and imines also participated
in the coupling reaction.
a
Diels–Alder adducts of the thioalde-
hyde and the diene were formed. The
treatment of a mixture of the thiofor-
mate and phenyl Grignard reagent
with iodine gave 1,2-bis(phenylsulfan-
yl)-1,2-diphenyl ethane as a product,
which indicated the formation of aryl-
sulfanyl benzylic Grignard reagents in
the reaction mixture. When electro-
Keywords: electrophilic addition ·
Grignard reaction · reaction mecha-
nisms · sequential reactions · thio-
formates
Introduction
as thiocarbonyl compounds.[4] One of the characteristic fea-
tures of this reaction is that the addition of Grignard re-
agents to dithioic acid esters can take place on both the
carbon and sulfur atoms of C=S groups, depending on the
substituents that are attached to the C=S carbon atom and
the substituents on the Grignard reagents. For example, an
ethyl-Grignard reagent adds onto the sulfur atom of dithio-
acetic acid ethyl ester,[4b] whereas the addition of an allyl-
Grignard reagent to aromatic dithioic acid esters takes place
at the carbon atom.[4c] Recently, the reactivity and regiose-
lectivity of perfluorinated dithioic acid esters toward
Grignard reagents has been extensively studied.[5] The thio-
philic attack of the reagent, followed by the elimination of a
fluorine atom, gives dithioketene acetals as the major prod-
ucts. In the addition of Grignard reagents to cyclic dithiocar-
bamates, two equivalents of the reagents are introduced
onto the carbon atom of the C=S group.[6] Two different
Grignard reagents have been shown to add onto the carbon
atom of the C=S group in thioformamides[7] in our series of
studies[8] on thio-[9] and selenocarbonyl compounds.[10] Very
recently, we also found that lithium silyl acetylides and
Grignard reagents sequentially added to O-alkyl thiofor-
mates (1) to generate propargyl-Grignard reagents (3),
which further added to a wide range of electrophiles to give
propargyl phenyl sulfides (4, Scheme 1).[11] In this reaction,
thiopropynal 2 may initially be generated and the phenyl
Grignard reagent would add onto the sulfur atom of com-
pound 2. In this sequence, four components are coupled in a
Since the first description of the addition of organomagnesi-
um reagents to carbonyl compounds by Victor Grignard, the
Grignard reaction has been the focus of tremendous
amounts of research and industrial effort.[1] To expand the
applicability of Grignard reactions, numerous studies have
been devoted to improving the methods that are used to
generate the reagents, to enhancing the efficiency of the ad-
dition step of Grignard reagents to electrophiles, and to ex-
panding the number of available electrophiles. With regard
to this latter issue, the possibility of using thiocarbonyl com-
pounds as an electrophile has been studied for many years,[2]
although there are much fewer results than with carbonyl
compounds. As early as 1910, the addition of Grignard re-
agents to carbon disulfide was reported to give dithioic acid
magnesium salts.[3] Dithioic acid esters have also been used
[a] Prof. Dr. T. Murai, K. Morikawa, T. Maruyama
Department of Chemistry
Faculty of Engineering, Gifu University
Yanagido, Gifu 501-1193 (Japan)
Fax : (+81)58-293-2614
E-mail: mtoshi@gifu-u.ac.jp
[b] Prof. Dr. T. Murai
JST, ACT-C
4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301573.
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Chem. Eur. J. 2013, 19, 13112 – 13119

FULL PAPER
Scheme 3. Plausible reaction pathway for the sequential addition reac-
tions.
Scheme 1. Sequential addition of lithium acetylides, phenyl Grignard re-
agent, and electrophiles to O-alkyl thioformates.
compound 9 to form phenylsulfanyl benzyl Grignard (10a).
The use of one equivalent of phenyl Grignard resulted in
the formation of compound 5a in a lower yield, along with
recovery of the starting ester (1a).
single operation.[12] A survey of the literature on the reactiv-
ity of O-alkyl thioformates (1) did not reveal any systematic
studies on the addition of Grignard reagents to compounds
1.[13] Herein, we report the details of the reaction of aromat-
ic Grignard reagents with O-alkyl thioformates (1) and elec-
trophiles, which provides new four-component coupling
products.
To confirm the possibility of the generation of compound
9, the hetero-Diels–Alder reaction of a putative intermedi-
ate, that is, thiobenzaldehyde 9, with a diene[16] was carried
out (Scheme 4). Thus, the reaction of compound 1a with
phenyl Grignard in the presence of cyclopentadiene gave
Results and Discussion
Initially, excess phenyl Grignard was added to thioformate
1a in THF. The starting ester (1a) was consumed within
70 s, but the reaction mixture contained several types of un-
identified products and, whilst benzyl phenyl sulfide 5a[14a]
was detected, the yield was only 7% (Scheme 2). This result
Scheme 4. Trapping experiment of thiobenzaldehyde that is generated
in situ.
adducts 11, albeit in low yields, but their diastereomeric
ratio was consistent with the trapping of thiobenzaldehyde
that was generated in situ by cyclopentadiene.[16a] The thio-
philic attack of isolated thiobenzaldehyde by Grignard re-
agents, in which tert-butyl groups are introduced at the
2,4,6-position of the aromatic ring, has been described previ-
ously and the selectivity of the reaction depended on the
solvent and Grignard reagent that were used.[17]
To further explore the reaction mode of thiobenzaldehyde
9, DFT calculations were carried out at the B3LYP/6-31+
G(d) level of theory, along with that of O-methyl thiofor-
mate (1b). The HOMOs of compounds 9 and 1b correspond
to the lone pairs of their sulfur atoms. The HOMOÀ1,
LUMO, and NPA charges of compounds 1b and 9 are
shown in Figure 1 and Figure 2, respectively. The HOMOÀ1
Scheme 2. Sequential addition of excess phenyl-Grignard reagent, fol-
lowed by hydrolysis.
is in marked contrast to the reaction of formates with aryl-
Grignard reagents [Eq. (1)]. Two equivalents of the
Grignard reagent were efficiently incorporated onto the
carbon atom of compound 7 to give the alcohol (8) in quan-
titative yield.[15] Then, several types of solvent were exam-
ined for the reaction shown in Scheme 2 and the combina-
tion of a solution of phenyl Grignard in Et2O and the sub-
strate in toluene gave compound 5a in good yield, along
with a small amount of thiol 6a, which was formed from the
addition of two equivalents of phenyl Grignard to the
carbon atom of compound 1a. As an initial step, phenyl
Grignard may add onto the carbon atom of compound 1a,
followed by the elimination of magnesium alkoxide to gen-
erate thiobenzaldehyde 9 as an intermediate (Scheme 3). In
the second step, phenyl Grignard adds, not onto the carbon
atom of compound 9, but rather onto the sulfur atom of
Figure 1. Natural population analysis (NPA) charge and molecular orbi-
tals of compound 1b.
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T. Murai et al.
Table 1. Reactions of thioformate 1a with the aryl-Grignard reagents.[a]
Figure 2. NPA charge and molecular orbitals of compound 9.
Entry
Ar
Concentration [m]
t
Yield [%]
5
6
of compound 1b is localized on the sulfur atom, whereas
that of compound 9 is spread over the sulfur and carbon
atoms of the C=S bond and over the carbon atoms in the ar-
omatic ring. In contrast, the LUMO of compound 9 is local-
ized on the sulfur and carbon atoms. More importantly,
unlike in compound 1b, the atomic charge on the sulfur
atom of compound 9 is rather positive, which implies that
the sulfur atom in compound 9 can accept nucleophilic
attack.
The addition of iodine to the reaction mixture of thiofor-
mate 1a and phenyl Grignard gave compound 12 as the
product, albeit in moderate yield [Eq. (2)]. Nevertheless, the
formation of compound 12 can be understood by the homo-
coupling reaction[18] of Grignard 10a (Ar=Ph) shown in
Scheme 3.
1
2
3
4
4-ClC6H4
4-MeOC6H4
2-MeOC6H4
o-Tol
0.83
0.93
0.98
0.86
30 s
5b 47 6b
2.5 min 5c 28 6c 13
2.5 min 5d 45 6d 21
0
30 s
5e 67 6e
0
[a] Thioformate 1a was reacted with the aryl Grignard reagents
(2.5 equiv) for an appropriate length of time. [b] Yield of isolated prod-
uct.
results are shown in Table 2. Silylation of Grignard 10a that
was generated in situ proceeded smoothly within 5 min to
give compound 13[20] in 68% yield (Table 2, entry 1). Allyla-
tion of compound 10a with allylic bromides 14a and 14b
also took place at room temperature within 5 min to lead to
homoallylic sulfides 15a and 15b (Table 2, entries 2 and 3),
whereas the reaction with compound 14c under identical
conditions gave the corresponding product (15c), but in
moderate yield (Table 2, entry 4). Whilst the reaction at
higher temperatures did not improve the yield of compound
15c, the use of lower temperatures for longer reaction times
gave compound 15c in higher yield (Table 2, entry 5). Like-
Then, a range of aromatic
Table 2. Sequential addition of the phenyl Grignard reagent and electrophiles to thioformate 1a.[a]
Grignard reagents were tested
in the reaction with ester 1a
(Table 1). The substituents on
the aryl groups in the Grignard
reagents, such as chlorine,
methyl, and methoxy groups,
had almost no effect on the re-
action course and compounds
5c,[14b] 5d,[14c] and 5e were ob-
tained. However, aromatic-
Grignard reagents with a me-
thoxy group gave thiols 6 as by-
products to some extent
(Table 1, entries 2 and 3).
Grignard reagents 10 are not
readily generated because the
starting bromides and iodides
are not readily available.[19] In
contrast, in this reaction, phe-
nylsulfanyl benzyl Grignard
(10a) was generated very rapid-
ly in the addition of phenyl
Grignard to ester 1a with high
efficiency. Thus, we envisioned
multi-component sequential ad-
dition reactions. First, silyl, al-
lylic, and benzyl halides were
Entry
E
T
[8C]
t
Product
Yield [%][b]
1
2
3
TMSCl (2.0 equiv)
RT
RT
RT
5 min
5 min
5 min
68
62[c]
69
(E/Z 78:22)
4
5
RT
À78
5 min
6.5 h
38[d]
89[d]
(47)[e]
13[f]
(syn/anti 29:71)
57[g]
6
7
RT
RT
5 min
2 min
(syn/anti 38:62)
8
RT
30 min
63
[a] Thioformate 1a was sequentially reacted with the phenyl Grignard reagent (2.5 equiv) and electrophiles
(1.6 equiv). [b] Yield of isolated product after column chromatography on silica gel. [c] Sulfane 5a was also
formed in 5% yield. [d] Yield based on 1H NMR spectroscopy by using Cl2CHCHCl2 as an internal standard.
[e] Yield of isolated product after HPLC. [f] Sulfane 5a was also formed in 57% yield. [g] Sulfane 5a was also
used as electrophiles and the formed in 2% yield.
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Sequential One-Pot Additions to O-Alkyl Thioformates
FULL PAPER
Table 3. Sequential addition of the phenyl Grignard reagent and carbon-
wise, the reaction with benzylic bromide 16a and chloride
16b required longer reaction times at room temperature,
but gave the desired products (17) in good yields (Table 2,
entries 7 and 8). In the reaction with compound 16a, two di-
astereomers of compound 17a were obtained in the ratio
38:62. These compounds were separated by flash column
chromatography on silica gel and a major isomer was isolat-
ed in high purity. The structure of the major isomer of com-
pound 17a was unequivocally confirmed to be anti, as
shown in Figure 3.
yl compounds to thioformate 1a.[a]
Entry
1
Carbonyl
compound
t
Product
Yield [%][b]
ACHTUNGTNER[NUNG min]
58[c]
(syn/anti 22:78)
1
52[d]
(syn/anti 23:77)
2
3
10
1
61[d]
4[e]
1
45[f]
[a] Thioformate 1a was sequentially reacted with the phenyl Grignard re-
agent (2.5 equiv) and carbonyl compounds (1.6 equiv). [b] Yield of isolat-
ed product after column chromatography on silica gel. [c] Yield of isolat-
ed product after GPC. [d] Less than 6% of compounds 5a and 6b were
also obtained. [e] PhMgBr (2.2 equiv) and compound 20b (1.3 equiv)
were used. [f] Sulfane 5a was also obtained in 18% yield.
Figure 3. ORTEP of the major isomer of compound 17a; thermal ellip-
soids are set at 50% probability. Selected bond lengths [ꢁ], bond angles
À
À
[8], and dihedral angles [8]: C1 S 1.813, C2 S 1.757; C2-S-C1 106.63, S-
C1=C3 107.94; C2-S-C1-C3 À161.10, C4-C1-C3-C5 177.99.
pound 20c and the self-aldol condensation of compound 20c
gave compound 23. Performing the reaction for a longer re-
action time did not decrease the formation of compounds
5a, 22c, and 23. Recently, several types of additives have
been elucidated to improve the selectivity of nucleophilic
addition to compound 20c and to decrease the Brønsted ba-
sicity of the Grignard reagents, which was ascribed to the
unwanted aldol condensation reaction of enolizable ke-
tones.[22] Early examples of these additives include lantha-
nide halides, such as CeCl3 and LaCl3.[23] Very recently, the
combination of diglyme and a catalytic amount of Bu4NCl
has been reported to enhance the efficiency of the addition
of several types of Grignard reagents to compound 20c to
give the desired adducts in high yields.[24] However, in our
case, this combination did not work well, and the yield of
compound 21c was not improved. Next, a variety of readily
available metal halides, such as LiX, MgCl2, CuCl, CuCl2,
and ZnX2, were added to the reaction mixture of phenyl
Grignard and compound 1a, followed by the addition of
Then, aldehydes 18 and ketones 19 were used as the elec-
trophile (Table 3). The addition of Grignard 10a that was
generated in situ to compounds 18 and 19 was complete
within 10 min and no further improvement in the yields was
achieved, even over longer reaction times. In all cases, de-
spite the use of excess phenyl Grignard, the products that
were derived from the addition of phenyl Grignard to car-
bonyl compounds were not observed. In the reactions of
compounds 18a and 18b, two diastereomers were obtained
in a ratio of about 22:78 (Table 3, entries 1 and 2). The use
of benzophenone (20a) gave product 21a in 61% yield
(Table 3, entry 3), whereas the reaction with cyclohexanone
(20b) gave product 21b in a lower yield. In this case, phenyl
benzyl sulfane (5a) was also formed in 18% yield.
The addition of Grignard reagents to acetophenone (20c)
has been reported to not only give the corresponding ad-
ducts but also undesired products that were derived from
the reduction of compound 20c and the self-aldol condensa-
tion reaction of compound 20c.[21] In fact, the use of com-
pound 20c as an electrophile in the sequential reaction of
compound 1a with phenyl Grignard also gave several prod-
ucts (Table 4, entry 1). Treatment with compound 20c for
1 min gave the desired product (21c) in 39% yield, along
with compounds 5a, 22c, and 23. In this case, compound
22c was formed by the addition of phenyl Grignard to com-
[25]
compound 20c. The use of 0.25 equivalents of ZnX2
slightly enhanced the efficiency of the addition reaction of
Grignard reagent 10a that was generated in situ (Table 4,
entries 2–4), although the diastereoselectivity of product 21c
decreased. A longer reaction time after the addition of
ketone 20c did not improve the yield of compound 21c. In
contrast, the addition of LiBr (0.25 equiv) greatly enhanced
the efficiency of the reaction that led to compound 21c
(Table 4, entry 5). In this case, product 22c was also formed
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T. Murai et al.
Table 4. Sequential addition of the phenyl Grignard reagent and aceto-
phenone (20c) to thioformate 1a.[a]
Entry
Additive (equiv)
none
t
Yield [%][b]
Finally, the availability of oxiranes and imines as electro-
philes was examined. The reaction of cyclohexene oxide
(24) with phenylsulfanyl benzyl Grignard (10a), which was
derived from compound 1a and phenyl Grignard, proceeded
smoothly [Eq. (5)]. The ring-opening step of compound 24
proceeded to completion within 1 min in a trans fashion
to give a diastereomeric mixture of two isomers of com-
pound 25[27] out of four possible isomers. For the addition to
imine 26, a much longer reaction time was necessary, but
the reaction gave the desired product (27) in good yield
[Eq. (6)].
21c
5a
22c
23
1
2
3
4
5
6
7
8
9
–
39
AHCTUNGTRENGN(UN 76:24)
46
AHCTUNGTRENGN(UN 62:38)
46
AHCTUNGTRENGN(UN 54:46)
49
21
23
27
23
5
38
8
ZnCl
ZnCl
ZnCl
G
1 h
13
33
18
42
36
37
38
39
28
22
12
22
21
22
24
23
1 h
1 h
A
LiBr (0.25)
LiBr (1.0)
LiBr (2.5)
LiCl (2.5)
LiI (2.5)
1 min
1 min
1 min
1 min
1 min
69[c]
A
69
AHCTUNGTRENGN(UN 48:52)
5
78 (56)[d,e]
7
4
8
AHCTUNGTRENGN(UN 35:65)
73
A
79
AHCTUNGTRENGN(UN 45:55)
[a] Thioformate 1a was sequentially reacted with the phenyl Grignard re-
agent (2.5 equiv) and acetophenone (20c, 2.0 equiv). [b] Yield based on
1H NMR spectroscopy by using Cl2CHCHCl2 as an internal standard.
[c] Thiol 6a was also obtained in 12% yield. [d] Yield of isolated product
after GPC. [e] The ratio of the diastereomers was 43:57.
In Figure 3, please add 50% probability.
in higher yield. This result shows that LiBr facilitates the ad-
dition of not only compound 10a, but also of excess phenyl
Grignard to compound 20c, as reported by Knochel and co-
workers.[26] Further studied of the additives and their
amounts revealed that the use of excess LiCl, LiBr, or LiI as
an additive gave compound 21c in more than 73% yield
(Table 4, entries 7–9).
With the results regarding additives in hand, LiBr was
added to the reactions with aldehyde 18b [Eq. (3)] and
ketone 20b [Eq. (4)]. In both cases, the products (19b and
21b) were obtained in higher yields than in Table 3, en-
tries 2 and 4.
Conclusion
In summary, we have described the first example of the se-
quential addition of aryl-Grignard reagents to O-alkyl thio-
formates. This reaction was complete within 30 s at room
temperature to selectively give aryl benzylic sulfanes in
good-to-high yields. In this reaction, two equivalents of the
aryl-Grignard reagents add to the O-alkyl thioformates. One
equivalent adds onto the carbon atom and the other formal-
ly adds onto the sulfur atom of the starting O-alkyl thiofor-
mate to generate arylsulfanyl benzylic Grignard reagents,
which further participate in additions to a wide variety of
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Sequential One-Pot Additions to O-Alkyl Thioformates
FULL PAPER
in Et2O (1.08 mL, 0.9 mmol) at RT and the solution was stirred at RT for
5 min. The resulting mixture was poured into a saturated aqueous solu-
tion of NH4Cl and extracted with Et2O. The organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (n-hexane/EtOAc, 1:0 to 50:1) to
give compounds 11 (30.6 mg) as a yellow oil along with sulfide 5a
(3.4 mg, 1%). Yield: 16% (endo/exo, 81:19); 1H NMR (CDCl3): d=1.60
(exo, d, J=9.2 Hz, 0.19H; CH2), 1.75 (endo, d, J=8.7 Hz, 0.81H; CH2),
1.80 (endo, d, J=9.2 Hz, 0.81H; CH2), 1.87 (exo, d, J=9.2 Hz, 0.19H;
CH2), 3.24 (exo, m, 0.19H; SCH(Ph)CH), 3.55 (endo, m, 0.81H;
electrophiles, including allylic and carbonyl compounds, ben-
zylic halides, oxiranes, and imines. The efficiency of the ad-
dition of Grignard reagents to carbonyl compounds was im-
proved by the addition of lithium halides to the reaction
mixture. As a further extension of this system, new types of
organosulfur compounds that show unique physical or bio-
logical properties are being investigated.
SCH(Ph)CH), 4.13 (endo, m, 0.81H; SCHCAHTUNGTREN(NUGN CH2)CH), 4.21 (exo, m,
Experimental Section
0.19H; SCH(CH2)CH), 4.91 (endo and exo, d, J=3.4 Hz, 1H; SCHPh),
AHCTUNGTRENNUNG
5.51 (endo, dd, J=4.8, 3.4 Hz, 0.81H; CH=CHCHS), 6.12 (exo, dd, J=
4.8, 3.4 Hz, 0.19H; CH=CHCHS), 6.40 (exo, dd, J=5.3, 2.4 Hz, 0.19H;
CH=CHCHS), 6.50 (endo, dd, J=4.8, 2.9 Hz, 0.81H; CH=CHCHS),
7.17–7.52 ppm (m, 5H; Ar); MS (EI): m/z: 188 [M]+; HRMS (EI): m/z
calcd for C12H12S: 188.0660 [M]+; found: 188.0648.
General remarks: IR spectra were obtained on a JASCO FTIR 410 spec-
trophotometer. H NMR (399.7 MHz) and 13C NMR spectra (100.4 MHz)
1
were recorded on a JNM-a400 spectrometer. 1H and 13C chemical shifts
are reported in d with reference to tetramethylsilane and CDCl3 as an in-
ternal standard, respectively. 13C NMR spectra were acquired in proton-
decoupled mode. Mass spectra (MS) and high-resolution mass spectra
(HRMS) were recorded on a JMS-700 mass spectrometer. Melting points
were determined on a Yanaco Seisakusyo MP-S2 micro-melting-point ap-
paratus and are uncorrected. Preparative recycling gel-permeation chro-
matography (GPC) was performed on Japan Analytical Industry LC-908
and LC9201R/U recycling preparative HPLC systems that were equipped
with JAIGEL-1H and JAIGEL-2H columns (eluent: CHCl3). HPLC was
performed on a Japan Analytical Industry LC-908 recycling preparative
HPLC system that was coupled to an RI indicator and a UV detector
(256 nm) with a Mightysil Si60 column (250 mmꢂ20 mm).
Synthetic procedure for the homocoupling reaction of Grignard reagent
10a that was generated in situ: To a solution of thioformate 1a (0.1443 g,
1.0 mmol) in Et2O (5.0 mL) was quickly added a 0.83m solution of phe-
nylmagnesium bromide in Et2O (3.01 mL, 2.5 mmol) at RT and the mix-
ture was stirred at RT for 30 s. Then, iodine (0.305 g, 1.2 mmol) was
added at RT and the mixture was stirred at RT for 40 min. The resulting
mixture was poured into a saturated aqueous solution of NH4Cl and ex-
tracted with Et2O. The organic layer was dried over MgSO4 and concen-
trated in vacuo. The residue was purified by flash column chromatogra-
phy on silica gel (n-hexane/EtOAc, 50:1) and GPC to give compound 12
1
as a yellow solid (67 mg). Yield: 33% (d.r. 68:32); H NMR (CDCl3): d=
Materials: Unless otherwise noted, the reagents were obtained commer-
cially and used without further purification. Et2O (dehydrated) and THF
(dehydrated) were purchased from Kanto Chemical Co. and used without
further purification. Thioformate 1a was prepared by the thionation of
O-cyclohexyl formate with Lawesson’s reagent.[28] Column chromatogra-
phy was performed on silica gel 60N (spherical, neutral, 40–50 mm) from
Kanto Chemical Co., Ltd. All manipulations were carried out under an
argon atmosphere.
4.54 (minor, s, 0.64H; SCH), 4.59 (major, s, 1.36H; SCH), 6.92–7.26 ppm
(major and minor, m, 20H; Ar); 13C NMR (CDCl3): d=58.1, 59.7 (SCH),
127.1, 127.2, 127.2, 127.4, 127.5, 127.9, 128.5, 128.7, 128.7, 129.2, 132.4,
132.7, 134.5, 134.6, 138.3, 139.5 ppm (Ar, aromatic carbon atoms were
partially overlapped); IR (KBr): n˜ =3060, 3023, 1451, 1437, 747, 703,
691 cmÀ1; MS (EI): m/z: 398 [M]+; HRMS (EI): m/z calcd for C26H22S2:
398.1163 [M]+; found: 398.1164.
General procedure for the sequential addition of Grignard reagents and
electrophiles to thioformate 1a: To a solution of thioformate 1a in Et2O
was added quickly a 0.83m solution of phenylmagnesium bromide in
Et2O (2.5 equiv) at RT and this mixture was stirred at RT for 30 s. Then,
a 0.33m solution of an electrophile in THF (2.0 equiv) was added at RT
and the mixture was stirred at RT for 5 min. The resulting mixture was
poured into a saturated aqueous solution of NH4Cl and extracted with
Et2O. The organic layer was dried over MgSO4 and concentrated in va-
cuo. The residue was purified by flash column chromatography on silica
gel, GPC, and/or HPLC.
General procedure for the sequential addition of Grignard reagents to
thioformate 1a: To a solution of thioformate 1a in Et2O was quickly
added a 0.83m solution of arylmagnesium bromide in Et2O (2.5 equiv) at
RT and the mixture was stirred at RT for 30 s. The resulting mixture was
poured into a saturated aqueous solution of NH4Cl and extracted with
Et2O. The organic layer was dried over MgSO4 and concentrated in va-
cuo. The residue was purified by flash chromatography on silica gel to
give aryl benzylic sulfanes 5.
2-Methoxybenzyl(2-methoxyphenyl)sulfane (5d): Purified by flash
column chromatography on silica gel (n-hexane/CH2Cl2, 3:1). Orange
solid; yield: 45%; m.p. 33.2–34.28C; 1H NMR (CDCl3): d=3.81 (s, 3H;
OMe), 3.86 (s, 3H; OMe), 4.12 (s, 2H; CH2), 6.83–6.87, 7.14–7.23 ppm
(m, 8H; Ar); 13C NMR (CDCl3): d=31.2 (SCH2), 55.4 (OMe), 55.6
(OMe), 110.1, 110.3, 120.2, 120.8, 125.0, 125.6, 127.0, 128.3, 129.9, 130.2,
157.2 ppm (Ar, aromatic carbon atoms were partially overlapped); IR
(KBr): n˜ =3061, 3024, 3001, 2959, 2937, 2919, 2834, 1599, 1574, 1493,
1475, 1464, 1433, 1290, 1278, 1246, 1181, 1162, 1099, 1071, 1046, 1022,
778, 764, 754, 683 cmÀ1; MS (EI): m/z: 260 [M]+; HRMS (EI): m/z calcd
for C15H16O2S: 260.0871 [M]+; found: 260.0858.
TrimethylACTHNUTRGNEUNG
(phenyl(phenylsulfanyl)methyl)silane (13):[20] Purified by flash
column chromatography on silica gel (n-hexane). Yield: 68%; 1H NMR
(CDCl3): d=0.02 (s, 9H; TMS), 3.65 (s, 1H; SCH), 6.90–7.20 ppm (m,
10H; Ar).
Phenyl(1-phenylbut-3-en-1-yl)sulfane (15a):[29] Purified by flash column
1
chromatography on silica gel (n-hexane). Yield: 62%; H NMR (CDCl3):
d=2.62 (m, 2H; CH2), 4.20 (t, J=7.3 Hz, 1H; SCH), 4.89–4.96 (m, 2H;
CH=CH2), 5.63 (ddt, J=17, 9.7, 6.8 Hz, 1H; CH=CH2), 7.08–7.32 ppm
(m, 10H; Ar).
(E)-Phenyl(1-phenylpent-3-en-1-yl)sulfane (15b): Purified by flash
column chromatography on silica gel (n-hexane). Yield: 69% (E/Z=
78:22); 1H NMR (CDCl3): d=1.51 (Z, d, J=6.3 Hz, 0.66H; CH3), 1.59
(E, d, J=5.8 Hz, 2.34H; CH3), 2.62–2.67 (E, m, 1.56H; CH2), 2.69–2.74
(Z, m, 0.44H; CH2), 4.18 (E and Z, m, 1H; SCH), 5.35 (E and Z, m, 1H;
CH=CHCH3), 5.45 (E and Z, m, 1H; CH=CHCH3), 7.14–7.41 ppm (E
and Z, m, 10H; Ar); 13C NMR (CDCl3): d=12.8, 17.8 (CH3), 33.6, 39.3
(CH2), 53.3, 53.5 (SCH), 126.0, 126.7, 126.8, 126.9, 126.9, 127.0, 127.0,
127.5, 127.7, 127.8, 128.1, 128.4, 128.5, 128.5, 128.7, 132.1, 132.1, 134.9,
141.5, 141.6 ppm (Ar and CH=CHCH3); IR (neat) 3059, 3025, 2963,
2915, 1583, 1491, 1479, 1452, 1437, 1025, 966, 746, 695 cmÀ1; MS (EI): m/
z: 254 [M]+; HRMS (EI): m/z calcd for C17H18S: 254.1129 [M]+; found:
254.1105.
2-Methylbenzyl(2-methylphenyl)sulfane (5e): Purified by flash column
chromatography on silica gel (n-hexane). Colorless oil; yield: 67%;
1H NMR (CDCl3): d=2.29 (s, 3H; CH3), 2.39 (s, 3H; CH3), 4.04 (s, 2H;
SCH2), 7.06–7.18, 7.28–7.30 ppm (m, 8H; Ar); 13C NMR (CDCl3): d=
19.0 (CH3), 20.2 (CH3), 36.5 (SCH2), 125.9, 126.1, 126.3, 127.4, 129.2,
129.7, 129.9, 130.3, 134.8, 135.9, 136.7, 138.1 ppm (Ar); IR (neat) 3060,
3015, 2971, 2930, 1588, 1492, 1467, 1378, 1064, 1047, 742, 450 cmÀ1; MS
(EI): m/z: 228 [M]+; HRMS (EI): m/z calcd for C15H16S: 228.0973 [M]+;
found: 228.0975.
Sequential addition of phenyl Grignard to thioformate 1a in the presence
of cyclopentadiene: To a solution of thioformate 1a (0.1446 g, 1.0 mmol)
in Et2O (5.0 mL) was added cyclopentadiene (1.68 mL, 20 mmol) at RT.
To this mixture was added a 0.83m solution of phenylmagnesium bromide
Chem. Eur. J. 2013, 19, 13112 – 13119
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13117

T. Murai et al.
Ethyl-2-methylene-4-phenyl-4-(phenylsulfanyl)butanoate (15c): Purified
by flash column chromatography on silica gel (n-hexane/EtOAc, 40:1)
and HPLC. Yield: 47%; 1H NMR (CDCl3): d=1.25 (t, J=7.1 Hz, 3H;
CH3), 2.86 (dd, J=14.0, 8.7 Hz, 1H; SCHCH2), 3.00 (dd, J=14.1, 6.5 Hz,
1H; SCHCH2), 4.15 (q, J=7.1 Hz, 2H; OCH2), 4.49 (dd, J=8.7, 6.5 Hz,
1H; SCH), 5.39 (d, J=1.3 Hz, 1H; C=CH2), 6.09 (d, J=1.3 Hz, 1H; C=
CH2), 7.13–7.31 ppm (m, 10H; Ar); 13C NMR (CDCl3): d=14.1 (CH3),
39.2 (SCHCH2), 51.6 (SCH), 60.6 (OCH2), 126.8, 127.2, 127.8, 127.9,
128.3, 128.6, 131.8, 134.8, 137.1, 140.9 (Ar, C=C), 166.6 ppm (C=O); IR
(neat) 3059, 3027, 2981, 2935, 1713, 1629, 1583, 1491, 1480, 1452, 1438,
1368, 1327, 1301, 1189, 1134, 1025, 951, 745, 697 cmÀ1; MS (EI): m/z: 312
[M]+; HRMS (EI): m/z calcd for C19H20O2S: 312.1184 [M]+; found:
312.1183.
(major, s, 0.57H; OH), 4.45 (major, s, 0.57H; SCH), 4.46 (minor, s,
0.43H; SCH), 7.05–7.33 ppm (major and minor, m, 15H; Ar).
2-(Phenyl(phenylsulfanyl)methyl)cyclohexanol (25):[27] Purified by flash
column chromatography on silica gel (n-hexane/EtOAc/CH2Cl2, 15:0:1 to
1:0:0 to 5:1:0) and GPC. Yield: 52% (trans-threo/trans-erythro, 82:18);
1H NMR (CDCl3): d=0.82–2.04 (trans-threo and trans-erythro, m, 10H;
CH2, OH, CHCHOH), 3.08 (trans-threo, td, J=10.2, 4.3 Hz, 0.68H;
CHOH), 3.80 (trans-erythro, td, J=9.7, 4.3 Hz, 0.32H; CHOH), 4.87
(trans-erythro, d, J=3.4 Hz, 0.32H; SCH), 4.90 (trans-threo, d, J=4.3 Hz,
0.68H; SCH), 7.02–7.49 ppm (trans-threo and trans-erythro, m, 10H; Ar).
N-(1,2-diphenyl-2-(phenylsulfanyl)ethyl)aniline (27): Purified by flash
column chromatography on silica gel (n-hexane/CH2Cl2, 10:1 to 2:1) and
GPC. Yield: 63% (d.r. 45:55); 1H NMR (CDCl3): d=4.46 (major, d, J=
8.0 Hz, 0.55H; NHCH or SCH), 4.60 (minor, d, J=4.9 Hz, 0.45H;
NHCH or SCH), 4.70 (major, d, J=7.6 Hz, 0.55H; NHCH or SCH), 4.66
(minor, s, 0.45H; NH), 4.74 (minor, d, J=4.5 Hz, 0.45H; NHCH or
SCH), 4.94 (major, s, 0.55H; NH), 6.47–6.53, 6.54–6.68, 6.95–7.24 ppm
(major and minor, m, 20H; Ar); 13C NMR (CDCl3): d=60.4, 60.7, 61.5,
62.5 (SCH, NHCH), 113.8, 113.8, 117.7, 117.8, 126.9, 127.1, 127.2, 127.3,
127.4, 127.4, 127.5, 127.6, 127.9, 127.9, 128.1, 128.7, 128.8, 128.8, 129.0,
129.0, 131.4, 132.0, 134.2, 134.8, 137.5, 138.9, 139.6, 140.3, 146.6,
146.7 ppm (Ar, aromatic carbon atoms were partially overlapped); IR
(KBr): n˜ =3420, 3374, 3072, 3055, 3015, 3000, 2906, 2832, 1599, 1583,
Phenyl(1,2-diphenylpropyl)sulfane (17a): Purified by flash column chro-
matography on silica gel (n-hexane/CH2Cl2, 30:1). Yield: 57% (syn/anti=
1
38:62); H NMR (CDCl3): d=1.18 (major, d, J=7.3 Hz, 2.4H; CH3), 1.54
(minor, d, J=6.8 Hz, 0.6H; CH3), 3.23–3.33 (m, 1H; CH), 4.31 (d, J
=9.2 Hz, 1H; SCH), 7.03–7.32 ppm (m, 15H; Ar); 13C NMR (CDCl3):
d=19.8 (major and minor, CH3), 45.5, 45.8 (CH), 60.9, 61.1 (SCH), 126.2,
126.5, 126.6, 126.6, 126.9, 127.4, 127.6, 127.7, 127.8, 127.9, 127.9, 128.1,
128.2, 128.4, 128.5, 128.6, 131.7, 132.2, 135.4, 135.4 140.7, 141.1, 143.7,
144.2 ppm (Ar); IR (KBr): n˜ =3059, 3023, 3001, 2967, 2914, 2868, 1598,
1583, 1490, 1478, 1449, 1437, 1091, 1069, 1024, 1007, 732, 693 cmÀ1; MS
(EI): m/z: 304 [M]+; HRMS (EI): m/z calcd for C21H20S: 304.1286 [M]+;
found: 304.1297.
1497, 1478, 1449, 1436, 1424, 1310, 1078, 1025, 748, 729, 698, 682 cmÀ1
;
MS (EI): m/z: 381 [M]+; HRMS (EI): m/z calcd for C26H23NS: 381.1551
[M]+; found: 381.1547.
Phenyl(1-phenyl-2-(4-vinyl)phenyl)sulfane (17b): Purified by flash
column chromatography on silica gel (n-hexane/CH2Cl2, 1:0 to 10:1).
Yield: 65%; 1H NMR (CDCl3): d=3.16 (dd, J=13.6, 8.7 Hz, 1H;
SCHCH2), 3.24 (dd, J=13.8, 6.1 Hz, 1H; SCHCH2), 4.36 (dd, J=8.2,
6.3 Hz, 1H; SCH), 5.17 (d, J=10.7 Hz, 1H; CH=CH2), 5.66 (d, J=
17.5 Hz, 1H; CH=CH2), 6.63 (dd, J=17.8, 10.9 Hz, 1H; CH=CH2), 6.94–
7.26 ppm (m, 14H; Ar); 13C NMR (CDCl3): d=42.4 (SCHCH2), 54.9
(SCH), 113.1, 125.9, 126.9, 127.1, 127.9, 128.1, 128.6, 129.2, 132.1, 134.9,
135.6, 136.4, 138.3, 141.0 ppm (Ar and CH=CH2); IR (neat) 3082, 3058,
3026, 3003, 1627, 1583, 1510, 1492, 1479, 1452, 1438, 1406, 1025, 989, 907,
827, 747, 696 cmÀ1; MS (EI): m/z: 316 [M]+; HRMS (EI): m/z calcd for
C22H20S: 316.1286 [M]+; found: 316.1275.
X-ray structure analysis: The analysis of compound 17a was carried out
on a Rigaku/MSC Mercury CCD diffractometer with graphite-monochro-
mated MoKa radiation (l=0.71069 ꢁ). Reflection data were collected at
123–203 K by using a Rigaku XR-TCS-2–050 temperature controller. The
structure was solved and refined by using direct methods with SHELXL-
97[31] and the Yadokari-XG crystallographic software package from the
Molecular Structure Corporation.[32] A crystal suitable for X-ray diffrac-
tion was obtained by the slow diffusion of distilled water into a solution
of compound 17a in acetone. A crystal was cut from the grown crystals
and attached onto the tip of a MiTeGen MicroMount. Crystal data and
the measurement procedure are summarized in the Supporting Informa-
tion, Table S1.
1,2-Diphenyl-2-(phenylsulfanyl)ethanol (19a):[20] Purified by flash column
CCDC-934116 (17a) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
chromatography on silica gel (n-hexane/EtOAc, 40:1 to 30:1). Yield:
1
58% (syn/anti, 22:78); H NMR (CDCl3): d=2.50 (s, 1H; OH), 4.37 (syn,
d, J=8.7 Hz, 0.22H; SCH), 4.46 (anti, d, J=5.3 Hz, 0.78H; SCH), 4.94
(syn, d, J=8.2 Hz, 0.22H; CHOH), 5.04 (anti, d, J=5.3 Hz, 0.78H;
CHOH), 7.02–7.30 ppm (syn and anti, m, 15H; Ar).
3-Methy-1-phenyl-1-(phenylsulfanyl)butan-2-ol (19b):[20] Purified by flash
column chromatography on silica gel (n-hexane/EtOAc, 1:0 to 30:1).
Yield: 60% (syn/anti, 48:52); 1H NMR (CDCl3): d=0.86 (syn, d, J=
6.8 Hz, 1.44H; CH3), 0.91 (anti, d, J=6.8 Hz, 1.56H; CH3), 0.95 (anti, d,
J=6.3 Hz, 1.56H; CH3), 0.98 (syn, d, J=6.8 Hz, 1.44H; CH3), 1.55–1.66
Acknowledgements
This research was supported by MEXT through a Grant-in-Aid for Scien-
tific Research on Innovative Areas “Organic Synthesis Based on Reac-
tion Integration. Development of New Methods and Creation of New
Substances.”
(syn, m, 0.48H; CHACHTUNGTRENNUNG(CH3)2), 1.74–1.86 (anti, m, 0.52H; CHAHCTUNGTREN(NUGN CH3)2), 2.44
(syn and anti, s, 1H; OH), 3.61 (anti, dd, J=6.3, 5.8 Hz, 0.52H; CHO),
3.74 (syn, dd, J=8.7, 3.4 Hz, 0.48H; CHO), 4.15 (syn, d, J=8.7 Hz,
0.48H; SCH), 4.31 (anti, d, J=5.3 Hz, 0.52H; SCH), 7.10–7.39 ppm (syn
and anti, m, 10H; Ar); MS (EI): m/z: 272 [M]+; HRMS (EI): m/z calcd
for C17H20OS: 272.1235 [M]+; found: 272.1231.
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Yield: 56% (d.r. 43:57); 1H NMR (CDCl3): d=1.51 (major, s, 1.71H;
CH3), 1.75 (minor, s, 1.29H; CH3), 2.86 (minor, s, 0.43H; OH), 3.01
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13118
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Sequential One-Pot Additions to O-Alkyl Thioformates
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Received: April 24, 2013
Published online: August 14, 2013
Chem. Eur. J. 2013, 19, 13112 – 13119
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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13119