Electrophilic Aromatic Formylation with Difluoro(phenylsulfanyl) methane

Article abstract of DOI:10.1055/s-0036-1591545

Difluoro(phenylsulfanyl)methane (PhSCF ₂ H) was found to undergo a reaction with aromatic compounds mediated by SnCl ₄, through a thionium intermediate characterized by NMR and TD-DFT analyses, leading to the formation of a mixture of S, S ′-diphenyl dithioacetal and aromatic aldehyde which, after oxidative hydrolysis, provides the aromatic aldehyde in good to excellent yields. The salient feature of the present work is the reaction of activated aromatic compounds containing a deactivating ester functional group, leading to the formylated products in good yields.

Full text of DOI:10.1055/s-0036-1591545

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
N. M. Betterley et al.
Paper
Synthesis
Electrophilic Aromatic Formylation with Difluoro(phenylsulfanyl)
methane
Nolan M. Betterleya
Sopanat Kongsriprapan1,a
Suppisak Chaturonrutsameea,b
Pramchai Deelertpaiboona
Panida Surawatanawonga
Manat Pohmakotra
O
R
Cl
C
SnCl4
H
C
PhSCF2H
R
PhS
H
CH2Cl2, rt
H2O
1H and 13C NMR
characterized
16 examples
yield: 42−99%
Darunee Soorukrama
Vichai Reutrakula
Chutima Kuhakarn*a
a Department of Chemistry and Center of Excellence for Innovation in
Chemistry (PERCH-CIC), Faculty of Science, Mahidol University,
Rama 6 Road, Bangkok 10400, Thailand
chutima.kon@mahidol.ac.th
b Research and Development Department, International Laboratories
Corp., Ltd., Bang Phli, Samut Prakan 10540, Thailand
Received: 18.01.2018
Accepted after revision: 25.01.2018
Published online: 07.03.2018
substitution using various formyl precursors which differ
by their reactivity and steric bulkiness; for example, formyl
fluoride/BF3,7 CO/HCl (Gattermann–Koch formylation),8
HCN/HCl or Zn(CN)2/HCl (Gattermann reaction),9
CHCl3/NaOH (Reimer–Tiemann reaction),10 DMF/POCl3
(Vilsmeier reagent),11 dichloromethyl methyl ether/Lewis
acid (Rieche formylation),12 hexamethylenetetramine/HOAc
or TFA,13 triformamide/AlCl3,14 tris(diformylamino)meth-
ane/AlCl3,15 tris(dichloromethyl)amine and oligoformyl-
amine derivatives/super acids.16 Of these methods, only
Rieche formylation works well for both activated aromatic
and deactivated compounds.17
DOI: 10.1055/s-0036-1591545; Art ID: ss-2018-z0794-op
Abstract Difluoro(phenylsulfanyl)methane (PhSCF2H) was found to
undergo a reaction with aromatic compounds mediated by SnCl4,
through a thionium intermediate characterized by NMR and TD-DFT
analyses, leading to the formation of a mixture of S,S′-diphenyl dithio-
acetal and aromatic aldehyde which, after oxidative hydrolysis, provides
the aromatic aldehyde in good to excellent yields. The salient feature of
the present work is the reaction of activated aromatic compounds con-
taining a deactivating ester functional group, leading to the formylated
products in good yields.
Key words electrophilic formylation, thionium cation, aldehydes, elec-
trophilic addition, carbocations
In continuation of our interest in developing methodol-
ogies for the installation of the gem-difluoromethylene mo-
tif into structurally different organic molecules by using
radical, carbanion and cross-coupling methodologies18 and
the synthetic exploitation of the α-fluoro carbocation spe-
cies generated from the reaction between Lewis acids and
gem-difluoro compounds,19 we report herein a novel use of
difluoro(phenylsulfanyl)methane (1) as an electrophilic
formylating agent for activated aromatic compounds, in-
cluding examples with a deactivating functional group.
Recently, we reported the reactivity of bromodifluoro-
(phenylsulfanyl)methane as the synthetic equivalent of the
sufanylcarbonyl cation and geminal carbonyl dication,
through Lewis acid activation, leading to the Friedel–Crafts
alkylation of activated aromatic compounds which, after
hydrolysis, yielded thioesters and/or benzophenones.19a In-
spired by these results, we envisaged difluoro(phenylsulfa-
nyl)methane (1) as a synthetic equivalent of a formyl cation
(Scheme 1).
Research directed at understanding the influence of flu-
orine atoms on reactive intermediates, including radicals,
cations and anions, has long been of interest.2 In particular,
fluorine was demonstrated to exhibit a stabilizing effect,
through 2p nonbonded electron-pair back-bonding, to the
carbocationic center to which the fluorine atoms are at-
tached.3 Some α-fluoro carbocations are sufficiently stabi-
lized to allow characterization by means of single-crystal
X-ray diffraction.4 Despite the unique properties, research
on α-fluoro carbocations and their synthetic applications in
organic synthesis have only been sporadically reported.5
The formylation reaction of aromatic compounds is a
fundamental reaction in organic chemistry and several
methods have been developed for this important synthetic
transformation.6 Generally, introduction of a formyl group
onto an aromatic ring is achieved by electrophilic aromatic
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
N. M. Betterley et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditionsa
O
C
O
C
F
C
F
Previous
Work
PhS
PhS
Ar
PhS
Br
ArH
ArH
MeO
MeO
CHO
Ar
SPh
and/or
OMe
O
C
O
C
O
C
OMe
PhSCF2H
SPh
3a
OMe
Ar
H
Ar
Ar
1
F
4a
O
C
Lewis acid
PhS
C
H
This Work
Ar
Ar
Ar
Ar
OMe
F
H
1
2a
SPh
Ar
Ar = 2,4,5-trimethoxyphenyl
5a
6a
Scheme 1 Synthetic methodology
Entry
Lewis acidb (equiv)
Yield (%)c
In an initial attempt and on the basis of our previously
reported difluoro(phenylsulfanyl)methane
work,20
3a
4a
36
5a
6a
(PhSCF2H, 1)21 was allowed to react with 1,2,4-trimethoxy-
benzene (2a, 1 equiv) mediated by stannic chloride (SnCl4, 2
equiv based on 1) in dichloromethane at room temperature
for 2 hours under an argon atmosphere. To our delight,
three products, S,S′-diphenyl dithioacetal 3a (40% yield), ar-
omatic aldehyde 4a (36% yield) and sulfide 5a (6% yield),
were isolated (Table 1, entry 1). Other Lewis acids, including
AlCl3, TiCl4, Ti(Oi-Pr)4 and TMSOTf, were examined; howev-
er, only SnCl4 exhibited superior results (Table 1, entries 2–
5). No improvement was observed when SnCl4 was em-
ployed in excess amount (5 equiv; Table 1, entry 6) and the
reaction failed to proceed at 0 °C (Table 1, entry 7). When
the reaction was exposed to oxidative quench employing
IBX (1.5 equiv) in DMSO/H2O (3:1 v/v) at room temperature
for 2 hours, before conventional aqueous workup, the aro-
matic aldehyde 4a was exclusively isolated in 75% yield after
chromatographic purification (Table 1, entry 8).22
Analysis of the product mixture (Table 1, entries 1–3, 6)
suggested 1 might be a limiting reagent, requiring 2 equiva-
lents for the formation of dithioacetal 3a. Satisfyingly, when
the amount of 1 was increased from 1 to 1.5 equivalents,
the desired aldehyde 4a was isolated in 98% yield after oxi-
dative aqueous workup (Table 1, entry 9). Finally, it is worth
mentioning that the use of a catalytic amount (20 mol%) of
mild Lewis acids, including Sc(OTf)3, Yb(OTf)3, In(OTf)3 and
Bi(OTf)3, proved to be insufficient to promote the reaction
in dichloromethane; 1,2,4-trimethoxybenzene was recov-
ered and the difluoro(phenylsulfanyl)methane was con-
sumed, giving diphenyl disulfide and thiophenol as byprod-
ucts.
1
SnCl4 (2)
AlCl3 (2)
40
6
6
–
–
3
–
–
–
–
–
–
2
7
20
–
23
24
–
3
TiCl4 (2)
25
–
4
Ti(Oi-Pr)4 (2)
TMSOTf (2)
SnCl4 (5)
SnCl4 (2)
SnCl4 (2)
SnCl4 (2)
5
–
–
–
6
42
–
37
–
6
7d
8e
9f
–
–
75
98
–
–
–
a Reaction conditions: 1 (1 equiv), 2a (0.5 mmol, 1 equiv), Lewis acid,
CH2Cl2 (1 mL), stirred, rt, 2 h.
b For reactions using AlCl3: 2a was added to a premixed solution of 1 and
AlCl3 at rt; for reactions using SnCl4, TiCl4, Ti(Oi-Pr)4 or TMSOTf: 1 was add-
ed to a solution of the Lewis acid in CH2Cl2, followed by 2a, at rt.
c Isolated yields after silica gel column chromatographic purification.
d Reaction was carried out at 0 °C.
e Reaction was quenched by treatment with a solution of IBX (1.5 equiv) in
DMSO/H2O (3:1 v/v) and the resulting mixture was stirred at rt for 2 h, fol-
lowed by aqueous workup.
f 1 (1.5 equiv) was used, followed by workup identical to that of entry 8.
3 and 4). Low yields were observed when anisole and N,N-
diethylaniline were employed as the substrates (Table 2, en-
tries 5 and 6).
Under the standard conditions, the reaction of
methoxy-substituted naphthalene derivatives also general-
ly worked well (Figure 1). N-Methyl-1H-indole also gave
moderate yields of its corresponding product 4l. Using 2,3-
dimethoxynaphthalene as a starting material resulted in
nonselective formylation at both the C1 (4ma) and C7 posi-
tion (4mb).
The synthetic utility of our developed method was fur-
ther demonstrated by employing this protocol for the in-
stallation of the formyl group onto activated aromatic com-
pounds containing an electron-withdrawing methyl ester
group (Table 3). Under our standard reaction conditions,
formylation readily proceeded yielding the corresponding
aldehydes 8, after oxidative quenching, in excellent yields
(Table 3, entries 1–3). In comparison, reaction of methyl
3,4,5-trimethoxybenzoate employing the well-known elec-
trophilic formylating reagents dichloro(methoxy)meth-
ane17,23 and the Vilsmeier–Haack reagent (pyrophosphoryl
After the optimum reaction conditions were identified
(Table 1, entry 9), the synthetic utility of the formylation re-
action of benzene and naphthalene derivatives, as well as
indole, was evaluated. From the results shown in Table 2,
the reactions of benzene derivatives in general gave moder-
ate to excellent yields of the corresponding aldehydes 4. Ac-
tivated 1,2,4-trimethoxybenzene and 1,3,5-trimethoxyben-
zene led to high yields of products 4 (Table 2, entries 1 and
2); however, the reactions of less activated aromatic com-
pounds, namely 1,2,3-trimethoxybenzene and 1,3-
dimethoxybenzene, resulted in good yields (Table 2, entries
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

C
N. M. Betterley et al.
Paper
Synthesis
Table 2 Reaction of Benzene Derivatives Using Difluoro(phenylsulfa-
nyl)methane (1) as Formylating Agenta
Table 3 Formylation Reaction of Activated Aromatic Compounds
Containing a Deactivating Ester Substituenta
R4
R5
R4
R5
R4
CO2Me
CHO
R4
CO2Me
PhSCF2H
PhSCF2H
R3
H
R3
CHO
1
R3
R3
H
1
SnCl4, rt, 2 h
R2
R1
R2
R1
4
R2
R1
2
R2
R1
8
7
Entry
R1
R2
R3
OMe
R4
R5
Yield (%) of 4b
Entry R1
R2
R3
R4
Method
Yield (%) of 8b
1
2
3
4
5
6
OMe
OMe
OMe
OMe
H
H
OMe
H
H
4a, 98
4b, 99
4c, 72
4d, 78
4e, 47
4f, 42
1
2
3
4
5
OMe
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
A
A
A
B
C
8a, 95
8b, 85
8c, 88
8a, 71
8a, 31
H
OMe
OMe
OMe
OMe
NEt2
OMe
H
H
OMe
H
H
OMe
OMe
OMe
Me
H
H
H
H
H
H
H
H
H
H
H
a Method A: PhSCF2H (1; 1.5 equiv), SnCl4 (2 equiv), CH2Cl2, rt, 2 h; then IBX
(1.5 equiv) in DMSO/H2O (3:1 v/v), rt, 2 h, before aqueous workup; Method
B: MeOCHCl2 (3 equiv), TiCl4 (0.1 M; 2 equiv), CH2Cl2, rt, 16 h; Method C:
pyrophosphoryl chloride (1.7 equiv), DMF (1.5 equiv), CH2Cl2, rt, 16 h.
b Isolated yields after silica gel column chromatographic purification.
a Reaction conditions : A solution of 1 (1.5 equiv) in CH2Cl2 (1 mL) was add-
ed to a solution of SnCl4 (2 equiv) in CH2Cl2 (1 mL) followed by the addition
of ArH (1 equiv) iin CH2Cl2 (1 mL) at rt. The reaction was treated with IBX
(1.5 equiv) in DMSO/H2O (3:1 v/v), rt, 2 h, before conventional aqueous
workup.
b Isolated yields after silica gel column chromatographic purification.
leading to the formation of dithioacetals 3 and aldehydes 4,
could be rationalized as shown in Scheme 2. We propose
that the mechanism proceeds through a short-lived fluoro-
(phenylsulfanyl)methylium cation (1a-cation) which is im-
mediately trapped by chloride ion from the SnFCl4 anion
leading to 1b.25 Under excess Lewis acid, 1b immediately
undergoes further fluoride abstraction by either SnFCl3 or
SnCl4, resulting in the formation of an α-chloro thionium
ion (1c-cation) as an active formylating species. Although
fluorine is known to stabilize carbocation centers through
back-bonding, under the conditions of excess SnCl4 the
stronger Sn–F bond (Sn–F 414 vs Sn–Cl 323 kJ/mol) drives
the reaction to a single α-chloro thionium ion intermediate.
CHO
OMe
OMe
OMe
CHO
CHO
MeO
4g (91)
4h (85)
4i (64)
CHO
CHO
CHO
OMe MeO
OMe
N
MeO
CH3
4k (97)
4l (64)
4j (93)
CHO
OHC
OMe
OMe
OMe
OMe
4mb (61)
4ma (38)
SnFCl4
PhS
F
Figure 1 Reaction of naphthalene and indole derivatives using difluo-
ro(phenylsulfanyl)methane (1) as formylating agent. Reagents and con-
ditions: A solution of 1 (1.5 equiv) in CH2Cl2 (1 mL) was added to a
solution of SnCl4 (2 equiv) in CH2Cl2 (1 mL) followed by the addition of
ArH (1 equiv) iin CH2Cl2 (1 mL) at rt. The reaction was treated with IBX
(1.5 equiv) in DMSO/H2O (3:1 v/v), rt, 2 h, before conventional aqueous
workup. In parentheses: isolated yields after silica gel column chro-
matographic purification.
SnCl4
F
Cl
PhS
1b
PhSCF2H
H
1
H
SnFCl3
or
SnCl4
[1a-cation]
path b PhSCF2H (1)
(F)Cl
H
SnF2Cl3
PhS
(F)Cl
H
PhSCF2H
Cl
(1)
Ph
S
PhS
PhS
SPh
path b'
1f
H
CF2H
chloride/DMF)24 proved to be less efficient: such reactions
required a longer time (16 h) and gave the corresponding
aldehyde 8a in lower yields (Table 3, entries 4 and 5). Unfor-
tunately, under our standard conditions the reaction did
not proceed when the number of activating methoxy
groups was decreased, for example when employing meth-
yl 4-methoxybenzoate or methyl benzoate as substrate.
On the basis of the experimental results and our prior
work, the proposed mechanism for the reaction of difluoro-
(phenylsulfanyl)methane (1) with aromatic compounds,
F(Cl)
[1c-cation]
[1e-cation]
H
PhS
[1g-cation]
SPh
path a ArH
ArH
O
H
Ar
SPh
hydrolysis
Cl
H
IBX
PhS
PhS
Ar
Ar
H
4
3
1d
Scheme 2 Proposed reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

D
N. M. Betterley et al.
Paper
Synthesis
1
Subsequent trapping of 1c-cation with an aromatic com-
pound yields 1d which undergoes hydrolysis during aque-
ous workup, providing the desired aldehyde 4 (path a). The
proposed mechanism is analogous to the well-known
Vilsmeier–Haack and Rieche formylation reaction mecha-
nisms in which the active formylating species is commonly
generated prior to addition of the aromatic compound. The
formation of dithioacetals 3 can be rationalized through ei-
ther path b or path b′. Reagent 1 attacks either the unstable
1a-cation (path b) or the more stable 1c-cation (path b′)
leading to (difluoromethyl)sulfonium species 1e-cation. In
previous work, we have demonstrated that such a di-
merization process is viable, leading to a stable bis(phenyl-
sulfanyl) cation (1g-cation).19b The resulting 1g-cation is
trapped by the aromatic compound, leading to dithioacetal
3 upon standard aqueous workup; whereas, upon oxidative
quench by IBX, dithioacetals 3 undergo oxidative hydrolysis
providing the desired aldehydes 4.22
13C and H NMR chemical shifts were in good agreement
with experimental values (R2 = 0.9798 for corrected 13C
NMR shifts) (Figure 2).
In conclusion, we have described the reactivity of diflu-
oro(phenylsulfanyl)methane (1) towards Lewis acids
through the formylation reaction of activated aromatic
compounds. Our finding is the first report on detailed spec-
troscopic and theoretical studies for the utilization of diflu-
oro(phenylsulfanyl)methane as a synthetic equivalent to a
formyl cation. A room-temperature stable α-chloro thioni-
um ion intermediate has been proposed as the active
formylating species and substantiated by means of NMR
spectroscopy and TD-DFT NMR calculations for the first
time. Our reported procedure offers a quick entry and a via-
ble alternative method to the existing methods available for
formylation reactions.
The formation of an α-chloro thionium ion intermediate
(1c-cation) is analogous to the α-chloro oxonium and imin-
ium ion intermediates proposed in the Rieche and Vilsmei-
er–Haack reactions, respectively. Based on chemical reac-
tivity and the yields of the products, the proposed 1c-cat-
ion appears to be more reactive as the formylating species.
To unequivocally provide mechanistic evidence and insight
into the active formylating species, 1c-cation was generat-
ed under anhydrous conditions in the absence of aromatic
All chemicals were obtained from commercial sources and used with-
out further purification. Anhydrous CH2Cl2 was freshly distilled under
argon from CaH2. 1H (500, 400 or 300 MHz) and 13C (125, 100 or 75
MHz) NMR spectra were recorded in CDCl3 solution with either a
Bruker Advance-500, Bruker AV-400 or Bruker DPX-300 spectrometer,
with TMS or CHCl3 as internal reference; δ values are in parts per mil-
lion (ppm) and coupling constants (J) in hertz (Hz). 19F NMR spectra
(376 MHz) were recorded on a Bruker AV-400 spectrometer, with
CF3Cl as internal reference. Mass spectra (HRMS) were recorded using
a Bruker micrOTOF spectrometer. All glassware and syringes were
oven-dried and kept in a desiccator before use. Radial chromatogra-
phy on a Chromatotron was performed with Merck silica gel 60 PF254
(Art. 7749). Preparative thin-layer chromatography (PTLC) was per-
formed using Merck silica gel 60 PF254 (Art. 7747). Analytical TLC was
performed with Merck TLC aluminum sheets coated with silica gel 60
PF254 (Art. 5554).
1
compound, and was characterized by H, 13C and 19F NMR
spectroscopy. The reaction is remarkably clean, leading to a
single species with a characteristic deshielded 1H NMR sig-
nal at δH 10.18 ppm and 13C NMR signal at δC 200.2 ppm. 19
F
NMR showed a single peak at δF –162.19 ppm as a singlet.
Splitting was not observed in either the 1H or 13C NMR
spectrum, suggesting fluorine is not attached to a carbon or
with connectivity to a proton. With limited literature for
comparison on 19F NMR shifts of tin(IV) fluoride/chloride
complexes, we have tentatively assigned this peak to a [Snn-
Fn+1Cln+2]– species as the counteranion, which is in the range
of similar complexes.26 To gain further confidence in the
structural assignment, DFT calculations [mPW1PW91/6-
31+G(d,p) in CH2Cl2] were performed on an optimized
structure [B3LYP/6-31G(d) in the gas phase] (see the Sup-
porting Information for computational details). Calculated
Reaction Optimization; General Procedure
In a round-bottomed flask equipped with a stirring bar and rubber
septum was placed a Lewis acid in anhydrous CH2Cl2 (1 mL). To this
solution was added PhSCF2H (1) in anhydrous CH2Cl2 (1 mL), followed
by a solution of 1,2,4-trimethoxybenzene (2a; 0.5 mmol) in anhy-
drous CH2Cl2 (1 mL). The reaction was allowed to proceed for 2 h be-
fore it was quenched with a solution of IBX (140 mg, 0.5 mmol) in
DMSO/H2O (4 mL; 3:1 v:v). After 2 h of stirring at rt, the reaction mix-
ture was quenched by addition of a saturated aqueous solution of so-
dium thiosulfate (10 mL), then basified with a saturated aqueous
solution of sodium hydrogen carbonate (10 mL), followed by stirring
and extraction with CH2Cl2 (3 × 10 mL). The combined organic layers
were washed with water (3 × 10 mL) and brine (10 mL), dried (anhy-
drous MgSO4), filtered and concentrated (aspirator). The residue was
purified by PTLC to provide 3a, 4a, 5a and 6a in various ratios and
yields (Table 1).
130.0
(128.6)
200.2
(201.2)
S
Cl
133.8
C
(129.9)
123.9
(130.7)
10.18
(10.90)
1-[Bis(phenylsulfanyl)methyl]-2,4,5-trimethoxybenzene (3a)
131.0
H
(133.7)
2 = 0.9798
[1c-cation]
White solid (Et2O/hexanes); mp 92.3–92.6 °C; Rf = 0.32 (hexanes/EtOAc,
5:2).
R
IR (KBr): 3056, 3000, 2945, 2831, 1608, 1582, 1515, 1438, 1237 (Ar–
O–C), 1205 (Ar–O–C), 1175 (Ar–O–C), 1033 cm–1 (Ar–O–C).
1H NMR (500 MHz, CDCl3): δ = 7.37–7.34 (m, 4 H), 7.26–7.19 (m, 6 H),
Figure 2 Selected experimental and computational (in parentheses)
13C and 1H NMR chemical shifts for weighted average E/Z conformers of
1c-cation
7.00 (s, 1 H), 6.43 (s, 1 H), 6.05 (s, 1 H), 3.86 (s, 3 H), 3.75 (s, 6 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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N. M. Betterley et al.
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Synthesis
13C NMR (125 MHz, CDCl3): δ = 150.2 (C), 149.4 (C), 143.3 (C), 135.0
(2 × C), 132.2 (4 × CH), 128.7 (4 × CH), 127.4 (2 × CH), 119.4 (C), 112.4
(CH), 97.6 (CH), 56.8 (CH3), 56.4 (CH3), 56.1 (CH3), 52.1 (CH).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C22H22O3S2Na: 421.0908;
found: 421.0910.
1H NMR (400 MHz): δ = 10.18 (s, 1 H), 7.45–7.42 (br s, 5 H).
13C NMR (100 MHz): δ = 200.2 (1 C), 133.8 (2 × CH), 131.0 (1 H), 130.0
(2 × CH), 123.9 (1 C).
19F NMR (376 MHz): δ = –162.19.
Aldehydes 4 and 8; General Procedure
2,4,5-Trimethoxybenzaldehyde (4a)
In a round-bottomed flask equipped with a stirring bar and rubber
septum was placed a 1 M solution of SnCl4 in anhydrous CH2Cl2 (1 mL,
1 mmol). To this solution was added PhSCF2H (1; 240.2 mg, 1.5 mmol)
in anhydrous CH2Cl2 (1.5 mL), followed by a solution of an aromatic
compound (0.5 mmol) in anhydrous CH2Cl2 (1 mL). The reaction was
allowed to proceed for 2 h before it was quenched with a solution of
IBX (140 mg, 0.5 mmol) in DMSO/H2O (4 mL; 3:1 v:v). After 2 h of
stirring at rt, the reaction mixture was quenched by addition of a sat-
urated aqueous solution of sodium thiosulfate (10 mL), then basified
with a saturated aqueous solution of sodium hydrogen carbonate (10
mL), followed by stirring and extraction with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with water (3 × 10 mL) and
brine (10 mL), dried (anhydrous MgSO4), filtered and concentrated
(aspirator). The residue was purified by PTLC, radial chromatography
or column chromatography to furnish analytically pure product.
White solid (96.14 mg, 98%) from EtOAc/hexanes; mp 112.4–
112.7 °C; Rf = 0.26 (hexanes/EtOAc, 2:1).
IR (KBr): 2924, 2855, 1660 (C=O), 1607, 1510, 1456, 1291 (Ar–O–C),
1218 (Ar–O–C), 1128 (Ar–O–C), 1026 cm–1 (Ar–O–C).
1H NMR (300 MHz, CDCl3): δ = 10.31 (s, 1 H), 7.32 (s, 1 H), 6.50 (s, 1
H), 3.98 (s, 3 H), 3.93 (s, 3 H), 3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 187.9 (CO), 158.8 (C), 155.7 (C), 143.5
(C), 117.2 (C), 108.9 (CH), 95.9 (CH), 56.2 (CH3), 56.1 (2 × CH3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H12O4Na: 219.0633;
found: 219.0629.
(Phenylsulfanyl)bis(2,4,5-trimethoxyphenyl)methane (5a)
White solid (EtOAc/hexanes); mp 92.3–92.7 °C; Rf = 0.24 (hex-
anes/EtOAc, 2:1).
2,4,6-Trimethoxybenzaldehyde (4b)
IR (neat): 3037, 2996, 2957, 2931, 1608, 1595, 1505, 1455, 1224 (Ar–
O–C), 1203 (Ar–O–C), 1175 (Ar–O–C), 1031 cm–1 (Ar–O–C).
1H NMR (500 MHz, CDCl3): δ = 7.25–7.09 (m, 7 H), 6.50 (s, 2 H), 6.34
White solid (97.12 mg, 99%) from EtOAc/hexanes; mp 118–120 °C;
Rf = 0.23 (hexanes/EtOAc, 5:1).
IR (KBr): 2976, 2949, 2880, 1664 (C=O), 1600, 1475, 1333, 1161, 1127,
(s, 1 H), 3.86 (s, 6 H), 3.78 (s, 6 H), 3.76 (s, 6 H).
1025 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 151.1 (2 × C), 148.9 (2 × C), 143.0
(2 × C), 137.3 (C), 129.4 (2 × CH), 128.5 (2 × CH), 125.8 (CH), 121.1
(2 × C), 113.5 (2 × CH), 98.3 (2 × CH), 57.0 (2 × CH3), 56.6 (2 × CH3),
56.0 (2 × CH3), 43.2 (CH).
1H NMR (300 MHz, CDCl3): δ = 10.36 (s, 1 H), 6.09 (s, 2 H), 3.89 (s, 9
H).
13C NMR (75 MHz, CDCl3): δ = 187.6 (CO), 166.2 (C), 164.1 (2 × C),
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C25H28O6SNa: 479.1504;
found: 479.1518.
108.9 (C), 90.3 (2 × CH), 56.0 (2 × CH3), 55.5 (CH3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H12O4Na: 219.0633;
found: 219.0627.
Tris(2,4,5-trimethoxyphenyl)methane (6a)
2,3,4-Trimethoxybenzaldehyde (4c)
White solid (EtOAc/hexanes); mp 184.3–185.2 °C; Rf = 0.16 (hex-
anes/EtOAc, 5:2).
White solid (70.63 mg, 72%) from EtOAc/hexanes; mp 38–41 °C;
IR (KBr): 2940, 1605, 1521, 1428 cm–1
.
Rf = 0.38 (hexanes/EtOAc, 5:2).
1H NMR (300 MHz, CDCl3): δ = 6.54 (s, 3 H), 6.41 (s, 3 H), 6.22 (s, 1 H),
3.87 (s, 9 H), 3.66 (s, 9 H), 3.63 (s, 9 H).
IR (neat): 2944, 2844, 1682 (C=O), 1590, 1291 (Ar–O–C), 1204 (Ar–O–
C), 1093 cm–1 (Ar–O–C).
1H NMR (300 MHz, CDCl3): δ = 10.25 (s, 1 H), 7.61 (d, J = 8.8 Hz, 1 H),
6.77 (d, J = 8.8 Hz, 1 H), 4.04 (s, 3 H), 3.95 (s, 3 H), 3.90 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 188.8 (CO), 159.3 (C), 156.9 (C), 141.6
(C), 124.2 (CH), 123.4 (C), 107.4 (CH), 62.3 (CH3), 60.9 (CH3), 56.2
(CH3).
13C NMR (75 MHz, CDCl3): δ = 151.5 (3 × C), 147.7 (3 × C), 142.5
(3 × C), 124.7 (3 × C), 114.0 (3 × CH), 98.5 (3 × CH), 57.1 (3 × CH3), 56.6
(3 × CH3), 55.9 (3 × CH3), 36.2 (1 × CH).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C28H34O9Na: 537.2101;
found: 537.2182.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H12O4Na: 219.0633;
1H, 13C and 19F NMR Characterization of Chloro(phenylsulfa-
nyl)methylium Trichlorodifluorostannate(IV) ([1c-cation])
found: 219.0635.
2,4-Dimethoxybenzaldehyde (4d)
In a screw-cap NMR tube equipped with a septum, a closed capillary
tube containing CDCl3, TMS and CFCl3 was inserted. The NMR tube
was gently heated under reduced pressure to remove trace moisture,
followed by the addition of a 1 M solution of SnCl4 in CH2Cl2 (0.4 mL,
0.4 mmol). A solution of PhSCF2H (1; 32 mg, 0.2 mmol) in CH2Cl2 (0.2
mL) was added dropwise via syringe. Upon the addition of PhSCF2H,
the colorless solution immediately turned a clear light orange color.
The reaction is not exothermic, yet small bubbles were observed as
the reaction proceeded. After 5 min of gently rotating the NMR tube,
a homogeneous clear orange solution was observed and 1H, 13C and
19F NMR data were collected.
White solid (64.81 mg, 78%) from EtOAc/hexanes; mp 70.2–72.5 °C;
Rf = 0.48 (hexanes/EtOAc, 5:1).
IR (KBr): 2951, 2863, 1660 (C=O), 1605, 1455, 1284 (Ar–O–C), 1217
(Ar–O–C), 1175 (Ar–O–C), 1023 cm–1 (Ar–O–C).
1H NMR (300 MHz, CDCl3): δ = 10.29 (s, 1 H), 7.81 (d, J = 8.7 Hz, 1 H),
6.55 (dd, J = 8.7, 2.2 Hz, 1 H), 6.45 (d, J = 2.2 Hz, 1 H), 3.90 (s, 3 H), 3.88
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 188.3 (CO), 166.2 (C), 163.6 (C), 130.7
(CH), 119.1 (C), 105.8 (CH), 97.9 (CH), 55.6 (2 × CH3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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N. M. Betterley et al.
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Synthesis
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H10O3Na: 189.0528; found:
189.0549.
IR (Nujol mull): 2924, 2854, 1673 (C=O), 1581, 1455, 1237, 1207,
1055, 803, 650 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 10.11 (s, 1 H), 8.81 (d, J = 2.4 Hz, 1 H),
8.20 (d, J = 9.2 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.19 (dd, J = 9.2, 2.5 Hz,
1 H), 6.75 (d, J = 8.0 Hz, 1 H), 4.04 (s, 3 H), 3.99 (s, 3 H).
4-Methoxybenzaldehyde (4e)
Colorless liquid (31.99 mg, 47%); Rf = 0.38 (hexanes/EtOAc, 5:1).
13C NMR (125 MHz, CDCl3): δ = 192.4 (CO), 161.0 (C), 160.9 (C), 141.0
(CH), 133.7 (C), 124.0 (C), 123.9 (CH), 120.3 (C), 118.4 (CH), 103.8
(CH), 101.3 (CH), 55.7 (CH3), 55.3 (CH3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H12O3Na: 239.0684;
found: 239.0664.
IR (neat): 2937, 2841, 1682 (C=O), 1599, 1577, 1160, 1024, 833 cm–1
1H NMR (400 MHz, CDCl3): δ = 9.86 (s, 1 H), 7.81 (d, J = 8.8 Hz, 2 H),
6.98 (d, J = 8.7 Hz, 2 H), 3.86 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 190.7 (CO), 164.5 (C), 131.9 (2 × CH),
129.8 (C), 114.2 (2 × CH), 55.5 (CH3).
.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C8H8O2Na: 159.0422; found:
159.0464.
2,6-Dimethoxy-1-naphthaldehyde (4j)
White solid (100.55 mg, 93%) from EtOAc/hexanes; mp 90–91 °C;
Rf = 0.45 (hexanes/EtOAc, 5:1).
4-(Diethylamino)benzaldehyde (4f)
IR (KBr): 3091, 2969, 2885, 1663 (C=O), 1515, 1372, 1240, 1170, 1061,
White solid (37.22 mg, 42%) from EtOAc/hexanes; mp 38–41 °C;
Rf = 0.33 (hexanes/EtOAc, 5:0.5).
844, 817 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 10.89 (s, 1 H), 9.23 (d, J = 9.4 Hz, 1 H),
7.99 (d, J = 9.2 Hz, 1 H), 7.32 (dd, J = 9.4, 2.8 Hz, 1 H), 7.30 (d, J = 9.2 Hz,
1 H), 7.11 (d, J = 2.8 Hz, 1 H), 4.05 (s, 3 H), 3.93 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 192.0 (CO), 162.5 (C), 156.6 (C), 136.1
(CH), 129.9 (C), 126.7 (C), 126.6 (CH), 121.9 (CH), 117.1 (C), 113.3
(CH), 106.6 (CH), 56.7 (CH3), 55.3 (CH3).
IR (neat): 2974, 2929, 2731, 1667 (C=O), 1595, 1527, 1408, 1274,
1173, 1156 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.71 (s, 1 H), 7.72 (d, J = 9.0 Hz, 2 H),
6.68 (d, J = 9.0 Hz, 2 H), 3.44 (q, J = 7.1 Hz, 4 H), 1.24 (t, J = 9.5 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 189.9 (CO), 152.2 (C), 124.7 (C), 110.6
(4 × CH), 44.7 (2 × CH2), 12.5 (2 × CH3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H15NONa: 200.1051;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H12O3Na: 239.0684;
found: 239.0656.
found: 200.1053.
2,7-Dimethoxy-1-naphthaldehyde (4k)
2-Methoxy-1-naphthaldehyde (4g)
White solid (104.87 mg, 97%) from EtOAc/hexanes; mp 98–100 °C;
Rf = 0.30 (hexanes/EtOAc, 5:1).
IR (neat): 3006, 2966, 2945, 1663 (C=O), 1518, 1249, 1054, 828 cm–1
1H NMR (500 MHz, CDCl3): δ = 10.89 (s, 1 H), 8.84 (d, J = 2.5 Hz, 1 H),
7.98 (d, J = 9.0 Hz, 1 H), 7.66 (d, J = 8.9 Hz, 1 H), 7.11 (d, J = 9.0 Hz, 1 H),
7.06 (dd, J = 9.0, 2.6 Hz, 1 H), 4.04 (s, 3 H), 3.97 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 192.0 (CO), 164.8 (C), 161.5 (C), 137.3
(CH), 133.5 (C), 129.7 (CH), 124.1 (C), 117.4 (CH), 115.8 (C), 109.5
(CH), 103.5 (CH), 56.4 (CH3), 55.4 (CH3).
White solid (84.72 mg, 91%) from EtOAc/hexanes; mp 82–84 °C;
Rf = 0.40 (hexanes/EtOAc, 5:1).
.
IR (neat): 3079, 3011, 2941, 2847, 1682 (C=O), 1574, 1513, 1430,
1251, 1220, 1095, 1060, 816, 765 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 10.92 (s, 1 H), 9.31 (d, J = 8.8 Hz, 1 H),
8.07 (d, J = 9.2 Hz, 1 H), 7.80 (d, J = 7.9 Hz, 1 H), 7.65 (t, J = 7.7 Hz, 1 H),
7.44 (t, J = 7.5 Hz, 1 H), 7.31 (d, J = 9.2 Hz, 1 H), 4.07 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 191.9 (CO), 163.9 (C), 137.5 (CH),
131.6 (C), 129.8 (CH), 128.5 (C), 128.2 (CH), 124.9 (CH), 124.7 (CH),
116.7 (C), 112.5 (CH), 56.5 (CH3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H12O3Na: 239.0684;
found: 239.0638.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H11O2: 187.0759; found:
187.0734.
1-Methyl-1H-indole-3-carbaldehyde (4l)
White solid (50.94 mg, 64%) from EtOAc/hexanes; mp 68–70 °C;
Rf = 0.07 (hexanes/EtOAc, 5:1).
1-Methoxy-2-naphthaldehyde (4h)
White solid (79.14 mg, 85%) from EtOAc/hexanes; mp 60–63 °C;
Rf = 0.38 (hexanes/EtOAc, 5:1).
IR (neat): 3107, 2806, 1651 (C=O), 1537, 1075, 787, 747 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 9.98 (s, 1 H), 8.34–8.30 (m, 1 H), 7.66
(s, 1 H), 7.37–7.28 (m, 3 H), 3.86 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 184.4 (CO), 139.2 (CH), 137.8 (C), 125.2
(C), 124.0 (CH), 122.9 (CH), 122.0 (CH), 118.0 (C), 109.8 (CH), 33.6
(CH3).
IR (KBr): 3079, 3011, 2941, 2847, 1682 (C=O), 1574, 1513, 1430, 1251,
1220, 1095, 1060, 816, 765 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 10.23 (s, 1 H), 9.34 (d, J = 9.5 Hz, 1 H),
8.36 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.73 (t, J = 7.7 Hz, 1 H),
7.66 (t, J = 7.7 Hz, 1 H), 6.95 (d, J = 8.1 Hz, 1 H), 4.12 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 192.2 (CO), 160.8 (CO), 139.6 (CH),
131.9 (C), 129.5 (CH), 126.4 (CH), 125.5 (C), 125.0 (C), 124.8 (CH),
122.3 (CH), 102.9 (CH), 55.9 (CH3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H9NONa: 182.0582;
found: 182.0544.
2,3-Dimethoxy-1-naphthaldehyde (4ma)
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H11O2: 187.0759; found:
187.0732.
White solid (41.08 mg, 38%) from EtOAc/hexanes; mp 153–155 °C;
Rf = 0.24 (hexanes/EtOAc, 5:1).
IR (KBr): 3069, 3002, 2972, 2838, 1689 (C=O), 1512, 1487, 1385, 1264,
1,6-Dimethoxy-2-naphthaldehyde (4i)
1239, 1054, 873, 796 cm–1
.
White solid (69.19 mg, 64%) from EtOAc/hexanes; mp 94–95 °C;
Rf = 0.38 (hexanes/EtOAc, 5:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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N. M. Betterley et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 10.30 (s, 1 H), 8.82 (s, 1 H), 7.96 (d, J =
8.1 Hz, 1 H), 7.85 (d, J = 7.0 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 1 H), 7.20 (s, 1
H), 4.10 (s, 3 H), 4.04 (s, 3 H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H16O6Na: 291.0844;
found: 291.0729.
13C NMR (125 MHz, CDCl3): δ = 194.2 (CO), 152.2 (C), 149.8 (C), 135.9
(CH), 133.4 (CH), 130.0 (C), 129.9 (C), 126.7 (C), 123.1 (CH), 106.6
(CH), 104.2 (CH), 56.0 (CH3), 55.7 (CH3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H12O3Na: 239.0684;
found: 239.0619.
Funding Information
We thank the Center of Excellence for Innovation in Chemistry
(PERCH-CIC), Office of the Higher Education Commission, Mahidol
University under the National Research Universities Initiative, Thai-
land Research Fund (IRN58W0005), Swedish Research Council
through the Swedish Research Links Programme in collaboration with
Professor Pher G. Andersson, Stockholm University, Sweden (2013-
6744), CNRS-PICS Program through collaboration with Professor Fabi-
en Gagosz, École Polytechnique, France (PICS 6663), and the Franco–
Thai Cooperation Program in Higher Education and Research (PHC-
Siam 2017) for financial support. C.K. also thanks the Thailand Toray
6,7-Dimethoxy-2-naphthaldehyde (4mb)
White solid (65.95 mg, 61%) from EtOAc/hexanes; mp 95–96 °C;
Rf = 0.16 (hexanes/EtOAc, 5:1).
IR (KBr): 3067, 2996, 2942, 1683 (C=O), 1513, 1488, 1410, 1259, 1161,
1055, 875, 860 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 10.12 (s, 1 H), 8.23 (d, J = 1.0 Hz, 1 H),
7.85 (dd, J = 8.4, 1.6 Hz, 1 H), 7.80 (d, J = 8.3 Hz, 1 H), 7.28 (s, 1 H), 7.20
(s, 1 H), 4.07 (s, 3 H), 4.06 (s, 3 H).
Science Foundation for Science and Technology Research Grants.
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13C NMR (125 MHz, CDCl3): δ = 192.1 (CO), 152.0 (C), 150.3 (C), 133.0
(C), 132.8 (C), 132.2 (CH), 128.4 (C), 127.2 (CH), 122.0 (CH), 107.6
(CH), 106.4 (CH), 56.1 (CH3), 56.0 (CH3).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591545.
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HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H12O3Na: 239.0684;
found: 239.0668.
References
Methyl 2-Formyl-3,4,5-trimethoxybenzoate (8a)
(1) Current address: Faculty of Science at Si Racha, Kasetsart Uni-
versity, Si Racha Campus, Chon Buri, Thailand.
(2) Chambers, R. D. Fluorine in Organic Chemistry; John Wiley &
Sons: New York, 1973.
(3) (a) Olah, G. A.; Cupas, C. A.; Comisarow, M. B. J. Am. Chem. Soc.
1966, 88, 362. (b) Olah, G. A.; Comisarow, M. B. J. Am. Chem. Soc.
1967, 89, 1027. (c) Olah, G. A.; Chambers, R. D.; Comisarow, M.
B. J. Am. Chem. Soc. 1967, 89, 1268. (d) Prakash, G. S.; Heiliger, L.;
Olah, G. A. J. Fluorine Chem. 1990, 49, 33. (e) Baird, N.; Datta, R.
Can. J. Chem. 1971, 49, 3708. (f) Ferraris, D.; Cox, C.; Anand, R.;
Lectka, T. J. Am. Chem. Soc. 1997, 119, 4319.
Pale yellow oil (120.76 mg, 95%); Rf = 0.41 (hexanes/EtOAc, 5:2).
IR (neat): 2935, 1758, 1455, 1108, 655 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 10.30 (s, 1 H), 6.95 (s, 1 H), 3.99 (s, 3
H), 3.95 (s, 3 H), 3.92 (s, 3 H), 3.91 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 189.2 (CO), 168.3 (CO), 157.1 (C),
155.2 (C), 144.0 (C), 128.6 (C), 123.8 (C), 108.0 (CH), 62.6 (CH3), 61.2
(CH3), 56.4 (CH3), 53.0 (CH3).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H14O6Na: 277.0688;
found: 277.0664. NMR data of 8a are in agreement with those previ-
ously reported.17
(4) (a) Christe, K. O.; Zhang, X.; Bau, R.; Hegge, J.; Olah, G. A.;
Prakash, G. S.; Sheehy, J. A. J. Am. Chem. Soc. 2000, 122, 481.
(b) Douvris, C.; Stoyanov, E. S.; Tham, F. S.; Reed, C. A. Chem.
Commun. 2007, 1145. (c) Ichikawa, J.; Fujiwara, M.; Miyazaki, S.;
Ikemoto, M.; Okauchi, T.; Minami, T. Org. Lett. 2001, 3, 2345.
(5) (a) Ichikawa, J.; Miyazaki, S.; Fujiwara, M.; Minami, T. J. Org.
Chem. 1995, 60, 2320. (b) Ichikawa, J. Pure Appl. Chem. 2000, 72,
1685. (c) Ichikawa, J.; Jyono, H.; Kudo, T.; Fujiwara, M.; Yokota,
M. Synthesis 2005, 39. (d) Ichikawa, J.; Kaneko, M.; Yokota, M.;
Itonaga, M.; Yokoyama, T. Org. Lett. 2006, 8, 3167. (e) Yokota,
M.; Fujita, D.; Ichikawa, J. Org. Lett. 2007, 9, 4639. (f) Ichikawa,
J.; Yokota, M.; Kudo, T.; Umezaki, S. Angew. Chem. Int. Ed. 2008,
47, 4870. (g) Isobe, H.; Hitosugi, S.; Matsuno, T.; Iwamoto, T.;
Ichikawa, J. Org. Lett. 2009, 11, 4026. (h) Wang, L.; Wei, J.; Wu,
R.; Cheng, G.; Li, X.; Hu, J.; Hu, Y.; Sheng, R. Org. Chem. Front.
2017, 4, 214.
Methyl 2-Formyl-4,5-dimethoxybenzoate (8b)
White solid (95.29 mg, 85%) from EtOAc/hexanes; mp 100–102 °C;
Rf = 0.35 (hexanes/EtOAc, 1:1).
IR (neat): 2926, 1658, 1445, 1206, 1108, 625 cm–1
1H NMR (300 MHz, CDCl3): δ = 10.67 (s, 1 H), 7.53 (s, 1 H), 7.49 (s, 1
.
H), 4.02 (s, 3 H), 4.01 (s, 3 H), 3.99 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.1 (CO), 166.2 (CO), 155.4 (C),
152.0 (C), 131.3 (C), 126.0 (C), 112.6 (CH), 109.7 (CH), 56.3 (CH3), 56.2
(CH3), 52.5 (CH3).
HRMS (ESI-TOF): m/z [M+] calcd for C11H12O5: 224.0685; found:
224.0672.
Methyl 2-Formyl-3,4,5-trimethoxy-6-methylbenzoate (8c)
(6) Kantlehner, W. Eur. J. Org. Chem. 2003, 2530.
(7) Simchen, G. In Houben–Weyl, 4th ed., Vol. E3; Falbe, J., Ed.;
Thieme: Stuttgart, 1983, 19–27.
(8) Gattermann, L.; Koch, J. A. Ber. Dtsch. Chem. Ges. 1897, 30, 1622.
(9) (a) Gattermann, L. Justus Liebigs Ann. Chem. 1906, 347, 347.
(b) Gattermann, L. Justus Liebigs Ann. Chem. 1907, 357, 313.
(c) Tanaka, M.; Iyoda, J.; Souma, Y. J. Org. Chem. 1992, 57, 2677.
White solid (118.0 mg, 88%) from EtOAc/hexanes; mp 135–137 °C;
Rf = 0.36 (hexanes/EtOAc, 3:10).
IR (neat): 3030, 1720, 1713, 1486, 1430, 1311, 1202, 1025, 738 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 10.26 (s, 1 H), 4.00 (s, 3 H), 3.95 (s, 3
H), 3.94 (s, 3 H), 3.90 (s, 3 H), 2.14 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 188.1 (CO), 169.2 (CO), 157.8 (C), 156.1
(C), 146.3 (C), 130.0 (C), 125.4 (C), 122.4 (C), 62.6 (CH3), 60.9 (CH3),
60.7 (CH3), 52.6 (CH3), 12.1 (CH3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

H
N. M. Betterley et al.
Paper
Synthesis
(10) (a) Reimer, K. Ber. Dtsch. Chem. Ges. 1876, 9, 423. (b) Wynberg,
H. The Reimer–Tiemann Reaction, In Comprehensive Organic
Reutrakul, V. Org. Lett. 2004, 6, 4547. (c) Pohmakotr, M.;
Boonkitpattarakul, K.; Ieawsuwan, W.; Jarussophon, S.;
Duangdee, N.; Tuchinda, P.; Reutrakul, V. Tetrahedron 2006, 62,
5973. (d) Surapanich, N.; Kuhakarn, C.; Pohmakotr, M.;
Reutrakul, V. Eur. J. Org. Chem. 2012, 5943. (e) Pohmakotr, M.;
Panichakul, D.; Tuchinda, P.; Reutrakul, V. Tetrahedron 2007, 63,
9429.
Chemistry;
2
V
o.
l
Trost, B.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 769.
(11) (a) Fischer, O.; Müller, A.; Vilsmeier, A. J. Prakt. Chem. 1925, 109,
69. (b) Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F.
Tetrahedron 1993, 49, 4015. (c) Lellouche, J.-P.; Kotlyar, V.
Synlett 2004, 564.
(12) (a) Rieche, A.; Gross, H.; Höft, E. Chem. Ber. 1960, 93, 88.
(b) Yakubov, A. P.; Tsyganov, D. V.; Belen’kii, L. I.; Krayushkin, M.
M. Tetrahedron 1993, 49, 3397.
(13) (a) Duff, J.; Bills, E. J. Chem. Soc. 1932, 1987. (b) Smith, W. E.
J. Org. Chem. 1972, 37, 3972.
(14) Kantlehner, W.; Vettel, M.; Gissel, A.; Haug, E.; Ziegler, G.;
Ciesielski, M.; Scherr, O.; Haas, R. J. Prakt. Chem. 2000, 342, 297.
(15) Bagno, A.; Kantlehner, W.; Scherr, O.; Vetter, J.; Ziegler, G. Eur. J.
Org. Chem. 2001, 2947.
(19) (a) Kuhakarn, C.; Surapanich, N.; Kamtonwong, S.; Pohmakotr,
M.; Reutrakul, V. Eur. J. Org. Chem. 2011, 5911. (b) Betterley, N.
M.; Surawatanawong, P.; Prabpai, S.; Kongsaeree, P.; Kuhakarn,
C.; Pohmakotr, M.; Reutrakul, V. Org. Lett. 2013, 15, 5666.
(20) Kongsriprapan, S.; Kuhakarn, C.; Deelertpaiboon, P.; Panthong,
K.; Tuchinda, P.; Pohmakotr, M.; Reutrakul, V. Pure Appl. Chem.
2012, 84, 1435.
(21) Hine, J.; Porter, J. J. J. Am. Chem. Soc. 1957, 79, 5493.
(22) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem.
Soc. 2004, 126, 5192. (b) Krishnaveni, N. S.; Surendra, K.;
Nageswar, Y.; Rao, K. R. Synthesis 2003, 2295.
(23) Hassall, C. H.; Morgan, B. A. J. Chem. Soc., Perkin Trans. 1 1973,
2853.
(24) Cheung, G. K.; Downie, I. M.; Earle, M. J.; Heaney, H.; Matough,
M. F. S.; Shuhaibar, K. F.; Thomas, D. Synlett 1992, 77.
(25) Hao, C.; Kaspar, J. D.; Check, C. E.; Lobring, K. C.; Gilbert, T. M.;
Sunderlin, L. S. J. Phys. Chem. A 2005, 109, 2026.
(16) (a) Kantlehner, W.; Wezstein, M.; Kreß, R.; Zschach, F.; Vetter, J.;
Ziegler, G.; Mezger, J.; Stoyanov, E. V.; Goeppert, A.; Sommer, J.
Z. Naturforsch., B 2006, 61, 448. (b) Kantlehner, W.; Leonhardt,
S.; Ziegler, G.; Scherr, O.; Kreß, R.; Goeppert, A.; Sommer, J. Z.
Naturforsch., B 2007, 62, 995.
(17) Dhanasekaran, S.; Bisai, V.; Unhale, R. A.; Suneja, A.; Singh, V. K.
Org. Lett. 2014, 16, 6068.
(18) (a) Reutrakul, V.; Thongpaisanwong, T.; Tuchinda, P.; Kuhakarn,
C.; Pohmakotr, M. J. Org. Chem. 2004, 69, 6913. (b) Pohmakotr,
M.; Ieawsuwan, W.; Tuchinda, P.; Kongsaeree, P.; Prabpai, S.;
(26) Dean, P.; Evans, D. J. Chem. Soc. A 1968, 1154.
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