Key words electrophilic formylation - thionium cation - aldehydes - electrophilic addition -
carbocations
Research directed at understanding the influence of fluorine 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 attached.[3 ] Some α-fluoro carbocations are sufficiently stabilized 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 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)methane/AlCl3 ,[15 ] tris(dichloromethyl)amine and oligoformylamine derivatives/super acids.[16 ] Of these methods, only Rieche formylation works well for both activated aromatic
and deactivated compounds.[17 ]
In continuation of our interest in developing methodologies for the installation of
the gem -difluoromethylene motif into structurally different organic molecules by using radical,
carbanion and cross-coupling methodologies[18 ] and the synthetic exploitation of the α-fluoro carbocation species 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, including
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 ] Inspired by these results, we envisaged difluoro(phenylsulfanyl)methane (1 ) as a synthetic equivalent of a formyl cation (Scheme [1 ]).
Scheme 1 Synthetic methodology
In an initial attempt and on the basis of our previously reported work,[20 ] difluoro(phenylsulfanyl)methane (PhSCF2 H, 1 )[21 ] was allowed to react with 1,2,4-trimethoxybenzene (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), aromatic 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; however, only SnCl4 exhibited superior results (Table [1 ], entries 2–5). No improvement was observed when SnCl4 was employed 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/H2 O (3:1 v/v) at room temperature for 2 hours, before conventional aqueous workup, the
aromatic aldehyde 4a was exclusively isolated in 75% yield after chromatographic purification (Table [1 ], entry 8).[22 ]
Table 1 Optimization of the Reaction Conditionsa
Entry
Lewis acidb (equiv)
Yield (%)c
3a
4a
5a
6a
1
SnCl4 (2)
40
36
6
–
2
AlCl3 (2)
6
7
23
–
3
TiCl4 (2)
25
20
24
3
4
Ti(Oi -Pr)4 (2)
–
–
–
–
5
TMSOTf (2)
–
–
–
–
6
SnCl4 (5)
42
37
6
–
7d
SnCl4 (2)
–
–
–
–
8e
SnCl4 (2)
–
75
–
–
9f
SnCl4 (2)
–
98
–
–
a Reaction conditions: 1 (1 equiv), 2a (0.5 mmol, 1 equiv), Lewis acid, CH2 Cl2 (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 added to a solution of the Lewis acid in CH2 Cl2 , 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/H2 O (3:1 v/v) and the resulting mixture was stirred at rt for 2 h, followed by aqueous
workup.
f 1 (1.5 equiv) was used, followed by workup identical to that of entry 8.
Analysis of the product mixture (Table [1 ], entries 1–3, 6) suggested 1 might be a limiting reagent, requiring 2 equivalents 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 oxidative 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 recovered and the difluoro(phenylsulfanyl)methane was consumed, giving diphenyl
disulfide and thiophenol as byproducts.
After the optimum reaction conditions were identified (Table [1 ], entry 9), the synthetic utility of the formylation reaction 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 moderate to excellent yields
of the corresponding aldehydes 4 . Activated 1,2,4-trimethoxybenzene and 1,3,5-trimethoxybenzene led to high yields
of products 4 (Table [2 ], entries 1 and 2); however, the reactions of less activated aromatic compounds,
namely 1,2,3-trimethoxybenzene and 1,3-dimethoxybenzene, resulted in good yields
(Table [2 ], entries 3 and 4). Low yields were observed when anisole and N ,N -diethylaniline were employed as the substrates (Table [2 ], entries 5 and 6).
Under the standard conditions, the reaction of methoxy-substituted naphthalene derivatives
also generally 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 position (4mb ).
Table 2 Reaction of Benzene Derivatives Using Difluoro(phenylsulfanyl)methane (1 ) as Formylating Agenta
Entry
R1
R2
R3
R4
R5
Yield (%) of 4
b
1
OMe
H
OMe
OMe
H
4a , 98
2
OMe
H
OMe
H
OMe
4b , 99
3
OMe
OMe
OMe
H
H
4c , 72
4
OMe
H
OMe
H
H
4d , 78
5
H
H
OMe
H
H
4e , 47
6
H
H
NEt2
H
H
4f , 42
a Reaction conditions : A solution of 1 (1.5 equiv) in CH2 Cl2 (1 mL) was added to a solution of SnCl4 (2 equiv) in CH2 Cl2 (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/H2 O (3:1 v/v), rt, 2 h, before conventional aqueous workup.
b Isolated yields after silica gel column chromatographic purification.
Figure 1 Reaction of naphthalene and indole derivatives using difluoro(phenylsulfanyl)methane
(1 ) as formylating agent. Reagents and conditions : A solution of 1 (1.5 equiv) in CH2 Cl2 (1 mL) was added to a solution of SnCl4 (2 equiv) in CH2 Cl2 (1 mL) followed by the addition of ArH (1 equiv) iin CH2 Cl2 (1 mL) at rt. The reaction was treated with IBX (1.5 equiv) in DMSO/H2 O (3:1 v/v), rt, 2 h, before conventional aqueous workup. In parentheses: isolated
yields after silica gel column chromatographic purification.
The synthetic utility of our developed method was further demonstrated by employing
this protocol for the installation of the formyl group onto activated aromatic compounds
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 electrophilic formylating reagents dichloro(methoxy)methane[17 ]
[23 ] and the Vilsmeier–Haack reagent (pyrophosphoryl 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). Unfortunately, under our standard conditions the reaction did
not proceed when the number of activating methoxy groups was decreased, for example
when employing methyl 4-methoxybenzoate or methyl benzoate as substrate.
Table 3 Formylation Reaction of Activated Aromatic Compounds Containing a Deactivating Ester
Substituenta
Entry
R1
R2
R3
R4
Method
Yield (%) of 8
b
1
OMe
OMe
OMe
H
A
8a , 95
2
H
OMe
OMe
H
A
8b , 85
3
OMe
OMe
OMe
Me
A
8c , 88
4
OMe
OMe
OMe
H
B
8a , 71
5
OMe
OMe
OMe
H
C
8a , 31
a Method A: PhSCF2 H (1 ; 1.5 equiv), SnCl4 (2 equiv), CH2 Cl2 , rt, 2 h; then IBX (1.5 equiv) in DMSO/H2 O (3:1 v/v), rt, 2 h, before aqueous workup; Method B: MeOCHCl2 (3 equiv), TiCl4 (0.1 M; 2 equiv), CH2 Cl2 , rt, 16 h; Method C: pyrophosphoryl chloride (1.7 equiv), DMF (1.5 equiv), CH2 Cl2 , rt, 16 h.
b Isolated yields after silica gel column chromatographic purification.
Scheme 2 Proposed reaction mechanism
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, 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 immediately 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. Subsequent trapping of 1c-cation with an aromatic compound yields 1d which undergoes hydrolysis during aqueous workup, providing the desired aldehyde
4 (path a). The proposed mechanism is analogous to the well-known Vilsmeier–Haack
and Rieche formylation reaction mechanisms 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 either 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 dimerization process is viable,
leading to a stable bis(phenylsulfanyl) 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 ]
Figure 2 Selected experimental and computational (in parentheses) 13 C and 1 H NMR chemical shifts for weighted average E /Z conformers of 1c-cation
The formation of an α-chloro thionium ion intermediate (1c-cation ) is analogous to the α-chloro oxonium and iminium ion intermediates proposed in the
Rieche and Vilsmeier–Haack reactions, respectively. Based on chemical reactivity and
the yields of the products, the proposed 1c-cation appears to be more reactive as the formylating species. To unequivocally provide
mechanistic evidence and insight into the active formylating species, 1c-cation was generated under anhydrous conditions in the absence of aromatic compound, and
was characterized by 1 H, 13 C and 19 F NMR spectroscopy. The reaction is remarkably clean, leading to a single species
with a characteristic deshielded 1 H NMR signal at δH 10.18 ppm and 13 C 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 1 H or 13 C NMR spectrum, suggesting fluorine is not attached to a carbon or with connectivity
to a proton. With limited literature for comparison on 19 F NMR shifts of tin(IV) fluoride/chloride complexes, we have tentatively assigned
this peak to a [Snn Fn+1 Cln+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 CH2 Cl2 ] were performed on an optimized structure [B3LYP/6-31G(d) in the gas phase] (see
the Supporting Information for computational details). Calculated 13 C and 1 H NMR chemical shifts were in good agreement with experimental values (R2 = 0.9798 for corrected 13 C NMR shifts) (Figure [2 ]).
In conclusion, we have described the reactivity of difluoro(phenylsulfanyl)methane
(1 ) towards Lewis acids through the formylation reaction of activated aromatic compounds.
Our finding is the first report on detailed spectroscopic and theoretical studies
for the utilization of difluoro(phenylsulfanyl)methane as a synthetic equivalent to
a formyl cation. A room-temperature stable α-chloro thionium 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 viable alternative method to the existing methods available
for formylation reactions.
All chemicals were obtained from commercial sources and used without further purification.
Anhydrous CH2 Cl2 was freshly distilled under argon from CaH2 . 1 H (500, 400 or 300 MHz) and 13 C (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 million (ppm) and coupling constants
(J ) in hertz (Hz). 19 F NMR spectra (376 MHz) were recorded on a Bruker AV-400 spectrometer, with CF3 Cl 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 chromatography on a Chromatotron was performed with Merck silica
gel 60 PF254 (Art. 7749). Preparative thin-layer chromatography (PTLC) was performed 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).
Reaction Optimization; General Procedure
Reaction Optimization; General Procedure
In a round-bottomed flask equipped with a stirring bar and rubber septum was placed
a Lewis acid in anhydrous CH2 Cl2 (1 mL). To this solution was added PhSCF2 H (1 ) in anhydrous CH2 Cl2 (1 mL), followed by a solution of 1,2,4-trimethoxybenzene (2a ; 0.5 mmol) in anhydrous CH2 Cl2 (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/H2 O (4 mL; 3:1 v:v). After 2 h of stirring at rt, the reaction mixture was quenched
by addition of a saturated 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 CH2 Cl2 (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 to provide
3a , 4a , 5a and 6a in various ratios and yields (Table [1 ]).
1-[Bis(phenylsulfanyl)methyl]-2,4,5-trimethoxybenzene (3a)
1-[Bis(phenylsulfanyl)methyl]-2,4,5-trimethoxybenzene (3a)
White solid (Et2 O/hexanes); mp 92.3–92.6 °C; Rf
= 0.32 (hexanes/EtOAc, 5:2).
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).
1 H NMR (500 MHz, CDCl3 ): δ = 7.37–7.34 (m, 4 H), 7.26–7.19 (m, 6 H), 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).
13 C 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 C22 H22 O3 S2 Na: 421.0908; found: 421.0910.
2,4,5-Trimethoxybenzaldehyde (4a)
2,4,5-Trimethoxybenzaldehyde (4a)
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).
1 H 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).
13 C 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 C10 H12 O4 Na: 219.0633; found: 219.0629.
(Phenylsulfanyl)bis(2,4,5-trimethoxyphenyl)methane (5a)
(Phenylsulfanyl)bis(2,4,5-trimethoxyphenyl)methane (5a)
White solid (EtOAc/hexanes); mp 92.3–92.7 °C; Rf
= 0.24 (hexanes/EtOAc, 2:1).
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).
1 H NMR (500 MHz, CDCl3 ): δ = 7.25–7.09 (m, 7 H), 6.50 (s, 2 H), 6.34 (s, 1 H), 3.86 (s, 6 H), 3.78 (s, 6
H), 3.76 (s, 6 H).
13 C 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).
HRMS (ESI-TOF): m /z [M + Na]+ calcd for C25 H28 O6 SNa: 479.1504; found: 479.1518.
Tris(2,4,5-trimethoxyphenyl)methane (6a)
Tris(2,4,5-trimethoxyphenyl)methane (6a)
White solid (EtOAc/hexanes); mp 184.3–185.2 °C; Rf
= 0.16 (hexanes/EtOAc, 5:2).
IR (KBr): 2940, 1605, 1521, 1428 cm–1 .
1 H 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).
13 C 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 C28 H34 O9 Na: 537.2101; found: 537.2182.
1 H, 13 C and 19 F NMR Characterization of Chloro(phenylsulfanyl)methylium Trichlorodifluorostannate(IV)
([1c-cation])
1 H, 13 C and 19 F NMR Characterization of Chloro(phenylsulfanyl)methylium Trichlorodifluorostannate(IV)
([1c-cation])
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 CH2 Cl2 (0.4 mL, 0.4 mmol). A solution of PhSCF2 H (1 ; 32 mg, 0.2 mmol) in CH2 Cl2 (0.2 mL) was added dropwise via syringe. Upon the addition of PhSCF2 H, 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 1 H, 13 C and 19 F NMR data were collected.
1 H NMR (400 MHz): δ = 10.18 (s, 1 H), 7.45–7.42 (br s, 5 H).
13 C NMR (100 MHz): δ = 200.2 (1 C), 133.8 (2 × CH), 131.0 (1 H), 130.0 (2 × CH), 123.9
(1 C).
19 F NMR (376 MHz): δ = –162.19.
Aldehydes 4 and 8; General Procedure
Aldehydes 4 and 8; General Procedure
In a round-bottomed flask equipped with a stirring bar and rubber septum was placed
a 1 M solution of SnCl4 in anhydrous CH2 Cl2 (1 mL, 1 mmol). To this solution was added PhSCF2 H (1 ; 240.2 mg, 1.5 mmol) in anhydrous CH2 Cl2 (1.5 mL), followed by a solution of an aromatic compound (0.5 mmol) in anhydrous
CH2 Cl2 (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/H2 O (4 mL; 3:1 v:v). After 2 h of stirring at rt, the reaction mixture was quenched
by addition of a saturated 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 CH2 Cl2 (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.
2,4,6-Trimethoxybenzaldehyde (4b)
2,4,6-Trimethoxybenzaldehyde (4b)
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, 1025 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 10.36 (s, 1 H), 6.09 (s, 2 H), 3.89 (s, 9 H).
13 C NMR (75 MHz, CDCl3 ): δ = 187.6 (CO), 166.2 (C), 164.1 (2 × C), 108.9 (C), 90.3 (2 × CH), 56.0 (2 × CH3 ), 55.5 (CH3 ).
HRMS (ESI-TOF): m /z [M + Na]+ calcd for C10 H12 O4 Na: 219.0633; found: 219.0627.
2,3,4-Trimethoxybenzaldehyde (4c)
2,3,4-Trimethoxybenzaldehyde (4c)
White solid (70.63 mg, 72%) from EtOAc/hexanes; mp 38–41 °C; Rf
= 0.38 (hexanes/EtOAc, 5:2).
IR (neat): 2944, 2844, 1682 (C=O), 1590, 1291 (Ar–O–C), 1204 (Ar–O–C), 1093 cm–1 (Ar–O–C).
1 H 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).
13 C 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 ).
HRMS (ESI-TOF): m /z [M + Na]+ calcd for C10 H12 O4 Na: 219.0633; found: 219.0635.
2,4-Dimethoxybenzaldehyde (4d)
2,4-Dimethoxybenzaldehyde (4d)
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).
1 H 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).
13 C 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 ).
HRMS (ESI-TOF): m /z [M + Na]+ calcd for C9 H10 O3 Na: 189.0528; found: 189.0549.
4-Methoxybenzaldehyde (4e)
4-Methoxybenzaldehyde (4e)
Colorless liquid (31.99 mg, 47%); Rf
= 0.38 (hexanes/EtOAc, 5:1).
IR (neat): 2937, 2841, 1682 (C=O), 1599, 1577, 1160, 1024, 833 cm–1 .
1 H 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).
13 C 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 C8 H8 O2 Na: 159.0422; found: 159.0464.
4-(Diethylamino)benzaldehyde (4f)
4-(Diethylamino)benzaldehyde (4f)
White solid (37.22 mg, 42%) from EtOAc/hexanes; mp 38–41 °C; Rf
= 0.33 (hexanes/EtOAc, 5:0.5).
IR (neat): 2974, 2929, 2731, 1667 (C=O), 1595, 1527, 1408, 1274, 1173, 1156 cm–1 .
1 H 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).
13 C 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 C11 H15 NONa: 200.1051; found: 200.1053.
2-Methoxy-1-naphthaldehyde (4g)
2-Methoxy-1-naphthaldehyde (4g)
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 .
1 H 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).
13 C 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 + H]+ calcd for C12 H11 O2 : 187.0759; found: 187.0734.
1-Methoxy-2-naphthaldehyde (4h)
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 (KBr): 3079, 3011, 2941, 2847, 1682 (C=O), 1574, 1513, 1430, 1251, 1220, 1095,
1060, 816, 765 cm–1 .
1 H 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).
13 C 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 + H]+ calcd for C12 H11 O2 : 187.0759; found: 187.0732.
1,6-Dimethoxy-2-naphthaldehyde (4i)
1,6-Dimethoxy-2-naphthaldehyde (4i)
White solid (69.19 mg, 64%) from EtOAc/hexanes; mp 94–95 °C; Rf
= 0.38 (hexanes/EtOAc, 5:1).
IR (Nujol mull): 2924, 2854, 1673 (C=O), 1581, 1455, 1237, 1207, 1055, 803, 650 cm–1 .
1 H 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).
13 C 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 C13 H12 O3 Na: 239.0684; found: 239.0664.
2,6-Dimethoxy-1-naphthaldehyde (4j)
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).
IR (KBr): 3091, 2969, 2885, 1663 (C=O), 1515, 1372, 1240, 1170, 1061, 844, 817 cm–1 .
1 H 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).
13 C 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 ).
HRMS (ESI-TOF): m /z [M + Na]+ calcd for C13 H12 O3 Na: 239.0684; found: 239.0656.
2,7-Dimethoxy-1-naphthaldehyde (4k)
2,7-Dimethoxy-1-naphthaldehyde (4k)
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 .
1 H 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).
13 C 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 ).
HRMS (ESI-TOF): m /z [M + Na]+ calcd for C13 H12 O3 Na: 239.0684; found: 239.0638.
1-Methyl-1H -indole-3-carbaldehyde (4l)
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).
IR (neat): 3107, 2806, 1651 (C=O), 1537, 1075, 787, 747 cm–1 .
1 H 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).
13 C 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 ).
HRMS (ESI-TOF): m /z [M + Na]+ calcd for C10 H9 NONa: 182.0582; found: 182.0544.
2,3-Dimethoxy-1-naphthaldehyde (4ma)
2,3-Dimethoxy-1-naphthaldehyde (4ma)
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, 1239, 1054,
873, 796 cm–1 .
1 H 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).
13 C 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 C13 H12 O3 Na: 239.0684; found: 239.0619.
6,7-Dimethoxy-2-naphthaldehyde (4mb)
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 .
1 H 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).
13 C 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 ).
HRMS (ESI-TOF): m /z [M + Na]+ calcd for C13 H12 O3 Na: 239.0684; found: 239.0668.
Methyl 2-Formyl-3,4,5-trimethoxybenzoate (8a)
Methyl 2-Formyl-3,4,5-trimethoxybenzoate (8a)
Pale yellow oil (120.76 mg, 95%); Rf
= 0.41 (hexanes/EtOAc, 5:2).
IR (neat): 2935, 1758, 1455, 1108, 655 cm–1 .
1 H 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).
13 C 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 C12 H14 O6 Na: 277.0688; found: 277.0664. NMR data of 8a are in agreement with those previously reported.[17 ]
Methyl 2-Formyl-4,5-dimethoxybenzoate (8b)
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 .
1 H 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).
13 C 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 C11 H12 O5 : 224.0685; found: 224.0672.
Methyl 2-Formyl-3,4,5-trimethoxy-6-methylbenzoate (8c)
Methyl 2-Formyl-3,4,5-trimethoxy-6-methylbenzoate (8c)
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 .
1 H 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).
13 C 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 ).
HRMS (ESI-TOF): m /z [M + Na]+ calcd for C13 H16 O6 Na: 291.0844; found: 291.0729.