Vilsmeier-Haack reagent-promoted formyloxylation of α-chloro-N-arylacetamides by formamide

Article abstract of DOI:10.1039/c5ra05779e

In this study, a Vilsmeier-Haack reagent-promoted formyloxylation of α-chloro-N-arylacetamides by formamide was developed. The reaction successfully provided the desired α-formyloxy-N-arylacetamides 4 and 7a-n in moderate to excellent yields (70-96%) by use of 3.0 equivalents of PBr₃ at 80-90 °C and was applicable to substrates bearing electron-donating or withdrawing groups at the aryl moiety. For α-chloro-N-(naphthalenyl)acetamide (8a), α-chloro-N-(quinolin-8-yl)acetamide (8b), and α-chloro-N-(thiazol-2-yl)acetamide (8c) possessing the α-chloro group, the reaction also provided the desired formyloxylated products 9a-c in 70-87% yields. A plausible mechanism was proposed through the activation of α-chloroacetamide by the Vilsmeier-Haack reagent to account for the new transformation.

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DOI: 10.1039/C5RA05779E
Vilsmeier–Haack
reagent-promoted
formyloxylation
of
α-chloro-N-arylacetamides by formamide
Jiann-Jyh Huang,a,b Shi-Han Lu,c Yu Hsuan Chung,a,b and Fung Fuh Wong*c
aDepartment of Applied Chemistry, National Chiayi University, No. 300, Syuefu Rd.,
Chiayi City 60004, Taiwan
bCenter of Energy Research & Sensor Technology, National Chiayi University, No.
300, Syuefu Rd., Chiayi City 60004, Taiwan
cSchool of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung
40402, Taiwan
*Corresponding Author. Tel.: +886 4 2205 3366 ext. 5603; Fax: +886 4 2207 8083.
E-mail address: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw (F. F.
Wong)
Keywords: Vilsmeier–Haack reagent, formyloxylation, formate ester, formamide,
phosphorous bromide, α-formyloxy-N-arylacetamide
Abstract
In this study, a Vilsmeier–Haack reagent-promoted formyloxylation of
α-chloro-N-arylacetamides by formamide was developed. The reaction successfully
provided the desired α-formyloxy-N-arylacetamides 4 and 7a–n in moderate to
excellent yields (70–96%) by use of 3.0 equivalents of PBr3 at 80–90 C and was
applicable to substrates bearing electron-donating or withdrawing groups at the aryl
moiety.
For
α-chloro-N-(naphthalenyl)acetamide
(8a),
α-chloro-N-(quinolin-8-yl)acetamide (8b), and α-chloro-N-(thiazol-2-yl)acetamide (8c)
possessing the α-chloro group, the reaction also provided the desired formyloxylated
products 9a–c in 70–87% yields. A plausible mechanism was proposed through the
activation of α-chloroacetamide by Vilsmeier–Haack reagent to account for the new
transformation.
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DOI: 10.1039/C5RA05779E
Introduction
In organic synthesis, formyloxylation reaction can be used to synthesize
compounds with a protected hydroxyl group1 from the corresponding alkyl halides.
Use of a formate anion as the nucleophile is the conventional way to generate the
desired formyloxylated product and is applicable to various substrates.2 An alternative
method is the use of amides like formamide and DMF as the formyloxy precursors
through O-alkylation. Reaction of simple non-activated alkyl halides with formamide
is reported to provide the corresponding formate ester at 140 C.3 If the substrates are
activated, formyloxylation reaction can take place at lower temperature. For example,
Dakanali et. al reported the formyloxylation of 2-bromoethylamines by DMF at 80 C
through the participation of neighboring group,4 Abad et. al reported the use of silver
salt as the catalyst to furnish the reaction at r.t. to 75 C,5 and Thirumamagal et. al
reported the CuCN-mediated O-alkylation of DMF at room temperature.6
α-Formyloxy carbonyl compounds are important intermediates7 for the
construction
of
various
heterocyclic
compounds
such
as
imidazopyrimidine-2,7-diones8 and oxazoles.9 α-Haloketones are also reported
formyloxylated by formamides in the presence of copper catalyst10 or Silphos agent
[PCl3–n(SiO2)n].11 However, the scopes of the reactions are limited, no other
α-halocarbonyl compound including amides and esters is reported. In our
development of Vilsmeier–Haack reagent for the synthesis of heterocyclic compounds
and performing functional group transformations,12 we serendipitously found that the
reagent was possible to active the α-halo group in the amide functionality toward
nucleophilic substitution. In this study, we reported the formyloxylation of
α-halo-N-arylacetamides by formamide promoted by Vilsmeier–Haack reagent. The
reaction successfully provided the corresponding α-formyloxylated amide in moderate
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to excellent yields. The reaction displayed the optimal results on α-chloroacetamides
and was applicable to substrates with various substituents on the aryl group.
Result and discussion
To seek the optimal reaction conditions for the formyloxylation of
α-halo-N-arylacetamides promoted by Vilsmeier–Haack reagent, compounds 1–313
bearing α-chloro, bromo, and iodo groups served as the model substrates to react with
formamide in the presence PBr3 at 80–90 C (Table 1). For compound 1 bearing the
α-chloro group, the reaction did not take place without PBr3, even in prolonged
reaction time (64 h, see entry 1 in Table 1). When 0.20 equivalents of PBr3 were used,
the desired α-formyloxylated compound 4 was isolated in 10% yield (entry 2).
Reaction of 1 with formamide in the presence of 0.50 equivalents of PBr3 for 4.0 h
gave the desired 4 in 53% yield (entry 3). Employing 1.0, 2.0 and 3.0 equivalents of
PBr3 to the reaction increased the yields of 4 to 84, 88, and 96%, respectively (entries
4–6). In these cases, a trace amount of hydrolyzed product 5 was observed.
Prolongation of the reaction time to 8.0 h (data not shown) and the use of excess PBr3
(10 equiv, entry 7) reduced the yield of 4. As a result, reaction of
α-halo-N-arylacetamides with formamide in the presence 3.0 equivalents of PBr3 at
80–90 C was chosen as the optimal reaction conditions for the following study.
Table 1
When N-phenylacetamide 2 possessing an α-bromo group served as the starting
material, the reaction gave the desired 4 in lower yield (73%, entry 8 in Table 1)
compared to that of 1 bearing an α-chloro group (96%, entry 6). Unlike the use of 1
that the major substance in the reaction other 4 was the un-reacted 1 (entries 1–4), the
major by-product was aniline resulted from the cleavage of C–N bond when 2 was
used. Use of compound 3 possessing an α-iodo group as the starting material
worsened the reaction, only provided the desired 4 in 9.0% yield and aniline had
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become the major product. To realize the different results from the use of
N-arylacetamides bearing different α-halo atoms, we reacted 2 and 3 with formamide
without PBr3 (entry 10 and 11). The reactions only provided aniline as the major
product and no desired 4 could be isolated. Use of 0.50 equivalents of PBr3 to 2 and 3
slightly improved the reaction, giving trace amounts of the desired 4 (entries 12 and
13). The results hinted the feasibility for the cleavage of C–N decreased in the order I
> Br >> Cl in the reaction, and the cleavage was inhibited by PBr3. Consequently,
α-halo-N-arylacetamides bearing α-chloro group is the suitable substrate for the
Vilsmeier–Haack reagent-promoted α-formyloxylation reaction.
We then turned to study the reactivity of various formamides as the formyloxy
source. Employing the optimal reaction conditions to 1 with N-substituted
formamides
including
N-methylformamide,
N-tert-butylformamide,
N,N-dimethylformamide, N,N-diisopropylformamide, pyrrolidine-1-carbaldehyde, and
piperidine-1-carbaldehyde provided the desired α-formyloxylated compound 4 in
18–64% yields (Table 2). The yields for the use of these substituted formamides were
lower than that for the use of unsubstituted formamide. As a result, formamide is the
best
formyloxy
source
for
the
α-formyloxylation
reaction
of
α-chloro-N-arylacetamides promoted by Vilsmeier–Haack reagent.
Table 2
To explore the scope of the new formyloxylation reaction,
α-chloro-N-arylacetamides 6a–n bearing various substituents, including fluoro, bromo,
trifluoromethyl, methyl, hydroxyl, methoxy, and cyano groups at the ortho, meta, or
para position of the phenyl group were reacted with formamide in the presence of 3.0
equivalents of PBr3 at 80–90 C for 4.0 h (Table 3). The reaction successfully
provided the desired α-formyloxylated products 7a–n in 70–91% yields. In these
reactions, compounds 6c, 6f, 6i, and 6l with a para substituent demonstrated better
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yields than their ortho and meta analogs. For compounds 6n beariDnOgI: 10tw.10o39/C5RA05779E
electron-donating methoxy groups, the reaction also gave the desired 7n in 76% yield.
No formyl group was introduced to the π-excessive aryl moiety in this reaction. The
results indicated that the new Vilsmeier–Haack reagent-promoted formyloxylation
reaction is tolerable in substrates with these substituents at the phenyl group. All the
α-formyloxy-N-arylacetamides 7a–n were fully characterized by spectroscopic
methods. For example, compound 7m presented a singlet peak at δ 4.79 ppm for
1
methylene group and 8.20 ppm for HC=O in H NMR. In 13C NMR spectrum,
compound 7m possessed characteristic absorptions at δ 164.57 ppm for H13C=O, at δ
158.67 ppm for NH13C=O, and at δ 62.26 ppm for –13CH2C=O. Its IR absorptions
showed peaks at 1701 cm–1 for the stretching of –NHC=O group, 1732 cm–1 for the
stretching of HC=O group, 2226 cm–1 for the stretching of–C N group, and at 3294
cm–1 for the stretching of the –NH group. Compound 7m was further characterized by
X-ray crystallography as shown in Figure 1.
Table 3
Figure 1
This
new
α-formyloxylation
reaction
was
also
applicable
to
α-chloro-N-(naphthalenyl)acetamide (8a), α-chloro-N-(quinolin-8-yl)acetamide (8b),
and α-chloro-N-(thiazol-2-yl)acetamide (8c) as shown in Scheme 1. The reaction
provided the corresponding α-formyloxylated products 9a, 9b, and 9c in 86%, 87%,
and 71% yields, respectively. Compounds 9a–c were also fully characterized by
spectroscopic methods. However, the α-formyloxylation reaction was limited to
N-aryl substrates. Reaction of 2-chloro-N-hexylacetamide (10) with formamide in the
presence of PBr3 did not provide the corresponding α-formyloxylated product 11 and
the starting material was recovered.
Scheme 1
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Scheme 2
We proposed a plausible reaction mechanism in Scheme 3 for the
formyloxylation of α-halo-N-arylacetamides using compound 1 as the example. As the
solvent, formamide would preferentially react with PBr3 to form the bromoiminium
12 (Vilsmeier–Haack reagent) upon heating. Reactive species 12 would acylate 1 to
generate O-acylated intermediate 13 (X = OCHN+H2, Y = N) or bromoiminium
intermediate 14 (X = Br, Y = N+H). Species 13 and 14 might exist for the conjugation
of their C=N double bond with the phenyl group would enhance the stability. For
N-alkyl amide 10 in Scheme 2, the C=N would not form or form in little extent than
its analog 1 for being not energetically favored. As a result, the C=N bond in N-aryl
substrate might be important to progress the reaction.
It is known that the carbonyl group accelerates the SN2 reaction at it α-carbon14
through the interaction of its π LUMO with the transition state.15 As a result, the
displacement of the α-halo group in simple α-halocarbonyl compounds proceeds
readily despite formamides are weak nucleophiles. In our case, however, the amide
group was more electron-rich than carbonyl group and thus has high-lying π LUMO
that provided less stabilization energy. The reaction did not take place even in
prolonged reaction time (see entry 1 in Table 1). Intermediates 13 and 14 are more
electron-withdrawing than the amide functionality in 1, thus had lower-lying π LUMO
that could stabilize the transition state of the SN2 reaction.16 The formyloxylation
reaction took place smoothly to provide intermediates 15 and 16. Subsequent
hydrolysis of 15 and 16 provided the desired α-formyloxylated product 4 and
by-product 5 to furnish the reaction.
Scheme 3
Conclusions
We have successfully developed a Vilsmeier–Haack reagent-promoted
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formyloxylation reaction for α-chloro-N-arylacetamides with formamide. The DreOaI:c10ti.1o0n39/C5RA05779E
gave the corresponding α-formyloxylated products in good to excellent yields
(70–96%). Substituents including fluoro, bromo, trifluormethyl, methyl, hydroxyl,
methoxy, and cyano groups are tolerable in the reaction. A plausible reaction
mechanism involving the formation of reactive iminium intermediates was proposed
to account the enhanced reactivity.
Experimental Section
All chemicals were reagent grade and used as purchased. All reactions were carried
out under argon or nitrogen atmosphere and monitored by TLC. Flash column
chromatography was carried out on silica gel (230–400 mesh). Analytical thin-layer
chromatography (TLC) was performed on precoated plates (silica gel 60 F-254)
purchased from Merck Inc. Mixtures of ethyl acetate and hexanes were used as
eluants. Infrared (IR) spectra were measured on a Bomem Michelson Series FT-IR
spectrometer. The wavenumbers reported are referenced to the polystyrene absorption
at 1601 cm–1. Absorption intensities are recorded by the following abbreviations: s,
strong; m, medium; w, weak. Proton NMR spectra were obtained on a Bruker (200
MHz or 500 MHz) spectrometer by use of CDCl3 as solvent. Multiplicities are
recorded by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; J, coupling constant (Hz). Carbon-13 NMR spectra were obtained on a
Bruker (50 MHz or 125 MHz) spectrometer by used of CDCl3 as solvent. Carbon-13
chemical shifts are referenced to the center of the CDCl3 triplet (δ 77.0 ppm).
High-resolution mass spectra were obtained from a JEOL JMS-HX110 mass
spectrometer.
General procedure for the formyloxylation of α-chloro-N-arylacetamides 1, 6a–n,
8a, 8b, and 8c with formamide in the presence of PBr3. α-Chloro-N-arylacetamides
1, 6a–n, 8a, 8b, and 8c (~1.0 mmol, 1.0 equiv) were dissolved in formamide (2.0 mL)
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and added with PBr3 (3.0 equiv). The reaction mixture was heated at 80–90 C for 4.0
h. The solution was added with saturate aqueous NaHCO3 (15 mL) and extracted with
CH2Cl2 (15 mL × 2). The combined organic layers were washed with saturated
aqueous NaHCO3 (15 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel to
give the corresponding α-formyloxylated products 4, 7a–n, 9a, and 9c in 70–96%
yields.
1
2-Oxo-2-(phenylamino)ethyl formate (4). Yield: 96%; yellow liquid; H NMR
(CDCl3, 200 MHz) δ 4.72 (s, 2 H, CH2), 7.11–7.15 (m, 1 H, ArH), 7.25–7.33 (dd, J =
8.2, 7.8 Hz, 2 H, ArH), 7.51 (d, J = 8.2 Hz, 2 H, ArH), 8.02 (br, 1 H, NH), 8.14 (s, 1 H,
O=C–H); 13C NMR (CDCl3, 50 MHz) δ 62.36, 120.19, 125.15, 129.16, 137.04,
158.80 (NC=O), 164.11 (HC=O); IR (KBr) 3298 (br, NH), 3061, 1730 (s, C=O), 1680
(s, C=O), 1163, 759 cm–1; EIMS m/z 179 (M+, 43), 120 (17), 93 (100), 92 (17), 77
(24), 65 (20), 51 (6); HRMS Calcd for C9H9NO3: 179.0582; Found: 179.0583.
2-[(2-Fluorophenyl)amino]-2-oxoethyl formate (7a). Yield: 74%; white solids; mp
43–45 °C; 1H NMR (CDCl3, 200 MHz) δ 4.79 (s, 2 H, CH2), 7.06–7.14 (m, 4 H, ArH),
8.20 (s, 1 H, O=C–H), 8.29 (br, 1 H, NH); 13C NMR (CDCl3, 50 MHz) δ 62.31,
114.81, 115.18, 121.91, 124.75, 125.20, 125.33, 150.88, 154.97, 158.87 (NC=O),
164.29 (HC=O); IR (KBr) 3275 (br, NH), 1732 (s, C=O), 1685 (s, C=O), 1458, 1161
(C–O), 756 cm–1; EIMS m/z 197 (M+, 26), 111 (100), 83 (15), 110 (10), 57 (5);
HRMS Calcd for C9H8FNO3: 197.0488; Found: 197.0490.
2-[(3-Fluorophenyl)amino]-2-oxoethyl formate (7b). Yield: 84%; white solids; mp
46–48 °C; 1H NMR (CDCl3, 200 MHz) δ 4.75 (s, 2 H, CH2), 6.82–6.86 (m, 1 H, ArH),
7.13–7.28 (m, 2 H, ArH), 7.44 (dd, J = 10.7, 3.5 Hz, 1 H, ArH), 8.02 (br, 1 H, NH),
13
8.17 (s, 1 H, O=C–H); C NMR (CDCl3, 50 MHz) δ 62.17, 107.44, 107.96, 111.64,
112.06, 115.40, 130.13, 130.31, 137.89, 138.10, 158.94 (NC=O), 160.41, 164.46
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(HC=O), 165.29; IR (KBr) 3290 (br, NH), 1732 (s, C=O), 1681 (s, C=O), 1543, 1157
(C–O), 775 cm–1; EIMS m/z 197 (M+, 40), 138 (12), 111 (100), 110 (16), 95 (16), 84
(11), 83 (19), 57 (8); HRMS Calcd for C9H8FNO3: 197.0488; Found: 197.0485.
2-[(4-Fluorophenyl)amino]-2-oxoethyl formate (7c). Yield: 88%; white solids; mp
49–51 °C; 1H NMR (CDCl3, 200 MHz) δ 4.76 (s, 2 H, CH2), 6.98–7.06 (m, 2 H, ArH),
7.24–7.81 (m, 2 H, ArH), 7.81 (br, 1 H, NH), 8.19 (s, 1 H, O=C–H); 13C NMR (CDCl3,
125 MHz) δ 62.31, 115.80, 115.98, 122.06, 122.12, 132.51, 158.75, 158.89 (NC=O),
160.58, 164.16 (HC=O); IR (KBr) 3336 (br, NH), 2924, 1735 (s, C=O), 1681 (s,
C=O), 1512, 1157 (C–O) cm–1; EIMS m/z 197 (M+, 40), 138 (12), 111 (100), 110 (16),
95 (16), 84 (11), 83 (19), 57 (8); HRMS Calcd for C9H8FNO3: 197.0488; Found:
197.0492.
2-[(2-Bromophenyl)amino]-2-oxoethyl formate (7d). Yield: 71%; white solids; mp
49–52 °C; 1H NMR (CDCl3, 200 MHz) δ 4.80 (s, 2 H, CH2), 6.99 (dd, J = 7.8, 7.2 Hz,
1 H, ArH), 7.30 (dd, J = 7.8, 7.2 Hz, 1 H, ArH), 7.53 (dd, J = 7.7, 6.0 Hz, 1 H, ArH),
13
8.22 (s, 1 H, O=C–H), 8.32 (dd, J = 7.7, 6.0 Hz, 1 H, ArH), 8.43 (br, 1 H, NH); C
NMR (CDCl3, 50 MHz) δ 62.30, 113.60, 121.84, 125.89, 128.49, 132.32, 134.49,
158.76 (NC=O), 164.25 (HC=O); IR (KBr) 3375 (br, NH), 1735 (s, C=O), 1531 (s,
C=O), 1438, 1157 (C–O), 582 cm–1; EIMS m/z 259 (M+ + 2, 13), 257 (M+, 13), 173
(57), 171 (59); HRMS Calcd for C9H8BrNO3: 256.9688; Found: 256.9686.
1
2-[(3-Bromophenyl)amino]-2-oxoethyl formate (7e). Yield: 78%; yellow liquid; H
NMR (CDCl3, 200 MHz) δ 4.75 (s, 2 H, CH2), 7.13–7.29 (m, 1 H, ArH), 7.41 (dd, J =
9.8, 7.5 Hz, 2 H, ArH), 7.77 (s, 1 H, ArH), 8.17 (s, 1 H, O=C–H); 13C NMR (CDCl3,
50 MHz) δ 62.21, 118.59, 122.67, 123.06, 128.12, 130.41, 137.72, 158.81 (NC=O),
164.33 (HC=O); IR (KBr) 3305 (br, NH), 1732 (s, C=O), 1682 (s, C=O), 1423, 1161
(C–O), 590 cm–1; EIMS m/z 259 (M+ + 2, 8), 257 (M+, 8), 231 (57), 229 (58), 200
(20), 198 (20), 173 (92), 171 (100); HRMS Calcd for C9H8BrNO3: 256.9688; Found:
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256.9686.
2-[(4-Bromophenyl)amino]-2-oxoethyl formate (7f). Yield: 89%; white solids; mp
47–50 °C; 1H NMR (CDCl3, 200 MHz) δ 4.73 (s, 2 H, CH2), 7.37–7.44 (m, 4 H, ArH),
8.03 (br, 1 H, NH) 8.15 (s, 1 H, O=C–H); 13C NMR (CDCl3, 50 MHz) δ 62.14, 117.76,
121.71 (2 × CH), 132.04 (2 × CH), 135.57, 158.95 (NC=O), 164.38 (HC=O); IR (KBr)
3433 (br, NH), 1732 (s, C=O), 1689 (s, C=O), 1261, 1161 (C–O), 574 cm–1; EIMS
m/z 259 (M+ + 2, 16), 257 (M+, 16), 191 (100), 178 (25) , 173 (33), 171 (33), 152 (11),
91 (17); HRMS Calcd for C9H8BrNO3: 256.9688; Found: 256.9683.
2-Oxo-2-{[2-(trifluoromethyl)phenyl]amino}ethyl formate (7g). Yield: 70%; white
solids; mp 47–49 °C; 1H NMR (CDCl3, 200 MHz) δ 4.80 (s, 2 H, CH2), 7.23–7.26 (m,
1 H, ArH), 7.57–7.63 (m, 2 H, ArH), 8.19 (s, 1 H, O=C–H), 8.20–8.24 (m, 1 H, ArH),
8.25 (br, 1 H, NH); 13C NMR (CDCl3, 50 MHz) δ 62.19, 119.98, 120.20, 120.58,
120.87, 121.20, 124.08, 125.14, 126.27, 126.63, 133.08, 133.93, 158.62 (NC=O),
164.57 (HC=O); IR (KBr) 3433 (br, NH), 1712 (s, C=O), 1670 (s, C=O), 1319, 1114
(C–O), 767 cm–1; EIMS m/z 247 (M+, 32), 168 (41), 161 (100), 141 (32), 114 (11);
HRMS Calcd for C10H8F3NO3:247.0456; Found: 247.0452.
2-Oxo-2-{[3-(trifluoromethyl)phenyl]amino}ethyl formate (7h). Yield: 78%;
1
yellow liquid; H NMR (CDCl3, 200 MHz) δ 4.79 (s, 2 H, CH2), 7.38–7.52 (m, 2 H,
ArH), 7.78–7.84 (m, 2 H, ArH), 7.98 (br, 1 H, NH); 8.20 (s, 1 H, O=C–H); 13C NMR
(CDCl3, 50 MHz) δ 62.20, 116.79, 116.86, 121.63, 121.70, 123.18, 129.73, 130.73,
131.53, 131.82, 132.58, 132.83, 137.04, 158.78 (NC=O), 164.50 (HC=O); IR (KBr)
3425 (br, NH), 1728 (s, C=O), 1689 (s, C=O), 1161 (C–O), 1122, 698 cm–1; EIMS
m/z 247 (M+, 32), 161 (100), 160 (13), 145 (15), 87 (22), 55 (37), 54 (15); HRMS
Calcd for C10H8F3NO3: 247.0456; Found: 247.0455.
2-Oxo-2-{[4-(trifluoromethyl)phenyl]amino}ethyl formate (7i). Yield: 91%; white
1
solids; mp 50–52 °C; H NMR (CDCl3, 500 MHz) δ 4.79 (s, 2 H, CH2), 7.59 (d, J =
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13
8.5 Hz, 2 H, ArH), 7.67 (d, J = 8.5 Hz, 2 H, ArH), 8.20 (s, 1 H, O=C–H); C NMR
(CDCl3, 125 MHz) δ 62.32, 119.77 (2 × CH + CH), 121.43, 122.27, 122.63, 123.83,
123.07, 126.43, 126.46, 139.60, 158.67 (NC=O), 164.44 (HC=O); IR (KBr) 3441 (br,
NH), 1743 (s, C=O), 1678 (s, C=O), 1539, 1165 (C–O), 740 cm–1; EIMS m/z 247 (M+,
34), 161 (100), 145 (21), 142 (12), 111 (7), 87 (13); HRMS Calcd for C10H8F3NO3:
247.0456; Found: 247.0461.
2-Oxo-2-(p-tolylamino)ethyl formate (7j). Yield: 89%; white solids; mp 39–41 °C;
1H NMR (CDCl3, 200 MHz) δ 2.30 (s, 3 H, CH3), 4.75 (s, 2 H, CH2), 7.13 (d, J = 8.3
Hz, 2 H, ArH), 7.40 (d, J = 8.3 Hz, 2 H, ArH), 7.77 (br, 1 H, NH), 8.18 (s, 1 H,
O=C–H); 13C NMR (CDCl3, 50 MHz) δ 20.88, 62.30, 119.87, 120.30 (2 × CH),
129.62 (2 × CH), 134.92, 158.89 (NC=O), 164.14 (HC=O); IR (KBr) 3429 (br, NH),
1732 (s, C=O), 1678 (s, C=O), 1265, 1165 (C–O) cm–1; EIMS m/z 193 (M+, 26), 165
(18), 134 (12), 107 (100), 106 (76), 91 (23), 77 (39), 65 (18); HRMS Calcd for
C10H11NO3: 193.0739; Found: 193.0735.
2-[(4-Hydroxyphenyl)amino]-2-oxoethyl formate (7k). Yield: 87%; yellow liquid;
1H NMR (CDCl3, 200 MHz) δ 4.77 (s, 2 H, CH2), 7.09 (d, J = 8.8 Hz, 2 H, ArH), 7.55
(d, J = 8.8 Hz, 2 H, ArH), 7.84 (br, 1 H, NH), 8.19 (s, 1 H, O=C–H), 8.27 (s, 1 H, OH);
13C NMR (CDCl3, 50 MHz) δ 62.29, 121.33 (2 × CH), 121.85 (2 × CH), 134.64,
158.77 (NC=O), 159.12, 164.22 (HC=O); IR (KBr) 3348.42 (br, NH + OH), 2920,
1728 (s, C=O), 1689 (s, C=O), 1192, 1165 (C–O) cm–1; EIMS m/z 195 (M+, 40), 109
(100), 108 (33), 81 (11); HRMS Calcd for C9H9NO4: 195.0532; Found: 195.0531.
2-[(4-Methoxyphenyl)amino]-2-oxoethyl formate (7l). Yield: 91%; brown solids;
1
mp 47–48 °C; H NMR (CDCl3, 200 MHz) δ 3.77 (s, 3 H, CH3), 4.75 (s, 2 H, CH2),
6.86 (d, J = 9.0 Hz, 2 H, ArH), 7.42 (d, J = 9.0 Hz, 2 H, ArH), 7.78 (br, 1 H, NH),
8.18 (s, 1 H, O=C–H); 13C NMR (CDCl3, 125 MHz) δ 55.47, 62.33, 114.28 (2 × CH),
122.11 (2 × CH), 129.50, 157.00, 158.85 (NC=O), 164.04 (HC=O); IR (KBr) 3309 (br,
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–1
+
NH), 1734 (s, C=O), 1668 (s, C=O), 1247, 1149 (C–O), 835 cm ; EIMS m/z 209 (M ,
64), 123 (49), 122 (35), 113 (24), 108 (29), 91 (100), 77 (20); HRMS Calcd for
C10H11NO4:209.0688; Found: 209.0687.
2-[(4-Cyanophenyl)amino]-2-oxoethyl formate (7m). Yield: 87%; white solids; mp
50–52 °C; 1H NMR (CDCl3, 200MHz) δ 4.79 (s, 2 H, CH2), 7.62 (d, J = 9.0 Hz, 2 H,
ArH), 7.70 (d, J = 9.0 Hz, 2 H, ArH), 8.04 (br, 1 H, NH), 8.20 (s, 1 H, O=C–H); 13C
NMR (CDCl3, 50 MHz) δ 62.26, 108.15, 118.52, 119.93 (2 × CH), 133.40 (2 × CH),
140.55, 158.67 (NC=O), 164.57 (HC=O); IR (KBr) 3294 (br, NH), 2225 (s, CN) 1732
(s, C=O), 1701 (s, C=O), 1315, 1161 (C–O) cm–1; EIMS m/z 204 (M+, 28), 119 (12),
118 (100), 117 (14), 91 (16), 90 (17); HRMS Calcd for C10H8N2O3: 204.0535; Found:
204.0537.
2-[(2,5-Dimethoxyphenyl)amino]-2-oxoethyl formate (7n). Yield: 76%; white
liquid; 1H NMR (CDCl3, 400 MHz) δ 3.72 (s, 3 H, CH3), 3.80 (s, 3 H, CH3), 4.73 (s, 2
H, CH2), 6.56 (dd, J = 11.6, 8.8 Hz, 1 H, ArH), 6.76 (d, J = 9.2 Hz, 1 H), 8.02 (d, J =
2.8 Hz, 1 H, ArH), 8.17 (s, 1 H, O=C–H), 8.43 (br, 1 H, NH); 13C NMR (CDCl3, 100
MHz) δ 55.62 (OCH3), 56.13 (OCH3), 62.27, 106.26 (CH), 109.02 (CH), 110.68 (CH),
126.95 (C), 142.18 (C), 153.65 (C), 158.99 (NC=O), 163.90 (HC=O); IR (KBr) 3745
(br, NH), 3251, 1770 (s, C=O), 1666 (s, C=O), 1535, 1219 (C–O) cm–1; EIMS m/z
239 (M+, 70), 224 (16), 165 (11), 138 (100); HRMS Calcd for C11H13NO5: 239.0794;
Found: 239.0785.
2-(Naphthalen-1-ylamino)-2-oxoethyl formate (9a). Yield: 86%; white solids; mp
47–49 °C; 1H NMR (CDCl3, 200 MHz) δ 4.90 (s, 2 H, CH2), 7.43–7.55 (m, 3 H, ArH),
7.71–7.90 (m, 4 H, ArH), 8.27 (s, 1 H, O=C–H); 13C NMR (CDCl3, 50 MHz) δ 62.75,
120.32, 121.19, 125.69, 126.23, 126.61, 126.68, 128.87, 128.89, 130.87, 134.14,
159.02 (NC=O), 164.89 (HC=O); IR (KBr) 3248 (br, NH), 1726 (s, C=O), 1666 (s,
C=O), 1217, 1163 (C–O), 767 cm–1; EIMS m/z 229 (M+, 55), 179 (22), 143 (100), 115
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(57), 93 (52), 77 (20); HRMS Calcd for C13H11NO3: 229.0739; Found: 229.0734.
2-Oxo-2-(quinolin-8-ylamino)ethyl formate (9b). Yield: 87%; white solids; mp
46–48 °C; 1H NMR (CDCl3, 200 MHz) δ 4.90 (s, 2 H, CH2), 7.47–7.56 (m, 3 H, ArH),
8.14 (d, J = 8.3 Hz, 1 H, ArH), 8.32 (s, 1 H, O=C–H), 8.68–8.82 (m, 2 H, ArH), 9.76
13
(br, 1 H, NH); C NMR (CDCl3, 50 MHz) δ 62.61, 117.01, 121.78, 122.46, 127.29,
127.99, 136.41, 138.55, 148.56, 148.58, 159.30 (NC=O), 164.59 (HC=O); IR (KBr)
3331 (NH), 1734 (s, C=O), 1683 (s, C=O), 1153 (C–O), 788 cm–1; EIMS m/z 230 (M+,
10), 172 (17) , 171 (100), 144 (46), 135 (23), 91 (12); HRMS calcd for C12H10N2O3:
230.0691; Found: 230.0695.
1
2-Oxo-2-(Thiazolylamino)ethyl formate (9c). Yield: 71%; yellow liquid; H NMR
(CDCl3, 400 MHz) δ 4.90 (s, 2 H, CH2), 7.03 (d, J = 3.6 Hz, 1 H), 7.47 (d, J = 3.6 Hz,
1 H), 8.17 (s, 1 H, O=C–H); 13C NMR (CDCl3, 100 MHz) δ 61.50, 114.39 (CH),
130.88 (C), 136.95 (CH), 159.07 (NC=O), 164.02 (HC=O); IR (KBr) 3745 (br, NH),
1728 (s, C=O), 1678 (s, C=O), 1276, 1161 (C–O) cm–1; EIMS m/z 186 (M+, 20), 127
(10), 100 (100), 91 (17), 73 (9), 58 (22), 55 (13); HRMS Calcd for C6H6N2O3S:
186.0099; Found: 186.0096.
Acknowledgments
We are grateful to the Tsuzuki Institute for Traditional Medicine, and the
Ministry of the National Science Council Taiwan (NSC-102-2113-M-039-003 and
102-2113-M-415-005-MY2) for financial support.
References
1
For the protection of a hydroxyl group by the formyl group, see (a) P. G. M.
Wuts and T. W. Greene, Greene’s Protective Groups in Organic Synthesis, John
Wiley & Sons, New York, 4th edn., 2007, p. 222; G. A. Olah, L. Ohannesian,
Chem. Rev., 1987, 87, 671–686.
2
R. C. Larock, Comprehensive Organic Transformations, John Wiley & Sons,
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New York, 2nd edn., 1999, p.1639.
J. S. Matthews and J. P. Cookson, J. Org. Chem., 1969, 34, 3204–3205.
3
4
M. Dakanali, G. K. Tsikalas, H. Krautscheid, and H. E. Katerinopoulos,
Tetrahedron Lett., 2008, 49, 1648–1651.
5
A. Abad, C. Agulló, A. C. Cuñat, and I. Navarro, Synthesis, 2005, 19,
3355–3361.
6
7
8
9
B. T. S. Thirumamagal and S. Narayanasamy, Syn. Commun., 2009, 2917–2992.
T. Okano, K. Miyamoto, and J. Kiji, Chem. Lett. 1995, 24, 246.
R. A. Coburn and M. D. Taylor, J. Heterocyclic Chem., 1982, 19, 567–572.
T. Gerhard, Chem. Ber. 1953, 86, 96–109.
10 Y.-P. Zhu, Q.-H. Gao, M. Lian, J.-J. Yuan, M.-C. Liu, Q. Zhao, Y. Yang, and
A.-X. Wu, Chem. Commun., 2011, 47, 12700–12702.
11 N. Iranpoor, H. Firouzabadi, and A. Jamalian, Tetrahedron Letts., 2005, 46,
7963–7966.
12 (a) C.-H. Chang, H. J. Tsai, Y.-Y. Huang, H.-Y. Lin, L.-Y. Wang, T.-S. Wu, and
F. F. Wong, Tetrahedron, 2013, 69, 1378–1386; (b) Y.-Y. Huang, L.-Y. Wang,
C.-H. Chang, Y.-H. Kuo, M. Kaneko, K. Takayama, H. Kimura, S.-H. Juang, F.
F. Wong, Tetrahedron, 2012, 68, 9658–9664; (c) K.-S. Wen, H.-Y. Lin, Y.-Y.
Huang, K. Kaneko, H. Takayama, M. Kimura, S.-H. Juang, and F. F. Wong,
Med. Chem. Res., 2012, 21, 3920–3928; (d) Y.-Y. Huang, K. Kaneko, H.
Takayama, M. Kimura, and F. F. Wong, Tetrahedron Lett., 2011, 52, 3782–3792;
(e) F. F. Wong and Y.-Y. Huang, Tetrahedron, 2011, 67, 3863–3867.
13 W.-N. Su, T.-P. Lin, K.-M. Cheng, K.-C. Sung, S.-K. Lin, and F. F. Wong, J.
Heterocyclic Chem., 2010, 47, 831–837.
14 F. G. Bordwell and W. T. Branner, Jr., J. Am. Chem. Soc., 1964, 86, 4645–4650.
15 F. A. Carey and R. J. Sundberg, Advanced Organic Chemistry, Part A: Structure
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and Mechanisms, Springer, New York, 5th edn., 2007, p. 418.
16 (a) R. D. Bach, B. A. Coddens, and G. J. Wolber, J. Org. Chem., 1986, 51,
1030–1033; (b) F. Carrion and M. J. S. Dewar, J. Am. Chem. Soc., 1984, 106,
3531–3539; (c) S. S. Shaik, J. Am. Chem. Soc., 1983, 105, 4359–4367; (d) D. J.
McLennan and A. Pross, J. Chem. Soc., Perkin Trans. 2, 1984, 2, 981–984; (e) T.
I. Yousaf and E. S. Lewis, J. Am. Chem. Soc., 1987, 109, 6137–6142.
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Table 1 Reaction of α-halo-N-arylacetamides 1–3 bearing α-chloro, bromo, and iodo
groups with formamide in the presence of different amounts of PBr3 at 80–90 C
α-halo
PBr3
time
(h)
yield of 4
entry
N-arylacetamide
group
(equiv)
(%)
a
1
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
I
–
64
64
–
1
1
1
1
1
1
1
2
3
2
3
2
2
0.20
0.50
1.0
2.0
3.0
10
10
53
3
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4
84
5
88
6
96
7
70
8
3.0
3.0
–
73b
9.0b
9
b
10
11
12
13
Br
I
–
b
–
–
Br
I
0.50
0.50
traceb
traceb
a Recovery of starting material.
b Aniline was the major by-product or product.
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Table 2 Study of the reactivity of various formamides in the formyloxylation DreOaI:c10ti.1o0n39/C5RA05779E
of α-chloro-N-phenylacetamide (1) promoted by Vilsmeier–Haack reagent
HCONR1R2
Yield of 4
entry
R1
H
R1
(%)
1
2
3
4
5
6
Me
t-Bu
Me
i-Pr
64
18
54
53
33
H
Me
i-Pr
pyrrolidinyl
piperidinyl
52
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Table 3 Reaction of α-chloro-N-arylacetamides possessing various substituenDtsOIa: 1t0t.1h0e39/C5RA05779E
phenyl group with formamide in the presence of PBr3.
substrate
6a
X
o-F
product
7a
yield (%)
74
m-F
84
6b
6c
7b
7c
p-F
88
o-Br
71
6d
6e
7d
7e
m-Br
78
p-Br
89
6f
7f
o-CF3
m-CF3
p-CF3
p-Me
p-OH
p-OMe
p-CN
2,4-di-OMe
70
6g
7g
78
6h
6i
7h
7i
91
89
6j
7j
87
6k
6l
7k
7l
91
87
6m
6n
7m
7n
76
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Figure 1 An ORTEP diagram of 2-formyloxy-N-(4-cyanophenyl)acetamide (7m)
O
O
Cl
O
H
HN
HN
HCONH2, PBr3
X
X
O
8090 C
8a. X = C
8b. X = N
9a. X = C (86%)
9b. X = N (87%)
O
O
Cl
O
H
HN
HN
HCONH2, PBr3
O
N
S
N
S
8090 C
8c
9c. (71%)
Scheme
1
Formyloxylation of α-chloro-N-(naphthalenyl)acetamide (8a),
α-chloro-N-(quinolin-8-yl)acetamide (8b), andα-chloro-N-(thiazol-2-yl)acetamide
(8c)
Scheme 2 Formyloxylation of 2-chloro-N-hexylacetamide (10). The reaction did not
provide the desired α-formyloxylation product 11 and recovery of 10 was observed.
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Scheme 3 Proposed mechanism of the Vilsmeier–Haack reagent-promoted
formyloxylation of α-chloro-N-phenylacetamide (1) by formamide
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Graphical abstract
Vilsmeier–Haack
reagent-promoted
formyloxylation
of
α-chloro-N-arylacetamides by formamide
Jiann-Jyh Huang, Shi-Han Lu, Yu Hsuan Chung, and Fung Fuh Wong*
α-formyloxylation of α-chloro-N-arylacetamides
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