Copper-catalyzed oxidative coupling of formamides with salicylaldehydes: Synthesis of carbamates in the presence of a sensitive aldehyde group

Article abstract of DOI:10.1021/jo402798k

A diverse library of novel carbamates was synthesized utilizing copper-catalyzed oxidative C-O coupling of formamides and salicylaldehydes. Sensitive aldehyde groups remained intact in the presence of an oxidant and a transition-metal salt. Salicylaldehydes bearing electron-donating, electron-withdrawing, and halogen groups as well as 1-hydroxy-2-naphthaldehydes provided the desired carbamates in good to excellent yields.

Full text of DOI:10.1021/jo402798k

Note
pubs.acs.org/joc
Copper-Catalyzed Oxidative Coupling of Formamides with
Salicylaldehydes: Synthesis of Carbamates in the Presence of a
Sensitive Aldehyde Group
Balaji D. Barve,†,‡ Yang-Chang Wu,†,§ Mohamed El-Shazly,†,⊥ Da-Wei Chuang,† Yuan-Bin Cheng,†
Jeh-Jeng Wang,*,‡ and Fang-Rong Chang*,†,∥
†Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
‡Department of Medicinal and Applied Chemistry, College of Life Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
§School of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan
⊥Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams University, Organization of
African Unity Street, 11566 Abassia, Cairo, Egypt
∥Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
S
* Supporting Information
ABSTRACT: A diverse library of novel carbamates was
synthesized utilizing copper-catalyzed oxidative C−O coupling
of formamides and salicylaldehydes. Sensitive aldehyde groups
remained intact in the presence of an oxidant and a transition-
metal salt. Salicylaldehydes bearing electron-donating, elec-
tron-withdrawing, and halogen groups as well as 1-hydroxy-2-
naphthaldehydes provided the desired carbamates in good to
excellent yields.
rganic carbamates represent important building blocks in
natural products, agrochemicals, and pharmaceutical
Scheme 1. Strategies for the Synthesis of o-Aldehyde-
Containing Phenol Carbamates
O
drugs.1,2 They play a significant role in organic chemistry as
starting materials, intermediates, and protecting and directed
metalating groups (DMGs).3 Carbamates are generally
prepared by employing chloroformates, isocyanates, and
phosgene.4,1a The combination of carbon dioxide, water, and
metal catalysts was introduced as a substitute for the toxic
phosgene.5,1a Recently, Kumar et al. as well as our group have
reported the synthesis of carbamates in high yields utilizing a
wide diversity of substrates including enol and o-keto phenol
derivatives under oxidative conditions.6 The o-keto group of a
phenolic substrate derivative is known to be comparatively
more stable under oxidative conditions in comparison to the o-
formyl group, which is sensitive to oxidants and transition
metals. Thus, the synthesis of o-formyl carbamates under
oxidative conditions while selectively preserving the aldehyde
group remains a challenging task. The preparation of this class
of compounds (2-formyl phenolic carbamates) has been
scarcely described in the literature (Scheme 1).7,3e
Recent advances in C−H activation suggested its potential in
providing an efficient route for the synthesis of carbamates.8,6
Functional-group-directed C−H bond functionalization and
cross-dehydrogenative couplings (CDC) under oxidative
conditions have emerged as attractive techniques for the
formation of carbon−carbon and carbon−heteroatom
bonds.9,8d
For the synthesis of the carbamate, a reliable, stable, and
commercially available aminocarbonyl source is required. N,N-
Dimethylformamide (DMF) represents a suitable amino-
carbonyl source, which is widely used in organic synthesis.10
It is also utilized for the preparation of ureas, α-ketoamides, and
2-vinylquinolines as well as for the cyanation of arene C−H
The major disadvantages of the reported methods are the use
of pyridine, air and moisture-sensitive reagents such as N,N-
dialkylcarbamoyl chlorides, sodium hydride, and sec-BuLi.
Longer reaction times, the need for temperature control,
tedious workup procedures, and limited substrate scope (only
two substrates were reported) are also additional limitations for
the previous reports. Therefore, an expedient, safe, and
environmentally benign methodology for the synthesis of
phenol carbamates with an o-aldehyde group is required.
Received: January 2, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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Note
bonds, for the amidation of acids and alcohols, and as a source
of aminyl radicals.11
resulted in low product yields, which may be attributed to the
lower solubility of these salts in the reaction medium.13 The
solubility information of selected copper catalysts is summar-
ized in Table S1 (see the Supporting Information).
To select the optimum oxidant for this protocol, various
organic and inorganic oxidants were evaluated. The use of
H2O2 (Table 2, entry 6) produced salicylic acid,12c but in the
Initially the reaction of salicylaldehyde (1a), 6.0 equiv of tert-
butyl hydroperoxide (TBHP), and DMF (2a) was conducted
under metal-free conditions or by using inexpensive catalysts
(1−2 mol %). However, the desired product was not detected
and the reaction did not proceed (Table 1, entries 1−6). The
success of using copper catalysts in the preparation of phenol
carbamates has encouraged us to investigate these catalyst
systems in our current study.6
a
Table 2. Oxidant Optimization
a
Table 1. Catalyst Optimization
b
entry
oxidant
yield (%)
c
1
NR
2
DDQ
PIFA
NaIO4
CAN
H2O2
NR
b
d
entry
catalyst
Fe2O3
yield (%)
3
ND
c
4
NR
e
1
NR
d
5
2
ND
6
f
3
Bu4NI
ND
ND
ND
80
7
benzoquinone
benzoyl peroxide
K3Fe(CN)6
oxone
NR
NR
NR
g
4
NaI
8
6
I2
9
7
Cu(OAc)2
Cu(OAc)2·H2O
CuSO4
e
10
11
12
13
14
15
16
17
18
8
55
e
MnO2
NR
NR
ND
96
9
50
tert-butyl perbenzoate
di-tert-butyl peroxide
TBHP
10
11
12
13
14
15
16
17
18
19
CuBr
65
40
70
50
60
96
45
75
55
40
CuBr2
Cu2O
m-CPBA
ND
ND
ND
NR
CuI
sodium chlorite
I2
Cu(NO3)·3H2O
CuCl
UHP
CuCl2
a
CuCl2·2H2O
Cu(OTf)2
CuSO4·5H2O
Reaction conditions: 1a (1.0 equiv), DMF (2.0 mL), CuCl (1.0−2.0
b
c
mol %), oxidant (6.0 equiv), 80 °C, 15 min. Isolated yields. No
reaction. Not detected. 5-Nitrosalicylaldehyde was formed. Salicylic
acid was formed. Catechol was formed.
d
e
f
g
a
Reaction conditions: 1a (1.0 equiv), DMF (2 mL), catalyst (1.0−2.0
b
mol %), TBHP (70 wt % in water, 6.0 equiv), 80 °C, 15 min. Isolated
presence of oxone (Table 2, entry 10) catechol was detected.14
Screening experiments (Table 2) revealed that TBHP is the
most efficient oxidant, providing the corresponding carbamate
in the highest possible yield (Table 2 entry 14). Different
solvents such as acetonitrile,12b−d methanol,14a water,12a,e and
1,1,2-trichloroethane11g were examined in a 1:1 ratio with
DMF, providing the desired carbamate but in lower yields
(<60%) (Supporting Information, Table S2). The effect of
temperature on the reaction progress was also evaluated, where
the lower temperatures (<70−80 °C) resulted in lower yields
(Supporting Information, Table S3).
On the basis of our screening experiments we found that
using CuCl (1−2 mol %), TBHP (6.0 equiv), and DMF (2a) at
80 °C resulted in the formation of the target carbamate (3a,
96%) from salicylaldehyde (1a) in 15 min. With the optimized
conditions in hand, we further investigated the scope of the
reaction using different combinations of substituted salicylalde-
hydes and several formamides (Table 3).
c
d
e
yields. No reaction. Not detected. A trace amount of salicylic acid
was formed.
Initially, we assumed that the aldehyde group in 1a was
susceptible to oxidation in the presence of TBHP (6.0 equiv)
and transition metals (copper salts) to form the corresponding
acid.12
Surprisingly, phenol carbamate was formed (3a, 80%)
without affecting the aldehyde group (Table 1, entry 7).
Aiming to optimize the reaction conditions, we tested different
copper catalysts and oxidants. As shown in Table 1, both Cu(I)
and Cu(II) salts were effective in catalyzing the reaction.
However, the results indicated that changing the counterion
significantly affects the product yield.11a Trace amounts of
salicylic acid were formed in the presence of Cu(OAc)2·H2O
and CuSO4 (Table 1, entries 8 and 9).12b
Recent reports revealed that aromatic aldehydes in the
presence of TBHP form the corresponding acyl radicals, which
undergo subsequent reactions.10a,11g,h In our current protocol,
we did not observe such transformations. Further screening of
the copper catalysts indicated that Cu(I)Cl (1−2 mol %) is the
best optimized catalyst, providing 3a in 96% yield (Table 1,
entry 15). It is worth mentioning that certain copper salts
The reaction of salicylaldehyde or its derivatives bearing
electron-donating groups offered the corresponding carbamates
in good to excellent yields (Table 3, 3a−o). Salicylaldehyde
derivatives substituted with methoxy groups on different
positions of the aromatic moiety led to the formation of the
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Note
a
Table 3. Synthesis of Carbamates from Salicylaldehydes and Naphthaldehyde
a
b
Reaction conditions: 1 (1.0 equiv), formamide (47 equiv), CuCl (1.0−2.0 mol %), TBHP (70 wt % in water, 6.0 equiv), 80 °C, 15 min. Reaction
c
time 90 min. 5.0 mol % of CuCl used.
a
desired carbamates in moderate to good yields (Table 3, 3p−
w).
Table 4. Ortho Group Effect Investigation
Dimethylamino-substituted salicylaldehyde reacted with
three different formamides, providing the target products in
moderate yields (Table 3, 3x−z). Salicylaldehydes with
electron-withdrawing groups such as −OCF3 were also
converted to carbamates in moderate to good yields (Table
3, 3aa−ad). Halogen-substituted salicylaldehydes provided
moderate to good yields of the target carbamates (Table 3,
3ae−an). We also applied this methodology to the synthesis of
naphthyl carbamates using 1-hydroxy-2-naphthaldehyde and
different formamides (Table 3, 3ao−as). Importantly, we did
not observe oxidation side products in any of the trans-
formations. However, we observed a chromatographically
inseparable polar mixture with lower yield substrates.
Interestingly in all of the conversions, the sensitive and
versatile aldehyde group, which remained intact in the presence
of oxidant and transition-metal catalyst,15 can be transformed
into other functional groups.16
b
entry
R
yield (%)
1
2
3
4
5
−NO2
−COOH
−CH3
−Cl
21 (6a)
c
NR
NR
NR
d
−NH2
ND
a
Reaction conditions: 4 (1.0 equiv), DMF (2.0 mL), CuCl (1.0−2.0
mol %), TBHP (70 wt % in water, 6.0 equiv), 80 °C, 15 min. Isolated
yields. No reaction. Not detected. A complex mixture was formed.
b
c
d
practicality of the method has been demonstrated by
performing the reaction on a multigram scale. The target
carbamate was formed in excellent yield (Scheme 2).
On the basis of our findings and previous literature results,
the reaction between compounds with dicarbonyl function-
alities and transition metals was proposed to proceed through
the formation of a coordination complex.17,6 The complex
We have also investigated the ortho effect on substrate
reactivity by replacing the o-formyl group with different
substituents (Table 4). Interestingly under our developed
protocol, the o-nitrophenol derivative provided the correspond-
ing carbamate, however in low yield (Table 4, 6a). The
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Note
nm). H and 13C NMR spectra were recorded with 200 MHz FT-
NMR instruments with Me4Si or solvent resonance as the internal
standard (1H NMR, Me4Si at δ 0 ppm, CDCl3 at δ 7.26 ppm; 13C
NMR, Me4Si at δ 0 ppm, CDCl3 at δ 77.0 ppm). 1H NMR
spectroscopic data are reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m =
multiplet), coupling constants (Hz), and integration. Melting points
(mp) were determined using a melting point apparatus and are
reported uncorrected. IR spectra were measured on a spectropho-
tometer. The UV−vis absorption spectra were recorded on a UV/vis
spectrophotometer in methanol. High resolution mass measurements
(HRMS) were performed on an FT-ESIMS spectrometer.
General Procedure for the Synthesis of Carbamates:
Preparation of 3a as a Representative Example. In a flask
charged with a stir bar, 1a (50.0 mg, 0.41 mmol, 1.0 equiv), copper salt
(1.0−2.0 mol %, CuCl), TBHP as the oxidant (0.24 mL, 2.4 mmol, 6.0
equiv. 70 wt % in water), and DMF as the formamide (1.5 mL, 19.3
mmol, 47.0 equiv) were mixed at room temperature. The reaction
temperature was increased to 80 °C, and the reaction mixture was
stirred for 15−90 min. After it was cooled to room temperature, the
reaction mixture was extracted with ethyl acetate and dried over
anhydrous Na2SO4. Removal of the solvent under vacuum yielded the
crude product, which was purified by flash chromatography (ethyl
acetate/hexane, 2/8) to afford the corresponding carbamate.
1
Scheme 2. Synthesis of Carbamate on a Multigram Scale
which is formed between an enol tautomer of the dicarbonyl
moiety and the transition metal can be further transformed into
different products, including carbamates.6 The structural
similarity between salicylaldehyde and the enol tautomer of
the dicarbonyl moiety suggested a similar attitude toward
transition metals, forming the coordination complex 7 (Scheme
3).17 This hypothesis was also supported by the failure to form
Scheme 3. Plausible Mechanism
Analytical Data for Carbamates. Dimethylcarbamic Acid 2-
1
Formylphenyl Ester (3a). Yield: 76 mg, 96%. Colorless liquid. H
NMR (200 MHz, CDCl3): δ 10.21 (s, 1H), 7.89 (d, J = 7.4 Hz, 1H),
7.62 (t, J = 7.4 Hz, 1H), 7.23−7.39 (m, 2H), 3.18 (s, 3H), 3.05 (s, 3H)
ppm. 13C NMR (50 MHz, CDCl3): δ 188.6, 154, 152.8, 135.0, 129.6,
128.3, 125.6, 123.4, 36.6, 36.4 ppm. FT IR (KBr pellet, cm−1): 2930,
2755, 1728, 1695, 1604, 1456, 1383, 1274, 1157, 1006, 841, 758, 633,
524. UV (MeOH): λmax (log ε) 209 (4.31), 244 (4.37), 290 (4.75) nm.
MS (ESI): m/z 194 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C10H11NO3Na 216.0637, found 216.0635.
Diethylcarbamic Acid 2-Formylphenyl Ester (3b)..3e,7b Yield: 31
1
mg, 63%. Colorless liquid. H NMR (200 MHz, CDCl3): δ 10.21 (s,
1H), 7.89 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.22−7.37 (m,
2H), 3.36−3.56 (m, 4H), 1.19−1.33 (m, 6H) ppm. 13C NMR (50
MHz, CDCl3): δ 188.6, 153.5, 153.1, 135.0, 129.5, 128.6, 125.6, 123.5,
42.4, 42.0, 14.2, 13.2 ppm. FT IR (KBr pellet, cm−1): 2978, 2875,
1723, 1700, 1605, 1457, 1422, 1271, 1210, 1153, 1096, 961, 739, 702,
UV (MeOH): λmax (log ε) 210 (4.37), 244 (4.43), 287 (4.50) nm. MS
(ESI): m/z 222 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C12H15NO3Na 244.0950, found 244.0949.
the target product using phenol as the starting material, which
implies the crucial role of the adjacent formyl group for the
formation of carbamate.6 Aiming to reveal the underlying
mechanism, we found that adding a radical scavenger such as
TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), BHT (2,6-di-
tert-butyl-4-methylphenol), or 1,4-cyclohexadiene resulted in
no product formation, which suggested a radical pathway.
Recent reports suggested that, in the presence of copper
catalyst, TBHP is decomposed to tert-butoxy radical, which can
abstract a hydrogen from the formamide, generating the
corresponding radical 8 (Scheme 3).10a,11c,d,f,g,i It is assumed
that radical 8 can react with the proposed complex 9, forming
the desired carbamates (Scheme 3).
In summary, a novel, green, and phosgene-free approach was
developed for the direct synthesis of carbamates, utilizing the
copper-catalyzed oxidative C−O coupling of salicylaldehydes
and formamides. Low catalyst loading and the use of
inexpensive, stable, and commercially available starting
materials as well as the high product yields and the excellent
functional group tolerance are among the major advantages of
this methodology. The developed protocol is base, additive, and
ligand free, proceeds under mild conditions, and can be used
for the selective protection of a hydroxyl group in the presence
of an oxidant-sensitive aldehyde group.
Diisopropylcarbamic Acid 2-Formylphenyl Ester (3c). Yield: 43
1
mg, 98%. Colorless gum. H NMR (200 MHz, CDCl3): δ 10.19 (s,
1H), 7.90 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.17−7.36 (m,
2H), 4.01−4.11 (m, 2H), 1.18−1.54 (m, 12H) ppm. 13C NMR (50
MHz, CDCl3): δ 187.6, 152.1, 151.9, 134.0, 128.3, 127.8, 124.5, 122.5,
45.8, 45.6, 21.6, 20.4, 20.1, 19.4 ppm. FT IR (KBr pellet, cm−1): 2971,
2929, 1720, 1695, 1605, 1431, 1371, 1317, 1212, 1152, 1042, 984, 896,
753. UV (MeOH): λmax (log ε) 209 (4.42), 244 (4.48), 289 (4.56) nm.
MS (ESI): m/z 250 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C14H19NO3Na 272.1263, found 272.1261.
Piperidine-1-carboxylic Acid 2-Formylphenyl Ester (3d). Yield: 46
1
mg, 88%. Colorless liquid. H NMR (200 MHz, CDCl3): δ 10.20 (s,
1H), 7.88 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.21−7.38 (m,
2H), 3.67 (br m, 2H), 3.54 (br m, 2H), 1.69 (br, 6 H) ppm. 13C NMR
(50 MHz, CDCl3): δ 188.7, 153.1, 152.9, 135.1, 129.7, 128.6, 125.6,
123.6, 45.7, 45.4, 25.9, 25.5, 24.2 ppm. FT IR (KBr pellet, cm−1):
2937, 2856, 1723, 1695, 1604, 1426, 1233, 1209, 1141, 1020, 955, 874,
757. UV (MeOH): λmax (log ε) 211 (4.39), 245 (4.46), 291 (4.53) nm.
MS (ESI): m/z 234 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C13H15NO3Na 256.0950, found 256.0949.
EXPERIMENTAL SECTION
Morpholine-4-carboxylic Acid 2-Formylphenyl Ester (3e). Yield:
■
1
39 mg, 41%. Colorless amorphous solid. Mp: 78−80 °C. H NMR
General Information. All chemicals used in this work were
purchased from commercial sources. Flash chromatography was
performed on silica gel 60 (230−400 mesh). Analytical thin-layer
chromatography (TLC) was performed on Kieselgel 60, F254 (0.20
nm), and visualization was accomplished with UV light (254 and 354
(200 MHz, CDCl3): δ 10.14 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.61 (t,
J = 7.7 Hz, 1H), 7.22−7.41 (m, 2H), 3.78 (br m, 6H), 3.62 (br m, 2H)
ppm. 13C NMR (50 MHz, CDCl3): δ 188.7, 153.0, 152.2, 135.1, 130.9,
128.5, 126.0, 123.6, 66.5 (2C), 45.1, 44.4 ppm. FT IR (KBr pellet,
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Note
cm−1): 2924, 2857, 1726, 1700, 1605, 1455, 1425, 1274, 1242, 1210,
1117, 1060, 857, 737, 575. UV (MeOH): λmax (log ε) 210 (4.39), 245
(4.46), 290 (4.53) nm. MS (ESI): m/z 236 [M + H]+. HRMS (ESI):
m/z [M + Na]+ calcd for C12H13NO4Na 258.0742, found 258.0741.
Dimethylcarbamic Acid 2-Formyl-6-methylphenyl Ester (3f).
Hz, 1H), 3.39−3.52 (m, 4H) 1.19−1.37 (m, 15H) ppm. 13C NMR (50
MHz, CDCl3): δ 190.0, 153.7, 151.0, 148.7, 132.4, 127.8, 126.0, 123.0,
42.4, 42.0, 34.5, 31.1 (3C), 14.2, 13.2 ppm. FT IR (KBr pellet, cm−1):
2967, 2918, 1721, 1692, 1604, 1473, 1423, 1265, 1214, 1155, 1123,
1040, 961, 739, 704. UV (MeOH): λmax (log ε) 210 (4.46), 249 (4.53),
301 (4.62) nm. MS (ESI): m/z 278 [M + H]+. HRMS (ESI): m/z [M
+ Na]+ calcd for C16H23NO3Na 300.1576, found 300.1578.
Diisopropylcarbamic Acid 2-Formyl-4-tert-butylphenyl Ester
(3m). Yield: 25 mg, 60%. Yellow liquid. 1H NMR (200 MHz,
CDCl3): δ 10.20 (s, 1H), 7.91 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.13
(t, J = 8.6 Hz, 1H), 4.01 (br m, 2 H), 1.24−1.36 (m, 21H) ppm. 13C
NMR (50 MHz, CDCl3): δ 189.0, 153.1, 151.0, 148.7, 132.5, 128.0,
125.8, 123.1, 47.5, 46.8, 34.6, 31.2 (3C), 22.7, 21.4, 20.4, 20.2 ppm. FT
IR (KBr pellet, cm−1): 2968, 2872, 1717, 1694, 1604, 1494, 1464,
1432, 1368, 1317, 1205, 1122, 1042, 985, 894, 754. UV (MeOH): λmax
(log ε) 214 (4.21), 249 (4.58), 298 (4.66) nm. MS (ESI): m/z 306 [M
+ H]+. HRMS (ESI): m/z [M + Na]+ calcd for C18H27NO3Na
328.1889, found 328.1886.
Piperidine-1-carboxylic Acid 2-Formyl-4-tert-butylphenyl Ester
(3n). Yield: 37 mg, 55%. Colorless liquid. 1H NMR (200 MHz,
CDCl3): δ 10.19 (s, 1H), 7.89 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.13
(t, J = 8.6 Hz, 1H), 3.67 (br m, 2 H), 3.54 (br m, 2H), 1.68 (br, 6H),
1.33 (s, 9H) ppm. 13C NMR (50 MHz, CDCl3): δ 189.1, 153.2, 151.0,
148.7, 132.5, 127.8, 126.1, 123.1, 45.7, 45.4, 34.6, 31.2 (3C), 25.9, 25.5,
24.2 ppm. FT IR (KBr pellet, cm−1): 2937, 2858, 1725, 1692, 1604,
1426, 1233, 1214, 1141, 1019, 904, 855, 748. UV (MeOH): λmax (log
ε) 214 (4.50), 248 (4.55), 296 (4.63) nm. MS (ESI): m/z 290 [M +
H]+. HRMS (ESI): m/z [M + Na]+ calcd for C17H23NO3Na 312.1576,
found 312.1577.
Morpholine-4-carboxylic Acid 2-Formyl-4-tert-butylphenyl Ester
(3o). Yield: 45 mg, 55%. Yellow amorphous solid. Mp: 78−80 °C. 1H
NMR (200 MHz, CDCl3): δ 10.13 (s, 1H), 7.87 (s, 1H), 7.65 (d, J =
8.6 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H), 3.77 (br m, 6H), 3.61 (br m,
2H), 1.30−1.36 (m, 9H) ppm. 13C NMR (50 MHz, CDCl3): δ 189.1,
153.2, 150.1, 149.1, 132.4, 127.7, 127.4, 123.1, 66.5 (2C), 45.1, 44.3,
34.6, 31.1 (3C) ppm. FT IR (KBr pellet, cm−1): 2963, 2863, 1727,
1691, 1604, 1424, 1365, 1241, 1213, 1120, 1057, 929, 864, 748. UV
(MeOH): λmax (log ε) 214 (4.49), 249 (4.56), 297 (4.64) nm. MS
(ESI): m/z 292 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C16H21NO4Na 314.1368, found 314.1369.
1
Yield: 83 mg, 99%. Colorless liquid. H NMR (200 MHz, CDCl3):
δ 10.11 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.26
(t, J = 7.7 Hz, 1H), 3.20 (s, 3H), 3.05 (s, 3H), 3.26 (s, 3H) ppm. 13C
NMR (50 MHz, CDCl3): δ 189.2, 153.9, 151.2, 136.8, 132.4, 129.0,
127.6, 125.7, 36.9, 36.6, 15.7 ppm. FT IR (KBr pellet, cm−1): 2921,
2851, 1727, 1704, 1603, 1689, 1469, 1383, 1162, 1008, 849.7, 736,
651. UV (MeOH): λmax (log ε) 210 (4.34), 248 (4.41), 294 (4.48) nm.
MS (ESI): m/z 208 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C11H13NO3Na 230.0793, found 230.0794.
Diethylcarbamic Acid 2-Formyl-6-methylphenyl Ester (3g). Yield:
1
16 mg, 40%. Colorless liquid. H NMR (200 MHz, CDCl3): δ 10.12
(s, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.26 (t, J =
7.5 Hz, 1H), 3.36−3.60 (m, 4H), 2.26 (s, 3H), 1.20−1.37 (m, 6H)
ppm. 13C NMR (50 MHz, CDCl3): δ 189.2, 153.3, 151.5, 136.8, 132.4,
129.2, 127.8, 125.7, 42.5, 42.1, 15.8, 14.3, 13.3 ppm. FT IR (KBr pellet,
cm−1): 2919, 1722, 1700, 1604, 1689, 1464, 1420, 1275, 1205, 1154,
1088, 959, 785, 647. UV (MeOH): λmax (log ε) 206 (4.38), 246 (4.46),
288 (4.53) nm. MS (ESI): m/z 236 [M + H]+. HRMS (ESI): m/z [M
+ Na]+ calcd for C13H17NO3Na 258.1106, found 258.1105.
Diisopropylcarbamic Acid 2-Formyl-6-methylphenyl ester (3h):
1
Yield: 43 mg, 90%. Yellow liquid. H NMR (200 MHz, CDCl3): δ
10.13 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.24
(t, J = 7.6 Hz, 1H), 3.93−4.24 (m, 2H), 2.26 (s, 3H), 1.18−1.37 (m,
12H) ppm. 13C NMR (50 MHz, CDCl3): δ 189.1, 152.5, 151.7, 136.8,
132.5, 130.3, 127.3, 125.6, 46.9 (2C), 22.6, 21.5, 20.4, 16.0, 14.0 ppm.
FT IR (KBr pellet, cm−1): 2924, 2852, 1717, 1681, 1605, 1589, 1465,
1428, 1378, 1315, 1186, 1150, 1042, 984, 894, 737. UV (MeOH): λmax
(log ε) 211 (4.44), 249 (4.52), 294 (4.59) nm. MS (ESI): m/z 264 [M
+ H]+. HRMS (ESI): m/z [M + Na]+ calcd for C15H21NO3Na
286.1419, found 286.1417.
Piperidine-1-carboxylic Acid 2-Formyl-6-methylphenyl Ester (3i).
1
Yield: 30 mg, 66%. Colorless liquid. H NMR (200 MHz, CDCl3): δ
10.13 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.31
(t, J = 7.6 Hz, 1H), 3.70 (br m, 2 H), 3.54 (br m, 2 H), 2.26 (s, 3H),
1.69 (br, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ 189.1, 152.7,
151.5, 136.7, 132.4, 129.2, 127.8, 125.7, 45.6 (2C), 26.4, 25.9, 24.3,
15.7 ppm. FT IR (KBr pellet, cm−1): 2925, 2855, 1722, 1684, 1603,
1589, 1425, 1393, 1256, 1232, 1184, 1142, 1021, 851, 739, 704. UV
(MeOH): λmax (log ε) 209 (4.41), 249 (4.49), 295 (4.56) nm. MS
(ESI): m/z 248 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C14H17NO3Na 270.1106, found 270.1105.
Morpholine-4-carboxylic Acid 2-Formyl-6-methylphenyl Ester
(3j). Yield: 33 mg, 72%. Colorless liquid. 1H NMR (200 MHz,
CDCl3): δ 10.07 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 7.7 Hz,
1H), 7.30 (t, J = 7.7 Hz, 1H), 3.81 (br m, 6H), 3.64 (br m, 2 H), 2.27
(s, 3H) ppm. 13C NMR (50 MHz, CDCl3): δ 189.3, 152.8, 150.4,
142.8, 136.9, 132.4, 129.3, 126.0, 66.6 (2C), 45.2, 44.4, 15.7 ppm. FT
IR (KBr pellet, cm−1): 2921, 2851, 1725, 1703, 1603, 1588, 1456,
1424, 1393, 1240, 1202, 1181, 1117, 1057, 923, 857, 784. UV
(MeOH): λmax (log ε) 210 (4.42), 249 (4.49), 294 (4.56) nm. MS
(ESI): m/z 250 [M + H]+ HRMS (ESI): m/z [M + Na]+ calcd for
C13H15NO4Na 272.0899, found 272.0898.
Dimethylcarbamic Acid 2-Formyl-6-methoxyphenyl Ester (3p).
Yield: 32 mg, 43%. Brown amorphous solid. Mp: 70−72 °C. 1H NMR
(200 MHz, CDCl3): δ 10.20 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.18−
7.33 (m, 2H), 3.88 (s, 3H), 3.19 (s, 3H), 3.05 (s, 3H), ppm. 13C NMR
(50 MHz, CDCl3): δ 189.0, 154.0, 152.3, 143.0, 129.9, 126.1, 120.3,
117.8, 56.4, 37.0, 36.7 ppm. FT IR (KBr pellet, cm−1): 2926, 2853,
1728, 1701, 1587, 1483, 1384, 1274, 1159, 1066, 916, 847, 784. UV
(MeOH): λmax (log ε) 219 (4.39), 252 (4.45), 313 (4.54) nm. MS
(ESI): m/z 224 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C11H13NO4Na 246.0742, found 246.0741.
Diethylcarbamic Acid 2-Formyl-6-methoxyphenyl Ester (3q).
1
Yield: 16 mg, 38%. Yellow gum. H NMR (200 MHz, CDCl3): δ
10.20 (s, 1H), 7.47 (d, J = 7.4, 1H), 7.20−7.28 (m, 2H), 3.87 (s, 3H),
3.39−3.54 (m, 4H), 1.19−1.31 (m, 6H) ppm. 13C NMR (50 MHz,
CDCl3): δ 188.9, 153.4, 152.3, 143.3, 130.0, 126.0, 119.9, 117.7, 56.3,
42.5, 42.3, 14.1, 13.3 ppm. FT IR (KBr pellet, cm−1): 2924, 2853,
1726, 1702, 1587, 1460, 1423, 1319, 1273, 1202, 1152, 1070, 956, 916,
783. UV (MeOH): λmax (log ε) 217 (4.44), 253 (4.50), 315 (4.60) nm.
MS (ESI): m/z 252 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C13H17NO4Na 274.1055, found 274.1054.
Piperidine-1-carboxylic Acid 2-Formyl-6-methoxyphenyl Ester
(3r). Yield: 21 mg, 49%. Colorless liquid. 1H NMR (200 MHz,
CDCl3): δ 10.21 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.20−7.28 (m, 2H),
3.88 (s, 3H), 3.69 (br m, 2H), 3.53 (br m, 2H), 1.68 (br 6H) ppm. 13C
NMR (50 MHz, CDCl3): δ 189.0, 152.8, 152.3, 143.3, 129.9, 126.1,
120.1, 117.7, 56.3, 46.0, 45.5, 25.8, 24.7, 24.3 ppm. FT IR (KBr pellet,
cm−1): 2935, 2856, 1725, 1701, 1587, 1486, 1428, 1393, 1274, 1202,
1141, 1020, 915, 849, 783. UV (MeOH): λmax (log ε) 219 (4.46), 253
(4.52), 314 (4.61) nm. MS (ESI): m/z 264 [M + H]+. HRMS (ESI):
m/z [M + Na]+ calcd for C14H17NO4Na 286.1055, found 286.1053.
Dimethylcarbamic Acid 2-Formyl-4-tert-butylphenyl Ester (3k).
1
Yield: 69 mg, 99%. Yellow liquid. H NMR (200 MHz, CDCl3): δ
10.20 (s, 1H), 7.88 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.30 (t, J = 8.8
Hz, 1H), 3.16 (s, 3H), 3.04 (s, 3H), 1.34 (s, 9H) ppm. 13C NMR (50
MHz, CDCl3): δ 189.0, 154.3, 150.9, 148.7, 132.4, 127.7, 126.2, 123.1,
36.8, 36.5, 34.5, 31.1 (3C) ppm. FT IR (KBr pellet, cm−1): 2965, 2869,
1729, 1692, 1603, 1583, 1488, 1385, 1261, 1162, 1007, 866, 118, 752.
UV (MeOH): λmax (log ε) 216 (4.43), 249 (4.49), 297 (4.57) nm. MS
(ESI): m/z 250 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C14H19NO3Na 272.1263, found 272.1264.
Diethylcarbamic Acid 2-Formyl-4-tert-butylphenyl Ester (3l).
1
Yield: 50 mg, 65%. Yellow liquid. H NMR (200 MHz, CDCl3): δ
10.20 (s, 1H), 7.89 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.16 (t, J = 8.6
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Note
Morpholine-4-carboxylic Acid 2-Formyl-6-methoxyphenyl Ester
(3s). Yield: 34 mg, 39%. Colorless liquid. 1H NMR (200 MHz,
CDCl3): δ 10.18 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.17−7.36 (m, 2H),
3.89 (s, 3H), 3.79 (br m, 6H), 3.61 (br m, 2H) ppm. 13C NMR (50
MHz, CDCl3): δ 188.8, 152.8, 152.2, 142.3, 129.8, 126.4, 120.9, 117.7,
66.6 (2C), 56.3, 45.4, 44.5 ppm. FT IR (KBr pellet, cm−1): 2921, 2852,
1729, 1700, 1586, 1485, 1426, 1393, 1274, 1204, 1179, 1117, 1056,
856, 767, 737. UV (MeOH): λmax (log ε) 214 (4.45), 252 (4.52), 313
(4.62) nm. MS (ESI): m/z 266 [M + H]+. HRMS (ESI): m/z [M +
Na]+ calcd for C13H15NO5Na 288.0848, found 288.0847.
ε) 209 (4.49), 249 (4.57), 333 (4.69), 342 (4.70) nm. MS (ESI): m/z
293 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C16H24N2O3Na 315.1685, found 315.1682.
Diisopropylcarbamic Acid 2-Formyl-5-(diethylamino)phenyl
1
Ester (3z). Yield: 22 mg, 53%. Yellow liquid. H NMR (200 MHz,
CDCl3): δ 9.85 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 6.52 (d, J = 9.0 Hz,
1H), 6.27 (s, 1H), 4.04−4.16 (br m, 2H), 3.36−3.47 (m, 4H), 1.17−
1.35 (m, 18H) ppm. 13C NMR (50 MHz, CDCl3): δ 186.4, 155.4,
153.6, 149.8, 131.6, 117.3, 108.3, 104.5, 46.7 (2C), 44.6 (2C), 22.4,
21.5, 20.5, 20.1, 12.5 (2C) ppm. FT IR (KBr pellet, cm−1): 2971, 2930,
1719, 1676, 1605, 1524, 1426, 1405, 1357, 1313, 1290, 1197, 1120,
1098, 1043, 995, 807, 752, 597 UV (MeOH): λmax (log ε) 208 (4.52),
250 (4.60), 333 (4.73), 341 (4.74) nm. MS (ESI): m/z 321 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H28N2O3Na 343.1998,
found 343.1997.
Dimethylcarbamic Acid 2-Formyl-4-(trifluoromethoxy)phenyl
Ester (3aa). Yield: 45 mg, 67%. White crystalline solid. Mp: 54−56
°C. 1H NMR (200 MHz, CDCl3): δ 10.2 (s, 1H), 7.88 (d, J = 2.4 Hz,
1H), 7.43 (d, J = 2.4 Hz, 1H), 7.34 (s, 1H), 3.17 (s, 3H), 3.05 (s, 3H)
ppm. 13C NMR (50 MHz, CDCl3): δ 187.1, 153.8, 151.3, 146.5, 129.4,
127.5, 125.8, 125.3, 121.2, 37.0, 36.6 ppm. FT IR (KBr pellet, cm−1):
2925, 2856, 1733, 1699, 1613, 1487, 1388, 1257, 1222, 1160, 1005,
863, 749, 635. UV (MeOH): λmax (log ε) 211 (4.47), 240 (4.52), 293
(4.60) nm. MS (ESI): m/z 278 [M + H]+. HRMS (ESI): m/z [M +
Na]+ calcd for C11H10F3NO4Na 300.0460, found 300.0459.
Diethylcarbamic Acid 2-Formyl-4-(trifluoromethoxy)phenyl Ester
(3ab). Yield: 18 mg, 52%. Yellow liquid. 1H NMR (200 MHz, CDCl3):
δ 10.18 (s, 1H), 7.73 (d, J = 2.2, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.34 (s,
1H), 3.36−3.56 (m, 4H), 1.19−1.33 (m, 6H) ppm. 13C NMR (50
MHz, CDCl3): δ 187.0, 153.1, 151.4, 146.4, 129.5, 127.5, 125.3, 121.1,
117.8, 42.7, 42.2, 14.3, 13.2 ppm. FT IR (KBr pellet, cm−1): 2924,
2854, 1730, 1700, 1613, 1423, 1258, 1221, 1187, 1147, 1098, 957, 880,
634. UV (MeOH): λmax (log ε) 209 (4.50), 241 (4.57), 291 (4.65) nm.
MS (ESI): m/z 306 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C13H14F3NO4Na 328.0773, found 328.0770.
Piperidine-1-carboxylic Acid 2-Formyl-4-(trifluoromethoxy)-
phenyl Ester (3ac). Yield: 20 mg, 53%. Yellow crystalline solid. Mp:
84−86 °C. 1H NMR (200 MHz, CDCl3): δ 10.2 (s, 1H), 7.73 (d, J =
2.3 Hz, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.32 (s, 1H), 3.67 (br m, 2 H),
3.54 (br m, 2H), 1.68 (br 6H) ppm. 13C NMR (50 MHz, CDCl3): δ
187.1, 152.5, 151.4, 146.4, 129.4, 127.5, 125.4, 122.9, 121.1, 45.8, 45.5,
25.9, 25.5, 24.1 ppm. FT IR (KBr pellet, cm−1): 2926, 1717, 1686,
1610, 1451, 1371, 1291, 1209, 1163, 1142, 1021, 979, 859, 743. UV
(MeOH): λmax (log ε) 210 (4.52), 239 (4.58), 287 (4.66) nm. MS
(ESI): m/z 318 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C14H14F3NO4Na 340.0773, found 340.0775.
Dimethylcarbamic Acid 2-Formyl-5-methoxyphenyl Ester (3t).
1
Yield: 46 mg, 63%. Colorless liquid. H NMR (200 MHz, CDCl3): δ
10.04 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.74−7.87 (m, 2H), 3.86 (s,
3H), 3.16 (s, 3H), 3.04 (s, 3H), ppm. 13C NMR (50 MHz, CDCl3): δ
187.4, 165.1, 154.8, 154.0, 131.6, 122.1, 112.1, 108.5, 55.7, 36.8, 36.5
ppm. FT IR (KBr pellet, cm−1): 3056, 2850, 1729, 1687, 1610, 1500,
1385, 1252, 1160, 1109, 1028, 945, 817, 737. UV (MeOH): λmax (log
ε) 207 (4.36), 223 (4.40), 274 (4.49) nm. MS (ESI): m/z 224 [M +
H]+. HRMS (ESI): m/z [M + Na]+ calcd for C11H13NO4Na 246.0742,
found 246.0740.
Diethylcarbamic Acid 2-Formyl-5-methoxyphenyl Ester (3u).
1
Yield: 16 mg, 39%. Colorless liquid. H NMR (200 MHz, CDCl3):
δ 10.1 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.75
(s, 1H) 3.87 (s, 3H), 3.39−3.52 (m, 4H), 1.19−1.33 (m, 6H) ppm.
13C NMR (50 MHz, CDCl3): δ 188.4, 165.2, 155.0, 153.4, 131.4,
122.3, 112.1, 108.5, 55.8, 42.4, 42.1, 14.1, 13.3 ppm. FT IR (KBr pellet,
cm−1): 2973, 2853, 1724, 1690, 1609, 1416, 1271, 1251, 1155, 1110,
1029, 972, 816, 786. UV (MeOH): λmax (log ε) 210 (4.42), 223 (4.45),
273 (4.54) nm. MS (ESI): m/z 252 [M + H]+. HRMS (ESI): m/z [M
+ Na]+ calcd for C13H17NO4Na 274.1055, found 274.1054.
Diisopropylcarbamic Acid 2-Formyl-5-methoxyphenyl Ester (3v).
1
Yield: 28 mg, 61%. Colorless crystalline solid. Mp: 78−80 °C. H
NMR (200 MHz, CDCl3): δ 10.04 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H),
6.85 (d, J = 8.8 Hz, 1H), 6.69 (s, 1H), 4.00 (br m, 2H), 3.89 (s, 3H)
1.26−1.34 (m, 12H) ppm. 13C NMR (50 MHz, CDCl3): δ 187.2,
165.2, 154.9, 152.7, 131.2, 122.5, 111.9, 108.6, 55.7, 46.8 (2C), 23.4,
21.2, 20.5, 20.1 ppm. FT IR (KBr pellet, cm−1): 2970, 2852, 1720,
1690, 1610, 1462, 1427, 1371, 1312, 1251, 1154, 1091, 1042, 995, 819,
752. UV (MeOH): λmax (log ε) 209 (4.47), 222 (4.49), 273 (4.58) nm.
MS (ESI): m/z 280 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C15H21NO4Na 302.1368, found 302.1366.
Piperidine-1-carboxylic Acid 2-Formyl-5-methoxyphenyl Ester
(3w). Yield: 29 mg, 68%. Brown liquid. 1H NMR (200 MHz,
CDCl3): δ 10.03 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.73−7.87 (m, 2H),
3.87 (s, 3H), 3.66 (br m, 2H), 3.54 (br m, 2H), 1.68 (br 6H) ppm. 13C
NMR (50 MHz, CDCl3): δ 187.5, 165.2, 156.0, 152.8, 131.5, 122.2,
112.2, 108.6, 55.9, 45.8, 45.4, 25.9, 25.6, 24.2 ppm. FT IR (KBr pellet,
cm−1): 2926, 2855, 1724, 1688, 1609, 1419, 1249, 1231, 1158, 1141,
1109, 1022, 900, 819, 749. UV (MeOH): λmax (log ε) 213 (4.45), 222
(4.47), 274 (4.55) nm. MS (ESI): m/z 264 [M + H]+. HRMS (ESI):
m/z [M + Na]+ calcd for C14H17NO4Na 286.1055, found 286.1053.
Dimethylcarbamic Acid 2-Formyl-5-(diethylamino)phenyl Ester
(3x). Yield: 35 mg, 51%. Yellow liquid. 1H NMR (200 MHz, CDCl3):
δ 9.84 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 6.69
(s, 1H), 3.36−3.46 (m, 4H), 3.15 (s, 3H), 3.04 (s, 3H), 1.68−1.26 (m,
6H) ppm. 13C NMR (50 MHz, CDCl3): δ 186.5, 155.1, 154.4, 153.1,
132.3, 116.9, 108.2, 104.7, 44.7 (2C), 36.8, 36.6, 12.5 (2C) ppm. FT
IR (KBr pellet, cm−1): 3055, 2929, 1726, 1671, 1604, 1547, 1526,
1451, 1406, 1383, 1357, 1266, 1196, 1164, 1101, 1013, 820, 737, 702.
UV (MeOH): λmax (log ε) 209 (4.44), 249 (4.52), 333 (4.64), 341
(4.65) nm. MS (ESI): m/z 264 [M + H]+. HRMS (ESI): m/z [M +
Na]+ calcd for C14H20N2O3Na 287.1372, found 287.1371.
Morpholine-4-carboxylic Acid 2-Formyl-4-(trifluoromethoxy)-
1
phenyl Ester (3ad). Yield: 13 mg, 34%. Colorless liquid. H NMR
(200 MHz, CDCl3): δ 10.12 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.45 (d,
J = 2.0 Hz, 1H), 7.33 (s, 1H), 3.78 (br m, 6H), 3.62 (br m, 2H) ppm.
13C NMR (50 MHz, CDCl3): δ 187.1, 152.6, 150.6, 146.7, 129.4,
127.6, 125.4, 122.2, 119.5, 66.5 (2C), 45.2, 44.5 ppm. FT IR (KBr
pellet, cm−1): 2923, 2856, 1728, 1701, 1611, 1491, 1424, 1255, 1226,
1184, 1118, 1054, 861, 745, 619. UV (MeOH): λmax (log ε) 210
(4.53), 241 (4.59), 293 (4.67) nm. MS (ESI): m/z 320 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C13H12F3NO5Na 342.0565,
found 342.0567.
Dimethylcarbamic Acid 2-Formyl-6-Chlorophenyl Ester (3ae).
1
Yield: 45 mg, 67%. Yellow liquid. H NMR (200 MHz, CDCl3): δ
10.13 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.41
(t, J = 7.7 Hz, 1H), 3.22 (s, 3H), 3.06 (s, 3H) ppm. 13C NMR (50
MHz, CDCl3): δ 187.9, 155.1, 153.1, 149.4, 135.4, 128.0, 126.6, 126.3,
37.0, 36.7 ppm. FT IR (KBr pellet, cm−1): 2926, 2851, 1729, 1699,
1594, 1464, 1456, 1387, 1282, 1222, 1162, 1141, 1073, 902, 767, 737,
677. UV (MeOH): λmax (log ε) 210 (4.38), 255 (4.46), 283 (4.51) nm.
MS (ESI): m/z 228 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C10H10ClNO3Na 250.0247, found 250.0246
Diethylcarbamic Acid 2-Formyl-5-(diethylamino)phenyl Ester
(3y). Yield: 12 mg, 33%. Yellow liquid. 1H NMR (200 MHz,
CDCl3): δ 9.87 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 8.8 Hz,
1H), 6.3 (s, 1H), 3.36−3.51 (m, 8H), 1.18−1.28 (m, 12H) ppm. 13C
NMR (50 MHz, CDCl3): δ 186.5, 155.4, 153.1, 131.9, 117.0, 112.5,
108.2, 104.5, 44.7 (2C), 42.3, 42.0, 14.2, 13.3, 12.5(2C) ppm. FT IR
(KBr pellet, cm−1): 2922, 2851, 1722, 1678, 1604, 1525, 1471, 1417,
1357, 1270, 1197, 1154, 1102, 972, 815, 700. UV (MeOH): λmax (log
Diethylcarbamic Acid 2-Formyl-6-chlorophenyl Ester (3af). Yield:
1
24 mg, 60%. Yellow liquid. H NMR (200 MHz, CDCl3): δ 10.14 (s,
1H), 7.80 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0
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Note
Hz, 1H), 3.40−3.58 (m, 4H), 1.20−1.38 (m, 6H) ppm. 13C NMR (50
MHz, CDCl3): δ 187.7, 152.5, 149.6, 135.5, 131.0, 129.2, 127.8, 126.5,
42.7, 42.4, 14.1, 13.2 ppm. FT IR (KBr pellet, cm−1): 2925, 2854,
1732, 1698, 1593, 1455, 1421, 1393, 1273, 1215, 1150, 1074, 955, 785,
738 UV (MeOH): λmax (log ε) 215 (4.44), 246 (4.50), 293 (4.57) nm.
MS (ESI): m/z 256 [M + H]+. HRMS (ESI): m/z [M + Na]+ calcd for
C12H14ClNO3Na 278.0560, found 278.0561.
Piperidine-1-carboxylic Acid 2-Formyl-4-bromophenyl Ester
(3am). Yield: 50 mg, 65%. White amorphous solid. Mp: 64−66 °C.
1H NMR (200 MHz, CDCl3): δ 10.12 (s, 1H), 7.99 (s, 1H), 7.70 (d, J
= 8.7 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 3.52−3.70 (br m, 4H), 1.67
(br 6H) ppm. 13C NMR (50 MHz, CDCl3): δ 187.2, 152.5, 152.2,
137.7, 132.0, 129.8, 125.5, 118.9, 45.8, 45.5, 25.9, 25.4, 24.1 ppm. FT
IR (KBr pellet, cm−1): 2938, 2858, 1725, 1692, 1593, 1427, 1391,
1206, 1179, 1140, 1111, 1018, 883, 855, 708, 660. UV (MeOH): λmax
(log ε) 216 (4.53), 248 (4.59), 305 (4.68) nm. MS (ESI): m/z 312 [M
+ H]+. HRMS (ESI): m/z [M + Na]+ calcd for C13H14BrNO3Na
334.0055, found 334.0057.
Diisopropylcarbamic Acid 2-Formyl-6-chlorophenyl Ester (3ag).
1
Yield: 21 mg, 47%. Yellow liquid. H NMR (200 MHz, CDCl3): δ
10.14 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.31
(t, J = 7.5 Hz, 1H), 3.97−4.24 (m, 2H), 1.31−1.42 (m, 12H) ppm. 13C
NMR (50 MHz, CDCl3): δ 187.9, 151.7, 149.7, 135.5, 131.0, 129.2,
127.5, 126.4, 47.2 (2C), 21.4 (2C), 20.1 (2C) ppm. FT IR (KBr pellet,
cm−1): 2971, 2930, 1727, 1698, 1593, 1429, 1371, 1313, 1226, 1136,
1041, 974, 893, 784, 749. UV (MeOH): λmax (log ε) 213 (4.48), 247
(4.54), 296 (4.62) nm. MS (ESI): m/z 284 [M + H]+. HRMS (ESI):
m/z [M + Na]+ calcd for C14H18ClNO3Na 306.0873, found 306.0875.
Piperidine-1-carboxylic Acid 2-Formyl-6-chlorophenyl Ester
(3ah). Yield: 29 mg, 69%. Colorless liquid. 1H NMR (200 MHz,
CDCl3): δ 10.14 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.2 Hz,
1H), 7.31 (t, J = 7.2 Hz, 1H), 3.73 (br m, 2 H), 3.54 (br m, 2H), 1.70
(br 6H) ppm. 13C NMR (50 MHz, CDCl3): δ 187.9, 151.9, 149.6,
135.4, 130.9, 129.0, 127.8, 126.5, 46.0, 45.7, 25.9, 25.5, 24.2 ppm. FT
IR (KBr pellet, cm−1): 2926, 2856, 1730, 1697, 1593, 125, 1393, 1216,
1139, 1019, 955, 849, 785, 744. UV (MeOH): λmax (log ε) 212 (4.45),
246 (4.52), 296 (4.60) nm. MS (ESI): m/z 268 [M + H]+. HRMS
(ESI): m/z [M + Na]+ calcd for C13H14ClNO3Na 290.0560, found
290.0561.
Morpholine-4-carboxylic Acid 2-Formyl-4-bromophenyl Ester
(3an). Yield: 24 mg, 31%. White amorphous solid. Mp: 130−132
1
°C. H NMR (200 MHz, CDCl3): δ 10.1 (s, 1H), 7.99 (s, 1H), 7.73
(d, J = 8.6 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 3.77 (br m, 6H), 3.59 (br
m, 2H) ppm. 13C NMR (50 MHz, CDCl3): δ 187.2, 152.6, 151.3,
137.8, 133.2, 129.7, 125.5, 119.3, 66.5 (2C), 45.1, 44.4 ppm. FT IR
(KBr pellet, cm−1): 2973, 2867, 1731, 1684, 1454, 1401, 1241, 1208,
1182, 1120, 1054, 988, 887, 806, 746. UV (MeOH): λmax (log ε) 219
(4.54), 255 (4.60), 333 (4.72) nm. MS (ESI): m/z 314 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12BrNO4Na 335.9847,
found 335.9849.
Dimethylcarbamic Acid 2-Formylnaphthyl Ester (3ao). Yield: 30
1
mg, 46%. Yellow amorphous solid. Mp: 125−127 °C. H NMR (200
MHz, CDCl3): δ 10.35 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.76−7.94
(m, 3H), 7.57−7.64 (m, 2H), 3.34 (s, 3H), 3.12 (s, 3H) ppm. 13C
NMR (50 MHz, CDCl3): δ 188.7, 154.3, 151.6, 137.4, 129.3, 128.2,
127.7, 127.2, 126.2, 125.0, 123.2, 122.7, 37.1, 36.8 ppm. FT IR (KBr
pellet, cm−1): 2925, 2854, 1731, 1681, 1627, 1465, 1364, 1232, 1146,
1080, 996, 817, 772, 747. UV (MeOH): λmax (log ε) 224 (4.43), 246
(4.48), 286 (4.54), 347 (4.62) nm. MS (ESI): m/z 244 [M +H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C14H13NO3Na 266.0793,
found 266.0792.
Morpholine-4-carboxylic Acid 2-Formyl-6-chlorophenyl Ester
1
(3ai). Yield: 45 mg, 75%. White crystalline solid. Mp: 73−75 °C. H
NMR (200 MHz, CDCl3): δ 10.1 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H),
7.69 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 3.80 (br m, 6H),
3.61 (br m, 2H) ppm. 13C NMR (50 MHz, CDCl3): δ 187.8, 151.9,
148.8, 135.4, 130.7, 129.0, 128.7, 126.8, 66.5 (2C), 45.3, 44.6 ppm. FT
IR (KBr pellet, cm−1): 2923, 2855, 1732, 1697, 1593, 1424, 1394,
1248, 1214, 1117, 1049, 984, 856, 787, 744. UV (MeOH): λmax (log ε)
213 (4.46), 246 (4.52), 296 (4.60) nm. MS (ESI): m/z 270 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12ClNO4Na 292.0353,
found 292.0352.
Diethylcarbamic Acid 2-Formylnaphthyl Ester (3ap). Yield: 19
1
mg, 49%. Yellow amorphous solid. Mp: 65−67 °C. H NMR (200
MHz, CDCl3): δ 10.35 (s, 1H), 7.99 (d, J = 7.4 Hz, 1H), 7.76−7.94
(m, 3H), 7.58−7.65 (m, 2H), 3.45−3.71 (m, 4H), 1.26−1.30 (m, 6H)
ppm. 13C NMR (50 MHz, CDCl3): δ 188.6, 153.7, 151.8, 137.5, 129.2,
128.2, 127.8, 127.3, 126.1, 125.2, 123.1, 122.7, 42.7, 42.3, 14.5, 13.3
ppm. FT IR (KBr pellet, cm−1): 2925, 2854, 1724, 1679, 1628, 1461,
1377, 1264, 1145, 1078, 954, 816, 767, 747. UV (MeOH): λmax (log ε)
225 (4.49), 245 (4.52), 286 (4.59), 347 (4.68) nm. MS (ESI): m/z
272 [M +H]+. HRMS (ESI): m/z [M + Na]+ calcd for C16H17NO3Na
294.1106, found 294.1107.
Dimethylcarbamic Acid 2-Formyl-4-bromophenyl Ester (3aj).
1
Yield: 30 mg, 44%. Colorless crystalline solid. Mp: 64−66 °C. H
NMR (200 MHz, CDCl3): δ 10.14 (s, 1H), 7.99 (s, 1H), 7.70 (d, J =
8.6 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 3.16 (s, 3H), 3.04 (s, 3H) ppm.
13C NMR (50 MHz, CDCl3): δ 187.2, 153.7, 152.0, 137.7, 132.1,
129.7, 125.5, 119.0, 37.0, 36.6 ppm. FT IR (KBr pellet, cm−1): 2923,
2852, 1732, 1691, 1593, 1471, 1383, 1211, 1157, 1004, 862, 809, 748.
UV (MeOH): λmax (log ε) 218 (4.47), 246 (4.52), 304 (4.61) nm. MS
(ESI): m/z 272 [M + 2]+. HRMS (ESI): m/z [M + Na]+ calcd for
C10H10BrNO3Na 293.9742, found 293.9741.
Diisopropylcarbamic Acid 2-Formylnaphthyl Ester (3aq). Yield:
1
11 mg, 26%. Yellow amorphous solid. Mp: 108−110 °C. H NMR
(200 MHz, CDCl3): δ 10.35 (s, 1H), 7.75−8.02 (m, 4H), 7.55−7.68
(m, 2H), 3.97−4.38 (m, 2H), 1.34−1.60 (m, 12H) ppm. 188.7, 153.0,
151.9, 137.6, 129.2, 128.2, 127.9, 127.2, 126.0, 125.3, 122.9, 122.8,
47.2, 47.1, 21.7 (2C), 20.4 (2C) ppm. FT IR (KBr pellet, cm−1): 2924,
2852, 1723, 1682, 1628, 1464, 1434, 1373, 1306, 1231, 1146, 1082,
1040, 970, 893, 816, 765. UV (MeOH): λmax (log ε) 224 (4.53), 250
(4.57), 286 (4.63), 338 (4.70) nm. MS (ESI): m/z 300 [M +H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H21NO3Na 322.1419,
found 322.1421.
Diethylcarbamic Acid 2-Formyl-4-bromophenyl Ester (3ak).
1
Yield: 21 mg, 57%. Yellow liquid. H NMR (200 MHz, CDCl3): δ
10.13 (s, 1H), 7.99 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 8.7
Hz, 1H), 3.35−3.52 (m, 4H), 1.20−1.32 (m, 6H) ppm. 13C NMR (50
MHz, CDCl3): δ 187.1, 153.1, 152.1, 137.7, 131.9, 129.8, 125.4, 118.8,
42.6, 42.1, 14.3, 13.2 ppm. FT IR (KBr pellet, cm−1): 2975, 2918,
1725, 1691, 1594, 1470, 1422, 1390, 1255, 1207, 1151, 1112, 959, 883,
738. UV (MeOH): λmax (log ε) 214 (4.51), 248 (4.57), 295 (4.65) nm.
MS (ESI): m/z 300 [M + H]+, 302 [M + 2]+. HRMS (ESI): m/z [M +
Na]+ calcd for C12H14BrNO3Na 322.0055, found 322.0053.
Diisopropylcarbamic Acid 2-Formyl-4-bromophenyl Ester (3al).
Yield: 14 mg, 35%. Yellow amorphous solid. Mp: 61−63 °C. 1H NMR
(200 MHz, CDCl3): δ 10.11 (s, 1H), 8.01 (s, 1H), 7.70 (d, J = 8.6 Hz,
1H), 7.11 (d, J = 8.6 Hz, 1H), 4.00−4.09 (m, 2H), 1.31−1.44 (m,
12H) ppm. 13C NMR (50 MHz, CDCl3): δ 187.2, 152.5, 152.1, 137.7,
131.8, 130.1, 125.5, 118.9, 47.1 (2C), 21.4 (2C), 20.4 (2C) ppm. FT
IR (KBr pellet, cm−1): 2970, 2930, 1721, 1695, 1593, 1472, 1430,
1372, 1315, 1255, 1202, 1111, 1041, 980, 884, 751. UV (MeOH): λmax
(log ε) 219 (4.56), 247 (4.61), 305 (4.70) nm. MS (ESI): m/z 350 [M
+ Na]+. HRMS (ESI): m/z [M + Na]+ calcd for C14H18BrNO3Na
350.0368, found 350.0371.
Piperidine-1-carboxylic Acid 2-Formylnaphthyl Ester (3ar). Yield:
1
21 mg, 51%. Yellow amorphous solid. Mp: 86−88 °C. H NMR (200
MHz, CDCl3): δ 10.35 (s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.81−7.91
(m, 3H), 7.59−7.65 (m, 2H), 3.59−3.88 (br m, 4H), 1.76 (br 6H)
ppm. 13C NMR (50 MHz, CDCl3): δ 188.7, 153.1, 151.8, 137.5, 129.3,
128.2, 127.7, 127.2, 126.1, 125.1, 123.1, 122.7, 46.0, 45.6, 26.2, 25.6,
22.6 ppm. FT IR (KBr pellet, cm−1): 2927, 2856, 1726, 1682, 1628,
1429, 1378, 1256, 1226, 1139, 1083, 1018, 956, 817, 769, 747. UV
(MeOH): λmax (log ε) 224 (4.50), 250 (4.55), 286 (4.61), 347 (4.69)
nm. MS (ESI): m/z 284 [M +H]+. HRMS (ESI): m/z [M + Na]+
calcd for C17H17NO3Na 306.1106, found 306.1108.
Morpholine-4-carboxylic Acid 2-Formylnaphthyl Ester (3as).
1
Yield: 40 mg, 58%. Yellow amorphous solid. Mp: 124−126 °C. H
NMR (200 MHz, CDCl3): δ 10.31 (s, 1H), 8.03 (d, J = 7.0 Hz, 1H),
7.78−7.93 (m, 3H), 7.59−7.65 (m, 2H), 3.90 (br m, 6H), 3.64 (br m,
3212
dx.doi.org/10.1021/jo402798k | J. Org. Chem. 2014, 79, 3206−3214

The Journal of Organic Chemistry
Note
2H) ppm. 13C NMR (50 MHz, CDCl3): δ 188.6, 153.1, 150.8, 137.4,
137.4, 129.4, 128.2, 127.5, 126.3, 124.8, 123.8, 122.6, 66.6 (2C), 45.3,
44.5, ppm. FT IR (KBr pellet, cm−1): 2924, 2855, 1728, 1680, 1627,
1429, 1377, 1277, 1227, 1173, 1117, 1086, 1043, 983, 818, 769, 748.
UV (MeOH): λmax (log ε) 224 (4.50), 249 (4.55), 386 (4.61), 347
(4.70) nm. MS (ESI): m/z 286 [M +H]+. HRMS (ESI): m/z [M +
Na]+ calcd for C16H15NO4Na 308.0899, found 308.0897.
Adv. Synth. Catal. 2012, 354, 2443. (d) Shang, J.; Liu, S.; Ma, X.; Lua,
L.; Deng, Y. Green Chem. 2012, 14, 2899. (e) Ca, N. D.; Gabriele, B.;
Ruffolo, G.; Veltri, L.; Zanetta, T.; Costa, M. Adv. Synth. Catal. 2011,
353, 133. (f) Shi, F.; Deng, Y. Chem. Commun. 2001, 443.
(6) (a) During our submission the Phan group investigated the use
of heterogeneous catalysts for the synthesis of carbamates from
phenol: Phan, N. T. S.; Nguyen, T. T.; Vu, P. H. L. ChemCatChem
2013, 5, 3068−3077. (b) Kumar, G. S.; Maheswari, C. U.; Kumar, R.
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11748. (c) Barve, B. D.; Wu, Y. C.; El-Shazly, M.; Chuang, D. W.;
Chung, Y. M.; Tsai, Y. H.; Wu, S. F.; Korinek, M.; Du, Y. C.; Hsieh, C.
T.; Wang, J. J.; Chang, F. R. Eur. J. Org. Chem. 2012, 6760.
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C.; Kamila, S.; De, A. Tetrahedron 2004, 60, 5215.
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(b) Shang, X.; Liu, Z. Q. Chem. Soc. Rev. 2013, 42, 3253. (c) Arockiam,
P.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (d) Song,
G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (e) Kuhl, N.;
Hopkinson, M. N.; Delord, J. W.; Glorius, F. Angew. Chem., Int. Ed.
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111, 1293. (g) Dyker, G. Handbook of C−H Transformations.
Applications in Organic Synthesis; Wiley-VCH: Weinheim, Germany,
2005.
Dimethylcarbamic Acid 2-Nitrophenyl Ester (6a).18 This com-
1
pound is known. Yield: 16 mg, 21%. Yellow liquid. H NMR (200
MHz, CDCl3): 8.10 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H),
7.28−7.39 (m, 2H), 3.15 (s, 3H), 3.04 (s, 3H) ppm. 13C NMR (50
MHz, CDCl3): δ 153.4, 145.1, 143.3, 134.4, 125.8, 125.6 (2C), 36.9,
36.6 ppm. MS (ESI): m/z 211 [M + H]+.
ASSOCIATED CONTENT
* Supporting Information
■
S
Tables giving solubility data and optimization of reaction
conditions and figures giving 1H and 13C NMR spectra of all of
the compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for J.-J.W.: jjwang@kmu.edu.tw
*E-mail for F.-R.C.: aaronfrc@kmu.edu.tw
■
(9) (a) Li, B. J.; Shi, Z. J. Chem. Soc. Rev. 2012, 41, 5588. (b) Yeung,
C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (c) Li, C. J. Acc. Chem.
Res. 2009, 42, 335 and references therein.
Notes
(10) (a) Ding, S.; Jiao, N. Angew. Chem., Int. Ed. 2012, 51, 9226 and
references therein. (b) Muzart, J. Tetrahedron 2009, 65, 8313.
(11) (a) Kumar, P. S.; Kumar, G. S.; Kumar, R. A.; Reddy, N. V.;
Reddy, K. R. Eur. J. Org. Chem. 2013, 1218. (b) Li, Y.; Guo, F.; Zha, Z.;
Wang, Z. Chem. Asian J. 2013, 8, 534. (c) Honglai, J.; Lin, A.; Zhu, C.;
Cheng, Y. Chem. Commun. 2013, 49, 819. (d) Li, D.; Wang, M.; Liu, J.;
Zhao, Q.; Wang, L. Chem. Commun. 2013, 49, 3640. (e) Kim, J.; Choi,
J.; Shin, K.; Chang, S. J. Am. Chem. Soc. 2012, 134, 2528. (f) Mai, W.
P.; Wang, H. H.; Li, Z. C.; Yuan, J. W.; Xiao, Y. M.; Yang, L. R.; Mao,
P.; Qu, L. B. Chem. Commun. 2012, 48, 10117. (g) Liu, Z.; Zhang, J.;
Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew. Chem., Int. Ed. 2012, 51,
3231. (h) Xu, K.; Hu, Y.; Zhang, S.; Zha, Z.; Wang, Z. Chem. Eur. J.
2012, 18, 9793. (i) We did not observe the formation of hydrazine by
the self-coupling reaction of aminyl radicals, which may be formed by
the decarbonylation of aminocarbonyl radical.
(12) (a) Sodhi, R. K.; Paul, S.; Clark, J. H. Green Chem. 2012, 14,
1649. (b) Das, R.; Chakraborty, D. Appl. Organomet. Chem. 2011, 25,
437. (c) Chakraborty, D.; Gowda, R. R.; Malik, P. Tetrahedron Lett.
2009, 50, 6553. (d) Mannam, S.; Sekar, G. Tetrahedron Lett. 2008, 49,
1083. (e) Shapiro, N.; Vigalok, A. Angew. Chem., Int. Ed. 2008, 47,
2849. (f) Grill, J. M.; Ogle, J. W.; Miller, S. A. J. Org. Chem. 2006, 71,
9291. (g) Abaee, M. S.; Sharifi, R.; Mojtahedi, M. M. Org. Lett. 2005,
26, 5893. (h) Heaney, H.; Newbold, A. J. Tetrahedron Lett. 2001, 42,
6607.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science Council of Taiwan
(NSC 99-2628-B-037-003-MY3) and the Department of
Health Executive Yuan, Taiwan (DOH101-TD-C-111-004) is
acknowledged. The authors thank the Center for Research
Resources and Development (CRRD), Kaohsiung Medical
University, for technical support and services in LC-MS and
NMR analysis.
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