Synthesis of carbamates by direct C-H bond activation of formamides

Article abstract of DOI:10.1002/ejoc.201201160

Copper catalysed oxidative coupling reaction of formamides with β-keto esters and 2-carbonyl-substituted phenols successfully proceeded through direct C-H bond activation of formamides. The corresponding carbamates were formed with high stereoselectivity

Full text of DOI:10.1002/ejoc.201201160

FULL PAPER
DOI: 10.1002/ejoc.201201160
Synthesis of Carbamates by Direct C–H Bond Activation of Formamides
Balaji D. Barve,[a,b] Yang-Chang Wu,[a,c,d,e] Mohamed El-Shazly,[a,f] Da-Wei Chuang,[a]
Yu-Ming Chung,[a] Yi-Hong Tsai,[a] Shou-Fang Wu,[a] Michal Korinek,[a] Ying-Chi Du,[a]
Chi-Ting Hsieh,[a] Jeh-Jeng Wang,*[b] and Fang-Rong Chang*[a,g,h,i]
Keywords: Synthetic methods / Oxidation / C–H activation / Regioselectivity / Carbamates / Copper
Copper catalysed oxidative coupling reaction of formamides
with β-keto esters and 2-carbonyl-substituted phenols suc-
cessfully proceeded through direct C–H bond activation of
formamides. The corresponding carbamates were formed
with high stereoselectivity under mild reaction conditions.
This protocol was successfully applied to the synthesis of
three novel halogenated carbamates and a carbaryl insecti-
cide derivative. Our results suggest the use of 6.0 equiv.
TBHP is crucial for this type of reaction.
pharmacological activities as neuroprotective, antibacterial,
antineoplastic and antifilarial agents as well as acetyl cho-
linesterase and endocannabinoid hydrolase inhibitors.[3]
Carbamates are traditionally prepared from chloroformates
or isocyanate by employing phosgene or its substitutes as
starting materials.[4] Metal-catalysed reactions as well as the
use of carbon dioxide were introduced to replace toxic
phosgene.[5] Recently, Hofmann and Curtius rearrange-
ments were applied for carbamate preparation.[6] Despite
these reported protocols, an efficient, safe and environmen-
tally benign methodology for carbamate synthesis is lack-
ing.[1a]
Introduction
Organic carbamates are important structural motifs in
many biologically active natural products, pharmaceutical
drugs and agrochemicals (Figure 1).[1] They also play a sig-
nificant role in organic chemistry as valuable intermediates
and protecting groups.[2] Carbamates possess excellent
[a] Graduate Institute of Natural Products, College of Pharmacy,
Kaohsiung Medical University,
Kaohsiung 807, Taiwan
Fax: +886-7-3114773
E-mail: aaronfrc@kmu.edu.tw
Homepage: http://cpharmacy.kmu.edu.tw/ezcatfiles/b023/img/
img/570/179.pdf
[b] Department of Medicinal and Applied Chemistry, College of
Life Sciences, Kaohsiung Medical University,
Kaohsiung 807, Taiwan
Fax: +886-7-3125339
E-mail: jjwang@kmu.edu.tw
Homepage: http://chem.kmu.edu.tw/front/bin/ptlist.phtml?Cat-
egory = 104
[c] Center for Molecular Medicine, China Medical University Hos-
pital,
Taichung 404, Taiwan
Figure 1. Selected biologically active carbamates.
[d] School of Chinese Medicine, College of Chinese Medicine,
China Medical University,
Taichung 404, Taiwan
[e] Natural Medicinal Products Research Center, China Medical
University Hospital,
Chemical transformations using transition-metal-cata-
lysed coupling are now playing a significant role in carbon–
carbon and carbon–heteroatom bond formation.[7] They
are successfully applied in the synthesis of complex natural
products and pharmaceutical drugs.[8] However, traditional
coupling reactions suffer from some drawbacks such as the
use of expensive transition metals with considerable toxic-
ity, high costs associated with the preparation of starting
materials, and poor atom economy. Direct C–H bond acti-
vation has emerged as an alternative route in organic syn-
thesis to overcome the drawbacks of traditional coupling
reactions.[9,10]
Taichung 404, Taiwan
[f] Department of Pharmacognosy and Natural Products Chemis-
try, Faculty of Pharmacy, Ain-Shams University, Organization
of African Unity
Street 11566, Abassia, Cairo, Egypt
[g] Cancer Center, Kaohsiung Medical University Hospital,
Kaohsiung 807, Taiwan
[h] R & D Center of Chinese Herbal Medicines & New Drugs,
College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 807, Taiwan
[i] Department of Marine Biotechnology and Resources, National
Sun Yatsen University,
Kaohsiung 804, Taiwan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201160.
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Synthesis of Carbamates from Formamides
In 2011, the Reddy group reported the synthesis of carb- Table 1. Catalyst screening for optimisation of reaction condi-
tions.[a]
amates using N,N-dimethylformamide (DMF) and 5 mol-%
CuBr2 at 80 °C for 3 h.[11] The developed protocol led to
the formation of O-(2-carbonylphenyl) carbamates in good
to high yields (62–86%) but enol carbamates were prepared
in only moderate yields (26–80%).
DMF, with its peculiar nature, is used in organic synthe-
sis as a solvent as well as a source of oxygen, Me2NCO,
Entry
Catalyst
Yield [%][b]
Me2N, CO, carbon, and CN.[12] Recently, direct C–H bond
activation of DMF and its derivatives was described.[13] The
reaction was proposed to proceed through a radical mecha-
nism.[11,14a] Inspired by these findings, we report herein a
high yielding protocol for the synthesis of enol and O-(2-
carbonylphenyl) carbamates involving oxidative coupling
and formamide C–H bond activation (Scheme 1).
1
2
3
4
5
6
7
8
–
n.r.[c]
n.d.[d]
n.d.
n.d.
n.d.
n.d.
80
Fe2O3
Bu4NI
NaI
ZnCl2
I2
CuBr2
CuSO4·5H2O
CuCl2
69
82
9
10
11
12
13
14
15
16
17
18
Cu2O
CuCl2·2H2O
CuBr
Cu(NO3)·2H2O
CuI
CuCl
Cu (OAc)2
CuSO4
Cu (OAc)2·H2O
30
62
60
64
40
99
70
67
65
[a] Reaction conditions: 1a (1 equiv.), DMF (2 mL), catalyst
(1 mol-%), TBHP (70 wt.-% in water, 6.0 equiv.), 70 °C, 15–30 min.
[b] Isolated yield. [c] n.r.: no reaction. [d] n.d.: not detected.
Scheme 1. Synthesis of carbamates by direct C–H bond activation
of formamides.
after 6 h using 1–5 mol-% CuCl or CuBr2, suggesting that
the use of 6.0 equiv. of TBHP is crucial for reaction comple-
tion, in contrast to the previous report in which the use of
Results and Discussion
Table 2. Oxidant screening for optimisation of reaction condi-
tions.[a]
Initially, the reaction between ethyl acetoacetate (1a),
6.0 equiv. of tert-butyl hydroperoxide (TBHP) and DMF
(2a) was tested under metal-free conditions or by using in-
expensive catalysts (1 mol-%) that are known to catalyse
radical reactions such as Fe2O3, NaI, Bu4NI, ZnCl2 or
I2.[10d,15] However, the reaction did not proceed and no
product was detected (Table 1, entries 1–6). The catalyst uti-
lised in a previous report was also tested, but under our
reaction conditions (1 mol-% CuBr2 and 6.0 equiv.
TBHP).[11] This reaction was complete within 30 min, the
expected enol carbamate 3a was formed in 80% yield
(Table 1, entry 7).
The use of 1 mol-% metal catalyst represents a marked
reduction in catalyst loading compared with the reported
protocol.[11] Additionally, the short reaction time (15–
30 min) and the high yield encouraged us to test other cop-
per catalysts and oxidants with the aim of optimising the
new reaction conditions. Catalysts screening established
that CuCl was the best catalyst, giving 3a in 99% yield
(Table 1, entry 15). Screening of different organic and inor-
ganic oxidants (Table 2) revealed that TBHP was the most
efficient oxidant, providing the highest yield of the target
carbamate. Aiming to decrease the amount of oxidant, the
reaction was repeated using 1.5, 2.5, 3.5 and 4.5 equiv. of
Entry
Oxidant
Yield [%][b]
1
2
3
4
5
6
7
8
m-CPBA
DDQ
PIFA
NaIO4
CAN
20
n.r.[c]
n.d.[d]
n.d.[e]
n.d.
n.d.
n.r.
H2O2
benzoquinone
benzoyl peroxide
K3Fe(CN)6
Oxone
n.d.
n.d.
n.d.[f]
n.d.
n.r.
n.d.
99
9
10
11
12
13
14
15
MnO2
tert-butyl perbenzoate
Di-tert-butyl peroxide
TBHP
–
n.r.
[a] Reaction conditions: 1a (1 equiv.), DMF (2 mL), CuCl (1 mol-
%), oxidant (6.0 equiv.), 70 °C, 15–30 min. [b] Isolated yield. [c] n.r.:
no reaction. [d] 0.75 equiv. of oxidant was used. [e] n.d.: not de-
TBHP. Unfortunately, the reaction was not complete even tected. [f] 1.0 equiv. of oxidant was used.
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Table 3. Formation of enol-carbamates.[a]
[a] Reaction conditions: 1a (1 equiv.), formamide (2 mL), CuCl (1 mol-%), TBHP (70 wt.-% in water, 6.0 equiv.), 70 °C, 15–30 min. [b]
Reaction time 45 min.
only 1.5 equiv. of TBHP was sufficient.[11] This finding is amates (Table 4). Several formamides reacted smoothly
also supported by recent research with detailed mechanistic with ortho-hydroxyacetophenone in excellent yields (for 5a–
studies showing that the use of 2–6 equiv. of oxidant is es- d). Electron-donating groups on the phenol ring resulted in
sential for similar reactions.[14a,15b,16]
lower yields compared to ortho-hydroxyacetophenone (5e–
With the optimised conditions in hand, we further inves- h). Salicylinide also participated in the reaction, forming
tigated the scope of the reaction using different substituted the corresponding carbamate in moderate yield (5i).
β-keto esters. All substrates were efficiently transformed
Halogen-substituted 2-carbonylphenols 5j–l reacted
into their corresponding enol carbamates (Table 3). DMF smoothly without any dehalogenation, providing novel ha-
with various substituted β-keto esters provided carbamates logenated carbamates.[1a] Notably, all reactions were per-
in excellent yields (Table 3, 3a–f). Interestingly, the active formed in open air and were not sensitive to moisture. To
methylene group of β-dicarbonyl esters did not participate test the applicability of our methodology, a carbaryl insecti-
in the reaction.[17] The lower yield of 1,3-cyclohexadione cide derivative was prepared in a single step from 2-acetyl
carbamate (3h) may be attributed to the lack of binding naphthol and DMF (Scheme 2).[18]
capacity of cyclic β-diketones to copper metal in a bidentate
Mechanistically, the reaction of simple phenol under the
fashion.[14b] DMF, with different substituted β-keto esters, above conditions resulted in no product formation, im-
rendered carbamates 3i–k in excellent yields. Cyclic and plying the importance of the adjacent carbonyl group for
bulky formamides 3l–p provided slightly lower yields, sug- carbamate formation. This was attributed to the tendency
gesting the negative effect of steric hindrance on the reac- of dicarbonyl compounds to form coordination complex 6
tion. The reaction exhibited high stereoselectivity, resulting with transition metals (Scheme 3).[14b,17] Copper complex 6
in the formation of the Z isomer of the carbamates.[11,14b]
decomposes TBHP to form hydroxyl and tert-butoxyl radi-
The developed protocol was also applicable to 2-carb- cals.[14b] The latter can abstract hydrogen from the reacting
onyl-substituted phenols forming the corresponding carb- formamide, generating the corresponding radical, which re-
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Synthesis of Carbamates from Formamides
Table 4. Formation of O-(2-carbonylphenyl) carbamates.[a]
[a] Reaction conditions: 4a (1 equiv.), formamide (2 mL), CuCl (1 mol-%), TBHP (70 wt.-% in water, 6.0 equiv.), 70 °C, 15–30 min. [b]
Reaction time 45 min.
acts with the copper complex affording the desired carb-
amates.[14a] Furthermore, it was reported that the use of
radical scavengers [2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT)] in
metal-catalyzed oxidative reactions with TBHP as an oxi-
dant, prevented C–O coupling, supporting the radical path-
way.[11,14b]
Scheme 2. Single step synthesis of a carbaryl insecticide derivative.
Conclusions
A high yielding, efficient, green methodology for the syn-
thesis of carbamates was developed that involves direct C–
H bond activation of formamides by oxidative coupling.
Compared to other carbamate synthetic protocols, this pro-
tocol involves moderate temperature, low catalyst loading,
great functional group tolerance, and short reaction time,
suggesting its potential application in research and industry.
Experimental Section
General: All chemicals used in this work were purchased from com-
mercial sources. Biotage Flash or Isco Companion systems were
used for flash chromatography. Analytical thin-layer chromatog-
Scheme 3. Plausible mechanism.
raphy (TLC) was performed on Kieselgel 60, F254 (0.20 nm, Merck)
Eur. J. Org. Chem. 2012, 6760–6766
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J.-J. Wang, F.-R. Chang et al.
FULL PAPER
and visualisation was accomplished with UV light (254 and
354 nm). 1H and 13C NMR spectra were recorded with Varian
Gemini-2000 (200 MHz FT-NMR) instruments with Me4Si or sol-
vent resonance as the internal standard (1H NMR: Me4Si at 0 ppm,
CDCl3 at δ = 7.26 ppm; 13C NMR: Me4Si at 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, quint = quintet, sext = sextet, sept = septet, br. = broad,
m = multiplet), coupling constants (Hz), and integration. High-
resolution mass measurements (HRESI-MS, ESI-MS) were per-
formed with a Bruker Daltonics APEX II spectrometer.
7.2 Hz, 2 H), 2.97 (s, 6 H), 2.03 (s, 3 H), 1.90 (s, 3 H), 1.25 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 166.7, 153.9,
152.5, 115.8, 60.2, 36.4, 36.1, 19.0, 14.5, 13.9 ppm. MS (ESI): m/z
= 216 [M+ + H].
3-Oxocyclohex-1-enyl Dimethylcarbamate (3h):[11] Yield 19%; yel-
1
low liquid. H NMR (200 MHz, CDCl3): δ = 5.89 (s, 1 H), 3.01 (s,
3 H), 2.98 (s, 3 H), 2.58 (t, J = 6.4 Hz, 2 H), 2.40 (t, J = 6.4 Hz, 2
H), 2.06 (quint, J = 6.4 Hz, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 199.7, 170.6, 152.1, 115.8, 36.6, 36.5, 29.6, 28.4,
21.2 ppm. MS (ESI): m/z = 184 [M+ + H].
Ethyl 3-(Diethylcarbamoyloxy)-3-phenylacrylate (3i):[11] Yield 99%;
yellow liquid. 1H NMR (200 MHz, CDCl3): δ = 7.56–7.61 (m, 2
H), 7.37–7.43 (m, 3 H), 6.23 (s, 1 H), 4.19 (q, J = 7.2 Hz, 2 H),
3.52 (q, J = 7.2 Hz, 2 H), 3.39 (q, J = 7.2 Hz, 2 H), 1.17–1.35 (m,
9 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 164.2, 158.1, 152.5,
134.5, 130.5, 128.6 (2 C), 125.9 (2 C), 106.5, 60.0, 42.3, 42.0, 14.1,
13.2 (2 C) ppm. MS (ESI): m/z = 292 [M+ + H].
General Procedures
Synthesis of Enol Carbamates and 2-Carbonyl-Substituted Phenol
Carbamates: To a flask charged with a stir bar, β-keto ester 1 or
phenol 4 (1 equiv.), copper salt (1 mol-%, CuCl), TBHP (70 wt.-%
in water 6.0 equiv.) and formamide (27 equiv.) were mixed at room
temperature. The reaction temperature was increased to 70 °C and
the reaction mixture was stirred for 30 min. After cooling to room
temp., the reaction mixture was extracted with ethyl acetate and
dried with anhydrous Na2SO4. Removal of the solvent under vac-
uum yielded the crude product, which was purified by flash
chromatography (ethyl acetate/hexane, 2:8) to afford the required
product 3 or 5.
Ethyl 3-(Diethylcarbamoyloxy)but-2-enoate (3j):[11] Yield 99%; yel-
low liquid. 1H NMR (200 MHz, CDCl3): δ = 5.54 (s, 1 H), 4.09 (q,
J = 7.2 Hz, 2 H), 3.30–3.43 (m, 4 H), 2.05 (s, 3 H), 1.18–1.31 (m,
9 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 163.9, 160.3, 152.2,
108.0, 59.7, 42.0, 41.8, 21.9, 14.1, 13.9, 13.2 ppm. MS (ESI): m/z =
230 [M+ + H].
Ethyl 3-(Dimethylcarbamoyloxy)but-2-enoate (3a):[11] Yield 99%;
1
Methyl 3-(Diethylcarbamoyloxy)but-2-enoate (3k):[11] Yield 99%;
yellow liquid. H NMR (200 MHz, CDCl3): δ = 5.55 (s, 1 H), 4.12
1
(q, J = 7.2 Hz, 2 H), 3.04 (s, 3 H), 2.98 (s, 3 H), 2.05 (s, 3 H), 1.24
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (50 Hz, CDCl3): δ = 163.9,
160.7, 152.9, 107.9, 59.7, 36.5 (2 C), 22.0, 14.1 ppm. MS (ESI): m/z
= 202 [M+ + H].
yellow liquid. H NMR (200 MHz, CDCl3): δ = 5.56 (s, 1 H), 3.66
(s, 3 H), 3.30–3.43 (m, 4 H), 2.06 (s, 3 H), 1.15–1.25 (m, 6 H) ppm.
13C NMR (50 MHz CDCl3): δ = 164.9, 161.3, 152.8, 108.1, 51.6,
42.6, 42.4, 22.5, 14.4, 13.8 ppm. MS (ESI): m/z = 216 [M+ + H].
Ethyl 3-(Dimethylcarbamoyloxy)-3-phenylacrylate (3b):[11] Yield
85%; yellow liquid. 1H NMR (200 MHz, CDCl3): δ = 7.57–7.63
(m, 2 H), 7.37–7.43 (m, 3 H), 6.24 (s, 1 H), 4.19 (q, J = 7.2 Hz, 2
H), 3.17 (s, 3 H), 3.03 (s, 3 H), 1.32 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 164.3, 158.4, 153.3, 134.2, 130.6 (2
C), 128.6 (2 C), 125.9, 106.2, 60.0, 36.6 (2 C), 14.0 ppm. MS (ESI):
m/z = 264 [M+ + H].
2-Ethoxycarbonyl-1-phenylvinyl Piperidine-1-carboxylate (3l):[11]
Yield 87%; yellow liquid. H NMR (200 MHz, CDCl3): δ = 7.57–
7.61 (m, 2 H), 7.37–7.41 (m, 3 H), 6.23 (s, 1 H), 4.21 (q, J = 7.2 Hz,
2 H), 3.67 (br. m, 2 H), 3.51 (br. m, 2 H), 1.67 (m, 6 H), 1.28 (t, J
= 7.2 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 163.6, 157.7,
151.4, 133.7, 129.9 (2 C), 127.9 (2 C), 125.2, 105.7, 59.4, 45.1, 44.6,
25.7, 24.9, 23.6, 13.5 ppm. MS (ESI): m/z = 304 [M+ + H].
1
Methyl 3-(Dimethylcarbamoyloxy)but-2-enoate (3c):[11] Yield 85%;
2-Ethoxycarbonyl-1-methylvinyl Piperidine-1-carboxylate (3m):[11]
Yield 78%; colourless liquid. 1H NMR (200 MHz, CDCl3): δ =
5.54 (s, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 3.50 (br. m, 4 H), 2.05 (s,
3 H), 1.62 (br., 6 H), 1.24 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 163.9, 160.5, 151.7, 107.8, 59.7, 45.5, 44.9,
29.6, 25.4, 24.2, 21.9, 14.1 ppm. MS (ESI): m/z = 242 [M+ + H].
1
yellow liquid. H NMR (200 MHz, CDCl3): δ = 5.56 (s, 1 H), 3.66
(s, 3 H), 3.04 (s, 3 H), 2.98 (s, 3 H), 2.06 (s, 3 H) ppm. 13C NMR
(50 MHz CDCl3): δ = 164.4, 161.1, 152.9, 107.3, 50.9, 36.4 (2 C),
22.0 ppm. MS (ESI): m/z = 188 [M+ + H].
tert-Butyl 3-(Dimethylcarbamoyloxy)but-2-enoate (3d):[11] Yield
88%; yellow liquid. 1H NMR (200 MHz, CDCl3): δ = 5.46 (s, 1
Ethyl 3-(Diisopropylcarbamoyloxy)-3-phenylacrylate (3n):[11] Yield
75%; yellow liquid. 1H NMR (200 MHz, CDCl3): δ = 7.56–7.60
(m, 2 H), 7.27–7.43 (m, 3 H), 6.21 (s, 1 H), 4.14–4.24 (m, 3 H), 4.94
(m, 1 H), 1.17–1.39 (m, 15 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 164.8, 158.4, 152.1, 135.5, 131.0 (2 C), 129.3 (2 C), 128.5, 107.3,
60.6, 47.7, 47.1, 21.9 (2 C), 21.1 (2 C), 14.9 ppm. MS (ESI): m/z =
320 [M+ + H].
H), 3.02 (s, 3 H), 2.98 (s, 3 H), 2.01 (s, 3 H), 1.44 (s, 9 H) ppm. 13
C
NMR (50 MHz, CDCl3): δ = 163.4, 158.6, 152.9, 109.9, 80.0, 36.4
(2 C), 28.0 (3 C), 21.7 ppm. MS (ESI): m/z = 230 [M+ + H].
Benzyl 3-(Dimethylcarbamoyloxy)but-2-enoate (3e):[11] Yield 99%;
yellow liquid. 1H NMR (200 MHz, CDCl3): δ = 7.34 (m, 5 H), 5.60
(s, 1 H), 5.1 (s, 2 H), 2.89 (s, 6 H), 2.05 (s, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 163.8, 161.2, 152.8, 135.8, 128.4 (2 C), 128.2
(2 C), 128.0, 107.7, 65.8, 36.3, 36.2, 22.0 ppm. MS (ESI): m/z =
264 [M+ + H].
Ethyl 3-(Diisopropylcarbamoyloxy)but-2-enoate (3o):[11] Yield 84%;
colourless oil. 1H NMR (200 MHz, CDCl3): δ = 5.53 (s, 1 H), 4.11
(q, J = 7.2 Hz, 2 H), 3.96 (m, 2 H), 2.04 (s, 3 H), 1.20–1.30 (m, 15
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 163.9, 159.7, 151.3,
107.9, 59.6, 46.5 (2 C), 21.8 (2 C), 21.2 (2 C), 20.4, 14.2 ppm. MS
(ESI): m/z = 258 [M+ + H].
Ethyl 2-(Dimethylcarbamoyloxy)cyclohex-1-ene-carboxylate (3f):[11]
Yield 99%; yellow liquid. 1H NMR (200 MHz, CDCl3): δ = 4.14
(q, J = 7.2 Hz, 2 H), 2.99 (s, 3 H), 2.96 (s, 3 H), 2.26–2.42 (br. m,
4 H), 1.64–1.74 (br. m, 4 H), 1.24 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 166.1, 155.9, 153.8, 117.6, 60.1, 36.4,
Ethyl
2-(Diisopropylcarbamoyloxy)cyclohex-1-ene-1-carboxylate
36.3, 29.6, 25.2, 22.0, 21.7, 13.9 ppm. MS (ESI): m/z = 242 [M+
+
(3p):[11] Yield 85%; yellow oil. 1H NMR (200 MHz, CDCl3): δ =
4.15 (q, J = 7.2 Hz, 2 H), 3.91–3.98 (m, 2 H), 2.40 (br. m, 2 H),
2.28 (br. m, 2 H), 1.71 (br., 4 H), 1.20–1.30 (m, 15 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 166.5, 154.6, 152.2, 117.7, 60.1, 46.3,
H].
Ethyl 3-Dimethylcarbamoyloxy-2-methyl-but-2-enoate (3g):[11] Yield
1
61%; yellow liquid. H NMR (200 MHz, CDCl3): δ = 4.16 (q, J =
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Synthesis of Carbamates from Formamides
29.3, 25.3, 23.4, 23.3, 22.0, 21.7, 21.2, 20.4, 20.1, 14.1 ppm. MS
(br., 1 H), 7.77 (dd, J = 1.8, 7.8 Hz, 1 H), 7.51–7.63 (m, 2 H), 7.29–
7.48 (m, 4 H), 7.09–7.16 (m, 2 H), 3.10 (s, 3 H), 3.01 (s, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 164.2, 155.2, 148.0, 138.1, 131.7,
130.4, 129.9 (2 C), 129.0 (2 C), 126.2, 124.3, 123.2, 119.6, 36.8,
36.6 ppm. MS (ESI): m/z = 285 [M+ + H].
(ESI): m/z = 298 [M+ + H].
2-Acetylphenyl Dimethylcarbamate (5a):[11] Yield 99%; yellow li-
1
quid. H NMR (200 MHz, CDCl3): δ = 7.77 (dd, J = 8.0, 1.8 Hz,
1 H), 7.55 (td, J = 8.0, 1.8 Hz, 1 H), 7.28 (td, J = 8.0, 1.8 Hz, 1
H), 7.14 (dd, J = 8.0, 1.8 Hz, 1 H), 3.15 (s, 3 H), 3.03 (s, 3 H), 2.56
(s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 197.9, 154.3, 149.8,
133.0, 131.4, 129.7, 125.2, 123.8, 36.6, 36.4, 29.4 ppm. MS (ESI):
m/z = 230 [M+ + Na].
2-Acetyl-4-flurophenyl Dimethylcarbamate (5j): Yield 80%; yellow
1
liquid. H NMR (200 MHz, CDCl3): δ = 7.44 (dd, J = 8.7, 3 Hz,
1 H), 7.12–7.21 (m, 2 H), 3.14 (s, 3 H), 3.03 (s, 3 H), 2.55 (s, 3
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 197.2, 162.5, 154.8,
146.4, 133.1, 126.1, 120.3, 116.9, 37.4, 37.0, 30.1 ppm. FTIR (KBr
2-Acetylphenyl Diethylcarbamate (5b):[11] Yield 99%; yellow liquid.
1H NMR (200 MHz, CDCl3): δ = 7.75 (dd, J = 7.8, 1.8, Hz, 1 H),
7.51 (td, J = 8.0, 1.8, Hz, 1 H), 7.27 (td, J = 7.6, 1.2, Hz, 1 H),
7.13 (d, J = 8.0 Hz, 1 H), 3.34–3.55 (m, 4 H), 2.55 (s, 3 H), 1.15–
1.36 (m, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 198.2, 153.7,
149.8, 132.9, 131.9, 129.6, 125.2, 123.7, 42.2, 41.9, 29.5, 14.1,
13.2 ppm. MS (ESI): m/z = 236 [M+ + H].
pellet): ν = 2933, 1727, 1691, 1618, 1585, 1483, 1389, 1265, 1159,
˜
1007, 815, 750, 558 cm–1. UV (MeOH): λmax (logε) = 206 (4.20),
235 (4.25), 289 (4.34) nm. MS (ESI): m/z = 225 [M+ + H]. HRMS
(ESI): m/z [M+ + Na] calcd. for C11H12FNO3Na 248.0699; found
248.0701.
2-Acetyl-4-bromophenyl Dimethylcarbamate (5k): Yield 74%;
colourless oil. 1H NMR (200 MHz, CDCl3): δ = 7.86 (d, J = 2.4
Hz, 1 H), 7.60 (dd, J = 2.4, 1.2 Hz, 1 H), 7.04 (d, J = 8.6 Hz, 1
H), 3.13 (s, 3 H), 3.02 (s, 3 H), 2.54 (s, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 196.5, 153.8, 148.8, 135.7, 132.9, 132.4,
2-Acetylphenyl Piperidine-1-carboxylate (5c):[11] Yield 99%; colour-
less oil. 1H NMR (200 MHz, CDCl3): δ = 7.77 (d, J = 7.8 Hz, 1
H), 7.48 (t, J = 8.0 Hz, 1 H), 7.27 (d, J = 7.4 Hz, 1 H), 7.13 (d, J
= 8.0 Hz, 1 H), 3.65 (br. m, 2 H), 3.52 (br. m, 2 H), 2.56 (s, 3 H),
1.61 (br., 6 H) ppm. 13C MR (50 MHz, CDCl3): δ = 198.0, 153.1,
149.9, 133, 131.6, 129.7, 125.3, 123.9, 45.6, 45.2, 29.7, 25.8, 25.6,
24.2 ppm. MS (ESI): m/z = 248 [M+ + H].
125.6, 118.3, 36.7, 36.4, 29.4 ppm. FTIR (KBr pellet): ν = 2928,
˜
1727, 1690, 1591, 1565, 1472, 1384, 1213, 1160, 1067, 864, 752,
657, 509 cm–1. UV (MeOH): λmax (logε) = 238 (4.40), 291 (4.49),
367 (4.59) nm. MS (ESI): m/z = 285 [M+ + H]. HRMS (ESI): m/z
[M+ + Na] calcd. for C11H12BrNO3Na 307.9898; found 307.9896.
2-Acetylphenyl Diisopropylcarbamate (5d):[11] Yield 87%; colourless
crystalline solid. 1H NMR (200 MHz, CDCl3): δ = 7.73 (d, J =
7.6 Hz, 1 H), 7.49 (t, J = 7.4 Hz, 1 H), 7.26 (t, J = 7.4 Hz, 1 H),
7.12 (d, J = 7.0 Hz, 1 H), 4.21 (m, 1 H), 3.90 (m, 1 H), 2.54 (s, 3
H), 1.33 (t, J = 6.6 Hz, 12 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 198.3, 152.8, 149.6, 132.8, 132.3, 129.4, 125.1, 123.7, 46.9, 46.5,
29.6, 29.5, 21.2, 20.9, 20.4 ppm. MS (ESI): m/z = 264 [M+ + H].
2-Acetyl-4-chlorophenyl Dimethylcarbamate (5l): Yield 66%;
colourless crystalline solid; m.p. 62–64 °C. 1H NMR (200 MHz,
CDCl3): δ = 7.72 (d, J = 2.6 Hz, 1 H), 7.45 (dd, J = 2.6, 0.6 Hz, 1
H), 7.09 (d, J = 8.6 Hz, 1 H), 3.13 (s, 3 H), 3.02 (s, 3 H), 2.54 (s,
3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 196.6, 153.9, 148.3,
132.7, 132.6, 130.8, 129.4, 125.3, 36.7, 36.4, 29.4 ppm. FTIR (KBr
Methyl 2-(Dimethylcarbamoyloxy)-5-methylbenzoate (5e):[11] Yield
pellet): ν = 2928, 1728, 1692, 1570, 1592, 1474, 1386, 1206, 1160,
˜
1
82%; yellow liquid. H NMR (200 MHz, CDCl3): δ = 7.77 (d, J =
1098, 865, 749, 669, 513 cm–1. UV (MeOH): λmax (logε) = 211
(4.25), 235 (4.30), 292 (4.39) nm. MS (ESI): m/z = 242 [M+ + H].
HRMS (ESI): m/z [M+ + Na] calcd. for C11H12ClNO3Na 264.0403;
found 264.0402.
1.6, Hz 1 H), 7.32 (dd, J = 7.8, 1.6 Hz 1 H), 7.05 (d, J = 8.2 Hz, 1
H), 3.88 (s, 3 H), 3.13 (s, 3 H), 3.08 (s, 3 H), 2.36 (s, 3 H) ppm. 13
C
NMR (50 MHz, CDCl3): δ = 165.3, 154.9, 149.1, 135.0, 134.1,
131.7, 123.8, 123.0, 119.6, 51.8, 36.6, 20.5 ppm. MS (ESI): m/z =
238 [M+ + H].
2-Acetylnaphthyl Dimethylcarbamate (5m): Yield 58%; yellow
amorphous solid; m.p. 86–88 °C. 1H NMR (200 MHz, CDCl3): δ
= 8.0–8.05 (m, 1 H), 7.70–7.84 (m, 3 H), 7.53–7.60 (m, 2 H), 3.31 (s,
3 H), 3.0 (s, 3 H), 2.65 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 198.0, 169.9, 154.1, 146.9, 136.1, 128.2, 127.8, 127.6, 127.0, 125.3,
2-Benzoyl-5-methoxyphenyl Dimethylcarbamate (5f):[11] Yield 80%;
colourless crystalline solid. 1H NMR (200 MHz, CDCl3): δ = 7.22–
7.77 (m, 2 H), 7.42–7.56 (m, 4 H), 6.76–6.85 (m, 2 H), 3.86 (s, 3
H), 2.8 (s, 3 H), 2.63 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 194.5, 162.9, 153.6, 151.5, 138.7, 132.2, 132.1, 129.4 (2 C), 128.0
(2 C), 124.1, 111.1, 108.8, 55.6, 36.4, 35.8 ppm. MS (ESI): m/z =
300 [M+ + H].
124.9, 122.8, 36.9, 36.7, 29.8 ppm. FTIR (KBr pellet): ν = 2923,
˜
1728, 1682, 1627, 1598, 1465, 1364, 1273, 1148, 1070, 817, 751,
681, 551 cm–1. UV (MeOH): λmax (logε) = 210 (4.29), 243 (4.35),
284 (4.42), 333 (4.49) nm. MS (ESI): m/z = 258 [M+ + H]. HRMS
(ESI): m/z [M+ + Na] calcd. for C15H15NO3Na 280.0950; found
280.0948.
2-Benzoyl-5-methoxyphenyl Diethylcarbamate (5g):[11] Yield 87%;
1
yellow oil. H NMR (200 MHz, CDCl3): δ = 7.71–7.79 (m, 2 H),
7.41–7.52 (m, 4 H), 6.78–6.84 (m, 2 H), 3.86 (s, 3 H), 3.21 (q, J =
7.0 Hz, 2 H), 3.03 (q, J = 7.0 Hz, 2 H), 1.0–1.13 (m, 6 H) ppm. 13
C
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for all reaction prod-
NMR (50 MHz, CDCl3): δ = 194.5, 162.7, 152.9, 151.3, 138.5,
132.3, 131.9, 129.6 (2 C), 128.1 (2 C), 124.4, 110.9, 108.6, 55.5,
41.9, 41.4, 13.7, 13.0 ppm. MS (ESI): m/z = 328.
ucts.
2-Benzoyl-5-methoxyphenyl Piperidine-1-carboxylate (5h):[11] Yield
67%; colourless oil. 1H NMR (200 MHz, CDCl3): δ = 7.74–7.78
(m, 2 H), 7.42–7.54 (m, 4 H), 6.76–6.85 (m, 2 H), 3.86 (s, 3 H),
3.29 (br. m, 2 H), 3.1 (br. m, 2 H), 1.46–1.56 (m, 6 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 194.5, 189.8, 162.8, 152.4, 151.3,
138.7, 132.3, 132.0, 129.5 (2 C), 128.1 (2 C), 124.3, 111.3, 108.6,
55.6, 44.9, 29.6, 25.3, 24.0 ppm. MS (ESI): m/z = 340 [M+ + Na].
Acknowledgments
Financial support from the National Science Council of Taiwan
(NSC) (grant number 99-2628-B-037-003-MY3) and the Depart-
ment of Health Executive Yuan, Taiwan (grant number DOH101-
TD-C-111-004) is acknowledged. The authors would like to thank
the Center for Research Resources and Development (CRRD),
Kaohsiung Medical University for technical support and services
in LC-MS and NMR analysis.
2-Phenylcarbamoylphenyl Dimethylcarbamate (5i):[11] Yield 64%;
yellow amorphous solid. 1H NMR (200 MHz, CDCl3): δ = 8.59
Eur. J. Org. Chem. 2012, 6760–6766
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6765

J.-J. Wang, F.-R. Chang et al.
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Received: June 6, 2012
Published Online: October 22, 2012
6766
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6760–6766