Synthesis of functionalized carbamates and quinones via sequential oxidation of salicylaldehydes using TBHP as the oxidant

Article abstract of DOI:10.1016/j.tetlet.2014.09.080

A sequential oxidative approach was designed to functionalize salicylaldehyde derivatives and provide corresponding bi-functional amide-carbamate and amide-quinone units. A combination of metal/metal free conditions and TBHP as the external oxidant provid

Full text of DOI:10.1016/j.tetlet.2014.09.080

Tetrahedron Letters 55 (2014) 6307–6310
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of functionalized carbamates and quinones via sequential
oxidation of salicylaldehydes using TBHP as the oxidant
⇑
K. Rajendra Prasad, P. Suresh, B. Ravikumar, N. Veera Reddy, K. Rajender Reddy
Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A sequential oxidative approach was designed to functionalize salicylaldehyde derivatives and provide
corresponding bi-functional amide-carbamate and amide-quinone units. A combination of metal/metal
free conditions and TBHP as the external oxidant provided the products in moderate to excellent yields
(49–91%).
Received 14 August 2014
Revised 16 September 2014
Accepted 16 September 2014
Available online 20 September 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Salicylaldehydes
Formamide
Carbamate
Oxidation
Quinones
Cross coupling chemistry is an extremely useful strategy for
making C–C and C-heteroatom bonds. Among them cross dehy-
drogenative couplings (CDC) involving C–H bond activations have
found a wider interest in recent years owing to their synthetic
advantage over the traditional methods, where the involvement
of pre-functionalized substrates makes the synthetic route longer,
less atom-economical and expensive.1 Tremendous progress has
been made in this area and the feasibility of these reactions was
successfully demonstrated for C–C bond formations involving cross
coupling between Csp3-H, Csp2-H and Csp-H bonds in the presence
of various transition metal catalysts.2 In parallel the CDC approach
was also efficiently utilized in the construction of various C-hetero
atom bond processes, notably the formation of C–N, C–O, C–S and
C–P bonds. Majority of these reactions were performed in the pres-
ence of oxidants, which significantly contributes for the thermody-
namic favourability of the reaction.3–6
Phenols are readily available and versatile building blocks in
synthetic organic chemistry. Although it is readily oxidized by
chemical and biological oxidants, its cross coupling chemistry is
particularly challenging because of the problems associated with
self coupling as well as formations of polymeric products. However,
recent investigations by several groups under CDC or oxidative
cross coupling strategies have shown the application of phenols
towards the synthesis of hemiacetals,7 spirolactones,7 dihydroben-
zofurans,8 furanones,9a coumestrol9b and dihydrooxazinones10
under metal and metal-free conditions. Similarly, the cross cou-
pling approach was successfully applied for aromatic aldehydes
for the construction of C–C, C–N and C–O bond formations.11–13
Whereas, a bi-functional moiety such as salicylaldehyde, which is
a highly functionalized aromatic molecule was scarcely been
explored in cross coupling chemistry.14
Our group has been working on oxidative couplings using metal
and non-metal catalysts for the last couple of years.15 During these
investigations it has been shown that direct coupling of aldehydes
with amines and alcohols provides amides and esters.16,17 Sim-
ilarly, synthesis of phenol- and enol-carbamates was demonstrated
via oxidative cross coupling of formamides with phenols and
b-keto esters using copper catalysts.18 Although the latter method
allowed accessing the phenol carbamates, the substrate scope was
limited to 2-carbonyl substituted derivatives. While extending this
work to salicylaldehyde derivatives, surprisingly it has been
observed that the aldehyde functionality was intact. This initial
observation prompted us to look at the possibility of utilizing both
phenolic and aldehyde functionalities under cross dehydrogena-
tion strategies. During the execution of this work with salicylalde-
hydes, Chang and co-workers reported the formation of
carbamates and acetals, where the sensitive aldehyde was
retained.19 A similar observation is also made by Patel and
co-workers in o-arylation of phenol with alkylbenzenes, where
sensitive aldehyde functionality was intact and moreover used as
directing group.20 However, our interest was to activate both the
functional groups either in one-pot or sequential manner to
provide multi-functional chromophores.
⇑
Corresponding author. Tel.: +91 040 27191532; fax: +91 040 27160921.
E-mail addresses: rajender@iict.res.in, rajenderkallu@yahoo.com (K.R. Reddy).
http://dx.doi.org/10.1016/j.tetlet.2014.09.080
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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K. Rajendra Prasad et al. / Tetrahedron Letters 55 (2014) 6307–6310
Table 1
Chromophores having both carbamate and amide functional-
Synthesis of N,N0-dialkyl salicylamides from salicylaldehydesa
ities at ortho-position on aromatic rings have potential usefulness.
For examples, these derivatives show pro-drug activity in inhibit-
ing or modulating the activity of heat shock protein 90 (Hsp90)
(Compound A)21 and also can be used in treatment of illnesses
related to glycine uptake inhibitors (GLYT1) (Compound B).22
Moreover, some of these compounds are used as intermediates in
the synthesis of semivioxanthin and 4-functionalized estrone
derivatives.23 Based on our previous experience with amide and
carbamate work under oxidative cross couplings, we envisaged
that salicylaldehydes having both aldehyde and phenolic function-
alities can be utilized under cross coupling strategy. In this Letter
we report a direct route to access both carbamate and amide
functionalities via sequential oxidative cross coupling of salicylal-
dehyde derivatives with amines and formamides (Scheme 1).
Moreover by application of this procedure one can avoid the usage
of isocyanates, amidoyl chlorides or acid chloride derivatives,
which are generally used in traditional routes. The usefulness
of sequential oxidations is also exploited in the synthesis of
functionalized quinones by making use of one of the amide
intermediates.24
Regarding the amidation of salicylaldehydes, initially it was
thought to investigate with KI/TBHP adopting our previously
reported procedure of oxidative amidation of aldehydes with
amines. However, it has been observed by our group that phenols
undergo electrophilic iodination under KI/TBHP combination and a
similar substitution with salicylaldehydes could hamper the cata-
lytic activity of potassium iodide.25 Among the several reported
procedures in the literature, the best alternative we thought of
for selective amidation of salicylaldehyde derivatives was
oxidative cross coupling under metal-free system reported by Wolf
and Kovi.26 When this procedure was adapted for the reaction
between salicylaldehyde and morpholine, interestingly the reac-
tions work very well and amide product resulted in 72% isolated
yield.27 Subsequently, this metal-free cross coupling strategy was
explored for the amidation with several substituted salicylaldehy-
des and amines. Both electron rich and electron deficient salicylal-
dehydes work very well and provided the respective amidation
products in good to excellent yields. For example, reaction of
morpholine with salicylaldehyde having p-NO2, p-Br, p-OMe and
m-OMe substitutions provided 70–76% of the amide product
(Table 1, 3a–3e). Similarly o-substitution with ethoxy-, methyl-
2 (1.3 mmol)
NH
O
OH
O
3
OH
TBHP in decane(1.5 mmol)
H
N
CH3CN(3 mL)
R
R
1 (1 mmol)
R = H, OCH3, OC2H5, NO2,
Br, CH3, t-Bu
80oC, 3h
N2
O
OH
O
OH
O
OH
O
OH
N
N
N
N
O
O
O
O
O
O
O
3a(72%)
3b(68%)
3c(70%)
3d(76%)
NO
OH
2
OCH
OH
3
Br
O
OH
O
N
O
N
OH
O
O
N
N
O
OCH
3
3e(76%)
3f(62%)
3g(71%)
3h(82%)
O
N
OH
O
OH
O
N
OH
O
N
OH
N
OCH
3
3l(67%)
3j(69%)
3k(75%)
3i(64%)
Br
O
N
OH
O
OH
O
N
OH
OH
O
N
OH
N
OCH
3
OCH
3
3n(68%)
3m(73%)
Br
3o(81%)
3p(72%)
O
N
OH
O
N
OH
O
N
O
N
OH
Ph
HO
3s(81%)
OH
3t(83%)
3r(59%)
3q(68%)
O
OH
O
O
OH
N
N
N
Ph
Ph
Ph
OCH
3
3u(81%)
Isolated yield.
3v(83%)
3w(85%)
a
and tert-butyl groups provided 62–82% of amide product (Table 1,
3f–3h). These results suggest that there is no regular pattern with
respect to electronic and steric influence of substitution on
salicylaldehydes. Further similar observations have been made by
variation of amines with pyrrolidine, piperidine, 4-Me-piperidine
and 4-OH-piperidine (Table 1, 3i–3s). In case of 4-benzylpiperi-
dine, the corresponding amides were formed in excellent yields
(Table 1, 3t–3w) and no oxidation of benzylic carbon was observed.
Formamides have been widely used in cross-coupling reactions
in recent years.28 Our previous work with formamides has shown
the possibility of direct coupling of these groups with substituted
phenols or amines to provide carbamates or ureas, respec-
tively.15f,18 In case of phenols, the reactivity was limited to
2-carbonyl substituted derivatives and corresponding carbamates
were synthesized successfully. Coordinating ability of carbonyl
functionality with copper metal was attributed to the high reactiv-
ity of these derivatives. Moreover, formation of carbamate product
with 2-hydroxy-N-phenylbenzamide provided the scope to extend
for amide functionalities.18 When (2-hydroxyphenyl) (morpho-
lino)methanone (3a) was treated with DMF under the previously
reported conditions, the corresponding carbamate product 5a
formed in high yield.29 Further substrate scope was investigated
with various amide (3a–3w) and formamides and the results are
summarized in Table 2. Irrespective of the substitutions on the aro-
matic ring of the amides the carbamate products (5a–5t) resulted
in good to excellent yields. However, in certain combination of
amides (3) with formamides, we encountered the isolation prob-
lem, because of the closer Rf values of reactants and products. This
could be one of the reasons for the low isolated yield of diethylfor-
mamide products (5r–5t). The product formation was also not
observed with sterically hindered amides 3h, 3r and 3w.
F
F
F
N
N
N
N
O
N
O
O
HO
O
O
O
N
O
N
S
N
O
O
B
A
R5
R6
N
O
O
O
N
OH
O
R1
OH
O
5
H
N
R1
O
O
R1
1
3
N
R1
Further investigations were focused on the functional group
transformation of N,N0-dialkyl salicylamides (3). Since we were
engaged in activation of C–H bonds adjacent to nitrogen hetero
atom, we looked at the possibility of intra molecular oxidative
6
O
Scheme 1.

K. Rajendra Prasad et al. / Tetrahedron Letters 55 (2014) 6307–6310
6309
Table 2
Table 3
Synthesis of ortho functionalized carbamates from N,N0-dialkyl salicylamidesa
Synthesis ortho functionalized benzoquinones from N,N1-dialkyl salicylamidesa
O
O
O
Cu(OAc)2(10mol%)
TBHP in decane(2eq)
O
OH
R1
O
4 (2 mL)
N
H
N
R1
R1
N
R1
OH
O
O
O
N
CH3CN(3 mL)
80oC, 1h
R1
Cu(OAc)2(10 mol%)
R1= H, OCH3, CH3, t-Bu
6
N
N
3 (1 mmol)R1
O
TBHP in decane (1.5 mmol)
80oC, 3h
R
5
O
O
O
O
O
O
O
O
3 (1 mmol)
R1 = Me, Et
O
R= ring substituents
N
N
N
N
O
O
O
O
O
O
O
O
O
6a(52%)b
O
6c
(58%)
6b(84%)
O
O
O
O
6d(64%)
O
O
O
O
N
O
O
N
O
O
N
O
O
N
O
O
N
O
N
O
N
O
N
N
N
N
N
O
O
O
O
O
O
O
5a
5b(56%)
5c(83%)
Br
(91%)
NO2
N
OCH3
O
O
5d(85%)
b
6g
O
O
b
6f
O
O
(49%)
6h(86%)
O
O
(81%)
6e
O
O
O
O
N
(43%)
O
N
O
O
O
O
O
N
O
O
O
N
O
N
O
O
O
O
N
O
O
N
N
N
N
N
OCH3
O
5h(83%)
5g
5e
(68%)
(68%)
5f
(79%)
6i(51%)b
O
6j
O
O
(89%)
6k(55%)
O
6l(68%)
O
O
O
O
O
O
O
O
O
O
O
N
O
O
O
N
N
N
O
N
O
O
N
N
N
N
N
N
N
N
Ph
O
Ph
HO
O
b
6n(54%)b
O
5l(83%)
5i (81%)
5j(67%)
6m
6o(78%)O
(55%)
Br
O
5k(59%)
Br
O
O
O
O
O
O
O
O
N
N
N
O
N
N
O
N
O
O
N
O
O
O
O
N
Ph
Ph
N
N
6p
(61%)
6q
(71%)
O
OCH3
HO
5p(85%)
5m(62%)
5n(73%)
5o (79%)
Ph
b Reaction was carried for 3 h.
O
O
O
a
Isolated yield.
O
N
O
N
O
O
O
O
O
N
O
N
N
N
O
O
O
OCH3
successful with N,N0-dialkyl salicylamides having substitutions
at para- to phenolic functional groups and moreover no
ortho-quinones products were observed.
5q (75%)
5r
(52%)
(53%)
OCH
5s(49%)
5t
Ph
3
NO
2
a
Isolated yield.
In conclusion, we have shown the selective and sequential oxi-
dative cross couplings as one of the novel ways for functional
group transformation involving multifunctional chromophores.
As an example, we have demonstrated the activation of both
aldehyde- and phenolic –OH of salicylaldehyde derivatives and
transform them directly into amide and carbamate groups sequen-
tially under metal/metal-free steps using TBHP as the oxidant. This
method has the advantage over conventional routes by avoiding
the use of hazardous reagents and additional steps. Moreover, we
have also shown the synthesis of functionalized 1,4-benzoquinone
by making use of one of the amide intermediates. The advantages
of sequential oxidative cross coupling for functional group trans-
formation on multifunctional chromophores are presently under
investigation.
cross couplings in 3, where phenolic –OH and C–H bond adjacent
to nitrogen couples to generate cyclic product C (Scheme 2).10,30
Surprisingly the reaction with 3a in the presence of copper catalyst
and TBHP as the oxidant resulted in corresponding 1,4-benzoqui-
none derivative (6a) rather than the cyclic product. Although the
oxidation of phenols to 1,4-benzoquinones is well known in the lit-
erature,31 the direct transformation of substituted salicylamide
derivatives to quinones is not reported. Looking at the synthetic
as well as biological importance of para-quinones, the scope of
the reaction was tested with various salicylamide derivatives and
the results are presented in Table 3.
The reaction of 2-hydroxyphenyl-morpholino methanone (3a)
with 10 mol % of Cu(OAc)2 catalyst resulted in 52% of the
1,4-benzoquinone product 6a in acetonitrile solvent and TBHP as
the external oxidant (Table 3).32 Salicylamide derivatives (3) hav-
ing substitutions at ortho- and meta- to the phenolic functionality
works very well and resulted in corresponding 1,4-benzoquinones
in moderate to good yields (Table 3). Among them methoxy substi-
tution at the meta-position provided higher para-quinone products
6b, 6f, 6j and 6o (Table 3). Even the substitution of the bulky
tert-butyl group at ortho- to the phenolic functionality works very
well and resulted in corresponding quinone product (6d and 6l).
No oxidation of benzylic carbon was observed during the synthesis
of 4-benzylpiperidine derivatives (6n–6q). The reaction was not
Acknowledgments
K.R.P., B.R.K. and N.V.R thank the Council of Scientific and Indus-
trial Research (CSIR) for the award of Research Fellowships. K.R.R.
thanks CSIR for financial support under net-work project CSC-
0123.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.
080.
O
N
O
O
References and notes
O
x
C
N
Cu-Cat, oxidant
O
O
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O
OH
O
N
3a
O
6a
Scheme 2.

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K. Rajendra Prasad et al. / Tetrahedron Letters 55 (2014) 6307–6310
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24. We have also performed the reactions in one-pot to achieve the quinones also.
For example, reacting salicylaldehyde (1 mmol) and morpholine (1.3 mmol)
with 10 mol % of Cu(OAc)2-catalyst in the presence of TBHP for 3 h in
acetonitrile resulted in <5% of quinone (6a) and 17% of amide (3a). We have
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1 mmol of salicylaldehyde and 1.3 equiv of secondary amine were dissolved in
3 mL of CH3CN and 1.5 equiv of TBHP in decane was added dropwise at room
temperature. The reaction mixture was heated to 80 °C and stirred for 3 h
under nitrogen atmosphere and then cooled in to room temperature. The
reaction mixture was poured into water and extracted with ethyl acetate. The
organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was directly purified by column chromatography (hexane–ethyl
acetate v/v 4:1) on silica gel to afford the desired product. The products
were confirmed by 1H, 13C, IR and Mass spectroscopic analysis.
(2-hydroxyphenyl)(morpholino)methanone (3a): Colorless solid, mp 152–
154 °C. 1HNMR (300 MHz, DMSO-d6):
d 9.53 (s, 1H), 7.33 (dt, J = 7.324,
1.678 Hz, 1H), 7.23 (dd, J = 7.782, 1.678 Hz, 1H), 7.01 (dd, J = 8.240, 1.068 Hz,
1H), 6.86 (dt, J = 7.477, 1.221 Hz, 1H), 3.72–3.78 (m, 8H); 13C NMR (75 MHz,
DMSO-d6) d 167.27, 153.23, 130.28, 128.21, 123.54, 119.19, 115.67, 66.23,
46.86, 41.73; IR (KBr, cmꢀ1): 2970, 2925, 2861, 1591, 1447, 1369, 1281, 1222,
1110, 1017, 844, 756, 640, 607, 556, 511; ESI-MS [M+Na]+ m/z 230; HRMS m/z
(ESI) calcd for C11H14NO3Na [M+H]+: 208.09681, found: 208.09676
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29. General procedure for the synthesis of ortho functionalized carbamates: To a
reaction vessel were added 1 mmol of (2-hydroxyphenyl)(pyrrolidin-
1-yl)methanone, 10 mol % of copper acetate and dissolved in 2 mL of
formamide. To the above reaction mixture 1.5 equiv of TBHP in decane was
added drop by drop at room temperature. The reaction temperature was raised
to 80 °C and stirred for 3 h. After completion of the reaction, the reaction
mixture was cooled to room temperature and extracted with ethyl acetate. The
organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (hexane–ethyl acetate v/v
7:3) to afford the corresponding product. The products were confirmed by 1H,
13C, IR and Mass spectroscopic analysis. 2-(morpholine-4-carbonyl)phenyl
isobutyrate (5a): 1H NMR (300 MHz, CDCl3): d 7.38–7.44 (br, 1H), 7.19–7.29
(br, 3H), 3.48–3.82 (br, 6H), 3.29–3.35 (br, 2H), 3.09 (s, 3H), 3.00 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 166.32, 153.43, 147.23, 129.66, 128.35, 126.74, 124.74,
122.59, 66.15, 66.07, 46.89, 41.42, 36.07, 35.87; IR (KBr, cmꢀ1): 2974, 2937,
2869, 1717, 1632, 1511, 1445, 1214, 1165, 753, 633, 489; ESI-MS [M+Na]+ m/z
301; HRMS m/z (ESI) calcd for C
14H18O4N2Na [M+Na]+: 301.11588,
found:301.11525
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32. General procedure for the synthesis of ortho functionalized benzoquinones: To
a reaction vessel were added (2-hydroxyphenyl)(pyrrolidin-1-yl)methanone
(1 mmol), copper acetate (10 mol %) and dissolved in CH3CN (3 mL). To the
above reaction mixture TBHP in decane was added drop by drop at room
temperature. The reaction temperature was raised to 80 °C and stirred for 1 h.
After removal of solvent under reduced pressure, the crude product was
purified by column chromatography (hexane: ethyl acetate v/v 1:1) to afford
the corresponding product. The products were confirmed by 1H, 13C, IR and
Mass spectroscopic analysis. 2-(Morpholine-4-carbonyl) cyclohexa-2,5-diene-
1,4-dione (6a): 1H NMR (300 MHz, CDCl3): d 6.82–6.84 (m, 2H), 6.76–6.78 (m,
1H), 3.70–3.80 (br, 4H), 3.64–3.68 (br, 2H), 3.26–3.30 (br, 2H); 13C NMR
(75 MHz, CDCl3) d 186.30, 184.28, 162.24, 142.64, 136.68, 135.97, 132.76,
66.43, 66.39, 47.25, 42.04; IR (KBr, cmꢀ1): 2962, 2924, 2851, 1631, 1442, 1265,
1201, 842, 543; ESI-MS [M+Na]+ m/z 244; HRMS m/z (ESI) calcd for C9H9NO2Na
[M+H]+: 222.07571, found: 222.07521.
18. Kumar, G. S.; Maheswari, C. U.; Kumar, R. A.; Kantam, M. L.; Reddy, K. R. Angew.
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El-Shazly, M.; Chuang, D.-W.; Cheng, Y.-B.; Wang, J.-J.; Chang, F.-R. Org. Lett.
2014, 16, 1912–1915.
20. Rout, S. K.; Guin, S.; Banerjee, A.; Khatun, N.; Gogoi, A.; Patel, B. K. Org. Lett.
2013, 15, 4106–4109.