Simple, copper(I)-catalyzed oxidation of benzylic/allylic alcohols to carbonyl compounds: Synthesis of functionalized cinnamates in one pot

Article abstract of DOI:10.1080/00397911.2013.879389

An environmentally benign [Cu(I)]-catalyzed oxidation of activated (benzylic/allylic) alcohols to the corresponding carbonyl compounds is presented. Interestingly, the reaction was also compatible with benzylic alcohols containing ortho-bromo substituents on the aromatic ring without competing with the expected intermolecular Buchwald coupling. Significantly, the catalytic system enables the synthesis of cinnamate-esters in a sequential domino one-pot fashion via oxidation followed by Wittig-Horner protocol. Copyright

Full text of DOI:10.1080/00397911.2013.879389

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A Simple, Copper(I) Catalyzed Oxidation of Benzylic/
Allylic Alcohols to Carbonyl Compounds: Synthesis of
Functionalized Cinnamates in One-pot
Alavala Gopi Krishna Reddy a , Mahendar Lodi a & Gedu Satyanarayana a
a Department of Chemistry , Indian Institute of Technology (IIT) Hyderabad , Andhra
Pradesh , India
Accepted author version posted online: 16 Apr 2014.Published online: 16 Apr 2014.
To cite this article: Alavala Gopi Krishna Reddy , Mahendar Lodi & Gedu Satyanarayana (2014): A Simple, Copper(I)
Catalyzed Oxidation of Benzylic/Allylic Alcohols to Carbonyl Compounds: Synthesis of Functionalized Cinnamates in One-
pot, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2013.879389
To link to this article: http://dx.doi.org/10.1080/00397911.2013.879389
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A Simple, Copper(I) Catalyzed Oxidation of Benzylic/Allylic Alcohols to Carbonyl
Compounds: Synthesis of Functionalized Cinnamates in One-pot
Alavala Gopi Krishna Reddy1, Mahendar Lodi1, Gedu Satyanarayana1
1Department of Chemistry, Indian Institute of Technology (IIT) Hyderabad, Andhra
Pradesh, India
Address correspondence to Dr. G. Satyanarayana, Department of Chemistry, Indian
Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate Campus,
Yeddumailaram – 502 205, Medak District, Andhra Pradesh, India Tel.: +91(40) 2301
6054, Fax: +91(40) 2301 6032, E-mail: gvsatya@iith.ac.in
Abstract
An environmentally benign [Cu(I)]-catalyzed oxidation of activated (benzylic/allylic)
alcohols to the corresponding carbonyl compounds is presented. Interestingly, the
reaction was also compatible to benzylic alcohols containing ortho-bromo substituent on
aromatic ring without competing with the expected intermolecular Buchwald coupling.
Significantly, the catalytic system enables the synthesis of cinnamate-esters in a
sequential domino one-pot fashion via oxidation followed by Wittig-Horner protocol.
KEYWORDS: Benzylic alcohols; allylic alcohols; [Cu]-catalysis; oxidation; carbonyl
compounds; cinnamates
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INTRODUCTION
The oxidation of alcohols to the corresponding carbonyl functionalities is one of the most
important and extensively used functional group transformations in organic synthesis.
Numerous classical oxidizing reagents like chromium[1] and manganese(IV)[2] oxides,
activated DMSO,[3] and hypervalent iodine based reagents,[4] have been used commonly
for small-scale applications; and pyridine,[2] SO3[5] and NaOCl/TEMPO,[6] have been
developed to accomplish this reaction on a larger scale. In many cases, these reagents are
required in stoichiometric quantities and usually produce environmentally hazardous by-
products and product purification is often challenging. Despite the industrial importance
of this oxidation process, only a few reports are available on efficient transition-metal
(mainly Cu, Pd and Ru) mediated catalytic oxidation of alcohols.[7] In particular, the
mentioned methods were successful only in the presence of an oxidant (i.e. molecular
oxygen, hydrogenperoxide, tertiarybutylperoxides, TBAD and aziridines etc.). It is
conspicuous that the oxidation processes using oxygen or air as the ultimate
stoichiometric oxidant are infrequent, owing to some disadvantages and hurdles that limit
its widespread use in organic synthesis. For example, due to safety concerns associated
with the combination of molecular oxygen (O2) and halogenated organic solvents and
reagents,[8a],[b] large scale applications on aerobic oxidations are constrained.[8b]
Thus, the exploration for methods to oxidize alcohols to the corresponding carbonyl
compounds, in the absence of stoichiometric amount of an oxidant (i.e. either as
molecular oxygen or as an oxidizing agent), to conduct in safe and milder reaction
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conditions using standard organic solvents, has always been in great demand.
Particularly, the oxidation of primary alcohols to aldehydes is a canny and challenging
method, for, the aldehyde products are more susceptible to over oxidation yielding
carboxylic acids. Moreover, utilizing such methods for subsequent transformation in one-
pot or sequential one-pot fashion is even more useful in organic synthesis for
constructing more than one new bonds.[6b,9] In continuation to our research interest in
transition-metal catalysis,[10] here in, we describe a non-toxic, mild, simple and
environmentally benign [Cu(I)]-mediated catalytic method for controlled oxidation of
activated (benzylic/allylic) alcohols to the corresponding carbonyl compounds and an
extension to the formation of functionalized cinnamates.
RESULTS AND DISCUSSION
The study was initiated with benzyl alcohol 1e, to sort out the best optimized oxidation
conditions, using copper catalyst and the results are as described in Table 1. The
treatment of 1e with CuI/Phen catalyst, base tBuOK and solvent CH3CN was unclear
(entry 1, Table 1). On the other hand, in the presence of the same catalyst, but with the
other bases such as Cs2CO3, K3PO4 and K2CO3 in xylene as solvent gave the aldehyde 2e,
in poor to moderate yields (entries 2 to 4, Table 1). Interestingly, yield of 2e was
reasonably increased by changing the solvent to toluene, and particularly, the
combination of CuI/Phen and Cs2CO3/K3PO4 has turned to be satisfying (entries 5 & 6,
Table 1). However, the other variations in the same solvent system retarded the reaction
(entries 7 to 18, Table 1). Gratifyingly, when dioxane was used as the solvent in the
presence of catalyst CuI/Phen (10/20 mol%) and base K3PO4 (2 equiv) gave the product
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aldehyde 2e in very good yield (80%, entry 21, Table 1). On the other hand, the other
variations in dioxane with different Cu(I) or Cu(II) salts with/without the
nitrogen/phosphorous based ligands, gave 2e only in poor yield.
Among all the screened conditions, the trial with catalyst CuI (10 mol%)/Phen (20 mol%)
and base K3PO4 (entry 21, Table 1) emerged to be the best (method A) with regard to the
yield of benzaldehyde product 2e. Therefore, these optimized reaction conditions were
applied to other primary benzylic alcohols to examine the scope and limitations of the
method. Promisingly, the reaction was quite successful and amenable for various systems
ranging from electron withdrawing to electron donating substituents on aromatic rings
and furnished the corresponding benzaldehydes 2a–2m in very good to excellent yields
(Table 2). Notably, the reaction was also compatible to alcohol systems 1f–1m
possessing ortho-bromo substituent on aromatic moiety without competing with the
expected intermolecular Buchwald coupling. Similarly, reaction was also amenable on
secondary benzylic/bi-benzylic alcohols 1o–1w and furnished the corresponding
benzo/bi-benzophenones 2o–2w. However, the reaction of secondary benzylic alcohols
1o–1w was found to be slower than that observed in the case of primary benzylic
alcohols 1a–1m and in a few cases ended-up with the recovery of small quantities of un-
reacted starting material even after 48 h, except the case with secondary bi-benzylic
alcohols 2x–2z where complete conversion has been observed. This may be explained
because of the steric effect of methyl (alkyl) group as well as the mild reactivity of the
catalyst that may prevent the alcohol to form a new co-ordination complex with [Cu]-
catalyst, which is responsible for further break down of the complex to yield the carbonyl
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compound. Notably, the slow reactivity of secondary benzylic alcohols is in good
agreement with that of few previous reports employed with [Cu]-catalyst under aerobic
alcohol oxidation.[11] In contrast, the reaction on cyclic equivalent of secondary benzylic
alcohol, 1aa, gave tetralone 2aa in good yield 60%. Similarly, the secondary alcohol 1ab
underwent oxidation to give the indanone 2ab in 78% based on the recovery of starting
material. Also, it was observed that the allylic alcohol 1ac amenable for oxidation to
yield the corresponding enaldehyde 2ac but still slower than that of primary benzylic
alcohols 1a–1m, while, the reaction on aliphatic primary alcohol 1ae was impeded and
led to the total recovery of starting material.
Moreover we have also performed the reaction on the alcohol 1e, in open air under
optimized conditions i.e. catalyst CuI (10 mol%)/Phen (20 mol%), base K3PO4 (2 equiv.)
in solvent dioxane. The yield of the product 2e was found to be less when compared to
the inert conditions (entry 31, Table 1), whereas, the solvent variation from dioxane to
toluene under the same reaction conditions effected the reaction drastically and produced
the aldehyde 2ae in quantitative yields (entry 32, Table 1). Hence, this condition turned
out to be the best condition (method B) in open air and was applied to other primary,
secondary and bi-benzylic alcohols ranging from withdrawing to donating substituents on
aromatic rings to analyze the validity of the method. Surprisingly, the reaction was quite
successful and amenable for various systems ranging from electron withdrawing to
electron donating substituents on aromatic rings and furnished the corresponding
benzaldehyde products 2a–2m in excellent yields and ketones 2o–2ab in very good
yields (Table 2). As was observed in the inert conditions (method A), the reactions in
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open air (method B) also required more time for secondary alcohols 2o–2ab when
compared to primary alcohols 2a–2m, but with complete conversion in either case unlike
inert conditions (method A). Similarly, the allylic alcohol 1ac was subjected for open air
oxidation to yield the corresponding enaldehyde 2ac in better yields compared to inert
conditions, albeit the reaction is slower than that of primary benzylic alcohols 1a–1m.
Whereas, the aliphatic secondary alcohol 1ad afforded the enone 2ad in good yield with
the recovery of the starting material in both inert and open air conditions. In case of the
aliphatic alcohol 1ae, the reaction did not progress and led to the complete recovery of
starting material as like in the case of inert conditions.
Overall, the presented catalytic system was found to be as efficient as those that have
been developed with the support of oxidant in the case of secondary alcohols[11a] and
aliphatic alcohols[11b–e] and also well efficient in both inert and open air conditions.
From the above observations, it is evident that most often primary benzylic alcohols
undergo oxidation in preference to that of secondary alcohols. These results, particularly
the poor reactivity of secondary alcohols, prompted us to see the possibility for selective
oxidation of primary alcohols over the secondary alcohols. Therefore, the primary 1i and
the secondary 1t benzylic alcohols were subjected to intermolecular competitive
oxidations. Interestingly, chemoselectivity has been observed as expected (Table 3).
Similar kind of selectivity was seen in the case of alcohols 1a and 1e (Table 3). Since
primary aliphatic alcohols were reluctant for the oxidation with this catalytic system, the
alcohols 1h and 1ac were subjected to reaction in-order to see the order of selectivity.
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The reaction afforded the isolation of 2h with the complete recovery of 1ac (Table 3).
The same phenomenon was observed intramolecularly with 100% selectivity in case of
isolated diol 1ad having both benzylic and aliphatic alcohol functionalities resulting in
2ad (Table 3).
A thorough understanding of the reaction mechanism may require a deeper insight,
nevertheless, plausible catalytic mechanistic path can be proposed in two different ways
as depicted in Scheme 1. In one possible route (path A), initially Cu(III) species B may
be generated via oxidative insertion of alcohol into Cu(I)-catalyst A. Though, Cu(III)
species are uncommon, but existence of this species is still acceptable, for example, Yian
Shi et al. proposed the existence of such intermediates in the conversion of alcohols to the
corresponding carbonyls[12] as well as deamination of olefins.[12] Finally, the intermediate
Cu(III) species B may breakdown to regenerate the Cu(I)-catalyst through a five
membered cyclic transition state C with the formation of carbonyl product 2 and the by-
product hydrogen gas. In an alternative route (path B),[7x] a new Cu(I) D intermediate
might form through simultaneous oxidative insertion of alcohol into Cu(I) catalyst A with
the expulsion of HI. The formation of new Cu(I) D intermediate is in good agreement to
that of proposed mechanisms in the previous report by Markó et al.[13] Finally, the
intermediate Cu(I) species D may collapse to regenerate another new Cu(I)-catalyst
through a four membered cyclic station state E with the formation of carbonyl product 2.
Now, this new Cu(I)-system E may be responsible for further catalytic cycle and involve
to convert all starting alcohol into the carbonyl product 2.
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After achieving the oxidation products, aldehydes and ketones 2a–2ad, we checked the
scope and applicability of our present oxidation method for a one-pot conversion of
alcohols 1 to corresponding cinnamates 3 by means of a sequential [Cu]-mediated
catalytic oxidation followed by Horner-Wadsworth-Emmons reaction. Usually, in
particular, the cinnamates 3 of secondary alcohols 1 have been achieved only by a step-
wise ketone formation followed by Horner-Wadsworth-Emmons reaction strategy. To the
best of our knowledge as per the literature there have been no reports on such cinnamates
based on our anticipated one-pot process. In order to achieve the cinnamates, under the
optimized open air [Cu]-mediated catalytic oxidation conditions, the reaction mixture,
after the formation of less polar spot on TLC for carbonyl compounds 2b–2w, was
subjected to in-situ Horner-Wadsworth-Emmons reaction by adding ylide, generated
from NaH and TEPA in THF at ice temperature under nitrogen atmosphere followed by
the reflux for 12 h. The reaction afforded the cinnamates 3b–3w in good yields (62–74%,
Table 4).
CONCLUSION
In conclusion, we have developed an oxidant free, non-toxic, simple and environmentally
benign catalytic method for chemoselective controlled oxidation of activated
(benzylic/allylic) alcohols to the corresponding carbonyl compounds, even amenable on
gram scale and the present strategy has been successfully implemented for the one-pot
generation of cinnamates. Further investigations to develop an efficient catalytic system
for the oxidation of aliphatic (un-activated) alcohols are under progress.
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EXPERIMENTAL
General Procedure-3 (For The Oxidation Followed By A Wittig-Horner Reaction;
GP-3)
In an oven dried Schlenk tube, were added alcohol 1 (68–131 mg, 0.50 mmol), CuI (9.5
mg, 10 mol%), 1,10-Phenanthroline (18 mg, 20 mol%) and K3PO4 (212 mg, 1 mmol)
followed by the addition of toluene (2 mL) at room temperature in open air. The stirred
reaction mixture was heated in an oil bath at 80 °C for 24 h. Progress of the oxidation
was monitored by TLC till the reaction is completed. To the cooled reaction mixture at 0
°C, was added ylide [2.5 mmol, generated from NaH (2.5 mmol) and TEPA (2.5 mmol)
in THF (1.5 mL)] in THF (1.5 mL) under nitrogen atmosphere. Then the reaction mixture
was refluxed at 65 °C for 12 h and monitored by TLC. Then, the reaction mixture was
quenched with aqueous NH4Cl solution and then extracted with CH2Cl2 (3 × 15 mL). The
organic layer was washed with saturated NaCl solution, dried (Na2SO4), and filtered.
Evaporation of the solvent under reduced pressure and purification of the crude material
by silica gel column chromatography (petroleum ether/ethyl acetate) furnished the
cinnamate 3 (62–74%).
Ethyl (2E)-3-(2-Bromo-4,5-Dimethoxyphenyl)But-2-Enoate (3w)
IR (MIR-ATR, 4000–600 cm-1): νmax=2978, 1712, 1640, 1598, 1500, 1439, 1260, 1233,
1159, 1033, 789 cm-1. 1H NMR (CDCl3, 400 MHz): δ=7.00 (s, 1H, Ar-H), 6.64 (s, 1H,
Ar-H), 5.79 (q, 1H, J=1.0 Hz, C(Me)=CHCOOEt), 4.20 (q, 2H, J=7.3 Hz, OCH2CH3),
3.86 (s, 3H, Ar-OCH3), 3.84 (s, 3H, Ar-OCH3), 2.45 [d, 3H, J=1.0 Hz,
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C(CH3)=CHCOOEt], 1.29 (t, 3H, J=7.3 Hz, OCH2CH3) ppm. 13C NMR (CDCl3, 100
MHz): δ=166.4 (s, O=C-O), 156.9 [s, C(CH3)=CHCOOEt], 149.0 (s, Ar-C), 148.2 (s, Ar-
C), 136.8 (s, Ar-C), 120.6 [d, C(CH3)=CHCOOEt], 115.7 (d, Ar-CH), 111.7 (d, Ar-CH),
110.7 (s, Ar-C), 59.9 (t, OCH2CH3), 56.2 (q, Ar-OCH3), 56.1 (q, Ar-OCH3), 20.5 [q,
C(CH3)=CHCOOEt], 14.3 (q, OCH2CH3) ppm. HR-MS (ESI+) m/z calculated for
[C14H17BrNaO4]+=[M+Na]+: 351.0202; found 351.0196.
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra. This material can be accessed on the
publisher’s website.
ACKNOWLEDGMENT
Financial support by the Department of Science and Technology [(CSIR),
02(0018)/11/EMR-II], New Delhi is gratefully acknowledged. A.G. K. R. and L. M.
thank CSIR, New Delhi, for the award of research fellowship.
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Table 1. Screening conditions for Cu-catalysed oxidation of benzyl alcohol 1e.
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Entry Catalyst Ligand
Base
Solvent
Temperature
(oC)
Time
(h)
Yield
of
2e
(%)[a]
CuI
CuI
CuI
CuI
CuI
CuI
CuI
1,10-
tBuOK
Cs2CO3
K3PO4
K2CO3
Cs2CO3
K3PO4
tBuOK
acetonitrile 80
24
24
24
24
24
24
24
─
1[b],[d]
2[d]
phenanthroline
1,10-
xylene
xylene
xylene
toluene
toluene
toluene
120
39
43
10
73
76
48
phenanthroline
1,10-
3[d]
120
120
110
110
110
phenanthroline
1,10-
4[c],
[d]
phenanthroline
1,10-
5[d]
6[d]
7[d]
phenanthroline
1,10-
phenanthroline
1,10-
phenanthroline
─
8[d]
9[d]
CuI
CuI
tBuOK
tBuOK
K2CO3
toluene
dioxane
toluene
110
80
24
24
24
36
45
5
─
10[c] CuI
1,10-
110
phenanthroline
1,10-
11[c] CuI
NaHCO3 toluene
110
110
24
24
0
phenanthroline
2,2’-bipyridyl
12
CuI
Cs2CO3
toluene
23
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13
CuI
K3PO4
K2CO3
Cs2CO3
tBuOK
K3PO4
K3PO4
K3PO4
tBuOK
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
dioxane
110
110
110
110
110
110
80
24
24
24
24
24
24
24
24
28
0
2,2’-bipyridyl
2,2’-bipyridyl
2,2’-bipyridyl
2,2’-bipyridyl
2,6-lutidine
α-picolinic acid
PPh3
14[c] CuI
15
CuI
CuI
CuI
CuI
15
20
33
30
10
60
16
17
18
19[c] CuI
20
CuI
CuI
CuI
1,10-
80
phenanthroline
1,10-
21[d]
K3PO4
dioxane
80
24
80
phenanthroline
─
22
K3PO4
K3PO4
K3PO4
dioxane
dioxane
dioxane
80
80
80
24
24
24
10
─
23[c] CuCl
24[c] CuCl
─
1,10-
10
phenanthroline
─
25[c] CuCl2
26[c] CuCl2
K3PO4
K3PO4
dioxane
dioxane
80
80
24
24
10
15
1,10-
phenanthroline
─
27[c] CuBr
28[c] CuBr
K3PO4
K3PO4
dioxane
dioxane
80
80
24
24
─
1,10-
15
phenanthroline
─
29[c] CuBr2
30[c] CuBr2
K3PO4
K3PO4
dioxane
dioxane
80
80
24
24
10
20
1,10-
phenanthroline
1,10-
31[e] CuI
K3PO4
dioxane
80
24
70
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phenanthroline
32[e]
CuI
1,10-
K3PO4
toluene
80
12
97
phenanthroline
[a] Isolated yield of chromatographically pure product.
[b] Reaction was not clean.
[c] Conversion of the reaction based on TLC.
[d] Reaction was carried out under inert atmosphere.
[e] Reaction was performed under open-air conditions fitted with a condenser.
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Table 2. Cu-mediated catalytic oxidation of benzylic/allylic alcohols 1 to give carbonyl
compounds 2.[a],[b]
[a] All reactions were performed on 0.5 mmol scale of the starting material 1.
[b] Isolated yields of chromatographically pure products.
[c] Yields are based on the recovery of the starting material.
[d] Reactions were carried out on 1 gm scale under open air conditions; accordingly it
took more time than that required for small scale.
[e] No reaction took place, only starting material recovered (80%). The first and second
numbers of parenthesis are isolated yields by the methods A and B respectively.
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Table 3. Selective oxidation of primary benzylic alcohols in preference to secondary
benzylic/primary aliphatic alcohols.[a],[b]
OH
O
CuI (10 mol%)
BnO
MeO
BnO
MeO
BnO
MeO
CHO
Br
BnO
OH
Ph
Ph
1,10-phenanthroline (20 mol%)
+
+
+
K3PO4 (2 equiv), dioxane (2 mL)
Br
Br
MeO
Br
80 ºC, 24 h
1i
1y
2i
2y
1y
(15%) + (60% recovered)
(71%)
OH
Me
O
CuI (10 mol%)
BnO
MeO
MeO
MeO
BnO
MeO
CHO
MeO
MeO
OH
OH
Me
1,10-phenanthroline (20 mol%)
+
+
K3PO4 (2 equiv), dioxane (2 mL)
80 ºC, 24 h
1a
1h
1r
2a
2h
2r
(69%)
(5%) +
1r
(74% recovered)
CHO
CuI (10 mol%)
CHO
Br
OH
1,10-phenanthroline (20 mol%)
+
K3PO4 (2 equiv), dioxane (2 mL)
Br
80 ºC, 24 h
2ae (0%) + 1ae (76% recovered)
1ae
(79%)
CHO
[Cu] / L
OH
OH
base, solvent
heat
OH
method A: 2af (58%) + 1af (30% recovered)
1af
method B: 2af (63%) + 1af (15% recovered)
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Table 4. Sequential one-pot [Cu]-mediated catalytic oxidation followed by Wittig-Horner
reaction.[a],[b]
[a] All reactions were performed on 0.5 mmol scale of the starting material 1.
[b] Isolated yields of chromatographically pure products 3.
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Scheme 1. Plausible mechanism for the conversion of benzylic/allylic alcohols 1 to the
corresponding carbonyl compounds 2.
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