Directing group assisted copper-catalyzed chemoselective O-aroylation of phenols and enols using alkylbenzenes

Article abstract of DOI:10.1021/ol401682a

By using alkylbenzenes as aroyl surrogates, copper(II) catalyzed chemoselective O-aroylations of 1,3-dicarbonyl compounds and phenolic-OH ortho to carbonyl (-CHO,-COR) groups have been achieved. A dual mechanism operating in tandem for these transformations has been supported by a crossover experiment.

Full text of DOI:10.1021/ol401682a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Directing Group Assisted Copper-
Catalyzed Chemoselective O‑Aroylation
of Phenols and Enols Using
Alkylbenzenes
Saroj Kumar Rout, Srimanta Guin, Arghya Banerjee, Nilufa Khatun, Anupal Gogoi,
and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039,
India
patel@iitg.ernet.in
Received June 16, 2013
ABSTRACT
By using alkylbenzenes as aroyl surrogates, copper(II) catalyzed chemoselective O-aroylations of 1,3-dicarbonyl compounds and phenolic ÀOH
ortho to carbonyl (ÀCHO, ÀCOR) groups have been achieved. A dual mechanism operating in tandem for these transformations has been
supported by a crossover experiment.
Esterifications are traditionally achieved by reacting
alcohols with carboxylic acids or its derivatives which
often require auxiliary chemicals.1 Besides the recently
improved traditional esterification of alcohols,2 the oxi-
dative esterification of aldehydes3 and carbonylation
of hydrocarbons are some alternative approaches to ester
synthesis.4 Of late, the construction of CÀC and CÀX
bonds via cross dehydrogenative couplings (CDC) is
attractive because it does not require substrate prefunc-
tionalizations and is atom economic.5 The importance
of CÀO bonds in synthetic organic chemistry has resulted
in the development of a variety of CÀH bond functiona-
lization methods mediated by various transition metals.6
Inthis context the ester synthesisisin the vanguard. Recent
synthesis of esters involve reactions of acids with cyclic
(1) Otera, J.; Nishikido, J. Esterification: Methods, Reactions, and
Application; Wiley-VCH: Weinheim, 2003.
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Angew. Chem., Int. Ed. 2011, 50, 5144. (g) Bai, X.; Ye, F.; Zheng, L.; Lai,
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Lei, A. Chem. Commun. 2013, 49, 1324.
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Barkakaty, B.; Talukdar, B.; Patel, B. K. J. Org. Chem. 2003, 68, 2944.
r
10.1021/ol401682a
XXXX American Chemical Society

ethers where the CÀO bond formation takes place at the
sp3 carbon atoms R to the ethereal oxygen.7 Besides these
a number of CDC based approaches employing metal
catalysts such as Cu,3k Ru,8 Rh,9 Ir,10 Pd,11 and Fe12 have
been reported. Pushing the ester synthesis to an extreme
limit of CÀH activation we have developed a metal-free
(Bu4NI and TBHP) CDC approach for the synthesis of
benzylic esters involving only alkylbenzene(s) as a self- or a
cross-coupling partner(s).13 Very specifically regarding the
substrate directed coupling for the synthesis of esters via
O-aroylation processes, there are only two reports where
2-acetylphenols and β-dicarbonyl derivatives or their ana-
logs have undergone directed O-aroylation using aldehydes
as the coupling partners (Scheme 1, path a and b).3d,14
Alkylbenzenes have been excellent aroyl surrogates15
and are the best alternatives toFriedelÀCrafts aroylations.
Benzylic esters are obtained by the CDC coupling of
aldehydes and alkylbenzenes using the Cu(II) catalyst
(Scheme 1, path c).3k Under similar conditions 2-hydro-
xyacetophenones gave phenol esters (Scheme 1, path a).14
Thus it would be interesting to see if salicaldehyde (1)
possessing both phenolic ÀOH and aldehydic functional-
itieswhentreatedwithanalkylbenzene wouldgivebenzylic
ester (Scheme 1, path c)3k or a phenol ester (Scheme 1,
path a).14 Phenolic ester (Scheme 1, path a) is indeed
obtained whether the aldehydic function would survive the
oxidative conditions or not.
With the above possibilities in mind under the identical
reaction conditions,3k when salicaldehyde (1) was treated
with toluene (a) the product isolated (35%) was found to
be a phenolic ester (1a) with the aldehydic group remaining
intact. This is the first observation of its kind where alkyl-
benzene serves as an aroyl source in the O-aroylation of the
ÀOH group for a substrate possessing an ortho ÀCHO
Scheme 1. CDC Protocols for CÀO Bond Formation via CÀH
Activations
Scheme 2. Substrate Scope for the Synthesis of Estersa,b
(7) Chen, L.; Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Lei, H.; Xu, K.; Wan,
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Chem. Soc. 2005, 127, 10840. (b) Zhang, J.; Gandelman, M.; Shimon,
L. J. W.; Milstein, D. Dalton Trans. 2007, 107, 113. (c) Gunanathan, C.;
Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 2009, 131, 3146.
(d) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Chem. Commun.
2008, 624.
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2003, 68, 1601. (b) Dam, J. H.; Osztrovszky, G.; Nordstrøm, L. U.;
Madsen, R. Chem.;Eur. J. 2010, 16, 6820. (c) Watson, A. J. A.;
Maxwell, A. C.; Williams, J. M. J. Org. Lett. 2009, 11, 2667. (d) Shimizu,
K.-I.; Ohshima, K.; Satsuma, A. Chem.;Eur. J. 2009, 15, 9977.
(11) (a) Gowrisankar, S.; Neumann, H.; Beller, M. Angew. Chem.,
Int. Ed. 2011, 50, 5139. (b) Liu, C.; Wang, J.; Meng, L.; Deng, Y.; Li, Y.;
Lei, A. Angew. Chem., Int. Ed. 2011, 50, 5144. (c) Liu, C.; Tang, S.;
Zheng, L.; Liu, D.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2012,
51, 5662. (d) Reddy, R. S.; Rosa, J. N.; Veiros, L. F.; Caddick, S.; Gois,
P. M. P. Org. Biomol. Chem. 2011, 9, 3126.
(12) Luo, F.; Pan, C.; Cheng, J.; Chen, F. Tetrahedron 2011, 67, 5878.
(13) Majji, G.; Guin, S.; Gogoi, A.; Rout, S. K.; Patel, B. K. Chem.
Commun. 2013, 49, 3031.
(14) Kumar, G. S.; Maheswari, C. U.; Kumar, R. A.; Kantam, M. L.;
Reddy, K. R. Angew. Chem., Int. Ed. 2011, 50, 1.
(15) (a) Guin, S.; Rout, S. K.; Banerjee, A.; Nandi, S.; Patel, B. K.
Org. Lett. 2012, 14, 5294. (b) Yin, Z.; Sun, P. J. Org. Chem. 2012,
77, 11339. (c) Wu, Y.; Choy, P. Y.; Mao, F.; Kwong, F. Y. Chem. Commun.
2013, 49, 689. (d) Weng, J.; Yu, Z.; Liu, X.; Zhang, G. Tetrahedron Lett.
2013, 54, 1205. (e) Xu, Z.; Xiang, B.; Sun, P. RSC Adv. 2013, 3, 1679.
a Reaction conditions: phenols (1À7) (1 mmol), alkylbenzenes (aÀc)
(5 mmol), Cu(OAc)2 2H2O (0.2 mmol), TBHP (2 mmol), 120 °C, time
3
3À7 h. b Reactions were monitored by TLC. Confirmed by spectroscopic
analysis. Yield of isolated pure product reported.
B
Org. Lett., Vol. XX, No. XX, XXXX

group. Yet, under the identical conditions phenol failed to
give any trace of ester, confirming the need for the ortho
carbonyl (ÀCHO) functionality for this esterification.
Encouraged by this unprecedented result, further opti-
mizations were carried out to achieve a better yield of
the product (1a). Details of optimizations are shown in Table
S1 (see Supporting Information [SI]). Substrate salicaldehyde
present in the aryl ring of 2-hydroxyacetophenone were
next investigated. The presence of electron-donating
substituents as in the case of 2-hydroxy-5-methylaceto-
phenone (5) underwent facile reactions with toluene (a),
p-xylene (b), and p-chlorotoluene (c) giving good to mod-
erate yields of their corresponding O-aroylated products,
5a, 5b, and 5c (Scheme 2). However, a substrate possessing
an electron-withdrawing group (ÀCl) as in the case of
5-chloro-2-hydroxyacetophenone (6) coupled with toluene
(a) and p-xylene (b) sluggishly provided poorer yields for
products 6a and 6b respectively. Due to the presence of
ÀCOCH3 as the directing group in 2,4-dihydroxyaceto-
phenone (7), the o-hydroxyl group is selectively aroylated
without affecting the p-hydroxyl group. Because of the
electron-donating ability of the p-hydroxyl group the yield
of the product 7b obtained was better compared to the
analogous substrate (6) possessing an electron-withdrawing
group (ÀCl) giving product 6b. Thus it is evident that the
presence of electron-donating groups in either of the aryl
rings (o-hydroxy carbonyl compounds and alkylbenzenes)
gives better yields while the presence of electron-withdraw-
ing groups result in inferior yields. However, alkyl hetero-
aryls such as 2-methylpyridine, 3-methylpyridine, and
2-methylimidazole did not serve as aroyl surrogates in
O-aroylation reactions.
(1) (1 equiv), toluene (5 equiv), catalyst Cu(OAc)2 2H2O
3
(20 mol %), and oxidant TBHP in decane (5À6 M) (2 equiv)
at a temperature of 120 °C gave the best possible yield after
3 h (Table S1, SI). These optimized conditions were used for
all other reactions.
Further reactions were investigated with a set of sub-
stituted alkylbenzenes and phenols possessing an ortho
ÀCHO group. The reaction of p-xylene (b) with 2-hydro-
xybenzaldehyde (1) gave a moderate yield of its mono
O-aroylated product (1b) without affecting the other methyl
group (Scheme 2). The structure of the product (1b) has been
unequivocally confirmed by crystal X-ray crystallography as
shown in Figure S1 (see SI). The survival of the aldehydic
group and retention of one of the aryl ÀCH3 groups in the
product (1b) can be clearly seen in Figure S1. The reaction
of p-chlorotoluene (c) possessing an electron-withdrawing
group (ÀCl) with 1 proceeded slowly giving product 1c
in 45% yield. This suggests a significant electronic effect on
the rates of the reactions and hence on the product yields
(Scheme 2). Next a sterically hindered phenol, 2-hydroxy-
3-methoxybenzaldehyde (2), was reacted with toluene (a)
and p-xylene (b), and the reaction provided their O-aroylated
products, 2a and 2b, respectively but in lower yields
(Scheme 2). The lesser yields of 2a and 2b could be attributed
to the steric factor imparted by the adjacent methoxy group
in 2. The naphthoic hyrdoxyl group possessing an aldehydic
functionality in its adjacent position as in the case of
2-hydroxy-1-naphthaldehyde (3) coupled efficiently with
p-xylene (b) giving O-aroylated product 3b in a modest yield
(Scheme 2).
Scheme 3. Substrate Scope for the Synthesis Enolestersa,b
The use of acid as a directing group as in the case of
salicylic acid failed to give phenol ester suggesting the poor
directing ability of the ÀCOOH group compared to the
ÀCHO group. While the carboxylic group in salicylic acid
failed to act as a directing group in providing phenol ester,
the aldehydic functionality in o-hydroxy aldehydes served
as an efficient directing group during the O-aroylation
process. So the obvious query arises whether the o-COCH3
group can serve as the directing group in this process.
The reaction of 2-hydroxyacetophenone (4) with a set of
methylarenes viz. toluene (a), p-xylene (b), and p-chloro-
toluene (c) gave moderate yields of their respective
O-aroylated products, 4a, 4b, and 4c (Scheme 2). Besides
alkylbenzenes, 2-methylnaphthalene (f) could also be em-
ployed as an aroyl source in the O-aroylation reaction
with 4 giving corresponding product 4f in modest yield
(Scheme 2).
a Reaction conditions: 1,3-dicarbonyl (8À10) (1 mmol), alkylben-
zenes (aÀe) (5 mmol), Cu(OAc)2 2H2O (0.2 mmol), TBHP (2 mmol),
3
120 °C, time 3À5 h. b Reactions were monitored by TLC. Confirmed by
spectroscopic analysis. Yield of isolated pure product reported.
The product yields obtained from substrate 4 are better
compared to those obtained using substrate 1 which is
probably due to the better stability of the acetyl group in 4
under the oxidative conditions compared to the aldehydic
functionality in 1 (Scheme 2). The substituent effects
o-Hydroxyl carbonyl compounds and the (Z)-enol
form of 1,3-dicarbonyl compounds have structural anal-
ogy so far as the orientation and positioning of carbonyl
and hydroxyl groups are concerned. To unravel the po-
tentiality of this approach various 1,3-dicabonyl substrates
Org. Lett., Vol. XX, No. XX, XXXX
C

were reacted with different alkylbenzenes. β-Carbonyl com-
pounds, methylacetoacetate (8) when treated with toluene
(a), p-xylene (b), and p-chlorotoluene (c), all gave their enol
esters 8a, 8b, and 8c respectively in good yields (Scheme 3).
It may be mentioned here that β-carbonyl compounds
and CÀH bonds adjacent to heteroatoms usually form
an (sp3)CÀ(sp3)C bond rather than (sp3)CÀO bond under
various metal catalyzed conditions.5a,b Apparently there
are few reports on (sp3)CÀO bond formations involving
β-carbonyl compounds resulting in enol ethers,16 enol
carbamates,14 and even enol esters.3d Moving further, with
this strategy other 1,3-dicarbonyl compounds such as ethy-
lacetoacetate (9) under the optimized conditions underwent
cross dehydrogenative coupling with toluene (a), o-xylene
(d), and p-nitrotoluene (e) giving enol esters 9a, 9d, and
9e respectively in good yields. Alkylbenzenes possessing
electron-withdrawing groups gave lesser yields of products
compared to those having electron-donating groups, an
observation consistent with the results in Scheme 2. Finally,
1,3-diphenyl-1,3-dione (10) formed enol esters 10a and
10e in modest yields when treated with toluene (a) and
p-nitrotoluene (e) (Scheme 3). All these reactions provided
highly stereoselective (Z)-enol esters with no loss in stereo-
selectivity (Scheme 3).
From the observations of the control experiments that
were performed, a dual mechanism operating in tandem
has been proposed for these reactions. The presence of
a radical quencher (TEMPO) retards the CDC reaction
between 2-hydroxyacetophenone (4) and toluene (a) giving
a <10% yield of the product indicating the radical nature
of the mechanism. The reagent TBHP is capable of serving
as both an oxidant and a radical initiator in these trans-
formations. A large kinetic isotope effect (KH/KD ∼7.8)
was observed when the reaction of deuterated toluene
(d8 toluene) was carried out with 2-hydroxyacetophenone
(4) suggesting that benzylic CÀH bond cleavage to be
the rate-determining step. Based on these observations,
two possible mechanisms can be envisaged. The first one
possibly involves the radical coupling of the benzylic
radical and the phenolic ÀOH via the Cu complexes I
and II to form O-benzylated intermediate III as depicted in
Scheme S1 (see SI). The O-benzylic position of III perhaps
undergoes oxidation to give corresponding phenol ester
(4a) as shown in Scheme S1. In an alternative mechanism,
the radical coupling of the in situ generated benzaldehyde
(from toluene) with phenolic OÀH cannot be ruled out
as shown in Scheme S2 (see SI). Further, the possibility of
both mechanisms operating in tandem cannot be ignored.
To ascertain the exact nature of the mechanism, a
crossover experiment was performed in which an equimo-
lar mixture of 2-hydroxyacetophenone (4), p-methyl-
benzaldehyde, and toluene (a) were reacted under the
present experimental conditions (Scheme 4). Interestingly,
Scheme 4. A Crossover Experiment
products 4a and 4b were formed in the ratio 1:2. This
experiment supports the dual nature of the mechanism:
one involving the benzyl radical path,17 and the other, the
aroyl radical (Schemes S1 and S2; see SI). Had the reac-
tion proceeded only via the aroyl radical path (Scheme S2),
then the product (4b) derived from activated aldehyde
p-methylbenzaldehyde could have been the sole product.
Theratio of theproductobtainedsuggeststhatthe reaction
proceeded faster with preformed aldehyde (Scheme S2; see
SI) than by the benzyl radical insertion path (Scheme S1;
see SI). In further support of the mechanism in Scheme S1,
when the presynthesized benzyl ether (III) was subjected to
the present reaction conditions it gave the expected product
(4a) (Scheme S3; see SI). However, the intermediate (III)
could not be detected during the GC-MS analysis of the
reaction mixture which is possibly due to its rapid oxidation
to the phenol ester (4a). Detection of traces of benzaldehyde
and benzylalcohol by GC-MS analysis of the reaction be-
tween 4a and toluene (a) originating possibly via the radical
oxidation of toluene supports mechanism S2 (see SI). All
other steps and proposed intermediates in Schemes S1 and S2
are similar to the one proposed by Li et al.3d
In conclusion, a new, efficient Cu-catalyzed directed
O-aroylation process (esterification) has been accom-
plished between alkylbenzenes and o-carbonylphenols
and β-dicarbonyl compounds using TBHP as the oxidant.
A dual mechanism operates in tandem for these transfor-
mations. This protocol simultaneously installs two CÀO
bonds at the expense of three benzylic sp3 CÀH bonds. The
phenolic group is selectively aroylated (esterified) even in
the presence of aldehydic functionality.
Acknowledgment. B.K.P. acknowledges the support
of this research by the Department of Science and Tech-
nology(DST) (SR/S1/OC-79/2009), New Delhi, andCSIR
(02(0096)/12/EMR-II. S.G., S.K.R., N.K., and A.B. thank
CSIR for fellowships. Thanks are due to Central Instru-
ments Facility (CIF) IIT Guwahati for NMR spectra.
Supporting Information Available. General informa-
tion, experimental procedures, spectral data, and copies
of 1H and 13C NMR spectra for all products. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(16) Kumar, G. S.; Pieber, B.; Reddy, K. R.; Kappe, C. O. Chem.;
Eur. J. 2012, 18, 6124.
(17) (a) Xie, P.; Xie, Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H. J. Am.
Chem. Soc. 2012, 134, 9902. (b) Xie, P.; Xia, C.; Huang, H. Org. Lett.
2013, 15, 3370.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX