Palladium-catalyzed acylation of 2-aryl-1,2,3-triazoles with aldehydes

Article abstract of DOI:10.1002/adsc.201300912

The palladium-catalyzed acylation of 2-aryl-1,2,3-triazoles with aldehydes via C-H bond activation is described. A wide variety of products was isolated in good to excellent yields. This finding provides a new and useful strategy for the synthesis of aromatic ketones.

Full text of DOI:10.1002/adsc.201300912

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DOI: 10.1002/adsc.201300912
Palladium-Catalyzed Acylation of 2-Aryl-1,2,3-triazoles with
Aldehydes
Zechao Wang,a Qinshan Tian,a Xin Yu,a and Chunxiang Kuanga,b,*
a
Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092, Peopleꢀs Republic of China
E-mail: kuangcx@tongji.edu.cn
Key Laboratory of Yangze River Water Environment, Ministry of Education, Siping Road 1239, Shanghai 200092,
b
Peopleꢀs Republic of China
Received: October 11, 2013; Revised: December 3, 2013; Published online: March 17, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300912.
Abstract: The palladium-catalyzed acylation of 2-
aryl-1,2,3-triazoles with aldehydes via C H bond
activation is described. A wide variety of products
was isolated in good to excellent yields. This finding
provides a new and useful strategy for the synthesis
of aromatic ketones.
tive auxiliaries in adjusting the palladium-catalyzed
C H activation. In 2008, Ackermann reported car-
[9]
À
À
boxylic acids as cocatalysts for generally applicable
direct arylations in apolar solvents.[10] In 2009, Acker-
mann also reported the ruthenium-catalyzed direct ar-
ylations of N-aryl-1,2,3-triazoles with aryl chlorides as
electrophiles.[11] 1,2,3-Triazoles, which have been
known for decades, have become one of the most im-
portant heterocycles in current chemical research.[12]
Recently, these compounds have found applications
in biological science,[13] material chemistry,[14] and me-
dicinal chemistry[15] (Scheme 2). Reports on the reac-
Keywords: acylation; 2-aryl-1,2,3-triazoles; cataly-
À
sis; C H activation; palladium
À
tion of a C H bond with C-hetero unsaturated bonds
Transition metal-catalyzed direct C H bond function- are rare.[16] Moreover, the catalytic and direct intro-
alization has emerged as an important transformation duction of carbonyl functional groups into the phenyl
À
in organic chemistry.[1] Palladium-catalyzed regiose- ring via C H bond cleavage is appealing in organic
À
lective C H functionalization has been extensively chemistry.[17] Many directing groups, such as acetyl,[18]
À
exploited.[2] The combination of transition metals and acetamino,[19] and carboxyl[20] groups, have been used
À
À
directing groups is a useful method to facilitate C H in C H bond activation, especially in ortho-aromatic
bond cleavage.[3] Recently, Cheng reported a palladi- C H bond functionalization.
Given the electron-
[21]
À
um-catalyzed direct access to ketones from aldehydes poor nature of the triazole ring, the direct acylation
[4]
À
via the C H cleavage of arenes. Later, Kim de-
scribed the palladium-catalyzed oxidative ortho-acyla-
tion of triflamide-protected benzylamines with aryl
[5]
À
and alkyl aldehydes via C H bond activation. At
the same time, Fu reported a novel and efficient pal-
ladium-catalyzed synthesis of aromatic ketones and
isoindolobenzimidazoles via selective aromatic C H
À
bond acylation with readily available carboxylic
acids.[6] In 2012, Floris Chevallier reported that 2-
Scheme 1. Synthesis of phenyl(2-phenyl-2H-1,2,3-triazol-4-
yl)methanone.
phenyl-2H-1,2,3-triazole prepared in situ from CuCl
and LiTMP by using a lithium-copper base produced
a phenyl ketone under particular reaction conditions
(Scheme 1).[7]
To the best of our knowledge, the direct acylation
of 1,2,3-triazole rings is limited to 2-aryl-1,2,3-tri-
ACHTUNGTRENNUNGazoles. In a broad spectrum of biologically active
products, 1,2,3-triazoles function as useful structural
elements.[8] Recently, Ye reported the application of
1,2,3-triazole-4-carboxylic acid derivatives as alterna- Scheme 2. Suvorexant.
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Table 1. Selected optimization of reaction conditions.[a]
Scheme 3. Transition metal-catalyzed oxidative acylation.
of 2-aryl-1,2,3-triazole has not yet been reported. In-
spired by our recent studies on transition metal-cata-
lyzed oxidative acylation of 2-aryl-1,2,3-triazoles with
aldehydes,[15c–h] we report herein the palladium-cata-
À
lyzed ortho-acylation of 2-aryl-1,2,3-triazoles via C H
bond activation (Scheme 3).
Our initial investigations focused on the reaction of
2-phenyl-2H-1,2,3-triazole (1a) with benzaldehyde
(2a). The combination of 2-phenyl-2H-1,2,3-triazole
(1a, 1 equiv.) with benzaldehyde (2a, 1.1 equiv.),
TBHP (2 equiv.), and Pd
at 808C for 15 h generated the acylated product [2-
(2H-1,2,3-triazol-2-yl)phenyl](phenyl)methanone (3a)
ACHTUNGRTEN(NNUG OAc)2 (10 mol%) in DCE
AHCTUNGTRENNUNG
with a yield of 80% (Table 1, entry 1). Based on this
initial finding, further investigations on the effect of
various reaction conditions were performed, as shown
in Table 1. Considering the stability of 1a, the use of
PdACHTUNGTRENNUNG(OAc)2 and tert-butyl hydroperoxide (TBHP,
70 wt% in water) was necessary in the model reac-
tion. Solvent screening showed that an improved
chemical yield could be obtained by using DCE as
the solvent, whereas other solvents, such as DMSO,
benzene, MeCN, 1,2-dioxane, and DMF, were less ef-
fective (Table 1, entries 2–6). The oxidants had a criti-
cal function in this reaction. Aldehydes are very sensi-
tive to several oxidants. Thus, the choice of oxidant is
crucial for the reaction conditions.[22] When various
oxidants were used, TBHP gave the best results,
[a]
Reaction conditions: 1a (0.4 mmol), 2a (0.44 mmol), cata-
lyst (quantity noted), oxidant (quantity noted), solvent
(2 mL) for 15 h in a pressure tube.
Isolated yield.
[b]
whereas a,a-dimethylbenzyl hydroperoxide (DTBP), amount of Pd
H2O2 (70 wt% in water), benzoyl peroxide (BPO), (Table 1, entry 26). The best result was obtained using
lauroyl peroxide (LPO), dicumyl peroxide (DCP), 10 mol% of Pd(OAc)2 and 1 equiv. of TBHP in DCM
Cu(OAc)2, Ag2CO3, K2S2O8, and O2 were all found to at 808C for 15 h to afford 3a in high yield (85%), as
be inferior (Table 1, entries 7–15). On the other hand, shown in entry 21.
ACHTUNGERTN(NUNG OAc)2 (5 mol%), the yield decreased
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
the use of oxidants such as Cu
was inefficient (Table 1, entries 12 and 13).
(OAc)2 and Ag2CO3
Having these optimized conditions in hand, we ex-
plored different substituted aldehydes, which were re-
The effect of various transition metal catalysts was acted with 2-phenyl-2H-1,2,3-triazole (1a) to generate
À
further investigated. The catalyst NiCl2 only gave the desired ortho C H bond acylation product, as
a 10% yield (Table 1, entry 16). The use of Cu
A
FeCl2, and AgNO3 was ineffective for this reaction duced moderate yields. Although we have not carried
(Table 1, entries 17–19). When PdCl2 was used as the out a detailed study of substituent effects, benzalde-
catalyst in the reaction, 3a was obtained with a yield hyde gave higher yields than those with electron-with-
of 52% (Table 1, entry 20). PdACTHNUTRGENUN(G OAc)2 showed excel- drawing or electron-donating groups. The use of sub-
lent activity among these catalysts. When the amount stituents with strong electron-withdrawing character
of TBHP (1 equiv.) was decreased, the conversion of (e.g., CF3) resulted in low yields. The use of 4-nitro-
the reaction increased up to 85% (Table 1, entry 21). benzaldehyde, N,N-dimethylformamide (DMF) and
More TBHP was able to oxidize the aldehydes. When formaldehyde failed to deliver the acylation product
the temperature was either increased or decreased, an via this procedure. Remarkably, halogen-substituted
obvious decline was observed in the yield (Table 1, aldehydes were smoothly converted to the corre-
entries 22–25). Meanwhile, when we decreased the sponding products 3g–l, which were obtained with
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Palladium-Catalyzed Acylation of 2-Aryl-1,2,3-triazoles with Aldehydes
À
Table 2. Scope of aldehydes for Pd-catalyzed C H acyla-
presence of an ortho-substituted group was not suita-
ble in this C H activation reaction. Moreover, the
ACHTUNGTRENNUNG
tion.[a]
À
steric effects of the ortho-substituted group was more
pronounced compared with those of the para-substi-
tuted group. To our delight, this reaction was not lim-
ited to aryl aldehydes. Aliphatic aldehydes also par-
ticipated in this reaction (3m--3p). The tolerance of
the reaction to these functional groups in the sub-
strates provides the possibility for the further useful
transformation of the products.
To evaluate further the substrate scope of this pro-
cess, a variety of 2-aryl-1,2,3-triazoles (1b–f) and alde-
hydes (2b, 2n, 2q) in identical reaction conditions
were screened, as shown in Table 3. As expected,
a series of functional groups on the phenyl ring of 2-
aryl-1,2,3-triazoles, such as Me, OMe, Cl, CF3 and
COOMe, were compatible with this procedure, and
the acylation products were isolated in moderate to
good yields (Table 2, entries 1–10). An interesting re-
gioselectivity was observed when a meta-substituent
existed at 2-phenyl-2H-1,2,3-triazole, in which only
the acylation at the para-position of this substituent
took place because of the steric hindrance (4a, 4d).
The substituted aldehydes with electron-withdrawing
groups on the benzene rings (e.g., 2q) were favored in
the reaction to form the desired products in good
yields (Table 3, entries 4–7). By contrast, electron-do-
nating aldehydes 2b were relatively less reactive in
these reaction conditions. We believe that this reac-
tion may be blocked by the electrophilic attack of the
Pd(II) center to the phenyl ring. The hindrance on
the aryl group of 2-aryl-1,2,3-triazoles limited the
yield of the reaction.
Based on previous studies and our observations,
a proposed mechanism is outlined for the Pd-cata-
À
lyzed C H acylation in Scheme 4. First, through the
chelate-directed C H activation of 2-phenyl-2H-1,2,3-
À
triazole, a five-membered cyclopalladated intermedi-
ate A, which was confirmed by many previous re-
ports, is formed.[4,21b,23] In fact, a similar metalocycle is
obtained through the use of a coordinating group that
À
helps direct the subsequent transition metal C H
bond insertion.[24] The high regioselectivity, as well as
the high catalytic activity of the isolated cyclopalla-
dated complex A, provides a strong evidence that
supports this step.[25] The reaction of benzaldehyde
with TBHP generates a reactive benzoyl radical,
which reacts with intermediate A to carry out the oxi-
dation of Pd(II) to the dimeric PdACHTUNGTRNEUNG
(III) or Pd(IV) B.[2d]
[a]
[b]
Reaction conditions: 1a (0.4 mmol), 2a–p (0.44 mmol),
Pd(OAc)2 (10 mol%), TBHP (0.4 mmol, 70 wt% in
water), DCE (2 mL) at 808C for 15 h in a pressure tube.
Finally, the intermediate B undergoes reductive elimi-
nation to generate the acylation product. At the same
time, Pd(II) is regenerated for the next catalytic
cycle.[26]
ACHTUNGTRENNUNG
Isolated yield.
In conclusion, we have demonstrated a simple and
yields of 55–72%. Different substituent positions of efficient method for the Pd-catalyzed oxidative ortho-
the benzaldehydes affected the yield of the products. acylation of 2-aryl-1,2,3-triazoles with aldehydes via
À
Thus, 3g–k were isolated in yields of 55–72%. The C H bond activation. This method is very convenient
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Zechao Wang et al.
Table 3. Scope of 2-aryl-1,2,3-triazoles.
Table 3. (Continued)
[a]
[b]
Reaction conditions:
1
(0.4 mmol),
2
(0.44 mmol),
Pd(OAc)2 (10 mol%), TBHP (0.4 mmol, 70 wt% in
AHCTUNGTRENNUNG
water), DCE (2 mL) at 808C for 15 h in pressure tubes.
Isolated yield.
and atom-economic for the direct synthesis of aromat-
ic ketones from aldehydes. The oxidant TBHP, which
is inexpensive and environmentally benign, was em-
ployed in these reactions. The reaction exhibited good
functional group tolerance. The mild reaction condi-
tions employed in this reaction provide future poten-
Scheme 4. Plausible mechanism.
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Palladium-Catalyzed Acylation of 2-Aryl-1,2,3-triazoles with Aldehydes
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Experimental Section
Typical Procedure for the Acylation of 2-Aryl-1,2,3-
triazoles
Benzaldehyde (2a) (46.64 mg, 0.44 mmol, 1.1 equiv.) was
added to an oven-dried, sealed tube charged with 2-phenyl-
2H-1,2,3-triazole (1a) (58 mg, 0.4 mmol, 1 equiv.), PdACTHNUTRGNEUNG(OAc)2
(9 mg, 0.04 mmol, 10 mol%), and TBHP (51.4 mg, 0.4 mmol,
1 equiv.) in DCE (2 mL). The reaction mixture was stirred
at 808C for 15 h. After the reaction was completed (as
monitored by TLC), the mixture was cooled to room tem-
perature. The solvent was then evaporated under vacuum.
The resulting residue was purified via flash column chroma-
tography (petroleum ether/ethyl acetate=10:1, v/v) to yield
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[2-(2H-1,2,3-triazol-2-yl)phenyl]ACTHNUTRGNEUNG(phenyl)methanone (3a).
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The present work was supported by the Natural Science
Foundation of China (No. 21272174), the Key Projects of
Shanghai in Biomedicine (No. 08431902700), and the Scien-
tific Research Foundation of the State Education Ministry for
Returned Overseas Chinese Scholars. We also thank the
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