Palladium-catalyzed oxidative acylation of N-benzyltriflamides with aldehydes via C-H bond activation

Article abstract of DOI:10.1002/adsc.201200889

A palladium-catalyzed ortho-acylation of N-benzyltriflamides with aldehydes via direct sp² C-H bond activation is described. Benzylamines with a triflamide directing group in the presence of palladium acetate, acetic acid, and tert-butyl hydroperoxide as an oxidant can be effectively coupled with aryl and alkyl aldehydes to provide ortho-acyl-N-benzyltriflamides with a high regioselectivity.

Full text of DOI:10.1002/adsc.201200889

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DOI: 10.1002/adsc.201200889
Palladium-Catalyzed Oxidative Acylation of N-Benzyltriflamides
À
with Aldehydes via C H Bond Activation
Satyasheel Sharma,a,b Jihye Park,a,b Eonjeong Park,a Aejin Kim,a Minyoung Kim,a
Jong Hwan Kwak,a Young Hoon Jung,a and In Su Kima,*
a
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
Fax : (+82)-31-292-8800; e-mail: insukim@skku.edu
These authors contributed equally
b
Received: October 3, 2012; Revised: November 2, 2012; Published online: January 29, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200889.
Abstract: A palladium-catalyzed ortho-acylation of
N-benzyltriflamides with aldehydes via direct sp2
C H bond activation is described. Benzylamines
with a triflamide directing group in the presence of
palladium acetate, acetic acid, and tert-butyl hydro-
peroxide as an oxidant can be effectively coupled
with aryl and alkyl aldehydes to provide ortho-acyl-
N-benzyltriflamides with a high regioselectivity.
and aryl aldehydes to afford aryl ketones.[13] Later,
2
À
palladium-catalyzed sp C H bond acylations of 2-ar-
ylpyridines,[14] oxime,[15] acetanilides,[16] and indole[17]
À
with aldehydes or alcohols were described. Decarbox-
[18]
À
ylative C H bond acylations of arylpyridines, acet-
A
anilides,[19] and enamides[20] using a-oxocarboxylic
acids as acyl surrogates were also reported. Further-
more, the Pd-catalyzed acylation of 2-arylpyridines
À
À
via C H bond activation and the C C bond cleavage
Keywords: acylation; N-benzyltriflamides; catalysis;
of a-diketones were reported.[21] Recently, the rhodi-
À
À
C H activation; palladium
um-catalyzed addition of aryl C H bonds to ethyl
glyoxylate[22] or aryl aldehydes[23] to produce the cor-
responding alcohols was demonstrated.
Inspired by our recent studies on rhodium-cata-
lyzed oxidative acylation of tertiary[24] and secon-
The transition metal-catalyzed cross-coupling reaction dary[25] benzamides with aldehydes, we herein report
is a powerful tool available for synthetic chemists to the palladium-catalyzed oxidative ortho-acylation of
create or reproduce intricate organic scaffolds.[1] In triflamide-protected benzylamines with aryl and alkyl
À
particular, carbon-carbon cross-coupling reactions in- aldehydes via C H bond activation (Figure 1). This
volving selective activation of carbon-hydrogen new method is complementary to Friedel–Crafts acy-
bonds, which cannot be easily cleaved under classical lation[26] and direct lithiation/acylation processes.[27]
reaction conditions, are extremely challenging due to
the minimization of stoichiometric metallic waste and
the costs associated with the preparation of starting
materials.[2] Since the pioneering discovery of C H
À
bond activation by Murai,[3] recent progress has been
focused on dehydrogenative cross-coupling between
2
3
2
À
À
sp or sp C H bonds and sp C H bonds of arenes or
alkenes.[4] In this area of research, various directing
groups such as ketones,[5] carboxylic acids,[6] amides,[7]
pyrrole/pyridine,[8] anilides,[9] carbamate,[10] urea[11]
and azine N-oxide[12] can provide an anchor for cata-
lytic ortho-metalation of aromatic rings. Although the
reactions using arenes or alkenes as coupling partners
have been well documented, the reactions between
2
À
the aromatic sp C H bond and aldehydes remain rel-
atively unexplored. In 2009, Cheng first reported
a palladium-catalyzed cross-coupling reaction be-
tween arenes containing a pyridine directing group Figure 1. Transition metal-catalyzed oxidative acylation.
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Palladium-Catalyzed Oxidative Acylation of N-Benzyltriflamides with Aldehydes
More importantly this method provides aryl ketones, Cp*Rh
G
N
2ACHTUNGTREN(NGNU p-cymene)]2, were
which are important structural units and synthetic in- performed, and PdAHCTUNGTR(EUNNNG OAc)2 was found to be the most
termediates in pharmaceuticals, natural products, and effective in this coupling reaction.
functional materials.[28]
Variation of the oxidant showed that TBHP is supe-
Our initial investigation focused on the coupling of rior to other oxidants such as (PhCOO)2, Ag2CO3,
benzylamine derivatives with p-anisaldehyde. After CuACHTUNGTRNEUNG(OAc)2, benzoquinone and (NH4)2S2O8 (Table 1,
extensive screening of benzylamine protecting groups, entries 2–6). Since aldehydes are sensitive to some ox-
including trifluoromethanesulfonyl, acetyl, pivaloyl, p- idants, choosing a proper oxidant is crucial for this
toluenesulfonyl and p-nitrobenzenesulfonyl, benzyl- transformation. Solvent screening showed that an im-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
gen peroxide (TBHP) in DMF solvent at 1008C for solvents, such as DCE, THF, toluene and t-amyl alco-
20 h to give the desired product 3a in 33% yield hol, were less effective (Table 1, entries 7–10). After
(Table 1, entry 1). Further investigation of the effect further optimization, the use of 50 mol% AcOH as an
2
À
of various transition metal catalysts, including additive resulted in the acylation of an sp C H bond
Pd
(OCOCF3)2,
Pd
(PPh3)2Cl2,
Pd
N
desired product 3a in 55% yield, as shown in entry 12.
However, either increasing the amount of AcOH or
adding other acid additives (TFA, TfOH) was rela-
tively ineffective (Table 1, entries 13–15). The best re-
sults were obtained using a treatment of 7.5 mol% of
Table 1. Selected optimization parameters for the reaction
conditions.[a]
PdACTHNUTRGEN(NUG OAc)2, 50 mol% of AcOH and 4 equiv. of TBHP
in MeCN:DMF (1:1) at 1008C for 40 h to afford 3a in
high yield (71%), as shown in entry 17.
With the optimized reaction conditions established,
the substrate scope with respect to aldehydes was ex-
amined, and the results are summarized in Scheme 1.
Benzaldehyde (2b) and aldehydes 2a and 2c–2e with
electron-donating groups, regardless of the substituent
position on the phenyl ring, displayed high reactivity
under the present reaction conditions to afford the
corresponding ortho-acylation products 3a–3e. This
reaction was also compatible with hydroxy-substituted
aldehyde 2f, which provides a versatile synthetic func-
tionality for further manipulation of the product.
In contrast, electron-deficient aldehydes 2g and 2h
were relatively less reactive under these reaction con-
ditions. Halogen-substituted aldehydes 2i and 2j were
smoothly converted to the corresponding products 3i
and 3j, respectively. In particular, the chloro moiety
of 3j remained intact during the course of the reac-
tion, allowing further cross-coupling reactions on the
product. In addition, 2-fluoroanisaldehyde (2k) and 2-
naphthaldehyde (2l) also smoothly underwent this re-
action to generate the corresponding products. To our
delight, this reaction is not limited to aryl aldehydes.
Aliphatic aldehydes such as 1-hexanal (2m) and iso-
butyraldehyde (2n) also participated in the oxidative
coupling to furnish 3m and 3n in 69% and 51%
yields, respectively.
Entry Oxidant
Additive Solvent
Yield
[%][b]
1
2
3
4
5
6
TBHP
(PhCOO)2
Ag2CO3
Cu(OAc)2
benzoquinone
(NH4)2S2O8
DMF
DMF
DMF
DMF
DMF
DMF
DCE
THF
33
17
G
N.R.
N.R.
N.R.
N.R.
23
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
7
8
9
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
12
7
toluene
t-amyl alcohol trace
10
11
12
13[c]
14
15
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN:DMF
(1:1)
42
55
50
32
12
62
71
AcOH
AcOH
TFA
TfOH
AcOH
AcOH
16[d] TBHP
17[d] TBHP
[a]
Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol),
Pd(OAc)2 (5 mol%), oxidant (3 equiv.), additive
To further explore the substrate scope and limita-
tions of this process, the coupling of a variety of N-
benzyltriflamides 1b–1k and p-anisaldehyde 2a under
identical reaction conditions was screened, as shown
in Scheme 2. The substituted N-benzyltriflamides 1b–
1j with electron-donating and electron-withdrawing
ACHTUNGTRENNUNG
(50 mol%), solvent (0.6 mL) at 1008C for 20 h under N2
in 13ꢁ100 mm2 pressure tubes.
Yield isolated by column chromatography.
AcOH (1 equiv.).
[b]
[c]
[d]
PdACHTUNGTRENNUNG(OAc)2 (7.5 mol%), TBHP (4 equiv.), 40 h.
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333

Satyasheel Sharma et al.
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Scheme 1. Scope of aldehydes. Yields given in parentheses are of isolated products after column chromatography.
Scheme 2. Scope of N-benzyltriflamides. Yields given in parentheses are combined isolated yields of monoacylated and di-
acylated products.
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Palladium-Catalyzed Oxidative Acylation of N-Benzyltriflamides with Aldehydes
Scheme 3. Competition experiments between an aryl aldehyde and an aliphatic aldehyde.
groups on the benzene rings were found to be favored
in the reaction to afford the desired products 4b–4j in
good yields. Notably, the reaction of meta-substituted
N-benzyltriflamides 1c preferentially occurred at the
more sterically accessible position to afford the corre-
sponding product 4c as a single regioisomer owing to
the steric effect that caused interference with either
the formation of the cyclopalladated intermediate or
the approach of the aldehyde into the cyclopalladated
intermediate. However, symmetric N-benzyltrifla-
mides 1e–1h gave a separable mixture of monoacylat-
ed and diacylated products under these reaction con-
ditions. Finally, a-substituted N-benzyltriflamide 1k
displayed a significantly decreased reactivity under
Scheme 4. Transformations of triflamide.
the present reaction conditions.
To gain an insight of the reaction pathway, we ex-
amined the effect of a radical scavenger, ascorbic
acid, under the standard reaction conditions in of synthetic utility. Further applications of this
a dose-dependent manner, resulting in the drastically method to the synthesis of biologically active com-
reduced formation of acylated products.[15,29] These re- pounds and a more detailed mechanistic investigation
sults indicate that the reaction proceeds through a rad- are in progress.
ical pathway (see the Supporting Information for
a plausible reaction mechanism). To further support
the radical pathway for this reaction, competition ex- Experimental Section
periments between aryl aldehyde and aliphatic alde-
hyde were undertaken (Scheme 3). Exposure of N- Typical Procedure for the Acylation of Triflamides
benzyltriflamide 1a to equimolar quantities of aryl al-
dehyde 2a and aliphatic aldehyde 2m under the stan-
dard conditions provided 3a and 3m in 62% yield in
a 3.5:1 ratio. These results indicate that an alkyl acyl
radical may be more prone to decarbonylate under
high temperature (1008C) and thus led to lower for-
mation of 3m.[30]
To an oven-dried sealed tube under one atmosphere of ni-
trogen gas charged with 2-methoxybenzyltriflamide (1a)
(80.8 mg,
0.3 mmol,
1 equiv.),
Pd
G
(5.1 mg,
0.0225 mmol, 7.5 mol%), TBHP (0.22 mL, 1.2 mmol,
4 equiv.), and AcOH (9 mL, 0.15 mmol, 50 mol%) in anhy-
drous DMF:CH3CN (0.6 mL, 1:1) was added 4-
methoxybenzACTHNUGTRNEUNGaldehyde (2a) (109.5 mL, 0.9 mmol, 3 equiv.).
The reaction mixture was allowed to stir at 1008C for 40 h.
After cooling at room temperature, the reaction mixture
was evaporated onto silica gel. Purification of the product
by column chromatography (SiO2: n-hexanes/EtOAc) pro-
vided 3a; yield: 85.9 mg (71%).
Further investigation on the synthetic utility of the
triflamide directing group was conducted. As shown
in Scheme 4, acylated compound 5a, obtained from
the reaction of N-benzyltriflamide 1g and aldehyde
2b, was easily transformed to 5b, which is a useful
synthetic precursor for the preparation of analgesic
nefopam.[31]
In conclusion, we have developed an efficient pro-
tocol for the Pd-catalyzed oxidative ortho-acylation of
N-benzyltriflamides with aldehydes via C H bond ac-
Acknowledgements
À
This work was supported by the National Research Founda-
tion of Korea (No. 2010-0002465) funded by the Ministry of
tivation. The triflamide directing group can be readily
transformed to functional groups with a broad range Education, Science and Technology.
Adv. Synth. Catal. 2013, 355, 332 – 336
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asc.wiley-vch.de
335

Satyasheel Sharma et al.
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