A palladium(II)-catalyzed synthesis of α-ketoamides via chemoselective aroyl addition to cyanamides

Article abstract of DOI:10.1002/adsc.201400011

An acyl moiety generated from α-oxocarboxylic acids via decarboxylation undergoes a palladium-catalyzed chemoselective insertion into organic cyanamides to afford N-monosubstituted α-ketoamides.

Full text of DOI:10.1002/adsc.201400011

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DOI: 10.1002/adsc.201400011
A Palladium(II)-Catalyzed Synthesis of a-Ketoamides via
Chemoselective Aroyl Addition to Cyanamides
Srimanta Guin,a Saroj Kumar Rout,a Anupal Gogoi,a Wajid Ali,a
and Bhisma K. Patela,*
a
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, Assam, India
Fax : (+91)-361-2690-9762; e-mail: patel@iitg.ernet.in
Received: January 3, 2014; Revised: March 15, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400011.
Abstract: An acyl moiety generated from a-oxocar- cyanamides to afford N-monosubstituted a-keto-
boxylic acids via decarboxylation undergoes a palladi-
ACHTUNGTRNEaNUNG mides.
um-catalyzed chemoselective insertion into organic
Keywords: chemoselectivity; decarboxylation; a-ke-
toamides; palladium catalysis
Introduction
The recent progress in the transition metal-cata-
lyzed decarboxylative strategy seems promising in
a-Ketoamides provide the gateway to access a variety achieving the desired bonds via the in situ generation
of other scaffolds through functional group transfor- of reactive organometallic species.[9] Strategically this
mations.[1] They are also important because of their has emerged as an alternative to C C bond forma-
À
relevance in biological and pharmacological activi- tions for various transition metal-catalyzed cross-cou-
ties.[2] The existing protocols for the construction of pling reactions or the C H activation/functionaliza-
À
this important motif can in general be grouped under tion processes[9a,10] and Heck-type reactions;[11] albeit
six main sub-heads depending on the strategies adopt- its utilization in 1,2-addition reactions is rare.[12]
A
ed. These include (i) the orthodox condensation/cou- flashback of these 1,2-addition reactions reveals an in-
pling of amines and a-oxocarboxylic acid deriva- triguing synthesis of ketones through decarboxylative
tives;[3] (ii) coupling between acid chlorides or alde- 1,2-carbopalladation of polar nitrile bond (path a,
hydes with isonitriles;[4] (iii) direct oxidation of a-hy- Scheme 1).[12b] The sulfinic acids (salts) also undergo
droxy, a-amino or benzylic amides;[5] (iv) amido desulfinative aryl insertion into nitriles to give ke-
double carbonylation reactions of diaryliodonium tones (path a, Scheme 1).[13] Besides nitriles, cyana-
salts or aryl halides;[6] (v) the oxidative C N bond for- mides too are potential candidates for the 1,2-addition
À
mation via the cross dehydrogenative coupling (CDC) reactions. Similar instances of 1,2-addition in cyana-
approach of various coupling partners involving either mides are reported for the palladium-catalyzed syn-
transition metal catalysts or metal-free conditions[7] thesis of arylamidines using aryltrifluoroborates[14a]
and (vi) some miscellaneous methods.[8] All the afore- and very recently using arylcarboxylic acids[14b] as the
mentioned strategies have been explored extensively; aryl precursor (path b, Scheme 1). While arylcarboxyl-
in particular the transition metal-catalyzed CDC ap- ic acids serve as latent aryl sources, the a-oxocarbox-
proach has become one of the most sought after tools. ylic acids are sources for the acyl/aroyl moiety in vari-
However, barring few exceptions,[7a,b,f] most of the ous coupling reactions.[9a] The a-oxocarboxylic acids
metal-catalyzed methodologies lack the synthesis of have mostly been used for the ortho-acylation of
À
N-aryl monosubstituted a-ketoamides as they are ap- arenes bearing various directing groups via the C H
plicable either to N,N-disubstituted or N-alkyl mono- activation strategy.[15] Other aspects on decarboxyla-
substituted a-ketoamides. This leaves an ample scope tion of a-oxocarboxylic acids consist of ketone syn-
to devise an alternative metal-catalyzed methodology thesis by the reaction of aryl halides or aryltrifluoro-
that will resolve the synthetic limitations associated borates using Cu or Pd catalysts.[16] The similar strat-
with N-aryl/alkyl monosubstituted a-ketoamides.
egy has also been utilized for the synthesis of a-keto-
amides by a Cu-catalyzed radical C C coupling with
À
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Table 1. Screening of reaction conditions.[a]
Entry Catalyst
(mol%)
Additive
(equiv.)
Solvent Yield
[%][b]
1
2
3
4
5
6
7
8
Pd
Pd
Pd
Pd
PdCl2 (10)
N
–
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
DCE
34
58
70
82
68
65
51
77
68
45
26
48
39
G
PdBr2 (10)
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
DCE
DCE
DCE
DCE
DCE
DCE
9
10
11
12
13
14
15
16
17
18
19
20
Scheme 1. Representative examples of 1,2-carbopalladation
reactions.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
00
formamides.[17] Prompted by these results, it was en-
visaged that a decarboxylative acyl group insertion
into the N-monosubstituted cyanamides by a 1,2-car-
bopalladation reaction could provide N-monosubsti-
tuted a-ketoamides (path c, Scheme 1).
ACHTUNGNERT(NGNU NH4)2S2O8 (2) DMSO 00
C
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Cu
FeCl3
AlCl3
N
00
00
00
[a]
Reaction conditions: phenylcyanamide (0.5 mmol), phe-
nylglyoxalic acid (0.5 mmol) at 808C for 2 h.
Isolated yield.
[b]
Results and Discussion
To check the viability of the envisioned strategy, an tyronitrile (AIBN) were examined (entries 8–13,
initial probe was made by reacting phenylcyanamide Table 1). However, all the additives tested were found
(1) with phenylglyoxalic acid (a) in the presence of to be inferior to (NH4)2S2O8. The choice of solvent
PdACHTUNGTRENNUNG(OAc)2 (10 mol%) in dichloroethane (DCE) at was vital for this model reaction. While solvent DCE
808C. The reaction provided the expected 2-oxo-N,2- afforded high yields (entry 4, Table 1), the use of
diphenylacetamide (1a) however in a modest yield of other solvents such as toluene or dioxane was far less
35% (entry 1, Table 1). Usually arylcyanamides are effective (entries 14 and 15, Table 1) and the reactions
susceptible towards polymerization;[18] which could be in DMF and DMSO were completely unproductive
one of the reasons for the lower yield obtained. Thus (entries 16 and 17, Table 1). The use of Lewis acids
suppressing the competing polymerization (trimeriza- such as CuACTHNUTRGNEG(UN OAc)2, FeCl3, AlCl3 was found to be com-
tion) of cyanamide is expected to provide a better pletely ineffective for this transformation (entries 18–
yield of product. Interestingly, the use of one equiva- 20, Table 1). Thus phenylcyanamide (1) (1 equiv.),
lent of (NH4)2S2O8 as oxidant in the model reaction phenylglyoxalic acid (a) (1 equiv.), catalyst PdACHTUNGTRENNUNG(TFA)2
improved the yield up to 58% (entry 2, Table 1) while (10 mol%), oxidant (NH4)2S2O8 (2 equiv.) in DCE at
a further 12% enhancement in the yield (70%) was a temperature of 808C were found to be the ideal
observed using two equivalents of the same oxidant conditions for this transformation providing the maxi-
(entry 3, Table 1). All the palladium salts were quite mum possible yield of 82% after 2 h. The results for
effective in bringing about the transformation. How- the optimization of reaction conditions are summar-
ever the maximum yield of the product was obtained ized in Table 1.
using Pd
use of Pd
Table 1). Thus Pd
of choice and used in subsequent screenings varying tained possibly via the decyanation of phenylcyan-
other parameters. An attempt to lower the catalyst amide (1). Treatment of phenylcyanamide (1) under
[Pd(TFA)2] loading to 5 mol% suppressed the yield the standard reaction conditions either in the pres-
A
Alternative to the expected 1,2-carbopalladation
ACHTUNGTRENNUNG
ACHTUNGTRENNUG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
considerably (entry 7, Table 1). Since the additive ence of (a) or without it gave no traces of aniline.
(NH4)2S2O8 was found to be an integral factor for this However, this does not completely rule out the ami-
transformation, other additives viz. K2S2O8, Oxoneꢁ, dation path because the aniline formed in situ may
di-tert-butyl peroxide (DTBP), tert-butyl hydroperox- undergo rapid condensation with phenylglyoxalic acid
ide (TBHP), benzoyl peroxide (BP) and azobisisobu- (a) to give (1a). A control reaction between aniline
2
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A Palladium(II)-Catalyzed Synthesis of a-Ketoamides via Chemoselective Aroyl Addition
Scheme 2. Proposed mechanism for the formation of a-ketoamide.
and phenylglyoxalic acid (a) in the presence of (A) to give a Pd(IV) species (B) in the presence of
PdACHTUNGTRENNUNG(TFA)2, additive (NH4)2S2O8 in DCE at a tempera- the oxidant (NH4)2S2O8. This is then followed by 1,2-
ture of 808C failed to provide (1a); thereby ruling out palladium migration[19] from N to C giving intermedi-
the usual amine-acid coupling route. These observa- ate (C). The subsequent reductive elimination regen-
tions make the 1,2-carbopalladation path more promi- erates Pd(II) for a further catalytic cycle alongside
nent at this stage. However, for the present transfor- a ketimine intermediate (D). The in situ hydrolysis
mation the use of oxidant (NH4)2S2O8 is indispensable (from the water contained in commercial grade DCE)
for obtaining a higher yield of the product. In con- of intermediate (D) results in the formation of a-ke-
trast, for 1,2-carbopalladation reactions[12,13,14] an oxi- toamide. The formations of the intermediate species
dant is really not essential. If not as an oxidant, then (B), (C) and (D) have been detected by the ESI/MS
what role does it play in the present transformation? analysis of reaction aliquot (see the Supporting Infor-
To ascertain this, other possible roles such as radical mation).[12b,14b] Thus, (NH4)2S2O8 plays the dual role of
initiator could be envisaged and accordingly a reaction an oxidant as well as a radical initiator in this reac-
was performed in the presence of the radical scaveng- tion.
er TEMPO (Scheme S1, see the Supporting Informa-
The attainment of optimal reaction conditions was
tion). This reaction led to the formation of benzoyl- then followed by the exploration of the substrate
TEMPO adduct (E) (Scheme 2) with complete sup- scope in a-oxocarboxylic acids as well as in cyana-
pression in the formation of product (1a). Thus it is mides. At first various substituted arylglyoxalic acids
possible that the role of (NH4)2S2O8 is to initiate the were reacted with phenylcyanamide (1) under the op-
formation of acyl radicals via the decarboxylation of timized conditions. All the reactions proceeded
initially formed acid radical. If on this basis a 1,2-car- smoothly; however, substantial substituent effects
bopalladation path is assumed, then the mechanism is came into play giving the expected products in a wide
expected to go via a PdACTHNUTRGNEUGN(III) species (Scheme S2, see range of yields (Scheme 3). The presence of weakly
the Supporting Information). The EPR silent nature electron-withdrawing substituents viz. 4-Cl (d) and 4-
of the reaction mixture recorded at 77 K after per- Br (e) in the phenyl ring of arylglyoxalic acids afford-
forming the reaction at 808C for 15 min (Scheme S2, ed high yields of a-ketoamides (1d) and (1e). For ar-
see the Supporting Information) rules out the forma- ylglyoxalic acids possessing electron-donating sub-
tion of PdACHTUNGTRENNUNG(III) species in the reaction and hence the stituents viz. 3-Me (b) and 4-OMe (c) the correspond-
1,2-carbopalladation path. In keeping with all these ing products (1b) and (1c) were isolated in slightly
observations, an alternate plausible mechanism is pro- lower yields (Scheme 3). An aliphatic glyoxalic acid
posed which involves the Pd(II)/Pd(IV) cycle viz. 2-oxopropanoic acid (f) also underwent the acyl
(Scheme 2). The Pd(II) initially undergoes complexa- insertion into the cyanamide (1) under the present re-
tion with cyanamide to give intermediate (A). The action conditions to give the corresponding a-keto-
acyl radical generated in the medium gets attached to
ACHTUNGTRENUNaNG mide (1f) in a poor yield of 17% (Scheme 3). The
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Scheme 3. Substrate scope for the formation of a-ketoamides. Reaction conditions: cyanamide (0.5 mmol), glyoxalic acid
(0.5 mmol) at 808C for 2 h. Isolated yields are given.
variation of substituents in cyanamides were exam- (3a) and (4a), respectively. However, substrates
ined keeping phenylglyoxalic acid (a) as constant. having electron-donating substituents in the ortho po-
Herein as well, a range of substituted arylcyanamides sition as in 2-OMe (5) gave a lower yield of the prod-
underwent facile reactions to furnish the a-ketoa- uct (5a). Similarly, lower yields of products (6a and
mides (Scheme 3). Electron-donating substituents viz. 7a) were observed for other ortho-substituted sub-
4-Me (2), 4-Bu (3) and 4-OBu (4) provided reasona- strates such as 2,4-di-Me (6) and 2,6-di-Me (7). The
bly good yields of their corresponding products (2a), lower yields of products obtained in these cases (5a–
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A Palladium(II)-Catalyzed Synthesis of a-Ketoamides via Chemoselective Aroyl Addition
lower yield could be possibly due to competitive poly-
merization of cyanamide under the reaction condi-
tions. Nevertheless, sequential addition of phenylcya-
namide (1) and phenylglyoxalic acid (a) in ten equal
lots in a time interval of 0.5 h improved the yield up
to 53%.
Conclusions
Figure 1. ORTEP view of 16a.[20]
In conclusion, we have demonstrated an efficient de-
carboxylative protocol for the synthesis of N-mono-
7a) is possibly because of steric effects imparted by susbtituted a-ketoamides. The reaction proceeds via
the ortho substituents (Scheme 3). For 3,4- a palladium-catalyzed decarboxylative acyl insertion
dimethylphenylcyanACTHNUTRGENUGNamide (8) where there is no ortho of a-oxocarboxylic acids into cyanamide involving
steric effect, the yield of product (8a) is significantly a unique 1,2-palladium migration from N to C. In ad-
higher compared to its isomeric precursors (6) and dition, wide functional group tolerance including reac-
(7). In the case of electron-withdrawing groups, all tive halides as well as nitrile and milder reaction con-
the halo (F, Cl, and Br) substituted substrates were ditions make this protocol a suitable alternative ap-
tolerated irrespective of their position of attachment proach.
in the aryl ring of cyanamides. In the case of para-
and meta-substituted halides (9–13), the yields of
their products (9a–13a) ranged from 75–84%. Howev- Experimental Section
er, the decrease in the yields for ortho halo-substitut-
ed substrates, 2-Cl (14) and 2,5-di-Cl (15) is again due General Procedure for the Synthesis of 2-Oxo-N,2-
to steric reasons (Scheme 3). Similar to cyanamide, diphenylacetamide (1a)
the cyano group is also expected to undergo decar-
An oven-dried flask was charged with PdACTHNURTGNENG(U TFA)2 (0.0166 g,
boxylative acyl insertion; thus, it would be interesting
to see for substrates having both these groups, for ex-
ample, 4-cyanophenylcyanamide (16) at which site (
0.05 mmol), (NH4)2S2O8 (0.228 g, 1 mmol), phenylcyanamide
(1) (0.059 g, 0.5 mmol), phenylglyoxalic acid (a) (0.075 g,
0.5 mmol) and solvent DCE (2 mL). The flask was kept in
a pre-heated oil bath at 808C and the reaction was contin-
ued for 2 h, during which the starting material (1) disap-
peared as judged from TLC. The reaction mixture was then
cooled to room temperature and diluted with ethyl acetate
(10 mL). The reaction mixture was filtered through a bed of
celite and washed with an additional amount of ethyl ace-
tate (2ꢂ10 mL). The combined organic layer was washed
with 5% NaHCO3 (2ꢂ5 mL) followed by water (2ꢂ5 mL).
The organic layer was dried over anhydrous Na2SO4 and
concentrated under vacuum. The crude product was purified
over a column of silica gel and eluted with 7% ethyl acetate
in hexane to give product 1a; yield: 0.092 g (82%).
À
À
À
CN or NH CN) the acyl insertion would take place.
Interestingly, the acyl addition took place chemoselec-
À
tively at the cyanamide C N bond giving the corre-
sponding a-ketoamide (16a) exclusively (Scheme 3).
The chemoselective formation of a-ketoamide (16a)
with the retention of the nitrile group has been con-
firmed by X-ray crystallography as shown in Figure 1.
Chemoselective acyl insertion at the cyanamide site
over the nitrile has been further elucidated by reac-
tions of (16) with arylglyoxalic acids (b) and (d)
giving a-ketoamides (16b) and (16d). Beside the sub-
stituted phenylcyanamides, when 1-naphthylcyana-
mide (17) was employed it afforded a-ketoamide
(17a) in 56% yield (Scheme 3). Similar to arylcyana-
mides, alkylcyanamides such as benzylcyanamide (18)
and cyclohexylcyanamide (19) provided the corre-
Acknowledgements
sponding ketoACHTUNGTRENNUNGamides (18a) and (19a) but in a slightly
lower yields (Scheme 3). Unlike in a-oxocarboxylic
acids where a substantial substituent effect was re-
B. K. P acknowledges the support of this research by the De-
partment of Science and Technology (DST), New Delhi (SR/
S1/OC-79/2009), and the Council of Scientific and Industrial
flected in the yields of the products, there seems to be Research (CSIR) (02
ACTHNUTRGNE(NUG 0096)/12/EMR-II). SG, SKR, WA
thank CSIR for fellowships.
no such correlation between the effect of substituents
in arylcyanamides and the product yields. To demon-
ACHTUNGTRENNUNG
strate the scalability of this methodology a reaction
was performed with phenylcyanamide (1) and phenyl-
glyoxalic acid (a) at a 5 mmol scale under the experi-
mental conditions. However, the reaction yielded the
a-ketoamide (1a) in an isolated yield of 38%. The
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These are not the final page numbers!

FULL PAPERS
8 A Palladium(II)-Catalyzed Synthesis of a-Ketoamides via
Chemoselective Aroyl Addition to Cyanamides
Adv. Synth. Catal. 2014, 356, 1 – 8
Srimanta Guin, Saroj Kumar Rout, Anupal Gogoi,
Wajid Ali, Bhisma K. Patel*
8
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These are not the final page numbers!