Transition metal-free synthesis of α-ketoamides from arylmethyl ketones and alkylphosphoramides

Article abstract of DOI:10.1039/c6ra16118a

A transition metal-free protocol has been developed for the synthesis of α-ketoamides from aryl methyl ketones and alkylphosphoramides in the presence of oxidant, aqueous tert-butyl hydroperoxide (TBHP). A series of aryl methyl ketones having both electron-donating as well as electron-withdrawing groups were successfully employed for the synthesis of their corresponding α-ketoamides using hexamethylphosphoramide and other alkylphosphoramides.

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Transition metal-free synthesis of α-ketoamides from arylmethyl
ketones and alkylphosphoramides
Ahalya Behera, Wajid Ali, Manisha Tripathy, Diptimayee Sahoo and Bhisma K. Patel*
5
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A transition metal-free protocol has been developed for the synthesis of α-ketoamides from aryl methyl ketones and
alkylphosphoramides in the presence of oxidant, aqueous tert-butyl hydroperoxide (TBHP). A series of aryl methyl ketones having both
10 electron-donating as well as electron-withdrawing groups were successfully employed for the synthesis of their corresponding α-
ketoamides using hexamethylphosphoramide and other alkylphosphoramides.
.
N,N-dimethyl-2-oxo-2-phenylacetamide (1a) was observed in
50 61% isolated yield. Previously, arylmethylketones have been
Introduction
employed for the synthesis of α-ketoamide by coupling it with
dialkylformamides and primary/secondary amines.10a-g Similarly
α-ketoamidehave have also been synthesised from ethylarenes
and dialkylformamide under a metal free condition.10h However,
55 synthesis of α-ketoamides using arylmethylketones as the α-
ketoaryl (ArCOCO-) equivalents and alkylphosphoramides as the
amine source has not been reported so far (Scheme 1). Invariably,
hexamethylphosphoramide is used as a solvent in organic
reactions, but its use as the source of amine for the synthesis of α-
60 ketoamide is explored for the first time.
15 Cross-dehydrogenative coupling (CDC) has contributed
tremendously in the development of atom and step-economic
process for the synthesis of complex molecular architectures from
simple precursors. The CDC process plays a pivotal role in
bringing about the transformation of C–H bonds of all types (sp,
20 sp2 and sp3) to C–C and C–heteroatom bonds.1 Of various C–
heteroatom bonds, the construction of C−N bond is one of the
most fundamental challenge in the synthesis of biologically
important molecules, natural products, pharmaceuticals and other
functional materials.2 Among diverse C−N bond forming
25 reactions, synthesis of α-ketoamide via C−N bond formation is
one of the important reaction, as it constitutes the basic subunits
of many vital molecules. These motifs are used in the designing
of peptidase inhibitors,3a histone deacetylases3b and human
cytosolic phospholipase A2,3c,d which is applicable for inhibiting
30 several classes of proteases such as serine, cysteine and HIV.3e-g
Because of the wide applicability of α-ketoamides, a number of
synthetic routes have been developed for their synthesis.4-8
Arylmethylketone can be converted into phenylglyoxal in the
presence of an appropriate oxidant that may serve as a α-ketyl
35 (ArCOCO-) surrogate.9 This α-ketyl group may couple with the in
situ generated amines from phosphoramides under an oxidative
condition to afford a α-ketoamide. Keeping this in mind, when
acetophenone
(a)
(0.5
mmol)
was
treated
with
hexamethylphosphoramide (HMPA) (1) (1.5 mmol) in the
40 presence of tetra-butylammonium iodide (nBu4NI) (20 mol%),
chlorobenzene (PhCl) (2 mL) and a decane solution of tert-
butylhydroperoxide (TBHP) (4 equiv.) at 130 oC, formation of
___________________________________________
Department of Chemistry, Indian Institute of Technology Guwahati, 781
45 039, Assam, India. Fax no. +91-3612690762; E-mail: patel@iitg.ernet.in
†Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra For ESI or other electronic format see DOI: 10.1039/xxxxxx.
Scheme 1 Synthesis α-ketoamides from arylmethylketones and
ethylarenes.
Results and discussion
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To further improve the yield of the coupled product (1a) obtained
from arylmethylketone (a) and hexamethylphosphoramide (1),
various reaction parameters were scrutinized. Initially, a variety
of oxidants such as aq. TBHP (66%), DTBP (36%), 30% aq.
H2O2 (00%), K2S2O8 (27%) and (PhCOO)2O (BPO) (15%), were
tested (Table 1, entries 2−6), from which aq. TBHP was found to
be the ideal (Table 1, entry 2). The use of other halogen
analogues such as TBAB, I2 and KI, in lieu of TBAI were found
to be far less effective (Table 1, entries 7−9). An increased
When the reaction was heated beyond 45 minutes, in addition to
the formation of α-ketoamide (1a), appearance of another product
in <15% having Rf lower than the α-ketoamide was also noticed.
Spectroscopic analysis of the product reveals its structure to be an
35 amide (1a′) (Scheme 2). Now a query arises whether product
(1a′) is formed via the decomposition of α-ketoamide (1a) or via
the coupling of benzaldehyde (obtained from the decomposition
of phenylglyoxal) and the dimethylamine (generated by the
decomposition of HMPA)? To check this, when a pre-synthesised
40 α-ketoamide (1a) was subjected to the present reaction condition,
formation of an amide (1a′) was not observed even after 24 h
(Scheme 2). Again, when phenylglyoxal (A) was taken in lieu of
acetophenone (a) under otherwise identical condition, formation
of amide (1a′) along with the formation of benzaldehyde (B) was
45 observed. This observation confirms the formation of
phenylglyoxal in small amount from acetophenone, which results
in the formation of amide (1a′) in the reaction. A similar reaction
with benzaldehyde in lieu of phenylglyoxal gave exclusively
N,N-dimethyl benzamide (1a') in 77% yield. This confirms the in
50 situ generation of benzaldehyde in the reaction medium. Finally,
the optimised condition for this transformation is the use of
acetophenone (0.5 mmol), hexamethylphosphoramide (1.5
5
10 amount of catalyst loading (30 mol%) was not so much beneficial
(Table 1, entry 10), nevertheless a higher loading of oxidant to 6
equiv. improve the product yield by another 6% (Table 1, entry
11). Further, increase in the oxidant loading to 8 equiv., did not
show any significant improvement in the product yield (Table 1,
15 entry 12). To further improve the yield of the product (1a),
various solvents viz. 1,2-dichloroethane (DCE), CH3CN and
EtOAc were screened (Table 1, entries 13–15) but all were found
to be inferior in comparision to PhCl ( Table 1, entry 11). Next,
the effect of reaction temperature on the product formation was
20 examined and it was found that the reaction carried out both at
higher (145oC) and lower (110 oC) temperature had adversely
affected the product (1a) yield (Table 1, entries 16 and 17).
Under otherwise identical conditions either in the absence of
TBAI or TBHP failed to give the desired product (Table 1, entries
25 18 and 19) suggesting the vital role of both, in achieving the
above transformation.
n
mmol), Bu4NI (20 mol%), chlorobenzene (2 mL) and aq. TBHP
o
(70 wt% in H2O) (3 mmol) at 130 C for 45 minutes (Table 1,
55 entry 11).
Table 1 Screening of the reaction conditionsa,b
Entry Catalyst
(mol%)
Oxidant
(equiv.)
Solvent Temp
(oC)
Yield
(%)
61c
66d
36
00
27
15
1
2
3
4
5
6
7
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAB
TBHP (4)
TBHP (4)
DTBP (4)
H2O2 (4)
K2S2O8 (4)
BPO (4)
TBHP(4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (6)
TBHP (8)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (4)
TBHP (4)
TBHP (4)
-
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DCE
130
130
130
130
130
130
130
130
130
130
130
130
130
52
8
9
I2 (20)
KI (20)
47d
12d
67d
72d
73d
54d
63d
65d
62d
50d
00d
00
Scheme 2 Control experiments for the formation of amide.
10
11
12
13
14
15
16
17
18
19
TBAI (30)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
-
With this optimised condition in hand, different arylmethylketones
(a−l) bearing both electron-donating and electron-withdrawing
groups were subjected to the current reaction condition with
hexamethylphosphoramide (1). As can be seen from Scheme 3, the
presence of substituents on the aryl ring of arylmethylketone play a
significant role on the yields of N,N-dimethyl-2-oxo-2-
phenylacetamides. Arylmethylketones substituted with electron-
donating group like −Me (b) gave its corresponding α-ketoamide
(1b) in 78% yield. On the other hand, the presence of moderately
electron-withdrawing groups such as –I (c), −Br (d), −Cl (e) and –
F (f) in the arylmethylketone reduced the product (1c−1f) yields
ranging between 70−54% (Scheme 3) compared to their electron-
neutral analogue. Further reduction in the product (1g) yield (48%)
was observed when a strongly electron-withdrawing group like –
CH3CN 130
EtOAc
PhCl
PhCl
PhCl
PhCl
130
145
110
130
130
TBAI (20)
aReaction conditions: acetophenone (a) (0.5 mmol), catalyst, HMPA
(1.5 mmol), solvent (2 mL), oxidant. bYields of isolated pure product.
cdecane solution of TBHP, daq. TBHP (70 wt% in water).
During the course of optimisation, it was observed that the
30 duration of reaction play a significant role on the product yield.
2
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CF3 (g) is present at the para position of arylmethylketone (g).
When the electron-withdrawing power of the substituent is
increased further, as in p-nitroacetopheneone (h), a complete
failure of the reaction was noticed. However, when the –CF3 group
was moved to the meta position (i), its electronic effect was not
such prominent to that when it is present at the para position
giving product (1i) in decent yield (63%). When a moderately
electron-withdrawing group such as –Br is present at the ortho
position of arylmethylketone (j) further reduction in the yield was
observed which may be due to both electronic as well as steric
reasons. Other than these, an excellent yield of N,N-dimethyl-2-
naphthamide (1k) was obtained from 2-acetonaphthone (k). A
good yield of the α-ketoamide (1l) formation was also observed
when 2-acetylthiophene (l) was used in the reaction process.
the amine source similar to acyclic phosphoramides. Tri(4-
methylpiperidine)phosphoramide (4) reacted with electron-neutral
(a), electron-donating 4′-Me (b) as well as electron-withdrawing
4′-F (f) acetophenones gave their respective α-ketoamide (4a,
87%), (4b, 72%) and (4f, 81%) in good yields (Scheme 4).
Scheme
4 Substrate scope for the formation of N,N-disubstituted
α−ketoamidesa,b. aReaction conditions: acetophenone (a) (0.5 mmol),
phosphoric acid triamide (2-4) (1.5 mmol), tetrabutylammoniun iodide
(nBu4NI) (20 mol%), TBHP (70 wt% in H2O) (6 equiv.), time (1−4 h) at
130 oC .bYields of isolated pure product.
Previously, it is known that acetophenone in the presence of a
suitable oxidant such as SeO2 is transformed to a phenylglyoxal.11
Therefore; we envisaged that in the presence of an oxidant such
as TBHP instead of SeO2, acetophenone may be converted to
phenylglyoxal in the reaction medium. To ascertain the exact
reaction intermediate when a reaction was performed with an
equimolar mixture of phenylglyoxal (A) and 4′-
methylacetophenone (b) under an otherwise identical condition.
Scheme 3 Substrate scope for the formation of N,N−dimethyl aromatic α-
ketoamidea,b. aReaction conditions: arylmethylketones (a−l) (0.5 mmol),
HMPA (1) (1.5 mmol), tetrabutylammonium iodide (nBu4NI) (20 mol%),
chlorobenzene (2 mL), TBHP (70 wt% in H2O) (6 equiv.), time (45 mins−2
h) at 130 oC. bYields of isolated pure product.
5
Adopting our previous optimised condition, a library of α-
ketoamides
were
also
synthesised
using
different
10 Isolation of the only product N,N-dimethyl-2-oxo-2-(p-
tolyl)acetamide (1b) (derived from the coupling of 4′-
methylacetophenone (b) and the in situ generated dimethylamine
from HMPA) in 65% yield suggests that the phenylglyoxal is not
the active intermediate in the reaction (Scheme 5). This
15 observation is consistent with the observation in Scheme 2.
arylmethylketones (a−l) and hexalkylphosphoramides (2−4) as
shown in Scheme 4. Acetophenone substituted with an electron--
donating group like 4′-methylacetophenone (b) gave lesser yield of
α-ketoamide (2b) compared to the un-substituted one (2a) when
coupled with hexaethylphosphoramide (2). On the other hand,
presence of electron-withdrawing groups like 4′-Cl (e) and 3′-CF3
(i) enhance the reactivity of arylmethylketones, providing their
corresponding α-ketoamides (2e and 2i) in 74% and 81% yields
respectively. 2′-Acetonaphthone (k) was also successfully
employed as a good ketoaryl source for the synthesis of α-
ketoamide
giving
product
(2k)
in
70%
yield.
Hexa(methoxyethyl)phosphoramide (3) was successfully used as
the amine source for the formation of different N,N-
bis(methoxyethyl) substituted phenylacetamides (3a, 3b, 3e, 3f, 3k
and 3l). Cyclic amine based phosphoramides were also utilised as
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Scheme 5 Cross-over experiment between 4′-methylacetophenone
(b) and phenylglyoxal.
Typical procedure for the synthesis of N,N-
dimethyl-2-oxo-2-phenylacetamide (1a)
By summing up all the above experimental results and from the
literature precedence,1i,10 a plausible mechanism is proposed for
the formation α-ketoamide (Scheme 6). Initially, from “nBu4NI-
TBHP” combination, the active iodine species ammonium
hypoiodite ([nBu4N]+[IO]-) (I) or iodite ([nBu4N]+[IO2]-) (II) is
generated.10m,13 The formation of hypervalent iodine species
([nBu4N]+[IO]-) (I) and ([nBu4N]+[IO2]-) (II) have been confirmed
An oven-dried round bottom flask was charged with
n
acetophenone (a) (60 mg, 0.5 mmol), Bu4NI (20mol%, 37 mg),
5
50 HMPA (1) (268 mg, 1.5 mmol), chlorobenzene (2 mL), TBHP
(70 wt% in H2O) (6 equiv.). The flask was fitted with a condenser
and the resultant reaction mixture was stirred in a pre-heated oil
o
bath maintained at 130 C. The reaction progress was monitored
by TLC. After 45 minutes, the reaction mixture was cooled to
55 room temperature. Then the reaction mixture was quenched with
saturated Na2S2O3 solution and extracted with ethyl acetate. The
ethyl acetate layer was dried over anhydrous Na2SO4. The solvent
was then evaporated under reduced pressure and the residue was
purified by column chromatography with an eluent hexane /
60 ethylacetate (80 / 20) to afford the desired product (1a) in an
isolated yield of 72% (63.7 mg).
10 by the detection of [IO]- and [IO2]- from the ESI mass analysis of
the reaction mixture (see SI).1i,10m The hypervalent iodine species
(I) or (II) then abstracts a hydrogen atom from the aryl methyl
ketone to generate a α-keto methyl radical (b′). This radical
species (b′) couples subsequently with the dimethylaminyl
15 radical (generated from the thermal decomposition of HMPA) to
give the intermediate (C). Another intermediate (D) is generated
from intermediate (C) via a one electron oxidation. HRMS
analysis of the reaction mixture confirmed the intermediacy of
both (C) and (D) (See SI). Then nucleophilic attack of a
20 hydroxide ion to the intermediate (D) produce a keto-hydroxy
intermediate (E), which is finally oxidised to the desired α-
ketoamide (1b) in the presence of TBHP. This mechanism also
accounts for the formation of a small amount of amidic product
(1b′) (Scheme 6). A small quantity of phenylglyoxal is formed by
25 the partial hydrolysis of the intermediate (D), which on
decarbonylation gave benzaldehyde.1h,12 The in situ generated
benzoyl radical from benzaldehyde in the presence of TBHP
couples with the dimethylaminyl radical generated from HMPA
to give N,N-dimethylbenzamide (1b′) as the side product
30 (Scheme 6).
Acknowledgements
B. K. P acknowledges the support of this research by the Science
and Engineering Research Board (SERB) (SB/S1/OC-53/2013),
65 New Delhi, and the Council of Scientific and Industrial Research
(CSIR) (02)(0096)/12/EMR-II) and MHRD:5-5/2014-TS-VII. W.
A. thank CSIR for fellowship.
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Scheme 6 Plausible mechanism for the synthesis of α-
ketoamides.
35 Conclusion
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DOI: 10.1039/C6RA16118A
Transition metalꢀfree synthesis of αꢀketoamides from arylmethyl ketones and
alkylphosphoramides
Ahalya Behera, Wajid Ali, Manisha Tripathy, Diptimayee Sahoo and Bhisma K. Patel*
Synthesis of αꢀketoamides from arylmethyl ketones and hexalkylphosphoramides using TBAI as the catalyst and TBHP as the
oxidant.