Facile preparation of pyrimidinediones and thioacrylamides: Via reductive functionalization of amides

Article abstract of DOI:10.1039/c7cc04170e

The development of an efficient protocol for the reductive functionalization of amides into pyrimidinediones and amino-substituted thioacrylamides is presented. Enamines are generated in a highly chemoselective amide hydrosilylation reaction catalyzed by

Full text of DOI:10.1039/c7cc04170e

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Facile Preparation of Pyrimidinediones and Thioacrylamides by
Reductive Functionalization of Amides
Paz Trillo,a† Tove Slagbrand,a† Fredrik Tinnis*a and Hans Adolfsson*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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The development of an efficient protocol for the reductive activation-functionalization of amides.9 The groups of Dixon
functionalization of amides into pyrimidinediones and amino- and Huang recently illustrated the prodigious potential of
substituted thioacrylamides is presented. Enamines are generated reductive functionalization of amides with their reported
in
a
highly chemoselective amide hydrosilylation reaction protocols for cyanation10 and alkynylation (Scheme 1a-b).11
catalyzed by molybdenum hexacarbonyl in combination with
1,1,3,3-tetramethyldisiloxane. The direct addition of either
isocyanate or isothiocyanate generates the corresponding
pyrimidinediones and 3-aminothioacrylamides in high yields.
a) Ir-Catalyzed Reductive Strecker reaction by Dixon and co-workers (ref. 10)
IrCl(CO)(PPh3)2 (1 mol%)
TMDS
CN
O
R2
R2
R1
N
R1
N
TMSCN
R3
R3
b) Chemoselective reductive alkynylation of amides by Huang and co-workers (ref. 11)
R'
The chemical stability of amides stems from the resonance
over the C-N and C-O bonds and this functional group is
considered as the least reactive among the carboxylic acid
derivatives.1 While these features makes the carboxamide an
attractive functionality which is included in a wide variety of
different compounds, the use of amides as synthetic
intermediates is less widespread.2 The concept of activation
and functionalization of amides has been known for over a
century;2a,3 however, recent research based on triflic
anhydride has made a substantial breakthrough in terms of
selectivity and mildness in the transformation of amides, with
notable contributions from Charette,4 Maulide5 and Huang.6
Activation of amides can also be performed employing mild
reduction protocols and functionalization can proceed through
trapping of either the electrophilic species (iminium ion) or the
nucleophilic species (enamine) being formed. The group of
Chida has for instance reported on several protocols for the
reductive functionalization of amides based on the Schwartz
reagent.7 Nagashima and co-workers have demonstrated a
powerful Ir-catalyzed protocol for the chemoselective
reduction of amides into amines or enamines,8 this system
have also been exploited in total synthesis and for the
O
IrCl(CO)(PPh3)2 (1 mol%)
TMDS
R2
R2
R3
R1
N
R3
N
CuBr (5 mol%)
R'
R1
This work: Reductive functionalization of amides into either pyrimidines or thioacryamides
O
R'
Mo(CO)6 (2 mol%)
TMDS
S
O
N
R1
R2
R'
R2
or
R'
N
O
N
H
N
R3
N
R3
NCO
R'
R1
R1
or
NCS
R'
Scheme 1. Ir-catalayzed reductive functionalization of amides
by the group of a) D. J. Dixon and b) P.-Q. Huang. This work,
Mo-catalyzed reductive functionalization of amides into
pyrimidinediones and thioacrylamides.
We have developed a highly chemoselective protocol for the
reduction of amides into amines, aldehydes or enamines based
on catalytic amounts of Mo(CO)6 in combination with TMDS
(1,1,3,3-tetramethyldisiloxane) as the reductant.12 This
catalytic system was recently applied in the reductive
functionalization of amides into 4,5-dihydrotriazoles13 and 4,5-
dihydroisoxazoles.14 Herein, we report on an efficient and high
yielding methodology for the reductive functionalization of
amides into pyrimidinediones and amino-substituted
thioacrylamides. The pyrimidine functionality is of great
biological significance and is found in nucleic acids and in
vitamins. This substrate class has also been demonstrated to
possess antineoplastic, antibacterial and antiviral properties.15
3-Aminothioacrylamides are well known as versatile synthons
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in organic chemistry.16 The reductive functionalization protocol the NMR spectroscopic analysis. Benzyl and aliphatic
presented herein is based on a mild hydrosilylation of amides isocyanates were also screened; however, unfortunately no
into the corresponding enamines. The enamine reaction pyrimidinediones were formed.
towards isocyanate and isothiocyanate for the preparation of
R
O
1. Mo(CO)6 (2 mol%)
these compounds is known, albeit there is a lack in terms of
versatility and the scopes of the available protocols are
limited.17
O
N
O
R
R1
R2
TMDS (1.5 equiv)
N
R3
N
2.
R
CNO (2.2 equiv)
R1
The initial screening for the Mo(CO)6-catalyzed reductive
functionalization of amides was aimed towards the formation
of β-amino-β-lactams, since phenylisocyanate is known to
react with enamines to form these products (Scheme 2, 4a’).18
The transformation would require one equivalent of the
isocyanate reagent; however, β-amino-β-lactam 4a’ could not
be observed and only pyrimidinedione 4a was formed (Scheme
2). Two equivalents of the isocyanate are needed in the
transformation of amide via enamine to pyrimidinedione and
an optimization of the conditions for the preparation of 4a was
performed.
R
N
Ph
N
Ph
Ph
O
N
O
O
N
O
O
O
R
O
O
N
N
N
N
S
Ph
Ph
Ph
4d, 57%b
4f
, 85%c
R = 4-Fluorobenzene
R = H,
OMe, 4b 92%
Br,
4c 76%
4a 75%
4e, 85%
NC
R
Ph
Ph
N
O
N
O
Ph
O
O
O
N
O
N
MeO2
C
Ph
N
N
Ph
N
Ph
4i, 76%e
4g, 64%
, 71%c,d
4h
MeO
O
Cl
Cl
O
O
O
O
N
N
N
N
N
N
N
O
O
O
O
O
4j, 40%
Ph
O
Ph
O
4l, 75%e
Ph
O
4k
, 83%
F
F
NC
CN
N
N
N
N
N
O
O
Ph 4n, 86%e
Ph 4o, 84%
4m, 94%
Ph
a
M) was performed at 65 °C for 0.5-5 h.
1. The reduction using Mo(CO)6 and TMDS (1.5 equiv) in EtOAc (1
2.
Isocyanate (2.2 equiv), 65 °C, 4 h. b 1. performed at 80 °C. c Isocyanate (3.5 equiv), 72 h. d 1. performed at 40 °C. e 2.
16 h.
Scheme 2. Observed formation of pyrimidinedione 4a
.
Table 1 Substrate evaluation in the reductive functionalization
The chemoselective reduction of the amides into enamines is of amides into pyrimidinediones.
performed using 2 mol% of Mo(CO)6 in combination with 1.5
equivalents of TMDS. The reactions are carried out in the We then decided to employ isothiocyanates to investigate if
environmentally friendly solvent ethyl acetate at 65 °C, and these substrates would lead to thioacrylamides as previously
the addition of 2.2 equivalents of phenylisocyanate to reported.19 The drawback of these protocols is that the
compound 2a afforded pyrimidine 4a in 75% isolated yield. enamines had to be prepared and isolated before use, which
The solubility of the pyrimidinedione products enables a facile can be problematic. Moreover, there is a two-step protocol
purification process and they could be collected from the available for thioacrylamide synthesis based on activation and
crude reaction media after precipitation with pentane. With functionalization of amides.20 In this case a selection of tertiary
the optimized conditions at hand we performed a substrate acetamides was treated with POCl3 and DMF to generate the
evaluation with initial focus on variation of the amides. corresponding chloro-substituted iminium perchlorates that
Methoxy- and bromo-substituted amide gave pyrimidine 4b were isolated. The desired thioacrylamides were subsequently
and 4c in 92% and 76% yields, respectively. The reduction of afforded by subjecting these compounds to an aqueous
aliphatic amide substrates is not as selective towards enamine solution of sodium sulfide (Na2S).
formation and some amount of amine is always observed, thus The evaluation isothiocyanate 5a (2.2 equiv) showed that no
only a 57% yield of compound 4d could be obtained. pyrimidinedithione
(6a’) was formed and that only the
Heteroaromatic substituted amides are well tolerated and corresponding amino-substituted thioacrylamide
pyrimidine 4e was isolated in 85% yield. We then evaluated generated (Scheme 4).
amides substituted with other reducible functional groups. The
(6a) was
highly chemoselective Mo(CO)6-catalyzed reduction of amides
ultimately gives access to pyrimidines functionalized with
cyano, ester, ketone and even an imine group (4f-4i) in high
yields. Notably, some of these enamines would be difficult to
prepare in situ from the corresponding aldehydes.
Next, a selection of isocyanates was evaluated and halogen,
cyano and keto-substituted substrates were all well tolerated Scheme 3. Evaluation of isothiocyanates in the transformation
4l 4o). The diminished yield of pyrimidine 4j is attributed to of amides into amino-substituted thioacrylamides.
(
-
sterical hindrance imposed by the methyl groups in ortho
position and for this compound we also observed rotamers in
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Thus, the reductive transformation of amides into substituted thioamide
COMMUNICATION
1
, the H NMR spectra in CDCl3 showed
7
thioacrylamides could be performed using 1.1 equivalents of that this compound is completely shifted towards the enol
isothiocyanate reagent and the scope can be found in Table 2. form.
The screening of different amides showed that functional
groups such as methoxy, bromo, thiophene and esters were emerging area of research and recent developments have
tolerated (6b 6e). A decreasing trend in yield can be seen shown that amides can be transformed under mild conditions
throughout amides derived from pyrrolidine 6a), N,N- to variety of different compounds. Herein, we have
In conclusion, reductive functionalization of amides is an
-
(
a
dimethyl (6h), piperidine (6f) and morpholine (6g), which could demonstrated that amides can be employed for a facile
be explained by the reactivity of the corresponding enamines transformation into either pyrimidinediones or 3-
where pyrrolidine enamine has the highest reactivity and aminothioacrylamides. All of the presented products are novel
morpholine based enamine is least reactive.21 We also and have not previously been reported and the majority of the
performed a small evaluation of different isothiocyanates such compounds were obtained in high yields. This protocol exhibits
as 1-isothiocyanatonaphthalene (6i) and p-Meo (6j), p-Cl (6k
)
high chemoselectivity and functional group tolerance
and p-Br-substituted (6l) isothiocyanatobenzenes in which all encompassing nitrile, ester, ketone and even aldimine
of the desired amino-substituted thioacrylamides were functionalities, which clearly demonstrates the value of the
obtained in high yields (82%-97%).
concept of mild reductive functionalization of amides.
The authors acknowledge the K. & A. Wallenberg Foundation
and the Swedish Research Council for financial support.
Notes and references
1
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the same enamine moiety employed in the reaction; however,
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aldehyde (7a) in good yield by treating compound 6a with
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HClaq (1
M) (Scheme 4).
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Ph
Ph
Ph
N
N
HO
N
N
O
H
H
H
r.t. o.n.
Ph
Ph
Ph
,
6a
7, 84% isolated yield
Scheme 4. Hydrolysis of enamine 6a into the corresponding
8
9
aldehyde.
A
similar
type
of
compound
(3-oxo-N,3-
diphenylpropanethioamide) was prepared by Pace et al. in
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