Catalyst free synthesis of mono- and disubstituted pyrimidines from O-acyl oximes

Article abstract of DOI:10.1016/j.tetlet.2018.05.023

Transition-metal or iodine catalyzed transformations of O-acyl oximes to various N-heterocycles are well established. Herein, we report a catalyst free, oxime carboxylate based, three-component condensation method to access mono- and disubstituted pyrimidines. A broad range of substituted pyrimidines were prepared in moderate to excellent yields. Control experiments reveal that in situ generated formamidine is the key intermediate.

Full text of DOI:10.1016/j.tetlet.2018.05.023

Accepted Manuscript
Catalyst free synthesis of mono- and disubstituted pyrimidines from O-acyl ox-
imes
Atul Upare, Pochampalli Sathyanarayana, Ranjith Kore, Komal Sharma,
Surendar Reddy Bathula
PII:
S0040-4039(18)30622-1
https://doi.org/10.1016/j.tetlet.2018.05.023
TETL 49970
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 March 2018
8 May 2018
11 May 2018
Please cite this article as: Upare, A., Sathyanarayana, P., Kore, R., Sharma, K., Bathula, S.R., Catalyst free synthesis
of mono- and disubstituted pyrimidines from O-acyl oximes, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.05.023
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tetrahedron Letters
Catalyst free synthesis of mono- and disubstituted pyrimidines from O-acyl
oximes
Atul Upare a,b, Pochampalli Sathyanarayanaa,b, Ranjith Korea, Komal Sharmaa, Surendar Reddy Bathulaa,b*
a Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad -500007, India.
b AcSIR ( Academy of Scientific & Innovative Research), Chennai-600113, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Transition-metal or iodine catalyzed transformations of O-acyl oximes to various
N-heterocycles are well established. Herein, we report a catalyst free, oxime carboxylate
based, three-component condensation method to access mono- and disubstituted
pyrimidines. A broad range of substituted pyrimidines were prepared in moderate to
excellent yields. Control experiments reveal that in situ generated formamidine is the key
intermediate.
Available online
Keywords:
Oxime acetate
Pyrimidine
2009 Elsevier Ltd. All rights reserved.
Catalyst free
C-N bond formation
Formamidine
1. Introduction
(1b) Synthesis of pyrimidines
(1a) General synthesis of pyrimidines
from acetophenone
Substituted pyrimidines are an important class of heteroaromatic
systems which are found in natural products,1 as well as in
therapeutics such as Voriconazole,2 Crestor, Gleevec3 and
Avitriptan.4 Furthermore, pyrimidines have also been utilized as key
intermediates in medicinal chemistry to generate new chemical
entities with a wide range of pharmacological activities.5 Pyrimidine
derivatives are typically accessed by the acid or base catalyzed
condensation of 1,3-dicarbonyl compounds with amidines (Pinner
pyrimidine synthesis, Scheme 1a).6 Additionally, acetophenones
have also been used as condensation partners in multicomponent
reactions (Scheme 1b). For example, Konakahara and co-workers
formamidine
acetate
O
NH
R1
R3
n-propanol
R
O
O
Baran8
R3
NH2
N
N
R2
R
acid or base
R2
R1
R
CH(OC2H5)3
NH4OAc
O
R
R1
R1
R2, R3 = H, Ph,CH3
ZnCl2, toluene
Konakahara7
(1c) Copper catalysed synthesis of various heterocycles from oxime acetates
Jiang13
R
N
reported
a
three-component coupling reaction employing
N
R2
R
N
R2
N
functionalized ketones, triethyl orthoformate and ammonium acetate
using ZnCl2 as a catalyst,7 while Baran and co-workers utilized the
reaction of formamidine acetate with ketones.8 Other acetophenone
based methods9 require relatively inaccessible catalysts and harsh
reaction conditions.
R1
R1
C
)
+
u
R
O
%
l
(
B
2
N
C
o
r
H
2
m
(
H
2
1
0
0
2
(
R2
)
m
I
u
o
l
%
C
N
R2
N
)
R1
R1
R1
R
R3
R4
OAc
Cul (5 mol%),
N
CuBr (5 mol%),
R1
R
R
On the other hand, O-acyl oximes represent emerging synthons for
the construction of biologically important nitrogen containing
heterocyclic frameworks. Simple handling requirements and the
capability to produce in situ enamines via an easily reducible N−O
bond are two distinctive features of O-acyl oximes as versatile
building blocks. Widely used strategies to activate the N-O bond of
this synthon are based on either (i) oxidative addition of transition-
metals such as ruthenium, rhodium, palladium and copper; or (ii)
illuminative 1e− reduction by UV, microwave, or visible light.10-12
R
N
H
Yoshikai15
Guan14
(1d)
This work
CH(OCH3)3
NH4OAc
OAc
toluene
N
N
N
+
R1
130 °C, 12 h
R
R
R1
Scheme 1. Synthesis of various N-heterocycles via oxime acetates.

2
Tetrahedron Letters
Lastly the nitrogen source was changed to ammonium chloride, but
In the past decade, various research groups have successfully
the yield was only 58% (Entry 14).
utilized the copper catalyzed N-O bond activation of O-acyl oximes
for the synthesis of N-heterocycles such as pyrroles, pyrrolines,
pyrazoles, pyridines and pyridine-fused polycyclic products (Scheme
1c). Based on this concept of in situ formation of enamines from
oxime acetates, we conceived the idea to construct pyrimidines by
the condensation of in situ formed enamine intermediates with
trimethyl orthoformate and ammonium acetate. Thus, we report
herein the synthesis of mono- and disubstituted pyrimidines from O-
acyl oximes under mild reaction conditions.
With the optimized conditions (Table 1, entry 5) in hand, the scope
of the substituted aromatic oxime acetate was investigated (Table 2).
Initially, a broad range of substituted acetophenone oxime esters
were studied. Various functional groups: alkyl 4b (85%) and 4h
(75%); methoxy 4c (88%), 4i (68%) and 4n (75%); halogens 4d
(70%), 4e (65%), 4m (61%), 4f (63%), 4j (62%), 4k (58%), 4m
(61%) and 4o (54%); nitro 4g (58%) and 4l (55%) were tolerated
under the optimized conditions. It is noteworthy that aryl oxime
acetates bearing electron-donating groups (4b, 4c, 4h, 4n) gave
better results than those with electron-withdrawing groups (4f, 4l, 4g,
4o). Gratifyingly, a heteroaromatic oxime acetate produced the
corresponding thienyl product (4p) in 58% yield.
2. Results and Discussion
To initiate our study, the model reaction between acetophenone
oxime acetate (1a, 1 mmol), CH(OCH3)3 (2, 4 mmol) and NH4OAc
(3, 3 mmol) as the nitrogen source was carried out in the presence of
Table 2. Synthesis of pyrimidines from substituted aromatic oxime
acetates.
o
CuI (10 mol%) in toluene at 100 C for 12 h (Table 1). As expected,
the desired product (4a) was obtained, albeit in low yield (40%, entry
1). Increasing the catalyst loading (30 mol%) did not show any
improvement in yield (40%, entry 2). Surprisingly, a similar effect
was observed in the absence of CuI at 100 oC which gave 4a in 38%
yield (Entry 3). This prompted us to optimise the reaction under
catalyst free conditions. Next, the reaction temperature without the
Cu catalyst was increased to 120 oC and 130 oC which resulted in the
formation of 4a after 12 h in 65% and 78 % yield, respectively
(Entries 4 and 5). A further increase in temperature did not improve
the yield (78%, entry 6).
Table 1. Optimisation of the reaction conditions.a
Reagents and conditions: 1 (1 mmol), 2 (4 mmol), 3 (3 mmol),
toluene (2 mL), sealed tube, 130 °C, 12 h.
Entry
Catalyst
(mol%)
Nitrogen
source
Temp
(°C)
Solvent
Yield
4a
Table 3. Synthesis of pyrimidines from aryl alkyl, aryl benzyl,
tetralone and cyclohexanone oxime acetates.
(%)
40
1
2
3
CuI (10)
CuI (30)
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OCl
100
100
100
120
130
140
130
130
130
130
130
130
130
130
toluene
toluene
toluene
toluene
toluene
toluene
-
DMSO
DMF
EtOH
40
38
65
-
-
-
-
-
-
-
-
-
-
-
-
4
5
6
7
8
78
78
48
n.db
n.d
n.d
30
48
52
58
9
10
11
12
13c
14
DCE
1,4-dioxane
toluene
toluene
a
Reagents and conditions: 1a (1 mmol), 2 (4 mmol), 3 (3 mmol),
toluene (2 mL), sealed tube, 130 °C, 12 h; b Isolated yield: n.d = not
detected; c NH4OAc (2 equiv.)
o
The yield of 4a was only 48% in the absence of solvent at 130 C
(Entry 7). Changing the solvent to DMSO, DMF or EtOH was also
not advantageous (Entries 8-10) leading to recovery of the oxime and
acetophenone. The use of DCE and 1,4-dioxane did not lead to an
improvement in yield (Entries 11 and 12). Lowering the amount of
ammonium acetate (2 mmol) led to a moderate yield (52%, entry 13).
Reagents and conditions: 5 (1 mmol), 2 (4 mmol), 3 (3 mmol),
toluene (2 mL), sealed tube, 130 °C, 12 h.
Expanding the scope of the reaction, a series of aryl/alkyl oxime
acetates was employed (Table 3). Propiophenone oxime acetate with
methoxy, chloro, and fluoro substituents on the aromatic ring formed

pyrimidines 6a-d in 61-70% yield. Furthermore, 1,2-diphenyl
ethanone oxime acetate and its substituted derivatives produced 6e-g
in 62-70% yield. Additionally, α-tetralone and 7-methoxy α-tetralone
furnished 6h (66%) and 6i (68%), respectively. It is noteworthy that
aliphatic oxime acetates such as cyclohexanone oxime acetate also
formed the corresponding pyrimidine 6j in 55% yield.
The aforementioned results prompted us to examine the reactions
of benzylidine acetone oxime acetate and benzyl acetone oxime
acetate (Table 4). To our delight, the corresponding products were
afforded with good regioselectivity. In the case of benzyl acetone
oxime acetate, the oxime adjacent methylene reacted to produce the
corresponding pyrimidines 8a (60%), 8b (63%) and 8c (68%). On
the other hand, in the case of benzylidine acetone oxime, the acetate
methyl group reacted to produce pyrimidines 10a (64%), 10b (67%)
and 10c (72%).
Scheme 2. Control experiments.
Table 4. Synthesis of pyrimidines from benzylidine acetone oxime
acetate and benzyl acetone oxime acetate.
Scheme 3. Proposed mechanism.
3. Conclusion
In summary, we have developed a catalyst free reaction for the
synthesis of pyrimidines from O-acyl oximes. This simple process
provides convenient access to a number of mono- and disubstituted
pyrimidines with diverse functional groups in good yields.
Preliminary mechanistic experiments indicate that the derivatization
of the oxime to an oxime acetate is essential and that in situ-
generated formamidine is the key intermediate.
Acknowledgments
This work was supported by DBT (GAP0556). We are thankful to
the NMR and Mass divisions of CSIR-IICT for providing analytical
facilities. A. U thanks CSIR for the Ph.D. fellowship. K. S thanks
SERB for the National PostDoctoral Fellowship (PDF/2016/000319).
Reagents and conditions: 7 or 9 (1 mmol), 2 (4 mmol), 3 (3 mmol),
toluene (2 mL), sealed tube, 130 °C, 12 h
In order to probe the mechanism, control experiments were
conducted (Scheme 2). Based on the literature,16 a reaction with
commercially available formamidine (instead of trimethyl
orthoformate and ammonium acetate) was performed under the
standard conditions. Pleasingly, the reaction gave pyrimidine 4b in
62% yield. Furthermore, acetophenone oxime 12 (instead of the
acetate derivative) was subjected to the standard conditions. No
product was detected demonstrating that derivatization of the oxime
to an oxime acetate is essential for the reaction to occur.
Acetophenone was also subjected to the standard conditions, but no
product formation was observed and the starting material was
recovered.
References and notes
1. Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P.r G. J. Am.
Chem. Soc, 2002, 124, 1594-1596.
2. Dickinson, R. P.; Bell, A. S.; Hitchcock, C. A.;
Narayanaswami, S.; Ray, S. J.; Richardson, K.; Troke, P. F.
Bioorg. Med. Chem. Lett, 1996, 6, 2031-2036.
3.
Frutos, R. P.; Wei, X.; Patel, N. D.; Tampone, T. G.; Mulder, J.
A.; Busacca, C. A.; Senanayake, C. H. J. Org. Chem, 2013, 78,
5800−5803.
4. Brodfuehrer, P. R.; Chen, B. C.; Sattelberg, T. T.; Smith, P. R.;
Reddy, J .P.; Stark, D. R.; Quinlan, S. L.; Reid, J. G.;
Thottathil, J. K.; Wang, S. J. Org. Chem, 1997, 62, 9192-9202.
5. Fuji, M.; Obora, Y. I. Org Lett, 2017, 19, 5569-5572.
6. Tejedor, D.; Lopez-Tosco, S.; García-Tellado, F. J. Org. Chem,
2013, 78, 3457−3463.
7. Sasada, T.; Kobayashi, F.; Sakai, N.; Konakahara, T. Org. Lett,
2009, 11, 2161-2164.
8. Baran, P.S.; Shenvi R.A.; Nguyen, S.A. Heterocycles, 2006
70, 581-586.
Based on these experiments the following mechanism was
proposed (Scheme 3). The reaction is initiated by the formation of
enamine intermediate A, a tautomer of oxime acetate 1a. Next,
intermediate C is formed by the condensation reaction of A with B
(in situ generated formamidine) via the expulsion of NH2OAc.17
Finally, intermediate C reacts with 2 to produce the corresponding
pyrimidine 4a.
,
9. Yang, G.; Jia, Q.; Chen, L.; Du, Z.; Wang, Jian; RSC Adv,
2015, 5, 76759–76763; Soheilizada, M.; Adib, M.; Sajjadifar,
S. J. Chem. Res, 2014, 524-527.
10. Huang, H.; Cai, J.; Deng, G. Org. Biomol. Chem, 2016, 14,
1519–1530; Vessally, E.; Saeidian, H.; Hosseinian, A.; Edjlali,
L.; Bekhradnia, A.; Curr. Org. Chem, 2017, 21, 249-271;
Kitamura, M.; Narasaka, K.; Chem. Rec, 2002, 2, 268-277;

4
Tetrahedron Letters
Narasaka, K.; Kitamura, M. Eur. J. Org. Chem, 2005, 2005,
4505-4519.
Yang, J.; Xu, Y.; Wu, W.; Jiang, H. Chem Commun, 2014, 50,
14793-14796; Jiang, H.; Yang, J.; Tang, X.; Li, J.; Wu, W. J.
Org. Chem, 2015, 80, 8763-8771.
11. Huang, H.; Cai, J.; Xie, H.; Tan, J.; Li, F.; Deng, G. Org. Lett,
2017, 19, 3743–3746.
14. Ran, L.; Ren, Z,-H.; Wang, Y,-Y.; Guan, Z,-H. Green Chem,
2014, 16, 112–115.
12. Narasaka, K.; Kitamura, M. Eur. J. Org. Chem, 2005, 21,
4505-4519; Narasaka, K. Pure Appl. Chem, 2002, 74, 143-149;
Zaman, S.; S. Mitsuru, S.; Abell, A. D. Org. Lett, 2005, 7, 609-
611; Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem, Int. Ed,
2009, 48, 572-577; Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc,
2010, 132, 3676-3677; Faulkner A.; Bower, J. F. Angew.
Chem., Int. Ed, 2012, 51, 1675-1679.
15. Wei Y.; Yoshikai, N. J. Am. Chem. Soc, 2013
, 135,
3756−3759; Tan, W. W.; Ong, Y. J.; Yoshikai, N. Angew.
Chem. Int. Ed, 2017, 56, 8240–8244.
16. Taylor, E. C.; Ehrhart, W. A. J. Am. Chem. Soc, 1960, 82,
3138–3141.
17. Fu, Y.; Wang, P.; Guo, X.; Wu, P.; Meng, X.; Chen, B. J. Org.
Chem, 2016, 81, 11671−11677; Ren, Z. H.; Zhang, Z. Y.;
Yang, B. Q.; Wang, Y. Y.; Guan, Z.H. Org. Lett, 2011, 13,
5394−5397.
13. Tang, X.; Huang, L.; Qi, C.; Wu W.; Jiang, H. Chem Commun,
2013, 49, 9597; Huang, H.; Ji, X.; Tang, X.; Zhang, M.; Li, X.;
Jiang, H. Org. Lett, 2013, 15, 6254-6257; Tang, X.; Huang, L.;

3
Graphical Abstract
Catalyst free synthesis of mono- and disubstituted
pyrimidines from O-acyl oximes
Atul Upare a,b, Pochampalli Sathyanarayanaa,b, Ranjith Korea, Komal Sharmaa, Surendar Reddy Bathulaa,b*
a Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad -500007,
India.
bAcSIR ( Academy of Scientific & Innovative Research), Chennai-600113, India

4
Tetrahedron
Highlights

Catalyst free reaction for the synthesis of
pharmacologically important pyrimidines from
O-acyl oximes is been developed.


The process is simple and inexpensive.
It provides convenient access to number of
mono- and disubstituted pyrimidines with
diverse functionalities in good yields.