Oxidative Annulations Involving DMSO and Formamide: K2S2O8 Mediated Syntheses of Quinolines and Pyrimidines

Article abstract of DOI:10.1021/acs.orglett.7b02838

An efficient strategy toward 4-arylquinolines and 4-arylpyrimidines from readily available precursors is described. Oxidative annulation promoted by K₂S₂O₈ involving anilines, aryl ketones, and DMSO as a methine (=CH-) equivalent leads to 4-arylquinolines via a cascade that entails generation of a sulfenium ion, subsequent C-N and C-C bond formations, and cyclization. The application of this strategy to the activation of acetophenone-formamide conjugates toward the synthesis of 4-arylpyrimidines is also described.

Full text of DOI:10.1021/acs.orglett.7b02838

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Letter
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Oxidative Annulations Involving DMSO and Formamide: K2S2O8
Mediated Syntheses of Quinolines and Pyrimidines
Santosh D. Jadhav and Anand Singh*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, U.P. India
S
* Supporting Information
ABSTRACT: An efficient strategy toward 4-arylquinolines
and 4-arylpyrimidines from readily available precursors is
described. Oxidative annulation promoted by K2S2O8 involving
anilines, aryl ketones, and DMSO as a methine (CH−)
equivalent leads to 4-arylquinolines via a cascade that entails
generation of a sulfenium ion, subsequent C−N and C−C
bond formations, and cyclization. The application of this
strategy to the activation of acetophenone−formamide
conjugates toward the synthesis of 4-arylpyrimidines is also
described.
he quinoline and pyrimidine substructure is frequently
encountered in natural products and synthetic compounds
Scheme 2. Hypothesis and Reaction Design
T
of medicinal value (Scheme 1).1 Application of these hetero-
Scheme 1. Bioactive Quinolines and Pyrimidines
cycles as functional materials is also an area of current interest.2
Modern methodologies have attempted to diversify this chemical
space by developing selective methods that provide access to
specific substitution patterns.3 However, the reliance on
elaborate precursors and expensive transition metal catalysts4
warrants the development of newer methods for the synthesis of
these important heterocycles.
We embarked on our study with a focus on employing readily
available and inexpensive starting materials to develop a reaction
manifold that would provide expeditious access to quinolines and
pyrimidines. Our disconnections for quinoline synthesis show
that two carbon atoms for the ring system would be derived from
acetophenone, one carbon atom from DMSO and the remaining
from aniline (Scheme 2b). For pyrimidine synthesis, an
analogous combination of acetophenone and formamide was
postulated, wherein two carbon atoms in the pyrimidine would
be derived from acetophenone and the remaining nitrogen and
carbon atoms from formamide (Scheme 2c). DMSO has been
previously employed as a one-carbon equivalent5 in homo-
logations6 and assembly of heterocycles.7 However, in most
methods involving an annulation, the substrates were designed to
intercept the in situ generated sulfenium ion (from DMSO) in an
intramolecular fashion (Scheme 2a). Tiwari and co-workers have
just reported the first intermolecular three component assembly
involving DMSO as a one-carbon source, taking advantage of the
homologation chemistry of acetophenone and the inertness of
anthranils to sulfenium ion.8 Our reaction design aims to engage
readily available anilines and acetophenones in a selective
Received: September 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02838
Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters
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manner, which is a challenge because both can independently
react with sulfenium ions. The key to the development of such a
reaction platform would be the ability to modulate the
nucleophilicities of the reactants. Thus, in our hypothesis for
quinoline synthesis, the goal would be to attenuate the
nucleophilicity of aniline (and enhance that of acetophenone)
so that a three component reaction can take place efficiently.
Along similar lines, we envisaged that formamide may also react
with acetophenone in the presence of K2S2O8 to furnish
pyrimidines.
We subjected various acetophenones and anilines to the
optimized conditions and the results are depicted in Scheme 3.
Scheme 3. Oxidative Synthesis of Quinolines
Our initial experiments began with the observation that 4-
methyl acetophenone and p-toluidine reacted with DMSO (used
as the solvent) in the presence of K2S2O8 to furnish the quinoline
product in 54% yield (Table 1 entry 1). In an attempt to increase
Table 1. Preliminary Experiments and Optimization
entry
aniline (equiv)
additive (equiv)
% yield (14)
1
2
3
4
1.2
1.2
1.5
1.5
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
54
59
64
67
13
51
57
61
77
trace
0
DABCO (0.5 equiv)
DABCO (0.5 equiv)
a
5
6
b
7
c
8
9
FeCl3 (10 mol %)
FeCl3 (10 mol %)
CuI (10 mol %)
d
10
The scope with respect to acetophenones was found to be
excellent. Electron-rich acetophenones reacted with anilines and
DMSO to afford quinolines in good yields (Scheme 3, products
14a−14e). Electron poor acetophenones including the 4-nitro
derivative provided moderate to good yields of the respective
quinolines (14g−14j). α-Substituted ketones such as α-tetralone
and propiophenone also furnished the products (14k and 14m)
in 51% and 43% yield, respectively. While evaluating anilines, we
discovered that derivatives in which the para-position was
substituted were suitable for this reaction. We suspect that para-
unsubstituted anilines underwent oxidative modification/degra-
dation under the reaction conditions, albeit no such compounds
could be isolated. Application of various anilines was successful
including the 4-methyl derivative (products 14a−14m), 4-
fluoroaniline (products 14o, 14q−14s), 4-chloroaniline (prod-
uct 14t), and also 2,4-disubstituted derivatives leading to
quinolines 14n and 14p. A reaction performed with 4′-
methylacetophenone on a 5 mmol scale provided the quinoline
14a in 71% yield.
During the course of our studies, we observed that the effect of
FeCl3 is more pronounced for reactions that involve an electron-
rich acetophenone. For acetophenone derivatives featuring
electron withdrawing substituents such as fluorine and nitro
group, the addition of FeCl3 has no effect on the outcome of the
reaction (Figure 1). This observation indicates that FeCl3 may
also be involved in assisting the enolization of acetophenones
and hence has more impact on the electron-rich derivatives,
which would be sluggish toward enolization compared to their
electron deficient counterparts.
11
12
Cu(OTf)2 (10 mol %)
54
a
b
c
(NH4)2S2O8 was used as oxidant. Reaction time was 12 h. Reaction
d
time was 16 h. 10 equiv of DMSO was used in toluene as solvent.
the nucleophilicity of the acetophenone, DABCO was included
in the reaction, but it did not improve the yield significantly
(Table 1 entry 2). In these reactions, Troger’s base 15 was
identified as the side product, which indicates that the aniline is
involved in more than one pathway. Increasing the amount of
aniline to 1.5 equiv afforded 64% yield of 14a (Table 1 entry 3).
The yield did not increase further by performing the reaction in
the presence of DABCO (Table 1 entry 4). Replacing K2S2O8 by
(NH4)2S2O8 caused the yield to diminish substantially to 13%
(Table 1 entry 5). Further increase in the amount of aniline
reduced the yield of the quinoline product, most likely due to the
consumption of K2S2O8 in the side reaction leading to the
Troger’s base. While monitoring these experiments (by TLC),
we observed that aniline was consumed before acetophenone,
which is not surprising given the higher nucleophilicity of aniline.
While the addition of DABCO did not result in increased
reactivity of acetophenone, we hoped that Lewis acids could
provide some success. Gratifyingly, the addition of catalytic
amounts of FeCl3 resulted in 77% yield of the quinoline product
(Table 1, entry 9). We ascertained that CuI resulted in complete
loss of reactivity, while Cu(OTf)2 resulted in diminished yield.
The success of FeCl3 in increasing the yield may stem from its
coordination to aniline thereby slowing down the undesired
formation of Troger’s base.
We next moved to evaluate our hypothesis for the synthesis of
pyrimidines using this concept. We were delighted to observe
B
DOI: 10.1021/acs.orglett.7b02838
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 5. Control Experiments
Figure 1. Insights into the role of FeCl3. Reaction conditions: K2S2O8
(3.0 equiv), DMSO (0.25 M), 120 °C, 24−36 h.
that the reaction of acetophenone and K2S2O8 in the presence of
formamide afforded pyrimidines in good yields. It was confirmed
that K2S2O8 was indispensable for this transformation as no
conversion occurred in its absence. Various other Lewis acids
were screened for the synthesis of 16a but K2S2O8 provided the
best outcome (FeCl3 (57%), Cu(OTf)2 (42%), BF3−OEt2
(41%), CuI (46%), and Zn(OTf)2 (49%)). A variety of
electronically distinct acetophenones underwent smooth reac-
tion, and all substitution patterns on the aromatic ring were
tolerated well (Scheme 4). α-Substituted acetophenones were
quinoline synthesis. An experiment performed with DMSO-d6
afforded the deuterated derivative 14u.
On the basis of above experimental results and literature
precedence, a plausible mechanism is outlined in Scheme 6.5a
Scheme 6. Proposed Mechanism
Scheme 4. Synthesis of 4-Arylpyrimidines
also viable partners as demonstrated by propiophenone and ethyl
2-benzoylacetate, which afforded pyrimidines 16m and 16n in
57% and 43% yield, respectively. In the heterocyclic realm, 2-
acetyl thiophene derivative provided pyrimidine 16o in 48%
yield. A reaction performed with 5 mmol of 4′-methylacetophe-
none afforded 16a in 66% yield.
In order to gain insight into the mechanism of quinoline
formation, we performed some control experiments depicted in
Scheme 5. Since it is known that acetophenone generates the α,β-
enone 17 upon reaction with DMSO and K2S2O8, it is possible
that it is an intermediate in this reaction. Subjecting enone 17 to
the standard conditions instead of acetophenone did provide the
quinoline product, although this does not unequivocally prove
the existence of this intermediate. If the reaction was performed
only with aniline under otherwise identical conditions, the
formation of Troger’s base 15 was observed indicating that this
alternate pathway is indeed operative as the side reaction during
The first question is whether intermediate 18 or 196a,9 is
primarily involved in the reaction. Results from Scheme 5a,b
indicate that both are possible, but our observation that aniline is
consumed faster in the reaction indicates that 18 is more likely to
form. Also, the higher nucleophilicity of aniline renders it more
likely to react faster with the sulfenium ion compared to
acetophenone. For the quinoline formation, the iminium
intermediate can be intercepted by the enolate 20 resulting in
the formation of the C−C bond. Cyclization followed by
dehydration would afford the dihydroquinoline derivative 22,
C
DOI: 10.1021/acs.orglett.7b02838
Org. Lett. XXXX, XXX, XXX−XXX

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Bawa, S. Eur. J. Med. Chem. 2015, 97, 871. (i) Suresh, K.; Sandhya, B.;
Himanshu, G. Mini-Rev. Med. Chem. 2009, 9, 1648. (j) Parker, W. B.
Chem. Rev. 2009, 109, 2880.
(2) (a) Wong, K.-T.; Hung, T. S.; Lin, Y.; Wu, C.-C.; Lee, G.-H.; Peng,
S.-M.; Chou, C. H.; Su, Y. O. Org. Lett. 2002, 4, 513. (b) Itami, K.;
Yamazaki, D.; Yoshida, J.-i. J. Am. Chem. Soc. 2004, 126, 15396.
(c) Rouffet, M.; de Oliveira, C. A. F.; Udi, Y.; Agrawal, A.; Sagi, I.;
McCammon, J. A.; Cohen, S. M. J. Am. Chem. Soc. 2010, 132, 8232.
(d) Bhalla, V.; Vij, V.; Kumar, M.; Sharma, P. R.; Kaur, T. Org. Lett. 2012,
14, 1012.
which can then be oxidized under the reaction conditions to
afford quinoline. For the formation of Troger’s base,
intermediate 18 can be trapped by aniline to afford the aminal
24, which can then lead to another iminium 26 after reacting with
the DMSO derived sulfenium ion. Intramolecular cyclization of
26 would provide the six-membered intermediate 27, which will
undergo a similar series of steps to eventually furnish Troger’s
base.10 In the case of pyrimidines, condensation of formamide
with acetophenone would provide imine 28, which can react
further with formamide to afford the diene intermediate 29.11
Activation of 29 by K2S2O8 in a manner analogous to that of
DMSO activation will lead to 30, which can undergo a 6π
electrocyclization to result in the ring formation. Subsequent
elimination would lead to the pyrimidine product.
In summary, we have described two oxidative annulation
reactions involving DMSO and formamide as routes toward
quinolines and pyrimidines, respectively. The reactions
developed employ readily available precursors, do not involve
precious transition metals, and provide convenient access to
these heterocycles by incorporating atoms from DMSO and
formamide into the ring systems. Our success in engaging aniline
in such an intermolecular setting demonstrates that it is not
necessary to rely on intricately designed precursors to obtain
selectivity in this reaction manifold. The concept of oxidative
activation of DMSO was successfully extended to pyrimidine
synthesis wherein two molecules of formamide were incorpo-
rated in the heterocyclic ring. Application of this method toward
the synthesis of other classes of heterocycles is being pursued in
our laboratories.
(3) (a) Mahfoudh, M.; Abderrahim, R.; Leclerc, E.; Campagne, J.-M.
Eur. J. Org. Chem. 2017, 2017, 2856. (b) Khong, S.; Kwon, O. J. Org.
Chem. 2012, 77, 8257. (c) 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. (d) Zhou, Y.; Tang, Z.; Song, Q. Adv. Synth. Catal. 2017,
359, 952. (e) Zhan, J.-L.; Wu, M.-W.; Chen, F.; Han, B. J. Org. Chem.
2016, 81, 11994. (f) Vander Mierde, H.; Ledoux, N.; Allaert, B.; Van Der
Voort, P.; Drozdzak, R.; De Vos, D.; Verpoort, F. New J. Chem. 2007, 31,
1572. (g) Pollack, S. R.; Kuethe, J. T. Org. Lett. 2016, 18, 6388.
(h) Chanda, T.; Verma, R. K.; Singh, M. S. Chem. - Asian J. 2012, 7, 778.
(i) Bharate, J. B.; Vishwakarma, R. A.; Bharate, S. B. RSC Adv. 2015, 5,
42020. (j) Yan, R.; Liu, X.; Pan, C.; Zhou, X.; Li, X.; Kang, X.; Huang, G.
Org. Lett. 2013, 15, 4876. (k) Matsubara, Y.; Hirakawa, S.; Yamaguchi,
Y.; Yoshida, Z.-i. Angew. Chem., Int. Ed. 2011, 50, 7670. (l) Wang, S.; Lu,
H.; Li, J.; Zou, D.; Wu, Y.; Wu, Y. Tetrahedron Lett. 2017, 58, 2723.
(4) (a) Thirupathi, N.; Puri, S.; Reddy, T. J.; Sridhar, B.; Reddy, M. S.
Adv. Synth. Catal. 2016, 358, 303. (b) Gadakh, S. K.; Dey, S.; Sudalai, A.
Org. Biomol. Chem. 2016, 14, 2969. (c) Neuhaus, J. D.; Morrow, S. M.;
Brunavs, M.; Willis, M. C. Org. Lett. 2016, 18, 1562. (d) O’Dell, D. K.;
Nicholas, K. M. J. Org. Chem. 2003, 68, 6427. (e) Sangu, K.; Fuchibe, K.;
Akiyama, T. Org. Lett. 2004, 6, 353. (f) Matsubara, Y.; Hirakawa, S.;
Yamaguchi, Y.; Yoshida, Z.-i. Angew. Chem. 2011, 123, 7812. (g) Zhang,
L.; Zheng, L.; Guo, B.; Hua, R. J. Org. Chem. 2014, 79, 11541.
(5) (a) Liu, Y.; Zhan, X.; Ji, P.; Xu, J.; Liu, Q.; Luo, W.; Chen, T.; Guo,
C. Chem. Commun. 2017, 53, 5346. (b) Mahajan, P. S.; Tanpure, S. D.;
More, N. A.; Gajbhiye, J. M.; Mhaske, S. B. RSC Adv. 2015, 5, 101641.
(c) Sun, K.; Wang, X.; Jiang, Y.; Lv, Y.; Zhang, L.; Xiao, B.; Li, D.; Zhu,
Z.; Liu, L. Chem. - Asian J. 2015, 10, 536. (d) Sun, K.; Lv, Y.; Zhu, Z.;
Zhang, L.; Wu, H.; Liu, L.; Jiang, Y.; Xiao, B.; Wang, X. RSC Adv. 2015, 5,
3094.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02838.
Full experimental procedures, analytical data, and NMR
spectra of all novel compounds (PDF)
(6) (a) Liu, Y.-F.; Ji, P.-Y.; Xu, J.-W.; Hu, Y.-Q.; Liu, Q.; Luo, W.-P.;
Guo, C.-C. J. Org. Chem. 2017, 82, 7159. (b) Jones-Mensah, E.; Karki,
M.; Magolan, J. Synthesis 2016, 48, 1421.
(7) (a) Xie, C.; Zhang, Z.; Li, D.; Gong, J.; Han, X.; Liu, X.; Ma, C. J.
Org. Chem. 2017, 82, 3491. (b) Lv, Y.; Li, Y.; Xiong, T.; Pu, W.; Zhang,
H.; Sun, K.; Liu, Q.; Zhang, Q. Chem. Commun. 2013, 49, 6439.
(c) Yuan, J.; Yu, J.-T.; Jiang, Y.; Cheng, J. Org. Biomol. Chem. 2017, 15,
1334.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: anands@iitk.ac.in.
ORCID
Anand Singh: 0000-0001-9703-6306
Notes
(8) Wakade, S. B.; Tiwari, D. K.; Ganesh, P. S. K. P.; Phanindrudu, M.;
Likhar, P. R.; Tiwari, D. K. Org. Lett. 2017, 19, 4948.
(9) (a) Wu, X.-F.; Natte, K. Adv. Synth. Catal. 2016, 358, 336. (b) Jiang,
X.; Wang, C.; Wei, Y.; Xue, D.; Liu, Z.; Xiao, J. Chem. - Eur. J. 2014, 20,
58.
(10) (a) Didier, D.; Tylleman, B.; Lambert, N.; Vande Velde, C. M. L.;
Blockhuys, F.; Collas, A.; Sergeyev, S. Tetrahedron 2008, 64, 6252.
(b) Li, Z.; Xu, X.; Peng, Y.; Jiang, Z.; Ding, C.; Qian, X. Synthesis 2005,
2005, 1228.
(11) (a) Tyagarajan, S.; Chakravarty, P. K. Tetrahedron Lett. 2005, 46,
7889. (b) Ingebrigtsen, T.; Helland, I.; Lejon, T. Heterocycles 2005, 65,
2593.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.S. acknowledges financial support from SERB (SERB/CHM/
2015202) and BRNS (BRNS/CHM/2014118). S.D.J. thanks
UGC, New Delhi for a research fellowship.
REFERENCES
■
(1) (a) Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J. Am.
Chem. Soc. 2002, 124, 1594. (b) Capdeville, R. B. E.; Zimmerman, J.;
Matter, A. Nat. Rev. Drug Discovery 2002, 1, 493. (c) Zhang, J.-Q.; Luo,
Y.-J.; Xiong, Y.-S.; Yu, Y.; Tu, Z.-C.; Long, Z.-J.; Lai, X.-J.; Chen, H.-X.;
Luo, Y.; Weng, J.; Lu, G. J. Med. Chem. 2016, 59, 7268. (d) Solomon, V.
R.; Lee, H. Curr. Med. Chem. 2011, 18, 1488. (e) Singh, S.; Kaur, G.;
Mangla, V.; Gupta, M. K. J. Enzyme Inhib. Med. Chem. 2015, 30, 492.
(f) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543. (g) Andrews, S.; Burgess,
S. J.; Skaalrud, D.; Kelly, J. X.; Peyton, D. H. J. Med. Chem. 2010, 53, 916.
(h) Afzal, O.; Kumar, S.; Haider, M. R.; Ali, M. R.; Kumar, R.; Jaggi, M.;
D
DOI: 10.1021/acs.orglett.7b02838
Org. Lett. XXXX, XXX, XXX−XXX