Oxidative Annulations Involving DMSO and Formamide: K2S2O8

Oct 5, 2017 - ... Involving DMSO and Formamide: K2S2O8 Mediated Syntheses of Quinolines and Pyrimidines. Santosh D. Jadhav and Anand Singh. Department...
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Letter Cite This: Org. Lett. 2017, 19, 5673-5676


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.


Scheme 2. Hypothesis and Reaction Design

he quinoline and pyrimidine substructure is frequently encountered in natural products and synthetic compounds of medicinal value (Scheme 1).1 Application of these heteroScheme 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 © 2017 American Chemical Society

carbon atoms from formamide (Scheme 2c). DMSO has been previously employed as a one-carbon equivalent5 in homologations6 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 Published: October 5, 2017 5673

DOI: 10.1021/acs.orglett.7b02838 Org. Lett. 2017, 19, 5673−5676


Organic Letters

We subjected various acetophenones and anilines to the optimized conditions and the results are depicted in Scheme 3.

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. Our initial experiments began with the observation that 4methyl 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

Scheme 3. Oxidative Synthesis of Quinolines

Table 1. Preliminary Experiments and Optimization


aniline (equiv)

1 2 3 4 5a 6 7b 8c 9 10d 11 12

1.2 1.2 1.5 1.5 1.5 2.0 1.5 1.5 1.5 1.5 1.5 1.5

additive (equiv) DABCO (0.5 equiv) DABCO (0.5 equiv)

FeCl3 (10 mol %) FeCl3 (10 mol %) CuI (10 mol %) Cu(OTf)2 (10 mol %)

% yield (14) 54 59 64 67 13 51 57 61 77 trace 0 54

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 paraunsubstituted anilines underwent oxidative modification/degradation 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), 4fluoroaniline (products 14o, 14q−14s), 4-chloroaniline (product 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 electronrich 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. We next moved to evaluate our hypothesis for the synthesis of pyrimidines using this concept. We were delighted to observe


(NH4)2S2O8 was used as oxidant. bReaction time was 12 h. cReaction time was 16 h. d10 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. 5674

DOI: 10.1021/acs.orglett.7b02838 Org. Lett. 2017, 19, 5673−5676


Organic Letters 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 reaction, 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, 2acetyl thiophene derivative provided pyrimidine 16o in 48% yield. A reaction performed with 5 mmol of 4′-methylacetophenone 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,βenone 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, 5675

DOI: 10.1021/acs.orglett.7b02838 Org. Lett. 2017, 19, 5673−5676


Organic Letters

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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 incorporated in the heterocyclic ring. Application of this method toward the synthesis of other classes of heterocycles is being pursued in our laboratories.


S Supporting Information *

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)


Corresponding Author

*E-mail: [email protected]. ORCID

Anand Singh: 0000-0001-9703-6306 Notes

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.


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DOI: 10.1021/acs.orglett.7b02838 Org. Lett. 2017, 19, 5673−5676