8222 | Chem. Commun., 2020, 56, 8222--8225 This journal is©The Royal Society of Chemistry 2020

Cite this:Chem. Commun., 2020,

56, 8222

Construction of multiple bonds via a dominoreaction of trifluoroacetimidoyl nitriles with in situgenerated bis-nucleophiles†

Deng-Yuan Li,a Jia-Yan Chen,a Da-Fu Feng,a Shuang Chen,a Xian-Kuan Xu,a

Li Dang b and Pei-Nian Liu *a

A transition-metal-free double addition/double rearrangement

domino reaction affording CF3-substituted pyrimidines was devel-

oped, which enables the one-pot construction of five new bonds,

namely three C–C bonds and two C–N bonds. The keys to achieve

this highly efficient reaction include the delicate design of the bis-

nucleophiles in situ generated from the dimerization of alkyl nitriles

and the use of trifluoroacetimidoyl nitriles containing CQQQN, CRRRN,

and CF3 groups as the reactant. The mechanistic studies by the

experiments and DFT calculations reveal that the transformation

involves two addition and two unprecedented rearrangement

processes.

Efficient construction of carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds is the central goal in synthetic organicchemistry, because these bonds are basic components thatconstitute organic compounds. In particular, the highly effi-cient construction of multiple C–C and C–X bonds in a singleoperation has attracted increasing attention because it repre-sents a straightforward and step-economic strategy for achiev-ing structural complexity from simple reactants.1 Dominoreactions provide feasible routes for the one-pot constructionof multiple bonds.2–4 For example, they have been applied suc-cessfully in the construction of various bioactive molecules,3,4

such as terpenes and steroids.3 However, the reported dominoreactions could only form three or four new bonds in oneoperation, while one-pot reactions that form five or more new

bonds remain a great challenge. In this study, a transition-metal-free domino reaction for the one-pot construction offive new bonds, namely three C–C bonds and two C–N bonds,was developed.

N-Heteroaromatic skeletons are among the most significantstructural components of pharmaceuticals, agrochemicals, andnatural products.5 Pyrimidine is one of the most prevalentcores and exhibits a range of attractive biological activities.6

Scheme 1a shows pyrimidine derivative I, a promising inhibitor

Scheme 1 Domino reaction to synthesize CF3-substituted pyrimidines.

a Shanghai Key Laboratory of Functional Materials Chemistry, Key Laboratory for

Advanced Materials and School of Chemistry and Molecular Engineering,

East China University of Science and Technology, Meilong Road 130,

Shanghai 200237, China. E-mail: liupn@ecust.edu.cnb Department of Chemistry and Key Laboratory for Preparation and Application of

Ordered Structural Materials of Guangdong Province, Shantou University,

Guangdong, 515063, China

† Electronic supplementary information (ESI) available: Experimental proceduresand characterization data of products, spectra of products. CCDC 1956510 for 3m.For ESI and crystallographic data in CIF or other electronic format see DOI:10.1039/d0cc02398a

Received 9th April 2020,Accepted 11th June 2020

DOI: 10.1039/d0cc02398a

rsc.li/chemcomm

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of melanoma.6a Compound II has been demonstrated to be activeagainst Aurora A kinase in oncological studies.6b Pyrimidinederivative III was recently identified as a dual leucine zipperkinase inhibitor for the treatment of neurodegeneration.6c Moreimportantly, inhibitor IV containing trifluoromethyl (CF3) grouphas displayed significantly improved diacylglycerol acyltransferase1 inhibition compared to that of the inhibitor without CF3, as wellas better tolerance and a superior safety profile.6d However, thesynthesis of CF3-substituted pyrimidines usually suffers fromlengthy routes and cumbersome procedures,7 and the directsynthesis method from easily accessible starting materials iseagerly desired.

Recently, we reported an efficient method to synthesize a newtype of compound, trifluoroacetimidoyl nitrile 2, which is apromising synthon containing imino (CQN), cyano (CRN),and CF3 groups.8 The reaction of trifluoroacetimidoyl nitriles 2with various nucleophiles such as aromatic anions, alkyl anions,terminal alkynes, alcohols and amines etc. undergoes addition/elimination process to afford imines due to the good leavingability of cyanide anion (CN�) (Scheme 1b, Pathway I).8 Toincrease the atom economy and make most use of the groupsin 2, we herein introduce the in situ generated bis-nucleophilefrom dimerization of alkyl nitrile 1. The bis-nucleophile under-goes double addition to 2, one to CQN group and another oneto CRN group, and subsequent two unprecedented rearrange-ment steps to provide 2-(trifluoromethyl)pyrimidin-4-amines3 with excellent regioselectivity and in good yields (Scheme 1b,Pathway II).

Studies were initiated using nitrile 2a as a model substrate(Table 1). This substrate was treated with n-BuLi (2.5 equiv.) inMeCN at �78 1C for 2 h. We are delighted that 2-(trifluoro-methyl)pyrimidin-4-amine 3a was isolated in 84% yield (entry 1),suggesting that MeCN acted as not only the solvent but also areactant. This result inspired us to investigate various sets of

reaction conditions in order to optimize the process. A series ofreactions were performed with the amount of MeCN reduced to10 equiv. and the results revealed that tetrahydrofuran (THF)was the best solvent among the tested solvents (entries 2–7). Thereduction of the amount of alkyl nitrile instead of using assolvent is important for the reaction scope expansion. Furtherreducing the amount of MeCN to 5 equiv. resulted in a loweryield of 3a (entry 8). Other bases, namely MeLi, lithium diiso-propylamide (LDA), and t-BuOK, did not improve the yield of 3a(entries 9–11). Raising the reaction temperature to �40 1C led tothe same yield (entry 12), while an even higher temperature(0 1C) reduced the yield to 51% (entry 13). A control experimentconfirmed that n-BuLi was essential for the formation of 3a(entry 14). It is noteworthy that 3a could easily convert to1-(trifluoromethyl)benzo[4,5]imidazo[1,2-c]pyrimidine (3a0) in61% yield through C–H activation (see ESI†), displaying thepotential application of the domino reaction for the constructionof important N-fused polycyclic skeletons.9

With the optimized reaction conditions in hand, weexplored the substrate scope of the domino reaction betweentrifluoroacetimidoyl nitriles and alkyl nitriles (Scheme 2). First,various alkyl mononitriles, namely butyronitrile, hexanonitrile,2-methoxyacetonitrile, and 2-(methylthio)acetonitrile, were sub-jected to the domino reaction with 2a, producing correspondingproducts 3b–3e in 46%–78% yields. However, the use of phenyl-acetonitrile and methyl 2-cyanoacetate did not lead to the desireddomino products, although the addition/elimination products,3-([1,10-biphenyl]-4-ylimino)-4,4,4-trifluoro-2-phenylbutanenitrileand methyl 3-([1,10-biphenyl]-4-ylamino)-2-cyano-4,4,4-trifluorobut-2-enoate, were obtained in 71% and 62% yields, respectively. Theresults suggest that the steric hindrance at the a-C of the alkylnitrile inhibits the domino reaction. Notably, adiponitrile, hepta-nedinitrile, and octanedinitrile produced single bicyclic products3f, 3g, and 3h in good yields, while other dinitriles such as

Table 1 Optimization of reaction conditionsa

Entry Base Solvent T (1C) Yieldb (3a, %)

1 n-BuLi MeCN �78 842 n-BuLi Toluene �78 283 n-BuLi DCE �78 364 n-BuLi 1,4-Dioxane �78 525 n-BuLi n-Hexane �78 766 n-BuLi Et2O �78 777 n-BuLi THF �78 828c n-BuLi THF �78 519 MeLi THF �78 2710 LDA THF �78 3611 t-BuOK THF �78 ND12 n-BuLi THF �40 8013 n-BuLi THF 0 5114 — THF �78 ND

a Reaction conditions: 1a (2 mmol), 2a (0.2 mmol), base (0.5 mmol),solvent (2 mL), �78 1C, under Ar. b Isolated yield. c 1a (1 mmol) was used.

Scheme 2 Substrate scope. Reaction conditions: 1 (2 mmol), 2(0.2 mmol), n-BuLi (0.5 mmol), THF (2 mL), �78 1C, under Ar. Isolatedyields are indicated. a Dinitrile (1 mmol) was used.

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8224 | Chem. Commun., 2020, 56, 8222--8225 This journal is©The Royal Society of Chemistry 2020

malononitrile and undecanedinitrile did not afford the desiredproducts.

Next, we investigated the domino reaction using a series oftrifluoroacetimidoyl nitriles. Trifluoroacetimidoyl nitriles 2containing electron-donating groups, namely Me and MeO, asR2 reacted with 1a, providing products 3i and 3j in yields of70% and 71%, respectively. Trifluoroacetimidoyl nitriles 2bearing F, Cl, and Br groups gave products 3k–3m in moderateyields. It is noteworthy that the structure of 3m was confirmedby single-crystal X-ray diffraction analysis (Fig. S3, ESI†), alongwith the general nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) spectra.

Naphthyl trifluoroacetimidoyl nitriles underwent the dom-ino reaction to provide corresponding products 3n and 3o inyields of 74% and 58%, respectively. Moreover, heterocyclic

trifluoroacetimidoyl nitriles derived from 1H-indole, 9-ethyl-9H-carbazole, and dibenzo[b,d]furan participated in the dominoreaction under the optimized conditions to produce corres-ponding products 3p–3r in yields of 52–80%. Next, the suitabilityof phenyl trifluoroacetimidoyl nitriles bearing various substitu-ents on the benzene ring for the domino reaction was evaluated.Reactions with nitriles bearing Me, MeO, Et2N, and Cl groups atthe para-position of the benzene ring underwent this reaction toproduce desired products 3s–3v. t-Bu- and trityl-substituted phenyltrifluoroacetimidoyl nitriles also successfully participated in thereaction to produce 3w and 3x. Multi-substituted trifluoroacetimidoylnitriles performed well in the reaction, affording products 3y and 3zin 59% and 64% yields, respectively.

To verify the versatility of the domino reaction, pentafluoro-propanimidoyl nitrile was synthesized and subjected to a reactionwith MeCN under the optimized conditions. Desired product 3aawas isolated in 63% yield, indicating that the current method is apowerful tool for the production of perfluoroalkyl pyrimidin-4-amines.

In order to clarify the mechanism of the domino reaction,b-cyanoenamine 4 was isolated in 30% yield through thedimerization of alkyl nitrile 1d (Scheme 3, eqn (1)).10 Moreover,when the reaction of 2a with 4 (1.5 equiv.) was performed in thepresence of 0.25, 1.5 or 2.5 equiv. of n-BuLi, 3d was isolated in18% and similar 56%, 58% yields, respectively (eqn (2)). Theresults demonstrate that the in situ generated bis-nucleophile,lithium b-cyanovinylamide 5, is the reaction intermediate inthe domino reaction.

When CD3CN was reacted with 2a under the standard condi-tions, [D]3a was isolated in 87% yield. Deuteration rates of 498%in the methyl group and 84% in the pyrimidine ring of [D]3a wereobserved (eqn (3)). The slight loss of deuterium rate in thepyimidine ring of [D]3a might attribute to the slight H/D exchangewith exogenous proton source such as H2O. The results confirm

Scheme 3 Preliminary mechanistic studies.

Scheme 4 Proposed reaction mechanism based on DFT calculation.

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the elimination of CN� from the bis-nucleophile intermediategenerated from the dimerization of the alkyl nitriles.

In addition, a crossover experiment involving substrates 2l,with Cl and CF3 substituents, and 2aa, with Me and CF2CF3

substituents, was carried out under the standard conditions,and corresponding products 3l and 3aa were obtained withoutcrossover products (eqn (4)).11a The result indicates that therearrangement of CF3 group is an intramolecular process.

To further elucidate the mechanism of the domino reaction,we performed density functional theory (DFT) calculations ondomino reaction starting from intermediate B and established theintramolecular addition and subsequent two rearrangement path-way as the lowest energy route (Scheme 4). Intermediate Bobtained from the doubtless addition of A to 2 undergoesintramolecular addition of the lithium imino species to theCRN group to generate cyclization intermediate C, with theextremely low barrier of 0.6 kcal mol�1. The proton exchange inC forms the active zwitterion intermediate D, which undergoesLi-promoted rearrangement of CF3 to afford intermediate F viaelimination11 and addition process, with respective reactionbarrier of 16.7 kcal mol�1 and 6.4 kcal mol�1. The next rearrange-ment of F occurs through the intramolecular addition of lithiumamide species to the imino group (reaction barrier: 16.8 kcal mol�1)and the following cleavage of C–C bond (reaction barrier:19.6 kcal mol�1), which accomplish the ring expansion toafford the zwitterion intermediate H. The elimination ofLiCN from H with the reaction barrier of 18.2 kcal mol�1

gives intermediate I, which can readily tautomerize to afford thefinal product 3. In the calculated energy landscape, the C–Ccleavage step from azabane intermediate G to six-membered ringintermediate H demonstrates highest reaction barrier, and thevalue of 19.6 kcal mol�1 is coherent with the low reactiontemperature of the domino reaction in the experiments.

In summary, a novel transition-metal-free double addition/double rearrangement domino reaction, which can constructthree C–C bonds and two C–N bonds in a single operation, hasbeen achieved. This highly efficient transformation affords CF3-substituted pyrimidines from trifluoroacetimidoyl nitriles andalkyl nitriles with excellent regioselectivity and in good yields.Mechanistic experimental studies and DFT calculations indicatethat the reaction involves the Thorpe reaction of alkyl nitrile toform a lithium b-cyanovinylamide, which undergoes subsequentaddition to a trifluoroacetimidoyl nitrile. The product forms aftersubsequent addition cyclization, unprecedented rearrangement ofCF3 group and another rearrangement to accomplish ring expan-sion. As the first example of the direct synthesis of CF3-substitutedpyrimidines, this protocol shines light on the step-economicconstruction of multiple bonds and may provide an efficientapproach to achieve structural diversity in N-heteroaromatics.

This work was supported by the National Natural ScienceFoundation of China (Project No. 91845110, 21672059 and21925201), the Program of the Shanghai Committee of Scienceand Technology (Project No. 18520760700) and the Program forEastern Scholar Distinguished Professor.

Conflicts of interest

The authors declare that they have no conflict of interest.

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