(3+3) Annulation of Nitroallylic Acetates with Stabilized Sulfur Ylides

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(3+3) Annulation of Nitroallylic Acetates with Stabilized Sulfur Ylides for the Synthesis of 2-Aryl Terephthalates Lakshminarayana Satham, and Irishi N. N. Namboothiri J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00917 • Publication Date (Web): 03 Jul 2018 Downloaded from http://pubs.acs.org on July 3, 2018

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The Journal of Organic Chemistry

(3+3) Annulation of Nitroallylic Acetates with Stabilized Sulfur Ylides for the Synthesis of 2-Aryl Terephthalates Lakshminarayana Satham and Irishi N. N. Namboothiri* Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076

ABSTRACT: A novel (3+3) annulation approach has been developed for the synthesis of 2aryl terephthalates from nitroallylic acetates and stabilized sulfur ylides. The 2-aryl terephthalates, which are also biaryls bearing a terephthalate moiety, are formed through a cascade of reactions such as γ-selective SN2’ reaction, γ-selective intramolecular Michael addition and two eliminations in the presence of Cs2CO3 in CH3CN at room temperature. The products are formal precursors of farnesyltransferase inhibitors and are also potential monomers in polymer chemistry. Farnesyltransferase (FTase) is a potential target for the treatment of cancer, malaria and many other diseases due to its ability to activate the disease causing Ras protein, via posttranslational farnesylation.1 Development of inhibitors of FTase is therefore an attractive objective.2 2-Aryl terephthalates (biaryl-1,4-diesters) are common precursors for many FTase inhibitors (Figure 1).3 Terephthalates are also key monomers in the synthesis of a wide variety of polymers and other materials.4 Functionalized aromatics, to which terephthalates belong, in general, are attractive building blocks in organic synthesis and are also integral parts of numerous natural products, bioactive molecules and functional materials.5 Such aromatics are conventionally synthesized via functional group modification on benzene skeleton involving diverse aromatic substitution 1 ACS Paragon Plus Environment

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and coupling strategies.6 These approaches, though widely employed, require precise positioning of appropriate functional groups or directing groups. Alternatively, different annulation modes are available in the synthetic chemist’s arsenal for the construction of aromatic ring under a variety of metal catalyzed and metal-free conditions.7

Figure 1. 2-Aryl Terephthalates-Formal Synthons of Farnesyltransferase (FTase) Inhibitors (Anti-cancer Agents)3 Among various annulation approaches, (3+3) annulation is an efficient cascade strategy for the quick construction of six-membered carbo- and heterocycles from open chain compounds in a highly regioselective manner.8-10 Although, there are several reports on the synthesis of 2-aryl terephthalates by conventional modification of benzene skeleton and functional group interconversion (Scheme 1a-c),11 to the best of our knowledge, there are no reports on the synthesis of 2-aryl terepthalates via a (3+3) annulation.

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Scheme 1. Approaches to 2-Aryl Terephthalates and Bielectrophilic Reactivity of Nitroallylic Acetate/Bromide In recent years, the Morita-Baylis-Hillman and Rauhut-Currier adducts of nitroalkenes have been extensively exploited by us and others for the synthesis of numerous multi-functional and bioactive molecules via various annulation strategies.12 In particular, nitroallylic acetates/bromides emerged as efficient bielectrophilic 2/3-carbon components for the synthesis various carbocycles and heterocycles via cascade SN2’ reaction-intramolecular 5exo-trig or 6-endo-trig cyclization (Scheme 1d).10,13-14 While 6-endo-trig is the only cyclization pathway for the primary nitroallylic acetates/bromides (E = H),10,14 both 5-exotrig and 6-endo-trig are in principle possible for the secondary nitroallylic acetates (E = CO2Et) in their reaction with various binucleophiles.10,13 In this context, synthesis of unsymmetrical terephthalates bearing a key aryl group and two different ester groups (biaryl3 ACS Paragon Plus Environment


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1,4-diesters) from nitroallylic acetates as the bielectrophiles and sulfonium ylides as the binucleophiles appeared appealing (Scheme 1e). A crotonate derived sulfonium bromide was identified as the key precursor to the sulfur ylide.15 As part of the optimization studies, nitroallylic acetate 2a was treated with sulfonium bromide 1a in the presence of different bases and solvents at room temperature (Table 1). At first, treatment of a 1:1.2 mixture of 2a and 1a with Cs2CO3 (2.0 equiv) in CH3CN (3 mL) led to complete consumption of the starting materials in 1 h to afford the product 2-aryl terephthalate 3a in 56% yield (entry 1). Lowering or increasing the base loading (1 or 3 equiv) or changing the ratio of 2a and 1a (1:1 or 1:1.5) provided inferior results. Further changing the base to K2CO3, NaOH or an amine base such as DBU resulted in longer reaction times and lower yields (entries 2-4). Attempts to further improve the yield by screening other polar aprotic solvents such as THF, DMF and acetone as well as a non-polar solvent such as toluene proved futile

(entries

5-8). Subsequently,

in

order to minimize

self-

dimerization/oligomerization/polymerization, sulfonium bromide 1a in CH3CN (1 mL) was added dropwise to a mixture of nitroallylic acetate 2a and Cs2CO3 (2.0 equiv) in CH3CN (2 mL) which furnished the product 3a in 57% yield in 15 min (entry 9), though performing this reaction at lower temperature (0 ºC) did not lead to better results. Table 1. Optimization of Reaction Conditions

base

solvent

time/h

yield/%a

1

Cs2CO3

CH3CN

1

56

2

K2CO3

CH3CN

24

46

entry


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a

3

NaOH

CH3CN

1.5

50

4

DBU

CH3CN

20

26

5

Cs2CO3

THF

24

44

6

Cs2CO3

DMF

10 min

-b

7

Cs2CO3

Acetone

3

-c

8

Cs2CO3

Toluene

30

40

9

Cs2CO3

CH3CN

15 min

57d

10

Cs2CO3

CH3CN

7

45d,e

After silica-gel column chromatography;

mixture;

c

Traces;

d

b

Complex

Dropwise addition of sulfonium

bromide 1a in CH3CN (1 mL); eAt 0 °C.

Under the above optimized conditions (Table 1), we proceeded to investigate the substrate scope for the synthesis of substituted 2-aryl terephthalates 3 (Scheme 2). Thus, nitroallylic acetates 2d-2f, besides model substrate 2a, bearing strongly electron donating aryl groups afforded the desired products 3a and 3d-3f in decent yield (49-57%). Product 3b possessing the parent phenyl group and 3c with a weakly electron donating aryl group were also formed in respectable yields (43-46%). Lower yields were encountered in the case of terephthalates 3g-3h with weakly deactivating halogens (31-41%), but pleasingly, terephthalate 3i containing a strongly deactivated aryl group was formed in good yield (55%). Terephthalates having heteroaryl groups 3j and 3k and a styrenyl group 3l were formed in moderate yields (32-41%). However, a fused aryl (naphthyl) containing terephthalate 3m was formed in good yield (52%). Attempted transformation of a β-alkyl bearing nitroallylic acetate 2n to the corresponding terephthalate 3n met with failure as a complex mixture was isolated.



Having synthesized terephthalates 3a-m, decorated with two different ester groups and an aryl group, using a methyl ester bearing sulfonium bromide 1a, we employed sulfonium bromides 1b-c equipped with ethyl ester and cyano groups. Thus, terephthalate 3o bearing identical ester groups and an electron rich aryl group was formed in 51% yield. Similarly, cyano group containing biaryls 3p and 3q were formed in very good yield (58-65%). Scheme 2. Scope of the (3+3) Annulation for One-pot Synthesis of 2-Aryl Terephthalatesa


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a

Yields after silica-gel column chromatography. No characterizable side products were

observed in these reactions. The structure and regiochemistry of 2-aryl terephthalates 3 were determined by detailed analysis of their spectral data. In particular, 1H NMR analysis of a representative compound 3j with the help of 1H-1H COSY spectrum showed strong coupling (ortho, J = 8.0 Hz) between two aryl protons which were assigned H1 and H2. Absence of further coupling for H1 and the presence of an additional weak meta-coupling (J = 1.6 Hz) for H2 (with H3) confirmed this assignment. The regiochemistry was further confirmed by 1H-1H NOESY analysis which showed the key NOE interaction between H3 and the furyl proton and no NOE interaction between the two ester alkyl groups. Finally, the structure and regiochemistry were unambiguously established by single crystal X-ray analysis (Figure 2).

Figure 2. NMR Analysis of 3j and X-ray Structure of Analog 3i A plausible mechanism for the formation of 2-aryl terephthalate 3 via a (3+3) annulation is depicted in Scheme 3. Deprotonation of sulfonium bromide 1 results in a stabilized sulfur ylide I whose more probable γ-selective addition to nitroallylic acetate 2 via soft-soft interaction in an SN2’ fashion generates intermediate II. A second γ-selective Michael addition, this time in an intramolecular 6-endo-trig fashion provides intermediate III, which upon two consecutive eliminations, namely of Me2S and HNO2, results in terephthalate 3. Formation of the same product via an initial SN2 reaction involving α-selective addition of



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ylide I to nitroallylic acetate 2 via hard-hard interaction appeared less probable due to the tertiary nature of the electrophilic center bearing the acetate group and mild basic conditions. Scheme 3. Plausible Reaction Mechanism

In conclusion, terephthalates bearing two different ester groups and an aryl group at position 2 (biaryl-1,4-diesters) have been synthesized in moderate to good yield through a novel (3+3) annulation of nitroallylic acetates with a crotonate derived sulfonium ylide. This annulation, involving a γ-selective SN2’ reaction and a γ-selective intramolecular Michael addition, is highly regioselective and offers formal precursors to farnesyltransferase inhibitors.16 General experimental details. The reagents and solvents were purchased from commercial sources and were used as received unless mentioned otherwise. The reactions were monitored by TLC. The melting points recorded are uncorrected. NMR spectra (1H, 1H decoupled

13

C,

and 1H-1H COSY) were recorded with tetramethylsilane (TMS) as the internal standard. The coupling constants (J values) are given in Hz. High resolution mass spectra were recorded under ESI Q-TOF conditions. X-ray data were collected on a diffractometer equipped with graphite monochromated Mo K radiation. The structure was solved by direct methods shelxs97 and refined by full-matrix least squares against F2 using shelxl97 software. Sulfonium bromides 115 and nitroallylic acetates 217 were prepared by literature methods. 8 ACS Paragon Plus Environment

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General procedure for the synthesis of 2-aryl terephthalates 3. To a stirred solution of MBH-acetate 2 (0.3 mmol, 1.0 equiv) in acetonitrile (2.0 mL) at rt, was added Cs2CO3 (0.6 mmol, 2.0 equiv) in one portion and subsequently sulfonium bromide 1 (0.36 mmol, 1.2 equiv) dropwise in acetonitrile (1.0 mL). Progress of the reaction was monitored by TLC analysis. After completion of reaction, the solvent was evaporated under reduced pressure and the residue was treated with water (5 mL). The aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layer was evaporated under reduced pressure and the residue was purified by silica gel column chromatography by eluting with 5-20% EtOAcpet ether (gradient elution) to afford pure product 3. 5-Ethyl 2-methyl 4'-methoxy-[1,1'-biphenyl]-2,5-dicarboxylate (3a). Pale yellow liquid; Yield 51 mg, 57%; IR (neat, cm-1) 1724 (vs), 1610 (m), 1H NMR (CDCl3, 400 MHz) δ 1.33 (t, J = 7.2 Hz, 3H), 3.61 (s, 3H), 3.78 (s, 3H), 4.33 (q, J = 7.2 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 7.9 Hz, 1H), 8.03 (dd, J = 7.9, 1.7 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 52.4, 55.4, 61.6, 113.9, 127.9, 129.6, 129.8, 131.8, 132.7, 132.8, 134.9, 142.1, 159.4, 165.9, 169.0; MS (ES+, Ar) m/z HRMS calcd for C18H18NaO5 (MNa+, 100) 337.1046, found 337.1047. 5-Ethyl 2-methyl [1,1'-biphenyl]-2,5-dicarboxylate (3b). Pale yellow liquid; Yield 37 mg, 43%; IR (neat, cm-1) 1724 (vs); 1H NMR (CDCl3, 500 MHz) δ 1.41 (t, J = 7.1 Hz, 3H), 3.65 (s, 3H), 4.41 (q, J = 7.1 Hz, 2H), 7.32-7.35 (m, 2H), 7.36-7.44 (m, 3H), 7.85 (d, J = 8.5 Hz, 1H), 8.05-8.08 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 14.5, 52.4, 61.6, 127.8, 128.3, 128.4, 128.5, 129.9, 131.8, 133.0, 134.9, 140.5, 142.6, 165.9, 168.8; MS (ES+, Ar) m/z HRMS calcd for C17H16NaO4 (MNa+, 100) 307.0941, found 307.0943. 5-Ethyl 2-methyl 4'-methyl-[1,1'-biphenyl]-2,5-dicarboxylate (3c). Pale yellow liquid; Yield 41 mg, 46%; IR (neat, cm-1) 1720 (vs); 1H NMR (CDCl3, 500 MHz) δ 1.40 (t, J = 7.2



Hz, 3H), 2.40 (s, 3H), 3.69 (s, 3H), 4.40 (q, J = 7.2 Hz, 2H), 7.22-7.24 (unresolved m, 4H), 7.83 (dd, J = 7.9, 0.6 Hz, 1H), 8.04 (dd, J = 7.9, 1.7 Hz, 1H), 8.06 (d, J = 1.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 14.4, 21.4, 52.4, 61.6, 128.0, 128.3, 129.1, 129.8, 131.8, 132.8, 134.9, 137.5, 137.6, 142.5, 165.9, 168.9; MS (ES+, Ar) m/z HRMS calcd for C18H18NaO4 (MNa+, 100) 321.1097, found 321.1099. 5-Ethyl 2-methyl 3'-methoxy-[1,1'-biphenyl]-2,5-dicarboxylate (3d). Pale yellow liquid; Yield 49 mg, 52%; IR (neat, cm-1) 1724 (vs), 1601 (s); 1H NMR (CDCl3, 400 MHz) δ 1.40 (t, J = 7.1 Hz, 3H), 3.67 (s, 3H), 3.83 (s, 3H), 4.40 (q, J = 7.1 Hz, 2H), 6.88-6.94 (m, 3H), 7.31 (t, J = 7.9 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 8.06 (dd, J = 8.5, 1.7 Hz, 1H), 8.07 (d, J = 1.7 Hz, 1H);

13

C NMR (CDCl3, 100 MHz) δ 14.5, 52.4, 55.5, 61.6, 113.4, 114.0, 121.0, 128.4,

129.4, 129.7, 131.7, 132.9, 135.1, 141.8, 142.3, 159.6, 165.9, 168.8; MS (ES+, Ar) m/z HRMS calcd for C18H18NaO5 (MNa+, 100) 337.1046, found 337.1048. 5-Ethyl 2-methyl 2',4'-dimethoxy-[1,1'-biphenyl]-2,5-dicarboxylate (3e). Yellow viscous liquid; Yield 50 mg, 49%; IR (neat, cm-1) 1726 (vs), 1611 (vs); 1H NMR (CDCl3, 400 MHz) δ 1.38 (t, J = 7.2 Hz, 3H), 3.69 (s, 6H), 3.85 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 6.48 (d, J = 2.3 Hz, 1H), 6.59 (dd, J = 8.3, 2.3 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 8.01 (dd, J = 7.9, 1.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 52.0, 55.3, 55.5, 61.4, 98.4, 104.6, 122.5, 127.8, 129.4, 130.6, 132.6, 133.1, 135.7, 138.7, 157.1, 161.0, 166.0, 168.4; MS (ES+, Ar) m/z HRMS calcd for C19H20NaO6 (MNa+, 100) 367.1152, found 367.1160. 5-Ethyl 2-methyl 3',4'-dimethoxy-[1,1'-biphenyl]-2,5-dicarboxylate (3f). Yellow viscous liquid; Yield 50 mg, 49%; IR (neat, cm-1) 1720 (vs); 1H NMR (CDCl3, 400 MHz) δ 1.39 (t, J = 7.1 Hz, 3H), 3.68 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 4.40 (q, J = 7.1 Hz, 2H), 6.86 (s, 1H), 6.89, 6.91 (ABq, J = 8.3 Hz, 2H), 7.78 (d, J = 8.1 Hz, 1H), 8.02 (dd, J = 8.1, 1.3 Hz, 1H),


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8.05 (d, J = 1.3 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.4, 52.5, 56.0, 56.1, 61.6, 111.1, 111.8, 120.9, 127.9, 129.6, 131.6, 132.8, 133.0, 135.2, 142.0, 148.9, 149.0, 165.9, 169.2; MS (ES+, Ar) m/z HRMS calcd for C19H20NaO6 (MNa+, 100) 367.1152, found 367.1163. 5-Ethyl 2-methyl 4'-bromo-[1,1'-biphenyl]-2,5-dicarboxylate (3g). Semi-solid; Yield 45 mg, 41%; IR (neat, cm-1) 1726 (vs); 1H NMR (CDCl3, 500 MHz) δ 1.40 (t, J = 7.1 Hz, 3H), 3.69 (s, 3H), 4.40 (q, J = 7.1 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 0.8 Hz, 1H), 8.08 (dd, J = 8.1, 0.8 Hz, 1H);

13

C NMR

(CDCl3, 125 MHz) δ 14.5, 52.5, 61.7, 122.2, 128.6, 130.1, 130.2, 131.5, 131.7, 133.2, 134.5, 139.5, 141.5, 165.7, 168.3; MS (ES+, Ar) m/z HRMS calcd for C17H1579BrNaO4 (MNa+, 100) 385.0046, found 385.0052. 5-Ethyl 2-methyl 4'-fluoro-[1,1'-biphenyl]-2,5-dicarboxylate (3h). White solid; Yield 28 mg, 31%; mp 76-78 oC; IR (neat, cm-1) 1725 (vs), 1607 (s); 1H NMR (CDCl3, 400 MHz) δ 1.40 (t, J = 7.1 Hz, 3H), 3.68 (s, 3H), 4.41 (q, J = 7.1 Hz, 2H), 7.10 (t, J = 8.6 Hz, 2H), 7.29 (d, J = 8.6, 5.3 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 8.07 (dd, J = 8.0, 1.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.5, 52.4, 61.7, 115.4 (d, JC-F = 21.7 Hz), 128.4, 130.0, 130.2 (d, JC-F = 8.4 Hz), 131.8, 133.1, 134.8, 136.5 (d, JC-F = 3.6 Hz) 141.6, 162.7 (d, JC-F = 246.9 Hz), 165.8, 168.5;

19

F NMR (CDCl3, 376 MHz) δ (ppm) -114.7; MS (ES+, Ar)

m/z HRMS calcd for C17H15FNaO4 (MNa+, 100) 325.0847, found 325.0846. 5-Ethyl 2-methyl 2'-nitro-[1,1'-biphenyl]-2,5-dicarboxylate (3i). White solid; Yield 55 mg, 55%; mp 115-117 oC; IR (neat, cm-1) 1722 (vs); 1H NMR (CDCl3, 500 MHz) δ 1.39 (t, J = 7.1 Hz, 3H), 3.68 (s, 3H), 4.40 (q, J = 7.1 Hz, 2H), 7.29 (dd, J = 7.6, 0.9 Hz, 1H), 7.56 (td, J = 7.6, 0.9 Hz, 1H), 7.66 (td, J = 7.6, 0.9 Hz, 1H), 7.90 (d, J = 0.4 Hz, 1H), 8.13-8.14 (unresolved m, 2H), 8.16 (dd, J = 7.6, 0.9 Hz, 1H); Confirmed by 1H-1H COSY experiment; 13

C NMR (CDCl3, 125 MHz) δ 14.4, 52.5, 61.8, 124.4, 128.8, 129.1, 130.7, 131.0, 131.6,



132.4, 133.1, 133.8, 136.6, 140.4, 148.1, 165.5, 166.2; MS (ES+, Ar) m/z HRMS calcd for C17H15NNaO6 (MNa+, 100) 352.0792, found 352.0788. Selected X-ray Data: C17H15NO6, M 329.30, Triclinic, space group P-1, a = 9.6495(3) Ǻ, b = 15.4042(4) Ǻ, c = 15.4078(9) Ǻ,  = 107.095(2)o, β = 99.206(2)°, γ = 98.222(2)o, V = 3092.28(15) Å3, Dc = 1.415 mg/m3, Z = 8, F(000) = 1376,  = 0.71073 Ǻ,  = 0.109 mm-1, Total/ unique reflections = 41061 / 10826 [R(int) = 0.0327],  range = 2.18 to 25.00°, Final R [I>2(I)]: R1 = 0.0537, wR2 = 0.1593, R (all data): R1 = 0.0816, wR2 = 0.1930. 4-Ethyl 1-methyl 2-(furan-2-yl)terephthalate (3j). Pale yellow liquid; Yield 33 mg, 41%; IR (neat, cm-1) 1722 (vs); 1H NMR (CDCl3, 400 MHz) δ 1.41 (t, J = 7.1 Hz, 3H), 3.86 (s, 3H), 4.41 (q, J = 7.1 Hz, 2H), 6.49 (dd, J = 3.4, 1.9 Hz, 1H), 6.66 (d, J = 3.4 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.99 (dd, J = 8.0, 1.6 Hz, 1H), 8.28 (d, J = 1.6 Hz, 1H);

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C NMR (CDCl3, 100 MHz) δ 14.4, 52.7, 61.6, 108.9, 111.9, 128.4, 129.1, 129.3,

130.0, 132.8, 133.7, 143.3, 151.6, 165.7, 169.2; MS (ES+, Ar) m/z HRMS calcd for C15H14NaO5 (MNa+, 100) 297.0733, found 297.0740. Confirmed by 1H-1H COSY and NOESY experiments. 4-Ethyl 1-methyl 2-(thiophen-2-yl)terephthalate (3k). Pale yellow liquid; Yield 31 mg, 36%; IR (neat, cm-1) 1724 (vs); 1H NMR (CDCl3, 500 MHz) δ 1.41 (t, J = 7.1 Hz, 3H), 3.76 (s, 3H), 4.41 (q, J = 7.1 Hz, 2H), 7.07-7.09 (m, 2H), 7.38 (dd, J = 3.9, 2.2 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 8.04 (dd, J = 8.1, 1.3 Hz, 1H), 8.15 (d, J = 1.3 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 14.5, 52.7, 61.7, 126.6, 127.0, 127.6, 128.8, 129.5, 132.2, 132.8, 134.4, 135.7, 141.1, 165.7, 168.8; MS (ES+, Ar) m/z HRMS calcd for C15H14NaO4S (MNa+, 100) 313.0505, found 313.0507. 4-Ethyl 1-methyl (E)-2-styrylterephthalate (3l). Light yellow solid; Yield 30 mg, 32%; mp 83-85 oC; IR (neat, cm-1) 1722 (vs); 1H NMR (CDCl3, 500 MHz) δ 1.44 (t, J = 7.2 Hz, 3H),


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3.95 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.13 (d, J = 16.2 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 7.57 (d, J = 7.4 Hz, 2H), 7.94 (d, J = 16.2 Hz, 1H), 7.95-7.97 (m, 2H), 8.39 (s, 1H);

13

C NMR (CDCl3, 125 MHz) δ 14.5, 52.6, 61.7, 126.5, 127.2, 127.8, 128.2,

128.3, 128.9, 130.9, 132.3, 132.8, 133.7, 137.3, 139.4, 166.0, 167.5; MS (ES+, Ar) m/z HRMS calcd for C19H18NaO4 (MNa+, 100) 333.1097, found 333.1098. 4-Ethyl 1-methyl 2-(naphthalen-1-yl)terephthalate (3m). Colourless liquid; Yield 54 mg, 52%; IR (neat, cm-1) 1721 (vs); 1H NMR (CDCl3, 500 MHz) δ 1.39 (t, J = 7.2 Hz, 3H), 3.40 (s, 3H), 4.41 (q, J = 7.2 Hz, 2H), 7.36 (d, J = 7.0 Hz, 1H), 7.38-7.41 (m, 1H), 7.45-7.50 (m, 2H), 7.52-7.55 (m, 1H), 7.91 (t, J = 8.5 Hz, 2H), 8.09 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.20 (dd, J = 8.2, 1.6 Hz, 1H);

13

C NMR (CDCl3, 125 MHz) δ 14.4, 52.2, 61.6, 125.3,

125.4, 125.9, 126.3, 126.4, 128.1, 128.4, 128.7, 130.2, 132.0, 132.9, 133.3, 133.4, 135.6, 138.7, 141.5, 165.8, 167.5; MS (ES+, Ar) m/z HRMS calcd for C21H18NaO4 (MNa+, 100) 357.1097, found 357.1095. Diethyl 4'-methoxy-[1,1'-biphenyl]-2,5-dicarboxylate (3o).18 Pale yellow liquid; Yield 60 mg, 51%; IR (neat, cm-1) 1722 (vs), 1610 (m); 1H NMR (CDCl3, 400 MHz) δ 1.07 (t, J = 7.1 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H), 3.84 (s, 3H), 4.14 (q, J = 7.1 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.81 (dd, J = 7.7, 0.9 Hz, 1H), 8.03 (dd, J = 7.7, 1.7 Hz, 1H), 8.04 (dd, J = 1.7, 0.9 Hz, 1H);

13

C NMR (CDCl3, 125 MHz) δ

14.0, 14.5, 55.5, 61.5, 61.6, 113.9, 127.9, 129.7 (× 2), 131.8, 132.7, 133.0, 135.5, 142.1, 159.5, 166.0, 168.7; MS (ES+, Ar) m/z HRMS calcd for C19H20NaO5 (MNa+, 100) 351.1203, found 351.1204. Ethyl 6-cyano-4'-methoxy-[1,1'-biphenyl]-3-carboxylate (3p). White crystalline solid; Yield 55 mg, 65%; mp 99-101 oC; IR (neat, cm-1) 2236 (w), 1719 (vs); 1H NMR (CDCl3, 500 MHz) δ 1.41 (t, J = 7.2 Hz, 3H), 3.88 (s, 3H), 4.42 (q, J = 7.2 Hz, 2H), 7.04 (d, J = 8.8 Hz,



Page 14 of 22

2H), 7.54 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.1 Hz, 1H), 8.04 (dd, J = 8.1, 1.5 Hz, 1H), 8.16 (d, J = 1.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 14.4, 55.6, 62.0, 114.5, 114.9, 118.5, 127.8, 129.8, 130.2, 130.9, 134.0, 134.4, 145.6, 160.5, 165.3; MS (ES+, Ar) m/z HRMS calcd for C17H15NNaO3 (MNa+, 55) 304.0944, found 304.0947. Ethyl 4-cyano-3-(naphthalen-1-yl)benzoate (3q).3e Light yellow solid; Yield 60 mg, 58%; mp 92-94 oC; IR (neat, cm-1) 2229 (m), 1722 (vs); 1H NMR (CDCl3, 400 MHz, 50 ºC) δ 1.40 (t, J = 7.1 Hz, 3H), 4.42 (q, J = 7.2 Hz, 2H), 7.45-7.51 (m, 3H), 7.54 (t, J = 8.2 Hz, 1H), 7.59 (t, J = 8.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 8.19-8.23 (m, 2H); Confirmed by 1H-1H COSY experiment;

13

C NMR (CDCl3, 100

MHz) δ 14.4, 62.0, 117.4, 117.5, 125.1, 125.3, 126.5, 127.0, 127.8, 128.8, 128.9, 129.8, 131.4, 132.4, 133.4, 133.9, 134.1, 135.2, 144.9, 165.2; MS (ES+, Ar) m/z HRMS calcd for C20H15NNaO2 (MNa+, 100) 324.0995, found 324.0995. ASSOCIATED CONTENT Supporting Information Available. Copies of NMR spectra for all the new compounds as well as CIF for terephthalate 3i. This material is available free of charge via the Internet at http://pubs.acs.joc. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCID Irishi N. N. Namboothiri: 0000-0002-8945-3932 Notes The authors declare no competing financial interest.


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ACKNOWLEDGMENT INNN thanks SERB-DST India (Grant # EMR/2014/000395) for financial assistance and LS thanks CSIR India, for a senior research fellowship. The authors thank Ms. Sreevani and Mr. Madhusudhan, Department of Chemistry, IIT Bombay, for help with X-ray data. REFERENCES (1) Selected recent reviews: (a) Berndt, N.; Sebti, S. M. Measurement of Protein Farnesylation and Geranylgeranylation in vitro, in Cultured Cells and in Biopsies, and the Effects of Prenyl Transferase Inhibitors. Nature Protocols 2011, 6, 1775-1791. (b) Brock, E. J.; Ji, K.; Reiners, J. J.; Mattingly, R. R. How to Target Activated Ras Proteins: Direct Inhibition vs. Induced Mislocalization. Mini-Rev. Med. Chem. 2016, 16, 358-369. (2) Selected recent reviews: (a) Moorthy, N. S. H. N.; Sousa, S. F.; Ramos, M. J.; Fernandes, P. A. Farnesyltransferase Inhibitors: A Comprehensive Review Based on Quantitative Structural Analysis. Curr. Med. Chem. 2013, 20, 4888-4923. (b) Sharma, K. A Review on Plasmodium falciparum-Protein Farnesyltransferase Inhibitors as Antimalarial Drug Targets. Current Drug Targets 2017, 18, 1676-1686. (c) Vasan, N.; Boyer, J. L.; Herbst, R. S. A RAS Renaissance: Emerging Targeted Therapies for KRAS-Mutated Non-Small Cell Lung Cancer. Clin. Cancer Res. 2014, 20, 3921-3930. (d) Ref 1b. (3) Selected articles: (a) McDermott, T. S.; Premchandran, R.; Bailey, A. E.; Bhagavatula, L.; Morton, H. E. Process Research and Initial Scale-up of ABT-839: A Farnesyl-transferase Inhibitor. ACS Symp. Ser. 2004, 870, 59-69. (b) Augeri, D. J.; O'Connor, S. J.; Janowick, D.; Szczepankiewicz, B.; Sullivan, G.; Larsen, J.; Kalvin, D.; Cohen, J.; Devine, E.; Zhang, H.; Cherian, S.; Saeed, B.; Ng, S. C.; Rosenberg, S. Potent and Selective Non-CysteineContaining Inhibitors of Protein Farnesyltransferase. J. Med. Chem. 1998, 41, 4288-4300. (c)



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(3+3) Annulation of Nitroallylic Acetates with Stabilized Sulfur Ylides

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