Synthesis of Substituted 2-Arylindanes from E-(2-Stilbenyl) methanols

Article pubs.acs.org/joc

Synthesis of Substituted 2‑Arylindanes from E‑(2Stilbenyl)methanols via Lewis Acid-Mediated Cyclization and Nucleophililc Transfer from Trialkylsilyl Reagents Pakornwit Sarnpitak,† Kanokrat Trongchit,† Yulia Kostenko,† Supaporn Sathalalai,† M. Paul Gleeson,‡ Somsak Ruchirawat,†,§ and Poonsakdi Ploypradith*,†,§ †

Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, and Program in Chemical Biology, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6, Talat Bangken, Laksi, Bangkok, Thailand 10210 ‡ Department of Chemistry, Kasetsart University, 50 Phahonyothin Road, Bangkok, Thailand 10900 § Center of Excellence on Environmental Health and Toxicology, Commission on Higher Education (CHE), Ministry of Education, Thailand S Supporting Information *

ABSTRACT: A preparative method for the synthesis of functionalized 2-arylindanes has been developed via the Lewis acidmediated ring closure of stilbenyl methanols followed by nucleophilic transfer from trialkylsilyl reagents. The reactions gave the corresponding products in moderate to high yields and diastereoselectivity. The solvent as well as the nucleophile played an important role in determining the type(s) of product arising either from nucleophilic addition (indanes) or loss of a proton β to the indanyl-type carbocations (indenes). Electron-donating groups on the fused aromatic ring (Y and Z = OMe) or the presence of electron-withdrawing groups (NO2) on the nonfused Ar ring facilitate the cyclization. In contrast, the presence of electron-donating groups (OMe) on the nonfused Ar ring impedes the process. In the case of Cl on the nonfused Ar ring, temperature modulates the resonance versus inductive field effects on the overall reaction pathways involving cyclization to form the indanyl-type cation. Quantum chemical calculations supported the intermediacy of the carbocation species and the transfer of hydride from triethylsilane (Nu = H) to the indanyl-type cations to form the trans-1,2-disubstituted indane as the single diastereomer product.

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INTRODUCTION

Indane constitutes an important core of natural products such as those shown in Figure 1, including quadrangularin A (1)1,2 as well as paucifloral F (2),3,4 α-amino acid derivatives (3),5 and medicinal agents6 such as the anticancer indane carbocyclic nucleosides (4).7 It should be noted that both quadrangularin A and paucifloral F feature the 2,3-trans-2-arylindane as their core structure. A number of useful preparative methods, including the reactions mediated by metal salt complexes, have been developed for various substituted indanes such as mutisianthol (5),8,9 trikentrins,10−15 herbindoles,10−15 and taiwaniaquinoids16,17 (e.g., (+)-trans-trikentrin A (6), herbindole A (7), and taiwaniaquinol A (8)). In recent years, the work in our group has involved the use of Lewis or Brønsted acids for a number of organic transformations.18,19 Herein, we wish to report a facile synthetic method for an efficient preparation of substituted 2-arylindanes with a range of substitutions around the indane core. Our strategy has focused on the formation of the cyclopentane ring via a Lewis acid-mediated ring closure of the olefin to form the indanyl cation which can be further reacted by a number of nucleophiles (see Scheme 1).20−22 © 2013 American Chemical Society

RESULTS AND DISCUSSION

The requisite starting material, benzyl alcohol 11, was readily available in two steps from 2-bromobenzaldehyde 9 via the Heck reaction23,24 to generate the stilbene 10 that reacted with phenyllithium to furnish the product, as shown in Scheme 2. Both steps proceeded smoothly in 78−84% and 98% yields, respectively. Optimization of the Reaction Conditions. First, as shown in Scheme 3, in the absence of a nucleophile, with BF3· Et2O as a Lewis acid, the reaction gave only the corresponding indene products 12 (1−10%) and 13 (5−9%) among unidentifiable byproducts, suggesting that, for compound 11, the ensuing loss of a benzylic proton β to the indanyl-type carbocation to give 12 or 1,2-hydride shift followed by loss of proton to produce 13 was not a major pathway. It should be noted that similar results were obtained with both stoichiometric and catalytic amounts of BF3·Et2O. Next, in order to minimize the structural complexity of the product(s), hydride was selected as a nucleophile. The effects of different Lewis and Brønsted acids, hydride sources, and Received: November 20, 2012 Published: July 26, 2013 8281

dx.doi.org/10.1021/jo4013755 | J. Org. Chem. 2013, 78, 8281−8296

The Journal of Organic Chemistry

Article

Figure 1. Natural and synthetic substituted indanes.

Table 1. Screening the Conditions for 14a

Scheme 1. A Strategy Toward the Substituted 2-Arylindanes

Scheme 2. Preparation of Benzyl Alcohol 10

entry

acidb

solvent

time (h)

yield (%)c

1 2d 3e 4f 5 6e 7g 8 9

BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O TFA CF3SO3H PTS-Si InCl3 ZnCl2

CH2Cl2 CH2Cl2 PhMe THF CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

0.1 1.0 0.1 240 1.5 1.5 1.5 4 25

90 54 60 0 35 60 0 83 99

Unless noted otherwise, the reactions were performed at 0 °C using 1.5 equiv of Lewis or Brønsted acid and 1.5 equiv of Et3SiH. bOther Lewis acids such as PdCl2, PtCl4, SnCl4, TiCl3, and AlCl3 gave no desired indane product. cIsolated yield. dCatalytic amount (15 mol %) of BF3·Et2O was employed. eThe product was obtained with trace amount of unidentified impurities. fAn unidentifiable mixture of compounds was obtained. gThe corresponding indanol 16 was obtained. a

product; only complex mixtures of unidentifiable byproducts were observed in those cases. InCl3, BF3·Et2O, and ZnCl2 gave the best yields (83−99%; entries 1, 8, and 9) of the 1,2-transdiphenylindane 14 as a single diastereomer, while other Lewis acids including PdCl2, PtCl4, TiCl3, AlCl3, and SnCl4 gave no desired product. Use of Brønsted acids (entries 5 and 6) such as trifluoroacetic acid (TFA)25 or trifluoromethanesulfonic acid (TfOH) gave the corresponding indane 14, albeit in lower yields (35 and 60%, respectively). It should be noted that the use of BF3·Et2O and Et3SiH is typically expected to yield the deoxygenated product 15 which, under these conditions, was not observed.26 A stoichiometric amount of BF3·Et2O was required, giving the product in much higher yield than the catalytic amount (90 vs 54% yields; entries 1 and 2). The effect of different solvents can be observed when BF3·Et2O was used (entries 1−4). Dichloromethane (CH2Cl2) gave the best result, providing 14 in 90% yield compared with 60% when toluene was used. It should be noted that the reaction performed in tetrahydrofuran (THF) did not furnish the product; decomposition of 11 into a mixture of unidentifiable compounds was

Scheme 3. Products from Different Reaction Conditions

solvents were investigated, and the results are summarized in Table 1. After some experimentation, it was found that the use of Et3SiH as a hydride source gave the best results, while other sources of hydride such as NaBH 4 , NaCNBH 3 , and diisobutylaluminium hydride (DIBAL-H) gave no desired 8282



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observed instead when the reaction was allowed to reach room temperature and stirred for 240 h. Interestingly, when ptoluenesulfonic acid on the surface of silica (PTS-Si) was employed (entry 7), the reaction furnished the corresponding indanol 16 as a 1.7:1 inseparable mixture of epimers at the C1 position in 80% yield, slightly favoring the trans relationship between the two adjacent stereocenters.27 Similar mixtures of the epimers were obtained from the reactions both in the presence and absence of Et3SiH, suggesting that water, presumably from the protonation of the hydroxy group by the immobilized PTS-Si or from solvent, rather than the hydride, acts as a nucleophile (see the discussion on the plausible mechanism in a subsequent section). Scope of Substrates. Because it was easier to handle and gave yields comparable to ZnCl2 with much shorter reaction time, BF3·Et2O was selected for the subsequent studies. We next investigated the effects of a different group at the benzylic position (X = alkyl or aryl). Starting from the aldehydes 9 and 17 or acetophenone 18, the corresponding Heck products 10, 19, and 20 could be prepared in good yields (70−99%). Subsequently, either (1) nucleophilic addition to the aldehyde 10 or 19 or (2) borohydride reduction of the aldehyde 10 or acetophenone 20 furnished the corresponding benzyl alcohols 21−28 in moderate to good yields (15−91%), as shown in Scheme 4. It should be noted that low yield (15%) was

Table 2. Scope of Substrates Containing Different R Groupsa

entry

compound

R

product

yield (%)b

1 2 3 4 5c 6 7 8

21 22 23 24 25 11 26 27

H Me i-Pr tert-Bu CH2SO2Me Ph 3,4-diOMePh 4-OCF3Ph

29 30 31 32 33 14 34 35

0 99 50 85 50 90 60 75

a

Unless noted otherwise, the reactions were performed in CH2Cl2 at 0 °C using 1.5 equiv of BF3·Et2O and 1.5 equiv of Et3SiH. bIsolated yield. cA 2:1 mixture of unassignable cis and trans isomers was obtained.

Table 3. Product Distribution as a Result of Acid and Solvent Effects on the Reactions of 28a

Scheme 4. Preparation of Benzyl Alcohols 21−28 entry

acid

solvent

36:37

yield (%)b

1 2d 3 4 5 6e 7e 8e 9 10

BF3·Et2O

CH2Cl2 CH2Cl2 MeCN PhMe DMEe 1,4-dioxane Et2O THF CH2Cl2 CH2Cl2

100:0 100:0 11:1 10:1 1.3:1 0.3:1 0:100 0:100 100:0 100:0

12c 86 83 67 86 95 68 72 63 99

InCl3 TFA

Unless noted otherwise, the reactions were performed at 0 °C using 1.5 equiv of BF3·Et2O and 1.5 equiv of Et3SiH. bIsolated yield. c Besides the desired product, only unidentified baseline materials were obtained. dCatalytic amount (15 mol %) of BF3·Et2O was used. eThe reactions took 15 h to complete. a

obtained from the addition of i-Pr group to the aldehyde 10 because of the competing “hydride” transfer from i-PrMgBr to the aldehyde, yielding the reduced product 21. The results of BF3·Et2O-mediated cyclization of 21−27 followed by hydride addition from Et3SiH are summarized in Table 2. Except for the primary benzyl alcohol 21, all the secondary benzyl alcohols containing alkyl or aryl substituents (11 and 22−27) gave the corresponding substituted trans-2phenylindanes 14 and 30−35 in moderate to excellent yields (50−99%). When compound 21 was subjected to the reaction conditions, only a complex mixture was obtained without any trace of the indane 29. Presumably, the corresponding initial primary benzylic carbocation generated from 21 was unstable under the reaction conditions and underwent decomposition prior to cyclization to the subsequent indanyl-type carbocation and hydride addition. It should be noted that the product 33 was obtained as a 2:1 mixture of unassignable cis and trans diastereomers. The effects of substituents on the fused benzene ring were also investigated. As summarized in Table 3, the presence of

two methoxy groups in 28 directed the reactions to provide the corresponding indane 36 (from nucleophilic addition of hydride to the indanyl cation) as well as the indene 37 (from the loss of proton at the 2-position), depending on the solvent. The indane was obtained in 86% yield exclusively from the reaction in CH2Cl2 (entries 1−2) while those in THF and Et2O (entries 7 and 8) furnished the indene exclusively in good yields (68 and 72%, respectively). When CH2Cl2 was used as solvent, the reaction employing catalytic amount of BF3·Et2O (15 mol %) proceeded more cleanly and gave 36 in much higher yield than that with 1.5 equiv of the Lewis acid. Interestingly, other solvents gave both products in different ratios (entries 3−6). It is evident that the more coordinating oxygen-containing solvents (1,2-dimethoxyethane (DME), 1,4dioxane, Et2O, and THF) furnished the indene more preferentially than other solvents. Thus, the different ratios of products 36 and 37 neither depend on nor reflect the relative polarity of solvents. As shown in Scheme 5, the mechanism for 8283



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After some experimentation by varying temperature and the amount of BF3·Et2O, the desired products 45−47 could be obtained in moderate to excellent yields (51−99%). Because 1.5 equiv of BF3·Et2O led to the complete consumption of the starting material 42 without any indane product, it was necessary to lower the amount of the Lewis acid in the final step to 15 mol % for 42 (this is similar to the reaction of 28 to form indane 36), and thus BF3·Et2O was employed with 43 and then with 44 for comparison.29 At 0 °C, both 43 and 44 gave the products 46 and 47 in good yield (71%); 42 gave the product 45 in much lower yield (51%). When lowering the temperature to −40 °C,30 only 44 gave 47 in virtually quantitative yield (99%) while both 42 and 43 gave the corresponding indane products 45 and 46 in moderate yields (58%). For comparison, compound 11, without any substituent on the Ar group (Ar = Ph), gave the product 14 in 54% yield (Table 1, entry 2) when 15 mol % of BF3·Et2O was used at 0 °C. It is apparent that changing the reaction temperature had little effect on the yield of this reaction for 42. In the cases of 43 and 44, lowering the temperature affected the yields of the reactions in the opposite directionlower in the case of 43 but higher in that of 44. To account for these results, the electronic nature of these substituents was considered. In the cases of 42 and 44, the methoxy (OMe) and the nitro (NO2) groups are clearly electron-donating (EDG) and electron-withdrawing (EWG) groups, respectively, via resonance effects, which modulate the electron density in the stibenyl olefin moiety (increased with OMe and decreased with NO2 with reference to H). However, in the case of Cl in 43, it appears that both resonance and inductive field effects govern the overall effects of the Cl substituent; the extent and contribution of each effect may vary under different reaction conditions.31 By resonance, the Cl substituent on an aromatic system is normally considered to be an EDG; however, inductively, Cl deactivates the aromatic ring and can be considered to be an EWG.31 In our case, the effects from Cl appeared to be temperature-dependent. At 0 °C, the inductive field effect of Cl seemed to predominate as the yields of 46 and 47 were similar (71%). In other words, Cl behaves as an EWG at 0 °C. At −40 °C, the resonance effect of Cl through the aromatic system appeared to contribute more significantly as the yield of 46 decreased to be similar to that of 45 (58%); Cl is an EDG under this reaction condition. These results suggested that the presence of the EWG on this aromatic ring facilitates the cyclization step of the initial carbocations to the indanyl-type cations. In contrast, the presence of the EDG on the same ring appears to encumber such cyclization (see Plausible Mechanisms for the Formation of the Products in a subsequent section). Scope of Nucleophiles. With the developed condition (BF3·Et2O in CH2Cl2) in hand, we then investigated the scope of nucleophilic transfer from the trialkylsilyl reagents as summarized in Table 4. The azide, allyl, chloride, bromide, and iodide groups were transferred smoothly from the corresponding trimethylsilyl (TMS)-containing reagents to the indanyl-type cation, yielding the corresponding products 48−54 in 33−75% yields without any additive (entries 1−3 and 7−9). The azidoindane 48 was obtained in a 9:1 diastereomeric ratio while the allyl indane 49 and the haloindanes 50−52 were obtained in 1:1−3:1 ratios, with slight preference for the 1,2trans relationship. Both alcohols 42 and 43, upon reacting with TMS-N3, gave the corresponding azidoindanes 53 and 54 in 61 and 65% yields, respectively, with slight preference for the 1,2-

Scheme 5. A Proposed Mechanism for the Formation of 36 and 37

the formation of indene 37 may proceed via the carbocation and involve p-quinone methide and the participation of either one or both of the methoxy groups (both intermediates A and B). The structure of indene 37 was confirmed by hydrogenation, which gave the corresponding indane 38 as a 9:1 mixture of diastereomers favoring the addition of hydrogen to the olefin from the face opposite the phenyl group. Use of InCl3 and TFA in CH2Cl2 as solvent gave only the indane 36 in 63 and 99% yields, respectively (entries 10 and 11). The electronic effects from the nonfused aromatic (Ar) group were also investigated. When 4-methoxystyrene, 4chlorostyrene, and 4-nitrostyrene were employed in the Heck reactions, the corresponding benzaldehydes 39−41 were obtained in moderate to good yields (65−93%), as shown in Scheme 6.28 Subsequent PhLi or PhMgBr addition gave the requisite benzyl alcohol 42−44 in good yields (70−71%); these alcohols were then subjected to BF3·Et2O-mediated cyclization followed by hydride transfer from Et3SiH. Scheme 6. Preparation of 2-Arylindanes 45−47 with Different Ar Groups via Heck Reactions

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Table 4. Scope of Nucleophilic Transfer from Trialkylsilyl Reagentsa

Ar

Nu

equiv of BF3·Et2O

additive

equiv of additive

Prod

Hα:Hβ

yield (%)b

4-OMePh 4-ClPh

N3 allyl allyl allyl allyl allyl Cl Br I F N3 N3

1.5 1.5 0.15 0.15 2.0 3.5 0.15 0.15 0.15 2.0 0.15 0.15

none none none TBAFd TBAF TBAF none none none none none none

0.0 0.0 0.0 1.5 1.5 3.0 0.0 0.0 0.0 0.0 0.0 0.0

48 49 49 49 49 49 50 51 52 12 53 54

9:1 1:1 1:1 N/A 1:1 1:2 3:1 2:1 3:1 N/A 2:1 3:1

75 99%). IR (neat): ν̅max 3027, 2932, 1606, 1502, 1453, 1301, 1219, 1098 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.18 (dd, 1H, J = 7.6, 15.3 Hz), 3.32 (dd, 8293



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21H), 7.33−7.54 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 35.2, 36.2, 48.5, 50.1, 53.5, 59.1, 59.3, 62.6, 116.2, 116.9, 123.5, 124.8, 124.9, 125.1, 126.4, 126.95, 126.99, 128.17, 128.26, 128.3, 128.4, 128.5, 128.6, 128.7, 136.1, 137.0, 140.3, 142.0, 143.3, 145.2, 145.5, 145.9, 146.0. TOF−HRMS calcd for C24H22 (M+) 310.1716, found 310.1714. trans-1-Chloro-2,3-diphenyl-2,3-dihydro-1H-indene (50). The product was obtained as a light orange oil (5% EtOAc/hexanes, 18.9 mg, 59%). IR (neat): ν̅max 3060, 3028, 2920, 1709, 1601, 1494, 1475, 1453 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.69 (t, 1H, J = 9.3 Hz), 4.00 (dd, 1H, J = 6.0, 9.0 Hz, minor), 4.42 (d, 1H, J = 9.9 Hz), 4.91 (d, 1H, J = 10.2 Hz, minor), 5.49 (d, 1H, J = 8.7 Hz), 5.60 (d, 1H, J = 5.4 Hz, minor), 6.94 (d, 4H, J = 7.2 Hz), 7.02−7.40 (m, 14H), 7.52 (t, 3H, J = 9.3 Hz). 13C NMR (75 MHz, CDCl3): δ 51.8 (minor), 57.4, 60.6 (minor), 66.90, 66.92 (minor), 67.5, 124.8, 124.9, 125.4, 126.6, 127.0, 127.2, 127.4, 127.7, 127.8, 127.9, 128.1, 128.3, 128.4, 128.5, 128.6, 128.7, 128.8, 129.0, 129.3, 129.4, 137.4, 139.0, 140.8,141.8, 142.3, 143.9, 146.9. TOF−HRMS calcd for C21H17 (M − Cl)+ 269.1325, found 269.1327. trans-1-Bromo-2,3-diphenyl-2,3-dihydro-1H-indene (51). The product was obtained as a light yellow oil (5% EtOAc/hexanes, 26.4 mg, 72%). IR (neat): ν̅max 3060, 3028, 2925, 1724, 1602, 1493, 1453 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.82−3.91 (m, 2H), 4.48 (d, 1H, J = 9.3 Hz), 4.83 (d, 1H, J = 10.2 Hz, minor), 4.91 (d, 1H, J = 10.2 Hz), 5.60 (d, 1H, J = 8.7 Hz), 5.78 (d, 1H, J = 5.1 Hz, minor), 6.90−6.95 (m, 2H), 7.07 (d, 2H, J = 6.6 Hz), 7.24−7.40 (m, 19H), 7.49−7.56 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 51.6 (minor), 57.7, 58.3, 60.2 (minor), 60.7 (minor), 67.7, 124.7 (minor), 124.9, 125.4 (minor), 125.8, 127.0, 127.1, 127.4, 127.7, 127.8, 128.0, 128.1, 128.50, 128.51, 128.6, 128.7, 129.0, 129.1, 129.3, 138.3, 139.2, 140.4, 141.9, 142.2, 142.7, 144.0, 147.0. TOF−HRMS calcd for C21H17 (M − Br)+ 269.1325, found 269.1320. trans-1-Iodo-2,3-diphenyl-2,3-dihydro-1H-indene (52). The product was obtained as a light pink oil (5% EtOAc/hexanes, 13.7 mg, 33%). 1H NMR (300 MHz, CDCl3): δ 3.23 (dd, 1H, J = 6.0, 12.0 Hz, minor), 3.96 (t, 1H, J = 9.2 Hz), 4.56−4.61 (m, 2H), 5.74 (d, 1H, J = 9.0 Hz), 5.99 (d, 1H, J = 5.4 Hz, minor), 6.84 (d, 1H, J = 7.5 Hz, minor), 6.89 (d, J = 7.2 Hz, 1H), 7.00−7.42 (m, 14H), 7.46−7.55 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 34.9, 43.5 (minor), 52.0 (minor), 59.2, 59.8 (minor), 69.1, 124.3, 124.8, 125.4, 127.0, 127.2, 127.4, 127.6, 127.8, 128.1, 128.2, 128.45, 128.50, 128.6, 128.71, 128.78, 128.81, 129.1, 139.4, 139.9, 142.0, 143.5, 143.8, 144.5. TOF−HRMS calcd for C21H17 (M − I)+ 269.1325, found 269.1333. trans-1-Azido-2-(4-methoxyphenyl)-3-phenyl-2,3-dihydro1H-indene (53a). The product was obtained as a yellow oil (2% EtOAc/hexanes, 16.5 mg, 42%). IR (neat): ν̅max 3028, 2092, 1248, 1178 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.43 (t, 1H, J = 9.0 Hz), 3.77 (s, 3H), 4.34 (d, 1H, J = 9.0 Hz), 4.98 (d, 1H, J = 12.0 Hz), 6.84 (dd, 2H, J = 3.0, 6.9 Hz), 6.95 (d, 1H, J = 9.0 Hz), 7.05−7.08 (m, 2H), 7.15−7.38 (m, 7H), 7.46 (d, 1H, J = 6.0 Hz). 13C NMR (75 MHz, CDCl3): δ 55.2, 56.7, 63.3, 70.9, 114.1, 123.8, 125.3, 126.9, 127.7, 128.5, 128.9, 128.9, 131.3, 141.1, 141.8, 144.3, 158.8. LRMS−EI m/z (relative intensity) 314 (23), 313 (100, (M−N2)+), 312 (79), 206 (86), 179 (95), 178 (95), 165 (45), 121 (90), 91 (20), 77 (30). TOF− HRMS calcd for C22H19N3O (M+) 341.1523, found 341.1522. cis-1-Azido-2-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-1Hindene (53b). The product was obtained as a yellow oil (2% EtOAc/ hexanes, 7.46 mg, 19%). IR (neat): ν̅max 3028, 2094, 1247, 1179 cm−1. 1 H NMR (300 MHz, CDCl3): δ 3.73−3.78 (m, 4H), 4.77 (d, 1H, J = 12.0 Hz), 5.03 (d, 1H, J = 6.0 Hz), 6.93 (d, 2H, J = 18.0 Hz), 6.99− 7.02 (m, 1H), 7.13−7.35 (m, 9H), 7.33−7.35 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 55.2, 59.7, 68.9, 113.7, 124.8, 125.6, 126.9, 127.5, 128.4, 128.6, 129.0, 129.5, 130.2, 139.6, 141.6, 147.1, 158.7. LRMS−EI m/z (relative intensity) 341 (M+), 314 (23), 313 (100), 312 (73), 206 (62), 179 (65), 178 (90), 165 (47), 149 (54), 121 (830, 97 (36), 77 (35). TOF−HRMS calcd for C22H19N3O (M+) 341.1523, found 341.1538. trans-1-Azido-2-(4-chlorophenyl)-3-phenyl-2,3-dihydro-1Hindene (54a). The product was obtained as a yellow oil (2% EtOAc/ hexanes, 6.41 mg, 47%). IR (neat): ν̅max 3328, 2921, 2094, 1600, 1492 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.45 (t, 1H, J = 9.0 Hz), 4.34

1H, J = 8.7, 15.1 Hz), 3.74 (s, minor), 3.76 (s, 3H), 3.92 (s, minor), 3.94 (s, 3H), 4.04 (dd, 1H, J = 8.1, 16.2 Hz), 4.37 (d, J = 9.0 Hz, minor), 4.60 (d, 1H, J = 8.1 Hz), 6.46 (s, minor), 6.58−6.60 (m, 2H), 6.66 (s, 1H), 6.80−6.82 (m, 2H), 6.94 (s, 1H), 6.96−7.05 (m, 6H), 7.16−7.25 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 36.9, 52.5, 56.0, 56.03, 56.9, 107.3, 108.4, 125.95, 125.97, 127.5, 127.6, 128.4, 129.0, 135.5, 136.9, 141.1, 141.2, 148.0, 148.5. LRMS−EI m/z (relative intensity) 330 (100, M+), 315 (11), 299 (24), 252 (17), 239 (47), 238 (28), 208 (31), 165 (33), 126 (20), 115 (18), 91 (37). TOF−HRMS calcd for C23H22O2 (M+) 330.1614, found 330.1623. trans-2-(4-Methoxyphenyl)-1-phenyl-2,3-dihydro-1H-indene (45). The product was obtained as a yellow oil (2% EtOAc/hexanes, 16.6 mg, 58%). IR (neat): ν̅max 3058, 3027, 1248, 1179 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.20 (dd, 1H, J = 10.0, 15.6 Hz), 3.38 (dd, 1H, J = 7.9, 15.6 Hz), 3.52−3.61 (m, 1H) 3.77 (s, 3H), 4.35 (d, 1H, J = 6.0 Hz), 6.79 (d, 2H, J = 8.7 Hz), 6.90 (d, 1H, J = 7.3 Hz), 7.07−7.31 (m, 10H). 13C NMR (75 MHz, CDCl3): δ 40.3, 55.2, 56.0, 59.9, 113.7, 124.1, 125.0, 126.5, 126.7, 126.9, 128.3, 128.4, 128.5, 130.7, 135.2, 142.7, 143.4, 146.0. LRMS−EI m/z (relative intensity) 300 (100, M+), 192 (63), 179 (74), 165 (37), 139 (41), 121 (43), 97 (49), 77 (21), 71 (60), 69 (89), 57 (61). TOF−HRMS calcd for C22H20O (M)+ 300.1509, found 300.1516. trans-2-(4-Chlorophenyl)-1-phenyl-2,3-dihydro-1H-indene (46). The product was obtained as a yellow oil (2% EtOAc/hexanes, 10.1 mg, 58%). IR (neat): ν̅max 3063, 3027, 2932, 2851, 1600 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.20 (dd, 1H, J = 10.1, 15.6 Hz), 3.40 (dd, 1H, J = 8.0, 15.7 Hz), 3.53−3.62 (m, 1H), 4.35 (d, 1H, J = 9.0 Hz), 6.91 (d, 1H, J = 9.0 Hz), 7.05−7.32 (m, 12H). 13C NMR (75 MHz, CDCl3): δ 40.1, 56.2, 59.9, 124.2, 125.0, 126.7, 126.9, 127.1, 128.5, 128.9, 132.1, 141.7, 142.4, 143.0. LRMS−EI m/z (relative intensity) 306 (12, M+2), 304 (37, M+), 192 (32), 179 (100), 178 (80), 165 (23), 149 (12), 125 (14), 77 (12), 69 (14). TOF−HRMS calcd for C21H16Cl (M − H)+ 303.0935, found 303.0943. trans-2-(4-Nitrophenyl)-1-phenyl-2,3-dihydro-1H-indene (47). The product was obtained as a yellow oil (2% EtOAc/hexanes, 15.5 mg, 99%). IR (neat): νm ̅ ax 3063, 3027, 2942, 2853, 1560, 1519, 1345 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.19 (dd, 1H, J = 10.0, 15.1 Hz), 3.39 (dd, 1H, J = 8.0, 15.7 Hz), 3.59−3.68 (m, 1H), 4.33 (d, 1H, J = 9.0 Hz), 6.85 (d, 1H, J = 7.2 Hz), 6.98 (d, 2H, J = 1.6 Hz), 7.00−8.02 (m, 6H), 7.27 (d, 2H, J = 7.2 Hz), 8.05 (d, 2H, J = 1.6 Hz). 13 C NMR (75 MHz, CDCl3): δ 39.8, 56.5, 59.9, 123.7, 124.2, 125.0, 127.0, 127.1, 128.3, 128.6, 141.8, 142.5, 145.2, 146.7, 151.1. LRMS−EI m/z (relative intensity) 315 (24, M+), 179 (64), 178 (56), 149 (65), 111 (27), 97 (56), 77 (43), 57 (71). TOF−HRMS calcd for C21H17NO2 (M+) 315.1254, found 315.1251. trans-1-Azido-2,3-diphenyl-2,3-dihydro-1H-indene (48). The product was obtained as a 9:1 mixture of diastereomers as light yellow oil (10% EtOAc/hexanes, 19.0 mg, 75%). IR (neat): νm ̅ ax 3029, 2915, 2092, 1601, 1494, 1454, 1314, 1248, 1075, 1029 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.49 (dd, 1H, J = 9.4, 9.5 Hz), 3.79−3.95 (m, minor), 4.39 (d, 1H, J = 9.9 Hz), 4.76−4.86 (m, minor), 5.03 (d, 1H, J = 8.7 Hz), 5.25 (d, J = 7.8 Hz, minor), 6.96 (d, 1H, J = 7.2 Hz), 7.07 (d, 2H, J = 6.6 Hz), 7.16−7.40 (m, 12H), 7.47 (d, 1H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ 53.2 (minor), 56.7, 60.3 (minor), 63.9, 68.8 (minor), 70.9, 123.8, 125.3, 127.0, 127.4, 127.8, 127.9, 128.3, 128.4, 128.5, 128.6, 128.7, 129.0, 129.2, 139.5, 140.1, 141.8, 144.3. LRMS−EI m/z (relative intensity) 283 (44), 282 (69), 269 (12), 206 (89), 192 (50), 191 (29), 179 (73), 178 (100), 165 (51), 152 (19), 91 (32), 77 (21), 69 (14), 57 (17). TOF−HRMS calcd for C21H17 (M − N3)+ 269.1325, found 269.1320, calcd for C21H16N (M − N2 − H)+ 282.1277, found 282.1275. trans-1-Allyl-2,3-diphenyl-2,3-dihydro-1H-indene (49). The product was obtained as a light yellow solid (2% EtOAc/hexanes, 22.0 mg, 68%). IR (neat): ν̅max 3062, 3026, 2920, 1639, 1601, 1492, 1475, 1452 cm−1. 1H NMR (300 MHz, CDCl3): δ 2.00−2.02 (m, 1H), 2.43−2.53 (m, 1H), 2.59−2.66 (m, 1H), 3.22 (t, 1H, J = 10.2 Hz), 3.46−3.59 (m, 2H), 3.90 (t, 1H, J = 8.4 Hz), 4.37 (d, 1H, J = 10.2 Hz), 4.73 (d, 1H, J = 9.3 Hz), 4.79 (d, 1H, J = 18.3 Hz), 4.91 (d, 1H, J = 9.9 Hz), 5.01 (d, 1H, J = 9.9 Hz), 5.07 (d, 1H, J = 17.1 Hz), 5.62−5.84 (m, 2H), 6.89−6.96 (m, 2H), 7.02 (d, 2H, J = 6.9 Hz), 7.16−7.29 (m, 8294



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(d, 1H, J = 9.0 Hz), 4.99 (d, 1H, J = 9.0 Hz), 6.96 (d, 1H, J = 9.0 Hz), 7.06 (d, 2H, J = 6.0 Hz), 7.17−7.40 (m, 9H), 7.47 (d, 1H, J = 6.0 Hz). 13 C NMR (75 MHz, CDCl3): δ 56.8, 63.4, 70.7, 123.9, 125.3, 127.2, 127.9, 128.5, 128.7, 128.9, 129.1, 129.3, 133.2, 137.9, 139.9, 141.4, 144.0. LRMS−EI m/z (relative intensity) 345 (1, M+), 319 (20), 318 (33), 317 (60), 316 (70), 206 (58), 192 (58), 179 (75), 178 (100), 165 (46), 140 (14), 125 (21), 77 (15). TOF−HRMS calcd for C21H15ClN (M − N2 − H)+ 316.0888, found 316.0903. cis-1-Azido-2-(4-chlorophenyl)-3-phenyl-2,3-dihydro-1H-indene (54b). The product was obtained as a yellow oil (2% EtOAc/ hexanes, 2.45 mg, 18%). IR (neat): ν̅max 3750, 3610, 3029, 2924, 2100, 1711, 1492 cm−1. 1H NMR (300 MHz, CDCl3): δ 3.75 (t, 1H, J = 9.0 Hz), 4.77 (d, 1H, J = 9.0 Hz), 5.06 (d, 1H, J = 6.0 Hz), 7.00 (s, 1H), 7.13 (d, 1H, J = 9.0 Hz), 7.26−7.36 (m, 10H), 7.475 (d, 1H, J = 3.0 Hz). 13C NMR (75 MHz, CDCl3): δ 53.6, 59.8, 68.5, 124.8, 125.7, 127.1, 127.7, 128.4, 128.3, 128.7, 129.7, 130.6. LRMS−EI m/z (relative intensity) 345 (1, M+), 319 (20), 318 (32), 317 (58), 316 (67), 206 (460, 179 (74), 178 (100), 165 (46), 140 (12), 127 (12), 125 (20), 77 (16). TOF−HRMS calcd for C21H15ClN (M − N2 − H)+ 316.0888, found 316.0896. Quantum Chemical Calculations. Quantum chemical calculations were performed using the M062X density functional theory (DFT) method, with the 6-31+G(g,p) basis set, and a polarizable continuum solvent model (PCM) of CH2Cl2. All minima and transition states were confirmed from frequency calculations, the former showing all positive frequencies and the latter a single negative frequency. The thermochemically corrected free energies are reported in Figure 2.

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(9) Bianco, G. G.; Ferraz, H. M. C.; Costa, A. M.; Costa-Lotufo, L. V.; Pessoa, C.; de Moraes, M. O.; Schrems, M. G.; Pfaltz, A.; Silva, L. F., Jr. J. Org. Chem. 2009, 74, 2561−2566. (10) Silva, L. F., Jr.; Craveiro, M. V.; Tébéka, I. R. M. Tetrahedron 2010, 66, 3875−3895. (11) Silva, L. F., Jr.; Craveiro, M. V. Org. Lett. 2008, 10, 5417−5420. (12) Buszek, K. R.; Brown, N.; Luo, D. Org. Lett. 2009, 11, 201−204. (13) Liu, W.; Lim, H. J.; RajanBabu, T. V. J. Am. Chem. Soc. 2012, 134, 5496−5499. (14) Jackson, S. K.; Kerr, M. A. J. Org. Chem. 2007, 72, 1405−1411. (15) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550−3577. (16) Hanson, J. R. Nat. Prod. Rep. 2004, 21, 312−320. (17) Liang, G.; Xu, Y.; Seiple, I. B.; Trauner, D. J. Am. Chem. Soc. 2006, 128, 11022−11023. (18) Batsomboon, P.; Phakhodee, W.; Ruchirawat, S.; Ploypradith, P. J. Org. Chem. 2009, 74, 4009−4012. (19) Radomkit, S.; Sarnpitak, P.; Tummatorn, J.; Batsomboon, P.; Ruchirawat, S.; Ploypradith, P. Tetrahedron 2011, 67, 3904−3914. (20) This strategy was pioneered and investigated as a means for the total synthesis of resveratrol-based natural products. Please see: Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L. J. Am. Chem. Soc. 2009, 131, 1753−1765. (21) Snyder, S. A.; Brill, Z. G. Org. Lett. 2011, 13, 5524−5527. (22) Lantaño, B.; Aguirre, J. M.; Finkielsztein, L.; Alesso, E. N.; Brunet, E.; Moltrasio, G. Y. Synth. Commun. 2004, 34, 625−641. (23) We found that the use of Pd(PPh3)4 usually gave the product 10 in higher yield but Pd(PPh3)2Cl2 was more stable and easier to handle. For reviews of Heck reactions, see: (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009−3066. (b) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945−2963. (c) McCartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122−5150. (24) For the seminal work on the Heck reactions, see: Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320−2322. (25) The corresponding trifluoroacetate indane products from the trifluoroacetate acting as a nucleophile to quench the indanyl-type cation was not observed either at 0 °C to room temperature or at −30 °C. The results were different from those obtained by Snyder and coworkers (see ref 20). (26) For example, see: Li, K.; Vanka, K.; Thompson, W. H.; Tunge, J. A. Org. Lett. 2006, 8, 4711−4714. (27) Stereochemical assignment of the indanol 16 obtained as a 1.7:1 inseparable mixture of epimers at C1 position is based on (1) the NMR assignment of peaks corresponding to protons at C1 (CHOH; δ 5.37 for major and 5.26 for minor), C2 (CHPh; δ 3.34 for major and 3.70 for minor), and C3 (CHArPh; δ 4.33 for major and 4.86 for minor) as well as (2) the J values between H2 and H3 which are consistently large for both isomers (9.3 and 9.9 Hz for H2; 9.2 and 10.1 Hz for H3), while the J value between H1 and H2 is large for the major isomer (8.4 Hz, suggesting trans relationship) compared with that of the minor isomer (5.4 Hz, suggesting cis relationship). These data are in accordance with the assigned structures of the major isomer possessing H1−H2 as well as H2−H3 in the trans relationship. On the other hand, the minor isomer appears to possess H1−H2 cis and H2− H3 trans relationship. In addition, the NOE experiments confirmed the assignments (see S5 in the Supporting Information; NOE values of 1.44% and 1.69% were observed for H1−H2 in the trans relationship of the major isomer, while those of 6.21% and 7.71% were observed for the H1−H2 in the cis relationship of the minor isomer. Similar NOE values of 0.96% and 1.35% were observed for the H2−H3 for both isomers, suggesting H2−H3 in the trans relationship.) (28) Because of the presence of some unidentifiable byproducts from the reaction which were difficult to separate, only about 30% of the pure compound 41 could be consistently isolated by chromatography on silica when DMF stored over 4 Å molecular sieves was employed as solvent. However, use of the reagent-grade solvent DMF, without additional purification or special storage, gave a better yield of 93%. (29) At 0 °C, similar yields (70% versus 71%) of 46 were obtained from 43 when 1.5 equiv and 15 mol % of BF3·Et2O was employed.

ASSOCIATED CONTENT

S Supporting Information *

General information, copies of 1H and 13C NMR spectra of all new compounds, the absolute energies and the vibrational frequencies and intensities of all stationary points obtained on the reaction pathway, and the Cartesian coordinates. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Thailand Research Fund (TRF; BRG5580010 for P.P. and RSA 5480016 for M.P.G.), National Science Foundation (NSF; NSF CHE-0850693 for Y.K.), and Kasetsart University are gratefully acknowledged.

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REFERENCES

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(30) The temperature was chosen from the work by Snyder (see ref 20). (31) It is normally difficult to separate the resonance and field effects of a group or substituent. A chloro substituent on an aromatic ring is denoted to be +M for electron-donating ability due to resonance and −I for electron-withdrawing ability due to inductive field effect. For groups which are both −I and +M, it is particularly difficult to predict whether resonance or field effects will predominate in the reaction conditions. For further discussion, see: Smith, , M. B.; March, , J. In March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed.; John Wiley & Sons, Inc.: NJ, 2007, pp 19−22, 46−48, 396−397, 485−486, 668, and references cited therein. (32) For an example of using Na2SO4 as a drying agent during a reaction, see: Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086−1087. (33) For examples of formal [3 + 2] cycloaddition involving intermolecular styrene addition to a benzylic carbocation under Lewis acid catalysis, forming an indane product, see: (a) Lantaño, B.; Aguirre, J. M.; Ugliarolo, E. A.; Benegas, M. L.; Moltrasio, G. Y. Tetrahedron 2008, 64, 4090−4102. (b) Lantaño, B.; Aguirre, J. M.; Ugliarolo, E. A.; Torviso, R.; Pomilio, N.; Moltrasio, G. Y. Tetrahedron 2012, 68, 913−921. (34) Our observations of the electronic effects of both the fused and nonfused aromatic rings are consistent with those of the formal intermolecular [3 + 2] cycloaddition between substituted benzhydrol and styrene derivatives (see ref 33). (35) Chang, M.-Y.; Lin, C.-H.; Chen, Y.-L.; Chang, C.-Y.; Hsu, R.-T. Org. Lett. 2010, 12, 1176−1179. (36) Fraser, R. R.; Faibish, N. C.; Kong, F.; Bednarski, K. J. Org. Chem. 1997, 62, 6164−6176. (37) Scott, V. J.; Ç elenligil-Ç etin, R.; Ozerov, O. V. J. Am. Chem. Soc. 2005, 127, 2852−2853. (38) It has been proposed that InCl3 and Et3SiH formed a Cl2In-H species. For example, see: Hayashi, N.; Shibata, I.; Baba, A. Org. Lett. 2004, 6, 4981−4983. (39) For allylsilane serving as an allyl anion equivalent, see: Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673−1675. (40) Nair, J.; Rajesh, C.; Dhanya, R.; Rath, N. P. Org. Lett. 2002, 4, 953−955. (41) Nekipelova, T. D.; Levina, I. I.; Levin, P. P.; Kuzmin, V. A. Russ. Chem. Bull. 2004, 54, 808−813. (42) Soli, E. D.; Manoso, A. S.; Patterson, M. C.; DeShong, P.; Favor, D. A.; Hirschmann, R.; Smith, A. B., III J. Org. Chem. 1999, 64, 3171− 3177. (43) For the role of silicon in stabilizing β-carbocations, see: (a) Lambert, J. B. Tetrahedron 1990, 46, 2677−2689. (b) Lambert, J. B.; Chelius, E. C. J. Am. Chem. Soc. 1990, 112, 8120−8126.

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Synthesis of Substituted 2-Arylindanes from E-(2-Stilbenyl) methanols

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