A Facile Approach to 2-Substituted Isoflav-3-enes via Isoflavylium Salts

Abstract

A compact and regioselective approach to 2-substituted isoflav-3-enes based on a preformed 2-unsubstituted isoflavene is described. Isoflavene oxidation by hydride ion abstraction to the corresponding isoflavylium salt using trityl hexafluorophosphate followed by nucleophilic addition to the 2-position resulted in the introduction of a range of substituent groups in generally moderate to good yields.

Isoflavonoids have gained increasing attention in recent years because of the range of biological activities they display. These activities include estrogen-receptor antagonism, [¹a] anticancer (protein kinase inhibition), [¹b] antiplatelet aggregation, [¹c] anti-inflammatory, [¹c] [d] antiallergy, [¹c] antifungal, [¹e] peroxisome proliferator-activated receptor binding, [¹f] and diuretic properties. [¹g] Isoflav-3-ene (1a) (haginin E, [²a] dehydroequol, phenoxodiol), is of great interest as it has been shown to possess significant anticancer activity. [²b] Additionally, 1a acts as a chemosensitizer to current cancer therapies. [²c]

As part of a general SAR program with compounds of type 1, we were interested in developing a facile and flexible route to 2-substituted derivatives based on the isoflav-3-ene derivatives 1a-c (Figure  [¹] ).

Previous approaches to 2-substituted isoflav-3-enes have included a number based on 3-arylcoumarins. For example, [³] DIBAL reduction of the protected 3-arylcoumarin 2 gave the hemiacetal 3, which on reaction with phenol afforded the 2-substituted isoflav-3-ene 4 in high yield; ­reaction of 4 with various Grignard reagents, which in most cases gave the 1,2-product over the 1,4-product, followed by desilylation provided access to 5 (Scheme  [¹] ). It was proposed that displacement with the Grignard reagent proceeded via a magnesium-coordinated intermediate rather than a free oxonium ion (isoflavylium ion) intermediate.

In a somewhat similar way, Cook and co-workers accessed 2,4-disubstituted isoflav-3-enes [4a] from 4-substituted 3-arylcoumarins but in this case the Grignard reagent was added to the DIBAL-H reduction product in situ; acid-­catalyzed cyclization then gave the isoflavenes. Direct Grignard addition to coumarins results in 2,2-disubstituted analogues. [4b] [c]

Isoflavones can also serve as precursors for unsymmetrically substituted 2,4-dialkylisoflav-3-enes via sequential reaction with an alkyl lithium followed by a trialkylaluminum reagent. [5]

In a quite different strategic approach, 2-amino substituted isoflav-3-enes have been prepared through microwave-assisted assembly of the substituted pyran ring from substituted o-hydroxybenzaldehydes and enamine precursors, and a subsequent Knoevenagel reaction; [6] 2-aryl-isoflav-3-enes have been prepared similarly from a trihydroxydeoxybenzoin precursor. [7]

Explicit production of an isoflavylium salt precursor for further 2-substituted isoflav-3-ene formation is an alternative and potentially more versatile route, which we have explored. In particular, we investigated direct formation of such salts by hydride ion removal from readily available 2-unsubstituted isoflav-3-ene precursors using trityl salts [8] and then nucleophilic addition to the 2-position. The results are now reported in this paper.

A number of trityl salts was investigated for the hydride abstraction step using the phenol-protected isoflav-3-ene derivatives 1b and 1c. These derivatives were formed in turn from 1a [9a] [b] using acetic anhydride and pyridine, or TBS chloride in the presence of imidazole, respectively.

Table 1 Synthesis of Isoflav-3-enes 7

Entry	Isoflavylium ion 6b,c	Counterion (X-)	Yield of 7b,c (%)
1	6b	BF4 -	43
2	6b	SnCl5 -	76
3	6b	PF6 -	80
4	6c	PF6 -	0

With the protected isoflavenes in hand, reaction optimization was explored utilizing TMS cyanide as the nucleophile source for attack on the salts 6b and 6c (Table  [¹] ). [¹0] Such nucleophilic addition with TMS cyanide (and other nucleophiles) to related 1-benzopyrylium salts had been demonstrated previously, [¹¹] but these salts were derived from a 2-substituted acetal precursor on treatment with BF₃˙OEt₂. With 1b, the best yields of 7b were obtained with the hexafluorophosphate and pentachlorostannate trityl salts, while 1c failed to give any of the desired product 7c with trityl hexafluorophosphate salt presumably due to desilylation of the phenolic silyl ether groups by PF₆ ^- anion acting as a source of fluoride. [¹²] In view of these results, and taking into account environmental issues associated with the stannate salt, trityl hexafluorophosphate and 1b were subsequently used to explore the generality of the addition reactions of the isoflavylium salt intermediate.

Various nucleophiles could be added via C-C and C-O bond formation to the 2-position of the salt generated in situ (Table  [²] ). [¹³] With the C-C bond formation, TMS- or tin-based reagents were used to deliver the nucleophilic component in good to modest yields. Alcohols could also be added readily, as expected, to give the 2-alkoxy derivatives. The structures of the products were confirmed through NMR spectroscopy, and high-resolution mass spectrometry data or elemental analytical data were consistent with the molecular formulae. [¹4] The regioselectivity of nucleophilic attack at the 2-position over the 4-position in the salt was confirmed by HMBC analysis with a key correlation being observed between a vinylic H4 and C5. This regioselectivity is consistent with the greater double-bond stabilization possible with a stilbenyl moiety compared to the styryl moiety, which would be present from 4-substitution.

Table 2 Synthesis of the Isoflav-3-enes 8

Entry	AR	Compound R	Yield (%) of 8a-g
1	2-TMS-thiazole	8a 2-thiazolyl	76
2	TMSC≡CH	8b C≡CH	7
3	TMSCH2N(Boc)2	8c CH2NHBoc	45
4	(Bu)3SnCH2CH=CH2	8d CH2CH=CH2	68
5	MeOH	8e OMe	63
6	EtOH	8f OEt	63
7	HOCH2CH2CH2Br	8g OCH2CH2CH2Br	66

The poor yield of the ethynyl isoflav-3-ene 8b was due to the formation of the dimeric product 9, which was isolated in 67% yield. This dimer could arise from fluoride-mediated ethynyl group addition to the isoflavylium ion (Scheme  [²] ).

In conclusion, a new and concise one-pot procedure has been developed for the synthesis of 2-substituted isoflav-3-enes from a readily available isoflav-3-ene precursor utilizing in situ generation of an isoflavylium salt intermediate. This is a flexible approach, which allows for the ready introduction of a range of synthetically versatile substituents in this heterocyclic system.

Acknowledgment

J.B.B. thanks the University of Wollongong and Novogen Ltd for financial contribution to the project. A University of Wollongong-Novogen scholarship to J.F. is also gratefully acknowledged.

References and Notes

• 1a Jain N. Kanojia RM. Xu J. Jian-Zhong G. Pacia E. Lai M.-T. Du F. Musto A. Allan G. Hahn D. Lundeen S. Sui Z. J. Med. Chem.  2006,  49:  3056 
  Search in Google Scholar
• 1b Sarkar FH. Li Y. Cancer Metastasis Rev.  2002,  25:  265 
  Search in Google Scholar
• 1c Fwu S.-Y. Chang C.-Y. Huang L.-J. Teng C.-M. Wang J.-P. Chen S.-C. Kuo S.-C. Chin. Pharm. J. (Taipei)  1999,  34:  255 
  Search in Google Scholar
• 1d Emmanuel T. Dieudonne N. Tanyi MJ. Tanee FZ. Albert K. Jean-Claude M. Rosa GM. Carmen RM. Salvador M. Luis RJ. J. Nat. Prod.  2003,  66:  891 
  Search in Google Scholar
• 1e Lozovaya VV. Lygin AV. Zernova OV. Li S. Hartman GL. Widholm JM. Plant Phys. Biochem.  2004,  42:  671 
  Search in Google Scholar
• 1f Kuroda M. Mimaki Y. Sashida Y. Mae T. Kishida H. Nishiyama T. Tsukagawa M. Konishi E. Takahashi K. Kawada T. Nakagawa K. Kitahara M. Bioorg. Med. Chem. Lett.  2003,  13:  4267 
  Search in Google Scholar
• 1g Martinez RM. Gimenez I. Lou JM. Mayoral JA. Alda JO. Am. J. Clin. Nutr.  1998,  68 (S1):  1354S 
  Search in Google Scholar
• 2a Miyase T. Sano M. Nakai H. Muraoka M. Nakazawa M. Suzuki M. Yoshino K. Nishihara Y. Tanai J. Phytochemistry  1999,  52:  303 
  Search in Google Scholar
• 2b Gamble JR. Xia P. Hahn CN. Drew JJ. Drogemuller CJ. Brown D. Vadas MA. Int. J. Cancer  2006,  118:  2412 
  Search in Google Scholar
• 2c Alvero AB. O’Malley D. Brown D. Kelly G. Garg M. Chen W. Rutherford T. Mor G. Curr. Oncol. Rep.  2006,  8:  104 
  Search in Google Scholar
• 3 Grese TA. Pennington LD. Tetrahedron Lett.  1995,  36:  8913 
  CrossrefSearch in Google Scholar
• 4a Cook CE. Twine CE. J. Chem. Soc., Chem. Commun.  1968,  791 
• 4b Cook CE. Wall ME. J. Org. Chem.  1968,  33:  2998 
  Search in Google Scholar
• 4c Cook CE. Corley RC. Wall ME. J. Org. Chem.  1965,  30:  4114 
  Search in Google Scholar
• 5 Alberola A. Andres C. Ortega AG. Pedrosa R. Vicente M. J. Heterocycl. Chem.  1986,  23:  1781 
  Search in Google Scholar
• 6 Varma RS. Dahiya R. J. Org. Chem.  1998,  63:  8038 
  CrossrefSearch in Google Scholar
• 7 Gauthier S. Caron B. Cloutier J. Dory YL. Favre A. Larouche D. Mailhot J. Ouellet C. Schwerdtfeger A. Leblanc G. Martel C. Simard J. Merand Y. Belanger A. Labrie C. Labrie F. J. Med. Chem.  1997,  40:  2117 
  CrossrefSearch in Google Scholar
• 8a

  Trityl perchlorate has been used previously to access chromylium salts from the dihydro precursors^8b but not, as far as we can ascertain, from 2-unsubstituted isoflav-3-enes. Isoflavylium salts can also be made, for example, by ring construction^8c or by trityl salt mediated elimination of 2-substituted isoflav-3-enes^8d
• 8b Canalini G. Degani I. Fochi R. Spunta G. Ann. Chim. (Rome)  1967,  57:  1045 
  Search in Google Scholar
• 8c Bouvier P. Andrieux J. Molho D. Tetrahedron Lett.  1974,  1033 
• 8d Dean FM. Varma RS. J. Chem. Soc., Perkin Trans. 1  1982,  1193 
• 9a

  Compound 1a is accessible from the commercially available precursors daidzein^9c or daidzein diacetate^9d,e
• 9b Faragalla JE. PhD Thesis   University of Wollongong; Australia: 2005. 
• 9c Heaton A, and Jeoffreys G. inventors; WO  2005103025.  ; Chem. Abstr. 2005, 143, 422198
• 9d Heaton A, and Kumar N. inventors; WO  2000049009.  ; Chem. Abstr. 2000, 133, 177059
• 9e Liepa AJ. Aust. J. Chem.  1981,  34:  2647 
  Search in Google Scholar
• 11 Doodeman R. Rutjes FPJT. Hiemstra H. Tetrahedron Lett.  2000,  41:  5979 
  CrossrefSearch in Google Scholar
• 12 Deprotection of TBS ethers by the related trityl tetrafluoroborate has been reported with the anion acting as a fluoride ion source. See: Metcalf BW. Burkhart JP. Jund K. Tetrahedron Lett.  1980,  21:  35 
  CrossrefSearch in Google Scholar

General Procedure (Table 1, Entry 3)
A mixture of powdered 3 Å MS, trityl hexafluorophosphate (2.2 mmol), and the isoflavene 1b (503 mg, 1.55 mmol) in freshly distilled, anhyd CH₂Cl₂ (50 mL, from CaH₂) was stirred at r.t. under nitrogen for 30 min. Trimethylsilyl cyanide (0.480 g, 4.8 mmol) was then added, and the reaction mixture was stirred for a further hour at r.t. The reaction mixture was then filtered, washed with CH₂Cl₂, concentrated under vacuum filtration, and subjected to silica gel chromatography, using CH₂Cl₂ as the mobile phase to afford the product as a colorless crystalline solid (431 mg, 80%).

General Procedure (Table 2, Entry 1)
A mixture of powdered 3 Å MS, trityl hexafluorophosphate (2.2 mmol), and the isoflavene 1b (451 mg, 1.39 mmol) in freshly distilled, anhyd CH₂Cl₂ (50 mL, from CaH₂) was stirred at r.t. under nitrogen for 30 min. The commercially available 2-trimethylsilylthiazole (0.403g, 2.564 mmol) was then added and the reaction mixture was stirred for a further hour at r.t. The reaction mixture was then filtered, washed with CH₂Cl₂, concentrated under vacuum filtration, and subjected to silica gel chromatography, using CH₂Cl₂ as the mobile phase to afford the product as a creamy white solid (430 mg, 76%).

Data for Selected Compounds7-Acetoxy-3- p -acetoxyphenyl-2-cyano-2 H -1-benzopyran (7b) White solid; mp 156-158 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 7.49 (d, J = 8.7 Hz, 2 H, H-2′/6′), 7.23 (d, J = 8.0 Hz,
1 H, H-5), 7.18 (d, J = 8.6 Hz, 2 H, H-3′/5′), 6.97 (s, 1 H, H4), 6.85 (dd, J = 2.5, 8.1 Hz, 1 H, H-6), 6.84 (s, 1 H, H-8), 6.01 (s, 1 H, H-2), 2.32 (s, 3 H, CH₃), 2.30 (s, 3 H, CH₃). ^¹³C NMR (75 MHz, CDCl₃): δ = 169.1 (C=O), 168.9 (C=O), 151.9 (C7), 151.1 (C8a), 150.3 (C4′), 131.9 (C3), 128.3 (C5), 126.2 (C2′), 125.9 (C1′), 122.4 (C3′), 122.3 (C4), 119.1 (C4a), 117.0 (C6), 110.5 (C8), 64.3 (C2), 21.1 (CH₃). MS (CI⁺): m/z (%) = 323 (100) [MH⁺ - HCN]. Anal. Calcd (%) for C₂₀H₁₅NO₅: C, 68.76; H, 4.33; N, 4.01. Found: C, 69.20; H, 4.34; N, 3.67.
7-Acetoxy-3- p -acetoxyphenyl-2-(2-thiazoyl)-2 H -1-benzopyran (8a)
Creamy white solid; mp 136-138 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.60 (br d, J = 2.7 Hz, 1 H, H-2′′), 7.37 (d, J = 8.7 Hz, 2 H, H-2′/6′), 7.23 (d, J = 6.3 Hz, 1 H, H-5), 7.08 (d, J = 2.7 Hz, 1 H, H-3′′), 6.93 (d, J = 8.4 Hz, 2 H, H-3′/5′), 6.89 (s, 1 H, H4), 6.57 (dd, J = 2.7, 8.4 Hz, 1 H, H-6), 6.53 (d, J = 2.4 Hz, 1 H,H-8), 6.44 (br s, 1 H, H-2), 2.13 (s, 3 H, CH₃), 2.10 (s, 3 H, CH₃). ^¹³C NMR (75 MHz, CDCl₃): δ = 169.5 (C=O), 169.3 (C=O), 169.3 (C1′′), 151.8 (C7), 151.7 (C8a), 150.8 (C4′), 143.3 (C4′′), 134.0 (C3), 131.5 (C1′), 127.9 (C5), 126.9 (C2′), 122.2 (C3′), 121.1 (C3′′), 120.9 (C4), 120.2 (C4a), 115.7 (C6), 110.6 (C8), 74.7 (C2), 21.3 (CH₃). HRMS (CI⁺): m/z calcd for [M + H]⁺ C₂₂H₁₇NO₅S + H: 408.0906; found: 408.0887.




7-Acetoxy-3- p -acetoxyphenyl-2-ethoxy-2 H -1-benzopyran (8f)
Creamy white solid; mp 134-136 ˚C. ^¹H NMR (300 MHz, CDCl₃): d = 7.53 (d, J = 9.0 Hz, 2 H, H-2′/6′), 7.23 (d, J = 8.4 Hz, 1 H, H-5), 7.12 (d, J = 8.4 Hz, 2 H, H-3′/5′), 6.98 (s, 1 H, H-4), 6.82 (d, J = 2.1 Hz, 1 H, H-8), 6.76 (dd, J = 8.4, 2.1 Hz, 1 H, H6), 5.95 (s, 1 H, H-2), 4.04-3.96 (m, 1 H, OCH ₂CH₃), 3.82-3.74 (m, 1 H, OCH ₂CH₃), 2.32 (s, 3 H, CH ₃CO), 2.30 (s, 3 H, CH ₃CO), 1.25 (t, J = 7.2 Hz, 3 H, CH₂CH ₃). ^¹³C NMR (75 MHz, CDCl₃): d = 169.5 (C=O), 169.3 (C=O), 151.4 (C7), 151.1 (C8a), 150.6 (C4′), 134.6 (C3), 129.7 (C1′), 128.0 (C5), 126.9 (C2), 122.1 (C3′), 121.5 (C4), 119.6 (C4a), 115.4 (C6), 110.4 (C8), 97.2 (C2), 64.1 (CH₂CH₃), 21.5 (CH₃CO), 15.7 (CH₂ CH₃). MS (CI⁺): m/z (%) = 323 (100; 2-unsubstituted isoflavylium ion). Anal. Calcd (%) for C₂₁H₂₀O₆: C, 68.40; H, 5.48. Found: C, 68.49; H, 5.53. 7-Acetoxy-3- p -acetoxyphenyl-2-[2-(7-acetoxy-3- p -acetoxyphenyl-2 H -1-benzopyranyl)ethynyl]-2 H -1-benzopyran (9) Solid; mp 237-238 ˚C (dec.). ^¹H NMR (300 MHz, DMF-d ₆; integrations and assignments for half dimer): d = 7.11 (d, J = 9.0 Hz, 2 H, H-2′/6′), 7.02 (d, J = 8.4 Hz, 1 H, H-5), 6.98 (s, 1 H, H4), 6.73 (dd, J = 2.4, 0.3 Hz, 1 H, H-8), 6.66 (d, J = 9.0 Hz, 1 H, H-3′), 6.53 (s, 1 H, H-2), 6.51 (dd, J = 8.4, 2.4 Hz, 1 H, H6), 1.94 (s, 3 H, CH₃), 1.88 (s, 3 H, CH₃). ^¹³C NMR (75 MHz, DMSO-d ₆): d = 169.2 (C=O), 169.1 (C=O), 151.8 (C7), 150.8 (C8a), 150.2 (C4′), 133.0 (C3), 128.4 (C1′), 128.2 (C5), 126.4 (C2′), 122.2 (C4), 121.5 (C3′), 119.4 (C6), 116.3 (C4a), 110.7 (C8), 92.5 (ethynyl C), 91.7 (C2), 20.4 (CH₃), 20.3 (CH₃). MS (ES⁺): m/z (%) = 323 (100; 2-unsubstituted isoflavylium ion). Anal. Calcd (%) for C₄₁H₃₄O₁₀: C, 69.28; H, 4.60. Found: C, 69.27; H, 4.62.

References and Notes

• 1a Jain N. Kanojia RM. Xu J. Jian-Zhong G. Pacia E. Lai M.-T. Du F. Musto A. Allan G. Hahn D. Lundeen S. Sui Z. J. Med. Chem.  2006,  49:  3056 
  Search in Google Scholar
• 1b Sarkar FH. Li Y. Cancer Metastasis Rev.  2002,  25:  265 
  Search in Google Scholar
• 1c Fwu S.-Y. Chang C.-Y. Huang L.-J. Teng C.-M. Wang J.-P. Chen S.-C. Kuo S.-C. Chin. Pharm. J. (Taipei)  1999,  34:  255 
  Search in Google Scholar
• 1d Emmanuel T. Dieudonne N. Tanyi MJ. Tanee FZ. Albert K. Jean-Claude M. Rosa GM. Carmen RM. Salvador M. Luis RJ. J. Nat. Prod.  2003,  66:  891 
  Search in Google Scholar
• 1e Lozovaya VV. Lygin AV. Zernova OV. Li S. Hartman GL. Widholm JM. Plant Phys. Biochem.  2004,  42:  671 
  Search in Google Scholar
• 1f Kuroda M. Mimaki Y. Sashida Y. Mae T. Kishida H. Nishiyama T. Tsukagawa M. Konishi E. Takahashi K. Kawada T. Nakagawa K. Kitahara M. Bioorg. Med. Chem. Lett.  2003,  13:  4267 
  Search in Google Scholar
• 1g Martinez RM. Gimenez I. Lou JM. Mayoral JA. Alda JO. Am. J. Clin. Nutr.  1998,  68 (S1):  1354S 
  Search in Google Scholar
• 2a Miyase T. Sano M. Nakai H. Muraoka M. Nakazawa M. Suzuki M. Yoshino K. Nishihara Y. Tanai J. Phytochemistry  1999,  52:  303 
  Search in Google Scholar
• 2b Gamble JR. Xia P. Hahn CN. Drew JJ. Drogemuller CJ. Brown D. Vadas MA. Int. J. Cancer  2006,  118:  2412 
  Search in Google Scholar
• 2c Alvero AB. O’Malley D. Brown D. Kelly G. Garg M. Chen W. Rutherford T. Mor G. Curr. Oncol. Rep.  2006,  8:  104 
  Search in Google Scholar
• 3 Grese TA. Pennington LD. Tetrahedron Lett.  1995,  36:  8913 
  CrossrefSearch in Google Scholar
• 4a Cook CE. Twine CE. J. Chem. Soc., Chem. Commun.  1968,  791 
• 4b Cook CE. Wall ME. J. Org. Chem.  1968,  33:  2998 
  Search in Google Scholar
• 4c Cook CE. Corley RC. Wall ME. J. Org. Chem.  1965,  30:  4114 
  Search in Google Scholar
• 5 Alberola A. Andres C. Ortega AG. Pedrosa R. Vicente M. J. Heterocycl. Chem.  1986,  23:  1781 
  Search in Google Scholar
• 6 Varma RS. Dahiya R. J. Org. Chem.  1998,  63:  8038 
  CrossrefSearch in Google Scholar
• 7 Gauthier S. Caron B. Cloutier J. Dory YL. Favre A. Larouche D. Mailhot J. Ouellet C. Schwerdtfeger A. Leblanc G. Martel C. Simard J. Merand Y. Belanger A. Labrie C. Labrie F. J. Med. Chem.  1997,  40:  2117 
  CrossrefSearch in Google Scholar
• 8a

  Trityl perchlorate has been used previously to access chromylium salts from the dihydro precursors^8b but not, as far as we can ascertain, from 2-unsubstituted isoflav-3-enes. Isoflavylium salts can also be made, for example, by ring construction^8c or by trityl salt mediated elimination of 2-substituted isoflav-3-enes^8d
• 8b Canalini G. Degani I. Fochi R. Spunta G. Ann. Chim. (Rome)  1967,  57:  1045 
  Search in Google Scholar
• 8c Bouvier P. Andrieux J. Molho D. Tetrahedron Lett.  1974,  1033 
• 8d Dean FM. Varma RS. J. Chem. Soc., Perkin Trans. 1  1982,  1193 
• 9a

  Compound 1a is accessible from the commercially available precursors daidzein^9c or daidzein diacetate^9d,e
• 9b Faragalla JE. PhD Thesis   University of Wollongong; Australia: 2005. 
• 9c Heaton A, and Jeoffreys G. inventors; WO  2005103025.  ; Chem. Abstr. 2005, 143, 422198
• 9d Heaton A, and Kumar N. inventors; WO  2000049009.  ; Chem. Abstr. 2000, 133, 177059
• 9e Liepa AJ. Aust. J. Chem.  1981,  34:  2647 
  Search in Google Scholar
• 11 Doodeman R. Rutjes FPJT. Hiemstra H. Tetrahedron Lett.  2000,  41:  5979 
  CrossrefSearch in Google Scholar
• 12 Deprotection of TBS ethers by the related trityl tetrafluoroborate has been reported with the anion acting as a fluoride ion source. See: Metcalf BW. Burkhart JP. Jund K. Tetrahedron Lett.  1980,  21:  35 
  CrossrefSearch in Google Scholar

General Procedure (Table 1, Entry 3)
A mixture of powdered 3 Å MS, trityl hexafluorophosphate (2.2 mmol), and the isoflavene 1b (503 mg, 1.55 mmol) in freshly distilled, anhyd CH₂Cl₂ (50 mL, from CaH₂) was stirred at r.t. under nitrogen for 30 min. Trimethylsilyl cyanide (0.480 g, 4.8 mmol) was then added, and the reaction mixture was stirred for a further hour at r.t. The reaction mixture was then filtered, washed with CH₂Cl₂, concentrated under vacuum filtration, and subjected to silica gel chromatography, using CH₂Cl₂ as the mobile phase to afford the product as a colorless crystalline solid (431 mg, 80%).

General Procedure (Table 2, Entry 1)
A mixture of powdered 3 Å MS, trityl hexafluorophosphate (2.2 mmol), and the isoflavene 1b (451 mg, 1.39 mmol) in freshly distilled, anhyd CH₂Cl₂ (50 mL, from CaH₂) was stirred at r.t. under nitrogen for 30 min. The commercially available 2-trimethylsilylthiazole (0.403g, 2.564 mmol) was then added and the reaction mixture was stirred for a further hour at r.t. The reaction mixture was then filtered, washed with CH₂Cl₂, concentrated under vacuum filtration, and subjected to silica gel chromatography, using CH₂Cl₂ as the mobile phase to afford the product as a creamy white solid (430 mg, 76%).

Data for Selected Compounds7-Acetoxy-3- p -acetoxyphenyl-2-cyano-2 H -1-benzopyran (7b) White solid; mp 156-158 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 7.49 (d, J = 8.7 Hz, 2 H, H-2′/6′), 7.23 (d, J = 8.0 Hz,
1 H, H-5), 7.18 (d, J = 8.6 Hz, 2 H, H-3′/5′), 6.97 (s, 1 H, H4), 6.85 (dd, J = 2.5, 8.1 Hz, 1 H, H-6), 6.84 (s, 1 H, H-8), 6.01 (s, 1 H, H-2), 2.32 (s, 3 H, CH₃), 2.30 (s, 3 H, CH₃). ^¹³C NMR (75 MHz, CDCl₃): δ = 169.1 (C=O), 168.9 (C=O), 151.9 (C7), 151.1 (C8a), 150.3 (C4′), 131.9 (C3), 128.3 (C5), 126.2 (C2′), 125.9 (C1′), 122.4 (C3′), 122.3 (C4), 119.1 (C4a), 117.0 (C6), 110.5 (C8), 64.3 (C2), 21.1 (CH₃). MS (CI⁺): m/z (%) = 323 (100) [MH⁺ - HCN]. Anal. Calcd (%) for C₂₀H₁₅NO₅: C, 68.76; H, 4.33; N, 4.01. Found: C, 69.20; H, 4.34; N, 3.67.
7-Acetoxy-3- p -acetoxyphenyl-2-(2-thiazoyl)-2 H -1-benzopyran (8a)
Creamy white solid; mp 136-138 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.60 (br d, J = 2.7 Hz, 1 H, H-2′′), 7.37 (d, J = 8.7 Hz, 2 H, H-2′/6′), 7.23 (d, J = 6.3 Hz, 1 H, H-5), 7.08 (d, J = 2.7 Hz, 1 H, H-3′′), 6.93 (d, J = 8.4 Hz, 2 H, H-3′/5′), 6.89 (s, 1 H, H4), 6.57 (dd, J = 2.7, 8.4 Hz, 1 H, H-6), 6.53 (d, J = 2.4 Hz, 1 H,H-8), 6.44 (br s, 1 H, H-2), 2.13 (s, 3 H, CH₃), 2.10 (s, 3 H, CH₃). ^¹³C NMR (75 MHz, CDCl₃): δ = 169.5 (C=O), 169.3 (C=O), 169.3 (C1′′), 151.8 (C7), 151.7 (C8a), 150.8 (C4′), 143.3 (C4′′), 134.0 (C3), 131.5 (C1′), 127.9 (C5), 126.9 (C2′), 122.2 (C3′), 121.1 (C3′′), 120.9 (C4), 120.2 (C4a), 115.7 (C6), 110.6 (C8), 74.7 (C2), 21.3 (CH₃). HRMS (CI⁺): m/z calcd for [M + H]⁺ C₂₂H₁₇NO₅S + H: 408.0906; found: 408.0887.




7-Acetoxy-3- p -acetoxyphenyl-2-ethoxy-2 H -1-benzopyran (8f)
Creamy white solid; mp 134-136 ˚C. ^¹H NMR (300 MHz, CDCl₃): d = 7.53 (d, J = 9.0 Hz, 2 H, H-2′/6′), 7.23 (d, J = 8.4 Hz, 1 H, H-5), 7.12 (d, J = 8.4 Hz, 2 H, H-3′/5′), 6.98 (s, 1 H, H-4), 6.82 (d, J = 2.1 Hz, 1 H, H-8), 6.76 (dd, J = 8.4, 2.1 Hz, 1 H, H6), 5.95 (s, 1 H, H-2), 4.04-3.96 (m, 1 H, OCH ₂CH₃), 3.82-3.74 (m, 1 H, OCH ₂CH₃), 2.32 (s, 3 H, CH ₃CO), 2.30 (s, 3 H, CH ₃CO), 1.25 (t, J = 7.2 Hz, 3 H, CH₂CH ₃). ^¹³C NMR (75 MHz, CDCl₃): d = 169.5 (C=O), 169.3 (C=O), 151.4 (C7), 151.1 (C8a), 150.6 (C4′), 134.6 (C3), 129.7 (C1′), 128.0 (C5), 126.9 (C2), 122.1 (C3′), 121.5 (C4), 119.6 (C4a), 115.4 (C6), 110.4 (C8), 97.2 (C2), 64.1 (CH₂CH₃), 21.5 (CH₃CO), 15.7 (CH₂ CH₃). MS (CI⁺): m/z (%) = 323 (100; 2-unsubstituted isoflavylium ion). Anal. Calcd (%) for C₂₁H₂₀O₆: C, 68.40; H, 5.48. Found: C, 68.49; H, 5.53. 7-Acetoxy-3- p -acetoxyphenyl-2-[2-(7-acetoxy-3- p -acetoxyphenyl-2 H -1-benzopyranyl)ethynyl]-2 H -1-benzopyran (9) Solid; mp 237-238 ˚C (dec.). ^¹H NMR (300 MHz, DMF-d ₆; integrations and assignments for half dimer): d = 7.11 (d, J = 9.0 Hz, 2 H, H-2′/6′), 7.02 (d, J = 8.4 Hz, 1 H, H-5), 6.98 (s, 1 H, H4), 6.73 (dd, J = 2.4, 0.3 Hz, 1 H, H-8), 6.66 (d, J = 9.0 Hz, 1 H, H-3′), 6.53 (s, 1 H, H-2), 6.51 (dd, J = 8.4, 2.4 Hz, 1 H, H6), 1.94 (s, 3 H, CH₃), 1.88 (s, 3 H, CH₃). ^¹³C NMR (75 MHz, DMSO-d ₆): d = 169.2 (C=O), 169.1 (C=O), 151.8 (C7), 150.8 (C8a), 150.2 (C4′), 133.0 (C3), 128.4 (C1′), 128.2 (C5), 126.4 (C2′), 122.2 (C4), 121.5 (C3′), 119.4 (C6), 116.3 (C4a), 110.7 (C8), 92.5 (ethynyl C), 91.7 (C2), 20.4 (CH₃), 20.3 (CH₃). MS (ES⁺): m/z (%) = 323 (100; 2-unsubstituted isoflavylium ion). Anal. Calcd (%) for C₄₁H₃₄O₁₀: C, 69.28; H, 4.60. Found: C, 69.27; H, 4.62.