Pergamon

0040-4039(95)00375-4

Tetrahedron Letters, Vol. 36, No. 16, pp. 2713-2716, 1995 Elsevier Science Ltd

Printed in Great Britain 0040-4039/95 $9.50+0.00

Cycloaddition Reactions of 1,4-Benzoquinone Mono- and Bisimides with Styrenyl Systems: New Syntheses of Nitrogen

Substituted Azapterocarpans, Pterocarpans, 2-Aryl-2,3- dihydroindoles and -dihydrobenzofurans

Thomas A. Engler,* Kenneth O. Lynch, Jr., Wenying Chai and Steven P. Meduna Department of Chemislry, University of Kansas, Lawrence, KS 66045-0046

Abstract: Lewis acid-promoted reactions of 1,4-benzoquinones and 1,4-benzoquinon¢ bis- and monoimides with various 2H-chromenes, N-tosyl-l,2-dihydroquinolines and styrenes regio- and stereoselecfively produce the title compounds in good yields.

Quinone chemistry has a long and rich history, z However, new facets of the synthetic utility of these molecules continue to emerge. For example, we recently reported Lewis acid-promoted reactions of stymnyl systems with 1,4-bcnzoquinones as efficient, regio- and stercoselective mutes to 2-aryl-2,3-dihydrobcnzofurans, pterocarpans, and other systems. 2 In comparison to the chemistry of quinones, the chemistry of quinone mono- and bisimides has not been as extensively explored.3, 4 Herein, we report that macdons of various quinone mono- and bisimides with stymnyl systems in the presence of Lewis acids pmvids mgio- and stereoselective mutes to the tide compounds in good yield. Our interest in these systems stems from the known biological activity of molecules incorporating similar structures - particularly the recently discovered anti-HIV activity found in several pterocarpans. 2 Nitrogen isosteres of these pterocarpans were viewed as useful compounds in the development of an SAR prof'de and perhaps as potendally more active anti-HIV agents as well A recent report on the synthesis of azapteroearpans prompts us to report our results at this time. 5

2-Alkoxy-l,4-bcnzoquinone bisimidcs 3a/b were prepared by methods reported by Boger. 4 Addition of BFyEt20 to solutions of 3a or 3b in CH2C12 at -78 °C followed by 2/-/-ehromenes l a or l b gave azaptero- carpuns 5a-c, respectively (ex 1 1 and Table 1). 6 Similar reactions of N-tosyl-7-methoxy-l,2-dihydroquinoline, 2a, 7 with bisimides 3a/b gave diazapterocarpans 6a/b6; however, reactions of the unsubstituted dihydro- quinoline 2b failed. Reactions of 2a with 2-alkoxy-1,4-benzoquinones 4a/b were also studied with 1:1 mixtures of TiCl4:Ti(OiPr)4 as promoters and were found to give azapterocarpans 7a/b 6 in good yields; again reactions of the unsubstituted dihydroquinoline 2h failed. The substitution patterns in ring D of 5-7 were assigned from the appearance of H-7 and H-10 as singlets in ]H NMR spectra and further supported by N-H absorbances at -3425 cm -1 in IR spectra of 5/6 and results of 1H-1H NOE and HMBC experiments on 5. 8 The stereochemisu'y of the B/C ring fusions was also determined by IH-1H NOE experiments.

R I ~ ~ O Lewis acid + I, y R 2 CH2CI2, -78 °C

1 a, X--O, R1=OC1-13 3 & Y=NSO2Ph, Z=NC(O)Ph, R2=CH3 I b, X=O, RI=H 3b, Y=NSO2Ph, Z=NC(O)Ph, R2=CH2Ph 2a, X=NTs, RlffiOCI-~ 4& Y.=Z=O, R2=CH3 2b, X=NTs, RI=H 4b, Y--Z--O, R2=CH2Ph

H 3 C O ~ 0 ~ _ NSO2Ph Lewis Mid + •

CH2C ~, -78 °C OR 2

1 a, X=O 8 a, R2--CH3 2e, X=NTs 8b, R2--CH2Ph

R I " ~ [ / x -

5-7 Y " ~ 1 0 ~ OR 2 (RLR 2, X-Z as in 1-4; see Table 1)

(1)

H3CO.~-, ~ .. X .~. T" IT I , (=) ~ ' ~ ~ NHSO2Ph

O g 9"10 (R2' X as iO " - - ' ~ 2 ' 1, 2 and 8; see Table 2) OR

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2714

1,4-Benzoquinone monoimides 8a/b were prepared by ceric ammonium nimate oxidation of the corresponding N-(4-methoxyaryl)-benzenesulfonamides.6,9 Treatment of the monoimides with a variety of Lewis acids in CH2C12 at -78 °C followed by addition of 7-mcthoxy-2H-chromenc, la, or dihydroquinolinc 2a gave nitrogen-substituted pterocarpans and azapterocarpans 9a/b and 10a/b, respectively (cq 2 and Table 2). 6 Again, cis ring fusions in 9/10 were evident from 1H-1H NOE experiments and the substitution pattern in ring D was indicated by JH-7AI-9 = 2 Hz and N-H absorbances of 3350-3360 cm -1 in their IR spectra. Reactions of monoimide 11 with 2H-chromene la also gave pterocarpan 12, 6 however, the yield (unoptimized) was only 12% (eq 3); considerable reduction of the monoimide was observed in the latter reactions.

O ~ ~ "OCH3 CH2CI2,-78m°C ~ , , ~ 1 s N H S O 2 P h

0 "--'zz.,,,,,~OCH3 1 a 1 1 1 2, 12%

The reactions described above are not limited to the chromenes and the dihydroqninoline. Indeed, BF3.Et20-promoted reaction of (E)-3,4-dimethoxy-l-propenylbenzene, 13a, with bisimide 3a regio- and stereoselecfively produced dihydroindole 146 in 66% yield (Scheme 1). Similarly, reactions of monoimides 8a/b with propenylbenzene 13a in the presence of any one of a number of Lewis acids gave dihydro- benzofurans 16a/b, 6 respectively (Table 3). In the lH NMR and IR spectra of indole 14, H-4 (identified by NOE Studies 10a) is observed as a singlet at 8.28 ppm, due to deshielding by the benzamide oxygen, and an N-H stretch is observed at 3426 cm -l. For dihydrobenzofurans 16a/b, H-4 and -6 are both observed as slighdy broad singlets in their NMR spectra, but NOE, HETCOR and HMBC experiments 10b clearly indicated the stereo-/regiochemistry shown as does an N-H stretch at 3350 cm -1. Finally, reactions of bisimide 3b with propenylbenzenes 13b/c yielded bicyclic adducts 15b/c, 6 respectively, apparently via hydrolysis of 15d/e on isolation. Similar bicyclic products have been found in reactions of 1,4-benzoquinones with styrenes. 2

Scheme 1

~ NC(O)Ph Y

PhSO2N'f ",,,~ ~ ~'OR 2 H3 C C ~,~ 3a/b = " ~ . ~ . . N H C ( O ) P h / H t H3 Y-JC'

x ~ C H 3 BFa'OEt2 ,,."'~,,," \ ~L' .,..[ or r

-78 *C H3CO" T SO2Ph x 0 O HaCO 1 4, 66* 1 5D, X=H, Y=O, 76%

15C, X=CH a, Y--O, 58% Lewis acid H3C 15d, X=H, Y=NSO2Ph

13b, X = H 1 3 a, X=3,4-(OCH3)2 CH2CI2, -78= oC ~ " ~ N H S O 2 P h / i t t 15e, X=CH 3, Y=NSOgPh

OR 2 8a/b H3CO 16 b, R2=CH2Ph

A mecba_r~stic rationale for the reactions described herein involves re~oselcctiv¢ activation of the quinone I~s- and monoLmidcs by coordination of the Lewis acid to the more basic benzoy]- and su]fony]-nitrogcns of 3 and 8, respectively, to ~v¢ complexes 17 and 20 (Scheme 2). Cyclo -2 or nuclcophilic-addition of the st3mcnyl C=C bonds of 1, 2 or 13 with the complexes ~vcs intermediates 18 and 21 or 19 and 22, respectively, which proceed on to the observed products by C-N bond formation and loss of H + (path a) or by dealkylation (path b). Regioselective Lewis acid-activation of quinone bisimides has been described in some detail by Boger 4 and the possibility of the cycloaddition route to 18/21 and then fragmentation to 19/22 is suggested by similar processes postulated in Lewis acid-promoted reactions of 1,4-benzoquinones with styrenes. 11 Alternatively, intermediates 18/21 may be formed from intermediates 19/22 produced in nucleophilic addition pathways. Similar mechanisms can be used to explain the formation of pterocarpans 7 and 12.

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Table 1. with 2H-Chromenes and N-Tosyl-7-methoxy-1,2-dihydroquinoline.

Lewis Acid-Promoted Reactions of 1,4-Benzoquinones and 1,4-Benzoquinone Bisimides

Chromene/ dihydroauinoline

B 1 X Y Z J~ 1 a, OCH30 3a, NSO2Ph NC(O)Ph CH3 1 a, OCH3 0 3b, NSO2Ph NC(O)Ph CH2Ph lb , H O 3b, NSO2Ph NC(O)Ph CH2Ph 2a, OCH 3 NTs 3a, NSO2Ph NC(O)Ph CH 3

"2e, OCH 3 NTs 3b, NSO2Ph NC(O)Ph CH2Ph 2a, OCH 3 NTs 4a, O O OH 3 2a, OCH 3 NTs 4b, O O CH2Ph

Table 2. Lewis Acid-Promoted Reactions of 1,4-Benzo- quinone Monoimides with 7-Methoxy-2H-chromene and

Product X B2 (equiv) (% yield)

la , O 8B, CH 3 BF3-OEt2(1.1) 9a (87) la , O 8b, CHaPh BF3.OEt2 (1.3) 9b (91) la , O 8a, CH 3 TiCI4 (1.1) 9a (90) la , O 8B, CH 3 SnC~, (1.0) 9a (85) 2 a, NTs 8 a, CH 3 BFa-OEt 2 (1.3) 1 0 a (70) 2a, NTs 8b, CHzPh BF3.OEt2 (1.3 ) 10b (53)

N-Tosyl-7-methoxy-1,2-dihydroquinoline. Chromenel dihvdroouinoline Monoimide Lewis Acid

Lewis Acid Product (equiv) (% yield)

BF3.OEI2 ( 1.2) 5 a (63) BF3.0Et2 (1.1) 5b (62) BF3,OEt 2 (2.0) 5¢ (47) BF3.OEt 2 (1.3) 6 a (93) BF3,OEt2 (1.2) 6b (42) TiCI4:Ti(OiPr)4 (2.7) 7a (83) TiCI4:Ti(OiPr)4 (2.2) 7b (100)

Table 3. Lewis Acid-Promoted Reactions of 1,4-Benzoquinone Monoimides with Styrene 1 3a.

Monoimide Lewis p.cid Product 82 (equiv) (% yield)

8a, CH 3 BF3.OEt 2 (1.1) 1 6a (82) 8b, CH2Ph BF343Et2(1.2) 16b (86) 8a, CH 3 TiCI4 (1.1) 16a (80) 8 a, CH 3 SnCI 4 (1.0) 1 6a (85)

Scheme 2 O NSO2Ph

~ , ~ o a 2 a R I ~ , ~ X R 14 I EA.

y 1, 2or 13 u~ LA" a = ~ N C ( O ) P h --- ~ NC(O)Ph " ? N ~t~'~' "OR 2

NSO2Ph L,~ ~J R"O_ PhO2S 17 L 18 " ~ 19

R 15 0

PhO2S" N " W_A" ~ II~'S~) R R I ~ J ' ~ ~X R w i LA" 1, 20r 13 a = NSO2Ph ,=

OR 2 2 Ph ~= ?

O OR 2

20 I~lT 1 21 22

5-6or I 4

9-10 or 16

For 18-19/21-22: X=CH20/CH2N(Ts ), R=H, R1--OCH3/H (from 112); or X=H, R=CH 3 (from I 3).

We continue to investigate the generality, mechanisms and applications of these reactions as well as the potential biological activity of the products obtained, and derivatives. The results of these studies will be

reported upon completion.

Acknowledgments: Financial supp¢~ was provided by the National Science Foundation (CHE-9116576 and OSR-9255223), the Alfred P. Sloun Foundation (as a Fellowship to TAE) and the University of Kansas General Research and J. R. and Incz Jay Funds. We thank Drs. David Vender Velde and Martha Morton of the University of Kansas NMR Laboratory for their helpful assistance.

2716

References and Notes

1. a) The Chemistry of Quinonoid Compounds, Vol. H, Parts 1 and2; Patai, S.; Rappoport, Z., Eds.; John WHey and Sons: New York, 1988. b) Bruce, J.M. In Rodd's Chemistry of Carbon Compounds, 2nd Ed., Vol. III (Aromatic Compounds), PartB; Coffey, S., Ed.; Elsevier: Amsterdam, 1974; Chapter 8.

2. a) Engler, T.A.; Combrink, K.D.; Letavic, M.A.; Lynch, K.O., Jr.; Ray, J.E.J. Org. Chem. 1994 59, 6567-6587. b) Engler, T.A.; Wei, D.; Letavic, M.A.; Combrink, K.D.; Reddy, J.P.J. Org. Chem. 1994 59, 6588-6599. e) Engler, T.A.; Lynch, K.O., Jr.; Reddy, J.P.; Gregory, G.S. Bioorg. Med. Chem. Lett. 1993 3, 1229-1232. d) Engler, T,A.; Reddy, J.P.; Combrink, K.D.; Vander Velde J. Org. Chem. 1990 55, 1248-1254.

3. a) Brown, E.R. in ref. la, Part 2, Chapter 21. b) Adams, R.; Reifschneider, W. Bull. Chim. Soc. Fr. 1958, 23-65.

4. For pertinent recent studies, a) Boger, D.L.; Zarrinmayeh, H. J. Org. Chem. 1990 55, 1379-1390. b) Boger, D.L.; Coleman, R.S.J. Am. Chem Soc. 1988 110, 4796-4807. c) Holmes, T.J., Jr.; Lawton, R.G. J. Org. Chem. 1983 48, 3146-3150.

5. TSk6s, A.L.; Antus, S. Liebigs Ann. Chem. 1994, 911-915. 6. All new compounds were characterized by high field (300/500 and 75/125 MI-Iz) IH and 13C NMR,

IR and mass spectral analysis, including exact mass, and/or combustion analysis. 7. As shown below, dihydroquinoline 2a was actually prepared and used as a 2:1 mixture of Za and L

The minor component i did not react in the Lewis acid-promoted reactions with 3, 4 or 8, and could be recovered cleanly, a) BLichi, G.; Wriest, H. J. Org. Chem. 1969 34, 1122-1124 and Das, T.K.; Gupta, A.D.; Ghosal, P.K.; Dutta, P.C. Indian J. Chem., Sect. B 1976 14b, 238. b) McCombie, S.W.; Oritz, C.; Ganguly, A.K. Tetrahedron Lett. 1993 34, 8033-8036.

1. TsCI, py, Ts 1. PhSH, CF3CO2H, T s Ts

2. K2CO3, DMF, 80 *C D 2. MCPBA, C1-12CI 2 fo,,~,,,,,,~,/ 3" di°xane' 90 °C' 53% for 2 steps t_ 0 (ref. a) Br'95% ~ 21 (2:1) HsCO i

8. Selected data from 1H-IH NOE (Fig. 1) and HMBC (Fig.2) experiments on 5a/b. 10%% 3%

H3CO, , , , . ,~ '~O~ . O~-,~,,Ph NH: I. 8.55 ppm H 3 ~ O ~ ~ I ~ H 0 ~ H ~ : m, 2.97 p ~ l- II I I M, \ ~ H-7: s, 8.43 ~ m

%.~t, / (=~r~.~NH H-7:,,e.~ppm t..~,.. ~ ~ . i_N. ' H-10:,,7.24~ H ~ l: I _ I ~ O C H phH'lO: s' 7"24 PP m V H N ~ , ~ ~ C-6a: 40.3 pore

SO2Ph F ig~ 1 ~2 ' "~,.~ j ' Rgure 2

9. Prepared from ccric ammopJum nitrate oxidations ofN-azTl-benzcnesu]fonamJdes iv /v (cf. Jacob, P., 1I[; Cagery, P.S.; Shulgin, A.T.; Castagno]i, N., Jr. J. Org. Chem. 1976 4_/, 3627-3629). The benzenesulfonamides were prepared from the corresponding 3-alkoxy-4-methoxyanilines 8////as shown.

~ NO 2 1. BnCI. KlCO 3 ~,-~,jNH 2 ~.jNHSO2Ph ~,,,,,.~NSOiPh • JL 5J _- :.j c, , ( , .6 j -

H3CO 2. SnCl2.H~O, HaCO" ~T ~ THF, [DMAP], rt HaCO" T CH~CNtI-I=O, rl O-" T OH EtOAc/EtOH, 70 °C, 86% OR 65% for iv; O R 64% for 81; OR

il, R--CH 3 (Aldrich) 88% for v iv, R..-CH 3 65% for 8b ill, R--CH2Ph v, R---CH2Ph

10. a) Fig. 3 - selected data from an ]H-1H NOE experiment on 14. b) Selected data from IH-IH NOE (Fig. 4), HETCOR (Fig. 5) and HMBC (Fig. 6) experiments on 16a/b.

16% 5% ~_ Ph ~ C-4:112.4 ppm 21%,- H3C - H --~I-"8% ,,, H3 q H (br s, 6.50/6.57 ppm) H~ H~ l H3~=H " ~ L :J:+h

,~O~Ph 6R,~. 6.42 ppm) C)I:~ C-6:108.7 ppm

Figure 3 Figure 4 Figure 5 Figure 6 ] 1. ];or ze, acfions o f similar intermediates formed in acid-catalyzed reactions o f N-acylqtdnonc i n ~ e

ketais with sWrenes, see Dal~dowicz, P.; Swcnton, J.S.J. Org. Chem. 1993 58, 4802-4804.

(Received in USA 12 January 1995; revised 21 February 1995; accepted 22 February 1995)