J. Am. Chem. SOC.1992, 114, 1010-1015
1010
Hz), 3.86 (dd, 1 H, J = 4, 12.5 Hz), 3.96 (ddd, 1 H, J = 5, 6, 8 Hz), 4.21 (dddd, 1 H, J = 5.5, 5.5, 8, 8 Hz); MS (SIMS) 194 (M + H)+; HRMS (FAB) m / z calcd for C7H,60SN(M H)+ 194.1028, found 194.1029. General Procedure for the Acid-Catalyzed Cyclization of Galantinic Acid and Its Analogues. Acid Treatment of Galantinic Acid. Galantinic acid ( 2 0 4 (4 mg, 0.02 mmol) was dissolved in 6 N aqueous HCI and heated (1 10 "C) in a sealed tube. After 14 h, the solution was concentrated in vacuo. The residue was passed through a column of Dowex 50Wx4 (100-200 mesh) ion exchange resin (H20, then 1 N aqueous NH3) to give a mixture of 3a and 3b (2.8 mg, 77%). The mixture was dissolved in 1 N HCI and concentrated in vacuo to give a mixture of 3a and 3b as hydrochlorides. Using these hydrochlorides, the product ratio (3a/3b) was calculated from the integration of the 'H NMR (D20, 270 MHz) spectrum of the mixture of 3s and 3 b the signal of 3@Hof 3a appeared at 6 2.20 (ddd, 1 H, J = 2.4, 5.3, 12.5 Hz) and that of 3aH and 3@Hof 3b appeared at 6 1.85 (m, 2 H).4 The ratio of 3 4 3 b was 9/1. Acid Treatment of 3-epi-Galantinic Acid (20b). According to the general procedure, 20b (5.5 mg, 0.03 mmol) gave a mixture of 3a and 3b (2.1 mg, 42%). The ratio of 3a/3b was 11/1. Acid Treatment of 3s. According to the general procedure, 3a (4 mg, 0.02 mmol) gave a mixture of 3a and 3b (4 mg, 100%). The ratio of 3a/3b was 8/1. Acid Treatment of 3b. N-(tert-Butoxycarbonyl)-3b(5 mg, 0.02 mmol) was exposed to 6 N aqueous HCI for 14 h at 110 O C in a sealed tube. The solution was concentrated in vacuo. The residue was dissolved in dioxane (0.5 mL) and H 2 0 (0.5 mL). The solution was adjusted to pH 8 by adding Et,N. To this solution was added Boc20 (10 p L , 0.04 mmol). The solution was stirred for 3 h at room temperature and then adjusted to pH 2 with 1 N aqueous HCI. The resulting solution was extracted with ethyl acetate several times, and the combined organic phase was dried (MgS04) and concentrated in vacuo. To a solution of the residue in E t 2 0was added diazomethane in Et20. The solution was concentrated in vacuo to give an oily residue, which was chromatographed on silica gel to give a mixture of 3a' and 3b' (2 mg, 38%; 3a'/3b' = 2/7 by 'H NMR analysis). Acid Treatment of E Unsaturated Acid 46. Protected E a,@-unsaturated acid 46 (17 mg, 0.06 mmol), which was prepared from 40a by hydrolysis (0.5 N NaOH, room temperature, 4 h), was treated with 6
+
N aqueous HCI according to the general procedure to give a mixture of 3a and 3b (8.4 mg, 88%). The ratio of 3a/3b was 2/1. Acid Treatment of 2 Unsaturated Acid 47. a,fl-Unsaturated &lactone 39 (17 mg, 0.06 mmol) was hydrolyzed with 0.5 N aqueous NaOH (140 p L ) for 4 h at 0 O C in THF (280 pL). The solution was adjusted to pH 2 with 1 N aqueous HCI, extracted with ethyl acetate, and washed with water. The organic phase was dried (MgSO.,) and concentrated in vacuo to give the N-protected form of the Z unsaturated acid 47. This was treated with 6 N aqueous HCI according to the general procedure to give a mixture of 3a and 3b (8.4 mg, 85%). The ratio of 3a/3b was 9/1. Acid Treatment of a,&Unsaturated Lactone 48. a,@-Unsaturated &lactone 39 (10 mg, 0.03 mmol), which was used as an equivalent compound of 48, was treated with 6 N aqueous HCI according to the general procedure to give a mixture of 3a and 3b (4.7 mg, 80%). The ratio of 3a/3b was 10/1. Acid Treatment of 3(S)-Hydroxy 6-Lactone 49. A solution of 45b (10 mg, 0.02 mmol) in methylene chloride (100 pL) and TFA (100 pL) was stirred for 20 min at room temperature. The solution was concentrated in vacuo to give 49 as the corresponding TFA salt. This was treated with 6 N aqueous HCI according to the general procedure to give a mixture of 3a and 3b (4 mg, 98%). The ratio of 3a/3b was 11/1. Acid Treatment of 3(R)-Hydroxy &Lactone 50. 3(R)-Hydroxy lactone 4243 (10 mg, 0.03 mmol), which was used as an equivalent compound of 50, was treated with 6 N aqueous HCI according to the general procedure to give a mixture of 3a and 3b (5.5 mg, 99%). The ratio of 3a/3b was 11/1.
Acknowledgment. W e are grateful to Professors Tetsuo Shiba and Tateaki Wakamiya for samples of galantin I and for their valuable suggestions and discussions. W e thank Professor Koji Nakanishi, Director, for encouragement. This work was supported in part by a grant-in-aid from the Ministry of Education, Science and Culture, Japan.
Supplementary Material Available: Detailed description of syntheses and spectral data of compounds la, 4a, and 4b and IH NMR spectra of la, 4a, 4b, 5c, 20a, 20b, and other key synthetic intermediates (12 pages). Ordering information is given on any current masthead page.
Regiospecific Synthesis of Polysubstituted Naphthalenes via Oxazoline-Mediated Nucleophilic Aromatic Substitutions and Additions Thomas G . Cant and A. I. Meyers* Contributionfrom the Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523. Received July 5, 1991
Abstract: An efficient procedure for the selective functionalization of several positions of 2-methoxynaphthalene is described. Nucleophilic aromatic substitutions were carried out by displacing both a methoxy group and a neutral amine ortho to an oxazoline 6. 4-Substituted naphthalenes 8 were obtained from nucleophilic aromatic addition of an allyllithium species to a position para to the oxazoline 6. The resultant dihydronaphthalenes were converted to the fully aromatic systems 9 or alternatively substituted in the 2-position to form 10. Reductive cleavage of the oxazoline moities in 7 and 9 proceeded smoothly, producing the substituted naphthaldehydes 11.
T h e functionalization of naphthalenes has become a prominent route by which many important organic compounds are accessed. In view of a recent report' describing substitution in the naphthalene series via aryne intermediates wherein a single substituent is introduced, we a r e prompted to disclose our own efficient effort
use of naphthalenes as a starting material in synthesis stems from the ubiquitous nature of fused 6,6-ring systems in naturally-occurring compounds, including saturated a s well a s unsaturated variants. Unfortunately, substituted naphthalenes have often
in performing multiple selective substitutions.* T h e widespread
(2) For our previous contributions, see: (a) Pansegrau, P. D.; Rieker, W. F.; Meyers, A. 1. J . Am. Chem. Soc. 1988,110, 7178-7184 (aryne chemistry). (b) Robichaud, A. J.; Meyers, A. I . J . Org. Chem. 1991,56, 2607-2609 and references cited therein (naphthalene substitutions).
( 1 ) Buchwald, S . L.; King, S. M. J. Am. Chem. SOC.1991, 113, 258-265.
0002-7863/92/ 15 14-1010$03.00/0
0 1992 American Chemical Society
Regiospecific Synthesis of Substituted Naphthalene Scheme I"
R
1; R - H 2; R - B r 3; R-COOH 4; R=COCI
5
le
I
6
"(a) Br2, HOAc. (b) (i) t-BuLi (2 equiv), THF; (ii) CO,(s). (c) Oxalyl chloride, methylene chloride. (d) Triethylamine, amino alcohol, 1,2-dichloroethane. ( e ) Thionyl chloride, benzene, methylene chloride.
proven difficult to obtain by efficient and general methods. Many substitution patterns are still virtually inaccessible by expedient chemical routes. The importance of developing methods for performing these transformations is well-supported by the steadily increasing activity in this area. A number of research groups, with widely varying interests, have made recent contributions to this field.3 Our own contributions to the development of this chemistry have centered around the versatile oxazoline moietyS4 Aromatic oxazolines possess five features important to our purposes: (a) a strongly activating inductive effect which allows displacement of methoxy and fluorine group^,^ (2) an ortho-directing e f f e ~ t (3) , ~ relative inertness toward reaction at the oxazoline ring,6 (4) facile preparation and removal: and (5) applicability to optically active systems through incorporation of an enantiomerically pure amino alcohol.' The utilization of aromatic oxazolines has resulted in the total syntheses of a number of natural products by us and others.* In pursuit of further elaborating the basic features, advantages, and limitations of this group, we have developed the related 2(2-methoxy- 1-naphthy1)oxazoline 6. In exploring this system, we have encountered expected as well as unexpected behavior, and thus we report herein a higly efficient route to 1,Zdisubstituted naphthalenes via nucleophilic aromatic substitution as well as an unprecedented addition of allyllithiums to yield 1,2,4-trisubstituted dihydronaphthalenes. The requisite naphthyloxazoline, 6,was prepared as illustrated in Scheme I. The bromination/lithiation/carboxylation sequence is a slight modification of the procedures utilized by F ~ s o n .The ~ (3) In addition to ref 1, see: (a) Tada, M.; Hiratsuka, M.; Goto, H. J . Org. Chem. 1990,55,4364-4370. (b) Tomioka, K.; Shindo, M.; Koga, K. J . Org. Chem. 1990, 55, 2276-2277. (c) Zoeller, J. R.; Sumner, C. E., Jr. J . Org. Chem. 1990,55, 319-324. (d) Seko, S.; Tanabe, Y.; Suzukamo, G. Tetrahedron Lett. 1990,31,6883-6886. (e) Gatti, N. Tetrahedron Lett. 1990,31, 3933-3936. (f) Deluca, M. E.; Hudlicky, T. Tetrahedron Lett. 1990, 31, 13-16. (9) Suzuki, T.; Hotta, H.; Hattori, T.; Miyano, S. Chem. Left. 1990, 807-810. (h) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977-991 (review). (4) For a review of earlier studies, see: Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837-860 and references cited therein. ( 5 ) (a) Snieckus, V. Chem. Reo. 1990, 90, 879-933 and references cited therein. (b) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356-363. (6) For a concise tabulation of the reactivity of oxazolines, see: Greene, T. W. Protective Groups in Organic Synthesis; J. Wiley and Sons: New York, 1981; pp 315-318. (7) Rawson, D. J.; Meyers, A. I. J . Org. Chem. 1991,56, 2292-2294 and references cited therein. (8) (a) Rizzacasa, M. A,; Sargent, M. V . J . Chem. SOC.,Chem. Commun. 1991, 278-280. (b) Comber, M. F.; Sargent, M. V. J . Chem. SOC.,Chem. Commun. 1991, 190-192. (c) Warshawsky, A. M.; Meyers, A. I . J . Am. Chem. SOC.1990, 112, 8090-8099 and references cited therein. (d) Patten, A. D.; Nguyen, N. H.; Danishefsky, S. J. J . Org. Chem. 1988.53, 1003-1007. ( e ) Andrews, R. C.; Teague, S . J.; Meyers, A. I . J . Am. Chem. SOC.1988, 110, 7854-7858. ( f ) Findlay, J. A,; Daljeet, A,; Murray, P. J.; Rej, R. N. Can. J . Chem. 1987, 65, 427-431. (9) (a) Fuson, R. C.; Chadwick, D. H. J . Org. Chem. 1949, 13,484-488. (b) Fuson, R. C. J . Am. Chem. SOC.1956, 78, 5409-5413.
J. Am. Chem. SOC.,Vol. 114, No. 3, 1992 1011 Table I. (2-Substituted- 1-naphthy1)oxazolines entry R M n-Bu Li a b S-BU Li C t-Bu Li d syn-propenyl Li e Ph Li f Ph MgBr g MezN Li h i-Pr,N Li i 0-methylephedrinyl Li
~
7, % yield 94 98 98 64 85 100 98 86 99
bromide, 2, was metalated via lithium-halogen exchange with 2 equiv of t-BuLi in T H F followed by quenching with solid C 0 2 to yield, upon workup, the acid 3. Alternatively, this transformation could be accomplished by way of the Grignard reaction as previously published. The lithiation sequence was, however, found to be more reliable and higher yielding, applicable to small (
