ORGANIC LETTERS
1-tert-Butoxy-2-tert-butoxycarbonyl1,2-dihydroisoquinoline: A Novel and Chemoselective tert-Butoxycarbonylation Reagent
2002 Vol. 4, No. 4 585-587
Hidekazu Ouchi, Yukako Saito, Yutaka Yamamoto, and Hiroki Takahata* Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical UniVersity, Sendai 981-8558, Japan.
[email protected] Received December 6, 2001
ABSTRACT
The use of 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI) as tert-butoxycarbonylation reagent for aromatic and aliphatic amine hydrochlorides and phenols in the absence of a base has been demonstrated. The reactions proceed chemoselectively in high yield under mild conditions.
The tert-butoxycarbonyl (Boc) group is one of the most important amino protecting groups, along with the benzyloxycarbonyl (Cbz) group, because N-Boc amino acids are resistant to racemization during peptide syntheses and the Boc group can be removed easily by acid-catalyzed hydrolysis.1 The Boc-NHR group is not hydrolyzed under basic conditions and is inert to many other nucleophiles. Among more than a few tert-butoxycarbonylating agents, di-tertbutyl dicarbonate (Boc2O, 1) is widely used because of its stability and availability.2 Recently, several reactions of 1 in the presence of DMAP have been examined with some amines, alcohols, diols, amino alcohols, and amino thiols.3 In the course of the tert-butoxycarbonylation of R-trimethylstannyl derivatives of pyridine, quinoline, and isoquinoline with 1,4 we found that 1 reacted with isoquinoline to afford (1) (a) Greene T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; pp 518-525. (b) Su¨ptitz, G. Synthesis 1990, 1035-1036. (2) Pearson, A. J.; Roush, W. R. In Handbook of Reagents for Organic Synthesis: ActiVating Agents and Protecting Groups; John Wiley & Sons: New York, 1999; pp 123-130. (3) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368-6380. (4) Yamamoto Y.; Ouchi H.; Tanaka T. Chem. Pharm. Bull. 1995, 43, 916-919. 10.1021/ol017183u CCC: $22.00 Published on Web 01/24/2002
© 2002 American Chemical Society
1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI, 2), which seems to be a promising tertbutoxycarbonylating agent.5 In this letter, we present the use of 2 as a novel tert-butoxycarbonylation reagent for amines and phenols. Exposure of isoquinoline to 1 in benzene at room temperature resulted in loss of carbon dioxide to 26 in quantitative yield, which is stable and can be stored at room temperature for over 1 month without any decomposition (Scheme 1).
Scheme 1
We set out to investigate tert-butoxycarbonylation of phenol (3a) using 2. A solution of 3a and 2 in benzene was
heated under reflux for 1 h to give phenyl tert-butyl carbonate (4a) quantitatively. Similar reactions of p-methoxy- and p-nitorophenol (3b and 3c) afforded the corresponding carbonates 4b and 4c in high yields, respectively (Table 1).
Table 2. tert-Butoxycarbonylation of Anilines by BBDI
Table 1. tert-Butoxycarbonylation of Phenols by BBDI
entry
R
temp
time (h)
product
yield (%)a
1 2 3 4
H OMe NO2 CH2OH
reflux reflux rt reflux
1 1 3 3
4a 4b 4c 4d
99 92 96 91
a
Isolated yield.
tert-Butoxycarbonylation of p-hydroxymethylphenol (3d) took place chemoselectively to give 4d without any contact with hydroxymethyl. Surprisingly, although tert-butoxycarbonylation of phenols in alkali media has been reported,7 this example of that in the absence of bases is first. However, under this condition tert-butoxycarbonylation of aniline did not occur, resulting in the recovery of 2. On the other hand, it was found tert-butoxycarbonylation of 3c (pKa ) 10.8)8 proceeds in more mild condition compared with those of 3a (pKa ) 18.0).8 With these results in hand, we considered that this reactivity is proportional to the acidity order of the substrates. Because a conjugate acid (pKa ) 3.6)8 of aniline (pKa ) 30.6)8 is stronger acid than 3a, we tried tert-butoxycarbonylation using the aniline hydrochloride (5a). Treatment of 5a with 2 in benzene at room temperature expectedly afforded N-Boc aniline 6a in 81% yield (Table 2, entry 1). The employment of dimethoxyethane (DME) instead of benzene as solvent dramatically increased the yield of 6a (entry 2). Similar treatment of p-methoxyaniline (5b) with 2 afforded N-Boc aniline 6b in high yield (entry 3). The high chemoselectivity was also demonstrated by the coexistence of an aliphatic hydroxyl group as shown in entry 4. Next, the tert-butoxycarbonylation of amino acids ester hydrochlorides (pKa ) 7.6-8.7)9 as the weaker conjugate (5) (a) Kunieda, T.; Higuchi, T.; Abe, Y.; Hirobe, M. Chem. Pharm. Bull. 1984, 32, 2174-2181. (b) Grapsas, I.; Cho, Y. G.; Mobashery, S. J. Org. Chem. 1994, 59, 1918-1922. (6) Synthesis of BBDI (2). A solution of di-tert-butyl dicarbonate (1, 7.86 g, 36 mmol) in benzene (10 mL) was added dropwise to a stirred solution of isoquinoline (3.87 g, 30 mmol) in benzene (20 mL), and the mixture was stirred for 6 h at room temperature. After concentration in vacuo, the residue was purified by recrystallization from pentane or distilled under reduced pressure to give 2 (8.36 g, 92%) as colorless prisms: bp 134-136 °C (1.0 mmHg); mp 114-115 °C; IR (KBr) cm-1 1712; 1H NMR (400 MHz, CDCl3) δ 1.29 (s, 9Η), 1.52 (s, 9Η), 6.10 (d, 1H, J ) 7.5 Hz), 6.66 (s, 1H), 6.88 (d, 1H, J ) 7.3 Hz), 7.18-7.29 (m, 4H); MS (EI) m/z 303 (M+). Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31; N, 4.62. Found: C, 71.38; H, 8.02; N, 4.54. (7) (a) Houlihan, F.; Bouchard, F.; Frechert, J. M. J.; Wilson, C. G. Can. J. Chem. 1985, 63, 153-162. (b) Hansen, M. M.; Riggs, J. R. Tetrahedron Lett. 1998, 39, 2705-2706. (8) pKa values were measured in dimethyl sulfoxide. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463. 586
entry
R
solvent
product
yield (%)a
1 2 3 4
H H OMe CH2CH2OH
benzene DME DME DME
6a 6a 6b 6c
81 97 98 97
a
Isolated yield.
acid was undertaken. Screening experiments were made with as a model compound using the quantity of 2 in DME. It was found the use of 3 equiv of 2 gave the best yield (93%), whereas those of 2 and 1.2 equiv resulted in 82% and 33% yields, respectively. Use of diethyl ether as a solvent provided a similar result (95%) with reflux. On the basis of these results obtained, the standard condition for the tert-butoxycarbonylation of several amino acid ester hydrochlorides with 2 (3 equiv) was in DME at room temperature or in diethyl ether under reflux. Thus the tertbutoxycarbonylation of various amino acids in this study was normally performed, and the corresponding N-Boc L-amino acid esters were obtained in high yields as shown in Table 3. The identification of N-Boc L-amino acid esters was L-Met-OMe‚HCl
Table 3. tert-Butoxycarbonylation of Amino Acids by BBDIa
entry
starting compound
methodb
product
yield (%)c
1 2 3 4 5 6 7 8 9 10 11
Met-OMe‚HCl Met-OMe‚HCl Ala-OEt‚HCl Leu-OEt‚HCl Val-OMe‚HCl Phe-OMe‚HCl Pro-OMe‚HCl Glu(OEt)-OEt‚HCl Ser-OMe‚HCl Cys-OMe‚HCl Tyr-OMe‚HCl
A B B B A A A B A A A
Boc-Met-OMe10 Boc-Met-OMe10 Boc-Ala-OEt11 Boc-Leu-OEt11 Boc-Val-OMe10 Boc-Phe-OMe12 Boc-Pro-OMe13 Boc-Glu(OEt)-OEt14 Boc-Ser-OMe15 Boc-Cys-OMe16 Boc-Tyr-OMe17
93 95 87 91 86 97 98 98 92 87 76d
a The reactions were performed with 3 equiv of BBDI. b Method A: in 1,2-dimethoxyethane at room temperature for overnight. Method B: in diethyl ether heated under reflux for overnight. c Isolated yield. d Small amount of Boc-Tyr(OBoc)-OMe was also obtained.
confirmed by comparison of 1H NMR and IR data and [R]D values with the reported data.10-17 As an application, the chemoselectivity of tert-butoxycarbonylation for amino and hydroxyl groups on a benzene Org. Lett., Vol. 4, No. 4, 2002
ring was investigated by the use of 4-aminophenol (7a) and 4-aminophenol hydrochloride (7b). When 7a was allowed to react with 2 equiv of 2 in benzene under reflux, O-Boc derivative 8a was obtained in 94% yield together with small amounts of N,O-(Boc)2 derivative 9. In contrast, when 7b was subjected to reaction with 2 equiv of 2, N-Boc derivative 8b was isolated in 93% yield together with small amounts of 9 (Scheme 2).
Scheme 3
Scheme 2
of these results, we speculated a plausible mechanism of this reaction as follows: Presumably 2 would be first protonated to form a cyclic six-membered intermediate A. Subsequently an attack of its resulting conjugated base to the activated carbonyl of A followed by cleavage can produce the tertbutoxycarbonylation product, isoquinoline or its salt, and tertbutyl alcohol.
Scheme 4
In addition, the tert-butoxycarbonylation of acidic substrates, such as benzoic acid derivatives 10a and 10b and benzenethiol (12), has been accomplished without any base as shown in Scheme 3. Accordingly, it was thus found that this tert-butoxycarbonylation depends on the strength of acidity. On the basis (9) pKa values were measured in dimethyl sulfoxide. David, L. H.; James, J. B.; Edward, J. J. G. J. Org. Chem. 1986, 51, 2579-2585. (10) Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. J. Org. Chem. 1982, 47, 1962-1965. (11) Cantacuze`ne, D.; Pascal, F.; Guerreiro, C. Tetrahedron 1987, 43, 1823-1826. (12) Bajgrowicz, J. A.; Hallaoui, A. E.; Jacquier, R.; Pigiere, C.; Viallefont, P. Tetrahedron 1985, 41, 1833-1843. (13) Keith, J.; King, -C. W. Tetrahedron 1991, 47, 7179-7184. (14) Santiago, C.; Paloma, L.-S.; Marta, F.; Marı´a, I. B.; Ana, M.; Marı´a, I. R.-F. Tetrahedron 1997, 53, 11745-11752. (15) Torrini, I.; Zecchini, P. Z.; Agrosi, F.; Paradisi, M. P. J. Heterocycl. Chem. 1986, 23, 1459-1463. (16) Threadgill, M. D.; Gledhill, A. P. J. Org. Chem. 1989, 54, 29402949. (17) Kolodziejczyk, A. M.; Manning, M. J. Org. Chem. 1981, 46, 19441946.
Org. Lett., Vol. 4, No. 4, 2002
In summary, we uncovered a novel and chemoselective tert-butoxycarbonylation reagent, BBDI, which was easily prepared in quantitative yield by the reaction of isoquinoline with Boc2O. BBDI effected easily the tert-butoxycarbonylation for acidic substrates in the absence of bases rather than basic ones, while that for acidic compounds such as phenols, carboxylic acids using Boc2O required some base. The scope and limitations of BBDI for tert-butoxycarbonylation are currently under investigation. Supporting Information Available: Experimental procedures and characterization data. This material is available free of charge via the Internet at http://pubs.acs.org. OL017183U
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