An Unusual N-Boc Deprotection of Benzamides under Basic Conditions

Chinese Journal of Chemistry, 2009, 27, 1645—1648 Communication

* E-mail: [email protected]; Fax: 0086-020-87113735 Received February 10, 2009; revised and accepted May 21, 2009.

© 2009 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

An Unusual N-Boc Deprotection of Benzamides under Basic Conditions

YIN, Biaolin*(尹标林) ZHANG, Yuanxiu(张愿秀)

School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong 510640, China

For the first time, an unusal cleavage of N-tert-butyloxycarbonyl (N-Boc) protection from N-Boc-protected benzamide under basic conditions in excellent yields is reported. The deprotection involves the N-Boc emigration from the benzamide to form 2-O-Boc group followed by O-Boc deprotection on the phenyl ring.

Keywords N-Boc-deprotection, benzamide, Boc emigration, basic medium

Introduction

The Boc (tert-butoxycarbonyl) protective group has found extensive use in organic synthesis, especially in the preparation of various functionalized heterocycles as well as natural or non-natural amino acid derivatives to build scaffolds or bioactive products.1 Therefore, new, mild and selective methods for its removal are of great importance. To date, many methods for cleavage of Boc have been documented, particularly, under strong acidic conditions such as HCOOH, CF3COOH, HCl, HBr, TsOH, MsOH or Lewis acids.2,3 The deprotection can also be achieved under thermal conditions (150 ℃)4 or by using ceric ammonium nitrate (CAN),5 CeCl3•7H2O- NaI system,6 SiO2,

7 TBAF,8,9 and so on. In addition, a very few examples for basic deprotection of N-Boc have also been reported, where the amine is highly activated and the acid-sensitive functional groups are unaffected. In these cases, Tom et al.10 reported an efficient way for Boc-deprotection using sodium tert-butoxide, neverthe-less, the substrates are only limited to primary Boc pro-tected amines and for secondary ones are not efficient. Recently, Berteina-Raboin et al.11 reported an interest-ing cleavage of Boc protection of some aromatic het-erocycles and lactams in mild basic conditions by so-dium carbonate. To the best of our knowledge, N-Boc deprotection of N-Boc acyclic amide under basic condi-tions has not been reported so far. Herein, we would like to detail the results.

Results and discussion

In our efforts to synthesize 2-hydroxyl, N-Boc ben-zamide 3a, attempts to selectively deprotect the O-Boc group via treatment of O-Boc, N-Boc benzamide 1a with 1.2 equiv. of Na2CO3 in refluxing DME failed to afford the expected compound 3a, instead, fully Boc deprotected derivative 2a was formed in 62% yield along with other unidentified by-products (Eq. 1). This

unexpected and interesting results nevertheless provided the first example of N-Boc deprotection of acyclic am-ide under basic conditions. Encouraged by this result, further studies were conducted to optimize the reaction conditions to improve the yield and the results are summarized in Table 1. Increasing the amount of Na2CO3 to 2.4 equiv. gave a lower yield (Entry 1) and lower reaction temperature (40 ℃) led to a higher yield (Entry 2). When other stronger bases such as K2CO3, LiOH, NaOH and KOH were used, 2a was formed in higher yields (Entries 3—6) and NaOH was shown as the best one in 85% yield (Entry 5). Increasing the amount of NaOH to 2.4 equiv. and lowering the reaction temperature to room temperature gave rise to a higher

Table 1 Optimization of the reaction conditions

Entry Reaction condition Yielda/%

1 Na2CO3 (2.4 equiv.)/DME-H2O/reflux 55

2 Na2CO3 (1.2 equiv.)/DME-H2O/40 ℃ 68

3 K2CO3 (1.2 equiv.)/DME-H2O/40 ℃ 74

4 LiOH (1.2 equiv.)/DME-H2O/40 ℃ 80

5 NaOH (1.2 equiv.)/DME-H2O/40 ℃ 85

6 KOH (1.2 equiv.)/DME-H2O/40 ℃ 82

7 NaOH (2.4 equiv.)/DME-H2O/r.t. 92

8 NaOH (2.4 equiv.)/MeOH-H2O/r.t. 83

9 NaOH (2.4 equiv.)/THF-H2O/r.t. 97 a Isolated yield.

1646 Chin. J. Chem., 2009, Vol. 27, No. 9 YIN & ZHANG


yield up to 92% (Entry 7). To our delight, when using THF-H2O as the co-solvent, the yield was increased to 97%. Based on the results, we concluded that NaOH (2.4 equiv.)/THF-H2O/r.t. are suitable conditions for this deprotection.

Conceptionally, the carbonyl group of the amide 4 is more electrophilic than that of the carbamate thus OH－ attacks preferentially C(1) to form benzene acid 5 (Eq. 2). With respect to compound 1a, obviously, the exis-tence of 2-O-Boc group on the phenyl ring is related to the N-Boc deprotection of benzamide. To explore the mechanism for this conversion, a series of substrates were treated with the above optimized reaction condi-tions. As can be seen in Eq. 3, both 2-hydroxyl N-Boc benzamid 1b and 2-acetoxyl N-Boc benzamid 1c gave the corresponding benzamides in excellent yield. How-ever, those substrates 1d — 1i lacking 2-hydroxyl, 2-O-Boc or 2-acetoxyl group on the phenyl ring (in-cluding those substrates carrying OH or O-Boc group at 3 or 4 position of the phenyl ring) did not provide the corresponding benzamide derivatives but benzene acid derivatives, as a result of the hydrolysis of the amide groups. Base on these results, the mechanism was pro-posed for this deprotection (Scheme 1). In the presence of 1 equiv. of NaOH, 1 is O-Boc (O-Ac) deprotected or deprotonated to form the anion intermediate A. A Boc emigration then occurs from the amide group forming compound 4 which has been detected by ESI-MS. Fi-nally, with the aid of another amount of NaOH, the O-Boc deprotection takes place again giving compound 2.

R R Yield/%

1b 2-OH 2b 2-OH 100

1c 2-OAc 2c 2-OH 98

1d H 2d H 0

1e 4-OBoc 2e 4-OH 0

1f 4-OH 2f 4-OH 0

1g 3-OBoc 2g 3-OH 0

1h 2-OMe 2h 2-OMe 0

1i 4-OAc 2i 4-OH 0

The scope of this deprotection was next examined

with different benzamides, and the results are summa-rized in Table 2. As can be seen, the properties of the substituted groups in the phenyl rings influenced the yields apparently. 1j with electron-withdrawing group on the phenyl ring gave lower yield than 1k with elec-tron-donating group (Entries 1 and 2). 2-O-Boc, N-Boc, N-phenyl benzamide 1l and 2-OH, N-Boc, N-phenyl benzamide 1m provided the same deprotected product 2l in almost the same yield (Entries 3 and 4). The selec-tivity of the N-Boc deprotection of amides was also studied using compound 1n bearing amide and aromatic amine N-Boc protection. Under this condition, only N-Boc deprotection of the amide group was observed (Entry 5). Likewise, after treatment of compound 1o containing O-Boc, alkyl amine and amide N-Boc pro-tection, the O-Boc and amide N-Boc were selectively deprotected in 89% yield (Entry 6) and the amine N-Boc pretection was not affected. In addition, the selective O-Boc and amide N-Boc deprotection also underwent well with Boc protected benzhydrazine derivatives 1p and 1q in excellent yield (Entries 7 and 8). Other N-Boc aromatic amides such as picolinic amide 1r and naph-thoic amide 1s and 1t were also deprotected in high yields under the same conditions with the aid of 2-hydroxy group (Entriers 10 and 11).

Scheme 1 The possible mechanism for the N-Boc deprotection

Conclusion

In summary, for the first time, an unusal cleavage of N-Boc protection of N-Boc-protected benzamide under basic condition in excellent yield is reported. The de-protection requires the formation of 2-oxygen anion under basic medium and involves the Boc emigration from amide group to form 2-O-Boc benzamide deriva-tives and O-Boc deprotection steps. This interesting results might be useful in the synthesis of some hetero-cyclic compounds and the studies are under way in our lab.

N-Boc-deprotection Chin. J. Chem., 2009 Vol. 27 No. 9 1647


Table 2 The scope of the N-Boc deprotection of benzamide

Entry Substrate Product Yield/%

1

85

2

100

3

92

4

93

5

86

6

89

7

95

8

90

9

87

10

90

11

88

1648 Chin. J. Chem., 2009, Vol. 27, No. 9 YIN & ZHANG


References and note

1 Jarowinski, K.; Kocienski, P. J. Chem. Soc., Perkin Trans. 1 2001, 2109.

2 Bose, D. S.; Kumar, K. K.; Reddy, A. V. N. Synth. Commun. 2003, 33, 445.

3 (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Or-ganic Synthesis, 3rd ed., John Wiley & Sons, 1999, and ref-erences cited therein. (b) Philip, J. K. Protecting Groups, 3rd ed., Georg Thieme, Stuttgart, New York, 2005, and references cited therein.

4 Wasserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron Lett. 1982, 23, 465.

5 Kuttan, A.; Nowshudin, S.; Rao, M. N. A. Tetrahedron Lett. 2004, 45, 2663.

6 Marcantoni, G.; Massccesi, M.; Torregiani, E.; Bar-toli, G.; Bosco, M.; Sambri, L. J. Org. Chem. 2001, 66, 4430.

7 Jackson, R. W. Tetrahedron Lett. 2001, 42, 5163. 8 Routier, S.; Saugé, L.; Ayerbe, N.; Coudert, G.; Mérour, J.-Y.

Tetrahedron Lett. 2002, 43, 589. 9 Jacquemard, U.; Bénéteau, V.; Lefoix, M.; Routier, S.;

Mérour, J.-Y.; Coudert, G. Tetrahedron 2004, 60, 10039. 10 Tom, N. J.; Simon, W. M.; Frost, H. N.; Ewing, M. Tetrahe-

dron Lett. 2004, 45, 905. 11 Kazzouli, S. E.; Koubachi, J.; Berteina-Raboin, S.;

Mouaddib, A.; Guillaumet, G. Tetrahedron Lett. 2006, 47, 8575.

12 Typical procedure for the N-Boc deprotection: The mixture of N-Boc protected benzamide 1a (427 mg, 1 mmol), NaOH (96 mg, 2.4 mmol) and 30 mL of THF-H2O (V/V, 1/1) was stirred at room temperature overnight. The reaction mixture was added saturated NH4Cl solution until pH＝7 at 0 ℃ then extracted with ethyl acetate (15 mL×3). The combined organic extracts were washed with brine and dried over Na2SO4. Removal of the solvents provided the residue which was purified by flash chromatgraphy afford the product 2a as a solid (414 mg, 97%).

(E0902103 Zhao, C.)

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An Unusual N-Boc Deprotection of Benzamides under Basic Conditions