The Mitsunobu reaction of tetrachlorophthalimide

Article abstract of DOI:10.1055/s-1999-2680

Tetrachlorophthalimide is shown to be an excellent agent for Mitsunobu displacement of primary hydroxyl groups in a wide variety of substrates. Secondary alcohols also react readily, except in carbohydrate derivatives where there is a low rate of success.

Full text of DOI:10.1055/s-1999-2680

LETTER
565
The Mitsunobu Reaction of Tetrachlorophthalimide
Zhaozhong J. Jia, Sandra Kelberlau, Lars Olsson, G. Anilkumar, Bert Fraser-Reid*
Natural Products and Glycotechnology Research Institute, Inc., 4118 Swarthmore Road, Durham, NC 27707, USA
Fax 919 493 6113; E-mail dglucose@aol.com
Received 9 March 1999
Abstract: Tetrachlorophthalimide is shown to be an excellent agent
for Mitsunobu displacement of primary hydroxyl groups in a wide
variety of substrates. Secondary alcohols also react readily, except
in carbohydrate derivatives where there is a low rate of success. In
a competition experiment between phthalimide and its tetrachloro
counterpart, there was no trace of a product from the former.
Key words: Mitsunobu, tetrachlorophthalimide, hydroxyl dis-
placement
Mitsunobu reactions have emerged as common synthetic
methods for substitution of hydroxyl groups by both inter-
molecular and intramolecular displacement.1 Thus cyclic
imides have been widely used for introducing amino func-
tionalities.2 In this connection, the phthaloyl group 1 is of
interest since it is also widely used for nitrogen protection
in organic syntheses.3 However to avoid the harsh proce-
dure needed for phthalimide deprotection, our group has
been interested in use of the tetrachloro analog (TCP) 2
for nitrogen protection.4 Mild cleavage of TCP is
possible5 in the presence of acetate, benzoate and unsub-
stituted phthalimide, as demonstrated in the synthesis of
nodulation factor NodRf-III (C18:1, MeFuc).6
at room temperature. Diethyl azodicarboxylate (DEAD,
1.3 eq) was added by syringe, and the reaction mixture,
usually a yellow clear solution, was stirred overnight.
THF was then removed in vacuo. The residue was dis-
solved in CHCl3 or CH2Cl2 and washed with water. Puri-
fication of the organic residue by column chromatography
The four electron-withdrawing chlorine atoms on the aro- was readily monitored by UV visualization.
matic ring not only faciliate nucleophilic attack at the im-
The results for a variety of primary alcohols are shown in
ide carbonyls, but should also enhance the acidity of the
Table 1. For simple primary alcohols (entries 1-4), the
imidic hydrogen. Thus tetrachlorophthalimide (TCP-NH)
yields are uniformly over 70%. The procedure also works
well to convert carbohydrate primary alcohols into TCP-
protected nitrogen functions (entries 5-8). The presence of
benzyl, allyl, benzoate or acetate protecting groups does
3 should be more effective than unsubstituted phthalimide
(Pht-NH) 4 in Mitsunobu reactions. In this manuscript we
report our work on this problem.
The Mitsunobu reactions with TCP-NH were studied by not compromise the outcome. The success of the n-pent-
the following general procedure: To the mixture of alco- enyl glucoside precursor (entry 8) allows the amino syn-
hol, triphenylphosphine (TPP, 1.3 eq) and TCP-NH (1.3 thon to be incorporated into these novel glycosyl donors,7
eq) was added anhydrous THF (0.1-0.2 M). The mixture, prior to coupling reactions.
usually a white slurry, was stirred vigorously under argon
Synlett 1999, No. 5, 565–566 ISSN 0936-5214 © Thieme Stuttgart · New York

566
Z. J. Jia et al.
LETTER
(-)-Menthol 5a was chosen as a secondary alcohol and Acetylation in methanol then gave the acetamide 14b in
was found to react readily to give 5b in 69% yield by the 70% overall yield from 13.
general procedure. However attempts with carbohydrate
secondary alcohols were not encouraging. For precursor
6, more than 90% starting material was recovered, after
stirring for 95 hours at room temperature. Product 7 was
obtained in only trace amounts. For precursor 8, no reac-
tion occurred at all after refluxing for over 100 hours. The
failure for these two reactions could be reasoned by the
difficulty for the bulky TCP-N nucleophile to approach
the already sterically-hindered secondary alcohol and the
difficulty for the sterically-hindered secondary alcohol to
approach the activated triphenylphosphine to form the
oxyphosponium salt.
In conclusion, tetrachlorophthalimide has been success-
fully employed in Mitsunobu reactions to convert a free
hydroxyl into a delicately tetrachlorophthalimido protect-
ed nitrogen function. This reaction provides new possibil-
ities in organic synthesis for nitrogen introduction, and
nitrogen protection-deprotection manipulations.
Acknowledgement
We gratefully acknowledge support by the National Institutes of
Health (GM 40171) and Insmed Pharmaceuticals, Inc., Richmond,
Virginia, USA.
The Mitsunobu efficiency was assessed by allowing TCP-
NH and Pht-NH to compete for sugar alcohol 9. Thus 1
equivalent of 9, 1.2 equivalents each of 3 and 4, 2.4 equiv-
alents each of DEAD and TPP were dissolved in THF and
References and Notes
(1) For reviews, see: (a) Hughes, D. L., Org. React. 1992, 42, 335;
(b) Castro, B.R., Org. React. 1983, 29, 1; (c) Mitsunobu, O.,
Synthesis 1981, 1.
(2) For recent applications, see: (a) Ong, C. W.; Wang, H. M.;
stirred at room temperature overnight. The isolated mate-
rial was shown by 1H and 13C NMR to be exclusively 10,
Chang, Y. A., J. Org. Chem. 1996, 61, 3996; (b) Cherney, R.
with a 88% isolated yield. Compound 11, synthesized in-
dependently, was not detected. This excellent Mitsunobu
selectivity can be reasoned by the more acidic proton in 3.
J.; Wang, L., J. Org. Chem. 1996, 61, 2544; (c) Walker, M. A.,
J. Org. Chem. 1995, 60, 5352; (d) Brown, F. K.; Brown, P. J.;
Bickett, D. M.; et al., J. Med. Chem. 1994, 37, 674.
(3) (a) Kocienski, P. J., Protecting Groups; Georg Thieme
Verlag: Stuttgart, 1994. (b) Lemieux, R. U.; Takeda, T.;
Chung, B. Y., Synthetic Methods for Carbohydrates; El
Khadem, H. S., Ed.; ACS Symposium Series, Washington,
D.C., 1976; vol. 39, p. 90.
(4) (a) Debenham, J. S.; Madsen, R.; Roberts, C.; Fraser-Reid, B.,
J. Am. Chem. Soc. 1995, 117, 3302; b) Debenham, J. S.;
Fraser-Reid, B., J. Org. Chem. 1996, 61, 432; (c) Debenham,
J. S.; Debenham, S. D.; Fraser-Reid, B., Bioorg. Med. Chem.
1996, 4, 1909.
(5) Debenham, J. S.; Rodebaugh, R.; Fraser-Reid, B., Liebigs
Ann./Recueil 1997, 791.
(6) (a) Debenham, J. S.; Rodebaugh, R.; Fraser-Reid, B., J. Org.
Chem. 1996, 61, 6478; (b) Debenham, J. S.; Rodebaugh, R.;
Fraser-Reid, B., J. Org. Chem. 1997, 62, 4591.
(7) (a) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, J. R.;
Merritt, J. R.; Rao, C. S.; Roberts, C.; Madsen, R., Synlett
1992, 927; (b) Fraser-Reid, B.; Madsen, R., Preparative
Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker,
Inc.: New York, 1997; Chap. 14, p. 339.
The merits of the process can be seen by the ease of depro-
tection. Thus treatment of 10 with 4.5 equivalents of eth-
ylenediamine in MeCN/THF/EtOH (2:1:1) at 60 °C was
complete after 2 hours. The product obtained in 97% yield
was the benzamide 12, identifiable by its mass spectrum
(FAB 505.2 M+), and its failure to react with acetic anhy-
dride in methanol. In the case of 13 (see Table 1, entry 7),
comparable deprotection gave amine 14a, survival of the
C2-OAc group being evident from the NMR spectrum.
Article Identifier:
1437-2096,E;1999,0,05,0565,0566,ftx,en;S07698ST.pdf
Synlett 1999, No. 5, 565–566 ISSN 0936-5214 © Thieme Stuttgart · New York