Bis(2-oxo-3-oxazolidinyl)phosphinic Chloride1

[68641-49-6]  · C6H8ClN2O5P  · Bis(2-oxo-3-oxazolidinyl)phosphinic Chloride  · (MW 254.57)

(reagent for activating carboxyl groups,1 converting acids to esters2 (including thioesters3 and phosphoesters4), amides5 (including peptides6-8 and b-lactams9,10), and anhydrides;11 reagent for kinetic resolution of racemic carboxylic acids and alcohols12)

Alternate Names: N,N-bis(2-oxo-3-oxazolidinyl)phosphordiamidic chloride; N,N-bis(2-oxo-3-oxazolidinyl)phosphorodiamidic chloride; phosphoric acid bis(2-oxooxazolidide)chloride; BOP-Cl; BOPDCl.

Physical Data: white powder, mp 195-198 °C; hygroscopic.

Solubility: slightly sol CH2Cl2, MeCN, THF, DMF; dec H2O.

Form Supplied in: white to off-white powder, typically 97% pure.

Analysis of Reagent Purity: IR (KBr): 1775 (C=O), 765 (P-Cl) cm-1.

Purification: the outcome of reactions can be greatly affected by the purity of the reagent; commercial samples may require to be washed with cold water and recrystallized from MeCN prior to use.13

Handling, Storage, and Precautions: store in a cool dry place under nitrogen to preclude contact with moisture and oxygen. Use only in a chemical fume hood. Wear suitable protective clothing and eye/face protection. Causes burns and is harmful if swallowed, inhaled, or absorbed through skin.

Carboxyl Group Activator.

BOP-Cl1 is used for a direct, one-pot conversion of carboxylic acids into esters (eq 1)2 (including thioesters3 and phosphoesters4), amides (eq 2),5 and anhydrides (eq 3).11 Conditions for minimizing side reactions and optimizing yields of both esters and amides are reported.2,5 Advantages offered over previously used reagents, such as N,N-Carbonyldiimidazole, carbodiimides, and unsymmetrical anhydrides, include good yields (typically >80%), mild reaction conditions, and tolerance of both steric bulk and a wide range of functional groups.

The mechanism of these reactions is assumed to involve displacement of chloride by the carboxylate anion to give a phosphorodiamidate (eq 4). Subsequent nucleophilic attack of an alcohol, amine, or a carboxylate anion affords phosphorodiamidic acid and esters, amides, and anhydrides, respectively (eq 5).

For lactonization (eq 6),14 including the synthesis of macrolactones,15 BOP-Cl is a useful reagent.

Chemo- and regioselective acylation with BOP-Cl is illustrated by the formation of 5-benzoyldeoxyadenosine in good yield (eq 7).16

For the synthesis of oligonucleotides, BOP-Cl is an effective coupling reagent, allowing phosphotriesters to be prepared in high yields without detectable side reactions (eq 8).17

b-Lactams may be prepared either by condensation of imines with carboxylic acids (eq 9)9 or by cyclization of b-amino acids (eq 10).10

BOP-Cl has been used quite extensively for the synthesis of peptides.6-8 It is particularly useful for coupling N-alkyl-a-amino acids with minimal racemization (eq 11),18,19 although the quality of BOP-Cl employed in these reactions can significantly affect yields,13 and the analogous azide, BOP-N3, has been proposed as an alternative reagent.20 Racemization can sometimes be suppressed by inclusion of additives such as 1-Hydroxybenzotriazole (HOBt) or Imidazole (eq 12),21 although under certain conditions HOBt can induce epimerization.22

Problems, notably racemization and poor yields due to oxazolone formation, are encountered when coupling N-acyl amino acids with BOP-Cl;6 1,3-Dicyclohexylcarbodiimide (DCC) is a better reagent to use in such cases. Some limitations of BOP-Cl for peptide couplings have been discussed;7 it is not recommended for b-branched a-amino acids (e.g. Boc-Val) or for couplings in which the nucleophile is a primary amine.8

Kinetic Resolution.

BOP-Cl is a condensation agent for the kinetic resolution of racemic carboxylic acids and alcohols with chiral alcohols (eq 13) and carboxylic acids, respectively.12

1. (a) Diago-Meseguer, J.; Palomo-Coll, A. L. S 1980, 547. (b) FF 1982, 10, 41; 1984, 11, 57; 1988, 13, 39.
2. Ballester-Rodes, M.; Palomo-Coll, A. L. SC 1984, 14, 515.
3. Arrieta, A.; Garcia, T.; Lago, J. M.; Palomo, C. SC 1983, 13, 471.
4. Katti, S. B.; Agarwal, K. TL 1986, 27, 5327.
5. Cabre, J.; Palomo, A. L. S 1984, 413.
6. Kolodziejczyk, A. M.; Wodecki, Z. J. Peptides, Proceedings of the 19th European Peptide Symposium, 1986; Theodoropoulos, D., Ed.; de Gruyter: Berlin, 1987; p 115.
7. Van der Auwera, C.; Anteunis, M. J. O. Int. J. Pept. Protein Res. 1987, 29, 574.
8. Colucci, W. J.; Tung, R. D.; Petri, J. A.; Rich, D. H. JOC 1990, 55, 2895.
9. Shridhar, D. R.; Ram, B.; Narayana, V. L. S 1982, 63.
10. Chung, B. Y.; Goh, W.; Nah, C. S. Bull. Korean Chem. Soc. 1991, 12, 457.
11. Cabre-Castellvi, J.; Palomo-Coll, A.; Palomo-Coll, A. L. S 1981, 616.
12. Mazon, A.; Najera, C.; Yus, M.; Heumann, A. TA 1992, 3, 1455.
13. Van der Auwera, C.; Anteunis, M. J. O. BSB 1986, 95, 203.
14. Cruickshank, K. A.; Reese, C. B. S 1983, 199.
15. Corey, E. J.; Hua, D. H.; Pan, B.-C.; Seitz, S. P. JACS 1982, 104, 6818.
16. Liguori, A.; Perri, E.; Sindona, G.; Uccella, N. T 1988, 44, 229.
17. Katti, S. B.; Agarwal, K. L. TL 1985, 26, 2547.
18. Tung, R. D.; Dhaon, M. K.; Rich, D. H. JOC 1986, 51, 3350.
19. Tung, R. D.; Rich, D. H. JACS 1985, 107, 4342.
20. Katti, S. B.; Misra, P. K.; Haq, W.; Mathur, K. B. IJC(B) 1988, 27, 3.
21. Van der Auwera, C.; Van Damme, S.; Anteunis, M. J. O. Int. J. Pept. Protein Res. 1987, 29, 464.
22. Anteunis, M. J. O.; Sharma, N. K. BSB 1988, 97, 281.

David C. Rees & Niall M. Hamilton

Organon Laboratories Ltd, Newhouse, Lanarkshire, UK

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