2966
L. Zhang et al. / Tetrahedron Letters 50 (2009) 2964–2966
Table 5
In summary, a simple, mild, and highly efficient condition for
Coupling results with chiral acyl chloridesa
amide formation using acyl chlorides has been developed. The
method is scalable and the reaction offers good to excellent yields
with a variety of substrates. The developed reaction conditions
greatly minimize the possibility for hydrolysis, racemization, and
other unwanted side reactions that usually occur during amide for-
mation with acyl chlorides. The methodology is extremely eco-
nomical, as simple inorganic bases can replace the use of
expensive coupling reagents and increase the utility of acyl chlo-
rides in amide synthesis.
Entry
7
8
Base
Yield/eeb (%)
Et3N
80/97 (9i)
28/>99 (9i)
98/>99 (9i)
H2N
NO2
OPh
Cl
1
NaOH
K3PO4
CO2H
O
(7i)
(8i)
Acknowledgments
H2N
Et3N
88/>99 (9j)
92/>99 (9j)
96/>99 (9j)
O
Cl
2
We thank Dr. Carl Busacca for insightful discussion. We thank
Dr. Heewon Lee for her assistance with chiral HPLC method devel-
opment and monitoring.
Ph
NaOH
K3PO4
O
(7j)
(8j)
Supplementary data
Ph
Et3N
5/71 (9k)
29/97 (9k)
82/97 (9k)
H2N
CO2H
(8k)
Cl
3c
Supplementary data associated with this article can be found, in
NaOH
K3PO4
O
(7k)
a
References and notes
Product yields have not been optimized. The products are purified by flash
column chromatography.
b
1. Stryer, L. In Biochemistry, 4th ed.; W.H. Freeman: New York, 1995; p 17.
Chapter 2.
2. Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb. Chem. 1999, 1, 55.
3. Termistoteles, D. J. Appl. 1983, 509, 442.
Enantiomeric excesses were determined by chiral HPLC using both enantio-
meric isomers as standard.
c
The enantiomeric excess of 7k is 97%.
4. Montalbetti, C.; Falque, V. Tetrahedron 2005, 61, 10827.
5. Bouron, E.; Goussard, G.; Marchand, C.; Bonin, M.; Pannecoucke, X.; Quirion, J.-C.;
Husson, H.-P. Tetrahedron Lett. 1999, 40, 7227.
6. Ghosh, S.; Elder, A.; Guo, J.; Mani, U.; Patane, M.; Carson, K.; Ye, Q.; Bennett, R.;
Chi, S.; Jenkins, T.; Guan, B. J. Med. Chem. 2006, 49, 2669.
acid potassium salt). Regardless of the reactivity or stability of the
substrates, yields were reliably 85–90% (entries 1–4). Clearly cou-
pling of acyl chlorides with unprotected amino acids using K3PO4 is
much more practical than that using triethylamine or aqueous
NaOH. The procedure had been successfully applied in our research
program to produce over 500 g desired product.11
7. Barton, P.; Laws, A. P.; Page, M. I. J. Chem. Soc., Perkin Trans. 2 1994, 9, 2021.
8. General procedure for coupling with amines (Table 3, 9a–9d). A solution of acyl
chloride (2 mmol) in THF (4 mL) was cooled to 0 °C under nitrogen. Potassium
phosphate (530 mg, 2.5 mmol) was added in one portion followed by the
addition of amine 8 (2 mmol). The mixture was allowed to react for 1 h at rt.
The reaction was quenched with water (6 mL) and EtOAc (2 mL). The organic
layer was evaporated under vacuum. The crude product was purified either by
crystallization or by silica gel column chromatography.
9. General procedure for coupling with amino acids (Table 4, 9e–9h). A solution of
acyl chloride (2 mmol) in THF (4 mL) was cooled to 0 °C under nitrogen.
Potassium phosphate (1.06 g, 5.0 mmol) was added in one portion followed by
the addition of amino acid 8 (2 mmol). The mixture was allowed to react for
12 h at rt. The reaction was quenched with water (10 mL) and EtOAc (4 mL).
The organic layer was discarded. The pH of aqueous layer was adjusted to 2 by
2 N HCl. The product was extracted with EtOAc (10 mL) and washed with water
(6 mL). The organic layer was evaporated under vacuum. The crude product
was purified either by crystallization or by silica gel column chromatography.
10. (a) Fischer, E. Chem. Ber. 1906, 3988; (b) Danger, G.; Boiteau, L.; Cottet, H.;
Pascal, R. J. Am. Chem. Soc. 2006, 128, 7412.
The final phase of our examination involved couplings between
chiral acyl chlorides and a variety of amines (Table 5). When (R)-2-
phenoxy-propionyl chloride 7i was reacted with 4-amino-2-nitro-
benzoic acid 8i (entry 1), the low reactivity of 8i caused more than
70% hydrolysis when NaOH was used as base. When triethylamine
was employed, side reactions and slight racemization were ob-
served. Both degradation and racemization were suppressed, how-
ever, when potassium phosphate was used as base. The reaction
between (R)-2-methoxy-2-phenyl-acetyl chloride 7j and cyclohex-
ylamine 8j proved robust and resulted in no racemization under all
conditions examined (entry 2). When (S)-2-phenylbutyryl chloride
7k was coupled with glycine 8k (entry 3), as suspected, the poly-
merization of glycine12 under basic conditions complicated the
reactions with either aqueous NaOH or triethylamine. Hydrolysis
under aqueous conditions, and a significant loss in chirality with
an organic base were observed. For comparison, the reaction using
potassium phosphate furnished 82% of the desired product without
detectable racemization.
11. Scale-up procedure for coupling with amino acids (Table 4, 9h). A solution of 2-
(naphthalen-1-yloxy)-acetyl chloride 7 h (463 g, 2.10 mol) in THF (6 L) was
cooled to 0 °C under nitrogen.
D,L-Phenylglycine 8h (302 g, 2.00 mol) was
added followed by potassium phosphate (929 g, 4.37 mol). The mixture was
allowed to react for 12 h at rt. The reaction was quenched with water (4 L).
Most of the THF (5 L) was distilled and MeCN (6 L) was added. The pH was
adjusted to 2–3 by 1 N HCl (4.4 L) and the reaction mixture was filtered. The
cake was washed with 1:1 MeCN/water (4 L) to afford 9h as a white solid
(576 g, 86% yield).
12. Tsuhako, M.; Ohashi, S.; Nariai, H.; Motooka, I. Chem. Pharm. Bull. 1982, 30,
3882.