J.G. Polisar, J.R. Norton / Tetrahedron 68 (2012) 10236e10240
10239
Table 7
Reaction of arylacetic acids with aromatic isonitrilesa
Isonitrile R1¼
Acid Ar¼
3 (Yield)b
Isonitrile R1¼
Acid Ar¼
3 (Yield)b
2-Cl-6-MeC6H3 (1b)
2,6-Xylyl (1d)
4-MeOC6H4 (1f)
Ph (1h)
4-Et2NC6H4 (1g)
Ph (1h)
4-ClC6H4 (1n)
4-MeOC6H4 (1f)
4-BrC6H4 (1o)
4-MeOC6H4 (1f)
3-CF3C6H4 (1p)
2,6-Xylyl (1d)
2,6-Xylyl (1d)
2,6-Xylyl (1d)
4-MeOC6H4 (1f)
4-MeC6H4 (1c)
4-MeC6H4 (1c)
Ph (2l)
2l
2l
2l
3bl (64%)
3dl (76%)
3fl (75%)
2-Naphth (1i)
Ph (1h)
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
3ie (72%)
3he (97%)
3de (91%)
3ee (73%)
3qe (81%)
3pe (63%)
3je (83%)
3oe (80%)
3ne (78%)
3ce (94%)
3ge (83%)
3fe (88%)
3re (75%)
2,6-Xylyl (1d)
2-Cle6-MeC6H3 (1e)
2-CF3C6H4 (1q)
3-CF3C6H4 (1p)
3-BrC6H4 (1j)
4-BrC6H4 (1o)
4-ClC6H4 (1n)
4-MeC6H4 (1c)
4-Et2NC6H4 (1g)
4-MeOC6H4 (1f)
4-O2NC6H4 (1r)
3hl (78%)
3gt (90%)
3hq (67%)
3nn (78%)
3fu (77%)
3os (70%)
3fr (88%)
3pm (68%)
3do (68%)
3dv (84%)
3dw (65%)
3fw (73%)
3cw (88%)
3cp (93%)
1-Naphth (2t)
4-O2NC6H4 (2q)
4-MeOC6H4 (2n)
3-MeOC6H4 (2u)
4-ClC6H4 (2s)
2-O2NC6H4 (2r)
4-MeC6H4 (2m)
3,4-(MeO)2C6H3 (2o)
4-FC6H4 (2v)
Indole-3-acetic (2w)
2w
2w
Diphenylacetic (2 p)
a
Toluene solution (0.02 M) of 2 heated with 2 equiv 1 at 110 ꢀC, 24 h.
Isolated yields based on 2.
b
washed further with Et2O (2ꢂ3 mL) and hexanes (2ꢂ3 mL). Drying
Ar), 7.22e7.24 (m, 1H, Ar), 9.10 (s, 1H, CHO) ppm. 13C NMR (75 MHz,
CDCl3):
in vacuo gave 77 mg (67%) as an off-white solid.9
d
¼25.26, 26.35, 29.82, 37.92, 54.03, 125.64, 126.94, 127.15,
134.52, 163.11, 171.58 ppm.
MS: 251.79 (Mþ1), 223.85 (Mꢁ27). IR (cmꢁ1): 1672 (br).
4.5. Representative procedure for compounds
in Tables 4 and 7
Acknowledgements
4.5.1. N-(2-Chloro-6-methylphenyl)-N-formyl-2-(thiophen-2-yl)
acetamide (3ee). 2-Chloro-6-methylphenyl isonitrile (104 mg, 2
equiv) was added to a flame-dried 50 mL round-bottom flask
containing 2-thiopheneacetic acid (49 mg) in toluene
(17.25 mL, 0.02 M). The flask was sealed with a wire-secured
septum, blanketed under argon, and heated as a sealed tube
in a 110 ꢀC oil bath overnight (18e24 h). Volatile residues were
removed in vacuo; purification by silica gel flash chromatog-
raphy using 5:1 hexanes/ethyl acetate gave 74 mg (73%) as an
off-white solid.9
We thank Prof. S. Danishefsky and co-workers for help discus-
sions, and Prof. T. Lambert and his group for many of the substituted
arylacetic acids. A 400 MHz NMR spectrometer used in this study
was acquired with support from the NSF (CHE-0840451). This work
was supported by the NSF (CHE-0749537) and by Boulder Scientific
and OFS Fitel.
Supplementary data
Full experimental procedures, characterization data, and copies
of 1H and 13C NMR of all new compounds. Supplementary data
associated with this article can be found in the online version, at
Note: The very polar isonitriles 1e, 1g, 1n, 1o, and 1r were added
to the reaction mixture without passing them through silica gel.
Yields are based on carboxylic acid.
4.6. Representative procedure for compounds in Table 5
References and notes
4.6.1. (Z)-3-(Butylamino)-1-(4-chlorophenyl)-3-oxoprop-1-en-2-yl
2-(4-chlorophenyl)acetate (5ks). n-Butyl isonitrile (69 mL, 2 equiv)
1. Gautier, A. Ann. Chim. (Paris) 1869, 17, 103 This article has often been cited in-
correctly. Although the chemistry of interest does not begin until page 223, the
article begins on page 103.
was added to a nitromethane solution (0.66 mL, 0.5 M) of 4-
chlorophenylacetic acid (56 mg, 0.33 mmol) in an oven dry screw
cap vial. After stirring 24 h at 40 ꢀC as a sealed tube, volatiles were
removed in vacuo; purification by silica gel flash chromatography
using 3:1 hexanes/ethyl acetate gave 43 mg (64%).16
2. (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126; (b) Passerini, M. Gazz. Chim. Ital.
1921, 51, 181; (c) Passerini, M. Gazz. Chim. Ital. 1922, 52, 432; (d) Banfi, L.; Riva,
R. Org. React. 2005, 65, 1; (e) Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 734;
€
(f) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
3. The possibility that N-formylamides could be formed from isonitriles and
carboxylic acids was suggested in 1968, although this study appears to have
gone largely unnoticed: Hoy, D. J.; Poziomek, E. J. J. Org. Chem. 1968, 33, 4050.
4. Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 5446.
Note: Removal of essentially all of the nitromethane was crucial
for successful chromatographic separation.
5. (a) Wu, X. Y.; Li, X.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 1523; (b) Li, X.;
Yuan, Y.; Kan, C.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 13225.
6. (a) Marcelli, T.; Himo, F. Eur. J. Org. Chem. 2008, 4751; (b) Jones, G. O.; Li, X.;
Hayden, A. E.; Houk, K. N.; Danishefsky, S. J. Org. Lett. 2008, 10, 4093.
7. (a) Mumm, O. Chem. Ber. 1910, 43, 886; (b) Mumm, O.; Hesse, H.; Volquartz, H.
Chem. Ber. 1915, 48, 379.
8. The carbonyl carbon of the mixed anhydride appears to be the preferred site of
nucleophilic attack. See Refs. 4 and 5.
9. A preliminary account of our work has appeared: Polisar, J. G.; Li, L.; Norton, J. R.
Tetrahedron Lett. 2011, 52, 2933.
4.7. Representative procedure for compounds in Table 6
4.7.1. (Z)-3-(Cyclohexylamino)-3-oxo-1-(thiophen-2-yl)prop-1-en-
2-yl 2-(thiophen-2-yl)acetate (3ae). Following the procedure in
Section 4.3, 2-thiopheneacetic acid in toluene (20 mL, 0.02 M stock
solution, 0.4 mmol) was added at a rate of 1.0 mL/h, and heating
was maintained for an additional 2e4 h (22e24 h total reaction
time). Volatile residues were removed in vacuo; purification by
silica gel flash chromatography using 4:1 hexanes/ethyl acetate
gave 81 mg (80%) as a pale yellow oil.
10. A 0.02 M toluene solution of the acid was added over the course of 45 h to
2 equiv of the isonitrile in 2 mL toluene at 110 ꢀC.
11. (a) Wu, X. Y.; Stockdill, J. L.; Wang, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2010,
132, 4098; (b) Li, X.; Danishefsky, S. J. Nat. Protoc. 2008, 3, 1666; (c) Wu, X. Y.;
Yuan, Y.; Li, X.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 4666.
12. Longer reaction times led to significant decarbonylation of the formyl group in
these products.
1H NMR (300 MHz, CDCl3):
2H, AreCH2), 4.28e4.37 (m, 1H, NeCHCy-ring), 6.89e6.97 (m, 2H,
d¼1.15e2.1 (m, 10H, Cy-ring), 4.23 (s,