Zinc chloride promoted formal oxidative coupling of aromatic aldehydes and isocyanides to α-ketoamides

Article abstract of DOI:10.1021/jo100302y

Reaction of aromatic aldehydes and isocyanides in the presence of N-methylhydroxyamine, acetic acid, and zinc chloride affords the aryl α-ketoamides in moderate to good yields.

Full text of DOI:10.1021/jo100302y

pubs.acs.org/joc
and in the elaboration of important heterocycles.3 As a
Zinc Chloride Promoted Formal Oxidative Coupling
of Aromatic Aldehydes and Isocyanides
to r-Ketoamides
consequence, the development of synthetic routes to produce
R-ketoamides has received considerable attention. Among
these methods, oxidation of R-hydroxyamides,4 R-amino-
amides (transamination),5 R-cyanoamides,6 and acyl cyano-
phosphoranes followed by amidation of the resulting R,β-
diketone nitriles,7 amidation of R-keto acids,8 etc. have been
widely used. Other significant methods include transition-
metal-catalyzed amino double carbonylation of aryl ha-
lides,9 reaction of isocyanide with aromatic acyl chloride or
anhydride followed by hydrolysis of the resulting R-ketoi-
midoyl chloride,10 oxidation of ynamines,11 arylaceta-
mides,12 and 2,2-dibromo-1-aryl ethanones,13 and Stetter
ꢀ
Marinus Bouma, Geraldine Masson,* and Jieping Zhu*
Centre de Recherche de Gif, Institut de Chimie des Substances
Naturelles, CNRS, F-91198 Gif-sur-Yvette Cedex, France
zhu@icsn.cnrs-gif.fr; masson@icsn.cnrs-gif.fr
Received February 19, 2010
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Reaction of aromatic aldehydes and isocyanides in the
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2748 J. Org. Chem. 2010, 75, 2748–2751
Published on Web 03/19/2010
DOI: 10.1021/jo100302y
r
2010 American Chemical Society

Bouma et al.
JOCNote
SCHEME 1. Synthesis of R-Ketoamide from Aliphatic Alde-
hydes and Isocyanides
TABLE 1. Optimization of Reaction Conditions for the Synthesis of
Aryl R-Ketoamidesa
3a
5
reaction of glyoxamides.14,15 New strategies involving metal-
catalyzed aerobic oxidative reactions have been developed.16
We recently disclosed a straightforward synthesis of
R-ketoamides via a formal oxidative coupling of aliphatic
aldehydes with isocyanides in the presence N-methylhydrox-
ylamine (4) and acetic acid (5) as mediators (Scheme 1).17,18
One notable attribute of the above protocol is that the for-
mal oxidative coupling proceeded under oxidant-free condi-
tions.19,20 Nevertheless, the so-developed conditions were
applicable only to aliphatic aldehydes. As a continuation of
this research program, we report herein the successful synth-
esis of aryl R-ketoamides21 by way of a formal oxidative
coupling of aromatic aldehydes and isocyanides.
entry
LA (equiv)
LiBr (3.0)
ZnCl2 (2.0)
ZnCl2 (3.0)
ZnCl2 (3.0)
ZnCl2 (3.0)
ZnCl2 (3.0)
ZnCl2 (3.0)
ZnCl2 (3.0)
(equiv) (equiv) MS solvent yieldb (%)
1
2
3
4
5
6
7
8
9
9.0
9.0
9.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
4
4
4
4
4
4
4
4
MeOH
MeOH
MeOH
MeOH
CH2Cl2
Toluene
THF
trace
trace
35
40
47
20
64
67
45
1.1
1.1
2.0
2.0
2.0
2.0
2.0
2.0
2.0
TFE
no THF
10 SnCl2 (3.0)
4
4
4
4
4
THF
THF
THF
THF
THF
50
11
trace
58c
0d
11 Zn(OAc)2 2H2O (3.0) 2.0
3
12 MgBr Et2O (3.0)
3
2.0
2.0
2.0
13 ZnCl2 (3.0)
14 ZnCl2 (3.0)
aReaction conditions: benzaldehyde (2a) (0.6 mmol), tert-butyl iso-
cyanide 3a (1.2 mmol), MeNHOH HCl (4a) (0.96 mmol), NaHCO3
Reaction of benzaldehyde (2a) and tert-butyl isocyanide
(3a) in the presence of N-methylhydroxyamine (4a) and
acetic acid (5) was used as a model reaction for conditions
surveys. Under our previously reported conditions, nitrone
6a resulting from the condensation of 2a with 4a was the
main product together with a trace amount of the desired
R-ketoamide 1a (Table 1). Reasoning that the low electro-
philicity of aromatic nitrones might be responsible for the
failure of coupling reactions involving aromatic aldehydes,
3
(0.96 mmol), AcOH (5) (1.8 mmol) in THF (0.6 mL) for 48 h. bYield after
column chromatography. cBnNHOH HCl was used. dt-BuNHOH HCl
was used.
3
3
we decided to explore the effect of Lewis acid on this process.
After reaction parameters including the nature of Lewis
acids (LiBr, ZnCl2, Zn(OAc)2, SnCl2, MgBr2),22 the solvents
(MeOH, CH2Cl2, THF, TFE), and the additives were sur-
veyed, the optimum conditions found consisted of perform-
ing the reaction in THF in the presence of ZnCl2 (3 equiv)
and 4 A molecular sieves.23 Under these conditions, the
N-tert-butyl-2-oxo-2-phenylacetamide (1a) was isolated in
64% yield. It is interesting to note that N-benzylhydroxyla-
mine can also mediate this coupling reaction to afford 1a in
58% yield (entry 13), while the bulky N-tert-butylhydrox-
ylamine was ineffective (entry 14).24
The scope and limitations of this novel synthesis of
R-ketoamides was next examined with representative aro-
matic aldehydes and isocyanides under optimized condi-
tions. As shown in Table 2, the presence of an electron-
donating group (MeO, Me) and an weak electron-withdraw-
ing group (halogens) at the para or meta position of the
aldehyde function are well tolerated (entries 1-6, Table 2).
(10) (a) Chen, J. J.; Deshpande, S. V. Tetrahedron Lett. 2003, 44, 8873.
(b) Ugi, I.; Fetzer, U. Chem. Ber. 1961, 94, 1116. (c) El Kaım, L.; Pinot-
¨
Perigord, E. Tetrahedron 1998, 54, 3799. One example of variation of the
ꢀ
isocyanide-Nef reaction: (d) Coffinier, D.; El Kaim, L.; Grimaud, L. Org.
Lett. 2009, 11, 1825. (e) Mossetti, R.; Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett.
2010, 12, 820.
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€
P.-Y.; Liu, R.; Zhao, K. J. Org. Chem. 2008, 73, 8780. (b) Muller, P.; Godoy,
J. Tetrahedron Lett. 1982, 23, 3661.
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48, 8982.
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S.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 14066.
(15) For other methods, see: (a) Cheah, W. C.; Black, D. S.; Goh, W. K.;
Kumar, N. Tetrahedron Lett. 2008, 49, 2965. (b) Faggi, C.; Neo, A. G.;
Marcaccini, S.; Menchi, G.; Revuelta, J. Tetrahedron Lett. 2008, 49, 2099.
(c) Khim, S.-K.; Nuss, J. M. Tetrahedron Lett. 1999, 40, 1827.
(16) (a) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 28. (b) El Kaim,
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L.; Gamez-Montano; Grimaud, L.; Ibarra-Rivera, T. Chem. Commun. 2008,
1350.
(17) Grassot, J.-M.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
947.
(22) Selected examples on Lewis acid-promoted/catalyzed Ugi-type reac-
tions, see: (a) Oertel, K.; Zech, G.; Kunz, H. Angew. Chem., Int. Ed. 2000, 39,
1431. (b) Cristau, P.; Vors, J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079. (c) Xia, Q.;
Ganem, B. Org. Lett. 2002, 4, 1631. (d) Janvier, P.; Bois-Choussy, M.;
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46, 8003. (b) Zinner, G.; Moderhack, D.; Kliegel, W. Chem. Ber. 1969, 102,
2536. (c) Moderhack, D. Justus Liebigs Ann. Chem. 1973, 359. (d) Zinner, G.;
Moderhack, D.; Hantelmann, O.; Bock, W. Chem. Ber. 1974, 107, 2947. For
the use of O-alkylhydroxylamines in the Ugi 4CR, see: (e) Basso, A.; Banfi,
L.; Guanti, G.; Riva, R.; Riu, A. Tetrahedron Lett. 2004, 45, 6109.
(19) Examples of oxidative MCRs: (a) Fontaine, P.; Masson, G.; Zhu, J.
Org. Lett. 2009, 11, 1555. (b) Fontaine, P.; Chiaroni, A.; Masson, G.; Zhu, J.
Org. Lett. 2008, 10, 1509. (c) Ngouansavanh, T.; Zhu, J. Angew. Chem., Int.
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2006, 45, 3495. (e) Leon, F.; Rivera, D. G.; Wessjohann, L. A. J. Org. Chem.
2008, 73, 1762.
(20) For an excellent review on the oxidative transformation of aldehyde
to esters and amides, see: Ekoue-Kovi, K.; Wolf, C. Chem.;Eur. J. 2008, 14,
6302.
(21) Examples of natural compounds: (a) Carroll, A. R.; Avery, V. M.
J. Nat. Prod. 2009, 72, 696. (b) Lindquist, N.; Fenical, W. Tetrahedron Lett.
1990, 31, 2521.
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Bienayme, H.; Zhu, J. Angew. Chem., Int. Ed. 2003, 42, 811. (e) Godet, T.;
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2004, 6, 3281. (f) Keung, W.; Bakir, F.; Patron, A. P.; Rogers, D.; Priest,
C. D.; Darmohusodo, V. Tetrahedron Lett. 2004, 45, 733. (g) Okandeji, B. O.;
Gordon, J. R.; Sello, J. K. J. Org. Chem. 2008, 73, 5595. (h) Yanai, H.;
Oguchi, T.; Taguchi, T. J. J. Org. Chem. 2009, 74, 3927.
(23) The role of molecular sieves is less determinant related to conditions
developed for aliphatic aldehydes (ref 17). Nevertheless, its presence in-
creased significantly the yield of R-ketoamides, probably by accelerating the
β-elimination step. After filtration, the R-ketoamides instead of R-iminoa-
mides were the product that we detected by TLC.
(24) Addition of isocyanides to the boron trifluoride complex of nitrones
has been reported to afford R-ketoamides in low yields (10-15%); see: Zeeh,
B. Synthesis 1969, 37. We thank one of the reviewers for pointing out this
important reference. Under our reaction conditions, the main side reaction
was the subsequent Passerini reaction of the resulting R-ketoamides.
J. Org. Chem. Vol. 75, No. 8, 2010 2749

Bouma et al.
SCHEME 2. Synthesis of Aryl Primary R-Ketoamide
JOCNote
TABLE 2. Synthesis of Aryl R-Ketoamides via a Coupling of an
Aromatic Aldehyde with Isocyanidea
SCHEME 3. Mechanism of the Formation of Aryl R-Ketoa-
mides
SCHEME 4. Zinc Chloride Promoted Coupling of Aliphatic
Aldehyde and Isocyanide
products in good yields (Table 2). Furthermore, the enantio-
merically pure (S)-R-methylbenzyl isocyanide participated in
the reaction to give the R-ketoamide 1o, albeit in moderate
yield (entry 13, Table 2). Chiral HPLC analysis of 1o and
(()-1o indicated that no epimerization occurred during this
coupling process.
The 1,1,3,3-tetramethylbutyl-isocyanide (Walborsky’s
reagent) is considered as a convertible isonitrile.25 In the
event, treatment a dichloromethane solution of 1l with TFA
afforded the desired primary ketoamide 7l in 85% yield
(Scheme 2).
The overall transformation may be understood by the
sequence of events proposed in Scheme 3. Nucleophilic
addition of isocyanide to the arylnitrone 6, activated by
ZnCl2, would afford the nitrilium intermediate which was
in turn trapped by acetic acid to provide the imidate 9.
Intramolecular acyl migration would furnish the R-acylox-
yaminoamide 10, which underwent β-elimination to afford
the iminoamide 11. Subsequent hydrolysis would then pro-
vide the observed R-ketoamides. With aromatic aldehydes,
we never isolated the initial Ugi adduct 10 in contrast to
previous work with aliphatic aldehydes. The fast β-elimina-
tion process (10 to 11) due to the increased acidity of R-CH of
intermediate 10 could account for this observation.
Interestingly, when these conditions were applied to aliphatic
aldehyde, the Passerini product 13 resulting from the Passerini
aReaction conditions: aldehyde (2) (0.6 mmol), isocyanide
3
(1.2 mmol), MeNHOH HCl (4a) (0.96 mmol), NaHCO3 (0.96 mmol),
3
AcOH (5) (1.8 mmol) in THF (0.6 mL) for 48 h. bYield after column
chromatography. cSubsequent Passerini reaction of 1h, acetic acid, and
isocyanide took place to afford the corresponding adduct in 38% yield
(cf. Scheme 4).
However, the presence of a strong electron-withdrawing
group (NO2) significantly reduced the yield of R-ketoamide
(entry 7). In this case, a Passerini adduct resulting from the
reaction of 1h, acetic acid, and isocyanide was isolated in
38% yield probably due to the high electrophilicity of the
carbonyl group in 1h. 2-Methylbenzaldehyde provided the
ketoamide 1i in low yield, probably for steric reasons. Both
aromatic and aliphatic isocyanides participated in the reac-
tion. In particular, the sterically hindered isocyanides such as
tert-butyl, 1-adamantyl, and 2,6-dimethylphenyl were found
to be suitable substrates giving the corresponding coupling
(25) (a) Walborsky, H. M.; Niznik, G. E. J. Am. Chem. Soc. 1969, 91,
7778–7780. (b) Walborsky, H. M.; Niznik, G. E. J. Org. Chem. 1972, 37, 187.
2750 J. Org. Chem. Vol. 75, No. 8, 2010

Bouma et al.
JOCNote
reaction of R-ketoamide 12 was isolated as major compound
even if only 1 equiv of isocyanide was used (Scheme 4).
Apparently, the oxo group of the aliphatic R-ketoamide 12
was electrophilic enough to react with isocyanide and acetic
acid in the presence of zinc chloride.26
In conclusion, we have developed a one-pot direct synth-
esis of aryl R-ketoamides by a ZnCl2-promoted formal
oxidative coupling of aromatic aldehydes and isocyanides.
The reaction is realized under mild conditions using both
N-methylhydroxylamine and acetic acid as shuttle mole-
cules. The protocol complemented to our previous one that
is applicable only to aliphatic aldehdydes.
hydroxylamine hydrochloride (80 mg, 0.96 mmol), and NaHCO3
(81 mg, 0.96 mmol) were added, the mixture was stirred for 30 min.
The isocyanide (1.2 mmol) and acetic acid (103 μL, 1.8 mmol) were
then added, and the mixture was stirred at room temperature for
48 h. The reaction mixture was then diluted with ethyl acetate and
filtered, the solvent was removed in vacuo, and the crude product
was purified by flash chromatography on silica gel.
N-tert-Butyl-2-oxo-2-phenylacetamide 1a: mp 77-78 °C;
NMR 1H δ (500 MHz, CDCl3) 8.32 (d, 2H, J = 7.6 Hz), 7.62
(t, 1H, J = 7.4 Hz), 7.48 (dd, 2H, J = 7.6 Hz, J = 7.4 Hz), 6.95
(bs, 1H, NH), 1.47 (s, 9H); NMR 13C δ (75 MHz, CDCl3) 188.5,
161.1, 134.1, 133.4, 131.1, 128.3, 51.6, 28.3; HRMS (ESI) calcd
for [M þ Na] þ C12H15NO2Na m/z = 228.1000, found m/z =
228.0991.
Experimental Section
Acknowledgment. Financial support from CNRS and
ANR is gratefully acknowledged. M.B. thanks the ICSN
for a doctoral fellowship.
General Procedure for the Synthesis of Aromatic r-Ketoa-
mides. A 5 mL round-bottomed flask, equipped with a Teflon-
coated stir bar, was flame-dried after ZnCl2 (245 mg, 1.8 mmol)
was added. Dry tetrahydrofuran (0.6 mL) and 4 A molecular sieves
(100.0 mg) were added. After the aldehyde (0.6 mmol), N-methyl-
Supporting Information Available: Experimental proce-
dures, product characterization, as well as copies of H NMR
1
of 1a-n. This material is available free of charge via the Internet
at http://pubs.acs.org.
(26) Wang, S.; Xang, M.-X.; Wang, D.-X.; Zhu, J. Eur. J. Org. Chem.
2007, 4076.
J. Org. Chem. Vol. 75, No. 8, 2010 2751