Ag-and Au-catalyzed addition of alcohols to ynimides: β-regioselective carbonylation and production of oxazoles

Article abstract of DOI:10.1021/ol400338x

Metal-catalyzed reactions of ynimides with alcohols to afford β-ketoimides and oxazoles are demonstrated. The triple bond of ynamides is generally activated by mineral acids or metal salts to lead to the regioselective addition of nucleophiles at the α-C-

Full text of DOI:10.1021/ol400338x

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1560–1563
Ag- and Au-Catalyzed Addition of
Alcohols to Ynimides: β‑Regioselective
Carbonylation and Production of Oxazoles
Takuya Sueda,* Arisa Kawada, Yumi Urashi, and Naoki Teno
Faculty of Pharmaceutical of Sciences, Hiroshima International University,
5-1-1 Hirokoshingai, Kure City, Hiroshima 737-0112, Japan
t-sueda@ps.hirokoku-u.ac.jp
Received February 5, 2013
ABSTRACT
Metal-catalyzed reactions of ynimides with alcohols to afford β-ketoimides and oxazoles are demonstrated. The triple bond of ynamides is
generally activated by mineral acids or metal salts to lead to the regioselective addition of nucleophiles at the R-C-atom, because of the inherent
electronic bias. In contrast, the two neighboring carbonyl groups of ynimides decrease the electron density of the triple bond and the nucleophiles
attack the carbonyl C-atom.
Coinage metal catalysts such as silver1 and gold2 salts
interact with the CÀC triple bond of alkynes to allow the
addition of various nucleophiles. For regioselective trans-
formations, intramolecular reactions have generally been
applied. In the case of intermolecular versions of the
reaction with unsymmetrical internal alkynes, mixtures of
regioisomers have been generated in most cases, accompanied
by a Markovnikov type addition.3 In contrast to such simple
alkynes, the inherent electronic bias of ynamides4 is perhaps
the feature needed to ensure the R-regioselective addition of
nucleophiles.5 Therefore, not only has the utility of ynamides
as the equivalent of ynamines been recognized in recent years,
but also their usefulness in the regioselective functionalization
of triple bonds in organic transformations has been signifi-
cantly expanded (Scheme 1).
We have recently reported the Cu-catalyzed coupling of
alkynyl(triaryl)bismuthonium salts with imides to furnish
the first reliable synthetic method of ynimides.6a More
recently, Davies has reported the first catalytic procedure
for the synthesis of N-alkynylphthalimides directly from
terminal alkynes.6c The electron-donating ability of the
N-atom to the triple bond still present in ynimides allows
for the R-regioselective carbonylation with acidic water
(see Supporting Information (SI)).
Compared with ynamides, the presence of two carbonyl
groups on the N-atom of ynimides decreases the electron
density of the triple bond, lowering the reactivity toward
electrophiles and protons. Instead, the neighboring carbonyl
carbons would become more electrophilic, as indicated
by the facile dephthalimidation with various nucleophiles
to give the free amino group. Thus, in the presence of an
appropriate metal catalyst, nucleophiles should add to the
neighboring carbonyl groups of ynimides, followed by
(1) For a review, see: Weibel, J.-M.; Blanc, A.; Pale, P. Chem. Rev.
2008, 108, 3149.
(2) For representative reviews, see: (a) Krause, N.; Winter, C. Chem.
ꢀ
Rev. 2011, 111, 1994. (b) Corma, A.; Leyva-Perez, A.; Sabater, M. J.
Chem. Rev. 2011, 111, 1657. (c) Belmont, P.; Parker, E. Eur. J. Org.
Chem. 2009, 6075. (d) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108,
3395. (e) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (f)
€
Arcadi, A. Chem. Rev. 2008, 108, 3266. (g) Furstner, A.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 3410. (h) Hashmi, A. S. K. Chem. Rev.
2007, 107, 3180. (i) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem.,
Int. Ed. 2006, 45, 7896.
(3) For examples: (a) Santos, L. L.; Ruiz, V. R.; Sabater, M. J.;
Corma, A. Tetrahedron 2008, 64, 7902. (b) Fukuda, Y.; Utimoto, K.
J. Org. Chem. 1991, 56, 3729.
(4) For representative reviews, see: (a) Evano, G.; Jouvin, K.; Coste,
A. Synthesis 2013, 45, 17. (b) Dekorver, K. A.; Li, H.; Lohse, A. G.;
Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064.
(c) Evano, G.; Coste, A.; Louvin, K. Angew. Chem., Int. Ed. 2010, 49,
2840. (d) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379.
(5) For the Au-catalyzed R-regioselective addition of nucleophiles to
ynamides, see: (a) Davis, P. W.; Cremonesi, A.; Martin, N. Chem.
Commun. 2011, 47, 379. (b) Li, C.; Zhang, L. Org. Lett. 2011, 13, 1738.
(6) (a) Sueda, T.; Oshima, A.; Teno, N. Org. Lett. 2011, 13, 3996. For
a recent report for ynimides, see: (b) Souto, J. A.; Becker, P. B.; Iglesias,
€
(c) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rorrlander, M.;
~
Skrydstrup, T. Org. Lett. 2009, 11, 4208. (d) Couty, S.; Meyer, C.; Cossy,
J. Angew. Chem., Int. Ed. 2006, 45, 6726.
A.; Muniz, K. J. Am. Chem. Soc. 2012, 134, 15505. (c) Alford, J. S.;
Davies, M. L. Org. Lett. 2012, 14, 6020.
r
10.1021/ol400338x
Published on Web 03/15/2013
2013 American Chemical Society

Table 1. Screening Data for the Ag- and Au-Catalyzed
β-Regioselective Carbonylation of Ynimide (1a)a
Scheme 1. Au Salt Catalyzed Markovnikov Addition toward
Internal Alkynes
ROH
yields,b %
additive
(mol %)
time
(h)
entry
R
equiv
2a
3
4
5-endo-dig cyclization and then ring cleavage. The β-regiose-
lective carbonylation would be performed via the migration
of the carbonyl oxygen to the β-C-atom of the ynimide
(Scheme 2). Here, we describe the Ag- and Au-catalyzed
addition of alcohols to ynimides to provide β-ketoimides and
2,5-disubstituted oxazole derivatives.
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Me
2.5
2.5
2.5
2.5
5.0
10
AuCl (10)
24
24
24
6
27c
0
0
Ph3AuNTf2 (5)
AgOTf (10)
AgBF4 (10)
AgBF4 (10)
AgBF4 (10)
AgBF4 (10)
AgBF4 (10)
AgBF4 (10)
Ph3PAuNTf2 (5)
AgBF4 (10)
Ph3PAuNTf2(5)
AgBF4 (10)
AgBF4 (10)
AgBF4 (10)
AgBF4 (10)
AgBF4 (10)
14d 12
6
81
68
49
45
31
13
62
0
10
9
21
41
51
64
85
37
5
6
4
4
20
24
24
0.5
1
Our preliminary attempts were conducted with Ag- and
Au-catalyzed reactions of N-(1-hexynyl)phthalimide (1a)
with MeOH in CH2Cl2 (Table 1). As expected, β-carbo-
nylated compounds 2a and 3a (R = Me) were obtained
and the corresponding R-keto compound was not ob-
served. In addition to β-carbonylated compounds, a small
amount of methyl ortho-(2-oxazolyl)benzoate (4a, R =
Me) was also obtained. The Ag salts were more reactive for
this system than Au salts (Table 1, entries 1À2 vs 3À4), and
the amount of MeOH affected the reaction time and
distribution of products (Table 1, entries 4À8). By using
a large excess of MeOH, only the β-carbonylation pro-
ceeded but a long reaction time was required (Table 1,
entry 8). Gratifyingly, we found that the presence of both
Ag and Au salts was crucial in terms of enhancing the
reaction rate (Table 1, entry 8 vs 10) and for reducing the
yield of side product 4a (Table 1, entry 4 vs 9). Several
alcohols were also tested for this transformation (Table 1,
entries 11À15). Evenbulky tert-BuOH was a good partner,
but H2O was less effective.7
50
0
2.5
0
10
Me
50
0.5
10
90
0
11
12
13
14
15
H
2.5
2.5
2.5
2.5
2.5
24
6
4e
0
0
0
0
0
0
Et
94
74
99
99
2
CF3CH2
i-Pr
24
24
24
16
1
t-Bu
0
a 1a (0.1 mmol) in CH2Cl2 (2 mL). b Yields were determined by 1H
NMR on the crude reaction mixture using 1,2-dichloroethane as an
internal standard. c 61% of 1a was recovered. d 66% of 1a was recovered.
e 96% of 1a was recovered.
10 mol % of AgBF4 in MeOH at rt (Table 2). When the
reaction was worked up with 1 M hydrochloric acid,
β-ketoimides (2 and 6) were obtained in good to excellent
yields and oxazoles (4 and 18) were not observed at all.
For reasons that are yet unclear, terminal ynimides and
ynimides bearing the TMS group led to inferior results.
In these cases, a quantitative yield of phthalimide was
observed in the 1H NMR spectrum of the crude products.
Although there are still some ambiguities, we postulate
a reaction mechanism for the complete regioselective
β-carbonylation that includes the Ag salt mediated nucleo-
philic addition of MeOH toward the carbonyl group of
ynimides (1 f 8),8 followed by the Au-mediated 5-endo-dig
cyclization (8 f 10),9 protodeauration (10 f 11), and its
ring cleavage (11 f 12) (Scheme 3). We speculate that
intermediate 10 is not generated from the direct Au-
mediated 5-endo-dig cyclization of ynimides followed by
the addition of methanol since only ynamides bearing
the tert-butyloxycarbonyl group on the N-atom were
The regioselective β-carbonylations of various ynimides
1 and 5 were examined with 5 mol % of Ph3PAuNTf2 and
Scheme 2. A Characteristic Feature of Ynimides
(8) σ-Coordination of Ag(I) is slightly preferred over π-coordination
(see ref 9b), and this preference would cause the successful nucleophilic
addition of alcohols to the carbonyl group of ynimides.
(9) The addition of silver salts generates cationic gold species, which
leads to an increase in the π-Lewis acidity of gold catalysts and the
reaction rate in many cases; see: (a) Leyva, A.; Corma, A. J. Org. Chem.
2009, 74, 2067. (b) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817. (c)
Munoz, M. P.; Adrio, J.; Carretero, J. C.; Echavarren, A. M. Organo-
metallics 2005, 24, 1293.
(7) MeOH adds to diphenylacetylene 2.5 times faster than H2O in the
presence of Au(I) catalysts; see: Leyva, A.; Corma, A. J. Org. Chem.
2009, 74, 2067.
~
Org. Lett., Vol. 15, No. 7, 2013
1561

Scheme 3. Plausible Reaction Mechanism for the Production of β-Ketoimides and ortho-(2-Oxazolyl)benzoates
Table 2. Scope and Limitation for the Production of
β-Ketoimidesa
Scheme 4. Reaction with Primary Aromatic Amine
ynimides
entry
R
time (h)
product
yieldb (%)
1
2
3
4
5
6
7
8
9
10
1b
1a
1c
1d
1e
1f
H
2
1
2b
2a
2c
2d
2e
2f
0
Bu
91
69
84
77
0
by a transfer of the carbonyl oxygen to the β-C-atom of
ynimides, but were not produced by the metal-catalyzed
anti-Markovnikov addition of MeOH.14 The π-electrophilic
Lewis acidity of the metal catalysts appears to play an
important role in determining the final outcome. When
the π-electrophilic Lewis acidity of metal catalysts is insuffi-
cient, cleavage of the ring of the intermediate 13 is required
to give the N-alkynyl amide derivative 14, which allows
the formation of o-(2-oxazolyl)benzoate 4 via voluntary
5-endo-dig cyclization.
cyclo-Pr
tert-Bu
Ph
24
1
1
TMS
1
5a
5b
5c
5d
Bu
1
6a
6b
6c
6d
86
89
88
83
cyclo-Pr
tert-Bu
Ph
3
3
1
a 1 or 5 (0.1 mmol) in MeOH (2 mL). b Isolated yield.
The side product 4 is a noteworthy compound since
oxazoles represent an important structural motif in bio-
active and pharmacological molecules.15 Furthermore, to
our knowledge, the reports for the synthesis of o-(2-
oxazolyl)benzoates are rare.16 Therefore, we investigated
the selective fromation of oxazole 4a from ynimide
1a (Table 3). The addition of Et3N for the purpose of
decreasing the π-acidity enhanced the production of
cycloisomerized by Ag10 or Au11 salts. 3a was easily con-
verted to β-ketoimide 2a by treatment with 1.0 M hydro-
chloric acid,12 but 2a and oxazole 4adid not afford 3ain the
acidic methanol solution or under the optimized reaction
conditions shown in Table 2. As shown in Scheme 4, only
imine 17 was obtained in excellent isolated yield from the
reaction of ynimide 1awith 1.0 equiv of aniline in CH2Cl2.13
These results indicate that β-ketoimides were produced
(14) For examples of umpolung-type additions of nucleophiles to
ynamides, see: (a) Koester, D. C.; Werz, D. B. Angew. Chem., Int. Ed.
2009, 48, 7971. (b) Das, J. P.; Cheshik, H.; Marek, I. Nat. Chem. 2009, 1,
128. (c) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 3802. (d)
Gourdet, B.; Rudkin, M. E.; Watts, C. A.; Lam, H. W. J. Org. Chem.
2009, 74, 7849. (e) Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am.
Chem. Soc. 2008, 130, 1820.
(10) Istrate, F. M.; Buzas, A. K.; Jurberg, I. D.; Odabachian, Y.;
Gagosz, F. Org. Lett. 2008, 10, 925.
ꢀ
(11) (a) Hashmi, A. S.; Salathe, R.; Frey, W. Synlett 2007, 1763. (b)
Buzas, A. K.; Istrate, F. M.; Gagosz, F. Tetrahedron 2009, 65, 1889 and
also ref 10.
(12) Acetals are generally obtained in the Au-catalyzed reaction of
alkynes in alcohols. For example, see: (a) Casado, R.; Contel, M.;
Laguna, M.; Romero, P.; Sanz, S. J. Am. Chem. Soc. 2003, 125, 11925.
(b) Tales, J. H.; Brode, S.; Chabanas, M. Angew. Chem., Int. Ed. 1998,
37, 1415. Also see refs 3b and 7.
(15) Oxazoles are synthesized from the cyclization of N-propargyl-
carboxamides by using a strong base, SiO2, CeCl3/NaI, FeCl3, and Au
ꢀ
salts in recent organic transformations; see: Tran-Dube, M.; Johnson,
S.; McAlpine, I. Tetrahedron Lett. 2013, 54, 196and references therein.
(16) Sakakibara, T.; Kume, T.; Ohyabu, T.; Hase, T. Chem. Pharm.
Bull. 1989, 37, 1694.
(13) For a Au(I)-catalyzed hydroamination of ynamides giving rise to
the Markovnikov products, see: Reference 5c.
1562
Org. Lett., Vol. 15, No. 7, 2013

Table 3. Screening Data for the Selective Formation of Oxazolea
Table 4. Scope and Limitation for the Synthesis of Oxazolesa
yields,b %
ynimide
time
(h)
product
MeOH time
4a 2a 1ac
entry
R1
1a Bu
1c cyclo-Pr Me
1d tert-Bu
1e Ph
R2
Me
conditions
(yield,b %)
entry
additive (equiv)
AgBF4 (0.1)
(equiv)
(h)
1
2
3
4
5
6
7
8
A
A
B
B
C
C
C
C
C
C
C
C
B
C
24
24
3
1
1
1
2
1
1
1
1
24
24
24
4a (79)
4c (86)
4d (98)
4e (97)
18a (87)
18b (66)
18c (66)
18d (65)
4g (91)
4h (90)
4i (92)
1
2
3
4
5
6
7
1.3
1.3
1.3
1.3
1.3
1.3
2.5
5
7
93
86
0
0
AgBF4 (0.3), TfOH (1.0)
AgBF4 (0.3), Ph3P (1.0)
AgBF4 (0.3), Et3N (1.0)
AgBF4 (0.3), Et3N (1.0)
Ag2O (0.3)
3
7
0
Me
Me
Me
24
24
24d
24
24
0
100
20
21
27
0
73
66
58
93
1
5a Bu
5b cyclo-Pr Me
1
0
5c tert-Bu
5d Ph
1a Bu
1a Bu
1a Bu
1a Bu
1a Bu
1e Ph
Me
Me
Et
CF3CH2
i-Pr
tert-Bu
Ph
tert-Bu
Ag2O (0.3)
0
9
a 1a (0.1 mmol) in CH2Cl2 (2 mL) at rt under N2. b Yields were
determined by 1H NMR on the crude reaction mixture using 1,2-
dichloroethane as an internal standard. c Recovered yield. d At 50 °C.
10
11
12
13
14
4j (72)
4k (0)
4lc (87)
4a (Table 3, entry 4), while use of Ph3P in the reaction
was not successful and the starting material 1a was recov-
ered quantitatively (Table 3, entry 3). Finally, Ag2O was
found to be an effective catalyst and the use of 2.5 equiv of
MeOH in CH2Cl2 led to a high yield of 4a (entry 7).
We also investigated the scope of the reaction with respect
to ynimides and alcohols in the presence of 30 mol % of
Ag2O (Table 4). Almost every o-(2-oxazolyl)benzoate 4
exhibited a strong luminescence on TLC plates under a
UV lamp (254 nm). The reaction proceeded successfully to
give simple N-alkynylphthalimides under the conditions of
2.5 equiv of MeOH at rt (Table 4, entries 1 and 2), whereas
more sterically demanding and aromatic17 substituted yni-
mides (Table 4, entries 3 and 4) and N-alkynylsuccinimides
(Table 4, entries 5À8) required large amounts of MeOH
and elevated temperatures to complete the reaction. R- and
β-Ketoimides were not observed in any of these reactions.
We were interested in applying this method to the use of
amines as the nucleophile instead of alcohols. We observed
that the reaction with aniline gave a mixture of the corre-
sponding ortho-(2-oxazolyl)benzamide (19, 80% yield) and
N-phenylphthalimide (20, 9% yield) (Scheme 4).
One might consider that oxazoles are generated via the
mechanism (2f16f4 in Scheme 3) of classical RobinsonÀ
Gabriel oxazoles formation from β-ketoamides.18 How-
ever these conditions generally require strong Lewis or
mineral acids. Furthermore, β-ketoimide 2a did not give
the corresponding oxazole 4a in MeOH in the presence
of 30 mol % of Ag2O at 80 °C. When the ynimide 1a was
employed in the presence of 5 mol % of Ph3PAuNTf2
under standard reaction conditions C in Table 4, 73% of
a Conditions A: ynimide (0.1 mmol), R2OH (2.5 equiv) in CH2Cl2
(2 mL) at rt under N2. Conditions B: ynimide (0.1 mmol), R2OH
(50 equiv) in (CH2Cl)2 (2 mL) at 80 °C under N2. Conditions C: ynimide
(0.1 mmol) in R2OH (2 mL) at 80 °C under N2. b Isolated yields. c The
structure was assigned by X-ray diffraction analysis; see SI.
oxazole 4a and 5% of β-ketoimide 2a were obtained. These
results again suggest that the presenceoftheπ-electrophilic
Lewis acids leads to β-carbonylation of ynimides. Actu-
ally, representative σ-electrophilic Lewis acids such as
CeCl3 or MgCl2 afforded the selective formation of 4a.
In contrast, Ag, Cu, and Au catalysts acted as a σ- and/or
π-electrophilic catalysts9b to give 4a and/or 2a depending
on their ligands and valence states (see SI).
In conclusion, we have demonstrated the first Ag- or
Au-catalyzed reactions of ynimides with alcohols to give
β-ketoimides and oxazoles. Although some mechanistic
details are still unexplored, we believe these products
are generated via the nucleophilic addition of alcohols to
the carbonyl group of ynimides. This work also offers
valuable insight into the chemistry of ynimides and would
substantially broaden the field of N-substituted alkynes
as building blocks in organic synthesis. Further studies
with various nucleophiles are ongoing in our laboratory.
Acknowledgment. We thank Prof. Yoshihisa Miwa
at the Hiroshima International University for X-ray struc-
tural analysis and also Dr. Shoji Yamaguchi at Setsunan
University for mass spectrometry.
Supporting Information Available. Additional results,
experimental procedures including spectroscopic and analytical
data of new compounds (PDF), and X-ray data (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(17) Similar reactivities are observed in Au(I)-catalyzed cycloisome-
rization of alkynes; see: Buzas, A. K.; Istrate, F. M.; Gagoxz, F.
Tetrahedron 2009, 65, 1889.
(18) (a) Robinson, R. J. Chem. Soc. 1909, 95, 2167. (b) Gabriel, S.
Ber. 1910, 43, 1283. (c) Wasserman, H. H.; Vinick, F. J. J. Org. Chem.
1973, 38, 2407.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
1563