Intramolecular Pd(II)-catalyzed cyclization of propargylamides: Straightforward synthesis of 5-oxazolecarbaldehydes

Article abstract of DOI:10.1021/jo800621n

(Chemical Equation Presented) Direct synthesis of 2-substituted 5-oxazolecarbaldehydes was performed by intramolecular reaction of propargylamides through treatment with a catalytic amount of Pd(II) salts in the presence of a stoichiometric amount of reox

Full text of DOI:10.1021/jo800621n

SCHEME 1. Pd(II)-Catalyzed Oxidative Cyclization of
1-Allyl-2-indolecarboxyamides 1 and 4
Intramolecular Pd(II)-Catalyzed Cyclization of
Propargylamides: Straightforward Synthesis of
5-Oxazolecarbaldehydes
Egle M. Beccalli,† Elena Borsini,‡ Gianluigi Broggini,*,‡
Giovanni Palmisano,‡ and Silvia Sottocornola‡
Istituto di Chimica Organica “A. Marchesini”, Facolta` di
Farmacia, UniVersita` di Milano, Via Venezian 21, 20133
Milano, Italy, and Dipartimento di Scienze Chimiche e
Ambientali, UniVersita` dell’Insubria, Via Valleggio 11,
22100 Como, Italy
gianluigi.broggini@uninsubria.it
ReceiVed March 22, 2008
in the presence of a stoichiometric amount of an oxidant agent.5
In particular, we recently found that N-allyl 1-allyl-2-indole-
carboxyamide 1 undergoes an intramolecular Pd(II)-catalyzed
process to give the tetracyclic structure 3 when treated with
PdCl2(MeCN)2 (2) and 1,4-benzoquinone (BQ) as reoxidant
(Scheme 1, eq 1).5e This result prompted us to investigate the
behavior of the related N-propargyl 1-allyl-2-indolecarboxya-
mide 4 toward Pd(II) complexes to achieve reaction conditions
suitable for a tandem reaction. When submitted to the conditions
which successfully promoted the cyclization of 1, compound 4
was recovered unchanged (Scheme 1, eq 2), while it reacted
only by exposition to ultrasound irradiations. However, the
reaction provided a product in 62% yield, whose analytical and
spectroscopic data accorded to the unexpected 5-oxazolecar-
baldehyde structure 5, arising from 5-exodig cyclization of the
propargylamide moiety without involving the allylindole portion
of the starting molecule (Scheme 1, eq 3).
Direct synthesis of 2-substituted 5-oxazolecarbaldehydes was
performed by intramolecular reaction of propargylamides
through treatment with a catalytic amount of Pd(II) salts in
the presence of a stoichiometric amount of reoxidant agent.
The heterocyclization process was well-tolerated by a wide
range of aryl, heteroaryl, and alkyl propargylamides. This
protocol constitutes a valuable synthetic pathway to 5-ox-
azolecarbaldehydes, alternative to the formylation on oxazole
rings, often unsatisfactory in term of regioselectivity and
yields.
Intramolecular palladium-promoted cyclizations have became
a milestone also in heterocyclic synthesis.1 A widespread array
of hetero(poly)cycles have been achieved by different method-
ologies, using a catalytic amount of palladium.2 Among the most
used reaction typologies, including the well-known Heck,
Buchwald-Hartwig, and cross-coupling reactions, the Pd(II)-
catalyzed oxidative reactions (i.e., Wacker-type reactions) play
a prominent role due to the simplified requirements of the
starting material.3,4
From this preliminary result, we envisioned the possible
development of a general method for producing 2-substituted
oxazoles directly formylated in the 5-position by using prop-
(4) (a) Zhang, Z.; Tan, J.; Wang, Z. Org. Lett. 2008, 10, 173. (b) Mun˜iz, K.;
Ho¨velmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763. (c) Popp, B. V.;
Wendlandt, J. E.; Landis, C. R.; Stahl, S. S. Angew. Chem., Int. Ed. 2007, 46,
601. (d) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066.
(e) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328. (f) Thiery, E.;
Chevrin, C.; Le Bras, J.; Harakat, D.; Muzart, J. J. Org. Chem. 2007, 72, 1859.
(g) Penn, L.; Shpruhman, A.; Gelman, D. J. Org. Chem. 2007, 72, 3875. (h)
Beniazza, R.; Dunet, J.; Robert, F.; Schenk, K.; Landais, Y. Org. Lett. 2007, 9,
3913. (i) Piera, J.; Persson, A.; Caldentey, X.; Ba¨ckvall, J.-E. J. Am. Chem.
Soc. 2007, 129, 14120. (j) Rogers, M. M.; Kotov, V.; Chatwichien, J.; Stahl,
S. S. Org. Lett. 2007, 9, 4331. (k) Zhang, Z.; Pan, J.; Wang, Z. Chem. Comm.
2007, 4686. (l) Devalina, R.; Sunanda, P.; Sulagna, B.; Jayanta, K. R. Tetrahedron
Lett. 2007, 48, 8005. (m) Lindh, J.; Enquist, P.-A.; Pilotti, A.; Nilsson, P.; Larhed,
M. J. Org. Chem. 2007, 72, 7957.
Our previous contribution in this area was concerned with
intramolecular cyclizations of alkenyl systems bearing a nu-
cleophilic moiety under conditions which require Pd(II) catalysis
† Istituto di Chimica Organica “A. Marchesini”, Facolta` di Farmacia,
Universita` di Milano, via Venezian 21, 20133 Milano, Italy.
‡ Dipartimento di Scienze Chimiche e Ambientali, Universita` dell’Insubria,
via Valleggio 11, 22100 Como, Italy.
(1) (a) Li, J. J.; Gribble G. W. Palladium in Heterocyclic Chemistry-A Guide
for the Synthetic Chemist, 2nd ed.; Elsevier: Amsterdam, The Netherlands, 2007.
(b) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (c) Zeni, G.; Larock,
R. C. Chem. ReV. 2006, 106, 4644.
(5) (a) Beccalli, E. M.; Broggini, G. Tetrahedron Lett. 2003, 44, 1919. (b)
Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C. J. Org. Chem. 2003, 68,
7625. (c) Beccalli, E. M.; Broggini, G.; Paladino, G.; Penoni, A.; Zoni, C. J.
Org. Chem. 2004, 69, 5627. (d) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Paladino, G. Tetrahedron 2005, 61, 1077. (e) Abbiati, G.; Beccalli, E. M.;
Broggini, G.; Martinelli, M.; Paladino, G. Synlett 2006, 73.
(2) Tsuji, J. Palladium Reagents and Catalysts: New PerspectiVes for the
21 st Century; Wiley and Sons: New York, 2003.
(3) (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (b) Sigman, M. S.;
Schultz, M. J. Org. Biomol. Chem. 2004, 2, 2551. (c) Beccalli, E. M.; Broggini,
G.; Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107, 5318.
4746 J. Org. Chem. 2008, 73, 4746–4749
10.1021/jo800621n CCC: $40.75 2008 American Chemical Society
Published on Web 05/20/2008

SCHEME 2. Palladium-Catalyzed Cyclization of
Propargylamide 6
TABLE 1. Optimization of the Palladium-Catalyzed Cyclization of
Propargylamide 6
entry
catalyst
oxidant
BQd
solventa
T (°C) yields of 7
1
2
3
4
5
6
7
8
2b
THF/DMF 5:3
THF/DMF 5:3
THF
CH2Cl2
THF/DMF 5:3
DMF
rtg
60
rt
28
37
2b
BQd
BQd
BQd
BQd
BQd
BQd
BQd
BQd
BQd
BQe
MnO2
PTSAc
PTSAc
rt
FIGURE 1. Behavior of propargylamides as tools for the transition
metal-catalyzed synthesis of oxazole derivatives.
PTSAc
rtg
2b
11
15
18
10
23
26
–
29
17
46
41
h
c
c
Pd(OAc)2
Pd(OAc)2
THF/DMF 5:3
DMF
60
100
r.t.
argylamides as starting material and working in the presence
of Pd(II) catalysis with a reoxidant agent.
9
2b
2b
2c
2c
2b
2c
2b
2b
THF/DMF 5:3
THF/DMF 5:3
THF/DMF 5:3
THF/DMF 5:3
THF/DMF 5:3i
THF/DMF 5:3
10
11
12
13
14
15
16
17
100
100
100
60
100
100
100
100
It is worthwhile to mention that the oxazole nucleus is present
as a key structural moiety in a wide number of natural and
unnatural biologically active products,6 among which there are
antitumor, antiviral, and antileukemia agents, as well as herpes
simplex virus inhibitors, serine-threonine phosphatase inhibitors,
antibacterials, antialgicidals, and peripheral analgesics. Conse-
quently, a new efficient synthesis of functionalized oxazoles
may well be a valuable goal. Some protocols for the construction
of the oxazole nucleus starting from propargylamides are already
known in the literature7 and three of them are based on transition
metal catalyzed cyclization (Figure 1).7g–i The first represents
an effective access to 2,5-disubstituted oxazoles A by a tandem
process with use of propargylamides and aryl iodides in the
presence of catalytic Pd(0) species.7g The second concerns the
synthesis of 4,4-disubstituted 4H-oxazol-5-ylidenacetic acid
methyl esters B by Pd(II)-catalyzed oxidative carbonylation.7h
The third involves AuCl3 as catalyst affording to 5-methylox-
azoles C.7i Following the oxidative Pd-catalyzed process
observed for compound 4, a new methodology to furnish directly
5-oxazolecarbaldehydes would be desirable.
f
BQ,d O2
O2
CuCl2c O2 DMFj
CuCl2
e
DMF
CuCl2c O2 DMFj
a If not differently stated, the reaction time was 3 h. b 5 mol %. c 10
mol %. d 1 equiv. e 3 equiv. f 2 equiv. g Reactions were carried out
under ultrasound irradiation. h Reactions were carried out under micro-
wave irradiation. i 90 min. j 2 h.
The effective cyclization of amide 6 prompted us to perform
a number of experiments to improve the reaction yield. As
summarized in Table 1, some features were clearly evidenced.
First, palladium catalyst was essential for a positive outcome
of the reaction. The use of an acidic catalyst, more specifically
p-toluenesulfonic acid (PTSA), was not able to convert the
amide 6 in any solvents (entries 3-5).8 An attempt to carry out
the reaction by exposition of microwave irradiation failed
because the decomposition of amide 6 was faster than the
cyclization process (entry 6). The presence of 2 in the catalyst
systems proved to be highly effective for the desired cyclization
product (entry 2 vs entry 7). The increase of reaction temperature
(entry 10) as well as of BQ amount did not improve significantly
the yields (entry 11). The reaction was inhibited working in
certain solvents or in the presence of a base. The use of other
oxidant systems gave rise to different results. While MnO2
totally inhibits the conversion of 6 (entry 12), the environmen-
tally friendly molecular oxygen showed a different behavior
depending on reaction conditions. In particular, when combined
with BQ or employed as sole oxidant (entries 13 and 14) it
slowed the desired reaction, but produced 7 in highest yield
when associated with CuCl2 in the role of cocatalyst (entry 15).
The oxidative cyclization took place also in the presence of an
excess of CuCl2 (entry 16). The role of CuCl2 is only of
reoxidant agent and the absence of palladium inhibits the
process.
On the basis of the above considerations, we aimed to
evaluate the generality of the envisioned reaction and first we
tested the behavior of the simple N-propargylbenzamide 6 under
the previous successful reaction conditions. The experiment was
accomplished by either ultrasound activation or heating at 60
°C and in both cases afforded the 2-phenyloxazole-5-carbalde-
hyde (7), which was isolated in 28% and 37% yields, respec-
tively, besides degradation materials (Scheme 2).
(6) (a) Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Fujita, S.;
Furuya, T. J. Am. Chem. Soc. 1986, 108, 2780. (b) Maryanoff, C. A. In
Heterocyclic Compounds; Turchi, I. J., Ed.; Wiley & Sons: New York, 1986;
Vol. 45, Chapter 5. (c) Carmeli, S.; Moore, R. E.; Patterson, G. M.; Cortbett,
T. H.; Valeriote, F. A. J. Am. Chem. Soc. 1990, 112, 8195. (d) Pattenden, G.
J. Heterocycl. Chem. 1992, 29, 607. (e) Lewis, J. R. Nat. Prod. Rep. 1995, 12,
135. (f) Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh, M. E.; Harnh,
N. K.; Kress, D. L.; Wepsiec, J. P. J. Org. Chem. 1997, 62, 8634. (g) Palmer,
D. C.; Venkatraman, S. In The Chemistry of Heterocycles Compounds, A Series
of Monographs, Oxazoles: Synthesis, Reactions and Spettroscopy, Part A; Palmer,
D.C. Ed.; John Wiley & Sons: Hoboken, NJ, 2003.
(7) (a) Schulte, K. E.; Reisch, J.; Sommer, M. Arch. Pharm. 1966, 107. (b)
Eloy, F.; Deryckere, A. Chim. The´r. 1973, 437. (c) Nilsson, B. M.; Hacksell, U.
J. Heterocycl. Chem. 1989, 26, 269. (d) Freedman, J.; Huber, E. W. J. Heterocycl.
Chem. 1990, 27, 343. (e) Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem.
1998, 63, 7132. (f) Clark, D. C.; Travis, D. A. Bioorg. Med. Chem. 2001, 9,
2857. (g) Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F. Org. Lett.
2001, 3, 2501. (h) Bacchi, A.; Costa, M.; Gabriele, B.; Pelizzi, G.; Salerno, G.
J. Org. Chem. 2002, 67, 4450. (i) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.;
Bats, J. W. Org. Lett. 2004, 6, 4391.
Having established the optimal reaction conditions, we
screened a series of propargylamides to generate different
2-substituted oxazole-5-carbaldehydes. The cyclization of sub-
strates 8a-j took place in higher yields working in conditions
(8) Kumar, D.; Sundaree, S.; Patel, G.; Rao, V. S. Tetrahedron Lett. 2008,
49, 867.
J. Org. Chem. Vol. 73, No. 12, 2008 4747

TABLE 2. Cyclization Yields of the Propargylamides 8a-j into
the 5-Oxazolecarbaldehydes 9a-j
SCHEME 3. Mechanism Proposed for Conversion of the
Amide 6 on the 5-Oxazolecarbaldehyde 7
SCHEME 4. Outcome of Pd(II)-Catalyzed Cyclization of
r,r-Disubstituted Propargylamide 13
of entries 2 or 15 of Table 1. The better results are collected in
Table 2. The access to the oxazole compounds 9 was ac-
complished on propargylamides of aromatic, heteroaromatic, and
aliphatic carboxyacids as well as of natural R-aminoacids. The
crucial feature of this approach lies in its ability to access to
5-oxazolecarbaldehydes bearing an electron-rich heterocycle in
position 2 (entries e-h). In fact, direct formylation of oxazoles
substituted in position 2 with a pyrrolyl, furyl, or thienyl ring
provides for a competitive functionalization involving both
heterocyclic rings.
Despite several investigations in different reaction conditions,
we have not found clear-cut evidence for determining the Pd
mechanistic role. Although highly speculative, we propose the
outcome of oxidative heterocyclization depicted in Scheme 3.
The complexation of amide 6 with Pd(II) salts takes place on
the C-C triple bond (intermediate 10) making it susceptible to
nucleophilic attack. The role of the nucleophile is covered by
the oxygen atom of the amide group, which gives rise to
5-exodig cyclization to produce the oxazole skeleton by forma-
tion of the σ-alkenylpalladium complex 11. The intervention
of water provided, through its enol form, the 4,5-dihydrooxazole-
5-carbaldehyde 12, neither isolated nor detected in the reaction
mixture (NMR). At this level the oxidizing system intervenes
with a double role, namely (i) to reoxidize the Pd(0) species,
formed at the end of the catalytic cycle, to the active Pd(II)
and (ii) to promote the dehydrogenation of 12 giving 7.9
13 foreseeing the impossibility of the 4,5-dihydrooxazole-5-
carbaldehyde intermediate to undergo the dehydrogenation step.
Accordingly, amide 13 was submitted to the conditions of entries
1
2 and 15 (Scheme 4, path a). In both conditions, the H NMR
spectrum of the crude mixture revealed only signals arising from
degradation of the starting material, plausibly because the lack
of hydrogen in the 4-position of the 4,5-dihydrooxazole
precluded the oxidative aromatization of the putative intermedi-
ate 14. On the other hand, the treatment of the amide 13 with
2 (10 mol %) and CuCl2 (3 equiv) in DMF gave a mixture (63%
yield) of compounds 15 and 16 (E/Z 6:1 ratio) (Scheme 4, path
b).10 This finding indicates that the presence of chloride ions
as potential nucleophiles warrants the formation of the stable
vinyl chlorides 15 and 16 instead of 14.
(9) (a) Street, L. J.; Sternfeld, F.; Jelley, R. A.; Reeve, A. J.; Carling, R. W.;
Moore, K. W.; McKernan, R. M.; Sohal, B.; Cook, S.; Pike, A.; Dawson, G. R.;
Bromidge, F. A.; Wafford, K. A.; Seabrook, G. R.; Thompson, S. A.; Marshall,
G.; Pillai, G. V.; Castro, J. L.; Atack, J. R.; MacLeod, A. M. J. Med. Chem.
2004, 47, 3642. (b) Wipf, P.; Reeves, J. T.; Balachandran, R.; Day, B. W. J. Med.
Chem. 2002, 45, 1901. (c) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996,
61, 8207. (d) Shimano, M.; Meyers, A. I. Tetrahedron Lett. 1997, 38, 5415. (e)
Meyers, A. I.; Tavares, F. X. Tetrahedron Lett. 1994, 35, 2481. (f) Barrish,
J. C.; Singh, J.; Spergel, S. H.; Han, W. C.; Kissick, T. P.; Kronenthal, D. R.;
Mueller, R. H. J. Org. Chem. 1993, 58, 4494.
In the search for evidence to support the proposed mechanism,
we applied our protocol to the R,R-disubstituted propargylamide
(10) McNulty, P. J.; Swithenbank, C.; Viste, K. L.; Von Meyer, W. C. Ger.
Offen. DE 2025961 19710114, 1971. Chem. Abstr. 1971, 74, 75602.
4748 J. Org. Chem. Vol. 73, No. 12, 2008

NMR (400 MHz, CDCl3) δ 3.90 (3H, s), 7.01 (2H, d, J ) 8.8 Hz),
7.93 (1H, s), 8.13 (2H, d, J ) 8.8 Hz), 9.79 (1H, s). 13C NMR
(100 MHz, CDCl3) δ 56.0 (q), 114.8 (d), 114.9 (d), 118.8 (s), 130.1
(d), 130.5 (d), 140.1 (d), 149.7 (s), 163.4 (s), 166.2 (s), 175.4 (d).
MS m/z 203 (M+). Anal. Calcd for C11H9NO3: C, 65.02; H, 4.46;
N, 6.89. Found: C, 64.88; H, 4.29; N, 7.16.
In conclusion, the direct and effective protocol to 2-substituted
5-oxazolecarbaldehydes described in this paper represents a
valuable alternative to the formylation on oxazole rings, often
unsatisfactory in terms of regioselectivity and yields. Moreover,
the protocol can be carried out by using aryl, heteroaryl, and
alkyl propargylamides, with tolerance of various functional
groups and sensitive heterocycles such as N-unsubstituted
pyrrole and furan. This protocol increases the versatility of the
propargylamides as tools in Pd-catalyzed reactions for the direct
synthesis of oxazoles and increases the availability of different
functionalized oxazoles accessible by transition metal catalysis.
2-(2-Phenylethyl)oxazole-5-carbaldehyde (9d). Yield 61%. Oil.
1
IR (nujol) 1683 cm-1. H NMR (400 MHz, CDCl3) δ 3.15-3.23
(4H, m), 7.21-7.33 (5H, m), 7.78 (1H, s), 9.74 (1H, s). 13C NMR
(100 MHz, CDCl3) δ 30.1 (t), 33.0 (t), 126.8 (d), 128.6 (d), 129.1
(d), 138.3 (d), 139.9 (s), 150.3 (s), 169.3 (s), 176.7 (d). MS m/z
201 (M+). Anal. Calcd for C12H11NO2: C, 71.63; H, 5.51; N, 6.96.
Found: C, 71.48; H, 5.79; N, 7.08.
Experimental Section
2-(2-Furyl)oxazole-5-carbaldehyde (9h). Yield 37%. Mp
1
138-140 °C (diisopropyl ether). IR (nujol) 1682 cm-1. H NMR
General Procedure for the Preparation of 2-Substituted
5-Oxazolecarbaldehydes. Entry 2: A solution of 6 or 8a-j (1.0
mmol), 2 (0.05 mmol), and BQ (1.0 mmol) in 8 mL of DMF/THF
(3:5) was heated at 60 °C for 3 h. After being washed with brine,
the solution was extracted with Et2O (2 × 20 mL). The organic
layer was dried over Na2SO4 and taken to dryness under reduced
pressure. The crude mixture was chromatographed on a silica gel
column giving 7 or 9a-j. Entry 15: A solution of CuCl2 (0.1
mmol) and 2 (0.05 mmol) in DMF (20 mL) was stirred at room
temperature for 30 min. A solution of 6 or 8a-j (1.0 mmol) in 15
mL of DMF was added, and then the resulting mixture was warmed
at 100 °C for 2 h under oxygen atmosphere. The solution was
treated with brine and extracted with Et2O (2 × 40 mL). The organic
layer was dried over Na2SO4 and taken to dryness under reduced
pressure. The crude mixture was chromatographed on a silica gel
column giving 7 or 9a-j.
(400 MHz, CDCl3) δ 6.62-6.63 (1H, m), 7.31 (1H, d, J ) 3.5
Hz), 7.68 (1H, s br), 7.94 (1H, s), 9.81 (1H, s). 13C NMR (100
MHz, CDCl3) δ 113.0 (d), 116.1 (d), 139.2 (d), 142.0 (s), 146.9
(d), 149.4 (s), 157.9 (s), 176.4 (d). MS m/z 163 (M+). Anal. Calcd
for C8H5NO3: C, 58.90; H, 3.09; N, 8.59. Found: C, 59.01; H, 2.81;
N, 8.35.
Acknowledgment. Thanks are due to the Ministero dell’-
Universita` e della Ricerca for financial support and for the Ph.D.
fellowship to S.S. (Progetto Giovani 2004).
Supporting Information Available: Experimental proce-
dures, characterization data, as well as 1H and 13C NMR spectra
for all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
2-(4-Methoxyphenyl)oxazole-5-carbaldehyde (9a). Yield 48%.
1
Mp 140-142 °C (diisopropyl ether). IR (nujol) 1680 cm-1. H
JO800621N
J. Org. Chem. Vol. 73, No. 12, 2008 4749