Pd-Catalyzed C4-Olefination of Oxazoles via C-H Bond Activation: Divergent Synthesis of Functionalized Amino Alcohol and Amino Acid Derivatives

Article abstract of DOI:10.1021/ol201865h

A Pd-catalyzed C4-olefination of oxazoles via C-H bond activation under mild conditions was achieved. The reaction was shown to be general over a range of substrates. New protocols for the divergent transformation of these products to provide functionaliz

Full text of DOI:10.1021/ol201865h

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5040–5043
Pd-Catalyzed C4-Olefination of Oxazoles
via CꢀH Bond Activation: Divergent
Synthesis of Functionalized Amino
Alcohol and Amino Acid Derivatives
Sunliang Cui,† Lukasz Wojtas,‡ and Jon C. Antilla*,†
Department of Chemistry and Department of Chemistry X-ray Facility, University of
South Florida, 4202 East Fowler Avenue, Tampa, Florida 33620, United States
jantilla@usf.edu
Received July 11, 2011
ABSTRACT
A Pd-catalyzed C4-olefination of oxazoles via CꢀH bond activation under mild conditions was achieved. The reaction was shown to be general
over a range of substrates. New protocols for the divergent transformation of these products to provide functionalized amino alcohol and amino
acid derivatives have also been established.
Transition-metal-catalyzed cross-coupling through
CꢀH bond activation has emerged as one of the most
powerful methods for the construction of CꢀC bonds.1
These processes preclude the need for a prior functionali-
zation step, making the overall chemical transformation
highly efficient, thus allowing for widespread application
toward the synthesis of various natural products and
pharmaceuticals.2,3 Recent reports on Pd-catalyzed
C(aryl)ꢀH olefination describe methods utilizing electro-
philic metalation of aromatic and heteroaromatic CꢀH
bonds.4 This strategy encouraged us to develop a Pd-catalyzed
olefination through CꢀH bond activation, and additionally
demonstrate the synthetic utility of the reaction for the
generation of compounds with useful molecular architecture.
Oxazoles are an important class of heterocycles that are
found in a wide number of natural products, pharmaceu-
ticals, polymeric materials, and fluorescent dyes.5 To date,
there have been numerous reported methods for the syn-
thesis of oxazole derivatives.6 In addition, the transition-
metal-catalyzed functionalization of oxazoles has also
† Department of Chemistry.
‡ Department of Chemistry X-ray Facility.
(1) For selected recent reviews, see: (a) Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318. (b) Chen,
X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 5094. (c) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.,
Int. Ed. 2009, 48, 9792. (d) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc.
Chem. Res. 2009, 42, 1074. (e) Xu, L. M.; Li, B. J.; Yang, Z.; Shi, Z.-J.
Chem. Soc. Rev. 2010, 39, 712. (f) Lyons, T. W.; Sanford, M. S. Chem.
(4) (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.;
Fujiwara, Y. Science 2000, 287, 1992. (b) Yokota, T.; Tani, M.;
Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2003, 125, 1476. (c) Dams,
M.; De Vos, D. E.; Celen, S.; Jacobs, P. A. Angew. Chem., Int. Ed. 2003,
42, 3512. (d) Frimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (e) Beck, E. M.; Grimster,
N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528.
(f) Aouf, C.; Thiery, E.; Bras, J. L.; Muzart, J. Org. Lett. 2009, 11, 4096.
(g) Yang, Y.; Cheng, K.; Zhang, Y. Org. Lett. 2009, 11, 5606. (h) Zhao,
J.; Huang, L.; Cheng, K.; Zhang, Y. Tetrahedron Lett. 2009, 50, 2758.
(i) Li, P.; Gu, J.-W.; Ying, Y.; He, Y.-M.; Zhang, H.-F.; Zhao, G.; Zhu,
S.-Z. Tetrahedron 2010, 66, 8387. (j) Li, M.; Li, L.; Ge, H. Adv. Syn.
Catal. 2010, 352, 2445. (k) Yu, H.; Jin, W.; Sun, C.; Chen, J.; Du, W.; He,
S.; Yu, Z. Angew. Chem., Int. Ed. 2010, 49, 5792.
€
Rev. 2010, 110, 1147. (g) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius,
F. Chem. Soc. Rev. 2011, 40, 4740.
(2) For selected reviews, see: (a) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442. (b) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(3) Selected examples of catalytic CꢀH bond functionalization in
total synthesis: (a) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125,
11510. (b) Covell, D. J.; Vermeulen, M. A.; Labenz, N. A.; White, M. C.
Angew. Chem., Int. Ed. 2006, 45, 8217. (c) Beck, E. M.; Hatley, R.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004. For elegant
examples of metal mediated CꢀH activation in synthesis, see: (d) Garg,
N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 9552.
(e) Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767.
r
10.1021/ol201865h
Published on Web 08/23/2011
2011 American Chemical Society

Table 1. Optimization for the Pd-Catalyzed Olefination of 1a with 2aa
entry
catalyst (10%)
oxidant (2 equiv)
solvent
temp (°C)
time (h)
yield (%)b
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(CH3CN)2
Pd(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
AgOAc
DMF
70
70
60
60
60
60
60
60
60
60
60
70
12
6
30
45
84
<5
ndd
<5
<5
nd
<5
51
nd
10
2
CH3CN
3c
CH3CN
6
4c
CH3CN
6
5c
BQ
CH3CN
6
6c
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
none
DMSO
6
7c
DMF- DMSO (1/1)
AcOH
6
8c
6
9c,e
10c,f
11c
12c
CH3CN
6
CH3CN
6
CH3CN
6
Acetone
20
a Conditions: molar ratio of 1a/2a = 1:3 (equiv), with a concentration of 1a being 0.25 M, PMP = para-methoxyphenyl. b Isolated yield. c Under
argon atmosphere. d nd = not detected. e Pyridine (0.1 equiv) was added. f NaHCO3 (2.2 equiv) was added.
been developed.7 Recently, Miura reported a Pd-catalyzed
oxidative C5-alkenylation of azoles.8 Herein, we report a
Pd-catalyzed C4-olefination of oxazoles via CꢀH bond
activation under mild conditions and the divergent trans-
formation of the products to functionalized amino alcohol
and amino acid derivatives (eq 1).
further functionalization by reaction with olefins. The
reaction of 1a with butyl acrylate (2a) was used to optimize
the reaction conditions (Table 1). With 10 mol % Pd(OAc)2
as catalyst and Cu(OAc)2 as oxidant, the reaction pro-
ceeded in N,N-dimethylformamide (DMF) for 12 h at
70 °C under an atmosphere of air, forming the desired
product 3a in 30% yield (Table 1, entry 1), while a 45%
yield was obtained in CH3CN at 70 °C (entry 2). There was
a remarkable improvement when the reaction was con-
ducted in CH3CN at 60 °C under an argon atmosphere
(84% yield, entry 3). Further optimization showed that
AgOAc and para-benzoquinone (BQ) were much less
efficient oxidants than Cu(OAc)2 (entries 4 and 5), and
the solvent screening showed that DMSO, DMF-DMSO
cosolvent and HOAc all dramatically decreased the reac-
tion efficiency (entries 6ꢀ8). Addition of either pyridine as
a ligand or NaHCO3 as a base deteriorated the yield
(entries 9 and 10) and PdCl2(CH3CN)2 could not catalyze
the reaction (entry 11). Attempts to use acetone as solvent
and a hydrogen acceptor to intercept the HPdOAc inter-
mediate for the purpose of regenerating the Pd(II) without
forming Pd(0) failed (Table 1, entry 12).10 The argon
atmosphere was crucial for this reaction because of the
decomposition of the olefination product when heated in
the presence of air.
Inspired by the Suga-Ibata reaction of oxazole 1a and
aldehydes for the synthesis of oxazolines,9 we envisioned
that 1a could be transformed to an electrophilic palladium
species via CꢀH activation, which could then be used for
(5) (a) Copp, B. R. Nat. Prod. Rep. 2003, 20, 535. (b) Desroy, N.;
Moreau, F.; Briet, S.; Le Fralliec, G.; Floquet, S.; Durant, L.; Vongsouthi,
V.; Gerusz, V.; Denis, A.; Escaich, S. Bioorg. Med. Chem. 2009, 17, 1276. (c)
Heng, S.; Gryncel, K. R.; Kantrowitz, E. R. Bioorg. Med. Chem. 2009, 17,
3916.
(6) (a) Williams, D. R.; Fu, L. Org. Lett. 2010, 12, 808. (b) Cano, I.;
Alvarez, E.; Nicasio, M. C.; Perez, P. J. J. Am. Chem. Soc. 2011, 133, 191.
ꢀ
ꢀ
(c) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482.
ꢁ
(7) (a) Besselievre, F.; Mahuteau-Betzer, F.; Grierson, D. S.; Piguel,
S. J. Org. Chem. 2008, 73, 3278. (b) Verrier, C.; Martin, T.; Hoarau, C.;
ꢁ
Marsais, F. J. Org. Chem. 2008, 73, 7383. (c) Besselievre, F.; Piguel, S.;
Mahuteau-Betzer, F.; Grierson, D. S. Org. Lett. 2008, 10, 4029. (d)
(9) (a) Suga, H.; Shi, X.; Ibata, T. J. Org. Chem. 1993, 58, 7397.
(b) Suga, H.; Ikai, K.; Ibata, T. Tetrahedron Lett. 1998, 869. (c) Suga, H.;
Ikai, K.; Ibata, T. J. Org. Chem. 1999, 64, 7040. (d) Evans, D. A.; Janey,
J. M.; Magomedow, N.; Tedrow, J. S. Angew. Chem., Int. Ed. 2001, 40,
1884.
ꢁ
Besselievre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553. (e) Cho,
H.; Joseph, J.; Chang, S. Angew. Chem., Int. Ed. 2010, 49, 9899.
(f) Kitahara, M.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. J. Am.
Chem. Soc. 2011, 133, 2160.
(8) Miyasaka, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2010, 75, 5421.
(10) Ruan, J.; Li, X.; Saidi, O.; Xiao, J. J. Am. Chem. Soc. 2008, 130,
2424.
Org. Lett., Vol. 13, No. 19, 2011
5041

With the optimized reaction conditions in hand, we next
examined the substrate scope. The reaction of 1a with
electron- deficient olefins, that is, alkyl acrylates (2aꢀc),
methyl vinyl ketone (MVK) (2d), and N,N-ethylphenyla-
crylamide (2e), afforded the products 3aꢀe in 52ꢀ84%
yield (Table 2, entries 1ꢀ5). Treatment of 1a with styrene
(2f) generated the desired product 3f in 73% yield (entry 6).
Similarly, the reaction of 1a with substituted styrenes
(2gꢀk) furnished the corresponding products in 65ꢀ87%
yield (entry 6). Vinyl trimethylsilane (2l), which is rarely
employed in CꢀH olefination, could also be applied to this
protocol, affording trimethylsilyl (TMS) substituted pro-
duct 3l in 84% yield (entry 7). Vinyl acetate (2m) only
showed the moderate reactivity to furnish product 3m in
26% yield with loss of the acetate group in the product
(entry 8). The diene was also investigated and the coupling
with 1-phenyl-1,3-diene proceeded at the terminal double
bond to give the dienyl oxazole 3n in 52% yield (entry 9).
Under similar reaction conditions, oxazole 1b was also
employed to test this Pd-catalyzed oxidative olefination,
giving the corresponding products in moderate yields
(eq 2).
Table 2. Pd-Catalyzed Olefination of Oxazole 1a via CꢀH
Activationa
With this result in hand, we planned to transform the
functionalized oxazole products to more synthetically
interesting motifs. Initially, we attempted to perform a
Pd/C hydrogenation to reduce the alkene in 3a at room
temperature with a hydrogen balloon. Gratifyingly, we
found that an acyclic 1,2-amido ether (an amino alcohol
derivative) product 4a was formed in 67% yield. The
hydrogenation was also efficient for other oxazole pro-
ducts and the results are shown in Scheme 1. The structure
of the amido ether was confirmed by single crystal X-ray
diffraction analysis of compound 4b (see Supporting
Information), in addition to standard characterization.
Amino alcohol derivatives are extensively used in med-
icinal chemistry,11 representing a wide range of β-adrenergic
blockers in the management of cardiovascular disorders.12
This method for Pd-catalyzed olefination and subsequent
Pd/C catalyzed reduction gives facile access to novel amino
alcohol derivatives in a general and efficient manner. The
hydrogenation also led to an unexpected ring-opening,
which was previously unreported for Pd-catalyzed ring
fragmentation of oxazoles. A control experiment employing
LiAlH4 as a reductant left the oxazole structure intact even
in refluxing THF. While the ring-opening mechanism is
(11) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835.
(12) (a) Connolly, M. E.; Kersting, F.; Bollery, C. T. Prog. Cardio-
Vasc. Dis. 1976, 19, 203. (b) Shanks, R. G.; Wood, T. M.; Dornhost,
A. C.; Clark, M. L. Nature 1966, 212, 88. (c) Triggle, D. J. In Burger’s
Medicinal Chemistry, 4th ed; Wolff, M. S., Ed.; Wiley-Interscience:
New York, 1981; p 225. (d) De Cree, J.; Geukens, H.; Leempoels, J.;
Verhaegen, H. Drug Dev. Res. 1986, 8, 109.
a Conditions: 1a (1 equiv), 2 (3 equiv), Pd(OAc)2 (10 mol %),
Cu(OAc)2 (2 equiv), CH3CN (1.2 mL), 60 °C, argon, 6 h. b Isolated yield
based on 1a.
5042
Org. Lett., Vol. 13, No. 19, 2011

currently unclear, we hypothesize that Pd/C plays a key role
in this process presumably by coordination to the oxazole
nitrogen.13
a concise synthesis of functionalized homophenylalanines
as shown in Scheme 2. Hydrolysis of oxazole 3f in AcClꢀ
MeOH provided an inseparable 1:1 mixture of 5 and 50,
and the subsequent hydrogenation furnished the homo-
phenylalanine product 6, which is an important synthon in
many angiotensin-converting enzyme inhibitors.14,15
Scheme 1. Pd/C Catalyzed Ring-Opening of Oxazoles 3 to
Functionalized Amino Alcohol Derivatives 4a,b
Scheme 2. Synthesis of Homophenylalanine Derivative 6
In conclusion, we have developed a Pd-catalyzed oxida-
tive C4-olefination of oxazoles through CꢀH bond activa-
tion under mild conditions. Protocols are provided for the
transformation of these products to functionalized amino
alcohol derivatives, and homophenylalanine derivatives
have also been established.
a Conditions: 3 (100 mg), 10% Pd/C (100 mg), MeOH (10 mL),
AcOEt (2 mL), H2 (balloon), rt, 24 h. b Isolated yield.
This new methodology also provides a versatile and
efficient approach to amino acid derivatives, and represents
Acknowledgment. We thank the University of South
Florida for financial support.
(13) For sodium-mediated similar reductive fragmentation of oxa-
zoles, see: Dornow, A.; Eichholtz, H. Chem. Ber. 1953, 86, 384.
(14) (a) Wyvratt, M. J. Clin. Physiol. Biochem. 1988, 6, 217.
(b) Brunner, H. R.; Nussberger, J.; Waeber, B. J. Cardiovasc. Pharma-
col. 1985, 7, S2.
(15) For a recent synthesis of homophenylalanine using oxidative
CꢀH/ CꢀH coupling, see: Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed.
2008, 47, 7075.
Supporting Information Available. Detailed experimen-
tal procedures, characterization for products, NMR
spectra and crystallographic information file for com-
pound 4b. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5043