Synthesis of oxazolines from amides via palladium-catalyzed functionalization of unactivated C(sp3)-H bond

Article abstract of DOI:10.1021/acs.orglett.5b00151

A complementary method that enables the expeditious synthesis of oxazolines from amides via Pd-catalyzed C(sp³)-H functionalization has been described. Preliminary studies indicate that the reaction might go through a chlorination/nucleophilic cyclization sequence, and the high efficiency of this sequence is enhanced by the in situ cyclative capture of the chlorinated intermediate. The resulting oxazolines can be further converted into the corresponding β-amino alcohols without chromatography.

Full text of DOI:10.1021/acs.orglett.5b00151

Letter
pubs.acs.org/OrgLett
Synthesis of Oxazolines from Amides via Palladium-Catalyzed
Functionalization of Unactivated C(sp3)−H Bond
Bo Li, Si-Qing Wang, Bin Liu, and Bing-Feng Shi*
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
S
* Supporting Information
ABSTRACT: A complementary method that enables the
expeditious synthesis of oxazolines from amides via Pd-
catalyzed C(sp3)−H functionalization has been described.
Preliminary studies indicate that the reaction might go through
a chlorination/nucleophilic cyclization sequence, and the high
efficiency of this sequence is enhanced by the in situ cyclative
capture of the chlorinated intermediate. The resulting
oxazolines can be further converted into the corresponding
β-amino alcohols without chromatography.
xazoline is a prevalent structural motif found in natural
products, pharmaceuticals, and advanced materials. It has
Scheme 1. Oxazoline Synthesis via C(sp3)−H Activation
O
also been widely applied in organic synthesis as versatile
synthetic intermediates, protecting groups, chiral auxiliaries,
and privileged ligands.1 In addition, the oxazoline scaffold has
been recognized as an effective directing group (DG) in
transition-metal-catalyzed C−H activation reactions.2 There-
fore, various strategies have been developed for the synthesis of
oxazolines.3 While these strategies are effective, the develop-
ment of a new complementary method for the synthesis of
oxazolines is still highly desirable.
a
Table 1. Optimization of the Initial Screening Results
In the past decade, transition-metal-catalyzed C−H function-
alization has emerged as an attractive and powerful strategy for
the synthesis of heterocycles.4 A variety of highly functionalized
heterocycles, such as carbazoles, indazoles, indoles, pyrrolidines,
indolines, and furans, have been accessed by this process.4
However, to the best of our knowledge, there are no examples
of preparation of oxazolines via C−H activation, due to the low
reactivity of C(sp3)−H bonds5 and the relative reluctance of
C(sp3)−O reductive elimination from the metal center.6−8 In
our continuing interest in the Pd-catalyzed functionalization of
unactivated C(sp3)−H bonds, we report herein the efficient
and highly functional group compatible synthesis of oxazolines
via Pd-catalyzed C(sp3)−H functionalization. Preliminary
studies indicate that the reaction might go through a
C(sp3)−H activation/chlorination/nucleophilic cyclization se-
quence10,11 and the high efficiency of this sequence is enhanced
by the in situ cyclative capture of the chlorinated intermediate.
Notably, the oxazolines can be transferred to β-amino alcohols
without chromatography (Scheme 1).
Pd(OAc)2
additive
(equiv)
temp
yield
b
entry
(X mol %)
[Cu]
(°C)
(%)
1
10
10
10
10
−
10
10
10
10
5
CuCl2
CuCl2
CuCl2
−
CuCl2
CuCl
CuBr2
CuI
−
120
120
120
120
120
120
120
120
100
120
75
2
Ag2CO3 (2)
HOAc (5)
HOAc (5)
HOAc (5)
HOAc (5)
HOAc (5)
HOAc (5)
HOAc (5)
HOAc (5)
trace
90
0
3
4
5
0
6
65
40
0
7
8
9
CuCl2
CuCl2
50
c
10
85
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (X mol %), [Cu] (2.0
b
equiv), additive, in toluene (2 mL) at temp °C for 24 h under air. 1H
c
NMR yields using CH2Br2 as the internal standard. Isolated yield.
Our synthetic attempts commenced with the conversion of
N-(1-methyl-1-pyridin-2-yl-ethyl)butyramide 1a to the corre-
sponding oxazoline 2a using Pd(OAc)2 as the catalyst and
CuCl2 as the chloride source.12 We were pleased to find that
the desired oxazoline 2a was obtained in 75% yield when the
reaction was conducted in toluene under air (Table 1, entry 1).
The addition of silver salts as the oxidant inhibited the reaction
(entry 2). The reaction was very efficient when 5 equiv of
HOAc were used (entry 3, 90% yield). Further investigations
Received: January 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00151
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
revealed that both Pd(OAc)2 and CuCl2 were crucial for the
reaction (entries 5 and 6). Different halogen sources, such as
CuCl, CuBr2, and CuI, were examined and CuCl2 was optimal
(entries 6−8). Finally, we found that 5 mol % Pd(OAc)2 was
sufficient to deliver the desired oxazoline 2a in a comparable
yield (entry 10).
With the optimized conditions in hand, we next explored the
generality and scope of the process. In general, substrates
bearing various side chains were smoothly converted to the
corresponding oxazolines in moderate to high yields as shown
in Figure 1. A variety of functional groups, such as acetoxyl,
highly strained cyclopropane. It is worth noting that the
substituent, such as chloro, on the pyridine ring was also
tolerated and gave 2t in moderate yield. The cyclization
structure was unambiguously confirmed by X-ray analysis of
compound 2r.13 A quaternary α-carbon was necessary for the
success of the reaction, since no desired product was observed
when amide 1u was used as the substrate.
We were delighted to find that substrates with methylene
C(sp3)−H bonds also reacted efficiently to give the desired
oxzalines in good yield (Table 2). Amides with linear chains
Table 2. Pd-Catalyzed Annulation of Methylene C (sp3)−H
a
Bonds
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol %), CuCl2 (0.4
mmol), and HOAc (1.0 mmol) in toluene (2 mL) at 120 °C for 24 h
b
c
under air. Isolated yields. 2 mL of toluene. 2 mL of toluene, 32 h.
and cyclic rings were all found to be suitable. Consistent with
our previous observations, the reactivity is enhanced if sterically
demanding substrates are used (entry 2, pivalamide 4b, 91%
yield).
Finally, a one-pot Pd-catalyzed annulation/hydrolysis
sequence was established for the synthesis of 2-hydroxy
aminoacyls 5 and 2-aminoethyl acyloxys 6 from the
corresponding amides 1. As shown in Table 3, amides 1
reacted under the standard conditions followed by hydrolysis
with acetic acid, to give the protected β-amino alcohols 5 or 6
in moderate to high yields. It is worth noting that the hydrolysis
of amides with linear aliphatic chains provided 2-hydroxy
aminoacyls 5 exclusively in reduced yields (45%−70% yield),
while the hydrolysis of the amides with bulky quaternary carbon
centers at the α-position proceeded more efficiently to give 2-
aminoethyl acyloxys 6 in high yields (6f, 95%; 6g, 94%). These
results indicated that steric factor has significant influence on
the type of products and reaction efficiency.
To further demonstrate the synthetic versatility of our
protocol, we successfully realized the conversion of amide 1a
into the corresponding β-amino alcohol 7 without chromatog-
raphy [eq 1]. The resulting β-amino alcohol can act as a
versatile building block for further transformation.
To gain greater insight into the mechanism of the annulation
reactions, preliminary mechanistic studies were also conducted.
Figure 1. Pd-catalyzed annulation of methyl C(sp3)−H bonds.
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol %), CuCl2 (0.4
mmol) and HOAc (1.0 mmol) in toluene (2 mL) at 120 °C for 24 h
under air. Isolated yields. For structure 2u, n.d. = not detected.
alkoxy, and Phth-protected amine, were tolerated under the
reaction conditions. Generally, amides bearing quaternary
carbon centers at the α-position were converted to the
corresponding oxazolines (2l−2r) more efficiently than amides
with a linear chain (2b−2j), indicating that steric congestion
around the amide improves the reaction efficiency. When
benzamide 1j and 2-phenyl-isobutyramide 1o were subjected to
the cyclization conditions, reduced yields were obtained, largely
due to the side reaction of halogenation on the aromatic ring.
Interestingly, the annulation of cyclopropanecarboxamide 1s
gave the oxazoline product 2s in 50% yield without affecting the
B
DOI: 10.1021/acs.orglett.5b00151
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. One-Pot Synthesis of 2-Hydroxy Aminoacyls and 2-
Aminoethyl Acyloxys
Scheme 2. Plausible Mechanism
catalyzed C(sp3)−H functionalization. The resulting oxazolines
can be further converted into the corresponding β-amino
alcohols without chromatography. Preliminary studies indicate
the reaction might go through a chlorinated intermediate and
the high efficiency of this sequence is enhanced by the in situ
cyclative capture of this intermediate.
a
b
ASSOCIATED CONTENT
* Supporting Information
5 h. 14 h.
■
S
Experimental details, spectral data for all new compounds, and
X-ray for 2r. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
First, 2-(tert-butyl)pyridine 8 was subjected to the standard
reaction conditions, and chlorinated products 8a and 8b were
obtained [eq 2].11d Second, the chlorinated product N-(1-
chloro-2-(pyridin-2-yl)propan-2-yl)butyramide 9 can be con-
verted to oxazoline 2a under the standard reaction conditions
[eq 3].
*E-mail: bfshi@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Basic Research Program of
China (2015CB856600), the NSFC (21422206, 21272206),
and Zhejiang Provincial NSFC (LZ12B02001) is gratefully
acknowledged.
REFERENCES
■
(1) (a) Meyers, A. I. Acc. Chem. Res. 1978, 11, 375. (b) Lipshutz, B.
H. Chem. Rev. 1986, 86, 795. (c) Gomez, M.; Muller, G.; Rocamora,
M. Coord. Chem. Rev. 1999, 193, 769. (d) Johnson, J. S.; Evans, D. A.
Acc. Chem. Res. 2000, 33, 325. (e) Liao, S.; Sun, X. L.; Tang, Y. Acc.
Chem. Res. 2014, 47, 2260.
Based on these observations, a C(sp3)−H activation/
chlorination/cyclization sequence pathway is proposed
(Scheme 2, path a). First, pyridyl-directed C(sp3)−H activation
gives palladacyle I, which undergoes oxidative addition with
CuCl2 to give high-valent Pd(IV) intermediate II. Reductive
elimination affords the chlorinated product III,12 which
undergoes nucleophilic cyclization to generate oxazoline 2.
The high efficiency of the whole sequence (up to 96% yield)
and the relatively low reactivity of the chlorination of 8 partially
indicate that the in situ cyclative capture of the chlorinated
intermediate can facilitate the sequence.15 It should be noted
that a mechanism involving the intramolecular C(sp3)−O
reductive elimination6 could not be completely excluded at this
stage (Scheme 2, path b).
(2) For an early example, see: Giri, R.; Chen, X.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2005, 44, 2112.
(3) Frump, J. A. Chem. Rev. 1971, 71, 483.
(4) For selected reviews, see: (a) Guo, X.-X.; Gu, D.-W.; Wu, Z.;
Zhang, W. Chem. Rev. DOI: 10.1021/cr500410y. (b) Mei, T.-S.; Kou,
L.; Ma, S.; Engle, K. M.; Yu, J.-Q. Synthesis 2012, 44, 1778. (b) Cho, S.
H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068.
(c) Thansandote, P.; Lautens, M. Chem.Eur. J. 2009, 15, 5874.
(5) For selected reviews on C(sp3)−H activation, see: (a) Girard, S.
A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74.
(b) Zhang, Q.; Chen, K.; Shi, B.-F. Synlett 2014, 25, 1941. (c) Rouquet,
G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726. (d) Zhang, C.;
Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464. (e) Baudoin, O.
Chem. Soc. Rev. 2011, 40, 4902. (f) Gutekunst, W. R.; Baran, P. S.
Chem. Soc. Rev. 2011, 40, 1976. (g) Hartwig, J. F. Chem. Soc. Rev. 2011,
40, 1992. (h) Li, H.; Li, B.-J.; Shi, Z.-J. Catal. Sci. Technol. 2011, 1, 191.
(i) Wasa, M.; Engle, K. M.; Yu, J.-Q. Isr. J. Chem. 2010, 50, 605.
In conclusion, we have developed a complementary strategy
to enable the expeditious synthesis of oxazolines via Pd-
C
DOI: 10.1021/acs.orglett.5b00151
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) For selected examples of heterocycle synthesis via intramolecular
C(sp2)−O formation, see: (a) Ueda, S.; Nagasawa, H. Angew. Chem.,
Int. Ed. 2008, 47, 6411. (b) Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J.
Am. Chem. Soc. 2010, 132, 12203. (c) Xiao, B.; Gong, T.-J.; Liu, Z.-J.;
Liu, J.-H.; Luo, D.-F.; Xu, J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 9250.
(d) Zhao, J.; Wang, Y.; He, Y.; Liu, L.; Zhu, Q. Org. Lett. 2012, 14,
1078. (e) Zhao, J.; Zhang, Q.; Liu, L.; He, Y.; Li, J.; Li, J.; Zhu, Q. Org.
Lett. 2012, 14, 5362. (f) Gallardo-Donaire, J.; Martin, R. J. Am. Chem.
Soc. 2013, 135, 9350. For a review, see: (g) Liu, B.; Shi, B.-F.
Tetrahedron Lett. 2015, 56, 15 and references therein.
(7) For seminal examples of Pt(II)-catalyzed lactone synthesis via
intramolecular C(sp3)−O formation, see: (a) Kao, L.-C.; Sen, A. J.
Chem. Soc., Chem. Commun. 1991, 1242. (b) Dangel, B. D.; Johnson, J.
A.; Sames, D. J. Am. Chem. Soc. 2001, 123, 8149.
(8) For selected examples of intermolecular oxygenation of
unactivated C(sp3)−H, see: (a) Desai, L. V.; Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2004, 126, 9542. (b) Ren, Z.; Mo, F.; Dong, G.
J. Am. Chem. Soc. 2012, 134, 16991. (c) Zhang, S.-Y.; He, G.; Zhao, Y.;
Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2012, 134, 7313.
(d) Rit, R. K.; Yadav, M. R.; Sahoo, A. K. Org. Lett. 2012, 14, 3724.
(e) Ye, X.; He, Z.; Ahmed, T.; Weise, K.; Akhmedov, N. G.; Petersen,
J. L.; Shi, X. Chem. Sci. 2013, 4, 3712. (f) Chen, F.-J.; Zhao, S.; Hu, F.;
Chen, K.; Zhang, Q.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, 4187.
(g) Zhou, L.; Lu, W. Org. Lett. 2014, 16, 508.
(9) (a) Zhang, Q.; Chen, K.; Rao, W.-H.; Zhang, Y.-J.; Chen, F.-J.;
Shi, B.-F. Angew. Chem., Int. Ed. 2013, 52, 13588. (b) Chen, K.; Hu, F.;
Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, 3906. (c) Zhang, Q.; Yin,
X.-S.; Zhao, S.; Fang, S.-L.; Shi, B.-F. Chem. Commun. 2014, 50, 8353.
(d) Chen, K.; Shi, B.-F. Angew. Chem., Int. Ed. 2014, 53, 11950.
(e) Chen, K.; Zhang, S.-Q.; Xu, J.-W.; Hu, F.; Shi, B.-F. Chem.
Commun. 2014, 50, 13924.
(10) For an example of synthesis of β-lactam via a C(sp3)−H
chlorination−amination sequence, see: Wasa, M.; Yu, J.-Q. J. Am.
Chem. Soc. 2008, 130, 14058.
(11) Pd-catalyzed halogenation of unactivated C(sp3)−H is
challenging, and few examples have been reported. For iodination,
see: (a) Reference 2a. (b) Giri, R.; Wasa, M.; Brazzano, S. P.; Yu, J.-Q.
Org. Lett. 2006, 8, 5685. For a recent example of bromination and
chlorination, see: (c) Rit, R. K.; Yadav, M. R.; Ghosh, K.; Shankar, M.;
Sahoo, A. K. Org. Lett. 2014, 16, 5258. For an isolated example, see:
(d) Stowers, K. J.; Kubota, A.; Sanford, M. S. Chem. Sci. 2012, 3, 3192.
(12) For early examples of Pd-catalyzed C−X bond formation with
CuX2 as oxidants and a chloride source, see: (a) Zhu, G.; Lu, X. J.
Organomet. Chem. 1996, 508, 83. (b) El-Qisairi, A. K.; Qaseer, H. A.;
Katsigras, G.; Lorenzi, P.; Trivedi, U.; Tracz, S.; Hartman, A.; Miller, J.
A.; Henry, P. M. Org. Lett. 2003, 5, 439. (c) Lei, A.; Lu, X.; Liu, G.
Tetrahedron Lett. 2004, 45, 1785. (d) Manzoni, M. R.; Zabawa, T. P.;
Kasi, D.; Chemler, S. R. Organometallics 2004, 23, 5618.
(13) CCDC 1040923 (2r) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(14) For early examples of using pyridyl as a DG for C(sp3)−H
activation, see: (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 2300. (b) Kalyani, D.; Deprez, N. R.; Desai, L. V.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. (c) Zaitsev, V. G.;
Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154.
(d) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657. (e) Chen, X.;
Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634.
(15) The nucleophilic cyclization of the chlorinated intermediate is
very fast, and efforts to capture this intermediate were unsuccessful.
D
DOI: 10.1021/acs.orglett.5b00151
Org. Lett. XXXX, XXX, XXX−XXX