Rhodium-Catalyzed Regioselective Domino Azlactone–Alkyne Coupling/Aza-Cope Rearrangement: Facile Access to 2-Allyl-3-oxazolin-5-ones and Trisubstituted Pyridines

Article abstract of DOI:10.1002/anie.201704022

Rhodium-catalyzed regioselective addition of azlactones to internal alkynes combined with aza-Cope rearrangement provides efficient atom economic access to 2-allyl-3-oxazolin-5-one derivatives. Extension to a triple domino process, in which the above process is combined with in situ azlactone formation starting from amino acids renders this process even more attractive. Subsequent thermolysis of the 2-allyl-3-oxazolines enabled the de novo synthesis of trisubstituted pyridines.

Full text of DOI:10.1002/anie.201704022

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Rhodium-Catalyzed Regioselective Domino Azlactone-Alkyne
Coupling/Aza-Cope Rearrangement: A Facile Access to 2-Allyl-3-
oxazolin-5-ones and Trisubstituted Pyridines
Authors: Bernhard Breit, Jinqiang Kuang, and Shaista Parveen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704022
Angew. Chem. 10.1002/ange.201704022
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10.1002/anie.201704022
Angewandte Chemie International Edition
COMMUNICATION
Rhodium-Catalyzed Regioselective Domino Azlactone-Alkyne
Coupling/Aza-Cope Rearrangement: A Facile Access to 2-Allyl-3-
oxazolin-5-ones and Trisubstituted Pyridines
Jinqiang Kuang, Shaista Parveen, and Bernhard Breit*
Previous work
Abstract: A merged rhodium-catalyzed regioselective addition of
azlactones to internal alkynes/aza-Cope rearrangement provides
efficient atom economic access to 2-allyl-3-oxazolin-5-one
derivatives. Extension to a triple domino process combining the
above process with an in situ azlactone formation starting from
a)
R
Nu
*
or
or
[Rh]/ligand
NuH
Me
R
R
R
amino acids renders this process even more attractive.
A
subsequent thermolysis of the 2-allyl-3-oxazolines enabled a de
novo synthesis of trisubstituted pyridines.
NuH = C-, N-, O-, and S- pronucleophiles
This work
R2
N
C-2
O
R2
N
R2
We recently reported a series of Rhodium-catalyzed regio- and
stereoselective coupling reactions of allenes and alkynes with
diverse N-, O-, S-, and C-pronucleophiles, efficiently achieving
b)
R3
O
O
[Rh]
aza-Cope
O
C-4
N
R1
R3
rearrangement
O
O
+
Me
R1
R1
R3
R3
R1
hydroamination,
hydrooxycarbonylation,
hydroalkoxylation,
hydrothiolation, and hydrocarbonation to access branched allylic
products.[1,2] These reactions represent facile and more
importantly atom-economic surrogates for traditional allylic
substitution methodology (Scheme 1, a).[3-7] To further expand
the synthetic potential of this methodology, we envisioned
involving azlactones as pronucleophiles. Azlactones (oxazol-5-
(4H)-ones), which represent “masked” amino acids, are
attractive coupling partners in terms of their potential for
synthetical applications highlighted in the synthesis of natural or
synthetic bioactive molecules.[8] We hypothesized that
synthetically and pharmaceutically useful 2-allyl-3-oxazolin-5-
one derivatives are more likely obtained over the isomeric 4-
allyl-2-oxazolin-5-one derivatives, since the latter is prone to
undergo a subsequent aza-Cope rearrangement as a tandem
process under the appropriate reaction conditions.[9,10]
Pyridines are an important class of heterocycles existing in
diverse natural and bio-active molecules, pharmaceuticals,
materials, and privileged ligands in organic synthesis.[11] Many
methods for their de novo synthesis are well established.[12]
Nevertheless, the development of facile and efficient methods
with broad functional group tolerance is still in demand.
Herein we report on a domino rhodium-catalyzed highly
regioselective addition of azlactones to internal alkynes/aza-
cope rearrangement, giving a facile access to 2-allyl-3-oxazolin-
5-on derivatives (Scheme 1, b) and their subsequent
transformation to trisubstituted pyridines.
Δ
R2
- CO2
N
Scheme 1. Rhodium-catalyzed coupling of allenes and alkynes with diverse
pronucleophiles.
We speculated that addition of a proper acid might facilitate
the reaction according to our previous experience.[1,2] Indeed,
addition of diphenylacetic acid improved the yield of 3 to 96%,
while addition of benzoic acid, pyridinium p-toluenesulfonate
(PPTS), and p-toluenesulfonic acid led to inferior results (Table
1, entries 2-5). Besides DCE, dichloromethane (DCM) and
acetonitrile also work well as solvent in the reaction, affording
the product 3 in 87% and 74% NMR yield, respectively (Table 1,
entries 6 and 7). The amount of 1-phenyl-1-propyne (2a) could
be further decreased to 1.5 equivalents when the reaction was
carried out at 60 °C, furnishing 3 in 98% NMR yield (94%
isolated yield) (Table 1, entry 11).
Table 1 Optimization of the reaction conditions.
Ph
N
Ph
N
Ph
O
[Rh(COD)Cl]2 (1 mol%)
DPEphos (2 mol%)
C-2
O
Ph
+
Me
O
N
+
Ph2CHCOOH (10 mol%)
solvent, 50 oC, 18 h
Ph
2a, X equiv
Ph
O
O
O
C-4
Ph
Ph
Ph
Initial reactivity assays were conducted with 2,4-
diphenyloxazol-5(4H)-one (1a, 0.2 mmol) and 1-phenyl-1-
propyne (2a, 2 equiv) as privileged substrates. To our delight in
the presence of [Rh(COD)Cl]2 (1 mol%), and DPEphos (2 mol%)
in dichloroethane (DCE) at 50 °C (Table 1, entry 1) the desired
tandem product 3 was obtained in 74% yield, along with 4% of
the linear C4 allylation product 4.
1a, 0.2 mmol
3a
major product
4a
minor product
Entry
X
Solvent
DCE
DCE
DCE
DCE
DCE
DCM
CH3CN
toluene
THF
Conversion
Yield of 3a
Yield of 4a
(%)
85
100
69
74
100
92
97
42
59
97
(%)[a]
74
96
60
57
36
87
74
27
42
95
(%)[a]
1[b]
2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.5
1.2
4
2
2
7
4
3
2
3
5
2
2
2
3[c]
4[d]
5[e]
6
7
8
9
10
11 [f]
12 [f]
[*]
Dr. J. Kuang, S. Parveen, Prof. Dr. B. Breit
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg,
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany).
E-mail: bernhard.breit@chemie.uni-freiburg.de
DCE
DCE
DCE
100
88
98 (94[g]
77
)
[a] 1H NMR yield using 1,3,5-trimethylbenzene as internal standard. [b] No
Supporting information for this article is given via a link at the end of
the document.
acid was added. [c] 10 mol% of PhCOOH instead of Ph2CHCOOH was added.
[d] 10 mol% of PPTS instead of Ph2CHCOOH was added. PPTS
=
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10.1002/anie.201704022
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COMMUNICATION
Ph
N
Ph
O
Ph
N
C-2
O
[Rh(COD)Cl]2 (4.5 mol%)
DPEphos (9 mol%)
pyridinium 4-toluenesulfonate [e] 10 mol% of TsOHxH2O instead of
Ph2CHCOOH was added. [f] The reaction was carried out at 60 °C. [g] Isolated
yield.
nC5H11
Me
O
N
+
+
Ph2CHCOOH (10 mol%)
nC5H11
O
O
O
C-4
Ph
Ph
nC5H11
4q, 80% (NMR)(dr = 3.7:1)
1a
1.5 equiv
DCE, rt, 23 h
3q, 8% (NMR)
DCE, 60 °C, 16 h
4q, 23% (NMR) (dr<1:20)
3q, 77% (NMR)
22% (isolated)
66% (isolated)
With the optimal conditions in hand, we then examined the
generality of the protocol applying various internal alkynes and
azlactones (Table 2). Aryl methyl alkynes bearing either
electron-donating or electron-withdrawing substituents on the
aromatic ring, including methoxy, fluoro, chloro, bromo, nitro,
acetyl, and formyl groups were compatible, and provided the
desired products in good to excellent yields (Table 2, 3a-3l).
Interestingly, internal alkynes substituted with thienyl and ester
functional groups were well tolerated, yielding products 3m and
3n in 87% and 51% yield, respectively. Moreover, azlactone
bearing a bulkier naphthyl group at C-4 position reacted well
with alkyne 2a, furnishing 3o in almost quantitative yield.
Scheme 2 Rhodium-catalyzed coupling of 1a with 2-octyne.
To improve utility of the method, we envisioned to explore a
combination of in situ azlactone formation from the
corresponding N-acyl amino acid with the new tandem process.
To our delight, in merely adding acetic anhydride (1.1 equiv) and
using DCM instead of DCE as solvent based on the above
conditions, various amino acids 5 reacted with alkyne 2a
efficiently to give products 3a, 3p, and 3r-3u (Table 3),
proceeding through tandem azlactone formation/azlactone-
alkyne coupling/aza-Cope rearrangement. 3-Oxazolin-5-one
embedded with a methyl group along with linear allylic group at
the C-2 position was also afforded, albeit in a low yield (Table 3,
3v).
Table 2 Substrate scope of the rhodium-catalyzed domino azlactone-alkyne
coupling/aza-Cope rearrangement.[a]
R2
N
R2
R2
[Rh(COD)Cl]2 (x mol%)
DPEphos (y mol%)
R3
+
C-2
O
Me
O
O
N
Table
rearrangement.[a]
3 Domino azlactone formation/azlactone-alkyne coupling/aza-Cope
+
N
Ph2CHCOOH (10 mol%)
DCE, 60 oC, 18 h
R3
R3
O
O
O
R1
C-4
R1
R1
1
2
3
4
R
R
O
R
major product
minor product
[Rh(COD)Cl]2 (x mol%)
DPEphos (y mol%)
Me
Ph
+
O
O
R=H
3a, 94%[b] (x= 1; y= 2)
3a / 4a > 95 / 5[c]
HOOC
NH
N
N
R= CF3
R=NO2
3f, 80% (x= 4; y= 8)
3f / 4f = 93 / 7
3g, 98% (x= 4; y= 8)
3g / 4g > 95 / 5
+
Ph
Ac2O (1.1 equiv)
DCM, 60 oC, 18 h
Ph
O
O
Ph
Ph
Ph
R= OMe 3b, 92% (x= 4; y= 8)
3b / 4b > 95 / 5
Ph
O
5
2a, 1.5 equiv
3
4
R= COMe 3h, 90% (x= 4; y= 8)
3h / 4h = 92 / 8
R= CHO 3i, 84% (x= 4; y= 8)
3i / 4i = 88 / 12
major product
minor product
R= Br
R= Cl
R= F
3c, 80% (x= 4; y= 8)
3c / 4c = 95 / 5
3d, 98% (x= 4; y= 8)
3d / 4d > 95 / 5
3e, 90% (x= 4; y= 8)
3e / 4e > 95 / 5
N
Me
F3C
Cl
R
O
Ph
R= Ph
3j, 90% (x= 4; y= 8)
3j / 4j = 95 / 5
Ph
Ph
Ph
Ph
Ph
O
O
O
O
N
N
N
N
Ph
O
Ph
O
Ph
O
O
O
O
Ph
Ph
Ph
Ph
O
N
N
N
S
3a, quant.[b] (x= 2; y= 4) 3p, 95% (x= 2; y= 4)
3a / 4a > 95 / 5[c]
3r, 80% (x= 4; y= 8)
3r / 4r > 95 / 5
3s, 89% (x= 4; y= 8)
3s / 4s > 95 / 5
Me
O
O
O
3p / 4p > 95 / 5
Me
Ph
Ph
Ph
MeO
Br
3m, 87% (x= 4; y= 8)
3m / 4m = 91 / 9
3l, 83% (x= 4; y= 8)
3l / 4l = 89 / 11
3k, 89% (x= 1; y= 2)
3k / 4k > 95 / 5
Me
O
Me
Ph
Ph
Ph
O
O
N
Ph
N
N
O
O
O
Ph
Ph
Ph
CO2Me
Ph
Ph
O
O
O
3t, 95% (x= 4; y= 8)
3t / 4t > 95 / 5
3u, 74% (x= 4; y= 8)
3u / 4u = 81 / 19
3v, 27% (x= 2; y= 4)
3v / 4v > 95 / 5
N
N
N
O
O
O
Ph
Ph
Ph
[a] N-Acyl amino acid 5 (0.2 mmol), 2a (0.3 mmol), [Rh(COD)Cl]2 (x mol%),
DPEphos (y mol%), Ac2O (0.22 mmol), DCM (0.6 mL). [b] Isolated yield. [c]
The 3/4 ratio was determined by 1H NMR spectroscopy of the crude reaction
mixture using 1,3,5-trimethylbenzene as internal standard.
3p, 98% (x= 1; y= 2)
3p /4p > 95 / 5
3n, 51% (x= 4; y= 8)
3n / 4n > 95 / 5
3o, 99% (x= 2; y= 4)
3o / 4o > 95 / 5
[a] 1 (0.2 mmol), 2 (0.3 mmol), [Rh(COD)Cl]2 (x mol%), DPEphos (y mol%),
Ph2CHCOOH (0.02 mmol), DCE (0.6 mL). [b] Isolated yield. [c] The 3/4 ratio
was determined by 1H NMR spectroscopy of the crude reaction mixture using
1,3,5-trimethylbenzene as internal standard.
To test the practicality of the methodology for 2-allyl-3-
oxazolin-5-one derivatives synthesis, compound 3a was
synthesized in 1.3 gram scale with 86% isolated yield (Eq. 1).
In case of 2-octyne, the corresponding branched C-4
product was also observed besides the linear C-2 product
(Scheme 2). Compared with the reaction performed at room
temperature, the yield of branched C-4 product 4q decreased
and those of the linear C-2 product 3q increased at 60 °C. At
this point the major diastereomer of the C-4 branched product
diminished and the minor one retained while raising temperature,
which gives preliminary insights in the reaction mechanism.[10c]
Ph
N
Ph
O
[Rh(COD)Cl]2 (1 mol%)
DPEphos (2 mol%)
Ph
Me
O
(1)
+
N
Ph2CHCOOH (10 mol%)
DCE, 60 oC, 23 h
Ph
O
O
Ph
Ph
4.2 mmol, 1.0 g
3a: 86% (1.3 g)
1.5 equiv
2-Allyl-3-oxazolin-5-one derivatives 3 might undergo carbon
dioxide extrusion upon thermolysis to yield a nitrile ylide
intermediate, which after an internal reorganization and
oxidation might furnish trisubstituted pyridines [10a] (Scheme 3).
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10.1002/anie.201704022
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COMMUNICATION
Based on our previous investigations,[1,2]
a plausible
R2
R2
R3
120 oC (MW)
xylene, 1.5 h
O
mechanism for the reaction is depicted in Scheme 5. Internal
alkyne 2 undergoes hydrometallation to form vinyl rhodium
species B, which then produces allene 2' through β-H
elimination. Hydrometallation of allene 2' yields π-allyl rhodium
complex C, which is in an equilibrium with its σ-allyl isomer C'.
The allylic carbon in complex C is supposedly attacked by the
azlactone nucleophile through its enol form to release branched
allylic product 4' and regenerate the rhodium hydride. However,
there is also the possibility for an inner sphere process as
observed for other pronucleophiles.[1] Finally, product 3 is
formed by a subsequent aza-Cope rearrangement of 4'.
N
N
R3
O
R1
R1
- CO2
oxidation
H
H
R2
R2
R2
N
N
N
R3
R3
R3
R1
R1
R1
Scheme 3 Thermal carbon dioxide extrusion and rearrangement to pyridine
including a mechanistic rationale.
R2
O
Indeed, a simple sequential protocol for the synthesis of
2,3,6-trisubstituted pyridines was developed. Thus, after the
rhodium-catalyzed domino azlactone-alkyne coupling/aza-Cope
rearrangement microwave heating in xylene furnished pyridines
with three distinct substituents (6c and 6d, Table 4).[12]
R2
R3
[3,3’]
O
N
N
O
O
O
R1
Ph
N
R1
Me
3
4’
R3
Ph
N
2
R3
O
O
Table 4 Sequential protocol for the synthesis of 2,3,6-trisubstituted pyridines.a
HO
Ph
Ph
[Rh]X
[Rh]X
1) [Rh(COD)Cl]2 (4 mol%)
H[Rh]X
R2
N
DPEphos (8 mol%)
Ph2CHCOOH (10 mol%)
DCE, 60 oC, 18 h
2) xylene, 120 oC (MW)
1.5 h
R2
R3
B
H
H
R3
[Rh]X
R3
A
Me
C'
C
O
H
+
N
R3
R3
O
R1
R1
1
2
6
R3
2'
N
N
Scheme 5 Proposed reaction mechanism.
To conclude, we have established a mild and efficient
method for the regioselective addition of azlactones to internal
alkynes and following aza-Cope rearrangement for the
construction of synthetically useful N,O-acetal derivatives.
Moreover, based on this, a sequential methodology for the de
novo synthesis of structurally appealing trisubstituted pyridines
has been developed as well. Further mechanistic studies and
elaboration of the method is being pursued in our laboratory.
6a, 89%
6b, 69%
N
N
S
F
6d, 78%
6c, 80%
[a] 1 (0.25 mmol), 2 (0.375 mmol), [Rh(COD)Cl]2 (0.01 mol), DPEphos (0.02
Acknowledgements
mol), Ph2CHCOOH (0.025 mmol), DCE (1.0 mL), xylene (1.0 mL).
This work was supported by the DFG and the Fonds of the
Chemical Industry. We thank Umicore, BASF, and Wacker for
generous gifts of chemicals. S.P. thanks the DAAD for a
fellowship.
The above protocol was also successfully applied to the
tandem azlactone formation/azlactone-alkyne coupling/aza-
Cope rearrangement (Scheme 4).
1) [Rh(COD)Cl]2 (4 mol%)
Br
Br
DPEphos (8 mol%)
Ac2O (1.1 equiv)
DCM, 60 oC, 18 h
Keywords: alkynes • rhodium • aza-Cope rearrangement •
Me
O
domino reactions • pyridines • azlactones
+
Ar
2) xylene, 120 oC (MW)
1.5 h
HOOC
NH
Ph
N
Ar
Ph
1.5 equiv
[1]
[2]
For a recent review, see: P. Koschker, B. Breit, Acc. Chem. Res. 2016,
49, 1524–1536.
Br
Br
Br
a) P. Spreider, A. Haydl, M. Heinrich, Angew. Chem. Int. Ed. 2016, 55,
15569-15573; Angew. Chem. 2016, 128, 15798-15802; b) T. M. Beck,
B. Breit, Eur. J. Org. Chem. 2016, 93, 5839-5844. c) N. Thieme, B.
Breit, Angew. Chem. Int. Ed. 2017, 56, 1520-1524; Angew. Chem. 2017,
129, 1542-1546; d) T. M. Beck, B. Breit, Angew. Chem. Int. Ed. 2017,
56, 1903-1907; Angew. Chem. 2017, 129, 1929-1933; e) J. Schmidt, C.
Li, B. Breit, Chem. Eur. J. 2017, 23, 6531-6534; f) V. Khakyzadeh, Y.-
H. Wang, B. Breit, Chem. Commun. 2017, 53, 4966-4968; g) S.
Parveen, C. Li, A. Hassan, B. Breit, Org. Lett. 2017, 19, 2326-2329.
N
N
N
Ph
6e, 49%
Ph
Ph
6g, 52%
S
Ph
F
6f, 60%
Scheme
4 Sequential protocol for the synthesis of 2,3,6-trisubstituted
pyridines starting form N-acyl amino acids.
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10.1002/anie.201704022
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COMMUNICATION
[3]
[4]
For reviews on transition-metal-catalyzed allylic substitutions, see: a) B.
M. Trost, Chem. Rev. 1996, 96, 395-422; b) B. M. Trost, M. L. Crawley,
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[7]
For selected examples on other transition metal catalyzed branch-
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10.1002/anie.201704022
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J. Kuang, S. Parveen, B. Breit*
Page No. – Page No.
Rhodium-Catalyzed Regioselective
Domino Azlactone-Alkyne
Coupling/Aza-Cope Rearrangement:
A Facile Access to 2-Allyl-3-oxazolin-
5-ones and Trisubstituted Pyridines
A triple domino process involving in situ azlactone formation/rhodium-catalyzed alkyne
coupling and aza-Cope rearrangement furnished in one step useful 2-allyl-3-oxazoline-5-
ones. Their thermolysis results in a de novo pyridine synthesis.
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