Synthesis of 2-oxazolones and α-aminoketones via palladium-catalyzed reaction of β,β-dibromoenamides

Article abstract of DOI:10.1021/ol102634c

β,β-Dibromoenamides show two different interesting reactivities based on the choice of R group under the reaction conditions. On the basis of mechanistic studies, both reactions proceed via an intermolecular Suzuki-Miyaura C-C coupling and an intramolecular C-O coupling.

Full text of DOI:10.1021/ol102634c

ORGANIC
LETTERS
2011
Vol. 13, No. 1
106-109
Synthesis of 2-Oxazolones and
r-Aminoketones via Palladium-Catalyzed
Reaction of ꢀ,ꢀ-Dibromoenamides
David I. Chai, Laura Hoffmeister, and Mark Lautens*
DaVenport Research Laboratory, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, Canada, M5S 3H6
mlautens@chem.utoronto.ca
Received October 30, 2010
ABSTRACT
ꢀ,ꢀ-Dibromoenamides show two different interesting reactivities based on the choice of R group under the reaction conditions. On the basis
of mechanistic studies, both reactions proceed via an intermolecular Suzuki-Miyaura C-C coupling and an intramolecular C-O coupling.
gem-Dihaloolefins have been important and versatile building
blocks in palladium-catalyzed tandem reactions allowing the
synthesis of ynamides, indoles, benzofurans, benzothiophenes,
and other heterocycles.1,2 However, nitrogen-substituted gem-
dihaloolefins have received less attention in this class of
transformation. A growing interest in the synthesis of
nitrogen-containing cyclic and acyclic systems is relevant
in the fields of chemistry, biochemistry, pharmaceutical
science, and material science.3
has recently grown, owing to their pharmacological activities
and as important intermediates in organic synthesis.
Cossy first reported the intermolecular Suzuki coupling of
ꢀ,ꢀ-dibromoenamides6 with boronic acids using Pd(PPh3)4 as
catalyst to give trisubstituted alkenes,5 but not via a tandem
a
process. We initially considered that ꢀ,ꢀ-dibromoenamides 1
and 2 would lead to interesting nitrogen-containing heterocyclic
compounds such as 3-substituted indoles 3 via double participa-
tion of the carbamate (R ) OtBu) or amide (R ) tBu) group.
Interestingly, we could observe the formation of compound 4
and 5 from 1 and 2, respectively7 (Scheme 1).
We initially assessed catalyst activity by conducting the
coupling of ꢀ,ꢀ-dibromoenamide 1a with phenylboronic acid.
After varying several parameters, we found that a Buchwald’s
Herein, we describe the development of new reactivity of
ꢀ,ꢀ-dibromoenamides to generate 2-oxazolones and R-ami-
noketones. Interest in 2-oxazolones4 and R-aminoketones5
(1) (a) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549. (b) Fang,
Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem. 2007, 72, 5152. (c) Sun, C.;
Xu, B. J. Org. Chem. 2008, 73, 7361. (d) Viera, T. O.; Meaney, L. A.; Shi,
Y.-L.; Alper, H. Org. Lett. 2008, 10, 4899. (e) Arthuls, M.; Pontikis, R.;
Florent, J.-C. Org. Lett. 2009, 11, 4608. (f) Bryan, C. S.; Braunger, J. A.;
Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 7064. (g) Chai, D.; Lautens,
M. J. Org. Chem. 2009, 74, 3054, and references therein. (h) Newman,
(4) (a) Nam, N.-H.; Kim, Y.; You, Y.-J.; Hong, D.-H.; Kim, H.-M.;
Ahn, B.-Z. Bioorg. Med. Chem. Lett. 2001, 11, 3073–3076. (b) Kudo, N.;
Taniguchi, M.; Furuta, S.; Sato, K.; Endo, T.; Honma, T. J. Agric. Food
Chem. 1998, 46, 5305–5312.
S. G.; Lautens, M. J. Am. Chem. Soc. 2010, 132, 11416
.
(5) Hanada, M.; Sugawara, K.; Koko, K.; Toda, S.; Nishiyama, Y.;
Tomita, K.; Yamamoto, H.; Konishi, M.; Oki, T. J. Antibiot. 1992, 45,
1746.
(2) For other coupling reactions of dibromides, see: (a) Evano, G.; Coste,
A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840, and references cited
therein. (b) Berciano, B. P.; Lebrequier, S.; Besselie`vre, F.; Piguel, S. Org.
Lett. 2010, 12, 4038. (c) Xu, H.; Zhang, Y.; Huang, J.; Chen, W. Org. Lett.
(6) For synthesis of dihalovinylamine, see: (a) Couty, S.; Barbazanges,
M.; Meyer, C.; Cossy, J. Synlett 2005, 6, 905. (b) Bru¨ckner, D. Tetetra-
hedron 2006, 62, 3809.
2010, 12, 3704
.
(3) (a) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155. (b) Cacchi, S.;
Fabrizi, G. Chem. ReV. 2005, 105, 2873. (c) Luo, J.-K.; Federspiel, R. F.;
Castle, R. N. J. Heterocycl. Chem. 1997, 34, 1597, and references cited
therein. (d) Sata, N. U.; Sugano, M.; Matsunaga, S.; Fusetani, N.
Tetrahedron Lett. 1999, 40, 719–722.
(7) The gem-dibromination of formamides only works when an N-
carbonyl protecting group on the formamide is present. Thus, ꢀ,ꢀ-dibro-
moenamides having a Boc or Piv group can be prepared. However, attempts
to react other carbonyl protecting groups such as methylformyl (-COOMe)
or benzoyl groups failed.
10.1021/ol102634c  2011 American Chemical Society
Published on Web 12/02/2010

Scheme 1
.
Reactivity of gem-Dibromovinyl Systems
Table 2. Reaction Scope of Pd-Catalyzed Oxazolone Synthesis
Varying Substituents on 1
entrya
starting material
product
yield (%)b
1
2
3
4
5
6
7
8
9
1a (R ) Ph)
1b (R ) Bn)
4a
4b
4c
4d
4e
4f
4g
4h
4i
80
80c
c
1c (R ) 4-CF3(C6H4)
1d (R ) 4-MeO(C6H4))
1e (R ) Me)
1f (R ) -(CH2)2Ph)
1g (R ) 2-F(Bn))
1h (R ) cyclohexyl)
1i (R ) CH(CH3)Ph)
-
75c
54c
66c
82c
94d
catalyst Pd-18 in dioxane at 100 °C with K3PO4/Et3N as bases
formed 2-oxazolone 4a in good yield in 12 h (Table 1, entry 4).
91d e
,
Table 1. Initial Observations
a Reactions were conducted with 1 (0.3 mmol), boronic acid (0.45
mmol), palladium (6 mol %), K3PO4 (0.6 mmol), Et3N (0.1 mL), and dioxane
(8 mL) at 100 °C for 14 h. b Isolated yield. c Identical result obtained with
either 1.5 or 3 equiv of phenylboronic acid. d 3 equiv of boronic acids was
used. e Chiral 1i with 98% ee provided 4ie in 98% ee.
Table 3. Reaction Scope of Pd-Catalyzed Oxazolone Synthesis
Varying Boronic Acids
starting
entrya material
Pd/ligand
base
product yieldb (%)
1
2
3
4
5
6
7
1a
1a
1a
1a
2a
2b
2b
Pd(OAc)2/S-Phos K2CO3
4a
4a
4a
4a
5a
5b
5b
trace
45
Pd(OAc)2/S-Phos K3PO4/Et3N
yield
PdCl2/S-Phos
Pd-1
K3PO4/Et3N
K3PO4/Et3N
K3PO4/Et3N
K3PO4/Et3N
K2CO3
61
entrya
starting material
R′
product (%)b
80
c
Pd-1
-
1
2
3
4
5
6
7
8
1b (R ) Bn)
Ph
4b
80c
50
56
65
50
41
Pd-1
55
72
1b
1b
1b
1b
1b
2-Me(C6H4)
3-Me(C6H4)
4-Me(C6H4)
4-F(C6H4)
4ba
4bb
4bc
4bd
4be
4i
4ia
4ib
4ic
4id
4ie
4if
PdCl2/S-Phos
a Reactions were conducted with 1 (0.15 mmol), boronic acid (0.225 mmol),
palladium (6 mol %), ligand (12 mol %), base (0.45 mmol), Et3N (0.05 mL, if
applicable), dioxane (4 mL for 3 or 2 mL for 4), and water (0.3 mmol, if
applicable) at 100 °C for 14 h. b Isolated yield. c 30% conversion.
4-MeO(C6H4)
,
1i (R ) CH(CH3)Ph) Ph
91d e
84d
25d
80d
75d
72d
1i
1i
1i
1i
1i
1i
1i
1i
1i
1i
2-Me(C6H4)
However, the coupling of ꢀ,ꢀ-dibromoenamide 2a under
the same reaction conditions provided <30% conversion to
compound 5a (Table 1, entry 5). On the other hand, the
coupling of the ꢀ,ꢀ-dibromoenamide 2b possessing a benzyl
group provided the aminoketone 5b in moderate yield. We
found that a combination of PdCl2 and S-Phos allowed an
efficient synthesis of the R-aminoketone 5b with K2CO3 as
base (Table 1, entry 7). In both cases, reactions without
boronic acids sometimes showed a trace amount of akynes,
when employing stronger bases such as KOtBu.
9
2,6-diMe(C6H3)
4-Me(C6H4)
4-F(C6H4)
4-OMe(C6H4)
(E)-2-styryl
3-thienyl
2-MeO(C6H4)
4-CF3(C6H4)
3-Cl(C6H4)
10
11
12
13
14
15
16
17
49d f
,
4ig
4ih
4ii
87d
73d
76d
86d
4ij
a Reactions were conducted with 1 (0.3 mmol), boronic acid (0.45 mmol),
palladium (6 mol %), K3PO4 (0.6 mmol), Et3N (0.1 mL), and dioxane (8 mL) at
100 °C for 14 h. b Isolated yield. c Identical result obtained with either 1.5 or 3
equiv of phenylboronic acid. d 3 equiv of boronic acids was used. e Chiral 1i with
98% ee provided 4ie in 98% ee. f 46% of bis-Suzuki coupling product 4if′ isolated.
Reactions of a series of ꢀ,ꢀ-dibromoenamide 1 and boronic
acids were examined under the optimized conditions (Tables
2 and 3). Both alkyl and aromatic substituents on nitrogen
were tolerated under these conditions. However, the electron-
poor amine system 1c was ineffective in this reaction,
(8) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008,
130, 6686.
Org. Lett., Vol. 13, No. 1, 2011
107

providing evidence that the cyclization requires the electron-
rich carbamate functional group, presumably due to its high
nucleophilicity (Table 2, entry 3). Excellent yields were
obtained with increasing steric hindrance (Table 2, entries
2, 5, 8, and 9), presumably because the carbon-bearing
bromines and the carbamate group become closer by steric
interactions between the R group and the OtBu group.
However, reactions with sterically hindered substrates re-
quired excess boronic acids in order to achieve full conver-
sion (Table 2, entries 13 and 14).
A variety of electron-rich, electron-poor, and sterically
hindered boronic acids were also effective under the
optimized conditions (Table 3). It is worth noting that the
chiral substrate 1i can be used in this transformation
without stereochemical scrambling at the chiral center
(Table 3, entry 7).
esized that the ketone formation proceeds by a participation
of the amide carbonyl group. Steric minimization between
the large R group and the tBu group in 2h seems to favor a
conformation in which the amide oxygen points away from
the reactive dibromide side. This conformation significantly
inhibits the reaction due to the restricted amide group
participation (Table 4, entry 19).
To explore if the amide participates in the reaction, we
performed an 18O-labeling experiment (eq 1). When the reaction
between 2e and potassium phenyl-tetrafluoroborate salt was
conducted in H2O18/dioxane (1:10), 18O was found in the amide
carbonyl group as clearly identified by IR analysis (1604.8 cm-1
(CdO18) vs 1635.7 cm-1 (CdO16), see the Supporting Informa-
tion for IR data). This result supports participation9 of the amide
group during the reaction, presumably through a cyclic oxo-
palladium intermediate.
We probed the scope of the reactions using substrate 2.
Once again, electron -rich, electron-poor, and sterically
hindered boronic acids coupled under the optimized condi-
tions (Table 4, entries 4-13, see the Supporting Information
Table 4. Reaction Scope of R-Aminoketone Synthesis
To study the mechanism further, 1i-D and 2b-D were
subjected to each of the reaction conditions (eqs 2 and 3).
The experiments gave 4i-D and 5b-D1 each with 98%
deuterium incorporated. These results eliminate the alkyne
from the reaction pathway.10 Interestingly, the use of D2O
for the coupling of 2b-D and phenylboronic acid resulted in
deuterium incorporation up to 80% (eq 3).
yield
entrya
starting material
2a (R ) Ph)
2a′ (R ) 4-OMe(C6H4)) Ph
2a′′ (R ) 4-NO2(C6H4)) Ph
2b (R ) Bn)
2b
2b
2b
2b
2b
R′
product (%)b
c
1
2
3
4
5
6
7
8
Ph
5a
5a′
5a′′
5b
5ba
5bb
5bc
5bd
5be
-
-
-
c
c
Ph
72
50
53
74
36
61
50
75
40
57
57
83
65
65
85
2-Me(C6H4)
3-Me(C6H4)
4-Me(C6H4)
2-Cl(C6H4)
4-F(C6H4)
9
10
11
12
13
14
15
16
17
18
19
2b
2b
2b
2b
2-F,4-Me(C6H3) 5bf
4-MeO(C6H4)
3-TMS(C6H4)
3-thienyl
Ph
5bg
5bh
5bi
5c
5d
5e
5f
5g
5h
2c (R ) Me)
2d (R ) 2-F(C6H4)CH2) Ph
2e (R ) 2-Cl(C6H4)CH2) Ph
2f (CH2CH2Ph)
2g (CH2CH2COOEt)
A number of experiments were planned to elucidate the order
of coupling by subjecting potential intermediates 6 and 7 to
the reaction conditions (Figure 1). Unfortunately, these inter-
mediates could not be prepared by a variety of synthetic
procedures.
Ph
Ph
Ph
c
2h (CH(CH3)Ph)
-
t
a Reactions were conducted with 2 (0.3 mmol), boronic acid (0.45
mmol), PdCl2 (6 mol %), S-Phos (12 mol %), K2CO3 (0.9 mmol), H2O (2
- 3 equiv), and dioxane (4 mL) at 100 °C for 14 h. b Isolated yield. c Starting
material recovered.
Initial cis-activation of 2 (R ) Bu) could lead to acyl
bromides 9, which decompose to the corresponding car-
boxylic acids (Figure 1). Since the carboxylic acids were
not observed during the reactions, the intermediate 9 (Figure
(9) Momiyama, N.; Kanan, M. W.; Liu, D. R. J. Am. Chem. Soc. 2007,
129, 2230.
for an X-ray crystal structure of 5b). However, unlike the
reactions of 1, no ketone products were observed when aryl-
substituted (Table 4, entries 1, 2, and 3) or sterically hindered
substrates were employed (Table 4, entry 19). We hypoth-
(10) The product 5-bD1 can undergo H/D exchange under the reaction
conditions. If H/D exchange happens, it is probably not possible to get
98% D on 5b-D1. In fact, reaction of 5b with 2 equiv of D2O did not undergo
H/D exchange under the reaction conditions.
108
Org. Lett., Vol. 13, No. 1, 2011

into the oxopalladium complex 13 via 12. This intermediate
13 subsequently undergoes reductive C-O coupling to give
the final 2-oxazolone product 4. Alternatively, cis-oxidative
addition of compound 1 or the cis-trans isomerization12 of
10 to 14 and subsequent C-O coupling results in 4-bromo-
2-oxazolone 16, which undergoes the Suzuki-Miyaura
coupling to provide the final product 4.
t
However, if R ) Bu on 1, the complex 18, which is
obtained from oxidative addition to 11 (R ) tBu), transforms
into the cationic oxo-palladium species 19. This cationic
complex 19 provides an intermediate 20 via nucleophilic
attack of water. Finally, reductive elimination of this
intermediate 20 provides compound 5 by decomposition13
of the amide hemiacetal 21, followed by protonation.
In summary, we have described a general and efficient
method for the synthesis of 2-oxazolones and R-aminoke-
tones from ꢀ,ꢀ-dibromoenamides and boronic acids using a
Pd(0) catalyst. The results of the mechanistic studies for the
2-oxazolone synthesis showed two possible pathways (trans-
and cis-activation), but those for the R-aminoketone synthesis
revealed one pathway in which the amide oxygen is
transferred to the vinyl group, later becoming the ketone
functional group. Thus, both reactions proceed via the
intermolecular Suzuki-Miyaura coupling/intramolecular C-O
coupling. These findings reveal cis-bromo-N-vinylamines 11
as precursors for cyclic oxopalladium intermediates such as
13 and 20 that can undergo intramolecular C-O coupling.
Figure 1. Potential intermeidates for 2-oxazolone and R-aminoke-
tone synthesis.
1) does not appear on the reaction pathway for R-aminoke-
tone synthesis.
The proposed mechanisms for 2-oxazolone and R-ami-
noketone synthesis are illustrated in Scheme 2. Pd(0) first
Scheme 2. Proposed Mechanisms
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council (NSERC), Merck for an
Industrial Research Chair, and the University of Toronto for
financial support.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL102634C
undergoes oxidative addition into the trans-C-Br bond of
1.11 The resulting intermediate 10 couples with boronic acid
to give the intermediate 11 (R ) OtBu), which transforms
(12) While two signals at 46.8 and 52.5 ppm (31P NMR) were initially
observed in 1:1 ratio at 60 °C, the signal at 46.8 ppm slowly disappeared.
We believe that these two signals correspond to trans- and cis-vinylpalla-
dium 10 and 14. See the Supporting Information for details.
(13) For hydrolysis of cyclic amide hemiacetals, see: (a) Marinelli, E. R.;
Johnson, F.; Iden, C. R.; Yu, P. L. I. Chem. Res. Toxicol. 1990, 3, 49. (b)
Vorbruggen, H.; Krolikiewicz, K. Tetrahedron 1993, 49, 9.
(11) (a) Shi, J.; Zeng, X.; Negishi, E. Org. Lett. 2003, 5, 1825. (b)
Negishi, E.; Shi, J.; Zeng, X. Tetrahedron 2005, 61, 9886.
Org. Lett., Vol. 13, No. 1, 2011
109