Carbonylation of propargyl carbamates with palladium(II) bisoxazoline catalysts: Efficient synthesis of 5-methoxy-3(2H)-furanones

Article abstract of DOI:10.1002/anie.201303684

Palladium and CO: Carbonylation of 1 with [Pd(tfa)₂(±)- L1] (tfa=trifluoroacetate) affords the spirofuranone 2 with inversion of the stereochemistry at C17 in 96 % yield. C17-epi-1 also gave the same product 2 with retention of the stereochemistry at C17. Labelling studies show that ¹³CO was incorporated into the C5′ position of the furanone ring. The first asymmetric version of this new reaction was achieved. Copyright

Full text of DOI:10.1002/anie.201303684

Angewandte
Chemie
Communications
Synthetic Methods
T. Kusakabe, T. Takahashi, R. Shen,
A. Ikeda, Y. D. Dhage, Y. Kanno, Y. Inouye,
H. Sasai, T. Mochida,
K. Kato*
&&&& — &&&&
Carbonylation of Propargyl Carbamates
with Palladium(II) Bisoxazoline Catalysts:
Efficient Synthesis of 5-Methoxy-3(2H)-
furanones
Palladium and CO: Carbonylation of
1 with [Pd(tfa)2(Æ)-L1] (tfa=trifluoroace-
tate) affords the spirofuranone 2 with
inversion of the stereochemistry at C17 in
96% yield. C17-epi-1 also gave the same
product 2 with retention of the stereo-
chemistry at C17. Labelling studies show
that 13CO was incorporated into the C5’
position of the furanone ring. The first
asymmetric version of this new reaction
was achieved.
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DOI: 10.1002/anie.201303684
Synthetic Methods
Carbonylation of Propargyl Carbamates with Palladium(II)
Bisoxazoline Catalysts: Efficient Synthesis of 5-Methoxy-3(2H)-
furanones**
Taichi Kusakabe, Takeo Takahashi, Rong Shen, Ayumi Ikeda, Yogesh Daulat Dhage,
Yuichro Kanno, Yoshio Inouye, Hiroaki Sasai, Tomoyuki Mochida, and Keisuke Kato*
3(2H)-Furanones are well known as basic components of
natural products which display a wide range of characteristic
physiological properties.[1] A number of synthetic strategies[2]
and pharmaceutically active substances[3] have been reported.
The transition metal catalyzed reaction of unsaturated
systems has recently proven to be a powerful method for
the construction of a variety of carbo- and heterocycles.[4]
Recently, we reported the cyclization/carbonylation/cycliza-
tion-coupling reaction (CCC-coupling reaction) of propargyl
acetates, amides, ureas,[5a,b] g-propynyl-1,3-diketones,[5c] N-
propargylanilines, and o-alkynylphenols[5d] catalyzed by pal-
ladium(II) bisoxazoline (box) complexes (Scheme 1a).
Symmetrical ketones bearing two oxazoles, cyclic
orthoesters, oxabicyclic groups, quinolones, and benzofurans
were obtained in a one-step procedure. The triple bond of the
substrate coordinates to palladium(II) and undergoes nucle-
ophilic attack by the intramolecular nucleophilic oxygen atom
with subsequent CO insertion to produce either the acyl
palladium intermediate A1 or A2. Coordination of the triple
Scheme 1. a) Previous work on CCC-coupling reaction. b) This work.
bond of the second molecule induces the second cyclization.
Reductive elimination then leads to formation of a ketone
with two heterocyclic groups. In the absence of the box ligand,
methanolysis of the acyl palladium intermediate (L = MeOÀ,
neutral complex) occurs predominantly. We believe that the
box ligand enhances the p-electrophilicity of palla-
dium(II),[5,6] and thus promotes coordination of the second
triple bond to the acyl palladium intermediate A1 or A2, thus
leading to the dimerization reaction. At the same time,
methanolysis of the acyl palladium intermediate A1 or A2 is
suppressed by coordination of the second triple bond. To
extend the concept of this tandem reaction, we planned to
investigate the [(box)PdII]-catalyzed carbonylation reaction
of analogous substrates, that is, carbamates 1 (Scheme 1b).
Based on our earlier results, the acyl palladium intermediate
A3 should be produced by a similar reaction of the
carbamates 1, and methanolysis of A3 should be suppressed
by coordination of the triple bond of a second molecule. If the
rate of decarboxylation of A3 is fast compared to that of the
CCC-coupling reaction, a new type of cascade reaction is
expected. Consequently, we report herein a new preparation
of the 5-methoxy-3(2H)-furanones 2 by the cyclization/
carbonylation/decarboxylation/cyclization sequence of the
propargyl carbamates 1 catalyzed by [(box)PdII] complexes.
Initially, we selected 1a as a standard substrate to search
for potential catalysts (Table 1). The reaction of 1a with
[(CH3CN)2PdCl2] (5 mol%) in the presence of p-benzoqui-
none (1.5 equiv) in methanol under a carbon monoxide
atmosphere (balloon) generated the acrylate 3a in 40% yield
along with a mixture of unidentified compounds (Table 1,
entry 1). The structure of 3a was determined by X-ray
crystallographic analysis.[7,8] The use of [(Ph3P)2PdCl2] and
Pd(tfa)2 afforded 3a in poor yields (entries 2 and 3). In
addition, [{(À)-sparteine}Pd(tfa)2] and [(2,2’-bipyridi-
ne)PdCl2] did not show catalytic activity. An attempt was
then made to use the box ligand according to our hypothesis,
and thus resulted in a new reaction pathway to afford the 5-
methoxy-3(2H)-furanones 2. Although the use of the box
ligands L2 and L3 (Figure 1) resulted in the formation of 2a in
[*] Dr. T. Kusakabe, T. Takahashi, R. Shen, A. Ikeda, Dr. Y. Kanno,
Prof. Dr. Y. Inouye, Prof. Dr. K. Kato
Faculty of Pharmaceutical Sciences, Toho University
2-2-1 Miyama, Funabashi, Chiba 274-8510 (Japan)
E-mail: kkk@phar.toho-u.ac.jp
Y. D. Dhage, Prof. Dr. H. Sasai
The Institute of Scientific and Industrial Research (ISIR), Osaka
University, Mihogaoka, Ibaraki-shi, Osaka 567-0047 (Japan)
Prof. Dr. T. Mochida
Department of Chemistry, Faculty of Sciences, Kobe University
Rokkodai, Nada, Kobe 657-8501 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research
(C) (No. 24590026).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303684.
2
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Table 1: Carbonylation of the carbamates 1.
99%), thus indicating that 3 is not an intermediate for
producing 2.
To elucidate the reaction mechanism, including the
stereochemical course of the furanone ring formation, we
investigated the reaction of the steroidal compound 1n as
a chiral substrate (Table 2). The reaction of 1n proceeded
Entry R1
R2
t [h]
2
3
Yield [%][a] Yield [%][a]
Table 2: Control reactions of steroid 1n.[a]
1[b,f]
2[c,f]
3[d,f]
4[e,f]
5[e,f]
6[e,f]
7[e,f]
8[e,g]
9[e,g]
1a: -(CH2)5-
18
24
23
22
17
22
16
3
20
4
3
3
21
2a: –
2a: –
2a: –
3a: 40
3a: 30
3a: 23
3a: –
3b: –
3c: –
3d: –
3e: –
3 f: –
3g: –
3h: –
3i: –
1a: -(CH2)5-
1a: -(CH2)5-
1a: -(CH2)5-
1b: -(CH2)6-
1c: Me
2a: 60
2b: 68
2c: 72
2d: 63
2e: 60
2 f: 60
2g: 60
2h: 73
2i: 73
2j: 58
Ph(CH2)2
CH3(CH2)4
CH3(CH2)8
iBu
Entry
Ligand (mol%)
Pd(tfa)2
(mol%)
t [h]
2n
Yield [%]
1d: Me
1e: Et
1
2
(R,R)-L1 (7.5)
(R,R)-L1 (15)
(R,R)-L1 (7.5)
(R,R)-L1 (7.5)
(S,S)-L1 (15)
[Pd(tfa)2(Æ)-L1]
5
12
5
5
12
5
1
1
1
1
4
1.5
87
97
92
72
10
96
1 f: Me
10[e,g] 1g: Et
Et
3[b]
4[c]
5
11[e,g] 1h: CH3(CH2)10 CH3(CH2)10
12[e,g] 1i: CH3(CH2)12
13[e,g] 1j: Me
CH3(CH2)12
Ph
3j: –
6[d]
[a] Yield is that of isolated product. [b] [(CH3CN)2PdCl2] (5 mol%) was
employed. [c] Pd(tfa)2 (5 mol%) was employed. [d] [(Ph3P)2PdCl2]
(5 mol%) was employed. [e] [Pd(tfa)2(Æ)-L1] (5 mol%) was employed.
[f] 458C. [g] RT.
[a] Reaction conditions: Ligand, Pd(tfa)2, p-benzoquinone (1.5 equiv),
CO, MeOH, 45 8C. Yield is that of isolated product. [b] C17-epi-1n was
used as substrate. [c] 13CO was employed and it was incorporated into
C5’ position of 2n. [d] RT.
smoothly in the presence of Pd(tfa)2/(R,R)-L1, thus affording
the spirofuranone 2n in good to excellent yield with inversion
of the stereochemistry at C17 (Table 2, entries 1 and 2). The
structure of 2n was determined by X-ray crystallographic
analysis.[7] Interestingly, the reaction of C17-epi-1n[11] using
the same catalyst, Pd(tfa)2/(R,R)-L1, afforded the same
product 2n in 92% yield with retention of the stereochemistry
À
at C17 (Table 2, entry 3). Once the propargylic C O bond is
cleaved, an SN1-type cyclization may occur from the less
hindered a face to form the furanone ring. From the
preliminary control reaction, carbon monoxide is indispen-
sable to promote the reaction. We confirmed this result
through 13C-isotope labeling which showed that 13CO was
clearly incorporated into the C5’ position of the furanone ring
(Table 2, entry 4). The reaction of 1n in the presence of
Pd(tfa)2/(S,S)-L1 scarcely proceeded, thus giving 2n in 10%
yield (Table 2, entry 5). These results (Table 2, entries 1 and
5) imply that the ligand control may strongly affect the
stereochemical course of the cyclization. Fortunately,
although half the amount of catalyst was ineffective,
5 mol% of the racemic complex [Pd(tfa)2(Æ)-L1] worked
well (Table 2, entry 6).
Recently, steroidal compounds containing spiro-hetero-
cycles have attracted much attention because of their
characteristic physiological activities [e.g., saridegib[12a] (IPI-
926, antineoplastic activity), hedgehog signaling inhibi-
tors,[12b–e] mifepristone (RU 486, progesterone antagonist),[12f]
selective estrogen receptor ligand,[12g] and selective androgen
receptor modulator (SARM)[12h]]. Thus, we investigated the
reaction of the steroidal carbamates 1o–t in the presence of
the racemic complex [Pd(tfa)2(Æ)-L1] (Figure 2). In all cases,
the reaction proceeded well, and the spirofuranones 2o–
t were obtained in excellent yields.
Figure 1. Ligands and additional substrates for Table 1.
lower yield (2–11%), [Pd(tfa)2(L1)][5d] accelerated the reac-
tion, and the yield improved to 60% (Table 1, entry 4).[9] The
reaction of the seven-membered ring substrate 1b and acyclic
substrates 1c–i containing two alkyl groups at the propargylic
position occurred smoothly in the presence of the [Pd-
(tfa)2(L1)], thus affording the 5-methoxy-3(2H)-furanones
2a–i in 60–73% yields (Table 1, entries 5–12). The substrate
1j, which possesses a phenyl group at the propargylic position,
was also converted into 2j in 58% yield (Table 1, entry 13).
The gem-dialkyl effect[10] plays a fundamental role in the
success of the reaction. Without it, the reactions of 1k and 1l
did not proceed, and the N-methyl derivative 1m gave the
product 2a in lower yield (27%; Figure 1). To investigate the
reaction mechanism, preliminary control reactions were
performed. In the absence of p-benzoquinone, the reaction
gave 2a in 3% yield along with recovery of 1a (77%). In the
absence of carbon monoxide, a complex mixture was
obtained. These results suggested that the PdII species acted
as the catalyst and carbon monoxide was incorporated in the
product. In addition, the reaction of 3 under the same reaction
conditions (Table 1, enties 4–7) did not proceed (recovery
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Scheme 2. Plausible reaction mechanism (in the presence of box
ligand).
Scheme 3. Plausible reaction mechanism with [(CH3CN)2PdCl2] (in the
absence of box ligand).
(Scheme 1a),[5,6] the box ligand promotes coordination of
the second substrate (L) to the acyl palladium intermediate
A3, thus preventing the methanolysis. In addition, the cationic
PdII center in A3 is more electrophilic and thus stimulates the
rapid decarboxylation more than the neutral PdII center in
A3’ (Schemes 2 and 3). When using [(CH3CN)2PdCl2] (in the
absence of box ligand), methanolysis of the acyl palladium
intermediate A3’ (reductive elimination) followed by isomer-
ization provides the ester 3 (Scheme 3).
To confirm the above hypothesis, the first asymmetric
reaction of the racemic substrate (Æ)-1u was investigated
(Scheme 4). The model substrate (Æ)-1u was designed based
Figure 2. Reaction of the steroids 1o–t with racemic complex [Pd-
(tfa)2(Æ)-L1]. Substrates (top )and products (bottom) shown. Reaction
conditions: [Pd(tfa)2(Æ)-L1] (5 mol%), p-bezoquinone (1.5 equiv), CO,
MeOH, 458C, 1–7h. Yields are those of isolated products.
A plausible mechanism for the reaction of 1 based on the
control experiments (Table 2) is shown in Schemes 2 and 3.
The triple bond of the substrate coordinates to palladium(II)
and undergoes nucleophilic attack by the intramolecular
nucleophilic nitrogen atom followed by CO insertion to
produce the acyl palladium intermediate A3 (Scheme 2). A
rapid decarboxylation may take place to generate zwitterionic
intermediate B, which then cyclizes and is followed by
addition of methanol and subsequent hydrolysis of the
imine moiety, thus producing the 5-methoxy-3(2H)-furanone
2. Based on our earlier results with similar substrates
Scheme 4. First asymmetric reaction of racemic substrate (Æ)-1u in
the presence of (R,R)-L1. Reaction conditions: (R,R)-L1 (7.5 mol %),
Pd(tfa)2 (5 mol %), p-benzoquinone (1.5 equiv), CO, MeOH.
4
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I. N. Lykakis, C. Efe, I. P. Zaravinos, T. Vidali, E. Kladou, M.
on the steroid 1n given the results in entries 1 and 5 of
Table 2. The reaction of (Æ)-1u using (R,R)-L1 afforded 91%
ee of 2u in 66% yield. The absolute stereochemistry of 2u was
determined by X-ray crystallographic analysis after conver-
sion to the corresponding bromide 4.[7] As expected, nucle-
ophilic attack of the oxygen atom took place from the re face,
which is consistent with that in the case of 1n.
In conclusion, we have presented a cyclization/carbon-
ylation/decarboxylation/cyclization sequence of the propargyl
carbamates 1 catalyzed by [(box)PdII] complexes. The 4-
methoxy-3(2H)-furanones 2 were obtained in moderate to
excellent yields. To elucidate the reaction mechanism, the first
asymmetric version of this new reaction was achieved. The
optically active spirofuranone 2u was obtained from the
racemic carbamate (Æ)-1u through a dynamic kinetic asym-
metric transformation.
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See the Supporting Information.
Published online: && &&, &&&&
Keywords: alkynes · carbonylation · heterocyles · palladium ·
.
synthetic methods
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[9] Typical experiment: A 30 mL two-neck round-bottom flask
containing a magnetic stirring bar, [Pd(tfa)2(Æ)-L1] (9.3 mg,
0.014 mmol), p-benzoquinone (46 mg, 0.42 mmol) and MeOH
(4 mL) was fitted with a rubber septum and a three-way stopcock
connected to a balloon filled with carbon monoxide. The
apparatus was purged with carbon monoxide by pump-filling
through the three-way stopcock. A MeOH solution (1 mL) of
substrate 1n (100 mg, 0.28 mmol) was added to the stirred
solution by syringe at an appropriate temperature. The remain-
ing substrate was washed in MeOH (1 mL) twice. After stirring
for 1.5 h at room temperature, the mixture was diluted with
CH2Cl2 (50 mL) and washed with 3% NaOH (40 mL). The
aqueous layer was extracted with CH2Cl2 (50 mL) twice and the
combined organic layers were dried over MgSO4 and concen-
trated in vacuo. The crude reaction mixture was purified by
column chromatography on silica gel. The fraction eluted with n-
hexane/ethyl acetate (1:1) afforded the spirofuranone 2n as
colorless needles.
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