TFP as a ligand in Au(i)-catalyzed dihydropyran synthesis. Unprecedented rearrangement of dihydropyrans into cyclopentenones

Article abstract of DOI:10.1039/c1cc13525b

Dihydropyrans have been prepared by the cyclisation of easily accessible propargyl vinyl ethers with (TFP)AuCl/AgBF₄ as a catalyst in high yields. These compounds undergo acid-catalysed rearrangement into cyclopentenone derivatives.

Full text of DOI:10.1039/c1cc13525b

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TFP as a ligand in Au(I)-catalyzed dihydropyran synthesis.
Unprecedented rearrangement of dihydropyrans into cyclopentenonesw
a
b
a
a
a
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Eliska Matousova, Ales Ruzicka, Jirı Kunes, Jarmila Kralova and Milan Pour*
ˇ
ˇ
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ˇ
ˇ
ˇ
ˇ
´
´
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Received 14th June 2011, Accepted 1st July 2011
DOI: 10.1039/c1cc13525b
Dihydropyrans have been prepared by the cyclisation of easily
accessible propargyl vinyl ethers with (TFP)AuCl/AgBF4 as a
catalyst in high yields. These compounds undergo acid-catalysed
rearrangement into cyclopentenone derivatives.
Heterocyclic compounds have been a continuous source of
novel pharmaceutical building blocks.1 In the preparation
of specifically substituted heterocycles, their assembly from
acyclic precursors bearing the required functionality already in
place2 has become a valuable alternative to the sequential
functionalization of their (often more easily available) cyclic
cores. Thus, following our work3 on the chemistry and biology
of 3,5-disubstituted pyranones, we became interested in
C3-substituted pyrans. An easy approach to these compounds
Scheme 1 AuI cyclisations of propargylic ethers.
has been paved by the elegant study of Toste et al.,4 who
prepared dihydropyrans 2 via AuI-catalyzed cyclisation5 of
simple enyne ethers 1 (Scheme 1) in the presence of H2O.
Conceptually,6 this work was based on the nucleophilic addition
to an oxocarbenium intermediate formed via the activation of the
triple bond in 1 by AuI followed by a nucleophilic attack by the
enol ether. However, the preparation7 of the starting propargylic
ethers 1 via the reaction of propargylic alcohols with ethyl
vinyl ether involved the use of highly toxic HgII salts,
substitutents R1 and R2 were limited to alkyl and substituted
alkyl groups, and the R2 group did not include hydrogen.
Clearly, ethers 3 that would afford pyrans with a C3 substituent
that could be further elaborated can be prepared in nearly
quantitative yields through the addition of propargylic alcohols
across the triple bond of alkyl propiolates8 or C3-fluorinated
alkynes in the presence of Et3N. Since we also intended to
effect the cyclisation of substrates with an arylalkynyl moiety,
ester 3a (R1 = Ph) was selected as the model compound.
To our disappointment though, the reaction of 3a under the
conditions described by Toste et al.4 (Scheme 1) resulted in a
painfully slow process. After 3 days at room temperature, a mere
28% of the desired product was detected in the reaction mixture,
and it became apparent that a change of the reaction conditions
and catalyst screening would be necessary. Hence, we turned
attention to cationic complexes of AuI as highly alkynophilic
catalysts9 for the cyclisation of enynes. The reaction of 3a with the
commercially available (PPh3)AuCl (5%) in combination with
10
AgSbF6 in CH2Cl2 gave rise to a partial decomposition of the
starting material.11 However, the addition of a few equivalents of
MeOH, reported by Echavarren et al.9a as the solvent of choice for
the cyclisations of less reactive enynes, dramatically changed the
situation.12 Presumably, MeOH enters the coordination sphere of
gold thereby furnishing [(PPh3)Au(MeOH)]+.9a Following a short
modification of the reaction conditions, it was quickly found
that (PPh3)AuCl (5%) with AgSbF6 and 3 equivalents of MeOH
afforded 68% of the corresponding dihydropyran ester 4a
(entry 1, Table 1), and the replacement of AgSbF6 with AgBF4
(entry 6) increased the yield to 82%.
In our next move towards ligand tuning,13 we turned our
attention to tris-2-furylphosphine (TFP) as the ligand.14 To
the best of our knowledge, no AuI complex with this phosphine
as the ligand has been employed as a catalyst in an organic
transformation. TFP has been the ligand of choice in a number of
difficult cases of Pd-catalyzed cross-couplings,15 since its low s
electron-donating ability has often enabled acceleration of the
reaction rates. Similarly, we hoped that its lower coordination
ability towards AuI could further boost the coordination of the
metal to the multiple bond. Therefore, (TFP)AuCl was prepared16
via ligand exchange from (tht)AuCl, and used in the reaction.
a Department of Inorganic and Organic Chemistry, Charles University
´
in Prague, Faculty of Pharmacy, Heyrovskeho 1203, CZ-500 03
Hradec Kralove, Czech Republic. E-mail: milan.pour@faf.cuni.cz
´
´
b Department of General and Inorganic Chemistry, University of
´
Pardubice, Faculty of Chemical Technology, Studentska 573,
CZ-53210 Pardubice, Czech Republic
w Electronic supplementary information (ESI) available: Experimental
details, 1H NMR and 13C NMR spectra of all products and crystallo-
graphic data of trans-4d. CCDC 829174. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1cc13525b
c
9390 Chem. Commun., 2011, 47, 9390–9392
This journal is The Royal Society of Chemistry 2011

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Table 1 Optimization of reaction conditions for cyclisation of 3a
Entry AuI (5%)
AgI (5%) Time/h Yield (%) trans/cis
1
2
3
4
5
6
7
8
9
(PPh3)AuCl
(Cy3P)AuCl
(TFP)AuCl
(dppf)Au2Cl2 AgSbF6
(dppe)Au2Cl2 AgSbF6
(PPh3)AuCl
(Cy3P)AuCl
(dppe)Au2Cl2 AgBF4
(TFP)AuCl AgBF4
AgSbF6
AgSbF6
AgSbF6
0.5
1
0.5
48
1
1.5
1
68
68
75
30
45
82
74
73
98
51/17
38/30
60/15
23/7
30/15
58/24
46/28
54/19
66/32
Scheme 2 Cyclisation of 5 and 6.
AgBF4
AgBF4
Interestingly, the cyclisation of 5 gave a somewhat lower yield
(38%) of dihydropyran 7, together with phenyl (2-methoxyethyl)
ketone17 (46%). Since the latter was also obtained as the
sole product of the reaction of 3-phenylprop-2-yn-1-ol under
identical conditions, propargylic ether 5 must have undergone a
partial fragmentation. On the other hand, ether 6 afforded pyran 8
as a single stereoisomer in a decent, 71% isolated yield. The
relative configuration of 8 was unequivocally assigned on the basis
of NOE measurements and analogy with dihydropyrans 4.
Next we attempted the elimination of MeOH leading to the
corresponding 2H-pyran, facilitated by the presence of an electron-
withdrawing group at C3. Surprisingly, upon treatment of 4a
with 85% H3PO4 and methanol at 80 1C, a single product in 60%
isolated yield (Scheme 3) was obtained, the spectral data of which
were identical18 with those of ester 9a. To acquire solid evidence
about the structure of 9a, the compound was subjected to
hydrolysis with LiOH and subsequent decarboxylation to yield
the well-known 2-phenylcyclopent-2-ene-1-one.19 Since the
attempts to rearrange other substrates than 4a were affected by
the limited solubility of their precursors in concentrated H3PO4,
modification of the reaction conditions was carried out (Table 3).
While the best yield of 9a obtained in the rearrangement of
4a was about 60%, the use of p-TsOH in toluene enabled us to
improve the solubility of dihydropyrans 4. Thus, a few
other compounds were subjected to the conditions described
in Table 3, entry 6. The results (Table 4) show that the
rearrangement proceeds with both alkyl and aryl groups at
C4, with moderate yields of cyclopentenones 9.
16
0.5
To our delight, the yield increased to almost quantitative 98%
(entry 9), and the reaction was over in less than 30 minutes. Other
phosphines (entries 2, 4, 5, 7, 8) gave lower yields of 4a (Table 1).
Similarly, lower catalyst loadings (3%, 1%) led to lower yields
and longer reaction times. Hence, the reactions with all other
substrates were carried out with 5% of (TFP)AuCl. The results
summarised in Table 2 show uniformly high isolated yields of the
corresponding dihydropyrans 4, with the exception of R1
=
Boc-indol-5-yl, for which a moderate 38% yield was achieved.
Compounds 4 were obtained as anomeric mixtures, with the
trans isomer as the major compound. Their structures were
unequivocally corroborated by X-ray analysis (Fig. 1).
We have also attempted the reaction under the above
conditions with the propargylic ether 5 (EWG = CF3) with
the aim of introducing a polyfluorinated side chain into the
resultant pyrans, and the trisubstituted derivative 6 (Scheme 2).
Table 2 Synthesis of dihydropyranes 4
Entry Substrate R
Product Time/h Yield (%) trans/cis
1
2
3
4
5
6
7
8
3b
3c
3d
3e
3f
3g
3h
3i
n-C5H11
Me
1-Naphthyl
3-Thienyl
Allyl
Benzyl
Benzyloxy
4-MeO-C6H4 4i
n-C3H7 4j
Boc-indol-5-yl 4k
4-CN-C6H4 4l
4b
4c
4d
4e
4f
1
1
1.5
1
2
1
2
1.5
1
83
70
84
87
67
75
70
89
77
38
92
62/21
57/13
61/23
61/26
52/15
57/18
49/21
63/26
65/12
25/13
68/24
4g
4h
9
10
11
3j
3k
3l
7
20
Scheme 3 Acid-catalyzed rearrangement of 4a.
Table 3 Optimization of reaction conditions for rearrangement of 4a
to 9a
Time/ Temp./ Yield
h
Entry Acid
Solvent
H3PO4
CH3COOH MeOH (3 eq.)
CH3COOH H2O (10 eq.)
Cosolvent
1C
(%)
1
2
3
4
5
6
H3PO4
H3PO4
H2SO4
PTSA (2 eq.) Toluene
PTSA (4 eq.) Toluene
PTSA (4 eq.) Toluene
MeOH (10 eq.) 4
80
80
80
80
80
80
60
23
45
42
53
62
4
5
4
4
6
—
H2O (1 eq.)
MeOH (1 eq.)
Fig. 1 X-Ray analysis of trans-4d.
c
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Chem. Commun., 2011, 47, 9390–9392 9391

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Table 4 Rearrangement to cyclopentenones 9
acknowledged for a useful discussion regarding the mechanism
of the rearrangement.
Notes and references
1 For a recent review, see: M. Baumann, I. R. Baxendale, S. V. Ley
and N. Nikbin, Beilstein J. Org. Chem., 2011, 7, 442.
2 For reviews concerning tandem reactions, see e.g.: (a) L. F. Tietze,
Chem. Rev., 1996, 96, 115; (b) D. E. Fogg and E. N. dos Santos,
Coord. Chem. Rev., 2004, 248, 2365; (c) K. C. Nicolaou,
D. J. Edmonds and P. Bulger, Angew. Chem., Int. Ed., 2006, 45,
7134–7186; (d) H. Pellissier, Tetrahedron, 2006, 62, 1619.
Entry
Substrate
R
Product
Yield (%)
1
2
3
4
5
4b
4c
4d
4e
4f
n-C5H11
n-C3H7
1-Naphthyl
Benzyl
4-CN-C6H4
9b
9c
9d
9e
42
44
45
38
3 (a) R. Schiller, L. Tichotova
I. Votruba, J. Kunes, M. Spula
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´
, J. Pavlı
k and M. Pour, Bioorg. Med. Chem.
k, R. Schiller, J. Kunes
´
k, V. Buchta, B. Melichar,
9f+9g
22 + 20a
´
´
a
9g R = 4-MeCO2-C6H4.21
´
´
Based on the structure of the starting material and the products,
the following mechanism has been proposed (Scheme 4). Acid-
promoted elimination of MeOH from 4a gives rise to 2H-pyran
10, which undergoes an electrocyclic ring opening.20 The cyclo-
pentene framework is then constructed in a subsequent intra-
molecular Prins cyclisation of the resultant dienal ester 11, which
is converted into methyl 3,5-dihydroxy-2-phenylcyclopent-1-
enecarboxylate 12. Finally, departure of H2O from C5 furnishes
an allylic carbocation 13, the stability of which is increased by the
presence of an aryl at C2. Following C3 to C2 hydride migration,
the formation of the oxo group leads to enone 14, the double bond
of which migrates into the most stable location. An experiment
with a labelled substrate (Scheme 4) lends further support to this
mechanism, since the terminal 13C-labelled carbon of phenyl-
acetylene used for the preparation of 13C-4a ended up as the
carbonyl group in the final compound 9a labelled with 13C.
In summary, we have broadened the scope of the Toste
protocol4 for the cyclisations of propargylic ethers to dihydro-
pyrans using TFP as a ligand to AuI for the first time. Secondly,
we have shown that the pyrans undergo an as yet undescribed
acid-promoted conversion into cyclopentenones.
4 B. D. Scherry, L. Maus, B. N. Laforteza and F. D. Toste, J. Am.
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J. Am. Chem. Soc., 2010, 132, 8276.
6 For
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7, 3925; (b) H. Menz and S. F. Kirsch, Org. Lett., 2006, 8, 4795;
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10 CH2Cl2 has been one of the most frequently used solvents for
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pez, E. Herrero-
Gomez, P. Perez-Galan, C. Nieto-Oberhuber and A. M. Echavarren,
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´
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´
´
´
´
´
´
´
This work was supported by the Czech Science Foundation
(project No. P207/10/2048) and by the Ministry of Education
of the Czech Republic (projects Nos. MSM0021620822 and
1M0508). E. M. acknowledges partial support from Charles
University (SVV-263-001). Professor L. N. Mander of the
Research School of Chemistry, ANU, Canberra, is gratefully
´
´
T. Lauterbach, K. Molawi, C. R. Solorio and A. M. Echavarren, Angew.
Chem., Int. Ed., 2009, 48, 6152.
11 A similar observation has been made by Kirsch et al., see ref. 6a.
12 No reaction took place in neat MeOH.
13 For ligand effects in gold catalysis, see e.g.: (a) M. P. Munoz,
J. Adrio, J. C. Carretero and A. M. Echavarren, Organometallics,
´ ´
2005, 24, 1293; (b) P. Mauleon, R. M. Zeldin, A. Z. Gonzalez and
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´ ´ ´
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21 A partial conversion of –CN into –COOMe occurred.
Scheme 4 Mechanism of the rearrangement (13C label is depicted in red).
9392 Chem. Commun., 2011, 47, 9390–9392
c
This journal is The Royal Society of Chemistry 2011