PIFA-mediated oxidative cycloisomerization of 2-propargyl-1,3-dicarbonyl compounds: Divergent synthesis of furfuryl alcohols and furfurals

Article abstract of DOI:10.1016/j.tetlet.2011.06.117

PhI(OCOCF₃)₂ (PIFA) in the presence of trifluoroacetic acid (TFA) in CH₂Cl₂ efficiently promotes the oxidative cycloisomerization of 2-propargyl 1,3-dicarbonyl compounds to give 4,5-disubstituted furfuryl alcoho

Full text of DOI:10.1016/j.tetlet.2011.06.117

Tetrahedron Letters 52 (2011) 4658–4661
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PIFA-mediated oxidative cycloisomerization of 2-propargyl-1,3-dicarbonyl
compounds: divergent synthesis of furfuryl alcohols and furfurals
⇑
⇑
Akio Saito , Toshiyuki Anzai, Asami Matsumoto, Yuji Hanzawa
Laboratory of Organic Reaction Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
PhI(OCOCF3)2 (PIFA) in the presence of trifluoroacetic acid (TFA) in CH2Cl2 efficiently promotes the oxi-
dative cycloisomerization of 2-propargyl 1,3-dicarbonyl compounds to give 4,5-disubstituted furfuryl
alcohols. PIFA in hexafluoroisopropanol (HFIP) or PIFA-BF3ÁOEt\2 in CH2Cl2 bring about the direct forma-
tion of furfurals from 2-propargyl 1,3-dicarbonyl compounds. In a few cases, PhI@O is suitable for the
direct formation of furfurals.
Received 6 June 2011
Revised 27 June 2011
Accepted 30 June 2011
Available online 7 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Oxidative cycloisomerization
Hypervalent iodine oxidant
Furfuryl alcohol
Furfural
Alkynyl ketone
The synthesis of furan compounds has attracted a great deal of
attention due to their widespread application not only to biologi-
cally active compounds1 but also to versatile building block in
organic synthesis.2 In particular, the metal-catalyzed cascade
reaction based on the cyclization of alkyl ketone derivatives with
electrophiles3 or nucleophiles4 has been developed as one of the
straightforward procedure for the synthesis of highly functional-
ized furans. Furthermore, the metal-catalyzed oxidative cycloiso-
merization of alkyl ketones with various oxidants provides us a
facile synthetic method to synthesize furan compounds concomi-
tantly with the incorporation of oxygen functional groups.5,6
There has been considerable growth in the application of hyper-
valent iodine reagents for carrying out synthetic organic transfor-
mation.7 For the synthesis of heterocyclic compounds, iodine(III)
oxidants, such as phenyliodine(III) diacetate (PIDA), and phenylio-
dine(III) bis(trifluoroacetate) (PIFA) are frequently used in the
metal-catalyzed oxidative addition of carbon or hetero atom nucle-
ophiles to alkyne compounds.8,9 Under the metal-free conditions,
PIFA also showed its efficiency in the intramolecular oxidative ami-
dation and carboxylation of 4-alkynylcarboxylic acid derivatives10
or in the oxidative cycloisomerization of enynols.11,12 These cycli-
zations are suggested to proceed through the activation of the tri-
ple bond by iodonium ions.10–12 Recently, we found that PIDA
efficiently promotes the formation of 2,5-disubstituted oxazolylm-
ethyl acetates via the oxidative cycloisomerization of propargyla-
mides (Scheme 1).13,14 As our further studies on the iodine(III)
oxidants-mediated oxidative cycloisomerization of alkyne com-
pounds, we describe herein the PIFA-mediated oxidative cycloiso-
merization of 2-propargyl 1,3-dicarbonyl compounds for the
divergent synthesis of 4,5-disubstituted furfuryl alcohols and
furfurals.
Based on our previous works of the metal-free oxidative cyclo-
isomerization of propargylamides,13 our preliminary examinations
focused on the reaction of 4,4-dibenzoyl-butyne (1a) with PIDA
(1.5 equiv) in AcOH or in hexafluoroisopropanol (HFIP)-AcOH
(Table 1, entries 1 and 2). It turned out that the expected furfuryl
acetate 2a was obtained in 59% or 65% yield at 60 °C. To our delight,
when PIFA (1.5 equiv) was employed as an oxidant in CH2Cl2, the
corresponding trifluoroacetate 3a was formed in 73% yield (by 1H
NMR analysis) at rt for 5 h (entry 3). Since a part of 3a was hydro-
lyzed into furfuryl alcohol 4a during the work-up and/or column
chromatography on silica gel, the crude reaction mixture was trea-
ted with K2CO3 in EtOH for 30 min. Thus, after the alcoholysis, 4a
was isolated in 69% yield (entry 3). By the addition of trifluoroace-
tic acid (TFA, 1.2 equiv), the use of 1.2 equiv PIFA brought about the
similar result to entry 3 (entry 4). It should be mentioned that
HN
O
N
O
PIDA
R1
R1
OAc
AcOH or HFIP-AcOH
⇑
Corresponding authors. Tel.: +81 (0) 42 721 1571; fax: +81 (0) 42 721 1569
(A.S.).
R2
R2
E-mail addresses: akio-sai@ac.shoyaku.ac.jp (A. Saito), hanzaway@ac.shoya
ku.ac.jp (Y. Hanzawa).
Scheme 1. Oxidative cycloisomerization of N-propargylamides by PIDA.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.117

A. Saito et al. / Tetrahedron Letters 52 (2011) 4658–4661
4659
Table 1
Screening of oxidants for the oxidative cycloisomerization of 1a
O
O
O
O
X
X
PIDA
Ph
Ph
I
O
OR
OCH(CF3)2
OCH(CF3)2
Oxidant
(X=OAc)
Ph
Ph
Ph
+
+
PIFA
(X=OCOCF3)
Additive / Solvent
O
O
O
Ph
Ph
Ph
O
1a
2a: R=Ac 4a: R=H
3a: R=COCF3
5a
6a
Entry
Oxidant (equiv)
Additive (equiv)
Solvent
AcOH
HFIP-AcOH (1:1)
CH2Cl2
CH2Cl2
DCE
HFIP
HFIP
HFIP
(°C)
(h)
2a or 3aa (%)
5aa (%)
Othera (%)
1
2
3
4
5
6
7
8
PIDA (1.5)
PIDA (1.5)
PIFA (1.5)
PIFA (1.2)
PIFA (3)
PIFA (3)
PIFA (3)
PIFA (3)
PIFA (2)
60
60
rt
20
4
5
5
18
4
19
22
2
23
21
4
59
65
1
1
9
4
73 (4a: 69)b
TFA (1.2)
rt
72 (4a: 70)b
90
60
rt
rt
rt
60
60
60
33
0
0
0
0
0
0
0
27
47
51
56
78 (77)
33
18
7
6a 28
1a 57
TFA (3)
BF3ÁOEt2 (1)
9
CH2Cl2
DCE–HFIP (3:1)
DCE
10
11
12
PhI@O (3)
PhI@O (3)
IBX (3)
Silica gelc
DMSO
a
b
c
Yields were determined by 1H NMR analysis. Yields in parentheses were isolated yields.
After the reaction of 1a with PIFA was completed, the crude reaction mixture was treated with K2CO3 in EtOH for 30 min.
Silica gel 60N (spherical form, neutral pH, particle size: 100–210 m) was used.
l
furfural 5a was observed as a by-product (1–9%) in all cases (en-
tries 1–4).
9 in 65% yield (entry 8). As shown in Table 3, by the PFIA-BF3ÁOEt2-
mediated systems (Method A), benzoylester 1b as well as 1a was
efficiently converted into the corresponding furfural 5b in 61%
yield (entry 2). In the reaction of aliphatic ketones 1c–g, however,
Method A did not bring about good results (24–48%, entries 3–7).
On the other hand, the use of PhI@O (3 equiv) as an oxidant in
DCE–HFIP (Method C) or PhI@O-silica gel in DCE (Method D) works
well for the formation of furfurals 5c–e (46–71%, entries 3–5). In
the cases of the bulky aliphatic ketones 1f, g, PIFA in HFIP (Method
B) yielded superior results to the Methods A and C (entries 6 and
7).
In summary, we have demonstrated the divergent synthesis of
4,5-disubstituted furfuryl alcohols and furfurals through the
PIFA-mediated oxidative cycloisomerization of 2-propargyl 1,3-
dicarbonyl compounds. For the divergent procedure, it is critical
to appropriately select additives (TFA and BF3ÁOEt2) and solvents
(CH2Cl2 and HFIP). In a few examples for the formation of furfurals,
PhI@O is an effective oxidant. Ongoing work is directed toward a
better understanding of the effects of additives and solvents for
the present reactions.
Our further efforts were focused on the direct formation of 5a
from 1a (Table 1, entries 5–12). Although the reaction of 1a with
3 equiv PIFA in DCE under the reflux conditions gave 5a in only
27% yield (entry 5), the use of HFIP as a solvent improved the yield
of 5a (47–56%, entries 6–9). In the refluxing HFIP, however, acetal
6a was yielded along with 5a (entry 6).15 An addition of BF3ÁOEt2
exerted a remarkable effect even on the 2 equiv PIFA-mediated for-
mation of 5a in CH2Cl2 to afford 5a in 77% yield (entry 10).16 Other
oxidants, such as PhI@O17 and 2-iodoxybenzoic acid (IBX)11b were
inferior to PIFA (entries 10–12).
Under the optimized conditions, we next turned our attention
to the scope of substrates in the formation of furfuryl alcohols 4
(Table 2)18 and furfurals 5 (Table 3).19 Thus, in the presence of
TFA (1.2 equiv), not only diketones 1a, d–g but ketoester 1b, c also
successfully reacted with PIFA (1.2 equiv) in CH2Cl2. After the alco-
holysis of 3, furfuryl alcohols 4 were obtained in 41–78% yields
(Table 2, entries 1–7). The present procedure could be applied to
the oxidative cyclization of allyl compound 7 to give dihydrofuran
Table 2
The oxidative cycloisomerization of various 2-propargyl-1,3-diketones 1 for the formation of furfuryl alcohols 4
O
O
O
O
O
R2
R1
Ph
Ph
PIFA (1.2 equiv)
TFA (1.2 equiv)
R2
R2
Ph
or
OCOCF3
OH
OH
K2CO3 / EtOH
rt, 30 min
or
CH2Cl2, rt, 5-9 h
O
O
O
R1
R1
Ph
O
O
1
7
3 or 8
4
9
Entry
Substrate
R1
R2
Product
Yielda (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
Ph
Me
Me
Et
iPr
tBu
-
Ph
OEt
4a
4b
4c
4d
4e
4f
70
60
68
41
64
71
78
65
OEt
Me
Et
iPr
tBu
-
1g
7
4g
9
a
Isolated yields.

4660
A. Saito et al. / Tetrahedron Letters 52 (2011) 4658–4661
Table 3
The oxidative cycloisomerization of various 2-propargyl-1,3-diketones 1 for the formation of furfurals 5
O
O
PIFA (2-3 equiv)
R2
R1
R2
O
or PhI=O (3 equiv)
addtive / solvent
R1
O
O
1
5
Entry
Substrate
Method Aa
Method Ba
(h)
Method C or Da
(h)
(°C)
(h)
5b (%)
(°C)
5b (%)
(°C)
5b (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
rt
rt
rt
rt
rt
rt
rt
2
3
17
5
9
78 (77)
60 (61)
48
rt
19
4
51
53
60
60
60
60
60
60
60
23
19
19
22
22
22
20
33
31
59 (57)
68 (71)
45 (46)
15
60
60
rt
rt
rt
19
19
19
22
21
53
30
26c
38
41
41 (41)
72 (68)
21
17
24d
1g
35
rt
0
a
Method A: PIFA (entries 1, 2, and 7: 2 equiv, entries 3–6: 3 equiv), BF3ÁOEt2 (1 equiv)/CH2Cl2. Method B: PIFA (entries 1–6: 3 equiv, entry 7: 2 equiv)/HFIP. Method C
(entries 1–3): PhI@O (3 equiv)/DCE–HFIP (3:1). Method D (entries 4–7): PhI@O (3 equiv), silica gel/DCE.
b
Yields were determined by 1H NMR analysis. Yields in parentheses were isolated yields.
Furfuryl alcohol 4d: 22%.
Furfuryl trifluoroacetate 3f: 17%.
c
d
7. Recent reviews: (a) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073; (b) Uyanik, M.;
Acknowledgments
Ishihara, K. Chem. Commun. 2009, 202086; (c) Zhdankin, V. V.; Stang, P. J. Chem.
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Miyamoto, K.; Ochiai, M. J. Synth. Org. Chem. Jpn. 2010, 68, 228; (h) Satam, V.;
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This work was partially supported by the Grants-in-Aid for
Young Scientists (B) 21790024 and for High Technology Research
Centre Project (19-8) from MEXT, Japan. A generous donation of
HFIP by Central Glass Co., Ltd is gratefully acknowledged.
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TFA (36 lL, 0.48 mmol) and PIFA (206 mg, 0.48 mmol) were added to a solution
of 1a (63.6 mg, 0.4 mmol) in CH2Cl2 (2.0 mL) at 0 °C, and the reaction mixture
was stirred at rt for 5 h. The mixture was diluted with ether and sat. NaHCO3
aq. was added. After the aqueous solution was extracted with ether, the
combined organic layer was dried with MgSO4, filtered, and concentrated in
vacuo. The resulting residue was treated with K2CO3 (120 mg) in EtOH (2.0 mL)
for 30 min. And then, the mixture was diluted with ether, filtered, and
concentrated in vacuo. The residue was purified by silica gel column

A. Saito et al. / Tetrahedron Letters 52 (2011) 4658–4661
4661
chromatography (hexane/AcOEt = 75/25) gave 4a (77.4 mg, 70%) as a colorless
oil. IR (neat)
cmÀ1; 3429, 1651. 1H NMR (300 MHz, CDCl3) d; 4.70 (s, 2H), 6.59
(s, 1H), 7.26–7.32 (m, 3H), 7.33–7.41 (m, 2H), 7.46–7.54 (m, 1H), 7.64–7.71 (m,
2H), 7.80–7.86 (m, 2H). 13C NMR (75 MHz, CDCl3) d; 57.3, 111.5, 121.4, 127.5,
128.2, 128.3, 129.1, 129.5, 129.7, 132.9, 137.8, 152.9, 155.9, 191.8. FAB-LM m/z:
279 (M++H). FAB-HM Calcd for C18H15O3: 279.1021. Found: 279.1021.
0.4 mmol) in HFIP (4.0 mL) at 0 °C, and the reaction mixture was stirred at rt
for 21 h. The mixture was diluted with ether and sat. NaHCO3 aq. was added.
After the aqueous solution was extracted with ether, the combined organic
layer was dried with MgSO4, filtered, and concentrated in vacuo. The
resulting residue was purified by silica gel column chromatography
m
(hexane/AcOEt = 80/20) gave 5g (68.0 mg, 72%) as
a colorless solid. Mp
19. Representative procedure for the preparation of furfurals: Method A;
solution of 1a (63.6 mg, 0.4 mmol) in CH2Cl2 (2.0 mL) was added to a mixture
L, 0.4 mmol) in CH2Cl2 (2.0 mL)
A
52 °C. IR (KBr)
m
cmÀ1; 1685. 1H NMR (300 MHz, CDCl3) d; 1.27 (s, 9H), 1.36
(s, 9H), 7.28 (s, 1H), 9.60 (s, 1H). 13C NMR (75 MHz, CDCl3) d; 27.4, 28.7, 35.1,
44.8, 120.6, 121.6, 148.8, 169.2, 177.4, 206.3. FAB-LM m/z: 237 (M++H). FAB-
HM Calcd for C14H21O3: 237.1491. Found: 237.1497. Method D; A solution of
1d (55.2 mg, 0.4 mmol) in DCE (2.0 mL) was added to a mixture of PhI@O
(264 mg, 1.2 mmol) and silica gel (240 mg) in DCE (2.0 mL) at rt, and the
reaction mixture was stirred at 60 °C for 22 h. The mixture was diluted with
ether and filtered. After concentration of the filtrate to dryness, purification of
the residue by silica gel column chromatography (hexane/AcOEt = 80/20)
gave oxazolylmethyl acetate 5d (42.9 mg, 71%) as a white solid. Mp 98 °C. IR
of PIFA (344 mg, 0.8 mmol) and BF3ÁOEt2 (50
l
at 0 °C, and the reaction mixture was stirred at rt for 2 h. The mixture was
diluted with ether and sat. NaHCO3 aq. was added. After the aqueous solution
was extracted with ether, the combined organic layer was dried with MgSO4,
filtered, and concentrated in vacuo. The resulting residue was purified by
silica gel column chromatography (hexane/AcOEt = 80/20) gave 5a (84.7 mg,
77%) as a colorless oil. IR (neat)
m
cmÀ1; 1680, 1664. 1H NMR (300 MHz,
CDCl3) d; 7.31–7.48 (m, 5H), 7.47 (s, 1H), 7.53–7.62 (m, 1H), 7.78–7.87 (m,
4H), 9.73 (s, 1H). 13C NMR (75 MHz, CDCl3) d; 122.6, 123.8, 127.9, 128.0,
128.4, 128.5, 129.5, 130.6, 133.4, 136.9, 150.2, 159.6, 177.4, 190.2. FAB-LM m/
z: 277 (M++H). FAB-HM Calcd for C18H13O3: 277.0865. Found: 277.0854.
Method B; PIFA (344 mg, 0.8 mmol) was added to a solution of 1g (88.9 mg,
(KBr)
m
cmÀ1; 1672. 1H NMR (300 MHz, CDCl3) d; 2.44 (s, 3H), 2.67 (s, 3H),
7.44 (s, 1H), 9.55 (s, 1H). 13C NMR (75 MHz, CDCl3) d; 14.8, 28.9, 121.2, 123.4,
150.2, 164.0, 177.2, 192.9. FAB-LM m/z: 153 (M++H). FAB-HM Calcd for
C8H9O3: 153.0552. Found: 153.0556.