[3+2]-Cycloaddition reactions of 2-phenyliodonio-5,5-dimethyl-1,3-dioxacyclohexanemethylide

Article abstract of DOI:10.1016/S0040-4039(00)01672-5

Iodonium ylide 2, derived from dimedone, undergoes thermal [3+2]-cycloaddition with acetylenes and nitriles with Rh₂(OAc)₄ to form the corresponding furans and oxazoles, respectively. Photochemically 2 reacts with various alkenes to

Full text of DOI:10.1016/S0040-4039(00)01672-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9299–9303
[3+2]-Cycloaddition reactions of
2-phenyliodonio-5,5-dimethyl-1,3-dioxacyclohexanemethylide
Efstathios P. Gogonas and Lazaros P. Hadjiarapoglou*
Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina,
45110 Ioannina, Greece
Received 21 September 2000; accepted 26 September 2000
Abstract
Iodonium ylide 2, derived from dimedone, undergoes thermal [3+2]-cycloaddition with acetylenes and
nitriles with Rh2(OAc)4 to form the corresponding furans and oxazoles, respectively. Photochemically 2
reacts with various alkenes to form E-dihydrofuran derivatives. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: hypervalent iodine; ylide; cycloaddition; furan; oxazole.
The transition-metal catalyzed decomposition of diazo compounds has tremendous potential
in organic synthesis.1 The in situ formation of metallo carbenoids and the transfer of the carbene
moiety to a suitable acceptor has found widespread application in the total synthesis of natural
products. However, a major drawback of this methodology is the use of diazo compounds,
which are potentially explosive, toxic, and/or carcinogenic.
Alternatively, iodonium ylides2 have been recognized as synthetic equivalents of the corre-
sponding diazo compounds without major drawbacks, except for the fact that an active
methylene compound is required for their facile preparation.3 The photochemical and/or
metal-catalyzed decomposition of these stable iodonium ylides affords4 products typical of
carbenoid reactions, although the involvement of carbenes (or carbenoids) in these reactions has
been questioned.5
Following our studies directed towards the development of new synthetic applications of
iodonium ylides,3b,5f,6 we thought that substituted furans and oxazoles could be easily obtained
from the reaction of a b-dicarbonyl iodonium ylide with alkynes and nitriles. In fact, the
isolation of an oxazole from the reaction of 2-phenyliodonio-5,5-dimethyl-1,3-dioxacyclohex-
anemethylide and acetonitrile has been reported.6b However, this thermal Cu-catalyzed cycliza-
tion was later questioned.5c Thus, we reasoned that we had to re-examine this useful reaction
* Corresponding author. Tel: +30 651 98380; fax: +30 651 98799; e-mail: lxatziar@cc.uoi.gr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01672-5

9300
and undertake a more systematic investigation. Indeed, we now wish to report the preliminary
results of the synthesis of furans, oxazoles and dihydrofurans by the reaction of iodonium ylide
2 with alkynes, nitriles, and alkenes.
Iodonium ylide 2 had been prepared in 95% yield from the reaction of 5,5-dimethyl-1,3-cyclo-
hexanedione (1) and diacetoxyiodobenzene (Scheme 1) employing Koser’s method.7
O
O
Ο
IPh
I
PhI(OAc)2
CH2Cl2
∆
O
O
OPh
1
2
3
Scheme 1.
Although iodonium ylide 2 is stable at −30°C for a prolonged period of time, it isomerized
into iodo ether 3 upon heating in various solvents.2a,8 This iodo ether is the major product in all
the non-catalyzed thermal reactions or a minor by-product of all the thermal Cu- and
Rh-catalyzed reactions of iodonium ylide 2.
Without solvent and an inert atmosphere, heating at reflux, a suspension of iodonium ylide 2,
alkyne 4a, and catalytic amounts of Rh2(OAc)4 for 15 min afforded,9 after the usual work-up,
furan 5a in 47% yield (Scheme 2). The reaction was extended to a variety of other terminal
alkynes 4b–d as well as nitriles 6a–e, affording the corresponding furans 5 and oxazoles 7 in
moderate yields (Table 1).
O
O
R C
4, 6
X
IPh
X
R
O
O
Rh2(OAc)4, ∆
2
5, 7
Scheme 2.
The employment of Cu(AcAc)2 as a catalyst leads to lower yields of the desired product and
to greater amounts of the iodoether; when the reactions with alkynes were repeated photochem-
ically much lower yields of the desired products were isolated from complex reaction mixtures.10
It is noteworthy that the cycloaddition proceeds without the use of an inert atmosphere. The
reaction also exhibits high regioselectivity. The oxygen atom of the iodonium ylide added
exclusively onto the more substituted carbon atom of the triple bond, i.e. terminal acetylenes,
afforded 2-substituted furans exclusively, the other possible regioisomer was not detected at all.
It is clear from the results listed above that variation in the reaction conditions have a
profound influence on the product distribution. The best yields (thermally) that we have
achieved so far have come from the treatment of iodonium ylide with an Rh-catalyst. Bearing
this in mind, we turned our attention to the cycloaddition reaction with alkenes. Although the
Rh2(OAc)4 catalyst, as well as PdCl2, works better than Cu(AcAc)2 or Hg(OAc)2, the photo-
chemical conditions (400 W medium pressure Hg lamp) in CH3CN were superior. The
irradiation of a suspension of iodonium ylide 2 and styrene (excess) 8a in CH3CN leads to the
isolation of dihydrofuran 9a in 96% yield, while the corresponding Rh-catalyzed thermal
reaction yields 9a in 75% yield only (Scheme 3).

9301
Table 1
Thermal (Rh-catalyzed) reactionsa of iodonium ylide 2
a/a
Substrate
Substituents
Reaction conditions
Product
Yield (%)b
R
X
Temp. (°C)
Time (min)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
6a
6b
6c
6d
6e
CH3OCH2
CH3CH2CH2
(CH3)3Si
C6H5
CH3
ClCH2
C6H5CH2
C6H5
p-CH3C6H4
CH
CH
CH
CH
N
N
N
N
N
Reflux
Reflux
Reflux
110
Reflux
90–100
90
15
17
20
3
60
30
30
30
30
5a
5b
5c
5d
7a
7b
7c
7d
7e
47
57
48
51
68
41
23
28
42
90–100
80–90
a All reactions were performed by heating a mixture of iodonium ylide (2.05 mmol), alkyne (excess) or nitrile
(excess) and catalytic amount of Rh2(OAc)4 at the given temperature for the required time.
b Isolated yield.
9a : R1=Ph, R2=R3=H (96%)
9b : R1=PhCH2, R2=R3=H (96%)
9c : R1=EtO, R2=R3=H (70%)
9d : R1=Ph, R2=Me, R3=H (76%)
9e : R1,R3=C3H6, R2=H (59%)
9f : R1,R3=OCH2CH2, R2=H (47%)
9g : R1,R3=C6H4CH2, R2=H(58%)
R2
R1
R3
O
O
R3
IPh
R2
R1
8
hν, CH3CN
O
O
2
9
Scheme 3.
Other acyclic as well as cyclic alkenes 8 were found to undergo photochemical cycloaddition
in moderate to excellent yields. This cycloaddition reaction also exhibits high regio- and
diastereoselectivity, leading to the isolation of one isomer. The oxygen atom of the iodonium
ylide added exclusively onto the more substituted carbon of the terminal olefins, i.e. leading to
2-substituted dihydrofurans. The stereochemistry of the double bond was not preserved within
the cycloaddition since the stereochemistry of the dihydrofurans 9 was clearly assigned as E
based upon the absence of signals between the bridged-protons in the ROESY spectrum, i.e. for
dihydrofuran 9g (Fig. 1).
Figure 1. Key ROESY interactions of compound 9g

9302
Although the exact mechanism of the cycloaddition reaction is still not clear, some points
needs to be mentioned. (1) The direct formation of the dihydrofuran is suggested since
isomerization11 of an initially formed cyclopropane to a dihydrofuran is less likely. (2) The
stereochemical outcome suggests a mechanism involving a freely rotating intermediate. A
concerted mechanism seems to be ruled out.
In conclusion, thermal metal-catalyzed or photochemical cycloaddition of iodonium ylide to
terminal acetylenes, nitriles, and alkenes offers a simple and new strategy for the synthesis of
substituted furans, oxazoles, and dihydrofurans. We are currently examining the optimization
and application of the methodology described herein towards the total synthesis of natural
products.
Acknowledgements
E.P.G. thanks the University of Ioannina for an INTERREG II fellowship. The authors also
thank Prof. Dr Waldemar Adam and Prof. Dr Armin de Meijere for their generous support.
References
1. For general references on synthetic applications of carbenes (or carbenoids), see: (a) Padwa, A.; Weingarten, M.
D. Chem. Rev. 1996, 96, 223–269. (b) Miller, D. J.; Moody, C. J. Tetrahedron 1995, 51, 10811–10843. (c) Ye, T.;
McKervey, M. A. Chem. Rev. 1994, 94, 1091–1160. (d) Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48,
5385–5453.
2. (a) Koser, G. F. In The Chemistry of Functional Groups, Supplement D; Wiley: New York, 1983; Chapter 18. (b)
Varvoglis, A. In The Organic Chemistry of Polycoordinated Iodine; VCH Publishers: New York, 1992. (c)
Varvoglis, A. In Hypervalent Iodine in Organic Synthesis; Academic Press: London, 1997.
3. (a) For a general synthesis of b-dicarbonyl iodonium ylides, see: Schank, K.; Lick, C. Synthesis 1983, 393–395.
(b) For a general synthesis of b-disulfonyl iodonium ylides, see: Hadjiarapoglou, L.; Varvoglis, A.; Alcock, N.
W.; Pike, G. A. J. Chem. Soc., Perkin Trans. 1 1988, 2839–2846.
4. Mu¨ller, P.; Fernandez, D. Helv. Chim. Acta 1995, 78, 947–958.
5. (a) Moriarty, R. M.; Prakash, O.; Vaid, R. K.; Zhao, L. J. Am. Chem. Soc. 1989, 111, 6443–6444. (b) Moriarty,
R. M.; Kim, J.; Guo, L. Tetrahedron Lett. 1993, 34, 4129–4132. (c) Spyroudis, S.; Tarantili, P. J. Org. Chem.
1993, 58, 4885–4889. (d) Moriarty, R. M.; May, E. J.; Prakash, O. Tetrahedron Lett. 1997, 38, 4333–4336. (e)
Moriarty, R. M.; May, E. J.; Guo, L.; Prakash, O. Tetrahedron Lett. 1998, 39, 765–766. (f) Alexiou, I.; Gogonas,
E. P.; Hadjiarapoglou, L. P. Synlett 1999, 1925–1926.
6. (a) Hadjiarapoglou, L.; Spyroudis, S.; Varvoglis, A. J. Am. Chem. Soc. 1985, 107, 7178–7179. (b) Hadjiara-
poglou, L. P. Tetrahedron Lett. 1987, 28, 4449–4450. (c) Hadjiarapoglou, L. P.; Schank, K. Tetrahedron Lett.
1989, 30, 6673–6676. (d) Hadjiarapoglou, L.; Varvoglis, A. J. Chem. Res. 1983, 306–307. (e) Hadjiarapoglou, L.;
Varvoglis, A. J. Chem. Soc., Perkin Trans. 1 1989, 379–382. (f) Hadjiarapoglou, L.; Varvoglis, A. J. Heterocycl.
Chem. 1988, 25, 1599–1600. (g) Hadjiarapoglou, L.; Varvoglis, A. Synthesis 1988, 913–915. (h) Hadjiarapoglou,
L. P.; Schank, K. Tetrahedron 1997, 53, 9365–9376. (i) Asouti, A.; Hadjiarapoglou, L. Tetrahedron Lett. 1998, 39,
9073–9076.
7. Koser, G. F.; Yu, S.-M. J. Org. Chem. 1975, 40, 1166–1168. We found that reproducible yields of >95% could
be isolated by following the described procedure, but with extending the stirring for 90 min at room temperature,
instead of 15 min.
8. Hayasi, Y.; Okada, T.; Kawanisi, M. Bull. Chem. Soc. Jpn. 1979, 43, 2506–2511.
9. Representative experimental procedure. Synthesis of 5d. A mixture of iodonium ylide (0.7 g, 2.05 mmol),
phenylacetylene (1.0 g, 9.80 mmol) and catalytic amounts of Rh2(OAc)4 was heated at 110°C for 3 min. The
reaction mixture was subjected to column chromatography (silica gel, CH2Cl2“CH2Cl2/EtOAc 4:1) to afford

9303
furan 5d10 (0.25 g, 47% yield), yellowish crystals: mp 102–103°C (CHCl3/petroleum ether); IR (KBr) w 3120, 3040,
3020, 2940, 2910, 2850, 1660, 1610, 1550, 1480, 1445, 1430, 1400, 1360, 1330, 1210, 1155, 1130, 1120, 1040, 1005,
1
970, 920, 900, 790, 750, 685, 650, 620 cm−1; H NMR (250 MHz, CDCl3) l 1.16 (s, 6H), 2.39 (s, 2H), 2.81 (s,
2H), 6.88 (s, 1H), 7.26–7.42 (m, 3H), 7.63–7.66 (m, 2H); 13C NMR (63 MHz, CDCl3) l 28.5, 35.2, 37.3, 51.9,
100.6, 121.5, 123.7, 127.9, 128.7, 129.7, 154.4, 165.7, 193.8. Synthesis of 7a. A suspension of iodonium ylide (0.7
g, 2.05 mmol), catalytic amounts of Rh2(OAc)4 in acetonitrile (10 mL) was refluxed for 60 min. The solvent was
removed, and the crude product was purified by column chromatography (silica gel, CH2Cl2“CH2Cl2/EtOAc
3:1) to afford oxazole 7a (0.25 g, 68% yield), white crystals: mp 76–77°C (petroleum ether); IR (neat) w, 2960,
2930, 2870, 1690, 1615, 1590, 1400, 1370, 1340, 1305, 1250, 1205, 1180, 1120, 1050, 1020, 975, 920, 900, 890, 805,
1
795, 690 cm−1; H NMR (250 MHz, CDCl3) l 1.11 (s, 6H), 2.37 (s, 2H), 2.43 (s, 3H), 2.73 (s, 2H); 13C NMR
(63 MHz, CDCl3) l 13.9, 28.5, 35.4, 35.9, 51.5, 133.2, 161.8, 163.1, 190.7; MS m/z 179 (43, M+), 164(16),
123(100), 95(44), 43(64); anal. calcd for C10H13NO2: C, 60.72; H, 7.31; N, 7.82. Found: C, 60.60; H, 7.25; N, 7.70.
10. Kalogiannis, S.; Spyroudis, S. J. Org. Chem. 1990, 55, 5041–5044.
11. Yoshida, J.; Yano, S.; Ozawa, T.; Kawabata, N. J. Org. Chem. 1985, 50, 3467–3473.
.