[2+2] and [2+4] type cycloadditions of isocyanates with ynolates

Article abstract of DOI:10.3987/COM-05-S(K)9

Ynolates react with isocyanates to give azetidine-2,4-diones via a [2+2] type cycloaddition. The [4+2] type cycloaddition proceeds in the reactions of vinyl isocyanates with ynolates to provide 2-pyridones.

Full text of DOI:10.3987/COM-05-S(K)9

HETEROCYCLES, Vol. 66, 2005
39
HETEROCYCLES, Vol. 66, 2005, pp. 39 – 43. © The Japan Institute of Heterocyclic Chemistry
Received, 25th July, 2005, Accepted, 15th August, 2005, Published online, 16th August, 2005. COM-05-S(K)9
[2 + 2] AND [2 + 4] TYPE CYCLOADDITIONS OF ISOCYANATES WITH
YNOLATES#
Mitsuru Shindo,*† Akiko Harada,‡ Kenji Matsumoto,‡ and Kozo Shishido‡
†Institute for Materials Chemistry and Engineering, Kyushu University, 6-1,
Kasugako-en, Kasuga 816-8580, Japan
shindo@cm.kyushu-u.ac.jp
‡Institute of Health Biosciences, The University of Tokushima Graduate School,
Sho-machi 1, Tokushima 770-8505, Japan
Abstract–Ynolates react with isocyanates to give azetidine-2,4-diones via a [2 +
2] type cycloaddition. The [4 + 2] type cycloaddition proceeds in the reactions of
vinyl isocyanates with ynolates to provide 2-pyridones.
The cycloaddition of isocyanates, electrophilic heterocumulenes, with double-bond-containing substrates
is a valuable method for the synthesis of heterocycles, such as azetidin-2-ones (β-lactams).1 In many
cases, activated isocyanates bearing an electron-withdrawing group have been used in the cycloadditions.2
Because ynolates are regarded as having electron-rich triple bond functionality, they are expected to
cycloadd to various kinds of dipoles.3 Since our development of a new synthetic method for ynolates,4 we
have found that the [2 + 2] cycloaddition with aldimines gives β-lactams5 and that the [3 + 2]
cycloaddition with nitrones furnishes 5-isoxazolidinones6 (Scheme 1). Based on the high nucleophilicity
of ynolates, we envisioned an efficient cycloaddition of ynolates to isocyanates under mild conditions to
provide heterocycles. We now disclose the [2 + 2] and [4 + 2] type cycloadditions of unactivated
isocyanates with ynolates furnish azetidine-2,4-diones and 2-pyridones.
The ynolate (2a),12 generated from ethyl 2,2-dibromopropionate (1a) with t-BuLi, was treated with phenyl
isocyanate (3) at -78 °C, stirred for 5 min, and quenched with acetic acid in THF. After the usual workup,
followed by column chromatography, the cyclized product, the azetidine-2,4-dione (6a), was isolated in
18% yield, along with the ethyl ester (7) (23%) and the ethyl carbamate (8) (37%), which would be
derived from the addition of lithium ethoxide, released in the preparation of the ynolate (2a), to the ketene
(4) and the isocyanate (3), respectively (Scheme 2).

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HETEROCYCLES, Vol. 66, 2005
H+
-78 °C
Bu
Ph
O
Ts
Bu
+
N
N
Ph
Ph
OLi
OLi
Ts
O
Me
H+
Bn
-78 °C
Me
Ph
N+
+
O
N
Bn
O-
Scheme 1
Ph
3
O
Me
O
N C O
t-BuLi
Me
Br Br
1a
CO2Et
PhN C
PhN
O
C Me
OLi
EtOLi
C
Me
2a
4
5a
EtOLi
O
O
H+
H+
PhNHCO2Et
37%
Ph
HN
PhN C
EtOLi
O
OEt
8
PhN
O
O
O
H+
Me
PhN C
O C
C Me
OEt
Me
23%
18%
6a
EtO2C
7
Scheme 2
To circumvent the generation of these side products, phenyl esters (9) were used as ynolate precursors,
since phenoxide should be less nucleophilic than ethoxide. Consequently, as shown in Scheme 3, the
azetidine-2,4-diones (6) were obtained in better yields.7,8
O
O
Ph
R
PhN
O
PhN
O
H+
N C O
t-BuLi
R
CO2Ph
Br Br
Me
Me
OLi
2
9
PhOLi
6a: R = Me: 33%
6b: R = Bu: 30%
6c: R = t-Bu: 29%
Scheme 3
The sterically hindered 2,6-dialkylphenyl isocyanates (10), however, did not give the azetidine-2,4-diones
but instead the phenyl esters (12), because the cyclization would be inhibited by steric hindrance (Scheme
4). This finding supports the generation of the ketene intermediates (e.g., 4, 11) via a stepwise mechanism,
and not the concerted mechanism, of the four membered ring formations using ynolates.9

HETEROCYCLES, Vol. 66, 2005
41
O
O
ArN C
C Bu
C
Ar
HN
O
R
ArN C
O C
Bu
2b
H+
C Bu
OPh
+
Bu
12
N C O
PhO2C
OLi
R
11
O
10
PhOLi
R = Me: 59%
R
Bu
CO2Ph
i-Pr: 44%
Ar:
Br Br
R
Scheme 4
We next examined the reaction of ynolates with a vinyl isocyanate (Scheme 5), which is a 1,4-dipole.10
The ynolate (2b) reacted with styryl isocyanate (13) at -100 °C to afford 4-hydroxy-2-pyridone (14) in
42% yield after quenching with 1 M HCl.11 The use of acetic anhydride in the workup instead of HCl
provided 4-acetoxy-2-pyridone (15) in slightly better yield, along with a small amount of the diacetate
(16). The hindered ynolates (R = t-Bu, SiMe3)12 also provided the pyridones (14) in moderate yields. This
cyclization can be regarded as a formal [4 + 2] cycloaddition via ynolates.13
O
H
N
N
O
O
R
O
R
H+
N C
-100 °C
0.5 h
R
Ph
C R
+
Ph
C
O
Ph
N C O
OLi
Ph
OH
13
2
14
R = Bu: 42%
t-Bu: 22%
Ac2O
R = Bu
H
Me3Si: 26%
Ac
O
R
N
O
N
+
Ph
16
Ph
R
OAc
3%
OAc
47%
15
Scheme 5
In conclusion, we have found that formal [2 + 2] and [4 + 2] cycloadditions of ynolates with isocyanates
provide 4-membered and 6-membered heterocycles. These new reactions demonstrate the synthetic
potential directed towards the synthesis of heterocycles via ynolates.
ACKNOWLEDGEMENTS
Support has been provided in part by a Grant-in-Aid for Scientific Research, the Ministry of Education,
Culture, Sports, Science and Technology, Japan.

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HETEROCYCLES, Vol. 66, 2005
REFERENCES AND NOTES
#Dedicated to the memory of the late Professor Kenji Koga.
1. For a review on isocyanates, see: S. Ozaki, Chem. Rev., 1972, 72, 457.
2. For reviews on activated isocyanates, see V. I. Gorbatenko, Tetrahedron, 1993, 49, 3227; J. K.
Rasmussen and A. Hassner, Chem. Rev., 1976, 76, 389; H. Ulrich, Chem. Rev., 1964, 64, 369.
3. For reviews, see: M. Shindo, Synthesis, 2003, 2275; M. Shindo, J. Syn. Org. Chem. Jpn., 2000, 58,
1155; M. Shindo, Yakugaku Zasshi, 2000, 120, 1233; M. Shindo, Chem. Soc. Rev., 1998, 27, 367.
4. M. Shindo, Tetrahedron Lett., 1997, 38, 4433; M. Shindo, Y. Sato, and K. Shishido, Tetrahedron,
1998, 54, 2411; M. Shindo, R. Koretsune, W. Yokota, K. Itoh, and K. Shishido, Tetrahedron Lett.,
2001, 42, 8357.
5. M. Shindo, S. Oya, Y. Sato, and K. Shishido, Heterocycles, 1998, 49, 113; M. Shindo, S. Oya, R.
Murakami, Y. Sato, and K. Shishido, Tetrahedron Lett., 2000, 41, 5943.
6. M. Shindo, K. Itoh, C. Tsuchiya, and K. Shishido, Org. Lett., 2002, 4, 3119; M. Shindo, K. Itoh, K.
Otsuki, C. Tsuchiya, and K. Shishido, Synthesis, 2003, 1441.
7. For selected reports on the preparation of azetidine-2,3-diones, see: S. S. Bari, I. R. Trehan, A. K.
Sharma, and M. S. Manhas, Synthesis, 1992, 439; H. Aoyama, M. Sakamoto, and Y. Omote, Chem.
Lett., 1982, 1211; G. Cainelli, D. Giacomini, M. Panunzio, G. Martelli, and G. Spunta, Tetrahedron
Lett., 1987, 28, 3593; K. Maruyama, T. Ishitoku, and Y. Kubo, J. Org. Chem., 1981, 46, 27; J. C.
Martin, R. D. Burpitt, P. G. Gott, M. Harris, and R. H. Meen, J. Org. Chem., 1971, 36, 2205.
8. A representative procedure: To a solution of phenyl 2,2-dibromopropionate (370 mg, 1.2 mmol) in
THF (8 mL) was added a solution of tert-butyllithium (1.52 M in pentane, 3.2 mL, 4.8 mmol) at
-78 °C. The reaction was stirred for 3 h then warmed to 0 °C. After 0.5 h, the reaction was cooled to
-78 °C, and a solution of phenyl isocyanate (119 mg, 1.0 mmol) in THF (2 mL) was added all at
once. After 3~10 min, the reaction was quenched with a solution of acetic acid (0.15 g, 2.5 mmol) in
THF (1 mL). After the usual workup and purification by column chromatography, 58 mg (33%) of
3-methyl-1-phenylazetidine-2,4-dione was isolated as colorless prisms; mp 35.2 °C (AcOEt/hexane);
1H-NMR (400 MHz, CDCl3) δ: 1.51 (d, J = 7.6 Hz, 3H), 3.91 (q, J = 7.6 Hz, 1H), 7.27 (t, J = 8 Hz,
1H), 7.41 (t, J = 8 Hz, 2H), 7.83 (d, J = 8 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ: 9.8, 56.2, 118.9,
126.7, 129.1, 134.1, 168.9; IR (CHCl3): 1860, 1765, 1733 cm-1; MS (EI): m/z 175 (M+); Anal. Calcd
for C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.42; H, 5.17; N, 7.98.
9. The theoretical study on the mechanism of the alkene-isocyanate cycloaddition to form β-lactams
indicates a concerted mechanism, see: F. P. Cossio, B. Lecea, X. Lopez, G. Roa, A. Arrieta, and J. M.
Ugalde, J. Chem. Soc., Chem. Commun., 1993, 1450.
10. For a review, see: J. H. Rigby, Synlett, 2000, 1.

HETEROCYCLES, Vol. 66, 2005
43
11. Synthesis of 4-hydroxy-2-pyridone using vinyl isocyanates with β-keto esters; see: J. H. Rigby and F.
J. Burkhardt, J. Org. Chem., 1986, 51, 1374.
12. The ynolates (R = t-Bu and SiMe3) were prepared from phenyl 2,2-dibromo-3,3-dimethylbutyrate,
and ethyl 2,2-dibromo-2-trimethylsilylacetate, respectively. For the preparation, see: M. Shindo, Y.
Sato, R. Koretsune, T. Yoshikawa, K. Matsumoto, K. Itoh, and K. Shishido, Chem. Pharm. Bull.,
2003, 51, 477.
13. For another example of a [4 + 2] cycloaddition of ynolates, see: H. Kai, K. Iwamoto, N. Chatani, and
S. Murai, J. Am. Chem. Soc., 1996, 118, 7634.