New synthesis of t-butyl arylpropiolates using diazo(trimethylsilyl)methylmagnesium bromide

Article abstract of DOI:10.1016/j.tetlet.2008.05.155

Diazo(trimethylsilyl)methylmagnesium bromide smoothly reacted with t-butyl aryl(oxo)acetates to afford the corresponding arylpropiolates via alkylidenecarbene intermediates. In this reaction system, the magnesium bromide salt of trimethylsilyldiazomethane was significantly efficient compared to the lithium one, commonly known as a reagent for the conversion of aldehydes and aryl ketones into acetylenes.

Full text of DOI:10.1016/j.tetlet.2008.05.155

Tetrahedron Letters 49 (2008) 4965–4967
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Tetrahedron Letters
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New synthesis of t-butyl arylpropiolates using
diazo(trimethylsilyl)methylmagnesium bromide
*
Yoshiyuki Hari, Koji Date, Ryosuke Kondo, Toyohiko Aoyama
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho, Nagoya 467-8603, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Diazo(trimethylsilyl)methylmagnesium bromide smoothly reacted with t-butyl aryl(oxo)acetates to
afford the corresponding arylpropiolates via alkylidenecarbene intermediates. In this reaction system,
the magnesium bromide salt of trimethylsilyldiazomethane was significantly efficient compared to the
lithium one, commonly known as a reagent for the conversion of aldehydes and aryl ketones into
acetylenes.
Received 22 April 2008
Revised 20 May 2008
Accepted 22 May 2008
Available online 12 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Aryl(oxo)acetates
Arylpropiolates
Diazo(trimethylsilyl)methylmagnesium
bromide
a
-Ketoesters
Trimethylsilyldiazomethane
Table 1
Arylpropiolates have attracted attention as useful intermediates
in organic synthesis,1 and have been generally prepared by modi-
fied Wittig methodology using acid chlorides and triphenylphos-
phoranylidene acetates followed by flash vacuum pyrolysis,2
Corey–Fuchs homologation3 of aryl aldehydes followed by treat-
ment of the resulting aryl acetylides with chloroformates, cross-
coupling reactions of aryl iodides with propiolates (modified Sono-
gashira reaction),4 or reaction of aldehydes with Ph3P and
Br3CCO2Et.5
Examination of reaction conditions
O
TMSC(M)N2
CO2R
MeO
CO2R
THF
Conditions
MeO
1 and 3a
2 and 4a
Entry Substrate
TMSC(M)N2
Conditions
Yield
(%)
Quite recently, we have reported a convenient preparation of
arylpropiolates from aryl aldehydes using lithium trimethylsilyl-
diazomethane (TMSC(Li)N2) in one-pot process, which involves
the homologation of aldehydes to aryl acetylenes6 via alkylidene-
carbene intermediates, followed by ethoxycarbonylation of the
resulting acetylenes with ethyl chloro(or cyano)formate.7 As an
extension of this work, we now wish to describe a new and conve-
nient synthesis of arylpropiolates from aryl(oxo)acetates via alkyl-
idenecarbene intermediates.
Initially, the examination of reaction conditions using
(p-methoxyphenyl)(oxo)acetates was carried out as shown in
Table 1.8,9 Similarly to the preparation of arylacetylenes from aryl
ketones,6 upon treatment of 1 with TMSC(Li)N2 in THF at À78 °C
followed by heating under reflux conditions, 1 was converted to
the desired (p-methoxyphenyl)propiolate 2, but the yield was very
1
2
1 (R = Et)
3a
TMSC(Li)N2 (1.2 equiv)
TMSC(Li)N2 (1.2 equiv)
À78 °C, 1 h?reflux, 3 h 11 (2)
À78 °C, 1 h?reflux, 3 h 20
(4a)
(R = But)
3a
3
4
5
6
TMSC(MgBr)N2
(1.5 equiv)
TMSC(MgBr)N2
(1.5 equiv)
TMSC(MgBr)N2
(1.5 equiv)
TMSC(MgBr)N2
(1.5 equiv)
À78 °C, 1.5 h?reflux,
54
(4a)
1 h
3a
3a
3a
À78 °C, 3 h?reflux, 1 h 56
(4a)
À78 °C, 3 h?reflux, 2 h 64
(4a)
À78 °C, 3 h?reflux, 3 h 60
(4a)
low (entry 1). In this reaction, there is a possibility that the reaction
of TMSC(Li)N2 with an ester moiety of 1 competes with that with a
ketone moiety. Therefore, the ethyl ester of 1 was replaced by more
bulky tert-butyl ester 3a. As a result, the use of 3a as a substrate led
to a slight increase in the yield of the corresponding acethylene 4a
(entry 2). Interestingly, by changing the counter cation of
TMSC(Li)N2 from Li to MgBr,10 the reaction efficiency was
* Corresponding author. Tel./fax: +81 52 836 3439.
E-mail address: aoyama@phar.nagoya-cu.ac.jp (T. Aoyama).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.155

4966
Y. Hari et al. / Tetrahedron Letters 49 (2008) 4965–4967
Table 2
References and notes
Examination of reaction conditions
1. For recent examples: Evans, P. A.; Lai, K. W.; Sawyer, J. R. J. Am. Chem. Soc. 2005,
O
127, 12466–12467; Leonard, K.; Pan, W.; Anaclerio, B.; Gushue, J. M.; Guo, Z.;
DesJarlais, R. L.; Chaikin, M. A.; Lattanze, J.; Crysler, C.; Manthey, C. L.; Tomczuk,
B. E.; Marugan, J. J. Bioorg. Med. Chem. Lett. 2005, 15, 2679–2684; Gabillet, S.;
Lecerclé, D.; Loreau, O.; Dézard, S.; Gomis, J.-M.; Taran, F. Synthesis 2007, 515–
522; Lewandowska, E. Tetrahdron 2007, 63, 2107–2122; Gabillet, S.; Lecerclé,
D.; Loreau, O.; Carboni, M.; Dézard, S.; Gomis, J.-M.; Taran, F. Org. Lett. 2007, 9,
3925–3927; Carboni, M.; Gomis, J.-M.; Loreau, O.; Taran, F. Synthesis 2008,
417–424.
TMSC(MgBr)N2 (1.5 eq.)
Ar
CO2But
Ar
CO2But
THF
–78 °C, 3 h → reflux, 2 h
3
4
Entry
Ar
Substrate
Yield (%)
1a
2
p-(MeO)Ph
Ph
p-ClPh
3a
3b
3c
3d
3e
3f
3g
3h
3i
64 (4a)
58 (4b)
52 (4c)
58 (4d)
61 (4e)
16 (4f)
27 (4g)
52 (4h)
54 (4i)
42 (4j)
2. Märkl, G. Chem. Ber. 1961, 94, 3005–3010.
3. Corey, E. J.; Fuchs, P. L. Tetrahdron Lett. 1972, 3769–3772.
4. Anastasia, L.; Negishi, E. Org. Lett. 2001, 3, 3111–3113 and references cited
therein; Lecerclé, D.; Mothes, C.; Taran, F. Synth. Commun. 2007, 37, 1301–
1311.
5. Kim, J.-G.; Kang, D. H.; Jang, D. O. Synlett 2008, 443–447.
6. Miwa, K.; Aoyama, T.; Shioiri, T. Synlett 1994, 107–108; Hari, Y.; Kanie, T.;
Aoyama, T. Tetrahedron Lett. 2006, 47, 1137–1139.
3
4
5
6
7
8
9
10
o-MePh
2-Naphthyl
2-Pyridyl
3-Pyridyl
2-Furyl
2-Thienyl
2-Benzo[b]thienyl
7. Hari, Y.; Date, K.; Aoyama, T. Heterocycles 2007, 74, 545–552.
8. General procedure: MgBr2 (1.0 M in ether and toluene (1:1) solution, 0.75 ml,
0.75 mmol) was added dropwise to a solution of TMSC(Li)N2, prepared from
TMSCHN2 (1.80 M in hexane solution, 0.42 ml, 075 mmol) and n-BuLi (1.60 M
in hexane solution, 0.47 ml, 0.75 mmol) in THF (4.0 ml), at À78 °C under an
argon atmosphere and the mixture was stirred at À78 °C for 0.5 h. After
addition of a solution of the t-butyl aryl(oxo)acetate 3 (0.5 mmol) in THF
(1.0 ml) at À78 °C, the reaction mixture was stirred at À78 °C for 3 h and then
refluxed for 2 h. After being quenched with satd NH4Cl aq at 0 °C, the mixture
was extracted with ethyl acetate (three times). The organic extracts were
washed with water and brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (BW-820
MH) to give the t-butyl arylpropiolate 4.
3j
a
Shown in entry 5 of Table 1.
O
CONMe2
MeO
5
9. Selected data for 2, 4a–j and 6: Compound 2a, Ref. 15. Compound 4a, 1H NMR
(CDCl3) d: 1.54 (s, 9H), 3.83 (s, 3H), 6.87 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz,
2H). 13C NMR (CDCl3) d: 28.1, 55.3, 81.4, 83.1, 84.5, 111.7, 114.1, 134.6, 153.2,
TMSC(MgBr)N2 (1.5 eq.)
THF
rt, 16 h → reflux, 2 h
(29%)
161.0. IR (neat)
NMR (CDCl3) d: 1.54 (s, 9H), 7.33 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H). 13
NMR (CDCl3) d: 28.2, 82.4, 82.8, 83.7, 118.5, 128.9, 133.9, 136.6, 152.8. IR (neat)
: 2212, 1709 cmÀ1. Compound 4d, 1H NMR (CDCl3) d: 1.55 (s, 9H), 2.48 (s, 3H),
7.12–7.25 (m, 2H), 7.31 (dt, J = 1.5, 7.5 Hz, 1H), 7.52 (dd, J = 1.3, 7.5 Hz, 1H). 13
NMR (CDCl3) d: 20.7, 28.1, 82.8, 83.3, 85.7, 119.7, 125.6, 129.6, 130.1, 133.1,
m
: 2205, 1699 cmÀ1. Compound 4b, Ref. 16. Compound 4c, 1H
C
m
C
MeO
CONMe2
141.9, 153.1. IR (neat) m
: 2206, 1701 cmÀ1. Compound 4e, 1H NMR (CDCl3) d:
1.57 (s, 9H), 7.49–7.58 (m, 2H), 7.77–7.85 (m, 4H), 8.13 (s, 1H). 13C NMR
6
(CDCl3) d: 28.2, 82.2, 83.5, 84.2, 117.1, 126.8, 127.6, 127.7, 128.0, 128.2, 128.2,
Scheme 1.
132.5, 133.6, 133.8, 153.0. IR (nujol) m
: 2216, 1703 cmÀ1. Compound 4f, 1H
NMR (CDCl3) d: 1.53 (s, 9H), 1.32 (ddd, J = 1.2, 4.8, 7.7 Hz, 1H), 7.56 (td, J = 1.2,
7.7 Hz, 1H), 7.69 (dt, J = 1.8, 7.7 Hz, 1H), 8.63 (ddd, J = 1.2, 1.8, 4.8 Hz, 1H). 13C
NMR (CDCl3) d: 28.1, 80.6, 81.6, 83.9, 124.2, 128.2, 136.1, 140.8, 150.3, 152.3. IR
dramatically improved and 4a was obtained in 54–64% yields
(entries 3–6).
(neat) m
: 2220, 1713 cmÀ1. Compound 4g, 1H NMR (CDCl3) d: 1.54 (s, 9H), 7.30
(ddd, J = 1.0, 4.9, 7.9 Hz, 1H), 7.84 (ddd, J = 1.6, 2.1, 7.9 Hz, 1H), 8.62 (dd, J = 1.6,
4.9 Hz, 1H), 8.78 (dd, J = 1.0, 2.1 Hz, 1H). 13C NMR (CDCl3) d: 28.1, 80.0, 84.0,
Next, using the optimized reaction conditions (entry 5 in
Table 1), the reactions with various t-butyl aryl(oxo)acetates were
examined (Table 2).8,9 Analogously to 3a, TMSC(MgBr)N2 smoothly
reacted with t-butyl aryl(oxo)acetates such as phenyl (3b), p-chlo-
rophenyl (3c), o-tolyl (3d), or 2-naphthyl (3e) ones to afford the
corresponding arylpropiolates 4b–e in 52–61% yields (entries 1–
5). Substituents on the benzene ring of 3 did not significantly affect
the yield of 4. Pyridyl derivatives 3f and 3g also underwent the
reaction giving desired 4f and 4g, but the yields were 16% and
27%, respectively (entries 6 and 7). The low yields of 4f and 4g were
probably due to poor migration ability of the electron-deficient
pyridine ring. The reactions with 3h–j bearing five-membered het-
eroacromatics also proceeded to give the corresponding propio-
lates 4h–j in moderate yields (entries 7–9). In addition, the
reaction was applicable to the synthesis of arylpropiolamide 6
from aryl(oxo)acetamide 5, though prolonged reaction time was
required and the yield was low (Scheme 1).9,11
84.9, 117.3, 123.0, 139.6, 150.2, 152.4, 153.0. IR (neat) m .
: 2216, 1713 cmÀ1
Compound 4h, 1H NMR (CDCl3) d: 1.53 (s, 9H), 6.44 (dd, J = 1.8, 3.5 Hz, 1H), 6.88
(dd, J = 0.8,3.5 Hz, 1H), 7.48 (dd, J = 0.8, 1.8 Hz, 1H). 13C NMR (CDCl3) d: 28.2,
74.1, 83.9, 86.9, 111.4, 120.3, 134.8, 145.7, 152.6. IR (neat) m .
: 2210, 1705 cmÀ1
Compound 4i, 1H NMR (CDCl3) d: 1.54 (s, 9H), 7.03 (dd, J = 3.6, 5.1 Hz, 1H), 7.42
(dd, J = 1.2, 5.1 Hz, 1H), 7.45 (dd, J = 1.2, 3.6 Hz, 1H). 13C NMR (CDCl3) d: 28.2,
77.7, 83.6, 86.1, 119.8, 127.3, 130.5, 135.9, 152.8. IR (neat) m .
: 2208, 1703 cmÀ1
Compound 4j, 1H NMR (CDCl3) d: 1.56 (s, 9H), 7.35–7.43 (m, 2H), 7.75–7.81 (m,
2H). 13C NMR (CDCl3) d: 28.1, 77.6, 83.9, 87.0, 119.6, 122.0, 124.4, 124.9, 126.5,
133.0, 138.3, 141.1, 152.5. IR (neat) m
: 2210, 1703 cmÀ1. Compound 6, 1H NMR
(CDCl3) d: 3.02 (s, 3H), 3.28 (s, 3H), 3.83 (s, 3H), 6.87 (d, J = 8.8 Hz, 2H), 7.49 (d,
J = 8.8 Hz, 2H). 13C NMR (CDCl3) d: 34.2, 38.5, 55.4, 80.8, 90.7, 112.4, 114.1,
134.0, 154.8, 160.8. IR (neat) m .
: 2206, 1628 cmÀ1
10. Reactions using TMSC(MgBr)N2: Hari, Y.; Tsuchida, S.; Aoyama, T. Tetrahedron
Lett. 2006, 47, 1977–1980; Hari, Y.; Tsuchida, S.; Sone, R.; Aoyama, T. Synthesis
2007, 3371–3375.
11. In this reaction, 5 was recovered in 5% yield.
12. Nimitz, J. S.; Mosher, H. S. J. Org. Chem. 1981, 46, 211–213; Creary, X. J. Org.
Chem. 1987, 52, 5026–5030.
13. Synthesis of 3a: A solution of 4-methoxyphenylmagnesium bromide, prepared
from 1-bromo-4-methoxybenzene (1.87 g, 10 mmol) and magnesium turnings
(225 mg, 10.5 mmol) in THF (10 ml), was added dropwise to tert-butyl ethyl
oxalate (1.92 g, 11 mmol) in THF (10 ml) at À78 °C under an argon atmosphere
and the mixture was stirred at À78 °C for 2 h. After being quenched with satd
NH4Cl aq at À78 °C, the mixture was extracted with ethyl acetate (three times).
The organic extracts were washed with water and brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (BW-820 MH, hexane–ethyl acetate = 50:1) to
give 3a (1.94 g, 82%) as a colorless oil.
In conclusion, the present method makes possible the easy con-
version of aryl(oxo)acetates, readily prepared from arylmetals
(arylmagnesium bromide or aryllithium) and oxalate deriva-
tives,12–14 to arylpropiolates and will provide an added flexibility
in the synthesis of arylpropiolates.
14. Selected data for 1, 3a–j and 5: Compound 1, Ref. 17. Compound 3a, Ref. 18.
Compound 3b, Ref. 18. Compound 3c, Ref. 18. Compound 3d, 1H NMR (CDCl3)
d: 1.62 (s, 9H), 2.61 (s, 3H), 7.24–7.36 (m, 2H), 7.46 (dt, J = 1.1, 7.4 Hz, 1H), 7.68
(dd, J = 1.1, 7.7 Hz, 1H). 13C NMR (CDCl3) d: 21.6, 28.0, 84.3, 125.7, 131.0, 132.0,
Acknowledgement
This work was financially supported by a Grant-in-Aid for
Scientific Research (KAKENHI).
132.2, 133.3, 141.1, 164.1, 188.9. IR (neat) m
: 1728, 1682 cmÀ1. Compound 3e,

Y. Hari et al. / Tetrahedron Letters 49 (2008) 4965–4967
4967
Ref. 17. Compound 3f, 1H NMR (CDCl3) d: 1.62 (s, 9H), 7.49 (ddd, J = 1.1, 4.8, 1H), 7.85–7.89 (m, 1H), 7.92 (dd, J = 1.2, 7.9 Hz, 1H), 8.31 (d, J = 0.7 Hz, 1H). 13
C
7.8 Hz, 1H), 7.86 (dt, J = 1.6, 7.8 Hz, 1H), 8.06 (td, J = 1.1, 7.8 Hz, 1H), 8.72 (ddd,
J = 1.1, 1.6, 4.8 Hz, 1H). 13C NMR (CDCl3) d: 28.3, 84.7, 123.2, 127.7, 136.9,
NMR (CDCl3) d: 28.0, 85.0, 122.8, 125.2, 126.6, 128.3, 134.4, 138.7, 138.8, 143.5,
160.9, 179.1. IR (nujol) m
: 1736, 1651 cmÀ1. 5, Ref. 19.
149.6, 150.6, 164.6, 187.2. IR (neat)
m
: 1736, 1711 cmÀ1. Compound 3g, 1H NMR
15. Sakamoto, T.; Shiga, F.; Yasuhara, A.; Uchiyama, D.; Kondo, Y.; Yamanaka, H.
Synthesis 1992, 746–748.
16. Lipshutz, B. H.; Huff, B. E.; McCarthy, K. E.; Miller, T. A.; Mukarram, S. M. J.;
Siahaan, T. J.; Vaccaro, W. D.; Wedd, H.; Falick, A. M. J. Am. Chem. Soc. 1990, 112,
7032–7041.
17. Adams, D. L.; Vaughan, W. R. J. Org. Chem. 1972, 37, 3906–
3913.
18. Yang, J. W.; Benjamin, L. Org. Lett. 2006, 8, 5653–5655.
19. Cunico, R. F.; Pandey, R. K. J. Org. Chem. 2005, 70, 5344–5346.
(CDCl3) d: 1.64 (s, 9H), 7.46 (ddd, J = 0.8, 4.9, 8.0 Hz, 1H), 8.30 (ddd, J = 1.8, 2.2,
8.0 Hz, 1H), 8.84 (dd, J = 1.8, 4.9 Hz, 1H), 9.20 (dd, J = 0.8, 2.2 Hz, 1H). 13C NMR
(CDCl3) d: 28.1, 85.4, 123.6, 128.5, 136.9, 151.3, 154.4, 162.0, 185.1. IR (neat) m:
1728, 1693 cmÀ1. Compound 3h, Ref. 16. Compound 3i, 1H NMR (CDCl3) d: 1.61
(s, 9H), 7.16 (dd, J = 4.0, 4.9 Hz, 1H), 7.16 (dd, J = 1.2, 4.9 Hz, 1H), 8.02 (dd,
J = 1.2, 4.0 Hz, 1H). 13C NMR (CDCl3) d: 28.0, 84.8, 128.4, 136.5, 136.7, 139.1,
161.1, 177.4. IR (neat)
m
: 1728, 1666 cmÀ1. Compound 3j, 1H NMR (CDCl3) d:
1.64 (s, 9H), 7.41 (ddd, J = 1.0, 7.1, 7.9 Hz, 1H), 7.49 (ddd, J = 1.2, 7.1, 8.2 Hz,