Fluoroquinolones from imidoylketenes and iminopropadienones, RN≤C≤C≤C≤O

Article abstract of DOI:10.1071/CH08515

3-Fluoro-, 4-fluoro-, and 2,3,4-trifluorophenyliminopropadienones have been generated by flash vacuum thermolysis (FVT) of 5-[(fluoroarylamino) methoxymethylene]-2,2-dimethyldioxan-4,6-dione (Meldrum's acid) derivatives. Their reaction with methanol affor

Full text of DOI:10.1071/CH08515

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2009, 62, 115–120
Fluoroquinolones from Imidoylketenes and
Iminopropadienones, R–N=C=C=C=O
Belinda E. FulloonA and Curt WentrupA,B
ASchool of Chemistry and Molecular Biosciences, The University of Queensland,
Brisbane, Qld 4072, Australia.
BCorresponding author. Email: wentrup@uq.edu.au
3-Fluoro-, 4-fluoro-, and 2,3,4-trifluorophenyliminopropadienones have been generated by flash vacuum thermolysis
(FVT) of 5-[(fluoroarylamino)methoxymethylene]-2,2-dimethyldioxan-4,6-dione (Meldrum’s acid) derivatives. Their
reaction with methanol affords interconverting imidoylketenes and oxoketenimines, which are employed in a synthe-
sis of fluoroquinolones. The same quinolones are obtained from methyl 1-fluoroaryl-1,2,3-triazole-4-carboxylates, which
on FVT eliminate N2 to generate oxoketenimines. Rearrangement of the oxoketenimines to imidoylketenes and cyclization
afford the quinolones.
Manuscript received: 24 November 2008.
Final version: 18 December 2008.
O
O
O
O
Introduction
O
Route b
X
O
O
Route a
O
O
X
N
C
Quinolones form an important class of biologically active com-
pounds, especially well known for their antibiotic properties.[1]
Because of a dwindling approval rate for new antibiotics,[2] and
a rapid rise in microbial resistance, there is an urgent need for
research into the development of new types of antibiotics, includ-
ing new syntheses of quinolones, particularly fluoroquinolones.
It was shown in previous work that certain quinolones can
be synthesized by flash vacuum thermolysis (FVT) of Mel-
drum’s acid derivatives,[3] 1,2,3-triazoles,[4] and pyrrole-2,3-
diones.[5]
The mechanism of thermolysis of 5-aminomethylene deriva-
tives of Meldrum’s acid 1 has been elucidated previously.[3,6]
There are two routes, a and b (Scheme 1). Briefly, FVT results in
fragmentation of 1 to an imidoylketene 2, which interconverts
thermally with an oxoketenimine 3. Owing to a favourable lone
pair–lowest unoccupied molecular orbital (LUMO) interaction,
the barrier for this 1,3-shift is very low for X = OMe, SMe,
NMe2, and halogens.[7] The formation of 2 and 3 (route a) takes
place in competition with elimination of HX (X = OMe, SMe,
or NMe2) and formation of a transient but detectable ketenimine
4 (route b).
N
C
R
ꢀ CO2
ꢀ Me2CO
ꢀ HX
RNH
R
H
2
4
1
ꢀ CO2
ꢀ Me2CO
∼X
O
HX
X
N=C=C=C=O
H
R
5
2HX
C
HX
R
N
X
O
3
N
R
X
6
O
O
C
Rn
Rn
N
H
X
N
X
7
2
Scheme 1. Imidoylketene 2, oxoketenimine 3, and iminopropadienone 5
formation from Meldrum’s acid derivatives 1.
Further fragmentation of 4 by elimination of acetone and
CO2 leads to the iminopropadienone 5. Usually, 2 and 3 can be
observed spectroscopically and trapped chemically using FVT
temperatures of ∼400–500◦C. Increasing proportions of imino-
propadienone 5 are formed as the FVT temperature is increased
and, above 500–700◦C, this becomes the only product.[3,6a,8]
Iminopropadienones 5 can be observed spectroscopically, usu-
ally at temperatures below −100◦ to −50◦C, but a few examples
of stable, isolable iminopropadienones have been reported,[3,9]
namely the neopentyl, mesityl, o-tert-butylphenyl, 1-naphthyl,
and pentafluorophenyl derivatives.
in route a. These ketenimines and ketenes may react further with
HX to generate malonic imide esters 6.[3]
When R is an aromatic group with at least one unsubstituted
ortho position, the ketenes 2 can undergo an electrocyclic reac-
tion, resulting in the formation of quinolones 7. Both reaction
routes, a and b, lead to ketenimines 3, which interconvert rapidly
with ketenes 2. Thus, this system can be employed as a synthe-
sis of quinolones 7. For preparative purposes, it is advantageous
to use high FVT temperatures, e.g. 700◦C, where the imino-
propadienones 5 are the exclusive primary reaction products.
Subsequent addition of nucleophile and warm-up generate the
quinolones.
The iminopropadienones 5 react with nucleophiles (e.g. the
HX formed in the elimination step, or with added nucleophile)
to afford the same ketenimines 3 and ketenes 2 as were formed
Here, we report the use of the Meldrum’s acid and triazole
routes to generate fluoroquinolones.
© CSIRO 2009
10.1071/CH08515
0004-9425/09/020115

116
B. E. Fulloon and C. Wentrup
O
O
O
4
O
5
8
MeO
ArFNH
8
O
O
FVT
MeO
ArF
C
Fn
ꢀ CO2
ꢀ Me2CO
N
H
N1 OMe
H
10
12
a ArF ꢁ 3-FC6H4
b ArF ꢁ 4-FC6H4
c ArF ꢁ 2,3,4-F3C6H2
a Fn ꢁ 7-F
b Fn ꢁ 6-F
c Fn ꢁ 6,7,8-F3
∼OMe
ꢀ MeOH
ꢀ CO2
ꢀ Me2CO
FVT
O
MeO
ArF
MeOH
H
N=C=C=C=O
C
ArF
N
9
11
Scheme 2. Fluorophenyliminopropadienone and fluoroquinolone formation.
200°
300°
400°
500°
700°
P
I
P
K
K
P
I
I
K
2400
2150
1900
2400
2150
1900
2400
2150
1900
2400
2150
1900
2400
2150 1900
Fig. 1. Flash vacuum thermolysis (FVT) of 2,2-dimethyl-5-[2,3,4-trifluorophenylamino(methoxy)]-1,3-dioxan-4,6-dione 8c at 200–700◦C.
IR spectra of the products at 77 K. K = ketene 10c, I = ketenimine 11c. P = iminopropadienone 9c. Abscissae in wavenumbers (cm−1).
Results and Discussion
intermediate, the fluorophenyliminopropadienone 9 appeared,
giving rise to a very strong absorption at ∼2224 cm−1.At 500◦C,
the iminopropadienone 9 was almost the only species, and by
700◦C, 9 was the only product observed in the IR spectrum.
TheseobservationsareillustratedinFigsS1–S3(AccessoryPub-
lication). Compounds 9 were relatively long-lived, remaining
observable on the deposition window until ∼10◦C. We reported
recently that pentafluorophenyliminopropadienone is stable in
solution at room temperature for extended periods, so that its
13C NMR spectrum can be obtained easily.[9] All these results
suggest a stabilizing ‘fluorine effect’ (see also below).
Quinolones from Meldrum’s Acids
TheMeldrum’sacidderivatives8(Scheme2)werepreparedfrom
5-[(bismethylthio)methylene]-2,2-dimethyldioxan-4,6-dione by
first displacing one methylthio group with the requisite fluoro-
aniline, and then displacing the second one with methanol using
HgO/HgCl2 as a catalyst. The 13C NMR spectra of 8 reveal only
one C=O peak for each compound. X-ray structures of a series
of similar compounds[10] revealed considerable twisting about
the central C5=C7 bond due to the push–pull effect, which also
results in low rotational barriers about this bond and an averaging
of the two C=O resonances.
The dioxans 8 were subjected to preparative FVT at 700◦C
with isolation of the products on a coldfinger (77 K) coated
with methanol. On completion of the pyrolysis, the coldfin-
ger was warmed to room temperature, allowing the methanol
to thaw and react with the iminopropadienones 9. The resulting
2-methoxyfluoroquinolones 12 were isolated in ∼50% yields.
Each of the isolated quinolones was free of other isomers. Thus,
8a and 8b yielded only 12a and 12b, respectively, as evidenced
by the 13C NMR spectra as well as comparison of the 1H NMR
spectra with those of known quinolones.[11]
The cumulenes formed by FVT of the dioxans 8a–c over the
temperature range 150–700◦C were examined by isolation of the
products as neat films at 77 K for IR spectroscopy. An example
is illustrated in Fig. 1, and results for the three dioxans are shown
in Figs S1–S3 (Accessory Publication).
At an FVT temperature of 150◦C, no reactions took place.
In each case, at 200◦C, the spectrum revealed the presence of a
ketene (10; IR (77 K) ∼2138 cm−1).At 300◦C, a ketenimine (11;
IR (77 K) ∼2044w cm−1) appeared as well. At 400◦C, a third

Fluoroquinolones from R–N=C=C=C=O
117
O
COOMe
MeO
ArF
COOMe
∼1,2-H
FVT
H
N
N
ꢀ N2
C
ArF
ArF
N
N
N
14
13
11
a ArF ꢁ 3-FC6H4
b ArF ꢁ 4-FC6H4
c ArF ꢁ 2,3,4-F3C6H2
∼OMe
COOMe
O
C
MeO
ArF
Fn
N
H
N
H
10
15
a Fn ꢁ 6-F
b Fn ꢁ 5-F
c Fn ꢁ 4,5,6-F3
O
Fn
N
H
OMe
12
a Fn ꢁ 7-F
b Fn ꢁ 6-F
c Fn ꢁ 6,7,8-F3
Scheme 3. The triazole route to quinolones and indoles.
Quinolones and Indoles from Triazoles
400°
500°
600°
I
The imidoylketenes 10 and oxoketenimines 11 can also be gener-
ated from 1,2,3-triazoles 13 via a 1,2-H shift in the intermediate
iminocarbene 14 (Scheme 3). Hence, FVT of triazoles can also
be employed as a synthesis of quinolones 12. However, a com-
peting reaction leading to indoles 15 via an electrocyclization
of imidoylcarbenes 14 diminishes the yield of quinolone. The
best yield of quinolone (∼60%) is obtained by FVT at high tem-
perature (700◦C), where cyclization of the imidoylketene 10 is
complete in the gas phase.
I
I
K
The cumulenes formed by FVT of the triazoles were mon-
itored by low-temperature IR spectroscopy in the same way as
described for the Meldrum’s acids above. An example is shown
in Fig. 2, and data for the three triazoles are in Fig. S4 (Accessory
Publication).
K
K
2200 2050 1900
2200 2050 1900
2200 2050 1900
The ketenimines 11 are observed as the principal products,
but smaller amounts of ketenes 10 are also observed at tem-
peratures below 600–700◦C; they disappear at high temperature
because of rapid cyclization to quinolone. No traces of imino-
propadienones 9 were detectable in the FVT reactions of the
triazoles. It is noted that the ketene peak (K, Figs 1 and 2)
is particularly strong in the case of the trifluorophenylimi-
doylketene 10c, thus again suggesting a ‘fluorine effect’ that
stabilizes ketenes. A stabilizing effect of fluorine was also
obtained for other fluorinated ketenes of the type C2F5–CO–
C(CF3)=C=O, the first isolable α-oxoketene.[12] α-Oxoketenes
and α-imidoylketenes are not usually isolable at room temper-
ature in the absence of steric protection or the fluorine effect.
α-Oxoketenimines are more stable and can be isolated in several
instances (see below).
Fig. 2. IR spectra (cumulene region) of the products of flash vac-
uum thermolysis (FVT) of 1-(trifluorophenyl)-4-carbomethoxy-1,2,3-
triazoles 13c at various temperatures. Abscissae in wavenumbers (cm−1).
K = imidoylketene10;I = oxoketenimine11.TheketenesKandketenimines
I are identical with the ones recorded in Fig. 1.
the C=N double bond, forming malonic amide esters. FVT of the
isolated ketenimines 11 at 400◦C with isolation of the product
at 77 K for IR spectroscopy reveals that the ketenimine–ketene
equilibrium 11ꢀ10 is set up anew: typical ketene-to-ketenimine
ratios are seen in the IR spectra, and quinolone 12 starts forming
(Figs S5–S7, Accessory Publication).
Conclusion and Outlook
Preparative FVT of the triazoles at 700◦C afforded
quinolones 12 in yields of ∼60%, together with indoles 15
(∼10%). When FVT is carried out at lower temperatures
(500◦C), the oxoketenimines 11 can be isolated in yields of
∼30%. They are distillable liquids and can be kept for a few
hours at room temperature but hydrolyze by addition of water to
Fluorinated quinolones have been obtained by FVT of Mel-
drum’s acid derivatives. Fluorinated quinolones and indoles are
obtained by FVT of 1,2,3-triazoles. There is a significant sta-
bilizing effect of fluorine on aryliminopropadienones 5 (9) and
arylimidoylketenes 10. The nature of this fluorine effect will be
investigated by means of theoretical calculations.

118
B. E. Fulloon and C. Wentrup
Experimental
1618, 1582, 1511, 1373, 1270, 1206, 1084, 1019. m/z (EIMS)
295 (M+), 237, 192, 161, 137, 109, 95, 75, 58, 43. (Found:
C 57.01, H 4.74, N 4.86. Calc. for C14H14NO5F: C 56.93, H
4.78, N 4.75%.)
Procedures for preparative FVT and Ar matrix isolation have
been published.[13] 1H and 13C NMR spectra of quinolones and
indoles were assigned by comparison with data for structurally
similar compounds.[3,4a,5,6,11]
5-[2,3,4-Trifluoroanilino(methylthio)methylene]-
2,2-dimethyl-1,3-dioxan-4,6-dione
5-[3-Fluoroanilino(methylthio)methylene]-2,2-dimethyl-
1,3-dioxan-4,6-dione
Synthesized using the procedure described above. White crys-
tals; yield 1.21 g (69%), mp 135–138◦C. δH (CDCl3) 1.75 (s, 6H,
CH3), 2.38 (s, 3H, SCH3), 7.03–7.09 (m, 2H), 12.42 (s, 1H, NH).
δC (CDCl3) 18.84 (SCH3), 26.28 (CH3), 87.62, 103.48, 112.11
(dd), 122.08 (m), 123.45 (dd), 140.56 (C–F, dt, J 255), 146.28
(C–F, ddd, J 255), 150.89 (C–F, ddd, J 254), 159.91, 179.50
(C=O). νmax(KBr)/cm−1 3072, 1712, 1652, 1556, 1496, 1402,
1376, 1271, 1056, 1018. m/z (EIMS) 347 (M+), 289, 242, 198,
170, 143, 131, 119, 99, 84, 69, 43. (Found: C 48.56, H 3.702,
N 3.73. Calc. for C14H12NO4F3S: C 48.41, H 3.48, N 4.03%.)
This compound was prepared by adaptation of a method des-
cribed by Huang et al.[14] A mixture of bismethylthiomethylene-
Meldrum’s acid[9] (1.24 g, 5.0 mmol), 3-fluoroaniline (0.55 g,
5.0 mmol), and ethanol (5 mL) was refluxed for 2 h. The sol-
vent was then evaporated, and the residue recrystallized from
THF/hexane to afford white crystals (1.35 g; 87%), mp 131–
133◦C. δH (CDCl3) 1.74 (s, 6H, CH3), 2.28 (s, 3H, SCH3),
7.04–7.31 (m, 4H), 11.35 (s, 1H, NH). δC (CDCl3) 18.96
(SCH3), 26.36 (CH3), 87.06, 103.26, 112.47, 114.71, 120.96,
130.66, 138.85, 163.83, 166.13 (C–F, d, J 235), 178.13 (C=O).
νmax(KBr)/cm−1 2956, 1708, 1653, 1549, 1392, 1375, 1205,
1023. m/z (electron ionization mass spectrometry (EIMS)) 311
(M+), 253, 206, 161, 134, 107, 95, 75, 43. (Found: C 54.1,
H 4.52, N 4.40. Calc. for C14H14NO4FS: C 54.01, H 4.53,
N 4.50%.)
5-[2,3,4-Trifluoroanilino(methoxy)methylene]-
2,2-dimethyl-1,3-dioxan-4,6-dione 8c
Synthesized using the procedure adapted described above.Yield
0.10 g (60%), mp 165–167◦C. δH (CDCl3) 1.77 (s, 6H, CH3),
4.17 (s, 3H, OCH3), 6.72–7.20 (m, 2H), 11.49 (s, 1H, NH). δC
(CDCl3) 26.35 (CH3), 63.61 (OCH3), 75.09, 103.49, 119.94 (m),
118.96 (dd), 121.15 (dd), 140.96 (C–F, dt, J 246), 147.31 (C–F,
ddd, J 244), 151.35 (C–F, ddd, J 248), 161.09, 172.46 (C=O).
νmax(KBr)/cm−1 2952, 1713, 1677, 1583, 1507, 1485, 1409,
1378, 1270, 1043. m/z (EIMS) 331 (M+), 273, 229, 198, 170,
145, 119, 93, 75, 43. (Found: C 50.84, H 3.52, N 4.16. Calc. for
C14H12NO5F3: C 50.75, H 3.65, N 4.23%.)
5-[3-Fluoroanilino(methoxy)methylene]-2,2-dimethyl-
1,3-dioxan-4,6-dione 8a
Toasolutionoftheabovedioxan(0.156 g, 0.5 mmol)inmethanol
(5 mL) was added HgO (yellow, 0.109 g, 0.5 mmol) and HgCl2
(0.135 g, 0.5 mmol), and the mixture was refluxed for 20 min.
The mixture was filtered and the filtrate evaporated. Water
(10 mL) was added to the residue to precipitate the product,
which was isolated and recrystallized from THF/hexane. Yield
0.10 g (70%), mp 148–150◦C. δH (CDCl3) 1.76 (s, 6H, CH3),
4.18 (s, 3H, OCH3), 6.57–7.04 (m, 4H), 11.28 (s, 1H, NH). δC
(CDCl3) 26.37 (CH3), 62.35 (OCH3), 75.42, 103.27, 111.10,
113.12, 119.34, 129.91, 137.58, 159.21, 162.35 (C–F, d, J 257),
166.74 (C=O). νmax(KBr)/cm−1 3072, 1719, 1675, 1600, 1497,
1392, 1365, 1269, 1089, 1018. (Found: C 57.11, H 4.91, N 4.59.
Calc. for C14H14NO5F: C 56.93, H 4.78, N 4.75%.)
FVT of Fluoroarylmethylene-Meldrum’s Acids 8
The dioxans 8 were subjected to analytical FVT over the tem-
perature range 150–700◦C, subliming at ∼110◦C at a vacuum
of ∼3 × 10−1 Pa. The products were collected on a KBr deposi-
tion disk at 77 K for IR spectroscopy. The results are illustrated
in Figs 1 and S1–S3. Ketenimines 11 (I) appeared at 2044,
2049, and 2047 cm−1 for 11a, 11b, and 11c, respectively. Imi-
doylketene 10 (K) appeared at 2138, 2139, and 2140 cm−1
,
respectively, for 11a, 11b, and 11c. Iminopropadienones 9 (P)
appeared at 2224s and 2190w, 2221s and 2184w, and 2219s and
2187w cm−1, respectively, for 9a, 9b, and 9c. At FVT temper-
atures of 500◦C and above, the corresponding fluoroquinolone
5-[4-Fluoroanilino(methylthio)methylene]-2,2-dimethyl-
1,3-dioxan-4,6-dione
12 also appeared in the IR spectra (1637, 1675, and 1634 cm−1
,
This compound was prepared by adaptation of the method
described above and obtained as white crystals; yield 1.20 g
(78%), mp 168–170◦C. δH (CDCl3) 1.75 (s, 6H, CH3), 2.29
(s, 3H, SCH3), 7.06–7.30 (m, 4H), 11.41 (s, 1H, NH). δC
(CDCl3) 18.91 (SCH3), 26.33 (CH3), 86.01, 103.18, 116.26,
116.73, 127.29, 133.10, 161.61 (C–F, d, J 252), 178.52 (C=O).
νmax(KBr)/cm−1 2958, 1715, 1658, 1552, 1508, 1402, 1376,
1271, 1214, 1020. m/z (EIMS) 311 (M+), 253, 209, 161, 134,
107, 59, 75, 58, 43. (Found: C 54.03, H 4.56, N 4.36. Calc. for
C14H14NO4FS: C 54.01, H 4.53, N 4.50%.)
respectively, for 12a, 12b, and 12c; not shown). The fluoro-
quinolones 12 were isolated and characterized in the preparative
FVT experiments at 700◦C as described below.
2-Methoxy-7-fluoro-4(1H)-quinolone 12a
The dioxan 8a (65 mg) was subjected to preparative FVT at
700◦C, subliming at ∼105◦C in the course of 4 h. Methanol was
usedasatrappingagentbycoatingontothecoldfingerbeforeand
after pyrolysis. On completion of pyrolysis, the coldfinger was
warmed to room temperature.The resulting yellow solid (21 mg;
50% yield) was identified as 2-methoxy-7-fluoroquinolone 12a,
mp 311–312◦C. δH ([D6]DMSO) 3.49 (s, 3H, CH3), 5.82 (s,
1H), 7.08 (ddd, 1H, H-6, J6,8 2.4, J6,F 8.6), 7.33 (dd, 1H, H-8,
J8,F 11.5), 7.90 (dd, 1H, H-5, J5,6 9.1, J5,F 6.6), 11.45 (s, 1H,
NH). δC ([D6]DMSO) 28.75 (CH3), 97.03, 101.40 (d), 108.81
(d), 112.84, 125.59 (d), 141.73 (d), 161.76 (C–F, d, J 253),
162.91, 164.87 (C=O). νmax(KBr)/cm−1 3391, 3098, 2954,
1641 (C=O), 1600, 1559, 1512, 1374, 1334, 1243, 1148, 1064.
5-[4-Fluoroanilino(methoxy)methylene]-2,2-dimethyl-
1,3-dioxan-4,6-dione 8b
Prepared by adaptation of the method described above and
obtained as white crystals; yield 0.11 g (74%), mp 190–191◦C.
δH 1.76 (s, 6H, CH3), 4.13 (s, 3H, OCH3), 7.04–7.33 (m, 4H),
11.36 (s, 1H, NH). δC (CDCl3) 26.17 (CH3), 62.93 (OCH3),
75.68, 103.19, 116.35, 125.20, 127.52, 131.02, 164.13 (C–F,
d, J 254), 171.40 (C=O). νmax(KBr)/cm−1 3071, 1721, 1654,

Fluoroquinolones from R–N=C=C=C=O
119
m/z (EIMS) 193 (M+), 163, 150, 135, 123, 107, 95, 75, 57.
(Found: C 61.88, H 3.98, N 7.15. Calc. for C10H8NO2F: C 62.18,
H 4.17, N 7.25%.)
97, 70, 52, 39. (Found: C 41.44, H 1.09, N 24.21. Calc. for
C6H2N3F3: C 41.61, H 1.16, N 24.28%.)
Methyl 1-(2,3,4-Trifluorophenyl)-1H-1,2,3-triazole-
4-carboxylate 13c
2-Methoxy-6-fluoro-4(1H)-quinolone 12b
The dioxan 8b was subjected to FVT at 700◦C and workup
as described for 8a above. The resulting yellow solid (17 mg;
49%) was identified as 2-methoxy-6-fluoroquinolone 12b, mp
188–190◦C. δH ([D6]DMSO) 3.52 (s, 3H, CH3), 5.90 (s, 1H,
CH), 7.47–7.49 (dd, 1H), 7.54–7.56 (m, 1H), 7.61–7.64 (dd,
1H), 11.50 (s, 1H, NH). δC ([D6]DMSO) 28.71 (CH3), 98.83,
108.25 (d), 116.71 (d), 117.13 (d), 118.79 (d), 136.72, 156.83
(C–F, d, J 239), 160.55, 162.68 (C=O). νmax(KBr)/cm−1 3360
(N–H), 2989, 1635, 1611, 1599, 1559, 1498, 1478, 1417, 1328,
1244, 1199, 1097, 1063. m/z (EIMS) 193 (M+), 163, 150, 135,
123, 107, 95, 75, 57. (Found: C 61.97, H 3.95, N 7.49. Calc. for
C10H8NO2F: C 62.18, H 4.17, N 7.25%.)
Prepared from 2,3,4-trifluorophenyl azide as described for 13a
above. Yield 1.39 g (59%), mp 119–121◦C. δH (CDCl3) 3.99
(s, 3H, OCH3), 7.18–7.23 (m, 1H), 7.73–7.78 (m, 1H), 8.56 (d,
1H). δC (CDCl3) 52.46 (OCH3), 113.14 (m), 118.91 (m), 122.02
(m), 128.23 (d), 140.56 (C–F, dt, J 251.2), 140.68, 143.75 (C–
F, ddd, J 245.6), 151.15 (C–F, ddd, J 239.5), 160.55 (C=O).
νmax(KBr)/cm−1 3128, 2954, 1732, 1529, 1513, 1443, 1348,
1274, 1213, 1159, 1041, 1018. m/z (EIMS) 257 (M+), 226, 198,
170, 143, 119, 81, 69, 53. (Found: C 46.49, H 2.31, N 16.29.
Calc. for C10H6N3O2F3: C 46.69, H 2.35, N 16.34%.)
General Procedure for FVT of Triazoles 13
(a) The triazole (∼10 mg) was subjected to analytical FVT over
the temperature range 300–700◦C, subliming at ∼95◦C.The sys-
tem was operated at a vacuum of ∼3 × 10−3 Pa, and the products
were collected on a KBr deposition disk cooled to 77 K. Neat-
film IR spectra were recorded for various FVT temperatures as
illustrated in Figs 2 and S4. The ketenimines 11 (I) and ketenes
10 (K) were identical to those derived from the Meldrum’s acid
derivatives as described above. Iminopropadienones 5 or 9 (P)
were absent in these spectra. Solid material that had condensed
in the quartz tube between the oven and the cold deposition win-
dow at FVT temperatures ≥400◦C was washed out with ethanol
and identified as mixtures of the corresponding quinolone and
indole by comparison with the characterization data described
above and below.
(b) The triazole (100–120 mg) 13 was subjected to FVT at
500◦C, subliming at ∼95◦C for 2 h.The pyrolysate was collected
in a U-tube cooled to 77 K. On completion, the system was pres-
surized to 101.3 kPa with N2 and warmed to room temperature.
An oil collected in the U-tube, was rinsed into a receiving flask
with CCl4, and the mixture was subjected to Kugelrohr distil-
lation (∼55◦C, 4.0 × 10−1 Pa), affording a clear oil, identified
as the methyl N-(fluorophenyl)ketenimine-1-carboxylate 11, in
yields of 20–33 mg (21–30%). The remaining material, after
the fluorophenyloxoketenimine 11 had distilled, was composed
of the corresponding quinolone (32–36 mg; 31–35% yield) and
indole (21–26 mg; 20–25%), which were separated by column
chromatography on silica gel, eluting with CHCl3/hexane 2:3
and identified by comparison with the characterization data
described above and below.
2-Methoxy-6,7,8-trifluoro-4(1H)-quinolone 12c
The dioxan 8c (85 mg) was subjected to FVT at 700◦C and
workup as above. The resulting yellow solid (16 mg; 47%) was
analyzed as 2-methoxy-6,7,8-trifluoroquinolone 12c, mp 302–
304◦C. δH ([D6]DMSO) 3.67 (d, 3H, OCH3), 5.91 (s, 1H), 7.66
(t, 1H), 11.86 (s, 1H, NH). δC ([D6]DMSO) 31.01 (OCH3),
98.81, 105.71 (m), 113.19 (m), 127.65, 139.68 (C–F, ddd, J 253),
141.77 (C–F, dt, J 267), 144.85 (C–F, ddd, J 264), 159.83, 163.41
(C=O). νmax(KBr)/cm−1 3390, 3087, 2959, 1639, 1617, 1527,
1490, 1396, 1325, 1244, 1076, 1007. m/z (EIMS) 229 (M+),
200, 186, 158, 143, 113, 99, 81, 75. (Found: C 52.53, H 2.46,
N 6.07. Calc. for C10H5NO2F3: C 52.65, H 2.23, N 6.14%.)
Methyl 1-(3-Fluorophenyl)-1H-1,2,3-triazole-
4-carboxylate 13a
Synthesized using a procedure adapted fromAbu-Orabi et al.[15]
3-Fluorophenyl azide[16] (2.30 g, 0.017 mol) was dissolved in
ethanol (110 mL). Methyl propiolate (1.43 g, 0.015 mol) was
added to the solution, and the mixture was refluxed for 18 h. The
solvent was removed by rotary evaporation and the remaining
solid recrystallized from ethanol/diethyl ether to produce white
crystals.Yield 2.40 g (65%), mp 132–134◦C. δH (CDCl3) 3.97 (s,
3H, OCH3), 7.15–7.55 (m, 4H), 8.52 (s, 1H). δC (CDCl3) 52.37,
108.61, 116.05, 116.48, 125.51, 131.46, 137.37, 140.67, 160.79
(C=O), 163.02 (C–F, d, J 251.7). νmax(KBr)/cm−1 3142, 2952,
1710, 1616, 1508, 1443, 1349, 1218, 1164, 1040. m/z (EIMS)
221 (M+), 190, 162, 148, 134, 107, 95, 75, 59, 44. (Found:
C 54.34, H 3.61, N 18.98. Calc. for C10H8N3O2F: C 54.28, H
3.65, N 19.00%.)
(c) The triazole 13 (100–110 mg) was subjected to prepara-
tive FVT at 700◦C, subliming at ∼95◦C for 2 h. A yellow-pink
solid was collected on the 77 K coldfinger. This material was
separated by column chromatography on silica gel as described
above to afford methyl fluoroindolecarboxylate 15 (9–13%) and
2-methoxyfluoroquinolone 12 (60–63%).
Methyl 1-(4-Fluorophenyl)-1H-1,2,3-triazole-
4-carboxylate 13b
Prepared according to the literature.[17]
2,3,4-Trifluorophenyl Azide
Methyl N-(3-Fluorophenyl)ketenimine-1-carboxylate 11a
Prepared from 2,3,4-trifluoroaniline by adaptation of a method
reported by Dyall et al.[18] for naphthyl azides. It was obtained
as a brown oil in a yield of 3.53 g (75%) on a 17-mmol scale and
purified by Kugelrohr distillation at 40◦C/10−2 Pa. δH (CDCl3)
6.79–6.99 (m, 2H). δC (CDCl3) 112.10 (d), 114.21 (d), 125.52
(d), 140.56 (C–F, dt, J 252.2), 143.74 (C–F, ddd, J 248.6), 148.65
(C–F, ddd, J 241.3). νmax(CCl4)/cm−1 2979, 2119, 1599, 1506,
1303, 1235, 1129, 1098, 1014. m/z (EIMS) 173 (M+), 145, 116,
νmax/cm−1 2955, 2046 (C=C=N), 1718 (C=O), 1607, 1439,
1348, 1254, 1148, 1080. δH (CDCl3) 3.72 (s, 3H, CH3), 4.65
(s, 1H), 7.00–7.34 (m, 4H). δC (CDCl3) 51.92 (OCH3), 53.10,
111.75 (d), 115.73 (d), 120.17, 130.81 (d), 138.20 (d), 162.99
(C–F, d, J 148.9), 168.11 (C=O), 178.50 (N=C). m/z (EIMS)
193 (M+), 163, 135, 123, 107, 95, 75, 57. High-resolution (HR)
MS calc. for C10H8NO2F 193.0539. Found 193.0545.

120
B. E. Fulloon and C. Wentrup
Methyl N-(4-Fluorophenyl)ketenimine-1-carboxylate 11b
Acknowledgement
νmax/cm−1 2953, 2047 (C=C=N), 1721 (C=O), 1506, 1443,
1234, 1149, 1040. δH (CDCl3) 3.71 (s, 3H, CH3), 4.61 (s, 1H),
7.03–7.32 (m, 4H). δC (CDCl3) 51.83 (OCH3), 52.83, 116.65
(d), 126.44 (d), 132.47, 162.42 (C–F, d, J 249.5), 168.41 (C=O),
177.15 (N=C). m/z (EIMS) 193 (M+), 162, 134, 107, 95, 75,
57. HRMS calc. for C10H8NO2F 193.0539. Found 193.0549.
The present work was supported by the Australian Research Council.
References
[1] (a)V.Andriole,TheQuinolones2000(AcademicPress:NewYork, NY).
(b) Fluoroquinolone Antibiotics (Eds A. R. Ronald, D. E. Low) 2003
(Birkhäuser: Basel).
[2] L. M. Jarvis, Chem. Eng. News 2008, 86, 15.
[3] H. Bibas, D. W. J. Moloney, R. Neumann, M. Shtaiwi, P. V. Bernhardt,
C. Wentrup, J. Org. Chem. 2002, 67, 2619. doi:10.1021/JO0110552
[4] (a)V.V. Ramana Rao, C. Wentrup, J. Chem. Soc., PerkinTrans. 1 1998,
2583. doi:10.1039/A802768D
(b) D. Clarke, R. W. Mares, H. McNab, J. Chem Soc., Perkin Trans. 1
1997, 1799. doi:10.1039/A700421D
[5] V. V. Ramana Rao, C. Wentrup, J. Chem. Soc., Perkin Trans. 1 2002,
1232. doi:10.1039/B202128E
Methyl N-(2,3,4-Trifluorophenyl)ketenimine-
1-carboxylate 11c
νmax/cm−1 2954, 2046 (C=C=N), 1725 (C=O), 1515, 1440,
1246, 1155, 1013. δH (CDCl3) 3.72 (s, 3H, CH3), 4.67 (s, 1H),
6.93–7.12 (m, 2H). δC (CDCl3) 51.99 (OCH3), 52.50, 111.99
(m), 120.67 (m), 122.05, 140.50 (C–F, dt, J 251.5), 146.23 (C–
F, ddd, J 226.3), 151.83 (C–F, ddd, J 220.2), 167.81 (C=O),
181.77 (N=C). m/z (EIMS) 229 (M+), 198, 170, 143, 123, 99,
75. HRMS calc. for C10H6NO2F3 229.0351. Found 229.0334.
[6] (a) C. Wentrup, V. V. Ramana Rao, W. Frank, B. F. Fulloon,
D. W. J. Moloney, T. Mosandl, J. Org. Chem. 1999, 64, 3608.
doi:10.1021/JO982471Y
(b) L. George, M. W. Wong, C. Wentrup, Org. Biomol. Chem. 2007,
5, 1437. doi:10.1039/B702518A
[7] (a) J. J. Finnerty, C. Wentrup, J. Org. Chem. 2004, 69, 1909.
doi:10.1021/JO035419X
(b) J. J. Finnerty, C. Wentrup, J. Org. Chem. 2005, 70, 9735.
doi:10.1021/JO051389H
[8] B. E. Fulloon, C. Wentrup, J. Org. Chem. 1996, 61, 1363.
doi:10.1021/JO951832W
[9] R. Koch,T. Bruhn, R. N.Veedu, C. Wentrup, J. Mol. Struct.Theochem.
2004, 686, 31. doi:10.1016/J.THEOCHEM.2004.07.027
[10] (a) P. V. Bernhardt, R. Koch, D. W. Moloney, M. Shtaiwi, C. Wentrup,
J. Chem. Soc., Perkin Trans. 2 2002, 515. doi:10.1039/B109624A
(b) R. N. Veedu, P. V. Bernhardt, R. Koch, C. Wentrup, Aust. J. Chem.
2008, 61, 805. doi:10.1071/CH08277
[11] (a) S.-C. Kuo, H.-Z. Lee, J.-P. Juang, Y.-T. Lin, T.-S. Wu, J.-J. Chang,
D. Lednicer, K. D. Paull, C. M. Lin, J. Med. Chem. 1993, 36, 1146.
doi:10.1021/JM00061A005
Methyl 6-Fluoroindole-3-carboxylate 15a
This compound is commercially available and has been synthe-
sized by Kleeman et al.[19] Mp 194–196◦C. δH (CDCl3) 3.89
(s, 3H, OCH3), 7.01 (ddd, 1H, H-5, J5,7 2.3, J5,F 8.8), 7.07 (dd,
1H, H-7, J7,F 9.1), 7.87 (d, 1H, H-2), 8.09 (dd, 1H, H-4, J4,5 9.0,
J4,F 5.4), 8.61 (bs, 1H, NH). δC (CDCl3) 51.14 (OCH3), 98.02
(d), 109.11, 110.94 (d), 122.29, 122.60 (d), 131.16, 136.02 (d),
160.34 (C–F, d, J 240.0), 165.26 (C=O). νmax(KBr)/cm−1 3247,
2947, 1669, 1531, 1143, 1282, 1196, 1141, 1101, 1055, 954. m/z
(EIMS) 193 (M+), 162, 134, 107, 81, 57, 39. (Found: C 62.08,
H 4.14, N 7.25. Calc. for C10H8NO2F: C 62.16, H 4.18,
N 7.25%.)
Methyl 5-Fluoroindole-3-carboxylate 15b
(b) C. W. Haigh, M. H. Palmer, B. Semple, J. Chem. Soc. 1965, 6004.
doi:10.1039/JR9650006004
(c) P. A. Claret, A. G. Osbourne, Spectrosc. Lett. 1976, 9, 167.
doi:10.1080/00387017608067425
This compound is commercially available and has been synthe-
sized by Karabelas et al.[20] Mp 200–202◦C. δH (CDCl3) 3.90
(s, 3H, OCH3), 7.01 (ddd, 1H, H-6, J4,6 2.1, J6,F 9.0, J6,7 8.5),
7.31 (dd, 1H, H-4, J4,6 2.1, J4,F 10.1), 7.82 (dd, 1H, H-7, J6,7 8.5,
J7,F 5.3), 7.93 (d, 1H, H-2), 8.55 (bs, 1H, NH). δC (CDCl3) 50.94
(OCH3), 106.70 (d, J3,F 4.9), 109.01 (d, J6,F 24.0), 111.60 (d, J4,F
26.4), 112.01(d, J7,F 10.1), 126.35(d, J3a,F 11.3), 131.97, 132.23,
159.11 (C–F, d, J5,F 237.7), 165.00 (C=O). νmax(KBr)/cm−1
3229, 2948, 1674, 1527, 1446, 1364, 1276, 1196, 1148, 1038,
931. m/z (EIMS) 193 (M+), 162, 134, 107, 81, 57, 39. (Found:
C 62.06, H 4.10, N 6.99. Calc. for C10H8NO2F: C 62.16, H 4.18,
N 7.25%.)
(d) D. Doddrell, M. Barfield, W. Adcock, M. Aurangzed, D. Jordan, J.
Chem. Soc., Perkin Trans. 2 1976, 402. doi:10.1039/P29760000402
(e) L. Ernst, S. Kang, J. Chem. Res. (M) 1981, 3019.
[12] (a) D. C. England, J. Org. Chem. 1981, 46, 153. doi:10.1021/
JO00314A033
(b) D. C. England, J. Org. Chem. 1984, 49, 4007. doi:10.1021/
JO00195A025
[13] (a) C. Wentrup, R. Blanch, H. Briehl, G. Gross, J. Am. Chem. Soc.
1988, 110, 1874. doi:10.1021/JA00214A034
(b) C. Addicott, C. Wentrup, Aust. J. Chem. 2008, 61, 592.
doi:10.1071/CH08252
[14] F. C. Ye, B.-C. Chen, X. Huang, Synthesis 1989, 317. doi:10.1055/
S-1989-27241
[15] S. T. Abu-Orabi, M. A. Atfah, F. M. Mari’I, A. A. Ali, J. Heterocycl.
Chem. 1989, 26, 1461.
[16] (a) E. Leyva, D. Munoz, M. S. Platz, J. Org. Chem. 1989, 54, 5938.
doi:10.1021/JO00286A028
Methyl 5,6,7-Trifluoroindole-3-carboxylate 15c
Mp 219–222◦C. δH (CDCl3) 3.90 (s, 3H, OCH3), 7.74 (t, 1H),
7.92 (d, 1H, H-2), 8.78 (bs, 1H, NH). δC (CDCl3) 50.87 (OCH3),
95.71, 102.81 (m), 109.53 (d), 120.77 (d), 128.33 (C–F, dt, J
242.5), 131.65, 136.25 (C–F, ddd, J 239.3), 147.29 (C–F, ddd,
J 230.0), 164.11 (C=O). νmax(KBr)/cm−1 3260, 2948, 1697,
1673, 1602, 1545, 1473, 1392, 1330, 1205, 1163, 1081, 1005,
967, 918. m/z (EIMS) 229 (M+), 198, 170, 143, 123, 99, 75,
69. (Found: C 52.21, H 2.58, N 6.12. Calc. for C10H6NO2F3:
C 52.39, H 2.64, N 6.11%.)
(b) A. R. Katritzky, H. J. Keogh, S. Ohlenrott, R. D. Topsom, J. Am.
Chem. Soc. 1970, 92, 6856.
[17] (a) G. Molteni, A. Ponti, Chem. Eur. J. 2003, 9, 2770.
doi:10.1002/CHEM.200204681
(b) G. Molteni, A. Ponti, Arkivoc 2006, xvi, 49.
[18] G. Bosher, L. K. Dyall, P. R. Sadler, Aust. J. Chem. 1972, 25, 599.
[19] H.-W. Kleeman, J.-C. Carry, P. Desmazeau, S. Mignani, J. Bouquerel,
A. Genevois-Borella, B. Ronan, Aventis Pharma GMBH, PCT Int.
Appl. WO2004007480, 22 January 2004.
[20] K. Karabelas, M. Lepisto, P. Sjo, A. B. Astrazeneca, PCT 2000, SE00,
WO0071537.
Accessory Publication
IR spectra of the products of FVT of 8a–c and 13a–c at vari-
ous temperatures (Figs S1–S7) are available from the journal’s
website.