Nucleus- and side-chain fluorinated 3-substituted indoles by a suitable combination of organometallic and radical chemistry

Article abstract of DOI:10.1016/j.jfluchem.2007.09.003

Regioselectively fluoro-, trifluoromethyl- and trifluoromethoxy-substituted 3-methyleneindolines have been prepared using a four-step procedure involving metalation/bromination of fluorinated Boc-protected anilines, N-propargylation of the resulting o-bro

Full text of DOI:10.1016/j.jfluchem.2007.09.003

Journal of Fluorine Chemistry 129 (2008) 97–107
www.elsevier.com/locate/fluor
Nucleus- and side-chain fluorinated 3-substituted indoles by a suitable
combination of organometallic and radical chemistry
b
Francesca Bellezza a, Antonio Cipiciani a, Renzo Ruzziconi b, , Sara Spizzichino
*
a CEMIN, ‘‘Centro di Eccellenza Materiali Innovativi Nanostrutturati’’, via Elce di Sotto, 8, 06123 Perugia, Italy
b
`
Dipartimento di Chimica, Universita di Perugia, via Elce di Sotto, 8, 06123 Perugia, Italy
Received 27 July 2007; received in revised form 1 September 2007; accepted 9 September 2007
Available online 14 September 2007
Abstract
Regioselectively fluoro-, trifluoromethyl- and trifluoromethoxy-substituted 3-methyleneindolines have been prepared using a four-step
procedure involving metalation/bromination of fluorinated Boc-protected anilines, N-propargylation of the resulting o-bromoarylcarbamate
and reductive radical cyclization of the product with tributyltin hydride/AIBN. 3-Methyleneindolines, as valuable, versatile intermediates, can be
transformed into highly functionalized 3-substituted indoles by ene-type reactions using different enophiles. Thus, fluoro-, trifluoromethyl- and
trifluoromethoxy-substituted diethyl 2-hydroxy-2-[(1H-indol-3-yl)methyl]malonates, ethyl 2-hydroxy-3-(1H-indol-3-yl)propionates and ethyl
2-hydroxy-3-(1H-indol-3-yl)-2-trifluormethylpropionates were obtained in 77–86% yield by simply heating the corresponding tert-butyl
3-methyleneindoline-1-carboxylate with an equimolar amount of diethyl ketomalonate, ethyl glyoxalate and ethyl 3,3,3-trifluoropyruvate,
respectively, at 100 8C, without solvent, for 0.5–4 h.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Fluorinated indolines; Indole derivatives; Arylcarbamate metalation; Radical cyclization; Carbonyl-ene reactions
1. Introduction
substituents into a strategic position of the indole nucleus
substantially affects the biological activity of this class of
molecules leading to unexpected pharmacokinetic or pharma-
codynamic properties [1e,f,5].
It is now recognized that fluorine can change the properties
of a biologically active molecule by influencing its metabolism.
Its ability to increase lipophilicity, its high electronegativity and
its reduced van der Waals radius, which make it like to an OH
group, with, however, a scarce propensity to form hydrogen
bonds, make fluorine a unique, valuable resource for increasing
the therapeutic efficacy of biologically active organic
molecules, especially when it is located in specific positions
[1]. Besides the fluorine atom, the introduction of a CF3 [2], or
the less common OCF3 group [3], into an aromatic ring appears
to be a successful combination for the biological activity of a
molecule to make the undertaking extremely attractive. The
indolic nucleus is involved in a variety of natural products also
by controlling essential biological functions both in the animal
and plant kingdom [4]. For the above reasons, it should not be
surprising if the introduction of fluorine or fluorinated
Although many methods have been developed to synthesize
indole derivatives [6], fluorinated analogues of indole-based,
biologically active molecules are not as well known.
Trifluoromethyl-substituted indoles are somewhat rare. Some
ofthemhave beenpreparedstarting fromcommerciallyavailable
(trifluoromethyl)aniline by complex procedures [7]. Direct
electrophilic trifluoromethylation of indoline and oxindoles
was recently attempted and gave access to regioselectively
substituted 6-(trifluoromethyl)oxindoles, in moderate to good
yields [8].
To ourknowledge, only two examples of 3-substituted indoles
bearing a trifluoromethoxy group are known to date [8,9].
We therefore found attractive to develop a simple, general
method for preparing regioselectively nucleous- and side-chain
fluoro-, trifluoromethyl- and trifluoromethoxy-substituted
indoles functionalyzed at the 3 position, based on a suitable
combination of organometallic and radical chemistry. The
results of this research are presented in this paper.
* Corresponding author. Fax: +39 075 5855262.
E-mail address: ruzzchor@unipg.it (R. Ruzziconi).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.09.003

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F. Bellezza et al. / Journal of Fluorine Chemistry 129 (2008) 97–107
2. Results and discussion
3-Methyleneindolines appear the most suitable building
block for preparing 3-substituted indoles and other valuable
biologically active molecules [10]. Undoubtedly, the radical
cyclization appears to be the simplest and most versatile
method to prepare substituted indoline and indole derivatives
[11], especially when the presence of electron-withdrawing
groups like fluoroalkyls or fluoroalkoxy groups in the benzene
ring precludes any other approach based on electrophilic
cyclization reactions [9]. The decisive step of this strategy, that
is common to different cyclization methods, is putting a
bromine or iodine atom next to the amino group in a
regioselective fashion. To do this, the concept of reagent-
controlled optional site selectivity disclosed by M. Schlosser
appears to be appropriate [12].
Scheme 2.
Following this idea, regioselectively fluorinated 3-methy-
leneindolines 2a–k (Scheme 1) were prepared in four steps
using commercially available anilines 1a–k as the starting
material.
In virtue of their electronic and steric effects, fluorine,
trifluoromethyl or trifluoromethoxy substituents could play a
crucial role in determining the orientation of the lithiation at
one of the two sites next to the nitrogen atom [12]. Accordingly,
when Boc-protected 3-aminobenzotrifluoride (3f) was allowed
to react with two equivalents of tert-butyllithium in THF for 3 h
at À50 8C, lithiation occurred exclusively at the most sterically
accessible position ortho to the amido group. This allowed the
corresponding 2-bromo-5-trifluoromethylanilide to be obtained
in 81% yield after treatment of the lithium intermediate with
CBr4. Under the above conditions, the meta isomer of N-(tert-
butoxycarbonyl)fluoroaniline was easily deprotonated at the
double activated position flanked by the two heterosubstituents
already at À75 8C, but, as previously reported by Clark and
Caroon [16], subsequent elimination of lithium fluoride is rapid
generating a transient dehydroarene. Nucleophilic cyclization
by the next tert-butoxycarbonyl anion gave rise to a 7-
lithiobenzoxazole, which can be trapped with any electrophile.
This and the above occurrence prevented us from enriching our
collection of fluorinated 3-methyleneindoline with the 4-
(trifluoromethyl)- and 4-fuoro-substituted regioisomers [17].
Nitrogen deprotonation of the resulting o-bromoarylcarba-
mate with sodium hydride in DMF, followed by treatment with
propargyl bromide at room temperature, occurred smoothly
allowing the corresponding aryl-N-propargyl carbamate 5a–k
to be obtained in good yield (62–88%) [18].
Due to its excellent coordination ability towards alkyl-
lithium reagents, the Boc-amido group can exert a powerful
o-directing effect on the metalation of Boc-protected aniline
[13]. With tert-butyllithium, this effect overcomes the
acidifying effect of strong electron-withdrawing groups, such
as trifluoromethyl or even fluorine, on the position next to
halogen. Therefore, Boc-protected fluoro-, trifluoromethyl- or
trifluoromethoxy-substituted anilines undergo lithiation at one
carbon next to nitrogen, regardless of the position of the
substituent in the aromatic ring [13e,14]. Despite the
commercial availability of some fluorinated o-bromoanilines,
aiming at assessing the reliability of the method, the above
procedure was adopted to prepare the essential o-bromoar-
ylcarbamates used in this work. Thus, commercially available
fluoro-, trifluoromethyl-, and trifluoromethoxyanilines 1a–k
were protected as the tert-butyl carbamate (3a–k) [15].
Metalation of the N-Boc-protected anilines with 2 equivalents
of tert-butyllithium in THF at À75 8C, followed by treatment of
the resulting dilithioanilide with CBr4, allowed the correspond-
ing o-bromoanilides 4a–k to be obtained in good yields
(Scheme 2).
Finally, tributyltin hydride-promoted reductive radical
cyclization of bromoaryl-N-propargylcarbamate in refluxing
benzene, in the presence of AIBN as initiator, allowed the
expected 3-methyleneindoline 2a–k to be obtained in
satisfactory yield (45–70%). The results are reported in Table 1.
Surprisingly, they are stable enough to be purified by
standard chromatographic methods without any isomerization
to the corresponding 3-methylindoles. As shown thoroughly by
Buchwald [10b] the remarkable reactivity of the exocyclic
carbon-carbon double bond makes 3-methyleneindolines
valuable, versatile precursors of several highly functionalized
3-substituted indoles. To test this, we tried to react the above
indolines with different enophilic carbonyl compounds. A
carbonyl-ene reaction, which is a high activation energy
process usually requiring the intervention of a Lewis acid
Scheme 1.

F. Bellezza et al. / Journal of Fluorine Chemistry 129 (2008) 97–107
99
Table 1
Regioselectively fluorinated 3-methyleneindolines 2a–k from anilines 1a–k
Aniline
Aryl carbamate 3,
a
yield %
o-Bromoaryl carbamate,
a
4, yield %
o-Bromoaryl N-(Propargyl)carb-
a
amate 5, yield %
N-Boc 3-methylene-
a
indoline 2, yield %
1a (X = H)
1b (X = 2-F)
3a, 91
3b, 87
–
4a, 78
4b, 82
4c, 75b
4d, 66
4e, 64
4f, 77
4g, 94
4h, 46
4i, 81
5a, 75
5b, 82
5c, 71
5d, 62
5e, 88
5f, 78
5g, 86
5h, 77
5i, 87
5j, 74
5k, 84
2a, 41
2b (X = 7-F), 58
2c (X = 6-F), 56
2d (X = 5-F), 48
2e (X = 7-CF3), 70
2f (X = 6-CF3), 69
2g (X = 5-CF3), 46
1c (X = 3-F)
1d (X = 4-F)
3d, 99
3e, 50
3f, 72
3g, 84
3h, 76
3i, 85
3j, 89
3k, 79
1e (X = 2-CF3)
1f (X = 3-CF3)
1g (X = 4-CF3)
1h (X = 2-OCF3)
1i (X = 4-OCF3)
1j (X = 2,4-bis CF3)
1k (X = 2-F-3-OCH3)
2h (X = 7-OCF3), 53
2i (X = 5-OCF3), 57
2j (5,7-bis CF3), 50
2k (7-F-6-OCF3), 45
4j, 63
4k, 62.
a
Yield of isolated product.
b
Prepared from commercial 2-bromo-5-fluoroaniline.
Scheme 3.
catalyst [19], in these cases, took place smoothly simply
heating a mixture of 3-methylene indolines 2 and the enophilic
species at 100 8C, without solvent nor catalyst, for variable
periods of time (0.5–2.0 h) depending on the nature of the
substituent in the aromatic ring. Thus, diethyl 2-[1-tert-
butoxycarbonyl-1H-indol-3-yl)methyl]malonate 6a–k and, as
demonstrative examples, some ethyl 3-(1-tert-butoxycarbonyl-
1H-indol-3-yl)-2-hydroxypropionates (7d,i,j) and ethyl 2-[(1-
tert-butoxycarbonyl-1H-indol-3-yl)methyl]-2-hydroxy-3,3,3-
trifluoropropionates (8b,d,i) were obtained in good yields
(77–86%) after the crude reaction mixture was passed through a
short column of silica gel (Scheme 3).
The latter, as valuable building blocks, provide a facile access
to 3-functionalized nucleous and side-chain regioselectively
fluorinated indole derivatives.
4. Experimental
1
1
If not specified otherwise, H NMR and H-decoupled 13C
NMRspectrawererecordedat400and100 MHz, respectively, in
CDCl3 solution using tetramethylsilane as an internal standard.
19F NMR spectra were recorded at 376 MHz in CDCl3 solution
usingCFCl3 asareferencestandard. J valuesareinHz. IRspectra
were registered in CHCl3 solution in the 4000–625 cmÀ1 range.
Further suggestions about working routine and technical details
can be found in previous publications from this laboratory [9,20].
The starting fluoro-, trifluoromethyl- and trifluoromethoxy-
substituted anilines and 2-bromo-5-fluoroaniline were commer-
cial products and were used without further purification.
3. Conclusion
In conclusion, a simple, general procedure has been devised
to prepare regioselectively fluorinated 3-methyleneindolines.

100
F. Bellezza et al. / Journal of Fluorine Chemistry 129 (2008) 97–107
4.1. Standard procedure for preparing fluorinated tert-
butyl arylcarbamates (3a–k)
(ddd, J = 9.9, 7.4 and 1.6, 1 H), 6.77 (broad s, 1 H), 1.52 (s, 9
H); 13C NMR d 152.3, 137.6, 131.1, 127.4, 122.7, 120.6 (q,
J = 250), 81.2, 28.2; 19F NMR d À58.0 (s).
A solution of the fluorinated aniline (0.10 mol) and di-tert-
butyl dicarbonate (73.4 ml, 0.15 mol) was refluxed in toluene
(400 ml). Di-tert-butyl dicarbonate was occasionally added
and the reflux continued until the aniline had completely
disappeared (tlc: SiO2, eluent petroleum ether/diethyl ether 8:2;
ArNH2, Rf 0.1–0.26; ArNHBoc Rf 0.51–0.61). The solvent was
evaporated at reduced pressure and the residue was passed
through a short SiO2 column (eluent, petroleum ether/diethyl
ether 95:5). Pure tert-butyl 3-trifluoromethy-, 4-trifluoromethyl-
and 4-trifluoromethoxyphenylcarbamate were obtained by
simple crystallization of the crude reaction products from
hexane. tert-Butyl 2-(trifluoromethyl)- and 2-(trifluoromethox-
y)phenylcarbamate were obtained by K2CO3-promoted half
hydrolysis of the corresponding di-tert-butyl dicarbamates in
methanol. Thelatter wereprepared byrefluxingtheanilinewith2
equiv. of di-tert-butyl dicarbonate in benzene, in the presence of
DMAP as the catalyst [15].
tert-Butyl N-[4-(trifluoromethoxy)phenyl]carbamate [14a]
(3i, 85%): mp 108–109 8C (petroleum ether); IR nmax 3439,
1
3032, 2983, 2934, 1727, 1522, 1265, 1158 cmÀ1; H NMR d
7.38–7.11 (symmetric m, AA’BB’system, 4 H), 6.63 (broad s, 1
H), 1.50 (s, 9 H); 13C NMR d 152.6, 144.3, 137.0, 121.7, 120.4
(q, J = 255), 119.4, 80.8, 28.2; 19F NMR d À58.7 (s).
tert-Butyl N-[2,4-bis(trifluoromethyl)phenyl]carbamate (3j,
89%): oil; IR nmax 3463, 2985, 2935, 1736, 1634, 1534, 1271,
1142 cmÀ1; 1H NMR d 8.44 (d, J = 8.8, 1 H), 7.81 (s, 1 H), 7.76
(d, J = 8.8, 1 H), 6.99 (broad s, 1 H), 1.54 (s, 9 H); 13C NMR d
152.1, 139.5, 129.8, 124.6 (q, J = 33), 123.4 (t, J = 4.4), 123.4
(q, J = 272), 123.4 (q, J = 272), 121.3, 117.9 (q, J = 30), 82.2,
28.0; 19F NMR d À61.9 (s), À62.9 (s).
tert-Butyl N-(2-fluoro-3-methoxyphenyl)carbamate (3k,
79%): mp 95–97 8C (petroleum ether); IR nmax 3441, 2983,
1731, 1624, 1539, 1456, 1242, 1156 cmÀ1; 1H NMR d 7.28 (dd,
J = 9.0 and 2.2, 1 H), 6.76 (t, J = 8.7, 1 H), 6.06 (broad s, 1 H),
3.87 (s, 3 H), 1.50 (s, 9 H); 13C NMR d 152.6, 148.4 (d,
J = 251), 148.0 (d, J = 10), 126.5, 125.3 (d, J = 12), 112.1, 81.2,
56.6, 28.1; 19F NMR d À155.9(s).
tert-Butyl N-(2-fluorophenyl)carbamate [21] (3b, 87%): oil;
IR nmax 3442, 3032, 2983, 2935, 1729, 1522, 1238, 1158 cmÀ1
;
1H NMR d 8.07 (broad t, J = 7.6, 1 H), 7.0 (m, 2 H), 6.9 (m, 1
H), 6.71 (s, 1 H),1.53 (s, 9 H); 13C NMR d 152.4, 152.0 (d,
J = 240), 126.8 (d, J = 9.9), 124.5 (d, J = 3.6), 122.8 (d,
J = 7.4), 120.0, 114.7 (d, J = 19), 80.9, 28.2; 19F NMR d À133.2
(s).
4.2. Standard procedure for the metalation and subsequent
bromination of tert-butyl arylcarbamates (4a–k)
tert-Butyl N-(4-fluorophenyl)carbamate [21] (3d, 99%): mp
125–126 8C (hexane); IR nmax 3441, 3028, 2982, 2935, 1725,
1512, 1254, 1154 cmÀ1; 1H NMR d 7.3 (symmetric m, 2 H), 7.0
(symmetric m, 2 H), 6.54 (broad s, 1 H), 1.50 (s, 9 H); 13C NMR
d 158.7 (d, J = 240), 152.9, 134.3 (d, J = 2.5), 120.3, 115.5 (d,
J = 22), 80.6, 28.3; 19F NMR d À120.6.
tert-Butyllithium (1.70 M in pentane, 22 ml, 37 mmol) was
added dropwise to a solution of tert-butyl arylcarbamate (5.0 g,
18 mmol) in anhydrous THF (50 ml) to À75 8C. The mixture
was allowed to react 3 h at À50 8C, then it was cooled again at
À75 8C and a solution of CBr4 (5.9 g, 18.05 mmol) in THF
(10 ml) was added dropwise. The brown mixture was allowed
to react until the starting carbamate disappeared completely
(tlc, SiO2, eluent petroleum ether/diethyl ether 8:2). After a few
min, the mixture was poured into icy water and extracted with
diethyl ether (3 Â 150 ml). The collected organic extracts were
dried with Na2SO4 and the solvent was evaporated at reduced
pressure. Chromatography of the crude product on silica gel
(eluent, petroleum ether/diethyl ether 9:1) allowed pure
bromoarylcarbamate to be recovered.
tert-Butyl N-[2-(trifluoromethyl)phenyl]carbamate [22] (3e,
50%): oil; IR nmax 3463,(free N-H), 3358 (ass. N-H), 2982,
2934, 1743, 1594, 1528, 1159, 1111 cmÀ1; 1H NMR d 8.13 (d,
J = 12.4, 1 H), 7.55 (dt, J = 7.9 and 0.6, 1 H), 7.50 (t, J = 8.0, 1
H), 7.12 (tt, J = 7.6 and 0.9, 1 H), 6.79 (broad s, 1 H), 1.52 (s, 9
H); 13C NMR d 152.5, 136.2, 132.8, 125.9 (q, J = 5.4), 124.1 (q,
J = 271), 123.0, 122.3, 118.9 (q, J = 30), 81.3, 28.2; 19F NMR d
À61.3 (s).
tert-Butyl N-[3-(trifluoromethyl)phenyl]carbamate [23] (3f,
72%): mp 74–75 8C (hexane); IR nmax 3438,(free N-H), 3311
(ass. N-H), 3098, 2983, 2934, 1729, 1530, 1156, 1133 cmÀ1; 1H
NMR d 7.72 (s, 1 H), 7.47 (d, J = 8.0, 1 H), 7.36 (t, J = 7.9, 1 H),
7.26 (d, J = 7.7, 1 H), 6.7 (broad s, 1 H), 1.51 (s, 9 H); 13C NMR
d 152.5, 138.9, 131.3, (q, J = 32), 129.4, 123.9 (q, J = 270),
121.4, 119.5 (d, J = 3.7), 115.1, 81.2, 28.2; 19F NMR d À63.2.
tert-Butyl N-[4-(trifluoromethyl)phenyl]carbamate [24] (3g,
84%): mp 120–121 8C (hexane); IR nmax 3436, 3030, 2983,
tert-Butyl N-(2-bromophenyl)carbamate (4a, 78%): oil; IR
(film) nmax 3416, 2979, 2932, 1737, 1519, 1156 cmÀ1; 1H NMR
d 8.14 (dd, J = 8.3 and 1.1, 1 H), 7.48 (dd, J = 8.0 and 1.5, 1 H),
7.26 (td, J = 8.3 and 1.4, 1 H), 7.00 (broad s, 1 H), 6.87 (ddd,
J = 8.0, 7.4 and 1.6, 1 H), 1.53 (s, 9 H); 13C NMR d 152.3,
136.3, 132.2, 128.2, 123.8, 120.1, 112.4, 81.0, 28.3. Anal.
Calcd. for C11H14BrNO2: C, 48.5; H, 5.2; N, 5.1. Found: C,
48.7; H, 5.2; N, 5.1.
tert-Butyl N-(2-bromo-6-fluorophenyl)carbamate (4b,
82%): mp 93–94 8C (petroleum ether); IR nmax 3426, 3038,
2984, 2933, 1733, 1498, 1250, 1159 cmÀ1; 1H NMR d 7.3 (m, 1
H), 7.1 (m, 2 H), 6.12 (broad s, 1 H), 1.48 s (9 H); 13C NMR d
158.1 (d, J = 252), 152.7, 128.0 (d, J = 5), 127.9, 124.9 (d,
J = 15), 122.0, 115.5 (d, J = 21), 81.2, 28.0; 19F NMR d À115.0
(t, J = 7.7). Anal. Calcd. for C11H13BrFNO2: C, 45.5; H, 4.5; N,
4.8. Found: C, 45.6; H, 4.7; N, 4.9.
1
2935, 1731, 1530, 1327, 1159, 1118 cmÀ1; H NMR d 7.53–
7.45 (four peaks AA’XX’system, 4 H), 6.75 (broad s, 1 H), 1.51
(s, 9 H); 13C NMR d 152.3, 141.5, 126.2 (q, J = 3.7), 124.7 (q,
J = 33), 124.2 (q, J = 270), 117.9, 81.2, 28.2; 19F NMR d À62.4.
tert-Butyl N-[2-(trifluoromethoxy)phenyl]carbamate [14a]
(3h, 76%): oil IR nmax 3461, 2983, 2935, 1740, 1524, 1252,
1156 cmÀ1 1H NMR d 8.17 (d, J = 8.2, 1 H), 7.2 (m, 2 H), 7.00

F. Bellezza et al. / Journal of Fluorine Chemistry 129 (2008) 97–107
101
tert-Butyl N-(2-bromo-5-fluorophenyl)carbamate (4c, pre-
pared from commercial 2-bromo-5-fluoroaniline and di-tert-
butyl dicarbonate, 75%): oil; IR nmax 3411, 3106, 2984, 2931,
tert-Butyl N-[2-bromo-4-(trifluoromethoxy)phenyl]carba-
mate (4i, 81%): mp 47–48 8C (petroleum ether); IR nmax
1
3414, 3030, 2984, 2934, 1730, 1522, 1259, 1155 cmÀ1; H
1
1731, 1606, 1521, 1154 cmÀ1; major conformer, H NMR d
NMR d 8.18 (d, J = 9.1, 1 H), 7.39 (d, J = 2.7, 1 H), 7.16 (dd,
J = 9.2 and 2.3, 1 H), 6.97 (broad s, 1 H), 1.52 (s, 9 H); 13C
NMR d 152.2, 143.8, 135.3, 125.1, 121.1, 120.4 (q,
J = 256),120.3, 111.9, 81.5, 28.2; 19F NMR d À58.8 (s). Anal.
Calcd. for C12H13BrF3NO3: C, 40.5; H, 3.7; N, 3.9. Found: C,
40.5; H, 3.7; N, 4.0.
7.94 (dd, J = 11 and 2.7, 1 H), 7.35 (dd, J = 8.8 and 5.8, 1 H),
6.96 (broad s, 1 H), 6.56 (ddd, J = 8.8, 7.6 and 3.0, 1 H), 1.46 (s,
9 H); 13C NMR d 162.3 (d, J = 243), 151.9, 137.5 (d, J = 12),
132.7 (d, J = 9.3), 110.5 (d, J = 23), 107.2 (d, J = 29), 105.9 (d,
J = 3.2), 81.5, 28.2; 19F NMR d À112.0 (s). Anal. Calcd. for
C11H13BrFNO2: C, 45.5; H, 4.5; N, 4.8. Found: C, 45.6; H, 4.6;
N, 5.0.
tert-Butyl N-[2-bromo-4,6-bis(trifluoromethyl)phenyl]car-
bamate (4j, 63%): mp 90–92 8C; IR nmax 3429, 2984, 1732,
1622, 1490, 1343, 1147 cmÀ1; 1H NMR d 8.08 (s, 1 H), 7.86 (s,
1 H), 6.26 (broad s, 1 H), 1.47 (s, 9 H); 13C NMR d 152.2, 137.6,
133.9, 130.6 (q, J = 34), 130.4 (q, J = 31), 127.3, 122.9, 122.2
(q, J = 272), 122.1 (q, J = 272), 81.9, 28.0; 19F NMR d À62.6
(s), À63.4 (s). Anal. Calcd. for C13H12BrF6NO2: C, 38.3; H,
3.0; N, 3.4. Found: C, 38.4; H, 3.0; N, 3.5.
tert-Butyl N-(2-bromo-4-fluorophenyl)carbamate [25] (4d,
66%): mp 30–32 8C; IR nmax 3417, 3086, 2984, 2935, 2873,
1728, 1516, 1258, 1158 cmÀ1; 1H NMR d 8.07 (dd, J = 9.0 and
5.6, 1 H), 7.24 (dd, J = 7.8 and 2.9, 1 H), 7.00 (dddd, J = 10.7,
7.8, 2.9 and 0.5, 1 H), 6.84 (broad s, 1 H), 1.51 (s, 9 H); 13C
NMR d 157.7 (d, J = 245), 152.5, 132.7, 121.2 (d, J = 7.3),
119.2 (d, J = 26), 115.0 (d, J = 22), 112.4 (d, J = 9.3), 81.2,
28.2; 19F NMR d À118.9 (s). Anal. Calcd. for C11H13BrFNO2:
C, 45.5; H, 4.5; N, 4.8. Found: C, 45.5; H, 4.6; N, 4.8.
tert-Butyl N-[2-bromo-6-(trifluoromethyl)phenyl]carbamate
(4e, 64%): oil; IR (film) nmax 3433, 3028, 2984, 2934, 1731,
1316, 1169, 1146 cmÀ1; 1H NMR d 7.81 (d, J = 8.0, 1 H), 7.60
(d, J = 7.8, 1 H), 7.24 (t, J = 8.0, 1 H), 6.23 (broad s, 0.7 H),
6.09 (broad s, 0.3 H), 1.50 (s, 6.3 H), 1.37 (s, 2.7 H); 13C NMR d
152.9, 136.8, 134.0, 130.2 (q, J = 29), 128.4, 126.9, 125.6 (q,
J = 4.6), 122.9 (q, J = 272), 81.1, 28.1; 19F NMR d À62.3 (s).
Anal. Calcd. for C12H13BrF3NO2: C, 42.4; H, 3.8; N, 4.1.
Found: C, 42.5; H, 3.9; N, 4.0.
tert-butyl
N-[6-bromo-2-fluoro-3-methoxyphenyl]carba-
mate (4k, 62%): mp 91–93 8C; IR nmax 3426, 3024, 2983,
1
2939, 2361, 1732, 1702, 1609, 1492, 1160 cmÀ1; H NMR d
7.28 (dd, J = 9.0 and 2.2, 1 H), 6.76 (t, J = 9.0, 1 H), 6.06 (broad
s, 1 H), 3.87 (s, 3 H), 1.50 (s, 9 H); 13C NMR d 152.6, 148.4 (d,
J = 251), 148.0 (d, J = 10), 126.5, 125.3 (d, J = 12), 112.1, 81.2,
56.6, 28.1; 19F NMR d À135.9 (s). Anal. Calcd. for
C12H15BrFNO3: C, 45.0; H, 4.7; N, 4.4. Found: C, 45.1; H,
4.8; N, 4.3.
4.3. Standard procedure for preparing tert-butyl aryl(N-
propargyl) carbamates (5a–k)
tert-butyl N-[2-bromo-5-(trifluoromethyl)phenyl]carbamate
(4f, 77%): oil; IR (film) nmax 3416, 3107, 2983, 2935, 1739,
Arylcarbamate (11.0 mmol) was added to a solution of NaH
(0.48 g, 12.1 mmol), in DMF (20 ml) under nitrogen atmo-
sphere. The mixture was allowed to react until the hydrogen
evolution ceased (1 h). Propargyl bromide (1.84 ml,
16.5 mmol) was added dropwise and the resulting brown
slurry was stirred at 25 8C until the starting arylcarbamate
disappeared (tlc, eluent, petroleum ether/diethyl ether 9:1). The
mixture was poured into water, extracted with diethyl ether
(3 Â 100 ml) and the collected organic extracts were dried with
Na2SO4. The solvent was evaporated at reduced pressure and
the residual crude was chromatographed on silica gel (eluent,
petroleum ether/diethyl ether 9:1) to recover the pure product.
tert-Butyl N-(2-bromophenyl)-N-( prop-2-ynyl)carbamate
(5a, 2.8:1 mixture of two conformers, 75%): mp 55–58 8C;
1
1525, 1157, 1130 cmÀ1; H NMR d 8.50 (s, 1 H), 7.60 (d,
J = 8.3, 1 H), 7.13 (dq, J = 8.3 and 0.7, 1 H), 7.10 (broad s, 1 H),
1.54 (s, 9 H); 13C NMR d 152.0, 137.0, 132.7, 130.8 (q, J = 33),
123.6 (q, J = 271), 120.0 (q, J = 3.8), 116.5 (q, J = 4.0), 115.4,
81.8, 28.2; 19F NMR d À63.3 (s). Anal. Calcd. for
C12H13BrF3NO2: C, 42.4; H, 3.8; N, 4.1. Found: C, 42.5; H,
3.9; N, 4.1.
tert-Butyl N-[2-bromo-4-(trifluoromethyl)phenyl]carbamate
(4g, 94%): mp 49–51 8C (hexane); IR nmax 3410, 3038, 2984,
2935, 1733, 1530, 1324, 1155 cmÀ1; 1H NMR d 8.31 (d, J = 8.7,
1 H), 7.75 (dq, J = 2.0 and 0.5, 1 H), 7.52 (dq, J = 8.7 and 0.6, 1
H), 7.15 (broad s, 1 H), 1.53 (s, 9 H); 13C NMR d 151.9, 139.4,
129.3 (q, J = 3.7), 125.4 (q, J = 24), 125.4 (q, J = 3.7), 123.3 (q,
J = 270), 119.2, 111.5, 81.9, 28.2; minor conformer (character-
istic absorptions): d 132.6, 112.2, 90.1, 80.9, 28.2; 19F NMR d
À62.5 (s). Anal. Calcd. for C12H13BrF3NO2: C, 42.4; H, 3.8; N,
4.1. Found: C, 42.3; H, 3.8; N, 4.2.
IR nmax 3309, 3064, 2982, 2933, 1702, 1478, 1388, 1165 cmÀ1
;
1
major conformer, H NMR d 7.59 (d, J = 7.7, 1 H), 7.36 (d,
J = 6.8, 1 H), 7.30 (t, J = 7.1, 1 H), 7.15 (td, J = 7.4 and 1.7, 1
H), 4.76 (dd, J = 18 and 2.2, 1 H), 3.93 (dd, J = 18 and 2.2, 1 H),
2.18 (s, 1 H), 1.33 (s, 9 H); 13C NMR d 153.6, 140.0, 132.9,
130.7, 129.0, 127.8, 123.5, 80.9, 79.2, 72.3, 38.0, 28.0; NMR
signals identifying the minor conformer, 1H NMR d 4.60 (broad
d, J = 18, 1 H), 2.21 (broad s, 1 H), 1.53 (s, 9 H); 13C NMR d
153.5, 140.4, 133.2, 131.0, 129.2, 128.2, 123.5, 81.4, 79.4, 72.0,
39.4, 28.2. Anal. Calcd. for C14H16BrNO2: C, 54.2; H, 5.2; N,
4.5. Found: C, 54.3; H, 5.3; N, 4.4.
tert-Butyl N-[2-bromo-6-(trifluoromethoxy)phenyl]carba-
mate (4h, 46%): mp 60–63 8C (hexane); IR nmax 3427,
3030, 2983, 1733, 1496, 1260, 1166 cmÀ1; 1H NMR d 7.54 (dd,
J = 8.1 and 1.3, 1 H), 7.25 (d quint., J = 8.3 and 1.4, 1 H), 7.15
(t, J = 8.2, 1 H), 6.05 (broad s, 1 H), 1.48 (s, 9 H); 13C NMR d
152.6, 145.7, 131.1, 129.7, 128.1, 123.5, 120.4 (q, J = 257),
81.2, 28.0; 19F NMR d À58.1 (s). Anal. Calcd. for
C12H13BrF3NO3: C, 40.5; H, 3.7; N, 3.9. Found: C, 40.4; H,
3.7; N, 4.0.
tert-Butyl N-(2-bromo-6-fluorophenyl)-N-( prop-2-ynyl)car-
bamate (5b, 3.3:1 mixture of two conformers, 82%): oil; IR

102
F. Bellezza et al. / Journal of Fluorine Chemistry 129 (2008) 97–107
nmax 3304, 2979, 2932, 1712, 1369, 1166 cmÀ1; major
1
conformer, H NMR d 7.37 (t, J = 8.0, 1 H), 7.17–7.04 (m, 2
28.1; 19F NMR d À61.9. Anal. Calcd. for C15H15BrF3NO2: C,
47.6; H, 4.0; N, 3.7. Found: C, 47.6; H, 4.1; N, 3.6.
H), 4.57–4.22 (eight peaks, AB portion of an ABX system, 2
H), 2.11 (t, X portion of an ABX system, 1 H), 1.33 (s, 9 H); 13
tert-Butyl N-[2-bromo-5-(trifluoromethyl)phenyl]-N-( prop-
2-ynyl)carbamate (5f, 2.5:1 mixture of two conformers, 78%):
oil; IR (film) nmax 3079, 2980, 2934, 1719, 1605, 1426, 1289,
1173 cmÀ1; major conformer 1H NMR, d 7.73 (d, J = 8.3, 1 H),
7.62 (s, 1 H), 7.42 (dd, J = 8.4 and 2.2, 1 H), 4.77 (dd, J = 18
and 2.2, 1 H), 3.96 (dd, J = 18 and 2.2, 1 H), 2.22 (broad t,
J = 2.3, 1 H), 1.33 (s, 9 H); 13C NMR d 153.1, 140.6, 133.6,
130.5 (d, J = 34),127.9, 125.6, 123.3 (q, J = 271), 81.6, 73.0,
37.8, 27.9; 19F NMR d À63.2 (s); NMR signal characterizing
the minor conformer, 1H NMR d 4.61 (d, J = 18, 1 H), 2.25 (s, 1
H), 1.53 (s, 9 H); 13C NMR d 84.3, 72.7, 39.3, 28.2; 19F NMR d
À63.1 (s). Anal. Calcd. for C15H15BrF3NO2: C, 47.6; H, 4.0; N,
3.7. Found: C, 47.8; H, 4.1; N, 3.7.
C
NMR d 159.7 (d, J = 252), 153.2, 126.9 (d, J = 8.8), 128.7,
128.2 (d, J = 3.5), 124.8, 115.2 (d, J = 21), 81.3, 78.0, 72.3,
37.3, 27.9; 19F NMR d À115.3 (dd, J = 8.4 and 5.9); NMR
signals identifying the minor conformer, 1H NMR d 4.45–4.15
(eight peaks, AB portion of an ABX system, 2 H), 2.15 (t, X
portion of an ABX system, 1 H), 1.52 (s, 9 H); 13C NMR d 160.1
(d, J = 252), 152.8 (129.8 (d, J = 8.8), 128.5, 128.4 (d, J = 3.5),
125.2, 115.6 (d, J = 21), 81.9, 78.3, 72.1, 38.8, 28.2; 19F NMR d
À114.6 (dd, J = 8.3 and 6.0). Anal. Calcd. for C14H15BrFNO2:
C, 51.2; H, 4.6; N, 4.3. Found: C, 51.4; H, 4.7; N, 4.2.
tert-Butyl N-(2-bromo-5-fluorophenyl)-N-( prop-2-ynyl)car-
bamate (5c, 2.8:1 mixture of two conformers, 71%): oil; IR
tert-Butyl N-[2-bromo-4-(trifluoromethyl)phenyl]-N-( prop-
2-ynyl)carbamate (5g, 2.5:1 mixture of two conformers, 86%):
oil; IR (film) nmax 3310, 3074, 2980, 2943, 1710, 1608, 1370,
(film) nmax 3308, 3088, 2998, 1703, 1588, 1476, 1164 cmÀ1
;
1
major conformer, H NMR d 7.49 (dd, J = 8.8 and 5.8, 1 H),
7.07 (dd, J = 8.8 and 2.8, 1 H), 4.70 (d, J = 18, 2 H), 3.87 (d,
J = 18, 1 H), 2.16 (broad s, 1 H), 1.29 (s, 9 H); 13C NMR d 161.6
(d, J = 246), 153.2, 141.5, 133.5 (d, J = 8.7), 118.2 (d, J = 23),
118.1, 116.3 (d, J = 22), 81.3, 72.7, 37.8, 28.0; 19F NMR d
1
1321, 1078 cmÀ1; major conformer, H NMR d 7.88 (s, 1 H),
7.60–7.48 (four peaks, AB system, JAB = 8.0, 2 H), 4.77 (d,
J = 18, 1 H), 3.97 (d, J = 18, 1 H), 2.21 (broad s, 1 H), 1.34 (s, 9
H); 13C NMR d 153.0, 143.3, 131.1, 131.0, 130.2, 124.1, 122.8
(q, J = 271), 121.6, 81.6, 78.6, 72.8, 37.8, 28.0; 19F NMR d
À63.1 (s); characteristic NMR signal of the minor conformer,
1H NMR d 4.67 (d, J = 17, 1 H), 2.24 (broad s, 1 H), 1.54 (s, 9
H); 13C NMR d 153.0, 143.5, 131.3, 130.3, 125.0, 124.0, 122.8
(d, J = 271), 86.7, 82.0, 72.4, 39.1, 28.0; 19F NMR d À63.2 (s).
Anal. Calcd. for C15H15BrF3NO2: C, 47.6; H, 4.0; N, 3.7.
Found: C, 47.6; H, 4.2; N, 3.8.
1
113.9 (s); NMR signals identifying the minor conformer, H
NMR d 4.55 (d, J = 18, 1 H), 1.47 (s, 9 H); 13C NMR d 78.8,
72.4, 39.3; 19F NMR d À113.4 (s). Anal. Calcd. for
C14H15BrFNO2: C, 51.2; H, 4.6; N, 4.3. Found: C, 51.1; H,
4.5; N, 4.3.
tert-Butyl N-(2-bromo-4-fluorophenyl)-N-( prop-2-ynyl)car-
bamate (5d, 3.1:1 mixture of two conformers, 62%): oil; IR
nmax 3306, 2979, 2932, 1709, 1492, 1168 cmÀ1; major
tert-Butyl
N-[2-bromo-6-(trifluoromethoxy)phenyl]-N-
1
conformer, H NMR d 7.3 (m, 2 H), 7.02 (dt, J = 8.0 and
( prop-2-ynyl)carbamate (5h, 4.3:1 mixture of two conformers,
77%): oil; IR (film) nmax 3310, 2980, 2932, 1718, 1370, 1252,
1173 cmÀ1; major conformer, 1H NMR d 7.53 (dd, J = 7.9 and
1.5, 1 H), 7.26 (dquint., J = 8.4 and 1.6, 1 H), 7.20 (t, J = 8.3, 1
H), 4.45–4.34 (eight peaks, AB portion of an ABX system,
2.8, 1 H), 4.76 (dd, J = 18 and 2.4, 1 H), 3.91 (dd, J = 18 and
2.4, 1 H), 2.19 (t, J = 2.4, 1 H), 1.33 (s, 9 H); 13C NMR d 161.2
(d, J = 250), 153.5, 136.3, 131.6 (d, J = 8.9), 124.0 (d,
J = 10.0), 120.0 (d, J = 25.3), 114.9 (d, J = 22.0), 81.0, 79.0,
72.6, 37.9, 28.0; 19F NMR d À112.4 (q, J = 7.7); NMR signals
of the minor conformer, 1H NMR d 4.60 (d, J = 18, 1 H), 2.23
(broad s, 1 H), 1.52 (s, 9 H); 13C NMR d 161.3 (d, J = 250),
153.5, 136.5, 131.9 (d, J = 8.5), 124.0 (d, J = 10), 120.3 (d,
J = 25), 115.2 (d, J = 22), 81.6, 78.9, 72.3, 39.3, 28.2; 19F NMR
d À112.1 (q, J = 6.0). Anal. Calcd. for C14H15BrFNO2: C, 51.2;
H, 4.6; N, 4.3. Found: C, 51.3; H, 4.6; N, 4.4.
J
AB = 17.6, JAX = JBX = 2.5, 2 H, major conformer), 2.11 (t,
J = 2.5, X portion of an ABX system, 1 H), 1.33 (s, 9 H); 13C
NMR d 152.9, 147.3, 132.7, 130.7, 129.3, 126.1, 122.9 (q,
J = 270), 119.0, 81.3, 77.3, 72.6, 37.4, 27.8; 19F NMR d À57.3
(s); NMR signals identifying the minor conformer, 1H NMR d
4.35–4.18 (eight peaks, AB portion of an ABX system,
JAB = 17.6, JAX = JBX = 2.5, 2 H), 2.15 (t, J = 2.5, X portion of
tert-Butyl N-[2-bromo-6-(trifluoromethyl)phenyl]-N-( prop-
2-ynyl)carbamate (5e, 4.3:1 mixture of two conformers, 88%):
oil; IR (film) nmax 3310, 3028, 2983, 2934, 1708, 1315,
an ABX system, 1 H), 1.53 (s, 9 H); 13C NMR d 153.5, 147.3,
132.9, 130.8, 129.5, 126.2, 123.0 (q, J = 270), 119.0, 81.9, 77.8,
72.1, 38.9, 28.1; 19F NMR d À57.1 (s). Anal. Calcd. for
C15H15BrF3NO3: C, 45.7; H, 3.8; N, 3.5. Found: C, 45.6; H, 3.8;
N, 3.6.
1
1144 cmÀ1; H NMR d 7.83–7.80 (m, 1 H), 7.62 (dd, J = 7.9
and 0.9, 1 H), 7.29 (t, J = 8.0, 1 H), 4.48–4.28 (eight peaks, AB
portion of an ABX system, JAB = 17, JAX = JBX = 2.6, 2 H),
2.07 (t, X portion of an ABX system, J = 2.6, 1 H), 1.30 (s, 9 H);
13C NMR d 152.9, 138.1, 136.5, 131.2 (q, J = 30), 129.0, 127.6,
125.9 (q, J = 5.0), 122.7 (q, J = 272), 81.3, 77.2, 73.6, 38.5,
27.8; 19F NMR d À61.6; NMR signals identifying the minor
conformer, 1H NMR d 4.37–4.21 (eight peaks, AB portion of an
ABX system, JAB = 17, JAX = JBX = 2.6, 2 H), 2.12 (t, X
portion of an ABX system, J = 2.6, 1 H), 1.51 (s, 9 H); 13C
NMR d 153.5, 138.6, 136.8, 131.7 (q, J = 30), 129.3, 128.0,
126.1 (q, J = 5.0), 122.7 (q, J = 272), 81.8, 77.7, 73.0, 39.6,
tert-Butyl
N-[2-bromo-4-(trifluoromethoxy)phenyl]-N-
( prop-2-ynyl)carbamate (5i, 3.0:1 mixture of two conformers,
87%): oil; IR (film) nmax 3310, 3098, 2980, 2934, 1714, 1577,
1490, 1258, 1010, 767 cmÀ1; major conformer, 1H NMR d 7.49
(s, 1 H), 7.40 (d, J = 8.3, 1 H), 7.18 (broad d, J = 8.3, 1 H), 4.77
(dd, J = 18 and 2.4, 1 H), 3.92 (dd, J = 18 and 2.4, 1 H), 2.22 (t,
J = 2.2, 1 H), 1.34 (s, 9 H); 13C NMR d 153.3, 148.2, 138.8,
131.5, 125.3, 124.2, 120.6, 120.2, 120.2 (q, J = 257), 84.1, 81.3,
72.7, 37.9, 28.0; 19F NMR d À58.5 (s); NMR signals
1
characterizing the minor conformer, H NMR d 4.61 (broad

F. Bellezza et al. / Journal of Fluorine Chemistry 129 (2008) 97–107
103
d, J = 17, 1 H), 2.24 (broad s, 1 H), 1.53 (s, 9 H); 13C NMR d
153.5, 148.2, 139.0, 131.8, 125.7, 124.1, 120.6, 120.2 (q,
J = 257), 84.1, 81.9, 72.4, 39.3, 28.2. Anal. Calcd. for
C15H15BrF3NO3: C, 45.7; H, 3.8; N, 3.5. Found: C, 45.9; H,
3.9; N, 3.6.
filtered through a short silica gel column (eluent, petroleum
ether). In some cases, a second treatment with DBU-I2 was
necessary in order to remove the residual organotin
derivatives. After the solvent evaporation chromatography
of the remaining white product on silica gel (eluent petroleum
ether) allowed pure tert-butyl 3-methyleneindoline-1-carbox-
ylate to be collected.
tert-Butyl N-[2-bromo-4,6-bis(trifluoromethyl)phenyl]-N-
( prop-2-ynyl)carbamate (5j, 4:1 mixture of two conformers,
74%): oil; IR (film) nmax 3309, 3092, 3029, 2983, 2935, 1714,
1619, 1334, 1174 cmÀ1; major conformer, 1H NMR d 8.14 (s, 1
H), 7.93 (broad s, 1 H), 4.56 (dd, J = 17 and 2.6, 1 H), 4.36 (dd,
J = 17 and 2.6, 1 H), 2.14 (t, J = 2.6, 1), 1.36 (s, 9); 13C NMR d
152.7, 142.0, 133.9, 132.5 (q, J = 31), 131.8 (q, J = 34), 129.1,
123.6, 122.6 (q, J = 271), 122.4 (q, J = 272), 82.5, 77.0, 74.7,
38.8, 28.2; 19F NMR d À62.2 (s), À63.4 (s); minor conformer:
1H NMR d 8.14 (s, 1 H), 7.93 (s, 1 H), 4.45 (dd, J = 17 and 2.6, 1
H), 4.30 (dd, J = 17 and 2.6, 1 H), 2.18 (t, J = 2.6, 1 H), 1.57 (s,
9 H); 13C NMR d 152.5, 142.0, 134.2, 133.0 (q, J = 31), 132.2
(q, J = 33), 129.6, 123.6, 123.5 (q, J = 271), 122.8 (q, J = 272),
83.0, 77.0, 74.1, 39.9, 28.5; 19F NMR d À62.4 (s), À63.6 (s).
Anal. Calcd. for C16H14BrF6NO2: C, 43.1; H, 3.2; N, 3.1.
Found: C, 43.2; H, 3.21; N, 3.2.
tert-Butyl 3-methyleneindoline-1-carboxylate (2a, 41%);
1
oil; IR (film) nmax 2976, 2929, 1708, 1390, 1149 cmÀ1; H
NMR d 7.93 (broad s, 0.62 H), 7.51 (broad s, 0.38 H), 7.41 (d,
J = 7.6, 1 H), 7.23 (t, J = 7.6, 1 H), 6.96 (td, J = 7.5 and 1.0, 1
H), 5.44 (t, J = 3.0, 1 H), 5.03 (broad s, 1 H), 4.57 (broad s, 2 H),
1.57 (s, 9 H); 13C NMR d 151.5, 141.1, 129.9, 122.2, 120.3,
115.3, 101.5, 101.1, 80.8, 53.4, 28.4. Anal. Calcd. for
C14H17NO2: C, 72.7; H, 7.4; N, 6.1. Found: C, 72.6; H, 7.4;
N, 5.9.
tert-Butyl 7-fluoro-3-methyleneindoline-1-carboxylate (2b,
58%): viscous oil; IR (CHCl3) nmax 3026, 2983, 2934, 1694,
1593, 1489, 1377, 1103 cmÀ1; 1H NMR d 7.2 (symmetric m, 1
H), 7.0 (symmetric m, 2 H), 5.45 (t, J = 3.0, 1 H), 5.06 (t,
J = 2.6, 1 H), 4.61 (t, J = 2.8, 2 H), 1 52 (s, 9 H); 13C NMR d
151.0 (d, J = 251), 151.9, 141.2 (d, J = 2.2), 133.9 (d, J = 3.0),
131.6 (d, J = 9.9), 124.2 (d, J = 6.9), 117.8 (d, J = 22), 116.0 (d,
J = 3.4), 81.5, 72.3, 55.2, 28.1; 19F NMR d À115.9 (dd, J = 8.6
and 6.0). Anal. Calcd. for C14H16FNO2: C, 67.4; H, 6.5; N, 5.6.
Found: C, 67.2; H, 6.5; N, 5.5.
tert-Butyl
N-(6-bromo-2-fluoro-3-methoxyphenyl)-N-
( prop-2-ynyl)carbamate (5k, 3.6:1 mixture of two confor-
mers, 84%): mp 89–91 8C; IR (film) nmax 3309, 3022, 1707,
1
1602, 1487, 1369, 1159 cmÀ1; major conformer, H NMR d
7.33 (dd, J = 9.0 and 2.2, 1 H), 6.85 (dd, J = 8.8 and 8.3, 1 H),
4.57 (dd, J = 18 and 2.5, 1 H), 4.29 (dd, J = 18 and 2.5, 1 H),
3.91 (s, 3 H), 2.15 (t, J = 2.5, 1 H), 1.38 (s, 9 H); 13C NMR d
153.2, 149.9 (d, J = 251), 147.7 (d, J = 10), 129.1 (d, J = 13),
126.7 (d, J = 4.6), 114.7, 113.3, 81.3, 78.1, 72.3, 56.5, 37.4,
tert-Butyl
6-fluoro-3-methyleneindoline-1-carboxylate
(2c, 56%): mp 83–85 8C; IR nmax 3024, 2984, 1702, 1614,
1492, 1389, 1170 cmÀ1; 1H NMR d 7.68 (broad s, 1 H), 7.34
(dd, J = 8.3 and 5.7, 1 H), 6.66 (td, J = 8.6 and 2.3, 1 H), 5.37
(broad s, 1 H), 4.98 (broad s, 1 H), 4.59 (broad s, 2 H), 1.55
(s, 9); 13C NMR d 164.1 (d, J = 245), 151.3, 139.9, 125.0,
121.2, 109.2 (d, J = 23), 103.3 (d, J = 29), 101.0, 100.5, 81.3,
54, 28.2; 19F NMR d À110, 7 (broad s, major conformer),
À110.9 (broad s, minor conformer). Anal. Calcd. for
C14H16FNO2: C, 67.4; H, 6.5; N, 5.6. Found: C, 67.6; H,
6.4; N, 5.7.
1
28.0; 19F NMR d À135.9 (s); minor conformer, H NMR d
7.34 (dd, J = 8.9 and 2.2, 1 H), 6.85 (dd, J = 8.8 and 8.3, 1 H),
4.46 (dd, J = 18 and 2.5, 1 H), 4.21 (dd, J = 18 and 2.5, 1 H),
3.88 (s, 3 H), 2.20 (t, J = 2.5, 1 H), 1.56 (s, 9 H); 13C NMR d
153.1, 149.9 (d, J = 251), 147.7 (d, J = 10), 129.0 (d, J = 13),
127.0 (d, J = 4.6), 114.9, 113.7, 81.9, 78.1, 72.1, 56.5,
38.9, 28.2; 19F NMR d À135.1 (s). Anal. Calcd. for
C15H17BrFNO3: C, 50.3; H, 4.8; N, 3.9. Found: C, 50.3;
H, 4.7; N, 4.0.
tert-Butyl 5-fluoro-3-methyleneindoline-1-carboxylate (2d,
48%): mp 71–73 8C; IR nmax 3034, 2982, 2934, 1698, 1602,
1483, 1391, 1150 cmÀ1; 1H NMR d 7.87 (broad s, 0.57 H), 7.42
(broad m, 0.43), 7.06 (dd, J = 8.2 and 2.6, 1 H), 6.91 (t, J = 8.3,
4.4. Standard procedure for the synthesis of tert-butyl 3-
methyleneindoline-1-carboxylates (2a–k)
1 H), 5.42 (s, 1 H), 5.06 (s, 1 H), 4.57 (s, 2 H), 1.54 (s, 9 H); 13
NMR d; 158.8 (d, J = 239), 151.4, 141.4, 140.4, 130.5, 116.4,
116.1 (d, J = 8.0), 106.9 (d, J = 23), 102.4, 80.8, 54.5, 28.3; 19
C
Tributyltin hydride (0.9 ml, 32.01 mmol) was added
dropwise to a solution of tert-butyl (2-bromoaryl)(prop-2-
ynyl)carbamates (15 mmol) and AIBN (50 mg, 1.5 mmol) in
benzene (150 ml). The solution was refluxed under nitrogen
atmosphere and, after 1 h, a second portion of AIBN (50 mg,
1.5 mmol) was added and reflux was continued until the
substrate had completely disappeared (TLC, SiO2, eluent,
petroleum ether/diethyl ether 8:2), ca. 2–3 h. The solvent was
evaporated at reduced pressure and diethyl ether (20–30 ml)
was added to the residual crude. Diazabicycloundecene
(DBU, 1.5 eq. with respect to Bu3SnH) was added and the
mixture was stirred for 30 min before 0.1 M iodine in diethyl
ether was added until a persistent yellow colour was
observed. The mixture was further stirred for 1 h and then
F
NMR d À121.9 (major conformer); À122.1 (minor conformer).
Anal. Calcd. for C14H16FNO2: C, 67.4; H, 6.5; N, 5.6. Found:
C, 67.3; H, 6.5; N, 5.6.
tert-Butyl 3-methylene-7-(trifluoromethyl)indoline-1-car-
boxylate (2e, 70%): mp 98–100 8C;; IR nmax 2983, 2933,
1724, 1604, 1440, 1157 cmÀ1; 1H NMR d 7.56 (d, J = 7.5, 1 H),
7.49 (d, J = 7.4, 1 H), 7.15 (t, J = 7.5, 1 H), 5.52 (t, J = 2.9, 1 H),
5.13 (t, J = 2.4, 1 H), 4.66 (t, J = 2.7, 2 H), 1.52, (s, 9 H); 13
C
NMR d 153.6, 142.0 (q, J = 1.6), 141.0, 133.1, 128.4 (q,
J = 4.4), 123.8, 123.7 (q, J = 270), 123.2, 120.9 (q, J = 33.1),
102.7, 82.2, 55.7, 27.8; 19F NMR d À59.8 (s). Anal. Calcd. for
C15H16F3NO2: C, 60.2; H, 5.4; N, 4.7. Found: C, 60.1; H, 5.5;
N, 4.8.

104
F. Bellezza et al. / Journal of Fluorine Chemistry 129 (2008) 97–107
tert-Butyl 3-methylene-6-(trifluoromethyl)indoline-1-car-
4.5. Standard procedure for the synthesis of fluorinated
diethyl 2-[(1H-indol-3-yl)methyl]-2-hydroxymalonates
(6a–k), ethyl 3-[(1H-indol-3-yl)methyl]-2-
hydroxypropionates (7d,i,j) and ethyl 2-[(1-tert-
butoxycarbonyl-1H-indol-3-yl)methyl]-2-hydroxy-3,3,3-
trifluoropropionates (8b,d,i)
boxylate (2f, mixture of two conformers, 69%): semi-solid;
IR (film) nmax 2980, 2934, 1713, 1615, 1393, 1325, 1166,
1127 cmÀ1; major conformer; 1H NMR d 8.22 (broad s, 0.6 H),
7.63 (broad s, 0.4 H), 7.46 (d, J = 8.0, 1 H), 7.19 (d, J = 8.0, 1
H), 5.56 (broad s, 1 H), 5.15 (broad s, 1 H), 4.60 (broad s, 2 H),
1.55 (s, 9 H); 13C NMR d 151.4, 145.4, 141.0, 139.7, 128.7,
131.6 (q, J = 34), 124.3 (q, J = 270), 119.2, 112.5, 103.9, 81.6,
53.5, 28.3; 19F NMR d À63.2. Anal. Calcd. for C15H16F3NO2:
C, 60.2; H, 5.4; N, 4.7. Found: C, 60.2; H, 5.3; N, 4.7.
tert-Butyl 3-methylene-5-(trifluoromethyl)indoline-1-car-
boxylate (2g, 46%): mp 93–95 8C; IR nmax 3031, 2982,
A mixture of tert-butyl 3-methyleneindoline-1-carboxylate
(0.33 mmol) and the suitable enophilic species (0.33 mmol)
was heated at 100 8C, under nitrogen atmosphere, for 0.5–2 h,
until the indoline completely disappeared (tlc, SiO2, eluent
petroleum ether/diethyl ether 9:1). In the case of ethyl
glyoxalate, a commercial technical solution, 50% in toluene,
was directly used. The crude mixture was taken up with diethyl
ether (2 ml) and Chromatographed on silica gel (eluent,
petroleum ether/diethyl ether 9:1) to allow the pure malonyl
derivative 6(a–k), the propionates 7(d,i,j) and 8(b,d,i) to be
recovered.
1
2934, 1706, 1621, 1386, 1274, 1152, 1127 cmÀ1; H NMR d
7.99 (broad s, 1 H), 7.59 (s, 1 H), 7.45 (d, J = 8.4, 1 H), 5.51 (t,
J = 3.2, 1 H), 5.10 (t, J = 2.5, 1 H), 4.59 (t, J = 2.8, 2 H), 1.56 (s,
9 H); 13C NMR d 151.3, 147.8, 139.7, 129.4, 127.0 (q, J = 3.4),
124.4 (q, J = 32), 124.3 (q, J = 270), 117.4, 115.2, 103.1, 81.6,
53.7, 28.2 19F NMR d À62.2. Anal. Calcd. for C15H16F3NO2: C,
60.2; H, 5.4; N, 4.7. Found: C, 60.2; H, 5.4; N, 4.7.
Diethyl 2-[(1-tert-butoxycarbonyl-1H-indol-3-yl)methyl]-2-
hydroxymalonate (6a, 79%): oil; IR nmax 3518 (broad), 3032,
2984, 2939, 1736, 1453, 1371, 1156, 732 cmÀ1; 1H NMR d 8.02
(broad d, J = 6.6, 1 H), 7.54 (d, J = 7.7, 1 H), 7.43 (s, 1 H), 7.21
(td, J = 7.1 and 1.3, 1 H), 7.14 (td, J = 8.4 and 1.1, 1 H), 4.19–
4.08 (m, 4 H), 3.82 (s, 1 H), 3.39 (s, 2 H), 1.58 (s, 9 H), 1.19 (t,
J = 7.1, 6 H); 13C NMR d 169.9, 149.6, 135.1, 130.9, 125.1,
124.2, 122.3, 119.5, 115.0, 113.6, 83.5, 79.1, 62.6, 30.3, 28.2,
14.1. Anal. Calcd. for C21H27NO7: C, 62.2; H, 6.7; N, 3.4.
Found: C, 62.4; H, 6.8; N, 3.4.
tert-Butyl 3-methylene-7-(trifluoromethoxy)indoline-1-car-
boxylate (2h, 53%): oil; IR nmax 3028, 2983, 2934, 1724, 1698,
1371, 1255, 1166 cmÀ1 1H NMR d 7.36 (d, J = 7.5, 1 H), 7.12
(broad d, J = 8.1, 1 H), 7.03 (t, J = 7.7, 1 H), 5.49 (t, J = 3.0, 1
H), 5.10 (t, J = 2.5, 1 H), 4.64 (t, J = 2.7, 2 H), 1 59 (s, 9 H); 13
C
NMR d 151.9, 141.0, 137.3 (q, J = 2.1), 137.2, 124.2, 124.1,
120.7 (q, J = 256), 119.2, 102.8, 81.8, 55.5, 27.9; 19F NMR d
À58.3 (s). Anal. Calcd. for C15H16F3NO3: C, 57.1; H, 5.1; N,
4.4. Found: C, 57.0; H, 5.2; N, 4.5.
tert-Butyl 3-methylene-5-(trifluoromethoxy)indoline-1-car-
boxylate (2i, 57%): oil; IR nmax 3019, 2982, 2932, 1698, 1602,
Diethyl
2-[(1-tert-butoxycarbonyl-7-fluoro-1H-indol-3-
yl)methyl]-2-hydroxymalonate (6b, 85%): mp 88–89 8C; IR
nmax 3689, 3516 (broad), 1737, 1494, 1370, 1235, 1155,
909 cmÀ1; 1H NMR d 7.56 (s, 1 H), 7.41 (dd, J = 7.9 and 0.9, 1
H), 7.17 (td, J = 7.9 and 4.0, 1 H), 7.02 (ddd, J = 12.6, 7.9 and
0.6, 1 H), 4.32–4.18 (symmetric m, 4 H), 3.88 (broad s, 1 H),
3.46 (s, 2 H), 1.65 (s, 9 H), 1.28 (t, J = 7.1, 6 H);13C NMR d
169.9, 149.9 (d, J = 251), 148.7, 135.2 (d, J = 4.0), 127.5,
123.1, 121.8 (d, J = 10), 115.4, 113.6, 111.5 (d, J = 22), 84.0,
79.1, 62.7, 30.0, 27.9, 13.9; 19F NMR d À116.8 (dd, J = 13 and
3.8). Anal. Calcd. for C21H26FNO7: C, 59.6; H, 6.2; N, 3.3.
Found: C, 59.7; H, 6.2; N, 3.4.
1
1390, 1255, 1170, 1151 cmÀ1; H NMR d 7.92 (broad s, 0.67
H), 7.47 (broad s, 0.33 H), 7.22 (s, 1 H), 7.06 (d, J = 8.6, 1 H),
5.46 (s, 1 H), 5.09 (broad s, 1 H), 4.59 (broad s, 2 H), 1.54 (s, 9
H); 13C NMR d 151.4, 144.4, 143.7, 140.0, 130.4, 122.7, 120.6
(q, J = 255), 116.0, 113.4, 102.9, 81.2, 53.7, 28.3; 19F NMR d
À58.7. Anal. Calcd. for C15H16F3NO3: C, 57.1; H, 5.1; N, 4.4.
Found: C, 57.3; H, 5.2; N, 4.4.
tert-Butyl 3-methylene-5,7-bis(trifluoromethyl)indoline-1-
carboxylate (2j, 50%): mp 38–40 8C; IR nmax 3022, 3000,
1
2936, 1705, 1697, 1623, 1508, 1455, 1371, 1160 cmÀ1; H
NMR d 7.76 (s, 1 H), 7.74 (s, 1 H), 5.64 (broad s, 1 H), 5.25
(broad s, 1 H), 4.71 (s, 2 H), 1.54 (s, 9 H); 13C NMR d 152.9,
144.6, 139.5, 134.0, 126.2 (q, J = 33), 123.4 (q, J = 270), 123.0
(q, J = 271), 120.8 (q, J = 34), 120.1, 105.0, 83.0, 56.1, 28.0;
19F NMR d À60.1 (s), À62.7 (s). Anal. Calcd. for
C16H15F6NO2: C, 52.3; H, 4.1; N, 3.8. Found: C, 50.2; H,
4.1; N, 3.9.
Diethyl
yl)methyl]-2-hydroxymalonate (6c, 70%): oil; IR nmax 3516
(broad), 3024, 2985, 1737, 1619, 1484, 1372, 1158, 909 cmÀ1
2-[(1-tert-butoxycarbonyl-6-fluoro-1H-indol-3-
;
1H NMR d 7.7 (broad s, 1 H), 7.45 (dd, J = 8.6 and 5.4, 1 H),
7.38 (s, 1 H), 6.89 (td, J = 8.6 and 2.3, 1 H), 4.18–4.11
(symmetric m, 4 H), 3.80 (s, 1 H), 3.35 (s, 2 H), 1.58 (s, 9 H),
1.19 (t, J = 7.1, 6 H); 13C NMR d 169.9, 160.9 (d, J = 238),
149.3, 135.2 (d, J = 13), 125.3 (d, J = 3.5), 120.3 (d, J = 9.8),
113.5, 110.5 (d, J = 24), 102.3 (d, J = 28), 84.0, 79.1, 62.6,
30.0, 28.1, 13.9; 19F NMR d À118.2 (s). Anal. Calcd. for
C21H26FNO7: C, 59.6; H, 6.19; N, 3.3. Found: C, 59.6; H, 6.1;
N, 3.3.
tert-Butyl 7-fluoro-6-methoxy-3-methyleneindoline-1-car-
boxylate (2k, 45%): oil; IR nmax 1729, 1650, 1626, 1352,
1311, 1136 cmÀ1 1H NMR d 7.11 (dd, J = 8.3 and 0.9, 1 H),
6.61 (dd, J = 8.2 and 7.0, 1 H), 5.32 (t, J = 2.9, 1 H), 4.95 (t,
J = 2.2, 1 H), 4.60 (t, J = 2.7, 2 H), 3.87 (s, 3 H), 1.52 (s, 9 H);
13C NMR d 152.0, 150.3 (d, J = 11), 141.5 (d, J = 251), 140.7,
132.4 (d, J = 7.2), 126.0, 115.3 (d, J = 4.2), 108.2, 100.3, 81.7,
56.8, 55.7, 28.1; 19F NMR d À139.2 (s). Anal. Calcd. for
C15H18FNO3: C, 64.5; H, 6.5; N, 5.0. Found: C, 57.3; H, 5.2; N,
4.4.
Diethyl
yl)methyl]-2-hydroxymalonate (6d, 80%): oil; IR nmax 3519
2-[(1-tert-butoxycarbonyl-5-fluoro-1H-indol-3-
(broad), 2985, 1736, 1474, 1372, 1278, 1157, 856, 720 cmÀ1
;
1H NMR d 7.96 (broad s, 1 H), 7.45 (s, 1 H), 7.19 (dd, J = 9.1
and 2.5, 1 H), 6.92 (td, J = 9.1 and 2.5, 1 H), 4.20–4.11 (m, 4 H),

F. Bellezza et al. / Journal of Fluorine Chemistry 129 (2008) 97–107
105
3.81 (s, 1 H), 3.33 (s, 2 H), 1.57 (s, 9 H), 4.82 (t, J = 7.1, 6 H);
13C NMR d 169.8, 169.8, 159.2 (d, J = 237), 149.3, 131.7 (d,
J = 13), 126.8, 116.0 (d, J = 9.1), 113.4 (d, J = 4.0), 112.0 (d,
C22H26F3NO8: C, 54.0; H, 5.3; N, 2.9. Found: C, 54.1; H,
5.3; N, 2.9.
Diethyl 2-[(1-tert-butoxycarbonyl-5,7-bis(trifluoromethyl)-
1H-indol-3-yl)methyl]-2-hydroxymalonate (6j, 81%): mp 120–
122 8C; IR nmax 3514 (broad), 2986, 2936, 1740 (vs, two broad
bands), 1625, 1278, 1151, 778, 747 cmÀ1; 1H NMR d 8.11 (s, 1
H), 7.85 (s, 1 H), 7.57 (s, 1 H), 4.2 (m, 4 H), 3.92 (s, 1 H), 3.49
(s, 2 H), 1.63 (s, 9 H), 1.28 (t, J = 7.1, 6 H); 13C NMR d 169.6,
149.0, 133.5, 131.9, 130.6, 124.7 (q, J = 33), 124.0 (q, J = 270),
123.3 (q, J = 270), 120.9, 120.0, 118.5 (q, J = 34), 113.4, 85.5,
78.8, 62.8, 29.6, 27.7, 13.9; 19F NMR d À58.1 (s), À61.7 (s).
Anal. Calcd. for C23H25F6NO7: C, 51.0; H, 4.6; N, 2.6. Found:
C, 51.2; H, 4.7; N, 2.4.
J = 25), 105.2 (d, J = 24), 83.8, 79.0, 62.7, 30.0, 28.1, 13.9; 19
F
NMR d À121.6 (s). Anal. Calcd. for C21H26FNO7: C, 59.6; H,
6.2; N, 3.3. Found: C, 59.8; H, 6.2; N, 3.3.
Diethyl 2-[(1-tert-butoxycarbonyl-7-(trifluoromethyl)-1H-
indol-3-yl)methyl]-2-hydroxymalonate (6e, 81%): mp 118–
120 8C; 1H NMR d 7.80 (d, J = 7.8, 1 H), 7.58 (d, J = 7.6, 1 H),
7.44 (s, 1 H), 7.30 (t, J = 7.8, 1 H), 4.25–4.15 (symmetric m, 4
H), 3.88 (broad s, 1 H), 3.45, s, 2 H), 1.60 (s, 9 H), 1.24 (t,
J = 7.8, 6 H); 13C NMR d 169.8, 149.7, 133.8, 130.5, 128.8,
124.1 (q, J = 270), 123.6, 123.5, 122.0, 118.1 (q, J = 33.1),
113.1, 84.6, 79.1, 62.7, 29.8, 27.8, 13.9; 19F NMR d À57.9 (s).
Anal. Calcd. for C22H26F3NO7: C, 55.8; H, 5.5; N, 3.0. Found:
C, 55.9; H, 5.6; N, 3.1.
Diethyl 2-[(1-tert-butoxycarbonyl-6-methoxy-7-fluoro-1H-
indol-3-yl)methyl]-2-hydroxymalonate (6k, 77%): viscous oil;
IR nmax 3514 (broad), 2986, 2936, 1737 (vs, broad), 1633, 1510,
1
Diethyl 2-[(1-tert-butoxycarbonyl-6-(trifluoromethyl)-1H-
indol-3-yl)methyl]-2-hydroxymalonate (6f, 79%): mp 46–
48 8C; IR nmax 3693, 3524, 3024, 2928, 1735, 1444, 1372,
1276, 1124, 909 cmÀ1; 1H NMR d 8.42 (broad s, 1 H), 7.70 (d,
J = 8.0, 1 H), 7.61 (s, 1 H), 7.45 (d, J = 8.0, 1 H), 4.27–4.15
(symmetric m, 4 H), 3.89 (s, 1 H), 3.45 (s, 2 H), 1.65 (s, 9 H),
1.25 (t, J = 6.9, 6 H); 13C NMR d 169.8, 149.1, 134.2, 133.4,
127.6, 124.8 (q, J = 270), 126.3 (q, J = 32.2), 120.1, 119.0 (q,
J = 3.5), 113.6, 112.7 (q, J = 4.5), 84.5, 79.0, 62.7, 30.3, 28.1,
13.9; 19F NMR d À61.5 (s). Anal. Calcd. for C22H26F3NO7: C,
55.8; H, 5.5; N, 3.0. Found: C, 55.8; H, 5.6; N, 2.8.
1370, 1279, 1238, 1156 cmÀ1; H NMR d 7.45 (s, 1 H), 7.29
(dd, J = 8.6 and 1.2, 1 H), 6.96 (dd, J = 8.6 and 6.8, 1 H), 4.2 (m,
4 H), 3.94 (s, 3 H), 3.86 (s, 1 H), 3.40 (s, 2 H), 1.63 (s, 9 H), 1.27
(t, J = 7.1 H, 6 H); 13C NMR d 169.8, 149.0, 145.7 (d, J = 11),
140.9 (d, J = 251), 128.7, 126.7, 122.8 (d, J = 7.0), 114.3 (d,
J = 4.6), 113.4, 110.5, 84.0, 79.1, 62.6, 57.8, 29.9, 27.9, 13.9;
19F NMR d À140.1 (d, J = 6.5). Anal. Calcd. for C22H28FNO8:
C, 58.3; H, 6.2; N, 3.1. Found: C, 58.2; H, 6.3; N, 3.0.
(Æ)-Ethyl 3-(1-tert-butoxycarbonyl-5-fluoro-1H-indol-3-
yl)-2-hydroxypropionates (7d, 63%): viscous oil; IR nmax
3479, 3021, 2984, 2933, 1732, 1474, 1383, 1278, 1157 cmÀ1
;
Diethyl 2-[(1-tert-butoxycarbonyl-5-(trifluoromethyl)-1H-
indol-3-yl)methyl]-2-hydroxymalonate (6g, 84%): oil; 1H
NMR d 8.19 (broad d, J = 7.9, 1 H), 7.86 (s, 1 H), 7.59 (s, 1
H), 7.51 (dd, J = 8.7 and 1.7, 1 H), 4.27–4.13 (symmetric m, 4
H), 3.90 (s, 1 H), 3.46 (s, 2 H), 1.65 (s, 9 H), 1.26 (t, J = 7.1, 6
H); 13C NMR d 169.8, 149.1, 136.7, 130.5, 127.1, 124.9 (q,
J = 270), 124.7 (q, J = 32), 120.9, 117.0, 115.4, 113.6, 84.4,
78.7, 62.7, 29.8, 28.2, 13.9; 19F NMR d À61.3 (s). Anal. Calcd.
for C22H26F3NO7: C, 55.8; H, 5.5; N, 3.0. Found: C, 55.6; H,
5.5; N, 3.0.
1H NMR d 8.07 (broad s, 1 H), 7.52 (s, 1 H), 7.22 (dd, J = 8.9
and 2.5, 1 H), 7.02 (td, J = 9.0 and 2.5, 1H), 4.49 (broad s, X
portion of an ABX system, 1 H), 4.2 (symmetric s, 2 H), 3.19–
3.03 (eight peaks, AB portion of an ABX system, 2 H), 2.94
(broad s, 1 H), 1.65 (s, 9 H), 1.28 (t, J = 7.2, 3 H); 13C NMR d
174.1, 159.2 (d, J = 237), 149.3, 131.6 (d, J = 4.5), 125.9, 116.1
(d, J = 9.0), 114.9 (d, J = 3.9), 112.1 (d, J = 25), 104.8 (d,
J = 24), 83.8, 70.1, 62.0, 29.8, 28.1, 14.1; 19F NMR À121.5
(broad s). Anal. Calcd. for C18H22FNO5: C, 61.5; H, 6.3; N, 4.0.
Found: C, 61.8; H, 6.4; N, 4.0.
Diethyl 2-[(1-tert-butoxycarbonyl-7-(trifluoromethoxy)-1H-
indol-3-yl)methyl]-2-hydroxymalonate (6h, 78%): mp 96–
97 8C; IR nmax 3522 (broad), 3030, 2986, 2936, 1737, 1490,
1356, 1260, 1222, 1155 cmÀ1; 1H NMR d 7.58 (dd, J = 7.5 and
0.7, 1 H), 7.51 (s, 1 H), 7.25–7.15 (m, 2 H), 4.25–4.17
(symmetric m, 4 H), 3.89 (s, 1 H), 3.42 (s, 2 H), 1.61 (s, 9 H),
1.23 (t, J = 7.1, 6 H); 13C NMR d 169.8, 148.4, 135.7, 135.0,
128.3, 126.9, 122.8, 120.9 (q, J = 255), 119.0, 118.9, 113.2,
84.3, 79.1, 62.7, 29.9, 27.9, 13.9; 19F NMR d À58.4 (s). Anal.
Calcd. for C22H26F3NO8: C, 54.0; H, 5.3; N, 2.9. Found: C,
54.2; H, 5.4; N, 2.8.
(Æ)-Ethyl 3-(1-tert-butoxycarbonyl-5-(trifluoromethoxy)-
1H-indol-3-yl)-2-hydroxypropionates (7i, 65%): mp 70–
72 8C; IR nmax 3538 (broad), 3031, 2985, 2934, 1732, 1450,
1384, 1258, 1158 cmÀ1; 1H NMR d 8.12 (broad d, J = 7.6, 1 H),
7.55 (s, 1 H), 7.41 (d, J = 1.0, 1 H), 7.17 (dd, J = 9.0 and 1.1, 1
H), 4.51–4.47 (four peaks, X portion of an ABX system, 1 H),
4.2 (symmetric m, 2 H), 3.21–3.05 (eight peaks, AB portion of
an ABX system, 2 H), 2.96 (d, J = 5.6, 1 H), 1.65 (s, 9 H), 1.27
(t, J = 7.1, 3 H); 13C NMR d 174.0, 149.2, 144.8, 133.6, 131.4,
126.1, 120.6 (q, J = 254), 117.7, 116.0, 115.0, 111.7, 84.1, 70.1,
62.0, 29.6, 28.1, 14.0; 19F NMR d À58.4 (s). Anal. Calcd. for
C19H22F3NO6: C, 54.7; H, 5.3; N, 3.4. Found: C, 54.7; H, 5.4;
N, 3.4.
Diethyl 2-[(1-tert-butoxycarbonyl-5-(trifluoromethoxy)-1H-
indol-3-yl)methyl]-2-hydroxymalonate (6i, 86%): oil; IR nmax
3526 (broad), 3036, 2986, 2939, 1736, 1450, 1383, 1258, 1158,
909 cmÀ1; 1H NMR d 8.08 (broad d, J = 8.5, 1 H), 7.55 (s, 1 H),
7.45 (s, 1 H), 7.13 (dd, J = 8.5 and 1.4, 1 H), 4.2 (symmetric m,
4 H), 3.91 (s, 1 H), 3.41 (s, 2 H), 1.63 (s, 9 H), 1.25 (t, J = 7.1, 6
H); 13C NMR d 169.8, 144.8, 133.4, 131.7, 127.0, 120.7 (q,
J = 254), 117.7, 115.9, 113.5, 112.2, 84.1, 78.9, 62.7, 30.2,
28.1, 14.1; 19F NMR d À58.4 (s). Anal. Calcd. for
(Æ)-Ethyl
3-(1-tert-butoxycarbonyl-5,7-bis(trifluoro-
methyl)-1H-indol-3-yl]-2-hydroxypropionates (7j, 62%): mp
98–100 8C; IR nmax 3536 (broad), 3021, 2986, 2936, 1764,
1
1734, 1332, 1278, 1150, 894 cmÀ1; H NMR d 8.05 (s, 1 H),
7.86 (s, 1 H), 7.56 (s, 1 H), 4.53–4.49 (four peaks, X portion of
an ABX system, 1 H), 4.2 (symmetric m, 2 H), 3.27–3.13 (eight
peaks, AB portion of an ABX system, 2 H), 3.02 (d, J = 5.0, 1

106
F. Bellezza et al. / Journal of Fluorine Chemistry 129 (2008) 97–107
H), 1.63 (s, 9 H), 1.28 (t, J = 7.2, 3 H); 13C NMR d 173.8, 149.1,
133.3, 132.1, 129.7, 124.7 (q, J = 33), 124.0 (q, J = 270), 123.3
(q, J = 271), 120.4, 120.3, 118.6 (q, J = 34), 114.9, 85.5, 70.0,
62.1, 29.1, 27.7, 14.0; 19F NMR d À58.1 (s), À61.7 (s). Anal.
Calcd. for C20H21F6NO5: C, 51.2; H, 4.5; N, 3.0. Found: C,
51.3; H, 4.6; N, 3.1.
References
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(Æ)-Ethyl 2-[(1-tert-butoxycarbonyl-7-fluoro-1H-indol-3-
yl)methyl]-2-hydroxy-3,3,3-trifluoropropionates (8b, 61%):
mp 105–107 8C; IR nmax 3514 (broad), 3026, 2985, 2933,
1740 (broad), 1494, 1371, 1281, 1155 cmÀ1; 1H NMR d 7.55 (s,
1 H), 7.39 (dd, J = 7.9, 1 H), 7.17 (td, J = 7.9 and 4.0, 1 H), 7.02
(ddd, J = 12, 7.9 and 0.9, 1 H), 4.2 (symmetric m, 2 H), 3.93 (d,
J = 1.0, 1 H), 3.46–3.21 (four peaks, AB portion of an ABX
system, 2 H), 1.64 (s, 9 H), 1.24 (t, J = 7.2, 3 H); 13C NMR d
168.9, 149.9 (d, J = 251), 148.6, 134.8 (d, J = 3.6), 127.8, 123.3
(q, J = 285), 123.3 (d, J = 7.1), 121.8, 115.2 (d, J = 3.7), 112.0,
111.7 (d, J = 22), 84.3, 75.5 (q, J = 29), 63.9, 27.9, 27.2, 13.8;
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Calcd. for C19H21F4NO5: C, 54.4; H, 5.0; N, 3.3. Found: C,
54.4; H, 5.1; N, 3.4.
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yl)methyl]-2-hydroxy-3,3,3-trifluoropropionates (8d, 60%):
mp 98–100 8C; IR nmax 3508, 3019, 2984, 2939, 1736, 1475,
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C19H21F4NO5, C, 54.4; H, 5.0; N, 3.3. Found: C, 54.6; H, 5.1;
N, 3.4.
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Chemical Sciences and Engineering (ISIC) of the ‘‘Ecole
´ ´
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