Comprehensive synthesis of photoreactive (3-trifluoromethyl)diazirinyl indole derivatives from 5- and 6-trifluoroacetylindoles for photoaffinity labeling

Article abstract of DOI:10.1021/jo301552m

5- and 6-trifluoromethyldiazirinyl indoles were synthesized from corresponding bromoindole derivatives for the first time. They acted as mother skeletons for the comprehensive synthesis of various bioactive indole metabolites. These can be used in biologi

Full text of DOI:10.1021/jo301552m

Article
pubs.acs.org/joc
Comprehensive Synthesis of Photoreactive (3-
Trifluoromethyl)diazirinyl Indole Derivatives from 5- and 6-
Trifluoroacetylindoles for Photoaffinity Labeling
Yuta Murai,† Katsuyoshi Masuda, Yasuko Sakihama,† Yasuyuki Hashidoko,† Yasumaru Hatanaka,§
and Makoto Hashimoto*,†
†Graduate School of Agriculture, Hokkaido University, Kita 9, Nishi 9, Kita-ku, Sapporo 060-8589, Japan
‡Suntory Institute for Bioorganic Research, 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8503, Japan
§Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
S
* Supporting Information
ABSTRACT: 5- and 6-trifluoromethyldiazirinyl indoles were synthe-
sized from corresponding bromoindole derivatives for the first time.
They acted as mother skeletons for the comprehensive synthesis of
various bioactive indole metabolites. These can be used in biological
functional analysis as diazirine-based photoaffinity labels.
trifluoromethyldiazirine at the 5- or 6-position and outlining
comprehensive derivatizations for their biologically active
indole derivatives.
INTRODUCTION
■
Indoles are electron-rich aromatic compounds that owe their
characteristic properties to the presence of a pyrrole moiety.
The indole substructure is a basic element for a number of
biologically active natural and synthetic products. The synthesis
and chemical modification of indoles, therefore, has attracted
enormous attention. Photolabeling is one of the methods used
to study the interactions between low molecular weight
biological substrate compounds with their biomolecular targets
or receptors. Target molecule affinity for the low molecular
weight substrate can provide selectivity in the photolabeling
reactions.1 Selection of a suitable photophore for photoaffinity
labeling is critical to obtain meaningful results, but there are
currently no “universal photoreactive spiecies”.2 The chemical
properties of 3-(trifluoromethyl)phenyldiazirineincluding the
stability of the functional group before irradiation, higher
reactivities of the generated species after irradiation, and
suppression of side reactionsgive this molecule many
advantages over aryl azides and benzophenones as photophores
for photoaffinity labeling.1c Although photoaffinity labeling
reagents containing arylazide3 or benzophenone4 derivatives of
the indole scaffold have been reported, to the best of our
knowledge, there have been no reports of synthetic studies on
3-(trifluoromethyl)phenyldiazirine containing indole derivatives
for use as the photoaffinity labeling reagents. A major advantage
of easy derivatizations from the mother photoreactive indole
skeleton into various indole-containing biologically active
compounds avoids the need to construct the 3-
(trifluoromethyl)diazirinyl moiety each time. In this study, we
focused on synthesizing photoreactive indoles, containing 3-
RESULTS AND DISCUSSION
■
Construction of a (trifluoromethyl)diazirinyl moiety on indole
at the 5- or 6-position began by treating the corresponding
bromide derivatives (1a and 1b) with potassium hydride−t-
BuLi followed by treatment with trifluoroacetylated reagents.
Trifluoroactylations of 5- or 6-bromoindole with trifluoroacetic
anhydride5 with potassium hydride−t-BuLi were not effective
(30−60%), and replacement of potassium hydride with sodium
hydride did not influence the isolated yield. Replacement of
trifluoroacetic anhydride with ethyl trifluoracetate or trifluor-
oacetyl piperidine improved the yield of the products (2a and
2b; ∼80%), because the leaving groups did not decrease the
reaction mixture basicity.
The trifluoroacetyl groups were converted to oximes with
hydroxylamine hydrochloride in pyridine (3a and 3b) followed
by tosylation with tosyl chloride in triethylamine and acetone at
0 °C. Tosylation with tosyl chloride in pyridine under reflux
was not acceptable because the product was broken down
under these conditions. The isolated yield for 4a and 4b
dramatically decreased (yield of purified tosyl oxime 4a: 28%)
due to the instability of the tosyl oxime of indole. To avoid the
decrease in yield, the tosyl oximes 4a and 4b were not isolated
and were directly subjected to conversion to diaziridine (5a and
Received: July 23, 2012
Published: September 11, 2012
© 2012 American Chemical Society
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5b) with liquid ammonia. This modification drastically
improved the yield (84−87% for two steps). Oxidation of
diaziridine to diazirine (6a and 6b) with activated MnO2 can
occur without any side reactions in good yield (80−92%). The
use of iodine in triethylamine, which is an alternative oxidation
method for diaziridine to diazirine, caused a side reaction of
iodination at the 3-position of the indole skeleton (7a and 7b;
Scheme 1).
Tryptophan is one of the most biologically significant
metabolites synthesized from indole. Although synthesis of
tryptophan from various aromatics has been reported,10 these
methods are too difficult to apply to the diazirinyl derivatives
because of the harsh conditions required for the constructions
of tryptophan skeletons. For example, (1) Larock hetero-
annulation or Mori−Ban−Hegedus indole synthesis of an o-
iodoaniline skeleton with Schollkopf reagent,11 (2) Heck-type
̈
synthesis of an o-iodoaniline skeleton with pyroglutamate
derivatives,12 and (3) Fisher indole synthesis of phenyl
hydrazones13 were ineffective when starting with diazirinyl
derivatives, as the diazirinyl moiety is decomposed during the
reactions. Tryptophan has been synthesized from indole with
serine in acetic acid and acetic anhydride under reflux
conditions.14 In the original report, active species were
generated at high temperature in the presence of indole
derivatives. The diazirinyl moieties of 6a and 6b were also
destroyed in acetic acid under the reflux conditions.. Active
species were generated from L-serine, acetic anhydride, and
acetic acid in reflux conditions without indole derivatives,
followed by addition of diazirinyl indoles to the mixture at low
temperature to prevent decomposition of the diazirinyl ring.
The racemate of diazirinyl N-acetyltryptophans 11a and 11b
was subjected to enzymatic resolution with L-acylase to afford
optically pure diazirinyl L-tryptophan without decomposition of
the diazirinyl moiety. The optical purities for 12a and 12b were
also confirmed by chiral column chromatography.
Scheme 1. Synthesis of (Trifluoromethyl)diazirinyl Indoles
6a and 6b
Indole-3-acetic acid (IAA), commonly known as auxin, is
essential throughout the life cycles of plants and controls
diverse cellular processes.15 The biology of IAA and the
underlying mechanisms of its action are not completely
understood because there are no biochemical tools with
which to investigate them. No IAA skeletons were found
when the diazirinyl indoles (6a and 6b) in acetone were reacted
with ethyl chloroacetate under reflux.16 The diazirinyl indoles
were reacted with oxalyl chloride,17 followed by methanolysis to
afford 3-(α-oxo, methyl ester) indole derivatives (13a and 13b).
The selective reduction of the α-keto moiety to methylene with
triethylsilane and trifluoroacetic acid, which has already been
reported to have no effect on the diazirinyl moiety,18 was not
successful, and reduction of both the α-keto and alkene moiety
between the 2- and 3-positions afforded 14a and 14b under
The derivatizations under mild conditions were preferable for
5- and 6-(trifluoromethyl)diazirinyl indoles (6a and 6b) as
these conditions avoided the decomposition of the diazirinyl
ring. Diazirinyl indoles were converted with POCl3 and DMF at
rt to 3-formylindole derivatives (8a and 8b) which were then
reduced with sodium borohydride in methanol6 to construct
indole carbinols (9a and 9b). These are reported to have
anticarcinogenic, antioxidant, and antiatherogenic effects.7
Gramine derivatives, which play a defensive role in plants,8
were constructed from diazirinyl indoles with CH2NMe2I at
rt for 24 h with moderate yields9 (10a and 10b; Scheme 2).
Scheme 2. Post-Functional Synthesis of Diazirinyl Indole Derivatives from Diazirinyl Indoles
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these conditions. Accordingly, the compound 14a was very
unstable, it was very difficult to obtain 13C NMR spectra.
Selective dehydrogenation at the 2,3-position of 14a and 14b
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or bis-
(trifluoroacetoxy)iodobenzene afforded a complex mixture.
Dehydrogenation with MnO2 can be applied to construct
indole skeleton 16b from 14b, but the condition promoted
decomposition of the diazirinyl moiety of the 5-trifluorome-
thyldiazirinyl derivative 14a. To construct 5-(trifluoromethyl)-
diazirinyl IAA methyl ester, 3-α-oxo, methyl ester 13a was
reduced with sodium borohydride to afford α-hydroxy ester
Table 1. Calculated Half-Lives of the Diazirinyl Moiety
Decomposition for Indole Derivatives in Methanol with
a
Black Light (100 W) at 1 cm Distance
compd
t1/2 (min)
compd
t1/2 (min)
6a
6b
7a
7b
9a
9b
9.6
9.8
5.3
5.7
8.6
9.2
10a
10b
12a
12b
17a
17b
6.9
7.9
8.0
8.6
7.9
8.0
a
19
Half-lives were calculated from decay of the A380 as a function of
(15a), followed by dehydration with P2I4 to afford diazirinyl
photolysis time in a semilog representation.
IAA methyl ester derivative 16a with moderate yield. The
conditions can also be applied to the 6- (trifluoromethyl)-
diazirinyl isomer (13b). Finally, hydrolysis of the methyl ester
under alkaline conditions afforded 5- and 6-diazirinyl IAA
derivatives without decomposition of photophores (17a and
17b; Scheme 3).
(B) and 6-diazirinyl (C) IAA. The results indicated that the
chemical modifications of IAA with trifluoromethyldiazirinyl
group at the 5- and 6-positions do not cause serious reduction
of biological activities (Figure 1).
Scheme 3. Synthesis of Diazirinyl Indole-3-Acetic Acid
Derivatives from Diazirinyl Indole Derivatives
CONCLUSION
■
Diazirinyl indoles were prepared, for the first time, from the
corresponding trifluoroacetyl indoles. These indole derivatives
acted as mother skeletons for the synthesis of diazirinyl
derivatives for many indole metabolites, including tryptophan.
Comprehensive synthesis of the photoaffinity labeled indole
derivatives described in this study would contribute to future
elucidation of the role of these indole metabolites in target
protein’s biological functional analysis. The photoreactive
tryptophan derivatives are now subjected to biological func-
tional analysis for gustatory response.23
EXPERIMENTAL SECTION
General Methods. All reactions were performed in a test tube
■
under air. Column chromatography was performed using silica gel
1
(200−400 mesh). H NMR, 13C NMR, and 19F NMR spectra were
recorded on 270, 400, or 500 MHz in CDCl3 and CD3OD. All new
compounds (except 14a) were further characterized by HRMS (ESI-
TOF). Commercially available reagents and solvents were used
without further purification. The reactions for diazirinyl compounds
were carried out in the dark.
The diazirinyl indole derivatives in methanol (1 mM, 1 mL)
were subjected to irradiation with black light to confirm their
photoreactive properties.20 The characteristic broad adsorp-
tions around 360 nm for diazirine indicated the presence of
(trifluoromethyl)diazirinyl moieties on indole rings. Irradiation
with black light (100 W) in methanol revealed that a decrease
in absorbance at around 380 nm that was associated with the
irradiation time. These results indicated that the irradiation
promoted decomposition of the diazirinyl ring and that a highly
reactive carbene intermediate was generated effectively. The
irradiation afforded a complex mixture due to the high reactivity
of carbenes. The half-lives (t1/2) of the diazirinyl indole
derivatives are listed in Table 1. All of the compounds have
suitable characteristics for the photoaffinity labeling reagents.
Indole-3-acetic acid (IAA), the main auxin in higher plants,
has profound effects on plant growth and development.21 The
synthetic diazirinyl IAA derivatives (17a and 17b) were
subjected to oat coleoptile segment growth bioassays.22 The
typical auxin responses, which were growth acceleration at
optimum concentration and growth inhibition at higher and
lower concentration than optimum concentration, were
observed for the synthetic compounds. The optimum
concentrations for elongation of coleoptile segments were
observed at between 10−4 and 10−6 M for IAA (A) as well as 5-
2,2,2-Trifluoro-1-(1H-indol-5-yl)ethanone (2a).5 A solution of
5-bromoindole 1a (1.57 g, 8.00 mmol) in THF (8 mL) was added
dropwise to a suspension of potassium hydride (1.09 g, 30%
suspension in mineral oil, 8.00 mmol) in THF (16.0 mL) at 0 °C
under N2. After being stirred for 1 h at 0 °C, the mixture was cooled to
−78 °C and a solution of t-BuLi (10 mL of 1.7 M pentane solution,
17.0 mmol) was added dropwise over a period of 15 min.
(Trifluoroacetyl)piperidine (2.40 mL, 17.0 mmol) was added at −78
°C, and the mixture was stirred for 2 h, quenched saturated
ammonium chloride (7.00 mL), and then extracted with diethyl
ether. The organic layer was washed with brine and dried over MgSO4.
The residue was purified by column chromatography (CH2Cl2/
hexane 1/4 to 1/2) to yield 5-(trifluoroacetyl)indole 2a (1.31 g, 77%)
as yellow amorphous mass.
2,2,2-Trifluoro-1-(1H-indol-6-yl)ethanone (2b). The same
treatment of 1b (1.0 g, 5.12 mmol) as that just described gave 2b
(0.89 g, 81%) as a pale yellow amorphous mass: 1H NMR (CDCl3) δ
8.61 (brs, 1H), 8.20 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.6
Hz, 1H), 7.51 (t, J = 2.9 Hz, 1H), 6.67 - 6.65 (m, 1H); 13C NMR
(CDCl3) δ 180.5 (q, 2JCF = 36.0 Hz), 135.0, 133.6, 129.9, 123.7, 121.2,
1
121.1, 117.2 (q, JCF = 291.9 Hz), 114.7, 103.7; 19F NMR (CDCl3) δ
−70.05; HRMS-ESI (m/z) [M + H]+ calcd for C10H6F3NO 214.0480,
found 214.0468.
2,2,2-Trifluoro-1-(1H-indol-5-yl)ethanone Oxime (3a). 5-
(Trifluoroacetyl)indole 2a (109 mg, 0.509 mmol) and hydroxylamine
hydrochloride (60.0 mg, 0.645 mmol) were dissolved in pyridine (3
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Figure 1. Typical experiments on elongation in oat coleoptile segments inoculated with IAA, 17a, and 17b. Coleoptile segments (10 mm, six
segments) were immersed in a treatment solution (IAA, 17a, and 17b) at 25 °C for 24 h, followed by measurements of segment lengths. Control
experiment, which was carried out without IAA derivatives, presented as DW (in distilled water).
mL). The reaction mixture was stirred at 80 °C for 3 h and
concentrated. The residue was dissolved in diethyl ether (20 mL). The
organic layer was washed with 1 M HCl and brine, dried over MgSO4,
filtrated, and concentrated. The residue was purified by column
chromatography (CH2Cl2 to AcOEt/hexane 1/3) to yield 5-
trifluorooxime indole 3a (101 mg, 87%, mixture of syn- and anti-
Hz, 1H), 6.60 (t, J = 2.9 Hz, 1H), 2.81 (d, J = 8.6 Hz), 2.28 (d, J = 8.6
1
Hz); 13C NMR (CDCl3) δ 136.4, 127.7, 125.5, 123.9 (q, JCF = 278.3
2
Hz), 123.1, 121.7, 121.2, 111.3, 103.1, 58.6 (q, JCF = 35.2 Hz); 19F
NMR (CDCl3) δ −75.45; UV (MeOH) λmax (ε) 380 (523); HRMS-
ESI (m/z) [M + H]+ calcd for C10H9F3N3 228.0749, found 228.0713.
6-(3-(Trifluoromethyl)diaziridin-3-yl)-1H-indole (5b). The
same treatment of 3b (152 mg, 0.67 mmol) and p-toluenesulfonyl
chloride (318 mg, 1.67 mmol), followed by treatment of liquid
ammonia, as that just described gave 5b (129 mg, 85%) as a colorless
1
isomers) as a colorless amorphous mass: H NMR (CD3OD) δ 7.70
(s, 0.7H), 7.63 (s, 0.3H), 7.42 (d, J = 8.6 Hz, 0.7H), 7.39 (d, J = 8.6
Hz, 0.3H), 7.28 (d, J = 3.2 Hz, 0.7H), 7.27 (d, J = 3.2 Hz, 0.3H), 7.21
(d, J = 8.6 Hz, 0.7H), 7.17 (d, J = 8.6 Hz, 0.3H), 6.50−6.48 (m, 1H);
13C NMR (CD3OD) δ 148.4 (q, 2JCF = 30.8 Hz), 138.0, 129.0, 126.7,
1
amorphous mass: H NMR (CDCl3) δ 8.31 (brs, 1H, 1-H), 7.68 (s,
1H), 7.67 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.30 (t, J = 2.9
Hz, 1H), 6.59−6.58 (m, 1H), 2.81 (d, J = 8.6 Hz), 2.27 (d, J = 8.6
1
123.0 (q, JCF = 273.5 Hz), 122.7 and 122.5, 122.3 and 122.0, 119.0,
Hz); 13C NMR (CDCl3) δ 135.2, 129.1, 126.0, 125.1, 123.8 (q, 1JCF
=
112.0, 103.1; 19F NMR (CD3OD) δ −62.07, −66.37; HRMS-ESI (m/
z) [M + H]+ calcd for C10H8F3N2O 229.0589, found 229.0553.
2,2,2-Trifluoro-1-(1H-indol-6-yl)ethanone Oxime (3b). The
same treatment of 2b (782 mg, 3.66 mmol) as that just described gave
3b (701 mg, 84%, mixture of syn- and anti- isomers) as a colorless
278.9 Hz), 121.0, 119.4, 111.2, 102.7, 58.6 (q, JCF = 36.4 Hz); 19F
NMR (CDCl3) δ −75.48; UV (MeOH) λmax (ε) 390 (307); HRMS-
ESI (m/z) [M + H]+ calcd for C10H9F3N3 228.0749, found 228.0743.
5-(3-(Trifluoromethyl)-3H-diazirin-3-yl)-1H-indole (6a). 5-Di-
aziridine indole 5a (73.5 mg, 0.32 mmol) and activated MnO2 (150.0
mg) were suspended in diethyl ether (15 mL). The reaction mixture
was stirred at rt for 1 h followed by filtration of the insoluble material.
The filtrate was concentrated, and the residue was purified by column
chromatography (CH2Cl2) to yield 5-diazirinyl indole 6a (60.4 mg,
83%) as a yellow oil: 1H NMR (CDCl3) δ 8.27 (s, 1H), 7.54 (s, 1H),
7.40 (d, J = 8.6 Hz, 1H), 7.27 (t, J = 2.9 Hz, 1H), 7.08 (d, J = 8.6 Hz,
1H), 6.58−6.57 (m, 1H); 13C NMR (CDCl3) δ 136.1, 127.9, 125.7,
2
1
amorphous mass: H NMR (CD3OD) δ 7.59 (d, J = 8.6 Hz, 0.7H),
7.57 (s, 0.7H), 7.55 (d, J = 8.6 Hz, 0.3H), 7.48 (s, 0.3H), 7.33 (t, J =
3.2 Hz, 0.7H), 7.31 (t, J = 3.2 Hz, 0.3H), 7.10 (d, J = 8.6 Hz, 0.7H),
7.08 (d, J = 8.6 Hz, 0.3H), 6.47−6.46 (m, 1H); 13C NMR (CD3OD) δ
148.1 (q, 2JCF = 30.8 Hz), 136.9, 130.5, 127.8 and 127.6, 123.0 (q, 1JCF
= 273.5 Hz), 120.9, 120.7, 120.3, 113.2 and 112.7, 102.6 and 102.5; 19
F
NMR (CD3OD) δ −61.85, −66.00; HRMS-ESI (m/z) [M + H]+ calcd
for C10H8F3N2O 229.0589, found 229.0627.
1
5-(3-(Trifluoromethyl)diaziridin-3-yl)-1H-indole (5a). 5-Tri-
fluorooxime indole 3a (336 mg, 1.47 mmol) was dissolved in acetone
(14 mL) and cooled to 0 °C. Triethylamine (0.710 mL) and p-
toluenesulfonyl chloride (562 mg, 2.95 mmol) were added to the
reaction, successively. The reaction mixture was stirred for 1 h at the
same temperature and concentrated in vacuo, and the residue was
dissolved in diethyl ether. In a shield tube, liquid ammonia (excess)
was added at −78 °C and the ether solution of the crude tosyl oxime
was added. The reaction mixture was warmed to rt and then stirred for
6 h at the same temperature. After excess ammonium gas was removed
in a draft chamber, the residual solution was concentrated. The crude
residue was purified by column chromatography (AcOEt/hexane 1/2)
122.5 (q, JCF = 275.1 Hz), 120.3 (2C), 120.0, 111.6, 103.1, 29.0 (q,
2JCF = 40.0 Hz); 19F NMR (CDCl3) δ −65.41; HRMS-ESI (m/z) [M
+ H]+ calcd for C10H7F3N3 226.0592, found 226.0589.
6-(3-(Trifluoromethyl)-3H-diazirin-3-yl)-1H-indole (6b). The
same treatment of 5b (73.4 mg, 0.32 mmol) as that just described gave
1
6b (66.8 mg, 92%) as a yellow oil: H NMR (CDCl3) δ 8.22 (brs,
1H), 7.66 (d, J = 8.6 Hz, 1H), 7.28 (t, J = 2.9 Hz, 1H), 7.27 (s, 1H),
6.98 (d, J = 8.6 Hz, 1H), 6.59−6.58 (m, 1H); 13C NMR (CDCl3) δ
1
135.3, 128.8, 126.1, 122.5 (q, JCF = 275.1 Hz), 122.4, 121.3, 117.9,
2
109.9, 102.8, 29.0 (q, JCF = 40.8 Hz); 19F NMR (CDCl3) δ −65.19;
HRMS-ESI (m/z) [M + H]+ calcd for C10H7F3N3 226.0592, found
226.0569.
1
to afford 5a (288 mg, 86%) as a colorless amorphous mass: H NMR
3-Iodo-5-(3-(trifluoromethyl)-3H-diazirin-3-yl)-1H-indole
(7a). Compound 5a (69.9 mg, 0.31 mmol) was dissolved in CH2Cl2 (3
(CDCl3) δ 8.32 (brs, 1H), 7.92 (s, 1H), 7.43 (s, 2H), 7.29 (t, J = 2.9
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mL) and triethylamine (0.200 mL, 1.44 mmol) at 0 °C. Iodine (86.2
mg, 0.34 mmol) was added in small portions until a brown color
persisted. The solution was washed with 1 M NaOH and brine and
dried over MgSO4. The organic layer was removed, and the residue
was purified by column chromatography (CH2Cl2/hexane 1/2) to
yield 7a (94.0 mg, 87%) as a brown oil: 1H NMR (CDCl3) δ 8.46 (brs,
1H), 7.38 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 2.9 Hz, 1H), 7.28 (s, 1H),
7.18 (d, J = 8.6 Hz, 1H); 13C NMR (CDCl3) δ 136.0, 129.9 (2C),
0.18 mmol) and N-methyl-N-methylenemethanaminium iodide (51.3
mg, 0.24 mmol) were dissolved in CH2Cl2 at rt. The reaction was
stirred for 24 h. The solution was concentrated, and then the residue
was purified by column chromatography (AcOEt to AcOEt/MeOH 9/
1) to yield 10a (46.9 mg, 91%) as a yellow amorphous mass: 1H NMR
(CDCl3) δ 9.68 (brs, 1H), 8.00 (s, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.34
(s, 1H), 7.12 (d, J = 8.6 Hz, 1H), 4.42 (s, 2H), 2.77 (s, 3H); 13C NMR
1
(CDCl3) δ 136.2, 131.1, 127.2, 122.4 (q, JCF = 274.7 Hz), 121.7,
2
2
121.2, 116.4, 113.1, 102.7, 52.3, 42.2, 28.9 (q, JCF = 40.8 Hz); 19F
122.4 (q, JCF = 275.9 Hz), 121.5, 121.5, 120.3, 111.9, 57.9, 28.9 (q,
1JCF = 39.6 Hz); 19F NMR (CDCl3) δ −65.38; UV (MeOH) λmax (ε)
NMR (CD3OD) δ −65.28; UV (MeOH) λmax(ε) 375 (368); HRMS-
ESI (m/z) [M + H]+ calcd for C13H14F3N4 283.1171, found 283.1149.
N,N-Dimethyl-1-(6-(3-(trifluoromethyl)-3H-diazirin-3-yl)-1H-
indol-3-yl)methanamine (10b). The same treatment of 6b (30.3
mg, 0.13 mmol) as that just described gave 10b (30.7 mg, 81%) as a
yellow amorphous mass: 1H NMR (CDCl3) δ 8.47 (brs, 1H), 7.70 (d,
J = 9.2 Hz, 1H), 7.21 (s, 1H), 7.19 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 9.2
Hz, 1H), 3.61 (s, 2H), 2.26 (s, 6H); 13C NMR (CDCl3) δ 135.8,
375 (457); HRMS-ESI (m/z) [M + H]+ calcd for C10H6F3IN3
351.9559, found 351.9562.
3-Iodo-6-(3-(trifluoromethyl)-3H-diazirin-3-yl)-1H-indole
(7b). The same treatment of 5b (89.9 mg, 0.40 mmol) as that just
described gave 7b (122.0 mg, 88%) as a brown oil: 1H NMR (CDCl3)
δ 8.39 (brs, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H),
7.22 (s, 1H), 7.01 (d, J = 8.6 Hz, 1H); 13C NMR (CDCl3) δ 135.2,
1
1
130.8, 130.3, 123.8, 122.3 (q, JCF = 275.9 Hz), 121.7, 118.8, 110.2,
128.8, 125.6, 122.5, 122.5 (q, JCF = 275.9 Hz), 119.9, 117.7, 113.6,
2
57.5, 28.9 (q, JCF = 40.8 Hz); 19F NMR (CDCl3) δ −64.94; UV
2
110.0, 54.3, 45.3, 29.0 (q, JCF = 39.6 Hz); 19F NMR (CDCl3) δ
(MeOH) λmax (ε) 386 (450); HRMS-ESI (m/z) [M + H]+ calcd for
C10H6F3IN3 351.9559, found 351.9540.
−65.34; UV (MeOH) λmax (ε) 385 (300); HRMS-ESI (m/z) [M +
H]+ calcd for C13H14F3N4 283.1171, found 283.1152.
5-(3-(Trifluoromethyl)-3H-diazirin-3-yl)-1H-indole-3-carbal-
dehyde (8a). Phosphorus oxychloride (26.9 mL, 0.29 mmol) was
added dropwise to DMF (630 mL) at −40 °C and stirred for 1 h. A
solution of 5-diairinyl indole 6a (44.1 mg, 0.20 mmol) in DMF (270
mL) was added dropwise to the above mixture at −40 °C. The
reaction was stirred at rt for 1 h and poured into ice−water, basified
with KOH, and stirred for 5 min. The resulting precipitate was purified
by column chromatography (AcOEt/hexane 1/1) to yield 8a (39.3
mg, 79%) as a yellow amorphous mass: 1H NMR (CD3OD) δ 9.89 (s,
1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.18 (d, J =
8.6 Hz, 1H); 13C NMR (CD3OD) δ 187.4, 140.9, 139.3, 125.9, 123.9
2-Acetamido-3-(5-(3-(trifluoromethyl)-3H-diazirin-3-yl)-1H-
indol-3-yl)propanoic Acid (11a). L-Serine (93.7 mg, 0.89 mmol)
was dissolved in AcOH (1.00 mL) and Ac2O (0.340 mL). After the
solution was stirred for 1 h at 75 °C, the solution was added to 5-
diazirinylindole 6a (100 mg, 0.45 mmol) at rt. The reaction mixture
was stirred for 1.5 h and then concentrated. The residue was dissolved
in diethyl ether, washed with 1 M HCl and brine, dried over MgSO4,
filtrated, and then concentrated. The residue was purified by column
chromatography (CH2Cl2 to AcOEt/MeOH/H2O 8/1/1) to yield 11a
1
(39.1 mg, 25%) as a yellow amorphous mass: H NMR (CD3OD) δ
7.41 (s, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.19 (s, 1H), 7.07 (d, J = 8.6
Hz, 1H), 4.61 (dd, J = 7.4, 5.2 Hz, 1H), 3.34 (dd, J = 14.6, 5.2 Hz,
1H), 3.13 (dd, J = 14.6, 7.4 Hz, 1H), 1.89 (s, 3H); 13C NMR
1
2
(q, JCF = 274.3 Hz), 123.9, 123.1, 121.4, 119.9, 114.1, 30.0 (q, JCF
=
40.8 Hz); 19F NMR (CD3OD) δ −67.12; HRMS-ESI (m/z) [M + H]+
calcd for C11H7F3N3O 254.0541, found 254.0521.
1
(CD3OD) δ 177.3, 173.0, 138.4, 129.3, 126.3, 124.1 (q, JCF = 273.5
6-(3-(Trifluoromethyl)-3H-diazirin-3-yl)-1H-indole-3-carbal-
dehyde (8b). The same treatment of 6b (28.8 mg, 0.13 mmol) as that
just described gave 8b (26.7 mg, 82%) as a yellow amorphous mass:
1H NMR (CD3OD) δ 9.90 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.20 (s,
2
Hz), 120.5, 119.9, 118.6, 113.1, 112.4, 56.0, 30.3 (q, JCF = 40.0 Hz),
28.3, 22.6; 19F NMR (CD3OD) δ −67.12; HRMS-ESI (m/z) [M +
H]+ calcd for C15H14F3N4O3 355.1018, found 355.0993.
2-Acetamido-3-(6-(3-(trifluoromethyl)-3H-diazirin-3-yl)-1H-
indol-3-yl)propanoic Acid (11b). The same treatment of 6b (53.6
mg, 0.24 mmol) as that just described gave 11b (19.8 mg, 24%) as a
1H), 7.38 (s, 1H), 7.08 (d, J = 8.0 Hz, 1H); 13C NMR (CD3OD) δ
1
187.3, 141.1, 138.5, 126.9, 125.2, 123.8 (q, JCF = 273.9 Hz), 123.3,
2
121.4, 119.9, 112.0, 30.0 (q, JCF = 40.0 Hz); 19F NMR (CD3OD) δ
1
yellow amorphous mass: H NMR (CD3OD) δ 7.62 (d, J = 8.6 Hz,
−67.00; HRMS-ESI (m/z) [M + H]+ calcd for C11H7F3N3O 254.0541,
found 254.0496.
1H), 7.23 (s, 1H), 7.21 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H), 4.70 (dd, J =
8.0, 5.2 Hz, 1H), 3.32 (dd, J = 14.9, 5.2 Hz, 1H), 3.13 (dd, J = 14.9, 8.0
Hz, 1H), 1.87 (s, 3H); 13C NMR (CD3OD) δ 175.0, 173.2, 137.5,
130.2, 127.0, 124.0 (q, J = 274.3 Hz), 122.5, 120.2, 117.7, 111.7, 111.2,
(5-(3-(Trifluoromethyl)-3H-diazirin-3-yl)-1H-indol-3-yl)-
methanol (9a). Compound 8a (39.3 mg, 0.16 mmol) was dissolved
in MeOH (3 mL) and cooled to 0 °C. NaBH4 (12.0 mg, 0.31 mmol)
was dissolved in CH3OH (4 mL) and added dropwise to the above
solution at 0 °C. The reaction was stirred at 0 °C for 1 h. After the
solution was concentrated, the residue was purified by column
chromatography (AcOEt) to yield 9a (20.6 mg, 52%) as a yellow oil:
1H NMR (CDCl3) δ 8.30 (brs, 1H), 7.56 (s, 1H), 7.36 (d, J = 8.6 Hz,
2
54.7, 30.2 (q, JCF = 39.6 Hz), 28.3, 22.4; 19F NMR (CD3OD) δ
−67.03; HRMS-ESI (m/z) [M + H]+ calcd for C15H14F3N4O3
355.1018, found 355.1013.
(S)-2-Aamino-3-(5-(3-(trifluoromethyl)-3H-diazirin-3-yl)-1H-
indol-3-yl)propanoic Acid (12a). N-Acetyl-5′-diazirinyl-DL-trypto-
phan 11a (13.3 mg, 37.0 μmol) was dissolved in 0.2 M phosphate
buffer (pH 7.6, 4 mL), and L-aminoacylase (1.0 mg) and 0.42 mM of
CoCl2 hexahydrate in the buffer (0.42 μmol) were added to the
solution, successively. The solution was incubated at 37 °C for 24 h.
The reaction mixture was subjected to chromatography (SEPABEADS
SP207, 100 mL of H2O, followed by 200 mL of MeOH). The MeOH
fraction was concentrated, and the residue was purified by column
chromatography (AcOEt/MeOH/H2O 8/1/1 to 4/1/1) to afford 5′-
diazirinyl-L-tryptophan 12a as a pale yellow amorphous mass (2.7 mg,
23%): [α]D = −17.9 (c 1 MeOH); 1H NMR (CD3OD) δ 7.57 (s, 1H),
7.44 (d, J = 8.6 Hz, 1H), 7.29 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 3.80
(dd, J = 9.2, 4.0 Hz, 1H), 3.46 (dd, J = 15.2, 4.0 Hz, 1H), 3.13 (dd, J =
15.5, 9.2 Hz, 1H); 13C NMR (CD3OD) δ 174.3, 138.8, 128.7, 127.2,
124.1 (q, 1JCF = 273.9 Hz), 121.1, 120.3, 118.8, 113.3, 110.3, 56.5, 30.2
(q, 2JCF = 40.0 Hz), 28.1; 19F NMR (CD3OD) δ −67.15; UV (MeOH)
λmax (ε) 380 (354); HRMS-ESI (m/z) [M + H]+ calcd for
C13H12F3N4O2 313.0912, found 313.0901; Chiral HPLC (Astec
Chirobiotic T, 10% MeOH) tR = 10.59 min.
1H), 7.23 (d, J = 2.3 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 4.87 (s, 2H),
1
1.65 (s, 1H); 13C NMR (CDCl3) δ 136.7, 126.6, 124.4, 122.5 (q, JCF
2
= 274.3 Hz), 120.9, 120.4, 118.3, 116.6, 111.8, 57.0, 29.0 (q, JCF
=
40.8 Hz); 19F NMR (CDCl3) δ −65.41; UV (MeOH) λmax (ε) 375
(423); HRMS-ESI (m/z) [M + H − N2]+ calcd for C11H9F3NO
228.0636, found 228.0607.
(6-(3-(Trifluoromethyl)-3H-diazirin-3-yl)-1H-indol-3-yl)-
methanol (9b). The same treatment of 8b (28.8 mg, 0.13 mmol) as
1
that just described gave 9b (26.7 mg, 82%) as a yellow oil: H NMR
(CDCl3) δ 8.27 (brs, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 2.3
Hz, 1H), 7.27 (s, 1H), 6.99 (d, J = 8.6 Hz, 1H), 4.88 (s, 2H), 1.58 (s,
1H); 13C NMR (CDCl3) δ 136.0, 127.5, 124.8, 123.0, 122.4 (q, 1JCF
=
2
274.3 Hz), 119.8, 118.0, 116.4, 110.2, 57.1, 29.0 (q, JCF = 39.6 Hz);
19F NMR (CDCl3) δ −65.22; UV (MeOH) λmax (ε) 387 (321);
HRMS-ESI (m/z) [M + H −- N2]+ calcd for C11H9F3NO 228.0636,
found 228.0636.
N,N-Dimethyl-1-(5-(3-(trifluoromethyl)-3H-diazirin-3-yl)-1H-
indol-3-yl)methanamine (10a). 5-(Diazirinyl)indole 6a (41.2 mg,
8585
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The Journal of Organic Chemistry
Article
1
(S)-2-Amino-3-(6-(3-(trifluoromethyl)-3H-diazirin-3-yl)-1H-
indol-3-yl)propanoic Acid (12b). The same treatment of 11b (14.2
mg, 0.04 mmol) as that just described gave 12b (3.5 mg, 33%) as a
yellow amorphous mass: [α]D = −25.3 (c 1 MeOH); 1H NMR
(CD3OD) δ 7.78 (d, J = 8.6 Hz, 1H), 7.33 (s, 1H), 7.28 (s, 1H), 6.93
(d, J = 8.6 Hz, 1H), 3.84 (dd, J = 8.6, 4.0 Hz, 1H), 3.47 (dd, J = 15.2,
4.0 Hz, 1H), 3.19 (d, J = 15.2, 8.6 Hz, 1H); 13C NMR (CD3OD) δ
a yellow amorphous mass: H NMR (CDCl3) δ 8.39 (brs, 1H), 7.58
(s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.10 (d, J =
8.6 Hz, 1H), 5.48 (d, J = 4.6 Hz, 1H), 3.78 (s, 3H), 3.38 (d, J = 4.6 Hz,
1H); 13C NMR (CDCl3) δ 174.1, 136.7, 125.4, 124.6, 122.4 (q, 1JCF
275.9 Hz), 120.9, 120.7, 118.7, 114.1, 112.0, 66.9, 53.0, 28.9 (q, 2JCF
=
=
40.8 Hz); 19F NMR (CDCl3) δ −65.44; HRMS-ESI (m/z) [M + H]+
calcd for C13H11F3N3O3 314.0753, found 314.0753.
1
174.2, 137.9, 129.8, 127.8, 124.0 (q, JCF = 273.5 Hz), 122.9, 120.5,
Methyl 2-Hydroxy-2-(6-(3-(trifluoromethyl)-3H-diazirin-3-
yl)-1H-indol-3-yl)acetate (15b). The same treatment of 13b
(104.0 mg, 0.33 mmol) as that just described gave 15b (80.5 mg,
2
118.0, 111.4, 110.1, 56.6, 30.2 (q, JCF = 40.0 Hz), 28.1; 19F NMR
(CD3OD) δ −67.09; UV (MeOH) λmax (ε) 388 (369); HRMS-ESI
(m/z) [M + H]+ calcd for C13H12F3N4O2 313.0912, found 313.0892;
Chiral HPLC (Astec Chirobiotic T, 10% MeOH) tR = 10.24 min.
Methyl 2-Oxo-2-(5-(3-(trifluoromethyl)-3H-diazirin-3-yl)-1H-
indol-3-yl)acetate (13a). Compound 6a (120 mg, 0.53 mmol) was
dissolved in ether (3 mL) and cooled to 0 °C. Oxalyl chloride (91 μL,
1.06 mmol) was added dropwise to the above solution, and the
reaction was warmed to rt and stirred for 12 h. After being stirred, the
reaction was cooled to 0 °C, and then MeOH was added to the
solution. The reaction mixture was warmed to rt and stirred for 6 h.
After the reaction mixture was concentrated, the residue was purified
by column chromatography (CHCl3 then CHCl3/MeOH 95/5) to
1
78%) as a yellow amorphous mass: H NMR (CDCl3) δ 8.36 (brs,
1H), 7.70 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 3.4 Hz, 1H), 7.24 (s, 1H),
6.97 (d, J = 8.6 Hz, 1H), 5.46 (d, J = 5.2 Hz, 1H), 3.76 (s, 3H), 3.35
(d, J = 5.2 Hz, 1H); 13C NMR (CDCl3) δ 174.2, 136.0, 126.3, 125.1,
123.2, 122.4 (q, 1JCF = 273.5 Hz), 120.1, 118.3, 114.0, 110.3, 67.0, 53.0,
28.9 (q, JCF = 40.8 Hz); 19F NMR (CDCl3) δ −65.22; HRMS-ESI
2
(m/z) [M + H]+ calcd for C13H11F3N3O3 314.0753, found 314.0744.
Methyl 2-(5-(3-(Trifluoromethyl)-3H-diazirin-3-yl)-1H-indol-
3-yl)acetate (16a). To a solution of 15a (64.3 mg, 0.21 mmol) in
CH2Cl2 (3 mL) was added P2I4 (228.0 mg, 0.41 mmol) at 0 °C. The
reaction mixture was stirred at rt for 6 h. The mixture was poured into
saturated NaHSO3, and CH2Cl2 and saturated NaHCO3 were added.
The organic layer was washed with brine, dried over MgSO4, filtered,
and evaporated. The crude product was purified by column
chromatography (AcOEt/hexane 1/3) to yield 16a (29.1 mg, 47%)
as a yellow amorphous mass: 1H NMR (CDCl3) δ 8.26 (brs, 1H), 7.45
(s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.08 (d, J =
8.6 Hz, 1H), 3.76 (s, 2H), 3.73 (s, 3H); 13C NMR (CDCl3) δ 172.2,
1
yield 13a (103 mg, 62%) as a yellow amorphous mass: H NMR
(DMSO-d6) δ 8.59 (s, 1H, 2′-H), 8.09 (s, 1H), 7.67 (d, J = 8.4 Hz,
1H), 7.18 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H); 13C NMR (DMSO-d6) δ
1
178.6, 163.3, 140.2, 137.3, 125.8, 122.2 (q, JCF = 274.4 Hz), 121.9,
2
121.8, 119.7, 114.0, 112.4, 54.9, 28.6 (q, JCF = 39.5 Hz); 19F NMR
(DMSO-d6) δ −64.53; HRMS-ESI (m/z) [M + H]+ calcd for
C13H9F3N3O3 312.0596, found 312.0574.
1
Methyl 2-Oxo-2-(6-(3-(trifluoromethyl)-3H-diazirin-3-yl)-1H-
indol-3-yl)acetate (13b). The same treatment of 6b (72.7 mg, 0.32
mmol) as that just described gave 13b (80.1 mg, 80%) as a yellow
136.4, 127.2, 124.6, 122.5 (q, JCF = 279.5 Hz), 120.5, 120.2, 118.1,
111.7, 108.9, 52.1, 30.8, 29.0 (q, 2JCF = 42.0 Hz); 19F NMR (CDCl3) δ
−65.41; HRMS-ESI (m/z) [M + H]+ calcd for C13H11F3N3O2
298.0803, found 298.0779.
1
amorphous mass: H NMR (DMSO-d6) δ 8.60 (s, 1H), 8.24 (d, J =
8.0 Hz, 1H), 7.49 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H); 13C
NMR (DMSO-d6) δ 178.6, 163.5, 140.3, 136.5, 126.9, 122.7, 122.2,
Methyl 2-(6-(3-(Trifluoromethyl)-3H-diazirin-3-yl)-1H-indol-
3-yl)acetate (16b). (a) From 15b. The same treatment of 15b
(45 mg, 0.143 mmol) as that just described gave 16b (26 mg, 61%) as
a yellow amorphous mass. (b) From 14b. Compound 14b (16.5 mg,
0.055 mmol) was dissolved in diethyl ether (3 mL). Activated MnO2
was suspended into the solution. The reaction was stirred at rt for 1 h
and filtrated. After concentration, the residue was purified by column
chromatography (CHCl3) to give 16b (13.2 mg, 81%) as a yellow
amorphous mass: 1H NMR (CDCl3) δ 8.24 (brs, 1H), 7.61 (d, J = 8.4
Hz, 1H), 7.23 (s, 1H), 7.21 (d, J = 2.2 Hz, 1H), 6.96 (d, J = 8.4 Hz,
1H), 3.77 (s, 2H), 3.71 (s, 3H); 13C NMR (CDCl3) δ 172.2, 135.6,
1
2
122.1 (q, JCF = 275.9 Hz).120.6, 112.3, 111.5, 52.7, 28.6 (q, JCF
=
38.4 Hz); 19F NMR (DMSO-d6) δ −64.53; HRMS-ESI (m/z) [M +
H]+ calcd for C13H9F3N3O3 312.0596, found 312.0585.
Methyl 2-(5-(3-(Trifluoromethyl)-3H-diazirin-3-yl)indolin-3-
yl)acetate (14a). Compound 13a (60.2 mg, 0.19 mmol) was
dissolved in TFA (300 μL), and Et3SiH (186 μL, 1.16 mmol) was
added at 0 °C. The reaction mixture was stirred at rt for 6 h and
evaporated with toluene. The residue was purified by column
chromatography (CH2Cl2, then CH2Cl2/MeOH 95/5) to yield 14a
(38.1 mg, 66%) as a yellow oil: 1H NMR (CDCl3) δ 6.93 (s, 1H), 6.87
(d, J = 8.2 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 3.83 (t, J = 9.1 Hz, 1H),
3.72 (s, 3H), 3.70−3.68 (m, 1H), 3.32 (dd, J = 8.7, 6.1 Hz, 1H), 2.73
(dd, J = 15.8, 6.1 Hz, 1H), 2.56 (dd, J = 15.8, 8.7 Hz, 1H). It is difficult
to measure 13C NMR due to the compound 14a was not stable in
CDCl3 solution. Although we checked the stability of 14a carefully, the
1
128.2, 125.1, 122.8, 122.4 (q, JCF = 276.0 Hz), 119.5, 117.8, 110.1,
108.7, 52.1, 30.9, 29.0 (q, JCF = 40.7 Hz); 19F NMR (CDCl3) δ
2
−65.15; HRMS-ESI (m/z) [M + H]+ calcd for C13H11F3N3O2
298.0803, found 298.0789.
2-(5-(3-(Trifluoromethyl)-3H-diazirin-3-yl)-1H-indol-3-yl)-
acetic Acid (17a). Compound 16a (43.5 mg, 0.15 mmol) was
dissolved in MeCN (3 mL) and MeOH (1.5 mL). NaOH (1 M, 1.5
mL) was added dropwise to the above solution at 0 °C. The reaction
was warmed to rt, stirred for 12 h, and then concentrated. The residue
was purified by column chromatography (AcOEt/MeOH 2/1) to yield
17a (35.6 mg, 85%) as a yellow amorphous mass: 1H NMR (CDCl3) δ
8.20 (brs, 1H), 7.43 (s, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 2.3
Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 3.79 (s, 2H); 13C NMR (CDCl3) δ
1
partial decomposition of 14a was observed after H NMR measure-
ment, which took less than 5 min.
Methyl 2-(6-(3-(Trifluoromethyl)-3H-diazirin-3-yl)indolin-3-
yl)acetate (14b). The same treatment of 13b (76.3 mg, 0.25
mmol) as that just described gave 14b (63.1 mg, 86%) as a yellow oil:
1H NMR (CDCl3) δ 7.31 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 6.99 (d, J
= 8.0 Hz, 1H), 4.05 (t, J = 10.0 Hz, 1H), 3.94−3.88 (m, 1H), 3.71 (s,
3H), 3.57 (dd, J = 8.6, 6.0 Hz, 1H), 2.84 (dd, J = 16.9, 6.0 Hz, 1H),
2.68 (dd, J = 16.9, 8.6 Hz, 1H); 13C NMR (CDCl3) δ 171.6, 142.1,
137.0, 130.2, 125.2, 124.5, 121.9 (q, 1JCF = 280.7 Hz), 114.4, 52.0, 51.9,
1
177.6, 136.3, 127.1, 124.8, 122.5 (q, JCF = 274.7 Hz), 120.7, 120.4,
118.0, 111.8, 108.2, 30.7, 29.0 (q, 2JCF = 39.6 Hz); 19F NMR (CDCl3)
δ −65.41; UV (MeOH) λmax (ε) 380 (402); HRMS-ESI (m/z) [M +
H]+ calcd for C12H9F3N3O2 284.0647, found 284.0647.
2
51.8, 37.9, 28.3 (q, JCF = 40.4 Hz); 19F NMR (CDCl3) δ −65.22;
HRMS-ESI (m/z) [M + H]+ calcd for C13H13F3N3O2 300.0960, found
300.0930.
2-(6-(3-(Trifluoromethyl)-3H-diazirin-3-yl)-1H-indol-3-yl)-
acetic Acid (17b). The same treatment of 16b (11.2 mg, 0.038
mmol) as that just described gave 17b (9.50 mg, 89%) as a yellow
amorphous mass: 1H NMR (CDCl3) δ 8.20 (brs, 1H), 7.60 (d, J = 8.6
Hz, 1H), 7.24 (s, 1H), 7.23 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 8.6 Hz,
1H), 3.78 (s, 2H); 13C NMR (CDCl3) δ 177.2, 135.6, 128.1, 125.2,
122.9, 122.4 (q, 1JCF = 273.5 Hz), 119.5, 118.0, 110.2, 108.1, 30.8, 29.0
Methyl 2-Hydroxy-2-(5-(3-(trifluoromethyl)-3H-diazirin-3-
yl)-1H-indol-3-yl)acetate (15a). To a solution of compound 13a
(108 mg, 0.34 mmol) in MeOH (6 mL) was added NaBH4 (13.0 mg,
0.36 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C,
the solvent was concentrated, and the residue was dissolved in AcOEt
(30 mL). The organic layer was washed with brine, dried over MgSO4,
filtered, and evaporated. The crude product was purified by column
chromatography (AcOEt/hexane 1/2) to yield 15a (70.8 mg, 65%) as
(q, JCF = 40.8 Hz); 19F NMR (CDCl3) δ −65.22; UV (MeOH)
2
λmax ;(ε) 380 (364); HRMS-ESI (m/z) [M + H]+ calcd for
C12H9F3N3O2 284.0647, found 284.0623.
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The Journal of Organic Chemistry
Article
Photolysis of Diazirinylindole Derivatives.20 A 1 mM
methanolic solution (1 mL) of the diazirinylindole derivatives was
placed in a quartz cuvette. After the inner atmosphere was replaced
with nitrogen, photolysis was carried out with 100 W black-light at a
distance 1 cm from the surface of light source. Specrtra were measured
after each minute, and then the half-life was calculated from the
decrements of the absorbance around 380 nm.
Biological Assay for on Elongation of Oat Coleoptile
Segments.21 Coleoptiles were obtained from dark-grown oat
seedlings. Coleoptile tips (5 mm in length) were removed, and the
next 10 mm was excised. Coleoptile segments were immersed in a
treatment solution (17a, 17b, and IAA) at 25 °C for 24 h, followed by
measurements of segments.
(16) Archana; Rani, P.; Bajaj, K.; Srivastava, V. K.; Chandra, R.;
Kumara, A. Arzneim.-Forsch./Drug Res. 2003, 53, 301−306.
(17) Demerson, C. A.; Humber, L. G.; Philipp, A. H. J. Med. Chem.
1976, 19, 391−395.
(18) Hashimoto, M.; Hatanaka, Y.; Nabeta, K. Heterocycles 2003, 59,
395−398.
(19) Collot, V.; Schmitt., M.; Mawah, P.; Bourguignon, J.-J.
Heterocycles 1999, 51, 2823−2847.
(20) Hatanaka, Y.; Hashimoto, M.; Nishihara, S.; Narimatsu, H.;
Kanaoka, Y. Carbohydr. Res. 1996, 294, 95−108.
(21) Zhao, Y. Annu. Rev. Plant Biol. 2010, 61, 49−64.
(22) Leonard, N. J.; Greenfield, J. C.; Schmitz, R. Y.; Skoog, F. Plant
Physiol. 1975, 55, 1057−1061.
(23) Masuda, K.; Koizumi, A.; Nakajima, K.; Tanaka, T.; Abe, K.;
Misaka, T.; Ishiguro., M. PLoS One 2012, 7, e35380.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR charts of the new compounds, overlay charts
of photolysis of diazirinyl indole derivatives, and photographs
of biological assays for on elongation of oat coleoptile
segments. All of these materials are available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hasimoto@abs.agr.hokudai.ac.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by Ministry of Education,
Science, Sports and Culture Grant-in-Aid for Scientific
Research (C), 19510210 and 21510219 (M.H.).
REFERENCES
■
(1) (a) Dorman
́
, G.; Prestwich, G. D. Trends Biotechnol. 2000, 18,
64−76. (b) Tomohiro, T.; Hashimoto, M.; Hatanaka, Y. Chem. Rec.
2005, 5, 385−395. (c) Hashimoto, M.; Hatanaka, Y. Eur. J. Org. Chem.
2008, 2513−2523.
(2) Brunner, J. Annu. Rev. Biochem. 1993, 62, 483−514.
(3) Melhado, L. L.; Leonard, N. J. J. Org. Chem. 1983, 48, 5130−
5133.
(4) Cherry, K.; Lebegue, N.; Leclerc, V.; Carato, P.; Yous, S.;
Berthelot, P. Tetrahedron Lett. 2007, 48, 5751−5753.
(5) Takami, H.; Koshimura, W.; Kumazawa, T. Heterocycles 1999, 51,
1119−1124.
(6) Shelke, S. V.; Cutting, B.; Jiang, X.; Koliwer-Brandl, H.; Strasser,
D.; S.Schwardt, O.; Kelm, S.; Ernst, B. Angew. Chem., Int. Ed. 2010, 49,
5721−5725.
(7) Broadbent, T. A.; Broadbent, H. S. Curr. Med. Chem. 1998, 5,
469−491.
(8) Semenov, B. B.; Granik, V. G. Pharm. Chem. J. 2004, 38, 287−
310.
(9) Greco, M. N.; Hawkins, M. J.; Powell, E. T.; Almond, H. R., Jr.;
de Garavilla, L.; Hall, J.; Minor, L. K.; Wang, Y.; Corcoran, T. W.;
Cera, E. D.; Cantwell, A. M.; Savvides, S. N.; Damiano, B. P.;
Maryanoff, B. E. J. Med. Chem. 2007, 50, 1727−1730.
(10) Bittner, S.; Scherzer, R.; Harlev, E. Amino Acids 2007, 33, 19−
42.
(11) Ma, J.; Yin, W.; Zhou, H.; Liao, X.; Cook, J. M. J. Org. Chem.
2009, 74, 264−273.
(12) Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C.
A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678−8693.
(13) Eto, H.; Eguchi, C.; Kagawa, T. Bull. Chem. Soc. Jpn. 1989, 62,
961−963.
(14) Snyder, H. R.; MacDonald, J. A. J. Am. Chem. Soc. 1955, 77,
1257−1259.
(15) Zhao, Y. Annu. Rev. Plant Biol. 2010, 61, 49−64.
8587
dx.doi.org/10.1021/jo301552m | J. Org. Chem. 2012, 77, 8581−8587