Solvent-free, uncatalyzed asymmetric "ene" reactions of: N-Tert-butylsulfinyl-3,3,3-Trifluoroacetaldimines: A general approach to enantiomerically pure α-(trifluoromethyl)tryptamines

Article abstract of DOI:10.1039/c7ob00670e

A novel approach to regioselectively substituted and stereoselectively α-Trifluoromethylated tryptamines is reported based on the ene reaction of Boc-protected 3-methyleneindolines with optically pure (R)-or (S)-Tert-butanesulfinyltrifluoroacetaldimine. B

Full text of DOI:10.1039/c7ob00670e

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Solvent-Free, Uncatalyzed Asymmetric “Ene” Reactions of N-tert-
Butylsulfinyl-3,3,3-trifluoroacetaldimines: General Approach to
Enantiomerically Pure α-(Trifluoromethyl)tryptamines
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Giuseppe Mazzeoa, Giovanna Longhia; Sergio Abbatea, Martina Palombab, Luana Bagnolib,
Francesca Marinib, Claudio Santib, Jianlin Han,c Vadim A. Soloshonokd e Emilio Di
,
Crescenzof, Renzo Ruzziconi,*f
A novel approach to regioselectively substituted and stereoselectively α-trifluoromethylated tryptamines is reported
based on the ene reaction of Boc-protected 3-methyleneindolines with optically pure (R)- or (S)-tert-
butanesulfinyltrifluoroacetaldimine. Boc- and sulfinylamido-protected α-trifluoromethyltryptamines are obtained in 60-
70% yield and 85/15 dr by just heating equimolar amounts of the two reaction partners at 80–90 °C for 2-3 h without
solvent. The absolute configuration of the amino α-carbon has been assigned based on the vibrational circular dichroim
(VCD) spectral analysis. The two protecting group can be chemoselectively removed allowing further regio- and
stereoselective elaboration of the ene products to various biologically interesting compounds.
.
Waals radius, render fluorine-containing indole derivatives of high
pharmaceutical potential.4,5 In particular, the introduction of a CF3,
Introduction
into
a structure of potentially bio-active compound, is an
Indole nucleus constitutes one of the most important scaffolds of
naturally occurring biologically active compounds. Indole-derived
molecules are being involved in numerous biological processes
controlling essential functions in virtually all living organisms.1 Since
the early days of medicine, indole structure has inspired design and
synthesis of a countless number of indole-based pharmaceutical
products.2
established paradigm in the modern medicinal chemistry and drug-
design.4-6 Over the past decades highly efficient methods have been
developed for asymmetric synthesis of trifluoromethylated amines
and their derivatives based on the use of very effective synthetic
building blocks.7 In the area of CF3-containing indoles, Han and
Soloshonok reported
a reliable and generalized access to
biologically interesting derivatives possessing the CF3CH(NH2)-
pharmacophoric group.8 Their approach is based on the reaction of
(S)- and (R)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine with a
number of substituted indoles under Lewis acid-catalysed
Friedel−Craꢀs approach.
Although many methods have been developed to synthesize indole
derivatives,3 biologically active fluorinated analogues are much less
common. However, the established ability of fluorine to increase
lipophilicity, its high electronegativity and relatively small van der
The high reaction rates together with excellent yields and
stereoselectivities observed in these reactions, underscored the
remarkable potential of the chiral sulfinyltrifluoroacetaldimine as a
valuable alternative to the several other reagents developed over
the last two decades for the synthesis of optically active
trifluoromethylated amines.9
Among the indole-derived biologically significant amines,
tryptamine is a very important alkaloid found in animals, fungi, and
plants10 and is structurally similar to the amino acid tryptophan,
from which it derives its name. Due to the pharmacological activity,
tryptamine derivatives have attracted considerable synthetic
interest throughout the years.11
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Among them, α-trifluormethyltryptamine, obtained by the sealed 5 mL glass tube and the resulting mixture was heated for 2–6
vinylnitrosoindole cycloaddition strategy of Zimmer and Reissig,12 h at 80° C.
has received a particular attention.13
More recently, Hanamoto and coworkers developed an original
approach to racemic β-trifluormethyltryptamines based on the
reaction of regioselectively substituted indoles with 1-tosyl-2-
(trifluoromethyl)aziridine in toluene at 100 °C, in the presence of
diethylzinc as a base.14 After the Ti(OiPr)4-catalyzed deprotection of
the amino group with Me3SiCl in THF, quantitative yields of the
expected product were obtained (Scheme 3).
Taking into account that the chemistry of trifluoroacetaldimines is
rather well-studied,7 it is very surprising that only a single example
of the corresponding ene-type reactions has been reported so far.15
Thus, regardless the apparent synthetic opportunities for the
preparation of polyfunctional biologically relevant compounds, ene
reactivity remains virtually unexplored area of the N-sulfinyl
imines.7,16 Therefore, we were very excited to face this challenge,
especially in its the most difficult, uncatalyzed and solvent-free
mode. We assumed that insufficient reactivity of the C=N bond can
be counterbalanced by electron rich carbon-carbon double bond of
the corresponding reaction partner. For example, few years ago we
showed that properly substituted 3-methyleneindolines constitute
valuable building blocks for the synthesis of highly functionalized 3-
alkylsubstituted indoles, by simply heating them with the equimolar
amount of strong electrophilic carbonyl compounds such as
glyoxylic esters, dialkyl 2-oxomalonates or ethyl trifluoropyruvate.17
While the electrophilicity of the C=N bond in N-
sulfinyltrifluoroacetaldimines is obviously lower, as compared with
the above mentioned carbonyl compounds, we thought that the
exceptional reactivity of the 3-methyleneindolines might be
sufficient for the ene reaction to take place. In this work, we report
that simple heating of N-Boc-protected 3-methyleneindolines with
(S)- and (R)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine, under
solvent-free conditions, leads to the corresponding ene reaction,
thus allowing for the efficient asymmetric synthesis of α-
(trifluoromethyl)tryptamines of high pharmaceutical interest.
Scheme 1
Upon cooling, silica gel column chromatography of the resulting
crude product allowed isolation of mixtures of (R,Rs)-6 and (S,Rs)-6
with yields and diastereomeric ratios presented in the Table. In
some cases the separation of both diastereomers was possible. The
diastereomeric ratios were determined by integration of the
doublets (J ~ 7 Hz) attributed to the trifluoromethyl groups at δ ~75-
–76 ppm in the 19F NMR spectrum of the crude mixture.
Table. 1-tert-Butoxycarbonyl-N-tert-butanesulfynyl-α-trifluoromethyltryptamines
from the reaction of 1-tert-butoxycarbonyl-3-methyleneindolines and (R)-N-tert-
butanesulfinyltrifluoro-acetaldimine at 80 °C without solvent.
Yield, % a
3-Methylene-indoline (Y)
Adduct
6a
((R,Rs)/(S,Rs))b
Result and Discussion
5-H
62 (83:17)
Substituted 3-methyleneindolines 1a-h were prepared
according to the four-step protocol, involving ortho-
metalation/bromination of starting anilines 2, N-propargylation of
the resulting tert-butyl N-(2-bromoaryl)carbamates 3 and tributyltin
hydride/AIBN-promoted reductive radical cyclization of the N-
propargylcarbamate 4 (Scheme 1).18
5-CH3
5-OCH3
5-Cl
6b
6c
6d
6e
6f
71 (86:14)
68 (85:15)
55 (88:12)
64 (86:14)
69 (84:16)
47 (85:15)
As was anticipated, mixing of 3-methyleneindolines 1 with
imine 5 at ambient temperature, did not lead to any reaction
products. Gradual increase of the temperature to 50 oC did not
result in any noticeable reaction, indicating that rather harsh
conditions might be needed to observe the desired reactivity.
Finally, we found that the target ene reaction takes place at about
80 oC, proceeding rather smoothly with appreciable yield and
stereochemical outcome of the corresponding addition products 6
(Scheme 1). In a typical experiment, the equimolar amounts of the
substituted 3-methyleneindolines 1a-h and (R)- or (S)-N-tert-
5-F
5-CF3
6-CF3
6g
a
b
Yield of the diastereomeric mixture. Determined by the integration of the CF3
doublets at δ –75.05 - –75.29 (major diastereomer) and δ –75.35 - –75.75 (minor
diastereomer) in the 19F NMR spectrum of the crude reaction mixture.
The absolute configuration (AC) at the newly created
-
HC*(CF3)NH- carbon of the major diastereomer 6e obtained from
butanesulfinyl-(3,3,3)-trifluoroacetaldimine
5 were mixed in a
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the reaction of 1-tert-butoxycarbonyl-5-fluoro-3-methyleneindoline diastereomer from the reactions of the methyleneindoline 1e with
1e) with (RS)-N-tert-butanesulfinyl-(3,3,3)-trifluoroacetaldimine (R)- the aldimines (S)-5 confirmed the previous assignment.
has been assigned by comparing the experimental vibrational Calculated IR spectra are less informative about diastereomeric
(
5
circular dichroism (VCD) and infrared (IR) spectra with the data discrimination but it is also worth noting that they nicely predict the
computed by means of Density Functional Theory (DFT): this experimental one.
Considering the stereochemical outcome obtained in these
reactions, we were rather satisfied with the chemical yields and the
diastereoselctivity averaging 60% and 85/15 ratio. One may agree
that for the reactions conducted at 80 °C without a solvent, these
values are quite appreciable. Furthermore, the diastereomeric ratio
in these ene reactions is not noticeably influenced by the nature of
substituents on the aromatic ring of starting 3-methylene-indolines
approach proved to be quite powerful and robust for AC
assignment of various organic molecules, especially for non-solid
samples.18-20 In setting up the calculation protocol, (S) AC (see SI)
was fixed on the sulfur atom. In order to find all possible
conformations, a conformational search was employed for the two
diastereomeric form (R,SS)-6e and (S,SS)-6e. All conformers were
fully optimized and then VCD and IR spectra were calculated at
different DFT levels of theory.21-22 The final computed spectra were
obtained as averages over the conformers Boltzmann’s populations
(see Supporting Information for protocol details). In Fig. 1a
1a-h. Thus, in the case of substrates bearing electron-withdrawing
and –donating, as well as sterically bulky substituents, the
diastereomeric ratios were ranging between 88/12 and 84/16.
From a mechanistic point of view, the observed mode of
experimental VCD and IR spectra of the two major diastereomers stereoselectivity could be explained by considering the ene reaction
like a [4+2] pericyclic reaction running across a unique transition
state so that the stereoselectivity could derive from the different
activation energy of the two possible transition states. As shown in
Fig. 2 (a), attack of the exocyclic methylene of indoline occurs
preferentially at the re face of C=N double bond leading to the
obtained from the reaction of 3-methyleneindoline 1e with (R)- and
(S)-N-tert-butanesulfinyltrifluoroacetaldimine, respectively, are
reported. For consistency with the previous results, the comparison
with the calculated spectra of diastereomers (S,RS)-6e and (R,RS)-6e
is shown in Fig. 1b
adduct (R,RS)-
6 as the main diastereomer. Presumably, the
activated complex assumes a distorted skew-boat conformation
with the bulky trifluoromethyl group occupying an equatorial
position.
O
O
H
H
H
H
O
O
N
H
N
N
F
H
S
re
si
N
F
O
H
H
H
Y
Y
S
O
F
H
F
F
F
(a)
(b)
"exo" attack at re face of
"endo" attack at si face of
aldimine leading to
aldimine leading to
(R,RS)-6 diastereomer
(S,RS)-6 diastereomer
Fig 1. (a): experimental VCD (top panel) and IR (bottom panel) spectra
of the two enantiomers of major diastereomer 6e recorded in CCl4 (see
Supporting Information for experimental details); (b) comparison of VCD
(top panel) and IR (bottom panel) spectra between experimental (RS)
enantiomer and calculated VCD and IR spectra for diastereomers (R,RS)-6e
and (S,RS)-6e at DFT/PBE0/TZVP level of theory. Experimental VCD
spectrum is reported as semi-difference of VCD spectra on the left.
Fig 2. Plausible TS configurations of the “ene” reaction of 3-methyl-eneindolines and
(RS)-tert-butanesulfinyltrifluoroacetaldimine
As a final goal of this study, we decided to demonstrate some
VCD spectra, in the range of 1050-1450 cm-1, are in good
enantiomeric relationship. Calculated VCD and IR spectra of the two
possible diastereomers (R,RS)-6e and (S,RS)-6e are compared with
the experimental spectra for (X,RS)-6e (Fig. 1b). The calculated VCD
curve, which better qualitatively predicts experimental spectrum, is,
without any doubt, the one of the corresponding (R,RS)-6e
diastereomer. Indeed, the intense experimental doublet centered
at ca. 1180 cm-1 is well predicted in signs by calculated (R,RS)-6e
VCD curve, while for (S,RS)-6e, smaller VCD features with opposite
behavior are calculated. The vibrational normal modes in
correspondence of the calculated doublet are comprised of C*-H
bending modes coupled with some other C-H bending and C-F
stretching (see SI for details). The C*-H bending mode has already
useful transformations of products
besides being a valuable chiral auxiliary, can be treated merely as
an amine protecting group. However, in products , both tert-
butanesulfinyl and Boc protective groups are liable towards acidic
conditions. Nevertheless, in the case of the di-protected indoles
6. tert-Butanesulfinyl group in 6,
6
6
,
the different nature of the two nitrogen protecting-groups could be
synthetically exploited by a selective removal under appropriate
hydrolytic conditions. Thus, when a solution of the di-protected
indole 6f was refluxed (48 h) in a 1:9 dioxane-water mixture,25 Boc
was selectively removed rendering the remaining sulfinyl group on
the amino nitrogen
(
7f)
useful for further stereoselective
transformations (Scheme 2).
been found as
a good probe for central carbon chirality
discrimination in a number of VCD spectra.23-24 The double check,
effected with the enantiomer (S,SS)-6e, obtained as the major
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green chemistry conditions, without a solvent, at 80 °C giving rise to
the target products with appreciable chemical yields and
diastereoselectivity. The absolute configuration of the obtained
product in one case has been determined by VCD spectra and DFT
calculations. The different protective (Boc and -SOtBu) groups at the
two nitrogen atoms of the resulting tryptamines, can be
chemoselectively removed, under different reaction conditions,
allowing the remaining protective group to carry on its specific
regio- (Boc) or stereoselective (-S*OtBu) orientation in further
synthetic transformations.
Acknowledgements
Scheme 2
Alternatively, sulfinyl group can be selectively removed in
nearly quantitative yield by heating at 50 °C a solution in 5:1
We gratefully acknowledge the financial support from the
IKERBASQUE, Basque Foundation for Science, University of Perugia
and the Department of Pharmaceutical Sciences for the Grant
Ricerca di Base 2014-2016. CINECA is gratefully acknowledged for
access to large computing facilities.
6
THF/H2O mixture in the presence of iodine (20%),26 making the Boc
protection at the heterocyclic nitrogen (8f) a potential ortho-
directing group to be exploited for possible further functionalization
with polar organometallic reagents. Under more forcing conditions
both Boc and sulfinyl groups are completely removed in few
minutes. Under such conditions, in the presence of aldehydes, the
one-pot synthesis of diastereomeric 1-alkyl(aryl)-substituted 3-
trifluoromethyltetrahydrocarbolines could be easily realized (see
for example Scheme 3).
Experimental
If not specified otherwise, 1H NMR and 1H-decoupled 13C NMR
spectra were recorded at 400 and 100 MHz, respectively, in CDCl3
solution using tetramethylsilane as an internal standard. 19F NMR
spectra were recorded at 376 MHz in CDCl3 solution using CFCl3 as a
reference standard. J values are expressed in Hz. Mass spectra were
obtained by electron impact fragmentation at 70 eV ionization
potential. The purity of all final products was testified by elemental
analyses of the diastereomeric mixtures performed on Carlo Erba
Elemental Analyzer Mod. 1106. VCD experiments were performed
with a Jasco FVS6000 spectrometer on 0.1 M/CDCl3 solutions in
0.200 mm BaF2 cells. DFT calculations were carried out by the use of
Gaussian09 set of programs20 (for further details see SI). Further
information about working routine and technical details can be
found in previous publications from this laboratory. The starting
fluoro-, trifluoromethyl- and trifluoromethoxy substituted anilines
and 2-bromo-5-fluoroaniline were commercial products and were
used without further purification.
New starting material used in this work:
tert-Butyl
N-(2-bromo-4-methoxyphenyl)-N-(prop-2-yn-1-
yl)carbamate. It was obtained in 75% of yield from p-anisidine
following the same protocol previously reported.17 Chromatography
of the crude on silica gel (eluent 9:1 v/v petroleum ether/diethyl
ether) allowed to recover a colorless oil consisting of a 3:1 mixture
of two conformers exhibiting the following spectral characteristics.
Major conformer: 1H NMR δ 7.28 (d, J = 8.6 Hz, 1 H), 7.14 (d, J = 2.7
Hz, 1 H), 6.84 (dd, J = 8.6 and 2.7, 1 H), 4.76 (dd, J = 17.6 and 2.3 Hz,
1 H), 3.91 (dd, J = 17.6 and 2.3 Hz, 1 H), 3.81 (s, 3 H), 2.20 (bs, 1 H),
1.36 (s, 9 H); 13C NMR δ 159.1, 154.0, 132.9, 131.0, 123.8, 117.8,
113.5, 80.7, 72.2, 55.6, 38.2, 28.1. Minor conformer, typical
absorptions: 1H NMR δ 7.35 (d, J = 8.6 Hz, 1 H), 7.15 (b, 1 H), 4.61 (d,
J = 17 Hz, 1 H), 3.79 (s, 3 H), 2.22 (bs, 1 H), 1.52 (s, 9 H) 13C NMR δ
156.7, 154.3, 133.2, 131.3, 118.2, 114.0, 81.3, 71.9, 39.5. Anal.:
calcd for C15H18BrNO3 (340.22) C, 52.96; H, 5.33; N, 4.12. Found C,
53.13; H, 5.36; N, 4.17.
Scheme 3
Chemistry and synthetic transformations of this new type
enantiomerically pure α-(trifluoromethyl)tryptamines are currently
under investigation and will be reported in a due course.
Conclusions
In conclusion, we have successfully realized the first example of
ene reaction between 1-tert-butoxycarbonyl-3-methylene-indolines
and (R)-N-tert-butanesulfinyltrifluoroacetaldimine allowing simple
and straightforward preparation of pharmaceutically important α-
(trifluoromethyl)tryptamines. The reactions are conducted under
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1-tert-Butoxycarbonyl-5-metoxy-3-methyleneindoline. It was
ARTICLE
(S,RS)-1-tert-butoxycarbonyl-3-[2-tert-butanesulfinylamido)-
prepared in 53% yield by tributyltin hydride-promoted radical 3,3,3-trifluoropropyl]-5-methylindole (6b(S)). Yellow Viscous oil 1H
cyclization of the above 2-bromoarylcarbamate as previously NMR in the mixture δ 7.92 (bs, 1 H), 7.52 (s, 1 H), 7.20 (s, 1 H), 7.09
reported.17 Chromatography of the crude product on silica gel, (d, J = 8.3 Hz, 1 H), 4.06 (quint, J = 5.8 Hz, 1 H), 3.54 (d, J = 6.0 Hz, 1
eluent, 9:1 petroleum ether/diethyl ether mixture, allowed to get a H), 3.21 (dd, J = 15 and 5.8 Hz, 1 H), 3.07 (dd, J = 15 and 6.8 Hz, 1 H),
pale yellow solid exhibiting the following spectroscopic and 2.39 (s, 3 H), 1.59 (s, 9 H), 0.93 (s, 9 H); 13C NMR δ 149.4, 133.6,
analytical characteristics. Mp 40-42 °C; 1H NMR δ 7.86 (d, J = 8.4 Hz, 132.3, 130.6, 126.5, 125.1 (q, J = 282 Hz), 124.8, 118.3, 115.0, 114.0,
1 H), 6.95 (s, 1 H), 6.82 (d, J = 7.7 Hz, 1 H), 5.43 (bs, 1 H), 5.03 (bs, 1 83.6, 58.2 (q, J = 29 Hz), 57.1, 28.1 (3 C), 25.3, 22.3 (3 C), 21.3; 19F
H), 4.56 (bs, 2 H), 3.81 (s, 3 H), 1.55 (s, 9 H). 13C NMR δ 155.5, 151.5, NMR δ −75.47 (d, J = 7.0 Hz, 3 F). Analysis of the diastereomeric
141.1, 130.0, 116.1, 116.0, 105.2, 101.6, 101.2, 80.5, 55.7, 53.6, mixture: calcd for C21H29F3N2O3S (446.53) C, 56.49; H, 6.55; N, 6.27.
28.4. Anal.: calcd for C15H19NO3 (261.32) C, 68.94; H, 7.33; N, 5.36. Found C, 56.47; H, 6.60; N, 6.37.
Found C, 68.67; H, 7.45; N, 5.41.
(R,RS)-1-tert-butoxycarbonyl-3-[2-tert-butanesulfinylamido)-
General Procedure for the synthesis of (R)-1-tert- 3,3,3-trifluoropropyl]-5-methoxyindole (6c). Whit solid, mp 113-115
1
butoxycarbonyl-3-[2-((R)-tert-butanesulfin-ylamido)-3,3,3-
trifluoropropyl]indoles.
°C; H NMR δ 7.94 (bd, 8.0 Hz, 1 H), 7.39 (s, 1 H), 6.88 (s, 1 H), 6.87
(d, J = 8.0 Hz, 1 H), 3.96 (m, 1 H), 3.81 (s, 3 H), 3.72 (d, J = 9.4 Hz, 1
H), 3.15 (dd, J = 15 and 4.3 Hz, 1 H), 2.92 (dd, J = 15 and 9.1 Hz, 1 H),
1.59 (s, 9 H), 0.96 (s, 9 H); 13C NMR δ 155.5, 148.9, 130.2, 129.5,
124,9, 124.6 (q, J = 282 Hz), 115.7, 113.5, 112.7, 100.7, 83.1, 57.3
(q, J = 29 Hz), 56.7, 55.2, 27.6 (3 C), 25.0, 21.6 (3 C); 19F NMR δ
−75.25 (d, J = 7.1 Hz, 3 F). Analysis: calcd for C21H29F3N2O4S (462.53)
C, 54.53; H, 6.32; N, 6.06. Found C, 55.40; H, 6.41; N, 6.12.
3-methyleneindoline 1a-f (1.0 mmol) and (R)- or (S)-tert-
butanesulfinyltrifluoacetaldimine were mixed in
a sealed vial
without solvent and heated at 70-80°C in a oil bath for the time
reported in the Table. After cooling, the diastereomeric ratio was
determined by 19F NMR analysis before the crude mixture was take
up with dichloromethane (1 mL) and chromatographed on silica gel
using 65:35 petroleum ether-ethyl acetate mixture as the eluent.
(R,RS)-1-tert-butoxycarbonyl-3-[2-tert-butanesulfinylamido)-
Yields are reported in the Table. For irresolvable diastereomeric 3,3,3-trifluoropropyl]-5-chloroindole (6d). White solid, mp 72–74 °C;
mixture, the structure of each diastereomer was inferred from the 1H NMR δ 8.07 (d, J = 8.4 Hz, 1 H), 7.53 (s, 1 H), 7.49 (d, J = 1.5 Hz, 1
specific 1H, 13C and 19F NMR signals in the spectrum of the H), 7.30 (dd, J = 9.0 and 1.9 H, 1 H), 4.01 (m, 1 H), 3.85 (d, J = 9.4 Hz,
diastereomeric mixture.
1 H), 3.21 (dd, J = 15 and 3.5 Hz, 1 H), 3.02 (dd, J = 15 and 9.2 Hz, 1
H), 1.68 (s, 9 H), 1.04 (s, 9 H); 13C NMR δ 149.0, 133.7, 131.2, 128.5,
126.1, 125.0 (q, J = 282 Hz), 124.8, 118.2, 116.4, 113.7, 84.3, 58.1
(q, J = 29 Hz), 57.1, 28.1 (3 C), 25.1, 22.2 (3 C); 19F NMR δ, −75.18 (d,
J = 6.3 Hz, 3 F). Analysis: calcd for C20H26ClF3N2O3S (466.94) C, 51.44;
H, 5.61; N, 6.00. Found C, 51.54; H, 5.71; N, 6.09.
(R,RS)-1-tert-butoxycarbonyl-3-[2-tert-butanesulfinylamido)-
3,3,3-trifluoropropyl]indole (6a(R)). Slight yellow very viscous oil. 1H
NMR δ 8.14 (bd, J = 7.6 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.50 (s, 1 H),
7.35 (t, J = 8.5 Hz, 1 H), 7.28 (t, J = 8.5 Hz, 1 H) 4.05 (m, 1 H), 3.74 (d,
J = 9.6 Hz, 1 H), 3.26 (dd, J = 15 and 4.0 Hz, 1 H), 3.03 (dd, J = 15 and
9.2 Hz, 1 H), 1.68 (s, 9 H), 1.01 (s, 9 H); 13C NMR δ 148.9, 134.9,
(R,RS)-1-tert-butoxycarbonyl-3-[2-((R)-tert-butanesulfinylamido)-
129.4, 124.6 (q, J = 281 Hz), 124.3, 124.2, 123.2, 117.9, 114.9, 113.8, 3,3,3-trifluoropropyl]-5-fluoroindole (6e(R)). Pale yellow viscous oil;
83.3, 57.6 (q, J = 29 Hz), 56.6, 27.6, 24.8, 21.6; 19F NMR δ −75.33 (d, 1H NMR δ 8.03 (bs, 1 H), 7.49 (s, 1 H), 7.14 (dd, J = 8.4 and 2.4 Hz, 1
J = 7.1 Hz, 3 F).
H), 7.06 (td, J = 9.2 and 2.8 Hz, 1 H), 4.16 (m, 1 H), 3.71 (d, J = 9.6
Hz, 1 H), 3.39 (dd, J = 15 and 4.0 Hz, 1 H), 3.19 (dd, J = 15 and 9.2 Hz,
1 H), 1.93 (s, 9 H), 1.34 (s, 9 H); 13C NMR δ 159.3 (d, J = 240 Hz),
149.2, 131.8, 130.9 (d, J = 9.5 Hz), 126.4, 125.1 (q, J = 282 Hz), 116.5
(d, J = 9.1 Hz), 113.9 (d, J = 4.0 Hz), 112.6 (d, J = 25 Hz), 104.2 (d, J =
24 Hz), 84.2, 57.9 (q, J = 29 Hz), 57.1, 28.2 (3 C), 25.5 (q, J = 1.9 Hz),
22.2 (3 C); 19F NMR δ −75.72 (d, J = 7.0 Hz, 3 F), −120.01 (s, 1 F).
(S,RS)-1-tert-butoxycarbonyl-3-[2-tert-butanesulfinylamido)-
3,3,3-trifluoropropyl]indole (6a(S)). Slight yellow very viscous oil; 1H
NMR δ 7.91 (m, 1 H), 7.55 (s, 1 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.26 (t, J
= 8.5 Hz, 1 H), 7.19 (t, J = 8.5 Hz, 1 H), 4.05 (quint, J = 6.8 Hz, 1H),
3.53 (d, J = 9.6 Hz, 1 H), 3.24 (dd, J = 15 and 6.0 Hz, 1 H), 3.10 (dd, J
= 15 and 6.4 Hz, 1 H), 1.59 (s, 9 H), 0.93 (s, 9 H); 19F NMR δ −75.52
(d, J = 7.1 Hz, 3 F). Analysis of the diastereomeric mixture: calcd for
(S,RS)-1-tert-butoxycarbonyl-3-[2-((R)-tert-butanesulfinylamido)-
C20H27F3N2O3S (432.50) C, 55.54; H, 6.29; N, 6.48. Found C, 55.41; H, 3,3,3-trifluoropropyl]-5-fluoroindole (6e(S)). Pale yellow oil; 1H NMR
6.34; N, 6.51.
δ 8.10 (bs, 1 H), 7.55 (s, 1 H), 7.18 (dd, J = 8.7 and 2.5 Hz, 1 H), 7.08
(td, J = 9.1 and 2.6 Hz, 1 H), 4.03 (m, 1 H), 3.55 (d, J = 7.4 Hz, 1 H),
3.22 (dd, J = 15 and 5.6 Hz, 1 H), 3.02 (dd, J = 15 and 6.8 Hz, 1 H),
1.68 (s, 9 H), 1.06 (s, 9 H); 13C NMR δ 159.3 (d, J = 239 Hz), 149.2,
131.8, 130.9 (d, J = 9.5 Hz), 126.4, 125.1 (q, J = 281 Hz), 116.5 (d, J =
9.1 Hz), 114.0 (d, J = 4.0 Hz), 112.6 (d, J = 25 Hz), 104.2 (d, J = 24 Hz),
84.2, 57.9 (q, J = 29 Hz), 57.1, 28.2 (3 C), 25.5 (q, J = 1.9 Hz), 22.2 (3
C); 19F NMR δ −74.71 (d, J = 6.7 Hz, 3 F), −120.01 (s, 1 F). Analysis of
the diastereomeric mixture: calcd for C20H26F4N2O3S (450.49) C,
53.32; H, 5.82; N, 6.22. Found C, 53.21; H, 5.90; N, 6.37.
(R,RS)-1-tert-butoxycarbonyl-3-[2-tert-butanesulfinylamido)-
3,3,3-trifluoropropyl]-5-methylindole (6b(R)). White solid, mp 77-79
1
°C; H NMR δ 8.00 (bd, J = 8.3 Hz, 1 H), 7.44 (s, 1 H), 7.27 (s, 1 H),
7.16 (d, J = 8.3 Hz, 1 H), 4.04 (m, 1 H), 3.58 (d, J = 9.6 Hz, 1 H), 3.24
(dd, J = 15 and 3.9 Hz, 1 H), 2.98 (dd, J = 15 and 9.6 Hz, 1 H), 2.47 (s,
3 H), 1.67 (s, 9 H), 1.01 (s, 9 H); 13C NMR δ 149.4, 133.7, 132.3,
130.0 (d, J = 9.5 Hz), 126.0, 125.1 (q, J = 282 Hz), 124.5, 118.3,
115.0, 114.0, 83.6, 58.2 (q, J = 29 Hz), 57.1, 28.1 (3 C), 25.3, 22.1 (3
C), 21.3; 19F NMR δ −75.34 (d, J = 7.0 Hz, 3 F).
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C7OB00670E
ARTICLE
(R,RS)-1-tert-butoxycarbonyl-3-[2-(tert-butanesulfinylamido)-
Journal Name
Analysis: calcd for C16H21F3N2O2S (362,41) C, 53.03; H, 5.84; N, 7.73.
3,3,3-trifluoropropyl]-5-(trifluoromethyl)indole (6f). Pale yellow oil; Found C, 53.17; H, 5.91; N, 7.66.
1H NMR δ 8.25 (d, J = 8.6 Hz, 1 H), 7.79 (s, 1 H), 7.61 (s, 1 H), 7.58 (d,
(R,RS)-3-[2-(tert-butanesulfinylamido)-3,3,3-trifluoropropyl]-5-
J = 8.8 Hz, 1 H), 4.02 (m, 1 H), 3.77 (d, J = 9.5 Hz, 1 H), 3.26 (dd, J =
15 and 4.3 Hz, 1 H), 3.09 (dd, J = 15 and 9.1 Hz, 1 H), 1.68 (s, 9 H),
1.03 (s, 9 H); 13C NMR δ 148.4, 136.4, 129.3, 125.9, 124.8 (q, J = 280
Hz), 124.6 (q, J = 32 Hz), 124.1 (q, J = 270 Hz), 121.0, 115.3, 115.2,
114.0, 84.2, 57.7 (q, J = 29 Hz), 56.6, 27.5 (3 C), 24.6, 21.5 (3 C); 19F
NMR δ −61.48 (3 F), −75.12 (d, J = 6.8 Hz, 3 F). Analysis: calcd for
C21H26F6N2O3S (500.50) C, 50.39; H, 5.24; N, 5.60. Found C, 50.31; H,
5.28; N, 5.69.
trifluoromethylindole (7f, 94%). White solid, mp 83-85 °C; 1H NMR
(acetone-d6) δ 10.1 (s, 1 H), 8.16 (s, 1 H), 7.59 (d, J = 8.4 Hz, 1 H),
7.56 (s, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 4.19 (m, 1 H), 3.39 (dd, J = 14
and 3.4 Hz, 1 H), 3.26 (dd, J = 14 and 11 Hz, 1 H), 2.1 (bs, 1 H), 0.83
(s, 9 H); 13C NMR (acetone-d6) δ 137.9, 130.1, 127.3, 126.5, 125.8 (q,
J = 282 Hz), 120.6, 117.7, 116.2, 111.9, 110.7, 59.5 (q, J = 28 Hz),
56.3, 24.3, 21.3 (3 C); 19F NMR (acetone-d6) δ −60.66 (s, 3 F), −75.93
(d, J = 7.3 Hz, 3 F); MS (70 eV) m/z (%) 342 (M+–C4H10, 10), 198
(100), 178 (6), 151 (8). Analysis: calcd for C16H18F6N2OS (400.38) C,
(R,RS)-1-tert-butoxycarbonyl-3-[2-(tert-butanesulfinylamido)-
3,3,3-trifluoropropyl]-6-(trifluoromethyl)indole
(6g(R)).
Viscous 48.00; H, 4.53; N, 7.00. Found C, 48.17; H, 4.62; N, 6.93.
1
yellow oil; H NMR δ 8.87 (bs, 1 H), 7.57 (s, 1 H), 7.55 (d, J = 8.2 Hz,
1 H), 7.46 (d, J = 8.2 Hz, 1 H), 3.98 (m, 1 H), 3.66 (d, J = 9.7 Hz, 1 H),
3.20 (dd, J = 15 and 4.2 Hz, 1 H), 3.01 (dd, J = 15 and 8.9, 1 H), 1.62
(s, 9 H), 0.97 (s, 9 H); 13C NMR δ 148.4, 134.0, 131.8, 126.8, 126.2 (q,
J = 32 Hz), 124.6 (q, J = 282 Hz), 124.2 (q, J = 270 Hz), 119.0 (q, J =
3.0 Hz), 118.4, 113.7, 112.5 (q, J = 4.1 Hz), 84.3, 57.6 (q, J = 29 Hz),
56.7, 27.5 (3 C), 24.6, 21.6 (3 C); 19F NMR δ −61.56 (3 F), −75.12 (d, J
= 7.1 Hz, 3 F).
Selective deprotection of the adduct 6f by removal of tert-
butanesulfinyl group.26
Iodine (25 mg, 0.05 mmol) was added to a solution of the
adduct 6f (0.25 g, 0.50 mmol) in 5:1 THF/H2O (15 mL) and the
mixture was stirred at 50 °C until the complete disappearance of
the starting material was observed (24 h, tlc, SiO2, eluent, 1:1
petroleum ether/ethyl acetate). After cooling, 1 M aqueous NaOH
(1 mL) was added and the mixture was poured into water (20 mL),
extracted with dichloromethane (3 × 25 mL) and the collected
organic phases were dried with Na2SO4. After the solvent was
evaporated at reduced pressure, chromatography of the residue on
silica gel (eluent, 6:4 petroleum ether/ethyl acetate) allowed to
(S,RS)-1-tert-butoxycarbonyl-3-[2-(tert-butanesulfinylamido)-
3,3,3-trifluoropropyl]-6-(trifluoromethyl)indole
(6g(S)).
Viscous
1
yellow oil; H NMR δ 8.41 (bs, 1 H), 7.73 (s, 1 H), 7.63 (d, J = 8.3 Hz,
1 H), 7.45 (d, J = 8.3 Hz, 1 H), 4.06 (quint, J = 5.9 Hz, 1 H), 3.71 (d, J =
7.7 Hz, 1 H), 3.26 (dd, J = 15 and 5.4 Hz, 1 H), 3.13 (dd, J = 15 and 6.4
Hz, 1 H), 1.63 (s, 9 H), 1.15 (s, 9 H); 13C NMR δ 148.5, 134.2, 132.0,
127.4, 126.2 (q, J = 32 Hz), 124.6 (q, J = 282 Hz), 124.2 (q, J = 270
Hz), 119.1, 118.8112.6, 112.5, 84.3, 57.0 (q, J = 29 Hz), 56.4, 27.6 (3
C), 25.0, 21.9 (3 C); 19F NMR δ −61.6 (3 F), −75.52 (d, J = 7.1 Hz, 3 F).
Analysis of the diastereomeric mixture: calcd for C21H26F6N2O3S
(500.50) C, 50.39; H, 5.24; N, 5.60. Found C, 50.24; H, 5.31; N, 5.72.
collect pure indole 8f
.
(R,RS)-1-(tert-butoxycarbonyl)-3-(2-amino-3,3,3-trifluoropropyl)-
5-(trifluoromethyl)-1H-indole (8f) as a pale yellow oil (0.19 g, 95%).
1H NMR δ 8.25 (d, J = 8.7 Hz, 1 H), 7.81 (s, 1 H), 7.66 (s, 1 H), 7.59 (d,
J 8.7 Hz, 1 H), 3.56 (m, 1 H), 3.20 (dd, J = 15 and 2.3 Hz, 1 H), 2.80
(dd, J = 15 and 10 Hz, 1 H), 1.70 (s, 9 H), 1.43 (bs, 2 H); 13C NMR δ
148.6, 136.6, 129.3, 125.8 (q, J = 280 Hz), 125.5, 124.5 (q, J = 32 Hz),
124.2 (q, J = 270 Hz), 120.9, 115.5, 115.2, 115.1, 84.0, 53.1 (q, J = 29
Hz), 27.6 (3C), 25.1; 19F NMR δ –61.45 (s, 3 F), –79.06 (d, J = 7.1 Hz,
Selective deprotection of the adducts 6c and 6f by removal of
tert-butoxycarbonyl (Boc) group.25
Adduct 6c (or 6f) (0.50 mmol) was added to a 1:9 dioxane/H2O 3 F). Analysis: calcd for C17H18F6N2O2 (396.33) C, 51.52; H, 4.58; N,
mixture (20 mL)and the resulting suspension was refluxed until the 7.07. Found C, 51.38; H, 4.65; N, 7.12.
starting material was completely disappeared (48 h, tlc, SiO2,
General procedure for the synthesis of tetrahydrocarbolines 9c
eluent, 1:1 petroleum ether/ethyl acetate). After cooling, the
reaction mixture was poured into water (30 mL), extracted with
dichloromethane (3 × 50 mL) and the collected organic phases were
dried with Na2SO4. After the solvent evaporation at reduced
pressure, chromatography of the crude product on silica gel (eluent,
1:1 petroleum ether/ethyl acetate) allowed to get pure indole.
and 10d
Conc. HCl (0.5 mL) was cautiously added to a solution of the
indole derivative (0.50 mmol) and the aldehyde (1.2 equiv.) and
6
the mixture was made to react at 75 °C until the starting indole was
disappeared (48 h, by tlc, SiO2, 1:3 petroleum ether/ethyl acetate).
After cooling at room temperature, aqueous 1 M KOH was added
until the pH 11-12 was reached, the mixture was extracted with
dichloromethane (3 × 20 mL) and the collected organic phases were
dried with Na2SO4. Alter the solvent was evaporated at reduced
pressure, chromatography of the residue on silica gel (eluent,
petroleum ether/ethyl acetate 1:3) allowed to get the expected
product which was characterized as follows:
(R,RS)-3-[2-(tert-butanesulfinylamido)-3,3,3-trifluoropropyl]-5-
1
methoxyindole (7c, 96%). White solid, mp 92-94 °C; H NMR δ 8.13
(bs, 1 H), 7.27 (d, J = 8.8 Hz, 1 H), 7.11 (s, 1 H), 6.99 (d, J = 2.4 Hz, 1
H), 6.87 (dd, J = 8.8 and 2.4 Hz, 1 H), 4.02 (m, 1 H), 3.88 (s, 3 H), 3.60
(d, J = 9.1 Hz, 1 H), 3.30 (dd, J = 15 and 3.4 Hz, 1 H), 3.09 (dd, J = 15
and 9.1 Hz, 1 H), 0.98 (s, 9 H); 13C NMR δ 154.2, 131.2, 127.6, 125.3
(q, J = 281 Hz), 124.4, 123.9, 112.4, 112.1, 108.9, 57.9 (q, J = 29 Hz),
56.9, 55.8, 25.4, 22.0 (3 C); 19F NMR δ −75.00 (d, J = 7.5 Hz, 3 F); MS
(70 eV) m/z (%) 304 (M+–C4H10, 20), 160 (100), 145 (21), 117 (14).
(R)-6-methoxy-3-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole (9c). (54%) From 7c (0.23 g, 0.50 mmol) and
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7OB00670E
Journal Name
ARTICLE
Gu, S. Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa and
H. Liu, Chem. Rev. 2016, 116, 422-518. (c) K. Izawa, J. L. Aceña, J.
Wang, V. A. Soloshonok and H. Liu, Eur. J. Org. Chem. 2016, 8–
16. (d) W. K. Hagmann, J. Med. Chem., 2008, 51 (15), 4359–
4369. (e) H.-J. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn,
formaldehyde (37% in H2O, 50 ꢀL, 18 mg, 0.6 mmol); White solid,
mp 60-62 °C; 1H NMR (DMSO-d6) δ 7.18 (d, J = 8.6 Hz, 1 H), 6.93 (d, J
= 1.7 Hz, 1 H), 6.67 (d, J = 8.6 and 1.7 Hz, 1 H), 3.94 (s, 2 H), 3.74 (s,
3 H), 3.6 (m, 1 H), 2.86 (dd, J = 3.2 and 14.0 Hz 1 H), 2.66 (dd, J =10.6
and 14.0 Hz, 1 H); 13C NMR (DMSO-d6) δ 153.5, 134.8, 131.2, 127.6,
127.0 (q, J = 278 Hz), 111.9, 110.6, 104.9, 100.0, 55.7, 55.2 (q, J = 28
Hz), 42.3, 21.8; 19F NMR (DMSO-d6) δ −75.16 (t, J = 3.5 Hz, 3 F). MS
(70 eV) m/z (%) 270 (M+, 81), 199 (15)173 (100), 158 (77), 130 (11).
Analysis: calcd for C13H13F3N2O (270,26) C, 57.78; H, 4.85; N, 10.37.
Found C, 57.59; H, 5.00; N, 10.22.
K. Müller, U. Obst-Sander and M. Stahl, ChemBioChem 2004, 5,
637–643.
5
For books, see: (a) “Fluorinated Pharmaceuticals: Advances in
Medicinal Chemistry” A. D Westwell Ed., Future Science, 2015.
(b) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly and N. A.
Meanwell, J. Med. Chem. 2015, 58 (21), 8315–8359. (c)
“Fluorine in Pharmaceutical and Medicinal Chemistry: From
Biophysical Aspects to Clinical Applications” V. Gouverneur,
Klaus Muller Eds. 1st Edition, Imperial College Press, 2012. (d)
“Fluorine in Medicinal Chemistry and Chemical Biology” I. Ojima
Ed., Wiley, 2009. J.-P. Bégué, D. Bonnet-Delpon, “Bioorganic and
Medicinal Chemistry of Fluorine” 1st Edition, Wiley, 2008. (e)
“Fluorine and Health” A. Tressaud, G. Haufe Eds., Elsevier, 2008.
W. Zhu, J. Wang, S. Wang, Z. Gu, J. L. Aceña, K. Izawa, H. Liu and
V. A. Soloshonok, J. Fluorine Chem., 2014, 167, 37–54.
(1R,3R)- and (1S,3R)-(R)-6-chloro-3-(trifluoromethyl)-2,3,4,9-
tetrahydro-1-(pyrid-3-yl)-1H-pyrido[3,4-b]indole (10d) (63%). From
7d (0.23 g, 0.5 mmol) and 3-pyridinecarbaldehyde (65 mg, 0.61
mmol). Diastereomeric mixture of (1R,3R)-10d and (1S,3R)-10d, dr =
2.2 (from the integral of the signals at δ −74.98 and −74.63,
respectively, in the 19F NMR spectrum of the crude reaction
mixture). white solid, mp > 300 °C. (1R,3R)-10d: 1H NMR (DMSO-d6)
δ 10.74 (s, 1 H), 8.63 (s, 1 H), 8.55 (d, J = 4,4 Hz, 1 H), 8.51 (s, 1 H),
7.74 (d, J = 7.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz), 7.42 (dd, J = 8.1 and 4.4
Hz, 1 H), 7.23(d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.6 Hz, 1 H), 5.31 (s, 1
H), 3.87 (m, 1 H), 3.5 (bs, 1 H), 2.9 (m, 2 H); 13C NMR (DMSO-d6) δ
150.4, 149.5, 137.0, 136.9, 136.8, 135.2, 128.0, 126.6 (q, J = 276 Hz),
124.1, 123.7, 121.4, 117.6, 113.1, 106.7, 55.5 (q, J = 23 Hz), 55.3,
6
7
For reviews, see: (a) S. Fioravanti, Tetrahedron, 2016, 72, 4449–
4489. (b) H. Mei, C. Xie, J. Han and V. A. Soloshonok, Eur. J. Org.
Chem. 2016, 5917–5932. (c) H. Mei, C. Xie, J. L Aceña, V. A.
Soloshonok, G.-V. Röschenthaler and J. Han, Eur. J. Org. Chem.
2015, 6401-6412. (d) J. Han, A. E. Sorochinsky, T. Ono and V. A.
Soloshonok, Current Organic Synthesis, 2011, 8, 281-294. (e) L.
Zhang, W. Zhang, W. Sha, H. Mei, J. Han and V. A. Soloshonok, J.
Fluorine Chem., 2017, DOI: 10.1016/j.jfluchem.2016.12.007.
(a) L. Wu, C. Xie, H. Mei, V. A. Soloshonok, J. Han and Y. Pan, J.
Org. Chem. 2014, 79, 7677−7681. (b) L. Wu, C. Xie, J. Zhou, H.
Mei, V. A. Soloshonok, J. Han and Y. Pan, J. Fluorine Chem.,
2015, 170, 57-65.
8
9
21.7; 19F NMR (DMSO-d6) δ −74.98 (d, J = 7.8 Hz). (1S,3R)-10d 1H
:
NMR δ 11.14 (s, 1 H), 8.6 (s, 1 H), 8.55 (d, J = 4,4 Hz, 1 H), 8.50 (s, 1
H), 7.61 (d, J = 8 Hz, 1 H), 7.57 (d, J = 8 Hz, 1 H), 7.37 (dd, J = 8.1 and
4.4 Hz, 1 H), 7.33(d, J = 8.5 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 1 H), 5.33 (s,
1 H), 3.72 (m, 1 H), 3.5 (bs, 1 H), ), 3.03 (dd, J = 16 and 5.3 Hz, 1 H),
2.76 (dd, J = 16 and 10 Hz, 1 H); 13C NMR δ 149.9, 148.9, 137.6,
137.0, 136.1, 135.6, 134.9, 127.0 (q, J = 276 Hz), 123.9, 123.7, 121.6,
117.7, 113.1, 107.0, 52.0, 50.8 (q, J = 28 Hz), 21.4; 19F NMR δ −74.63
(d, J = 7.8 Hz). Analysis of the diastereomeric mixture: calcd for
C17H13ClF3N3 (351.76) C, 58.05; H, 3.73; N, 11.95. Found C, 58.13; H,
3.82; N, 12.10.
(a) G.-L. Cheng, H. Wang, X.-F. Lin and Q. Wu, Current Org.
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Resnati, Tetrahedron Lett. 1993, 34, 3621-3624.
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