Synthesis of Branched Tryptamines via the Domino Cloke-Stevens/Grandberg Rearrangement

Article abstract of DOI:10.1021/acs.joc.6b02578

The rearrangement of cyclopropylketone arylhydrazones generated in situ from arylhydrazine hydrochlorides and ketones leads to formation of tryptamine derivatives. The use of (2-arylcyclopropyl)ethanones in the reactions with model 4-bromophenylhydrazine hydrochloride gives branched tryptamines with aryl groups in the α-position to the amino group, while (2-methylcyclopropyl)ethanone gives a mixture of α- and β-substituted products in a ratio of 1:3. The method was found effective in the synthesis of enantiomerically pure tryptamine. Thus, (R,R)-(2-phenylcyclopropyl)ethanone gives the (S)-α-phenyltryptamine derivative with an enantiomeric excess over 99%.

Full text of DOI:10.1021/acs.joc.6b02578

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Note
Synthesis of branched tryptamines via the
domino Cloke–Stevens/Grandberg rearrangement
Rinat F Salikov, Konstantin P. Trainov, Anastasia A Levina,
Irina K Belousova, Michael G Medvedev, and Yury V. Tomilov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02578 • Publication Date (Web): 08 Dec 2016
Downloaded from http://pubs.acs.org on December 9, 2016
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Synthesis of branched tryptamines via the domino Cloke–Stevens/Grandberg
rearrangement
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Rinat F. Salikov,a Konstantin P. Trainov,a,b Anastasia A. Levina,a,b Irina K. Belousova,a,c
Michael G. Medvedev,d Yury V. Tomilova*
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a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky
prospect, 119991 Moscow, Russian Federation, Tel./fax: +7ꢀ499ꢀ135ꢀ63ꢀ90; eꢀmail:
tom@ioc.ac.ru
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b Higher Chemical College, Russian Academy of Sciences, Moscow, Russian Federation
c Moscow Chemical Lyceum, 4 Tamozhennyj Proezd, 111033 Moscow, Russian Federation
d A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
Moscow, Russian Federation
A B S T R A C T
The rearrangement of cyclopropylketone arylhydrazones generated in situ from arylhydrazine
hydrochlorides and ketones leads to formation of tryptamine derivatives. The use of (2ꢀ
arylcyclopropyl)ethanones in the reactions with model 4ꢀbromophenylhydrazine hydrochloride gives
branched tryptamines with aryl groups in the αꢀposition to amino group, while (2ꢀ
methylcyclopropyl)ethanone gives a mixture of αꢀ and βꢀsubstituted products in a ratio of 3:1. The
method was found effective in the synthesis of enantiomerically pure tryptamine. Thus, (R,R)ꢀ(2ꢀ
phenylcyclopropyl)ethanone gives (S)ꢀαꢀphenyltryptamine derivative with an enantiomeric excess over
99%.
Keywords: branched tryptamine derivatives, Fischer indole synthesis, Grandberg rearrangement, Clokeꢀ
Stevens rearrangement, cyclopropyl ketones
Tryptamine derivatives possess high potential for the treatment of various diseases ranging
from migraine1 and obesity2 to tumors3–5. Nevertheless, the application of many amines in
pharmaceutics is limited to a large extent by their ready degradation in an organism by such
enzymes as monoamine oxydase.6 The chain branching in amines is known to be one of the
methods to reduce the rate of drug metabolism.7 The majority of known methods for the
synthesis of branched tryptamines so far are based on modifications of indole derivatives.8–17
There are scarce methods to construct a substituted aminoethylene fragment and an indole ring
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simultaneously. Thus, the tandem hydroformylation/Fischer indole synthesis starting from
branched amino olefins and arylhydrazines gives branched tryptamines.18 Tricyclic constrained
tryptamine analogues are available via Fisher indolization of arylhydrazines and chiral bicyclic
imines.19
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Recently20 we have given a report on a new approach to tryptamines via ClokeꢀStevens21,22
and subsequent Grandberg23 rearrangements of cyclopropylethanone arylhydrazones, wherein 4ꢀ
bromophenylhydrazones demonstrated higher yields of tryptamines. With regard to our previous
investigations
on
the
cyclopropyliminium
(Cloke–Stevens)
rearrangement
of
cyclopropylazoles24–26 including those27 substituted at the cyclopropyl moiety, we assumed, that
cyclopropyl methyl ketone arylhydrazones substituted at the small cycle rearrange into branched
tryptamines. The substituted ketones are easily available via the subsequent aldol condensation28
and CoreyꢀChaykovsky29 cyclopropanation.
In the previous studies we have found that the rearrangement proceeds using cyclopropyl
methyl ketone and either arylhydrazine hydrochloride or free arylhydrazine as starting material,
the latter requiring addition of ammonium iodide, in either ethanol or acetonitrile.5,20 The use of
arylhydrazine and NH4I gave lower yield of desired tryptamines and increased the yield of
undesired tetrahydropyridazines. Although the reaction is slower in acetonitrile due to both the
poor solubility of starting hydrochloride and its aprotic properties this protocol is appealing since
in most cases the product is separated by filtration.
The mechanism20 that we suggested previously for the rearrangement of cyclopropylketone
arylhydrazones formed in situ from the corresponding ketones and arylhydrazine hydrochlorides
involves nucleophilic ringꢀopening of cyclopropane by chlorideꢀanion with subsequent ringꢀ
closure to give fiveꢀ or sixꢀmembered cycles. Herein, when 2ꢀsubstituted cyclopropylketones are
introduced into the reaction (Table 1) the ringꢀopening can proceed via attack at two inequivalent
carbon atoms in the cycle (paths a and b). However the use of 2ꢀarylcyclopropylethanones 1a–f
as starting material leads to ringꢀopening in intermediate 2 at the more substituted carbon atom
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(path a) to give γꢀchloroketone arylhydrazones 3 while path b is not realized. Subsequent
cyclization gives tetrahydropyridazines 4a–i as minor products and arylaminopyrrolines 5, which
in turn undergo a Fischerꢀtype rearrangement into tryptamine derivative hydrochlorides 6a–i as
major products. It is worth noting that the formation of only trace amounts of
tetrahydropiridazines 4e,f,i is observed, while the yields of compounds 4a–d,g,h are 5–19%, all
products 4 tending to resinification.
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Table 1. Rearrangement of 2ꢀarylcyclopropylketone 4ꢀbromophenylhydrazones into tryptamines and
tetrahydropyridazines.
Entry
Ketone R1
R2
Br
Br
Products (yield, %)a
1
2
3
4
5
6
7
8
9
Ph
6a (62)
4a (5)
1a
1b
1c
1d
1e
4ꢀMeC6H4
6b (68)
6c (51)
6d (50)
6e (57)
6f (66)
6g (49)
6h (76)
6i (42)
4b (9)
4ꢀMeOC6H4 Br
4c (12)
Br
Br
4ꢀFC6H4
4d (19)
6e (traces)
6f (traces)
4g (11)
4ꢀClC6H4
2,4ꢀCl2C6H3 Br
1f
1a
Ph
Ph
Ph
F
1a
1a
H
4h (12)
6i (traces)
Me
a Yields are given after purification by column chromatography.
Concerning the reaction scope, the method is most useful for the synthesis of 5ꢀsubstituted
tryptamines. However, an approach to other derivatives has been developed via regiocontrol in
the Grandberg rearrangement by protection of an oꢀposition in arylhydrazines with bromine.30 It
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is also noteworthy that strong electronꢀwithdrawing groups in the aromatic moiety reduce the
cyclopropane ringꢀopening, as we have shown previously.20
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In contrast to arylated derivatives, (2ꢀmethylcyclopropyl)ethanone (1g) hydrazone rearranged
with ringꢀopening proceeding preliminary at the less substituted carbon atom (path b) into βꢀ
substituted tryptamine and minor formation of αꢀsubstituted tryptamine. The products were
converted into acylated derivatives 7 and 8 (Scheme 1) and the use of HPLC was required to
separate the mixture. The introduction of methyl 2ꢀacetylcyclopropanecarboxylate into the
reaction did not give the desired tryptamine. It is worth mentioning, that besides NMR
spectroscopy the αꢀ and βꢀsubstituted tryptamines are easily distinguished by massꢀspectrometry,
namely, by the presence of a specific Cα–Cβ fragmentation pattern.
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Scheme 1. Rearrangement of (2ꢀmethylcyclopropyl)ethanone 4ꢀbromophenylhydrazone into a mixture of
αꢀ and βꢀmethylated tryptamines 7 and 8.
We have also applied this approach in the synthesis of an optically pure tryptamine derivative.
The reaction of (R,R)ꢀ1a (ee >99%) with 4ꢀbromophenylhydrazine hydrochlorides and
subsequent acylation of tryptamine hydrochloride (S)ꢀ6a obtained led to formation of acylated
tryptamine (S)ꢀ9 with an enantiomeric excess over 99% (Scheme 2). Direct acylation of the
reaction mixture without separation of (S)ꢀ6a gave a higher yield (72%) of acylated tryptamine 9,
but with lower enantiomeric excess (92%) of (S)ꢀ9. It is worth noting that in this case double
inversion of a carbon atom which is implied by the mechanism proposed changes configuration
from (R) to (S) due to the CIP priority change. The absolute configuration was determined on the
basis of single crystal Xꢀray data.
Scheme 2. Transformation of (R,R)ꢀ1a into (S)ꢀαꢀphenyltryptamine (S)ꢀ6a, and further into (S)ꢀ9.
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Thus we have developed a new method for the synthesis of αꢀarylated tryptamines based on
the rearrangement of (2ꢀarylcyclopropyl)ethanone arylhydrazones. The introduction of
cyclopropyl ketone containing a methyl group into the reaction gave a mixture of isomers with
predominant formation of βꢀsubstituted derivative. We have also demonstrated the potential of
our method in the synthesis of an optically pure αꢀphenyltryptamine derivative from a chiral
ketone.
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Experimental section
1
13
General. H NMR, C NMR and 19F NMR spectra were recorded at 300, 75 and 282 MHz,
respectively, in CDCl3 or DMSOꢀd6 with tetramethylsilane as an internal reference standard. The
NMR signal assignment was accomplished using DEPT, COSY, HSQC, HMBC spectra. High
resolution mass spectra (HRMS) were recorded using an ESIꢀTOF spectrometer. Column
chromatography was performed with SiO2 (230−400 mesh). Unless noted otherwise, all of the
reagents were obtained from commercial suppliers and used without additional purification.
DCM was preliminary distilled over NaOH. 2ꢀArylcyclopropylethanones,29 arylidenacetones,28
2ꢀmethylcyclopropylethanone,31 and (R,R)ꢀ2ꢀphenylcyclopropylethanone32,33 were synthesized
according to the literature procedures.
The Xꢀray crystal structure analysis of (S)ꢀ9 was made on a diffractometer with a CCD
detector (MoKα radiation, λ = 0.71073 Å, graphite monochromator, T = 120 K, 2θmax = 61.4°).
The structure was solved in Olex2,34,35 with the ShelXT36 structure solution program using
Direct Methods and refined with the ShelXL36,37 refinement package using Least Squares
minimization. Absorption correction was performed by multiꢀscan method implemented in
SADABS38. The absolute configuration of the only stereocenter was determined to be S by
anomalous dispersion (Flack parameter: 0.005(4)). Nonꢀhydrogen atoms were refined
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anisotropically. Crystal data for (S)ꢀ9: C19H19BrN2O (M = 122.94 g/mol): monoclinic, space
group P21 (no. 4), a = 8.1146(11) Å, b = 19.140(3) Å, c = 11.5187(16) Å, β = 110.431(3), V =
1676.5(4) Å3, Z = 4, T = 120 K, ꢁ(MoKα) = 12.607 mm–1, Dcalc = 2.557 g/cm3, 23329
reflections measured (3.774 ≤ 2Θ ≤ 61.432), 10315 unique (Rint = 0.0445, Rsigma = 0.0837) which
were used in all calculations. The final R1 was 0.0384 (I > 2σ(I)) and wR2 was 0.0776 (all data).
Crystal structure has been deposited with Cambridge Crystallographic Data Center (CCDC
reference number 1496493).
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General Procedure for the Preparation of 2-Arylcyclopropylethanones 1. Potassium tertꢀ
butoxide (9.9 mmol) was added to a solution of Me3SOI (9.1 mmol) in anhydrous DMSO (20
mL) and the mixture stirred for 0.5 h. Arylideneacetone (8.3 mmol) was added and the mixture
stirred for 3 h. The reaction mixture was treated with water and extracted with CH2Cl2. The
organic layer was washed with water, brine, dried over anhydrous Na2SO4, and evaporated.
Column chromatography on SiO2 (chloroform–hexanes, 2:1) gave the desired product.
1-(2-(4-Methoxyphenyl)cyclopropyl)ethanone (1c). Colorless oil (0.91 g, 58%). IR (KBr)
3002, 2957, 2836, 1696, 1516, 1249 cm–1. MS (m/z (rel intens, %)) 190 (38, M+), 147 (100), 132
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(9), 115 (12), 91 (18). HRMS: calcd for C12H15O2 M+H, 191.1067, found: m/z 191.1067. H
NMR (300 MHz, CDCl3): δ 7.10–6.96 (m, 2H, H(2,6)), 6.90–6.78 (m, 2H, H(3,5)), 3.79 (s, 3H,
MeO), 2.50 (ddd, 1H, CHAr, J = 9.2, 6.7, 4.1 Hz), 2.30 (s, 3H, Me), 2.15 (ddd, 1H, CHAc, J =
8.2, 5.0, 4.1 Hz), 1.64 (ddd, 1H, CH2, J = 9.2, 5.0, 4.3 Hz), 1.33 (ddd, 1H, CH2, J = 8.2, 6.7, 4.3
Hz). 13C NMR (75 MHz, CDCl3): δ 207.0 (CO), 158.5 (C(4)), 132.4 (C(1)), 127.3 (C(2,6)),
114.1 (C(3,5)), 55.4 (MeO), 32.8 (CHAc), 30.8 (Me), 28.7 (CHAr), 18.9 (CH2).
1-(2-(4-Chlorophenyl)cyclopropyl)ethanone (1e). Colorless oil (1.05 g, 65%). IR (KBr)
3005, 2923, 1699, 1496, 1393 cm–1. MS (m/z (rel intens, %)) 194, 196 (63, M+), 151, 153 (100),
144 (14), 116 (39), 115 (52). HRMS: calcd for C11H12ClO M+H, 195.0571, found: m/z 195.0570.
1H NMR (300 MHz, CDCl3): δ 7.27–7.22 (m, 2H, H(3, 5)), 7.05–6.99 (m, 2H, H(2, 6)), 2.50
(ddd, 1H, CHAr, J = 9.1, 6.6, 4.1 Hz), 2.30 (s, 3H, Me), 2.18 (ddd, 1H, CHAc, J = 8.3, 5.2, 4.1
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Hz), 1.66 (ddd, 1H, CH2, J = 9.4, 5.2, 4.4 Hz), 1.33 (ddd, 1H, CH2, J = 8.3, 6.6, 4.4 Hz). 13C
NMR (75 MHz, CDCl3): δ 206.5 (CO), 139.0 (C(4)), 132.3 (C(1)), 128.7 (C(3, 5)), 127.5 (C(2,
6)), 32.8 (CHAc), 30.9 (Me), 28.3 (CHAr), 19.1 (CH2).
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1-(2-(2,4-Dichlorophenyl)cyclopropyl)ethanone (1f). Colorless oil (1.18 g, 62%). IR (KBr)
3007, 2920, 1699, 1479, 1396 cm–1. MS (m/z (rel intens, %)) 228, 230 (100, M+), 185, 187 (85),
178, 180 (33), 150, 152 (57), 149, 151 (51), 115 (50). HRMS: calcd for C11H11Cl2O M+H,
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229.0181, found: m/z 229.0184. H NMR (300 MHz, CDCl3): δ 7.38 (d, 1H, H(3), J = 2.1 Hz),
7.17 (dd, 1H, H(5), J = 8.3, 2.1 Hz), 6.97 (d, 1H, H(6), J = 8.3 Hz), 2.63 (ddd, 1H, CHAr, J =
8.9, 7.0, 4.4 Hz), 2.34 (s, 3H, Me), 2.07–2.00 (m, 1H, CHAc), 1.71–1.64 (m, 1H, CH2), 1.36
(ddd, 1H, CH2, J = 7.9, 7.0, 4.4 Hz). 13C NMR (75 MHz, CDCl3): δ 206.5 (CO), 136.6 and 136.5
(C(1) and C(4)), 133.2 (C(2)), 129.3 (C(3)), 128.4 (C(6)), 127.2 (C(5)), 31.2 (CHAc), 30.8 (Me),
26.7 (CHAr), 16.9 (CH2).
General Procedure for the Preparation of Tryptamines 6 and Tetrahydropyridazines 4.
A mixture of arylhydrazine hydrochloride (1.2 mmol) and 2ꢀarylcyclopropylethanone 1a–f (1.56
mmol) in acetonitrile (10 mL) was heated at reflux for 16 h. Tryptamines 6a,b,d–g precipitated
and were filtered, while derivatives 6c,h–i were extracted with water from the mixture diluted
with chloroform. Tryptamines 6a–i contaminated with NH4Cl were additionally purified by flash
column chromatography (CHCl3–EtOH, 4:1). The organic phases (filtrates or extracts) were
evaporated and subjected to column chromatography (CHCl3–hexane, 2:1) to give
tetrahydropyridazines 4a–d,g,h.
2-(5-Bromo-2-methyl-1H-indol-3-yl)-1-phenylethan-1-aminium chloride (6a). Colorless
crystals (0.27 g, 62%), mp: 151–153°C. IR (KBr) 3459, 2958, 2911, 1608, 1502, 1465 cm–1. MS
(m/z (rel intens, %)) 223, 225 (21, C10H10BrN+), 222, 224 (15, C10H9BrN+), 143 (14, C10H9N+),
+
106 (100, CHPhNH2 ). HRMS: calcd for C17H18BrN2 M – Cl, 329.0648, 331.0627, found m/z
1
+
329.0639, 331.0622. H NMR (300 MHz, DMSOꢀd6): δ 11.00 (s, 1H, NH), 8.84 (s, 3H, NH3 ),
7.56 (d, 1H, H(4), J = 1.5 Hz), 7.24–7.38 (m, 5H, Ph), 7.16 (d, 1H, H(7), J = 8.5 Hz), 7.05 (dd,
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1H, H(6), J = 8.5, 1.5 Hz), 4.20–4.33 (m, 1H, CH), 3.42 (dd, 1H, CH2, J = 14.0, 4.1 Hz), 3.08
(dd, 1H, CH2, J = 14.0, 10.4 Hz), 1.82 (s, 3H, Me). 13C NMR (75 MHz, DMSOꢀd6): δ 137.8 (iꢀ
Ph), 135.3 (C(2)), 133.7 (C(5)), 130.0 (C(7a)), 128.3, 127.4 (oꢀ,mꢀPh), 128.2 (pꢀPh), 122.4
(C(6)), 119.6 (C(4)), 112.3 (C(7)), 111.0 (C(3a)), 104.3 (C(3)), 55.3 (CH), 30.3 (CH2), 10.7
(Me).
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2-(5-Bromo-2-methyl-1H-indol-3-yl)-1-(p-tolyl)ethan-1-aminium chloride (6b). Colorless
crystals (0.31 g, 68%), mp: 169–171°C. IR (KBr) 3417, 3346, 2921, 2887, 1627, 1518, 1470 cm–
1. MS (m/z (rel intens, %)) 223, 225 (7, C10H10BrN+), 222, 224 (8, C10H9BrN+), 143 (7,
C10H9N+), 120 (100, CH(C7H7)NH2 ). HRMS: calcd for C18H20BrN2 M – Cl, 343.0804,
+
345.0785, found m/z 343.0792, 345.0778. 1H NMR (300 MHz, DMSOꢀd6): δ 11.02 (s, 1H, NH),
+
8.80 (s, 3H, NH3 ), 7.46 (d, 1H, 1H, H(4), J = 0.8 Hz), 7.19 (d, 2H, H(2´,6´), J = 7.8 Hz), 7.15
(d, 1H, H(7), J = 8.6 Hz), 7.10 (d, 2H, H(3´,5´), J = 7.8 Hz), 7.04 (dd, 1H, H(6), J = 8.6, 0.8 Hz),
4.21 (br.s, 1H, CH), 3.41 (m, 1H, Ha from CH2), 3.06 (dd, 1H, Hb from CH2, J = 13.1, 10.7 Hz),
2.27 (s, 3H, ArMe), 1.88 (s, 3H, Me). 13C NMR (75 MHz, DMSOꢀd6): δ 137.6 (C(1´)), 135.3
(C(2)), 134.8 (C(4´)), 133.7 (C(5)), 130.0 (C(7a)), 128.8 (C(3´, 5´)), 127.4 (C(2´,6´)), 122.3
(C(6)), 119.6 (C(4)), 112.2 (C(7)), 111.0 (C(3a)), 104.4 (C(3)), 55.1 (CH), 30.3 (CH2), 20.7
(ArMe), 10.8 (Me).
2-(5-Bromo-2-methyl-1H-indol-3-yl)-1-(4-methoxyphenyl)ethan-1-aminium
chloride
(6c). Colorless crystals (0.24 g, 51%), mp: 97–99°C. IR (KBr) 3410, 2912, 1610, 1512, 1248
cm–1. MS (m/z (rel intens, %)) 223, 225 (7, C10H10BrN+), 222, 224 (16, C10H9BrN+), 143 (6,
+
C10H9N+), 136 (100, CH(MeOC6H4)NH2 ). HRMS: calcd for C18H20BrN2O M – Cl, 359.0754,
361.0734, found m/z 359.0758, 361.0740. 1H NMR (300 MHz, DMSOꢀd6): δ 11.02 (s, 1H, NH),
+
8.76 (s, 3H, NH3 ), 7.50 (d, 1H, H(4), J = 1.5 Hz), 7.25 (d, 2H, H(2´,6´), J = 8.6 Hz), 7.15 (d, J =
8.5 Hz, 1H, H(7)), 7.04 (dd, J = 8.5, 1.5 Hz, 1H, H(6)), 6.86 (d, 2H, H(3´,5´), J = 8.6 Hz), 4.27–
4.15 (m, 1H, CH), 3.72 (s, 3H, MeO), 3.39 (dd, 1H, Ha from CH2, J = 13.7, 3.6 Hz), 3.06 (dd,
1H, Hb from CH2, J = 13.7, 10.5 Hz), 1.90 (s, 3H, Me); 13C NMR (75 MHz, DMSOꢀd6): δ 159.3
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(C(4´)), 135.3 (C(2)), 133.7 (C(5)), 130.0 (C(7a)), 129.7 (C(1´)), 128.8 (C(2´, 6´)), 122.3 (C(6)),
119.7 (C(4)), 113.7 (C(3´,5´)), 112.2 (C(7)) 111.0 (C(3a)), 104.5 (C(3)), 55.1 (MeO), 54.9 (CH),
30.3 (CH2), 10.9 (Me).
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Colorless crystals (0.23 g, 50%), decomp. over 200°C. IR (KBr) 3405, 2852, 1517, 1470,
1224 cm–1. MS (m/z (rel intens, %)) 223, 225 (45, C10H10BrN+), 222, 224 (46, C10H9BrN+), 143
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(20, C10H9N+), 124 (100, CH(FC6H4)NH2 ). HRMS: calcd for C17H17BrFN2 M – Cl, 347.0554,
+
349.0533, found m/z 347.0560, 349.0536. 1H NMR (300 MHz, DMSOꢀd6): δ 11.02 (s, 1H, NH),
+
8.85 (s, 3H, NH3 ), 7.50 (d, 1H, H(4), J = 1.7 Hz), 7.38 (dd, 2H, H(3´,5´), J = 8.6, 5.5 Hz), 7.16
(d, 1H, H(7), J = 8.4 Hz), 7.13 (d, 2H, H(2´,6´), J = 10.1 Hz), 7.05 (dd, 1H, H(6), J = 8.4, 1.7
Hz), 4.39–4.22 (m, 1H, CH), 3.42 (m, 1H, Ha from CH2), 3.08 (dd, 1H, Hb from CH2, J = 13.9,
10.4 Hz), 1.90 (s, 3H, Me). 13C NMR (75 MHz, DMSOꢀd6): δ 162.0 (d, C(4´), J = 244.5 Hz),
135.3 (C(2)), 134.1 (d, C(1´), J = 3.0 Hz), 129.9 (C(7a)), 129.7 (d, C(2´,6´), J = 8.3 Hz), 122.4
(C(6)), 119.6 (C(4)), 115.1 (d, C(3´,5´), J = 21.4 Hz), 112.3 (C(7)), 111.1 (C(3a)), 104.2 (C(3)),
54.7 (CH), 30.3 (CH2), 10.8 (Me). 19F NMR (282 MHz, DMSOꢀd6): δ –113.8 (m).
2-(5-Bromo-2-methyl-1H-indol-3-yl)-1-(4-chlorophenyl)ethan-1-aminium chloride (6e).
Colorless crystals (0.27 g, 57%), mp: 274–277°C. IR (KBr) 3362, 2983, 2807, 1593, 1511, 1498
cm–1. MS (m/z (rel intens, %)) 223, 225 (90, C10H10BrN+), 222, 224 (86, C10H9BrN+), 142 (33)
+
and 140 (100, CH(ClC6H4)NH2 ). HRMS: calcd for C17H17BrClN2 M – Cl, 363.0258, 365.0237,
367.0209, found m/z 363.0244, 365.0234, 367.0209. 1H NMR (300 MHz, DMSOꢀd6): δ 11.04 (s,
+
1H, NH), 8.91 (s, 3H, NH3 ), 7.49 (d, 1H, H(4), J = 1.8 Hz), 7.41–7.31 (m, 4H, C6H4), 7.16 (d,
1H, H(7), J = 8.5 Hz), 7.05 (dd, 1H, H(6), J = 8.5, 1.8 Hz), 4.31 (m, 1H, CH), 3.41 (dd, 1H, Ha
from CH2, J = 14.0, 4.2 Hz), 3.08 (dd, 1H, Hb from CH2, J = 14.0, 10.4 Hz), 1.90 (s, 3H, Me).
13C NMR (75 MHz, DMSOꢀd6): δ 136.9 (C(4´)), 135.3 (C(2)), 133.7 (C(5)), 133.0 (C(1´)), 129.9
(C(7a)), 129.4 and 128.2 (C(2´,3´,5´,6´)), 122.4 (C(6)), 119.6 (C(4)), 112.3 (C(7)), 111.1 (C(3a)),
104.1 (C(3)), 54.6 (CH), 30.1 (CH2), 10.8 (Me).
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chloride
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(6f). Colorless crystals (0.34 g, 66%), mp: 184–187°C. IR (KBr) 3372, 2919, 2869, 1590, 1513,
1475 cm–1. MS (m/z (rel intens, %)) 400 (3), 398 and 396 (6, M – Cl), 223, 225 (68,
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C10H10BrN+), 222, 224 (66, C10H9BrN+), 176 (63) and 174 (100, CH(Cl2C6H3)NH2 ), 143 (40,
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+
C10H9N+), 147 (24) and 145 (41, C6H3Cl2 ). HRMS: calcd for C17H16BrCl2N2 M – Cl, 396.9868,
398.9847, found: m/z 396.9853, 398.9835. 1H NMR (300 MHz, DMSOꢀd6): δ 11.04 (s, 1H, NH),
+
8.96 (s, 3H, NH3 ), 8.07 (d, 1H, H(6´), J = 8.4 Hz), 7.58 (dd, 1H, H(5´), J = 8.4, 1.8 Hz), 7.46 (d,
1H, H(4), J = 1.7 Hz), 7.40 (d, 1H, H(3´), J = 1.8 Hz), 7.15 (d, 1H, H(7), J = 8.5 Hz), 7.03 (dd,
1H, H(6), J = 8.5, 1.7 Hz), 4.75 (dd, 1H, CH, J = 9.6, 4.5 Hz), 3.44 (dd, 1H, Ha from CH2, J =
14.0, 4.5 Hz), 3.14 (dd, 1H, Hb from CH2, J = 14.0, 9.6 Hz), 2.01 (s, 3H, Me). 13C NMR (75
MHz, DMSOꢀd6): δ 135.4 (C(2)), 134.9 (C(4´)), 133.9 (C(5)), 133.8 and 133.7 (C(1´) and C(2´)),
130.2 (C(7a)), 130.0 (C(6´)), 128.6 (C(3´)), 127.8 C(5´)), 122.4 (C(6)), 119.3 (C(4)), 112.2
(C(7)), 111.0 (C(3a)), 103.4 (C(3)), 50.8 (CH), 29.5 (CH2), 10.9 (Me).
2-(5-Fluoro-2-methyl-1H-indol-3-yl)-1-phenylethan-1-aminium chloride (6g). Colorless
crystals (0.18 g, 49%), mp: 234–236°C. IR (KBr) 3415, 3342, 3011, 2910, 1584, 1487 cm–1. MS
(m/z (rel intens, %)) 268 (2, M+–HCl) 163 (30, C10H10FN+), 162 (43, C10H9BrN+), 161 (16,
C10H8BrN+), 106 (100, C7H8N+). HRMS: calcd for C17H18FN2 M – Cl, 269.1449, found: m/z
1
269.1438. H NMR (300 MHz, DMSOꢀd6): δ 10.87 (s, 1H, NH), 8.53 (s, 3H, NH3), 7.36 – 7.26
(m, 5H, Ph), 7.21 (dd, 1H, H(4), J = 10.3, 2.4 Hz), 7.17 (dd, 1H, H(6), J = 8.8, 4.6 Hz), 6.77 (m,
1H, H(6)), 4.26 (dd, 1H, CHPh, J = 9.9, 4.4 Hz), 3.40 (dd, 1H, Ha from CH2, J = 13.9, 4.4 Hz),
3.07 (dd, 1H, Hb from CH2, J = 13.8, 9.9 Hz), 1.84 (s, 3H, Me). 13C NMR (75 MHz, DMSOꢀd6):
δ 156.7 (d, C(5), J = 230.3 Hz), 138.6 (iꢀPh), 135.7 (C(2)), 131.7 (C(7a)), 128.51 (d, C(3a), J =
9.9 Hz), 128.2, 127.4 (oꢀ,mꢀPh), 128.0 (pꢀPh), 111.1 (d, C(7), J = 9.8 Hz), 107.7 (d, C(6), J =
25.9 Hz), 105.0 (d, C(3), J = 4.4 Hz), 102.3 (d, C(4), J = 23.4 Hz), 55.4 (CH), 30.8 (CH2), 10.8
(Me). 19F NMR (282 MHz, DMSOꢀd6): δ –126.5 (m).
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2-(2-Methyl-1H-indol-3-yl)-1-phenylethan-1-aminium chloride (6h). Colorless crystals
(0.27 g, 76%), mp: 97–99°C. IR (KBr) 3400, 3337, 3029, 2912, 1601, 1462 cm–1. MS (m/z (rel
intens, %)) 250 (4, M+–HCl) 145 (30, C10H11N+), 144 (98, C10H10N+), 143 (28, C10H9N+), 106
(100, C7H8N+). HRMS: calcd for C18H21BrN2 M – Cl, 251.1543, found: m/z 251.1547. 1H NMR
(300 MHz, DMSOꢀd6): δ 10.72 (s, 1H, NH), 7.46 (d, 1H, H(4), J = 7.5 Hz), 7.33 – 7.25 (m, 5H,
Ph), 7.21 (d, 1H, H(7), J = 7.6 Hz), 6.97 (t, 1H, H(6), J = 7.6 Hz), 6.94 – 6.88 (m, 1H, H(5)),
6.22 (br.s, 3H, NH3), 4.22 (dd, 1H, CH, J = 8.3, 5.7 Hz), 3.23 (dd, 1H, Ha from CH2, J = 13.7,
5.7 Hz), 3.01 (dd, 1H, Hb from CH2, J = 13.7, 8.3 Hz), 1.94 (s, 3H). 13C NMR (75 MHz, DMSOꢀ
d6): δ 141.6 (iꢀPh), 135.1 (C(7a)), 133.1 (C(2)), 128.3 (C(3a)), 128.1, 127.0 (oꢀ,mꢀPh), 127.4 (pꢀ
Ph), 119.9 (C(6)), 118.1 (C(5)), 117.4 (C(4)), 110.3 (C(7)), 105.6 (C(3)), 55.9 (CH), 32.5 (CH2),
10.9 (Me).
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2-(2,5-Dimethyl-1H-indol-3-yl)-1-phenylethan-1-aminium chloride (6i). Colorless crystals
(0.15 g, 42%)), mp: 154–157°C. IR (KBr) 3397, 3249, 3008, 2912, 2858, 1591, 1457 cm–1. MS
(m/z (rel intens, %)) 280 (6, M+–HCl) 175 (62, C11H13NO+), 174 (100, C11H12NO+), 159 (17,
C10H9NO+), 106 (66, C7H8N+). HRMS: calcd for C18H21BrN2 M – Cl, 251.1543, found: m/z
251.1547. HRMS: calcd for C18H21BrN2 M – Cl, 265.1699, found: m/z 265.1694. 1H NMR (300
MHz, DMSOꢀd6): δ 10.59 (s, 1H, NH), 7.36 – 7.27 (m, 5H, Ph), 7.21 (m, 1H, H(4)), 7.08 (d, 1H,
H(7), J = 8.2 Hz), 6.78 (dd, 1H, H(6), J = 8.2, 1.6 Hz), 4.26 (dd, 1H, CHPh, J = 9.7, 4.7 Hz),
3.36 (dd, 1H, Ha from CH2, J = 13.8, 4.7 Hz), 3.06 (dd, 1H, Hb from CH2, J = 13.8, 9.7 Hz), 2.34
(s, 3H, Me), 1.85 (s, 3H, Me). 13C NMR (75 MHz, DMSOꢀd6): δ 139.1 (iꢀPh), 133.4, 133.3
(C(2,3a)), 128.4 (C(7a)), 128.2, 127.3 (oꢀ,mꢀPh), 127.9 (pꢀPh), 126.4 (C(5)), 121.4 (C(6)), 117.1
(C(4)), 110.0 (C(7)), 104.2 (C(3)), 55.5 (CH), 31.2 (CH2), 21.3 (Me), 10.8 (Me).
1-(4-Bromophenyl)-3-methyl-6-phenyl-1,4,5,6-tetrahydropyridazine
(4a).
Colorless
crystals (5%), mp: 124–128°C. IR (KBr) 3444, 2928, 2906, 1584, 1486 cm–1. MS (m/z (rel
intens, %)) 328, 330 (100, M+), 251, 253 (10), 183, 185 (28), 155, 157 (61). HRMS: calcd for
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C17H17BrN2 M + H, 329.0648, 331.0628, found: m/z 329.0638, 331.0626. H NMR (300 MHz,
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CDCl3): δ 7.27–7.10 (m, 5H, Ar), 7.01 (d, 2H, oꢀPh, J = 7.2 Hz), 6.91 (d, 2H, H(3´,5´), J = 8.9
Hz), 4.98 (br.s, 1H, CHPh), 2.21–2.04 (m, 2H, H(4)), 1.92 (s, 3H, Me), 1.95–1.85 (m, 1H, H(5)),
1.82–1.67 (m, 1H, H(5)). 13C NMR (75 MHz, CDCl3): δ 146.2 (CBr), 143.3 (C=N), 140.8 (iꢀPh),
131.7 (C(2´,6´)), 128.9 (mꢀPh), 127.3 (pꢀPh), 126.2 (oꢀPh), 114.6 (C(3´,5´)), 110.9 (C(1´)), 54.7
(C(6)), 25.2 (C(4)), 24.5 (Me), 21.7 (C(5)).
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1-(4-Bromophenyl)-3-methyl-6-(p-tolyl)-1,4,5,6-tetrahydropyridazine (4b). Colorless
crystals (9%), mp: 115–117°C. IR (KBr) 3437, 2951, 2919, 1588, 1490 cm–1. MS (m/z (rel
intens, %)) 342, 344 (100, M+), 183, 185 (23), 170, 172 (67), 155, 157 (48). HRMS: calcd for
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C18H19BrN2 M + H, 343.0804, 345.0785, found: m/z 343.0804, 345.0814. H NMR (300 MHz,
CDCl3): δ 7.26 (d, 2H, H(3´,5´), J = 9.0 Hz), 7.13 (d, 2H, H(3´´,5´´), J = 7.8 Hz), 7.02 (d, 2H,
H(2´,6´), J = 9.0 Hz), 7.01 (d, 2H, H(2´´,6´´), J = 7.8 Hz), 5.05 (m, 1H, CH), 2.34 (s, 3H, ArMe),
2.28–2.10 (m, 2H, H(4)), 2.03 (s, 3H, Me), 2.05–1.79 (m, 2H, H(5)). 13C NMR (75 MHz,
CDCl3): δ 146.2 (C(4´)), 143.4 (C(3)), 137.7 and 136.8 (C(1´,4´)), 131.6 (C(3´,5´)), 129.6
(C(3´´,5´´)), 126.1 (C(2´´,6´´)), 114.6 (C(2´,6´)), 110.8 (C(1´´)), 54.5 (C(6)), 25.2 (C(4)), 24.4
(Me), 21.7 (C(5)), 21.1 (ArMe).
1-(4-Bromophenyl)-6-(4-methoxyphenyl)-3-methyl-1,4,5,6-tetrahydropyridazine
(4c).
Colorless oil (12%). IR (KBr) 3436, 2930, 2906, 1586, 1505, 1489 cm–1. MS (m/z (rel intens,
%)) 358, 360 (100, M+), 188 (36), 172 (89), 161 (39), 134 (64). HRMS: calcd for C18H19BrN2O
1
M+H, 359.0754, 361.0734, found: m/z 359.0745, 359.0761. H NMR (300 MHz, CDCl3): δ
7.30–7.22 (m, 2H, H(3´,5´)), 7.07–6.98 (m, 4H, H(2´´,3´´,5´´,6´´)), 6.88–6.81 (m, 2H, H(2´,6´)),
5.04 (m, 1H, CH), 3.79 (s, 3H, MeO), 2.29–2.06 (m, 2H, H(4)), 2.02 (s, 3H, Me), 2.04–1.79 (m,
2H, H(5)). 13C NMR (75 MHz, CDCl3): δ 158.9 (C(4´´)), 146.2 (C(4´)), 143.4 (C(3)), 132.7
(C(1´´)), 131.7 (C(3´,5´)), 127.4 (C(2´´,6´´)), 114.7 C(2´,6´)), 114.4 (C(3´´,5´´)), 110.9 (C(1´)),
55.5 (MeO), 54.2 (C(6)), 25.4 (C(5)), 24.5 (Me), 21.8 (C(4)).
1-(4-Bromophenyl)-6-(4-fluorophenyl)-3-methyl-1,4,5,6-tetrahydropyridazine
(4d).
Colorless crystals (19%), mp: 97–99°C. IR (KBr) 2956, 2933, 1589, 1510, 1489 cm–1. MS (m/z
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(rel intens, %)) 346, 348 (100, M+), 155, 157 (60). HRMS: calcd for C17H16BrFN2 M + H,
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347.0554, 349.0533, found: m/z 347.0538, 349.0545. H NMR (300 MHz, CDCl3): δ 7.17 (d,
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2H, J = 7.5 Hz), 6.98 (dd, 2H, J = 8.2, 5.6 Hz), 6.92 (d, 2H, J = 6.0 Hz), 6.89 (d, 2H, J = 6.5 Hz),
4.97 (s, 1H, CHAr), 2.21–1.99 (m, 2H, H(4)), 1.93 (s, 3H, Me), 1.98–1.86 (m, 1H, H(5)), 1.79–
1.64 (m, 1H, H(5)). 13C NMR (75 MHz, CDCl3): δ 162.14 (d, C(4´´), J = 245.5 Hz), 146.0
(C(4´)), 143.4 (C(3)), 136.4 (C(1´´)), 131.7 (C(2´,6´)), 127.91 (d, C(2´´,6´´), J = 8.0 Hz), 115.90
(d, C(3´´,5´´), J = 21.5 Hz), 114.6 (C(3´,5´), 111.1 (C(1´)), 54.1 (C(6)), 25.3 (C(5)), 24.4 (Me),
21.6 (C(4)). 19F NMR (282 MHz, CDCl3): δ –115.60 (m).
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1-(4-Fluorophenyl)-3-methyl-6-phenyl-1,4,5,6-tetrahydropyridazine
(4g).
Colorless
crystals (0.035 g, 11%), mp: 71–73°C. IR (KBr) 3029, 2932, 1506, 1209, 824 cm–1. MS (m/z (rel
intens, %)) 268 (100, M+), 191 (10), 156 (10), 123 (22), 95 (34). HRMS: calcd for C17H18FN2 M
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+ H, 269.1499, found: m/z 269.1499. H NMR (300 MHz, CDCl3): δ 7.36–7.22 (m, 3H,
H(3´´,4´´,5´´)), 7.15 (d, 2H, H(2´´,6´´), J = 7.1 Hz), 7.11 – 6.98 (m, 2H, H(2´,6´)), 6.80–6.90 (m,
2H, H(3´,5´)), 5.01–5.08 (m, 1H, H(6)), 2.34 – 2.11 (m, 1H), 2.04 (s, 1H), 2.04 – 1.77 (m, 1H).
13C NMR (75 MHz, CDCl3): δ 156.6 (d, C(4´), J = 236.8 Hz), 143.6 (d, C(1´), J = 1.8 Hz), 142.4
(C(3)), 141.1 (C(1´´)), 128.7 (C(3´´,5´´)), 127.0 (C(4´´)), 126.1 (C(2´´,6´´)), 115.2 (d, C(3´,5´), J
= 22.2 Hz), 114.0 (d, C(2´,6´), J = 7.4 Hz), 55.1 (C(6)), 25.2 (C(4)), 24.2 (Me), 21.6 (C(5)). 19F
NMR (282 MHz, CDCl3): δ –127.8 (m).
3-Methyl-1,6-diphenyl-1,4,5,6-tetrahydropyridazine (4h). Colorless crystals (0.036 g,
12%), mp: 141–143°C. IR (KBr) 3020, 2934, 1594, 1498, 1149, 750 cm–1. MS (m/z (rel intens,
%)) 250 (100, M+), 180 (10), 173 (16), 156 (10), 117 (9), 77 (22). HRMS: calcd for C17H19N2 M
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+ H, 251.1543, found: m/z 251.1541. H NMR (300 MHz, CDCl3): δ 7.38–7.13 (m, 9H, Ar),
6.79 (t, 1H, H(4´), J = 6.9 Hz), 5.13–5.18 (m, 1H, H(6)), 2.34–2.14 (m, 2H, H(4)), 2.05 (s, 1H),
2.09–1.77 (m, 2H, H(5)). 13C NMR (75 MHz, CDCl3): δ 147.1 (C(1´)), 142.5 (C(3)), 141.3
(C(1´´)), 129.0 (C(3´,5´)), 128.8 (C(3´´,5´´)), 127.1 (C(4´´)), 126.3 (C(2´´,6´´)), 118.8 (C(4´)),
113.1 (C(2´,6´)), 54.8 (C(6)), 25.2 (C(4)), 24.4 (Me), 21.9 (C(5)).
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(S)-N-(2-(5-bromo-2-methyl-1H-indol-3-yl)-1-phenylethyl)acetamide (S)-9. A mixture of
4ꢀbromophenylhydrazine hydrochloride (0.22 g, mmol) and (R,R)ꢀ2ꢀ
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phenylcyclopropylethanone (R,R)ꢀ1a (0.21 g, 1.2 mmol) in acetonitrile (20 mL) was heated at
reflux for 16 h. The mixture was filtered and the residue dried in vacuo to give crude (S)ꢀ6a
which was treated with dichloromethane (20 mL) and triethylamine (0.081 g, 0.8 mmol). A
solution of acetyl chloride (0.058 g, 0.7 mmol) in CH2Cl2 (2 mL) was added dropwise in 5 min
and the mixture stirred for 1 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with a
1M solution of K2CO3, brine and the organic layer dried over anhydrous Na2SO4, and
evaporated. Column chromatography on silica gel (chloroform–AcOEt, 1:1) gave the desired
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product (S)ꢀ9 (0.25 g, 68%, ee 99%). Colorless crystalls, mp: 168–169°C, [α]D +66 (c 1,
EtOAc). IR (KBr) 3425, 32.95, 2361, 1613 cm–1. MS (m/z (rel intens, %)) 370, 371 (10, M+),
311, 313 (27), 222, 224 (100), 148 (5), 143 (16), 106 (24). HRMS: calcd for C19H19BrN2O M+H,
371.0754, 373.0734, found: m/z 371.0754, 373.0743. 1H NMR (300 MHz, CDCl3): δ 8.13 (s, 1H,
H(1)), 7.46 (d, J = 1.8 Hz, 1H, H(4)), 7.33–7.21 (m, 3H, mꢀ, pꢀPh), 7.16 (dd, 1H, H(6), J = 8.5,
1.8 Hz), 7.12–7.03 (m, 3H, oꢀPh, H(7)), 6.05 (d, 1H, NHAc, J = 7.9 Hz), 5.28 (dd, 1H, CH, J =
13.9, 6.2 Hz), 3.27–3.03 (m, 2H, CH2), 1.97 (s, 3H, Ac), 1.87 (s, 3H, Me). 13C NMR (75 MHz,
CDCl3): δ 169.6 (Ac), 141.7 (iꢀPh), 134.7 (C(2)), 133.9(C(3a)), 131.1 (C(7a)), 128.6 (mꢀPh),
127.5 (pꢀPh), 126.7 (oꢀPh), 123.8 (C(6)), 120.7 (C(4)), 112.8 (C(5)), 111.8 (C(7)), 106.5 (C(3)),
54.5 (CH), 31.9 (CH2), 23.6(Ac), 11.3 (Me).
Racemic Tryptamine 9. A solution of AcCl (0.040 g, 0.5 mmol) in dichloromethane (2 mL)
was added to the mixture of 6a (0,10 g, 0.27 mmol) and TEA (0.08 g, 0.8 mmol) in CH2Cl2 (10
mL) dropwise in 5 min and the mixture stirred for 1 h. The mixture was diluted with CH2Cl2 (20
mL) and washed with a 1M solution of K2CO3, brine and the organic layer dried over anhydrous
Na2SO4 and evaporated. Column chromatography (chloroform–EtOH, 9:1) gave the desired
product in a yield of 81% (0.081 g). Colorless crystals, mp: 167–169°C; other physical
properties correspond to those of (S)ꢀ9.
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Rearrangement of 2-Methylcyclopropylethanone 4-Bromophenylhydrazone. A mixture
of 4ꢀbromophenylhydrazine hydrochloride (0.40 g, 1.8 mmol) and 2ꢀmethylcyclopropylethanone
7 (0.22 g, 2.2 mmol) in acetonitrile (20 mL) was refluxed for 18 h. The solvent was removed in
vacuo and the residue was treated with dichloromethane (20 mL) and triethylamine (0.40 g, 4.0
mmol). A solution of AcCl (0.17 g, 2.2 mmol) in CH2Cl2 (3 mL) was added dropwise in 5 min
and the mixture stirred for 1 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with a
1M solution of K2CO3, brine and the organic layer dried over anhydrous Na2SO4, and
evaporated. Column chromatography on SiO2 (chloroform–EtOH, 9:1) gave a mixture of
tryptamines 7 and 8 in a yield of 68% (0.38 g, ratio 3:1). The major isomer 7 was purified using
preparative normalꢀphase HPLC сolumn (21×250 mm, 5 ꢁm), flow rate 12 mL min−1, mobile
phase: isocratic, isopropanol–hexane, 17% isopropanol; retention time 19.65 min. The minor
isomer was analyzed in the mixture.
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Nꢀ(2ꢀ(5ꢀBromoꢀ2ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)propyl)acetamide 7. Colorless crystals, mp: 95–97°C.
IR (KBr) 3413, 3272, 2965, 2928, 1655 cm–1. MS (m/z (rel intens, %)) 308, 310 (22, M+), 249,
251 (20, M+ – AcNH2), 236, 238 (100, M+ – CH2NAc), 157 (27, M+ – CH2NHAc – Br), 106 (24,
+
PhCHNH2 ). HRMS: calcd for C14H17BrN2O M+H, 309.0597, 311.0577, found: m/z 309.0586,
311.0566. 1H NMR (300 MHz, CDCl3): δ 8.13 (s, 1H, H(1)), 7.70 (d, 1H, H(4), J = 1.5 Hz), 7.21
(dd, 1H, H(6), J = 8.5, 1.5 Hz), 7.16 (d, 1H, H(7), J = 8.5 Hz), 5.42 (br.s, 1H, NH), 3.82 (ddd,
1H, Ha from CH2, J = 12.9, 7.3, 5.7 Hz), 3.38–3.25 (m, 1H, Hb from CH2), 3.26–3.16 (m, 1H,
CH), 2.39 (s, 3H, Ac), 1.88 (s, 3H, Me), 1.41 (d, 3H, Me, J = 6.9 Hz). 13C NMR (75 MHz,
CDCl3): δ 170.2 (Ac), 134.3 (C(3a)), 133.2 (C(2)), 129.1 (C(7a)), 123.9, (C(6)), 121.5 (C(4)),
112.9 (C(3)), 112.6 (C(5)), 112.1 (C(7)), 45.1 (CH2), 31.4 (CH), 23.4 (Ac), 18.4 and 12.2 (2 Me).
Nꢀ(1ꢀ(5ꢀBromoꢀ2ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)propanꢀ2ꢀyl)acetamide 8. Colorless crystals. 1H NMR
(300 MHz, CDCl3): δ 8.35 (br.s, 1H, NH), 7.62 (d, 1H, H(4), J = 1.8 Hz), 7.18 (dd, 1H, H(6), J =
1.8, 8.3 Hz), 7.11 (d, 1H, H(7), J = 8.3 Hz), 5.50 (s, 1H, NHAc), 4.18–4.33 (m, 1H, CH), 2.73–
2.90 (m, 2H, CH2), 2.37 (s, 3H, Me), 1.93 (s, 3H, Ac), 1.09 (d, 3H, Me, J = 6.7 Hz). 13C NMR
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(75 MHz, CDCl3): δ 169.7 (CO), 134.2 (C(2)), 134.0 (C(3a)), 131.3 (C(7a)), 123.8 (C(6)), 120.9
(C(4)), 112.3 (C(5)), 111.8 (C(7)), 107.7 (C(3)), 46.6 (CH), 30.7 (CH2), 23.7 (Ac), 20.1 and 12.1
(2 Me).
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ACKNOWLEGEMENTS
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The work was financially supported by the Russian Science Foundation (Grant 14ꢀ13ꢀ01054).
We are grateful to Prof. Viktor V. Semenov for providing the arylhydrazine starting materials,
Dr. Evgeny V. Shulishov for NMR spectra and Petr A. Zhmurov for the establishment of
enantiomeric excess.
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Supporting Information. H and 13C NMR spectra for new compounds, a thermal ellipsoid
plot, chiral HPLC data and a CIFꢀfile for compound (S)ꢀ9.
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