N- and O-alkylation of 3-indolylcyclopropylacetic acid derivatives

Article abstract of DOI:10.1023/A:1021392216350

2,2-Dimethyl-3-(2-methyl-3-indolyl)cyclopropylacetic acid, its amide and esters, and the corresponding alcohol, viz., the product of ester reduction by LiAlH₄, were synthesized. The chemoselectivity of N- and O-alkylation of these compounds was

Full text of DOI:10.1023/A:1021392216350

Russian Chemical Bulletin, International Edition, Vol. 51, No. 10, pp. 1829—1840, October, 2002
1829
Nꢀ and ОꢀAlkylation of 3ꢀindolylcyclopropylacetic acid derivatives
E. A. Burakova,a O. N. Burchak,b and A. M. Chibiryaeva
ꢀ
аDepartment of Natural Sciences, Novosibirsk State University,
2 ul. Pirogova, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383 2) 34 4752. Eꢀmail: chibirv@nioch.nsc.ru
bN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383 2) 34 4752
2,2ꢀDimethylꢀ3ꢀ(2ꢀmethylꢀ3ꢀindolyl)cyclopropylacetic acid, its amide and esters, and the
corresponding alcohol, viz., the product of ester reduction by LiAlH4, were synthesized. The
chemoselectivity of Nꢀ and Oꢀalkylation of these compounds was studied. Selective monoꢀ
alkylation at the nitrogen atom of the heterocycle, Оꢀalkylation to the side chain, or dialkylation
at both nucleophilic sites can be carried out under conditions of phaseꢀtransfer catalysis. The
Nꢀacylation at the indole fragment of nitrile of this acid occurs only under the Vilsmeier—Haak
formylation conditions.
Key words: Fischer indole synthesis; 3ꢀindolylcyclopropylacetic acid and its esters, nitriles,
amides; hydrolysis; Nꢀalkylation and Nꢀsulfonylation of indoles; Oꢀalkylation of carboxylic
acids and alcohols; phaseꢀtransfer catalysis; Vilsmeier—Haak reaction.
NꢀAlkylation and Nꢀacylation of indoles are the main
methods for the synthesis of 1ꢀsubstituted indole derivaꢀ
tives and are often used in syntheses of various biologiꢀ
cally active compounds, for example, alkaloids.1,2 Alꢀ
though the development of methods of indole alkylation
produced new alkylating systems,3—5 alkylation under the
phaseꢀtransfer catalysis conditions by quaternary ammoꢀ
nium salts and crown ethers found the most accepꢀ
tance.6—8 This method makes it possible to retain other
reactive functional groups in the molecule and avoid the
formation of products of C(3)ꢀalkylation of the heteroꢀ
cycle. It is known that 2ꢀ and 3ꢀalkyl substituents, being
simultaneously present in the heterocycle ring, decrease
the reactivity of indoles with respect to their unsubstituted
and monosubstituted analogs8—10 and, in some cases, reꢀ
sult in the formation of 3ꢀalkylated 3Нꢀindole only.11,12
The purpose of this work is to study the chemoꢀ
selectivity of Nꢀalkylation of 2,3ꢀdialkylindoles under the
phaseꢀtransfer catalysis conditions, using 3ꢀindolylcycloꢀ
propylacetic acid and its derivatives in the presence of
other competitive functional groups (—COOH, —COOR,
—CONH2, and —OH) as an example.
precursor of the indoles is monoterpene ketone 1 obtained
from (+)ꢀ3ꢀcarene.13 The side chain of the heterocycle of
these compounds contains functional groups that can unꢀ
dergo alkylation simultaneously with the indole ring or
enter into other transformations under the alkylation conꢀ
ditions. Compounds 4—7 were obtained as follows. Niꢀ
trile 2, which was synthesized from ketone 1 by the Fischer
indole reaction,14 was treated with an alkaline solution of
Н2О2 to transform into the corresponding amide 5 in 68%
yield. However, we failed to completely hydrolyze niꢀ
trile 2 to the acid or transform it into the ester by the
Pinner reaction: the products obtained did not contain
the cyclopropane fragment in the molecule (1Н NMR
spectroscopic data). Therefore, ester 4 was synthesized
from ωꢀketo ester 3 obtained from nitrile 1.15 Ester 4 can
readily be transformed into acid 6 or alcohol 7 by mild
alkaline hydrolysis or reduction with LiAlH4, respectively.
Using indole 2 as an example, we demonstrated the
efficiency of an alkyl halide—50% NaOH—TEBAC sysꢀ
tem for the synthesis of the corresponding Nꢀalkyl derivaꢀ
tives, but no 3ꢀalkylation products were found (Scheme 2).
In the case of allyl bromide, the reaction occurred in a
low yield (∼10%). Therefore, the anhydrous system alkyl
halide—ButOK—18ꢀcrownꢀ6 was used for the synthesis
of Nꢀallylindole 12, and the yield of the product was 72%.
NꢀMethylindole 8 is formed virtually similarly in both
systems in 77% yield. However, the reaction duration is
2—4ꢀfold longer when alkylation is performed under the
anhydrous conditions.
Results and Discussion
As model compounds for studying the competitive
Nꢀ and Оꢀalkylation reactions (Scheme 1) 2,3ꢀdisubstiꢀ
tuted indoles 2 and 4—7 were synthesized. The common
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1682—1693, October, 2002.
1066ꢀ5285/02/5110ꢀ1829 $27.00 © 2002 Plenum Publishing Corporation

1830
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Burakova et al.
Scheme 1
Reagents and conditions: a. 1) HCl gaseous, MeOH, 20 °C, 3 h; 2) H2O, 12 h (Ref. 15). b. (1) PhNHNH2/MeOH, ∼20 °C, 2 h;
(2) PPE, CH2Cl2, ∼20 °C, 12 h (Ref. 14). c. H2O2/NaOH/MeOH/H2O, ∼35 °C, 6 h. d. NaOH/EtOH/H2O, ∼20 °C, 3 h. e. H2SO4 conc.,
∼20 °C, 24 h. f. LiAlH4/Et2O, ∼20 °C, 0.5 h.
Scheme 2
Only bisindolylmethane 14 is formed under the aqueous
conditions (NaOH—TEBAC) when dibromomethane is
used as the alkylating agent, regardless of alkyl haꢀ
lide : indole molar ratios, and the Nꢀ(bromomethyl) deꢀ
rivative is not formed.
The reaction of amide 5 under aqueous condiꢀ
tions ceases at the stage of Nꢀmethylindole 15 formaꢀ
tion, although a twofold excess of methyl iodide is used
(Scheme 3). The alkylation of the amide group, which can
occur under similar conditions of phaseꢀtransfer catalyꢀ
sis,16—19 is not observed. According to the spectroscopic
and physicochemical data, we obtained the same comꢀ
pound using the encounter synthesis by the hydrolysis of
nitrile 8 under conditions of the Radziszewski reaction.
The alkylation of alcohol 7 and ester 4 is less selective,
and the yields of 1ꢀalkylated indole derivatives 16 and 18
are 43 and 32%, respectively. The alkylation of alcohol 7
with one equivalent of methyl iodide afforded a mixture
of products, among which compound 16 predominated
(1Н NMR spectroscopic data). The product of N,Oꢀdiꢀ
alkylation (17) becomes the main component when
an excess of EtBr is used as the alkylating agent (see
Scheme 3). Based on these data, we can assume that
alkylation by methyl iodide would afford both monoꢀ
alkylation (Nꢀ or Oꢀ) and dialkylation products.
Reagents and conditions: a. RHal/CH2Cl2/50% aqueous
NaOH/TEBAC, ∼50 °C, 3 h. b. RHal (R = Me, All)/C6H6 or
ButOMe/ButOK/18ꢀcrownꢀ6, reflux, 8—14 h.
In the reaction of ester 4 with CH2Br2 under aqueousꢀ
alkaline conditions, a partial hydrolysis of the ester group

N,OꢀAlkylation of indole derivatives
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1831
spect.20 This method has previously been used for the
Nꢀalkylation of methyl 3ꢀindolyl acetate and some deꢀ
rivatives of this acid.21 In our case, the Nꢀbenzyl derivaꢀ
tive of indolo acid 6 (compound 19) can be obtained in
69% yield by storing a mixture of ester 4 with a sixfold
excess of benzyl chloride and TEBAC at 70—75 °С.
It was of interest to alkylate indolylcyclopropylacetic
acid at the carboxyl group avoiding the interaction with
the heterocycle. This transformation was successfully perꢀ
formed in an alkyl halide—Na2CO3—DMF system. Esꢀ
ters 20—25 were obtained under the same conditions in
yields from 30 to 88%, including bromineꢀcontaining
compounds 21 and 22, which were synthesized using an
excess of alkylating agents, viz., 1,2ꢀdibromoethane and
1,5ꢀdibromopentane, respectively (Scheme 4). The exꢀ
pected bisindoles 24 and 25 are formed in a twofold exꢀ
cess of acid 6 with respect to dihalides.
Scheme 3
The exhaustive Nꢀ and Oꢀalkylation of acid 6 was
carried out under the conditions used earlier for the
Nꢀalkylation of ester 4. Dibenzyl derivative 26 was obꢀ
tained upon storing the acid at ∼60—65 °С for 6 h (see
Scheme 4).
An aqueousꢀalkaline medium used along with TEBAC
allows the Nꢀsulfonylation of the indole cycle of nitrile 2
by pꢀtoluenesulfonyl chloride and pꢀbromobenzeneꢀ
sulfonyl chloride (compounds 27 and 28), and sulfoꢀ
nylation occurs much more rapidly and in a higher yield
than alkylation (Scheme 5). This reaction is often used in
synthesis for the introduction of the —SO2Ar protective
group at the nitrogen atom of various indole comꢀ
pounds.22—24
The attempts of Nꢀacetylation or Nꢀbenzoylation of
indole 2 under the conditions repeatedly described for the
acylation of 2,3ꢀunsubstituted or monosubstituted inꢀ
doles25—27 were unsuccessful: none of the experiments
exhibited acylation. The single Nꢀacyl derivative, viz.,
formylindole 29, was obtained in 75% yield only under
the Vilsmeier—Haak conditions.28,29 When 1,2,3ꢀtrialkylꢀ
substituted indole 8 is used, formylation occurs, as exꢀ
pected,30,31 at the methyl group to position 2 of the hetꢀ
erocycle to form aldehyde 30.
It should be mentioned in conclusion that the initial
compounds are not epimerized in all reactions presented
(cf. Ref. 32): all final products demonstrate the cisꢀarꢀ
rangement of the substituents in the cyclopropane fragꢀ
ment. The cisoid arrangement of the substituents is unꢀ
ambiguously indicated by the 3J4,6 spinꢀspin coupling conꢀ
stant, which varies from 8.0 to 9.7 Hz, depending on the
compound. In addition, all synthesized compounds posꢀ
sess an optical activity ([α]578 +36—+167). These two
facts suggests that the products are not racemized during
the reactions under study.
Reagents and conditions: a. RHal/CH2Cl2/50% aqueous
NaOH/TEBAC, ∼20 °C, 5—20 h. b. PhCH2Cl/50% aqueous
NaOH/TEBAC, ∼75 °C, 4 h.
occurs in parallel with alkylation already at room temꢀ
perature. That is why, the yield of product 18 is only 32%.
The use of the anhydrous system (ButOK—18ꢀcrownꢀ6)
is less efficient for the synthesis of bisindolo ester 18. The
Nꢀalkylation of ester 4 with simultaneous hydrolysis of
the ester group under the soꢀcalled "extractive alkylation"
conditions seems more convenient in the preparative reꢀ
Thus, in this work we showed that for 2,3ꢀdialkylꢀ
substituted 3ꢀindolylcyclopropylacetic acid and its some
derivatives the heterocycle can selectively be Nꢀalkylated

1832
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Burakova et al.
Scheme 4
Reagents and conditions: a. RHal/Na2CO3/DMF, ∼20 °C, 10—40 h. b. PhCH2Cl/50% aqueous NaOH/TEBAC, ∼65 °C, 6 h.
without formation of the 3ꢀalkylation products or alkylaꢀ
tion can be performed only to the side chain of the hetꢀ
erocycle. If necessary, the conditions for exhaustive
N,Oꢀdialkylation can easily be selected. In addition, these
compounds exhibited a low reactivity in the Nꢀacylation
of the indole heterocycle.
Experimental
Thinꢀlayer chromatography was carried out on Silufol plates.
In order to develop spots, the plates were sprayed with ethanolic
solutions of vanillin (1 g of vanillin and 10 mL of concentrated
H2SO4 in 100 mL of 95% EtOH) or ninhydrin (0.25 g of ninhyꢀ
drin and 25 mL of АсОН in 100 mL of 95% EtOH) and then
heated. Silica gel (KSK trade mark) with a particle size of
0.140—0.315 mm activated at 140 °C for 6—7 h was used for
preparative column chromatography.
Scheme 5
All organic solvents were distilled before use; triethylbenzylꢀ
ammonium chloride (TEBAC), ButOK, and 18ꢀcrownꢀ6 were
commercially available (Fluka AG). Keto nitrile 1 ([α]57823 –12.0
20
(in the pure form)) and methyl ester 3 ([α]D –22.1 (c 1.99),
34
cf. Ref. 33: [α]D –26.6 (c 6.32)) were synthesized using a
described procedure.15
UV spectra were obtained on a Specord Mꢀ40 spectrophoꢀ
tometer in 95% EtOH (c = 1•10–4 mol L–1). IR spectra were
recorded on a Bruker Vectorꢀ22 instrument. Mass spectra were
obtained on a Finnigan MAT 8200 spectrometer (50—100 °C,
1
EI, 70 eV). H and 13C NMR spectra were recorded on Bruker
ACꢀ200 (200.13 MHz (1H) and 50.32 MHz (13C)), Bruker
AMꢀ400 (400.13 MHz (1H) and 100.61 MHz (13C)), and Bruker
DRXꢀ500 (500.13 MHz (1H) and 125.77 MHz (13C)) spectromꢀ
eters for solutions with a concentration of 70—100 mg mL–1 at
25—27 °C. The signals from the following solvents were used as
the internal standard: CDCl3 (δН = 7.24 ppm, δС = 76.90 ppm),
CD3OD (δ = 3.31 ppm, δ = 49.00 ppm), (CD3)2SO (δ
=
Н
С
Н
2.50 ppm, δ = 39.50 ppm), (CD3)2CO (δ = 2.04 ppm, δ
=
С
Н
С
29.80 ppm), and pyridineꢀd5 (δ = 8.71, 7.55, and 7.19 ppm,
Н
δ
= 149.90, 135.50, and 123.50 ppm). Optical rotation angles
С
were measured on a Polamat A polarimeter for solutions in
CHCl3 (if another solvent is not indicated). Melting points were
determined on a Kofler stage.
NꢀAlkylation of indole 2 (general procedures). Method А. A
50% aqueous solution of NaOH (10 mL) and alkyl halide were
successively added with stirring to a solution of indole 2 and
Reagents and conditions: a. ArSO2Cl/CH2Cl2/50% aqueous
NaOH/TEBAC, ∼20 °C, 1 h. b. POCl3/DMF, ∼20 °C, 5—70 h.

N,OꢀAlkylation of indole derivatives
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1833
TEBAC (0.10 g) in CH2Cl2 (10 mL), and the mixture was vigorꢀ
ously stirred either at ∼20 °C or on heating. After the initial
indole disappeared (TCL monitoring), the reaction mixture was
diluted with water (20 mL), the organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (2×10 mL). The
combined organic extract was washed with a saturated solution
of NaCl and dried with anhydrous Na2SO4. The solvent was
removed in vacuo, and the residue was chromatographed using
an EtOAc—petroleum ether mixture as the eluent. The product
was obtained as a viscous light yellow oil. The crystalline subꢀ
stances were recrystallized.
Method B. Solutions of indole 2 (1 equiv.) and alkyl halide
(2.2 equiv.) in ButOMe were consecutively added with stirꢀ
ring to a suspension of 18ꢀcrownꢀ6 (0.1 equiv.) and ButOK
(1.1 equiv.) in anhydrous ButOMe, and the mixture was stirred
for 1 h at ∼20 °C and boiled for several hours until the initial
indoles disappeared (TLC monitoring). The reaction mixture
was diluted with water (20 mL), the organic layer was separated,
and the aqueous layer was extracted with ButOMe (3×15 mL).
The combined organic extract was washed with a saturated soluꢀ
tion of NaCl and dried above anhydrous Na2SO4. The solvent
was removed in vacuo, and the residue was chromatographed on
silica gel using an EtOAc—petroleum ether mixture as the eluent.
ОꢀAlkylation of acid 6 (general procedure). Method C.
Na2CO3 (0.11 g, 1.1 mmol) was added to a solution of acid 6
(0.26 g, 1.0 mmol) in DMF (10 mL), and the mixture was stirred
for 10 min. Then alkyl halide was added, and the mixture was
stirred at ∼20 °C for several hours. After the starting acid disapꢀ
peared (TLC monitoring), the reaction mixture was diluted with
water (50 mL) and extracted with ButOMe (3×15 mL). The
organic extract was washed with a saturated solution of NaCl
and dried with anhydrous Na2SO4. The solvent was removed in
vacuo, and the residue was chromatographed on silica gel using
an EtOAc—petroleum ether mixture as the eluent.
Methyl (+)ꢀ[(1R,3S)ꢀ2,2ꢀdimethylꢀ3ꢀ(2ꢀmethylꢀ1Hꢀindolꢀ3ꢀ
yl)cyclopropyl] acetate (4). A solution of keto ester 3 (0.59 g,
3.0 mmol) and phenylhydrazine (0.36 g, 3.3 mmol) in MeOH
(10 mL) was stored for 2 h at 20 °С, and the solvent was removed
in vacuo. The residue in the form of a light yellow oil was disꢀ
solved in anhydrous CH2Cl2 (10 mL), PPE (2.0 g) was added,34
and the mixture was stirred to complete dissolution and left for
12 h at 20 °С. After the solvent was removed, a residual dark
brown oil was stirred with an aqueous solution (15 mL) of
Na2CO3 (0.5 mol L–1) and extracted with ButOMe (3×10 mL).
The ether extract was dried with anhydrous Na2SO4, and the
solvent was removed in vacuo. The residue was chromatographed
on a column packed with SiO2 using an AcOEt—petroleum
ether mixture as the eluent to isolate product 4 in 89% yield
(0.72 g) as a viscous light orange oil with [α]57823 +63.9 (c 4.21).
UV (EtOH), λmax/nm (ε): 226 (22500), 275 (7900), 292 (6400).
IR (CCl4), ν/cm–1: 3475 (NHindole), 3050 (C—Harom), 1745
(C=O), 1455 (C=Carom), 1430, 1170, and 1155 (С—O—C).
1H NMR (СDCl3), δ: 0.98 (s, 3 H, Н3С(9)); 1.37 (s, 3 Н,
Н3С(10)); 1.38 (ddd, 1 H, Н(6), J1 = 9.0 Hz, J2 = 8.6 Hz, J3 =
6.0 Hz); 1.75 (dq, 1 H, Н(4), J1 = 8.6 Hz, J2 = 1.0 Hz); 2.07 (dd,
1 H, Н(7α), J1 = 18.0 Hz, J2 = 9.0 Hz); 2.33 (d, 3 H, Н3С(1),
J = 1.0 Hz); 2.63 (dd, 1 H, Н(7β), J1 = 18.0 Hz, J2 = 6.0 Hz);
3.67 (s, 3 Н, Н3С(7a)); 7.04 (ddd, 1 H, Н(3a), J1 = 7.0 Hz, J2 =
6.5 Hz, J3 = 2.0 Hz); 7.09 (ddd, 1 H, Н(4a), J1 = 7.0 Hz, J2 =
(br.s, 1 H, NH). 13C NMR (СDCl3), δ: 12.66 (q, С(1)); 17.07
(q, С(9)); 18.20 (s, C(5)); 22.36 and 22.46 (both d, С(4), C(6));
28.73 (q, С(10)); 31.49 (t, С(7)); 51.30 (q, С(7a)); 108.30
(s, C(3)); 109.90 (d, C(5a)); 118.89, 119.32, and 120.83 (all d,
C(2a), C(3a), C(4a)); 129.75 (s, C(1a)); 133.83 and 135.49
(both s, C(2), С(6a)); 174.35 (s, С(8)). MS, m/z (Irel (%)): 271
[M]+ (41), 199 (15), 198 (100), 196 (13), 183 (13), 182 (20), 168
(15), 167 (9), 144 (9), 131 (14). Found: m/z 271.1575 [М]+.
С
17H21NO2. Calculated: М = 271.1572.
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(2ꢀmethylꢀ1Hꢀindolꢀ3ꢀ
yl)cyclopropyl]acetamide (5). Powdered NaOH (0.12 g,
3.0 mmol) was added together with dropwise adding of a 30%
aqueous solution of Н2О2 (3 mL) to a solution of nitrile 2 (0.71 g,
3.0 mmol) in MeOH (20 mL) maintaining the temperature at
30—40 °С. After the starting nitrile disappeared (∼6 h, TLC
monitoring), the reaction mixture was cooled to ∼20 °C, and the
solution was saturated with solid NaCl and extracted with CHCl3
(3×10 mL). A chloroformic extract was washed with an aqueous
solution of Na2SO3 (0.5 mol L–1) and dried with anhydrous
MgSO4. The solvent was removed in vacuo, the yellow oil that
formed was treated with a C6H6—CHCl3 (1 : 1) mixture (10 mL)
on heating, and the precipitate that formed was filtered off.
After recrystallization from an aqueous solution of dioxꢀ
ane, amide 5 was obtained in 68% yield (0.52 g) with m.p.
32
157—159 °C, [α]578 +166.8 (c 1.81, MeOH). UV (EtOH),
λ
max/nm (ε): 227 (34700), 284 (7400), 291 (6700). IR (KBr),
ν/cm–1: 3450 (NHindole), 3400 (NHamide), 3200 (NHamide), 3070
(C—Harom), 1665 (C=O), 1455 (C=Carom), 730 (C—Harom).
1H NMR (СDCl3—CD3OD), δ: 0.91 (s, 3 H, Н3С(9)); 1.26
(ddd, 1 H, Н(6), J1 = 9.5 Hz, J2 = 9.2 Hz, J3 = 5.5 Hz); 1.28 (s,
3 Н, Н3С(10)); 1.64 (dq, 1 H, H(4), J1 = 9.2 Hz, J2 = 1.2 Hz);
1.82 (dd, 1 H, H(7α), J1 = 17.0 Hz, J2 = 9.5 Hz); 2.25 (d, 3 H,
Н3С(1), J = 1.2 Hz); 2.50 (dd, 1 H, H(7β), J1 = 17.0 Hz, J2
=
5.5 Hz); 3.39 (s, 2 H, NHamide); 6.89—6.97 (m, 2 H, H(3a),
H(4a)); 7.10 (m, 1 H, H(2a)); 7.37 (m, 1 H, H(5a)); 8.82 (br.s,
1 H, NHindole). 13C NMR (СDCl3—CD3OD), δ: 12.53 (q, С(1));
16.70 (q, С(9)); 18.13 (s, С(5)); 22.20 and 22.44 (both d, С(4),
C(6)); 28.46 (q, С(10)); 32.73 (t, С(7)); 107.34 (s, C(3)); 109.90
(d, С(5a)); 118.32, 118.92, and 120.25 (all d, C(2a), C(3a),
C(4a)); 129.39 (s, C(1a)); 134.27 and 135.50 (both s, C(2),
С(6a)); 176.76 (s, С(8)). MS, m/z (Irel (%)): 257 [М + Н]+ (9),
256 [М]+ (47), 212 (12), 199 (16), 198 (100), 196 (13), 183 (15),
182 (29), 168 (19), 167 (12), 144 (30), 143 (8), 131 (40), 130
(15). Found: m/z 256.1573 [М]+. С16H20N2O. Calculated:
М = 256.1576.
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(2ꢀmethylꢀ1Hꢀindolꢀ3ꢀ
yl)cyclopropyl]acetic acid (6). A 10% aqueous solution of NaOH
(5 mL) was added to a solution of ester 4 (0.54 g, 2.0 mmol) in
EtOH (10 mL). The mixture was stirred and left at ∼20 °C for
3 h. Then the mixture was neutralized with an aqueous solution
of HCl (1 mol L–1) to pH 5 and extracted with ButOMe
(3×15 mL). The extract was dried with anhydrous Na2SO4, and
the solvent was removed in vacuo. The residue was chromatoꢀ
graphed, and acid 6 was obtained in 65% yield (0.33 g) as light
yellow crystals with m.p. 67—69 °С (from EtOAc—hexane),
23
[α]578 +90.6 (c 2.34). UV (EtOH), λmax/nm (ε): 227 (29400),
284 (6100), 292 (5600). IR (CCl4), ν/cm–1: 3475 (NHindole),
3055 (C—Harom), 1705 (C=O), 1455 (C=Carom), 1290 and 1225.
1H NMR (СDCl3—CCl4), δ: 1.03 (s, 3 H, Н3С(9)); 1.39 (ddd,
1 H, Н(6), J1 = 9.0 Hz, J2 = 9.0 Hz, J3 = 5.8 Hz); 1.41 (s, 3 Н,
Н3С(10)); 1.75 (dq, 1 H, Н(4), J1 = 9.0 Hz, J2 = 1.0 Hz); 2.10
7.0 Hz, J3 = 2.0 Hz); 7.22 (dd, 1 H, Н(2a), J1 = 6.5 Hz, J2
=
2.0 Hz); 7.47 (dd, 1 H, Н(5a), J1 = 7.0 Hz, J2 = 2.0 Hz); 7.75

1834
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Burakova et al.
(dd, 1 H, Н(7α), J1 = 18.2 Hz, J2 = 9.0 Hz); 2.32 (d, 3 H,
Н3С(1), J = 1.0 Hz); 2.71 (dd, 1 H, Н(7β), J1 = 18.2 Hz, J2 =
5.8 Hz); 6.02—7.13 (m, 3 H, H(2a), H(3a), H(4a)); 7.46 (d,
1 H, Н(5a), J = 7.5 Hz); 7.66 (s, 1 H, Nindole); 11.78 (br.s, 1 H,
СОOH). 13C NMR (СDCl3—CCl4), δ: 12.90 (q, С(1)); 17.26
(q, С(9)); 18.28 (s, C(5)); 22.10 and 22.47 (both d, C(4), С(6));
28.91 (q, С(10)); 31.61 (t, С(7)); 108.13 (s, C(3)); 109.96
(d, C(5a)); 119.11, 119.34, and 121.02 (all d, C(2a), C(3a),
C(4a)); 129.72 (s, C(1a)); 133.38 and 135.54 (both s, C(2),
С(6a)); 180.48 (s, С(8)). MS, m/z (Irel (%)): 257 [M]+ (38), 199
(16), 198 (100), 183 (13), 182 (16), 168 (13), 167 (7), 144 (12),
131 (15), 43 (7). Found: m/z 257.1423 [М]+. С16H19NO2. Calꢀ
culated: М = 257.1416.
ous EtOH, and product 8 was obtained in 77% yield (0.39 g)
with m.p. 118—121 °С (from aqueous EtOH), [α]578 +128.7
23
(c 3.92). UV (EtOH), λmax/nm (ε): 228 (35600), 286 (7200), 294
(6800). IR (KBr), ν/cm–1: 3050 (C—Harom), 2250 (C≡N), 1460
(C=Carom), 1370, 1240, 735, and 705 (C—Harom). 1H NMR
(acetoneꢀd6), δ: 1.08 (s, 3 H, Н3С(9)); 1.34 (ddd, 1 H, H(6),
J1 = 9.0 Hz, J2 = 8.5 Hz, J3 = 6.0 Hz); 1.36 (s, 3 H, Н3С(10));
1.80 (dq, 1 H, H(4), J1 = 8.5 Hz, J2 = 1.0 Hz); 1.96 (dd, 1 H,
H(7α), J1 = 17.5 Hz, J2 = 9.0 Hz); 2.37 (d, 3 H, Н3С(1), J =
1.0 Hz); 2.74 (dd, 1 H, H(7β), J1 = 17.5 Hz, J2 = 6.0 Hz); 3.65
(s, 3 H, Н3С(7a)); 6.98 (ddd, 1 H, H(4a), J1 = 9.0 Hz, J2
8.0 Hz, J3 = 1.0 Hz); 7.09 (ddd, 1 H, H(3a), J1 = 9.0 Hz, J2 =
7.5 Hz, J3 = 1.0 Hz); 7.26 (dd, 1 H, H(2a), J1 = 7.5 Hz, J2
=
=
(+)ꢀ2ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(2ꢀmethylꢀ1Hꢀindolꢀ3ꢀ
yl)cyclopropyl]ethanol (7). A solution of ester 4 (0.27 g, 1.0 mmol)
in Et2O was added dropwise to a suspension of LiAlH4 (0.08 g,
2.0 mmol) in Et2O (10 mL), and the reaction mixture was stirred
for 30 min at ∼20 °C. The residue of LiAlH4 was decomposed
with EtOAc (10 mL), after which an aqueous solution (50 mL)
of HCl (4 mol L–1) was added to the mixture. The organic layer
was separated, and the aqueous solution was extracted with
EtOAc (2×10 mL). The combined organic extract was washed
with a solution of Na2CO3 (0.5 mol L–1) and a saturated soluꢀ
tion of NaCl. After drying the extract above anhydrous Na2SO4,
removal of the solvent in vacuo, and chromatography of the
residue on silica gel (30% EtOAc in petroleum ether as the eluꢀ
ent), alcohol 7 was obtained in 79% yield (0.19 g) as a viscous
1.0 Hz); 7.48 (dd, 1 H, H(5a), J1 = 8.0 Hz, J2 = 1.0 Hz).
13C NMR (acetoneꢀd6), δ: 11.94 (q, С(1)); 15.25 (t, С(7));
16.91 (q, С(9)); 19.12 (s, С(5)); 23.67 and 23.83 (both d, С(4),
С(6)); 28.69 (q, С(10)); 29.71 (q, С(7a)); 106.50 (s, С(3));
109.54 (d, С(5a)); 119.47, 119.67, and 121.27 (all d, С(2a),
С(3a), С(4a)); 120.89 (s, С(8)); 129.37 (s, С(1a)); 137.30 and
137.95 (both s, С(2), С(6a)). MS, m/z (Irel (%)): 252 [M]+ (16),
213 (17), 212 (100), 198 (5), 197 (11), 196 (14), 182 (16), 181
(6), 97 (5). Found: m/z 252.1627 [М]+. С17H20N2. Calculated:
М = 252.1626.
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(2ꢀmethylꢀ1ꢀpropylꢀ1Hꢀindolꢀ
3ꢀyl)cyclopropyl]acetonitrile (9) was synthesized using method A
from indole 2 (0.48 g, 2.0 mmol) and PrnBr (0.37 g, 3.0 mmol).
The reaction was carried out for 3 h on heating (∼50 °С). After a
standard treatment and chromatography, product 9 was obꢀ
25
light yellow oil with [α]578 +60.3 (c 2.02). UV (EtOH),
22
λ
max/nm (ε): 228 (30600), 284 (6300), 293 (5900). IR (CHCl3),
tained in 63% yield (0.35 g) with [α]578 +126.5 (c 3.15).
ν/cm–1: 3625 (OH), 3470 (NHindole), 1460 (C=Carom), 1015,
785, 730, and 660 (C—Harom). 1H NMR (СDCl3), δ: 0.97 (ddd,
1 Н, H(6), J1 = 8.8 Hz, J2 = 4.0 Hz, J3 = 3.5 Hz); 1.02 (s, 3 Н,
Н3С(9)); 1.25 (dddd, 1 Н, H(7α), J1 = 18.5 Hz, J2 = 7.1 Hz,
J3 = 7.1 Hz, J4 = 4.0 Hz); 1.34 (s, 3 Н, Н3С(10)); 1.69 (dq, 1 Н,
H(4), J1 = 8.8 Hz, J2 = 1.0 Hz); 1.89 (br.s, 1 Н, OH); 1.98
(dddd, 1 Н, H(7β), J1 = 18.5 Hz, J2 = 7.1 Hz, J3 = 7.1 Hz, J4 =
3.5 Hz); 2.34 (d, 3 Н, Н3С(1), J1 = 1.0 Hz); 3.68 (t, 2 Н,
Н2С(8), J = 7.1 Hz); 7.02—7.19 (m, 3 H, H(2a), H(3a), H(4a));
7.51—7.58 (m, 1 H, H(5a)); 7.88 (br.s, 1 Н, NH). 13C NMR
(СDCl3), δ: 13.04 (q, C(1)); 17.24 (q, C(9)); 18.03 (s, C(5));
22.68 and 23.83 (both d, C(4), C(6)); 29.23 (q, C(10)); 30.17
(t, C(7)); 63.16 (t, C(8)); 108.79 (s, C(3)); 109.86 (d, C(5a));
118.55, 119.55, and 120.51 (all d, C(2a), C(3a), C(4a)); 129.86
(s, C(1a)); 133.75 and 135.37 (both s, C(2), C(6a)). MS,
m/z (Irel (%)): 243 [M]+ (50), 212 (26), 199 (17), 198 (100), 183
(17), 182 (23), 170 (14), 169 (13), 168 (26), 167 (14), 144 (26),
131 (25), 130 (11). Found: m/z 243.1624 [М]+. С16H21NO.
Calculated: М = 243.1623.
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(1,2ꢀdimethylꢀ1Hꢀindolꢀ3ꢀ
yl)cyclopropyl]acetonitrile (8). Method 1. Compound 8 was synꢀ
thesized using method А from indole 2 (0.48 g, 2.0 mmol) and
MeI (0.43 g, 3.0 mmol). The reaction was carried out at ∼20 °C
for 4 h. After a standard treatment, a crystalline substance (0.49 g)
was obtained, whose recrystallization from 80% aqueous EtOH
gave product 8 in 82% yield (0.41 g).
Method 2. Compound 8 was synthesized using method B
from 18ꢀcrownꢀ6 (0.05 g, ∼0.2 mmol), ButOK (0.26 g, 2.3 mmol),
indole 2 (0.48 g, 1.0 mmol), and MeI (0.43 g, 3.0 mmol) in
ButOMe (70 mL). The mixture was refluxed for 8 h until the
reaction ceased. After a standard treatment, a crystalline subꢀ
stance (0.50 g) was isolated and recrystallized from 80% aqueꢀ
UV (EtOH), λmax/nm (ε): 229 (32900), 286 (7100), 294 (6700).
IR (CHCl3), ν/cm–1: 2250 (С≡N), 1730, 1465 (C=Сarom), 1355,
1220, 1190. 1H NMR (СDCl3—CCl4), δ: 0.96 (t, 3 Н, Н3С(9a),
J = 7.5 Hz); 1.13 (s, 3 Н, Н3С(9)); 1.22—1.37 (m, 1 Н, H(6));
1.41 (s, 3 Н, Н3С(10)); 1.77 (m, 2 Н, Н2С(8a)); 1.85 (d, 1 Н,
H(4), J = 9.7 Hz); 1.95 (dd, 1 Н, H(7α), J1 = 18.0 Hz, J2
9.0 Hz); 2.37 (s, 3 Н, Н3С(1)); 2.61 (dd, 1 Н, H(7β), J1
=
=
18.0 Hz, J2 = 6.0 Hz); 4.01 (t, 2 Н, Н2С(7a), J = 7.8 Hz);
6.92—7.08 (m, 2 Н, H(3a), H(4a)); 7.20 (m, 1 Н, H(2a)); 7.40
(m, 1 Н, H(5a)). 13C NMR (СDCl3—CCl4), δ: 11.43 and 11.78
(both q, C(1), C(9a)); 15.01 (t, C(7)); 16.51 (q, C(9)); 18.61
(s, C(5)); 22.48 (t, C(8a)); 23.08 and 23.27 (both d, C(4),
C(6)); 28.47 (q, C(10)); 44.68 (t, C(7a)); 105.98 (s, C(3));
108.77 (d, C(5a)); 118.81, 118.91, and 120.72 (all d, C(2a),
C(3a), C(4a)); 119.50 (s, C(8)); 128.21 (s, C(1a)); 135.31 and
136.10 (both s, C(2), C(6a)). MS, m/z (Irel (%)): 280 [M]+
(16), 241 (19), 240 (100), 224 (6), 210 (6), 182 (6). Found:
m/z 280.1931 [М]+. C19H24N2. Calculated: М = 280.1939.
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(1ꢀbutylꢀ2ꢀmethylꢀ1Hꢀindolꢀ
3ꢀyl)cyclopropyl]acetonitrile (10) was synthesized using method
A from indole 2 (0.48 g, 2.0 mmol) and BunBr (0.41 g, 3.0 mmol).
The reaction was carried out at ∼50 °С for 3 h. After a standard
treatment and chromatography, product 10 was obtained in
24
75% yield (0.44 g) with [α]578 +88.1 (c 1.79). UV (EtOH),
λ
max/nm (ε): 229 (36300), 286 (7700), 294 (7500). IR (CCl4),
ν/cm–1: 3055 (C—Harom), 2250 (С≡N), 1465 (C=Сarom), 1365,
740 (С—Нarom). 1H NMR (СDCl3—CCl4), δ: 1.05 (t, 3 Н,
Н3С(10a), J = 8.0 Hz); 1.16 (s, 3 Н, Н3С(9)); 1.32—1.48 (m,
3 Н, H(6), Н2С(9a)); 1.44 (s, 3 Н, Н3С(10)); 1.76 (m, 2 Н,
Н2С(8a)); 1.85 (d, 1 Н, H(4), J = 9.7 Hz); 1.99 (dd, 1 Н,
H(7α), J1 = 18.0 Hz, J2 = 9.5 Hz); 2.40 (s, 3 Н, Н3С(1)); 2.65
(dd, 1 Н, H(7β), J1 = 18.0 Hz, J2 = 6.0 Hz); 4.06 (t, 2 Н,

N,OꢀAlkylation of indole derivatives
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1835
Н2С(7a), J = 7.8 Hz); 7.04—7.16 (m, 2 Н, H(3a), H(4a));
7.23 (m, 1 Н, H(2a)); 7.43 (m, 1 Н, H(5a)). 13C NMR
(СDCl3—CCl4), δ: 11.76 (q, C(10a)); 13.84 (q, C(1)); 15.02
(t, C(7)); 16.53 (q, C(9)); 18.62 (s, C(5)); 20.24 (t, C(9a));
22.46 and 23.07 (both d, C(4), C(6)); 28.48 (q, C(10)); 32.23
(t, C(8a)); 42.96 (t, C(7a)); 105.97 (s, C(3)); 108.72 (d, C(5a));
118.81, 118.90, and 120.72 (all d, C(2a), C(3a), C(4a)); 119.52
(s, C(8)); 128.22 (s, C(1a)); 135.22 and 136.03 (both, C(2),
C(6a)). MS, m/z (Irel (%)): 294 [M]+ (11), 255 (20), 254 (100),
238 (5), 224 (4), 182 (7), 181 (4), 180 (3), 168 (5), 167 (4),
41 (4). Found: m/z 294.2100 [М]+. C20H26N2. Calculated:
М = 294.2096.
J3 = 2.0 Hz); 7.22 (dd, 1 H, H(2a), J1 = 8.0 Hz, J2 = 2.0 Hz);
7.47 (dd, 1 H, H(5a), J1 = 7.0 Hz, J2 = 2.0 Hz). 13C NMR
(СDCl3), δ: 11.49 (q, С(1)); 15.04 (t, С(7)); 16.45 (q, С(9));
18.62 (s, С(5)); 22.48 and 22.96 (both d, С(4), С(6)); 28.32
(q, С(10)); 45.22 (t, С(7a)); 106.30 (s, С(3)); 108.85 (d, С(5a));
115.98 (t, С(9a)); 118.80, 119.06, and 120.81 (all d, С(2a),
С(3a), С(4a)); 120.05 (s, С(8)); 128.26 (s, С(1a)); 133.15
(d, С(8a)); 135.86 and 136.21 (both s, С(2), С(6a)). MS,
m/z (Irel (%)): 279 [M + H]+ (5), 278 [M]+ (17), 239 (18), 238
(100), 223 (5), 208 (7), 197 (6), 182 (12), 181 (6), 167 (7),
41 (5). Found: m/z 278.1781 [М]+. С19H22N2. Calculated:
М = 278.1783.
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(1ꢀhexylꢀ2ꢀmethylꢀ1Hꢀindolꢀ
3ꢀyl)cyclopropyl]acetonitrile (11) was synthesized using method
A from indole 2 (0.48 g, 2.0 mmol) and 1ꢀbromohexane (0.49 g,
3.0 mmol). The reaction was carried out at ∼50 °С for 3 h. After
a standard treatment and chromatography, product 11 was obꢀ
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(1ꢀbenzylꢀ2ꢀmethylꢀ1Hꢀindolꢀ
3ꢀyl)cyclopropyl]acetonitrile (13) was synthesized using method A
from indole 2 (0.48 g, 2.0 mmol) and PhCH2Cl (0.38 g,
3.0 mmol). The reaction was carried out at ∼50 °С for 3 h. After
a standard treatment and recrystallization from EtOH, product
13 was isolated in 84% yield (0.55 g) with m.p. 64—66 °С (from
23
tained in 42% yield (0.27 g) with [α]578 +88.1 (c 2.85).
24
UV (EtOH), λmax/nm (ε): 229 (33500), 286 (7100), 292 (6800).
IR (CCl4), ν/cm–1: 3060 (C—Harom), 2245 (С≡N), 1740,
1470 (C=Сarom), 1370, 1240, 1135, 810 (C—Нarom). 1H NMR
(СDCl3—CCl4), δ: 0.92 (m, 3 Н, Н3С(12a)); 1.14 (s, 3 Н,
Н3С(9)); 1.31—1.39 (m, 7 Н, H(6), H2С(9a), H2С(10a),
H2С(11a)); 1.42 (s, 3 Н, Н3С(10)); 1.74 (m, 2 Н, Н2С(8a));
1.83 (dq, 1 Н, H(4), J1 = 8.4 Hz, J2 = 1.0 Hz); 1.93 (dd, 1 Н,
H(7α), J1 = 17.5 Hz, J2 = 9.2 Hz); 2.38 (d, 3 Н, Н3С(1), J =
1.0 Hz); 2.63 (dd, 1 Н, H(7β), J1 = 17.5 Hz, J2 = 5.8 Hz); 4.03
(t, 2 Н, H2С(7a), J = 7.5 Hz); 7.01 (m, 1 Н, H(3a)); 7.09 (m,
1 Н, H(4a)); 7.20 (m, 1 Н, H(2a)); 7.40 (m, 1 Н, H(5a)).
13C NMR (СDCl3—CCl4), δ: 11.81 (q, C(12a)); 13.97 (q, C(1));
15.05 (t, C(7)); 16.55 (q, C(9)); 18.66 (s, C(5)); 22.52 (t, C(11a));
22.47 and 23.08 (both d, C(4), C(6)); 26.72 (t, C(10a)); 28.53
(q, C(10)); 30.07 and 31.47 (both t, C(8a), C(9a)); 43.23
(t, C(7a)); 106.00 (s, C(3)); 108.74 (d, C(5a)); 118.65, 118.95,
and 120.78 (all d, C(2a), C(3a), C(4a)); 119.56 (s, C(8)); 128.24
(s, C(1a)); 135.23 and 136.03 (both s, C(2), C(6a)). MS,
m/z (Irel (%)): 322 [M]+ (9), 283 (22), 282 (100), 266 (3),
196 (3), 182 (5), 181 (3), 168 (4), 43 (7), 41 (4). Found:
m/z 322.0296 [М]+. C22H30N2. Calculated: М = 322.0292.
(+)ꢀ{(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ[2ꢀmethylꢀ1ꢀ(2ꢀpropenylꢀ1Hꢀ
indolꢀ3ꢀyl)]cyclopropyl]acetonitrile (12) was synthesized using
method B from 18ꢀcrownꢀ6 (0.03 g, ∼0.1 mmol), ButOK (0.12 g,
1.1 mmol), indole 2 (0.24 g, 1.0 mmol), and 3ꢀbromopropene
(0.27 g, 2.2 mmol) in anhydrous ButOMe (25 mL). The mixture
was refluxed for 14 h to the end of the reaction. After a standard
treatment and chromatography, crystalline product 12 was obꢀ
tained in 72% yield (0.20 g), with m.p. 55—57 °С (from EtOH),
[α]57824 +125.5 (c 4.11). UV (EtOH), λmax/nm (ε): 228 (25800),
286 (6000), 294 (5700). IR (KBr), ν/cm–1: 3030 (C—Harom),
2240 (C≡N), 1465, 1455 (C=Carom), 1375, 1320, 930, 765, and
755 (C—Harom). 1H NMR (СDCl3), δ: 1.12 (s, 3 H, Н3С(9));
1.35 (ddd, 1 H, H(6), J1 = 9.5 Hz, J2 = 9.0 Hz, J3 = 6.0 Hz);
1.40 (s, 3 H, Н3С(10)); 1.86 (dq, 1 H, H(4), J1 = 9.0 Hz, J2 =
1.0 Hz); 1.95 (dd, 1 H, H(7α), J1 = 18.0 Hz, J2 = 9.5 Hz); 2.34
EtOH), [α]578 +110.1 (c 3.96). UV (EtOH), λmax/nm (ε): 203
(35300), 226 (37600), 286 (8400), 294 (7900). IR (KBr), ν/cm–1
:
3050 (C—Harom), 2245 (C≡N), 1490, 1465, 1450 (C=Carom),
1190, 730, and 720 (C—Harom). 1H NMR (СDCl3), δ: 1.15 (s,
3 H, Н3С(9)); 1.38 (ddd, 1 H, H(6), J1 = 9.2 Hz, J2 = 9.0 Hz,
J3 = 5.5 Hz); 1.41 (s, 3 H, Н3С(10)); 1.90 (dq, 1 H, H(4), J1 =
9.0 Hz, J2 = 1.2 Hz); 1.99 (dd, 1 H, H(7α), J1 = 17.5 Hz, J2 =
9.2 Hz); 2.32 (d, 3 H, Н3С(1), J = 1.2 Hz); 2.68 (dd, 1 H,
H(7β), J1 = 17.5 Hz, J2 = 5.5 Hz); 5.31 (s, 2 H, Н2С(7a));
6.91—6.99 (m, 2 H, H(3a), H(4a)); 7.06—7.15 (m, 3 H, H(9a),
H(11a)); 7.16—7.33 (m, 3 H, H(2a), H(10a)); 7.48—7.56 (m,
1 H, H(5a)). 13C NMR (СDCl3), δ: 11.73 (q, С(1)); 15.06
(t, С(7)); 16.46 (q, С(9)); 18.64 (s, С(5)); 22.42 and 22.97
(both d, С(4), С(6)); 28.30 (q, С(10)); 46.47 (t, С(7a)); 106.67
(s, С(3)); 109.03 (d, С(5a)); 118.85, 119.20, and 121.02 (all d,
С(2a), С(3a), С(4a)); 120.02 (s, С(8)); 125.74 (two d, С(9a));
127.19 (d, С(11a)); 128.31 (s, С(1a)); 128.66 (two d, С(10a));
136.02 and 136.65 (both s, С(2), С(6a)); 137.57 (s, С(8a)). MS,
m/z (Irel (%)): 328 [М]+ (13), 289 (24), 288 (100), 182 (5),
92 (6), 91 (85), 65 (6), 28 (4). Found: m/z 328.1945 [М]+.
С23H24N2. Calculated: М = 328.1939.
(+)ꢀMethyleneꢀbis{3ꢀ[(1R,3S)ꢀ3ꢀ(cyanomethyl)ꢀ2,2ꢀdiꢀ
methylꢀ2ꢀmethylcyclopropyl]ꢀ1Hꢀindoleꢀ1ꢀyl} (14) was syntheꢀ
sized using method A from indole 2 (0.48 g, 2.0 mmol) and
CH2Br2 (0.70 g, 4.0 mmol). The reaction mixture was vigorꢀ
ously stirred for 10 h at ∼20 °C until the starting indole disapꢀ
peared (TLC monitoring). After a standard treatment and reꢀ
crystallization from DMF, product 14 was obtained in 77%
yield (0.38 g) with m.p. 259—262 °С (from DMF), [α]57822 +71.3
(c 0.64, DMF). UV (EtOH), λmax/nm (ε): 226 (58600), 284
(15500), 293 (14100). IR (KBr), ν/cm–1: 3050 (C—Harom), 2245
(C≡N), 1455 (C=Carom), 1300, 730 (C—Harom). 1H NMR (pyriꢀ
dineꢀd5), δ: 1.01 (s, 3 H, Н3С(9)); 1.27 (s, 3 Н, Н3С(10)); 1.29
(ddd, 1 H, H(6), J1 = 9.0 Hz, J2 = 8.8 Hz, J3 = 6.0 Hz); 1.75 (d,
1 H, H(4), J1 = 8.8 Hz); 1.95 (dd, 1 H, H(7α), J1 = 17.5 Hz, J2 =
9.0 Hz); 2.19 (s, 3 H, Н3С(1)); 2.59 (dd, 1 H, H(7β), J1
=
(d, 3 H, Н3С(1), J = 1.0 Hz); 2.65 (dd, 1 H, H(7β), J1
=
17.5 Hz, J2 = 6.0 Hz); 6.39 (s, 1 H, Н2С(7a)); 7.12—7.19 (m,
2 H, H(3a), H(4a)); 7.28 (d, 1 H, H(2a), J = 8.2 Hz); 7.62 (d,
1 H, H(5a), J = 8.0 Hz). 13C NMR (pyridineꢀd5), δ: 12.30
(q, С(1)); 15.17 (t, С(7)); 16.59 (q, С(9)); 18.88 (s, C(5)); 23.45
and 23.49 (both d, С(4), С(6)); 28.33 (q, С(10)); 53.71 (t, С(7a));
109.14 (s, C(3)); 109.93 (d, C(5a)); 119.98, 120.40, and 122.11
(all d, C(2a), C(3a), C(4a)); 120.46 (s, С(8)); 129.55 (s, C(1a));
18.0 Hz, J2 = 6.0 Hz); 4.67 (dt, 2 H, Н2С(7a), J1 = 5.0 Hz, J2 =
1.5 Hz); 4.78 (ddt, 1 H, Htrans(9a), J1 = 17.0 Hz, J2 = 2.0 Hz,
J3 = 1.5 Hz); 5.11 (ddt, 1 H, Hcis(9a), J1 = 10.5 Hz, J2 = 2.0 Hz,
J3 = 1.5 Hz); 5.93 (ddt, 1 H, H(8a), J1 = 17.0 Hz, J2 = 10.5 Hz,
J3 = 5.0 Hz); 7.07 (ddd, 1 H, H(3a), J1 = 8.0 Hz, J2 = 5.5 Hz,
J3 = 2.0 Hz); 7.14 (ddd, 1 H, H(4a), J1 = 7.0 Hz, J2 = 5.5 Hz,

1836
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Burakova et al.
136.64 and 137.48 (both s, C(2), С(6a)). MS, m/z (Irel (%)):
488 [M]+ (6), 448 (12), 252 (19), 251 (100), 224 (5), 223
(17), 209 (5), 208 (12), 196 (9), 182 (5), 181 (8). Found:
m/z 488.2947 [М]+. С33H36N4. Calculated: М = 488.2940.
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(1,2ꢀdimethylꢀ1Hꢀindolꢀ3ꢀ
yl)cyclopropyl]acetamide (15). Method 1. Powdered NaOH
(0.24 g, 6.0 mmol) was added to a solution of indole 8 (1.01 g,
4.0 mmol) in MeOH (20 mL), and then a 30% aqueous solution
of Н2О2 (10 mL) was added dropwise maintaining the temperaꢀ
ture at 30—40 °С. After the initial nitrile disappeared (∼8 h,
TLC monitoring), the reaction mixture was cooled to ∼20 °C,
and the solution was saturated with solid NaCl and extracted
with CHCl3 (3×10 mL). The chloroformic extract was washed
with an aqueous solution of Na2SO3 (0.5 mol L–1) and dried
with anhydrous MgSO4. The solvent was removed in vacuo, and
amide 15 was obtained in 78% yield (0.84 g), as a light yellow
glassy substance.
Method 2. Compound 15 was synthesized using method A
from indole 2 (0.51 g, 2.0 mmol) and MeI (0.71 g, 5.0 mmol).
The reaction was carried out for 20 h on heating (∼45 °С). After
a standard treatment and chromatography, product 15 was obꢀ
tained in 67% yield (0.36 g) as a colorless glassy substance with
[α]57831 +107.1 (c 1.40). UV (EtOH), λmax/nm (ε): 230 (25500),
287 (5300), 293 (5100). IR (CHCl3), ν/cm–1: 3540 and 3410
(NHamide), 1675 (C=O), 1460 (C=Carom), 1375, 1240. 1H NMR
(t, C(7)); 63.09 (t, C(8)); 108.71 (s, C(3)); 109.21 (d, C(5a));
118.94, 119.15, and 119.48 (all d, C(2a), C(3a), C(4a)); 129.99
(s, C(1a)); 136.62 and 137.80 (both s, C(2), C(6a)). MS,
m/z (Irel (%)): 258 [M + H]+ (10), 257 [M]+ (52), 226 (21), 213
(17), 212 (100), 196 (15), 182 (17), 158 (13), 145 (16). Found:
m/z 257.1780 [М]+. C17H23NO. Calculated: М = 257.1780.
(+)ꢀ2ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(1ꢀethylꢀ2ꢀmethylꢀ1Hꢀ
indolꢀ3ꢀyl)cyclopropyl]ꢀ1ꢀethoxyethane (17) was synthesized usꢀ
ing method A from alcohol 7 (0.24 g, 1.0 mmol), TEBAC (0.04 g,
0.2 mmol), and EtBr (0.22 g, 2.0 mmol). The reaction mixture
was stirred for 5 h at ∼20 °C, and then two additional portions of
EtBr (0.11 g, 1.0 mmol each) were added with an interval of 2 h
(0.44 g of EtBr in all) to complete the reaction (TLC monitorꢀ
ing, the total reaction time was 10 h). After a standard treatment
and chromatography, dialkylation product 17 was obtained in
25
82% yield (0.25 g) as a yellow oil with [α]578 +47.3 (c 1.43,
EtOAc). UV (EtOH), λmax/nm (ε): 206 (17500), 229 (22900),
286 (6100), 293 (5800). IR (CHCl3), ν/cm–1: 1730, 1465
(C=Carom), 1375, 1350, 1105. 1H NMR (СDCl3—CCl4), δ: 0.97
(s, 3 H, Н3С(9)); 1.14—1.27 (m, 2 H, H(6), H(7α)); 1.15 (t,
3 Н, Н3С(10a), J = 7.0 Hz); 1.26 (t, 3 Н, Н3С(8a), J = 7.0 Hz);
1.30 (s, 3 H, Н3С(10)); 1.62 (d, 1 H, Н(4), J = 9.0 Hz);
1.97—2.05 (m, 1 H, H(7β)); 2.33 (s, 3 Н, Н3С(1)); 3.37 (t, 2 Н,
Н2С(8), J = 7.0 Hz); 3.39 (q, 2 Н, Н2С(9a), J = 7.0 Hz); 4.02
(q, 2 Н, Н2С(7a), J = 7.0 Hz); 6.87—6.98 (m, 2 H, H(3a),
H(4a)); 7.08 (m, 1 H, H(2a)); 7.41 (m, 1 H, H(5a)). 13C NMR
(СDCl3—CCl4), δ: 11.74 (q, С(1)); 15.24 and 15.30 (both q,
С(8a), С(10a)); 17.53 (q, С(9)); 18.03 (s, C(5)); 23.21 (d, C(4));
24.57 (d, С(6)); 27.30 (t, С(7)); 29.63 (q, С(10)); 37.53
(t, С(7a)); 66.00 (t, С(9a)); 71.05 (t, С(8)); 108.02 (d, C(5a));
108.50 (s, C(3)); 118.39, 119.91, and 120.33 (all d, C(2a), C(3a),
C(4a)); 129.23 (s, C(1a)); 134.06 and 135.61 (both s, C(2),
С(6a)). MS, m/z (Irel (%)): 299 [M]+ (35), 240 (32), 227 (21),
226 (100), 196 (18), 159 (24), 154 (22), 95 (18), 73 (42), 69 (19),
67 (17), 43 (48), 41 (31), 31 (18), 29 (23), 28 (16). Found:
m/z 299.2250 [М]+. C20H29NO. Calculated: М = 299.2249.
(+)ꢀMethyleneꢀbis{2ꢀmethylꢀ3ꢀ[(1R,3S)ꢀ2,2ꢀdimethylꢀ3ꢀ
(methoxycarbonyl)cyclopropyl]ꢀ1Hꢀindolꢀ1ꢀyl} (18) was syntheꢀ
sized using method A from indole 4 (0.54 g, 2.0 mmol) and
CH2Br2 (0.70 g, 4.0 mmol, 0.28 mL). The reaction mixture was
vigorously stirred for 10 h at ∼20 °C until the starting indole
disappeared (TLC monitoring). After a standard treatment and
chromatography using a 10% EtOAc—petroleum ether mixture
as the eluent, product 18 was obtained in 32% yield (0.18 g) as a
viscous light yellow oil with [α]57818 +60.9 (c 1.61). UV (EtOH),
(СDCl3), δ: 1.00 (s, 3 H, Н3С(9)); 1.34 (ddd, 1 H, H(6), J1
=
9.5 Hz, J2 = 8.5 Hz, J3 = 6.0 Hz); 1.38 (s, 3 Н, Н3С(10)); 1.77
(d, 1 H, H(4), J = 8.5 Hz); 1.89 (dd, 1 H, H(7α), J1 = 17.5 Hz,
J2 = 9.5 Hz); 2.34 (s, 3 H, Н3С(1)); 2.57 (dd, 1 H, H(7β), J1 =
17.5 Hz, J2 = 6.0 Hz); 3.61 (s, 3 H, Н3С(7a)); 5.54 and 5.90
(both br.s, 1 H each, CONH2); 6.98—7.14 (m, 3 H, H(2a),
H(3a), H(4a)); 7.49 (d, 1 H, H(5a), J = 8.0 Hz). 13C NMR
(СDCl3), δ: 11.64 (q, С(1)); 13.98 (q, С(9)); 18.22 (s, C(5));
22.43 and 22.77 (both d, C(4), С(6)); 28.73 (q, С(10)); 29.25
(q, С(7a)); 32.99 (t, С(7)); 107.16 (s, C(3)); 108.21 (d, C(5a));
118.47, 119.23, and 120.29 (all d, C(2a), C(3a), C(4a)); 128.53
(s, C(1a)); 135.86 and 136.58 (both s, C(2), С(6a)); 175.74
(s, С(8)). MS, m/z (Irel (%)): 270 [M]+ (30), 213 (16), 212
(100), 197 (13), 196 (18), 182 (16), 158 (14), 145 (23). Found:
m/z 270.1732 [М]+. С17H22N2O. Calculated: М = 270.1732.
(+)ꢀ2ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(1,2ꢀdimethylꢀ1Hꢀindolꢀ3ꢀ
yl)cyclopropyl]ethanol (16) was synthesized using method A from
alcohol 7 (0.24 g, 1.0 mmol), TEBAC (0.04 g, 0.2 mmol), and
MeI (0.14 g, 1.0 mmol). The reaction mixture was stirred for 5 h
at ∼20 °C, and an addition portion of MeI (0.05 g, 0.35 mmol)
was added to cease the reaction (TLC monitoring). After a stanꢀ
dard treatment and chromatography, Nꢀmethylindole 16 was
obtained in 43% yield (0.11 g) as a light yellow oily substance
λ
max/nm (ε): 227 (52300), 284 (13200), 293 (11800). IR (CCl4),
ν/cm–1: 3050 (C—Harom), 1745 (C=O), 1455 (C=Carom),
1300, 1190, and 1160 (С—O—C), 735 (C—Harom). 1H NMR
(СDCl3—CCl4), δ: 0.87 (s, 3 H, Н3С(9)); 1.34 (s, 3 Н, Н3С(10));
1.35 (ddd, 1 H, H(6), J1 = 9.0 Hz, J2 = 8.5 Hz, J3 = 6.0 Hz);
1.70 (dq, 1 H, H(4), J1 = 9.0 Hz, J2 = 1.0 Hz); 1.91 (dd, 1 H,
H(7α), J1 = 17.5 Hz, J2 = 8.5 Hz); 2.05 (d, 3 H, Н3С(1), J =
1.0 Hz); 2.45 (dd, 1 H, H(7β), J1 = 17.5 Hz, J2 = 6.0 Hz); 3.60
(s, 3 H, Н3С(8a)); 6.17 (s, 1 H, Н2С(7a)); 7.01—7.07 (m, 3 H,
H(2a), Н(3a), H(4a)); 7.44 (m, 1 H, H(5a)). 13C NMR
(СDCl3—CCl4), δ: 12.30 (q, С(1)); 17.15 (q, С(9)); 18.23
(s, C(5)); 22.27 and 22.45 (both d, C(4), С(6)); 28.89 (q, С(10));
31.29 (t, С(7)); 51.19 (q, С(8a)); 52.63 (t, С(7a)); 108.63
(d, C(5a)); 110.06 (s, C(3)); 119.65, 119.86, and 121.57 (all d,
C(2a), C(3a), C(4a)); 129.15 (s, C(1a)); 135.01 and 136.51
(both s, C(2), С(6a)); 173.55 (s, С(8)). MS, m/z (Irel (%)):
27
with [α]578 +52.3 (c 1.99, EtOAc). UV (EtOH), λmax/nm (ε):
205 (16500), 229 (22500), 286 (5800), 293 (5700). IR (CCl4),
ν/cm–1: 3635 (О—Н), 3060 (C—Harom), 1715, 1470 (C=Carom),
1375, 1220, 810, 740 (C—Harom). 1H NMR (acetoneꢀd6), δ:
1.00 (s, 3 Н, Н3С(9)); 1.00—1.31 (m, 2 H, H(6), H(7α)); 1.33
(s, 3 Н, Н3С(10)); 1.64 (dq, 1 Н, H(4), J1 = 8.8 Hz, J2
=
1.2 Hz); 2.01—2.09 (m, 1 H, H(7β)); 2.38 (d, 3 Н, Н3С(1), J =
1.2 Hz); 2.98 (br.s, 1 Н, OH); 3.62 (s, 3 Н, Н3С(7a)); 3.62 (t,
2 Н, Н2С(8), J = 7.0 Hz); 6.96—7.06 (m, 2 H, H(3a), H(4a));
7.24 (dd, 1 Н, H(2a), J1 = 7.2 Hz, J2 = 1.2 Hz); 7.52 (dd, 1 Н,
H(5a), J1 = 7.2 Hz, J2 = 1.2 Hz). 13C NMR (acetoneꢀd6), δ:
12.16 (q, C(1)); 17.77 (q, C(9)); 18.63 (s, C(5)); 23.70 (d, C(4));
25.06 (d, C(6)); 29.59 (q, C(10)); 29.80 (q, C(7a)); 31.34

N,OꢀAlkylation of indole derivatives
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1837
554 [M]+ (3), 285 (21), 284 (55), 271 (25), 256 (16), 242 (34),
199 (17), 198 (100), 196 (15), 183 (15), 182 (21), 168 (17), 144
(19), 131 (25), 45 (14). Found: m/z 554.3159 [М]+. C35H42N2O4.
Calculated: М = 554.3144.
285 [M]+ (34), 199 (16), 198 (100), 196 (11), 183 (10), 182 (16),
168 (12), 167 (8), 144 (14), 131 (27). Found: m/z 285.1730
[М]+. С18H23NO2. Calculated: М = 285.1729.
2ꢀBromoethyl (+)ꢀ[(1R,3S)ꢀ2,2ꢀdimethylꢀ3ꢀ(2ꢀmethylꢀ1Hꢀ
indolꢀ3ꢀyl)cyclopropyl] acetate (21) was synthesized using
method C from acid 6 (0.26 g, 1.0 mmol) and 1,2ꢀdibromoethane
(0.56 g, 3.0 mmol). The reaction time was 10 h. After a standard
treatment and chromatography, ester 21 was obtained in 30%
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(1ꢀbenzylꢀ2ꢀmethylꢀ1Hꢀindolꢀ
3ꢀyl)cyclopropyl]acetic acid (19). A mixture of ester 4 (0.38 g,
1.4 mmol), PhCH2Cl (1.01 g, 8.0 mmol), and TEBAC (0.02 g)
was heated with vigorous stirring to 60 °С. After the ester and
TEBAC dissolved completely, a 50% aqueous solution of NaOH
(2 mL) was added. The suspension that formed was stirred for
4 h at 70—75 °С until initial ester 4 disappeared (TLC monitorꢀ
ing). The reaction mixture was cooled and extracted with
ButOMe (2×15 mL). The aqueous layer was acidified with
10% HCl to pH ∼5 and extracted with CHCl3 (3×20 mL). The
extract was washed with water (15 mL) and a saturated solution
of NaCl and dried with anhydrous Na2SO4. After the solvent
was removed in vacuo and the residue was chromatographed
using 10% EtOAc in hexane as the eluent, acid 19 was isolated
29
yield (0.11 g) as a viscous light yellow oil with [α]578 +48.2
(c 1.23). UV (EtOH), λmax/nm (ε): 227 (25500), 284 (5900), 291
(5700). IR (CCl4), ν/cm–1: 3480 (NHindole), 3060 (C—Harom),
1745 (C=O), 1460 (C=Carom), 1150 (C—O—C), 740
(C—Harom). 1H NMR (acetoneꢀd6), δ: 0.98 (s, 3 Н, Н3С(9));
1.34 (ddd, 1 Н, H(6), J1 = 9.0 Hz, J2 = 8.8 Hz, J3 = 5.8 Hz);
1.35 (s, 3 Н, Н3С(10)); 1.72 (dq, 1 Н, H(4), J1 = 9.0 Hz, J2 =
0.8 Hz); 2.04 (dd, 1 Н, H(7α), J1 = 17.5 Hz, J2 = 8.8 Hz); 2.37
(d, 3 Н, Н3С(1), J = 0.8 Hz); 2.70 (dd, 1 Н, H(7β), J1
=
17.5 Hz, J2 = 5.8 Hz); 3.59 (t, 2 Н, Н2С(8a), J = 6.0 Hz); 4.38
(t, 2 Н, Н2С(7a), J = 6.0 Hz); 6.89—7.01 (m, 2 H, H(3a),
H(4a)); 7.23 (m, 1 H, H(2a)); 7.43 (m, 1 H, H(5a)); 9.92 (br.s,
1 Н, NH). 13C NMR (acetoneꢀd6), δ: 13.10 (q, C(1)); 17.48
(q, C(9)); 18.83 (s, C(5)); 23.09 and 23.34 (both d, C(4), С(6));
29.13 (q, C(10)); 30.33 (t, C(8a)); 32.21 (t, C(7)); 64.51
(t, C(7a)); 107.96 (s, C(3)); 111.07 (d, C(5a)); 119.17, 119.75
and 121.12 (all d, C(2a), C(3a), C(4a)); 130.59 (s, C(1a)); 135.30
and 136.94 (both s, C(2), C(6a)); 173.58 (s, C(8)). MS,
m/z (Irel (%)): 365 [M + 2 H]+ (10), 363 [M]+ (11), 199 (26),
198 (100), 183 (11), 182 (14), 168 (13), 144 (12), 131 (22).
Found: m/z 363.0851 [М]+. C18H22BrNO2. Calculated:
М = 363.0834.
5ꢀBromoamyl (+)ꢀ[(1R,3S)ꢀ2,2ꢀdimethylꢀ3ꢀ(2ꢀmethylꢀ1Hꢀ
indolꢀ3ꢀyl)cyclopropyl] acetate (22) was synthesized using
method C from acid 6 (0.26 g, 1.0 mmol) and 1,5ꢀdibromoꢀ
pentane (0.69 g, 3.0 mmol) during 32 h. After a standard treatꢀ
ment and chromatography, ester 22 was obtained in 38% yield
(0.15 g) as a viscous light yellow oil with [α]57829 +50.4 (c 2.26).
UV (EtOH), λmax/nm (ε): 227 (21900), 283 (6400), 291(5900).
IR (CHCl3), ν/cm–1: 3470 (NHindole), 1730 (C=O), 1460
(C=Carom), 1160 (C—O—C). 1H NMR (СDCl3—CCl4), δ: 0.93
(s, 3 Н, Н3С(9)); 1.34 (s, 3 Н, Н3С(10)); 1.33—1.66 (m, 5 Н,
H(6), Н2С(9a), Н2С(10a)); 1.67 (d, 1 Н, H(4), J = 9.0 Hz);
25
in 69% yield (0.34 g) as a light yellow oil with [α]578 +44.4
(c 1.31). UV (EtOH), λmax/nm (ε): 209 (22600), 227 (22600),
286 (6200). IR (CCl4), ν/cm–1: 3540 (O—H), 3030 (C—Harom),
1740, 1710 (C=O), 1465 (C=Carom), 785, and 740 (C—Harom).
1H NMR (acetoneꢀd6), δ: 1.02 (s, 3 H, Н3С(9)); 1.38 (s, 3 H,
Н3С(10)); 1.40 (ddd, 1 H, H(6), J1 = 9.0 Hz, J2 = 9.0 Hz, J3 =
6.0 Hz); 1.77 (d, 1 H, H(4), J = 9.0 Hz); 2.05 (dd, 1 H, H(7α),
J1 = 18.0 Hz, J2 = 9.0 Hz); 2.30 (s, 3 H, Н3С(1)); 2.68 (dd, 1 H,
H(7β), J1 = 18.0 Hz, J2 = 6.0 Hz); 5.30 (s, 2 H, Н2С(7a));
6.92—7.21 (m, 8 H, H(2a), H(3a), H(4a), H(9a), H(10a),
H(11a)); 7.57—7.61 (m, 1 H, H(5a)); 11.87 (br.s, 1 Н, COOH).
13C NMR (acetoneꢀd6), δ: 11.94 (q, С(1)); 17.47 (q, С(9));
18.67 (s, С(5)); 23.18 and 23.34 (both d, C(4), С(6)); 29.12
(q, С(10)); 31.91 (t, С(7)); 46.75 (t, С(7a)); 108.62 (s, С(3));
109.78 (d, С(5a)); 119.52, 120.07, and 121.35 (all d, С(2a),
С(3a), С(4a)); 126.67 (two d, С(10a)); 127.73 (d, С(11a));
129.29 (two d, С(9a)); 129.78 (s, С(1a)); 136.66 and 137.56
(both s, С(2), С(6a)); 139.29 (s, С(8a)); 175.57 (s, С(8)). MS,
m/z (Irel (%)): 347 [M]+ (15), 289 (19), 288 (85), 221 (6), 92 (9),
91 (100), 65 (8), 28 (7). Found: m/z 347.1883 [М]+. C23H25NO2.
Calculated: М = 347.1885.
Ethyl (+)ꢀ[(1R,3S)ꢀ2,2ꢀdimethylꢀ3ꢀ(2ꢀmethylꢀ1Hꢀindolꢀ3ꢀ
yl)cyclopropyl] acetate (20) was synthesized using method C from
acid 6 (0.26 g, 1.0 mmol) and EtBr (0.32 g, 3.0 mmol) with
stirring for 16 h. After a standard treatment and chromatoꢀ
graphy, ester 20 was obtained in 88% yield (0.25 g) as a light
yellow oil with [α]57826 +68.8 (c 4.42). UV (EtOH), λmax/nm (ε):
228 (155600), 286 (6800), 294 (6200). IR (CCl4), ν/cm–1: 3480
(NHindole), 3055 (C—Harom), 1735 (C=O), 1455 (C=Carom),
1170 и 1155 (С—O—C), 725 (C—Harom). 1H NMR (СDCl3), δ:
0.99 (s, 3 H, Н3С(9)); 1.25 (t, 3 Н, Н3С(8a), J = 7.5 Hz); 1.37
(ddd, 1 H, Н(6), J1 = 9.0 Hz, J2 = 8.0 Hz, J3 = 6.0 Hz); 1.39 (s,
3 Н, Н3С(10)); 1.74 (dq, 1 H, Н(4), J1 = 8.0 Hz, J2 = 1.2 Hz);
2.04 (dd, 1 H, Н(7α), J1 = 17.5 Hz, J2 = 9.0 Hz); 2.32 (d, 3 H,
Н3С(1), J = 1.2 Hz); 2.61 (dd, 1 H, Н(7β), J1 = 17.5 Hz, J2 =
6.0 Hz); 4.14 (q, 2 H, H2С(7a), J = 7.5 Hz); 6.95—7.13 (m, 3 H,
H(2a), H(3a), H(4a)); 7.43 (m, 1 H, H(5a)); 7.82 (br.s, 1 H,
NH). 13C NMR (СDCl3), δ: 12.93 (q, С(1)); 14.28 (q, С(8а));
17.26 (q, С(9)); 18.21 (s, C(5)); 22.43 and 22.55 (both d, C(4),
С(6)); 28.96 (q, С(10)); 31.75 (t, С(7)); 59.88 (t, С(7а)); 108.25
(s, C(3)); 109.90 (d, C(5a)); 118.97, 119.35, and 120.89 (all d,
C(2a), C(3a), C(4a)); 129.77 (s, C(1a)); 133.39 and 135.57
(both s, C(2), С(6a)); 173.47 (s, С(8)). MS, m/z (Irel (%)):
1.74—1.81 (m, 2 Н, Н2С(8a)); 1.94 (dd, 1 Н, H(7α), J1
=
17.5 Hz, J2 = 9.0 Hz); 2.24 (s, 3 Н, Н3С(1)); 2.54 (dd, 1 Н,
H(7β), J1 = 17.5 Hz, J2 = 5.5 Hz); 3.26 (t, 2 Н, Н2С(11a), J =
6.8 Hz); 4.00 (t, 2 Н, Н2С(7a), J = 6.5 Hz); 6.09—7.01 (m, 3 H,
H(2a), H(3a), H(4a)); 7.33 (m, 1 H, H(5a)); 7.75 (br.s, 1 Н,
NH). 13C NMR (СDCl3—CCl4), δ: 12.91 (q, C(1)); 17.26
(q, C(9)); 18.16 (s, C(5)); 22.36 and 22.54 (both d, C(4), С(6));
24.60 (t, C(9a)); 27.63 (t, C(8a)); 28.93 (q, C(10)); 31.65
(t, C(11a)); 32.19 (t, C(7)); 32.60 (t, C(10a)); 63.82 (t, C(7a));
108.09 (s, C(3)); 109.90 (d, C(5a)); 118.93, 119.25, and 120.84
(all d, C(2a), C(3a), C(4a)); 129.71 (s, C(1a)); 133.35 and 135.54
(both s, C(2), C(6a)); 173.36 (s, C(8)). MS, m/z (Irel (%)): 407
[M + 2 H]+ (10), 405 [M]+ (9), 199 (16), 198 (100), 183 (11),
182 (14), 168 (11), 144 (10), 131 (31), 69 (20), 43 (12), 41 (15),
28 (10). Found: m/z 405.1303 [М]+. C21H28BrNO2. Calculated:
М = 405.1304.
Benzyl (+)ꢀ[(1R,3S)ꢀ2,2ꢀdimethylꢀ3ꢀ(2ꢀmethylꢀ1Hꢀindolꢀ3ꢀ
yl)cyclopropyl] acetate (23) was synthesized using method C from
acid 6 (0.26 g, 1.0 mmol) and PhCH2Cl (0.14 g, 1.1 mmol). The
reaction time was 12 h. After a standard treatment and chromaꢀ

1838
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Burakova et al.
tography, ester 23 was obtained in 66% yield (0.23 g) as a viscous
light yellow oil with [α]578 +50.4 (c 2.46). UV (EtOH),
H(7β), J1 = 17.5 Hz, J2 = 5.8 Hz); 4.05 (m, 2 Н, Н2С(7a));
6.99—7.08 (m, 3 H, H(2a), H(3a), H(4a)); 7.43 (d, 1 H, H(5a),
J = 7.5 Hz); 7.90 (br.s, 1 Н, NH). 13C NMR (СDCl3—CCl4), δ:
12.84 (q, C(1)); 17.23 (q, C(9)); 18.11 (s, C(5)); 22.30 and
22.48 (both d, C(4), C(6)); 22.52 (t, C(9a)); 28.29 (t, C(8a));
28.90 (q, C(10)); 31.61 (t, C(7)); 63.79 (t, C(7a)); 107.98
(s, C(3)); 109.95 (d, C(5a)); 118.87, 119.25, and 120.78 (all d,
C(2a), C(3a), C(4a)); 129.68 (s, C(1a)); 133.43 and 135.52
(both s, C(2), C(6a)); 173.54 (s, C(8)). MS, m/z (Irel (%)):
582 [M]+ (4), 199 (16), 198 (100), 182 (7), 168 (6), 144 (8), 131
(6), 28 (7). Found: m/z 582.3459 [М]+. C37H46N2O4. Calcuꢀ
lated: М = 582.3457.
27
λ
max/nm (ε): 227 (30900), 284 (6600), 293 (6100). IR (CCl4),
ν/cm–1: 3480 (NHindole), 3070 (C—Harom), 1740 (C=O), 1460
(C=Carom), 1150 (C—O—C), 735 and 695 (C—Harom). 1H NMR
(acetoneꢀd6), δ: 0.94 (s, 3 Н, Н3С(9)); 1.32 (s, 3 Н, Н3С(10));
1.38 (ddd, 1 Н, H(6), J1 = 9.0 Hz, J2 = 8.8 Hz, J3 = 5.8 Hz);
1.71 (dq, 1 Н, H(4), J1 = 9.0 Hz, J2 = 1.2 Hz); 2.05 (dd, 1 Н,
H(7α), J1 = 17.5 Hz, J2 = 8.8 Hz); 2.34 (d, 3 Н, Н3С(1), J =
1.2 Hz); 2.70 (dd, 1 Н, H(7β), J1 = 17.5 Hz, J2 = 5.8 Hz); 5.11
(s, 2 Н, Н2С(7a)); 6.86—7.01 (m, 2 H, H(3a), H(4a)); 7.23 (m,
1 H, H(2a)); 7.30—7.36 (m, 5 H, H(9a), H(10a), H(11a)); 7.42
(m, 1 H, H(5a)); 9.88 (br.s, 1 Н, NH). 13C NMR (acetoneꢀd6),
δ: 13.08 (q, C(1)); 17.48 (q, C(9)); 18.79 (s, C(5)); 23.24 and
23.39 (both d, C(4), C(6)); 29.03 (q, C(10)); 32.39 (t, C(7));
66.37 (t, C(7a)); 108.00 (s, C(3)); 111.07 (d, C(5a)); 119.19,
119.79, and 121.12 (all d, C(2a), C(3a), C(4a)); 128.74 (d,
C(11a)); 128.94 (two d, C(9a)); 129.20 (two d, C(10a)); 130.63
(s, C(1a)); 135.32 (s, C(8a)); 136.96 and 137.58 (both s, C(2),
C(6a)); 173.76 (s, C(8)). MS, m/z (Irel (%)): 347 [M]+ (30), 257
(11), 256 (63), 199 (17), 198 (100), 196 (12), 183 (12), 182 (17),
171 (12), 170 (87), 168 (16), 144 (13), 131 (12), 91 (37). Found:
m/z 347.1883 [М]+. C23H25NO2. Calculated: М = 347.1885.
Ethylene glycol (+)ꢀdiꢀ[(1R,3S)ꢀ2,2ꢀdimethylꢀ3ꢀ(2ꢀmethylꢀ
1Hꢀindolꢀ3ꢀyl)cyclopropyl] acetate (24) was synthesized using
method C from acid 6 (0.26 g, 1.0 mmol) and 1,2ꢀdibromoethane
(0.09 g, 0.5 mmol). The reaction time was 40 h. After a standard
treatment and chromatography, ester 24 was obtained in 44%
Benzyl (+)ꢀ[(1R,3S)ꢀ2,2ꢀdimethylꢀ3ꢀ(1ꢀbenzylꢀ2ꢀmethylꢀ
1Hꢀindolꢀ3ꢀyl)cyclopropyl] acetate (26). A mixture of acid 6
(0.26 g, 1.0 mmol), PhCH2Cl (0.51 g, 4.0 mmol), and TEBAC
(0.01 g) was heated with vigorous stirring to 60 °С. After the acid
and TEBAC were completely dissolved, a 50% aqueous solution
of NaOH (2 mL) was added. The suspension that formed was
stirred for 6 h at 60—65 °С until the initial acid disappeared
(TLC monitoring), during which the mixture was rarefied. The
reaction mixture was cooled and extracted with ButOMe
(3×20 mL). The combined extract was washed with water
(15 mL) and a saturated solution of NaCl and dried with anhyꢀ
drous Na2SO4. After the solvent was removed in vacuo and the
residue was chromatographed using 10% EtOAc in hexane as
the eluent, indolo ester 26 was isolated in 73% yield (0.32 g) as a
23
light yellow oil with [α]578 +35.8 (c 1.96). UV (EtOH),
λ
max/nm (ε): 210 (26200), 226 (23100), 286 (6400). IR (CCl4),
yield (0.12 g) as a colorless glassy substance with [α]578 +55.4
ν/cm–1: 3030 (C—Harom), 1740 (C=O), 1465 (C=Carom), 1455,
1155 (C—O—C), 805 (C—Harom). 1H NMR (СDCl3—ССl4), δ:
0.92 (s, 3 Н, Н3С(9)); 1.32 (s, 3 Н, Н3С(10)); 1.34 (ddd, 1 H,
H(6), J1 = 9.0 Hz, J2 = 8.5 Hz, J3 = 6.0 Hz); 1.75 (d, 1 Н, Н(4),
J = 9.0 Hz); 2.03 (dd, 1 Н, H(7α), J1 = 17.5 Hz, J2 = 8.5 Hz);
2.20 (s, 3 Н, Н3С(1)); 2.61 (dd, 1 Н, H(7β), J1 = 17.5 Hz, J2 =
6.0 Hz); 5.03 (s, 2 Н, Н2С(12a)); 5.19 (s, 2 Н, Н2С(7a));
6.81—7.28 (m, 13 H, H(2a), H(3a), H(4a), H(9a), H(10a),
H(11a), H(14a), H(15a), H(16a)); 7.40—7.44 (m, 1 H, H(5a)).
13C NMR (СDCl3—ССl4), δ: 11.73 (q, C(1)); 17.37 (q, C(9));
18.33 (s, C(5)); 22.52 and 22.94 (both d, C(4), С(6)); 29.00
(q, C(10)); 31.61 (t, C(7)); 46.49 (t, C(7a)); 71.92 (t, C(12a));
108.29 (s, C(3)); 108.71 (d, C(5a)); 119.11, 119.57, and 121.00
(all d, C(2a), C(3a), C(4a)); 125.79, 128.32, 128.36, 128.74
(all two d each, C(9a), C(10a), C(14a), C(15a)); 127.60, and
127.98 (both d, C(11a), C(16a)); 128.95 (s, C(1a)); 135.23
and 136.76 (both s, C(2), C(6a)); 136.26 (s, C(8a)); 137.95
(s, C(13a)); 172.96 (s, C(8)). MS, m/z (Irel (%)): 437 [M]+ (8),
346 (7), 289 (17), 288 (77), 260 (9), 234 (5), 221 (8), 182 (5),
92 (9), 91 (100), 65 (7), 28 (5). Found: m/z 437.2357 [М]+.
25
(c 1.45). UV (EtOH), λmax/nm (ε): 227 (112500), 284 (23100),
291 (21600). IR (CHCl3), ν/cm–1: 3470 (NHindole), 1735
(C=O), 1460 (C=Carom), 1155 (C—O—C), 790, 730, and 670
1
(C—Harom). H NMR (СDCl3), δ: 0.89 (s, 3 Н, Н3С(9)); 1.31
(s, 3 Н, Н3С(10)); 1.35 (ddd, 1 Н, H(6), J1 = 9.0 Hz, J2
=
8.8 Hz, J3 = 5.8 Hz); 1.68 (dq, 1 Н, H(4), J1 = 9.0 Hz, J2
=
1.0 Hz); 2.05 (dd, 1 Н, H(7α), J1 = 17.5 Hz, J2 = 8.8 Hz); 2.26
(d, 3 Н, Н3С(1), J = 1.0 Hz); 2.60 (dd, 1 Н, H(7β), J1
=
17.5 Hz, J2 = 5.8 Hz); 4.21 (s, 2 Н, Н2С(7a)); 6.95—7.10 (m,
2 H, H(3a), H(4a)); 7.16—7.22 (m, 1 H, H(2a)); 7.39—7.45 (m,
1 H, H(5a)); 7.66 (br.s, 1 Н, NH). 13C NMR (СDCl3), δ: 12.81
(q, C(1)); 17.01 (q, C(9)); 18.16 (s, C(5)); 22.07 and 22.34
(both d, C(4), C(6)); 28.65 (q, C(10)); 31.51 (t, C(7)); 61.92
(t, C(7a)); 108.09 (s, C(3)); 109.91 (d, C(5a)); 118.85, 119.26,
and 120.76 (all d, C(2a), C(3a), C(4a)); 129.65 (s, C(1a)); 133.86
and 135.37 (both s, C(2), C(6a)); 173.65 (s, C(8)). MS,
m/z (Irel (%)): 540 [M]+ (5), 199 (16), 198 (100), 183 (8), 182
(9), 168 (8), 144 (8), 131 (11), 28 (8). Found: m/z 540.3001 [М]+.
C34H40N2O4. Calculated: М = 540.2988.
1,5ꢀPentanediol (+)ꢀdiꢀ[(1R,3S)ꢀ2,2ꢀdimethylꢀ3ꢀ(2ꢀmethylꢀ
1Hꢀindolꢀ3ꢀyl)cyclopropyl] acetate (25) was synthesized using
method C from acid 6 (0.26 g, 1.0 mmol) and 1,5ꢀdibromoꢀ
pentane (0.12 g, 0.5 mmol). The reaction time was 32 h. After a
standard treatment and chromatography, ester 25 was obtained
C
30H31NO2. Calculated: М = 437.2355.
(+)ꢀ{(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ[2ꢀmethylꢀ1ꢀ(tolueneꢀ4ꢀsulfoꢀ
nyl)ꢀ1Hꢀindolꢀ3ꢀyl]cyclopropyl}acetonitrile (27) was obtained
using method A from indole 2 (0.48 g, 2.0 mmol) and TsCl
(0.57 g, 3.0 mmol). The reaction was carried out at ∼20 °C for
1 h. After a standard treatment and chromatography, product 27
was obtained in 95% yield (0.74 g) as a light yellow oil with
25
in 76% yield (0.22 g) as a light yellow oil with [α]578 +71.8
(c 1.81). UV (EtOH), λmax/nm (ε): 209 (22400), 227 (23700),
284 (8700), 291 (8000). IR (CHCl3), ν/cm–1: 3470 (NHindole),
1725 (C=O), 1460 (C=Carom), 1295, 1175 (C—O—C). 1H NMR
(СDCl3—CCl4), δ: 0.98 (s, 3 Н, Н3С(9)); 1.30—1.45 (m, 2 H,
H(6), Н2С(9a)); 1.36 (s, 6 Н, Н3С(10)); 1.60 (m, 2 Н, Н2С(8a));
30
[α]578 +61.3 (c 2.77). UV (EtOH), λmax/nm (ε): 221 (22700),
255 (13500). IR (ССl4), ν/cm–1: 3080 (C—Harom), 2250 (С≡N),
1575, 1455 (С=Harom), 1390, 1240, 1185 (S=O), 800 (С—Нarom).
1H NMR (СDCl3—CCl4), δ: 0.91 (s, 3 Н, Н3С(9)); 1.32—1.46
(m, 2 Н, H(6), H(7β)); 1.34 (s, 3 Н, Н3С(10)); 1.54 (dd, 1 Н,
1.72 (d, 1 Н, H(4), J = 9.0 Hz); 2.02 (dd, 1 Н, H(7α), J1
=
17.5 Hz, J2 = 8.5 Hz); 2.28 (s, 3 Н, Н3С(1)); 2.59 (dd, 1 Н,
H(7α), J1 = 17.0 Hz, J2 = 9.2 Hz); 1.65 (dq, 1 Н, H(4), J1
=

N,OꢀAlkylation of indole derivatives
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1839
9.7 Hz, J2 = 1.2 Hz); 2.32 (d, 3 Н, Н3С(1), J = 1.2 Hz); 2.48 (s,
3 Н, Н3С(11a)); 7.12—7.21 (m, 5 Н, H(2a), H(3a), H(4a),
H(9a)); 7.53 (d, 1 Н, H(5a), J = 8.0 Hz); 8.15 (m, 2 Н, H(8a)).
13C NMR (СDCl3—CCl4), δ: 14.19 (t, C(7)); 14.73 (q, C(1));
16.25 (q, C(9)); 18.67 (s, C(5)); 21.39 (q, C(11a)); 22.15 and
22.32 (both d, C(4), C(6)); 28.18 (q, C(10)); 115.13 (d, C(5a));
116.46 (s, C(3)); 118.74 (s, C(8)); 118.97, 123.45, and 124.26
(all d, C(2a), C(3a), C(4a)); 126.10 (two d, C(9a)); 129.54
(two d, C(8a)); 130.77 (s, C(1a)); 136.08 and 137.00 (both s,
C(2), C(6a)); 136.47 (s, C(10a)); 144.48 (s, C(7a)). MS,
m/z (Irel (%)): 392 [M]+ (21), 353 (25), 352 (100), 197 (34),
196 (31), 182 (34), 181 (11), 155 (14), 91 (29). Found:
m/z 392.1553 [М]+. C23H24N2O2S. Calculated: М = 392.1558.
(+)ꢀ{(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ[2ꢀmethylꢀ1ꢀ(4ꢀbromoꢀ
benzenesulfonyl)ꢀ1Hꢀindolꢀ3ꢀyl]cyclopropyl}acetonitrile (28) was
obtained using method A from indole 2 (0.48 g, 2.0 mmol) and
4ꢀBrC6H4SO2Cl (0.77 g, 3.0 mmol). The reaction was carried
out at ∼20 °C for 1 h. After a standard treatment and chromatogꢀ
raphy, product 28 was obtained in 95% yield (0.87 g) as a light
yellow oil with [α]57829 +51.0 (c 2.55). UV (EtOH), λmax/nm (ε):
224 (23000), 256 (16800). IR (ССl4), ν/cm–1: 3070 (C—Harom),
2250 (С≡N), 1575, 1455 (C=Сarom), 1390, 1185 (S=O), 1090,
7.24—7.26 (m, 2 H, H(3a), H(4a)); 7.44—7.47 (m, 1 H, H(2a));
8.21 (br.s, 1 H, H(5a)); 9.31 (br.s, 1 H, H(7a)). 13C NMR
((CD3)2SO), δ: 15.75 (q, С(1)); 18.31 (t, С(7)); 20.19 (q, С(9));
21.98 (s, С(5)); 25.40 and 26.12 (both d, C(4), C(6)); 31.75
(q, С(10)); 118.22 (s, С(3)); 123.21 (d, С(5a)); 124.48 (s, С(8));
127.67 (both d, С(3a), С(4a)); 128.00 (d, С(2a)); 134.70
(s, С(1a)); 138.26 and 139.35 (both s, C(2), C(6a)); 164.25
(d, С(7a)). MS, m/z (Irel (%)): 266 [М]+ (36), 227 (16), 226
(100), 223 (8), 197 (41), 183 (18), 182 (21), 168 (20), 167 (11),
144 (8). Found: m/z 266.1416 [М]+. С17H18N2O. Calculated:
М = 266.1419.
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(1ꢀmethylꢀ2ꢀ(2ꢀoxoethyl)ꢀ
1Hꢀindolꢀ3ꢀyl)cyclopropyl]acetonitrile (30). A solution of indole 8
(0.25 g, 1.0 mmol) in DMF (2 mL) was added dropwise with
cooling to 0 °С to a mixture of DMF (1 mL) and POCl3 (1.5 mL,
16.3 mmol). The mixture was stirred at ∼20 °C for 5—6 h until
the initial indole disappeared (TLC monitoring). The reaction
mixture was diluted with water, neutralized with an aqueous
solution of Na2CO3 (0.5 mol L–1) to pH ∼ 8, and extracted
with ButOMe (3×15 mL). The combined ethereal extract was
washed with a saturated solution of NaCl and dried with anꢀ
hydrous MgSO4. The solvent was removed in vacuo, and a crysꢀ
talline substance that obtained was recrystallized from an
EtOAc—hexane mixture. Aldehyde 30 was isolated in 75%
yield (0.21 g) with m.p. 75—77 °С (from EtOAc—hexane),
1
1070. H NMR (СDCl3—CCl4), δ: 0.94 (s, 3 Н, Н3С(9)); 1.25
(ddd, 1 Н, H(6), J1 = 9.0 Hz, J2 = 8.4 Hz, J3 = 5.8 Hz); 1.34 (s,
3 Н, Н3С(10)); 1.65 (dq, 1 Н, H(4), J1 = 8.4 Hz, J2 = 0.8 Hz);
1.66 (dd, 1 Н, H(7α), J1 = 18.0 Hz, J2 = 9.0 Hz); 2.37 (dd, 1 Н,
H(7β), J1 = 18.0 Hz, J2 = 5.8 Hz); 2.48 (d, 3 Н, Н3С(1), J =
0.8 Hz); 7.16—7.33 (m, 3 H, H(2a), H(3a), H(4a)); 7.46—7.56
(m, 4 H, H(8a), H(9a)); ∼8.09 (m, 1 H, H(5a)). 13C NMR
(СDCl3—CCl4), δ: 14.69 (q, C(1)); 14.92 (t, C(7)); 16.34
(q, C(9)); 18.70 (s, C(5)); 22.25 and 22.38 (both d, C(4), C(6));
28.20 (q, C(10)); 114.77 (d, C(5a)); 116.55 (s, C(3)); 118.71
(s, C(8)); 119.22, 123.70, and 124.51 (all d, C(2a), C(3a) and
C(4a)); 127.60 (two d, C(8a)); 128.78 (s, C(10a)); 130.64
(s, C(1a)); 132.39 (two d, C(9a)); 136.59 and 137.94 (both s,
C(2), C(6a)); 136.26 (s, C(7a)). MS, m/z (Irel (%)): 458
[M + 2 H]+ (22), 456 [M]+ (20), 419 (22), 418 (100), 417 (21),
416 (96), 237 (12), 198 (12), 197 (69), 196 (57), 182 (68), 181
(19), 167 (13), 141 (12), 115 (12). Found: m/z 456.0514 [М]+.
25
[α]578 +47.6 (c 1.43, EtOAc). UV (EtOH), λmax/nm (ε): 228
(33800), 287 (7200), 294 (7100). IR (KBr), ν/cm–1: 3050
(C—Harom), 2725 (С—Haldehyde), 2240 (C≡N), 1720 (С=О),
1700, 1465 (C=Carom), 1350, 740, and 700 (C—Harom). 1H NMR
(СDCl3), δ: 1.07 (s, 3 H, Н3С(9)); 1.37 (s, 3 H, Н3С(10)); 1.38
(ddd, 1 H, H(6), J1 = 9.0 Hz, J2 = 8.8 Hz, J3 = 6.0 Hz); 1.86 (d,
1 H, H(4), J1 = 8.8 Hz); 1.91 (dd, 1 H, H(7α), J1 = 17.5 Hz,
J2 = 9.0 Hz); 2.65 (dd, 1 H, H(7β), J1 = 17.5 Hz, J2 = 6.0 Hz);
3.59 (s, 3 H, Н3С(8a)); 3.90 (m, 2 H, Н2С(1)); 7.05—7.26 (m,
3 H, H(2a), Н(3a), Н(4a)); 7.52 (m, 1 H, H(5a)); 9.31 (t, 1 H,
H(7a), J = 1.8 Hz). 13C NMR (СDCl3), δ: 14.96 (t, С(7)); 16.73
(q, С(9)); 18.72 (s, С(5)); 28.23 (q, С(10)); 22.48 and 22.59
(both d, С(4), С(6)); 30.06 (q, С(8a)); 41.19 (t, С(1)); 108.83
(s, С(3)); 109.06 (d, С(5a)); 119.31, 119.37, and 121.87 (all d,
С(2a), С(3a), С(4a)); 119.78 (s, С(8)); 127.61 (s, С(1a));
130.35 (s, С(2)); 137.38 (s, С(6a)); 196.60 (d, С(7a)). MS,
m/z (Irel (%)): 280 [M]+ (26), 241 (18), 240 (100), 212 (16),
197 (11), 196 (33), 184 (13), 182 (13), 181 (14). Found:
m/z 280.1575 [М]+. C18H20N2O. Calculated: М = 280.1576.
C
22H21BrN2O2S. Calculated: М = 456.0508.
(+)ꢀ[(1R,3S)ꢀ2,2ꢀDimethylꢀ3ꢀ(1ꢀformylꢀ2ꢀmethylꢀ1Нꢀindolꢀ
3ꢀyl)cyclopropyl]acetonitrile (29). A solution of indole 2 (0.48 g,
2.0 mmol) in DMF (2 mL) was added dropwise to a mixture of
POCl3 (0.5 mL) and DMF (1 mL) with cooling to 0 °С and
stirring and stored for 3 days at ∼20 °C. The mixture was diluted
with water (10 mL), neutralized with an aqueous solution of
Na2CO3 to pH 8 (0.5 mol L–1, ∼50 mL), and extracted with
ButOMe (3×10 mL). The extract was washed with a saturated
solution of NaCl and dried with anhydrous Na2SO4. After the
solvent was removed in vacuo, a crystalline substance (0.45 g)
was obtained, whose recrystallization from EtOH gave product
29 in 75% yield (0.40 g) with m.p. 152—155 °С (from EtOH),
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 98ꢀ03ꢀ32910
and the Collective Project No 00ꢀ03ꢀ32721 for Search for
Information in the STN Database (the STN International
Databases) through the STN Center of the Novosibirsk
Institute of Organic Chemistry, SB of the RAS) and the
Presidium of the Siberian Branch of the RAS (Grant for
Young Researchers, 2000). A. M. Chibiryaev thanks the
Science Support Foundation (Grant for Talented Young
Researches).
25
[α]578 +94.3 (c 1.38, EtOAc). UV (EtOH), λmax/nm (ε): 205
(20300), 247 (15300), 300 (4500). IR (KBr), ν/cm–1: 3000
(C—Harom), 2240 (C≡N), 1710 (С=О), 1690, 1610, 1450
1
(C=Carom), 1440, 1345, 1325, 1175, 745 (C—Harom). H NMR
((CD3)2SO), δ: 0.96 (s, 3 H, Н3С(9)); 1.34 (s, 3 H, Н3С(10));
1.38 (ddd, 1 H, H(6), J1 = 9.5 Hz, J2 = 9.0 Hz, J3 = 6.0 Hz);
1.69 (dq, 1 H, H(4), J1 = 9.0 Hz, J2 = 1.5 Hz); 2.03 (dd, 1 H,
H(7α), J1 = 18.0 Hz, J2 = 9.5 Hz); 2.50 (d, 3 H, Н3С(1), J =
1.5 Hz); 2.81 (dd, 1 H, H(7β), J1 = 18.0 Hz, J2 = 6.0 Hz);
References
1. J. E. Saxton, Nat. Prod. Rep., 1994, 11, 493.

1840
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Burakova et al.
2. M. Ihara and K. Fukumoto, Nat. Prod. Rep., 1996, 13, 241.
3. M. Botta, F. De Angelis, and R. Nicoletti, J. Heterocycl.
Chem., 1979, 16, 501.
19. R. Sato, T. Senzaki, T. Goto, and M. Saito, Bull. Chem. Soc.
Jpn., 1986, 59, 2950.
20. J. Dockx, Synthesis, 1973, 441.
4. S. S. Bhagwat and C. Gude, Tetrahedron Lett., 1994,
35, 1847.
5. J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. H.
Shanghnessy, and L. M. AlcazarꢀRoman, J. Org. Chem.,
1999, 64, 5575.
6. Yu. Sh. Gol´dberg, Izbrannye glavy mezhfaznogo kataliza [Seꢀ
lected Chapters of Phaseꢀtransfer Catalysis], Zinatne, Riga,
1989, 554 pp. (in Russian).
7. E. V. Dehmlow, Angew Chem., Int. Ed. Engl., 1977, 16, 493.
8. W. C. Guida and D. J. Mathre, J. Org. Chem., 1980, 45, 3172.
9. G. R. Newkome and W. W. Paudler, Contemporary Heteroꢀ
cyclic Chemistry: Syntheses, Reactions, and Applications,
J. Wiley and Sons, New York, 1982, 422 pp.
10. Y. Kikugawa and Y. Miyake, Synthesis, 1981, 461.
11. J. G. Rodriguez and A. Urrutia, J. Heterocycl. Chem., 1999,
36, 129.
12. C. W. G. Fishwick, A. D. Jones, and M. B. Mitchell, Heteroꢀ
cycles, 1991, 32, 685.
13. A. V. Tkachev, A. V. Rukavishnikov, A. M. Chibirjaev, and
L. B. Volodarsky, Synth. Commun., 1990, 20, 2123.
14. O. N. Burchak, A. M. Chibiryaev, and A. V. Tkachev,
Heterocycl. Commun., 2000, 6, 73.
21. N. N. Suvorov, Yu. I. Smushkevich, V. S. Velezheva, V. S.
Rozhkov, and S. V. Simakov, Khim. Geterotsikl. Soedin., 1976,
191 [Chem. Heterocycl. Compd., 1976 (Engl. Transl.)]; Chem.
Abstrs., 1976, 84, 179957.
22. M. Rubiralta, A. Diez, I. Reig, and J. Castells, Heterocycles,
1990, 31, 173.
23. V. O. Illi, Synthesis, 1979, 136.
24. M. Kakushima, P. Hamel, R. Frenette, and J. Rokach, J. Org.
Chem., 1983, 48, 3214.
25. V. O. Illi, Syntesis, 1979, 387.
26. Y. Kikugava, Synthesis, 1981, 460.
27. H. Takechi, M. Machida, and Y. Kanaoka, Chem. Pharm.
Bull., 1988, 36, 3770.
28. S. Clementi, P. Linda, and G. Marino, J. Chem. Soc., Chem.
Commun., 1972, 427.
29. A. Cipiciani, S. Clementi, P. Linda, G. Marino, and
G. Savelli, J. Chem. Soc., Perkin Trans. 2, 1977, 1284.
30. A. Chatterjee and K. M. Biswas, J. Org. Chem., 1973,
38, 4002.
31. C. Bastianelli, A. Cipiciani, S. Clementi, and G. Giulietti,
J. Heterocycl. Chem., 1981, 18, 1275.
32. O. N. Burchak, A. M. Chibiryaev, and A. V. Tkachev, Izv.
Akad. Nauk, Ser. Khim., 2002, 1209 [Russ. Chem. Bull., Int.
Ed., 2002, 51, 1308].
33. Y. Gopichand, A. S. Khanra, R. B. Mitra, and K. K.
Chakravarti, Ind. J. Chem., 1975, 13, 433.
34. W. Pollmann and G. Schramm, Biochem. Biophis. Acta,
1964, 1.
15. A. V. Rukavishnikov, Ph. D. (Chem.) Thesis, Novosibirsk
Institute of Organic Chemistry, Siberian Branch of the Rusꢀ
sian Academy of Sciences, Novosibirsk, 1993, 222 pp. (in
Russian).
16. A. Koziara, S. Zawadzki, and A. Zwierzak, Synthesis,
1979, 527.
17. H. Takahata, T. Hashizume, and T. Yamazaki, Heterocycles,
1979, 12, 1449.
18. T. Gajda and A. Zwierzak, Synthesis, 1981, 1005.
Received January 11, 2002;
in revised form April 23, 2002