tert-butyl (2S)-(p-tolylsulfonyloxy)propionate - A suitable reagent for the direct alkylation of indole derivatives

Article abstract of DOI:10.1007/s10593-008-0160-z

A new method is proposed for the synthesis of indole derivatives containing a chiral substituent at the nitrogen atom, which includes the direct alkylation of indole derivatives with tert-butyl (2S)-(p-tolylsulfonyloxy)propionate, obtained from commercial ethyl (S)-lactate with subsequent conversion to the corresponding p-toluenesulfonyloxy derivative by hydrolysis, and esterification.

Full text of DOI:10.1007/s10593-008-0160-z

Chemistry of Heterocyclic Compounds, Vol. 44, No. 9, 2008
tert-BUTYL (2S)-(p-TOLYLSULFONYLOXY)-
PROPIONATE – A SUITABLE REAGENT FOR
THE DIRECT ALKYLATION OF INDOLE
DERIVATIVES*
A. V. Kurkin, D. S. Belov, and M. A Yurovskaya
A new method is proposed for the synthesis of indole derivatives containing a chiral substituent at the
nitrogen atom, which includes the direct alkylation of indole derivatives with tert-butyl (2S)-(p-tolyl-
sulfonyloxy)propionate, obtained from commercial ethyl (S)-lactate with subsequent conversion to the
corresponding p-toluenesulfonyloxy derivative by hydrolysis, and esterification.
Keywords: tert-butyl (2S)-(p-tolylsulfonyloxy)propionate, isatins, nonracemic N-substituted indoles,
1,2,3,4-tetrahydrocarbazoles and γ-carbolines, ethyl (S)-lactate.
The leading role of derivatives of indole derivatives among physiologically active compounds of both
natural and synthetic sources is well known. A considerable number of indole derivatives have been synthesized
with the objective of developing new biologically active compounds and medicinals. The results of
investigations associated with the synthesis of derivatives of esters of N-(1H-indolyl)alanines were recently
patented and the possibility of using them for the treatment of diabetes, obesity, hyperlipidemia, and
atherosclerosis has been demonstrated. The authors paid particular attention to the development of the synthesis
of enantiomerically pure compounds, since the optical purity of the substrates determines the biological activity
and permits, for example, the use of such derivatives of indole for the combination therapy of diabetes [1]. In
this connection especial value is attached to the development of methods for the synthesis of derivatives of
indole with chiral substituents in particular, at the nitrogen atom of indole. However the authors of the patent [1]
used, in place of asymmetric synthesis to prepare the required chiral structures, the separation of racemic
substrates using chromatography on columns with a chiral stationary phase.
In our view the use of asymmetric synthesis has considerably greater promise for the preparation of
derivatives of indole with chiral substituents at the nitrogen atom. In principle, there are two methods to solve
the problem of the synthesis of derivatives of indole with a chiral substituent at the nitrogen atom. The first
method – synthesis from a chiral predecessor – was developed by us in detail previously [2]. The second method
– introduction of a chiral substituent at the nitrogen atom of an available indole structure – is the subject of this
paper. The standard route for the N-alkylation of indole structures is connected with the preliminary generation
of an N-anion under basic conditions and its interaction with activated alkylating agents.
_______
* Dedicated to Academician B. A. Trofimov on his 70th birthday.
__________________________________________________________________________________________
M. V. Lomonosov Moscow State University, Moscow 119992, Russia; e-mail:
kurkin@direction.chem.msu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1391-1398,
September, 2008. Original paper submitted May 31, 2008.
0009-3122/08/4409-1123©2008 Springer Science+Business Media, Inc.
1123

O
O
O
O
NaOH, H2O
20°C
Me2C=CH2
TsCl, Et3N
PhH
Me
Me
Me
Me
OEt
OEt
t
OBu-
OH
H2SO4, CH2Cl2
OH
OTs
OTs
3a, 97%
OTs
1, 93%
2, 80%
O
O
O
Me2C=CH2
t-BuONO
Me
Me
Me
OBu -t
OH
OH
AcOH, NaOAc
H2SO4 CH2Cl2
OAc
5, 94%
NH2
OAc
4, 74%
NaOH, H2O
O
O
O
Me2C=CH2
a TsCl
b Tf2O
Me
Me
Me
OBu -t
t
OBu-
OH
H2SO4, CH2Cl2
OR
OH
6, 68%
OH
3a, R = Ts, 90%
3b, R = Tf, 89%
We used as the alkylating agent commercially available ethyl (S)-lactate, converted into an activated
derivative (triflate, mesylate, tosylate, or acetate). Alkylation was carried out in the presence of sodium hydride in
DMF. However variation of the reaction conditions and of the activating group did not lead to the chiral products of
alkylation. The process of alkylation in the chosen conditions is accompanied by complete racemisation, resulting
from enolisation of the substrates in the presence of strong bases. Analogous results were obtained on alkylation of
various substituted isatins even in the presence of much weaker bases (e.g., K2CO3).
It is known [3] that tert-butyl esters of amino acids are favored in comparison with the generally used
methyl and ethyl esters, and are used in peptide synthesis. In particular, they are more stable in basic media, and
the effect of bases on substrates with a chiral carbon atom in the α-position to the tert-butoxycarbonyl group
does not lead to racemisation, whereas this tert-butyl group is easily removed under mild conditions under the
influence of an acid, and, in distinction from benzyl esters, it is stable to hydrogenation in the presence of
catalysts. The absence of racemisation is evidently determined by spatial effects.
Based on literature data [3], we decided to use tert-butyl (S)-lactate as an alkylating agent to obtain
derivatives of indole with a chiral substitutent at the nitrogen atom. For the synthesis of the chiral alkylating
agent, we tested the three different routes shown in the scheme.
NaH, DMF
NaH, DMF
N
O
Me
OBu
-t
3a,b
N
N
OEt
H
Me
OEt
R = Tf, Ts
RO
Me
O
O
7
ee 15–95%
8
ee 0%
All three of the developed routes easily lead to the production in good yields of the tert-butyl ester,
using as starting materials (S)-lactic acid, its ethyl ester, or alanine. We used the synthesized alkylating agents to
introduce a chiral substituent at the nitrogen atom of indole (Table 1).
1124

Table 1. Alkylation of Indole with Derivatives of tert-Butyl (S)-Lactate
Com-
pound
Reaction condition
Yield, %
ee, %*
3a
3a
3a
3b
3b
3b
DMF, NaH 1.1 equiv., ~20°C, 2 h
DMF, NaH 0.9 equiv., ~20°C, 2 h
DMF, NaH 0.9 equiv., 80°C, 1 h
DMF, NaH 1.1 equiv., ~80°C, 2 h
DMF, NaH 0.9 equiv., ~20°C, 2 h
DMF, NaH 0.9 equiv., 80°C, 1 h
25
20
37
27
31
38
0
95
15
0
91
20
_______
* In all cases the enantiometric purity of the compounds obtained was
determined via 1H NMR spectra recorded in the presence of chiral ligands.
Although the corresponding product of alkylation, ester 7, was produced in the chosen conditions of
alkylation in yields no greater than 38%, nevertheless we succeeded in obtaining optimal conditions for obtaining
indoles with a chiral substituent at the nitrogen atom with an optical purity of the product greater than 95% ee.
Experiments on the optimization of the alkylation conditions showed that an increase in the amount of
base (1.1 equiv in place of 0.9 equiv) and also an increase of the reaction temperature to 80°C led to a decrease
in the enantiometric excess of the reaction product, apparently as a result of the ease of racemisation of the
reagent under these conditions. The best result (ee, 95%) was obtained using the tosyl activating group, 0.9
equiv of base at a temperature of ~ 20°C.
The method was universal, for example, it was successfully extended to tricyclic structures of the indole
series, including the known variously physiologically active 1,2,3,4-tetrahydro-γ-carbolines, which creates the
prospect of success among such structures of new biologically active compounds:
R1
R1
R
R
X
NaH, DMF
X
3a
N
N
H
t
OBu-
Me
O
9a–c
9 a,b X = CH, R1 = H; a R = H, b R = Me, c X = N, R = R1 = Me
By HPLC analysis with a chiral carrier we observed from compound 9a made by this method that the
process was stereoselective (ee 95%).
Substituted isatins were also used as substrates for alkylation:
O
R
O
R
NaH, DMF
N
O
3a
N
O
H
OBu-
t
Me
10 a–c
O
10 a R = H, b R = Br, c R = Me
1125

There was virtually no racemisation in the case of the isatins: the enantiometric excess reached 90-97%.
Thus the demonstrated effectiveness of the proposed reagents for the preparation of different chiral
derivatives of indole (with further optimization of the preparative yields) permits the hope for its wide use to
obtain derivatives also of other NH-acid heterocycles with chiral substituent on the nitrogen atom.
EXPERIMENTAL
The chromato-mass spectroscopic studies of the reaction mixtures and the isolated compounds were
carried out using a Carlo Erba/Kratos Fractovap Series 4200 chromatograph with a 25 m×0.2 mm Hewlett
Packard Ultra-1 column, with an 0.33 mm thick phase, helium carrier gas (1 ml/min); 1:10 divided flow,
evaporator temperature 280°C, and a temperature gradient from 150 to 280° C (5°C/min). The mass
1
spectroscopic detector ITD-700 (Finnigan MAT); EI ionization, 70 eV, mass range 39-400 m/z. H and 13C
NMR spectra were recorded with a Bruker Avance-400 (400 and 100 MHz respectively) with TMS as internal
standard. Specific rotations were measured with a Jasco DIP-360 polarimeter (589 nm). Melting points were
measured in a open capillary and were not corrected. The course of the reactions and the purity of the products
were measured by TLC on Silufol UV-254 plates and gas chromatography with a mass spectroscopic detector.
Ethyl (2S)-2-(p-Tolylsulfonyloxy)propanoate (1). A solution of ethyl 2-(S)-lactate (30 g, 254 mmol)
and p-toluenesulfonyl chloride (58.1 g, 304 mmol) in benzene (130 ml) was stirred for 15 min at ~ 20°C.
Triethylamine (53.4 ml, 380 mmol) was added dropwise with vigrous stirring and cooling. The reaction mixture
was stirred for 4 h (monitored by TLC), filtered, and the filtrate was washed with water, dried over anhydrous
Na2SO4, and evaporated in vacuum. The residue was recrystallized from a 3:2 ether–petroleum ether mixture
25
1
(100 ml) to give ester 1 (64.3 g, 93%); mp 33-33.5°C, [α]D = -36.7°C (1% solution in chloroform). H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.23 (3H, t, J = 7.1, CH3CH2); 1.53 (3H, d, J = 6.95, CH3CH); 2.47 (3H, s,
CH3 tosyl); 4.12 (2H, q, J = 7.1, CH3CH2); 4.96 (1H, q, J = 6.95, CHCH3); 7.36 (2H, d, J = 8.2, Ar); 7.84 (2H,
d, J = 8.2, Ar). Found, %: C 52.91; H 5.98. C12H16O5S. Calculated, %: C 52.93; H 5.92.
(2S)-2-(p-Tolylsulfonyloxy)propanoic Acid (2). Compound 1 (12 g, 44 mmol) was added to a solution
of sodium hydroxide (2.1 g, 52.5 mmol) in a mixture of water (18 ml) and ethanol (12 ml) and stirred for 5 h at
~20°C, diluted with water, extracted with methylene chloride (2×50 ml); the aqueous phase was acidified with 6
N HCl to pH 4 and extracted with methylene chloride (3×50 ml). The extract was dried over anhydrous Na2SO4,
and evaporated in vacuum. The residue crystallized on standing to give compound 2 (10.3 g, 80 %); mp
25
1
120-121°C. [α]D = -34.9° (1% solution in chloroform). H NMR spectrum, δ, ppm, (J, Hz): 1.57 (3H, d,
J = 7.0, CH3CH); 2.48 (3H, s, CH3 tosyl); 4.99 (1H, q, J = 7.0, CHCH3); 7.38 (2H, d, J = 8.2, Ar); 7.84 (2H, d,
J = 8.2, Ar); 7.52-8.63 (1H, br. s, CO2H). Found, %: C 49.19; H 5.00. C10H12O5S. Calculated, %: C 49.17;
H 4.95.
tert-Butyl (2S)-2-( p-Tolylsulfonyloxy)propanoate (3a). Conc. H2SO4 (1.8 ml) was added to a solution
of compound 2 (26.2 g, 107 mmol) in methylene chloride (180 ml); the mixture was cooled to -15°C, and
liquefied isobutene (90 ml) was added in one portion. The temperature was raised to room temperature and the
mixture was stirred for 3 days. The mixture was washed with 1 N sodium hydroxide until alkaline. The organic
layer was separated, dried with anhydrous Na2SO4, and evaporated in vacuum to give compound 3a (31.2 g,
97%); Rf 0.91 (3:1 ether–petroleum ether), mp 105-107°C, [α]D25 = -50.1° (1% solution in chloroform).1H NMR
spectrum, δ, ppm, (J, Hz): 1.40 (9H, s, (CH3)3C); 1.54 (3H, d, J = 6.9, CH3CH); 2.47 (3H, s, CH3 tosyl); 4.96
(1H, q, J = 6.9, CH3CH); 7.36 (2H, d, J = 8.2, Ar); 7.84 (2H, d, J = 8.2, Ar). Found, %: C 55.94, H 6.78.
C14H10O5S. Calculated, %: C 55.98; H 6.71.
O-Acetyl-(S)-lactic Acid (4) [4], tert-Butyl O-Acetyl-(S)-lactate (5) [5], tert-Butyl (S)-Lactate (6) [5],
and tert-Butyl (2S)-(Trifluoromethylsulfonyloxy)propionate (3b) [6] were prepared by known methods. Their
melting points , specific rotations, and spectral characteristics agreed with literature values.
1126

Alkylation of Derivatives of Indole with tert-Butyl (2S)-(p-Tolylsulfonyloxylactate (General
Method). A solution of a derivative of indole (0.9 mmol) in DMF (25 ml) was added to a suspension of sodium
hydride (0.7 mmol) in DMF (50 ml) and stirred for 30 min. Then compound 3a (1 mmol) was added in small
portions and the mixture was stirred for 1 day. The reaction mixture was poured into water and extracted with
methylene chloride (3×50 ml). The organic layers were combined, dried with anhydrous Na2SO4, and the solvent
evaporated in vacuum. The residue was purified by chromatography on a silica gel column in a 10:1 system of
petroleum ether–methylene chloride.
tert-Butyl 2-(Indolyl-1)propanoate (7). Yield 20%. Viscous liquid. Mass spectrum, m/z (Irel, %): 245
[M+] (15); 189 [M+–C(CH3)3] (24); 144 [M+–CO2–t-Bu] (100); 115 [M+–CH3CHCO2–t-Bu] (9); 89 (9); 57 (90);
1
43 (68); 39 (56). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.41 (9H, s, C(CH3)3); 1.80 (3H, d, J = 7.3,
CH3CH); 5.06 (1H, q, J = 7.3, CHCH3); 6.56 (1H, d, J = 2.8, H-3 indole); 7.13 (1H, t, J = 7.1, Ar); 7.23 (1H, t,
J = 8.3, Ar); 7.28 (1H, d, J = 3.5, Ar); 7.35 (1H, d, J =8.3, Ar); 7.65 (1H, d, J = 7.8, Ar). Found, %: C 73.49,
H 7.90, N 5.75. C15H19NO2. Calculated, %: C 73.44; H 7.81; N 7.71.
1
Ethyl 2-(Indolyl-1-)propanoate (8). Yield 41%. Viscous liquid. H NMR spectrum (C6D6), δ, ppm (J,
Hz): 0.71 (3H, t, J = 7.0, CH3CH2); 1.24 (3H, d, J = 6.9, CH3CH); 3.78 (2H, q, J = 7.0, CH3CH2); 4.76 (1H, q,
J = 7.0, CHCH3); 6.62 (1H, d, J = 3.1, H-3 indole); 7.13 (1H, d, J = 3.1, H-2 indole); 7.18 (1H, t, J = 7.8, Ar);
13
7.24-7.32 (2H, m, Ar); 7.69 (1H, d, J = 7.8, Ar). C NMR spectrum (CDCl3), δ, ppm: 16.03 (CH3CH2); 19.27
(CH3); 59.34 (CH); 63.68 (CH2); 102.81 (CH); 110.91 (CH); 120.13 (2C, CH); 122.25 (CH); 124.81 (CH);
129.21 (C); 136.52 (C); 173.68 (C=O). Found, %: C 71.89; H 6.95; N 6.45. C13H15NO2. Calculated, %,:
C 71.87; H 6.96; N 6.45.
tert-Butyl (2R)-2-(1,2,3,4-Tetrahydro-9H-carbazol-9-yl)propanoate (9a). Yield 30%. Viscous liquid.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.40 (9H, s, (CH3)3C); 1.71 (3H, d, J = 7.3, CH3); 1.80-1.98 (4H, m,
CH2CH2CH2CH2); 2.67-2.79 (4H, m, CH2CH2CH2CH2); 4.96 (1H, q, J = 7,3, CH); 7.16 (1H, t, J = 7.1, Ar); 7.25
(1H, t, J = 8.3, Ar); 7.34 (1H, d, J = 8.3, Ar); 7.16 (1H, d, J = 7.8, Ar). Found, %: C 76.26; H 8.47; N 4.68.
C19H25NO2. Calculated, %: C 76.22; H 8.42; N 4.68.
tert-Butyl (2R)-2-(6-Methyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)propanoate (9b). Yield 25%.
Viscous liquid. Mass spectrum, m/z (Irel, %): 313 [M+] (5); 257 [M+ - C(CH3)3] (20); 212 [M+–CO2– t-Bu] (32);
1
184 [M+–CH3CHCO2–t-Bu] (18); 168 (9); 128 (7); 97 (11); 57 (100), 43 (77); 39 (40). H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.39 (9H, s, (CH3)3C); 1.69 (3H, d, J = 7.3, CH3); 1.83-2.00 (4H, m, CH2CH2CH2CH2);
2.45 (3H, s, Ar–CH3); 2.65-2.77 (4H, m, CH2CH2CH2CH2), 4.92 (1H, q, J = 7.3, CH); 6.94 (1H, d, J = 8.4, Ar);
7.17 (1H, d, J = 8.4, Ar); 7.26 (1H, s, Ar). 13C NMR spectrum (CDCl3), δ, ppm: 16.59 (CH3); 21.08 (C-4); 21.36
(CH3-Ar); 22.81 (C-3); 23.11 (C-2); 23.45 (C-1); 27.89 ((CH3)3); 53.01 (CH); 81.78 (C(CH3)3); 109.67 (C-8);
112.88 (C-4a); 117.65 (C-7); 121.97 (C-5); 125.93 (C-6); 127.90 (C-4b); 133.84 (C-9a); 145.13 (C-8a); 170.43
(CO). Found, %: C 76.66; H 8.67; N 4.48. C20H27NO2. Calculated, %: C 76.64; H 8.68; N 4.47.
tert-Butyl (2R)-2-(2,8-Dimethyl-1,2,3,4-tetrahydro-γ-carbolin-5-yl)propanoate (9c). Yield 18%.
1
Viscous liquid. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.41 (9H, s, (CH3)3C); 1.73 (3H, d, J = 7.3, CH3);
2.44 (3H, s, 8-CH3); 2.60 (3H, s, 2-CH3); 2.80-2.85 (4H, m, CH2CH2); 3.68 (2H, s, H-1); 4.95 (1H, q, J = 7.3,
CH); 7.24 (1H, m, Ar); 7.34 (1H, d, J = 8.4, Ar); 7.62 (1H, d, J = 7.8, Ar). 13C NMR spectrum (CDCl3), δ, ppm:
16.59 (CH3); 21.42 (1C, 4-CH2); 22.95 (8-CH3); 27.89 ((CH3)3); 45.35 (2-CH3); 46.35 (2-CH3); 51.72 (3-CH2);
53.01 (CH); 81.78 (C(CH3)3); 108.10 (6-CH); 108.66 (C-9b); 117.86 (7-CH3); 122.71 (9-CH); 126.23 (8-CH3C);
128.66 (C-9a); 133.40 (C-4a); 135.18 (C-5a); 169.39 (C=O). Found, %: C 73.16; H 8.57; N 8.58. C20H28N2O2.
Calculated, %: C 73.14; H 8.59; N 8.53.
1
tert-Butyl (2R)-2-(Isatin-1-yl)propanoate (10a). Yield 15%, ee 97%. Viscous liquid. H NMR
spectrum (CDCl3); δ, ppm (J, Hz): 1.44 (9H, s, (CH3)3C); 1.64 (3H, d, J = 7.3, CH3); 5.15 (1H, q, J = 7.3, CH);
7.14 (1H, d, J = 8.2, H-7); 7.17 (1H, t, J = 8.2, H-6); 7.62 (1H, d, J = 8.1, H-4); 7.68 (1H, t, J = 8.1, H-5).
13C NMR spectrum (CDCl3); δ, ppm: 16.60 (CH3); 27.90 ((CH3)3); 52.98 (CH); 81.81 (C(CH3)3); 111.70 (CH);
118.12 (C); 123.93 (CH); 125.31 (CH); 138.80 (CH); 150.14 (C); 158.11 (C=O); 169.86 (C=O); 183.14 (C=O).
Found, %: C 65.38; H 6.29; N 5.01. C15H17NO4. Calculated, %: C 65.44; H 6.22; N 5.09.
1127

tert-Butyl (2R)-2-(5-Bromisatin-1-yl)propanoate (10b). Yield 36%, ee 95%. Viscous liquid. 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.44 (9H, s, (CH3)3C); 1.64 (3H, d, J = 7.3, CH3); 5.08 (1H, q, J = 7.3, CH);
6.78 (1H, d, J = 8.6, Ar); 7.68 (1H, dd, J = 8.3, J = 1.8, Ar); 7.76 (1H, d, J = 1.8, Ar). Found, %: C 50.82;
H 4.61; N 3.90. C15H16BrNO4. Calculated, %: C 50.87; H 4.55; N 3.95.
tert-Butyl (2R)-2-(5-Methylisatin-1-yl)propanoate (10c). Yield 28%, ee 95%. Viscous liquid. Mass
spectrum, m/z (Irel, %): 289 [M+] (25); 160 [M+–CH3CHCO2–t-Bu] (100); 168 (9); 128 (7); 97 (11); 117 (34); 91
1
(50); 57 (80); 43 (77). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.43 (9H, s, (CH3)3C); 1.64 (3H, d, J = 7.3,
CH3); 2.44 (3H, s, CH3, isatin); 5.01 (1H, q, J = 7.3, CH); 6.68 (1H, d, J = 8.3, Ar); 7.61 (1H, d, J = 8.3, Ar);
7.71 (1H, s, Ar). 13C NMR spectrum (CDCl3), δ, ppm: 16.60 (CH3); 23.02 (CH3, isatin); 27.92 ((CH3)3); 53.05
(CH); 81.82 (C(CH3)3); 111.59 (CH); 118.08 (C); 125.49 (CH); 133.38 (C); 139.10 (CH); 148.01 (C); 158.18
(CO); 169.91 (CO); 183.37 (CO). Found, %: C 66.51; H 6.69; N 4.86. C16H19NO4. Calculated, %: C 66.42;
H 6.62; N 4.84.
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