Synthesis of optically active 2- and 3- indolylglycine derivatives and their oxygen analogues

Article abstract of DOI:10.1021/jo300708h

2-Indolylglycine derivative and its oxygen analogue have been synthesized by Sonogashira coupling followed by cyclization in one pot between 2-iodoheteroarenes and ethynyloxazolidinone where 3-indolylglycine derivative and its oxygen analogue have been sy

Full text of DOI:10.1021/jo300708h

Note
pubs.acs.org/joc
Synthesis of Optically Active 2- and 3- Indolylglycine Derivatives and
their Oxygen Analogues
Koushik Goswami, Indranil Duttagupta, and Surajit Sinha*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
S
* Supporting Information
ABSTRACT: 2-Indolylglycine derivative and its oxygen
analogue have been synthesized by Sonogashira coupling
followed by cyclization in one pot between 2-iodoheteroarenes
and ethynyloxazolidinone where 3-indolylglycine derivative
and its oxygen analogue have been synthesized from silylated
internal alkyne using Larock’s heteroannulation as the key reaction.
ynthesis of indolylglycines is getting importance because of
their presence in various bis-indole alkaloids, namely,
corresponding methyl esters 1a and 1b (Scheme 2). The internal
alkynes (3a or 3b)7 were prepared according to the literature
procedure from ethynyloxazolidine 12,8a which in turn was
synthesized from Garner’s aldehyde8b,c using Bestmann−
Ohira8d,e reagent.
For the synthesis of 2-indolylglycine, we initially followed
Knight’s9 iodocyclization method on 2-alkynylaniline 8b and
obtained the desired product 9 in poor yield. When compound
8c was subjected under Larock’s10 iodocyclisation condition, an
unexpected nucleophilic attack of Boc led to the formation of 10
instead of expected indole derivative 11. Cyclisation of 8a using
palladium catalysis4c resulted in a complex mixture. From this
outcome we realized the problem associated with the N-
protecting group of oxazolidine ring (Scheme 3).
S
dragmacidins1a and hamacanthins.1b Moreover, they can be
used in peptide synthesis to limit conformational flexibility, to
enhance enzymatic stability and bioavailability compared to
native peptides. Synthesis of optically active 3-indolyglycine
derivative has been reported using three distinct approaches: (a)
through Friedel−Crafts2a−c reaction taking the advantage of
nucleophilic properties at 3-position of indole, (b) via Sharpless
asymmetric aminohydroxylation,2d and (c) diastereoselective
approach using chiral glyoxalate imines2e or optically active
ylide.2f Other analogues such as 2-indolylglycine and 2-
benzofuranyl glycine derivatives are found to be commercially
available; however, to the best of our knowledge, there is no
literature report on their synthesis except a racemic route of 2-
benzofuranyl glycine.2g Herein, we describe the synthesis of these
heteroaryl amino acid derivatives using chiral pool approach.
Retrosynthetic strategy A was used for the synthesis of 3-
indolylglycine derivative 1a and its “O” analogue 1b using
Larock’s heteroannulation3 as the key reaction, whereas
retrosynthesis B was used for 2-indolylglycine derivative 2a
and its “O” analogue 2b by way of intermediate 7. In order to
avoid epimerization at the α-C4b and undesired intramolecular
nucleophilic (O or N) attack to Pd(II)−alkyne complexes,4a,c the
masked form of propargylglycine derivative was chosen instead
of propargylglycine derivative itself (Scheme 1).
In an attempt to solve the problem, acetonide protection was
removed from ethynyloxazolidine 12, and the resulting amino
alcohol 13 on teartment with thionyl chloride furnished
ethynyloxazolidinone 1411 (Scheme 4).
We were pleased to say that coupling of 14 with tosylated 2-
iodoaniline under Sonogashira12 condition gave the desired
cyclized product 15a in one pot. Protection of 15a with Boc2O
and subsequent carbamate deprotection by cesium carbonate13
gave Boc-protected amino alcohol 17a. The alcohol was then
converted to its methyl ester 2a by means of two step oxidation6
followed by treatment with diazomethane. Similarly, 2-
benzofuranylglycine derivative 2b has been synthesized from 2-
iodophenol using the same protocol as stated for nitrogen
analogue (Scheme 5).
In conclusion, the synthesis of optically active 2- and 3-
indolylglycine derivatives and their oxygen analogues is
described. Though the synthesis of 3-indolylglycine was reported
by few groups but we are the first to report the synthesis of 1b, 2a
and 2b using chiral pool approach. It is anticipated that minor
modifications of the starting materials and methods presented
here should give various other analogues of these amino acids.
Accordingly, acetylated 2-iodoaniline was treated with
silylated internal alkyne 3a under Larock’s heteroannulation3
condition to get 2,3-disubstitued indole derivative 4c. Treatment
of 4c with TBAF at 0 °C resulted in 5c due to simultaneous
deprotection of sillyl and acetyl groups. Changing the protecting
group from acetyl to tosyl enhanced the yield of hetero-
annulation reaction, and the tosyl group remained unaffected
under the condition of sillyl deprotection. Similarly, the oxygen-
analogue 5b was synthesized from 2-iodophenol, and a better
yield was obtained when TBDMS-substituted internal alkyne 3b
was used instead of TMS-protected 3a. Then oxazolidine
deprotection5 of 5a and 5b furnished Boc-protected amino
alcohols 6a and 6b, respectively, which after oxidation6,5
followed by esterification with diazomethane afforded the
Received: April 11, 2012
Published: July 26, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 1. Retrosynthetic Pathway
a
Scheme 2. Synthesis of 3-Indolylglycine Derivative and Its Oxygen Analogue
a
Reaction conditions: (a) 3a, Pd(OAc)2, PPh3, n-Bu4Cl, DIPEA, DMF, 90 °C, 12 h; (b) 3b, Pd(OAc)2, LiCl, Na2CO3, DMF, 90 °C, 25 h; (c) TBAF,
THF, 0 °C to rt, 2 h; (d) PTSA, MeOH, rt, 2 h; (e) (i) Dess−Martin periodinane, DCM, rt, 30 min, (ii) NaClO2, NaH2PO4, t-BuOH, H2O, rt, 1.5 h,
(iii) CH2N2, ether, (for 1a); (f) (i) 1 M Jones reagent, acetone, 0 °C, (ii) CH2N2, ether, (for 1b).
Scheme 3. Attempted Synthesis toward 2-Substituted Indole Derivative
a
removal of all volatiles under reduced pressure on rotary evaporation.
Chromatographic purification of products was accomplished using
column chromatography on silica gels (mesh 100−200). Thin-layer
chromatography (TLC) was carried out on aluminum sheets, silica gel
60 F254 (layer thickness 0.25 mm). Visualization of the developed
chromatogram was performed by UV light and/or phosphomolybdic
acid stains. Optical rotations were measured at stated temperature and
solvent. Concentration was in gm/100 mL when [α]D was recorded. 1H
and 13C NMR spectra were recorded at 500 and 125 MHz, respectively,
using CDCl3 as solvent. Chemical shifts (δ) are given in ppm relative to
the solvent residual peak or TMS as internal standard. The following
abbreviations are used for multiplicity of NMR signals: s = singlet, d =
doublet, t = triplet, m = multiplet, br = broad. High resolution mass
spectra (HRMS) were measured in a QTOF I (quadrupole-hexapole-
TOF) mass spectrometer.
Scheme 4. Synthesis of Propargylcarbamate
a
Reaction conditions: (a) PTSA, MeOH, rt, 2 h, 61%; (b) SOCl2
(distilled), THF, rt, 18 h, 80%.
EXPERIMENTAL SECTION
■
General Information. All reagents were purchased from
commercial sources and used without further purification, unless
otherwise stated. Petroleum ether (PE) refers to the fraction of
petroleum boiling between 60 and 80 °C. THF is the abbreviation of
tetrahydrofuran. All reactions were carried out in oven-dried glassware
under an argon atmosphere using anhydrous solvents and standard
syringe and septum techniques unless otherwise indicated. Organic
extracts were dried over anhydrous Na2SO4 and then filtered prior to
Experimental Procedures. (R)-tert-Butyl 2,2-Dimethyl-4-(2-
(trimethylsilyl)-1-tosyl-1H-indol-3-yl)oxazolidine-3-carboxylate
(4a). To a solution of tosylated 2-iodoaniline (100 mg, 0.27 mmol) and
(R)-tert-butyl 2,2-dimethyl-4-(2-(trimethylsilyl)ethynyl)oxazolidine-3-
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The Journal of Organic Chemistry
Note
a
Scheme 5. Synthesis of 2-Indolylglycine Derivative and Its Oxygen Analogue
a
Reaction conditions: (a) 14, Pd(OAc)2, PPh3, CuI, DIPA, DMF, 65 °C, 3 h (for 15a), 12 h (for 15b); (b) Boc2O, THF, Et3N, DMAP, rt, 16 h (for
16a), 48 h (for 16b); (c) Cs2CO3, MeOH, rt, 3 h; (d) (i) Dess−Martin periodinane, DCM, rt, 30 min, (ii) NaClO2, NaH2PO4, t-BuOH, H2O, rt, 1.5
h, (iii) CH2N2, ether (for 2a); (e) (i) 1 M Jones reagent, acetone, 0 °C, (ii) CH2N2, ether (for 2b).
carboxylate 3a (90 mg, 0.30 mmol) in dry DMF (3 mL) was added
Pd(OAc)2 (6.0 mg, 0.027 mmol) followed by PPh3 (28 mg, 0.11 mmol),
and the reaction vessel was evacuated and flushed with argon three
times. To the reaction mixture were added tetrabutyl-ammonium
chloride (75 mg, 0.27 mmol) followed by diisopropylethylamine
(DIPEA) (0.14 mL, 0.81 mmol) and again flushed with argon. It was
heated at 90 °C for overnight. The reaction mixture was cooled to room
temperature, and the solvent was removed. The crude residue was
subjected for column purification, eluting with petroleum ether−AcOEt
(93:7), to afford 4a as waxy solid (94 mg, 64%): 1H NMR (500 MHz,
CDCl3) δ 7.96 (d, 1H, J = 6.5 Hz), 7.73 (br m, 1H), 7.39 (d, 2H, J = 7.0
Hz), 7.21 (br s, 1H), 7.11 (t, 1H, J = 7.7 Hz), 7.03 (d, 2H, J = 8.0 Hz),
5.32 (br s, 1H), 3.97 (br s, 1H), 3.69 (br s, 1H), 2.24 (s, 3H), 1.78 (s,
3H), 1.61 (s, 3H), 0. 93−1.37 (2 br s, 9H), 0.57 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 152.4, 144.2, 140.6, 136.3, 134.4, 130.2, 129.8, 129.6,
129.1, 126.6, 125.4, 123.8, 120.6, 116.2, 95.3, 80.1, 69.0, 55.2, 28.1, 25.5,
21.6, 3.0; HRMS (ESI) (M + Na)+ calculated for C28H38N2O5SSiNa+ =
565.2168, found 565.2169.
(R)-tert-Butyl 2,2-Dimethyl-4-(1-tosyl-1H-indol-3-yl)oxazolidine-
3-carboxylate (5a). To a solution of 4a (80 mg, 0.15 mmol) in
tetrahydrofuran (3 mL) was added tetrabutyl ammonium fluoride (0.18
mL of 1.0 M in THF, 0.18 mmol) at 0 °C, and the mixture was stirred at
rt for 1 h. After removal of solvent the crude residue was charged directly
into column, eluting with petroleum ether−AcOEt (92:8), to give 5a as
white foam (58 mg, 82%): [α]25D = −65.6 (c 1.79, CHCl3); IR (neat/
CHCl3) ν 1697 cm −1; 1H NMR (500 MHz, CDCl3) δ 7.94−7.99 (br m,
1H), 7.73 (br s, 2H), 7.62 (d, 1H, J = 8.0 Hz), 7.43−7.48 (br m, 1H),
7.30 (br s, 1H), 7.20−7.25 (m, 3H), 5.22 (br s, 0.35 H), 5.06 (br s, 0.65
H), 4.26 (dd, 1H, J = 6.7, 8.7 Hz), 3.98 (d, 1H, J = 8.0 Hz), 2.32 (s, 3H),
1.17−1.78 (m, 15H); 13C NMR (125 MHz, CDCl3) δ 152.1, 145.0,
135.5, 130.0, 128.7, 126.9, 124.8, 124.5, 124.0, 123.3, 119.8, 113.9, 94.7,
94.2*, 80.5, 80.1*, 68.6, 68.2*, 53.9, 28.5, 28.4, 27.4, 26.5*, 24.6, 23.5*,
21.6 (*Asterisk denotes conformer peaks); HRMS (ESI) (M + Na)+
calculated for C25H30N2O5SNa+ = 493.1773, found 493.1774.
(br m, 1H), 4.27−4.30 (dd, J = 6.7, 8.7 Hz), 4.11 (br s, 1H), 1.26−1.77
(m, 15H); 13C NMR (125 MHz, CDCl3) δ 155.8, 152.2, 143.5, 143.0*,
125.9, 124.5, 122.7, 121.4, 120.3, 111.8, 94.7, 94.2*, 80.6, 80.3*, 68.5,
67.9*, 52.9, 28.5, 27.4, 26.4*, 24.7, 23.6* (*Asterisk denotes conformer
peaks); HRMS (ESI) (M + Na)+ calculated for C18H23NO4Na+
340.1525, found 340.1525.
=
tert-Butyl (R)-2-Hydroxy-1-(1-tosyl-1H-indol-3-yl)ethylcarbamate
(6a). To a solution of 5a (50 mg, 0.106 mmol) in methanol (1.5 mL)
was added p-toluensulfonic acid (PTSA) monohydrate (10 mg, 0.053
mmol), and the mixture was stirred at room temperature for 2 h. The
solution was then neutralized with saturated aqueous NaHCO3, diluted
with AcOEt (2 mL), and washed with brine (2 × 1 mL). The organic
phase was dried (Na2SO4) and concentrated. The residue was eluted
from a column with petroleum ether−AcOEt (7: 3) to give 6a (37 mg,
80%) as white foam: [α]25 = −36.4 (c 1.33, CHCl3), lit.2d [α]20
=
D
D
+38.6 (c 1.25, CHCl3, antipode of 6a); IR (neat/CHCl3) ν 1699, 3392
cm −1; 1H NMR (500 MHz, CDCl3) δ 7.97 (d, 1H, J = 8.0 Hz), 7.76 (d,
2H, J = 8.0 Hz), 7.54−7.56 (m, 2H), 7.33 (t, 1H, J = 7.5 Hz), 7.21−7.26
(m, 3H), 5.06−5.10 (m, 2H), 3.97 (s, 2H), 2.34 (s, 3H), 2.25 (br s, 1H),
1.45 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ 156.1, 145.2, 135.4, 135.3,
130.1, 129.2, 127.0, 125.2, 123.8, 123.5, 121.1, 119.9, 113.9, 80.3, 65.1,
49.6, 28.4, 21.6; HRMS (ESI) (M + Na)+ calculated for
C22H26N2O5SNa+ = 453.1460, found 453.1460.
tert-Butyl (R)-1-(Benzofuran-3-yl)-2-hydroxyethylcarbamate (6b).
To a solution of 5b (52 mg, 0.16 mmol) in methanol (2.0 mL) was
added p-toluenesulfonic acid (PTSA) monohydrate (15 mg, 0.08
mmol), and the mixture was stirred at room temperature for 2.5 h. The
solution was then neutralized with saturated aqueous NaHCO3, diluted
with AcOEt (3 mL), and washed with brine (2 × 1.5 mL). The organic
phase was dried (Na2SO4) and concentrated. The residue was eluted
from a column with petroleum ether−AcOEt (8: 2) to give 6b (38 mg,
85%) as white foamy solid: [α]25D = −20.3 (c 3.05, CHCl3); IR (neat/
CHCl3) ν 1695, 3319 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.60−7.61
(m, 2H), 7.48 (d, 1H, J = 8.5 Hz), 7.31 (t, 1H, J = 7.5 Hz), 7.24 (t, 1H, J =
7.7), 5.23 (br s, 1H), 5.06 (br s, 1H), 3.98 (m, 2H), 2.72 (br s, 1H), 1.45
(s, 9H); 13C NMR (125 MHz, CDCl3) δ 156.2, 155.6, 142.4, 126.4,
124.9, 123.0, 120.1, 119.3, 111.9, 80.4, 65.2, 49.1, 28.5; HRMS (ESI) (M
+ Na)+ calculated for C15H19NO4Na+ = 300.1212, found 300.1211.
tert-Butyl (R)-(Methoxycarbonyl)(1-tosyl-1H-indol-3-yl)-
methylcarbamate (1a). To a solution of amino alcohol 6a (25 mg,
0.058 mmol) in dichloromethane (1 mL) was added solid periodinane
(27 mg, 0.064 mmol) portion wise, and the mixture was stirred for 0.5 h.
After consumption of starting material (TLC), it was diluted with ether
(1.6 mL), and the resulting suspension was added to 1.3 (M) NaOH
(0.6 mL). The reaction mixture was stirred for 15 min, and the ether
layer was washed with 0.6 mL of 1.3 M NaOH and 2 mL of water. The
organic layer was dried, filtered, concentrated in vacuo and used in the
next step without any purification.
(R)-tert-Butyl 4-(Benzofuran-3-yl)-2,2-dimethyloxazolidine-3-car-
boxylate (5b). To a solution of 2-iodophenol (109 mg, 0.495 mmol)
and (R)-tert-butyl 4-(2-(tert-butyldimethylsilyl)ethynyl)-2,2-dimethy-
loxazolidine-3-carboxylate 3b (140 mg, 0.413 mmol) in dry DMF (3
mL) were added lithium chloride (17 mg, 0.41 mmol) and sodium
carbonate (131 mg, 1.24 mmol). The reaction vessel was evacuated and
flushed with argon three times. Then Pd(OAc)2 (10 mg, 0.041 mmol)
was added to it. The reaction mixture was again flushed with argon and
heated at 90 °C for 25 h. The reaction mixture was cooled to room
temperature, and the solvent was removed under reduced pressure. The
crude residue was subjected for column purification, eluting with
petroleum ether−AcOEt (96:4), to afford a mixture of 4b (major) and
3b as colorless liquid (127 mg).
To a solution of the mixture of 4b and 3b (125 mg, 0.29 mmol with
respect to 4b) in tetrahydrofuran (4 mL) was added tetrabutylammo-
nium fluoride (0.28 mL of 1.0 M in THF, 0.28 mmol) at 0 °C, and the
mixture was stirred at rt for 1 h. After removal of solvent the crude
residue was charged directly into column, eluting with petroleum ether−
To a solution of the above crude aldehyde in t-BuOH (0.16 mL) and
2-methyl-2-butene (0.08 mL) was added a solution of NaClO2 (20 mg)
and NaH2PO4 (20 mg) in H2O (0.3 mL) at rt. The reaction mixture was
stirred for 1.5 h and diluted with saturated aqueous NH4Cl solution (0.5
mL). The organic layer was extracted with AcOEt (3 × 1.5 mL). The
combined organic layers were dried, filtered and concentrated in vacuo
to give the crude product, which was purified by silica gel column
AcOEt (96:4), to give 5b as white foam (70 mg, 53% after 2 steps):
1
[α]25 = −61.5 (c 1.17, CHCl3); IR (neat/CHCl3) ν 1697 cm −1; H
D
NMR (500 MHz, CDCl3) δ 7.76 (br s, 1H), 7.54−7.61 (br m, 1H), 7.48
(d, 1H, J = 8.0 Hz), 7.29−7.30 (m, 1H), 7.23−7.26 (m, 1H), 5.09−5.24
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Note
chromatography, eluting with petroleum ether−AcOEt (60:40), to
afford the corresponding acid as white foam (15 mg).
139.9, 137.5, 135.3, 130.3, 128.8, 126.3, 125.3, 124.2, 121.5, 114.5, 109.2,
71.6, 51.2, 21.6; HRMS (ESI) (M + Na)+ calculated for
C18H16N2O4SNa+ = 379.0728, found 379.0727.
To the solution of above acid (15 mg, 0.034 mmol) in ether (1 mL)
was added excess ethereal diazomethane at 0 °C, and the mixture was
stirred for 10 min. After evaporation of ether it was directly charged into
column, eluting with DCM−AcOEt (95:5), to give 1a as a waxy solid
(13.5 mg, 51%, after 3 steps from amino alcohol 6a): [α]26D = −25.7 (c
(S)-4-(Benzofuran-2-yl)oxazolidin-2-one (15b). To a stirred
degassed solution of 2-iodophenol (54 mg, 0.25 mmol) and 14 (25
mg, 0.22 mmol) in diisopropylamine (3.0 mL) under nitrogen were
added Pd(OAc)2 (5 mg, 0.022 mmol), PPh3 (23 mg, 0.088 mmol) and
copper iodide (4 mg, 0.022 mmol), respectively. The yellowish solution
was degassed again and heated at 65 °C for 12 h. After solvent
evaporation in vacuo the residue was directly charged into column,
eluting with petroleum ether:AcOEt (1:1), to give 15b, 20 mg (44%) as
yellowish white solid: [α]26D = −12.4 (c 0.66, CHCl3); IR (neat/CHCl3)
ν 1707, 1741, 3244 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, 1H, J
= 7.5 Hz), 7.46 (d, 1H, J = 8.5 Hz), 7.29−7.32 (m, 1H), 7.23−7.26 (m,
1H), 6.73 (s, 1H), 6.22 (s, 1H), 5.11 (dd, 1H, J = 5.5, 9.0 Hz), 4.70−4.74
(m, 1H), 4.54 (dd, 1H, J = 5.7, 8.7 Hz); 13C NMR (125 MHz, CDCl3) δ
159.4, 155.4, 154.2, 127.7, 125.1, 123.4, 121.5, 111.5, 104.6, 69.1, 50.5;
HRMS (ESI) (M + Na)+ calculated for C11H10NO3+ = 204.0655, found
204.0654.
1
0.76, CHCl3); IR (neat/CHCl3) ν 1714, 1745, 3443 cm −1; H NMR
(500 MHz, CDCl3) δ 7.95 (d, 1H, J = 8.5 Hz), 7.76 (d, 2H, J = 8.5 Hz),
7.63 (d, 1H, J = 8.0 Hz), 7.57 (s, 1H), 7.33 (t, 1H, J = 7.7 Hz), 7.22−7.26
(m, 3H), 5.58 (d, 1H, J = 7 Hz), 5.43 (d, 1H, J = 6.0 Hz), 3.74 (s, 3H),
2.34 (s, 3H), 1.44 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 171.2, 155.0,
145.3, 135.4, 135.2, 130.1, 128.8, 127.1, 125.3, 124.8, 123.7, 120.1, 118.3,
113.8, 80.6, 53.0, 50.5, 28.4, 21.7; HRMS (ESI) (M + Na)+ calculated for
C23H26N2O6SNa+ = 481.1409, found 481.1408.
tert-Butyl (R)-(Methoxycarbonyl)(benzofuran-3-yl)-
methylcarbamate (1b). To a solution of amino alcohol 6b (20 mg,
0.072 mmol) in acetone (1 mL) at 0 °C was added freshly prepared
Jones reagent (1 M, 0.22 mL, 0.22 mmol) dropwise under nitrogen.
After completion of the reaction (TLC), it was quenched with isopropyl
alcohol (0.25 mL) and partitioned with AcOEt (15 mL) and saturated
NH4Cl (5 mL). After stirring the solution for 1 h, the aqueous layer was
separated and re-extracted with AcOEt (15 mL), and the combined
organic layers were dried, filtered, and concentrated in vacuo to about 5
mL in volume. The solution of the crude acid was cooled to 0 °C. Excess
ethereal diazomethane was added, and the reaction was stirred for 10
min. The diazomethane was blown off with nitrogen, and the organic
layer was washed with aqueous NaHCO3 (4 mL), saturated NH4Cl (4
mL), dried, filtered, and concentrated in vacuo to give the crude product,
which was purified by column chromatography, eluting with DCM−
AcOEt (95:5), to afford 1b (9 mg, 41%) as white foam: [α]25D = −75.1
(c 0.99, CHCl3); IR (neat/CHCl3) ν 1714, 1747, 3363 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.65−7.67 (m, 2H), 7.49 (d, 1H, J = 8.0 Hz),
7.31−7.34 (m, 1H), 7.25−7.28 (m, 1H), 5.60 (d, 1H, J = 7.0 Hz), 5.50
(br s, 1H), 3.76 (s, 3H), 1.45 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
171.2, 155.7, 155.1, 143.3, 125.7, 125.1, 123.2, 120.2, 116.9, 111.9, 80.6,
53.0, 49.6, 28.4; HRMS (ESI) (M + Na)+ calculated for C16H19NO5Na+
= 328.1161, found 328.1161.
(R)-4-Ethynyloxazolidin-2-one (14). To a solution of 12 (550 mg,
2.0 mmol) in methanol (12 mL) was added p-toluenesulfonic acid
(PTSA) monohydrate (190 mg, 1.0 mmol), and the mixture was stirred
at rt for 3 h. The solution was then neutralized with saturated aqueous
NaHCO3, diluted with AcOEt (30 mL), and washed with brine (2 × 10
mL). The organic phase was dried (Na2SO4) and concentrated. The
residue was eluted from a column with petroleum ether−AcOEt (7: 3)
to give 13 (226 mg, 61%) as colorless oil.
Thionyl chloride (0.43 mL, 6 mmol) was added to the solution of
aminoalcohol 13 (226 mg, 1.2 mmol) in 12 mL of dry THF under argon
atmosphere, and the reaction mixture was stirred at room temperature
for 18 h. Evaporation of the solvent under reduced pressure gave the
crude, which was purified by flash chromatography (1:1 ethyl acetate/
petroleum ether) to get pure propargylcarbamate 14 as yellowish solid
(106 mg, 80%): [α]26 = −7.7 (c 1.67, CHCl3); IR (neat/CHCl3) ν
3246, 2121, 1761 cm −1D; 1H NMR (500 MHz, CDCl3) δ 6.08 (br s, 1H),
4.54−4.61(m, 2H), 4.36−4.40 (m, 1H), 2.48 (s, 1H); HRMS (ESI) (M
+ H)+ calculated for C5H6O2N+ = 112.0399, found 112.0393.
(R)-tert-Butyl 2-Oxo-4-(1-tosyl-1H-indol-2-yl)oxazolidine-3-car-
boxylate (16a). To a well stirred solution of 15a (110 mg, 0.31
mmol) in dry THF (8 mL) was added Et3N (0.06 mL, 0.44 mmol),
Boc2O (107 mg, 0.49 mmol). After 10 min DMAP (3.8 mg, 0.031
mmol) was added, and the reaction was stirred at room temperature for
16 h. After that the solution was concentrated under reduced pressure,
and the residue was purified by column chromatography with petroleum
ether:AcOEt (80:20) as eluent to give 16a (119 mg, 84%): [α]26
=
D
+91.5 (c 0.73, CHCl3); IR (neat/CHCl3) ν 1718, 1817 cm −1; 1H NMR
(500 MHz, CDCl3) δ 8.03 (d, 1H, J = 8.5 Hz), 7.75 (d, 2H, J = 8.5 Hz),
7.48 (d, 1H, J = 8.0 Hz), 7.31 (t, 1H, J = 7.5 Hz), 7.23−7.26 (m, 3H),
6.63 (s, 1H), 6.04 (d, 1H, J = 7.5 Hz), 4.71 (t, 1H, J = 8.8 Hz), 4.42 (dd,
1H, J = 2.5, 9.0 Hz), 2.35 (s, 3H), 1.42 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 152.0, 149.1, 145.6, 138.4, 137.2, 135.3, 130.3, 128.8, 126.8,
125.4, 124.2, 121.4, 114.4, 108.4, 84.5, 68.6, 54.0, 28.0, 21.7; HRMS
(ESI) (M + Na)+ calculated for C23H24N2O6SNa+ = 479.1253, found
479.1254.
(S)-tert-Butyl 4-(Benzofuran-2-yl)-2-oxooxazolidine-3-carboxy-
late (16b). To a stirred solution of 15b (20 mg, 0.098 mmol) in dry
THF (2 mL) were added Et3N (0.02 mL, 0.14 mmol), Boc2O (34 mg,
0.15 mmol). After 10 min DMAP (1.2 mg, 0.001 mmol) was added, and
the reaction was stirred at room temperature for 48 h. After that the
solution was concentrated under reduced pressure, and the residue was
purified by column chromatography with petroleum ether:AcOEt
(80:20) as eluent to give 16b (17 mg, 57%): [α]26D = −102.0 (c 0.97,
1
CHCl3); IR (neat/CHCl3) ν 1716, 1801 cm−1; H NMR (500 MHz,
CDCl3) δ 7.56 (d, 1H, J = 8.0 Hz), 7.48 (d, 1H, J = 8.5 Hz), 7.32 (t, 1H, J
= 7.2 Hz), 7.24−7.27 (m, 1H), 6.73 (s, 1H), 5.46 (dd, 1H, J = 4.2, 8.7
Hz), 4.61 (t, 1H, J = 8.7 Hz), 4.45 (dd, 1H, J = 4.0, 9.0 Hz), 1.42 (s, 9H);
13C NMR (125 MHz, CDCl3) δ ; 155.1, 153.1, 151.8, 148.8, 127.7,
125.2, 123.4, 121.5, 111.6, 105.2, 84.6, 66.0, 53.0, 28.0; HRMS (ESI) (M
+ Na)+ calculated for C16H17NO5Na+ = 326.1004, found 326.1005.
tert-Butyl (R)-2-Hydroxy-1-(1-tosyl-1H-indol-2-yl)ethylcarbamate
(17a). To a well stirred solution of 16a (100 mg, 0.22 mmol) in dry
MeOH (4 mL) was added Cs2CO3 (15 mg, 0.044 mmol) in one portion,
and the solution was stirred at room temperature for 3 h. Then the
solution was neutralized with solid citric acid and concentrated under
reduced pressure. The residue was dissolved in AcOEt (15 mL), washed
with brine (15 mL), H2O (15 mL) and dried over Na2SO4. The residue
was purified by column chromatography using petroleum ether:AcOEt
(7:3) as eluent to give 17a (80 mg, 85%) as waxy solid: [α]26D = +174.2
(c 1.58, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.07 (d, 1H, J = 8.5
Hz), 7.87 (d, 2H, J = 7.0 Hz), 7.41 (d, 1H, J = 7.5 Hz), 7.24−7.26 (m,
1H,), 7.17−7.20 (m, 3H), 6.69 (s, 1H), 5.74 (s, 1H), 5.55 (d, 1H, J = 5.5
Hz), 4.03−4.10 (m, 2H), 2.30 (s, 3H), 1.84 (br s, 1H), 1.48 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 155.6, 145.0, 140.5, 137.7, 134.8, 129.9,
129.6, 127.2, 124.7, 124.0, 120.9, 115.2, 111.0, 80.0, 65.5, 51.6, 28.5,
(R)-4-(1-Tosyl-1H-indol-2-yl)oxazolidin-2-one (15a). To a stirred
degassed solution of N-tosyl-2-iodoaniline (184 mg, 0.49 mmol) and 14
(50 mg, 0.45 mmol) in diisopropylamine (5.0 mL) and DMF (2.0 mL)
under nitrogen were added Pd(OAc)2 (10 mg, 0.045 mmol), PPh3 (47
mg, 0.18 mmol) and copper iodide (8.5 mg, 0.045 mmol), respectively.
The yellowish solution was degassed again and heated at 65 °C for 3 h.
After solvent evaporation in vacuo, the residue was directly charged into
column, eluting with petroleum ether:AcOEt (1:1), to give 15a, 112 mg
(70%) as yellowish white foam: [α]26 = +146.7 (c 2.00, CHCl3); IR
D
(neat/CHCl3) ν 1755, 3271 cm −1; 1H NMR (500 MHz, CDCl3) δ 8.09
(d, 1H, J = 8.5 Hz), 7.62 (d, 2H, J = 8.5 Hz), 7.48 (d, 1H, J = 7.5 Hz),
7.33 (t, 1H, J = 8.0 Hz), 7.21−7.27 (m, 3H), 6.80 (s, 1H), 6.60 (s, 1H),
5.50 (dd, 1H, J = 4.0, 8.5 Hz), 4.88 (t, 1H, J = 8.8 Hz), 4.48 (dd, 1H, J =
4.5, 9.0 Hz), 2.35 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.2, 145.6,
21.6; HRMS (ESI) (M + Na)+ calculated for C22H26N2O5SNa+
453.1460, found 453.1457.
=
(S)-tert-Butyl 1-(Benzofuran-2-yl)-2-hydroxyethylcarbamate
(17b). To a well stirred solution of 16b (17 mg, 0.056 mmol) in dry
7084
dx.doi.org/10.1021/jo300708h | J. Org. Chem. 2012, 77, 7081−7085

The Journal of Organic Chemistry
Note
MeOH (1 mL) was added Cs2CO3 (3.6 mg, 0.011 mmol) in one
portion, and the solution was stirred at room temperature for 3 h. Then
the solution was neutralized with solid citric acid and concentrated
under reduced pressure. The residue was dissolved in AcOEt (4 mL),
washed with brine (2 mL), H2O (2 mL) and dried over Na2SO4. The
residue was purified by silica gel chromatography using petroleum
ether:AcOEt (7:3) as eluent to give 17b (13 mg, 85%) as white foamy
solid: [α]26D = −60.9 (c 1.19, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.51 (d, 1H, J = 7.5 Hz), 7.43 (d, 1H, J = 8.0 Hz), 7.19−7.27 (m, 2H),
6.64 (s, 1H), 5.40 (d, 1H, J = 7.5 Hz), 5.00 (br s, 1H), 4.01 (br m, 1H),
3.92−3.94 (m, 1H), 2.48 (br s, 1H), 1.45 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 155.8, 155.4, 155.0, 128.2, 124.3, 123.0, 121.1, 111.3, 104.2,
80.4, 64.3, 51.3, 28.5; HRMS (ESI) (M + Na)+ calculated for
C15H19NO4Na+ = 300.1212, found 300.1212.
tert-Butyl (R)-(Methoxycarbonyl)(1-tosyl-1H-indol-2-yl)-
methylcarbamate (2a). To a solution of amino alcohol 17a (50 mg,
0.116 mmol) in dichloromethane (2 mL) was added solid periodinane
(55 mg, 0.13 mmol) portion wise, and the mixture was stirred for 0.5 h. It
was then diluted with ether (3.0 mL), and the resulting suspension was
added to 1.3 (M) NaOH (1.2 mL). After stirring the mixture for 15 min,
ether layer was washed with 1.2 mL of 1.3 M NaOH and 4 mL of water.
The organic layer was dried, filtered, concentrated in vacuo and used in
the next step without further purification.
ASSOCIATED CONTENT
* Supporting Information
Spectroscopic data as well as copies of the spectra of all new
compounds are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: ocss5@iacs.res.in.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.S. thanks DST, India, for financial support by a grant [SR/S1/
OC-38/2007]. K.G. is thankful to IACS and I.D. is thankful to
CSIR for their fellowships.
REFERENCES
■
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stirred for 1.5 h and diluted with saturated aqueous NH4Cl solution (1
mL). The organic layer was extracted with AcOEt (3 × 3 mL). The
combined organic layers were dried, filtered and concentrated in vacuo
to give the crude product, which was purified by column
chromatography, eluting with petroleum ether−AcOEt (60:40), to
afford the corresponding acid as white foam (32 mg).
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stirred for 15 min. After evaporation of ether, it was directly charged into
column, eluting with DCM−AcOEt (95:5), to obtain 2a as a waxy solid
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(28 mg, 53%): [α]26 = −52.2 (c 1.85, CHCl3); IR (neat/CHCl3) ν
D
1708, 1735, 3371 cm −1; 1H NMR (500 MHz, CDCl3) δ 7.86 (d, 1H, J =
9.5 Hz), 7.73 (d, 2H, J = 8.5 Hz), 7.48 (d, 1H, J = 7.5 Hz), 7.19−7.26 (m,
4H), 6.78 (s, 1H), 6.10 (d, 1H, J = 8.5 Hz), 5.85 (br s, 1H), 3.74 (s, 3H),
2.34 (s, 3H), 1.45 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 170.2, 155.2,
145.1, 136.9, 136.6, 135.8, 129.9, 128.8, 127.1, 125.3, 123.8, 121.5, 114.6,
113.3, 80.5, 53.1, 52.7, 28.5, 21.7; HRMS (ESI) (M + Na)+ calculated for
C23H26N2O6SNa+ = 481.1409, found 481.1409.
(R)-Methyl 2-(Benzofuran-2-yl)-2-(tert-butoxycarbonylamino)-
acetate (2b). To a solution of amino alcohol 17b (12 mg, 0.043
mmol) in acetone (0.70 mL) at 0 °C was added freshly prepared Jones
reagent (1 M, 0.13 mL, 0.13 mmol) dropwise under nitrogen. After
completion of the reaction (TLC), it was quenched with isopropyl
alcohol (0.14 mL) and partitioned with AcOEt (10 mL) and saturated
NH4Cl (3.5 mL). After stirring the solution for 1 h, the aqueous layer
was separated and re-extracted with AcOEt (10 mL), and the combined
organic layers were dried, filtered, and concentrated in vacuo to about 5
mL in volume. The solution of the crude acid was cooled to 0 °C. Excess
ethereal diazomethane was added to it, and the reaction was stirred for
10 min. The organic layer was washed with aqueous NaHCO3 (3 mL),
saturated NH4Cl (3 mL), dried, filtered, and concentrated in vacuo to
give the crude product, which was purified by column chromatography,
eluting with DCM−AcOEt (95:5), to afford 2b (5.6 mg, 43%) as white
foam: [α]26D = −110.3 (c 0.44, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.55 (d, 1H, J = 7.5 Hz), 7.45 (d, 1H, J = 8.0 Hz), 7.29 (t, 1H, J = 7.5 Hz),
7.23 (t, 1H, J = 7.5 Hz), 6.75 (s, 1H), 5.62 (m, 2H), 3.79 (s, 3H), 1.45 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 169.4, 155.1, 155.0, 151.8, 128.0,
124.9, 123.2, 121.5, 111.6, 105.5, 80.8, 53.3, 52.2, 28.4; HRMS (ESI) (M
+ Na)+ calculated for C16H19NO5Na+ = 328.1161, found 328.1162.
1992, 721. (e) Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann, H. J.
Synthesis 2004, 59.
̈
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7085
dx.doi.org/10.1021/jo300708h | J. Org. Chem. 2012, 77, 7081−7085