Rh-IndOlefOx catalyzed conjugate addition/Heck-type coupling of organoboronics to a lactam or a lactone

Article abstract of DOI:10.1016/j.tet.2012.01.040

Four indole-olefin-oxazoline (IndOlefOx) ligands were synthesized and evaluated in Rh-catalyzed reactions between organoboronics and a lactam or a lactone. In addition to the expected conjugate addition products, the formation of significant amounts of Heck-type products was observed. The scope and limitations of these reactions were investigated.

Full text of DOI:10.1016/j.tet.2012.01.040

Tetrahedron 68 (2012) 2313e2318
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
RheIndOlefOx catalyzed conjugate addition/Heck-type coupling of
organoboronics to a lactam or a lactone
*
ꢀ
Noora Kuuloja, Matti Vaismaa, Robert Franzen
Department of Chemistry and Bioengineering, Laboratory of Chemistry, Tampere University of Technology, Korkeakoulunkatu 8, 33720 Tampere, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Four indole-olefin-oxazoline (IndOlefOx) ligands were synthesized and evaluated in Rh-catalyzed re-
actions between organoboronics and a lactam or a lactone. In addition to the expected conjugate addition
products, the formation of significant amounts of Heck-type products was observed. The scope and
limitations of these reactions were investigated.
Received 6 September 2011
Received in revised form 28 December 2011
Accepted 16 January 2012
Available online 21 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Carbonecarbon bond formation is the basis for the construction
of nature’s essential molecules, and it has a central role in chemical
sciences. Several chiral ligands have been designed, utilized and
combined with organometallic reagents to yield single enantio-
mers in asymmetric CeC bond formation. The chiral bicyclic dienes,
invented by Hayashi and Carreira in 2003, can be mentioned as the
first example of the olefin-type ligands.1 Due to their high efficiency
in Rh-catalyzed conjugate additions, several structurally different
olefin ligands have thereafter been developed (Fig. 1).2,3 Recently,
a new type of olefin ligand has been reported by Glorius et al.4a This
olefin-oxazoline (OlefOx) ligand-type is based on a conjugated
double bond and a chiral oxazoline-moiety. Unlike traditional diene
ligands, the chirality of the olefin-oxazoline (OlefOx) ligands can be
generated from cheap and easily available aminoalcohols. Very
recently a stilbene framework has moreover been modified by the
replacement of chiral oxazoline ring with chiral sulfoxide group.5
Recently, we have reported the Rh-catalyzed conjugate addition
of different organoboron compounds to cyclohexenone utilizing
IndOlefOx I (indole-olefin-oxazoline) ligands (Fig. 2).4b Our goal has
thereafter been to expand the reaction towards more challenging
heterocyclic carbonyl compounds such as unsaturated lactones6 and
lactams.7 For acyclic unsaturated carbonyl compounds it has been
reported that competitive Heck-type coupling reaction becomes
more dominant when the substrate has a more electron-rich car-
bonyl.8 In most cases unsaturated ketones favour the formation of
the 1,4-addition product whereas unsaturated amides give a mix-
ture of conjugate addition and Heck-type coupling products, re-
spectively. The Heck-product is preferentially produced when
unsaturated esters are used as substrates. However, so far only one
Fig. 1. Examples of different olefin ligands.
example of these competitive reactions for cyclic derivatives can be
found in the literature.9 In this paper, we report the synthesis of new
IndOlefOx ligands and their utilization in the Rh-catalyzed conju-
gate addition between organoboronics and 5,6-dihydro-pyranone
* Corresponding author. Tel.: þ358 (0)40 848 0950; fax: þ358 3 3115 2108;
ꢀ
e-mail address: robert.franzen@tut.fi (R. Franzen).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.040

2314
N. Kuuloja et al. / Tetrahedron 68 (2012) 2313e2318
reaction with ligand 2 produced good yield, but surprisingly the
major product resulted from a Heck-type coupling (HC) (14b).
When using an unsaturated lactam (15) as a reactant, both ligands
(1 and 2) gave similar results with 56% yield. As it was expected
the major product resulted from conjugate addition (CA) (15a), but
also 20% of Heck-type coupling (HC) product (15b) formed.9
Fig. 2. Structure of IndOlefOx I and IndOlefOx II ligands.
or Boc-protected pyrrolidone. Both of these starting materials pro-
duce versatile intermediates, which further can be utilized in the
preparation of biologically interesting compounds.9,10 The compe-
tition between conjugate addition and Heck-type coupling has been
investigated in detail.
Scheme 2. Conjugate addition versus Heck-type coupling reaction.
It is well known that structure of the ligand and especially
R-groups in oxazoline rings induce the enantioselectivity. Accord-
ing to published results, the structure of the ligand also has a re-
markable influence on the CA/HC ratio.8a,d We started to investigate
the influence of the ligand structure, the role of rhodium source, the
role of the organoboron compound and the structure of the un-
saturated carbonyl substrate in terms of yield, CA/HC ratio and
enantioselectivity (Tables 1 and 2). Commercially available [Rh(cod)
Cl]2 produced CA products selectively in both tested reactions
(Tables 1 and 2, entry 1). When the Rh-source was changed to
[Rh(eth)2Cl]2, the amount of HC product increased in case of an
unsaturated lactone (Table 1, entry 2). Complexation of IndOlefOx
ligands with rhodium increased the amount of HC product even
more (Table 1, entries 3e6). The unsaturated lactam did not pro-
duce any product with [Rh(eth)2Cl]2 (Table 2, entry 2). However,
when [Rh(eth)2Cl]2 was complexed with IndOlefOx ligands, re-
actions proceeded with moderate yields (Table 2, entries 3e6). The
structure of IndOlefOx ligand did not remarkably affect the reaction
rate. An exception was the tert-butyl ligand 3, which produced
lower ee% and relatively less CA product (Table 2, entry 4). In case of
the unsaturated lactone, the ligand structure had more distinct
effect on the CA/HC ratio. In the reaction with ligand 3, the ee% and
yield decreased, however, the amount of CA product increased
relatively (Table 1, entry 4). Previously, it has been suggested that
electron donating methoxy-groups at 3- and 4-positions in struc-
turally similar ligands increase the enantioselectivity.4 However,
a 3,4-dimethoxy-motif in IndOlefOx ligand 5 did not have any in-
fluence on enantioselectivity, but in case of an unsaturated lactone
2. Result and discussion
2.1. Preparation of ligands
After our first report on the use of IndOlefOx I ligand,4b we de-
cided to structurally further modify our ligands. Thus a new type,
IndOlefOx II, was designed and synthesized (Fig. 2). In this modi-
fication, the olefin-moiety could be conveniently introduced at the
indole’s N1-position making the synthetic route shorter than for
IndOlefOx I (four steps vs seven steps).
The preparation of IndOlefOx II-type ligands is illustrated in
Scheme 1. Compound 6 was obtained from commercially available
2-indolecarboxylic acid by esterification. Copper-catalyzed N-al-
kylation with vinyl halides11 and conjugate addition with phenyl-
acetylene12 were attempted. However, the outcome and the trans-
selectivity were not satisfactory. When phenylacetylene was used
as reagent, reaction produced both the cis- and trans-isomer. These
isomers could be separated by column chromatography and pure
ligands with cis- and trans-configurations were obtained.13 Finally
we explored the reaction using styrene oxides as substrates.14 This
reaction proceed via the lactone intermediate and produced se-
lectively the trans-product (7,8). After BOP-assisted amide cou-
pling, amido alcohols 9e12 were converted to IndOlefOx II ligands
2e5 according to a published procedure.4b,15
Scheme 1. Preparation of IndOlefOx II ligands 2e5.
2.2. Conjugate addition versus Heck-type coupling
it produced the HC product with high selectivity (Table 1, entry 6).
As a conclusion, the best yields for both the unsaturated lactam and
the lactone were obtained with ligand 2. Because of the highest
yield, good enantioselectivity of the CA product and the moderate
CA/HC ratio, other reaction conditions with this particular IndOle-
fOx ligand were further studied.
We next turned our attention to different organoboron reagents
(Tables 1 and 2, entries 7e10). There are only a few articles that
have reported a systematic investigation of different types of
organoboronic substrates in the 1,4-addition reaction.3e,4b,5b,17,18 In
our investigation, best results were obtained with phenylboronic
acid in terms of yield and enantioselectivity. Unfortunately, pinacol
As a starting point, we investigated ligands 1, 2 and cis-2
(Fig. 2) in rhodium catalyzed conjugate addition between phe-
nylboronic acid and 2-cyclohexenone (13) (Scheme 2). In the re-
actions with ligands 1 and 2 the product (13a) was isolated with
moderate yield and enantioselectivity. When ligand cis-2 was
subjected to the analogous conditions, product (13a) was obtained
in 42% yield and low enantioselectivity (22%), which indicate
that trans-configuration is essential for the high reactivity and
selectivity.16 When an unsaturated lactone (14) was used as a re-
actant, the reaction with ligand 1 failed. On the contrary, the same

N. Kuuloja et al. / Tetrahedron 68 (2012) 2313e2318
2315
Table 1
donating substituent or when it had a weak electron withdrawing
group. We noticed that a strong electron-withdrawing substituent
(such as a nitro-group) directed the reaction towards a proto-
deboronation product without formation of addition product.
Theselectionof a suitableamountofbasewasshowntobe crucial
when IndOlefOx-type ligands were used in the reactions (Table 3). It
is known that additional amounts of base are necessary in the in situ
generation of a rhodium-hydroxide specie making it more reactive
towards transmetallation with organoboronic acids.20,21 However,
the base also favours the formation of the Heck-type coupling pro-
duct.8d We therefore screened the effect of the base on the CA/HC
ratio (Table 3). When only verysmall amount of base was used (Table
3, entries 2 and 8), yields were lower, but the amount of the CA
product increased. In case of the lactone, Heck-type coupling was
almost selective when 1 equiv of base was used (Table 3, entry 6).
Herein the low yield could be explained by the partial hydrolysis of
lactone under basic conditions. In case of an unsaturated lactam, the
amount of base had no influence to the CA/HC ratio (Table 3, entries
8e10,12). The presence of water and 0.3 equiv of base were required
to achieve reasonable yields in this particular reaction.
Effect of ligand on the CA/HC selectivity
Entry AreB
Ligand Rh-source
Yielda CA/HCb eec
(%)
(%)
1
2
3
4
5
6
7
8
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhBpin
PhBF3K
d
d
2
[Rh(cod)Cl]2
65
100:0
rac
[Rh(eth)2Cl]2 35
[Rh(eth)2Cl]2 80
[Rh(eth)2Cl]2 52
[Rh(eth)2Cl]2 45
[Rh(eth)2Cl]2 67
[Rh(eth)2Cl]2 41
[Rh(eth)2Cl]2 Trace
[Rh(eth)2Cl]2 47
[Rh(eth)2Cl]2 46
[Rh(eth)2Cl]2 63
[Rh(eth)2Cl]2 49
[Rh(eth)2Cl]2 0e
69:41 rac
20:80 85
28:72 64
18:82 83
7:93 83
26:74
3
4
5
2
2
2
2
2
d
d
19:81 79
14:86 79
20:80 77
31:69 dd
9
Ph4BNa
10
11
12
13
Ph4BNHEt3
4-MeOeC6H4B(OH)2
4-CleC6H4B(OH)2
4-NO2eC6H4B(OH)2
Different solvent mixtures were also investigated, i.e., dioxane,
toluene/water (10:1), toluene/EtOH (10:1) and EtOH/H2O (10:1),
but solvent effect on the CA/HC selectivity was negligible. The
amount of the CA product as well as the yield slightly increased in
toluene/water (10:1). However in this solvent the ee of CA products
decreased dramatically (from 80% to 20% in case of the lactone and
from 97% to 83% in case of the lactam).
2
2
d
d
a
Yield of isolated mixture of CA and HC products.
Determined by 1H NMR spectroscopy.
Determined by HPLC analysis with chiral stationary phase column (Chiralpak IC).
b
c
d
The ee could not be verified as the separation between the one enantiomer and
the Heck-type product was poor in HPLC.
e
Mostly protodeboronation product formed.
Table 3
Effect amount of base on the CA/HC selectivitya
Table 2
Effect of ligand on the CA/HC selectivity
Entry
n
X
O
KOH (equiv)
Yieldb (%)
CA/HCc
1
2
3
4
5
6
7
8
1
d
10
24
33
62
80
39
n.r
21
22
56
n.r
45
n.r
36:64
46:54
37:63
31:69
20:80
3:97
d
0.01
0.05
0.1
0.3
1
Entry AreB
Ligand Rh-source
Yielda CA/HCb eec
(%)
(%)
1d
2
3
4
5
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
d
d
2
3
4
[Rh(cod)Cl]2
[Rh(eth)2Cl]2
[Rh(eth)2Cl]2 56
[Rh(eth)2Cl]2 40
[Rh(eth)2Cl]2 50
[Rh(eth)2Cl]2 44
77
d
100:0
d
rac
d
0
N-Boc
d
78:22 95
68:32 89
80:20 96
80:20 97
0.05
0.2
0.3
0.3d
0.5
1
86:14
85:15
78:22
d
9
10
11
12
13
6
5
7
8
PhBpin
PhBF3K
2
2
[Rh(eth)2Cl]2
[Rh(eth)2Cl]2
d
d
d
81:19
d
d
d
d
9
Ph4BNa
2
2
2
2
[Rh(eth)2Cl]2 20
[Rh(eth)2Cl]2 70
[Rh(eth)2Cl]2 53
[Rh(eth)2Cl]2 35
60:40 84
80:20 77
79:21 94
75:25 96
10
11
12
13
Ph4BNHEt3
4-MeOeC6H4B(OH)2
4-CleC6H4B(OH)2
4-NO2eC6H4B(OH)2
a
ee was determined by HPLC analysis with chiral stationary phase column
(Chiralpak IC), ee was 85% in case of lactone (entries 1e6) and 95% in case of lactam
(entries 7e13).
2
[Rh(eth)2Cl]2
0e
d
d
b
Yield of isolated mixture of CA and HC products.
c
Determined by 1H NMR spectroscopy.
a
Yield of isolated mixture of CA and HC products.
Determined by 1H NMR spectroscopy.
Determined by HPLC analysis with chiral stationary phase column (Chiralpak IC).
Toluene/H2O (3:1) was used as a solvent.
d
b
c
Absence of water, KOH was added as solid.
d
e
3. Conclusion
Mostly protodeboronation product formed.
As a conclusion, several indole-olefin-oxazoline (IndOlefOx)
ligands were synthesized and evaluated in the Rh-catalyzed re-
actions between organoboronics and a lactam or a lactone sub-
strate. In addition to the expected conjugate addition products, we
observed the formation of significant amounts of Heck-type prod-
ucts. These two competitive reactions have not been studied with
unsaturated cyclic carbonyl compounds previously.
ester of phenylboronic acid and phenyltrifluoroborate were not
suitable for these reactions. On the contrary, although a good yield
was achieved with Ph4BNHEt319 in case of the unsaturated lactam,
enantioselectivity was proved moderate (Table 2, entry 10). Fur-
thermore a set of arylboronic acids with different electronic effects
were tested (entries 11e13). In these experiments, reaction selec-
tivity was observed analogous when the arylborate had an electron

2316
N. Kuuloja et al. / Tetrahedron 68 (2012) 2313e2318
4. Experimental
yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate)
(2.27 mmol). The pH of the reaction mixture was adjusted be-
tween 9 and 10 with DIPEA. As the reaction reached completion
according to TLC, the reaction mixture was poured into a 1 M HCl
(aq) solution with stirring. A white solid was collected by
filtration.
4.1. General methods
All solvents and chemicals were used as received. Dioxane
and 1 M KOH(aq) solutions were bubbled with argon before use.
2-Bromo-1-(3,4-dimethoxyphenyl)ethanone,22
1-Boc-1H-pyrrol-
2(5H)one,23 (S)-2-(1H-indol-2yl)-4-isopropyl-4,5-dihydrooxazole24
and ethyl-1H-indole-2-carboxylate4b were prepared according to
literature procedures. TLC was performed on precoated (silica gel 60
F254) aluminium plates and visualized using UV-light, KMnO4 or
Hanessian’s stain (5 g CeSO4, 25 g (NH4)Mo7O24$4H2O, 450 mL water,
50 mL concd H2SO4) Silica gel 60, particle size 0.040e0.063 nm was
used for chromatography. 1H and 13C NMR spectra were measured at
300 and 75 MHz, respectively, using CDCl3, DMSO-d6 oracetone-d6 as
4.3.1. (S,E)-N-(1-Hydroxy-3-methylbutan-2-yl)-1-styryl-1H-indole-
2-carboxamide (9). White solid; 0.69 g, 74% yield; 198e200 ꢀC; 1H
NMR (300 MHz, DMSO-d6)
d
8.33 (d, J¼8.9 Hz, 1H), 8.26 (d,
J¼14.7 Hz, 1H), 7.96 (d, J¼8.3 Hz, 1H), 7.49 (d, J¼7.8 Hz, 1H), 7.63 (d,
J¼7.9, 2H), 7.49e7.26 (m, 6H), 6.98 (d, J¼14.7 Hz, 1H), 4.74e4.71 (m,
1H), 3.84e3.78 (m, 1H), 3.58e3.49 (m, 2H), 2.53 (sex, J¼6.6 Hz, 1H),
0.93 (d, J¼5.1 Hz, 3H), 0.92 (d, J¼5.1 Hz, 3H); 13C NMR (75 MHz,
DMSO-d6) d 162.3, 137.1,136.6, 133.6,129.4, 127.9, 127.7, 126.6, 126.4,
solvents. Chemical shifts are reported in
d
values (ppm) relatively to
125.2, 122.6, 122.1, 120.8, 113.1, 107.7, 62.0, 57.1, 29.4, 20.4, 19.3; IR
(KBr):
1543 (s), 1474 (m), 1450 (s), 1385, 1311, 1255, 1222 (m), 1070, 935,
806 (w), 741 (s), 690 (m), 540, 509 (w); HMRS calculated for
(C22H25N2O2): 349.1913; found: 349.1916 (0.9 ppm).
tetramethylsilane. High resolution mass spectrum (ES, positive) was
determined on a Micromass LCT, Tof-MS. MSeMS measurements
have been performed using a Waters Synapt-G2 (ESþ) spectrometer.
Optical rotation was obtained on a polarimeter at 589 nm using 1 mL
cell with a length of 1 dm. IR (KBr) spectra were recorded by a Perkin
Elmer Spectrum One FTIR spectrometer.
n
¼3282 (m), 3080, 3057 (w), 2959 (m), 2872 (w), 1654, 1634,
4.3.2. (S,E)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)-1-styryl-1H-in-
dole-2-carboxamide (10). White solid; 0.96 g, 80% yield; mp
4.2. Preparation of compounds 7 and 8
146e147 ꢀC; 1H NMR (300 MHz, acetone-d6)
1H), 7.91 (d, J¼8.5 Hz, 1H), 7.68 (dt, J¼7.8, 1.0 Hz, 1H), 7.59e7.56 (m,
2H), 7.42e7.17 (m, 6H), 6.98 (d, J¼14.8 Hz, 1H), 4.11e4.06 (m, 1H),
3.87e3.85 (m, 1H), 3.78e3.72 (m, 2H), 1.04 (s, 9H); 13C NMR
d
8.32 (d, J¼14.8 Hz,
General procedure for the synthesis of (E)-styryl-indole-2-
carboxylic acids.14 NaH (23.3 mmol) was added to a stirred solu-
tion of ethyl indole-2-carboxylate (21.2 mmol) in 40 mL of dry DMF.
Reaction mixture was stirred at room temperature until hydrogen
evolution had stopped. Styrene oxide (41.6 mmol) was added and
the reaction mixture was heated at 110 ꢀC for 24 h. The mixture was
poured in water (200 mL) and a brown precipitate was formed.
After decantation of water, the precipitate was slurried with hexane
and filtered. Product was collected by filtration.
(75 MHz, acetone-d6)
126.9, 125.4, 122.8, 122.3, 121.5, 113.4, 107.4, 62.1, 60.3, 35.1, 27.4; IR
(KBr):
d 163.2, 137.9, 137.3, 134.3, 129.6, 128.5, 128.0,
n
¼3314 (s), 3027, 3060 (m), 2961 (s), 1940, 1892, 1805, 1776
(w), 1651, 1631, 1475, 1450, 1390, 1367 (s), 1337, 1311, 1296, 1281,
1258 (m), 1220 (s), 1168, 1146, 1081, 1051, 1021, 948 (m), 874, 846,
808, 782 (w), 743, 693 (s), 668, 638, 620, 596, 570, 543, 506, 474
(w); HMRS calculated for (C23H27N2O2): 363.2073; found: 363.2072
(0.3 ppm).
4.2.1. (E)-1-Styryl-1H-indole-2-carboxylic acid (7). Light yellow
solid; 3.90 g, 70% yield; mp 209e210 ꢀC; 1H NMR (300 MHz, DMSO-
4.3.3. (S,E)-N-(1-Hydroxy-3-phenylpropan-2-yl)-1-styryl-1H-indole-
2-carboxamide (11). Due to the difficult purification the compound
was directly submitted to oxazoline formation. White solid; 1.22 g,
d6)
d
8.16 (d, J¼14.7 Hz, 1H), 7.85 (d, J¼8.6 Hz, 1H), 7.76 (d, J¼8.0 Hz,
1H), 7.59 (d, J¼7.5 Hz, 2H), 7.43e7.38 (m, 4H), 7.32e7.20 (m, 2H),
6.98 (d, J¼14.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
d
163.2, 138.1,
93% yield; 1H NMR (300 MHz, acetone-d6)
d
8.22 (d, J¼14.9 Hz, 1H),
136.3, 129.5, 129.4, 128.1, 127.3, 126.8, 126.6, 126.5, 123.4, 122.8,
7.67e7.14 (m, 14H), 6.92 (d, J¼14.9 Hz, 1H), 4.44e4.37 (m, 1H),
3.71e3.68 (m, 2H), 3.07 (dd, J¼13.9, 6.2 Hz, 1H), 2.95 (dd, J¼13.7,
8.3 Hz, 1H).
122.3, 113.3, 112.7; IR (KBr):
n
¼3452, 3428 (w), 3067, 3029, 3005,
2920, 2871, 2787, 2553 (m), 1685 (s), 1523 (s), 1477 (m), 1448, 1431
(s), 1351, 1316 (m), 1301, 1280, 1256, 1200 (s), 1139 (m), 951, 939,
908, 824 (m), 741 (s), 694 (m), 582, 545 (w); HRMS calculated for
(C17H14NO2): 264.1025; found: 264.1025.
4.3.4. (S,E)-1-(3,4-Dimethoxystyryl)-N-(1-hydroxy-3-methylbutan-
2-yl)-1H-2-carboxamide (12). Light brown solid; 0.79 g, 89% yield;
mp 198e110 ꢀC; 1H NMR (300 MHz, acetone-d6)
d 8.15 (d,
4.2.2. (E)-1-(3,4-Dimethoxystyryl)-1H-indole-2-carboxylic acid (8).
Light yellow solid; 1.30 g, 67% yield; mp 186e188 ꢀC; 1H NMR
J¼14.7 Hz, 1H), 7.84 (dd, J¼8.5, 0.8 Hz, 1H), 7.66 (dt, J¼7.9, 0.9 Hz,
1H), 7.33 (ddd, J¼8.4, 7.1, 1.3 Hz, 1H), 7.21e7.08 (m, 4H), 6.97 (d,
J¼8.3 Hz, 1H), 6.88 (d, J¼14.7 Hz, 1H), 4.00e3.92 (m, 1H), 3.87 (s,
3H), 3.84 (s, 3H), 3.73 (d, J¼5.2 Hz, 2H), 1.03 (d, J¼2.0 Hz, 3H), 1.01
(300 MHz, DMSO-d6)
d
8.00 (d, J¼14.6 Hz, 1H), 7.80 (d, J¼8.5 Hz, 1H),
7.74 (d, J¼8.0 Hz, 1H), 7.39e7.37 (m, 2H), 7.22e7.10 (m, 3H),
6.99e6.86 (m, 2H), 3.81 (s, 3H), 3.77 (s, 3H); 13C NMR (75 MHz,
(d, J¼2.0 Hz, 3H); 13C NMR (75 MHz, acetone-d6)
d 162.2, 150.0,
DMSO-d6)
d
162.5, 148.9,148.6,137.6, 128.7, 128.4, 126.5, 126.6, 124.2,
149.5, 137.4, 133.4, 129.4, 127.7, 124.5, 122.0, 121.4,119.3, 112.5, 112.4,
122.8, 122.6, 121.4, 118.9, 112.5, 112.0, 111.6, 109.8, 55.5; IR (KBr):
110.0, 106.4, 62.4, 57.1, 55.5, 19.4, 18.5; IR (KBr):
n
¼3419, 3281 (m),
n¼3505, 3422 (w), 3085, 3050, 2987, 2957, 2929, 2853, 2781, 2667
3050 (w), 2958, 2933 (m), 2871, 2835 (w), 1634 (s), 1583 (m), 1543,
1516, 1450 (s), 1543, 1516, 1450 (s), 1391, 1338, 1311 (m), 1263, 1230
(s), 1170 (m), 1139 (s), 1076 (m), 1025 (s), 932, 847, 802 (w), 745 (m),
622, 559, 547, 479 (w); HMRS calculated for (C24H29N2O4):
409.2127; found: 409.2131 (1.0 ppm).
(m), 1683 (s), 1604, 1582 (w), 1516 (s), 1478 (m), 1450, 1433 (s), 1354
(w),1295,1252,1236,1218 (s),1171 (m),1135,1028 (s), 939, 905, 784,
750 (m), 583 (w); HMRS calculated for (C19H18NO4): 324.1236;
found: 324.1232 (1.2 ppm).
4.3. Preparation of compounds 9e12
4.4. Preparation of ligands 2e5
General procedure for the synthesis of amidoalcohols.4b,15 The
N-substituted indole-2-carboxylic acid (2.16 mmol) was dissolved
in a mixture of DCM (5 mL) and DMF (0.5 mL). Amino alcohol
(2.38 mmol) was added, followed by BOP (benzotriazole-1-
General procedure for the synthesis of ligands.4b,15 Mesylchloride
(3.6 mmol) was carefully added to the stirred mixture of amido
alcohol (1.44 mmol), Et3N (11.5 mmol) and DMAP (0.29 mmol,
20 mol %) in DCM (15 mL). The reaction was monitored by TLC

N. Kuuloja et al. / Tetrahedron 68 (2012) 2313e2318
2317
(Hex/EtOAc 3:1), to observe the formation and disappearance of
mesylate intermediate. The reaction was quenched with water and
diluted with DCM. Product was extracted with DCM (2ꢁ50 mL).
Combined DCM fractions were washed with water (50 mL) and
brine (50 mL) and dried over Na2SO4. After filtration the solvents
were removed in vacuo and crude product was purified by silica gel
column chromatography (Hex/EtOac 6:1) to afford the corre-
sponding IndOlefOx ligand.
33.6,19.2, 19.1; IR (KBr):
n
¼3089, 3016, 3055 (w), 2955, 2932, 2865,
2837 (m), 1658, 1646 (s) 1604, 1583 (m), 1515, 1463, 1451, 1413 (s),
1339, 1283 (m), 1264, 1230, 1179, 1143 (s), 1092 (m), 1027 (s), 986,
963, 944, 935 (m), 855 (w), 806, 794 (m), 765, 749 (w), 733 (s), 547
(w); MSeMS (ESþ) 391 (Mþ1, 41), 375 (C23H23N2O3, 32), 306
(C19H16NO3, 36), 290 (C18H16NO3, 29), 278 (C18H16NO2, 100), 262
(C17H12NO2, 62), 234 (C16H12NO, 23) 185 (C11H9N2O, 23); HMRS
calculated for (C24H27N2O3): 391.2022; found: 391.2030 (2.0 ppm).
4.4.1. (S,E)-4-Isopropyl-2-(1-styryl-1H-indol-2-yl)-4,5-
4.5. General procedure for the Rh-catalyzed conjugate
addition and Heck-reaction
dihydrooxazole (2). White solid; 0.37 g, 71% yield; mp 82e93 ꢀC;
20
[
a]
þ6.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d 8.62 (d,
D
J¼14.8 Hz, 1H), 7.88 (d, J¼8.5 Hz, 1H), 7.69 (d, J¼7.9 Hz, 1H), 7.69 (d,
J¼7.9 Hz, 1H), 7.54 (d, J¼8.9 Hz, 2H), 7.41e7.18 (m, 6H), 6.93 (d,
J¼14.8 Hz, 1H), 4.40 (dd, J¼7.5, 8.5 Hz, 1H), 4.20e4.05 (m, 2H), 1.84
(sex, J¼6.7 Hz, 1H), 1.08 (d, J¼6.7 Hz, 3H), 0.99 (d, J¼6.7 Hz, 3H); 13C
The ligand (0.057 mmol) and [Rh(ethylene)2Cl]2 (10 mg,
0.026 mmol) were placed in flask and flushed with argon. Dioxane
(1.6 mL) was added and the reaction mixture was stirred at room
temperature for ten minutes. The organoboron compound
(0.78 mmol) was added as a solid followed by 1 M KOH (aq)
(0.16 mL) and the lactam or the lactone (0.52 mmol). The reaction
mixture heated to 70 ꢀC and stirred for 24 h. Reaction was
quenched with aq satd NH4Cl solution and the product was
extracted to EtOAc. Combined EtOAc fractions were washed with
brine and dried over Na2SO4. After filtration and concentration in
vacuo the crude product was obtained as pale green oil. Product
was purified using column chromatography. The purification
afforded a mixture of conjugate addition and Heck-type coupling
products. 1H NMR data were in accordance with those reported in
the literature.9,25e27
NMR (75 MHz, CDCl3)
d 157.4, 137.6, 136.3, 128.7, 127.8, 127.1, 127.0,
126.7, 126.0, 124.8, 122.2, 121.4, 120.6, 112.7, 109.7, 73.5, 69.6, 33.3,
18.9, 18.8; IR (KBr):
n
¼3031, 3050, 3069 (w), 2963, 2944, 2866 (m),
1655 (s), 1599, 1608 (w), 1519 (m), 1448 (s) 1411, 1354, 1304 (m),
1187, 1177 (s), 1155, 1112 (m), 1088, 985, 948, 936, 815 (m), 744 (s),
697 (m), 544 (w); MSeMS (ESþ) 331 (Mþ1, 4), 246 (C17H12NO, 40),
218 (C16H12N, 100); HMRS calculated for (C22H23N2O): 331.1810;
found: 331.1818 (2.4 ppm).
4. 4. 2. (S, E)-4-Benzyl-2-(1-styryl-1H-indol-2-yl)-4, 5-
dihydrooxazole.(3). White solid; 0.41 g, 48% yield; mp 94e96 ꢀC;
20
[
a]
ꢂ2.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d 8.50 (d,
D
J¼14.7 Hz, 1H), 7.86 (dd, J¼8.5, 0.7 Hz, 1H), 7.68 (d, J¼7.9 Hz, 1H),
7.50e7.47 (m, 2H), 7.47e7.18 (m, 12H), 6.93 (d, J¼14.7 Hz, 1H),
4.68e4.63 (m, 1H), 4.38 (dd, J¼8.8, 8.5 Hz, 1H), 4.10 (dd, J¼7.9,
7.7 Hz,1H), 3.10 (dd, J¼13.7, 7.0 Hz,1H), 2.84 (dd, J¼13.7, 7.0 Hz,1H);
Acknowledgements
€
We thank Mrs. Paivi Joensuu (University of Oulu) for analyzing
the HRMS data. Financial support from Graduate School of
Organic Chemistry and Chemical Biology (GSOCCB) is gratefully
acknowledged.
13C NMR (75 MHz, CDCl3)
d 158.2, 138.4, 136.4, 129.6, 129.0, 128.7,
128.0, 127.5, 127.1, 126.7, 126.4, 125.1, 122.5, 121.6, 121.5, 112.9, 110.1,
71.3, 68.9, 42.3; IR (KBr):
n
¼3074 (w), 3023 (w), 2964 (w), 2928 (w),
2881 (w), 2900 (w), 1651 (s), 1519 (m), 1449 (s), 1416 (m), 1309 (m),
1190 (s), 1089 (m), 980 (s), 937 (m), 929 (m), 813 (m), 743 (s), 707
(s), 697 (s), 498 (m); MSeMS (ESþ) 379 (Mþ1, 14), 246 (C17H12NO,
63), 218 (C16H12N, 100); HMRS calculated for (C26H23N2O):
379.1810; found: 379.1814
Supplementary data
These data include all experimental procedures, characteriza-
tion data of ligands and products; copies of 1H and 13C NMR spectra
and HPLC profiles compounds described in this article. Supple-
mentary data related to this article can be found in the online
version, at doi:10.1016/j.tet.2012.01.040
4.4.3. (S,E)-4-(tert-Butyl)-2-(1-styryl-1H-indol-2-yl)-4,5-
dihydrooxazole (4). White solid; 0.49 g, 64% yield; mp 104e106 ꢀC;
20
[
a]
þ16.1 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d 8.66 (d,
D
J¼14.8 Hz, 1H), 7.87 (d, J¼8.5 Hz, 1H), 7.68 (d, J¼8.0 Hz, 1H),
7.55e7.51 (m, 2H), 7.41e7.17 (m, 7H), 6.93 (d, J¼14.8 Hz, 1H),
4.34e4.27 (m, 1H), 4.21e4.12 (m, 2H), 0.98 (s, 9H); 13C NMR
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