Diastereotopic group selection in hydroxy-directed intramolecular C-H alkenylation of indole under oxidative palladium(II) catalysis

Article abstract of DOI:10.1002/adsc.201301108

Group-selective palladium(II)-catalyzed ring closures involving C-H bond alkenylation are reported. The cyclization precursors contain a prochiral bis(homoallylic) alcohol unit tethered to either an arene or an indole. The homobenzylic hydroxy group in these substrates is positioned to act as a directing group in the ortho-selective C-H bond activation prior to the cyclization event. Arene-derived precursors reacted poorly, even when applying a protocol that had proven effective in intermolecular hydroxy-directed C-H bond alkenylations. No asymmetric induction was obtained with chiral ligands, mono-N-protected amino acids (MPAAs) in particular. Conversely, the cyclization of indole-derived precursors was substantially more efficient, and installation of a substituent in the benzylic position rendered these intramolecular C-H bond alkenylations diastereoselective. The diastereotopic group selection is high with diastereomeric ratios ranging from dr=91:9 to 94:6.

Full text of DOI:10.1002/adsc.201301108

FULL PAPERS
DOI: 10.1002/adsc.201301108
Diastereotopic Group Selection in Hydroxy-Directed
ꢀ
Intramolecular C H Alkenylation of Indole under Oxidative
Palladium(II) Catalysis
Sandeep R. Kandukuri,a,b Lin-Yu Jiao,a Axel B. Machotta,c
and Martin Oestreicha,c,*
a
Institut fꢀr Chemie, Technische Universitꢁt Berlin, Strasse des 17. Juni 115, 10623 Berlin, Germany
Fax : (+49)-30-314-28829; e-mail: martin.oestreich@tu-berlin.de
NRW Graduate School of Chemistry, Organisch-Chemisches Institut, Westfꢁlische Wilhelms-Universitꢁt Mꢀnster,
b
Corrensstrasse 40, 48149 Mꢀnster, Germany
Organisch-Chemisches Institut, Westfꢁlische Wilhelms-Universitꢁt Mꢀnster, Corrensstrasse 40, 48149 Mꢀnster, Germany
c
Received: December 9, 2013; Revised: February 5, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301108.
Abstract: Group-selective palladium(II)-catalyzed mono-N-protected amino acids (MPAAs) in particu-
ꢀ
ring closures involving C H bond alkenylation are lar. Conversely, the cyclization of indole-derived pre-
reported. The cyclization precursors contain a prochi- cursors was substantially more efficient, and installa-
ral bis(homoallylic) alcohol unit tethered to either tion of a substituent in the benzylic position ren-
ꢀ
an arene or an indole. The homobenzylic hydroxy dered these intramolecular C H bond alkenylations
group in these substrates is positioned to act as a di- diastereoselective. The diastereotopic group selection
ꢀ
recting group in the ortho-selective C H bond acti- is high with diastereomeric ratios ranging from dr=
vation prior to the cyclization event. Arene-derived 91:9 to 94:6.
precursors reacted poorly, even when applying a pro-
tocol that had proven effective in intermolecular hy-
droxy-directed C H bond alkenylations. No asym- Keywords: C H bond activation; copper; cycliza-
metric induction was obtained with chiral ligands, tion; diastereoselectivity; palladium
ꢀ
ꢀ
ꢀ
Introduction
bond exactly as the C X group in our prefunctional-
ized cyclization precursors (X=OTf). Hence, we rea-
The ability of an allylic hydroxy group to control the soned that the same ring closure would occur under
regioselectivity of intermolecular Heck alkenylation oxidative palladium(II) catalysis, perhaps even enan-
and arylation reactions is long known.[1,2] Aside from tioselectively with Yuꢂs mono-N-protected amino
this established motif, a phenolic hydroxy group was acids (MPAAs) as supporting ligands[8] (Scheme 1,
found to be the pivotal structural element in a Heck lower part).
macrocyclization.[3] A few years ago, our laboratory
The new cyclization precursors for C H bond acti-
ꢀ
disclosed a unique desymmetrizing Heck cyclization vation would be derived from either benzene or C-3-
where an oxygen donor equilibrates diastereomeric substituted indole. Substitution in the benzylic posi-
alkene-palladium(II) intermediates, thereby allowing tion would add a stereocenter vicinal to the former
for high enantioselection in the overall transformation prochiral carbon atom, and diastereotopic group-se-
(Scheme 1, upper part).[4] These examples illustrate lective cyclizations[9] would then be possible
the capability of an adequately positioned hydroxy (Figure 1).
group to interact with moderately oxophilic palladi-
ACHTUNGTRENNUNGum(II) atoms. The hydroxy group therefore holds po-
tential to act as a directing group in palladium(II)-cat- Results and Discussion
ꢀ
alyzed processes involving C H bond activation. Re-
cently, Yu and co-workers accomplished a hydroxy-di- As mentioned above, Yu and co-workers had devel-
[5–7]
ꢀ
rected C H alkenylation of arenes.
The tertiary al- oped a general methodology for the hydroxy-directed,
[5]
ꢀ
ꢀ
cohol in that system is located relative to the C H intermolecular C H alkenylation of arenes. Howev-
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Sandeep R. Kandukuri et al.
Table 1. Solvent screening under Yuꢂs catalytic set-up.[a]
Entry
Solvent
Temp.
[8C]
Time
[h]
Conv.
[%][b]
Yield
[%][b]
1
C6F6
90
64
64
44
16
16
18
18
44
90
67
80
52
30
42
34
95
35
9
17
4
0
4
2
toluene
mesitylene
n-hexane
THF
t-AmOH
DMF
110
130
110
110
110
110
90
Scheme 1. Different roles of a tertiary hydroxy group in pal-
ladium(0)- and palladium(II)-catalyzed intramolecular al-
ACHTUNGTRENNUNGkenylation.
3[c]
4
5
6
7
8
0
DCE
42[d]
[a]
All reactions were conducted according to the General
Procedure 1 in the indicated solvent and at the indicated
temperature.
Both conversion and yield were determined by GLC
analysis using n-tetracosane as internal standard.
PdACTHNUTRGEN(UNG OAc)2 (1.0 equiv.) without oxidant.
Isolated yield after flash column chromatography on
silica gel.
[b]
[c]
[d]
Figure 1. General structural motif for enantio- and diaste-
reoselective cyclizations.
er, application of that protocol to the intramolecular
desymmetrization outlined before failed (cf.
Scheme 1, lower part). Conversion was moderate but
the desired ring closure only occurred to a small
ꢀ
extent, even with an OMe group para to the C H
bond. We then decided to replace the styrene units by
a,b-unsaturated acceptors because the latter had also
performed better in the intermolecular case.[5] The
new precursor indeed cyclized at almost full conver-
sion in promising yield under Yuꢂs catalytic set-up
with leucine-derived ligand L1[8] (1b!2b, Table 1,
entry 1). Remarkably, the use of solvents other than
C6F6 largely led to decomposition (Table 1, entries 2–
Figure 2. Performance of MPAAs L2–L4 under optimized
conditions (Table 1, entry 8).
7). 1,2-Dichloroethane (DCE) proved to be an excep- amples with more reactive acetylated ligands L2–
tion, and 2b was isolated in 42% yield (Table 1, L4[8f,g] (Figure 2).
entry 8). That yield did not improve any further in
We then tested a few representative cyclization pre-
mixtures of C6F6 and DCE in various ratios. A brief cursors each with a different electronic situation at
survey of the terminal oxidant using C6F6 as solvent the arene ring (1a–1e, Table 2). Substrates 1a–1e were
did not lead to any improvement, e.g., Cu
ACHTUNGTRENNUNG
(2.0 equiv.) or O2 (ballon) afforded poor yields at less
AHCTUNGTRENNUNG
than 30% conversion. Also, isomerically pure L1 and thesis (see the Supporting Information for experimen-
several related Yu-type ligands (not shown) did not tal details). The optimized protocol (Table 1) was
induce any enantioselectivity within the experimental slightly modified by doubling of the amount of
error. To illustrate these findings, we show three ex- Li2CO3 (2.0 equiv. instead of 1.0 equiv).[10] That minor
2
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Diastereotopic Group Selection in Hydroxy-Directed Intramolecular C H Alkenylation
[a]
ꢀ
Table 2. Hydroxy-directed desymmetrizing C H bond alkenylation of tethered arenes.
Entry
1
Arene
Annulated arene
Conv. [%][b]
Yield [%][c]
1a
92
20
2
3
4
1b
1c
1d
1e
98
92
53
90
52
32
<5[d]
5
10
[a]
All reactions were conducted according to the General Procedure 1.
Conversion was determined by GLC analysis by using n-tetracosane as internal standard.
Isolated yield after flash column chromatography on silica gel.
[b]
[c]
[d]
Determined by GLC analysis by using n-tetracosane as internal standard.
change further increased the yield of the model cycli-
The efficacy of the intramolecular desymmetriza-
zation 1b!2b (Table 2, entry 2). Yields were, howev- tion of arenes 1a–1e is poor, and it is essentially just
er, substantially lower for the ring closures of the a single precursor that cyclizes in reasonable yield but
parent (unsubstituted) system and the precursor with without any asymmetric induction. We, therefore,
an Me instead of an OMe group (1a!2a and 1c!2c, turned toward indoles tethered to bis(homoallylic) al-
ꢀ
Table 2, entries 1 and 3). The related electron-defi- cohols where the C H bond activation is expected to
cient arene with a CF3 group did not cyclize at all be more facile.[11,12] We initially prepared indoles 3a
(1d!2d, Table 2, entry 4). Shifting the position of the and 3b substituted at the C-3 carbon atom. These
ꢀ
OMe group from para to meta relative to the C H would not undergo the desired ring closure under the
bond resulted in an unreactive precursor that decom- previous catalytic set-ups. After considerable experi-
posed quantitatively (1e!2e, Table 2, entry 5). The mentation, we found out that the hydroxy- but not
dramatic effect of the substitution pattern for the the methoxy-containing precursor[13] cyclizes cleanly
electron-rich arene was unexpected as Yu and co- in the absence of any added ligand with CuACHTUNRGTNEUNG(OAc)2 as
workers had observed a less pronounced influence in terminal oxidant to yield the annulated indole (3a!
ꢀ
the intermolecular hydroxy-directed C H bond alke- 4a but not 3b!4b, Scheme 2). That finding corrobo-
nylation (92% for para versus 71% yield for meta).[5] rates that the hydroxy group acts as a directing group.
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Sandeep R. Kandukuri et al.
kenylations of indoles and pyrroles under oxidative
palladium(II) catalysis before.[15] An alternative ap-
proach to breaking the symmetry of the bis(homoal-
lylic) alcohol fragment is by diastereotopic group se-
lection.[9] That would require the installation of a sub-
stituent R1 in the benzylic position of precursors 3 or
5 (11–14, Table 3). Diastereoselective cyclizations of
alkenes with an additional stereocenter in the tether
ꢀ
involving C H bond alkenylation are rare though.
Stoltz and co-workers had reported such ring closures
yet diastereoselectivity was good in one case only:
dr=50:50 with an Me group in the benzylic and dr=
85:15 with an Me group in the homobenzylic position
in a five-membered ring formation of an indole.[16]
We prepared six substrates 11–14 with different
groups in the benzylic position and various alkyl
esters. It turned out that the latter had a profound
effect on conversion and isolated yield, increasing
with the length of the alkyl chain (Bu>Et>Me,
Table 3, entries 1–3). The diastereomeric ratio was not
affected by the R1 group. The cyclization of 11c af-
Scheme 2. Desymmetrizing ring closures of indoles tethered
to bis(homoallylic) alcohols.
Also, the cognate substrate with the a,b-unsaturated forded cis-15c with good diastereoselectivity in excel-
acceptors afforded the new ring in good isolated yield lent 81% yield. R1 groups other than Me allowed for
(5!6, Scheme 2).
even higher diastereocontrol but i-Pr was already too
The terminally unsubstituted bis(homoallylic) unit bulky for the ring closure to occur (Table 3, entries 4–
also participated in the ring closure but exo-to-endo 6). The relative configuration was assigned as cis by
double bond migration and subsequent elimination of nOe measurements (see the Supporting Information
water resulted in aromatization of the newly formed for details).
ring (7!8, Scheme 3, upper part).[14] AgOAc was su-
The cyclic tertiary alcohols were prone to facile
perior to CuACHTUNGTRENNUNG(OAc)2 as terminal oxidant, and the car- acid-mediated elimination, affording the correspond-
bazole was formed in 36% isolated yield. Cyclization ing carbazoles after aromatization. CDCl3 with traces
of 9, prepared from 7 by ring-closing metathesis, fur- of acid was sufficient, and formation of the carbazole
nished the indole-annulated bicycle 10 in 22% isolat- already occurred during NMR measurements. For ex-
ed yield (9!10, Scheme 3, lower part).
ample, cis-15c converted quantitatively into 19c after
The results obtained with the indole motif were en- one week in CDCl3 at room temperature (Scheme 4).
couraging (Scheme 2) but we were not able to devel- Neat samples of the tertiary alcohols were stable for
op an asymmetric procedure in the presence of extended periods of time. This finding was not totally
a chiral ligand. Addition of ligands generally thwarted unexpected as we had already seen carbazole forma-
ꢀ
the C H bond activation/cyclization sequence. That tion with the parent bis(homoallylic) substrate (cf.
was particularly disappointing as we had accom- 7!8, Scheme 3, upper part).[14]
ꢀ
plished enantioselective intramolecular C H bond al-
Conclusions
Our initial goal was to achieve enantiotopic group se-
ꢀ
lection in a palladium(II)-catalyzed C H alkenylation
of bis(homoallylic) alcohols. The hydroxy group was
ꢀ
believed to act as a directing group in the C H bond
activation step. We were, however, not able to identi-
fy a suitable chiral ligand, and ring closures occurred
completely unselectively. In turn, the related diaste-
reoselective variant where an existing stereocenter in
the cyclization precursor controls the desymmetriza-
tion of the bis(homoallylic) alcohol unit proceeded
with high levels of diastereoselection. An indole-de-
rived substrate cyclized with dr=91:9 in 81% isolated
Scheme 3. Miscellaneous ring closures.
yield.
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Diastereotopic Group Selection in Hydroxy-Directed Intramolecular C H Alkenylation
[a]
ꢀ
Table 3. Diastereotopic group selection in the intramolecular C H bond alkenylation of indole.
Entry
1
Indole
Annulated indole
Conv. [%][b]
Yield [%][c]
dr[d]
11a
60
50[e]
92:8
2
3
4
5
11b
11c
12a
13a
14b
87
95
80
30
62
68[e]
91:9
91:9
94:6
81
55
<10[f]
–
[g]
6
30
94:6
[a]
All reactions were conducted according to the General Procedure 2.
Conversion was determined by GLC analysis by using n-tetracosane as internal standard.
[b]
[c]
[d]
[e]
[f]
Isolated yield after flash column chromatography on silica gel.
1
Diastereomeric ratio was determined by H NMR spectroscopy prior to purification.
Contaminated with traces of the cyclization precursor.
Determined by GLC analysis by using n-tetracosane as internal standard.
Not determined.
[g]
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Sandeep R. Kandukuri et al.
out on a device of the type VarioEL from Elementaranaly-
sensysteme GmbH in the Microanalytical Laboratory at the
Organisch-Chemisches Institut of the Westfꢁlische Wil-
helms-Universitꢁt Mꢀnster or on a Flash 1112 from Thermo
Fisher Scientific at the Institut fꢀr Chemie of the Technische
Universitꢁt Berlin. Melting points (mp) were determined
with a Stuart SMP20 apparatus and are not corrected. High
resolution mass spectrometry (HR-MS) analyses were per-
formed by the Analytical Facility at the Institut fꢀr Chemie
of the Technische Universitꢁt Berlin.
General Procedure for the Hydroxy-Directed
ꢀ
Intramolecular Palladium(II)-Catalyzed C H
Alkenylation Using AgOAc as Terminal Oxidant
(GP1)
Scheme 4. Acid-mediated dehydration and aromatization.
Pd
ACHTUNGTRENNUNG
(2.0 equiv.),
AHCTUNGTRENNUNG
Experimental Section
20 mol%) were added to a flame-dried sealed Schlenk tube
followed by the addition of a solution of the bis(homoallyl-
ic) alcohol (1.0 equiv.) in 1,2-dichloroethane (0.1M). The re-
action mixture was then heated at the indicated temperature
and for the indicated time. The reaction was monitored by
GLC analysis using tetracosane as internal standard. After
cooling to room temperature, the reaction mixture was fil-
tered through a pad of Celiteꢅ. The filtrate was concentrated
under reduced pressure. Purification by flash column chro-
matography on silica gel using mixtures of cyclohexane and
tert-butyl methyl ether as eluents afforded the analytically
pure product.
General Information
All reactions were performed in flame-dried glassware using
conventional Schlenk techniques under a static pressure of
nitrogen or argon. Liquids and solutions were transferred
with syringes. Solvents were purified and dried following
standard methods. Technical grade solvents for extraction
and chromatography (cyclohexane, dichloromethane, ethyl
acetate, n-pentane, diethyl ether, and tert-butyl methyl
ether) were distilled prior to use. Hexafluorobenzene and
1,2-dichloroethane were dried over calcium hydride. Analyt-
ical thin-layer chromatography (TLC) was performed on
silica gel 60 F254 glass plates from Merck. Flash column chro-
matography was performed on silica gel 60 (40–63 mm, 230–
400 mesh, ASTM) by Merck or Grace GmbH using the indi-
General Procedure for the Hydroxy-Directed
ꢀ
Intramolecular Palladium(II)-Catalyzed C H
Alkenylation Using Cu
(GP2)
N
1
cated solvents. H, 13C, and 19F NMR spectra were recorded
in CDCl3 or DMSO-d6 on Bruker AV 400 and Bruker AV
500 instruments. Chemical shifts are reported in parts per
million (ppm) downfield from tetramethylsilane (TMS) and
are referenced to the residual solvent resonance as the inter-
PdACHTNUTGRNEN(UG OAc)2 (10 mol%), CuAHCUTGNTREN(NUNG OAc)2 (2.0–4.0 equiv.), and a solu-
tion of the bis(homoallylic) alcohol (1.0 equiv.) in dry THF
(0.1M) were added to a flame-dried sealed Schlenk tube.
The reaction mixture was then heated at the indicated tem-
perature and for the indicated time. The reaction was moni-
tored by GLC or TLC analysis. After cooling to room tem-
perature, the reaction mixture was diluted with ethyl acetate
and filtered through a pad of Celiteꢅ. The filtrate was con-
centrated under reduced pressure, and (if applicable) the
1
nal standard (CHCl3: d=7.26 ppm for H and CDCl3: d=
77.16 ppm for 13C; DMSO: d=2.50 ppm for H and DMSO-
1
d6: d=39.52 ppm for 13C). Data are reported as follows:
chemical shift, multiplicity (br s=broad singlet, s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet), coupling
constants (Hz), and integration. Infrared (IR) spectra were
recorded on an Agilent Technologies Cary 630 FT-IR spec-
trophotometer equipped with an ATR unit and are reported
(br=broad; vw=very weak, w=weak, m=medium, s=
strong) in wavenumbers (cmꢀ1). Gas liquid chromatography
(GLC) was performed on an Agilent Technologies 7890A
gas chromatograph equipped with an HP-5 capillary column
(30 mꢄ0.32 mm, 0.25 mm film thickness) by Agilent Tech-
nologies using the following program: N2 carrier gas, injec-
tion temperature 2508C, detector temperature 3008C; tem-
perature program: start temperature 408C, heating rate
108C·minꢀ1, end temperature 2808C for 10 or 20 min. Enan-
tiomeric excesses were determined by analytical high-per-
formance liquid chromatography (HPLC) analysis on an
Agilent Technologies 1200 Infinity instrument. Optical rota-
1
diastereomeric ratio was determined by H NMR spectros-
copy. Purification by flash column chromatography on silica
gel using mixtures of cyclohexane and tert-butyl methyl
ether or ethyl acetate as eluents afforded the analytically
pure product.
Diethyl (2E,7E)-5-benzyl-5-hydroxynona-2,7-diendioate
(1a, Table 2, entry 1): Prepared from 4-benzylhepta-1,6-dien-
4-ol (S2a, 552 mg, 2.73 mmol, 1.00 equiv.) and Hoveyda–
Grubbs II catalyst (34 mg, 55 mmol, 2.0 mol%) according to
GPS2. Purification by flash column chromatography on
silica gel (cyclohexane:tert-butyl methyl ether=3:1) afford-
ed the analytically pure product as a light brown oil; yield:
304 mg (32%). GLC (HP-5): tR =26.2 min; Rf =0.52 (cyclo-
˜
hexane:tert-butyl methyl ether=1:1); IR (ATR): n=3477
tion was determined with
Schmidt+Haensch; the analytes were measured as a solution
a
Polartronic H532 from
(br), 3447 (br), 2981 (m), 2936 (m), 1699 (s), 1650 (s), 1267
1
(s), 1164 (s), 702 (s) cmꢀ1; H NMR (400 MHz, CDCl3): d=
in CHCl3 in 1 dm cuvettes. Elemental analysis were carried
1.29 (t, J=7.1 Hz, 6H), 1.71 (br s, 1H), 2.33 (dd, J=7.5 Hz,
6
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Diastereotopic Group Selection in Hydroxy-Directed Intramolecular C H Alkenylation
J=1.4 Hz, 4H), 2.80 (s, 2H), 4.20 (q, J=7.1 Hz, 4H), 5.90
(dt, J=15.6 Hz, J=1.3 Hz, 2H), 7.01 (dt, J=15.6 Hz, J=
7.7 Hz, 2H), 7.18–7.23 (m, 2H), 7.26–7.36 (m, 3H);
13C NMR (100 MHz, CDCl3): d=14.4, 42.1, 45.9, 60.5, 73.9,
125.2, 127.2, 128.7, 130.7, 136.0, 143.6, 166.2; HR-MS (ESI):
m/z=369.1677, calcd. exact mass for [M+Na]+
(C20H26O5Na): 369.1672; elemental analysis calcd. for
C20H26O5: C 69.34, H 7.56; found: C 69.49, H 7.23.
Diethyl (2E,7E)-5-hydroxy-5-(3-methoxybenzyl)nona-2,7-
diendioate (1b, Table 2, entry 2): Prepared from 4-(3-me-
thoxybenzyl)hepta-1,6-dien-4-ol (S2b, 501 mg, 2.78 mmol,
1.00 equiv.) and Hoveyda–Grubbs II catalyst (27 mg,
44 mmol, 2.0 mol%) according to GPS2. Purification by flash
column chromatography on silica gel (cyclohexane:tert-butyl
methyl ether=2.5:1) afforded the analytically pure product
as a light brown oil; yield: 476 mg (58%). GLC (HP-5): tR =
29.0 min; Rf =0.57 (cyclohexane:tert-butyl methyl ether=
(100 MHz, CDCl3): d=14.4, 42.2, 45.7, 60.6, 73.9, 123.9 (q,
J=3.6 Hz), 124.0 (q, J=272.2 Hz), 125.6, 127.4 (q, J=
4.0 Hz), 128.9, 130.9 (q, J=32.3 Hz), 134.1, 137.3, 142.9,
166.1; 19F NMR (471 MHz, CDCl3): d=ꢀ62.6 (s, 3F); HR-
MS (ESI): m/z=453.1286, calcd. exact mass for [M+K]+
(C21H25F3O5K): 453.1286; elemental analysis calcd. for
C21H25F3O5: C 60.86, H 6.08; found: C 61.20, H 6.23.
Diethyl (2E,7E)-5-hydroxy-5-(4-methoxybenzyl)nona-2,7-
diendioate (1e, Table 2, entry 5): Prepared from 4-(4-me-
thoxybenzyl)hepta-1,6-dien-4-ol (S2e, 499 mg, 2.15 mmol,
1.00 equiv.) and Hoveyda–Grubbs II catalyst (27 mg,
43 mmol, 2.0 mol%) according to GPS2. Purification by flash
column chromatography on silica gel (cyclohexane:tert-butyl
methyl ether=3:1) afforded the analytically pure product as
a light brown oil; yield: 493 mg (61%). GLC (HP-5): tR =
29.5 min; Rf =0.56 (cyclohexane:tert-butyl methyl ether=
˜
1:2); IR (ATR): n=3487 (br), 2981 (br), 2935 (m), 1713 (s),
1
1:2); IR (ATR): n=3482 (br), 2980 (br), 1711 (s), 1650 (s),
1650 (s), 1510 (s), 1245 (s), 1163 (s), 1034 (s) cmꢀ1; H NMR
˜
1260 (s), 1160 (s), 1038 (s) cmꢀ1
;
1H NMR (400 MHz,
(400 MHz, CDCl3): d=1.29 (t, J=7.1 Hz, 6H), 1.77 (br s,
1H), 2.31 (dd, J=7.4 Hz, J=1.3 Hz, 4H), 2.74 (s, 2H), 3.79
(s, 3H), 4.19 (q, J=7.2 Hz, 4H), 5.89 (d, J=15.6 Hz, 2H),
6.85 (d, J=8.6 Hz, 2H), 7.01 (dt, J=15.6 Hz, J=7.6 Hz,
2H), 7.12 (d, J=8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=14.4, 42.0, 44.9, 55.3, 60.5, 73.9, 114.1, 125.1, 127.9, 131.6,
143.7, 158.8, 166.2; HR-MS (ESI): m/z=399.1777, calcd.
exact mass for [M+Na]+ (C21H28O6Na): 399.1778.
CDCl3): d=1.29 (t, J=7.1 Hz, 6H), 1.78 (s, 1H), 2.33 (d, J=
7.5 Hz, 4H), 2.77 (s, 2H), 3.79 (s, 3H), 4.19 (q, J=7.1 Hz,
4H), 5.90 (dt, J=15.6 Hz, J=1.3 Hz, 2H), 6.73–6.84 (m,
3H), 7.01 (dt, J=15.6 Hz, J=7.5 Hz, 2H), 7.21–7.25 (m,
1H); 13C NMR (100 MHz, CDCl3): d=14.4, 42.2, 45.9, 55.3,
60.5, 73.8, 112.5, 116.4, 123.0, 125.2, 129.7, 137.5, 143.6,
159.8, 166.2; HR-MS (ESI): m/z=377.1958, calcd. exact
mass for [M+H]+ (C21H29O6): 377.1959.
AHCTUNGTREG(NNUN 1E,6E)-4-(N-Methyl-1H-indol-3-ylmethyl)-1,7-diphenyl-
Diethyl (2E,7E)-5-hydroxy-5-(3-methylbenzyl)nona-2,7-di-
endioate (1c, Table 2, entry 3): Prepared from 4-(3-methyl-
hepta-1,6-dien-4-ol (3a, Scheme 2): To a three-necked flask
equipped with a reflux condenser, DIBAL-H (1.0M in cy-
clohexane, 57.0 mL, 57.0 mmol, 15.0 equiv.), dry THF
(60 mL), and diyne (S7, 1.54 g, 3.80 mmol, 1.00 equiv.) were
added. The reaction mixture was heated to 688C for 3 days,
and 2N NaOH (5 mL) was added at 08C. To the reaction
mixture, tert-butyl methyl ether (150 mL) and 2N HCl
(150 mL) were added. The organic phase was washed with
saturated aqueous NaHCO3 solution (80 mL) and dried over
anhydrous MgSO4. The solvent was removed under reduced
pressure. Purification by flash column chromatography on
silica gel (cyclohexane:tert-butyl methyl ether=6:1) afford-
ed the analytically pure product as a light red oil; yield:
1.30 g (84%, E:Zꢁ99:1). The diastereomeric ratio was de-
benzyl)hepta-1,6-dien-4-ol
(S2c,
503 mg,
2.33 mmol,
1.00 equiv.) and Hoveyda–Grubbs II catalyst (29 mg,
46 mmol, 2.0 mol%) according to GPS2. Purification by flash
column chromatography on silica gel (cyclohexane:tert-butyl
methyl ether=3:1) afforded the analytically pure product as
a light brown oil; yield: 614 mg (73%). GLC (HP-5): tR =
26.9 min; Rf =0.57 (cyclohexane:tert-butyl methyl ether=
˜
1:1); IR (ATR): n=3486 (br), 2980 (m), 2934 (m), 1714 (s),
1
1650 (s), 1265 (s), 1162 (s), 1039 (s), 980 (s) cmꢀ1; H NMR
(400 MHz, CDCl3): d=1.30 (t, J=7.2 Hz, 6H), 1.64 (br s,
1H), 2.33 (dd, J=7.8 Hz, J=1.4 Hz, 4H), 2.35 (s, 3H), 2.77
(s, 2H), 4.20 (q, J=7.1 Hz, 4H), 5.90 (dt, J=15.6 Hz, J=
1.4 Hz, 2H), 6.97–7.06 (m, 4H), 7.07–7.12 (m, 1H), 7.22–
7.24 (m, 1H); 13C NMR (100 MHz, CDCl3): d=14.4, 21.5,
42.2, 45.8, 60.5, 73.8, 125.2, 127.7, 128.0, 128.7, 131.5, 135.9,
138.4, 143.7, 166.2; HR-MS (ESI): m/z=361.2018, calcd.
exact mass for [M+H]+ (C21H29O5): 361.2010.
Diethyl (2E,7E)-5-hydroxy-5-[3-(trifluoromethyl)benzyl]-
nona-2,7-diendioate (1d, Table 2, entry 4): Prepared from 4-
[3-(trifluoromethyl)benzyl]hepta-1,6-dien-4-ol (S2d, 501 mg,
1.85 mmol, 1.00 equiv.) and Hoveyda–Grubbs II catalyst
(23 mg, 37 mmol, 2.0 mol%) according to GPS2. Purification
by flash column chromatography on silica gel (cyclohexane:
tert-butyl methyl ether=3:1) afforded the analytically pure
product as a light brown oil; yield: 650 mg (85%). GLC
(HP-5): tR =25.5 min; Rf =0.52 (cyclohexane:tert-butyl
1
termined by H NMR spectroscopy. Rf =0.34 (cyclohexane:-
˜
tert-butyl methyl ether=2:1); IR (ATR): n=3385 (br), 3026
1
(s), 2925 (s) cmꢀ1; H NMR (400 MHz, CDCl3): d=1.89 (br
s, 1H), 2.50 (d, J=7.1 Hz, 4H), 3.02 (s, 2H), 3.79 (s, 3H),
6.37 (dt, J=15.8 Hz, J=7.0 Hz, 2H), 6.40 (d, J=15.9 Hz,
2H), 7.00 (s, 1H), 7.14 (ddd, J=8.0 Hz, J=7.0 Hz, J=
1.1 Hz, 1H), 7.21–7.27 (m, 3H), 7.30–7.39 (m, 9H), 7.66
(ddd, J=8.0 Hz, J=1.3 Hz, J=0.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=32.9, 35.5, 43.2, 74.9, 109.3, 109.4,
119.3, 119.7, 121.8, 126.1, 126.3, 127.3, 128.7, 128.7, 129.1,
133.5, 137.0, 137.7; HR-MS (ESI): m/z=430.2141, calcd.
exact mass for [M+Na]+ (C29H29NONa): 430.2141; elemen-
tal analysis calcd. for C29H29NO: C 85.47, H 7.17, N 3.44;
found: C 85.07, H 7.25, N 3.05.
˜
methyl ether=1:1); IR (ATR): n=3450 (br), 2983 (br), 2937
ACHTUNGTREN(NUNG 1E,6E)-4-Methoxy-4-(1-methyl-1H-indol-3-ylmethyl)-1,7-
(m), 1699 (s), 1651 (s), 1327 (s), 1270 (m), 1160 (s), 1119 (s)
diphenylhepta-1,6-diene (3b, Scheme 2): To a suspension of
NaH (60% in mineral oil, 0.061 g, 1.5 mmol, 1.2 equiv.) in
dry THF (2 mL) at 08C, a solution of tertiary alcohol 3a
(0.510 g, 1.27 mmol, 1.00 equiv.) in dry THF (4 mL) and
methyl iodide (0.27 g, 1.9 mmol, 1.5 equiv.) were successive-
ly added dropwise. After 30 min, the ice bath was removed,
cmꢀ1 1H NMR (400 MHz, CDCl3): d=1.29 (t, J=7.1 Hz,
;
6H), 1.83 (br s, 1H), 2.32 (dd, J=7.5 Hz, J=1.2 Hz, 4H),
2.86 (s, 2H), 4.20 (q, J=7.1 Hz, 4H), 5.90 (d, J=15.7 Hz,
2H), 6.99 (dt, J=15.6 Hz, J=7.7 Hz, 2H), 7.40–7.47 (m,
2H), 7.49 (br s, 1H), 7.51–7.56 (m, 1H); 13C NMR
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

FULL PAPERS
Sandeep R. Kandukuri et al.
and vigorous stirring was continued at room temperature for
4 h. Then, saturated aqueous NH4Cl (30 mL) was added at
08C. After 20 min, tert-butyl methyl ether (80 mL) was
added, and the organic phase was washed with saturated
aqueous NaHCO3 solution (30 mL). The combined organic
phases were dried over anhydrous MgSO4 and concentrated
under reduced pressure. Purification by flash column chro-
matography on silica gel (cyclohexane:tert-butyl methyl
ether=97:3) afforded the analytically pure product as a col-
orless oil; 0.509 g (95%). Rf =0.67 (cyclohexane:tert-butyl
J=0.9 Hz, 1H), 7.25 (ddd, J=8.5 Hz, J=7.5 Hz, J=1.3 Hz,
1H), 7.33 (ddd, J=8.3 Hz, J=1.3 Hz, J=0.9 Hz, 1H), 7.66
(ddd, J=7.9 Hz, J=1.1 Hz, J=0.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=32.8, 35.0, 43.5, 73.8, 109.3, 109.4,
118.5, 119.2, 119.7, 121.7, 128.6, 129.1, 134.3, 137.0; HR-MS
(ESI): m/z=256.1698, calcd. exact mass for [M+H]+
(C17H22NO): 256.1696.
1-[(1-Methyl-1H-indol-3-yl)methyl]cyclopent-3-enol
(9,
Scheme 3): Prepared from 4-(1-methyl-1H-indol-3-ylmeth-
yl)-1,6-heptadien-4-ol (7, 500 mg, 1.96 mmol, 1.00 equiv.),
and Grubbs II catalyst (34 mg, 0.039 mmol, 2.0 mol%) ac-
cording to GPS3. Purification by flash column chromatogra-
phy on silica gel (cyclohexane:tert-butyl methyl ether=3:1)
afforded the analytically pure product as a light brown oil;
yield: 280 mg (63%). GLC (HP-5): tR =21.2 min; Rf =0.40
˜
methyl ether=3:1); IR (ATR): n=3056 (m), 3026 (m), 2935
(s), 2825 (m) cmꢀ1 1H NMR (500 MHz, CDCl3): d=2.55
;
(ddd, J=14.5 Hz, J=7.1 Hz, J=1.0 Hz, 2H), 2.56 (ddd, J=
14.6 Hz, J=7.1 Hz, J=1.0 Hz, 2H), 3.06 (s, 2H), 3.49 (s,
3H), 3.79 (s, 3H), 6.31–6.37 (m, 2H), 6.41 (d, J=16.1 Hz,
2H), 7.09 (s, 1H), 7.14 (ddd, J=7.8 Hz, J=7.7 Hz, J=
0.6 Hz, 1H), 7.23–7.27 (m, 4H), 7.30–7.35 (m, 4H), 7.37 (d,
J=7.8 Hz, 4H), 7.63 (d, J=8.0 Hz, 1H); 13C NMR
(126 MHz, CDCl3): d=30.1, 32.8, 39.0, 49.5, 80.0, 109.2,
109.7, 118.9, 119.3, 121.4, 126.1, 126.2, 127.2, 128.2, 128.6,
129.1, 133.0, 136.6, 137.8; HR-MS (ESI): m/z=444.2298,
calcd. exact mass for [M+Na]+ (C30H31NONa): 444.2298; el-
emental analysis calcd. for C30H31NO: C 85.47, H 7.41, N
3.32; found: C 85.60, H 7.32, N 2.93.
Diethyl (2E,7E)-5-(1-methyl-1H-indol-3-ylmethyl)-5-hy-
droxy-2,7-diendioate (5, Scheme 2): Prepared from cyclo-
pentenol 9 (254 mg, 1.11 mmol, 1.00 equiv.) and Hoveyda–
Grubbs II catalyst (14 mg, 22 mmol, 2.0 mol%) according to
GPS2. Purification by flash column chromatography on
silica gel (cyclohexane:tert-butyl methyl ether=1:1) afford-
ed the analytically pure product as a light brown oil; yield:
274 mg (62%). GLC (HP-5): tR =36.3 min; Rf =0.40 (cyclo-
˜
(cyclohexane:tert-butyl methyl ether=1:1); IR (ATR): n=
3418 (br), 3050 (m), 2906 (br), 1613 (m), 1545 (w), 1471 (s),
1423 (m), 1374 (m), 1327 (s), 1257 (m), 1126 (m), 949 (m),
1
886 (s), 735 (s), 666 (m) cmꢀ1; H NMR (400 MHz, CDCl3):
d=2.00 (s, 1H), 2.37 (d, J=15.5 Hz, 2H), 2.67 (d, J=
15.5 Hz, 2H), 3.12 (s, 2H), 3.79 (s, 3H), 5.72 (s, 1H), 7.00 (s,
1H), 7.15 (ddd, J=8.3 Hz, J=7.4 Hz, J=0.9 Hz, 1H), 7.25
(ddd, J=8.4 Hz, J=7.6 Hz, J=1.1 Hz, 1H), 7.33 (ddd, J=
8.2 Hz, J=1.1 Hz, J=0.9 Hz, 1H), 7.67 (ddd, J=8.0 Hz, J=
1.2 Hz, J=1.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
32.8, 36.5, 46.9, 81.6, 109.3, 110.6, 119.2, 119.5, 121.7, 128.1,
128.9, 128.9, 137.0; HR-MS (ESI): m/z=228.1386, calcd.
exact mass for [M+H]+ (C15H18NO): 228.1383.
Dimethyl (2E,7E)-5-hydroxy-5-[1-(1-methyl-1H-indol-3-
yl)ethyl]nona-2,7-dienedioate (11a, Table 3, entry 1): Pre-
pared from 1-[1-(1-methyl-1H-indol-3-yl)ethyl]cyclopent-3-
enol (S16, 100 mg, 0.410 mmol, 1.00 equiv.) and Hoveyda–
Grubbs II catalyst (5.8 mg, 8.2 mmol, 2.0 mol%) according to
GPS2. Purification by flash column chromatography on
silica gel (cyclohexane:ethyl acetate=3:1) afforded the ana-
lytically pure product as a light yellow oil; yield: 130 mg
(82%). GLC (HP-5): tR =27.4 min; Rf =0.26 (cyclohexa-
˜
hexane:tert-butyl methyl ether=1:1); IR (ATR): n=3496
(br), 2930 (br), 1714 (s), 1651 (s), 1468 (m), 1368 (m), 1329
(w), 1266 (s), 1165 (s), 1041 (m), 981 (m), 739 (s) cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=1.29 (t, J=7.2 Hz, 6H),
1.85 (s, 1H), 2.44 (d, J=7.6 Hz, 4H), 2.94 (s, 2H), 3.79 (s,
3H), 4.20 (q, J=7.1 Hz, 4H), 5.89 (dt, J=15.6 Hz, J=
1.4 Hz, 1H), 6.95 (s, 1H), 7.05 (dt, J=15.6 Hz, J=7.6 Hz,
1H), 7.13 (ddd, J=8.1 Hz, J=7.5 Hz, J=1.0 Hz, 1H), 7.24
(ddd, J=8.0 Hz, J=7.5 Hz, J=1.1 Hz, 1H), 7.32 (ddd, J=
8.2 Hz, J=1.2 Hz, J=1.0 Hz, 1H), 7.59 (ddd, J=7.9 Hz, J=
1.3 Hz, J=0.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
14.4, 33.0, 35.6, 42.2, 60.5, 74.1, 108.3, 109.5, 119.5, 119.6,
122.1, 124.9, 128.7, 128.8, 137.2, 144.1, 166.3; HR-MS (ESI):
m/z=422.1940, calcd. exact mass for [M+Na]+
(C23H29NO5Na): 422.1938.
˜
ne:ethyl acetate=2:1); IR (ATR): n=3478 (br), 2946 (w),
1714 (s), 1651 (m), 1540 (w), 1460 (w), 1433 (m), 1328 (m),
1269 (s), 1168 (s), 1034 (m), 977 (m), 837 (s), 739 (s) cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=1.39 (d, J=7.3 Hz, 3H),
1.80 (s, 1H), 2.35 (dd, J=15.1 Hz, J=7.9 Hz, 1H), 2.47
(ddd, J=14.9 Hz, J=7.4 Hz, J=1.0 Hz, 1H), 2.51–2.56 (m,
2H), 3.26 (q, J=7.4 Hz, 1H), 3.73 (s, 3H), 3.74 (s, 3H), 3.79
(s, 3H), 5.84 (d, J=15.5 Hz, 1H), 5.91 (d, J=15.5 Hz, 1H),
6.95 (s, 1H), 6.98–7.04 (m, 1H), 7.06–7.14 (m, 2H), 7.23 (d,
J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz,
1H); 13C NMR (126 MHz, CDCl3): d=16.0, 33.0, 38.7, 39.3,
40.8, 51.6, 51.6, 76.3, 109.5, 114.8, 119.6, 119.9, 122.1, 123.9,
124.2, 127.7, 128.2, 137.0, 144.7, 145.0, 166.7, 166.7; HR-MS
(APCI): m/z=386.1960, calcd. exact mass for [M+H]+
(C22H28NO5): 386.1962.
4-(1-Methyl-1H-indol-3-ylmethyl)hepta-1,6-dien-4-ol (7,
Scheme 3): Prepared from methyl 2-(1-methyl-1H-indol-3-
yl)acetate (S4, 8.08 g, 39.7 mmol, 1.00 equiv.) and allylmag-
nesium bromide (0.740M in Et2O, 110 mL, 81.5 mmol,
2.05 equiv.) according to GPS1. Purification by flash column
chromatography on silica gel (cyclohexane:tert-butyl methyl
ether=3:1) afforded the analytically pure product as a pale
yellow oil; yield: 10 g (98%). GLC (HP-5): tR =21.8 min;
Rf =0.50 (cyclohexane:tert-butyl methyl ether=1:1); IR
Diethyl (2E,7E)-5-hydroxy-5-[1-(1-methyl-1H-indol-3-yl)-
AHCTUNGTRENNUNG
(S16, 241 mg, 1.00 mmol, 1.00 equiv.) and Hoveyda–Grubbs
II catalyst (12.8 mg, 20.0 mmol, 2.00 mol%) according to
GPS2. Purification by flash column chromatography on
silica gel (cyclohexane:ethyl acetate=4:1) afforded the ana-
lytically pure product as a yellow oil; yield: 360 mg (87%).
GLC (HP-5): tR =29.1 min; Rf =0.30 (cyclohexane:ethyl ace-
˜
(ATR): n=3549 (br), 3072 (w), 2912 (w), 1638 (m), 1472 (s),
1374 (m), 1328 (m), 1157 (m), 1129 (m), 995 (m), 910 (m),
736 (s) cmꢀ1 1H NMR (400 MHz, CDCl3): d=1.03 (br s,
;
1H), 2.33 (d, J=7.3 Hz, 4H), 2.94 (s, 2H), 3.79 (s, 3H),
5.12–5.20 (m, 4H), 5.97 (ddt, J=16.8 Hz, J=10.2 Hz, J=
7.3 Hz, 2H), 6.98 (s, 1H), 7.15 (ddd, J=8.4 Hz, J=7.4 Hz,
˜
tate=2:1); IR (ATR): n=3552 (br), 2967 (w), 1709 (s), 1649
8
asc.wiley-vch.de
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

ꢀ
FULL PAPERS
Diastereotopic Group Selection in Hydroxy-Directed Intramolecular C H Alkenylation
(s), 1541 (w), 1466 (m), 1367 (m), 1327 (m), 1265 (s), 1170
(s), 1038 (s), 978 (s), 843 (s), 738 (s) cmꢀ1 1H NMR
2H), 7.24 (ddd, J=7.1 Hz, J=7.1 Hz, J=0.7 Hz, 1H), 7.32
(d, J=8.2 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H); 13C NMR
(126 MHz, CDCl3): d=13.0, 22.5, 33.0, 40.0, 40.7, 47.3, 51.6,
51.6, 76.5, 109.5, 112.0, 119.5, 120.0, 122.0, 123.8, 124.1,
128.1, 129.0, 137.3, 144.9, 145.2, 166.7, 166.7; HR-MS
(APCI): m/z=400.2116, calcd. exact mass for [M+H]+
(C23H30NO5): 400.2118.
;
(400 MHz, CDCl3): d=1.29 (t, J=7.2 Hz, 6H), 1.39 (d, J=
7.6 Hz, 3H), 1.83 (br s, 1H), 2.35 (ddd, J=14.6 Hz, J=
7.7 Hz, J=1.0 Hz, 1H), 2.47 (ddd, J=14.8 Hz, J=7.4 Hz,
J=1.5 Hz, 1H), 2.51–2.56 (m, 2H), 3.26 (q, J=7.1 Hz, 1H),
3.78 (s, 3H), 4.19 (q, J=7.2 Hz, 2H), 4.19 (q, J=7.2 Hz,
2H), 5.83 (dt, J=15.7 Hz, J=1.3 Hz, 1H), 5.90 (dd, J=
15.7 Hz, J=1.2 Hz, 1H), 6.94 (s, 1H), 6.96–7.02 (m, 1H),
7.08 (d, J=7.9 Hz, 1H), 7.13 (dd, J=7.9 Hz, J=1.0 Hz, 1H),
7.23 (ddd, J=7.2 Hz, J=7.1 Hz, J=1.0 Hz, 1H), 7.31 (d, J=
8.2 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=14.3, 14.4, 16.0, 32.9, 38.7, 39.2, 40.8, 60.3, 60.4,
76.3, 109.5, 114.8, 119.5, 119.9, 122.0, 124.3, 124.6, 127.6,
128.2, 137.0, 144.3, 144.7, 166.3, 166.3; HR-MS (APCI):
m/z=414.2277, calcd. exact mass for [M+H]+ (C24H32NO5):
414.2275.
Dimethyl (2E,7E)-5-hydroxy-5-[2-methyl-1-(1-methyl-1H-
indol-3-yl)propyl]nona-2,7-dienedioate
(13a,
Table 3,
entry 5): Prepared from 1-[2-methyl-1-(1-methyl-1H-indol-3-
yl)propyl]cyclopent-3-enol (S18, 134 mg, 0.500 mmol,
1.00 equiv.) and Hoveyda–Grubbs II catalyst (6.2 mg,
10 mmol, 2.0 mol%) according to GPS2. Purification by flash
column chromatography on silica gel (cyclohexane:ethyl
acetate=4:1!3:1) afforded the analytically pure product as
a white solid; yield: 130 mg (63%); mp 156–1578C. GLC
(HP-5): tR =34.5 min; Rf =0.36 (cyclohexane:ethyl acetate=
˜
Dibutyl (2E,7E)-5-hydroxy-5-[1-(1-methyl-1H-indol-3-yl)-
2:1); IR (ATR): n=3454 (br), 2949 (w), 1696 (s), 1648 (m),
A
1438 (w), 1336 (w), 1267 (s), 1232 (m), 1193 (m), 1042 (m),
1
979 (s), 824 (w), 737 (s) cmꢀ1; H NMR (500 MHz, CDCl3):
(S16, 100 mg, 0.410 mmol, 1.00 equiv.) and Hoveyda–Grubbs
II catalyst (5.8 mg, 8.2 mmol, 2.0 mol%) according to GPS2.
Purification by flash column chromatography on silica gel
(cyclohexane:ethyl acetate=5:1) afforded the analytically
pure product as a yellow oil; yield: 150 mg (78%). GLC
(HP-5): tR =29.1 min; Rf =0.45 (cyclohexane:ethyl acetate=
d=0.76 (d, J=6.2 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 1.85 (br
s, 1H), 2.17–2.30 (m, 2H), 2.32–2.40 (m, 1H), 2.65–2.69 (m,
2H), 3.07 (s, 1H), 3.70 (s, 3H), 3.76 (s, 3H), 3.81 (s, 3H),
5.62 (d, J=15.6 Hz, 1H), 5.95 (d, J=15.6 Hz, 1H), 6.86–6.92
(m, 1H), 7.02–7.08 (m, 2H), 7.11 (ddd, J=7.2 Hz, J=
7.2 Hz, J=0.7 Hz, 1H), 7.22 (dd, J=7.2 Hz, J=7.2 Hz, 1H),
7.31 (d, J=8.2 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H); 13C NMR
(126 MHz, CDCl3): d=23.7, 28.2, 33.0, 40.5, 42.2, 51.5, 51.7,
77.3, 109.2, 110.3, 119.2, 119.3, 121.8, 124.0, 124.4, 127.8,
136.4, 144.5, 166.7, 166.7; HR-MS (APCI): m/z=414.2267,
calcd. exact mass for [M+H]+ (C24H32NO5): 414.2275.
˜
2:1); IR (ATR): n=3495 (br), 2956 (w), 1710 (s), 1649 (m),
1463 (m), 1372 (m), 1266 (s), 1167 (s), 1061 (m), 1027 (m),
1
977 (s), 840 (w), 737 (s) cmꢀ1; H NMR (500 MHz, CDCl3):
d=0.95 (t, J=7.4 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H), 1.37–
1.45 (m, 7H), 1.62–1.68 (m, 4H), 1.81 (br s, 1H), 2.35 (ddd,
J=14.6 Hz, J=7.7 Hz, J=0.9 Hz, 1H), 2.48 (ddd, J=
14.8 Hz, J=7.4 Hz, J=1.3 Hz, 1H), 2.51–2.59 (m, 2H), 3.27
(q, J=7.2 Hz, 1H), 3.78 (s, 3H), 4.11–4.15 (m, 4H), 5.84 (d,
J=15.8 Hz, 1H), 5.91 (d, J=15.5 Hz, 1H), 6.95 (s, 1H),
6.97–7.03 (m, 1H), 7.07 (dd, J=7.9 Hz, J=7.8 Hz, 1H), 7.12
(ddd, J=7.9 Hz, J=7.9 Hz, J=0.9 Hz, 1H), 7.24 (ddd, J=
7.0 Hz, J=7.0 Hz, J=0.8 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H),
7.63 (d, J=8.0 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=
14.0, 16.1, 19.4, 30.9, 33.0, 38.7, 39.3, 40.9, 64.4, 64.5, 76.4,
109.6, 115.0, 119.6, 120.0, 122.2, 124.5, 124.8, 127.7, 128.3,
137.1, 144.4, 144.7, 166.5, 166.5; HR-MS (APCI): m/z=
470.2891, calcd. exact mass for [M+H]+ (C28H40NO5):
470.2901.
Diethyl (2E,7E)-5-hydroxy-5-[(1-methyl-1H-indol-3-yl)-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Hoveyda–Grubbs II catalyst (10 mg, 16 mmol, 2.0 mol%) ac-
cording to GPS2. Purification by flash column chromatogra-
phy on silica gel (cyclohexane:ethyl acetate=4:1) afforded
the analytically pure product as a brown oil; yield: 260 mg
(68%). GLC (HP-5): tR =32.2 min; Rf =0.18 (cyclohexa-
˜
ne:ethyl acetate=3:1); IR (ATR): n=3492 (br), 2979 (w),
1699 (s), 1649 (m), 1470 (m), 1367 (m), 1326 (m), 1266 (s),
1217 (m), 1166 (s), 1094 (m), 1037 (s), 978 (s), 848 (w), 737
1
(s), 702 (s) cmꢀ1; H NMR (500 MHz, CDCl3): d=1.24 (d,
Dimethyl (2E,7E)-5-hydroxy-5-[1-(1-methyl-1H-indol-3-
yl)ACHTUNGTRENNUNGpropyl]nona-2,7-dienedioate (12a, Table 3, entry 4): Pre-
J=7.2 Hz, 3H), 1.26 (d, J=7.2 Hz, 3H), 2.03 (br s, 1H),
2.33–2.44 (m, 2H), 2.45–2.56 (m, 2H), 3.74 (s, 3H), 4.10–
4.18 (m, 4H), 4.26 (s, 1H), 5.64 (d, J=15.7 Hz, 1H), 5.72 (d,
J=15.7 Hz, 1H), 6.88–6.94 (m, 2H), 7.06 (ddd, J=8.0 Hz,
J=8.0 Hz, J=1.0 Hz, 1H), 7.14–7.18 (m, 2H), 7.22–7.26 (m,
3H), 7.31 (s, 1H), 7.49 (dd, J=8.3 Hz, J=1.1 Hz, 2H), 7.56
(d, J=8.0 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=14.4,
14.4, 33.0, 41.0, 41.1, 50.6, 60.4, 60.5, 76.8, 109.3, 113.6, 118.9,
119.3, 121.9, 124.8, 125.1, 126.9, 127.7, 128.3, 128.6, 129.6,
136.5, 141.2, 143.5, 143.7, 166.5; HR-MS (APCI): m/z=
476.2436, calcd. exact mass for [M+H]+ (C29H34NO5):
476.2431.
pared from 1-[1-(1-methyl-1H-indol-3-yl)propylcyclopent-3-
enol (S17, 90 mg, 0.35 mmol, 1.0 equiv.) and Hoveyda–
Grubbs II catalyst (4.4 mg, 7.0 mmol, 2.0 mol%) according to
GPS2. Purification by flash column chromatography on
silica gel (cyclohexane:ethyl acetate=3:1) afforded the ana-
lytically pure product as a light yellow oil; yield: 111 mg
(80%). GLC (HP-5): tR =33.8 min; Rf =0.30 (cyclohexa-
˜
ne:ethyl acetate=2:1); IR (ATR): n=3505 (br), 2947 (w),
1707 (s), 1650 (m), 1432 (m), 1371 (w), 1327 (m), 1266 (s),
1
1165 (s), 1033 (m), 977 (m), 840 (w), 737 (s) cmꢀ1; H NMR
(500 MHz, CDCl3): d=0.75 (t, J=7.4 Hz, 3H), 1.77–1.89
(m, 3H), 2.38 (dd, J=14.7 Hz, J=8.2 Hz, 1H), 2.47 (ddd,
J=15.0 Hz, J=7.4 Hz, J=1.2 Hz, 1H), 2.50–2.58 (m, 2H),
2.95 (dd, J=11.5 Hz, J=3.5 Hz, 1H), 3.73 (s, 3H), 3.74 (s,
3H), 3.79 (s, 3H), 5.83 (d, J=15.8 Hz, 1H), 5.88 (d, J=
15.8 Hz, 1H), 6.92 (s, 1H), 6.98–7.04 (m, 1H), 7.07–7.14 (m,
ACHTUNGERTN(NUNG E,E)-4-(2-Ethoxy-2-oxoethylidene)-2-(4-ethoxy-4-oxobut-
2-enyl)-1,2,3,4-tetrahydro-2-naphthol (2a, Table 2, entry 1):
Prepared from diethyl (2E,7E)-5-benzyl-5-hydroxynona-2,7-
diendioate (1a, 69.3 mg, 0.200 mmol, 1.00 equiv.), PdACHTUNGTRENNUNG(OAc)2
(4.5 mg, 20 mmol, 10 mol%), AgOAc (134 mg, 0.800 mmol,
4.00 equiv.), Li2CO3 (30 mg, 0.40 mmol, 2.0 equiv.), and L1
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!

FULL PAPERS
Sandeep R. Kandukuri et al.
(12 mg, 40 mmol, 20 mol%) according to GP1 at 908C for
64 h. Purification by flash column chromatography on silica
gel (cyclohexane:
tert-butyl methyl ether=1:2) afforded the analytically pure
product as a light yellow oil; yield: 13.5 mg (20%). GLC
(HP-5): tR =27.6 min; Rf =0.5 (cyclohexane:tert-butyl methyl
according to GP1 at 908C for 64 h. Purification by flash
column chromatography on silica gel (cyclohexane:tert-butyl
methyl ether=1:2) afforded the analytically pure product as
a light yellow oil; yield: 22.6 mg (32%). GLC (HP-5): tR =
29.0 min; Rf =0.50 (cyclohexane:tert-butyl methyl ether=
˜
1:2); IR (ATR): n=3470 (br), 2923 (s), 2853 (m), 1705 (s),
˜
ether=1:2); IR (ATR): n=3455 (br), 2920 (m), 1706 (s),
1604 (m), 1457 (m), 1368 (m), 1269 (m), 1154 (s), 1041 (m),
1619 (m), 1369 (m), 1269 (m), 1156 (s), 1042 (s), 985 (w),
985 (w), 863 (w), 813 (m), 730 (m) cmꢀ1 1H NMR
;
864 (m), 764 (s) cmꢀ1; H NMR (400 MHz, CDCl3): d=1.29
(400 MHz, CDCl3): d=1.27–1.33 (m, 6H), 1.82 (br s, 1H),
2.32 (s, 3H), 2.46 (ddd, J=14.0 Hz, J=7.5 Hz, J=1.4 Hz,
1H), 2.53 (ddd, J=14.0 Hz, J=7.5 Hz, J=1.4 Hz, 1H), 2.87
(d, J=16.3 Hz, 1H), 2.92 (d, J=16.3 Hz, 1H), 3.10 (dd, J=
16.4 Hz, J=1.8 Hz, 1H), 3.52 (dd, J=16.5 Hz, J=1.4 Hz,
1H), 4.16–4.22 (m, 4H), 5.89 (ddd, J=15.6 Hz, J=1.7 Hz,
J=1.2 Hz, 1H), 6.43 (dd, J=2.4 Hz, J=1.4 Hz, 1H), 6.96 (s,
1H), 7.03–7.12 (m, 2H), 7.59 (d, J=8.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=14.4, 14.5, 21.4, 40.1, 41.8, 44.1, 60.1,
60.5, 71.6, 114.2, 124.5, 125.3, 128.0, 130.2, 130.9, 136.1,
140.8, 143.5, 151.1, 166.2, 167.1; HR-MS (ESI): m/z=
381.1663, calcd. exact mass for [M+Na]+ (C21H26O5Na):
381.1672.
1
(t, J=7.2 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H), 1.75 (br s, 1H),
2.48 (ddd, J=14.3 Hz, J=7.5 Hz, J=1.4 Hz, 1H), 2.54 (ddd,
J=14.0 Hz, J=7.5 Hz, J=1.4 Hz, 1H), 2.93 (d, J=16.3 Hz,
1H), 2.97 (d, J=16.3 Hz, 1H), 3.09 (dd, J=16.4 Hz, J=
2.0 Hz, 1H), 3.57 (dd, J=16.3 Hz, J=1.5 Hz, 1H), 4.17–4.23
(m, 4H), 5.91 (ddd, J=15.6 Hz, J=1.6 Hz, J=1.3 Hz, 1H),
6.47 (dd, J=2.3 Hz, J=1.6 Hz, 1H), 7.08 (m, 1H), 7.15 (dd,
J=7.5 Hz, J=0.8 Hz, 1H), 7.22–7.26 (m, 1H), 7.32 (ddd, J=
8.2 Hz, J=7.4 Hz, J=1.2 Hz, 1H), 7.69 (dd, J=8.0 Hz, J=
0.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=14.4, 14.5,
40.0, 41.8, 44.3, 60.2, 60.5, 71.6, 115.3, 124.6, 125.4, 127.1,
130.3, 130.5, 133.1, 136.2, 143.4, 151.1, 166.2, 167.0; HR-MS
(ESI): m/z=367.1510, calcd. exact mass for [M+Na]+
(C20H24O5Na): 367.1516.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Table 1, entries 1–8 and Table 2, entry 2): Prepared from di-
ethyl (2E,7E)-5-hydroxy-5-(3-methoxybenzyl)nona-2,7-dien-
dioate (1b, 27 mg, 0.071 mmol, 1.0 equiv.), PdACTHNUTRGNEUNG(OAc)2
ACHTUNGTRENNUNG
10 mol%), AgOAc (134 mg, 0.800 mmol, 4.00 equiv.),
Li2CO3 (30 mg, 0.40 mmol, 2.0 equiv.), and L1 (12 mg,
40 mmol, 20 mol%) according to GP1 at 908C for 64 h. Pu-
rification by flash column chromatography on silica gel (cy-
clohexane:tert-butyl methyl ether=1:2) afforded the analyti-
cally pure product as a light yellow oil; yield: 7.5 mg (10%).
GLC (HP-5): tR =31.1 min; Rf =0.40 (cyclohexane:tert-butyl
(1.6 mg, 7.1 mmol, 10 mol%), AgOAc (47.4 mg, 0.284 mmol,
4.00 equiv.), Li2CO3 (10.5 mg, 0.140 mmol, 2.00 equiv.), and
L1 (4.5 mg, 14 mmol, 20 mol%) according to GP1 at 908C
for 62 h. Purification by flash column chromatography on
silica gel (cyclohexane:tert-butyl methyl ether=1:1) afford-
ed the analytically pure product as a light brown oil; yield:
14 mg (52%). GLC (HP-5): tR =32.5 min; Rf =0.35 (cyclo-
hexane:tert-butyl methyl ether=1:2); HPLC (Daicel Chiral-
pak AD-H column, column temperature 208C, solvent n-
heptane:i-PrOH=90:10, flow rate 0.70 mL·minꢀ1, l=
˜
methyl ether=1:2); IR (ATR): n=3467 (br), 2979 (m), 1706
(s), 1619 (m), 1497 (m), 1430 (w), 1367 (m), 1271 (m), 1228
(w), 1151 (s), 1035 (s), 985 (m), 863 (m), 810 (m), 729 (m)
cmꢀ1 1H NMR (400 MHz, CDCl3): d=1.29 (t, J=7.2 Hz,
;
3H), 1.32 (t, J=7.1 Hz, 3H), 1.70 (br s, 1H), 2.47 (ddd, J=
14.0 Hz, J=7.5 Hz, J=1.3 Hz, 1H), 2.54 (ddd, J=14.0 Hz,
J=7.5 Hz, J=1.4 Hz, 1H), 2.86 (d, J=1.1 Hz, 1H), 2.90 (d,
J=16.1 Hz, 1H), 3.06 (dd, J=16.3 Hz, J=2.0 Hz, 1H), 3.53
(dd, J=16.3 Hz, J=1.2 Hz, 1H), 3.82 (s, 3H), 4.19 (q, J=
7.2 Hz, 2H), 4.21 (q, J=7.1 Hz, 2H), 5.90 (ddd, J=15.6 Hz,
J=1.2 Hz, J=1.1 Hz, 1H), 6.43 (dd, J=1.7 Hz, J=1.6 Hz,
1H), 6.92 (dd, J=8.4 Hz, J=2.6 Hz, 1H), 7.04–7.12 (m,
2H), 7.17 (d, J=2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=14.4, 14.5, 40.0, 41.1, 44.2, 55.6, 60.3, 60.5, 71.8, 108.8,
115.4, 117.4, 125.3, 128.4, 131.3, 133.9, 143.4, 151.1, 158.6,
166.2, 166.9; HR-MS (ESI): m/z=397.1613, calcd. exact
mass for [M+Na]+ (C21H26O6Na): 397.1622.
˜
230 nm): tR =62.3 min and tR =87.7 min; IR (ATR): n=3450
(br), 2980 (m), 2931 (m), 1700 (s), 1594 (s), 1498 (m), 1445
(w), 1368 (m), 1268 (m), 1235 (m), 1151 (s), 1039 (s), 984
(m), 832 (m) cmꢀ1 1H NMR (400 MHz, CDCl3): d=1.28–
;
1.34 (m, 6H), 1.73 (br s, 1H), 2.42 (dd, J=14.1 Hz, J=
1.3 Hz, 1H), 2.60 (dd, J=14.1 Hz, J=1.4 Hz, 1H), 2.88 (d,
J=16.4 Hz, 1H), 2.97 (d, J=16.4 Hz, 1H), 3.09 (dd, J=
16.5 Hz, J=8.2 Hz, 1H), 3.56 (ddd, J=16.5 Hz, J=8.3 Hz,
J=1.5 Hz, 1H), 3.82 (s, 3H), 4.20 (m, 4H), 5.91 (ddd, J=
15.6 Hz, J=1.3 Hz, J=1.3 Hz, 1H), 6.36 (dd, J=1.7 Hz, J=
1.7 Hz, 1H), 6.65 (d, J=2.7 Hz, 1H), 6.80 (dd, J=8.9 Hz,
J=2.7 Hz, 1H), 7.08 (ddd, J=15.5 Hz, J=7.7 Hz, J=7.7 Hz,
1H), 7.65 (d, J=8.9 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=14.4, 14.4, 40.1, 42.0, 44.1, 55.4, 60.0, 60.5, 71.5, 112.8,
113.7, 114.2, 125.2, 125.6, 126.2, 138.2, 143.5, 151.0, 161.4,
166.2, 167.2; HR-MS (ESI): m/z=375.1802, calcd. exact
mass for [M+H]+ (C21H27O6): 375.1802.
AHCTUNGTREG(NNUN E,E)-1-Benzylidene-9-methyl-3-(3-phenyl-2-propenyl)-
1,2,3,4-tetrahydrocarbazol-3-ol (4a, Scheme 2): Prepared
from (E,E)-4-(N-methyl-1H-indol-3-ylmethyl)-1,7-diphenyl-
hepta-1,6-dien-4-ol (3a, 73.0 mg, 0.179 mmol, 1.00 equiv.),
PdACHTNUGTRENNUG(OAc)2 (4.0 mg, 18 mmol, 10 mol%), and CuACHTUNGTRENNUNG(OAc)2
A
(68.3 mg, 0.376 mmol, 2.10 equiv.) according to GP2 at 708C
for 65 h. Purification by flash column chromatography on
silica gel (cyclohexane:tert-butyl methyl ether=6:1) afford-
ed the analytically pure product as a light yellow oil (25%
of starting material 3a was recovered); yield: 51.5 mg
(71%). Rf =0.31 (cyclohexane:tert-butyl methyl ether=3:1);
2-enyl)-7-methyl-1,2,3,4-tetrahydro-2-naphthol (2c, Table 2,
entry 3): Prepared from diethyl (2E,7E)-5-hydroxy-5-(3-
methylbenzyl)nona-2,7-dienedioate (1c, 72 mg, 0.20 mmol,
1.0 equiv.), Pd
(134 mg, 0.800 mmol,
0.40 mmol, 2.0 equiv.), and L1 (12 mg, 40 mmol, 20 mol%)
˜
IR (ATR): n=3548 (w), 2905 (br), 1597(m), 1493 (m), 1466
10
asc.wiley-vch.de
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

ꢀ
FULL PAPERS
Diastereotopic Group Selection in Hydroxy-Directed Intramolecular C H Alkenylation
(m), 1447 (m), 1359 (s), 1072 (m), 738 (s), 694 (s) cmꢀ1
;
236.1433, calcd. exact mass for [M+H]+ (C17H18N):
236.1434.
5-Methyl-5,6,9,10-tetrahydro-6,9-methanocyclohepta[b]in-
dol-9-ol (10, Scheme 3): Prepared from 1-[(1-methyl-1H-
indol-3-yl)methyl]cyclopent-3-enol (9, 37 mg, 0.16 mmol,
1H NMR (400 MHz, CDCl3): d=2.07 (br s, 1H), 2.40 (dd,
J=13.7 Hz, J=8.5 Hz, 1H), 2.61 (dd, J=13.8 Hz, J=6.8 Hz,
1H), 2.96 (dd, J=13.6 Hz, J=1.2 Hz, 1H), 3.00 (dd, J=
13.6 Hz, J=1.2 Hz, 1H), 3.04 (d, J=16.1 Hz, 1H), 3.09 (d,
J=16.1 Hz, 1H), 3.95 (s, 3H), 6.13 (ddd, J=15.9 Hz, J=
8.4 Hz, J=6.8 Hz, 1H), 6.42 (d, J=15.9 Hz, 1H), 7.03 (s,
1H), 7.13–7.15 (m, 3H), 7.18–7.35 (m, 7H), 7.39–7.41 (m,
3H), 7.53 (ddd, J=7.8 Hz, J=1.2 Hz, J=0.9 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=32.9, 35.2, 40.6, 43.8, 73.8,
109.5, 112.4, 118.9, 119.6, 123.1, 125.2, 126.3, 126.8, 126.9,
126.9, 127.0, 127.3, 128.6, 128.6, 128.9, 129.4, 134.1, 134.4,
137.2, 140.3; HR-MS (ESI): m/z=428.1985, calcd. exact
mass for [M+Na]+ (C29H27NONa): 428.1985.
1.0 equiv.), Pd
ACHTUNGRTENN(UNG OAc)2 (3.70 mg, 16.2 mmol, 10.0 mol%), and
Cu(OAc)2 (63 mg, 0.34 mmol, 2.1 equiv.) according to GP2
AHCTUNGTRENNUNG
at 708C for 21 h. Purification by flash column chromatogra-
phy on silica gel (cyclohexane:tert-butyl methyl ether=1:1)
afforded the analytically pure product as a light yellow oil;
yield: 8.0 mg (22%). GLC (HP-5): tR =22.1 min; Rf =0.40
˜
(cyclohexane:tert-butyl methyl ether=1:1); IR (ATR): n=
3459 (br), 2979 (br), 1703 (s), 1601 (s), 1466 (m), 1367 (m),
1266 (m), 1230 (m), 1153 (s), 1043 (m), 850 (m), 805 (w),
1
G
740 (s) cmꢀ1; H NMR (400 MHz, CDCl3): d=2.00 (s, 1H),
2.18 (d, J=9.2 Hz, 1H), 2.29 (dd, J=9.1 Hz, J=5.0 Hz, 1H),
2.94 (d, J=15.2 Hz, 1H), 3.06 (d, J=15.2 Hz, 1H), 3.70 (s,
3H), 3.73 (dd, J=4.7 Hz, J=4.8 Hz, 1H), 5.74 (d, J=5.6 Hz,
1H), 6.27 (dd, J=5.6 Hz, J=5.5 Hz, 1H), 7.06 (ddd, J=
8.3 Hz, J=7.6 Hz, J=1.0 Hz, 1H), 7.13 (ddd, J=8.0 Hz, J=
7.7 Hz, J=1.2 Hz, 1H), 7.24 (ddd, J=8.1 Hz, J=1.1 Hz, J=
0.9 Hz, 1H), 7.43 (ddd, J=7.8 Hz, J=1.2 Hz, J=1.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=29.4, 33.0, 38.1, 51.5,
83.0, 106.2, 109.2, 117.5, 119.3, 120.5, 127.5, 135.7, 136.6,
137.8, 140.6; HR-MS (ESI): m/z=226.1227, calcd. exact
mass for [M+H]+ (C15H16NO): 226.1226.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
according to GP2 at 708C for 65 h. Purification by flash
column chromatography on silica gel (cyclohexane:tert-butyl
methyl ether=1:1) afforded the analytically pure product as
a light yellow oil; yield: 21 mg (70%). GLC (HP-5): tR =
41.5 min; Rf =0.47 (cyclohexane:tert-butyl methyl ether=
˜
1:2); IR (ATR): n=2923 (br), 1637 (w), 1601 (m), 1463 (s),
1402 (m), 1300 (m), 1233 (s), 1136 (m), 1058 (w), 1098 (w),
Methyl cis-(E,E)-4-[3-hydroxy-1-(2-methoxy-2-oxoethyli-
dene)-4,9-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]but-
2-enoate (cis-15a, Table 3, entry 1): Prepared from dimethyl
(2E,7E)-5-hydroxy-5-[1-(1-methyl-1H-indol-3-yl)ethyl]nona-
2,7-dienedioate (11a, 39 mg, 0.10 mmol, 1.0 equiv.),
1
993 (m), 909 (s), 768 (m), 744 (s) cmꢀ1; H NMR (400 MHz,
CDCl3): d=1.30 (t, J=7.2 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H),
2.03 (br s, 1H), 2.56 (dd, J=14.2 Hz, J=1.4 Hz, 1H), 2.63
(dd, J=14.2 Hz, J=1.4 Hz, 1H), 3.03 (s, 2H), 3.12 (dd, J=
15.0 Hz, J=1.8 Hz, 1H), 3.72 (d, J=15.0 Hz, 1H), 3.89 (s,
3H), 4.17–4.25 (m, 4H), 5.93 (ddd, J=15.6 Hz, J=1.7 Hz,
J=1.2 Hz, 1H), 6.25 (s, 1H), 7.10–7.16 (m, 2H), 7.31–7.33
(m, 2H), 7.53 (ddd, J=8.0 Hz, J=1.3 Hz, J=1.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=14.4, 14.5, 33.1, 34.6, 40.4,
44.1, 60.3, 60.5, 73.5, 109.9, 114.1, 117.1, 119.7, 120.1, 125.0,
125.3, 126.2, 132.5, 141.0, 143.6, 144.0, 166.3, 166.9; HR-MS
(ESI): m/z=420.1770, exact mass for [M+Na]+
(C23H27NO5Na): 420.1781.
PdACHTNUGTRENNUG(OAc)2 (2.3 mg, 10 mmol, 10 mol%), and CuACHTUNGTRENNUNG(OAc)2
(74 mg, 0.40 mmol, 4.0 equiv.) in THF (1.0 mL) according to
GP2 at 808C for 72 h. Purification by flash column chroma-
tography on silica gel (cyclohexane:ethyl acetate=3:1) af-
forded the analytically pure product as a light brown oil;
yield: 19 mg (50%). GLC (HP-5): tR =37.2 min; Rf =0.25
˜
(cyclohexane:ethyl acetate=2:1); IR (ATR): n=3545 (br),
2948 (w), 1704 (s), 1651 (m), 1465 (m), 1265 (s), 1033 (m),
1
978 (s), 839 (w), 734 (s) cmꢀ1; H NMR (400 MHz, CDCl3):
1,9-Dimethyl-3-(prop-2-enyl)carbazole (8, Scheme 3): Pre-
pared from 4-(1-methyl-1H-indol-3-ylmethyl)hepta-1,6-dien-
4-ol (7, 51 mg, 0.20 mmol, 1.0 equiv.), PdACTHNURTGNENG(U OAc)2 (4.5 mg,
20 mmol, 10 mol%), AgOAc (67 mg, 0.40 mmol, 2.0 equiv.)
in 1,2-dichloroethane (2 mL) according to GP1 at 808C for
48 h. Purification by flash column chromatography on silica
gel (cyclohexane:tert-butyl methyl ether=49:1) afforded the
analytically pure product as a pale yellow solid; yield: 18.2 g
(36%); mp 62–648C. GLC (HP-5): tR =23.5 min; Rf =0.68
d=1.38 (d, J=7.0 Hz, 3H), 2.10 (br s, 1H), 2.39–2.44 (m,
1H), 2.51–2.55 (m, 1H), 3.00 (dd, J=14.7 Hz, J=1.8 Hz,
1H), 3.29 (q, J=7.6 Hz, 1H), 3.72 (s, 3H), 3.77 (s, 3H), 3.79
(d, J=14.9 Hz, 1H), 3.87 (s, 3H), 5.76 (d, J=16.0 Hz, 1H),
6.20 (d, J=1.2 Hz, 1H), 7.08 (dd, J=7.0 Hz, J=1.8 Hz, 1H),
7.11–7.15 (m, 1H), 7.31–7.34 (m, 2H), 7.59 (d, J=7.9 Hz,
1H); 13C NMR (126 MHz, CDCl3): d=15.9, 33.1, 36.3, 37.2,
42.1, 51.4, 52.4, 75.3, 110.0, 112.9, 119.2, 119.9, 120.1, 123.0,
124.8, 124.9, 125.4, 131.8, 141.2, 144.4, 166.6, 167.1; HR-MS
(APCI): m/z=384.1813, calcd. exact mass for [M+H]+
(C22H26NO5): 384.1805.
˜
(cyclohexane:tert-butyl methyl ether=9:1); IR (ATR): n=
2950 (br), 2088 (br), 1635 (w), 1599 (m), 1463 (s), 1398 (m),
1347 (m), 1231 (m), 908 (s), 749 (s) cmꢀ1
;
1H NMR
Ethyl
cis-(E,E)-4-[1-(2-ethoxy-2-oxoethylidene)-3-hy-
(400 MHz, CDCl3): d=2.84 (s, 3H), 3.52 (d, J=6.7 Hz, 2H),
4.09 (s, 3H), 5.08 (ddt, J=10.0 Hz, J=2.0 Hz, J=0.4 Hz,
1H), 5.23 (ddt, J=17.0 Hz, J=2.0 Hz, J=0.3 Hz, 1H), 6.06
(ddt, J=17.0 Hz, J=10.2 Hz, J=6.7 Hz, 1H), 7.01 (s, 1H),
7.19 (ddd, J=8.0 Hz, J=7.5 Hz, J=0.9 Hz, 1H), 7.35 (d, J=
8.5 Hz, 1H), 7.44 (ddd, J=8.2 Hz, J=7.7 Hz, J=1.1 Hz,
1H), 7.75 (s, 1H), 8.03 (ddd, J=7.8 Hz, J=1.2 Hz, J=
0.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=20.4, 32.4,
40.2, 108.6, 115.3, 117.9, 118.8, 120.1, 120.4, 122.9, 123.9,
125.6, 129.9, 130.8, 138.5, 138.7, 142.1; HR-MS (ESI): m/z=
droxy-4,9-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]but-
2-enoate (cis-15b, Table 3, entry 2): Prepared from diethyl
(2E,7E)-5-hydroxy-5-[1-(1-methyl-1H-indol-3-yl)ethyl]nona-
2,7-dienedioate (11b, 41 mg, 0.10 mmol, 1.0 equiv.),
PdACHTNUGTRENNUG(OAc)2 (2.3 mg, 10 mmol, 10 mol%), and CuACHTUNGTRENNUNG(OAc)2
(74 mg, 0.40 mmol, 4.0 equiv.) in THF (1.0 mL) according to
GP2 at 808C for 72 h. Purification by flash column chroma-
tography on silica gel (cyclohexane:ethyl acetate=4:1) af-
forded the analytically pure product as a light brown oil;
yield: 28 mg (68%). GLC (HP-5): tR =30.9 min; Rf =0.35
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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ÞÞ
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FULL PAPERS
Sandeep R. Kandukuri et al.
˜
(cyclohexane:ethyl acetate=2:1); IR (ATR): n=3457 (br),
1H NMR (400 MHz, CDCl3): d=1.01 (t, J=7.3 Hz, 3H),
1.44–1.51 (m, 1H), 1.90 (br s, 1H), 2.13–2.19 (m, 1H), 2.32–
2.41 (m, 2H), 3.01 (dd, J=8.8 Hz, J=4.6 Hz, 1H), 3.06 (dd,
J=15.6 Hz, J=2.1 Hz, 1H), 3.70 (s, 3H), 3.74 (d, J=4.7 Hz,
1H), 3.76 (s, 3H), 3.89 (s, 3H), 5.65 (d, J=15.5 Hz, 1H),
6.19 (d, J=0.9 Hz, 1H), 6.98–7.05 (m, 1H), 7.13 (ddd, J=
7.1 Hz, J=7.1 Hz, J=0.7 Hz, 1H), 7.31–7.34 (m, 2H), 7.57
(d, J=7.7 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=13.7,
24.7, 33.4, 37.6, 43.0, 44.3, 51.4, 51.5, 75.6, 109.9, 112.0, 120.1,
120.6, 124.4, 124.6, 125.0, 126.7, 131.6, 141.1, 144.4, 144.6,
166.6, 167.2; HR-MS (APCI): m/z=398.1967, calcd. exact
mass for [M+H]+ (C23H28NO5): 398.1962.
2973 (w), 2924 (w), 1701 (s), 1595 (s), 1461 (m), 1364 (m),
1340 (m), 1263 (m), 1225 (m), 1151 (s), 1035 (s), 972 (m),
853 (m), 739 (s) cmꢀ1; H NMR (500 MHz, CDCl3): d=1.28
1
(t, J=7.2 Hz, 3H), 1.34 (t, J=7.2 Hz, 3H), 1.39 (d, J=
7.2 Hz, 3H), 2.14 (br s, 1H), 2.42 (dd, J=14.5 Hz, J=
7.8 Hz, 1H), 2.54 (ddd, J=14.5 Hz, J=8.0 Hz, J=1.2 Hz,
1H), 3.03 (d, J=14.7 Hz, 1H), 3.29 (q, J=7.0 Hz, 1H), 3.78
(d, J=14.7 Hz, 1H), 3.88 (s, 3H), 4.17 (q, J=7.2 Hz, 2H),
4.23 (dq, J=7.0 Hz, J=1.6 Hz, 2H), 5.76 (d, J=15.5 Hz,
1H), 6.20 (s, 1H), 7.09 (dd, J=15.7 Hz, J=7.7 Hz, 1H),
7.11–7.15 (m, 1H), 7.31–7.34 (m, 2H), 7.60 (d, J=7.9 Hz,
1H); 13C NMR (126 MHz, CDCl3): d=14.4, 14.5, 15.9, 33.2,
36.4, 37.2, 42.2, 60.3, 60.4, 75.3, 110.1, 113.4, 120.0, 120.1,
124.2, 124.8, 125.1, 125.7, 131.7, 141.2, 143.9, 144.3, 166.2,
166.8; HR-MS (APCI):
Ethyl
cis-(E,E)-4-[1-(2-ethoxy-2-oxoethylidene)-3-hy-
droxy-9-methyl-4-phenyl-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]but-2-enoate (cis-18b, Table 3, entry 6): Prepared from
diethyl
(phenyl)methyl]nona-2,7-dienedioate
0.10 mmol, 1.0 equiv.), Pd(OAc)2 (2.3 mg, 10 mmol,
10 mol%), and Cu(OAc)2 (74 mg, 0.40 mmol, 4.0 equiv.) in
(2E,7E)-5-hydroxy-5-[(1-methyl-1H-indol-3-yl)-
m/z=412.2115, calcd. exact mass for [M+H]+ (C24H30NO5):
412.2118.
AHCTUNGTRENNUNG
(14b, 47 mg,
AHCTUNGTRENNUNG
Butyl
cis-(E,E)-4-[1-(2-butoxy-2-oxoethylidene)-3-hy-
AHCTUNGTRENNUNG
droxy-4,9-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]but-
2-enoate (cis-15c, Table 3, entry 3): Prepared from dibutyl
(2E,7E)-5-hydroxy-5-[1-(1-methyl-1H-indol-3-yl)ethyl]nona-
2,7-dienedioate (11c, 47 mg, 0.10 mmol, 1.0 equiv.),
THF (1.0 mL) according to GP2 at 808C for 72 h. Purifica-
tion by flash column chromatography on silica gel (cyclo-
hexane:ethyl acetate=3:1) afforded the analytically pure
product as a light brown oil; yield: 14 mg (30%). GLC (HP-
5): tR =34.0 min; Rf =0.25 (cyclohexane:ethyl acetate=2:1);
PdACHTUNGTRENNUNG(OAc)2 (2.3 mg, 10 mmol, 10 mol%), and CuCAHTUNGTREN(NUGN OAc)2
(74 mg, 0.40 mmol, 4.0 equiv.) in THF (1.0 mL) according to
GP2 at 808C for 72 h. Purification by flash column chroma-
tography on silica gel (cyclohexane:ethyl acetate=6:1) af-
forded the analytically pure product as a brown oil; yield:
38 mg (81%). GLC (HP-5): tR =37.5 min; Rf =0.55 (cyclo-
˜
IR (ATR): n=2918 (m), 2849 (m), 1713 (s), 1596 (m), 1461
(m), 1339 (m), 1258 (s), 1165 (m), 1092 (m), 1022 (s), 797
1
(s), 745 (s), 699 (s) cmꢀ1; H NMR (400 MHz, CDCl3): d=
1.28 (t, J=7.4 Hz, 3H), 1.34 (t, J=7.4 Hz, 3H), 1.63 (br s,
1H), 2.52 (dd, J=14.9 Hz, J=7.2 Hz, 1H), 2.60 (dd, J=
14.9 Hz, J=8.1 Hz, 1H), 3.34 (dd, J=14.9 Hz, J=0.9 Hz,
1H), 3.45 (d, J=14.9 Hz, 1H), 3.96 (s, 3H), 4.18 (q, J=
7.0 Hz, 2H), 4.23 (q, J=7.0 Hz, 2H), 4.42 (s, 1H), 5.83 (d,
J=15.6 Hz, 1H), 6.23 (d, J=1.3 Hz, 1H), 6.87–6.92 (m,
2H), 7.13 (dd, J=7.8 Hz, J=7.8 Hz, 1H), 7.17–7.21 (m,
3H), 7.28–7.32 (m, 4H); 13C NMR (100 MHz, CDCl3): d=
14.4, 14.5, 29.8, 31.1, 35.3, 37.7, 42.6, 61.4, 74.6, 108.4, 114.4,
120.0, 121.8, 122.3, 124.7, 124.9, 125.8, 127.8, 129.0, 129.5,
130.4, 131.2, 138.2, 144.1, 148.9, 166.7, 166.8; HR-MS
(APCI); m/z=474.2278, calcd. exact mass for [M+H]+
(C29H32NO5): 474.2275.
˜
hexane:ethyl acetate=2:1); IR (ATR): n=3499 (br), 2955
(w), 1705 (s), 1652 (m), 1461 (m), 1370 (m), 1258 (s), 1166
(s), 1062 (m), 1028 (m), 988 (s), 839 (w), 737 (s) cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=0.94 (t, J=7.2 Hz, 3H),
0.91 (t, J=7.2 Hz, 3H), 1.38 (d, J=7.2 Hz, 3H), 1.39–1.47
(m, 4H), 1.61–1.71 (m, 4H), 2.42 (dd, J=14.5 Hz, J=7.2 Hz,
1H), 2.53 (ddd, J=14.5 Hz, J=7.9 Hz, J=1.1 Hz, 1H), 3.04
(dd, J=14.9 Hz, J=1.8 Hz, 1H), 3.29 (q, J=7.0 Hz, 1H),
3.79 (d, J=14.9 Hz, 1H), 3.88 (s, 3H), 4.11 (t, J=6.6 Hz,
2H), 4.17 (t, J=6.6 Hz, 2H), 5.76 (dt, J=15.6 Hz, J=
1.7 Hz, 1H), 6.20 (d, J=1.4 Hz, 1H), 7.08 (dd, J=15.6 Hz,
J=7.7 Hz, 1H), 7.11–7.16 (m, 1H), 7.31–7.34 (m, 2H), 7.60
(d, J=8.1 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=13.9,
13.9, 15.9, 19.4, 29.8, 30.8, 30.9, 33.2, 36.6, 37.1, 42.2, 64.3,
64.3, 75.3, 110.0, 113.4, 120.0, 120.1, 124.2, 124.8, 125.1,
125.7, 131.7, 141.2, 143.9, 144.3, 166.3, 166.9; HR-MS
(APCI):
Butyl (E)-4-[1-(2-butoxy-2-oxoethyl)-4,9-dimethyl-9H-car-
bazol-3-yl]but-2-enoate (19c, Scheme 4): GLC (HP-5):
Yellow solid; yield: quantative; mp 89–918C. tR =39.8 min;
˜
Rf =0.55 (cyclohexane:ethyl acetate=2:1); IR (ATR): n=
2955 (w), 2870 (w), 1713 (s), 1648 (m), 1578 (w), 1465 (m),
1377 (w), 1321 (m), 1265 (s), 1156 (s), 1120 (m), 1062 (m),
m/z=468.2748, calcd. exact mass for [M+H]+ (C28H38NO5):
468.2744.
1023 (m), 983 (m), 730 (s) cmꢀ1 1H NMR (500 MHz,
;
Methyl
cis-(E,E)-4-[4-ethyl-3-hydroxy-1-(2-methoxy-2-
CDCl3): d=0.91 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H),
1.31–1.42 (m, 4H), 1.59–1.66 (m, 4H), 2.80 (s, 3H), 3.74 (dd,
J=6.1 Hz, J=1.3 Hz, 2H), 4.10 (s, 3H), 4.13 (t, J=6.7 Hz,
2H), 4.14 (d, J=7.3 Hz, 2H), 4.15 (s, 2H), 5.70 (dt, J=
15.6 Hz, J=1.9 Hz, 1H), 7.08 (s, 1H), 7.22 (dt, J=15.6 Hz,
J=6.4 Hz, 1H), 7.28 (dd, J=6.7 Hz, J=0.6 Hz, 1H), 7.44 (d,
J=8.3 Hz, 1H), 7.51 (dd, J=8.3 Hz, J=7.9 Hz, 1H), 8.27 (d,
J=8.0 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=13.7, 13.8,
16.7, 19.2, 19.3, 30.7, 30.8, 32.1, 36.0, 39.0, 64.2, 65.1, 108.5,
114.2, 119.1, 121.9, 122.9, 123.5, 123.7, 125.3, 126.4, 131.2,
131.9, 138.7, 142.2, 148.1, 166.9, 172.2; HR-MS (APCI):
m/z=450.2645, calcd. exact mass for [M+H]+ (C28H36NO4):
450.2639.
oxoethylidene)-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]but-2-enoate (cis-16a, Table 3, entry 4): Prepared from di-
methyl (2E,7E)-5-hydroxy-5-[1-(1-methyl-1H-indol-3-yl)pro-
pyl]nona-2,7-dienedioate (12a, 40 mg, 0.10 mmol, 1.0 equiv.),
PdACHTUNGTRENNUNG(OAc)2 (2.3 mg, 10 mmol, 10 mol%), and CuCAHTUNGTREN(NUGN OAc)2
(74 mg, 0.40 mmol, 4.0 equiv.) in THF (1.0 mL) according to
GP2 at 808C for 72 h. Purification by flash column chroma-
tography on silica gel (cyclohexane:ethyl acetate=4:1) af-
forded the analytically pure product as a light brown oil;
yield: 22 mg (55%). GLC (HP-5): tR =37.5 min; Rf =0.30
˜
(cyclohexane:ethyl acetate=2:1); IR (ATR): n=3502 (br),
2949 (w), 1702 (s), 1648 (m), 1430 (m), 1369 (w), 1325 (m),
1260 (s), 1163 (s), 1030 (m), 978 (m), 838 (w), 737 (s) cmꢀ1
;
12
asc.wiley-vch.de
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
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ꢀ
FULL PAPERS
Diastereotopic Group Selection in Hydroxy-Directed Intramolecular C H Alkenylation
e) J. L. Bras, J. Muzart, Chem. Rev. 2011, 111, 1170–
1214; f) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
1215–1292; g) C. Liu, H. Zhang, W. Shi, A. Lei, Chem.
Rev. 2011, 111, 1780–1824; h) K. M. Engle, T.-S. Mei,
M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788–802.
[8] For the use of MPAAs as ligands, see: a) B.-F. Shi, N.
Maugel, Y.-H. Zhang, J.-Q. Yu, Angew. Chem. 2008,
120, 4960–4964; Angew. Chem. Int. Ed. 2008, 47, 4882–
4886; b) B.-F. Shi, Y.-H. Zhang, J. K. Lam, D.-H. Wang,
J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 460–461;
c) ref.[5]; d) Y. Lu, D. Leow, X. Wang, K. M. Engle, J.-
Q. Yu, Chem. Sci. 2011, 2, 967–971; e) M. Wasa, K. M.
Engle, D. W. Lin, E. J. Yoo, J.-Q. Yu, J. Am. Chem.
Soc. 2011, 133, 19598–19601; f) G. Li, D. Leow, L. Wan,
J.-Q. Yu, Angew. Chem. 2013, 125, 1283–1285; Angew.
Chem. Int. Ed. 2013, 52, 1245–1247; g) G.-J. Cheng, Y.-
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K. N. Houk, J.-Q. Yu, Y.-D. Wu, J. Am. Chem. Soc.
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Acknowledgements
S.R.K. and L.-Y.J. thank the NRW Graduate School of
Chemistry and the China Scholarship Council (CSC), respec-
tively for predoctoral fellowships (2009–2012 and 2011–2015,
respectively). M.O. is indebted to the Einstein Foundation
(Berlin) for an endowed professorship. We thank Dr. Sebas-
tian Kemper (TU Berlin) for expert advice with the NMR
measurements and we are grateful to Felix Pape (TU Berlin)
for his experimental contributions.
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[16] We are not aware of another example of an intramolec-
ular C-2 alkenylation of an indole where an existing
stereocenter induces reasonable diastereoselectivity in
the construction of a quaternary carbon atom: ref.[12a]
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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These are not the final page numbers!

FULL PAPERS
14 Diastereotopic Group Selection in Hydroxy-Directed
ꢀ
Intramolecular C H Alkenylation of Indole under
Oxidative Palladium(II) Catalysis
Adv. Synth. Catal. 2014, 356, 1 – 14
Sandeep R. Kandukuri, Lin-Yu Jiao, Axel B. Machotta,
Martin Oestreich*
14
asc.wiley-vch.de
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!