Palladium-catalyzed α,β-dehydrogenation of acyclic ester equivalents promoted by a novel electron deficient phosphinooxazoline ligand

Article abstract of DOI:10.1016/j.tet.2019.05.065

A unique example of Pd-catalyzed decarboxylative dehydrogenation of fully substituted N-acyl allyl enol carbonates is enabled by a new electron deficient phosphinooxazoline (PHOX) ligand. The reaction proceeds from the Z-enol carbonate to provide dehydrogenation products exclusively in high E/Z selectivity, while the E-enol carbonate provides the α-allylation product with only minor dehydrogenation. The reaction proceeds with a broad scope of Z-enol carbonates derived from N-acyl indoles to furnish acyclic formal α,β-unsaturated ester equivalents.

Full text of DOI:10.1016/j.tet.2019.05.065

Accepted Manuscript
Palladium-catalyzed α,β-dehydrogenation of acyclic ester equivalents promoted by a
novel electron deficient phosphinooxazoline ligand
Tyler J. Fulton, Brenda Wu, Eric J. Alexy, Haiming Zhang, Brian M. Stoltz
PII:
S0040-4020(19)30627-1
https://doi.org/10.1016/j.tet.2019.05.065
TET 30386
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 April 2019
Revised Date: 24 May 2019
Accepted Date: 29 May 2019
Please cite this article as: Fulton TJ, Wu B, Alexy EJ, Zhang H, Stoltz BM, Palladium-catalyzed α,β-
dehydrogenation of acyclic ester equivalents promoted by a novel electron deficient phosphinooxazoline
ligand, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.05.065.
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ACCEPTED MANUSCRIPT

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1
Palladium-catalyzed α,β-dehydrogenation of acyclic ester equivalents
promoted by a novel electron deficient phosphinooxazoline ligand
Tyler J. Fultona, Brenda Wua, Eric J. Alexya, Haiming Zhangb*, and Brian M. Stoltza*
aWarren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering,
California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125, United States of America
bSmall Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States of America
Abstract
A unique example of Pd-catalyzed decarboxylative dehydrogenation of fully substituted N-acyl allyl enol carbonates is enabled by a new
electron deficient phosphinooxazoline (PHOX) ligand. The reaction proceeds from the Z-enol carbonate to provide dehydrogenation
products exclusively in high E/Z selectivity, while the E-enol carbonate provides the α-allylation product with only minor
dehydrogenation. The reaction proceeds with a broad scope of (Z)-enol carbonates derived from N-acyl indoles to furnish acyclic formal
α,β-unsaturated ester equivalents.
Dedicated to Professor John F. Hartwig on his receipt of the Tetrahedron Prize.
Keywords:
Dehydrogenation;
Palladium
PHOX ligand
*Corresponding author. Tel.: +1-650-467-8758; e-mail: zhang.haiming@gene.edu.
*Corresponding author. Tel.: +1-626-395-6064; fax: +1-626-395-8436; e-mail: stoltz@caltech.edu.

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Introduction
as well as palladium catalyzed dehydrogenations.7 One-
step allyl-palladium catalyzed dehydrogenations have
recently been developed by Newhouse, with pioneering
studies from Tsuji,8 as an effective method to generate
α,β-unsaturated carbonyls,9 carboxylic acids,10 and
carboxylic acid derivatives,11 however, there are limited
examples regarding acyclic systems bearing α-
substitution, especially in high E/Z selectivity. Moreover,
to the best of our knowledge, this is the first example of an
Our lab has recently become interested in developing
palladium-catalyzed asymmetric allylic alkylation
reactions of acyclic stereodefined fully substituted enol
carbonates to generate acyclic quaternary stereogenic
centers. In our initial efforts, we reported the application
of a highly E-selective enolization1 of acylic α-aryl
ketones to generate stereodefined fully substituted acyclic
ketone enol carbonates which we employed in a highly
enantioselective Pd-catalyzed allylic alkylation to generate
all carbon quaternary centers.2 More recently, we became
intrigued by the possibility of extending this reactivity
toward acyclic ester enolate equivalents to generate α-
quaternary carboxylic acid derivatives. In our initial
optimization of this transformation, we investigated new
electron deficient phosphinooxazoline (PHOX) ligands
with N-acyl hetereocycle derived enol carbonates as ester
enolate equivalents. To our delight, we found that the
combination of N-acyl indole derived enol carbonate 1 and
fluorinated ligand (S)-F13-t-BuPHOX afforded allylation
product 2 in an excellent 94% ee and promising 80% yield
(Scheme 1). Further investigation of this reaction revealed
that despite excellent conversion of 1, allylation product 2
was isolated in only 80% yield with a 15% yield of α,β-
unsaturation product 3a. Surprisingly, when a 79:21 Z/E
mixture of enol carbonate 1 was utilized, α,β-unsaturation
product 3a predominated, suggesting a preference for the
Z-enol carbonate to undergo α,β-dehydrogenation rather
electron
deficient
PHOX
ligand
promoting
dehydrogenation reactivity with an allyl-palladium
species. This new reactivity complements the available
methodology for the generation of α,β-unsaturated
compounds and could serve as a new avenue for
methodology development in the α,β-unsaturation of
carbonyl compounds.
2. Results and discussion
We began our investigation with an examination of the
ligand system (Table 1). To our surprise, when analogous
achiral F13-glyPHOX ligand was employed, no reaction
occurred even with elevated reaction temperatures of up to
60 ºC (Table 1, entry 1). Though the t-Bu group was
Table 1. Investigation of the ligand.a
than
a
standard α-alkylation.
Control experiments
revealed that the reaction does not proceed in the absence
of (S)-F13-t-BuPHOX ligand with either enol carbonate
mixture, instead providing >95% recovery of the starting
material with unaffected E/Z enol carbonate ratios. The
high synthetic value of α,β-unsaturated carboxylic acids
and their derivatives coupled with the limited synthetic
methods which enable access to this motif prompted
further investigation of this unusual reactivity with our
newly synthesized fluorinated PHOX ligand.
a
Numerous distinct strategies have been developed to
Conditions: 0.2 mmol substrate, 0.5 mol % Pd2(dba)3, 1.2 mol % ligand, 2.0
mL solvent, 25 °C. Yields of isolated products. E/Z ratios measured by 1H
b
NMR integration.
Scheme 1. Initial reaction discovery.
required on the ligand scaffold, both enantiomeric series of
the F13-t-BuPHOX provided α,β-dehydrogenation product
3a in essentially identical yield and E/Z selectivity (entries
2 and 3). These results demonstrate that this unique
resolution of the enol carbonate geometries is likely the
result of the electron withdrawing nature of the F13-t-
BuPHOX ligand in combination with the preference for
dehydrogenation of the Z-enol carbonate. While the E-
enol carbonate can be obtained with excellent selectivity
(generally >98:2) utilizing previously reported selective
enolization conditions1a, selective formation of the Z-enol
carbonate is more challenging with modest selectivity of
79:21 Z/E obtained in THF with KHMDS as the base
(Scheme 2).
access α,β-unsaturated moieties from carbonyl and
carboxylic acid motifs including selenium,3 sulfur,4
hypervalent iodine,5 and quinone6 based transformations,

Scheme 3. Investigation of Tsuji’s classic dehydrogenation.
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Scheme 2. E- and Z-selective enol carbonate formation.
(Scheme 3).
S
ubse
que
nt
opti
miz
atio
n of the reaction aimed to identify conditions which
favored dehydrogenation for both enol carbonate
geometries. Other solvents common for dehydrogenation
reactions were examined, but provided no improvement
over the 3:1 hexanes/toluene solvent system (Table 2,
entries 1–6). With either toluene or MTBE as a solvent
full conversion of 1 is observed, albeit with lower
selectivity for dehydrogenation product 3a over alkylation
product 2 compared with 3:1 hexanes/toluene (entries 2
and 3). In THF, the reaction becomes sluggish and 65% of
the enol carbonate mixture is recovered after 24 h with no
change in the ratio of enol carbonates (entry 4). Polar,
aprotic solvents such as DMF and MeCN utilized in allyl-
palladium catalyzed dehydrogenation by Tsuji8 provide no
reaction (entries 5 and 6). Newhouse and co-workers have
previously demonstrated the application of zinc salts to
disfavor allylation via a postulated transmetalation to
afford a less nucleophilic zinc enolate in allyl-palladium
catalyzed dehydrogenations.9–11 To our disappointment,
the incorporation of ZnCl2 in our reaction conditions as a
stoichiometric additive stymies both allylation and
dehydrogenation pathways (entry 7). Heating the reaction
with a 75:25 Z/E mixture of 1 to 60 ºC also fails to
promote any measurable level of conversion. Notably,
when ZnCl2 is used with a >98:2 E/Z mixture of enol
carbonates, trace conversion to the allylation product is
observed after prolonged heating (>24 h) at 60 ºC, further
exemplifying the importance of enolate geometry in this
transformation. In addition, we found N-acyl indole
derived enol carbonate 1 was incompatible with Tsuji’s
classic decarboxylative dehydrogenation conditions,8a
instead providing complex mixtures of decarboxylative
allylation and protonation with recovered enol carbonate
Bereft of reaction conditions favoring dehydogenation
for both enolate geometries, we examined the reaction
scope with pure Z-enol carbonates to simplify reaction
analysis and product purification. A variety of N-acyl
indoles were enolized using Z-selective conditions (vide
supra) and trapped as the corresponding allyl enol
carbonates. The geometrically pure Z-enol carbonates
were then isolated by preparative chromatography and
subjected to our standard reaction conditions (Table 3).
Pleasingly, a broad range of alkyl and aryl group
substitutions were well tolerated under the reaction
conditions and α,β-unsaturated products were obtained in
high yield and excellent E-selectivity. With pure Z-enol
carbonate 1, product 3a was obtained in >99% yield and in
10:1 E/Z selectivity. Unsubstituted compound 3b was
obtained in 84% yield despite elevated potential to
undergo intermolecular conjugate addition during the
course of the reaction. Longer alkyl chains were well
tolerated with n-butyl product 3c isolated in 97% yield and
15:1 E/Z selectivity. Sterically encumbered i-propyl
product 3d was also well tolerated with >98:2
E
selectivity, albeit in a diminished 77% yield. Product 3e
bearing 1,2- diphenyl substitution could be obtained in
75% yield and 6:1 E/Z selectivity. A variety of aryl
groups were also compatible with the dehydrogenation
reaction. Notably, ortho-substituted product 3f was
obtained in an excellent 91% yield and 10:1 E/Z
selectivity. Electron rich p-OMe-C6H4 aryl compound 3g
was isolated in an excellent 94% yield and 18:1 E/Z
selectivity. Finally, products with electron poor aryl
groups p-F-C6H4 (3h) and p-Cl-C6H4 (3i) were also
obtained in high yields (89% and 79% yield, respectively)
and excellent E-selectivity (12:1 and 8:1 E/Z,
respectively).
Table 2. Optimization of the Pd-catalyzed dehydrogenation.
While we were pleased with the scope of α,β-
unsaturated N-acyl indoles afforded by the Pd-catalyzed
decarboxylative dehydrogenation, we ultimately desired to
extend this methodology toward a general manifold of
carbonyl compounds. In these initial efforts, we
deternubed this reaction was unsuccessful with other
substrates commonly utilized in Pd-catalyzed asymmetric
decarboxylative allylic alkylation in our laboratory (Figure
1). Cyclic allyl enol carbonate 4 and β-ketoesters 5–7
failed to convert to either allylation or dehydrogenation
products with these reaction conditions. Even with the
a
Conditions: 0.2 mmol substrate, 0.5 mol % Pd2(dba)3, 1.2 mol % ligand, 2.0
mL solvent, 25 °C, 24 h reaction time. b Yields of isolated products. E/Z ratios
measured by 1H NMR integration.
Incomplete conversion.
performed at 40 ºC. e Reaction performed at 60 ºC.
Reaction
c
d

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Table 3. Substrate scope of the Pd-catalyzed decarboxylative
dehydrogenation.a
analogous acyclic phenyl ketone derived allyl enol
carbonate 8 (75:25 Z/E) no conversion was observed.
Future efforts will be directed toward investigation of the
3. Conclusion and outlook
In summary, we have developed the first
example of an allyl-palladium catalyzed decarboxylative
dehydrogenation reaction of fully substituted N-acyl indole
derived allyl enol carbonates promoted by a newly
developed electron deficient PHOX ligand. The reaction
was quite general with respect to N-acyl indole derived
allyl enol carbonates and occurs only with F13-t-BuPHOX
ligand. Other substrate classes typically utilized in
decarboxylative allylic alkylation in our laboratory proved
unreactive. Future efforts will aim to probe the nature of
this unusual resolution of enolate geometries and expand
a
Conditions: 0.2 mmol substrate, 0.5 mol % Pd2(dba)3, 1.2 mol % ligand,
2.0 mL solvent, 25 °C, 16 h reaction time. Yields of isolated product.
Product E/Z ratios were measured by 1H NMR integration.
Figure 2. Plausible catalytic cycle.
this methodology into a more general transformation for
α,β-dehydrogenation. Ultimately, this methodology
provides new precedent for ligand controlled selectivity of
dehydrogenation over allylic alkylation with allyl-
palladium catalysis.
Figure 1. Unsuccessful substrates for the Pd-catalyzed
decarboxylative dehydrogenation.
dehydrogenation reaction with substrate classes
unsuccessful in this unique system toward a more general
transformation and understanding the nature of the ligand
promoted dehydrogenation.
4. Selected experimentals
4.1 General
We posit
a
plausible catalytic cycle for this
Unless otherwise stated, reactions were performed in
flame-dried glassware under an argon or nitrogen
atmosphere using dry, deoxygenated solvents. Solvents
were dried by passage through an activated alumina
column under argon. Reaction progress was monitored by
thin-layer chromatography (TLC) or Agilent 1290 UHPLC-
MS. TLC was performed using E. Merck silica gel 60 F254
precoated glass plates (0.25 mm) and visualized by UV
fluorescence quenching, p-anisaldehyde, or KMnO4
staining. Silicycle SiliaFlash® P60 Academic Silica gel
(particle size 40–63 nm) was used for flash
chromatography. The Z-enol carbonates were purified by
transformation can proceed as shown in Figure 2 where
the allyl group of the enol carbonate ultimately serves as a
hydride acceptor. A ligated Pd0 species can undergo
oxidative addition to allyl enol carbonate 1, generating
palladium carboxylate 9. Subsequent decarboxylation
produces allyl palladium complex 10 and enolate 11 which
can form carbon-bound palladium enolate 12. At this
stage, β-hydride elimination can occur to furnish product
3a and palladium hydride 13.
Finally, reductive
elimination of 13 regenerates the Pd0 species and generates
propene as a by-product.

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preparative LC on a Teledyne Isco ACCQPrep HP125;
1158, 1144, 1079, 1016, 946, 881, 815, 752, 703 cm–1;
HRMS (MM:ESI-APCI+) m/z calc’d for C18H16NO [M+H]+:
262.1226, found 262.1222.
1
column: C–18, 100 Å, 5 µm, ID 20 mm. H NMR spectra
were recorded on Varian Inova 500 MHz and Bruker 400
MHz spectrometers and are reported relative to residual
CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a
Varian Inova 500 MHz spectrometer (125 MHz) and
Bruker 400 MHz spectrometers (100 MHz) and are
reported relative to CHCl3 (δ 77.16 ppm). Data for 1H NMR
are reported as follows: chemical shift (δappm)
(multiplicity, coupling constant (Hz), integration).
Multiplicities are reported as follows: s = singlet, d =
doublet, t = triplet, q = quartet, p = pentet, sept =
septuplet, m = multiplet, br s = broad singlet, br d = broad
doublet. Data for 13C NMR are reported in terms of
chemical shifts (δappm). IR spectra were obtained by use
of a Perkin Elmer Spectrum BXII spectrometer or Nicolet
6700 FTIR spectrometer using thin films deposited on
NaCl plates and reported in frequency of absorption (cm–
1). Optical rotations were measured with a Jasco P-2000
polarimeter operating on the sodium D-line (589 nm),
using a 100 mm path-length cell. High resolution mass
spectra (HRMS) were obtained from Agilent 6200 Series
TOF with an Agilent G1978A Multimode source in
electrospray ionization (ESI+), atmospheric pressure
chemical ionization (APCI+), or mixed ionization mode
(MM: ESI-APCI+). Reagents were purchased from
commercial sources and used as received unless
otherwise stated.
4.2.2 1-(1H-indol-1-yl)-2-phenylprop-2-en-1-one (3b)
Purified by column chromatography (5% Et2O in hexanes)
to provide a colorless oil (41.4 mg, 0.167 mmol, 84%
yield);1H NMR (400 MHz, CDCl3) δ 8.57–8.54 (m, 1H), 7.57
(dt, J = 7.7, 1.0 Hz, 1H), 7.51–7.45 (m, 2H), 7.43–7.28 (m,
6H), 6.54 (d, J = 3.7 Hz, 1H), 6.08 (s, 1H), 5.70 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 168.7, 144.5, 135.7, 135.4,
131.0, 129.2, 129.2, 127.1, 126.2, 125.3, 124.3, 121.0,
118.6, 116.8, 109.3; IR (Neat Film, NaCl) 3055, 2926, 1692,
1535, 1496, 1471, 1450, 1378, 1348, 1293, 1205, 1156,
1072, 1016, 931, 880, 752, 696 cm–1; HRMS (MM:ESI-
APCI+) m/z calc’d for C17H14NO [M+H]+: 248.1070, found
248.1063.
4.2.3 (E)-1-(1H-indol-1-yl)-2-phenylhept-2-en-1-one (3c)
Purified by column chromatography (3% Et2O in hexanes)
to provide a colorless oil (58.9 mg, 0.194 mmol, 97% yield,
1
14:1 E/Z); H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.3 Hz,
1H), 7.54 (dd, J = 7.5, 0.9 Hz, 1H), 7.42 – 7.26 (m, 7H),
6.57–6.48 (m, 2H), 6.33 (t, J = 7.5 Hz, 1H), 2.36 (q, J = 7.5
Hz, 2H), 1.50 (tt, J = 8.2, 6.9 Hz, 2H), 1.37 (dq, J = 14.4, 7.2
Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 169.2, 140.2, 136.8, 136.0, 135.2, 130.8, 129.0, 128.8,
128.2, 127.2, 125.0, 123.9, 120.9, 116.7, 108.5, 31.5, 28.9,
22.6, 14.0; IR (Neat Film, NaCl) 3053, 2957, 2928, 2858,
1688, 1636, 1600, 1585, 1534, 1494, 1472, 1450, 1379,
1333, 1205, 1157, 1143, 1113, 1078, 1016, 938, 882, 816,
769, 752, 702 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for
C21H22NO [M+H]+: 304.1696, found 304.1688.
4.2 General procedure for dehydrogenation
A representative procedure for the decarboxylative
dehydrogenation of N-acyl indole derived enol carbonates:
In a nitrogen-filled glovebox, a solution of Pd2(dba)3
(1.8 mg/mL) and (S)-F13-t-BuPHOX (2.8 mg/mL) in toluene
was stirred for 30 min at 25 °C, then 0.5 mL of the
resulting catalyst solution was added to a one dram vial
containing the allyl enol carbonate substrate (0.2 mmol)
dissolved in hexanes (1.5 mL). The vial was sealed with a
Teflon-lined cap, removed from the glovebox, and stirred
at 25 °C for 16 h unless noted otherwise. The crude
reaction mixture was concentrated then purified by silica
gel flash chromatography to provide the desired
dehydrogenation product.
4.2.4 (E)-1-(1H-indol-1-yl)-4-methyl-2-phenylpent-2-en-
1-one (3d)
Purified by column chromatography (3% Et2O in hexanes)
to provide a colorless oil (44.3 mg, 0.153 mmol, 77% yield,
1
>20:1 E/Z); H NMR (400 MHz, CDCl3) δ 8.46 (dd, J = 8.3,
1.0 Hz, 1H), 7.55 (ddd, J = 7.7, 1.3, 0.7 Hz, 1H), 7.42–7.27
(m, 8H), 6.54 (d, J = 3.8 Hz, 1H), 6.10 (d, J = 10.5 Hz, 1H),
2.80 (dhept, J = 10.5, 6.6 Hz, 1H), 1.11 (d, J = 6.6 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 169.2, 146.6, 136.0, 135.3,
134.5, 130.9, 128.9, 128.8, 128.8, 127.2, 125.0, 123.9,
120.9, 116.7, 108.5, 28.3, 22.7; IR (Neat Film, NaCl) 3054,
2962, 2868, 1687, 1534, 1494, 1450, 1377, 1334, 1238,
1201, 1112, 1078, 1017, 882, 795, 769, 752, 698 cm–1;
HRMS (MM:ESI-APCI+) m/z calc’d for C20H20NO [M+H]+:
290.1539, found 290.1528.
4.2.1 (E)-1-(1H-indol-1-yl)-2-phenylbut-2-en-1-one (3a)
Purified by column chromatography (5% Et2O in hexanes)
to provide a colorless oil (52.1 mg, 0.199 mmol, >99%
1
yield, 10:1 E/Z); H NMR (400 MHz, CDCl3) δ 8.47 (dq, J =
8.3, 0.9 Hz, 1H), 7.54 (dq, J = 7.6, 0.8 Hz, 1H), 7.43–7.27
(m, 8H), 6.50 (dd, J = 3.8, 0.7 Hz, 1H), 6.46 (q, J = 7.2 Hz,
1H), 1.99 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
169.2, 138.0, 136.0, 134.9, 134.6, 130.8, 129.1, 128.8,
128.2, 127.2, 125.6, 125.0, 123.9, 120.9, 116.7, 108.5,
15.3; IR (Neat Film, NaCl) 3054, 2918, 2854, 1682, 1585,
1535, 1495, 1472, 1451, 1385, 1359, 1331, 1240, 1204,
4.2.5 (E)-1-(1H-indol-1-yl)-2,3-diphenylprop-2-en-1-one
(3e)
Purified by column chromatography (5% Et2O in hexanes)
to provide a colorless oil (48.3 mg, 0.149 mmol, 75% yield,
6:1 E/Z); 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.2 Hz,
1H), 7.70 (dd, J = 11.3, 7.5 Hz, 2H), 7.65 (d, J = 3.8 Hz, 1H),

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7.59–7.44 (m, 7H), 7.44–7.30 (m, 5H), 6.71 (d, J = 3.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 169.2, 136.4, 136.1,
135.3, 134.6, 130.9, 130.0, 129.3, 129.2, 128.9, 128.7,
128.5, 127.1, 126.0, 125.1, 124.1, 121.0, 116.8, 108.9.; IR
(Neat Film, NaCl) 3053, 3026, 2923, 1684, 1535, 1492,
1472, 1450, 1381, 1333, 1235, 1206, 1155, 1141, 1112,
1077, 1016, 908, 882, 862, 753, 721, 694 cm–1; HRMS
(MM:ESI-APCI+) m/z calc’d for C23H18NO [M+H]+:
324.1383, found 324.1380.
1450, 1385, 1331, 1224, 1202, 1160, 1101, 1080, 1016,
948, 881, 842, 786, 770, 754 cm–1; HRMS (MM:ESI-APCI+)
m/z calc’d for C18H15FNO [M+H]+: 280.1132, found
280.1137.
4.2.9 (E)-2-(4-chlorophenyl)-1-(1H-indol-1-yl)but-2-en-1-
one (3i)
Purified by column chromatography (5% Et2O in hexanes)
to provide a colorless oil (46.7 mg, 0.158 mmol, 79% yield,
1
8:1 E/Z); H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.1 Hz,
1H), 7.59–7.51 (m, 1H), 7.40–7.26 (m, 7H), 6.53 (d, J = 3.7
4.2.6 (E)-1-(1H-indol-1-yl)-2-(o-tolyl)but-2-en-1-one (3f)
Purified by column chromatography (3% Et2O in hexanes)
to provide a colorless oil (50.1 mg, 0.182 mmol, 91% yield,
Hz, 1H), 6.46 (q, J = 7.2 Hz, 1H), 1.97 (d, J = 7.1 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 168.7, 136.9, 135.9, 135.3,
134.2, 133.2, 130.4, 129.2, 129.0, 127.0, 125.1, 124.1,
120.9, 116.6, 108.8, 15.3; IR (Neat Film, NaCl) 3051, 2916,
1688, 1534, 1491, 1472, 1451, 1384, 1330, 1204, 1143,
1089, 1016, 947, 881, 838, 802, 770, 754 cm–1; HRMS
(MM:ESI-APCI+) m/z calc’d for C18H15ClNO [M+H]+:
296.0837, found 296.0835.
1
12:1 E/Z); H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.2 Hz,
1H), 7.46 (dd, J = 7.7, 1.1 Hz, 1H), 7.31–7.26 (m, 1H), 7.25
(d, J = 3.8 Hz, 1H), 7.22–7.16 (m, 3H), 7.12 (d, J = 7.9 Hz,
2H), 6.42 (d, J = 3.8 Hz, 1H), 6.35 (q, J = 7.2 Hz, 1H), 2.28
(s, 3H), 1.91 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 169.4, 138.0, 137.9, 135.9, 134.0, 131.9, 130.8, 129.7,
129.5, 128.9, 127.2, 125.5, 124.9, 123.9, 120.8, 116.7,
108.4, 21.4, 15.3; IR (Neat Film, NaCl) 3027, 2919, 2856,
1688, 1533, 1513, 1472, 1450, 1384, 1329, 1239, 1206,
1157, 1143, 1113, 1080, 1017, 946, 882, 828, 770, 753,
723 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H18NO
[M+H]+: 276.1383, found 276.1375.
Supplementary data
NMR spectra for compounds 3a–3i, as well as
experimental and characterization data for substrate and
ligand synthesis.
Acknowledgments
We thank NIH-NIGMS (R01GM080269), the
Gordon and Betty Moore Foundation, and Caltech for
financial support. E.J.A. thanks the National Science
Foundation for a predoctoral fellowship. We thank Dr.
David VanderVelde (Caltech) for NMR expertise. Dr. Scott
Virgil (Caltech) is thanked for instrumentation and
assistance.
4.2.7 (E)-1-(1H-indol-1-yl)-2-(4-methoxyphenyl)but-2-en-
1-one (3g)
Purified by column chromatography (8% Et2O in hexanes)
to provide a colorless oil (55.0 mg, 0.189 mmol, 94% yield,
19:1 E/Z); 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.3 Hz,
1H), 7.54 (d, J = 7.7 Hz, 1H), 7.41–7.24 (m, 5H), 6.96–6.87
(m, 2H), 6.50 (d, J = 3.8 Hz, 1H), 6.40 (q, J = 7.1 Hz, 1H),
3.81 (s, 3H), 1.99 (d, J = 7.1 Hz, 3H).;13C NMR (100 MHz,
CDCl3) δ 169.6, 159.4, 137.6, 135.9, 133.6, 130.8, 130.3,
127.3, 127.2, 124.9, 123.9, 120.8, 116.7, 114.2, 108.4,
55.4, 15.3; IR (Neat Film, NaCl) 2934, 2361, 1684, 1607,
1511, 1450, 1328, 1292, 1250, 1202, 1178, 1110, 1079,
1032, 948, 881, 838, 815, 770, 753 cm–1; HRMS (MM:ESI-
APCI+) m/z calc’d for C19H18NO2 [M+H]+: 292.1332, found
292.1340.
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