Friedel-Crafts Hydroxyalkylation of Indoles Mediated by Trimethylsilyl Trifluoromethanesulfonate

Article abstract of DOI:10.1021/acs.joc.5b01681

Indoles and N-alkylindoles undergo Friedel-Crafts addition to aldehydes in the presence of trimethylsilyl trifluoromethanesulfonate and a trialkylamine to produce 3-(1-silyloxyalkyl)indoles. Neutralization of the reaction mixture with pyridine followed by deprotection under basic conditions with tetrabutylammonium fluoride provides the 1:1 adduct as the free alcohol. This method prevents spontaneous conversion of the desired products to the thermodynamically favored bisindolyl(aryl)methanes, a process typically observed when indoles are reacted with aldehydes under acidic conditions.

Full text of DOI:10.1021/acs.joc.5b01681

Note
pubs.acs.org/joc
Friedel−Crafts Hydroxyalkylation of Indoles Mediated
by Trimethylsilyl Trifluoromethanesulfonate
C. Wade Downey,* Christopher D. Poff, and Alissa N. Nizinski
University of Richmond, Gottwald Center for the Sciences, 28 Westhampton Way, Richmond, Virginia 23173, United States
S
* Supporting Information
ABSTRACT: Indoles and N-alkylindoles undergo Friedel−Crafts
addition to aldehydes in the presence of trimethylsilyl trifluoro-
methanesulfonate and a trialkylamine to produce 3-(1-silyloxyalkyl)-
indoles. Neutralization of the reaction mixture with pyridine
followed by deprotection under basic conditions with tetrabuty-
lammonium fluoride provides the 1:1 adduct as the free alcohol. This
method prevents spontaneous conversion of the desired products to
the thermodynamically favored bisindolyl(aryl)methanes, a process
typically observed when indoles are reacted with aldehydes under acidic conditions.
he condensation of N-alkylindoles with aryl aldehydes has
been known since the 19th century, when Fischer
bulk of the trimethylsilyl-protected product should slow
undesired ionization and decomposition processes. Develop-
ment of such a method was made more attractive by the utility
of the products, which show significant promise as (1-indolyl)-
alkylating agents under mild conditions.6
We began our discovery and optimization process with
representative substrates N-methylindole and benzaldehyde
(Table 1). To begin, the reactants were dissolved in methylene
chloride and treated with TMSOTf and i-Pr2NEt for 1 h at
−78 °C. During preliminary purification via silica gel filtration,
T
observed the formation of triarylmethane products in the
presence of Lewis acids (eq 1).1 These bisindolyl products
result from the rapid conversion of the initial alcohol product to
a stabilized carbocation, which is subsequently attacked by a
second indole. The isolation of 1:1 indole:aldehyde adducts
has been reported for very electron-poor electrophiles, such
as when the carbonyl acceptor features an α-trifluoromethyl
group2 and, in rare cases, when the indole nitrogen is unpro-
tected.3 To our knowledge, however, no general method exists
for the synthesis of the corresponding N-alkylated derivatives
via a convergent Friedel−Crafts route. In this note, we report
the Friedel−Crafts silyloxyalkylation of indoles and N-alkylated
indoles with aldehydes mediated by trimethylsilyl trifluoro-
methanesulfonate (TMSOTf) and i-Pr2NEt.
Table 1. Optimization of the Synthesis of 1:1 Adduct A
The most commonly used methods for the generation of 3-
(1-hydroxyalkyl)indoles require highly basic conditions such as
reduction of the corresponding ketone with lithium aluminum
hydride4 or Grignard5 addition to relatively expensive indole-
carboxaldehydes (eq 2). The unusual potential of TMSOTf
to act as a Lewis acid and to generate an ionization-resistant
O-silylated product appeared to be perfectly suited for this
reaction. The Lewis acidity of the silicon center provides a
classic catalyst for electrophilic aromatic substitution, and the
a
Reaction conditions: (1) 0.2 mmol of N-methylindole, 0.28 mmol of
benzaldehyde, 0.3 mmol of TMSOTf, 0.28 mmol of i-Pr2NEt, 2 mL of
b
Et2O, − 78 °C, 1 h; (2) 0.5 mmol of pyridine. Ratio determined by
c
1H NMR spectroscopy. Benzaldehyde was replaced with benzalde-
hyde dimethyl acetal.
Received: July 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01681
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The Journal of Organic Chemistry
Note
however, the color of the reaction mixture rapidly changed
from orange to pink, and NMR analysis revealed the formation
of triarylmethane B. The same color change was observed at
extended reaction times, even at low temperatures. Addition of
pyridine to quench the reaction mixture, a method employed in
previous studies to prevent TMSOTf-mediated decomposition
reactions,7 did not prevent triarylmethane formation when
methylene chloride was used as solvent (entry 1). When
methylene chloride was replaced with diethyl ether as the
reaction solvent, the reaction became noticeably heterogeneous,
an observation consistent with the precipitation of mildly acidic
trialkylammonium salts. Nonetheless, a color change to pink
was still observed during workup (entry 2). When both diethyl
ether and the pyridine quench were employed, the color change
was prevented, and observation of the silyloxyalkylation adduct
(A) was confirmed by NMR spectroscopy (entry 2). Puri-
fication on silica gel deactivated by triethylamine provided the
desired product in 76% yield (eq 3).
Table 2. Addition of N-Methylindole to Aldehydes
a
Reaction conditions: (1) 1.0 mmol of N-methylindole, 1.4 mmol of
aldehyde, 1.5 mmol of TMSOTf, 1.4 mmol of i-Pr2NEt, 10 mL of
Et2O, − 78 °C, 1 h; (2) 2.6 mmol of pyridine; (3) 1.1 mmol of TBAF,
b
c
10 mL of THF. Isolated yield after chromatography. 2:1 adduct
d
observed exclusively. 1.6 mmol of i-Pr2NEt used.
the aldehyde reaction partner (entries 6−8). Cinnamaldehyde
also gave satisfactory results. Attempts to add N-methylindole
to aliphatic aldehydes were disappointing, however. Under the
reaction conditions, enolizable aldehydes such as isobutyr-
aldehyde and cyclohexanecarboxaldehyde were rapidly trans-
formed into enol silanes and did not undergo addition.
When the nitrogen-protecting group on the indole was
replaced with synthetically convenient benzyl or allyl groups,
reactivity was maintained and good yields were observed
(eq 4). These compounds appeared to be somewhat more
robust with respect to product decomposition and formation of
the 2:1 adducts than the N-methylated series. In contrast,
replacement of TMSOTf with TESOTf or TBSOTf resulted in
lower conversion to the desired product and a significant
increase in the generation of 2:1 adducts. This change in
reactivity may be caused by a significantly slower rate of
addition of indole to the silyl triflate-activated aldehyde,
allowing ionization of the desired product to become kinetically
competitive under the reaction conditions.
Despite existing as the protected trimethylsilyl ether rather
than the free alcohol, adduct 1 proved to be quite prone to
decomposition. Warmer temperatures or the omission of the
pyridine quench resulted in significant to complete degradation
of the desired product to 2:1 adduct B (Table 1, entries 2 and
4). At lower temperatures, however, it appears that the large
silyl group significantly slows coordination of Lewis acidic
species to the silyloxy group, preventing ionization and eventual
conversion to the bisindolyl byproduct. The effectiveness of the
pyridine quench, which likely sequesters any silyl cations in
solution as well as lowers the pH of the solution, provides some
support for this hypothesis. Removal of the TMS group under
acidic conditions (methanol, trifluoroacetic acid) resulted in
complete conversion to the thermodynamically favored 2:1
adduct B, further demonstrating the sensitivity of the desired
product to acids. When benzaldehyde was replaced with
benzaldehyde dimethyl acetal under otherwise optimized
reaction conditions, only adduct B was observed (Table 1,
entry 5). Presumably, the small methoxy group in the desired
product coordinates readily with Lewis acidic species present in
solution (e.g., TMSOTf, R3NH+), leading to rapid ionization.
Indeed, we have previously observed the activation of certain
methyl ethers with TMSOTf, leading to C-alkylation by
suitable nucleophiles.8
With the reaction conditions for carbon−carbon bond
formation optimized, we focused on the synthesis of a wider
range of hydroxyalkylated indoles. Although acid-catalyzed
removal of the trimethylsilyl group resulted in decomposition
(vide supra), deprotection was readily achieved under basic
conditions through treatment of the unpurified product with
tetrabutylammonium fluoride (TBAF). Thus, reaction of
N-methylindole with various aldehydes provided the hydrox-
yalkylation product in good yields (Table 2). A variety of
electron-poor aromatic aldehydes performed well under the
reaction conditions (entries 3−5), but the product derived
from the electron-rich anisaldehyde was too prone to ionization
for the 1:1 adduct to be isolated (entry 2). Larger aromatic
groups and heterocyclic groups, however, were well-tolerated in
Given the success of various N-protected indoles under the
optimized reaction conditions, we were intrigued by the
potential application to unprotected indoles and the challenge
of accommodating an N−H bond under silylating conditions.
Although Friedel−Crafts additions of free indoles to aromatic
aldehydes have been reported previously, known methods are
low yielding,2c require a large excess of indole,2a,b or are mostly
limited to very electron-poor aldehydes.2a,c Unfortunately,
when free indole was treated with benzaldehyde under our
standard reaction conditions (1.5 equiv of TMSOTf, 1.4 equiv
of i-Pr2NEt), Friedel−Crafts addition was significantly out-
performed by competing silylation at the indole nitrogen.
B
DOI: 10.1021/acs.joc.5b01681
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The Journal of Organic Chemistry
Note
By increasing the stoichiometry of the TMSOTf and base,9
however, conversion to the desired products 4 was clearly
observed. A very brief survey of the reaction scope of free
indoles is described in Table 3. Of particular interest are
electrospray ionization unless otherwise indicated. Melting points
were determined using a capillary melting point apparatus.
General Procedure A. Friedel−Crafts Silyloxyalkylation of
N-Alkylindoles. To an oven-dried round-bottomed flask under a
N2 atmosphere were added diethyl ether (10 mL), N-alkylindole
(1.0 mmol), i-Pr2NEt (250 μL, 186 mg, 1.44 mmol), and aldehyde
(1.40 mmol). The reaction mixture was cooled to −78 °C in a dry ice/
acetone bath, and trimethylsilyl trifluoromethanesulfonate (270 μL,
332 mg, 1.50 mmol) was added dropwise. The orange reaction mixture
was stirred for 1 h and then quenched with pyridine (210 μL). The
reaction mixture was passed through a column of silica (2 cm × 1 cm)
with Et2O. The solvent was removed in vacuo, and the residue was
redissolved in tetrahydrofuran (10 mL). To the solution was added
tetrabutylammonium fluoride as a 1.0 M solution in THF (1.10 mL,
1.10 mmol). The reaction mixture was stirred for 5 min and then
partitioned between diethyl ether (20 mL) and saturated sodium
bicarbonate (20 mL). The layers were separated, and the organic layer
was washed with water (20 mL). The organic layer was diluted with
hexanes (60 mL) and dried with sodium sulfate. The sodium sulfate
was removed by filtration, and the filtrate was concentrated in vacuo.
Column chromatography of the residue (0−20% EtOAc/hexanes with
1% diethylamine) provided the product, which was stored at −20 °C
after isolation.
a
Table 3. Addition of Free Indoles to Aldehydes
a
Reaction conditions: (1) 1.0 mmol of indole, 1.4 mmol of aldehyde,
General Procedure B. Friedel−Crafts Silyloxyalkylation of Free
Indoles. To an oven-dried round-bottomed flask under a N2 atmo-
sphere were added diethyl ether (10 mL), free indole (1.0 mmol),
i-Pr2NEt (437 μL, 324 mg, 2.51 mmol), and aldehyde (1.40 mmol).
The reaction mixture was cooled to −78 °C in a dry ice/acetone bath,
and trimethylsilyl trifluoromethanesulfonate (398 μL, 489 mg,
2.20 mmol) was added dropwise. The orange reaction mixture was
stirred for 1 h and then quenched with pyridine (210 μL). The
reaction mixture was passed through a column of silica (2 cm × 1 cm)
with Et2O. The solvent was removed in vacuo, and the residue was
redissolved in tetrahydrofuran (10 mL). To the solution was added
tetrabutylammonium fluoride as a 1.0 M solution in THF (2.10 mL,
2.10 mmol). The reaction mixture was stirred for 5 min and then
partitioned between diethyl ether (20 mL) and saturated sodium
bicarbonate (20 mL). The layers were separated, and the organic layer
was washed with water (20 mL). The organic layer was diluted with
hexanes (60 mL) and dried with sodium sulfate. The sodium sulfate
was removed by filtration, and the filtrate was concentrated in vacuo.
Column chromatography of the residue (0−20% EtOAc/hexanes with
1% diethylamine) provided the product, which was stored at −20 °C
after isolation.
2.2 mmol of TMSOTf, 2.5 mmol of i-Pr2NEt, 10 mL of Et2O, − 78 °C,
1 h; (2) 2.6 mmol of pyridine; (3) 2.1 mmol of TBAF, 10 mL of THF.
b
Isolated yield after chromatography, adjusted for residual solvent.
c
Product yield adjusted for approximately 10% impurities as
1
determined by H NMR spectroscopy.
brominated adducts 4b and 4c, which provide the possibility of
further elaboration by cross-coupling reactions.10
In summary, we have described the Friedel−Crafts
silyloxyalkylation of indoles and their subsequent deprotection
to yield hydroxyalkylated products. These 1:1 adducts of
indoles and aldehydes have largely eluded researchers for over a
century, but the unique ability of TMSOTf to act as both a
Lewis acid and a protecting agent provides convenient access to
this decomposition-prone class of compounds. The products
may be isolated in either the hydroxyalkylated or silyloxyalky-
lated form. Their use as efficient electrophiles under related
conditions remains to be explored.
1-Methyl-3-(phenyl((trimethylsilyl)oxy)methyl)-1H-indole
(1). The title compound12 was prepared similarly to General
Procedure A: To an oven-dried round-bottomed flask under a N2
atmosphere were added diethyl ether (10 mL), N-methylindole
(125 μL, 131 mg 1.0 mmol), i-Pr2NEt (210 μL, 156 mg, 1.21 mmol),
and benzaldehyde (140 μL, 146 mg, 1.40 mmol). The reaction mixture
was cooled to −78 °C in a dry ice/acetone bath, and trimethylsilyl
trifluoromethanesulfonate (270 μL, 332 mg, 1.50 mmol) was added
dropwise. The orange reaction mixture was stirred for 1 h and then
quenched with pyridine (210 μL). The reaction mixture was passed
through a column of silica (2 cm × 1 cm) with Et2O. The solvent was
removed in vacuo. Column chromatography of the residue (0−10%
EtOAc/hexanes with 1% diethylamine) provided the product as a
colorless oil (235 mg, 76%), which was stored at −20 °C after
isolation: IR (film) 3058, 3016, 2959, 2150, 1081, 1046, 1012, 885,
EXPERIMENTAL SECTION
■
General Methods. Reactions were carried out under an
atmosphere of nitrogen with a septum cap in oven-dried glassware
with magnetic stirring. Diethyl ether was purified by passage through a
bed of activated alumina.11 Trimethylsilyl trifluoromethanesulfonate
(TMSOTf) was stored in a Schlenk flask under an inert atmosphere.
Hunig’s base (i-Pr2NEt) was distilled from calcium hydride and stored
in a Schlenk flask under an inert atmosphere. N-Methylindole was
passed through a plug of silica with ether and concentrated in vacuo.
Benzaldehyde, 4-fluorobenzaldehyde, 4-methoxybenzaldehyde, 2-fur-
analdehyde, 2-thiophenecarboxaldehyde, and cinnamaldehyde were
distilled prior to use. All other chemicals were used as received.
Purification of reaction products was carried out by flash chro-
matography using silica gel (230−400 mesh). Analytical thin-layer
chromatography was performed on silica gel plates. Visualization was
accomplished with UV light and phosphomolybdic acid stain, followed
by heating. Infrared spectra were recorded on an FT-IR spectrometer.
1H NMR spectra were recorded on a 500 or 300 MHz spectrometer
and are reported in ppm using solvent as an internal standard (CDCl3
at 7.28 ppm). Data are reported as (ap = apparent, s = singlet, d =
doublet, t = triplet, q = quartet, sx = sextet, sp = septet, m = multiplet,
b = broad; coupling constant(s) in Hz; integration). Proton-decoupled
13C NMR spectra were recorded on a 125 or 75 MHz spectrometer
and are reported in ppm using solvent as an internal standard (CDCl3
at 77.0 ppm). High-resolution mass spectra were obtained by
1
838, 738, 702 cm−1; H NMR (500 MHz, CD2Cl2) δ 7.66 (d, J =
7.9 Hz, 1H), 7.63 (d, J = 7.4 Hz, 2H), 7.49−7.43 (m, 2H), 7.42−7.34
(m, 2H), 7.31 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.16 (ddd, J = 7.9, 7.0,
1.0 Hz, 1H), 7.03 (s, 1H), 6.27 (s, 1H), 3.80 (s, 3H), 0.26 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 145.2, 137.5, 128.1, 127.1, 127.0, 126.6,
126.3, 121.6, 119.9, 119.1, 119.0, 109.3, 71.0, 32.6, 0.0; HRMS (EI,
TOF) exact mass calcd for C16H14N [M − OSiMe3]+, 220.1121;
found, 220.1124.
(1-Methyl-1H-indol-3-yl)(phenyl)methanol (2a). The title
compound4a was prepared according to General Procedure A,
using N-methylindole (128 μL, 135 mg 1.03 mmol) and benzaldehyde
C
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The Journal of Organic Chemistry
Note
(140 μL, 146 mg, 1.40 mmol). The product was isolated as a yellow
solid (164 mg, 68%): mp 65−70 °C; IR (film) 3420, 2939, 2863, 1469,
(125 MHz, CDCl3) δ 141.8, 137.6, 133.4, 132.9, 128.1, 127.8, 127.7,
127.6, 126.4, 126.1, 125.8, 125.2, 124.6, 121.9, 119.7, 119.3, 118.2,
109.5, 70.1, 32.6; HRMS (EI, TOF) exact mass calcd for C20H17NONa
[M + Na]+, 310.1202; found, 310.1190; exact mass calcd for C20H15N
[M − OH]+, 270.1277; found, 270.1268.
1
1371, 1330, 1241, 1194, 1059, 1033, 801, 740, 702 cm−1; H NMR
(500 MHz, CD2Cl2) δ 7.61 (dt, J = 8.0, 1.0 Hz, 1H), 7.58−7.53 (m,
2H), 7.45−7.39 (m, 2H), 7.38−7.32 (m, 2H), 7.27 (ddd, J = 8.2, 7.0,
1.1 Hz, 1H), 7.11 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.91 (s, 1H), 6.17 (s,
1H), 3.76 (s, 3H), 2.44 (bs, 1H); 13C NMR (125 MHz, CDCl3) δ
144.2, 137.5, 128.2, 127.3, 127.2, 126.4, 126.3, 121.8, 120.0, 119.6,
119.2, 118.4, 109.4, 70.1, 32.6; HRMS (EI, TOF) exact mass calcd for
C16H15NONa [M + Na]+, 260.1046; found, 260.1043; exact mass
calcd for C16H14N [M − OH]+, 220.1121; found, 220.1124.
Furan-2-yl(1-methyl-1H-indol-3-yl)methanol (2g). The title
compound12 was prepared according to General Procedure A, using
N-methylindole (128 μL, 135 mg, 1.03 mmol) and 2-furanaldehyde
(128 μL, 134 mg, 1.40 mmol). The product was isolated as a dark red
oil (165 mg (corrected to account for residual diethyl ether), 71%): IR
(film) 3386, 3052, 2967, 2932, 2874, 1551, 1474, 1329, 1191, 1063,
1
(1-Methyl-1H-indol-3-yl)(4-nitrophenyl)methanol (2c). The
title compound12 was prepared according to General Procedure A,
using N-methylindole (128 μL, 135 mg 1.03 mmol) and
4-nitrobenzaldehyde (211 mg, 1.40 mmol), except that a different
amount of i-Pr2NEt was used (292 μL, 217 mg 1.68 mmol). The
product was isolated as a pale brown solid (206 mg, 71%): mp 123−
127 °C; IR (film) 3524, 310, 3043, 2928, 1593, 1507, 1331, 1042, 805,
1009, 993, 784, 733 cm−1; H NMR (500 MHz, CD2Cl2) δ 7.71 (dt,
J = 8.0, 1.0 Hz, 1H), 7.52 (dd, J = 1.8, 0.9 Hz, 1H), 7.42 (dt, J = 8.3,
0.9 Hz, 1H), 7.36 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.22 (ddd, J = 7.9,
7.0, 1.1 Hz, 1H), 7.13 (s, 1H), 6.48 (dd, J = 3.2, 1.9 Hz, 1H), 6.39 (dt,
J = 3.2, 0.8 Hz, 1H), 6.17 (s, 1H), 3.77 (s, 3H), 3.01 (bs, 1H); 13C
NMR (125 MHz, CDCl3) δ 156.7, 142.0, 137.4, 127.5, 126.3, 121.9,
119.7, 119.3, 115.2, 110.3, 109.5, 106.7, 64.2, 32.6.; HRMS (EI, TOF)
exact mass calcd for C14H13NO2Na [M + Na]+, 250.0839; found,
250.0844; exact mass calcd for C14H12NO [M − OH]+, 210.0913;
found, 210.0908.
(1H-Indol-3-yl)(thiophen-2-yl)methanol (2h). The title com-
pound12 was prepared according to General Procedure A, using
N-methylindole (128 μL, 135 mg, 1.03 mmol) and 2-thiophenecarbox-
aldehyde (131 μL, 157 mg, 1.40 mmol). The product was isolated as a
pale brown solid (210 mg, 84%): IR (film) 3360, 3047, 2923, 2872,
1609, 1549, 1473, 1423, 1329, 1239, 1155, 1131, 1063, 1024, 978, 853,
764, 739, 701 cm−1; 1H NMR (500 MHz, CD2Cl2) δ 7.61 (dt, J = 8.0,
0.9 Hz, 1H), 7.38 (dt, J = 8.3, 0.9 Hz, 1H), 7.32 (dd, J = 5.0, 1.3 Hz,
1H), 7.27 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.14−7.10 (m, 2H), 7.07 (dt,
J = 3.5, 1.1 Hz, 1H), 7.02 (dd, J = 5.1, 3.5 Hz, 1H), 6.40 (s, 1H), 3.79
(s, 3H), 2.57 (bs, 1H); 13C NMR (125 MHz, CDCl3) δ 148.8, 137.5,
127.2, 126.6, 126.0, 124.6, 124.3, 121.9, 119.6, 119.3, 117.6, 109.5,
66.6, 32.7; HRMS (EI, TOF) exact mass calcd for C14H13NOSNa
[M + Na]+, 266.0610; found, 266.0614; exact mass calcd for C14H13NS
[M − OH]+, 226.0685; found, 226.0678.
(E)-1-(1-Methyl-1H-indol-3-yl)-3-phenylprop-2-en-1-ol (2i).
The title compound12 was prepared according to General Procedure
A, using N-methylindole (128 μL, 135 mg, 1.03 mmol) and trans-
cinnamaldehyde (176 μL, 185 mg, 1.40 mmol). The product was
isolated as an orange-brown oil (172 mg (yield corrected for presence of
residual diethyl ether), 63%): IR (film) 3364, 3050, 3021, 2926, 2863,
1548, 1473, 1447, 1328, 1242, 1154, 1112, 1066, 1012, 962, 737, 692
cm−1; 1H NMR (500 MHz, CD2Cl2) δ 7.83 (dt, J = 8.0, 1.0 Hz, 1H),
7.55−7.47 (m, 2H), 7.44−7.36 (m, 3H), 7.35−7.28 (m, 2H), 7.19
(ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.13 (s, 1H), 6.85 (d, J = 16.0, 1H),
6.69 (dd, J = 15.9, 6.1 Hz, 1H), 5.74 (d, J = 6.1 Hz, 1H), 3.79 (s, 3H),
2.33 (bs, 1H); 13C NMR (125 MHz, CDCl3) δ 137.5, 137.1, 131.9,
129.6, 128.6, 127.5, 126.8, 126.5, 126.3, 121.8, 119.7, 119.2, 116.9,
109.5, 68.7, 32.6; HRMS (EI, TOF) exact mass calcd for C18H16NO
[M − H]+, 262.1226; found, 262.1218 (weak peak observed only at
130 °C); exact mass calcd for C18H16N [M − OH]+, 246.1277; found,
246.1274.
(1-Benzyl-1H-indol-3-yl)(phenyl)methanol (3a). The title
compound5 was prepared according to General Procedure A, using
N-benzylindole (206 mg, 1.00 mmol) and benzaldehyde (142 μL,
149 mg, 1.40 mmol). The product was isolated as a pale yellow oil
(235 mg, 75%): IR (film) 3343, 1636, 1550, 1452, 1332, 1264, 1170,
1032, 990, 731, 695 cm−1; 1H NMR (500 MHz, CD2Cl2) δ 7.66 (d, J =
8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.55−7.32 (m, 7H), 7.32−7.18
(m, 3H), 7.14 (t, J = 7.5 Hz, 1H), 7.07 (s, 1H), 6.21 (s, 1H), 5.31 (s,
2H), 2.58 (bs, 1H); 13C NMR (125 MHz, CDCl3) δ 144.1, 137.7,
137.1, 128.7, 128.3, 127.6, 127.3, 126.8, 126.8, 126.8, 126.6, 126.5,
122.1, 119.9, 119.5, 119.1, 110.0, 70.3, 50.1; HRMS (EI, TOF)
exact mass calcd for C22H19NONa [M + Na]+, 336.1359; found,
336.1357.
1
741, 718 cm−1; H NMR (500 MHz, CD2Cl2) δ 8.25−8.19 (m, 2H),
7.76−7.71 (m, 2H), 7.55 (dt, J = 8.0, 1.0 Hz, 1H), 7.36 (dt, J = 8.3,
0.9 Hz, 1H), 7.26 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.10 (ddd, J = 8.0,
7.0, 1.0 Hz, 1H), 6.94 (s, 1H), 6.26 (s, 1H), 3.78 (s, 3H), 2.50 (bs,
1H); 13C NMR (125 MHz, CDCl3) δ 151.4, 147.1, 137.5, 127.7,
127.0, 125.8, 123.3, 122.1, 119.5, 119.3, 117.0, 109.6, 69.2, 32.7;
HRMS (EI, TOF) exact mass calcd for C16H13N2O3 [M − H]+,
281.0921 (weak peak observed only at 130 °C); found, 281.0927;
exact mass calcd for C16H13N2O2 [M − OH]+, 265.0972; found,
265.0960.
(4-Fluorophenyl)(1-methyl-1H-indol-3-yl)methanol (2d). The
title compound12 was prepared according to General Procedure A,
using N-methylindole (128 μL, 135 mg 1.03 mmol) and
4-fluorobenzaldehyde (150 μL, 174 mg, 1.40 mmol). The product
was isolated as an off-white solid (183 mg, 79%): mp 87−92 °C; IR
(film) 3339, 3054, 2921, 1594, 1506, 1466, 1218, 1154, 979, 817,
1
740 cm−1; H NMR (500 MHz, CD2Cl2) δ 7.56 (dt, J = 8.1, 1.1 Hz,
1H), 7.55−7.48 (m, 2H), 7.36 (d, J = 8.3 Hz, 1H), 7.26 (ddd, J = 8.2,
6.9, 1.2 Hz, 1H), 7.14−7.05 (m, 3H), 6.90 (s, 1H), 6.15 (s, 1H), 3.77
(s, 3H), 2.40 (bs, 1H); 13C NMR (125 MHz, CDCl3) δ 162.0 (d, JF
244.2 = Hz), 140.0 (d, JF 3.0 = Hz), 137.5, 128.1 (d, JF = 8.0 Hz),
127.3, 126.1, 121.9, 119.5, 119.2, 118.2, 114.9 (d, JF = 21.4 Hz), 109.4,
69.5, 32.6; HRMS (EI, TOF) exact mass calcd for C16H14NOFNa
[M + Na]+, 278.0952; found, 278.0954; exact mass calcd for
C16H13NF [M − OH]+, 238.1027; found, 238.1037.
(4-Bromophenyl)(1-methyl-1H-indol-3-yl)methanol (2e). The
title compound12 was prepared according to General Procedure A,
using N-methylindole (128 μL, 135 mg 1.03 mmol) and
4-bromobenzaldehyde (259 mg, 1.40 mmol). The product was
isolated as an off-white solid (254 mg, 78%): mp 90−92 °C; IR
(film) 3360, 3047, 2936, 1558, 1479, 1337, 1235, 1068, 1011, 811, 741
1
cm−1; H NMR (500 MHz, CD2Cl2) δ 7.59 (dt, J = 8.0, 1.0 Hz, 1H),
7.57−7.51 (m, 2H), 7.45−7.40 (m, 2H), 7.37 (dt, J = 8.3, 0.9 Hz, 1H),
7.29 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.13 (ddd, J = 7.9, 7.0, 1.1 Hz,
1H), 6.87 (s, 1H), 6.09 (s, 1H), 3.75 (s, 3H), 2.65 (bs, 1H); 13C NMR
(125 MHz, CDCl3) δ 143.3, 137.5, 131.2, 128.2, 127.5, 126.1, 122.0,
120.8, 119.5, 119.3, 117.8, 109.5, 69.4, 32.6; HRMS (EI, TOF) exact
mass calcd for C16H13NOBr [M − H]+, 314.0175, 316.0154; found,
314.0163, 316.0158 (weak peaks observed only at 130 °C); exact mass
calcd for C16H13NBr [M − OH]+, 298.0226, 300.0207; found,
298.0212, 300.0195.
(1-Methyl-1H-indol-3-yl)(naphthalen-2-yl)methanol (2f). The
title compound12 was prepared according to General Procedure A,
using N-methylindole (128 μL, 135 mg 1.03 mmol) and
2-naphthaldehyde (219 mg, 1.40 mmol). The product was isolated
as brown solid (227 mg, 77%): mp 54−57 °C; IR (film) 3364, 3048,
1
1473, 1424, 1329, 1240, 1155, 1028, 996, 818, 738 cm−1; H NMR
(500 MHz, CD2Cl2) δ 8.12 (bs, 1H), 7.95 (ddd, J = 6.8, 5.3, 2.7 Hz,
2H), 7.90 (d, J = 8.5 Hz, 1H), 7.69 (dt, J = 8.0, 1.0 Hz, 1H), 7.63 (dd,
J = 8.5, 1.8 Hz, 1H), 7.62−7.56 (m, 2H), 7.39 (dt, J = 8.3, 1.0 Hz, 1H),
7.32 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.16 (ddd, J = 8.0, 7.0, 1.1 Hz,
1H), 6.90 (s, 1H), 6.33 (s, 1H), 3.71 (s, 3H), 2.90 (bs, 1H); 13C NMR
(1-Allyl-1H-indol-3-yl)(phenyl)methanol (3b). The title com-
pound12 was prepared according to General Procedure A, using
N-allylindole (160 mg, 1.02 mmol) and benzaldehyde (145 μL,
152 mg, 1.43 mmol). The product was isolated as a yellow oil
D
DOI: 10.1021/acs.joc.5b01681
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The Journal of Organic Chemistry
Note
(205 mg, 76%): IR (film) 3343, 1643, 1550, 1465, 1332, 1264, 1177,
13C NMR (125 MHz, CDCl3) δ 141.4, 136.7, 133.3, 132.9, 128.0,
127.8, 127.6, 126.0, 125.8, 125.7, 125.0, 124.6, 122.8, 122.3, 119.7
(double intensity), 119.5, 111.2, 70.3; HRMS (EI, TOF) exact mass
calcd for C19H15NONa [M + Na]+, 296.1046; found, 296.1048; exact
mass calcd for C19H14N [M − OH]+, 256.1121; found, 256.1110.
1
989, 919, 813, 735, 697 cm−1; H NMR (500 MHz, CD2Cl2) δ 7.58
(dt, J = 8.0, 1.0 Hz, 1H), 7.56−7.52 (m, 2H), 7.43−7.37 (m, 2H),
7.36−7.29 (m, 2H), 7.21 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.07 (ddd, J =
8.0, 7.0, 1.0 Hz, 1H), 6.97 (s, 1H), 6.18 (d, J = 3.9 Hz, 1H), 6.03 (ddt,
J = 17.1, 10.2, 5.5 Hz, 1H), 5.22 (dq, J = 10.3, 1.4 Hz, 1H), 5.12 (dq,
J = 17.1, 1.6 Hz, 1H), 4.72 (dt, J = 5.5, 1.6 Hz, 2H), 2.30 (d, J = 4.1
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 144.1, 136.9, 133.5, 128.2,
127.2, 126.4, 126.4, 126.3, 121.8, 119.7, 119.3, 118.8, 117.0, 109.8,
70.2, 48.8; HRMS (EI, TOF) exact mass calcd for C18H17NONa
[M + Na]+, 286.1202; found, 286.1197.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01681.
■
S
(1H-Indol-3-yl)(phenyl)methanol (4a). The title compound3a
was prepared according to General Procedure B, using indole (117 mg,
1.00 mmol) and benzaldehyde (142 μL, 149 mg, 1.40 mmol). The
product was isolated as a white solid (163 mg (yield corrected for
residual diethyl ether), 73%): mp 80−83 °C; IR (film) 3536, 3408,
3305, 3060, 2925, 2848, 1548, 1493, 1455, 1420, 1338, 1227, 1101,
Spectral data (PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: wdowney@richmond.edu.
■
1
989, 741, 699 cm−1; H NMR (500 MHz, CD2Cl2) δ 8.30 (s, 1H),
Notes
7.61 (dq, J = 8.0, 0.9 Hz, 1H), 7.58−7.49 (m, 2H), 7.46−7.32 (m,
4H), 7.23 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.11 (ddd, J = 8.0, 7.0, 1.0
Hz, 1H), 6.99 (dd, J = 2.5, 0.8 Hz, 1H), 6.18 (s, 1H), 2.52 (bs, 1H);
13C NMR (125 MHz, CDCl3) δ 144.0, 136.7, 128.2, 127.3, 126.5,
125.8, 122.8, 122.2, 119.7, 119.6, 119.5, 111.3, 70.3; HRMS (EI, TOF)
exact mass calcd for C15H13NONa [M + Na]+, 246.0889; found,
246.0887; exact mass calcd for C15H12N [M − OH]+, 206.0964; found,
206.0954.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation RUI program
(CHE-1057591) and the Camille and Henry Dreyfus
Foundation for funding. C.D.P. gratefully acknowledges the
Howard Hughes Medical Institute and the University of
Richmond College of Arts and Sciences for summer research
fellowships. We are indebted to the National Science
Foundation (CHE-0541848) and the University of Califor-
nia−Riverside for mass spectral data.
(5-Bromo-1H-indol-3-yl)(phenyl)methanol (4b). The title
compound3c was prepared according to General Procedure B, using
5-bromoindole (196 mg, 1.00 mmol) and benzaldehyde (142 μL,
149 mg, 1.40 mmol). The product was isolated as an off-white solid
(223 mg (yield corrected for residual ethyl acetate), 72%): mp 35−38 °C;
IR (film) 3422, 3297, 2870, 1450, 1223, 1099, 983, 952, 881, 794, 732,
1
699 cm−1; H NMR (500 MHz, CD2Cl2) δ 8.47 (s, 1H), 7.76 (d, J =
REFERENCES
■
1.6 Hz, 1H), 7.53−7.48 (m, 2H), 7.45−7.39 (m, 2H), 7.38−7.33 (m,
1H), 7.29 (dd, J = 8.6, 1.9 Hz, 1H), 7.23 (dd, J = 8.6, 0.6 Hz, 1H), 6.94
(d, J = 2.5 Hz, 1H), 6.10 (s, 1H), 2.69 (bs, 1H); 13C NMR (125 MHz,
CDCl3) δ 143.5, 135.3, 128.4, 127.6, 127.5, 126.4, 125.0, 124.1, 122.1,
119.2, 112.9, 112.8, 70.1; HRMS (EI, TOF) exact mass calcd for
C15H11NOBr [M − H]+, 300.0019, 301.9999 (weak peaks observed
only at 130 °C); found, 300.0010, 302.0025; exact mass calcd for
C15H11NBr [M − OH]+, 284.0069, 286.0050; found, 284.0069,
286.0043.
(1) (a) Fischer, E. Ber. Dtsch. Chem. Ges. 1886, 19, 2988−2992. For
representative recent examples, see: (b) Shi, X.-L.; Xing, X.; Lin, H.;
Zhang, W. Adv. Synth. Catal. 2014, 356, 2349−2354. (c) Liang, D.;
Huang, W.; Yuan, L.; Ma, Y.; Ma, J.; Ning, D. Catal. Commun. 2014,
55, 11−14. (d) Karam, A.; Alonso, J. C.; Gerganova, T. I.; Ferreira, P.;
Bion, N.; Barrault, J.; Jerome, F. Chem. Commun. 2009, 7000−7002.
(2) For representative examples, see: (a) Borkin, D. A.; Landge, S.
M.; Toeroek, B. Chirality 2011, 23, 612−616. (b) Nikitin, G. I.;
Glukhovtsev, V. G.; Il’in, Yu. V.; Ignatenko, A. V. Isv. Akad. Nauk, Ser.
Khim. 1982, 447−449. (c) Carmona, D.; Lamata, P.; Sanchez, A.;
Pardo, P.; Rodriguez, R.; Ramirez, P.; Lahoz, F. J.; Garcia-Orduna, P.;
Oro, L. A. Organometallics 2014, 33, 4016−4026. (d) Dong, H.-M.;
Lu, H.-H.; Lu, L.-Q.; Chen, C.-B.; Xiao, W.-J. Adv. Synth. Catal. 2007,
349, 1597−1603.
(4-Bromophenyl)(1H-indol-3-yl)methanol (4c). The title com-
pound6a was prepared according to General Procedure B, using indole
(117 mg, 1.00 mmol) and 4-bromobenzaldehyde (259 mg,
1.40 mmol). The product was isolated as a white solid (287 mg
(yield corrected for residual ethyl acetate), 87%): mp 38−42 °C; IR
(film) 3403, 3312, 3058, 2928, 2858, 1485, 1420, 1338, 1232, 1069,
1
819, 778, 741 cm−1; H NMR (500 MHz, CD2Cl2) δ 8.37 (s, 1H),
(3) For an asymmetric example catalyzed by a cinchona alkyloid, see:
(a) Li, H.; Wang, Y.-Q.; Deng, L. Org. Lett. 2006, 8, 4063−4065. For
an elegant method catalyzed by tetramethylguanidine ion, see:
(b) Guo, Z.-L.; Peng, Y.-G.; Zhang, J.-W.; Liu, S.; Feng, Z.; Gong,
L.-Z. Org. Lett. 2009, 11, 4620−4623. For a pioneering method
employing CsCO3, see: (c) Elayaraja, R.; Karunakaran, R. J.
Tetrahedron Lett. 2012, 53, 6901−6904.
(4) For typical examples of a hydride-reduction route to
representative product 2a, see: (a) Fusco, R.; Sannicolo, F. J. Org.
Chem. 1984, 49, 4374−4378. (b) Dhiman, S.; Ramasastry, S. S. V. Org.
Biomol. Chem. 2013, 11, 8030−8035.
7.58 (d, J = 8.1 Hz, 1H), 7.56−7.49 (m, 2H), 7.42−7.33 (m, 3H), 7.25
(ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.13 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H),
6.89 (d, J = 2.5 Hz, 1H), 6.09 (s, 1H), 2.84 (bs, 1H); 13C NMR (125
MHz, CDCl3) δ 143.0, 136.7, 131.2, 128.2, 125.5, 122.8, 122.4, 120.9,
119.8, 119.5, 119.3, 111.3, 69.6; HRMS (EI, TOF) exact mass calcd for
C15H11NOBr [M − H]+, 300.0019, 301.9999; found, 300.0025,
301.9963 (weak peaks observed only at 130 °C); exact mass calcd for
C15H11NBr [M − OH]+, 284.0069, 286.0050; found, 284.0074,
286.0061.
(1H-Indol-3-yl)(naphthalen-2-yl)methanol (4d). The title
compound3b was prepared according to General Procedure B, using
indole (117 mg, 1.00 mmol) and 2-naphthaldehyde (219 mg,
1.40 mmol). The product was isolated as a pinkish white solid,
(5) For a recent example of a Grignard addition route to compounds
similar to those produced here, see: Chen, C.; Feng, H.-X.; Li, Z.-L.;
Cai, P.-W.; Liu, Y.-K.; Shan, L.-H.; Zhou, X.-L. Tetrahedron Lett. 2014,
55, 3774−3776.
1
although purity appears to be only ∼90% by H NMR spectroscopy
(6) For the use of (indolyl) (aryl)methanols and their analogues as
alkylating agents, see: (a) Guo, Z.-L.; Xue, J.-H.; Fu, L.-N.; Zhang, S.-
E.; Guo, Q.-X. Org. Lett. 2014, 16, 6472−6475. (b) Reference 2b.
(c) Zhuo, M.-H.; Jiang, Y.-J.; Fan, Y.-S.; Gao, Y.; Liu; Song; Zhang, S.
Org. Lett. 2014, 16, 1096−1099.
(7) Downey, C. W.; Fleisher, A. S.; Rague, J. T.; Safran, C. L.;
Venable, M. E.; Pike, R. D. Tetrahedron Lett. 2011, 52, 4756−4759.
(254 mg (yield corrected for residual ethyl acetate and trace impurities),
77%): mp 136−138 °C °C; IR (film) 3433, 3337, 3052, 1664, 1544,
1459, 1339, 1250, 1116, 1007, 827, 787, 748 cm−1; 1H NMR
(500 MHz, CD2Cl2) δ 8.27 (bs, 1H), 8.08 (s, 1H), 7.95−7.82 (m,
3H), 7.64−7.57 (m, 2H), 7.56−7.49 (m, 2H), 7.42 (dt, J = 8.2, 0.9 Hz,
1H), 7.20 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.11 (dd, J = 2.5, 0.8 Hz,
1H), 7.07 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 6.36 (s, 1H), 2.46 (s, 1H);
E
DOI: 10.1021/acs.joc.5b01681
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The Journal of Organic Chemistry
Note
(8) Downey, C. W.; Covington, S. E.; Obenschain, D. C.; Halliday,
E.; Rague, J. T.; Confair, D. N. Tetrahedron Lett. 2014, 55, 5213−5215.
(9) Previous work with carboxylic acid nucleophiles required a similar
strategy. See: Downey, C. W.; Johnson, M. W.; Lawrence, D. H.;
Fleisher, A. S.; Tracy, K. J. J. Org. Chem. 2010, 75, 5351−5354.
(10) For example, see: Ramgren, S. D.; Hie, L.; Ye, Y.; Garg, N. K.
Org. Lett. 2013, 15, 3950−3953.
(11) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518−1520.
(12) To our knowledge, this compound has not been previously
synthesized and isolated.
F
DOI: 10.1021/acs.joc.5b01681
J. Org. Chem. XXXX, XXX, XXX−XXX