5-hydroxyindoles by intramolecular alkynol-furan diels-alder cycloaddition

Article abstract of DOI:10.1021/jo3022605

A convergent approach provides a convenient access to synthetically and biologically useful 3,4-disubstituted 5-hydroxyindoles. The one-pot procedure uses microwave heating to initiate an intramolecular [4 + 2]-cycloaddition of an alkynol segment onto a furan followed by a fragmentation, aromatization, and N-Boc deprotection cascade. Yields range from 15 to 74%, with aromatic substituents providing better conversions. 4-Trimethylsilylated analogues undergo a 1,3-silatropic rearrangement to give the O-TMS ethers.

Full text of DOI:10.1021/jo3022605

Article
pubs.acs.org/joc
5‑Hydroxyindoles by Intramolecular Alkynol−Furan Diels−Alder
Cycloaddition
Matthew LaPorte, Ki Bum Hong, Jie Xu, and Peter Wipf*
Department of Chemistry and Center for Chemical Methodologies & Library Development, University of Pittsburgh, Pittsburgh,
Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: A convergent approach provides a convenient
access to synthetically and biologically useful 3,4-disubstituted
5-hydroxyindoles. The one-pot procedure uses microwave
heating to initiate an intramolecular [4 + 2]-cycloaddition of
an alkynol segment onto a furan followed by a fragmentation,
aromatization, and N-Boc deprotection cascade. Yields range
from 15 to 74%, with aromatic substituents providing better conversions. 4-Trimethylsilylated analogues undergo a 1,3-silatropic
rearrangement to give the O-TMS ethers.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
The hypothesis that an alkynyl intermediate 3 would lead to the
formation of 5-hydroxyindole 10 was readily tested. Furanyl-
stannane 13 was prepared from iodide 119 and N-Boc-2-
aminofuran 1210 in the presence of NaH (Scheme 3). Stannane
13 underwent a rapid transmetalation (5 min) to 1 with n-BuLi
at −78 °C, and after the addition of 1 equiv of 1,3-
diphenylprop-2-yn-1-one 14a, the tertiary alcohol 15a was
isolated in 57% yield. Microwave heating to 220 °C for 1 h
effected the desired IMDAF process and aromatization to give
5-hydroxyindole 16a in 74% yield after chromatographic
purification of the reaction mixture on SiO2. The Boc group
was cleaved off under the thermal conditions.8 Interestingly, the
ethoxycarbonyl protective group7c on nitrogen led to lower
yields, possibly due to an N→O acyl shift in intermediate 3.
In order to further investigate the scope of this new process,
we converted commercially available carbonyl compounds into
ynones 14b−e according to literature protocols.11,12 The
lithium reagent derived from stannane 13 was then added to
these ynones to give the corresponding alkynols 15b−e in
unoptimized 44−52% yield. As shown in Table 1, microwave
irradiation of 15b−e in o-dichlorobenzene for 1 h produced the
expected 5-hydroxyindoles 16b−e in moderate (36%) to good
(63%) yields.
Second only to pyridines, indoles are among the most common
aromatic scaffolds present in bioactive molecules.1 The 5-
hydroxyindole moiety alone currently has >15000 substructure
hits from >140000 literature references in SciFinder. In
addition to their prominence in the neurotransmitter serotonin
and its many analogues, 5-hydroxyindoles are found in a vast
array of pharmacologically active agents and natural products
(Figure 1). Furthermore, the hydroxy group can be readily
converted to derivatives that allow scaffold extensions, cross-
coupling or nucleophilic addition reactions of the indole
nucleus.2
The Nenitzescu reaction is frequently used for the
construction of 5-hydroxyindoles.3 Alternative protocols
include the coumarin−indole transformation4 and the Pd-
catalyzed coupling of 2-iodoanilines with alkynes (Scheme 1).5
All of these protocols start with a functionalized 6-membered
ring, and add the pyrrole moiety in a linear sequence. We have
recently reported an alternative strategy for a convergent indole
synthesis that uses an intramolecular Diels−Alder furan
(IMDAF) cycloaddition to assemble both benzene and pyrrole
moieties simultaneously.6,7 We are now reporting an extension
of this procedure to the direct preparation of 5-hydroxyindoles.
In our previous reaction sequence,6 the 1,2-addition of
lithiated 1 to enone 2 provided the allylic alcohol 3 (Scheme
2). Microwave heating of 3 led to the tricyclic IMDAF product
4 and subsequently through sequential elimination of 2 equiv of
water via 5 and 6 to indoles 7. We reasoned that the use of an
alkynone in place of the enone would give us the opportunity
to branch out from this reaction pathway, eliminate the
bridging oxygen atom in 4 to give 8, aromatize the intermediate
at an earlier stage to give phenol 9, and finally only eliminate a
single molecule of water and, concomitantly, the N-protective
group8 to yield 5-hydroxyindole 10.
The reaction tolerated both aromatic and heteroaromatic
groups (i.e., phenyl, 16a, and thiophene, 16b) as well as
branched and cyclic aliphatic substituents (i.e., n-hexyl, 16c,
phenethyl, 16d, and c-hexyl, 16e) at the R1 position. We
explored fewer variations of the R2 groups, but as the n-butyl
derivative 16e demonstrated, aliphatic groups appear to be
acceptable substituents at R2. The lowest yield, 36%, was
Special Issue: Robert Ireland Memorial Issue
Received: October 16, 2012
Published: November 8, 2012
© 2012 American Chemical Society
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Figure 1. Representative biologically active 5-hydroxyindoles.
Scheme 1. Methods for Formation of 5-Hydroxyindoles
obtained with R1 and R2 both being aliphatic residues, which
could indicate that either indole stabilization through
conjugative substituents at R1 and R2 or the presence of
sterically bulky groups such as phenyl rings promotes product
formation. Therefore, we tested silylated alkynes derived from
silyl ketones as substrates that provide steric shielding in the
absence of π-electron resonance effects.
to ultimately afford the 4-substituted 5-hydroxyindoles 16j−q.
Similar to our previous observations, aromatic substrates gave
better isolated yields compared to the alkyl-substituted alkynols
(Table 3).
Indoles with 4-aryl residues 16j−n were isolated in 42−64%
yield, and no obvious trend for electron-withdrawing or
-donating substituents was observed. The two alkyl-chain
containing products 16o and 16p were formed in low (15−
20%) yields, and the 3-chloropropyl analogue 16p partially
cyclized and produced an additional 7% of the corresponding
pyran 18. The cyclized ether17 could also be obtained in 53%
yield by treatment of isolated 16p with NaH in THF. Finally,
the cyclohexene derivative 15q led to the introduction of a 4-
alkene group in 16q, but the yield (23%) was similarly low as
observed for aliphatic substrates. Nonetheless, this method-
ology allows for the rapid introduction of a diverse range of
substituents at carbons 3 and 4 of the 5-hydroxyindole scaffold.
When the four trimethylsilyl (TMS) alkynols 15f−i13 were
subjected to the microwave-mediated cycloaddition conditions
at 180 °C, the cycloaddition occurred smoothly and provided
indole products in good yields (Scheme 4 and Table 2).
However, rather than the expected 4-trimethylsilyl derivatives
16′f−i, a mixture of 5-(trimethylsilyloxy)indoles 17f−i and the
corresponding 5-hydroxyindoles 16f−i was isolated. Presum-
ably, the TMS-ethers result from a 1,3-silatropic C to O
rearrangement,14 induced by the thermal conditions and
rendered quantitative by the strong O−Si bond. In order to
generate a homogeneous product fraction, the crude reaction
mixtures were treated with 2% HCl in MeOH to desilylate
17f−i and cleanly afford the 5-hydroxyindole products 16f−i.15
As a further test of this methodology, the reaction sequence
was extended to aldehyde substrates, and the secondary
alkynols 15j−q were prepared16 in unoptimized 20−57% yields
by addition of lithiated 13 to ynals 14j−q (Scheme 5). As
expected, the microwave conditions promoted cycloadditions
CONCLUSION
■
The use of alkynones and alkynals as starting materials extends
our microwave-assisted IMDAF-aromatization cascade reaction
to the direct formation of synthetically and biologically valuable
5-hydroxyindoles. The requisite substituted alkynes are readily
available, and the methodology represents an unusual
convergent formation of both the benzene and the pyrrole
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Scheme 2. Proposed Reaction Pathways for Indole and 5-Hydroxyindole Formation by Intramolecular Diels−Alder Reaction
with Furans
Scheme 3. Formation of Propargyl Alcohol and Thermal Cycloaddition Reaction
substituents that can stabilize the charged and/or reactive
intermediates 4, 8, and 9 in the cascade indole formation
process. We also observed an interesting 1,3-silatropic
rearrangement of the putative 4-silylated intermediates 16′.
Overall, due to the straightforward access to ynones and ynals,
the convergent nature of the retrosynthetic disconnection, and
the convenient thermal reaction conditions, this new reaction
provides a significant alternative to other common methods for
5-hydroxyindole construction, especially for projects where a
diverse range of 3- and 4-substitutions is desired.
Table 1. Synthesis of 5-Hydroxyindoles 16b−e from Tertiary
Alkynols 15b−e
a
b
entry
15
% yield
R1
R2
16
% yield
1
2
3
4
b
c
52
44
47
49
2-thiophene-yl
n-hexyl
Ph
b
c
61
58
63
36
Ph
d
e
CH2CH2Ph
Ph
d
e
c-hexyl
n-butyl
a
b
Yields of isolated alkynols 15. Yields of isolated indoles 16.
subunits of the indole ring system. Yields range from 15 to 74%,
and the efficiency of the conversion benefits from aromatic
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Scheme 4. Formation of 3-Substituted 5-Hydroxyindoles from Silylated Alkynones
Table 2. Synthesis of 5-Hydroxyindoles 16f−i from Tertiary
Alkynols 15f−i
Table 3. Synthesis of 5-Hydroxy Indoles 16j−q from
Secondary Alkynols 15j−q
a
b
a
b
entry
15
% yield
R1
16
% yield
entry
15
% yield
R2
16
% yield
1
2
3
4
f
58
60
58
52
Ph
f
63
60
63
47
1
2
3
4
5
6
7
8
j
43
57
52
26
20
54
52
38
Ph
j
48
42
47
64
44
15
g
h
i
2-naphthyl
2-benzofuryl
c-propyl
g
h
i
k
l
3-OMePh
4-MePh
k
l
m
n
o
p
q
4-CF3Ph
m
n
o
p
q
a
b
4-F-Ph
Yields of isolated alkynols 15. Yields of isolated indoles 16.
(CH2)2CH(CH3)2
(CH2)3Cl
c
20
1-cyclohexene
b
23
c
EXPERIMENTAL SECTION
■
a
Yields of isolated alkynols 15. Yields of isolated indoles 16. The
General Information. Microwave reactions were performed at
200−250 W using a Biotage Initiator. Ketones 14a and 14b are
commercially available and were used without further purification.
Ketones 14c,11,18 14d,11,19 14e,12,20 14f,21,22 14g,21,23 14h,21 and
14i,21,24 and aldehydes 14j,25 14k,11,26 14l,11,27 14m,11,28 14n,11,29
14o,25 14p,25,30 and 14q25,31 were prepared according to literature
procedures.
1-(Benzofuran-2-yl)-3-(trimethylsilyl)prop-2-yn-1-one (14h). Ac-
cording to a literature protocol,21 14h was obtained as a yellow oil
(2.50 g, 84%): IR (neat) 2963, 2158, 1630, 1548 cm−1; 1H NMR (400
MHz, acetone-d6) δ 7.94 (s, 1 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.66 (d, J
= 8.5 Hz, 1 H), 7.60 (ddd, J = 1.2, 7.0, 7.0 Hz, 1 H), 7.40 (ddd, J = 0.9,
8.0, 8.0 Hz, 1 H), 0.34 (s, 9 H); 13C NMR (100 MHz, acetone-d6) δ
165.9, 157.3, 154.0, 130.3, 127.9, 125.3, 124.9, 118.9, 113.2, 101.1,
pyran-containing indole product 1817 was also isolated in 7% yield
(see the Supporting Information).
99.7, −0.78; HRMS (TOF APCI+) m/z calcd for C14H15O2Si (M +
H) 243.0841, found 243.0865.
General Protocol A. tert-Butyl Furan-2-yl(2-hydroxy-2,4-diphe-
nylbut-3-ynyl)carbamate (15a). A flame-dried 25-mL round-bottom
flask was charged with a solution of furanylstannane 13 (0.608 g, 1.25
mmol) in dry THF (4 mL). The solution was cooled to −78 °C and
treated with BuLi (1.0 mL, 1.6 M in hexanes) using a syringe pump
over 10 min. The reaction mixture was then treated with alkyne 14a
(0.253 g, 1.23 mmol) in THF (4 mL) via syringe pump over 10 min.
After 1 h, the orange solution was diluted with satd NH4Cl, extracted
Scheme 5. Formation of 4-Substituted 5-Hydroxyindoles from Alkynals
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with EtOAc, washed with brine, dried (Na2SO4), filtered, and
concentrated. The crude residue was purified by chromatography on
SiO2 (ISCO-Companion, 0−100% EtOAc/hexanes, 25 min gradient)
to give alcohol 15a (0.29 g, 0.72 mmol, 57%) as a yellow oil: IR (neat)
3395, 2982, 1713, 1681 cm−1; 1H NMR (400 MHz, acetone-d6) δ 7.73
(d, J = 7.2 Hz, 2 H), 7.44−7.28 (m, 8 H), 7.24 (dd, J = 1.0, 2.2 Hz, 1
H), 6.32 (dd, J = 2.4, 3.2 Hz, 1 H), 6.02 (br s, 1 H), 5.39 (br s, 1 H),
4.16−4.04 (m, 2 H), 4.07 (d, J = 14.2 Hz, 1 H), 1.29 (s, 9 H); 13C
NMR (75 MHz, acetone-d6) δ 150.0, 144.2, 138.9, 132.6, 129.4, 129.3,
128.8, 128.5, 127.1, 123.8, 111.7, 91.9, 86.4, 81.7, 73.8, 60.8, 28.2;
HRMS (TOF ES+) m/z calcd for C25H25NO4Na (M + Na) 426.1681,
found 426.1698.
tert-Butyl Furan-2-yl(2-hydroxy-4-phenyl-2-(thiophen-2-yl)but-3-
ynyl)carbamate (15b). According to general protocol A, 15b was
obtained as a yellow oil (0.350 g, 52%, SiO2, EtOAc/hexanes, 1:6): IR
(neat) 3384, 2982, 2918, 1713, 1681 cm−1; 1H NMR (400 MHz,
acetone-d6) δ 7.46−7.37 (m, 6 H), 7.27−7.25 (m, 2 H), 7.01 (dd, J =
3.6, 4.4 Hz, 1 H), 6.34 (dd, J = 2.4, 3.2 Hz, 1 H), 6.08 (br s, 1 H), 5.78
(br s, 1 H), 4.20 (s, 2 H), 1.35 (s, 9 H); 13C NMR (100 MHz,
acetone-d6) δ 149.8, 149.1, 138.9, 132.6, 132.4, 129.5, 129.3, 127.5,
126.1, 125.7, 123.5, 111.8, 91.2, 86.0, 81.8, 60.8, 28.2; HRMS (TOF
ES+) m/z calcd for C23H23NO4SNa (M + Na) 432.1245, found
432.1281.
tert-Butyl Furan-2-yl(2-hydroxy-2-(phenylethynyl)octyl)-
carbamate (15c). According to general protocol A, 15c was obtained
as a yellow oil (0.225 g, 44%, SiO2, EtOAc/hexanes, 1:6): IR (neat)
3422, 2956, 2931, 2855, 1718, 1686, 1591 cm−1; 1H NMR (400 MHz,
acetone-d6) δ 7.34−7.32 (m, 5 H), 7.27 (br s, 1 H), 6.35 (s, 1 H), 6.14
(s, 1 H), 4.53 (br s, 1 H), 3.91 (s, 2 H), 1.72−1.51 (m, 4 H), 1.39 (s, 9
H), 1.29 (br s, 6 H), 0.87 (t, J = 6.0 Hz, 3 H); 13C NMR (100 MHz,
acetone-d6) δ 150.2, 139.0, 132.5, 129.2, 129.1, 124.1, 111.8, 102.9,
92.2, 85.4, 81.8, 72.1, 58.5, 40.8, 32.6, 28.3, 24.9, 23.3, 14.4; HRMS
(TOF ES+) m/z calcd for C25H33NO4Na (M + Na) 434.2307, found
434.2281.
tert-Butyl Furan-2-yl(2-hydroxy-2-phenethyl-4-phenylbut-3-
ynyl)carbamate (15d). According to general protocol A, 15d was
obtained as a yellow oil (0.310 g, 47%, SiO2, EtOAc/hexanes, 1:6): IR
(neat) 3409, 3054, 2976, 2928, 1712, 1591 cm−1; 1H NMR (400 MHz,
acetone-d6) δ 7.43−7.16 (m, 11 H), 6.37 (dd, J = 2.0, 3.2 Hz, 1 H),
6.17 (dd, J = 0.8, 3.2 Hz, 1 H), 4.78 (br s, 1 H), 4.01 (s, 2 H), 3.00−
2.85 (m, 2 H), 2.06−1.99 (m, 2 H), 1.40 (s, 9 H); 13C NMR (100
MHz, acetone-d6) δ 150.2, 143.3, 139.1, 132.6, 129.3, 129.23, 129.20,
126.6, 124.0, 111.8, 103.0, 91.8, 85.8, 81.8, 71.8, 58.3, 42.9, 31.4, 28.3;
HRMS (TOF ES+) m/z calcd for C27H29NO4Na (M + Na) 454.1994,
found 454.2024.
tert-Butyl 2-Cyclohexyl-2-hydroxyoct-3-ynyl(furan-2-yl)-
carbamate (15e). According to general protocol A, 15e was obtained
as a yellow oil (0.438 g, 49%, SiO2, EtOAc/hexanes, 1:9): IR (neat)
3422, 3285, 2931, 2855, 1694, 1590 cm−1; 1H NMR (400 MHz,
acetone-d6) δ 7.31 (dd, J = 0.8, 1.6 Hz, 1 H), 6.39 (dd, J = 2.4, 3.2 Hz,
1 H), 6.13 (dd, J = 0.8, 3.2 Hz, 1 H), 4.15 (br s, 1 H), 3.89 (d, J = 14.4
Hz, 1 H), 3.79 (d, J = 14.4 Hz, 1 H), 2.16 (app t, J = 6.8 Hz, 2 H),
2.03−2.01 (m, 1 H), 1.75−1.63 (m, 4 H), 1.49−1.44 (m, 13 H), 1.22−
1.13 (m, 6 H), 0.91 (t, J = 6.8 Hz, 3 H); 13C NMR (100 MHz,
acetone-d6) δ 150.3, 139.0, 111.9, 111.7, 102.8, 86.3, 81.8, 81.7, 74.7,
57.1, 46.4, 31.7, 28.8, 28.4, 28.3, 27.5, 27.3, 27.1, 27.0, 22.6, 18.9, 13.9;
HRMS (EI) m/z calcd for C23H35NO4Na (M + Na) 412.2464, found
412.2472.
tert-Butyl Furan-2-yl(2-hydroxy-2-phenyl-4-(trimethylsilyl)but-3-
ynyl)carbamate (15f). According to general protocol A, 15f was
obtained as a yellow oil (0.335 g, 58%, SiO2, EtOAc/hexanes, 1:6): IR
(neat) 3390, 2956, 2918, 1713, 1681 cm−1; 1H NMR (400 MHz,
acetone-d6) δ 7.66 (d, J = 7.2 Hz, 2 H), 7.34 (dd, J = 6.8, 7.2 Hz, 2 H),
7.29−7.26 (m, 2 H), 6.34 (s, 1 H), 5.96 (br s, 1 H), 5.34 (br s, 1 H),
4.00 (s, 2 H), 1.30 (s, 9 H), 0.14 (s, 9 H); 13C NMR (100 MHz,
acetone-d6) δ 149.8, 143.8, 138.7, 128.6, 128.4, 127.1, 111.7, 108.2,
102.7, 90.3, 81.7, 73.5, 60.8, 28.2, 0.09; HRMS (TOF ES+) m/z calcd
for C22H29NO4SiNa (M + Na) 422.1764, found 422.1778.
protocol A, 15g was obtained as a yellow oil (0.413 g, 60%, SiO2,
EtOAc/hexanes, 1:9): IR (neat) 3395, 2956, 2140, 1718, 1681 cm−1;
1H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 1.5 Hz, 1 H), 7.90−7.83
(m, 3 H), 7.72 (dd, J = 1.8, 8.7 Hz, 1 H), 7.52−7.49 (m, 2 H), 7.13 (br
s, 1 H), 6.26 (br s, 1 H), 5.78 (br s, 1 H), 4.09 (s, 2 H), 1.41 (s, 9 H),
0.22 (s, 9 H); 13C NMR (100 MHz, acetone-d6) δ 148.9, 140.4, 137.8,
133.1, 133.0, 128.2, 127.5, 127.4, 126.03, 125.99, 125.0, 124.6, 110.8,
107.3, 101.9, 89.8, 80.8, 72.7, 59.6, 27.2, −0.74; HRMS (TOF ES+)
m/z calcd for C26H31NO4SiNa (M + Na) 472.1920, found 472.1915.
tert-Butyl 2-(Benzofuran-2-yl)-2-hydroxy-4-(trimethylsilyl)but-3-
ynyl(furan-2-yl)carbamate (15h). According to general protocol A,
15h was obtained as a yellow oil (0.151 g, 58%, SiO2, ISCO-
Companion, 0−100% EtOAc/hexanes, 15 min gradient): IR (neat)
3377, 2969, 1718, 1681 cm−1; 1H NMR (400 MHz, acetone-d6) δ 7.59
(d, J = 7.6 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.28 (ddd, J = 1.2, 7.2,
7.2 Hz, 1 H), 7.26−7.21 (m, 1 H), 7.16 (dd, J = 0.8, 1.6 Hz, 1 H), 6.89
(d, J = 0.8 Hz, 1 H), 6.22 (br s, 1 H), 5.94 (br s, 1 H), 5.64 (br s, 1 H),
4.25 (s, 2 H), 1.27 (s, 9 H), 0.17 (s, 9 H); 13C NMR (75 MHz,
acetone-d6) δ 158.0, 156.0, 149.3, 138.7, 129.0, 125.1, 123.6, 122.0,
112.0, 111.5, 105.3, 105.2, 103.0, 90.8, 81.7, 69.6, 57.4, 28.1, −0.06;
HRMS (TOF ES+) m/z calcd for C24H29NO5SiNa (M + Na)
462.1713, found 462.1749.
tert-Butyl 2-Cyclopropyl-2-hydroxy-4-(trimethylsilyl)but-3-ynyl-
(furan-2-yl)carbamate (15i). According to general protocol A, 15i
was obtained as a yellow oil (0.139 g, 52%, SiO2, ISCO-Companion,
0−100% EtOAc/hexanes, 15 min gradient): IR (neat) 3427, 2974,
1718 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J = 1.2, 2.0 Hz 1
H), 6.33 (dd, J = 2.4, 3.6 Hz, 1 H), 6.06 (br s, 1 H), 3.96 (br s, 2 H),
1.45 (s, 9 H), 1.15−1.08 (m, 1 H), 0.71−0.66 (m, 1 H), 0.49−0.45
(m, 3 H), 0.12 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 156.1, 148.9,
137.9, 110.9, 103.6, 101.7, 89.8, 82.2, 73.4, 59.0, 28.1, 18.2, 1.58, 1.35,
−0.14; HRMS (TOF ES+) m/z calcd for C19H29NO4SiNa (M + Na)
386.1764, found 386.1757.
tert-Butyl Furan-2-yl(2-hydroxy-4-phenylbut-3-ynyl)carbamate
(15j). According to general protocol A, 15j was obtained as a yellow
oil (0.210 g, 43%, SiO2, EtOAc/hexanes, 1:6): IR (neat) 3422, 2974,
2931, 1705, 1625 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.44−7.42 (m,
2 H), 7.32−7.26 (m, 3 H), 7.22 (s, 1 H), 6.37 (s, 1 H), 6.11 (br s, 1
H), 4.86−4.83 (m, 1 H), 4.00 (dd, J = 8.0, 14.4 Hz, 1 H), 3.88 (dd, J =
3.6, 14.4 Hz, 1 H), 1.47 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ
148.2, 138.3, 134.8, 131.7, 128.4, 128.2, 122.3, 111.0, 101.8, 87.3, 82.1,
62.3, 54.8, 28.0; HRMS (EI) m/z calcd for C19H21NO4Na (M + Na)
350.13968, found 350.1361.
tert-Butyl Furan-2-yl(2-hydroxy-4-(3-methoxyphenyl)but-3-ynyl)-
carbamate (15k). According to general protocol A, 15k was obtained
as a yellow oil (0.250 g, 57%, SiO2, EtOAc/hexanes, 1:6): IR (neat)
1
3459, 2982, 1712, 1599 cm−1; H NMR (400 MHz, CDCl3) δ 7.22
(app t, J = 8.4 Hz, 2 H), 7.02 (d, J = 7.6 Hz, 1 H), 6.96 (s, 1 H), 6.89
(dd, J = 2.4, 8.4 Hz, 1 H), 6.37 (app t, J = 2.8 Hz, 1 H), 6.11 (br s, 1
H), 4.84 (dd, J = 4.0, 7.6 Hz, 1 H), 4.00 (dd, J = 8.0, 14.4 Hz, 1 H),
3.88 (dd, J = 4.0, 14.4 Hz, 1 H), 3.80 (s, 3 H), 1.47 (s, 9 H); 13C NMR
(100 MHz, acetone-d6) δ 160.5, 149.8, 139.2, 130.4, 124.8, 117.3,
115.7, 111.8, 89.8, 85.4, 81.6, 61.5, 55.7, 55.0, 28.3; HRMS (TOF ES
+) m/z calcd for C20H23NO5Na (M + Na) 380.1474, found 380.1477.
tert-Butyl Furan-2-yl(2-hydroxy-4-(p-tolyl)but-3-yn-1-yl)-
carbamate (15l). According to general protocol A, 15l was obtained
1
as a yellow oil (0.144 g, 52%, SiO2, EtOAc/hexanes, 1:15): H NMR
(400 MHz, CDCl3) δ 7.30 (d, J = 8.0 Hz, 2 H), 7.19 (dd, J = 0.8, 2.0
Hz, 1 H), 7.10 (d, J = 7.6 Hz, 2 H), 6.34 (dd, J = 2.0, 3.2 Hz, 1 H),
6.08 (br s, 1 H), 4.83−4.78 (m, 1 H), 3.97 (dd, J = 8.0, 14.4 Hz, 1 H),
3.85 (dd, J = 4.0, 14.4 Hz, 1 H), 2.34 (s, 3 H), 1.61 (br s, 1 H), 1.45 (s,
9 H); 13C NMR (125 MHz, CDCl3) δ 155.0, 148.2, 138.4, 138.2,
131.6, 128.9, 119.3, 110.9, 101.8, 86.9, 85.8, 81.9, 62.0, 54.7, 28.0, 21.3;
HRMS (TOF ES+) m/z calcd for C20H23NO4Na (M + Na) 364.1525,
found 364.1494.
tert-Butyl Furan-2-yl(2-hydroxy-4-(4-(trifluoromethyl)phenyl)but-
3-yn-1-yl)carbamate (15m). According to general protocol A, 15m
was obtained as a yellow oil (0.067 g, 26%, SiO2, EtOAc/hexanes,
1:15): 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 8.5 Hz, 2 H), 7.49
(d, J = 8.5 Hz, 2 H), 7.18 (dd, J = 1.0, 2.0 Hz, 1 H), 6.34 (dd, J = 2.0,
tert-Butyl Furan-2-yl(2-hydroxy-2-(naphthalen-2-yl)-4-
(trimethylsilyl)but-3-ynyl)carbamate (15g). According to general
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3.0 Hz, 1 H), 6.07 (br s, 1 H), 4.84 (dd, J = 4.0, 8.0 Hz, 1 H), 3.98 (dd,
J = 8.0, 14.5 Hz, 1 H), 3.89 (dd, J = 4.0, 14.5 Hz, 1 H), 1.44 (s, 9 H);
13C NMR (125 MHz, CDCl3) δ 148.2, 138.4, 132.0, 130.2 (q, J = 32.5
Hz), 126.2, 125.2 (q, J = 3.8 Hz), 123.8 (d, J = 270.5 Hz), 111.1,
101.8, 90.1, 84.4, 82.2, 62.2, 60.4, 54.6, 28.1; HRMS (TOF ES+) m/z
calcd for C20H21F3NO4 (M + H) 396.1423, found 396.1404.
tert-Butyl (4-(4-Fluorophenyl)-2-hydroxybut-3-yn-1-yl)(furan-2-
yl)carbamate (15n). According to general protocol A, 15n was
obtained as a yellow oil (0.042 g, 20%, SiO2, EtOAc/hexanes, 1:15):
1H NMR (400 MHz, CDCl3) δ 7.40−7.36 (m, 2 H), 7.19 (dd, J = 0.8,
2.0 Hz, 1 H), 7.02−6.96 (m, 2 H), 6.34 (dd, J = 2.0, 4.0 Hz, 1 H), 6.07
(br s, 1 H), 4.80 (dd, J = 4.0, 8.0 Hz, 1 H), 3.97 (dd, J = 8.0, 14.4 Hz, 1
H), 3.86 (dd, J = 4.0, 14.4 Hz, 1 H), 3.25−3.21 (m, 1 H), 1.45 (s, 9
H); 13C NMR (125 MHz, CDCl3) δ 162.6 (d, J = 248.8 Hz), 148.2,
138.4, 133.7 (d, J = 8.8 Hz), 118.4, 115.5 (d, J = 21.2 Hz), 111.0,
101.8, 87.1, 84.8, 82.2, 62.3, 54.8, 28.1; HRMS (TOF ES+) m/z calcd
for C19H20FNO4Na (M + Na) 368.1274, found 368.1258.
H); 13C NMR (100 MHz, acetone-d6) δ 148.5, 138.7, 137.3, 132.9,
131.5, 128.0, 127.2, 127.1, 126.9, 126.6, 125.8, 123.7, 120.0, 113.4,
112.4, 111.0; HRMS (TOF ES+) m/z calcd for C18H13NOSK (M +
K) 330.0355, found 330.0370.
3-Hexyl-4-phenyl-1H-indol-5-ol (16c). According to general
protocol B, 16c was obtained as a brown oil (0.054 g, 58%, SiO2,
EtOAc/hexanes, 1:6): IR (neat) 3535, 3472, 3403, 1725, 1591 cm−1;
1H NMR (400 MHz, acetone-d6) δ 9.76 (br s, 1 H), 7.44−7.32 (m, 5
H), 7.21 (d, J = 8.4 Hz, 1 H), 6.99 (d, J = 2.4 Hz, 1 H), 6.80 (d, J = 8.0
Hz, 2 H), 2.09−2.03 (m, 2 H), 1.21−1.01 (m, 6 H), 0.97−0.89 (m, 2
H), 0.81 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, acetone-d6) δ
146.4, 137.4, 131.8, 130.7, 127.1, 126.2, 125.6, 123.0, 118.8, 115.8,
111.0, 110.6, 31.1, 30.8, 26.2, 22.0, 13.1; HRMS (TOF ES+) m/z calcd
for C20H24NO (M + H) 294.1858, found 294.1841.
3-Phenethyl-4-phenyl-1H-indol-5-ol (16d). According to general
protocol B, 16d was obtained as a brown solid (0.063 g, 63%, SiO2,
EtOAc/hexanes, 1:6): mp 102−103 °C; IR (neat) 3528, 3409, 3067,
3054, 1559 cm−1; 1H NMR (400 MHz, acetone-d6) δ 9.87 (br s, 1 H),
7.49−7.40 (m, 5 H), 7.27 (d, J = 8.4 Hz, 1 H), 7.18−7.14 (m, 2 H),
7.10−7.06 (m, 2 H), 6.92 (s, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 6.83−
6.81 (m, 2 H), 2.49−2.37 (m, 4 H); 13C NMR (100 MHz, acetone-d6)
δ 147.6, 143.1, 138.6, 132.9, 131.8, 128.8, 128.5, 128.4, 127.4, 126.4,
125.9, 124.7, 119.7, 116.0, 112.1, 111.7, 38.6; HRMS (EI) m/z calcd
for C22H19NO (M+) 313.1467, found 313.1464.
tert-Butyl Furan-2-yl(2-hydroxy-7-methyloct-3-ynyl)carbamate
(15o). According to general protocol A, 15o was obtained as a yellow
oil (0.073 g, 54%, SiO2, ISCO-Companion, 0−100% EtOAc/hexanes,
1
20 min gradient): IR (neat) 3429, 2933, 2881, 1714 cm−1; H NMR
(400 MHz, acetone-d6) δ 7.29 (d, J = 1.2 Hz, 1 H), 6.38 (dd, J = 2.0,
3.2 Hz, 1 H), 6.10 (d, J = 2.8 Hz, 1 H), 4.50−4.41 (m, 2 H), 3.68 (d, J
= 6.4 Hz, 2 H), 2.19 (ddd, J = 2.0, 7.2, 7.2 Hz, 2 H), 1.67 (sept, J = 6.8
Hz, 1 H), 1.42 (s, 9 H), 1.36 (d, J = 7.2 Hz, 1 H), 1.33 (d, J = 7.2 Hz, 1
H), 0.87 (d, J = 6.4 Hz, 6 H); 13C NMR (100 MHz, acetone-d6) δ
149.9, 139.1, 111.8, 102.6, 85.9, 81.4, 80.7, 61.2, 55.5, 38.4, 28.3, 27.8,
22.5, 17.2; HRMS (TOF ES+) m/z calcd for C18H27NO4Na (M + Na)
344.1838, found 344.1830.
4-Butyl-3-cyclohexyl-1H-indol-5-ol (16e). According to general
protocol B, 16e was obtained as a brown oil (0.050 g, 36%, SiO2, 0−
1
10%, EtOAc/hexanes): IR (neat) 3395, 1681 cm−1; H NMR (400
MHz, acetone-d6) δ 9.64 (br s, 1 H), 7.26 (s, 1 H), 7.02 (d, J = 2.4 Hz,
1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 3.00−2.87
(m, 4 H), 2.07−2.04 (m, 3 H), 1.87−1.76 (m, 3 H), 1.64−1.58 (m, 2
H), 1.54−1.43 (m, 7 H), 1.00 (t, J = 6.8 Hz, 3 H); 13C NMR δ 148.1,
132.8, 126.1, 123.1, 121.5, 119.7, 112.0, 109.5, 36.9, 36.7, 34.0, 29.0,
27.9, 27.0, 26.7, 23.7, 14.3; HRMS (EI) m/z calcd for C18H25NO (M+)
271.1936, found 271.1928.
tert-Butyl 7-Chloro-2-hydroxyhept-3-ynyl(furan-2-yl)carbamate
(15p). According to general protocol A, 15p was obtained as a yellow
oil (0.089 g, 52%, SiO2, ISCO-Companion, 0−100% EtOAc/hexanes,
1
15 min gradient): IR (neat) 3440, 2969, 1705, 1617 cm−1; H NMR
(400 MHz, CDCl3) δ 7.19 (s, 1 H), 6.35 (app t, J = 2.4 Hz, 1 H), 6.05
(br s, 1 H), 4.58−4.55 (m, 1 H), 3.84 (dd, J = 8.4, 14.4 Hz, 1 H), 3.73
(dd, J = 4.4, 14.4 Hz, 1 H), 3.62 (t, J = 6.4 Hz, 2 H), 2.38 (ddd, J = 2.0,
6.8, 6.8 Hz, 2 H), 1.94 (ddd, J = 6.8, 6.8, 13.2 Hz, 2 H), 1.45 (s, 9 H);
13C NMR (100 MHz, acetone-d6) δ 149.8, 111.8, 84.2, 81.7, 81.5, 61.1,
General Protocol C. 3-Phenyl-1H-indol-5-ol (16f).15 A solution
of alcohol 15f (0.057 g, 0.14 mmol) in o-DCB (1.0 mL) was subjected
to microwave irradiation at 180 °C for 30 min. The reaction mixture
was cooled to 0 °C and treated with dry methanolic HCl (2%, 0.2
mL). After 5 min, the solution was concentrated, and the crude residue
was purified by chromatography on SiO2 (ISCO-Rf, 0−100%, EtOAc/
hexanes; 12 min gradient) to give indole 16f (0.019 g, 63%) as a light
brown oil: IR (neat) 3385, 1687 cm−1; 1H NMR (300 MHz, acetone-
d6) δ 10.26 (br s, 1 H), 7.76 (s, 1 H), 7.67 (dd, J = 1.2, 8.4 Hz, 2 H),
7.55 (d, J = 2.7 Hz, 1 H), 7.42 (app t, J = 7.8 Hz, 2 H), 7.38 (d, J = 2.4
Hz, 1 H), 7.32 (d, J = 8.7 Hz, 1 H), 7.25−7.19 (m, 1 H), 6.79 (dd, J =
2.4, 8.7 Hz, 1 H); 13C NMR (75 MHz, acetone-d6) δ 152.2, 137.2,
132.7, 129.2, 127.2, 126.9, 125.7, 123.9, 116.8, 112.8, 112.5, 103.9;
HRMS (TOF ES+) m/z calcd for C14H12NO (M + H) 210.0919,
found 210.0925.
55.3, 44.5, 32.3, 28.3, 16.6; HRMS (TOF ES+) m/z calcd for
C16H22ClNO4Na (M + Na) 350.1135, found 350.1100.
tert-Butyl 4-Cyclohexenyl-2-hydroxybut-3-ynyl(furan-2-yl)-
carbamate (15q). According to general protocol A, 15q was obtained
as a yellow oil (0.313 g, 38%, SiO2, EtOAc/hexanes, 1:6): IR (neat)
1
3435, 2982, 1705, 1612 cm−1; H NMR (400 MHz, CDCl3) δ 7.16
(dd, J = 0.8, 2.0 Hz, 1 H), 6.32 (dd, J = 2.4, 3.2 Hz, 1 H), 6.08−6.05
(m, 2 H), 4.69−4.65 (m, 1 H), 3.87 (dd, J = 8.0, 14.4 Hz, 1 H), 3.73
(dd, J = 8.0, 14.4 Hz, 1 H), 2.07−2.04 (m, 4 H), 1.62−1.52 (m, 4 H),
1.43 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 148.2, 138.3, 135.6,
119.9, 110.9, 101.7, 84.6, 81.9, 62.1, 54.8, 28.9, 28.0, 25.5, 22.1, 21.4;
HRMS (TOF ES+) m/z calcd for C19H25NO4Na (M + Na) 354.1681,
found 354.1674.
3-(Naphthalen-2-yl)-1H-indol-5-ol (16g). According to general
protocol C, 16g was obtained as a brown oil (0.028 g, 60%, SiO2, flash
system, 0−100%, EtOAc/hexanes; 15 min gradient): IR (neat) 3390,
1699 cm−1; 1H NMR (300 MHz, acetone-d6) δ 10.27 (br s, 1 H), 8.12
(s, 1 H), 7.88 (d, J = 8.7 Hz, 2 H), 7.84−7.79 (m, 2 H), 7.72 (s, 1 H),
7.64 (d, J = 2.7 Hz, 1 H), 7.47−7.44 (m, 2 H), 7.41−7.35 (m, 2 H),
7.30 (d, J = 8.7 Hz, 1 H), 6.77 (dd, J = 2.4, 8.7 Hz, 1 H); 13C NMR
(75 MHz, acetone-d6) δ 152.4, 134.9, 134.8, 132.8, 132.4, 128.7, 128.2,
127.1, 126.7, 126.6, 125.5, 124.7, 124.4, 116.6, 112.9, 112.6, 104.2;
HRMS (TOF ES+) m/z calcd for C18H13NO (M+) 259.0997, found
259.0970.
3-(Benzofuran-2-yl)-1H-indol-5-ol (16h). According to general
protocol C, 16h was obtained as a light orange solid (0.022 g, 63%,
SiO2, ISCO-Rf, 0−100%, EtOAc/hexanes; 15 min gradient): mp 169−
172 °C; IR (neat) 3364, 3295, 1629 cm−1; 1H NMR (300 MHz,
acetone-d6) δ 10.55 (br s, 1 H), 7.94 (s, 1 H), 7.88 (d, J = 3.0 Hz, 1
H), 7.62−7.53 (m, 1 H), 7.52−7.50 (m, 2 H), 7.38 (d, J = 8.7 Hz, 1
H), 7.25−7.21 (m, 2 H), 6.95 (d, J = 1.0 Hz, 1 H), 6.86 (dd, J = 2.4,
8.7 Hz, 1 H); 13C NMR (75 MHz, acetone-d6) δ 154.6, 154.3, 152.8,
132.3, 130.7, 126.0, 125.1, 123.4, 123.3, 120.5, 113.1, 110.8, 107.2,
General Protocol B. 3,4-Diphenyl-1H-indol-5-ol (16a). A
solution of alcohol 15a (0.087 g, 0.21 mmol) in o-DCB (2.1 mL)
was subjected to microwave irradiation at 220 °C for 60 min. The
crude solution was purified by chromatography on SiO2 (0−20%,
EtOAc/hexanes) to give indole 16a (0.046 g, 74%) as a light brown
1
solid: mp 184−185 °C; IR (neat) 3504, 3403, 3054, 1599 cm−1; H
NMR (400 MHz, acetone-d6) δ 10.32 (br s, 1 H), 7.37 (d, J = 8.8 H, 1
H), 7.28 (d, J = 2.8 Hz, 1 H), 7.12−7.10 (m, 2 H), 7.08 (s, 1 H),
7.03−6.99 (m, 3 H), 6.96−6.82 (m, 6 H); 13C NMR (100 MHz,
acetone-d6) δ 148.0, 137.2, 132.9, 131.5, 129.5, 127.7, 127.4, 126.5,
125.6, 125.3, 124.9, 119.5, 119.0, 112.9, 112.0; HRMS (TOF APCI+)
m/z calcd for C20H16NO 286.1232 (M + H), found 286.1226.
4-Phenyl-3-(thiophene-2-yl)-1H-indol-5-ol (16b). According to
general protocol B, 16b was obtained as a brown solid (0.057 g,
61%, SiO2, EtOAc/hexanes, 1:6): mp 166−167 °C; IR (neat) 3528,
3390, 3067, 1574 cm−1; 1H NMR (400 MHz, acetone-d6) δ 10.42 (br
s, 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 7.36 (s, 1 H), 7.19−7.16 (m, 2 H),
7.13−7.09 (m, 4 H), 7.01 (dd, J = 1.2, 5.2 Hz, 1 H), 6.95 (d, J = 8.8
Hz, 1 H), 6.55 (dd, J = 3.6, 5.2 Hz, 1 H), 6.04 (dd, J = 1.2, 3.6 Hz, 1
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104.7, 98.6; HRMS (TOF ES+) m/z calcd for C16H11NO2 (M+)
249.0790, found 249.0783.
H), 7.23 (app t, J = 2.0 Hz, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 6.73 (d, J =
8.4 Hz, 1 H), 6.41 (br s, 1 H), 2.90 (t, J = 8.0 Hz, 2 H), 1.77 (sept, J =
6.8 Hz, 1 H), 1.59−1.53 (m, 2 H), 0.99 (d, J = 6.4 Hz, 6 H); 13C NMR
(75 MHz, acetone-d6) δ 148.0, 132.0, 129.7, 125.3, 118.9, 112.5, 109.5,
100.3, 39.7, 28.9, 25.5, 22.9; HRMS (TOF ES−) m/z calcd for
C13H16NO (M-H) 202.1232, found 202.1229.
4-(3-Chloropropyl)-1H-indol-5-ol (16p). According to general
protocol D, 16p was obtained as a brown oil (0.007 g, 20%, SiO2,
flash system, 0−100%, EtOAc/hexanes; 15 min gradient): IR (neat)
3409, 2934, 1705 cm−1; 1H NMR (400 MHz, acetone-d6) δ 9.99 (br s,
1 H), 7.50 (s, 1 H), 7.26 (app t, J = 2.8 Hz, 1 H), 7.12 (d, J = 8.4 Hz, 1
H), 6.75 (d, J = 8.4 Hz, 1 H), 6.47 (app s, 1 H), 3.66 (t, J = 6.8 Hz, 2
H), 3.04 (t, J = 7.6 Hz, 2 H), 2.15 (pent, J = 7.2 Hz, 2 H); 13C NMR
(75 MHz, acetone-d6) δ 148.3, 131.9, 129.9, 125.6, 116.9, 112.4, 110.1,
100.2, 45.7, 33.7, 24.9; HRMS (TOF ES+) m/z calcd for C11H13NOCl
(M + H) 210.0686, found 210.0657.
4-Cyclohexenyl-1H-indol-5-ol (16q). According to general protocol
B, 16q was obtained as a brown oil (0.021 g, 23%, SiO2, EtOAc/
hexanes, 1:6): IR (neat) 3403, 2931, 1705, 1612 cm−1; 1H NMR (400
MHz, acetone-d6) δ 9.94 (br s, 1 H), 7.19 (t, J = 2.8 Hz, 1 H), 7.12
(dd, J = 0.8, 8.8 Hz, 1 H), 6.84 (s, 1 H), 6.70 (d, J = 8.8 Hz, 1 H),
6.30−6.29 (m, 1 H), 5.76−5.76 (m, 1 H), 2.41−2.37 (m, 2 H), 2.24−
2.20 (m, 2 H), 1.82−1.78 (m, 4 H); 13C NMR (100 MHz, acetone-d6)
δ 147.1, 135.9, 132.1, 128.9, 127.6, 125.6, 121.3, 112.6, 110.9, 101.5,
26.3, 23.9, 23.2; HRMS (TOF ES+) m/z calcd for C14H15NO (M+)
213.1154, found 213.1171.
3-Cyclopropyl-1H-indol-5-ol (16i). According to general protocol
C, 16i was obtained as a light yellow oil (0.018 g, 47%, SiO2, flash
system, 0−100%, EtOAc/hexanes; 15 min gradient): IR (neat) 3435,
3364, 1581 cm−1; 1H NMR (400 MHz, acetone-d6) δ 9.56 (br s, 1 H),
7.50 (s, 1 H), 7.10 (d, J = 8.4 Hz, 1 H), 7.00 (d, J = 2.4 Hz, 1 H), 6.89
(d, J = 1.6 Hz, 1 H), 6.63 (dd, J = 2.0, 8.4 Hz, 1 H), 1.83−1.76 (m, 1
H), 0.78−0.74 (m, 2 H), 0.52−0.50 (m, 2 H); 13C NMR (100 MHz,
acetone-d6) δ 151.1, 132.3, 129.7, 122.2, 117.6, 112.2, 112.0, 103.4, 6.6,
6.0; HRMS (TOF ES+) m/z calcd for C11H12NO (M + H) 174.0919,
found 174.0913.
General Protocol D. 4-Phenyl-1H-indol-5-ol (16j). A solution of
alcohol 15j (0.052 g, 0.16 mmol) in 1,2-dichloroethane (1.0 mL) was
subjected to microwave irradiation at 180 °C for 30 min. The crude
solution was concentrated and purified by chromatography on SiO2
(flash system, 0−100% EtOAc/hexanes, 15 min gradient) to give 16j
as a light brown oil (0.016 g, 48%): IR (neat) 3535, 3409, 3045, 2918,
1
1580 cm−1; H NMR (400 MHz, acetone-d6) δ 9.95 (br s, 1 H), 7.48
(d, J = 7.6 Hz, 2 H), 7.31 (app t, J = 7.6 Hz, 2 H), 7.20−7.15 (m, 2 H),
7.13−7.11 (m, 2 H), 6.73 (d, J = 8.8 Hz, 1 H), 6.14 (br s, 1 H); 13C
NMR (100 MHz, acetone-d6) δ 145.9, 135.6, 130.9, 129.9, 129.3,
127.8, 127.7, 125.1, 117.8, 111.9, 111.3, 101.6; HRMS (TOF APCI+)
m/z calcd for C14H12NO (M + H) 210.0919, found 210.0895.
4-(3-Methoxyphenyl)-1H-indol-5-ol (16k). According to general
protocol D, 16k was obtained as a light brown oil (0.015 g, 42%, SiO2,
flash system, 0−100%, EtOAc/hexanes; 15 min gradient): IR (neat)
3528, 3403, 2924, 1712, 1580 cm−1; 1H NMR (400 MHz, acetone-d6)
δ 10.11 (br s, 1 H), 7.37 (t, J = 8.4 Hz, 1 H), 7.30−7.26 (m, 3 H),
7.20−7.18 (m, 2 H), 6.90 (dd, J = 2.4, 8.0 Hz, 1 H), 6.87 (d, J = 8.8
Hz, 1 H), 6.30 (app t, J = 2.4 Hz, 1 H), 3.85 (s, 3 H); 13C NMR (100
MHz, acetone-d6) δ 160.5, 147.7, 140.1, 132.3, 129.8, 129.4, 126.3,
123.6, 118.8, 116.8, 113.2, 112.9, 112.0, 101.6, 55.5; HRMS (TOF ES
+) m/z calcd for C15H13NO2 (M+) 239.0946, found 239.0940.
4-(p-Tolyl)-1H-indol-5-ol (16l). According to general protocol D,
16l was obtained as a light brown solid (0.011 g, 47%, SiO2, EtOAc/
hexanes, 1:8): mp 112−114 °C; IR (neat) 3523, 3409, 3021, 2917
cm−1; 1H NMR (500 MHz, CDCl3) δ 8.11 (br s, 1 H), 7.47 (d, J = 8.5
Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.27 (dd, J = 0.5, 8.5 Hz, 1 H),
7.17 (app t, J = 3.0 Hz, 1 H), 6.94 (d, J = 9.0 Hz, 1 H), 6.32 (ddd, J =
1.0, 2.0, 3.0 Hz, 1 H), 5.00 (br s, 1 H), 2.45 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 146.0, 137.4, 132.5, 130.9, 130.0, 129.8, 127.9, 125.0,
117.8, 111.9, 111.1, 101.7, 21.3; HRMS (TOF ES+) m/z calcd for
C15H14NO (M + H) 224.1075, found 224.1074.
4-(4-(Trifluoromethyl)phenyl)-1H-indol-5-ol (16m). According to
general protocol D, 16m was obtained as a light brown solid (0.013 g,
64%, SiO2, EtOAc/hexanes, 1:8): mp 140−142 °C; IR (neat) 3491,
2922 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.17 (br s, 1 H), 7.79 (d, J
= 8.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.32 (dd, J = 0.5, 8.5 Hz, 1
H), 7.21 (app t, J = 3.0 Hz, 1 H), 6.92 (d, J = 9.0 Hz, 1 H), 6.31 (ddd,
J = 1.0, 2.5, 3.0 Hz, 1 H), 4.76 (br s, 1 H); 13C NMR (125 MHz,
CDCl3) δ 145.9, 139.9, 131.0, 130.4, 129.5 (q, J = 32.2 Hz), 127.7,
126.0 (q, J = 3.6 Hz), 125.5, 124.2 (q, J = 270.1 Hz), 116.7, 112.3,
112.0, 101.4; HRMS (TOF ES+) m/z calcd for C15H11NOF3 (M + H)
278.0793, found 278.0794.
3,7,8,9-Tetrahydropyrano[3,2-e]indole (18).17 A solution of
phenol 16p (0.023 g, 0.11 mmol) in THF (1.5 mL) was treated
with NaH (0.008 g, 0.20 mmol, 60% dispersion) followed by TBAI
(0.045 g, 0.19 mmol) at room temperature. After 30 min, the solution
was diluted with brine and extracted with diethyl ether. The organic
layers were dried (Na2SO4), filtered, and concentrated. The crude
residue was purified by chromatography on SiO2 (ISCO-Rf, 0−100%
EtOAc/hexanes, 15 min gradient) to give pyran 18 (0.010 g, 53%) as a
1
light yellow semisolid: IR (neat) 3428, 2934, 1493 cm−1; H NMR
(400 MHz, acetone-d6) δ 9.91 (br s, 1 H), 7.11 (app t, J = 2.8 Hz, 1
H), 6.99 (d, J = 8.8 Hz, 1 H), 6.43 (d, J = 8.8 Hz, 1 H), 6.21 (br s, 1
H), 3.99 (t, J = 5.2 Hz, 2 H), 2.76 (t, J = 6.8 Hz, 2 H), 2.72−2.68 (m, 2
H); 13C NMR (75 MHz, acetone-d6) δ 148.9, 131.4, 128.7, 125.3,
112.9, 112.2, 110.4, 99.7, 66.4, 23.1, 22.5; HRMS (TOF ES+) m/z
calcd for C11H12NO (M + H) 174.0919, found 174.0895.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
1
Copies of H NMR spectra for 14e,i,k−q and copies of H
NMR and 13C NMR spectra for all other compounds, except
the commercial compounds 14a and 14b. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pwipf@pitt.edu.
4-(4-Fluorophenyl)-1H-indol-5-ol (16n). According to general
protocol D, 16n was obtained as a brown solid (0.006 g, 44%, SiO2,
EtOAc/hexanes, 1:8): mp 145−148 °C; IR (neat) 3491, 3409, 2919
cm−1; 1H NMR (500 MHz, CDCl3) δ 8.13 (br s, 1 H), 7.57−7.53 (m,
2 H), 7.29 (dd, J = 1.0, 9.0 Hz, 1 H), 7.25−7.21 (m, 2 H), 7.18 (app t,
J = 3.0 Hz, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 6.28 (ddd, J = 1.0, 2.0, 3.0
Hz, 1 H), 4.80 (br s, 1 H); 13C NMR (125 MHz, CDCl3) δ 162.3 (d, J
= 245.0 Hz), 146.0, 131.8 (d, J = 7.5 Hz), 131.5 (d, J = 2.5 Hz), 130.9,
128.0, 125.2, 116.9, 116.2 (d, J = 24.2 Hz), 112.1, 111.4, 101.5; HRMS
(TOF ES+) m/z calcd for C14H11NOF (M + H) 228.0825, found
228.0827.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NIH/NIGMS CMLD
program (GM067082). We thank Dr. Nilesh Zaware
(University of Pittsburgh) for preliminary studies on the
synthesis of 16a.
4-Isopentyl-1H-indol-5-ol (16o). According to general protocol D,
16o was obtained as a brown oil (0.005 g, 15%, SiO2, ISCO-Rf, 0−
100%, EtOAc/hexanes; 15 min gradient): IR (neat) 3405, 2974, 1686
DEDICATION
■
1
cm−1; H NMR (400 MHz, acetone-d6) δ 9.92 (br s, 1 H), 7.31 (s, 1
Dedicated to the memory of Professor Robert E. Ireland.
173
dx.doi.org/10.1021/jo3022605 | J. Org. Chem. 2013, 78, 167−174

The Journal of Organic Chemistry
Article
(28) Belot, S.; Vogt, K. A.; Besnard, C.; Krause, N.; Alexakis, A.
Angew. Chem., Int. Ed. 2009, 48, 8923−8926.
REFERENCES
■
(1) (a) Ertl, P.; Jelfs, S.; Muhlbacher, J.; Schuffenhauer, A.; Selzer, P.
̈
(29) Wadsworth, D. H.; Geer, S. M.; Detty, M. R. J. Org. Chem. 1987,
52, 3662−3668.
J. Med. Chem. 2006, 49, 4568−4573. (b) Taber, D. F.; Tirunahari, P.
K. Tetrahedron 2011, 67, 7195−7210.
(2) (a) Riendeau, D.; Aspiotis, R.; Ethier, D.; Gareau, Y.; Grimm, E.
(30) C., M.; Randell-Sly, H. E.; Woodward, R. L.; Currie, G. S. Org.
Lett. 2005, 7, 2249−2251.
(31) Hauptmann, H.; Mader, M. Synthesis 1978, 307−309.
́
L.; Guay, J.; Guiral, S.; Juteau, H.; Mancini, J. A.; Methot, N.; Rubin, J.;
Friesen, R. W. Bioorg. Med. Chem. Lett. 2005, 15, 3352−3355. (b) Im,
G.-Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H.-Y.;
Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010, 132, 17933−17944.
(3) (a) Allen, G. R. Org. React. 1973, 20, 337−454. (b) Humphrey,
G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875−2911. (c) Velezheva,
V. S.; Sokolov, A. I.; Kornienko, A. G.; Lyssenko, K. A.; Nelyubina, Y.
V.; Godovikov, I. A.; Peregudov, A. S.; Mironov, A. F. Tetrahedron Lett.
2008, 49, 7106−7109.
(4) Stoffman, E. J. L.; Clive, D. L. J. Org. Biomol. Chem. 2009, 7,
4862−4870 and references cited therein.
(5) Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Per
Garcia-Martin, M. A.; Gonzal
5812.
́
ez, M.;
́
ez, J. M. J. Org. Chem. 1996, 61, 5804−
(6) (a) Petronijevic, F.; Timmons, C.; Cuzzupe, A.; Wipf, P. Chem.
Commun. 2009, 104−106. (b) Petronijevic, F. R.; Wipf, P. J. Am.
Chem. Soc. 2011, 133, 7704−7707.
(7) For pioneering applications of IMDAF cycloadditions to indoline
and natural product synthesis, see: (a) Li, G.; Padwa, A. Org. Lett.
2011, 13, 3767−3769. (b) Boonsompat, J.; Padwa, A. J. Org. Chem.
2011, 76, 2753−2761. (c) Padwa, A.; Brodney, M. A.; Liu, B.; Satake,
K.; Wu, T. J. Org. Chem. 1999, 64, 3595−3607.
(8) For thermal cleavage of Boc-groups, see: (a) Wasserman, H. H.;
Berger, G. D.; Cho, K. R. Tetrahedron Lett. 1982, 23, 465−468.
(b) Rawal, V. H.; Cava, M. P. Tetrahedron Lett. 1985, 26, 6141−6142.
(c) Wipf, P.; Furegati, M. Org. Lett. 2006, 8, 1901−1904.
(9) Ahman, J.; Somfai, P. Synth. Commun. 1994, 24, 1117−1120.
(10) Padwa, A.; Brodney, M. A.; Lynch, S. M. Org. Synth. 2002, 78,
202−204.
(11) Wang, B.; Bonin, M.; Micouin, L. J. Org. Chem. 2005, 70, 6126−
6128.
(12) Nielsen, T. E.; Cubillo de Dios, M. A.; Tanner, D. J. Org. Chem.
2002, 67, 7309−7313.
(13) For the preparation of TMS-substituted ynones, see: Morisaki,
Y.; Luu, T.; Tykwinski, R. R. Org. Lett. 2006, 8, 689−692.
(14) (a) Eastham, S. A.; Ingham, S. P.; Hallett, M. R.; Herbert, J.;
Modi, A.; Morley, T.; Painter, J. E.; Patel, P.; Quayle, P.; Ricketts, D.
C.; Raftery, J. Tetrahedron 2008, 64, 936−948. (b) Wu, H.-I.; Yen, C.-
H.; Chuang, C.-T. Tetrahedron Lett. 1996, 37, 7395−7398.
(15) Satomura, M. J. Org. Chem. 1993, 58, 3757−3760.
(16) For synthesis of ynal substrates, see: Frimpong, K.; Wzorek, J.;
Lawlor, C.; Spencer, K.; Mitzel, T. J. Org. Chem. 2009, 74, 5861−5870.
(17) (a) Macor, J. E.; Ryan, K.; Newman, M. E. Tetrahedron 1992,
48, 1039−1052. (b) Macor, J. E.; Blank, D. H.; Post, R. J. Tetrahedron
Lett. 1994, 35, 45−48.
(18) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214−
3217.
(19) Jackson, M. M.; Leverett, C.; Toczko, J. F.; Roberts, J. C. J. Org.
Chem. 2002, 67, 5032−5035.
(20) Chen, J.-Y.; Lin, T.-C.; Chen, S.-C.; Chen, A.-J.; Mou, C.-Y.;
Tsai, F.-Y. Tetrahedron 2009, 65, 10134−10141.
(21) Morisaki, Y.; Luu, T.; Tykwinski, R. R. Org. Lett. 2006, 8, 689−
692.
(22) Friscourt, F.; Boons, G.-J. Org. Lett. 2010, 12, 4936−4939.
(23) Santra, S.; Ranjan, P.; Bera, P.; Ghosh, P.; Mandal, S. K. RSC
Adv. 2012, 2, 7523−7533.
(24) Wipf, P.; Weiner, W. S. J. Org. Chem. 1999, 64, 5321−5324.
(25) Frimpong, K.; Wzorek, J.; Lawlor, C.; Spencer, K.; Mitzel, T. J.
Org. Chem. 2009, 74, 5861−5870.
(26) Park, S. P.; Ahn, S.-H.; Lee, K.-J. Tetrahedron 2010, 66, 3490−
3498.
(27) Wei, W.; Hamamoto, Y.; Ukaji, Y.; Inomata, K. Tetrahedron:
Asymmetry 2008, 19, 476−481.
174
dx.doi.org/10.1021/jo3022605 | J. Org. Chem. 2013, 78, 167−174