One-pot total synthesis: The first total synthesis of chiral alkaloid pimprinol A and the facile construction of its natural congeners from amino acids

Article abstract of DOI:10.1016/j.tet.2014.08.022

In this work, we accomplished the first total synthesis of chiral alkaloid pimprinol A and the facile construction of its natural congeners: pimprinine, pimprinethine, pimprinaphine, WS-30581A, WS-30581B, laboradorin 1, uguenenazole, balsoxine, texamine in one-pot from commercially available starting materials including amino acids. Further investigating into the mechanism revealed that this improved transformation was achieved by the integration of iodination, Kornblum oxidation, condensation, decarboxylation, annulation, and oxidation reaction sequence.

Full text of DOI:10.1016/j.tet.2014.08.022

Tetrahedron 70 (2014) 7470e7475
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot total synthesis: the first total synthesis of chiral alkaloid
pimprinol A and the facile construction of its natural congeners
from amino acids
*
Jiachen Xiang, Jungang Wang, Miao Wang, Xianggao Meng, Anxin Wu
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 May 2014
Received in revised form 27 July 2014
Accepted 8 August 2014
Available online 15 August 2014
In this work, we accomplished the first total synthesis of chiral alkaloid pimprinol A and the facile
construction of its natural congeners: pimprinine, pimprinethine, pimprinaphine, WS-30581A, WS-
30581B, laboradorin 1, uguenenazole, balsoxine, texamine in one-pot from commercially available
starting materials including amino acids. Further investigating into the mechanism revealed that this
improved transformation was achieved by the integration of iodination, Kornblum oxidation, conden-
sation, decarboxylation, annulation, and oxidation reaction sequence.
Keywords:
One-pot total synthesis
Amino acid
Ó 2014 Elsevier Ltd. All rights reserved.
Iodination
Kornblum oxidation
5-(3-Indolyl)oxazole alkaloid
1. Introduction
During the last century, much research has concentrated on the
isolation, biological activities, and synthesis of 5-(3-indolyl)oxa-
zoles alkaloids (Scheme 1) due to their biological and pharmaceu-
tical significance.1 For example, pimprinine demonstrated good
monoamine oxidase (MAO) inhibition, an antiepileptic effect, and
promising anti-parkinsonian-like activity in mice.1 The known
synthesis of these alkaloids requires multi-steps to build up the
oxazole core.2e7 Kumar and co-workers described a five-step-
synthetic route to form pimprinine and analogues in about 42%
overall yield.3 In addition, Horne and co-workers reported a three-
step protocol for the construction of pimprinethine, WS-30581A,
and WS-30581B, the overall yield was up to 70%.4 Most recently,
a group of new siblings of 5-(3-indolyl)oxazole family each con-
taining a hydroxyl group on their side chains, named pimprinols
AeC, have been isolated from Streptomyces sp. Lv3-13. As yet, re-
ports have not been provided on the synthesis of pimprinol A.
Development of expeditious and efficient protocols with fewer
synthetic steps and inexpensive commercial starting materials still
highly valuable for the synthesis of the 5-(3-indolyl)oxazole alka-
loid family.
Scheme 1. Naturally occurring 5-(3-indolyl)oxazoles.
Amino acids are readily available and versatile organic building
blocks ubiquitously masked in a broad range of natural products.8
Employing amino acids as substrates to transform into natural
products, which contain amino acid moieties promise higher effi-
ciency in organic synthesis and hold value in inherently biomimetic
significance yet still a hot topic in the total synthesis field.9 We are
pleased to recognize that side chains in the 5-(3-indolyl)oxazole
alkaloids family were shown to accurately correspond to accessible
amino acids. For example, the side chain of pimprinol A contains
a two-carbon unit, a hydroxy group and more specifically, a chiral
center. This fragment is identical with the side chain of L-threonine.
Therefore, using amino acids as potential reagent becomes a selec-
tion priority. In 2013, Nachtsheim and co-workers developed
a general synthetic method of oxazole containing compounds from
amino acids using iodine and triple equivalents of strong oxidant
Oxone.10 In such transformation, Oxone played an essential role in
the catalytic cycle and limited the scope of the substrates due to
* Corresponding author. Tel./fax: þ86 (0)27 6786 7773; e-mail address: chwuax@
mail.ccnu.edu.cn (A. Wu).
http://dx.doi.org/10.1016/j.tet.2014.08.022
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

J. Xiang et al. / Tetrahedron 70 (2014) 7470e7475
7471
some side effects brought by this strong oxidant. Firstly, threonine,
which branched sensitive hydroxyl groups could not afford the
desired products pimprinol A (3g) with efficiency since the hy-
droxyl groups were easily to be oxidized to carbonyl group under
the existence of Oxone.11 Secondly, the author only used multi-
substituted phenyl or naphthyl methyl ketones as substrates,
however,1H-indole rings may be poor tolerant in this harsh oxidant
condition.12 Thirdly, the author claimed clearly that phenylalanine
can’t afford the desired product, which means pimprinethine (3e)
could not be obtained in this condition. Furthermore, the author
didn’t give results of using glycine as substrate and when using
alanine as substrate the yield turned out poor (20% yield), which
determined that pimprinine (3a) could not be installed in high
yield. In fact, most of natural products including 5-(3-indolyl)oxa-
zoles alkaloids contain sensitive groups, protecting group-free
synthesis and relatively mild reaction need to be established. In-
spired by Nachtsheim’s outstanding work and based on our re-
search interests in one-pot total synthesis,14e,f we herein detailed
an improved method of using chemical equivalent iodine instead of
Oxone to milden the reaction condition and successfully achieve
the first accomplishment of oxidant sensitive chiral alkaloid pim-
prinol A and its natural congeners directly in one-pot (Scheme 2).
Scheme 3. Retrosynthetic analysis and the forward process for one-pot synthesis of
pimprinol A.
With the optimal conditions in hand, the improved method
was applied to the synthesis of 5-(3-indolyl)oxazoles in one-pot
(Table 2). Including pimprinol A (3g), both the natural products
and unnatural analogues with different side chains were obtained
in moderate to good yields except 3o. Specifically, the functional
group tolerability of hydroxyl groups (3g and 3k) and active
methylene groups like 3e and 3l is acceptable. Those kinds of
2-arylmethylene oxazoles were failed to construct in the reported
literature, which were attributed to the unavoidable side reaction
Scheme 2. Our synthesis of oxazole alkaloids from amino acid.
2. Results and discussion
The retrosynthetic analysis as applied to pimprinol A is depicted
in Scheme 3a. According to extensive literature research including
our original work,13,14 the unstable intermediates 2-(1H-indol-3-
yl)-2-oxoacetaldehyde (1ab) was chosen as a common precursor.
The oxazole ring, which presents as a core fragment in the desired
product can be obtained from oxazoline I via an iodine-mediated
oxidation.15 Furthermore, I is generated smoothly through an an-
nulation reaction of II, which is a decarboxylation product by in-
termediate III.16 III can be produced by condensation of common
Table 1
Optimization of the reaction conditionsa
precursor 1ab and L-threonine, in a word, reaction sequence 2 was
determinated. Furthermore, the iodination/Kornblum oxidation
reaction sequence to afford 1ab from 1-(1H-indol-3-yl)ethanone
(1) can be seen as reaction sequence 1. The forward synthetic
process is described in Scheme 3b and we envision the integration
of reaction sequences 1 and 2 is possible to be executed in one-pot.
In order to optimize the reaction, 1-(1H-indol-3-yl)ethanone (1)
Entry
1a
2
3
4
I2 (equiv)
Additive (equiv)
Temp (ꢀC)
Time (h)
Yieldd (%)
1.5
0.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
3.0
2.0
d
100
95
100
100
100
80
100
110
120
110
110
110
1
2
1
1
1
1
1
1
1
1
1
2
0
49
44
0
0
0
68
66
62
70
66
65
Oxone (3.0)
K2S2O8 (1.0)
H2O2 (3.0)
TBHP (3.0)
d
d
d
d
d
d
d
and -threonine (2g) were selected as model reagents. As the cat-
L
5
alyst iodine and the oxidant DMSO were indispensable in the re-
action, 1, 2g, I2, and DMSO were added together and heated at
100 ꢀC. Unfortunately, the desired 5-(3-indolyl)oxazole products
were not observed. Then some extra oxidants were used as addi-
tives (Table 1, entries 2e5), the reaction did proceed in the presence
of Oxone or K2S2O8, but the efficiency was unsatisfactory as we
predicted (entries 2 and 3, yields 49% and 44%). We were pleased to
find that using one-pot two-stage method could enhance the yield
significantly at the temperatures higher that 100 ꢀC (entries 7e9). I2
(2 equiv) was optimal (entry 10) and shown to provide the best
outcome in pimprinol A. However, an extended reaction time was
shown to be slightly detrimental to the yield.
6b
7
8
9
10
11
12c
a
Reaction conditions (entries 1e5): 1 (0.5 mmol), 2g (1.0 mmol), I2, DMSO
(3.0 mL).
b
Reaction conditions (entries 6e11): 1 (0.5 mmol), I2, DMSO (3.0 mL), heat for
45 min, then add 2g (1.0 mmol), heat at the same temperature for 15 min.
c
Add 2g (1.0 mmol), heat at the same temperature for 30 min.
Isolated yields.
d

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J. Xiang et al. / Tetrahedron 70 (2014) 7470e7475
Table 2
Table 3
Synthesis of natural 5-(3-indolyl)oxazoles and their unnatural analoguesa
A further application of this method using some simpler aryl methyl ketones as
substratesa
Some simpler aryl methyl ketones as substrates were further
scanned (Table 3). Three natural 2,5-diaryloxazole alkaloids:
uguenenazole (5b),20 balsoxine (5c),21 texamine (5d),22 were ob-
tained smoothly in high yields via this one-pot variation. To the best
of our knowledge, those alkaloids have been constructed using at
most seven linear-step sequence by others.23
According to our retrosynthetic analysis, the key intermediate in
our reaction is the common precursor aromatic
(1ab) rather than -hydroxylated aromatic ketone, so the mecha-
nism is somehow different from the reported in the literature.10
a-keto aldehyde
a
A
possible reaction pathway was determined (Scheme 4) based on
the control experiments (see Supplementary data) and previous
reports.14e16 The
a-iodo ketone 1aa was initially obtained by the
iodination of 1. Then, 1aa was oxidized by DMSO via a classic
Kornblum oxidation to provide 1ab and its hydrated hemiacetal
form 1ac (not shown here). Following the addition of substrate 2,
intermediate 1ad was formed through condensation. After the
condensation, there may be two possible reaction pathways, which
both make sense.16b In pathway A, after ketoeenol tautomerization,
decarboxylation reaction occurred. Then annulation product 1af
was formed through the attack of the hydroxyl group of 1ae. Sub-
sequently, 3 could be afforded by iodine-mediated oxidation re-
action. In the pathway B, annulation reactions happened at the first
place to form 1af0, then desired product 3 was obtained through
iodine-mediated decarboxylation and oxidation reactions. But after
of amino acids homocondensation.10 Moreover, the bis-indole
product 3l could be constructed directly, providing potential sig-
nificance for synthesis research and bioactive study.17 5-(1H-Indol-
3-yl)oxazole (3n) has also been obtained from glycine, which
means this transformation can be applied as an alternative method
to access to 5-aryloxazoles.18 We can see clearly that using chemical
equivalent of iodine instead of strong oxidant Oxone the functional
group tolerability of the reaction enhanced. So this improved
method with relatively mild condition featured powerful in the
synthesis of this kind of alkaloids and achieved reasonable im-
provement. Unfortunately, cysteine cannot afford the desired
product smoothly since the active thiol group disturbs the reaction
approach (3o). The structure of pimprinol A (3g) and pimprinethine
(3b) was further determined by X-ray crystal single diffraction
analysis,19 3g as an example was shown in Fig. 1.
imine formation, the proton at the a-position of amino acid should
be more acidic. The arrow showing the enol formation would be
hard to reach. So we think pathway A is more optimistic. The
construction of compounds 5 underwent an identical mechanism.
Fig. 1. Crystal structure of pimprinol A (3g).
Scheme 4. Probable reaction pathways.

J. Xiang et al. / Tetrahedron 70 (2014) 7470e7475
7473
3. Conclusion
13C NMR (100 MHz, DMSO-d6)
d
(ppm) 158.32, 147.40, 136.39,
123.55, 122.92, 122.13, 120.05, 119.49, 119.23, 112.07, 103.93, 13.60.
HRMS (ESI): m/z [MþH]þ calcd for C12H11N2O: 199.0866; found:
199.0865.
In conclusion, we described a synthesis of 5-(3-indolyl)oxazoles
alkaloids from amino acids in one-pot. Such approach is inherently
biomimetic and holds significant promise in the field of natural
product total synthesis. We have accomplished the first total syn-
thesis of chiral alkaloid pimprinol A and applied to the facile syn-
thesis of pimprinine, pimprinethine, pimprinaphine, WS-30581A,
WS-30581B, laboradorin 1, uguenenazole, balsoxine, texamine,
4.3.2. 2-Ethyl-5-(1H-indol-3-yl)oxazole (3b pimprinethine). Yield
82%; yellow solid; mp¼154e155 ꢀC; IR (KBr): 3453, 3132, 2928,
2885, 1652, 1622, 1455, 1376, 1244, 1122, 1000 cmꢁ1 1H NMR
.
(600 MHz, CDCl3)
d
(ppm) 8.88 (s, 1H), 7.81 (d, J¼7.8 Hz, 1H), 7.48 (d,
directly. In the reaction process, the common precursor aromatic
a
-
J¼2.4 Hz, 1H), 7.39 (d, J¼7.8 Hz, 1H), 7.26e7.19 (m, 2H), 7.14 (s, 1H),
keto aldehydes, which were generated by iodination/Kornblum
oxidation sequence from aromatic ketones, were trapped in situ by
amino acids via condensation/decarboxylation/annulation/oxida-
tion reaction sequence to eventually approach to natural products.
Further exploration of the substrate scope is currently underway in
our laboratory.
2.85 (q, 2H), 1.39 (t, J¼7.8 Hz, 3H). 13C NMR (100 MHz, DMSO-d6)
d
(ppm) 163.69,147.30,136.27,124.09, 122.88,121.65,120.73,119.90,
119.60, 111.55, 105.81, 21.70, 11.31. HRMS (ESI): m/z [MþH]þ calcd
for C13H13N2O: 213.1022; found: 213.1021.
4.3.3. 5-(1H-Indol-3-yl)-2-propyloxazole (3c WS-30581A). Yield
75%; yellow solid; mp¼131e133 ꢀC; IR (KBr): 3169, 2930, 2873,
1617, 1577, 1450, 1252, 1121, 1002 cmꢁ1. 1H NMR (600 MHz, CDCl3)
4. Experimental
4.1. General
d
(ppm) 8.79 (s, 1H), 7.84 (d, J¼7.8 Hz, 1H), 7.51 (d, J¼1.8 Hz, 1H),
7.43 (d, J¼7.8 Hz, 1H), 7.28e7.23 (m, 2H), 7.16 (s, 1H), 2.83
(t, J¼7.2 Hz, 2H), 1.88 (m, 2H), 1.05 (t, J¼7.2 Hz, 3H). 13C NMR
All substrates and reagents were commercially available and
used without further purification. TLC analysis was performed
using pre-coated glass plates. Column chromatography was per-
formed using silica gel (200e300 mesh). IR spectra were recorded
on a PerkineElmer PE-983 infrared spectrometer as KBr pellets
with absorption in cmꢁ1. 1H NMR spectra were recorded in CDCl3 or
(100 MHz, DMSO-d6) d (ppm) 162.75, 147.30, 136.27, 124.06, 122.82,
121.67, 120.69, 119.86, 119.51, 111.55, 105.73, 30.08, 20.60, 13.72.
HRMS (ESI): m/z [MþH]þ calcd for C14H15N2O: 227.1179; found:
227.1179.
4.3.4. 2-Butyl-5-(1H-indol-3-yl)oxazole (3d WS-30581B). Yield
77%; light yellow solid; mp¼125e126 ꢀC; IR (KBr): 3099, 2950,
2926, 2868, 1632, 1612, 1571, 1452, 1239, 1122, 1098, 1009 cmꢁ1. 1H
DMSO-d6 on 400/600 MHz NMR spectrometer and resonances (d)
are given in parts per million (ppm) relative to tetramethylsilane.
Data are reported as follows: chemical shift, multiplicity
(s¼singlet, d¼doublet, t¼triplet, m¼multiplet q¼quadruple),
coupling constants (Hz), and integration. 13C NMR spectra were
recorded in CDCl3 or DMSO-d6 on 100/150 MHz NMR
NMR (600 MHz, CDCl3)
d
(ppm) 9.06 (s, 1H), 7.83 (d, J¼7.8 Hz, 1H),
7.49 (d, J¼2.4 Hz, 1H), 7.40 (d, J¼7.8 Hz, 1H), 7.24 (m, 2H), 7.15
(s, 1H), 2.84 (t, J¼7.8 Hz, 2H), 1.81 (m, 2H), 1.44 (m, 2H), 0.95
(t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d (ppm) 162.96, 147.40,
spectrometer and resonances (
d
) are given in parts per million
136.34, 124.09, 122.83, 121.79, 120.70, 119.87, 119.40, 111.62, 105.66,
(ppm). HRMS were obtained on a Bruker 7-Tesla FT-ICR MS
equipped with an electrospray source. The X-ray crystal-structure
determinations of 3b and 3g were obtained on a Bruker SMART
APEX CCD system. Melting points were determined using XT-4
apparatus and not corrected. Enantiomeric ratios were de-
termined by chiral HPLC with different chiral columns (Chiralpak
OD column) with hexane and i-PrOH as solvents. Optical rotation
was measured with polarimeter: Atopol IV (an average value of
three times parallel tests).
29.24, 27.90, 22.27, 13.72. HRMS (ESI): m/z [MþH]þ calcd for
C15H17N2O: 241.1335; found: 241.1334.
4.3.5. 2-Benzyl-5-(1H-indol-3-yl)oxazole (3e pimprinaphine). Yield
51%; light red solid; mp¼202e203 ꢀC; IR (KBr): 3737, 2935, 1719,
1647, 1560, 1454, 1111, 1006 cmꢁ1 1H NMR (600 MHz, DMSO-d6)
.
d
(ppm) 11.56 (s, 1H), 7.82 (d, J¼7.8 Hz, 1H), 7.73 (d, J¼2.4 Hz, 1H),
7.46 (d, J¼8.4 Hz, 1H), 7.36e7.34 (m, 3H), 7.21 (m, 5H), 4.20 (s, 2H).
13C NMR (100 MHz, DMSO-d6)
(ppm) 160.07, 147.89, 136.41,
d
136.32, 128.81, 128.66, 126.86, 123.60, 123.18, 122.18, 120.13, 119.50,
4.2. General procedure for synthesis of 3 and 5 (3b as an
example)
119.39, 112.13, 103.80, 33.82. HRMS (ESI): m/z [MþH]þ calcd for
C
18H15N2O: 275.1179; found: 275.1178.
A
mixture of 1-(1H-indol-3-yl)ethanone
1
(0.5 mmol), I2
4.3.6. 5-(1H-Indol-3-yl)-2-isobutyloxazole (3f laboradorin 1). Yield
76%; yellow solid; mp¼147e148 ꢀC; IR (KBr): 2962, 1615, 1581,
(1.0 mmol) in DMSO (3.0 mL) was stirred at 110 ꢀC for 45 min till
almost full conversion of the substrates was indicated by TLC
analysis, then added 2-aminobutanoic acid 2b (1.0 mmol) and
stirred at 110 ꢀC for 15 min. Then added 50 mL water and 30 mL
saturated brine solution to the mixture and extracted with EtOAc
three times (3ꢂ50 mL). The extract was washed with 10% Na2S2O3
solution, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (eluent: petroleum ether/EtOAc¼4:1)
to afford the product 3b as a yellow solid.
1456, 1352, 1250, 1166, 1127 cmꢁ1 1H NMR (600 MHz, CDCl3)
.
d
(ppm) 9.15 (s, 1H), 7.84 (d, J¼7.7 Hz, 1H), 7.51 (s, 1H), 7.42
(d, J¼7.9 Hz, 1H), 7.25 (m, 7.1 Hz, 2H), 7.17 (s, 1H), 2.73
(d, J¼7.2 Hz, 2H), 2.26e2.20 (m, 1H), 1.03 (d, J¼6.6 Hz, 6H). 13C
NMR (100 MHz, CDCl3)
d (ppm) 162.26, 147.42, 136.27, 124.03,
122.81, 121.75, 120.68, 119.81, 119.29, 111.58, 105.61, 37.05, 27.63,
22.34. HRMS (ESI): m/z [MþH]þ calcd for C15H17N2O: 241.1335;
found: 241.1334.
4.3.7. (R)-1-(5-(1H-Indol-3-yl)oxazol-2-yl)ethanol (3g pimprinol
4.3. Characterization data
A). Yield 70%; light brown solid; [
a
]
þ5.67 (c 0.1, MeOH) (an av-
D
erage value of three times parallel tests). Mp¼151e152 ꢀC
(according to the report pimprinol A exists as yellow oil in small
amounts, but we find that when we added n-hexane as solvent it
turned into light brown solid); IR (KBr): 3348, 3267, 2988, 2927,
1637, 1577, 1458, 1442, 1258, 1084 cmꢁ1. 1H NMR (600 MHz, CD3OD)
4.3.1. 5-(1H-Indol-3-yl)-2-methyloxazole (3a pimprinine). Yield
80%; light yellow solid; mp¼203e204 ꢀC; IR (KBr): 3133, 3116,
2929, 2898, 1637, 1585, 1453, 1364, 1350, 1123, 1024 cmꢁ1. 1H NMR
(600 MHz, CDCl3)
(s, 1H), 7.43 (d, J¼7.8 Hz, 1H), 7.26 (m, 2H), 7.15 (s, 1H), 2.54 (s, 3H).
d
(ppm) 8.61 (s, 1H), 7.84 (d, J¼7.8 Hz, 1H), 7.51
d
(ppm) 7.82 (d, J¼7.8 Hz, 1H), 7.65 (s, 1H), 7.44 (d, J¼7.8 Hz, 1H),

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J. Xiang et al. / Tetrahedron 70 (2014) 7470e7475
7.21e7.14 (m, 3H), 4.96 (m, 1H), 1.63 (d, J¼6.0 Hz, 3H). 13C NMR
108.74, 103.84, 24.38. HRMS (ESI): m/z [MþH]þ calcd for
(150 MHz, CD3OD)
d
(ppm) 165.02, 150.42, 138.13, 125.31, 124.02,
C20H16N3O: 314.1293; found: 314.1289.
123.45, 121.39, 120.48, 119.13, 112.80, 105.31, 64.18, 21.49. 1H NMR
(600 MHz, DMSO-d6)
d
(ppm) 11.57 (s, 1H), 7.87 (d, J¼7.8 Hz, 1H),
4.3.13. 5-(1H-Indol-3-yl)-2-phenyloxazole (3m). Yield 74%; white
solid; mp¼226e228 ꢀC; IR (KBr): 3171, 3081, 2934, 2893,1637,1613,
7.77 (s, 1H), 7.47 (d, J¼7.8 Hz, 1H), 7.34 (s, 1H), 7.20 (t, J¼7.2 Hz, 1H),
7.15 (t, J¼7.2 Hz, 1H), 5.72 (d, J¼5.4 Hz, 1H), 4.92e4.68 (m, 1H), 1.51
1547, 1483, 1450, 1369, 1256, 1163, 1163, 1008 cmꢁ1 1H NMR
.
(d, J¼6.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6)
d
163.52, 147.51,
(600 MHz, DMSO-d6) d (ppm) 11.72 (s, 1H), 8.11 (s, 1H), 8.10 (s, 1H),
136.36, 123.63, 123.21, 122.13, 120.08, 119.54, 118.87, 112.08, 103.83,
62.05, 21.44. HRMS (ESI): m/z [MþH]þ calcd for C13 H13N2O2:
229.0970; found: 229.0972. HPLC (Chiralpak OD column, hexane/2-
propanol¼90:10, 1.0 mL/min, 254 nm, 25 ꢀC, t1¼6.48 min,
t2¼10.25 min).
7.99 (s, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.57e7.48 (m, 4H), 7.24 (d,
J¼7.8 Hz, 1H), 7.21 (d, J¼7.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d
(ppm) 158.10, 148.33, 136.48, 130.03, 129.16, 127.27, 125.57, 123.92,
123.57, 122.30, 120.86, 120.36, 119.60, 112.23, 103.69. HRMS (ESI):
m/z [MþH]þ calcd for C17H13N2O: 261.1022; found: 261.1021.
4.3.8. 5-(1H-Indol-3-yl)-2-isopropyloxazole (3h). Yield 75%; yellow
solid; mp¼125e126 ꢀC; IR (KBr): 3171, 2975, 2927, 1636, 1616, 1570,
4.3.14. 5-(1H-Indol-3-yl)oxazole (3n). Yield 70%; light yellow solid;
mp¼156e157 ꢀC; IR (KBr): 3174, 2986, 2930, 1632, 1576, 1526, 1449,
1352, 1297, 1244, 1164, 1110, 1090, 1010 cmꢁ1. 1H NMR (600 MHz,
1449,1256,1123,1106 cmꢁ1. 1H NMR (600 MHz, CDCl3)
d (ppm) 9.01
(s, 1H), 7.85 (d, J¼7.8 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J¼7.8 Hz, 1H),
DMSO-d6)
d
(ppm) 11.61 (s, 1H), 8.35 (s, 1H), 7.87 (d, J¼7.8 Hz, 1H),
7.29e7.22 (m, 2H), 7.16 (s, 1H), 3.21e3.16 (m, 1H), 1.44 (d, J¼7.0 Hz,
7.82 (s, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 7.21 (d, J¼7.2 Hz, 1H), 7.16 (d,
6H). 13C NMR (100 MHz, CDCl3)
d
(ppm) 166.93, 147.17, 136.26,
J¼7.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d (ppm) 149.61, 147.69,
124.13, 122.86, 121.66, 120.73, 119.91, 119.34, 111.53, 105.75, 28.43,
20.54. HRMS (ESI): m/z [MþH]þ calcd for C14H15N2O: 227.1179;
found: 227.1177.
136.24, 123.53, 123.38, 122.21, 120.20, 119.43, 118.71, 112.09, 103.60.
HRMS (ESI): m/z [MþH]þ calcd for C11H9N2O: 185.0709; found:
185.0710.
4.3.9. 2-(sec-Butyl)-5-(1H-indol-3-yl)oxazole (3i). Yield 71%; light
yellow solid; mp¼144e145 ꢀC; IR (KBr): 3172, 3118, 2966, 2931,
1637, 1616, 1569, 1450, 1350, 1247, 1106, 1070, 1001 cmꢁ1. 1H NMR
4.3.15. 2-Ethyl-5-phenyloxazole (5a). Yield 95%; yellow oil; IR
(KBr): 3443, 3060, 2981, 2940, 2880, 1558, 1488, 1449, 1376, 1290,
1262, 1188, 1133, 1069, 1049 cmꢁ1 1H NMR (600 MHz, CDCl3)
.
(600 MHz, CDCl3)
d
(ppm) 9.05 (s, 1H), 7.81 (d, J¼7.2 Hz, 1H), 7.51
d
(ppm) 7.61 (d, J¼6.0 Hz, 2H), 7.39 (s, 2H), 7.29 (s, 1H), 7.21 (s, 1H),
(s, 1H), 7.42 (d, J¼8.4 Hz, 1H), 7.24 (m, 2H), 7.15 (s, 1H), 3.01 (dd,
J¼13.8, 7.2 Hz, 1H), 1.89 (dd, J¼14.1, 6.6 Hz, 1H), 1.73 (dd, J¼13.9,
7.8 Hz, 1H), 1.40 (d, J¼7.2 Hz, 3H), 0.96 (t, J¼7.2 Hz, 3H). 13C NMR
2.85 (d, J¼5.4 Hz, 2H), 1.39 (t, J¼5.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) d (ppm) 165.30, 150.75, 128.72, 128.06, 123.84, 121.61, 77.32,
77.01, 76.84, 21.70, 11.11. HRMS (APCI): m/z [MþH]þ calcd for
(100 MHz, CDCl3)
d
(ppm) 166.37, 147.32, 136.27, 124.07, 122.89,
C11H12NO: 174.0914; found: 174.0913.
121.81, 120.78, 119.84, 118.79, 111.59, 105.57, 35.23, 28.26, 17.99,
11.63. HRMS (ESI): m/z [MþH]þ calcd for C15H17N2O: 241.1335;
found: 241.1334.
4.3.16. 5-(4-Methoxyphenyl)-2-phenyloxazole (5b uguenenazole).-
Yield 88%; white solid; mp¼78e79 ꢀC. IR (KBr): 3057, 2969, 2840,
1656, 1607, 1498, 1252, 1173, 1021 cmꢁ1. 1H NMR (600 MHz, CDCl3)
4.3.10. 5-(1H-Indol-3-yl)-2-(2-(methylthio)ethyl)oxazole (3j). Yield
78%; yellow solid; mp¼149e150 ꢀC; IR (KBr): 3169, 3136, 2933,
1637, 1615, 1572, 1454, 1434, 1264, 1274, 1111, 1010 cmꢁ1. 1H NMR
d
(ppm) 8.09 (d, J¼7.2 Hz, 2H), 7.64 (d, J¼8.4 Hz, 2H), 7.50e7.41 (m,
3H), 7.32 (s, 1H), 6.96 (d, J¼8.4 Hz, 2H), 3.84 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d (ppm) 160.48, 159.76, 151.26, 130.08, 128.74,
(600 MHz, CDCl3)
d
(ppm) 8.82 (s, 1H), 7.83 (d, J¼7.8 Hz, 1H), 7.51 (d,
127.47, 126.09, 125.69, 121.83, 120.79, 114.34, 55.31. HRMS (APCI):
J¼2.4 Hz, 1H), 7.43 (d, J¼8.4 Hz, 1H), 7.29e7.22 (m, 2H), 7.18 (s, 1H),
m/z [MþH]þ calcd for C16H14NO2: 252.1019; found: 252.1021.
3.16 (t, J¼7.8 Hz, 2H), 2.98 (t, J¼7.8 Hz, 2H), 2.15 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d
(ppm) 160.68, 147.72, 136.22, 123.99, 122.88,
4.3.17. 5-(3,4-Dimethoxyphenyl)-2-phenyloxazole
(5c
balsox-
121.84, 120.76, 119.79, 119.64, 111.57, 105.48, 31.27, 28.52, 15.44.
HRMS (ESI): m/z [MþH]þ calcd for C14H15N2OS: 259.0900; found:
259.0898.
ine). Yield 87%; white solid; mp¼95e97 ꢀC. IR (KBr): 3079, 3000,
2955, 2929, 2831, 2055, 1827, 1638, 1545, 1508, 1455, 1350, 1281,
1285, 1228, 1138, 1007, 1027 cmꢁ1 1H NMR (600 MHz, CDCl3)
.
d
(ppm) 8.10 (d, J¼7.2 Hz, 2H), 7.47 (m, 3H), 7.34 (d, J¼2.4 Hz, 1H),
7.30 (d, J¼8.4 Hz,1H), 7.19 (s, 1H), 6.93 (d, J¼8.4 Hz, 1H), 3.98 (s, 3H),
3.92 (s, 3H). 13C NMR (100 MHz, CDCl3)
(ppm) 160.55, 151.22,
4.3.11. (5-(1H-Indol-3-yl)oxazol-2-yl)methanol (3k). Yield 73%;
yellow solid; mp¼189e190 ꢀC; IR (KBr): 3440, 1637, 1427, 1386,
d
1115, 1079 cmꢁ1
.
1H NMR (600 MHz, DMSO-d6)
d
(ppm) 11.55 (s,
149.37, 149.25, 130.12, 128.73, 127.41, 126.11, 122.14, 120.96, 117.19,
111.39, 107.33, 55.95. MS (EI): m/z (%)14¼282.25 (19), 281.24 (100),
266.20 (26), 238.25 (11), 107.17 (9).
1H), 7.85 (d, J¼8.4 Hz, 1H), 7.75 (d, J¼2.4 Hz, 1H), 7.45 (d, J¼7.8 Hz,
1H), 7.35 (s, 1H), 7.19 (t, J¼7.2 Hz, 1H), 7.13 (t, J¼7.2 Hz, 1H), 5.66
(t, J¼6.6 Hz, 1H), 4.53 (d, J¼6.0 Hz, 2H). 13C NMR (100 MHz, DMSO-
d6)
d
(ppm) 160.92, 147.97, 136.42, 123.64, 123.32, 122.22, 120.17,
4.3.18. 5-(Benzo[d][1,3]dioxol-5-yl)-2-phenyloxazole
(5d
tex-
119.58, 119.16, 103.82, 56.03. HRMS (ESI): m/z [MþH]þ calcd for
amine). Yield 82%; light yellow solid; mp¼135e137 ꢀC. IR (KBr):
C
12H11N2O2: 215.0815; found: 215.0813.
3063, 2916, 1602, 1547, 1493, 1328, 1240, 1104, 1036 cmꢁ1. 1H NMR
(600 MHz, CDCl3)
3H), 7.30 (s, 1H), 7.23 (d, J¼7.8 Hz, 1H), 7.16 (s, 1H), 6.87 (d, J¼8.4 Hz,
1H), 6.00 (s, 2H). 13C NMR (100 MHz, CDCl3)
(ppm) 160.56, 151.09,
d
(ppm) 8.08 (d, J¼6.6 Hz, 2H), 7.45 (m, J¼7.8 Hz,
4.3.12. 2,5-Di(1H-indol-3-yl)oxazole (3l). Yield 59%; yellow solid;
mp¼199e200 ꢀC; IR (KBr): 3391, 3184, 2923, 1836, 1699, 1654, 1627,
d
1447, 1113 cmꢁ1. 1H NMR (600 MHz, DMSO-d6)
d
(ppm) 11.50 (s,1H),
148.16, 147.85, 130.18, 128.76, 127.37, 126.13, 122.27, 122.15, 118.31,
10.99 (s, 1H), 7.78 (d, J¼6.0 Hz, 1H), 7.67 (d, J¼2.4 Hz, 1H), 7.62
(d, J¼6.6 Hz, 1H), 7.44 (d, J¼5.4 Hz, 1H), 7.39e7.35 (m, 1H), 7.34
(s, 1H), 7.30 (d, J¼2.4 Hz, 1H), 7.17 (t, J¼5.4 Hz, 1H), 7.09 (t, J¼6.6 Hz,
2H), 7.01 (t, J¼6.6 Hz, 1H), 4.27 (s, 2H). 13C NMR (100 MHz, DMSO-
108.81, 104.78, 101.36. HRMS (APCI): m/z [MþH]þ calcd for
C16H12NO3: 266.0812; found: 266.0814.
4.3.19. 1-(1H-Indol-3-yl)-2-iodoethanone (1aa). Yield 99%; light
pink solid; mp¼207e208 ꢀC; IR (KBr): 3218, 1699, 1635, 1520, 1436,
d6)
d (ppm) 160.67, 147.38, 136.28, 136.22, 126.88, 123.64, 123.48,
122.89, 122.03, 121.14, 119.95, 119.46, 119.16, 118.54, 111.99, 111.47,
1315, 1240, 1129, 1092, 1107 cmꢁ1 1H NMR (600 MHz, DMSO-d6)
.

J. Xiang et al. / Tetrahedron 70 (2014) 7470e7475
7. He, W. M.; Li, C. Q.; Zhang, L. M. J. Am. Chem. Soc. 2011, 133, 8482e8485.
7475
d
(ppm) 12.12 (s, 1H), 8.49 (d, J¼3.0 Hz, 1H), 8.13 (d, J¼7.2 Hz, 1H),
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d (ppm) 188.32, 136.75, 135.10, 125.47, 123.09,
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122.0, 121.25, 112.83, 112.22, 6.06. MS: m/z¼285.11.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (Grants 21272085, 21032001) for financial support. We
would also like to thank Dr. Chuanqi Zhou, Hebei University, for
analytical support.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.08.022.
References and notes
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