Microwave-assisted synthesis of 3-substituted indoles via intramolecular arene-alkene coupling of o-iodoanilino enamines

Article abstract of DOI:10.1016/j.tet.2013.06.101

A generally applicable and high-yielding protocol for the synthesis of 3-substituted indole derivatives is described. Key features include microwave-assisted intramolecular arene-alkene coupling of o-iodoanilino enamines, and expedient synthesis of o-iodo

Full text of DOI:10.1016/j.tet.2013.06.101

Tetrahedron 69 (2013) 7211e7219
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Microwave-assisted synthesis of 3-substituted indoles via
intramolecular areneealkene coupling of o-iodoanilino enamines
,
Won-Il Lee a, Jong-Wha Jung b, Jaehoon Sim a, Hongchan An a, Young-Ger Suh a
*
a College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
b College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 701-702, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A generally applicable and high-yielding protocol for the synthesis of 3-substituted indole derivatives is
described. Key features include microwave-assisted intramolecular areneealkene coupling of o-iodoa-
nilino enamines, and expedient synthesis of o-iodoanilino enamine substrates employing N,O-acetal TMS
ethers, which could be conveniently derived from the corresponding amides. Our unique procedure
seems quite efficient and provides an easy access to a variety of 3-substituted indoles as privileged
structure for a wide range of biological targets.
Received 23 April 2013
Received in revised form 24 June 2013
Accepted 27 June 2013
Available online 4 July 2013
Keywords:
Indole
Ó 2013 Elsevier Ltd. All rights reserved.
Areneealkene coupling
Microwave
Enamine
N,O-Acetal TMS ether
1. Introduction
almotriptan,19 are 5-hydroxytryptamine 1B/1D receptor agonists,
which belong to this category. 3-Substituted indoles were also
Indole is one of the most prevalent scaffolds in natural products,
pharmaceuticals, and agrochemicals.1 Many bioorganic materials,
such as serotonin and melatonin contain indole moiety. The indole
scaffold is an important privileged structure2 in medicinal chem-
istry and their derivatives are observed in a large spectrum of drugs
or drug candidates.3 In particular, 3-substituted indoles are found
in a wide range of synthetic and natural products, which possess
diverse biological activities (Fig. 1). Among those, the 3-aryl indoles
are found in, such as progesterone receptor antagonists for uterine
fibroids,4 protein tyrosine phosphatase 1B inhibitors for type 2
diabetes,5 antidepressants including binedaline,6 sigma 2 receptor
ligands as the antipsychotic drugs,7 and PPAR alpha agonists.8 In
addition, the 3-acyl indoles are also found in platelet-activating
utilized for the syntheses of many natural products and the phar-
macologically important substances.20
factor receptor (PAFR) antagonists for septic shock,9 steroid 5
a-
reductase inhibitors for benign prostatic hyperplasia,10 5-HT3 an-
tagonists,11 and tachykinin NK1 antagonists as the antimigraine
agents.12 Tropisetron13 and ramosetron hydrochloride14 were
launched as a 5-HT3 antagonist for the chemotherapy-induced
emesis. The 3-alkyl indoles are found in tachykinin NK1 antago-
nists as bronchodilator,15 dopamine autoreceptor agonists,16 and 5-
HT1A receptor agonists.17 The launched drugs, eletriptan18 and
Fig. 1. Examples of bioactive 3-substituted indoles.
There have been numerous synthetic methods for indole syn-
thesis.21 In particular, a large number of synthetic methods for the
3-substituted indoles have been reported possibly due to the rel-
atively feasible 2-substitution of indoles. The 3-substituted indole
* Corresponding author. Tel.: þ82 2 880 7875; fax: þ82 2 888 0649; e-mail
address: ygsuh@snu.ac.kr (Y.-G. Suh).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.101

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W.-I. Lee et al. / Tetrahedron 69 (2013) 7211e7219
derivatives were synthesized by a variety of synthetic methods22
and many advances were achieved by Pd-catalyzed trans-
formation for the essential tolerability of functional groups. In these
aspects, the intramolecular Heck or Heck-type reactions involving
cyclization of o-haloanilino allylamine/double bond isomeriza-
tion,23 aminopalladation/reductive elimination domino reaction,24
and Pd-catalyzed cyclization of o-haloanilino enamines25e27 have
been developed. The cyclization methods through intramolecular
Heck or Heck-type reactions mainly utilize o-haloanilino allyl-
amines except for a few examples. In contrast, the protocols in-
volving o-haloanilino enamines were mostly limited to the
enamines possessing electron-withdrawing groups, such as car-
bonyl, sulfonyl, nitrile, and nitro (Fig. 2, Eq. 1). Thus the intra-
molecular areneealkene coupling reaction, which is usefully
applicable to diverse enamine substrates (Fig. 2, Eq. 2), is yet to be
explored for the synthesis of a wide range of the 3-substituted in-
doles, to the best of our knowledge. We herein report a microwave-
assisted synthetic method for the 3-substituted indoles via intra-
molecular areneealkene coupling reaction of the enamines pos-
sessing both electron withdrawing and donating groups.
conventional amidations, efficient preparation of the enamine
precursors from N,O-acetal TMS ether by our strategy was antici-
pated. It is noteworthy that a large number of bioactive natural
products consist of characteristic enamine moiety.31
Microwave irradiation is known to be beneficial for the intra-
molecular Heck reaction due to the direct and uniform input of
energy into the reaction mixture.32 Thus, we explored the
microwave-assisted areneealkene coupling reaction for indole
synthesis based on the transformation of N-aryl b-nitroenamines
into 3-nitroindoles.27b
We commenced our work by the preparation of o-iodoanilino
enamines from the corresponding amides (Scheme 1). The carba-
mate 1 underwent conventional amidation to give the amides 2a,b.
Next, the amides 2a,b were reduced with DIBAL-H, and the resulting
N,O-acetals were subsequently trapped with TMSOTf in situ to afford
the N,O-acetal TMS ethers 3a,b. Finally, the N,O-acetal TMS ethers
€
3a,b were treated with BF3$OEt2 in the presence of Hunig base to
afford the corresponding (E)-enamines 4a,b successfully. The ge-
ometryof alkenewas determined based on the coupling constants of
1H NMR spectra. Encouraged by the successful transformation of
N,O-acetal TMS ethers into the desired o-iodoanilino enamines, we
turned our attention to the optimization of the microwave-assisted
intramolecular areneealkene coupling reaction.
Fig. 2. Synthesis of 3-substituted indoles via intramolecular areneealkene coupling of
enamines.
2. Result and discussion
Scheme 1. Reagents and conditions: (a) LHMDS, propionyl chloride for 2a or phe-
nylacetyl chloride for 2b, THF, ꢀ78 ꢁC to ꢀ5 ꢁC, 93% for 2a, 83% for 2b; (b) DIBAL-H,
pyridine, TMSOTf, CH2Cl2, ꢀ78 ꢁC to ꢀ40 ꢁC; (c) BF3$OEt2, DIPEA, CH2Cl2, ꢀ5 ꢁC to
rt, 65% for 4a, 75% for 4b (two steps).
Enamines are frequently employed as an excellent substrate for
the annulation reactions.28 Thus, versatile and efficient synthetic
method for enamines is importantly utilized in the indole synthesis
via intramolecular areneealkene coupling reaction. Inspired by the
synthesis of N-vinyl-2-oxazolidinone via N,O-acetal,29 we envi-
sioned that N,O-acetal TMS ether (III) could be a suitable precursor
for anilino enamine (II) (Fig. 3). Recently we reported the prepa-
ration of N,O-acetal TMS ether (III) from the corresponding amide
(IV).30 Taking advantage of easy access to a variety of amides using
After extensive examination of the cyclization conditions of the
o-iodoanilino enamine 4a under microwave irradiation (Table 1),
Pd(OAc)2 and PPh3 (entry 8) were turned out to be the best com-
bination. In addition, Jeffrey’s condition33 dramatically increased
the chemical yield (entry 9). It is noteworthy that Pd(PPh3)4 was not
effective at all (entry 12) for the desired cyclization, which well
supported that the combination of Pd(OAc)2 and PPh3 is more ef-
fective than Pd(PPh3)4 for the generation of active zerovalent Pd
catalyst in Heck-type reaction.34 We also examined the synthesis of
the 3-phenylindole. The yield for the enamine 4b under the same
cyclization conditions (entry 14) significantly decreased. However,
chemical yield was recovered by the use of potassium acetate
(entry 18) although the role of the acetate ion in the cyclization
reaction is not understood clearly.34 Cyclization for indole-3-
carboxylate, which was attempted under the same conditions,
suffered from the unexpected deprotection of carbamate (entry 19).
Fortunately, carbamate protection with a bulkier protective group,
such as Boc suppressed the undesirable side reaction (entry 20).
The chemical yield of the cyclization under the conditions without
microwave irradiation (entry 21) was quite lower compared to that
of the microwave-assisted conditions in spite of the prolonged re-
action time (12 h vs 1.5 h). The reaction mainly resulted in
remaining of the substrate.
Fig. 3. Synthetic strategy for 3-substituted indoles.

W.-I. Lee et al. / Tetrahedron 69 (2013) 7211e7219
7213
Table 1
Optimization of areneealkene coupling reactiona
Entry
R1
R2
Catalyst
Ligand
Base
Additive
Et4NCl
Solvent
Temperature (ꢁC)
Yieldb (%)
1
2
3
4
5
6
7
8
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Boc
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
CO2Me
CO2Me
Me
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2dba3
Et3N
DMF
DMF
1,4-Dioxane
DMF
NMP
DMA
DMF
CH3CN
CH3CN
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
100
85
d
DABCO
Cs2CO3
Cs2CO3
Cy2NMe
KOAc
NaOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4,
NaOtBu
KOAc
d
X-Phos
125
125
100
100
150
80
80
80
80
80
80
80
80
80
80
80
80
80
d
X-Phos
d
tBu3PHBF4
DavePhos
d
Pd2dba3
Et4NCl
AgOAc
d
PdCl2(dppf)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
d
PPh3
PPh3
PPh3
P(o-tol)3
<10
85
23
d
9
Et4NCl
Et4NCl
Et4NCl
Et4NCl
Et4NCl
Et4NCl
Et4NCl
Et4NCl
Et4NCl
Et4NCl
Et4NCl
Et4NCl
10
11
12
14
15
16
17
18
19
20
21d
d
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
15
<10
26
d
91
15c
95
<30
KOAc
KOAc
KOAc
Boc
a
Reactions were conducted with 4 (1.0 equiv), Pd catalyst (20 mol %), phosphine ligand (40 mol %), base (3.0 equiv), and additive (2.0 equiv) in solvent at given temperature
for 1.5 h under microwave irradiation.
b
Isolated yield.
See text.
c
d
The reaction was conducted under the conventional heating conditions and the starting material remained after 12 h. X-Phos¼2-dicyclohexylphosphino-20,40,60-triiso-
propylbiphenyl, dba¼dibenzylideneacetone, dppf¼1,10-bis(diphenylphosphino)ferrocene, DavePhos¼2-dicyclohexylphosphino-20-(N,N-dimethylamino)biphenyl, o-tol¼o-
tolyl.
Having successfully optimized the reaction conditions, we ex-
amined the scope of the established protocol. The electronic and
steric effects as well as the functional diversity of the substituents
at the 3-position of indole were investigated. As shown in Scheme
2, the Boc-protected o-iodoanilines were acylated to provide the
amides 6aeg. The amides 6aeg were reduced with DIBAL-H, fol-
lowed by in situ silylation to afford the N,O-acetal TMS ethers 7aeg,
which were finally subjected to the elimination conditions to pro-
vide the o-iodoanilino enamines 8aeg.
propiolate in the presence of catalytic amount of DABCO35
(Scheme 3).
Scheme 3. Reagents and conditions: (a) LHMDS, acetyl chloride for 6h, propionyl
chloride for 6i, phenylacetyl chloride for 6j, THF, ꢀ78 ꢁC to ꢀ5 ꢁC, 95% for 6h, 98% for
6i, 80% for 6j; (b) DIBAL-H, pyridine, TMSOTf, CH2Cl2, ꢀ78 ꢁC to ꢀ40 ꢁC; (c) BF3$OEt2,
DIPEA, CH2Cl2, ꢀ5 ꢁC to rt, 62% for 8h, 75% for 8i, 73% for 8j (two steps); (d) DABCO,
methyl propiolate, CH2Cl2, 0 ꢁC to rt, 98%.
Scheme 2. Reagents and conditions: (a) LHMDS, propionyl chloride, THF, ꢀ78 ꢁC to
ꢀ5 ꢁC, 85e93%; (b) DIBAL-H, pyridine, TMSOTf, CH2Cl2, ꢀ78 ꢁC to ꢀ40 ꢁC; (c) BF3$OEt2,
DIPEA, CH2Cl2, ꢀ5 ꢁC to rt, 63e75% (two steps).
With the requisite o-iodoanilino enamines 8aek in our hands,
cyclization using the microwave-assisted areneealkene coupling
reaction was explored.
As summarized in Scheme 4, a variety of the 3-substituted in-
doles were obtained in high yields from the corresponding en-
amines under the optimized conditions. The o-iodoanilino
enamines possessing various substituents on the benzene ring in-
cluding 3-CF3 (8a), 3-MeO (8b), 4-CF3 (8c), 4-MeO (8d), 5-CF3 (8e),
Likewise, the o-iodoanilino enamines 8hej were prepared
from the Boc-protected o-iodoaniline 5h using the corresponding
acid chlorides. Enamine 8k was readily prepared in 98%
yield from the Boc-protected o-iodoaniline 5h and methyl

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W.-I. Lee et al. / Tetrahedron 69 (2013) 7211e7219
5-MeO (8f), and 5-Cl (8g) underwent facile cyclization regardless of
the steric (8a,b) and electronic (8aef) effects of the substituent as
well as the substitution position. Moreover, indoles possessing the
3-alkyl (9i), aryl (9j), and carboalkoxy (9k) substituents as well as
the non-substituted indole (9h) were successfully prepared. It is
also noteworthy that the synthesis of indoles possessing both the
electron donating, withdrawing substituents at the 3-position un-
der the same reaction conditions has not been reported until the
present report.
mechanisms have been reported for Pd-catalyzed intramolecular
cyclizations in which palladacyles were involved.38
Scheme 5. Plausible mechanisms.
3. Conclusion
aIsolated yields.
In conclusion, we have developed a versatile and high-yielding
protocol for the preparation of 3-substituted indoles using
microwave-assisted intramolecular areneealkene coupling re-
action of o-iodoanilino enamines. The o-iodoanilino enamines were
readily prepared from the N,O-acetal TMS ethers, which were
conveniently derived from the corresponding amides. We believe
our protocol would provide a variety of 3-substituted indoles as
privileged structure for a wide range of biological targets.
Scheme 4. Scope of cyclization.a
Plausible mechanisms for the current intramolecular arene-
ealkene coupling are proposed in Scheme 5. The reaction is likely
initiated by the oxidative addition of o-iodoanilino enamine 8 to
Pd(0). Then, the reaction may proceed via intramolecular Heck-
type reaction (pathway a). It is known that trans-alkene is mainly
formed in the conventional Heck reaction by virtue of syn-b-elim-
ination. But in this system, the cyclic structure of the carbopalla-
dium complex 12 limits the bond rotation after insertion, so there is
4. Experimental section
4.1. General
no syn-H and the syn-
mechanism cannot take place. However, it was also known that
base-catalyzed anti- -H elimination via the E2-like mechanism
could not be completely ruled out.32 In addition, there is a recent
report that base-assisted anti- -H elimination is favored in the
systems that do not have syn- -H from the theoretical study by DFT
b-H elimination of conventional Heck
b
Commercially available reagents and solvents were used with-
out additional purification. All reactions were performed under
inert atmosphere of nitrogen. The microwave reactions were car-
ried out using a CEM microwave reactor in closed vials. Melting
points were taken on a BUCHI Melting Point B-540 and were un-
corrected. IR spectra were obtained on PerkineElmer 1710 FT-IR. 1H
NMR and 13C NMR were recorded on a Bruker AscendÔ 400 MHz or
JEOL JNM ECA-600 MHz spectrometer using CDCl3, DMSO-d6 or
methanol-d4 as solvents. All chemical shifts are given in parts per
b
b
methods.36 An alternative mechanism involving enamine arylation
has been suggested by Latham and Stanforth37 (pathway b). After
oxidative addition to the Pd(0), intramolecular enamine arylation,
followed by subsequent deprotonation and reductive elimination
may occur to provide the corresponding indole (pathway b). Similar

W.-I. Lee et al. / Tetrahedron 69 (2013) 7211e7219
7215
million. Data are reported as follows: chemical shift, multiplicity,
coupling constants (Hertz), and integration. High-resolution mass
spectra were recorded on JMS-AX 505WA or JMS-700 (JMS).
28.3; HR-MS (FABþ) calcd for C12H16INO3 [M]þ 349.0175; found
349.0176.
4.1.1.6. tert-Butyl 5-chloro-2-iodophenylcarbamate (5g). Yield
85.4%; colorless oil; FT-IR (thin film, neat) nmax 3841, 3735, 3391,
4.1.1. Preparation of Boc-protected anilines 5aeg.39 General pro-
cedure for 5a, 5ceg: To a solution of the aniline (5.40 mmol) in
anhydrous THF (35 mL) was added Boc2O (12.42 mmol) followed
by DMAP (0.54 mmol). The solution was stirred at reflux for 6 h
then concentrated to dryness and partitioned between 0.5 N-HCl
(100 mL) and EtOAc (100 mL). The aqueous layer was extracted
with EtOAc (2ꢂ50 mL) and the combined organic layer was
washed with brine (50 mL), dried over Na2SO4, filtered, and
concentrated to afford the crude di-Boc product. The crude
material was dissolved in methanol (35 mL), treated with po-
tassium carbonate (16.2 mmol), and stirred at reflux for 6 h. The
mixture was concentrated to dryness and partitioned between
0.5 N-HCl (100 mL) and EtOAc (100 mL). The aqueous phase was
extracted with EtOAc (2ꢂ50 mL) and the combined organic layer
was washed with brine (50 mL), dried over Na2SO4, filtered, and
concentrated in reduced pressure. The crude product was puri-
fied by flash silica gel column chromatography (n-hexane/
EtOAc¼9:1) to afford carbamate 5.
2971, 1738, 1569, 1507, 1436, 1405, 1367 cmꢀ1 1H NMR (400 MHz,
;
CDCl3):
d
8.17 (d, J¼2.3 Hz, 1H), 7.63 (d, J¼8.5 Hz, 1H), 6.85 (br s, 1H),
6.77 (dd, J¼8.5, 2.5 Hz, 1H), 1.54 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
152.1, 139.8, 139.2, 135.4, 124.5, 119.6, 85.0, 81.6, 28.2; HR-MS
(FABþ) calcd for C11H13ClINO2 [M]þ 352.9680; found 352.9669.
4.1.1.7. tert-Butyl 2-iodo-3-methoxyphenylcarbamate (5b).40 To
a solution of tert-butyl 3-methoxyphenylcarbamate (995 mg,
4.456 mmol) in anhydrous ether (60 mL) was added tert-butyl-
lithium (10.5 mL of 1.7 M, 17.850 mmol) at ꢀ78 ꢁC slowly. The re-
action mixture was warmed to ꢀ20 ꢁC and stirred for 3 h. The
solution was again cooled to ꢀ78 ꢁC and quenched by the addition
of a solution of iodine (1.697 g in 10 mL of ether, 6.686 mmol) via
a cannula, ensuring the reaction temperature did not rise above
ꢀ65 ꢁC. After 1 h, the reaction mixture was warmed to room
temperature slowly and stirred for 12 h. After addition of a satu-
rated aqueous Na2S2O3 solution, the mixture was extracted with
ether. The organic layer was washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography (n-hexane/
EtOAc¼30:1) to afford 1.08 g (69.4%) of 5b as a gel-type compound;
FT-IR (thin film, neat) nmax 3461, 3386, 3014, 2970, 2945, 2349,
2309, 1738, 1647, 1592, 1574, 1542, 1517, 1469, 1408, 1366 cmꢀ1; 1H
4.1.1.1. tert-Butyl 2-iodo-3-(trifluoromethyl)phenylcarbamate (5a).
Yield 93.2%; white solid; mp 50e52 ꢁC; FT-IR (thin film, neat) nmax
3390, 2970, 2349, 2309, 1739, 1647, 1589, 1517, 1456, 1367, 1322 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
7.20 (br s, 1H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
8.24 (d, J¼8.1 Hz, 1H), 7.43e7.33 (m, 2H),
d
152.5, 140.7,
134.3 (q, J¼30.4 Hz), 128.9, 123.4, 122.8 (q, J¼273.8 Hz), 122.2 (q,
J¼6.0 Hz), 86.8, 81.6, 28.2; HR-MS (FABþ) calcd for C12H13F3INO2 [M]þ
386.9943; found 386.9948.
NMR (400 MHz, CDCl3):
d
7.74 (d, J¼8.3 Hz, 1H), 7.29e7.22 (m, 1H),
7.05 (br s, 1H), 6.53 (d, J¼8.2 Hz, 1H), 3.88 (s, 3H), 1.54 (s, 9H); 13C
NMR (100 MHz, CDCl3):
d 158.2, 152.6, 140.2, 129.6, 112.4, 105.3,
80.9, 56.5, 28.3; HR-MS (FABþ) calcd for C12H16INO3 [M]þ 349.0175;
found 349.0185.
4.1.1.2. tert-Butyl 2-iodo-4-(trifluoromethyl)phenylcarbamate (5c).
Yield 90.5%; white solid; mp 73e75 ꢁC; FT-IR (thin film, neat) nmax
1
3394, 3015, 2970, 1739, 1606, 1573, 1526, 1456, 1366, 1323 cmꢀ1; H
4.1.2. General procedure for 2a, 6aeg. To a stirred solution of 5
(2.5 mmol) in THF (5 mL) was added LHMDS (1.0 M solution in THF,
3.75 mmol) and stirred for 1 h. Propionyl chloride (5.0 mmol) was
added at ꢀ78 ꢁC and stirred for 10 min. The reaction mixture was
allowed to ꢀ5 ꢁC and stirred for 2 h then quenched with saturated
aqueous sodium bicarbonate solution and extracted with EtOAc.
The organic layer was washed with brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The crude product
was purified by silica gel column chromatography (n-hexane/
EtOAc¼5:1) to afford amide 6.
NMR (400 MHz, CDCl3):
d
8.24 (d, J¼8.7 Hz, 1H), 7.98 (d, J¼1.3 Hz, 1H),
7.57 (dd, J¼8.7, 2.0 Hz, 1H), 7.02 (br s, 1H), 1.55 (s, 9H); 13C NMR
(100 MHz, CDCl3):
d
152.1, 141.9, 135.8 (q, J¼3.9 Hz), 126.4 (q,
J¼3.7 Hz), 126.0 (q, J¼33.2 Hz), 123.0 (q, J¼272.0 Hz), 118.8, 87.0, 81.9,
28.2; HR-MS (FABþ) calcd for C12H13F3INO2 [M]þ 386.9943; found
386.9947.
4.1.1.3. tert-Butyl 2-iodo-4-methoxyphenylcarbamate (5d). Yield
85.3%; colorless oil, FT-IR (thin film, neat) nmax 3401, 2971, 2835,
2349, 2309, 1736, 1647, 1602, 1572, 1516, 1457, 1366 cmꢀ1; 1H NMR
(400 MHz, CDCl3):
d
7.81 (d, J¼8.6 Hz, 1H), 7.30 (d, J¼2.8 Hz, 1H),
4.1.2.1. Methyl 2-iodophenyl(propionyl)carbamate (2a). Yield
93.1%; white solid; mp 83e85 ꢁC; FT-IR (thin film, neat) nmax 2970,
6.89 (dd, J¼9.0, 2.8 Hz, 1H), 6.54 (br s, 1H), 3.76 (s, 3H), 1.52 (s, 9H);
13C NMR (100 MHz, CDCl3):
d
156.0, 153.0, 132.3, 123.7, 122.0, 114.9,
2952, 2310, 1753, 1698, 1469, 1439, 1363, 1300 cmꢀ1 1H NMR
;
90.3, 80.7, 55.7, 28.3; HR-MS (FABþ) calcd for C12H16INO3 [M]þ
349.0175; found 349.0171.
(400 MHz, CDCl3):
d
7.86 (d, J¼7.9 Hz, 1H), 7.41e7.35 (m, 1H), 7.16
(dd, J¼7.8, 1.3 Hz, 1H), 7.08e7.02 (m, 1H), 3.69 (s, 3H), 3.13e2.96 (m,
2H),1.20 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 175.5,153.3,
4.1.1.4. tert-Butyl 2-iodo-5-(trifluoromethyl)phenylcarbamate (5e).
Yield 88.5%; white solid; mp 86e88 ꢁC; FT-IR (thin film, neat) nmax
140.8, 139.2, 129.5, 129.2, 129.1, 99.5, 53.8, 31.5, 8.8; HR-MS (FABþ)
calcd for C11H13INO3 [MþH]þ 333.9940; found 333.9945.
3015, 2970, 2349, 2309, 1739, 1647, 1581, 1523, 1427, 1366 cmꢀ1; H
1
NMR (400 MHz, CDCl3):
d
8.41 (s, 1H), 7.86 (d, J¼8.3 Hz, 1H), 7.01 (d,
4.1.2.2. tert-Butyl 2-iodo-3-(trifluoromethyl)phenyl(propionyl)ca
rbamate (6a). Yield 90.2%; white solid; mp 105e107 ꢁC; FT-IR (thin
film, neat) nmax 2970, 2943, 2349, 2309, 1742, 1648, 1565, 1542, 1508,
J¼8.2 Hz, 1H), 6.96 (br s, 1H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
152.2, 139.6, 139.3, 131.8 (q, J¼32.8 Hz), 123.7 (q, J¼272.6 Hz), 120.6
(q, J¼3.7 Hz), 116.2 (q, J¼4.0 Hz), 91.9, 81.8, 28.2; HR-MS (FABþ) calcd
1424, 1370, 1319, 1301 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 7.61 (dd,
for C12H13F3INO2 [M]þ 386.9943; found 386.9933.
J¼7.9, 1.3 Hz, 1H), 7.52e7.45 (m, 1H), 7.32 (dd, J¼7.8, 1.1 Hz, 1H),
3.17e2.99 (m, 2H), 1.37 (s, 9H), 1.22 (t, J¼7.3 Hz, 3H); 13C NMR
4.1.1.5. tert-Butyl 2-iodo-5-methoxyphenylcarbamate (5f). Yield
85.1%; colorless oil; FT-IR (thin film, neat) nmax 3015, 2970, 2349,
(100 MHz, CDCl3):
d
176.0,151.0,144.4,135.5 (q, J¼30.9 Hz),132.1,129.0,
126.7 (q, J¼5.8 Hz), 122.5 (q, J¼274.0 Hz), 98.5, 83.7, 31.7, 27.7, 8.9; HR-
2309, 1739, 1647, 1565, 1542, 1517, 1433, 1365 cmꢀ1 1H NMR
;
MS (FABþ) calcd for C15H18F3INO3 [MþH]þ 444.0284; found 444.0291.
(400 MHz, CDCl3):
d
7.79 (s, 1H), 7.57 (d, J¼8.8 Hz, 1H), 6.83 (br s,
1H), 6.40 (dd, J¼8.8, 1.4 Hz, 1H), 3.80 (s, 3H), 1.54 (s, 9H); 13C NMR
4.1.2.3. tert-Butyl 2-iodo-3-methoxyphenyl(propionyl)carbamate
(6b). Yield 88.2%; white solid; mp 76e78 ꢁC; FT-IR (thin film, neat)
(100 MHz, CDCl3):
d
160.7, 152.4, 139.6, 138.7, 111.6, 105.1, 81.1, 55.4,

7216
W.-I. Lee et al. / Tetrahedron 69 (2013) 7211e7219
nmax 3015, 2970, 2944, 2349, 2309, 1739, 1648, 1581, 1542, 1508,
1433, 1366 cmꢀ1 1H NMR (400 MHz, CDCl3):
7.36e7.29 (m, 1H),
129.2, 128.4, 127.0, 99.5, 54.1, 44.2; HR-MS (FABþ) calcd for
C
;
d
16H15INO3 [MþH]þ 396.0097; found 396.0093.
6.83e6.74 (m, 2H), 3.90 (s, 3H), 3.10e2.90 (m, 2H), 1.38 (s, 9H), 1.20
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
175.9, 159.2, 151.4,
4.1.2.10. tert-Butyl acetyl(2-iodophenyl)carbamate (6h). Com
143.3, 129.5, 121.6, 109.9, 92.1, 83.1, 56.6, 31.7, 27.8, 9.0; HR-MS
pound 6h was prepared according to the method for synthesis of 6a
except for acetyl chloride instead of propionyl chloride: yield 95.1%;
white solid; mp 105e107 ꢁC; FT-IR (thin film, neat) nmax 3057, 3001,
2976, 2933, 1742, 1705, 1580, 1541, 1469, 1414, 1394, 1370,
(FABþ) calcd for C15H21INO4 [MþH]þ 406.0515; found 406.0516.
4.1.2.4. tert-Butyl 2-iodo-4-(trifluoromethyl)phenyl(propionyl)car
bamate (6c). Yield 89.6%; white solid; mp 98e100 ꢁC; FT-IR (thin
film, neat) nmax 2971, 2942, 2349, 1744, 1604, 1457, 1395, 1371,
1304 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
7.87 (dd, J¼7.9, 1.3 Hz, 1H),
7.41e7.36 (m, 1H), 7.16 (dd, J¼7.9, 1.5 Hz, 1H), 7.08e7.02 (m, 1H),
1322, 1301 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
8.12e8.09 (m, 1H),
2.64 (s, 3H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 172.3, 151.5,
7.67e7.62 (m, 1H), 7.28e7.23 (m, 1H), 3.15e2.98 (m, 2H), 1.39 (s,
141.6, 139.2, 129.4, 129.1, 129.1, 99.4, 83.4, 27.8, 26.6; HR-MS (FABþ)
9H), 1.21 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
175.9,
calcd for C13H17INO3 [MþH]þ 362.0253; found 362.0258.
150.8, 145.3, 136.2 (q, J¼3.8 Hz), 131.2 (q, J¼33.2 Hz), 129.5, 126.2
(q, J¼3.6 Hz), 122.6 (q, J¼272.9 Hz), 99.6, 83.9, 31.6, 27.8, 8.9; HR-
MS (FABþ) calcd for C15H18F3INO3 [MþH]þ 444.0284; found
444.0278.
4.1.2.11. tert-Butyl 2-iodophenyl(propionyl)carbamate (6i). Com
pound 6i was prepared according to the method for synthesis of 7a:
yield 98.0%; colorless gel-type compound; FT-IR (thin film, neat)
nmax 2980, 2942, 1726, 1579, 1469, 1367, 1331 cmꢀ1 1H NMR
;
4.1.2.5. tert-Butyl 2-iodo-4-methoxyphenyl(propionyl)carbamate
(6d). Yield 85.3%; colorless oil; FT-IR (thin film, neat) nmax 2970,
2943, 2349, 2309, 1739, 1647, 1595, 1647, 1595, 1565, 1542, 1508,
(400 MHz, CDCl3):
d
7.85 (d, J¼7.8 Hz, 1H), 7.38e7.31 (m, 2H),
7.02e6.93 (m, 1H), 2.44 (q, J¼7.5 Hz, 2H), 1.44 (s, 9H), 1.16 (t,
J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 170.7, 152.1, 143.2,
1490, 1441, 1366 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
7.37 (d,
139.5, 129.3, 128.9, 111.0, 99.9, 81.8, 28.1, 27.3, 9.0.
J¼2.6 Hz,1H), 7.03 (d, J¼8.7 Hz,1H), 6.91 (dd, J¼8.7, 2.6 Hz,1H), 3.80
(s, 3H), 3.06e2.88 (m, 2H), 1.40 (s, 9H), 1.20 (t, J¼7.3 Hz, 3H); 13C
4.1.2.12. tert-Butyl 2-iodophenyl(2-phenylacetyl)carbamate (6j).
Compound 6j was prepared according to the method for synthesis
of 6a except for phenylacetyl chloride ꢁinstead of propionyl chloride:
yield 80.2%; white solid; mp 103e105 C; FT-IR (thin film, neat) nmax
2971, 1739, 1496, 1469, 1455, 1369 cmꢀ1; 1H NMR (400 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d 176.1, 158.9, 151.8, 134.7, 129.2, 124.0,
114.8, 99.6, 83.0, 55.6, 31.6, 27.8, 9.1; HR-MS (FABþ) calcd for
C
15H21INO4 [MþH]þ 406.0515; found 406.0509.
4.1.2.6. tert-Butyl 2-iodo-5-(trifluoromethyl)phenyl(propionyl)car
d
7.84 (d, J¼7.9 Hz, 1H), 7.38e7.20 (m, 6H), 7.10 (d, J¼7.8 Hz, 1H),
7.02 (t, J¼7.6 Hz, 1H), 4.42 (d, J¼16.1 Hz, 1H), 4.32 (d, J¼16.1 Hz, 1H),
1.38 (s, 9H); 13C NMR (100 MHz, CDCl3):
173.1, 151.4, 141.6, 139.2,
bamate (6e). Yield 88.4%; colorless viscous oil; FT-IR (thin film,
neat) nmax 3461, 2970, 2943, 2349, 2309, 1742, 1648, 1604, 1565,
1542, 1508, 1474, 1413, 1370, 1332 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
134.4, 129.9, 129.3, 129.2, 129.0, 128.3, 126.8, 99.5, 83.5, 44.2, 27.8;
HR-MS (FABþ) calcd for C19H21INO3 [MþH]þ 438.0566; found
438.0568.
d
8.00 (d, J¼8.3 Hz, 1H), 7.40 (d, J¼1.9 Hz, 1H), 7.29 (dd, J¼8.3, 1.9 Hz,
1H), 3.16e2.98 (m, 2H), 1.39 (s, 9H), 1.22 (t, J¼7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3):
d
175.9, 150.9, 142.7, 139.9, 131.8 (q, J¼33.4 Hz),
126.1 (q, J¼3.8 Hz), 125.7 (q, J¼3.6 Hz), 123.4 (q, J¼272.4 Hz), 104.2,
83.9, 31.6, 27.7, 8.9; HR-MS (FABþ) calcd for C15H18F3INO3 [MþH]þ
444.0284; found 444.0272.
4.1.3. General procedure for 4a, 8aej. To a solution of 6 (1.4 mmol)
in dry CH2Cl2 (20 mL) was added DIBAL-H (1.0 M solution in DCM,
2.8 mmol) at ꢀ78 ꢁC. After stirring for 1 h, the reaction mixture
was treated with pyridine (4.2 mmol) and then TMSOTf
(3.5 mmol). The mixture was stirred at ꢀ78 ꢁC for 10 min, and
then slowly warmed to ꢀ40 ꢁC and stirred for 1 h then quenched
with 15% aqueous sodium potassium tartarate solution, and di-
luted with diethyl ether. The resultant mixture was warmed to
room temperature and stirred vigorously until two layers were
completely separated. The mixture was extracted with diethyl
ether and the organic layer was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude
product was purified by amino silica gel column chromatography
(n-hexane/EtOAc¼30:1) to afford the mixture of 7 as a major
product and small amount of 5 and used without further purifi-
cation. This mixture was dissolved in dry CH2Cl2 and added N,N-
diisopropylethylamine (3.67 mmol), BF3$OEt2 (2.75 mmol) at
ꢀ5 ꢁC and stirred for 10 min then allowed to room temperature.
After stirring for 2 h, the reaction mixture was quenched with
Et3N and extracted with CH2Cl2. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography (n-
hexane/EtOAc¼9:1) to afford enamine 8.
4.1.2.7. tert-Butyl 2-iodo-5-methoxyphenyl(propionyl)carbamate
(6f). Yield 86.7%; white solid; mp 111e113 ꢁC; FT-IR (thin film, neat)
nmax 3461, 2970, 2943, 2349, 2309, 1739, 1647, 1593, 1571, 1542,
1508, 1473, 1456, 1366 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 7.70 (d,
J¼8.7 Hz,1H), 6.73 (d, J¼2.8 Hz,1H), 6.66 (dd, J¼8.7, 2.8 Hz,1H), 3.78
(s, 3H), 3.08e2.92 (m, 2H), 1.40 (s, 9H), 1.20 (t, J¼7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3):
d 175.8, 160.5, 151.4, 142.5, 139.2, 115.5,
115.3, 88.1, 83.2, 55.5, 31.6, 27.8, 9.0; HR-MS (FABþ) calcd for
C
15H21INO4 [MþH]þ 406.0515; found 406.0515.
4.1.2.8. tert-Butyl
5-chloro-2-iodophenyl(propionyl)carbamate
(6g). Yield 88.6%; white solid; mp 69e71 ꢁC; FT-IR (thin film, neat)
nmax 2970, 2349, 1740, 1457, 1367 cmꢀ1; H NMR (400 MHz, CDCl3):
1
d
7.77 (d, J¼8.5 Hz, 1H), 7.17 (d, J¼2.3 Hz, 1H), 7.05 (dd, J¼8.5, 2.3 Hz,
1H), 3.13e2.94 (m, 2H), 1.40 (s, 9H), 1.21 (t, J¼7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 175.8, 150.9, 142.9, 139.8, 134.7, 129.5, 129.5, 97.0,
83.7, 31.6, 27.8, 8.9; HR-MS (FABþ) calcd for C14H18ClINO3 [MþH]þ
410.0020; found 410.0019.
4.1.2.9. Methyl 2-iodophenyl(2-phenylacetyl)carbamate (2b). Co
mpound 2b was prepared according to the method for synthesis of
2a except that phenylacetyl chloride was used instead of propionyl
chloride: yield 83.3%; colorless viscous oil; FT-IR (thin film, neat)
4.1.3.1. (E)-Methyl 2-iodophenyl(prop-1-enyl)carbamate (4a). Yi
eld 65.4%; colorless gel-type compound; 1H NMR (400 MHz,
CDCl3): Note: a splitting or broadening of some peaks was observed
nmax 3029, 2970, 1746, 1496, 1469, 1438, 1365 cmꢀ1
;
1H NMR
due to rotamers
d
7.92 (dd, J¼7.9, 1.1 Hz, 1H), 7.45e7.39 (m, 1H),
(400 MHz, CDCl3):
d
7.92e7.82 (m, 1H), 7.45e7.02 (m, 8H), 4.45 (d,
7.25e7.17 (m, 1H), 7.13e6.82 (m, 2H), 4.33e4.19 (m, 1H), 3.87 and
3.69 (s, 3H), 1.62 (dd, J¼6.7, 1.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
J¼16.0 Hz, 1H), 4.34 (d, J¼16.0 Hz, 1H), 3.73 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d
172.9, 153.5, 140.8, 139.4, 134.0, 129.8, 129.4,
d 153.4, 141.0, 139.9, 129.8, 129.5, 129.4, 128.2, 106.9, 99.9, 53.4, 14.9.

W.-I. Lee et al. / Tetrahedron 69 (2013) 7211e7219
7217
4.1.3.2. (E)-Methyl 2-iodophenyl(styryl)carbamate (4b). Yield:
75.2%; colorless gel-type compound; FT-IR (thin film, neat) nmax
3003, 2970, 2952, 2349, 1741, 1634, 1578, 1471, 1439, 1366,
1333 cmꢀ1; 1H NMR (400 MHz, DMSO-d6, 80 ꢁC): Note: a splitting or
4.1.3.8. (E)-tert-Butyl 2-iodo-5-methoxyphenyl(prop-1-enyl)car-
bamate (8f). Yield 70.2%; colorless viscous oil; FT-IR (thin film,
neat) nmax 2970, 2349, 2309, 1739, 1717, 1669, 1648, 1594, 1566,
1542,1508,1490,1456,1366,1322 cmꢀ1; 1H NMR (400 MHz, DMSO-
broadening of some peaks was observed due to rotamers
d
8.03 (dd,
d6, 80 ꢁC):
d
7.47e7.42 (m,1H), 7.15e7.08 (m,1H), 7.05e6.99 (m,1H),
6.92 (d, J¼14.2 Hz, 1H), 4.24e4.10 (m, 1H), 3.80 (s, 3H), 1.60e1.54
(m, 3H), 1.38 (s, 9H); 13C NMR (100 MHz, DMSO-d6, 80 ꢁC):
158.2,
J¼7.9, 1.3 Hz, 1H), 7.79 (d, J¼14.6 Hz, 1H), 7.60e7.53 (m, 1H),
7.48e7.42 (m, 1H), 7.30e7.20 (m, 5H), 7.17e7.09 (m, 1H), 5.10 (d,
J¼14.7 Hz, 1H), 3.84 and 3.66 (s, 3H); 13C NMR (100 MHz, DMSO-d6,
d
150.5, 133.9, 129.4, 128.2, 123.8, 114.6, 104.3, 99.6, 79.9, 55.2, 27.4,
13.9; HR-MS (FABþ) calcd for C15H20INO3 [M]þ 389.0488; found
389.0484.
80 ꢁC):
d 152.3, 139.9, 139.3, 135.6, 129.7, 129.5, 129.3, 128.1, 127.8,
125.7, 124.7, 111.0, 99.3, 53.0; HR-MS (FABþ) calcd for C12H13INO4
[MþH]þ 361.9889; found 361.9900.
4.1.3.9. (E)-tert-Butyl 5-chloro-2-iodophenyl(prop-1-enyl)carba-
mate (8g). Yield 65.4%; white solid; mp 113e115 ꢁC; FT-IR (thin
film, neat) nmax 3015, 2970, 2349, 2309, 1739, 1670, 1647, 1571, 1542,
4.1.3.3. (E)-tert-Butyl 2-iodo-3-(trifluoromethyl)phenyl(prop-1-
enyl)carbamate (8a). Yield 71.5%; colorless oil; FT-IR (thin film,
neat) nmax 2971, 2935, 2888, 1719, 1668, 1579, 1516, 1456, 1423,
1508, 1434, 1366, 1316 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 7.81 (d,
1368, 1330, 1306 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6, 80 ꢁC):
J¼8.3 Hz, 1H), 7.30e6.79 (m, 3H), 4.28e4.16 (m, 1H), 1.62 (d,
d
7.75e7.61 (m, 2H), 7.55e7.49 (m, 1H), 6.95 (d, J¼14.2 Hz, 1H),
4.21e4.08 (m, 1H), 1.62e1.56 (m, 3H), 1.37 (s, 9H); 13C NMR
(100 MHz, DMSO-d6, 80 ꢁC):
J¼6.7 Hz, 3H), 1.60e1.32 (m, 9H); 13C NMR (100 MHz, CDCl3):
d
151.1, 143.0, 140.3, 134.7, 129.9, 129.3, 127.7, 106.3, 97.4, 81.6, 28.1,
d
150.0, 143.8, 134.1 (q, J¼30.1 Hz),
15.0; HR-MS (FABþ) calcd for C14H17ClINO2 [M]þ 392.9993; found
392.9985.
133.0, 129.5, 127.7, 126.2 (q, J¼5.8 Hz), 122.3 (q, J¼274.0 Hz), 105.1,
98.9, 80.6, 27.3, 14.0; HR-MS (EIþ) calcd for C15H17F3INO2 [M]þ
427.0256, found 427.0257.
4.1.3.10. tert-Butyl 2-iodophenyl(vinyl)carbamate (8h). Yield
62.3%; white solid; mp 71e73 ꢁC; FT-IR (thin film, neat) nmax 2978,
4.1.3.4. (E)-tert-Butyl 2-iodo-3-methoxyphenyl(prop-1-enyl)car-
bamate (8b). Yield 64.3%; white solid; mp 80e82 ꢁC; FT-IR (thin
film, neat) nmax 3005, 2970, 2349, 2309, 1739, 1715, 1669, 1648,
1581, 1572, 1542, 1508, 1469, 1456, 1430, 1366, 1323 cmꢀ1; 1H NMR
(400 MHz, CDCl3): Note: a splitting or broadening of some peaks was
1718, 1633, 1580, 1472, 1457, 1368, 1344, 1316 cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6, 80 ꢁC):
d
7.97 (d, J¼7.8 Hz, 1H), 7.53e7.43 (m,
1H), 7.29e7.23 (m, 1H), 7.22e7.09 (m, 2H), 4.24 (d, J¼8.8 Hz, 1H),
3.60 (d, J¼15.8 Hz, 1H), 1.39 (s, 9H); 13C NMR (100 MHz, DMSO-d6,
80 ꢁC):
d 150.3, 140.0, 139.0, 132.8, 129.4, 129.1, 129.0, 99.3, 92.7,
observed due to rotamers
d
7.40e7.27 (m, 1H), 7.07e6.71 (m, 3H),
80.6, 27.3; HR-MS (FABþ) calcd for C13H17INO2 [MþH]þ 346.0304;
4.27e4.15 (m, 1H), 3.91 (s, 3H), 1.59 (dd, J¼6.7, 0.9 Hz, 3H), 1.57 and
found 346.0301.
1.35 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 159.5, 151.6, 143.2, 129.5,
127.8, 122.0, 109.5, 105.6, 92.2, 80.8, 56.5, 28.0, 14.9; HR-MS (FABþ)
calcd for C15H20INO3 [M]þ 389.0488; found 389.0489.
4.1.3.11. (E)-tert-Butyl 2-iodophenyl(prop-1-enyl)carbamate (8
i). Yield 75.2%; white solid; mp 92e94 ꢁC; FT-IR (thin film, neat)
nmax 2970, 2349, 1739, 1721, 1669, 1472, 1440, 1366, 1323 cmꢀ1; 1H
NMR (400 MHz, CDCl3): Note: a splitting or broadening of some peaks
4.1.3.5. (E)-tert-Butyl 2-iodo-4-(trifluoromethyl)phenyl(prop-1-
enyl)carbamate (8c). Yield 75.1%; colorless oil; FT-IR (thin film,
neat) nmax 2970, 2937, 2349, 2309, 1720, 1669, 1678, 1603, 1565,
1476, 1456, 1368, 1324 cmꢀ1; 1H NMR (400 MHz, DMSO-d6, 80 ꢁC):
was observed due to rotamers d 7.95e7.85 (m,1H), 7.45e7.34 (m,1H),
7.26e7.23 and 7.22e7.13 (m, 1H), 7.10e6.99 and 6.93e6.85 (m, 2H),
4.25e4.14 (m, 1H), 1.61 (dd, J¼6.7, 1.3 Hz, 3H), 1.57 and 1.36 (s, 9H);
d
8.26e8.19 (m, 1H), 7.87e7.75 (m, 1H), 7.52e7.43 (m, 1H), 6.93 (d,
J¼14.3 Hz, 1H), 4.25e4.11 (m, 1H), 1.62e1.55 (m, 3H), 1.38 (s, 9H);
13C NMR (100 MHz, DMSO-d6, 80 ꢁC):
149.8, 145.1, 135.5 (q,
13C NMR (100 MHz, CDCl3):
d 151.6, 141.7, 139.6, 129.7, 129.2, 129.0,
128.0, 105.9, 99.9, 81.1, 28.1, 15.1; 1H NMR (600 MHz, DMSO-d6,
80 ꢁC):
d
d
9.30 (d, J¼9.9 Hz, 1H), 8.73e8.68 (m, 1H), 8.45e8.39 (m,
J¼3.9 Hz), 130.3, 129.3 (q, J¼32.5 Hz), 127.5, 126.0 (q, J¼3.7 Hz),
123.4, 122.2 (q, J¼272.9 Hz), 105.5, 100.3, 80.7, 27.3, 13.9; HR-MS
(FABþ) calcd for C15H17F3INO2 [M]þ 427.0256; found 427.0257.
1H), 8.31e8.24 (m, 1H), 8.03 (d, J¼17.8 Hz, 1H), 4.58e4.47 (m, 1H),
1.34 (d, J¼8.3 Hz, 3H), 1.08 (s, 9H); 13C NMR (150 MHz, DMSO-d6,
80 ꢁC):
d 178.1,166.4,164.0,152.1,151.5,150.2,121.1,114.6, 90.5, 24.5,
7.8; HR-MS (FABþ) calcd for C14H18INO2 [MþH]þ 359.0382; found
4.1.3.6. (E)-tert-Butyl 2-iodo-4-methoxyphenyl(prop-1-enyl)car-
bamate (8d). Yield 68.2%; white solid; mp 115e117 ꢁC; FT-IR (thin
film, neat) nmax 3004, 2970, 2936, 2349, 2309, 1738, 1715, 1669,
1648, 1590, 1570, 1542, 1507, 1475, 1457, 1424, 1366, 1352,
359.0380.
4.1.3.12. (E)-tert-Butyl 2-iodophenyl(styryl)carbamate (8j). Yield
73.2%; colorless viscous oil; FT-IR (thin film, neat) nmax 2971, 1718,
1646, 1579, 1471, 1447, 1367, 1323 cmꢀ1; 1H NMR (400 MHz, DMSO-
1322 cmꢀ1 1H NMR (400 MHz, CDCl3): Note: a splitting or broad-
;
ening of some peaks was observed due to rotamers
d
7.73 (d, J¼8.6 Hz,
d6, 80 ꢁC):
d
8.04e7.98 (m,1H), 7.73 (d, J¼14.7 Hz,1H), 7.58e7.50 (m,
1H), 7.07e6.71 (m, 2H), 6.65 (d, J¼8.6 Hz, 1H), 4.31e4.18 (m, 1H),
1H), 7.40e7.33 (m, 1H), 7.28e7.16 (m, 5H), 7.16e7.07 (m, 1H), 5.14
(d, J¼14.7 Hz, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, DMSO-d6,
3.79 (s, 3H), 1.61 (d, J¼6.7 Hz, 3H), 1.57 and 1.38 (s, 9H); 13C NMR
(100 MHz, CDCl3):
d
160.7, 160.5, 151.4, 151.1, 142.4, 139.8, 139.5,
80 ꢁC):
d 150.4, 140.3, 139.1, 135.9, 129.4, 129.3, 129.1, 128.0, 127.8,
128.2,127.8,115.8,115.5,115.1,105.8, 88.2, 81.8, 81.0, 55.4, 28.3, 28.0,
15.0; HR-MS (FABþ) calcd for C15H20INO3 [M]þ 389.0488; found
389.0472.
125.5, 124.6, 110.1, 99.2, 81.0, 27.3; HR-MS (FABþ) calcd for
C
19H20INO2 [M]þ 421.0539; found 421.0539.
4.1.3.13. Methyl 3-(tert-butoxycarbonyl(2-iodophenyl)amino)ac-
4.1.3.7. (E)-tert-Butyl 2-iodo-5-(trifluoromethyl)phenyl(prop-1-
enyl)carbamate (8e). Yield 63.2%; colorless viscous oil; 1H NMR
rylate (8k). DABCO (3.690 mg, 0.033 mmol) was added to a mixture
of 5h (105 mg, 0.329 mmol) and methyl propiolate (27.660 mg,
0.329 mmol) in DCM (2 mL) with ice-cooling. The mixture was then
stirred at 0 ꢁC for 3 h. The solvent was removed in vacuo and the
residue was purified by flash column chromatography (n-hexane/
EtOAc¼20:1) to afford 139.7 mg (98.0%) of 8k as a colorless viscous
oil. FT-IR (thin film, neat) nmax 2971, 1736, 1632, 1579, 1471, 1437,
(400 MHz, DMSO-d6, 80 ꢁC):
d
8.21 (d, J¼8.3 Hz, 1H), 7.61e7.57 (m,
1H), 7.49e7.43 (m, 1H), 6.93 (dd, J¼14.3, 1.4 Hz, 1H), 4.23e4.12 (m,
1H), 1.61 (dd, J¼6.7, 1.5 Hz, 3H), 1.39 (s, 9H); 13C NMR (100 MHz,
DMSO-d6, 80 ꢁC):
d
149.9, 142.2, 140.4, 130.1 (q, J¼32.8 Hz), 127.7,
126.0 (q, J¼3.5 Hz), 125.2 (q, J¼3.7 Hz), 123.0 (q, J¼272.5 Hz), 105.4,
105.3, 80.7, 27.3, 13.9.
1369 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
8.38 (d, J¼12.7 Hz, 1H),

7218
W.-I. Lee et al. / Tetrahedron 69 (2013) 7211e7219
7.93 (d, J¼7.9 Hz, 1H), 7.48e7.39 (m, 1H), 7.19 (d, J¼7.7 Hz, 1H),
7.14e7.07 (m, 1H), 4.55 (d, J¼14.1 Hz, 1H), 3.68 (s, 3H), 1.45 (s, 9H);
2971, 2939, 2836, 1729, 1621, 1576, 1489, 1442, 1391, 1373, 1353,
1324 cmꢀ1 1H NMR (400 MHz, CDCl3):
7.72 (br s, 1H), 7.35 (d,
J¼8.5 Hz, 1H), 7.23 (s, 1H), 6.87 (d, J¼8.5 Hz, 1H), 3.88 (s, 3H), 1.66 (s,
9H); 13C NMR (100 MHz, CDCl3):
157.8, 149.9, 136.4, 125.2, 121.4,
;
d
13C NMR (100 MHz, CDCl3):
d 167.7, 150.7, 142.7, 140.1, 140.0, 130.1,
129.7, 129.1, 99.6, 98.7, 83.7, 51.2, 27.9; HR-MS (FABþ) calcd for
d
C
15H19INO4 [MþH]þ 404.0359; found 404.0367.
119.3, 116.3, 111.6, 99.3, 83.0, 55.6, 28.2, 9.6; HR-MS (EIþ) calcd for
C
15H19NO3 [M]þ 261.1365, found 261.1361.
4.1.4. General method for 9iel, 9jel, 9aek. The mixture of 8
(0.42 mmol), Pd(OAc)2 (0.084 mmol), PPh3 (0.168 mmol), KOAc
(1.26 mmol), and Et4NCl (0.84 mmol) in acetonitrile (2.5 mL) was
placed in a 10 mL vial closed with a silicon septum and containing
a magnetic stirring bar. The tube was placed in the microwave
cavity (Discover, CEM) and subjected to MW irradiation (100 W,
80 ꢁC, 1.5 h). After cooling to room temperature, the reaction
mixture was filtered through Celite pad and washed with EtOAc.
The filtrate was concentrated under reduced pressure and the
residue was purified by flash column chromatography (n-hexane/
EtOAc¼30:1) to afford desired indole 9.
4.1.4.7. tert-Butyl 3-methyl-6-(trifluoromethyl)-1H-indole-1-
carboxylate (9e). Yield 91.3%; white solid; mp 104e106 ꢁC; FT-IR
(thin film, neat) nmax 3014, 2970, 2945, 2349, 2309, 1739, 1647,
1542, 1508, 1445, 1367 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
8.45 (br
s, 1H), 7.57 (d, J¼8.2 Hz, 1H), 7.51e7.43 (m, 2H), 2.28 (d, J¼1.1 Hz,
3H), 1.67 (s, 9H); 13C NMR (100 MHz, CDCl3):
149.3, 134.6, 133.8,
d
126.2 (q, J¼31.9 Hz), 125.2, 124.9 (q, J¼271.8 Hz), 119.2, 119.0 (q,
J¼3.6 Hz), 116.1, 112.7 (q, J¼4.5 Hz), 84.0, 28.1, 9.5; HR-MS (EIþ)
calcd for C15H16F3NO2 [M]þ 299.1133, found 299.1126.
4.1.4.8. tert-Butyl 6-methoxy-3-methyl-1H-indole-1-carboxylate
(9f). Yield 88.4%; colorless oil; FT-IR (thin film, neat) nmax 2970,
2941, 2349, 2309, 1729, 1604, 1565, 1542, 1508, 1480, 1455, 1392,
4.1.4.1. Methyl 3-methyl-1H-indole-1-carboxylate (9iel).41 Yield
88.1%; colorless viscous oil; 1H NMR (400 MHz, CDCl3):
d 8.14 (br s,
1H), 7.50 (d, J¼7.7 Hz, 1H), 7.38e7.30 (m, 2H), 7.28e7.22 (m, 1H),
1373 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
7.99 (br s, 1H), 7.33 (s, 1H),
4.01 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3):
131.4, 124.5, 122.6, 122.3, 118.9, 117.2, 115.0, 53.5, 9.6.
d 151.5, 135.4,
6.96e6.88 (m, 2H), 3.87 (s, 3H), 2.23 (s, 3H), 1.65 (s, 9H); 13C NMR
(100 MHz, CDCl3):
d 155.7, 149.7, 132.2, 130.1, 123.4, 116.1, 115.8,
112.6, 101.7, 83.0, 55.7, 28.2, 9.7; HR-MS (EIþ) calcd for C15H19NO3
[M]þ 261.1365, found 261.1364.
4.1.4.2. Methyl 3-phenyl-1H-indole-1-carboxylate (9jel). Yield
91.3%; colorless viscous oil; FT-IR (thin film, neat) nmax 3015, 2970,
2951, 1739, 1647, 1607, 1565, 1542, 1508, 1455, 1442, 1376,
4.1.4.9. tert-Butyl 6-chloro-3-methyl-1H-indole-1-carboxylate
(9g). Yield 85.3%; colorless oil; FT-IR (thin film, neat) nmax 3015,
2970, 2945, 1738, 1647, 1564, 1543, 1508, 1456, 1436, 1366,
1310 cmꢀ1
;
1H NMR (400 MHz, methanol-d4):
d
8.24 (d, J¼8.0 Hz,
1H), 7.85e7.76 (m, 2H), 7.69e7.61 (m, 2H), 7.52e7.44 (m, 2H),
7.41e7.26 (m, 3H), 4.07 (s, 3H); 13C NMR (100 MHz, methanol-d4):
1314 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
8.15 (br s, 1H), 7.37 (d,
J¼8.3 Hz, 1H), 7.32 (s, 1H), 7.20 (d, J¼8.3 Hz, 1H), 2.23 (s, 3H), 1.66 (s,
9H); 13C NMR (100 MHz, CDCl3):
149.4, 135.8, 130.2, 129.9, 123.3,
d
152.9, 137.5, 134.9, 130.2, 130.0, 129.0, 128.4, 125.9, 124.4, 124.2,
123.5, 121.0, 116.3, 54.5; HR-MS (EIþ) calcd for C16H13NO2 [M]þ
251.0946, found 251.0945.
d
122.8, 119.6, 116.1, 115.4, 83.7, 28.1, 9.5; HR-MS (EIþ) calcd for
C
14H16ClNO2 [M]þ 265.0870, found 265.0873.
4.1.4.3. tert-Butyl 3-methyl-4-(trifluoromethyl)-1H-indole-1-
carboxylate (9a). Yield 89.2%; colorless oil; FT-IR (thin film, neat)
nmax 3005, 2970, 2942, 1738, 1723, 1669, 1648, 1579, 1542, 1509,
4.1.4.10. tert-Butyl 1H-indole-1-carboxylate (9h). Yield 86.2%;
colorless oil; FT-IR (thin film, neat) nmax 3153, 3119, 3054, 2979,
2933, 2308, 1735, 1607, 1534, 1474, 1452, 1381, 1370, 1349,
1456, 1423, 1367, 1330, 1306 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
8.44 (d, J¼8.3 Hz, 1H), 7.57 (d, J¼7.6 Hz, 1H), 7.48 (s, 1H), 7.37e7.30
1333 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
8.15 (d, J¼7.5 Hz, 1H), 7.59
(m, 1H), 2.34 (s, 3H), 1.66 (s, 9H); 13C NMR (100 MHz, CDCl3):
(d, J¼3.2 Hz, 1H), 7.56 (d, J¼7.7 Hz, 1H), 7.34e7.27 (m, 1H), 7.25e7.18
d
149.1, 137.0, 127.0 (q, J¼1.6 Hz), 126.1, 124.4 (q, J¼271.8 Hz), 123.1,
(m, 1H), 6.57 (d, J¼3.7 Hz, 1H), 1.67 (s, 9H); 13C NMR (100 MHz,
121.8 (q, J¼32.6 Hz), 120.2 (q, J¼6.2 Hz), 118.9, 115.3, 84.0, 28.2, 11.9
(q, J¼5.3 Hz); HR-MS (EIþ) calcd for C15H16F3NO2 [M]þ 299.1133,
found 299.1126.
CDCl3): d 149.8, 135.1, 130.5, 125.8, 124.1, 122.6, 120.9, 115.1, 107.2,
83.6, 28.2; HR-MS (EIþ) calcd for C13H15NO2 [M]þ 217.1103, found
217.1105.
4.1.4.4. tert-Butyl 4-methoxy-3-methyl-1H-indole-1-carboxylate
(9b). Yield 88.3%; colorless oil; FT-IR (thin film, neat) nmax 2970,
2349, 2309, 1738, 1647, 1605, 1566, 1542, 1508, 1496, 1435, 1368,
4.1.4.11. tert-Butyl 3-methyl-1H-indole-1-carboxylate (9i). Yield
88.4%; colorless oil; FT-IR (thin film, neat) nmax 3052, 2979, 1933,
1732, 1609, 1575, 1476, 1454, 1423, 1389, 1372, 1357, 1308 cmꢀ1; 1H
1352,1308 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
7.73 (d, J¼7.1 Hz,1H),
NMR (400 MHz, CDCl3):
d
8.11 (br s, 1H), 7.49 (d, J¼7.7 Hz, 1H),
7.22e7.14 (m, 2H), 6.62 (d, J¼8.0 Hz, 1H), 3.88 (s, 3H), 2.40 (s, 3H),
7.40e7.19 (m, 3H), 2.27 (s, 3H), 1.66 (s, 9H); 13C NMR (100 MHz,
1.64 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
154.6, 149.8, 137.1, 125.0,
CDCl3): d 149.8, 135.4, 131.4, 124.2, 122.8, 122.2, 118.9, 116.3, 115.1,
121.4, 120.5, 116.7, 108.2, 103.0, 83.1, 55.2, 28.2, 12.4; HR-MS (EIþ)
calcd for C15H19NO3 [M]þ 261.1365, found 261.1366.
83.1, 28.2, 9.6; HR-MS (EIþ) calcd for C14H17NO2 [M]þ 231.1259;
found 231.1258.
4.1.4.5. tert-Butyl 3-methyl-5-(trifluoromethyl)-1H-indole-1-
carboxylate (9c). Yield 89.3%; white solid; mp 78e80 ꢁC; FT-IR
(thin film, neat) nmax 3014, 2970, 2945, 2349, 2309, 1739, 1625,
4.1.4.12. tert-Butyl 3-phenyl-1H-indole-1-carboxylate (9j). Yield
91.2%; colorless oil; FT-IR (thin film, neat) nmax 3055, 2979, 2933,
1734, 1608, 1564, 1494, 1475, 1452, 1375, 1336, 1309 cmꢀ1; 1H NMR
1542, 1508, 1448, 1370, 1315 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
(400 MHz, CDCl3):
7.71 (s. 1H), 7.67e7.61 (m, 2H), 7.50e7.43 (m, 2H), 7.40e7.33 (m,
d
8.23 (d, J¼7.6 Hz, 1H), 7.82 (d, J¼7.6 Hz, 1H),
d
8.21 (d, J¼7.1 Hz, 1H), 7.76, (s, 1H), 7.55 (d, J¼8.7 Hz, 1H), 7.44 (s,
1H), 2.29 (s, 3H), 1.67 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
149.4,
2H), 7.32e7.26 (m, 1H), 1.69 (s, 9H); 13C NMR (100 MHz, methanol-
137.0, 131.1, 124.9 (q, J¼271.7 Hz), 124.6 (q, J¼32.0 Hz), 124.4, 120.9
(q, J¼3.6 Hz), 116.4, 116.3 (q, J¼4.1 Hz), 115.3, 84.0, 28.2, 9.4; HR-MS
(EIþ) calcd for C15H16F3NO2 [M]þ 299.1133, found 299.1131.
d4): d 151.0, 137.3, 135.0, 130.2, 129.9, 128.9, 128.3, 125.7, 124.1, 123.7,
123.5, 120.9, 116.4, 85.1, 28.4; HR-MS (EIþ) calcd for C19H19NO2 [M]þ
293.1416, found 293.1416.
4.1.4.6. tert-Butyl 5-methoxy-3-methyl-1H-indole-1-carboxylate
(9d). Yield 86.1%; colorless oil; FT-IR (thin film, neat) nmax 3126,
4.1.4.13. 1-tert-Butyl 3-methyl-1H-indole-1,3-dicarboxylate (9k).
Yield 95.3%; white solid; mp 122e124 ꢁC; FT-IR (thin film, neat)

W.-I. Lee et al. / Tetrahedron 69 (2013) 7211e7219
7219
nmax 2971, 1744, 1718, 1560, 1481, 1452, 1372, 1333, 1309 cmꢀ1
NMR (400 MHz, CDCl3): 8.27 (s, 1H), 8.22e8.12 (m, 2H),
7.42e7.31 (m, 2H), 3.94 (s, 3H), 1.69 (s, 9H); 13C NMR (100 MHz,
;
1H
13. (a) Richardson, B. P.; Engel, G.; Donatsch, P.; Stadler, P. A. Nature 1985, 316,
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d
CDCl3):
d 164.6, 148.9, 135.5, 132.1, 127.5, 125.1, 123.9, 121.6, 115.1,
112.2, 85.0, 51.4, 28.1; HR-MS (FABþ) calcd for C15H18NO4 [MþH]þ
276.1236; found 276.1237.
Acknowledgements
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This work was supported by the National Research Foundation
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Supplementary data
Copies of 1H NMR and 13C NMR are available. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.06.101.
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