The ultra high pressure conjugate addition of indoles to electron- deficient olefins

Article abstract of DOI:10.1139/v98-158

The addition of indole and methyl indole at both high and ambient pressures to a series of Michael acceptors under the influence of ytterbium triflate was investigated. Under ambient pressure the more reactive and less sterically hindered electrophiles ga

Full text of DOI:10.1139/v98-158

1
256
The ultra high pre s s ure c onjuga te a ddition of
indole s to e le c tron-de fic ie nt ole fins
Pa u l Ha rrin gton a n d Mic h a e l A. Ke rr
Abstract: The addition of indole and methyl indole at both high and ambient pressures to a series of Michael
acceptors under the influence of ytterbium triflate was investigated. Under ambient pressure the more reactive and less
sterically hindered electrophiles gave the expected 3-alkylated indoles in good to excellent yields. The more
problematic Michael acceptors were subjected to pressures of 13 kbar. In all cases a dramatic reduction in reaction
time and a significant improvement in yields was observed. In the cases involving 3-methylcyclohex-2-en-1-one, a by-
product was formed and was characterized by single crystal X-ray diffraction. α,β-Unsaturated ketones gave the best
yields. Enals tended to polymerize while enoates proved to be much too unreactive. A particularly reactive malonate
derived ester and β-nitrostyrene gave good yields at ambient pressures.
Key words: hapalindole, indole, Michael addition, high pressure, ytterbium triflate, Lewis acid.
Résumé : On a étudié la réaction d’addition de l’indole et du méthylindole sur une série d’accepteurs de Michael sous
l’influence de triflate d’ytterbium et à des pressions tant ambiante qu’élevée. À la pression ambiante, les électrophiles
les plus réactifs présentant le moins d’encombrement stérique conduisent, avec des rendements allant de bons à
excellents, aux indoles alkylés en position 3 attendus. Les accepteurs de Michael plus problématiques ont été soumis à
des pressions de 13 kbar. Dans tous les cas, on a observé une réduction dramatique du temps de réaction et une
amélioration significative des rendements. Dans les cas impliquant la 3-méthylcyclohex-2-én-1-one, il se forme un
sous-produit qui a été caractérisé par diffraction des rayons X par un cristal unique. Les cétones α,β-insaturées donnent
les meilleurs rendements. Les énals tendent à se polymériser alors que les énolates se sont avérés beaucoup moins
réactifs. Un malonate particulièrement réactif, obtenu à partir de l’ester et du β-nitrostyrène, donne de bons rendements
à des pressions ambiantes.
Mots clés : hapaindole, indole, addition de Michael, pression élevée, triflate d’ytterbium, acide de Lewis.
[
Traduit par la Rédaction] Harrington and Kerr 1265
the stereochemistry of the compounds; many have a dia-
stereomeric relationship. This class of compounds provides
an excellent opportunity for both stereochemical confirma-
tion of the reported structures by synthesis and for the prep-
aration of certain members for biochemical studies.
We have recently been involved in studies directed to-
wards the total synthesis of a class of bioactive indole alka-
loids known as the hapalindoles. These cytotoxic
compounds are a class of at least 20 members, isolated from
the blue-green algae Hapalosiphon fontinalis by Moore et
(
1). The algae were isolated from soil samples collected
from the Marshall Islands in 1981 and showed antibacterial,
antimycotic, and antialgal activities. Initial reports disclosed
the presence of two related compounds, hapalindole A and B
(
1a). Hapalindole A is responsible for the bulk of the biolog-
ical activity. Three years later, the same group reported the
structures of an additional 18 related compounds isolated
from the same organism (1b). The structures possess either
the tetracyclic framework present in hapalindole A and B or
a tricyclic skeleton (possibly a biogenetic precursor) repre-
sented by hapalindoles C and D. There is large variation in
The study of the chemistry of these compounds (2) as
well as activity towards the synthesis of interesting natural
products has been steady. There have been several syntheses
of a few members of this class of compounds to date (3).
Our retrosynthesis of hapalindole C (Scheme 1) centers
around the nucleophilic addition of an indole moiety 6 to a
suitable terpenoid fragment 7 to produce the key intermedi-
ate 5. Subsequent conversion to the target molecule 3 would
involve only the addition of the geminally disposed vinyl
Received November 6, 1996.1
2
P. Harrington and M.A. Kerr. Department of Chemistry,
Acadia University, Wolfville, NS B0P 1X0, Canada.
1
Revision received July 8, 1998.
Author to whom correspondence may be addressed.
2
Telephone: (902) 585-1109. Fax: (902) 542-1454. E-mail:
michael.kerr@acadiau.ca
Can. J. Chem. 76: 1256–1265 (1998)
© 1998 NRC Canada

Harrington and Kerr
1257
Scheme 1. Proposed retrosynthesis of hapalindole C.
Table 1. Ambient pressure alkylations of indoles with α,β-unsaturated ketones catalyzed by Yb(OTf)3.
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Can. J. Chem. Vol. 76, 1998
[
1]
and methyl substituents and conversion of the ester to an
isonitrile. The use of the menthane class of terpenes as start-
ing materials would imply that this approach has the poten-
tial to provide homochiral material.
alkyl-derived protecting groups for the nitrogen (i.e., benzyl,
methoxymethyl, etc.). The use of an electron-withdrawing
substitiuent (i.e., a p-toluenesulphonyl group) on the indole
nitrogen greatly attenuated the nucleophilic character of the
indole and the reactions with the Michael acceptors were
suppressed. The 1-triisopropylsilyl derivative underwent the
conjugate addition but at a slower rate and with the concom-
itant loss of the silyl protecting group. The absence of cata-
lyst resulted in low yields of addition with only the most
reactive Michael acceptors (methyl vinyl ketone, β-nitro-
styrene).
Several trends from Table 1 are worthy of note. As ex-
pected, steric hindrance plays an important role in the suc-
cess or failure of the reaction; an increase in steric bulk on
the Michael acceptor generally impedes the reaction. A sin-
gle β-substituent on the enone does little to slow the reaction
While one could envision the addition of the indole frag-
ment via an organometallic species such as a Grignard re-
agent or a copper derivative (via the readily available 3-
haloindole), we were intrigued by the natural enamine char-
acter, which is present in indoles and imparts a relatively
high degree of nucleophilicity to the 3-position (4). Because
of our interest in the use of hyperbaric conditions to promote
useful chemical reactions, we were curious as to whether or
not the nucleophilicity of the indole would be sufficient to
add to Michael acceptors and whether the nucleophilicity
would be enhanced at ultra high pressures.
The addition of indole to electron-deficient olefins is not a
new reaction; however, the utility of this process is restricted
in that only highly reactive Michael acceptors can be used
with acceptable results (5). Recently Kotsuki et al. disclosed
their results of a study that investigated the addition of
indoles to epoxides at ultra high pressures using catalysts
such as ytterbium triflate and silica gel (6). At almost the
same time, we reported our preliminary results (7), which
showed that indoles add in a 1,4-fashion to α,β-unsaturated
ketones under the influence of ytterbium triflate (eq. [1]). In
this paper we wish to provide details of the preliminary
study as well as report the results of our work involving the
ultra high pressure variant of this reaction.
(
entries 3 and 4) while a second β-substituent greatly reduces
the reactivity of the olefin towards the indole (entries 5 and
and entry 10). The fact that reactions involving trans-3-
6
pentene-2-one (entries 3 and 4) provide improved yields
over methyl vinyl ketone (entries 1 and 2) may be due to the
fact that the former enone is much less prone to polymeriza-
tion as a side reaction. Overall, the reactions were quite
clean with the only major contaminant being the unreacted
starting materials. If this methodology is to be truly useful
for the synthesis of the hapalindoles, substrates such as
cyclohexenone must work well. Under ambient pressures,
the cyclohexenones gave surprisingly low yields with rela-
tively little starting material recovered. An interesting by-
product was formed in 6% yield in the reaction of 1-
Ytterbium triflate has become, in recent years, a widely
used Lewis acid in organic synthesis (8). While researching
Lewis acids for use at elevated pressures, a report by Jenner
indicated that ytterbium triflate might be a suitable candidate
1
methylindole with 3-methyl-2-cyclohexenone. The H and
13
C NMR spectra of this by-product were complicated and
(
9). The reaction in eq. [1] may also be considered to be a
the structure remained a mystery for some time. The identity
of the compound was ultimately found to be the triindolyl
cyclohexane 8 using single crystal X-ray diffraction. A com-
plete set of crystallographic data for compound 8 is avail-
type of Friedel–Crafts alkylation, a class of reactions that
has seen the use of lanthanide triflates (10).
3
able as supplementary material. The ORTEP representation
4
,5
is shown in Fig. 1. In hindsight, the formation of this ma-
terial is not surprising. The addition of a single molecule of
the indole in a 1,4-fashion would afford a ketone that may
undergo what may be considered a vinylogous ketalization
reaction.
When investigating the effects of pressure on a reaction it
is prudent to run the reaction at ambient pressure in order to
isolate and quantify the effects of pressure on the reaction
course. During such a reaction it was noticed that indoles
added to many of the Michael acceptors under the influence
of ytterbium triflate at ambient pressures. Table 1 summa-
rizes the results of the addition of indole and 1-methylindole
to a series of α,β-unsaturated ketones under ambient pres-
sure. A methyl group was chosen as a simple model for
The fact that a simple ketone can undergo such a reaction
under these conditions was confirmed by the fact that when
two equivalents of indole were combined with one equiva-
lent of cyclohexanone, 9 was formed as the sole product
(eq. [2]). This type of reaction catalyzed by protic acid has
3
Supplementary material may be purchased from: The Depository of Unpublished Data, Document Delivery, CISTI, National Research
Council of Canada, Ottawa, Canada, K1A 0S2. Tables of atomic coordinates and bond lengths and angles have also been deposited with the
Cambridge Crystallographic Data Centre and can be obtained on request from: The Director, Cambridge Crystallographic Data Centre, Uni-
versity Chemical Laboratory, 12 Union Road, Cambridge, CB2 1EZ, U.K. Tables of structure factors are no longer being deposited, and
may be obtained on request from the author.
4
5
The figure shows one molecule of acetonitrile, which was co-crystallized.
Empirical formula: C H N (acetonitrile included): fw = 526.70, space group P2 /n, a = 13.893(3) Å, b = 8.213(2) Å, c = 26.097(5) Å,
3
6
38
4
1
3
3
V = 2969.3(11) Å , ρ = 1.178 mg/m , T = 293 K, λ = 1.54178 Å.
c
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Harrington and Kerr
1259
[
2]
Fig. 1. ORTEP representation of by-product 8.
Table 2. Yb(OTf)3 catalyzed alkylations of 1-methylindole with
α,β-unsaturated ketones at 13 kbar.
been reported (11). In addition, Wang and co-workers dis-
closed formally this same observation using a host of lanth-
anide triflates (12).
Cyclopent-2-en-1-one underwent addition in 95% yield;
significantly higher than cyclohex-2-ene-1-one (entry 9).
Finally, note that even when the β-substituent on the enone
is a rather bulky isopropyl group (entry 7), the yield is still
quite high.
The most notable limitation apparent from the results in
Table 1 is that in cases where steric hindrance is significant,
this methodology fails to produce useful amounts of adducts.
In an effort to overcome this difficulty, reactions using these
substrates were subjected to hyperbaric conditions (Table 2).
In general, the reactions were performed at 13 kbar (1 bar =
6
1
00 kPa) using acetonitrile as the solvent. In all cases, there
was a notable reduction in reaction time and an increase in
the yield of adduct. The most dramatic increase in isolated
yield was observed with 4-phenyl-3-buten-2-one as the Mi-
chael acceptor (67% compared to 10% under ambient condi-
tions, entry 3). Also of note is the fact that under these
conditions, N-methyl indole added to cyclohex-2-en-1-one in
5
6% yield, an improvement from the 37% yield observed
high pressure facilitates the addition of indoles to enones is
not surprising since formation of the transition state should
result in a significant reduction in molar volume. (13). The
use of high pressures to promote conjugate additions is not
new and has been reported (14).
under ambient conditions. The same enones bearing an addi-
tional β-substituent proved extremely unreactive even under
high-pressure conditions; however, small amounts of the ex-
pected adducts were isolated and characterized. The fact that
6
Although a thorough screening of solvents was not performed, a brief experimental survey revealed that acetonitrile is the solvent of choice
for these reactions.
©
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260
Can. J. Chem. Vol. 76, 1998
Table 3. Yb(OTf) catalyzed alkylations of indoles with other
Michael acceptors.
was formed. The low yield may be attributed to the tendency
of these types of compounds to exist, to a large degree, in
the enol form.
3
In summary, we have shown that the use of ytterbium
triflate to catalyze the addition of indoles to α,β-unsaturated
ketones provides a useful complement to the existing meth-
ods available for the 3-alkylation of indole. Of interst to us
for the synthesis of hapalindole alkaloids is the fact that
cyclohexenones can be made to undergo reaction in accept-
able yields under hyperbaric conditions, in contrast to more
disappointing results using ambient conditions. Using this
methodology, we intend to pursue as targets the interesting
class of hapalindole alkaloids. Progress towards this end will
be reported in due course.
General
Melting points were determined using a MEL-TEMP II
melting point apparatus and are uncorrected. NMR spectra
were obtained using a Bruker AM250 spectrometer in
CDCl as the solvent and are recorded in parts per million
3
1
downfield from tetramethylsilane. H NMR spectra were re-
corded at 250 MHz and C NMR spectra were recorded at
3 MHz. Infrared spectra were measured on a Perkin–Elmer
1
3
6
model 683 infrared spectrophotometer using a thin film of
the compound on a sodium chloride plate. Mass spectra
were recorded using a CEC model 21-11-B double-focusing
mass spectrometer using a heated quartz direct-introduction
probe with an 8000 V accelerating voltage. Crystallographic
analysis was performed using a Rigaku AAFC5R diffrac-
tometer with a 12 MW rotating anode X-ray generator. Thin-
layer chromatography was performed on E. Merck precoated
TLC plates (Silica gel 60 F-254). Flash column chromatog-
raphy was performed with EM Science Silica gel 60 (230–
4
00 mesh). High-pressure reactions were performed in a
LECO Tem-Pres HPC-200 chemical reactor in heat shrink-
able Teflon tubes. Samples for melting point determination
®
were recrystallized from methylene chloride and hexanes.
Commercial reagents and solvents were used as supplied
without further purification.
For the sake of exploring the general scope of this reac-
tion, other electrophiles were also subjected to the above
conditions and with some success. While many common
electron-deficient olefins (phenyl vinyl sulphone, acrylo-
nitrile, ethyl cinnamate, methyl propiolate, crotonaldehyde,
and cinnnamaldehyde) failed to give satisfactory results,
several reactive Michael acceptors proceeded to give the ex-
pected products (Table 3). As expected, β-nitrostyrene (en-
tries 1 and 2) was quite reactive at ambient pressure. The
fact that 1-methylindole gave an abnormally low yield is cu-
rious and may be due to the formation of a series of by-
products that were not characterized. Note that even the re-
action with a highly reactive diester such as diethyl
benzalmalonate (entries 3 and 4) was sluggish and took sev-
eral days to go to completion, albeit in good yield. Methyl
acrylate was unreactive at ambient pressure but gave an
isolable amount of material under hyperbaric conditions.
Finally, it should be noted that when 2-carbomethoxy-2-
cyclohexenone was treated with indole in the presence of
Typical procedure for the ambient pressure reaction of
indoles with α,β-unsaturated ketones
To a solution of the indole in acetonitrile was added the
enone as a solid or a neat liquid. Ytterbium trifluorometh-
anesulphonate trihydrate was added and the mixture was
stirred in a capped flask for the required amount of time. Af-
ter thin-layer chromatography indicated the disappearance of
starting material or after 1 week, which ever came first, the
solvent was removed in vacuo and the residue was taken up
in diethyl ether. Filtration of the ether suspension through a
®
pad of Celite followed by removal of the solvent in vacuo
yielded the crude reaction product, which was purified by
flash chromatography on a column of silica gel (elution with
an appropriate mixture of ethyl acetate and hexanes).
4
-(3-Indolyl)-2-butanone (Table 1, entry 1)
Standard procedure: indole (263 mg, 2.24 mmol), methyl
vinyl ketone (500 µL, 6.11 mmol), Yb(OTf) ·3H O (28 mg,
3
2
4
2 µmol), acetonitrile (2 mL). The mixture was stirred for
Yb(OTf) , a small amount of the desired Michael adduct
3
©
1998 NRC Canada

Harrington and Kerr
1261
4
h after which time an additional 300 µL of methyl vinyl
Rf = 0.41 (30% EtOAc – hexanes). IR (neat), ν: 3040, 2950,
ketone (3.66 mmol) was added. After a total time of 22 h,
the mixture was worked up in the usual way. Flash chroma-
tography using gradient elution (20–50% EtOAc – hexanes)
afforded 304 mg pure material (72%) as a white solid, mp
2870, 1700, 1605, 1540, 1475, 1415, 1345, 1320, 1260,
–
1
1
1220, 1145, 1125, 1095, 1005, 755, 735 cm . H NMR
(250 MHz, CDCl ), δ: 1.36 (d, J = 7.0 Hz, 3H), 2.08 (s, 3H),
3
2.68 (dd, J = 16.2, 8.2 Hz, 1H), 2.91 (dd, J = 15.9, 6.1 Hz,
1H), 3.61 (m, 1H), 3.70 (s, 3H), 6.81 (s, 1H), 7.09 (tm, J =
7.3 Hz, 1H), 7.21 (tm, J = 7.5 Hz, 1H), 7.27 (dm, J =
9
5–96°C. R = 0.31 (30% EtOAc – hexanes). IR (thin film),
f
–
1 1
ν: 3315, 1700 cm . H NMR (250 MHz, CDCl ), δ: 2.14 (s,
3
3
1
3
H), 2.84 (t, J = 7.3 Hz, 2H), 3.05 (tm, J = 7.3 Hz, 2H), 6.98
7.6 Hz, 1H), 7.62 (dm, J = 7.6 Hz, 1H). C NMR (63 MHz,
(
(
=
dm, J = 2.4 Hz, 1H), 7.12 (td, J = 7.0, 1.2 Hz, 1H), 7.19
td, J = 7.0, 1.2 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.59 (d, J
CDCl ), δ: 21.5, 27.0, 30.4, 32.6, 51.6, 109.3, 118.7, 119.2,
3
119.5, 121.6, 125.0, 126.6, 137.2, 208.6. MS (70 eV), m/e:
1
3
+
7.0 Hz, 1H), 7.98 (bs, 1H). C NMR (63 MHz, CDCl ), δ:
215(M ), 172, 159, 158(100), 115. HRMS (for C H NO):
3
14 17
1
1
1
1
9.4, 30.1, 44.1, 111.3, 115.1, 118.7, 119.3, 121.6, 122.1,
27.2, 136.4, 209.0. MS (70 eV), m/e: 188 (M+1), 187 (M ),
215.1310 (calcd.); 215.1309 (found).
+
31, 130(100), 117, 115, 42. HRMS (for C H NO):
4-(3-Indolyl)-4-methyl-2-pentanone (Table 1, entry 5)
Standard procedure: indole (263 mg, 2.24 mmol), mesityl
oxide (500 µL, 4.36 mmol), Yb(OTf) ·3H O (32 mg,
1
2
13
87.0997 (calcd.); 187.1008 (found).
3
2
4
-(3-(1-Methylindolyl))-2-butanone (Table 1, entry 2)
Standard procedure: 1-methylindole (273 mg, 2.08 mmol),
47 µmol), acetonitrile (2 mL). The mixture was stirred for 7
d and worked up in the usual way. Flash chromatography us-
ing gradient elution (10–20% EtOAc – hexanes) afforded
methyl vinyl ketone (500 µL, 6.11 mmol), Yb(OTf) ·3H O
3
2
(
31 mg, 46 µmol), acetonitrile (2 mL). The mixture was
91 mg pure material (19%) as a yellow oil. R = 0.37 (30%
EtOAc – hexanes). IR (neat), ν: 3400, 2950, 2915, 1685,
f
stirred for 7 h and worked up in the usual way. Flash chro-
matography using gradient elution (10–30% EtOAc – hex-
anes) afforded 307 mg pure material (73%) as a white solid.
1450, 1410, 1345, 1325, 1235, 1200, 1115, 1100, 1005, 760,
–
1 1
735 cm . H NMR (250 MHz, CDCl ), δ: 1.53 (s, 6H), 1.72
3
R = 0.33 (30% EtOAc – hexanes). IR (neat), ν: 3040, 2905,
(s, 3H), 2.95 (s, 2H), 6.89 (d, J = 2.4 Hz, 1H), 7.08–7.21 (m,
2H), 7.34 (dm, J = 7.3 Hz, 1H), 7.80 (dm, J = 7.9 Hz, 1H),
f
–
1 1
1
700, 1475, 1460, 735 cm . H NMR (250 MHz, CDCl ),
3
1
3
δ: 2.13 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 3.03 (tm, J =
8.01 (bs, 1H). C NMR (63 MHz, CDCl ), δ: 28.9, 29.7,
3
.6 Hz, 2H), 3.72 (s, 3H), 6.83 (s, 1H), 7.10 (ddd, J = 8.2,
.7, 1.5 Hz, 1H), 7.22 (td, J = 7.9, 6.7, 1.5 Hz, 1H), 7.28
31.8, 34.5, 55.1, 111.7, 119.1, 120.6, 120.7, 121.7, 123.5,
125.5, 137.2, 209.5. MS (70 eV), m/e: 216 (M+1), 215(M ),
200, 159, 158(100), 157, 143, 142, 115, 42. HRMS (for
+
dm, J = 7.9 Hz, 1H), 7.57 (dm, J = 7.6 Hz, 1H). 13C NMR
C H NO): 215.1310 (calcd.); 215.1324 (found).
3
14 17
1
18.7 (two carbons), 121.5, 126.3, 127.5, 136.9, 208.9. MS
+
(
70 eV), m/e: 202(M+1), 201(M ), 158, 145, 144(100), 143,
15. HRMS (for C H NO): 201.1154 (calcd.); 201.1123
4-(3-(1-Methylindolyl))-4-methyl-2-pentanone (Table 1, entry 6)
Standard procedure: 1-methylindole (290 mg, 2.21 mmol),
mesityl oxide (500 µL, 4.36 mmol), Yb(OTf) ·3H O (31 mg,
1
1
3
15
(
found).
3
2
4
6 µmol), acetonitrile (2 mL). The mixture was stirred for 7
4
-(3-Indolyl)-2-pentanone (Table 1, entry 3)
Standard procedure: indole (258 mg, 2.20 mmol), 3-
d and worked up in the usual way. Flash chromatography us-
ing gradient elution (10–20% ethyl acetate – hexanes) af-
penten-2-one (500 µL, 5.12 mmol), Yb(OTf) ·3H O (33 mg,
forded 195 mg pure material (38%) as a yellow oil. R =
0.49 (30% EtOAc – hexanes). IR (neat), ν: 3020, 2940,
3
2
f
4
1
9 µmol), acetonitrile (2 mL). The mixture was stirred for
4 h and worked up in the usual way. Flash chromatography
1700, 1605, 1535, 1475, 1415, 1350, 1230, 1145, 1100,
–
1 1
using gradient elution (20–50% EtOAc – hexanes) afforded
75 mg pure material (85%) as a white solid. R = 0.33
1010, 980, 760, 730 cm . H NMR (250 MHz, CDCl ), δ:
3
3
1.53 (s, 6H), 1.73 (s, 3H), 2.94 (s, 2H), 3.73 (s, 3H), 6.79 (s,
1H), 7.11 (ddd, J = 8.2, 7.0, 1.2, 1H), 7.22 (ddd, J = 7.9, 7.0,
1.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.79 (dd, J = 7.9,
f
(
30% EtOAc – hexanes). IR (neat), ν: 3400, 3045, 2950,
–
1 1
2
1
8
6
1
7
915, 1705, 1610, 735 cm . H NMR (250 MHz, CDCl ), δ:
3
1
3
.38 (d, J = 7.0 Hz, 3H), 2.08 (s, 3H), 2.70 (dd, J = 16.2,
.2 Hz, 1H), 2.93 (dd, J = 16.2, 6.1 Hz, 1H), 3.63 (m, 1H),
.93 (d, J = 2.1 Hz, 1H), 7.11 (ddd, J = 8.2, 7.3, 1.5 Hz,
H), 7.18 (ddd, J = 8.2, 7.0, 1.5 Hz, 1H), 7.33 (d, J =
1.2 Hz, 1H). C NMR (63 MHz, CDCl ), δ: 29.0, 31.9,
3
32.7, 34.5, 55.2, 109.7, 118.7, 120.9, 121.3, 122.2, 125.4,
+
126.0, 137.8, 209.2. MS (70 eV), m/e: 230 (M+1), 229 (M ),
173, 172 (100), 130, 115. HRMS (for C H NO): 229.1467
1
5
19
.9 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 8.02 (bs, 1H). 13
C
(calcd.); 229.1473 (found).
NMR (63 MHz, CDCl ), δ: 21.3, 27.1, 30.4, 51.5, 111.4,
3
19.1, 119.3, 120.2, 121.0, 122.1, 126.3, 136.6, 208.9. MS
+
1
3
15
Yb(OTf) ·3H O (30 mg, 44 µmol), acetonitrile (2 mL). The
3
2
4
-(3-(1-Methylindolyl))-2-pentanone (Table 1, entry 4)
Standard procedure: 1-methylindole (295 mg, 2.25 mmol),
-penten-2-one (500 µL, 5.12 mmol), Yb(OTf) ·3H O
mixture was stirred for 4 d and worked up in the usual way.
Flash chromatography using gradient elution (5–20% EtOAc
– hexanes) afforded 438 mg pure material (77%) as a low-
3
3
2
(
33 mg, 49 µmol), acetonitrile (2 mL). The mixture was
melting solid. R = 0.50 (30% EtOAc – hexanes). IR (neat),
f
stirred for 10 h and worked up in the usual way. Flash chro-
matography using gradient elution (5–20% EtOAc – hex-
anes) afforded 461 mg pure material (95%) as a yellow oil.
ν: 2940, 2915, 2860, 1700, 1475, 1460, 1415, 1360, 1345,
–
1
1
1320, 1250, 1225, 1150, 1125, 1005, 730 cm . H NMR
(250 MHz, CDCl ), δ: 0.86 (d, J = 6.7 Hz, 3H), 0.91 (d, J =
3
©
1998 NRC Canada

1
262
Can. J. Chem. Vol. 76, 1998
6
3
7
1
.7 Hz, 3H), 1.96 (s, 3H), 2.05 (m, 1H), 2.78–2.86 (m, 2H),
.30 (td, J = 6.7, 6.4 Hz, 1H), 3.71 (s, 3H), 6.79 (s, 1H),
.08 (ddd, J = 7.5, 6.7, 1.3, 1H), 7.19 (td, J = 7.4, 1.0 Hz,
H), 7.26 (dm, J = 7.9 Hz, 1H), 7.63 (dm, J = 7.9 Hz, 1H).
mixture was stirred for 7 d and worked up in the usual way.
Flash chromatography using gradient elution (10– 30%
EtOAc – hexanes) afforded 16 mg pure material (3%) as a
yellow oil. R = 0.36 (30% EtOAc – hexanes). IR (neat), ν:
f
1
3
C NMR (63 MHz, CDCl ), δ: 20.4, 20.6, 30.1, 32.7, 32.8,
3030, 2920, 1690, 1535, 1475, 1410, 1365, 1320, 1300,
3
–
1
1
3
1
2
2
9.2, 47.2, 109.2, 115.9, 118.6, 119.5, 121.3, 126.7, 127.7,
1275, 1235, 1215, 1140, 1130, 1100, 1010, 730 cm . H
+
36.9, 209.3. MS (70 eV), m/e: 244 (M+1), 243 (M ), 201,
NMR (250 MHz, CDCl ), δ: 1.41–1.59 (m, 1H), 1.53 (s,
3
00 (100), 186, 158, 157, 143, 69. HRMS (for C H NO):
3H), 1.76–1.94 (m, 2H), 2.24–2.32 (m, 2H), 2.46 (d, J =
14.4 Hz, 1H), 2.58 (m, 1H), 2.89 (dd, J = 14.4, 1.5 Hz, 1H),
1
6
21
43.1623 (calcd.); 243.1626 (found).
3
.70 (s, 3H), 6.80 (s, 1H), 7.08 (ddd, J = 8.3, 7.3, 1.2 Hz,
3
-(3-Indolyl)cyclohexanone (Table 1, entry 8)
1H), 7.21 (tm, J = 7.3 Hz, 1H), 7.29 (d, J = 8.2, Hz, 1H),
7.74 (d, J = 7.9 Hz, 1H). C NMR (63 MHz, CDCl ), δ:
22.4, 29.6, 32.7, 36.8, 40.0, 41.0, 54.4, 109.6, 118.5, 120.3,
1
3
Standard procedure: indole (241 mg, 2.06 mmol), 2-
cyclohexen-1-one (500 µL, 5.16 mmol), Yb(OTf) ·3H O
3
3
2
(
30 mg, 44 µmol), acetonitrile (2 mL). The mixture was
120.9, 121.5, 125.4, 126.9, 137.8, 212.5. MS (70 eV), m/e:
242 (M+1), 241 (M ,100), 226, 198, 184, 171, 131(100),
+
stirred for 2 d and an additional 9 mg (15 µmol) of catalyst
was added. The mixture was stirred for an additional 5 d and
worked up in the usual way. Flash chromatography using
gradient elution (10–30% EtOAc – hexanes) afforded
130, 42. HRMS (for C H NO): 241.1467 (calcd.);
1
6
19
241.1488 (found).
1
1
3
1
7
3
1
92 mg pure material (44%) as a pale yellow solid, mp 106–
3-(3-(1-Methylindolyl))cyclopentanone (Table 1, entry 11)
Standard procedure: 1-methylindole (322 mg, 2.45 mmol),
2-cyclopenten-1-one (500 µL, 6.18 mmol), Yb(OTf) ·3H O
07°C. R = 0.26 (30% EtOAc – hexanes). IR (neat), ν:
f
270, 2940, 2860, 1695, 1610, 1485, 1440, 1420, 1330,
255, 1210, 1175, 1100, 1050, 1020, 1000, 870, 800, 755,
3
2
(32 mg, 47 µmol), acetonitrile (2 mL). The mixture was
stirred for 4 d and worked up in the usual way. Flash chro-
matography using gradient elution (20–30% EtOAc – hex-
anes) afforded 496 mg pure material (95%) as a yellow oil.
Rf = 0.38 (30% EtOAc – hexanes). IR (neat), ν: 3040, 2945,
2920, 2870, 1730, 1605, 1475, 1415, 1395, 1365, 1320,
–
1
1
30 cm . H NMR (250 MHz, CDCl ), δ: 1.78–2.08 (m,
3
H), 2.25 (m, 1H), 2.38–2.46 (m, 2H), 2.62 (ddd, J = 14.0,
0.5, 1.1 Hz, 1H), 2.79 (ddt, J = 14.0, 4.6, 1.5 Hz, 1H), 3.42
(
7
(
m, 1H), 6.95 (dd, J = 2.4, 0.6 Hz, 1H), 7.11 (ddd, J = 7.8,
.0, 1.2 Hz, 1H), 7.19 (ddd, J = 7.8, 6.9, 1.5 Hz, 1H), 7.35
dm, J = 7.9 Hz, 1H), 7.61 (dm, J = 7.9 Hz, 1H), 8.12 (bs,
–
1
1
1310, 1235, 1145, 1125, 1005, 730 cm . H NMR
1
3
1
4
2
1
2
H). C NMR (63 MHz, CDCl ), δ: 24.9, 31.8, 36.0, 41.6,
(250 MHz, CDCl ), δ: 2.03–2.52 (m, 5H), 2.71 (dd, J = 18.3,
3
3
8.1, 111.4, 119.0, 119.4, 119.6, 120.5, 122.2, 126.2, 136.5,
7.6 Hz, 1H), 3.67 (m, 1H), 3.70 (s, 3H), 6.80 (d, J = 0.6 Hz,
1H), 7.11 (ddd, J = 7.9, 6.7, 1.5 Hz, 1H), 7.23 (td, J = 7.3,
1.2 Hz, 1H), 7.29 (dm, J = 8.1 Hz, 1H), 7.59 (td, J = 7.9,
+
12.1. MS (70 eV), m/e: 214 (M+1), 213 (M ), 170, 157,
56(100), 144, 143, 130, 128, 117. HRMS (for C H NO):
1
4
15
1
3
13.1154 (calcd.); 213.1166 (found).
0.9 Hz, 1H). C NMR (63 MHz, CDCl ), δ: 30.0, 32.6,
3
3
3.6, 38.1, 45.4, 109.4, 116.9, 118.8, 119.1, 121.8, 124.7,
3
-(3-(1-Methylindolyl))cyclohexanone (Table 1, entry 9)
Standard procedure: 1-methylindole (268 mg, 2.04 mmol),
-cyclohexen-1-one (500 µL, 5.16 mmol), Yb(OTf) ·3H O
126.9, 137.3, 219.3. MS (70 eV), m/e: 214 (M+1), 213
(M ,100), 184, 170, 158 157, 156 144. HRMS (for
C H NO): 213.1154 (calcd.); 213.1167 (found).
+
2
3
2
15 17
(
34 mg, 50 µmol), acetonitrile (2 mL). The mixture was
stirred for 7 d and worked up in the usual way. Flash chro-
matography using gradient elution (10–30% EtOAc – hex-
anes) afforded 171 mg pure material (37%) as a yellow oil.
4-(3-Indolyl)-4-phenyl-2-butanone (Table 1, entry 12)
Standard procedure: indole (250 mg, 2.13 mmol),
benzalacetone (370 mg, 2.53 mmol), Yb(OTf) ·3H O
(31 mg, 46 µmol), acetonitrile (2 mL). The mixture was
stirred for 7 d and worked up in the usual way. Flash chro-
matography using gradient elution (10–50% EtOAc – hex-
anes) afforded 89 mg pure material (16%) as a white solid,
3
2
Rf = 0.37 (30% EtOAc – hexanes). IR (neat), ν: 3040, 2920,
2
1
855, 1700, 1605, 1540, 1460, 1415, 1365, 1305, 1250,
210, 1145, 1120, 1045, 1005, 795, 730 cm . H NMR
–
1
1
(
250 MHz, CDCl ), δ: 1.78–2.08 (m, 3H), 2.23 (m, 1H),
3
2
2
3
1
=
.38–2.46 (m, 2H), 2.60 (ddd, J = 14.0, 10.4, 1.2 Hz, 1H),
.78 (ddt, J = 14.0, 4.6, 1.5 Hz, 1H), 3.43 (m, 1H), 3.73 (s,
H), 6.82 (d, J = 0.6 Hz, 1H), 7.10 (ddd, J = 7.9, 7.3,
.2 Hz, 1H), 7.22 (ddd, J = 8.2, 7.5, 1.2 Hz, 1H), 7.29 (td, J
mp 98–99°C. R = 0.27 (30% EtOAc – hexanes). IR (neat),
f
ν: 3400, 3050, 3020, 2910, 1695, 1590, 1485, 1445, 1405,
–
1
1
345, 1330, 1230, 1215, 1150, 1090, 1000, 735, 695 cm .
1
H NMR (250 MHz, CDCl ), δ: 2.09 (s, 3H), 3.17 (dd, J =
3
1
3
8.2, 1.1 Hz, 1H), 7.60 (td, J = 7.9, 0.9 Hz, 1H). C NMR
1
6.2, 7.9 Hz, 1H), 3.27 (dd, J = 16.2, 7.3 Hz, 1H), 4.85 (bt,
(
1
63 MHz, CDCl ), δ: 24.9, 32.0, 32.7, 35.9, 41.6, 48.3,
09.4, 118.2, 118.9, 119.1, 121.8, 125.3, 126.6, 137.2, 211.9.
3
J = 7.6 Hz, 1H), 6.98 (dd, J = 2.4, 0.6 Hz, 1H), 7.03 (ddd, J
=
7.9, 7.0, 1.2 Hz, 1H), 7.13–7.35 (m, 7H), 7.44 (dd, J = 7.0,
+
1
3
MS (70 eV), m/e: 228 (M+1), 227 (M ,100), 184, 170, 157,
1
.2 Hz, 1H), 8.04 (bs, 1H). C NMR (63 MHz, CDCl ), δ:
3
1
2
44, 115. HRMS (for C H NO): 227.1311 (calcd.);
15 17
30.4, 38.4, 50.4, 111.2, 118.8, 119.4, 121.4, 122.2, 126.4,
27.1302 (found).
-Methyl-3-(3-(1-methylindolyl))cyclohexanone (Table 1,
1
2
26.5, 127.7, 128.5, 136.6, 144.0, 207.8. MS (70 eV), m/e:
64 (M+1), 263 (M ,100), 221, 220, 207, 206, 42. HRMS
+
3
(
for C H NO): 263.1310 (calcd.); 263.1312 (found).
18 17
entry 10)
Standard procedure: 1-methylindole (292 mg, 2.23 mmol),
-methyl-2-cyclohexen-1-one (400 µL, 3.53 mmol),
Yb(OTf) ·3H O (37 mg, 55 µmol), acetonitrile (2 mL). The
4
-(3-(1-Methylindolyl))-4-phenyl-2-butanone (Table 1, entry 13)
Standard procedure: 1-methylindole (290 mg, 2.21 mmol),
3
3
2
benzalacetone (386 mg, 2.64 mmol), Yb(OTf) ·3H O
3 2
©
1998 NRC Canada

Harrington and Kerr
1263
(
34 mg, 50 µmol), acetonitrile (2 mL). The mixture was
46 µmol), acetonitrile (2 mL). The mixture was stirred for
30 h and was worked up in the usual way. Flash chromatog-
raphy using gradient elution (10–30% EtOAc – hexanes) af-
forded 596 mg pure material (89%) as a pale yellow solid,
stirred for 7 d and was worked up in the usual way. Flash
chromatography using gradient elution (10–30% EtOAc –
hexanes) afforded 63 mg pure material (10%) as a yellow
oil. R = 0.31 (30% EtOAc – hexanes). IR (neat), ν: 3045,
mp 102–103°C. R = 0.34 (30% EtOAc – hexanes). IR
f
f
3
1
015, 2920, 1700, 1590, 1540, 1475, 1410, 1360, 1345,
320, 1235, 1145, 1070, 1005, 730, 695 cm . H NMR
(neat), ν: 3420, 3050, 3020, 1595, 1545, 1485, 1445, 1415,
–
1
1
–1 1
1370, 1330, 1255, 1215, 1090, 1000, 965, 740, 695 cm . H
(
250 MHz, CDCl ), δ: 2.07 (s, 3H), 3.14 (dd, J = 16.2,
NMR (250 MHz, CDCl ), δ: 4.92 (dd, J = 12.4, 8.4 Hz, 1H),
3
3
7
4
1
.9 Hz, 1H), 3.25 (dd, J = 16.2, 7.3 Hz, 1H), 3.73 (s, 3H),
.85 (bt, J = 7.6 Hz, 1H), 6.80 (s, 1H), 7.00 (tm, J = 7.5 Hz,
5.04 (dd, J = 12.4, 7.5 Hz, 1H), 5.17 (bt, J = 7.9 Hz, 1H),
6.98 (d, J = 2.8 Hz, 1H), 7.06 (td, J = 7.5, 0.9 Hz, 1H),
7.15–7.35 (m, 7H), 7.43 (dm, J = 7.9 Hz, 1H), 8.03 (bs, 1H).
H), 7.11–7.32 (m, 7H), 7.42 (dm, J = 7.9 Hz, 1H). 13
C
1
3
NMR (63 MHz, CDCl ), δ: 30.3, 32.7, 38.3, 50.4, 109.2,
C NMR (63 MHz, CDCl ), δ: 41.6, 79.6, 111.4, 119.0,
3
3
1
1
17.3, 118.9, 119.5, 121.7. 126.3, 126.9, 127.7, 128.5,
120.0, 121.7, 122.7, 126.1, 127.6, 127.8, 129.0, 136.5,
139.2. MS (70 eV), m/e: 267 (M+1), 266 (M , 100), 220,
+
37.3, 144.1, 207.5. MS (70 eV), m/e: 278 (M+1), 277
+
(
M ,100), 221, 220, 218, 204. HRMS (for C H NO):
219, 218, 217, 206, 204, 42. HRMS (for C H N O ):
1
9
19
16 14
2
2
2
77.1467 (calcd.); 277.1464 (found).
266.1055 (calcd.); 266.1055 (found).
3
-(3-Indolyl)-3-phenylpropiophenone (Table 1, entry 14)
Standard procedure: indole (253 mg, 2.16 mmol),
2
2
-(3-(1-Methyl-indolyl))-2-phenylnitroethane (Table 3, entry
)
Standard procedure: 1-methylindole (287 mg, 2.19 mmol),
chalcone (528, 2.54 mmol), Yb(OTf) ·H O (34 mg,
5
d and was worked up in the usual way. Flash chromatogra-
phy using gradient elution (10–30% EtOAc – hexanes) af-
forded 366 mg pure material (52%) as a white solid, mp
3
2
0 µmol), acetonitrile (2 mL). The mixture was stirred for 7
β-nitrostyrene (387 mg, 2.59 mmol), Yb(OTf) ·3H O
3
2
(
37 mg, 55 µmol), acetonitrile (2 mL). The mixture was
stirred for 19 h and was worked up in the usual way. Flash
chromatography using gradient elution (10–50% EtOAc –
hexanes) afforded 241 mg pure material (39%) as a white
solid, mp 94–95°C. Rf = 0.38 (30% EtOAc – hexanes). IR
1
3
1
31–132°C. R = 0.36 (30% EtOAc – hexanes). IR (neat), ν:
f
410, 3045, 3020, 1670, 1590, 1570, 1485, 1440, 1405,
–
1 1
325, 1255, 1195, 1090, 1010, 995, 970, 735, 690 cm . H
(
neat), ν: 3050, 3020, 2910, 1595, 1540, 1465, 1445, 1415,
NMR (250 MHz, CDCl ), δ: 3.71 (dd, J = 16.8, 7.6 Hz, 1H),
3
–1
1
370, 1325, 1240, 1150, 1120, 1075, 1005, 735, 695 cm .
3
6
7
1
.81 (dd, J = 16.8, 6.7 Hz, 1H), 5.06 (bt, J = 7.3 Hz, 1H),
.95 (d, J = 2.4 Hz, 1H), 7.00 (td, J = 7.5. 0.9 Hz, 1H),
.10–7.55 (m, 12H), 7.92 (dm, J = 7.0 Hz, 1H), 7.97 (bs,
1
H NMR (250 MHz, CDCl ), δ: 3.71 (s, 3H), 4.91 (dd, J =
3
1
2.5, 8.6 Hz, 1H), 5.03 (dd, J = 12.4, 7.5 Hz, 1H), 5.17 (bt,
1
3
J = 7.9 Hz, 1H), 6.84 (d, J = 0.6 Hz, 1H), 7.06 (ddd, J = 7.9,
H). C NMR (63 MHz, CDCl ), δ: 38.2, 45.2, 111.2,
3
6
0
.6, 1.5 Hz, 1H), 7.18–7.33 (m, 7H), 7.44 (td, J = 7.9,
119.3, 119.4, 119.6, 121.5, 122.1, 126.3, 126.6, 127.7, 128.1,
1
3
.9 Hz, 1H). C NMR (63 MHz, CDCl ), δ: 32.9, 41.6,
3
1
28.5, 128.6, 133.1, 136.6, 137.1, 144.3, 198.6. MS (70 eV),
+
79.6, 109.6, 112.8, 119.0, 119.5, 122.3, 126.4, 126.6, 127.5,
m/e: 326 (M+1), 325 (M ), 220, 207, 206 (100), 178, 105,
7. HRMS (for C H NO): 325.1467 (calcd.); 325.1472
1
2
27.8, 128.9, 137.3, 139.4. MS (70 eV), m/e: 281 (M+1),
7
2
3
19
+
80 (M , 100), 235, 234, 233, 221, 220, 218, 217, 157, 146,
(
found).
115, 77, 50. HRMS (for C H N O ): 280.1212 (calcd.);
17 16 2 2
2
80.1204 (found).
3
-(3-(1-Methylindolyl))-3-phenylpropiophenone (Table 1,
entry 15)
Standard procedure: 1-methylindole (287 mg, 2.19 mmol),
chalcone (535, 2.57 mmol), Yb(OTf) ·3H O (32 mg,
Ethyl 2-ethoxycarbonyl-3-(3-indolyl)-3-phenyl propanoate
(Table 3, entry 3)
3
2
4
7 µmol), acetonitrile (2 mL). The mixture was stirred for 7
Standard procedure: indole (255 mg, 2.18 mmol), diethyl
benzalmalonate (600 mg, 2.68 mmol), Yb(OTf) ·3H O
(32 mg, 47 µmol), acetonitrile (2 mL). The mixture was
stirred for 4 d and was worked up in the usual way. Flash
chromatography using gradient elution (20–50% EtOAc –
hexanes) afforded 610 mg pure material (77%) as a white
d and was worked up in the usual way. Flash chromatogra-
phy using gradient elution (5–70% EtOAc – hexanes) af-
forded 687 mg pure material (93%) as a pale yellow solid,
3
2
mp 181–182°C. R = 0.41 (30% EtOAc – hexanes). IR
f
(
neat), ν: 3050, 2910, 1665, 1590, 1560, 1535, 1475, 1440,
–
1
1
405, 1360, 1325, 1305, 1290, 1235, 1145, 730, 690 cm .
solid, mp 164–165°C. R = 0.30 (30% EtOAc – hexanes). IR
f
1
H NMR (250 MHz, CDCl ), δ: 3.69 (s, 3H), 3.74–3.79 (m,
(neat), ν: 3440, 1735, 1705, 1445, 1360, 1310, 1260, 1240,
3
–
1 1
2
H), 5.06 (bt, J = 7.3 Hz, 1H), 6.83 (s, 1H), 7.00 (td, J =
.7, 1.2 Hz, 1H), 7.14–7.52 (m, 12H), 7.93 (dm, J = 7.0 Hz,
1180, 1165, 1145, 1085, 740, 695 cm . H NMR (250 MHz,
6
1
CDCl ), δ: 0.97 (t, J = 7.0 Hz, 3H), 1.00 (t, J = 7.0 Hz, 3H),
3
1
3
H). C NMR (63 MHz, CDCl ), δ: 37.2, 38.2, 45.4, 109.2,
3.97 (q, J = 7.1 Hz, 2H), 4.00 (q, J = 7.1 Hz, 2H), 4.29 (d, J
= 11.9 Hz, 1H), 5.08 (d, J = 11.6 Hz, 1H), 7.02 (ddd, J =
7.8, 7.0, 0.9 Hz, 1H), 7.09–7.30 (m, 6H), 7.34–7.38 (m, 2H),
3
117.8, 118.9, 119.6, 121.7, 126.3, 127.0, 127.9, 128.1, 128.5,
1
3
28.6, 133.0, 137.2, 137.4, 144.4, 198.5. MS (70 eV), m/e:
+
13
40 (M+1), 339 (M ), 234, 221, 220 (100). HRMS (for
7.54 (dd, J = 7.9, 0.6 Hz, 1H), 8.05 (bs, 1H). C NMR
C H NO): 339.1623 (calcd.); 339.1628 (found).
(63 MHz, CDCl ), δ: 13.8 (two carbons), 42.9, 58.4, 61.5
2
4
21
3
(
two carbons), 111.0, 116.9, 119.4, 119.5, 129.9, 122.2,
2
-(3-Indolyl)-2-phenylnitroethane (Table 3, entry 1)
Standard procedure: Indole (295 mg, 2.52 mmol), β-
126.8, 128.2, 128.4, 136.2, 141.4, 167.9, 168.1. MS (70 eV),
m/e: 366 (M+1), 365 (M ), 246, 207, 206 (100). HRMS (for
+
nitrostyrene (468 mg, 3.14 mmol), Yb(OTf) ·3H O (31 mg,
C H NO ): 365.1627 (calcd.); 365.1660 (found).
3
2
22 23
4
©
1998 NRC Canada

1
264
Can. J. Chem. Vol. 76, 1998
Ethyl 2-ethoxycarbonyl-3-(3-(1-methylindolyl))-3-phenyl
propanoate (Table 3, entry 4)
4-(3-(1-Methylindolyl))-4-phenyl-2-butanone (Table 2, entry
3)
Standard procedure: 1-methylindole (270 mg, 2.06 mmol),
Standard procedure: 1-methylindole (295 mg, 2.25 mmol),
benzalacetone (547 mg, 3.74 mmol), Yb(OTf) ·3H O
diethyl
benzalmalonate
(600
mg,
2.68
mmol),
3
2
Yb(OTf) ·3H O (35 mg, 52 µmol), acetonitrile (2 mL). The
(33 mg, 49 µmol), acetonitrile (2 mL). The mixture was
pressurized for 26 h and was worked up in the usual way.
Flash chromatography using gradient elution (20– 30%
EtOAc – hexanes) afforded 417 mg pure material (67%) as a
yellow oil, identical in all respects to the compound pre-
pared under ambient pressure (Table 1, entry 13).
3
2
mixture was stirred for 2 d and was worked up in the usual
way. Flash chromatography using gradient elution (10–30%
EtOAc – hexanes) afforded 530 mg pure material (68%) as a
white solid, mp 87–88°C. R = 0.37 (30% EtOAc – hex-
f
anes). IR (neat), ν: 2925, 2870, 1735, 1695, 1605, 1535,
–
1
1
1
460, 1415, 1360, 1020, 860, 735, 695 cm . H NMR
(
250 MHz, CDCl ), δ: 0.98 (t, J = 7.2 Hz, 3H), 0.99 (t, J =
3-(3-Indolyl)cyclohexanone (Table 2, entry 4)
3
7
.0 Hz, 3H), 3.71 (s, 3H), 3.97 (q, J = 7.2 Hz, 2H), 3.99 (q,
J = 7.0 Hz, 2H), 4.27 (d, J = 11.6 Hz, 1H), 5.06 (d, J =
1.9 Hz, 1H), 7.01 (s, 1H), 7.02 (td, J = 7.3, 1.4 Hz, 1H),
Standard procedure: indole (276 mg, 2.36 mmol), 2-
cyclohexen-1-one (500 µL, 5.16 mmol), Yb(OTf) ·3H O
3
2
1
7
7
(33 mg, 49 µmol), acetonitrile (2 mL). The mixture was
pressurized for 2 d and was worked up in the usual way.
Flash chromatography using gradient elution (20–30%
EtOAc – hexanes) afforded 263 mg pure material (52%) as a
pale yellow solid, identical in all respects to the compound
prepared under ambient pressure (Table 1, entry 8).
.09–7.25 (m, 6H), 7.36 (dm, J = 7.0 Hz, 1H), 7.55 (dt, J =
.9, 0.6 Hz, 1H). 1 C NMR (63 MHz, CDCl ), δ: 13.7 (two
3
3
carbons), 32.7, 42.8, 58.4, 61.3, 61.4, 109.0, 115.3, 118.9,
119.4, 121.7, 125.6, 126.6, 127.1, 128.1, 129.4, 136.9,
+
1
2
41.6, 167.8, 168.0. MS (70 eV), m/e: 380 (M+1), 379 (M ),
33, 221, 200 (100), 218, 217, 206. HRMS (for
C H NO ): 379.1783 (calcd.); 379.1811 (found).
3-Methyl-3-(3-(1-methylindolyl))cyclohexanone (Table 2,
entry 5)
2
3
25
4
Standard procedure: 1-methylindole (292 mg, 2.23 mmol),
-methyl-2-cyclohexen-1-one (400 µL, 3.53 mmol),
Typical procedure for the high-pressure reaction of
indoles with α,β-unsaturated ketones
3
Yb(OTf) ·3H O (32 mg, 47 µmol), acetonitrile (2 mL). The
3
2
The indole and the enone were dissolved in acetonitrile in
a length of 1 cm diameter heat- shrinkable Teflon® tubing
mixture was pressurized for 7 d and was worked up in the
usual way. Flash chromatography using gradient elution
10–30% EtOAc – hexanes) afforded 59 mg pure material
11%) as a yellow oil, identical in all respects to the com-
(
about 10 cm in length) that had been clamped at one end
(
(
using a brass clamp. The catalyst was added and the con-
tents of the tube were mixed. Excess air was squeezed from
the reaction vessel and the tube was then sealed with another
brass clamp. The vessel was placed in the high-pressure re-
actor and was subjected to 1.2 GPa (13 kbar) for an appro-
priate period of time. The solvent was removed in vacuo and
the crude residue was purified by flash chromatography on a
column of silica gel (elution with an appropriate mixture of
ethyl acetate and hexanes).
pound prepared under ambient pressure (Table 1, entry 9).
3
-Methyl-3-(3-(1-methylindolyl))cyclopentanone (Table 2,
entry 6)
Standard procedure: 1-methylindole (316 mg, 2.41 mmol),
-methyl-2-cyclopenten-1-one (500 µL, 5.05 mmol),
Yb(OTf) ·3H O (31 mg, 46 µmol), acetonitrile (2 mL). The
3
3
2
mixture was pressurized for 5 d and was worked up in the
usual way. Flash chromatography using gradient elution
10–30% EtOAc – hexanes) afforded 17 mg pure material
4
-(3-(1-Methylindolyl))-4-methyl-2-pentanone (Table 2,
entry 1)
Standard procedure: 1-methylindole (288 mg, 2.20 mmol),
mesityl oxide (500 µL, 4.36 mmol), Yb(OTf) ·3H O (33 mg,
(
(
1
3%) as a yellow oil. IR (thin film), ν: 2940, 2910, 2860,
730, 1600, 1475. 1455, 1410, 1390, 1365, 1320, 1230,
–1
1
3
2
1145, 1120, 730 cm . H NMR (250 MHz, CDCl ), δ: 1.60
3
4
9 µmol), acetonitrile (2 mL). The mixture was pressurized
(
(
1
7
0
3
1
s, 3H), 2.13–2.37 (m, 3H), 2.44 (d, J = 17.7 Hz, 1H), 2.58
m, 1H), 2.80 (d, J = 17.7 Hz, 1H), 3.73 (s, 3H), 6.78 (s,
H), 7.11 (ddd, J = 8.1, 6.7, 1.4 Hz, 1H), 7.24 (tm, J =
for 2 d and was worked up in the usual way. Flash chroma-
tography using gradient elution (10–20% EtOAc – hexanes)
afforded 360 mg pure material (72%) as a yellow oil. The
material was identical in all respects to the compound pre-
pared under ambient pressure (Table 1, entry 6).
.5 Hz, 1H), 7.32 (dm, J = 7.9 Hz, 1H), 7.71 (dd, J = 7.9,
13
.9 Hz, 1H). C NMR (63 MHz, CDCl ), δ: 28.0, 32.7,
3
5.8, 36.9, 39.9, 51.9, 109.7, 118.7, 119.8, 120.6, 121.7,
+
25.0, 126.5, 135.5, 200.9. MS (70 eV), m/e: 227 (M ,100),
4
-(3-(1-Methylindolyl))-5-methyl-2-hexanone (Table 2,
entry 2)
Standard
.23 mmol), 5-methyl-3-hexen-2-one (500 µL, 3.79 mmol),
Yb(OTf) ·3H O (33 mg, 49 µmol), acetonitrile (2 mL). The
212, 198, 184, 172, 171 (100), 156, 144. HRMS (for
C H NO): 227.1311 (calcd.); 227.1315 (found).
1
5
17
procedure:
1-methylindole
(2.92
mg,
2
Methyl 3-(3-(1-methylindolyl))-propanoate (Table 3, entry
5)
3
2
mixture was pressurized for 18 h and was worked up in the
usual way. Flash chromatography using gradient elution (5–
Standard procedure: 1-methylindole (322 mg, 2.45 mmol),
methyl acrylate (500 µL, 5.55 mmol), Yb(OTf) ·3H O
(36 mg, 53 µmol), acetonitrile (2 mL). The mixture was
pressurized for 7 d and was worked up in the usual way.
Flash chromatography using gradient elution (5–30% EtOAc
– hexanes) afforded 40 mg pure material (8%) as a yellow
3
2
2
0% EtOAc – hexanes) afforded 455 mg pure material
84%) as a low-melting solid, identical in all respects to the
compound prepared under ambient pressure (Table 1, entry
).
(
7
©
1998 NRC Canada

Harrington and Kerr
1265
oil. R = 0.49 (30% EtOAc – hexanes). IR (neat), ν: 2935,
Muratake, H. Kumagami, and M. Natsume. Tetrahedron, 46,
6351 (1990); (e) H. Muratake and M. Natsume. Tetrahedron,
f
2
1
910, 2840, 1730, 1545, 1460, 1425, 1370, 1315, 1180,
155, 1125, 1110, 1060, 730 cm . H NMR (250 MHz,
–
1
1
4
6, 6331 (1990); (f) H. Muratake and M. Natsume. Tetrahe-
dron Lett. 1815 (1989).
. R.J. Sunnberg. The chemistry of indoles. Academic Press,
New York. 1970.
. (a) J. Szmuszkovic. J. Am. Chem. Soc. 79, 2819 (1957);
CDCl ), δ: 2.73 (t, J = 7.6 Hz, 2H), 3.11 (t, J = 7.6 Hz, 2H),
3
4
5
3
6
=
.69 (s, 3H), 3.74 (s, 3H), 6.88 (s, 1H), 7.13 (ddd, J = 7.8,
.7, 1.2 Hz, 1H), 7.25 (td, J = 7.3, 1.2 Hz, 1H), 7.31 (dm, J
1
3
7.2 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H). C NMR (63 MHz,
(
b) W.E. Noland, G,M. Christensen, G.L. Sauer, and G.G.S.
CDCl ), δ: 20.5, 32.6, 35.0, 51.6, 109.2, 113.4, 118.8 (two
3
Dutton. J. Am. Chem. Soc. 77, 456 (1955); (c) R.L. Garnick,
S.B. Levery, and P.W. Le Quesne. J. Org. Chem. 43, 1226
carbons), 121.6, 126.3, 127.5, 137.0, 173.9. MS (70 eV),
+
m/e: 217 (M ), 145, 144 (100), 143, 131, 130, 77. HRMS
(
1978), and refs. cited therein; (d) Z. Iqbal, A.H. Jackson, and
(
for C H NO ): 217.1103 (calcd.); 217.1107 (found).
13 15 2
K.R.N. Rao. Tetrahedron Lett. 2577 (1988); (e) G. Dujardin
and J.–M. Poirer. Bull. Soc. Chim. Fr. 131, 900 (1994).
. H. Kotsuki, M. Teraguchi, N. Shimomoto, and M. Ochi. Tetra-
hedron Lett. 3727 (1996).
6
7
This research has been financially supported by the Natu-
. P.E. Harrington and M.A. Kerr. Synlett, 1047 (1996).
ral Sciences and Engineering Research Council (NSERC),
Sepracor Canada Ltd., and Acadia University. We are grate-
ful to Drs. Don Hooper and Michael Lumsden of the Atlan-
tic Region Magnetic Resonance Centre and Dr. Stuart
Grossert of the Dalhousie University mass spectrometry fa-
cility for their technical assistance. We thank Drs. Stanley
Cameron and Witek Kwiatkowski of Dalhousie University
for crystallographic analyses. Paul Harrington thanks
NSERC for a summer assistantship.
8. (a) R.W. Marshman. Aldrichimica Acta, 28, 77 (1995); (b) S.
Kobayashi. Synlett, 689 (1994).
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1
1
1
(
1996).
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physics: a practical approach. Edited by W.B. Holzapfel and
N.S. Isaacs. Oxford University Press, New York. 1997. p. 307;
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. (a) R.E. Moore, C. Cheuk, X.–Q. Yang, G.M.L. Patterson, R.
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(
b) F.-G. Klarner, M.K. Diedrich, and A.E. Wigger. Chemistry
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1
997. p. 53.
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1
4. (a) R.A. Bounce, M.F. Schlecht, W.G. Dauben, and C.H.
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and J.M. Gerdes. Tetrahedron Lett. 3841 (1983); (c) W.G.
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3
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(
2
d) W.G. Dauben and H.O. Krabbenhoft. J. Org. Chem. 42,
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©
1998 NRC Canada