The versatile role of norbornene in C-H functionalization processes: concise synthesis of tetracyclic fused pyrroles via a threefold domino reaction

Article abstract of DOI:10.1016/j.tet.2008.01.146

The synthesis of novel tetracyclic fused pyrroles from 1-(2-iodophenyl)-1H-pyrrole and various bromoalkyl-aryl alkynes via a palladium(0)-catalyzed and norbornene-mediated threefold domino reaction is reported. PdCl₂ and tri-2-furylphosphine (TFP) in the presence of norbornene and Cs₂CO₃ in CH₃CN at 90 °C gave a variety of tetracyclic fused pyrroles in usually high yields. In the described reaction sequence two of the three carbon-carbon bonds are formed by functionalization of an unactivated aryl C-H bond.

Full text of DOI:10.1016/j.tet.2008.01.146

Tetrahedron 64 (2008) 6002–6014
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The versatile role of norbornene in C–H functionalization processes: concise
synthesis of tetracyclic fused pyrroles via a threefold domino reaction
*
Kersten M. Gericke, David I. Chai, Mark Lautens
Department of Chemistry, Davenport Chemical Laboratories, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of novel tetracyclic fused pyrroles from 1-(2-iodophenyl)-1H-pyrrole and various bro-
moalkyl-aryl alkynes via a palladium(0)-catalyzed and norbornene-mediated threefold domino reaction
is reported. PdCl2 and tri-2-furylphosphine (TFP) in the presence of norbornene and Cs2CO3 in CH3CN at
90 ꢀC gave a variety of tetracyclic fused pyrroles in usually high yields. In the described reaction sequence
two of the three carbon–carbon bonds are formed by functionalization of an unactivated aryl C–H bond.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 21 September 2007
Received in revised form 12 January 2008
Accepted 14 January 2008
Available online 16 April 2008
Keywords:
C–H activation
Domino reaction
Palladium
Catalysis
Norbornene
ortho-Functionalization
Fused pyrroles
Catellani reaction
1. Introduction
intermolecular addition of an arylpalladium(II) halide across
a strained alkene; subsequently an intramolecular C–H function-
The development of highly efficient synthetic procedures to-
ward complex molecules is an important aim in modern pre-
parative organic chemistry. One way to improve efficiency is the
use of domino reactions, which allows for multiple bond forming
steps in a single reaction.1 In domino reactions, each new bond
delivers a reactive species, which undergoes further steps without
changing the reaction conditions. These reaction cascades ulti-
mately lead to the formation of complex molecules usually starting
from simple substrates. The carbon–hydrogen bond represents the
apex of functional group simplicity, therefore, catalytic activation
represents a powerful methodology for the construction of carbon–
carbon bonds, and has recently garnered significant attention
within the research community.2 The main advantage of this
strategy is that prefunctionalization of one or both coupling part-
ners is not required; this simplifies the preparation of substrates,
shortens the synthetic route, and therefore minimizes waste
production.
alization of a pendant heterocycle occurs (Scheme 1).4 This reaction
sequence can either lead to the formation of annulated products
like 2, or when norbornadiene is used as strained alkene, a retro-
Diels–Alder reaction takes place after the annulation furnishing
compounds of type 3. In addition, it has been shown that aryl ha-
lides 4 react under palladium(0)-catalysis with norbornene 5
N
X
Pd(OAc)2, PPh3
Cs2CO3
Strained Alkene
Toluene
2, X = CH2, O
N
or
Br
The strained alkene norbornene occupies a special position
within the field of C–H functionalization.3 We have recently
reported on an annulation reaction, which involves the
1
N
3
* Corresponding author. Fax: þ1 416 946 8185.
Scheme 1. Palladium-catalyzed annulation of aryl heterocycles with strained alkenes.
E-mail address: mlautens@chem.utoronto.ca (M. Lautens).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.146

K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
6003
R
R
cyclobutene
formation
Br
R
annulation
R = NHAc,
OH, ...
+
6
4
5
7
Scheme 2. Palladium-catalyzed reaction of aryl halides with norbornene.
delivering cyclobutene products 6 via an ortho-C–H functionaliza-
tion (Scheme 2).5 If the R group adjacent to the halide is nucleo-
philic, a different reaction mode occurs and annulation products of
type 7 are formed.6 If norbornene is used along with an alkyl halide,
ortho-functionalization occurs prior to expulsion of norbornene
producing an aryl palladium bond that can react with an acceptor,
the Catellani reaction.7 We have previously reported on the effi-
cient synthesis of functionalized fused aromatic carbo- and het-
erocycles using primary and secondary alkyl halides.8
Except for the non-substituted compound 10a, which was syn-
thesized from lithiated phenylacetylene and 1,3-dibromopropane
in 60% yield,11 all other bromoalkyl-aryl alkynes were accessible
utilizing the same straightforward strategy. Starting from various
commercially available aryl iodides 11b–n, a Sonogashira cross-
coupling12 with pent-4-yn-1-ol 12 led to the desired products 13b–
n in excellent yields. The subsequent Appel reaction13 converted
the alcohols smoothly, in very high yields, into the bromoalkyl-aryl
alkynes 10b–n.
Herein we describe a powerful combination of these concepts,
namely the use of domino reactions and C–H functionalization, for
an efficient synthesis of tetracyclic fused pyrrole derivatives. The
retrosynthetic analysis of compound 8 is outlined in Scheme 3. The
first disconnection results from a carbon–carbon bond formation
between a vinylpalladium(II) species and the pyrrole moiety via
a C–H functionalization. The vinylpalladium(II) species should in
turn result from a cyclocarbopalladation of an arylpalladium(II)
species onto a tethered alkyne. Finally, the generation of the aryl-
palladium(II) species as well as the introduction of the alkyne
tether could be achieved by a norbornene-mediated ortho-alkyl-
ation of aryl iodide 9 using various bromoalkyl-aryl alkynes 10
again via C–H functionalization.
We then turned our attention to the domino reaction of 1-(2-
iodophenyl)-pyrrole 914 and alkynes 10a–n. Carrying out the re-
action using alkyne 10g (2 equiv) under our standard conditions for
the ortho-alkylation of aryl iodides (10 mol % Pd(OAc)2, 20 mol %
TFP, 3 equiv Cs2CO3, CH3CN, 90 ꢀC, 24 h) led to the formation of the
desired tetracycle 8g in about 40% yield. Beside compound 8g we
could also isolate the corresponding acetoxyalkyl-aryl alkyne,
which is formed via a substitution reaction of 10g and the acetate
released by the catalyst. Switching the stoichiometry to 2 equiv of 9
and 1 equiv of 10g resulted in a much cleaner conversion, which, in
turn, led to a much easier purification and therefore higher yields.
Finally, we changed the catalyst to PdCl2 to avoid the consumption
of the limiting alkyne reagent 10g from reaction with acetate as
described before. Through these changes we could increase the
yield of product 8g up to 90% by using 5 mol % PdCl2 and 10 mol %
TFP (Table 2). Since the initiating ortho-alkylation is known to be
very sensitive in terms of ligand, base, and solvent, we did not
undertake further attempts to improve the reaction conditions.
Screening of the prepared alkynes 10a–n indicated that the
process is rather general concerning the substituent on the aryl
moiety. Whereas the non-substituted alkyne 10a furnished the
tetracycle 8a in 80% yield, the electron-rich systems like 10b, 10g,
and 10k gave even higher yields. In contrast, the rather electron-
deficient systems like 10c, 10d, and 10e delivered the desired
products 8c, 8d, and 8e in slightly lower yields. The fact that a chloro
substituent is tolerated under the applied reaction conditions shows
promise for further functionalization using modern cross-coupling
technology. Furthermore, it has been shown that the reaction con-
ditions are compatible with trifluoromethyl and ester groups de-
livering the compounds 8f and 8i in moderate to good yields. The
rather low yield (47%) of the electron-rich 2,5-dimethoxy aryl
product 8j can be explained by steric effects whereas the low yield of
8h is likely caused by an interaction between the vinylpalladium(II)
species, which is formed after the cyclocarbopalladation and the
nitrogen of the anilide. Interestingly, both the naphthyl- and the
indole alkynes led to the tetracycles 8k and 8m in good yields,
leading to the possibility for the introduction of a broader number
of aromatic and heterocyclic moieties. In the case of the pyrazole-
terminated alkyne we again propose that the low yield (15%) of
product 8n is primarily due to the interaction of the non-protected
nitrogen of the heterocycle and the vinylpalladium intermediate. It
is worth noting that all synthesized compounds exhibit strong
fluorescence during irradiation with UV-light at 366 nm. Fortu-
nately, we were able to obtain a single-crystal of tetracycles 8d and
8n, so that the structures could be unambiguously proven by X-ray
analysis (Figs. 1 and 2).15
C–H functionalization
R
R
N
N
cyclocarbo-
palladation
+
I
C–H functionalization/
ortho-alkylation
Br
8
9
10
Scheme 3. Retrosynthetic analysis of tetracyclic pyrrole 8.
We report that this reaction proceeds to construct three carbon–
carbon bonds in a single step without any change of the reaction
conditions. Due to the employment of two C–H functionalization
processes, only very simple and easily accessible substrates are
required to synthesize the complex and unique tetracyclic pyrroles.
These novel compounds should be of pharmaceutical interest since
pyrroles in general and also the pyrrolo[1,2-a] motif are known to
be present in a broad variety of biologically active natural products
and drug molecules.9 Moreover, structures of similar type are
known to exhibit fluorescent properties and are useful for elec-
troluminescent devices in the field of material science.10
2. Results and discussion
We began our investigation with the synthesis of bromoalkyl-
aryl alkynes 10a–n (Table 1). In order to investigate the influence of
the adjacent aryl moiety, we decided to introduce different sub-
stituents at all possible positions. At this point we hypothesized that
the electron density of the aryl group would affect the character of
the alkyne and therefore influencing both the cyclocarbopalladation
and the final C–H functionalization step. Furthermore, we also
prepared the naphthalene-, indole-, and pyrazole-substituted
alkynes.
The proposed mechanism of the observed domino reaction is
outlined in Scheme 4. We hypothesize that the reaction is initiated
by an oxidative addition of a preformed Pd(0)-complex into aryl

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K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
Table 1
Synthesis of bromoalkyl-aryl alkynes 10b–n via a Sonogashira/Appel sequence
3–5 mol% Pd(PPh3)2Cl2
3–5 mol% CuI
1.2 equiv. CBr4
1.2 equiv. PPh3
CH2Cl2, 25 °C, 1 h
OH
Br
NEt3, 25 or 50 °C, 16 h
I
+
OH
R
R
R
11b–n
12
13b–n
10b–n
Entry
1
Aryl iodide
Product 13/10 (yield %)
R
I
13b, R = OH (97%)
10b, R = Br (98%)
11b
R
I
2
3
O2N
O2N
13c, R = OH (98%)
10c, R = Br (91%)
11c
NO2
R
NO2
I
I
I
I
13d, R = OH (91%)
10d, R = Br (97%)
11d
Cl
R
Cl
4
5
6
13e, R = OH (93%)
10e, R = Br (92%)
11e
CF3
R
CF3
13f, R = OH (85%)
10f, R = Br (92%)
11f
OMe
R
OMe
13g, R = OH (99%)
10g, R = Br (92%)
11g
NHAc
R
NHAc
I
7
13h, R = OH (90%)
10h, R = Br (94%)
11h
R
EtO2C
EtO2C
I
8
11i
13i, R = OH (97%)
10i, R = Br (98%)
OMe
OMe
R
I
9
OMe
13j, R = OH (97%)
10j, R = Br (98%)
OMe
11j

K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
6005
Table 1 (continued)
Entry
Aryl iodide
Product 13/10 (yield %)
R
MeO
MeO
MeO
MeO
I
10
11
12
OMe
13k, R = OH (89%)
10k, R = Br (94%)
OMe
11k
I
R
13l, R = OH (95%)
10l, R = Br (93%)
11l
R
I
TsN
N
Ts
13m, R = OH (95%)
10m, R = Br (92%)
11m
I
R
N
TsN
N
13
N
Ts
11n
13n, R = OH (97%)
10n, R = Br (93%)
Table 2
Threefold domino reaction for the construction of tetracyclic fused pyrroles 8a–n
5 mol% PdCl2, 10 mol% TFP
1 equiv. norbornene, 3 equiv. Cs2CO3
CH3CN, 90 °C (sealed tube), 24 h
R
Br
N
N
+
I
R
9
10a–n
8a–n
Entry
Alkyne
Product 8 (yield %)
N
1
10a
8a (80%)
N
2
10b
8b (85%)
NO2
N
3
10c
8c (72%)
(continued on next page)

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K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
Table 2 (continued )
Entry
Alkyne
Product 8 (yield %)
N
NO2
4
5
6
10d
8d (81%)
N
Cl
10e
8e (72%)
N
CF3
10f
8f (51%)
N
OMe
7
10g
8g (90%)
N
NHAc
8
10h
8h (25%)
N
CO2Et
9
10i
8i (60%)
MeO
N
OMe
10
10j
8j (47%)
OMe
OMe
OMe
N
11
10k
8k (87%)

K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
6007
Table 2 (continued )
Entry
Alkyne
Product 8 (yield %)
N
12
10l
8l (67%)
NTs
N
13
10m
8m (75%)
NTs
N
N
14
10n
8n (15%)
Figure 2. ORTEP diagram of compound 8n.
Figure 1. ORTEP diagram of compound 8d (disorder at two positions at C14).
iodide A generating the arylpalladium(II) species B. Subsequent
syn-carbopalladation of the reactive olefin norbornene in an exo-
fashion leads to complex C. Instead of undergoing the previously
described formation of annulated pyrrole D via a seven-membered
palladacycle, C forms the five-membered palladacycle E. Thus,
under the reaction conditions the rate of the ortho-functionaliza-
tion to give E is faster than the competitive annulation onto the
pyrrole resulting in the formation of compound D. This dramatic
alteration of the reaction mechanism is caused by change of the
solvent from toluene to acetonitrile; as shown when reaction of 9
with 10g in toluene gave only trace amounts of the desired tetra-
cycle 8g.
reactions, does not occur due to the relatively high strain.16 The
octahedral palladium(IV)-complex H can now undergo rapid re-
ductive elimination furnishing the ortho-alkylated intermediate I.
Due to increased steric demand and no possibility of syn-b-H
elimination, a retro-carbopalladation of norbornene occurs pro-
viding arylpalladium(II) species J. The latter performs an intra-
molecular carbopalladation onto the tethered alkyne producing the
second carbon–carbon bond. Following formation of the fused cy-
clohexane, vinylpalladium(II) intermediate K induces another C–H
functionalization at the adjacent electron-rich pyrrole ring. This
process could either proceed via a direct C–H insertion leading to
palladacycle L or via an electrophilic aromatic substitution by at-
tack of the pyrrole onto the palladium(II) species. Reductive elim-
ination from the seven-membered palladacycle L leads finally to
the construction of the third carbon–carbon bond delivering the
desired tetracyclic structure M.
Once formed, E undergoes an oxidative addition of bromoalkyl-
aryl alkyne G and formation of palladium(IV)-complex H takes
place. Reductive elimination of the five-membered palladacycle E
to yield cyclobutene F, a common byproduct in Catellani-type

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K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
N
L
Pd
L
I
N
N
R
A
Reductive
elimination
PdL2I
0
CsX +CsHCO3
Cs2CO3
Pd L2
Oxidative
addition
L
C–H
functionalization
B
Carbopalladation
LX
Pd
N
N
H
N
R
toluene
N
PdL2I
R
H
K
D
C
Cs2CO3
acetonitrile
CsI + CsHCO3
C–H
functionalization
M
Cyclo-
carbopalladation
N
N
N
PdL2Br
X
R
Pd
L
J
E
L
F
Oxidative
addition
Reductive
elimination
N
N
Br
R
G
PdL2Br
PdL2Br
Palladium(IV) complex
R
I
H
Retro-carbopalladation
R
Scheme 4. Proposed mechanism of the threefold domino reaction.
3. Conclusion
(77.23 ppm for CDCl3 and 128.4 ppm for C6D6). No special notation
is used for equivalent carbons. IR spectra were obtained using
a Nicolet DX FT-IR spectrometer as thin films on NaCl plates. High-
resolution mass spectra were obtained using a VG 70-250S (double
focusing) mass spectrometer at 70 eV unless otherwise noted.
Tetrahydrofuran (THF) was distilled under nitrogen from Na/ben-
zophenone immediately prior to use. Dichloromethane and aceto-
nitrile were distilled under nitrogen from CaH2 immediately prior
to use. Neutral silica (Silicycle, Quebec, Canada) for flash chroma-
tography was used as received. Thin layer chromatography (TLC)
was carried out on precoated SIL G/UV254 (0.2 mm) plates from EM
Separations. All reagents and metal catalysts were purchased from
Sigma–Aldrich, Lancaster, Alfa Aesar or Strem-Chemical Company
and used without further purification unless otherwise noted. Tri-
2-furylphosphine (TFP) was synthesized according to the pro-
cedure of Santelli-Rouvier and Santelli.17 CuI was thoroughly
washed for 16 h with hot THF using a Soxhlet extractor. All re-
actions were performed in dry glassware under an atmosphere of
argon.
In summary, we have developed a concise route toward the
synthesis of interesting tetracyclic fused pyrrole derivatives, some
of which show strong fluorescence under UV-irradiation. This
methodology utilizes a novel palladium-catalyzed and norbornene-
mediated threefold domino process, which constructs three chal-
lenging carbon–carbon bonds in a one-pot procedure; two of them
from unactivated aryl C–H bonds. Moreover, this approach stands
out for its efficiency, the use of easy accessible substrates, and
a broad functional group tolerance. Further studies of the described
methodology regarding the introduction of other heterocycles are
in progress.
4. Experimental
4.1. General
The following includes general experimental procedures, spe-
cific details for representative reactions, and isolation and spec-
troscopic information for new compounds. Melting points were
recorded using a Fisher–Johns melting point apparatus and are
uncorrected. 1H, 13C, and 19F NMR spectra were recorded at room
temperature using a Varian Gemini-300, Unity-400 or Mercury 400
machine. 1H spectra were referenced to tetramethylsilane (TMS,
0 ppm) and 13C spectra were referenced to solvent carbons
4.1.1. (5-Bromo-pent-1-ynyl)-benzene (10a)
To a solution of phenylacetylene (6.51 g, 63.7 mmol,1.0 equiv) in
THF (25 mL) was added dropwise nBuLi (39.8 mL, 63.7 mmol,
1.0 equiv, 1.6 M in hexane) at 0 ꢀC. After addition the reaction
mixture was allowed to warm up to 25 ꢀC and stirring was con-
tinued for 1 h. Afterwards, 1,3-dibromopropane (7.3 mL, 70 mmol,

K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
6009
1.1 equiv) was added in one portion at ꢁ78 ꢀC. After 2 h at this
temperature the reaction mixture was stirred for another 12 h
under reflux. The reaction was quenched by adding small pieces of
ice at 0 ꢀC, H2O (200 mL) was added and the mixture was extracted
with Et2O (3ꢂ200 mL). The combined organic phases were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was subjected to silica gel flash chromatography
(hexane) and concentration of the appropriate fractions in vacuo
afforded the alkyne 10a (8.50 g, 60% yield) as colorless liquid. 1H
ol (2.43 g, 2.69 mL, 28.9 mmol, 1.2 equiv), PdCl2(PPh3)2 (592 mg,
0.84 mmol, 3.5 mol %), and CuI (161 mg, 0.84 mmol, 3.5 mol %) in
Et3N (120 mL) were stirred for 16 h at 25 ꢀC. After silica gel flash
chromatography using 20/40% EtOAc/hexanes as eluent the de-
sired compound 13d (4.50 g, 91%) was delivered as slightly yellow
solid. Mp 29–31 ꢀC; IR (CHCl3) 3624, 3417, 2954, 2400, 2231, 1609,
1526, 1345, 1052, 853 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 7.98 (dd,
J¼7.9, 1.2 Hz, 1H), 7.58 (dd, J¼7.9, 1.2 Hz, 1H), 7.53 (dt, J¼6.8, 1.7 Hz,
1H), 7.41 (mc,1H), 3.86 (mc, 2H), 2.63 (t, J¼6.9 Hz, 2H),1.90 (mc, 2H),
NMR (CDCl3, 300 MHz)
d
7.43–7.34 (m, 2H), 7.32–7.24 (m, 3H), 3.57
1.60 (br s, 1H) ppm; 13C NMR (CDCl3, 75.5 MHz)
d 150.2, 135.0,
(t, J¼6.6 Hz, 2H), 2.60 (t, J¼6.6 Hz, 2H), 2.12 (mc, 2H) ppm; 13C NMR
132.8, 128.2, 124.6, 119.3, 98.6, 76.6, 61.6, 31.1, 16.6 ppm; HRMS-EI:
(CDCl3, 75.5 MHz)
d 131.8, 128.5, 128.0, 123.8, 88.15, 81.86, 32.66,
[Mþ] calcd for C11H11NO3: 205.0739, found: 205.0745.
31.80, 18.29 ppm; IR (neat) 3056, 2959, 2841, 1597, 1489, 1441, 1430,
1351, 1271, 1247, 1070, 914, 850 cmꢁ1; HRMS-EI: [Mþ] calcd for
4.2.4. 5-(2-Chlorophenyl)pent-4-yn-1-ol (13e)
C
11H11Br: 222.0044, found: 222.0044.
Following the general procedure for the Sonogashira coupling 1-
chloro-2-iodobenzene (11e, 3.00 g, 12.6 mmol, 1.0 equiv), 4-pen-
tyn-1-ol (1.72 g, 1.41 mL, 15.1 mmol, 1.2 equiv), PdCl2(PPh3)2
(265 mg, 0.38 mmol, 3.0 mol %), and CuI (72 mg, 0.38 mmol, 3.0 mol
%) in Et3N (80 mL) were stirred for 16 h at 25 ꢀC. After silica gel flash
chromatography using 10/25% EtOAc/hexanes as eluent the de-
sired compound 13e (2.28 g, 93%) was delivered as colorless oil. IR
(neat) 3300, 2948, 2232, 1473, 1429, 1128, 1065, 1033, 962, 925, 755,
4.2. General procedure for the Sonogashira coupling of aryl
iodides and 4-pentyn-1-ol
To the corresponding aryl iodides 11b–n (1.0 equiv) in Et3N (3–
5 mL/mmol) were added subsequently PdCl2(PPh3)2 (3–5 mol %),
CuI (3–5 mol %) and 4-pentyn-1-ol (1.2 equiv) at 25 ꢀC. Stirring was
continued for 16 h at 25 ꢀC (for very electron-rich or sterically
hindered aryl iodides the temperature was raised to 50 ꢀC). The
reaction mixture was treated with satd NH4Cl solution (200–
300 mL) and the resulting mixture was extracted with CH2Cl2
(3ꢂ150 mL). The combined organic phases were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by silica gel flash chromatography and con-
centration of the appropriate fractions in vacuo afforded the de-
sired compounds 13b–n.
662 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
(m, 2H), 3.86 (t, J¼6.9 Hz, 2H), 2.61 (t, J¼6.9 Hz, 2H), 1.90 (mc, 2H),
d 7.45–7.35 (m, 2H), 7.24–7.14
1.64 (br s,1H) ppm; 13C NMR (CDCl3, 75.5 MHz)
d 135.9,133.5,129.3,
128.9, 126.6, 123.7, 95.3, 78.3, 61.9, 31.4, 16.4 ppm; HRMS-EI: [Mþ]
calcd for C11H11ClO: 194.0498, found: 194.0499.
4.2.5. 5-(2-(Trifluoromethyl)phenyl)pent-4-yn-1-ol (13f)
Following the general procedure for the Sonogashira coupling 1-
iodo-2-(trifluoromethyl)benzene (11f, 5.00 g, 18.4 mmol, 1.0 equiv),
4-pentyn-1-ol (1.86 g, 2.06 mL, 22.1 mmol, 1.2 equiv), PdCl2(PPh3)2
(387 mg, 0.55 mmol, 3.0 mol %), and CuI (105 mg, 0.55 mmol,
3.0 mol %) in Et3N (70 mL) were stirred for 16 h at 25 ꢀC. After silica
gel flash chromatography using 20/33% EtOAc/hexanes as eluent
the desired compound 13f (3.57 g, 85%) was delivered as slightly
yellow oil. IR (neat) 3314, 2948, 2234, 1604, 1574, 1490, 1451, 1319,
4.2.1. 5-(4-Methylphenyl)pent-4-yn-1-ol (13b)
Following the general procedure for the Sonogashira coupling 4-
iodo-toluene (11b, 5.00 g, 22.9 mmol, 1.0 equiv), 4-pentyn-1-ol
(2.32 g, 2.56 mL, 27.5 mmol, 1.2 equiv), PdCl2(PPh3)2 (526 mg,
0.75 mmol, 3.3 mol %), and CuI (143 mg, 0.75 mmol, 3.3 mol %) in
Et3N (80 mL) were stirred for 16 h at 25 ꢀC. After silica gel flash
chromatography using 10/25% EtOAc/hexanes as eluent the de-
sired compound 13b (3.86 g, 97%) was delivered as colorless solid.
Mp 34–36 ꢀC; IR (CHCl3) 3623, 3432, 2952, 2400, 1510, 1432, 1052,
1266, 1130, 1063, 1033, 958, 922, 765, 751, 650 cmꢁ1
(CDCl3, 300 MHz)
;
1H NMR
d
7.62 (d, J¼7.6 Hz, 1H), 7.53 (d, J¼7.2 Hz, 1H), 7.45
(t, J¼7.2 Hz, 1H), 7.35 (t, J¼7.6 Hz, 1H), 3.83 (mc, 2H), 2.59 (t,
J¼6.9 Hz, 2H), 1.88 (mc, 2H), 1.50 (br s, 1H) ppm; 13C NMR (CDCl3,
925, 819 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
7.28 (d, J¼8.0 Hz, 2H),
75.5 MHz) d 134.1,131.8,131.4,127.6,126.0,125.9,125.8,125.7,122.3,
7.09 (d, J¼8.0 Hz, 2H), 3.82 (t, J¼6.1 Hz, 2H), 2.53 (t, J¼6.1 Hz, 2H),
122.0, 95.8, 77.4, 61.6, 31.3, 16.2 ppm; 19F NMR (CDCl3, 282 MHz)
2.33 (s, 3H), 1.85 (mc, 2H), 1.69 (br s, 1H) ppm; 13C NMR (CDCl3,
d
ꢁ62.9 ppm; HRMS-EI: [Mþ] calcd for C12H11F3O: 228.0762, found:
75.5 MHz)
d
146.9, 137.9, 131.6, 129.2, 120.8, 88.7, 81.4, 62.1, 31.6,
228.0758.
21.6, 16.2 ppm; HRMS-EI: [Mþ] calcd for C12H14O: 174.1045, found:
174.1044.
4.2.6. 5-(2-Methoxyphenyl)pent-4-yn-1-ol (13g)
Following the general procedure for the Sonogashira coupling 1-
iodo-2-methoxybenzene (11g, 5.00 g, 21.4 mmol, 1.0 equiv), 4-
pentyn-1-ol (2.15 g, 2.38 mL, 25.6 mmol, 1.2 equiv), PdCl2(PPh3)2
(526 mg, 0.75 mmol, 3.5 mol %), and CuI (143 mg, 0.75 mmol,
3.5 mol %) in Et3N (70 mL) were stirred for 16 h at 25 ꢀC. After silica
gel flash chromatography using 20/50% EtOAc/hexanes as eluent
the desired compound 13g (3.73 g, 99%) was delivered as slightly
yellow oil. IR (neat) 3373, 3074, 2946, 2836, 2229, 1595, 1576, 1491,
4.2.2. 5-(4-Nitrophenyl)pent-4-yn-1-ol (13c)
Following the general procedure for the Sonogashira coupling 4-
iodo-nitrobenzene (11c, 4.98 g, 20.0 mmol, 1.0 equiv), 4-pentyn-1-
ol (2.02 g, 2.23 mL, 24.0 mmol, 1.2 equiv), PdCl2(PPh3)2 (421 mg,
0.60 mmol, 3 mol %), and CuI (114 mg, 0.60 mmol, 3 mol %) in Et3N
(70 mL) were stirred for 16 h at 25 ꢀC. After silica gel flash chro-
matography using 25/50% EtOAc/hexanes as eluent the desired
compound 13c (4.02 g, 98%) was delivered as slightly orange solid.
Mp 31–33 ꢀC; IR (CHCl3) 3371, 2952, 2447, 2227, 1593, 1516, 1341,
1464, 1435, 1261, 1180, 1162, 1117, 1049, 1025, 925, 754, 696 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
7.36 (dd, J¼7.6, 1.6 Hz, 1H), 7.25 (mc,
1174, 1108, 1060, 854, 689 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
8.16
1H), 6.88 (dt, J¼7.6, 1.2 Hz, 1H), 6.85 (d, J¼8.1 Hz, 1H), 3.89–3.82 (m,
(mc, 2H), 7.52 (mc, 2H), 3.83 (mc, 2H), 2.60 (t, J¼6.9 Hz, 2H),1.89 (mc,
5H), 2.60 (t, J¼6.8 Hz, 2H), 2.13 (br s, 1H), 1.89 (mc, 2H) ppm; 13C
2H), 1.41 (br t, J¼4.9 Hz, 1H) ppm; 13C NMR (CDCl3, 75.5 MHz)
NMR (CDCl3, 75.5 MHz) d 160.1, 133.5, 129.3, 120.6, 112.9,110.7, 94.0,
d
132.5, 131.1, 123.7, 95.9, 79.9, 61.7, 31.3, 16.3 ppm; HRMS-EI: [Mþ]
77.6, 62.4, 55.9, 31.5, 17.0 ppm; HRMS-EI: [Mþ] calcd for C12H14O2:
190.0994, found: 190.0988.
calcd for C11H11NO3: 205.0739, found: 205.0736.
4.2.3. 5-(2-Nitrophenyl)pent-4-yn-1-ol (13d)
Following the general procedure for the Sonogashira coupling 2-
iodo-nitrobenzene (11d, 6.00 g, 24.1 mmol, 1.0 equiv), 4-pentyn-1-
4.2.7. N-(2-(5-Hydroxypent-1-ynyl)phenyl)acetamide (13h)
Following the general procedure for the Sonogashira coupling
N-(2-iodophenyl)acetamide (11h, 4.00 g, 15.3 mmol, 1.0 equiv),

6010
K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
4-pentyn-1-ol (1.54 g, 1.71 mL, 18.3 mmol, 1.2 equiv), PdCl2(PPh3)2
(537 mg, 0.77 mmol, 5.0 mol %), and CuI (146 mg, 0.77 mmol,
5.0 mol %) in Et3N (120 mL) and DMF (10 mL) were stirred for 16 h
at 25 ꢀC. After silica gel flash chromatography using 33/66%
EtOAc/hexanes as eluent the desired compound 13h (2.99 g, 90%)
was delivered as slightly yellow oil. IR (neat) 3388, 2930, 2225,
(2.02 g, 2.23 mL, 24.0 mmol, 1.2 equiv), PdCl2(PPh3)2 (414 mg,
0.59 mmol, 3.0 mol %), and CuI (112 mg, 0.59 mmol, 3.0 mol %) in
Et3N (70 mL) were stirred for 16 h at 25 ꢀC. After silica gel flash
chromatography using 20/33% EtOAc/hexanes as eluent the de-
sired compound 13l (3.86 g, 97%) was delivered as slightly yellow
oil. IR (neat) 3351, 3057, 2945, 2224, 1716, 1585, 1506, 1429, 1395,
1653, 1579, 1521, 1447, 1387, 1304, 1269, 1097, 1061, 760, 662 cmꢁ1
1H NMR (CDCl3, 300 MHz)
;
1051, 799, 774 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 8.32 (mc, 1H),
d
8.35 (d, J¼8.3 Hz, 1H), 8.05 (br s, 1H),
7.85–7.45 (m, 2H), 7.62 (dd, J¼7.1, 1.2 Hz,1H), 7.52 (mc, 2H), 7.39 (dd,
7.32 (dd, J¼9.3, 1.6 Hz, 1H), 7.26 (mc, 1H), 7.00 (d, J¼7.6 Hz, 1H), 3.85
(t, J¼6.0 Hz, 2H), 2.65 (t, J¼7.0 Hz, 2H), 2.22 (s, 3H), 1.95–1.84 (m,
J¼8.2, 7.4 Hz, 2H), 3.90 (t, J¼6.1 Hz, 2H), 2.71 (t, J¼6.8 Hz, 2H), 1.97
(mc, 2H), 1.57 (br s, 1H) ppm; 13C NMR (CDCl3, 75.5 MHz)
d 133.7,
3H) ppm; 13C NMR (CDCl3, 75.5 MHz)
d
168.8, 139.2, 131.7, 129.1,
133.4, 130.3, 128.5, 128.3, 126.8, 126.5, 126.4, 125.4, 121.7, 94.6, 79.4,
62.1, 31.8, 16.5 ppm; HRMS-EI: [Mþ] calcd for C15H14O: 210.1045,
found: 210.1047.
123.5, 119.5, 112.8, 97.3, 76.6, 61.7, 31.5, 25.0, 16.6 ppm; HRMS-EI:
[Mþ] calcd for C13H15NO2: 217.1103, found: 217.1100.
4.2.8. Ethyl 3-(5-hydroxypent-1-ynyl)benzoate (13i)
4.2.12. 5-(1-Tosyl-1H-indol-3-yl)pent-4-yn-1-ol (13m)
Following the general procedure for the Sonogashira coupling
ethyl 3-iodobenzoate (11i, 5.52 g, 20.0 mmol, 1.0 equiv), 4-pentyn-
1-ol (2.02 g, 2.23 mL, 24.0 mmol, 1.2 equiv), PdCl2(PPh3)2 (421 mg,
0.60 mmol, 3.0 mol %), and CuI (114 mg, 0.60 mmol, 3.0 mol %) in
Et3N (80 mL) were stirred for 16 h at 25 ꢀC. After silica gel flash
chromatography using 20/40% EtOAc/hexanes as eluent the de-
sired compound 13i (4.51 g, 97%) was delivered as slightly yellow
oil. IR (neat) 3362, 2947, 2234, 1716, 1604, 1574, 1490, 1451, 1318,
1266, 1170, 1134, 1111, 1063, 1033, 957, 765, 751, 650 cmꢁ1; 1H NMR
Following the general procedure for the Sonogashira coupling
3-iodo-1-tosyl-1H-indole18 (11m, 3.00 g, 7.55 mmol, 1.0 equiv),
4-pentyn-1-ol (0.76 g, 0.84 mL, 9.06 mmol, 1.2 equiv), PdCl2(PPh3)2
(265 mg, 0.38 mmol, 5.0 mol %), and CuI (72 mg, 0.38 mmol,
5.0 mol %) in Et3N (80 mL) were stirred for 16 h at 25 ꢀC. After
silica gel flash chromatography using 40% EtOAc/hexanes as eluent
the desired compound 13m (2.51 g, 94%) was delivered as white
solid. Mp 100–102 ꢀC; IR (CHCl3) 3615, 3017, 1952, 2399, 1597,
1447, 1374, 1277, 1188, 1176, 1129, 1104, 1089, 668 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz)
d
8.06 (t, J¼1.6 Hz, 1H), 7.94 (dt, J¼7.8, 1.6 Hz, 1H),
(CDCl3, 300 MHz) 7.95 (mc, 1H), 7.72 (mc, 2H), 7.65 (s, 1H), 7.58
d
7.36 (dt, J¼7.8, 1.6 Hz, 1H), 4.38 (q, J¼7.2 Hz, 2H), 3.83 (t, J¼6.2 Hz,
2H), 2.56 (t, J¼6.2 Hz, 2H), 1.88 (mc, 2H), 1.64 (br s, 1H), 1.39 (t,
(mc, 1H), 7.35–7.20 (m, 3H), 7.15 (d, J¼8.1 Hz, 2H), 3.81 (t, J¼6.3 Hz,
2H), 2.53 (t, J¼7.1 Hz, 2H), 2.27 (s, 3H), 1.95–1.80 (m, 3H) ppm; 13C
J¼7.2 Hz, 3H) ppm; 13C NMR (CDCl3, 75.5 MHz)
d
166.3,135.8, 132.8,
NMR (CDCl3, 75.5 MHz) d 145.4, 135.1, 134.4, 131.3, 130.1, 128.5,
130.8, 128.9, 128.5, 124.4, 90.6, 80.4, 61.8, 61.4, 31.5, 16.1, 14.5 ppm;
HRMS-EI: [Mþ] calcd for C14H16O3: 232.1099, found: 232.1103.
127.1, 125.5, 123.8, 120.7, 113.7, 106.0, 94.1, 72.0, 61.8, 31.7, 21.7,
16.4 ppm; HRMS-EI: [Mþ] calcd for C20H19NO3S: 353.1079, found:
353.1079.
4.2.9. 5-(2,6-Dimethoxyphenyl)pent-4-yn-1-ol (13j)
Following the general procedure for the Sonogashira coupling 2-
iodo-1,3-dimethoxybenzene (3.00 g, 11.4 mmol, 1.0 equiv), 4-pen-
tyn-1-ol (11j, 1.15 g, 1.27 mL, 9.09 mmol, 1.2 equiv), PdCl2(PPh3)2
(399 mg, 0.57 mmol, 5.0 mol %), and CuI (108 mg, 0.57 mmol,
5.0 mol %) in Et3N (100 mL) were stirred for 16 h at 50 ꢀC. After
silica gel flash chromatography using 20/50% EtOAc/hexanes as
eluent the desired compound 13j (2.23 g, 89%) was delivered as
colorless oil. IR (neat) 3382, 3005, 2937, 2838, 1583, 1473, 1432,
4.2.13. 5-(1-Tosyl-1H-pyrazol-5-yl)pent-4-yn-1-ol (13n)
Following the general procedure for the Sonogashira coupling 5-
iodo-1-tosyl-1H-pyrazole (11n, 2.00 g, 5.57 mmol, 1.0 equiv), 4-
pentyn-1-ol (0.58 g, 0.64 mL, 6.89 mmol, 1.2 equiv), PdCl2(PPh3)2
(201 mg, 0.29 mmol, 5.0 mol %), and CuI (55 mg, 0.29 mmol,
5.0 mol %) in Et3N (50 mL) were stirred for 16 h at 25 ꢀC. After silica
gel flash chromatography using 40% EtOAc/hexanes as eluent the
desired compound 13n (1.69 g, 97%) was delivered as colorless wax.
IR (CHCl3) 3395, 3015, 2951, 2243, 1596, 1516, 1437, 1384, 1304, 1191,
1300, 1252, 1110, 1031, 958, 924, 777, 754, 727, 667 cmꢁ1
(CDCl3, 300 MHz)
7.19 (t, J¼8.5 Hz, 1H), 6.52 (d, J¼8.5 Hz, 2H),
3.89–3.82 (m, 8H), 2.68 (t, J¼6.7 Hz, 2H), 1.90 (mc, 2H), 1.74 (br s,
1H) ppm; 13C NMR (CDCl3, 75.5 MHz)
161.5, 129.3, 103.6, 101.8,
98.5, 73.9, 62.8, 56.2, 31.3, 17.8 ppm; HRMS-EI: [Mþ] calcd for
13H16O3: 220.1099, found: 220.1097.
;
1H NMR
d
1178, 1135, 1029, 909 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 8.04 (d,
J¼1.6 Hz, 1H), 7.90 (dt, J¼8.4, 1.8 Hz, 2H), 7.34 (mc, 2H), 6.39 (d,
J¼2.7 Hz, 1H), 3.77 (t, J¼6.1 Hz, 2H), 2.51 (t, J¼7.0 Hz, 2H), 2.43 (s,
3H), 1.83 (mc, 2H), 1.65 (br s, 1H) ppm; 13C NMR (CDCl3, 75.5 MHz)
d
C
d 146.3, 141.3, 133.9, 131.6, 130.3, 128.5, 112.2, 93.5, 72.8, 61.6, 31.0,
21.9, 16.1 ppm; HRMS-EI: [Mþ] calcd for C15H16N2O3S: 304.0882,
found: 304.0880.
4.2.10. 5-(3,4,5-Trimethoxyphenyl)pent-4-yn-1-ol (13k)
Following the general procedure for the Sonogashira coupling 5-
iodo-1,2,3-trimethoxybenzene (11k, 2.00 g, 6.80 mmol, 1.0 equiv),
4.3. General procedure for the conversion of primary alcohols
into bromides via Appel reaction
4-pentyn-1-ol
(686 mg,
0.76 mL,
27.5 mmol,
1.2 equiv),
PdCl2(PPh3)2 (239 mg, 0.34 mmol, 5.0 mol %), and CuI (65 mg,
0.34 mmol, 5.5 mol %) in Et3N (80 mL) were stirred for 16 h at 50 ꢀC.
After silica gel flash chromatography using 20/40% EtOAc/
hexanes as eluent the desired compound 13k (1.62 g, 95%) was
delivered as slightly yellow solid. Mp 44–46 ꢀC; IR (CHCl3) 2940,
To the corresponding alcohols 13b–n (1.0 equiv) and CBr4
(1.2 equiv) in CH2Cl2 (3–5 mL/mmol) was added PPh3 (1.2 equiv) in
small portions at 0 ꢀC. The reaction mixture was allowed to warm
up to 25 ꢀC and stirring was continued for 1 h. Afterwards, the
solvent was removed in vacuo, the crude product was purified by
silica gel flash chromatography, and concentration of the appro-
priate fractions in vacuo afforded the desired compounds 10b–n.
1579, 1505, 1464, 1411, 1346, 1236, 1130, 999, 836 cmꢁ1 1H NMR
;
(CDCl3, 300 MHz)
d 6.63 (s, 2H), 3.86–3.78 (m, 11H), 2.54 (t,
J¼7.0 Hz, 2H), 1.87 (mc, 2H), 1.57 (br t, J¼4.7 Hz, 1H) ppm; 13C NMR
(CDCl3, 75.5 MHz)
d 153.2, 138.6, 119.0, 109.0, 88.7, 81.3, 62.0, 61.1,
56.3, 31.6, 16.2 ppm; MS-EI m/z: 250 (Mþ, 100), 235 (36%); HRMS-
4.3.1. 1-(5-Bromopent-1-ynyl)-4-methylbenzene (10b)
EI: [Mþ] calcd for C14H18O4: 250.1205, found: 250.1206.
Following the general procedure for the Appel reaction alcohol
13b (3.80 g, 21.8 mmol, 1.0 equiv), CBr4 (8.69 g, 26.2 mmol,
1.2 equiv), and PPh3 (6.87 g, 26.2 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 5% EtOAc/hexanes as eluent
the desired compound 10b (5.07 g, 98%) as slightly yellow oil.
4.2.11. 5-(Naphthalen-1-yl)pent-4-yn-1-ol (13l)
Following the general procedure for the Sonogashira coupling 1-
iodo-naphthalene (11l, 5.00 g, 19.7 mmol, 1.0 equiv), 4-pentyn-1-ol

K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
6011
IR (neat) 3026, 2921, 2867, 1906, 1509, 1430, 1351, 1272, 1246, 1106,
817 cmꢁ1 1H NMR (CDCl3, 300 MHz)
7.29 (d, J¼8.1 Hz, 2H), 7.09
(d, J¼8.1 Hz, 2H), 3.58 (t, J¼6.5 Hz, 2H), 2.59 (t, J¼6.7 Hz, 2H), 2.33
(s, 3H), 2.12 (mc, 2H) ppm; 13C NMR (CDCl3, 75.5 MHz)
138.0,
131.7, 129.2, 120.6, 87.3, 81.9, 32.8, 31.8, 21.7, 18.4 ppm; HRMS-EI:
[Mþ] calcd for C12H13Br: 236.0201, found: 236.0201.
1.2 equiv), and PPh3 (6.24 g, 23.8 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 10% EtOAc/hexanes as eluent
the desired compound 10g (4.63 g, 92%) as colorless oil. IR (neat)
3003, 2959, 2834, 1595, 1575, 1493, 1464, 1434, 1350, 1292, 1260,
;
d
d
1180, 1162, 1117, 1048, 1025, 850, 795, 754 cmꢁ1
300 MHz)
;
1H NMR (CDCl3,
d
7.37 (dd, J¼7.2, 1.6 Hz, 1H), 7.25 (dt, J¼8.1, 1.8 Hz, 1H),
6.88 (dt, J¼7.5, 1.2 Hz, 1H), 6.85 (d, J¼8.2 Hz, 1H), 3.87 (s, 3H), 2.66
4.3.2. 1-(5-Bromopent-1-ynyl)-4-nitrobenzene (10c)
(t, J¼6.8 Hz, 2H), 2.16 (mc, 2H) ppm; 13C NMR (CDCl3, 75.5 MHz)
Following the general procedure for the Appel reaction alcohol
13c (2.20 g, 10.7 mmol, 1.0 equiv), CBr4 (4.29 g, 12.9 mmol,
1.2 equiv), and PPh3 (3.38 g, 12.9 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 10% EtOAc/hexanes as eluent
the desired compound 10c (2.65 g, 91%) as light-brown solid. Mp
d 160.2, 133.7, 129.4, 120.6, 112.9, 110.8, 92.4, 78.1, 56.0, 32.8, 31.9,
18.8 ppm; HRMS-EI: [Mþ] calcd for C12H13BrO: 252.0150, found:
252.0153.
4.3.7. N-(2-(5-Bromopent-1-ynyl)phenyl)acetamide (10h)
35–36 ꢀC; IR (CHCl3) 3017, 2226, 1594, 1521, 1345, 1108, 854 cmꢁ1
;
Following the general procedure for the Appel reaction alcohol
13h (2.80 g, 12.9 mmol, 1.0 equiv), CBr4 (5.13 g, 15.5 mmol,
1.2 equiv), and PPh3 (4.07 g, 15.5 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 10% EtOAc/hexanes as eluent
the desired compound 10h (3.32 g, 92%) as white solid. Mp 63–
65 ꢀC; IR (CHCl3) 3397, 3017, 2398, 1696, 1580, 1520, 1447, 1369,
1H NMR (CDCl3, 300 MHz)
2H), 3.58 (t, J¼6.6 Hz, 2H), 2.69 (t, J¼6.6 Hz, 2H), 2.17 (mc, 2H) ppm;
d
8.16 (d, J¼8.8 Hz, 2H), 7.53 (d, J¼8.8 Hz,
13C NMR (CDCl3, 75.5 MHz)
d 147.0, 132.5, 130.8, 123.7, 94.3, 80.4,
32.4, 31.4, 18.5 ppm; HRMS-EI: [Mþ] calcd for C11H10BrNO2:
266.9895, found: 266.9901.
1306, 1267, 668 cmꢁ1
; d 8.37 (d,
1H NMR (CDCl3, 300 MHz)
4.3.3. 1-(5-Bromopent-1-ynyl)-2-nitrobenzene (10d)
J¼8.3 Hz, 1H), 7.89 (br s, 1H), 7.36 (dd, J¼7.5, 1.4 Hz, 1H), 7.30 (mc,
1H), 7.01 (dt, J¼7.0, 0.8 Hz, 1H), 3.62 (t, J¼6.4 Hz, 2H), 2.74 (t,
J¼6.7 Hz, 2H), 2.23 (s, 3H), 2.17 (mc, 2H) ppm; 13C NMR (CDCl3,
Following the general procedure for the Appel reaction alcohol
13d (4.50 g, 21.9 mmol, 1.0 equiv), CBr4 (8.72 g, 26.3 mmol,
1.2 equiv), and PPh3 (6.89 g, 26.3 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 10% EtOAc/hexanes as eluent
the desired compound 10d (5.70 g, 97%) as slightly yellow oil. IR
(neat) 2913, 2228, 1608, 1568, 1521, 1479, 1435, 1343, 1246, 1145,
75.5 MHz)
d 168.4, 139.2, 131.9, 129.4, 123.5, 119.4, 112.3, 95.3, 77.3,
32.6, 31.1, 25.2, 18.4 ppm; HRMS-EI: [Mþ] calcd for C13H14BrNO:
279.0259, found: 279.0251.
853, 784, 746 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
8.00 (dd, J¼8.1,
4.3.8. Ethyl 3-(5-bromopent-1-ynyl)benzoate (10i)
1.0 Hz, 1H), 7.59 (dd, J¼8.1, 1.9 Hz, 1H), 7.54 (dt, J¼7.4, 1.3 Hz, 1H),
Following the general procedure for the Appel reaction alcohol
13i (4.50 g, 19.4 mmol, 1.0 equiv), CBr4 (7.73 g, 23.3 mmol,
1.2 equiv), and PPh3 (6.11 g, 23.3 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 5% EtOAc/hexanes as eluent
the desired compound 10i (5.62 g, 98%) as colorless oil. IR (neat)
2978, 2232,1718,1576,1430,1367,1296,1227,1167,1105,1081,1026,
7.42 (mc, 1H), 3.64 (t, J¼6.3 Hz, 2H), 2.70 (t, J¼6.6 Hz, 2H), 2.17 (mc,
2H) ppm; 13C NMR (CDCl3, 75.5 MHz)
d 150.2, 135.0, 132.9, 128.4,
124.7, 119.1, 97.0, 77.2, 32.6, 31.3, 18.7 ppm; HRMS-EI: [Mþ] calcd for
11H10BrNO2: 266.9895, found: 266.9887.
C
4.3.4. 1-(5-Bromopent-1-ynyl)-2-chlorobenzene (10e)
754, 684 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
8.06 (t, J¼1.5 Hz, 1H),
Following the general procedure for the Appel reaction alcohol
13e (2.31 g, 11.9 mmol, 1.0 equiv), CBr4 (4.72 g, 14.2 mmol,
1.2 equiv), and PPh3 (3.74 g, 14.2 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 5% EtOAc/hexanes as eluent
the desired compound 10e (5.70 g, 92%) as colorless oil. IR (neat)
3065, 2961, 2231, 1473, 1437, 1430, 1350, 1272, 1246, 1127, 1061,
7.95 (dt, J¼8.0, 1.2 Hz, 1H), 7.56 (d, J¼7.7 Hz, 1H), 7.36 (t, J¼8.0 Hz,
1H), 4.38 (q, J¼7.1 Hz, 2H), 3.59 (t, J¼6.5 Hz, 2H), 2.63 (t, J¼6.9 Hz,
2H), 2.15 (mc, 2H), 1.40 (t, J¼7.1 Hz, 3H) ppm; 13C NMR (CDCl3,
75.5 MHz)
d 166.1, 135.8, 132.8, 130.9, 129.0, 128.5, 124.1, 89.2, 80.9,
61.3, 32.6, 31.7, 18.3,14.5 ppm; HRMS-EI: [Mþ] calcd for C14H15BrO2:
294.0255, found: 294.0260.
1033, 754, 726, 668, 663 cmꢁ1
7.35 (m, 2H), 7.19 (mc, 2H), 3.64 (t, J¼6.5 Hz, 2H), 2.68 (t, J¼6.8 Hz,
2H), 2.17 (mc, 2H) ppm; 13C NMR (CDCl3, 75.5 MHz)
136.0, 133.5,
; d 7.45–
1H NMR (CDCl3, 300 MHz)
4.3.9. 2-(5-Bromopent-1-ynyl)-1,3-dimethoxybenzene (10j)
d
Following the general procedure for the Appel reaction alcohol
13j (2.10 g, 9.53 mmol, 1.0 equiv), CBr4 (3.78 g, 11.4 mmol,
1.2 equiv), and PPh3 (2.99 g, 11.4 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 10% EtOAc/hexanes as eluent
the desired compound 10j (2.64 g, 98%) as colorless oil. IR (neat)
3001, 1936, 1837, 1583, 1473, 1432, 1301, 1253, 1111, 1034, 776, 725,
129.4, 129.0, 126.6, 123.6, 93.8, 78.8, 32.6, 31.6, 18.5 ppm; HRMS-EI:
[Mþ] calcd for C11H10BrCl: 255.9654, found: 255.9661.
4.3.5. 1-(5-Bromopent-1-ynyl)-2-(trifluoromethyl)benzene (10f)
Following the general procedure for the Appel reaction alcohol
13f (3.40 g, 14.9 mmol, 1.0 equiv), CBr4 (5.93 g, 17.9 mmol,
1.2 equiv), and PPh3 (4.69 g, 17.9 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 5% EtOAc/hexanes as eluent
the desired compound 10f (3.99 g, 92%) as colorless oil. IR (neat)
3402, 3071, 2957, 2924, 2868, 2232, 1603, 1574, 1490, 1450, 1319,
658 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
J¼8.5 Hz, 2H), 3.87 (s, 6H), 3.69 (t, J¼6.7 Hz, 2H), 2.72 (t, J¼6.7 Hz,
d
7.19 (t, J¼8.5 Hz,1H), 6.52 (d,
2H), 2.17 (mc, 2H) ppm; 13C NMR (CDCl3, 75.5 MHz)
d
161.6, 129.3,
103.7, 101.9, 96.9, 74.2, 56.3, 32.8, 32.0, 19.1 ppm; HRMS-EI: [Mþ]
calcd for C13H15BrO2: 222.0255, found: 282.0258.
1266, 1247, 1171, 1134, 1111, 1061, 1033, 765, 751 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz)
d
7.62 (d, J¼8.0 Hz, 1H), 7.53 (d, J¼7.6 Hz, 1H),
4.3.10. 5-(5-Bromopent-1-ynyl)-1,2,3-trimethoxybenzene (10k)
Following the general procedure for the Appel reaction alcohol
13k (1.50 g, 5.99 mmol, 1.0 equiv), CBr4 (2.38 g, 7.19 mmol,
1.2 equiv), and PPh3 (1.89 g, 7.19 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 10% EtOAc/hexanes as eluent
the desired compound 10k (1.76 g, 94%) as colorless oil. IR (neat)
2938, 2837, 1734, 1576, 1505, 1464, 1431, 1410, 1344, 1322, 1236,
7.45 (t, J¼7.6 Hz, 1H), 7.36 (t, J¼8.0 Hz, 1H), 3.63 (t, J¼6.4 Hz, 2H),
2.66 (t, J¼6.8 Hz, 2H), 2.15 (mc, 2H) ppm; 13C NMR (CDCl3,
75.5 MHz)
d 134.1, 131.9, 131.6, 127.7, 125.9 (q), 125.6, 122.1, 122.0,
94.4, 78.0, 32.4, 31.5, 18.5 ppm; 19F NMR (CDCl3, 282 MHz)
d
ꢁ62.9 ppm; HRMS-EI: [Mþ] calcd for C12H10BrF3: 289.9918,
found: 289.9934.
;
1166, 1130, 1004, 832, 757, 733, 631 cmꢁ1 1H NMR (CDCl3,
4.3.6. 1-(5-Bromopent-1-ynyl)-2-methoxybenzene (10g)
Following the general procedure for the Appel reaction alcohol
13g (3.50 g, 19.9 mmol, 1.0 equiv), CBr4 (7.89 g, 23.8 mmol,
300 MHz)
d
6.63 (s, 2H), 3.85 (s, 6H), 3.64 (m, 3H), 3.58 (t, J¼6.6 Hz,
2H), 2.60 (t, J¼6.8 Hz, 2H), 2.14 (mc, 2H) ppm; 13C NMR (CDCl3,
75.5 MHz) d 153.2, 138.7, 119.0, 109.0, 88.2, 81.7, 61.1, 56.3, 32.7, 31.8,

6012
K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
18.3 ppm; MS-EI m/z: 250 (Mþ, 100), 235 (36%); HRMS-EI: [Mþ]
calcd for C14H17BrO3: 312.0361, found: 312.0358.
4.4.1. 7-Phenyl-5,6-dihydro-4H-benzo[de]pyrrolo[1,2-a]-
quinoline (8a)
Following the general procedure for the domino reaction 1-(2-
4.3.11. 1-(5-Bromopent-1-ynyl)naphthalene (10l)
iodophenyl)-1H-pyrrole 9 (215 mg, 0.80 mmol, 2.0 equiv) and
Following the general procedure for the Appel reaction alcohol
13l (3.93 g, 18.7 mmol, 1.0 equiv), CBr4 (7.44 g, 22.4 mmol,
1.2 equiv), and PPh3 (5.89 g, 22.4 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 2.5% EtOAc/hexanes as eluent
the desired compound 10l (4.75 g, 93%) as colorless oil. IR (neat)
3056, 2960, 2227, 1942, 1585, 1430, 1395, 1270, 1246, 799,
bromoalkyl-aryl alkyne 10a (113 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 5% NEt3/hexanes the desired
tetracycle 8a (102 mg, 80%) as yellow oil. IR (CHCl3) 3051, 2928,
2860, 2826, 1589, 1494, 1467, 1439, 1358, 1334, 1310, 1252, 1167,
1072,1049,1028, 814, 787, 756, 702 cmꢁ1; 1H NMR (400 MHz, C6D6)
d
7.18 (dd, J¼2.8, 1.6 Hz, 1H), 6.97 (dd, J¼8.4, 0.8 Hz, 1H), 6.93 (dd,
774 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
8.30 (mc,1H), 7.79 (dd, J¼8.7,
J¼8.4, 1.6 Hz, 2H), 6.87–6.68 (m, 4H), 6.46 (dq, J¼7.6, 0.8 Hz, 1H),
6.30 (dd, J¼3.6, 2.8 Hz, 1H), 5.86 (dd, J¼4.0, 1.6 Hz, 1H), 2.24 (t,
J¼6.4 Hz, 2H), 2.09 (t, J¼6.0 Hz, 2H), 1.13 (mc, 2H) ppm; 13C NMR
8.1 Hz), 7.62 (d, J¼7.1 Hz, 1H), 7.59–7.45 (m, 2H), 7.38 (t, J¼7.2 Hz,
2H), 3.64 (t, J¼6.4, 0.5 Hz, 2H), 2.76 (t, J¼6.7 Hz, 2H), 2.21 (mc,
2H) ppm; 13C NMR (CDCl3, 75.5 MHz)
d
133.7, 133.4, 130.5, 128.5,
(100 MHz, CDCl3) d 138.5, 138.4, 133.4, 130.0, 128.5, 128.4, 128.3,
126.9, 126.6, 126.4, 125.5, 121.5, 93.2, 80.0, 32.8, 31.9, 18.7 ppm;
HRMS-EI: [Mþ] calcd for C15H13Br: 272.0201, found: 272.0199.
128.0, 127.8, 127.5, 127.0, 123.1, 122.7, 121.6, 113.0, 112.9, 111.9, 103.0,
31.3, 28.2, 23.2 ppm; HRMS-EI: [Mþ] calcd for C21H17N: 283.1361,
found: 283.1358.
4.3.12. 3-(5-Bromopent-1-ynyl)-1-tosyl-1H-indole (10m)
Following the general procedure for the Appel reaction alcohol
13m (2.05 g, 5.80 mmol, 1.0 equiv), CBr4 (2.31 g, 6.96 mmol,
1.2 equiv), and PPh3 (1.83 g, 6.96 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 10% EtOAc/hexanes as eluent
the desired compound 10m (2.31 g, 92%) as pale yellow solid. Mp
80–82 ꢀC; IR (CHCl3) 1448, 1374, 1277, 1188, 1176, 1129, 1103, 1089,
4.4.2. 7-(4-Methylphenyl)-5,6-dihydro-4H-benzo[de]pyrrolo-
[1,2-a]quinoline (8b)
Following the general procedure for the domino reaction 1-(2-
iodophenyl)-1H-pyrrole
9 (215 mg, 0.80 mmol, 2.0 equiv) and
bromoalkyl-aryl alkyne 10b (95 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 1% EtOAc/hexanes the desired
tetracycle 8b (101 mg, 85%) as slightly yellow foam. IR (CHCl3) 3018,
1019 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
7.99 (d, J¼8.3 Hz, 1H), 7.77
(d, J¼8.3 Hz, 2H), 7.68 (s, 1H), 7.60 (d, J¼8.5 Hz, 1H), 7.39–7.25 (m,
2H), 7.20 (d, J¼8.5 Hz, 2H), 3.61 (t, J¼6.4 Hz, 2H), 2.68 (t, J¼6.8 Hz,
2H), 2.32 (s, 3H), 2.16 (mc, 2H) ppm; 13C NMR (CDCl3, 75.5 MHz)
2940, 1399, 1728, 1591, 1512, 1473, 1359, 1313, 1052, 928 cmꢁ1 1H
;
NMR (300 MHz, C6D6)
d
7.63 (dd, J¼2.9, 1.4 Hz, 1H), 7.43 (d,
J¼7.8 Hz,1H), 7.30 (dt, J¼8.4, 0.8 Hz, 2H), 7.12 (dd, J¼7.8, 6.5 Hz, 3H),
6.91 (dd, J¼7.4, 0.8 Hz, 1H), 6.75 (dd, J¼3.8, 2.9 Hz, 1H), 6.37 (dd,
J¼3.8, 1.4 Hz, 1H), 2.70 (t, J¼6.0 Hz, 2H), 2.59 (t, J¼6.0 Hz, 2H), 2.21
d
145.5, 135.2, 134.4, 131.2, 130.2, 128.6, 127.1, 125.6, 123.9, 120.6,
113.8, 105.7, 92.6, 72.6, 32.6, 31.7, 21.8, 18.6 ppm; HRMS-EI: [Mþ]
calcd for C20H18BrNO2S: 415.0241, found: 415.0253.
(s, 3H), 1.60 (mc, 2H) ppm; 13C NMR (75.5 MHz, CDCl3)
d 138.4,
136.9,135.5,133.3,132.7,129.9,129.2,126.8,123.1,122.7,121.7,112.9,
112.1, 111.9, 109.7, 103.1, 31.3, 28.2, 23.2, 21.1 ppm; HRMS-EI: [Mþ]
calcd for C22H19N: 297.1518, found: 297.1515.
4.3.13. 3-(5-Bromopent-1-ynyl)-1-tosyl-1H-pyrazole (10n)
Following the general procedure for the Appel reaction alcohol
13n (1.50 g, 4.93 mmol, 1.0 equiv), CBr4 (1.96 g, 5.91 mmol,
1.2 equiv), and PPh3 (1.55 g, 5.91 mmol, 1.2 equiv) furnished after
silica gel flash chromatography using 10% EtOAc/hexanes as eluent
the desired compound 10n (1.68 g, 93%) as pale yellow solid. Mp
95–97 ꢀC; IR (CHCl3) 3017, 2245, 1596, 1517, 1437, 1387, 1305, 1191,
4.4.3. 7-(4-Nitrophenyl)-5,6-dihydro-4H-benzo[de]pyrrolo-
[1,2-a]quinoline (8c)
Following the general procedure for the domino reaction 1-(2-
iodophenyl)-1H-pyrrole
9 (215 mg, 0.80 mmol, 2.0 equiv) and
1178, 1136, 1028 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
8.04 (d,
bromoalkyl-aryl alkyne 10c (107 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 2% EtOAc/hexanes the desired
tetracycle 8c (95 mg, 72%) as orange foam. IR (CHCl3) 3018, 1945,
J¼2.5 Hz, 1H), 7.90 (dt, J¼7.7, 2.0 Hz, 2H), 7.33 (d, J¼8.1 Hz, 2H),
6.39 (d, J¼3.0 Hz, 1H), 3.52 (t, J¼6.4 Hz, 2H), 2.58 (t, J¼6.9 Hz, 2H),
2.42 (s, 3H), 2.10 (mc, 2H) ppm; 13C NMR (CDCl3, 75.5 MHz)
d
146.3,
2399, 1599, 1520, 1466, 1430, 1348, 1107, 1067, 1016, 928, 853 cmꢁ1
;
141.1, 133.9, 131.7, 130.3, 128.5, 112.2, 92.0, 73.4, 32.4, 22.0,
18.3 ppm; HRMS-EI: [Mþ] C15H15BrN2O2S: 366.0038, found:
366.0035.
1H NMR (300 MHz, C6D6)
d
8.35 (dt, J¼8.5, 2.1 Hz, 2H), 7.85 (dd,
J¼3.6, 1.6 Hz, 1H), 7.76 (d, J¼8.2 Hz, 1H), 7.60 (dt, J¼8.9, 2.1 Hz, 2H),
7.45 (t, J¼8.1 Hz, 1H), 7.15 (dd, J¼7.1, 1.0 Hz, 1H), 6.70 (dd, J¼3.8,
1.4 Hz,1H), 5.94 (dd, J¼3.8,1.3 Hz, 2H), 3.64 (t, J¼6.0 Hz, 2H), 2.68 (t,
J¼6.0 Hz, 2H), 1.93 (mc, 2H) ppm; 13C NMR (75.5 MHz, CDCl3)
4.4. General procedure for the domino reaction of
1-(2-iodophenyl)-1-H-pyrrole 9 and bromoalkyl-aryl
alkynes 10a–n
d 147.5, 145.3, 139.0, 133.4, 131.3, 131.1, 127.9, 126.1, 124.0, 123.8,
121.0, 113.0, 112.4, 112.3, 102.3, 31.3, 28.3, 23.2 ppm; HRMS-EI: [Mþ]
calcd for C21H16N2O2: 328.1212, found: 328.1197.
A 10 mL sealable tube was charged with 1-(2-iodophenyl)-1H-
pyrrole 9 (215 mg, 0.80 mmol, 2.0 equiv), bromoalkyl-aryl alkynes
10a–n (0.40 mmol, 1.0 equiv), norbornene (37.7 mg, 0.40 mmol,
1.0 equiv), Cs2CO3 (391 mg, 1.20 mmol, 3.0 equiv), PdCl2 (3.5 mg,
0.020 mmol, 5 mol %), tri-2-furylphosphine (9.3 mg, 0.040 mmol,
10 mol %), and CH3CN (4 mL). The mixture was stirred at 25 ꢀC for
10 min while being purged with argon. Afterwards, the tube was
sealed and submitted to a pre-heated oil bath (90 ꢀC) for 24 h. The
reaction mixture was treated with H2O (50 mL) and the resulting
mixture was extracted with CH2Cl2 (3ꢂ30 mL). The combined or-
ganic phases were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by silica
gel flash chromatography and concentration of the appropriate
fractions in vacuo afforded the desired compounds 8a–n.
4.4.4. 7-(2-Nitrophenyl)-5,6-dihydro-4H-benzo[de]pyrrolo-
[1,2-a]quinoline (8d)
Following the general procedure for the domino reaction 1-(2-
iodophenyl)-1H-pyrrole
9 (215 mg, 0.80 mmol, 2.0 equiv) and
bromoalkyl-aryl alkyne 10d (107 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 2% EtOAc/hexanes the desired
tetracycle 8d (106 mg, 71%) as orange solid. Mp 185–187 ꢀC; IR
(CHCl3) 3018, 2399, 1608, 1528, 1426, 1353, 1045, 929 cmꢁ1 1H
;
NMR (300 MHz, C6D6)
1.6 Hz, 1H), 7.78–7.67 (m, 2H), 7.59 (mc, 1H), 7.50–7.38 (m, 2H), 7.13
d
8.10 (dd, J¼8.2, 1.4 Hz, 1H), 7.81 (dd, J¼2.8,
(mc, 1H), 6.65 (dd, J¼3.7, 3.0 Hz, 1H), 5.80 (dd, J¼3.5, 1.4 Hz, 1H),
3.02 (t, J¼6.1 Hz, 2H), 2.58 (t, J¼6.1 Hz, 2H), 1.93 (mc, 2H) ppm; 13
C
NMR (75.5 MHz, CDCl3)
d 149.5, 138.5, 133.1, 133.1, 132.7, 132.6,
130.9, 128.8, 127.4, 124.4, 124.0, 123.6, 123.3, 120.8, 112.6, 112.1,

K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
6013
112.0, 101.2, 31.0, 27.8, 22.8 ppm; HRMS-EI: [Mþ] calcd for
21H16N2O2: 328.1212, found: 328.1205.
(400 MHz, C6D6)
d
7.52 (dd, J¼2.9, 1.4 Hz, 1H), 7.32 (d, J¼8.4 Hz, 1H),
C
7.24 (t, J¼7.8 Hz, 1H), 7.15–7.05 (m, 2H), 7.00–6.94 (m, 2H), 6.82 (dd,
J¼7.6, 0.4 Hz, 1H), 6.62 (t, J¼2.8 Hz, 1H), 6.12 (dd, J¼4.0, 1.2 Hz, 1H),
2.58 (t, J¼5.6 Hz, 2H), 2.36 (t, J¼6.4 Hz, 2H), 1.48 (mc, 2H), 1.14 (s,
4.4.5. 7-(2-Chlorophenyl)-5,6-dihydro-4H-benzo[de]pyrrolo-
[1,2-a]quinoline (8e)
3H) ppm; 13C NMR (100 MHz, CDCl3)
d 167.7, 138.7, 136.9, 130.3,
Following the general procedure for the domino reaction 1-(2-
129.1, 127.8, 127.7, 126.8, 125.1, 124.7, 123.9, 123.6, 123.5, 121.4, 121.2,
121.0, 113.4, 112.6, 112.2, 103.0, 31.1, 27.8, 23.1 ppm; HRMS-EI: [Mþ]
calcd for C23H20O2N: 340.1576, found: 340.1584.
iodophenyl)-1H-pyrrole
9 (215 mg, 0.80 mmol, 2.0 equiv) and
bromoalkyl-aryl alkyne 10e (103 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 5% NEt3/hexanes the desired
tetracycle 8e (92 mg, 72%) as yellow foam. IR (CHCl3) 2935, 2860,
1650,1589,1551,1538,1483,1433,1354,1310,1252,1215,1174,1123,
4.4.9. Ethyl 3-(5,6-dihydro-4H-benzo[de]pyrrolo[1,2-a]quinolin-7-
yl)benzoate (8i)
1066, 1028, 790, 767, 750, 685 cmꢁ1
;
1H NMR (400 MHz, C6D6)
Following the general procedure for the domino reaction 1-(2-
d
7.53 (dd, J¼2.8, 1.2 Hz, 1H), 7.33 (d, J¼8.0 Hz, 1H), 7.29 (dd, J¼7.6,
iodophenyl)-1H-pyrrole 9 (215 mg, 0.80 mmol, 2.0 equiv) and
0.8 Hz, 1H), 7.13–7.05 (m, 2H), 6.82–6.96 (m, 3H), 6.65 (dd, J¼3.6,
2.8 Hz, 1H), 6.06 (dd, J¼4.0, 1.6 Hz, 1H), 2.62 (t, J¼6.4 Hz, 2H), 2.56
(ddd, J¼16.0, 7.6, 4.4 Hz, 1H), 2.36 (ddd, J¼16.0, 7.6, 4.4 Hz, 1H), 1.58
bromoalkyl-aryl alkyne 10i (118 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 5% NEt3/hexanes the desired
tetracycle 8i (85 mg, 60%) as white foam. IR (CHCl3) 3420, 2976,
2928, 1721, 1602, 1589, 1480, 1463, 1436, 1365, 2190, 1256, 1212,
(mc, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d 134.5, 131.7, 129.8,
129.0,128.0,127.7,127.2,126.9,125.7,124.0,123.2,121.2,113.0,112.2,
1164, 1106, 1076, 783, 746, 692 cmꢁ1 1H NMR (400 MHz, C6D6)
;
112.1, 102.4, 31.1, 27.8, 23.0 ppm; HRMS-EI: [Mþ] calcd for
d
8.35 (t, J¼1.2 Hz, 1H), 8.21 (dt, J¼8.0, 1.2 Hz, 1H), 7.56 (dd, J¼2.8,
C
21H16ClN: 317.0971, found: 317.0975.
1.6 Hz, 1H), 7.36 (mc, 2H), 7.18–7.08 (m, 2H), 6.85 (dd, J¼7.6, 0.8 Hz,
1H), 6.67 (dd, J¼3.6, 2.8 Hz, 1H), 6.15 (dd, J¼4.0, 1.6 Hz, 1H), 4.10 (q,
J¼7.2 Hz, 2H), 2.60 (t, J¼5.2 Hz, 2H), 2.39 (t, J¼5.2 Hz, 2H), 1.47 (mc,
4.4.6. 7-(2-(Trifluoromethyl)phenyl)-5,6-dihydro-4H-
benzo[de]pyrrolo[1,2-a]quinoline (8f)
2H), 0.96 (t, J¼4.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d 166.1,
Following the general procedure for the domino reaction 1-(2-
iodophenyl)-1H-pyrrole 9 (215 mg, 0.80 mmol, 2.0 equiv) and bro-
moalkyl-aryl alkyne 10f (116 mg, 0.40 mmol) furnished after silica
gel flash chromatography using 5% NEt3/hexanes the desired tetra-
cycle 8f (72 mg, 51%) as white solid. Mp 172–174 ꢀC; IR (CHCl3) 3413,
2928,1650,1463,1422, 1258, 1314, 1263, 1212,1174,1161, 1120, 1103,
138.8, 138.5, 134.2, 131.5, 131.2, 128.9, 128.7, 128.0, 127.8, 127.4, 127.1,
123.2, 123.1, 121.4, 113.1, 112.1, 102.9, 60.8, 31.2, 28.1, 23.1, 14.1 ppm;
HRMS-EI: [Mþ] C24H21O2N: 355.1572, found: 355.156733.
4.4.10. 7-(2,6-Dimethoxyphenyl)-5,6-dihydro-4H-
benzo[de]pyrrolo[1,2-a]quinoline (8j)
1066,1032, 780, 770, 746, 682 cmꢁ1; 1H NMR (400 MHz, C6D6)
d
7.18
Following the general procedure for the domino reaction 1-(2-
(d, J¼8.0 Hz, 1H), 7.14 (dd, J¼2.9, 1.4 Hz, 1H), 6.95 (d, J¼8.2 Hz, 1H),
6.72–6.55 (m, 4H), 6.47 (dd, J¼7.2,1.2 Hz,1H), 6.27 (dd, J¼3.7, 2.9 Hz,
1H), 5.54 (dd, J¼3.7, 1.4 Hz, 1H), 2.25 (t, J¼6.0 Hz, 2H), 2.09 (ddd,
J¼16.0, 7.8, 4.1 Hz, 1H), 2.86 (ddd, J¼16.0, 7.6, 4.1 Hz, 1H), 1.26–1.12
iodophenyl)-1H-pyrrole 9 (215 mg, 0.80 mmol, 2.0 equiv) and
bromoalkyl-aryl alkyne 10j (113 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 5% EtOAc/hexanes the desired
tetracycle 8j (65 mg, 47%) as slightly yellow foam. IR (CHCl3) 3018,
(m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d
138.5,133.6,132.2,132.0,
2340, 1588, 1523, 1471, 1432, 1112, 1045, 929 cmꢁ1 1H NMR
;
128.1, 128.0, 127.8, 127.34, 127.32, 125.7, 124.0, 123.3, 121.1, 113.0,
112.9, 112.2, 111.9, 111.8, 102.9, 102.8, 31.1, 28.2, 22.9 ppm; HRMS-EI:
[Mþ] calcd for C22H16F3O3: 351.1235, found: 351.1237.
(300 MHz, C6D6)
d
7.57 (mc, 1H), 7.37 (d, J¼8.4 Hz, 1H), 7.24 (t,
J¼8.4 Hz, 1H), 7.08 (t, J¼7.9 Hz, 1H), 6.86 (d, J¼7.4 Hz, 1H), 6.74 (t,
J¼3.0 Hz, 1H), 6.48 (d, J¼8.2 Hz, 2H), 6.29 (mc, 1H), 3.24 (s, 6H), 2.77
(t, J¼6.2 Hz, 2H), 2.71 (t, J¼6.2 Hz, 2H), 1.74 (mc, 1H) ppm; 13C NMR
4.4.7. 7-(2-Methoxyphenyl)-5,6-dihydro-4H-benzo[de]pyrrolo-
[1,2-a]quinoline (8g)
(75.5 MHz, CDCl3) d 158.9, 138.0, 133.5, 132.3, 129.3, 128.2, 127.9,
127.6, 126.6, 124.5, 122.8, 121.9, 121.8, 115.6, 112.7, 112.1, 111.3, 104.4,
Following the general procedure for the domino reaction 1-(2-
101.5, 55.3, 31.3, 28.0, 23.2 ppm; HRMS-ESI: [Mþ] calcd for
iodophenyl)-1H-pyrrole
9
(215 mg, 0.80 mmol, 2.0 equiv) and
C
23H21NO2þHþ: 344.1645, found: 344.1659.
bromoalkyl-aryl alkyne 10g (101 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 5% NEt3/hexanes the desired
tetracycle 8g (113 mg, 90%) as slightly yellow foam. IR (CHCl3) 3018,
2940, 2836, 2400, 1591, 1494, 1467, 1435, 1361, 1244, 1114, 1048,
4.4.11. 7-(3,4,5-Trimethoxyphenyl)-5,6-dihydro-4H-
benzo[de]pyrrolo[1,2-a]quinoline (8k)
Following the general procedure for the domino reaction 1-(2-
iodophenyl)-1H-pyrrole 9 (215 mg, 0.80 mmol, 2.0 equiv) and
1026 cmꢁ1; 1H NMR (300 MHz, C6D6)
d
7.60 (dd, J¼2.8, 1.5 Hz, 1H),
7.40 (d, J¼8.3 Hz, 1H), 7.24 (mc, 1H), 7.12 (d, J¼7.6 Hz, 1H), 6.98 (dt,
J¼7.6, 1.2 Hz, 1H), 7.36 (dd, J¼7.83, 1.7 Hz, 1H), 7.24 (mc, 1H), 6.89
(mc, 1H), 6.76–6.64 (m, 2H), 6.28 (dd, J¼3.5, 1.2 Hz, 1H), 3.18 (s, 3H),
2.77–2.54 (m, 4H), 1.77–1.58 (m, 2H) ppm; 13C NMR (75.5 MHz,
bromoalkyl-aryl alkyne 10k (125 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 5% EtOAc/hexanes the desired
tetracycle 8k (130 mg, 87%) as slightly yellow foam. IR (CHCl3)
3684, 3017, 2940, 2399, 1727, 1583, 1505, 1475, 1464, 1411, 1345,
CDCl3)
d
157.8, 138.3, 133.5, 132.6, 131.6, 129.2, 127.3, 126.9, 125.2,
1128, 1001, 928 cmꢁ1
;
1H NMR (300 MHz, C6D6)
d
7.68 (dd, J¼3.0,
140.0, 123.1, 121.7, 120.9, 112.9, 112.2, 111.8, 111.5, 102.5, 55.1, 31.4,
28.1, 23.2 ppm; HRMS-EI: [Mþ] calcd for C22H19NO: 313.1467,
found: 313.1467.
1.5 Hz, 1H), 7.48 (dd, J¼7.4, 1.5 Hz, 1H), 7.21–7.14 (m, 1H), 6.95 (mc,
1H), 6.82–6.78 (m, 1H), 6.60 (s, 2H), 7.37 (d, J¼8.4 Hz, 1H), 7.24 (t,
J¼8.4 Hz, 1H), 7.08 (t, J¼7.9 Hz, 1H), 6.86 (d, J¼7.4 Hz, 1H), 6.74 (dd,
J¼3.8, 1.5 Hz, 1H), 2.76 (t, J¼6.3 Hz, 2H), 2.65 (t, J¼6.3 Hz, 2H), 1.72–
4.4.8. N-(2-(5,6-Dihydro-4H-benzo[de]pyrrolo[1,2-a]quinolin-7-
yl)phenyl)acetamide (8h)
1.62 (m, 2H) ppm; 13C NMR (75.5 MHz, CDCl3)
d 154.1, 138.6, 138.5,
133.6,133.3,132.5,128.7,127.0,123.3,122.7,121.6,113.0,112.2,112.0,
107.4, 103.2, 60.5, 55.7, 31.3, 28.4, 23.3 ppm; HRMS-ESI: [Mþ] calcd
for C24H23NO3þHþ: 374.1750, found: 374.1767.
Following the general procedure for the domino reaction 1-(2-
iodophenyl)-1H-pyrrole 9 (215 mg, 0.80 mmol, 2.0 equiv) and bro-
moalkyl-aryl alkyne 10h (112 mg, 0.40 mmol) furnished after silica
gel flash chromatography using 10% EtOAcþ5% NEt3/hexanes the
desired tetracycle 8h (34 mg, 25%) as yellow foam. IR (CHCl3) 3399,
3311, 2997, 2935, 2867, 1677, 1575, 1514, 1477, 1463, 1443, 1358,
1300, 1242, 1212, 1171, 1038, 1008, 957, 777, 746, 695 cmꢁ1; 1H NMR
4.4.12. 7-(Naphthalen-1-yl)-5,6-dihydro-4H-benzo[de]pyrrolo-
[1,2-a]quinoline (8l)
Following the general procedure for the domino reaction 1-(2-
iodophenyl)-1H-pyrrole
9 (215 mg, 0.80 mmol, 2.0 equiv) and

6014
K.M. Gericke et al. / Tetrahedron 64 (2008) 6002–6014
bromoalkyl-aryl alkyne 10l (109 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 1% EtOAc/hexanes the desired
tetracycle 8l (89 mg, 67%) as slightly yellow foam. IR (CHCl3) 3018,
Research Chair, and the University of Toronto. K.M.G. thanks the
Deutsche Forschungsgemeinschaft (DFG) for a postdoctoral schol-
arship. We thank Brian Mariampillai, Frederic Menard, and
Dr. David Hulcoop for helpful discussions, and Dr. A. Lough for
X-ray analysis.
2399, 1594, 1519, 1476, 1427, 1360, 1046, 929 cmꢁ1 1H NMR
;
(400 MHz, C6D6)
d
7.52 (dd, J¼2.9, 1.4 Hz, 1H), 7.32 (d, J¼8.4 Hz, 1H),
7.24 (t, J¼7.8 Hz, 1H), 7.15–7.05 (m, 2H), 7.00–6.94 (m, 2H), 6.82 (dd,
J¼7.6, 0.4 Hz, 1H), 6.62 (t, J¼2.8 Hz, 1H), 6.12 (dd, J¼4.0, 1.2 Hz, 1H),
2.58 (t, J¼5.6 Hz, 2H), 2.36 (t, J¼6.4 Hz, 2H), 1.48 (mc, 2H), 1.14 (s,
References and notes
3H) ppm; 13C NMR (100 MHz, CDCl3)
d 138.5, 136.1, 134.3, 133.6,
1. (a) Tietze, L. F.; Beifuss, U. Angew. Chem. 1993, 105, 134–170; Angew. Chem., Int.
Ed. Engl. 1993, 32, 131–132; (b) Tietze, L. F. Chem. Rev. 1996, 96, 115–136; (c)
Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006.
132.7, 132.4, 128.5, 128.1, 127.1, 126.6, 126.4, 126.2, 126.1, 125.8,
124.3, 123.2, 121.5, 113.1, 112.2, 111.8, 103.2, 31.2, 28.0, 23.0 ppm;
HRMS-EI: [Mþ] calcd for C25H19N: 333.1518, found: 333.1519.
2. For a recent review, see: Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174–238.
3. For early examples, see: (a) Albrecht, K.; Reiser, O.; Weber, M.; Knieriem, B.; de
Meijere, A. Tetrahedron 1994, 50, 383–401; (b) Takahashi, A.; Inukai, T. J. Chem.
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4.4.13. 7-(1-Tosyl-1H-indol-3-yl)-5,6-dihydro-4H-
benzo[de]pyrrolo[1,2-a]quinoline (8m)
Following the general procedure for the domino reaction 1-(2-
iodophenyl)-1H-pyrrole
9 (215 mg, 0.80 mmol, 2.0 equiv) and
bromoalkyl-aryl alkyne 10m (167 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 5% EtOAc/hexanes the desired
tetracycle 8m (134 mg, 75%) as slightly yellow foam. IR (CHCl3)
3685, 3018, 2940, 2400, 1728, 1597, 1475, 1446, 1428, 1372, 1256,
6. For annulation onto an alkene, see: (a) Grigg, R.; Kennewell, P.; Teasdale, A.;
Sridharan, V. Tetrahedron Lett. 1993, 34, 153–156; For annulation onto a nitrile,
see: (b) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9276–9287;
For annulation onto phenols and anilines, see: (c) Catellani, M.; Del Rio, A. Russ.
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T. Heterocycles 2002, 57, 1781–1786; (d) Lautens, M.; Paquin, J.-F.; Piguel, S.;
Dahlmann, M. J. Org. Chem. 2001, 66, 8127–8134.
7. (a) Catellani, M.; Fagnola, M. C. Angew. Chem. 1994, 106, 2559–2561; Angew.
Chem., Int. Ed. Engl. 1994, 33, 2421–2422; (b) Catellani, M.; Frignani, F.; Rangoni,
A. Angew. Chem. 1997, 109, 142–145; Catellani, M.; Frignani, F.; Rangoni, A.
Angew. Chem., Int. Ed. 1997, 36, 119–122; (c) Catellani, M.; Mealli, C.; Motti, E.;
Paoli, P.; Perez-Carreno, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336–
4346; (d) Catellani, M. Synlett 2003, 298–313; (e) See Ref. 5a.
8. (a) Rudolph, A.; Rackelmann, N.; Lautens, M. Angew. Chem., Int. Ed. 2007, 46,
1485–1488; (b) Mitsudo, K.; Thansandote, P.; Wilhelm, T.; Mariampillai, B.;
Lautens, M. Org. Lett. 2006, 8, 3939–3942; (c) Jafarpour, F.; Lautens, M. Org. Lett.
2006, 8, 3601–3604; (d) Martins, A.; Marquardt, U.; Kasravi, N.; Alberico, D.;
Lautens, M. J. Org. Chem. 2006, 71, 4937–4942; (e) Blaszykowski, C.; Aktou-
dianakis, E.; Bressy, C.; Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 2043–2045;
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Paquin, J.-F.; Lautens, M. Tetrahedron 2005, 61, 6283–6297; (i) Pache, S.; Laut-
ens, M. Org. Lett. 2003, 5, 4827–4830; (j) Lautens, M.; Piguel, S. Angew. Chem.
2000, 112, 1087–1088; Angew. Chem., Int. Ed. 2000, 39, 1045–1046.
9. (a) Gribble, G. W. Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. S. V., Eds.; Pergamon: New York, NY, 1996; Vol. 2, pp 207–257;
(b) Le Quesne, P. W.; Dong, Y.; Blythe, T. A. Alkaloids: Chem. Biol. Perspect. 1999,
13, 237–287; (c) Janosik, T.; Bergman, J. Progress in Heterocyclic Chemistry;
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Sirisom, N. S.; Zhang, H.-Z. Patent WO 2004055163, 2004.
1174, 1128, 987, 931 cmꢁ1 1H NMR (300 MHz, C6D6)
; d 8.24 (d,
J¼7.2 Hz, 1H), 7.68 (t, J¼4.0 Hz, 3H), 7.58 (dd, J¼3.0, 1.4 Hz, 1H), 7.40
(d, J¼7.5 Hz, 1H), 7.18–7.08 (m, 3H), 6.96–6.85 (m, 2H), 6.64 (dd,
J¼3.6, 3.0 Hz, 1H), 6.51 (dd, J¼8.8, 0.6 Hz, 2H), 6.05 (dd, J¼3.8,
1.4 Hz, 1H), 2.65 (t, J¼6.3 Hz, 2H), 2.48–2.22 (m, 2H), 1.65 (s, 3H),
1.58–1.37 (m, 2H) ppm; 13C NMR (75.5 MHz, CDCl3)
d 144.5, 141.3,
138.6, 135.8, 133.5, 131.9, 131.1, 129.7, 127.4, 126.8, 126.0, 125.3,
125.0,123.7,123.3,121.3,120.0,118.9,114.3,112.9,112.2,112.0,102.8,
31.2, 28.2, 23.1, 20.9 ppm; HRMS-ESI: [Mþ] calcd for C30H24N2O2S:
476.1559, found: 476.1578.
4.4.14. 7-(1-Tosyl-1H-pyrazol-3-yl)-5,6-dihydro-4H-
benzo[de]pyrrolo[1,2-a]quinoline (8n)
Following the general procedure for the domino reaction 1-(2-
iodophenyl)-1H-pyrrole
9 (215 mg, 0.80 mmol, 2.0 equiv) and
bromoalkyl-aryl alkyne 10n (147 mg, 0.40 mmol) furnished after
silica gel flash chromatography using 5% EtOAc/hexanes the desired
tetracycle 8n (26 mg, 15%) as slightly yellow solid. IR (CHCl3) 2399,
1718, 1559, 1506, 1473, 1379, 1176, 1032, 928 cmꢁ1 1H NMR
;
(300 MHz, CD2Cl2)
d
8.22 (d, J¼2.4 Hz, 1H), 7.92 (dt, J¼8.5, 1.9 Hz,
2H), 7.79 (dd, J¼3.0, 1.4 Hz, 2H), 7.72 (d, J¼8.0 Hz, 1H), 7.45–7.34 (m,
3H), 7.12 (mc, 1H), 6.66–6.61 (m, 2H), 6.05 (dd, J¼3.8, 1.3 Hz, 1H),
2.99 (t, J¼6.2 Hz, 1H), 2.73 (t, J¼6.2 Hz, 2H), 2.43 (s, 3H), 1.84 (mc,
10. Nakatsuka, M.; Shimamura, T. JP Patent 2000311787, 2000.
11. Crandall, J. K.; Michaely, W. J. J. Org. Chem. 1984, 49, 4244–4248.
12. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–4470.
13. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801–811.
14. Mamane, V.; Hannen, P.; Fuerstner, A. Chem.dEur. J. 2004, 10, 4556–4575.
15. CCDC-672235 8d and CCDC-672236 8n contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
2H) ppm; 13C NMR (75.5 MHz, CDCl3)
d 154.1, 146.3, 139.3, 134.3,
133.3, 131.9, 130.1, 128.2, 128.0, 126.2, 125.5, 123.5, 123.5, 120.7,
118.5, 112.6, 112.1, 112.0, 110.9, 102.0, 31.1, 28.2, 23.1, 21.6 ppm;
HRMS-ESI: [Mþ] calcd for C25H21N3O2S: 427.1354, found: 427.1341.
16. The existence of cyclobutene F as intermediate, which re-enters the catalytic
cycle via C–C bond activation is possible but unlikely. Cyclobutenes are often
observed as byproducts within Catellani-type reactions, which means that they
are stable under the applied reaction conditions.
17. Santelli-Rouvier, C.; Coin, C.; Toupet, L.; Santelli, M. J. Organomet. Chem. 1995,
495, 91–96.
Acknowledgements
We gratefully acknowledge the financial support of the Natural
Sciences and Engineering Research Council (NSERC) of Canada, the
Merck Frosst Centre for Therapeutic Research for an Industrial
18. Witulski, B.; Buschmann, N.; Bergstrasser, U. Tetrahedron 2000, 56, 8473–8480.