Three-component one-pot process to propargylic amines and related amide and sulfonamide compounds: application to the construction of 2-(aminomethyl)benzofurans and indoles

Article abstract of DOI:10.1016/j.tet.2007.07.096

An efficient palladium-copper-catalyzed three-component assembling of propargyl halides, aryl or heteroaryl halides, and secondary amines is described. A wide variety of tertiary propargylic amines were synthesized in good to excellent yields from easily accessible starting materials. This three-component assembling was also effective when using potassium phthalimide or di-tert-butyliminodicarbonate instead of secondary amines. Consequently, it provides a quick entry to N-protected propargylic amines suitable intermediates for the synthesis of primary and secondary propargylic amines. In a similar way, related compounds including propargylic amide, carbamate and sulfonamide derivatives were efficiently obtained. This catalytic domino three-component process has been applied successfully to the construction of functionalized 2-(aminomethyl)benzo[b]furan or indole derivatives of biological interest.

Full text of DOI:10.1016/j.tet.2007.07.096

Tetrahedron 63 (2007) 10671–10683
Three-component one-pot process to propargylic amines and
related amide and sulfonamide compounds: application to the
construction of 2-(aminomethyl)benzofurans and indoles
a a,b
Olivier Russo, Samir Messaoudi, Abdallah Hamze,
a,b
b
a,b
a,b
a,b
Nathan €a el Olivi, Jean-Fran c¸ ois Peyrat, Jean-Daniel Brion, Sames Sicsic,
a,c
a,b,
*
Isabelle Berque-Bestel and Mou ^a d Alami
a
Univ Paris-Sud, BioCIS UMR 8076, Laboratoire de Chimie The´rapeutique, Faculte´ de Pharmacie, rue J.B. Cle´ment F-92296
Ch a^ tenay-Malabry, France
b
CNRS, BioCIS UMR 8076, Laboratoire de Chimie The´rapeutique, Faculte´ de Pharmacie, rue J.B. Cle´ment F-92296
Ch a^ tenay-Malabry, France
Inserm U869, Universite´ Victor Segalen, 146 rue le´o Saignat, F-33076 Bordeaux, France
c
Received 21 June 2007; revised 24 July 2007; accepted 26 July 2007
Available online 1 August 2007
Abstract—An efficient palladium–copper-catalyzed three-component assembling of propargyl halides, aryl or heteroaryl halides, and
secondary amines is described. A wide variety of tertiary propargylic amines were synthesized in good to excellent yields from easily acces-
sible starting materials. This three-component assembling was also effective when using potassium phthalimide or di-tert-butyliminodicar-
bonate instead of secondary amines. Consequently, it provides a quick entry to N-protected propargylic amines suitable intermediates for the
synthesis of primary and secondary propargylic amines. In a similar way, related compounds including propargylic amide, carbamate and
sulfonamide derivatives were efficiently obtained. This catalytic domino three-component process has been applied successfully to the con-
struction of functionalized 2-(aminomethyl)benzo[b]furan or indole derivatives of biological interest.
Ó 2007 Elsevier Ltd. All rights reserved.
1
2
1
. Introduction
several enzymes (e.g., ABT-761 is a selective 5-lipoxyge-
nase inhibitor). These compounds are also versatile synthetic
intermediates for the synthesis of various nitrogen heterocy-
Functionalized propargylic amines are important structural
elements of natural products and therapeutic drug mole-
cules. Many molecules bearing this original motif are
well-known to exhibit strong inhibitory activities toward
3
cles and allyl- or alkylamines having highly potent biolog-
ical activities (Scheme 1). For instance, CP-724,714 is
a selective ErbB2 angiogenesis inhibitor currently being
4
O
Me
F
OMe
HN
O
HN
N
HO
N
NH2
Me
S
N
O
ABT-761
CP-724,714
N
COOH
N
OMe
O
N
N
Me
N
N
H
A
Scheme 1.
*
0
Corresponding author. E-mail: mouad.alami@u-psud.fr
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.096

10672
O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
investigated for the treatment of breast, ovarian, and other
types of cancer and compound A is a a b integrin antago-
nist indicated in osteoporosis disease.
conditions are set up in such a way to promote the reaction
cascade. Typically, the reaction was carried out by adding
propargyl bromide 1a (1.2 equiv) to a mixture containing
aryl halide (1 equiv), secondary amine, PdCl (PPh )
5
v
3
2
3 2
In recent years, great efforts have been made to find new
routes to propargylic amines including amination of propar-
(5 mol %), and CuI (10 mol %). As expected, aryl iodides
underwent the three-component reaction without any heat-
ing and much more rapidly than aryl bromides. The reaction
with these latter required a 60 C heating during several
hours for completion.
6
gylic electrophiles (halides, triflates, or phosphates), TiCl
mediated amination of propargyl ester, addition of
4
7
ꢀ
8
1
-alkynes to pre-formed imines, or Sonogashira coupling
9
of aryl halides with propargyl amines. However, while these
reactions are suitable methods, they require the preparation
of either or both reagents. The obvious and certainly the
most popular way to prepare propargylic amines is the
Mannich three-component condensation of 1-alkynes, alde-
It is interesting to note that the presence of an electron-
donating or electron-withdrawing substituent in ortho or
para position of the aromatic ring did not interfere with
the outcome of the coupling reaction. In all cases studied,
propargylic amines 2a–h were formed in good to excellent
yields (Table 1, entries 1–8). Carrying out the three-compo-
nent reaction with multiple halogenated aromatic substrates
such as 1,4-diiodobenzene or 1,3,5-tribromobenzene fur-
1
0
hydes, and amines. While there are many commercially
available amines and aldehydes, the number of terminal
alkynes is limited (particularly functionalized terminal aryl-
alkynes) and their preparation requires multistep sequence
synthesis. Moreover, such terminal alkynes are sensitive
substrates when bearing an electron-withdrawing substituent
1
7
nished the corresponding bis-(2i) or tris-coupling product
(2j) in high yields (entries 9 and 10). Interestingly, this dom-
ino three-component coupling reaction was also effective
with heteroaromatic halides and yielded the corresponding
propargylic amines 2k–m in good yields (entries 11–13).
1
1
(
NO , CN, CF , etc.) on the aromatic ring. From the stand-
2 3
point of flexibility, a method employing a common starting
material as a precursor would have obvious advantages.
In the following examples, it is interesting to note that al-
2
. Results and discussion
1
8
kenyl chlorides in spite of their poor reactivity were read-
ily used in this domino process without any difficulty. In the
case of chloroenynes, the reaction requires the use of
1
2
We wish to detail herein our results, previously reported,
concerning a three-component nitrogen propargylation/
alkynylation of organic halides leading to the synthesis of
aryl- or heteroarylpropargylic amines as well as related
amide and sulfonamide compounds. The basic concept of
our process, illustrated in Scheme 2, is based on a tandem
nitrogen propargylation/Sonogashira–Linstrumelle reaction
using amines or potassium di-tert-butyliminodicarbonate,
propargyl bromide, and aryl halides under palladium–copper
catalysis. The commercial availability of such compounds
makes this approach sufficiently diversity oriented, thus
fulfilling the recent demand for the generation of large com-
1
9
PdCl (PhCN) as catalyst instead of PdCl (PPh ) and af-
2
2
2
3 2
forded the enediyne product 2n in an excellent yield (entry
4). Starting from a E/Z (1:1) mixture of 1,2-dichloroethyl-
1
2
0
ene, the corresponding E-chloroenyne 2o was selectively
obtained in a good yield (E/Z 9:1, entry 15). Substituted
propargyl chloride such as 3-chloro-oct-1-yne was also
effective for the reaction and its coupling with methyl-4-
iodobenzoate or 4-iodobenzonitrile, provided the desired
propargylic amines 2p and 2q in excellent yields (entries
1
6 and 17).
1
3
binatorial chemical libraries. Additionally, this novel
domino three-component coupling reaction provides
a quick and efficient entry to functionalized 2-(amino-
1
4
2.2. Access to protected and unprotected propargylic
amines
methyl)benzo[b]furan or indole derivatives of biological
interest.
1
5
Besides the synthesis of tertiary propargylic amines 2, our
simple methodology could open an easy access to protected
and unprotected functionalized aryl propargylic amines 3–5.
An access to primary propargylic amine can be envisaged
through the direct coupling of propargylic amine with aryl
H
N
+
X-R
N
Br
PdLn / CuI
21
R
halides. Nevertheless, this approach is uncertain, yields
being generally enhanced after protection of the propargylic
1a
2
R = aryl, heteroaryl, alkenyl
X = I, Br, Cl
2
2
amine. Moreover, in the case of heteroaryl halides such as
-bromopyridine, attempts coupling with commercially
2
Scheme 2.
available prop-2-ynylamine at room temperature under var-
ious combinations of palladium catalyst and amines (e.g.,
Pd(PPh ) , PdCl (PPh ) , Et NH, Et N, piperidine with or
2
.1. Access to tertiary propargylic amines
3
4
2
3 2
2
3
1
6
without CuI) resulted in an unsatisfactory yield of 5c cer-
tainly due to the instability of the resulting compound under
the conditions used.
In order to prepare highly functionalized tertiary propargylic
amines 2, we first carried out the reaction with secondary
amines. As depicted in Table 1, a broad range of commer-
cially available cyclic or acyclic secondary amines were
studied in combination with functionalized aryl iodides or
aryl bromides. In the following couplings, the amines were
With regards to efficiency, instead of using previously syn-
thesized protected propargylic amine, we were interested
in forming the N-protected propargylic amine in situ. To
this end, we planned to use a potassium salt of phthalimide
or di-tert-butyliminodicarbonate during the reaction. Thus,
1
6
used as substrate and solvent of the reaction. The reagents
and catalysts are mixed together and experimental

O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
10673
Table 1. Three-component assembling process of propargyl halides 1, secondary amines, and aryl or heteroaryl halides under palladium–copper catalysis:
synthesis of tertiary propargylic amines 2
a
Yield (%)
Entry
Amine
Propargylic halide 1
RX
Propargylic amine 2
Br
1
Piperidine
1a
I
2a
N
92
O
Br
2
3
4
5
6
Morpholine
1a
I
NHBoc
CN
2b
83
85
94
69
82
N
NHBoc
CN
Et2N
2c
Br
Et
Et
2
2
NH
NH
1a
I
Et2N
2d
Br
1a
I
NO2
NO2
NO2
iPr2N
2e
Br
i-Pr NH
2
1a
I
NO2
EtO2C
I
EtO2C
Br
Piperidine
1a
2f
N
O
Br
7
8
9
Morpholine
Morpholine
Morpholine
1a
Br
CO Et
2g
93
86
98
2
N
CO2Et
O
Br
1a
Br
NO2
2h
N
NO2
N
O
O
Br
1a
I
I
2i
N
O
N
Br
Br
2j
10
Morpholine
1a
62
Br
Br
O
O
N
N
N
Et2N
N
N
Br
1
1
1
1
2
3
Et
2
NH
1a
2k
74
78
79
Br
Br
Br
Piperidine
1a
2l
N
N
I
Et2N
Br
Et
2
NH
1a
2m
N
Cl
N
Cl
Br
b
14
Piperidine
1a
2n
87
N
Cl
(
continued)

10674
O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
Table 1. (continued)
a
Yield (%)
Entry
Amine
Propargylic halide 1
RX
Propargylic amine 2
Cl
E/Z 1/1
Cl
Br
Cl
Cl
c
1
5
6
Piperidine
1a
2o
63
N
E:Z = 9:1
2
Et N
1
Et
2
NH
1b
I
CO Me
2p
CO2Me
74
89
2
C5H11
C5H11
Cl
N
1
7
Piperidine
1b
I
CN
2q
CN
C5H11
C5H11
a
2 3 2
Isolated yield based on RX. Unless otherwise stated, all reactions were conducted with RX (1 equiv), propargyl halide 1 (1.2 equiv), PdCl (PPh ) (5 mol %),
and CuI (10 mol %) in secondary amine used as a solvent.
b
c
2 2 2 3 2
PdCl (PhCN) was used instead of PdCl (PPh ) ; see Ref. 19.
Isolated yield based on propargyl bromide 1a (1 equiv). The reaction was performed in the presence of an excess (10 equiv) of 1,2-dichloroethylene
1
(
E/Z¼1:1); see Ref. 20; E/Z ratio was determined by H NMR.
the three-component reaction was carried out in a sequential
way by mixing in a first step in DMF propargyl bromide 1a
di-tert-butyliminodicarbonate and afforded the correspond-
ing protected propargylic amines 3e and 3f in moderate to
good yields (entries 5 and 6).
2
3
(
2.0 equiv) and the potassium salt (2.0 equiv) then in a sec-
ond step, by introducing heteroaryl halide (1 equiv), triethyl-
amine, PdCl (PPh ) (5 mol %), and CuI (10 mol %). The
In order to demonstrate that compounds 3 are suitable inter-
mediates for obtaining unprotected propargylic amines 4 and
5, we then studied the deprotection of the amino function of
compounds 3 (Table 3). According to the conditions used, it
would be then possible to selectively obtain secondary prop-
argyl amine derivatives 4 and their corresponding primary
analogues 5, which are unknown in the literature. Thus, se-
lective monodeprotection of the amino function of com-
pounds 3a–d was accomplished according to Hernandez’s
2
3 2
results summarized in Table 2 show that this three-compo-
nent coupling reaction worked very well with bromopyr-
ꢀ
completion. Under these conditions, the use of potassium
di-tert-butyliminodicarbonate in combination with 2-, 3- or
idine substrates but required heating at 80 C for
4
-bromopyridine provided the N-protected primary
propargylic amines 3a–c in excellent yields (Table 2, entries
–3). 2,6-Dibromopyridine also undergoes assembling reac-
1
2
4
tion to give the dicoupling product 3d in 53% yield (entry 4).
This three-component coupling reaction was also effective
when using potassium phthalimide instead of potassium
procedure (LiBr/MeCN, condition A) leading to the corre-
sponding monoprotected propargylic amines 4a–d in good
yields (Table 3, entries 1–4). To obtain the corresponding
Table 2. Three-component coupling of propargyl bromide 1a, potassium salts and bromopyridine substrates under palladium–copper catalysis: synthesis of
protected propargylic amines 3
a
Yield of 3 (%)
Entry
Potassium salt
Propargylic halide 1
ArX
Protected propargylic
amines 3
N
(Boc)2N
(Boc)2N
N
Br
1
2
3
4
(Boc)
(Boc)
(Boc)
(Boc)
2
2
2
2
NK
NK
NK
NK
1a
3a
3b
3c
93
74
82
53
Br
N
N
Br
1a
Br
Br
(Boc)2N
Br
1a
N
N
Br
1a
3d
N
Br
N
N
Br
(
Boc)2N
N(Boc)2
PhtN
PhtN
N
Br
5
PthNK
PthNK
1a
3e
3f
82
50
Br
Br
N
N
Br
6
1a
a
Isolated yield based on ArX.

O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
10675
Table 3. Deprotection of the amino function of compounds 3; synthesis of secondary and primary propargylic amines 4 and 5
a
b
Yield (%)
Entry
Propargylic amines 3
N
Conditions
Propargylic amines 4 and 5
N(Boc)2
N
NHBoc
NHBoc
NHBoc
1
3a
3b
3c
A
4a
4b
4c
73
75
71
65
94
95
63
N
N(Boc)2
N(Boc)2
N
2
3
4
5
6
A
A
A
B
B
C
N
N
3d
4d
N
N
(
Boc)2N
N(Boc)2
BocHN
NHBoc
N
N(Boc)2
N(Boc)2
N
NH2 , 2 HCl
NH2 , 2 HCl
NH2
3a
5a
N
N
3b
5b
N
NPht
N
7
3e
5c
a
ꢀ
ꢀ
ꢀ
Conditions A: LiBr (3 equiv), MeCN, 65 C, 14 h; conditions B: HCl/MeOH 4 N, 20 C, 1.5 h; conditions C: hydrazine hydrate (4 equiv), EtOH, 70 C.
Isolated yield based on starting material 3.
b
ꢀ
primary propargylic amines, two conditions were examined.
Thus, starting from phthalylpropargylamine 3e, the use of
and should be stored under nitrogen at ꢁ15 C in order to
limit their decomposition.
2
3
hydrazine hydrate in EtOH (condition C) provided 5c in
3% yield (entry 7) whereas, the corresponding hydrochlo-
6
2.3. Access to propargylic amides and related com-
pounds
ride derivative 5a was obtained in almost quantitative yield
when the reaction was carried out from 3a under acidic con-
2
5
ditions (HCl/MeOH, condition B, entry 5). In a similar
way, analogue 5b could be synthesized from 3b (entry 6).
It should be noted that 5a and 5b are sensitive compounds
The high efficiency of this three-component coupling reac-
tion prompted us to extend this methodology to amides,
sulfonamides, and carbamates. In this case, the reaction
Table 4. Three-component coupling of sodium salts of amides, sulfonamides or carbamates formed in situ with propargyl bromide 1a, aryl or heteroaryl halides
under palladium–copper catalysis: synthesis of propargylic amides and related compounds 6
a
Yield (%)
Entry
‘NH’
Propargylic halide 1
ArX
Propargylic amine 6
O
N
Br
O
O
1
1a
I
CO Et
6a
81
2
NH
CO2Et
O
N
Br
2
3
1a
I
I
OMe
6b
82
48
NH
OMe
OMe
Boc
Boc
Bu NH
Br
6c BuN
1a
OMe
Ts
N
Ts
iBu NH
Br
4
1a
6d iBu
N
N
70
68
Br
NO2
NO2
SO2
Br
5
1a
I
OMe
6e
S
NHBu
Bu
N
O
O
OMe
a
Isolated yield based on ArX.

10676
O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
Table 5. Three-component coupling of propargyl bromide 1a, secondary amine or potassium salt and ortho-substituted aryl halides under palladium–copper
catalysis: synthesis of benzo[b]furan and indole derivatives 7 and 8
a
Entry
ArX
Amine
Product (yield)
Deprotected product
b
(
yield)
I
NEt2
1
Et
2
NH
7a (75%)
—
—
O
O
OH
I
2
3
4
5
6
7
Piperidine
N
7b (62%)
7c (20%)
7d (66%)
—
—
OH
I
N(Boc)2
N(Boc)2
K(NBoc)
2
2r (71%)
—
O
OH
I
OH
NPht
NH2
8d (77%)c
KNPht
—
O
O
OH
I
NEt2
Piperidine
Piperidine
—
2s (92%)
—
—
NHAc
I
NHAc
N
7e (97%)
—
NHTs
I
N
Ts
N(Boc)2
NHBoc
2
7f (93%)
7g (80%)
—
—
8f (89%)d
K(NBoc)
K(NBoc)
N
N
NHTs
Br
Ts
Ts
N
N(Boc)2
N
8
2
—
N
NHTs
Ts
a
Isolated yield based on ArX.
Isolated yield based on compounds 7.
b
c
ꢀ
The deprotection of the amino function of 7d was performed according to conditions C (4 equiv of hydrazine hydrate, EtOH, 70 C).
ꢀ
d
The deprotection of the amino function of 7f was performed according to conditions A (3 equiv of LiBr, MeCN, 65 C).
requires in a preliminary stage the deprotonation of the nitro-
gen atom. The results are summarized in Table 4. Typically,
the protocol implied treatment of amide, sulfonamide or car-
bamate by NaH in DMF for 30 min at room temperature fol-
lowed by the addition of propargyl bromide 1a (1.2 equiv)
and subsequent reaction with aryl halide (1 equiv) in the
presence of triethylamine, PdCl (PPh ) (5 mol %), and
2.4. Access to heterocycles
Being given the high flexibility of this catalytic domino
three-component reactions, we expected that the newly de-
veloped procedure would serve as an extremely useful and
quick synthetic route to obtain functionalized 2-(aminome-
thyl)benzo[b]furan or indole derivatives 7. These classes
of substituted heterocyclic compounds offer a high degree
of structural diversity and have proven to be broadly useful
as biologically active compounds, including calindol. In
this context, we were interested to investigate the construc-
2
3 2
2
7
CuI (10 mol%). Firstly, we evaluated this methodology on
2
6
cyclic amide such as pyrrolidin-2-one. Thus under the
protocol described above, this domino three-component
coupling reaction provides efficiently the corresponding
propargylic amides 6a and 6b; in addition the yields (81–
1
5b
2
8
tion of polycyclic furan and indole skeletons by a tandem
nitrogen propargylation/Sonogashira-cyclization sequence.
8
2%, entries 1 and 2, Table 4) are independent of the elec-
tronic effect of substituents. Replacing the cyclic amide by
a carbamate also provided the coupling product 6c, although
in a much lower yield (entry 3). Finally, the coupling process
with sulfonamides was carried out in combination with
Starting from 2-iodophenol and secondary dialkylamine, the
reagents and catalysts are mixed together and experimental
conditions are set up in such a way to promote the reaction
cascade. With diethylamine or piperidine, the cyclized ben-
zofuran derivatives 7a and 7b were obtained in 75 and 62%
yields, respectively (Table 5, entries 1 and 2). To obtain un-
protected (aminomethyl)benzo[b]furan 8d, this domino cou-
pling–cyclization process was examined in the presence of
potassium salts. Thus, the use of potassium di-tert-butylimi-
nodicarbonate results, however, in partial cyclization of the
coupling intermediate 2r presumably for steric hindrance
considerations and benzofuran derivative 7c was isolated
2
-bromopyridine and 4-iodoanisole. As expected, this
three-component one-pot process proceeded well and
resulted in the formation of the corresponding propargylic
sulfonamides 6d and 6e in 70 and 68% yields, respectively
(
entries 4 and 5). Altogether, these results demonstrated
the efficiency of this three-component coupling reaction
based on nitrogen propargylation/Sonogashira coupling to
provide a broad variety of aryl propargylic amines and
related amides, sulfonamide or carbamate derivatives.

O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
10677
in a low yield (20%, entry 3). Replacing potassium di-tert-
butyliminodicarbonate by potassium phthalimide allows
the cyclization step to occur in a highly effective way to
provide the cyclized product 7d in good overall yield
million from the central peak of deuteriochloroform
(77.14). IR spectra were measured on a Bruker Vector 22
ꢁ
1
spectrophotometer (neat, cm ). Elemental analyses were
performed with a Perkin–Elmer 240 analyser. Analytical
TLC were performed on Merck precoated silica gel 60F
plates. Merck silica gel 60 (230–400 mesh) was used for
column chromatography. Melting points (mp) were recorded
on a B €u chi B-450 apparatus and were uncorrected.
(
66%, entry 4). Further deprotection of the amino function
of 7d with hydrazine hydrate according to conditions C
cf.: Table 3) afforded the corresponding primary amine
d in 77% yield.
(
8
Based on this synthetic protocol, the coupling of 2-iodoace-
talinide in the presence of piperidine and propargyl bromide
3.3. Typical procedure for the three-component forma-
tion of tertiary propargylic amines 2
2
1
a provided the sp –sp coupling product 2s in a quantitative
yield (entry 5). No indole was formed, suggesting that the
organopalladium intermediate is not reactive enough to cy-
clize to the indole. To activate the intermediate, we intro-
Under an inert atmosphere, propargyl bromide (1.2 equiv)
purchased from Aldrich was slowly added, at 0 C, to a solu-
ꢀ
tion containing aryl iodide (1 equiv), PdCl (PPh )
2
3 2
2
8b
duced a tolylsulfonyl group onto the aniline nitrogen.
(5 mol%), CuI (10 mol %) and secondary amine (used as
a solvent). The reaction mixture was stirred at room temper-
Thus, performing this domino coupling–cyclization process
with o-iodo-N-tosylanilide in the presence of piperidine
yielded the indole derivative 7e very efficiently (entry 6). In-
terestingly, as well as piperidine, potassium di-tert-butylimi-
nodicarbonate was also a good reactant in this assembling
process and provided with o-iodo-N-tosylanilide and the
parent bromopyridyl derivative the corresponding cyclized
indoles 7f and 7g in 93 and 80% yields, respectively (entries
ꢀ
ature (or heated at 80 C when using an aryl bromide) and
monitored by TLC until complete consumption of starting
materials then concentrated in vacuo. Purification by chro-
matography on silica gel afforded pure propargylic amine 2.
ꢁ1
3.3.1. Compound 2a. Yield: 92%. IR (neat) nmax/cm :
2933, 1488, 1442; H NMR (200 MHz, CDCl ): d 7.50–
1
3
7
and 8). In both cases, the assembling process required heat-
7.25 (m, 5H), 3.42 (s, 2H), 2.54 (t, J¼4.8 Hz, 4H), 1.80–
ꢀ
13
ing at 100 C for completion. Finally, subsequent selective
deprotection of 7f using Hernandez’s procedure (LiBr/
MeCN, condition A) afforded efficiently the indole 8f,
which could serve as efficient building-block for further
N-functionalization (entry 7).
1.55 (m, 4H), 1.55–1.30 (m, 2H); C NMR (50 MHz,
CDCl ): d 130.7 (2C), 127.2 (2C), 126.8, 122.5, 84.2,
3
84.1, 52.4 (2C), 47.5, 25.1 (2C), 23.1; MS (IE) m/z 199
([M] 14%), 115 (100%). Anal. Calcd for 2a (C H N):
C, 84.37; H, 8.60; N, 7.03. Found: C, 83.96; H, 8.79; N, 6.92.
+
14 17
1
In conclusion we successfully developed an expeditious new
three-component assembling of amines, organic halides,
and propargyl halides for the synthesis of functionalized
propargylic amines (including N-protected propargylic
amines), amides, sulfonamides, carbamates in high yields.
The procedure can be extended to the preparation of indole
and benzofuran derivatives. Variation is allowed in each of
the three-component, thus making a wide range of accessible
products. This process is not only of interest for combinato-
rial synthesis of propargylic amines and heterocycles, but in
many cases, also offers considerable synthetic advantages in
term of yield, selectivity, and simplicity of the reaction
procedure.
3.3.2. Compound 2b. Yield: 83%. R (AcOEt)¼0.32; H
f
NMR (200 MHz, CDCl ): d 7.34 (s, 4H), 6.79 (br s, 1H),
3
3.78 (t, J¼4.6 Hz, 4H), 3.49 (s, 2H), 2.64 (t, J¼4.6 Hz,
1
3
4H), 1.52 (s, 9H); C NMR (50 MHz, CDCl ): d 152.4,
3
138.5, 132.0 (2C), 117.8 (2C), 116.6, 85.2, 82.6, 80.0, 66.4
(2C), 52.0 (2C), 47.7, 28.0 (3C). Anal. Calcd for 2b
(C H N O ): C, 68.33; H, 7.65; N, 8.85. Found: C,
1
8 24 2 3
68.02; H, 7.79; N, 8.91.
3.3.3. Compound 2c. Yield: 85%. R (cyclohexane/AcOEt
f
ꢁ1
1
1:1)¼0.27; IR (neat) nmax/cm : 2971, 2227, 1604;
H
NMR (200 MHz, CDCl ): d 7.55–7.41 (m, 4H), 3.60 (s,
3
1
3
2H), 2.56 (q, J¼7.2 Hz, 4H), 1.06 (t, J¼7.2 Hz, 6H);
C
NMR (50 MHz, CDCl ): d 132.1 (2C), 131.8 (2C), 128.2,
3
1
18.3, 111.2, 89.6, 83.4, 47.2 (2C), 41.4, 12.4 (2C); MS
+
3
. Experimental
(IE) m/z 213 ([M+H] 100%). Anal. Calcd for 2c
C H N ): C, 79.21; H, 7.60; N, 13.20. Found: C, 78.92;
H, 7.82; N, 13.31.
(
1
4 16 2
3
.1. Materials
ꢀ
All glasswares were oven-dried at 140 C. THF was distilled
from sodium–benzophenone ketyl and DMF from calcium
hydride and usual solvents were purchased from SDS (Paris,
France).
3.3.4. Compound 2d. Yield: 94%. R (cyclohexane/AcOEt
f
ꢁ1
1:1)¼0.23; IR (neat) nmax/cm : 2971, 1593, 1516, 1339,
1
852; H NMR (200 MHz, CDCl ): d 8.14 (d, J¼8.5 Hz,
3
2H), 7.53 (d, J¼8.5 Hz, 2H), 3.66 (s, 2H), 2.61 (q,
1
3
J¼7.1 Hz, 4H), 1.10 (t, J¼7.1 Hz, 6H);
C NMR
(50 MHz, CDCl ): d 146.5, 132.0 (2C), 129.9, 123.1 (2C),
3
3
.2. Instrumentation
90.5, 83.0, 47.0 (2C), 41.3, 12.2 (2C); MS (IE) m/z 232
([M] 14%), 217 (100%), 160 (47%). Anal. Calcd for 2d
+
The compounds were all identified by usual physical
methods, i.e., H NMR, C NMR, IR, and elemental analy-
1
13
(C H N O ): C, 67.22; H, 6.94; N, 12.06. Found: C,
1
3 16 2 2
1
13
sis. H NMR and C NMR spectra were measured in CDCl
with a Bruker Avance 300. H chemical shifts are reported in
parts per million from the peak of residual chloroform
67.01; H, 7.19; N, 11.92.
3
1
3.3.5. Compound 2e. Yield: 69%. R (cyclohexane/AcOEt
f
1
3
ꢁ1
(
7.27 ppm). C chemical shifts are reported in parts per
6:4)¼0.17; IR (neat) nmax/cm : 2968, 1593, 1516, 1338,

10678
O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
1
8
7
2
52; H NMR (200 MHz, CDCl ): d 8.11 (d, J¼8.7 Hz, 2H),
3.3.11. Compound 2k. Yield: 74%. R (MeOH/AcOEt
f
3
ꢁ
1
.48 (d, J¼8.7 Hz, 2H), 3.68 (s, 2H), 3.25 (hept, J¼6.6 Hz,
2:8)¼0.40; IR (neat) nmax/cm : 2970, 1582, 1462, 1427,
1
3
1
H), 1.10 (d, J¼6.6 Hz, 12H); C NMR (50 MHz, CDCl ):
778; H NMR (200 MHz, CDCl ): d 8.53 (br s, 1H), 7.58
3
3
d 146.6, 131.9 (2C), 130.6, 123.1 (2C), 95.3, 81.7, 48.6 (2C),
34.8, 20.5 (4C); MS (IE) m/z 260 ([M] 4%), 245 (100%).
Anal. Calcd for 2e (C H N O ): C, 69.20; H, 7.74; N,
(t, J¼7.7 Hz, 1H), 7.36 (d, J¼7.4 Hz, 1H), 7.17 (br s, 1H),
+
3.64 (s, 2H), 2.61 (q, J¼7.1 Hz, 4H), 1.07 (t, J¼7.1 Hz,
1
3
6H); C NMR (75 MHz, CDCl ): d 149.7, 143.3, 135.9,
3
1
5
20
2
2
1
0.76. Found: C, 68.95; H, 7.95; N, 10.61.
127.1, 122.5, 84.9, 84.6, 47.3 (2C), 41.2, 12.6 (2C); MS
+
+
(IE) m/z 189 ([M+H] 100%), 211 ([M+Na] 19%). Anal.
Calcd for 2k (C H N ): C, 76.55; H, 8.57; N, 14.88.
Found: C, 76.19; H, 8.61; N, 14.95.
3
2
.3.6. Compound 2f. Yield: 82%. R (Et O)¼0.5; IR (neat):
f
2
12 16 2
ꢁ
1
1
971, 2935, 1727, 1453, 1133, 833 cm
;
H NMR
(
(
300 MHz, CDCl ): d 7.76 (dd, J¼7.7, 1.4 Hz, 1H), 7.45
3
d, J¼7.7 Hz, 1H), 7.32 (td, J¼7.5, 1.3 Hz, 1H), 7.22 (td,
3.3.12. Compound 2l. Yield: 78%. R (Et O)¼0.27; IR
f
2
ꢁ
1
1
J¼7.6, 1.3 Hz, 1H), 4.28 (q, J¼7.1 Hz, 2H), 3.46 (s, 2H),
(neat): 2932, 2806, 1344, 1106, 993 cm
;
H NMR
2
1
.55–2.51 (m, 4H), 1.59–1.52 (m, 4H), 1.37 (m, 2H),
.29 (t, J¼7.1 Hz, 3H); C NMR (75 MHz, CDCl3):
(300 MHz, CDCl ): d 8.81 (d, J¼2.0 Hz, 1H), 8.40 (d,
3
1
3
J¼1.8 Hz, 1H), 7.98 (d, J¼8.4 Hz, 1H), 7.66 (d, J¼8.1 Hz,
d 166.2, 134.2, 132.3, 131.3, 129.9, 127.5, 123.5, 90.3,
3.7, 60.9, 53.3 (2C), 48.6, 25.9 (2C), 23.8, 14.2; MS m/z
1H), 7.60 (dt, J¼8.4, 1.4 Hz, 1H), 7.44 (td, J¼8.0, 1.0 Hz,
13
8
1H), 3.45 (s, 2H); 2.54–2.50 (m, 4H), 1.59–1.46 (m, 4H),
1.38–1.40 (m, 2H); C NMR (75 MHz, CDCl ): d 152.3,
+
+
(ES ) 272.0 [M+H] . Anal. Calcd for 2f (C H NO ):
C, 75.25; H, 7.80; N, 5.16. Found: C, 75.49; H, 8.01; N,
5
1
7
21
2
3
146.7, 138.3, 133.1, 129.8, 129.3, 127.4, 127.1, 117.4,
88.7, 82.2, 53.5 (2C), 48.5, 25.9 (2C), 23.8; MS m/z (ES )
+
.23.
+
2
51.0 [M+H] .
3
1
.3.7. Compound 2g. Yield: 93%. R (cyclohexane/AcOEt
f
ꢁ
1
:1)¼0.2; IR (neat) nmax/cm : 2961, 1714, 1606, 1268;
3.3.13. Compound 2m. Yield: 79%. R (Et O)¼0.41; IR
f
2
ꢁ1
1
1
H NMR (200 MHz, CDCl ): d 7.86 (d, J¼8.5 Hz, 2H),
(neat): 2934, 1726, 1484, 1249, 834 cm
;
H NMR
3
7
.37 (d, J¼8.5 Hz, 2H), 4.25 (q, J¼7.1 Hz, 2H), 3.64 (t,
J¼4.7 Hz, 4H), 3.40 (s, 2H), 2.51 (t, J¼4.7 Hz, 4H), 1.26
(300 MHz, CDCl ): d 8.33 (d, J¼2.1 Hz, 1H), 7.56 (dd,
3
J¼8.3, 2.3 Hz, 1H), 7.17 (d, J¼8.7 Hz, 1H), 3.55 (s, 2H),
1
3
13
(
t, J¼7.1 Hz, 3H); C NMR (50 MHz, CDCl ): d 165.5,
2.50 (q, J¼7.2 Hz, 4H), 1.02 (t, J¼7.2 Hz, 6H); C NMR
3
131.2 (2C), 129.6, 129.1 (2C), 127.2, 87.0, 84.6, 66.5
2C), 60.7, 52.1(2C), 47.7, 14.0; MS (IE) m/z 274
(75 MHz, CDCl ): d 152.2, 150.2, 141.0, 123.7, 119.3,
3
+
(
(
(
89.5, 80.3, 47.3 (2C), 41.5, 12.5 (2C); MS m/z (ES ) 223.0
[M+H] . Anal. Calcd for 2m (C H ClN ): C, 64.71; H,
6.79; N, 12.58. Found: C, 64.41; H, 6.93; N, 12.75.
+
+
+
[M+H] 100%), 296 [M+Na] . Anal. Calcd for 2g
C H NO ): C, 70.13; H, 7.01; N, 5.12. Found: C, 70.05;
1
2
15
2
1
6
19
3
H, 7.41; N, 5.60.
3
(neat): 2934, 2796, 1489, 1106, 781 cm
.3.14. Compound 2n. Yield: 87%. R (CH Cl )¼0.5; IR
f
2
2
ꢁ
1
1
3
.3.8. Compound 2h. Yield: 86%. R (cyclohexane/AcOEt
f
; H NMR
(300 MHz, CDCl ): d 7.41–7.15 (m, 5H), 6.10 (d,
ꢀ
1
cm : 2927, 2828, 1592, 1511, 1109; H NMR (200 MHz,
:1)¼0.18; mp (yellow solid)¼89–90 C; IR (neat) nmax/
3
ꢁ1
1
J¼16.0 Hz, 1H), 5.99 (d, J¼16.0 Hz, 1H), 3.32 (s, 2H),
CDCl ): d 8.13 (d, J¼8.8 Hz, 2H), 7.53 (d, J¼8.8 Hz, 2H),
3.44–3.39 (m, 4H), 1.56–1.50 (m, 4H), 1.37–1.32 (m, 2H);
C NMR (75 MHz, CDCl ): d 131.5 (2C), 128.5, 128.3
3
3
1
3
3
4
1
.73 (t, J¼4.7 Hz, 4H), 3.51 (s, 2H), 2.60 (t, J¼4.7 Hz,
1
3
H); C NMR (50 MHz, CDCl ): d 147.0, 132.3 (2C),
3
(2C), 122.9, 120.7, 120.5, 94.1, 91.1, 87.8, 83.5, 53.5 (2C),
+
+
29.8, 123.4 (2C), 89.9, 66.7 (2C), 52.4 (2C), 47.9; MS
48.6, 25.9 (2C), 23.9; MS m/z (ES ) 250.0 [M+H] . Anal.
Calcd for 2n (C H N): C, 86.70; H, 7.68; N, 5.62. Found:
C, 86.18; H, 7.91; N, 5.85.
+
(
(
IE) m/z 247 ([M+H] 100%). Anal. Calcd for 2h
C H N O ): C, 63.40; H, 5.73; N, 11.38. Found: C,
1
8 19
1
3 14 2 3
6
3.09; H, 5.82; N, 11.71.
3.3.15. Compound 2o. Under an inert atmosphere, prop-
argyl bromide (1.0 equiv) purchased from Aldrich was
slowly added, at 0 C, to a solution containing CuI
3
2
.3.9. Compound 2i. Yield: 98%. R (MeOH/AcOEt
f
ꢀ
cm : 2925, 2824, 1504, 1460; H NMR (200 MHz,
ꢀ
:8)¼0.55; mp (yellow solid)¼110–114 C; IR (neat) nmax/
ꢁ1
1
(10 mol %), dichloroethylene (E/Z¼1:1, 10 equiv), piperi-
CDCl ): d 7.34 (s, 4H), 3.75 (t, J¼4.8 Hz, 8H), 3.49 (s,
dine (4 equiv) and PdCl (PPh ) (5 mol %) in Et O. The re-
2
3
3 2
2
1
3
4
d 131.5 (4C), 122.7 (2C), 85.8 (2C), 85.1 (2C), 66.8 (4C),
H), 2.62 (t, J¼4.8 Hz, 8H); C NMR (50 MHz, CDCl ):
action mixture was stirred at room temperature for 4 h and
then concentrated in vacuo. Purification by chromatography
on silica gel afforded pure propargylic amine 2o. Yield: 63%
3
+
5
Anal. Calcd for 2i (C H N O ): C, 74.04; H, 7.46; N,
8
2.4 (4C), 48.0 (2C); MS (IE) m/z 325 ([M+H] 100%).
(mixture E/Z¼9:1). R neutral alumina (cyclohexane/
2
0
24
2
2
f
1
.64. Found: C, 73.82; H, 7.72; N, 8.75.
CH Cl 2:8)¼0.30. E-Isomer:
H NMR (200 MHz,
CDCl ): d 6.50 (d, J¼13.6 Hz, 1H), 5.94 (td, J¼13.6,
2
2
3
3
2
.3.10. Compound 2j. Yield: 62%. R (MeOH/AcOEt
f
2.2 Hz, 1H), 3.34 (d, J¼2.2 Hz, 2H), 2.47 (t, J¼5.4 Hz,
ꢁ
1
13
:8)¼0.22; IR (neat) nmax/cm : 2854, 2812, 1581, 1112;
4H), 1.67–1.41 (m, 6H); C NMR (50 MHz, CDCl ):
3
1
H NMR (200 MHz, CDCl ): d 7.36 (s, 3H), 3.70 (t,
3
d 129.7, 113.5, 88.0, 79.7, 53.3 (2C), 48.2, 25.7, 23.7 (2C).
Z-Isomer: H NMR (200 MHz, CDCl ): d 6.34 (d,
1
J¼4.7 Hz, 12H), 3.43 (s, 6H), 2.56 (t, J¼4.7 Hz, 12H);
3
1
3
C NMR (50 MHz, CDCl ): d 134.1 (3C), 123.4 (3C),
3
J¼7.4 Hz, 1H), 5.88 (td, J¼7.4, 1.8 Hz, 1H), 3.46 (d,
13
8
(
5.3 (3C), 83.8 (3C), 66.7 (6C), 52.2 (6C), 47.8 (3C); MS
IE) m/z 448 ([M+H] 100%). Anal. Calcd for 2j
J¼1.8 Hz, 2H), 2.54 (t, J¼5.2 Hz, 4H), 1.67–1.41 (m, 6H);
+
C NMR (50 MHz, CDCl ): d 127.6, 111.8, 93.7, 78.8,
53.0 (2C), 48.2, 25.7, 23.7 (2C); MS (IE) m/z 184 ([M]
100%).
3
+
(
C H N O ): C, 72.46; H, 7.43; N, 9.39. Found: C,
2
7 33 3 3
7
2.22; H, 7.61; N, 9.55.

O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
10679
ꢀ
3
9
.3.16. Compound 2p. Yield: 74%. R (cyclohexane/AcOEt
f
EtOAc 7:3)¼0.30; mp (white solid)¼71–73 C; IR (neat)
ꢁ1
n
max
ꢁ
1
1
1
:1)¼0.27; IR (neat) nmax/cm : 2931, 1726, 1605; H NMR
/cm : 2979, 1725, 1688, 1459, 1142; H NMR
(
200 MHz, CDCl ): d 7.94 (d, J¼8.0 Hz, 2H), 7.44 (d,
(200 MHz, CDCl ): d 8.53 (d, J¼4.9 Hz, 1H), 7.60 (td,
3
3
J¼8.0 Hz, 2H), 3.88 (s, 3H), 3.67 (t, J¼7.3 Hz, 1H), 2.80–
J¼7.7, 1.8 Hz, 1H), 7.35 (d, J¼7.7 Hz, 1H), 7.19 (td, J¼4.9,
1
3
2
0
.35 (m, 4H), 1.70–1.30 (m, 8H), 1.08 (t, J¼7.2 Hz, 6H),
1.8 Hz, 1H), 4.60 (s, 2H), 1.52 (s, 18H); C NMR (50 MHz,
CDCl ): d 151.6 (2C), 150.0, 143.2, 136.1, 127.2, 122.8,
1
3
.89 (t, J¼6.8 Hz, 3H); C NMR (50 MHz, CDCl ):
3
3
d 166.4, 131.5 (2C), 129.3, 129.0 (2C), 128.4, 92.7, 84.0,
3.7, 52.0, 44.9 (2C), 34.0, 31.5, 26.4, 22.5, 13.9, 13.7
85.6, 83.1, 81.9 (2C), 36.5, 28.2 (6C); MS (ESI) m/z 333
[M+H] , 355 [M+Na] . Anal. Calcd for 3a (C H N O ):
18 24 2 4
C, 65.04; H, 7.28; N, 8.43. Found: C, 64.86; H, 7.39; N, 8.25.
+
+
5
+
(
2
2C); MS (IE) m/z 316 ([M+H] 100%). Anal. Calcd for
p (C H NO ): C, 76.15; H, 9.27; N, 4.44. Found: C,
20 29 2
7
6.02; H, 9.62; N, 4.65.
3.4.2. Compound 3b. The reaction was performed from
ꢀ
3
-bromopyridine at 80 C; yield: 74%. R (cyclohexane/
f
ꢁ
1
3
9
4
1
.3.17. Compound 2q. Yield: 89%. R (cyclohexane/AcOEt
f
EtOAc 7:3)¼0.30; IR (neat) nmax/cm : 2980, 1790, 1749,
1
1
:1)¼0.31; H NMR (200 MHz, CDCl ): d 7.60–7.45 (m,
1391, 1367, 1258, 1144; H NMR (300 MHz, CDCl3):
d 8.60 (br s, 1H), 8.47 (dd, J¼4.9, 1.8 Hz, 1H), 7.65 (dt,
3
H), 3.49 (t, J¼7.4 Hz, 1H), 2.58 (m, 2H), 2.40 (m, 2H),
1
3
.80–1.10 (m, 14H), 0.89 (t, J¼6.8 Hz, 3H); C NMR
J¼7.9, 1.8 Hz, 1H), 7.19 (ddd, J¼7.9, 4.9, 0.9 Hz, 1H),
1
3
(
50 MHz, CDCl ): d 132.2 (2C), 131.9 (2C), 128.5, 118.5,
3
4.67 (s, 2H), 1.65 (s, 18H); C NMR (75 MHz, CDCl ):
3
1
2
11.1, 93.5, 84.3, 58.6 (2C), 50.6, 33.1, 31.5, 26.4, 26.1,
4.5 (2C), 22.5, 14.0; MS (IE) m/z 295 ([M+H] 100%).
d 152.5, 151.7 (2C), 148.7, 138.7, 123.0, 120.1, 88.9, 83.2
(2C), 79.1, 36.6, 28.1 (6C); MS (ESI) m/z 333 [M+H] .
+
+
Anal. Calcd for 2q (C H N ): C, 81.59; H, 9.51; N, 8.90.
2
Anal. Calcd for 3b (C H N O ): C, 65.04; H, 7.28; N,
18 24 2 4
2
0
26
Found: C, 81.05; H, 9.72; N, 9.35.
8.43. Found: C, 64.86; H, 7.40; N, 8.20.
1
3.3.18. Compound 2r. Yield: 71%. H NMR (200 MHz,
CDCl ): d 7.32 (m, 2H), 6.92 (m, 2H), 4.68 (s, 1H), 4.48
(
3.4.3. Compound 3c. The reaction was performed from
ꢀ
4-bromopyridine at 80 C; yield: 82%. R (cyclohexane/
f
3
1
3
1
s, 2H), 1.58 (s, 18H); C NMR (50 MHz, CDCl3):
d 157.9, 151.4 (2C), 131.2, 130.5, 120.0, 114.7, 114.2,
2.8, 83.5, 83.3 (2C), 36.5, 28.1 (6C). Anal. Calcd for 2r
C H NO ): C, 65.69; H, 7.25; N, 4.03. Found: C, 65.28;
EtOAc 7:3)¼0.24; H NMR (200 MHz, CDCl ): d 8.55 (br
3
1
3
s, 2H), 7.25 (br s, 2H), 4.60 (s, 2H), 1.55 (s, 18H);
NMR (50 MHz, CDCl ): d 151.6 (2C), 149.8 (2C), 131.2,
C
9
3
(
128.6 (2C), 80.4, 83.3, 80.0 (2C), 36.5, 28.2 (6C); MS
(ESI) m/z 333 [M+H] . Anal. Calcd for 3c
1
9
25
5
+
H, 7.41; N, 4.18.
(C H N O $0.3H O): C, 64.00; H, 7.36; N, 8.29. Found:
C, 64.26; H, 7.73; N, 7.87.
18 24 2 4 2
3
9
1
.3.19. Compound 2s. Yield: 92%. Rf (Et O/MeOH
2
:1)¼0.32; IR (neat): 3306, 2974, 2828, 1660, 1531, 1448,
ꢁ
1 1
244, 757 cm ; H NMR (300 MHz, CDCl ): d 8.22 (d,
3
3.4.4. Compound 3d. The reaction was performed from 2,6-
ꢀ
J¼8.2 Hz, 1H), 7.98 (s, 1H), 7.80 (dd, J¼7.7, 1.4 Hz, 1H),
dibromopyridine at 80 C; yield: 53%. R (cyclohexane/
f
ꢁ
1
7
3
.16 (td, J¼8.6, 1.4 Hz, 1H), 6.89 (td, J¼7.6, 0.7 Hz, 1H),
.61 (s, 2H), 2.54 (q, J¼7.2 Hz, 4H), 2.02 (s, 3H), 1.02 (t,
EtOAc 7:3)¼0.30; IR (neat) nmax/cm : 2975, 2935, 1740,
1
1720, 1700, 1365, 1145, 1110; H NMR (200 MHz,
CDCl ): d 7.52 (dd, J¼7.3, 8.3 Hz, 1H), 7.23 (d,
1
3
J¼7.2 Hz, 6H); C NMR (75 MHz, CDCl ): d 167.9,
3
3
1
3
1
(
38.9, 131.7, 128.9, 123.1, 119.3, 112.2, 91.5, 80.2, 47.3
2C), 41.4, 24.52, 12.55 (2C); MS m/z (ES ) 268.0
J¼7.8 Hz, 2H), 4.55 (s, 4H), 1.46 (s, 36H); C NMR
+
(50 MHz, CDCl ): d 151.5 (4C), 143.3 (2C), 136.3, 126.1
3
+
+
[M+Na +H] . Anal. Calcd for 2s (C H N O): C, 73.74;
H, 8.25; N, 11.47. Found: C, 73.52; H, 8.51; N, 11.55.
(2C), 86.1 (2C), 83.1 (4C), 81.4 (2C), 36.4 (2C), 28.1
(12C); MS (ESI) m/z 586 [M+H] . Anal. Calcd for 3d
1
5 20 2
+
(C H N O .0.75 H O): C, 62.13; H, 7.50; N, 7.01. Found:
C, 62.34; H, 7.83; N, 6.66.
31 43 3 8 2
3
.4. Typical procedure for the three-component forma-
tion of di-Boc- and phthalimide-protected propargylic
amines 3
3.4.5. Compound 3e. The reaction was performed from
ꢀ
2
-bromopyridine at 80 C; yield: 82%. R (cyclohexane/
f
ꢀ
To a suspension of potassium phthalimide or potassium
di-tert-butyliminodicarbonate (2 mmol, 2 equiv) in anhy-
drous DMF (5 mL) was added propargyl bromide purchased
from Aldrich (80 wt % solution in toluene, 2 mmol,
EtOAc 7:3)¼0.12; mp (beige solid)¼127–129 C; IR (neat)
ꢁ
1
n /cm : 3044, 1774, 1708, 1582, 1560, 1465, 1411,
1387, 1269, 781; H NMR (200 MHz, CDCl ): d 8.50 (d,
max
1
3
J¼4.9 Hz, 1H), 7.87–7.69 (m, 4H), 7.59 (td, J¼7.7, 1.8 Hz,
2
2
equiv). The mixture was stirred at room temperature for
h and then added via a cannula to a solution containing
1H), 7.37 (d, J¼7.7 Hz, 1H), 7.18 (td, J¼4.9, 1.8 Hz, 1H),
1
3
4.68 (s, 2H); C NMR (50 MHz, CDCl ): d 167.0 (2C),
3
PdCl (PPh ) (0.05 mmol, 0.05 equiv), CuI (0.10 mmol,
2
150.0, 136.2, 134.3 (2C), 132.0 (2C), 127.3, 123.6 (2C),
123.2, 85.2, 82.9, 26.9; MS (ESI) m/z 263 [M+H] . Anal.
3 2
+
0
(
.1 equiv), and aryl halide (1 mmol, 1 equiv) in NEt3
10 mL). The resulting solution was stirred at room temper-
Calcd for 3e (C H N O $0.4H O): C, 71.31; H, 4.05; N,
1
6
10
2
2
2
ꢀ
ature (for aryl iodides) or heated at 80 C (for aryl bromides)
until the disappearance of starting material as judged by
TLC. Solvents were removed in vacuum and the crude prod-
uct was purified by silica gel column chromatography to
yield the expected adducts 3.
10.40. Found: C, 71.50; H, 3.98; N, 9.66.
3.4.6. Compound 3f. The reaction was performed from
ꢀ
3-bromopyridine at 80 C; yield 50%. R (cyclohexane/
f
ꢀ
NMR (200 MHz, CDCl ): d 8.64 (br s, 1H), 8.50 (br s, 1H),
1
EtOAc 1:1)¼0.12; mp (beige solid)¼175–177 C;
H
3
3
2
.4.1. Compound 3a. The reaction was performed from
ꢀ
7.94 (m, 2H), 7.74 (m, 3H), 7.20 (dd, J¼4.9, 7.6 Hz, 1H),
13
-bromopyridine at 80 C; yield: 93%. R (cyclohexane/
f
4.69 (s, 2H); C NMR (50 MHz, CDCl ): d 166.5 (2C),
3

10680
O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
ꢀ
1
1
8
52.0, 148.3, 138.3, 133.7 (2C), 131.5, 123.0 (2C), 122.3,
5.6, 79.3, 27.2; MS (ESI) m/z 263 [M+H] . Anal. Calcd
7:3)¼0.27; mp (beige solid)¼103–105 C; H NMR
+
(200 MHz, CDCl ): d 8.54 (d, J¼4.3 Hz, 1H), 7.81 (d,
3
for 3f (C H N O $0.4H O): C, 71.31; H, 4.05; N, 10.40.
1
Found: C, 71.25; H, 3.94; N, 9.81.
J¼8.3 Hz, 2H), 7.60 (dt, J¼7.7, 1.7 Hz, 1H), 7.24 (m, 3H),
6.99 (d, J¼7.8 Hz, 1H), 4.38 (s, 2H), 3.08 (d, J¼7.5 Hz,
6
10
2
2
2
2
H), 2.34 (s, 3H), 1.99 (m, 1H), 1.00 (d, J¼6.6 Hz, 6H);
1
3
3
.5. Typical procedure for the three-component forma-
C NMR (50 MHz, CDCl ): d 149.2, 143.3, 142.4, 136.1,
3
tion of propargylic amides, sulfonamides, and Boc-
protected amines 6
135.9, 129.5 (2C), 127.8 (2C), 127.0, 123.0, 84.9, 82.1,
54.1, 37.4, 26.4, 21.4, 20.0 (2C); MS (ESI) m/z 365
+
+
[M+Na] , 343 [M+H] . Anal. Calcd for 6d (C H N O S):
C, 66.64; H, 6.48; N, 8.18. Found: C, 66.41; H, 6.35; N, 7.99.
19 22 2 2
To a solution of amide, sulfonamide or Boc-protected amine
1.20 mmol, 1.20 equiv) in anhydrous DMF (1 mL per mmol
(
1
of amide and Boc-protected amine, 2 mL per mmol of
sulfonamide) was added NaH (60% in mineral oil,
3.5.5. Compound 6e. Yield: 68%. H NMR (200 MHz,
CDCl ): d 8.08 (m, 1H), 7.62 (m, 3H), 7.15 (d, J¼8.8 Hz,
3
1
0
.45 mmol, 1.45 equiv) and the mixture was stirred for
.5 h at room temperature. Propargyl bromide (80 wt % so-
2H), 6.78 (d, J¼8.8 Hz, 2H), 4.39 (s, 2H), 3.79 (s, 3H),
3.46 (t, J¼7.4 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.93
1
3
lution in toluene, 1.55 mmol, 1.55 equiv) was then intro-
duced dropwise. The resulting mixture was stirred at room
temperature for 2 h and then added via a cannula to a solution
containing PdCl (PPh ) (0.05 mmol, 0.05 equiv), CuI
(t, J¼7.2 Hz, 3H); C NMR (50 MHz, CDCl ): d 159.9,
3
148.5, 131.2 (2C), 133.5, 133.1, 131.5, 130.9, 124.1, 114.0
(2C), 85.7, 80.7, 55.4, 46.8, 37.3, 29.7, 19.8, 13.6; MS
(ESI) m/z 403 [M+H] . Anal. Calcd for 6e
+
2
3 2
(
in NEt3 (10 mL). The resulting solution was stirred at
room temperature (for aryl iodides) or heated at 80 C (for
0.10 mmol, 0.10 equiv), and aryl halide (1 mmol, 1 equiv)
(C H N O S): C, 56.69; H, 5.51; N, 6.96. Found: C,
2
56.41; H, 5.75; N, 7.19.
0 22 2 5
ꢀ
aryl bromides) until the disappearance of starting material
as judged by TLC. Solvents were removed in vacuum and
the crude product was purified by silica gel column chroma-
tography to yield the expected adducts.
3.6. Typical procedure for the three-component forma-
tion of 2-(aminomethyl)benzo[b]furans and indoles 7
3.6.1. From secondary amine. Under an inert atmosphere,
propargyl bromide (1.2 equiv) purchased from Aldrich was
ꢀ
aryl iodide (1 equiv), PdCl (PPh ) (5 mol %), CuI
3
4
8
.5.1. Compound 6a. The reaction was performed from
-iodobenzoic acid ethyl ester at room temperature; yield:
slowly added, at 0 C, to a solution containing o-substituted
2
3 2
ꢀ
1
1%. Mp (white solid)¼87–89 C; H NMR (200 MHz,
(10 mol %) and secondary amine (used as a solvent). The re-
ꢀ
CDCl ): d 7.94 (d, J¼8.5 Hz, 2H), 7.43 (d, J¼8.5 Hz, 2H),
action mixture was stirred at 50 C and monitored by TLC
3
4
2
.33 (m, 4H), 3.52 (t, J¼7.1 Hz, 2H), 2.39 (t, J¼8.0 Hz,
until complete consumption of starting materials then con-
centrated in vacuo. Purification by chromatography on silica
gel yielded the expected cyclized products 7a, 7b, and 7e.
1
3
H), 2.03 (m, 2H), 1.35 (t, J¼7.0 Hz, 3H); C NMR
(
50 MHz, CDCl ): d 174.6, 165.6, 131.7 (2C), 130.2,
3
1
1
29.4 (2C), 127.1, 86.3, 83.3, 61.8, 46.6, 32.8, 30.7, 17.7,
4.3; MS (ESI) m/z 294 [M+Na] . Anal. Calcd for 6a
+
3.6.1.1. Compound 7a. Yield: 75%. R (cyclohexane/
f
ꢁ
1
(C H NO ): C, 70.83; H, 6.32; N, 5.16. Found: C, 69.95;
H, 6.69; N, 4.86.
AcOEt 1:1)¼0.20; IR (neat) nmax/cm : 2970, 2810, 1600;
1
6
17
3
1
H NMR (200 MHz, CDCl ): d 7.60–7.50 (m, 2H), 7.30–
3
7
.20 (m, 2H), 6.61 (s, 1H), 3.83 (s, 2H), 2.66 (q,
1
3
3
4
.5.2. Compound 6b. The reaction was performed from
-iodoanisole at room temperature; yield: 82%. R (cyclo-
J¼7.1 Hz, 4H), 1.16 (t, J¼7.1 Hz, 6H); C NMR
(50 MHz, CDCl ): d 155.8, 155.0, 128.4, 123.6, 122.4,
f
3
1
hexane/AcOEt 2:8)¼0.24; H NMR (200 MHz, CDCl ):
120.5, 111.1, 104.9, 49.7, 47.0 (2C), 11.8 (2C); MS (ESI)
m/z 204 [M+H] . Anal. Calcd for 7a (C H NO): C,
76.81; H, 8.43; N, 6.89. Found: C, 76.11; H, 8.71; N, 7.09.
3
+
d 7.33 (d, J¼8.8 Hz, 2H), 6.80 (d, J¼8.8, Hz, 2H), 4.28 (s,
1
3 17
2
H), 3.77 (s, 3H), 3.52 (t, J¼7.0 Hz, 2H), 2.39 (t,
1
3
J¼8.0 Hz, 2H), 2.03 (m, 2H); C NMR (50 MHz,
CDCl ): d 174.4, 159.8, 133.3 (2C), 114.7 (2C), 114.0,
3.6.1.2. Compound 7b. Yield: 62%. R (cyclohexane/
f
3
ꢁ
1
8
2
3.9, 81.8, 55.3, 46.5, 32.8, 30.8, 29.7, 17.8; MS (ESI) m/z
52 [M+Na] . Anal. Calcd for 6b (C H NO ): C, 73.34;
AcOEt 1:1)¼0.30; IR (neat) nmax/cm : 2940, 2850, 2800,
+
1
1450; H NMR (200 MHz, CDCl ): d 7.55–7.45 (m, 2H),
3
1
4
15
2
H, 6.59; N, 6.11. Found: C, 71.84; H, 6.86; N, 5.70.
7.25–7.15 (m, 2H), 6.55 (s, 1H), 3.64 (s, 2H), 2.47 (t,
J¼5.3 Hz, 4H), 1.65–1.40 (m, 6H); C NMR (50 MHz,
1
3
3
4
.5.3. Compound 6c. The reaction was performed from
-iodoanisole at room temperature; yield: 48%. H NMR
CDCl ): d 155.0, 154.95, 128.3, 123.6, 122.5, 120.5,
3
1
111.2, 105.3, 56.1, 54.3 (2C), 25.7 (2C), 24.0; MS (ESI)
m/z 216 [M+H] . Anal. Calcd for 7b (C H NO): C,
78.10; H, 7.96; N, 6.51. Found: C, 77.62; H, 8.23; N, 6.89.
+
(
200 MHz, CDCl ): d 7.33 (d, J¼8.8 Hz, 2H), 6.80 (d,
3
14 17
J¼8.8 Hz, 2H), 4.22 (s, 2H), 3.77 (s, 3H), 3.35 (t,
J¼7.3 Hz, 2H), 1.58 (m, 2H), 1.47 (s, 9H), 1.32 (m, 2H),
1
3
0
.93 (t, J¼7.2 Hz, 3H); C NMR (50 MHz, CDCl ):
3.6.1.3. Compound 7e. Yield: 97%. R (cyclohexane/
f
3
ꢀ
d 159.6, 155.2, 133.1 (2C), 115.3, 114.0 (2C), 84.0, 83.0,
9.8, 55.3, 46.2, 36.9, 30.3, 28.5 (3C), 20.1, 14.0; MS
AcOEt 1:1)¼0.20; mp (white solid)¼119–120 C; IR
ꢁ
1
1
7
(neat) n /cm : 2937, 2800, 2760, 1450, 1370; H NMR
max
+
(ESI) m/z 340 [M+Na] . Anal. Calcd for 6c (C H NO ):
C, 71.89; H, 8.57; N, 4.41. Found: C, 69.56; H, 8.26; N, 4.15.
(200 MHz, CDCl ): d 8.00–7.90 (m, 3H), 7.40–7.30 (m,
3
1
9
27
3
1H), 7.20–7.00 (m, 4H), 6.41 (s, 1H), 3.71 (s, 2H), 2.40–
1
3
2.30 (m, 4H), 2.20 (s, 3H), 1.50–1.30 (m, 6H); C NMR
(50 MHz, CDCl ): d 144.3, 138.5, 137.1, 136.5, 129.3
(2C), 129.0, 127.2 (2C), 134.0, 123.1, 120.4, 114.5, 111.1,
3
bromopyridine at 80 C; yield: 70%. R (cyclohexane/AcOEt
.5.4. Compound 6d. The reaction was performed from 2-
ꢀ
3
f

O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
10681
5
[
6.2, 54.6 (2C), 25.9 (2C), 24.3, 21.4; MS (ESI) m/z 369
M+H] . Anal. Calcd for 7e (C H N O S): C, 68.45; H,
3.7. Typical procedure for the deprotection of di-Boc-
and phthalyl-protected amines
+
2
1 24 2 2
6
.56; N, 7.60. Found: C, 68.12; H, 6.92; N, 7.29.
Conditions A. To a stirred solution of di-Boc-protected
compound (1.0 equiv) in anhydrous acetonitrile (2 mL)
was added LiBr (3.0 equiv) and the mixture was heated at
3
.6.2. From potassium amide. To a suspension of potas-
sium phthalimide or potassium di-tert-butyliminodicarbon-
ate (2 mmol, 2 equiv) in anhydrous DMF (5 mL) was
added propargyl bromide (80 wt % solution in toluene,
ꢀ
65 C overnight. After cooling at room temperature, the sol-
vent was concentrated in vacuum and the crude product was
purified by silica gel column chromatography to yield the
mono-Boc-protected adduct.
2
mmol, 2 equiv). The mixture was stirred at room temper-
ature for 2 h and then added via a cannula to a solution
containing PdCl (PPh ) (0.05 mmol, 0.05 equiv), CuI
2
3 2
(
(
0.10 mmol, 0.1 equiv), and o-substituted aryl halide
1 mmol, 1 equiv) in NEt (10 mL). The resulting solution
Conditions B. To a solution of di-Boc-protected compound
(1 equiv) in MeOH (15 mL) was added 2 mL of 4.9 N
HCl/MeOH solution at 0 C. The reaction was stirred at
3
ꢀ
ꢀ
room temperature for 3 h. After evaporation of the solvent
was stirred at 80 C until the disappearance of starting ma-
terial as judged by TLC. Solvents were removed in vacuum
and the crude product was purified by silica gel column
chromatography to yield the expected adducts 7c, 7d, 7f,
and 7g.
under vacuum and drying, anhydrous Et O (20 mL) was
2
added and the hydrochloride salt precipitated was collected
by filtration.
1
3.6.2.1. Compound 7c. Yield: 20%. H NMR (200 MHz,
CDCl ): d 7.58 (m, 1H), 7.49 (m, 1H), 7.29 (m, 2H), 6.64 (s,
Conditions C. To a stirred solution of phthalylamine
(1.0 equiv) in EtOH (35 mL) was added at room temperature
hydrazine hydrate (4.0 equiv), and the mixture was heated at
3
1
3
1
CDCl ): d 154.8 (2C), 152.1 (2C), 128.4, 124.0, 122.7,
H), 4.99 (s, 2H), 1.58 (s, 18H); C NMR (50 MHz,
ꢀ
reflux for 2 h. After cooling at 0 C, a gray-white solid
3
1
m/z 348 [M+H] . Anal. Calcd for 7c (C H NO ): C,
20.9, 111.2, 103.9, 83.0 (2C), 43.3, 28.1 (6C); MS (ESI)
precipitated and was collected by filtration then rinsed
with ice-cold EtOH (2ꢂ25 mL). The filtrate was concen-
trated in vacuum and the crude product was purified by
silica gel column chromatography to yield the expected
adducts.
+
1
9
25
5
6
5.69; H, 7.25; N, 4.03. Found: C, 65.36; H, 7.06; N, 4.15.
3
.6.2.2. Compound 7d. Yield: 66%. R (cyclohexane/
f
ꢀ
neat) n /cm : 2990, 1775, 1705, 1390, 950; H NMR
AcOEt 7:3)¼0.52; mp (white solid)¼155–157 C; IR
ꢁ1
1
(
(
(
3.7.1. Compound 4a. Prepared from 3a according to condi-
tions A. Yield: 73%. R (CH Cl /MeOH 98:2)¼0.17; mp
max
400 MHz, CDCl ): d 7.87 (dd, J¼5.4, 3.1 Hz, 2H), 7.72
3
f
2
2
ꢀ
1
dd, J¼5.4, 3.1 Hz, 2H), 7.50 (dd, J¼7.7, 1.1 Hz, 1H),
(beige solid)¼83–85 C; H NMR (200 MHz, CDCl ):
3
7
.42 (dd, J¼8.0, 0.6 Hz, 1H), 7.26–7.20 (m, 1H), 7.18 (dt,
d 8.51 (d, J¼4.6 Hz, 1H), 7.59 (dt, J¼7.7, 1.8 Hz, 1H),
7.36 (d, J¼7.8 Hz, 1H), 7.18 (ddd, J¼7.6, 4.9, 1.1 Hz,
1H), 5.00 (br s, 1H), 4.14 (d, J¼5.6 Hz, 2H), 1.42 (s, 9H);
1
3
J¼7.5, 1.1, 1H), 6.73 (s, 1H), 5.01 (s, 2H); C NMR
(
(
100 MHz, CDCl ): d 167.5 (2C), 155.0, 152.0, 134.2
3
1
3
2C), 132.1 (2C), 128.2, 124.4, 123.5 (2C), 122.9, 121.1,
111.4, 105.4, 35.0; MS (ESI) m/z 332 [M+Na+MeOH] .
Anal. Calcd for 7d (C H NO ): C, 73.64; H, 4.00; N,
C NMR (50 MHz, CDCl ): d 155.4, 150.0, 143.0, 136.2,
3
+
127.1, 123.0, 85.9, 82.5, 80.1, 31.1, 28.4 (3C). Anal. Calcd
for 4a (C H N O $0.25H O): C, 65.94; H, 7.04; N,
11.83. Found: C, 66.00; H, 7.00; N, 11.27.
1
7
11
3
13 16
2
2
2
5
.05. Found: C, 73.49; H, 4.03; N, 5.01.
3
.6.2.3. Compound 7f. Yield: 93%. R (Et O/cyclohex-
f
3.7.2. Compound 4b. Prepared from 3b according to condi-
tions A. Yield: 75%. R (cyclohexane/AcOEt 1:1)¼0.27; mp
2
ꢁ
1
ane 3:7)¼0.50; IR (neat) nmax/cm : 2980, 1790, 1745,
f
1
ꢀ
1
1
700, 1475, 1455, 1143, 730; H NMR (300 MHz,
(beige solid)¼79–81 C; H NMR (200 MHz, CDCl ):
3
CDCl ): d 8.08 (d, J¼7.9 Hz, 1H), 7.75 (d, J¼8.3 Hz, 2H),
d 8.58 (br s, 2H), 7.66 (d, J¼7.8 Hz, 1H), 7.21 (br s, 1H),
3
1
3
7
2
.42 (m, 1H), 7.23 (m, 4H), 6.43 (s, 1H), 5.28 (s, 2H,),
.30 (s, 3H), 1.47 (s, 18H); C NMR (75 MHz, CDCl3):
5.08 (br s, 1H), 4.14 (d, J¼5.6 Hz, 2H), 1.44 (s, 9H);
C
NMR (50 MHz, CDCl ): d 155.4, 152.4, 148.7, 138.7,
1
3
3
d 152.1 (2C), 144.9, 138.5, 137.0, 135.6, 129.9 (2C),
29.5, 126.6 (2C), 124.1, 123.5, .120.5, 114.3, 107.3, 82.8
126.6, 118.2, 89.3, 80.2, 79.8, 31.3, 28.5 (3C). Anal. Calcd
for 4b (C H N O $H O): C, 66.44; H, 7.01; N, 11.92.
Found: C, 66.78; H, 6.99; N, 11.34.
1
1
3
16
2
2
2
+
(
Anal. Calcd for 7f (C H N O S): C, 62.38; H, 6.44; N,
2C), 45.2, 27.9 (6C), 21.4; MS (ESI) m/z 523 [M+Na] .
2
6 32 2 6
5
.60. Found: C, 62.10; H, 6.60; N, 5.32.
3.7.3. Compound 4c. Prepared from 3c according to condi-
ꢀ
1
tions A. Yield: 71%; mp (beige solid)¼85–87 C; H NMR
3
.6.2.4. Compound 7g. Yield: 80%. R (cyclohexane/
f
(200 MHz, CDCl ): d 8.38 (d, J¼5.7 Hz, 2H), 7.08 (d,
3
ꢀ
NMR (200 MHz, CDCl ): d 8.44 (br s, 1H), 8.28 (d,
1
AcOEt 4:6)¼0.35; mp (amber solid)¼99–101 C;
H
J¼5.9 Hz, 2H), 4.84 (br s, 1H), 3.99 (d, J¼5.6 Hz, 2H),
1
3
1.30 (s, 9H); C NMR (50 MHz, CDCl ): d 155.4, 149.8
3
3
J¼8.4 Hz, 1H), 7.71 (d, J¼8.4 Hz, 2H), 7.20 (m, 3H), 6.59
(2C), 131.1, 125.8 (2C), 90.8, 80.6, 80.3, 31.2, 28.5 (3C).
Anal. Calcd for 4c (C H N O ): C, 67.22; H, 6.94; N,
12.06. Found: C, 67.07; H, 7.27; N, 12.13.
1
3
(
s, 1H), 5.26 (s, 2H), 2.31 (s, 3H), 1.44 (s, 18H); C NMR
50 MHz, CDCl ): d 152.2 (2C), 147.9, 146.3, 146.2,
1
3 16 2 2
(
3
1
1
45.5, 142.7, 135.3, 130.2 (2C), 126.7 (2C), 121.4, 118.9,
08.4, 83.2 (2C), 45.0, 28.0, 21.6 (6C); MS (ESI) m/z 502
3.7.4. Compound 4d. Prepared from 3d according to condi-
tions A. Yield: 65%. R (cyclohexane/AcOEt 6:4)¼0.23; mp
+
+
[
(
M+H] , 1025 [2M+Na] . Anal. Calcd for 7g
C H N O S): C, 59.86; H, 6.23; N, 8.38. Found: C,
f
ꢀ
2970, 2930, 1690, 1615, 1440, 1265, 1165, 1135; H NMR
ꢁ1
(beige solid)¼140–142 C; IR (neat) n /cm : 3355,
max
2
5
31
3
6
1
5
9.14; H, 6.39; N, 8.22.

10682
O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
(
300 MHz, CDCl ): d 7.63 (dd, J¼7.5, 8.2 Hz, 1H) 7.35 (d,
Acknowledgements
3
J¼7.8 Hz, 2H) 4.80 (br s, 2H) 4.20 (d, J¼5.5 Hz, 4H), 1.48
1
3
(
(
s, 18H); C NMR (75 MHz, CDCl ): d 151.1 (2C), 143.1
3
The CNRS is gratefully acknowledged for support of this re-
search and for a doctoral fellowship to N.O. Thanks also to
the MNSER for a doctoral fellowship to O.R.
2C), 136.5, 126.2 (2C), 86.2 (2C), 82.0 (2C), 80.2 (2C),
+
31.0 (2C), 28.4 (6C); MS (ESI) m/z 386 [M+H] . Anal.
Calcd for 4d (C H N O ): C, 65.44; H, 7.06; N, 10.90.
2
1 27 3 4
Found: C, 65.48; H, 6.95; N, 10.83.
References and notes
3.7.5. Compound 5a. Prepared from 3a according to condi-
tions B. Yield: 94%. Rf (AcOEt/MeOH/NH OH
1
. (a) Shirota, F. N.; DeMaster, E. G.; Nagasawa, H. T. J. Med.
Chem. 1979, 22, 463–464; (b) Yu, P. H.; Davies, B. A.;
Boulton, A. A. J. Med. Chem. 1992, 35, 3705–3713.
. Connolly, P. J.; Wetter, S. K.; Beers, K. N.; Hamel, S. C.; Chen,
R. H. K.; Wachter, M. P.; Ansell, J.; Singer, M. M.; Steber, M.;
Ritchie, D. M.; Argentieri, D. C. Bioorg. Med. Chem. Lett.
4
aq,20%
1
ꢁ1
8
NMR (200 MHz, CD OD): d 8.62 (br s, 1H), 7.92 (t,
7:10:3)¼0.18; IR (neat) nmax/cm : 3387, 3082, 1728; H
3
2
J¼7.7 Hz, 1H), 7.64 (m, 1H), 7.51 (m, 1H), 4.09 (s, 2H);
1
3
C NMR (50 MHz, CD OD): d 149.0, 141.3, 140.4,
3
130.2, 126.5, 85.6, 84.0, 30.5. The compound 5a is not suf-
ficiently stable to be fully characterized.
1
999, 9, 979–984.
. (a) Corriu, R. J. P.; Bolin, G.; Moreau, J. J. E. Tetrahedron Lett.
991, 32, 4121–4124; (b) Campi, E. M.; Jackson, W. R.;
3
1
3.7.6. Compound 5b. Prepared from 3b according to condi-
tions B. Yield: 94%. Rf (AcOEt/MeOH/NH OH
Nilsson, Y. Tetrahedron Lett. 1991, 32, 1093–1094; (c)
Mandai, T.; Ryoden, K.; Kawada, M.; Tsuji, J. Tetrahedron
Lett. 1991, 32, 7683–7686; (d) Clive, D. L. J.; Cole, D. C.;
Tao, Y. J. Org. Chem. 1994, 59, 1396–1406.
. Ripin, D. H. B.; Bourassa, D. E.; Brandt, T.; Castaldi, M. J.;
Frost, H. N.; Hawkins, J.; Johnson, P. J.; Massett, S. S.;
Neumann, K.; Phillips, J.; Raggon, J. W.; Rose, P. R.;
Rutherford, J. L.; Sitter, B.; Stewart, A. M., III; Vetelino,
M. G.; Wei, L. Org. Process Res. Dev. 2005, 9, 440–450.
. Hertner, F. W.; Hsiao, Y.; Eng, K. K.; Rivera, N. R.; Palucki,
M.; Tan, L.; Yasuda, N.; Hughes, D. L.; Weissman, S.;
Zewge, D.; King, T.; Tschaen, D.; Volante, R. P. J. Org.
Chem. 2004, 69, 8723–8730.
4
aq,20%
ꢁ1
8
1
1
7:10:3)¼0.21; IR (neat) nmax/cm : 3380, 3013, 2922,
1
609, 1555; H NMR (200 MHz, CD OD): d 7.25 (br s,
3
H), 7.05 (d, J¼5.6 Hz, 1H), 6.90 (d, J¼8.0 Hz, 1H), 6.30
4
1
3
(
m, 1H), 2.31 (s, 2H); C NMR (50 MHz, CD OD):
3
d 151.2, 147.2, 142.3, 139.5, 125.7, 86.8, 77.4, 27.4. The
compound 5b is not sufficiently stable to be fully character-
ized.
5
6
3.7.7. Compound 5c. Prepared from 3e according to condi-
tions C. Yield: 63%. Rf (AcOEt/MeOH/NH OH
4
aq,20%
ꢁ1
8
1
8:10:2)¼0.18; IR (neat) nmax/cm : 3360, 1585, 1560,
1
465, 1430, 1380, 1270; H NMR (200 MHz, CDCl3):
. (a) Kopka, I. E.; Fataftah, Z.; Rathke, M. W. J. Org. Chem.
1
d 8.48 (m, 1H), 7.58 (td, J¼7.8, 1.8 Hz, 1H), 7.32 (d,
980, 45, 4616–4622; (b) Imada, Y.; Yuassa, M.; Nakamura,
I.; Murahashi, S. I. J. Org. Chem. 1994, 59, 2282–2284; (c)
Czernecki, S.; Valery, J. M. J. Carbohydr. Chem. 1990, 9,
J¼7.8 Hz, 1H), 7.14 (m, 1H), 3.60 (s, 2H), 1.60 (br s, 2H);
1
3
C NMR (50 MHz, CD OD): d 149.8, 143.1, 136.0,
3
1
26.7, 122.6, 90.4, 81.9, 32.00; MS (ESI) m/z 133
M+H] . Anal. Calcd for 5c (C H N ): C, 72.70; H, 6.10;
767–770; (d) Basak, A.; Rudra, K. R. Tetrahedron Lett. 2000,
41, 7231–7234; (e) Basak, A.; Shain, J. C. Tetrahedron Lett.
1998, 39, 3029–3030; (f) Glase, S. A.; Akunne, H. C.;
+
[
N, 21.20. Found: C, 72.52; H, 6.20; N, 21.25.
8
8 2
Heffner, T. G.; Jaen, J. C.; Mackenzie, R. G.; Meltzer, L. T.;
Pudsley, T. A.; Smith, S. J.; Wise, L. D. J. Med. Chem. 1996,
39, 3179–3187.
3
.7.8. Compound 8d. Prepared from 7d according to condi-
tions C. Yield: 77%. Rf (AcOEt/MeOH/NH OH
4
aq,20%
ꢁ
1
8
8:10:2)¼0.54; IR (neat) nmax/cm : 3055, 2917, 1600,
7. Mahrwald, R.; Quint, S. Tetrahedron Lett. 2001, 42, 1655–
656.
8. (a) Fisher, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319–4321;
b) Wie, C.; Li, C. J. J. Am. Chem. Soc. 2002, 124, 5638–
5639; (c) Jiang, B.; Si, Y. G. Tetrahedron Lett. 2003, 44,
767–6768; (d) D ꢀı ez, R.; Badorrey, R.; D ꢀı az-de-Villegas,
1
1585, 1475, 1455, 1254, 740; H NMR (300 MHz,
CD OD): d 7.52 (m, 1H), 7. 45 (m, 1H), 7.21 (m, 2H),
1
3
1
3
6
(
.64 (m, 1H), 4.85 (s, 2H), 3.93 (s, 2H); C NMR
75 MHz, CD OD): d 159.4, 156.4, 132.4, 125.0, 123.8,
(
3
+
122.0, 111.8, 103.7, 39.7; MS (ESI) m/z 148 [M+H] .
Anal. Calcd for 8d (C H NO): C, 73.45; H, 6.16; N, 9.52.
Found: C, 73.52; H, 6.01; N, 9.62.
6
9
9
M. D.; G ꢀa lvez, J. A. Eur. J. Org. Chem. 2007, 2114–2120.
. (a) Mladenova, M.; Alami, M.; Linstrumelle, G. Synth.
Commun. 1995, 25, 1401–1410; (b) Bleicher, L. S.; Cosford,
N. D. P.; Herbaut, A.; Mc Callum, J. S.; Mc Donald, I. A.
J. Org. Chem. 1998, 63, 1109–1118; (c) Lemhadri, M.;
Doucet, H.; Santelli, M. Synthesis 2005, 1359–1367.
10. (a) Tramontini, M. Synthesis 1973, 703–775; (b) Li, C. J.; Wei,
C. Chem. Commun. 2002, 268–269; (c) Wie, C.; Li, Z.; Li, C.
J. Org. Lett. 2003, 5, 4473–4475; (d) Wie, C.; Li, C. J. Am.
Chem. Soc. 2003, 125, 9584–9585; (e) Kabalka, G. W.;
Venkataiah, B.; Dong, G. Tetrahedron Lett. 2004, 45, 729–
731; (f) Lo, V. K.-Y.; Liu, Y.; Wong, M. K.; Che, C.-M. Org.
Lett. 2006, 8, 1529–1532; (g) Aschwanden, P.; Stephenson,
C. R. J.; Carreira, E. M. Org. Lett. 2006, 8, 2437–2440.
11. Kwatra, M. M.; Simon, D. Z.; Salvador, R. L.; Cooper, P. D.
J. Med. Chem. 1978, 21, 253–257.
9
3
.7.9. Compound 8f. Prepared from 7f according to condi-
tions A. Yield: 89%. R (cyclohexane/AcOEt 7:3)¼0.64;
f
ꢁ
1
IR (neat) n /cm : 3345, 2978, 2930, 1700, 1600, 1500,
max
1
1
450, 1365, 1270, 1245, 1225, 1170, 1090, 935; H NMR
(
300 MHz, CDCl ): d 7.98 (d, J¼8.4 Hz, 1H), 7.54 (d,
3
J¼8.4 Hz, 2H), 7.34 (m, 1H), 7.15 (m, 2H), 6.86
(
(
(
d, J¼8.4 Hz, 2H), 6.51 (s, 1H), 5.42 (br s, 1H), 4.53
1
3
d, J¼6.4 Hz, 2H), 2.21 (s, 3H), 1.33 (s, 9H); C NMR
75 MHz, CDCl ): d 155.6, 145.1, 138.4, 137.1, 135.8,
3
1
1
30.0 (2C), 129.4, 126.4 (2C), 124.7, 123.8, 121.1, 114.6,
11.3, 79.6, 38.7, 28.4 (3C), 21.5; MS (ESI) m/z 401
+
[
M+H] . Anal. Calcd for 8f (C H N O S): C, 62.98; H,
2
1 24 2 4
6
.04; N, 6.99. Found: C, 70.01; H, 5.95; N, 7.02.

O. Russo et al. / Tetrahedron 63 (2007) 10671–10683
10683
1
2. (a) Olivi, N.; Spruyt, P.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
Tetrahedron Lett. 2004, 45, 2607–2610; (b) Russo, O.;
Alami, M.; Brion, J.-D.; Sicsic, S.; Berque-Bestel, I.
Tetrahedron Lett. 2004, 45, 7069–7072.
21. Hashmi, A. S. K.; Haufe, P.; Rivas, N. A.; Bats, J. W. Adv.
Synth. Catal. 2004, 346, 421–424.
22. Denton, T. T.; Zhang, X.; Cashman, J. R. J. Med. Chem. 2005,
48, 224–239.
1
3. Youngman, M. A.; Dax, S. L. J. Comb. Chem. 2001, 3, 469–
23. Kitbunnadaj, R.; Zuiderveld, O. P.; De Esch, I. J.; Vollinga,
R. C.; Bakker, R.; Lutz, M.; Spek, A. L.; Cavoy, E.; Deltent,
M. F.; Menge, W. M.; Timmerman, H.; Leurs, R. J. Med.
Chem. 2003, 46, 5445–5457.
4
72.
4. For the multicomponent synthesis of heterocycles, see for in-
1
stance: (a) Braun, R. U.; M €u ller, T. J. J. Synthesis 2004,
2
391–2406; (b) Braun, R. U.; Zeitler, K.; M €u ller, T. J. J. Org.
Lett. 2001, 3, 3297–3300.
24. Hernandez, J. N.; Ramirez, M. A.; Martin, V. S. J. Org. Chem.
2003, 68, 743–746.
1
5. (a) Wyatt, P. G.; Allen, M. J.; Chilcott, J.; Gardner, C. J.;
Livermore, D. G.; Mordaunt, J. E.; Nerozzi, F.; Patel, M.;
Perren, M. J.; Weingarten, G. G.; Shabbir, S.; Woollard,
P. M.; Zhou, P. Bioorg. Med. Chem. Lett. 2002, 12, 1405–
25. Berque-Bestel, I.; Soulier, J. L.; Giner, M.; Rivail, L.; Langlois,
M.; Sicsic, S. J. Med. Chem. 2003, 46, 2606–2620.
26. (a) Hilt, G.; Galbiati, F. Synlett 2005, 829–833; (b) Nilsson,
B. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem. 1990, 33,
580–584; (c) Youseung, K.; Soon bang, K.; Gyochang, K.;
Min Seok, J.; Jae Yang, K.; Dae Yong, J. U.S. Pat. Appl.
Publ. 2003, 119,880, 26 June 2003.
1
411; (b) Kessler, A.; Faure, H.; Petrel, C.; Ruat, M.;
Dauban, P.; Dodd, R. H. Bioorg. Med. Chem. Lett. 2004, 14,
345–3349; (c) Mustafa, S. M.; Bavadekar, S. A.; Ma, G.;
3
Moore, B. M.; Feller, D. R.; Miller, D. D. Bioorg. Med.
Chem. Lett. 2005, 15, 2758–2760.
6. Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
27. (a) Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess,
W. J.; Payne, D. J.; Rittenhouse, S. F.; Moore, T. D.; DeWolf,
W. E.; Keller, P. M.; Qiu, X.; Janson, C. A.; Vaidya, K.;
Fosberry, A. P.; Smyth, M. G.; Joworski, D. D.; Slatter-
Radosti, C.; Huffman, W. F. Bioorg. Med. Chem. Lett. 2001,
11, 2241–2244; (b) Kabalka, G. W.; Wang, L.; Pagni, R. M.
Tetrahedron Lett. 2001, 42, 6049–6051; (c) Zhang, H.-C.;
Brumfield, K. K.; Jaroskova, L.; Maryanoff, B. E.
Tetrahedron Lett. 1998, 39, 4449–4452.
1
3
4, 6403–6406.
1
1
7. Unroe, M. R.; Reinhardt, B. A. Synthesis 1987, 981–985.
8. Alami, M.; Peyrat, J.-F.; Brion, J.-D. Synthesis 2000, 1499–
1
518.
9. (a) Alami, M.; Linstrumelle, G. Tetrahedron Lett. 1991, 32,
109–6112; (b) Alami, M.; Ferri, F.; Gaslain, Y. Tetrahedron
1
6
Lett. 1996, 37, 57–58; (c) Alami, M.; Crousse, B.; Ferri, F.
J. Organomet. Chem. 2001, 624, 114–123.
0. Alami, M.; Peyrat, J.-F.; Brion, J.-D. Tetrahedron Lett. 2002,
28. For reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2857–2911; (b) Cacchi, S.; Fabrizi, G. Chem.
Rev. 2005, 105, 2873–2920; (c) Cacchi, S.; Fabrizi, G.;
Goggiomani, A. Heterocycles 2001, 56, 613–632.
2
4
3, 3007–3009 and references cited therein.