H-bonding vs Protonation of Alkynes in Regioselective Hydroamination Reactions: A Glimpse into the Reactivity of Arylogous Ynolethers and Ynamines

Article abstract of DOI:10.1021/acs.joc.9b02471

In this paper is described the competition and transition between hydrogen bonding and protonation of alkynes connected, on one side, to various aromatic rings and to chiral amino ester appendages on the other side. While the first mode of activation indu

Full text of DOI:10.1021/acs.joc.9b02471

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Article
H–bonding vs Protonation of Alkynes in Regioselective
Hydroamination Reactions: A Glimpse into the
Reactivity of Arylogous Ynolethers and Ynamines
Masahiro Abe, Alexandre Jean, Jerome Blanchet, Jacques
Rouden, Jacques Maddaluno, and Michael De Paolis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02471 • Publication Date (Web): 01 Nov 2019
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H–bonding vs Protonation of Alkynes in Regioselective Hydroamination
Reactions: A Glimpse into the Reactivity of Arylogous Ynolethers and
Ynamines
[
a]
[a,b]
[a]
Jérôme Blanchet,[b] Jacques Rouden,[b] Jacques
Masahiro Abe,
Alexandre Jean,
[a]
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Maddaluno and Michaël De Paolis*
[a]
Normandie Université, UNIROUEN, INSA de Rouen, CNRS, Laboratoire COBRA (UMR
014 & FR 3038), 76000 Rouen, France.
6
[b]
Normandie Université, ENSICAEN, CNRS, Laboratoire LCMT (UMR 6507 & FR 3038),
1
4000 Caen, France.
X
various aromatics
including indoles
X
H
N
CO Et
2
P
X
protonation
of alkyne
HN
P
CO Et
2
•
via
H
N
chiral amino ester
X
P
CO Et
H
2
N
P
illustrated with:
(
OH, Br)
Ph
R
HN
R
(EWG or EDG) X
R2
O
X
including
electron poor
indole
R
N
N
N
P
N
CO Et
P
CO2Et
2
R1
Me, H)
P
P
(
CO Et
2
1
0 examples,
12 examples,
up to 99% ee, dr = 5:1 to 20:1
4 examples, R = OMe, H, OAc
up to 97% ee, dr > 20:1
up to 99% ee, dr > 20:1
ABSTRACT In this paper is described the competition and transition between hydrogen-
bonding and protonation of alkynes connected, on one side, to various aromatic rings and to
chiral amino ester appendages on the other side. While the first mode of activation induced the
cyclization into pyrrolidines, the protonation of the alkyne led preferentially to
tetrahydropyridines due to the higher level of the HOMO of the considered arylogous
ynolethers and ynamines. The transition between H-bonding and protonation was observed with
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the alkyne substituted with 2-methoxyphenyl, for which the cyclization delivered either 5- or
6
-membered rings depending on the temperature of the experiment. From there, the cyclization
of dialkoxy- and trialkoxyphenyl substituted alkynes into 6-membered rings, i.e.
tetrahydropyridines, was developed. When next applied to alkynylindoles, the same pattern of
cyclization provided 6–membered rings as an illustration of the reactivity of arylogous
ynamines. Thanks to the high reactivity of the intermediate cationic species, weak nucleophile
such as NH-oxazolidinone participated efficiently in the hydroamination reaction of
alkynylindoles. Pyrrolidines, tetrahydropyridines and piperidines decorated with various
aromatics and substituents were thus prepared in enantio- and stereoselective manner.
Capitalizing on the enamine moiety of the azaheterocycles, the molecular diversity was
extended through stereoselective oxidation and ring contraction processes.
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INTRODUCTION
1
Found in natural products, biomolecules, and catalysts, pyrrolidines are ranked among the most
popular non-planar heterocycles and numerous methodologies have consequently been
2
developed to prepare them. The main strategies leading to such structures rely on metal-
catalyzed3-8 or organocatalyzed9-13 [3+2] cycloadditions, Tsuji-Trost cyclizations,14
cyclopropane ring openings with imine,15 and organo-SOMO cycloaddition of β-amino
1
6
aldehydes and olefins. Another general approach entails the hydroamination cyclization of
17
alkynes (Scheme 1A). The hydroamination reaction constitutes an atom-efficient and versatile
+
access to enamines when alkynes are involved. Upon activation of the alkyne with H , 5- or 6-
membered ring can be expected. To set the stage for such a reaction, the asymmetric Mannich
coupling can conveniently assemble the chiral alkynylaryl amine intermediates.18a We
previously illustrated this strategy through the metal-free intramolecular hydroamination
reaction of alkynes substituted with basic N-heteroarenes 3 for which the cyclization into
pyrrolidines 4 was triggered by simple protonation of the basic heterocycles (Scheme 1B).18b
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In the absence of basic site, the activation of the alkyne requires different strategy. In this paper,
the competition between H-bonding and protonation of alkynes, substituted with electron-rich,
very rich or electron-poor arenes, is examined in the framework of the hydroamination reaction
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(Scheme 1C). H-Bonding activation of the alkynes produced pyrrolidines while the protonation
of the alkyne led to stabilized cation and induced the formation of tetrahydropyridines,
highlighting the arylogous ynolethers and ynamines reactivity.
A. the issue of the hydroamination regioselectivity
H
Ar
Ar
hydroamination
Ar
N
N
N
vs
B. our initial study involving basic N-heteroarenes
CHO
CO Et
2
H+
Mannich
N
+
CO Et
2
N
HN
PMP
CO Et
2
N
N
PMP
1a
2
3a
E
-4a
PMP
N
PMP: 4-MeOC H
the pyridinium elicited the cyclization
6
4
C. this work describes activation of alkynes by H-bonding or protonation for hydroamination
substrate controlled cyclisation pattern
H
Ar
or
Ar
CO Et
HN
PMP
c-v
Ar = electron rich arenes and indoles
CO Et
N
2
Ar
N
CO2Et
2
PMP
PMP
4
3
5
Scheme 1. Regioselectivity in Alkynes Hydroamination Reactions
The versatility of these original scaffolds was demonstrated through synthetic manipulations
leading to highly functionalized molecules containing pyrrolidine, tetrahydropyridine and
piperidine cores in excellent enantio- and stereoselectivity.
RESULTS AND DISCUSSIONS
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A.
H-bonding with alkynylaryl amino esters. Hydroamination reaction of alkynes in
acidic conditions is challenging because it involves a protonated amine, less reactive than a free
base. In addition, it is difficult to protonate alkynes into vinylic cationic species. Therefore,
harsh reaction conditions are required for the acidic cyclization of alkynylphenyl amines into
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pyrrolidines. While the electronic density of the alkyne is expected to be a key contributor for
establishing H-bonding, we were curious to examine the impact on the activation of the
electronic delocalisation of the aromatic substituents within the alkyne: the arylogous reactivity.
To evaluate this point, alkynes 3c-h, connected to either electron-rich or electron-poor arenes,
were prepared by a sequence entailing an enantioselective Mannich coupling of aldehydes 1c-
h with imine 2 (Scheme 2). Under the smooth catalysis of the readily available organocatalyst
7
, adducts 3c-h were isolated in 40-69% yield after an olefination step. As it happens, excellent
level of enantio- (93-98% ee) and stereoselectivity (dr > 20:1) were observed which gave the
2
0
opportunity to study the hydroamination reaction while preserving the chiral information. The
cyclization was first attempted in catalytic conditions (20 mol% CF CO H) which were
3
2
efficient for converting 2-alkynylpyridine amine 3b into (E)-4b (67% yield, Scheme 3).
However, alkynylphenyl amine 3c reacted very differently and an incomplete, but encouraging,
conversion of 60% was observed after five days of exposure to 5 equiv. of CF CO H.
3
2
Pleasingly, activation with camphor acid (CSA, 5 equiv.) combined with heating (MeNO2,
0°C, 19 h) allowed a somewhat faster cyclization of 3c into 4c (Scheme 2). To cope with the
8
moisture-sensitivity of enamine 4c, the substrate was directly hydrogenated (H , Pd/C, THF,
2
Scheme 2) into pyrrolidine 6c in 48% yield (2-step) while generating a new carbon stereocenter
(
dr > 20:1).21
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NHTf
Ar
CO Me
2
CHO
7
HN
1
Ar
2. CSA
Ar
CO Me
2
. (10 mol%);
3. H2, Pd/C
or
+
2
N
N
PMP
50°C
CO2Et
CO Et
2
CO Me
2
PMP
3c-h
4. NaBH(OAc)3
Ar 1c-h
Ph P
3
8
4c-h
6c-h, dr > 20:1
HN
PMP
CO2Et
not isolated
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Me
CO Me
R
2
CO Me
2
OMe
N
PMP
CO Et
N
2
CO Et
2
PMP NH
PMP NH
PMP
EtO C
6c, 48% 80°C 19 h [H2]
6d, 42% 48 h [H2]
2
EtO C
2
CO Me
2
95% ee
95% ee
CO Me
2
3c, R = H, 98% ee
d, R = Me, 96% ee
3e, 98% ee
OMe
3
CO Me
2
CO Me
2
CO Me
OMe
2
MeO
N
PMP
N
HN
CO Et
2
CO Et
2
CO Et
2
PMP
PMP
3f, 93% ee
6
e, 63% 41 h [H2]
6f, 45% 45 h [H2]
Br
NO2
93% ee
93% ee
CO Me
CO Me
2
2
Br
NO2
PMP NH
PMP NH
N
N
EtO C
EtO C
CO Et
CO Et
2
2
2
2
PMP
g, 34% 120 h
NaBH(OAc)3]
PMP
CO Me
CO Me
2
2
6
[
6h, 49% 18 h
[NaBH(OAc)3]
3g, 99% ee
3h, 99 % ee
Scheme 2. Asymmetric preparation of 3c-i and hydroamination reaction of alkynylaryl
amines with camphorsulfonic acid (CSA)
CF CO H (0.2 equiv)
3
2
CO Et
2
HN
PMP
CO Et
N
N
2
N
CH Cl 7 h, rt
2
2,
PMP 4b, 67% (E/Z = 20:1)
3b
Scheme 3. Catalytic hydroamination reaction of 2-alkynylpyridine amine 3b
Satisfyingly, only a slight erosion of enantiopurity was measured (3c, 98% ee vs 6c, 95% ee).
The intramolecular hydroamination of alkynes with chiral amino ester derivatives was therefore
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demonstrated in acidic conditions. Moreover, the hydroamination occurred with electron-rich
alkynes, as illustrated with 3d and 3e. Thus, pyrrolidines 6d,e bearing tolyl or anisole
substituents were isolated after this 2-step sequence in 42% (95% ee, dr > 20:1, 48 h) and 63%
yields (93% ee, dr > 20:1, 41 h), respectively. In both cases, only a minor erosion of the
enantiopurity was noted. With 3-methoxybenzene and 2-bromobenzene substituted alkynes 3f
and 3g, the activation was similarly effected and the pyrrolidines 6f and 6g were respectively
isolated in 45% (93% ee, dr > 20:1, 45 h) and in 34% yields (dr > 20:1, 120 h) after the reduction
of the intermediate enamines 4f,g. To preserve synthetically useful appendages such as bromo
substituent and α,β-unsaturated ester, the reduction of 4g was chemoselectively performed with
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NaBH(OAc) affording all-cis-pyrrolidine 6g (Scheme 2). As for the reactivity of 2-
3
nitrobenzene substituted alkyne 3h (99% ee) in acidic conditions, we were uncertain whether
H-bonding could still be established with such an electron-depleted alkyne. It was therefore
gratifying to isolate the pyrrolidine cis-6h in 49% yield (2-step) after treatment of 3h with CSA
(18 h) and subsequent chemoselective reduction of the corresponding enamine 4h with
excellent stereocontrol (dr > 20:1). In the case of 3h, the mode of activation was still
questionable owing to the alkyne low-energy LUMO which could favour a spontaneous
cyclization without acid. To clarify this point, the thermal activation of 3h was attempted in the
absence of any acid but the starting material was completely recovered, underlining the role of
H-bonding in the process (Scheme 4).23,24
NO2
NO2
CO Me
2
H
MeNO2, 80°C
1 h
N
CO2Me
2
N
PMP
CO Et
PMP
2
CO Et
2
3h
4h
Scheme 4. Ruling out of the spontaneous cyclization of 3h
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In regards to the regioselectivity of the cyclization (5- vs 6-), we noted that the cyclization of
alkyne 3e into 4e in acidic conditions (50°C, 27 h or 20°C, 61 h) was accompanied by traces of
the tetrahydropyridine 5e visible in the crude mixture (Scheme 5, Eq. 1). We assumed that this
product resulted from the protonation of the alkyne into a vinyl cation, stabilized as vinylidene
o-quinone oxonium methide I, which underwent hydroamination.
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9
0
CO Me
2
OMe
CSA
+
5e (traces)
CO Me
20°C
2
N
PMP
CO Et
2
Eq. 1
4e
MeO
CO Et
2
HN
PMP
CO2Me
OMe
CSA
3e
OMe
•
via
H
80°C
N
CO Et
2
H
PMP
Eq. 2
N
5e
PMP
1
0% conversion (4e/5e ~ 1:9)
I
full conversion (4e/5e ~ 3:7)
Scheme 5. From H-bonding activation to protonation of 3e
At higher temperature, 5e becomes the major isomer (1 h, 80°C, 10% conversion, 4e/5e ~ 1:9,
Scheme 5, Eq. 2). Further extending the reaction time (4 h) led to full conversion at the expense
of the selectivity (4e/5e ~ 3:7), a phenomenon assigned to a partial degradation of the crude
1
reaction mixture ( H NMR) probably related to the poor stability of 5e at 80°C in acidic
2
5
conditions. At any rate, the formation of 5e, even though as a mixture with 4e, led us to
consider that the protonation of the alkyne could be anchimerically assisted by the 2-
2
6
methoxyphenyl substituent, unveiling an unexpected reactivity of arylogous ynolethers. So
far, a similar reactivity was documented for the carbocyclization of 2-alkynylbiaryls and with
vinylidene o-quinone methide generated from the tautomerization of 2-(phenylethynyl)phenol
2
7
in basic conditions. To dodge the stability issue encountered with 5e, we surmised that more
electron-rich 1,3-dimethoxy- and 1,3,5-trimethoxybenzene derivatives 3j,k would be
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protonated in milder conditions (Scheme 6). Both 3j and 3k were thus conveniently prepared
in good yields and enantiopurity (3j: 59% yield, 93% ee; 3k: 71% yield, 94% ee). Satisfyingly,
the bolstering of the HOMO of the alkyne facilitated the protonation step and resulted in the
selective formation of 5j.
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MeO
Ph
MeO
HN
N
MeO
O
CSA (2 equiv),
CH NO rt, 2 h
PhNCO
MeO
MeO
PMP
EtO C
PhMe, 100°C
2 h
3
2,
MeO
PMP
N
PMP NH
CO Et
2
2
EtO C
2
CO Me
5j
9j, 39% (2-step)
3j, 93% ee
2
no pyrrolidine observed
MeO
MeO
Ph
OMe
R
OMe
MeO
HN
R
O
CSA (2 equiv),
CH NO rt, 1 h
PhNCO
MeO
3
2,
N
PhMe, rt, 17 h
R
PMP NH
PMP
EtO C
N
PMP
2
EtO C
CO2Et
2
CO Me
5k
3k, 94% ee
2
9
k, 63% (2-step)
no pyrrolidine observed
R = OMe
AcO
AcO
OMe
OMe
CSA (2 equiv),
CH3NO2, T°C
OMe
N
CO Et
2
+
PMP NH
PMP
AcO
N
PMP
T = 20°C: 4l/5l = 1:1
T = 40°C: 4l/5l = 2:8
CO2Et
EtO C
2
3l
4l
5l
Scheme 6. Cyclization of electron-rich alkynylaryls 3j-l
In addition, the cyclization of 3j was completed in two hours at rt, thereby avoiding any
degradation of the enamine which was stabilized afterward by grafting an electron-withdrawing
appendage. To that end, 5j was exposed to phenyl isocyanate in refluxing toluene which led to
the stable vinylogous urea 9j (39% yield, 2-step), possibly resulting from the [2+2]
2
8
cycloaddition of enamine to isocyanate into β-lactam (not shown) and fragmentation. This
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derivatisation improved the stability of the scaffold and increased the molecular complexity
thereby introduced. As expected, increasing further the HOMO level of the alkyne gave better
results. 1,3,5-Trimethoxybenzene alkyne 3k was thus even more reactive than 3j, allowing the
selective cyclization into 5k to occur after only 1 h at rt. Thereafter, the substrate 5k was
efficiently reacted with phenyl isocyanate (17 h, rt), delivering 9k in 63% yield (2-step).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Next, 4-acetoxy-2-methoxybenzene alkyne 3l was employed to evaluate the impact of the
acetoxy group on the interactions with the alkyne. Significantly, a mixture of 4l/5l (1:1) was
observed at rt (20°C, 16 h, 10% conversion). Raising the temperature to 40°C (14 h, 100%
conversion) led to an increased production of 5l (4l/5l = 2:8, not isolated). Compared to 3e
which was converted into the 5-membered ring 4e at this temperature but after longer reaction
time, alkynylaryl amine 3l displayed an increased reactivity while the production of the 6-
membered ring 5l became predominant.29
B. Arylogous ynamine reactivity toward protons. In view of the exquisite reactivity
displayed by alkynes connected to electron-rich aromatics, we set out to explore the activation
of alkynylindole 3m (Scheme 7). As a case of arylogous ynamines, electron-rich indoles should
raise the HOMO level of the connected alkyne, warranting thus the regioselective
hydroamination in 5m after formation of the stabilized cation II in mild conditions. This would
avoid the decomposition of the tetrahydropyridine core which could then serve in building
tetrasubstituted piperidines 10. These scaffolds are, in addition, highly relevant heterocycles
found in natural products and molecules of pharmacological suitability such as sertindole,
naratriptan and 3-(4-fluoropiperidin-3-yl)-2-phenylindole used in the treatment of
30
31
schizophrenia. Although the reactivity of ynamines has been well explored, little is known
about their more stable arylogous counterparts.
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
HN
HN
E
H
H
HN


•
E ; Nu
H
HN
H
Nu N
H
N
N
PMP
H
N
PMP
CO Et
2
CO Et
PMP
2
PMP
10
CO Et
2
II CO Et
5m
3
m
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
F
SO NHMe
2
F
NH
HN
N
O
N
HN
N
N
F
HN
h5-HT2A receptor antagonists
Sertindole
Naratriptan
Cl
Scheme 7. Application to 3-alkynylindole amines and selected molecules with
pharmacological pertinence entailing the indolylpiperidine scaffold
As above, the assemblage of the alkynylindole amines was carried out from aldehydes 1m-t
and imine 2 (Scheme 8). The resulting α-substituted aldehyde 3m-t can either be engaged in a
Wittig olefination, as was 3m (66% yield, 97% ee), or reduced (with NaBH ) and lactonized,
4
as illustrated with 3n (50% yield, 3-step). To inspect the scope of the process, alkynes 3o-t
connected to indoles substituted in 5-, 4- and 2-position were prepared in good yields. Even
though indoles are known to dimerize in acidic conditions,32 the smooth conversion of 3-
alkynylindole 3m into tetrahydropyridine 5m was noted in the presence of CSA (2 equiv, rt).
To enhance the stability of 5m, the indole was N-Boc protected and the tetrahydropyridine was
subsequently reduced into piperidines 10m with excellent stereoselectivity (dr > 20:1). This
protocol ‒ entailing acidic cyclization followed by subsequent N-Boc protection and/or
reduction ‒ was then carried out with 3-alkynylindoles 3n-r containing various structural
elements.
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NHTf
N
Ar
Ar
CHO
H
Ar
4. NaBH(OAc)3
1
. 7 (10 mol%);
2. CSA, rt
N
N
PMP
RO C
PMP
+
2
HN
PMP
Wittig reagent 8
3
. Boc O
RO2C
CO R
2
2
or NaBH4
2
1
0
5
Ar
1m-t
3m-t
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
X
H
H
N
N
2
R
Boc
N
X 5
N
O
N
Boc
PMP
PMP NH
PMP NH
O
N
O
PMP
EtO C
CO Me
2
EtO C
2
2
5
'n, 56% (2 steps)
CO Me
O
2
99% ee
10m: X = H, 43%, 98% ee
0o: X = OMe, 77%, 98% ee
0p: X = Br, 43%, 99% ee
3
m, X = R = H, 98% ee
1
1
3
n
3o, X = OMe, R = H
3p, X = Br, R = H,
3q, X = CN, R = H
CO Me
2
10q: X = CN, 55%, 99% ee
3
r, X = H, R = Me
without step 3
H
H
N
N
CO Et
N
2
X inversion
PMP
HN
PMP
PMP
N
Me
4
HN
4
HN
Boc
Br
CO Et
N
CO Et
2
PMP
2
CO Me
2
5
'r, 58% (2 steps)
EtO C
2
99% ee
1
0s: X = Ph, 45%, 98% ee
10t: X = Br, 43%, 99% ee
3s
3t
CO Me
2
CO Me
2
1
Scheme 8. Cyclization of 3m-t in tetrahydropyridines (dr > 20:1, H NMR)
The process was successful in all cases, leading to tetrahydropyridines 5’n and 5’r after a simple
N-Boc protection and to trisubstituted piperidines 10o-q after reduction in good yields (43-77%
yield, over 2-3 steps) and with excellent selectivities (98-99% ee, dr > 20:1). Substitution of the
indole in 5-position with a methoxy group notably increased the efficiency of the sequence as
3o was converted into 10o in 77% yield (3-step), probably due to the electronic delocalization
of the alkoxy within the indole ring raising further the HOMO of the alkyne. Compared to 3m,
indole substitution with bromo or cyano groups was inconsequential on the activation of 3p and
3
q since 10p and 10q were isolated in 43% and 55% yields, respectively. Similarly, 5’r was
isolated from the cyclization of 3r in 58% yield (2-step) and 99% ee after N-Boc protection.
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Furthermore, the N-Boc indole protection contributed to the high cis-stereoselectivity observed
during the reduction of tetrahydropyridines 5m-q.33 Indeed, the reduction of the scaffold
without N-Boc indole protection furnished the thermodynamically more stable trans-isomer, as
observed with the conversion of 5m into trans-12 in 74% yield (98% ee, cis/trans = 1:5)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Scheme 9A, Entry 1).
A.
Entry T (ºC) cis/trans
HN
1
2
3
4
5
0
-20
-40
-60
-60 to 0
1:5
1:5
3:5
1:1
1:5
NaBH(OAc)
AcOH
HN
3 HN
+
CH Cl
T
2,
N
2
N
N
PMP
PMP
PMP
74%
EtO C
EtO C
EtO C
2
2
2
5m
cis-12
trans-12, 98% ee
controlled epimerization
intermediate
H+
HN
HN
HN
-60 to 0°C
N
N
H
N
PMP
PMP
PMP
EtO C
EtO C
2
2
cis-12
trans-12
11 CO Et
2
B.
PMP
CO Et
2
NH
N
R
N
NaBH(OAc)3
AcOH
H+
PMP
R
CO Et
2
N
CO Et
NH
2
CH Cl 0°C
2 2,
R
PMP
HN
trans-10s: R = Ph
trans-10t: R= Br
5
s: R= Ph
cis-10s: R= Ph
cis-10t: R= Br
dr > 20:1
not observed
5
t: R= Br
Scheme 9. Controlled epimerization of cis-12 into trans-12 and stereoselective production of
trans-10s and trans-10t
We decided to examine this phenomenon in details and attempted to enhance the selectivity of
the reduction by decreasing the temperature. A series of experiments revealed that the
production of trans-12 results most probably from a controlled epimerization of cis-12. A
similar selectivity was indeed noted at ‒20°C (Entry 2), while at ‒40°C the selectivity ebbed
(dr = 3:5, Entry 3). When the reduction was performed at ‒60°C, an equal ratio of cis/trans-12
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was observed (Entry 4). Since low temperatures classically increase the selectivity of
nucleophile additions, the fact that the reverse is observed rather suggest that low temperature
slowed the cis→trans epimerization. When the mixture was brought from ‒60°C to 0°C (Entry
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
), the epimerization was activated and trans-12 was predominantly obtained (dr = 1:5).
Furthermore, the tetrahydropyridines 5s and 5t (Scheme 9B) were converted with full trans-
selectivity into 10s and 10t (dr > 20:1, 43-45% yield for 2 steps).34
With 3-carboxaldehyde-2-alkynylindole 3u, the cyclization followed a divergent pathway and
pyrrolidine 4u was instead observed (Scheme 10). In this case, we believe that the protonation
of the carboxaldehyde, and the subsequent electronic-depletion of the alkyne, facilitated the
aza-Michael addition.35
OH
OHC
CHO
CSA, rt
CO Et
NaBH(OAc)3
AcOH
N
Bn
N
HN
PMP
2
N
CO Et
2
N
N
Bn
Bn
PMP
PMP
3
u
4u (not isolated)
CO Me
12
-
H O
(
66%, 2 steps)
2
2
CO Me
2
Me
+
CO Et
N
2
CO Et
N
N
Bn
N
2
Bn
PMP
3, 14%
PMP
1
6u, 62% (2-step), 95% ee
Scheme 10. Reactivity of electron-poor alkynylindole
Direct exposure of 4u to NaBH(OAc) induced both the reduction of the enamine and the
3
carboxaldehyde into pyrrolidine 6u (62% yield, dr >20:1, 95% ee). Incidentally, we isolated
alongside an intriguing pyrrolidine carbazole 13 (14%). Noting that the reductive process
entailed the deoxygenation of the carboxaldehyde, we surmised that both products–6u and 13–
stem from the same precursor, i.e. the sensitive enamine alcohol 12. Upon dehydration and
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
formation of a stabilized cation, reduction of this intermediate would give 6u, while 6π
electrocyclization of a plausible methylene indolenine intermediate (not shown) followed by
air oxidation would explain the formation of 13.36
0
1
2
3
4
5
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7
8
9
0
1
2
3
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9
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9
0
1
2
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5
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9
0
1
2
3
4
5
6
7
8
9
0
So far, the hydroamination reaction had relied on anisidine (PMP) as nitrogen protecting group
and it was anticipated that the hydroamination would be less efficient with an oxazolidinone
due to the electronic delocalisation of the nitrogen. Still, the stabilization of the resulting
enamine was sought in view of facilitating future synthetic manipulations. Moreover, being
able to forge C-N bond from NH-oxazolidinone in acidic conditions would be rewarding as it
would broaden the scope of the method. To prepare the acyclic oxazolidinone substrate, a new
route was designed. In situ generated N-Cbz imine from 14, as described by Melchiorre, was
thus coupled with aldehyde 1v at 0°C (168 h) in presence of the Hayashi-Jørgensen catalyst 15
37
(
Scheme 11). The resulting aldehyde 3v was directly reduced into 16 in 61% yield (2-step)
and 93% ee. The two resulting hydroxyls of 16 were discriminated by treatment with tBuOK
which induced the formation of the oxazolidinone, then the remaining hydroxyl was acetylated
to give 17 in 45% yield (2-step). In the presence of TFA (20 equiv.), the alkyne 17 was cyclized
into 18 (70 % yield) in a sequence entailing the indole deprotection and the hydroamination
reaction. The N-alkylation of the oxazolidinone in acidic conditions with the vinyl cation,
probably stabilized as in III, is noteworthy. From a practical standpoint, compound 18
displayed better stability to air and moisture which should facilitate further derivatisations.
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9
OHC
CHO
CO Et
2
OH
15 (10 mol%)
K2HPO4
HN
Cbz
NHCbz
NaBH4
HN
Cbz
+
OH
N
TolO S
CO Et CHCl , 0°C
2
2
3
Boc
16, 61% yield,
(2-step), 93% ee
1
v
14
3v
N
N
Boc
Boc
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1. tBuOK
F3C
2
. Ac O
2
CF3
CF3
OAc
H
N
HN
O
N
Boc
O
TMSO
15
CF3
17, 45% yield (2-step)
AcO
HN
H
OAc
CF CO H
3
2
OAc
18, 70%
•
HN
N
N
Boc
O
CH2Cl2, 3 h, rt
O
HN
17
HN
O
O
O
O
III
Scheme 11. Acid-promoted hydroamination reaction of 3-alkynylindole with oxazolidinone
In summary, the regioselectivity of the hydroamination reaction of alkynylaryl amines in acidic
conditions was found to be dictated by the HOMO of the alkyne connected to the aryl group.
+
As detailed in Scheme 12, the H /π interactions with the HOMO of the alkyne is most likely at
the origin of the production of 5-membered rings as demonstrated with various alkynylaryl
amines (Scheme 2). It is assumed that the hydroamination occurred due to the lowering of the
38
LUMO of the alkyne. This selectivity was also observed by Cossy with the cyclization of
alkynylphenyl amines.19a,b
When the HOMO of the alkyne was very high, protonation occurred and the stabilized vinyl
cation reacted with the nitrogen to form 6-membered rings. To be synthetically useful, the
regioselectivity had to be high and the cyclization had to take place in mild conditions due to
the acid-sensitivity of the cyclized compounds. It was the case when very electron-rich arenes
were connected to the alkyne. Thus, di-, trialkoxyarenes and indoles connected to alkynes
efficiently steered the cyclization toward the production of 6-membered rings (Schemes 6, 8,
1
1).
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Ar
Ar = Ph, 2-, 3-alkoxy-, bromo-,
N
alkyl-, nitrobenzene
H
Ar
NH
protonation
Ar
Ar
Ar = 2,4-di-,2,4,6-trialkoxybenzene,
indoles
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
H-bonding
N
N
Scheme 12. Summary of the regioselectivity switch
C. Synthetic manipulations. To unveil an additional site of chemical diversity, the nitrogen
deprotection of 10m was attempted (Scheme 13).
CO Me
2
CO Me
2
CAN
MeCN/H O, 0°C
N
CO Et
2
N
CO Et
2
2
H
N
Boc
N
Boc
19, 70%, 99% ee
10m
OMe
Scheme 13. Nitrogen deprotection
It was unclear though, whether the oxidants employed for the removal of the PMP could be
compatible with indoles. As it happens, the formation of NH-piperidine 19, a derivative of
pipecolic acid, was achieved in good yield (70%) and with excellent enantiopurity (99% ee)
provided the indole was N-Boc protected.
The enamine functional group is a source of molecular diversity and, prior to exploiting their
nucleophilic characters, we demonstrated that isomerization of enamines 4c-g, prepared from
3
9
3c-g, by a simple exposure to basic conditions (DBU) gave pyrroles 20c-g (Scheme 14). In
view of the occurrence of N-aryl-pyrrole scaffold in medicinal chemistry, material sciences and
natural products, this short and efficient sequence (38-55 % yield over 2 steps) might also be
of value.
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CO Me
CO Me
2
2
Ar
Ar
PTSA
DBU
3
c-g
N
N
CO Et
CO Et
2
2
PMP
4c-g
not isolated
PMP
20c-g
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R
OMe
CO M
2
CO Me
CO2Me
2
Br
N
OMe
N
CO Me
2
N
CO2Et
CO Et
CO2Et
2
PMP
PMP
0c, R = H, 40% (2 steps)
0d, R = Me, 38% (2 steps)
N
PMP
CO Et
2
PMP
2
2
0f, 55% (2 steps)
20e, 45% (2 steps)
20g, 48% (2 steps)
2
Scheme 14. Organocatalytic access to pyrroles 20c-g
In a second stage, we sought to capitalize on the enamine nucleophilic character to build upon
functionalized scaffold such as 3-hydroxypiperidines, tetra- and pentasubstituted piperidines in
enantio- and stereoselective manners. To that end, the oxidation of enamine 5’m was initially
®
explored but, among the screened oxidants (mCPBA, oxone , PhNO, dilauroyl peroxide, air),
none succeeded in delivering hydroxy or keto derivatives. An indirect approach was therefore
devised in which 10m was first brominated (NBS/DBU) into bromo enamine 21 (Scheme 15).
Then, reduction gave bromo piperidine 22 in 94% yield (2-step) as a single all-cis-stereoisomer
(dr > 20:1, 2D NMR spectroscopy) and, upon exposure to AgOTf (1.5 equiv) and DMF/H O
2
(
15 equiv), compound 22 was converted into 3-hydroxypiperidine 23 with retention of
configuration which, as well as the piperidine structure, was ascertained by 2D NMR
spectroscopy. This retention can probably be explained, in view of literature precedents, by the
formation of aziridinium 22’ and the ring opening with an oxo-nucleophile.40
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1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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5
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5
5
5
5
5
6
H H
N
H
X
H
H
HO
H
Br
NOESY
CO Et
3
2
N
NaBH CN
AgOTf,
3
H
H
N
CO Et
2
2
CO Et
AcOH
2
DMF, H2O
PMP
PMP
N
Boc
N
Boc
PMP
N
Boc
22, 94% (2-step)
23, 82%
5
'm: X = H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NBS
DBU
21: X = Br
N
PMP
N
Boc
22'
Scheme 15. Diastereoselective functionalization of tetrahydropyridine 10m
This hypothesis was given credit when the same experiment was carried out in the absence of
DMF and H O, which was ascertained with 4 Å molecular sieves (Scheme 16A).
2
A. Ring contraction of 22
CO Et
MeO C
2
2
H CO Et
2
CO Me
2
H
N
Br
Friedel-Crafts
N
AgOTf, MS 4A
H
H
cyclization
N
CO Et
H
2
OMe
OMe
PMP
N
N
IV
22
N
24, 87%
Boc
Boc
Boc
NOESY
B. Ring contration of 23
CO Me
O
H
2
HO
IBX
DMSO
H
N
N
H
CO Me
PMP
2
N
CO Et
Boc
2
CO Et
2
PMP
N
23
25, 81%, 99% ee
Boc
Scheme 16. Ring contraction of piperidines 22 and 23
The reaction pathway was then nicely steered toward a ring-contracted pyrrolidine 24 isolated
in 87% yield and as a single stereoisomer (dr > 20:1, 2D NMR spectroscopy).41 This is
consistent with a scenario in which aziridinium 22’ would collapse into cation IV, followed by
C-C bond formation in a Friedel-Crafts reaction involving the PMP group.
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In the same vein, exposure of the α-amino alcohol 23 to IBX (2-iodoxybenzoic acid) triggered
the contraction of the piperidine ring into α-keto pyrrolidine 25 in 81% yield as a single
stereoisomer (dr > 20:1, 2D NMR spectroscopy) and 99% ee (Scheme 16B).42
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
To prevent the ring contraction of the piperidine, the protection of the nitrogen with an electron-
withdrawing group was considered. More challenging than anticipated, the removal of the PMP
from 26 with CAN caused the decomposition of the starting materials, probably due to the 3-
acetoxy substituent (Scheme 17). This problem was addressed by operating with
43
dimethylacetamide as an additive. Followed by N-acetylation, this procedure furnished the
elaborated 3-acetoxypiperidine 27 in a fair yield of 43% from 26. As an additional site of
diversity, the ketone moiety of the stable tetrasubstituted piperidine 28 was unveiled in 63%
yield in a 3-step sequence.
CO Me
2
CO Me
MeO C
2
2
1
. H2, Pd/C
AcO 3
AcO
O
CAN, DMA
2. K2CO3
N
CO Et
2
N
CO Et
2
3. IBX
N
CO2Et
then Ac O
2
PMP
N
Ac
Ac
N
N
Boc
Boc
Boc
28, 63% (3-step)
26
27, 43% (2-step)
Scheme 17. Preparation of 3-ketopiperidine (DMA: dimethylacetamide)
CONCLUSIONS
We show in this paper that the intramolecular hydroamination of alkynes connected to
aromatics by amino ester derivatives is an efficient process in acidic conditions. Our results
suggest that the subtle competition and transition between H-bonding and protonation of
alkynes can drive the reactivity. Whereas the first mode of activation induced the cyclization
of alkynes connected to aromatics into chiral trisubstituted pyrrolidines, alkyne protonation and
subsequent cyclization into 6-membered ring was noted upon heating with 2-alkoxybenzene
substituent. With very electron-rich alkynes such as those bearing 2,4-di-, 2,4,6-trialkoxyarenes
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2
2
2
2
2
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or indoles, this pattern became exclusive, even in mild conditions which is important in view
of the stability of the cyclized compounds. With the latter family of reagents, the cyclization
into pyrrolidine was observed only when the indole is electron-poor, as with 3u. Further
extending the range of possible application and disconnections, we demonstrated that cationic
species are generated from arylogous ynamines in acidic conditions and that they readily react
with NH-oxazolidinone. Regarding the preservation of the chiral information, demonstrations
were made that enantiopure amino esters and their derivatives can serve as unprecedented
partners in intramolecular hydroamination reactions of alkynylaryls and indoles in acidic
conditions. The production of highly functionalized pyrrolidines or piperidines in high enantio-
and stereoselectivity is thus noteworthy, whichever pattern was followed.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
An emphasis on the synthetic derivations of these new azaheterocycles is also disclosed, giving
a glimpse into the molecular space now within reach. Thus, the enantio- and stereoselective
preparation of elaborated piperidines 21-28 and ring-contracted pyrrolidines 24,25 was
demonstrated by derivatization of the tetrahydropyridine scaffold, relying on the electronic
donation properties of the indole. The present study provides a foretaste of the reactivity of
arylogous ynolethers and ynamines toward electrophiles for which the potential remains yet to
be delineated.
EXPERIMENTAL SECTION
1
13
General Information: The H NMR and C NMR (75 MHz) spectra were recorded on Bruker
1
13
Avance III (300 MHz, H; 75 MHz, C) spectrometer. Spectra were referenced to residual
1
3
1
chloroform (7.26 ppm, 1H; 77.00 ppm, C) and dimethyl sulfoxide (2.50 ppm, H; 39.51 ppm
1
3
13
C). Chemical shifts (δ) are reported in ppm. C NMR were recorded with proton broadband
13
1
decoupling ( C{ H} NMR). Low resolution mass spectra were recorded using electrospray
ESI) or chemical (CI) ionization techniques. High-resolution mass data were recorded on Q-
(
TOF instrument with an electrospray source in APCI, EI, or ESI mode. Visualization was
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accomplished with UV (254 nm), KMnO and 2,4-dinitrophenyl hydrazine (2,4-DNPH, 5 % in
4
HCl 2 M) staining solutions. All reactions requiring anhydrous conditions were performed in
oven (120°C) and/or heat gun dried glassware under an atmosphere of desiccated Argon.
Dichloromethane was passed through Pure-SolvTM 400 Solvent Purification System. AcOEt
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and MeNO were dried on molecular sieves (4Å) which were activated in a flask under high
2
vacuum and heating with heat gun (× 3). Catalyst 7, derived from (3S)-(+)-1-benzyl-3-
aminopyrrolidine [114715-38-7] available from TCI, and imine 2 were prepared according to
known procedures.20 Catalyst 15 was prepared according to known procedures.37a Unless
otherwise mentioned, flash column chromatography (fcc) was performed using silica gel
(Kieselgel 60, 40–63 μm, Merck). Optical rotations were measured on a Perkin–Elmer 241 LC
-1
2
-1
polarimeter in a 10 cm cell. [α]D Values are given in units of 10 deg.cm .g . The absolute
configuration of the Mannich adducts was deduced by analogy with the model presented in our
previous study. Analytical high performance liquid chromatographies (HPLC) were carried out
with a Waters instrument [detector M996 (200–400 nm) and pump 600] and the conditions are
indicated for each compounds. Unless otherwise indicated, enantiomeric excess (ee) were
1
determined by chiral HPLC and diastereoisomeric ratio (dr) were measured by H NMR
spectroscopy (300 MHz). The racemates were synthesized using rac-7 which was prepared
from rac-1-benzyl-3-aminopyrrolidine [18471-40-4] available from TCI. Aldehydes 1c,d,f are
4
2
known compounds and were prepared according to reported procedures. Fresh solution of
NaBH(OAc) in CH Cl was prepared as follow : AcOH (0.82 mL, 14.4 mmol, 30 equiv.) was
3
2
2
added dropwise to a solution of NaBH (144.1 mg, 2.4 mmol, 5 equiv.) in CH Cl (5 mL) at rt
4
2
2
over 10 min. The mixture was stirred for 30 min at rt and was used immediately.
Representative procedure A for preparation of 3c-u: To a cold solution (-40°C) of aldehyde
(1.45 g, 9.12 mmol, 1 equiv) and imine 2 (1.90 g, 9.12 mmol, 1 equiv) in DMF (30 mL) was
added the catalyst 7 (198 mg, 0.912 mmol, 0.1 equiv) in one portion. The mixture was stirred
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1
1
1
1
1
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
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4
4
4
4
4
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6
for 6 h (TLC monitoring). Then, the flask was removed from the cold bath and CH Cl (60 mL)
2
2
followed by ylide 8 (3.04 g, 9.12 mmol, 1.0 equiv) were sequentially added. After 1 h of reaction
at rt, H O was added and the contents were transferred into a decantation funnel to separate the
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
aqueous layer which was extracted with AcOEt (× 3). The combined organic layers were brined,
dried on MgSO , filtered and concentrated under reduced pressure by rotary evaporation. The
4
crude material (6.04 g) was purified by fcc (pentane/AcOEt: 1/2→1/3) on silica gel which was
washed with 1% Et N in AcOEt for alkynylaryl amines 3c-h.
3
(4R,5R,E)-6-Ethyl 1-methyl 5-((4-methoxyphenyl)amino)-4-(3-phenylprop-2-yn-1-yl)hex-
2
-enedioate 3c: Obtained as yellow oil in 69 % yield and > 98 % ee (see the representative
1
procedure A). H NMR (300 MHz, CDCl ) δ 1.25 (t, J = 7.3 Hz, 3H), 2.64 (dd, J = 5.9, 16.7
3
Hz, 1H), 2.86 (dd, J = 8.4, 16.7 Hz, 1H), 3.10 (m, 1H), 3.74 (s, 3H), 3.76 (s, 3H), 3.90 (d, J =
9
.4 Hz, 1H), 4.19 (m, 2H), 4.38 (dd, J = 4.1, 9.4 Hz, 1H), 5.97 (dd, J = 0.8, 15.7 Hz, 1H), 6.76
1
3
1
(
m, 4H), 6.92 (dd, J = 8.7, 15.7 Hz, 1H), 7.31 (m, 3H), 7.42 (m, 2H); C{ H} NMR (75 MHz,
CDCl ) δ 172.7, 166.2, 153. 3, 145.7, 141.3, 131.6 (2C), 128.4 (2C), 128.1, 123.9, 123.3, 116.4
3
(2C), 114.8 (2C), 86.6, 83.3, 61.6, 60.9, 55.7, 51.8, 44.6, 21.6, 14.3; IR (neat): 3363, 2951,
-1
®
1
723, 1368, 3363, 2952, 1236, 1511 cm ; HPLC: Daicel Chiralpak IA (80% n-heptane, 20%
iPrOH), 20°C, 1 mL/min, t = 7.0 min (major), t = 9.6 min (minor); HRMS (TOF MS ES+)
1
2
+
20
calculated for (M+H) C H NO : 422.1967, found: 422.1972; [α] +7.22 (c 1.8, CHCl ); R
f
2
5
28
5
D
3
=
0.5 (pentane /AcOEt: 4/1).
(4R,5R,E)-6-Ethyl 1-methyl 5-((4-methoxyphenyl)amino)-4-(3-(p-tolyl)prop-2-yn-1-
yl)hex-2-enedioate 3d: Prepared according to the general procedure A from 1d (270 mg, 1,57
1
mmol) as yellow oil in 40 % yield (275 mg), 96% ee. H NMR (300 MHz, CDCl ) δ 1.25 (t, J
3
=
7.1 Hz, 3H), 2.35 (s, 3H), 2.62 (dd, J = 5.8, 16.7 Hz, 1H), 2.85 (dd, J = 8.3, 16.7 Hz, 1H),
3
1
.08 (m, 1H), 3.73 (s, 3H), 3.75 (s, 3H), 4.18 (m, 2H), 4.38 (d, J = 3.8 Hz, 1H), 5.97 (d, J =
5.7 Hz, 1H), 6.76 (s, 4H), 6.91 (dd, J = 8.7, 15.7 Hz, 1H), 7.12 (d, J = 7.9 Hz, 2H), 7.32 (d, J
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1
=
7.9 Hz, 2H); C{ H} NMR (75 MHz, CDCl ) δ 172.6, 166.1, 153.2, 145.6, 141.2, 138.0,
3
1
31.4 (2C), 129.0 (2C), 123.7, 120.1, 116.3 (2C), 114.7 (2C), 85.7, 83.3, 61.4, 60.8, 55.5, 51.6,
44.7, 21.5, 21.3, 14.2; IR (neat): 3365, 2951, 1724, 1510, 1436, 1236, 1179, 1035, 909, 817,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
®
7
29 cm ; HPLC: Daicel Chiralpak IC (90% n-heptane, 10% iPrOH), 20°C, 1 mL/ min, 243
nm, t = 21.89 min. (major), t = 30.71 min. (minor); HRMS (TOF MS ES+) calculated for
1
2
+
(
M+H) C H NO : 436.2124, found : 436.2121; R = 0.23 (cyclohexane/AcOEt: 4/1).
26 30 5 f
(4R,5R,E)-6-Ethyl 1-methyl 5-((4-methoxyphenyl)amino)-4-(3-(2-methoxyphenyl)prop-2-
yn-1-yl)hex-2-enedioate 3e: Prepared according to the general procedure A from 1e (100 mg,
1
0
,52 mmol) as yellow oil in 69 % yield (190 mg) and > 98 % ee. H NMR (300 MHz, CDCl )
3
δ 1.17 (t, J = 7.3 Hz, 3H), 2.67 (dd, J = 5.4, 16.7 Hz, 1H), 2.92 (dd, J = 8.6, 16.7 Hz, 1H), 3.10
(m, 1H), 3.73 (s, 3H), 3.75 (s, 3H), 3.87 (m, 4H), 4.11 (m, 2H), 4.41 (dd, J = 4.1, 10.2 Hz, 1H),
5
.90 (d, J = 15.5 Hz, 1H), 6.70 (m, 4H), 6.84 (m, 3H), 7.21 (t,, J = 8.6 Hz, 1H), 7.31 (dd, J =
1
3
1
1
.6, 7.5 Hz, 1H); C{ H} NMR (75 MHz, CDCl ) δ 172.8, 166.2, 160.2, 153.2, 145.8, 141.4,
3
133.4, 129.4, 123.8, 120.4, 116.5 (2C), 114.8 (2C), 112.5, 110.5, 90.8, 79.6, 61.5, 60.8, 55.7
2C), 51.7, 44.9, 21.9, 14.3; IR (neat): 3366, 2951, 2836, 1723, 1511, 1236, 1024, 823, 752
(
-1
®
cm ; HPLC: Daicel Chiralpak IA (80% n-heptane, 20% iPrOH), 20°C, 245 nm, 1 mL/min, t
1
+
= 8.14 min (major), t =13.0 min. (minor); HRMS (TOF MS ES+) calculated for (M+H)
2
20
C H NO : 452.2073, found: 452.2075; [α] +14.3 (c 1.00, CHCl ); R = 0.3 (pentane/AcOEt:
2
6
30
6
D
3
f
4
/1).
(
4R,5R,E)-6-Ethyl 1-methyl 5-((4-methoxyphenyl)amino)-4-(3-(3-methoxyphenyl)prop-2-
yn-1-yl)hex-2-enedioate 3f: Prepared according to the general procedure A from 1f (50 mg,
1
0
1
.26 mmol) as yellow oil in 41 % yield (56 mg) and 93 % ee. H NMR (300 MHz, CDCl ) δ
3
.16 (t, J = 7.1 Hz, 3H), 2.55 (dd, J = 5.9, 16.6 Hz, 1H), 2.77 (dd, J = 8.3, 16.6 Hz, 1H), 3.01
(
m, 1H), 3.64 (s, 3H), 3.66 (s, 3H), 3.71 (s, 3H), 3.82 (br s, 1H), 4.10 (m, 2H), 4.29 (d, J = 3.7
Hz, 1H), 5.89 (d, J = 15.7 Hz, 1H), 6.67 (s, 4H), 6.77–6.83 (m, 2H), 6.86 (br s, 1H), 6.93 (d,
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
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5
5
5
5
5
6
13
1
1
1
H, J = 7.7 Hz), 7.14 (dd, J = 7.7, 15.7 Hz, 1H); C{ H} NMR (75 MHz, CDCl ) δ 172.5,
3
66.1, 159.2, 153.2, 145.6, 141.1, 129.3, 124.2, 124.1, 123.8, 116.5, 116.3 (2C), 114.7, 114.5
(2C), 86.4, 83.2, 61.5, 60.8, 55.6, 55.1, 51.6, 44.6, 21.5, 14.2; IR (neat): 3362, 2952, 2825,
0
1
2
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9
0
1
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9
0
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8
9
0
1
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7
8
9
0
1
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4
5
6
7
8
9
0
-1
®
1
719, 1512, 1287, 1239, 1163, 1034, 822, 688 cm ; HPLC: Daicel Chiralpak IA (95% n-
heptane, 5% iPrOH), 20°C, 1 mL/ min, 247.7 nm, t = 28.8 min. (major), t = 42.5 min (minor);
1
2
+
HRMS (TOF MS ES+) calculated for (M+H) C H NO : 452.2073, found: 452.2071; R =
26 30
6
f
0.19 (cyclohexane/AcOEt: 5/1).
(4R,5R,E)-6-Ethyl
1-methyl
4-(3-(2-bromophenyl)prop-2-yn-1-yl)-5-((4-
methoxyphenyl)amino)hex-2-enedioate 3g: Prepared according to the general procedure A
1
from 1g (250 mg, 1.059 mmol) as orange oil in 61 % yield (265 mg) and > 98 % ee. H NMR
(300 MHz, CDCl ) δ 1.18 (t, J = 6.8 Hz, 3H), 2.62 (dd, J = 5.5, 17.4 Hz, 1H), 2.85 (dd, J = 8.3,
3
1
1
7.4 Hz, 1H), 3.07 (m, 1H), 3.66 (s, 3H), 3.68 (s, 3H), 3.81 (br s, 1H), 4.12 (m, 2H), 4.40 (m,
H), 5.92 (d, J = 15.8 Hz, 1H), 6.69 (m, 4H), 6.87 (dd, J = 8.8, 15.8 Hz, 1H), 7.08 (m, 1H),
1
3
1
7.20 (m, 1H), 7.37 (dd, J = 1.6, 7.7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H); C{ H} NMR (75 MHz,
CDCl ) δ 172.7, 166.2, 153.2, 145.5, 141.2, 133.4, 132.4, 129.2, 127.0, 125.5, 125.4, 124.1,
3
1
16.5 (2C), 114.8 (2C), 91.6, 81.9, 61.6, 60.8, 55.7, 51.7, 44.8, 21.8, 14.3; IR (neat): 3362,
-1
®
2927, 1721, 1512, 1467, 1433, 1239, 1178, 1027, 984, 822, 751 cm ; HPLC: Daicel Chiralpak
IA (80% n-heptane, 20% iPrOH), 20°C, 1 mL/min, 245 nm, t = 7.6 min. (major), t = 11.8 min.
1
2
+
79
(
minor); HRMS (TOF MS ES+) calculated for (M+H) C H NO Br: 500.1073, found:
25 27 5
5
00.1072; [α]20 +11.9 (c 1.45, MeOH); R = 0.5 (pentane/AcOEt: 3/1).
D f
(4R,5R,E)-6-Ethyl 1-methyl 5-((4-methoxyphenyl)amino)-4-(3-(2-nitrophenyl)prop-2-yn-
1
0
1
-yl)hex-2-enedioate 3h: Prepared according to the general procedure A from 1h (110 mg,
1
,54 mmol) as red oil in 67 % yield (180 mg) and > 99 % ee. H NMR (300 MHz, CDCl ) δ
3
.19 (t, J = 7.1 Hz, 3H), 2.68 (dd, J = 6.1, 17.2 Hz, 1H), 2.85 (dd, J = 8.2, 17.2 Hz, 1H), 3.07
(
m, 1H), 3.66 (s, 3H), 3.69 (s, 3H), 3.80 (br s, 1H), 4.12 (m, 2H), 4.34 (m, 1H), 5.92 (d, J =
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5.9 Hz, 1H), 6.68 (m, 4H), 6.84 (dd, J = 8.9, 15.9 Hz, 1H), 7.37 (m, 1H), 7.50 (m, 2H), 7.94
1
3
1
(d, J = 8.1 Hz, 1H); C{ H} NMR (75 MHz, CDCl ) δ 172.5, 166.2, 153.3, 150.0, 145.2, 141.1,
3
134.9, 132.8, 128.5, 124.6, 124.2, 118.5, 116.3 (2C), 114.8 (2C), 95.2, 78.5, 61.6, 60.7, 55.7,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
7
1.8, 44.5, 22.0, 14.3; IR (neat): 336, 2952, 2227, 1721, 1511, 1437, 1343, 1238, 1180, 1032,
-1
®
29 cm ; HPLC: Daicel Chiralpak IA (80% n-heptane, 20% iPrOH), 20°C, 1 mL/min, 210
+
nm, t = 13.6 min (major), t = 23.2 min. (minor); HRMS (TOF MS ES+) calculated for (M+H)
1
2
2
0
C H N O : 467.1818, found: 467.1798; [α] ‒9.0 (c 1.14, CHCl ); R = 0.5 (pentane/AcOEt:
2
5
27
2
7
D
3
f
2
/1).
(4R,5R,E)-6-Ethyl
1-methyl
4-(3-(2,4-dimethoxyphenyl)prop-2-yn-1-yl)-5-((4-
methoxyphenyl)amino)hex-2-enedioate 3j: Prepared according to the general procedure A
from 1j (75.1 mg, 0.344 mmol), purified by fcc (PhMe/AcOEt: 20/1→10/1) and isolated in
1
5
7
9% yield (98.5 mg, 0.205 mmol) and 93% ee as yellow oil. H NMR (300 MHz, CDCl ) δ
3
.30 (d, J = 9.0 Hz, 1H), 6.92 (dd, J = 15.7, 8.7 Hz, 1H), 6.83–6.71 (m, 4H), 6.48–6.40 (m, 2H),
5.96 (dd, J = 15.7, 0.9 Hz, 1H), 4.47 (d, J = 3.8 Hz, 1H), 4.25–4.10 (m, 2H), 3.91 (br s, 1H),
.84 (s, 3H), 3.81 (s, 3H), 3.75 (s, 3H), 3.73 (s, 3H), 3.17–3.04 (m, 1H), 2.89 (dd, J = 16.7, 8.6
3
1
3
1
Hz, 1H), 2.65 (dd, J = 16.7, 5.6 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H); C{ H} NMR (75 MHz,
CDCl ) δ 173.0, 166.4, 161.5, 161.0, 153.4, 146.1, 141.6, 134.2, 123.9, 116.6, 114.9, 105.2,
3
1
2
9
04.8, 98.6, 89.2, 79.6, 61.6, 61.0, 55.8, 55.8, 55.6, 51.8, 45.1, 22.1, 14.4; IR (neat): 3356, 2949,
839, 1722, 1606, 1507, 1463, 1438, 1417, 1300, 1277, 1238, 1208, 1160, 1130, 1113, 1029,
-1
®
84, 933, 823, 734, 637, 606, 484 cm ; HPLC: Daicel Chiralpak IA (70% n-heptane, 30%
iPrOH), 20°C, 1 mL/min, 254 nm, t = 9.5 min (major), t = 13.8 min (minor); HRMS (TOF
1
2
+
20
MS ESI+) calculated for (M+H) C H NO : 482.2179, found: 482.2184; [α] +8.8 (c 0.80,
2
7
32
7
D
CHCl ); R = 0.26 (PhMe/AcOEt: 10/1).
3
f
(4R,5R,E)-6-Ethyl
1-methyl
5-((4-methoxyphenyl)amino)-4-(3-(2,4,6-
trimethoxyphenyl)prop-2-yn-1-yl)hex-2-enedioate 3k: Prepared according to the general
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1
1
1
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1
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1
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1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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6
procedure A from 1k (248.3 mg, 1.0 mmol), purified by fcc (pentane/AcOEt: 4/1→3/1) and
1
isolated in 71% yield (365.6 mg, 0.71 mmol) and 94% ee as yellow oil. H NMR (300 MHz,
CDCl ) δ 6.94 (dd, J = 15.7, 8.7 Hz, 1H), 6.83–6.70 (m, 4H), 6.11 (s, 2H), 5.96 (dd, J = 15.7,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
3
1
.9 Hz, 1H), 4.58 (d, J = 3.9 Hz, 1H), 4.24–4.11 (m, 2H), 3.93 (br s, 1H), 3.84 –3.82 (m, 9H),
.74 (s, 3H), 3.72 (s, 3H), 3.17 –3.08 (m, 1H), 2.94 (dd, J = 16.7, 8.9 Hz, 1H), 2.69 (dd, J =
1
3
1
6.7, 5.3 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H); C{ H} NMR (75 MHz, CDCl ) δ 173.1, 166.4,
3
162.5, 161.3, 153.2, 146.2, 141.7, 123.8, 116.6, 114.8, 94.6, 93.5, 90.5, 75.8, 61.5, 60.9, 56.0,
5
1
5.8, 55.5, 51.7, 45.2, 22.5, 14.4; IR (neat): 3365, 2939, 2839, 1722, 1658, 1602, 1579, 1511,
-1
462, 1437, 1415, 1339, 1227, 1204, 1156, 1125, 1031, 947, 814, 736, 636, 471 cm ; HPLC:
®
Daicel Chiralpak IA (50% n-heptane, 50% iPrOH), 20°C, 1 mL/min, 220 nm, t = 8.8 min
1
+
(
major), t = 13.5 min (minor); HRMS (TOF MS ES+) calculated for (M+H) C H NO :
2
28 34
8
5
12.2284, found: 512.2275; [α]20 +15 (c 1.00, CHCl ); R = 0.15 (PE/AcOEt: 3/1).
D
3
f
rac-6-Ethyl
1-methyl
(E)-4-(3-(4-acetoxy-2-methoxyphenyl)prop-2-yn-1-yl)-5-((4-
methoxyphenyl)amino)hex-2-enedioate 3l: Prepared according to the general procedure A
from 1l (108.8 mg, 0.44 mmol), purified by fcc (PhMe/AcOEt: 10/1→cyclohexane/AcOEt:
1
4
/1→3/1) and isolated in 47% yield (105.3 mg, 0. 21 mmol) as yellow oil. H NMR (300 MHz,
CDCl ) δ 7.39–7.33 (m, 1H), 6.92 (dd, J = 15.7, 8.7 Hz, 1H), 6.81–6.71 (m, 4H), 6.69–6.62 (m,
3
2
3
1
H), 5.96 (dd, J = 15.7, 0.9 Hz, 1H), 4.45 (d, J = 4.2 Hz, 1H), 4.25–4.11 (m, 2H), 3.84 (s, 3H),
.75 (s, 3H), 3.73 (s, 3H), 3.17–3.04 (m, 1H), 2.89 (dd, J = 16.8, 8.6 Hz, 1H), 2.65 (dd, J =
1
3
1
6.8, 5.7 Hz, 1H), 2.30 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); C{ H} NMR (75 MHz, CDCl ) δ
3
172.9, 169.3, 166.3, 161.1, 153.4, 151.5, 145.8, 141.4, 133.8, 124.0, 116.6, 114.9, 113.6, 110.4,
1
2
05.0, 90.9, 79.0, 61.6, 60.9, 56.0, 55.8, 51.8, 45.0, 22.0, 21.3, 14.4; IR (neat): 3372, 3954,
-1
910, 2844, 1728, 1602, 1512, 1369, 1276, 1203, 1153, 1031, 824 cm ; HRMS (TOF MS ESI+)
+
calculated for (M+H) C H NO : 510.2128, found: 510.2122; R = 0.11 (cyclohexane/AcOEt:
2
8
32
8
f
3
/1).
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(
E)-6-Ethyl
1-methyl
4-(3-(1H-indol-3-yl)prop-2-yn-1-yl)-5-((4-
methoxyphenyl)amino)hex-2-enedioate 3m: Prepared according to the general procedure A
from 1m (360.0 mg, 1.82 mmol), purified by fcc (PE/AcOEt: 3/1) and isolated in 66% yield
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(552.2 mg, 1.20 mmol) and 98% ee as yellow oil. H NMR (300 MHz, CDCl ) δ 8.75 (br s,
3
1
6
H), 7.76 (dd, J = 6.4, 2.3 Hz, 1H), 7.35–7.14 (m, 4H), 7.04 (dd, J = 15.7, 8.7 Hz, 1H), 6.88–
.71 (m, 4H), 6.07 (d, J = 15.7 Hz, 1H), 4.53 (br s, 1H), 4.29–4.08 (m, 2H), 4.02 (br s, 1H),
3.78 (s, 3H), 3.73 (s, 3H), 3.25–3.10 (m, 1H), 2.97 (dd, J = 16.7, 8.3 Hz, 1H), 2.76 (dd, J =
13
1
1
1
6.7, 5.8 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H); C{ H} NMR (75 MHz, CDCl ) δ 172.9, 166.4,
3
53.2, 146.1, 141.3, 135.2, 128.6, 127.9, 123.8, 122.8, 120.4, 119.7, 116.4, 114.9, 111.5, 98.2,
87.5, 76.8, 61.5, 60.8, 55.6, 51.7, 45.0, 22.0, 14.2; IR (neat): 3286, 2929, 1723, 1660, 1511,
-1
®
1
436, 1387, 1238, 1180, 1093, 1032, 823, 745, 660, 513, 426 cm ; HPLC: Daicel Chiralpak
IA (60% n-heptane, 40% iPrOH), 20°C, 1 mL/min, 254 nm, t = 6.1 min (major), t = 9.1 min
1
2
+
(minor); HRMS (TOF MS ESI+) calculated for (M+H) C H N O : 461.2076, found:
2
7
29
2
5
4
61.2066; [α]20 +2.4 (c 1.01, CHCl ); R = 0.32 (PE/AcOEt: 2/1).
D 3 f
(3R,4S)-4-(3-(1H-indol-3-yl)prop-2-yn-1-yl)-3-((4-methoxyphenyl)amino)dihydrofuran-
2
(3H)-one 3n: A mixture of aldehyde 1m (295.6 mg, 1.5 mmol) and imine 2 (326.4 mg, 1.58
mmol, 1.05 equiv) was dissolved in DMF (4.5 mL). The solution was cooled to -40 °C and
catalyst 7 (32.7 mg, 0.15 mmol, 0.1 equiv.) was added in one portion. The reaction mixture was
stirred at -40 °C for 7 h, and it was diluted with CH Cl (9.0 mL) before introduction of NaBH
2
2
4
(56.7 mg, 1.5 mmol, 1.5 equiv.). The contents were stirred at -40 °C for 2 h before introduction
of H O. The aqueous layer was separated and extracted with AcOEt (× 3). The combined
2
organic layers were brined, dried over MgSO , filtered, and concentrated under reduced
4
pressure by rotary evaporation. This crude material was dissolved in PhMe (30 mL) and 2-
hydroxypyridine (171.2 mg, 1.8 mmol, 1.2 equiv.) was added. The solution was stirred at 120°C
for 5 h in oil bath, brought to rt and concentrated under reduced pressure. The residue was
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5
6
purified by fcc (pentane/AcOEt: 2/1→PhMe/AcOEt: 6/1) to isolate 3n in 59% yield (321.2 mg,
1
0
.891 mmol) as brown solid. Mp = 175-176 °C (PhMe/AcOEt); H NMR (300 MHz, CDCl ) δ
3
8.17 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.39–7.32 (m, 2H), 7.26–7.15 (m, 2H), 6.83 (d, J = 8.9
Hz, 2H), 6.66 (d, J = 8.9 Hz, 2H), 4.70 (d, J = 9.7 Hz, 1H), 4.53 (dd, J = 9.7, 5.4 Hz, 1H), 4.24
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(dd, J = 7.3, 2.8 Hz, 1H), 4.17 (s, 1H), 3.77 (s, 3H), 3.23–3.11 (m, 1H), 2.67 (dd, J = 17.1, 4.1
1
3
1
Hz, 1H), 2.45 (dd, J = 17.2, 9.3 Hz, 1H); C{ H} NMR (75 MHz, CDCl ) δ 175.8, 153.3,
3
140.8, 135.2, 129.2, 128.6, 127.9, 123.2, 120.8, 120.0, 115.3, 114.5, 111.5, 98.6, 87.2, 70.0,
5
1
6.8, 55.9, 39.9, 18.5; IR (neat): 3351, 3215, 2956, 2910, 2839, 2223, 1767, 1511, 1386, 1242,
-1
183, 1157, 1216, 1110, 1032, 994, 820, 764, 752, 601, 527, 424 cm ; HRMS (TOF MS ES+)
+
20
calculated for (M+H) C H N O : 361.1552, found: 361.1551; [α] –191 (c 0.10, MeOH);
2
2
21
2
3
D
Rf = 0.23 (pentane/AcOEt: 2/1).
(E)-6-Ethyl
1-methyl
4-(3-(5-methoxy-1H-indol-3-yl)prop-2-yn-1-yl)-5-((4-
methoxyphenyl)amino)hex-2-enedioate 3o: Prepared according to the general procedure A
from 1o (298.5 mg, 1.31 mmol), purified by fcc (pentane/AcOEt: 2/1) and isolated in 52% yield
1
(
332.1 mg, 0.68 mmol) as yellow oil. H NMR (300 MHz, CDCl ) δ 8.43 (br s, 1H), 7.31 (d, J
3
=
2.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 15.7, 8.7 Hz,
1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 6.82–6.71 (m, 4H), 6.03 (dd, J = 15.7, 0.9 Hz, 1H), 4.48 (br
s, 1H), 4.27–4.12 (m, 2H), 4.02–3.91 (m, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.72 (s, 3H), 3.22–
4
.07 (m, 1H), 2.96 (dd, J = 16.7, 8.2 Hz, 1H), 2.74 (dd, J = 16.7, 5.9 Hz, 1H), 1.25 (t, J = 7.1
1
3
1
Hz, 3H); C{ H} NMR (75 MHz, CDCl ) δ 172.9, 166.4, 155.0, 153.3, 146.2, 141.4, 130.3,
3
129.3, 128.4, 123.8, 116.5, 115.0, 113.5, 112.3, 101.3, 98.3, 87.7, 76.84, 61.6, 61.0, 55.8, 55.7,
5
1.8, 45.1, 22.1, 14.3; IR (neat): 3364, 2946, 1721, 1653, 1511, 1485, 1438, 1237, 1211, 1176,
-1
+
1
096, 1027, 911, 820, 800, 730, 520 cm ; HRMS (TOF MS ESI+) calculated for (M+H)
2
0
C H N O : 491.2182, found: 491.2173; [α]
–3.2 (c 1.10, CHCl ); R = 0.25
2
8
31
2
6
D
3
f
(pentane/AcOEt: 2/1).
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(
E)-6-Ethyl
1-methyl
4-(3-(5-bromo-1H-indol-3-yl)prop-2-yn-1-yl)-5-((4-
methoxyphenyl)amino)hex-2-enedioate 3p: Prepared according to the general procedure A
from 1p (414.2 mg, 1.50 mmol), purified by fcc (pentane/AcOEt: 2/1) and isolated in 58% yield
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(470.7 mg, 0.87 mmol) as yellow oil. H NMR (300 MHz, CDCl ) δ 8.58 (br s, 1H), 7.85 (d, J
3
=
1.9 Hz, 1H), 7.33–7.27 (m, 2H), 7.22–7.17 (m, 1H), 6.98 (dd, J = 15.7, 8.7 Hz, 1H), 6.77 (s,
H), 6.03 (dd, J = 15.7, 1.0 Hz, 1H), 4.43 (br s, 1H), 4.28–4.13 (m, 2H), 3.91 (br s, 1H), 3.78
(s, 3H), 3.74 (s, 3H), 3.20–3.06 (m, 1H), 2.93 (dd, J = 16.8, 8.2 Hz, 1H), 2.71 (dd, J = 16.8, 5.8
4
13
1
Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H); C{ H} NMR (75 MHz, CDCl ) δ 173.0, 166.5, 153.4, 146.0,
3
1
41.3, 133.9, 130.4, 128.8, 126.0, 124.0, 122.5, 116.5, 115.0, 114.1, 113.0, 98.4, 88.2, 76.0,
61.7, 61.0, 55.8, 51.9, 45.1, 22.1, 14.4; IR (neat): 3351, 2956, 2832, 1719, 1658, 1510, 1457,
-1
1
276, 1235, 1179, 1138, 1099, 1031, 886, 822, 796, 730, 611, 544, 513, 421 cm ; HRMS (TOF
+
79
20
MS ESI+) calculated for (M+H) C H N O Br: 539.1182, found: 539.1168; [α] +3.3 (c
2
7
28
2
5
D
0.10, CHCl ); R = 0.17 (pentane/AcOEt: 2/1).
3
f
(E)-6-Ethyl
1-methyl
4-(3-(5-cyano-1H-indol-3-yl)prop-2-yn-1-yl)-5-((4-
methoxyphenyl)amino)hex-2-enedioate 3q: Prepared according to the general procedure A
from 1q (420.5 mg, 1.89 mmol), purified by fcc (pentane/AcOEt: 3/2) and isolated in 65% yield
1
(595.5 mg, 1. 23 mmol) as yellow oil. H NMR (300 MHz, CDCl ) δ 9.15 (br s, 1H), 8.03 (s,
3
1
0
–
H), 7.45–7.37 (m, 3H), 6.99 (dd, J = 15.7, 8.7 Hz, 1H), 6.82–6.69 (m, 4H), 6.05 (dd, J = 15.7,
.9 Hz, 1H), 4.43 (br s, 1H), 4.29–4.13 (m, 2H), 3.94 (br s, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.21
3.06 (m, 1H), 2.93 (dd, J = 16.8, 7.8 Hz, 1H), 2.73 (dd, J = 16.8, 6.2 Hz, 1H), 1.26 (t, J = 7.1
1
3
1
Hz, 3H); C{ H} NMR (75 MHz, CDCl ) δ 172.8, 166.5, 153.4, 145.9, 141.2, 137.0, 129.8,
3
1
5
28.6, 125.8, 125.5, 124.1, 120.5, 116.4, 115.0, 112.7, 103.6, 99.6, 89.1, 75.2, 61.8, 61.0, 55.8,
2.0, 44.9, 22.0, 14.4; IR (neat): 3342, 2951, 2834, 2222, 1720, 1657, 1618, 1471, 1511, 1435,
-1
1366, 1289, 1238, 1180, 1099, 1030, 983, 912, 819, 729, 639, 498, 417 cm ; HRMS (TOF MS
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