Studies of the new reactivity of chiral acrylamides and unprotected pyrroles: Diastereoselective and carbonyl compatible 1,4-addition

Article abstract of DOI:10.1055/s-0033-1341275

A diversity of new functionalized cyclic and acyclic chiral pyrroloamides compounds were synthesized in good yields and diastereoselectivities in the case of cyclic pyrroloamides. This simple and robust process involves the creation of a C-C bond between unprotected pyrroles and cyclic or hindered chiral acrylamides. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341275

LETTER
▌1555
lSettteur dies of the New Reactivity of Chiral Acrylamides and Unprotected Pyrroles:
Diastereoselective and Carbonyl Compatible 1,4-Addition
Synthesis of New Functionalized Cyclic and Acyclic Chiral Pyrroloamides
Alexandre Gratais, Xavier Pannecoucke, Samir Bouzbouz*
Laboratoire de Chimie Organique, CNRS, INSA, Université de Rouen, COBRA UMR 6014, 76183 Mont Saint Aignan Cedex, France
E-mail: samir.bouzbouz@univ-rouen.fr
Received: 05.03.2014; Accepted after revision: 31.03.2014
biologically active compounds,4 asymmetric FC alkyl-
Abstract: A diversity of new functionalized cyclic and acyclic chi-
ations of unprotected pyrroles are less explored and have
ral pyrroloamides compounds were synthesized in good yields and
been rarely reported.5
diastereoselectivities in the case of cyclic pyrroloamides. This sim-
ple and robust process involves the creation of a C–C bond between
unprotected pyrroles and cyclic or hindered chiral acrylamides.
As preliminary results toward the development of new
peptidomimetic systems deriving from pyrroles, we here-
in report the first study on the reactivity and the diastereo-
selectivity of acyclic and cyclic chiral acrylamides with
Key words: acrylamides, Lewis acid, Friedel–Crafts reaction, pyr-
role, lactams, peptides
unprotected pyrroles under Lewis acid activation
(Scheme 1).
As the challenge was the reactivity of the polyfunctional-
One of the challenging goals of synthetic chemistry is the
development of new reactions and strategies that allow
easy conversion of simple functionalized compounds into
complex molecules. The ‘ideal synthesis’ of these func-
tionalized compounds requires the development of simple
reactions from commercially available and inexpensive
starting materials. The development of the Friedel–Crafts1
(FC) reaction was a great progress in the chemistry of nat-
ural product synthesis and facilitated the discovery of new
molecules. In our ongoing program on the reactivity of
chiral acrylamides and the use of nonprotected pyrroles as
new scaffolds in peptidomimetic chemistry, we were in-
terested in the FC reaction. From the literature, different
asymmetric and catalytic versions of FC alkylations have
been developed.2 In most cases, N-substituted pyrroles
serve as nucleophiles with simple electrophilic partners
such as acrylates, α,β- unsaturated ketones, acrolein, or an
acryloxazolidinone.3 However, despite their prevalence in
ized chiral acrylamides, the methodological study was
conducted with substituted pyrroles, which have the ben-
efit to be more nucleophilic, and this avoids polysubstitu-
tions. Concerning the FC alkylation of pyrroles, the exact
nature and role of the activator were not clear at the begin-
ning of this study. So, first of all, various Lewis acids6
were screened in the FC reaction of kryptopyrrole 1a and
chiral acrylamide 2 (Table 1).
Table 1 Screening of Lewis Acids for the Reaction between 1a and
Acrylamide 2
Et
H
Et
N
H
H
H
1a
N
CO2Me
Ph
N
CO2Me
Ph
N
Lewis acid,
CH2Cl2, 25 °C
H
O
O
2
3
O
R
R6
Entry
Lewis acid
Lewis acid loading Time
(equiv)
Yield
(%)
R5
N
R2
H
R4
O
1
2
Cu(OTf)
Cu(OTf)2
TESOTf
BF3·OEt2
BCl3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.1
0.1
76 h
76 h
4 h
NR
NR
75
43
35
53
49
75
80
72
70
NH
O
R
R6
R5
R1
R2
R1
R3
or
N
1,4-addition
H
R4
3
O
+
R3
Lewis acid
activation
R1
H
N
or
H
R2
4
24 h
2 h
O
n
R3
N
5
N
H
O
O
R
6
InCl3
6 h
N
acyclic and cylic
chiral acrylamides
7
SnCl4
24 h
40 min
2 min
6 h
O
R
8
TiCl4
Scheme 1 Pyrrole-based peptidomimetics
9
AlCl3
SYNLETT 2014, 25, 1555–1560
Advanced online publication: 13.05.2014
DOI: 10.1055/s-0033-1341275; Art ID: st-2014-d0198-l
© Georg Thieme Verlag Stuttgart · New York
10
11
AlCl3
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
TESOTf
4 h

1556
A. Gratais et al.
LETTER
A subsequent solvent screening revealed that CH2Cl2 was acid (80%, Table 1, entry 9) in only two minutes reaction
the solvent of choice with regard to stability and reactivity time. The catalytic version of this reaction was possible
of the intermediates. Only toluene gave similar results, but with longer reaction time using AlCl3 (72%, Table 1, en-
for practical reasons in the following experiments CH2Cl2 try 10) or TESOTf (70%, Table 1, entry 11). As a short re-
was used.
action time is important to avoid the formation of by-
products, a stoichiometric amount of AlCl3 was chosen
for further works.
To optimize the reaction conditions, various Lewis acids
were screened in CH2Cl2 at room temperature. For the FC
reaction of 1a with 2, copper salts did not afford any prod- In order to extend the scope of the reaction to other pyr-
uct even after three days (Table 1, entries 1 and 2). How- roles having the C-2 position substituted, 2,4-dimethyl-
ever, all the other tested Lewis acids gave the desired pyrrole 1b and 2-ethylpyrrole 1c were engaged using the
product 3 in moderate to very good yield (Table 1, entries best Lewis acid, AlCl3. The desired products were ob-
3–9). The best result was obtained with AlCl3 as a Lewis tained in short reaction times (1–2 h) from acrylamide 2
Table 2 Addition of Pyrrole 1a to Substituted Acrylamides
Et
H
N
H
1a
Et
R1
R1
H
R2
N
CO2Me
Ph
H
N
CO2Me
Ph
N
AlCl3, CH2Cl2
25 °C
R3
O
H
R2 R3
O
6 R1 = Me, R2 = R3 = H
7 R1 =H, R2 = Me, R3 = H
8 R1 = H, R2 = Ph, R3 = H
9 R1 = H, R2 = R3 = Me
11 R1 = Me, R2 = R3 = H
12 R1 = H, R2 = Me, R3 = H
13 R1 = H, R2 = Ph, R3 = H
14 R1 = H, R2 = R3 = Me
10 R1 = H, R2 = CF3, R3 = Me
15 R1 = H, R2 = CF3, R3 = Me
Entry
Acrylamide
Time
1 h
Product
Yield (%)
Et
H
N
CO2Me
Ph
N
H
O
1
6
69
11 (dr = 1:1)
Et
H
N
CO2Me
Ph
N
H
O
2
3
4
5
7
8
6 h
80
65
67
61
12 (dr =1:1)
Et
H
N
CO2Me
Ph
N
H
4 h
Ph
O
13 (dr = 1:1)
Et
H
N
CO2Me
Ph
N
H
9
48 h
76 h
O
14
Et
H
N
CO2Me
Ph
N
H
10
CF3
O
15 (dr = 3.5:1)
Synlett 2014, 25, 1555–1560
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of New Functionalized Cyclic and Acyclic Chiral Pyrroloamides
1557
R2
In the first experiment, we tried the γ-lactam derived from
phenylalanine 16,11 and we were pleased to obtain the de-
sired product 23 with 85% yield and a very promising
4.5:1 diastereomeric ratio (Table 3, entry 1). To see the in-
fluence of the side chain of the amino acid on the diaste-
reoselectivity, a solution of 1a and AlCl3 was reacted with
compounds 17–22,12 leading quickly to the corresponding
products 24–29 with high diastereoselectivities (dr from
3.5:1 to 16:1) and yields (65–71%). The best results were
obtained for the valine- and methionine-derived γ-lactams
(Table 3, entries 2 and 7). Some amino ester derivatives
were slower to react (Table 3, entries 4 and 6). The reac-
tion can also be performed in a catalytic manner. Howev-
er, in this case a lower conversion (50%) and longer
reaction times (24 h) were observed, leading to lower
yields. Moreover, this catalytic version did not affect the
diastereomeric ratio.
R1
H
R2
N
H
1b, 1c
H
N
CO2Me
H
N
CO2Me
Ph
R1
N
AlCl3, CH2Cl2
25 °C, 1–2 h
O
H
Ph
O
2
4 R1 = Me, R2 = Me 77%
5 R1 = Et, R2 = H 72%
Scheme 2 Addition of pyrroles 1b and 1c to the acrylamide 2
giving adducts 4 (77%) and 5 (72%; Scheme 2), respec-
tively.
In the following study, for reactivity reasons pyrrole
1awas used; it is classified as a strong nucleophile in com-
parison with other pyrroles according to the empirical and
experimental scale established in the literature.7
To extend this study, we also tried the addition of pyrrole
1a to two six-membered ring systems. Despite the chiral
4-substituted piperidinones being the key intermediates
for the synthesis of many therapeutic products,13 exam-
ples in the literature of the addition of aromatic ring sys-
tems to α,β-unsaturated δ-lactams are rare.14 The
treatment of the two acrylamides 30 and 31 with a solution
of 1a and AlCl3 quickly led to the corresponding products
32 (60%, dr = 3:1) and 33 (81%, dr = 4:1). The obtained
yields were satisfactory, and the diastereoselectivities re-
mained correct, even if lower than those with γ-lactams
considering the distant 1,5-control (Scheme 3).
We then decided to study the behavior of substituted part-
ners in this reaction, especially the diastereoselectivity
and the influence of the steric hindrance of acrylamides.
Different substituted acrylamides (6–10) were subjected
to the addition of pyrrole 1a and the results are reported in
Table 2.
Desired products were obtained with longer reaction
times with metacrylamide 6, crotonamide 7 and cinnam-
amide 8, giving the adducts 11 (69%, Table 2, entry 1), 12
(80%, Table 2, entry 2), and 13 (65%, Table 2, entry 3). In
all cases, no diastereoselectivity was observed. The reac-
tivity of the gem-disubstituted acrylamide 9 with pyrrole
1a gave product 14 with a good yield (67%, Table 2, entry
4); however, due to steric hindrance a longer reaction time
was required for completion of the reaction. Similarly, the
reaction of pyrrole 1a with 3-(trifluoromethyl)croton-
amide 10 gave pyrroloamide 15 in 61% yield (Table 2, en-
try 5). In this particular case, three days of reaction did not
allow the total conversion of starting material into the cor-
responding adduct, but we were pleased to observe a dia-
stereomeric ratio of 3.5:1. Only few references
concerning 1,4-addition on 4,4-disubstituted α,β-unsatu-
rated amides are mentioned in the literature.8 Moreover
product 15 is one of the few examples of FC reaction cre-
ating trifluoromethylated all-carbon quaternary stereo-
centers.9
In order to assess the compatibility of our method with
peptidomimetic chemistry, pyrrole 1a was added to di-,
tri-, and tetrapeptidic acrylamides 34–3615 (Scheme 4).
The reaction times for the three peptides were very short
despite the constraints of structure that may exist in par-
Table 3 Addition of Pyrrole 1a to Various Chiral α,β-Unsaturated
γ-Lactams
Et
Et
H
N
N
H
H
O
O
1a
N
N
OMe
OMe
AlCl3, CH2Cl2
25 °C
O
R
O
R
16–22
23–29
As previously shown (Table 2, entries 1–3), no diastereo-
selectivity was obtained when adding pyrroles to acryl-
amides 6, 7 and 8. But what would be the
diastereoselectivity of pyrrole addition in the case of rigid
system such as chiral α,β-unsaturated γ-lactam? To an-
swer to this question, pyrrole 1a was added under our
classical conditions to various α,β-unsaturated γ-lactams
derived from amino acids. Indeed, chiral γ-lactams have
attracted considerable attention due to their presence in a
large variety of biologically active compounds,10,11 but a
highly diastereoselective, straightforward, and economic
method is still of great interest.
Entry Lactam (R)
Time
Adduct Yield dr
1
2
3
4
5
6
7
16 (Bn)
3 h
23
24
25
26
27
28
29
85
68
61
63
65
57
65
4.5:1
>16:1
>8:1
5.5:1
3.5:1
>8:1
16:1
17 (i-Pr)
18 (i-Bu)
1 h
3 h
19 [CH2(3-indolyl)]
20 (CH2CO2Me)
21 (CH2OTBDPS)
22 (CH2CH2SMe)
16 h
4 h
24 h
3 h
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1555–1560

1558
A. Gratais et al.
LETTER
This result shows that the addition is compatible with
complex peptidic systems, and the presence of other am-
ides does not inhibit the reactivity of pyrrole 1a, which
opens the possibility of synthesizing more complex sys-
tems in a single reaction (Scheme 1).
Et
Et
H
N
H
1a
N
O
O
H
N
N
OMe
OMe
AlCl3, CH2Cl2
25 °C
1
As we were pleased to observe intermediate A by H
O
R
O
R
NMR(see experimental section), we can propose a proba-
ble reaction mechanism (Scheme 6).
30 R = Bn
31 R = (CH2)2SMe
32 R = Bn, 60%, dr = 3:1
33 R = (CH2)2SMe, 81%, dr = 4:1
Scheme 3 Addition of pyrrole 1a to chiral α,β-unsaturated piperidi- After activation of pyrrole 1a with AlCl3, intermediate A
is generated, containing a highly acidic sp3 carbon. The re-
nones
action of the acrylamide is probably due to the activation
of the carbonyl group of this compound by the AlCl3–
ticular in the case of the tetrapeptidic acrylamide 34. The
1,4-addition products 37–39 could be obtained in good
yield (60–85%).
pyrrole complex producing intermediate B. Next, an intra-
molecular 1,4-addition of the pyrrole group onto the acti-
vated Michael acceptor intermediate takes place to
produce C which after an 1,3-prototropy leads to D and
after hydrolysis to product 3.
This reactivity was extended to the cyclic dipeptidic sys-
tem. Treatment of compound 40 with a solution of 1 and
AlCl3 gave the product 41 with a 72% yield and a good
diastereomeric ratio of 7:1 (Scheme 5).
In summary, the present work demonstrates the efficiency
of the Friedel–Crafts reaction between unprotected pyr-
roles and chiral acrylamides. This reaction was performed
Et
Et
H
O
H
N
H
O
H
N
N
OMe
OMe
1a
N
H
N
H
N
H
O
O
O
AlCl3, CH2Cl2, 25 °C
68%
O
Ph
Ph
37
34
Et
Et
O
H
N
O
H
N
H
N
O
O
H
H
N
H
N
N
OMe
1a
H
N
H
OMe
N
H
O
O
O
AlCl3, CH2Cl2, 25 °C
85%
Ph
Ph
O
O
Ph
Ph
35
38
Et
Et
Ph
O
Ph
O
Ph
O
Ph
O
O
H
N
O
O
H
H
H
N
H
N
H
N
OMe
N
OMe
N
H
N
H
1a
N
H
N
H
N
H
O
O
AlCl3, CH2Cl2, 25 °C
60%
Ph
Ph
39
36
Scheme 4 Addition of pyrrole 1a to peptidic acrylamides
Et
Et
H
N
H
1a
N
H
O
O
N
N
OMe
OMe
AlCl3, CH2Cl2
25 °C
N
N
H
H
O
O
O
O
Ph
Ph
41
72%, dr = 7:1
40
Scheme 5 Addition of pyrrole 1a to chiral dipeptidic α,β-unsaturated γ-lactams
Synlett 2014, 25, 1555–1560
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of New Functionalized Cyclic and Acyclic Chiral Pyrroloamides
1559
R
O
R2
CO2Me
R1
NH
R2
R2
R1
R1
2
H
AlCl3
R = Bn
R1
Cl
Cl
H
N
Al–
+
R1
R1
N
CH2Cl2
N
H
R
– HCl
H
+
–AlCl3
O
1a
CO2Me
N
R1 = Me, R2 = Et
A
H
B
R2
R2
R1
R1
R2
R1
H
H2O
+
N
Al–
R1
Cl
Cl
R1
Cl
Cl
N
Al–
R1
N
H
R
R
+
R
O
O
••
O
N
CO2Me
CO2Me
N
H
N
CO2Me
H
H
D
C
3
R = Bn
Scheme 6 Proposed addition mechanism of pyrrole 1a to acrylamide
(3) (a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jørgensen,
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in short reaction times, with good yields, and the additions
were even highly diastereoselective in the case of amino
acid derived cyclic systems. Substituted or cyclic acryl-
amides can be used and a wide range of side chains were
investigated. This method demonstrates that despite the
presence of other carbonyls in the polypeptidic systems,
these do not have a negative effect on the interaction be-
tween acrylamide and the Lewis acid. Further develop-
ment of this methodology and its application to natural
products and peptidomimetic synthesis are in progress in
our laboratory and will be reported in due course.
Acknowledgment
This work has been partially supported by CNRS, région Haute
Normandie, European Fund for Regional Development (35476) and
Labex SynOrg (ANR-11-LABX-0029).
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
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(12) Compounds 14–20 were synthesized by Ring-Closing
Metathesis at room temperature (Scheme 7). The role of
allyltrimethylsilane is to activate the catalytic cycle. These
results will be published in the future: Gratais A., Bouzbouz
S. unpublished work.
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(15) Compounds 32–34 were synthesized by classical peptidic
coupling sequence from Boc-Leu-OH or Boc-Phe-OH.
O
Hoveyda–Grubbs
2
nd generation
O
N
N
SiMe3
R
CO2Me
R
CO2Me
CH2Cl2, 25 °C
Scheme 7
Synlett 2014, 25, 1555–1560
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