Dehydrogenative Allylic Aminations of But-3-enoic Acid Derivatives

Article abstract of DOI:10.1055/s-0035-1562453

Two complementary Pd-catalyzed protocols enabling the γ-selective intermolecular allylic amination of but-3-enoic acid derivatives are reported. These transformations can be successfully achieved via either a direct Pd(II)-catalyzed protocol or by way of a one-pot Pd(II)/Pd(0)-catalyzed sequence, depending on the nature of the nitrogen nucleophile used.

Full text of DOI:10.1055/s-0035-1562453

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–M
A
paper
Synthesis
D. Diamante et al.
Paper
Dehydrogenative Allylic Aminations of But-3-enoic Acid Derivatives
Daria Diamantea,1
Direct Pd(II) cat. amination
"
N"H =
Sara Gabrielia,1
Tiziana Benincorib
Gianluigi Broggini*b
Julie Oble*a
Pd(OAc)2 cat., DIPEA
BQ, "N"H
O
O
Ts
N
R'
(R' = OMe, Me)
"
N"
Y
H
Y = NHR, OMe, Ph
1 examples (10–95%)
O
BQ = benzoquinone
2
O
S
O
Giovanni Poli*a
Y
O
S
O
O
t-Bu
N
OMe
N
H
H
H
a
Sorbonne Université s, UPMC Univ Paris 06, Institut Parisien
a. Pd(OAc)2 cat., BQ
LiOH.H O, PivOH
2
O
N
Y = NHR, OMe, Ph
de Chimie Moléculaire, UMR CNRS 8232, Case 229, 4 Place
Jussieu, 75252 Paris Cedex 05, France
julie.oble@upmc.fr
O
NHR
b. (+)-BINAP cat.,
DIPEA, phthalimide
giovanni.poli@upmc.fr
Dipartimento di Scienza e Alta Tecnologia, Università degli
O
b
7
examples (20–90%)
Studi dell’Insubria, via Valleggio 11, 22100 Como, Italy
gianluigi.broggini@uninsubria.it
Sequential Pd(II) cat./Pd(0) cat. amination
In memory of Professor Jean Normant: a great chemist, an
extraordinary man.
Received: 25.05.2016
Accepted after revision: 10.06.2016
Published online: 22.07.2016
lylic amination reactions on simple alpha-olefins have al-
ready been reported, several challenging variations are
6,7
DOI: 10.1055/s-0035-1562453; Art ID: ss-2016-c0379-op
still awaiting implementation. In particular, the direct in-
termolecular oxidative allylic amination8 of but-3-enoic
acid (B3A) derivatives is a thus far unknown synthetic
transformation, the development of which would be desir-
Abstract Two complementary Pd-catalyzed protocols enabling the γ-
selective intermolecular allylic amination of but-3-enoic acid derivatives
are reported. These transformations can be successfully achieved via
either a direct Pd(II)-catalyzed protocol or by way of a one-pot
Pd(II)/Pd(0)-catalyzed sequence, depending on the nature of the nitro-
gen nucleophile used.
9
able. Indeed, this substrate appears to be ideally biased for
C–H activation, its allylic position being at the same time α
10,11
to a carboxyl function (Scheme 1).
Key words palladium, catalysis, C–H activation, allylic amination, al-
lylic acyloxylation, but-3-enoic acid derivatives
O
Y
B2A
O
O
HNR2
– HX – [Pd(0)]
O
R2N
I
Owing to the abundance of C–N bonds in a wide range
of natural substances, biological frameworks (e.g., amino
acids), as well as in polymers and pharmaceutical products,
several studies have been devoted to the development of ef-
Y
Y
Y
γ-AB2
and/or
O
[
Pd]X
II
H
I
Y
B3A
[Pd]X2 cat
NR2 α-AB3
[Ox], – HX
2
ficient and selective amination reactions. Traditional
R'CO2H
– HX,
IV
III
methods for C–N bond formation rely on the substitution
reaction of an organohalide (or pseudohalide) by a nitro-
gen-based nucleophile (Gabriel-type reaction) or reductive
–
[Pd(0)]
Pd(0) cat VIa
or
PdX2 cat
O
O
O
R'
2a
amination. While these methods are reliable and robust,
they require the pre-oxidation of the precursor in order to
install the appropriate leaving group or carbonyl moiety,
respectively. Thus, reactions that directly and selectively
convert a C–H bond into a C–N bond significantly simplify
synthetic sequences, avoiding the preparation and handling
of pre-oxidized materials.3 In this context, alpha-olefins
and their derivatives are ideal low-cost starting materials
for their catalytic functionalization to produce more com-
plex structures for fine chemistry purposes, such as allyl
PdX O
V
and/
or
Y
VIb
Y
O
O
O
O
O
Y
R' IIγ
R' IIα
III
Scheme 1 Possible synthetic routes to allylic amination of but-3-enoic
acid derivatives
In particular, we reasoned that allylic C–H activation of
a generic B3A derivative to give the corresponding η -allyl-
palladium complex I (step I) could be more easily reached
from a B3A derivative than from the isomeric but-2-enyl
3
4
5
amines. Although some Pd-catalyzed dehydrogenative al-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

B
Synthesis
D. Diamante et al.
Paper
B2A example for two reasons: (a) the former non-conjugat-
ed isomer is thermodynamically less stable and thus is ex-
pected to be more reactive than the latter, (b) Pd-catalyzed
allylic C–H activations on linear alkenes are almost exclu-
sively known on terminal alkenes. Subsequent direct in situ
Table 1 Optimization of the Pd(II)-Catalyzed Direct Amination
Pd(OAc)2 (10 mol%)
DIPEA (6 mol%)
O
Ts
N
O
Ts
Ph
+
CO2Me BQ (2 equiv)
O
N
N
H
N
Ph
H
solvent
reflux, time (h)
H
H
OMe
3
trapping of the η -allyl complex I with an appropriate ni-
1a
A
2a
12
trogen nucleophile may then afford the desired allylic am-
ination product (step II). Alternatively, analogous oxidative
conditions in the presence of an acyloxy donor ligand may
lead to α- and/or γ-allylic acylation products IIα and/or IIγ
via either trapping of I by the acyloxy ligand (step III) or
through an acyloxypalladation/dehydropalladation se-
Entry
Ligand
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
yesa
no
MTBE
MTBE
THF
72
72
72
18
24
24
72
75
53
66
50
95
yesa
no
13
quence (steps IV + V). Finally, these allylic esters may un-
dergo in situ conversion into α- and/or γ-amino but-2-eno-
ic (γ-AB2) derivatives via a redox neutral Pd(0)- or Pd(II)-
catalyzed allylic amination (step VI). Worthy of note, the
Pd-catalyzed direct allylic acyloxylation of but-3-enoates
THF
no
DMSO
MeCN
6c
no
a
2 2
Ligand: PhS(O)CH CH S(O)Ph (15 mol%).
Yield of isolated product.
Reaction conditions: 1a (1.0 equiv), TsNHCO Me (A) (2.0 equiv), Pd(OAc)
2 2
b
c
(
steps I + III), has been recently reported by the group of
10
(10 mol%), DIPEA (6 mol%), BQ (2 equiv) in MeCN (0.2 M).
Szabò using hypervalent iodine as the terminal oxidant.
Furthermore, a related strategy based on the one-pot, two-
step (Pd/Ir catalysis) conversion of terminal alkenes into
enantioenriched branched allylic amines through the inter-
mediacy of linear allylic benzoates was recently reported by
Hartwig and Sharma.14 However, this very elegant strategy
targets only branched allylic amines and does not address
B3A derivatives.
With optimum conditions in hand [Pd(OAc) (10 mol%),
2
DIPEA (6 mol%), BQ (2.0 equiv), MeCN, reflux], we explored
the scope of the Pd(II)-catalyzed amination with N-Ts-car-
bamate A (Scheme 2). The effect of the substitution on the
aryl ring of various N-benzyl-3-butenamides was investi-
gated first. Electron-donor groups at para positions (1b,c)
Following our continued interest in the synthesis of ni-
trogen-based scaffolds via Pd-catalyzed allylic amination,15
we describe herein the synthesis of γ-AB2 derivatives from
B3A derivatives via a direct oxidative path {I + II;
Pd(II)/[Ox]} as well as through a one-pot consecutive path {I
Pd(OAc)2 (10 mol%)
O
DIPEA (6 mol%)
BQ (2 equiv)
Ts
N
O
R
Ts
CO2Me
R
O
N
H
N
H
N
H
+
MeCN, reflux, 16–24 h
H
OMe
+
III; Pd(II)/[Ox] (→IIγ) + VIa; Pd(0)}. Optimizations, the
1b–i
A
2b–i
scope and limitations of these two complementary routes,
which depend on the nature of the nitrogen nucleophile
used, are reported.
Focusing first on the direct Pd(II)-catalyzed strategy, we
chose the reaction between B3A benzyl amide 1a and N-Ts-
carbamate A as our first model transformation to study. The
reaction conditions developed by White16 for an intermo-
lecular allylic amination using the same carbamate A as the
O
O
O
OMe
N
N
H
N
H
H
R'
R''
R' = Me, 2b 34%
R' = OMe, 2c 35%
2d 84%
R'' = NO2, 2e 10%
R'' = CF3, 2f 74%
O
O
O
O
N
H
nucleophile were first selected, namely Pd(OAc) (10 mol%),
N
H
N
H
2
PhS(O)CH CH S(O)Ph (15 mol%), DIPEA (6.0 mol%), and
2
2
2g 46%
2h 90%
2i 41%
benzoquinone (BQ) (2.0 equiv) (Table 1). The first experi-
ments, performed in MTBE at reflux for 72 hours, gave the
desired γ-AB2 amide 2a in similar yields, regardless of
whether the reaction was run with or without the disulfox-
ide ligand (Table 1, entries 1 and 2). Furthermore, no trace
of the α-AB3 isomer was detected. The use of THF as the
solvent, with (Table 1, entry 3) or without (Table 1, entry 4)
the disulfoxide ligand, or the use of DMSO (Table 1, entry 5)
did not improve the yield. Gratifyingly, the use of MeCN at
reflux temperature gave 2a in 95% yield in only 24 hours
O
O
Bn
OMe
N
N
No reaction with tertiary amides
H
H
Bn
Me
1k
1j
O
Ts
N
O
Ts
CO2Me
same conditions
O
N
H
Y
Y
+
MeCN, reflux, 24 h
H
OMe
Y = Ph (1l), OMe (1m)
A
2l 40%
m 93%
2
(
Table 1, entry 6).17
Scheme 2 Scope of the Pd(II)-catalyzed allylic amination with N-Ts-car-
bamate A
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

C
Synthesis
D. Diamante et al.
Paper
led to the corresponding γ-AB2 amides with moderate
yields (~35% yield), the disappointing yield being probably
due to the instability of the products in the oxidizing medi-
um. Nevertheless, a satisfactory 84% yield was obtained
with the meta-methoxy derivative (1d). Electron-with-
drawing para-substitution, such as nitro (1e) also gave the
desired γ-AB2 amide in low yield, due to difficulties in
product isolation, whereas a para-trifluoromethyl group
Indeed, the Pd(0)-catalyzed allylation of less acidic N–
H-based nucleophiles, such as N-phthalimide (pK = 8.3), is
a
well known.18 Nevertheless, merging these two Pd-cata-
lyzed protocols in a single synthetic operation is a decep-
tively simple task. First of all, we surmised that a buffered
medium for the acyloxylation step was mandatory to en-
sure the compatibility of the two protocols. Accordingly, we
adopted the conditions reported by Le Bras and co-workers,
(
1f) was well tolerated. N-Furfuryl (1g), N-phenyl (1h) and
who used the LiOH/RCO H couple for analogous dehydroge-
2
N-phenylethyl (1i) B3A secondary amides led to the expect-
ed γ-AB2 derivatives in moderate to good yields, while no
reaction occurred with B3A tertiary amides (1j and 1k). Fi-
nally, this protocol was not limited to amides. Indeed, a ke-
tone (1l) and an ester (1m) could also be aminated under
these conditions.
The behavior of other nitrogen nucleophiles was inves-
tigated next (Scheme 3). Accordingly, N-Ts-acetamide B,
which is electronically and sterically not too different from
A, reacted with 1a to give the corresponding γ-AB2 amide
native Pd(II)-catalyzed acyloxylations.19 Preliminary exper-
iments were first conducted on the model B3A amide 1a to
assess the influence of the nature and the amount of the
added carboxylic acid (see Supporting Information), the op-
timum choice being: pivalic acid (10.0 equiv), LiOH·H O (2.0
2
equiv), Pd(OAc)2 (10 mol%), BQ (2.0 equiv) and MeCN
(Scheme 4). This slightly modified Le Bras protocol turned
out to be effective for all secondary as well as tertiary B3A
amides 1a–k, and for the ester 1m, affording the corre-
sponding γ-oxylated but-2-enyl acid derivatives 6a–k,m (γ-
OB2A) in satisfactory yields (Scheme 4).20 However, ketone
1l gave a mixture of the expected 4-pivaloxy-1-phenylbut-
2-en-1-one (6la) and 3,4-dipivaloxy-1-phenylbutan-1-one
(6lb), this latter deriving from conjugate addition of a piva-
late anion onto the α,β-unsaturated ketone 6la.
We next focused our attention on the second step, i.e.,
the globally isohypsic21 Pd(0)-catalyzed amination using
phthalimide as the nucleophile. In order to ultimately
merge the two protocols into a single synthetic operation,
we decided to optimize this step in MeCN, and using
3
a in 61% yield. The acylated sultam, saccharin (C), gave the
desired γ-AB2 derivatives 4a–e. Similarly, the γ-AB2 amides
a–d could be isolated when using N-sulfinyl-carbamate D.
5
On the other hand, N-Ts-amine, phthalimide and camphor-
sultam did not react. These results suggest that the NH
acidity of the nucleophile is crucial for the coupling, the
ideal pK being in the range of 5–6.
a
We surmised that an alternative Pd-catalyzed sequence,
this time involving an initial oxidative allylic acyloxylation,
followed by an isohypsic amination (Scheme 1), {I + III;
Pd(II)/[Ox] (→IIγ) + VIa; Pd(0)} might overcome the draw-
backs associated with the former route.
Pd(OAc) as the catalyst. It is worth mentioning that Pd(0)-
2
Pd(OAc)2 (10 mol%)
DIPEA (6 mol%)
BQ (2 equiv)
O
O
C
Ts
N
O
Ts
O
NHBn
+
N
H
Me
NHBn
H
MeCN, reflux, 24 h
Me
O
1a
B
3a 61%
O
same conditions
as above
O
O
O
S
O
S
N
N
H
R
NH
MeCN,
reflux, 24–48 h
N
H
+
H
R
O
O
1a–e
4
4
4
a (R = H) 40%, 4b (R = 4-Me) 33%
c (R = 4-MeO) 57%, 4d (R = 3-MeO) 82%,
e (R = 4-O2N) 30%
C
O
S
OMe
O
O
O
same conditions
as above
O
S
O
N
N
+
t-Bu
N
H
OMe
NH
H
R
H
MeCN,
reflux, 30–48 h
R
t-Bu
1a–d
D
5
5
a (R = H) 47%, 5b (R = 4-Me) 27%
c (R = 4-MeO) 16%, 5d (R = 3-MeO) 50%
Scheme 3 Scope of the Pd(II)-catalyzed allylic amination of B3A amides 1a–e with N-Ts-amide B, saccharin (C) and N-sulfinyl-carbamate D
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

D
Synthesis
D. Diamante et al.
Paper
.
The role of the phosphine ligand was first examined in
1
. LiOH H2O (2 equiv)
PivOH (10 equiv)
. Pd(OAc)2 (10 mol%)
BQ (2 equiv)
the presence of Et N and phthalimide (1.5 equiv). While
3
2
O
O
monodentate PPh and bidentate DPPE brought about no
3
PivO
reaction (Table 2, entries 1 and 2), the use of other biden-
tate ligands such as DPPF, XANTPHOS and BINAP did afford
the desired γ-AB2A amide 7a, albeit in modest yields (Table
Y
Y
MeCN, 40 °C, 20–24 h
6
3
a–k,m
5–98%
1
1
a–k Y = NR'R''
Y = OMe
m
2
, entries 3–5). BINAP was thus selected as the most suit-
Scheme 4 Pd(II)-catalyzed allylic pivaloxylation. Reaction conditions:
pivalic acid (10.0 equiv), LiOH·H O (2.0 equiv), Pd(OAc) (10 mol%), BQ
2.0 equiv), 1 (1.0 equiv), MeCN (0.2 M).
able ligand for the subsequent tests. Increasing the reaction
time did not significantly improve the reaction yield (Table
2
2
(
2
, entry 6). Hünig’s base (DIPEA) was also able to promote
the amination, affording a slight increase of the yield (Table
, entry 7). Finally, the use of three equivalents of phthalim-
2
catalyzed allylations require the presence of a ligand (usu-
ally a phosphine) to prevent dimerization of the transient
η -allyl complex (and to bring about ionization in some in-
ide allowed us to obtain 7a in 83% yield (Table 2, entry 8).
With satisfactory protocols for both the separate steps
in hand, we next investigated merging the two protocols
into a single operation (Table 3). Allylic pivaloxylation was
carried out according to the conditions reported in Scheme
4, during 8 h. Then, DIPEA (11.5 equiv), phthalimide (3.0
equiv) and BINAP (20 mol%) were added to the reaction
mixture, and heating at reflux temperature was maintained
for an additional 18 hours. Treatment of B3A 1a according
to the above combined one-pot protocol gave γ-AB2 7a in
90% yield (Table 3, entry 1).
3
stances), and when a PdX precatalyst is used, to reduce it
2
to the competent Pd(0) catalyst. Furthermore, when the
3
counterion of the ensuing η -allyl complex is not basic
enough to carry out pronucleophile deprotonation, a base is
22
also needed. Accordingly, given the important amount of
pivalic acid needed in the first step, an excess of base (11.5
equiv) was planned for the one-pot protocol, so as to obtain
a buffered medium. Allylation of phthalimide with γ-OB2A
6
a was then considered, to investigate the influence of the
These new conditions were then tested on other B3A
amides. Substrates with electron-donating groups at para
positions of B3A N-benzyl amides 1b,c gave the desired γ-
AB2 products with moderate yields (Table 3, entries 2 and
nature of the ligand, of the base, as well as of the amount of
pronucleophile required. The results are presented in Table
2.
3), while a meta-methoxy group (1d) afforded the corre-
Table 2 Optimization of the Pd(0)-Catalyzed Amination of 6a with
sponding product in a more satisfactory 76% yield (Table 3,
entry 4). Reactions of N-furfuryl- (1g), N-phenyl- (1h) and
N-phenylethyl (1i) B3A amides led to the corresponding γ-
AB2 products in moderate to good yields (Table 3, entries
7–9). However, B3A N-benzyl amides with electron-with-
drawing para-substitution were not tolerated (Table 3, en-
tries 5 and 6), only pivaloxylated compounds being detect-
ed in these cases in the final crude mixtures. As previously
observed in the direct amination, no reaction occurred with
tertiary amide 1j. Furthermore, reaction of ester 1m also
met with failure, the second step once again being the halt-
ed stage (Table 3, entries 10 and 11).24
Phthalimide23
Pd(OAc)2 (10 mol%)
ligand (x mol%)
phthalimide (y equiv)
base (11.5 equiv)
O
O
PivO
PhthN
NHBn
MeCN, reflux, 24 h
NHBn
6a
7a
Entry
Ligand (x mol%)
Ph P (40)
PhthNH (y equiv) Base
Yield (%)a
1
2
3
4
5
6b
7
3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
Et
Et
Et
Et
Et
Et
3
3
3
3
3
3
N
N
N
N
N
N
SM
SM
28
25
30
34
40
83
DPPE (20)
Although at present only speculative, the results in Ta-
ble 3 can be accounted for on the basis of a hydrogen-bond
directed addition of phthalimide enolate at the distal allyl
DPPF (20)
XANTPHOS (20)
BINAP (20)
BINAP (20)
BINAP (20)
BINAP (20)
3
terminus of the transient η -allylpalladium complex (Figure
25
1). Such an H-bond, however, is disrupted if the amide
substituent is too electron-withdrawing, as in the case of
the γ-OB2A derivatives 1e and 1f (Table 3, entries 5 and 6).
This rationale would also justify the inertness of the tertia-
ry amide 1j and of the ester 1m, both of which lack the di-
recting N–H moiety.
DIPEA
8c
DIPEA
a
Yield of isolated product. SM = starting material.
Reaction time = 48 h.
Reaction conditions: 6a (1.0 equiv), phthalimide (3.0 equiv), Pd(OAc) (10
2
b
c
mol%), (+)-BINAP (20 mol%), DIPEA (11.5 equiv), MeCN (0.2 M).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

E
Synthesis
D. Diamante et al.
Paper
Table 3 Scope of the Sequential One-Pot Pd(II)/Pd(0)-Catalyzed Allylic
Amination with Phthalimide
Table 3 (continued)
a
Entry
Substrate
Product
Yield (%)b
.
a. LiOH H2O (2.0 equiv)
O
O
O
PivOH (10 equiv)
PhthN
11
OMe
7m
0c
Y
Y
b. Pd(OAc)2 (10 mol%)
BQ (2 equiv)
1
m
1
7
a
MeCN, 40 °C, 8 h
c. phthalimide (3.0 equiv)
DIPEA (11.5 equiv)
+)-BINAP (20 mol%)
0 °C, 18 h
Reaction conditions: (a) pivalic acid (10.0 equiv), LiOH·H
b) Pd(OAc) (10 mol%), BQ (2.0 equiv), 1 (1 equiv), MeCN (0.2 M); (c)
phthalimide (3.0 equiv), (+)-BINAP (20 mol%), DIPEA (11.5 equiv).
Yield of isolated product.
Only pivaloxylated compound 6 was detected at the end of the reaction.
Phthalimide (1.5 equiv) was used.
2
O (2.0 equiv);
(
2
b
(
7
c
d
Entry
1
Substrate
Product
Yield (%)b
90
O
N
H
7a
P
P
1
1
a
O
Pd
R
O
O
N
H
N
H
2
3
4
5
7b
7c
7d
7e
22
O
N
O
b
N
H
53
Figure 1 Working model for the Pd(0)-catalyzed addition of phthalim-
ide enolate to the η -allylpalladium moiety of the transient intermedi-
3
OMe
OMe
1
1
c
ate
O
O
N
H
76
In conclusion, two new complementary strategies for
Pd-catalyzed dehydrogenative aminations of B3A deriva-
tives have been developed. Depending on the type of nitro-
gen nucleophile, and more precisely on the acidity of the
N–H function in these nucleophiles, a direct Pd(II)-cata-
lyzed allylic amination, or a sequential one-pot [direct
Pd(II)-catalyzed pivaloxylation/Pd(0)-catalyzed amination]
procedure allowed the construction of different γ-AB2 de-
rivatives. Extension of this methodology to direct the reac-
tion toward the α-AB3 isomers as well as to obtain more
elaborated nitrogen-containing frameworks is currently
underway in our laboratories.
d
N
H
tracesc
NO2
CF3
1
e
O
N
H
0c
6
7f
1
1
1
1
f
O
O
O
7
8
9
N
H
7g
7h
7i
20
g
h
i
Unless otherwise mentioned, all reactions were carried out under an
argon atmosphere. Glassware was flame-dried under an argon gas
flow prior to use. Reactions were run in flasks or sealed tubes with
magnetic stirring. Reagents and solvents were purchased from com-
mercial sources and used as received. CH Cl , THF, MeCN and DMF
32d
N
H
2
2
were dried on an MB SPS-800 Mbraun purification system. Nucleo-
philes were synthesized according to literature procedures:
O
O
82
N
H
8d
26
27
TsNHCOOMe, TsNHCOMe, t-BuSONHCOOMe. TLC was performed
on Merck 60 F254 silica gel and revealed with either an ultraviolet
lamp (254 nm) or a specific color reagent (potassium permanganate,
p-anisaldehyde, etc.). Silica gel (Merck Geduran® SI 60, 40–63 mm)
was used for flash column chromatography. Preparative thin-layer
chromatography was realized with PLC silica gel 60 F254 (1 mm,
Bn
N
0c
10
7j
Bn
1
j
2
0 × 20 cm). Melting points were measured in capillary tubes on a
Stuart Scientific SMP3 apparatus and are uncorrected. IR spectra were
recorded on a Bruker Tensor 27 (ATR diamond) spectrophotometer
–1
1
13
and reported as characteristic bands (cm ). NMR spectra ( H, C)
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

F
Synthesis
D. Diamante et al.
Paper
1
were recorded on Bruker AM 300 MHz or Bruker AVANCE 400 MHz
spectrometers. NMR experiments were carried out in deuterochloro-
form (CDCl ) and deuterodimethyl sulfoxide (DMSO-d ). Chemical
H NMR (400 MHz, CDCl ): δ = 7.25–7.20 (m, 2 H), 6.91–6.87 (m, 2 H),
3
6.01–5.90 (m, 1 H), 5.81 (br s, 1 H), 5.26–5.21 (m, 2 H), 4.40 (d, J = 5.6
Hz, 2 H), 3.82 (s, 3 H), 3.06 (dt, J = 7.2, 1.3 Hz, 2 H).
3
6
shifts are given in parts per million (ppm), using the CDCl or DMSO-
13
3
C NMR (100 MHz, CDCl ): δ = 170.2, 159.1, 131.3, 130.2, 129.1,
3
d6 residual signal as reference. Coupling constants (J) are given in
hertz (Hz). High-resolution mass spectra (HRMS) were recorded at
the Institut Parisien de Chimie Moléculaire (FR 2769) (electrospray
source).
119.9, 114.1, 55.3, 43.2, 41.6.
+
HRMS (ESI): m/z [M + Na] calcd for C12H15NNaO : 228.0995; found:
2
228.0992.
N-(3-Methoxybenzyl)-3-butenamide (1d)
Allyl Amides 1a–j; General Procedure (GP1)
Following GP1 with 3-methoxybenzylamine (1.0 equiv, 0.47 mL, 3.6
mmol). The crude product was purified by flash chromatography on
silica gel (eluent: EtOAc/cyclohexane, 1:1) to afford 1d in 82% yield
To a stirred solution of the appropriate amine (1.0 or 2.0 equiv) in
CH Cl (0.2 M) at 0 °C were added DCC (1.3 equiv), DMAP (0.13 equiv)
2
2
and 3-butenoic acid (1.3 equiv). The reaction mixture was stirred for
0 min at 0 °C, then for 24 h at r.t. The precipitate was filtered off and
washed with CH Cl (25 mL). The organic layer was treated with sat.
(611 mg, 2.97 mmol).
1
Orange oil.
2
2
aq NaHCO3 solution, then the aqueous layer was extracted with
CH Cl . The organic layers were dried over MgSO and concentrated
under reduced pressure. The crude product was purified by silica gel
IR (ATR): 3180, 1575, 1541, 1320 cm–1
.
2
2
4
1
H NMR (400 MHz, CDCl ): δ = 7.28–7.23 (m, 1 H), 6.87–6.82 (m, 3 H),
3
6.01 (m, 1 H), 5.99–5.91 (m, 1 H), 5.26–5.21 (m, 2 H), 4.42 (d, J = 5.7
column chromatography to afford the corresponding allyl amide 1.
Hz, 2 H), 3.81 (s, 3 H), 3.06 (dt, J = 7.1, 1.3 Hz, 2 H).
13
C NMR (100 MHz, CDCl ): δ = 170.4, 159.8, 139.7, 131.3, 129.7,
3
N-Benzyl-3-butenamide (1a)
1
19.9, 119.8, 113.3, 112.9, 55.2, 43.6, 41.6.
Following GP1 with benzylamine (1.0 equiv, 1.02 mL, 9.3 mmol). The
crude product was purified by flash chromatography on silica gel
HRMS (ESI): m/z [M + Li]+ calcd for C12H15LiNO : 212.1258; found:
2
212.1264.
(eluent: EtOAc/cyclohexane, 1:1) to afford 1a in quantitative yield (1.9
g, 10.8 mmol).
N-(4-Nitrobenzyl)-3-butenamide (1e)
White solid.
Following GP1 with 4-nitrobenzylamine hydrochloride (1.0 equiv,
1
H NMR (300 MHz, CDCl ): δ = 7.40–7.29 (m, 5 H), 6.07–5.91 (m, 2 H),
3
3
00 mg, 1.6 mmol) and DMAP (1.2 equiv, 233 mg, 1.9 mmol). The
crude product was purified by flash chromatography on silica gel
eluent: EtOAc/cyclohexane, 1:1) to afford 1e in 60% yield (200 mg,
.91 mmol).
5.29–5.23 (m, 2 H), 4.48 (d, J = 5.7 Hz, 2 H), 3.09 (td, J = 1.3, 7.2 Hz, 2
H).
(
0
Spectroscopic data are in good agreement with those reported in the
28
literature.
White solid; mp 83–84 °C.
IR (ATR): 3229, 3055, 2926, 1638, 1601, 1545, 1509, 1345 cm–1
.
N-(4-Methylbenzyl)-3-butenamide (1b)
1
H NMR (400 MHz, CDCl ): δ = 8.23–8.19 (m, 2 H), 7.47–7.44 (m, 2 H),
Following GP1 with 4-methylbenzylamine (1 equiv, 500 mg, 4.1
mmol). The crude product was purified by flash chromatography on
silica gel (eluent: EtOAc/cyclohexane, 1:1) to afford 1b in 76% yield
3
6
.05 (br s, 1 H), 5.98 (tdd, J = 7.2, 10.2, 17.3 Hz, 1 H), 5.32–5.27 (m, 2
H), 4.57 (d, J = 6.1 Hz, 2 H), 3.13 (dt, J = 7.2, 1.2 Hz, 2 H).
13
(588 mg, 3.11 mmol).
C NMR (100 MHz, CDCl ): δ = 170.6, 145.7, 145.1, 130.9, 128.2,
3
123.9, 120.5, 42.8, 41.5.
White solid; mp 100–102 °C.
+
IR (ATR): 3291, 1626, 1532, 1412 cm–1
HRMS (ESI): m/z [M + Na] calcd for C11
H
12
N
2
NaO
3
: 243.0740; found:
.
243.0743.
1
H NMR (400 MHz, CDCl ): δ = 7.10–7.05 (m, 4 H), 5.86 (ddt, J = 16.7,
3
1
0.5, 7.2 Hz, 1 H), 5.77 (br s, 1 H), 5.17–5.11 (m, 2 H), 4.32 (d, J = 5.6
N-[4-(Trifluoromethyl)benzyl]but-3-enamide (1f)
Hz, 2 H), 2.97 (dt, J = 7.1, 1.3 Hz, 2 H), 2.26 (s, 3 H).
Following GP1 with 4-(trifluoromethyl)benzylamine (1.0 equiv, 500
mg, 5.81 mmol). The crude product was purified by flash chromatog-
raphy on silica gel (eluent: EtOAc/cyclohexane, 1:1) to afford 1f in 70%
yield (990 mg, 4.07 mmol).
1
3
C NMR (100 MHz, CDCl ): δ = 170.2, 137.3, 135.1, 131.3, 129.4,
3
1
27.1, 119.9, 43.4, 41.6, 21.1.
HRMS (ESI): m/z [M + Na]+ calcd for C12H15NNaO: 212.1046; found:
12.1046.
2
White solid; mp 118–120 °C.
IR (ATR): 3476, 1647, 1545, 1328, 1029 cm–1
.
N-(4-Methoxybenzyl)-3-butenamide (1c)
1
H NMR (400 MHz, CDCl ): δ = 7.60 (d, J = 7.9 Hz, 2 H), 7.39 (d, J = 8.0
Following GP1 with 4-methoxybenzylamine (1.0 equiv, 0.47 mL, 3.64
mmol). The crude product was purified by flash chromatography on
silica gel (eluent: EtOAc/cyclohexane, 1:1) to afford 1c in 96% yield
3
Hz, 2 H), 6.09 (br s, 1 H), 5.96 (ddt, J = 17.3, 10.3, 7.2 Hz, 1 H), 5.29–
5.23 (m, 2 H), 4.50 (d, J = 6.0 Hz, 2 H), 3.09 (dt, J = 7.1, 1.3 Hz, 1 H).
13
(715 mg, 3.5 mmol).
C NMR (100 MHz, CDCl ): δ = 170.6, 142.3, 129.8 (q, J = 33.3 Hz),
3
1
31.1, 127.8, 125.7, 124.2 (q, J = 270 Hz), 120.2, 43.0, 41.5.
White solid; mp 88–90 °C.
IR (ATR): 3285, 1636, 1548, 1511, 1300, 1173 cm–1
19F NMR (282 MHz, CDCl
): δ = –62.54.
.
3
+
HRMS (ESI): m/z [M + Na] calcd for C12H12F3NNaO: 266.0763; found:
266.0761.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

G
Synthesis
D. Diamante et al.
Paper
N-(2-Furanylmethyl)-3-butenamide (1g)
(30 mL) was stirred for 2 h at r.t. Then, at 0 °C, but-3-enoyl chloride (1
equiv, 648 mg, 6.2 mmol) [freshly prepared from SOCl2 (2.0 equiv)
and 3-butenoic acid (1.0 equiv), stirred for 4 h at 60 °C, carefully
evaporated and immediately used without purification] was added
dropwise. The mixture was stirred for 10 min at 0 °C, then at r.t. over-
night. The reaction was treated with HCl (1 M solution), then sat. aq
Following GP1 with furfurylamine (2.0 equiv, 1.03 mL, 11.6 mmol).
The crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/cyclohexane, 1:1) to afford 1g in 52% yield (490 mg,
2.97 mmol).
White solid.
NaHCO3 solution and H O were carefully added. The aqueous layer
2
1
H NMR (400 MHz, CDCl ): δ = 7.27 (q, J = 2.4 Hz, 1 H), 6.95 (br s, 1 H),
3
was extracted with CH Cl , then the organic layers were dried over
2
2
6.27–6.25 (m, 1 H), 6.14 (q, J = 3.2 Hz, 1 H), 5.95–5.74 (m, 1 H), 5.15–
MgSO and concentrated under reduced pressure. The crude product
4
5.09 (m, 2 H), 4.38–4.31 (m, 2 H), 2.96 (t, J = 5.4 Hz, 2 H).
was purified by silica gel column chromatography (eluent: EtOAc/cy-
clohexane, 6:4) to afford the amide 1k in 54% yield (430 mg, 3.33
mmol).
Spectroscopic data are in good agreement with those reported in the
29
literature.
Pale yellow oil.
N-Phenyl-3-butenamide (1h)
IR (ATR): 2969, 1664, 1381, 1176, 1002 cm–1
.
Following GP1 with aniline (2.0 equiv, 1.05 mL, 5.8 mmol). The crude
product was purified by flash chromatography on silica gel (eluent:
EtOAc/cyclohexane, 4:6) to afford 1h in 68% yield (630 mg, 3.9 mmol).
1
H NMR (400 MHz, CDCl ): δ = 6.02–5.92 (m, 1 H), 5.19–5.18 (m, 1 H),
.16–5.15 (m, 1 H), 3.69 (s, 3 H), 3.23 (d, J = 6.7 Hz, 2 H), 3.18 (s, 3 H).
3
5
13
C NMR (100 MHz, CDCl ): δ (major rotamer) = 172.4, 131.2, 118.1,
3
White solid.
6
1.3, 37.2, 25.2.
1
H NMR (300 MHz, CDCl ): δ = 7.56–7.53 (m, 3 H), 7.37–7.29 (m, 2 H),
HRMS (ESI): m/z [M + Na]+ calcd for C H NNaO : 152.0687; found:
1
3
6 11 2
7
(
.13 (t, J = 7.4 Hz, 1 H), 6.06 (tdd, J = 7.1, 10.8, 16.0 Hz, 1 H), 5.37–5.31
m, 2 H), 3.21 (td, J = 1.2, 7.0 Hz, 2 H).
Spectroscopic data are in good agreement with those reported in the
52.0682.
Phenyl Allyl Ketone (1l)
Under an air atm, to a solution of 1-phenylbut-3-en-1-ol (1.0 equiv,
00 mg, 2.02 mmol) in acetone (10 mL) at 20 °C was added a solution
30
literature.
3
N-Phenethyl-3-butenamide (1i)
of Jones reagent (1.5 mL) via a dropping funnel. After 10 min (a color
change from orange to blue), the reaction mixture was treated with
H O and extracted with Et O. The organic layer was treated with sat.
Following GP1 with phenylethylamine (2.0 equiv, 1.46 mL, 11.0
mmol). The crude product was purified by flash chromatography on
silica gel (eluent: EtOAc/cyclohexane, 1:1) to afford 1i in 40% yield
2
2
aq NaHCO solution, then the aqueous layer was extracted with Et O.
3
2
(424 mg, 2.24 mmol).
The organic layers were dried over MgSO and concentrated under re-
4
duced pressure. The crude product was purified by silica gel column
chromatography (eluent: EtOAc/cyclohexane, 1:1) to afford the ke-
tone 1l in 80% yield (235 mg, 1.61 mmol).
Pale yellow solid; mp 63–65 °C.
IR (ATR): 3264, 3078, 2930, 1633, 1552 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.35–7.17 (m, 5 H), 6.08 (br s, 1 H),
3
Colorless oil.
5.89 (tdd, J = 7.1, 10.3, 17.3 Hz, 1 H), 5.23–5.16 (m, 2 H), 3.50 (q, J = 6.7
1
H NMR (400 MHz, CDCl ): δ = 7.97 (d, J = 7.5 Hz, 2 H), 7.57 (t, J = 7.5
Hz, 2 H), 2.97 (td, J = 1.3, 7.1 Hz, 2 H), 2.83 (t, J = 7.1 Hz, 2 H).
3
Hz, 1 H), 7.47 (t, J = 7.5 Hz, 2 H), 6.09 (tdd, J = 6.8, 10.4, 17.3 Hz, 1 H),
13
C NMR (100 MHz, CDCl ): δ = 170.4, 138.8, 131.3, 128.7, 128.6,
3
5.18–5.27 (m, 2 H), 3.76 (td, J = 1.4, 8.2 Hz, 2 H).
126.5, 119.8, 41.7, 40.6, 35.6.
Spectroscopic data are in good agreement with those reported in the
HRMS (ESI): m/z [M + Na]+ calcd for C12H15NNaO: 212.1046; found:
12.1039.
31
literature.
2
Pd(II)-Catalyzed Direct Amination (2a–i,l,m, 3a, 4a–e and 5a–d);
General Procedure (GP2)
N,N-Dibenzyl-3-butenamide (1j)
Following GP1 with dibenzylamine (1.0 equiv, 0.31 mL, 1.6 mmol).
The crude product was purified by flash chromatography on silica gel
In a sealed tube, B3A derivative 1 (1 equiv) was dissolved in MeCN
(0.2 M), and subsequently Pd(OAc)2 (10 mol%), the nucleophile (2
(eluent: EtOAc/cyclohexane, 1:1) to afford 1j in 69% yield (290 mg, 1.1
equiv), DIPEA (6 mol%) and BQ (2 equiv) were added to the mixture.
The reaction mixture was stirred at reflux for 16–48 h and, after cool-
ing to r.t., was treated with sat. aq K CO solution and diluted with
mmol).
Yellow oil.
2
3
IR (ATR): 3027, 2919, 1646, 1418, 696 cm–1
.
Et
ers were dried over MgSO
The crude product was purified by silica gel column chromatography
eluent: EtOAc/cyclohexane) to afford the aminated compound 2, 3, 4
O. The aqueous layer was extracted with Et
O, then the organic lay-
2
2
1
4
and concentrated under reduced pressure.
H NMR (300 MHz, CDCl ): δ = 7.35–7.03 (m, 10 H), 5.96 (tdd, J = 6.6,
3
10.2, 16.9 Hz, 1 H), 5.13–4.97 (m, 2 H), 4.52 (s, 2 H), 4.36 (s, 2 H), 3.15
(
(dt, J = 6.6, 1.6 Hz, 2 H).
or 6 depending on the nucleophile used.
13
C NMR (100 MHz, CDCl ): δ = 171.5, 137.3, 136.4, 131.7, 129.0,
3
1
28.6, 128.4, 127.7, 127.5, 126.4, 117.9, 50.0, 48.2, 38.7.
HRMS (ESI): m/z [M + Na]+ calcd for C18H19NNaO: 288.1359; found:
88.1361.
Methyl (E)-[4-(Benzylamino)-4-oxobut-2-en-1-yl](tosyl)carba-
mate (2a)
2
Following GP2 with amide 1a (1.0 equiv, 100 mg, 0.57 mmol) and
methyl tosylcarbamate (A) (2.0 equiv, 260 mg, 1.13 mmol) for 24 h.
The crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/cyclohexane, 1:1) to afford 2a in 95% yield (219 mg,
0.54 mmol).
N-Methoxy-N-methylbut-3-enamide (1k)
A mixture of N,O-dimethylhydroxylamine hydrochloride (1.0 equiv,
604 mg, 6.2 mmol) and Et N (2.0 equiv, 12.4 mmol, 1.72 mL) in CH Cl
3
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

H
Synthesis
D. Diamante et al.
Paper
1
White solid; mp 145–146 °C.
H NMR (400 MHz, CDCl ): δ = 7.83–7.80 (m, 2 H), 7.31–7.28 (m, 3 H),
3
IR (ATR): 3317, 1737, 1673, 1634, 1440, 1165, 981, 700 cm–1
6.88–6.83 (m, 4 H), 6.22 (t, J = 5.8 Hz, 1 H), 6.04 (td, J = 1.7, 15.3 Hz, 1
H), 4.58 (dd, J = 1.7, 5.4 Hz, 2 H), 4.46 (d, J = 5.7 Hz, 2 H), 3.79 (s, 3 H),
.
1
H NMR (300 MHz, CDCl ): δ = 7.88–7.82 (m, 2 H), 7.42–7.30 (m, 7 H),
3
3
.68 (s, 3 H), 2.42 (s, 3 H).
6.91 (dt, J = 15.2, 5.3 Hz, 1 H), 6.03 (dt, J = 15.2, 1.7 Hz, 1 H), 5.84 (br s,
13
C NMR (100 MHz, CDCl ): δ = 164.7, 159.9, 152.3, 145.0, 139.6,
1
H), 4.63 (dd, J = 5.2, 1.7 Hz, 2 H), 4.55 (dd, J = 5.8, 1.9 Hz, 2 H), 3.73
3
138.1, 135.9, 129.7, 129.5, 128.5, 125.6, 120.1, 113.5, 113.0, 55.2, 54.0,
(
s, 3 H), 2.46 (s, 3 H).
47.4, 43.6, 21.6.
13
C NMR (100 MHz, CDCl ): δ = 164.5, 152.4, 145.0, 138.3, 137.9,
3
+
HRMS (ESI): m/z [M + Na] calcd for C21H N NaO S: 455.1247; found:
136.0, 129.4, 128.8, 128.6, 128.0, 127.6, 125.4, 54.0, 47.4, 43.8, 21.6.
24
2
6
455.1232.
+
HRMS (ESI): m/z [M + Na] calcd for C20H22N NaO S: 425.1142; found:
2
5
425.1149.
Methyl (E)-{4-[(4-Nitrobenzyl)amino]-4-oxobut-2-en-1-yl}(to-
syl)carbamate (2e)
Methyl (E)-{4-[(4-Methylbenzyl)amino]-4-oxobut-2-en-1-yl}(to-
Following GP2 with amide 1e (1.0 equiv, 100 mg, 0.45 mmol) and
methyl tosylcarbamate (A) (2.0 equiv, 208 mg, 0.98 mmol) for 24 h.
The crude product was purified by flash chromatography on silica gel
syl)carbamate (2b)
Following GP2 with amide 1b (1.0 equiv, 100 mg, 0.53 mmol) and
methyl tosylcarbamate (A) (2.0 equiv, 242 mg, 1.06 mmol) for 16 h.
The crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/cyclohexane, 1:1) to afford 2e in 10% yield (16 mg,
0.036 mmol).
(eluent: EtOAc/cyclohexane, 1:1) to afford 2b in 34% yield (34 mg,
Pale yellow solid; mp 182–184 °C.
0.082 mmol).
IR (ATR): 3304, 2921, 1743, 1626, 1517, 1346, 1164, 776 cm–1
.
Beige solid; mp 171–172 °C.
IR (ATR): 3292, 2926, 1623, 1359, 1232, 1168 cm–1
1H NMR (400 MHz, CDCl
.40–7.38 (m, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 6.86 (td, J = 5.0, 15.2 Hz, 1
H), 6.05–6.00 (m, 2 H), 4.55–4.52 (m, 4 H), 3.62 (s, 3 H), 2.37 (s, 3 H).
): δ = 8.14–8.10 (m, 2 H), 7.76–7.74 (m, 2 H),
.
3
7
1
H NMR (400 MHz, CDCl ): δ = 7.86–7.83 (m, 2 H), 7.33–7.28 (m, 2 H),
3
7
.22–7.16 (m, 4 H), 6.78 (td, J = 5.3, 15.3 Hz, 1 H), 6.00 (td, J = 1.7, 15.2
Hz, 1 H), 5.82 (br s, 1 H), 4.60 (dd, J = 1.7, 5.3 Hz, 2 H), 4.48 (d, J = 5.6
Hz, 2 H), 3.71 (s, 3 H), 2.44 (s, 3 H), 2.36 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 164.9, 153.3, 147.4, 145.5, 145.1,
3
139.4, 135.9, 129.5, 128.5, 128.4, 124.7, 123.9, 54.1, 47.5, 43.0, 21.7.
+
13
HRMS (ESI): m/z [M + Na] calcd for C20
H
21
N
3
NaO
7
S: 470.0992; found:
C NMR (100 MHz, CDCl ): δ = 164.5, 152.4, 144.9, 138.2, 137.4,
3
470.1004.
136.0, 134.9, 129.4, 128.6, 128.0, 125.5, 54.1, 47.4, 43.6, 21.6, 21.1.
+
HRMS (ESI): m/z [M + Na] calcd for C21H24N NaO S: 439.1298; found:
2
5
Methyl (E)-(4-Oxo-4-{[4-(trifluoromethyl)benzyl]amino}but-2-
en-1-yl)(tosyl)carbamate (2f)
439.1305.
Following GP2 with amide 1f (1.0 equiv, 100 mg, 0.41 mmol) and
methyl tosylcarbamate (A) (2.0 equiv, 188 mg, 0.82 mmol) for 24 h.
The crude product was purified by flash chromatography on silica gel
Methyl (E)-{4-[(4-Methoxybenzyl)amino]-4-oxobut-2-en-1-yl}(to-
syl)carbamate (2c)
Following GP2 with amide 1c (1.0 equiv, 100 mg, 0.49 mmol) and
methyl tosylcarbamate (A) (2.0 equiv, 223 mg, 0.97 mmol) for 24 h.
The crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/cyclohexane, 1:1) to afford 2f in 74% yield (142 mg,
0.30 mmol).
White solid; mp 173–174 °C.
IR (ATR): 3316, 2925, 1737, 1676, 1636, 1361, 1169, 911, 733 cm–1
.
(eluent: EtOAc/cyclohexane, 1:1) to afford 2c in 35% yield (73 mg, 0.17
mmol).
1
White solid; mp 158–159 °C.
H NMR (400 MHz, CDCl ): δ = 7.76–7.74 (m, 2 H), 7.54–7.52 (m, 2 H),
3
IR (ATR): 3297, 2960, 1744, 1624, 1515, 1358, 1168, 770 cm–1
7.36–7.33 (m, 2 H), 7.24–7.22 (m, 2 H), 6.83 (dt, J = 15.3, 5.2 Hz, 1 H),
.
5
2
.98 (dt, J = 15.2, 1.6 Hz, 1 H), 5.91 (br s, 1 H), 4.52 (dd, J = 5.2, 1.7 Hz,
H), 4.49 (d, J = 6.0 Hz, 2 H), 3.62 (s, 3 H), 2.35 (s, 3 H).
1
H NMR (400 MHz, CDCl ): δ = 7.86–7.82 (m, 2 H), 7.33–7.24 (m, 4 H),
3
6.92–6.85 (m, 3 H), 6.00 (td, J = 1.7, 15.2 Hz, 1 H), 5.73 (br s, 1 H), 4.61
13
C NMR (100 MHz, CDCl ): δ = 164.8, 152.3, 145.0, 142.0, 138.9,
(dd, J = 1.7, 5.3 Hz, 2 H), 4.47 (d, J = 5.7 Hz, 2 H), 3.83 (s, 3 H), 3.71 (s, 3
3
1
1
35.9, 129.7 (q, J = 32.0 Hz), 129.5, 128.5, 128.0, 125.7 (q, J = 3.7 Hz),
25.0, 122.9 (q, J = 272.0 Hz), 54.1, 47.4, 43.2, 21.6.
H), 2.44 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 164.4, 159.2, 152.4, 145.0, 138.2,
3
19
F NMR (282 MHz, CDCl ): δ = –62.53.
136.0, 130.0, 129.5, 129.4, 128.6, 125.5, 114.1, 55.3, 54.1, 47.4, 43.3,
3
21.7.
HRMS (ESI): m/z [M + Na]+ calcd for C21H21F N NaO S: 493.1015;
3 2 5
+
found: 493.1012.
HRMS (ESI): m/z [M + Na] calcd for C21H24N NaO S: 455.1247; found:
2
6
455.1260.
Methyl (E)-{4-[(Furan-2-ylmethyl)amino]-4-oxobut-2-en-1-yl}(to-
syl)carbamate (2g)
Methyl (E)-{4-[(3-Methoxybenzyl)amino]-4-oxobut-2-en-1-yl}(to-
syl)carbamate (2d)
Following GP2 with amide 1g (1 equiv, 100 mg, 0.60 mmol) and
methyl tosylcarbamate (A) (2 equiv, 277 mg, 1.2 mmol) for 24 h. The
crude product was purified by flash chromatography on silica gel
Following GP2 with amide 1d (1.0 equiv, 100 mg, 0.49 mmol) and
methyl tosylcarbamate (A) (2 equiv, 223 mg, 0.97 mmol) for 24 h. The
crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/cyclohexane, 7:3) to afford 2g in 46% yield (109 mg,
0.28 mmol).
(eluent: EtOAc/cyclohexane, 1:1) to afford 2d in 84% yield (176 mg,
0.4 mmol).
Brown oil.
White solid; mp 127–128 °C.
IR (ATR): 3304, 2956, 1747, 1628, 1357, 1165, 759 cm–1
.
IR (ATR): 3292, 2955, 1744, 1627, 1357, 1165, 765 cm–1
.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

I
Synthesis
D. Diamante et al.
Paper
1
IR (ATR): 2958, 1737, 1676, 1359, 1169, 907, 729 cm–1
.
H NMR (400 MHz, CDCl ): δ = 7.76–7.73 (m, 2 H), 7.28 (dd, J = 0.8, 1.9
3
Hz, 1 H), 7.24–7.22 (m, 2 H), 6.78 (td, J = 5.2, 15.3 Hz, 1 H), 6.25 (dd, J =
1
H NMR (400 MHz, CDCl ): δ = 7.95 (td, J = 1.8, 8.7 Hz, 2 H), 7.93–7.87
3
1.9, 3.2 Hz, 1 H), 6.19–6.17 (m, 1 H), 5.96 (br s, 1 H), 5.93 (td, J = 1.7,
15.3 Hz, 1 H), 4.51 (dd, J = 1.7, 5.3 Hz, 2 H), 4.42 (d, J = 5.5 Hz, 2 H),
3.61 (s, 3 H), 2.35 (s, 3 H).
(m, 2 H), 7.62–7.57 (m, 1 H), 7.52–7.49 (m, 2 H), 7.37–7.31 (m, 2 H),
7
.13 (td, J = 1.8, 15.5 Hz, 1 H), 7.02 (td, J = 6.0, 15.5 Hz, 1 H), 4.76 (dd,
J = 2.0, 6.2 Hz, 2 H), 3.74 (s, 3 H), 2.45 (s, 3 H).
13
13
C NMR (100 MHz, CDCl ): δ = 164.6, 152.4, 150.9, 145.0, 142.3,
3
C NMR (100 MHz, CDCl ): δ = 189.7, 152.4, 145.1, 141.8, 137.3,
3
138.5, 135.9, 129.5, 128.5, 125.2, 110.5, 107.7, 54.0, 47.4, 36.6, 21.7.
1
36.0, 133.1, 129.5, 128.7, 128.6, 126.8, 54.2, 47.9, 21.7.
+
HRMS (ESI): m/z [M + Na] calcd for C 8H N NaO S: 415.0934; found:
+
1
20
2
6
HRMS (ESI): m/z [M + Na] calcd for C19H19NNaO S: 396.0876; found:
3
5
415.0938.
96.0884.
Methyl (E)-[4-Oxo-4-(phenylamino)but-2-en-1-yl](tosyl)carba-
mate (2h)
Methyl (E)-4-{[N-(Methoxycarbonyl)-4-methylphenyl]sulfonami-
do}but-2-enoate (2m)
Following GP2 with amide 1h (1.0 equiv, 50 mg, 0.31 mmol) and
methyl tosylcarbamate (A) (2.0 equiv, 142 mg, 0.62 mmol) for 24 h.
The crude product was purified by flash chromatography on silica gel
Following GP2 with methyl but-3-enoate (1m) (1.0 equiv, 50 mg, 0.5
mmol) and methyl tosylcarbamate (A) (2.0 equiv, 228 mg, 0.99 mmol)
for 48 h. The crude product was purified by flash chromatography on
silica gel (eluent: EtOAc/cyclohexane, 1:1) to afford 2m in 93% yield
(eluent: EtOAc/cyclohexane, 1:1) to afford 2h in 90% yield (52 mg,
0.14 mmol).
(137 mg, 0.42 mmol).
Brown solid; mp 153–155 °C.
IR (ATR): 3353, 2916, 1689, 1536, 1440, 1254, 1185, 1080 cm–1
Beige solid; mp 132–133 °C.
IR (ATR): 2955, 1749, 1716, 1435, 1356, 1167 cm–1
.
.
1
H NMR (400 MHz, CDCl ): δ = 7.78–7.75 (m, 2 H), 7.62 (br s, 1 H),
1
3
H NMR (400 MHz, CDCl ): δ = 7.86–7.84 (m, 2 H), 7.36–7.34 (m, 2 H),
3
7.49 (d, J = 8.0 Hz, 2 H), 7.26–7.18 (m, 4 H), 7.04 (t, J = 7.4 Hz, 1 H),
6.94 (td, J = 5.4, 15.7 Hz, 1 H), 6.04 (td, J = 1.7, 15.7 Hz, 1 H), 4.62 (dd,
6.89 (td, J = 5.2, 15.2 Hz, 1 H), 6.14 (td, J = 1.7, 15.2 Hz, 1 H), 4.56 (dd,
J = 1.7, 3.5 Hz, 2 H), 3.77 (s, 3 H), 3.73 (s, 3 H), 2.47 (s, 3 H).
J = 1.7, 5.1 Hz, 2 H), 3.63 (s, 3 H), 2.34 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 166.2, 152.3, 145.1, 142.2, 135.9,
3
13
C NMR (100 MHz, CDCl ): δ = 162.9, 152.4, 145.0, 139.2, 136.3,
3
129.5, 128.6, 123.0, 54.1, 51.7, 47.2, 21.6.
135.9, 129.5, 129.0, 128.5, 126.0, 124.4, 119.9, 54.1, 47.5, 21.6.
+
HRMS (ESI): m/z [M + Na] calcd for C14H17NNaO S: 350.0669; found:
6
+
HRMS (ESI): m/z [M + Na] calcd for C19H20N NaO S: 411.0985; found:
2
5
350.0668.
411.0975.
(
E)-N-Benzyl-4-(N-tosylacetamido)but-2-enamide (3a)
Methyl (E)-[4-Oxo-4-(phenethylamino)but-2-en-1-yl](tosyl)carba-
mate (2i)
Following GP2 with amide 1a (1.0 equiv, 100 mg, 0.57 mmol) and N-
tosylacetamide (B) (2.0 equiv, 261 mg, 1.14 mmol) for 24 h. The crude
product was purified by flash chromatography on silica gel (eluent:
EtOAc/cyclohexane, 1:1) to afford 3a in 61% yield (133 mg, 0.34
mmol).
Following GP2 with amide 1i (1.0 equiv, 100 mg, 0.53 mmol) and
methyl tosylcarbamate (A) (2.0 equiv, 243 mg, 1.01 mmol) for 24 h.
The crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/cyclohexane, 1:1) to afford 2i in 41% yield (90 mg, 0.22
Beige solid; mp 161–162 °C.
mmol).
IR (ATR): 3315, 2923, 1705, 1635, 1557, 1355, 1242, 1154 cm–1
1H NMR (400 MHz, CDCl
): δ = 7.72–7.69 (m, 2 H), 7.30–7.21 (m, 7 H),
.77 (dt, J = 15.2, 5.2 Hz, 1 H), 5.88 (dt, J = 15.2, 1.7 Hz, 1 H), 5.69 (br s,
1 H), 4.51 (dd, J = 1.7, 5.2 Hz, 2 H), 4.43 (d, J = 5.7 Hz, 2 H), 2.36 (s, 3 H),
.
White solid; mp 145–147 °C.
IR (ATR): 3309, 3026, 2960, 1745, 1627, 1546, 1398, 1128, 907 cm–1
3
.
6
1
H NMR (400 MHz, CDCl ): δ = 7.76–7.73 (m, 2 H), 7.27–7.12 (m, 7 H),
3
6
1
2
.74 (td, J = 5.3, 15.3 Hz, 1 H), 5.85 (td, J = 1.7, 15.3 Hz, 1 H), 5.48 (br s,
H), 4.50 (dd, J = 1.7, 5.3 Hz, 2 H), 3.61 (s, 3 H), 3.56–3.50 (m, 2 H),
.78 (t, J = 7.0 Hz, 2 H), 2.36 (s, 3 H).
2
1
.24 (s, 3 H).
3
C NMR (100 MHz, CDCl ): δ = 164.5, 145.3, 138.6, 138.1, 137.9,
3
1
36.4, 129.9, 128.8, 128.0, 127.8, 127.7, 125.7, 47.0, 43.8, 24.6, 21.6.
13
C NMR (100 MHz, CDCl ): δ = 164.7, 152.4, 144.9, 138.7, 137.9,
3
+
HRMS (ESI): m/z [M + Na] calcd for C20H22N NaO S: 409.1192; found:
4
2
4
135.9, 129.4, 128.8, 128.7, 128.5, 126.6, 125.6, 54.0, 47.3, 40.7, 35.6,
09.1178.
21.7.
+
HRMS (ESI): m/z [M + Na] calcd for C21H24N NaO S: 439.1298; found:
2
5
(
E)-N-Benzyl-4-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-
439.1311.
yl)but-2-enamide (4a)
Following GP2 with amide 1a (1.0 equiv, 100 mg, 0.57 mmol) and sac-
charin (C) (2.0 equiv, 208 mg, 1.14 mmol) for 48 h. The crude product
was purified by flash chromatography on silica gel (eluent: EtOAc/cy-
clohexane, 1:1) to afford 4a in 40% yield (80 mg, 0.02 mmol).
Methyl (E)-(4-Oxo-4-phenylbut-2-en-1-yl)(tosyl)carbamate (2l)
Following GP2 with phenyl allyl ketone (1l) (1.0 equiv, 100 mg, 0.68
mmol) and methyl tosylcarbamate (A) (2.0 equiv, 309 mg, 1.35 mmol)
for 24 h. The residue was taken up in CH Cl and treated with an equal
2
2
White solid; mp 149–150 °C.
volume of 1 M KOH for 15 min. After decantation and phase separa-
IR (ATR): 3312, 1744, 1625, 1325, 1185, 973, 752 cm–1
.
tion, the organic layer was dried over MgSO and concentrated in vac-
4
uo. The crude product was purified by flash chromatography on silica
gel (eluent: EtOAc/cyclohexane, 1:1) to afford 2l in 40% yield (102 mg,
1
H NMR (400 MHz, CDCl ): δ = 8.00–7.98 (m, 1 H), 7.87–7.75 (m, 3 H),
.27–7.17 (m, 5 H), 6.84 (td, J = 5.5, 15.3 Hz, 1 H), 6.01 (td, J = 1.7, 15.2
3
7
0.27 mmol).
Hz, 1 H), 5.75 (br s, 1 H), 4.44–4.40 (m, 4 H).
Brown oil.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

J
Synthesis
D. Diamante et al.
Paper
13
+
C NMR (100 MHz, CDCl ): δ = 164.2, 158.5, 137.8, 137.7, 135.6,
HRMS (ESI): m/z [M + Na] calcd for C19H18N NaO S: 409.0829; found:
2 5
3
135.0, 134.5, 128.7, 127.9, 127.6, 127.1, 126.7, 125.3, 121.1, 43.8, 39.2.
409.0840.
+
HRMS (ESI): m/z [M + Na] calcd for C18H16N NaO S: 379.0723; found:
2
4
379.0709.
(E)-4-(1,1-Dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-N-(4-nitro-
benzyl)but-2-enamide (4e)
(
E)-4-(1,1-Dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-N-(4-meth-
Following GP2 with amide 1e (1.0 equiv, 65 mg, 0.29 mmol) and sac-
charin (C) (2.0 equiv, 108 mg, 0.59 mmol) for 48 h. The crude product
was purified by flash chromatography on silica gel (eluent: EtOAc/cy-
clohexane, 1:1) to afford 4e in 30% yield (35 mg, 0.09 mmol).
ylbenzyl)but-2-enamide (4b)
Following GP2 with amide 1b (1.0 equiv, 100 mg, 0.53 mmol) and sac-
charin (C) (2.0 equiv, 193 mg, 1.05 mmol) for 24 h. The crude product
was purified by flash chromatography on silica gel (eluent: EtOAc/cy-
clohexane, 1:1) to afford 4b in 33% yield (64 mg, 0.17 mmol).
Beige solid; mp 168–169 °C.
IR (ATR): 3291, 2924, 1735, 1519, 1344, 1259, 968, 730 cm–1
.
White solid; mp 171–172 °C.
IR (ATR): 3291, 2922, 1731, 1621, 1334, 1186 cm–1
1
H NMR (400 MHz, CDCl ): δ = 8.11–8.08 (m, 2 H), 8.00 (ddd, J = 7.3,
3
.
1.4, 0.7 Hz, 1 H), 7.89–7.77 (m, 3 H), 7.39–7.35 (m, 2 H), 6.88 (td, J =
5.4, 15.3 Hz, 1 H), 6.07 (td, J = 1.7, 15.3 Hz, 1 H), 5.93 (br s, 1 H), 4.52
1
H NMR (400 MHz, CDCl ): δ = 8.01–7.98 (m, 1 H), 7.87–7.77 (m, 3 H),
3
(d, J = 6.3 Hz, 2 H), 4.44 (dd, J = 1.7, 5.4 Hz, 2 H).
7
.10–7.04 (m, 4 H), 6.83 (td, J = 5.4, 15.2 Hz, 1 H), 5.99 (td, J = 1.7, 15.2
Hz, 1 H), 5.66 (br s, 1 H), 4.41 (dd, J = 1.7, 5.4 Hz, 2 H), 4.37 (d, J = 5.6
Hz, 2 H), 2.25 (s, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 164.5, 158.6, 147.4, 145.4, 137.7,
3
136.6, 135.1, 134.6, 128.3, 127.0, 126.1, 125.4, 123.9, 121.1, 42.9, 39.2.
13
+
C NMR (100 MHz, CDCl ): δ = 164.2, 158.5, 137.7, 137.3, 135.5,
HRMS (ESI): m/z [M + Na] calcd for C18H15N NaO S: 424.0574; found:
3
3
6
135.0, 134.7, 134.5, 129.4, 127.9, 127.1, 126.8, 125.3, 121.1, 43.6, 39.2,
424.0584.
21.1.
+
HRMS (ESI): m/z [M + Na] calcd for C19H18N NaO S: 393.0879; found:
Methyl (E)-[4-(Benzylamino)-4-oxobut-2-en-1-yl](tert-butyl-
2
4
393.0876.
sulfinyl)carbamate (5a)
Following GP2 with amide 1a (1.0 equiv, 100 mg, 0.57 mmol) and
methyl (tert-butylsulfinyl)carbamate (D) (2.0 equiv, 204 mg, 1.14
mmol) for 48 h. The crude product was purified by flash chromatog-
raphy on silica gel (eluent: EtOAc/cyclohexane, 1:1) to afford 5a in
(
E)-4-(1,1-Dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-N-(4-meth-
oxybenzyl)but-2-enamide (4c)
Following GP2 with amide 1c (1.0 equiv, 100 mg, 0.49 mmol) and sac-
charin (C) (2.0 equiv, 178 mg, 0.97 mmol) for 24 h. The crude product
was purified by flash chromatography on silica gel (eluent: EtOAc/cy-
clohexane, 1:1) to afford 4c in 57% yield (106 mg, 0.27 mmol).
47% yield (93 mg, 0.26 mmol).
Yellow oil.
IR (ATR): 3327, 2951, 1702, 1670, 1494, 1371, 1250, 1033 cm–1
.
White solid; mp 164–165 °C.
IR (ATR): 3293, 2933, 1734, 1513, 1182, 909, 730 cm–1
1
H NMR (400 MHz, CDCl ): δ = 7.35–7.27 (m, 5 H), 6.80 (td, J = 5.5,
3
.
15.4 Hz, 1 H), 6.08 (br s, 1 H), 5.95 (td, J = 1.6, 15.3 Hz, 1 H), 4.46 (d, J =
5.7 Hz, 2 H), 4.12 (ddd, J = 1.7, 5.4, 16.9 Hz, 1 H), 3.94 (ddd, J = 1.7, 5.4,
1
1
H NMR (400 MHz, CDCl ): δ = 8.09 (ddd, J = 0.7, 1.5, 7.2 Hz, 1 H),
3
6.9 Hz, 1 H), 3.77 (s, 3 H), 1.21 (s, 9 H).
7.97–7.85 (m, 3 H), 7.23–7.20 (m, 2 H), 6.93 (td, J = 5.4, 15.3 Hz, 1 H),
13
6.88–6.85 (m, 2 H), 6.08 (td, J = 1.7, 15.2 Hz, 1 H), 5.74 (br s, 1 H), 4.51
C NMR (100 MHz, CDCl ): δ = 164.9, 155.4, 139.3, 138.0, 128.7,
3
(dd, J = 1.7, 5.5 Hz, 2 H), 4.44 (d, J = 5.6 Hz, 2 H), 3.80 (s, 3 H).
127.9, 127.5, 125.7, 60.2, 53.6, 43.7, 39.1, 22.5.
13
+
C NMR (100 MHz, CDCl ): δ = 164.1, 159.1, 158.5, 137.7, 135.5,
HRMS (ESI): m/z [M + Na] calcd for C17H24N NaO S: 375.1349; found:
3
2
4
135.0, 134.5, 129.9, 129.3, 127.1, 126.7, 125.3, 121.2, 114.1, 55.3, 43.3,
375.1334.
39.2.
+
HRMS (ESI): m/z [M + Na] calcd for C19H18N NaO S: 409.0829; found:
Methyl (E)-(tert-Butylsulfinyl){4-[(4-methylbenzyl)amino]-4-
2
5
409.0836.
oxobut-2-en-1-yl}carbamate (5b)
Following GP2 with amide 1b (1.0 equiv, 100 mg, 0.53 mmol) and
methyl (tert-butylsulfinyl)carbamate (D) (2.0 equiv, 190 mg, 1.06
mmol) for 30 h. The crude product was purified by flash chromatog-
raphy on silica gel (eluent: EtOAc/cyclohexane, 6:4) to afford 5b in
(
E)-4-(1,1-Dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-N-(3-meth-
oxybenzyl)but-2-enamide (4d)
Following GP2 with amide 1d (1.0 equiv, 100 mg, 0.48 mmol) and sac-
charin (C) (2.0 equiv, 178 mg, 0.97 mmol) for 48 h. The crude product
was purified by flash chromatography on silica gel (eluent: EtOAc/cy-
clohexane, 1:1) to afford 4d in 82% yield (154 mg, 0.4 mmol).
27% yield (51 mg, 0.14 mmol).
Yellow oil.
IR (ATR): 3295, 2925, 1717, 1674, 1634, 1443, 1307, 1089, 907, 729
–
1
White solid; mp 138–140 °C.
cm .
IR (ATR): 3287, 2921, 1731, 1625, 1331, 1213, 1013 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.12–7.05 (m, 4 H), 6.73 (ddd, J = 5.4,
3
1
6.1, 15.4 Hz, 1 H), 5.83 (td, J = 1.6, 15.3 Hz, 1 H), 5.73 (br s, 1 H), 4.37
H NMR (400 MHz, CDCl ): δ = 8.11–8.02 (m, 1 H), 7.95–7.87 (m, 3 H),
.25 (dd, J = 7.5, 9.0 Hz, 1 H), 6.93 (td, J = 5.4, 15.3 Hz, 1 H), 6.82–6.84
3
(d, J = 5.7 Hz, 2 H), 4.04 (ddd, J = 1.5, 6.1, 16.9 Hz, 1 H), 3.87 (ddd, J =
7
1
.7, 5.5, 16.9 Hz, 1 H), 3.70 (s, 3 H), 2.26 (s, 3 H), 1.14 (s, 9 H).
(m, 3 H), 6.10 (td, J = 1.7, 15.2 Hz, 1 H), 5.80 (br s, 1 H), 4.52 (dd, J = 1.7,
13
5
.4 Hz, 2 H), 4.48 (d, J = 5.7 Hz, 2 H), 3.80 (s, 3 H).
C NMR (100 MHz, CDCl ): δ = 164.7, 155.4, 139.3, 137.3, 134.9,
3
1
3
129.4, 128.0, 125.8, 60.2, 53.6, 43.6, 39.1, 29.7, 22.5.
C NMR (100 MHz, CDCl ): δ = 164.2, 159.9, 158.5, 139.3, 137.8,
3
1
1
35.7, 135.0, 134.5, 129.8, 127.1, 126.7, 125.4, 121.0, 120.2, 113.4,
13.2, 55.2, 43.8, 39.2.
HRMS (ESI): m/z [M + K]+ calcd for C18H26KN O S: 405.1245; found:
2
4
405.1232.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

K
Synthesis
D. Diamante et al.
Paper
Methyl (E)-(tert-Butylsulfinyl){4-[(4-methoxybenzyl)amino]-4-
IR (ATR): 3282, 1771, 1701, 1629, 977, 720 cm–1
.
oxobut-2-en-1-yl}carbamate (5c)
1
H NMR (400 MHz, DMSO-d ): δ = 8.39 (t, J = 5.7 Hz, 1 H), 7.92–7.85
6
Following GP2 with amide 1c (1.0 equiv, 100 mg, 0.49 mmol) and
methyl (tert-butylsulfinyl)carbamate (D) (2.0 equiv, 174 mg, 0.97
mmol) for 30 h. The crude product was purified by flash chromatog-
raphy on silica gel (eluent: EtOAc/cyclohexane, 1:1) to afford 5c in
(m, 4 H), 7.29–7.27 (m, 2 H), 7.22–7.20 (m, 2 H), 6.68 (dt, J = 15.4, 4.6
Hz, 1 H), 5.96 (dt, J = 15.5, 1.8 Hz, 1 H), 4.33 (dd, J = 4.6, 1.9 Hz, 2 H),
4.28 (d, J = 5.9 Hz, 2 H).
13
C NMR (100 MHz, DMSO-d ): δ = 167.4, 164.0, 139.1, 136.3, 134.5,
6
16% yield (29 mg, 0.08 mmol).
131.6, 128.3, 127.4, 126.8, 124.4, 123.2, 42.1, 38.0.
Yellow oil.
+
HRMS (ESI): m/z [M + Na] calcd for C19H16N NaO: 343.1059; found:
343.1053.
2
IR (ATR): 2927, 1717, 1513, 1250, 1089, 909, 731 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.14 (d, J = 8.7 Hz, 2 H), 6.79 (d, J = 8.7
3
Hz, 2 H), 6.72 (td, J = 5.7, 15.3 Hz, 1 H), 5.83 (td, J = 1.7, 15.2 Hz, 1 H),
(E)-4-(1,3-Dioxoisoindolin-2-yl)-N-(4-methylbenzyl)but-2-en-
5.68 (br s, 1 H), 4.35 (d, J = 5.7 Hz, 2 H), 4.08–4.01 (m, 1 H), 3.87 (ddd,
amide (7b)
J = 1.7, 5.4, 16.9 Hz, 1 H), 3.72 (s, 3 H), 3.70 (s, 3 H), 1.14 (s, 9 H).
Following GP5 with amide 1b (1.0 equiv, 100 mg, 0.52 mmol). The
crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/cyclohexane, 1:1) to afford 7b in 22% yield (38 mg,
0.11 mmol).
13
C NMR (100 MHz, CDCl ): δ = 164.7, 159.1, 155.4, 139.3, 130.0,
3
129.3, 125.8, 114.1, 60.2, 55.3, 53.6, 43.3, 39.1, 22.5.
HRMS (ESI): m/z [M + K]+ calcd for C18H26KN O S: 421.1194; found:
2
5
421.1199.
Pale yellow solid; mp 180–182 °C.
IR (ATR): 3274, 2923, 1771, 1713, 1666, 1623, 1547, 1458, 1351, 1218,
–
1
Methyl (E)-(tert-Butylsulfinyl){4-[(3-methoxybenzyl)amino]-4-
1118 cm .
oxobut-2-en-1-yl}carbamate (5d)
1
H NMR (300 MHz, CDCl ): δ = 7.83–7.75 (m, 2 H), 7.69–7.62 (m, 2 H),
3
Following GP2 with amide 1d (1.0 equiv, 100 mg, 0.49 mmol) and
methyl (tert-butylsulfinyl)carbamate (D) (2.0 equiv, 175 mg, 0.97
mmol) for 48 h. The crude product was purified by flash chromatog-
raphy on silica gel (eluent: EtOAc/cyclohexane, 1:1) to afford 5d in
7.12–7.03 (m, 4 H), 6.80–6.74 (m, 1 H), 5.82 (dt, J = 15.3, 1.6 Hz, 1 H),
5.58 (br s, 1 H), 4.39–4.32 (m, 4 H), 2.25 (d, J = 4.3 Hz, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 167.6, 164.5, 137.4, 136.8, 134.8,
3
134.2, 132.0, 129.4, 127.9, 125.7, 123.5, 43.6, 38.2, 21.0.
50% yield (93 mg, 0.24 mmol).
+
HRMS (ESI): m/z [M + Na] calcd for C20H18N NaO : 357.1210; found:
2
3
Pale brown oil.
357.1222.
IR (ATR): 3294, 2958, 1716, 1675, 1634, 1442, 1264, 907, 728 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.20–7.15 (m, 1 H), 6.80–6.69 (m, 4 H),
(E)-4-(1,3-Dioxoisoindolin-2-yl)-N-(4-methoxybenzyl)but-2-
3
5.90 (br s, 1 H), 5.86 (td, J = 1.6, 15.3 Hz, 1 H), 4.38 (d, J = 5.7 Hz, 2 H),
enamide (7c)
4
.05 (ddd, J = 1.5, 6.1, 16.9 Hz, 1 H), 3.87 (ddd, J = 1.7, 5.4, 16.9 Hz, 1
Following GP5 with amide 1c (1.0 equiv, 100 mg, 0.48 mmol). The
crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/cyclohexane, 1:1) to afford 7c in 53% yield (90 mg, 0.26
mmol).
H), 3.72 (s, 3 H), 3.70 (s, 3 H), 1.14 (s, 9 H).
13
C NMR (100 MHz, CDCl ): δ = 164.8, 159.8, 155.4, 139.5, 139.4,
3
129.7, 125.7, 120.2, 113.5, 113.0, 60.2, 55.2, 53.6, 43.7, 39.1, 22.5.
HRMS (ESI): m/z [M + K]+ calcd for C18H26KN O S: 421.1194; found:
White solid; mp 178–180 °C.
2
5
421.1203.
IR (ATR): 3284, 2926, 1708, 1620, 1513, 1247 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.81–7.76 (m, 2 H), 7.71–7.65 (m, 2 H),
3
Sequential Pd(II)/Pd(0)-Catalyzed Amination (7a–d,g–i); General
Procedure (GP5)
7
5
.16–7.10 (m, 2 H), 6.80–6.73 (m, 3 H), 5.81 (td, J = 1.6, 15.3 Hz, 1 H),
.61 (br s, 1 H), 4.32–4.36 (m, 4 H), 3.71 (s, 3 H).
A sealed tube was charged with LiOH·H O (2.0 equiv) and t-BuCO H
13
2
2
C NMR (100 MHz, CDCl ): δ = 167.6, 164.4, 159.1, 136.8, 134.2,
3
(10.0 equiv) and was heated at 40 °C for 10 min. Next, BQ (2.0 equiv),
131.9, 129.9, 129.3, 125.7, 123.5, 114.1, 55.3, 43.4, 39.2.
Pd(OAc) (10 mol%) and MeCN (0.2 M) were added. The mixture was
2
+
HRMS (ESI): m/z [M + Na] calcd for C20H N NaO : 373.1159; found:
stirred for 15 min at r.t., and then the corresponding amide (1a–d,g–i)
18
2
4
373.1163.
(1.0 equiv) was added. The mixture was stirred at 40 °C for 8 h. The
progress of the reaction was monitored by TLC. DIPEA (11.5 equiv),
32
phthalimide (3.0 equiv) and (+)-BINAP (20 mol%) were added and
the mixture was stirred at 70 °C for 18 h. After cooling to r.t., the mix-
ture was filtered through a SiO2 pad and washed with EtOAc (3 × 20
mL), then concentrated under reduced pressure. The crude residue
was purified by silica gel column chromatography to afford the corre-
sponding γ-AB2 amide 7a–d,g–i.
(E)-4-(1,3-Dioxoisoindolin-2-yl)-N-(3-methoxybenzyl)but-2-
enamide (7d)
Following GP5 with amide 1d (1.0 equiv, 100 mg, 0.48 mmol). The
crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/cyclohexane, 1:1) to afford 7d in 76% yield (129 mg,
0.37 mmol).
White solid; mp 143–144 °C.
IR (ATR): 3275, 2897, 1702, 1631, 1423, 1046, 718 cm–1
(
E)-N-Benzyl-4-(1,3-dioxoisoindolin-2-yl)but-2-enamide (7a)
.
Following GP5 with amide 1a (1.0 equiv, 100 mg, 0.57 mmol). The
crude product was purified by flash chromatography on silica gel
1
H NMR (400 MHz, CDCl ): δ = 7.84–7.75 (m, 2 H), 7.75–7.62 (m, 2 H),
3
7.18–7.10 (m, 1 H), 6.84–6.70 (m, 4 H), 5.83 (dt, J = 15.3, 1.7 Hz, 1 H),
(
0
eluent: EtOAc/cyclohexane, 1:1) to afford 7a in 90% yield (142 mg,
.44 mmol).
White solid; mp 184–185 °C.
5
.66 (br s, 1 H), 4.43–4.31 (m, 4 H), 3.72 (d, J = 5.9 Hz, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 167.6, 164.4, 159.9, 139.4, 136.9,
3
134.2, 131.9, 129.8, 125.5, 123.5, 120.1, 113.4, 113.1, 55.2, 43.7, 38.2.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

L
Synthesis
D. Diamante et al.
Paper
+
HRMS (ESI): m/z [M + Na] calcd for C20H18N NaO : 373.1159; found:
Acknowledgment
2
4
373.1157.
We thank Omar Khaled for HRMS analyses. CNRS, UPMC, and Labex
Michem are acknowledged for financial support. Support through
CMST COST Action, CM1205 (CARISMA) is also gratefully acknowl-
edged.
(
E)-4-(1,3-Dioxoisoindolin-2-yl)-N-(furan-2-ylmethyl)but-2-
enamide (7g)
Following GP5 with amide 1g (1.0 equiv, 85 mg, 0.51 mmol). The
crude product was purified by flash chromatography on silica gel
(
0
eluent: EtOAc/cyclohexane, 1:1) to afford 7g in 20% yield (30 mg,
.097 mmol).
Supporting Information
Pale yellow solid; mp 144–145 °C.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562453.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
IR (ATR): 3297, 2917, 1703, 1632, 1556, 1425, 1347, 716 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.78 (dd, J = 3.0, 5.4 Hz, 2 H), 7.66 (dd,
3
J = 3.0, 5.4 Hz, 2 H), 7.25 (dd, J = 0.9, 1.9 Hz, 1 H), 6.76 (td, J = 5.5, 15.3
Hz, 1 H), 6.22 (dd, J = 1.9, 3.2 Hz, 1 H), 6.14 (dd, J = 0.9, 3.3 Hz, 1 H),
References
5
4
.82 (td, J = 1.6, 15.3 Hz, 1 H), 5.75 (br s, 1 H), 4.39 (d, J = 5.6 Hz, 2 H),
.34 (dd, J = 1.7, 5.5 Hz, 2 H).
(1) Present address: Università degli Studi dell’Insubria, Como,
Italy.
1
3
(2) (a) Amino Group Chemistry, From Synthesis to the Life Sciences;
Ricci, A., Ed.; Wiley-VCH: Weinheim, 2008. (b) Hili, R.; Yudin, A.
K. Nat. Chem. Biol. 2006, 2, 284.
C NMR (100 MHz, CDCl ): δ = 167.6, 164.3, 150.8, 142.2, 137.1,
3
1
34.2, 131.9, 125.4, 123.5, 110.5, 107.7, 38.2, 36.5.
+
HRMS (ESI): m/z [M + Na] calcd for C17H14N NaO : 333.0846; found:
3
2
4
(
3) For recent books on C–H bond functionalizations, see:
a) Catalytic Transformations via C–H Activation, In Science of
Synthesis; Vol. 1 and 2; Yu, J.-Q., Ed.; Thieme: Stuttgart, 2016.
b) Li, J. J. C–H Bond Activation in Organic Synthesis; CRC Press:
Boca Raton, 2015.
33.0857.
(
(E)-4-(1,3-Dioxoisoindolin-2-yl)-N-phenylbut-2-enamide (7h)
(
Following GP5 with amide 1h (1.0 equiv, 80 mg, 0.49 mmol) and
phthalimide (1.5 equiv, 109 mg, 0.744 mmol). The crude product was
purified by flash chromatography on silica gel (eluent: EtOAc/cyclo-
hexane, 1:1) to afford 7h in 32% yield (44 mg, 0.14 mmol).
(4) For a review on allylic amination, see: Johannsen, M.; Jorgensen,
K. A. Chem. Rev. 1998, 98, 1689.
(5) For books on Pd-catalyzed alkene functionalization, see:
(a) Tsuji, J. Palladium Reagents and Catalysts, 2nd ed.; Wiley:
Pale yellow solid; mp 173–174 °C.
New York, 2004. (b) Hoosokawa, T. Aminopalladation and
Related Reactions Involving Other Group 15 Atom Nucleophiles:
Aminopalladation-Dehydropalladation and Related Reactions, In
Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-i., Ed.; John Wiley & Sons: New York, 2003.
IR (ATR): 3366, 1769, 1706, 1388, 947, 756 cm–1
.
1
H NMR (300 MHz, CDCl ): δ = 7.93–7.84 (m, 2 H), 7.75 (dd, J = 5.4, 3.2
3
Hz, 2 H), 7.51 (d, J = 7.1 Hz, 2 H), 7.31 (t, J = 7.9 Hz, 2 H), 7.19 (s, 1 H),
7.10 (t, J = 7.5 Hz, 1 H), 6.95 (dt, J = 14.7, 5.5 Hz, 1 H), 6.05 (d, J = 15.0
Hz, 1 H), 4.48 (d, J = 5.4 Hz, 2 H).
(6) For a selection of reviews on allylic C–H functionalization, see:
(a) Liron, F.; Oble, J.; Lorion, M. M.; Poli, G. Eur. J. Org. Chem.
13
C NMR (100 MHz, CDCl ): δ = 167.6, 138.0, 137.6, 134.3, 132.0,
3
2014, 20, 1539. (b) Breder, A. Synlett 2014, 25, 899. (c) Ramirez,
129.0, 126.1, 124.6, 123.3, 119.9, 38.2.
T. A.; Zhao, B.; Shi, Y. Chem. Soc. Rev. 2011, 41, 931. (d) Engelin,
C. J.; Fristrup, P. Molecules 2011, 16, 951. (e) Jensen, T.; Fristrup,
P. Chem. Eur. J. 2009, 15, 9632.
+
HRMS (ESI): m/z [M + Na] calcd for C18H14N NaO : 329.0897; found:
2
3
329.0901.
(
7) For reviews on aminopalladation, see: (a) Kočovský, P.; Bäckvall,
J.-E. Chem. Eur. J. 2015, 21, 36. (b) McDonald, R. I.; Liu, G.; Stahl,
S. S. Chem. Rev. 2011, 111, 2981. (c) Keith, J. A.; Henry, P. M.
Angew. Chem. Int. Ed. 2009, 48, 9038. (d) Minatti, A.; Muñiz, K.
Chem. Soc. Rev. 2007, 36, 1142. (e) Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318.
8) For literature precedents on intermolecular Pd(II)-catalyzed
allylic amination, see: (a) Patillo, C. C.; Strambeanu, I. I.; Calleja,
P.; Vermeulen, N. A.; Mizuno, T.; White, M. C. J. Am. Chem. Soc.
2016, 138, 1265. (b) Shimizu, Y.; Obora, Y.; Ishii, Y. Org. Lett.
(
E)-4-(1,3-Dioxoisoindolin-2-yl)-N-phenethylbut-2-enamide (7i)
Following GP5 with amide 1i (1.0 equiv, 100 mg, 0.53 mmol). The
crude product was purified by flash chromatography on silica gel
(eluent: EtOAc/cyclohexane, 1:1) to afford 7i in 82% yield (145 mg,
0
.43 mmol).
(
Pale yellow solid; mp 148–150 °C.
IR (ATR): 3284, 2929, 1711, 1391, 717 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.78 (dd, J = 3.1, 5.4 Hz, 2 H), 7.66 (dd,
3
J = 3.1, 5.5 Hz, 2 H), 7.25–7.09 (m, 5 H), 6.71 (td, J = 5.6, 15.2 Hz, 1 H),
5
2
1
2010, 12, 1372. (c) Yin, G.; Wu, Y.; Liu, G. J. Am. Chem. Soc. 2010,
.76 (td, J = 1.6, 15.2 Hz, 1 H), 5.41 (br s, 1 H), 4.33 (dd, J = 1.6, 5.7 Hz,
H), 3.49 (dt, J = 5.9, 6.9 Hz, 2 H), 2.75 (t, J = 6.9 Hz, 2 H).
132, 11978. (d) Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am.
Chem. Soc. 2009, 131, 11701. (e) Liu, G.; Yin, G.; Wu, L. Angew.
Chem. Int. Ed. 2008, 7, 4733. (f) Reed, S. A.; White, M. C. J. Am.
Chem. Soc. 2008, 130, 3316. (g) For a recent example on inter-
molecular Pd(II)-catalyzed allylic azidation, see: Chen, H.; Yang,
W.; Wu, W.; Jiang, H. Org. Biomol. Chem. 2014, 12, 3340.
3
C NMR (100 MHz, CDCl ): δ = 167.7, 164.6, 138.7, 136.5, 134.2,
3
1
31.9, 128.7, 128.6, 126.5, 125.8, 123.5, 40.6, 38.2, 35.5.
+
HRMS (ESI): m/z [M + Na] calcd for C20H18N NaO : 357.1210; found:
3
2
3
57.1211.
(
9) For the synthesis of α- and/or γ-amino acid derivatives from
dienolates of α,β-unsaturated esters, see: Yamamoto, Y.;
Hatsuya, S.; Yamada, J.-I. Tetrahedron Lett. 1989, 30, 3445.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

M
Synthesis
D. Diamante et al.
Paper
(
10) For a precedent of Pd-catalyzed C–H activation on the ester
O
O
benzyl but-3-enoate, and the ketone 1-phenylbut-3-en-1-one,
see: (a) Alam, R.; Pilarski, L. T.; Pershagen, E.; Szabò, K. J. J. Am.
Chem. Soc. 2012, 134, 8778. (b) Pilarski, L. T.; Janson, P. G.;
Szabò, K. J. J. Org. Chem. 2011, 76, 1503. (c) Pilarski, L. T.;
Selander, N.; Bose, D.; Szabò, K. J. Org. Lett. 2009, 11, 5518.
11) For a precedent of Pd-catalyzed C–H activation on a bis-allylic
position, see: Trost, B. M.; Hansmann, M. M.; Thaisrivongs, D. A.
Angew. Chem. Int. Ed. 2012, 51, 4950.
OMe
OMe
N
54%
1
k
Me
O
Pd(OAc)2 (10 mol%)
BQ (2.0 equiv)
AcOH, 50 °C, 24 h
AcO
OMe
N
Me
(
(
(
N
1
k'
Me
12) For a review on the basics of the Pd-catalyzed allylation reac-
tion, see: Poli, G.; Prestat, G.; Liron, F.; Kammerer-Pentier, C.;
Kazmaier, U. Top. Organomet. Chem. 2011, 38, 1.
Scheme 5
13) For an example assumed to take place via this mechanism, see:
Bottarelli, P.; Costa, M.; Della Ca’, N.; Fava, E. Tetrahedron Lett.
(
20) See the Supporting Information for detailed procedures and full
characterization of the pivaloxylated compounds 6a–k, and 6m.
21) We use the term ‘globally isohypsic’ as the global transforma-
tion is redox neutral, although the mechanism implies a
Pd(0)/Pd(II) redox.
2
013, 54, 2362.
(
(
(
14) Sharma, A.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 17983.
15) (a) Lorion, M. M.; Duarte, F. J. S.; Calhorda, M. J.; Oble, J.; Poli, G.
Org. Lett. 2016, 18, 1020. (b) Duarte, F. J. S.; Poli, G.; Calhorda, M.
J. ACS Catal. 2016, 6, 1772. (c) Lorion, M. M.; Oble, J.; Poli, G.
Pure Appl. Chem. 2016, 88, 381. (d) Rajabi, J.; Lorion, M. M.; Ly,
V. L.; Liron, F.; Oble, J.; Prestat, G.; Poli, G. Chem. Eur. J. 2014, 20,
(
(
22) Giambastiani, G.; Poli, G. J. Org. Chem. 1998, 63, 9608.
23) Acronyms of the ligands used: 1,2-bis(diphenylphosphino)eth-
ane (DPPE); 1,1′-bis(diphenylphosphino)ferrocene (DPPF); 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS);
1539. (e) Lorion, M. M.; Nahra, F.; Ly, V. L.; Mealli, C.; Mesaoudi,
2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP).
A.; Liron, F.; Oble, J.; Poli, G. Chem. Today 2014, 32, 30. (f) Nahra,
F.; Liron, F.; Prestat, G.; Mealli, C.; Messaoudi, A.; Poli, G. Chem.
Eur. J. 2009, 15, 11078.
(
24) Given the problematic reactivity of ketone 1l in the Pd(II)-cata-
lyzed allylic pivaloxylation, this substrate was not tested in the
sequential protocol. N-Ts-carbamate A and saccharin (C) were
unproductive in these sequential conditions.
(
16) (a) Qi, X.; Rice, G. T.; Lall, M. S.; Plummer, M. S.; White, M. C. Tet-
rahedron 2010, 66, 4816. (b) See ref. 8d.
(
25) For a precedent of H-bond-directed addition of phthalimide to
(
17) A blank test performed as in Table 1 (entry 6), but in the
absence of the nucleophile gave back the unreacted amide,
which confirmed that these reaction conditions do not bring
about double bond migration from B3A to B2A. Furthermore,
preliminary acetoxylation experiments on Weinreb amides 1k
and 1k′ gave the corresponding γ-acetoxylated product only
when starting from 1k, while only the starting material was
recovered when starting from 1k′ (Scheme 5). This further con-
firms that, under the above conditions, allylic C–H activation
does not take place from the internal alkene.
3
η -allylpalladium moieties, see: (a) Cook, G. R.; Yu, H.;
Sankaranarayanan, S.; Shanker, P. S. J. Am. Chem. Soc. 2003, 125,
5115. (b) Cook, G. R.; Shanker, P. S.; Pararajasingham, K. Angew.
Chem. Int. Ed. 1999, 38, 110.
(
(
26) Xie, W.; Yang, J.; Wang, B.; Li, B. J. Org. Chem. 2014, 79, 8278.
27) Mistico, L.; Ay, E.; Huynh, V.; Bourderioux, A.; Chaumeil, H.;
Chemla, F.; Ferreira, F.; Oble, J.; Pérez-Luna, A.; Poli, G.; Prestat,
G. J. Organomet. Chem. 2014, 76, 124.
(28) Orliac, A.; Gomez Pardo, D.; Bombrun, A.; Cossy, J. Org. Lett.
2013, 15, 902.
(
18) See for example: Luzzio, F. A. Product Class 2: Triacylamines,
Imides (Diacylamines), and Related Compounds, In Science of Syn-
thesis, Houben-Weyl Methods of Molecular Transformations; Vol.
(
(
29) Jacobi, P. A.; Li, Y. J. Am. Chem. Soc. 2001, 123, 9307.
30) Abdou, A. M.; Botros, S.; Hassan, R. A.; Kamel, M. M.; Taber, D. F.;
Taher, A. T. Tetrahedron 2015, 71, 139.
22; Thieme: Stuttgart, 2005, Chap. 21.2, 259.
(31) Moriyama, K.; Takemura, M.; Togo, H. J. Org. Chem. 2014, 79,
(
19) Thiery, E.; Aouf, C.; Belloy, J.; Harakat, D.; Le Bras, J.; Muzart, J.
6094.
J. Org. Chem. 2010, 75, 1771.
(32) The R-configured ligand was used for practical reasons,
although its enantiopurity was obviously not needed.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M