NH2-directed C-H alkenylation of 2-vinylanilines with vinylbenziodoxolones

Article abstract of DOI:10.1021/acs.orglett.7b02630

The first directing-group-mediated C-H alkenylation with alkenyl-λ3-iodanes as electrophilic alkene-transfer reagents has been developed. The application of free aromatic amines as challenging but synthetically valuable directing groups in combination with an IrIII catalyst enabled the synthesis of highly desirable 1, 3- dienes in excellent yields of up to 98% with high to perfect (Z, E) stereoselectivity. A broad substrate scope and further synthetic modifications are demonstrated.

Full text of DOI:10.1021/acs.orglett.7b02630

Letter
pubs.acs.org/OrgLett
NH2‑Directed C−H Alkenylation of 2‑Vinylanilines with
Vinylbenziodoxolones
Andreas Boelke, Lucien D. Caspers, and Boris J. Nachtsheim*
Institute for Organic and Analytical Chemistry, University of Bremen, 28359 Bremen, Germany
S
* Supporting Information
ABSTRACT: The first directing-group-mediated C−H alkenylation
with alkenyl-λ3-iodanes as electrophilic alkene-transfer reagents has
been developed. The application of free aromatic amines as
challenging but synthetically valuable directing groups in combina-
tion with an IrIII catalyst enabled the synthesis of highly desirable 1,3-
dienes in excellent yields of up to 98% with high to perfect (Z,E)
stereoselectivity. A broad substrate scope and further synthetic
modifications are demonstrated.
Scheme 1. Transition-Metal-Catalyzed C−H Alkenylations
ransition-metal-catalyzed C−H activation provides a
Tstraightforward approach for the direct functionalization
of C−H bonds.1 In particular, the direct alkenylation of
(hetero)aryl and olefinic C−H bonds is an intensely
investigated reaction because of the high synthetic versatility
of vinylated (hetero)arenes and 1,3-dienes.2−4 To enable
controlled C−H alkenylations, common directing groups such
as nitrogen-containing heterocycles, oximes, amides, carba-
mates, and N-oxides have frequently been used.2 In sharp
contrast, free amines, hydrazines, and hydroxyl groups have
been described only rarely in such transformations because of
undesired side reactions such as catalyst deactivation and
subsequent heterocycle formation.5 This can be bypassed by in
situ protection, as demonstrated by Cheng and co-workers.6
Miura and co-workers described direct ortho-alkenylations of
benzylamines with alkenes using a Rh(III) catalyst in
combination with Cu(II) as a co-oxidant (Scheme 1a).7 Sha
and co-workers reported the efficient alkenylation of indoles at
C2 directed by free phenolic hydroxyl groups or aromatic
amines under similar oxidative conditions (Scheme 1b).8 Our
group is interested in the directed transformation of C(sp2)−H
bonds in combination with hypervalent-iodine-based group-
transfer reagents. Recently, we demonstrated the use of alkynyl-
substituted aryl-λ3-iodanes such as benziodoxolones and
alkynyl(aryl)iodonium salts in direct alkynylations of 2-
vinylphenols and anilines to give highly substituted 1,3-enynes.9
Now we want to demonstrate that alkenyl-substituted λ3-
iodanes can be used in similar C−H-activating alkenylations to
give 1,3-dienes (Scheme 1c). In contrast to diaryl-10 and
alkynyl-λ3-iodanes,9,11 their utilization has not been described
to date in C−H-activating reactions of arenes and alkenes.
Initially, we investigated the coupling between 2-(prop-1-en-
2-yl)aniline (1a) as the free-amine-containing substrate and
phenylvinylbenziodoxolone (3a, Ph-VBX; Table 1), published
recently by Olofsson and co-workers,12 as the alkene-transfer
reagent. Choosing the optimized reaction conditions of our
directed C−H alkynylation,9a using [IrCp*Cl2]2 as the catalyst,
Directed by Free Hydroxyl and Amine Groups
KOAc as the base, and pyridine as an additive, we were pleased
to isolate 2a in 79% yield after 73 h (Table 1, entry 1).
The product showed high (Z,E) isomeric purity with
complete Z stereoselectivity for the addition of the styryl
moiety to the exocyclic double bond. Exchange of pyridine with
AgOAc or AgNTf2 led to dramatically prolonged reaction times
(Table 1, entries 2 and 3). We therefore performed the reaction
without any additives, which resulted in a decreased reaction
time (53 h) and an increased yield of 87% (Table 1, entry 4).
Received: August 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02630
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b c
, ,
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope
b
additive
(mol %)
base
(mol %)
temp
(°C)
time
(h)
yield (%)
c
entry
1
(Z,E/Z,Z)
pyridine (5)
KOAc
(80)
rt
73
185
216
53
79 (96:4)
82 (97:3)
72 (96:4)
87 (96:4)
40 (95:5)
85 (97:3)
86 (97:3)
82 (97:3)
89 (97:3)
84 (98:2)
88 (96:4)
2
3
4
AgOAc (15)
KOAc
(80)
rt
AgNTf2 (15) KOAc
(80)
rt
−
−
−
−
−
−
−
−
KOAc
(80)
rt
d
5
KOAc
(150)
rt
163
4.5
1.5
5
6
7
8
9
KOAc
(80)
60
60
60
60
60
60
KOAc
(20)
K2CO3
(20)
NaOBz
(20)
1
e
10
NaOBz
(20)
4
f
11
NaOBz
(20)
1.5
a
Reaction conditions: 1a (26.6 mg, 0.2 mmol) and 3a (84.0 mg, 0.24
mmol) in 1,2-dichloroethane (DCE) (2 mL) without exclusion of air
b
or moisture. Isolated yields after column chromatography.
c
d
1
Determined by H NMR spectroscopy. 4 was used instead of 3a.
e
f
Toluene was used as the solvent. MeCN was used as the solvent.
Using (E)-styryl(phenyl)iodonium tetrafluoroborate (4) in-
stead of Ph-VBX gave 2a in only 40% yield after 7 days (Table
1, entry 5), thus demonstrating Ph-VBX to be the superior
alkene-transfer reagent.
a
Dramatic acceleration of the reaction was achieved by
increasing the temperature to 60 °C. Full conversion of 1a was
observed after just 4.5 h, affording 2a in 85% yield with high
stereoselectivity (Table 1, entry 6). On the basis of these
results, we investigated the influence of the base. By decreasing
the amount of KOAc to 20 mol %, we were pleased to observe
a further reduced reaction time of 1.5 h while maintaining the
previous yield (Table 1, entry 7). With K2CO3 the reaction was
significantly slower and gave a slightly lower yield, whereas
sodium benzoate led to full conversion of the starting material
after only 1 h with an increased yield of 89% (Table 1, entries 8
and 9). Finally, different solvents were tested. Although toluene
and MeCN were suitable, further improvement in the yield and
reaction time could not be achieved (Table 1, entries 10 and
11), leaving 1,2-DCE the solvent of choice.
Reaction conditions: 1 (0.20 mmol), 3a−c (0.24−0.30 mmol),
[IrCp*Cl2]2 (2.5 mol %), and NaOBz (20 mol %) in DCE (2 mL) at
b
60 °C. Isolated yields after column chromatography are shown.
c
1
(Z,E)/(Z,Z) isomeric ratios were determined by H NMR spectros-
d
e
copy. (Z,E)/(Z,Z)/(E,Z) or (E,E) isomeric ratio. 1.5 equiv of 3a was
used. A 1:1 mixture of isomers was used for the reaction.
f
different halogen substituents (4-Br, 4-Cl) as well as the more
electron-rich 5-methyl-substituted derivative 1d showed high
reactivities similar to that of the unsubstituted substrate 1a,
affording the desired dienes 2b−d in 86−98% yield with high
stereoselectivity. In contrast, compound 2e with strongly
electron-donating OMe substituents was isolated in a slightly
decreased yield of 76% after a prolonged reaction time (2.5 h)
as an inseparable mixture of four isomers (67:20:11:2) in favor
of the desired (Z,E) configuration.
With the optimized reaction conditions in hand, we
investigated the substrate scope of this transformation (Scheme
2). Electron-poor 2-(prop-1-en-2-yl)anilines 1b and 1c with
We then varied the substitution pattern of the exocyclic
double bond. 2-Vinylaniline (1f, R2 = H) showed good
B
DOI: 10.1021/acs.orglett.7b02630
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
reactivity, yielding the unsubstituted diene 2f in 77% with
perfect selectivity for the (Z,E) configuration. Substrates with
different alkyl side chains (R2 = Et, iPr, Cy) reacted well,
affording the corresponding products 2g−i in 88−91% yield
with excellent isomeric ratios of up to 99:1 in 1−2 h. However,
in case of the sterically more demanding isopropyl and
cyclohexyl derivatives 1h and 1i, 1.5 equiv of Ph-VBX was
necessary to achieve full substrate conversion.
Scheme 4. Further Derivatizations of Model Compound 2a
Next, different α-aryl vinylanilines (R2 = aryl, 1j−s) were
investigated. In most cases, slightly prolonged reaction times
were observed, and 1.5 equiv of Ph-VBX was needed, thus
indicating a lower reactivity in comparison with the α-alkyl
vinylanilines. The isolated yields, however, were excellent. The
desired dienes 2j−o were obtained in 92−97% yield with high
to excellent stereoselectivities after 1.0−2.5 h regardless of the
electronic nature of the substituents. Only the 3,5-(CF3)2-
substitued derivative 2p was isolated in a slightly decreased
yield of 77% after a prolonged reaction time. Very electron-
poor derivatives 1q−s with either a nitro group or a halogen
functionality on both aromatic rings afforded the desired
products 2q−s in excellent yields of 89−96% with high (Z,E)/
(Z,Z) isomeric ratios.
Finally, we investigated different VBX derivatives as alkene
transfer reagents. When p-toloylvinylbenziodoxolone (3b, p-
Tol-VBX) was used, high reactivity similar to that with Ph-VBX
was observed, and the desired product 2t was isolated in 91%
yield after 1.5 h. The reaction with p-methoxyphenylvinylben-
ziodoxolone (3c, PMP-VBX) afforded 2u in 80% yield with a
perfect (Z,E) configuration ratio after 1 h.
When the reaction was performed with meta- and para-
substituted anilines 1v and 1w, no conversion of the starting
materials was observed after 4 h in both cases, thus
demonstrating the importance of the free amino group at the
ortho position to the exocyclic double bond as the directing
group.
Furthermore, the use of the highly substituted alkenylanilines
1x and 1y as well as 2-phenylaniline (1z) did not lead to any
conversion of the substrates after 12 h, which limits the scope
of reaction to the use of unsubstituted vinylidenes.
We performed a gram-scale alkenylation of 1a with a
decreased catalyst loading of 1 mol % (Scheme 3) to prove the
gave sulfonamide 6 in 92% yield, which was further cyclized
with BF3 under mild conditions to obtain indoline rac-7 in 67%
yield with good trans diastereoselectivity.18 Mild and selective
N-alkynylation of mesylamide 6 was achieved using TIPS-EBX
(9) as the alkyne-transfer reagent. In situ cleavage of the TIPS
moiety under the basic reaction conditions gave the free
ynamide 8 in 77% yield.
In summary, we have developed a unique and highly effective
NH2-directed C−H alkenylation of 2-vinylanilines using
vinylbenziodoxolones as electrophilic alkene-transfer reagents.
This method provides direct access to the corresponding 1,3-
dienes in excellent yields of up to 98% with high to perfect
(Z,E) stereoselectivity. Moreover, no formation of undesired
second alkenylation products was observed. Finally, the
synthetic value of the obtained 1,3-dienes was successfully
demonstrated in a variety of transformations. Further studies
regarding selective isomerization reactions and deeper mech-
anistic investigations are underway.
Scheme 3. Gram-Scale Synthesis of 1,3-Diene 2a
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02630.
Complete optimization table, detailed experimental
procedures, characterization data, and 1H and 13C spectra
for all new compounds (2a−u and 5−8) (PDF)
economic viability of our method. Despite the lower catalyst
loading, the reaction still showed high reactivity, affording diene
2a in an excellent yield of 91% after 5 h.
AUTHOR INFORMATION
1,3-Dienes are versatile substrates and building blocks for the
synthesis of a variety of carbo- and heterocycles as well as
natural products13−16 and also starting materials for polymer-
izations.17 Therefore, we investigated a variety of chemical
transformations with the obtained 1,3-dienes to demonstrate
their synthetic value (Scheme 4). Compound 2a was used as
the model substrate. In a BF3-mediated condensation−
cyclization cascade, diene 2a was converted to N-arylindole 5
with p-benzoquinone in 70% yield. Mesylation of compound 2a
■
Corresponding Author
*E-mail: nachtsheim@uni-bremen.de.
ORCID
Boris J. Nachtsheim: 0000-0002-3759-2770
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b02630
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Letter
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ACKNOWLEDGMENTS
■
We thank the Fonds der Chemischen Industrie (FCI) for
financial support (Sachkostenzuschuss).
Commun. 2014, 50, 4459. (e) Brand, J. P.; Gonzal
Waser, J. Chem. Commun. 2011, 47, 102.
́
ez, D. F.; Nicolai, S.;
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