Sulfinyl isobutyramide as an auxiliary for palladium(II)-catalyzed C-H arylation and iodination of benzylamine derivatives

Article abstract of DOI:10.1039/c7ob01163f

A novel readily available bidentate 2-methylsulfinyl isobutyramide directing group has been developed for benzylamine derivatives. It promoted ortho-C-H arylation and iodination of various substrates in good to excellent yields. The auxiliary is promising to be used in organic synthesis due to its versatility and convenient preparation from inexpensive materials.

Full text of DOI:10.1039/c7ob01163f

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Sulfinyl Isobutyramide as an Auxiliary for Palladium(II)-Catalyzed
C–H Arylation and Iodination of Benzylamine Derivatives†
Rui Wang,‡a,b Yongzheng Ding‡a,b and Gang Li*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel readily available bidentate 2-methylsulfinyl isobutyramide
directing group has been developed for benzylamine derivatives.
It promoted ortho-C–H arylation and iodination of various
substrates in good to excellent yields. The auxiliary is promising to
be used in organic synthesis due to its versatility and convenient
preparation from inexpensive materials.
During the last decade, great progress has been made in the
field of transition-metal-catalyzed direct C–H functionalization,
which largely relies on the use of elaborately designed
directing groups (DGs) to control the site-selectivity and
1
promote the reactivity of substrates. The currently widely
Scheme 1 Alkylsulfinyl-based bidentate amide DGs.
employed bidentate DG is one representative type of such DGs
1g,i,k,2
for C–H activation.
After the seminal work of Daugulis to
Although monodentate sulfoxides have been well-explored
as versatile DGs9a by the groups of Antonchick, Wencel-
use picolinamide and 8-aminoquinoline amide for the
palladium-catalyzed γ- and β-arylation of amine and carboxylic
9b
9c,f,g
9d,e
9a
3
Delord and Colobert,
Zhang,
and others, sulfoxide-
acid derivatives, respectively,
a variety of innovative
4a
4b,d based bidentate DGs are very limited and only two types of
4i arylsulfinyl amide bidentate DGs were reported for carboxylic
bidentate DGs have been disclosed by Chatani, Chen,
Sahoo, Carretero, Shi, Ma, Ackermann, Dai and Yu,
4c
4e
4f,p
4g
4h
10
4j
4k,l
4m
4n,o
and others2,4q-v to
acid derivatives recently. First, Wencel-Delord and Colobert
reported an elegant work of enantiopure sulfinyl aniline
Zhao, Niu and Song, Hong, Shi,
assist a large variety of C–H transformations with different
3
2,5,6
auxiliary assisted asymmetric C(sp )–H arylation and alkylation
transition-metals.
Due to the tremendous advances in C–H
1
0a
of cyclopropane carboxylic acid. Shortly afterwards, Chen
functionalization, such methods have gradually been applied
7
and He disclosed a pair of ortho-sulfinylaniline auxiliaries for
to synthesize biologically active compounds. However,
3
challenging palladium-catalyzed β-C(sp )–H arylation of
industrial scale use of these methods continues to be
7c,e-f
aliphatic carboxylic acid derivatives with sterically hindered
extremely scarce.
As a notable exception, the industrial
10b
aryl iodides.
However, to the best of our knowledge, a
ton-scale synthesis of flubendiamide employs a C–H iodination
sulfoxide-based bidenate DG has not been developed for
c,8 amines to date. Since the potential of bidentate DGs to
promote various C–H functionalizations has been successfully
proved, the development of a novel bidentate DG that is
assisted by a robust bidentate DG containing chelating
moieties of a methylsulfoxide and an amide (Scheme 1a).7
Inspired by this industrial application, we envisioned a
sulfoxide-based
(i.e.,
2-methylsulfinyl
isobutyramide)
robust and conveniently available is highly desirable. Herein,
we disclose an original bidentate 2-methylsulfinyl
bidentate DG could be developed for an amine substrate (e.g.
benzylamine) to effect a C–H bond activation (Scheme 1b).
3a,11
12
isobutyramide auxiliary for C–H arylation
and iodination
Notably, the precursor of 2-
methylsulfinyl isobutyramide, 2-methylsulfinyl isobutyric acid
), could be readily available from inexpensive materials,
13,14
of benzylamines (Scheme 1b).
a.Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian
Institute of Research on the Structure of Matter, Chinese Academy of Sciences,
Fuzhou, Fujian, 350002, P. R. China. E-mail: gangli@fjirsm.ac.cn.
(2
b.
University of Chinese Academy of Sciences, Beijing 100049, P. R. China.
which is beneficial for its potentially practical use in organic
synthesis (Scheme 2).
†
Electronic Supplementary Information (ESI) available: Experimental procedures
and data for new compounds. See DOI: 10.1039/x0xx00000x
These authors contributed equally.
‡
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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4
a
di even when the conversions were not high, which is
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DOI: 10.1039/C7OB01163F
possibly due to the strong coordination of the 2-methylsulfinyl
isobutyramide to the palladium center and that the mono-
arylated product 4amono is at least as reactive towards C–H
activation as the substrate 3a. The reaction condition
screening began with testing different solvents, and HFIP
Scheme 2 Synthesis of 2-methylsulfinyl isobutyric acid 2.
1
0,16
turned out to be the optimal solvent (entries 2-5).
Then the
Our study commenced with preparing 2-methylsulfinyl
isobutyric acid ( ) from inexpensive ethyl 2-bromo-2-
methylpropanoate ( ) in a multiple-gram scale under mild
conventional conditions. Then condensation of benzylamine
with acid afforded 3a as the substrate for investigating the
reaction temperature was evaluated and higher catalytic
turnover of the Pd catalyst was observed at 100 °C (entry 6-7),
although it was later found that high yield of desired product
could also be obtained at 80 °C by extending the reaction time
2
1
15
2
to 48 hours (vide infra). Furthermore, K
be most effective when screening bases both at 120 and
00 °C (entries 8-12). Importantly, the use of heavy metal salts
2 4
HPO was proved to
capability of 2-methylsulfinyl isobutyramide as a bidentate DG.
After screening a wide variety of reaction conditions with
1
Pd(OAc)
2
as the catalyst, we were delighted to find that the
HPO
was crucial and AgOAc worked much better than other salts
used (entries 13-16). Moreover, less coupling partner of 4-
iodotoluene resulted in worse conversion of the substrate
reaction of 3a with 4-iodotoluene, AgOAc, and K
2
4
afforded desired arylated products 4a in 91% combined yield
in HFIP (hexafluoro-2-propanol) at 100 °C for 12 hours (Table 1,
entry 1). During the reaction condition optimization, it was
noticed that the reaction preferred to give di-arlylated product
(entry 17). Finally, longer reaction time led to more production
of di-arylated product with the highest catalytic turnover of
the Pd catalyst and this condition was used to expand the
substrate scope (entry 18). It should be mentioned that many
efforts were made to improve the generation of mono-
arylated product. For instance, competing monodentate or
bidentate ligands, such as pyridine-based ligands and mono-
protected amino acid ligands, were added as additives which
might promote the release of Pd catalyst from the mono-
Table 1 Optimization of ortho-C–H arylation reaction conditions
Table 2 Substrate scope of ortho-C–H arylationa
Yield (%)
[
Entry
Variation from the standard condition
4amono, 4adi]b
1
2
3
4
5
6
7
8
9
none
91 [3, 88]
8 [8, trace]
10 [10, trace]
20 [14, 6]
45 [10, 35]
36 [3, 33]
91 [6, 85]
78 [7, 71]
20 [11, 9]c
34 [14, 20]c
trace
t-Amyl-OH instead of HFIP
t-BuOH instead of HFIP
DCE instead of HFIP
TFE instead of HFIP
at 80 °C
at 120 °C
K
3
PO
KH PO
Na HPO
Li PO instead of K
KHCO instead of K
AgOTFA instead of AgOAc
4
instead of K
instead of K
instead of K
2
HPO
4
at 120 °C
2
4
2
HPO
4
at 120 °C
at 120 °C
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
2
4
2
HPO
4
3
4
2
HPO
4
3
2
HPO
4
trace
26 [6, 20]
27 [trace, 27]
17 [trace, 17]
16 [5, 11]
77 [5, 72]
91 [trace, 91]
Ag
Ag
2
CO
3
instead of AgOAc
instead of AgOAc
3
PO
4
Cu(OAc) instead of AgOAc
2
2 equiv of p-Tol-I
24 h instead of 12 h
a
Reaction conditions: 3a (0.1 mmol), p-Tol-I (0.3 mmol), Pd(OAc)
0.01 mmol), AgOAc (0.25 mmol), K HPO (0.3 mmol), HFIP (1.0 mL),
2
(
1
2
4
b
1
2 h, 100 °C. The yield was determined by H NMR using CH
2
Br as
2
c
a
Reaction conditions: 3 (0.2 mmol), p-Tol-I (0.6 mmol),
the internal standard. Base (0.2 mmol) and p-Tol-I (0.2 mmol). HFIP,
hexafluoro-2-propanol; TFE, 2,2,2-trifluoroethanol.
Pd(OAc)
2
(0.02 mmol), AgOAc (0.5 mmol), K
2
HPO
4
(0.6 mmol),
b
HFIP (2.0 mL), 24 h, 100 °C. Isolated yields. The yield in 4
mmol (3d) scale. The yield of the reaction run at 80 °C, 48 h.
c
2
| J. Name., 2012, 00, 1-3
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(5f)
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arylated product to avoid subsequent second C–H activation excellently as coupling partners. Other groups such as CF
3
and CO
2
Me (5g) at the para-position of io
D
d
O
o
I
b
: 1
e
0
n
.1
z
0
e
3
n
9
e
/C
w
7O
e
B
re01
a
16ls
3F
o
(see ESI†). However, all of these efforts to reverse the ratio of
tolerated to deliver the desired products. Moreover, meta-
substituted iodobenzenes with methyl (5h), chloro (5i), and
CO Me (5j) groups were also viable, producing good to
2
excellent yields of arylated products. However, ortho-
substituted aryl iodides were unreactive under the optimized
reaction conditions possibly due to the steric hindrance of the
mono-arylated product failed (see ESI† for more reaction
screenings).
With the optimized conditions in hand, we examined the
substrate scope of this reaction (Table 2). The model substrate
3
a gave 82% isolated yield of 4adi in 24 hours. Ortho-
substituted substrates with both electron-donating methoxyl
and electron-withdrawing fluoro and chloro groups were
suitable substrates, producing good yields of desired products
13d
ortho-substituents.
To examine the versatility of the 2-methylsulfinyl
isobutyramide as a bidentate DG of benzylamine for different
transformations, ortho-C–H iodination was then investigated.
After screening the reaction conditions, it was found that high
combined yield of iodinated products could be obtained for 3a
with NIS (N-Iodosuccinimide) as the iodination reagent in DCE
with HFIP as a co-solvent at 100 °C for 12 hours (see ESI† for
reaction condition screenings). Thus, 86% of combined yield of
iodinated products were delivered for simple benzylamine
(
4b
-
4d). High yields of arylated products were also obtained
4h), and the
with several meta-substituted substrates (4e
-
small fluoro group allowed the formation of minor di-arylated
product. Notably, 89% yield of ortho-arylated product 4f were
delivered at a lower temperature of 80 °C for 48 hours, while
the arylation of benzylamines using the privileged bidentate
picolinamide DG normally required high temperatures (120 to
3
,11a,b
1
50 °C ).
To our delight, para-substituents such as
4m) were tolerated,
(
Table 4,
groups at the ortho-position were well tolerated to produce
high yields of desired products ( 11). Moreover, several meta-
and para-substituted substrates proceeded smoothly to
generate the desired iodinated products (12 16). Finally,
excellent yield of iodinated product was also obtained with the
,4-dichlorinated benzylamine derivative (17).
6). Both electron-donating and electron-withdrawing
methoxyl (4i), methyl (4j), and halides (4k
-
leading to high yields of di-arylated products. It is worth noting
that benzylamines bearing chloro or bromo substituents (4k
and 4m) were compatible substrates, which may allow further
elaborations at these halogenated positions. Furthermore, di-
substituted substrates were also briefly tested to give
acceptable yields of desired products (4n and 4o). Finally, the
arylated product could be transformed to a Boc protected
ortho-arylated benzylamine, together with removal of the
amide auxiliary in a one-pot reaction under conventional
conditions (see ESI† for details).
7
-
-
2
Table 4 Scope of ortho-C–H iodinationa
The scope of the reaction was then further expanded with
other aryl iodides using 3d as the substrate (Table 3).
Pleasingly, iodobenzene (5a) as well as para-methoxylated (5b
)
and para-halogenated iodobenzenes (5c
-5e) worked
Table 3 Scope of aryl iodide coupling partnersa
a
Reaction conditions: 3 (0.20 mmol), NIS (0.44 mmol),
Pd(OAc)
2
(0.02 mmol), DCE/HFIP (1.6 mL/0.4 mL), 12 h,
b
1
00 °C . Isolated yields. The yield in 3 mmol (3d) scale. NIS,
N-Iodosuccinimide.
Conclusions
a
General reaction conditions: 3d (0.10 mmol), ArI (0.30
(0.01 mmol), AgOAc (0.25 mmol), K HPO
In conclusion, a novel 2-methylsulfinyl isobutyramide
bidentate DG has been developed for ortho-C–H arylation and
mmol), Pd(OAc)
2
2
b
4
(
0.30 mmol), HFIP (1.0 mL), 24 h, 100 °C . Isolated yields. 20 h.
c
d
4
8 h. In a 0.2 mmol scale.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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iodination of benzylamine derivatives, leading to good to
excellent yields of desired products with a variety of substrates.
The versatility of the DG for promoting different C–H
transformations paved the way for further exploration of the
directing ability of this auxiliary. Other C–H functionalizations
such as activation of C(sp )–H bonds using this auxiliary and
development of chiral variants of it are currently underway in
our lab.
D. Ma, Angew. Chem., Int. Ed., 2013, 52, 12152;Vi(ehw)AQrti.clGe Oun,liHne.
H. Al Mamari, K. Graczyk, E. Diers and L. Ackermann, Angew.
DOI: 10.1039/C7OB01163F
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Strategic Priority Research Program of the Chinese Academy of
Sciences (Grant No. XDB20000000), the “National 1000 Youth
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Organic & Biomolecular Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C7OB01163F
An original readily available and versatile bidentate 2-methylsulfinyl isobutyramide directing
group has been developed for benzylamine derivatives.