Sulfur-Directed Ligand-Free C-H Borylation by Iridium Catalysis

Article abstract of DOI:10.1021/acs.orglett.7b03008

An iridium-catalyzed ortho C-H borylation reaction directed by cyclic dithioacetal moiety is disclosed. A series of borylation products were obtained in moderate to good yields under mild conditions in exclusive mono- and ortho-regioselectivity. Thus, the 1,3-dithiane or 1,3-dithiolane group serves as a remarkable effective directing group for C-H borylation without any ligand assistance. The further transformations of the borylation products are also carried out to change boryl group to other functional groups.

Full text of DOI:10.1021/acs.orglett.7b03008

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Sulfur-Directed Ligand-Free C−H Borylation by Iridium Catalysis
Li Liu,† Guanghui Wang,† Jiao Jiao,‡ and Pengfei Li*,†
†Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710054, China
‡Department of Applied Chemistry, School of Science, Xi’an Jiaotong University, Xi’an 710049 China
S
* Supporting Information
ABSTRACT: An iridium-catalyzed ortho C−H borylation reaction directed
by cyclic dithioacetal moiety is disclosed. A series of borylation products
were obtained in moderate to good yields under mild conditions in exclusive
mono- and ortho-regioselectivity. Thus, the 1,3-dithiane or 1,3-dithiolane
group serves as a remarkable effective directing group for C−H borylation
without any ligand assistance. The further transformations of the borylation
products are also carried out to change boryl group to other functional
groups.
Scheme 1. Transition-Metal-Catalyzed Ortho C−H
rganoboron compounds are well-known as valuable
synthetic scaffolds in preparation of drugs, agrochemicals
Borylation of Thioethers
O
and organic materials.1 In comparison with the conventional
methods based on functional group transformations, the direct
C−H borylation, as a more atom-efficient approach for
preparation of organoboron compounds, has gained tremen-
dous attention in the past decades.2 Among these, one of the
important and effective strategies for regioselective borylation is
ortho C−H borylation directed by a functional group within a
substrate. Currently, effective directing groups have included
esters, ethers, amines, imines, amides, carbamates, phosphines,
and hydrosilanes.3 These groups are mainly based on the
coordinative oxygen, nitrogen, phosphine atoms, etc., which are
essential to stabilize the metallacycle intermediate. In contrast,
sulfur, generally regarded as a strongly coordinative atom with
transition metals, has been far less explored in directed C−H
activation. Thioether is widely present in many bioactive
compounds and natural products. Moreover, its transforma-
tions to various functional groups are well investigated.
Therefore, the utilization of thioether as a directing group for
ortho C−H borylation should be of great potential in preparing
transformative boron- and sulfur-containing building blocks.
However, only limited examples have recently been disclosed
for ortho C−H borylation directed by thioethers. Braun and co-
workers used an −SCF3 group as a directing group to achieve
Rh-catalyzed ortho C−H borylation reactions (Scheme 1, eq 1);
monoborylation and 2,6-diborylation products could be
obtained.4 Kuninobu and Kanai also reported an ortho C−H
borylation using aryl alkyl thioethers as the substrates.5 A Lewis
acidic boryl group that was incorporated into a bipyridine
ligand was thought to be key for recognizing the thioether
group through acid−base interaction and promoted the ortho
selective C−H borylation (Scheme 1, eq 2). During the
submission of this manuscript, iridium-catalyed ortho C−H
borylation of phenol and aniline derivatives using a
methylthiomethyl (MTM) protecting group has appeared.6 In
this work, we report an iridium-catalyzed ligand-free ortho C−H
monoselective borylation reaction of various 2-aryl 1,3-
dithianes and 1,3-dithiolanes (Scheme 1, eq 3). Notably, the
dithioacetal compounds can be readily prepared from aldehydes
and have previously been widely used as protected carbonyls or
umpolung synthons in organic synthesis.7,8
As shown in Table 1, the reaction conditions were
investigated with 2-phenyl-1,3-dithiane as a model substrate,
which was readily prepared in one step from benzaldehyde.
Several transition-metal catalysts were initially tested. Pd-
(OAc)2 is totally ineffective for the reaction (Table 1, entry 1).
Ruthenium and rhodium catalysts promoted the reaction to
furnish ortho monoborylation product 2a exclusively, although
Received: September 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Sulfur-Directed Ortho C−H
Scheme 2. Scope of Iridium-Catalyzed Ortho C(sp2)−H
a
a
Borylation
Borylation of 2-Aryl-1,3-dithianes and 1,3-Dithiolanes
b
b
entry
[M]
ligand
conv (%)
yield (%)
1
Pd(OAc)2
0
15
20
28
91
10
17
55
80
43
53
10
58
60
0
12
17
86
87
8
2
Ru(PPh3)3Cl2
[RhCl(cod)]2
[Ir(OMe)(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
3
4
5
6
PPh3
PCy3
dtbpy
7
15
53
77
42
51
6
8
9
10
11
12
13
14
55
56
a
Reaction conditions: 1a (0.5 mmol), B2pin2 (0.6 mmol), [M] 2 mol
b
% in 1.0 mL of solvent, 80 °C, 20 h. Conversion, yields were based on
1H NMR analysis of the crude products with 1a as the limiting reagent.
in quite low yields (Table 1, entries 2 and 3). To our delight,
the reaction proceeded in high conversion using 1 mol % of
[IrOMe(cod)]2 or [IrCl(cod)]2, giving the desired product in
86% and 87% yield, respectively (Table 1, entries 4 and 5).
Attempts at addition of P- or N-based ligands were
unsuccessful; all of the reactions were dramatically inhibited
(Table 1, entries 6−8). At last, various solvents were also
screened (Table 1, entries 9−14), and the results showed that
nonpolar solvent n-hexane was the best and gave highest
conversion to 2a.
With the optimized reaction conditions in hand, we explored
the substrate scope by varying both the substituents on the aryl
group and the size of the dithioacetal ring. (Scheme 2). In
general, the sterically less encumbered five-membered 1,3-
dithiolane substrates (2c, 2e, 2j, 2l, 2n) were also effective for
this reaction system, although the reaction temperature had to
be raised to 100 °C. Both electron-withdrawing and electron-
donating groups at the para or meta position were found to be
compatible in the present ortho-borylation reaction, giving the
desired products in moderate to good yields (2b−p). Reactive
halogen groups such as −Br and −I atoms were retained (2i, 2j,
2o, 2p). Interestingly, the substrates bearing potentially
competitive directing groups such as an ester group (1d, 1e)3
or an −SMe group (1g)5 exclusively yielded the monobor-
ylation products at the ortho position of 1,3-dithiane. These
results make the current method complementary to the
previous works in controlling site selectivity of the borylation
of multisubstituted arenes. Ortho-substituted 2-aryl 1,3-
dithianes, however, were much less reactive under the present
conditions. While 2-(o-tolyl)-1,3-dithiane (1q) gave mono-
borylation product 2q in 70% yield accompanied by benzylic
C−H borylation product (2q′, not shown) in 20% yield,
substrates such as 1r and 1s were totally unreactive. These
results were consistent with the fact that no 2,6-diborylation
products have been detected in all cases. The ortho-substituent
might inhibit the reaction by sterically or electronically forcing
a
Reaction conditions: 1 (0.5 mmol), B2pin2 (0.6 mmol), [IrCl(cod)]2
(0.005 mmol) in 1.0 mL of n-hexane, 80 °C, 20 h, yields were based
b
on isolated spectroscopically pure materials. Reaction temperature:
100 °C. Reaction temperature: 90 °C. Monoborylation of methyl
group (2q′) was observed in 20% yield.
c
d
improper conformation of the dithioacetal group, which is
necessary for successful directed borylation. Furthermore, 2-
naphthaldehyde-derived 1,3-dithiane and 1,3-dithiolane could
be selectively borylated at the 3-position (2t, 2u). Five-
membered heteroaryl 1,3-dithianes also yielded 2v and 2w in
moderate yields. In the case of ferrocene-containing substrate,
excellent regioselectivity was observed in this reaction system
(2x). Finally, a 1.5 mmol scale reaction of 1a under the
standard conditions provided 2a in 76% isolated yield.
We then tested if this catalytic system could be applicable to
substrates bearing flexible acyclic thioethers (Scheme 3).
Treatment of benzyl(methyl)sulfane (3a) under the standard
conditions resulted in the formation of ortho-monoborylation
(4a) and 2,6-diborylation product (5a) in 50% and 46% yield,
respectively. Similarly, benzyl(phenyl)sulfane (3b) gave the
monoborylation compound 4b in 52% yield and the
diborylation product 5b in 47% yield. The fact that the sum
B
DOI: 10.1021/acs.orglett.7b03008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 3. Thioether Directed C−H Borylation
Scheme 5. Proposed Mechanism of Ortho-Borylation of 1a
a
Reaction conditions: substrate 3 (0.5 mmol), B2pin2 (0.6 mmol),
[IrCl(cod)]2 (0.005 mmol) in 1.0 mL of n-hexane, 80 °C, 20 h.
b
Isolated yield.
of the yields of the monoborylation and the diborylation
products was over 100% indicated that HBpin also took part in
this reaction.
Based on the observation where 1q afforded 20% of C(sp3)−
H borylation product 2q′ (Scheme 2), we also explored this
method in benzylic C(sp3)−H borylation (Scheme 4), which
a,b
Scheme 4. Thioether-Directed C(sp3)−H Borylation
afforded monoborylation products. More comprehensive
study of the mechanism is ongoing to understand the reaction.
Further transformations of the boryl group in 2a were
conducted to demonstrate the potential synthetic usefulness of
the borylation product as shown in Scheme 6. Consequently,
a
Reaction conditions: substrate 6 (0.5 mmol), B2pin2 (0.5 mmol),
[IrCl(cod)]2 (0.005 mmol) in 1.0 mL of n-hexane, 90 °C, 20 h.
Isolated yield. NA: not applicable.
b
has yet been revealed using a sulfur-directing group in the past.9
Thus, under the typical conditions, thioanisole (6a) gave ortho-
borylation products (9a) in 24% yield, and ortho-methylphenyl
methyl thioether 6b yielded a mixture of benzylic mono-
borylation (7b), benzylic diborylation (8b), and ortho-
borylation (9b) products. When 6c was subjected to this
reaction, the corresponding benzylic monoborylation (7c) and
diborylation (8c) products were formed in good overall yield
(75%).
Scheme 6. Transformation of Borylation Product 2a
In considering the possible mechanism of this ligand-free
iridium-catalyzed borylation, we were inspired by a phosphine-
directed ligand-free C−H borylation disclosed by Clark and co-
workers.3k Thus, a thioether moiety might serve as both a
directing group and a supporting ligand in the current
borylation reaction (Scheme 5). Reaction of [IrCl(cod)]2
with the dithioacetal substrate and B2pin2 might form Ir(III)
intermediate A via ligand exchange and oxidative addition. A
plausible intramolecular C−H activation of A then might
generate iridacycle B featuring a C,S-bidentate ligand that
might serve as a supporting ligand for the formally ligand-free
catalysis. Intramolecular C−H oxidative addition might
generate Ir(V) intermediate C which then could undergo
reductive elimination to form D. Ligand exchange of D with the
substrate 1a could produce the borylation product 2a and
Ir(III) hydride E, which finally could undergo σ-bond
metathesis with B2pin2 to regenerate B. Compared to the
flexible benzyldiphenylphosphines4 where ortho-diborylation
products were often formed together with monoborylation
products, the more rigid cyclic dithioacetal substrates should be
more sensitive to ortho-substituents and therefore solely
copper-catalyzed or mediated reactions of 2a with NaN3,
CuCl2, diphenyl disulfide, diphenyl diselenide, and diphenyl
ditelluride under operationally simple conditions smoothly
afforded 2-(2-azidophenyl)-1,3-dithiane (10), 2-(2-
(phenylthio)phenyl)-1,3-dithiane (11), 2-(2-chlorophenyl)-
1,3-dithiane (12), 2-(2-(phenylselanyl)phenyl)-1,3-dithiane
(13), and 2-(2-(phenyltellanyl)phenyl)-1,3-dithiane (14) in
moderate to good yields. The cleavage of the 1,3-dithiane was
C
DOI: 10.1021/acs.orglett.7b03008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3558. (g) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.;
Singleton, D. A.; Maleczka, R. E.; Smith, M. R., III J. Am. Chem. Soc.
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corresponding product 15 in excellent yield.
2012, 134, 11350. (h) Ros, A.; Lop
́
ez-Rodríguez, R.; Estepa, B.;
In summary, we have developed a sulfur-directed, particularly
a cyclic dithioacetal group-directed, ligand-free C−H borylation
reaction using commercially available iridium catalyst. This
highly ortho- and monoselective borylation under operationally
simple conditions provides a new, practical, and complementary
approach for the rapidly developing regioselective C−H
borylation chemistry.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03008.
(4) Kallane, S. I.; Braun, T. Angew. Chem., Int. Ed. 2014, 53, 9311.
(5) Li, H.; Kuninobu, Y.; Kanai, M. Angew. Chem., Int. Ed. 2017, 56,
1495.
(6) Li, H.; Kuninobu, Y.; Kanai, M. Org. Lett. 2017, DOI: 10.1021/
acs.orglett.7b02936.
(7) (a) Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147.
(b) Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365.
(8) For other masked benzaldehydes for directed borylation, see refs
3h, m, and 3n.
Detailed experimental procedures; spectral data of
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lipengfei@mail.xjtu.edu.cn.
ORCID
(9) Directed benzylic C(sp3)−H borylations: (a) Shimada, S.;
Batsanov, A. S.; Howard, J. A. K.; Marder, T. B. Angew. Chem., Int. Ed.
2001, 40, 2168. (b) Ishiyama, T.; Ishida, K.; Takagi, J.; Miyaura, N.
Chem. Lett. 2001, 30, 1082. (c) Tang, C. Y.; Smith, W.; Thompson, A.
L.; Vidovic, D.; Aldridge, S. Angew. Chem., Int. Ed. 2011, 50, 1359.
(d) Cho, S. H.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 8157.
(e) Cho, S. H.; Hartwig, J. F. Chem. Sci. 2014, 5, 694. (f) Palmer, W.
N.; Obligacion, J. V.; Pappas, I.; Chirik, P. J. J. Am. Chem. Soc. 2016,
138, 766. (g) Patel, C.; Abraham, V.; Sunoj, R. B. Organometallics
2017, 36, 151.
Pengfei Li: 0000-0002-4736-2477
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NSFC (Nos. 21672168
and 21702157), the Ministry of Science and Technology of
PRC (No. 2014CB548200), and the Department of Science
and Technology of Shaanxi Province (No. 2015KJXX-02). P.L.
is a “Chung Ying Young Scholar” of Xi’an Jiaotong University.
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DOI: 10.1021/acs.orglett.7b03008
Org. Lett. XXXX, XXX, XXX−XXX