Iron catalyzed oxidative assembly of N-heteroaryl and aryl metal reagents using oxygen as an oxidant

Article abstract of DOI:10.1039/c4cc08494b

An equivalent amount of N-heteroaryl and aryl Grignard or lithium reagents, after mediation by an equivalent of titanate, was facilely coupled to furnish N-heteroaryl-aryl compounds under the catalysis of FeCl₃/TMEDA at ambient temperature using oxygen as an oxidant. Most of the common N-heteroaryls were all good candidates, and thus provided a general, green and pratical protocol for the flexible construction of various N-heteroaryl-aryl structures. This journal is

Full text of DOI:10.1039/c4cc08494b

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COMMUNICATION
Iron Catalyzed Oxidative Assembly of Nꢀheteroaryl
and Aryl Metal Reagents Using Oxygen as an Oxidant
Cite this: DOI: 10.1039/x0xx00000x
Kun Ming Liu, Lian Yan Liao, and Xin Fang Duan*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
An equivalent amount of Nꢀheteroaryl and aryl Grignard or
lithium reagents, after mediated by an equivalent of titanate,
was facilely coupled to furnish Nꢀheteroarylꢀaryl compounds
under the catalysis of FeCl3/TMEDA at ambient temperature
using oxygen as an oxidant. Most of common Nꢀheteroaryls
were all good candidates, and thus provided a general, green
and pratical protocol for the flexible construction of various
Nꢀheteroarylꢀaryl structures.
Scheme 1. Ironꢀcatalyzed oxidative crossꢀcoupling of titanate
mediated two aryl metal reagents.
Herein we wish to report a novel ironꢀcatalyzed oxidative arylꢀaryl
crossꢀcoupling of titanateꢀmediated two aryl Grignard or lithium
reagents using oxygen as an oxidant (Scheme 1). Aryl magnesium
halides (ArMgX, 1) are transmetalated to the corresponding titanium
reagents [ArTi(OR)3, 2] using ClTi(OR)3.11 Subsequent reaction in
situ with Nꢀheteroaryl metal reagents (ArNM, 3) results in the
formation of a mixed titanate of type 4 (ArN[ArTi(OR)3]M),12 which
is treated with FeCl3/TMEDA/O2 to provide the biaryl products
through an ironꢀcatalyzed oxidative crossꢀcoupling (Scheme 1).
Because the pyridyl skeletons are prevalent in natural products,
pharmaceuticals and functional materials,13 and at the same time, the
preparation of benchꢀstable 2ꢀpyridyl metal reagents (such as
boronic derivatives) and their cross couplings are usually a
challenging task in organic synthesis,14 our initial study focused on
the model reaction between the 2ꢀpyridyl and phenyl Grignard
Biaryls, including those containing Nꢀheteroaryl components occur
ubiquitously in biologically active compounds, natural products and
functional materials. Transitionꢀmetal catalyzed crossꢀcoupling
reactions of an organometallic reagent with an aryl halide or
pseudohalide are among the most common methods for making
these biaryls and heterobiaryls.1 Recently, oxidative couplings of
organometallics2 have attracted much attention due to the advantages
such as: (a) a wide variety of metal reagents can be used, and in
particular the great advances in the direct metalation of arenes and
heteroarenes enable this type of oxidative couplings using simple or
functionalized arenes;3 and (b) it can avoid the use of halides or
halide equivalents as well as the process of their oxidative addition
to a transition metal complex that usually requires special ligands for
unreactive halides.4 Actually, if molecular oxygen is used as an
oxidant, an ideal oxidative coupling of this type will provide the
desired products with peroxide inorganic salts as side products.
These advantageous features are fully displayed in the Fe or Mnꢀ
catalyzed aerobic oxidative homocouplings of Grignard reagents
reported by Cahiez, Lei and coꢀworkers.5,6 However, the crossꢀ
couplings of this type are very challenging because of the potential
side homocoupling reactions of the two metal reagents. Only few
examples of this oxidative crossꢀcoupling have been described to
date, most of which are achieved between different hybridized
carbon atoms such as C(sp)―C(sp2);7 C(sp)―C(sp3);8 C(sp2)―
C(sp3).9 The examples of oxidative arylꢀaryl cross couplings are
very rare.7b, 10 Obviously, the similar reactivity of the organometallic
reagents makes the arylꢀaryl oxidative cross couplings remarkably
challenging.
FeCl3
TMEDA
PhPy PyPy
+
5aa
PhPh
91%
2%
+
+
PhMgBr
2-PyMgBr
DCE
1a
3a
<10%, trace
FeCl3
TMEDA
3a
PhTi(OPri)3
in situ
from 1a
92%, trace
Py[PhTi(OPri)3]MgBr
DCE
4aa
M = MgBr:
2%
FeCl3
TMEDA
90%, trace
88%, trace
PhTi(OPri)3
2-PyM
Py[PhTi(OPri)3]M
DCE
M = Li:
3%
purified solid
1a
Ph[PyTi(OPri)3]MgBr
2-PyTi(OPri)3
ClTi(OPri)3
2-PyMgBr
+
×
4'aa
3a
Scheme 2. The influence of titanate mediation in the ironꢀcatalyzed
oxidative crossꢀcouplings. Reaction conditions: 10 mol% FeCl3 / 30
mol% TMEDA, RT. DCE = 1,2ꢀdichloroethane.
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reagents, hoping to find an alternative method for making Nꢀ
heteroaryl structures using readily available 2ꢀpyridyl Grignard or
lithium reagents under mild conditions. As illustrated in Scheme 2,
almost no crossꢀcoupling product was observed without the
mediation of a titanate. In this case the homocoupling of phenyl
group took place rapidly with high yield. To our delight, after
PhMgBr was transmetalated into PhTi(OPri)3, and subsequently into
4aa through the inꢀsitu treatment with 3a, the oxidative coupling
generated the crossꢀcoupling product (5aa) in a high yield. The
comparison experiments in which the mixed titanate 4aa were
formed from the purified PhTi(OPri)3 and 2ꢀPyM (M = MgBr, Li)
also gave similarly high yield of 5aa, indicating that the formation of
the mixed titanate (4aa) was crucial to the high selectivity of the
oxidative crossꢀcoupling while the influence of magnesium or
lithium salts from 1a or 3a was not significant. Further attempts on
the crossꢀcoupling using the mixed titanate (4′aa, through
transmetalation in a reverse sequence, Scheme 2) was unsuccessful
because of the instability of 2ꢀPyTi(OPri)3 (our experiments showed
that a combination of 2ꢀPyMgX and ClTi(OPri)3 resulted in a black
complex mixture).11a These observations showed that the formation
of the mixed titanate of type 4aa could adjust the reactivity of both
ArMgX and 2ꢀPyM in a suitable and combined manner (the Ph
group through C―Ti bond and the 2ꢀPy group through an ateꢀ
complex), which not only played a key role in the high selectivity of
crossꢀcoupling, but also provided a method to circumvent the
problem of the instability of 2ꢀPyTi(OPri)3.
Table 1. The optimization studies on the oxidative crossꢀcoupling reaction of
titanateꢀmediated 1a and 3a.a
entry
1
2
3
4
5
6
7
8
catalystb
titanate
[O]
O2
time (h)
yield (%)c
ꢀꢀ
PdCl2/dpppd
NiCl2/dppp
FeCl3
ClTi(OPri)3
ClTi(OPri)3
ClTi(OPri)3
ClTi(OPri)3
ClTi(OPri)3
ClTi(OPri)3
ClTi(OPri)3
12
12
12
4
4
4
4
4
4
4
4
8
4
24
8
DCE
DCE
DCE
DCE
DCE
DCE
16
64
87
82
78
72
92
90
90
97
92
95
76
96
FeCl3/PBu3
FeCl3/PCy3
FeCl3/dppp
FeCl3/dmadppd
FeCl3/tmeda
FeCl3/tmeda
FeCl3/tmeda
FeCl3/tmeda
Fe(acac)3/tmeda
FeCl3/tmedae
FeCl3/tmedae
FeCl3/tmedae
ClTi(OiPr)3 DCE
9
ClTi(OEt)3
DCE
DCE
DCE
DCE
DCE
Dry airf
10
11
12
13
14
15
tmpcd
tbepcd
tbepc
tbepc
tbepc
tbepc
f
O2
aThe reaction was carried out on a 1 mmol scale at room temperature.
bUnless indicated otherwise, the catalyst metals were charged in 10 mol
% with 20 mol % (monodentate), 10 mol % (bidentate) ligand or 30 mol
% TMEDA. cIsolated yield. dBelow are their structures e8 mol% FeCl3 /
20 mol% TMEDA. f1 atm.
O
Ti
O
O
OiPr
Cl
Ph2P
PPh2
Ti
dppp
O
Cl
O
OiPr
Me2N
PPh2
tmpc
dmadpp
tbepc
Further optimization studies on the oxidative crossꢀcoupling reaction
of 1a and 3a were performed with the results being summarized in
Table 1. Compared with iron catalysis, the Pd or Niꢀcatalyzed
reactions gave rather low or no yields of crossꢀcoupling product
(entries 1 and 2), indicating a significant synergetic effect between
iron and titanium.15 While the simple phosphine ligands such as
PBu3, PCy3, dppp, dmadpp can improve the crossꢀcoupling,
FeCl3/TMEDA proved to be the most effective catalyst system,
which promote the oxidative crossꢀcouplings in a yield up to 92%
(entries 3ꢀ8). Also, we examined the influence of different titanates
(entries 9ꢀ11). It could be seen that most of tested titanates promoted
the crossꢀ coupling in high yields. To our delight, the crossꢀcoupling
occurred in a quantitative yield by using easily prepared and
handling solid tbepc (entry 11). Fe(acac)3 could also promote the
cross coupling equally well, yet with prolonged reaction time (entry
12). Lowering the loading of catalyst to 8 mol % FeCl3 / 20 mol %
TMEDA did not affect the yield (entry 13). At this point, an
equivalent amount of two different aryl Grignard reagents, after
mediated with a titanate, was quantitatively coupled at room
temperature under the catalysis of iron using DCE as an oxidant.
Bearing in mind that atmospheric oxygen or oxygen is indeed the
greenest candidate oxidant, we tried to use atmospheric oxygen or
oxygen as an oxidant in this reaction (entries 14 and 15). It was
observed that while dry air could give an acceptable yield (76%) in
prolonged reaction time, the reaction using oxygen could proceed
equally well with those using DCE.
conditions, C―Br and C―Cl bonds were tolerated as well (5ae, 5da
and 5fe). Other metal reagents of pyridine analogues such as 2ꢀ
phenylpyridine, quinoline and isoquinoline also underwent the
reaction quite well (5faꢀ5ig). Under Pd or Ni catalysis, the reactions
giving biheteroaryls are often challenging due to the chelation of the
product with the catalyst metal.17 In contrast, the present coupling
could assemble this type of biheteroaryls such as 5fa, 5fe, 5hf and
5pf in good yields. Besides, the coupling of isoquinoline metal
reagent with a sterically hindered Grignard reagent could afford a
useful axially chiral ligand (5ih)18 in a high yield. Further studies on
the scope of this oxidative biaryl crossꢀcoupling reaction indicate
that in addition to pyridine and (iso)quinoline derivatives, most of
other common Nꢀheteroarenes such as benzoimidazole, benzoꢀ
thiazole, benzoxazole, quinoxaline, pyrimidine, pyrazole, purine and
19
caffeine could all undergo the reaction well (5jaꢀ5rk).3d,
Once
again, various aryl Grignard reagents with functional groups were
amenable to the coupling. Noticeably, lithiation of benzoxazole at Cꢀ
2
and subsequent quenchment with electrophiles are often
challenging due to the isomerization of this metal species to 2ꢀ
(isocyano)phenolate.20 Under our conditions, 2ꢀbenzoxazolyl lithium
(lithiating benzoxazole using TMPLi at ―40 °C), after mediated by
tbepc, underwent the crossꢀcoupling at ambient temperature to afford
the product 5ma and 5mi in a 88% and 81% yield respectively. Since
the methods for the direct metalation of a wide variety of Nꢀ
heteroarenes have been well established,3 taking full advantage of
these achievements, this oxidative crossꢀcoupling reaction can
provide a general and very mild protocol for preparing various Nꢀ
heteroarylꢀaryl structures with various Nꢀheteroarenes as starting
materials.
Since the present coupling allowed the flexible assembly of various
aryl and Nꢀheteroaryl metal reagents, we believe that it should find
wide application in the rapid access to the biologically active
compounds through the combination of two metal reagents of key
structural units or by a lateꢀstage functionalization of naturally
occurring privileged structures. To demonstrate the feasibility of this
The above reaction represents the first example of ironꢀcatalyzed
oxidative arylation of 2ꢀpyridyl metal reagents, providing a very
mild method for making 2ꢀarylpyridines complementary to the
16
existing methods.14,
On the basis of these findings, we then
investigated the scope of this oxidative crossꢀcoupling reaction
between various aryl and Nꢀheteroaryl Grignard or lithium reagents.
The results are summarized in Table 2. This crossꢀcoupling reaction
showed a very broad scope with remarkable functionalꢀgroup
tolerance. Aryl Grignard reagents functionalized with a sensitive
ester and CN group could couple well in high yields (5ac and 5ad).
Various 2ꢀpyridyl metal reagents also gave similarly good results
(5baꢀ5ea). Notably, under the present ironꢀcatalyzed coupling
2 | J. Name., 2012, 00, 1-3
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Table 2. Substrate Scope
5ab (4ꢀOMe) 96%a,c,d,e
5ac (4ꢀCOOEt) 87%a
5ad (2ꢀCN) 81%a
5ba (3ꢀMe) 78%a
5ca (6ꢀOMe) 87%a
5da (5ꢀCl) 87%a
5fa (Ph) 82%a
5fe (4ꢀBrC6H4) 61%a
5ae (4ꢀBr) 76%a
5ea (3ꢀCOOEt) 91%b
Scheme 3. Total Synthesis of Caboxamycin
5ig (4ꢀFC6H4) 89%b
5ga (Ph) 82%b
5hb (4ꢀMeOC6H4) 80%b
5hf (2ꢀthiophenyl) 86%b
5ih
(2ꢀMeOꢀ1ꢀ
5gb(4ꢀMeOC6H4) 76%b
naphthyl) 91%b
5ja (H) 92%b
5ka (Ph) 92%b
5la (Ph) 94%b
5jg (4ꢀF) 83%b
5ki (1ꢀNaphthyl) 92%b
5lj (3ꢀCF3C6H4) 92%b
Scheme 4. Direct Arylation of (S)ꢀnicotine
5oe (4ꢀBrC6H4)77%b
5oj (2ꢀCF3C6H4) 87%b
5ma (Ph) 88%b
5nb(4ꢀMeOC6H4) 78%a
5ng (4ꢀFC6H4) 87%a
Conclusions
5mi (1ꢀNaphthyl) 81%b
We have developed the first general ironꢀcatalyzed oxidative
arylꢀaryl crossꢀcoupling reaction of titanateꢀmediated Nꢀ
heteroaryl and aryl Grignard or lithium reagents using oxygen
as an oxidant. Under FeCl3/TMEDA catalysis, an equivalent
amount of a broad range of aryl and Nꢀheteroaryl metal
reagents, after simply sequentially combined with a titanate,
can oxidatively couple well under mild reaction conditions in
high yields. Since both iron and titanium are abundant, nonꢀ
toxic metals (Titanium is the seventh most abundant metal on
Earth, and the hydrolysis of a lot of titanium compounds will
produce nontoxic and environmentally friendly TiO2.23), and at
the same time oxygen is the greenest oxidant, the present
5ra (Ph) 84%b
5rk (2ꢀEtOOCC6H4)
80%b
5pf (2ꢀthiophenyl) 82%b
5pj (2ꢀCF3C6H4) 72%b
5qa (Ph) 87%b
5qd(2ꢀNCC6H4) 84%b
aNꢀheteroaryl Grignard reagents were prepared via bromine or iodineꢀ
magnesium exchange using iꢀPrMgCl or iꢀPrMgClꢁLiCl. bNꢀheteroaryl
Grignard or lithium reagents were prepared through the metalation of
heteroarenes using TMPMgCl or TMPLi (see Supporting Information for
details). cIsolated yields. d1 atm. eIn most cases, no homodimers of ArNM method proves to be ecoꢀfriendly and highly efficient for the
were observed while 2~6% yields of homodimers of ArM was generated.
flexible construction of various Nꢀheteroarylꢀaryl compounds.
Furthermore, we also believe that the present way of using
titanium centre to ligand and assemble two different anions as
well as the synergetic effect between iron and titanium would
provide guidance for the design of the other crossꢀcoupling
reactions between two nucleophiles. Preliminary mechanistic
investigations showed that this oxidative coupling was not
influenced by the addition of radical scanvenger (TMPO),
suggesting that a radical intermediate may not be involved.
Further mechanistic studies and the development of the
reactions with broader scope are being investigated in our
laboratories.
approach, we investigated the total synthesis of caboxamycin
(Scheme 4)21 and the functionalization of (S)ꢀnicotine (Scheme 5).
The multiꢀgram scale total synthesis of caboxamycin involved an
oxidative coupling of lithium reagent of 6 with a Grignard reagent as
the key step, which furnished the intermidate (7) in 82% yield. The
debenzylation of 7 through atmospheric pressure hydrogenation
afforded caboxamycin in a 80% overall yield. Taking advantage of
the regioslective metalation of (S)ꢀnicotine,22 the lateꢀstage
functionalization of (S)ꢀnicotine also proceeded smoothly, giving the
arylated nicotine (9) in a 92% yield (Scheme 5). Notably, the
successful use of this mixed metal reagent of nicotine
[ArNBF3(MgCl), (8)]22b,c showed the generality in the types of metal
reagents for this oxidative coupling. Overall, the above two
examples fully demonstrate the flexibility and the potential of the
present oxidative biaryl crossꢀcoupling for further development and
applications.
We gratefully acknowledge National Nature Science
Foundation of China (21242006, 21372031).
Notes and references
College of Chemistry, Beijing Normal University, Beijing, 100875,
China. Eꢀmail: xinfangduan@vip.163.com
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4 | J. Name., 2012, 00, 1-3
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Journal Name
ChemComm
View Article Online
COMMUNICATION
DOI: 10.1039/C4CC08494B
Graphical abstract
Iron Catalyzed Oxidative Assembly of Nꢀheteroaryl and Aryl Metal Reagents Using Oxygen as an Oxidant
O
Ti
MgBr
O
O
OPri
Cl
N
N
+
FeCl3 (8 mol %)
TMEDA (20 mol %)
O2 (1 atm), THF, RT
M
N
N
1.0 equiv
1.0 equiv
92%
nontoxic abundant TM
RT and O2 as oxidant
broad substrate scope with high selectivity
scalability (up to 10 mmol)
Nꢀheteroaryl and aryl metal reagents, after mediated by a titanate, were crossꢀcoupled under the catalysis of iron using oxygen.
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