Amino-directed RhIII-catalyzed C-H activation leading to one-pot synthesis of N-H carbazoles

Article abstract of DOI:10.1002/chem.201203856

One-pot synthesis: An efficient amino-directed one-pot synthesis of N-H carbazoles from unprotected 2-aminobiaryl compounds is reported. The free amino unit acts as both a directing group for ortho C-H activation and a functional group for construction of an N-heterocyclic ring (see scheme). Copyright

Full text of DOI:10.1002/chem.201203856

COMMUNICATION
DOI: 10.1002/chem.201203856
III
À
Amino-Directed Rh -Catalyzed C H Activation Leading to One-Pot
À
Synthesis of N H Carbazoles
Qibai Jiang, Dandan Duan-Mu, Wei Zhong, Hao Chen,* and Hong Yan*[a]
Carbazole derivatives are prominent structural motifs of
many bioactive natural products, pharmaceuticals and mate-
rials,[1,2] and intense efforts have focused on the develop-
ment of effective methods to synthesize these compounds.[3]
Recently, intramolecular amination strategies[3g,4–7] have
been reported, as shown in Scheme 1. These have included
type of substrates a single-component metal catalyst may
À
À
not efficiently facilitate the cleavage of both C H and N H
bonds. Thus, there is a clear need to develop a new strategy
À
for efficient and straightforward preparation of N H carba-
zoles from non-protected 2-aminobiaryl substrates without
halogenation or azidation, tedious protection and deprotec-
tion processes, or the use of harsh reaction conditions.
À
The construction of C N bonds from amines and organo-
boron reagents, assisted by CuII species, has been explor-
ed[3h,10] and, in particular, the metal-mediated C H activa-
À
tion of arenes[11,12] and subsequent borylation[13,14] has been
achieved. These examples offer the possibility of forming a
À
À
C N bond from a C B bond. In the case of 2-aminobiaryl
À
substrates, the free-amino-directed ortho C H activation
À
and subsequent C B formation might occur. The amino
group might also be sufficiently reactive to lead to intramo-
À
À
lecular cyclization by C N formation via a C B bond.
À
Herein, we report that N H carbazoles can be directly ob-
tained from non-protected 2-aminobiaryl starting com-
Scheme 1. Intramolecular amination for carbazole synthesis.[4–9]
pounds through the use of tandem [Cp*Rh
ACHTUNGRTENN(UNG OTf)2]/Cu-
AHCTUNGTRENNUNG
À
one-pot reaction via a reactive C H borylated intermediate.
Initially, the borylation of 2-aminobiaryl derivatives was
studied because this type ofreaction has not been previously
À
transition-metal-catalyzed C N formation with halide-func-
tionalized arenes;[4] metal-catalyzed or organocatalytic intra-
À
molecular C H amination to form N-substituted carbazo-
reported. The well-established [IrACTHNGUTRE(NNUG OMe)ACTHUNGTRNEUN(NG cod)]/dtbpy cata-
les;[3g,5–7] aryl azides as substrates for N H carbazoles via
lytic system[13a,b] was chosen (COD=1,5-cyclooctadiene,
dtbpy=4,4’-di-tert-butyl-2,2’-bipyridine), and bis(pinacola-
to)diboron (B2pin2) was used as a boron source to form a
À
metal carbeneoid insertion,[8] thermal cyclization (5508C),[9a]
À
À
or Pt C-catalyzed C H activation (>2508C) of 2-aminobi-
phenyl.[9b,c] To use these strategies either pre-activated sub-
strates,[4–8] high loadings of palladium catalysts (5–
20%),[3g,4–7] or very high temperatures[9] are needed. Addi-
tionally, aryl azides are not safe for a large-scale synthesis,
and are usually prepared from 2-aminobiaryl compounds.
Despite these successes, the direct use of non-protected 2-
aminobiaryl compounds for non-protected carbazole synthe-
sis has given only low yields (ꢀ34%) under mild conditions
with the existing catalytic system,[6] suggesting that for this
À
C B bond (Table 1). Unexpectedly, the desired compound
(2a) was isolated in very poor yield (Table 1, entry 1). Fur-
ther reaction attempts with other Ir or Rh catalysts showed
little improvement (Table 1, entries 2–4, SI-Table 1 in the
À
Supporting Information), demonstrating that the C H acti-
vation of such a substrate is difficult under the conditions
that were ideal for the reaction of other arenes.[13,14] Addi-
tion of an oxidant, such as PhIACHTNUTRGENN(UG OAc)2 or CuACHTUGNTNER(NUGN OAc)2, in-
creased the yields (Table 1, entries 5 and 6, and SI-Table 2 in
the Supporting Information), although the presence of di-
oxygen led to no product (Table 1, entry 7). However, when
K2CO3 was added, 2a was no longer isolated and instead,
[a] Q. Jiang, D. Duan-Mu, Dr. W. Zhong, Prof. Dr. H. Chen,
Prof. Dr. H. Yan
State Key Laboratory of Coordination Chemistry
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing, Jiangsu 210093 (P.R. China)
Fax : (+86)25-83314502
À
the N H carbazole product 3a was isolated in moderate
yields (Table 1, entries 8 and 9, and SI-Table 4 in the Sup-
porting Information). The reaction of 2a with CuACHTUNGTRENNUNG(OAc)2/
K2CO3 was found to proceed rapidly and quantitatively to
form 3a (less than 1 hr, see SI-Table 3 in the Supporting In-
formation), as occurred with other borylated species.[3h,10]
E-mail: hyan1965@nju.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203856.
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Table 1. Selected screening conditions for the synthesis of 2a and 3a.
electronic and steric factors may result in lower
yields of 3t and 3u. This catalytic system is likely to
be suitable for a broad range of substituted 2-ami-
nobiaryls.
To understand the role of each compound in the
À
formation of the N H carbazole products, control
experiments were performed (see SI-1, 2, 4, and 7
in the Supporting Information). The reaction of 1a
and B2pin2 mediated only by [Cp*RhACTHNUTRGNEG(NU OTf)2] led to
the isolation of the borylated species 2a, demon-
Catalyst
(0.5 mol%)
Oxidant/base
T
[8C]
Solvent
2a (1a)
3a
strating that the RhIII species acts as a catalyst to
[%][d]
[%][d]
À
À
drive C H activation and C B formation. When
Cu(OAc)2 was added to this reaction, the yield of
1
2
3
4
[Ir
[Rh
[Cp*Rh
[Cp*Rh
[Cp*Rh
[Cp*Rh
[Cp*Rh
[Cp*Rh
[Cp*Ir(OTf)2]
[Cp*Rh
(OTf)2][c]
[Cp*Rh(OTf)2]
[Cp*Ir(OTf)2]
[Ir(OMe)(cod)]
[Rh(OMe)(cod)]
U
N
–
–
–
–
80
80
80
THF
THF
THF
5 (>90)
3 (>90)
10 (81)
15 (75)
21 (68)
30 (59)
0 (100)
0 (32)
0 (45)
0 (28)
0 (9)
0 (38)
–
–
–
–
–
AHCTUNGTRENNUNG
G
G
E
N
2a was increased to 30% from 15% (Table 1, en-
tries 4 and 6). The further addition of K2CO3 led to
no formation of 2a, but instead 3a in a yield of
55% (Table 1, entry 8), indicating that the addition
of base assisted the conversion of 2a to 3a. Remov-
al of the RhIII, CuII, boron reagent, or base from
the reaction mixture as shown in Table 2 led to no
E
110
110
110
110
110
110
110
130
130
130
130
toluene
toluene
toluene
toluene
toluene
toluene
toluene
o-xylene
o-xylene
o-xylene
o-xylene
5[a]
6[a]
7[a]
8[b]
9[b]
10
E
PhI
Cu(OAc)2
O2 or air
Cu
Cu
Cu
Cu
Cu
Cu
Cu
E
R
R
–
–
R
N
E
55
43
62
80
52
38
42
G
R
N
T
R
11[b]
12[b]
13[b]
14[b]
T
N
formation of 3a. CuACTHNUTRGNE(UGN OAc)2 played a dual role both
A
E
G
as an oxidant to convert RhI back to RhIII, and as
G
0 (51)
0 (46)
E
A
À
the catalyst for C N formation. Experimentally,
Reaction condtions: B2pin2 (1.0 equiv), dtbpy (1.0 mol%; appliable for IrI and RhI), 2 equivalents of the CuII species gave the highest
808C (THF), 1108C (toluene), or 1308C (o-xylene), 24 h, Ar. [a] Oxidant (2.2 equiv)
or O2 (1 atm) or air; [b] Cu
(1.0%); [d] Yield of isolated product.
yield of 3a (SI-Table 4 int eh Supporting Informa-
tion). The presence of a base was required to de-
protonate N H to promote the final C N forma-
tion. The boron reagent B2pin2 was used for C H
ACHTUGNERTN(NUNG OAc)2 (2.2 equiv) and K2CO3 (2.5 equiv); [c] catalyst
À
À
À
À
These findings suggest that the C B formation for 2a,
rather than the C N formation for 3a, is the rate-determin-
borylation and was consumed in the reaction, as detected by
11B NMR spectroscopy. Replacement of B2pin2 by different
concentrations of BF3·Et2O gave no 3a, further confirming
À
ing step in the one-pot reaction under the catalytic condi-
tions used. The use of polar solvents, such as dimethylforma-
mide (DMF) or DMSO, and other boron sources led to sim-
ilar yields (SI-Table 4 in the Supporting Information). An
increased loading of the RhIII catalyst had no significant im-
provement on the yield (Table 1, entry 10). Upon elevating
the temperature to 1308C, however, the yields were remark-
ably increased (Table 1, entry 11 and SI-Table 4 in the Sup-
porting Information). The use of IrI or RhI instead of RhIII
catalysts gave lower yields (Table 1, entries 13 and 14).
À
that C B formation played a vital role in the formation of
3a.
On the basis of experimental observations and previous,
related mechanistic studies,[4–14] a plausible mechanism for
À
the formation of N H carbazoles is proposed in Scheme 2.
Next, the effects of electronic and steric factors of 2-ami-
nobiaryl substrates were studied. Following a procedure for
Suzuki coupling, the substituted derivatives of 1a were pre-
pared by using the appropriate boronic acids and 2-iodoani-
lines or 2-bromoanilines (see SI-5 in the Supporting Infor-
mation). The resulting 2-aminobiaryl derivatives with either
an electron-donating or an electron-withdrawing group (e.g.,
Ph, OMe, COCH3, Cl, F, CF3) on the aryl rings gave rise to
À
À
the corresponding N H carbazole products (3a–3w,
Scheme 2. Proposed mechanism for the formation of N H carbazoles (by
using 3a as an example).
Table 2) in yields of 63–93%. In general, a substrate that
contained an electron-donating group in both rings A and B
(see Table 2 for labeling) led to a higher yield (e.g. 3b, 3c
vs. 3h, 3i, and 3p; 3v, 3w vs. 3t, 3u), but the yields were
lower for products containing an ortho substituent in ring A,
probably due to steric hindrance (e.g., 3b vs. 3d; 3e vs. 3g).
The introduction of a fluorine unit in ring B of 1k–1s did
not significantly alter yields of the products 3k–3s. Both
III
À
The initial amino-directed C H activation by Rh is as-
sumed to lead to an arylrhodium intermediate (I), analogous
À
to the extensively reported, related metal-induced C H acti-
vation of arenes.[11,12] Then, transmetalation with the diboron
reagent occurs to give rise to II (similar examples are
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One-Pot Synthesis of N H Carbazoles
COMMUNICATION
À
Table 2. One-pot synthesis of N H carbazoles.
This catalytic system could potentially be used for the syn-
thesis of biologically active natural products. Girinim-
bines,[17] Mahanimbines[18] and Murrayamines[19] have been
reported to show potent biological activity and the total syn-
theses of these natural carbazole alkaloids[3a,20] requires 2-
hydroxy-3-methylcarbazole (3x) as a key precursor. With
the catalytic reaction developed in this study, 3x can be ob-
tained in two steps with a good yield (Scheme 3, SI-5 and 6
in the Supporting Information), in contrast to existing syn-
thetic routes that require multiple steps and give overall
yields of around 35%.[20b]
Scheme 3. Synthesis of 3x.
À
In summary, we have developed a synthesis of N H car-
III
À
bazole products by free amino-directed, Rh -catalyzed C
H borylation and CuII-mediated ring closure of the resulting
borylated anilines. This has led to the first efficient dehydro-
genative cyclization of non-protected 2-aminobiaryl deriva-
tives for the construction of non-protected carbazoles in a
simple one-pot reaction with good to excellent yields. The
free amine unit serves as both a directing group and a reac-
known[10a,13a,b]), followed by reductive elimination to release
the borylated species 2a, which had been isolated in the ab-
sence of either base or CuII, or of both. The resulting RhI
species is re-oxidized to RhIII by CuII to complete the cata-
lytic cycle. The subsequent intramolecular cyclization of 2a
À
À
À
proceeds via C B and N H cleavage, mediated by Cu-
tive group. This direct C H amination is suitable for a
broad range of substrates and has advantages over previous-
À
A
uct 3a, in a similar manner to the C N formation from
ly reported examples[3g,4–7] by using a low loading of noble
metal catalyst (Rh<0.5%) and inexpensive CuACTHNUGTRENUNG(OAc)2; thus
À
amines and organoboron reagents.[3h,10]
In this study, the low yields of the stepwise borylation to
2a (Table 1, entries 1–6 and SI-Table 1 in the Supporting In-
formation) might be attributed to the excess distribution of
the NH2 groups of the 2-aminobiaryl substrates around the
catalyst preventing the metal from efficiently activating the
it could prove potentially useful for the synthesis of medical-
ly important compounds.
À
C H bond. However, in a one-pot reaction, the facile con-
version of 2a to 3a releases the catalyst from the accumula-
tion of 2a and thus drives the overall reaction forwards. The
boron reagent might not serve as an efficient Lewis acid in
this reaction system because the interaction between B2pin2
and 2-aminobiphenyl is trivial, as indicated by 1H and
11B NMR data. It is worth mentioning that amine-group-di-
Experimental Section
General procedure: A mixture of 2-aminobiaryl (0.5 mmol), [Cp*Rh-
ACHTUNGRENN(UG OTf)2] (1.4 mg, 2.5 mmol), CuCAHTUNGTREN(NNGU OAc)2 (199.1 mg, 1.1 mmol), B2pin2
(127.0 mg, 0.5 mmol), and K2CO3 (172.4 mg, 1.25 mmol) in ortho-xylene
(15 mL) was stirred at 1308C under an Ar atmosphere for 24 h. After
cooling, saturated, aqueous NH4Cl (100 mL) and EtOAc (20 mL) were
added. The aqueous phase was extracted with additional EtOAc (2ꢁ
10 mL). The combined organic phases were dried over Na2SO4 and then
concentrated to give a brown oil. Further separation by column chroma-
tography on silica gel gave the corresponding product.
2
[15a]
À
rected CACHTUNGTRENNUNG(sp ) H oxidative activation from alkylamines
and arylamide[15b,c] has been reported, but free aryl-amino-
[6,16]
À
directed C H activation remains more elusive.
Chem. Eur. J. 2013, 00, 0 – 0
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Acknowledgements
The support from the National Basic Research Program of China
(2013CB922101 and 2010CB923303), the Natural Science Foundation of
China (20925104, 21271102 and 21021062) and the Natural Science Foun-
dation of JiangSu Province (BK2010052 and BK2010358) is greatly ac-
knowledged.
À
À
Keywords: amino-directed · boranes · C H activation · C
N formation · homogeneous catalysis · rhodium
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One-Pot Synthesis of N H Carbazoles
COMMUNICATION
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Received: October 29, 2012
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
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www.chemeurj.org
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H. Chen, H. Yan et al.
Carbazoles
Q. Jiang, D. Duan-Mu, W. Zhong,
H. Chen,* H. Yan* .............. &&& — &&&
III
À
Amino-Directed Rh -Catalyzed C H
Activation Leading to One-Pot
One-pot synthesis: An efficient amino-
amino unit acts as both a directing
À
Synthesis of N H Carbazoles
À
À
directed one-pot synthesis of N H car-
group for ortho C H activation and a
bazoles from unprotected 2-amino-
functional group for construction of an
N-heterocyclic ring (see scheme).
biaryl compounds is reported. The free
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www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!