Umpolung reactivity of indole through gold catalysis

Article abstract of DOI:10.1002/anie.201103014

Electrophilic indole? Indoles, which are typically nucleophilic, can be made electrophilic through gold catalysis. By using an ortho-azido group to deliver a nitrene intramolecularly, an arylalkyne is converted into a gold carbene intermediate containing an indole skeleton that is highly electrophilic at the 3-position. A range of functionalized indoles is readily accessed by utilizing this strategy.

Full text of DOI:10.1002/anie.201103014

Communications
DOI: 10.1002/anie.201103014
Heterocycles
Umpolung Reactivity of Indole through Gold Catalysis**
Biao Lu, Yingdong Luo, Lianzhu Liu, Longwu Ye, Yanzhao Wang, and Liming Zhang*
The 3-position of indole is highly electron rich and typically
functions as the primary nucleophilic site that reacts with a
large array of electrophiles, thereby leading to various
functionalized indoles.[1] The reversal of this prime reactivity,
that is, making the 3-position of indole electrophilic, would be
of significant synthetic utility and provide a complementary
strategy to access derivatives[2] otherwise difficult to prepare
conventionally. This umpolung[3] reactivity of indole has,
however, only been realized in a limited number of cases.[4]
For the past few years we have engaged in extensive
studies of gold-catalyzed intra-[5] and intermolecular[6] alkyne
oxidations using oxygen-delivering oxidants,[7] wherein reac-
tive a-oxo gold carbene intermediates are presumably
generated[8] and responsible for the diverse reaction out-
comes. Lately we extended this strategy to the use of nitrene
precursors as oxidants, thus providing access to reactive a-
imino gold carbenes (Scheme 1a);[9] however, the chemistry
formed gold carbene B would serve as an electrophilic indole
equivalent, as depicted in its resonance form C, thereby
realizing umpolung reactivity of the 3-position of indole
(Scheme 1b).[14]
We started by using ortho-azidophenylalkyne (1a) as the
substrate and anisole as the nucleophile, and the initial
[15]
reaction was run in toluene using Ph3PAuNTf2
as the
catalyst. To our delight, the desired indole regioisomers 2a
and 2a’ were indeed formed (Table 1, entry 1), thus confirm-
ing that the azido group could function as a nitrene precursor
and a gold carbene of type B might be indeed formed.
Moreover, this proposed reactive intermediate seemingly
reacted mainly via its cationic resonance form C[16] as no
Bꢀchner reaction,[17] that is, the formation of cycloheptatriene
products that is characteristic of carbene chemistry, occurred.
The regioselectivity on the anisole ring is consistent with an
electrophilic aromatic substitution mechanism. To our sur-
prise, the majority of the gold intermediate B/C reacted
with the solvent toluene, thereby yielding a mixture of
regioisomers (p-3/o-3/m-3 = 41:11:8%). Although the
concentration of toluene is approximately 190 times
that of anisole, anisole is much more nucleophilic than
toluene.[18] These results indicate that the intermediate C
is strongly electrophilic and hence less selective. This
conclusion is consistent with the ratio of p-3 versus m-3
(ca. 5), which is lower than that in the case of nitration
(>10),[19] thus suggesting that C might be even more
+
electrophilic than NO2 . Since products of type 2a, 2a’,
and 3 are also good nucleophiles, we anticipated that it is
essential to use excess intended nucleophiles to mini-
mize their competing reactions with highly electrophilic
C.
Scheme 1. Gold-catalyzed nitrene transfer: realizing umpolung reactivity at
the 3-position of indole. Ts=4-toluenesulfonyl.
Other solvents were screened to minimize solvent
has so far been limited to ynamides,[10] which are activated
alkynes. In our effort to expand the scope of this type of gold-
catalyzed nitrene transfer,[11] we decided to use an azido group
as a nitrene precursor, a choice that was inspired by previous
studies of gold-[12] and platinum-catalyzed[13] pyrrole synthesis.
participation (Table 1, entries 2–4). Whereas benzene also
interfered the desired reaction (entry 2), neither 1,2-DCE
(entry 3) nor chlorobenzene (entry 4) did; a better reaction
yield was realized in 1,2-DCE. Examination of different gold
catalysts (entries 5–10) at a beneficial higher reaction temper-
ature (comparing entries 3 and 5) revealed that IPrAuNTf2
(entry 6) gave the best yield and bulky tBuXPhosAuNTf2
gave the best para/ortho ratio (entry 8). We also ran the
reaction using anisole as the solvent at a higher concentration
(0.2m). Somewhat to our surprise, the reaction was dramat-
ically faster and finished after 5 minutes at 808C; moreover,
the yield was excellent. Perhaps even more surprising is that
the para/ortho ratio decreased as the reaction temperature
was lowered (compare entries 11–13). This may suggest the
involvement of another reaction mechanism. As shown in
Scheme 2, at a higher temperature (e.g., 808C) the formation
of B/C should be facilitated, but at a lower temperature (e.g.,
À208C) its precursor, that is, A, may persist and play an
increasing role in the reaction by reacting with nucleophiles
ꢀ
We reasoned that closely and rigidly positioned C C bonds in
ortho-azidoarylalkynes might facilitate an intramolecular
nitrene transfer from the azido group. Importantly, the thus-
[*] Dr. B. Lu, Y. Luo, Dr. L. Liu, Dr. L. Ye, Y. Wang, Prof. Dr. L. Zhang
Department of Chemistry and Biochemistry
University of California, Santa Barbara, CA (USA)
E-mail: zhang@chem.ucsb.edu
Homepage: http://www.chem.ucsb.edu/~zhang/index.html
[**] We thank the NIGMS (R01 GM084254) and UCSB for generous
financial support, and Dr. Guang Wu for helping with X-ray
crystallography. L.Z. is a Sloan Fellow.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103014.
8358
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Angew. Chem. Int. Ed. 2011, 50, 8358 –8362

Table 1: Initial discovery and reaction conditions optimization.[a]
Table 2: The scope of o-azidoarylalkyne substrates.[a]
Entry
1 (R)
R’
2
2/2’
Yield
[%][b]
Entry Catalyst
Solvent
T [8C]
t
Yield 2a/
[%][b] 2a’
1
2
3
4
5
6
7
8
1b (n-butyl)
H
H
H
H
H
H
H
H
2b
2c
2d
2e
2 f
2g
2h
2i
7:1
74
83
51[c]
76
75
82
75
91
76
95
82
78
1
2
3
4
5
6
7
Ph3PAuNTf2
toluene
benzene
1,2-DCE
PhCl
1,2-DCE
1,2-DCE
1,2-DCE
60
60
60
60
80
80
80
11 h 20[c]
11 h 40[d]
11 h 52
11 h 44
11 h 60
11 h 81
11 h 60
2.4
2.4
1.9
2.1
1.9
4.3
2.7
1c (PhCH2CH2)
1d (BnOCH2)
1e (cyclopropyl)
1 f (cyclopentyl)
1g (cyclohexyl)
1h (tert-butyl)
1i (H)
1j (p-MeOC6H4)
1k (p-MeO2CC6H4)
1l (n-butyl)
5:1
5:1
8:1
15:1
16:1
25:1
3:1
7:1
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
IPrAuNTf2
Cy-JohnPhos-
AuNTf2
9
H
H
2j
2k
2l
8
9
tBuXPhosAuNTf2
(ArO)3PAuNTf2
1,2-DCE
1,2-DCE
1,2-DCE
anisole (0.2m) 80
anisole (0.2m) 40
80
80
80
11 h 66
11 h 73
11 h <20
8.6
2.0
–
10
11
12[d]
7:1
8:1
7:1
[e]
4,6-Me2
3,5-Cl2
10
11
12
13
AuCl3
1m (n-butyl)
2m
tBuXPhosAuNTf2
tBuXPhosAuNTf2
tBuXPhosAuNTf2
5 min >95[f] 6.5
1.5 h >95 5.2
[a] Reaction was run in a vial. [b] Combined yield of 2 and 2’ upon
isolation. [c] About 4% of 7 [see Eq. (2)] was formed. [d] Reaction time:
1 h.
anisole (0.2m) À20 12 h >95 3.9
[a] [1]=0.05m. [b] Estimated by 1H NMR spectroscopy using diethyl
phthalate as the internal reference. [c] The regioisomers 3 (see below)
were formed from reaction with the solvent, toluene. [d] 2,3-Diphenyl-
indole (4; see below) was formed in 10% yield. [e] Ar=2,4-di-tert-
butylphenyl. [f] Yield of isolated product: 89%. 1,2-DCE=1,2-dichloro-
ethane.
anisole as the solvent, primary alkyl groups such as n-butyl
(Table 2, entry 1) and phenethyl (entry 2) reacted
smoothly. A lower yield was obtained with 1d containing
a benzyl ether (entry 3), and cyclic secondary alkyl groups
(entries 4–6) as well as a tert-butyl group (entry 7) all led to
good yields. Interestingly, substrate 1i having a terminal
alkyne also worked (entry 8), and aryl groups with either a
p-MeO (entry 10) or
a
p-methoxycarbonyl group
(entry 11) were readily tolerated and the corresponding
indoles were isolated in good to excellent yields. In all the
cases, the regioselectivities correlated well with the bulk of
the substitutent, and the best 2/2’ ratio was realized with
the tert-butyl alkyne 1h (entry 7). In addition, substrates
with substituted benzene rings reacted with good efficien-
cies, thus affording highly substituted indole products
(entries 11 and 12).
The applicability of this chemistry to other nucleo-
philes was then probed by using the reaction conditions
from entry 6 in Table 1, and the successful examples are
shown in Table 3. As expected, p-xylene, when used as the
solvent, served as a suitable nucleophile for this chemistry
(entry 1). In the case of naphthalene, the a position is
preferred because of its stronger nucleophilicity (entry 2).
More-activated benzene rings (entries 3 and 4) gave good
yields of the desired products, and a good selectivity (10:1)
was observed with 1,3-dimethoxybenzene, thus reflecting
the more congested nature of the 2-position. In the case of
N-methylpyrrole, apparently the electronic and the steric
factors were working against each other, therefore no
regioselectivity was observed (entry 5); however, the overall
efficiency was excellent. Increasing the steric hindrance at the
pyrrole 2-position by installing a TIPS group on the ring
nitrogen atom indeed made the reaction proceed selectively
at the 3-position (entry 6). When N-benzylindole was used as
Scheme 2. Rationale for the inverse relationship between regioselectivities
and reaction temperatures.
À
through an SN2’ process. Since the Au C bond length in B/C
À
should be shorter than the Au C bond in A, one might expect
that the more the reaction goes through B/C the more
regioselective it is and the bulky ligand (i.e., tBuXPhos) can
be more sterically imposing.[20]
The scope of the o-azidoarylalkynes was subsequently
examined by first varying the alkyne substituent. By using
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Table 3: The scope of different nucleophiles.[a]
the nucleophile, to our surprise, at
least three inseparable regioisomers
were formed, suggesting that its
benzene ring participated in this
reaction as the nucleophilic site. To
our delight, with the strongly elec-
tron-withdrawing nitro group on
the indole benzene ring, the substi-
tution selectively occurred on the 3-
position, thus affording nonsym-
metrical 3,3’-bis(indole)s with good
yields (entries 7 and 8). The use of
the more polar azidoalkyne sub-
strate 1k facilitated purification of
the products. With the indole 2-
position substituted and its benzene
ring again deactivated, the electro-
philic substitution proceeded as
expected at the 3-position to yield
the bis(indole) 5i. Notably, the 3,3-
bis(indole) structure has been
found in natural products[21] and
compounds of medical interest,[22]
and their syntheses often require
multiple steps.[23] Dimedone methyl
ether could react as a nucleophile as
well, albeit accompanied by in situ
hydrolysis and in a relatively low
reaction yield (entry 10). In addi-
tion to carbon nucleophiles, alco-
hols could react with intermediates
of type C (entries 11 and 12). The
moderate yields were to some
extent due to the susceptibility of
the products towards aerobic oxi-
dation. Interestingly, with allyl alco-
hol as the nucleophile, the product
underwent a one-pot Claisen rear-
rangement, thus yielding the indol-
3-one 5m in a serviceable yield
(entry 13). Notably, no desired
product was observed when using
N-methyltosylamide as the nucleo-
phile.
Entry
NuH
t
5
5/5’[b]
Yield
[%][c]
[h]
1
2
p-xylene[d]
5
3
3
3
–
70
78
84
84
6:1
3
4
10:1
–
5
8
1:1
–
91
6[e]
12
3
69[f]
83
7
–
8
9
3
3
–
–
81
64
10
1
–
49
This umpolung reactivity of
indole was briefly tested in intra-
molecular scenarios. With the azi-
doalkyne 1c, in the absence of an
external nucleophile such as anisole
(e.g., in Table 2, entry 2), the teth-
ered benzene ring reacted as the
nucleophile, efficiently trapping the
electrophilic indole 3-position, and
thereby forming the tetracyclic
product 6 in a good yield [Eq. (1)].
To our surprise even a seven-mem-
11
12
13
nBuOH
15
12
10
–
–
–
66
62
65
nBuOH
allyl alcohol
1
bered ring
7 could be readily
[a] [1]=0.1m. [b] Regioisomers not separated. Ratio determined by H NMR spectroscopy. [c] Yield of
isolated product. [d] Used as solvent. [e] 10mol% of IPrAuNTf2 used. [f] The regioselectivity is >9:1,
and the yield reported is that of the major isomer. Bn=benzyl; TIPS=triisopropylsilyl.
formed through this intramolecular
trapping [Eq. (2)]; moreover, this
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reaction appeared to be rather facile as the tetracyclic product
7 was formed in approximately 4% yield even when the
anisole was used as the solvent (Table 2, entry 3), again
implicating the high electrophilicity of the intermediate B/C.
In summary, we have developed a new approach to
achieving umpolung reactivity of indole at the 3-position
through gold catalysis. By using an ortho-azido group to
deliver a nitrene intramolecularly, an arylalkyne can be
converted into a gold carbene intermediate containing the
indole skeleton that is highly electrophilic at the 3-position.
The reaction of this electrophilic indole intermediate with
various nucleophiles provides a novel and expedient synthesis
of a range of functional indoles.
Experimental Section
General procedure for the gold-catalyzed formation of indole 5: o-
Azidoarylalkyne
1
(0.30 mmol) and IPrAuNTf2 (12.9 mg,
[10] For a review on ynamides, see: K. K. A. De, H. Li, A. G. Lohse,
R. Hayashi, Z. Lu, Y. Zhang, R. P. Hsung, Chem. Rev. 2010, 110,
5064.
[11] a) Z. Li, D. A. Capretto, R. O. Rahaman, C. He, J. Am. Chem.
Soc. 2007, 129, 12058; b) Z. Li, X. Ding, C. He, J. Org. Chem.
2006, 71, 5876.
0.015 mmol) were added to a solution of a nucleophile (1.2 mmol)
in 1,2-DCE (3 mL) at room temperature. The reaction mixture was
heated at 808C, and the progress of the reaction was monitored by
TLC. The reaction typically took 3 h. Upon completion, the mixture
was concentrated and the residue was purified by silica gel flash
chromatography (eluent: hexanes/ethyl acetate) to afford the desired
products.
[12] D. J. Gorin, N. R. Davis, F. D. Toste, J. Am. Chem. Soc. 2005, 127,
11260.
[13] K. Hiroya, S. Matsumoto, M. Ashikawa, K. Ogiwara, T.
Sakamoto, Org. Lett. 2006, 8, 5349.
[14] This work is prompted by the submission of a closely related
report by Prof. Fabien Gagosz: A. Wetzel, F Gagosz, Angew.
Chem., DOI: 10.1002/ange.201102707; Angew. Chem. Int. Ed.,
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[17] M. P. Doyle, M. A. McKervey, T. Ye, Modern catalytic methods
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[18] According to the Mayr– Patz equation (H. Mayr, M. Patz,
Angew. Chem. 1994, 106, 990; Angew. Chem. Int. Ed. Engl. 1994,
33, 938): logk208C = sN(N + E) (N: nucleophilicity parameter, E:
electrophilicity parameter, sN: nucleophile-specific sensitivity
parameter), with 4,4’-bis(p-methoxy)benzhydrylium ion as the
electrophile (E = 0), anisole [N/sN(anisole): À1.18/1.20] (H.
Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66)
would react 3 ꢂ 104 times faster than toluene [N/sN(toluene):
À4.47/1.32] (H. Mayr, T. Bug, M. F. Gotta, N. Hering, B. Irrgang,
B. Janker, B. Kempf, R. Loos, A. R. Ofial, G. Remennikov, H.
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Received: May 2, 2011
Published online: July 14, 2011
Keywords: catalysis · gold · indole · nitrenes · umpolung
.
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Communications
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