Palladium(II)-catalyzed efficient C-3 functionalization of indoles with benzylic and allylic alcohols under Co-catalyst, acid, base, additive and external ligand-free conditions

Article abstract of DOI:10.1002/adsc.201300048

The bis(acetonitrile)palladium(II) chloride complex, PdCl ₂(MeCN)₂, efficiently catalyzes the regioselective alkylation of indoles with various benzylic and allylic alcohols under moisture and air insensitive conditions. Notably the

Full text of DOI:10.1002/adsc.201300048

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DOI: 10.1002/adsc.201300048
Palladium(II)-Catalyzed Efficient C-3 Functionalization of
Indoles with Benzylic and Allylic Alcohols under Co-Catalyst,
Acid, Base, Additive and External Ligand-Free Conditions
Debjit Dasa and Sujit Royb,*
a
Organometallics & Catalysis Laboratory, Department of Chemistry, Indian Institute of Technology, Kharagpur – 721302,
India
b
Organometallics & Catalysis Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar – 751013,
India
Fax : (+91)-674-230-6303; phone: (+91)-674-257-6021; e-mail: sujitroy.chem@gmail.com or sroy@iitbbs.ac.in
Received: January 19, 2013; Revised: March 26, 2013; Published online: April 30, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300048.
Abstract: The bis(acetonitrile)palladium(II) chlo-
ride complex, PdCl2A(MeCN)2, efficiently catalyzes
tion.[1c,5] One may also appreciate that a major diffi-
culty in the direct alkylation reaction from an alcohol
using a transition metal catalyst is the inertness of the
OH group towards such activation.[1c,6] In light of the
above, the available reports on the palladium-cata-
lyzed syntheses of allylindoles from the corresponding
alcohols are noteworthy.[7] In 1980 Billups et al. first
reported that the reaction of indole and allyl alcohol
in refluxing benzene under the catalytic influence of
palladium acetylacetonate/PPh3 gave rise to 3-allylin-
dole in 45% yield along with 1-allylindole (7%) and
1,3-bisallylindole (9%).[7a] More recently Tamaru et
al. achieved the desired transformation using
CTHUNGTRENNUNG
the regioselective alkylation of indoles with various
benzylic and allylic alcohols under moisture and air
insensitive conditions. Notably the reaction does
not require any other co-catalyst, acid, base, addi-
tive, or external ligand.
Keywords: alkylation; allylic alcohols; benzylic al-
cohols; homogeneous catalysis; indoles; palladi-
ACHTUNGTRENNUNGum(II) complex
Pd
ACHTUGNRTNE(NUNG PPh3)4 as the catalyst (5 mol%) and Et3B (30–
240 mol%) as the promoter.[7b] A closely related
The functionalization of indoles via low cost, selec- enantioselective variant of this approach was later
tive, and eco-friendly strategies has attracted wide at- proposed by Trost et al. using Pd2dba3·CHCl3 as the
tention since structural motifs bearing the ꢀindole catalyst and 9-BBN-C6H13 (105 mol%) as an addit-
coreꢁ are frequently found in natural products, phar-
ive.[7c] Pullarkat et al. employed a palladacycle cata-
ACHTUNGTRENNUNG
maceuticals, and other functional synthetics.[1] Con- lyst (10 mol%) for the C-3 allylation of 2-substituted
ventionally 3-alkylated indoles are synthesized from indoles.[7d] Breit et al. accomplished the allylation of
alkyl halides and surrogates by carbon-carbon bond indoles using the unique concept of self-assembling
forming reactions such as (i) acid- or base-promoted palladium phosphane catalysts.[7e] Recent reports on
alkylation[1c,2] or (ii) transition metal-catalyzed alkyla- the development of multimetallic catalysts based on
tion.[1c,3] Among the transition metals, the palladium- palladium for alcohol activation are also notewor-
catalyzed reactions of indoles with reactive electro- thy.[7f,g]
philes (halides, acetates, etc.) have become powerful
In light of the above literature reports, we were
tools to synthesize functionalized indoles.[1c,4] In con- pleasantly surprised with the serendipitous result
trast, examples of palladium-catalyzed C-alkylation of when a simple monometallic palladium(II) complex,
indole using an alcohol are few. Indeed the direct cou- namely PdCl2ACTHNUTRGNEN(UG MeCN)2, catalyzed the alkylation of
pling of indole with an alcohol is considered to be indole with benzylic and allylic alcohols with high ef-
synthetically attractive, mechanistically challenging ficiency and exclusive C-3 regioselectivity. We also
and environmentally benign due to ready availability noted that the reaction neither requires the assistance
and significantly lower toxicity of alcohols (compared of external acid/base, additive and ligand, nor is it
to alkylating agents like halides, acetates, etc.), and sensitive towards moisture and air. The details of our
the fact that only stoichiometric amounts of water are findings are presented below.
generated as the side product in the alkylation reac-
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Palladium(II)-Catalyzed Efficient C-3 Functionalization of Indoles with Benzylic and Allylic Alcohols
Table 1. Catalysts screening.[a]
Interestingly, all of the tested Lewis acids inclusive
of BF3·Et2O, FeCl3, InCl3, Ti{OCH(CH3)2}4, SnCl4 and
N
ACHTUNGTRENNUNG
transition metal catalysts [(PPh3)AuCl]/AgOTf were
less effective (entries 4–9). Likewise, catalytic
amounts of Brønsted acids like pTSA or TfOH (en-
tries 1 and 2) and metal triflates (entries 10–13) gave
lower yields, whereas TFA (entry 3) and late transi-
tion metal salts like RuACTHNURTGNEUNG(PPh3)3Cl2 or K2PtCl4 were to-
tally inactive (entries 19 and 20). In a few of the cases
where a Lewis or a Brønsted acid was used as cata-
lyst, the observed low yield was due to the formation
of unwanted side products (like a-methylstyrene, olig-
omers).[9]
Entry Catalyst
Solvent Yield of 3a [%][b]
1
2
3
pTSA
TfOH
TFA
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
10
35
0
Having established the optimum conditions,
a number of N-substituted (alkyl-, benzyl-, allyl-,
propargyl-)indoles as well as ring-substituted indoles
were alkylated at 908C in DCE using various tertiary
as well as secondary benzylic alcohols, giving rise to
the desired products in good to excellent yields
(Figure 1).[10] Significantly, in all cases where we have
used N-unprotected indole, the reactions were com-
pletely C-3 selective, and no N-alkyl product was
formed. Interestingly, g-hydroxylactam could be used
efficiently as an alkylating agent yielding the corre-
sponding alkylated products 3q and 3r with quantita-
tive conversions and excellent yields (Figure 1). The
structure of 3q was established by X-ray crystallo-
graphic analysis (Figure 2). It was also observed that
alkylation of indole proceeded best with electron-rich
alcohols, whereas electron-deficient 2-(4-chlorophe-
nyl)propan-2-ol and primary benzyl alcohols were in-
effective.
4
5
BF3·Et2O
FeCl3
27
49
43
15
35
33
22
13
37
36
82
0
18
11
0
0
0
6
InCl3
7
TiACHTUNGTRENNUNG{OCHACHTUNGTRENNUNG(CH3)2}4
8
SnCl4
9
ACHTUNGTRENNUNG[(PPh3)AuCl]/AgOTf DCE
10
11
12
13
14
15
16
17
18
19
20
21
22
23[c]
24
Bi
Cu
Sc(OTf)3
La(OTf)3
PdCl2A(MeCN)2
2A(bpy)
2A(PPh3)2
N
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
MeOH
H2O
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
CHTUNGTRENNUNG
C
Pd
Pd
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
Ru
A
PdCl
PdCl
none
none
N
42
8
0
Next, we studied the coupling between substituted
allylic alcohols and a diverse range of indoles using
catalytic PdCl2ACHTNUGRTNE(NUG MeCN)2 (3 mol%) in DCE as solvent
DCE
0
[a]
A mixture of 1a (0.30 mmol), 2a (0.25 mmol), and cata-
lyst (5 mol%) in 2 mL of solvent was stirred at 908C for
6 h.
(Table 2). These results have been most gratifying as
the reactions took place at room temperature and
under additive- and ligand-free conditions for most
cases.
The allylation reaction with alcohol 4g was sluggish
at room temperature but the rate increased signifi-
cantly at 908C (entry 14). In our hands, aliphatic allyl-
ic alcohols were inactive even at higher temperatures.
[b]
[c]
Yield by 1H NMR using triphenylmethane as external
standard.
Carried out in deionized water at 808C.
In a model study we examined the reaction of 1- The formation of regioisomers (a and g) was noticed
benzyl-1H-indole 2a with 2-phenylpropan-2-ol 1a in in the case of alcohols 4e–4g. Note that the use of
the presence of different Brønsted acids, Lewis acids, propargylic alcohol 4h as an alkylating agent gave the
palladium and other transition metal catalysts (with desired alkylation product 5n in 12% yield only
5 mol% loadings) at 908C for 6 h (Table 1).[8] Among (entry 15, Table 2).
the tested Pd complexes, only PdCl
promising catalytic activity in 1,2-dichloroethane ticed that whenever PdCl CTHNUGTRENNUNG
(MeCN)2 showed
During the course of this experimentation we no-
2A(MeCN)2 was added to a so-
(DCE) as the solvent and afforded the desired C-3 lution of only indole or to a mixture containing indole
alkylated 1-benzyl-3-(2-phenylpropan-2-yl)-1H-indole and the electrophile in DCE or DCM as solvent,
3a as the only product (entries 14–18). Notably, it is a dark red color was formed. The color change was
not necessary to exclude air or moisture from this re- also visualized even when indole and PdCl2ACTHNUTRGNEN(UG MeCN)2
action. Lower conversion was observed in coordinat- were mixed in the solid state (please see Figure S1 in
ing solvents like acetonitrile or methanol (entries 21 the Supporting Information). Prompted by this obser-
and 22).
vation, we carried out the reaction of indole and
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Figure 1. Substrate scope of the direct benzylation of indoles.
PdCl2ACHTNUTRGENNG(U MeCN)2 in dicholoromethane at room temper-
ature and isolated a dark red solid in 55% yield
(Scheme 1). The complex of indole with PdCl2
ACHNUTERTG(GNNUN MeCN)2 conformed to a composition C16H14Cl4N2Pd2
(hereafter complex 1). Shul’man et al. had earlier pro-
posed the formation of a halide-bridged Pd(II) dimer
of general formula Pd2ACHTNUTRGNE(UNG indole)2X4 (X=halogen) from
the reaction of Pd(II) with indole.[11]
In our view, complex 1 is overall a neutral complex;
the formal oxidation number of palladium being two.
The chloride ligand could be in the outer-sphere or in
the inner-sphere. When in the outer sphere, one can
write it as a chloride anion. X-ray crystallography can
provide the answer to this issue. So far we have failed
to grow crystals of the desired quality for structure
Figure 2. ORTEP diagram of compound 3q with 30% proba-
bility thermal ellipsoids.
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Palladium(II)-Catalyzed Efficient C-3 Functionalization of Indoles with Benzylic and Allylic Alcohols
Table 2. Pd(II)-catalyzed alkylation of indoles.[a]
Entry 4 Alcohol
Indole
Time
[h]
Product 5
Yield of 5 [%]
1[b]
2
3
4
5
4a Ar=C6H5
R1 =H, R2 =H
R1 =H, R2 =H
R1 =H, R2 =Br
R1 =H, R2 =OMe
R1 =Me, R2 =H
R1 =-CH2CꢀCH,
R2 =H
4
4
10
10
4
5a
5a
5b
5c
5d
5e
0
4a
4a
4a
4a
4a
80
92
95
81
88
6
2
7
4a
R1 =-(CH2)7CH3,
R2 =H
6
5f
95
8
9
10
4b Ar=4-MeC6H4
4c Ar=4-BrC6H4
4c
R1 =-CH2Ph, R2 =H
R1 =-Me, R2 =H
R1 =-CH2C=CH2,
R2 =H
4
5
6
5g
5h
5i
80
66
70
11
12
4d
4e
R1 =H, R2 =H
6
83
65 (a/
g=72:28)
R1 =-CH2Ph, R2 =H
12
82 (a/
g=54:46)
13
4f
4g
R1 =H, R2 =H
8
3
60 (a/
g=74:26)
14[c]
R1 =Et, R2 =H
15[d] 4h
R1 =H, R2 =H
10
12
[a]
All reactions were carried out with alcohol (0.6 mmol), indole (0.5 mmol) and PdCl
at room temperature (308C).
Carried out without catalyst.
Carried out at 908C.
Carried out with 5 mol% catalyst at 908C.
2ACHTNUGTREN(NNUG MeCN)2 (3 mol%) in 2 mL of DCE
[b]
[c]
[d]
1
determination. However, H and 13C NMR spectra of in the free indole to 10.59 ppm (Figure 3). The iden-
complex 1 in CDCl3 showed characteristic features. tification of the 1-NH proton was also supported by
Noticeably, the proton resonance of 1-NH in complex a deuterium exchange experiment. Therefore we
1 did not disappear but showed a shift from 8.13 ppm ruled out N to Pd coordination in complex 1. The res-
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to the formation of complex 1 which, in turn, accounts
for its promising reactivity in the alkylation reactions.
It also explains the inactivity or less reactivity of
other Pd(II) complexes with strong donor ligands
(like PPh3, bipy or acetate) (Table 1, entries 15–17).
Complex 1 is partially soluble and stable in solvents
like DCM, DCE and CHCl3 but is unstable in metha-
nol and showed poor reactivity in MeOH/acetonitrile
(Table 1, entries 21 and 22). On the other hand, reac-
Scheme 1. Preparation of Pd(II) complex 1.
onance of 3-CH in complex 1 appeared at 6.34 ppm, tion of allyl alcohol 4a with 1 equiv. of complex 1 in
an upfield shift with respect to that of free indole CDCl3 at room temperature yielded the correspond-
(6.57 ppm). The 13C NMR chemical shift values for C- ing symmetrical diallyl ether 6a (as a 1:1 mixture of
3 in free indole and complex 1 appeared at 102.8 and diastereomers) along with unreacted alcohol 4a
77.4 ppm, respectively. We propose that this dramatic (Scheme 2). The formation of 6a from alcohol 4a pro-
change is due to the conversion of an aromatic vided initial support towards the activation of alcohol
carbon to a tetrahedral carbon (please see the Sup- by Pd(II) via a typical Friedel–Crafts-type pathway.[14]
1
porting Information).[12] The H signal for 2-CH in
Although detailed mechanistic studies must be
complex 1 appeared at 8.22 ppm; a downfield shift awaited, on the basis of the above results, in particu-
from that of free indole. The 13C resonance for C-2 lar the observed enhanced reactivity of 28 and 38 elec-
(analogous to an imine carbon) in complex 1 was also tron-rich aryl alcohols compared to 18 or electron-
downfield shifted to 142.8 ppm (please see the Sup- poor aryl alcohols, we tentatively suggest that an elec-
porting Information).[13]
The above findings support that in complex 1 palla-
dation occurred at the 3-C atom of the indole ring.[12]
To our gratification complex 1 could be successfully
utilized as a catalyst for the coupling of indole with
alcohols. We presume that the labile nature of the
acetonitrile ligand in PdCl2A(MeCN)2 might be the key and complex 1.
Scheme 2. Formation of diallyl ether 6a from allyl alcohol 4a
CTHUNGTRENNUNG
Figure 3. 1H NMR spectrum of indole and complex 1.
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Palladium(II)-Catalyzed Efficient C-3 Functionalization of Indoles with Benzylic and Allylic Alcohols
trophilic mechanism involving the intermedicacy of X-Ray Crystallography
a carbenium ion may be operating in the present
CCDC 918766 (3q) contains the supplementary crystallo-
Pd(II)-catalyzed alkylation of indole.[5f,14,15] In the case
of N-unprotected indoles, one cannot completely rule
out the possibility of a pathway involving Brønsted
acid-type catalysis.[16,17] Such a pathway may operate
in tandem with the proposed Friedel–Crafts alkyla-
tion.
graphic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
In summary, PdCl2ACTHNUTRGNE(NUG MeCN)2 has been found to be
an effective catalyst for regioselective functionaliza-
tion of indoles with benzylic and allylic alcohols. Co-
Acknowledgements
S.R. and D.D. thank DST and CSIR for funds and fellow-
catalysts, acid/base, additive, external ligand are not ships.
required in this alkylation, which is thus of great
promise. The easy handling of the catalyst makes the
reaction more attractive, simple and practical.
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Experimental Section
Syntheses and Characterization of [(C8H7N)PdCl2]2
(Complex 1)
Solid PdCl2ACHTUNGTRENNUNG(MeCN)2 (130 mg, 0.5 mmol) was added in one
portion to a stirred solution of indole (59 mg, 0.5 mmol) in
CH2Cl2 (5 mL) resulting in a sharp color change. After
15 min, petroleum ether (30 mL) was added while stirring
was continued for a further period of 5 min. The dark red
solid was separated by filtration, washed with petroleum
1
ether and dried in vacuum; yield: 55%. H NMR (200 MHz,
CDCl3): d=6.34 (s, 1H), 7.31–7.52 (m, 3H), 8.02. (d, 1H,
J=7.6 Hz), 8.22 (br s, 1H), 10.59 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=77.4, 114.3, 125.10, 125.14, 128.2,
130.6, 134.4, 142.8; anal. calcd. for C16H14Cl4N2Pd2: C 32.63,
H 2.40, N 4.76; found: C 32.29, H 2.21, N 4.93.
Procedures for the Catalytic C3-Functionalization of
Indole
a) Representative Procedure for the Benzylation of Indoles
with Benzylic Alcohols: A mixture of phenylpropan-2-ol 1a
(82 mg, 0.60 mmol), 1-benzyl-1H-indole 2a (103.4 mg,
[5] The importance of alcohol as an alkylating agent is of
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0.5 mmol), PdCl2ACHTUNGTRENNUNG(MeCN)2 (6.5 mg, 0.025 mmol) in 2 mL of
DCE was stirred at 908C for the appropriate time. Then, the
solvent was removed under reduced pressure, and the mix-
ture was subjected to column chromatography over silica gel
(100–200 mesh, eluent: petroleum ether 60–808C/ethyl ace-
tate, 50:1 v/v) to afford the desired alkylated product 3a as
a colorless oil; yield: 146 mg (90%).
b) Representative Procedure for the Alkylation of Indoles
with Allylic Alcohols: A mixture of (E)-1,3-diphenylprop-2-
en-1-ol 4a (126 mg, 0.60 mmol), 1H-indole (58.5 mg,
0.5 mmol), PdCl
(MeCN)2 (3.9 mg, 0.015 mmol) in 2 mL of
[6] Selected references a) A. B. Zaitsev, S. Gruber, P. A.
Plꢃss, P. S. Pregosin, L. F. Veiros, M. Wçrle, J. Am.
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DCE was stirred at room temperature (308C) for the appro-
priate time. Then, the solvent was removed under reduced
pressure, and the mixture was subjected to column chroma-
tography over silica gel (100–200 mesh, eluent: petroleum
ether 60–808C/ethyl acetate, 9:1 v/v) to afford the alkylated
product 5a as a yellow solid; yield: 124 mg (80%).
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dararaju, M. Achard, C. Bruneau, Chem. Soc. Rev.
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[8] Cozzi et al. showed that FC benzylations can proceed
with activated alcohols just “on water” in absence of
a catalyst. Please see: P. G. Cozzi, L. Zoli, Angew.
Chem. 2008, 120, 4230; Angew. Chem. Int. Ed. 2008, 47,
4162. In our hands the model reaction did not proceed
in deionized water under catalyst-free conditions
(Table 1, entry 23). In this context one may note that in
many cases the SN1-type reactions of alcohols are pro-
moted by the generated carbenium ion (see ref.[5f]). If
the electrophilicity of the carbenium ion is very high,
the reaction cannot occur in water. We thank one of
the reviewers for pointing out this fact.
[9] In presence of a Lewis acid, 38 benzylic alcohols are
known to undergo elimination reactions and the result-
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see: a) F. Howard, S. Sawadjoon, J. S. M. Samec, Tetra-
hedron Lett. 2010, 51, 4208; b) H. B. Sun, B. Li, R.
Hua, Y. Yin, Eur. J. Org. Chem. 2006, 4231.
[10] The plausible intermediacy of a-methyl arylalkene has
been ruled out from independent experiments using
indole and a-methylstyrene in the presence of Pd(II)
catalyst.
[13] Due to the presence of the 1-NH proton and extended
conjugation the shift of the C-2 resonance is not so
large. For comparison, please see: a) O. Yamauchi, M.
Takani, K. Toyoda, H. Masuda, Inorg. Chem. 1990, 29,
1857; b) W. H. Myers, M. Sabat, W. D. Harman, J. Am.
Chem. Soc. 1991, 113, 6682; c) L. M. Hodges, M. W.
Moody, W. D. Harman, J. Am. Chem. Soc. 1994, 116,
7931.
[14] For Friedel–Crafts type activation of alcohols by Pd(II)
please see: a) Y. Bikard, R. Mezaache, J.-M. Weibel, A.
Benkouider, C. Sirlin, P. Pale, Tetrahedron 2008, 64,
10224; b) Y. Bikard, J.-M. Weibel, C. Sirlin, L. Dupuis,
J.-P. Loeffler, P. Pale, Tetrahedron Lett. 2007, 48, 8895.
[15] Recently Yuan et al. reported that the PdCl2-mediated
allylation with allyl acetate involves the in situ genera-
tion of Pd(0). It is suggested that the latter catalyzes
the allylation via Tsuji–Trost mechanism. Please see: F.
Yuan, L. Gaoa, F. Han, Tetrahedron 2012, 68, 6837.
Note that allyl acetates are much stronger electrophiles
than allyl alcohols. In our case a Pd(0) complex like
Pd2ACTHNUTRGNE(UGN dba)3 did not show any reactivity in the model re-
action (Table 1, entry 18). Thus we tentatively rule out
a Tsuji–Trost pathway. In the case of allylic alcohols,
a prior activation of the allylic p-bond by Pd(II) is
a possibility and is worthy of future investigation.
[16] We thank one of the reviewers for this insightful sug-
gestion.
[17] In this context the studies by Focante and others dem-
onstrating the dramatic enhancement of CH-acidity in
indoles and other N-heteroaromatics upon reaction
with boron electrophiles may be considered as an inter-
esting parallel. For details, please see: a) F. Focante, P.
Mercandelli, A. Sironi, L. Resconi, Coord. Chem. Rev.
2006, 250, 170; b) S. Guidotti, I. camurati, F. Focante,
L. Angellini, G. Moscardi, L. Resconi, R. Leardini, D.
Nanni, P. Mercandelli, A. Sironi, T. Beringhelli, D.
Maggioni, J. Org. Chem. 2003, 68, 5445.
[11] V. M. Shul’man, T. V. Zagorskaya, I. M. Cheremisina,
G. K. Parygina, E. A. Kravtsova, Zh. Neorg. Khim.
1972, 17, 2498.
[12] The NMR features observed by us are very similar to
those of indole-Pd(II) complexes reported earlier.
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Adv. Synth. Catal. 2013, 355, 1308 – 1314