Indole synthesis by palladium-catalyzed tandem allylic isomerization-furan Diels-Alder reaction

Article abstract of DOI:10.1039/c7ob01654a

A Pd(0)-catalyzed elimination of an allylic acetate generates a π-allyl complex that is postulated to initiate a novel intramolecular Diels-Alder cycloaddition to a tethered furan (IMDAF). Under the reaction conditions, this convergent, microwave-accelerated cascade process provides substituted indoles in moderate to good yields after Pd-hydride elimination, aromatization by dehydration, and in situ N-Boc cleavage.

Full text of DOI:10.1039/c7ob01654a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Indole Synthesis by Palladium-Catalyzed Tandem Allylic
Isomerization – Furan Diels-Alder Reaction
Jie Xua and Peter Wipf*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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A Pd(0)-catalyzed elimination of an allylic acetate generates a
p
-
5-hydroxyindole
8
.
The mechanistic analysis of this
allyl complex that is postulated to initiate a novel intramolecular transformation inspired us to consider alternative
Diels-Alder cycloaddition to a tethered furan (IMDAF). Under the disconnections to accomplish an equivalent, convergent indole
reaction conditions, this convergent, microwave-accelerated synthesis.
cascade process provides substituted indoles in moderate to good
yields after Pd-hydride elimination, aromatization by dehydration,
and in situ N-Boc cleavage.
OH
(–)-catharantine
N
N
N
OH
O
O
O
H
N
N
N
H
O
OMe
N
N
N
H
H
H
O
Indole heterocycles have an exceptional legacy in organic and
biological chemistry. The indole is a privileged scaffold for
pharmaceuticals, and its frequent presence in alkaloids and
biopolymers has inspired numerous synthetic methods (Fig.
1).1,2 Most indole preparations start with an aniline, followed
by ring fusion to generate the pyrrole moiety; in contrast,
convergent syntheses that assemble both benzene and pyrrole
rings are quite rare.3 Kanematsu and coworkers applied this
strategy to generate indolines from Diels-Alder reactions of
allenic dienamides,4 and Padwa and coworkers pioneered the
use of the intramolecular Diels-Alder cycloaddition to 2-
amidofurans (IMDAF) in the synthesis of indoline natural
products.5 Our group further extended this approach to the
direct preparation of indoles and 5-hydroxyindoles by
introducing a different retrosynthetic disconnection and an in
situ water elimination step (Fig. 2).6,7,8 Heating of a secondary
MeO2C
OH
NH2
serotonin
HO
N
OAc
CO2Me
MeO
(–)-ergotamine
N
(–)-vinblastine
H
N
H
H
N
N
O
HN
H
N
S
O
NH
N
Cl
O
O
N
O
HO
HO
Cl
O
H
N
O
O
N
H
NH
N
O
NH
sumatriptan
N
S
(–)-diazonamide A
HCV NS5B inhibitor
Fig. 1. Selected alkaloids and pharmaceuticals with 3-alkylated
indole scaffolds.
IMDAF preparation of indolines:
R
Δ
Br
+
R
R
N
NH
O
O
N
Boc
Boc
Boc
or tertiary alcohol, obtained by combining
a lithiated
alkylamidofuran with an a,b-unsaturated aldehyde or ketone,
in a microwave reactor to 180-200 °C initiates a cascade
process that results in the elimination of 1 to 2 equiv of H2O
and the fragmentation of the Boc-protective group to provide
the desired aromatic heterocycles (Fig. 3). Depending on the
Previous IMDAF indole syntheses (2009-2017):
R
R'
Li
R'
R'
R
Δ
R
R
+
+
N
O
O
N
O
O
N
H
O
O
Boc OH
Boc
R
R'
Li
R
HO
R'
Δ
R'
level of unsaturation, IMDAF intermediate
ether bridge opening to allylic alcohol , double dehydration
and
retro-ene Boc-thermolysis9 to give indole
Alternatively, if starting material contains an alkyne, leads
to bisallylic alcohol , and dehydration of phenol generates
2 aromatizes after
N
N
N
H
Boc OH
Boc
4
a
5.
This work:
R3 R4
R2
1
2
R1
R3
R2
R4
R2
R3
R1
Pd(0)
6
7
+
OAc
X
Δ
N
O
N
H
OAc
NH
Boc
O
Boc R1
R4
Fig. 2. Use of intramolecular Diels-Alder cycloadditions to
furans for indoline and direct (non-oxidative) indole
syntheses.6,7,8
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biologically active compounds we were most interested in (Fig.
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DOI: 10.1039/C7OB01654A
1). While the use of 20 mol % of the more electron-rich and
R
O
R
R
OH
R'
OH
OH
R'
more air-stable alkyl phosphine PBn3 in place of PPh3 increased
the yield dramatically to 74%,12 other alkyl phosphines such as
P(n-Bu)3 and P(t-Bu)3 actually lowered the yield significantly, or
failed to provide product (Table 1, Entries 1-4).
H
R'
HO
HO
R'
from
R
[4+2]
N
O
+
N
alkene
N
Boc OH
N
1
2
Boc
3
Boc
OH
4
Boc
from
alkyne
-2 H2O
-Boc
R
H
R
R
OH
R'
HO
HO
R'
R'
+
N
N
N
H
OAc
N
N
7
O
O
Boc
5
Boc
6
Boc
Boc
-H2O
-Boc
[Pd]
11
10
R
R'
HO
+
MsO
OAc
NH
O
N
O
O
N
H
N
H
Boc
13
Boc
12
8
[Pd]
9
Fig.
3. Suggested reaction mechanisms for indole ring
N
formation from allylic and propargylic amido alcohols 1 6,7,8
.
Boc
[Pd]
Fig. 4. Retrosynthetic strategy to generate indoles from Boc-
Since the preparation of the amido alcohol
1 required the use
aminofuran 12 and allylic mesylate 13
.
of a tributylstannane-derived reactive organolithium reagent,
we were interested in extending the scope of this new IMDAF
indole synthesis by a transposition of the allylic carbon-oxygen
MsO
bond as shown in 11 10
thus enabling the use of a simple SN2-
,
N
O
O
OAc
Pd(PPh3)4
(5 mol %)
Boc OAc
14
OAc
9, 11
reaction for N-alkylation and combination of building blocks 12
and 13 (Fig. 4). Activation of 11 and isomerization of the
alkene into the desired homoallylic position versus the Boc-
+
16
NH
N
O
O
12
NMP, PPh3
(20 mol %)
NaH, DMF
0 °C to rt, 3 h; 60%
Boc
Boc
12
15
microwave
heating
N
Boc
17
amine was going to be accomplished by means of
p-allyl
Br
OAc
palladium complex 10 11
.
18
NaH, DMF
0 °C to rt, 5 h; 77%
Pd(PPh3)4 (5 mol %)
NMP, PPh3 (20 mol %)
Results and Discussion
OAc
N
O
N
H
180 °C (µW), 20 min; 45%
Mesylate 14 and N-Boc-2-aminofuran 12 were combined to
afford a model system, (Z)-allylic acetate 15, for the study of
this transformation (Scheme 1). On exposure of 15 in a
concentration of 1.0 M in NMP to 5 mol % of Pd(PPh3)4 and 20
mol % of PPh3 under microwave irradiation conditions, starting
material and five distinct new products were identified: the
Boc
19
20
Scheme 1. Exploratory studies for the Pd-catalyzed cascade
conversion of allylic acetates to indoles.
Table 1. Isolated yields for the formation of skatole 20 in a 0.1
M solution of furan 19 in NMP in the presence of Pd(PPh3)4 (5
mol %) and ligand (20 mol %) under microwave irradiation at
180 °C for 20 min.
desired indole 9, the (E)-allylic acetate 11, the deallylated N-
Boc-2-aminofuran 12, the isomerized allylic acetate 16, and
the ester elimination product, diene 17. Below 100 °C, mainly
isomerization products 11 and 16 were formed. At
temperatures between 100 °C and 150 °C, elimination
products 12 and 17 were prominent. For example, at 100 °C,
6% starting material 15, 27% isomerized compound 11, 9%
terminal alkene 16, and 33% diene 17 were isolated, whereas
130 °C produced 22% of 11, 43% of 17, and 21% of 12. Finally,
Entry Ligand
Yield Entry Ligand
Yield
40%
59%
71%
1
2
3
4
5
PPh3
PBn3
45%
74%
6
dppp
7
dppb
P(n-Bu)3 25%
P(t-Bu)3 0%
8
P(OEt)3
9
P(Oi-Pr)3 83%
P(OPh)3 27%
at 180 °C for 20 min, 19% of the desired indole
9 was isolated.
dppe
48%
10
Moreover, under otherwise identical conditions, the
trisubstituted (E)-alkene 19 provided skatole 20 in 45% yield.
Diphosphine ligands, i.e. dppe, dppp, and dppb,13 delivered
quite consistent yields in the 40-60% range (Entries 5-7).
Overall, however, alkyl phosphites proved to be superior for
the preparation of 20, since P(OEt)3 gave the indole in 71%
yield, and P(Oi-Pr)3 produced 83% (Entries 8 and 9).14
Triphenylphosphite was inferior as a ligand, furnishing only
Based on these encouraging preliminary data, we selected the
conversion of 19 to 20 for a more extensive screen of ligand
conditions, a decision that was guided in part by the assump-
tion that the 3-methyl substituent on indole 20 was
representative for the 3-alkylated indole natural products and
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27% of product (Table 1, Entry 10), and thus supporting the Table 2. Pd(0)-catalyzed cascade formation of indoles from
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DOI: 10.1039/C7OB01654A
overall observation that both the electron density and the furans. Conditions: NMP, 5 mol % Pd(PPh3)4, 20 mol % P(OiPr)3,
steric size of the palladium ligands had a major influence on microwave irradiation at 180 °C for 20 min; 0.2 M furan
the reaction outcome. Finally, we also varied palladium concentration.
loadings, and found that 5 mol % of Pd(PPh3)4 was indeed
Entry Furan
1
Indole
Yield
86%
optimal, and that the use of Pd2(dba)3, PdCl2, or Pd(OAc)2
resulted in a decrease in turnover efficiency.15 We also briefly
explored a conventional thermal conversion of 19 to 20 under
the optimized time, temperature, catalyst and ligand
conditions; but, to our surprise, only recovered starting
material. The mechanistic relevance and generality of this
observation remains to be addressed in future studies of this
reaction, in particular since the analogous, transition metal
OAc
N
O
N
H
Boc
21
22
84%
59%
77%
87%
41%
2
3
4
5
6
OAc
N
O
Boc
N
23
H
24
THPO
free conversion of
1 to 5 generally occurred with comparable
OAc
THPO
N
O
efficiency under both conventional thermal and microwave
conditions.6,7,8 Finally, using Wilkinson’s catalyst, Rh(PPh3)3Cl,
in the presence of phosphite ligands led to partial recovery of
starting material in addition to unidentified decomposition
products both at 150 °C and 180 °C.
Boc
N
H
25
26
Ph
OAc
Ph
N
O
Boc
N
H
27
28
The optimized reaction conditions (5 mol % Pd(PPh3)4, 20 mol
% P(OiPr)3, microwave irradiation at 180 °C for 20 min in 0.2 M
solution of substrate in NMP) were applied to determine the
OAc
N
O
Boc
N
H
29
30
scope of this cascade Tsuji-Trost p-allyl-palladium formation/
F3C
OAc
IMDAF reaction/ aromatization sequence. Alkyl and aryl
substitutions on the furan were compatible with indole
formation; with the highest yields arising from mildly electron-
donating functionalities. For example, the 3-methylated furan
21 provided the 3,7-dimethylated indole 22 in 86% yield (Table
2, Entry 1). Moving the methyl substituent into the furan 5-
position as in 23 did not influence the outcome of the reaction,
but the THP-ether at this position in 25 led to a noticeable
drop in the yield of the isolated 5-functionalized indole 26 to
59% (Entry 2 and 3). The presence of strongly electron-
N
O
F3C
Boc
31
N
H
32
F3C
CF3
48%
7
OAc
N
O
Boc
F3C
33
F3C
N
H
34
F
66%
64%
52%
8
OAc
N
O
F
Boc
35
N
H
36
withdrawing trifluoromethyl groups had only
a slightly
MeO
9
detrimental effect on the isolated yield. While 5-phenyl furan
27 provided 5-phenyl indole 28 in 77% (Entry 4) and the meta-
toluene analog 29 was converted in 87% yield (Entry 5), the
corresponding trifluoromethylated 31 gave indole 32 in a
lower yield of 41% (Entry 6). Additional trifluoromethyl groups,
as in 33 (Entry 7), however, did not further decrease the
isolated yield. Also, para-fluorinated 35 gave indole 36 in an
acceptable yield of 66% (Entry 8), equivalent to the 64%
conversion of para-methoxy furan 37 to indole 38 (Entry 9).
OAc
N
O
MeO
Boc
37
N
H
38
t-Bu
10
OAc
N
O
t-Bu
Boc
N
H
39
40
t-Bu
27%
11
OAc
N
O
t-Bu
N
H
Boc
41
42
An alkyne substitution at the furan C-5 position was briefly
explored with substrate 39, which gave 5-alkynylindole 40 in a
moderate yield of 52% (Entry 10). However, with an additional
substituent at C-4, the trisubstituted furan 41 produced only
27% of the isolated indole 42 (Table 2, Entry 11). The
conversions of alkynylfurans also led to a noticeably larger
number of side products than the other substrates, suggesting
the possibility for thermal decomposition of starting materials
and/ or products under the reaction conditions.
Originally, our design of this new reaction sequence was based
on the mechanistic hypothesis that the
formed by the Pd(0)-catalyzed elimination of allylic acetate 43
p
-allyl species 44
,
,
was capable of an IMDAF reaction either directly or by virtue
of the -bonded allylic palladium complex 45 (Fig. 5).
s
However, it is entirely feasible that a Friedel-Crafts type
intramolecular attack on the electron-rich furan ring leads to
the transient palladium-complex 46, which, upon reductive
elimination, results in the bicyclo[5.2.1] p .
-complex 47 16
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R4
R3
OAc
R5
N
O
Acknowledgements
R
Boc
43
The authors thank Boehringer-Ingelheim Pharmaceuticals,
Ridgefield, CT, USA, for discretionary funding supporting this
research. P.W. also thanks the Alexander von Humboldt
Foundation for a generous Research Award.
PdLn
-AcO
PdIILn
R4
R3
R5
R4
R
[4+2]
R
O
R5
N
O
N
Notes and references
Boc
Boc
R3
PdIILn
1
S. Lal and T. J. Snape, Curr. Med. Chem., 2012, 19, 4828-
4837; E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med.
Chem., 2014, 57, 10257-10274.
44
45
PdLn
2
3
M. Inman and C. J. Moody, Chem. Sci., 2013, 4, 29-41.
D. F. Taber and P. K. Tirunahari, Tetrahedron, 2011, 67, 7195-
7210.
-H
-PdIIHLn
Ln
R
N
PdIILn
R
PdII
O
R5
R4
R5
R4
R5
R4
R
4
5
K. Hayakawa, T. Yasukouchi and K. Kanematsu, Tetrahedron
Lett., 1986, 27, 1837-1840.
O
O
N
N
Boc
A. Padwa and A. C. Flick, Adv. Heterocycl. Chem., 2013, 110
,
R3
Boc
R3
Boc
R3
1-41; A. Padwa, M. A. Brodney, B. Liu, K. Satake and T. Wu, J.
Org. Chem., 1999, 64, 3595-3607.
F. Petronijevic, C. Timmons, A. Cuzzupe and P. Wipf, Chem.
Commun., 2009, 104-106; F. R. Petronijevic and P. Wipf, J.
Am. Chem. Soc., 2011, 133, 7704-7707.
49
48
46
6
-H2O
-Boc
PdLn
R
R
7
8
9
M. LaPorte, K. B. Hong, J. Xu and P. Wipf, J. Org. Chem.,
2013, 78, 167-174.
R5
R4
R5
R4
O
S. R. McCabe and P. Wipf, Angew. Chem., Int. Ed., 2017, 56
324-327.
,
N
N
H
Boc
R3
47
R3
H. H. Wasserman, G. D. Berger and K. R. Cho, Tetrahedron
50
Lett., 1982, 23, 465-468; P. Wipf and M. Furegati, Org. Lett.,
2006, 8, 1901-1904.
Fig. 5. Possible reaction mechanisms for indole formation from
allylic acetate 43
10 D. C. Braddock and A. Matsuno, Tetrahedron Lett., 2002, 43,
3305-3308.
.
11 N. T. Patil and Y. Yamamoto, Top. Organomet. Chem., 2006,
19, 91-113.
Both pathways converge mechanistically in the formation of
the intermediate -complex 48, which, after elimination of
palladium hydride, forms the ether-bridged 49. The latter
compound has already been shown6,7 to readily aromatize to
indole 50 under thermal conditions after water and Boc-group
eliminations.
12 PBn3 has previously been found to provide a superior
s
alternative to PPh3 and PBu3 in p-allyl palladium chemistry:
Wipf and S. R. Spencer, J. Am. Chem. Soc., 2005, 127, 225-
235.
13 For an analysis of Pd-allyl complexes with the diphosphine
ligands 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-
bis(diphenylphosphino)propane (dppp), and 1,4-bis-
(diphenylphosphino)butane (dppb), see: J. Wassenaar, E.
Jansen, W.-J. van Zeist, F. M. Bickelhaupt, M. A. Siegler, A. L.
Conclusions
Spek and J. N. H. Reek, Nat. Chem., 2010, 2, 417-421.
14 B. Aakermark, K. Zetterberg, S. Hansson, B. Krakenberger and
A. Vitagliano, J. Organomet. Chem., 1987, 335, 133-142.
15 J. Xu, Master of Science Thesis, 2013, University of
Pittsburgh, Pittsburgh, USA.
Based on a mechanistic hypothesis, we have developed a tin-
and organolithium-free variant of our IMDAF indole synthesis.
This new approach takes advantage of the reactivity of an
intermediate
p-allyl palladium complex and provides the
16 For intra- and intermolecular transition-metal-catalyzed
Friedel−Crafts-type allylations of arenes, see: C. A. Discolo, A.
G. Graves and D. R. Deardorff, J. Org. Chem., 2017, 82, 1034-
1045; A. V. Malkov, S. L. Davis, I. R. Baxendale, W. L. Mitchell
and P. Kocovsky, J. Org. Chem., 1999, 64, 2751-2764; I.
Fernandez, R. Hermatschweiler, F. Breher, P. S. Pregosin, L. F.
desired heterocycles in a convergent fashion in moderate to
high yields from readily available starting materials. The scope
of the cascade reaction was demonstrated to extend to 5-, 6-,
and 7-substituted indoles bearing alkyl-, alkynyl-, aryl-, and
heteroatom-functionalized side chains. The use of microwave
heating allows for a rapid and convenient access to these
synthetically and biologically useful scaffolds. Further
applications and mechanistic studies that address possible
concerted [4+2] or alternative stepwise Friedel-Crafts-type
reaction manifolds will be reported in due course.
Veiros and M. J. Calhorda, Angew. Chem., Int. Ed., 2006, 45
,
6386-6391; Y. Suzuki, T. Nemoto, K. Kakugawa, A. Hamajima
and Y. Hamada, Org. Lett., 2012, 14, 2350-2353; Z.-L. Zhao,
Q.-L. Xu, Q. Gu, X.-Y. Wu and S.-L. You, Org. Biomol. Chem.,
2015, 13, 3086-3092.
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