A tandem "on-palladium" Heck-Jeffery amination route toward the synthesis of functionalized indole-2-carboxylates

Article abstract of DOI:10.1002/ejoc.201101072

A direct synthesis of functionalized indole-2-carboxylates involving a Pd^II-catalyzed annulation of ortho-iodoanilines onto a vinyl ether is described. The reaction mechanism is shown to be distinct from a stepwise Heck, intramolecular amination pathway, likely involving a tandem "on-palladium" Heck-Jeffery amination process incorporating a novel intramolecular amination step.

Full text of DOI:10.1002/ejoc.201101072

FULL PAPER
DOI: 10.1002/ejoc.201101072
A Tandem “On-Palladium” Heck–Jeffery Amination Route Toward the
Synthesis of Functionalized Indole-2-carboxylates
James McNulty*[a] and Kunal Keskar[a]
Keywords: Nitrogen heterocycles / Cross-coupling / Amination / Homogeneous catalysis / Palladium
A direct synthesis of functionalized indole-2-carboxylates in-
volving a PdII-catalyzed annulation of ortho-iodoanilines
onto a vinyl ether is described. The reaction mechanism is
shown to be distinct from a stepwise Heck, intramolecular
amination pathway, likely involving a tandem “on-palla-
dium” Heck–Jeffery amination process incorporating a novel
intramolecular amination step.
alkoxyacrylate yielding functionalized indole-2-carboxyl-
ates via an on-palladium tandem Heck–Jeffery amination
(HJA) process.
Introduction
The indole nucleus occupies a privileged position
amongst the nitrogen heterocycles, a consequence of its oc-
currence in the amino acid tryptophan. Indole derivatives
are significant in terms of the varied structures and wide
ranging biological activities demonstrated by both indole-
containing secondary metabolites and wholly synthetic de-
rivatives. The provenance of the indole nucleus in many of
the classic alkaloid skeletons (aspidospermae, corynanthe,
iboga, ergot etc) and simpler trypthophan degradation
products (gramine, serotonin etc.) inspired an early interest
in both the structure and synthesis of indole derivatives,[1]
a trend that continues unabated.[2] Recent approaches
towards indole synthesis are for the most part based on
transition-metal promoted routes,[3] some of which con-
verge on intermediates common to the classic syntheses.[1]
The myriad of biological activities documented for both
natural and synthetic indole derivatives continues to expand
and includes toxicity, anticancer, antiviral, antimicrobial,
neurological, and hormonal (plant and mammalian) activi-
ties.[4] These factors have assured a continued focus on the
synthesis of functionalized indoles and their biological
evaluation. The recent interest in indole-2-carboxylic acid
derivatives as non-nucleoside reverse transcriptase[5a] and
integrase[5b] inhibitors for HIV treatment, in conjunction
with a report from our group[6] relating to the synthesis of
vinyl ethers prompted us to investigate a possible tandem
Pd-mediated Heck–Jeffery amination process as a direct
route to such indole derivatives. In this communication we
report the successful annulation of 2-iodoanilines onto an
We recently described a general route towards the synthe-
sis of vinyl ethers involving the reaction of α-alkoxy-func-
tionalized ylides with carbonyl compounds.[6] Therein it was
shown that the reaction of a dialkyl acetal with a trialkyl-
phosphane hydrobromide yielded the α-alkoxyphospho-
nium salt derived of the acetal. Ylide generation and ole-
fination allowed access to a wide range of functionalized
vinyl ethers and alkoxy-1,3-dienes. As an extension of this
work, we have now successfully converted ethyl glyoxylate
diethyl acetal (1, Scheme 1) into the functionalized phos-
phonium salt 2. Salt 2 was also obtainable from the corre-
sponding chloroacetal. Ylide generation from 2 and trap-
ping with formaldehyde allowed us to access the α-alkoxy
acrylate 3 as well as various α-alkoxycinnamates 4 through
trapping of the ylide with aromatic aldehydes.
[a] Department of Chemistry and Chemical Biology, McMaster
University,
1280 Main Street West, Hamilton, ON, L8S 4M1, Canada
Fax: +1-905-522-2509
E-mail: jmcnult@mcmaster.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101072 or from
the author.
Scheme 1. Synthesis of α-alkoxyacrylates and cinnamates using
functionalized ylides.
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A Tandem “On-Palladium” Heck–Jeffery Amination
While the Heck reaction of ortho-haloanilines and acryl- demonstrate that under normal Heck conditions reductive
ate esters is known to provide acceess to ortho-aminocinna- elimination to yield the cinnamate precedes a possible intra-
mates in moderate yield,[7] it is well known that nucleo- molecular N-insertion, thus precluding a direct indole syn-
philic[8a] and Pd-mediated[8c–8d] Heck-type addition to α- thesis. These results led us to postulate a catalytic cycle as
alkoxyacrylates such as 3 is sluggish due to electronic deac- depicted in Scheme 3, in which, under Jeffery-type condi-
tivation of the olefin. The only report of such a process tions (PdII precursor, no ligand, TBAB etc),[7a] an intramo-
using an ortho-iodo aniline[8d] was shown to yield a quinol- lecular ligand exchange (II to III), followed by reductive
inone 6 (Scheme 2) through intramolecular N-acylation of elimination (loss of HI/base not shown) and elimination of
the intermediate Heck adduct 5. This result and others[7] ethanol would deliver the indole 7 directly. The develop-
Scheme 2. Annulation of ortho-iodoanilines with alkoxy acrylate 3 via a standard Heck and the tandem “on-palladium” Heck–Jeffery
amination process (isolated yields given).
Scheme 3. Proposed catalytic cycle for annulation of ortho-iodoanilines with alkoxy acrylate 3 via the tandem “on-palladium” Heck–
Jeffery amination process.
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J. McNulty, K. Keskar
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ment of such a tandem HJA process to functionalized furnished only the quinolinone 6, with no trace of the corre-
ortho-iodo anilines and vinyl ethers would allow for a direct sponding indole-2-carboxylate ester, as previously report-
“on-palladium” route to indole-2-carboxylates. A Heck– ed.[8d] We experimented with various parameters of the re-
Jeffery route to indoles has been reported from N-acyl en- action under Jeffery-type conditions[7a] and determined that
amines, involving a subsequent enamine hydrolysis and the desired indole-2-carboxylate derivative was formed un-
Reissert-type ring closure.[9a] This process does not involve der a narrow subset of conditions. A summary of various
an intramolecuar ligand exchange. The intramolecular trap- conditions attempted is reported in Table 1. For compari-
ping of Heck-type intermediates via aminopalladation is a son, these reactions were stopped after 24 h and the isolated
known process in the synthesis of pyrrolidines, but to the yield of ethyl indole-2-carboxylate determined. Although
best of our knowledge has not been applied towards the the reaction was sluggish, it was found best performed in
synthesis of indoles.[9b]
dipolar aprotic solvents using Pd(OAc)2 as catalyst. The re-
action requires base and sodium hydrogen carbonate
proved most effective, although is perhaps not critical (en-
tries 1–3).
Results and Discussion
The reaction of ortho-iodoaniline with α-ethoxyacrylate
No reaction occurs at room temperature while heating in
3, investigated under standard Heck conditions (Scheme 2) acetonitrile at 80 °C as solvent proved slightly superior to
Table 1. Optimization of the Heck–Jeffery amination process for the synthesis of indole-2-carboxylate 7. General reaction screening
conditions: iodoaniline (0.18 mmol), ethyl 2-ethoxyacrylate (0.27 mmol), TBAB (0.36 mmol), Pd-source (0.018 mmol), ligand
(0.009 mmol), base (0.54 mmol), solvent (1.5 mL).
[a] 24 h reaction with 2.8 equiv. of acrylate. [b] 1,2-Bis(di-tert-butylphosphanylmethyl)benzene.
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A Tandem “On-Palladium” Heck–Jeffery Amination
DMF. Further experiments (entries 4–9) allowed us to with Pd(OAc)2 and found to slowly convert to 6, with no
identify satisfactory conditions (entry 9). Several failed op- trace of the indole-2-carboxylate being observed. Treatment
timization attempts provided circumstantial evidence indi- of
5
under the Heck–Jeffery conditions described
cating the lack of involvement of a Pd0-species as the active (Scheme 2) slowly (over 48 h) yielded quinolinone 6 (60%),
catalyst, differing from a straightforward Heck reaction.[7c] unreacted cinnamate 5 (30%) and a trace of the indole 7
For example, the reaction failed completely when con- observed only by thin-layer chromatography. We attribute
ducted in an ionic liquid solvent [entries 10 and 11, IL-109 the trace indole formation to hydrolysis of the enol ether in
= trihexyl(tetradecyl)phosphonium bistriflimide], a media 10 followed by Reissert-type closure. These results indicate
known to be highly effective in Pd0-mediated amination[6b] that under the Heck–Jeffery conditions, elimination from
and Heck processes.[6e] Furthermore, the addition of intermediate II to give 5 is essentially irreversible and that
ligands including P-phenylphosphadamantane (Cytop indole formation is in accord with the “on-palladium” cata-
292),[6c] triphenylphosphane or bidentate bis(di-tert-butyl- lytic cycle indicated in Scheme 3.
phosphanyl)-o-xylene[6d] with Pd(OAc)2 (entries 12–16)
The scope of this new route to valuable indole-2-carb-
proved to shut down the catalytic cycle completely. The di- oxylate derivatives[5] was investigated with a mini-panel of
rect use of Pd0 catalyst precursors proved also to be ineffec- readily available ortho-iodoanilines and is summarized in
tive.
Table 2. The HJA process allowed general conversion to the
Extension of the reaction time of the optimized protocol corresponding indole-2-carboxylate derivative in 48 to 77%
(Table 1, entry 9) to 96 h gave maximum yield of ethyl in-
dole-2-carboxylate 7a as shown in Scheme 2, bottom. Un-
der these conditions, annulation of 2-iodoaniline onto the
Table 2. Synthesis of functionalized indole-2-carboxylates.
alkoxyacrylate occurred yielding indole-2-carboxylate 7a as
the major product, contrasting sharply to the Heck pro-
cess[8d] (Scheme 2, top) that yields the quinolinone. Forma-
tion of a small amount of the quinolinone 6 and a trace
amount of the cinnamate 5 under the HJA conditions most
likely represents “leakage” from the catalytic cycle via
Heck-type β-hydride elimination from intermediate II. This
step could potentially be reversible via an aminopalladation
process. In order to test this hypothesis, we desired to inves-
tigate the reversibility of this elimination step and show that
5 is not converted into the indole under these conditions
through re-entry to the catalytic cycle or by other means.
To this end, we synthesized the ortho-aminocinnamate 5 in-
dependently through the route shown in Scheme 4. Ole-
fination of 2-nitrobenzaldehyde 8 with the functionalized
ylide 9 (derived from 2) yielded the 2-nitrocinnamate 10.
Dissolving metal reduction (Fe, NH4Cl) of 10 gave the ani-
line 5 (12%) as well as quinolinone 6 (48%). Compounds 5
and 6 were readily separated by silica-gel chromatography.
Compound 5 was treated under standard Heck conditions
Scheme 4. Independent synthesis of the α-ethoxycinnamate 5 and
conversion to 6 thermally and under Heck–Jeffery amination con-
[a] Based on recovered starting iodoaniline. [b] Ethyl 2-ethoxy-3-
phenylacrylate was used as the acrylate source.
ditions.
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J. McNulty, K. Keskar
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isolated yields, always accompanied by 5 to 10% of the cor-
responding quinolinone, produced via the “leakage” path-
way. The indole-2-carboxylate derivatives were easily sepa-
rable from the quinolinones on silica gel and the numbers
reported in Table 1 are final isolated yields. The annulation
also proved chemoselective in the presence of lesser reactive
aryl halides, allowing access to useful chloro- and fluoro-
functionalized indole-2-carboxylates.
Conclusions
In conclusion, we report the successful annulation of or-
tho-iodoanilines onto an α-ethoxy acrylate resulting in a ge-
neral synthesis of indole-2-carboxylate derivatives. The re-
action appears to be mechanistically distinct from a stan-
dard Heck reaction. Under Heck–Jeffery conditions, evi-
dence is presented consistent with an all “on-palladium”
mechanism, involving a critical intramolecular amination,
or ligand exchange step, (II–III, Scheme 3) that intervenes
and effectively competes with the standard Heck process
(II–5). Further investigation into the mechanism, scope and
application of the method is in progress.
Lastly, several of our results have brought into question
the accepted mechanism of the Heck–Jeffery reaction. The
dichotomy (see Scheme 2) between the standard Pd0-medi-
ated Heck reaction of vinyl ethers such as 3 and that de-
scribed herein under the “on-palladium” Heck–Jeffery am-
ination process is indicative of the involvement of a distinct
catalytic species for the HJA process. Proposed catalytic cy-
cles involving Jeffery conditions typically invoke Pd0/PdII
intermediates,[7a] although they invariably require PdII pre-
cursors. The present HJA process requires a PdII precursor,
Pd0 pre-catalysts and/or addition of ligands do not promote
this direct indole formation, but instead result in exit from
the catalytic cycle via intermediate II giving quinolinone
6.[8d] The HJA process proceeds slowly under conditions
where typical Pd0-mediated pathways would be expected to
be rapid and the normal Heck-type adducts should be
formed. The present results also show that the normal Heck
adducts do not re-enter the catalytic cycle, indole formation
likely occurs via an independent on-palladium route. One
explanation may be that excess halide anion present during
the HJA process (requires TBAB) hinders β-hydride elimi-
nation (Scheme 3, II to 5) on the standard PdII intermedi-
ate, a process known in the Heck reaction itself,[10e] leaving
little option but intramolecular ligand exchange, leading to
the indole-2-carboxylate. However this explanation does
not account for the lack of reactivity under conditions of
Experimental Section
General: All reactions were carried out under argon atmosphere in
oven dried glassware. Acetonitrile and DMF were obtained from
Sigma–Aldrich. Iodoaniline derivatives were obtained from Sigma–
Aldrich, AlfaAesar and AB Chem, Canada. THF was distilled
from sodium/benzophenone. Melting points were recorded in open
capillary tubes using a calibrated Büchi B540 apparatus. Thin-layer
chromatography (TLC) was carried out using aluminium sheets
pre-coated with silica gel 60F254 (Merck) and was visualized under
254/360 nm UV. 1H and 13C spectra were recorded on a AV 600
spectrometer in CDCl3 with TMS as internal standard. Chemical
shifts (δ) are reported in ppm downfield of TMS and coupling con-
stants (J) are expressed in Hertz (Hz).
General Procedure for the Heck–Jeffery Indole-2-carboxylate Syn-
thesis: Into a flame-dried Schlenk tube, containing a magnetic stir-
ring bar, was weighed the corresponding 2-iodoaniline (0.040 g,
0.18 mmol 1.0 equiv.), ethyl 2-ethoxyacrylate (0.052 g, 0.36 mmol,
2.0 equiv.), TBAB (0.118 g, 0.36 mmol, 2.0 equiv.), NaHCO3
(0.092 g, 1.09 mmol, 6.0 equiv.), Pd(OAc)2 (0.0061 g, 15 mol-%)
low halide concentration (Table 1, entry 8), or in ionic li- and dry acetonitrile (1.8–2.0 mL). The reaction mixture was stirred
at 80 °C for 96 h monitored by TLC. The reaction mixture was
allowed to cool to room temperature. Solvent was evaporated under
vacuum and crude reaction mixture was extracted with ethyl acet-
ate and washed with brine. The combined organic extracts were
dried with sodium sulfate, filtered, and concentrated. The product
was purified using silica gel column chromatography using 2–5%
ethyl acetate in hexanes to yield corresponding ethyl 1H-indole-2-
carboxylate. Data are summarized below for the entries in Table 1.
quids containing non-nucleophilic counter anions (Table 1,
entries 10 and 11). Additionally, this does not satisfactorily
account for the inability of direct Pd0 sources to promote
the HJA process as described nor why Pd0 sources under
standard Pd0/PdII Heck conditions gives only quinolinones
(Scheme 2, top),[8d] not indole-2-carboxylates. Another pos-
sible explanation for this dichotomy is that while the stan-
dard Heck process proceeds via Pd0/PdII intermediates, the
on-palladium HJA reaction proceeds via a different cycle
possibly involving PdII/PdIV intermediates, Scheme 3 (L =
AcO–). Such catalytic cycles have been proposed and de-
emed to be “unlikely” in the Heck reaction.[7c] The in-
creased electrophilicity of the Pd-centre on intermediate II
under such conditions, may be expected to favour intramo-
lecular ligand exchange onto the appended ortho-amino
group, and thus account for the successful direct annulation
to the indole derivatives. Known catalytic processes involv-
ing PdII/PdIV intermediates typically proceed under oxidat-
ive conditions,[10] at least one report on the intramolecular
trapping of Heck adducts on-Pd via a PdII/PdIV pathway is
known.[10d] The present HJA process would require a direct
oxidative addition of an aryl iodide to a PdII catalyst to
access the PdIV intermediate.
Ethyl 1H-Indole-2-carboxylate (7a):[11] M.p. 123–125 °C (ref.[12]
1
m.p. 121–123 °C). H NMR (600 MHz, CDCl3): δ = 8.92 (br. s, 1
H), 7.69 (d, J = 8.12 Hz, 1 H), 7.42 (d, J = 8.12 Hz, 1 H), 7.32 (m,
1 H), 7.23 (m, 1 H), 7.15 (m, 1 H), 4.42 (q, J = 7.20 Hz, 2 H), 1.42
(t, J = 7.20 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
162.16, 136.94, 127.66, 125.49, 122.75, 120.94, 111.98, 108.79,
61.17, 14.55 ppm.
Ethyl 6-Chloro-1H-indole-2-carboxylate (7b):[12] M.p. 169–171 °C
(ref.[12] m.p. 163–165 °C). 1H NMR (600 MHz, CDCl3): δ = 9.07
(br. s, 1 H), 7.59 (d, J = 8.50 Hz, 1 H), 7.42 (s, 1 H), 7.19 (s, 1 H),
7.12 (dd, J = 8.50, 1.8 Hz, 1 H), 4.20 (q, J = 7.10 Hz, 2 H), 1.42
(t, J = 7.10 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
161.95, 137.18, 131.43, 128.37, 126.17, 123.67, 122.01, 111.84,
108.75, 61.39, 14.52 ppm.
Ethyl 6-Methoxy-1H-indole-2-carboxylate (7c):[13] M.p. 131–133 °C
(ref.[14] m.p. 135–136 °C). 1H NMR (600 MHz, CDCl3): δ = 8.88
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A Tandem “On-Palladium” Heck–Jeffery Amination
[2]
(br. s, 1 H), 7.54 (d, J = 8.6 Hz, 1 H), 7.16 (m, 1 H), 6.83 (s, 1 H),
6.82 (dd, J = 8.6, 2.2 Hz, 1 H), 4.39 (q, J = 7.18 Hz, 2 H), 3.86 (s,
3 H), 1.41 (t, J = 7.18 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 162.16, 159.01, 138.06, 126.56, 123.51, 122.00, 112.41, 109.15,
93.86, 60.93, 55.62, 14.57 ppm.
For a selection of recent syntheses of functionalized indoles
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indole synthesis, see: a) S. Cacchi, G. Fabrizi, A. Goggiamani,
Org. Biomol. Chem. 2011, 9, 641–652; b) S. Cacchi, G. Fabrizi,
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Ethyl 5-Fluoro-1H-indole-2-carboxylate (7d):[11] M.p. 147–149 °C
(ref.[11] m.p. 147–148 °C). 1H NMR (600 MHz, CDCl3): δ = 9.00
(br. s, 1 H), 7.36 (dd, J = 8.9, 4.3 Hz, 1 H), 7.32 (dd, J = 9.2,
2.4 Hz, 1 H), 7.18 (m, 1 H), 7.09 (td, J = 9.02, 2.48 Hz, 1 H), 4.42
(q, J = 7.10 Hz, 2 H), 1.42 (t, J = 7.10 Hz, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 161.89, 158.31 (d, J = 237.59 Hz), 129.20,
127.82 (d, J = 10.4 Hz), 114.59 (d, J = 26.89 Hz), 112.91 (d, J =
9.59 Hz), 108.57 (d, J = 5.25 Hz), 106.92 (d, J = 23.26 Hz), 61.34,
14.53 ppm.
Ethyl 5-Chloro-1H-indole-2-carboxylate (7e):[12] M.p. 167 °C (ref.[12]
1
m.p. 167–169 °C). H NMR (600 MHz, CDCl3): δ = 9.12 (br. s, 1
H), 7.66 (d, J = 1.83 Hz, 1 H), 7.35 (d, J = 8.35 Hz, 1 H), 7.27 (dd,
J = 8.73, 1.92 Hz, 1 H), 7.15 (m, 1 H), 4.42 (q, J = 7.10 Hz, 2 H),
1.42 (t, J = 7.10 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
161.91, 135.22, 128.89, 128.55, 126.59, 125.97, 121.89, 113.12,
108.08, 61.42, 14.51 ppm.
[3]
Ethyl 5-Methyl-1H-indole-2-carboxylate (7f):[15] M.p. 161–162 °C
1
(ref.[16] m.p. 163 °C). H NMR (600 MHz, CDCl3): δ = 8.85 (br. s,
1 H), 7.46 (d, J = Hz 0.64 H, 1 H), 7.31 (d, J = 8.46 Hz, 1 H), 7.15
(m, 2 H), 4.41 (q, J = 7.10 Hz, 2 H), 2.44 (s, 3 H), 1.42 (t, J =
7.10 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 162.22, [4]
135.38, 130.23, 127.93, 127.65, 127.45, 121.98, 111.64, 108.27,
61.08, 21.55, 14.55 ppm.
Ethyl 5,6-Dimethyl-1H-indole-2-carboxylate (7g):[17] M.p. 162–
165 °C. 1H NMR (600 MHz, CDCl3): δ = 8.71 (br. s, 1 H), 7.43 (s,
1 H), 7.18 (s, 1 H), 7.12 (dd, J = 2.00, 0.84 Hz, 1 H), 4.39 (q, J =
7.18 Hz, 2 H), 2.37 (s, 3 H), 2.34 (s, 3 H), 1.41 (t, J = 7.18 Hz, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 162.27, 136.13, 135.32,
129.99, 126.85, 126.14, 122.30, 112.30, 112.00, 108.28, 60.96, 20.91
20.22, 14.57 ppm.
[5]
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Ethyl 5-Cyano-1H-indole-2-carboxylate (7h):[18] M.p. 179–180 °C,
1H NMR (600 MHz, CDCl3): δ = 9.20 (s, 1 H), 8.08 (s, 1 H), 7.54
(dd, J = 8.6, 1.3 Hz, 1 H), 7.50 (d, J = 8.6 Hz, 1 H), 7.28 (d, J =
1.2 Hz, 1 H), 4.44 (q, J = 7.1 Hz, 2 H), 1.43 (t, J = 7.1 Hz, 3 H)
ppm. 13C NMR (151 MHz, CDCl3): δ = 161.41, 138.08, 129.96,
128.68, 127.73, 127.32, 120.08, 113.07, 109.00, 104.55, 61.76, 14.49
ppm.
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Acknowledgments
We thank Natural Sciences and Engineering Research Council of
Canada (NSERC), Cytec Canada Inc. and McMaster University
for the financial support of this work.
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Eur. J. Org. Chem. 2011, 6902–6908