Palladium(II)-catalyzed oxidative carbocyclization of aza-enallenes

Article abstract of DOI:10.1002/anie.201000726

(Chemical equation presented) Live and let diene: A palladium(II)-catalyzed oxidative carbocyclization reaction of aza-enallenes provides access to potentially valuable heterocyclic dienes. In the presence of a dieneophile during the carbocyclization step, the products can react further in a one-pot cyclization/ Diels-Alder sequence to give polycyclic products. BQ = para-benzoquinone.

Full text of DOI:10.1002/anie.201000726

Communications
DOI: 10.1002/anie.201000726
Carbocyclization
Palladium(II)-Catalyzed Oxidative Carbocyclization of Aza-
Enallenes**
Andreas K. ꢀ. Persson and Jan-E. Bꢁckvall*
À
Metal-mediated C H bond functionalizations offer the
synthetic chemist a powerful tool in the quest for producing
ever more complex and demanding organic structures.[1] This
À
process transforms various C H bonds into more syntheti-
[2]
À
À
À
cally useful C O, C N, or C C bonds. In particular, the
Scheme 1. Preparation and carbocyclization of aza-enallenes.
À
metal-catalyzed activation of allylic C H bonds has received
BQ=para-benzoquinone, THF=tetrahydrofuran.
much attention, and, as a consequence, there are numerous
examples of metal-mediated allylic oxidations in the liter-
ature.[3] Early procedures suffered from moderate selectivity
and the use of stoichiometric amounts of metal.[4] Most of
these drawbacks have long since been overcome, which has
resulted in a vast array of catalytic allylic oxidations,[5–9]
including asymmetric protocols,[6] being made available to
the synthetic chemist. More recent work on palladium(II)-
catalyzed allylic oxidation reactions has extended the syn-
thetic utility of these protocols, and has also allowed the
reaction of 1a with different palladium sources. As shown in
Table 1, the only simple palladium(II) salt that resulted in an
acceptable yield of 2a was Pd(OAc)2. Under these conditions,
the only by-product detected was the Diels–Alder adduct 5
Table 1: Investigation of different PdII sources in the oxidative carbocyc-
lization of aza-enallene (1a).[a]
[8–10]
À
selective formation of carbon carbon bonds.
In all of
these oxidation reactions, an efficient re-oxidation system is
key to their success, with molecular oxygen as the preferred
terminal oxidant.[11]
We have previously reported various palladium-catalyzed
transformations of allenes.[12–14] These studies have focused on
a variety of C-allenyl compounds that contain olefinic side
chains. Such substrates are well-suited for palladium(II)-
Entry [PdII]
Conv. [%][b] Product ratio Yield of 2a [%][c]
(2a/3/4/5)
À
catalyzed carbon carbon bond-forming oxidative cyclization
reactions,[13] as well as palladium(0)-catalyzed cyclization
reactions.[14] In a recent investigation, we showed that water
(aqueous media) can act as a nucleophile in the oxidative
carbocyclization[15] of diene–allene compounds using molec-
ular oxygen as the terminal oxidant.[13c]
1
2
3
4
5
6
Pd(OAc)2
[PdCl2(CH3CN)2] 100
Pd(tfa)2
Pd(acac)2
Pd(OAc)2, L1[d]
none
100
90:0:0:10
5:45:45:5
1:49:49:1
s.m.
80
<5
<1
0
95
0
0
s.m.
0
0
s.m.
0
We recently reported a copper-catalyzed coupling of
sulfonamides and halo-allenes that provided access to aza-
enallenes,[16] which might be suitable for a carbocyclization
protocol. Herein, we report that aza-enallenes 1a react with
catalytic amounts of Pd(OAc)2 in an overall oxidative
carbocyclization process to give 2a (Scheme 1).
[a] Reaction conditions: PdII source (5 mol%), BQ (1.05 equiv), aza-
enallene (1.00 equiv) THF, 508C, 5 h. [b] Product distribution and
conversion determined using NMR analysis. [c] Yield based on an
internal standard (anisole). [d] L1=1,10-phenanthroline. s.m.=starting
material.
In our previous work on the preparation of aza-enal-
lenes,[16] we noticed that these compounds were highly
sensitive towards acidic conditions. Initially, we studied the
between carbocyclization product and para-benzoquinone
(BQ). Replacing Pd(OAc)2 with Pd(TFA)2 (TFA = trifluoro-
acetate) or [PdCl2(CH3CN)2] gave only trace amounts of
carbocyclization product (Table 1, entries 2 and 3), and
instead the formation of tosylamide derivative 3 and aldehyde
4 predominated.[17]
No conversion was observed with [Pd(acac)2] or Pd-
(OAc)2 with 1,10-phenanthroline, and the starting material
was recovered in these cases (Table 1, entries 4 and 5). A
control experiment without palladium, under the same
conditions, showed no decomposition or conversion of 1a
by NMR spectroscopy (Table 1, entry 6). The catalyst screen-
ing showed that Pd(OAc)2 was the most effective catalyst
[*] A. K. ꢀ. Persson, Prof. J.-E. Bꢁckvall
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, SE-106 91 Stockholm (Sweden)
Fax: +46-8-154908
E-mail: jeb@organ.su.se
[**] Financial support from the Swedish Research Council, the European
Research Council (ERC AdG 247014), and The Berzelii Center
EXSELENT is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000726.
4624
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Angew. Chem. Int. Ed. 2010, 49, 4624 –4627

Angewandte
Chemie
Table 2: Substrate scope.[a]
among the simple PdII catalysts that
were tested. To gain some insight
into the formation of the Diels–
Alder adduct in the catalytic reac-
tion, some in situ NMR experi-
ments were performed. The reac-
tion of aza-enallene 1a with
1.05 equivalents of BQ in the pres-
ence of 2 mol% of Pd(OAc)2 in
[D8]THF at 488C was monitored by
Entry
1
Aza-enallene
Product
Yield [%][b]
74
1a
1b
2a
2b
94[c]
1H NMR
spectroscopy,
which
showed that a Diels–Alder product
was formed when the reaction had
reached around 40% conversion.
(see the Supporting Information,
Figure S1) This observation sug-
gests that the byproduct arises
from a reaction between carbocycl-
ized product 2a and BQ. After
2.5 hours, products 2a and 5 were
formed in a 91:9 ratio, and the yield
of 2a was 82%, based on the
internal standard. Interestingly, the
formation of 2a shows a sigmoidal
growth curve (Figure S1, Support-
2
3
64[d]
1c
2c
95 (Z)
4
5
1d
1e
2d
2e
71
84
ing Information).
A
plausible
70
6
1 f
2 f/2 f’
3:1
explanation for this phenomenon
is that the commercially available
trimeric palladium acetate needs to
be activated or dissociated in order
to produce the monomeric species
required for catalysis.[18] Another
explanation could be that the
Diels–Alder adduct participates as
a ligand in the reaction; this type of
activation has been previously sug-
gested for the diacetoxylation of
1,3-dienes.[19]
81
7
8
1g
1h
2g
86[c]
no reaction
0[e]
[a] Reaction conditions (unless otherwise noted): Pd(OAc)2 (2 mol%), BQ (1.05 equiv), aza-enallene
(1.00 equiv), THF, 508C, 4 h. [b] Yield of isolated product. [c] Pd(OAc)2 (5 mol%), [Co] cat. 6 (5 mol%)/
O2, 6 h. [d] 24 h reaction time. [e] Starting material can be recovered.
Once the optimum conditions
for the transformation were found,
we investigated the scope of the
procedure, and the results are given in Table 2. In general,
aza-enallenes cyclized to afford their corresponding hetero-
cycles in good to high yields. Carbocyclization of aza-allene
1a (Table 2, entry 1) afforded pyrroline 2a in 74% yield after
4 hours. Aza-enallene 1b, which has a terminal alkene
(Table 2, entry 2), gave N-tosyl-protected pyrrole 2b in
64% yield. This substrate reacted sluggishly and required
24 hours to reach full conversion. We believe that this is due
to the fact that b-hydride elimination to form the exocyclic
double bond is slow. The initial b-elimination product can be
detected by NMR spectroscopy, but it is unstable under the
reactions conditions and isomerizes into aromatic compound
2b during the reaction. Interestingly, substrate 1c cyclized in
95% yield in 4 hours to give 2c (> 99% Z) without any
detectable amounts of aromatized product or Diels–Alder
adduct (Table 2, entry 3). This result can be explained by the
extended conjugation added by the phenyl group, which
makes the structure less prone to undergo Diels–Alder
reactions and/or isomerization. Although this product is
stable under the reaction conditions, purification by column
chromatography on basic alumina was necessary to avoid
formation of the aromatized product.[20]
Subjecting 1,1-disubstituted olefins 1d–g to the coupling
conditions resulted in good yields of carbocyclization prod-
ucts (Table 2, entries 4–7). In all cases, the reactions pro-
ceeded with 100% conversion and the desired products were
only accompanied by small amounts of the corresponding
Diels–Alder adduct. Substrates that contained an internal
substituent on the double bond failed to undergo carbocyc-
lization, even at elevated temperatures and over prolonged
reaction times (Table 2, entry 8).
We then decided to investigate the effectiveness of the
Diels–Alder reaction and found that increasing the amount of
BQ to 2.1 equivalents and running the reaction at 508C for
12 hours exclusively afforded endo-Diels–Alder adduct 5 in
95% yield (Scheme 2). This result indicates that oxidative
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Communications
dienophiles in a tandem reaction (Scheme 4, procedure B).
For example, oxidative cyclization with the addition of
1 equivalent of maleimide resulted in a tandem oxidative-
cyclization/Diels–Alder reaction to give polycyclic product 7
in 93% yield after 16 hours at 508C (92% endo, trans/cis
85:15).[23,24]
In conclusion, we have extended our oxidative carbocyc-
lization methodology to include aza-enallene substrates. The
heterocyclic products are useful intermediates in the synthesis
of complex molecules. The biomimetic oxidation can be
combined with a Diels–Alder procedure in a tandem oxida-
tive-carbocyclization/Diels–Alder sequence in one pot. Inves-
tigation of the scope of the one-pot Diels–Alder reaction
sequence is underway.
Scheme 2. Selective formation of Diels–Alder product 5.
carbocyclization proceeds selectively without the formation
of any isomerized or over-oxidized products.
To broaden the synthetic utility of this transformation, an
aerobic (biomimetic) version was investigated using catalytic
amount of quinone. We have previously reported such
procedures for a variety of palladium-catalyzed reactions,
where O2 is employed as a terminal oxidant.[5b,11a,21] Recently,
our group developed and utilized a new type of hybrid Experimental Section
Catalyst screening: Pd(OAc)2 (0.6 mg, 0.0026 mmol) and para-
catalyst (6), in which hydroquinone is tethered to the salen-
type framework (Scheme 3).[21,22] With 6 as the sole co-
benzoquinone (5.8 mg, 0.054 mmol) were dissolved in THF (1 mL).
Aza-enallene 1a (15.0 mg, 0.051 mmol) was then added in one
portion. The vessel was sealed and stirred for 5 h at 508C; after 5 h,
the solvent was evaporated and ansiole (5.5 mL, 0.051 mmol) was
added. The residual oil was taken up into CDCl3 and analyzed by
1H NMR spectroscopy.
Catalytic carbocyclization of 1a: Aza-enallene 1a (50 mg,
0.17 mmol), para-benzoquinone (19.5 mg, 0.18 mmol), and Pd(OAc)2
(0.77 mg, 0.0034 mmol) were dissolved in THF (2 mL). The solution
was then stirred for 4 h in air. The reaction was monitored using TLC
analysis, eluting with pentane/EtOAc (15:1). After cooling to room
temperature, the solution was diluted with Et2O and washed once
with 2m NaOH. The aqueous phase was back-extracted once using
Et2O. The combined organic layers were dried (MgSO4) and
evaporated. Purification of the slightly brown residue by column
chromatography (pentane/EtOAc, 15:1) gave 37 mg of 2a (74%
yield) as a white solid. 1H NMR (400 MHz, CDCl3): d = 7.67 ppm (d,
J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 5.49 (ddd, J =
17.1, 10.1, 8.0 Hz, 1H), 4.97 (d, J = 17.1 Hz, 1H), 4.93 (d, J = 10.2 Hz,
1H), 4.81 (m, 2H), 3.65–3.50 (m, 2H), 3.44–3.40 (m, 1H), 2.43 (s, 3H),
1.86 (s, 3H). 13C NMR (100 MHz, CDCl3): d = 140.0, 138.8, 136.1,
132.8, 129.8, 128.4, 127.7, 127.2, 115.8, 112.8, 54.4, 46.5, 21.6, 20.8.
HRMS (ESI) calcd for [M+Na]+ C16H19NNaO2S 312.1028; found
312.1034.
Scheme 3. Structure of oxygen-activating [Co] catalyst 6.
catalyst a higher yield of cyclized product was expected, as
secondary Diels–Alder reactions of 2a would be minimized.
To our delight, subjecting 1a to 5 mol% Pd(OAc)2 and
5 mol% of cobalt catalyst 6 in tetrahydrofuran at 508C under
1 atmosphere of O2 (balloon) smoothly gave the desired
cyclized product 2a in 94% yield after 6 hours without the
formation of any detectable Diels–Alder adducts (Scheme 4,
procedure A; Table 2, entry 1). Under the same aerobic
conditions, 1g afforded 2g in 86% yield (Scheme 4, proce-
dure A; Table 2, entry 7).
Received: February 5, 2010
Published online: May 20, 2010
The development of a biomimetic version that employs O2
oxidation opens up the possibility of using a variety of
Keywords: allenes · carbocyclization · heterocycles · oxidation ·
.
palladium
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[24] An excess of maleimide slowed the rate of reaction, and the use
of 2 equivalents of maleimide gave only 50% conversion after
16 hours. Most likely, the maleimide blocks coordination of para-
benzoquinone.
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