Domino carbopalladation-carbonylation: Generating quaternary stereocenters while controlling β-hydride elimination

Article abstract of DOI:10.1021/ol1009703

A domino carbopalladation-carbonylation sequence for substrates possessing β-hydrogens is explored. This allows for the construction of complex architectures with vicinal stereocenters in a concise and rapid fashion via the stereocontrolled formation of two carbon-carbon bonds. An integral aspect of this domino reaction is the ability to control β-hydride elimination of the organopalladium intermediate and instead form the carbonylation product.

Full text of DOI:10.1021/ol1009703

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3732-3735
Domino Carbopalladation-Carbonylation:
Generating Quaternary Stereocenters while
Controlling ꢀ-Hydride Elimination
Brinton Seashore-Ludlow† and Peter Somfai*,†,‡
Organic Chemistry, KTH Chemical Science and Engineering, Royal Institute of
Technology, SE-10044 Stockholm, Sweden, and Institute of Technology, UniVersity of
Tartu, Nooruse 1, 50441 Tartu, Estonia
somfai@kth.se
Received April 28, 2010
ABSTRACT
A domino carbopalladation-carbonylation sequence for substrates possessing ꢀ-hydrogens is explored. This allows for the construction of
complex architectures with vicinal stereocenters in a concise and rapid fashion via the stereocontrolled formation of two carbon-carbon
bonds. An integral aspect of this domino reaction is the ability to control ꢀ-hydride elimination of the organopalladium intermediate and
instead form the carbonylation product.
The core scaffolds of numerous natural products and
synthetic targets contain quaternary and vicinal stereo-
centers, which are challenging to construct even with
current technology.1 One reliable method for the assembly
of such complex and congested architectures is the Heck
reaction, of which even asymmetric variants are available.2
An expansion of this method has led to “tandem Heck
reactions”, where via molecular queuing a second reaction
sequence ensues subsequent to carbopalladation and prior
to ꢀ-hydride elimination.3 Despite the utility of such
domino reactions, the substrates are often specifically
engineered to avoid competitive ꢀ-hydride elimina-
tion, thus limiting the scope and applicability of such se-
quences.
Recent advances in the area of alkyl cross-coupling, as
well as initial results in the trapping of organopalladium
species, have led to an increased ability to control ꢀ-hydride
elimination.4 However, few of these methods address the
construction of quaternary and vicinal stereocenters with two
pendant hydrogens. We became interested, therefore, in
designing a domino carbopalladation-carbonylation strategy
aimed at the simultaneous construction of vicinal stereo-
† Royal Institute of Technology.
‡ University of Tartu.
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10.1021/ol1009703  2010 American Chemical Society
Published on Web 08/05/2010

centers and two carbon-carbon bonds for substrates pos-
sessing ꢀ-hydrogens (Scheme 1).5 In such a sequence, the
organopalladium 4 (arrow C). This intermediate can then
suffer decomposition via ꢀ-hydride elimination, yielding
alkene 5 (arrow E), or intermediate 4 can be captured by
CO, affording an acylpalladium species (arrow D). Nucleo-
philic attack on this acylpalladium species by methanol
delivers the desired product 6 and regenerates the catalyst
after loss of HI. Thus, careful examination of the desired
transformation reveals several seemingly incongruent reactiv-
ity profiles. We postulated that we could dictate the course
of the reaction by moderating the steric and electronic
environment of the metal catalyst, as well as by modulating
the CO pressure. The results of this endeavor are detailed
below.
Scheme 1. Domino Carbopalladation-Carbonylation Strategy
organopalladium species derived from the initial carbopal-
ladation event would be captured by CO instead of undergo-
ing ꢀ-hydride elimination.6 The benefits of this approach
would be the rapid, stereospecific7 synthesis of vicinal
stereocenters for a new class of substrates, as well as the
expeditious construction of complex architectures primed for
further functionalization.
Central to the development of this transformation is the
capacity to control the decomposition of the various orga-
nopalladium species, as there are several competing pathways
that can transpire (Scheme 2). For example, after oxidative
To prove our concept, we decided to focus our attention
on the construction of 3,3-disubstituted oxindoles, a class
of biologically important building blocks.10 Model system
7 was chosen for this task, as the desired product 8 maps
onto the core structures of the communesins11 and pero-
phoramidine, giving an advanced intermediate that would
be cumbersome to construct as a single diastereomer via
alternative routes.12 This system would give alkene 9 in the
case of the Heck reaction pathway (Scheme 2, arrows A, C,
E) and ester 10 in the case of the early carbonylation pathway
(Scheme 2, arrows A, B). We aimed to control the distribu-
tion of these three possible products.
The reaction was first tested at atmospheric pressure (Table
1, entry 1), but this produced only the Heck product 9 in
86% yield. We were delighted that by increasing the pressure
to 100 psi with the same ligand 39% of the desired product
8 was obtained. However, there was also 24% of the Heck
product 9 and 20% of the early ester product 10 (Table 1,
entry 2). We experimented with both the palladium source
and ligand and determined that dppf, 1,1′-bis(di-tert-bu-
tylphosphino)ferrocene, PCy3, and P(2-furyl)3 gave the best
results (Table 1, entries 7-9 and 12). Since the mass balance
was starting material with P(2-furyl)3 as the ligand, we
decided to focus our attention on improving this set of
conditions, reasoning that finding the optimal solvent and
Scheme 2
.
Pathways Available to the Organopalladium Species
Where Alternatives Are Lettered A-E
(8) This acylpalladium species can then undergo carbopalladation,
leading to further byproducts. For examples of carbonylation-carbopallada-
tion-carbonylation sequences, see ref 3a for detailed outline.
(9) This acylpalladium species can then undergo carbopalladation,
leading to further byproducts.
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insertion, the organopalladium 2 could be trapped by CO,8
leading to the undesired ester 3 (arrow B). However,
depending on the rate of cyclization, the organopalladium 2
can also undergo carbopalladation of the alkene, leading to
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(7) Assuming syn palladation.
Org. Lett., Vol. 12, No. 17, 2010
3733

Table 1. Optimization of Domino Carbopalladation-Carbonylation for Amide 7a
yield (%)c
entry
Pd source
Pd(OAc)2
pressureb
ligand
8
9
10
1
2
3
4
5
6
7
8
atm
100
100
100
100
200
100
200
100
200
200
100
PPh3
PPh3
86
24
Pd(OAc)2
39
14
24
9
31
50
47
50
31
44
45
20
18
14
5
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
(tBu)3PHBF4
d
SiMesHBF4
7
5
10
9
xanthphose
P(biphenyl)(tBu)2
dppf
9
11
10
17
10
17
17
11
PCy3
9
25
10
10
11
12
P(2-furyl)3
P(2-furyl)3
P(2-furyl)3
4
a Reactions were run on 0.041 mmol scale of 7 in DMA and MeOH with 10 mol % of palladium (5 mol % in the case of Pd2(dba)3·CHCl3) and 30 mol
% of ligand and 4.4 equiv of Et3N at the indicated pressure and 70 °C (internal temperature); 11 is 1,1′-bis(di-tert-butylphosphino)ferrocene. b Pressure in
psi,priortoheating.c Theyields(%)arefrom1HNMRofthecrudeproductwith1-methoxynaphthaleneasaninternalstandard.d 1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydro-
imidazolium tetrafluoroborate. e 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
base combination could boost the reactivity but, as shown
in the mechanism above, should not necessarily impact the
product distribution.
Further optimization of the reaction parameters included
determining the optimal solvent and base. The solvent screen
revealed that DMA was the best solvent.13 A variety of bases
were then examined, showing that solid bases were not
effective (Table 2, entry 4). A clear relationship between
of starting material was seen with DMAP; however, 28% of
a new side product 12 was also detected under these
conditions. Regioisomer 12 presumably arises from ꢀ-hydride
elimination followed by reinsertion of the Pd-H into the
coordinated alkene and then trapping of this resultant
organopalladium with CO. We hypothesized that this was
due to the inability of DMAP to reduce the Pd-H intermedi-
ate to Pd(0). To retain the reactivity seen with the DMAP
while minimizing the formation of 12, we opted to use a
catalytic amount of DMAP in conjunction with a stoichio-
metric base to reduce the Pd-H intermediate (Table 2, entries
8 and 9). Using DABCO as the stoichiometric base gave
the desired effect, minimizing the formation of 12, while
increasing the formation of ester 8.
Table 2. Optimization of Base for the Domino
Carbopalladation-Carbonylation of Amide 7a
yield (%)b
With these optimized conditions in hand, we then explored
the scope of this transformation. The performance of the
reaction is highly dependent on the N-protecting group, as
the unprotected amide yields products related only to early
esterification (Table 3, entry 2).15 Increasing the steric bulk
of the protecting group to a 4-CF3 benzyl group resulted in
an improved yield (entries 1 and 3). Surprisingly, use of a
4-MeO-substituted benzyl group gave identical yields,
implying that this is purely a steric effect (entry 4). These
results indicate that a larger protecting group amplifies the
rate of carbopalladation and suppresses the formation of the
early esterification product. The protecting groups also
minimized the formation of the ꢀ-hydride elimination/
entry
base
8
9
10
12
1
2
3
4
5
6
7
8
9
Et3N
DBU
45
22
38
9
23
40
51
27
55
4
10
4
13
6
10
4
17
17
DABCO
Cs2CO3
19
TMG
Cy2NMe
DMAP
DMAP + Et3N
DMAP + DABCO
28
7
6
8
8
6
8
a Reactions were run on 0.041 mmol scale in DMA and MeOH with 5
mol % of Pd2(dba)3·CHCl3 and 30 mol % of P(2-furyl)3 and 4.4 equiv of
the indicated base at 100 psi and 70 °C (internal temperature). Entries 9
and 10, 0.4 equiv of DMAP and 4 equiv of alternative base. Remainder of
mass balance is starting material. The yields (%) are from H NMR of
the crude product with 1-methoxynaphthalene as an internal standard.
b
1
(13) See Supporting Information for further details.
(14) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6477–6487.
(15) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler,
S. N. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew.
Chem. 2009, 121, 1862–1865.
basicity and reaction yield was also not observed (Table 2).14
An improvement of the conditions and complete consumption
3734
Org. Lett., Vol. 12, No. 17, 2010

was reduced, with an aryl substituent R to the olefin as we
isolated both the corresponding Heck product 25, as well as
the isomeric ester product arising from a ꢀ-hydride elimina-
tion/reinsertion process (entry 7). This lowered selectivity
was expected as the aryl moiety allows for more facile
ꢀ-hydride elimination. We also examined the use of the Z
double bond isomers 26 and 29 (entries 8 and 9), which
showed reduced reactivity, yet followed same protecting
group trend. Interestingly, none of the reinsertion product
nor the ꢀ-hydride elimination product was observed for these
cases. However, approximately 35% of the early carbonyl-
ation product was isolated. Ideally, this reaction should be
examined for tetrasubstituted olefins, and currently, this is
under investigation in our laboratory.
Table 3. Scope of the Domino Carbopalladation-Carbonylation
Sequencea
Figure 1. Byproduct observed with DMAP as base.
In conclusion, we have developed a domino carbopalla-
dation-carbonylation process that allows substrates to pos-
sess ꢀ-hydrogens, resulting in the stereospecific formation
of two new carbon-carbon bonds. This novel sequence not
only expands the scope of the traditional carbonylation
reactions but also provides valuable information on our
ability to dictate the fate of an organopalladium intermediate.
We hope to apply this rationale to new reaction manifolds,
allowing for greater diversity in palladium-catalyzed reac-
tions.
Acknowledgment. The authors would like to thank the
Knut and Alice Wallenberg Foundation, the Swedish Re-
search Council, and the Estonian Science Foundation (Grant
No. 7808) for funding. We would like to thank Lauri Toom
(University of Tartu) for help with NMR spectra.
a Reactions were run on 0.08 mmol scale in DMA and MeOH with 5
mol % of Pd2(dba)3·CHCl3 and 30 mol % of P(2-furyl)3 and 4 equiv of
DABCO and 0.4 equiv of DMAP at 100 psi (prior to heating) and 70 °C
(internal temperature). b Isolated yields. c With 7% of ester isomer from
reinsertion also isolated.
Supporting Information Available: Detailed experimen-
tal procedures and spectra reported for compounds 8-10 and
12-31. This material is available free of charge via the
Internet at http://pubs.acs.org.
reinsertion product corresponding to ester 12, which is
unexpected based on the mechanism. Two bicyclic systems
were constructed with good yields under these conditions
(entries 5 and 6). The selectivity of the esterification reaction
OL1009703
Org. Lett., Vol. 12, No. 17, 2010
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