Domino carbopalladation-carbonylation: Investigation of substrate scope

Article abstract of DOI:10.1002/adsc.201100678

This work gives an in depth account of our domino carbopalladation- carbonylation method for substrates possessing β-hydrogens. The scope of the method is examined for allylic amines containing trisubstituted olefins and we detail our attempts toward the diastereospecific synthesis of contiguous quaternary centers using this technology. The results give key insights into the relative rates of the competing reactions of the alkyl palladium intermediates, which is crucial for the understanding and development of new domino processes.

Full text of DOI:10.1002/adsc.201100678

UPDATES
DOI: 10.1002/adsc.201100678
Domino Carbopalladation-Carbonylation: Investigation of
Substrate Scope
Brinton Seashore-Ludlow,a Jakob Danielsson,a and Peter Somfaia,b,*
a
Organic Chemistry, Chemical Science and Engineering, KTH Royal Institute of Technology, 10044 Stockholm, Sweden
Fax : (+46)-8-791-2233; e-mail: somfai@kth.se
Section for Organic Chemistry, Institute of Technology, University of Tartu, 50411 Tartu, Estonia
b
Received: August 26, 2011; Revised: October 31, 2011; Published online: January 13, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100678.
Abstract: This work gives an in depth account of
our domino carbopalladation-carbonylation method
for substrates possessing b-hydrogens. The scope of
the method is examined for allylic amines contain-
ing trisubstituted olefins and we detail our attempts
toward the diastereospecific synthesis of contiguous
quaternary centers using this technology. The re-
sults give key insights into the relative rates of the
competing reactions of the alkyl palladium inter-
mediates, which is crucial for the understanding and
development of new domino processes.
The Heck reaction has proven to be a valuable and
dependable method for the synthesis of quaternary
stereocenters, as has been demonstrated time and
again by its frequent use in the total synthesis of com-
plex natural products.[3] Given the recent focus on the
efficiency of synthetic transformations,[4] it is not then
surprising that “tandem Heck” reactions have
emerged as a powerful tool.[5] In these processes car-
bopalladation is repeated one or several times prior
to b-hydride elimination, allowing for the rapid build-
up of molecular complexity from relatively simple
starting materials. Related domino or cascade reac-
tions have also been developed, where b-hydride
elimination is not the termination event, but instead it
is replaced by a coupling or ꢀanion captureꢁ event.[6]
The advantage of such sequences is that two new
bonds are formed with the concomitant introduction
of functionality into the compound. However, it has
traditionally been assumed that in order for these se-
quences to be viable, no pendant b-hydrogens may be
Keywords: carbonylation; domino reactions; Heck
reaction; oxindoles; quaternary stereocenters
Introduction
Vicinal all-carbon quaternary stereocenters are a present in the intermediary alkyl palladium species,
common structural motif in numerous natural prod- limiting the scope of such reactions.
ucts and biologically relevant synthetic compounds.[1]
We recently reported a domino carbopalladation-
Nevertheless, due to the inherent steric repulsion ex- carbonylation reaction for substrates possessing b-hy-
isting in these particular molecular constellations, the drogens, which establishes two new carbon-carbon
construction of contiguous all-carbon quaternary ste- bonds, as well as vicinal stereocenters in one step
reocenters remains a challenge to synthetic chemists.[2] (Scheme 1).[7] In this sequence the alkyl palladium in-
Techniques that enable stereodefined entry to these termediate is trapped by CO instead of undergoing b-
types of architectures would greatly facilitate many hydride elimination. This method is based on the
synthetic organic pursuits.
recent advances in alkyl-alkyl cross-coupling, where
Scheme 1. Schematic representation of the carbopalladation-carbonylation reaction.
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Brinton Seashore-Ludlow et al.
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Scheme 2. Potential reaction manifolds during the carbopalladation-carbonylation cascade.
b-hydride elimination can be circumvented by judi- ing product 5). Again we aimed to control the rates
cious choice of catalyst and reaction conditions.[8] Sev- of these two competing processes by modulating the
eral groups have also detailed the anion capture of an steric and electronic properties of the metal, as well
alkyl palladium intermediate possessing b-hydrogens, as by the pressure of CO. Overall, a balance between
thus offering diversification to the conventional Heck the seemingly incongruent demands for CO pressure
reaction.[9] However, to the best of our knowledge must be found, as too high CO pressure will lead
none of these technologies address the formation of solely to early ester 3 and too low pressure will yield
vicinal stereocenters or all-carbon quaternary centers. only to Heck product 5.
The main challenge of our previous work was to
Our earlier study focused on the construction of
control the decomposition of the implicated organo- 3,3-disubstituted oxindoles, a class of biologically im-
palladium intermediates and in order to access the de- portant compounds.[11] We were able to realize the de-
sired reactivity it was first necessary to examine the sired transformation (Scheme 2, arrows A!C!D)
divergent pathways available to intermediate
2
using a,b-unsaturated amides containing trisubstituted
(Scheme 2).[10] Understanding the relative rates of olefins in moderate to good yields (Scheme 3). This
these competing processes, as well as how to promote sequence creates contiguous stereocenters in a dia-
or suppress these reaction manifolds is essential to stereostereospecific manner, as well as two new
the achieving the desired transformation. After oxida- carbon-carbon bonds in a single reaction. Comparing
tive addition into iodide 1 (arrow A) organopalladium our method to previously described techniques where
2 is generated. As there are no pendant b-hydrogens the capture of an alkyl palladium intermediate was
in this intermediate, two diverging reactions can achieved over facile b-hydride elimination, reveals
ensue: (i) either early CO insertion (arrow B) eventu- that our method is uniquely effective in providing the
ally yielding ester 3 or (ii) carbopalladation (arrow C) desired ester. For example, substrate 9 was subjected
generating organopalladium intermediate 4. It was en- to the domino carbopalladation-carbonylation condi-
visioned that the rates of these competing reactions tions described by Aggarwal,[9d] resulting only in
could be controlled mainly by carbon monoxide pres- Heck product 11[12] [Scheme 4 (A), i.e., A!C!E in
sure, but also by the steric and electronic properties Scheme 2). Similarly, the conditions for cascade car-
of the palladium catalyst. Organopalladium 4 arising bopalladation-boronic ester coupling detailed by
from carbopalladation contains b-hydrogens and it Ahn[9f] provided only a mixture of the b-hydride elim-
can also decompose via two different pathways: (i) by ination products 11 and 12.[13] [Scheme 4 (B), again
CO insertion and nucleophilic attack (arrow D giving A!C!E in Scheme 2]. These results indicate that as
desired product 6) or (ii) by b-hydride elimination re- predicted the presence of two pendant hydrogens sig-
sulting in an overall Heck reaction (arrow E produc- nificantly increases the rate of b-hydride elimination,
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Domino Carbopalladation-Carbonylation: Investigation of Substrate Scope
Scheme 3. Examples of the domino carbopalladation-carbonylation sequence with trisubstituted olefins.
nal all-carbon quaternary stereocenters, while allow-
ing for access to both diasteresomers of such scaffolds
by simple choice of double bond isomer. However,
tetrasubstituted olefins pose several significant chal-
lenges to the presented method. First, to the best of
our knowledge the alkoxycarbonylation of a tertiary
center has not been reported under palladium cataly-
sis, although the analogous hydroformylation reaction
using rhodium catalysts has recently been reported.[14]
Second, the carbopalladation of tetrasubstituted ole-
fins is known to be more difficult than for the corre-
sponding trisubstituted olefins and few tetrasubstitut-
ed olefins have been used in the Heck reaction.[3b,15]
Furthermore, in the majority of these examples the
tetrasubstitued olefin is in conjugation with a carbon-
yl moiety. Thus, we set out to synthesize a set of tetra-
substituted olefins and then to test their activity in
the carbopalladation-carbonylation sequence.
Scheme 4. Examination of the other reported methods for
circumventing b-hydride elimination. Compare to the results
for substrate 9 in Scheme 3.
and further demonstrates that the present method has
To this end tetrasubstituted olefin 13 was construct-
increased the ability to control the fate of the inter- ed and then subjected to the Heck reaction conditions
mediate alkyl palladium species thereby facilitating (Scheme 5), yielding product 14[16] as a single isomer.
the development of further domino processes. Given This clearly demonstrates that this tetrasubstituted
the success we had with a,b-unsaturated amides con- olefin can participate in the desired carbopalladation
taining trisubstituted olefins, we then wanted to fur- event (Scheme 2, arrow C), and thus suggests the po-
ther explore the scope of the reaction. Two important tential viability of the carbopalladation-carbonlyation
classes of substrates are a,b-unsaturated amides with transformation. However, when olefin 13 was subject-
tetrasubstituted olefins and allylic amines having tri- ed to the standard conditions developed for the tri-
substituted olefins. The results of these studies are de- substituted olefins, only the early esterification prod-
tailed herein and offer important insights into the rel- uct 15 (analogous to ester 3 in Scheme 2) was formed
ative rates of the competing steps available to the or-
ganopalladium intermediates.
Results and Discussion
a,b-Unsaturated Amides: Tetrasubstituted Olefins
For tetrasubstituted olefins this reaction sequence
would result in the diastereospecific synthesis of vici- Scheme 5. Heck reaction of tetrasubstituted olefin 13.
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Brinton Seashore-Ludlow et al.
UPDATES
furyl)3 or P(Cy)3, as the electronics of the phosphine
ligand are known to effect the reversibility of the car-
bonyl insertion.[20] Under both of these conditions we
isolated only the Heck product 16, indicating that the
rate of carbonyl insertion is indeed decreased when
using i-PrOH and that the product distribution is al-
tered (Scheme 7, compare with MeOH as nucleophile
Scheme 3).[21] However, when tetrasubstituted olefin
13 was subjected to the same conditions once again
only the early ester product 17 was observed
(Scheme 8). This implies that at one atmosphere of
Scheme 6. Attempts at the domino carbopalladation-carbon-
ylation sequence for tetrasubstituted olefin 13.
in 58% yield (Scheme 6). The formation of ester 15 in CO the carbopalladation of the tetrasubstituted olefin
favour of the desired carbopalladation-carbonylation of the arylpalladium intermediate 2 poses a formida-
product indicates that with the tetrasubstituted olefin ble kinetic barrier as compared to CO insertion into
the carbonylation of the arylpalladium intermediate 2 the same species 2.
is fast as compared to the carbopalladation event
Following the same mechanistic reasoning from
(Scheme 2, compare arrows B and C). It was then above we then envisioned that an alternative method
proposed that a lower CO pressure might favour the to retard the rate of early carbonylation would be to
desired reaction manifold, but repeating the reaction minimize the amount of alcohol present. To this end
at atmospheric CO pressure once again afforded only substrate 18 was synthesized, as we believed that the
ester 15.
formation of the 11-membered ring ester 19 (corre-
From the above results it is clear that the carbony- sponding to early ester 3 in Scheme 2) would be suffi-
lation of the aryl palladium species (corresponding to ciently kinetically disfavoured to allow carbopallada-
intermediate 2, Scheme 2) is faster than carbopallada- tion to contend with early carbonylation.[22] This sub-
tion of the tetrasubstituted olefin to such an extent strate was then examined at atmospheric CO pres-
that only the early carbonylation products could be sure, which surprisingly resulted in the 11-membered
isolated at atmospheric CO pressure. Consequently ring ester 19 and an unexpected by-product 20 both
we sought alternative methods to affect the relative originating from an early carbonylation event
rates of these two processes in order to access the de- (Scheme 9). Taken together these results indicate that
sired reaction manifold. Several proposed mecha- the carbopalladation of the tetrasubstituted olefins is
nisms for the alkoxycarbonylation of arylpalladium significantly kinetically disfavored as compared to the
species exist. When using an alcohol in conjunction analogous tertiary substrates. It also indicates that even
with an amine base the alkoxycarbonylation of iodo- at atmospheric CO pressure insertion of CO into the
benzene and its derivatives is generally believed to arylpalladium intermediate 2 is considerably favoured
ꢀ
proceed via the reductive elimination of an arylCO
as compared to carbopalladation of the alkene to give
[17,18]
ꢀ
Pd OR species.
From this mechanistic informa-
tion it is predicted that the rate of the ester formation
should be dependent on the sterics of the alcohol, as
long as carbon monoxide insertion into the Pd-aryl
bond is reversible.[19] Thus, a more sterically hindered
alcohol should retard the rate of early ester formation
with the anticipation that carbopalladation would
then be able to compete with this process (Scheme 2,
arrows B vs. C). This hypothesis was first examined
Scheme 8. Attempt at the domino carbopalladation-carbon-
on trisubstituted olefin 7 using i-PrOH, and PACTHUNRTGNEUNG(2- lylation of tetrasubstituted olefin 13 using i-PrOH.
Scheme 7. Attempts at the domino carbopalladation-carbonylation of trisubstituted olefin 7 using i-PrOH.
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Domino Carbopalladation-Carbonylation: Investigation of Substrate Scope
Scheme 9. Attempt at domino carbopalladation-carbonylation with an internal nucleophilic trap.
Table 1. Domino carbopalladation-carbonylation of allylic
desired intermediate 3. Early carbonylation could po-
tentially be avoided by generating CO slowly during
the reaction or utilizing a CO surrogate;[23] however,
the overall goal of this endeavour was to allow for the
presence of pendant b-hydrogens and at atmospheric
CO pressure b-hydride elimination was shown to out
compete carbonylation for the trisubstituted analogues
(Scheme 3).[7] Thus, the use of this method to construct
vicinal quaternary centers remains elusive.
amine 21.[a]
Entry Conditions Ligand
Yield[b] [%] ratio 21:23:24
1[c]
2[c]
3[c]
4
A
B
B
C
C
PPh3
(2-furyl)3 62
PPh3 50
(2-furyl)3 46
PPh3 75
69
100:0:0
50:50:0
90:10:0
67:0:33
75:0:25
PACHTUNGTRENNUNG
Allylic Amines
PACHTUNGTRENNUNG
Allylic amines comprise another competent and
widely used class of substrates for the Heck reac-
tion.[3] In contrast to the a,b-unsaturated amides dis-
cussed above, allylic amines possess an electron-rich
olefin, and this would allow us to further determine
the role of the electron density of the double bond
moiety in the domino carbopalladation-carbonylation
sequence. Allylic amine 21 has previously been ex-
plored in cascade reactions where b-hydride elimina-
tion has been thwarted.[9d,f] Aggarwal and co-workers
detailed conditions where allylic amine 21 gave the
desired carbopalladation product 22 or the early ester
5
[a]
Conditions A: 2 atm CO, 4 equiv. Et3N, 5 mol%
Cl2Pd(PPh3)2, PPh3 (0.2 equiv.), MeOH, DMF-H2O
(1:2:0.1), see ref.[9d] Condtitons B: 2.5 mol% Pd2
(dba)3·CHCl3, 0.3 equiv. phosphine, 2 equiv. NaOAc in
DMF (0.2M), see ref.[9d] Conditions C: DMA and MeOH
with 5 mol% Pd2A(dba)3·CHCl3, 30 mol% (2-furyl)3,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
G
PACHTUNGTRENNUNG
4 equiv. of DABCO and 0.4 equiv. DMAP at 100 psi
(prior to heating) and 808C (internal temperature).
Isolated yields.
[b]
[c]
From ref. [9d]
product 23 in good yields and varying ratios (Table 1, Unlike substrate 21 the amines 25 and 29 would gen-
entries 1–3). These results show that b-hydride elimi- erate vicinal stereocenters in the desired ester corre-
nation can be minimized with the best results ob- sponding to 26 (analogous to ester 6 in Scheme 2).
tained when using PdCl
ing allylic amine 21 to the conditions developed ester 27a (corresponding to ester 3 in Scheme 2) was
above for trisubstituted olefins, which revealed that the major product when both PPh3 and P(2-furyl)3
2ACTHNUGTREN(NUNG PPh3)2. We began by subject- First sulfonamide 25a was examined, but the early
AHCTUNGTRENNUNG
the early ester product 23 is not stable to the reaction were used as the ligands and the products were ob-
conditions, as instead sulfonamide 24[9d] is isolated.[24] tained in rather poor yields (Table 2, entries 1 and 2).
Interestingly, under these conditions PPh3 proves to This indicated that the carbopalladation step was
be a better ligand giving both higher yields and selec- again kinetically less favorable for the arylpalladium
tivity than the previously used PACTHNUTRGENUG(N 2-furyl)3 (Table 1, intermediate (i.e. 2 in Scheme 2) than CO insertion
entries 4 and 5). These results are somewhat surpris- into the same species. We anticipated that changing
ing as based purely on sterics the monosubstituted the protecting group would influence the rate of car-
olefin 21 should undergo carbopalladation faster than bopalladation as seen previously in the a,b-unsaturat-
a trisubstituted olefin. Thus, the high ratio of early ed amides.[25] However, when the acetyl-protected
ester product can be attributed to either the electron substrate 25b was subjected to the reaction conditions
density of the olefin or the less rigid confirmation of it also gave the undesired ester 27b as the major prod-
the molecule as compared to the a,b-unsaturated uct, as well as varying amounts of the Heck product
amides from our earlier investigation.
28 (entries 3 and 4). The electronic nature of aryl
To further explore the differences between the al- group of the allylic amines 25a and b should be simi-
lylic amines and the a,b-unsaturated amides several lar to the aryl moiety in the a,b-unsaturated amides
other allylic amine scaffolds were also examined. above (e.g., amide 7). Consequently, the different re-
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Brinton Seashore-Ludlow et al.
UPDATES
Table 2. Domino carbopalladation-carbonylation of allylic amines 25a and 25b.[a]
Entry
R
25
Conditions
PPh3
Yield[b] [%] of 26
Yield[b] [%] of 27
Yield [%] of 28
1
2
3
4
Ts
Ts
Ac
Ac
a
a
b
b
12
9
8
24
26
39
43
0
0
26
6
P
A
P
A
10
[a]
Reaction run in DMA and MeOH with 5 mol% Pd
2CAHUTTNGREN(NGU dba)3·CHCl3, 30 mol% PACHTUTGNREN(NUNG 2-furyl)3, 4 equiv. of DABCO and 0.4 equiv
DMAP at 100 psi (prior to heating) and 808C (internal temperature).
[b]
Products 26 and 27 were isolated as a mixture. The yields given are calculated from ratio of the two products in the
1H NMR.
Conclusions
In conclusion we have explored our method for
domino carbopalladation-carbonylation for substrates
with pendant b-hydrogens. The scope of the reaction
was examined and tetrasubstituted olefins were tested
as a method to access vicinal all-carbon quaternary
stereocenters, however, the carbopalladation of the
tetrasubstituted olefins proved kinetically too disfav-
oured for this particular approach. Allylic amines
Scheme 10. Use of an NMe protecting group.
activity displayed by these substrates, which is deter- were also examined and the electronics of the double
mined by the rates of carbopalladation versus early bond, as well as the conformation of the scaffold were
CO insertion (arrow B vs. C in Scheme 2), is probably found to be important aspects in the rate of carbopal-
dictated by conformational preferences, as the allylic ladation as compared to carbonyl insertion. Taken to-
amine substrates are less rigid than the amide sub- gether these experiments offer valuable insight into
strates, as well as the electronic nature of the double how to control and dictate the fates of various alkyl
bond. Interestingly, the more electron-rich aryl group palladium intermediates.
in substrate 29 with N-Me functionality gave the
double CO insertion product 30 as the sole product
and the mass balance was unreacted starting material
(Scheme 10). This product arises from the insertion of
Experimental Section
CO into the aryl palladium intermediate, followed by
carbopalladation and subsequent CO insertion to
yield the double insertion product (Scheme 2, arrows
B, C, then E). This is in agreement with the observa-
tions made by Heck that the CO insertion is consider-
ably faster for electron-rich aryl groups, thus opening
a new reaction manifold for the aryl palladium inter-
General Experimental Methods
1H and 13C NMR spectra were recorded at 500 MHz
(125 MHz) or 400 MHz in CDCl3 using the residual peak of
CHCl3 (1H NMR d=7.26 ppm) and CDCl3 (13C NMR d=
77.16 ppm) as an internal standard. Chemical shifts are re-
ported in the d scale with multiplicity (br=broad, s=singlet,
d=doublet, t=triplet, q=quartet and m=multiplet), cou-
mediate.[26] Unfortunately the allylic amine substrates pling constant (Hz) and integration. Dichloromethane
(CH2Cl2), ether (Et2O), hexanes, toluene (PhMe), dimethyl-
formamide (DMF) and tetrahydrofuran (THF) were dried
by passage through a solvent column composed of activated
alumina. Anhydrous methanol was stored under under N2.
Anhydrous dimethylacetamide (DMA) and dimethyl sulfox-
ide (DMSO) were stored over activated molecular sieves
(4 ꢃ). Air- and moisture-sensitive reactions were carried out
in flame-dried, septum-capped flasks under an atmospheric
pressure of nitrogen. All liquid reagents were transferred
via oven-dried syringes. Pressurized reactions were carried
out in an autoclave with pressure regulator. Commercially
25a, b and 29 were overall less selective for the desired
ester than their a,b-unsaturated amide counterparts in-
dicating that a more electron-rich double bond in com-
bination with less restricted rotation in these systems
negatively influences the rate of carbopalladation as
compared to CO insertion. Further optimization of
these substrates is complicated by the high levels of b-
hydride elimination and early ester formation since
minimization of these two by-products would necessi-
tate opposite modulation of the CO pressure.
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Domino Carbopalladation-Carbonylation: Investigation of Substrate Scope
available compounds were used without further purification
unless otherwise indicated. TLC analyses were run on TLC
alumina sheets (silica gel 60 F254) and were visualized using
UV and a solution of phosphomolybdic acid in ethanol
(5 wt%), KMnO4 stain or p-anisaldehyde stain. Flash chro-
matography was performed using silica gel 60 (35–63 mm).
Melting points are not corrected.
eluent to afford 13 as a colorless oil; yield: 210 mg (99%).
1H NMR (500 MHz, CDCl3) d (major isomer)=7.96–7.89
(m, 1H), 7.50–7.16 (m, 6H), 7.11–7.05 (m, 1H), 6.84–6.77
(m, 2H), 3.35 (s, 3H), 2.64–2.52 (m, 1H), 2.41 (dq, J=14.7,
7.4 Hz, 1H), 1.40 (s, 3H), 0.88 (t, J=7.4 Hz, 3H); d (minor
isomer)=7.97–7.89 (m, 1H), 7.48–7.16 (m, 8H), 7.11–7.04
(m, 1H), 3.37 (s, 3H), 2.68–2.55 (m, 2H), 1.89 (s, 3H), 0.96
(t, J=7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3): d=172.65,
172.39, 145.75, 145.27, 142.35, 141.13, 140.28, 140.12, 140.05,
139.90, 129.87, 129.81, 129.65, 129.38, 128.99, 128.80, 128.48,
128.26, 128.07, 127.98, 126.97, 126.64, 98.49, 98.00, 77.32,
77.07, 76.81, 38.48, 36.44, 29.74, 28.91, 17.36, 16.88, 12.62,
12.50; IR (neat): nmax =2970, 2935, 1643, 1470, 1358, 1018,
768, 702 cmꢀ1; HR-MS (FAB+): m/z=406.0653, calcd. for
C19H20INO (M+H): 406.0662.
Typical Procedure for the Carbopalladation-
Carbonylation Reaction: (RS)-Methyl 2-[(RS)-3-{2-
[(tert-Butyldimethylsilyl)oxy]ethyl}-1-methyl-2-
oxoindolin-3-yl]-4-[(tert-butyldiphenylsilyl)oxy]-
butanoate (8)
To a flame-dried 4-mL vial was added the amide 7 (0.059 g,
0.081 mmol, 1.0 equiv.). Then Pd2dba3·CHCl3 (4.5 mg,
0.0042 mmol, 0.05 equiv.) was added, followed by the PACTHNUTRGNEUNG(2-
furyl)3 (5.7 mg, 0.025 mmol, 0.30 equiv.), DABCO (36 mg,
0.33 mmol, 4.4 equiv.) and DMAP (4.0 mg, 0.033 mg,
0.4 equiv.). Then DMA (1.28 mL) and MeOH (0.32 mL)
were added. A needle was inserted into the septa of the re-
action vessel and the vessel was place in an autoclave con-
taining approximately 2 mL silicone oil in the bottom. The
autoclave was pressurized to 100 psi (or desired pressure)
and then the autoclave was heated in an oil bath until the
internal temperature reached 708C. After 24 h the autoclave
was cooled and depressurized. The reaction mixture was
transferred to a separatory funnel and diluted with EtOAc
and H2O. The aqueous layer was extracted 3 times with
EtOAc, dried over MgSO4, filtered and concentrated. The
crude residue was subjected to column chromatography
(hexane:EtOAc) solvent. Isolated was a 9:1 mixture of 8
and 11; yield:0.030 g (0.045 mmol, 56%). This was separated
further by preparative TLC for characterization; yield of 8:
50%. 1H NMR (500 MHz, CDCl3): d=7.64–7.55 (m, 4H),
7.43–7.32 (m, 6H), 7.28 (dd, J=7.7, 1.0 Hz, 1H), 7.10 (d, J=
7.0 Hz, 1H), 7.02 (t, J=7.5 Hz, 1H), 6.80 (d, J=7.8 Hz,
1H), 3.62 (dt, J=10.5, 5.4 Hz, 1H), 3.59–3.51 (m, 1H), 3.47
(s, 3H), 3.36–3.21 (m, 2H), 3.16 (s, 3H), 3.03 (dd, J=10.9,
2.9 Hz, 1H), 2.29 (t, J=6.9 Hz, 2H), 2.07–1.94 (m, 2H), 1.02
(s, 9H), 0.74 (s, 9H), ꢀ0.16 (s, 3H), ꢀ0.17 (s, 3H); 13C NMR
(126 MHz, CDCl3): d=177.9, 172.7, 144.0, 135.6, 135.5,
133.6, 133.6, 129.9, 129.6, 128.2, 127.6, 123.7, 122.1, 107.8,
62.1, 59.3, 51.4, 51.3, 48.7, 36.2, 29.4, 26.8, 26.2, 25.8, 19.2,
18.2, ꢀ5.6; IR (neat): nmax =3070, 3053, 2954, 2858, 1718,
1612, 1471, 1255 cmꢀ1; HR-MS (FAB+): m/z=660.3535,
calcd. for C38H53NO5Si2 (M+H): 660.3535.
(E)-1,3-Dimethyl-3-(1-phenylprop-1-enyl)indolin-2-
one (14)
To a solution of 13 (28.5 mg, 0.07 mmol), Pd2dba3·CHCl3
(4.0 mg, 0.003 mmol) and PACTHNUTRGNE(NUG 2-furyl)3 (4.9 mg, 0.02 mmol) in
DMA (0.7 mL) was added Et3N (39 mL, 0.28 mmol) and the
mixture heated to 808C and stirred for 1 h. It was then
cooled to room temperature, poured into H2O and extracted
with three times using CH2Cl2. The combined organic layers
were dried over MgSO4, filtered and concentrated at re-
duced pressure. The residue was purified by silica gel chro-
matography (hexane/EtOAc 8:1) to afford 14 as a colourless
1
oil; yield: 10.2 mg (60%). H NMR (500 MHz, CDCl3): d=
7.19–7.13 (m, 2H), 7.09–7.06 (m, 3H), 7.02 (td, J=7.5,
0.8 Hz, 1H), 6.73–6.69 (m, 2H), 6.61 (d, J=7.7 Hz, 1H),
6.00 (q, J=6.7 Hz, 1H), 2.98 (s, 3H), 1.57 (s, 3H), 1.45 (d,
J=6.7 Hz, 3H); 13C NMR (126 MHz, CDCl3): d=179.1,
143.2, 140.7, 138.0, 133.8, 129.5, 127.8, 127.4, 126.5, 123.7,
123.5, 122.3, 107.8, 54.6, 26.0, 21.0, 14.8; IR (neat): nmax
=
3054, 2931, 1712, 1612, 1492, 1469, 1373, 1346, 1119, 1030,
756, 702 cmꢀ1; HR-MS (FAB+): m/z=406.0653, calcd. for
C19H19INO (M+H): 406.0662.
(E)-Methyl 2-(N,2-Dimethyl-3-phenylpent-2-
enamido)benzoate (15)
Prepared from 13 as described for 8 to afford 15 as a colour-
less oil that was purified by silica gel chromatography (hex-
1
anes/EtOAc 4:1); yield: 18.6 mg (58%). H NMR (500 MHz,
CDCl3): d (major rotamer)=7.84 (dd, J=7.8, 1.5 Hz, 1H),
7.40 (td, J=7.7, 1.6 Hz, 1H), 7.32–6.96 (m, 5H), 6.59–6.55
(m, 2H), 3.73 (s, 3H), 3.19 (s, 3H), 2.27–2.13 (m, 2H), 1.13
(s, 3H), 0.62 (t, J=7.4 Hz, 3H); d (minor rotamer)=7.81
(dd, J=7.8, 1.4 Hz, 1H), 7.44 (td, J=7.7, 1.6 Hz, 1H), 7.32–
6.96 (m, 7H), 3.71 (s, 3H), 3.27 (s, 3H), 2.35 (m, 2H), 1.67
(s, 3H), 0.77 (t, J=7.5 Hz, 3H); 13C NMR (126 MHz,
CDCl3): d (mixture of rotamers)=172.7, 172.0, 166.0, 165.9,
143.3, 142.5, 142.5, 140.1, 140.0, 133.2, 132.7, 131.7, 131.1,
130.0, 128.9, 128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9,
127.7, 127.5, 126.8, 126.5, 52.4, 52.2, 39.0, 37.2, 29.1, 28.6,
17.2, 16.3, 12.5, 12.4; IR (neat): nmax =2970, 1724, 1639, 1600,
1489, 1438, 1369, 1292, 1261, 1122, 1076, 710 cmꢀ1; HR-MS
(FAB+): m/z=338.1747, calcd. for C21H23NO3 (M+H):
338.1751.
(E)-N-(2-Iodophenyl)-N,2-dimethyl-3-phenylpent-2-
enamide (13)
To a suspension of NaH (60% in mineral oil, 105 mg,
2.61 mmol) in THF (8 mL) at room temperature was added
a solution of 33 (205 mg, 0.52 mmol in THF (3 mL). The so-
lution was stirred for 10 min followed by addition of MeI
(163 mL, 2.61 mmol). After stirring at room temperature for
50 min, the solvent was evaporated at reduced pressure and
the residue dissolved in Et2O. H2O was added and the layers
separated. The aqueous layer was extracted using Et2O and
the combined organic layers dried over MgSO4, filtered and
concentrated at reduced pressure. The residue was purified
by silica gel chromatography using hexane/EtOAc 12:1 as
Adv. Synth. Catal. 2012, 354, 205 – 216
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211

Brinton Seashore-Ludlow et al.
UPDATES
brine, dried over MgSO4, filtered and concentrated at re-
duced pressure. The residue was purified by silica gel chro-
matography (hexanes/EtOAc 4:1 to 3:1) to afford 19; yield:
(E)-Isopropyl 2-(N,2-Dimethyl-3-phenylpent-2-
enamido)benzoate (17)
1
Prepared from 13 as described for 8 except using i-PrOH
(dried over 4 ꢃ MS) instead of methanol to afford 17 as a
white solid that was purified by silica gel chromatography
(hexanes/EtOAc 4:1); yield: 9 mg (32%); mp 99.5–
100.28C.1H NMR (500 MHz, CDCl3): d (major isomer)=
7.93 (dd, J=7.8, 1.5 Hz, 1H), 7.54–7.07 (m, 6H), 6.69–6.65
(m, 2H), 5.16 (m, 1H), 3.27 (s, 3H), 2.42–2.35 (m, 1H),
2.31–2.22 (m, 1H), 1.30–1.27 (m, 6H), 1.25 (s, 3H), 0.74 (t,
J=7.4 Hz, 3H); d (minor isomer)=7.85 (dd, J=7.8, 1.4 Hz,
1H), 7.54–7.07 (m, 8H), 5.13–5.07 (m, 1H), 3.38 (s, 3H),
2.48–2.42 (m, 2H), 1.76 (s, 3H), 1.31–1.27 (m, 6H), 0.86 (t,
J=7.5 Hz, 1H); 13C NMR (126 MHz, CDCl3): d (mixture of
isomers)=172.6, 171.9, 165.2, 165.0, 143.0, 142.5, 142.0,
140.2, 140.1, 132.8, 132.5, 131.8, 130.7, 129.9, 129.9, 129.2,
128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 128.0, 127.4, 126.8,
126.5, 69.3, 68.4, 39.2, 37.3, 29.2, 28.6, 21.8, 21.8, 17.2, 16.3,
12.5, 12.4; IR (neat): nmax =2977, 2935, 1720, 1643, 1489,
9 mg (24%). H NMR (500 MHz, CDCl3): d=7.81 (dd, J=
7.7, 1.5 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.58 (td, J=7.8,
1.6 Hz, 1H), 7.48–7.43 (m, 1H), 7.39–7.32 (m, 2H), 7.30–
7.25 (m, 1H), 7.23–7.15 (m, 4H), 7.02–6.97 (m, 2H), 5.06 (d,
J=13.0 Hz, 1H), 4.98 (d, J=13.0 Hz, 1H), 3.21 (s, 3H), 1.35
(s, 3H); 13C NMR (126 MHz, CDCl3): d=170.04, 166.35,
142.88, 141.97, 138.84, 138.46, 133.84, 133.22, 132.11, 130.81,
130.44, 129.34, 129.11, 128.26, 127.80, 127.56, 127.50, 127.49,
127.11, 126.86, 67.65, 37.64, 17.80; IR (neat): nmax =1736,
1647, 1493, 1446, 1358, 1292, 1122, 702 cmꢀ1; HR-MS
(FAB+); m/z=384.1595, calcd. for C25H21NO3 (M+H):
384.1594.
(Z)-1’,4-Dimethyl-5-phenyl-1H-spiro
ACHTUNGTREN[NUNG benzo[c]oxe-
pine-3,2’-benzo[d][1,3]oxazin]-4’(1’H)-one (20)
A
ACHTUNGTRENNUNG
Prepared from 18 in the reaction that also yielded 19, af-
fording 20; yield: 13 mg (35%). 1H NMR (500 MHz,
CDCl3): d=8.04 (d, J=7.7 Hz, 1H), 7.54–7.34 (m, 5H),
7.22–7.11 (m, 4H), 6.94 (t, J=7.5 Hz, 1H), 6.84 (d, J=
7.8 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 5.35 (d, J=13.2 Hz,
1H), 4.43 (d, J=13.2 Hz, 1H), 2.92 (s, 3H), 1.86 (s, 3H);
13C NMR (126 MHz, CDCl3): d=162.06, 147.53, 143.48,
142.67, 139.09, 137.13, 135.88, 133.39, 131.68, 130.23, 128.94,
128.78, 127.64, 127.51, 127.12, 126.79, 119.14, 114.89, 112.84,
111.87, 65.54, 31.92, 20.77; IR (neat): nmax =1728, 1608, 1489,
1350, 1130, 1076, 945, 729 cmꢀ1; HR-MS (FAB+): m/z=
384.1582, calcd. for C25H21NO3 (M+H): 384.1594.
1450, 1369, 1284, 1107, 1072, 771, 706 cmꢀ1
; HR-MS
(FAB+): m/z=366.2061, calcd. for C23H27NO3 (M+H):
366.2064.
(Z)-3-[2-(Hydroxymethyl)phenyl]-N-(2-iodophenyl)-
N,2-dimethyl-3-phenylprop-2-enamide (18)
First the amide 37 (35 mg, 0.06 mmol) was methylated as de-
scribed for 13 to afford to afford methylated 37a as a colour-
less oil that was purified by silica gel chromatography hexa-
nes:EtOAc (10:1); yield: 35 mg (98%).
To a solution of methylated 37a (35 mg, 0.058 mmol) in
THF (0.5 mL) at 08C was added tetrabutylammonium fluo-
ride (37 mg, 0.117 mmol) and the resultant mixture stirred
for 5 min. It was then warmed to room tempertaure and
stirred overnight. The solvent was removed at reduced pres-
sure and the residue purified using silica gel chromatogra-
phy (hexane/EtOAc 4:1 to 3:1) to afford 18 as a white solid;
yield: 26.5 mg (95%); mp 157.5–158.38C. 1H NMR
(500 MHz, CDCl3): d (major rotamer)=7.68 (d, J=7.8 Hz,
1H), 7.43–7.00 (m, 11H), 6.82 (t, J=7.6 Hz, 1H), 6.08 (br s,
1H), 4.23 (br s, 2H), 3.21 (s, 3H), 2.19 (s, 3H); d (minor
rotamer)=7.82 (d, J=6.9 Hz, 1H), 7.47–6.93 (m, 11H), 6.73
(d, J=7.3 Hz, 1H), 4.60 (s, 2H), 2.97 (s, 3H); 13C NMR
(126 MHz, CDCl3): d (mixture of rotamers)=172.84, 172.29,
145.36, 144.32, 140.38, 139.78, 139.16, 138.78, 132.20, 131.22,
130.05, 129.70, 129.20, 128.63, 128.53, 128.45, 128.36, 128.05,
127.85, 127.53, 127.49, 127.36, 98.64, 97.57, 63.39, 63.02,
38.91, 37.31, 17.10; IR (neat): nmax =3383, 1624, 1481, 1439,
(E)-N-(2-Iodophenyl)-4-methyl-N-(2-methylpent-2-
en-1-yl)benzenesulfonamide (25a)
To a solution of NaH (60% in mineral oil, 9 mg, 0.22 mmol,
1.2 equiv.) in 300 mL DMF was added N-(2-iodophenyl)-4-
methylbenzenesulfonamide[27] (70 mg, 0.19 mmol, 1.0 equiv.)
via cannula (0.5 mL, 0.5 mL rinse, DMF). The mixture was
stirred for 35–40 min and then (E)-1-bromo-2-methylpent-2-
ene[28] (45 mg, 0.28 mmol, 1.5 equiv.) was added via cannula
(0.5 mL, 0.5 mL rinse, DMF). The reaction was stirred over-
night and then poured into water. The aqueous phase was
extracted 3 times with EtOAc, dried over MgSO4, filtered
and concentrated. The crude residue was subjected to
column chromatography 210: 40 hexanes:EtOAc to give the
desired product 25a; yield: 83 mg (0.18 mmol, 97%).
1H NMR (500 MHz, CDCl3): d=7.86 (dd, J=7.9, 1.4 Hz,
1H), 7.62 (d, J=8.3 Hz, 2H), 7.30 ꢀ7.22 (m, 3H), 6.97 (td,
J=7.7, 1.5 Hz, 1H), 6.89 (dd, J=7.9, 1.5 Hz, 1H), 4.92 (t,
J=7.2 Hz, 1H), 4.19 (d, J=13.3 Hz, 1H), 3.89 (d, J=
13.3 Hz, 1H), 2.43 (s, 3H), 1.82 (p, J=7.4 Hz, 2H), 1.71 (s,
3H), 0.69 (t, J=7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3):
d=143.7, 141.5, 140.6, 136.6, 134.1, 131.0, 129.6, 129.6, 128.6,
128.5, 128.4, 102.6, 59.8, 21.7, 21.2, 15.5, 13.6; IR (neat):
1389, 1080, 1018, 764 cmꢀ1
484.0767, calcd. for C24H22INO2 (M+H): 484.0768.
; HR-MS (FAB+): m/z=
(Z)-5,7-Dimethyl-8-phenyldibenzo
ACHUTGTNRENN[GU c,i]ACHUTNGTREN[NUNG 1,5]oxaaza-
cycloundecene-6,15(5H,13H)-dione (19)
AHCTUNGTRENNUNG
nmax =2962, 2929 2871, 1596, 1465, 1349 cmꢀ1
; HR-MS
A
round-bottom flask was charged with 18 (46.2 mg,
0.096 mmol), Pd2dba3·CHCl3 (5.2 mg, 0.005 mmol), (2-
PACHTUNGTRENNUNG
(FAB+): m/z=456.0477, calcd. for C19H22INO2S (M+H):
furyl)3 (6.7 mg, 0.03 mmol), DABCO (46.7 mg 0.38 mmmol),
DMAP (4.7 mg, 0.038 mmol) and DMA (1 mL). The solu-
tion was frozen in a dry-ice/acetone bath, the flask was evac-
uated and filled with CO two times. The mixture was then
heated to 808C and stirred for 4 h, then cooled to room tem-
perature and diluted with EtOAc. This mixture washed with
456.0489.
212
asc.wiley-vch.de
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 205 – 216

Domino Carbopalladation-Carbonylation: Investigation of Substrate Scope
137.2, 134.2, 133.6, 132.6, 131.7, 131.2, 130.4, 130.2, 128.8,
128.5, 59.8, 52.6, 21.7, 21.5, 14.7, 13.8; IR (neat): nmax =2962,
2873, 1730, 1598, 1160 cmꢀ1
HR-MS (FAB+): m/z=
(E)-N-(2-Iodophenyl)-N-(2-methylpent-2-en-1-yl)-
acetamide (25b)
;
To a solution of NaH (60% in oil, 24 mg, 0.60 mmol,
1.2 equiv.) in DMF (2 mL) was added N-(2-iodophenyl)ace-
tamide[29] (130 mg, 0.50 mmol, 1.0 equiv.) in DMF via cannu-
la (2 mL, plus 1 mL rinse). The solution was stirred for 35–
388.1572, calcd. for C21H25NO4S (M+H): 388.1577.
(RS)-Methyl 2-[(RS)-1-acetyl-3-methylindolin-3-yl]-
butanoate (26b)
40 min
and
then
(E)-1-bromo-2-methylpent-2-ene[28]
(122 mg, 0.75 mmol, 1.5 equiv.) was added via cannula
(0.5 mL, 0.5 mL rinse DMF). The reaction was stirred over-
night and then poured into water. The aqueous layer was ex-
tracted 3 times with EtOAc, dried over MgSO4, filtered and
concentrated. Flash chromatography of the crude residue
230:20 hexanes:EtOAc to 220:30 hexanes:EtOAc provided
substrate 25b; yield: 155 mg (0.45 mmol, 90%). 1H NMR
(500 MHz, CDCl3): d=7.90 (dd, J=8.3, 1.3 Hz, 1H), 7.32
(td, J=7.7, 1.3 Hz, 1H), 7.05–6.99 (m, 2H), 4.99–4.90 (m,
2H), 3.31 (d, J=14.2 Hz, 1H), 1.90 (p, J=7.4 Hz, 2H), 1.78
(s, 3H), 1.65 (s, 3H), 0.78 (t, J=7.5 Hz, 3H); 13C NMR
(126 MHz, CDCl3): d=170.1, 144.4, 140.2, 132.2, 130.7,
129.7, 129.4, 129.1, 100.3, 55.2, 23.1, 21.1, 14.8, 13.9; IR
The conditions were the same as for the synthesis of amide
8, except that the internal temperature was 80–858C. De-
sired 26b and early ester 27b were isolated as a mixture and
then a small amount was repurified for characterization pur-
poses. Using PACHTNUGTRENUNG(2-furyl)3 allylic amine 25b (57 mg, 0.16 mmol,
1.0 equiv.) was submitted to reaction: isolated were 25 mg
26b and 27b (0.085 mmol, 53% combined 1:4.5 26b:27b) and
2 mg 28b (0.010 mmol, 6%).
When using PPh3 allylic amine 25b (39 mg, 0.11 mmol,
1.0 equiv.) was submitted to the reaction: isolated were:
15 mg 26b and 27b (1:4.6 mixture 0.053 mmol, 47% com-
bined), and 7 mg 28b (0.030 mmol, 26%). 1H NMR
(500 MHz, CDCl3): d=8.20 (d, J=8.1 Hz, 1H), 7.25–7.20
(m, 1H), 7.08–7.03 (m, 2H), 4.53 (d, J=11.2 Hz, 1H), 3.73
(s, 3H), 3.59 (d, J=11.2 Hz, 1H), 2.55 (dd, J=11.8, 3.1 Hz,
1H), 2.25 (s, 3H), 1.60–1.49 (m, 1H), 1.36 (s, 3H), 1.12
(dqd, J=14.9, 7.5, 3.1 Hz, 1H), 0.78 (t, J=7.4 Hz, 3H);
13C NMR (126 MHz, CDCl3): d=175.7, 168.8, 142.7, 137.2,
128.6, 124.1, 122.1, 117.2, 57.7, 56.5, 51.7, 45.9, 27.3, 24.5,
21.7, 12.5; IR (neat): nmax =2964, 2875, 1730, 1666,
(neat): nmax =2962, 2929, 2871, 1664 1469 1282 734 cmꢀ1
;
HR-MS (FAB+): m/z=344.0499, calcd. C14H18INO (M+
H): 344.0506.
ACHTUNGTRENNUNG(2RS)-Methyl 2-[(RS)-3-Methyl-1-tosylindolin-3-yl]-
butanoate (26a)
1402 cmꢀ1
; HR-MS (FAB+): m/z=276.1594, calcd. for
The reaction conditions were the same as those for the syn-
thesis of amide 8 except that the internal temperature was
between 80–858C. The desired ester 26a and early ester 27a
were isolated as a mixture. These were separated by reverse
phase HPLC for characterization:
With PPh3 substrate 25a (45 mg, 0.10 mmol, 1 equiv.) was
submitted to the reaction and isolated mixture of early ester
27a and desired 26a (13 mg, 0.035 mmol, 37%, 2:1 mixture
of early ester 27a:desired ester 26a).
C16H21NO3 (M+H): 276.1594, found .
(E)-Methyl 2-[N-(2-Methylpent-2-en-1-yl)acet-
amido]benzoate (27b)
1
See procedure for 26b. H NMR (500 MHz, CDCl3): d=7.95
(dd, J=7.8, 1.6 Hz, 1H), 7.53 (td, J=7.7, 1.6 Hz, 1H), 7.42
(td, J=7.6, 1.2 Hz, 1H), 7.10 (dd, J=7.9, 1.1 Hz, 1H), 4.90
(t, J=7.0 Hz, 1H), 4.74 (d, J=14.0 Hz, 1H), 3.88 (s, 3H),
3.53 (d, J=14.0 Hz, 1H), 1.90 (m, 2H), 1.81 (s, 3H), 1.64 (s,
3H), 0.78 (t, J=7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3):
d=170.5, 166.4, 142.4, 132.9, 132.2, 131.8, 131.1, 129.8, 129.4,
128.3, 56.6, 52.8, 23.0, 21.5, 14.8, 13.9; IR (neat): nmax =2962,
2873, 1730, 1666, 1400, 1288 cmꢀ1; HR-MS (FAB+): m/z=
276.1594, calcd. for C16H21NO3 (M+H): 276.1594.
With
PACHTUNGTRENNUNG(2-furyl)3 substrate 25a (31 mg, 0.069 mmol,
1 equiv.) submitted to reaction: 49% recovered 25a starting
material, isolated mixture of early ester 27a and desired 26a
(yield: 9.4 mg, 0.024 mmol, 35%, 3:1 mixture of early ester
27a: desired ester 26a). 1H NMR (500 MHz, CDCl3): d=
7.72 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.1 Hz, 1H), 7.25–7.20
(m, 3H), 6.99 (t, J=7.5 Hz, 1H), 6.93 (d, J=6.9 Hz, 1H),
4.27 (d, J=11.3 Hz, 1H), 3.67 (s, 3H), 3.46 (d, J=11.3 Hz,
1H), 2.40 (dd, J=11.9, 3.1 Hz, 1H), 2.36 (s, 3H), 1.31–1.18
(m, 1H), 1.12 (s, 3H), 0.93–0.80 (m, 1H), 0.66 (t, J=7.4 Hz,
3H); 13C NMR (126 MHz, CDCl3): d=174.9, 144.2, 141.6,
137.3, 134.1, 129.8, 128.7, 127.5, 123.8, 122.8, 114.5, 58.2,
55.9, 51.6, 45.8, 27.0, 21.7, 21.6, 12.5; IR (neat): nmax =2964,
2875, 1730, 1598, 1479, 1457 cmꢀ1; HR-MS (FAB+): m/z=
388.1573, calcd. for C21H25NO4S (M+H): 388.1577.
(E)-1-(3-Methyl-3-(prop-1-en-1-yl)indolin-1-yl)-
ethanone (28b)
See procedure for 26b (structure was further confirmed by
simple Heck reaction of substrate 25b to yield abn identical
compound albeit with different ratios of the double bond
1
isomers). H NMR (500 MHz, CDCl3): d=8.21–8.15 (m, 1H
major and minor), 7.24–7.19 (m, 1H major and minor), 7.12
(d, J=6.9 Hz, 1H major and minor), 7.08–7.01 (m, 1H
major and minor), 5.67–5.55 (m, 1H major), 5.44 (dq, J=
12.9, 6.4 Hz, 1H minor), 5.11–5.02 (m, 1H major and
minor), 3.90 (d, J=10.2 Hz, 1H major and minor), 3.76 (d,
J=10.1 Hz, 1H minor), 3.64 (d, J=10.2 Hz, 1H major),
2.40–2.30 (m, 3H major), 2.22 (s, 3H minor), 2.19 (s, 3H
major), 1.69 (dd, 3H minor), 1.43 (s, 3H minor), 1.37 (s, 3H
major); 13C NMR (126 MHz, CDCl3): d (major reported
only)=168.6, 133.9, 128.0, 123.8, 122.3, 118.6, 117.0, 60.6,
46.0, 26.5, 24.3, 17.9; IR (neat): nmax =2962, 2921, 2871, 1664,
(E)-Methyl 2-[4-Methyl-N-(2-methylpent-2-en-1-yl)-
phenylsulfonamido]benzoate (27a)
1
See the procedure for 26a. H NMR (500 MHz, CDCl3): d=
7.84 (dd, J=7.6, 1.9 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.38
(td, J=7.6, 1.9 Hz, 1H), 7.34 (td, J=7.5, 1.4 Hz, 1H), 7.23
(d, J=8.0 Hz, 2H), 6.91 (dd, J=7.8, 1.2 Hz, 1H), 5.02 (t, J=
6.9 Hz, 1H), 4.13 (s, 2H), 3.77 (s, 3H), 2.41 (s, 3H), 1.83 (p,
J=7.4 Hz, 2H), 1.65 (s, 3H), 1.55 (s, 2H), 0.71 (t, J=7.5 Hz,
3H); 13C NMR (126 MHz, CD3CN): d=167.5, 144.8, 138.6,
Adv. Synth. Catal. 2012, 354, 205 – 216
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
213

Brinton Seashore-Ludlow et al.
UPDATES
1481, 1402 cmꢀ1; HR-MS (FAB+): m/z=216.1382, calcd. for
C14H17NO (M+H): 216.1383.
ed under reduced pressure. The residue was purified by
silica gel chromatography using hexanes/EtOAc 20:1 as
eluent to afford 31 as a colourless oil; yield: 530 mg
1
(1.82 mmol, 36%). H NMR (500 MHz, CDCl3): d=4.26 (q,
(E)-2-Iodo-N-methyl-N-(2-methylpent-2-en-1-yl)-
aniline (29)
J=7.1 Hz, 2H), 2.79 (q, J=7.4 Hz, 2H), 2.00 (s, 3H), 1.34
(t, J=7.1 Hz, 3H), 1.19 (t, J=7.4 Hz, 3H); 13C NMR
(126 MHz, CDCl3): d=166.4, 159.1, 122.5, 118.3 (q, J=
319.6 Hz), 61.6, 25.9, 14.1, 14.0, 11.3; IR (neat): nmax =2985,
(2E)-2-Methyl-2-pentenal (68 uL, 0.6 mmol, 1.2 equiv.) was
added to the HCl salt of N-methyl-2-iodoaniline[29] (0.134 g,
0.5 mmol, 1.0 equiv.) in MeOH (2 mL). This mixture was
stirred for 1 hour and then Et3SiH (82 mL, 1.0 mmol,
2.0 equiv.) and InCl3 (22 mg, 0.1 mmol, 0.2 equiv.) were
added to the flask and the reaction mixture was stirred for
an additional 24 h. The reaction was then quenched with sa-
turated aqueous K2CO3 solution and transferred to a separa-
tory funnel. The aqueous layer was extracted three times
with EtOAc, and then the combined organic layers were
washed with brine and dried over Na2SO4, filtered and con-
centrated. The crude residue was subjected to column chro-
matography to afford the product; yield: 0.0937 g
(0.297 mmol, 60%). 1H NMR (500 MHz, CDCl3): d=7.85
(dd, J=7.8, 1.5 Hz, 1H), 7.31 (ddd, J=8.7, 6.5, 1.5 Hz, 1H),
7.08 (dd, J=8.0, 1.5 Hz, 1H), 6.78 (td, J=7.7, 1.5 Hz, 1H),
5.42 (td, J=7.1, 1.2 Hz, 1H), 3.44 (s, 2H), 2.58 (s, 3H), 2.06
(p, J=7.3 Hz, 2H), 1.72 (s, 3H), 0.97 (t, J=7.5 Hz, 3H);
13C NMR (126 MHz, CDCl3): d=154.8, 139.9, 131.8, 130.3,
128.9, 125.2, 122.3, 98.8, 64.9, 41.8, 21.1, 14.6, 14.1; IR
(neat): nmax =2960, 2872, 2792, 1579, 1471 cmꢀ1; HR-MS
(FAB+): m/z=316.0554, calcd. for C13H18IN (M+H):
316.0557.
2946, 1728, 1666, 1415, 1215, 1141, 1095, 1002, 957, 856 cmꢀ1
;
HR-MS (FAB+): m/z=291.0504, calcd. for C9H13F3O5S
(M+H): 291.0509.
(E)-Ethyl 2-Methyl-3-phenylpent-2-enoate (32)[31]
To a mixture of PdACTHNUTRGNEUN(G PPh3)4 (155 mg, 0.13 mmol), Na2CO3
(851 mg, 8.03 mmol), and phenylboronic acid (359 mg,
2.94 mmol) was added a solution of 31 in DME (15.2 mL)
followed by addition of H2O (5.1 mL). The mixture was
stirred at ambient temperature for 20 h and then diluted
with H2O and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered and concentrated at
reduced pressure. The residue was purified by silica gel
chromatography (pentane/EtOAc 50:1) to afford 32 as a col-
ourless oil; yield: 437 mg (75%). 1H NMR (500 MHz,
CDCl3): d=7.33 (m, 2H), 7.27–7.23 (m, 1H), 7.11–7.07 (m,
2H), 4.24 (q, J=7.1 Hz, 2H), 2.58 (q, J=7.4 Hz, 2H), 1.68
(s, 3H), 1.32 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H).
(E)-N-(2-Iodophenyl)-2-methyl-3-phenylpent-2-en-
amide (33)
(RS)-Methyl 2-[(SR)-1,3-dimethyl-4-oxo-1,2,3,4-
To a solution of AlMe3 (2.28 mmol) in toluene (4.1 mL) at
08C was added 2-iodoaniline (473 mg, 2.16 mmol) in toluene
(3 mL). The solution was stirred for 5 min and then warmed
to room temperature and stirred for an additional 2 h. Sub-
strate 32 in toluene (3 mL) was then added and the mixture
heated to 608C with stirring for 15 h and then cooled to
room temperature. The reaction mixture was diluted with
CH2Cl2 and quenched with 1M HCl. The layers were sepa-
rated and the aqueous phase extracted using CH2Cl2. The
combined organic layers were dried over MgSO4, filtered
and concentrated at reduced pressure. The residue was puri-
fied by silica gel chromatography (hexanes/EtOAc 20:1) to
afford 33 as a white solid; yield: 681 mg (89%); mp 158.2–
tetrahydroquinolin-3-yl]butanoate (30)
Same procedure as for the synthesis of amide 8 except with
an internal temperature in the reactor of 808C and allylic
amine 29 (26 mg, 0.084 mmol, 1 equiv). Compound 30 was
isolated; yield: 8 mg (0.034 mmol, 39%, the mass balance
was starting material amine 29). 1H NMR (500 MHz,
CDCl3): d=7.93 (dd, J=7.9, 1.6 Hz, 1H), 7.40 (ddd, J=8.6,
7.1, 1.7 Hz, 1H), 6.76 (t, J=7.5 Hz, 1H), 6.70 (d, J=8.5 Hz,
1H), 3.66 (s, 3H), 3.53 (d, J=12.6 Hz, 1H), 3.35 (d, J=
12.6 Hz, 1H), 3.06 (dd, J=11.8, 2.9 Hz, 1H), 3.01 (s, 3H),
1.77–1.66 (m, 1H), 1.46 (dqd, J=15.0, 7.5, 2.9 Hz, 1H), 1.13
(s, 3H), 0.88 (t, J=7.3 Hz, 3H); 13C NMR (126 MHz,
CDCl3): d=196.1, 175.2, 151.51, 135.2, 129.0, 118.7, 117.2,
112.9, 58.1, 51.3, 50.8, 47.2, 39.2, 21.2, 19.3, 13.0; IR (neat):
nmax =2996, 2875, 1732, 1670, 1606, 1500 cmꢀ1; HR-MS
(FAB+): m/z=276.1584, calcd. for C16H21NO3 (M+H):
276.1594.
1
159.48C. H NMR (500 MHz, CDCl3): d=8.39 (d, J=8.0 Hz,
1H), 7.82 (dd, J=7.9, 1.3 Hz, 1H), 7.66 (s, 1H), 7.41–7.37
(m, 3H), 7.33–7.29 (m, 1H), 7.19 (d, J=7.3 Hz, 2H), 6.88
(td, J=7.9, 1.4 Hz, 1H), 2.60 (q, J=7.1 Hz, 2H), 1.86 (s,
3H), 0.98 (t, J=7.3 Hz, 3H); 13C NMR (126 MHz, CDCl3):
d=170.0, 144.9, 140.2, 138.9, 138.3, 129.3, 128.6, 128.3, 128.2,
127.1, 126.0, 122.0, 89.8, 29.0, 17.7, 13.4; IR (neat): nmax
=
(E)-Ethyl 2-Methyl-3-(trifluoromethylsulfonyloxy)-
2970, 2935, 1643, 1470, 1358, 1018, 768, 702 cmꢀ1; HR-MS
(FAB+): m/z=392.0505, calcd. for C18H18INO (M+H):
392.0505.
pent-2-enoate (31)[30]
To solution of ethyl 2-methyl-3-oxopentanoate (805 mg,
5.09 mmol) in hexane (25 mL) and H2O (6.3 mL) at 08C
was added 25 wt% aqueous Me4NOH (9.3 mL, 25.4 mmol)
in one portion. The mixture was stirred vigorously for 5 min
followed by dropwise addition of Tf2O (1.72 mL,
10.18 mmol). Stirring was continued for 1 h, followed by ad-
dition of H2O. The phases were separated and the aqueous
phase was extracted three times using EtOAc. The com-
bined organic layer was washed with H2O and brine and
dried over MgSO4. The solution was filtered and concentrat-
(Z)-Ethyl 2-Methyl-3-phenyl-3-(trifluoromethyl-
sulfonyloxy)prop-2-enoate (34)[8]
To a solution of ethyl 2-methyl-3-oxo-3-phenylpropanoate
(1.12 g, 5.82 mmol) in hexane (30 mL) at 08C was added sa-
turated aqueous LiOH (8.8 mL). The mixture was stirred
for 5 min, followed by dropwise addition of Tf2O (2.45 mL,
14.5 mmol). Stirring was continued for 30 min and the mix-
214
asc.wiley-vch.de
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 205 – 216

Domino Carbopalladation-Carbonylation: Investigation of Substrate Scope
ture was then diluted with EtOAc and H2O. The aqueous 1678, 1508, 1430, 1253, 837 cmꢀ1; HR-MS (FAB+): m/z=
layer was extracted with EtOAc and the combined organic 584.1475, calcd. for C29H34INO2Si (M+H): 584.1476.
layers were washed with H2O and brine, dried over MgSO4,
filtered and concentrated at reduced pressure. The residue
was purified by silica gel chromatography (hexanes/EtOAc
Acknowledgements
20:1) to afford 34 as a clear oil; yield: 821 mg (42%).
1H NMR (500 MHz, CDCl3): d=7.49–7.37 (m, 5H), 4.36 (q,
The authors would like to thank the Knut and Alice Wallen-
berg Foundation, the Swedish Research Council and the Es-
tonian Science Foundation (Grant no. 7808) for funding.
J=7.1 Hz, 2H), 1.98 (s, 3H), 1.38 (t, J=7.2 Hz, 3H);
13C NMR (126 MHz, CDCl3): d=165.6, 147.8, 131.4, 130.6,
129.2, 128.6, 123.6, 118.1 (q, J=320.6 Hz), 62.0, 16.3, 14.0;
IR (neat): nmax =2989, 1724, 1662, 1423, 1215, 1142, 976,
841 cmꢀ1
; HR-MS (FAB+): m/z=339.0507, calcd. for
C13H13F3O5S (M+H): 339.0509.
References
(Z)-Ethyl 3-[2-(Hydroxymethyl)phenyl]-2-methyl-3-
phenylprop-2-enoate (35)
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J=11.6, 7.4 Hz, 1H), 3.94 (qd, J=7.1, 0.8 Hz, 2H), 2.73–
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0.23 mmol) and imidazole (32.6 mg, 0.48 mmol) was added
DMF (0.5 mL) and the mixture heated to 408C with stirring
overnight. The mixture was diluted with CH2Cl2 and washed
with H2O, dried over MgSO4, filtered and concentrated at
reduced pressure. The residue was purified by silica gel
chromatography (hexane/EtOAc 25:1) to afford 36 as a col-
ourless oil; yield: 80 mg (100%). 1H NMR (500 MHz,
CDCl3): d=7.59–7.15 (m, 9H), 4.77–4.63 (m, 1H), 4.52–4.34
(m, 1H), 3.89 (q, J=7.1 Hz, 2H), 2.19 (s, 3H), 0.93 (s, 9H),
0.82 (t, J=7.1 Hz, 3H), 0.00 (s, 6H); 13C NMR (126 MHz,
CDCl3): d=170.5, 145.4, 139.5, 139.3, 139.2, 129.5, 129.3,
128.6, 128.0, 127.7, 127.5, 126.1, 125.6, 62.5, 60.3, 25.9, 18.4,
17.7, 13.4, ꢀ5.5; IR (neat) nmax =2954, 2931, 2858, 1712,
1465, 1253, 1122, 1076, 840, 775 cmꢀ1; HR-MS (FAB+):
m/z=411.2344, calcd. for C25H34O3Si (M+H): 411.2350.
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7.10 (m, 1H), 6.79 (td, J=7.7, 1.5 Hz, 1H), 6.68 (d, J=
7.8 Hz, 1H), 4.54 (br d, J=10.8 Hz, 1H), 4.24 (br d, J=
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129.0, 128.8, 128.3, 128.1, 128.0, 127.7, 127.1, 125.0, 94.7,
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UPDATES
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ꢀ
ꢀ
of an acyl palladium species RCO Pd OR’ as pro-
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ꢀ
ꢀ
if reductive elimination of an RCO Pd OR’ intermedi-
ate is operative. If, on the other hand, reductive elimi-
ꢀ
ꢀ
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ꢀ
ꢀ
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216
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ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 205 – 216