Evaluation of palladacycles as a non-rhodium based alternative for the asymmetric conjugate 1,4-addition of arylboronic acids to α,β -unsaturated enones

Article abstract of DOI:10.1002/adsc.201400473

The asymmetric conjugate 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds is an extremely versatile and widely used organic transformation. While the rhodium(I)-catalysed reaction has been thoroughly explored, the asymmetric palladi

Full text of DOI:10.1002/adsc.201400473

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DOI: 10.1002/adsc.201400473
Evaluation of Palladacycles as a Non-Rhodium Based Alternative
for the Asymmetric Conjugate 1,4-Addition of Arylboronic Acids
to a,b-Unsaturated Enones
Jonathan Wong,a Kennard Gan,a Houguang Jeremy Chen,a
and Sumod A. Pullarkata,*
a
Division of Chemistry and Biological Chemistry, School of Physical & Mathematical Science, Nanyang Technological
University, Singapore 637371, Singapore
Fax : (+65)-6791-1961; phone: (+65)-6316-8906; e-mail: sumod@ntu.edu.sg
Received: May 12, 2014; Revised: July 14, 2014; Published online: September 26, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400473.
Abstract: The asymmetric conjugate 1,4-addition of action and the conjugate addition of arylboronic
arylboronic acids to a,b-unsaturated carbonyl com- acids to a wide range of a,b-unsaturated enones, cat-
pounds is an extremely versatile and widely used or- alysed by an easily accessible and robust chiral phos-
ganic transformation. While the rhodium(I)-cata- phapalladacycle in high yields and enantioselectivi-
lysed reaction has been thoroughly explored, the ties.
asymmetric palladium-catalysed protocol is far less
developed and understood, particularly with acyclic
enones as substrates. Herein, we report the systemat- Keywords: addition reactions; asymmetric synthesis;
ic evaluation of a series of metallacycles for this re- boronic acids; metallacycles; phosphapalladacycles
Introduction
a-proton[6] and the presence of the carbonyl function-
ality.[6] While the rhodium-catalysed asymmetric con-
Since the discovery of the Suzuki coupling in 1979,[1] jugate addition reaction on enones has been quite
the employment of boronic acids in organic synthesis thoroughly developed,[7] the high cost of rhodium pro-
has shown a prolific development in both synthetic hibits its implementation on a large scale.[8]
utility and functional group tolerance.[2] The allure of
In light of the prohibitive cost of rhodium, we di-
boronic acids can be simultaneously attributed to rected our attention towards the search for a more
their thermal stability, as well as their ability to resist cost-efficient modus of asymmetric carbon-carbon
oxidation in the absence of an inert environment.[3] bond formation via the Hayashi–Miyaura addition re-
These exceptional qualities allow boronic acids to be action. In spite of the obvious dominance of rhodium,
exploited as a convenient, commercially available, nu- other metals such as palladium[9] and platinum[9g,10]
cleophilic carbon source in the presence of a transition have also been used for the addition of boronic acids
metal catalyst, without the need for forcing condi- to enones. However, these protocols have drawbacks
tions. With these outstanding advantages, it is there- of lengthened reaction times (18 h,[9e] 23 h,[9a,d] 24 h,[9j]
fore not surprising that chemists have used boronic 40 h[9i] vs. 10 h), elevated temperatures (508C,[9e]
acids in organic synthesis as well as in the total syn- 608C,[9b] 808C[9j] vs. room temperature), onerous addi-
thesis of natural products.[2f,4] Since the introduction tives [Cu
C
vs. PPh3), high catalyst
[9b]
of the Hayashi–Miyaura reaction in 1998,[5] the asym- loading (10 mol%[9b] vs. 5 mol% of metal) or poor
metric 1,4-conjugate addition of arylboronic acids to enantioselectivity (42%,[9j] 76%[9k] vs. 92%).[11] In
a,b-unsaturated carbonyl compounds has become other works, the asymmetric variant was not studie-
a component in the synthetic repertoire of organic d.[9a-d, f-i,10] A major challenge in the use of palladium
chemists. Such a protocol has the dual benefit of is posed by the competitive b-hydride elimination in
forming a chiral centre at the b-position, as well as place of protonolysis, which leads to the formation of
leaving a carbon skeleton capable of further function- catalytically inactive palladium(0), thus imparing the
al group transformation in lieu of the low pKa of the catalytic potential of the system.[12] Recently, the palla-
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Jonathan Wong et al.
dium-catalysed addition of boronic acids has been
gaining momentum as evidenced by the addition of
boronic acids to imines,[13] aldehydes[10,14] as well as the
formation of all-carbon quaternary centres.[15] Howev-
er, the addition of arylboronic acids onto acyclic
enones via palladium-based catalysts is largely unde-
veloped, disregarding key structural elements such as
the b,b-diaryl skeleton which is of utility in further
transformations.
Scheme 1. Preliminary screening of metallacycles.
Table 1. Catalyst screening for the asymmetric conjugate
In view of the aforementioned factors and as part
of our continuing interest in metallacycle-based cata-
1,4-addition of phenylboronic acid to 2-cyclohexenone.[a]
[16]
[17]
[18]
À
À
À
Entry
Catalyst
Time [h]
Yield [%][b]
ee[c]
lysts for C C, C N and C P bond formations,
we decided to explore the development of an efficient
metallacycle-based protocol for this important reac-
tion. A metallacycle can be loosely defined as an or-
ganometallic complex with at least one carbon-metal
covalent bond, intramolecularly stabilised by a donor
atom (N, P, As etc), forming a chelate.[19] The pres-
1
2
3
4
5
6
7
8
(S)-4
(S)-5
(S)-6
(S)-7
(S)-8
(S)-9
(S)-10
24
24
10
10
10
24
24
24
not observed
39
89
87
62
23
45
–
9
92 (+)[d]
75
54
75
67
–
À
ence of this C M bond reduces the propensity of the
metal to undergo reduction, preferring to remain in
a positive oxidation state. Metallacycles incorporating
metals such as palladium and platinum have shown
unprecedented reactivity in a myriad of addition and
substitution reactions.[16–18,19b,20] As a complement to
the convenient nature of boronic acids, metallacycles
also possess a high degree of air/moisture stability as
well as tolerance to elevated temperatures due to
their structural rigour.[21] In addition, asymmetry in
the reaction can be induced via chiral elements locat-
ed on the organic backbone.[20c]
Pd
G
not observed
[a]
The reaction was carried out with 2-cyclohexen-1-one
(0.1 mmol), phenylboronic acid (0.5 mmol), metallacycle/
catalyst (5 mol% of metal), PPh3 (5.0 mol%) and K3PO4
(0.05 mmol) in 1 mL of toluene at room temperature.
Isolated percentage yield.
[b]
[c]
The ee % was determined by chiral HPLC. (+/À) was
determined by optical rotation and is shown in parenthe-
ses.
[d]
Chiral centre has the R configuration.[5]
While the metal of choice has a profound impact
on the efficacy of the catalytic system, the constitu-
tional provisions of the ligand backbone to the reac-
tion cannot be discounted.[22] Although a multitude of
chiral ligands has been successfully employed in the
Hayashi–Miyaura reaction, a void exists in the com-
parison of ligand structures and its impact on the re-
action outcome.
Herein, a range of metallacycles was synthesised
and their competence in the asymmetric conjugate ad-
dition of arylboronic acids to enones was systemati-
cally compared. Following which, the protocol was ex-
tended to include acyclic enones with high yields and
enantioselectivities.
Results and Discussion
Using 2-cyclohexen-1-one 1a and phenylboronic acid
2a as representative substrates, a catalyst screening
was carried out (Scheme 1, Table 1) using metallacy-
cles (S)-4 to (S)-10 (Figure 1) to catalyse the above
reaction. It was observed that a platinacycle with the
Figure 1. Evaluated metallacycles.
chiral naphthylamine ligand backbone (S)-4 was cata- ed onto a palladium centre in (S)-5, the reaction pro-
lytically inactive, with starting materials being quanti- ceeded, albeit with low yield and enantioselectivity
tatively recovered after 24 h (Table 1, entry 1). How- (entry 2). The introduction of the phosphino moiety
ever, when the same ligand backbone was coordinat- in place of the amino moiety on the naphthyl core in
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Evaluation of Palladacycles as a Non-Rhodium Based Alternative
Table 2. Condition screening for the phosphapalladacycle-
catalysed asymmetric conjugate 1,4-addition of phenylbor-
onic acid to 2-cyclohexenone.[a]
(S)-6 drastically improved the reactivity of the palla-
dium centre affording the addition product in 89%
yield and 91% ee (entry 3). This is in line with current
literature which suggests that a phosphine donor on
the palladium is needed for the asymmetric conjugate
addition of boronic acids to proceed and a similar
trend has been observed by us with palladacycles in
Entry
Solvent
Base
Additive
Yield[b]
ee[c]
1
2
3
4
5
6
7
8
toluene
p-xylene
dioxane
DCM
1,2-DCE
DMF
MeCN
MeOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
–
Cs2CO3
Et3N
KF
K3PO4
K3PO4
K3PO4
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
–
89
79
22
79
82
–
23
38
11
21
23
62
45
20
–
92
79
>99
85
85
–
34
53
63
79
76
85
73
73
–
[18b,c,e,f]
À
C P bond formation scenarios.
Taking into ac-
count this additional consideration, three more phos-
phapalladacycles, (S)-7 to (S)-9 were tested. The
benzyl skeleton of (S)-7 proved to be equally reactive
to the detriment of enantioselectivity (entry 4). The
latter can be attributed to the lack of conformational
rigidity of the metallacycle which is usually imparted
by a locking of the conformation via the steric inter-
action between the methyl moiety on the chiral
centre and a protruding hydrogen on the naphthyl
skeleton.[23] The introduction of a methyl group ortho
to the palladium atom in (S)-8 was intended to in-
crease the steric bulk of the catalyst within the coordi-
nation sphere, thereby increasing enantioselectivity.
However, when (S)-8 was used as a catalyst, the yield
of the reaction dropped to 61% (entry 5). While the
previous phosphino moieties were diphenylphosphino
groups, (S)-9 used the sterically more demanding,
electron-donating, di(tert-butyl)phosphino group. The
yield of the reaction dropped to 23%, suggesting that
this reaction is very sensitive to the steric environ-
9
10
11
12
13
14
15
PACHTUNGTRENNUG
[a]
The reaction was carried out with 2-cyclohexen-1-one
(0.1 mmol), phenylboronic acid (0.5 mmol), (S)-6
(2.5 mol%), PPh3 (5.0 mol%) and K3PO4 (0.05 mmol) in
1 mL of toluene at room temperature.
[b]
[c]
Isolated percentage yield.
The ee % was determined by chiral HPLC. (+/À) was
determined by optical rotation and shown in parentheses.
3,4-Dimethyl-1-phenylphosphole.
[d]
ment of the catalyst (entry 6). As (S)-6 proved to be Methanol was also used but the product was only
the most effective catalyst, the dimeric compound was formed in low yields and enantioselectivity (entry 8).
converted into the monomeric, cationic form with While 1,4-dioxane yielded the product in extremely
a perchlorate counterion, (S)-10. The monomeric high enantioselectivity, the yield of the reaction was
form was found to be inefficient, yielding the desired poor at 22% (entry 3). Following the solvent selec-
addition adduct in low yields after 24 h (entry 7). In tion, we proceeded to analyse the impact of bases
order to showcase the catalytic potential of the phos- (entries 9–12). When the reaction was run in the ab-
phapalladacycle (S)-6, palladium(II) acetate was uti- sence of a base, the enantiomerically-enriched prod-
lised. The reaction yielded no observable product uct was isolated in 11% yield (entry 9). A modifica-
after 24 h under similar conditions (entry 8).
tion of the base to cesium carbonate or potassium
With the catalyst design optimised, further optimi- fluoride did not enhance either the isolated yield or
sation of the other reaction conditions was carried out the enantioselectivity (entries 10 and 12) and the de-
(Scheme 2, Table 2). Firstly, a range of solvents was ployment of an organic base lowered the yield to
screened to determine the appropriate reaction 23% (entry 11), suggesting that it functioned more as
medium (Table 2, entries 1–8). It appears that the re- a ligand instead of a base. Lastly, additives were
action favours relatively non-polar, aprotic solvents screened. It was found that in the absence of an addi-
with toluene (entry 1) yielding the best results. DMF, tional additive, the catalyst decomposed rapidly, with
being an extremely polar aprotic solvent did not pro- significant amounts of palladium(0) being deposited
vide a suitable reaction environment for the addition on the walls of the reaction vessel. This suggests that
to take place, with no product being formed (entry 6). in the absence of an additional phosphine, the system
tended to undergo b-hydride elimination more rapid-
ly, reducing the catalyst and leading to low yields
(entry 13). It was also found that a bulkier phosphine
did not afford the product in a higher yield (entry 14)
and the introduction of a planar phosphorus ligand in
the form of DMPP did not yield any observable prod-
uct (entry 15).
With reaction conditions optimised, the functional
Scheme 2. Screening of reaction conditions.
group tolerance of the protocol was tested and the re-
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Table 3. Substrate screening for the asymmetric conjugate 1,4-addition of arylboronic acids on different a,ß-unsaturated ke-
tones.[a]
[a]
The reaction was carried out with enone (0.1 mmol), boronic acid (0.5 mmol), (S)-6 (2.5 mol%), PPh3 (5.0 mol%) and
K3PO4 (0.05 mmol) in 1 mL of toluene at room temperature.
Isolated percentage yield.
[b]
[c]
The ee% was determined by chiral HPLC. (+/À) was determined by optical rotation and is shown in parentheses.
Chiral centre has S configuration.[5]
[d]
[e]
Chiral centre has R configuration.[5]
[f]
Chiral centre has S configuration.[9e]
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Evaluation of Palladacycles as a Non-Rhodium Based Alternative
sults are shown in Table 3. It can be seen that the pro- col and the results are compiled in Table 4. Electron-
tocol is applicable to various cyclic enones with both rich boronic acids show excellent reactivity yielding
five- and seven-membered rings showing promising the desired product in high yields (entries 5 and 6).
results (Table 3, entries 1 and 2). The dimished yield Naphthalen-2-ylboronic acid also shows a high degree
and lowered enantioselectivity of the five-membered of reactivity, giving the addition adduct in almost
enone can be attributed to the extreme reactivity of quantitative yield (entry 1). When 4-bromobenzene-
the molecule and the planarity of the molecule re- boronic acid was reacted with trans-chalcone, the 1,4-
spectively.[24] Following the conjugate addition of the product was obtained in 88% yield, with no homocou-
aryl group onto cyclic enones, the substrate scope was pling product observed (entry 4). Also, electron-defi-
further expanded to include acyclic enones. The asym- cient boronic acids such as 4-trifluoromethylbenzene-
metric addition onto acyclic enones poses an addition- boronic acid are able to furnish the product, but in
al problem as the transition state of the reaction can lower yields and poorer enantioselectivities. It is note-
exist in both the s-cis and s-trans forms,[24] thereby worthy that the same product produced by altering
lowering the enantioselectivity. However, the addition the substrates show opposite enantioselectivities, pro-
of arylboronic acids onto a wide variety of substrates viding a variety of synthetic routes to the same prod-
proved to be successful, with the catalytic system tol- uct (Table 3 entry 6 vs. Table 4 entry 6; Table 3
erating a wide range of functional groups. Introduc- entry 3 vs. Table 4 entry 2, etc.).
tion of highly electron-withdrawing groups such as tri-
fluoromethyl (entry 8) on the phenyl ring do not
seem to have much of an impact on the reactivity of Proposed Reaction Mechanism
the reaction as evidenced from the high yields. A sim-
ilar trend was observed with electron-donating sub- The proposed mechanism of the reaction is shown in
stituents such as the methyl and methoxy moieties Figure 2 and is analogous to the Rh(I) catalytic cycle
(entries 7 and 6, respectively) which should have hin- based on mechanistic studies done by Hayashi et al.
dered the reaction progress.
in 2002[25] with modifications made based on DFT
Interestingly, the reaction also proceeded smoothly studies done by Houk et al.[26] and Wu et al.[27] The
with halogens (entries 3–5), yielding the addition ad- cycle starts with a hydroxo-palladium species (11).
ducts in high yields and enantioselectivities. This Transmetallation occurs between 11 and phenylboron-
result was particularly surprising, especially for the ic acid, forming a phenyl-palladium bond. Upon coor-
bromo-substituted enone, where the coupling product dination of the enone onto the palladium centre, the
was not observed. This suggests that palladium(0) was metal-bound phenyl group inserts into the carbon-
not being produced via the b-hydride elimination carbon double bond of the enone, forming 13. While
pathway, showing that the system remains catalytical- Hayashi found evidence for the existence of a oxa-p-
ly active through the reaction duration. It is notewor- allylrhodium species,[25] other researchers determined
thy that this system can be extended to aliphatic, acy- that there was a preference for palladium complexes
clic enones, albeit with a slightly diminished yield (en- to form in a C-bound fashion (13a) instead of an O-
tries 12 and 13).
bound manner (13c), although it is believed all three
Having screened a range of enones, a selection of exist in equilibrium.[28] However, the earlier men-
boronic acids was reacted with trans-chalcone in tioned DFT studies[26,27] have shown that while the
order to investigate the efficacy of the catalytic proto- alkene insertion reaction generates the C-bound eno-
Table 4. Substrate screening for the asymmetric conjugate 1,4-addition of various arylboronic acids on trans-chalcone.[a]
Entry
Enone
Ar
Product
Yield[b]
ee[c]
1
2
3
4
5
6
7
(1o)
(1o)
(1o)
(1o)
(1o)
(1o)
(1o)
2-naphthyl (2c)
4-F-C6H4 (2d)
4-Cl-C6H4 (2e)
4-Br-C6H4 (2f)
4-Me-C6H4 (2b)
4-MeO-C6H4 (2g)
4-CF3-C6H4 (2h)
N
97
92
56
88
89
83
47
77 (À)[d]
79 (+)
82 (À)[d]
56 (À)
69 (À)[d]
85 (À)[d]
80 (À)[d]
[a]
The reaction was carried out with 2-cyclohexen-1-one (0.1 mmol), phenylboronic acid (0.5 mmol), (S)-6 (2.5 mol%), PPh3
(5.0 mol%) and K3PO4 (0.05 mmol) in 1 mL of toluene at room temperature.
Isolated percentage yield.
[b]
[c]
[d]
The ee % was determined by chiral HPLC. (+/À) was determined by optical rotation and is shown in parentheses.
Chiral centre has R configuration.[9e]
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the addition product, regenerating catalytically active
11.[29] It has been mentioned by Wu and co-workers
that the ligand has a profound, but yet only partially
understood impact on the reactivity of the catalyst,
potentially explaining the vast difference in results be-
tween the different metallacycles previously screened.
Conclusions
Herein, we have reported a phosphapalladacycle-cata-
lysed asymmetric conjugate 1,4-addition onto enones,
utilising boronic acids as an aryl source. This protocol
has the advantages of tolerating a wide range of func-
tional groups, both on the enone and on the boronic
acid, yielding the addition products in high yields and
enantioselectivities. Furthermore, the reaction takes
place at room temperature without the need for oner-
ous additives within a short amount of time. In addi-
tion, key structural features of the catalyst that aid in
reaction progress were identified. We believe that this
protocol will be a useful addition in the field that has
so far been dominated by rhodium-based catalysts.
Research is currently being undertaken in our group
to extend this protocol to a wider range of a,b-unsatu-
rated compounds.
Experimental Section
All reactions with air- or moisture-sensitive manipulations
were carried out under positive pressure of nitrogen using
standard Schlenk techniques. All solvents were used as re-
ceived and where necessary, dried and distilled according to
literature methods.[30] Column chromatography was per-
formed on Silica Gel 60 (Merck). NMR spectra were re-
corded on Bruker AV300 spectrometer (300 MHz for 1H,
75 MHz for 13C, 282 MHz for 19F). Chemical shifts are re-
ported in d (ppm), referenced to an internal standard of
SiMe4 (d=0.00 ppm) for 1H NMR and chloroform-d (d=
77.00 ppm) for 13C NMR. Multiplicities are given as: s (sin-
glet), brs (broad singlet), d (doublet), dd (doublet of dou-
blets), t (triplet), q (quartet), m (multiplet). The number of
protons (n) for a given resonance are given by nH and cou-
pling constants are given as a J value in Hz. Optical rota-
tions were measured on the specific solution on a 0.1 dm
cell at 238C with a Jusco P-1030 polarimeter equipped with
a sodium vapour lamp at 589 nm. Enantiomeric excesses
(ees) were determined by chiral HPLC using an Agilent
1200 Series instrument or Shimatsu LC-20AD instrument
using Diacel Chiracel columns. HR-MS (ESI) were recorded
on a time-of-flight (TOF) machine. Commercially unavaila-
ble enones[31] and chiral palladacycles[18f,32] were prepared ac-
cording to literature methods. Other chemicals were used as
received from the supplier without any further purification.
Figure 2. Proposed catalytic cycle.
late (13a), the rate-determining transition state for
protonolysis to occur is the O-bound enolate. Evi-
dently, the stability of the O-bound enolate is essen-
tial for promoting protonolysis, yielding the addition
product and surpressing b-hydride elimination, giving
the substitution product. Furthermore, it is plausible
that the addition of triphenylphosphine in the system
limited the availability of a vacant site, hindering the
b-hydride elimination which would have generated
a Heck-type product. Following the alkene insertion,
Caution! Perchlorate salts of metal complexes are poten-
tially explosive compounds and should be handled with
protonolysis of the palladium-enolate bond yielded care.
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Evaluation of Palladacycles as a Non-Rhodium Based Alternative
(minor), 49.2 min (major); HR-MS (ESI): m/z=321.1060,
calcd. for C21H18ClO (M+ +H): 321.1046.
Typical Procedure for Phosphapalladacycle-Catalysed
Asymmetric Conjugate 1,4-Addition of Arylboronic
Acids on a,b-Unsaturated Ketones
(+)-3-(4-Bromophenyl)-1,3-diphenylpropan-1-one (3fa):
yield: 88%; white solid; 78% ee; 1H NMR (300 MHz,
3
3
To a reaction vessel was added enone (0.1 mmol), boronic
acid (0.5 mmol), K3PO4 (10.6 mg, 0.05 mmol), (S)-6 (2.4 mg,
0.0025 mmol) and PPh3 (1.3 mg, 0.0050 mmol) and dissolved
in toluene (1 mL). The reaction was stirred and monitored
by TLC. Upon reaction completion, the crude reaction mix-
ture was chromatographed over silica (hexanes/EtOAc),
yielding the analytically pure product.
CDCl3): d=3.71 (dd, JH,H =7.2 Hz, JH,H =0.9, 2H), 4.79 (t,
3JH,H =7.2 Hz, 1H), 7.12–7.58 (m, 13H), 7.90–7.91 (m, 2H);
13
C NMR (75 MHz, CDCl3): d=44.5, 45.3, 120.2, 126.6,
127.7 (2C), 128.0 (2C), 128.6 (2C), 128.7 (2C), 129.6 (2C),
131.6 (2C), 133.2, 136.9, 143.1, 143.6, 197.6; HPLC (Diacel
Chiralcel AD-H, n-hexane:2-propanol=98:2, 0.5 mLminÀ1,
240 nm): retention time=43.1 min (minor), 53.5 min
(major); HR-MS (ESI): m/z=365.0554, calcd. for
C21H18BrO (M+ +H): 365.0541.
(+)-3-Phenylcyclohexanone (3aa): yield: 89%; colourless
1
oil; 92% ee; H NMR (300 MHz, CDCl3): d=1.82–1.93 (m,
2H), 2.11–2.18 (m, 2H), 2.32–2.64 (m, 4H), 2.96–3.05 (m,
1H), 7.21–7.36 (m, 5H); 13C NMR (75 MHz, CDCl3): d=
25.5, 32.8, 41.2, 44.7, 48.9, 126.6 (2C), 126.7, 128.7 (2C),
144.3, 211.0: HPLC (Diacel Chiralcel AD-H, n-hexane:2-
propanol=98:2, 1.0 mLminÀ1, 270 nm): retention time=10.2
(minor), 12.0 (major); HR-MS (ESI): m/z=175.1110, calcd.
for C12H15O (M+ +H): 175.1123.
(À)-3-Phenylcyclopentanone (3ba): yield: 64%; colourless
oil; 50% ee; 1H NMR (300 MHz, CDCl3): =1.96–2.07 (m,
1H), 2.24–2.51 (m, 4H), 2.63–2.71 (m, 1H), 3.37–3.49 (m,
1H), 7.22–7.37 (m, 5H); 13C NMR (75 MHz, CDCl3): d=
31.2, 38.8, 42.2, 45.8, 126.70 (2C), 126.71, 128.6 (2C), 143.0,
218.3; HPLC (Diacel Chiralcel OB-H, n-hexane:2-propa-
nol=98:2, 0.8 mLminÀ1, 230 nm): retention time=55.3
(major), 64.6 (minor); HR-MS (ESI): m/z=161.0973, calcd.
for C11H13O (M+ +H): 161.0966.
(+)-3-(4-Methoxyphenyl)-1,3-diphenylpropan-1-one (3ga):
yield: 95%; white solid; 81% ee; 1H NMR (300 MHz,
3
CDCl3): d=3.71 (d, JH,H =7.4 Hz, 2H), 3.87 (s, 3H), 4.79 (t,
3JH,H =7.5 Hz, 1H), 6.80–6.83 (m, 2H), 7.14–7.20 (m, 3H),
7.27–7.31 (m, 4H), 7.41–7.47 (m, 2H), 7.50–7.60 (m, 1H),
7.92–7.95 (m, 2H); 13C NMR (75 MHz, CDCl3): d=44.9,
45.2, 55.2, 113.9 (2C), 126.3, 127.3 (2C), 128.1 (2C), 128.5
(2C), 128.6 (2C), 128.8 (2C), 133.0, 136.3, 137.1, 144.5,
158.1, 198.2; HPLC (Diacel Chiralcel AD-H, n-hexane:2-
propanol=98:2, 0.5 mLminÀ1,270 nm): retention time=66.4
min (minor), 71.0 min (major); HR-MS (ESI): m/z=
317.1540, calcd. for C22H21O2 (M+ +H): 317.1542.
(+)-1,3-Diphenyl-3-(para-tolyl)propan-1-one (3ha): yield:
1
97%; white solid; 81% ee; H NMR (300 MHz, CDCl3): d=
3
2.30 (s, 3H), 3.74 (d, 3JH,H =7.2 Hz, 2H), 4.82 (t, JH,H
=
7.2 Hz, 1H), 7.08–7.11 (m, 2H), 7.15–7.22 (m, 3H), 7.25–
7.63 (m, 8H), 7.94–7.96 (m, 2H); 13C NMR (75 MHz,
CDCl3): d=20.9, 44.8, 45.6, 126.3, 127.7 (2C), 127.8 (2C),
128.0 (2C), 128.5 (2C), 129.3 (2C), 133.0, 135.9, 137.1, 141.1,
144.4, 198.1; HPLC (Diacel Chiralcel AD-H, n-hexane:2-
propanol=98:2, 0.5 mLminÀ1, 270 nm): retention time=32.0
min (minor), 39.3 min (major); HR-MS (ESI): m/z=
301.1587, calcd. for C22H21O (M+ +H): 301.1592.
(+)-3-Phenylcycloheptanone (3ca): yield: 72%; colourless
1
oil; 87% ee; H NMR (300 MHz, CDCl3): d=1.44–1.51 (m,
1H), 1.64–1.81 (m, 2H), 1.95–2.11 (m, 3H), 2.57–2.67 (m,
3H), 2.85–2.98 (m, 2H), 7.16–7.33 (m, 5H); 13C NMR
(75 MHz, CDCl3): d=24.2, 29.2, 39.2, 42.7, 43.9, 51.2, 126.3,
126.4 (2C), 128.6 (2C), 146.9, 213.4; HPLC (Diacel Chiral-
cel AD-H, n-hexane:2-propanol=98:2, 0.5 mLminÀ1,
254 nm): retention time=19.1 (minor), 21.5 (major); HR-
MS (ESI): m/z=189.1273, calcd. for C17H17O (M+ +H):
189.1279.
(+)-1,3-Diphenyl-3-[4-(trifluoromethyl)phenyl]propan-1-
one (3ia): yield: 92%; white solid; 69% ee; 1H NMR
3
(300 MHz, CDCl3): d=3.75 (dd, 3JH,H =7.3 Hz, JH,H
=
3
(À)-3-(4-Fluorophenyl)-1,3-diphenylpropan-1-one (3da):
2.1 Hz, 2H), 4.89 (t, JH,H =7.2 Hz, 1H), 7.17–7.58 (m, 12H),
yield: 88%; white solid; 81% ee; 1H NMR (300 MHz,
7.92–7.95 (m, 2H); 13C NMR (75 MHz, CDCl3): d=44.4,
3
CDCl3): d=3.71 (d, 3JH,H =7.2 Hz, 2H), 4.81 (t, JH,H
=
1
3
45.7, 124.2 (q, JC,F =270.0 Hz), 125.5 (q, JC,F =3.8 Hz, 2C),
2
7.2 Hz, 1H), 6.90–6.98 (m, 2H), 7.15–7.30 (m, 7H), 7.40–
126.8, 127.8 (2C), 128.0 (2C), 128.2 (2C), 128.66 (q, JC,F
=
3
7.57 (m, 3H), 7.91 (d, JH,H =1.5, 2H); 13C NMR (75 MHz,
31.5 Hz), 128.67 (2C), 128.8 (2C), 133.3, 136.8, 143.3, 148.2,
197.4; 19F{1H} NMR (282 MHz, CDCl3): d=À62.4; HPLC
(Diacel Chiralcel AD-H, n-hexane:2-propanol=98:2,
0.5 mLminÀ1, 240 nm): retention time=30.3 min (minor),
34.4 min (major); HR-MS (ESI): m/z=355.1318, calcd. for
C22H18F3O (M+ +H): 355.1310.
2
CDCl3): d=44.8, 45.2, 115.3 (d, JC,F =21.0 Hz, 2C), 126.5,
3
127.7 (2C), 128.0 (2C), 128.6 (3C), 129.27 (d, JC,F =8.3 Hz,
2C), 133.1 (2C), 137.0, 139.3 (d, 4JC,F =3.8 Hz), 161.4 (d,
1JC,F =243.0 Hz), 197.8; 19F{1H} NMR (282 MHz, CDCl3):
d=À116.8; HPLC (Diacel Chiralcel AD-H, n-hexane:2-
propanol=98:2, 0.5 mLminÀ1, 280 nm, retention time: 38.9
min (minor), 42.1 min (major); HR-MS (ESI): m/z=
305.1335, calcd. for C21H18FO (M+ +H): 305.1342.
(+)-3-(Naphthalen-2-yl)-1,3-diphenylpropan-1-one (3ja):
yield: 88%; yellow solid; 85% ee; 1H NMR (300 MHz,
3
3
CDCl3): d=3.86 (dd, JH,H =7.5 Hz, JH,H =2.7 Hz, 2H), 5.02
(t, 3JH,H =7.2 Hz, 1H), 7.17–7.58 (m, 11H), 7.74–7.79 (m,
4H), 7.93–7.96 (m, 2H); 13C NMR (75 MHz, CDCl3): d=
44.6, 46.0, 125.5, 125.8, 126.0, 126.4, 126.7, 127.6, 127.8, 128.0
(2C), 128.1 (2C), 128.3, 128.58 (2C), 128.59 (2C), 132.2,
133.1, 133.5, 137.1, 141.5, 144.0, 198.0; HPLC (Diacel Chiral-
cel AD-H, n-hexane:2-propanol=98:2, 0.5 mLminÀ1,
270 nm): retention time=58.7 min (minor), 62.8 min
(major); HR-MS (ESI): m/z=337.1583, calcd. for C25H21O
(M+ +H): 337.1592.
(+)-3-(4-Chlorophenyl)-1,3-diphenylpropan-1-one (3ea):
yield: 92%; white solid; 78% ee; H NMR (300 MHz,
3
3
CDCl3): d=3.70 (dd, JH,H =7.3 Hz, JH,H =0.9, 2H), 4.78 (t,
3JH,H =7.3 Hz, 1H), 7.16–7.30 (m, 9H), 7.41–7.46 (m, 2H),
7.52–7.58 (m, 1H), 7.91–7.94 (m, 2H); C NMR (75 MHz,
13
CDCl3): d=44.6, 45.3, 126.6, 127.7 (2C), 128.0 (2C), 128.6–
128.7 (6C), 129.2 (2C), 132.1, 133.2, 136.9, 142.6, 143.7,
197.7; HPLC (Diacel Chiralcel AD-H, n-hexane:2-propa-
nol=98:2, 0.5 mLminÀ1, 280 nm): retention time=40.2 min
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3397

FULL PAPERS
Jonathan Wong et al.
(+)-3-([1,1’-Biphenyl]-4-yl)-1,3-diphenylpropan-1-one
2C), 133.1 (2C), 137.0, 139.3 (d, 4JC,F =3.8 Hz), 161.4 (d,
C,F =243.0 Hz), 197.8; 19F{1H} NMR (282 MHz, CDCl3): d=
À116.8; HPLC (Diacel Chiralcel AD-H, n-hexane:2-propa-
nol=98:2, 0.5 mLminÀ1, 280 nm): retention time=38.3 min
(major), 40.5 min (minor): HR-MS (ESI): m/z=305.1345,
calcd. for C21H18FO (M+ +H): 305.1342.
(3ka): yield: 85%; yellow solid; 79% ee; 1H NMR
J
3
(300 MHz, CDCl3): d=3.77 (dd, 3JH,H =7.4 Hz, JH,H
=
0.9 Hz, 2H), 4.87 (t, 3JH,H = =7.5 Hz, 1H), 7.16–7.57 (m,
17H), 7.93–7.96 (m, 2H); 13C NMR (75 MHz, CDCl3): d=
44.7, 45.6, 126.4, 127.0 (2C), 127.1, 127.3 (2C), 127.8 (2C),
128.1 (2C), 128.2 (2C), 128.6 (3C), 128.7 (2C), 133.1, 137.0,
139.3, 140.8, 143.2, 144.1, 197.9; HPLC (Diacel Chiralcel
AD-H, n-hexane:2-propanol=98:2, 0.5 mLminÀ1, 230 nm):
retention time=57.3 min (minor), 68.6 min (major); HR-
MS (ESI): m/z=363.1785, calcd. for C27H23O (M+ +H):
363.1749.
(À)-3-(4-Chlorophenyl)-1,3-diphenylpropan-1-one (3oe):
yield: 56%; white solid; 82% ee; 1H NMR (300 MHz,
3
3
CDCl3): d=3.70 (dd, JH,H =7.3 Hz, JH,H =0.9, 2H), 4.78 (t,
3JH,H =7.3 Hz, 1H), 7.16–7.30 (m, 9H), 7.41–7.46 (m, 2H),
7.52–7.58 (m, 1H), 7.91–7.94 (m, 2H); 13C NMR (75 MHz,
CDCl3): d=44.6, 45.3, 126.6, 127.7 (2C), 128.0 (2C), 128.6–
128.7 (6C), 129.2 (2C), 132.1, 133.2, 136.9, 142.6, 143.7,
197.7; HPLC (Diacel Chiralcel AD-H, n-hexane:2-propa-
nol=98:2, 0.5 mLminÀ1, 280 nm): retention time=37.7 min
(major), 45.4 min (minor); HR-MS (ESI): m/z=321.1032,
calcd. for C21H18ClO (M+ +H): 321.1046.
(+)-3-(Benzo[d]ACHTUNGTRENNUNG[1,3]dioxol-5-yl)-1,3-diphenylpropan-1-
one (3la): yield: 95%; yellow oil; 81% ee; 1H NMR
3
(300 MHz, CDCl3): d=3.77 (d, JH,H =7.2 Hz, 2H), 4.74 (t,
3JH,H =6.9 Hz, 1H), 5.87 (s, 2H), 6.68–6.75 (m, 3H), 7.15–
7.19 (m, 1H), 7.23–7.29 (m, 4H), 7.41–7.45 (m, 2H), 7.51–
7.57 (m, 1H), 7.91–7.94 (m, 2H); 13C NMR (75 MHz,
CDCl3): d=44.8, 45.6, 100.9, 108.2, 108.4, 120.7, 127.4, 127.6
(2C), 128.0 (2C), 128.56 (2C), 128.58 (2C), 133.1, 138.1,
133.2, 146.0, 147.7, 198.0; HPLC (Diacel Chiralcel AD-H, n-
hexane:2-propanol=98:2, 0.5 mLminÀ1, 230 nm): retention
time=77.7 min (minor), 83.8 min (major); HR-MS (ESI):
m/z=311.1337, calcd. for C22H19O3 (M+ +H): 331.1334.
(À)-4-Phenyl-4-(para-tolyl)butan-2-one (3mb): yield:
(À)-3-(4-Bromophenyl)-1,3-diphenylpropan-1-one (3of):
yield: 88%; white solid; 56% ee; 1H NMR (300 MHz,
3
3
CDCl3): d=3.71 (dd, JH,H =7.2 Hz, JH,H =0.9, 2H), 4.79 (t,
3JH,H = =7.2 Hz, 1H), 7.12–7.58 (m, 13H), 7.90–7.91 (m,
2H); 13C NMR (75 MHz, CDCl3): d=44.5, 45.3, 120.2, 126.6,
127.7 (2C), 128.0 (2C), 128.6 (2C), 128.7 (2C), 129.6 (2C),
131.6 (2C), 133.2, 136.9, 143.1, 143.6, 197.6; HPLC (Diacel
Chiralcel AD-H, n-hexane:2-propanol=98:2, 0.5 mLminÀ1,
254 nm): retention time=41.6 min (major), 51.6 min
(minor); HR-MS (ESI): m/z= calcd. for C21H18BrO (M+ +
H): 365.0541.
1
63%; colourless oil; 87% ; H NMR (300 MHz, CDCl3): d=
3
2.07 (s, 3H), 2.28 (s, 3H), 3.16 (d, JH,H =7.5 Hz, 2H), 4.54
(t, 3JH,H =7.5 Hz, 1H), 7.06–7.29 (m, 9H); 13C NMR
(75 MHz, CDCl3): d=20.9, 30.6, 45.7, 49.8, 126.4, 127.5
(2C), 127.6 (2C), 128.6 (2C), 129.3 (2C), 136.0, 140.8, 144.1,
207.0; HPLC (Diacel Chiralcel AD-H, n-hexane:2-propa-
nol=98:2, 0.5 mLminÀ1, 270 nm): retention time=16.2 min
(major), 18.0 min (minor); HR-MS (ESI): m/z=239.1442;
calcd. for C17H19O (M+ +H): 239.1436.
(À)-1,3-Diphenyl-3-(para-tolyl)propan-1-one (3ob): yield:
1
89%; white solid; 69% ee; H NMR (300 MHz, CDCl3): d=
3
2.30 (s, 3H), 3.74 (d, 3JH,H =7.2 Hz, 2H), 4.82 (t, JH,H
=
7.2 Hz, 1H), 7.08–7.11 (m, 2H), 7.15–7.22 (m, 3H), 7.25–
13
7.63 (m, 8H), 7.94–7.96 (m, 2H);
C NMR (75 MHz,
CDCl3): d=20.9, 44.8, 45.6, 126.3, 127.7 (2C), 127.8 (2C),
128.0 (2C), 128.5 (2C), 129.3 (2C), 133.0, 135.9, 137.1, 141.1,
144.4, 198.1; HPLC (Diacel Chiralcel AD-H, n-hexane:2-
propanol=98:2, 0.5 mLminÀ1, 254 nm): retention time=30.3
min (major), 39.3 min (minor); HR-MS (ESI): m/z=
301.1593, calcd. for C22H21O (M+ +H): 301.1592.
(À)-4-Phenylpentan-2-one (3na): yield: 66%; yellow oil;
3
93% ee; 1H NMR (300 MHz, CDCl3): d=1.27 (d, JH,H
=
7.2 Hz, 3H), 2.06 (s, 3H), 2.71 (m, 2H), 3.30 (m, 1H), 7.16–
7.32 (m, 5H); 13C NMR (75 MHz, CDCl3): d=22.0, 30.5,
35.5, 126.3, 127.8 (2C), 128.5 (2C), 146.2, 207.8; HPLC
(Diacel Chiralcel AS-H, n-hexane:2-propanol=98:2,
0.5 mLminÀ1, 200 nm): retention time=13.3 min (minor),
14.5 min (major); HR-MS (ESI): m/z=163.1121, calcd. for
C11H15O (M+ +H): 163.1123.
(À)-3-(4-Methoxyphenyl)-1,3-diphenylpropan-1-one (3og):
yield: 83%; white solid; 85% ee; 1H NMR (300 MHz,
3
CDCl3): d=3.71 (d, JH,H =7.4 Hz, 2H), 3.87 (s, 3H), 4.79 (t,
3JH,H =7.5 Hz, 1H), 6.80–6.83 (m, 2H), 7.14–7.20 (m, 3H),
7.27–7.31 (m, 4H), 7.41–7.47 (m, 2H), 7.50–7.60 (m, 1H),
7.92–7.95 (m, 2H); 13C NMR (75 MHz, CDCl3): d=44.9,
45.2, 55.2, 113.9 (2C), 126.3, 127.3 (2C), 128.1 (2C), 128.5
(2C), 128.6 (2C), 128.8 (2C), 133.0, 136.3, 137.1, 144.5,
158.1, 198.2: HPLC (Diacel Chiralcel AD-H, n-hexane:2-
propanol=98:2, 0.5 mLminÀ1, 270 nm): retention time=68.4
min (major), 71.6 min (minor); HR-MS (ESI): m/z=
317.1546, calcd. for C22H21O2 (M+ +H): 317.1542.
(À)-3-(Naphthalen-2-yl)-1,3-diphenylpropan-1-one (3oc):
yield: 97%; yellow solid; 77% ee; 1H NMR (300 MHz,
3
3
CDCl3): d=3.86 (dd, JH,H =7.5 Hz, JH,H =2.7 Hz, 2H), 5.02
(t, 3JH,H =7.2 Hz, 1H), 7.17–7.58 (m, 11H), 7.74–7.79 (m,
4H), 7.93–7.96 (m, 2H); 13C NMR (75 MHz, CDCl3): d=
44.6, 46.0, 125.5, 125.8, 126.0, 126.4, 126.7, 127.6, 127.8, 128.0
(2C), 128.1 (2C), 128.3, 128.58 (2C), 128.59 (2C), 132.2,
133.1, 133.5, 137.1, 141.5, 144.0, 198.0; HPLC (Diacel Chiral-
cel AD-H, n-hexane:2-propanol=98:2, 0.5 mLminÀ1,
210 nm): retention time=58.8 min (major), 63.0 min
(minor); HR-MS (ESI): m/z=337.1586, calcd. for C25H21O
(M+ +H): 337.1592.
(À)-1,3-Diphenyl-3-(4-(trifluoromethyl)phenyl)propan-1-
one (3oh): yield: 47%; white solid; 93% ee; 1H NMR
3
(300 MHz, CDCl3): d=3.75 (dd, 3JH,H =7.3 Hz, JH,H
=
2.1 Hz, 2H), 4.89 (t, 3JH,H = =7.2 Hz, 1H), 7.17–7.58 (m,
(+)-3-(4-Fluorophenyl)-1,3-diphenylpropan-1-one (3od):
12H), 7.92–7.95 (m, 2H); 13C NMR (75 MHz, CDCl3): d=
yield: 92%; white solid; 79% ee; 1H NMR (300 MHz,
44.4, 45.7, 124.2 (q, JC,F =270.0 Hz), 125.5 (q, JC,F =3.8 Hz,
2C), 126.8, 127.8 (2C), 128.0 (2C), 128.2 (2C), 128.66 (q,
2JC,F =31.5 Hz), 128.67 (2C), 128.8 (2C), 133.3, 136.8, 143.3,
148.2, 197.4; 19F{1H} NMR (282 MHz, CDCl3): d=À62.4;
HPLC (Diacel Chiralcel IC, n-hexane:2-propanol=98:2,
0.5 mLminÀ1, 254 nm): retention time=12.9 min (major),
1
3
3
CDCl3): d=3.71 (d, 3JH,H =7.2 Hz, 2H), 4.81 (t, JH,H
=
7.2 Hz, 1H), 6.90–6.98 (m, 2H), 7.15–7.30 (m, 7H), 7.40–
3
7.57 (m, 3H), 7.91 (d, JH,H =1.5, 2H); 13C NMR (75 MHz,
2
CDCl3): d=44.8, 45.2, 115.3 (d, JC,F =21.0 Hz, 2C), 126.5,
3
127.7 (2C), 128.0 (2C), 128.6 (3C), 129.27 (d, JC,F =8.3 Hz,
3398
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Adv. Synth. Catal. 2014, 356, 3391 – 3400

FULL PAPERS
Evaluation of Palladacycles as a Non-Rhodium Based Alternative
13.6 min (minor); HR-MS (ESI): m/z=355.1340, calcd. for
C22H18F3O (M+ +H): 355.1310.
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Acknowledgements
We are grateful to Nanyang Technological University (RG
12/12) for its support of this research.
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