Diene-ligated iridium complexes as catalysts for allylation and methallylation reactions of ketones

Article abstract of DOI:10.1055/s-0030-1258196

An iridium-catalyzed allylation reactions of ketones using dienes as ligands has been developed. A variety of ketones underwent allylation and methallylation reactions at room temperature in good yields under these conditions. Competition experiments demonstrate that the reaction is selective for electron-deficient ketones. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258196

SPECIAL TOPIC
3259
Diene-Ligated Iridium Complexes as Catalysts for Allylation and
Methallylation Reactions of Ketones
I
ridium-Catalyz
i
ed
A
lly
m
lation Reactions of
o
K
etones thy J. Barker, Elizabeth R. Jarvo*
Department of Chemistry, University of California, Irvine 92697-2025, USA
Fax +1(949)8249920; E-mail: erjarvo@uci.edu
Received 30 June 2010
inconsistent with direct addition of the allylic boronic es-
ter to the ketone.4 We therefore hypothesized that a nu-
cleophilic allyliridium intermediate is formed in situ and
subsequently reacts with the ketone.
Abstract: An iridium-catalyzed allylation reactions of ketones us-
ing dienes as ligands has been developed. A variety of ketones un-
derwent allylation and methallylation reactions at room temperature
in good yields under these conditions. Competition experiments
demonstrate that the reaction is selective for electron-deficient ke-
tones.
We next sought to define a role for boric acid and the bo-
rate byproducts that are present in the reaction. In our ini-
tial studies we found that boric acid is a critical additive
Key words: iridium, allylation, diene ligands, boric acid
Dienes have been shown to be effective ligands in catalyt-
ic organometallic reactions.1 The recent development of
dienes and phosphino-olefins as ligands in transition met-
al catalysis has caused them to be seen as viable alterna-
tives to phosphines.2 In this communication we describe
an iridium-catalyzed allylation and methallylation reac-
tion of ketones with dienes as ligands. Mechanistic exper-
iments are consistent with an open transition state for the
allyl transfer event, involving participation of both a nu-
cleophilic allyliridium complex and borate Lewis acid.
OMe
O
Bn
P
N
O
1
DOLEFIN
MeO
During the course of our investigation on the iridium-cat-
alyzed allylation reaction of ketones, we screened a num-
ber of phosphines and dienes in an effort to form a
nucleophilic iridium species (Table 1).3–5 While there was
no reaction with no exogenous ligand added to the
[Ir(coe)2Cl]2 source (entry 1), addition of a number of bis-
phosphines and dienes provided the homoallylic alcohol
4a in moderate to good yield.6 Of the bisphosphine
ligands examined, (R,R)-Me-DUPHOS gave the highest
yield (entry 5). A phosphino-olefin ligand 1 (Figure 1) re-
ported by Carreira and co-workers gave modest reactivity
(entry 6).7 Recently reported diene ligands gave a large
range of reactivity. In the reactions with commercially
available DOLEFIN and norbornadiene, isomerization of
allylboronic ester to the 1-propenylboronic ester was the
major side reaction pathway observed, resulting in low
yields of homoallylic alcohol 4a (entries 7 and 8).8 Cy-
clooctadiene and diene 2 (Figure 1) provided the highest
yields of the desired product (entries 9 and 10).2b
Ph
2
Figure 1 Diene and phosphino-olefin ligands
Table 1 Ligand Screen for Iridium Allylation of Acetophenone (3a)
[Ir(cod)2Cl]2 (2 mol%)
ligand (5 mol%)
t-BuOK (20 mol%)
O
OH
B(pin)
1.5 equiv
Ph
+
THF, 24 h, r.t.
3a
4a
Entry
Ligand
Yielda (%)
1
2
none
<5
44
0
(R)-BINAP
3
(R,R,S,S)-TANGPHOS
(R)-(MeO)-BIPHEP
(R,R)-Me-DUPHOS
1
4
44
68
25
0
5
We sought to investigate the mechanism of the transfor-
mation and determine the key participants in the transition
state for the C–C bond-forming event. We previously re-
ported deuterium labeling studies that support the pres-
ence of a rapidly isomerizing allyliridium species and are
6
7
DOLEFIN
8
norbornadiene
cyclooctadiene
2
15
78
82
9
SYNTHESIS 2010, No. 19, pp 3259–3262
x
x.
x
x
.
2
0
1
0
10
Advanced online publication: 04.08.2010
DOI: 10.1055/s-0030-1258196; Art ID: C04110SS
© Georg Thieme Verlag Stuttgart · New York
a Isolated yield after silica gel chromatography.

3260
T. J. Barker, E. R. Jarvo
SPECIAL TOPIC
for the reaction, since in the absence of boric acid a slower
reaction was observed (Scheme 1). There are several po-
tential roles for boric acid in the reaction.9,10 One potential
role for boric acid would be to serve as a Lewis or
Brønsted acid to activate the ketone.11 In the absence of
boric acid, boronate byproducts could serve as an alterna-
tive Lewis acid. Chiral boronate 5 was synthesized12 as a
mechanistic probe to determine whether or not the borate
byproducts participate in the transition state for the C–C
bond-forming event (Scheme 2). When boronate 5 was
subjected to the reaction conditions, a modest enantiomer-
ic excess was observed in the iridium-catalyzed reaction.
Significantly, the enantiomeric excess was higher in the
iridium-catalyzed reaction than the background reaction
in the absence of iridium complex. These results are con-
sistent with a transition state for the C–C bond-forming
event that involves both borate ester and iridium complex.
Based on all of our mechanistic data, we propose an open
transition state with the boric acid or borate ester acting as
a Lewis acid and an allyliridium species acting as the nu-
cleophile. The insensitivity of this transformation to
asymmetric induction from ligands on the iridium could
also indirectly support an open transition state.
Table 2 Substrate Scope of Iridium-Catalyzed Reaction
R2
R2
OH
[Ir(cod)Cl]2 (2 mol%)
t-BuOK (40 mol%)
O
B(pin)
+
R1
R1
B(OH)3 (20 mol%)
THF, 22 °C, 3 h
3
(1.5 equiv)
4
Entry
R1
Ph
R2
H
Product
Yielda (%)
1
4a
4b
4c
4d
4e
4f
78
83
70
51
77
87
78
63
2
4-BrC6H4
4-MeOC6H4
3-pyridyl
2-thienyl
Ph
H
3
H
4
H
5
H
6b
7
Me
Me
Me
4-BrC6H4
4-MeOC6H4
4g
4h
8b
a Isolated yield after silica gel chromatography.
b Reaction time was 6 h.
good yields of the substituted homoallylic alcohols (en-
tries 6–8).
OH
O
[Ir(cod)Cl]2 (2 mol%)
B(OH)3 (20 mol%)
A competition experiment was performed to determine
whether or not the reaction could exhibit selectivity for
electronically differentiated ketones (Scheme 3).13 Under
standard reaction conditions, p-bromoacetophenone (3g)
reacted preferentially over p-methoxyacetophenone (3h)
giving yields of the homoallylic alcohols 4g and 4h of
73% and 5%, respectively. Analysis of the reaction mix-
ture by gas chromatography also confirmed the presence
of unreacted p-bromoacetophenone (3g) (15%) and p-
methoxyacetophenone (3h) (83%). It can be concluded
that electron-rich ketones react more slowly in this iridi-
um-catalyzed allylation reaction.
B(pin)
+
t-BuOK (40 mol%)
THF, 22 °C, 6 h
1.5 equiv
6 h: 73% yield
OH
O
[Ir(cod)Cl]2 (2 mol%)
no B(OH)3
B(pin)
+
t-BuOK (20 mol%)
THF, 22 °C
1.5 equiv
6 h: 28% yield
24 h: 78% yield
Scheme 1 Effect of boric acid on iridium allylation
O
OH
O
OH
Ph
[Ir(cod)Cl]2 (2 mol%)
t-BuOK (40 mol%)
4g
Br
Br
3g
+
[Ir(cod)Cl]2 (2 mol%)
B(OH)3 (20 mol%)
73% yield
Ph
THF, r.t., 48 h
1 equiv
+
15% recovered 3g
CO2i-Pr
allylB(pin) (1.4 equiv)
t-BuOK (40 mol%)
THF, 6 h
with Ir: 90% yield, 20% ee
without Ir: 25% yield, 8% ee
+
O
O
B
OH
CO2i-Pr
O
3h
MeO
5 (1.5 equiv)
4h
MeO
1 equiv
Scheme 2 Reaction with chiral allylboronate
5% yield
83% recovered 3h
Using our optimized conditions, allylations of a variety of
ketones 3 were performed, giving good yields of the ho-
moallylic alcohol products 4 (Table 2). Electron-with-
drawing (entry 2) as well as electron-donating (entry 3)
substituents are tolerated with all reactions complete with-
in three hours. Heteroaromatic ketones are also competent
substrates (entries 4 and 5). Substitution on the allylic bo-
ronic ester was also tolerated. Methallylation provided
Scheme 3 Competition experiment
In summary, we have demonstrated that a diene-ligated
iridium complex allylates ketones in the presence of boric
acid in good yields. Ligands have been shown to have a
strong impact on the reactivity of iridium complexes.
Mechanistic studies support boric acid acting as a mild
Lewis acid that coordinates to the ketone, facilitating an
Synthesis 2010, No. 19, 3259–3262 © Thieme Stuttgart · New York

SPECIAL TOPIC
Iridium-Catalyzed Allylation Reactions of Ketones
3261
tion by chromatography (silica gel, pentane–Et2O, 90:10) afforded
4a (63 mg, 78%) as a colorless oil. Compounds 4c,f,g were purified
using AgNO3-impregnated silica gel.16 Characterization data for
compounds 4a–c,17 4d,e,4 and 4f18 have been previously reported.
allyl transfer from a nucleophilic allyliridium species.
Competition experiments performed showed the reaction
was selective for electron-poor ketones.
2-(4-Bromophenyl)-4-methylpent-4-en-2-ol (4g)
All reactions were carried out in a glovebox under an atmosphere of
N2. All glassware was flame-dried prior to use. THF was degassed
with argon and then passed through two 4 × 92 cm columns of an-
hyd neutral A-2 alumina (8 × 14 mesh; LaRoche Chemicals; acti-
vated under a flow of argon at 350 °C for 12 h) to remove H2O. 1H
IR (thin film): 3467, 3074, 2978, 1487 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.44 (d, J = 8.4 Hz, 2 H), 7.33 (s,
J = 8.4 Hz, 2 H), 4.90 (s, 1 H), 4.74 (s, 1 H), 2.60 (d, J = 13.4 Hz, 1
H), 2.49 (d, J = 13.4 Hz, 1 H), 2.38 (s, 1 H) 1.54 (s, 3 H), 1.43 (s, 3
H).
1
NMR spectra were recorded on CRYO-500 (500 MHz H, 125.7
MHz 13C) or DRX-400 (400 MHz 1H, 100 MHz 13C) spectrometers.
IR spectra were obtained on a Mattson Instruments Galaxy 5000
spectrophotometer. Analytical TLC was performed using silica gel
60 F254 precoated plates (0.25 mm thickness); visualization: irradi-
ation with a UV lamp and/or staining with p-anisaldehyde soln.
Flash chromatography was performed using silica gel 60A (170–
400 mesh) from Fisher Scientific. Enantiomeric excess of the ho-
moallylic alcohol was determined on a Berger Analytical SFC in-
strument using a Daicel Chiralpak AD-H column (3% MeOH, 7.6
bar, 2.5 mL/min). GC analysis was performed on a Agilent Tech-
nologies 6850 instrument using dodecane as an internal standard.
Allylboronic acid pinacol ester was supplied by Frontier Scientific,
Inc. and was distilled through a 15-cm Vigreux fractionating col-
umn connected to a short-path distillation head (95 °C/23 mbar) to
remove B(OH)3. (R)-BINAP, (R,R,S,S)-TANGPHOS, (R,R)-Me-
DUPHOS, and [Ir(cod)Cl]2 were purchased from Strem, stored in
the glovebox, and used as received. Phosphino-olefin 1 and diene 2
were synthesized according to known procedures.2b,7 DOLEFIN
was purchased from Aldrich. [Ir(coe)2Cl]2 was synthesized accord-
ing to a known procedure.14 Methallylboronic acid pinacol ester was
synthesized according to a known procedure.15 t-BuOK was pur-
chased from Alfa Aesar, stored in a glovebox and used as received.
Chiral allylboronate 5 was synthesized according to a known proce-
dure.12 All ketones were purchased commercially and liquids were
distilled prior to use. HRMS was performed by the University of
California, Irvine Mass Spectrometry Center.
13C NMR (125 MHz, CDCl3): d = 147.3, 142.4, 131.3, 127.0, 120.6,
116.3, 73.2, 52.1, 31.0, 24.5.
HRMS (TOF MS APCI+): m/z [M + NH4]+ calcd for C12H19BrNO:
272.0650; found: 272.0648.
2-(4-Methoxyphenyl)-4-methylpent-4-en-2-ol (4h)
IR (thin film): 3474, 3072, 2974, 1512, 1248 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37 (dd, J = 6.7, 2.1 Hz, 2 H),
6.87 (dd, J = 6.7, 2.1 Hz, 2 H), 4.90 (s, 1 H), 4.75 (s, 1 H), 3.81 (s,
3 H), 2.62 (d, J = 13.3 Hz, 1 H), 2.51 (d, J = 13.3 Hz, 1 H) 2.33 (s,
1 H), 1.56 (s, 3 H), 1.43 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 158.4, 142.9, 140.4, 126.1, 115.8,
113.5, 73.2, 55.4, 52.3, 30.9, 24.5.
HRMS (TOF MS APCI+): m/z [M + NH4]+ calcd for C13H22NO2:
224.1651; found: 224.1652.
Acknowledgement
This work was supported by the University of California, Irvine
Academic Senate Council on Research, Computing, and Library
Resources. We thank Frontier Scientific for a gift of allylboronic
ester.
References
2-Phenylpent-4-en-2-ol (4a); Typical Procedure for Allylation
Reactions with [Ir(coe)2Cl]2 (Table 1)
(1) For reviews, see: (a) Johnson, J. B.; Rovis, T. Angew. Chem.
Int. Ed. 2008, 47, 840. (b) Defieber, C.; Grützmacher, H.;
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Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc.
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(3) For reviews on allylation reactions, see: (a) Yamamoto, Y.;
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(4) Barker, T. J.; Jarvo, E. R. Org. Lett. 2009, 11, 1047.
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In a flame-dried 5-mL round-bottom flask in a glovebox,
[Ir(coe)2Cl]2 (9 mg, 0.010 mmol, 0.02 equiv) and cyclooctadiene (3
mg, 0.025 mmol, 0.05 equiv) were stirred in THF (1 mL) for 3 h.
After 3 h, t-BuOK (11 mg, 0.10 mmol, 0.2 equiv), acetophenone
(3a, 58 mL, 0.50 mmol, 1 equiv), allylboronic acid pinacol ester
(140 mL, 0.75 mmol, 1.5 equiv), and 1,4-bis(trifluoromethyl)ben-
zene (79 mL, 0.50 mmol, 1 equiv) (as an internal standard) were add-
ed. The mixture was capped with a septa and stirred in the glovebox
at r.t. for 24 h. The reaction was removed from the glovebox and
quenched with sat. NH4Cl soln (1 mL) and stirred for 10 min. The
aqueous layer was extracted with Et2O (3 × 5 mL) and the combined
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo. Purification by chromatography (silica gel, pentane–Et2O,
90:10) afforded 4a (63 mg, 78%) as a colorless oil.
2-Phenylpent-4-en-2-ol (4a); Typical Procedure for Allylation
Reactions with [Ir(cod)Cl]2 (Table 2)
To a flame-dried 5-mL round-bottom flask in a glovebox was added
[Ir(cod)Cl]2 (7 mg, 0.010 mmol, 0.02 equiv), t-BuOK (22 mg, 0.20
mmol, 0.4 equiv), boric acid (6.2 mg, 0.10 mmol, 0.2 equiv), THF
(1 mL), acetophenone (3a, 58 mL, 0.50 mmol, 1 equiv), and allylbo-
ronic acid pinacol ester (140 mL, 0.75 mmol, 0.5 equiv). The mix-
ture was capped with a septa and stirred in the glovebox at r.t. for 3
h. The reaction was removed from the glovebox and quenched with
sat. NH4Cl soln (1 mL) and stirred for 10 min. The aqueous layer
was extracted Et2O (3 × 5 mL) and the combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuo. Purifica-
(6) No enantiomeric excess was observed in the products of the
reactions with the chiral ligands in Table 1.
(7) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M.
Angew. Chem. Int. Ed. 2007, 46, 3139.
Synthesis 2010, No. 19, 3259–3262 © Thieme Stuttgart · New York

3262
T. J. Barker, E. R. Jarvo
SPECIAL TOPIC
(8) Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E. M. Org.
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with an iridium chloride precatalyst to form a more active
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e.g., [Ir(cod)OMe]2, are competent catalysts for the reaction,
consistent with this hypothesis.
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Synthesis 2010, No. 19, 3259–3262 © Thieme Stuttgart · New York