Bidentate hydroxyalkyl NHC ligands for the copper-catalyzed asymmetric allylic substitution of allyl phosphates with grignard reagents

Article abstract of DOI:10.1002/chem.201203969

Demonstrating their potential: Bidentate alkoxy NHC ligands have been used in the copper-catalyzed asymmetric allylic alkylation of allyl phosphates with Grignard reagents (see scheme). The method provides access to tertiary and quaternary chiral centers with high regio- and enantioselectivity. The system is also applied to the synthesis of chiral E,E-dienes, a key structural motif prevalent in natural products. Copyright

Full text of DOI:10.1002/chem.201203969

COMMUNICATION
DOI: 10.1002/chem.201203969
Bidentate Hydroxyalkyl NHC Ligands for the Copper-Catalyzed Asymmetric
Allylic Substitution of Allyl Phosphates with Grignard Reagents
Magaly Magrez, Yann Le Guen, Olivier Baslꢀ, Christophe Crꢀvisy,* and
Marc Mauduit*[a]
The development of new selective methods for transition-
phosphate unit in key intermediate geometries.[9] However,
only moderate selectivity was achieved with more atom-eco-
nomical, easily prepared and highly modular Grignard re-
agents. Feringa and more recently Alexakis examined re-
spectively ferrocenyl-based phosphine and phosphite ligands
in copper-catalyzed asymmetric allylic substitution and ob-
served a dramatic drop in selectivity and/or activity when
combination of allyl phosphate and Grignard nucleophiles
was considered.[10,11] Our recent success in the copper-cata-
lyzed asymmetric allylic alkylations of allyl phosphates with
dialkylzinc using our bidentate chiral N-heterocyclic carbene
ligand[12] prompted us to investigate the challenging and un-
precedented regio- and enantioselective substitution of allyl
phosphate with Grignard reagents.
Bidentate hydroxyalkyl NHC ligands, derived from the
amino acid chiral pool, have been brought to light after
their successful application in the copper-catalyzed asym-
metric conjugated addition of Grignard reagents with b-sub-
stituted cyclic enones to construct with efficiency all-carbon
quaternary stereogenic centers.[13] More recently, Hayashi
and co-workers demonstrated the efficiency of our ligand
family in the asymmetric addition of organoboronates with
different electrophiles, including cinnamyl phosphates.[14] On
the other hand, a practical advantage of Grignard reagents
is their ability to deprotonate imidazolium salts and gener-
ate in situ the desired complex without requiring a pre-
formed copper or silver carbene.[5] Therefore, we began our
investigation by testing the reaction of cinnamyl phosphate
with ethylmagnesium bromide in presence of a catalytic
À
metal-catalyzed C C bond formation involving cheap and
readily available Grignard reagents constitutes a major en-
deavor.[1] In the past decade, enantioselective allylic alkyla-
tion has been extensively studied, and substitution reactions
with organomagnesium nucleophiles, predominantly cata-
lyzed by copper salts, have experienced tremendous im-
provement.[2] Nevertheless, the scope of substrates providing
À
the desired C C bond formation product with controlled
regio- and enantioselectivity remains limited, with very reac-
tive Grignard reagents, to allyl ester[3] and allyl halide[4,5]
electrophiles. Therefore, applications to other electrophilic
partners would offer important alternatives to extend the
synthetic potential of this highly valuable transformation.
Herein, we present an unprecedented copper-catalyzed
highly regio- and enantioselective alkylation of secondary
and tertiary allyl phosphates with Grignard reagents.
In the past decade, allyl phosphates have clearly manifest-
ed potentials in asymmetric substitution reactions with orga-
nometallic reagents (Scheme 1).[6] Hoveyda and co-workers
largely contributed to the popularity of allyl phosphates as
electrophilic partners by developing numerous highly selec-
tive methods to create chiral centers with both diorgano-
zinc[7] and triorganoaluminum[8] reagents. Nakamura and co-
workers also achieved high selectivity with diorganozinc spe-
cies and also highlighted the importance of the Lewis basic
amount of different copper salts and the bidentate hy
ACHTUNGTRENNUNGdroxy-
AHCTUNGTREGaNNNU lkyl NHC carbene ligand precursor L1. As illustrated in
pioneer studies, significant synergic effects between temper-
ature, solvent and order of substrate addition were also ob-
served in the present study (see the Supporting Informa-
tion). While modest selectivity was obtained with CuBr and
CuTC, copper(I) triflate sources afforded the desired SN2’
product in good regio- and enantioselectivity (Table 1, en-
tries 3–5). The timorous catalytic activity observed at À788C
was improved at À208C without affecting selectivity. More
interestingly, copper(II) triflate and ligand L1 in a 1:1 ratio
afforded optimum regioselectivity (>98:2 SN2’:SN2 ratio)
and excellent enantioselectivity (95:5 e.r.) at À788C in di-
ethyl ether as solvent (Table 1, entry 6). Importantly no
other copper(II) source outdid the performance of Cu-
Scheme 1. Regio- and enantioselective alkylation of allyl phosphates.
[a] M. Magrez, Y. L. Le Guen, Dr. O. Baslꢀ, Dr. C. Crꢀvisy,
Dr. M. Mauduit
Ecole Nationale Supꢀrieure de Chimie de Rennes, CNRS
UMR 6226, Av. du Gꢀnꢀral Leclerc, CS 50837
35708 Rennes Cedex 7 (France)
Fax : (+33)223238108
E-mail: marc.mauduit@ensc-rennes.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203969.
AHCTUNGRTEG(NUNN OTf)2, and in most cases, only provided moderate selectivi-
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1199

Table 1. Screening of copper sources in the catalylic allylic alkylation of
cinnamyl phosphate with ethylmagnesium bromide.
the stereogenic center of the chelating side arm, consider
AHCTUNGTREGlNNUN y impacted regio- and enantioselectivity. First, a small ero-
ACHTUNGTRENNUNGab-
sion of regio- and enantioselectivity was observed with
ligand L2, which contains mesityl group instead of 2,6-diiso-
propylphenyl (Dipp) group (compare Table 2, entry 1 and
2). A larger drop of enantioselectivity was observed with
2,4,6-triphenylphenyl (L3) and anthracenyl (L4) groups, af-
fording the desired alkylated product in 71:29 and 74:26 e.r.,
respectively (Table 2, entries 3 and 4). Moreover, selectivity
was dramatically altered when benzylic substituents were
evaluated (Table 2, entries 5 and 6), with the exception of
the significantly congested bis-o-tolyl methyl group (L7).
This screening demonstrates the critical importance of the
sterically congested aromatic Dipp to achieve both excellent
regio- and enantioselectivity. Indeed, replacement of the
NAr motif by a more flexible bulky cyclododecyl group
(L9) was also associated with diminished selectivity
(Table 2, entry 9). On the other hand, the contribution of
the chelating amino alcohol side arm in the enantioselectivi-
ty control was clearly highlighted by the poor chiral induc-
tion offered with the Leucinol motif of L10 (compare
Table 2, entry 2 and 10).
Entry
Copper salt
Conv. [%][a]
SN2’:SN2[b]
e.r.[c]
80:20
86:14
87.5:12.5
89.5:10.5
91.5:8.5
95:5
79:21
86:14
81:19
86:14
1
2
3
4
5
6
7
8
CuBr
CuTC
T
63
63
21
85:15
92:8
>98:2
>98:2
93:7
>98:2
>98:2
77:33
>98:2
94:6
N
15
R
>99[d]
>99
90
N
T
[Cu(naphthenate)2]
CuF2
>99
32
72
9
10
11
[Cu
N
none
48
67:33
61.5:48.5
[a] 1H NMR analysis, based on remaining starting material. [b] 1H NMR
analysis. [c] Chiral-phase GC analysis. [d] At À208C.
The potential of our new enantioselective catalytic system
was then evaluated with different Grignard reagents and
cinnamyl phosphates (Table 3). Linear Grignard reagents af-
forded good regio- (88:12 to>98:2) and enantioselectivity
(up to 97:3 e.r.). According to literature precedents, substitu-
tion with methyl group is often associated with reduced ac-
tivity and/or selectivity.[2] Remarkably, under the optimized
reaction conditions, the desired methylated products were
generated with good yields and excellent regioselectivities,
ty. Poor activity and selectivity were observed when evaluat-
ing our NHC ligand model in the copper free allylic alkyla-
tion with Grignard reagents (Table 1, entry 11).[5]
Further evaluations of the imidazolinium salt library high-
lighted the multifaceted carbene ligand architecture and its
importance in achieving high selectivity (Table 2).[13] In fact,
both a decrease in the steric demand at the NAr unit and at
Table 2. Chiral hydroxyalkyl bidentate NHC ligand precursors.[a]
Table 3. Copper/NHC-catalyzed allylic substitution of allyl phosphates
with Grignard reagents.[a]
Entry R1
R2
T [oC] Conv [%][ b]
(Yield [%])[c]
SN2’:SN2[d] e.r.[e]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Me
À40
À40
99 (64)
99 (81)
99 (80)
99 (64)
99 (92)
83:17
94:6
97:3
89:11
94:6
2:98
>98:2
88:12
88:12
89:11
89:11
89:11
>98:2
92:8
94:6
iBu[f]
84:16
90:10
73:27
90:10[g]
–
1-Butenyl À18
iPr
À18
1-Pentenyl À18
Entry
L
Conversion [%][b]
SN2’:SN2[c]
e.r.[d]
95:5
93:7
71:29
Vinyl, Ph
À40
À40
À40
À40
>99
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
>99
>99
40
97
95
>99
>99
>99
93
>98:2
98:2
91:9
95:5
88:12
97:3
93:7
92:8
88:12
92:8
1-naph Et
1-naph iBu[f]
1-naph Me
99 (80)
99 (78)
99 (71)
99 (83)
99 (79)
99 (91)
99 (80)
99 (46)
99 (81)
96:4
92:8[h]
97:3
9
74:26
10
11
12
13
14
15
1-naph 1-Butenyl À40
92:8
83:17
95:5
70.5:29.5
82.5:7.5
91.5:8.5
87:13
63.5:36.5
74:26
1-naph iPr
À40
1-naph 1-Pentenyl À18
Cy
Cy
Cy
Et
Me
À40
À40
94:6
91:9
9
10
1-Butenyl À20
>98:2
83:17[g]
>99
[a] Standard reaction conditions at 1 mmol scale. [b] 1H NMR analysis,
based on remaining starting material. [c] Yield of isolated product.
[d] 1H NMR analysis of the crude mixture. [e] Chiral-phase GC or HPLC
analysis. [f] 4 h reaction. [g] Determined on the RCM product.[16] [h] De-
termined on the hydroboration/oxidation product.
[a] Reactions performed on a 1 mmol scale with CuACTHNUGTRENUNG(OTf)2 (1 mol%),
EtMgBr (1.2 equiv) at À788C in Et2O. [b] 1H NMR analysis, based on re-
maining starting material. [c] 1H NMR analysis of the crude mixture.
[d] Chiral-phase GC analysis.
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Chem. Eur. J. 2013, 19, 1199 – 1203

Allylic Substitution of Allyl Phosphates
COMMUNICATION
in particular when reacting with a substrate bearing a steri-
cally demanding naphthyl unit (97:3 e.r.; Table 3, entry 9).
The bulkier iPrMgBr and iBuMgBr Grignard reagents af-
forded excellent regioselectivity but with reduced enantiose-
lectivity (Table 3, entries 2, 4 and 11). It is also important to
note that sp2 Grignard reagents afforded excellent but oppo-
site regioselectivity (>98% SN2) in favour of the achiral
linear product (entry 6).[15] Intensive research is currently in
progress to elucidate and take advantage of this extreme a-
selective behavior.
The scope of the reaction was then extended to tertiary
allylic phosphates (Scheme 2). In most cases, the desired all-
carbon quaternary stereogenic centers were produced with
Scheme 3. NHC/Cu-catalyzed allylic substitution with E,E-diene phos-
phate 5. All reactions were performed on a 1 mmol scale. Conversions
and SN2’ ratios were determined by 1H NMR analysis of the crude mix-
ture. Enantiomeric ratios were obtained from GC or HPLC analysis.
by copper salt.[7b,17] Recently, Alexakis and Li reported an
highly regio- and enantioselective copper/phosphoramidite
catalytic system that focussed on the use of enyne substrates
and with few additional tests on E,E-dienes.[17] In fact, asym-
metric addition with conjugated dienes is an apparently
more challenging process with reduced discrimination be-
tween the different electrophilic positions compared to
enyne substrates.[7b,17] Under the present standard reaction
conditions, the challenging regio- and enantioselective sub-
stitution with Grignard reagents and E,E-diene phosphates
was evaluated. Remarkably, the alkylation reaction at
À788C with EtMgBr appeared to be totally regioselective in
favor of the desired g-product but with modest enantiomeric
ratio. Under the same reaction conditions, an important al-
teration of regioselectivity was observed with E,E-diene
bromide, while E,E-diene acetate remained unreactive (see
the Supporting Information for details). Nevertheless, and
to our delight, the reaction between diethylzinc and the
Scheme 2. NHC/Cu-catalyzed asymmetric allylic substitution with tertiary
allyl phosphates. All reactions were performed on a 1 mmol scale. Con-
versions and SN2’ ratios were determined by 1H NMR analysis of the
crude mixture. Enantiomeric ratios were obtained from GC or HPLC
analysis of the substitution product or its corresponding RCM product.[16]
diene phosphate 5 was efficiently catalyzed by CuACHTUNGTRENNUNG(OTf)2
[a] Performed with CuACHTUNGTRENNUNG(OTf)2 (5 mol%), see the Supporting Information
with ligand L1 and provided exclusively the g-product with
high 93:7 enantiomeric ratio. Very interestingly, the selectiv-
ity was further improved in presence of dimethylzinc re-
agent to afford exclusively the desired methylated 1,4-diene
with 96:4 e.r. It is important to note that the ability to effi-
ciently transfer a methyl group to extended multiple bond
electrophilic system with high selectivity represents a benefi-
cial and special attribute of the chiral bidentate alkoxy
NHC copper system.[7b,17] These encouraging results demon-
strated that AAA with extended multiple bond systems con-
stitutes an efficient strategy to selectively construct optically
active methylated 1,4-dienes, a key structural motif preva-
lent in natural products (Scheme 4).[18,19]
for details.
high regio- (up to>98% SN2’) and stereoselectivity (up to
93:7 e.r.). Substrates bearing an ortho-bromine substituent
were less reactive, and the reaction must be performed at
258C for 3 h. To establish the multi-attribute utility of our
copper/hydroxyalkyl NHC system, the asymmetric all-
carbon quaternary center formation with dialkylzinc re-
agents was also evaluated. Perceptible improvements of se-
lectivity were observed for the addition of diethylzinc to
generate products 4a and 4e with 96:4 and 98:2 e.r., respec-
tively. It is also important to note that the formation of
product 4e with organozinc species required both prolonged
reaction time and increased catalyst loading to achieve simi-
lar conversion to that with EtMgBr.
In conclusion, an efficient and selective copper-catalyzed
method has been developed for the asymmetric allylic al
ACHTUNGTRENNUNGkyl-
AHCTUNGTREGaNNNU tion of allyl phosphates with Grignard reagents using hy-
Given the modularity and regioselectivity of this asym-
metric allylic alkylation (AAA) system, an ambitious cata-
lytic process involving diene phosphates as electrophile was
then investigated (Scheme 3). Only rare examples refer to
the use of extended multiple bond system in AAA catalyzed
droxyalkyl carbenes as chiral ligands. This strategy afforded
tertiary and quaternary carbon stereogenic centers with high
regioselectivity and enantiomeric ratio. Moreover, the suc-
cessful employment of E,E-diene phosphates as electro-
philes allowed the stereoselective synthesis of 1,4-dienes
Chem. Eur. J. 2013, 19, 1199 – 1203
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C. Crꢀvisy, M. Mauduit et al.
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Scheme 4. Bioactive natural products containing the chiral 1,4-E,E-diene
motif.
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with stereogenic sp3 carbon atoms at the central position.
Extension and development of the described process with
Grignard reagents are currently under investigation in our
laboratory.
Experimental Section
[5] For copper-free AAA, see: a) Y. Lee, A. H. Hoveyda, J. Am. Chem.
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Copper-catalyzed allylic alkylation of organomagnesium reagent to allylic
phosphates: A dried Schlenk tube, under an argon atmosphere, was
charged with CuACHTUNGTRENNUNG(OTf)2 (1 mol%) and ligand L (1 mol%). Freshly distil-
led diethyl ether (0.5 mL) was then added. After the reaction mixture
was stirred for 10 min at room temperature then 10 min at 08C, the
Grignard reagent (1.2 equiv) was added. After cooling, the reaction
vessel to the required temperature, a solution of the phosphate (1 mmol)
in diethyl ether (2 mL) was added. The reaction mixture was stirred for
20 min at the required temperature. Upon completion of the reaction, 1m
HCl was added and the compound was extracted with diethyl ether. The
combined organic layers were then washed with saturated NaHCO3 solu-
tion, brine, and dried over MgSO4. The solvents were carefully removed
under reduced pressure. The crude product was purified by silica gel
chromatography (pentane) to afford the corresponding product as a col-
orless oil.
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Acknowledgements
This work was supported by the Ministꢂre de la Recherche et de la Tech-
nologie and by the Universitꢀ Europꢀenne de Bretagne (grant to M.M.).
[9] N. Yoshikai, K. Miura, E. Nakamura, Adv. Synth. Catal. 2009, 351,
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[10] A modest ee (58%), low conversion (10%), and good SN2’ selectivi-
ty (80%) was obtained with the Josiphos ligand for the addition of
MeMgBr to cinnamyl phosphate; see: F. Lꢃpez, A. W. van Zijl, A. J.
Minnaard, B. L. Feringa, Chem. Commun. 2006, 409–411.
[11] A modest ee (42%), good conversion (85%), and modest SN2’ selec-
tivity (70%) was obtained with a phosphite ligand for the addition
of EtMgBr to cinnamyl phosphate; see: M. Magre, J. Mazuela, M.
Diꢀguez, O. Pꢅmies, A. Alexakis, Tetrahedron: Asymmetry 2012, 23,
67–71.
Keywords: allylic substitution · carbene ligands · chiral
dienes · copper · Grignard reagents
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Allylic Substitution of Allyl Phosphates
COMMUNICATION
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[16] The RCM reactions were performed using M853 catalyst (see the
Supporting Information for details).
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[19] For recent examples of the total synthesis in the Phorbasin and Jer-
ˇ
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Received: November 6, 2012
Revised: November 23, 2012
Published online: December 19, 2012
Chem. Eur. J. 2013, 19, 1199 – 1203
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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