Catalytic enantioselective alkylation of aldehydes by using organozinc halide reagents

Article abstract of DOI:10.1002/chem.201204346

Functionalized alkylzinc halides can be employed in the enantioselective addition to aldehydes by using a titanium(IV) catalyst derived from a H ₈-binaphthol derivative in the presence of [Ti(OiPr)₄] and MgBr₂. A range of functionalities, including olefin, chlorine atoms, protected alcohols, amides, and cyano groups, are tolerated in the present reaction, providing the corresponding functionalized alcohols in high yields and enantioselectivities (see scheme). Copyright

Full text of DOI:10.1002/chem.201204346

COMMUNICATION
DOI: 10.1002/chem.201204346
Catalytic Enantioselective Alkylation of Aldehydes by Using Organozinc
Halide Reagents
Yuichiro Kinoshita, Shinichi Kanehira, Yasuki Hayashi, and Toshiro Harada*[a]
Recent advances in functionalized organometallic re-
agents have considerably increased the scope of carbon nu-
cleophiles, allowing short and efficient syntheses of poly-
functional target molecules without unproductive protec-
tion/deprotection steps.[1] Despite the progress in catalytic
enantioselective addition of functionalized aryl groups to al-
dehydes,[2] very few examples have been reported for the re-
action of functionalized alkyl reagents. Knochel and co-
workers reported the enantioselective addition of function-
alized dialkylzinc reagents, [FG-(CH2)n]2Zn (1), to alde-
hydes catalyzed by a chiral bis-triflylamide titanium com-
plex.[3,4] The zinc reagents 1 were prepared by CuI-catalyzed
I/Zn exchange of the corresponding iodo precursors with
Et2Zn followed by disproportionation of the resulting [FG-
(CH2)n]ZnEt by the subsequent removal of Et2Zn in vacuo
[Scheme 1, Eq. (1)].[3] Alternatively, such reagents can be
prepared by hydroboration of the terminal alkene precur-
sors with Et2BH and subsequent B/Zn transmetalation of
the resulting [FG-(CH2)n]BEt2 with Et2Zn followed by the
removal of surplus Et3B and Et2Zn [Scheme 1, Eq. (2)].[4]
We were attracted to the possible use of functionalized al-
kylzinc bromides, FG-(CH2)n-ZnBr (2), in the enantioselec-
tive carbonyl addition. The zinc reagents 2 possess superb
functional group tolerance.[1] They are readily prepared in
an atom-economical manner by oxidative addition of active
Rieke-zinc[5] to the alkyl bromides [Scheme 1, Eq. (3)].
More conveniently, the reaction can be carried out with zinc
dust in the presence of LiCl to give zinc reagent 2’ com-
plexed with LiCl [Scheme 1, Eq. (4)].[6] Taking advantage of
the intrinsic low reactivity, the zinc reagents have been uti-
lized in the formation of carbon–carbon bonds by transition-
metal catalysis as represented by the Negishi cross-coupling
reaction.[7,1] Recently, Knochel et al. reported that the addi-
tion of organozinc halides to aldehydes, ketones, and carbon
dioxide is accelerated significantly by mixing them with a
stoichiometric amount of MgCl2.[8] However, to date, a cata-
lytic system has not been developed by which functionalized
alkylzinc halides undergo enantioselective addition to alde-
hydes.
Herein, we report the first successful example of catalytic
enantioselective alkylation of aldehydes by using functional-
ized alkylzinc halides 2 and 2’. The reactivity of the zinc re-
agents is shown to be enhanced by mixing them with [Ti-
AHCTUNGRTENGUN(N OiPr)4] and MgBr2. In the presence of a chiral titanium cat-
alyst derived from (R)-DPP-H8-BINOL (3d; BINOL=bi-
naphthol, DPP=3,5-diphenylphenyl; 5 mol%), a variety of
functionalized alkylzinc reagents, prepared from readily
available bromide precursors, underwent enantioselective
addition to aldehydes to give the corresponding functional-
ized alcohols in high enantioselectivity.
Recent reports from this laboratory showed that Grignard
reagents can be used in the enantioselective addition to al-
dehydes by using titanium(IV) catalysts derived from (R)-
DPP-BINOL (3b) and (R)-DPP-H8-BINOL (3d) in the
presence of excess [TiACTHNUTRGNEUNG
(OiPr)4].[9,2l,m] In the present study, we
first examined butylation of 1-naphthaldeyde (4a) by using
nBuZnBr (2a) under similar conditions. Thus, when 4a was
treated with a commercial THF solution of nBuZnBr
(2.4 equiv) in the presence of (R)-DPP-BINOL (3b)
Scheme 1. Preparation of functionalized alkylzinc reagents.
(5 mol%) and [TiACTHNUTRGNEUNG(OiPr)4] (7.2 equiv) at 08C for 24 h, buty-
[a] Y. Kinoshita, S. Kanehira, Y. Hayashi, Prof. Dr. T. Harada
Department of Chemistry and Materials Technology
Kyoto Institute of Technology, Matsugasaki, Sakyo-ku
Kyoto 606-8585 (Japan)
lation product (R)-5aa was obtained in 90% ee (Table 1,
entry 1 and Scheme 2). However, the chemical yield was
moderate and aldehyde 4a was recovered in 42%.
Fax : (+81)75-724-7581
To improve the conversion of the aldehyde, the effect of
metal salt additives was examined. Of these, magnesium hal-
ides were particularly effective in accelerating the reac-
E-mail: harada@chem.kit.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204346.
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Table 1. Optimization of reaction conditions for catalytic enantioselec-
(entry 15). When nBuZnBr·LiCl (2a’), prepared either from
2a and LiCl (entry 10) or from butyl bromide, zinc dust, and
LiCl (entry 11),[6] was employed, 5aa was obtained without
a significant decrease in the chemical yield and enantioselec-
tivity.
Under the conditions of entry 8 in Table 1, the scope of
the present reaction for aldehydes was examined in the re-
action using BuZnBr (2a) and BuZnBr·LiCl (2a’) (Table 2).
tive butylation of aldehyde 4a by using nBuZnBr (2a).[a]
Ligand
MgBr2 [equiv]
Solvent
Yield [%]
ee [%]
1[b]
2
3
4
5
6
7
8
3b
3b
3b
3b
3b
3b
3b
3d
3d
3d
3d
3d
3a
3c
–
0
THF
THF
CH2Cl2
Et2O
55
94
96
92
97
65
45
95
64
88
87
60
58
66
38
90
55
87
87
92
88
92
93
82
93
91
90
76
71
–
2.4
2.4
2.4
1.2
1.2
0.6
1.2
1.2
1.2
1.2
0
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9[c]
10[d]
11[e]
12[f]
13
14
15[g]
Table 2. Catalytic enantioselective butylation of aldehydes 4 by using
nBuZnBr (2a) or nBuZnBr·LiCl (2a’).[a]
1.2
1.2
1.2
Aldehyde
Zinc
reagent
Product
Yield
[%]
ee
[%]
[a] Unless otherwise noted, reactions were carried out with 4a (0.42m),
2a (2.4 equiv), MgBr2, [Ti(OiPr)4] (7.2 equiv), and ligand 3 (5 mol%) at
08C for 3 h. [b] The reaction was carried out at 0.21m of 4a in THF for
24 h. [c] The reaction was carried out with [Ti(OiPr)4] (3.2 equiv). [d] The
reaction was carried out in the presence of LiCl (2.4 equiv). [e] BuZnBr·-
LiCl prepared in THF from nBuBr, Zn, and LiCl was used. [f] MgCl2
(1.2 equiv) was added. [g] The reaction was carried out in the absence of
a ligand.
AHCTUNGTRENNUNG
1
2
3
4
5
1-NaphCHO (4a)
PhCHO (4b)
2a
2a’
2a
2a’
2a
2a
2a
5aa
5ba
5ca
5da
5ea
5 fa
5ga
95
87
86
92
82
72
69
71
75
84
51
93
86
89
92
91
44
78
86
74
83
83
AHCTUNGTRENNUNG
p-MeC6H4CHO (4c)
p-ClC6H4CHO (4d)
m-MeOC6H4CHO (4e)
o-BrC6H4CHO (4 f)
2-ThienylCHO (4g)
6
7
8[b]
9
PhCH=CHCHO (4h)
PhCH2CH2CHO (4i)
2a
2a’
2a
5ha
5ia
10[b]
11[c]
[a] Unless otherwise noted, reactions were carried out with aldehydes 4
(0.42m), 2a or 2a’ (2.4 equiv), MgBr2 (1.2 equiv), [Ti(OiPr)4] (7.2 equiv),
AHCTUNGTRENNUNG
and 3d (5 mol%) in CH2Cl2 at 08C for 3 h. [b] The reaction was carried
out with MgBr2 (0.6 equiv) for 21 h. [c] The reaction was carried out with
MgBr2 (0.6 equiv) at 58C for 4 d.
The reaction of benzaldehyde (4b) and its para- and meta-
substituted derivatives (4c–e) afforded the corresponding
butylation products in high yields and in high selectivities
(86–92% ee) either with 2a or with 2a’ (entries 2–5). On the
other hand, moderate enantioselectivity was observed for
ortho-substituted derivative 4 f (entry 6). For the reaction of
heteroaromatic aldehyde 4g and a,b-unsaturated aldehyde
4h, satisfactory yields and selectivities could be attained by
applying a 4:1 ratio of 2a (or 2a’)/MgBr2 with a longer reac-
tion time (entries 8 and 10). Aliphatic aldehyde 4i was con-
siderably less reactive. However, the reaction at 58C for
4 days afforded butylation product 5ia in relatively high
enantioselectivity (entry 11).
Reactions were then carried out with a variety of zinc re-
agents 2b–k’ that were prepared from bromide precursors
by treatment with zinc dust in the presence of LiCl
(Table 3).[6] Zinc reagents, prepared from a long-chain alkyl
bromide, homoallyl and bis-homoallyl bromide, and an w-
chloroalkyl bromide, all underwent smooth addition to aro-
matic aldehydes 4 to furnish the corresponding secondary al-
cohols in high selectivity (86–93% ee) (entries 1–4). w-Sily-
loxy- and alkoxy-substituted alkylzinc reagents 2 f’–h’ also
underwent enantioselective addition to give the correspond-
ing mono-protected diols of high 90–92% ee (entries 5–7).
Scheme 2. Catalytic enantioselective butylation of aldehyde 4a by using
BuZnBr (5a).
tion.[10] In the presence of MgBr2 (2.4 equiv), 5aa was ob-
tained in high yield within 3 h, but in decreased enantiose-
lectivity (entry 2). The enantioselectivity was improved by
using the mixed reagent of nBuZnBr (2a), [TiACTHNURGTNEUNG(OiPr)4], and
MgBr2 after removal of THF in vacuo followed by dissolu-
tion in CH2Cl2 or in Et2O (entries 3 and 4). Further im-
provements in the enantioselectivity were attained by reduc-
ing the amount of MgBr2 (1.2–0.6 equiv) (entries 5 and 7)
and by using a titanium catalyst derived from (R)-DPP-H8-
BINOL (3d) (entry 8). The reaction was slow when using
less polar toluene as a solvent (entry 6), decreasing the
amount of [TiACHTUNGTRENNUNG(OiPr)4] to 3.6 equiv (entry 9), applying a 4:1
ratio of 2a/MgBr2 (entry 7), and using MgCl2 instead of the
bromide (entry 12). The use of parent BINOL (3a) and H8-
BINOL (3c) resulted in significant decrease in the product
yield and enantioselectivity (entries 13 and 14). It should be
noted that, in the absence of the catalyst, butylation pro-
ceeded slowly to give racemic 5aa in moderate yield
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Enantioselective Alkylation of Aldehydes
COMMUNICATION
Table 3. Catalytic enantioselective addition of functionalized alkyl groups to aldehyde by using zinc reagents
lower concentration, is an
active alkylating agent.[12] By
analogy, it is likely that alkyl-
zinc bromides 2 react reversibly
2’.[a]
with [Ti
ACHTUNGTRENNUNG
alkyltitanium
[Scheme 3, Eq. (5)], which un-
dergo enantioselective addition
to aldehydes by the catalysis of
a 3d-based titanium complex.
In the absence of MgBr2 addi-
tive, the rate of alkylation was
Aldehyde RZnBr·LiCl
Product
Yield ee
[%] [%]
1
2
3
4a
4a
4d
C12H23ZnBr·LiCl (2b’)
5ab 76
91
93
91
slowed down at
a relatively
lower conversion, resulting in
low product yield even after a
longer reaction time (24 h;
Table 1, entry 1). Although we
have no experimental evidence,
a possible interpretation for this
phenomena is that zinc reagent
2 is consumed additionally by
aggregation with (iPrO)ZnBr,
produced from Equation (5)
given in Scheme 3, to form di-
CH2=CH
N
5ac
96
CH2=CH
N
5dd 81
4
5
6
4a
4e
4d
ClC4H8ZnBr·LiCl (2e’)
5ae
5ef
91
96
86
91
90
TIPSO
TIPSO
ACHTUGNTRENUN(GN CH2)3ZnBr·LiCl (2 f’)
nuclear
zinc
complex
6
[Eq. (6)]. In the presence of
MgBr2, zinc reagent 2 might
form hetero-dinuclear complex
7 as suggested by a recent struc-
tural study [Eq. (7)].[13] The ob-
served enhancement in the re-
action rate, leading to the rapid
conversion of aldehydes within
3 h, might be due to the genera-
tion of the alkyltitanium re-
agent at higher concentration in
(CH2)6ZnBr·LiCl (2g’)
5dg 92
5ah 77
7
8
9
4a
4a
4a
TrO
N
92
3
MeO
5ai
5aj
93
87
PipCOC10H20ZnBr·LiCl (2j’)
(NC)C8H16ZnBr·LiCl (2k’)
85
86
equilibrium
[Scheme 3,
Eq. (8)], in which co-produced
(iPrO)ZnBr is complexed with
MgBr2.
10 4a
5ak 80
[a] Reactions were carried out with aldehydes 4 (0.42m), 2’ (2.4 equiv), [Ti
(5 mol%) at 08C for 3 h in CH2Cl2. [b] Pip=piperidin-1-yl.
ACHTUNGTNER(NUGN OiPr)4] (7.2 equiv), and 3d
An exception was 3-methoxypropyl derivative 2i’, for which
a non-enantioselective reaction was observed (entry 8). It is
probable that a background racemic reaction was promoted
by an intramolecular coordination of the zinc atom of 2i’ by
the neighboring methoxy group. Zinc reagents 2j and 2k’
bearing a remote tertiary amide and cyano group, respec-
tively, could be used in the present reaction (entries 9 and
10).[11] The corresponding functionalized secondary alcohols
were obtained in high yields and good enantioselectivities.
In a relevant enantioselective alkylation of aldehydes with
diorganozincs (R2Zn) in the presence of [TiCAHTUNGTRENNNUG
been proposed that [RTi
N
Scheme 3. Formation of alkyltitanium species in equilibrium.
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T. Harada et al.
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ton, J. Ko, L. Sole, L. Pu, J. Org. Chem. 2010, 75, 2836–2850; for the
In summary, we have demonstrated that alkylzinc bro-
mide reagents can be used in the enantioselective alkylation
of aldehydes with a titanium(IV) catalyst derived from a H8-
BINOL derivative in the presence of [TiACTHNUTGRNEUNG(OiPr)4] and MgBr2.
At the low catalyst loading (5 mol%), a variety of function-
alized alkylzinc reagents, prepared readily from the corre-
sponding bromide precursors, underwent enantioselective
addition to aromatic, heteroaromatic and a,b-unsaturated
aldehydes to provide the corresponding functionalized alco-
hols in high enantioselectivity.
Experimental Section
(R)-1-(3-Methoxyphenyl)-4-triisopropylsilanyloxybutan-1-ol (5ef): Typi-
cal procedure for enantioselective alkylation of aldehyde by using func-
tionalized zinc reagents 2’ prepared from bromide precursors; A two-
layer mixture of MgBr2 in Et2O (1 mL) was prepared by the reaction of
Mg turnings (15 mg, 0.6 mmol) with 1,2-dibromoethane (0.6 mmol,
reaction of aryl Grignard reagents in combination with [TiACHTUNGTRENNUNG(OiPr)4],
see; l) Y. Muramatsu, S. Kanehira, M. Tanigawa, Y. Miyawaki, T.
Harada, Bull. Chem. Soc. Jpn. 2010, 83, 19–32; m) D. Itakura, T.
Harada, Synlett 2011, 2875–2879.
[3] a) M. J. Rozema, C. Eisenberg, H. Lꢂtjens, R. Ostwald, K. Belyk, P.
Knochel, Tetrahedron Lett. 1993, 34, 3115–3118; b) C. Eisenberg, P.
Knochel, J. Org. Chem. 1994, 59, 3760–3761; c) C. Lutz, P. Knochel,
J. Org. Chem. 1997, 62, 7895–7898.
[4] F. Langer, L. Schwink, A. Devasagayaraj, P.-Y. Chavant, P. Knochel,
J. Org. Chem. 1996, 61, 8229–8243.
[5] R. D. Rieke, P. T. Li, T. P. Burns, S. T. Uhm, J. Org. Chem. 1981, 46,
4323–4324.
[6] A. Krasovskiy, V. Malakhov, A. Gavryushin, P. Knochel, Angew.
Chem. 2006, 118, 6186–6190; Angew. Chem. Int. Ed. 2006, 45, 6040–
6044.
[7] a) G. Wang, N. Yin, E. Negishi, Chem. Eur. J. 2011, 17, 4118–4130;
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Diederich), Wiley-VCH, Weinheim, 2004, pp. 815–877.
[8] a) A. Metzger, S. Bernhardt, G. Manolikakes, P. Knochel, Angew.
Chem. 2010, 122, 4769–4773; Angew. Chem. Int. Ed. 2010, 49, 4665–
4668; see also, b) S. Bernhardt, A. Metzger, P. Knochel, Synthesis
2010, 3802–3810; c) S. Bernhardt, G. Manolikakes, T. Kunz, P. Kno-
chel, Angew. Chem. 2011, 123, 9372–9376; Angew. Chem. Int. Ed.
2011, 50, 9205–9209.
52 mL). Freshly prepared TIPSO
ACHTUGNRTNE(NUNG CH2)3ZnBr·LiCl (2 f’) (0.68m in THF,
1.8 mL, 1.2 mmol)[6] and [Ti
AHCTUNGTRENNUNG
this mixture at room temperature. After being stirred for 10 min, solvents
were removed quickly in vacuo (0.05 mmHg, 2 min) and the resulting
oily residue was dissolved in CH2Cl2 (1.2 mL) to form clear solution.
Then, ligand 3d (13.1 mg, 0.025 mmol) and m-anisaldehyde (4e) (68 mg,
0.50 mmol) were added to this solution at 08C. After being stirred for 3 h
at 08C, the reaction mixture was quenched by the addition of aqueous
1n HCl and extracted with ethyl acetate (3ꢁ20 mL). The organic layers
were washed successively with aqueous 5% NaHCO3 and brine, dried
over MgSO4, and concentrated in vacuo. Purification of the residue by
flash chromatography on silica gel (ethyl acetate/hexane 1:99) afforded
167 mg (95% yield, 91% ee) of 5ef. [a]2D5 =21.4 (c=1.25 in CHCl3);
1H NMR (500 MHz, CDCl3): d=1.04–1.15 (m, 21H), 1.62–1.77 (m, 2H),
1.80–1.94 (m, 2H), 2.53 (br, 1H), 3.73–3.78 (m, 2H), 3.82 (s, 3H), 4.71
(dd, J=4.8, 8.0 Hz, 1H), 6.80 (ddd, J=0.8, 2.6, 8.1 Hz, 1H), 6.94 (m,
2H), 7.24 ppm (t, J=8.3 Hz, 1H); 13C NMR (125.8 MHz, CDCl3): d=
12.0, 18.0, 29.4, 36.8, 55.2, 63.6, 74.1, 111.2, 112.8, 118.2, 129.3, 146.8,
159.7 ppm; HRMS (FAB): m/z calcd for C20H36O3Si: 352.2434; found:
352.2434. Enantioselectivity was determined by HPLC analysis (Chiralcel
OD-H column, iPrOH/hexane=2:98; flow rate: 1 mLminÀ1, tR =17.8 min
(major R enantiomer); 19.7 min (minor S enantiomer). The absolute ster-
eochemistry was assumed by analogy.
[9] a) Y. Muramatsu, T. Harada, Angew. Chem. 2008, 120, 1104–1106;
Angew. Chem. Int. Ed. 2008, 47, 1088–1090; b) Y. Muramatsu, T.
Harada, Chem. Eur. J. 2008, 14, 10560–10563.
[10] For other additives (2.4 equiv), the following results were obtained
under similar conditions: LiBr; 24% yield, 56% ee, ZnBr2; no reac-
Acknowledgements
tion, Mg
ACHTUNGTNER(NUGN OiPr)2; 32% yield and 61% ee.
[11] Under similar conditions, the reaction of EtOCOCATHNUGTRNE(NGU CH2)3ZnBr was
This work was supported by KAKENHI (No. 20550095 and 24550118)
from the Ministry of Education, Culture, Sports, Science, and Technology
(MEXT), Japan and by the Kyoto Institute of Technology Research
Fund.
sluggish and products were obtained as a mixture of isopropyl and
ethyl ester.
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2003, 36, 739–749.
Keywords: alkylation · asymmetric catalysis · asymmetric
synthesis · organozinc reagents · titanium
[13] a) L. Jin, C. Liu, J. Liu, F. Hu, Y. Lan, A. S. Batsanov, J. A. K.
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[1] P. Knochel, H. Leuser, L.-Z. Gong, S. Perrone, F. F. Kneisel in The
Chemistry of Organozinc Compounds (Eds.: Z. Rappoport, I.
Marek), Wiley, Chichester, 2006, pp. 287–393.
[2] For transition-metal catalyzed addition of arylboronic acids, see;
a) M. Sakai, M. Ueda, N. Miyaura, Angew. Chem. 1998, 110, 3475–
Received: December 6, 2012
Published online: && &&, 0000
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Enantioselective Alkylation of Aldehydes
COMMUNICATION
Asymmetric Catalysis
Y. Kinoshita, S. Kanehira, Y. Hayashi,
T. Harada* .................... &&&& — &&&&
Catalytic Enantioselective Alkylation
of Aldehydes by Using Organozinc
Halide Reagents
Functionalized alkylzinc halides can be
employed in the enantioselective addi-
tion to aldehydes by using a titaniu-
m(IV) catalyst derived from a H8-
binaphthol derivative in the presence
ine atoms, protected alcohols, amides,
and cyano groups, are tolerated in the
present reaction, providing the corre-
sponding functionalized alcohols in
high yields and enantioselectivities
(see scheme).
of [Ti
ACHTUNGTRENNUNG(OiPr)4] and MgBr2. A range of
functionalities, including olefin, chlor-
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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