On the scope of trimethylaluminium-promoted 1,2-additions of ArZnX reagents to aldehydes

Article abstract of DOI:10.1002/chem.200901803

A practical asymmetric 1, 2 addition of functionalised arylzinc hal ides to aromatic and aliphatic aldehydes is described by the use of amino alcohol catalysis in the presence of AlMe₃. The process is simple to carry out, uses only commercially available reagents/ligands and provides moderate to good (80-96% ee) enantioselectivities for a wide range of substrates. Either commercial ArZnX reagents or those prepared in situ from low cost aryl bromides can be used. In the latter case electrophilic functional groups are tolerated (CO₂Et, CN). The reaction relies on rapid exchange between ArZnX and AlMe₃ to generate mixed organometallic species that lead to the formation of a key intermediate that is distinctly different from the classic "anti" transition states of Noyori. NMR monitoring and related experments have been used to probe the validity of the proposed selective transition state.

Full text of DOI:10.1002/chem.200901803

FULL PAPER
DOI: 10.1002/chem.200901803
On the Scope of Trimethylaluminium-Promoted 1,2-Additions of ArZnX
Reagents to Aldehydes
Daniel Glynn, Jonathan Shannon, and Simon Woodward*[a]
Abstract: A practical asymmetric 1,2-
addition of functionalised arylzinc hal-
ides to aromatic and aliphatic alde-
hydes is described by the use of amino-
alcohol catalysis in the presence of
AlMe3. The process is simple to carry
out, uses only commercially available
reagents/ligands and provides moderate
to good (80–96% ee) enantioselectivi-
ties for a wide range of substrates.
Either commercial ArZnX reagents or
those prepared in situ from low cost
aryl bromides can be used. In the latter
case electrophilic functional groups are
tolerated (CO2Et, CN). The reaction
relies on rapid exchange between
ArZnX and AlMe3 to generate mixed
organometallic species that lead to the
formation of a key intermediate that is
distinctly different from the classic
“anti” transition states of Noyori.
NMR monitoring and related experi-
ments have been used to probe the val-
idity of the proposed selective transi-
tion state.
Keywords: alcohols
catalysis organometallic com-
pounds · synthesis · zinc
· asymmetric
·
Introduction
Since the seminal papers of Oguni (1984, first use of an ami-
noalcohol ligand),[1] Noyori (1986, first highly enantioselec-
tive catalyst),[2] Chaloner (1987, first use of an ephedrine-
based ligand)[3] and Soai (1991, first asymmetric use of Ph–
zinc reagents)[4] the addition of ZnR2 species to aldehydes
has become one of the “workhorse” reactions of asymmetric
catalysis (Scheme 1). The legions of papers generated by
this field are well documented in comprehensive reviews.[5]
However, fewer endeavours (summarised in Table 1) have
concentrated on methods for adding nucleophiles other than
the ubiquitous ZnEt2 or ZnMe2.
Scheme 1. Routes to diorganozinc species and their use in asymmetric
1,2-additions; R=transferred organo group, Z=ideally a non transfera-
ble group to avoid loss of valuable nucleophile.
Notwithstanding the successes of Table 1, a significant irri-
tation in this field is a lack of low cost, widely commercially
available, diorganozinc reagents (other than ZnR2, R=Me,
Et, Ph). This situation necessitates the preparation of the
zinc organometallic prior to its use. Generally, these reac-
tions can be both technically demanding and necessitate the
handling of very air-sensitive/pyrophoric reagents. Recently,
we described the first general method for direct activation
of poorly nucleophilic, but commercially available, ArZnX
(X=Br, I) for enantioselective addition to aromatic alde-
hydes.[12] This paper provides details of the full scope, exten-
sions and limitations of such procedures and casts some
light on the origins of the reactionꢀs selectivity.
Results and Discussion
[a] D. Glynn, Dr. J. Shannon, Prof. S. Woodward
School of Chemistry, The University of Nottingham
Nottingham NG7 2RD (UK)
There are more than 160 commercially available organozinc
halides with over 70 being functional arylzinc halides.[13]
However, at the outset of our investigations no asymmetric
1,2-addition of organozinc halides to aldehydes was known.
We aimed to use a promoter to convert the organozinc
Fax : (+44)115-9513464
E-mail: simon.woodward@nottingham.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901803.
Chem. Eur. J. 2010, 16, 1053 – 1060
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1053

Table 1. Highlight publications in non-Et/Me organozinc 1,2-additions to aldehydes.
R1CHO
R-Zn-Z[a]
ee [%]
Comments
Ref.
[6]
aryl, alkenyl
aryl, alkenyl, alkyl
2-BrPh
aryl
aryl
Zn{(CH2)nFG}2
T
80–96
50–94
68–88
78–99
93–98
63–99
n must be >3, transmetallated from BEt2 derivative with ZnEt2.
by exchange with ZnEt2 preventing uncatalysed additions by ZnPh2
via transmetallation from BPh3 and positive solvent additive effects
ArLi + ZnCl2 plus sequestration of LiCl by Et2NCH2CH2NEt2
[7]
PhZnEt
PhZnEt
ArZnBu
ZnR2 (R=Alkyl, aryl)
RCH=CHZnEt
[8]
[9]
[10]
[11]
RMgX + Zn
ACHTUNGTNERNUG(OMe)2 giving precipitation of MgCAHUTNGTREN(NUNG OMe)2
aryl
via transmetallation from RCH=CHM (M=ZrClCp2, BR2)
halide into a reactive mixed organozinc species which would
selectively add to an aldehyde in the presence of a chiral
ligand (Scheme 1). Initial investigations were carried out
with aryl species, especially PhZnBr, due to the innately
more transferable nature of the phenyl group and to allow
stereochemical correlation with known literature examples.
Table 2. Promoter effects in reactions of 4-chlorobenzaldehyde 1a with
PhZnBr 2a.[a]
Scope of the promoter: Our experience with the promoted
zinc Schlenk equilibrium[14] led us to investigate the utility
of Lewis acids with known high halide affinities as PhZnBr
activators (Table 2). A readily attained system of 0.5m
PhZnBr in THF, 4-chlorobenzaldehyde and (1R,2S)-N,N-di-
butylnorephedrine (hereafter (1R,2S)-DBNE) was selected
for this initial screening for a number of reasons: i) the ami-
noalcohol ligand used is commercially available in both
enantiomeric forms; ii) PhZnBr is also commercially avail-
able as a 0.5m THF solution via the Rieke Corporation;
iii) the product (S)-3aa is already known and an already es-
tablished literature HPLC assay[8] provides both the ee value
and absolute sense of the asymmetric induction for this sub-
strate. We have carried out reactions using both enantiomers
of DBNE but for convenience within this paper all Tables
report the outcomes from use of the (1R,2S) ligand. Initially,
we sort to promote the formation of mixed organozinc spe-
cies through exchange of PhZnX with ZnR2 (R=Me, Et) by
analogy with the preparation of PhZnEt from ZnPh2 and
ZnEt2 by Pu[7] and Bolm.[8] Unfortunately, none of the di-
Entry
Additive
T [8C]
Yield 3aa [%][b]
ee (S)-3aa [%][b]
1
2
3
4
5
6
7
8
ZnMe2
ZnEt2
ZnBu2
AlMe3
AlEt3
0
0
0
0
0
0
RT
15
15
15
15
40
0
0
0
86
43
58
57
48
35
0
n.d.[c]
n.d.
43
13
27
24
n.d.
n.d
n.d.
n.d.
MAO
DABAL-Me3
Al
BEt3
(OMe)3
BF3·Et2O
(iBu)3
9
10
11
BACHTUNGTRENNUNG
0
[a] PhZnBr 2a (1 mL of 0.5m solution in THF, 0.5 mmol), additive
(0.5 mmol), (1R,2S)-DBNE (6.9 mL, 0.025 mmol) and toluene (2 mL)
stirred at RT for 20 min. Subsequently 4-chlorobenzaldehyde 1a
(0.25 mmol in 2 mL toluene) was added over 5 min at correct tempera-
ture. [b] Isolated yield; ee determined by HPLC analysis (Chiracel AD
column; sense of induction by polarimetry, see ref. [15] and Supporting
Information). [c] Not determined.
tioselectivity basis the use of aliphatic aldehydes was nor-
mally optimal (Table 3, entries 10–13). Such behaviour is
commonly attributed to the presence of a greater non-cata-
lysed background reaction for aromatic aldehydes in asym-
metric zinc-based 1,2-addition chemistry. Conveniently, in
all cases only trace amounts of competing methyl transfer
addition was observed. In eight cases the sense of enantiofa-
cial selectivity could be explicitly checked against literature
results.[15] In the remaining cases the stereochemistry has
been tentatively assigned based on our preliminary disclosed
model.[12] This is further discussed later (see Section on Ste-
reochemical correlations). The most challenging substrates
proved to be 2-substituted benzaldehyde derivatives. If the
substituent at this position became too large the enantiose-
lectivity started to fall (Table 3, entries 3 vs 8). It is interest-
ing to note that preparation of hindered 3ja was particularly
effective and that other synthetic methodology, including
asymmetric ketone hydrogenation,[16] can find this motif
challenging. Finally, we noted that under these conditions
acidic functional groups in the aldehyde component were
not tolerated including: NH2 and NHBoc. These reactions
ACHTUNGTRENNUNGorganozinc promoters tried (entries 1–3) led to the desired
outcome. Boron-based promotion (entries 9–11) was, at
best, only partially effective. Unexpectedly however, a
number of organoaluminium species (entries 4–8) gave en-
couraging results of which AlMe3 was the best.
Scope of the aldehyde and organozinc components: Slowing
the rate of addition of the substrate 1a led to significant im-
provements in both the yield and enantioselectivity provid-
ing synthetically useful levels (Table 3, entry 1). To identify
potential limitations in this basic procedure a range of cases
in both coupling partners has been investigated. Initially, we
screened a range of aldehydes using a standard PhZnBr/
AlMe3 conditions.
In general, the procedure of Table 3, using commercially
available PhZnBr 2a, gave moderate to acceptable behav-
iour across a wide range of both aromatic and aliphatic alde-
hydes (Table 3) with respect to both yield and ee value.
From an isolated yield perspective aromatic aldehydes
(Table 3, entries 1–9) were preferred, whereas from an enan-
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Chem. Eur. J. 2010, 16, 1053 – 1060

1,2-Additions of ArZnX Reagents to Aldehydes
FULL PAPER
Table 3. Aldehyde scope in reactions with PhZnBr 2a.[a]
(MeO)PhZnBr 2c inadequate enantioselectivities were at-
tained (49% ee in addition to 1a) necessitating the use of
the iodide reagent for additions to the more reactive aryl al-
dehydes (entries 4–5 vs 6–8). The most significant chemose-
lectivity issues arose in the use of the 4-CN derivative 2d. In
this case both the enantioselectivity and chemical yield were
suppressed (Table 5, entry 9). In the case of the latter, the
low yields were associated with co-formation of 4,4’-dicyan-
nobiphenyl. The aldehyde is suspected of being a sacrificial
oxidant in this reaction leading this Wurtz coupling product
but we were unable to detect the expected alcohol or pina-
col reduction products of benzaldehyde.
Entry R1
Product Yield 3 [%] ee 3 [%][b] Stereo-
correlation[c]
3
1
2
3
4
5
6
7
8
4-ClPh
3aa
3ba
3ca
3da
3ea
3 fa
3ga
3ha
67
62
51
76
55
61
58
51
70
92
55
41
51
89 (S) (+)
90 (S) (À)
78 (S) (À)
90 (S) (+)
88 (S) (+)
89 (S) (À)
91 (S) (À)
86 (S) (+)
86 (S) (À)
96 (R) (+)
92 (R) (+)
96 (R) (+)
80 (R) (+)
[d,e]
3-ClPh
2-ClPh
4-FPh
4-BrPh
4-MePh
3-MePh
2-MePh
4-(MeO)Ph 3ia
tBu
iPr
c-C6H11
nBu
–
3
–
3
3
Use of in situ prepared ArZnX 2 reagents: One significant
disadvantage of the use of commercially produced ArZnX 2
reagents is their high costs (which can amount to greater
than 150 Euro per 100 mmol). In our hands, attempted in-
house reaction of LiC10H8 with ZnCl2 followed by addition
of ArX (X=Br, I) under literature procedures[17] led to
ArZnX 2 with vastly inferior properties. Such solutions af-
forded products 3 in diminished yields and with low ee
values regardless of the procedures employed to remove by-
product lithium salts from them (ICPMS analyses revealed
that, in the case of PhZnBr 2a, we typically prepared re-
agents containing less than 20 ppm lithium ions). Because of
these limitations we sought for an alternative method to
unlock the synthetic potential of commercial aryl bromides.
In 2003 a robust method for the formation of ArZnBr 2
–
3
3
9
3
3
3
3
10
11
12
13
3ja
3ka
3la
3ma
[a] PhZnBr 2a (1 mL of 0.5m solution in THF, 0.5 mmol), AlMe3
(0.25 mL of 2m toluene solution, 0.5 mmol), (1R,2S)-DBNE (6.9 mL,
0.025 mmol) and toluene (2 mL) stirred at RT for 20 min. Subsequently
aldehyde 1 (0.25 mmol in 2 mL toluene) was added over 1 h at RT. Isolat-
ed yield and ee determined by HPLC analysis. [b] If no stereo-correlation
available assignments made on the basis Scheme 2. [c] In accord with
Scheme 2 (via polarimetry, see ref. [15] and Supporting Information).
[d] Only [a]D value known (no stereo assignment available in literature),
assigned here that (S) corresponds to the (À) antipode. [e] Literature
comparison data not available.
Table 4. Scope of ArZnX 2 1,2-additions to aromatic and aliphatic aldehydes.[a]
resulted in very poor conver-
sions even when excesses of
ArZnX 2 were used. Next the
possibility of using arylzinc
halide nucleophiles 2 bearing
functional groups of various re-
activity was investigated. For
completeness additions to both
aromatic and aliphatic alde-
Entry
R1
Ar
X
Product
Yield 3 [%]
ee 3 [%][b]
Stereo-
correlation[c]
[e]
2
3
5
6
7
8
9
10
11
12
13
14
15
4-(MeO)Ph
c-C6H11
4-ClPh
tBu
c-C6H11
nBu
Ph
Ph
tBu
iPr
4-FPh
2-FPh
Br
Br
I
Br
Br
Br
Br
I
Br
Br
Br
Br
Br
Br
3ib
3li
3ac
3jc
3lc
3mc
3nd
3ne
3je
3ke
3le
3me
3jf
72
74
94
96
93
87
50
73
76
48
53
63
88
85
87 (R) (+)[d]
89 (R) (+)
87 (S) (+)
93 (R) (+)
88 (R) (+)
82 (R) (+)
79 (R) (À)
81 (R) (À)
96 (R) (+)
93 (R) (+)
97 (R) (+)
85 (R) (+)
84 (R) (À)
75 (R) (À)
–
–
–
hydes
were
investigated
(Table 4). The versatility of the
methodology is clear as electro-
philic components are tolerated
in the nucleophilic coupling
partner 2.
Using commercial Rieke cor-
poration derived ArZnX 2 re-
agents, a general processes af-
fording synthetically useful iso-
4-(MeO)Ph
4-(MeO)Ph
4-(MeO)Ph
4-(MeO)Ph
4-(CN)Ph
4-(EtO2C)Ph
4-(EtO2C)Ph
4-(EtO2C)Ph
4-(EtO2C)Ph
4-(EtO2C)Ph
3
–
3
–
–
–
–
–
–
-
c-C6H11
nBu
tBu
lated yields and stereoselectivi- 16
c-C6H11
3lf
–
ties (>10:1 e.r.) for a range of
17
4-FPh
4-(MeO)Ph
Br
ent-3ib
68
87 (S) (À)
–
ArZnX species 2b–f was at-
tained. In the majority of cases
the efficacy of the reaction was
independent of the halide in
the ArZnX 2 reagent. Howev-
[a] ArZnBr 2b–f (1 mL of 0.5m THF solution, 0.5 mmol), AlMe3 (0.25 mL of 2m solution in toluene,
0.5 mmol), (1R,2S)-DBNE (6.9 mL, 0.025 mmol) and toluene (2 mL) stirred at RT for 20 min. Subsequently al-
dehyde 1 (0.25 mmol in 2 mL toluene) was added over 1 h at RT. Yield by isolation and ee determined by
HPLC analysis. [b] Stereochemical assignments made on the basis Scheme 2. [c] In accord with Scheme 2 (via
polarimetry, see ref. [15] and Supporting Information). [d] Very low specific rotation value. [e] Literature com-
er, in the case of 4- parison data not available.
Chem. Eur. J. 2010, 16, 1053 – 1060
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1055

S. Woodward et al.
Table 5. Optimisation of in situ PhZnBr 2a preparation procedure.[a]
level of CoBr2/ZnBr2 (Table 5, entry 3) below this level
poorer yields of 3ja (Table 5, entry 4) suggesting inefficient
formation of PhZnBr 2a. It is well known that both the par-
ticle size and surface covering of elemental zinc samples
profoundly affect its reactivity. To insure maximum reprodu-
cibility of the procedure for in situ ArZnBr 2 generation
procedure various commercially available zinc samples were
subjected to the trial. A very high correlation between the
yield of the coupled product 3ja and the median size of the
zinc particles was found (see Supporting Information). Free
flowing zinc powders with diameters in the range 1–10 mm
(microns) were highly active in the preparation of ArZnX 2
reagents under these “modified Gosmini conditions” provid-
ed these particles were not aggregated into larger species
(as evidenced by electron microscopy). Oxide coating of the
particles, normally considered to be the most detrimental
factor for the formation of organozinc reagents, was not a
major problem in the zinc samples we examined by EDX-
backscatter techniques. Of far greater importance was the
median particle size—those zinc sources with individual or
aggregated median diameters >10 mm (microns) performed
poorly regardless of the zinc purity level. Two routinely
robust sources have been suggested (see Supporting Infor-
mation). If poor results are encountered it is recommended
that the quality of the zinc dust should be checked by elec-
tron microscopy.
Entry CoBr2 (mol%) ZnBr2 (mol%) Yield 3ja [%] ee 3ja [%][b]
1
2
3
4
5
10
5
2.5
1.3
2.5
10
5
2.5
1.3
–
58
62
86
30
88
91 (R) (+)
91 (R) (+)
91 (R) (+)
91 (R) (+)
91
[a] MeCN (5 mL) stirred with zinc (0.94 g, 14.4 mmol), CoBr2 (87 mg,
10 mol%, or as otherwise indicated), ZnBr2 (90 mg, 10 mol%, or as oth-
erwise indicated), CF3CO2H (20 mL, 0.27 mmol), allylchloride (60 mL,
0.74 mmol) and PhBr (4.0 mmol) stirred 1.5 h. An aliquot of derived
PhZnBr 2a (2 mL of 0.8m MeCN solution, 1.6 mmol) was added to
AlMe3 (0.5 mL of a 2m toluene solution, 1.0 mmol), (1S,RS)-DBNE
(20 mL, 0.025 mmol, 10 mol%) tridecane (50 mL) (internal standard) and
toluene (4 mL) and the mixture stirred at RT for 20 min. Subsequently
aldehyde 1 (63 mg, 0.75 mmol in toluene (2 mL) was added over 1 h at
RT yield and ee determined by GC analysis (see Supporting Informa-
tion). [b] Facial selectivity authenticated against known literature values
(via polarimetry, see ref. [15] and Supporting Information).
from ArBr and Zn was published by Gosmini et al.[18] This
chemistry gives excellent yields of FG-ArZnBr (2, FG=3-
or 4-substituted CO2R, CN, OAc, OMe, all provide 80–99%
2) and the procedure was subsequently expanded to allow
use of ArCl, ArOSO2R (R=CF3, Me) as starting materi-
als.[19,20] These zinc powder derived ArZnBr reagents 2 have
been employed in a range of
The optimised in situ procedure was used to prepare a
range of ArZnX 2 reagents (X=Br, I) which were then
used directly (in two-fold excess) to arylate a range of alde-
hydes (Table 6).
“Negishi-type” couplings,[20] but
Table 6. Direct use of aryl bromides in preparation of secondary alcohols.[a]
to the best of our knowledge no
asymmetric process has been
disclosed. Of significant con-
cern to us was the possibility
that the additives used to pro-
mote this chemistry would
downgrade the performance of
Entry
R1
Ar
X
Product
Yield 3 [% ]
ee 3 [%][b]
Stereo-
correlation[c]
ArZnBr/AlMe3/ACHTUNGTRENNUNG(1R,2S)-DBNE
in subsequent chiral catalysis.
After some preliminary trials
we found that mixtures of
CoBr2 with or without added
ZnBr2 were optimal for test
substrates 2a and 1j (Table 5,
entry 1). When 10 mol% of
CoBr2 and ZnBr2 were used
this modified Gosmini protocol
gave acceptable yields and
enantiomeric excesses. Howev-
er, to minimise the possibilities
for Zn/Co induced side reac-
tions in the second step the
cobalt/zinc loading was system-
atically lowered. Best results
3
3
3
1
2
3
4
5
6
7
8
tBu
c-C6H11
nBu
tBu
iPr
c-C6H11
tBu
nBu
Ph
Ph
Ph
Br
Br
Br
Br
Br
Br
I
I
I
Br
I
Br
3ja
3la
3ma
3je
3ke
3le
3jc
3mc
3jc
3lc
91
82
72
76
68
67
81
63
81
92
78
75
93 (R) (+)
89 (R) (+)
84 (R) (+)
92 (R) (À)
84 (R) (À)
94 (R) (À)
69 (R) (+)
30 (R) (+)
89[e] (R) (+)
30 (R) (+)
57 (R) (+)
81 (S) (+)
[d]
4-(EtO2C)Ph
4-(EtO2C)Ph
4-(EtO2C)Ph
4-(MeO)Ph
4-(MeO)Ph
4-(MeO)Ph
4-(MeO)Ph
4-(MeO)Ph
3-(AcO)Ph
–
–
–
3
3
3
9
tBu
10
11
12
c-C6H11
c-C6H11
4-FPh
–
–
–
3lc
3dh
[a] MeCN (5.0 mL) stirred with zinc (0.94 g, 14.4 mmol), CoBr2 (22 mg, 2.5 mol%), ZnBr2 (23 mg, 2.5 mol%),
CF3CO2H (20 mL, 0.27 mmol), allylchloride (60 mL, 0.74 mmol) and ArBr (4.0 mmol) stirred 2 h. An aliquot of
derived ArZnBr (2 mL of 0.8m MeCN solution, 1.6 mmol) was added to AlMe3 (0.5 mL of 2.0m toluene solu-
tion, 1.0 mmol), (1R,2S)-DBNE (20 mL, 0.075 mmol) and toluene (4 mL) and the mixture stirred at RT for
20 min. Subsequently aldehyde 1 (0.75 mmol in toluene 2 mL) was added over 1 h at RT. Isolated yield and ee
determined by HPLC analysis. [b] Facial selectivity assigned on the basis of Scheme 2. In accord with
Scheme 2 (via polarimetry, see ref. [15] and Supporting Information). [d] Literature comparison data not avail-
were attained at a 2.5 mol% able. [e] In the presence of 0.02m LiBr.
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1,2-Additions of ArZnX Reagents to Aldehydes
FULL PAPER
Application of the two-step processes of Table 6 allowed
use of electronically neutral (Table 6, entries 1–3), electron-
ic-deficient (Table 6, entries 4–6) and electronic-rich
(Table 6, entries 7–12) zinc reagents derived from ArX. Al-
though the ee values of realised 3 are modest, many are still
at a synthetically usable level. Some limitations were noted:
use of 1,4-C6H4Br(CN) led to acceptable levels of stereose-
lectivity (e.g., 85% ee for additions to 1l). However, unac-
ceptable synthetic yields were isolated due to competing di-
merisation to 4,4’-dicyanobiphenyl (typically a 2:1 dimer/1,2-
addition product ratio) as had been the case for Rieke-de-
rived 4-CNPhZnBr 2d. The reagent 4-NO2C6H4ZnBr could
not also not be used as only a very low yield of the organo-
metallic was realised in the zinc insertion step. In general,
the enantioselectivities realised through application of the
ArBr/Zn dust procedure were only slightly below those real-
ised through the commercial Rieke samples of 2 with the ex-
ception of the 4-MeOPhZnBr 2c. While the Rieke derived
2c gave acceptable levels of selectivity (82–93% ee for 3c;
Table 4, entries 6–8). Those using 2c attained directly from
4-MeOPhBr/Zn yielded 3c with poor selectivity (30–69% ee
for 3, Table 6, entries 7–8, 10–11). Due to this very dramatic
difference in the level of selectivity generated by these nom-
inally identical samples of 4-MeOPhZnBr 2c (commercial
Rieke zinc produced vs in situ “Gosmini-derived” reagents)
further investigations were carried out. Samples of 2c from
both “commercial Rieke” and “modified Gosmini condi-
tions” derived 4-MeOPhZnBr 2c were quenched with water
leading to immediate quantitative precipitation of ZnO,
ArH and HBr. The supernatant aqueous solutions were sub-
jected to titration with standard base and metal ICPMS
analysis. While both contained 0.5m “MeOPhÀ”, within ex-
perimental error (based on NaOH titration), the lithium
content of the two samples was very different. Commercial
Rieke-derived 2c contained 0.02m Li+ while 2c prepared
either by “in-house” ZnCl2/2LiC10H8 and extensive washing
of the precipitated Zn* or by the Gosmini direct insertion
procedure contained <0.0001m Li+. The possibility that Li+
might enhance the stereoselectivity was investigated through
deliberately by preparing a 0.5m solution of Zn dust (Gos-
mini) derived 2c from 4-MeOPhBr containing 0.02m LiBr to
generate an equivalent level of lithium ions. This reagent
lineated by Noyori in seminal early studies on aminoalcohol
catalysis of ZnR2 additions to RCHO.[2,5] We have proposed
that this reversal of stereoselectivity might be accounted for
by equilibration of the “Noyori-anti” transition state A with
an alternative Lewis acid promoted structure B.[12] In early
work Soai showed that, using stoichiometric (1R,2S)-DBNE,
phenylzinc reagents derived from ZnCl2 and PhMgBr also
add to the Si face of aldehydes.[4] Such behaviour is likely to
be closely related to our own system due to the presence of
Lewis acidic MgX2 in the reaction mixture, but no comment
was made by Soai.
Scheme 2. Predictive mnemonic for the stereochemistry of the products 3
and associated transition states.
Within the wider range of combinations of Tables 2–6
eleven explicit stereochemical correlations with previous lit-
erature results can be called upon (Tables 3, 4, 6).[15] As de-
termined (via polarimetry) all of the isolated samples of 3
produced here from use of (1R,2S)-DBNE are in accord
with the mnemonic of Scheme 2. In our original communica-
tion[12] several structural changes to the aminoalcohol ligand
that were consistent with transition state B being the active
form of the catalyst. As screening of further aminoalcohol
and related ligands did not provide more selective catalysts
than the commercially available DBNE ligand this was not
pursued further.
was added to 1j to under standard AlMe /
(1R,2S)-DBNE
Spectroscopic and mechanistic studies: The key prediction
of Scheme 2 is that, after addition of AlMe3 to PhZnBr 2a,
that PhZnMe and B will be generated at some level in the
reaction mixture. We have undertaken 13C NMR studies in
an attempt probe the speciation of the reaction mixture. As
the 13C NMR spectrum of PhZnBr 2a had not been ade-
quately described in the literature its 1H coupled carbon
spectrum was recorded. In THF at ambient temperature
catalysis to afford 3jc in 89% ee (Table 6, entry 9). The im-
plication of this result is that, in at least the case of reagent
2c, LiBr provides a powerful structural modification of the
active catalyst structure leading to a ꢂ3 improvement in the
reactionꢀs selectivity (5.45:1 vs 17.18:1 with LiBr). Further
investigations of the generality this “Li-promoter effect” are
under active investigation in our laboratory.
0.4–0.5m PhZnBr 2a provides the expected five signals
2,3
Stereochemical correlations: In our preliminary work[12] all
of the reactions we tried were in accord with the mnemonic
of Scheme 2 whereby the aryl nucleophile attacks from the
Si face of the aldehyde when the (1R,2S)-DBNE aminoalco-
hol ligand is used. This facial selectivity is opposite to that
which is expected for the classic anti transition state A de-
against a C6D6 reference. The
J
coupling patterns allow
CH
the triplet fine structure on the signal at 124.4 ppm to be
equated with the para carbon, while the related couplings
allow the signals at 125.5 and 138.5 ppm can be equated
with the ortho and meta positions, respectively. A final,
1
rather broad (w = ~25 Hz), signal at 159.6 ppm is assigned to
2
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1057

S. Woodward et al.
the ipso carbon. As ambient temperature is optimal for the
catalytic addition reaction (Tables 2–6) NMR studies of
PhZnBr 2a and AlMe3 were also carried out at room tem-
perature. Up to 17 potential ex-
sought. We deliberately investigate the reactivity of poten-
tial secondary exchange products from the PhZnBr/AlMe3
mixtures with aldehydes 1a (Table 7).
change partners can be generat-
Table 7. Asymmetric addition of organometallic mixtures to 4-chlorobenzaldehyde 1a in presence of (1R,2S)-
DBNE.[a]
ed
from
PhZnBr/AlMe3,
namely, ZnPhxBryMez (x+y+z
= 2) and AlPhxBryMez (x+y+
z = 3) if complete exchange of
all substituents is possible. The
addition of AlMe3 (1.0 equiv)
to PhZnBr 2a (0.4–0.5m in 4:1
THF/toluene) thus produces a
relatively complicated 13C NMR
spectrum at ambient tempera-
ture. Only overlapped broad
ipso carbon signals are ob-
served ꢀ160 ppm so that
number of aryl species in the
mixture cannot be directly de-
termined on this basis. The
total number of signals in the
much better dispersed meta
region (136–141 ppm) indicates
there are five aryl species pres-
ent in the mixture (2 major, 3
very minor; see Supporting In-
formation). At room tempera-
Entry
ꢃPhMX’
Additive
Solvent
Yield [%]
ee [%]
Configuration[b]
1
2
3
4
5
6
7
8
9
PhZnBr
PhZnBr
PhZnBr
PhZnBr
PhZnBr
PhZnEt
PhZnEt
AlPh3
toluene/THF 4.25:1
toluene/THF 4.25:1
toluene/THF 4.25:1
toluene/THF 4.25:1
toluene/THF 4.25:1
toluene
toluene/THF 4.25:1
toluene/THF 4.25:1
toluene/THF 4.25:1
toluene/THF 4.25:1
trace
40
67
34
0
89
86
0
83
25
0
S
ZnMe2
AlMe3
AlMe2Cl
AlMeCl2
S
S
40
0[c]
80
R
S
75
87
72
84
AlPh3
AlPh3
ZnMe2
AlMe3
0
0
10
[a] “PhMBr” (1 mL, 0.5 mmol, 0.5m solution in THF), Additive (0.25 mL, 0.5 mmol), (1R,2S)-DBNE (6.9 mL,
0.025 mmol) and toluene (2 mL) stirred at RT for 20 min. Then 1a (0.25 mmol in 2 mL) was added over 1 h at
RT. Isolated yield; ee determined by HPLC analysis. [b] Determined by comparing [a]D with literature
(ref. [15]). [c] Mainly just recovered starting material.
ture the main component in the PhZnBr/AlMe3 mixture is
PhZnBr 2a based on signal position comparison with a gen-
uine sample (meta 138.5 ppm). The concentration of the
second highest component (meta 136.4 ppm, ortho
125.1 ppm, para 123.9 ppm) increases as the temperature de-
creases and this also causes a decrease in the concentration
of PhZnBr 2a, suggesting that these two components are in
equilibrium. By using genuine PhZnMe, in an equivalent
solvent system, we could equate the second most populated
aryl species (meta 136.4 ppm) to PhZnMe in line with the
proposal for the formation of B (Scheme 2). The observed
slowing of the PhZnBr/PhZnMe 13C NMR exchange below
08C exactly mirrors the real temperature behaviour of the
catalytic system for the addition of PhZnBr 2a to 1a. The ee
of the isolated 3 falls smoothly from 90% at ambient tem-
perature to 83% at À208C for catalytic trials carried out at
intervening temperatures. We propose that the 3 minor spe-
cies present in the reaction mixture (meta signals at 136.9,
136.2 and 140.1 ppm) are associated with secondary ex-
changes of the primary PhZnMe/AlMe2Br products but due
to their low abundance they were not assigned. The methyl
region of the 13C NMR spectrum of PhZnBr/AlMe3 mixtures
at room temperature is uninformative. Just two signals, a
broad signal at 8.5 ppm (assigned to average Al/Me environ-
ments) and a sharper signal 10.4 ppm (assigned to average
Zn/Me signals) are seen.
Firstly, aside from any effects due to organometallic speci-
ation, a clear solvent effect is apparent. The use of THF/tol-
uene mixtures favours the “anti-Noyori” (S)-3aa product
over the use of pure toluene (Table 7, entries 1 and 7 vs 6).
It is THF favours the formation of Shiina-type[21] intermedi-
ates related to B but with the AlMe2X unit replaced by less
effective zinc-based Lewis acids (Table 7, entry 7). The via-
bility of AlMe2Cl (Table 7, entry 4) is also consistent with
proposal B. The exchange of one “Me” for a “Cl” in the
AlMe2X motif of B still affords a closely related selective
catalyst. Use of AlMeCl2 leads to an inactive catalyst
(Table 7, entry 5). An exchange with ArZnBr is expected to
form AlCl2Br. Aluminium trihalides promote the formation
of halide bridged oligomers and it is likely that such behav-
iour prevents access to the equivalent B catalyst. It is clear
that AlPh3 is not an active intermediate in the PhZnBr/
AlMe3 exchange process as its use results in no conversion
(Table 7, entries 7–9). While it is not possible to draw a com-
plete overview of the behaviour of this system, due to the
complexity of potential secondary exchanges, the data are
all most in accord with the proposed transition state B.
Conclusions
The combination ArZnX/AlMe3 offers good potential for
the synthesis of chiral secondary alcohols through (1R,2S)-
DBNE promoted additions to prochiral aldehydes. The pro-
cedure reliably delivers moderate to good enantioselectivi-
Because of the potential for extensive substituent ex-
change in 13C NMR spectra of PhZnBr/AlMe3 mixtures an
alternative insight into the active catalytic structure was
1058
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Chem. Eur. J. 2010, 16, 1053 – 1060

1,2-Additions of ArZnX Reagents to Aldehydes
FULL PAPER
ties (80-96% ee) with highly reliable enantioface selectivity
and functional group tolerance in both coupling partners.
Uniquely, the required FG–ArZnBr species can be generat-
ed in situ directly from FG–ArBr (FG=OMe, CO2Et, CN)
and zinc dust. The enantioselectivity of the reaction may
also be upgraded by an unprecedented lithium effect
through simple addition of LiBr to the ArZnBr species.
Overall, the simplicity of the process together with its func-
tional group tolerance and wide commercial availability of
all the starting materials make this an attractive process for
synthetic chemistry.
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Experimental Section
General experimental procedure: Proton and 13C NMR spectra were re-
corded on a Bruker AV400 in CDCl3. Chemical shifts are reported as d
values in ppm relative to CHCl3 (7.27 ppm for 1H; 77.0 ppm for 13C) in
CDCl3. IR spectra were measured on a Bruker Tensor 27 FT-IR spec-
trometer. Mass spectra (MS) were recorded at high resolution (HRMS)
on a micromass LCT or VG micromass 70E mass spectrometers using
electrospray ionisation (ESI). Column chromatography was performed
with Fluorochem Davisil silica gel (35–70 mm) using mixtures of ethyl
acetate and petrol ether (40–608C) as eluents. Toluene was freshly dis-
tilled from sodium/benzophenone under argon. Aldehydes were distilled
under reduced pressure in a Kugelrohr. All other commercially available
compounds were used without further purification.
[12] J. Shannon, D. Bernier, D. Rawson, S. Woodward, Chem. Commun.
2007, 3945–3947.
General procedure for the asymmetric 1,2-addition of ArZnBr 2 to alde-
hydes 1: A flame-dried Schlenk tube with stirr bar and under argon was
charged with arylzinc bromide (2.0 mL of 0.5m THF solution, 1.0 mmol).
To this toluene (4 mL), trimethyl aluminium (0.5 mL of 2m toluene solu-
tion, 1.0 mmol) (CAUTION! pyrophoric) and (1R,2S)-(+)-dibutylnore-
phedrine (20 mL, 10 mol%) was added and the solution left to stir for
ca.10 min. Pivaldehyde (0.75 mmol) dissolved in toluene (2 mL) was
added using a syringe pump dropwise over 2 h. The solution was left to
stir for 16 h overnight. For details of individual preparations see Support-
ing Information.
[13] The structures of >160 commercially available RZnX species are
available through the Sigma–Aldrich web site: http://www.sigmaal-
drich.com.
[14] a) P. Goldsmith, S. Woodward, Angew. Chem. 2005, 117, 2275–2277;
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non, J. C. Stephens, S. Woodward, Chem. Eur. J. 2007, 13, 2462–
2472.
[15] Polarimetry data used for known examples of 3 [R1,Ar] as portrayed
in Scheme 3: a) (+)-(S)-3aa[4-ClPh,Ph] {[a]D =+13.7 (c=20,
CHCl3, 208C, for >99% ee)} B. Wu, H. S. Mosher, J. Org. Chem.
1986, 51, 1904–1906; b) (À)-(S)-3ca[2-ClPh,Ph] {[a]D =À21.5 (c=
1.14, CHCl3, for 97% ee)} T. Ohkuma, M. Koizumi, H. Ikehara, T.
Yokozawa, R. Noyori, Org. Lett. 2000, 5, 659–663; c) (+)-(S)-3ea[4-
BrPh,Ph] {[a]D =+21.0 (c=0.8, C6H6, 208C for >99% ee)} B. Wu,
H. S. Mosher, J. Org. Chem. 1986, 51, 1904–1906; d) (À)-(S)-3 fa[4-
MePh,Ph] {[a]D =À9.7 (c=4.4, C6H6 for 96% ee)} B. Weber, D. See-
bach, Tetrahedron. 1994, 50, 7473–7484; e) (+)-(S)-3ha[2-MePh,Ph]
{[a]D =+6.4 (c=0.91, CHCl3, 228C for 93% ee)} T. Ohkuma, M.
Koizumi, H. Ikehara, T. Yokozawa, R. Noyori, Org. Lett. 2000, 5,
659–663; f) (À)-(S)-3ia[4-MeOPh,Ph] {[a]D =À13.9 (c=1.00, ben-
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Chem. 2007, 2608–2610; g) (+)-(R)-3ja [tBu,Ph] {[a]D =+25.9 (c=
2.24, C6H6, 228C for >99% ee) R. MacLeod, F. J. Welch, H. S.
Mosher, J. Am. Chem. Soc. 1960, 82, 876–880; h) (+)-(R)-3ka
[iPr,Ph] {[a]D =+47.7 (c=7.0, Et2O, 20 8C for >99% ee)} R. Ma-
cLeod, F. J. Welch, H. S. Mosher, J. Am. Chem. Soc. 1960, 82, 876–
880; i) (+)-(R)-3la [c-C6H11,Ph] {[a]D =+28.3 (c=3.0, C6H6, 228C)
for >99% ee)} J. P. Vigneron, J. Jacquet, Tetrahedron 1976, 32, 939–
944; j) (+)-(R)-3ma [nBu,Ph] {[a]D =+37.6 (c=3, C6H6, ꢀ208C) for
>99% ee)} J.-P. Mazaleyrat, D. J. Cram, J. Am. Chem. Soc. 1981,
103, 4585–4586; k) (+)-(R)-3jc [tBu,4-MeOPh] {[a]D =+15.2 (c=
5.87, C6H6, 258C for >99% ee)} T. Kinoshita, K. Komatsu, K. Ikai,
T. Kashimura, S. Tanikawa, A. Hatanaka, K. Okamoto, J. Chem.
In situ preparation and use of FG–ArZnBr and use: A modified proce-
dure, based on that of Gosmini was employed.[22] Under a argon atmos-
phere, a flame-dried Schlenk tube was charged with zinc dust (1.74 g,
26.6 mmol), CoBr2 (42 mg, 0.19 mmol), ZnBr2 (44 mg, 0.19 mmol), freshly
distilled acetonitrile (7 mL), trifluoroacetic acid (35 mL, 53 mg,
0.46 mmol) and allyl chloride (60 mL, 56 mg, 0.74 mmol). The suspension
was then stirred at room temperature for 15 min. To the resultant light
brown mixture the functionalised arylbromide (8.0 mmol) was added in
acetonitrile (3 mL) in two portions and the light brown mixture left to
stir (1.5 h). The solution, nominally 0.8m in ArZnBr 2, was then left to
stand for 30 min and a suitable amount of the supernatant solution trans-
ferred via syringe to the reaction vessel. The organozinc reagent was
used as above; full compound data for the derived alcohols is available in
the Supporting Information.
Acknowledgements
We thank GlaxoSmithKline (GSK) for support of a studentship in associ-
ation with the Engineering and Physical Sciences Research Council
(EPSRC). We are also appreciative to GSK for help with HPLC and
ICPMS assays and for valuable suggestions (Mr. Andrew Kennedy).
Helpful input from the COST D40 Programme on “Innovative Catalysis”
is acknowledged by S.W. and from the UK government (EPSRC grant
EP/F033478/1).
Soc. Perkin Trans.
2
1988, 1875–1884; l) (À)-(S)-3mc [nBu,4-
MeOPh]) {[a]D =À22.5 (c=1.1, MeOH, ꢀ208C for 97% ee)} B.
Weber, D. Seebach, Tetrahedron 1994, 50, 7473–7484.
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[18] H. Fillon, C. Gosmini, J. Pꢅrichon, J. Am. Chem. Soc. 2003, 125,
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Received: June 30, 2009
Revised: September 4, 2009
Published online: November 24, 2009
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Chem. Eur. J. 2010, 16, 1053 – 1060