Full text of DOI:10.3390/molecules23040961

molecules
Communication
Catalytic Enantioselective Addition of
Organozirconium Reagents to Aldehydes
Ricard Solà 1, Marcos Veguillas 1 ID , María José González-Soria 1, Nicholas Carter 1,
M. Angeles Fernández-Ibáñez 2,* and Beatriz Maciá 1,
*
ID
1
Division of Chemistry & Environmental Science, Manchester Metropolitan University, Oxford Road,
Manchester M1 5GD, UK; rsolamestres@gmail.com (R.S.); marcos_veguillas@yahoo.es (M.V.);
mariajo.gonzalez.s@gmail.com (M.J.G.-S.); ncarter1@sheffield.ac.uk (N.C.)
Van ’t Hoff Institute for Molecular Sciences, Science Park 904, Amsterdam 1090 GS, The Netherlands
Correspondence: M.A.FernandezIbanez@uva.nl (M.A.F.-I.); b.macia-ruiz@mmu.ac.uk (B.M.);
Tel.: +31-(0)205-258-753 (M.A.F.-I.); Tel.: +44-(0)161-247-1416 (B.M.)
2
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 6 April 2018; Accepted: 17 April 2018; Published: 20 April 2018
Abstract: A catalytic enantioselective addition reaction of alkylzirconium species to aromatic
aldehydes is reported. The reaction, facilitated by a chiral nonracemic diol ligand complex with
Ti(OiPr)4, proceeds under mild and convenient conditions, and no premade organometallic reagents
are required since the alkylzirconium nucleophiles are generated in situ by hydrozirconation of
alkenes with the Schwartz reagent. The methodology is compatible with functionalized nucleophiles
and a broad range of aromatic aldehydes.
Keywords: alkenes; asymmetric catalysis; titanium; addition to aldehydes; Schwartz reagent
1. Introduction
Chiral alcohol-containing molecules are recurrent, high-value targets in the pharmaceutical,
agricultural, and material science sectors, amongst others; the development of efficient methods for
their construction remains a high priority in organic synthesis [1].
The catalytic enantioselective 1,2-addition reaction of organometallic reagents to carbonyl
compounds is one of the most efficient approaches to chiral alcohols. This transformation
has been extensively studied with dialkylzinc [
more recently, excellent results with Grignard [21
2
–
17] and trialkylaluminium [18
–20] reagents;
38] reagents
–
35] and organolithium [36
–
have also been reported. The high reactivity and sometimes pyrophoric character of these
premade, non-stabilized organometallic nucleophiles, however, restricts the implementation of these
methodologies in industrial processes and large-scale reactions [39]. Other complicating factors
are the frequent requirement for cryogenic temperatures (necessary in order to obtain high levels
of enantioselectivity but often prohibitively expensive at large scale) and incompatibilities with
several functional groups [40,41]. The use of less reactive nucleophiles circumvents some of these
issues. Organozirconium reagents [42
but the use of catalysts or a stoichiometric mediator [50
subsequent carbon-carbon bond formation. Thus, in the presence of Ag(I), ZnBr2, or Me2Zn,
organozirconium reagents can readily be added to aldehydes [61 68], ketones [69 70], and also
74], epoxides [75], and isocyanates [76], although enantioselective protocols have been rare
–
48] are relatively inert toward carbonyl compounds [49],
–
60] enables the nucleophilic attack and
–
,
enones [71
–
so far [77
–92]. In 1994, Wipf reported [63,64] a high-yielding protocol for the in situ transmetalation of
alkenylzirconocenes to alkenylzinc species with stoichiometric amounts of Me2Zn, and succeeded in
developing a catalytic asymmetric methodology for their subsequent additions to aldehydes [93 94].
A similar strategy was adopted by Walsh et al. for the addition of alkenylzirconocenes to ketones
,
Molecules 2018, 23, 961; doi:10.3390/molecules23040961
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catalysed by a bis-(sulphonamide) diol ligand in the presence of stoichiometric Ti(OiPr)4 [95]. We are
not aware, however, of any successful report addressing the catalytic asymmetric addition of
alkylzirconocene nucleophiles to carbonyls [14,31,96].
The use of alkylzirconocene reagents in synthesis is greatly facilitated by their ready accessibility
via (in situ) hydrozirconation of alkenes using Schwartz reagent [97–99] (Cp2ZrHCl). This offers two
key advantages: (i) alkenes, as starting materials, are inexpensive, abundant, and easy to handle [100];
(ii) hydrozirconation reaction conditions are compatible with many functional groups [101].
Here, we report the first enantioselective catalytic 1,2-addition of alkylzirconium reagents to
aldehydes, based on a titanium-Ar-BINMOL complex. This methodology affords high levels of
enantioselectivity at industrially relevant temperatures and the reaction tolerates functional groups
that are not compatible with other organometallic reagents.
2. Results and Discussion
Provided with both axial and tetrahedral chirality, 1,1-binaphthalene-2-
(Ar-BINMOLs)—developed by Kiyooka, Lai, and Xu [102 105]—have recently emerged as very
efficient ligands for the titanium-assisted catalytic addition of organometallic reagents to carbonyl
compounds [21 23 30 36 37]. Here, we started our investigations by evaluating the use of the very
versatile Ph-BINMOL [23 102 105] ligand in the addition of 1-hexene to benzaldehyde (Table 1).
Following known procedures [97 99], the treatment of 1-hexene with 2.0 eq. of Schwartz reagent
α-arylmethan-2-ols
–
,
, , ,
,
–
–
(Cp2ZrHCl) provided the corresponding organozirconium reagent, which was then added to a solution
of benzaldehyde (1.0 eq., 0.125 M) and Ph-BINMOL (20 mol%) in DCM at RT (Table 1). As expected,
very low conversion to the desired alcohol 3aa was observed (13%, entry 1). Under similar conditions
(0.125 M in benzaldehyde), the reaction was attempted in the presence of 2.5–2.8 eq. of various
additives (AgOTs, Ti(OiPr)4, TiCl(OiPr)3, CuI, and Et2Zn) in DCM at RT. No conversion was observed
except in the presence of 2.0 eq. of Et2Zn (19% conversion to racemic 3aa; entry 2). In accordance
with Srebnik’s observations [62], more concentrated reaction conditions (0.5 M benzaldehyde in DCM)
provided higher conversion to the desired product 3aa (44%, entry 3), although the enantioselectivity
of the process remained zero.
An extensive screening of zinc additives revealed that the use of ZnBr2 (0.5 eq.) in combination
with Ti(OiPr)4 (1.5 eq.) provides the desired alcohol 3aa in 83% isolated yield and 80% ee, using only
1.4 eq. of the alkene and 1.2 eq. of the Schwartz reagent, in DCM (0.5 M benzaldehyde) at RT (entry 4).
It is important to mention that the reaction proved to be very sensitive to the concentration and no
conversion was observed under more diluted conditions (0.11 M benzaldehyde in DCM, entry 5).
Working at the preferred 0.5 M concentration of substrate in DCM, variation of the titanium
source (TiCl(OiPr)3 instead of Ti(OiPr)4), however, resulted in increased reduction of the starting
material to phenylmethanol, whilst the desired product 3aa was obtained in a racemic form
(entry 6). Co-solvents—tert-butylmethyl ether, THF, toluene, and diethyl ether—were also assayed
in combination with DCM, which we found to be optimal for the hydrozirconation step; all attempts
provided lower conversion and enantioselectivity than the use of DCM alone.
Changes in the titanium loading (entries 7–8) or the amount of ZnBr2 (entries 9–10), only afforded
increased amounts of the undesired reduced product and lower enantioselectivities. To our surprise,
when the reaction was carried out at lower temperature (0 ◦C, overnight), lower enantioselectivity
was observed (35% ee, entry 11), whilst higher temperatures (35 ◦C) provided slightly higher
enantioselectivity than RT (82% ee, compare entries 12 and 4), but lower conversion (51%). By way of
comparison, the reaction was assessed using (R)-BINOL (20 mol %) as ligand; 9% conversion to the
desired product 3aa was obtained in 56% ee (entry 13).

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Table 1. Optimisation of reaction conditions for the addition of 1-hexene (2a) to benzaldehyde (1a) a.
Ti(OiPr)4
(eq.)
Cp2ZrHCl
1-hexene
(eq.)
ZnBr2
(eq.)
Undesired
Conv. (%) b
Entry
ee (%) c
(eq.)
Phenylmethanol (%) b
1 d
2 d
3
2
2
2
2
2
2
-
-
-
-
13
19
44
0
0
0.
0
0
e
-
-
e
n.d. (83) f
4
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
2.0
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.2
2.2
1.5
1.5
0.5
0.5
0.5
0.5
0.5
0.2
0.7
0.5
0.5
0.5
0.5
0.5
10
n.d.
78
57
89
73
74
67
36
83
59
5
80
0
0
35
62
80
66
35
82
5 g
6
1
22
43
5
18
20
6
51
9
h
-
7
8
9
10
11 i
12 j
13 k
14
15 j
1.0
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
56
11
90
99 (87) f
93 (R) l
a
Reaction conditions: 1a (0.15 mmol, 1.0 eq.), (Ra,S)-Ph-BINMOL (0.2 eq.), Ti(OiPr)4 (1.5 eq.), DCM (0.5 M), room
temperature, overnight. Determined by CG-MS. c Determined by Chiral GC (see supplementary material for
b
d
e
f
further details). 0.125 M in benzaldehyde. Reaction carried out with Et2Zn instead of ZnBr2. Isolated yield after
flash chromatography. 0.11 M 1a in DCM. h Reaction carried out with 1.5 eq. of TiCl(OiPr)3 instead of Ti(OiPr)4.
g
i
l
Reaction carried out at 0 ◦C. j Reaction carried out at 35 ◦C. k (R)-BINOL (20 mol %) used as ligand. Configuration
determined based on the optical rotation, by comparison with literature.
Lowering the amounts of the Schwartz reagent and the alkene provided higher enantioselectivity
(90%) but lower conversion to the desired 3aa, due to a substantial increase in the reduction by-product
(entry 14). Fortunately, improved results were obtained with increased amounts of Schwartz reagent
and the alkene, and, after fine adjustments, 99% conversion and 93% ee could be reached in 5 h when
◦
2.0 eq. of Schwartz reagent were used in combination with 2.2 eq. of alkene in DCM at 35 C (entry 15).
Regarding the mechanism of the addition reaction, a number of pathways are possible.
The transmetallation of the organozirconium reagent with ZnBr2 [106
–108], followed by second
transmetallation with the appropriate organotitanium species is a very plausible route [97
–
99].
However, the activation of aldehydes by complexation with zinc halides [109] is a well-known
process that cannot be discarded at this stage of our investigations. It is worth pointing out the
versatility of Ar-BINMOL ligands, in particular the simple and readily available Ph-BINMOL, which is
able to catalyse the carbonyl addition of a broad spectrum of organometallic reagents, including
organozinc [110], organomagnesium [21,23,30], organolithium [36–38], organoaluminum [20],
organotitanium [111], and, now, organozirconium reagents. As far as we know, this catalytic
system allows the broadest variety of organometallic reagents in enantioselective 1,2-addition to
carbonyl groups.
With the optimised conditions in hand, we tested the scope of the reaction with different aromatic
aldehydes (Table 2). Thus, the reaction of 1-hexene (2a) with p-tolualdehyde afforded product 3ba with
good yield (74%) and excellent enantioselectivity (91%, entry 1). In the case of m- and o-tolualdehyde
(entries 2 and 3), where the methyl substituent in the aromatic ring is closer to the reactive site, higher
percentages of the corresponding aryl methanol (reduction of the aldehyde) and dehydration products
4
(Figure 1) were obtained, as well as lower enantioselectivity (89% and 76%, respectively); this is
probably due to increased steric hindrance close to the carbonyl group. The reaction with p-bromo and
p-chlorobenzaldehyde afforded moderated yields (56% and 59%) and excellent enantioselectivities

Molecules 2018, 23, 961
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(91% and 90%, entries 4 and 5, respectively). The use of p-acetylbenzaldehyde as starting material
(entry 6), provided the corresponding alcohol 3ga in excellent enantioselectivity (94%) but lower
yield (32%). This is probably due to the reduction of the acetyl group by β-hydride transfer from
the organometallic reagent (by-product 5, Figure 1). Gratifyingly, the methodology proved to be
compatible with other functional groups such as p-CN (entry 7) and p-CF3 (entry 8), leading to good
yield (55–58%) and high enantioselectivity (87% ee). Unfortunately, aliphatic and α,β-unsaturated
aldehydes gave very low conversions under these reaction conditions.
Table 2. Enantioselective catalysed addition of 1-hexene (2a) to aromatic aldehydes—Scope of the
reaction a.
Conv. (%) b
Undesired Arylmethanol (%) b
ee (%) d
91 (R)
Entry
Product
Yield (%) c
1
94
6
74
2
77
15 e
54
89 (R)
28 f
10
3
4
54
87
49
56
76 (R)
91 (R)
5 g
92
76
6
59
32
90 (R)
94 (R)
OH
4 h
6
3ga
O
7 f
81
69
19
28
58
55
87 (R)
87 i (R)
8
a
Reaction conditions:
3
(0.15 mmol, 1.0 eq.), (Ra,S)-Ph-BINMOL (0.2 eq.), Ti(OiPr)4 (1.5 eq.), 1-hexene (2.2 eq.),
Cp2ZrHCl (2.0 eq.), ZnBr2 (0.5 eq.), DCM (0.375 M), 35 ◦C, 5–12 h. Determined by GC-MS. c Isolated yield after
flash chromatography. Determined by Chiral GC. Configuration based on literature data (see supplementary
material for details). 8% of dehydration product
b
d
e
f
4
was observed by GC-MS. 18% of dehydration product
4
g
h
was observed by GC-MS. The reaction was carried out in DCM (0.3 M). 19% of
5 was observed by GC-MS.
i
Determined on the corresponding acetate derivative (see supplementary material for further details).

Molecules 2018, 23, 961
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Figure 1. By-products of the reaction.
Next, we tested the scope of the reaction with different alkenes (Table 3). Thus, the reaction of
4-phenyl-1-butene (2b) with benzaldehyde (1a) provided the corresponding alcohol 3ab in excellent
yield (93%) and good enantioselectivity (77% ee, entry 1). The methodology is also compatible with
functionalised alkenes. The reaction of benzaldehyde with 4-[(tert-butyldimethylsilyl)oxy]-1-butene
(2c) led to the desired alcohol 3ac in moderate yield (42%) but good enantioselectivity (88% ee, entry 2).
Similar results were obtained when 4-halo-1-butenes 2d and 2e were used as nucleophiles (entries 3
and 4), providing 3ad and 3ae in moderate yields and 85 and 74% ee, respectively. The use of
5-bromopent-1-ene (2f) provided 3af in 31% yield and 81% ee.
Table 3. Enantioselective catalysed addition of alkenes to benzaldehyde—Scope of the reaction a.
Conv. (%) b
ee (%) d
77 (R)
Entry
Product
Yield (%) c
1 e
>99
93
2
3
n.d.
75 (10) f
67
42
40
88 (R)
85 g (R)
4
5
41
31
74 (R)
61
81 (R)
a
Reaction conditions: 1a (0.15 mmol, 1.0 eq.), (Ra,S)-Ph-BINMOL (0.2 eq.), Ti(OiPr)4 (1.5 eq.),
2
(2.2 eq.), Cp2ZrHCl
(2.0 eq.), ZnBr2 (0.5 eq.), DCM (0.375 M), 35 ◦C, 5–12 h. Determined by GC-MS. Isolated yield after flash
chromatography. Determined by Chiral GC. Configuration based on literature data (see supplementary material
b
c
d
e
f
for details). Reaction carried out with 3.0 eq. of
2
and 2.8 eq. of Cp2ZrHCl. 15% of dehydration product
4
was
observed by GC-MS. g Determined on the corresponding cyclised derivative
details).
6 (see supplementary material for
As an application of this methodology, product 3ad was transformed into its corresponding
tetrahydropyran adduct . Tetrahydropyran rings are very important structural moieties, which
6
are present in a large variety of natural products such as polyether antibiotics and marine
macrocycles [112–116]. Additionally, they are also employed in the perfume industry or as flavouring
ingredients in the food industry [117].
Thus, following a straightforward procedure [118], alcohol 3ad was dissolved in dry THF and
treated with 2 eq. of KOtBu at RT. Tetrahydropyran
6 was obtained in 84% yield and 85% ee after
purification by column chromatography (Scheme 1). It is worth pointing out that no racemization
occurs during the cyclization [119]. This strategy constitutes a novel and straightforward method for

Molecules 2018, 23, 961
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the synthesis of chiral tetrahydropyran derivatives via an enantioselective 1,2-addition of an alkene to
a carbonyl followed by an intramolecular SN2 reaction.
Scheme 1. Formation of the chiral tetrahydropyran 6 from chiral chloroalcohol 3ad.
3. Materials and Methods
General procedure for the catalytic enantioselective 1,2-addition of alkenes to aldehydes: To
a stirred suspension of Cp2ZrHCl (77 mg, 0.3 mmol, 2.0 eq.) in dry DCM (0.3 mL) at RT, the
corresponding alkene (0.33 mmol, 2.2 eq.) was added dropwise and the solution was stirred at RT for
30 min. The mixture turned into a clear yellow solution, which indicated the successful formation of the
organozirconium reagent. Next, flamed-dried ZnBr2 (0.075 mmol, 0.5 eq.) was added into the solution
and the mixture was stirred at RT for 2 min. Subsequently, a solution of Ti(OiPr)4 (0.225 mmol, 1.5 eq.)
and (Ra,S)-Ph-BINMOL (20 mol %) in dry DCM (0.1 mL) was added and stirred for further 2 min at RT.
◦
Finally, the aldehyde (0.15 mmol) was added and the solution was stirred at 35 C for 3–18 h (reaction
was monitored by TLC). (Note that liquid aldehydes were previously distilled before its addition
whilst solid aldehydes were dissolved in dry DCM (0.1 or 0.2 mL depending on its solubility) and
added to the solution.) The reaction was quenched by the addition of water (1 mL). The layers were
separated, and the aqueous layer was extracted with Et2O (3
were dried with anhydrous MgSO4, filtered, and concentrated under vacuum. The crude reaction
product was purified by flash silica gel chromatography.
×
10 mL). The combined organic layers
4. Conclusions
In conclusion, we have developed a new and efficient procedure for the titanium-assisted
catalytic asymmetric addition of alkylzirconium reagents to aromatic aldehydes, based on the use of
a readily available Ar-BINMOL ligand and ZnBr2. The alkylzirconium nucleophiles are generated
in situ by hydrozirconation of alkenes with Schwartz reagent, thus avoiding the use of premade
organometallic reagents. The reaction—which proceeds under mild conditions and industrially
relevant temperatures—allows the synthesis of the corresponding chiral secondary alcohols in
moderate to good yields (32–93%) and good to excellent enantioselectivities (76–91% ee). It is worth
mentioning that the methodology is compatible with the presence of several functional groups in
both the aldehyde (including halogens, ketone, cyano, and trifluoromethyl) and the alkene (including
halogens and TBS protected alcohol). The usefulness of this novel method has been demonstrated with
the enantioselective synthesis of a chiral tetrahydropyran by a subsequent intramolecular cyclization
on a functionalised addition product.
Supplementary Materials: Experimental methods and spectroscopic data for new compounds are available online.
Acknowledgments: B.M. thanks the European Commission for a Marie Curie Career Integration Grant, the EPSRC
for a First Grant and the R.S. for a travel grant. G.P. Howell is thanked for helpful comments on the manuscript.
Author Contributions: R.S., M.V., B.M., and M.A.F.-I. conceived and designed the experiments; R.S., M.V.,
M.J.G.-S., and N.C. performed the experiments and analyzed the data; B.M. and M.A.F.-I. contributed
reagents/materials/analysis tools and wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2018, 23, 961
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