Highly enantioselective addition of dimethylzinc to fluorinated alkyl ketones, and the mechanism behind it

Article abstract of DOI:10.1039/c8cc06358c

Chiral-diamine catalyzed addition of ZnMe₂ to PhC(O)CF₂X (in dichloromethane at -30 °C) affords fluorinated alkyl tertiary alcohols in high yield (quantitative for X = H, F, Cl; 84% for X = CF₃) and up to 99% ee. These con

Full text of DOI:10.1039/c8cc06358c

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Highly Enantioselective Addition of Dimethylzinc to Fluorinated
Alkyl Ketones, and the Mechanism Behind It
Received 00th January 20xx,
Accepted 00th January 20xx
Tomaz Neves-Garcia, Andrea Vélez, Jesús M. Martínez-Ilarduya,* and Pablo Espinet*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Chiral-diamine catalyzed addition of ZnMe2 to PhC(O)CF2X (in
dichloromethane at –30 °C affords fluorinated alkyl tertiary
alcohols in high yield (quantitative for X = H, F, Cl; 84% for X = CF3)
and up to 99% ee. These conditions are similarly very efficient for
other various ArC(O)CF3 molecules. A fine analysis of the results
can be made based on a double-cycle mechanism.
(1)
Trifluoromethylketones (TFMKs) are particularly interesting
reagents because they can be used for the synthesis of chiral
organofluorine compounds.5 These are important synthetic
targets because of the unique bioactivity of fluorinated
biochemicals compared to their non-fluorinated congeners.
Diamines and bisoxazolines can catalyse the addition of ZnEt2
to TFMKs, as reported by our group and others.6-10 In the
absence of these ligands, the undesired reduction of the
TFMKs (a background slower reaction) is the only process
observed.8,11
The ligand catalyzed addition of diorganozinc reagents to
aldehydes and ketones is a most useful C–C bond formation
reaction that allows, in its enantioselective version, to prepare
enantiomerically enriched chiral alcohols.1 It works in mild
conditions and the good tolerance of the organozinc
compounds to many functionalities, such as ester, amide,
nitrile or nitro groups, increases its versatility. Chiral alcohols
are structural components of many compounds with biological
activity.2
Using the chiral diamines L* (Figure 1) or ent-L* 12
from (R,R)-1,2-diphenylethylenediamine and (S)-2,2’-
,
built
bis(bromomethyl)-1,1’-binaphthalene, we achieved to produce
very high yields and the best enantioselectivities reported so
far for the addition to PhC(O)CF3 of ZnEt2 (99% yield, and 93%
ee at 244 K),13 or for the less reactive ZnMe2 (98% yield, and
83% ee at 236 K/rt).8 The reactions were carried out in
hexane/toluene for ZnEt2, and in toluene for ZnMe2.
Compared to aldehydes, the application of the asymmetric
addition reaction to ketones has been a major challenge.
Ketones are less reactive than aldehydes, and they have less
steric and electronic differences between the two substituents
of the carbonyl group, which makes the face
enantiodiscrimination for the attack less efficient. In spite of
that and the possibility of other reactions products competing
with the addition product (
products ( , Eq. 1, for alkyls with
condensation products (
, Eq. 1, for R' = Me),3 some methods
A
, Eq. 1), such as reduction
(R)
N
(R)
N
B
β
hydrogen atoms) or aldol
(S)
(S)
C
to synthesize chiral tertiary alcohols have been published
including one of the following processes: i) activation of the
ketone with a Lewis acid catalyst; ii) activation the organozinc
reagent with a Lewis base catalyst; iii) double activation of the
ketone and the organozinc with a bifunctional catalyst (acid
and Lewis base).1j,4
Fig. 1 Diamine L* used for the addition of ZnR2 (R = Me, Et) to TFMKs.
Enantioselective
Rh-catalysed
arylations
of
aryltrifluoromethyl ketones with arylboronic acids have been
reported, with variable success from bad to very good
depending on the chiral ligand,16b-f Recently, other fluorinated
alkyl ketones (FAKs) have been made commercially available
or, alternatively, suitable synthetic methods have been
reported for them.14,15 Their Rh-catalysed arylation to alcohols
with arylboronic acids has been reported, but in a non-
enantioselective approach.16a However, alkylations are not
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accessible by this method. With this paper in evaluation, the strongly supported by our recent experimental and calculated
copper-catalysed asymmetric methylation, using ZnMe2 and evidence on the speciation of ZnMe2 in THF, which confirms
sophisticated phosphines, of fluoroalkylated piruvates was unambiguously the formation of ZnMe2(THF)2 species and
published
to
provide
good-to-high
yields
and evaluates the coordination free energy involved.19
ZnMe2(DMF)2 analogues should be even more stable. On the
enantioselectivities.16g
In this study we extend our enantioselective alkylation other hand, modest coordinating ability of toluene to Zn(C6F5)2
studies with L* to the new CF2X fluorinated alkyl ketones, and has been reported,20 whereas the coordination ability of
study the effect of the solvent (dichloromethane vs. toluene) hexane or DCM must be negligible.
Moreover, in view of the significant ee improvement achieved
Monitoring of conversions for the reactions in equation 2
for these FAKs upon changing the solvent, we study also the showed that the reactions in DCM corresponding to ketones
solvent effect on (R-C6H4)C(O)CF3 TFMKs and find very 1a
-
3a at –30 °C were complete in 3 h, which prompted us to
important improvements in yield and ee in DCM.
carry out these reactions at a lower temperature in order to
The FAKs PhC(O)CF2X (X = H, 1a; F, 2a; Cl, 3a; CF3, 4a) were increase their ees, which obviously is detrimental for the
tested in the nucleophilic addition reaction of ZnMe2 using conversion time. The reactions with 1a 3a at –50 °C showed
-
ZnMe2/ketone/L* = 1.2/1/0.1 ratio (Eq. 2). ZnMe2 was chosen complete conversion in 24 h, but only similar ees, although 3b
as the more challenging reaction test because of its much was obtained as a single enantiomer. On the other hand, for
lower reactivity and the lower ee it provided in our previous 4a only 11% conversion was achieved in 24 h at –50 °C;
studies, compared to ZnEt2.8 The reactions were carried out at fortunately the reaction at 0 °C was complete in 24 h giving 4b
–30 °C for 24 h using toluene or dichloromethane (DCM) as in 90% ee. As it is usually the case, optimizing the results
solvents. The conversions and enantiomeric excesses of the requires some trade off between best reaction rate and best
products PhC(CF2X)(Me)OH (1b
-
4b) were obtained by 19F NMR enantioselectivity for each case. The comparative low
was not predicted from its expectedly
integration of the reaction mixtures after hydrolisis,17 and by reactivity of ketone
4
chiral GC or HPLC analysis. The S-configuration of the major more stabilized LUMO, which, on the contrary, should favour
enantiomer of 1b was confirmed by comparison with literature the nucleophilic attack. The higher bulkiness of the
data.18
perfluoroethyl group can be responsible for this behaviour.
In order to discuss these catalytic results we need to
remind the singular double cycle mechanism that we proposed
for the actuation of L* 13
Our mechanistic studies for ZnEt2
.
(2)
addition reactions revealed that the reasons for the
outstanding singular efficiency of L* compared to other related
ligands are: i) in contrast to other chelating ligands, due to its
very high steric congestion the potentially chelating L*
coordinates initially as monodentate only, producing 3-
The results collected in Table 1 show total conversion to
the alcohol in both solvents, except for 4a, and a remarkable
increase in conversion and, more important, in
enantioselectivity when DCM is used as solvent instead of
toluene. The alkylation of 4a leads to a single enantiomer
(>99% ee).
coordinated Et2ZnL*, and cycle
I is not very efficient; ii) at
variance with other ligands, L* triggers a second much more
efficient catalytic cycle II, in which L* acts as bridging
bidentate, which leads to autocatalytic asymmetric
enhancement through dinuclear intermediates with L*
bridging the two Zn centers. We assume that the same double
cycle mechanism operates for ZnMe2.
Table 1. Screening of Enantioselective Addition of ZnMe2 to Fluorinated Alkyl Ketones
PhC(O)CF2X.
toluene
conv.%
DCM
conv.%
FAK
1a
2a
3a
4a
X
H
F
Cl
ee%
68
86
88
58
ee%
78
92
98
> 99
> 99
> 99
> 99
59
> 99
> 99
> 99
84
CF3
The ketone was added to a ZnMe2/L* = 1.2/0.1 solution at –30 °C and the mixture
stirred at this temperature for 24 h.
Solvent effects were recently reported by Sasaki using as
model reaction the addition of ZnEt2 to PhCOCF3 at –50 °C for
20 h, in the presence of (Me2PhC)BOX as ligand.10 In these
conditions, the use of THF or DMF as solvent prevented the
reaction to occur, probably because their coordinating ability
to ZnEt2 prevents the coordination of the catalytic chiral
ligand. In contrast, in hexane, toluene, diethyl ether or DCM L*).
the reactions proceed smoothly, with DCM providing the best
performance and enantioselectivity. This interpretation is
Scheme 1. Double catalytic cycle for the addition reaction of ArCOCF3 with ZnEt2 (N–N =
2 | J. Name., 2012, 00, 1-3
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Since the catalysis operates via two competing catalytic enantioselectivity in DCM as solvent, improving very
cycles, one of mononuclear species and another of bridged significantly the results in toluene in the same conditions. As
binuclear species, any molecular or solvent changes should be expected, ketones with EWG on the aromatic ring show very
expected to induce non linear changes on conversion and ee, fast reactions and after 2 h they are almost complete. On the
and the effects can have some complexity. A prior equilibrium other hand, substrates bearing EDG, namely MeO, MeS, and
exists between mononuclear species in cycle I, and binuclear EtS, show low rates and relatively long induction periods when
species in cycle II. Thus, the formation of binuclear versus the evolution of the reaction is checked by 19F NMR. These
mononuclear species can be seriously conditioned by the TFMKs have a potentially coordinating heteroatom that can
coordinating ability of the solvent (toluene > DCM) or other contribute, similar to a coordinating solvent, to make cycle II
coordinating molecules in solution, and by the electronic and less- or non-operative. The effect should be more important
steric effects of the aryl substituents. All these effects are for OMe, with a harder donor atom, than for SR. The expected
particularly harmful for the formation of dimers operating in result if the percentage of catalysis via cycle
I increases in
cycle II. detriment of cycle II is somewhat slower rates and, more
In order to examine these effects, the reaction of important, lower ees, as observed. Interestingly, the bulkiness
PhC(O)CF3 (2a) and ZnMe2 was carried out, in toluene and in of the phenyl substituent 4-Pri seems to influence very
DCM at –30 °C, for three different percentages of L* respect to negatively the yield of the addition product regardless of the
2a: 2.5, 5, and 10%. These experiments showed higher solvent. In this case it is necessary to increase the temperature
reaction rates in DCM compared to toluene, and they showed in order to get 10b (71% yield and 46% ee, 24 h at 25 °C).
also that increasing the L*/2a ratio causes an increase in the
Table 2. Enantioselective Addition of ZnMe2 to various TFMKs (R-C6H4)C(O)CF3 in
reaction rate. This is in agreement with the higher
coordinating ability of toluene to ZnMe2, compared to DCM,
which makes the L* coordination equilibrium in neat toluene
less efficient than in DCM. In spite of the modest coordinating
ability of toluene to Zn, its use as neat solvent is detrimental
for the formation of dimers, and the participation cycle II (fast)
decreases, making the reaction slower and less
enantiomerically efficient. This justifies very well why the
enantioselectivity is higher in DCM than in toluene.
toluene and DCM.
toluene
conv.% ee%
DCM
conv.% ee%
TFMK
2a
R
H
> 99
> 99
> 99
> 99
> 99
> 99
< 1
> 99
17
> 99
> 99
> 99
86
90
82
82
88
57
-
94
50
76
76
72
> 99
> 99
> 99
> 99
> 99
> 99
< 2
> 99
64
> 99
> 99
> 99
92
92
90
88
92
88
-
96
16
84
90
86
5a
4-F
6a
4-Cl
7a
4-Br
8a
9a
4-Me
4-Et
10a
11a
12a
13a
14a
15a
4-Pri
3,5-Me2
2-OMe
4-OMe
4-SMe
4-SEt
Obviously, the percentage of active Me2ZnL* increases
with the percentage of L* added and, since L is always in
catalytic concentration only, it is positive for the formation of
the dimeric active species also. On the other hand, since the
ees remain almost constant regardless of the L*/2a ratio, this
suggests that the most ee efficient cycle II in Scheme 1 is in all
cases the pathway providing most of the product.
The ketone was added to a ZnMe2/L* = 1.2/0.1 solution at –30 °C and this
temperature was maintained for 24 h.
The excellent results in DCM moved us to revisit our
previous studies on (R-C6H4)C(O)CF3 ketones,8,9 applying the
new methodology for less stringent conditions (–30 °C, 24 h,
Finally, the most irregular result in DCM is observed for
12a, with the phenyl substituent 2-OMe, which shows slow
reactions in both solvents, with much lower enantioselectivity
in DCM compared to toluene. The contrast between 2-OMe in
12a and 4-OMe in 13a is striking. We suggest that only 2-OMe
is structurally appropriate to chelate the Zn atoms (Figure 2,
right), in contrast to 4-OMe (Figure 2, left). Not only this O,O-
chelating structure is incompatible with entering cycle II, but it
probably requires higher energy in order to dissociate the O-
DCM as solvent). The (R-C6H4)C(O)CF3 ketones (na
used in the study are listed in the first column of Table 2, and
give rise to the corresponding nb alcohols. Alcohols 5b 8b and
, n = 2, 5-15)
-
13b have been obtained previously by enantioselective
trifluoromethylation of aryl ketones,21 but with noticeably
lower yields and ees. The R configuration was dominant in the
reported cases, whereas the S configuration for the major
enantiomers is obtained in our case using L*. Obviously the
availability of ent-L* would allow us to obtain the R isomers if
desired with the same good conversions and ees. For
comparative purposes the reactions were also carried out in
toluene in the same conditions. The reactions made in toluene
at –30 °C afford higher enantioselectivity than the ones
published before by our group (carried out starting at –37 °C
and leaving to raise to room temperature), confirming the
positive influence on enantioselectivity of keeping the
temperature low during the addition reaction.
Me coordination and proceed via cycle I. Thus the bad results
observed for 12a strongly suggest that this ketone does not
follow the mechanism operating for all the other ketones.
The experimental results in Table 2 show very good
Figure 2 Proposed chelated reaction intermediate for 12a , diverting the reaction to
less efficient pathways than those followed in Scheme 1 for 13a or the other TFMKs.
conversions (except for 10a and 12a
) and excellent
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11 S. Sasaki, T. Yamauchi, H. Kubo, M. Kanai, A. Ishii and K.
Higashiyama, Tetrahedron Letters, 2005, 46, 1497.
12 T. Arai, M. Watanabe and A. Yanagisawa, Org. Lett., 2007, 9,
3595.
13 M. Calvillo-Barahona, J. A. Casares, C. Cordovilla, M. N.
Genov, J. M. Martínez-Ilarduya and P. Espinet, Chem. Eur. J.,
2014, 20, 14800.
14 D. J. Leng, C. M. Black and G. Pattison Org. Biomol. Chem.,
2016, 14, 1531.
In summary, the use of the ligand L* and the very positive
effect of the non coordinating solvent DCM on the
enantioselectivity of the addition reaction of ZnMe2 to
different FAKs have allowed us to prepare for the first time
almost single enantiomers of the fluorinated tertiary alcohols
derived from PhC(O)CF2X (X = Cl, CF3). In most other cases, the
same reaction affords the fluorine-containing tertiary alcohols
in very good yield (often 99%) and with high enantioselectivity
(often >90% ee). Thanks to the availability of the ligands L*
and ent-L*, the fluorinated chiral alcohols could be produced
in the desired configuration. The influence of the solvents and
the aryl substituents in reactions with (R-C6H4)C(O)CF3 ketones
is easily understood in the context of the two-cycle mechanism
of catalysis operating for L*, which in turn reinforces our
mechanistic proposal. As an exception, (R-C6H4)C(O)CF3 with R
= 2-OMe perhaps does not follow this mechanism.
15 L. I. Panferova, F. M. Miloserdov, A. Lishchynskyi, M.
Martínez Belmonte, J. Benet-Buchholz and V. V. Grushin,
Angew. Chem. Int. Ed., 2015, 34, 5218.
16 (a) L. S. Dobson and G. Pattison, Chem. Commun., 2016, 52
,
11116; (b) S. L. X. Martina, R. B. C. Jagt, J. G. De Vries, B. L.
Feringa and A. J. Minnaard, Chem. Commun., 2006, 4093; (c)
V. Valdivia,I. Fernandez and N. Khiar, Org. Biomol. Chem.,
2014, 12, 1211. (d) R. Luo, K. Li, Y. Hu and W. Tang, Adv.
Synth. Catal., 2013, 355, 1297; (e) V. R. Jumde, S. Facchetti
and A. Iuliano, Tetrahedron: Asymmetry, 2010, 21, 2775; (f) J.
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K. Torii and K.Mikami K. Beilstein J. Org. Chem. 2018, 14,
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Thanks are given to: the Junta de Castilla
y León
(VA051P17) for funding, and for a grant (A. V.); the Spanish
MINECO projects CTQ-2016-80913-P and CTQ2014-52796-P;
the "Programa de Becas Iberoamérica + Asia de Banco
Santander-UVa" for a scholarship (to T. N.-G.).
17 The reaction in DCM has only advantages both in conversion
and in enantioselectivity. Furthermore, the volatility of the
solvent makes the final isolation of the chiral alcohol easier.
All the syntheses are reported in the ESI. A typical
preparative procedure using higher amount of starting
ketone is reported here: Ketone 3a (500 mg, 2.6 mmol, 1 eq)
was added to a previously prepared solution containing
ZnMe2 (6.3 mL of a 0.5 M solution in DCM, 3.1 mmol, 1.2 eq)
and L* (201.7 mg, 0.26 mmol, 0.1 eq) in a 100 mL screw tap
Schlenk, immersed in a –85 °C bath of isopropanol. After
addition of the ketone, the reaction was placed during 24 h
in an isopropanol bath with the temperature regulated at –
30 °C by a cryoprobe. Then the mixture was carefully
hydrolysed by dropwise addition of 2 M HCl (15 mL). The
aqueous layer was separated from the DCM layer, and
Notes and references
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extracted with Et2O (2
× 15 mL). Addition of the Et2O extracts
over the DCM layer produced a white precipitate essentially
corresponding to a salt derivate from the ligand, which was
not separated. The combined organic layers were dried over
MgSO4, filtered and concentrated under airflow until ca. 4
mL. The solution was then passed through a short silica gel
column to filter off the insolubles. The resulting solution
afforded alcohol 3b as a colourless oil upon evaporation of
the solvent by airflow. Yield: 525.7 mg, 2.5 mmol, 97%.
Warning: all these alcohols are fairly volatile and attention
must be paid to the moment when all the DCM has been
removed, in order to minimize loses of the desired product.
18 X. Shen, W. Zhang, C. Ni, Y. Gu and J. Hu, J. Am. Chem. Soc.,
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20 Bochmann has reported the formation in toluene of
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(a) M. Hatano, T. Mizuno and K. Ishihara, Synlett, 2010, 13
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4 | J. Name., 2012, 00, 1-3
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TOC
Highly Enantioselective Addition of Dimethylzinc to Fluorinated Alkyl
Ketones, and the Mechanism Behind It
Tomaz Neves-Garcia, Andrea Vélez, Jesús M. Martínez-Ilarduya,* and Pablo
Espinet*
Switching solvent from toluene to dichloromethane produces very important
enhancement in yield and enantiomeric excess of the nucleophilic addition.