Chiral Lithium Amido Aryl Zincates: Simple and Efficient Chemo- and Enantio-Selective Aryl Transfer Reagents

Article abstract of DOI:10.1002/anie.201813510

An enantioselective aryl transfer is promoted using chiral tricoordinated lithium amido aryl zincates that are easily accessible reagents and whose chiral appendage is simply recovered for reuse. The arylation reaction is run in good yields (60 % average on twenty substrates) and high enantiomeric excesses (95 % ee average). This occurs whatever the ortho, meta, or para substituent borne by the substrate and a complete chemoselectivity is observed with respect to the aldehyde function. Sensitive groups such as nitriles, esters, ketones, and enolisable substrates resist to the action of the ate reagent, warranting a large scope to this methodology.

Full text of DOI:10.1002/anie.201813510

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201813510
German Edition: DOI: 10.1002/ange.201813510
Enantioselective Aryl Transfer
Chiral Lithium Amido Aryl Zincates: Simple and Efficient Chemo- and
Enantio-Selective Aryl Transfer Reagents
Pauline Chaumont-Olive, Mathieu Rouen, Gabriella Barozzino-Consiglio,
Amel Ben Abdeladhim, Jacques Maddaluno, and Anne Harrison-Marchand*
Abstract: An enantioselective aryl transfer is promoted using
chiral tricoordinated lithium amido aryl zincates that are easily
accessible reagents and whose chiral appendage is simply
recovered for reuse. The arylation reaction is run in good yields
(60% average on twenty substrates) and high enantiomeric
excesses (95% ee average). This occurs whatever the ortho,
meta, or para substituent borne by the substrate and a complete
chemoselectivity is observed with respect to the aldehyde
function. Sensitive groups such as nitriles, esters, ketones, and
enolisable substrates resist to the action of the ate reagent,
warranting a large scope to this methodology.
specific metal (M1 = M2: the reaction intermediate is a homo-
(bi)metallic complex)[2] or two dissimilar metals (M1 ¼ M2:
hetero(bi)metallic complex).[3–5]
Two limitations still remain regarding the most frequently
depicted examples of aryl transfer processes involving either
an aldehyde (Z = O, Y = H) or an imine (Z = NR’): i) high
ee values are observed only with aromatic aldehydes substi-
tuted at the ortho position; and ii) the reaction hardly applies
to aromatic substrates and/or reagents bearing sensitive
functionalities such as a nitrile, an ester, or a ketone.[6]
Simultaneously addressing the challenge of both chemo-
and enantio-selectivities promises considerable added value
to a reaction triggering a one-step access to highly function-
alized molecular targets of biological interest. In this context,
ate complexes, such as lithium- zincates,[7] magnesates,[8] and
aluminates,[9] have shown a high tolerance toward ester,
nitrile, carbamate, amide, and even ketone functions when
conducting deprotonative metalations of aromatic substrates.
The question whether this compatibility would persist when
considering ate species for their nucleophilic rather than basic
properties still remains unanswered. Although ate complexes
have been seldom considered for nucleophilic additions,
precursory developments by Gau with aluminum titana-
tes,[4k–n] Higashiyama with lithium titanates,[4p] Woodward
with aluminum zincates,[5a] or Mongin with lithium magne-
sates and zincates,[10] show the potential of such species to
perform enantioselective nucleophilic arylation reactions.
However, these studies have rarely focused on the case of
substrates bearing a sensitive function.
B
ecause of the many opportunities it opens, such as the
ꢀ
creation of C C bonds, the formation of stereogenic tertiary,
but also quaternary centers, as well as direct access to the
highly prized benzhydryl skeletons,[1] the asymmetric aryl
transfer reaction (Scheme 1) has been among the most
Scheme 1. General scheme of the enantioselective aryl transfer reac-
Very recently, our group described an efficient method-
ology to carry out enantio- and chemo-selective nucleophilic
1,2 additions on aldehydes using cheap and easily accessible
chiral tricoordinated lithium amido zincates (Scheme 2).[11]
This study highlighted an unprecedented chiral nucleophilic
ate complex offering numerous advantages that are: i) a low
cost and easy handling and access, ii) a high level of efficiency
tion.
scrutinized chemical transformations in the 2000–2015
period.[2–5] Numerous efficient and varied methodologies
have been set up, and it is interesting to note that these
developments mainly involve organo(bi)metallic combina-
tions with one organometallic partner providing the nucleo-
philic aryl moiety (ArM1) while the second brings the chiral
vector (L*M2). These bimetallic species consist of either one
[*] Dr. P. Chaumont-Olive, Dr. M. Rouen, Dr. G. Barozzino-Consiglio,
A. Ben Abdeladhim, Dr. J. Maddaluno, Dr. A. Harrison-Marchand
Normandie Univ, UNIROUEN, INSA de Rouen, CNRS
Laboratoire COBRA (UMR 6014 & FR 3038)
76000 Rouen (France)
E-mail: anne.harrison@univ-rouen.fr
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201813510.
Scheme 2. General scheme of the enantioselective nucleophilic 1,2-
addition of chiral tricoordinated lithium amido alkyl- or aryl- zincates
on aldehydes.
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Table 1: Results obtained when optimizing the enantioselective nucleo-
philic 1,2-arylation of 3a with the chiral zincate made of Ph2Zn and CLA
1-Li.
for enantioselective nucleophilic 1,2-alkylations with up to
97% ee, iii) a high reactivity towards the aldehyde function
while fully preserving the sensitive ester and nitrile groups,
and iv) the easy recycling of the chiral inductor, the chiral
lithium amide (CLA) 1-Li, thanks to a single acid-base wash.
An unoptimized preliminary result featured in our
previous article led us to conclude that extending the
procedure above to the enantioselective nucleophilic aryla-
tion reaction was an attractive option. That result corresponds
to the stereoselective nucleophilic addition of a phenyl group
on ortho-tolualdehyde in the presence of the chiral tricoordi-
nated lithium amido aryl zincate resulting from the combina-
tion of Ph2Zn 2a and CLA 1-Li (Yield 34%, 54% ee). In this
paper, we show that highly enantio- and chemo-selective
arylation reactions can be performed using a comparable
methodology.
The main problem encountered while running the pre-
liminary result mentioned above was the mediocre solubility
of Ph2Zn in diethyl ether (Et2O), a drawback disrupting the
reproducibility of the experiments. We thus first focused on
finding a procedure which secured the consistency of both
yields and enantiomeric excesses. Note that Ph2Zn is com-
mercially available as a white-grey powder highly sensitive to
oxygen and moisture. Three practical protocols based on
handlings under an inert atmosphere were tested to prepare
the zincate. These are: A) pouring Ph2Zn onto a freshly
prepared solution of 1-Li in Et2O using a solid-addition
glassware; B) adding a freshly prepared Et2O-solution of 1-Li
on solid Ph2Zn via a cannula; and C) syringing a heteroge-
neous preformed Ph2Zn solution in Et2O onto a freshly
prepared solution of 1-Li in the same solvent. The three
experiments were run with 3a and after 1 h at ꢀ788C, only
procedure C led to the expected alcohol 4 (Scheme 3).
Entry Sonication c’
[M]
c
[M]
zincate/3a
t
Yield ee[a,b]
[h] [%]
[%]
[c]
1
2
3
4
No
Yes
Yes
Yes
0.034 1:0.8
3
1
1
1
34
57
54
69
54
91
94
95
0.098 0.034 1:0.8
0.098 0.039 1:0.8
0.098 0.039 1:0.6
[a] Determined by chiral HPLC; [b] major alcohol: 4-R; [c] c’ not
determined.
and 4). These adjustments led to a 69% yield and an ee as high
as 95%. These conditions were considered optimal as the
introduction of the chiral zincate in excess is reasonable
because the chiral inductor is quantitatively recovered and
recycled, as was shown in our previous article and is verified
in this study.[11]
The next objective consisted of studying the scope of the
method and a first series involved twelve aromatic aldehydes
substituted in ortho, meta, or para (3b to 3m, Scheme 4 and
Table 2). All experiments were run for 1 h and repeated for 3
and/or 12 h when the yield was below 40%.
Scheme 4. Scope of the enantioselective nucleophilic 1,2-arylation
methodology on aromatic aldehydes substituted by non-sensitive
groups on the ortho, para, or meta position.
Scheme 3. Optimisation of the enantioselective nucleophilic 1,2-aryla-
tion on 3a with the chiral lithium amido aryl zincate made of Ph2Zn
and CLA 1-Li.
The results in Table 2 show excellent ee values (ꢁ 90%)
regardless of the substrate. Interestingly, reaching good levels
of induction is not found to be restricted to ortho substituted
aromatic, which was a major limitation in the approaches
reported in the literature. Also note that the sense of
induction is always in favor of alcohol R. Closer examination
of the data reveals that the highest yields reached after 1 h of
reaction correspond to aromatic aldehydes substituted in
ortho by an electron-withdrawing group (entries 5 to 8).
However, with the other substrates, substituted in para
(entries 11–13) or meta (entries 14–17) by an electron-with-
drawing substituent, or in ortho by an electron-donating
group (entries 1–4), the yields could be easily improved by
simply increasing the reaction time (see entries 11 and 12, 15
and 16, as well as 2 and 3). Only para-tolualdehyde 3h failed
Adjustments aimed at refining the conditions for the
preparation of Ph2Zn in Et2O and obtaining an easy protocol
were run. We found that reproducible results were obtained
working with a heterogeneous solution of Ph2Zn in dry Et2O
of which c’ = 0.098m and subjected to 45 minutes of ultra-
sounds (power level 60 Hz) before use. Running then the
arylation in the same conditions as for the preliminary results
(zincate/3a ratio 1:0.8 and c = 0.034, Table 1, entry 1) but only
for 1 hour (instead of 3 h) enabled us to isolate 4 in a 57%
yield and 91% ee (Table 1, entry 2). The yield was further
improved by i) increasing c from 0.034 to 0.039m, and
ii) changing the zincate/3a ratio from 1:0.8 to 1:0.6 (entries 3
2
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Table 2: Results of the scope presented in Scheme 4.
ent tends to slow down the reaction since the yields did not
exceed 60%, even after 12 h. The level of induction is also
slightly below those mentioned in the previous series, ranging
from 77 to 89% ee. However, the crucial information that
emerges from these experiments is that cyano, ester, and even
keto groups are compatible with the ate reagent. Indeed, the
NMR analyses of the crude products indicate that beside
alcohols 17 to 20, only unreacted starting material 3n to 3q
was recovered, respectively. Note that in the case of aldehydes
3p and 3q, the reaction mixture was quenched with deuteri-
ated methanol (MeOD).
As no deuteration of the ester and acetyl groups was
noted, experiments involving non-aromatic enolisable alde-
hydes such as cyclohexylcarboxaldehyde 3r and dihydro-
cinnamaldehyde 3s (Scheme 5 and Table 3, entries 8 and 9)
were run. Quenching the reaction with MeOD after 1 h
showed the sole presence of arylation products 21 and 22
(ee values in the 70–80% range) next to unreacted undeu-
teriated starting material. Although yields and inductions
remain to be improved, the two last sets of tests show that the
arylation method developed in this work is strictly chemo-
selective of the aldehyde function.
Entry
Aldehyde
Alcohol
t [h]
Yield [%]
ee[a,b] [%]
1
2
3
4
5
6
7
8
3a
3b
3b
3c
3d
3e
3 f
3g
3h
3h
3i
3i
3j
3k
3l
3l
4
5
5
6
7
8
9
10
11
11
12
12
13
14
15
15
16
1
1
12
1
1
1
1
1
1
12
1
12
1
12
1
3
69
38
64
47
57
73
77
76
16
11
37
50
44
50
40
57
72
95
95
91
95
95
92
93
96
86
92
97
94
95
90
84
91
90
9
10
11
12
13
14
15
16
17
3m
12
[a] Determined by chiral HPLC; [b] major alcohol: 4–16-R.
(entries 9 and 10) with a yield remaining below 20% whatever
the reaction time.
The following step consisted of assessing the chemo-
selectivity of the method by reacting the Ph2Zn/1-Li complex
with ortho and meta-cyanobenzaldehyde 3n and 3o, para-
methoxycarbonyl benzaldehyde 3p and meta-acetyl benzal-
dehyde 3q (Scheme 5). The results obtained (Table 3,
entries 1–7) show that the presence of the sensitive substitu-
Last, but not least, is the result obtained with pivalalde-
hyde, which provided arylation product 23 in 49% NMR yield
associated to the highest 99% ee.
Repeating a procedure by Koszinovski[12] enabled to
isolate salt-free Ph2Zn 2a and p-Tol2Zn 2b[13] which were
involved in the enantioselective nucleophilic addition reac-
tion optimized above with ortho-tolualdehyde (Scheme 6).
Scheme 6. Enantioselective nucleophilic 1,2-arylation of ortho tolualde-
hyde in the presence of 1-Li with salt free freshly prepared Ph2Zn and
p-Tol2Zn.
The freshly prepared Ph2Zn led to alcohol 4 with yield and
induction comparable to those obtained with the commercial
batch (Yield 63%, 95% ee). Alcohol 24 resulting from the
arylation implying p-Tol2Zn was isolated after 1 h in 57%
yield and 95% ee in favor of the R enantiomer. The
modulation of the nucleophilic aryl group is to be extended
to other Ar fragments, which requires the development of
effective methods to access salt-free diarylzinc.[14,15] However,
the two results in Scheme 6 augur well for the applicability of
the methodology to various Ar2Zn.
The new methodology was applied to the synthesis of
molecules of interest. Thus, (R)-Orphenadrine and (R)-Neo-
benodine, of which antihistaminic and anticholinergic proper-
ties are well known, were prepared in two to three straight-
forward synthetic steps, respectively from commercial o-
TolCHO 3a and p-ClC6H4CHO 3i (Scheme 7).
Scheme 5. Scope of the enantioselective nucleophilic 1,2-arylation
methodology on aldehydes with sensitive groups.
Table 3: Results of the scope presented in Scheme 5.
Entry
Aldehyde
Alcohol
t [h]
Yield [%]
ee[a,b] [%]
1
2
3
4
5
6
7
8
9
3n
3n
3o
3o
3p
3p
3q
3r
17
17
18
18
19
19
20
21
22
1
12
1
12
1
12
1
24
39
58
59
47
42
39
21
24
86
87
80
77
81
87
89
80
74[c]
1
1
3s
Good overall yields (up to 54%) and excellent ee values
(up to 95%) were obtained. In both cases, the enantioselec-
[a] Determined by chiral HPLC; [b] major alcohol: 17–21-R; [c] major
alcohol: 22-S.
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Scheme 7. Syntheses of (R)-Orphenadrine and (R)-Neobenodine.
tive key reaction was run first, leading to benzhydrols 4 and
12, with the amino ethereal appendage introduced after-
wards.[4d] Because of the low yields obtained from p-TolCHO
(< 12%, Table 2, entries 9 and 10), the synthesis of the (R)-
Neobenodine was initiated from p-ClC6H4CHO with the
chlorine atom replaced by a methyl appendage thanks to
a halogen-metal exchange run in a quantitative yield as the
final step.
In conclusion, this note highlights the potential and
flexibility of chiral tricoordinated lithium amido zincates in
enantioselective nucleophilic 1,2-additions. These reagents
are easily accessible and recyclable and allow aryl transfer
reactions, as simply as demonstrated earlier for alkylations,[11]
with high stereoselectivities, good yields and a total chemo-
selectivity towards the aldehyde function, leaving intact other
sensitive functions such as ester, nitrile and ketone groups or
enolisable sites. The methodology optimized was effectively
applied to the syntheses of molecules of pharmaceutical
interest.
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Acknowledgements
The authors thank the Labex SynOrg (PC, ANR-11-LABX-
0029), the Agence Nationale pour la Recherche (MR, ANR-
07-BLAN-0294-01), the CNRS (GB and JM) and the
University of Rouen (ABA and AHM) for financial supports.
The Rꢀgion Normandie is also acknowledged for material
support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: chiral lithium amido zincate ·
enantioselective aryl transfer · nucleophilic 1,2 arylation ·
(R)-Neobenodine · (R)-Orphenadrine
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Org. Chem. 2010, 3696 – 3703; p) X. Jia, A. Lin, Z. Mao, C. Zhu,
Y. Cheng, Molecules 2011, 16, 2971 – 2981; q) R. Infante, J. Nieto,
C. Andrꢀs, Org. Biomol. Chem. 2011, 9, 6691 – 6699; r) X. Song,
Y.-Z. Hua, J.-G. Shi, P.-P. Sun, M.-C. Wang, J. Chang, J. Org.
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Angew. Chem. Int. Ed. 2008, 47, 1503 – 1507; Angew. Chem. 2008,
120, 1526 – 1530; b) G. Bentabed-Ababsa, F. Blanco, A. Der-
dour, F. Mongin, F. Trꢀcourt, G. Quꢀguiner, R. Ballesteros, B.
Abarca, J. Org. Chem. 2009, 74, 163 – 169.
[9] For chemoselective aromatic deprotonative metalations with
aluminates, see a) H. Naka, M. Uchiyama, Y. Matsumoto,
A. E. H. Wheatley, M. McPartlin, J. V. Morey, Y. Kondo, J.
Am. Chem. Soc. 2007, 129, 1921 – 1930; b) S. H. Wunderlich, P.
Knochel, Angew. Chem. Int. Ed. 2009, 48, 1501 – 1504; Angew.
Chem. 2009, 121, 1530 – 1533.
[10] a) D. Catel, F. Chevallier, F. Mongin, P. C. Gros, Eur. J. Org.
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Gros, Tetrahedron: Asymmetry 2012, 23, 1678 – 1682; c) D. Catel,
O. Payen, F. Chevallier, F. Mongin, P. C. Gros, Tetrahedron 2012,
68, 4018 – 4028; d) D. Tilly, K. Snꢀgaroff, G. Dayaker, F.
Chevallier, P. C. Gros, F. Mongin, Tetrahedron 2012, 68, 8761 –
8766.
[11] M. Rouen, P. Chaumont, G. Barozzino-Consiglio, J. Maddaluno,
A. Harrison-Marchand, Chem. Eur. J. 2018, 24, 9238 – 9242.
[12] J. E. Fleckenstein, K. Koszinowski, Organometallics 2011, 30,
5018 – 5026.
[13] Both Ph2Zn and p-Tol2Zn synthesized following Koszinovskiꢅs
procedure were contaminated by biaryl biproducts Ph-Ph and p-
Tol-p-Tol, respectively. As the latter must not prevent the
addition reaction of nucleophilic arylation studied, the two
organozincs were reacted in the presence of these impurities.
[14] Study in progress.
´
Chem. 2014, 79, 6087 – 6093; s) S. Jarzynski, G. Utecht, S.
´
[15] The arylation has been conducted adding LiCl after the
formation of the zincate (before that of the aldehyde) or at the
same time than the aldehyde. In both cases, no reaction was
observed. Only starting material was recovered, a result inter-
preted in the hypothesis that LiCl and the lithium amide would
form a strong dipole-dipole mixed aggregate letting unreactive
free Ph2Zn in the medium. F. Patꢀ, N. Duguet, H. Oulyadi, A.
Harrison-Marchand, C. Fressignꢀ, J.-Y. Valnot, M.-C. Lasne, J.
Maddaluno, J. Org. Chem. 2007, 72, 6982 – 6991.
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1774 – 1779; t) Y. Wang, H. Zong, H. Huang, L. Song, Tetrahe-
dron: Asymmetry 2017, 28, 90 – 97.
[6] Among studies regarding enantioselective aryl transfers, only
a few, that are [2l], [2m], [2p], [4i], [5a], [5g], and [5r–t], are
punctually considering aromatic substrates and/or aryl nucleo-
philes substituted by a CN or a CO2R group, and even more
rarely is encountered the possibility of engaging a ketone
function only found in [2q], [4n], and [5c].
[7] For chemoselective aromatic deprotonative metalations with
zincates, see a) Y. Kondo, M. Shilai, M. Uchiyama, T. Sakamoto,
J. Am. Chem. Soc. 1999, 121, 3539 – 3540; b) K. Snꢀgaroff, S.
Komagawa, F. Chevallier, P. C. Gros, S. Golhen, T. Roisnel, M.
Uchiyama, F. Mongin, Chem. Eur. J. 2010, 16, 8191 – 8201.
Manuscript received: November 27, 2018
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Enantioselective Aryl Transfer
Chemo- and enantio-selective nucleo-
philic aryl transfer: The key reactant is
a chiral tricoordinated lithium amido aryl
zincate of which the chiral appendage is
simply recovered and reused. The aryla-
tion leaves intact sensitive functions such
as esters, nitriles, ketones or enolisable
sites, while running with aldehyde groups
in good yields and high ee values, this
whatever the ortho, meta, or para sub-
stituent borne by the substrate if aro-
matic.
P. Chaumont-Olive, M. Rouen,
G. Barozzino-Consiglio,
A. Ben Abdeladhim, J. Maddaluno,
A. Harrison-Marchand*
&&& — &&&
Chiral Lithium Amido Aryl Zincates:
Simple and Efficient Chemo- and Enantio-
Selective Aryl Transfer Reagents
6
www.angewandte.org
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
These are not the final page numbers!