Efficient Synthesis of 2-Amino-1-Arylethanols Through a Lewis Base-Catalyzed SiCl4-Mediated Asymmetric Passerini-Type Reaction

Article abstract of DOI:10.1002/ejoc.202001172

We herein report, a practical and efficient strategy for the synthesis of enantiomerically enriched 2-amino-1-arylethanols, a structural motif commonly encountered in the family of β-adrenergic blockers or agonists, through a Lewis base-catalyzed SiCl

Full text of DOI:10.1002/ejoc.202001172

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Efficient Synthesis of 2-Amino-1-Arylethanols Through a Lewis
Base-Catalyzed SiCl4-Mediated Asymmetric Passerini-Type
Reaction
Authors: Aurélie Gernet, Virginie Ratovelomanana-Vidal, Jean-Luc
Pirat, David Virieux, and Tahar Ayad
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001172
Link to VoR: https://doi.org/10.1002/ejoc.202001172
01/2020

10.1002/ejoc.202001172
European Journal of Organic Chemistry
COMMUNICATION
Efficient Synthesis of 2-Amino-1-Arylethanols Through a Lewis
Base-Catalyzed SiCl4-Mediated Asymmetric Passerini-Type
Reaction
Aurélie Gernet,[a] Virginie Ratovelomanana-Vidal,[b] Jean-Luc Pirat,[a] David Virieux*[a] and Tahar Ayad*[a,
b]
[a]
A. Gernet, Prof. J.-L. Pirat, Prof. D. Virieux and Dr. T. Ayad
Institut Charles Gerhardt – UMR 5253, CNRS, AM2N
ENSCM
8 rue de l'Ecole Normale, 34296 Montpellier
E-mail: tahar.ayad@@enscm.fr, david.virieux@enscm.fr
https://www.icgm.fr/recherche-am2n/methodologie-de-synthese-et-molecules/groupe-virieux
Dr. Virginie Ratovelomanana-Vidal and Dr. T. Ayad
Institute of Chemistry for Life & Health Sciences
PSL University, Chimie ParisTech-CNRS
[b]
11 rue Pierre et Marie Curie 75005 Paris
E-mail: tahar.ayad@chimieparistech.psl.eu
Supporting information for this article is given via a link at the end of the document.
ring-opening of epoxides[9] and aziridines,[10] as well as
oxyamination reactions.[11] It has been also established that
optically active nitroaldol or cyanohydrin adducts obtained from
the corresponding benzaldehydes can lead to the 2-amino-1-
arylethanols.[12] Reductive cross-coupling reactions of imines with
carbonyl derivatives have also been developed.[13] However,
although efficient, most of these methods suffer from some
disadvantages such as the need of stoichiometric amounts of
chiral reducing agent or auxiliary, the use of expensive noble
metal catalysts, stereochemistry issues along with structurally
limited substrates/products and multiple synthetic steps that often
require tedious purifications. Consequently, there is still much
room for the development of more sustainable and
straightforward protocols for the synthesis of 2-amino-1-
arylethanols with high levels of chemical efficiency and
stereocontrol.
Abstract: We herein report, a practical and efficient strategy for the
synthesis of enantiomerically enriched 2-amino-1-arylethanols, a
structural motif commonly encountered in the family of -adrenergic
blockers or agonists, through a Lewis base-catalyzed SiCl4-mediated
asymmetric Passerini-type reaction of isocyanides with aldehydes.
The protocol features a simple one-pot, two-step procedure, the use
of commercially available starting materials, a broad functional group
tolerance and high levels of selectivity up to 98.5:1.5 er. Application
to the synthesis of the salbutamol acetate salt, a drug widely used as
a bronchodilator to manage asthma and other chronic obstructive
airway diseases is also reported.
Enantiomerically pure 1,2-amino alcohols are highly valuable
scaffolds that, besides their wide applications in organic synthesis
both as chiral ligands and auxiliaries, are found in many naturally
occurring
compounds
and
pharmacologically
relevant
molecules.[1] In particular, 2-amino-1-arylethanols that belong to
the family of -adrenergic blocking or activating agents, are a
group of molecules that inhibits or activates β-adrenergic
receptors. They are widely prescribed in the therapy of asthma,
bronchitis, and congestive heart failure. Representative examples
of this class of efficient drugs are depicted in Figure 1. Timolol[2]
is a non-selective -adrenergic antagonist used for the treatment
of glaucoma and ocular hypertension. Salbutamol,[3] also known
as albuterol and marketed as Ventolin® is one of the oldest
selective β2-adrenoreceptor stimulants with a rapid and potent
bronchodilator activity intensively used to treat asthma, while
Bambuterol[4] and Clenbuterol[5] are two selective long-acting
bronchodilators with distinct mechanisms, generally prescribed
for their extended durations of action.
Figure 1. Representative 2-Amino-1-Arylethanol Drugs.
Given the high medicinal value of 2-amino-1-arylethanols, it is
not surprising, therefore, that the development of truly efficient
methods for their preparation in enantiomerically pure or enriched
forms has been explored and still remains a paramount goal of
practical significance in both academia and industry.[6] To date,
current stereoselective approaches rely on addition-type
reactions that include either functional group manipulations of
vicinal N,O-compounds such as diastereoselective nucleophilic
additions[7] and asymmetric reductions of imines and ketones,[8]
or addition of N/O-compounds on suitable substrates such as
As part of our ongoing research program dedicated to the
design and synthesis of new chiral diphosphine dioxide ligands
and their applications[14,15] as chiral Lewis bases for asymmetric
catalysis,[16] we report in this contribution a practical and efficient
new one-pot, two-step strategy for the preparation of optically
active 2-amino-1-arylethanols through a Lewis base-catalyzed
SiCl4-mediated cascade process. This protocol involves a
Passerini-like reaction between various aldehydes and
isocyanides,[17] that furnished not "truncated" Passerini
1
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10.1002/ejoc.202001172
European Journal of Organic Chemistry
COMMUNICATION
compounds but 2-aminoalcohols instead, via subsequent in situ
reduction of the resulting -trichlorosilyloxyimidoyl chloride
intermediates.[18] Notably, our approach even enables the facile
introduction of a bulky tert-butyl group attached to the nitrogen
atom, that besides being a common feature of a broad range of
β-adrenergic medicines as highlighted in Figure 1, has proven to
be an essential structural feature for achieving high selectivity for
a specific -adrenergic receptor and provides better stability
against unwanted metabolic N-dealkylation reaction.[19]
We began our investigation by searching the most efficient
chiral Lewis base catalysts to perform the asymmetric α-addition
of tBu-isocyanide 1a to benzaldehyde 2a, which resulted in the
formation of 2-(tert-butylamino)-1-phenylethan-1-ol 3a.
diisopropylethylamine for 6 h. As depicted in Table 1, the reaction
proceeded smoothly to give the desired amino alcohol 3a with
complete conversion for all Lewis base catalysts examined.
However, both the chemical yields and enantiomeric ratios were
greatly affected by the structure of the catalysts (entries 1−5). For
instance, reactions conducted with the “home-made” bis-
(triazolyl)diphenylphosphine dioxide catalysts A and B delivered
the desired 2-(tert-butylamino)-1-phenylethan-1-ol 3a in
acceptable yields of 69% and 62%, but with disappointing
enantiomeric ratios of 63:37 and 54:46, respectively (entries 1 and
2). Comparable results were achieved with atropisomeric (S)-
BINAPO C and (S)-SYNPHOSO D ligands. Gratifyingly, very
promising results were obtained from Denmark’s doubly
atropisomeric bis-phosphoramide catalyst E, a highly efficient
chiral Lewis base that have found widespread applications in
promoting various stereoselective transformations, giving 3a in
73% isolated yield and with a good enantiomeric ratio of 90:10. A
rapid solvent screening revealed that dichloromethane was ideal
in view of the chemical efficiency and stereocontrol (entries 6−9).
In addition, we found that the enantiomeric ratio is significantly
improved by preventing the non-selective pathway through the
slow addition of tBu-isocyanide over 4 h (entry 10). Further
attempts to increase the selectivity of the process by lowering the
catalyst loading did not meet with success. Indeed, reaction
performed with 3 mol % of bis-phosphoramide catalyst E
furnished compound 3a with an enantiomeric ratio similar to that
reported for 5 mol %, while a marked drop in the selectivity was
observed when using only 1 mol % of organocatalyst E. This
result suggested that lowering the catalyst loading presumably
slowed down the enantioselective pathway by decreasing the
concentration of the in situ generated reactive chiral hypervalent
silicate intermediate, thus favoring the non-selective reaction
Table 1. Optimization of Reaction Conditions[a]
Entry
1[e]
Cat./mol%
A/5
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
Conv. [%][b]
100
100
100
100
100
80
Yield [%)][c]
er [%][d]
63:37
54:46
58:42
52:48
90:10
81:19
85:15
nd
69
62
61
70
73
58
60
26
29
61
77
62
2[e]
B/5
3[e]
C/5
4[e]
D/5
5[e]
E/5
6[e]
E/5
7[e]
E/5
EtCN
90
induced by SiCl4 itself (entries 11−12).
8[e]
E/5
toluene
THF
44
With the optimized reaction conditions in hand, we next
explored the substrate scope of this Lewis base-catalyzed SiCl4-
mediated asymmetric Passerini-type reaction. As shown in Table
2, good yields and high levels of asymmetric induction up to
98.5:1.5 er were generally obtained for all aromatic aldehyde
substrates probed with a significant structural variation. We
observed that both reactivity and enantioselectivity highly
depended on the position and electronic nature of the R1
substituent attached to the aryl ring. For instance, α-addition of
tBu-isocyanate 1a to benzaldehyde derivatives 2at that bear
electron-withdrawing groups such as –CF3 or –Br at the para
position resulted in the formation of the corresponding 2-amino-1-
arylethanols 3b and 3c in 73% and 76% yields and with high
enantiomeric ratios of 96.5:3.5 and 6.5:93.5, respectively (entries
2 and 3). Comparable high catalytic activity was achieved with
para substituted aldehydes having electron donating groups such
as –Me and –OC(Me)2OCH2-, giving aminoalcohols 3d and 3f in
75% and 71% yields and excellent stereocontrol with 98.5:1.5 and
98:2 er, respectively (entries 4 and 6). Notably, and for unclear
reasons, the reaction performed with p-MeO anisaldehyde 3e led
to a slightly lower selectivity of 91:9 er, albeit with a similarly good
yield of 75% (entry 5). The catalytic efficiency is restored when
the reaction is carried out with meta-substituted arylaldehydes
possessing electron-donating groups, providing products 3g−i
with enantiomeric ratios between 92:8 and 96:4 and isolated
yields varying from 73 to 77% (entries 7–9). In contrast, the
presence of electron-withdrawing substituents such as –Br or –
CF3 at the meta position resulted in the formation of 3j and 3k in
high chemical yields but with a significant decline in the observed
selectivity with 86:14 and 84.5:13.5 er, respectively (entries 10
and 11). Interestingly, steric hindrance of the substrates does not
affect the outcome of the catalysis, in particular for ortho-
substituted aldehydes. Indeed, compounds 3l and 3m with either
9[e]
E/5
49
nd
10[f]
11[f]
12[f]
E/5
CH2Cl2
CH2Cl2
CH2Cl2
100
100
100
97:3
E/3
96:4
E/1
89:11
[a] Reaction performed at 78 oC using x mol % of catalyst with PhCHO (1
mmol), tBuNC (1.2 mmol), SiCl4 (1.1 mmol 1M in CH2Cl2) and iPr2NEt (0.2
mmol) in 1 mL of solvent for 6 h. [b] Determined by 1H NMR. [c] Yields. [d]
Determined by HPLC. The absolute configuration was determined to be R by
comparing the sign of the specific rotation with the literature data. [e] Dropwise
addition of tBuNC in CH2Cl2 over 15 min. [f] Dropwise addition of tBuNC in
CH2Cl2 over 4 h.
Toward this end, several Lewis base organocatalysts (AE)
were screened. Initial experiments were carried out in
dichloromethane at 78 °C, with a dropwise addition of tBu-
isocyanide over a period of 15 min using a combination of 5 mol %
of catalyst with 1.1 equivalent of SiCl4 and a catalytic amount of
2
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10.1002/ejoc.202001172
European Journal of Organic Chemistry
COMMUNICATION
an electron-withdrawing Cl-group or an electron-donating Me-
group, were generated in good yields and with excellent
enantiomeric ratios of 96:4 and 97.5:2.5, respectively (entries 12
and 13). The same trend was observed when sterically hindered
1-naphthaldehyde was used, giving 3n in 70% yield with an
excellent er of 96.5:3.5, whereas the reaction performed with the
less hindered 2-naphthaldehyde delivered product 3o in 80%
13
14
3m
3n
tBu
tBu
71
70
97.5:2.5
96.5:3.5
yield and
a marked decrease in the selectivity with an
15
16
17
18
3o
3p
3q
3r
tBu
tBu
tBu
tBu
79
68
72
72
87:13
91.5:8.5
9:91
enantiomeric ratio of 87:13 (entries 14 and 15). Notably, alkyl
substituted aldehydes proved to be suitable partners for this
process, affording the corresponding adducts 3p and 3q in 68%
and 72 % yields and with good enantiofacial discrimination of
91.5:8.5 and 9:91, respectively (entries 16 and 17). Moreover, it
turned out that the reaction proceeded likewise with substrate
having a thienyl group, although a significant drop in the catalytic
activity was observed in this case, giving 3r in 72% yields and a
disappointing enantiomeric ratio of 75:25 (entry 18). Finally, the
nature of the isocyanide on the catalytic activity was briefly
studied. As illustrated in Table 2, iPr-isocyanide is not a good
partner in this reaction providing low reactivity, while the use of
Cy-isocyanide gave the desired 2-amino-1-arylethanol 3t with a
marked decrease of both yield and selectivity compared to the
result obtained with tBu-isocyanide (entries 19 and 20).
75:25
19
20
3s
3t
iPr
36
53
nd
Cy
62.5:37.5
[a] Reaction performed at 78 oC in CH2Cl2 using 3 mol % of (S,S)-E with various
aldehydes (1 mmol), SiCl4 (1.1 mmol 1M in CH2Cl2), iPr2NEt (0.2 mmol) in 1 mL
of CH2Cl2 and with a dropwise addition of a CH2Cl2 solution of isocyanides over
4 h (1.2 mmol). [b] Yields. [c] Determined by HPLC.
Table 2. Amino Alcohol Syntheses: Substrate Scope[a]
Interestingly, scale-up of the reaction at lower catalyst loading
of 1 mol% occurred without problems. For instance, a five-fold
scale-up at 5 mmol (≃ 1 g) of the acetonide protected aldehyde
2f gave the optically enriched key intermediate of salbutamol 3f
in 68% yield without erosion of the enantioselectivity (up to 2:98
er). To avoid racemization, deprotection of the isopropylidine ketal
moiety was performed under mild aqueous acidic conditions,
leading to the antiasthmatic drug (R)-salbutamol acetate salt 4f in
88% yield with 1H and 13C NMR spectral as well as specific
rotation data in full agreement with those reported in the literature
(Scheme 1).[18,20] This result clearly underlines the practicality and
the usefulness of the herein reported protocol to access
medicinally valuable chiral 2-amino-1-arylethanols.
Entry
1
R1
R2
Yield [%)][b]
77
er [%][c]
96:4
3a
3b
tBu
2
tBu
73
96.5:3.5
3
4
3c
3d
tBu
tBu
76
75
6.5:93.5
98.5:1.5
5
6
3e
3f
tBu
tBu
75
71
91:9
2:98
7
3g
tBu
73
93.5:6.5
Scheme 1. Scale-up Synthesis of (R)-Salbutamol Acetate 4f.
8
3h
3i
tBu
tBu
tBu
tBu
tBu
74
77
80
78
70
92:8
9
96:4
To conclude, we reported an atom economical and attractive
route to pharmaceutically relevant 2-amino-1-arylethanols
through Lewis base-catalyzed SiCl4-mediated cascade
procedure. This metal-free, one-pot two-step process has some
attractive features such as the use of commercially available
starting materials, operational simplicity, a broad functional group
tolerance and high levels of selectivity up to 98.5:1.5. Moreover,
we demonstrated the effectiveness and scalability of our
approach through the gram-scale preparation of the Salbutamol
acetate salt, a drug widely used as a bronchodilator to manage
asthma and other chronic obstructive airway diseases.
10
11
12
3j
86:14
84.5:14.5
96:4
3k
3l
3
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10.1002/ejoc.202001172
European Journal of Organic Chemistry
COMMUNICATION
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Acknowledgements
A. G. gratefully acknowledge financial support from the Centre
National de la Recherche Scientifique (CNRS) and the Ministère
de l’Enseignement Supérieur, de la Recherche et de l’Innovation.
[13] O. N. Burchak, S. Py, Tetrahedron 2009, 65, 73337356.
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Conflict of interest
The authors declare no conflict of interest.
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Keywords: Passerini Reaction • 2-Amino-1-arylethanols •
Asymmetric Catalysis • Lewis Base • Salbutamol
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10.1002/ejoc.202001172
European Journal of Organic Chemistry
COMMUNICATION
Organocatalysis
An atom economical and metal-free, one-pot two-step asymmetric synthesis of highly valuable 2-amino-1-arylethanols has been
established from commercially available starting materials. The effectiveness and scalability of our approach has been demonstrated
via the synthesis of the Salbutamol acetate salt, a bronchodilator widely used to treat asthma.
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This article is protected by copyright. All rights reserved.