Kinetic diastereomer differentiation in Au(III)- and Bi(III)-catalyzed benzylic arylation: Concise and stereocontrolled synthesis of 2-amino-1,1-diarylalkanes

Article abstract of DOI:10.1021/ol500902p

Benzylic alcohols carrying an adjacent α-nitro or α-azido group on the alkane chain are converted into syn-1,1-diaryl-2-nitro- and 2-azidoalkanes with electron-rich arenes in stereoselective reactions catalyzed by Bronsted and Lewis acids. Gold(III) chloride and bismuth(III) triflate were found to be especially efficient as catalysts, showing kinetically controlled differentiation in the reactivity of diastereomeric α-substituted benzyl alcohols. Applications to therapeutically relevant syn- and anti- 2-amino-1,1-diarylalkanes are projected.

Full text of DOI:10.1021/ol500902p

Letter
pubs.acs.org/OrgLett
Kinetic Diastereomer Differentiation in Au(III)- and Bi(III)-Catalyzed
Benzylic Arylation: Concise and Stereocontrolled Synthesis of
2‑Amino-1,1-diarylalkanes
Etienne Chenard and Stephen Hanessian*
́
́ ́ ́ ́
Department of Chemistry, Universite de Montreal, C.P. 6128, Succ. Centre-Ville, Montreal, Quebec H3C 3J7, Canada
S
* Supporting Information
ABSTRACT: Benzylic alcohols carrying an adjacent α-nitro or α-
azido group on the alkane chain are converted into syn-1,1-diaryl-2-
nitro- and 2-azidoalkanes with electron-rich arenes in stereo-
selective reactions catalyzed by Brønsted and Lewis acids. Gold(III)
chloride and bismuth(III) triflate were found to be especially
efficient as catalysts, showing kinetically controlled differentiation in
the reactivity of diastereomeric α-substituted benzyl alcohols.
Applications to therapeutically relevant syn- and anti- 2-amino-
1,1-diarylalkanes are projected.
he phenylethylamine moiety is a well-known pharmaco-
Tphoric unit in a number of CNS-active drugs, varying in
their biological activities and structural complexity, as
exemplified by amphetamine, the simplest of potent stimulants,
to morphine, the most powerful analgesic.1 The inclusion of an
arene moiety at the benzylic position of a phenylethylamine
core unit generates a new family of 2-amino-1,1-diarylalkanes
with equally important biological functions in the CNS and
cardiovascular areas (Figure 1).2
rotation is minimized due to 1,3-allylic strain, thus allowing
differentiation of the nucleophile approach on the planar C(sp2)
carbocation (Figure 2).4
Figure 2. Mechanistic rationale for diastereoselectivity.
These seminal findings were exploited in the first Au(III)-
catalyzed benzylation of arenes by Beller et al.,5 leading to 1,1-
diarylalkanes in high yields and chemoselectivities. Concur-
rently, Bach et al.6 reported highly diastereoselective Friedel−
Crafts arylations of α-functionalized benzylic carbocations to
give syn- and anti- adducts depending on the nature of the
resident functional group on the alkane chain. A single example
of a nitro substituent showed excellent syn-selectivity with 1,3-
dimethoxybenzene as the nucleophile utilizing 10 mol % AuCl3
in nitromethane as solvent.4e,6 Anti-selectivity has been
observed in the Friedel−Crafts alkylation of α-aryl benzylic
cations with indoles as nucleophile catalyzed by TFA or BF3·
Et2O.7
Herein we report on the stereocontrolled arylations of a
series of α-nitro and α-azido benzylic alcohols as a concise
method to access a variety of 2-amino-1,1-diarylalkanes.8 It was
anticipated that the use of a Brønsted or Lewis acid would lead
to the formation of a quinonoid oxocarbenium ion
intermediate, which would be attacked at the benzylic position
to generate the corresponding diastereomeric products.4 Using
Figure 1. Phenylethylamine core in selected CNS-active compounds.
Despite their apparent structural simplicity, stereocontrolled
access to 2-amino-1,1-diarylalkanes remains a challenge.3 One
approach involves the generation of a benzylic carbocation and
the introduction of an arene moiety in an SN1-like process.
Indeed, scholarly reports by Bach,4a−d Prakash,4b,d and Olah4b,d
have shown that highly diastereoselective introduction of
electron-rich arenes and some heteroarenes as nucleophiles
can be achieved under Brønsted acid catalysis even at −78 °C.
The stereoselectivity has been rationalized on the basis of
resonance stabilized benzylic carbenium ions, bearing a
substituent on the adjacent α-stereocenter, in which bond
Received: March 26, 2014
Published: May 7, 2014
© 2014 American Chemical Society
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Letter
a
the ( )-nitroalcohol derivative 1 as a model with 1,3-
dimethoxybenzene as an arene nucleophile in the presence of
a series of catalysts led to the syn-diastereomer 2 in good to
excellent yields.9
Scheme 1. Synthesis of the anti-Diastereomer 13
5,6,11
Based on preliminary observations, it was decided AuCl3
and Bi(OTf)312 would be used as catalysts in this series, with a
variety of aromatic and heteroaromatic nucleophiles. Excellent
diastereoselectivities favoring the syn-orientation and in
preparatively useful yields were obtained in general as shown
in Table 1.
a
Table 1. Scope of 2-Nitro-1,1-Diarylalkanes
a
1
Ratios were determined by H NMR analysis of the crude materials,
and yields were obtained after purification.
within 24 h. In contrast, the anti-diastereomer of 15a was
recovered unchanged after 24 h (Scheme 2).
a
Scheme 2. Reactivity of Diastereomers
a
1
Ratios were determined by H NMR analysis of the crude materials,
b
and yields were obtained after purification. Full conversion was
achieved within 30 min with 10 mol % of Bi(OTf)3 in MeNO2.9 Over
c
a
1
Ratios were determined by H NMR analysis of the crude materials,
b
95% of the starting material 1 was consumed within 45 min, to give 3
and yields were obtained after purification. From TLC analysis, the
d
with 10 mol % of Bi(OTf)3 in MeNO2.9,10 SFC separation and H
1
c
reaction did not achieve full conversion over a period of 24 h. Full
e
NMR of the pure sample of 3 gave a ratio of 9:1. The crude 1H NMR
conversion within 16 h by TLC analysis. dNo conversion was observed
by TLC analysis, after 24 h.
spectrum showed a 9:1 ratio of the regioisomers.9 Full conversion was
f
achieved within 2 h, and a 92% yield of 9 was obtained with 10 mol %
of Bi(OTf)3 in MeNO2.9 dr was calculated after purification.
g
This trend was also observed with the p-methoxybenzyl
nitroalcohol 1, in the presence of 1,3-dimethoxybenzene, 1-
methoxynaphthalene, and 1,2,3-trimethoxybenzene as the arene
nucleophile.9 Monitoring the reaction of a 3:1 syn/anti mixture
The relative stereochemistry of the syn-diastereomers was
determined by X-ray crystallographic analysis of 3, which
concurs with literature precedents and the general mechanistic
rationale shown in Figure 2.4a−e Reaction times varied with the
nature of the arene nucleophile, position of the methoxy group
in the benzylic alcohol reacting partner, catalyst, and solvent.13
A solvent scan revealed that dichloromethane and nitro-
methane were excellent, while toluene and diethyl ether
resulted in lower conversion and the formation of byproducts.
The anti-isomer 13 can be obtained simply by starting with
the nitroalcohol 12 and using anisole as the nucleophile. The
reaction was completed within 5 min to give 13 as the major
isomer, albeit in modest yield due to the comparatively weaker
nucleophilicity of anisole (Scheme 1).13 As expected, excellent
conversion to 14 was observed when the more nucleophilic 1,3-
dimethoxybenzene was used, highlighting the mutually
cooperative effects of the reacting partners.14
1
of 1 by H NMR revealed virtual consumption of the syn-
diastereomer within 60 min, while the anti-diastereomer
required an additional 28 h to be almost fully consumed
(Figure 3A), giving the same syn-adduct 2 as the major isomer
(>20:1). Keeping AuCl3 as the catalyst and using nitromethane
as the solvent, the reaction was almost completed after only 2 h
(Figure 3B). Faster conversion was observed when Bi(OTf)3
was used as the catalyst in nitromethane (Figure 3C).9
The kinetically controlled selective reactivity of the syn-
isomer 1, with a 3JHa‑Hb ≈ 9 Hz,15 can be rationalized based on a
prevailing conformation favoring an antiperiplanar disposition
of the alkyl group, and a gauche interaction between the nitro
and hydroxy groups as illustrated in A (Figure 4). The 3JHa‑Hb
5−6 Hz of the anti-isomer B suggests an average of more than
one prevailing conformer in solution, such as B1, B2, and B3,
hence a slower formation of the oxocarbenium ion.
≈
In the course of our studies, we observed a preferential
kinetic reactivity of the syn-nitroalcohols over the anti-isomers.
Thus, when syn-o-methoxybenzyl nitroalcohol 15a was used,
the syn-1,1-diaryl product 16 was obtained as the major isomer
The syn-isomers may benefit from a hyperconjugative
donating effect in the antiperiplanar orientation in conformer
A, which may also be a partial contributor in conformer B3 of
the anti-isomer. The X-ray crystal structure of the methoxy-
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Organic Letters
Letter
a
Table 2. Synthesis of a Series of 2-Azido-1,1-diarylalkanes
1
Figure 3. H NMR time course for the syn- and anti-diastereomers of
1 as an initial 3:1 mixture: (A) using AuCl3 in CD2Cl2; (B) using
AuCl3 in CD3NO2; (C) using Bi(OTf)3 in CD3NO2.
a
Ratios were determined from 1H NMR analysis of the crude
b
materials, and yields were obtained after purification. SFC separation
of diastereomers was possible with 18 and 19.9 See Supporting
c
Information for results with Bi(OTf)3 as the catalyst and MeNO2 as
d
e
the solvent. Product was prepared from L-Phe.9 Diaryl 22 was
obtained in 91% yield starting from the corresponding azidoacetate of
f
17. 20 mol % of p-TsOH·H2O was used as the catalyst since AuCl3 or
g
Bi(OTf)3 resulted in a low yield. Dr was calculated after purification.
h
i
55% of the starting material was recovered. 20 mol % of p-TsOH·
j
H2O was used, and the reaction was performed in MeNO2. Nu =
−NHSO2C6H4Me.
ylfuran proved to be poor nucleophiles in the case of the azido
substrates. However, better yields and excellent syn-selectivity
were still observed with 20 mol % of p-TsOH hydrate (Table 2,
entries 7, 9, and 10).
This approach was also successful with p-toluenesulfonamide
as the nucleophile to generate a C−N bond (Table 2, entry 11).
By reversing the aromatic moieties with 2,4-dimethoxyphenyl
α-azidoalcohol (as in the nitro series, Scheme 2), the anti-
isomer-19 was obtained in a 33% yield with dr = 10:1 (Table 2,
entry 12).
Figure 4. Possible conformers of syn- and anti-isomers (A, B).
naphthyl analogue 3 conforms with projection C, in which C1
and C2 hydrogens are oriented in an antiperiplanar manner and
steric effects are minimized compared to alternative con-
formations (Figure 4). This observation is also corroborated by
The syn-stereochemistry of the products in this series was
confirmed by correlation with the α-nitro series by conversion
to 2-amino-1,1-diarylpentane analogue 29 (Scheme 3).9 Using
AuCl3 in CD2Cl2 the relatively faster reaction of the syn-
diastereomer compared to the anti-isomer in the azido series
1
the large coupling constant (3JHc‑Hd ≈ 11 Hz) from H NMR
analysis.4e,9
Next, we explored different benzylic substitutions with α-
azidoalkanes which are easily prepared either from the
corresponding α-amino acids16 in enantiopure form or via
synthesis from cheap starting materials.9 Using the same
general protocol, a 2:1 syn/anti mixture of α-azidoalcohol 17
9
1
was also observed by monitoring the reaction by H NMR.
In conclusion, we have developed stereocontrolled methods
for the synthesis of a variety of 2-nitro and 2-azido 1,1-
diarylalkanes using AuCl3 and Bi(OTf)3 as preferred catalysts.
These should be immediate precursors to biologically relevant
2-amino-1,1-diarylalkanes.17 An interesting kinetic differentia-
tion was noticed between syn- and anti-α-nitro (and α-azido)
benzylic alcohols during the AuCl3 and Bi(OTf)3 catalyzed
arylation reactions. Further studies in benzylic functionaliza-
tions are in progress and will be reported in due course.
3
3
(syn J
= 7.6 Hz; anti J
= 4.9 Hz in CDCl3) led to
Ha‑Hb
Ha‑Hb
the syn-isomer 18 in excellent yield and good selectivity within
45 min (Table 2, entry 1). Compounds 19−23 were prepared
in a similar manner (Table 2, entries 2−6). A solvent scan in
this series also indicated a preference for dichloromethane and
nitromethane while toluene and diethyl ether resulted in lower
conversions. Interestingly, 1-methoxynaphthalene and 1-meth-
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Letter
Beilstein J. Org. Chem. 2011, 7, 897. (d) See also: Hashmi, A. S.;
Toste, D. F. Modern Gold Catalyzed Synthesis; Wiley-VCH: Weinheim,
Germany, 2012.
Scheme 3. Confirmation of the Relative Configuration
(12) For benzylation of silyl enol ethers with Bi(OTf)3 as the catalyst,
see: (a) Rubenbauer, P.; Bach, T. Tetrahedron Lett. 2008, 49, 1305.
(b) Nitsch, D.; Huber, S. M.; Pothig, A.; Narayanan, A.; Olah, G. A.;
Prakash, G. K.; Bach, T. J. Am. Chem. Soc. 2014, 136, 2851. (c) For
benzylation of aryls using Bi(OTf)3, see: (d) Rubenbauer, P.;
Herdtweck, E.; Strassner, T.; Bach, T. Angew. Chem., Int. Ed. 2008,
47, 10106. For a review on Bi(OTf)3, see: (e) Gaspard-Iloughmane,
H.; Le Roux, C. Eur. J. Org. Chem. 2004, 2517.
(13) For a discussion of nucleophilicities, see: Mayr, H.; Kempf, B.;
Ofial, A. R. Acc. Chem. Res. 2002, 36, 66.
(14) (a) Bug, T.; Lemek, T.; Mayr, H. J. Org. Chem. 2004, 69, 7565.
(b) Petruzziello, D.; Gualandi, A.; Grilli, S.; Cozzi, P. G. Eur. J. Org.
Chem. 2012, 6697.
(15) Seebach, D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E. Helv.
Chim. Acta 1982, 65, 1101.
(16) (a) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett.
1996, 37, 6029. (b) Lundquist, J. T., IV; Pelletier, J. C. Org. Lett. 2001,
3, 781. (c) See also: Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-
Lomas, M. Helv. Chim. Acta 1991, 74, 2073.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and analytical data for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
(17) (a) For a direct arylation of benzylic ethers by photoredox
organocatalysis, see: Qvortrup, K.; Rankic, D. A.; MacMillan, D. W. J.
Am. Chem. Soc. 2014, 136, 626. (b) For 1,1-diarylalkanes synthesized
using a Ni-catalyzed arylation methodology, see: Yonova, I. M.;
Johnson, A. G.; Osborne, C. A.; Moore, C. E.; Morrissette, N. S.; Jarvo,
E. R. Angew. Chem., Int. Ed. 2014, 53, 2422. (c) For ligand-controlled
C(sp3)−H arylations of amino acids, see: He, J.; Li, S.; Deng, Y.; Fu,
H.; Laforteza, B. N.; Spangler, J. E.; Homs, A.; Yu, J.-Q. Science 2014,
343, 1216.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: stephen.hanessian@umontreal.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank NSERC for financial assistance. We wish to thank
■
Robert Giacometti (Universite
structure determinations.
́ ́
de Montreal) for the X-ray
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