A Straightforward Sequential Approach for the Enantioselective Synthesis of Optically Active α-Arylmethanol-1,2,3-Triazoles

Article abstract of DOI:10.1002/ejoc.201800751

Herein we describe a compelling sequential methodology for obtaining optically active α-arylmethanols-1,2,3-triazoles. The approach is based on the enantioselective alkynylation of aldehydes followed by a one-pot two-step desilylation/Cu^I-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC), providing the corresponding products with excellent yields and high levels of enantioselectivity. Furthermore, the click chemistry can be performed without affecting the enantiomeric excess. The application of the reaction has been demonstrated in the synthesis of a 1,2,3-triazole analog of antihistaminic and anticholinergic drug (R)-orphenadrine.

Full text of DOI:10.1002/ejoc.201800751

A Journal of
Accepted Article
Title: A Straightforward Sequential Approach for the Enantioselective
Synthesis of Optically Active α-Arylmethanol-1,2,3-Triazoles
Authors: Ricardo Samuel Schwab, Floyd Custódio Diniz Andrade,
Lucas Valentin Bosi Loss Pugnal, Hugo Luis Inforsati Betim,
Jéssica Facundo Vani, and Julio Zukerman Schpector
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800751
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10.1002/ejoc.201800751
European Journal of Organic Chemistry
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A Straightforward Sequential Approach for the Enantioselective
Synthesis of Optically Active α-Arylmethanol-1,2,3-Triazoles
Floyd C. D. Andrade,[a] Lucas V. B. L. Pugnal,[a] Hugo L. I. Betim,[a] Jéssica F. Vani,[a] Julio Zukerman-
Schpector,[b] Ricardo S. Schwab*[a]
Abstract: Herein we describe a compelling sequential methodology
for obtaining optically active α-arylmethanols-1,2,3-triazoles. The
approach is based on the enantioselective alkynylation of aldehydes
followed by a one-pot two-step desilylation/Cu(I)-catalyzed azide-
alkyne 1,3-dipolar cycloaddition (CuAAC), providing the
corresponding products with excellent yields and high levels of
enantioselectivity. Furthermore, the click chemistry can be performed
without affecting the enantiomeric excess. The application of the
reaction has been demonstrated in the synthesis of a 1,2,3-triazole
anolog of antihistaminic and anticholinergic drug (R)-orphenadrine.
Bolm and Rudolph reported the first general procedure for the
catalytic asymmetric arylation of aldehydes.[11] In this protocol,
arylboronic acids were used as the aryl source, which allowed to
broaden the scope of the reaction. Although this method
represented a great advance for the synthesis of chiral
diarylmethanols, the main limitation remains the range of the
substituted aryl group that is to be transferred.
Introduction
Optically active di(hetero)arylmethanols are highly privileged
scaffolds used as building blocks in organic synthesis; they have
been used as precursors for the preparation of a number of
biologically active compounds, namely local anesthetics,
antiarrhythmics, antidepressants, diuretics, laxatives, and
anticholinergics.[1] Some important representative examples of
those include (S)-carbinoxamine A,[2] (R)-orphenadrine B,[3] (R)-
neobenodine C[4] and (R,R)-clemastine D,[5] which all display
antihistaminic activity (Figure 1). Furthermore, chiral
dithienylmethanols such as E have showed relevant antiallergic
and antiischmic activity.[6] Also, BMS-184394 F has been
investigated for the treatment of migraine with an oral absorption
performance[7] and (S)-BMS 184394 G, displays activity against
breast cancer and leukemia.[8]
The traditional routes for the synthesis of these frameworks
usually comprise the enantioselective arylation of aromatic
aldehydes in the presence of a chiral ligand.[1a,9] Besides the high
cost of the diphenylzinc reagent used as the aryl source in the first
step,[10] the synthesis of different substituted diarylzinc
compounds is an additional limitation of this method. Inthis sense,
Figure 1. Examples of biologically active compounds.
Consequently, the investigation for straightforward efficient
strategies to access diverse heteroarylmethanols is of great
importance. Contributions to this field were given by Walsh and
co-workers, which described in 2009 a versatile method for the
preparation of enantioenriched (di)(hetero)arylmethanols starting
from readily available aryl and heteroaryl bromides.[12] Although
very efficient, this approach requires the use of excess
butyllithium. Recently, Harada and coworkers also reported an
interesting new methodology for the synthesis of such
compounds through the reaction of aldehydes with
organotitanium reagents.[13]
In this context, heteroarylmethanols containing a triazole ring are
of particular interest owing to their biological activity.[14] As a
matter of fact, a myriad of bioactive molecules bearing a 1,2,3-
triazole ring incorporated into their structure have already been
synthesized.[15] Furthermore, these scaffolds may act as stable
connectors against metabolic degradations owing to their stability
and solubility, a consequence of the hydrogen bonding formation
ability of this core to biomolecular targets, thus making it very
attractive for applications involving biological systems.[16]
[a]
MSc. F. C. D. Andrade, L. V. B. L. Pugnal, H. L. I. Betim, J. F. Vani,
Prof. Dr. R. S. Schwab
Centre of Excellence for Research in Sustainable Chemistry
(CERSusChem), Departamento de Química
Universidade Federal de São Carlos - UFSCar
Rodovia Washington Luís, km 235 - SP-310, São Carlos, São
Paulo, Brazil-13565-905
E-mail: rschwab@ufscar.br
[b]
Prof. Dr. J. Zukerman-Schpector
Departamento de Química
Universidade Federal de São Carlos - UFSCar
Supporting information for this article is given via a link at the end of
the document.
Although there are elegant methods for the synthesis of triazole-
containing heteroarylmethanols, the introduction of chiral
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10.1002/ejoc.201800751
European Journal of Organic Chemistry
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substituents at the C-4 position of 1,4-disubstitued-1,2,3-triazoles
still remains a challenge. Furthermore, the majority of the existing
procedures require several steps to attain the desired product,
often providing an overall low yield.[17] In this regard, the extension
of the substrates scope is still largely required, thus, to set out a
modular synthetic route for the preparation of optically active
hydroxy-triazoles is also an important issue.
Inspired by these works and aiming to surpass their
limitations, we herein disclose an efficent and straightforward
synthetic route for the preparation of optically active α-
arylmethanol-1,2,3-triazoles through
a
two-step sequential
approach requiring the enantioselective alkynylation of aldehydes
with ethynyltrimethylsilane to give the corresponding
enantioenriched trimethylsilylpropargylic alcohol, which was
desilylated in situ and then employed in CuAAC in the presence
of several azides (Scheme 1, Reaction 4).
In view of the increasing demand for different new chiral
triazole-containing heteroarylmethanols, Gotor and coworkers
reported a one-pot two-step stereoselective bioreduction of an α-
azido- and alkynyl ketone followed by copper catalyzed azide-
alkyne cycloaddition reaction (CuAAC) (Scheme 1, Reaction
1).[18] Although this method affords the products with high
enantioselectivity, the use of alkynones as substrates rather limits
the applications of this protocol, and therefore, only a few
examples were reported. Afterwards, Pathak and co-workers
reported a convenient protocol for the synthesis of enantiopure
hydroxyltriazoles from vinyl selenones derived from sugar
epoxides (Scheme 1, Reaction 2).[19] Although this methodology
consists of a useful route to 1,4,5-trisubstituted-1,2,3-triazoles
bearing the chiral alcohol attached to the C-4 or C-5 position of
the triazole ring, this synthetic route involves numerous steps to
acquire the desired product with a low overall yield. Another
approach, disclosed by Pericàs’s group (Scheme 1, Reaction 3),
involves the nucleophilic addition of a Grignard reagent to
iodobenzaldehyde followed by an enzymatic kinetic resolution
Results and Discussion
Our concept for the formation of enantioenriched α-
arylmethanols-1,2,3-triazoles
1 is based on the observed
reactivity of TMS-propargylic alcohol 2, which can be easily
desilylated and then employed in 1,3-dipolar cycloadditions with
different azides (Scheme 2). In turn, the optically active
trimethylsilylpropargylic alcohol 2 can be achieved from the
enantioselective alkynylation of a wide range of aldehydes 4 with
ethynyltrimethylsilane catalyzed by β-sulfonamide alcohol zinc
complexes.
step, a CuAAC and, finally, the protection of the alcohol;[20]
.
Although this is a very useful strategy for the synthesis of the
aforementioned molecules, the number of steps and the
requirement of a kinetic resolution step may be seen as
drawbacks.
Scheme 2. Retrosynthetic strategy for the synthesis of optically active α-
arylmethanol-1,2,3-triazoles: (i) CuAAC reaction followed by deprotection of the
group trimethylsilyl and (ii) asymmetric addition.
We started our studies by preparing the optically active TMS-
propargylic alcohol 2a following the procedure described by
Wang[21] using the inexpensive N-tosyl aminoalcohol 5 as a chiral
ligand (Table 1). By using the reported protocol, the TMS-
propargylic alcohol 2a was acquired in a great yield, but a
relatively low enantiomeric excess (75%) was observed (entry 1).
In order to overcome this issue, our strategy was to evaluate the
effect of the temperature of the reaction medium during the
addition of the aldehyde, the asymmetric step of the process
(Table 1). Interestingly, when the last step of the reaction was
performed at 15°C rather than at room temperature (entry 2),
there was a slight increase in the ee to 88%, maintaining the
excellent yield. To our delight, when the reaction was performed
at 10°C (entry 3), the ee was raised to 96% with no change in the
yield. The further decrease of the temperature to 5°C and 0°C
(entries 4 and 5) did not lead to further improvement in ee and
gave significant drops in the yield, possibly due to the lower
solubility of the reagents at such low temperatures.
Scheme 1. Background on the synthesis of hydroxy-1,2,3-triazoles.
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Table 1. Optimization of temperature for the catalytic enantioselective
corresponding propargyl alcohol, which undergoes the CuAAC.
Here, the Cu(II) pre-catalyst can be reduced by alcoholic solvents
to Cu(I), the active catalytic species.[24]
alkynylation.
Also, re-optimization studies were required to adapt the reported
methodology by Boons’s group to the challenging substrates used
in this work.[25] Accordingly, we carried out the reaction between
TMS-propargylic alcohol 2a and 4-azidobenzonitrile 3a using
MeOH as solvent under microwave irradiation (Table 2). While a
wide temperature range was evaluated, the best yield was
observed at 55°C (entry 5), with higher temperatures leading to
the decomposition of the aryl azide to the corresponding
aniline.[26] The reaction could also be performed at room
temperature (entry 8) with a good yield (88%), although a
considerably longer time was necessary for it to achieve
completion (Table 2).
Entry
Temperature (oC)
Yield (%)[a]
1
2
3
4
5
5
0
r.t
99
75
15
99
88
10
99
96
91
85
85
82
ee (%)[b]
[a] Isolated yield of the procuct 2a. bEnantiomeric excess determinated by
chiral HPLC analysis (Chiralpak OD-H colunm). The absolute configurations
were assigned by comparasion with literature data.[21]
Table 2. Evaluation of the effect of the temperature in the desilylation/1,3-dipolar
cycloaddition one-pot sequence.[a]
Taking into consideration that the development of more
sustainable methods is one of our prime concerns, we have
studied the use of p-cymene as solvent, since it can be produced
from renewable resources and displays properties similar to those
of toluene.[22] Unfortunately, although an excellent yield was
observed for product 2, the ee was considerably lower (77%, vs
96% for the reaction in toluene). Thus, further extensive
optimization studies would be required for the improvement of the
enantioselectivity of the protocol using this solvent, and,
therefore, toluene was chosen as solvent.
Entry
1
2
3
4
5
6
7
8
Temperature (oC)
Yield (%)[b]
120
37
100
45
80
86
60
94
55
99
50
88
40
83
r.t.[c]
88
[a] The reaction was conducted at 0.15 M of TMS-propargylic alcohol 2a (0.5
mmol) and 4-azidobenzonitrile 3a (0.5 mmol), and CuF2 (1.0 mmol) in MeOH
(3.0 mL) under microwave irradiation for 20 min. [b] Isolated yield. [c] The
reaction was conducted at room temperature for 24 h.
With Wang’s adapted procedure in hand,
a series of
trimethylsilylpropargylic alcohols 2a-k were prepared in excellent
yields and high enantioselectivity (up to 97% ee) (for more details,
see the Scheme S1 in Supporting Information). The absolute
configuration of the products was determined to be (R) by
chemical correlation with literature data.[21,23]
Next, we turned our attention to the direct one-pot formation of
optically active 1,4-disubstituted α-arylmethanol-1,2,3-triazoles
from the reaction between TMS-propargylic alcohols 2 and azides
3 in the presence of 2 equiv. of copper(II) fluoride as the pre-
catalyst and fluorine source for desilylation under microwave
irradiation (Scheme 3).
With the optimized conditions in hand for the synthesis of the
desired α-arylmethanol-1,2,3-triazoles, we then evaluated the
scope and limitations of the developed protocol (Table 3). Several
aromatic azides 3a-l bearing electron-donating and -withdrawing
substituents could be used in the reaction, affording the
corresponding products in moderate to excellent yields (Table 3,
1aa-al, 33-99%). Notably, the reaction was affected by steric
effects in the aryl moiety of the azides; as a general trend, when
substituents were present in the ortho position of the aryl ring,
there was a significant decrease in the yield for both electron-
donating and -withdrawing groups. Still, it is worth mentioning that
when 2-IPh (3g) and 2-NO2Ph (3h) aryl azides were used, the
reaction times were longer. In case of para-substituted azides 4-
CF3Ph (3b), 4-NO2Ph (3c), 4-OMePh (3d) and 4-IPh (3e), the
products were obtained in excellent yields (76-97%) when
compared to the correspondent ortho-substituted ones (33-59%).
Given the importance of the naturally occurring coumarins and
their synthetic derivatives in several fields,[27] we demonstrated
that the enantiomerically enriched α-arylmethanol-1,2,3-triazol
1am, can be obtained with 96% ee in 81% yield, by starting from
the azide bearing a heterocyclic ring derived from coumarin.
Otherwise, when alkyl azides were applied in this transformation,
moderate yields were observed (Table 2, 1an). It is important to
highlight that no racemization was observed during this one-pot
two-step desilylation-1,3-dipolar cycloaddition reaction, as proven
by comparing analysis of the starting material 2a and the product
1aa (97% ee) via UPC² equipped with chiral columns. Moreover,
Scheme 3. Synthesis of chiral 1,4-dissubstituted-α-arylmethanols-1,2,3-
triazoles.
As showed in Scheme 3, the synthesis of 1 takes place via a two-
step one-pot process in which 2 is initially deprotected to give the
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10.1002/ejoc.201800751
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we also explored the synthesis of chiral 1,4-dissubstituted α-
arylmethanol-1,2,3-triazoles containing a selenium moiety, due to
the rise of organoselenium compounds as an exceptional
scaffolds in biochemical processes, serving as important
therapeutic compounds.[28] Extending this methodology to 2-azido
arylselenide 3j and aryldiselenide 3k analogues, we prepared
products 1aj and 1ak with 98 and 97% ee in 93 and 72% yield,
respectively.
Table 3. Scope of azides.[a]
[a] Reaction conditions: a mixture of 2a (0.3 mmol, 0.10 M), 3a-n (0.3 mmol), and CuF2 (0.6 mmol) in MeOH (3.0 mL) was stirred at 55 oC under microwave irradiation
for 30 min (for more details, see the Table S1 in Supporting Information). Yields of isolated products after column chromatography. The ee values were determined
by UPC2 analysis of the corresponding products (see the Supporting Information). Absolute configurations were assigned by correlation with TMS-propargylic
alcohol 2a and the assumption of a single reaction pathway for all substrates. [b] After recrystallization.
substrates such as aldehydes bearing 1,2,3-triazoles, a gap
To further demonstrate the efficiency of our methodology, we
used a conventional protocol to prepare compound 1ac and
compared its outcome to the one from our approach. In
comparison with our protocol, the enantioselective arylation using
Bolm and Rudolph’s[11] approach afforded the final product 1ac’
in a 14 % yield and 44 % ee. This result shows that this approach,
though very versatile, is not applicable to more complex
which was successfully filled by our protocol.
We next evaluated the reactivity of 4-azidobenzonitrile 3a with
different TMS-propargylic alcohols 2a-k (Table 4) under the same
reaction
conditions.
Notably,
TMS-propargyl
alcohols
functionalized with electron-donating groups in the aryl moiety
displayed better results in comparison to those with electron-
withdrawing groups. In the reaction using 4-OMePh (2b), and 2-
OMePh (2c), the yields were 88% and 91% respectively, which
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10.1002/ejoc.201800751
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were significantly higher than the results for 4-NO2Ph (2f), and 4-
CF3Ph (2g) (65% and 76%, respectively). We found no significant
influence of steric effects of the TMS-propargylic alcohols 2 on the
outcome of this reaction, and all products were obtained without
significant variations in yield. An excellent result was also
achieved using TMS-propargyl alcohol 2d affording the product
1da with 97% ee in 99% yield. The corresponding enantiomer ent-
1da was obtained with 99% ee after recrystallization (for more
details, see Figure S74 in Supporting Information). The absolute
configuration of this novel chiral α-arylmethanol-1,2,3-triazole
could be confirmed by X-Ray analysis of ent-1da (Table 4).[29] The
TMS-propargylic alcohols 2h-i, derived from heteroaromatic
aldehydes, also afforded the triazoles 1ah and 1ia in good to
moderate yields. It is also demonstrated that TMS-propargylic
allylic alcohol 2j, is well-tolerated, affording the corresponding
chiral α-allyllmethanol-1,2,3-triazole 1ja in moderate yield 50 %.
Moreover, TMS-propargylic alkyl alcohol 2k, also undergoes the
desired transformation as show for the formation of the α-
alkylmethanol-1,2,3-triazoles 1ka in an excellent yield. It is
noteworthy that once again we did not observe any loss of ee in
the products when compared to the TMS-propargylic alcohols.
Table 4. Scope of TMS-propargylic alcohols 2.[a]
[a] Reaction conditions: a mixture of 2a-k (0.3 mmol, 0.1 M), 3a (0.3 mmol), and CuF2 (0.6 mmol) in MeOH (3.0 mL) was stirred at 55 oC under microwave irradiation
for 30 min. Yields of isolated products after column chromatography. The ee values were determined by UPC2 analysis of the corresponding products (see the
Supporting Information). Absolute configurations were assigned by correlation with TMS-propargylic alcohol 2a-k and the assumption of a single reaction pathway
for all substrates. [b] After recrystallization, the triazole product ent-1da was obtained with ee = >99%.
removed under reduced pressure and the resulting product 2a
Encouraged by these results, we decided to exploit the possibility
of developing the synthesis of optically active 1,4-disubstituted-α-
arylmethanol-1,2,3-triazole 1aa without the previous purification
of the intermediate TMS-propargylic alcohol 2a (Scheme 4).
Thus, after the enantioselective alkynylation, the solvent was
was then allowed to react with 4-azidobenzonitrile 3a in the
presence of CuF2 under standard conditions. Unfortunately, this
procedure was unsuccessful, probably due to presence of salty
byproducts in the reaction medium. However, to our delight, this
issue was overcome by conducting a washing of the organic
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10.1002/ejoc.201800751
European Journal of Organic Chemistry
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phase with water. Gratifyingly, after this procedure, product 1aa
was obtained with the same efficiency when compared with the
reaction using the purified intermediate 2a.
of the different groups toward biological activity of this class of
compounds.
Experimental Section
General Information
Hydrogen nuclear magnetic resonance spectra (1H NMR) were
1
obtained, on Bruker Advance 400 MHz spectrometer. H NMR
Scheme 4. Synthesis of 1,4-disubstituted-α-arylmethanol-1,2,3-triazole 1aa.
Reagents and conditions: (i) Et2Zn, DIPEA, ligand 5, toluene, 42oC, 12h, to this
solution was then added Ti(OiPr)4, r.t., 1h, after at 10oC PhCHO was added,
24h. (ii) CuF2, MeOH, MW, 55oC, 30 min.
spectra were referenced to the residual hydrogen signal in CDCl3
at δ = 7.26 ppm, or to the residual hydrogen signal in DMSO-d6 at
δ= 2.50 ppm. Coupling constants (J) are reported in Hertz [Hz]
using the standard notation to described the multiplicity of signals.
Carbon-13 nuclear magnetic resonance spectra (13C NMR) were
obtained at 101 MHz. 13C spectra were referenced to the CDCl3
triplet signal at δ = 77.0 ppm, or to septet signal at δ = 39.52 ppm
in DMSO-d6. High resolution mass spectra were recorded, on
Bruker Daltronics, using an electrospray ionization (ESI) (Hybrid
linear ion trap–orbitrap FT-MS and QqTOF/MS - Microtof - QII
models by using ESI ionization. Elemental Analysis was obtained,
on Fisons EA 1108 CHNS-O. HPLC chromatograms were
obtained on a Shimadzu apparatus, LC-10AT Pump, SPD-10A
UV-Vis Detector, SCL-10A System Controller, using a Chiralpak
AD-H (4,6 mmØ x 250 mmL, particle size 5 µm) or a Chiralcel OD-
H (4,6 mmØ x 250 mmL, particle size 5 µm). UltraPerformance
Convergence Chromatography was performed on a Waters
ACQUITY UPC2 system using a Trefoil CEL1 (OD) column (2.5
μm, 3 mm x 150 mm), CEL2 (OZ) column (2.5 μm, 3 mm x 150
mm) or AMY1 (AD) column (2.5 μm, 3 mm x 150 mm). Optical
rotations were measured with a Perkin-Elmer Polarimeter, Mod.
241, at 589 nm, 21°C. The microwave-assisted reactions were
carried out in a CEM Discovery focused oven. Flash column
chromatography was performed using Merck Silica Gel (230-400
mesh). Thin layer chromatography (TLC) was performed using
Merck Silica Gel GF254, 0.25 mm thickness. For visualization,
TLC plates were either placed under short wave ultraviolet light
(254 nm), stained with iodine vapor, or acidic vanillin. The yields
of the products included in all tables refer to isolated yields. All
commercially available reagents were purchased from Sigma
Aldrich Chemical Co. and used without purification, unless
otherwise noted. The following solvents were dried and purified
by distillation from the reagents indicated: tetrahydrofuran from
Having developed successful strategy for the synthesis of
optically active 1,4-dissubstituted-α-arylmethanol-1,2,3-triazoles,
next, we focused on the synthesis of the analog of (R)-
orphenadrine, an anticholinergic marked drug for treating muscle
pain and to help with motor control in Parkinson´s disease.[30] As
shown in Scheme 5, a mixture of the enantioenriched α-
arylmethanol-1,2,3-triazole 1af (96% ee) and 2-bromo-N,N-
diethyl-acetamide in THF was treated with sodium hydride at
room temperature for 3 h to afford the amide intermediate 1afa.
Further reduction of amide with LiAlH4 in THF furnished the
corresponding 1,2,3-triazole 1afa’ analog of antihistaminic and
anticholinergic drug (R)-orphenadrine in 89% overall yield and
96% ee.
Scheme 5. Synthesis of 1,2,3-triazole analog of anticholinergic drug (R)-
orphenadrine.
Conclusions
In summary, we have reported a straightforward and versatile
synthetic route for the preparation of a wide range of optically
active α-arylmethanol-1,2,3-triazoles using an enantioselective
addition of alkynylzinc to aldehydes, to generate a variety of chiral
TMS-propargylic alcohol, which could be easily desilylated and
reacted with azides, by a one-pot two step protocol. We also
emphasize that this modular approach affords the products in high
enantioselectivity and excellent yields which makes the
methodology highly efficient and practical for the synthesis of this
class of compounds when compared with the previously reported
ones. In particular the synthetic utility of the chiral product was
highlighted by the efficient preparation of enantiomerically
enriched 1,2,3-triazole analog of anticholinergic and
antihistaminic agent (R)-orphenadrine. Further research efforts
are currently underway in our laboratories to investigate the effect
sodium with
a benzophenone as indicator; toluene from
phosphorous pentoxide. The azides were conveniently prepared
from classical procedures.[31] The racemic TMS-propargylic
alcohols were prepared according the procedures described on
the literature.[32]
General Procedure for the Catalytic Enantioselective Addition of
ethynyltrimethylsilane to Aldehydes
N,N-Diisoproylethylamine (DIPEA) (0.085 mL; 0.5 mmol) was
added to a solution of the chiral ligand 5 (72.3 mg; 0.2 mmol; 20
mol%) in toluene (12 mL) under Argon atmosphere, followed by
the dropwise addition of Et2Zn (1 M in hexane, 3.5 mL, 3.5 mmol).
After the addition of ethynyltrimethylsilane (3 mmol; 0.424 mL),
the mixture was heated at 42°C for 12h. Then, Ti(OiPr)4 (0.059
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10.1002/ejoc.201800751
European Journal of Organic Chemistry
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mL; 0.04 mmol; 20 mol %) was added and stirred for another 1 h
at room temperature. The reaction was cooled to 10°C, and after
the addition of the aldehyde (1 mmol; 1 equiv.), the reaction was
kept in this temperature for 24h. Next, the reaction was quenched
with a saturated solution of NH4Cl (30 mL) and extracted with ethyl
acetate (3x 30 mL), dried over Na2SO4 and the solvent was
removed under vacuum. The crude product was purified by flash
chromatography on silica gel (Hexane-EtOAc, 95:5) affording the
chiral TMS-protected propargylic alcohol products 2a-k. The
enantiomeric excess of the product was determined using HPLC
equipped with a chiral column. Absolute configuration was
designated comparing on literature data.[21,23]
min); CO2 to 60:40 (over 4 min), 60:40 (2 min)], 2.0 mL/min, 35
⁰C, 137.9 bar, λ = 220 nm, tmajor = 5.690 min; tminor = 6.199 min.
m.p.: 194.45-196.20°C. [훂]ퟐ퐃ퟏ= -71.34 (c 0.27, CHCl3). H NMR:
1
(400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.46-8.38 (m, 2H), 8.28-8.21
(m, 2H), 7.48 (d, J = 7.3 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.32-
7.23 (m, 1H), 6.22 (d, J = 4.4 Hz, 1H), 5.94 (d, J = 4.4 Hz, 1H).
13C NMR: (101 MHz, DMSO-d6) δ 153.35, 146.53, 143.46, 140.91,
128.14, 127.25, 126.51, 125.47, 120.64, 120.42, 67.89. HRMS:
(m/z) calculated for C15H13N4O3 [M+H]+ 297.0988, found 297.0981.
(R)-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-
yl)(phenyl)methanol (1ad): white brown solid, 78% Yield (65.9
mg). 95% ee determined by UPC2 analysis: AMY1 column,
CO2/iPrOH gradient [CO2 (1 min); CO2 to 60:40 (over 4 min),
General Procedure for the Synthesis of 1,4-
dissubstituted-α-arylmethanols-1,2,3-triazole
60:40 (4 min)], 2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, , tmajor
=
5.314 min; tminor = 5.963 min. m.p.: 113.1-117.0°C. [훂]ퟐ퐃ퟏ= -5.05 (c
0.23, CHCl3). 1H NMR: (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.56-
7.52 (m, 2H), 7.52-7.48 (m, 2H), 7.40-7.34 (m, 2H), 7.33-7.28 (m,
1H), 6.98-6.92 (m, 2H), 6.11 (s, 1H), 3.83 (s, 3H), 3.35 (s, 1H).
13C NMR: (101 MHz, CDCl3) δ 159.83, 141.93, 130.43, 128.63,
128.02, 126.45, 122.20, 119.79, 114.71, 69.11, 55.61. HRMS:
(m/z) calculated for C16H16N3O2 [M+H]+ 282.1243, found
282.1270.
To a solution of azides 3a-n (0.3 mmol, 1.0 equiv) and TMS-
protected chiral propargyl alcohol 2a-k (0.3 mmol, 1.0 equiv) in
methanol (3 mL) was added CuF2 (60.6 mg, 0.6 mmol, 2.0 equiv).
The reaction was placed in a CEM Discover microwave reactor
and the temperature was kept at 55 °C for 30 min. The solvent
was removed under vacuum and the crude product was purified
by flash chromatography using silica gel (n-hexane–EtOAc, 7:3)
affording the chiral 1,4-dissubstituted-α-arylmethanols-1,2,3-
triazole 1.
(R)-(1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)methanol
(1ae): white solid, 76% Yield (85.6 mg). 99% ee determined by
UPC2 analysis: CEL1 column, CO2/iPrOH gradient [CO2 (1 min);
CO2 to 60:40 (over 4 min), 60:40 (2 min)], 2.0 mL/min, 35 ⁰C,
137.9 bar, λ = 220 nm, tmajor = 6.314 min; tminor = 6.494 min. m.p.:
146.4-146.6°C. [훂]ퟐ퐃ퟏ = -43.48 (c 0.21, CHCl3). 1H NMR: (400
MHz, CDCl3) δ 7.85-7.78 (m, 2H), 7.69 (s, 1H), 7.53-7.48 (m, 2H),
7.46-7.42 (m, 2H), 7.42-7.37 (m, 2H), 7.36-7.31 (m, 1H), 6.11 (s,
1H). 13C NMR: (101 MHz, CDCl3) δ 141.72, 138.96, 136.74,
128.89, 128.40, 126.56, 122.16, 119.35, 93.82, 69.36. HRMS:
(m/z) calculated for C15H13IN3O [M+H]+ 378.0103, found
378.0094.
(R)-4-(4-(hydroxy(phenyl)methyl)-1H-1,2,3-triazol-1-yl)
benzonitrile (1aa): pale yellow solid, >99% Yield (82.8 mg). 97%
ee determined by UPC2 analysis: AMY1 column, CO2/iPrOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (2 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 5.194 min; tminor
= 5.593 min. m.p.: 196.4-198.8°C. [훂]ퟐ퐃ퟏ= -64.96 (c 0.22, CHCl3).
1H NMR: (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.17 (d, J = 8.7 Hz,
2H), 8.06 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 7.4 Hz, 2H), 7.35 (t, J =
7.5 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 6.21 (d, J = 4.4 Hz, 1H), 5.93
(d, J = 4.4 Hz, 1H). 13C NMR: (101 MHz, DMSO-d6) δ 153.31,
143.59, 139.67, 134.29, 128.26, 127.35, 126.62, 120.53, 120.39,
118.22, 110.92, 68.03. HRMS: (m/z) calculated for C16H13N4O
[M+H]+ 277.1089, found 277.1087.
(R)-phenyl(1-phenyl-1H-1,2,3-triazol-4-yl)methanol
(1af):
white solid, 63% Yield (55.5 mg). 96% ee determined by UPC2
analysis: AMY1 column, CO2/iPrOH gradient [CO2 (1 min); CO2
to 60:40 (over 4 min), 60:40 (2 min)], 2.0 mL/min, 35 ⁰C, 137.9
bar, λ = 220 nm, tmajor = 4.784 min; tminor = 5.174 min. m.p.: 105.9-
106.3°C. [훂]ퟐ퐃ퟏ = -49.14 (c 0.24, CHCl3). 1H NMR: (400 MHz,
CDCl3) δ 7.70 (d, J = 0.6 Hz, 1H), 7.69-7.66 (m, 1H), 7.66-7.64
(m, 1H), 7.54-7.45 (m, 4H), 7.44-7.36 (m, 3H), 7.35-7.29 (m, 1H),
6.12 (s, 1H).13C NMR (101 MHz, CDCl3) δ 152.11, 141.79, 136.96,
129.71, 128.81, 128.68, 128.12, 126.46, 120.58, 119.59, 69.11.
HRMS: (m/z) calculated for C15H13N3NaO [M+Na]+ 274.0956,
found 274.0957.
(R)-phenyl(1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-
yl)methanol (1ab): light yellow solid, 81% Yield (77.1 mg). 97%
ee determined by UPC2 analysis: AMY1 column, CO2/iPrOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (4 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 4.551 min; tminor
= 4.976 min. m.p.: 174.7-182.4°C. [훂]ퟐ퐃ퟏ= -12.48 (c 0.246, CHCl3).
1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.5 Hz, 2H), 7.80-7.78
(m, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.53-7.48 (m, 2H), 7.42-7.36 (m,
2H), 7.36-7.30 (m, 1H), 6.12 (s, 1H), 2.88 (s, 1H). 13C NMR: (101
MHz, CDCl3) δ 152.58, 141.55, 139.33, 130.78 (q, J = 33.3 Hz),
128.76, 128.28, 127.06 (q, J = 3.5 Hz), 126.43, 123.50 (q, J =
272.2 Hz), 120.44, 119.37, 69.16. HRMS: (m/z) calculated for
C16H13F3N3O [M+H]+ 320.1011, found 320.1011.
(R)-(1-(2-iodophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)methanol
(1ag): white yellow solid, 40% Yield (45.7 mg). 97% ee
determined by UPC2 analysis: AMY1 column, CO2/EtOH gradient
[CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (3 min)], 2.0
(R)-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)methanol
(1ac): light yellow solid, 89% Yield (79.4 mg). 96% ee determined
by UPC2 analysis: AMY1 column, CO2/iPrOH gradient [CO2 (1
mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 5.337 min; tminor
=
5.593 min. m.p.: Decomp. 147°C. [훂]ퟐ퐃ퟏ= -17.60 (c 0.23, CHCl3).
1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 8.0, 1.2 Hz, 1H), 7.59
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10.1002/ejoc.201800751
European Journal of Organic Chemistry
FULL PAPER
(d, J = 0.6 Hz, 1H), 7.54-7.51 (m, 2H), 7.50-7.46 (m, 1H), 7.43-
7.37 (m, 3H), 7.35-7.30 (m, 1H), 7.22 (ddd, J = 7.9, 7.4, 1.7 Hz,
1H). 6.15 (s, 1H), 3.16 (s, 1H). 13C NMR (101 MHz, CDCl3) δ
151.10, 141.71, 140.21, 139.98, 131.53, 129.23, 128.69, 128.19,
127.86, 126.57, 123.44, 93.98, 69.25. HRMS: (m/z) calculated for
C15H13IN3O [M+H]+ 378.0103, found 378.0110.
7.20 (td, J = 7.9, 1.3 Hz, 1H), 6.13 (s, 1H), 3.67 (s, 1H). 13C NMR:
(101 MHz, CDCl3) δ 151.18, 141.77, 136.93, 134.88, 133.35,
130.19, 129.97, 129.65, 128.85, 128.66, 128.58, 128.10, 127.70,
126.54, 126.14, 122.78, 69.25. EA: calculated for C30H24N6O2Se2,
C = 54.72%, H = 3.67%, N = 12.76%, found C = 53.58%, H =
3.33%, N = 12.89%.
(R)-(1-(2-nitrophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)methanol
(1ah): brown solid, 33% Yield (29.4 mg). >99% ee determined by
UPC2 analysis: AMY1 column, CO2/EtOH gradient [CO2 (1 min);
CO2 to 60:40 (over 4 min), 60:40 (2 min)], 2.0 mL/min, 35 ⁰C,
137.9 bar, λ = 220 nm, tmajor = 5.213 min. [훂]ퟐ퐃ퟏ= -16.21 (c 0.23,
CHCl3). 1H NMR: (400 MHz, CDCl3) δ 8.05 (dd, J = 8.1, 1.5 Hz,
1H), 7.74 (td, J = 7.7, 1.5 Hz, 1H), 7.70-7.63 (m, 1H), 7.61 (s, 1H),
7.55 (dd, J = 7.8, 1.5 Hz, 1H), 7.51-7.46 (m, 2H), 7.40-7.34 (m,
2H), 7.33-7.28 (m, 1H), 6.10 (s, 1H), 3.50 (s, 1H). 13C NMR: (101
MHz, CDCl3) δ 151.95, 144.38, 141.52, 133.89, 130.84, 130.20,
128.71, 128.20, 128.00, 126.59, 125.59, 123.14, 69.04. HRMS:
(R)-phenyl(1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-
yl)methanol (1al): pale yellow solid, 86% Yield (85.4 mg). 97%
ee determined by UPC2 analysis: CEL2 column, CO2/ACN
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (5 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 5.065 min; tminor
= 5.259 min. m.p.: 111.9-113.4°C. [훂]ퟐ퐃ퟏ= -42.46 (c 0.25, CHCl3).
1H NMR: (400 MHz, CDCl3) δ 7.97-7.94 (m, J = 3.6 Hz, 1H), 7.92-
7.88 (m, 1H), 7.78 (s, 1H), 7.71-7.60 (m, 2H), 7.54-7.49 (m, 2H),
7.43-7.37 (m, 2H), 7.37-7.30 (m, 1H), 6.13 (s, 1H), 3.45 (s,
1H).13C NMR: (101 MHz, CDCl3) δ 152.70, 141.66, 137.22,
132.32 (q, J = 33.4 Hz), 130.51, 128.70, 128.16, 126.44, 125.38
(m/z) calculated for C15H13N4O3 [M+H]+ 297.0988, found 297.0986. (q, J = 3.3 Hz), 123.55, 123.29 (q, J = 272.6 Hz), 119.61, 117.40
(q, J = 3.6), 68.97. HRMS: (m/z) calculated for C16H13F3N3O
(R)-(1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-
[M+H]+ 320.1011, found 320.1004.
yl)(phenyl)methanol (1ai): white solid, 59% Yield (50.1 mg) 97%
ee determined by UPC2 analysis: AMY1 column, CO2/iPrOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (2 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 4.942 min; tminor
= 5.454 min. m.p.: 123.6-125.8°C. [훂]ퟐ퐃ퟏ= -23.59 (c 0.24, CHCl3).
1H NMR: (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.70 (dd, J = 7.9, 1.7
Hz, 1H), 7.54-7.49 (m, 2H), 7.41 (d, J = 1.7 Hz, 1H), 7.39-7.34 (m,
3H), 7.33-7.27 (m, 1H), 7.10-7.00 (m, 2H), 6.12 (s, 1H), 3.81 (s,
3H), 3.63 (s, J = 4.0 Hz, 1H). 13C NMR: (101 MHz, CDCl3) δ
151.19, 142.06, 130.18, 128.55, 127.93, 126.58, 126.24, 125.58,
123.58, 121.14, 112.21, 69.18, 55.94. HRMS: (m/z) calculated for
C16H16N3O2 [M+H]+ 282.1243, found 282.1242.
(R)-7-hydroxy-3-(4-(hydroxy(phenyl)methyl)-1H-1,2,3-triazol-
1-yl)-2H-chromen-2-one (1am): white pale solid, 80% yield (80.4
mg). 96% ee determined by UPC2 analysis: AMY1 column,
CO2/EtOH gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40
(5 min)], 2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 350 nm, tmajor = 5.306
min; tminor = 6.380 min. m.p.: Decomp. 278°C. [훂]ퟐ퐃ퟏ= -43.40 (c
0.22, MeOH). 1H NMR: (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.31
(s, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 7.3 Hz, 2H), 7.35 (dd,
J = 10.3, 4.7 Hz, 2H), 7.26 (dd, J = 8.3, 6.3 Hz, 1H), 6.89 (dd, J =
8.6, 2.2 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 5.91 (d, J = 4.1 Hz, 1H).
13C NMR: (101 MHz, DMSO-d6) δ 162.31, 156.31, 154.55,
151.61, 143.69, 136.04, 130.87, 128.12, 127.17, 126.39, 122.77,
119.38, 114.21, 110.33, 102.10, 67.76. HRMS: (m/z) calculated
for C18H14N3O4 [M+H]+ 336.0984, found 336.0984.
(R)-phenyl(1-(2-(phenylselanyl)phenyl)-1H-1,2,3-triazol-4-
yl)methanol (1aj): light pale yellow solid, 93% Yield (113.0 mg).
98% ee determined by UPC2 analysis: AMY1 column, CO2/EtOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (2 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 5.760 min; tminor
= 6.003 min. m.p.: 149.3-150.0°C. [훂]ퟐ퐃ퟏ= -24.07 (c 0.22, CHCl3).
1H NMR: (400 MHz, CDCl3) δ 7.59 (d, J = 0.5 Hz, 1H), 7.52 (dd,
J = 8.2, 1.2 Hz, 2H), 7.45-7.42 (m, 2H), 7.39 (dd, J = 8.0, 6.4 Hz,
3H), 7.35-7.31 (m, 4H), 7.30-7.26 (m, 3H), 6.12 (s, 1H), 3.17 (s,
1H). 13C NMR: (101 MHz, CDCl3) δ 151.20, 141.74, 136.89,
134.90, 133.32, 130.20, 129.99, 129.66, 128.83, 128.67, 128.59,
128.11, 127.69, 126.54, 126.13, 122.80, 69.21. HRMS: (m/z)
calculated for C21H18N3OSe [M+H]+ 408.0615, found 408.0610.
(R)-(1-benzyl-1H-1,2,3-triazol-4-yl)(phenyl)methanol
(1an):
off-white solid, 53% Yield (42.0 mg). 98% ee determined by UPC2
analysis: AMY1 column, CO2/iPrOH gradient [CO2 (1 min); CO2
to 60:40 (over 4 min), 60:40 (2 min)], 2.0 mL/min, 35 ⁰C, 137.9
bar, λ = 220 nm, tmajor = 4.942 min; tminor = 5.455 min. m.p.: 119.9-
124.9°C. [훂]ퟐ퐃ퟏ = -33.74 (c 0.23, CHCl3). 1H NMR: (400 MHz,
CDCl3) δ 7.44-7.40 (m, 2H), 7.36-7.33 (m, 4H), 7.33-7.26 (m, 2H),
7.25-7.21 (m, 2H), 7.19 (s, 1H), 6.00 (s, 1H), 5.46 (s, 2H), 3.23 (s,
1H). 13C NMR: (101 MHz, CDCl3) δ 151.71, 141.88, 134.44,
129.12, 128.77, 128.59, 128.41, 128.06, 128.00, 126.43, 121.08,
69.22, 54.22. HRMS: (m/z) calculated for C16H16N3O [M+H]+
266.1293, found 266.1290.
(1R,1'R)-((diselanediylbis(2,1-phenylene))bis(1H-1,2,3-
triazole-1,4-diyl))bis (phenylmethanol) (1ak): white solid, 72%
Yield (71.5 mg). 97% ee determined by UPC2 analysis: AMY1
column, CO2/MeOH gradient [CO2 (1 min); CO2 to 60:40 (over 4
min), 60:40 (2 min)], 2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm,
(R)-4-(4-(hydroxy(4-methoxyphenyl)methyl)-1H-1,2,3-triazol-
1-yl)benzonitrile (1ba): light yellow solid, 88% Yield (80.5 mg).
96% ee determined by UPC2 analysis: AMY1 column, CO2/iPrOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (4 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 5.487 min; tminor
= 5.877 min. m.p.: 168.9-169.5°C.[훂]ퟐ퐃ퟏ= -72.36 (c 0.24, CHCl3).
1H NMR: (400 MHz, CDCl3) δ 7.89-7.85 (m, 2H), 7.83-7.79 (m,
tmajor = 7.551 min; tminor = 6.135 min. m.p.: 156.7-158.6°C. [훂]퐃ퟐퟏ
=
-19.68 (c 0.22, CHCl3). 1H NMR: (400 MHz, CDCl3) δ 7.95 (d, J =
7.8 Hz, 1H), 7.58 (s, J = 10.5 Hz, 1H), 7.51 (d, J = 7.3 Hz, 2H),
7.46 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 8.2 Hz, 3H), 7.33-7.25 (m, 1H),
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10.1002/ejoc.201800751
European Journal of Organic Chemistry
FULL PAPER
3H), 7.43-7.38 (m, 2H), 6.97-6.87 (m, 2H), 6.06 (d, J = 2.2 Hz,
1H), 3.81 (s, 3H), 2.98 (d, J = 3.3 Hz, 1H). 13C NMR: (101 MHz,
CDCl3) δ 159.65, 153.05, 139.78, 133.88, 133.66, 127.81, 120.54,
119.09, 117.65, 114.17, 112.42, 68.89, 55.33. HRMS: (m/z)
calculated for C17H15N4O2 [M+H]+ 307.1195, found 307.1192.
ee determined by UPC2 analysis: AMY1 column, CO2/EtOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (2 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 5.318 min; tminor
= 5.899 min. m.p.: 174.7-176.6°C. [훂]ퟐ퐃ퟏ= -64.12 (c 0.32, ACN).
1H NMR: (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.24 (d, J = 8.8 Hz,
2H), 8.18-8.13 (m, 2H), 8.11-8.04 (m, 2H), 7.76 (d, J = 8.7 Hz,
2H), 6.56 (d, J = 4.7 Hz, 1H), 6.10 (d, J = 4.6 Hz, 1H). 13C NMR:
(101 MHz, DMSO-d6) δ 151.95, 150.88, 146.70, 139.47, 134.22,
127.64, 123.42, 120.96, 120.34, 118.07, 110.94, 66.89. HRMS:
(m/z) calculated for C16H12N5O3 [M+H]+ 322.0940, found 322.0945.
(R)-4-(4-(hydroxy(2-methoxyphenyl)methyl)-1H-1,2,3-triazol-
1-yl)benzonitrile (1ca): pale yellow solid, 91% Yield (83.8 mg).
97% ee determined by UPC2 analysis: CEL1 column, CO2/EtOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (2 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 6.222 min; tminor
= 5.968 min. m.p.: 140.1-141.7°C. [훂]ퟐ퐃ퟏ= -66.58 (c 0.28, CHCl3).
1H NMR: (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.16 (d, J = 8.8 Hz,
2H), 8.05 (d, J = 8.7 Hz, 2H), 7.54 (dd, J = 7.8, 1.4 Hz, 1H), 7.36-
7.21 (m, 1H), 7.06-6.92 (m, 2H), 6.20 (d, J = 4.9 Hz, 1H), 5.94 (d,
J = 4.9 Hz, 1H), 3.75 (s, 3H). 13C NMR: (101 MHz, DMSO-d6) δ
155.77, 152.64, 139.59, 134.18, 131.25, 128.42, 127.21, 120.59,
120.28, 120.24, 118.12, 110.75, 61.53, 55.39. HRMS: (m/z)
calculated for C17H15N4O2 [M+H]+ 307.1195, found 307.1198.
(R)-4-(4-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-1H-1,2,3-
triazol-1-yl)benzonitrile (1ga): white solid, 76% Yield (78.7 mg).
79% ee determined by UPC2 analysis: CEL1 column, CO2/iPrOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (2 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 4.369 min; tminor
= 4.635 min. m.p.: 169.3-170.0°C. [훂]ퟐ퐃ퟏ= -39.60 (c 0.39, CHCl3).
1H NMR: (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.15 (d, J = 8.5 Hz,
2H), 8.06 (d, J = 8.6 Hz, 2H), 7.77-7.66 (m, 4H), 6.46 (d, J = 4.5
Hz, 1H), 6.04 (d, J = 4.2 Hz, 1H). 13C NMR: (101 MHz, DMSO-d6)
δ 152.36, 148.00, 139.50, 134.20, 127.85 (q, J = 31.7 Hz), 127.20,
125.08 (q, J = 3.2 Hz), 124.27 (q, J = 290.2 Hz), 120.78, 120.34,
118.08, 110.90, 67.14. HRMS: (m/z) calculated for C17H12F3N4O
[M+H]+ 345.0963, found 345.0958.
(R)-4-(4-((4-bromophenyl)(hydroxy)methyl)-1H-1,2,3-triazol-
1-yl)benzonitrile (1da): white solid, >99% Yield (106.3 mg). 97%
ee determined by UPC2 analysis: AMY1 column, CO2/EtOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (4 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 275 nm, tmajor = 6.396 min; tminor
= 9.020 min. m.p.: 147.6-150.8°C. [훂]ퟐ퐃ퟏ= -57.75 (c = 0.33, CHCl3). (S)-4-(4-(hydroxy(thiophen-2-yl)methyl)-1H-1,2,3-triazol-1-
1H NMR: (400 MHz, CDCl3) δ 7.88-7.83 (m, 2H), 7.82-7.78 (m, 3),
7.53-7.47 (m, 2H), 7.39-7.35 (m, 2H), 6.08 (s, 1H), 3.45 (s, 1H).
13C NMR: (101 MHz, CDCl3) δ 152.37, 140.35, 139.65, 133.95,
131.92, 128.13, 122.34, 120.60, 119.19, 117.62, 112.61, 68.55.
HRMS: (m/z) calculated for C16H12BrN4O [M+H]+ 355.0194, found
355.0195.
yl)benzonitrile (1ha): light yellow solid, 83% Yield (70.0 mg).
91% ee determined by UPC2 analysis: AMY1 column, CO2/iPrOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (2 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 5.386 min; tminor
= 5.806 min. m.p.: 167.4-167.8°C.[훂]ퟐ퐃ퟏ= -11,90 (c 0.23, CHCl3).
1H NMR: (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.26-8.14 (m, 2H),
8.11-8.04 (m, 2H), 7.46 (dd, J = 5.0, 1.3 Hz, 1H), 7.04 (d, J = 3.5
Hz, 1H), 6.98 (dd, J = 5.0, 3.5 Hz, 1H), 6.55 (d, J = 4.7 Hz, 1H),
6.18 (d, J = 4.8 Hz, 1H). 13C NMR: (101 MHz, DMSO-d6) δ 152.56,
147.64, 139.55, 134.22, 126.56, 125.26, 124.50, 120.51, 120.34,
118.10, 110.89, 64.12. HRMS: (m/z) calculated for C14H11N4OS
[M+H]+ 283.0654, found 283.0653.
(S)-4-(4-((4-bromophenyl)(hydroxy)methyl)-1H-1,2,3-triazol-
1-yl)benzonitrile (ent-1da): white solid, >99% Yield (106.0 mg).
99% ee determined by UPC2 analysis: AMY1 column, CO2/EtOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (4 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 275 nm, tmajor = 8.971 min; tminor
= 6.419 min. [훂]ퟐ퐃ퟏ= +48.65 (c 0.11, CH2Cl2).
(S)-4-(4-(furan-2-yl(hydroxy)methyl)-1H-1,2,3-triazol-1-
yl)benzonitrile (1ia): dark yellowsolid, 63% Yield (50.7 mg). 89%
ee determined by UPC2 analysis: AMY1 column, CO2/iPrOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (4 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 5.038 min; tminor
= 5.238 min. m.p.: 167.9-169.4°C [훂]ퟐ퐃ퟏ= -29.63 (c 0.23, CHCl3).
1H NMR: (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.93 (d, J = 8.9 Hz,
2H), 7.85 (d, J = 8.9 Hz, 2H), 7.45 (dd, J = 1.6, 1.1 Hz, 1H), 6.41-
6.39 (m, 2H), 6.15 (s, 1H). 13C NMR: (101 MHz, CDCl3) δ 153.42,
149.72, 143.18, 139.90, 134.11, 120.79, 119.83, 117.80, 112.75,
110.75, 108.45, 63.38. HRMS: (m/z) calculated for C14H11N4O2
[M+H]+ 267.0882, found 267.0890.
(R)-4-(4-((2-bromophenyl)(hydroxy)methyl)-1H-1,2,3-triazol-
1-yl)benzonitrile (1ea): white solid, 81% Yield (86.6 mg). 93% ee
determined by UPC2 analysis: AMY1 column, CO2/EtOH gradient
[CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (2 min)], 2.0
mL/min, 35 ⁰C, 137.9 bar, λ = 220 nm, tmajor = 6.953 min; tminor
=
6.577 min. m.p.: 168.5-170.4°C. [훂]ퟐ퐃ퟏ= -28.40 (c 0.22, CHCl3). 1H
NMR: (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.21-8.14 (m, 2H),
8.11-8.03 (m, 2H), 7.75 (dd, J = 7.8, 1.6 Hz, 1H), 7.59 (dd, J = 8.0,
1.0 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.26 (dd, J = 7.7, 1.6 Hz, 1H),
6.37 (d, J = 4.8 Hz, 1H), 6.17 (d, J = 4.7 Hz, 1H). 13C NMR: (101
MHz, DMSO-d6) δ 151.33, 141.99, 139.50, 134.20, 132.24,
129.38, 128.82, 127.86, 121.72, 121.17, 120.31, 118.09, 110.86,
66.70. HRMS: (m/z) calculated for C16H12BrN4O [M+H]+ 355.0194,
found 355.0187.
(R,E)-4-(4-(1-hydroxy-3-phenylallyl)-1H-1,2,3-triazol-1-
yl)benzonitrile (1ja): pale yellow solid, 50% Yield (45.8 mg). 81%
ee determined by UPC2 analysis: AMY1 column, CO2/iPrOH
gradient [CO2 (1 min); CO2 to 60:40 (over 4 min), 60:40 (3 min)],
2.0 mL/min, 35 ⁰C, 137.9 bar, λ = 250 nm, tmajor = 5.392 min; tminor
(R)-4-(4-(hydroxy(4-nitrophenyl)methyl)-1H-1,2,3-triazol-1-
yl)benzonitrile (1fa): light yellow solid, 65% Yield (62.7 mg). 84%
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10.1002/ejoc.201800751
European Journal of Organic Chemistry
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= 5.710 min. [훂]ퟐ퐃ퟏ= -33.93 (c 0.25, CHCl3). m.p.: 147.5-148.8°C.
1H NMR: (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.92-7.87 (m, 2H),
7.84-7.79 (m, 2H), 7.44-7.39 (m, 2H), 7.36-7.30 (m, 2H), 7.29-
7.23 (m, 1H), 6.82 (d, J = 15.8 Hz, 1H), 6.51 (dd, J = 15.9, 6.5 Hz,
1H), 5.71 (d, J = 6.5 Hz, 1H), 3.05 (s, 1H). 13C NMR: (101 MHz,
CDCl3) δ 151.58, 139.77, 136.01, 133.95, 132.16, 128.69, 128.23,
126.74, 120.58, 119.02, 117.68, 112.50, 67.81. HRMS: (m/z)
calculated for C18H15N4O [M+H]+ 303.1246, found 303.1249.
NaH (60% in mineral oil; 26 mg, 0.66 mmol) at 0°C. The mixture
was stirred at r.t. for 3h, quenched with water and extracted with
EtOAc (4 x 4mL). The combined extracts were washed with brine,
dried with Na2SO4 anhydrous and concentrated under vacuum.
The crude product was purified by flash chromatography on silica
gel (Hexane-EtOAc, 1:1) affording the intermediate 1,2,3-triazol
1
acetamide 1afa as a colorless oil with 145 mg (91% yield). H
NMR (400 MHz, CDCl3) δ 7.96 (d, J = 0.5 Hz, 1H), 7.73-7.67 (m,
2H), 7.57- 7.52 (m, 2H), 7.52- 7.46 (m, 2H), 7.44-7.36 (m, 3H),
7.35-7.29 (m, 1H), 5.88 (s, 1H), 4.26 (dd, J = 29.5, 13.7 Hz, 2H),
3.38 (q, J = 7.1 Hz, 2H), 3.24 (q, J = 7.1 Hz, 2H), 1.12 (td, J = 7.1,
2.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 167.84, 149.81, 139.32,
137.03, 129.69, 128.72, 128.66, 128.29, 127.29, 120.53, 120.43,
76.76, 41.16, 40.19, 14.23, 12.93. HRMS: (m/z) calculated for
C21H24N4NaO2 [M+Na]+ 387.1797, found 387.1788.
(R)-4-(4-(1-hydroxyoctyl)-1H-1,2,3-triazol-1-yl)benzonitrile
(1ka): white solid, >99% Yield (89.4 mg). 63% ee determined by
UPC2 analysis: AMY1 column, CO2/iPrOH gradient [CO2 (1 min);
CO2 to 60:40 (over 4 min), 60:40 (2 min)], 2.0 mL/min, 35 ⁰C,
137.9 bar, λ = 220 nm, tmajor = 4.592 min; tminor = 4.835 min. [훂]퐃ퟐퟏ
=
-2.75 (c 0.22, CHCl3). m.p.: 130.5-131.15°C. 1H NMR: (400 MHz,
CDCl3) δ 8.00 (d, J = 0.6 Hz, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.83
(d, J = 8.9 Hz, 2H), 4.99 (dd, J = 7.6, 5.4 Hz, 1H), 2.58 (s, 1H),
2.02-1.84 (m, 2H), 1.54-1.46 (m, 1H), 1.45 (s, 1H), 1.38-1.32 (m,
2H), 1.31-1.23 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR: (101
MHz, CDCl3) δ 153.27, 139.99, 134.07, 120.64, 118.55, 117.84,
112.50, 67.30, 37.53, 31.91, 29.51, 29.33, 25.46, 22.76, 14.21.
HRMS: (m/z) calculated for C17H23N4O [M+H]+ 299.1872, found
299.1877.
The acetamide 1afa was dissolved in THF (4 mL) and LiAlH4 (61
mg, 1.6 mmol) was added to the stirred solution at 0°C. The
.
mixture was refluxed for 24h and allowed to cool. Na2SO4 10H2O
was gradually added to the mixture. The whole mixture was stirred
at r.t. for 6h, filtered with EtOAc to remove the white precipitate
and concentrated under vacuum. The residue was purified by
flash chromatography on silica gel (EtOAc-MeOH, 8:2) affording
the product 1afa’ as a yellow oil with 137 mg (98% yield). [훂]퐃ퟐퟏ
=
-24.90 (c 0.15, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H),
7.71- 7.66 (m, 2H), 7.52-7.46 (m, 4H), 7.44-7.35 (m, 3H), 7.34-
7.28 (m, 1H), 5.72 (s, 1H), 3.67 (td, J = 6.4, 1.8 Hz, 2H), 2.79 (dd,
J = 11.1, 6.4 Hz, 2H), 2.60 (d, J = 7.2 Hz, 4H), 1.03 (t, J = 7.2 Hz,
6H). 13C NMR (101 MHz, CDCl3) δ 150.67, 140.32, 137.07,
129.68, 128.69, 128.64, 128.04, 126.83, 120.56, 119.90, 77.03,
67.59, 52.16, 47.52, 11.60. HRMS: (m/z) calculated for
C21H27N4O [M+H]+ 351.2185, found 351.2181.
General procedure for the asymmetric arylation of 1-(4-
nitrophenyl)-1H-1,2,3-triazole-4-carbaldehyde:
In a Schlenk tube under argon atmosphere, diethylzinc (3.6 mmol,
3.6 mL; 1M hexane solution) was added to a solution of
penhylboronic acid (154 mg, 1.2 mmol) dropwise in dry toluene (2
o
mL). After stirring for 15 min at 60 C, the mixture is cooled to
room temperature and a toluene solution of chiral ligand 5 (72.3
mg; 0.2 mmol; 20 mol%) was introduced. The reaction was stirred
for an additional 15 min and 1-(4-nitrophenyl)-1H-1,2,3-triazole-4-
carbaldehyde (109 mg; 0.5 mmol; 1 equiv.) was subsequently
o
Acknowledgements
added. After stirring for 4 h at 10 C the reaction was quenched
with water (2 mL) and the aqueous layer was extracted with ethyl
acetate (3 x 5 mL). The combined organic layers were dried with
Na2SO4, filtered, and concentrated. The crude product was
purified by flash chromatography on silica gel (Hexane-EtOAc,
7:3) affording the product 1ac’ with 14% yield.
The authors gratefully acknowledge Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP, grants 2013/06558-
3 and 2014/50249-8), GlaxoSmithKline (GSK), Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and
Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq grant 475203/2013-5) for financial support and fellowships.
(S)-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)(phenyl)methanol
(1ac’): light yellowsolid, 14% Yield (18.8 mg). 44% ee determined
by UPC2 analysis: AMY1 column, CO2/iPrOH gradient [CO2 (1
min); CO2 to 60:40 (over 4 min), 60:40 (2 min)], 2.0 mL/min, 35
⁰C, 137.9 bar, λ = 220 nm, tmajor = 6.200 min; tminor = 5.695 min.
[훂]ퟐ퐃ퟏ= +30.00 (c 0.15, CHCl3).
Keywords: di(hetero)arylmethanols • 1,2,3-triazoles • propargylic
alcohols • enantioselective alkynylation • 1,3-dipolar cycloaddition
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Chiral Alcohols*
Floyd C. D. Andrade, Lucas V. B. L.
Pugnal, Hugo L. I. Betim, Jéssica F. Vani,
Julio Zukerman-Schpector, Ricardo S.
Schwab*
Page No. – Page No.
Click here! Chiral arylmethanols bearing 1,2,3-triazoles are achieved using a
straightforward sequential approach based on the enantioselective alkynylation of
aldehydes followed by a one-pot two-step desilylation/CuAAC, providing the
corresponding products with excellent yields and high levels of enantioselectivity.
The application of the reaction has been demonstrated in the synthesis of a 1,2,3-
triazole anolog of antihistaminic and anticholinergic drug (R)-orphenadrine.
A
Straightforward
Sequential
Approach for the Enantioselective
Synthesis of Optically Active α-
Arylmethanol-1,2,3-Triazoles
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