Synergistic Effect of Copper and Ruthenium on Regioselectivity in the Alkyne-Azide Click Reaction of Internal Alkynes

Article abstract of DOI:10.1021/acs.oprd.8b00163

Cu(I) salts have been shown to improve the regioselectivity and rate of the Ru-catalyzed alkyne-azide click reaction of internal alkynes with azides. While Cu and Ru individually provide complementary regioselectivity in the case of terminal alkynes, the

Full text of DOI:10.1021/acs.oprd.8b00163

Article
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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Synergistic Effect of Copper and Ruthenium on Regioselectivity in
the Alkyne−Azide Click Reaction of Internal Alkynes
Sivaraj Ramasamy,† Chittibabu Petha,† Shankar Tendulkar,† Prantik Maity,† Martin D. Eastgate,‡
and Rajappa Vaidyanathan*,†
†Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link
Road, Bommasandra IV, Bangalore 560099, India
‡Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
S
* Supporting Information
ABSTRACT: Cu(I) salts have been shown to improve the regioselectivity and rate of the Ru-catalyzed alkyne−azide click
reaction of internal alkynes with azides. While Cu and Ru individually provide complementary regioselectivity in the case of
terminal alkynes, the synergistic effect of these two species in situ significantly improves regiochemical outcomes in the case of
internal alkynes. The substrate scope of these new reaction conditions is also reported.
are no reported examples of catalysis by copper (Scheme
1).2g,7,8
INTRODUCTION
■
The 1,2,3-triazole motif has gained widespread adoption as a
structural feature within modern pharmaceuticals.1 The surge in
this area can be attributed to the development of the alkyne−
azide (3 + 2) cycloaddition reaction, which is also referred to as
RESULTS AND DISCUSSION
■
We were interested in the regioselective synthesis of 1,4,5-
trisubstituted triazole 5, a key intermediate for a medicinal
chemistry program. We envisioned that 5 could be accessed via
a RuAAC reaction between propargylic alcohol 7 and TMS-
methyl azide. Our initial attempts at this transformation
provided a 2.5:1 mixture of regioisomeric triazoles 5 and 6
(entry 1, Scheme 2). As we sought to explore a larger-scale
manufacturing route for this compound, we realized that this
ratio needed significant enhancement. Moreover, the reaction
required heating at >50 °C; the known thermal sensitivity of
the alkyne−azide click (AAC) or the Huisgen 1,3-dipolar
̈
cycloaddition reaction.2 Most of the initial work on this class of
reactions centered on the coupling and cyclization of terminal
alkynes with substituted azides to provide disubstituted 1,2,3-
triazoles. The original thermal cyclizations provided a mixture
of regioisomeric triazoles (relative positions of the alkyl/aryl
group on the acetylene and the substituent on the azide).
Subsequently, the Cu-3 and Ru-mediated4 versions of this
reaction (CuAAC and RuAAC, respectively) were developed to
provide complementary regiochemical outcomes (Scheme 1).
Scheme 2
Scheme 1
The exclusive product in the CuAAC reaction is the 1,4-
regioisomer 1, and the RuAAC protocol furnishes the 1,5-
regioisomer 2. The mechanisms of these two complementary
approaches have been extensively explored and elucidated by
several groups.5 In the case of unsymmetrical internal alkynes
bearing simple alkyl and aryl substituents, the RuAAC reaction
provides regioisomers 3 and/or 4 in different ratios depending
on the nature of R1 and R3,5b,6 whereas in stark contrast there
Received: May 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00163
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alkyl-azides warranted further investigation to decrease the
reaction temperature and increase the operating window for
safe scale-up.
grinding of the insoluble material by the magnetic stir bar in the
flask, and sought to overcome this problem by replacing CuI
with a soluble Cu source. A few commercially available Cu salts
were screened as additives in the reaction and provided only a
modest enhancement in regioselectivity (entries 5−7, Table 1).
Likewise, the addition of ligands with CuI did not exert any
further beneficial effect on regioselectivity (entries 8 and 9).
A major breakthrough was achieved upon the use of [n-
Bu4N+]2[Cu2I4]2− generated in situ by premixing CuI and n-
Bu4NI in equimolar amounts before the addition of 7, TMS-
methyl azide, and [Ru(PPh3)2(Cp*)Cl].10 We were delighted
to find that this soluble additive not only increased the
regioselectivity to ∼11:1 (entry 10, Table 1) but also enhanced
the reaction rate (complete conversion within 10 min at ∼55
°C or within 2 h at 35 °C). Reactions using the soluble Cu
source in the absence of Ru did not proceed at all (entry 11) in
line with literature reports. Similarly, the RuAAC reaction with
As the synthetic development efforts progressed, we were
intrigued by the fact that one of the batches of alkyne 7
provided a slightly higher ratio of regioisomers 5 and 6 (3.9:1)
than the initial attempt (compare entries 1 and 2, Scheme 2).
This variability could be attributed to several reaction
parameters, one of which was the quality of starting material
7. Analysis of multiple batches of 7 for trace contaminants
revealed that the batches exhibiting higher regioselectivity also
contained higher levels of Pd and Cu, remnants from the
Sonogashira coupling reaction used to produce 7.
We therefore spiked small quantities of Pd2dba3, CuI, and
CuSO4 into test reactions, starting with analytically pure
samples of 7 (containing <10 ppm of Cu and Pd), to observe
their impact on yield and/or selectivity of the resulting
cyclization.9 Although all of these reactions went to completion,
the ones spiked with Pd2dba3 and CuSO4 did not provide any
̀
n-Bu4NI did not improve the conversion or selectivity vis-a-vis
the base case, confirming that Cu, not iodide, was responsible
for the rate and selectivity enhancements (compare entries 12
and 1). These results implied that Ru is required for reactivity
(Cu alone does not work), and the presence of Cu(I) augments
both the regioselectivity and reaction rate.
̀
improved selectivity vis-a-vis the baseline reaction (compare
entries 2 and 4 with entry 1, Table 1). However, we were
Table 1. Screening of Various Cu Additives for the RuAAC
Reaction of 7 with TMSCH2N3
For obtaining further insight into the rate enhancement due
to Cu with respect to the base case using Ru alone, four
reactions were set up using 7, TMS-methyl azide, [Ru-
(PPh3)2(Cp*)Cl], and various Cu additives (Figure 1). It was
found that the reaction using 10 mol % of premixed CuI and n-
Bu4NI was faster (65% conv in 60 min; t1/2 = 46 min)11 than
the reaction where these additives were added to the reaction
mixture without premixing (53% conv in 60 min; t1/2 = 57
min). The reaction with just CuI was slower (35% conv in 60
min; t1/2 = 85 min), while the base case in the absence of any
a
b
entry
additive
[Pd2dba3]
conv (%)
5:6
1
2
3
4
5
6
7
8
9
>99
>99
>99
>99
44
2.5:1
2.4:1
6.2:1
2.7:1
3.5:1
4.5:1
3.0:1
4.3:1
4.2:1
11:1
Cu additive was significantly slower (20% conv in 60 min; t1/2
=
CuI
133 min). These results clearly demonstrated the beneficial
effect of Cu on the reaction rate12 as well as the superiority of
the soluble complex [n-Bu4N+]2[Cu2I4]2− as an additive.
A preliminary DSC examination of the reaction mixture
during the conversion of 7 to 5 (and 6) under the Ru-alone
conditions revealed a thermal event at ∼90 °C. The rate
enhancement afforded by the addition of [n-Bu4N+]2[Cu2I4]2−
allowed us to carry out the transformation at 30−35 °C as
opposed to the 50−55 °C required for the Ru alone conditions,
thus widening the safety window for executing the process. The
new process using [n-Bu4N+]2[Cu2I4]2− was safely and
successfully carried out on a 40 kg scale in the pilot plant.13
The scope and generality of this synergistic catalysis were
then explored. To this end, several internal alkynes (each
bearing one alkyl and one aryl substituent) were synthesized
and subjected to the AAC reaction with either TMSCH2N3 or
PhCH2N3 to provide the corresponding trisubstituted 1,2,3-
triazoles. The reactions were carried out with either 5 mol %
[Ru(PPh3)2(Cp*)Cl] alone or a mixture of 5 mol %
[Ru(PPh3)2(Cp*)Cl] and 10 mol % [n-Bu4N+]2[Cu2I4]2−.
The reaction progress and ratios of the regioisomers were
determined by HPLC analysis, and the results are summarized
in Table 2. In all of the cases, the predominant regioisomer
contained the aryl group at the 4-position of the triazole. The
addition of [n-Bu4N+]2[Cu2I4]2− led to a significant increase in
regioselectivity compared to the “Ru alone” conditions. The
reactions with 2- and 3-alkynylpyridines exhibited a high degree
of regioselectivity in the presence of added Cu (11a−c). The
simple phenyl substituted analogues (11d−g) also followed this
CuSO4
[Cu(OAc)]
[Cu(OTf)·PhMe]
[Cu(MeCN)4]PF6
CuI + PCy3
71
66
97
CuI + P(2-Py)3
[n-Bu4N+]2[Cu2I4]2−
[n-Bu4N+]2[Cu2I4]2−
n-Bu4NI
92
c
10
>99
<1
cd
,
11
12
c
76
2.6:1
a
All reactions were carried out on a 50 mg scale using a batch of 7
b
containing <10 ppm of Cu. HPLC ratio measured after TMS
removal. Carried out at 30−35 °C. Carried out in the absence of Ru.
c
d
delighted to find that the reaction with CuI gave a 6.2:1
selectivity (entry 3, Table 1). These observations were
noteworthy and suggested that the enhancement of regiose-
lectivity was due to the presence of Cu(I) and not Pd or
Cu(II). This finding was exciting because it revealed an
unprecedented synergistic effect of Ru and Cu on the
regiochemical outcome of the AAC reaction for internal
alkynes as opposed to the complementary effects reported in
the literature (albeit for terminal alkynes).
Although the 6.2:1 ratio of regioisomers using CuI was a
welcome development, we recognized very quickly that the
ratio was inconsistent, going down to ∼4:1 on a 1 g scale. We
hypothesized that this variability was due to the partial
solubility of CuI in the reaction medium, which could be
impacted by various factors, including particle attrition by
B
DOI: 10.1021/acs.oprd.8b00163
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Figure 1. Impact of Cu additives on reaction rate.
Table 2. Substrate Scope of the Synergistic Ru/Cu-Catalyzed AAC
trend; similar enhanced selectivities were observed with
hydroxy (11d), acetoxy (11e), and simple alkyl (11f and
11g) substituents on the distal alkyne carbon. These results
implied that the increased selectivity in the presence of Cu was
not due to the coordinating ability of substituents on the
alkyne. Further, the presence of Cu provided improved
regioselectivities with alkynes containing both electron-
donating and electron-withdrawing substituents on the
aromatic ring (11h−n).
The mechanistic aspects of this transformation clearly need
further interrogation. The major products of the Ru-mediated
reactions are essentially similar to the ones observed by Fokin
et al.,5b wherein the acetylenic carbon bearing the aryl group
becomes C4 of the triazole and the carbon bearing hydrogen
donor groups becomes C5 (11a−e and 11h−k). In the absence
of such directing groups, other electronic and steric factors
influence regioselectivity, as demonstrated by Nolan5a and
Fokin.5b Our results indicate that the presence of Cu bolsters
C
DOI: 10.1021/acs.oprd.8b00163
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Article
the inherent selectivity observed with Ru and also accelerates
the reactions. The exact role of Cu in this reaction is unclear at
this point and warrants further examination.
nitrogen atmosphere. CuI (10 mol %) and n-Bu4NI (10 mol %)
were added to the round-bottomed flask and stirred for 10−15
min to obtain a clear solution. The alkyne (1.0 equiv) and azide
(1.5 equiv) were added to the flask, and nitrogen was sparged
through the mixture for 10 min followed by the addition of
[Ru(PPh3)2(Cp*)Cl] (5 mol %) . The mixture was stirred for
4−12 h at 30−35 °C, and the progress of the reaction and the
product ratios were monitored by HPLC. In certain instances,
the in situ yields of the reactions were determined by 1H NMR
spectroscopy using durene (1,2,4,5-tetramethylbenzene) as an
internal standard. After completion of the reaction, the mixture
was diluted with THF and filtered through a plug of silica gel.
The filtrate was concentrated in vacuo and purified by a Mass-
Based Preparative Purification System to give the desired
product.
CONCLUSIONS
■
In summary, we have discovered the synergistic effect of Ru and
Cu in the alkyne−azide Click reaction of internal alkynes. This
observation is particularly significant in light of the well-
documented complementarity of these metals in the case of
terminal alkynes. The addition of Cu also resulted in rate
enhancement, which allows the transformation to be affected at
lower temperatures, a distinct advantage from a safety
standpoint. Because a majority of alkynes used in AAC
reactions are accessed via the Sonogashira reaction (which
employs Cu), there is a significant likelihood of residual Cu in
these substrates. As organic/process chemists, it behooves us to
pay close attention to byproducts of reactions, some of which
can exert a profound influence on subsequent transformations;
fortuitously, the Cu “contaminant” in this case had a beneficial
rather than deleterious impact! Although the actual role of Cu
in the reaction pathway still needs to be unequivocally
established, the utility of this observation in triazole synthesis
is clear.
(4-(5-Bromo-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-tria-
zol-5-yl)methanol (Desilyl-5) and (5-(5-Bromo-6-methylpyr-
idin-2-yl)-1-methyl-1H-1,2,3-triazol-4-yl)methanol (Desilyl-
6). The reactions were carried out on a 5 g scale.
Upon completion of the reaction performed according to
procedure B, TBAF (1.2 equiv w.r.t 7) was added, and the
mixture was stirred for 1 h. The reaction mixture was purified
by column chromatography using ethyl acetate (Rf = 0.5) to
afford 4.9 g (79%) of compound desilyl-5 as a white solid (mp
1
133−137 °C). H NMR (400 MHz, CDCl3) δ 8.04−8.02 (m,
EXPERIMENTAL SECTION
1H), 7.96 (d, J = 8.0 Hz, 1H), 6.85 (t, J = 6.8 Hz, −OH), 4.83
(d, J = 6.8 Hz, 2H), 4.08 (s, 3H), 2.70 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 156.1, 148.8, 144.1, 141.2, 136.2, 119.8, 119.6,
53.4, 35.1, 24.7; HRMS (ESI-TOF) (m/z) calcd for
C10H12BrN4O 283.0194 [M + H]+, found 283.0168.
■
General Information. All reactions were performed under
a nitrogen atmosphere. All compounds were purified by flash
chromatography using silica gel (5−20 μm) as needed. Thin
layer chromatography (TLC) was performed on glass plates
coated with silica gel 60 with F254 indicator. 1,4-Dioxane was
degassed by sparging with N2 and stored over activated 4 Å MS
under a nitrogen atmosphere in a glovebox. Chemical shifts for
protons are reported in parts per million downfield from
tetramethylsilane and are referenced to residual protium in the
NMR solvent (CHCl3 = δ 7.26; (CD3)2SO = δ 2.50). Chemical
shifts for carbons are reported in parts per million downfield
from tetramethylsilane and are referenced to the carbon
resonances of the solvent (CDCl3 = δ 77.16). Melting points
were obtained using a Stuart SMP10 instrument. HRMS was
recorded on Thermo Velos Orbitrap mass spectrophotometer
(ESI and APCI Source).
Compound desilyl-6 was isolated (0.3 g (5%); Rf = 0.45) as a
white solid (mp 125−128 °C). 1H NMR (400 MHz, CDCl3) δ
7.98 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 4.77 (d, J =
6.4 Hz, 2H), 4.66 (t, J = 6.4 Hz, −OH), 4.24 (s, 3H), 2.71 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 157.8, 146.0, 144.6, 141.0,
133.8, 122.9, 121.5, 55.7, 37.2, 25.0; HRMS (ESI-TOF) (m/z)
calcd for C10H12BrN4O 283.0194 [M + H]+, found 283.0175.
(4-(6-Methylpyridin-2-yl)-1-((trimethylsilyl)methyl)-1H-
1,2,3-triazol-5-yl)methanol (11a) and (5-(6-Methylpyridin-2-
yl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)methanol
(12a). The reactions were carried out on a 200 mg scale.
The mixture from procedure B was purified by the Mass-
Based Preparative Purification System using 10 mM ammo-
nium acetate and acetonitrile to afford 200 mg (53%) of
Materials. Commercial reagents were purchased from
Sigma-Aldrich, Acros, Fisher, Strem, TCI, Combi Blocks, Alfa
Aesar, or Cambridge Isotopes Laboratories and used as
received. All the alkynes 7,14 10a,14 10c,15 10d,16 10e,16
10f,17 10g,17 10h,18 10i,18 10j,18 10k,19 10l,18 and 10m18 were
prepared by Sonogashira coupling following literature proce-
dures and were purified by column chromatography.
1
compound 11a as an off-white solid (mp 116−119 °C). H
NMR (300 MHz, CDCl3) δ 7.92 (d, J = 7.8 Hz, 1H), 7.55 (t, J
= 7.8 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 5.26 (br, −OH), 4.59
(s, 2H), 3.61 (s, 2H), 2.38 (s, 3H), 0.00 (s, 9H);13C NMR (75
MHz, CDCl3) δ 159.2, 152.4, 146.9, 140.2, 138.3, 124.1, 120.4,
55.9, 41.8, 26.4, 0.0; HRMS (ESI-TOF) (m/z) calcd for
C13H21N4OSi 277.1485 [M + H]+, found 277.1469.
General Procedure. A. Without Cu. To an oven-dried 3-
neck round-bottomed flask fitted with a thermo jacket and
reflux condenser was added THF (20 mL/g w.r.t. the alkyne)
was added under a nitrogen atmosphere. The alkyne (1.0
equiv) and azide (1.5 equiv) were added to the round-
bottomed flask, and nitrogen was sparged through the mixture
for 10 min followed by the addition of [Ru(PPh3)2(Cp*)Cl] (5
mol %). The mixture was stirred for 4−12 h at 30−35 °C, and
the progress of the reaction and the product ratios were
monitored by HPLC. The products from these reactions were
not isolated.
Compound 12a was isolated as an off-white solid (30 mg
1
(8%); mp 106−108 °C). H NMR (300 MHz, CDCl3) δ 7.70
(t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.8 Hz,
1H), 4.65 (s, 2H), 4.36 (bs, −OH), 3.99 (s, 2H), 2.53 (s, 3H),
0.00 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 161.0, 148.6,
139.5, 125.0, 122.9, 58.6, 43.1, 26.4, 3.0, 0.0; HRMS (ESI-
TOF) (m/z) calcd for C13H21N4OSi 277.1485 [M + H]+,
found 277.1469.
(1-Benzyl-4-(6-Methylpyridin-2-yl)-1H-1,2,3-triazol-5-yl)-
methanol (11b) and (1-Benzyl-5-(6-methylpyridin-2-yl)-1H-
1,2,3-triazol-4-yl)methanol (12b). The reactions were carried
out on a 5 g scale.
B. With [n-Bu4N+]2[Cu2I4]2−. To an oven-dried 3-neck
round-bottomed flask fitted with a thermo jacket and reflux
condenser was added THF (20 mL/g w.r.t. the alkyne) under a
D
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The product was purified by column chromatography using
EtOAc/n-heptane (3:7, Rf = 0.5) to afford 6.45 g (68%) of
compound 11b as an off-white solid (mp 105−108 °C). H
NMR (300 MHz, CDCl3) δ 8.17 (d, J = 7.8 Hz, 1H), 7.76 (t, J
= 7.8 Hz, 2H), 7.37−7.30 (m, 3H), 7.22−7.19 (m, 2H), 7.12
(d, J = 7.8 Hz, 1H), 5.62 (s, 2H), 4.70 (s, 2H), 2.56 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 157.2, 150.0, 145.8, 138.1,
136.3, 134.7, 129.1, 128.5, 127.0, 122.2, 118.5, 53.7, 52.4, 24.0;
HRMS (ESI-TOF) (m/z) calcd for C16H17N4O 281.1402 [M +
H]+, found 281.1394.
compound 11e as a brown oil. 1H NMR (300 MHz, CDCl3) δ
7.75−7.73 (m, 2H), 7.48−7.31 (m, 6H), 7.24−7.21 (m, 2H),
5.71 (s, 2H), 5.14 (s, 2H), 1.94 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.2,148.0, 134.8, 130.3, 129.0, 128.8, 128.6, 128.5,
128.4, 127.5, 53.5, 52.6, 20.5; HRMS (ESI-TOF) (m/z) calcd
for C18H18N3O2 308.1399 [M + H]+, found 308.1394.
Compound 12e was isolated as a brown oil (0.59 g (5%)).
1H NMR (300 MHz, CDCl3) δ 7.46−7.43 (m, 3H), 7.28−7.26
(m, 3H), 7.19−7.16 (m, 2H), 7.06−7.03 (m, 2H), 5.45 (s, 2H),
5.11 (s, 2H), 2.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
170.6, 140.4, 137.3, 135.1, 129.9, 129.7, 129.0, 128.8, 128.3,
127.5, 126.1, 57.3, 52.1, 20.8; HRMS (ESI-TOF) (m/z) calcd
for C18H18N3O2 308.1399 [M + H]+, found 308.1375.
1-Benzyl-5-methyl-4-phenyl-1H-1,2,3-triazole (11f) and 1-
Benzyl-4-methyl-5-phenyl-1H-1,2,3-triazole (12f). The reac-
tions were carried out on a 200 mg scale. The in situ yield of
the reaction using procedure B was 74.1% by 1H NMR
spectroscopy.
1
Compound 12b was isolated as an off-white solid (0.6 g
1
(6%); Rf = 0.3; mp 102−105 °C). H NMR (300 MHz,
CDCl3) δ 7.70−7.64 (m, 2H), 7.63−7.43 (m, 3H), 7.32−7.12
(m, 3H), 5.86 (s, 2H), 4.81−4.79 (d, J = 6.0 Hz, 2H), 4.05−
4.00 (t, J = 6.1 Hz, −OH), 2.62 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.0, 146.7, 145.8, 137.6, 135.5, 133.2, 132.2, 128.8,
127.1, 123.3, 120.9, 56.5, 52.9, 24.0; HRMS (ESI-TOF) (m/z)
calcd for C16H17N4O 281.1402 [M + H]+, found 281.1394.
(4-(Pyridin-3-yl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-
5-yl)methanol (11c) and (5-(Pyridin-3-yl)-1-((trimethylsilyl)-
methyl)-1H-1,2,3-triazol-4-yl)methanol (12c). The reactions
were carried out on an 8 g scale.
The mixture from procedure B was purified by a Mass-Based
Preparative Purification System with 10 mM ammonium
acetate and acetonitrile to afford 82 mg (38%) of compound
1
11f as a brown oil. H NMR (300 MHz, CDCl3) δ 7.70−7.68
The product was purified by column chromatography using
EtOAc (Rf = 0.7) to afford 9.65 g (60%) of compound 11c as a
(m, 2H), 7.45−7.41 (m, 2H), 7.37−7.31 (m, 4H), 7.21−7.19
(m, 2H), 5.54 (s, 2H), 2.33 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 145.0, 134.9, 131.6, 129.2, 129.0, 128.7, 128.3, 127.7,
127.2, 127.1, 52.0, 9.2; HRMS (ESI-TOF) (m/z) calcd for
C16H16N3 250.1344 [M + H]+, found 250.1339.
1
light yellow solid (mp 105−108 °C). H NMR (400 MHz,
CDCl3) δ 8.51 (br, 1H), 8.22 (br, 1H), 7.92 (d, J = 8.1 Hz,
1H), 7.14 (br, 1H), 5.52 (br, OH), 4.59 (s, 2H), 3.70 (s, 2H),
0.00 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 148.2, 147.4,
141.7, 135.4, 133.2, 128.2, 124.0, 52.1, 39.5, −1.9; HRMS (ESI-
TOF) (m/z) calcd for C12H19N4OSi 263.1328 [M + H]+,
found 263.1324.
Compound 12f was isolated as a brown oil (12 mg (6%)).
1H NMR (300 MHz, CDCl3) δ 7.43−7.41 (m, 3H), 7.26−7.24
(m, 3H), 7.15−7.13 (m, 2H), 7.03−7.00 (m, 2H), 5.43 (s, 2H),
2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.6, 135.6,
134.6, 129.5, 129.2, 128.9, 128.7, 128.0, 127.5, 127.3, 52.0, 10.7;
HRMS (ESI-TOF) (m/z) calcd for C16H16N3 250.1344 [M +
H]+, found 250.1340
1-Benzyl-5-ethyl-4-phenyl-1H-1,2,3-triazole (11g) and 1-
Benzyl-4-ethyl-5-phenyl-1H-1,2,3-triazole (12g). The reac-
tions were carried out on a 10 g scale.
Compound 12c was isolated as a light yellow solid (0.48 g
1
(3%); Rf = 0.4; mp 106−108 °C). H NMR (300 MHz,
CDCl3) δ 8.63−8.60 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.40−
7.36 (m, 1H), 4.57 (s, 2H), 3.62 (s, 2H), 2.78 (br, OH), 0.00
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 150.5, 150.0, 145.4,
137.3, 132.8, 123.8, 123.7, 55.8, 40.1, 1.0; HRMS (ESI-TOF)
(m/z) calcd for C12H19N4OSi 263.1328 [M + H]+, found
263.1330.
The product was purified by column chromatography using
EtOAc/n-heptane (1:5; Rf = 0.2) to afford 11.5 g (57%) of
(1-Benzyl-4-phenyl-1H-1,2,3-triazol-5-yl)methanol (11d)
and (1-Benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)methanol
(12d). The reactions were carried out on a 5 g scale.
The product was purified by column chromatography using
EtOAc/n-heptane (1:1; Rf = 0.6) to afford 7.7 g (77%) of
1
compound 11g as a pale yellow oil. H NMR (400 MHz,
CDCl3) δ 7.72−7.70 (m, 2H), 7.44−7.41 (m, 2H), 7.36−7.28
(m, 4H), 7.24−7.20 (m, 2H), 5.56 (s, 2H), 2.80 (q, J = 7.6 Hz,
2H), 1.07 (t, J = 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
144.5, 135.3, 134.7, 131.7, 129.0, 128.7, 128.3, 127.7, 127.1,
127.0, 52.0, 16.6, 13.0; HRMS (ESI-TOF) (m/z) calcd for
C17H18N3 264.1501 [M + H]+, found 264.1495.
1
compound 11d as an off-white solid (mp 132−135 °C). H
NMR (400 MHz, CDCl3) δ 7.66−7.64 (m, 2H), 7.42−7.29 (m,
6H), 7.26−7.24 (m, 2H), 5.63 (s, 2H), 4.68−4.68 (m, 2H),
2.86 (br, OH); 13C NMR (75 MHz, CDCl3) δ 146.4, 135.0,
131.7, 130.5, 129.1, 128.8, 128.5, 128.3, 127.7, 127.5, 52.6, 52.6;
HRMS (ESI-TOF) (m/z) calcd for C16H16N3O 266.1293 [M +
H]+, found 266.1278.
Compound 12g was isolated as a pale yellow oil (0.45 g
1
(2%)). H NMR (300 MHz, CDCl3) δ 7.43−7.39 (m, 3H),
7.26−7.23 (m, 3H), 7.13−7.11 (m, 2H), 7.02−7.00 (m, 2H),
5.40 (s, 2H), 2.70 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.8 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 147.2, 135.6, 134.1, 129.7,
129.2, 128.8, 128.6, 128.0, 127.6, 127.4, 52.0, 18.6, 14.2; HRMS
(ESI-TOF) (m/z) calcd for C17H18N3 264.1501 [M + H]+,
found 264.1476.
Compound 12d was isolated as an off-white solid (0.61 g
(6%); mp 121−124 °C). 1H NMR (400 MHz, CDCl3) δ 7.47−
7.42 (m, 3H), 7.28−7.26 (m, 2H), 7.24 (m, 2H), 7.06−7.05
(m, 2H), 5.48 (s, 2H), 4.68 (s, 2H), 2.41 (br, OH); 13C NMR
(75 MHz, CDCl3) δ 145.0, 135.9, 135.3, 129.7, 129.7, 129.0,
128.8, 128.2, 127.3, 126.4, 55.8, 52.1; HRMS (ESI-TOF) (m/z)
calcd for C16H16N3O 266.1293 [M + H]+, found 266.1275.
(1-Benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)methyl Acetate
(11e) and (1-Benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)methyl
Acetate (12e). The reactions were carried out on a 7 g scale.
The product was purified by column chromatography using
EtOAc/n-heptane (1:1; Rf = 0.5) to afford 8.7 g (70%) of
(1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazol-5-yl)-
methanol (11h) and (1-Benzyl-5-(4-methoxyphenyl)-1H-
1,2,3-triazol-4-yl)methanol (12h). The reactions were carried
out on a 10 g scale.
The product was purified by column chromatography using
EtOAc/n-heptane (3:7; Rf = 0.5) to afford 12.7 g (70%) of
compound 11h as a semi-solid. 1H NMR (300 MHz, CDCl3) δ
7.57−7.55 (m, 2H), 7.33−7.21 (m, 5H), 6.92−6.88 (m, 2H),
E
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Article
5.59 (s, 2H), 4.65−4.64 (m, 2H), 3.79 (s, 3H), 3.55 (br,
−OH); 13C NMR (75 MHz, CDCl3) δ 159.6, 146.1, 135.0,
131.3, 129.0, 128.4, 127.4, 123.0, 114.1, 55.2, 55.2, 52.4, 52.3;
HRMS (ESI-TOF) (m/z) calcd for C17H18N3O2 296.1399 [M
+ H]+, found 296.1380.
146.4, 135.0, 131.9, 131.6, 129.8, 129.1, 128.5, 127.4, 120.0,
114.3, 112.8, 55.3, 55.3, 52.7, 52.6; HRMS (ESI-TOF) (m/z)
calcd for C18H18N3O3 324.1348 [M + H]+, found 324.1333.
Compound 12k was isolated as a light brown solid (0.85 g
1
(8%); mp 94−97 °C). H NMR (300 MHz, CDCl3) δ 7.37−
Compound 12h was isolated as a semi-solid (2.5 g (14%)).
1H NMR (300 MHz, CDCl3) δ 7.30−7.26 (m, 4H), 7.19 (q, J
= 8.7 Hz, 2H), 7.09−7.05 (m, 2H), 7.00 (d, J = 8.7 Hz, 2H),
5.45 (s, 2H), 4.67 (s, 2H), 3.85 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 160.3, 144.8, 135.7, 135.3, 131.9, 131.8, 130.9, 128.5,
128.4, 128.2, 127.9, 127.0, 118.1, 114.2, 55.1, 51.7; HRMS
(ESI-TOF) (m/z) calcd for C17H18N3O2 296.1399 [M + H]+,
found 296.1374
7.32 (m, 1H), 7.29−7.20 (m, 3H), 7.09−7.06 (m, 2H), 7.00−
6.98 (m, 1H), 6.85−6.83 (m, 1H), 6.75−6.74 (m, 1H), 5.48 (s,
2H), 4.68 (s, 2H), 3.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
159.8, 135.5, 130.1, 129.6, 129.4, 128.8, 128.2, 127.6, 127.3,
121.9, 115.7, 114.8, 112.8, 58.8, 55.6, 52.1; HRMS (ESI-TOF)
(m/z) calcd for C18H18N3O3 324.1348 [M + H]+, found
324.1326.
Methyl 4-(1-Benzyl-5-(hydroxymethyl)-1H-1,2,3-triazol-4-
yl)benzoate (11l) and (1-Benzyl-5-(4-methoxyphenyl)-1H-
1,2,3-triazol-4-yl)methanol (12l). The reactions were carried
out on a 100 mg scale.
(1-Benzyl-4-(3-methoxyphenyl)-1H-1,2,3-triazol-5-yl)-
methanol (11i) and Methyl 4-(1-Benzyl-5-(hydroxymethyl)-
1H-1,2,3-triazol-4-yl)benzoate (12i). The reactions were
carried out on a 100 mg scale. The in situ yield of the reaction
The mixture from procedure B was purified by the Mass-
Based Preparative Purification System with 10 mM ammonium
acetate and acetonitrile to afford 113 mg (68%) of compound
1
using procedure B was 76.4% by H NMR spectroscopy.
The mixture from procedure B was purified by the Mass-
Based Preparative Purification System with 10 mM ammonium
acetate and acetonitrile to afford 41 mg (23%) of compound
1
11l as a pale brown solid (mp 139−142 °C). H NMR (300
MHz, CDCl3) δ 7.80 (d, J = 6.0 Hz, 2H), 7.65 (d, J = 6.3 Hz,
2H), 7.37−7.33 (m, 3H), 7.28−7.25 (m, 2H), 5.67 (s, 2H),
4.71−4.70 (m, 2H), 2.80 (br, OH); 13C NMR (75 MHz,
CDCl3) δ 145.3, 134.7, 134.1, 132.3, 130.2 (q, J = 32.5 Hz),
129.5, 129.2, 128.8, 127.8, 127.5, 125.6, 122.2, 118.6, 52.5;
HRMS (ESI-TOF) (m/z) calcd for C17H15F3N3O 334.1167 [M
+ H]+, found 334.1162.
1
11i as a pale brown solid (mp 114−117 °C). H NMR (300
MHz, CDCl3) δ 8.28 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.91 (d,
J = 7.8 Hz, 1H), 7.55−7.43 (m, 1H), 7.38−7.26 (m, 5H), 5.70
(s, 2H) 4.71 (s, 2H), 3.89 (s, 3H) 3.03 (br, OH); 13C NMR
(75 MHz, CDCl3) δ 166.9, 145.4, 134.9, 132.2, 132.0, 131.1,
130.6, 129.2, 129.1, 129.0, 128.6, 128.5, 127.5, 52.5, 52.3;
HRMS (ESI-TOF) (m/z) calcd for C17H18N3O2 296.1399 [M
+ H]+, found 296.1383.
Compound 12l was isolated as a pale brown solid (8 mg
(5.0%); mp 137−141 °C). 1H NMR (300 MHz, CDCl3) δ 7.76
(d, J = 6.0 Hz, 2H), 7.71 (d, J = 6.3 Hz, 2H), 7.31−7.28 (m,
3H), 7.06−7.03 (m, 2H), 5.50 (s, 2H), 4.70 (br, 2H), 2.48 (s,
OH); HRMS (ESI-TOF) (m/z) calcd for C17H15F3N3O
334.1167 [M + H]+, found 334.1141.
(1-Benzyl-4-(4-bromophenyl)-1H-1,2,3-triazol-5-yl)-
methanol (11m) and (1-Benzyl-5-(4-bromophenyl)-1H-1,2,3-
triazol-4-yl)methanol (12m). The reactions were carried out
on a 9 g scale.
Compound 12i was isolated as a semi-solid (5 mg (3%)). 1H
NMR (300 MHz, CDCl3) δ 8.14−8.11 (d, J = 7.8 Hz 1H), 7.90
(s, 1H), 7.54−7.49 (m, 1H), 7.45−7.42 (m, 1H), 7.28−7.26
(m, 3H), 7.06−7.04 (m, 2H), 5.48 (s, 2H), 4.67 (s, 2H), 3.90
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.1, 135.0, 134.1,
134.0, 131.0, 130.7, 130.6, 130.5, 129.2, 128.8, 128.3, 127.4,
116.3, 58.8, 52.4; HRMS (ESI-TOF) (m/z) calcd for
C17H18N3O2 296.1399 [M + H]+, found 296.1373
The product was purified by column chromatography using
EtOAc/n-heptane (3:7; Rf = 0.5) to afford 8.2 g (56%) of
compound 11m as an off-white solid (mp 136−139 °C). H
NMR (300 MHz, CDCl3) δ 8.15 (s, 4H), 8.00−7.94 (m, 3H),
7.89−7.88 (m, 2H), 6.27 (s, 2H), 5.30−5.29 (m, 2H), 3.48 (br,
OH); 13C NMR (75 MHz, CDCl3) δ 145.4, 134.8, 132.0, 131.8,
129.4, 129.2, 129.2, 128.7, 127.5, 122.6, 52.6, 52.5; HRMS
(ESI-TOF) (m/z) calcd for C16H15BrN3O 344.0398 [M + H]+,
found 344.0392.
Methyl 4-(1-Benzyl-5-(hydroxymethyl)-1H-1,2,3-triazol-4-
yl)benzoate (11j) and Methyl 4-(1-Benzyl-4-(hydroxymeth-
yl)-1H-1,2,3-triazol-5-yl)benzoate (12j). The reactions were
carried out on a 200 mg scale.
1
The mixture from procedure B was purified by column
chromatography using EtOAc/n-heptane (1:3; Rf = 0.4) to
1
afford 140 mg (22%) of compound 11j as a semi-solid. H
NMR (300 MHz, CDCl3) δ 8.04 (d, J = 6.0 Hz, 2H), 7.75 (d, J
= 6.3 Hz, 2H), 7.37−7.32 (m, 3H), 7.28−7.26 (m, 2H), 5.67 (s,
2H), 4.72−4.71 (m, 2H), 3.90 (s, 3H), 3.10 (br, OH); 13C
NMR (75 MHz, CDCl3) δ 169.9, 145.4, 135.0, 134.8, 132.5,
130.0, 129.6, 129.2, 128.6, 127.5, 127.4, 52.7, 52.5, 52.2; HRMS
(ESI-TOF) (m/z) calcd for C18H18N3O3 324.1348 [M + H]+,
found 324.1343.
Compound 12m was isolated as an off-white solid (0.74 g
1
(5%); mp 121−124 °C). H NMR (300 MHz, CDCl3) δ 7.58
(d, J = 8.4 Hz, 2H), 7.29−7.26 (m, 3H), 7.13 (d, J = 8.7 Hz,
2H), 7.07−7.03 (m, 2H), 5.64 (s, 2H), 4.67 (d, J = 6.3 Hz,
2H), 2.27 (t, J = 6.3 Hz, OH); 13C NMR (75 MHz, CDCl3) δ
145.2, 135.0, 134.9, 132.2, 131.2, 128.9, 128.3, 127.2, 125.2,
124.3, 55.5, 52.2; HRMS (ESI-TOF) (m/z) calcd for
C16H15BrN3O 344.0398 [M + H]+, found 344.0394.
Minor regioisomer (12j) not isolated.
Methyl 3-(1-Benzyl-5-(hydroxymethyl)-1H-1,2,3-triazol-4-
yl)benzoate (11k) and Methyl 3-(1-Benzyl-4-(hydroxymeth-
yl)-1H-1,2,3-triazol-5-yl)benzoate (12k). The reactions were
carried out on a 6 g scale.
(4-(4-Bromophenyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-tri-
azol-5-yl)methanol (11n) and (5-(4-Bromophenyl)-1-
((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)methanol (12n).
The reactions were carried out on a 100 mg scale.
The mixture from procedure B was purified by the Mass-
Based Preparative Purification System with 10 mM ammonium
acetate and acetonitrile to afford 113 mg (70%) of compound
11n as a pale brown oil. 1H NMR (300 MHz, CDCl3) δ 7.62−
7.56 (m, 4H), 4.83 (d, J = 3.9 Hz, 2H), 3.86 (s, 2H), 2.46 (t, J =
The product was purified by column chromatography using
EtOAc/n-heptane (1:1; Rf = 0.5) to afford 7.46 g (73%) of
1
compound 11k as a light brown solid (mp 91−94 °C). H
NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 8.01−7.93 (m, 1H),
7.92−7.91 (m, 1H), 7.52(t, J = 7.6 Hz, 1H), 7.39−7.28 (m,
5H), 5.71 (s, 2H), 4.72 (d, J = 5.2 Hz, 2H), 3.90 (s, 3H), 2.12
(t, J = 5.6 Hz, OH); 13C NMR (75 MHz, CDCl3) δ 159.9,
F
DOI: 10.1021/acs.oprd.8b00163
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Article
3.9 Hz, OH), 0.23 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
144.5, 132.0, 131.7, 130.0, 129.0, 122.3, 52.7, 39.4, 1.9; HRMS
(ESI-TOF) (m/z) calcd for C13H19BrN3OSi 340.0481 [M +
H]+, found 340.0475.
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1996; Vol. 4, pp 1−126.
Compound 12n was isolated as a pale brown oil (8 mg
1
(5.0%)). H NMR (300 MHz, CDCl3) δ 7.70−7.66 (m, 2H),
7.34−7.30 (m, 2H), 4.67 (d, J = 4.2 Hz, 2H), 3.72 (s, 2H), 2.73
(br, OH), 0.12 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 144.4,
134.8, 132.4, 131.2, 126.0, 124.0, 55.8, 40.0, 1.0; HRMS (ESI-
TOF) (m/z) calcd for C13H19BrN3OSi 340.0481 [M + H]+,
found 340.0473.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00163.
■
S
HPLC chromatograms of reaction mixtures using general
procedures A and B, 1H and 13C NMR spectra of all new
compounds, NOE spectra of compounds 11f, 11g, 11n,
and 12n, and X-ray crystallographic analysis of 11d
(PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: vaidy@bms.com.
ORCID
Martin D. Eastgate: 0000-0002-6487-3121
Rajappa Vaidyanathan: 0000-0002-2236-5719
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Alla Venu, Ramarao Gurunadha, Yogesh Gowda,
Sabuj Mukherjee, Richard Fox, and Christina Risatti for their
suggestions and contributions. Analytical support from Naresh
Marella and Murali Arumugam is gratefully acknowledged.
Single-crystal X-ray analysis was performed by Amol
Dikundwar and Pema Chodon. We thank Rajgopal Sharma
and Souvik Rakshit for helpful suggestions during the
preparation of this manuscript. Our sincere thanks to David
Kronenthal and Robert Waltermire for their support of this
work.
REFERENCES
■
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Organic Process Research & Development
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(9) Although the initial conditions in Scheme 1 used dioxane, we
realized that the yields and selectivities were very similar in THF and
chose to use the latter in the screening experiments and subsequent
reactions.
(10) Maligres, P. E.; Krska, S. W.; Dormer, P. G. A Soluble
Copper(I) Source and Stable Salts of Volatile Ligands for Copper-
Catalyzed C−X Couplings. J. Org. Chem. 2012, 77, 7646.
(11) The reaction using only 5 mol % of premixed CuI and n-Bu4NI
was slower, resulting in 50% conversion in 60 min.
(12) In all of these cases, the selectivities were similar to the
corresponding experiments in Table 1. The conversions in Figure 1
refer to the conversion of 7 to a mixture of 5 and 6 as monitored by
HPLC area.
(13) A complete account of the scale-up of this process, including
detailed process safety data, will be communicated in due course.
(14) Bach, P.; Nilsson, K.; Svensson, T.; Bauer, U.; Hammerland, L.
G.; Peterson, A.; Wallberg, A.; Osterlund, K.; Karis, D.; Boije, M.;
Wensbo, D. Structure−activity relationships for the linker in a series of
H
DOI: 10.1021/acs.oprd.8b00163
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