Synthesis and computational analysis of densely functionalized triazoles using o -nitrophenylalkynes

Article abstract of DOI:10.1021/jo202467k

Dipolar cylcoadditions with azides using a series of o-nitrophenylethynes and disubstituted alkynes were studied experimentally and computationally. Density functional theory computations reveal the steric and electronic parameters that control the regios

Full text of DOI:10.1021/jo202467k

Article
pubs.acs.org/joc
Synthesis and Computational Analysis of Densely Functionalized
Triazoles Using o-Nitrophenylalkynes
Melissa L. McIntosh, Ryne C. Johnston, Ommidala Pattawong, Bradley O. Ashburn, Michael R. Naffziger,
Paul Ha-Yeon Cheong,*,† and Rich G. Carter*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon 97331, United States
S
* Supporting Information
ABSTRACT: Dipolar cylcoadditions with azides using a series
of o-nitrophenylethynes and disubstituted alkynes were studied
experimentally and computationally. Density functional theory
computations reveal the steric and electronic parameters that
control the regioselectivity of these cycloadditions. Several new
substrates were predicted that would either give enhanced
regiocontrol or invert the regiochemical preference. Experimen-
tally, the alkynes were screened in the [3 + 2] cycloaddition with
benzyl azide. Of the 11 alkynes screened experimentally, the acetylenes containing halogen substitution directly on the alkyne
provided the highest levels of regioselectivity. These haloalkynes were also shown to tolerate variation of the azide moiety with
continued good levels of regioselectivity in most cases. Diverse functional groups can be incorporated through the cycloaddition
process and their subsequent orthogonal modification was demonstrated.
(Scheme 2).11 In this strategy, electron-deficient aryl (normally
o-nitrophenyl) alkynes are used in cycloaddition/cycloreversion
INTRODUCTION
Dipolar cycloadditions have captured the attention of organic
■
reactions with acyclic and cyclic dienes. This process has
chemists since their discovery over 50 years ago by Robert
Huisgen.1 Advances in the field have provided wide-ranging
proven to be highly regioselective and allows efficient access to
numerous classes of tetra-ortho-substituted biaryl compounds.
access to heterocyclic natural products, pharmaceuticals and
The o-nitro moiety on the aromatic ring is likely critical to
materials applications. While techniques for constructing these
structures have been greatly expanded by transition-metal
establishing the high regioselectivity and generality of this
catalysis,2 the search for alternate methods to increase the
process. While the increased steric bulk of placing two ortho
substituents on the aromatic ring of the aryl alkyne would
available substrate scope continue to be important in this area.
appear to be disruptive to the construction of a highly
Much of the recent excitement in this field has focused on
congested system, the electron-withdrawing nature of the o-
the development of copper-catalyzed dipolar cycloadditions
[often referred to as “Click” chemistry or the copper(I)-
catalyzed azide−alkyne cycloaddition (CuAAC)] utilizing
nitro moiety is able to override many steric effects, leading to
the construction of >50 examples of tetra-ortho-substituted
biaryl compounds 13 through this method to date.11
azides and alkynes. Alkyne/azide “Click” chemistry has become
the gold standard for dipolar cycloadditions (Scheme 1, eq 1).3
Interestingly, placement of the nitro moiety in the para
The broad utility of this process4 can be found in the numerous
position relative to the alkyne is not beneficial to the chemical
yield of the process.11e Our laboratory11 and others12 have
hypothesized possible mechanistic pathways for this trans-
formation, all of which involve the [2.2.2]-bicyclic intermediate
12. Our original mechanism invoked a [4 + 2]-cycloaddition to
generate bicycle 12. Alternatively, we have observed under
certain cases that intermediate 12 may also be obtained via a [2
+ 2]-cycloaddition followed by [1,3]-shift to yield the same
intermediate 12.11h Through either path, [4 + 2]-cycloreversion
extrudes an ethylene moiety and establishes aromaticity, which
likely is the driving force for the biaryl formation.
applications in polymer chemistry, materials science,5 pharma-
cology,6 and chemical biology.7 These transformations are
generally limited to monosubstituted alkynes and provide
excellent levels of chemical selectivity for the 1,4-triazole. In
recent years, ruthenium-based catalysis has been shown to
reverse the regioselecitivity to now favor the 1,5-triazole.4,8
Strained alkynes have extended the reach of this chemistry to
include disubstituted alkynes;9 however, these examples are
usually limited to strained cyclic alkynes or metal-catalyzed
systems10 and suffer from less than ideal regioselectivity
(Scheme 1, eq 2). Despite these considerable advances in the
field, control of regioselectivity in reactions involving
disubstituted alkynes as well as the search for a nonmetal
based solution remain challenges in this field.
Given the importance of the azide/alkyne dipolar cyclo-
additions coupled with the existing limitations in regioselective
control present with disubstituted alkynes, an exploration of the
Our laboratory has recently developed a Diels−Alder
approach to construct highly substituted biaryl scaffolds
Received: December 2, 2011
Published: January 11, 2012
© 2012 American Chemical Society
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Scheme 1. Alkyne/Azide Dipolar Cycloadditions
Scheme 2. Diels−Alder Approach to Biaryls
potential utility of our previously reported o-nitrophenylalkynes
in dipolar cycloaddition processes might be warranted.
Interestingly, despite the wealth of chemistry directed toward
triazole synthesis, only limited publications have appeared
utilizing o-nitrophenylalkynes as dipolarophiles.13,14 Alternate
dipolar cycloadditions toward these o-nitrophenyl heterocycles
have also been disclosed.15 The mechanism of the thermal
dipolar cycloaddition between an azide and alkyne has been the
subject of much discussion. In 1968, Firestone proposed a
diradical mechanism for the azide/alkyne coupling16 while
Huisgen favored the concerted mechanism.17 More recently,
Houk reported the FMO analyses and underlying chemical
principles that control the chemo- and regioselectivities of 1,3-
dipolar cycloadditions.18 In this article, we disclose the coupling
of experiments with computations to understand and guide the
regioselectivity of dipolar cycloadditions of azides and o-
nitrophenylalkynes 10.
Scheme 3. Synthesis of Alkynyl Halides
RESULTS AND DISCUSSION
■
Our laboratory has synthesized a range of alkynes derived from
our o-nitrophenylalkyne core to provide chemists with useful
building blocks for rapid construction of biaryl templates.11 In
support of our continued effort in this direction, we wanted to
expand the scope of o-nitrophenylalkyne substrates available for
this reaction (Scheme 3). In particular, we were intrigued by
the possibility of exploiting alkynyl halides as viable
dipolarophiles. While we expressed some reservations about
their potential stability due to the electron deficient aromatic
ring, cycloaddition products derived from these alkynes would
be potentially quite useful for further functionalization. It
should be noted that iodoalkynes have recently been shown to
be effective in a CuI/TTTA catalyst system for Click chemistry
by Sharpless and Fokin;19 however, we wished to expand the
range of accessible substrates to include chloro- and bromo-
containing alkynes. Fortunately, these alkynyl halides 22−25
were readily accessible via Corey−Fuchs olefination20 of the
known aldehydes 15−1711,21 followed by NaHMDS-mediated
elimination of the dihalides 18−2122,23 in high yield. These
alkynes were sufficiently stable for chromatographic purification
and subsequent reaction; however, protection from light and
storage at −30 °C improved their lifetime significantly. Not
surprisingly, the chloroalkynes 22,24 23, and 25 were
significantly more stable than the corresponding bromoalkyne
24.
We also were interested in accessing alkyl, aryl disubstituted
alkynes to probe in the cycloaddition process (Scheme 4). We
initially intended to explore a standard alkylation strategy for
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nitrophenyl group. In the parent compound series where R2 =
H, the 1,4-addition process is slightly preferred (TS-I-1,4 more
stable compared to TS-I-1,5 by 0.3 kcal/mol). This poor
selectivity reveals that the electron-withdrawing ability and the
steric encumbrance of the o-chloro-o-nitrophenyl group are
vanishingly small.
Scheme 4. Synthesis of Methylated Alkynes
When the R2 is a sterically encumbering group, such as a
SiMe3 (TS-II series), the steric interaction between the azidyl
substituent and the o-chloro-o-nitrophenyl group dominates,
favoring the 1,5-addition (TS-II-1,5) by 1.9 kcal/mol. Steric
bulk alone, however, does not explain the selectivity, as is the
case when R2 = NMe2. While NMe2 and SiMe3 are similar in
size (A values of 2.1 and 2.5, respectively), the former gives
exclusively the opposite 1,4-product by 6.3 kcal/mol. Similar to
a nucleophilic enamine, the ynamine favors nucleophilic
addition to the terminal electrophilic nitrogen of the azide
(TS-III-1,4) over addition to the nucleophilic internal azidyl
nitrogen in TS-III-1,5.
Some of the computed substrates were challenging to test
experimentally. Prior attempts to make silyl-substituted alkynes
derived from o-nitrophenylalkyne have proven challenging due
to stability issues of the product (e.g., 44b).29 Hsung and co-
workers have showcased the utility of ynamines in cyclo-
addition chemistry.30 Unfortunately, attempts to synthesize
ynamine-derived alkynes 43a−c have also proven unsuccessful
to date, likely due to the instability of the ynamine o-
nitrophenyl species.
Our experimental investigation into the reactivity of the o-
nitrophenylalkynes is illustrated in Table 2. In all cases,
computational predictions were in good agreement with the
experimentally observed regioselectivity. We initially screened
in three categories: monosubstituted alkynes (entries a−c),
disubstituted alkynes (entries d−g), and halogenated alkynes
(entries h−k). Within the monosubstituted alkynes, we first
screened the parent o-nitrophenylacetylene 40a under thermal
conditions. Interestingly, this thermal reaction has not been
previously reported; however, Feringa and co-workers recently
disclosed a phosphoramidite-accelerated copper-catalyzed
version of this transformation, which provided the triazole in
62% yield as a single regioisomer.14 The authors comment that
significant differences in rate and chemical yield are observed
with these reactions, with electron deficient alkynes such as 40a
providing the longest reactions times and lowest yields.
Although entry a was observed to be high-yielding (84%), the
regioselectivity was poor (entry a). As expected, more standard
CuACC conditions (CuSO4, ascorbic acid, and t-BuOH/H2O
(1:1), rt) provided a greatly improved regioselectivity. Similarly,
the 2-chloro-6-nitrophenylacetylene (40b) provided only
modest regiosiomeric control in the transformation (entry b).
These thermal results are in stark contrast to the high
regioselectivity we observed with these alkynes in a range of
biaryl-forming cycloadditions.11 Replacement of the halogen on
the aromatic ring with a methyl group (alkyne 40c) reduced the
chemical reactivity to thermal cycloaddition, requiring 96 h to
proceed with reasonable conversion (entry c). As seen with
entry a, these monosubstituted alkynes are more effectively
utilized (98% yield, single regioisomer) using standard Click
conditions. Use of disubstituted alkynes 38−39 and 41−42
provided similar levels of regioselectivity to the monosub-
stituted alkynes under thermal conditions (entries d−g).
Product 50e was confirmed by X-ray crystallographic analysis.
The most selective of this grouping was the ester alkyne 41
which provided 3.2:1 rr (49f:50f) as compared to computa-
incorporating a methyl moiety on the alkyne (e.g., LDA, THF;
MeI). Unfortunately, this transformation proved unreliable,
giving highly variable yields (0−65%). During this same period,
we were exploring the possibility of alternate pathways to access
this substitution pattern using the unconjugated aldehydes 31
and 32. These aldehydes are accessible via divergence of our
standard pathway for accessing aldehydes such as aldehyde
16.11b,25 Hydrolysis of the intermediate enamines 2926 and 30
provides a high-yielding route to aldehydes 31 and 32.
Treatment of these compounds with the Ohira−Bestmann
reagent27 33 generated the desired methylated alkynes 38 and
39 in good yields. This transformation likely proceeds via initial
formation of the unconjugated alkynes 34 and 35, which
undergo base-catalyzed isomerization first to allenes 36 and 37
and ultimately to aryl alkynes 38 and 39. This strategy should
provide a nice alternative to standard alkylations for accessing
methyl, aryl disubstituted alkynes.
In parallel to this experimental work, we computationally
explored the regioselectivities of the [3 + 2] dipolar
cycloaddition process between azides and substituted alkynes
as shown in Table 1. The computational predictions (column
5) were obtained from the relative energies of the 1,4- and 1,5-
addition transition states at the B3LYP/6-311++G(2df,p)//
B3LYP/6-31G(d) level of theory, as implemented in the
Gaussian 09 suite of programs. To reduce the computational
cost, benzyl groups were abbreviated to methyl.28 The
computed selectivities indicate that variations in R1 result in
negligible changes in selectivity; however, the regioselectivities
vary greatly with the R2 substituent. Select 1,3-dipolar
cycloaddition transition states with R1 = Cl are shown in
Figure 1 to illustrate the steric and electronic control present in
this system. In all cases, both the 1,4- and the 1,5-addition show
the azide attack to occur perpendicular to the o-chloro-o-
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Table 1. Computational Scope of 1,3-Dipolar Cycloadditions
a
entry
alkyne
R1
R2
computed ratio (47:48)
a
b
c
d
e
f
40a
40b
40c
39
H
H
3.9:1
1.5:1
3.4:1
1:1.5
1:1.6
2.5:1
1.9:1
9.5:1
11:1
Cl
Me
Me
Cl
Cl
Cl
H
H
H
Me
Me
38
41
CO2Me
C(OH)Ph2
Cl
g
h
i
42
22
25
Me
Cl
Cl
H
Cl
j
23
Cl
19:1
k
l
24
Br
12:1
43a
44a
45a
43b
44b
43c
44c
45c
NMe2
SiMe3
CN
>100:1
1:17
m
n
o
p
q
r
H
H
7.0:1
>100:1
5.3:1
>100:1
1:14
Me
Me
Cl
Cl
Cl
NMe2
CN
NMe2
SiMe3
CN
s
14:1
a
Relative energies of the 1,4- and 1,5-addition transition states at the B3LYP/6-311++G(2df,p)//B3LYP/6-31G(d) level of theory using Guassian
09.
tional predictions of 2.5:1 rr. Placement of an ester on the
alkyne has proven to be a highly reactive and regioselective
substrate 4111c in our previous Diels−Alder reactions to form
biaryl compounds. While this substrate 41 continued to prove
reactive, the regioselectivity in the transformation was modest
(3.2:1 rr, 92% overall yield). Interestingly, tertiary-alcohol-
containing alkyne 42, which had also proven highly selective in
Diels−Alder processes, gave no selectivity (1:1 rr) in a sluggish
reaction (45 h, 120 °C, 51% yield). We next turned to the
previously unknown halogenated, disubstituted alkynes (entries
h−k) derived from our o-nitrophenylalkyne core to provide
chemists with useful building blocks for rapid construction of
triazole templates. Computational analysis had indicated the
increased regioselectivity was likely with these compounds. We
were pleased to observe a noticeable increase in selectivity
(5.7:1 rr) at 67% yield with the first halogenated alkyne 22. The
required 48 h, 120 °C conditions for reaction completion likely
contributed to the reduced level of regioselectivity. Interest-
ingly, replacement of the o-chloro moiety for a methyl group
(entry i) provided similar regioselectivity. Use of our o-chloro-
o-nitrophenylalkynes 23 and 24 proved to be more activated
and nicely generated the cycloaddition product in high levels of
regioselectivity (9:1 ratio) and chemical yield (64−72%)
(entries j and k). On the basis of these results, it became
clear that halogenated alkynes are advantageous for accessing
high levels of regioselectivity in these systems.
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explored the scope of this transformation using a collection
of known azides (Table 3). Use of cinnamyl azide gave
comparable levels of regioselectivity for the chloroalkyne 23 but
reduced levels of regioselectivity with the bromoalkyne 24
(entries a−b). Aryl azides appeared to be problematic in the
reaction as reduced regioselectivity and chemical yields were
observed for both the bromo- and chloroalkynes. Finally, tert-
butyl azidoacetate generated the corresponding triazoles in high
regioselectivity, but in modest yield.
We also explored the Suzuki coupling capabilities of the
synthesized heterocycles (Scheme 5). We have previously
reported the utility of boroxines in cross-coupling protocols
using the Organ’s catalyst PEPPSI-IPr.11g,31 For the more
challenging ester containing substrate 49f, we found Buchwald’s
Ph2X-Phos ligand32 to be superior to PEPPSI-IPr. The
structure of 53 was confirmed by X-ray crystallographic
analysis. It should be noted that while we employed commercial
“phenylboronic acid” in this transformation, significant
amounts of the boroxine could be observed by NMR in the
unpurified reagent and no water was added to this trans-
formation, again indicating that the boroxine may be the viable
coupling component in the process. Further derivatization of
the heterocyclic scaffold was also possible. Nitro reduction
could be accomplished using Zn/HOAc to yield the lactam 54
in modest yield. We have previously observed the in situ
formation of the lactam moiety on related biaryl systems.11c
DIBAL-H reduction of the ester moiety could be accomplished
to provide the alcohol 55. Subsequent reduction of the nitro
moiety revealed the amino alcohol 56. Alternatively, the ester
could be saponified to reveal the carboxylic acid 57 in excellent
yield.
CONCLUSION
■
In summary, we have demonstrated the utility of substituted o-
nitrophenylalkynes in dipolar cycloadditions on a range of
substrates. The regioselectivity of the triazole dipolar cyclo-
additions was highly dependent on the nature of the
dipolarophile. Density functional theory investigations revealed
how various substitutions on the o-nitrophenylalkynes control
the regioselectivity through a combination of steric and
electronic effects. The synthesized scaffolds were converted
into a range of derivatives to demonstrate the utility of the
cycloaddition approach to densely functionalized heterocycles.
EXPERIMENTAL SECTION
■
Aldehyde 17. To a stirred solution of 27 (4.56 g, 4.00 mL, 30.17
mmol) in DMF (75 mL) was added N,N-dimethylformamide dimethyl
acetal (DMF·DMA) (10.8 g, 12.0 mL, 90.3 mmol). After being heated
at 140 °C for 72 h, the dark red solution was cooled to rt and added
quickly to a rapidly stirred solution of NaIO4 (21.04 g, 98.37 mmol) in
H2O (74 mL) and DMF (24 mL) at 0 °C. The reaction flask was
washed with DMF (5 mL) at 0 °C and added to NaIO4 mixture. The
reaction was stirred at 0 °C for 2 h before being warmed to rt. The
orange solution was filtered and rinsed with Et2O (200 mL). The
filtrate was then washed with H2O (3 × 25 mL) and satd aq NaCl (3 ×
25 mL). The dried (Na2SO4) extract was concentrated in vacuo to a
dark red oil and purified via flash chromatography over silica gel;
eluting with 10−30% Et2O/hexanes gave known aldehyde 1721 (4.390
g, 26.58 mmol, 89%) as an orange solid: 1H NMR (300 MHz, CDCl3)
δ 10.32 (s, 1H), 7.99 (dd, J = 1.5, 7.5 Hz, 1H), 7.65−7.50 (m, 2H),
2.45 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 190.4, 148.7, 139.2,
137.0, 131.9, 131.3, 121.9, 19.4 ppm.
Figure 1. Computed transition states for 1,3-dipolar cycloadditions
between various o-chloronitrophenylalkynes and methyl azide are
shown. The B3LYP/6-311++G(2df,p)//B3LYP/6-31G(d) level of
theory was used, and the computational predictions of regioselectivity
are in good agreement with experiments (Table 2). Distances are in
angstroms; relative free energies are in kcal/mol. Computationally
predicted regiomeric ratios are in parentheses.
The halogenated alkynes proved to be our most
regioselective while still experimentally accessible substrates
for the dipolar cycloadditions. Consequently, we briefly
Chloroacetylene 23. To a stirred solution of 16 (3.118 g, 16.80
mmol) and CH2Cl2 (170 mL) were added CCl4 (3.98 g, 2.50 mL, 25.9
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Table 2. Scope of Azide Dipolar Addition with o-Nitrophenyl Acetylenes
entry
alkyne
R1
R2
time (h)
temp (°C)
overall yield (%)
experimental ratio (49:50)
computed ratio (47:48)
a
a
a
b
c
d
e
f
40a
40b
40c
39
H
H
48
26
96
72
24
24
45
24
24
70
72
80
80
84 (79)
3.4:1 (1:0)
3.9:1
1.5:1
3.4:1
1:1.5
1:1.6
2.5:1
1.9:1
9.5:1
11:1
19:1
12:1
Cl
Me
Me
Cl
Cl
Cl
H
H
59
2:1
a
a
H
80
79 (98)
2.3:1 (1:0)
Me
Me
120
120
80
43
65
92
51
66
68
72
64
1:1
2:1
38
41
CO2Me
3.2:1
1:1
g
h
i
42
C(OH)Ph2
120
120
120
80
22
Cl
Cl
Cl
Br
5.7:1
7:1
25
Me
Cl
Cl
j
23
9:1
k
24
80
9:1
a
reaction conditions: CuSO4, ascorbic acid, t-BuOH:H2O (1:1), rt.
Table 3. Brief Exploration of Azide Scope in Cycloaddition
entry
alkyne
R
X
time (h)
temp (°C)
overall yield (%)
ratio (51:52)
a
b
c
d
e
f
23
24
23
24
23
24
(E)-PhCHCHCH2-
(E)-PhCHCHCH2-
Ph
Cl
Br
Cl
Br
Cl
Br
48
29
72
53
48
48
80
80
49
69
36
24
37
58
11:1
4:1
2:1
1:1
9:1
9:1
80
Ph
120
80
t-BuO2CCH2-
t-BuO2CCH2-
80
mmol) and PPh3 (13.36 g, 50.93 mmol) at rt. After 30 h, the black
solution was concentrated in vacuo until ca. 50 mL of mixture
remained. The residue was then purified via flash chromatography over
silica gel, eluting with 10−30% EtOAc/hexanes to give 19 (3.567 g) as
an impure yellow oil.
To a stirred solution of impure 20 (3.051 g, 8.937 mmol) and THF
(22 mL) was added NaHMDS (9.00 mL, 9.00 mmol, 1 M in THF) at
−78 °C via syringe over 5 min and allowed to slowly warm to 0 °C.
After 2 h, the dark brown mixture was quenched with satd aq NH4Cl
(20 mL) and extracted with EtOAc (3 × 20 mL). The combined
organic parts were washed with H2O (2 × 10 mL) and satd aq NaCl
(2 × 10 mL). The dried (MgSO4) extract was concentrated in vacuo
to a brown solid and purified via flash chromatography over silica gel,
eluting with PhMe to give 24 (1.971 g, 7.567 mmol, 85%) as a yellow
solid: mp 86−88 °C; IR (thin film) 2220, 1527, 1340, cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.85 (dd, J = 8.1, 1.2 Hz, 1H), 7.51 (dd, J = 8.1,
1.2, 1H), 7.37 (t, J = 8.2 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ
151.7, 139.6, 133.7, 128.9, 122.8, 117.7, 72.2, 65.3 ppm; HRMS (EI+)
calcd for C8H3NO2ClBr 258.9036, found 258.9035.
To a stirred solution of impure 19 (3.567 g, 14.12 mmol) and THF
(35.0 mL) was added NaHMDS (14.30 mL, 14.30 mmol, 1 M in
THF) at −78 °C. After 1 h, the dark brown solution was quenched
with satd aq NH4Cl (20 mL), extracted with EtOAc (3 × 50 mL), and
washed with satd aq NaCl (2 × 10 mL). The dried (MgSO4) extract
was concentrated in vacuo and purified by flash chromatography over
silica gel, eluting with 20−50% EtOAc/hexanes to give 23 (2.954 g,
13.67 mmol, 97%) as a bright yellow crystalline solid: mp 93−94 °C;
1
IR (thin film) 2217, 1526, 1338, 1118, 797, 750, 737 cm−1; H NMR
(300 MHz, CDCl3) δ 7.96 (dd, J = 8.1, 1.2 Hz, 1H), 7.72 (dd, J = 8.1,
1.2 Hz, 1H), 7.43 (t, J = 8.2 Hz, 1H) ppm; 13C NMR (75 MHz,
CDCl3) δ 151.7, 139.5, 13.7, 128.9, 122.7, 117.3, 82.3, 61.8 ppm;
HRMS (EI+) calcd for C8H3NO2Cl2 214.9541, found 214.9539.
Bromoacetylene 24. To a stirred solution of 16 (2.628 g, 14.16
mmol), CH2Cl2 (94 mL), and CBr4 (7.104 g, 21.42 mmol) at 0 °C,
was added PPh3 (11.23 g, 42.81 mmol, 0.4 M in CH2Cl2) via cannula
over 5 min. After 15 h, the black solution was concentrated to ca. 60
mL and transferred to a flash column. Purification of the residue via
flash chromatography over silica gel, eluting with 0−20% EtOAc/
hexanes gave known 2023 (4.117 g) as a crude orange solid.
Chloroacetylene 22. To a stirred solution of 15 (4.584 g, 30.33
mmol) and CH2Cl2 (500 mL), was added CCl4 (8.61 g, 5.40 mL, 56.0
mmol), and PPh3 (23.94 g, 91.27 mmol) at rt. After 6 h, the black
solution was concentrated in vacuo until ca. 100 mL of mixture
remained. The residue was then purified via flash chromatography over
silica gel, eluting with 10−30% EtOAc/hexanes to give known 1822
(4.567 g, 20.95 mmol, 69%) as a crude yellow solid.
To a stirred solution of impure 18 (4.567 g, 20.95 mmol) and THF
(50 mL) was added NaHMDS (21.0 mL, 21.0 mmol, 1 M in THF) at
−78 °C over 10 min. After 1 h, the reaction was warmed to 0 °C and
quenched with satd aq NH4Cl (50 mL). The solution was diluted with
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red oil: IR (thin film) 3081, 2847, 2808, 1634, 1585, 1524, 1378, 1101,
Scheme 5. Derivativization of Triazoles
1
952, 866, 835, 774, 752, 723 cm−1; H NMR (300 MHz, CDCl3) δ
7.49 - 7.32 (m, 2H), 6.97 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 13.8 Hz,
1H), 5.10 (d, J = 13.8 Hz, 1H), 2.86 (s, 6H) ppm; 13C NMR (75
MHz, CDCl3) δ 150.0, 145.5, 133.0, 132.1, 131.9, 123.1, 122.1, 86.9,
39.3 ppm; HRMS (EI+) calcd for C10H11N2O2Cl 226.0509, found
226.0508.
2-(2′-Chloro-6′-nitrophenyl)acetaldehyde (31). A 2-L, single-
necked, round-bottomed flask, equipped with a powder funnel and
magnetic stirring bar, was charged with DMF (1 L) and 2-chloro-6-
nitrotoluene 26 (69.74 g, 406.5 mmol, 1 equiv). N,N-Dimethylforma-
mide dimethyl acetal (162 mL, 1.22 mol, 3 equiv) was added via
syringe to the yellow solution. The powder funnel was replaced by a
Fredrichs condenser, and the mixture was brought to 135 °C in a
silicon oil bath over 2 h. The reaction was covered with aluminum foil
to aid heating. After 18 h, the reaction evolved to a brick red solution
and showed complete conversion via TLC. The mixture was cooled to
room temperature over 2 h and then carefully poured over 2 min into
a rapidly, mechanically stirred, ice-cooled solution of satd aq NaHCO3
(500 mL) and Et2O (500 mL) in a 2-L Erlenmeyer flask. After 15 min,
the solution was transferred to a separatory funnel and allowed to
settle for 15 min. A 1-L portion of the mixture was collected in an
Erlenmeyer flask, and the remaining solution in the separatory funnel
was washed with 5% aq NaHCO3 (4 × 300 mL). The ethereal
partition was collected and set aside. The previously collected 1-L
portion was transferred to a separatory funnel and extracted with ether
(3 × 400 mL) via separatory funnel. The ethereal partitions were
combined and concentrated via rotary evaporation (38 °C, 28 mmHg)
to give enamine 2926 as a dark red liquid.33
A 2-L, three-necked, round-bottomed flask, equipped with a
mechanical stirrer, yellow poly cap, and powder funnel, was immersed
in an ice-cold water bath, charged with the red enamine 29 oil, and
diluted with Et2O (300 mL). To the solution was added 1 M HCl
(300 mL), and the powder funnel was replaced by a 90° gas inlet
adapter open to the air. The mixture was allowed to warm to rt over
2.5 h with vigorous stirring. The biphasic solution was transferred to a
2-L separatory funnel, and the ethereal partition was collected. The
aqueous partition was acidified to pH = 1 with 3 M HCl and was
extracted with MTBE (2 × 200 mL). The ethereal partitions were
combined and washed with 10% aq NaHCO3 (2 × 50 mL), H2O (100
mL), and brine (2 × 50 mL), dried over Na2SO4, filtered, and
concentrated via rotary evaporation (38 °C, 28 mmHg) and then
under high vacuum (50 °C, 0.50 mmHg) to provide aldehyde 31 as a
red oil (69.34 g 347.4 mmol, 85%): IR (thin film) 3432, 2844, 2733,
1731, 158, 1351, 1109, 1019, 876, 802, 730, 667 cm−1; 1H NMR (300
MHz, CDCl3) δ 9.74 (s, 1H), 7.97 (dd, J = 8.4, 1.2 Hz, 1H), 7.74 (dd,
J = 8.4, 1.2 Hz, 1H), 7.46 (t, J = 8.4, 1H), 4.31 (s, 2H) ppm; 13C NMR
(75 MHz, CDCl3) δ 195.5, 150.8, 137.1, 134.3, 129.0, 126.8, 123.5,
44.5 ppm; HRMS (EI+) calcd for C8H7NO3Cl (M+) 200.0114, found
200.0117.
H2O, extracted with Et2O (3 × 50 mL), and washed with satd aq NaCl
(1 × 100 mL) and brine (2 × 50 mL). The dried (MgSO4) extract was
concentrated in vacuo to give known 2224 (3.218 g, 17.82 mmol, 85%)
as a beige solid: mp 79−81 °C; IR (neat) 3103, 2845, 2220, 1569,
1519, 1341, 786, 742 cm−1; 1H NMR (700 MHz, CDCl3) δ 8.08 (dd, J
= 1.0, 8.3 Hz, 1H), 7.68 (dd, J = 1.2, 7.8 Hz, 1H), 7.61 (td, J = 1.3, 7.6
Hz, 1H), 7.51 (td, J = 1.5, 7.4 Hz, 1H) ppm; 13C NMR (125 MHz,
CDCl3) δ 150.2, 135.3, 132.9, 129.0, 124.8, 117.7, 76.3, 64.8 ppm;
HRMS (CI+) calcd for C8H5ClNO2 (M + H) 182.0009, found
182.0005.
Chloroacetylene 25. To a stirred solution of 17 (5.828 g, 33.29
mmol) and CH2Cl2 (350 mL) were added CCl4 (8.29 g, 5.20 mL,
52.93 mmol) and PPh3 (27.77 g, 105.9 mmol) at rt. After 30 h, the
black solution was concentrated in vacuo until ca. 100 mL of mixture
remained. The residue was then purified via flash chromatography over
silica gel, eluting with 0−10% EtOAc/hexanes to give impure 21
(6.038 g) as a yellow oil.
To a stirred solution of impure 21 (3.316 g, 14.29 mmol) and THF
(36.0 mL) was added NaHMDS (15.0 mL, 15.0 mmol, 1 M in THF)
at −78 °C over 10 min turning from an orange to darks brown
solution. After 1 h, the reaction was warmed to 0 °C and quenched
with satd aq NH4Cl (50 mL). After 5 min, the orange-brown solution
was extracted with Et2O (3 × 50 mL) and washed with satd aq NaCl
(2 × 20 mL). The dried (MgSO4) extract was concentrated in vacuo
and purified via flash chromatography over silica, eluting with 35%
hexanes/PhMe to give 25 (2.372 g, 12.13 mmol, 85%) as a yellow
solid: mp 93−94 °C; IR (thin film) 2213, 1526, 1456, 1381, 802, 740,
Aldehyde 32. To a stirred solution containing 27 (5.26 g, 6.00 mL,
34.8 mmol) and DMF (80 mL) was added N,N-dimethylformamide
dimethyl acetal (14.0 mL, 12.6 g, 105.7 mmol) was added via syringe
to the yellow solution and heated to 140 °C. After 24 h, the reaction
evolved to a brick red solution, cooled to room temperature, quenched
with aq NaHCO3 (200 mL, 5% w/v), and extracted with Et2O (3 ×
150 mL). The ethereal partition were combined and concentrated in
vacuo to give enamine 30 as a dark red liquid (ca. 200 mL).
To a mechanically stirred solution of the dark red enamine 30 and
Et2O (250 mL), was added aq HCl (250 mL, 10% v/v). After 2.5 h of
vigorous stirring, the biphasic solution was extracted with Et2O (3 ×
100 mL). The ethereal partitions were combined and washed with aq
NaHCO3 (2 × 100 mL, 10% w/v) and sat aq NaCl (2 × 100 mL).
The dried (Na2SO4) extract was concentrated in vacuo to provide
crude 32 as a red oil. Purification via flash chromatography over silica
gel, eluting with PhMe, gave known 3234 (5.121 g, 28.58 mmol, 82%)
as a dark orange oil: IR (thin film) 3430, 2842, 2732, 1724, 1610,
1
693 cm−1; H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.2, 1H), 7.51
(d, J = 7.6 Hz, 1H), 7.37 (t, J = 8.0, 1H), 2.55 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 151.2, 144.2, 133.9, 128.2, 122.0, 116.9, 80.3,
63.4, 21.2 ppm; HRMS (CI+) calcd for C9H7NO2Cl (M + H)
196.0165, found 196.0154.
Enamine 29. To a stirred solution of 26 (3.855 g, 22.46 mmol) in
DMF (50 mL) was added N,N-dimethylformamide dimethyl acetal
(DMF·DMA) (8.07 g, 9.00 mL, 67.75 mmol). After heating at 140 °C
for 16 h, the dark red solution was cooled to rt, diluted with Et2O (200
mL), and washed with HCl (2 × 50 mL, 10% v/v), sat aq NaHCO3 (2
× 50 mL), and sat aq NaCl (2 × 5 mL). The dried (Na2SO4) extract
was concentrated in vacuo to give 29 (4.940 g, 111.0 mmol, 97%) as a
1
1524, 1348, 935, 803, 731, 672 cm−1; H NMR (300 MHz, CDCl3) δ
9.86 (t, J = 0.9 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 7.4 Hz,
1H), 7.37 (t, J = 7.9 Hz, 1H), 4.02 (s, 2H), 2.38 (s, 3H) ppm; 13C
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NMR (75 MHz, CDCl3) δ 196.8, 150.5, 140.3, 135.1, 128.0, 126.5,
122.7, 43.9, 20.4 ppm; HRMS (CI+) calcd for C9H10NO3 (M+)
180.0661, found 180.0666.
1H), 6.94 (d, J = 6.8 Hz, 2H), 5.43 (s, 2H) ppm; 13C NMR (100
MHz, CDCl3) δ 148.5, 134.4, 133.9, 133.2, 133.10, 133.08, 131.0,
128.7, 128.4, 127.8, 124.9, 122.2, 52.8 ppm; HRMS (ES+) calcd for
C15H13N4O2 (M + H) 281.1039, found 281.1029.
Triazole 49a. To a stirred solution of 40a (73.5 mg, 500 μmol)
and H2O/t-BuOH (3.00 mL, 1:1) was added ascorbic acid (14.5 mg,
82.5 μmol), Cu2SO4·5H2O (6.5 mg, 26 μmol) and azide 48 (199.5 mg,
1.5 mmol) sequentially at rt. After 19 h, the mixture was filtered and
washed with hexanes to give the sole regioisomer 49a14 (110.1 mg,
393 μmol, 79%) as a beige solid.
Propyne 38. To a stirred solution of 31 (5.412 g, 27.11 mmol) and
MeOH (385 mL) were added K2CO3 (7.635 g, 55.24 mmol) and 3327
(6.253 g, 32.55) dropwise via syringe at rt. After 4 h, the dark red
mixture was quenched with pH 7 buffer (350 mL), concentrated in
vacuo, and filtered. The orange solid was washed with H2O (20 mL),
dissolved in EtOAc (100 mL), and washed with satd aq NaCl (2 × 15
mL). The dried (MgSO4) extract was concentrated in vacuo to give 38
(4.467 g, 22.84 mmol, 84%) as an orange solid: mp 100−102 °C; IR
Triazoles 49b and 50b. To a pressure vessel containing 40b11a,b
(45.6 mg, 0.251 mmol) were added PhMe (500 μL) and azide 48 (100
mg, 750 μmol) at rt. The reaction mixture was sealed under Ar and
heated to 80 °C. After 26 h, the crude mixture was cooled to rt, filtered
through Celite eluting with 100% EtOAc and concentrated in vacuo to
give an inseparable mixture of regioisomers (46.6 mg, 0.148 mmol,
59%, 2:1 rr (49b:50b)): mp 174−175 °C; IR (thin film) 3077, 2879,
1527, 1362, 1229, 1089, 760, 729 cm−1; 1H NMR (700 MHz, CDCl3)
δ 7.95 (d, J = 8.2 Hz, 1H of minor), 7.80 (dd, J = 8.1, 1.2 Hz, 1H of
major), 7.75 (s, 1H of major), 7.72 (dd, J = 8.1, 1.2 Hz, 1H of major),
7.71 (d, J = 8.2 Hz, 1H of minor), 7.69 (s, 1H of minor), 7.61 (t, J =
8.2 Hz, 1H of minor), 7.49 (t, J = 8.1 Hz, 1H of major), 7.45−7.35 (m,
3H of major), 7.35−7.25 (m, 2H of major), 7.25 (t, J = 7.3 Hz, 1H of
minor), 7.20 (t, J = 7.5 Hz, 2H of minor), 7.03 (d, J = 7.5 Hz, 2H of
minor), 5.67 (s, 2H of major), 5.45 (dd, J = 15.0 Hz, 2H of minor)
ppm; 13C NMR (175 MHz, CDCl3) δ 151.4, 139.6, 135.9, 134.4,
134.1, 133.4, 131.6, 129.9, 129.2, 128.8, 128.7, 128.6, 128.3, 127.8,
124.5, 124.2, 123.1, 122.6, 54.3, 53.4; HRMS (EI+) calcd for
C15H11N4O2Cl (M + H) 314.0570, found 314.0581.
1
(thin film) 3086, 2249, 2208, 1519, 1346, 881, 809, 742 cm−1; H
NMR (300 MHz, CDCl3) δ 7.80 (dd, J = 8.1, 1.0 Hz, 1H), 7.64 (dd, J
= 8.1, 1.0 Hz, 1H), 7.32 (t, J = 8.2 Hz, 1H), 2.20 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 151.8, 138.6, 133.2, 127.7, 122.4, 118.8, 101.5,
71.8, 5.0; HRMS (EI+) calcd for C9H6NO2Cl (M+) 195.0087, found
195.0088.
Propyne 39. To a stirred solution of 32 (4.786 g, 26.71 mmol) and
MeOH (480 mL) were added K2CO3 (7.322 g, 52.98 mmol) and 3327
(6.208 g, 32.31 mmol) dropwise via syringe at rt. After 15 h, the dark
red mixture was quenched with pH 7 buffer (480 mL), concentrated in
vacuo, and filtered. The orange solid was washed with H2O (20 mL),
dissolved in EtOAc (100 mL), and washed with satd aq NaCl (2 × 25
mL). The dried (MgSO4) extract was concentrated in vacuo and
purified via flash chromatography over silica gel, eluting with 0−15%
EtOAc/hexanes to give 39 (2.845 g, 16.34 mmol, 61%) as an orange
solid: mp 42−44 °C; IR (thin film) 2251, 2208, 1607, 1528, 804, 743,
1
710 cm−1; H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 1H),
7.27 (d, J = 7.5 Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H), 2.48 (s, 3H), 2.16 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 150.8, 143.2, 133.3, 127.0, 121.3,
118.1, 99.12, 73.3, 20.9, 4.5; HRMS (EI+) calcd for C10H9NO2 (M+)
175.0633, found 175.0633.
Triazoles 49c and 50c. To a pressure vessel containing 40c (39.9
mg, 0.248 mmol) were added PhMe (500 μL) and azide 48 (133 mg,
1 mmol) at rt. The reaction mixture was sealed under Ar and heated to
80 °C. After 96 h, the crude mixture was cooled to rt and concentrated
in vacuo to give an inseparable mixture of regioisomers (70.2 mg,
0.197 mmol, 79%, 2.3:1 rr (49c:50c)). Regioisomer mixture: mp 152−
Acetylene 40c. To a stirred solution of 17 (1.655 g, 10.00 mmol),
K2CO3 (3.620 g, 26.20 mmol), and MeOH (140 mL) was added
diazophosphonate 3327 (2.350 g, 12.23 mmol) slowly, at rt, in ca. 0.2
mL portions over 1 h. After 3 h, the solution was quenched with pH 7
buffer (200 mL) and concentrated in vacuo to remove the MeOH and
give crude 40c as an orange solid (1.387 g). The solid was filtered, and
the mother liquor was diluted with EtOAc (150 mL) and washed with
satd aq NaCl (2 × 50 mL). The dried (MgSO4) extract was
concentrated in vacuo and purified by flash chromatography over silica
gel, eluting with 1% EtOAc/hexanes, to give crude 40c (138.5 mg).
The crude material isolated from recrystallization and column
chromatography were combined and recrystallized with hexane to
give 40c as a pale yellow solid (1.422 g, 8.823 mmol, 88%): mp 58−59
°C; IR (thin film) 3284, 2108, 1529, 1349, 797, 778, 736, 645 cm−1;
1H NMR (300 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 1H), 7.51 (d, J =
7.6 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 3.75 (s, 1H), 2.56 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 151.4, 144.2, 133.8, 128.5, 121.8, 116.7,
89.7, 76.7, 21.2; HRMS (EI+) calcd for C9H7NO2 (M+) 161.0477,
found 161.0467.
1
153 °C; IR (neat) 3077, 1529, 1362, 807 cm−1; H NMR (700 MHz,
CDCl3) δ 7.94 (d, J = Hz, 1H of minor), 7.70 (d, J = 7.8 Hz, 1H of
major), 7.60 (s, 1H of minor), 5.64 (s, 2H of major), 7.56 (t, J = 7.9
Hz, 1H of minor), 7.52 (d, J = 7.5 Hz, 1H of minor), 7.59−7.18 (m,
8H of major), 7.21 (t, J = 7.5 Hz, 2H of minor), 7.00 (d, J = 7.4 Hz,
2H of minor), 5.65 (d, 1H of minor), 5.13 (d, J = 15.0 Hz, 1H of
minor), 2.26 (s, 3H of major); 13C NMR (175 MHz, CDCl3) δ 150.8,
149.7, 142.1, 141.5, 140.7, 134.8, 134.6, 134.1, 133.8, 133.7, 131.4,
130.7, 129.2, 129.1, 128.8, 128.7, 128.6, 128.5, 127.8, 124.4, 123.2,
122.3, 121.4, 121.1, 54.2, 53.0, 20.7, 19.6 ppm; HRMS (ES+) calcd for
C16H15N4O2 (M + H) 295.1195, found 295.1208.
Triazole 49c. To a stirred solution of 40c (111.6 mg, 692.3 μmol)
and H2O/t-BuOH (3.00 mL, 1:1) were added ascorbic acid (20.1 mg,
114 μmol), Cu2SO4·5H2O (9.0 mg, 36 μmol), and azide 48 (293.4 mg,
2.196 mmol) sequentially at rt. Upon addition of azide 48 a white ppt
formed. After 12 h, the mixture was filtered and washed with hexanes
to give the sole regioisomer 49c (199.6 mg, 678.3 μmol, 98%) as a
pure white solid.
Triazole 49a and 50a. To a pressure vessel containing 40a (73.5
mg, 0.500 mmol) were added PhMe (1 mL) and azide 48 (199.5 mg,
1.5 mmol) sequentially at rt. The reaction mixture was sealed under Ar
and heated to 80 °C. After 48 h, the crude mixture was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 20−40% EtOAc/hexanes to give sequentially
49a (91.5 mg, 327 μmol, 65%) as a white solid followed by 50a (26.1
mg, 93.2 μmol, 19%) as a pale yellow solid. NMR analysis of the crude
mixture indicated the ratio to be 2.7:1 rr (49a:50a). Major regioisomer
Triazole 49d and Triazole 50d. To a pressure vessel containing
37 (69.2 mg, 390.5 μmol) were added PhMe (800 μL) and azide 48
(174.3 mg, 1.309 mmol) at rt. The reaction mixture was sealed under
Ar and heated to 120 °C. After 72 h, the reaction was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 20−40% EtOAc/Hexanes to give an inseparable
mixture of regioisomers (50.3 mg, 168 μmol, 43%, 1:1 rr (49d:50d))
as a yellow oil. Regioisomer mixture: IR (neat) 1529, 1496, 1455,
49a:14 mp 103−105 °C; IR (neat) 1528, 1359 cm−1; H NMR (400
1
MHz, CDCl3) δ 8.05 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H),
7.74 (s, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.38−
7.41 (m, 3H), 7.33 (d, J = 6.5 Hz, 2H), 5.61 (s, 2H) ppm; 13C NMR
(100 MHz, CDCl3) δ 148.2, 142.4 134.3, 132.5, 131.1, 129.2, 128.94,
128.89, 128.0, 124.7, 124.0, 122.9, 54.3 ppm; HRMS (ES+) calcd for
C15H13N4O2 (M + H) 281.1039, found 281.1029. Minor regioisomer
50a: mp 73−75 °C; IR (neat) 1528, 1350 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.13 (d, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.62 (t, J = 7.6 Hz,
1H), 7.55 (t, J = 7.3 Hz, 1H), 7.18−7.24 (m, 3H), 7.01 (d, J = 7.7 Hz,
1
1353, 1016, 914, 804, 754, 731 cm−1; H NMR (400 MHz, CDCl3) δ
7.88 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.58−7.47 (m, 2H),
7.46−7.39 (m, 2H), 7.38−7.27 (m, 3H), 7.26−7.09 (m, 5H), 6.92 (d, J
= 7.3 Hz, 2H), 5.56 (s, 2H), 5.49 (d, J = 14.9 Hz, 1H), 5.05 (d, J =
14.9 Hz, 1H), 2.15 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.50 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 150.9, 149.8, 142.5, 142.1,
141.5, 140.2, 134.8, 134.7, 134.3, 134.0, 132.0, 130.7, 129.4, 129.1,
128.6, 128.6, 128.5, 128.3, 128.3, 126.7, 124.9, 122.2, 121.7, 121.0,
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53.2, 52.0, 20.2, 19.1, 10.2, 8.2 ppm; HRMS (EI+) calcd for
C17H16N4O2 (M+) 308.1273, found 308.1288.
127.7, 127.5, 127.4, 127.2, 123.3, 123.2, 53.5 ppm; HRMS (ES+) calcd
for C27H19ClN4NaO3 (M + Na) 505.1043, found 505.1047.
Triazole 49e and Triazole 50e. To a pressure vessel containing
36 (316.2 mg, 1.909 mmol) were added PhMe (2.00 mL) and azide 48
(1.066 mg, 8.006 mmol) at rt. The reaction mixture was sealed under
Ar and heated to 120 °C. After 24 h, the reaction was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 20−40% EtOAc/hexanes to give an inseparable
mixture of regioisomers (405.4 mg, 1.233 mmol, 65%, 2:1 rr
(49e:50e)) as a yellow oil. Regioisomer mixture: IR (neat) 1733,
Triazole 49h and 50h. To a pressure vessel containing 22 (90.5
mg, 0.500 mmol) were added PhMe (1 mL) and azide 48 (199.5 mg,
1.5 mmol) sequentially at rt. The reaction mixture was sealed under Ar
and heated to 120 °C. After 24 h, the crude mixture was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 10−30% EtOAc/hexanes to give sequentially
49h (87.9 mg, 280 μmol, 56%) as an orange oil followed by 50h (16
mg, 50.9 μmol, 10%) as a pale yellow solid. NMR analysis of the crude
mixture indicated the ratio to be 5.7:1 rr (49h:50h). Major
1
1533, 1455, 1437, 1359, 1122, 883, 806, 728 cm−1; H NMR (300
1
regioisomer 49h: IR (neat) 1533, 1352 cm−1; H NMR (400 MHz,
MHz, CDCl3) δ 7.95 (dd, J = 8.1, 1.3 Hz, 1H of minor), 7.90 (dd, J =
8.1, 1.2 Hz, 1H of major), 7.76 (dd, J = 8.1, 1.2 Hz, 1H of major), 7.69
(dd, J = 8.1, 1.3 Hz, 1H of minor), 7.59 (t, J = 8.1 Hz, 1H of minor),
7.55 (t, J = 8.1 Hz, 1H of major), 7.48−7.34 (m, 3H of major/minor),
7.24−7.14 (m, 2H of major/minor), 6.99−6.94 (m, 1H of minor),
5.40 (d, J = 12.7 Hz, 1H of minor), 5.62 (s, 2H of major), 5.32 (d, J =
12.7 Hz, 1H of minor), 2.16 (s, 3H of minor), 2.12 (s, 3H of major)
ppm; 13C NMR (75 MHz, CDCl3) δ 151.7, 138.7, 137.9, 134.6, 134.2,
133.6, 132.8, 132.6, 131.5, 130.4, 129.1, 128.6, 128.4, 128.34, 128.31,
128.1, 126.7, 125.2, 123.1, 122.7, 52.1, 53.5, 10.3, 8.5 ppm; HRMS (EI
+) calcd for C16H13N4O2Cl (M+) 328.0727, found 328.0723.
CDCl3) δ 8.05 (d, J = 8.1 Hz, 1H), 7.70−7.72 (m, 2H), 7.61 (t, J = 7.3
Hz, 1H), 7.35 (m, 5H), 5.61 (s, 2H) ppm; 13C NMR (100 MHz,
CDCl3) δ 148.5, 139.9, 133.6, 133.0, 132.2, 130.0, 129.1, 128.8, 128.7,
127.7, 124.9, 124.1, 123.7, 52.4 ppm; HRMS (ES+) calcd for
C15H12N4O2Cl (M + H) 315.0649, found 315.0649. Minor
regioisomer 50h: mp 100−102 °C; IR (neat) 1528, 1346, 1284
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.1 Hz, 1H), 7.70 (t,
J = 7.8 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.20−7.25 (m, 3H), 7.02 (d,
J = 7.5 Hz, 1H), 6.96 (d, J = 7.2, 2H), 5.60 (d, J = 15.1 Hz, 1H), 5.23
(d, J = 15.1 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 148.1,
134.8, 133.6, 133.5, 133.1, 131.6, 130.0, 128.8, 128.7, 127.9, 125.4,
120.4, 54.2 ppm; HRMS (EI+) calcd for C15H11N4O2Cl (M+)
314.0571, found 314.0567.
Triazole 49f and 50f. To a pressure vessel containing 41 (220 mg,
917 μmol) were added PhMe (2 mL) and azide 48 (366 mg, 2.75
mmol) sequentially at rt. The reaction mixture was sealed under Ar
and heated to 80 °C. After 24 h, the crude mixture was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 30−40% EtOAc/hexanes to give sequentially 49f
(240.9 mg, 646 μmol, 70% yield) as an orange oil followed by 50f
(74.4 mg, 199 μmol, 22%) as a white solid. NMR analysis of the crude
mixture indicated the ratio to be 3.2:1 rr (49f:50f). Major regioisomer
49f: IR (neat) 1731, 1536, 1479, 1347, 1260, 1212, 1158, 1101 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 0.6, 8.3 Hz, 1H), 7.79
(dd, J = 0.6, 8.1 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.33−7.38 (m, 3H),
7.29 (d, J = 6.4 Hz, 2H), 6.02 (s, 2H), 3.66 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 158.0, 150.2, 144.4, 137.0, 135.0, 134.2, 130.6,
128.9, 128.4, 127.3, 125.9, 125.6, 123.0, 54.3, 52.6 ppm; HRMS (EI+)
calcd for C17H13N4O4Cl (M+) 372.0625, found 372.0637. Minor
regioisomer 50f: mp 125−129 °C; IR (neat) 1733, 1536, 1474, 1355,
1209, 1063 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 1.0, 8.2
Hz, 1H), 7.76 (dd, J = 1.0, 8.0 Hz, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.24−
7.27 (m, 1H), 7.20 (t, J = 7.3 Hz, 2H), 7.02 (d, J = 7.4 Hz, 2H), 5.52
(d, J = 15.0 Hz, 1H), 5.39 (d, J = 14.9 Hz, 1H), 3.82 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 160.8, 149.0, 137.6, 136.8, 135.1, 134.7,
132.4, 131.9, 128.9, 128.7, 128.5, 123.6, 121.7, 53.9, 52.2 ppm; HRMS
(EI+) calcd for C17H13N4O4Cl (M+) 372.0625, found 372.0621.
Triazole 49g and 50g. To a pressure vessel containing 42 (10 mg,
27.5 μmol) were added PhMe (60 μL) and azide 48 (11 mg, 82.5
μmol) sequentially at rt. The reaction mixture was sealed under Ar and
heated to 120 °C. After 45 h, the crude mixture was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 0−40% EtOAc/hexanes to give a mixture of
regioisomers (7.0 mg, 2.00 μmol, 51%, 1:1 rr (49g:50g)). Analytical
samples of the individual isomers could be obtained by preparative
thin-layer chromatography over silica gel, eluting with 30% EtOAc/
hexanes to give sequentially 50g then 49g. Regioisomer 49g: IR (neat)
Triazole 49i and Triazole 50i. To a pressure vessel containing 25
(639.2 mg, 3.268 mmol) were added PhMe (6.00 mL) and azide 48
(1.531 mg, 11.50 mmol) at rt. The reaction mixture was heated to 120
°C. After 24 h, the reaction was cooled to rt, concentrated in vacuo,
and purified via flash chromatography over silica gel, eluting with 20−
40% EtOAc/Hexanes to give an inseparable mixture of regioisomers
(733.6 mg, 2.23 mmol, 68%, 7:1 rr (49i:50i)) as a yellow oil.
1
Regioisomer mixture: IR (neat) 1534, 1459, 1369 cm−1; H NMR
(400 MHz, CDCl3) δ 8.03 (d, J = 8.1 Hz, 1H for minor), 7.90 (d, J =
8.0 Hz, 1H for major), 7.61−7.59 (m, 1H for minor), 7.58 (d, J = 8.0
Hz, 1H for major), 7.51 (t, J = 8.0 Hz, 1H for major), 7.48 (d, J = 8.1
Hz, 1H for minor), 7.44−7.32 (m, 3H for major/minor), 7.31−7.25
(m, 2H for major), 7.19 (t, J = 7.2 Hz, 2H for minor), 6.96 (d, J = 7.4
Hz, 2H for minor), 5.89 (d, J = 14.8 Hz, 1H for minor), 5.65 (s, 2H
for major), 5.09 (d, J = 14.8 Hz, 1H for minor), 2.24 (s, 3H for major),
1.59 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 150.2, 149.1, 142.4,
141.5, 139.1, 135.4, 134.8, 133.8, 133.0, 131.4, 130.0, 129.1, 128.9,
128.8, 128.6, 128.5, 127.3, 124.6, 122.8, 122.8, 122.3, 119.0, 54.4, 52.3,
20.1, 19.1 ppm; HRMS (CI+) calcd for C16H14N4O2Cl (M+)
329.0805, found 329.0791.
Triazole 49j and Triazole 50j. To a pressure vessel containing 23
(54.2 mg, 253 μmol) were added PhMe (500 μL) and azide 48 (100
mg, 750 μmol) at rt. The reaction mixture was sealed under Ar and
heated to 80 °C. After 70 h, the reaction was cooled to rt, concentrated
in vacuo, and purified via flash chromatography over silica gel, eluting
with 0−30% EtOAc/hexanes to give a mixture of regioisomers (63.3
mg, 181 μmol, 72%, 9:1 (49j:50j)) as a yellow solid. Analytical
samples of the individual isomers could be obtained by preparative
thin layer chromatography over silica gel, eluting with 30% EtOAc/
Hexanes to give sequentially 49j then 50j. Major regioisomer 49j: IR
(neat) 1608, 1533, 1355, 1226, 991, 883, 808, 759, 727, 704 cm−1; 1H
NMR (700 MHz, CDCl3) δ 7.99 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.1
Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.37 (t, J =
7.2 Hz, 1H), 7.29 (d, J = 7.1 Hz, 2H), 5.66 (s, 2H) ppm; 13C NMR
(175 MHz, CDCl3) δ 151.0, 137.5, 134.1, 133.7, 131.1, 129.1, 128.6,
127.2, 125.5, 123.2, 123.1, 52.4 ppm; HRMS (ES+) calcd for
C15H11N4O2Cl2 (M + H) 349.0259, found 349.0270. Minor
regioisomer 50j: IR (neat) 3090, 2920, 1533, 1345, 1285, 804, 745
1
3286, 2919, 1531, 1447, 1346, 1025, 737 cm−1; H NMR (700 MHz,
CDCl3) δ 7.76 (dd, J = 1.0, 8.3 Hz, 1H), 7.45 (dd, J = 1.0, 8.0 Hz, 1H),
7.31 (m, 4H), 7.27 (m, 3H), 7.15 (m, 4H), 7.11 (m, 2H), 7.07 (m,
3H) 5.41 (s, 2H), 3.04 (s, 1H) ppm; 13C NMR (175 MHz, CDCl3) δ
149.1, 142.9, 142.6, 140.0, 138.1, 137.7, 135.5, 134.0, 129.5, 128.7,
128.23, 128.16, 128.13, 128.07, 127.9, 127.5, 126.5, 126.2, 123.1, 53.8
ppm; HRMS (ES+) calcd for C27H19ClN4NaO3 (M + Na) 505.1043,
found 505.1047. Regioisomer 50g: IR (neat) 3401, 3062, 2925, 1724,
1532, 1448, 1347, 758 cm−1; 1H NMR (700 MHz, CDCl3) δ 7.16 (dd,
J = 1.0, 8.3 Hz, 1H), 7.46 (dd, J = 1.1, 8.0 Hz, 1H), 7.37 (t, J = 8.2 Hz,
1H), 7.24 (m, 3H), 7.18 (t, J = 7.7 Hz, 1H), 7.13 (m, 4H), 6.98 (d, J =
7.6 Hz, 1H), 5.36 (d, J = 15.0 Hz, 1H), 5.24 (d, J = 14.9 Hz, 1H), 3.29
(s, 1H) ppm; 13C NMR (175 MHz, CDCl3) δ 150.0, 149.1, 144.73,
144.68, 137.6, 134.0, 133.0, 130.8, 128.8, 128.64, 128.56, 128.5, 127.8,
1
cm−1; H NMR (700 MHz, CDCl3) δ 8.07 (dd, J = 1.1, 8.3 Hz, 1H),
7.75 (dd, J = 1.2, 8.1 Hz, 1H), 7.66 (t, J = 8.2 Hz, 1H), 7.26 (t, J = 7.5
Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 7.1 Hz, 2H), 5.44 (d, J =
14.9, 1H), 5.40 (d, J = 14.9, 1H) ppm; 13C NMR (175 MHz, CDCl3)
δ 149.6, 138.0, 134.7, 132.5, 132.3, 129.2, 128.9, 128.8, 128.4, 127.8,
123.6, 120.0 ppm; HRMS (ES+) calcd for C15H11N4O2Cl2 (M + H)
349.0259, found 349.0245.
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The Journal of Organic Chemistry
Article
Triazole 49k and Triazole 50k. To a pressure vessel containing
24 (21 mg, 80.7 μmol) were added PhMe (160 μL) and azide 48 (32
mg, 240 μmol) at rt. The reaction mixture was sealed under Ar and
heated to 80 °C. After 72 h, the reaction was cooled to rt, concentrated
in vacuo, and purified via flash chromatography over silica gel, eluting
with 0−40% EtOAc/hexanes to give a mixture of regioisomers (20.2
mg, 51.6 μmol, 64%, 9:1 (49k:50k)) as a red-orange solid. Analytical
samples of the individual isomers could be obtained by preparative
thin layer chromatography over silica gel, eluting with 30% EtOAc/
Hexanes to give sequentially 49k then 50k. Major regioisomer 49k:
mp 126−128 °C; IR (neat) 3088, 3034, 2924, 1533, 1455, 1353, 988,
2H) ppm; 13C NMR (175 MHz, CDCl3) δ 150.0, 137.8, 135.9, 135.2,
134.7, 132.2, 130.0, 128.6, 126.6, 123.6, 121.7, 120.7, 120.3, 53.1 ppm;
HRMS (ES+) calcd for C17H13BrClN4O2 (M + H) 418.9910, found
418.9916.
Triazole 51c and 52c. To a pressure vessel containing 23 (19 mg,
88.8 μmol) were added PhMe (190 μL) and azide (33 mg, 277 μmol)
sequentially at rt. The reaction mixture was sealed under Ar and
heated to 80 °C. After 72 h, the crude mixture was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 0−40% EtOAc/hexanes to give a mixture of
regioisomers (11.5 mg, 34.3 μmol, 36%, 2:1 rr (51c:52c)). Analytical
samples of the individual isomers could be obtained by preparative
thin layer chromatography over silica gel, eluting with 30% EtOAc/
hexanes to give sequentially 51c then 52c. Major regioisomer 51c: IR
1
759 cm−1; H NMR (700 MHz, CDCl3) δ 8.02 (d, J = 8.1 Hz, 1H),
7.81 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.42−7.38 (m, 3H),
7.27 (m, 2H), 5.70 (s, 2H) ppm; 13C NMR (175 MHz, CDCl3) δ
150.9, 140.8, 137.6, 134.1, 133.9, 131.0, 129.1, 128.6, 127.2, 123.8,
123.1, 112.2, 53.2 ppm; HRMS (ES+) calcd for C15H11N4O2ClBr (M
+ H) 392.9754, found 392.9770. Minor regioisomer 50k: IR (neat)
1
(neat) 3082, 2919, 1533, 1501, 1351, 1242, 983, 760, 746 cm−1; H
NMR (700 MHz, CDCl3) δ 8.03 (dd, J = 1.0, 8.3 Hz, 1H), 7.85 (dd, J
= 1.1, 8.1 Hz, 1H), 7.73 (m, 2 H), 7.63 (m, 4H) ppm; 13C NMR (175
MHz, CDCl3) δ 151.1, 137.8, 137.6, 134.9, 134.2, 131.2, 130.2, 129.6,
125.6, 125.4, 125.0, 123.1 ppm; HRMS (ES+) calcd for C14H9Cl2N4O2
(M + H) 335.0103, found 335.0110. Minor regioisomer 52c: IR (neat)
3084, 2924, 2854, 1717, 1537, 1498, 1348, 1307, 1262, 1098, 994, 759
1
3096, 2922, 1532, 1455, 1347, 1263, 743 cm−1; H NMR (300 MHz,
CDCl3) δ 8.08 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.66 (t, J
= 8.1 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H), 7.20 (t, J = 7.5 Hz, 2H), 7.01
(d, J = 7.6 Hz, 2H), 5.46 (d, J = 15.0 Hz, 1H) 5.42 (d, J = 15.2 Hz,
1H) ppm; HRMS (ES+) calcd for C15H11N4O2ClBr (M + H)
392.9754, found 392.9753.
1
cm−1; H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 1.0, 8.3 Hz, 1H),
7.81 (dd, J = 1.0, 8.1 Hz, 1H), 7.68 (t, J = 8.2 Hz, 2H), 7.43 (m, 5H)
ppm; 13C NMR (100 MHz, CDCl3) δ 149.9, 137.8, 136.2, 135.3,
135.0, 132.4, 130.0, 129.9, 127.7, 124.0, 123.8, 120.7, 120.4 ppm;
HRMS (ES+) calcd for C14H9Cl2N4O2 (M + H) 335.0103, found
335.0098.
Triazole 51a and 52a. To a pressure vessel containing 23 (17.8
mg, 83.2 μmol) were added PhMe (190 μL) and azide (45.8 mg, 288
μmol) sequentially at rt. The reaction mixture was sealed under Ar and
heated to 80 °C. After 48 h, the crude mixture was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 0−30% EtOAc/hexanes to give a mixture of
regioisomers (15.2 mg, 40.5 μmol, 49%, 11:1 rr (51a:52a)). Analytical
samples of the individual isomers could be obtained by preparative
thin layer chromatography over silica gel, eluting with 30% EtOAc/
hexanes to give sequentially 51a then 52a. Major regioisomer 51a: IR
Triazole 51d and 52d. To a pressure vessel containing 24 (19.8
mg, 76.1 μmol) were added PhMe (160 μL) and azide (29.1 mg, 244
μmol) sequentially at rt. The reaction mixture was sealed under Ar and
heated to 80 °C. After 53 h, the crude mixture was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 0−40% EtOAc/hexanes to give a mixture of
regioisomers (mg, μmol, 24%, 1:1 rr (51d:52d)). Analytical samples of
the individual isomers could be obtained by preparative thin layer
chromatography over silica gel, eluting with 30% EtOAc/hexanes to
give sequentially 51d then 52d. Major regioisomer 51d: IR (neat)
1
(neat) 3083, 3028, 2926, 1533, 1449, 1355, 1266, 966, 760 cm−1; H
NMR (700 MHz, CDCl3) δ 7.99 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.0
Hz, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.43 (d, J = 7.5 Hz, 2H), 7.37 (t, J =
7.4 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 6.56 (d, J = 15.9 Hz, 1H), 6.40
(tt, J = 5.8, 15.8 Hz, 1H), 5.24 (d, J = 5.6 Hz, 2H) ppm; 13C NMR
(175 MHz, CDCl3) δ 151.1, 137.5, 137.4, 135.5, 134.7, 134.1, 131.1,
128.7, 128.5, 126.8, 125.3, 123.3, 123.1, 120.7, 50.7 ppm; HRMS (ES
+) calcd for C17H13N4O2Cl2 (M + H) 375.0416, found 375.0410.
Minor regioisomer 52a: IR (neat) 2921, 2849, 1533, 1450, 1348, 1046,
1
2920, 1533, 1499, 1350, 808, 759, 745 cm−1; H NMR (700 MHz,
CDCl3) δ 8.06 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.70 (d, J
= 7.6 Hz, 2 H), 7.65 (t, J = 8.3 Hz, 1 H), 7.64 (m, 3H) ppm; 13C NMR
(175 MHz, CDCl3) δ 151.0, 141.0, 137.7, 135.6, 134.2, 131.1, 130.3,
129.5, 125.5, 123.7, 123.1, 112.2 ppm; HRMS (ES+) calcd for
C14H9BrClN4O2 (M + H) 378.9597, found 378.9612. Minor
regioisomer 52d: IR (neat) 3083, 2922, 2851, 1535, 1497, 1347,
1292, 1092, 992, 758 cm−1; 1H NMR (700 MHz, CDCl3) δ 8.10 (d, J
= 8.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.68 (t, J = 8.2 Hz, 1 H), 7.45
(m, 4 H), 7.28 (m, 1H) ppm; HRMS (ES+) calcd for C14H9BrClN4O2
(M + H) 378.9597, found 378.9587.
1
733 cm−1; H NMR (700 MHz, CDCl3) δ 8.07 (d, J = 8.2 Hz, 1H),
7.78 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 8.2 Hz, 1H), 7.30−7.28 (m, 3H),
7.19 (d, J = 5.8 Hz, 2H), 6.28 (d, J = 15.3 Hz, 1H), 6.21 (m, 1H), 5.06
(qd, J = 5.8, 14.6 Hz, 2H) ppm; HRMS (ES+) calcd for
C17H13N4O2Cl2 (M + H) 375.0416, found 375.0397.
Triazole 51b and 52b. To a pressure vessel containing 24 (21.0
mg, 80.7 μmol) were added PhMe (160 μL) and azide (39.3 mg, 247
μmol) sequentially at rt. The reaction mixture was sealed under Ar and
heated to 80 °C. After 29 h, the crude mixture was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 0−40% EtOAc/hexanes to give a mixture of
regioisomers (22.3 mg, 53.1 μmol, 69%, 4:1 rr (51b:52b)). Analytical
samples of the individual isomers could be obtained by preparative
thin layer chromatography over silica gel, eluting with 30% EtOAc/
hexanes to give sequentially 51b then 52b. Major regioisomer 51b: mp
133−136 °C; IR (neat) 3083, 3028, 2925, 1532, 1449, 1355, 1222,
Triazole 51e and 52e. To a pressure vessel containing 23 (19.9
mg, 93.0 μmol) were added PhMe (190 μL) and azide (46.8 mg, 298
μmol) sequentially at rt. The reaction mixture was sealed under Ar and
heated to 80 °C. After 48 h, the crude mixture was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 0−40% EtOAc/hexanes to give a mixture of
regioisomers (12.8 mg, 34.3 μmol, 37%, 9:1 rr (51e:52e)). Analytical
samples of the individual isomers could be obtained by preparative
thin layer chromatography over silica gel, eluting with 30% EtOAc/
hexanes to give sequentially 51e then 52e. Major regioisomer 51e: mp
95−97 °C; IR (neat) 3086, 2982, 2932, 1747, 1536, 1354, 1238, 1156,
1
760, 737 cm−1; H NMR (700 MHz, CDCl3) δ 8.02 (dd, J = 1.0, 8.2
1
Hz, 1H), 7.81 (dd, J = 1.0, 8.1 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.43
(d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H),
6.53 (d, J = 15.9 Hz, 1H), 6.40 (tt, J = 5.7, 15.9 Hz, 1H), 5.28 (d, J =
5.7 Hz, 2H) ppm; 13C NMR (175 MHz, CDCl3) δ 151.0, 140.6, 137.6,
135.6, 134.7, 134.1, 131.0, 128.7, 128.4, 126.8, 123.8, 123.1, 120.9,
112.0, 51.6 ppm; HRMS (ES+) calcd for C17H13BrClN4O2 (M + H)
418.9910, found 418.9930. Minor regioisomer 52b: IR (neat) 2919,
2851, 1532, 1449, 1351, 1263, 732 cm−1; 1H NMR (700 MHz, CDCl3)
δ 8.06 (dd, J = 1.0, 8.0 Hz, 1H), 7.78 (dd, J = 1.0, 8.0 Hz, 1H), 7.62 (t,
J = 8.0 Hz, 1H), 7.28 (m, 3H), 7.19 (dd, J = 1.4, 7.3 Hz, 2H), 6.29 (d, J
= 15.9 Hz, 1H), 6.40 (tt, J = 5.7, 15.9 Hz, 1H), 5.28 (d, J = 5.7 Hz,
993, 760 cm−1; H NMR (700 MHz, CDCl3) δ 8.02 (dd, J = 1.1, 8.2
Hz, 1H), 7.82 (dd, J = 1.2, 8.1 Hz, 1H), 7.63 (t, J = 8.2 Hz, 1H), 5.14
(s, 2H), 1.52 (s, 9H) ppm; 13C NMR (175 MHz, CDCl3) δ 163.7,
151.0, 137.6, 137.2, 134.1, 131.1, 126.2, 123.0, 84.4, 50.3, 27.9 ppm;
HRMS (ES+) calcd for C14H15Cl2N4O4 (M + H) 373.0470, found
373.0472. Minor regioisomer 52e: IR (neat) 2923, 2852, 1748, 1538,
1369, 1239, 1156, 757 cm−1; 1H NMR (700 MHz, CDCl3) δ 8.20 (dd,
J = 1.0, 8.3 Hz, 1H), 7.90 (dd, J = 1.1, 8.1 Hz, 1H), 7.76 (t, J = 8.3 Hz,
1H), 4.91 (d, J = 17.3 Hz, 1H), 4.81 (d, J = 17.3 Hz, 1H), 1.28 (s, 9H)
ppm; HRMS (ES+) calcd for C14H15Cl2N4O4 (M + H) 373.0470,
found 373.0487.
1110
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Article
Triazole 51f and 52f. To a pressure vessel containing 24 (26.1
mg, 100 μmol) were added PhMe (200 μL) and azide (47.2 mg, 300
μmol) sequentially at rt. The reaction mixture was sealed under Ar and
heated to 80 °C. After 48 h, the crude mixture was cooled to rt,
concentrated in vacuo, and purified via flash chromatography over
silica gel, eluting with 0−35% EtOAc/hexanes to give a mixture of
regioisomers (24.5 mg, 58.7 μmol, 58%, 9:1 rr (51f:52f)). Analytical
samples of the individual isomers could be obtained by preparative
thin layer chromatography over silica gel, eluting with 30% EtOAc/
hexanes to give sequentially 51f then 52f. Major regioisomer 51f: mp
140−142 °C; IR (neat) 3084, 2981, 2934, 1748, 1534, 1455, 1370,
52.7, 52.4 ppm; HRMS (CI+) calcd for C22H19N4O3 (M + H)
387.1457, found 387.1455.
Amino Alcohol 56. To a flask containing triazole 55 (10.9 mg, 28
μmol) stirring in glacial acetic acid (120 μL) at rt was added Zn dust
(5.5 mg, 84 μmol). After 2 h, the reaction was quenched with satd aq
NaHCO3 (3 mL). The reaction mixture was diluted with EtOAc (5
mL), and the organic layer was washed with satd aq NaHCO3 (3 mL)
and DI water (3 mL). The aqueous layer was extracted with EtOAc (5
mL). The organic layer was washed with satd aq NaCl (5 mL). The
organic layer was then dried over MgSO4 and concentrated in vacuo.
The solid was purified by flash chromatography over silica gel, eluting
0−100% EtOAc/hexanes, to give 56 (8.4 mg, 24 μmol, 84%) as a pale
1
1236, 990, 760 cm−1; H NMR (700 MHz, CDCl3) δ 8.01 (d, J = 8.0
1
yellow solid: IR (neat) 3361, 1616, 1462, 1004, 761, 729 cm−1; H
Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 8.2 Hz, 1H), 5.17 (d, J =
18.2 Hz, 2H), 1.51 (s, 9H) ppm; 13C NMR (175 MHz, CDCl3) δ
161.8, 151.0, 140.5, 137.6, 134.1, 131.1, 123.6, 123.0, 113.0, 84.3, 51.2,
27.9 ppm; HRMS (ES+) calcd for C14H15BrClN4O4 (M + H)
416.9965, found 416.9977. Minor regioisomer 52f: IR (neat) 3087,
NMR (400 MHz, CDCl3) δ 7.32−7.12 (overlapping m, 13H), 7.12 (d,
J = 7.5 Hz, 1H), 6.87 (d, J = 8.03 Hz, 1H), 5.54 (d, J = 8.59 Hz, 2H),
4.32 (bs, 2H), 3.98 (d, J = 13.83 Hz, 1H), 3.77 (d, J = 13.78, 1H), 0.53
(bs, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 146.7, 143.0, 142.4,
141.4, 134.8, 132.9, 130.0, 129.8, 128.8, 128.3, 128.2, 127.5, 126.9,
120.2, 115.5, 114.0, 52.9, 52.4 ppm; HRMS (CI+) calcd for
C22H21N4O (M + H) 357.1715, found 357.1716.
1
2982, 2929, 1748, 1537, 1353, 1238, 1156, 858, 758, 744 cm−1; H
NMR (700 MHz, CDCl3) δ 8.18 (dd, J = 1.0, 8.3 Hz, 1H), 7.90 (dd, J
= 1.0, 8.1 Hz, 1H), 7.75 (t, J = 8.3 Hz, 1H), 4.92 (d, J = 17.2 Hz, 1H),
4.83 (d, J = 17.2 Hz, 1H), 1.40 (s, 9H) ppm; HRMS (ES+) calcd for
C14H15BrClN4O4 (M + H) 416.9965, found 416.9973.
Carboxylic Acid 57. To a vial containing triazole 53 (88 mg, 212
μmol) stirring in EtOH (1 mL) was added LiOH·H2O (36 mg, 848
μmol) at rt. After 9 h, the reaction was quenched with aq HCl (3 mL,
6 N) and concentrated in vacuo. The reaction solid was taken up in
EtOAc (5 mL) and DI water (5 mL). The aqueous layer was extracted
with EtOAc (2 × 5 mL). The organic layer was washed with brine (2
× 5 mL), dried over MgSO4, and concentrated in vacuo. The solid was
purified by flash chromatography over silica gel, eluting 0−10%
MeOH/DCM, to give 57 (64.7 mg, 161 μmol, 76%) as a white solid:
Triazole 53. To a microwave vessel containing 46f (25 mg, 80
μmol) were added sequentially PhB(OH)2 (45.6 mg, 240 μmol),
Cs2CO3 (79.9 mg, 240 μmol), Ph2XPhos (7.4 mg, 16 μmol),
Pd(OAc)2 (1.8 mg, 8 μmol), and 2-MeTHF (400 μL). The solution
was sealed under argon and heated to 100 °C in a microwave. After 1
h, the mixture was filtered over a pad of Celite, eluting with Et2O, and
concentrated in vacuo. The residue was purified by flash
chromatography over silica gel, eluting 0−30% EtOAc/hexanes, to
give 53 (27.8 mg, 67 μmol, 84%) as a pale yellow solid: mp 110−113
°C; IR (neat) 3062, 3034, 2955, 1732, 1540, 1479, 1355, 1266, 1218,
1105, 820, 734 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = Hz,
1H), 7.69 (m, 2H), 7.30 (m, 3H), 7.21 (t, J = 7.30 Hz, 1H), 7.16 (t, J =
7.36 Hz, 2H), 6.99 (m, 4H), 5.84 (q, J = 14.81, 34.16 Hz, 2H), 3.57 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 157.9, 149.6, 146.1, 145.4,
138.7, 135.2, 134.4, 129.8, 129.1, 128.7, 128.1, 128.0, 127.6, 126.9,
125.7, 124.6, 123.4, 54.0, 52.3 ppm; HRMS (EI+) calcd for
C23H18N4O4 (M+) 414.1328, found 414.1331.
Lactam 54. To a flask containing triazole 53 (25.3 mg, 61 μmol)
stirring in glacial acetic acid (240 μL) at rt was added Zn dust (12.1
mg, 185 μmol). After 20 h, a second portion of Zn dust (16.8 mg,
0.257 mmol) was added. After 3 h, the reaction was quenched with
satd aq NaHCO3 (15 mL). The reaction mixture was diluted with
EtOAc (15 mL), and the organic layer was washed with satd
aqNaHCO3 (15 mL), DI water (15 mL), and satd aq NaCl (15 mL).
The organic layer was then dried over MgSO4 and concentrated in
vacuo. The pink solid was purified by trituration with EtOAc to give
54 (11.0 mg, 31 μmol, 52%) as a white solid: mp 257−258 °C; IR
(neat) 3060, 2923, 1695, 1664, 1675, 1558, 1373, 698 cm−1; 1H NMR
(400 MHz, CDCl3) δ 10.62 (s, 1H), 7.57 (m, 3H), 7.51 (m, 5H), 7.40
(m, 1H), 7.32 (m, 8H), 6.12 (s, 2H) ppm; 13C NMR (100 MHz,
CDCl3) δ 154.9, 147.7, 140.4, 140.2, 136.6, 135.2, 129.5, 128.9, 128.8,
128.6, 128.0, 127.9, 126.7, 123.6, 115.4, 112.6, 53.4 ppm; HRMS (ES
+) calcd for C22H17N4O (M + H) 353.1402, found 353.1385.
Alcohol 55. To a flask containing triazole 53 (25 mg, 60 μmol)
stirring in DCM (600 μL) at −78 °C was added DIBAL-H (180 mL,
18 μmol). After 1.5 h, the mixture was warmed to 0 °C and the
reaction quenched with Rochelle’s salt. The reaction mixture was
diluted with DCM (10 mL), and the aqueous layer was extracted with
DCM (3 × 10 mL). The combined organics were washed with brine
(2 × 10 mL), dried over MgSO4 ,and concentrated in vacuo. The solid
was purified by flash chromatography over silica gel, eluting 0−30%
EtOAc/hexanes, to give 55 (16.5 mg, 43 μmol, 71%) as a beige solid:
mp 148−150 °C; IR (neat) 3315, 3063, 2927, 1532, 1359, 732, 703
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 7.55. 1.81 Hz, 1H),
7.69 (m, 2H), 7.31 (m, 6H), 7.14 (dd, J = 7.91, 1.54 Hz, 2H), 7.01 (m,
2H) 5.58 (s, 2H), 4.02 (m, 2H), 0.49 (t, J = 7.00 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ 151.4, 144.5, 140.5, 138.8, 134.7, 133.8,
133.2, 130.0, 129.5, 128.9, 128.5, 128.2, 128.0, 126.9, 123.6, 123.5,
1
IR (neat) 3381, 2924, 1607, 1530, 1497, 1356, 764 cm−1; H NMR
(400 MHz, MeOD) δ 8.10 (m, 1H), 7.2 (d, J = 5.2 Hz, 2H), 7.14−
7.27 (m, 8H), 6.96 (m, 2H), 6.08 (d, J = 14.8 Hz, 1H), 5.81 (d, J =
14.8 Hz, 1H) 4.88 (s, 1H) ppm; 13C NMR (100 MHz, MeOD) δ
152.0, 145.5, 139.2, 136.5, 134.2, 129.3, 129.0, 128.2, 127.5, 127.3,
127.0, 126.5, 125.1, 122.8, 121.9, 52.7 ppm; HRMS (TOF+) calcd for
C22H16N4NaO4 (M + Na) 423.1069, found 423.1064.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C spectra for all new compounds are
provided. X-ray crystallographic data (CIF) for compounds 50e
and 53 are also provided. Cartesian coordinates, energies, and
additional computational informational are provided. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: paulc@science.oregonstate.edu; rich.carter@
oregonstate.edu.
■
†Corresponding author for computational work.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Science
Foundation (NSF) (CHE-0848704). NSF (CHE-0722319)
and the Murdock Charitable Trust (2005265) are acknowl-
edged for their support of the NMR facility. We thank Dr. Lev
N. Zakharov (OSU and University of Oregon) for X-ray
crystallographic analysis of compounds 50e and 53, Jeff Morre
(OSU) for mass spectra data, and Professor Stephen Buchwald
(MIT) for the generous gift of Ph2X-Phos ligand. We
acknowledge Christopher M. Sullivan and Matthew Peterson
of the Center for Genome Research and Biocomputing
(CGRB), Oregon State University, for computing cluster
management. Finally, we are grateful to Dr. Roger Hanselmann
(Rib-X Pharmaceuticals) for his helpful discussions.
́
1111
dx.doi.org/10.1021/jo202467k | J. Org. Chem. 2012, 77, 1101−1112

The Journal of Organic Chemistry
Article
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