Modular approaches to diversified soft lewis basic complexants through Suzuki-Miyaura cross-coupling of bromoheteroarenes with organotrifluoroborates

Article abstract of DOI:10.1021/acs.joc.5b02662

Remediation or transmutation of spent nuclear fuel obtained as a function of energy production and legacy waste remains a significant environmental concern. Substantive efforts over the last three decades have focused on the potential of soft-Lewis basic complexants for the chemoselective separation of trivalent actinides from lanthanides in biphasic solvent systems. Recent efforts in this laboratory have focused on the concept of modularity to rapidly prepare complexants and complexant scaffolds not easily accessible via traditional linear methods in a convergent manner to better understand solubility and complexation structure/activity function in process-relevant solvents. The current work describes an efficient method for the construction of diversified complexants through multi-Suzuki-Miyaura cross-coupling of bromoheteroarenes with organotrifluoroborates affording efficient access to 22 novel materials in 43-99% yield over two, three, or four cross-couplings on the same scaffold. Optimization of the catalyst/ligand system, application, and limitations are reported herein.

Full text of DOI:10.1021/acs.joc.5b02662

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Article
Modular Approaches to Diversified Soft Lewis Basic
Complexants through Suzuki-Miyaura Cross-Coupling
of Bromoheteroarenes with Organotrifluoroborates
Ai Lin Chin, and Jesse Dwayne Carrick
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02662 • Publication Date (Web): 11 Jan 2016
Downloaded from http://pubs.acs.org on January 17, 2016
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Modular Approaches to Diversified Soft Lewis Basic Complexants through
Suzuki-Miyaura Cross-Coupling of Bromoheteroarenes with
Organotrifluoroborates
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Ai Lin Chin and Jesse D. Carrick*
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Department of Chemistry, Tennessee Technological University, 55 University Drive, Cookeville,
TN 38501
Pd(OAc)2 (5 mol%),
R2
R2
RuPhos (10 mol%)
R3BF3K (2.1 equiv),
Cs2CO3 (3 equiv)
R3
Br
N
N
N
N
R1
N
R1
N
N
N
Tol:H2O (4:1), 115 oC, 16 h
(43-99%)
2 steps
R3
R1 = H, CH3, or Br
R2 = H or CH3
Br
23 Examples
R3 = alkyl, cyclopropyl, or Ph
PCy2
O
O
RuPhos
Abstract
Remediation or transmutation of spent nuclear fuel obtained as a function of energy
production and legacy waste remains a significant environmental concern. Substantive efforts
over the last three decades have focused on the potential of softꢀLewis basic complexants for the
chemoselective separation of trivalent actinides from lanthanides in biphasic solvent systems.
Recent efforts in this laboratory have focused on the concept of modularity to rapidly prepare
complexants and complexant scaffolds not easily accessible via traditional linear methods in a
convergent manner to better understand solubility and complexation structure/activity function in
processꢀrelevant solvents. The current work describes an efficient method for the construction of
diversified complexants through multiꢀSuzukiꢀMiyaura crossꢀcoupling of bromoheteroarenes
with organotrifluoroborates affording efficient access to 22 novel materials in 43–99% yield over
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two, three, or four crossꢀcouplings on the same scaffold. Optimization of the catalyst/ligand
system, application, and limitations are reported herein.
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Introduction
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The preparation of functionalized 1,2,4ꢀtriazinyl complexants for use in separation science,1
materials,2 and pharmaceuticals3 is wide and varied. This laboratory has been working on the
design, synthesis, and evaluation of softꢀLewis basic nitrogen donor complexants for
chemoselective minorꢀactinide separation of Am3+ over lanthanides in spent nuclear fuel.4
Effective sequestration of the minor actinides is required due to their strong neutron adsorbing
properties which preclude their inclusion in more advanced fuels. Kolarik demonstrated the
utility of 1,2,4ꢀtriazinyl moiety for chemoselective separations with the synthesis of 2,6ꢀbisꢀ(5,6ꢀ
dialkylꢀ1,2,4ꢀtriazinꢀ3ꢀyl) pyridines (BTPs) as selective heterocyclic complexants for trivalent
actinides [An(III)] over trivalent lanthanides [Ln(III)].5 The formation of 1,2,4ꢀtriazines in the
literature was first reported by Case.6 Previous results from this laboratory highlighted the
ability to access complexants derived from a variety of complexant scaffolds including monoꢀ
1,2,4ꢀtriazinylpyridines
(MTP),
bisꢀ1,2,4ꢀtriazinylpyridines
(BTP),7
and
bisꢀ
triazinylphenanthrolines (BTPhen)8 via telescopedꢀcondensation through the requisite
hydrazonamide precursor and a 1,2ꢀdicarbonyl without additives, prolonged reaction times, or
complicated isolation procedures (Figure 1). The preparation of functionalized bisꢀ1,2,4ꢀ
triazinylbipyridines has also been reported.
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N
N
R
R
R
R
N
N
N
N
R
R
N
1
N
2
N
N
N
MTP-Scaffold
BTP-Scaffold
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N
N
N
N
N
N
N
N
3
4
R
N
N
R
R
N
N
N
N
R
N
N
R
R
R
R
BTBP-Scaffold
BTPhen-Scaffold
Figure 1. Common SoftꢀNꢀdonor 1,2,4ꢀtriazinyl scaffolds.
One of the key challenges in this area is the development of a complexant which displays
high distribution values for An(III) in biphasic media, while possessing robust stability to hydroꢀ
and radiolytic degradation. Ideally a suitable complexant should also maintain solubility in
inexpensive, processꢀrelevant solvents including C7SBꢀIsopar, decane, or octanol. Triazinyl
complexants possessing two or more αꢀhydrogens relative to the 1,2,4ꢀtriazine are susceptible to
oxidative degradation in higher concentrations of nitric acid which adds an additional avenue of
complexity. Solubility of polar nitrogenꢀbased complexants in nonpolar solvents presents
obvious challenges, but also substantive opportunities for novel material and method
development. Juxtaposition of favorable complexation and solubility properties serves as a
strategic goal of work in this laboratory. The incorporation of an aromatic substituent directly
on the 1,2,4ꢀtriazine offers the potential for improved stability, but at a cost of decreased
solubility. The balancing of material robustness and solubility is a key focus of the current
study. A merged strategy towards favorable solubility and complexation performance could be
realized by employing metalꢀmediated crossꢀcoupling strategies to diversify functionality
necessary for solubility by increasing the aliphatic nature of the substituents. Linear routes to
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functionalized complexants through condensation methods are inefficient for the rapid
production of diversified substrates, often requiring the preparation of the 1,2ꢀdicarbonyl moiety
prior to the condensation event due to limited commercial availability. Modular approaches
through a common haloheteroarene scaffold which provide rapid access to functionally diverse
materials offer the potential for improved outcomes. It is postulated that triazinyl functionality
plays a limited role in chelation efficacy, but solubility performance of complexants could
potentially be improved by incorporation of aliphatic moieties via the SuzukiꢀMiyaura crossꢀ
coupling. The ubiquity of the SuzukiꢀMiyaura crossꢀcoupling in the preparation of diversified
arenes,9 functionalized heterocycles,10 complex natural products,11 and commodity chemicals in
organic and aqueous environments12 is understood.
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Examples of multiple SuzukiꢀMiyaura couplings13 executed on similar electronic
environments present on a discrete scaffold with any degree of functionality are not extensive in
the primary literature.14 Although efficient methods for the functionalization of unhindered aryl
halides via the SuzukiꢀMiyaura coupling are extensive with low catalyst/ligand loadings,
applications to nitrogen containing heterocyclic moieties frequently results in lower turnover
numbers and isolated yield. Inspired by the elegant work of Buchwald15 and Molander16 in this
area we set out to define the reaction parameters for an efficient multi crossꢀcoupling protocol
for haloheteroarene complexant scaffolds. Frequently, synthetic preparation of functionalized
1,2ꢀdicarbonyls can involve several nonconvergent reaction steps. Previous work in the group
with standard condensation methods of hydrazonamides towards the 1,2,4ꢀtriazine have
demonstrated that the electronic donating ability of the pꢀsubstituent of a 4,4’ꢀbenzil derivative
can play an important role in the outcome of the condensation event. As an example,
deactivating or electron withdrawing functionality typically results in high conversion and good
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isolated yield. The converse is also true when working with 4,4’ꢀbenzils with resident electron
donating substituents. A convergent approach leveraging modularity of a discrete complexant
scaffold and subsequent diversification through metalꢀmediated crossꢀcoupling would appear
relevant and timely towards mitigating inconsistent condensation performance. Several issues of
concern prior to project initiation included the potential for dative chelation of the substrate to
the metal, the necessity of multiple crossꢀcouplings thereby increasing the probability of
unwanted side reactions, and the challenge of executing crossꢀcoupling of functionalized
heteroarenes with sp3ꢀhybridized organotrifluoroborates. Herein we report a general method for
the SuzukiꢀMiyaura crossꢀcoupling of haloheteroarenes containing one, two, or three reaction
sites with various sp3 and sp2ꢀhybridized organotrifluoroborates in modest to excellent isolated
yield over one, two, three, or four steps, respectively.
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Results and Discussion
A summary of method development conditions explored is described in Table 1. As part of
due diligence all conditions listed were discretely evaluated with five organoboron reagents
including: potassium butyltrifluoroborate, 2ꢀmethylpropylboronic acid, (2ꢀmethylpropyl)boronic
acid Nꢀmethyliminodiacetic acid (MIDA) ester,17 potassium phenyltrifluoroborate, and
phenylboronic acid. These organoboron reagents were studied to ascertain any relationship
between successful metalꢀmediated coupling with a given catalyst/ligand combination in concert
with a particular organoboron reagent. Molander has reported the frequent necessity of
optimizing coupling conditions to a specific organoboron reagent. With respect to sp3 reagents,
2ꢀmethylpropylboronic acid and (2ꢀmethylpropyl)boronic acid MIDA ester were unsuccessful in
all conditions screened. Crossꢀcoupling with phenylboronic acid afforded modest levels of
conversion with entries (2, 11, and 13) and potassium phenyltrifluoroborate was successful with
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entries (2, 6, and 7). Due to incomplete conversion and a sizeable impurity profile, each of the
aforementioned reactions was not further pursued and specific reasons for the lack of conversion
to the desired products remains unclear. The aforementioned observations are commensurate
with previous observations on the challenge of developing a crossꢀcoupling protocol for a given
substrate that is suitable for all organoboron reagents.
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Table 1. Double Suzuki-Miyaura Cross-Coupling of Complexant Scaffolds Method
Development
Br
n
Catalyst, Ligand, Base
N
N
N
N
CH3(CH2)3BF3K,
N
N
N
5
N
6
solvent:H2O,
Temp (oC), 16 h
n = 3
Br
n
Temp
(°C)
Yield
(%)
Entry
Catalyst
Ligand
ꢀꢀꢀꢀꢀ
Base
Solvent
PEPPSI
(5 mol %)
PdCl2(dppf) CH2Cl2
(4 mol %)
KOtBu
(1.3 equiv)
Cs2CO3
(3 equiv)
IPA
(0.5 M)
CPME:H2O
(10:1)ꢀ0.1 M
1
2
23
0
0
ꢀꢀꢀꢀ
90
PdCl2
(4 mol %)
Pd(OAc)2
PPh3
Cs2CO3
(3 equiv)
Cs2CO3
(3 equiv)
K3PO4
(3 equiv)
K3PO4
(3 equiv)
Cs2CO3
(3 equiv)
K3PO4
(3 equiv)
K3PO4
(3 equiv)
K3PO4
(3 equiv)
K3PO4
THF:H2O
(9:1)ꢀ0.5 M
Tol:H2O
3
66
0
(12 mol %)
[nBuPAd2] HI
(6 mol %)
CyPFꢀtBu
(10 mol %)
CyPFꢀtBu
(10 mol %)
SPhos
(10 mol %)
tBuBrettPhos
(10 mol %)
RockPhos
(10 mol %)
RuPhos
(10 mol %)
RuPhos
(10 mol %)
RuPhos
(10 mol %)
SPhos
(10 mol %)
RuPhos
4
100
100
100
100
100
100
100
110
120
< 20
11
0
(4 mol %)
(10:1)ꢀ0.25 M
Pd(MeCN)2Cl2
(5 mol %)
Tol:H2O
(9:1)ꢀ0.5 M
Tol:H2O
(9:1)ꢀ0.3 M
Tol:H2O
(9:1)ꢀ0.25 M
Tol:H2O
(9:1)ꢀ0.5 M
Tol:H2O
(9:1)ꢀ0.5 M
Tol:H2O
(9:1)ꢀ0.5 M
tBuOH:H2O
(1:1)ꢀ0.1 M
Tol:H2O
(19:1)ꢀ0.1 M
CpMe:H2O
(9:1)ꢀ0.5 M
5
Pd2(dba)3
(5 mol %)
SPhos Pd G2 precatalyst
(5 mol %)
tBuBrettPhos precatalyst
(5 mol %)
RockPhos precatalyst
(5 mol %)
RuPhos precatalyst
(5 mol %)
6
7
0
8
8
9
0
10
11
12
67
0
PdCl2(COD)
(5 mol %)
Pd2(dba)3
(5 mol %)
Pd(OAc)2
(5 mol %)
(3.5 equiv)
K2CO3
(2 equiv)
K3PO4—H2O
(3 equiv)
91
13
14
23
0
Pd(OAc)2
Cs2CO3
CpMe:H2O
100
50
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(5 mol %)
Pd(OAc)2
(5 mol %)
(10 mol %)
RuPhos
(10 mol %)
(3 equiv)
Cs2CO3
(3 equiv)
(4:1)ꢀ0.2 M
Tol:H2O
(4:1)ꢀ0.2 M
15
100
97
7
8
9
Key: PyCFꢀtBu = 1ꢀdicyclohexylphosphinoꢀ2ꢀdiꢀtꢀbutylphosphinoethylferrocene
Utilization of the PdꢀNꢀheterocyclic carbene based PEPPSI catalyst (entry 1) developed by
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Organ was unsuccessful with 5.18 Tetrakis(triphenylphosphine)palladium(0),19
PdCl2(dppf)·CH2Cl2,20 PdCl2, as well as adaptation of the Molander procedures21 using
Pd(OAc)2 and the air stable iodide salt of diadamantylbutylphosphine (entries 2–4) afforded little
to no conversion of the starting material to the requisite dialkyl moiety. Adaptation of
established Hartwig amination conditions22 to the transformation of interest (entry 56) was also
unsuccessful. Screening of our recently disseminated procedure for Pdꢀcatalyzed diamination23
in the context of the current SuzukiꢀMiyaura crossꢀcouplings (entry 6) also proved unfruitful.
Entries 7–9 evaluated functionalized alkylbiarylphosphine ligands24 with the methanesulfonic
acid matched Pd(II) precatalysts developed in the Buchwald laboratories25 to promote oxidative
addition and subsequent reductive elimination, without substantive success. However, minimal
conversion of 8 mol % was observed in the case of entry 8 using tBuBrettPhos. A significant
productive result was observed in the case of entry 10 using the Buchwald RuPhos ligand and
matched precatalysts. Further exploration of alkoxyꢀsubstituted dialkylbiaryl phosphines with
various palladium catalysts seemed prudent. Variability of Pdꢀsources provided substantive
improvement in the case of entry 12.26 Near quantitative conversion of starting material was
observed in entry 15 changing from a Pd0 source to Pd(II).27 Use of toluene resulted in a cleaner
impurity profile upon evaluation of the crude reaction mixture by NMR (entry 15), therefore
affording a potentially useful candidate system.28
After proceeding with the conditions in entry 15 as the candidate system additional
optimization was undertaken to improve overall reaction time. A baseꢀscreening revealed no
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substantive improvement over the candidate system as stronger bases such as LiHMDS or
NaOtBu afforded no conversion and weaker bases such as K2CO3 or K3PO4 provided lower
conversion relative to Cs2CO3. The use of higher boiling solvents including nBuOH, DMF, and
pꢀxylene were studied to evaluate any correlation between solvent dielectric constant and/or
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higher temperature without substantive improvement.
Evaluation of higher reaction
concentration at 0.5, 1.0, and 2.0 M in toluene did not provide any advantage over the initial
concentration of 0.25 M with respect to improving reaction time. Increasing the equivalents of
the organotrifluoroborate also did not lead to higher conversion. During the course of scaffold
evaluation it was observed that the impurity profile of certain reactions could be improved with
increased catalyst/ligand loading. With a viable proof of concept established, we embarked on
applying the method to scaffolds with one, two, three, or four reaction sites (Table 2).
Table 2 highlights the diversity of scaffold derivatives suitable for multi SuzukiꢀMiyaura
crossꢀcoupling using the optimized reaction conditions. Treatment of scaffolds 5 and 7 with
potassium methyltrifluoroborate afforded the dialkylated pꢀtolyl derivatives (11–12). Evaluation
of 5 and related scaffold congeners (7 and 8) with butyl and octyltrifluoroborate reagents was
successful in entries 3–8, although entry 4 with scaffold 5 did demonstrate inconsistent
conversion. Utilization of branched alkyltrifluoroborates was also amenable to the reaction
conditions. Scaffolds (5, 7–8) in entries (9–11) provided the desired dialkylated products in
good isolated yield over two steps. A secondary goal from the beginning of this project was to
establish reaction conditions that would be tolerant of a wide variety of organotrifluoroborates
with various atomic hybridizations, steric, and electronic properties. Incorporation of the
challenging cyclopropyl moiety via double SuzukiꢀMiyaura crossꢀcoupling with the described
method was successful for the preparation of 21 and 22. Evaluation of sp2ꢀhybridized
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trifluoroborates for the production of the phenyl derivatives (entries 14–15) also was
successful.29 The next series of experiments sought to expand the diversity of scaffold
application by studying the efficacy of the method towards scaffolds with three or four reaction
sites, respectively, as well as 6ꢀbromopyridinyl complexant scaffolds.
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Table 2. Suzuki-Miyaura Cross-Coupling with Diversified Organotrifluoroborates
5
6
7
8
Pd(OAc)2 (5 mol%),
R2
R2
RuPhos (10 mol%)
R3BF3K (2.1 equiv),
Cs2CO3 (3 equiv)
R3
Br
5 R1, R2 = H
7 R1 = CH3, R2 = H
8 R1 = H, R2 = CH3
9 R1 = Br, R2 = H
10 R1 = L, R2 = H
N
N
N
N
R1
N
R1
N
Tol:H2O (4:1), 115 oC, 16 h
N
N
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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R3
Br
= L
Entry
Yielda
Yielda
Entry
Substrate
RBF3K
Product
Substrate
RBF3K
Product
n
11 (56)b
12 (99)
1
2
5
7
N
CH3BF3K
N
R1
N
17
BF3K
N
26 (52)e
n
9
n
N
N
n = 2
N
N
11 R1=H
12 R1=CH3
n
R2
N
n
27 (71)f
BF3K
N
18
n
10
6
(97)
13 (48)b, c
14 (45)
15 (61)
16 (92)
17 (80)
L
N
n
n = 2
3
4
5
6
7
8
5
5
N
N
N
R1
7
7
8
8
CH3(CH2)nBF3K
n = 3, or 7
N
N
n
6
R1=R2=H, n = 3
13 R1=R2=H, n = 7
= L
n
14 R1=H, R2=CH3, n = 3
15 R1=H, R2=CH3, n = 7
16 R1=CH3, R2=H, n = 3
17 R1=CH3, R2=H, n = 7
28 (78)g
19
N
N
N
BF3K
Br
N
N
n
38
N
N
N
R2
n
18 (91)d
19 (74)
20 (89)
N
N
9
10
11
5
7
8
N
N
R1
N
Br
20
N
Ph
N
PhBF3K
BF3K
29 (64)h
n
N
40
N
N
N
N
18 R1=R2=H, n = 2
19 R1=H, R2=CH3, n = 2
20 R1=CH3, R2=H, n = 2
n
Br
Br
n
21
30 (99)i
BF3K
BF3K
12
13
5
7
n
n = 2
21 (62)
22 (87)
N
R1
N
n
N
N
21 R1=H
22 R1=CH3
O
BF3K
O
Ph
Ph
22 4,4'ꢀdibromobenzil
31 (43)
N
14
15
23 (60)
24 (52)b,d
5
7
R1
N
PhBF3K
N
23 R1=H
24 R1=CH3
N
O
n
n
O
N
N
25 (47)e
23
4,4'ꢀdibromobenzil
32 (78)
BF3K
N
n
16
CH3(CH2)3BF3K
9
n
N
n = 3
n = 2
n
n
aIsolated, purified yield over one, two, or three synthetic steps depending on scaffold: 5, 7ꢀ8, 9, or 10, b10.0 mol % catalyst, 20 mol % ligand, utilized, cAverage yield from 3
experiments, dAverage yield from 2 experiments e 15 mol % catalyst, 30 mol % ligand, 3.15 equiv of RBF3K utilized, f40 mol % catalyst, 80 mol % ligand, 4.20 equiv of RBF3K
utilized, g10 mol % catalyst, 20 mol % ligand, 1.05 equiv of RBF3K utilized, h5 mol % catalyst, 10 mol % ligand, 1.05 equiv of RBF3K utilized, iYield calculated from 1H NMR of
crude reaction mixture,
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At this point in the study we wished to ascertain the applicability of the optimized
conditions towards substrates with more than two reactive sites. Treatment of 5,6ꢀbisꢀ(4ꢀbromoꢀ
phenyl)ꢀ3ꢀ(6ꢀbromoꢀpyridinꢀ2ꢀyl)ꢀ[1,2,4]triazine with 15 mol % of Pd(OAc)2 and 30 mol % of
RuPhos provided the desired trialkylated compounds 25 and 26 in acceptable isolated yield over
three steps even though each of the reactions performed involved metalꢀmediated crossꢀcoupling
at two very electronically diverse sites. With the momentum of the previous results serving as
impetus, we next evaluated a tetrabromoꢀBTP previously prepared in this laboratory under the
described conditions. Much to our delight complete conversion of scaffold 10 was obtained at
10/20 mol % catalyst/ligand loading per reaction site for a substrate which has the potential to
serve as a dative ligand for palladium and contains four reaction sites. Purification of this
material was challenging, but the desired product could be accessed in 71% yield under the
reported conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Evaluation of crossꢀcoupling with 6ꢀbromotriazinyl pyridine scaffolds was investigated next.
Preparation of these novel scaffolds was executed via treatment of the requisite
pyridinecarbonitrile with hydrazine hydrate at elevated temperature, followed by direct isolation
and telescoping of the intermediary hydrazonamide to the corresponding 1,2,4ꢀtriazinyl
derivative via condensation with an appropriate 1,2ꢀdicarbonyl pursuant to methods developed in
this laboratory (Scheme 1).30
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Scheme 1. Preparation of Novel 6-bromotriazinyl Pyridine Scaffolds Utilized
5
6
7
O
O
N
N
8
9
Br
N
38
THF, 66 C
°
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
(NH2)2 H2O
THF, 40 C
O
NH2
NH2
R
Br
N
CN
Br
N
°
R
R
N
37
R
R = H, CH3, or Br
N
N
Br
N
THF, 66 C
°
N
39 R = H
40 R = CH3
41 R = Br
Treatment with potassium organotrifluoroborates (entries 19–20) proved amenable to the
described conditions, although an increase in catalyst and ligand loading was required to
maintain high levels of conversion.31 The broad applicability of the described work is not just
limited to multiple SuzukiꢀMiyaura couplings of complexant scaffolds. Alternatively explored
substrates including 1,4ꢀdibromobenzene (entry 21), as well as 4,4’ꢀdibromobenzil all
successfully underwent the reported transformation (entries 22–23). The case of 4,4’ꢀ
dibromobenzil is very instructive given the ability to utilize the derived compounds in
subsequent condensation chemistry to afford more diverse complexants which may not be
suitable for metalꢀmediated crossꢀcoupling.
In order to validate the applicability of the
described method towards the preparation of larger quantities of material, a tenꢀfold scaleꢀup
experiment with 1 mmol of 5 was executed with potassium 3,3ꢀdimethylbutyltrifluoroborate
(Scheme 2). Thus, treatment of 5 using the standard conditions afforded quantitative conversion
of the starting material by NMR and resulted in a 99% isolated yield upon purification by
automated flashꢀcolumn chromatography.
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Scheme 2. Double Suzuki-Miyaura Cross-Coupling Scale-Up Reaction
5
6
7
8
Pd(OAc)2 (5 mol%),
RuPhos (10 mol%)
Br
n
RBF3K (2.1 equiv),
9
N
N
N
N
Cs2CO3 (3 equiv)
N
N
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
N
N
Tol:H2O (4:1), 115 oC, 16 h
(99%ꢀ2 steps)
Br
n
1 mmol scale
n = 2
A proposed catalytic cycle for the conversion of 5 is described in Figure 2. Treatment of
palladium acetate with the RuPhos ligand affords Pd0 which complexes an additional RuPhos to
provide the postulated catalytically active species. Oxidative addition of the catalyst into the Cꢀ
Br bond of the heteroarene scaffold 5 affords a palladium (II) intermediate (33) for ligand
exchange. Sigmaꢀbond metathesis of an in situ generated alkoxide provides intermediate 34.
Transmetallation of the organohydroxyborate species (35) followed by reductive elimination
affords the new CꢀC bond (36) and regenerates the putative catalyticallyꢀactive species for
additional turnovers. Whether the substrate scope evaluated undergoes iterative coupling via 36,
or a related intermediate, progressing through the described catalytic cycle for each discrete
coupling or if simultaneous diꢀ, triꢀ, or tetracoupling occurs is subject to interpretation as a
concrete mechanistic hypothesis was not evaluated in the context of the described work.
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Pd(OAc)2
L
Br
N
O
PCy2R
N
+
5
6
Ac2O
N
N
PdLn
5 or 36
36
R
Start
reductive
elimination
oxidative
addition
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
Br
N
N
RBF3K + CsOH
N
N
N
N
N
35
N
Pd(II)Ln
33
Pd(II)Ln
X
[RBF(OH)2]ꢀ
ꢀorꢀ
[RBF2OH]ꢀ
R
[ROBF(OH)2]ꢀ
Cs2CO3
ꢀorꢀ
[ROBF2OH]ꢀ
Br
ligand
substitution
0.50 CsBr
N
N
transmetallation
N
N
34
PdLn
RO
Figure 2. Proposed Catalytic Cycle for SuzukiꢀMiyaura Coupling of Complexant Scaffolds.
Conclusion
In summary, we have developed an efficient set of reaction parameters for the efficient
preparation of multi crossꢀcoupled complexant scaffolds. The described method accomplishes
the desired monoꢀ, diꢀ, and triꢀ SuzukiꢀMiyaura crossꢀcouplings on bromoheteroarene
complexant scaffolds with modest loadings as low as 2.5 mol % of catalyst and 5.0 mol % of
ligand per reaction site for several MTPꢀderivatives enabling for the first time modulation of
electronic and solubility properties of a given complexant scaffold directly from a common
precursor without the inefficiency of linear synthetic routes anchored in condensation strategies.
The twentyꢀthree examples described highlight the versatility of the transformation with
structurally diverse scaffolds as well as electronically and sterically varied sp2 and sp3 hybridized
organotrifluoroborates. The novel complexants prepared will be evaluated in the context of
biphasic separation assays with Am3+. Future work will focus on delineation of the listed method
to additional BTP and BTPhen scaffold for thorough analysis of complexant core rigidity on
performance with the same substituents, as well achieving success on currently recalcitrant
examples.
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Experimental Section
5
6
Preparation of scaffolds 5, 7–8, and 10 has been previously reported.32
7
8
9
General. All reagents were purchased from U.S. chemical suppliers, stored according to
published protocols, and used as received unless indicated otherwise. All experiments were
performed in ovenꢀ or flameꢀdried glassware under an inert atmosphere of Ar except where
indicated. Reaction progress was monitored using thinꢀlayer chromatography on glassꢀbacked
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
silica gel plates and/or HꢀNMR analysis of crude reaction mixtures. RF values for compounds
that resulted in a concentrically observed spot on normal phase silica gel are reported using the
conditions listed. All reported yields listed are for pure compounds and corrected for residual
1
solvent, if applicable, from H NMR spectroscopy unless otherwise indicated. Infrared spectral
data was acquired from the (form) listed. All 1H and 13C NMR chemical shifts are reported using
the δ scale and are referenced to the residual solvent signal: CDCl3 (δ 7.26) or DMSOꢀd6 (δ 2.50)
for 1HꢀNMR and chloroform (δ 77.0), DMSOꢀd6 (δ 39.52) for 13CꢀNMR. Splittings are reported
as follows: (s) = singlet, (d) = doublet, (t) = triplet, (dd) = doublet of doublets, (dt) = doublet of
triplets, (br) = broad, and (m) = multiplet. High resolution mass spectrometry (HRMS) data was
obtained utilizing electron impact ionization (EI) with a magnetic sector (EBE trisector), double
focusingꢀgeometry mass analyzer unless indicated otherwise.
General Procedure for Suzuki-Miyaura Coupling of Complexant Scaffolds. To an 8 mL
reaction vial equipped with a magnetic stir bar at ambient temperature were charged Pd(OAc)2,
RuPhos, Cs2CO3 (3 equiv), the requisite substrate (0.107 mmol), and the desired
organotrifluoroborate (equivalents listed for each reaction). The mixture was slurried in Tol:H2O
(4:1) (0.2 M) and heated to 115 °C for 16 hours upon which time the crude mixture was analyzed
1
by H NMR. Absorption of the crude mixture onto normal phase silica gel followed by
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purification on a 4 g normal phase silica gel column by automated flashꢀcolumn chromatography
using an EtOAc:hexanes or MTBE:hexanes gradient mobile phases afforded the desired product
in the reported yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-Pyridin-2-yl-5,6-di-p-tolyl-[1,2,4]triazine (11). Prepared according to the general procedure
discussed above with substrate 5: (10.0 mol % catalyst, 20.0 mol % ligand, 2.10 equiv
CH3BF3K), RF = 0.24, 100% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield
1
0.0204 g, 56%; orange oil; H NMR (600 MHz, CDCl3): δ = 8.93 (d, J = 4.5 Hz, 1H), 8.70 (d, J
= 8.0 Hz, 1H), 7.94 (dt, J = 7.8, 1.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H),
13
7.50–7.47 (m, 1H), 7.21 (7.8 Hz, 2H), 7.19 (7.8 Hz, 2H), 2.40 (s, 3H), 2.38 (s, 3H); C NMR
(150 MHz, CDCl3): δ = 160.3, 156.4, 156.1, 152.9, 150.3, 141.2, 139.9, 137.2, 132.9, 132.6,
129.9, 129.4, 129.34, 129.27, 125.3, 124.1, 21.5, 21.4; IR (CDCl3): ῡmax = 3032, 2972, 2921,
1608, 1585, 1491, 1389, 1369, 821 cm−1; HRMS (EI): m/z calculated for C22H18N4: 338.1531;
found: 338.1536.
3-(6-Methyl-pyridin-2-yl)-5,6-di-p-tolyl-[1,2,4]triazine (12). Prepared according to the general
procedure discussed above with substrate 7: (5.0 mol % catalyst, 10.0 mol % ligand, 2.10 equiv
of CH3BF3K), RF = 0.29, 50% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield
1
0.0376 g, 99%; yellow solid; mp 146.8–149.9 °C; H NMR (600 MHz, CDCl3): δ = 8.47 (d, J =
7.5 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.58–7.55 (m, 2H), 7.36 (d, J =
7.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 2.78 (s, 3H), 2.42 (s, 3H), 2.40 (s,
13
3H); C NMR (150 MHz, CDCl3): δ = 160.6, 159.4, 156.1, 155.8, 152.6, 141.2, 139.8, 137.1,
133.0, 132.7, 129.9, 129.4, 129.3, 129.2, 125.1, 121.3, 24.9, 21.5, 21.4; IR (CDCl3): ῡmax = 3031,
2921, 2859, 1609, 1590, 1492, 1382, 1360, 819, 724 cm−1; HRMS (EI): m/z calculated for
C23H20N4: 352.1688; found: 352.1689.
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5,6-Bis-(4-butyl-phenyl)-3-pyridin-2-yl-[1,2,4]triazine (6). Prepared according to the general
procedure discussed above with substrate 5: (5.0 mol % catalyst, 10.0 mol % ligand, 2.10 equiv
of CH3(CH2)3BF3K), RF = 0.36, 100% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
isolated yield 0.0439 g, 97%; orange gum; H NMR (500 MHz, CDCl3): δ = 9.03 (d, J = 4.4 Hz,
1H), 8.80 (d, J = 8.0 Hz, 1H), 8.07 (dt, J = 8.0, 1.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.61–7.60
(m, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 2.66 (t, J =
7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.66–1.56 (m, 4H), 1.41–1.30 (m, 4H), 0.94 (t, J = 7.5 Hz,
3H), 0.92 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = 158.7, 156.7, 156.3, 151.4,
148.8, 146.6, 145.2, 139.2, 132.53, 132.50, 130.2, 129.4, 128.7, 128.6, 125.9, 124.4, 35.51,
35.46, 33.2, 33.1, 22.3, 22.2, 13.90, 13.87 ; IR (CDCl3): ῡmax = 3032, 2956, 2929, 2858, 1609,
1584, 1467, 1452, 1389, 1369, 836 cm−1; HRMS (EI): m/z calculated for C28H30N4: 422.2470;
found: 422.2475.
5,6-Bis-(4-octyl-phenyl)-3-pyridin-2-yl-[1,2,4]triazine (13). Prepared according to the general
procedure discussed above with substrate 5: (10.0 mol % catalyst, 20.0 mol % ligand, 2.10 equiv
of CH3(CH2)7BF3K), RF = 0.55, 100% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient);
isolated yield 0.0248 g, 48% (average yield from three experiments: 58%, 53%, 34%); brown
1
gum; H NMR (500 MHz, CDCl3): δ = 9.16 (d, J = 4.5 Hz, 1H), 8.92 (d, J = 8.2 Hz, 1H), 8.24
(t, J = 8.2 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.75 (brꢀt, J = 6.5 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H),
7.22 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz,
2H), 1.68–1.57 (m, 4H), 1.36–1.20 (brꢀm, 20H), 0.92–0.85 (m, 6H); 13C NMR (150 MHz,
CDCl3): δ = 157.6, 157.0, 156.4, 150.2, 147.8, 147.0, 145.5, 140.8, 132.4, 132.1, 130.5, 129.4,
128.8, 128.7, 126.3, 124.7, 35.9, 35.8, 31.8, 31.4, 31.0, 31.X (overlaps with 31.0), 29.41 (29.3X;
three resonances overlap with 29.41), 29.25, 29.22, 22.6, 22.5X (overlaps with 22.6), 14.1,
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14.0X (overlaps with 14.1); IR (CDCl3): ῡmax = 3032, 2925, 2854, 1609, 1493, 1467, 1390, 1369,
835 cm−1; HRMS (EI): m/z calculated for C36H46N4: 534.3722; found: 534.3734.
7
8
9
5,6-Bis-(4-butyl-phenyl)-3-(4-methyl-pyridin-2-yl)-[1,2,4]triazine (14). Prepared according to
the general procedure discussed above with substrate 7: (5.0 mol % catalyst, 10.0 mol % ligand,
2.10 equiv of CH3(CH2)3BF3K), RF = 0.34, 50% EtOAc:hexanes; eluent, EtOAc/hexanes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(gradient); isolated yield 0.0184 g, 45%; yellowꢀorange gum; H NMR (500 MHz, CDCl3): δ =
8.82 (d, J = 8.2 Hz, 1H), 8.30 (t, J = 8.0 Hz, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz,
1H), 7.62 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 3.26 (s, 3H),
2.66 (t, J = 8.0 Hz, 2H), 2.63 (t, J = 8.0 Hz, 2H), 1.67–1.55 (m, 4H), 1.42–1.29 (m, 4H), 0.95 (t,
J = 7.5 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = 157.6, 157.5, 156.6,
155.2, 147.9, 147.1, 145.8, 144.0, 132.0, 131.9, 130.9, 129.5, 128.85, 128.82, 128.7, 123.6,
35.59, 35.52, 33.2, 33.1, 22.3, 22.2, 21.3, 13.92, 13.88; IR (neat): ῡmax = 3030, 2955, 2927, 2857,
1609, 1590, 1490, 1454, 1381, 1359, 833, 796 cm−1; HRMS (EI): m/z calculated for C29H32N4:
436.2627; found: 436.2619.
3-(4-Methyl-pyridin-2-yl)-5,6-bis-(4-octyl-phenyl)-[1,2,4]triazine (15). Prepared according to
the general procedure discussed above with substrate 7: (5.0 mol % catalyst, 10.0 mol % ligand,
2.10 equiv of CH3(CH2)7BF3K), RF = 0.47, 50% EtOAc:hexanes; eluent, EtOAc/hexanes
1
(gradient); isolated yield 0.0314 g, 61%; brownꢀorange gum; H NMR (500 MHz, CDCl3): δ =
8.66 (d, J = 8.2 Hz, 1H), 8.09 (t, J = 8.2 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz,
2H), 7.55 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 3.04 (s, 3H),
2.67–2.59 (m, 4H), 1.67–1.56 (m, 4H), 1.38–1.20 (brꢀm, 20H), 0.91–0.83 (m, 6H); 13C NMR
(125 MHz, CDCl3): δ = 158.4, 157.7, 156.9, 156.3, 150.1, 146.6, 145.3, 140.7, 132.4, 132.36,
130.4, 129.4, 128.7, 128.66, 127.0, 122.5, 35.8, 35.78, 31.82, 31.8X (overlaps with 31.82), 31.1,
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31.0, 29.38, 29.3X (overlaps with 29.38), 29.22, 29.2X (overlaps with 29.22), 29.17, 29.1X
(overlaps with 29.17), 22.62, 22.6X (overlaps with 22.62), 14.16, 14.1X (overlaps with 14.16);
IR (neat): ῡmax = 3031, 2923, 2853, 1609, 1590, 1492, 1464, 1381, 1360, 830 cm−1; HRMS (EI):
m/z calculated for C37H48N4: 548.3879; found: 548.3887.
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5,6-Bis-(4-butyl-phenyl)-3-(6-methyl-pyridin-2-yl)-[1,2,4]triazine (16). Prepared according to
the general procedure discussed above with substrate 8: (5.0 mol % catalyst, 10.0 mol % ligand,
2.10 equiv of CH3(CH2)3BF3K), RF = 0.40, 50% EtOAc:hexanes; eluent, EtOAc/hexanes
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(gradient); isolated yield 0.0429 g, 92%; orange solid; mp 79.9–84.0 °C; H NMR (500 MHz,
CDCl3): δ = 8.57 (d, J = 7.0 Hz, 1H), 7.97 (t, J = 7.0 Hz, 1H), 7.77 (d, J = 7.5 Hz, 2H), 7.57 (d, J
= 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 2.92
(s, 3H), 2.68–2.60 (m, 4H), 1.65–1.56 (m, 4H), 1.40–1.30 (m, 4H), 0.93 (t, J = 7.5 Hz, 3H), 0.92
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(t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl3): δ = 158.9, 158.8, 156.6, 156.1, 151.1, 146.4,
145.1, 139.3, 132.7, 132.6, 130.2, 129.4, 128.7, 128.6, 126.2, 122.0, 35.51, 35.46, 33.3, 33.1,
23.7, 22.3, 22.2, 13.91, 13.87; IR (neat): ῡmax = 3030, 2928, 2858, 1609, 1590, 1491, 1464, 1381,
1360, 833, 796, 729 cm−1; HRMS (EI): m/z calculated for C29H32N4: 436.2627; found:
436.2617.
3-(6-Methyl-pyridin-2-yl)-5,6-bis-(4-octyl-phenyl)-[1,2,4]triazine (17). Prepared according to
the general procedure discussed above with substrate 8: (5.0 mol % catalyst, 10.0 mol % ligand,
2.10 equiv of CH3(CH2)7BF3K), RF = 0.51, 50% EtOAc:hexanes; eluent, EtOAc/hexanes
(gradient); isolated yield 0.0473 g, 80%; orange gum; 1H NMR (500 MHz, CDCl3): δ = 8.63 (d,
J = 8.0 Hz, 1H), 8.04 t, J = 8.0 Hz, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.5 Hz, 2H), 7.51
(d, J = 7.5 Hz, 1H), 7.19 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 3.00 (s, 3H), 2.65–2.59
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(m, 4H), 1.67–1.55 (m, 4H), 1.38–1.21 (brꢀm, 20H), 0.90–0.84 (m, 6H); C NMR (125 MHz,
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CDCl3): δ = 158.5, 158.1, 156.8, 156.2, 150.4, 146.6, 145.3, 140.2, 132.5, 132.4, 130.4, 129.4,
128.73, 128.66, 126.8, 122.3, 35.9, 35.8, 31.8, 31.7X (overlaps with 31.8), 31.1, 31.0, 29.4,
29.3X (overlaps with 29.4), 29.24, 29.2X (overlaps with 29.24), 29.19, 29.1X (overlaps with
29.19), 32.2, 22.6, 22.5X (overlaps with 22.6), 14.1, 14.0X (overlaps with 14.1); IR (CDCl3):
ῡmax = 3030, 2925, 2854, 1609, 1590, 1493, 1465, 1381, 1360 cm−1; HRMS (EI): m/z calculated
for C37H48N4: 548.3879; found: 548.3871.
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5,6-Bis-[4-(3,3-dimethyl-butyl)-phenyl]-3-pyridin-2-yl-[1,2,4]triazine
(18).
Prepared
according to the general procedure discussed above with substrate 5: (5.0 mol % catalyst, 10.0
mol % ligand, 2.10 equiv of (CH3)3C(CH2)2BF3K), RF = 0.51, 100% EtOAc:hexanes; eluent,
EtOAc/hexanes (gradient); isolated yield 0.0467 g, 91% (average yield from two experiments:
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94%, 89%); yellowꢀorange solid; mp 151.3–157.5 °C; H NMR (500 MHz, CDCl3): δ = 9.06
(d, J = 5.0 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.12 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H),
7.67–7.63 (brꢀm, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz,
2H), 2.65–2.57 (m, 4H), 1.56–1.47 (m, 4H), 0.97 (s, 9H), 0.95 (s, 9H); 13C NMR (125 MHz,
CDCl3): δ = 158.1, 156.8, 156.3, 150.8, 148.3, 147.5, 146.0, 140.0, 132.4, 132.3, 130.4, 129.5,
128.72, 128.65, 126.1, 124.5, 45.9, 45.8, 31.3, 31.2, 30.6, 30.5X (overlaps with 30.6), 29.3,
29.2X (overlaps with 29.3); IR (neat): ῡmax = 3055, 2928, 1587, 1488, 1443, 1432, 1372, 1350,
825, 773 cm−1; HRMS (EI): m/z calculated for C32H38N4: 478.3096; found: 478.3105.
5,6-Bis-[4-(3,3-dimethyl-butyl)-phenyl]-3-(4-methyl-pyridin-2-yl)-[1,2,4]triazine
(19).
Prepared according to the general procedure discussed above with substrate 7: (5.0 mol %
catalyst, 10.0 mol % ligand, 2.10 equiv of (CH3)3C(CH2)2BF3K), RF = 0.53, 50%
EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0390 g, 74%; orange solid;
mp 137.9–144.4°C; 1H NMR (500 MHz, CDCl3): δ = 8.61 (d, J = 8.0 Hz, 1H), 8.03 (t, J = 8.0
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Hz, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 7.5 Hz, 1H), 7.22 (d, J =
8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 2.98 (s, 3H), 2.65–2.56 (m, 4H), 1.56–1.46 (m, 4H), 0.97
(s, 9H), 0.95 (s, 9H); 13C NMR (125 MHz, CDCl3): δ = 158.6, 158.3, 156.7, 156.1, 150.6, 147.2,
145.9, 140.0, 132.5, 132.4, 130.4, 129.5, 128.7, 128.6, 126.6, 122.2, 45.84, 45.77, 31.2, 31.1,
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30.58, 30.5X (overlaps with 30.58), 29.31, 29.2X (overlaps with 29.31), 23.4; IR (neat): ῡmax
=
3031, 2953, 2865, 1609, 1492, 1383, 1364, 727, cm−1; HRMS (EI): m/z calculated for C33H40N4:
492.3253; found: 492.3236.
5,6-Bis-[4-(3,3-dimethyl-butyl)-phenyl]-3-(6-methyl-pyridin-2-yl)-[1,2,4]triazine
(20).
Prepared according to the general procedure discussed above with substrate 8: (5.0 mol %
catalyst, 10.0 mol % ligand, 2.10 equiv of (CH3)3C(CH2)2BF3K), RF = 0.59, 50%
EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0473 g, 89%; orange solid;
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mp 145.1–149.5 °C; H NMR (500 MHz, CDCl3): δ = 8.60 (d, J = 7.5 Hz, 1H), 8.01 (t, J = 8.2
Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 1H), 7.21 (d, J =
8.2 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 2.96 (s, 3H), 2.64–2.55 (m, 4H), 1.54–1.45 (m, 4H), 0.96
(s, 9H), 0.94 (s, 9H); 13C NMR (125 MHz, CDCl3): δ = 158.6, 158.4, 156.6, 156.1, 150.7, 147.2,
145.9, 139.8, 132.6, 132.5, 130.4, 129.5, 128.7, 128.6, 126.5, 122.2, 45.85, 45.77, 31.25, 31.15,
30.6, 30.5X (overlaps with 30.6), 29.3, 29.2X (overlaps with 29.3), 23.4, ;IR (CDCl3): ῡmax
=
3004, 2926, 2854, 1609, 1591, 1491, 1383, 1361, 827, 731 cm−1; HRMS (EI): m/z calculated for
C33H40N4: 492.3253; found: 492.3258.
5,6-Bis-(4-cyclopropyl-phenyl)-3-pyridin-2-yl-[1,2,4]triazine (21). Prepared according to the
general procedure discussed above with substrate 5: (10.0 mol % catalyst, 20.0 mol % ligand,
2.10 equiv of C3H5BF3K), EtOAc/hexanes (gradient); isolated yield 0.0260 g, 62% (average of
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two experiments: 46%, 78%); orange film; H NMR (500 MHz, CDCl3): δ = 9.11 (d, J = 5.0 Hz,
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1H), 8.86 (d, J = 8.2 Hz, 1H), 8.17 (t, J = 7.5 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.69 (brꢀt, J =
6.50 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 1.96–
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1.86 (m, 2H), 1.07–1.00 (m, 4H), 0.79–0.73 (m, 4H); C NMR (125 MHz, CDCl3): δ = 157.7,
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156.6, 156.0, 150.4, 148.4, 148.0, 146.8, 140.3, 132.1, 131.8, 130.4, 129.4, 126.2, 125.8, 125.7,
124.5, 20.5, 20.4X (overlaps with 20.5), 15.6, 15.5, 10.2, 10.0; IR (CDCl3): ῡmax = 3005, 1608,
1492, 1391, 1371, 903, 728 cm−1; HRMS (EI): m/z calculated for C26H22N4: 390.1844; found:
390.1847.
5,6-Bis-(4-cyclopropyl-phenyl)-3-(6-methyl-pyridin-2-yl)-[1,2,4]triazine
(22).
Prepared
according to the general procedure discussed above with substrate 7: (5.0 mol % catalyst, 10.0
mol % ligand, 2.10 equiv of C3H5BF3K), RF = 0.27, 50% EtOAc:hexanes; eluent,
EtOAc/hexanes (gradient); isolated yield 0.0379 g, 87%; orangeꢀyellow solid; mp 128.7–130.3
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°C; H NMR (500 MHz, CDCl3): δ = 8.58 (d, 8.2 Hz, 1H), 7.99 (t, J = 8.2 Hz, 1H), 7.79 (d, J =
8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 8.2 Hz, 2H), 7.05 (d,
J = 8.2 Hz, 2H), 2.94 (s, 3H), 1.95–1.86 (m, 2H), 1.05–1.00 (m, 4H), 0.78–0.72 (m, 4H); 13C
NMR (125 MHz, CDCl3): δ = 158.7, 158.5, 156.4, 155.8, 150.8, 148.0, 146.5, 139.5, 132.3,
132.2, 130.3, 129.4, 126.4, 125.7, 125.6, 122.0, 23.55, 23.5X (2 resonances overlap with 23.55),
15.6, 15.4, 10.2, 9.9; IR (CDCl3): ῡmax = 3004, 2926, 2854, 1609, 1591, 1491, 1383, 1361, 827,
731 cm−1; HRMS (EI): m/z calculated for C27H24N4: 404.2001; found: 404.1991.
5,6-Bis-biphenyl-4-yl-3-pyridin-2-yl-[1,2,4]triazine (23). Prepared according to the general
procedure discussed above with substrate 5: (5.0 mol % catalyst, 10.0 mol % ligand, 2.10 equiv
of C6H6BF3K), RF = 0.34, 100% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated
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yield 0.0298 g, 60%; orange solid; mp 126.9–131.3 °C; H NMR (500 MHz, CDCl3): δ = 8.95
(d, J = 5.0 Hz, 1H), 8.74 (dt, J = 7.5, 1.5 Hz, 1H), 7.96 (dt, J = 7.5, 1.5 Hz, 1H), 7.86–7.84 (m,
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2H), 7.81–7.78 (m 2H), 7.68–7.61 (m, 8H), 7.51–7.49 (m, 1H), 7.48–7.44 (m, 4H), 7.40–7.36
(m, 2H); 13C NMR (125 MHz, CDCl3): δ = 160.6, 156.1, 155.9, 152.9, 150.5, 143.6, 142.6,
140.1, 139.9, 137.1, 134.5, 134.2, 130.5, 130.0, 128.9, 128.8X (overlaps with 128.9), 128.0,
127.9, 127.34, 127.27, 127.13, 127.11, 125.4, 124.2; IR (CDCl3): ῡmax = 3029, 3001, 1606, 1583,
1483, 1388, 1370, 860, 768, 698 cm−1; HRMS (EI): m/z calculated for C32H22N4: 462.1844;
found: 462.1853.
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5,6-Bis-biphenyl-4-yl-3-(6-methyl-pyridin-2-yl)-[1,2,4]triazine (24). Prepared according to the
general procedure discussed above with substrate 7: (5.0 mol % catalyst, 10.0 mol % ligand,
2.10 equiv of C6H6BF3K), RF = 0.45, 100% EtOAc; eluent, EtOAc/hexanes (gradient); isolated
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yield 0.0211 g, 52%; orange solid; mp 131.7–138.2 °C; H NMR (500 MHz, CDCl3): δ = 8.50
(d, J = 7.5 Hz, 1H), 7.86 (brꢀd, J = 8.0 Hz, 2H), 7.83 (t, J = 7.5 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H),
7.68–7.61 (m, 8H), 7.46 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.40–7.35 (m, 3H), 2.78 (s,
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3H); C NMR (125 MHz, CDCl3): δ = 160.8, 159.5, 155.8, 155.5, 152.4, 143.6, 142.5, 140.1,
140.0, 137.2, 134.5, 134.3, 130.5, 130.0, 128.9, 128.8X (overlaps with 128.9), 128.0, 127.8,
127.3, 127.2, 127.12, 127.10, 125.2, 121.4, 24.9; IR (neat): ῡmax = 3031, 2963, 1606, 1485, 1383,
1360, 728, 696 cm−1; HRMS (EI): m/z calculated for C33H24N4: 476.2001; found: 476.2014.
5,6-Bis-(4-butyl-phenyl)-3-(6-butyl-pyridin-2-yl)-[1,2,4]triazine (25). Prepared according to
the general procedure discussed above with substrate 9: (15.0 mol % catalyst, 30.0 mol %
ligand, 3.15 equiv of CH3(CH2)3BF3K), RF = 0.86, 40 % EtOAc:hexanes; eluent, EtOAc/hexanes
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(gradient); isolated yield 0.0207 g, 47%; brownꢀorange gum; H NMR (600 MHz, CDCl3): δ =
8.43 (d, J = 7.8 Hz, 1H), 781 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz,
2H), 7.33 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 3.02–2.98 (m,
2H), 2.68–2.61 (m, 4H), 1.86–1.80 (m, 2H), 1.66–1.57 (m, 4H), 1.51–1.43 (m, 2H), 1.41–1.31
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(m, 4H), 0.98 (t, J = 7.5 Hz, 3H), 0.96–0.91 (m, 6H); C NMR (150 MHz, CDCl3): δ = 163.5,
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160.8, 156.0, 155.7, 152.6, 146.1, 144.7, 137.0, 133.2, 132.9, 129.9, 129.4, 128.6, 128.5, 124.2,
121.4, 38.3, 35.52, 35.48, 33.29, 33.21, 32.0, 22.6, 22.32, 22.26, 14.0, 13.92, 13.89; IR (neat):
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max = 3031, 2956, 2928, 2858, 1589, 1572, 1491, 1457, 1382, 1362, 832, 728 cm−1; HRMS (EI):
m/z calculated for C32H38N4: 478.3096; found: 478.3087.
5,6-Bis-[4-(3,3-dimethyl-butyl)-phenyl]-3-[6-(3,3-dimethyl-butyl)-pyridin-2-yl]-
[1,2,4]triazine (26). Prepared according to the general procedure discussed above with substrate
9: (20.0 mol % catalyst, 40.0 mol % ligand, 3.15 equiv of (CH3)3C(CH2)2BF3K), RF = 0.71, 30%
EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0220 g, 52%; orangeꢀyellow
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solid; mp 160.9–163.3 °C; H NMR (500 MHz, CDCl3): δ = 8.61 (d, J = 8.2 Hz, 1H), 8.08 (brꢀt,
J = 8.2 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.21
(d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 3.38–3.29 (brꢀs, 2H), 2.64–2.56 (m, 4H), 1.79–1.74
(m, 2H), 1.55–1.46 (m, 4H), 1.04 (s, 9H), 0.97 (s, 9H), 0.95 (s, 9H); 13C NMR (150 MHz,
CDCl3): δ = 163.5, 158.2, 156.6, 156.0, 150.4, 147.2, 145.9, 140.2, 132.6, 132.4, 130.59, 129.5,
128.65, 128.58, 125.7, 124.4, 45.84, 45.78, 44.0, 31.3, 31.2, 30.8, 30.7X (overlaps with 30.8),
30.6, 29.4, 29.32, 29.31; IR (CDCl3): ῡmax = 3036, 2951, 2864, 1610, 1587, 1490, 1466, 1391,
1362, 834 cm−1; HRMS (EI): m/z calculated for C38H50N4: 562.4035; found: 562.4044.
1,4-Bis-(3,3-dimethylbutyl)-Bis-[1,2,4]-triazinylpyridine (27). Prepared according to the
general procedure discussed above with substrate 10: (40.0 mol % catalyst, 80.0 mol % ligand,
4.20 equiv of (CH3)3C(CH2)2BF3K), RF = 0.57, 50 % EtOAc:hexanes; eluent, EtOAc/hexanes
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(gradient); isolated yield 0.0669 g, 71%; orange solid; mp 214.1ꢀ217.3 °C; H NMR (600 MHz,
CDCl3): δ = 8.87 (d, J = 7.8 Hz, 2H), 8.18 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 4H), 7.61 (d, J
= 8.0 Hz, 4H), 7.23 (d, J = 8.0 Hz, 4H), 7.21 (d, J = 8.0 Hz, 4H), 2.66–2.60 (m, 8H), 1.56–1.50
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(m, 8H), 0.98 (s, 18H), 0.97 (s, 18H); 13C NMR (150 MHz, CDCl3): δ = 160.2, 156.3, 156.0,
153.7, 149.9, 145.6, 138.2, 133.0, 132.8, 130.1, 129.4, 128.6, 128.5, 125.3, 45.89, 45.85, 31.3,
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=
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3032, 2953, 2865, 1609, 1493, 1365 cm−1; HRMS (EI): m/z calculated for C59H71N7: 877.5771;
found: 877.5806.
3-[6-(3,3-Dimethyl-butyl)-pyridin-2-yl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-
benzo[1,2,4]triazine (28). Prepared according to the general procedure discussed above: (10.0
mol % catalyst, 20.0 mol % ligand, 1.05 equiv of (CH3)3C(CH2)2BF3K), RF = 0.78, 50%
EtOAc:hexanes; eluent, MTBE/hexanes (gradient); isolated yield 0.0293 g, 78%; yellow gum;
1H NMR (600 MHz, CDCl3): δ = 8.21 (d, J = 7.8 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.29 (d, J =
7.8 Hz, 1H), 2.97–2.92 (m, 2H), 1.86 (s, 4H), 1.75–1.70 (m, 2H), 1.49 (s, 6H), 1.41 (s, 6H), 0.99
(s, 9H); 13C NMR (150 MHz, CDCl3): δ = 164.0, 163.9, 162.7, 161.2, 153.2, 136.9, 123.8, 120.9,
43.9, 37.1, 36.4, 34.1, 33.8, 33.3, 30.6, 29.7, 29.4, 29.2; IR (CDCl3): ῡmax = 3064, 2938, 2860,
1588, 1571, 1508, 1455, 1388, 1372. 1361, 819, 719 cm−1; HRMS (EI): m/z calculated for
C22H32N4: 352.2627; found: 352.2629.
3-(6-Phenyl-pyridin-2-yl)-5,6-di-p-tolyl-[1,2,4]triazine (29). Prepared according to the general
procedure discussed above: (5.0 mol % catalyst, 10.0 mol % ligand, 1.05 equiv of C6H6BF3K),
RF = 0.78, 50% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0240 g, 64%;
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brownꢀyellow solid; mp 210.3–213.0 °C; H NMR (500 MHz, CDCl3): δ = 8.63 (d, J = 7.5 Hz,
1H), 8.22 (d, J = 7.8 Hz, 2H), 8.14–8.07 (brꢀm, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 7.5
Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.54 (t, J = 7.0 Hz, 2H), 7.51–7.46 (m, 1H), 7.21 (d, J = 4.5
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Hz, 2H), 7.20 (d, J = 4.5 Hz, 2H), 2.40 (s, 3H), 2.39 (s, 3H); C NMR (150 MHz, CDCl3): δ =
160.5, 157.8, 156.1, 155.8, 152.9, 141.3, 140.0, 138.9, 137.8, 133.0, 132.87, 129.9, 129.8X
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(overlaps with 129.9), 129.4, 129.3, 129.2X (overlaps with 129.3), 128.7, 127.2, 122.4, 121.9,
21.5, 21.5; IR (neat): ῡmax = 3033, 2922, 2854, 1608, 1579, 1488, 1461, 1378, 822, 765, 698
cm−1; HRMS (EI): m/z calculated for C28H22N4: 414.1844; found: 414.1859.
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1,4-Bis-(3,3-dimethyl-butyl)-benzene (30). Prepared according to the general procedure
discussed above with 1,4ꢀdibromobenzene: (5.0 mol % catalyst, 10.0 mol % ligand, 2.10 equiv
of (CH3)3C(CH2)2BF3K), RF = 0.80, 10% EtOAc:hexanes; eluent, MTBE/hexanes (gradient);
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isolated yield 0.0258 g, 99%; white solid; mp 79.1–81.3 °C. H NMR (500 MHz, CDCl3): δ =
7.10 (s, 4H), 2.56–2.51 (m, 4H), 1.51–1.46 (m, 4H), 0.96 (s, 18 H); 13C NMR (125 MHz,
CDCl3): δ = 140.6, 128.2, 45.5, 30.7, 30.5, 29.3; IR (neat): ῡmax = 2954, 2866, 1514, 1467, 1365,
906, 730 cm−1; HRMS (EI): m/z calculated for C18H30: 246.2348; found: 246.2340.
1,2-Bis-(4-cyclopropyl-phenyl)-ethane-1,2-dione (31). Prepared according to the general
procedure discussed above with 4,4’ꢀdibromobenzil: (5.0 mol % catalyst, 10.0 mol % ligand,
2.10 equiv of C3H5BF3K), RF = 0.79, 30 % EtOAc:hexanes; eluent, MTBE/hexanes (gradient);
isolated yield 0.0169 g, 43%; light yellow solid; mp 85.0–91.9 °C; 1H NMR (500 MHz,
CDCl3): δ = 7.83 (d, J = 8.4 Hz, 4H), 7.13 (d, J = 8.4 Hz, 4H), 1.98–1.91 (m, 2H), 1.12–1.06 (m,
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4H), 0.82–0.77 (m, 4H); C NMR (125 MHz, CDCl36): δ = 194.4, 152.7, 130.5, 130.1, 125.8,
16.0, 10.8; IR (CDCl3): ῡmax = 3086, 3004, 2972, 1667, 1601, 1220, 1170 cm−1; HRMS (EI): m/z
calculated for C20H18O2: 290.1307; found: 290.1309.
1,2-Bis-[4-(3,3-dimethyl-butyl)-phenyl]-ethane-1,2-dione (32). Prepared according to the
general procedure discussed above with 4,4’ꢀdibromobenzil: (5.0 mol % catalyst, 10.0 mol %
ligand, 2.10 equiv of (CH3)3C(CH2)2BF3K), RF = 0.90, 30% EtOAc:hexanes; eluent,
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MTBE/hexanes (gradient); isolated yield 0.0401 g, 78%; offꢀwhite solid; mp 73.9–78.0 °C; H
NMR (500 MHz, CDCl3): δ = 7.87 (d, J = 8.2 Hz, 4H), 7.30 (d, J = 8.2 Hz, 4H), 2.66–2.61 (m,
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130.1, 129.0, 45.8, 31.7, 30.6, 29.2; IR (neat): ῡmax = 3031, 2954, 2866, 1671, 1604, 1217, 1172,
732 cm−1; HRMS (EI): m/z calculated for C26H34O2: 378.2559; found: 378.2556.
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6-Bromo-2-hydrazonamide (37). To an 8 mL reaction vial equipped with a magnetic stirring
bar at ambient temperature was charged 6ꢀpyridineꢀ2ꢀcarbonitrile (0.500 g, 2.73 mmol, 1.00
equiv). After dissolution in anhydrous THF (4.00 mL, 8.00 vol) the clear solution was cooled to
0 °C treated drop wise with hydrazine monohydrate (60ꢀ65% hydrazine) (1.28 mL, 16.39 mmol,
6.00 equiv) and continued for one hour. Afterwards, the homogeneous mixture was allowed to
gradually warm to ambient temperature and heated to 40 °C for 12 hours. Afterwards, the
heterogeneous mixture was filtered under vacuum at ambient temperature to afford a white filter
cake that was conditioned with 5 mL of 0 °C hexanes. The resulting solids were analyzed by 1H
NMR confirming consumption of all starting material and were telescoped directly to the
condensation step with the appropriate 1,2ꢀdicarbonyl without further purification. RF = 0.48,
25% EtOAc:hexanes; white solid; mp 214.1–221.5 °C; 1H NMR (600 MHz, DMSOꢀd6): δ = 7.89
(d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 5.61 (brꢀs, 2H), 5.50 (brꢀs,
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2H); C NMR (150 MHz, DMSOꢀd6): δ = 153.3, 141.4, 139.6, 139.3, 126.7, 118.3; IR (neat):
ῡmax = 3444, 3253, 3169, 1642, 1579, 1546, 1450, 1397, 1374, 799 cm−1; HRMS (EI): m/z
calculated for C6H7BrN4: 213.9854; found: 213.9853.
3-(6-Bromo-pyridin-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-benzo[1,2,4]triazine (38).
To an 8 mL reaction vial equipped with a magnetic stir bar at ambient temperature was added 37
(0.120 g, 0.56 mmol, 1.00 equiv) and 3,3,6,6ꢀtetramethylꢀcyclohexaneꢀ1,2ꢀdione (0.094 g, 0.56
mmol, 1.00 equiv) in anhydrous THF (1.10 mL, 0.5 M). The resulting yellowꢀcolored mixture
was heated to 66 °C for 12 hours. Afterwards the mixture was cooled to ambient temperature
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and adsorbed onto 5 g of normal phase SiO2. The adsorbed solids were purified using automated
flashꢀcolumn chromatography with standard UV detection at 254 nm on a 5 g normal phase
silica gel column and elution with an EtOAc:hexanes gradient mobile phase. The requisite
fractions were concentrated under reduced pressure at ambient temperature to afford the title
compound. RF = 0.74, 40% EtOAc:hexanes; EtOAc/hexanes (gradient); isolated yield 0.165 g,
85% (over two steps from 37); yellow solid; mp 119.5–123.7 °C; 1H NMR (600 MHz, CDCl3): δ
= 8.42 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 1.86 (brꢀs, 4H),
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1.49 (s, 6H), 1.41 (s, 6H); C NMR (150 MHz, CDCl3): δ = 164.5, 163.4; 159.8; 154.7; 142.7;
139.0; 129.6; 122.4; 37.3; 36.5; 33.7; 33.3; 29.7; 29.2; IR (neat): ῡmax = 3063, 2964, 2932, 1578,
1557, 1517, 1503, 1456, 1386, 809, 742 cm−1; HRMS (EI): m/z calculated for C16H19BrN4:
346.0793; found: 346.0792.
3-(6-Bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine (39). To an 8 mL reaction vial equipped
with a magnetic stir bar at ambient temperature was added 37 (0.120 g, 0.56 mmol, 1.00 equiv)
and benzil (0.117 g, 0.56 mmol, 1.00 equiv) in anhydrous THF (1.10 mL, 0.5 M). The resulting
yellowꢀcolored mixture was heated to 66 °C for 12 hours. Afterwards the mixture was cooled to
ambient temperature and adsorbed onto 5 g of normal phase SiO2. The adsorbed solids were
purified using automated flashꢀcolumn chromatography with standard UV detection at 254 nm
on a 5 g normal phase silica gel column and elution with an EtOAc:hexanes gradient mobile
phase. The requisite fractions were concentrated under reduced pressure at ambient temperature
to afford the title compound. RF = 0.71, 40% EtOAc:hexanes; EtOAc/hexanes (gradient);
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isolated yield 0.208 g, 96% (over two steps from 37); yellow solid; mp 161.3–166.4 °C; H
NMR (600 MHz, CDCl3): δ = 8.64 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.73–7.67 (m,
3H), 7.66–7.63 (m, 2H), 7.48–7.43 (m, 2H), 7.42–7.35 (m, 4H); 13C NMR (150 MHz, CDCl3): δ
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= 159.6, 156.6, 156.2, 153.9, 142.9, 139.2, 135.4, 130.9, 130.1, 130.0, 129.9, 129.5, 128.7,
128.6, 122.9; IR (neat): ῡmax = 3058, 1575, 1557, 1492, 1443, 1377, 1359, 768, 696 cm−1; HRMS
(EI): m/z calculated for C20H13BrN4: 388.0324; found: 388.0324.
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3-(6-Bromo-pyridin-2-yl)-5,6-di-p-tolyl-[1,2,4]triazine (40). To an 8 mL reaction vial
equipped with a magnetic stir bar at ambient temperature was added 37 (0.040 g, 0.18 mmol,
1.00 equiv) and 4,4’ꢀdimethylbenzil (0.045 g, 0.18 mmol, 1.00 equiv) in anhydrous THF (0.37
mL, 0.5 M). The resulting yellowꢀcolored mixture was heated to 66 °C for 12 hours. Afterwards
the mixture was cooled to ambient temperature and adsorbed onto 5 g of normal phase SiO2.
The adsorbed solids were purified using automated flashꢀcolumn chromatography with standard
UV detection at 254 nm on a 5 g normal phase silica gel column and elution with an
EtOAc:hexanes gradient mobile phase. The requisite fractions were concentrated under reduced
pressure at ambient temperature to afford the title compound. RF = 0.35, 25% EtOAc:hexanes;
EtOAc/hexanes (gradient); isolated yield 0.041 g, 52% (over two steps from 37); yellow solid;
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mp 133.2–136.0 °C; H NMR (600 MHz, CDCl3): δ = 8.61 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 7.8
Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.21 (d, J =
8.0 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 2.40 (s, 3H), 2.39 (s, 3H); 13C NMR (150 MHz, CDCl3): δ
= 159.3, 156.4, 155.9, 154.1, 142.8, 141.4, 140.1, 139.1, 132.6, 132.4, 129.9, 129.37, 129.3X
(two resonances overlap with 129.37), 129.30, 122.8, 21.49, 21.40; IR (CDCl3): ῡmax = 3037,
2921, 2863, 1608, 1573, 1556, 1487, 1373 cm−1; HRMS (EI): m/z calculated for C22H17BrN4:
416.0637; found: 416.0637.
5,6-Bis-(4-bromo-phenyl)-3-(6-bromo-pyridin-2-yl)-[1,2,4]triazine (41). To an 8 mL reaction
vial equipped with a magnetic stir bar at ambient temperature was added 37 (0.050 g, 0.23 mmol,
1.00 equiv) and 4,4’ꢀdibromobenzil (0.086 g, 0.23 mmol, 1.00 equiv) in anhydrous THF (0.47
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