Ruthenium(II)-Catalyzed C-H (Hetero)Arylation of Alkenylic 1,n-Diazines (n = 2, 3, and 4): Scope, Mechanism, and Application in Tandem Hydrogenations

Article abstract of DOI:10.1021/acs.joc.7b03024

A general ruthenium(II)-catalyzed methodology enabling the (hetero)arylation of alkenylic C-H bonds utilizing a series of synthetically appealing diazines as directing groups is presented. Despite the presence of additional nitrogen lone pairs remote from

Full text of DOI:10.1021/acs.joc.7b03024

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Article
Ruthenium(II)-Catalyzed C-H (Hetero)Arylation of Alkenylic 1,n-Diazines (n =
2, 3 and 4): Scope, Mechanism and Application in Tandem Hydrogenations
Rafael Gramage-Doria, Sylvain Achelle, Christian Bruneau,
Francoise Robin-le Guen, Vincent Dorcet, and Thierry Roisnel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03024 • Publication Date (Web): 10 Jan 2018
Downloaded from http://pubs.acs.org on January 10, 2018
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Page 1 of 21
The Journal of Organic Chemistry
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Ruthenium(II)-Catalyzed C-H (Hetero)Arylation of Alkenylic
1,n-Diazines (n = 2, 3 and 4): Scope, Mechanism and Applica-
tion in Tandem Hydrogenations
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Rafael Gramage-Doria,†* Sylvain Achelle,‡ Christian Bruneau,† Françoise Robin-le Guen,‡ Vincent
Dorcet,§ and Thierry Roisnel§
†Organometallics: Materials and Catalysis Laboratory, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS, Uni-
versité de Rennes 1, Avenue du Général Leclerc 263, 35042 Rennes, France.
‡Organometallics: Materials and Catalysis Laboratory, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS, Uni-
versité de Rennes 1, IUT de Lannion, rue Edouard Branly, BP 30219, 22302 Lannion, France.
§X-ray Diffraction Centre, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS, Université de Rennes 1, Avenue
du Général Leclerc 263, 35042 Rennes, France.
Supporting Information
Scheme 1. Differences Associated to Key Ruthenacycle
Intermediates in C(sp2)-H Bond Activation
ABSTRACT: A general ruthenium(II)-catalyzed method-
ology enabling the (hetero)arylation of alkenylic C-H
bonds utilizing a series of synthetically appealing diazines
as directing groups is presented. Despite the presence of
additional nitrogen lone pairs remote from the C-H bond
activation site, which could eventually poison the catalyst,
the reaction times are short (3 hours), thus being suitable
for selective double C-H bond arylation. Mixtures of E:Z
isomeric products were observed in some cases, which
were further hydrogenated in a tandem manner in the pres-
ence of the remaining ruthenium catalyst from the first
step; representing an alternative approach to more difficult
C(sp3)-H bond functionalization. According to mechanistic
studies, the unexpected E:Z product formation seems to
occur by thermal C=C bond isomerization after the reduc-
tive elimination step. KEYWORDS: diazines, C-H acti-
vation, cross-coupling, ruthenium, hydrogenation
X
H
N
N
X
X
H
N
N
X
[Ru]
[Ru]
Ru
Ru
vs.
H
H
R
R
I
(known)
II
(elusive)
X = N, O, CH; R = H, Alk, Ar
ruthenium6 or cobalt7 is highly attractive. For instance, the
ruthenium(II)-catalyzed (hetero)arylation of C(sp2)-H
bonds belonging to 1,2-disubstituted alkene groups
(Scheme 1, right) have been much less explored as com-
pared to C(sp2)-H bonds belonging to aromatic (or trisub-
stituted) alkene groups (Scheme 1, left).6 Since the bond
dissociation energies of such C(sp2)-H bonds are rather
similar (ΔGo = 112.9 kcal/mol for phenyl vs ΔGo = 110.7
kcal/mol for vinyl),8 the lower number of studies associated
to alkenylic C-H bonds compared to aromatic ones in ru-
thenium(II) catalysis might be attributed to the difficulty to
accommodate the key metallacycle intermediate II vs I
(Scheme 1).9 Presumably, a higher degree of flexibility
needs to be overcome for the formation of II as compared
to the formation of the more rigid I (Scheme 1). To cir-
cumvent this issue, very strong directing groups (i.e. pyri-
dine, oxazoline, imidazole) are traditionally installed at
close proximity of the alkene C-H bond expected to be
cross-coupled (Scheme 2, eq 1).10 Herein we report on
ruthenium(II) catalysis enabling the mono- and bis-
(hetero)arylation of alkenylic C(sp2)-H bonds in the pres-
ence of directing groups bearing also remote nitrogen lone
pairs such as 4-pyrimidine, 2-pyrazine and 3-pyridazine
(Scheme 2, eq 2). It is disclosed that (i) the presence of
additional nitrogen lone pairs in the directing group remote
n
INTRODUCTION
Transition metal-catalyzed C-H bond functionalization has
emerged in the last decades as a sustainable and efficient
approach to convert a myriad of low-functionalized starting
materials into high added value chemicals.1 Consequently,
the formation of new carbon-carbon bonds from C-H bonds
is a powerful approach since it reduces the number of syn-
thetic steps and costs devoted to the functionalization of the
starting materials, and it reduces the amount of chemical
waste as compared to classical cross-coupling reactions
such as Suzuki, Heck, Kumada, Stille, Negishi, and others.2
In particular, palladium,3 rhodium4 and iridium5 are the
metals of choice to perform such types of C-H bond func-
tionalization due to their high intrinsic catalytic reactivity.
However, expanding the catalytic performance to readily
available and more abundant transition metals such as
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Page 2 of 21
from the C-H bond activation site does not poison the ac-
where16 and the new compounds have been fully character-
ized (see SI).
1
2
3
4
5
6
7
8
tivity of the ruthenium catalyst in the (hetero)arylation of
alkenylic C-H bonds and (ii) the ruthenium-catalyzed C-H
bond cross-coupling reactions are compatible with subse-
quent C=C double bond hydrogenation leaving the het-
eroaromatic ring unreacted.
Scheme 3. Synthesis of 1
1a (R = p-SMe), 59%
1b (R = p-NMe2), 78%
1c (R = p-NPh2), 46%
1d (R = p-N(CH2)5), 67%
1e (R = p-OMe), 57%
1f (R = m-Me), 64%
1g (R = o-Me), 69%
CHO
N
N
N
N
N
N
Scheme 2. Ruthenium(II)-Catalyzed C(sp2)-H Arylation
of 1,2-Disubstituted Alkenes
i
+
R
R
R
9
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1h (R = p-SMe), 70%
1i (R = p-NMe2), 53%
1j (R = p-N(CH2)5), 49%
1k (R = p-OMe), 65%
1l (R = m-Me), 54%
1m (R = o-Me), 33%
CHO
X
H
N
R
X
H
N
R
ii
N
[Ru] cat.
"Ar"
Ar
X = N, O, CH
R = H, Alk, Ar
H
+
Known: (1)
N
R
Y
Y
1n (R = p-SMe), 29%
1o (R = p-NMe2), 41%
1p (R = p-N(CH2)5), 19%
1q (R = p-OMe), 36%
1r (R = m-Me), 37%
1s (R = o-Me), 30%
Z
X
N
Z
X
N
N
CHO
N
N
N
N
ii
[Ru] cat.
"Ar"
+
X = N; Y = Z = CH
Y = N; X = Z = CH
Z = N; X = Y = CH
This work: (2)
Ar
H
H
H
R
R
Ar
Ar
CHO
R
N
N
N
i
+
2
These types of diazines are relevant motifs in
fields as diverse as biology11 and materials science.12 For
example, trisubstituted alkene-containing diazine III dis-
plays antiuterotropic and antiestrogenic properties,13a IV
displays trichomonacidal and antiinflammatory proper-
ties,13b and V (with the alkene double bond hydrogenated
or not) is an inhibitor of the phosphodiesterase 4 (Figure
1).13c,d Their preparation, however, relies on long and tedi-
ous multi-step synthesis generating large amounts of chem-
ical waste.13 For this reason, providing new and more effi-
cient synthetic shortcuts is highly desired.14 Furthermore,
diazine-containing molecules can be hydrogenated to rele-
vant cyclic amines.15
1t (R = p-SMe), 59%
1u (R = p-NMe2), 77%
1v (R = p-N(CH2)5), 63%
1w (R = p-OMe), 90%
1x (R = m-Me), 56%
R
R
Reaction conditions:
i) Aliquat 336 (cat.), NaOH 5 M
ii) KOH, DMSO
Searching for the Optimal Reaction Conditions. The
best reaction conditions enabling the arylation of 1a lead-
ing to product 2a in the presence of two equivalents of 4-
bromothioanisole were searched (Table 1). Full conversion
of 1a was observed according to TLC and GC-MS analysis
after 3 hours by using 2.5 mol% of [RuCl2(p-cymene)]2 as
precatalyst, KOAc (5 mol%) and K2CO3 (3 equiv) in N-
methyl-2-pyrrolidone (NMP) under argon atmosphere at
NEt2
O
o
150 C. It is noteworthy that similar reaction conditions
were suitable for the arylation of arylpyridine and benzo-
N
N
N
1
ylpyridines.17 The H NMR spectrum of the crude reaction
N
N
N
O
mixture indicated the exclusive formation of a single prod-
OMe
uct (2a) that was recovered by column chromatography
III
IV
V
1
OMe
with an isolated yield of 94% (Table 1, entry 1). The H
NMR spectrum of product 2a indicated the disappearance
of the doublet centered at δ = 7.83 ppm corresponding to
the olefinic C-H bond expected to react, and the appearance
of the non-reacted alkenylic C-H bond as a singlet at δ =
6.99 ppm. The molecular structure of 2a was further deter-
mined by a single-crystal X-ray diffraction study (see SI).18
Further experiments indicated the need of all reagents for
the success of the reaction (Table 1, entries 2-4). The use of
stoichiometric amounts of KOAc provided similar results
(Table 1, entry 5) as the standard reaction conditions, indi-
cating that catalytic amounts of KOAc were enough to
reach such a high reactivity; likely due to the in situ for-
mation of catalytically active [Ru(OAc)2(p-cymene)] spe-
cies as it was evidenced when employing [Ru(OAc)2(p-
cymene)] as pre-catalyst (Table 1, entry 6).19 Other potassi-
um carboxylate salts such as pivalate and mesylate were
found as efficient as acetate (Table 1, entries 7-8). PPh3 as
Figure 1. Selected examples of pharmaceutically-relevant alkene-
and alkane-containing diazines.
n
RESULTS AND DISCUSSION
Synthesis of the Starting Materials. The 1,2-trans-
disubstituted alkene moieties bearing 4-pyrimidine (1a-1g),
2-pyrazine (1h-1m) and 3-pyridazine (1n-1s) as directing
groups were prepared by base-mediated condensation of
the functionalized benzaldehydes with the corresponding
methyldiazines, respectively (Scheme 3). A similar proce-
dure applied to 4,6-dimethylpyrimidine and using 2 equiva-
lents of the functionalized benzaldehydes enabled the syn-
thesis of the corresponding 4,6-bis((E)-styryl)pyrimidines
1t-1x. Some of these compounds have been reported else-
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The Journal of Organic Chemistry
additive did not change the outcome of the reaction, how- 96% and 95% yield, respectively, both with a 96:4 isomeric
1
2
3
4
5
6
7
8
ever a yield of only 46% of 2a was obtained because the
chromatographic separation became troublesome (Table 1,
entry 9). The presence of air and the decrease of the reac-
tion temperature were detrimental to the reaction (Table 1,
entries 10-12).
ratio. Esters and ketones were tolerated under the studied
reaction conditions as exemplified in the synthesis of 3i and
3j in 95% and 96% yield, respectively. In these cases the
Table 2. Scope of the Alkenylic C-H Bond Arylationa,b
Y
Y
Z
X
N
Z
X
N
R2
Table 1. Optimization of the Reaction Conditionsa
[RuCl2(p-cymene)]2 (2.5 mol%)
R2
KOAc (5 mol%)
H
9
N
N
+
H
H
K2CO3, NMP, 150 oC, 3 h
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60
N
SMe
N
SMe
[RuCl2(p-cymene)]2 (2.5 mol%)
KOAc (5 mol%)
Br
(2 eq.)
H
+
H
H
R1
R1
K2CO3, NMP, 150 oC, 3 h
1a-e, 1h-k, 1n-q
2-4
Br
4-alkenylpyrimidines (2)
(2 eq.)
N
SMe
SMe
N
N
N
R
1a
2a (X-ray)
N
NMe2
N
NPh2
H
Entry
1
Deviation from standard conditions
none
2a (%)b
>99 (94)c
0
H
H
2
without [RuCl2(p-cymene)]2
without KOAc
R
3
35
NMe2
NPh2
2d (R = N(CH2)5), 93%
2e (R = OMe), 95%
2b, 96%
2-alkenylpyrazines (3)
2c, 89%
4
without K2CO3
0
5
100 mol% KOAc
>99
N
N
H
N
H
CF3
6
with [Ru(OAc)2(p-cymene)]d
KOPiv instead of KOAc
MesCO2K instead of KOAc
with 10 mol% PPh3
>99
R2
N
N
N
N
7
>99
CF3
8
>99
>99 (46)c
9
10
11
12
Air instead of Argon
100 oC instead of 150 oC
120 oC instead of 150 oC
0
R1
SMe
SMe
traces
traces
3a (R1 = R2 = SMe), 97%
3b (R1 = R2 = NMe2), 94% (X-ray)
3c (R1 = R2 = N(CH2)5), 85%
3m, 77% (75:25)
3n, 68% (88:12)
a1a (0.25 mmol), 4-bromothioanisole (0.50 mmol), [RuCl2(p-cymene)]2
(2.5 mol%), KOAc (5 mol%), K2CO3 (0.75 mmol), NMP (1 mL, 0.25 M)
at 150 C for 3 h under Argon atmosphere. Yield estimated by GC-MS
and 1H NMR spectroscopy. cIsolated yields. d5 mol% of [Ru(OAc)2(p-
cymene)] was used instead of 2.5 mol% of [RuCl2(p-cymene)]2 and 5
mol% of KOAc.
N
3d (R1 = R2 = OMe), 93%
N
3e (R1 = NMe2, R2 = H), 94% (X-ray)
3f (R1 = NMe2, R2 = tBu), 97% (86:14)
3g (R1 = SMe, R2 = Ph), 96% (96:4)
3h (R1 = SMe, R2 = CH=CH2), 95% (96:4)
3i (R1 = NMe2, R2 = CO2Me), 95% (76:24)
3j (R1 = NMe2, R2 = C(O)Me), 96% (75:25)
3k (R1 = NMe2, R2 = CN), 91% (85:15)
3l (R1 = NMe2, R2 = F), 85% (85:15)
o
b
S
SMe
Substrate Scope. The methodology was applied to other
4-alkenylpyrimidines leading to the corresponding arylated
products 2 in high yields (Table 2). The bis-aryl symmet-
rical compounds containing para-substituted linear aliphat-
ic amines such as NMe2 (2b), aromatic amines such as
NPh2 (2c) and cyclic aliphatic amines such as N(CH2)5 (2d)
were obtained in 96%, 89% and 93% yield, respectively.
The methodology was found to be compatible with para-
OMe groups providing compound 2e in 96% isolated yield.
2-Alkenylpyrazines 3 were also obtained under the stand-
ard reaction conditions (Table 2). The bis-aryl symmetrical
para-substituted compounds 3a-3d were obtained in 97%
(SMe), 94% (NMe2), 85% (N(CH2)5) and 93% (OMe)
isolated yields, respectively. When bromobenzene was
used as coupling partner, 3e was obtained in 94% yield as a
single isomer. Other non-symmetrical di-aryl products were
also formed but unexpectedly as mixtures of E:Z isomers at
some extents (Table 2). As such, para-substituted tert-butyl
derivative 3f was obtained in 97% yield with a 86:14 iso-
meric ratio (non-isomerized:isomerized product ratio).
Biphenyl 3g and styrene 3h derivatives were obtained in
3o, 58% (95:5)
N
N
H
N
N
H
NMe2
NMe2
3q, 95% (93:7)
3p, 92% (93:7)
3-alkenylpyridazines (4)
4a (R1 = SMe, R2 = p-SMe), 94%
N
N
R2
4b (R1 = NMe2, R2 = p-NMe2), 91% (X-ray)
4c (R1 =N(CH2)5, R2 = p-N(CH2)5), 88%
4d (R1 = OMe, R2 = p-OMe), 95%
4e (R1 = NMe2, R2 = H), 94% (93:7) (X-ray)
4f (R1 = SMe, R2 = m-Me), 86% (57:43)
4g (R1 = SMe, R2 = p-Me), 93% (68:32)
4h (R1 = N(CH2)5, R2 = p-OMe), 71% (58:42)
4i (R1 = NMe2, R2 = 6-methoxynaphthalen-2-yl), 84% (56:44)
H
R1
aAs Table 1, entry 1. bIsolated yields. Isomeric ratio (non-
isomerized:isomerized product ratio) determined by H NMR spectrosco-
py analysis are displayed in brackets.
1
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isomeric ratio was ca. 75:25. The para-CN-containing isomeric ratios. 4h was obtained in 71% yield and an iso-
1
2
3
4
5
6
7
8
product 3k was obtained in 91% yield and 85:15 isomeric
ratio. The same ratio was observed with para-F-containing
3l (85% yield). Substituents with different Hammet sigma
constants (i.e. σp = +0.66 for CN and σp = +0.06 for F)
provided the same isomeric ratio (85:15), thus making
difficult to correlate the isomeric ratio with the electronic
properties of the different substituents. Trifluoromethyl
derivative 3m was prepared in 77% yield and an isomeric
ratio of 75:25. Heteroaromatic coupling partners were also
successfully cross-coupled via the ruthenium(II)-catalyzed
alkenylic C-H bond functionalization (Table 2). For in-
stance, 4-pyridine substituted and 3-thiophene substituted
pyrazines 3n and 3o were isolated in 68% and 58% yield,
respectively, with an isomeric ratio of 88:12 and 95:5,
respectively. Ortho- and meta-methyl substituted deriva-
tives 3p and 3q were obtained in 92% and 95% yield, re-
spectively, with a 93:7 isomeric ratio.
meric ratio of 58:42. Methoxynaphthalene-containing de-
rivative 4i was obtained in 84% yield (56:44 isomeric ra-
tio). Additionally, the molecular structures of pyrazine
derivatives 3b and 3e; and pyridazines 4b and 4e were
determined by single crystal X-ray diffraction studies (see
SI).18 Unfortunately, the starting materials were fully re-
covered
when
using
4-bromonitrobenzene,
4-
bromobenzaldehyde and bromoferrocene as coupling part-
ners.17b The catalytic system was found also unsuitable for
methylation and benzylation with methyl iodide and ben-
zylbromide as coupling partners, respectively. To further
evaluate the potential of the ruthenium(II)-catalyzed aryla-
tion, the catalyst loading was decreased for the formation
of product 2e. With 5 times less ruthenium complex (0.5
mol% of [RuCl2(p-cymene)]2) full conversion was retained
(TON = 100 per Ru-center) and with 0.01 mol% of
9
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17
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42
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45
46
47
48
49
50
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53
54
55
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57
58
59
60
[RuCl2(p-cymene)]2 (which corresponds to
a
sub-
strate:catalyst ratio of 5000:1) a TON of 500 was observed
but with a low 10% conversion.
During the synthesis of 3o small amounts of the
bis-thiophene derivative 3oo were identified by GC-MS
analysis. Furthermore, performing the ruthenium(II)-
catalyzed reaction with 1h as substrate in the presence of 5
equivalents of 3-bromothiophene, 6 equivalents of K2CO3,
10 mol% of KOAc and 5 mol% of [RuCl2(p-cymene)]2 as
precatalyst during 12 h afforded this bis-thiophene 3oo in
89% isolated yield (Scheme 4).20 The arylation at the C2
position of the firstly introduced thiophene moiety was
inferred by multidimensional NMR spectroscopy analysis
(see SI). It was also found that 3o did not afford 3oo with-
out the presence of the ruthenium catalyst. Further work
will have to be performed to verify whether the reaction
proceeded via an unprecedented seven-membered ruthena-
cycle intermediate (Scheme 4) or if other mechanisms
(electrophilic aromatic substitution, concerted metallation
deprotonation or Heck-type) were also operating at some
extent.19,21
Table 3. Scope with Bulky Coupling Partnersa,b
Y
Y
Z
X
N
Z
X
N
R2
As Table 1, entry 1
+
H
H
H
R2
Br
R1
(2 eq.)
R1
1f-g, 1l-m,1r-s
2-4
N
N
N
N
N
N
N
N
2f, 95%
2g, 88%
2i, 58%c
2h, 95% (93:7)
Scheme 4. In situ Alkenylic C-H Bond Functionalization
and C2 Hetero(Arylation) on Thiophene
N
N
N
N
N
N
N
N
N
N
N
[RuCl2(p-cymene)]2
(5 mol%)
[Ru]
S
N
N
7
N
S
KOAc (10 mol%)
S
H
H
3r, 97%
3s, 94%
3u, 47%c
3t, 97% (94:6)
K2CO3 (6 eq.), NMP (2 mL)
150 oC, 12 h
S
N
N
N
N
N
N
S
N
N
(5 eq.)
SMe
SMe
SMe
1h
(0.25 mmol)
3oo, 89%
plausible
intermediate
Br
Pyridazines (4) featuring the other diazine direct-
4m, 44%c
ing group of the series, were found to behave in a similar
manner (Table 2) as pyrimidines (2) and pyrazines (3). For
instance, the symmetrical products containing p-SMe (4a),
p-NMe2 (4b), p-N(CH2)5 (4c) and p-OMe (4d) were ob-
tained in 88-95% isolated yields. The ruthenium(II)-
catalyzed alkenylic C-H bond arylation was also compati-
ble (ca. 90% yield) with phenyl derivatives (4e) and meta-
and para-tolyl derivatives 4f and 4g, although with variable
4j, 96%
4k, 86%
4l, 92%
aAs Table 1, entry 1. bIsolated yields. cAfter 18 h. Isomeric ratio (non-
isomerized:isomerized product ratio) determined by H NMR spectrosco-
py analysis are displayed in brackets.
1
The ruthenium(II)-catalyzed C-H bond arylation
was applied for more challenging both bulky substrates and
bulky aryl bromides (Table 3). The three types of diazines
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The Journal of Organic Chemistry
bearing methyl substituents at meta position reacted in an tion of the postulated ruthenacycle Ru-1 was also attempt-
1
efficient manner (3 h) in the presence of the in situ generat-
ed ruthenium catalyst with 3-bromotoluene and 2-
bromotoluene, respectively, leading to 2f, 2g, 3r, 3s, 4j and
4k in 95%, 88%, 97%, 94%, 96% and 86% yield as single
isomers, respectively. Bulky diazines containing a methyl
substituent at ortho position reacted under standard reaction
conditions with less bulky 1-bromo-4-tert-butylbenzene
leading to 2h and 3t in 95% and 97% yield, respectively,
containing <8% of the isomerized product. A pyridazine
derivative containing a methyl substituent in ortho position
of the phenyl ring led to 4l after reaction with 3-
bromotoluene in 92% isolated yield as a single isomer. On
the other hand, the three types of diazines bearing methyl
substituents at ortho position reacted with bulky 2-
bromotoluene leading to 2i, 3u, and 4m in moderate yields
of 58%, 47% and 44%, respectively, after long reaction
times of 18 hours. Although 1 was fully converted under
these reaction conditions, other unidentified byproducts
were formed at the end of the reactions during the synthesis
of 2i, 3u and 4m, highlighting that the catalysis is sensitive
to the simultaneous bulkiness of both coupling partners. In
all these examples of bulky coupling partners, nearly no
isomerization was observed in the resulting products.
ed starting from substrate 1e (Figure 2b). Applying stand-
ard reaction conditions for the synthesis of ruthenacycles
with aromatic C(sp2)-H bonds (KOAc, LiCl, MeOH, 20 oC,
24-72 h)9 failed leading to mixture of species containing
free substrate, substrate-coordinated ruthenium species and
ruthenacycle species (see SI). However, when leaving the
reaction mixture for a very long time (three weeks), and
besides formation of variable amounts of insoluble species,
a ruthenium complex Ru-1 was formed. The molecular
structure of Ru-1, which could not be isolated due to its
lack of stability, was inferred from HRMS analysis whose
spectrum displayed strong peaks having exactly the isotop-
ic profile expected for Ru-1 (see SI). Attempts to perform
the synthesis of Ru-1 by increasing the temperature to 60
oC for 12 h led to decomposition of the starting material
and recovery of the unexpected ruthenium complex Ru-2
(Figure 2b). The molecular structure of Ru-2 was fully
characterized by multidimensional NMR analysis, includ-
ing DOSY and molecular modeling (see SI).26 So far, we
cannot conclude whether carbon monoxide in Ru-2 origi-
nated from dehydrogenation of methanol or from decompo-
sition of acetate anions. We also detected formation of free
p-cymene when performing attempts to identify ruthena-
cycle intermediates based on 1 at higher temperatures (see
SI). In addition, the catalysis was also evaluated in the
formation of 4d starting from diazine 1q and other aryl
halides (Figure 2c). The catalytic reaction was found equal-
ly efficient with 4-iodoanisole, whereas 4-chloroanisole
provided the expected product in a low yield of 12% (Fig-
ure 2c). Such findings might indicate that the rate-limiting
step could be the oxidative addition of the aryl halide on
ruthenium(II) species going to ruthenium (IV) species.
Performing the catalytic reaction in the presence of a radi-
cal scavenger, namely 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO), provided the expected products in low yields
depending on the equivalents of TEMPO used (Figure 2d),
which makes difficult to completely rule out a SET-type
(SET = single electron transfer) aryl-bromide cleavage
process before the reductive elimination step.10d,27 We also
noted that the outcome of the catalytic reaction was unaf-
fected by the presence of mercury,28 thus suggesting that
the catalytic system operated under a homogeneous regime
(see SI). The fact that mixtures of isomerized products
were obtained was also investigated. We noticed that sub-
strates 1 did not undergo isomerization under the reaction
conditions and that the trans-configuration was retained at
2
3
4
5
6
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
It is relevant to mention that 4-methylpyrimidine
(Scheme 5, eq 1) and 2-methylpyrazine (Scheme 5, eq 2),
respectively, did not react with benzophenone applying the
classical reactions conditions reported in Scheme 3. Conse-
quently, the presented ruthenium(II)-catalyzed methodolo-
gy represents an efficient entry to access trisubstituted
alkenes containing this type of diazines as heteroyclic mo-
tifs. The step- and atom-economy in this method is obvious
as compared to classical reactions that also lead to trisubsti-
tuted alkene motifs at the expenses of large amounts of
chemical waste such as lithium salts (Peterson olefina-
tion),22 titanium and zinc salts (McMurry reaction)23 or
phosphonium salts (Wittig reaction).24
Scheme 5. Attempts to Synthesize Molecules Similar to
2 and 3 via Classical Procedures
O
Aliquat 336 (cat.)
NaOH 5 M
Ph
Ph
N
N
N
N
N
N
+
+
(1)
(2)
Ph
Ph
Ph
Ph
Ph
Ph
O
KOH, DMSO
N
N
o
150 C over at least 24 h. The isomerization compound 2j
was followed on time with and without the presence of the
ruthenium catalyst under the standard reaction conditions
(Figure 2e). The isomerization took place regardless of the
presence of the ruthenium catalyst, although in the presence
of the ruthenium catalyst the thermodynamic equilibrium
was reached faster (ca. 12 h) than in the absence of the
ruthenium catalyst (ca. 15 h). Using toluene as solvent and
potassium mesylate as additive provided similar results
highlighting that the nature of the solvent or the potassium
salt had little impact on the isomerization process. Conse-
quently, the product isomerization is likely to be caused by
Mechanistic studies. To gain a better understanding of
the reaction mechanism operating under the studied reac-
tion conditions, deuteration experiments were performed
using argon-bubbled NMP:D2O (v/v 9:1) as a solvent mix-
ture with compounds bearing the three different diazine
directing groups (Figure 2a). In all cases, >99% deuteration
occurred in the alkenylic C-H bond that is functionalized in
the catalytic experiments (Figure 2a). The deuteration was
fast (3 h) regardless of the presence of base (K2CO3). This
observation is in line with a reversible 5-membered ruthe-
nacycle formation that cleaves the C-H bond.25 The isola-
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Page 6 of 21
thermal flip of the sterically-encumbered C=C double bond
Considering the above-stated findings and previ-
within the final product.29
ous reports10,19,25,27 a mechanism is proposed in Scheme 6,
which involves first, formation of ruthenium-carboxylate
species as the active catalyst that binds to the substrate via
N-coordination. Carboxylate and carbonate anions might
facilitate deprotonation and reversible ruthenacycle for-
mation. Oxidative addition on the aryl halide, probably via
SET, followed by reductive elimination leads to the product
that isomerized until reaching the thermodynamic equilib-
ria.
1
2
3
4
5
6
7
8
Figure 2. Mechanistic Investigations
Y
Y
>99% D
X
N
Z
Z
X
N
[RuCl2(p-cymene)]2
(2.5 mol%)
KOAc (5 mol%)
H
H/D
+
(a)
D2O
H
H
with or without K2CO3
NMP, 150 oC, 3 h
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
Scheme 6. Postulated Mechanism
R
R
1e, 1k, 1o
1e-d, 1k-d, 1o-d
X
Ar1
Ar2
N
Y
Z
N
[RuCl2(p-cymene)]2 (0.5 eq)
KOAc (4 eq)
N
H
Ru
[RuCl2(p-cymene)]2
LiCl (10 eq)
H
Cl
MeOH, 20 oC, 3 weeks
2 KOAc
isomerization
N
N
X
X
2 KCl
Y
Z
N
Ar2
Ar1
Y
Z
N
H
Ru-1
not isolated,
OMe
H
(b)
Ar1
H
[Ru]
O
H
H
AcO
observed by HRMS
O
OAc-
OAc-
reductive
elimination
directing
group
binding
[RuCl2(p-cymene)]2 (0.5 eq)
KOAc (4 eq)
OMe
OAc
1e
Ru
LiCl (10 eq)
X
[Ru]
H
Ar2
[Ru]
H
CO
Y
Z
N
X
X = N; Y = Z = CH
Y = N; X = Z = CH
Z = N; X = Y = CH
Y
Z
N
MeOH, 60 oC, 12 h
OAc
Ar1
Ar1
H
H
Ru-2
OMe
ruthenacycle
formation
oxidative
addition
OAc-
not isolated,
observed by NMR
2-
K+, Br-, CO3
X
[Ru]
Y
Z
N
N
N
OAc
Ar1
N
N
OMe
OMe
HOAc
K2CO3
Ar2Br + K2CO3
As Table 1, entry 1
H
H
+
(c)
H
H
X = I, >99% yield
X = Cl, 12% yield
KHCO3 + KOAc
X
Extension and Application of the Methodology. The
efficiency of the catalytic system was further evaluated for
pyrimidines appended with two alkene groups, namely 4,6-
dialkenylpyrimidines 1t-x (Scheme 7). In this case, the
ruthenium catalyst loading and the reaction time were dou-
bled as compared to the standard reaction conditions; and
the concentration was reduced by an order of two to ensure
a proper solubility of the reagents into the reaction mixture.
Under these reaction conditions, bis-arylation proceeded
selectively leading to 5a-5e in good yields (61 to 84%
isolated yields). The reaction was found to be compatible
with thioethers (5a), linear aliphatic amines (5b), cyclic
aliphatic amines (5c), ethers (5d) and alkyl groups, includ-
ing substituents at meta position (5e). The molecular struc-
ture of 5a was also confirmed by X-ray crystallographic
analysis (see SI).18 Unfortunately, when using aryl bro-
mides that would lead to non-symmetrical products, mix-
tures of all possible isomers were obtained.
1q
OMe 4d
OMe
X
Y
X
Y
R
R
N
N
H
As Table 1, entry 1
n eq. of TEMPO
+
(d)
H
H
Br
1c
1k
2c, 36% (n = 1)
3d, 9% (n = 2)
R
H
R
N
N
N
N
As Table 1, entry 1
(e)
H
NMe2
NMe2
2j (65:35)
2j (40:60)
1
0.8
0.6
0.4
0.2
0
1
E
Z
E
Z
with Ru cat.
without Ru cat.
0.8
0.6
0.4
0.2
0
0
5
10
Time (h)
15
20
0
5
10
15
20
Time (h)
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We further extended such approach for the tandem
Scheme 7. Ruthenium(II)-Catalyzed Double Arylation
of Alkenylic C(sp2)-H Bonds
double C-H bond arylation and double hydrogenation as
exemplified in the synthesis of 7 in 67% yield (Scheme 8).
Such approach overcomes the issue of obtaining mixture of
E:Z isomers during the C-H bond functionalization and it
actually constitutes an alternative pathway to directly per-
forming a more difficult ruthenium-catalyzed C(sp3)-H
functionalization.30 Additionally, attempting an intramo-
lecular oxidative C-C coupling reaction from 2b in the
presence of FeCl3 (3.5 equiv) further evidenced the unique
reactivity of such compounds (Scheme 9).31 The expected
product 9 was not formed and the product resulting from a
Friedel-Crafts transformation was observed (8). The mo-
lecular structure of 8 was further confirmed by X-ray crys-
tallographic analysis (see SI).18 This observation indicates
that the products resulting from the catalytic experiments
have different reactivity when compared to all-carbon pol-
yaromatic compounds.32 The chloro-containing compound
8 might be used for the further design of new aromatic or
conjugated species containing unique diazine moieties.
1
2
R
R
3
4
5
6
7
8
9
R
H
N
N
H
R
[RuCl2(p-cymene)]2 (5 mol%)
KOAc (10 mol%)
H
H
H
N
N
+
K2CO3 (6 eq.), NMP (2 mL)
150 oC, 6 h
Br
(4 eq.)
H
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
R
R
R
1t-x
(0.25 mmol)
5a (R = p-SMe), 75% (X-ray)
5b (R = p-NMe2), 69%
5c (R = p-N(CH2)5), 61%
5d (R = p-OMe), 78%
5e (R = m-Me), 84%
Nevertheless, advantage was taken from the unex-
pected mixture of isomeric products in order to obtain a
sole final product by performing a tandem selective alkene
hydrogenation with molecular hydrogen in the presence of
the remaining ruthenium species as catalyst (Table 4).17b In
this way, 4-alkylpyrimidines 6a and 6b were synthesized in
87% and 75% yields, respectively. The racemic mixture of
the hydrogenated products was further confirmed by an X-
ray diffraction study on 6b that showed the presence of
both enantiomers (see SI).18 2-Alkylpyrazine 6c and 3-
alkylpyridazine 6d were obtained in 71% and 52% yields,
respectively. The three diazine directing groups were found
to be compatible with the reaction conditions employed in
the hydrogenation step and different functional groups (Ph,
Me, SMe, NMe2, OMe, N(CH2)5) were tolerated. Replacing
NMP by toluene as solvent did not change the outcome of
the C-H bond functionalization step, however it poisoned
the hydrogenation step, indicating that polar solvents are
more suitable for this type of tandem reactions.17b
Scheme 8. Tandem Double Alkenylic C-H Bond Aryla-
tion and Hydrogenation
Me2N
Me2N
1) [RuCl2(p-cymene)]2 (5 mol%)
KOAc (10 mol%)
H
N
N
H
1-Bromo-4-tert-butylbenzene (4 eq.)
K2CO3 (6 eq.), NMP (2 mL)
150 oC, 6 h
H
H
N
N
2) H2 (1 bar), 150 oC, 12 h
Me2N
Me2N
1u
7, 67%
Scheme 9. Friedel-Crafts Reaction under Oxidative C-
C Coupling Reaction Conditions
Table 4. Tandem C-H Bond Arylation/Hydrogenationa,b
N
N
N
Y
Y
N
NMe2
N
H
NMe2
N
H
NMe2
FeCl3
Z
X
N
Z
X
N
H
R2
R2
Cl
1) As Table 1, entry 1
CH2Cl2, rt
H
H
H
+
H
2) H2 (1 bar), 150 oC, 12 h
Br
NMe2
8, 45% (X-ray)
NMe2
9, not formed
NMe2
2b
(2 eq.)
R1
R1
1a-b, 1h, 1p
6
n
CONCLUSION
N
N
N
N
OMe
N
N
In summary, we have developed a ruthenium(II)-catalyzed
methodology enabling the (hetero)arylation of 1,2-di-
substituted alkenylic C(sp2)-H bonds with synthetically
useful diazine directing groups such as pyrimidines, pyra-
zines and pyridazines. Despite the presence of additional
nitrogen lone pairs remote from the C-H bond activation
site, the catalytic reactions were fast and efficient affording
the desired products in high yields. The presented rutheni-
um-catalyzed protocol represents a new pathway to access
trisubstituted heteroaromatic-containing alkenes, otherwise
impossible (or very difficult) to obtain by traditional syn-
N(CH2)5
6d, 52%
SMe
R1
6a (R1 = SMe), 87%
6b (R1 = NMe2), 75% (X-ray)
6c, 71%
aFirst step as Table 1, entry 1 and second step by introducing a balloon
filled with molecular hydrogen. bIsolated yields.
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thetic routes. Mechanistic investigations of the ruthenium CH2Cl2 (3 × 20 mL). The combined organic extract was
1
2
3
4
5
6
7
8
catalysis indicated that the key ruthenacycle intermediate of
type II (Scheme 1 and Figure 2b) is kinetically difficult to
trap, which in turn was probably responsible for the high
reactivity thereby observed. Such observation strongly
contrasts with the ease of the formation of ruthenacycles of
type I (Scheme 1) based on trisubstituted olefinic C-H
bonds.9 The mixture of isomeric products observed in some
catalytic experiments is a consequence of the high tempera-
ture used. The ruthenium(II)-based catalytic system was
found to be applicable for double arylation and for the
tandem C-H bond arylations/hydrogenations using the
same ruthenium complex for both transformations. This
route constitutes a masked approach for the functionaliza-
tion of C(sp3)-H bonds and it highlights the suitability of
ruthenium species as catalysts for tandem reactions includ-
ing C-H bond functionalizations.10b,17b The resulting prod-
ucts obtained in the catalytic experiments were found to
behave differently from what would be expected in intra-
molecular oxidative C-C coupling reactions providing the
Friedel-Crafts-like product.
dried with MgSO4 and the solvents evaporated. The crude
product was purified by silica gel column chromatography
with mixtures of petroleum ether and ethyl acetate as the
eluent. Substrates 1a-1d16a and 1e16b,16c have been reported
and characterized elsewhere.
(E)-4-(3-Methylstyryl)pyrimidine (1f). Purified by silica gel
column chromatography (petroleum ether/AcOEt, 70:30,
v/v) as a pale yellow oil that crystallize slowly (126 mg,
64% yield). Mp 61-62°C. 1H NMR (300.1 MHz, CDCl3): δ
= 9.15 (s, 1 H), 8.62 (d, 1 H, J = 5.4 Hz), 7.83 (d, 1 H, J =
15.9 Hz), 7.38-7.36 (m, 2 H), 7.28-7.23 (m, 2 H), 7.16-7.13
(m, 1 H), 7.00 (d, 1 H, J = 15.9 Hz), 2.35 (s, 3 H) ppm.
13C{1H} NMR (JMOD, 75 MHz, CDCl3): δ = 162.3, 158.8,
157.3, 138.5, 137.6, 135.5, 130.4, 128.8, 128.3, 125.3,
124.9, 118.6, 21.4 ppm. HRMS m/z [M+H]+ Calculated for
C13H13N2: 197.10732; found 197.1073 (0 ppm).
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
(E)-4-(2-Methylstyryl)pyrimidine (1g). Purified by silica
gel column chromatography (petroleum ether/AcOEt,
1
70:30, v/v) as a colourless oil (136 mg, 69% yield). H
NMR (300 MHz, CDCl3): δ = 9.18 (s, 1 H), 8.67 (d, 1 H, J
= 5.4 Hz), 8.19 (d, 1 H, J = 15.9 Hz), 7.67-7.64 (m, 1 H),
7.30-7.23 (m, 4 H), 6.97 (d, 1 H, J = 15.9 Hz), 2.50 (s, 3 H)
ppm. 13C{1H} NMR (JMOD, 75 MHz, CDCl3): δ = 162.3,
158.9, 157.3, 137.2, 135.2, 134.6, 130.8, 129.3, 126.7,
126.3, 126.0, 118.8, 19.9 ppm. HRMS m/z [M+H]+ Calcu-
lated for C13H13N2: 197.10732; found 197.1072 (1 ppm).
n
EXPERIMENTAL SECTION
General Methods. All reagents were obtained from com-
mercial sources and used as supplied. All reactions were
carried out in flame-dried glassware under argon atmos-
phere unless otherwise noted. Catalytic experiments were
performed in Schlenk-type flasks under argon atmosphere
unless otherwise noted. Organic solutions were concentrat-
ed under reduced pressure using a rotary evaporator. Thin-
layer chromatography (TLC) was carried out on 0.25 mm
Merck silica gel (60-F254). Flash column chromatography
was performed using silica gel Silica 60 M, 0.04-0.063
mm. N-methyl-2-pyrrolidone (NMP) was distilled under
reduced pressure and stored under molecular sieves and
argon atmosphere. Technical grade petroleum ether (40-60)
and ethyl acetate containing 1% of triethylamine were used
for column chromatography. CDCl3 was stored under ni-
trogen over molecular sieves. NMR spectra were recorded
on an AVANCE III 400 spectrometer and a Bruker AC-300
(ii): General Procedure for the Synthesis of 2-((E)-
styryl)pyrazines (1h-1m). 2-methylpyrazine (5 mmol) and
the corresponding aldehyde (5 mmol) were dissolved in
DMSO (3 mL). Powdered KOH (1.1 g, 20.0 mmol) was
added and the reaction mixture was stirred at room temper-
ature for 8 h. The mixture was then poured into 75 mL of
water. The aqueous layer was extracted with ethyl acetate
(5 × 15 mL) and the combined organic extract was dried
with MgSO4 and the solvents evaporated (In some cases,
the crude product can be directly obtained by filtration).
The crude product was purified by silica gel column chro-
matography with mixtures of petroleum ether and ethyl
acetate as the eluent, or by crystallization from the indicat-
ed solvent. Substrates 1i16a,16d and 1k16c,16d have been re-
ported and characterized elsewhere.
1
spectrometer. H NMR spectra were referenced to residual
protiated solvent (δ = 7.26 ppm for CDCl3 and δ = 2.05
ppm for acetone-d6) and 13C chemical shifts are reported
relative to deuterated solvents (δ = 77.0 ppm for CDCl3 and
δ = 29.8 ppm for acetone-d6) [Note: acetone-d6 contains
traces of water at ca. 3 ppm]. The peak patterns are indicat-
ed as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet, and br. for broad. HRMS were recorded on a
Waters Q-Tof 2 mass spectrometer at the corresponding
facilities of the CRMPO, Centre Régional de Mesures
Physiques de l’Ouest, Université de Rennes 1.
(E)-2-(4-(Methylthio)styryl)pyrazine (1h). Purified by crys-
tallization from a mixture of CH2Cl2/n-heptane as a beige
1
solid (649 mg, 70% yield). Mp 134-135°C. H NMR (300
MHz, CDCl3): δ = 8.61 (br. s, 1 H), 8.52 (br. s, 1 H), 8.38
(d, 1 H, J = 2.4 Hz), 7.69 (d, 1 H, J = 15.9 Hz), 7.51 (d, 2
H, J = 8.7 Hz), 7.25 (d, 2 H, J = 8.7 Hz), 7.10 (d, 1 H, J =
15.9 Hz), 2.51 (s, 3 H) ppm. 13C{1H} NMR (JMOD, 75
MHz, CDCl3): δ = 151.4, 144.3, 143.7, 142.6, 140.0, 134.6,
132.8, 127.7, 126.4, 123.2, 15.5 ppm. HRMS m/z [M+H]+
Calculated for C13H13N2S: 229.0794; found 229.0792 (1
ppm).
Synthesis and characterization of substrates (1). (i):
General Procedure for the Synthesis of 4-((E)-
styryl)pyrimidines (1a-1g). A stirred mixture of the corre-
sponding 4-methylpyrimidine derivative (1 mmol) and the
corresponding aldehyde (1 mmol) in aqueous sodium hy-
droxide (5 M, 15 mL) containing Aliquat 336 (0.1 mmol)
was heated under reflux for 2 h. The mixture was allowed
to cool down and the aqueous layer was extracted with
(E)-2-(4-(Piperidin-1-yl)styryl)pyrazine (1j). Purified by
crystallization from a mixture of CH2Cl2/n-heptane as a
1
yellow solid (649 mg, 49% yield). Mp 146-147. H NMR
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1
(300 MHz, CDCl3): δ = 8.58 (br.s, 1 H), 8.48 (br. s, 1 H),
solid (246 mg, 19% yield). Mp 180-181°C. H NMR (300
MHz, CDCl3): δ = 8.96 (dd, 1 H, J = 4.8 Hz, J = 1.5 Hz),
7.60-7.54 (m, 2 H), 7.47 (d, 2 H, J = 8.7 Hz), 7.35 (dd, 1 H,
J = 8.4 Hz, J = 4.8 Hz), 7.12 (d, 1 H, J = 15.9 Hz), 6.89 (d,
2 H, J = 8.7 Hz), 3.24 (t, 4 H, J = 4.8 Hz), 1.68-1.59 (m, 6
H) ppm. 13C{1H} NMR (JMOD, 75 MHz, CDCl3): δ =
158.9, 152.3, 149.1, 135.2, 128.6, 126.3, 126.0, 123.4,
121.3, 115.4, 49.5, 25.6, 24.3 ppm. HRMS m/z [M+H]+
Calculated for C17H20N3: 266.1652; found 266.1650 (1
ppm).
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7
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8.31 (d, 1 H, J = 2.4 Hz), 7.65 (d, 1 H, J = 15.9 Hz), 7.48
(d, 2 H, J = 8.7 Hz), 6.96 (d, 1 H, J = 15.9 Hz), 6.90 (d, 2
H, J = 8.7 Hz), 3.25 (t, 4 H, J = 4.8 Hz), 1.69-1.60 (m, 6 H)
ppm. 13C{1H} NMR (JMOD, 75 MHz, CDCl3): δ = 152.3,
152.1, 144.2, 143.4, 141.8, 135.2, 128.6, 126.2, 120.3,
115.5, 49.6, 25.6, 24.3 ppm. HRMS m/z [M+H]+ Calculat-
ed for C17H20N3: 266.1652; found 266.1658 (2 ppm).
(E)-2-(3-(Methyl)styryl)pyrazine (1l). Purified by silica gel
9
column chromatography (petroleum ether/AcOEt, 50:50,
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15
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19
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32
33
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1
v/v) as a pale yellow oil (525 mg, 54% yield). H NMR
(E)-2-(3-(Methyl)styryl)pyridazine (1r). Purified by silica
(300 MHz, CDCl3): δ = 8.64 (br. s, 1 H), 8.53 (br. s, 1 H),
8.40 (br. s, 1 H), 7.72 (d, 1 H, J = 15.9 Hz), 7.42-7.39 (m, 2
H), 7.32-7.29 (m, 1 H), 7.18-7.12 (m, 2 H), 2.40 (s, 3 H)
ppm. 13C{1H} NMR (JMOD, 75 MHz, CDCl3): δ = 151.5,
144.3, 143.7, 142.6, 138.4, 136.0, 135.3, 129.8, 128.7,
128.0, 124.6, 123.9, 21.4 ppm. HRMS m/z [M+H]+ Calcu-
lated for C13H13N2: 197.1073; found 197.1075 (1 ppm).
gel column chromatography (petroleum ether/AcOEt,
50:50, v/v) as a pale yellow oil (360 mg, 37% yield). H
1
NMR (300 MHz, CDCl3): δ = 9.04 (dd, 1 H, J = 4.8 Hz, J =
1.8 Hz), 7.67-7.59 (m, 2 H), 7.44-7.35 (m, 3 H), 7.30-7.25
(m, 2 H), 7.16-7.13 (m, 1 H), 2.38 (s, 3 H) ppm. 13C{1H}
NMR (JMOD, 75 MHz, CDCl3): δ = 158.3, 149.6, 138.4,
135.9, 135.3, 129.9, 128.8, 128.0, 126.4, 124.9, 124.5,
123.9, 21.4 ppm. HRMS m/z [M+H]+ Calculated for
C13H13N2: 197.1073; found 197.1073 (0 ppm).
(E)-2-(2-(Methyl)styryl)pyrazine (1m). Purified by crystal-
lization from a mixture of CH2Cl2/n-heptane as a beige
1
solid (323 mg, 33% yield). Mp 65-66°C. H NMR (300
(E)-2-(2-(Methyl)styryl)pyridazine (1s). Purified by silica
MHz, CDCl3): δ = 8.65 (br. s, 1 H), 8.57 (br. s, 1 H), 8.43
(br. s, 1 H), 8.05 (d, 1 H, J = 15.9 Hz), 7.70-7.67 (m, 1 H),
7.28-7.25 (m, 3 H), 7.08 (d, 1 H, J = 15.9 Hz), 2.51 (s, 3 H)
ppm. 13C{1H} NMR (JMOD, 75 MHz, CDCl3): δ = 151.5,
144.3, 143.8, 142.7, 136.9, 135.1, 133.0, 130.7, 128.8,
126.3, 125.8, 125.2, 19.9 ppm. HRMS m/z [M+H]+ Calcu-
lated for C13H13N2: 197.1073; found 197.1075 (1 ppm).
gel column chromatography (petroleum ether/AcOEt,
1
50:50, v/v) as a pale yellow oil (295 mg, 30% yield). H
NMR (300 MHz, CDCl3): δ = 9.04 (dd, 1 H, J = 4.8 Hz, J =
1.8 Hz), 8.00 (d, 1 H, J = 15.9 Hz), 7.70-7.67 (m, 1 H),
7.61 (dd, 1 H, J = 8.7 Hz, J = 1.8 Hz), 7.44 (dd, 1 H, J =
8.4 Hz, J = 4.8 Hz), 7.27-7.21 (m, 4 H), 2.48 (s, 3 H) ppm.
13C{1H} NMR (JMOD, 75 MHz, CDCl3): δ = 158.4, 149.6,
136.8, 135.0, 133.0, 130.7, 128.9, 126.5, 126.4, 126.2,
125.9, 124.2, 19.9 ppm. HRMS m/z [M+H]+ Calculated for
C13H13N2: 197.1073; found 197.1075 (1 ppm).
(iii): General Procedure for the Synthesis of 3-(E)-
styrylpyridazines (1n-1s). 3-methylpyridazine (5 mmol)
and the corresponding aldehyde (5 mmol) were dissolved
in DMSO (3 mL). Powdered KOH (1.1 g, 20.0 mmol) was
added and the reaction mixture was stirred at room temper-
ature for 8 h. The mixture was then poured into 75 mL of
water. The aqueous layer was extracted with ethyl acetate
(5 × 15 mL) and the combined organic extract was dried
with MgSO4 and the solvents evaporated (In some cases,
the crude product can be directly obtained by filtration).
The crude product was purified by silica gel column chro-
matography with mixtures of petroleum ether and ethyl
acetate as the eluent, or by crystallization from the indicat-
ed solvent. Substrates 1o16a,16e and 1q16c,16e have been re-
ported and characterized elsewhere.
(iv): General procedure for the synthesis 4,6-bis((E)-
styryl)pyrimidines (1t-1x). A stirred mixture of 4,6-
dimethylpyrimidine (1 mmol) and the corresponding alde-
hyde (2 mmol) in aqueous sodium hydroxide (5 M, 15 mL)
containing Aliquat 336 (0.1 mmol) was heated under reflux
for 2 h. The mixture was allowed to cool, and the precipi-
tate was filtered off, washed with water, and purified by
crystallization from a mixture of CH2Cl2/n-heptane. Sub-
strates 1u16f and 1w16b,16g have been reported and character-
ized elsewhere.
4,6-bis((E)-4-(Methylthio)styryl)pyrimidine (1t). Obtained
as a pale yellow solid (223 mg, 59% yield). Mp 138-139°C.
1H NMR (300 MHz, CDCl3): δ = 9.06 (s, 1 H), 7.84 (d, 2
H, J = 15.9 Hz), 7.52 (d, 4 H, J = 8.4 Hz), 7.26 (s, 1 H),
7.24 (d, 4 H, J = 8.4 Hz), 7.01 (d, 2 H, J = 15.9 Hz), 2.51
(s, 6 H) ppm. 13C{1H} NMR (JMOD, 75 MHz, CDCl3): δ =
162.8, 158.7, 140.7, 136.4, 132.4, 128.0, 126.3, 124.9,
116.2, 15.4 ppm. HRMS m/z [M+H]+ Calculated for
C22H21N2S2: 377.1141; found 377.1146 (1 ppm).
(E)-3-(4-(Methylthio)styryl)pyridazine (1n). Purified by
silica gel column chromatography (AcOEt) as a beige solid
1
(272 mg, 29% yield). Mp 144-145°C. H NMR (300 MHz,
CDCl3): δ = 9.04 (dd, 1 H, J = 4.8 Hz, J = 1.5 Hz), 7.67-
7.59 (m, 2 H), 7.52 (d, 2 H, J = 8.7 Hz), 7.43 (dd, 1 H, J =
8.4 Hz, J = 4.8 Hz), 7.30 (d, 1 H, J = 15.9 Hz), 7.32-7.26
(d, 2 H, J = 8.7 Hz), 2.52 (s, 3 H) ppm. 13C{1H} NMR
(JMOD, 75 MHz, CDCl3): δ = 158.3, 149.5, 140.1, 134.5,
132.6, 127.7, 126.4, 126.3, 124.3, 123.9, 15.4 ppm. HRMS
m/z [M+H]+ Calculated for C13H13N2S: 229.0794; found
229.0796 (1 ppm).
4,6-bis((E)-4-Piperidin-1-ylstyryl)pyrimidine (1v). Ob-
tained as a yellow solid (283 mg, 63% yield). Mp 181-
182°C. 1H NMR (300 MHz, CDCl3): δ = 9.00 (s, 1 H), 7.80
(d, 2 H, J = 15.9 Hz), 7.50 (d, 4 H, J = 8.7 Hz), 7.19 (s,1
H), 6.91 (d, 4 H, J = 8.7 Hz), 6.88 (d, 2 H, J = 15.9 Hz),
3.27 (t, 8 H, J = 4.8 Hz), 1.70-1.61 (m, 12 H) ppm. 13C{1H}
(E)-3-(4-(Piperidin-1-yl)styryl)pyridazine (1p). Purified by
silica gel column chromatography (AcOEt) as a yellow
ACS Paragon Plus Environment

The Journal of Organic Chemistry
NMR (JMOD, 75 MHz, CDCl3): δ = 163.0, 158.6, 152.5,
Page 10 of 21
HRMS m/z [M+H]+ Calculated for C22H25N4: 345.20737;
found 345.2074 (0 ppm), [M+Na]+ Calculated for
C22H24N4Na: 367.18932; found 367.1891 (1 ppm).
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7
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136.8, 129.0, 125.8, 122.1, 115.3, 49.5, 25.6, 24.3 ppm.
HRMS m/z [M+H]+ Calculated for C30H35N4: 451.2856;
found 451.2863 (2 ppm).
4,4'-(2-(Pyrimidin-4-yl)ethene-1,1-diyl)bis(N,N-diphenyla-
niline) (2c). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 90:10 to 80:20, v/v) as an orange
solid (132 mg, 89%). Mp 167-169°C. 1H NMR (400.1
MHz, acetone-d6): δ = 8.99 (s, 1 H), 8.43 (d, 1 H, J = 5.4
Hz), 7.30-7.37 (m, 10 H), 7.04-7.15 (m, 16 H), 6.98 (d, 2
H, J = 8.7 Hz), 6.95 (s , 1 H), 6.75 (d, 1 H, 4.8 Hz) ppm.
13C{1H} NMR (100 MHz, acetone-d6): δ = 164.4, 159.6,
156.6, 150.6, 149.6, 149.0, 148.4, 148.1, 135.6, 133.6,
131.6, 130.4, 130.3, 129.7, 125.9, 125.5, 125.2, 124.6,
124.3, 124.0, 122.6, 120.8 ppm. HRMS m/z [M+H]+ Calcu-
lated for C42H33N4: 593.26997; found 593.2703 (1 ppm).
4,6-bis((E)-3-Methylstyryl)pyrimidine (1x). Obtained as a
cream solid (174 mg, 56% yield). Mp 139-140°C. 1H NMR
(300 MHz, CDCl3): δ = 9.10 (s, 1 H), 7.87 (d, 2 H, J = 15.9
Hz), 7.43-7.40 (m, 4 H), 7.32-7.26 (m,3 H), 7.19-7.16 (m, 2
H), 7.06 (d, 2 H, J = 15.9 Hz), 2.40 (s, 6 H) ppm. 13C{1H}
NMR (JMOD, 75 MHz, CDCl3): δ = 162.8, 158.7, 138.5,
137.2, 135.7, 130.2, 128.8, 128.3, 125.7, 124.9, 116.3, 21.4
ppm. HRMS m/z [M+H]+ Calculated for C22H21N2:
313.1699; found 313.1695 (1 ppm).
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General Procedure for the Ruthenium-Catalyzed mono-
Arylation and Characterization of Products (2-4). The
corresponding substrate 1 (0.25 mmol, 1 eq.), the corre-
sponding arylbromide (0.5 mmol, 2 eq.), K2CO3 (0.75
mmol, 0.104 g, 3 eq.), KOAc (0.0125 mmol, 0.0012 g, 0.05
eq.), [RuCl2(p-cymene)]2 (0.00625 mmol, 0.0038 g, 0.025
eq.) and NMP (1 mL) were introduced in a dry Schlenk
tube under Argon atmosphere. The reaction mixture was
stirred at 150 oC during 3 h. Then, the reaction mixture was
cooled down to room temperature and poured into 30 mL
of water. The aqueous layer was extracted with ethyl ace-
tate (3 × 20 mL) and the combined organic extract was
dried with MgSO4. After solvents evaporation, the desired
product was purified by silica gel column chromatography
with mixtures of petroleum ether and ethyl acetate contain-
ing 1% of triethylamine as the eluent.
4-(2,2-bis(4-(Piperidin-1-yl)phenyl)vinyl)pyrimidine (2d).
Purified by silica gel column chromatography (petroleum
ether/AcOEt, 90:10, v/v) as a yellow solid (99 mg, 93%).
1
Mp 176-177°C. H NMR (400.1 MHz, acetone-d6): δ =
8.96 (d, 1 H, J = 0.7 Hz), 8.27 (d, 1 H, J = 5.4 Hz), 7.26 (d,
2 H, J = 8.9 Hz), 7.02 (d, 2 H, J = 8.9 Hz), 6.98 (d, 2 H, J =
8.9 Hz), 6.92 (d, 2 H, J = 8.9 Hz), 6.80 (s, 1 H), 6.60 (dd, 1
H, J = 5.4 Hz, 1.1 Hz), 3.25-3.27 (m, 8 H), 1.61-1.71 (m,
12 H) ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ =
165.0, 159.6, 156.2, 153.2, 153.0, 151.9, 132.4, 131.4,
129.9, 129.6, 123.1, 120.3, 116.4, 115.6, 50.3, 50.0, 26.4,
26.3, 25.1, 25.0 ppm. HRMS m/z [M+H]+ Calculated for
C28H33N4: 425.26997; found 425.2703 (1 ppm).
4-(2,2-bis(4-Methoxyphenyl)vinyl)pyrimidine (2e). Purified
by silica gel column chromatography (petroleum
ether/AcOEt, 90:10 to 80:20, v/v) as a cream solid (76 mg,
95%). Mp 152-153°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 8.99 (d, 1 H, J = 1.1 Hz), 8.34 (d, 1 H, J = 5.4 Hz), 7.34
(d, 2 H, J = 8.9 Hz), 7.11 (d, 2 H, J = 8.8 Hz), 7.00 (d, 2 H,
J = 8.8 Hz), 6.95 (d, 2 H, J = 8.9 Hz), 6.89 (s, 1 H), 6.62
(dd, 1 H, J = 5.4 Hz, 1.1 Hz), 3.86 (s, 3 H), 3.83 (s, 3 H)
ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ = 164.5,
161.4, 160.9, 159.6, 156.6, 150.7, 135.3, 132.1, 131.9,
130.2, 125.1, 120.6, 115.2, 114.7, 55.7, 55.6 ppm. HRMS
m/z [M+H]+ Calculated for C20H19N2O2: 319.1441; found
319.1442 (0 ppm), [M+Na]+ calculated for C20H18N2O2Na:
341.12605; found 341.1258 (1 ppm).
4-(2,2-bis(4-(Methylthio)phenyl)vinyl)pyrimidine
Purified by silica gel column chromatography (petroleum
(2a).
ether/AcOEt, 80:20 to 60:40, v/v) as a colourless solid (82
1
mg, 94%). Mp 155-157°C. H NMR (400.1 MHz, acetone-
d6): δ = 9.00 (d, 1 H, J = 1.0 Hz), 8.40 (d, 1 H, J = 5.4 Hz),
7.32-7.34 (m, 4 H), 7.28 (d, 2 H, J = 8.7 Hz), 7.14 (d, 2 H,
J = 8.3 Hz), 6.99 (s, 1 H), 6.73 (dd, 1 H, J = 5.4 Hz, 1.2,
Hz), 2.54 (s, 3 H), 2.52 (s, 3 H) ppm. 13C{1H} NMR (100
MHz, acetone-d6): δ =164.0, 159.6, 157.0, 150.1, 141.2,
140.5, 139.1, 136.2, 131.1, 129.2, 127.0, 126.5, 126.4,
120.9, 15.0, 15.0 ppm. HRMS m/z [M+H]+ Calculated for
C20H19N2S2: 351.09842; found 351.0979 (2 ppm), [M+Na]+
calculated for C20H18N2S2Na: 373.08036; found 370.0801
(1 ppm). Crystals suitable for single crystal X-ray diffrac-
tion studies were grown by slow diffusion of n-hexane into
a concentrated solution of 2a in ethyl acetate at room tem-
perature.
4-(2,2-di-m-Tolylvinyl)pyrimidine (2f). Purified by silica
gel column chromatography (petroleum ether/AcOEt,
90:10, v/v) as a colourless solid (68 mg, 95%). Mp 130-
132°C. 1H NMR (400.1 MHz, acetone-d6): δ = 9.02 (d, 1 H,
J = 0.6 Hz), 8.34 (d, 1 H, J = 5.4 Hz), 7.32 (t, 1 H, J = 7.5
Hz), 7.28-7.24 (m, 3 H), 7.20 (d, 1 H, J = 7.6 Hz), 7.22 (d,
1 H, J = 7.6 Hz), 7.03-6.98 (m, 3 H), 6.59 (dd, 1 H, J = 5.4
Hz, J = 1.1 Hz), 2.32 (s, 3 H), 2.31 (s, 3 H) ppm. 13C{1H}
NMR (100 MHz, acetone-d6): δ = 163.9, 159.6, 156.8,
151.4, 142.7, 140.0, 139.5, 138.8, 130.8, 130.4, 129.9,
129.7, 129.2, 129.1, 127.4, 127.1, 125.9, 120.7, 21.4, 21.3
ppm. HRMS m/z [M+Na]+ Calculated for C20H18N2Na:
309.13622; found 309.1362 (0 ppm).
4,4'-(2-(Pyrimidin-4-yl)ethene-1,1-diyl)bis(N,N-dimethyla-
niline) (2b). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 80:20 to 70:30, v/v) as a yellow
solid (83 mg, 96%). Mp 160-162°C. 1H NMR (400.1 MHz,
acetone-d6): δ = 8.94 (d, 1 H, J = 1.2 Hz), 8.25 (d, 1 H, J =
5.5 Hz), 7.26 (d, 2 H, J = 8.8 Hz), 7.01 (d, 2 H, J = 8.8 Hz),
6.78 (d, 2 H, J = 8.8 Hz), 6.76 (s, 1 H), 6.73 (d, 2 H, J = 8.8
Hz), 6.59 (dd, 1 H, J = 5.5 Hz, 1.2 Hz), 3.00 (s, 6 H), 3.01
(s, 6 H) ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ =
165.3, 159.6, 156.0, 152.5, 152.1, 151.6, 131.6, 130.7,
130.1, 127.5, 122.2, 120.1, 113.0, 112.5, 40.3, 40.4 ppm.
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Page 11 of 21
The Journal of Organic Chemistry
(Z)-4-(2-(m-Tolyl)-2-(o-tolyl)vinyl)pyrimidine (2g). Puri- = 8.7 Hz), 6.73 (d, 2 H, J = 8.9 Hz), 2.99 (s, 6 H), 2.99 (s, 6
H) ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ = 154.9,
151.8, 151.4, 149.3, 145.7, 144.6, 140.8, 131.7, 131.0,
129.8, 127.9, 121.5, 113.1, 112.6, 40.3 ppm. HRMS m/z
[M+Na]+ Calculated for C22H24N4Na: 367.18932; found
367.1893 (0 ppm), [M+H]+ calculated for C22H25N4:
345.20737; found 345.2073 (0 ppm). Crystals suitable for
single crystal X-ray diffraction studies were grown by slow
diffusion of n-hexane into a concentrated solution of 3b in
ethyl acetate at room temperature.
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fied by silica gel column chromatography (petroleum
ether/AcOEt, 90:10, v/v) as a colourless solid (63 mg,
88%). Mp 128-130°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 9.02 (br s, 1 H), 8.35 (d, 1 H, J = 5.3 Hz), 7.38-7.36 (m, 2
H), 7.31-7.29 (m, 2 H), 7.26 (d, 1 H, J = 7.6 Hz), 7.21-7.15
(m, 3 H), 7.10 (d, 1 H, J = 7.6 Hz), 2.33 (s, 3 H), 2.04 (s, 3
H) ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ = 163.5,
159.6, 157.2, 150.5, 141.4, 139.4, 139.0, 136.7, 131.6,
130.5, 130.0, 129.4, 129.3, 128.2, 127.4 (x 2), 125.1, 119.8,
21.4, 19.6 ppm. HRMS m/z [M+Na]+ Calculated for
C20H18N2Na: 309.13622; found 309.1366 (1 ppm).
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2-(2,2-bis(4-(Piperidin-1-yl)phenyl)vinyl)pyrazine
(3c).
Purified by silica gel column chromatography (petroleum
(E)-4-(2-(4-(tert-Butyl)phenyl)-2-(o-tolyl)vinyl)pyrimidine
(2h). Purified by silica gel column chromatography (petro-
leum ether/AcOEt, 95:5, v/v) as a cream solid (78 mg,
95%). Mp 141-143°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 9.01 (d, 1 H, J = 1.1 Hz), 8.33 (d, 1 H, J = 5.4 Hz), 7.44
(d, 2 H, J = 8.5 Hz), 7.41-7.35 (m, 2 H), 7.35 (d, 2 H, J =
8.5 Hz), 7.30 (ddd, 1 H, J =7.1 Hz, J =7.1 Hz, J =1.9 Hz),
7.20 (s, 1 H), 7.10 (d, 1 H, J = 7.4 Hz), 6.45 (dd, 1 H, J =
5.4 Hz, J = 1.1 Hz), 2.04 (s, 3 H), 1.32 (s, 9 H) ppm.
13C{1H} NMR (100 MHz, acetone-d6): δ = 163.5, 159.6,
157.1, 152.9, 150.1, 139.5, 138.3, 136.6, 131.6, 129.9,
129.2, 127.5, 127.5, 126.7, 126.4, 119.6, 35.2, 31.4, 19.6
ppm. HRMS m/z [M+Na]+ Calculated for C23H24N2Na:
351.18317; found 351.1830 (0 ppm), [M+H]+ Calculated
for C23H25N2: 329.20122; found 329.2009 (1 ppm).
ether/AcOEt, 90:10 to 80:20, v/v) as an orange solid (90
mg, 85%). Mp 159-160°C. H NMR (400.1 MHz, acetone-
1
d6): δ = 8.37 (s, 1 H), 8.08 (s, 1 H), 7.91 (s, 1 H), 7.21 (d, 2
H, J = 8.7 Hz), 6.98 (d, 2 H, J = 8.7 Hz), 6.85-6.80 (m, 5
H), 3.17 (m, 8 H), 1.64 (m, 8 H), 1.56 (m, 4 H) ppm.
13C{1H} NMR (100 MHz, acetone-d6): δ = 154.6, 153.0,
152.7, 148.8, 145.7, 144.7, 141.1, 132.8, 131.6, 130.0,
129.7, 122.5, 116.5, 115.8, 50.2, 50.1, 26.4, 26.3, 25.1
ppm. HRMS m/z [M+Na]+ Calculated for C28H32N4Na:
447.25192; found 447.2518 (0 ppm), [M+H]+ calculated
for C28H33N4: 425.26997; found 425.2698 (0 ppm).
2-(2,2-bis(4-Methoxyphenyl)vinyl)pyrazine (3d). Purified
by silica gel column chromatography (petroleum
ether/AcOEt, 90:10 to 80:20, v/v) as a yellow solid (74 mg,
93%). Mp 129-130°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 8.46 (dd, 1 H, J = 2.3 Hz, J = 1.7 Hz), 8.21 (d, 1 H, J =
2.5 Hz), 7.92 (d, 1 H, J = 1.1 Hz), 7.34 (d, 2 H, J = 8.9 Hz),
7.11 (d, 2 H, J = 8.8 Hz), 6.97 (d, 2 H, J = 8.8 Hz), 6.96 (s,
1 H), 6.94 (d, 2 H, J = 8.9 Hz), 3.84 (s, 3 H), 3.83 (s, 3 H)
ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ = 161.1,
160.7, 154.0, 147.9, 145.7, 144.8, 141.7, 135.5, 132.5,
132.0, 130.0, 124.2, 115.1, 114.6, 55.6, 55.5 ppm. HRMS
m/z [M+Na]+ Calculated for C20H18N2O2Na: 341.12605;
found 341.1261 (0 ppm), [M+H]+ Calculated for
C20H19N2O2: 319.14410; found 319.1440 (0 ppm).
4-(2,2-di-o-Tolylvinyl)pyrimidine (2i). Purified by silica gel
column chromatography (petroleum ether/AcOEt, 90:10,
v/v) as a colourless solid (42 mg, 58%). Mp 129-131°C. 1H
NMR (400.1 MHz, acetone-d6): δ = 9.03 (s, 1 H), 8.39 (d, 1
H, J = 5.1 Hz), 7.32-7.09 (8 H), 6.74 (s, 1 H), 6.63 (dd, 1
H, J = 5.1 Hz, J = 1.2 Hz), 2.37 (s, 3 H), 2.06 (s, 3 H) ppm.
13C{1H} NMR (100 MHz, acetone-d6): δ = 163.8, 159.6,
157.1, 150.4, 142.5, 140.3, 136.6, 136.5, 132.0, 131.7,
131.5, 130.7, 130.4, 129.2, 128.9, 127.1, 126.6, 120.4,
21.0, 20.0 ppm. HRMS m/z [M+Na]+ Calculated for
C20H18N2Na: 309.13622; found 309.1364 (1 ppm).
(E)-N,N-Dimethyl-4-(1-phenyl-2-(pyrazin-2-yl)vinyl)anili-
ne (3e). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 90:10 to 80:20, v/v) as a yellow
solid (71 mg, 94%). Mp 147-148°C. 1H NMR (400.1 MHz,
CDCl3): δ = 8.42 (t, 1 H, J = 1.8 Hz), 8.13 (d, 1 H, J = 1.8
Hz), 7.83 (s, 1 H), 7.38-7.36 (m, 3 H), 7.27 (d, 2 H, J = 8.9
Hz), 7.24-7.21 (m, 2 H), 7.02 (s, 1 H), 6.66 (d, 2 H, J = 8.9
Hz), 2.99 (s, 6 H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ = 153.3, 150.6, 148.2, 145.0, 143.6, 140.2, 139.8, 129.9,
129.3, 128.9, 128.8, 128.1, 121.5, 111.7.7, 40.2 ppm.
HRMS m/z [M+Na]+ Calculated for C20H19N3Na:
324.14712; found 324.1469 (1 ppm). Crystals suitable for
single crystal X-ray diffraction studies were grown by slow
diffusion of n-hexane into a concentrated solution of 3e in
ethyl acetate at room temperature.
2-(2,2-bis(4-(Methylthio)phenyl)vinyl)pyrazine (3a). Puri-
fied by silica gel column chromatography (petroleum
ether/AcOEt, 90:10 to 80:20, v/v) as a cream solid (85 mg,
97%). Mp 132-133°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 8.48 (br s, 1 H), 8.26 (d, 1 H, J = 2.2 Hz), 8.01 (s, 1 H),
7.35 (d, 2 H, J = 8.6 Hz), 7.31 (d, 2 H, J = 8.3 Hz), 7.28 (d,
2 H, J = 8.6 Hz), 7.14 (d, 2 H, J = 8.3 Hz), 7.07 (s, 1 H),
2.53 (s, 3 H), 2.52 (s, 3 H) ppm. 13C{1H} NMR (100 MHz,
acetone-d6): δ = 153.5, 147.5, 145.8, 144.9, 142.2, 140.7,
140.2, 139.3, 136.6, 131.3, 129.1, 127.0, 126.6, 125.5,
15.1, 15.0 ppm. HRMS m/z [M+Na]+ Calculated for
C20H18N2NaS2: 373.08036; found 373.0804 (0 ppm).
4,4'-(2-(Pyrazin-2-yl)ethene-1,1-diyl)bis(N,N-dimethylanil-
ine) (3b). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 80:20, v/v) as an orange solid (81
(E)-4-(1-(4-(tert-Butyl)phenyl)-2-(pyrazin-2-yl)vinyl)-N,N-
dimethylaniline (3f). Purified by silica gel column chroma-
tography (petroleum ether/AcOEt, 90:10, v/v) as a yellow
solid (87 mg, 97%). Mp 126-127°C. 1H NMR (400.1 MHz,
acetone-d6): δ = 8.43 (dd, 1 H, J = 2.4 Hz, J = 1.7 Hz), 8.15
1
mg, 94%). Mp 135-136°C. H NMR (400.1 MHz, acetone-
d6): δ = 8.43 (dd, 1 H, J = 2.2 Hz, J = 1.8 Hz), 8.13 (d, 1 H,
J = 2.5 Hz), 7.91 (d, 1 H, J = 1.1 Hz), 7.26 (d, 2 H, J = 8.9
Hz), 7.01 (d, 2 H, J = 8.7 Hz), 6.81 (s, 1 H), 6.76 (d, 2 H, J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
(d, 1 H, J = 2.4 Hz), 7.78 (d, 1 H, J = 1.2 Hz), 7.47 (d, 2 H,
Page 12 of 21
7.22 (d, 2 H, J = 9.0 Hz), 7.05 (s, 1 H), 6.72 (d, 2 H, J = 9.0
Hz), 2.98 (s, 6 H), 2.62 (s, 3 H) ppm. 13C{1H} NMR (100
MHz, acetone-d6): δ = 197.5, 153.5, 151.8, 147.8, 146.1,
145.6, 144.7, 141.8, 137.4, 131.1, 129.4, 129.1, 129.0,
122.4, 112.6, 40.2, 26.7 ppm. HRMS m/z [M+Na]+ Calcu-
lated for C22H21N3ONa: 366.15768; found 366.1577 (0
ppm).
1
2
3
4
5
6
7
8
J = 8.3 Hz), 7.24 (d, 2 H, J = 9.0 Hz), 7.14 (d, 2 H, J = 8.3
Hz), 6.96 (s, 1 H), 6.71 (d, 2 H, J = 9.0 Hz), 2.98 (s, 6 H),
1.36 (s, 9 H) ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ
= 154.1, 151.8, 151.7, 148.6, 145.4, 144.7, 141.3, 138.0,
130.4, 130.2, 129.5, 126.6, 122.3, 112.6, 40.3, 35.2, 31.6
ppm. HRMS m/z [M+Na]+ Calculated for C24H27N3Na:
380.20972; found 380.2097 (0 ppm), [M+H]+ calculated
for C24H28N3: 358.22777; found 358.2274 (1 ppm).
(E)-4-(1-(4-(Dimethylamino)phenyl)-2-(pyrazin-2-yl)vinyl)
benzonitrile (3k). Purified by silica gel column chromatog-
raphy (petroleum ether/AcOEt, 90:10 to 70:30, v/v) as an
orange solid (74 mg, 91%). Mp 122-123°C. 1H NMR
(400.1 MHz, acetone-d6): δ = 8.34 (dd, 1 H, J = 2.2 Hz J =
1.7 Hz), 8.22 (d, 1 H, J = 2.4 Hz), 8.06 (d, 1 H, J = 1.3 Hz),
7.80 (d, 2 H, J = 8.3 Hz), 7.39 (d, 2 H, J = 8.3 Hz), 7.21 (d,
2 H, J = 8.9 Hz), 7.08 (s, 1 H), 6.73 (d, 2 H, J = 8.9 Hz),
2.99 (s, 6 H) ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ
= 153.1, 151.9, 147.2, 146.5, 145.9, 144.6, 142.1, 133.2,
131.9, 129.5, 129.1, 122.2, 119.3, 112.7, 112.1, 40.2 ppm.
HRMS m/z [M+Na]+ Calculated for C21H18N4Na:
349.14237; found 349.1421 (1 ppm).
9
(E)-2-(2-([1,1'-Biphenyl]-4-yl)-2-(4-(methylthio)phenyl)vi-
nyl)pyrazine (3g). Purified by silica gel column chromatog-
raphy (petroleum ether/AcOEt, 90:10 to 80:20, v/v) as a
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
colourless solid (91 mg, 96%). Mp 119-120°C. H NMR
(400.1 MHz, acetone-d6): δ = 8.48 (dd, 1 H, J = 2.4 Hz, J =
1.7 Hz), 8.25 (d, 1 H, J = 2.4 Hz), 8.04 (d, 1 H, J = 1.2 Hz),
7.75-7.72 (m, 4 H), 7.48 (dd, 2 H, J = 8.0 Hz, J = 7.3 Hz),
7.40-7.36 (m, 3 H), 7.31-7.28 (m, 4 H), 7.13 (s, 1 H), 2.52
(s, 3 H) ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ =
153.4, 147.5, 145.8, 144.9, 142.3, 141.6, 141.0, 140.7,
139.4, 139.3, 131.4, 129.8, 129.0, 128.5, 128.1, 127.6,
126.6, 125.7, 15.1 ppm. HRMS m/z [M+Na]+ Calculated
for C25H20N2SNa: 403.12394; found 403.1241 (0 ppm).
(Z)-4-(1-(4-Fluorophenyl)-2-(pyrazin-2-yl)vinyl)-N,N-dim-
ethylaniline (3l). Purified by silica gel column chromatog-
raphy (petroleum ether/AcOEt, 90:10, v/v) as a yellow solid
(E)-2-(2-(4-(Methylthio)phenyl)-2-(4-vinylphenyl)vinyl)py-
razine (3h). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 90:10 to 80:20, v/v) as a colour-
1
(68 mg, 85%). Mp 119-120°C. H NMR (400.1 MHz, ace-
tone-d6): δ = 8.41 (dd, 1 H, J = 1.7 Hz, J = 2.1 Hz), 8.18 (d,
1 H, J = 2.5 Hz), 7.89 (d, 1 H, J = 1.1 Hz), 7.25-7.15 (m, 4
H), 7.23 (d, 2 H, J = 9.0 Hz), 6.99 (s, 1 H), 6.72 (d, 2 H, J =
9.0 Hz), 2.98 (s, 6 H) ppm. 13C{1H} NMR (100 MHz, ace-
tone-d6): δ = 163.3 (d, JC,F = 245.7 Hz), 153.8, 151.8,
147.6, 145.6, 144.7, 141.6, 137.2 (d, JC,F = 3.4 Hz), 132.8
(d, JC,F = 8.1 Hz), 129.9, 129.4, 122.3, 116.4 (d, JC,F = 21.6
Hz), 112.6, 40.3 ppm. 19F{1H} NMR (376 MHz, acetone-
d6): δ = -115.2 ppm. HRMS m/z [M+Na]+ Calculated for
C20H18N3FNa: 342.13770; found 342.1381 (1 ppm).
1
less solid (78 mg, 95%). Mp 124-125°C. H NMR (400.1
MHz, acetone-d6): δ = 8.47 (dd, 1 H, J = 2.3 Hz, J = 1.7
Hz), 8.24 (d, 1 H, J = 2.5 Hz), 7.98 (d, 1 H, J = 1.3 Hz),
7.52 (d, 2 H, J = 8.2 Hz), 7.34 (d, 2 H, J = 8.6 Hz), 7.27 (d,
2 H, J = 8.6 Hz), 7.17 (d, 2 H, J = 8.2 Hz), 7.10 (s, 1 H),
6.81 (dd, 1 H, J = 17.6 Hz, J = 11.0 Hz), 5.88 (dd, 1 H, J =
17.6 Hz, J = 0.5 Hz), 5.30 (dd, 1 H, J = 11.0 Hz, J = 0.5
Hz), 2.51 (s, 3 H) ppm. 13C{1H} NMR (100 MHz, acetone-
d6): δ = 153.3, 147.6, 145.8, 144.8, 142.2, 140.7, 139.8,
139.1, 138.4, 137.2, 131.0, 129.0, 127.6, 126.6, 125.5,
114.9, 15.1 ppm. HRMS m/z [M+Na]+ Calculated for
C21H18N2SNa: 353.10829; found 353.1084 (0 ppm).
(Z)-4-(1-(3,5-bis(Trifluoromethyl)phenyl)-2-(pyrazin-2-yl)
vinyl)-N,N-dimethylaniline (3m). Purified by silica gel
column chromatography (petroleum ether/AcOEt, 90:10,
1
(E)-Methyl-4-(1-(4-(dimethylamino)phenyl)-2-(pyrazin-2-
yl)vinyl)benzoate (3i). Purified by silica gel column chro-
matography (petroleum ether/AcOEt, 90:10 to 80:20, v/v)
v/v) as a yellow solid (84 mg, 77%). Mp 105-107°C. H
NMR (400.1 MHz, acetone-d6): δ = 8.33 (d, 1 H, J = 1.0
Hz), 8.25 (d, 1 H, J = 2.4 Hz), 8.22 (dd, 1 H, J = 2.3 Hz, J
= 1.5 Hz), 8.04 (s, 1 H), 7.80 (s, 2 H), 7.24 (d, 2 H, J = 8.9
Hz), 7.19 (s, 1 H), 6.75 (d, 2 H, J = 8.9 Hz), 3.00 (s, 6 H)
ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ = 152.5,
152.0, 146.5, 144.3, 142.7, 131.9 (q, JC,F = 33.2 Hz), 131.6,
131.8, 129.6, 129.2 (q, JC,F = 3.7 Hz), 124.5 (q, JC,F = 272.9
Hz), 122.3, 121.9 (h, JC,F = 3.7 Hz), 113.1, 112.7, 40.2
ppm. 19F{1H} NMR (376 MHz, acetone-d6): δ = -62.1 ppm.
HRMS m/z [M+Na]+ Calculated for C22H17N3F6Na:
460.12189; found 460.1220 (0 ppm), [M+H]+ calculated
for C22H18N3F6: 438.13994; found 438.1388 (3 ppm).
1
as a yellow solid (85 mg, 95%). Mp 130-132°C. H NMR
(400.1 MHz, acetone-d6): δ = 8.38 (dd, 1 H, J = 2.7 Hz, J =
1.2 Hz), 8.19 (d, 1 H, J = 2.4 Hz), 8.04 (d, 2 H, J = 8.3 Hz),
7.92 (d, 1 H, J = 1.2 Hz), 7.33 (d, 2 H, J = 8.3 Hz), 7.22 (d,
2 H, J = 9.0 Hz), 7.05 (s, 1 H), 6.72 (d, 2 H, J = 9.0 Hz),
3.91 (s, 3 H), 2.98 (s, 6 H) ppm. 13C{1H} NMR (100 MHz,
acetone-d6): δ = 166.9, 153.5, 151.8, 147.8, 146.3, 145.6,
144.7, 141.8, 131.1, 130.5, 130.1, 129.4, 129.0, 122.3,
112.7, 52.4, 40.2 ppm. HRMS m/z [M+Na]+ Calculated for
C22H21N3O2Na: 382.15260; found 382.1527 (0 ppm).
(E)-1-(4-(1-(4-(Dimethylamino)phenyl)-2-(pyrazin-2-yl)vi-
nyl)phenyl)ethanone (3j). Purified by silica gel column
chromatography (petroleum ether/AcOEt, 90:10 to 80:20,
(Z)-2-(2-(4-(Methylthio)phenyl)-2-(pyridin-4-yl)vinyl)pyra-
zine (3n). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 60:40 to 50:50, v/v) as a cream
solid (52 mg, 68%). Mp 109-110°C. 1H NMR (400.1 MHz,
acetone-d6): δ = 8.61 (d, 2 H, J = 5.6 Hz), 8.40 (dd, 1 H, J
= 2.6 Hz, J = 1.4 Hz), 8.31 (d, 1 H, J = 2.6 Hz), 8.21 (d, 1
H, J = 1.2 Hz), 7.33 (d, 2 H, J = 8.7 Hz), 7.29 (d, 2 H, J =
1
v/v) as a yellow solid (82 mg, 96%). Mp 117-118°C. H
NMR (400.1 MHz, acetone-d6): δ = 8.39 (dd, 1 H, J = 2.4
Hz, J = 1.6 Hz), 8.19 (d, 1 H, J = 2.6 Hz), 8.02 (d, 2 H, J =
8.3 Hz), 7.92 (d, 1 H, J = 1.3 Hz), 7.33 (d, 2 H, J = 8.3 Hz),
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The Journal of Organic Chemistry
142.2, 140.5, 139.5, 138.7, 131.0, 130.0, 129.7 (x 2), 129.1,
8.7 Hz), 7.23 (s, 1 H), 7.19 (d, 2 H, J = 5.9 Hz), 2.52 (s, 3
H) ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ = 152.4,
151.0, 148.5, 146.1, 145.5, 144.8, 143.0, 141.1, 128.8,
126.7, 125.7, 125.6, 125.4, 15.0 ppm. HRMS m/z [M+Na]+
Calculated for C18H15N3SNa: 328.08789; found 328.0878
(0 ppm).
129.0, 127.6, 126.2, 125.8, 21.4, 21.3 ppm. HRMS m/z
[M+H]+ Calculated for C20H19N2: 287.15427; found
287.1540 (1 ppm), [M+Na]+ calculated for C20H18N2Na:
309.13622; found 309.1364 (1 ppm).
1
2
3
4
5
(Z)-2-(2-(m-Tolyl)-2-(o-tolyl)vinyl)pyrazine (3s). Purified
by silica gel column chromatography (petroleum
ether/AcOEt, 90:10, v/v) as a colourless solid (67 mg,
94%). Mp 104-105°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 8.48 (dd, 1 H, J = 2.4 Hz, J = 1.5 Hz), 8.25 (d, 1 H, J =
2.4 Hz), 7.79 (d, 1 H, J = 0.8 Hz), 7.36-7.34 (m, 2 H), 7.29-
7.24 (m, 4 H), 7.19-7.15 (m, 2 H), 7.11 (d, 1 H, J = 7.4
Hz), 2.32 (s, 3 H), 2.05 (s, 3 H) ppm. 13C{1H} NMR (100
MHz, acetone-d6): δ = 153.0, 147.6, 144.9 (x 2), 142.5,
141.7, 139.8, 138.9, 137.0, 131.6, 130.4, 130.1, 129.3,
129.2, 128.1, 127.4, 126.6, 124.9, 21.4, 19.7 ppm. HRMS
m/z [M+H]+ Calculated for C20H19N2: 287.15427; found
287.1538 (2 ppm), [M+Na]+ calculated for C20H18N2Na:
309.13622; found 309.1361 (0 ppm).
6
7
8
9
(Z)-2-(2-(4-(Methylthio)phenyl)-2-(thiophen-3-yl)vinyl)pyr-
azine (3o). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 90:10 to 80:20, v/v) as a colour-
1
less solid (45 mg, 58%). Mp 97-98°C. H NMR (400.1
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
MHz, acetone-d6): δ = 8.50 (dd, 1 H, J = 2.4 Hz, J = 1.6
Hz), 8.27 (d, 1 H, J = 2.4 Hz), 8.00 (d, 1 H, J = 1.4 Hz),
7.60 (dd, 1 H, J = 4.9 Hz, J = 2.9 Hz), 7.37 (d, 2 H, J = 8.6
Hz), 7.30-7.29 (m, 1 H), 7.28 (d, 2 H, J = 8.6 Hz), 7.07 (s,
1 H), 6.94 (dd, 1 H, J = 4.9 Hz, J = 1.2 Hz), 2.52 (s, 3 H)
ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ = 153.4,
145.5, 144.8, 142.5, 142.3, 140.7, 140.2, 138.9, 129.7,
128.7, 127.7, 126.6, 126.2, 126.1, 15.1 ppm. HRMS m/z
[M+Na]+ Calculated for C17H14N2S2Na: 333.04906; found
333.0491 (0 ppm).
(E)-2-(2-(4-(tert-Butyl)phenyl)-2-(o-tolyl)vinyl)pyrazine
(3t). Purified by silica gel column chromatography (petro-
leum ether/AcOEt, 90:10, v/v) as a colourless solid (80 mg,
97%). Mp 117-118°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 8.52 (dd, 1 H, J = 2.4 Hz, J = 1.5 Hz), 8.31 (d, 1 H, J =
2.4 Hz), 8.16 (d, 1 H, J = 1.2 Hz), 7.35 (d, 2 H, J = 8.4 Hz),
7.33-7.30 (m, 1 H), 7.27-7.21 (m, 3 H), 7.08 (d, 2 H, J =
8.4 Hz), 6.63 (s, 1 H), 2.14 (s, 3 H), 1.30 (s, 9 H) ppm.
13C{1H} NMR (100 MHz, acetone-d6): δ = 153.6, 151.9,
149.0, 145.9, 144.9, 144.0, 142.5, 137.5, 136.6, 131.4,
130.5, 130.0, 128.8, 128.0, 126.6, 126.2, 35.1, 31.5, 20.5
ppm. HRMS m/z [M+H]+ Calculated for C23H25N2:
329.20122; found 329.2018 (2 ppm), [M+Na]+ calculated
for C23H24N2Na: 351.18317; found 351.1834 (1 ppm).
(Z)-N,N-Dimethyl-4-(2-(pyrazin-2-yl)-1-(o-tolyl)vinyl)anili-
ne (3p). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 90:10, v/v) as a yellow solid (73
1
mg, 92%). Mp 124-125°C. H NMR (400.1 MHz, CDCl3):
δ = 8.41 (s, 1 H), 8.13 (d, 1 H, J = 1.8 Hz), 7.68 (s, 1 H),
7.33-7.21 (m, 5 H), 7.16 (s, 1 H), 7.11 (d, 1 H, J = 7.4 Hz),
6.65 (d, 1 H, J = 8.8 Hz), 2.97 (s, 6 H), 2.07 (s, 3 H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δ = 152.9, 150.5, 147.0,
144.0, 143.6, 140.3, 139.0, 136.2, 130.8, 129.4, 128.2,
128.0, 127.9, 126.6, 121.5, 111.9, 40.2, 19.4 ppm. HRMS
m/z [M+Na]+ Calculated for C21H21N3Na: 338.16277;
found 338.1624 (1 ppm), [M+H]+ calculated for C21H22N3:
316.18082; found 316.11803 (2 ppm).
(Z)-N,N-Dimethyl-4-(2-(pyrazin-2-yl)-1-(m-tolyl)vinyl)anil-
ine (3q). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 90:10, v/v) as a yellow solid (75
2-(2,2-di-o-Tolylvinyl)pyrazine (3u). Purified by silica gel
column chromatography (petroleum ether/AcOEt, 90:10,
v/v) as a colourless solid (34 mg, 47%). Mp 105-106°C. 1H
NMR (400.1 MHz, acetone-d6): δ = 8.50 (dd, 1 H, J = 2.3
Hz, J = 1.6 Hz), 8.28 (d, 1 H, J = 2.4 Hz), 7.91 (d, 1 H, J =
1.3 Hz), 7.29-7.16 (m, 7 H), 7.10 (d, 1 H, J = 7.3 Hz), 6.81
(s, 1 H), 2.36 (s, 3 H), 2.05 (s, 3 H) ppm. 13C{1H} NMR
(100 MHz, acetone-d6): δ = 153.2, 147.8, 145.3, 145.0,
142.8, 140.6, 136.7, 136.5, 132.0, 131.7, 131.0, 130.5,
130.4, 129.0, 128.7, 127.1, 126.6, 21.0, 20.0 ppm. HRMS
m/z [M+Na]+ Calculated for C20H18N2Na: 309.13622;
found 309.1363 (0 ppm), [M+H]+ calculated for C20H18N2:
287.15427; found 287.1539 (1 ppm).
1
mg, 95%). Mp 122-123°C. H NMR (400.1 MHz, CDCl3):
δ = 8.42 (t, 1 H, J = 1.8 Hz), 8.13 (d, 1 H, J = 2.5 Hz), 7.83
(s, 1 H), 7.28 (d, 2 H, J = 8.9 Hz), 7.25 (d, 1 H, J = 7.7 Hz),
7.18 (d, 1 H, J = 7.6 Hz), 7.07 (s, 1 H), 7.02 (t, 1 H, J = 8.0
Hz), 7.00 (s, 1 H), 6.66 (d, 2 H, J = 8.9 Hz), 2.98 (s, 6 H)
2.31 (s, 3 H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ =
153.4, 150.6, 148.4, 145.0, 143.6, 140.0, 139.7, 138.6,
130.3, 129.3, 128.9, 128.8, 128.8, 126.6, 121.3, 111.7,
40.2, 21.4 ppm. HRMS m/z [M+Na]+ Calculated for
C21H21N3Na: 338.16277; found 338.1624 (1 ppm), [M+H]+
calculated for C21H22N3: 316.18082; found 316.1801 (2
ppm).
3-(2,2-bis(4-(Methylthio)phenyl)vinyl)pyridazine
(4a).
Purified by silica gel column chromatography (petroleum
ether/AcOEt, 50:50 to 40:60, v/v) as a cream solid (82 mg,
94%). Mp 156-157°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 8.91 (dd, 1 H, J = 4.9 Hz, J = 1.5 Hz), 7.36-7.24 (m, 8
H), 7.12 (d, 2 H, J = 8.3 Hz), 6.89 (dd, 1 H, J = 8.7 Hz, J =
1.5 Hz), 2.53 (s, 3 H), 2.52 (s, 3 H) ppm. 13C{1H} NMR
(100 MHz, acetone-d6): δ = 160.2, 149.8, 147.8, 140.7,
139.4, 136.2, 131.3, 129.0, 127.1, 126.8, 126.6, 126.0,
125.7, 15.1, 15.0 ppm. HRMS m/z [M+Na]+ Calculated for
C20H18N2NaS2: 373.08036; found 373.0802 (0 ppm).
2-(2,2-di-m-Tolylvinyl)pyrazine (3r). Purified by silica gel
column chromatography (petroleum ether/AcOEt, 90:10,
v/v) as a colourless solid (69 mg, 97%). Mp 106-107°C. 1H
NMR (400.1 MHz, acetone-d6): δ = 8.49 (br s, 1 H), 8.25
(br s, 1 H), 7.90 (br s, 1 H), 7.30 (t, 1 H, J = 7.5 Hz), 7.27-
7.23 (m, 3 H), 7.18 (d, 1 H, J = 7.9 Hz), 7.16 (d, 1 H, J =
7.9 Hz), 7.07 (s, 1 H), 7.03 (br s, 1 H), 6.99 (d, 1 H, J = 7.4
Hz), 2.32 (s, 3 H), 2.30 (s, 3 H) ppm. 13C{1H} NMR (100
MHz, acetone-d6): δ = 153.4, 148.7, 145.6, 144.8, 142.9,
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4,4'-(2-(pyridazin-3-yl)ethene-1,1-diyl)bis(N,N-dimethylan- lated for C20H19N3Na: 324.14712; found 324.1473 (1 ppm).
1
2
3
4
5
6
7
8
iline) (4b). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 50:50 to 30:70, v/v) as a yellow
solid (78 mg, 91%). Mp 189-190°C. 1H NMR (400.1 MHz,
acetone-d6): δ = 8.91 (dd, 1 H, J = 4.8 Hz, J = 1.5 Hz), 7.36
(d, 2 H, J = 8.9 Hz), 7.25 (dd, 1 H, J = 8.7 Hz, J = 4.8 Hz),
7.21 (s, 1 H), 7.08 (d, 2 H, J = 8.8 Hz), 6.90 (dd, 1 H, J =
8.8 Hz, J =1.5 Hz), 6.84 (d, 2 H, J = 8.3 Hz), 6.82 (d, 2 H,
J = 8.7 Hz), 3.08 (s, 6 H), 3.08 (s, 6 H) ppm.13C{1H} NMR
(100 MHz, acetone-d6): δ = 161.4, 151.8, 151.4, 149.8,
149.0, 131.7, 131.1, 129.8, 127.5, 126.3, 125.4, 121.3,
113.1, 112.6, 40.3 ppm. HRMS m/z [M+Na]+ Calculated
for C22H24N4Na: 367.18932; found 367.1894 (0 ppm),
[M+H]+ calculated for C22H25N4: 345.20737; found
345.2072 (0 ppm). Crystals suitable for single crystal X-ray
diffraction studies were grown by slow diffusion of n-
hexane into a concentrated solution of 4b in ethyl acetate at
room temperature.
Crystals suitable for single crystal X-ray diffraction studies
were grown by slow diffusion of n-hexane into a concen-
trated solution of 4e in ethyl acetate at room temperature.
(Z)-3-(2-(4-(Methylthio)phenyl)-2-(m-tolyl)vinyl)pyridazine
(4f). Purified by silica gel column chromatography (petro-
leum ether/AcOEt, 60:40, v/v) as a cream solid (68 mg,
86%). Mp 118-119°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 8.92 (dd, 1 H, J = 4.9 Hz, J = 1.4 Hz, minor), 8.90 (dd, 1
H, J = 4.9 Hz, J = 1.4 Hz, major), 7.37-6.99 (10 H major
and 10 H minor), 6.91 (dd, 1 H, J = 8.7 Hz, J = 1.3 Hz,
minor), 6.76 (dd, 1 H, J = 8.7 Hz, J = 1.3 Hz, major), 2.53
(s, 3 H, minor), 2.52 (s, 3 H, major), 2.34 (s, 3 H, minor),
2.31 (s, 3 H, major) ppm. 13C{1H} NMR (100 MHz, ace-
tone-d6): δ = 160.3 (major), 160.2 (minor), 149.9 (minor),
149.8 (major), 148.6 (major), 148.4 (minor), 143.0 (major),
140.6 (minor), 140.3 (major), 139.9 (minor), 139.7 (major),
139.3 (minor), 138.8 (major), 136.4 (minor), 131.3 (major),
131.0 (minor), 130.2 (major), 129.9 (major), 129.8 (minor),
129.2 (minor), 128.9 (major), 127.6 (minor), 127.0 (major),
126.8 (minor), 126.6 (major), 126.5 (minor), 126.3 (major),
126.0 (minor), 125.9 (major), 125.8 (minor), 125.6 (major),
125.0 (minor), 21.4 (minor) 21.3 (major), 15.1 (major),
15.0 (minor) ppm. HRMS m/z [M+Na]+ Calculated for
C20H18N2NaS: 341.10829; found 341.1084 (0 ppm),
[M+H]+ calculated for C20H19N2NaS: 319.12635; found
319.1260 (1 ppm).
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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
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60
3-(2,2-bis(4-(Piperidin-1-yl)phenyl)vinyl)pyridazine (4c).
Purified by silica gel column chromatography (petroleum
ether/AcOEt, 50:50, v/v) as a yellow solid (79 mg, 88%).
1
Mp 176-178°C. H NMR (400.1 MHz, acetone-d6): δ =
8.83 (dd, 1 H, J = 4.6 Hz, J = 1.5 Hz), 7.27 (d, 2 H, J = 8.9
Hz), 7.17 (s, 1 H), 7.16 (dd, 1 H, J = 8.5 Hz, J = 4.8 Hz),
7.01-6.90 (m, 6 H), 6.80 (dd, 1 H, J = 8.6 Hz, J =1.4 Hz),
3.26-3.21 (m, 8 H), 1.68-1.60 (m, 12 H) ppm.13C{1H}
NMR (100 MHz, acetone-d6): δ = 161.2, 153.0, 152.8,
149.3, 149.2, 149.1, 132.9, 131.6, 129.6, 126.4, 125.6,
122.3, 116.5, 115.8, 50.3, 50.2, 26.4, 26.3, 25.1, 25.0 ppm.
HRMS m/z [M+Na]+ Calculated for C28H32N4Na:
447.25192; found 447.2521 (0 ppm), [M+H]+ calculated
for C28H33N4 : 425.26997; found 425.2701 (0 ppm).
(E)-3-(2-(4-(Methylthio)phenyl)-2-(p-tolyl)vinyl)pyridazine
(4g). Purified by silica gel column chromatography (petro-
leum ether/AcOEt, 70:30 to 60:40, v/v) as a brown solid
1
(74 mg, 93%). Mp 119-120°C. H NMR (400.1 MHz, ace-
tone-d6): δ = 8.91 (dd, 1 H, J = 4.8 Hz, J = 1.6 Hz, minor),
8.90 (dd, 1 H, J = 4.8 Hz, J = 1.4 Hz, major), 7.37-7.21 (8
H major and 8 H minor), 7.12 (d, 2 H, J = 8.3 Hz, minor),
7.08 (d, 2 H, J = 8.0 Hz, major), 6.90 (dd, 1 H, J = 8.7 Hz,
J = 1.6 Hz, minor), 6.80 (dd, 1 H, J = 8.7 Hz, J = 1.6 Hz,
major), 2.53 (s, 3 H, minor), 2.52 (s, 3 H, major), 2.39 (s, 3
H, major), 2.36 (s, 3 H, minor) ppm. 13C{1H} NMR (100
MHz, acetone-d6): δ = 160.3 (major and minor), 149.8
(minor), 149.7 (major), 148.4 (major), 146.4 (minor), 140.6
(major), 140.2 (minor), 140.2 (minor), 139.5 (major), 139.4
(minor), 139.0 (major), 136.9 (major), 136.5 (minor), 131.3
(major), 130.6 (major and minor), 130.0 (minor), 128.9
(major), 128.6 (minor), 127.0 (major), 126.8 (minor), 126.6
(major and minor), 126.0 (minor), 125.8 (major), 125.6
(minor), 125.5 (major), 21.3 (major), 21.1 (minor), 15.1
(major), 15.0 (minor) ppm. HRMS m/z [M+Na]+ Calculat-
ed for C20H18N2NaS: 341.10829; found 341.1084 (0 ppm),
[M+H]+ calculated for C20H19N2S: 319.12635; found
319.1261 (1 ppm).
3-(2,2-bis(4-Methoxyphenyl)vinyl)pyridazine (4d). Purified
by silica gel column chromatography (petroleum
ether/AcOEt, 50:50 to 40:60, v/v) as a cream solid (76 mg,
95%). Mp 147-148°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 8.88 (dd, 1 H, J = 4.7 Hz, J = 1.2 Hz), 7.35 (d, 2 H, J =
8.8 Hz), 7.24 (s, 1 H), 7.22 (dd, 1 H, J = 8.9 Hz, J = 5.0
Hz), 7.10 (d, 2 H, J = 8.7 Hz), 6.97 (d, 2 H, J = 8.7 Hz),
6.95 (d, 2 H, J = 9.0 Hz), 6.80 (dd, 1 H, J = 8.7 Hz, J =1.4
Hz), 3.84 (s, 3 H), 3.83 (s, 3 H) ppm.13C{1H} NMR (100
MHz, acetone-d6): δ = 161.1, 160.7, 160.6, 149.5, 148.4,
135.5, 132.1, 132.0, 129.9, 126.5, 125.8, 124.2, 115.2,
114.6, 55.6, 55.5 ppm. HRMS m/z [M+H]+ Calculated for
C20H19N2O2: 319.14410; found 319.1442 (0 ppm), [M+K]+
calculated for C20H18N2O2K: 357.09999; found 357.1000 (0
ppm).
(E)-N,N-Dimethyl-4-(1-phenyl-2-(pyridazin-3-yl)vinyl)anil-
ine (4e). Purified by silica gel column chromatography
(petroleum ether/AcOEt, 70:30 to 80:20, v/v) as a yellow
solid (71 mg, 94%). Mp 125-126°C. 1H NMR (400.1 MHz,
CDCl3): δ = 8.81 (d, 1 H, J = 4.0 Hz), 7.38-7.37 (m, 4 H),
7.28 (d, 2 H, J = 8.9 Hz), 7.23-7.20 (m, 2 H), 6.95 (dd, 1
H, J = 8.7 Hz, J = 4.8 Hz), 6.66 (d, 2 H, J = 8.9 Hz), 6.58
(dd, 1 H, J = 8.8 Hz, J = 1.1 Hz), 2.98 (s, 6 H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δ = 160.2, 150.6, 148.6,
148.2, 139.6, 129.9, 129.1, 128.9, 128.8, 128.1, 125.8,
124.8, 121.3, 111.7, 40.2 ppm. HRMS m/z [M+Na]+ Calcu-
(Z)-3-(2-(4-Methoxyphenyl)-2-(4-(piperidin-1-yl)phenyl)vi-
nyl)pyridazine (4h). Purified by silica gel column chroma-
tography (petroleum ether/AcOEt, 90:10 to 60:40, v/v) as
1
an orange solid (66 mg, 71%). Mp 122-124°C. H NMR
(400.1 MHz, acetone-d6): δ = 8.86 (dd, 1 H, J = 4.9 Hz, J =
1.5 Hz, major), 8.85 (dd, 1 H, J = 4.9 Hz, J = 1.5 Hz, mi-
nor), 7.36 (d, 2 H, J = 8.9 Hz, major), 7.27 (d, 2 H, J = 8.9
Hz, minor), 7.23-6.93 (8 H major and 8 H minor), 6.87 (dd,
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The Journal of Organic Chemistry
1 H, J = 8.8 Hz, J = 1.5 Hz, major), 6.75 (dd, 1 H, J = 8.8
287.1536 (2 ppm), [M+Na]+ calculated for C20H18N2Na
309.13622; found 309.1360 (1 ppm).
1
2
3
4
5
6
7
8
Hz, J = 1.5 Hz, minor), 3.85 (s, 3 H, minor), 3.84 (s, 3 H,
major), 3.33-3.23 (4 H major and 4 H minor), 1.69-1.61 (6
H major and 6 H minor) ppm. 13C{1H} NMR (100 MHz,
acetone-d6): δ = 161.4 (minor), 161.1 (minor), 161.0 (ma-
jor), 160.7 (major), 153.0 (minor), 152.8 (major), 149.4
(minor), 149.3 (major), 133.3 (major), 132.7 (minor), 132.5
(major), 132.4 (minor), 132.0 (major), 131.6 (minor), 130.1
(major), 129.5 (minor), 129.3 (minor), 126.7 (minor), 126.6
(major), 126.4 (major), 125.7 (major), 123.7 (minor), 122.8
(major), 118.6 (minor), 116.5 (major), 115.8 (minor), 115.2
(minor), 114.6 (major), 55.6 (major), 55.6 (minor), 50.2
(major), 50.1 (minor), 26.4 (major), 26.3 (minor), 25.1
(major), 25.0 (minor) ppm. HRMS m/z [M+Na]+ Calculat-
ed for C24H25N3ONa: 394.18898; found 394.1895 (1 ppm).
(Z)-3-(2-(m-Tolyl)-2-(o-tolyl)vinyl)pyridazine (4k). Purified
by silica gel column chromatography (petroleum
ether/AcOEt, 70:30, v/v) as a cream solid (62 mg, 86%).
Mp 116-117°C. 1H NMR (400.1 MHz, CDCl3): δ = 8.88 (d,
1 H, J = 3.8 Hz), 7.61 (s, 1 H), 7.34 (td, 1 H, J = 7.5 Hz, J
= 1.0 Hz), 7.32-7.27 (m, 2 H), 7.27-7.25 (m, 1 H), 7.22 (d,
1 H, J = 7.4 Hz), 7.17-7.14 (m, 2 H), 7.12 (d, 1 H, J = 7.4
Hz), 7.02 (dd, 1 H, J = 8.6 Hz, J = 4.7 Hz), 2.34 (s, 3 H),
2.05 (s, 3 H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ =
159.4, 148.8, 147.8, 140.5, 138.4, 138.2, 136.2, 130.9,
129.6, 129.4, 128.4 (x 2), 127.4, 126.7, 125.5, 125.4, 125.1,
124.2, 21.5, 19.6 ppm. HRMS m/z [M+H]+ Calculaed for
C20H19N2: 287.1527; found 287.1537 (2 ppm), [M+Na]+
calculated for C20H18N2Na: 309.13622; found 309.1360 (1
ppm).
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(Z)-4-(1-(6-Methoxynaphthalen-2-yl)-2-(pyridazin-3-yl)vin-
yl)-N,N-dimethylaniline (4i). Purified by silica gel column
chromatography (petroleum ether/AcOEt, 70:30 to 60:40,
1
(E)-3-(2-(m-Tolyl)-2-(o-tolyl)vinyl)pyridazine (4l). Purified
by silica gel column chromatography (petroleum
ether/AcOEt, 70:30, v/v) as a cream solid (66 mg, 92%).
Mp 123-124°C. 1H NMR (400.1 MHz, CDCl3): δ = 8.94 (br
s, 1 H), 7.27 (td, 1 H, J = 7.2 Hz, J = 1.5 Hz), 7.24-7.07 (m,
6 H), 6.98-6.93 (m, 4 H), 2.23 (s, 3 H), 2.15 (s, 3 H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δ = 159.8, 149.5, 149.1,
142.6, 139.0, 138.4, 136.1, 130.6, 129.9, 129.8, 129.0,
128.5, 128.0, 127.3, 126.9, 126.7, 125.7, 124.9, 21.3, 20.5
ppm. HRMS m/z [M+H]+ Calculated for C20H19N2:
287.15427; found 287.1538 (2 ppm), [M+Na]+ calculated
for C20H18N2Na: 309.13622; found 309.1362 (0 ppm).
v/v) as a yellow solid (80 mg, 84%). Mp 135-136°C. H
NMR (400.1 MHz, acetone-d6): δ = 8.89 (dd, 1 H, J = 4.8
Hz, J = 1.5 Hz, minor), 8.80 (dd, 1 H, J = 4.8 Hz, J = 1.5
Hz, major), 7.86 (d, 1 H, J = 8.3 Hz, minor), 7.82-7.56 (3 H
major and 3 H minor), 7.76 (d, 1 H, J = 8.9 Hz, major),
7.36 (d, 1 H, J = 2.4 Hz, major), 7.32-7.21 (2 H major and
3 H minor), 7.33 (d, 1 H, J = 2.4 Hz, minor), 7.28 (d, 2 H, J
= 8.9 Hz, major), 7.17 (dd, 1 H, J = 9.0 Hz, J = 2.6 Hz,
major), 7.16 (dd, 1 H, J = 9.0 Hz, J = 2.6 Hz, minor), 7.04
(d, 2 H, J = 8.9 Hz, minor), 6.94 (dd, 1 H, J = 8.8 Hz, J =
1.5 Hz, minor), 6.77 (d, 2 H, J = 8.3 Hz, minor), 6.74 (d, 2
H, J = 8.9 Hz, major), 6.68 (dd, 1 H, J = 8.8 Hz, J = 1.5 Hz,
major), 3.95 (s, 3 H, major), 3.94 (s, 3 H, minor), 3.01 (s, 6
H, minor), 2.99 (s, 6 H, major) ppm. 13C{1H} NMR (100
MHz, acetone-d6): δ = 161.1 (major), 160.8 (minor), 159.3
(minor), 159.2 (major), 151.8 (major), 151.5 (minor), 149.6
(minor), 149.5 (major), 149.3 (minor), 149.2 (major), 139.0
(minor), 135.7 (minor), 135.6 (major), 135.3 (major), 131.8
(major), 130.8 (minor), 130.4 (major), 130.0 (minor), 129.6
(major), 129.5 (minor), 129.2 (major), 128.3 (major), 128.2
(minor), 127.6 (minor), 127.1 (major), 126.9 (minor), 126.7
(minor), 126.3 (major), 125.7 (minor), 125.6 (major), 124.9
(minor), 122.5 (major), 120.0 (major), 119.9 (minor), 113.1
(minor), 112.7 (major), 106.7 (major), 106.6 (minor), 58.8
(minor), 55.7 (major), 40.3 (major and minor) ppm. HRMS
m/z [M+H]+ Calculate d forC25H24N3O: 382.19139; found
382.1912 (0 ppm), [M+Na]+ calculated for C25H23N3ONa:
404.17333; found 404.1728 (1 ppm).
3-(2,2-di-o-Tolylvinyl)pyridazine (4m). Purified by silica
gel column chromatography (petroleum ether/AcOEt,
70:30, v/v) as a cream solid (32 mg, 44%). Mp 121-123°C.
1H NMR (400.1 MHz, acetone-d6): δ = 8.93 (dd, 1 H, J =
4.9 Hz, J = 1.6 Hz), 7.30-7.18 (m, 8 H), 7.12-7.10 (m, 1 H),
7.07 (s, 1 H), 6.79 (dd, 1 H, J = 8.6 Hz, J = 1.6 Hz), 2.38
(s, 3 H), 2.04 (s, 3 H) ppm. 13C{1H} NMR (100 MHz, ace-
tone-d6): δ = 160.0, 150.0, 148.2, 142.8, 140.2, 136.7,
136.5, 132.0, 131.8, 131.0, 130.7, 130.5, 129.1, 128.7,
127.2, 126.6, 126.2, 126.1, 21.0, 20.0 ppm. HRMS m/z
[M+H]+ Calculated for C20H19N2: 287.15427; found
287.1533 (3 ppm), [M+Na]+ calculated for C20H18N2Na:
309.13622; found 309.1360 (1 ppm).
Synthesis and Characterization of 3oo. Substrate 1h
(0.25 mmol, 0.057 g, 1 eq.), 3-bromothiophene (1.25
mmol, 0.2038 g, 0.12 mL, 5 eq.), K2CO3 (1.5 mmol, 0.207
g, 6 eq.), KOAc (0.025 mmol, 0.0025 g, 0.1 eq.), [RuCl2(p-
cymene)]2 (0.0125 mmol, 0.0077 g, 0.05 eq.) and NMP (2
mL) were introduced in a dry Schlenk tube under Argon
3-(2,2-di-m-Tolylvinyl)pyridazine (4j). Purified by silica gel
column chromatography (petroleum ether/AcOEt, 80:20 to
60:40, v/v) as a cream solid (69 mg, 96%). Mp 110-111°C.
1H NMR (400.1 MHz, acetone-d6): δ = 8.91 (br s, 1 H),
7.36 (s, 1 H), 7.31 (t, 1 H, J = 7.3 Hz), 7.29-7.17 (m, 6 H),
7.02 (s, 1 H), 6.98 (d, 1 H, J = 7.5 Hz), 6.77 (d, 1 H, J = 8.4
Hz), 2.33 (s, 3 H), 2.30 (s, 3 H) ppm. 13C{1H} NMR (100
MHz, acetone-d6): δ = 160.2, 149.8, 149.2, 142.9, 140.0,
139.6, 138.7, 131.0, 130.1, 129.8 (x 2), 129.1, 129.0, 127.6,
126.6, 126.2, 125.9, 125.8, 21.4, 21.3 ppm. HRMS m/z
[M+H]+ Calculated for C20H19N2: 287.15427; found
o
atmosphere. The reaction mixture was stirred at 150 C
during 12 h. Then, the reaction mixture was cooled down to
room temperature and poured into 30 mL of water. The
aqueous layer was extracted with ethyl acetate (3 × 20 mL)
and the combined organic extract was dried with MgSO4.
After solvents evaporation, 3oo was purified by silica gel
column chromatography with mixtures of petroleum ether
and ethyl acetate containing 1% of triethylamine as the
eluent.
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(Z)-2-(2-([2,3'-bithiophen]-3-yl)-2-(4-(methylthio)phenyl) 4,4',4'',4'''-(Pyrimidine-4,6-diylbis(ethene-2,1,1-triyl))tetra-
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3
4
5
6
7
8
vinyl)pyrazine (3oo).
kis(N,N-dimethylaniline) (5b). Purified by silica gel column
chromatography (petroleum ether/AcOEt, 80:20 to 60:40,
v/v) as a yellow solid (105 mg, 69%). Mp dec. >250°C. H
1
i
S
l
a
c
k
h
e
NMR (400.1 MHz, acetone-d6): δ = 8.73 (d, 1 H, J = 1.0
Hz), 7.14 (d, 4 H, J = 8.9 Hz), 6.77 (d, 4 H, J = 8.8 Hz),
6.66-6.70 (m, 8 H), 6.51 (s, 2 H), 6.26 (d, 1 H, J = 0.7 Hz),
2.97 (s, 12 H), 2.95 (s, 12 H) ppm. 13C{1H} NMR (100
MHz, acetone-d6): δ = 164.0, 159.0, 151.8, 151.3, 150.6,
131.7, 131.3, 129.9, 127.8, 122.7, 119.7, 113.2, 112.5,
40.5, 40.3 ppm. HRMS m/z [M+H]+ Calculated for
C40H45N6: 609.37002; found 609.3702 (0 ppm).
b
S
n
j
N
d
g
m
N
f
o
p
r
SMe
q
9
Purified by silica gel column chromatography (petroleum
ether/AcOEt, 90:10 to 70:30, v/v) as an orange solid (87
mg, 89%). Mp 121-122°C. H NMR (400.1 MHz, acetone-
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17
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1
d6): δ (assignment by COSY) = 8.40 (dd, 1 H, J = 2.4 Hz, J
= 1.7 Hz; Hb), 8.23 (d, 1 H, J = 2.4 Hz; Ha), 8.00 (d, 1 H, J
= 1.2 Hz; Hc), 7.58 (d, 1 H, J = 5.2 Hz; Hh), 7.46 (d, 2 H, J
= 8.6 Hz; Hp), 7.34-7.30 (m, 2 H; Hl and Hn), 7.27 (d, 2 H, J
= 8.6 Hz; Hq), 7.22 (s, 1 H; He), 7.11 (dd, 1 H, J = 4.9 Hz, J
= 1.4 Hz; Hm), 6.92 (d, 1 H, J = 5.2 Hz; Hi), 2.51 (s, 3 H,
Me) ppm. 13C{1H} NMR (100 MHz, acetone-d6): δ (as-
signment by HMQC and HMBC) = 152.9 (Cd), 144.8 (Cb),
144.7 (Cc), 142.5 (Ca), 142.2 (Cf), 140.8 (Cr), 137.6 (Co),
136.5 (Cj), 135.6 (Cg), 134.8 (Ck), 131.2 (Ci), 128.2 (Cp),
127.6 (Ce), 127.5 (Cm), 127.0 (Cn), 126.7 (Cq), 125.9 (Ch),
122.6 (Cl), 15.0 (Me) ppm. HRMS m/z [M+Na]+ Calculated
for C21H16N2S3Na: 415.03678; found 415.0371 (1 ppm).
4,6-bis(2,2-bis(4-(Piperidin-1-yl)phenyl)vinyl)pyrimidine
(5c). Purified by silica gel column chromatography (petro-
leum ether/AcOEt, 90:10 to 80:20, v/v) as an orange solid
1
(117 mg, 61%). Mp dec. >250°C. H NMR (400.1 MHz,
acetone-d6): δ = 8.76 (d, 1 H, J = 1.0 Hz), 7.15 (d, 4 H, J =
8.7 Hz), 6.88 (d, 4 H, J = 8.7 Hz), 6.86 (d, 4 H, J = 8.7 Hz),
6.77 (d, 4 H, J = 8.7 Hz), 6.55 (s, 2 H), 6.09 (d, 1 H, J = 1.0
Hz), 3.17-3.24 (m, 16 H), 3.60-3.65 (m, 24 H) ppm.
13C{1H} NMR (100 MHz, acetone-d6): δ = 163.8, 159.0,
153.0, 152.6, 150.3, 132.8, 131.6, 129.8, 129.7, 123.5,
120.2, 116.5, 115.7, 50.6, 50.2, 26.3, 25.1 ppm. HRMS m/z
[M+H]+ Calculated for C52H61N6: 769.49522; found
769.4963 (1 ppm).
General Procedure for the Ruthenium-Catalyzed dou-
ble-Arylation and Characterization of Products (5). The
corresponding substrate 1 (0.25 mmol, 1 eq.), the corre-
sponding arylbromide (1 mmol, 4 eq.), K2CO3 (1.5 mmol,
0.207 g, 6 eq.), KOAc (0.025 mmol, 0.0025 g, 0.1 eq.),
[RuCl2(p-cymene)]2 (0.0125 mmol, 0.0077 g, 0.05 eq.) and
NMP (2 mL) were introduced in a dry Schlenk tube under
Argon atmosphere. The reaction mixture was stirred at 150
oC during 6 h. Then, the reaction mixture was cooled down
to room temperature and poured into 30 mL of water. The
aqueous layer was extracted with ethyl acetate (3 × 20 mL)
and the combined organic extract was dried with MgSO4.
After solvents evaporation, the desired product 5 was puri-
fied by silica gel column chromatography with mixtures of
petroleum ether and ethyl acetate containing 1% of tri-
ethylamine as the eluent.
4,6-bis(2,2-bis(4-Methoxyphenyl)vinyl)pyrimidine
(5d).
Purified by silica gel column chromatography (petroleum
ether/AcOEt, 90:10 to 70:30, v/v) as a brown solid (109
1
mg, 78%). Mp dec. >250°C. H NMR (400.1 MHz, ace-
tone-d6): δ = 8.81 (d, 1 H, J = 1.0 Hz), 7.22 (d, 4 H, J = 8.9
Hz), 6.88-6.92 (m, 12 H), 6.66 (s, 2 H), 6.22 (d, 2 H, J =
1.0 Hz), 3.82 (s, 12 H) ppm. 13C{1H} NMR (100 MHz,
acetone-d6): δ = 163.7, 161.2, 160.6, 159.2, 149.5, 135.6,
132.7, 131.9, 130.1, 125.2, 120.0, 115.0, 114.6, 55.6 ppm.
HRMS m/z [M+H]+ Calculated for C36H33N2O4: 557.24348;
found 557.2439 (1 ppm).
4,6-bis(2,2-di-m-Tolylvinyl)pyrimidine (5e). Purified by
silica gel column chromatography (petroleum ether/AcOEt,
90:10, v/v) as a cream solid (103 mg, 84%). Mp dec.
>250°C.1H NMR (400.1 MHz, acetone-d6): δ = 8.83 (d, 1
H, J = 1.0 Hz), 7.24-7.13 (m, 10 H), 7.03 (d, 2 H, J = 7.5
Hz), 6.83 (s, 2 H), 6.77 (s, 2 H), 6.76 (d, 2 H, J = 7.5 Hz),
6.29 (br s, 1 H), 2.28 (s, 6 H), 2.26 (s, 6 H) ppm. 13C{1H}
NMR (100 MHz, acetone-d6): δ = 163.5, 159.0, 150.3,
142.9, 139.8, 138.8, 138.6, 131.0, 130.1, 129.5, 129.2,
129.1, 129.0, 127.7, 126.9, 125.9, 120.6, 21.4, 21.3 ppm.
HRMS m/z [M+H]+ Calculated for C36H33N2: 493.26382;
found 493.2631 (2 ppm), [M+Na]+ calculated for
C36H32N2Na: 515.24577; found 515.2455 (0 ppm).
4,6-bis(2,2-bis(4-(Methylthio)phenyl)vinyl)pyrimidine (5a).
Purified by silica gel column chromatography (petroleum
ether/AcOEt, 90:10 to 70:30, v/v) as a yellow solid (116
mg, 75%). Mp dec. >250°C. 1H NMR (400.1 MHz,
CDCl3): δ = 8.92 (s, 1 H), 7.16 (s, 8 H), 7.13 (d, 4 H, J =
8.3 Hz), 6.88 (d, 4 H, J = 8.3 Hz), 6.73 (s, 2 H), 6.27 (s, 1
H), 2.47 (s, 6 H), 2.47 (s, 6 H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δ = 162.6, 158.6, 148.6, 139.8, 138.8, 138.6,
135.1, 130.2, 128.4, 126.4, 125.8, 125.6, 119.2, 15.6, 15.4
ppm. HRMS m/z [M+H]+ Calculated for C36H33N2S4:
621.15211; found 621.1521 (0 ppm), [M+Na]+ calculated
for C36H32N2NaS4: 643.13406; found 643.1330 (2 ppm).
Crystals suitable for single crystal X-ray diffraction studies
were grown by slow diffusion of n-hexane into a concen-
trated solution of 5a in ethyl acetate at room temperature.
General Procedure for the Ruthenium-catalyzed mono-
arylation/hydrogenation and Characterization of Prod-
ucts (6). The corresponding substrate 1 (0.25 mmol, 1 eq.),
the corresponding arylbromide (0.5 mmol, 2 eq.), K2CO3
(0.75 mmol, 0.104 g, 3 eq.), KOAc (0.0125 mmol, 0.0012
g, 0.05 eq.), [RuCl2(p-cymene)]2 (0.00625 mmol, 0.0038 g,
0.025 eq.) and NMP (1 mL) were introduced in a dry
Schlenk tube under Argon atmosphere. The reaction mix-
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The Journal of Organic Chemistry
o
ture was stirred at 150 C during 3 h. Then, the reaction
mixture was cooled down to room temperature and flushed
with vacuum/hydrogen over 3-5 cycles. The Schlenk tube
was connected to a balloon filled with H2 (1 bar) and the
3-(2-(4-Methoxyphenyl)-2-(4-(piperidin-1-yl)phenyl)ethyl)
pyridazine (6d). Purified by silica gel column chromatog-
raphy (petroleum ether/AcOEt, 90:10 to 60:40, v/v) as an
orange solid (49 mg, 52%). Mp 114-115°C. 1H NMR
(400.1 MHz, acetone-d6): δ = 8.94 (dd, 1 H, J = 4.8 Hz, J =
1.3 Hz), 7.37 (d, 1 H, J = 8.3 Hz, J = 4.8 Hz), 7.30 (d, 1 H,
J = 8.3 Hz, J = 1.5 Hz), 7.22 (d, 2 H, J = 8.7 Hz), 7.16 (d, 2
H, J = 8.6 Hz), 6.82 (d, 2 H, J = 8.6 Hz), 6.79 (d, 2 H, J =
8.7 Hz), 4.53 (t, 1 H, J = 8.2 Hz), 3.72 (s, 3 H), 3.65 (d, 2
H, J = 8.2 Hz), 3.07 (t, 4 H, J = 5.3 Hz), 1.66-1.60 (m, 4
H), 1.55-1.51 (m, 2 H) ppm. 13C{1H} NMR (100 MHz,
acetone-d6): δ = 163.1, 159.0, 151.6, 150.3, 137.6, 135.6,
129.6, 129.1, 127.5, 126.6, 117.0, 114.5, 55.4, 51.1, 50.2,
43.0, 26.6, 25.0 ppm. HRMS m/z [M+Na]+ Calculated for
C24H27N3ONa: 396.20463; found 396.2048 (0 ppm).
1
2
3
4
5
6
7
8
o
reaction mixture was stirred at 150 C during 12 h. Then,
the reaction mixture was cooled down to room temperature
and poured into 30 mL of water. The aqueous layer was
extracted with ethyl acetate (3 × 20 mL) and the combined
organic extract was dried with MgSO4. After solvents
evaporation, the desired product 6 was purified by silica gel
column chromatography with mixtures of petroleum ether
and ethyl acetate containing 1% of triethylamine as the
eluent.
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4-(2-(4-(Methylthio)phenyl)-2-phenylethyl)pyrimidine (6a).
Purified by silica gel column chromatography (petroleum
ether/AcOEt, 80:20, v/v) as a colourless solid (67 mg,
87%). Mp 119-120°C. 1H NMR (400.1 MHz, acetone-d6): δ
= 9.00 (s, 1 H), 8.49 (d, 1 H, J = 5.0 Hz), 7.33 (d, 2 H, J =
8.0 Hz), 7.29-7.22 (m, 5 H), 7.18-7.12 (m, 3 H), 4.70 (t, 1
H, J = 8.1 Hz), 3.54 (d, 2 H, J = 8.1 Hz), 2.66 (s, 3 H) ppm.
13C{1H} NMR (100 MHz, acetone-d6): δ = 169.2, 159.3,
157.4, 145.0, 141.9, 137.3, 129.3, 129.2, 128.7, 127.3,
127.1, 122.3, 50.2, 43.7, 15.5 ppm. HRMS m/z [M+Na]+
Calculated for C19H18N2NaS: 329.10829; found 329.1083
(0 ppm).
Procedure for the Ruthenium-catalyzed double-
arylation/hydrogenation and Characterization of 7.
Substrate 1u (0.25 mmol, 0.093 g, 1 eq.), 1-bromo-4-tert-
butylbenzene (1 mmol, 0.213 g, 0.17 mL, 4 eq.), K2CO3
(1.5 mmol, 0.207 g, 6 eq.), KOAc (0.025 mmol, 0.0025 g,
0.1 eq.), [RuCl2(p-cymene)]2 (0.0125 mmol, 0.0077 g, 0.05
eq.) and NMP (2 mL) were introduced in a dry Schlenk
tube under Argon atmosphere. The reaction mixture was
stirred at 150 oC during 6 h. Then, the reaction mixture was
cooled down to room temperature and flushed with vacu-
um/hydrogen over 3-5 cycles. The Schlenk tube was con-
nected to a balloon filled with H2 (1 bar) and the reaction
N,N-Dimethyl-4-(1-phenyl-2-(pyrimidin-4-yl)ethyl)aniline
(6b). Purified by silica gel column chromatography (petro-
leum ether/AcOEt, 90:10 to 80:20, v/v) as a colourless solid
o
mixture was stirred at 150 C during 12 h. Then, the reac-
tion mixture was cooled down to room temperature and
poured into 30 mL of water. The aqueous layer was ex-
tracted with ethyl acetate (3 × 20 mL) and the combined
organic extract was dried with MgSO4. After solvents
evaporation, the desired product 7 was purified by silica gel
column chromatography with mixtures of petroleum ether
and ethyl acetate containing 1% of triethylamine as the
eluent.
1
(57 mg, 75%). Mp 124-125°C. H NMR (400.1 MHz, ace-
tone-d6): δ = 9.00 (s, 1 H), 8.47 (d, 1 H, J = 4.9 Hz), 7.30
(d, 2 H, J = 7.8 Hz), 7.25-7.21 (m, 3 H), 7.19 (dd, 1 H, J =
5.0 Hz, J = 0.9 Hz), 7.14 (d, 2 H, J = 8.7 Hz), 7.13-7.09 (m,
1 H), 6.63 (d, 2 H, J = 8.7 Hz), 4.58 (t, 1 H, J = 8.1 Hz),
3.49 (d, 2 H, J = 8.1 Hz, J = 2.4 Hz), 2.85 (s, 6 H) ppm.
13C{1H} NMR (100 MHz, acetone-d6): δ = 169.7, 159.2,
157.2, 150.2, 146.0, 132.5, 129.2, 129.1, 128.6, 126.8,
122.3, 113.4, 50.0, 44.2, 40.6 ppm. HRMS m/z [M+Na]+
Calculated for C20H21N3Na: 326.16277; found 326.1630 (1
ppm). Crystals suitable for single crystal X-ray diffraction
studies were grown by slow diffusion of n-hexane into a
concentrated solution of 6b in ethyl acetate at room tem-
perature.
4,4'-(Pyrimidine-4,6-diylbis(1-(4-(tert-butyl)phenyl)ethane-
2,1-diyl))bis(N,N-dimethylaniline) (7). Purified by silica gel
column chromatography (petroleum ether/AcOEt, 90:10,
1
v/v) as a yellow solid (107 mg, 67%). Mp dec. >250°C. H
NMR (400.1 MHz, CDCl3): δ = 8.91 (br. s, 1 H), 7.26 (d, 4
H, J = 8.1 Hz), 7.10 (d, 4 H, J = 8.1 Hz), 7.03 (dd, 4 H, J =
8.7 Hz, J = 1.1 Hz), 6.68 (s, 1 H), 6.65 (d, 4 H, J = 8.7 Hz),
4.31 (t, 2 H, J = 7.9 Hz), 3.32 (d, 4 H, J = 7.9 Hz), 2.91 (s,
12 H), 1.29 (s, 18 H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δ = 168.3, 157.9, 149.0, 148.8, 141.1, 131.8,
128.5, 127.3, 125.2, 121.0, 112.7, 48.9, 43.9, 40.7, 34.3,
31.3 ppm. HRMS m/z [M+H]+ Calculated for C44H55N4:
639.44212; found 639.4414 (1 ppm).
2-(2-(4-(Methylthio)phenyl)-2-(p-tolyl)ethyl)pyrazine (6c).
Purified by silica gel column chromatography (petroleum
ether/AcOEt, 90:10 to 80:20, v/v) as a colourless solid (57
1
mg, 71%). Mp 99-101°C. H NMR (400.1 MHz, acetone-
d6): δ = 8.48 (dd, 1 H, J = 2.4 Hz, J = 1.5 Hz), 8.34 (d, 1 H,
J = 1.0 Hz), 8.32 (d, 1 H, J = 2.4 Hz), 7.27 (d, 2 H, J = 8.3
Hz), 7.21 (d, 2 H, J = 7.9 Hz), 7.16 (d, 2 H, J = 8.3 Hz),
7.06 (d, 2 H, J = 7.9 Hz), 4.61 (t, 1 H, J = 8.1 Hz), 3.56 (d,
2 H, J = 8.1 Hz), 2.42 (s, 3 H), 2.23 (s, 3 H) ppm. 13C{1H}
NMR (100 MHz, acetone-d6): δ = 156.6, 146.0, 144.9,
143.1, 142.2, 142.0, 137.1, 136.5, 129.9, 129.3, 128.5,
127.3, 50.5, 41.5, 20.9, 15.5 ppm. HRMS m/z [M+Na]+
Calculated for C20H20N2NaS: 343.12394; found 343.1239
(0 ppm).
Synthesis and Characterization of 8. To a solution of 2b
(0.22 mmol, 0.076 g, 1 eq.) in dichloromethane (1.8 mL)
was added anhydrous FeCl3 (0.77 mmol, 0.124 g, 3.5 eq.)
under Argon atmosphere. The reaction solution was stirred
at room temperature under Argon atmosphere for 8 h, and
then quenched with methanol. Then, the reaction mixture
was poured into 30 mL of water. The aqueous layer was
extracted with ethyl acetate (3 × 20 mL) and the combined
ACS Paragon Plus Environment

The Journal of Organic Chemistry
organic extract was dried with MgSO4. After solvents
evaporation, product 8 was purified by silica gel column
chromatography with mixtures of petroleum ether and ethyl
acetate containing 1% of triethylamine as the eluent.
Page 18 of 21
o
j
i
n
m
1
2
3
4
5
6
7
8
g
h
l
k
p
Ru
a
H
CO
b
c
d
e
4,4'-(2-Chloro-2-(pyrimidin-4-yl)ethene-1,1-diyl)bis(N,N-
dimethylaniline) (8). Purified by silica gel column chroma-
tography (petroleum ether/AcOEt, 80:20 to 60:40, v/v) as
f
OMe
1
an orange solid (38 mg, 45%). Mp 236-237°C. H NMR
1H NMR (400.1 MHz, CDCl3): δ (assignment by COSY,
HMQC and HMBC) = 7.54 (d, 2 H, J = 8.7 Hz; Hd), 6.91
(d, 2 H, J = 8.7 Hz; He), 6.70 (s, 1 H; Ha), 5.58 (d, 1 H, J =
5.8 Hz; Hl), 5.20 (d, 1 H, J = 5.6 Hz; Hj), 5.15 (d, 1 H, J =
5.8 Hz; Hk), 4.66 (d, 1 H, J = 5.6 Hz; Hi), 3.87 (s, 3 H;
OMe), 2.36 (sept, 1 H, J = 6.9 Hz; Hn), 2.12 (s, 3 H; Hg)
0.96 (d, 3 H, J = 6.9 Hz; Ho), 0.93 (d, 3 H, J = 6.9 Hz; Hp)
ppm. 13C{1H} NMR (100 MHz, CDCl3): δ (assignment by
COSY, HSQC and HMQC) = 18.7 (Cg), 22.0 (Co), 22.2
(Cp), 30.8 (Cn), 55.3 (OMe), 82.8 (Ci), 85.3 (Ck), 88.5 (Cj),
92.8 (Cl), 102.8 (Cm), 103.5 (Ch), 113.2 (Ce), 125.7 (Ca),
127.7 (Cd), 145.1 (Cc), 159.5 (Cf), 172.1 (Cb), 222.8 (CO)
ppm. Due to the lack of stability of the complex, HRMS
and elemental analysis were not successful. Although
DOSY is not the ideal technique to determine exactly the
volume of small species, it is enough accurate to qualita-
tively differentiate between monomers and higher aggre-
gates (dimers, trimmers, etc.).33 For Ru-2, an experimental
diffusion value of D (CDCl3) = 1.43x10-9 m2s-1 was found,
which corresponds to rh = 2.8 Å applying the Stokes-
Einstein equation at 298 K with a viscosity for CHCl3 of
5.42x10-4 Nm-2s. Molecular modelling (PM3-minimized)
indicates that a monomeric structure such as Ru-2 has a
radius of ca. 5.5 Å. This data enables to qualitatively dis-
card the presence of dimers or higher aggregates.
(400.1 MHz, acetone-d6): δ = 9.08 (d, 1 H, J = 1.1 Hz),
8.47 (d, 1 H, J = 5.2 Hz), 7.24 (d, 2 H, J = 8.9 Hz), 7.03
(dd, 1 H, J = 5.2 Hz, J = 1.3 Hz), 6.77 (d, 2 H, J = 8.9 Hz),
6.74 (d, 2 H, J = 8.9 Hz), 6.52 (d, 2 H, J = 8.9 Hz), 3.00 (s,
6 H), 2.91 (s, 6 H) ppm. 13C{1H} NMR (100 MHz, ace-
tone-d6): δ = 166.7, 159.5, 157.2, 151.4, 151.2, 147.1,
132.7, 132.2, 129.2, 128.9, 123.2, 122.1, 112.2, 111.9,
40.3, 40.1 ppm. HRMS m/z [M+H]+ Calculated for
C22H24N435Cl: 379.16840; found 379.16800 (1 ppm),
[M+Na]+ calculated for C22H23N435ClNa: 401.15034; found
401.1500 (1 ppm). Crystals suitable for single crystal X-ray
diffraction studies were grown by slow diffusion of n-
hexane into a concentrated solution of 8 in ethyl acetate at
room temperature.
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Synthesis and Identification of Ru-1. Substrate 1e (0.25
mmol, 0.053 g, 1 eq.), [RuCl2(p-cymene)]2 (0.125 mmol,
0.077 g, 0.5 eq.), KOAc (1 mmol, 0.098 g, 4 eq.), LiCl (2.5
mmol, 0.106 g, 10 eq.), and MeOH (5 mL) were introduced
under argon atmosphere in a dry Schlenk tube and stirred at
room temperature. After 2 h, a NMR spectrum was record-
ed indicating the presence of substrate 1e, ruthenium-
coordinated substrate (Ru-1e) and traces of ruthenacycles
(see Fig. S36). The reaction was stirred at room tempera-
ture for 3 weeks. Then, the solvents were removed under
vacuum and dichloromethane (3 x 10 mL) was added to
reaction mixture followed by filtration over celite. After
solvents evaporation under vacuum and heptane washing,
n
ASSOCIATED CONTENT
1
Supporting Information.
The Supporting Information is available free of charge on
the ACS Publications website at DOI.
Determination of isomeric ratio of products, mechanistic
investigations, NMR spectral data and cartesian coordiantes
(PDF)
Single-crystal X-ray diffraction data for 2a (CIF)
Single-crystal X-ray diffraction data for 3b (CIF)
Single-crystal X-ray diffraction data for 3e (CIF)
Single-crystal X-ray diffraction data for 4b (CIF)
Single-crystal X-ray diffraction data for 4e (CIF)
Single-crystal X-ray diffraction data for 5a (CIF)
Single-crystal X-ray diffraction data for 6b (CIF)
Single-crystal X-ray diffraction data for 8 (CIF)
the crude mixture was analysed by H NMR spectroscopy
(see Fig. S36) indicating the disappearance of the starting
material (i.e. no singlet at 9.13 ppm and no doublet at 8.63
ppm) and some peaks belonging to chloride- and acetate-
containing ruthenacycle complexes (see Fig. S37).27 HRMS
m/z [M+H]+ Calculated for C23H26N2O35Cl102Ru:
483.07716; found 483.0773 (0 ppm), [M+Na]+ calculated
for C23H25N2O35Cl102RuNa: 505.05911; found 505.0591 (0
ppm), [M+K]+ calculated for C23H25N2O35Cl102RuK:
521.03305; found 521.0329 (0 ppm), [M-Cl]+ calculated for
C23H25N2O102Ru: 447.10049; found 447.1004 (0 ppm).
Synthesis and Characterization of Ru-2. Substrate 1e
(0.25 mmol, 0.053 g, 1 eq.), [RuCl2(p-cymene)]2 (0.125
mmol, 0.077 g, 0.5 eq.), KOAc (1 mmol, 0.098 g, 4 eq.),
LiCl (2.5 mmol, 0.106 g, 10 eq.), and MeOH (5 mL) were
introduced under argon atmosphere in a dry Schlenk tube
n
AUTHOR INFORMATION
Corresponding Author
o
and stirred for 12 h at 60 C. Then, solvents were removed
*rafael.gramage-doria@univ-rennes1.fr
under vacuum and the crude reaction mixture was purified
by silica gel column chromatography with 1% of triethyla-
mine (petroleum ether/AcOEt, 30:70 to 20:80, v/v) afford-
ing Ru-2 as an orange solid (41 mg, 39%).
Notes
The authors declare no competing financial interest.
n
ACKNOWLEDGEMENTS
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The Journal of Organic Chemistry
Chem. Commun. 2008, 2260. (d) Achelle, S.; Baudequin C. Targets
The authors thank the CNRS, Université de Rennes 1 and
Heterocycl. Syst. 2013, 17, 1. (e) Achelle, S.; Baudequin, C.; Plé, N.
Dyes Pigm. 2013, 98, 575. (f) Achelle, S.; Plé, N.; Turck, A. RSC
Adv. 2011, 1, 364.
1
2
3
4
5
6
7
8
Rennes Métropole for financial support. C.B. and R.G.-D.
acknowledge the contribution of the COST Action
CA15106 (C-H Activation in Organic Synthesis CHAOS).
(13) (a) Bencze, W. L. PCT. US Appl. 3075971, 1963. (b) Humber,
L. G. PCT. US Appl. 3519621, 1970. (c) Warrellow, G. J.; Boyd, E.
W.; Alexander, R. P. PCT. Int. Appl. WO9414742A1, 1994. (d)
Alexander, R. P.; Warrellow, G. J.; Eaton, M. A. W.; Boyd, E. C.;
Head, J. C.; Porter, J. R.; Brown, J. A.; Reuberson, J. T.; Hutchinson,
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contain the supplementary crystallographic daa for this article. These
data can be obtained free of charge from The Cambridge Crsyta-
n
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50 examples
up to 97% yield
5 examples
up to 87% yield
including heteroaryls and mechanistic investigations
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