Synthesis of aminopyridines and aminopyridones by cobalt-catalyzed [2+2+2] cycloadditions involving yne-ynamides: Scope, limitations, and mechanistic insights

Article abstract of DOI:10.1002/chem.201103906

An in-depth study of the cobalt-catalyzed [2+2+2] cycloaddition between yne-ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal-catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron-deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne-ynamide allows the regioselectivity to be switched toward 3- or 4-aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne-ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3-aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4-aminopyridines arise from an insertion pathway.

Full text of DOI:10.1002/chem.201103906

FULL PAPER
DOI: 10.1002/chem.201103906
Synthesis of Aminopyridines and Aminopyridones by Cobalt-Catalyzed
[2+2+2] Cycloadditions Involving Yne-Ynamides: Scope, Limitations, and
Mechanistic Insights
Pierre Garcia,[a] Yannick Evanno,[b] Pascal George,[b] Mireille Sevrin,[b] Gino Ricci,[c]
Max Malacria,*[a] Corinne Aubert,*[a] and Vincent Gandon*[a]
Abstract: An in-depth study of the
cobalt-catalyzed [2+2+2] cycloaddition
between yne-ynamides and nitriles to
afford aminopyridines has been carried
out. About 30 nitriles exhibiting
a broad range of steric demand and
electronic properties have been evalu-
ated, some of which open new perspec-
tives in metal-catalyzed arene forma-
tion. In particular, the use of
ble the incorporation of electron-defi-
cient nitriles into the pyridine core.
Modification of the substitution pattern
at the yne-ynamide allows the regiose-
lectivity to be switched toward 3- or 4-
aminopyridines. Application of this
synthetic methodology to the construc-
tion of the aminopyridone framework
using a yne-ynamide and an isocyanate
was also briefly examined. DFT com-
putations suggest that 3-aminopyridines
are formed by formal [4+2] cycloaddi-
tion between the nitrile and the inter-
mediate
cobaltacyclopentadiene,
Keywords: alkynes · cobalt · cyclo-
addition · nitrogen heterocycles ·
whereas 4-aminopyridines arise from
an insertion pathway.
reaction mechanisms
intermediates
·
reactive
[CpCo(CO)ACHTUNGTRENNUNG(dmfu)] (dmfu=dimethyl
fumarate) as a precatalyst made possi-
Introduction
structed by cobalt-catalyzed [2+2+2] cycloaddition between
an ynamide,[5] an alkyne, and a nitrile.[4a,c,6] As a sequel, we
report herein, a detailed investigation on the reactivity of
yne-ynamides towards nitriles in the presence of the air-
Pyridine derivatives are important organic targets because
they constitute a ubiquitous scaffold of bioactive and natural
products. Pyridines are also present in many promising ma-
terials.[1] Of all the synthetic pathways leading to the pyri-
dine core, the metal-catalyzed [2+2+2] cycloaddition reac-
tion is probably one of the most elegant because it is 100%
atom economical as far as the substrates are concerned.[2,3]
Thus, in recent years, particular interest has been paid in
our laboratory to the formation of pyridines using this strat-
egy.[4] Specifically, we have shown that polycyclic 3- and 4-
aminopyridines could be rapidly and regioselectively con-
stable precatalyst [CpCo(CO)ACTHNUGRTNEUNG(dmfu)] (dmfu=dimethyl fu-
marate).[7] The nature of the nitriles as well as the substitu-
tion pattern at each alkyne terminus of the yne-ynamides
have been scrutinized. Our results stimulated DFT computa-
tions aimed at getting a better overview of the mechanism
of pyridine formation by cobalt-catalyzed [2+2+2] cycload-
ditions.
Results and Discussion
In a preliminary report, we showed that a few nitriles and
yne-ynamides could be efficiently and regioselectively con-
verted into bicyclic 3- and 4-aminopyridines under cobalt
catalysis.[4c] To study the scope of this reaction, we decided
to broaden the variety of substrates, starting with yne-yna-
mide 1a and aliphatic nitriles (Table 1). This first set of ex-
periments revealed the importance of steric factors in this
process. Indeed, whereas the use of acetonitrile furnished 3-
aminopyridine 2 in 72% yield, bulky pivalonitrile gave rise
to 3 in only 36% yield (Table 1, entries 1 and 2). Among
methylene-substituted derivatives, 2-phenylacetonitrile read-
ily transformed into 4 and was isolated in 89% yield
(Table 1, entry 3). On the other hand, haloacetonitriles were
found to be inappropriate partners (Table 1, entry 4). Degra-
dation of the catalyst was actually observed in this case,
[a] P. Garcia, Prof. Dr. M. Malacria, Dr. C. Aubert, Prof. Dr. V. Gandon
UPMC, Univ Paris 06, IPCM 7201
4 Place Jussieu
75252 Paris Cedex 05 (France)
Fax : (+33)144-27-73-60
E-mail: vincent.gandon@u-psud.fr
corinne.aubert@upmc.fr
[b] Dr. Y. Evanno, Dr. P. George, Dr. M. Sevrin
Sanofi recherche & dꢀveloppement
1 avenue Pierre Brossolette
91385 Chilly-Mazarin (France)
[c] Dr. G. Ricci
Sanofi-Chimie
45 chemin de Mꢀtꢀline
04200 Sisteron (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103906.
Chem. Eur. J. 2012, 18, 4337 – 4344
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Table 1. Reaction of alkyl nitriles with yne-ynamide 1a.
Table 2. Reaction of yne-ynamides 1a–c with electron-deficient nitriles.
Entry
Ynamide
R
Product
Yield
[%][a]
[b]
Entry
R
Product
Yield
[%][a]
1
2
3
4
5
1a
1a
1a
1b
1c
Me
10
11
12
13
14
–
OMe
OBn
OBn
OBn
51
59
61
52
1[b]
2
Me
tBu
Bn
CH2X
CH2OMe
CH2SMe
CH2NMe2
CH2SO2Ph
CH2CO2tBu
CH2CO2H
2
3
4
–
5
6
7
–
8
–
72
36
89
0
73
73
83
0
3
4[c]
5
[a] Isolated product yield. [b] Trace amounts.
6
7
8
9
entries 2–5). With the latter, we could also use three- and
four-carbon tethered yne-ynamides for the construction of
dihydropyrrolopyridine 13 and tetrahydropyridoazepine 14.
The good results obtained with these electron-deficient ni-
triles are intriguing. Indeed, cyanoformates are known to
react sluggishly with 1,7-octadiyne under cobalt cataly-
sis.[12,13] Because a new catalyst was used during our work,
we wanted to know whether the efficiency of the incorpora-
tion of cyanoformates in the [2+2+2] process was inherent
to the complex or to the ynamide itself. To this end, a short
comparative study was carried out (Table 3). With the classi-
81
0
10
[a] Isolated product yield. [b] Nitrile: 10 equiv. [c] X=Cl, Br, or I.
both visually (the red color changing to green) and by
1H NMR spectroscopic analysis.[8] Methoxy-, methylthio-,
and dimethylaminoacetonitrile were converted into the ex-
pected 3-aminopyridines in high yields (73, 73, and 83%, re-
spectively; Table 1, entries 5, 6 and 7). Whereas no reaction
took place with phenylsulfonylacetonitrile (Table 1, entry 8),
tert-butyl cyanoacetate proved perfectly compatible (81%,
Table 1, entry 9). However, the use of the corresponding cy-
anoacetic acid resulted in catalyst degradation (Table 1,
entry 10).
Inspired by our recent work on cobalt-catalyzed cycload-
ditions involving alkynyl halides,[9] we envisaged the use of
cyanogen bromide as nitrile partner (Scheme 1). Although
the expected bicyclic aminopyridine was not observed in
this case, the unprecedented cyanoynamide 9 was isolated in
38% yield.[10,11]
cal air-sensitive complex [CpCo
and diyne 1d gave rise to pyridines in low yields (Table 3,
entries 1 and 2). In sharp contrast, with [CpCo(CO)(dmfu)],
(C2H4)2],[14] both ynamide 1a
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
the products were obtained in 59 and 60% yield in each
case (Table 3, entries 3 and 4). With 1a, only the 3-amino-
pyridine 12 was detected, whereas with 1d, a 1.5:1 mixture
of regioisomers 15 and 16 was obtained. Thus, beyond the
great advantage of [CpCo(CO)ACTHNUTRGENUGN(dmfu)] in terms of air-stabil-
ity, it appears that this catalyst expands the field of applica-
tions of cobalt-catalyzed transformations by allowing the
use of electron-poor nitriles. This effect cannot be attributed
to the difference in electronic properties between yne-
ynamides and diynes. However, the ynamide do actually
play a role by controlling the regioselectivity of nitrile incor-
poration.
Table 3. Yne-ynamide 1a versus diyne 1d in the reaction with benzyl cy-
anoformate.
Scheme 1. Unexpected reactivity of yne-ynamide 1a with BrCN.
Because BrCN failed to deliver a pyridine that was ame-
nable to functionalization at C6, we turned our attention to
pyruvonitrile and cyanoformates (Table 2). With the former,
only trace amounts of the expected product were observed
in the 1H NMR spectrum of the crude mixture (Table 2,
entry 1). Gratifyingly, methyl and benzyl cyanoformates fur-
nished the desired products in reasonable yields (Table 2,
Entry
Substrate
LL’
Product
Yield
[%][a]
1
2
3
4
1a
1d
1a
1d
A
12
15
12
15/16
24
17
59
N
(CO)
(CO)
G
R
60 (1.5:1)
1
[a] Ratio determined by H NMR spectroscopic analysis.
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Chem. Eur. J. 2012, 18, 4337 – 4344

Synthesis of Aminopyridines and Aminopyridones
FULL PAPER
Table 4. Cycloadditions between yne-ynamides and aromatic nitriles.
thiophenecarbonitrile, with 29
and 30 being isolated in 84 and
90%
yield,
respectively
(Table 4, entries 13 and 14).
Another approach to the syn-
thesis of aminopyridines by
metal-catalyzed [2+2+2] cyclo-
addition involves the use of cy-
anamides.[16] We have previous-
ly reported that yne-ynamide
1a could be reacted with N-cya-
nomorpholine to give 2,5-diami-
nopyridine 31 in 85% yield
(Table 5, entry 1).[4c] Regretta-
bly, the other heterosubstituted
nitriles that were evaluated
next proved quite reluctant, af-
fording yields of 20–51%. With
N-cyanopyrrolidine, the expect-
ed pyridine was isolated in
Entry Ynamide Ar
Product Yield
[%][a]
Entry Ynamide Ar
Product Yield
[%][a]
1
2
3
4
5
6
7
1a
1e
1 f
1b
1c
1a
1g
Ph
Ph
Ph
Ph
Ph
17
18
19
20
21
82
92
61
90
91
90
79
8
1a
1a
1a
1a
1a
1a
1a
2,4,6-F3-C6H2
24
100
40
9
4-(MeO)-C6H4 25
10
11
12
13
14
4-pyridyl
3-pyridyl
2-pyridyl
2-furyl
26
27
28
29
30
92
90
50 (81)[b]
4-(F3C)-C6H4 22
4-(F3C)-C6H4 23
84
90
2-thienyl
[a] Isolated product yield. [b] Reaction conducted on 1 g scale with 20 mol% catalyst.
The case of aromatic nitriles was studied next (Table 4).
Benzonitrile allowed the formation of a range of cycload-
ducts in good to high yields (Table 4, entries 1–5), as well as
electron-deficient 4-(trifluoromethyl)benzonitrile (Table 4,
entries 6 and 7) and 2,4,6-trifluorobenzonitrile (Table 4,
entry 8). The latter proved particularly well-tolerated be-
cause product 24 was isolated quantitatively. On the other
hand, with the electron-rich 4-(methoxy)benzonitrile, the
isolated yield was less than half of the previous yield
(Table 4, entry 9). Use of regioisomeric cyanopyridines also
permitted a highly efficient process to proceed (Table 4, en-
tries 10–12), even for the formation of a 2,2’-bipyridine scaf-
fold (Table 4, entry 12), although in this case an increase of
catalyst loading to 20 mol% was required to reach 81%
yield.[15] In spite of this limitation, it is worthy of note that
the synthesis of 28 could be carried out on a 1 g scale. Final-
ly, the reaction proved to be also compatible with oxygen-
and sulfur-containing heteroaromatics 2-furonitrile and 2-
32% yield (Table 5, entry 2). Nonetheless, it was possible to
reach 75% yield with prolonged heating (48 h). Proto-
desilylation occurred on silica gel during purification of the
crude mixture obtained after the reaction of 1g (Table 5,
entry 3).[4c,17] Five- and seven-membered rings could also be
assembled by using ynamides 1b (Table 5, entry 4) and 1c
(Table 5, entry 5). Interestingly, the use of ethyl thiocyanate
allowed the formation of the original 2-ethylthio-5-amino-
pyridines 36 and 37 (Table 5, entries 6 and 7).
All the yne-ynamides discussed above display only one
substituted alkyne terminus at the ynamide moiety, and
transform into 3-aminopyridines. We have previously report-
ed that the regioselectivity of the title reaction could be re-
versed to yield 4-aminopyridines when the alkyne terminus
of the yne moiety was the only substituted region
(Scheme 2).[4c] In the absence of substituents at both extrem-
ities, a mixture of regioisomers is formed.
Table 5. Synthesis of heterosubstituted aminopyridines.
Scheme 2. Regioselectivity of nitrile incorporation.
Entry
Ynamide
X-R
Product
Yield
[%][a]
In the context of this more detailed study, we wanted to
test yne-ynamides that were substituted at both alkyne ter-
mini. For this purpose, while maintaining the TMS group at
the ynamide fragment, we introduced methyl, ethyl, and
phenyl groups at the yne moiety. These substrates were re-
acted with benzonitrile, phenylacetonitrile, and dimethyl-
aminoacetonitrile (Table 6). This time, only 3-aminopyri-
dines were formed. However, the steric demand of R1 is
1
2
3
4
5
6
7
1a
1a
1g
1b
1c
1b
1a
N-morpholyl
N-pyrrolidyl
N-pyrrolidyl
N-pyrrolidyl
N-pyrrolidyl
SEt
31
32
33
34
35
36
37
85
32 (75)[b]
49[c]
51
20
37
33
SEt
[a] Isolated product yield. [b] 48 h instead of 15 h. [c] Protodesilylation
occurred: TMS/H 1:1.7.
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M. Malacria, C. Aubert, V. Gandon et al.
Table 6. Influence of the alkyne substitution.
tives has long been a matter of debate. DFT computations
have significantly contributed to this debate and have pro-
vided a pertinent overview of the mechanism, notably with
respect to the reaction of the key metallacyclopentadiene in-
termediate with the third alkyne unit, which may proceed
by insertion or formal [4+2] cycloaddition.[21] As far as pyri-
dines are concerned, although several computational studies
have also been reported, several issues are still not clearly
understood. In 2006, Kirchner et al. described the two path-
ways, summarized in Scheme 5,[22] concerning the cycloaddi-
tion of two acetylene units with hydrogen cyanide. Initially,
the 1,5-cyclooctadiene (COD) ligand is substituted by two
acetylenes to give the bis-alkyne complex A. Oxidative cyc-
lization follows to give metallacycle B. Hydrogen cyanide
binds to cobalt in an h2 fashion and inserts to give the
Co(V) carbene D. Reductive elimination leads to the h4-pyr-
idine complex E. In the second pathway, the COD ligand is
replaced by one acetylene and hydrogen cyanide to give AN
and then BN. Complexation of the second acetylene unit
Entry
Ynamide
R2 =Ph
R2 =Bn
R2 =CH2NMe2
1
2
3
1j
1k
1l
41 (76%)
44 (57%)
–
42 (68%)
45 (47%)
–
43 (83%)
46 (58%)
[a]
[a]
[a]
–
[a] No reaction.
a critical issue, as shown by the decrease in yields between
R1 =Me (Table 6, entry 1) and R1 =Et (Table 6, entry 2). No
cycloaddition took place with R1 =Ph (Table 6, entry 3); in
this case, the starting yne-ynamide was recovered in 90%,
along with a small amount of a cobalt complex.
We reacted yne-ynamide 1l with one equivalent of
[CpCo(CO)ACHTUNGTRENNUNG(dmfu)] in the absence of nitrile and isolated the
same complex in almost quantitative yield (Scheme 3).[18]
The product results from a formal [2+2] cycloaddition and
its formation inhibits completion of the three-component cy-
cloaddition pathway because the metal is irreversibly
trapped.[19]
Scheme 3. Formation of the h4-cyclobutadiene complex 47.
To conclude the experimental part of this work, we briefly
turned our attention to the synthesis of the aminopyridones,
by using yne-ynamides and isocyanates as unsaturated part-
ners.[20] The preliminary result depicted in Scheme 4 demon-
strates the feasibility of this process. However, two impor-
tant limitations were revealed: 1) a large excess of isocya-
nate was required to reach good conversion, and 2) the two
regioisomers were isolated in virtually a 1:1 ratio.
Scheme 4. First attempt of Co-catalyzed [2+2+2] aminopyridone synthe-
sis between an yne-ynamide and an isocyanate.
Scheme 5. Insertion versus [4+2] pathways in the Co-catalyzed [2+2+2]
cycloaddition of acetylene and hydrogen cyanide to give pyridine
[B3LYP/SDD (Co)/6-31G
of the TS are given over the arrows].
(d,p) (N, H, C), DG in kcal molÀ1, the energies
ACHTUNGTRENNUNG
Mechanism: The mechanism of the cobalt-catalyzed
[2+2+2] cycloaddition of alkynes to give benzene deriva-
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Synthesis of Aminopyridines and Aminopyridones
FULL PAPER
leads to CN and then EN by [4+2] cycloaddition with the het-
erodiene framework. Comparison of the energies shows that
the insertion pathway is favored over [4+2] cycloaddition.
In 2009, Koga et al. studied the [2+2+2] cycloaddition of
acetylene with acetonitrile by means of two-state DFT cal-
culations involving a singlet 18-electron species and a triplet
16-electron species (Scheme 6).[23] The intermediate metalla-
Koga et al. later showed that the insertion pathway be-
comes the best option with HCN or F3CCN (Scheme 8).[24]
Thus, by virtue of the energy of the frontier orbitals, it was
concluded that electron-rich nitriles tend to follow the [4+2]
mechanism, whereas electron-poor nitriles follow the inser-
tion mechanism.
3
cycle B actually reacts in its triplet ground state B with the
nitrile to give the singlet h1 complex C’, which subsequently
rearranges into the h2-nitrile complex C. The latter under-
goes [4+2] cycloaddition to give E’ and then E.
Scheme 8. Insertion pathway in the Co-catalyzed [2+2+2] cycloaddition
of acetylene and hydrogen cyanide and trifluoroacetonitrile [B3LYP/6-
31GACHTNUTGRNEUNG
(d,p) (all atoms) DE in kcal molÀ1, the energies of the TS or a mini-
mum energy crossing point (·) are given over the arrows].
Scheme 6. ACHTUNGTRENNUNG[4+2] Pathway in the Co-catalyzed [2+2+2] cycloaddition of
To shed more light on the insertion versus [4+2] cycload-
dition issue, we decided to confront these theoretical studies
with the case of ynamides. In our own computations, we first
used acetonitrile and N-ethynylpent-4-ynamine as the model
substrates. We chose to use the same level of theory as that
acetylene and acetonitrile to give 2-methylpyridine [B3LYP/6-31GACTHNUTRGNE(NUG d,p)
(all atoms) DE in kcalmolÀ1, the energy of the TS are given over the
arrows].
The insertion pathway was also computed (Scheme 7). In
this case, the regioisomeric carbenes D and D’ were located
and their transformation into E was modeled in two steps;
the first involving the formation of two azacobaltacyclohep-
tadienes F and F’. Because it was not possible to connect B
to D or D’, the insertion pathway was ruled out.
employed by Koga et al. [B3LYP/6-31GACTHNGUTER(NNUG d,p) (all
atoms)].[25,26] We focused on the regioselectivity of nitrile in-
corporation into the cobaltacyclopentadiene starting from
the singlet species GH (Scheme 9). In agreement with
Kogaꢂs work in the acetonitrile series, we were unable to
connect GH with carbene JH, the precursor of the 3-amino-
pyridine framework. The formation of the 3-aminopyridine
framework could be modeled by [4+2] cycloaddition
through HH and then IH. Surprisingly, attempts to locate the
regioisomer H’H on the potential energy surface were unsuc-
cessful. It seems that the enamine moiety of the metallacy-
cle readily reacts with the sp carbon of the nitrile to give
carbene J’H directly. Reductive elimination from the latter
species provides the h4-pyridine complex I’H, displaying a 4-
aminopyridine framework. Experimentally, 4-aminopyri-
dines are the major products when ynamides bear no sub-
stituent on the alkyne terminus (Scheme 2).[4c] The calcula-
tions corroborate this fact, with the transition states of the
[4+2] pathway lying higher in energy than those of the in-
sertion route.
Because the yne-ynamides used experimentally display an
electron-withdrawing group at the nitrogen atom, the transi-
tion states were reoptimized in the benzenesulfonyl (Bs)
series (Scheme 10). The deactivating effect of the Bs group
on the nitrogen strongly increases the energies of both the
Scheme 7. Incomplete insertion pathways in the Co-catalyzed [2+2+2]
cycloaddition of acetylene and acetonitrile to give 2-methylpyridine
[B3LYP/6-31GACHTUNGTRENNUNG
(d,p) (all atoms) DE in kcal molÀ1, the energies of the TS
are given over the arrows].
Chem. Eur. J. 2012, 18, 4337 – 4344
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4341

M. Malacria, C. Aubert, V. Gandon et al.
manner, we have found that the substitution of the metalla-
cycle by a nitrogen atom makes the insertion pathway more
favorable. This subtle balance dictates the regioselective
outcome of the formation of pyridines.
Conclusion
In summary, 28 nitriles were screened for the synthesis of
aminopyridines through cobalt-catalyzed [2+2+2] cycloaddi-
tion with yne-ynamides. Although a few substrates such as
haloacetonitriles were not tolerated, we found that most ni-
triles are suitable partners. In particular, it was possible to
use cyanoformates to reach the expected cycloadducts. The
success of this transformation is attributable to the use of
[CpCo(CO)ACTHNUGRTNEUNG(dmfu)] as a precatalyst. The formation of 3-
and 4-aminopyridines is regioselective, and depends on the
substitution pattern of the reactive yne-ynamides. This fea-
ture allowed us to complete the overview of the mechanism
of pyridine formation by cobalt-catalyzed [2+2+2] cycload-
dition by means of DFT computations. Indeed, the calcula-
tions suggest that 3-aminopyridines are formed by formal
[4+2] cycloaddition between the nitrile and the intermediate
cobaltacyclopentadiene. On the other hand, 4-aminopyri-
dines arise from an insertion pathway, which was not expect-
ed on the basis of previous computational studies. When
both alkyne termini are substituted, the construction of ami-
nopyridines is hampered by the formation of a stable h4-cy-
clobutadiene cobalt complex. Extension of this reaction to
the synthesis of aminopyridones is possible, although the re-
gioselectivity issue remains to be solved. This aspect is being
extensively investigated in our laboratory.
Scheme 9. Insertion versus [4+2] pathways in the Co-catalyzed [2+2+2]
cycloaddition between N-ethynylpent-4-ynamine and acetonitrile
[B3LYP/6-31GACHTUNGTRENNUNG
(d,p) (all atoms) (DE), [DH], {DG} in kcal molÀ1, the ener-
gies of the TS are given over the arrows).
Experimental Section
Compound 14: Benzyl cyanoformate (70 mg, 0.43 mmol) and
[CpCo(CO)ACTHNUTRGENUG(N dmfu)] (9 mg, 0.03 mmol) were added to a solution of the
starting ynamide (102 mg, 0.30 mmol) in toluene (6 mL) under an argon
atmosphere. After heating to reflux for 15 h, the mixture was allowed to
cool to RT, the mixture was purified by flash chromatography, eluting
first with petroleum ether and then with petroleum ether/ethyl acetate
(9:1) to give 14 as a brown solid (78 mg, 52%). M.p. 2008C; 1H NMR
(CDCl3, 400 MHz): d=0.47 (s, 9H), 1.11 (dd, J=24.9, 13.0 Hz, 1H), 1.48
(td, J=13.6, 2.0 Hz, 1H), 1.54–1.73 (m, 2H), 1.75–1.92 (m, 1H), 2.21 (dd,
J=14.3, 4.4 Hz, 1H), 2.41 (s, 3H), 3.04 (t, J=14.8 Hz, 1H), 4.49 (dd, J=
11.6, 3.2 Hz, 1H), 5.43 (q, J=12.7 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H),
7.33–7.42 (m, 3H), 7.45 (d, J=8.4 Hz, 2H), 7.51 (d, J=7.3 Hz, 2H),
7.65 ppm (s, 1H); 13C NMR (CDCl3, 100 MHz): d=0.1 (CH3), 21.7
(CH3), 24.6 (CH2), 27.4 (CH2), 33.1 (CH2), 50.7 (CH2), 67.1 (CH2), 125.1
(CH), 127.5 (CH), 128.1 (CH), 128.3 (CH), 128.7 (CH), 129.9 (CH),
136.0 (C), 138.8 (C), 143.4 (C), 143.7 (C), 147.3 (C), 150.0 (C), 165.3 (C),
Scheme 10. Insertion versus [4+2] pathways in the Co-catalyzed [2+2+2]
cycloaddition between N-ethynyl-N-(pent-4-ynyl)benzenesulfonamide
and acetonitrile [B3LYP/6-31GACHTUNTRGNEU(GN d,p) (all atoms) (DE), [DH], {DG} in kcal
molÀ1, the energies of the TS are given over the arrows).
[4+2] cycloaddition and insertion steps. However, formation
of the 4-aminopyridine framework remains favored.
172.0 ppm (C); IR (neat): n=2940, 1741, 1719, 1156 cmÀ1; HRMS: m/z:
˜
calcd for [C27H33N2O4SSi]+: 509.19248; found: 509.19079.
Thus, as a counterpart to the previous studies, which
showed that the switch between the two pathways was criti-
cally dependent on the nature of the nitrile, we established
that the electronic properties of the metallacycle itself are
a critical feature. Indeed, although electron-rich acetonitrile
is supposed to react with cobaltacyclopentadienes in a [4+2]
Compound 36: Ethyl thiocyanate (39 mg, 0.45 mmol) and [CpCo(CO)-
AHCTUNGTREG(NNUN dmfu)] (9 mg, 0.03 mmol) were added to a solution of the starting
ynamide (100 mg, 0.30 mmol) in toluene (6 mL) under an inert atmos-
phere. After heating to reflux for 15 h, the mixture was allowed to cool
to RT and purified by flash chromatography, eluting first with petroleum
ether and then with petroleum ether/ethyl acetate (9:1) to give 36 as
a white solid (41 mg, 33%). M.p. 1958C; 1H NMR (CDCl3, 400 MHz):
4342
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Chem. Eur. J. 2012, 18, 4337 – 4344

Synthesis of Aminopyridines and Aminopyridones
FULL PAPER
d=0.41 (s, 9H), 1.04–1.14 (m, 1H), 1.38–1.44 (m, 4H), 1.71–1.86 (m,
1H), 2.08 (dt, J=15.6, 4.8 Hz, 1H), 2.40 (s, 3H), 3.17 (dq, J=14.3,
7.2 Hz, 1H), 3.32 (dq, J=14.5, 7.2 Hz, 1H), 3.42–3.52 (m, 1H), 3.92–4.03
(m, 1H), 6.66 (s,1H), 7.19 (d, J=8.1 Hz, 2H), 7.34 ppm (d, J=8.1 Hz,
2H); 13C NMR (CDCl3, 100 MHz): d=0.2 (CH3), 15.3 (CH3), 21.7 (CH3),
22.8 (CH2), 24.3 (CH2), 25.5 (CH2), 45.5 (CH2), 119.4 (CH), 127.7 (CH),
129.8 (CH), 135.5 (C), 136.3 (C), 143.8 (2 C), 155.6 (C), 167.6 ppm (C);
IR (neat): n˜ =2952, 1162 cmÀ1; HRMS: m/z: calcd for [C20H29N2O2S2Si]+:
421.14342; found: 421.14299.
49, 2840; b) A. K. Dekorver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu,
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Compound 47: [CpCo(CO)ACTHNUTRGNE(NUG dmfu)] (22 mg, 0.07 mmol) was added to a so-
lution of the starting ynamide (30 mg, 0.07 mmol) in toluene (2 mL)
under an inert atmosphere. After heating to reflux for 15 h the mixture
was allowed to cool to RT and purified by flash chromatography, eluting
with petroleum ether/ethyl acetate (4:1) to give 47 as a red oil (39 mg,
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[8] The catalyst is air stable and can be purified over silica; the pres-
ence of which can be checked by TLC analysis.
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1
99%). H NMR (CDCl3, 400 MHz): d=0.39 (s, 9H), 1.03 (br s, 1H), 1.66
(br s, 1H), 1.94 (ddd, J=16.5, 6.6, 4.0 Hz, 1H), 2.38 (s, 3H), 2.43–2.48
(m, 1H), 3.59 (br s, 2H), 4.69 (s, 5H), 7.18 (d, J=7.7 Hz, 2H), 7.23–7.29
(m, 5H), 7.68 ppm (d, J=8.1 Hz, 2H); 13C NMR (CDCl3, 100 MHz): d=
2.1 (CH3), 20.3 (CH2), 20.9 (CH2), 21.7 (CH3), 46.8 (CH2), 52.6 (C), 70.7
(C), 75.5 (C), 81.5 (CH), 95.1 (C), 125.6 (CH), 127.4 (CH), 127.9 (CH),
128.1 (CH), 129.9 (CH), 136.1 (C), 138.9 (C), 143.8 ppm (C). IR (neat):
n˜ =2952, 1164 cmÀ1
;
HRMS: m/z: calcd for [C28H32N2O2CoSSi]+:
533.12495; found: 533.12395.
[10] Here, the reaction might proceed through a Von Braun-like mecha-
ꢀ
nism: nucleophilic attack of the ynamide onto the C N bond, releas-
ing BrÀ, which subsequently abstracts TMS. For a review on the Von
Acknowledgements
We thank Sanofi-Aventis, the IUF, Ministꢃre de la recherche and CNRS
for financial support. We used the computing facility of the CRIHAN
(project 2006–013).
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Received: February 1, 2012
Published online: March 1, 2012
4344
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Chem. Eur. J. 2012, 18, 4337 – 4344