Efficient generation of pyridines by ruthenium carbene mediated [2 + 2 + 2] cyclotrimerization

Article abstract of DOI:10.1021/ol301498z

Hoveyda-Grubbs' catalyst is able to catalyze crossed [2 + 2 + 2] cyclotrimerizations of diynes with nitriles. Pyridines are obtained with excellent yields when using activated nitriles and low to moderate yields with nonactivated nitriles which are unreac

Full text of DOI:10.1021/ol301498z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Efficient Generation of Pyridines by
Ruthenium Carbene Mediated [2 þ 2 þ 2]
Cyclotrimerization
ꢀ
Sandra Medina, Gema Domınguez, and Javier Perez-Castells*
´
´
Facultad de Farmacia, Dpto. Quımica, Universidad San Pablo CEU, Urb.
Monteprıncipe, ctra. Boadilla km 5,300 Boadilla del Monte, 28668 Madrid
´
jpercas@ceu.es
Received May 31, 2012
ABSTRACT
HoveydaꢀGrubbs’ catalyst is able to catalyze crossed [2 þ 2 þ 2] cyclotrimerizations of diynes with nitriles. Pyridines are obtained with excellent
yields when using activated nitriles and low to moderate yields with nonactivated nitriles which are unreactive under previously described
ruthenium catalyzed reaction conditions. Both terminal and internal alkynes give the reaction using this experimental procedure.
Metal catalyzed [2 þ 2 þ 2] cycloadditions allow the
synthesis of carbo- and heterocycles, involving the forma-
tion of several CꢀC bonds in a single step. This elegant,
atom-efficient, and group tolerant process is catalyzed
by complexes of more than 17 metals.1 The transition-
metal-mediated cyclocotrimerization of alkynes with cyano
reactions between acetylenes and nitriles, or by reactions
of alkynenitriles with alkynes. The reaction tolerates a
wide variety of functional groups in the substrates, giving
access to densely functionalized pyridinic products.3
With regard to the catalysts generally used for pyridine
asembly through [2 þ 2 þ 2] cyclizations, Co complexes of
the type [CpCoL2] (L = CO, PR3, olefin) have been
extensively studied4 as well as Rh,5 Fe,6 and Ni7 catalysts.
Ruthenium catalysts such as [CpRuCl(cod)] are able to
catalyze trimerization of alkynes8 and are useful in the [2 þ
2 þ 2] cycloaddition of 1,6-diyneswithnitriles, isocyanates,
groups was first pioneered by Wakatsuki and Yamazaki
€
2
followed by Bonnemann. Afterward Vollhardt’s group
reported cycloadditions of diynes and alkynenitriles lead-
ing to pyridines, mediated by cobalt. Later, other groups
developed mild and catalytic reaction conditions using
other metals and asymmetric reactions mainly en route to
axially chiral products. De novo construction of pyridine
ring systems is achieved now by reaction of diynes and
oligoynes with nitriles, by completely intermolecular
(3) Specific reviews on pyridine synthesis: (a) Heller, B.; Hapke, M.
Chem. Soc. Rev. 2007, 36, 1085–1094. (b) Henry, G. D. Tetrahedron
2004, 60, 6043–6061. (c) Varela, J.; Saa, C. Synlett 2008, 2571–2578.
(4) (a) Heller, B.; Sundermann, B.; Fischer, C.; You, J.; Chen, W.;
Drexler, H. J.; Knochel, P.; Bonrath, W.; Gutnov, A. J. Org. Chem.
~
2003, 68, 9221–9225. (b) Bonaga, L. V. R.; Zhang, H.-C.; Moretto, A. F.;
(1) Reviews: (a) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006,
348, 2307–2327. (b) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org.
Chem. 2005, 4741–4767. (c) Saito, S.; Yamamoto, Y. Chem. Rev. 2000,
100, 2901–2916. (d) Agenet, N.; Busine, O.; Slowinski, F.; Gandon, V.;
Aubert, C.; Malacria, M. Org. React. 2007, 68, 1–302. (e) Galan, B. R.;
Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830–2834. (f) Leboeuf, D.;
Gandon, V.; Malacria, M. In Handbook of Cyclization Reactions; Ma, S.,
Ed.; John Wiley & Sons, Inc.: 2010; Vol. 1, pp 367ꢀ405. (g) Inglesby, P. A.;
Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791–2805. (h) Weding, N.;
Hapke, M. Chem. Soc. Rev. 2011, 40, 4525–4538. (i) Dominguez, G.;
Ye, H.; Gauthier, D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am.
Chem. Soc. 2005, 127, 3473–3485. (c) Senaiar, R. S.; Young, D. D.;
Deiters, A. Chem. Commun. 2006, 1313–1315. (d) Young, D. D.; Deiters,
A. Angew. Chem., Int. Ed. 2007, 46, 5187–5190.
(5) Wada, A.; Noguchi, K.; Hirano, M.; Tanaka, K. Org. Lett. 2007,
9, 1295–1298.
(6) (a) D’Souza, B. R.; Lane, T. K.; Louie, J. Org. Lett. 2011, 13,
2936–2939. (b) Kumar, P.; Prescher, S.; Louie, J. Angew. Chem., Int. Ed.
2011, 50, 10694–10698. (c) Wang, C.; Li, X.; Wu, F.; Wan, B. Angew.
Chem., Int. Ed. 2011, 50, 7162–7166.
ꢀ
Perez-Castells, J. Chem. Soc. Rev. 2011, 40, 3430–3444.
(2) (a) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Chem. Commun.
€
(7) (a) Stolley, R. M.; Maczka, M. T.; Louie, J. Eur. J. Org. Chem.
2011, 3815–3824. (b) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie,
J. J. Am. Chem. Soc. 2005, 127, 5030–5031.
1973, 280–281. (b) Bonnemann, H. Angew. Chem., Int. Ed. Engl. 1985,
24, 248–262.
r
10.1021/ol301498z
XXXX American Chemical Society

and isothiocyanatestoaffordpyridines, bicyclic pyridones,
and thiopyridones in good yields.9 In particular, dicya-
nides, cyanamides, and halonitriles exhibited exceptionally
high reactivity toward the [Cp*RuCl(cod)] catalyzed cy-
cloaddition with 1,6-diynes leading to bicyclic pyridines
under mild conditions.10
Table 1. Selection of Reaction Conditions for the Crossed
Cyclotrimerization Reaction of 1a with Malononitrile
There are a few precedents in using Grubbs’ first gen-
eration catalysts [Ru]-I to mediate in cyclotrimerization
[2 þ 2 þ 2] reactions for the synthesis of benzene rings.11
Blechert et al. reported for the first time that [Ru]-I is an
efficient catalyst for the intramolecular cyclotrimerization
of alkynes. A cascade metathetic mechanism was postu-
lated in these examples where vinyl carbene complexes
would be the reactive intermediates.12 We have recently
published the use of second generation Grubbs’ catalysts
[Ru]-II and reusable HoveydaꢀGrubbs’ complex [Ru]-III
for the synthesis of fused benzenes.13
yield (%)a
entry solvent temp (°C)
time
cat. (mol %) 1a
2a
We present here the synthesis of a wide variety of highly
functionalized pyridines, obtained for the first time through
an easy experimental procedure based on ruthenium carbene
catalysts.
1
2
3
4
5
6
7
8
9
DCE
rt
48 h
16 h
16 h
16 h
16 h
16 h
16 h
1 h
5
5
5
5
5
5
5
5
5
2
5b
5c
5
5
70
ꢀ
30
78
92
85
ꢀ
DCE
80
DCE
90
ꢀ
acetone
MeCN
EtOAc
dioxane
DCE
75
ꢀ
In order to optimize the reaction, diyne 1a was reacted
with malononitrile under a variety of reaction conditions
(Table 1). The first tests were carried out in DCE with
5 mol % of catalyst [Ru]-IIIand 5 equivalents of nitrile. They
showed the need for heating to achieve total conversion
and reach good yields of product 2a (entries 1 and 2,
Table 1). The reaction was then performed in a sealed tube
which increased the yield to 92% (entry 3). This improve-
ment may be due to an increase in the population of the
reactive conformation of the diyne under higher pressure.
Next we check different solvents under these latter condi-
tions (acetone, MeCN, EtOAc, dioxane, entries 4ꢀ7). We
observed good results except for MeCN, possibly due to
the poor solubility of the catalysts. However, DCE con-
tinued to be the best choice. Entries 8 and 9 show reactions
in which reaction time was reduced to 1 h and 15 min
respectively which allowed the best results (99%, entry 9).
However when reducing the catalyst loading to 2 mol %
the reaction was not complete (entry 10). Next, for com-
parison, we used our best conditions (5 equiv of nitrile, in
90
80
ꢀ
90
85
47
95
99
73
15
80
78
ꢀ
90
ꢀ
90
ꢀ
DCE
90
15 min
ꢀ
10 DCE
11 DCE
12 DCE
13 DCE
14 DCE
90
15 min
27
55
ꢀ
90
15 min
90
15 min
90, rt
90, rt
10 min, 48 hd
10 min, 16 he
18
80
a Reactions were conducted in a sealed tube except entries 1ꢀ2 (entry
2 under reflux), at 66.6 mM concentration of diyne with 5 equiv of nitrile.
b With [Ru]-I as the catalyst. c With [Ru]-II as the catalyst. d Catalyst is
dissolved and heated at 90 °C in a sealed tube for 10 min and then cooled
to rt, and reagents were added and then stirred at rt for 48 h. e Catalyst
and nitrile are dissolved and heated at 90 °C in a sealed tube for 10 min
and then cooled to rt, and diyne was added and then stirred at rt for 16 h.
DCE at 90 °C, sealed tube), using [Ru]-I and [Ru]-II as the
catalysts (entries 11ꢀ12). The first generation Grubbs’
catalyst proceeded with low yield while [Ru]-II gave a good
result slightly below to that achieved with [Ru]-III. The
ability of [Ru]-III to catalyze these cyclotrimerizations
(8) (a) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Nishiyama, H.;
Itoh, K. Org. Biomol. Chem. 2004, 2, 1287–1294. (b) Yamamoto, Y.;
Arakawa, T.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2003, 125, 12143–
12160. (c) Yamamoto, Y.; Hata, K.; Arakawa, T.; Itoh, K. Chem.
Commun. 2003, 1290–1291. (d) Hoven, G. B.; Efskind, J.; Romming,
C.; Undheim, K. J. Org. Chem. 2002, 67, 2459–2463.
(9) (a) Yamamoto, Y.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2001,
123, 6189–6190. (b) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett.
2001, 3, 2117–2119. (c) Yamamoto, Y.; Kinpara, K.; Saigoku, T.;
Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc.
2005, 127, 605–613.
(14) General procedure for synthesis of pyridines. Over a solution of
the diyne and the nitrile in 2 mL of 1,2-dichloroethane contained in a
pressure flask, a solution of [Ru]-III in 2 mL of the same solvent was
added. The flask was sealed and introduced in a 90 °C bath, and the
resulting mixture was stirred until the reaction was completed (TLC).
After cooling the flask to rt the reaction mixture was filtered through
celite, the solvent was eliminated under reduced pressure, and the residue
was purified by column chromatography. Preparation of dibenzyl 3-
(cyanomethyl)-1,4-dimethyl-5H-cyclopenta[c]pyridine-6,6(7H)-dicarbox-
ylate, 2a. From 1a (0.100 g, 0.260 mmol), malononitrile (0.085 g, 1.290
mmol) and [Ru]-III (0.008 g, 0.013 mmol), following the general
procedure for the synthesis of pyridines (reaction time: 15 min) and
upon purification by column chromatography (Hex/EtOAc 4:1 to 2:1),
0.117 g (99%) of 2a is obtained as a white solid (mp = 105ꢀ106 °C). 1H
NMR (300 MHz, CDCl3) δ 7.33ꢀ7.31 (m, 6H, Ph), 7.24ꢀ7.21 (m, 4H,
Ph), 5.14 (s, 4H, 2ꢁCH2O), 3.81 (s, 2H, CH2CN), 3.56 (s, 2H, CH2C),
3.55 (s, 2H CH2C), 2.38 (s, 3H, CH3), 2.22 (s, 3H, CH3). 13C NMR
(75 MHz, CDCl3) δ 170.8, 151.2, 149.7, 146.6, 135.1, 134.1, 128.6, 128.5,
128.1, 125.1, 116.9, 67.8, 59.7, 39.7, 38.9, 24.7, 21.6, 14.7. IR (KBr): 2240,
1732, 1586 cmꢀ1. Anal. Calcd for C28H26N2O4: C, 73.99; H, 5.77; N,
6.16. Found: C, 73.80; H, 5.83; N, 6.20.
(10) (a) Yamamoto, Y.; Kinpara, K.; Ogawa, R.; Nishiyama, H.;
Itoh, K. Chem.;Eur. J. 2006, 12, 5618–5631. (b) Varela, J. A.; Castedo,
L.; Saa, C. J. Org. Chem. 2003, 68, 8595–8598.
(11) (a) Roy, R.; Das, S. K. Chem. Commun. 2000, 519–529. (b) Das,
S. K.; Roy, R. Tetrahedron Lett. 1999, 40, 4015–4018. (c) Witulski, B.;
ꢀ
ꢀ
Stengel, T.; Fernandez-Hernandez, J. M. Chem. Commun. 2000, 1965–
1966. (e) Young, D. D.; Senaiar, R. S.; Deiters, A. Chem.;Eur. J. 2006,
12, 5563–5568. (f) Hoven, G. B.; Efskind, J.; Romming, C.; Undheim, K.
J. Org. Chem. 2002, 67, 2459–2463.
(12) Peters, J.-U.; Blechert, S. Chem. Commun. 1997, 1983–1984.
ꢀ
(13) Mallagaray, A.; Medina, S.; Domınguez, G.; Perez-Castells, J.
´
Synlett 2010, 2114–2116.
B
Org. Lett., Vol. XX, No. XX, XXXX

possiblyhastodo withitstransformation mediated byheat
into a different species. Therefore we checked if, after the
catalysts modification, the [2 þ 2 þ 2] reaction could
proceed at rt. Thus, after heating the catalyst during
10 min at 90 °C in a sealed tube we added the reagents
and stirred the mixture at rt (entry 13). After 48 h the
reaction was not complete, and 78% of 2a was isolated
recovering 18% of the starting diyne. On the other hand,
heating of the catalyst at high temperature with the nitrile
and further addition of the diyne at rt precluded the
reaction (entry 14). This result could be due to the forma-
tion of an inactive species upon reaction of the metal with
the nitrile preventing its coordination with the diyne.
Once the best conditions for the cyclotrimerization of
diynes with alkynes were selected, we studied the scope of
the process reacting different diynes with nitriles.14 Diynes
1aꢀe were reacted with dinitriles, R-halonitriles, benzoni-
triles, cyanoformate, and benzoylcyanide (Table 2). The
reactions with malononitrile (entries 1ꢀ5) gave good to
excellent yields (71ꢀ99%). The exception was dipropargyl
ether 1e which gave 51% of pyridine 2e along with 21% of
the diyne dimer 3. This diyne is very reactive and has a
great tendency to oligomerize or polymerize as we ob-
served in previous works.13 Saa10b and Yamamoto’s
groups9c,10a have studied thoroughly the scope of the
pyridine synthesis through CpRuCl-catalyzed [2 þ 2 þ 2]
cyclotrimerization reactions. These groups described that
only dinitriles (that could include further unsaturation, e.g.
alkylidene, arene), nitriles which incorporate electron-
deficient and -rich substituents, and R-halonitriles reacted
with diynes. This especially good performance, in contrast
with the behavior of benzonitriles or simple aliphatic
nitriles, is thought to be due to an assisting effect of the
additional functional group. These groups observedthat in
the cycloaddition reaction with dicyanides only one nitrile
group reacted, leaving the other one unchanged, exactly
what we have observed with [Ru]-III. Thus we reacted 1a
with benzodinitrile (entry 6) obtaining an excellent yield of
2f. On the other hand, fumaronitrile (entries 7ꢀ9) and
succinonitrile (entry 10) were less reactive giving moderate
yields (43ꢀ64%) of the pyridines but with recovery of the
starting material. In addition, we reacted chloro- and
dichloroacetonitrile with 1a and 1d which gave the chloro-
methyl pyridines 2k, 2l, and dichloropyridine 2m in mod-
erate to good yields (entries 11ꢀ13), whereas diyne 1e
(entry 14) gave a poor yield of 2n. Reactions of 1a and 1d
with ethyl cyanoformate gave pyridines 2o and 2p with
good yields (entries 15ꢀ16). Product 2q was prepared with
moderate yield using benzoylcyanide as a reagent (entry 17).
Although previous reports in the literature9,10 were dis-
couraging in the consecution of Ru-catalyzed cyclotri-
merizations of diynes with benzonitriles, we tried our
conditions with diynes 1aꢀb and benzonitrile or p-methyl-
benzonitrile. The results were poor with 5 mol % equiv of
catalyst (entry 18) but could be increased up to a 22ꢀ30%
yield of pyridine if the catalyst loading was doubled
(entries 19ꢀ21). These results although not satisfactory
have not been described previously in the literature with
typical Ru catalysts and may imply a higher activity of the
active species in our procedure.
Table 2. Scope of the Crossed Cyclotrimerization Reaction
entry diyne
X
R1
R2
time (h) prod. yield (%)a,b
1
1a (BnO2C)2Cc Me CH2CN
1b (EtO2C)2C Me CH2CN
0.25 2a
0.25 2b
99
2
99
3
1c TsN
1d (BnO2C)2Cc H CH2CN
1e CH2CN
Me CH2CN
0.5
2c
83
4
0.25 2d
71
51d
5
O
H
0.5
19
1.5
0.5
1
2e
2f
6
1a (BnO2C)2Cc Me p-C6H4CN
1a (BnO2C)2Cc Me CH=CHCN
94
7
2g
2h
2i
58 (40)e
43 (47)e
63 (18)e
64 (24)e
79
8
1c TsN
Me CH=CHCN
9
1d (BnO2C)2Cc H CH=CHCN
1a (BnO2C)2Cc Me CH2 CH2CN
1a (BnO2C)2Cc Me CH2Cl
1d (BnO2C)2Cc H CH2Cl
1d (BnO2C)2Cc H CHCl2
10
11
12
13
14
15
16
17
18
19
20
21
1
2j
1
2k
2l
1
46
1
2m 63
1e
O
H
CHCl2
0.5
1
2n
2o
2p
2q
2r
2r
2s
2t
24
68
74
49
11
22f
30f
25f
1a (BnO2C)2Cc Me CO2Et
1d (BnO2C)2Cc H CO2Et
1a (BnO2C)2Cc Me COPh
1b (EtO2C)2C Me Ph
1b (EtO2C)2C Me Ph
1a (BnO2C)2Cc Me Ph
1
1
16
16
16
1a (BnO2C)2Cc Me p-C6H4-CH3 16
a Reactions were conducted in a sealed tube at 66.6 mM con-
centration of diyne with 5 equiv of nitrile and 5 mol % of [Ru]-III.
b Yield (%) of pure product. c Bn = benzyl. d 21% of 3 was isolated.
e Parentheses: yield of starting diyne recovered. f 10 mol % of catalyst
was used.
The next step was the study of the regioselectivity of the
pyridine synthesis with nonsymmetric diynes. Thus, we
prepared diynes 1fꢀg and reacted them with some of the
above used nitriles (Scheme 1). The reactions proceeded
with excellent yield with malononitrile (2u, 2x) and mod-
erate yields with fumaronitrile (2v). On the other hand
benzonitrile and the R-halonitriles used produced the
corresponding pyridines (2w, 2y, 2z, and 2r) with lower
yields. In all the examples the regioselectivity was complete
(15) Nonsymmetric diynes are known to give selectively the pyridine
with the nitrogen adjacent to the more bulky substituent; see: (a) Zou,
Y.; Liu, Q.; Deiters, A. Org. Lett. 2011, 13, 4352–4355. (b) Gray, B. L.;
Wang, X.; Brown, W.; Kuai, C. L.; Schreiber, S. L. Org. Lett. 2008, 10,
2621–2624. (c) Garcia, P.; Evanno, Y.; George, P.; Sevrin, M.; Ricci, G.;
Malacria, M.; Aubert, C.; Gandon, V. Org. Lett. 2011, 13, 2030–2033.
Org. Lett., Vol. XX, No. XX, XXXX
C

in favor of the less hindered product as observed in most
studies with nonsymmetric diynes.15
Scheme 3. Possible Reaction Course for the Pyridine Formation
Scheme 1. Crossed Cyclotrimerization of Nonsymmetric Diynes
carbene is transformed into a species structurally related
with the aforementioned CpRuCl-based complexes. This
would be in contrast with the mechanism assumed pre-
viously for [2 þ 2 þ 2] cyclotrimerizations of alkynes
catalyzed by the [Ru]-I catalyst which was based on a
cascade metathetic process.12 Our results point to a possible
different pathway that could be similar to the one depicted
in Scheme 3 which was proposed by Varela and Saa for
CpRuCl-type complexes.16 Heating the initial [Ru]-III
complex produces a new activated species as observed
by us and other groups,17 capable of coordination with
dinitriles to give the dinuclear complex A. This complex
allows formation of the intermediate ruthenacyclopenta-
diene B by reaction with diyne 1. Pyridine 2 would be
formed by insertion of the Ru-bound cyano group into the
RuꢀC bond.
When using Ru catalysts in the [2 þ 2 þ 2] cyclotrimer-
ization of diynes, we have found no precedents of the
formation of fused six-membered rings upon reaction of
1,7-diynes. We envisioned the possibility of reacting a
benzene-templated 1,7-diyne (4), under our conditions,
and were pleased to obtain the benzonaphthyridine 5 in
good yield. This product was obtained in a total regiose-
lective manner as the isomer depicted in Scheme 2.
Scheme 2. Synthesis of Benzonaphthyridine 5
In conclusion, we have achieved a new protocol for
crossed diyneꢀnitrile cyclotrimerizations mediated by Ho-
veydaꢀGrubbs’ complex [Ru]-III. This catalytic protocol
offers an efficient access to substituted pyridines.
Acknowledgment. Funding of this project by Spanish
MEC (No. CTQ2009-007738/BQU) and FUSP-CEU
ꢀ
(PC16/09) is acknowledged. S.M. thanks the Fundacion
San Pablo-CEU for predoctoral fellowship.
With all these results in hand it is noteworthy the similar
behavior that [Ru]-III catalysis has with regard to
CpRuCl-based complexes. Provided that ruthenium car-
bene complexes have the tendency to be transformed in
other species by loss of the phosphine and the benzylidene
moieties, it is possible that, under our conditions, the
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, and spectra for compounds
1ꢀ5. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ
(16) Varela, J. A.; Saa, C. J. Organomet. Chem. 2009, 694, 143–149.
(17) Mallagaray, A.; Mohammadiannejad-Abbasabadi, K.; Medina,
ꢀ
S.; Domınguez, G.; Perez-Castells, J. Org. Biomol. Chem. 2012, 10,
´
6665–6672 and references cited therein.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX