- Email: [email protected]
Cobalt-catalyzed synthesis of pyridines from 1-alkynes and nitriles: substrate structure and regioselectivity
Journal of Molecular Catalysis, 41 (1987)
261-
270
261
COBALT-CATALYZED SYNTHESIS OF PYRIDINES FROM l-ALKYNES AND NITRILES: SUBSTRATE STRUCTURE AND REGIOSELECTIVITY PIETRO DIVERSI, GIOVANNI INGROSSO,* DAR10 VANACORE Dipartimento di Chimica e Chimica Industriale, 56100 Pisa (Italy)
ANTONIO LUCHERINI*
and
Universitci di Piss, Via Risorgimento
35,
(Received July 9, 1986; accepted December 23,1986)
Summary A study has been carried out of the influence exerted by the substrate structure on the regioselectivity of the synthesis of trisubstituted pyridines by cocyclization of 1-alkynes (R-CCH) and nitriles (R’-CN) catalyzed by the complexes [CoCp*(C2H&], (IVa) (Cp* = 77’~C5H5)and (IVb) (Cp* = q5-C5Mes). In most cases two isomers, i.e. the 2,4,6- and 2,3,6-trisubstituted pyridines, form, whose distribution depends upon the steric and electronic effects induced by R and R’. From highly sterically hindered alkynes and nitriles only the 2,4,6-trisubstituted isomer is formed. When R is a strong electron-withdrawing group (COOMe), the 2,3,5+isubstituted pyridine is formed in addition to the 2,4,6- and 2,3,6_trisubstituted ones, whose distribution can be varied by altering the steric features of nitriles.
Introduction Transition-metal catalyzed cocyclization of alkynes and nitriles has allowed the one-pot synthesis of a variety of pyridine derivatives [l, 21. Starting from 1-alkynes, only the pyridinic isomers (I) and (II) have so far been observed, in addition to variable amounts of benzene derivatives.
R-CCH
+
R’-CN
-
R&&R: R@R;R@; (II
*Authors to whom correspondence 0304-5102/87/$3.50
(Ill
should be addressed. 0 Elsevier Sequoia/Printed
in The Netherlands
262
When Cp*-containing catalysts are employed, the isomer distribution depends upon the nature of the Cp* ligand, the highest (I) to (II) ratios having been observed in the presence of pentamethylcyclopentadienylic catalysts [ 2, 31. Furthermore, a systematic study of the catalytic properties of the two rhodium complexes, [RhCp*(CzH&] (Cp* = n5-C5H5 and g5C5Mes), has pointed out that the regioselectivity of the cocyclization reactions increases markedly by increasing the cone angle, not only of the groups attached to the CC triple bond but also of those attached to the CN triple bond, thus allowing the regiospecific synthesis of 2,4,6trisubstituted pyridines [ 21. We have now extended the study of these aspects to the cobalt complexes [CoCp*(C,H&], and we have observed the same general trend. More interestingly, it has also been observed that, depending upon the nature of the alkyne substituents R, the isomer (III), which has never been observed previously, is formed in addition to (I) and (II). R
R
TX 0
N
R’
(1111
A brief report on preliminary results has already been communicated
[41. Results and discussion The complexes (IVa) and (IVb) are known to be active catalyst precursors for the synthesis of pyridine derivatives and have been extensively studied using a continuous flow apparatus [ 11. [CoCp*(CzH&]
(IVa), Cp* = 715-C5H5 (IVb), Cp* = g5-C5Me5
Since we were interested in batch reactions, we have preliminarily carried out a study of the activity and the chemoselectivity of (IVa) and (IVb) as a function of various reaction parameters, using the cocyclization of 1-hexyne and propionitrile as the test reaction. The choice of these substrates was suggested by the fact that a similar study on the reactions of these comonomers had already been done for the case of the Cp*-containing rhodium catalysts [ 2, 51. On the basis of this study, the optimum reaction conditions are: temperature, 50 “C for (IVa) and 110 “C for (IVb); alkyne-to-cobalt molar ratio 100, nitrile-to-alkyne molar ratio 3, and reaction time 48 h, for both (IVa) and (IVb). Thus, these experimental conditions have been adopted for studying the influence of the structural features of 1-alkynes and nitriles on both the
263 TABLE 1 Cocylization (IVb)a Run
R
of terminal alkynes (R-CCH)
R’
Pyridine yield (%)b (IVa)
(IVb)
with nitriles (R’-CN)
Benzene yield (%)h.” (IVa)
(IVb)
catalyzed by (IVa) and
Chemoselectivity (%)d
Pyridinic isomer (I)
(IVa)
(%)e
(IVb)
(IVa) 1 2 3 4 5 6 I 8 9 10 11 12 13 14
(IVb)
BU” BU” BU” Bu” Bu” Bu” Bu” Bu” Bu”
Me Et Pr’ Bu” Bu’ But Ph (CHs)&N N_(CHsk
71 84 71 69 66 22 48 16 62
83 82 69 80 40 16 71 55 80
12 6 11 15 15 44 22 6 8
5 I 8 10 10 11 13 5 5
91 95 91 87 87 43 17 95 92
96 95 93 92 86 69 89 94 96
54 55 55 61 60 98 54 56 57
69 66 10 69 70 99 72 69 68
Bu” But Ph CHsOH CH&Me
CH&OOBut Et Et Et Et
22f 9 72 40 73
42 5 15 38 80
43 3 27 8 4
3 7 17 8 1
43 82 80 88 96
95 52 57 88 94
50 99 72 50 57
71 100 81 53 62
aUnless otherwise noted, typical reaction conditions were: alkyne, 8.74 mmol; [nitrile]/ [alkyne], 3; [alkyne]/[Co], 100; reaction time, 48 h; reaction temperature, 50 “C in the case of (IVa) and 110 “C in the case of (IVb); solvent, benzene (5 ml) in the case of (IVa) and o-xylene (6 ml) in the case of (IVb). bBased on the starting alkyne. CMixtures of 1,3,5- and 1,2,4trisubstituted isomers. d(Mol of pyridine derivatives)/(niol of pyridine derivatives + mol of benzene derivatives) X 100. e(I) = 2,4,6-trisubstituted isomer, the content of the 2,3,6trisubstituted isomer being given by the complement to 100. fCarried out at 110 “C.
chemo- and the regioselectivities of the reaction. Using a variety of substrates (Table l), the yields of pyridine derivatives obtained with (IVa) and (IVb) are quite similar, while the benzene yields are significantly higher in the case of (IVa). In the cases of both (IVa) and (IVb), a dramatic lowering of the pyridine yields results as a consequence of the increased cone angle of the groups attached to the CC and to the CN triple bonds (Table 1; runs 6, 10 and 11). The influence exerted by the presence of the phenyl group in the substrate is not easily understood; indeed, by cocylization of benzonitrile and 1-hexyne, the pyridine yield obtained in the presence of (IVa) is much lower than that obtained with (IVb), while in the reaction of phenylacetylene with propionitrile the pyridine yield is very low when using (IVb) as catalyst precursor. Finally, it is to be noted that the pyridine yields obtained from the reaction of 3-methoxy-1-propyne with propionitrile are
264 mwh higher than those obtained from the reaction of the ~~~s~o~d~g (Table 1; runs 13 and 14); how~ver~ propargylic alcohol with ~ropionit~e these last yields are not so low as to imply a marked dea~tlv~tion of the catalyst by the hydruxy groups as responsible fur the observed diferences in the gieldds, As fs~~as the regioselectivity is concerned, it must be pointed out that all the reactions summarized in Table 1 lead to two pyridinic isomers, ie. (I) and (II), and that, as expected [33, the average percentage of the most abundant isomer (I) is higher in the case af the reactions catalyzed by (IVb). The influence exerted by the nitrile-attached substituents on the regiaseleo tivity is documented by iuns 1 - 10 (Table I), which clearly indicate that the pyridinic isomer (I) forms almost ~~os~~ifi~~ly when strong sterie ~~etio~s are in~~u~~ (run 6), no matter if (IVa) or (Wb) is used, The same effect is observed on using sterically hindered l-alkynes (run lx), even if, in the case of the reactioms of phenyla~etylene~ a more moderate effect results (run 12). In the case of the cocyclization of methyl propiolate and various nitriles, pyridines are formed only in the presence of the catalyst precursor (IVa), while in the presence of (IVb) as well as of various rhodiumebased catalysts [2], the methyl propiolate self-cyclotrimerization occurs as the only catalytic reaction. Interestingly, three isomeric pyridines, (V), (VI) and (VII), instead of two, form:
IV1
(VI)
fVlll
In addition to these compounds, significant yields of benzene derivatives are obtained. However, these can be contained by using nitrile-to-alkyne ratios of 5, so that chemoselectivities up to 77% (referred to pyridine derivatives) are reached. The reaction temperature plays a key role in the chemoselectivity and on the pyridinic isomer distribution. As is shown in Fig, 1, the pyridine yields reach their maximum valne at 50 “C and then drop at higher ~rn~er~t~~s~ while the benzene yields increase so that they markedly exceed the yields of pyridines. Figure 1 shows that the percentage of the most abundant isomer, (V), does not vary on changing the reaction temperature, while the content of isomer (VI) diminishes and, consequently, the percentage of isomer (VII) increases. Once again we have observed that the cone angle of the nitrile-attached substituents influences both the chemoselectivity (Table 2) and the isomer distribution (Fig. 2). In particular, increasing the steric hindrance on the nitrile increases the 2,4,6-trisubstituted isomer (V), so that, in the cocyclizatian of methyl propiolate and pivalonitrile, the 2-t-butyl-4,6bis(meth~~y~~bonyl)pyridine forms as the unique product (Fig, 2).
265
Fig. 1. Influence of the reaction temperature on pyridines (0) and benzenes (A) yield (top) and on the isomer distribution (bottom) in the cycbtrimerization of methyl propiolate and propionitrile. Reaction conditions: catalyst precursor, (IVa); methyl propiolate, 11.69 mmol; reaction time, 1 h; [propionitrile]/~methyl propiolate], 5; [methyl propiolate]l[Co], 100.
100
MeOOC-CCH/R’--CN
lc.1,
Fig. 2. Isomer distribution as a function of nitrile substituents in the cocyclization of methyl propiolate catalyzed by (IVa). (m), 2,4,6_trisubstituted isomer; (O), 2,3,6trisubstituted isomer; (m), 2,3,5_trisubstituted isomer.
266 TABLE 2 Cocylization of methyl propiolate with nitriles (R’-CR) R’
Me Et Bun Bu’ pr’ But
catalyzed by (IVa)a
Yield b (%)
Isomeric distribution0 (V)
(VI)
(VW
Benzene derivatives yield (%)b*d
10 38 48 34 42 7
45 48 56 63 70 100
30 40 30 25 22 0
25 12 14 12 8 0
36 22 25 32 40 36
Pyridine derivatives
Chemoseleetivity (%)e
30 72 74 61 61 23
aReaction conditions: methyl propiolate, 11.89 mmol; solvent, benzene (6 ml); [nitrile]) [methyl propiolate], 5; [methyl propiolate]/[Co], 100; temperature, 50 “C; reaction time, 24 h. bBased on starting alkyne. ‘Qvaluated by GLC and ‘H NMR spectroscopy; (V) = 2,4,6trisubstituted isomer; (VI) = 2,3,6-trisubstituted isomer; (VII) = 2,3,5trisubstituted isomer. dMixtures of 1,3,5- and 1,2,4-tris(methoxycarbonyl)benzene. e(Mol of pyridinic derivatives)/(mol of pyridinic derivatives + mol of benzenic derivatives) X 100.
Conclusion This study shows that the regioselectivity of the cocyclization of l-alkynes and nitriles is markedly influenced by the structure of reactive substrates, steric effects being largely prevalent over the electronic ones when strong steric constraints are introduced by the substrates. An interesting perspective that emerges from the observed trend is that the employment of l-alkynes or nitriles carrying easily-removable highly sterically hindered groups may lead regiospecifically to intermediates for the synthesis of a variety of 2,4,6_functionalized pyridine nuclei. Another interesting outcome of the present study is the formation of the 2,3~5-t~substituted pyridine in addition to the 2,4,6- and 2,3,6-trisubstituted isomers from the reaction of methyl propiolate with various nitriles. All the above findings can be easily rationalized assuming that, as already proposed [I, 6,7], the catalytic species generated by (IVa) and (IVb) still contain the fragment [ CoCp*], and that the mechanism of pyridine formation involves the occurrence of a cobaltacyclopentadiene intermediate. Thus, the observed pyridinic isomer distribution can be accounted for on the basis of the factors which determine the regioselectivity of the oxidative cyclization reaction [8, 91 and the regioselectivity of the nitrile incorporation step. As far as the latter is concerned, we have rationalized [2] the influence of the nitrile-attached substituents on the isomer distribution in the
case of the rhodium-catalyzed pyridine synthesis by suggestingthat nitrile reacts on being bonded to the metal in a ‘side-on’ way [lo). Since the effects observed here with cobalt catalysts are practically identical, we suggestthat the above ideas may also be operative in this case. The formation of the ‘unexpected’ 2,3,5trisubstituted isomer (VII), in addition to (V) and (VI), in the case of the reactions of methyl propiolate can be easily explained according to the above mechanistic assumptions. Indeed, if one takes into account that the metallacycles (VIII) and (IX) (Scheme 1) are much more favoured than (X) by a combination of steric [9] and electronic f3] effects, the absence of the isomer (XV) is easily understood. Moreover, since on the basis of pure steric eonsiderationsthe intermediate (XI) is favoured over (XII) and (XIII) due to the absence of steric repulsions between COOMe and R’ groups, it appears clear why the pyridine (V) forms in largeramounts than (VI) and (VII) do. On the other hand, when the steric restrictions induced by R’ are not so strong, the increased nucleophilicity of the methoxycarbonyl-substituted cobalt-bonded carbon atoms makes both the intermediates(XII) and (XIII) operative to some extent, and then the pyridines (VII) and (Vi) are formed, respectively. This electronic effect is completely overcome by the steric one when encumbered nitriles are used, and (V) is then the only observable pyridine derivative.
Meooc
moot
fAoot
?.MOC-CCH
R'-CN
3
CpWo kOOC
CooMe
MOOC
fIXI
[VII
IX,,,,
f &-
coowc
R’
COOUS
cc
cp*cCo
EOMI*
COOMC
R’-CN
c
cp*cl
COO&
fXfVl
R’
MaooC
b 0
fXVi
R’
‘W NMIt spectra were run at 60 MHz on a Varian T60 instrument using Me4Si as internal standard, Mass spectra were obtained with a HewlettPackard Model’ 5995A gas chromatograph-mass spectrometer, GbC analyses were performed on a Perkin-Elmer Sigma 3B instrument equipped with flame ianization detectors, using 6 ft X l/8 in stainless steel columns packed with 8% Carbawax f 2% Chromosorb AW DMCS 80 - 100 mesh (CW-ZOM) and with 2.5% silicon gum rubber on Chromosorb AW DMSC 80 - 100 mesh (SE-30). Diethyl ether and THF were refluxed and distilled from sodium and then from lithium aluminum hydride. Pentane, benzene, toluene and o-xylene were washed with concentrated sulfuric acid, dried on calcium chloride and then distilled from lithium aluminum hydride. Unless otherwise noted, other solvents were reagent grade. (~~~y~lo~n~d~eny~)bis(ethylene) cobalt(I) [ll] and b~s(ethylene)(~5-pe~tamethyl~y~lopen~dienyl) cobalt(I) 1121 were prepared as described. Phenylacetylene (Fluka), propargylic alcohol (Fluka) and 3-methoxy-l-propyne were distilled under dinitrogen before use. All other alkynes (Fluka) were used without further purification, Acetanitrile and propionitrile (Fluka) were distilled from P4010 ‘and stored under dry dinitrogen atmosphere. All other nitriles (Fluka) were used without further purification. TABLE 3 ‘H NMR and MS spectral data for pyridine derivatives*
Pyridine derivative
M+ (m/e)
IN NMR
R’ = R” = CH2e(CH,f),CH,s R = CH,“(CH&&N
268
8.25, d (J = 7.8), Hd; 6.8, d (J = 7.8), He; 6.75, s, Ha and Hb; 3.1 - 2.17, bm, He and Hh; 2.17 _ 0.63, bm, Hf, Hg, and Hi.
R’ = R” = CHze(CHzf )&Hsg R = CH&OOC(CH&
293
7.13, d (J = 8.0), Hd; 6.63, d (J = SO), He; 6.73, d (J = 3.0), Ha; 6.60, d (J = 3.0), Hb; 3.53, s, Hh (2,4,6- or 2,3,6-isomer); 3.45, s, Hh (2,4,6-or 2,37,6-isomer); 2.73 -2.17, bm, We; 2.05 - 0.63, bm, Hf and Hg; 1.25, s, H’.
R’ = CH2WCHsf R” = CH@XX$ R = CHZ%X?I1
195
7.5, d (J= 8.0), Hd;7.13,d (J= &O),HO; 7.13, s, Ha; 6.92, s, Hb; 4.40, s, He; 4.25, s, Wg; 3.3, s, Hf; 3.23, s, Hh; 2.68, q (J ^x7.0), Hs; 1.22, t (J = 7.0), H’.
+Measured on mixtures of the two pyridinic isomers in CCl4, at 37 “C, using Me& as internal standard, and given as chemical shift (6), multiplicity, coupling constants in Hz, assignment, bm = broad multiplet, d = doublet, q = quartet, s = singlet, t = triplet.
TABLE 4 ‘H NMR and MS data for the pyridine derivatives obtained from methyl prapiolate and various nitriles*
Pyridine derivative
M+ (mfe)
‘H NMR
R = CHsh
209
8.60, d (J = 3.0), He; 8.27, d (J- 3.0), Hf; 8.23 * 7.57, bm, Ha, Hb, HC, and Hd; 3.88, bm, Hs; 2.82, s, Hh; 2.65, s, Hh.
R = CH&‘CH$
223
9.22, d (J = 3.0), He; 8.68, d (J = 3.0), Hf; 8.42, d (J t 2.0), Ha; 8.27, d (J = 8.0), II’+ 7.97, d (J =: 8.0), He; 7.92, d (J = 2.0), Hb; 4,0, bm, Hs; 3.13, bm, Hh; 1.33, bm, Hi.
R = C( CHsbj3
251
8.22, d (J= 3,0), Ha;?.92,d 3.93, s, Hg; 1.42, s, Hh.
R = CHb(GH&
237
9.06, d (J = 3,0), He; 8.38, d (a = 3.0), H’; 8.15, d(JG 2,0),HB;8.02,d (J= 8.0f,Hd;7.75, d (a= S.O), HC; 7.65, d (J= 2.0), Hb; 3.92, bm, Hs; 3.18, bm, Hh; 1.48 - 1.18, bm, @.
R = CHzh(CH&X$
251
8.93, d (J= 3.0), He;8.41,d (.J= 8.0), Hf; 8.12, d (dm 2.0), Ha; 8.07, d (J= 8.0), Hd; 7.75, d (J = 8.0), He; 7.65, d (J = 2.0), Hu; 3.92, bm, Hg; 3.28 - 2.65, bm, Hb; 2.0 - 0.7, bm, Hi and H1.
R = CHZhCHi(CHfl)2
251
8.93, d (J = 3.0), He; 8.41, d (J = 3.9), Hf; 8.12, d (6- 2.0), Ha;8.07,d (J= 8.0), Hd;7.75, d (J= 8.6), He; 7.65, d (J= 2.0), Hb; 2.9, bm, Hh; 2.5 - 1.9, bm, Ip; 0.92, bm, I-II.
(J= 3.0), Hb;
*Measured on mixtures of the three pyridinic isomers in CC&, at 37 “C, using Me,@ as internal standard, and given as chemical shift (6 ), multiplicity, coupling constants in Hz, assignment, bm = broad multiplet, d = doublet, s = singlet.
General procedure for the catalytic mmtions A Pyrex Carius tube (25 ml capacity) fitted with a Corning Rotaflo Teflon tap (DISA, Milan) was charged under dinitrogen atmosphere with a freshly prepared solution of catalyst precursor in the appropriate solvent and with nitrile and acetylenic compound, at -80 “C. Benzene, toluene or o-xylene can be used i~d~f~~otly as solvents, the choice being based on the reaction temperature. The Teflon tap was turned off and the Carius tube was immersed in a tbennostatted (HI.2 “C) oil bath and kept at the desired
tempc?rature for the appropriate reaction time. After cooling, the reaction mixtures were ‘worked up and analyzed as already described [2]. In the Tables 3 and 4, the ‘H NMR data for the pyridinic isomers that are not given in [ZJ are reported.
Ackxmwledgements This work was s~ppurt~ by %1grztrrt frum the C,N,R. mme ‘Chimica Fir3ee ~~nd~a~~ Pro
(Rcrme)
1 H. Biinnemann and W. Brijoux, in R. Ugo (ea.), Aspects of Homogens~us Cutulysis, Vol. 5, Reidel, Dordrecht, 1984, p, 77; II. Bijnnemann, Angew. Chem. Znt. Ed. Engl., 24 (1985) 248. 2 0. Cioni, P. Diversi, G. Ingrosso, A, L&e&i and P. Ronca, J. Mol. C&et., 40 (1987) 837. 8 ?I. Biirmemann, W. Brijoux, R. Brinkmann, W. Meurers, W. Von Philipshorn and 2: EgoIf, J. urg~~~m~~ui~. C&em., 27.2 (lS84) 231. 4 P, Dlversi, G. Ingr-, A. Lueherini and D. Vanaewe, Gi~maie dE C%bzicu, Ctzwegno %%ove Sin&&: Sirmione, Italy, 22 - 27 Septemiw 1985, Abstracts p. 352. 5 P. Diversi, G. Ingrosso, A. Luclherini and A. ~jnut~ll~, J_ Xi.% C&XI., d0 (1987) 359. 6 Y. Wakatsuki and I-I. Yamazaki, L Chem. Sot., Dalton T&ma, fIQR3) 1278. 7 R. Biinnemann, Angew. C&em. ZnL Ed. Engi., 17 (1978) 505. 8 A. Stockis and R. Hoffmann, J, Am. Chem. See., 102 (1980) 2962. 9 Y. Wakatsuki, 0. Namura, K. Kitaurs, K, Morokuma and II. Yamazaki, J. Am. Chern. Sac., 105 (1983) 1907. 16 I‘. C. Wright, G. Wilkinson, M, Motavalli and M. B. Hurstbus@, J, Chem. Sot., Dalton Ttons., (19’76) 2017. ll. K, Jonas, E. Deffense and D. Habermaan, Angeul. Chem. Znt, Ed. Engl., 22 (1983) 716. 12 R. G, Beevor, S. A. Frith and J. I$. Spencer, 6. OrgonometelL Chem., 221 (1931) C25.
261-
270
261
COBALT-CATALYZED SYNTHESIS OF PYRIDINES FROM l-ALKYNES AND NITRILES: SUBSTRATE STRUCTURE AND REGIOSELECTIVITY PIETRO DIVERSI, GIOVANNI INGROSSO,* DAR10 VANACORE Dipartimento di Chimica e Chimica Industriale, 56100 Pisa (Italy)
ANTONIO LUCHERINI*
and
Universitci di Piss, Via Risorgimento
35,
(Received July 9, 1986; accepted December 23,1986)
Summary A study has been carried out of the influence exerted by the substrate structure on the regioselectivity of the synthesis of trisubstituted pyridines by cocyclization of 1-alkynes (R-CCH) and nitriles (R’-CN) catalyzed by the complexes [CoCp*(C2H&], (IVa) (Cp* = 77’~C5H5)and (IVb) (Cp* = q5-C5Mes). In most cases two isomers, i.e. the 2,4,6- and 2,3,6-trisubstituted pyridines, form, whose distribution depends upon the steric and electronic effects induced by R and R’. From highly sterically hindered alkynes and nitriles only the 2,4,6-trisubstituted isomer is formed. When R is a strong electron-withdrawing group (COOMe), the 2,3,5+isubstituted pyridine is formed in addition to the 2,4,6- and 2,3,6_trisubstituted ones, whose distribution can be varied by altering the steric features of nitriles.
Introduction Transition-metal catalyzed cocyclization of alkynes and nitriles has allowed the one-pot synthesis of a variety of pyridine derivatives [l, 21. Starting from 1-alkynes, only the pyridinic isomers (I) and (II) have so far been observed, in addition to variable amounts of benzene derivatives.
R-CCH
+
R’-CN
-
R&&R: R@R;R@; (II
*Authors to whom correspondence 0304-5102/87/$3.50
(Ill
should be addressed. 0 Elsevier Sequoia/Printed
in The Netherlands
262
When Cp*-containing catalysts are employed, the isomer distribution depends upon the nature of the Cp* ligand, the highest (I) to (II) ratios having been observed in the presence of pentamethylcyclopentadienylic catalysts [ 2, 31. Furthermore, a systematic study of the catalytic properties of the two rhodium complexes, [RhCp*(CzH&] (Cp* = n5-C5H5 and g5C5Mes), has pointed out that the regioselectivity of the cocyclization reactions increases markedly by increasing the cone angle, not only of the groups attached to the CC triple bond but also of those attached to the CN triple bond, thus allowing the regiospecific synthesis of 2,4,6trisubstituted pyridines [ 21. We have now extended the study of these aspects to the cobalt complexes [CoCp*(C,H&], and we have observed the same general trend. More interestingly, it has also been observed that, depending upon the nature of the alkyne substituents R, the isomer (III), which has never been observed previously, is formed in addition to (I) and (II). R
R
TX 0
N
R’
(1111
A brief report on preliminary results has already been communicated
[41. Results and discussion The complexes (IVa) and (IVb) are known to be active catalyst precursors for the synthesis of pyridine derivatives and have been extensively studied using a continuous flow apparatus [ 11. [CoCp*(CzH&]
(IVa), Cp* = 715-C5H5 (IVb), Cp* = g5-C5Me5
Since we were interested in batch reactions, we have preliminarily carried out a study of the activity and the chemoselectivity of (IVa) and (IVb) as a function of various reaction parameters, using the cocyclization of 1-hexyne and propionitrile as the test reaction. The choice of these substrates was suggested by the fact that a similar study on the reactions of these comonomers had already been done for the case of the Cp*-containing rhodium catalysts [ 2, 51. On the basis of this study, the optimum reaction conditions are: temperature, 50 “C for (IVa) and 110 “C for (IVb); alkyne-to-cobalt molar ratio 100, nitrile-to-alkyne molar ratio 3, and reaction time 48 h, for both (IVa) and (IVb). Thus, these experimental conditions have been adopted for studying the influence of the structural features of 1-alkynes and nitriles on both the
263 TABLE 1 Cocylization (IVb)a Run
R
of terminal alkynes (R-CCH)
R’
Pyridine yield (%)b (IVa)
(IVb)
with nitriles (R’-CN)
Benzene yield (%)h.” (IVa)
(IVb)
catalyzed by (IVa) and
Chemoselectivity (%)d
Pyridinic isomer (I)
(IVa)
(%)e
(IVb)
(IVa) 1 2 3 4 5 6 I 8 9 10 11 12 13 14
(IVb)
BU” BU” BU” Bu” Bu” Bu” Bu” Bu” Bu”
Me Et Pr’ Bu” Bu’ But Ph (CHs)&N N_(CHsk
71 84 71 69 66 22 48 16 62
83 82 69 80 40 16 71 55 80
12 6 11 15 15 44 22 6 8
5 I 8 10 10 11 13 5 5
91 95 91 87 87 43 17 95 92
96 95 93 92 86 69 89 94 96
54 55 55 61 60 98 54 56 57
69 66 10 69 70 99 72 69 68
Bu” But Ph CHsOH CH&Me
CH&OOBut Et Et Et Et
22f 9 72 40 73
42 5 15 38 80
43 3 27 8 4
3 7 17 8 1
43 82 80 88 96
95 52 57 88 94
50 99 72 50 57
71 100 81 53 62
aUnless otherwise noted, typical reaction conditions were: alkyne, 8.74 mmol; [nitrile]/ [alkyne], 3; [alkyne]/[Co], 100; reaction time, 48 h; reaction temperature, 50 “C in the case of (IVa) and 110 “C in the case of (IVb); solvent, benzene (5 ml) in the case of (IVa) and o-xylene (6 ml) in the case of (IVb). bBased on the starting alkyne. CMixtures of 1,3,5- and 1,2,4trisubstituted isomers. d(Mol of pyridine derivatives)/(niol of pyridine derivatives + mol of benzene derivatives) X 100. e(I) = 2,4,6-trisubstituted isomer, the content of the 2,3,6trisubstituted isomer being given by the complement to 100. fCarried out at 110 “C.
chemo- and the regioselectivities of the reaction. Using a variety of substrates (Table l), the yields of pyridine derivatives obtained with (IVa) and (IVb) are quite similar, while the benzene yields are significantly higher in the case of (IVa). In the cases of both (IVa) and (IVb), a dramatic lowering of the pyridine yields results as a consequence of the increased cone angle of the groups attached to the CC and to the CN triple bonds (Table 1; runs 6, 10 and 11). The influence exerted by the presence of the phenyl group in the substrate is not easily understood; indeed, by cocylization of benzonitrile and 1-hexyne, the pyridine yield obtained in the presence of (IVa) is much lower than that obtained with (IVb), while in the reaction of phenylacetylene with propionitrile the pyridine yield is very low when using (IVb) as catalyst precursor. Finally, it is to be noted that the pyridine yields obtained from the reaction of 3-methoxy-1-propyne with propionitrile are
264 mwh higher than those obtained from the reaction of the ~~~s~o~d~g (Table 1; runs 13 and 14); how~ver~ propargylic alcohol with ~ropionit~e these last yields are not so low as to imply a marked dea~tlv~tion of the catalyst by the hydruxy groups as responsible fur the observed diferences in the gieldds, As fs~~as the regioselectivity is concerned, it must be pointed out that all the reactions summarized in Table 1 lead to two pyridinic isomers, ie. (I) and (II), and that, as expected [33, the average percentage of the most abundant isomer (I) is higher in the case af the reactions catalyzed by (IVb). The influence exerted by the nitrile-attached substituents on the regiaseleo tivity is documented by iuns 1 - 10 (Table I), which clearly indicate that the pyridinic isomer (I) forms almost ~~os~~ifi~~ly when strong sterie ~~etio~s are in~~u~~ (run 6), no matter if (IVa) or (Wb) is used, The same effect is observed on using sterically hindered l-alkynes (run lx), even if, in the case of the reactioms of phenyla~etylene~ a more moderate effect results (run 12). In the case of the cocyclization of methyl propiolate and various nitriles, pyridines are formed only in the presence of the catalyst precursor (IVa), while in the presence of (IVb) as well as of various rhodiumebased catalysts [2], the methyl propiolate self-cyclotrimerization occurs as the only catalytic reaction. Interestingly, three isomeric pyridines, (V), (VI) and (VII), instead of two, form:
IV1
(VI)
fVlll
In addition to these compounds, significant yields of benzene derivatives are obtained. However, these can be contained by using nitrile-to-alkyne ratios of 5, so that chemoselectivities up to 77% (referred to pyridine derivatives) are reached. The reaction temperature plays a key role in the chemoselectivity and on the pyridinic isomer distribution. As is shown in Fig, 1, the pyridine yields reach their maximum valne at 50 “C and then drop at higher ~rn~er~t~~s~ while the benzene yields increase so that they markedly exceed the yields of pyridines. Figure 1 shows that the percentage of the most abundant isomer, (V), does not vary on changing the reaction temperature, while the content of isomer (VI) diminishes and, consequently, the percentage of isomer (VII) increases. Once again we have observed that the cone angle of the nitrile-attached substituents influences both the chemoselectivity (Table 2) and the isomer distribution (Fig. 2). In particular, increasing the steric hindrance on the nitrile increases the 2,4,6-trisubstituted isomer (V), so that, in the cocyclizatian of methyl propiolate and pivalonitrile, the 2-t-butyl-4,6bis(meth~~y~~bonyl)pyridine forms as the unique product (Fig, 2).
265
Fig. 1. Influence of the reaction temperature on pyridines (0) and benzenes (A) yield (top) and on the isomer distribution (bottom) in the cycbtrimerization of methyl propiolate and propionitrile. Reaction conditions: catalyst precursor, (IVa); methyl propiolate, 11.69 mmol; reaction time, 1 h; [propionitrile]/~methyl propiolate], 5; [methyl propiolate]l[Co], 100.
100
MeOOC-CCH/R’--CN
lc.1,
Fig. 2. Isomer distribution as a function of nitrile substituents in the cocyclization of methyl propiolate catalyzed by (IVa). (m), 2,4,6_trisubstituted isomer; (O), 2,3,6trisubstituted isomer; (m), 2,3,5_trisubstituted isomer.
266 TABLE 2 Cocylization of methyl propiolate with nitriles (R’-CR) R’
Me Et Bun Bu’ pr’ But
catalyzed by (IVa)a
Yield b (%)
Isomeric distribution0 (V)
(VI)
(VW
Benzene derivatives yield (%)b*d
10 38 48 34 42 7
45 48 56 63 70 100
30 40 30 25 22 0
25 12 14 12 8 0
36 22 25 32 40 36
Pyridine derivatives
Chemoseleetivity (%)e
30 72 74 61 61 23
aReaction conditions: methyl propiolate, 11.89 mmol; solvent, benzene (6 ml); [nitrile]) [methyl propiolate], 5; [methyl propiolate]/[Co], 100; temperature, 50 “C; reaction time, 24 h. bBased on starting alkyne. ‘Qvaluated by GLC and ‘H NMR spectroscopy; (V) = 2,4,6trisubstituted isomer; (VI) = 2,3,6-trisubstituted isomer; (VII) = 2,3,5trisubstituted isomer. dMixtures of 1,3,5- and 1,2,4-tris(methoxycarbonyl)benzene. e(Mol of pyridinic derivatives)/(mol of pyridinic derivatives + mol of benzenic derivatives) X 100.
Conclusion This study shows that the regioselectivity of the cocyclization of l-alkynes and nitriles is markedly influenced by the structure of reactive substrates, steric effects being largely prevalent over the electronic ones when strong steric constraints are introduced by the substrates. An interesting perspective that emerges from the observed trend is that the employment of l-alkynes or nitriles carrying easily-removable highly sterically hindered groups may lead regiospecifically to intermediates for the synthesis of a variety of 2,4,6_functionalized pyridine nuclei. Another interesting outcome of the present study is the formation of the 2,3~5-t~substituted pyridine in addition to the 2,4,6- and 2,3,6-trisubstituted isomers from the reaction of methyl propiolate with various nitriles. All the above findings can be easily rationalized assuming that, as already proposed [I, 6,7], the catalytic species generated by (IVa) and (IVb) still contain the fragment [ CoCp*], and that the mechanism of pyridine formation involves the occurrence of a cobaltacyclopentadiene intermediate. Thus, the observed pyridinic isomer distribution can be accounted for on the basis of the factors which determine the regioselectivity of the oxidative cyclization reaction [8, 91 and the regioselectivity of the nitrile incorporation step. As far as the latter is concerned, we have rationalized [2] the influence of the nitrile-attached substituents on the isomer distribution in the
case of the rhodium-catalyzed pyridine synthesis by suggestingthat nitrile reacts on being bonded to the metal in a ‘side-on’ way [lo). Since the effects observed here with cobalt catalysts are practically identical, we suggestthat the above ideas may also be operative in this case. The formation of the ‘unexpected’ 2,3,5trisubstituted isomer (VII), in addition to (V) and (VI), in the case of the reactions of methyl propiolate can be easily explained according to the above mechanistic assumptions. Indeed, if one takes into account that the metallacycles (VIII) and (IX) (Scheme 1) are much more favoured than (X) by a combination of steric [9] and electronic f3] effects, the absence of the isomer (XV) is easily understood. Moreover, since on the basis of pure steric eonsiderationsthe intermediate (XI) is favoured over (XII) and (XIII) due to the absence of steric repulsions between COOMe and R’ groups, it appears clear why the pyridine (V) forms in largeramounts than (VI) and (VII) do. On the other hand, when the steric restrictions induced by R’ are not so strong, the increased nucleophilicity of the methoxycarbonyl-substituted cobalt-bonded carbon atoms makes both the intermediates(XII) and (XIII) operative to some extent, and then the pyridines (VII) and (Vi) are formed, respectively. This electronic effect is completely overcome by the steric one when encumbered nitriles are used, and (V) is then the only observable pyridine derivative.
Meooc
moot
fAoot
?.MOC-CCH
R'-CN
3
CpWo kOOC
CooMe
MOOC
fIXI
[VII
IX,,,,
f &-
coowc
R’
COOUS
cc
cp*cCo
EOMI*
COOMC
R’-CN
c
cp*cl
COO&
fXfVl
R’
MaooC
b 0
fXVi
R’
‘W NMIt spectra were run at 60 MHz on a Varian T60 instrument using Me4Si as internal standard, Mass spectra were obtained with a HewlettPackard Model’ 5995A gas chromatograph-mass spectrometer, GbC analyses were performed on a Perkin-Elmer Sigma 3B instrument equipped with flame ianization detectors, using 6 ft X l/8 in stainless steel columns packed with 8% Carbawax f 2% Chromosorb AW DMCS 80 - 100 mesh (CW-ZOM) and with 2.5% silicon gum rubber on Chromosorb AW DMSC 80 - 100 mesh (SE-30). Diethyl ether and THF were refluxed and distilled from sodium and then from lithium aluminum hydride. Pentane, benzene, toluene and o-xylene were washed with concentrated sulfuric acid, dried on calcium chloride and then distilled from lithium aluminum hydride. Unless otherwise noted, other solvents were reagent grade. (~~~y~lo~n~d~eny~)bis(ethylene) cobalt(I) [ll] and b~s(ethylene)(~5-pe~tamethyl~y~lopen~dienyl) cobalt(I) 1121 were prepared as described. Phenylacetylene (Fluka), propargylic alcohol (Fluka) and 3-methoxy-l-propyne were distilled under dinitrogen before use. All other alkynes (Fluka) were used without further purification, Acetanitrile and propionitrile (Fluka) were distilled from P4010 ‘and stored under dry dinitrogen atmosphere. All other nitriles (Fluka) were used without further purification. TABLE 3 ‘H NMR and MS spectral data for pyridine derivatives*
Pyridine derivative
M+ (m/e)
IN NMR
R’ = R” = CH2e(CH,f),CH,s R = CH,“(CH&&N
268
8.25, d (J = 7.8), Hd; 6.8, d (J = 7.8), He; 6.75, s, Ha and Hb; 3.1 - 2.17, bm, He and Hh; 2.17 _ 0.63, bm, Hf, Hg, and Hi.
R’ = R” = CHze(CHzf )&Hsg R = CH&OOC(CH&
293
7.13, d (J = 8.0), Hd; 6.63, d (J = SO), He; 6.73, d (J = 3.0), Ha; 6.60, d (J = 3.0), Hb; 3.53, s, Hh (2,4,6- or 2,3,6-isomer); 3.45, s, Hh (2,4,6-or 2,37,6-isomer); 2.73 -2.17, bm, We; 2.05 - 0.63, bm, Hf and Hg; 1.25, s, H’.
R’ = CH2WCHsf R” = CH@XX$ R = CHZ%X?I1
195
7.5, d (J= 8.0), Hd;7.13,d (J= &O),HO; 7.13, s, Ha; 6.92, s, Hb; 4.40, s, He; 4.25, s, Wg; 3.3, s, Hf; 3.23, s, Hh; 2.68, q (J ^x7.0), Hs; 1.22, t (J = 7.0), H’.
+Measured on mixtures of the two pyridinic isomers in CCl4, at 37 “C, using Me& as internal standard, and given as chemical shift (6), multiplicity, coupling constants in Hz, assignment, bm = broad multiplet, d = doublet, q = quartet, s = singlet, t = triplet.
TABLE 4 ‘H NMR and MS data for the pyridine derivatives obtained from methyl prapiolate and various nitriles*
Pyridine derivative
M+ (mfe)
‘H NMR
R = CHsh
209
8.60, d (J = 3.0), He; 8.27, d (J- 3.0), Hf; 8.23 * 7.57, bm, Ha, Hb, HC, and Hd; 3.88, bm, Hs; 2.82, s, Hh; 2.65, s, Hh.
R = CH&‘CH$
223
9.22, d (J = 3.0), He; 8.68, d (J = 3.0), Hf; 8.42, d (J t 2.0), Ha; 8.27, d (J = 8.0), II’+ 7.97, d (J =: 8.0), He; 7.92, d (J = 2.0), Hb; 4,0, bm, Hs; 3.13, bm, Hh; 1.33, bm, Hi.
R = C( CHsbj3
251
8.22, d (J= 3,0), Ha;?.92,d 3.93, s, Hg; 1.42, s, Hh.
R = CHb(GH&
237
9.06, d (J = 3,0), He; 8.38, d (a = 3.0), H’; 8.15, d(JG 2,0),HB;8.02,d (J= 8.0f,Hd;7.75, d (a= S.O), HC; 7.65, d (J= 2.0), Hb; 3.92, bm, Hs; 3.18, bm, Hh; 1.48 - 1.18, bm, @.
R = CHzh(CH&X$
251
8.93, d (J= 3.0), He;8.41,d (.J= 8.0), Hf; 8.12, d (dm 2.0), Ha; 8.07, d (J= 8.0), Hd; 7.75, d (J = 8.0), He; 7.65, d (J = 2.0), Hu; 3.92, bm, Hg; 3.28 - 2.65, bm, Hb; 2.0 - 0.7, bm, Hi and H1.
R = CHZhCHi(CHfl)2
251
8.93, d (J = 3.0), He; 8.41, d (J = 3.9), Hf; 8.12, d (6- 2.0), Ha;8.07,d (J= 8.0), Hd;7.75, d (J= 8.6), He; 7.65, d (J= 2.0), Hb; 2.9, bm, Hh; 2.5 - 1.9, bm, Ip; 0.92, bm, I-II.
(J= 3.0), Hb;
*Measured on mixtures of the three pyridinic isomers in CC&, at 37 “C, using Me,@ as internal standard, and given as chemical shift (6 ), multiplicity, coupling constants in Hz, assignment, bm = broad multiplet, d = doublet, s = singlet.
General procedure for the catalytic mmtions A Pyrex Carius tube (25 ml capacity) fitted with a Corning Rotaflo Teflon tap (DISA, Milan) was charged under dinitrogen atmosphere with a freshly prepared solution of catalyst precursor in the appropriate solvent and with nitrile and acetylenic compound, at -80 “C. Benzene, toluene or o-xylene can be used i~d~f~~otly as solvents, the choice being based on the reaction temperature. The Teflon tap was turned off and the Carius tube was immersed in a tbennostatted (HI.2 “C) oil bath and kept at the desired
tempc?rature for the appropriate reaction time. After cooling, the reaction mixtures were ‘worked up and analyzed as already described [2]. In the Tables 3 and 4, the ‘H NMR data for the pyridinic isomers that are not given in [ZJ are reported.
Ackxmwledgements This work was s~ppurt~ by %1grztrrt frum the C,N,R. mme ‘Chimica Fir3ee ~~nd~a~~ Pro
(Rcrme)
1 H. Biinnemann and W. Brijoux, in R. Ugo (ea.), Aspects of Homogens~us Cutulysis, Vol. 5, Reidel, Dordrecht, 1984, p, 77; II. Bijnnemann, Angew. Chem. Znt. Ed. Engl., 24 (1985) 248. 2 0. Cioni, P. Diversi, G. Ingrosso, A, L&e&i and P. Ronca, J. Mol. C&et., 40 (1987) 837. 8 ?I. Biirmemann, W. Brijoux, R. Brinkmann, W. Meurers, W. Von Philipshorn and 2: EgoIf, J. urg~~~m~~ui~. C&em., 27.2 (lS84) 231. 4 P, Dlversi, G. Ingr-, A. Lueherini and D. Vanaewe, Gi~maie dE C%bzicu, Ctzwegno %%ove Sin&&: Sirmione, Italy, 22 - 27 Septemiw 1985, Abstracts p. 352. 5 P. Diversi, G. Ingrosso, A. Luclherini and A. ~jnut~ll~, J_ Xi.% C&XI., d0 (1987) 359. 6 Y. Wakatsuki and I-I. Yamazaki, L Chem. Sot., Dalton T&ma, fIQR3) 1278. 7 R. Biinnemann, Angew. C&em. ZnL Ed. Engi., 17 (1978) 505. 8 A. Stockis and R. Hoffmann, J, Am. Chem. See., 102 (1980) 2962. 9 Y. Wakatsuki, 0. Namura, K. Kitaurs, K, Morokuma and II. Yamazaki, J. Am. Chern. Sac., 105 (1983) 1907. 16 I‘. C. Wright, G. Wilkinson, M, Motavalli and M. B. Hurstbus@, J, Chem. Sot., Dalton Ttons., (19’76) 2017. ll. K, Jonas, E. Deffense and D. Habermaan, Angeul. Chem. Znt, Ed. Engl., 22 (1983) 716. 12 R. G, Beevor, S. A. Frith and J. I$. Spencer, 6. OrgonometelL Chem., 221 (1931) C25.