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Note: Due to time constraints, this is not an exhaustive exploration of the myriad ways to create substituted pyridines. This summary focuses on ring-construction reactions, rather than functionalization of existing pyridine rings. Quinolines and Isoquinolines can be considered substituted pyridines; however they possess their own rich chemistry and deserve their own summary. This review summarizes their chemistry only insofar as it pertains to pyridine chemistry in general.
This procedure served as a key step in an elegant synthesis of the Rubrolone chromophore Kelly et. al., Tet. Lett. 1986, 27, 6049-6050. O O
NNMe2
BuLi; PhSCu;
O NC C3H7 ; O
nPr
nPr
O
AcOH reflux
OTBS H Me
31%
MEMO OTBS H Me N O HH O O OTBS H Me 1. TBAF,
MEMCl
N
88%
N
+
MEMO HH O O
H H O
nPr
nPr
nPr
67%
HO O N
38% (recycled)
Me HO HO HO HO O N O H O O
46%
NH3
N
HO O
nPr
nPr
Rubralone chromophore
Rubralone
2. Hantzsch Synthesis
NH3
N H
Condensation of an aldehyde, two equivalents of a 1,3-dicarbonyl, and ammonia yields symmetrical pyridines.
O H O O N O O
Me
NH2OH
N OH
-H2O
N H
Me
Several variations on these themes have been developed, such as the use of dimethyl hydrazones Kelly and Liu, JACS, 1985, 107, 4998-4999.
NNMe2
Modifications have been made to allow for synthesis of asymmetric pyridines, by performing one or more of the condensation steps prior to the reaction. Robinson et. al. J. Het. Chem. 1998, 35, 65.
Ph Ph R1 X
BuLi; PhSCu;
O
Yields were generally acceptable for enone procedure, low for acyl cyanide procedure. Reaction requires extended time.
X Ph N
R1 R2
+
Ph O Ph O R2 R2
moderate to good yields for X = NO2, NHAc, or CN, R1= H, Me, or CN, R2 = Ph, Me, or 2-furyl
; AcOH (reflux)
NNMe2
82%
O N
BuLi; PhSCu;
O
+
Ph O O R1
X Ph N
R1 R2
; 45%
procedures have also been developed using enamine esters and enones
O'Malley
3. Bohlmann-Rahtz Synthesis
R2O2C
+
R1 NH2 E
EtOH 50 C
+
H2N N CF3 R2
120-160 C
R1
NH2
E= RCO or CN
R1
High temperatures in the dehydration step can be avoided by performing the condensation under acidic conditions. Bagley et. al. Synlett, 2001, 1149-1151.
R4
+
O H2N CF3 CH3
R2 CH3
R2
+
R1 NH2 O R3
AcOH or amberlyst 15 50 C
R4 R2 R1 N R3
yields 65-95% for R1= Me or 2-furyl, R2= EtO2C or tBuO2C R3= Me or CO2Et, R4= Alkyl, Ph, H, or TMS
Shibata, Synthesis, 1997, 13211-1324 When applied to quinolines, this is referred to as the Friedlander condensation. This procedure was used by Danishefsky and Stork in their syntheses of Camptothecin. Danishefsky et. al. JACS, 1971, 93, 4074
CO2Me NH2 CO2H CO2H N O
NaOH
N N O CO2H
+ O
CHO
The Bohlmann-Rahtz procedure served as a key step in the synthesis of the thiopeptide promothiocin A Moody et. al. JACS, 2000, 122, 3301-3313
O EtO2C N O Me NHBoc O Me OBn EtO2C N O Me NHBoc NH2 Me
Stork has developed a method of using isoxazoles as masked 3-amino-2-enones Stork et. al. JOC. 1971, 36
Me ClH2C O N Me O O Me
+
Me
K2CO3 61%
N Me
BnO
EtO2C N
N Me O
O Me N Me
5. Krhnke annulation
Condensation of a-pyridinium methyl ketone salts and eneones that proceeds through a 2,3-ene-1,5dione O R2 Gives good yields for R= alkyl, aryl, or alkenyl. R3= COOH gives somewhat lower O R2 R2 yields (40-80%). N R1 NH4OAc, AcOH R1 R3 N
Br I N
Me NHBoc
+
O O F
NH4OAc 90 C, 3 h 47%
N F
(Malkov et. al. Tet. Lett. 2001, 42, 3045-3048) 1-cyanomethylpyridinium salts can also be used to give 2-aminopyridines Krhnke, Synthesis, 1976, 1-24.
R1 N CN X O R3
R2
O'Malley
Cycloaddition approaches to pyridines
1. Diels-Alder reactions with 1-azadienes
The Kondrat'eva synthesis was used by Weinreb in his synthesis of Eupolauramine. Weinreb et. al., JOC, 1984, 49, 4325-4339.
O NMe
The most straightforeward cycloaddition approach to pyridines involves a Diels-Alder reaction of an 1-azadiene with an alkene or alkyne, followed by subsequent oxidation. However, this route is rarely used, as the Diels-Alder reaction is disfavored on electronic, conformational, and thermodynamic grounds. A modification of this approach uses an electron donating group on the nitrogen, which is subsequently eliminated.
O Me O
CO2Me N O
CO2Me
DBN 76%
OMe
+
N NMe2 O
Me N O
Eupolauramine Pyrimidines are also capable of serving as pyrrole precursors in a DA/Retro-DA sequence. The regiochemistry of the resulting pyridine is dependent upon the dienophile and the substitution pattern of the parent pyrimidine.
CO2Et Me N CO2Me EtO2C N N CO2Et Me NEt2 N N EtO2C MeO MeO N N Me MeO N N NEt2 Me N NEt2 N Me CO2Et Me CO2Et N CO2Et NO2 N CO2Et NEt2 CO2Et Et2N
Me N NMe2
MeO2C
CO2Me
Me N
CO2Me
90%
Me
Villacampa et. al. Tetrahedron, 1994, 50, 10047-10054 This technique was used by Boger in his approach to the Rubrolone aglycon Boger et. al. JACS, 2000, 122, 12169-12173.
O
81%
Et2N
175 C, 36 h O 70%
nPr
N OMe Me
NO2 N Me
Me OMe NO2 Me
nPr
N OMe
Pyrimidines with two or three complementary electron donating groups are capable of undergoing normal Diels-Alder reactions with activated dienophiles, although yields are moderate at best.
Me2N N N NMe2 OMe MeO2C CO2Me Me2N N NMe2 CO2Me CO2Me
70%
R1 O N Me
R2
R1 R2 O N Me
R1 R2 N HO Me N R2 HO Me
R1 R2
Pyrazines can also undergo inverse electron demand DA/retro DA cascades to give pyridines, although this is less common.
Me N Me CO2Me NEt2 NEt2 N CO2CH3
Me
(-H2O)
(-HR1)
N N
-HCN 70%
O'Malley
1,2,4-triazenes readily undergo inverse demand Diels-Alder reaction with electron-rich dienophiles with well-defined regioselectivity. This makes them attractive precursors to pyridines, as addition across C-3/C-5 is favored for all dieneophiles, with the exception of some ynamines. The most popular version of this reaction uses a pyrrolidine enamine or a ketone and pyrrolidine as the dienophile; this is called the Boger pyridine synthesis.
Reaction of excess acetylene with one equivalent of a nitrile and ca. 1 mol % of a cobalt catalyst, such as CpCo(COD), leads to 2-substituted pyridines in good yield under conditions where an initial excess of nitrile is present. However, when unsymmetrical acetylenes are used mixtures of regioisomeric products are often obtained. Electron-poor nitriles do not work in this reaction. Bnneman, ACIEE, 1978, 17, 505-515 Yields are > 90% for R= alkyl, Ph, or Bn. R= ethenyl gives 78%. 100-600 turnovers per hour are possible.
R2
N N N
74%
N N O
RCN
CpCo(COD), 120-130 C
R2
N R2
R1CN
Et Et N Et
CpCo(COD), 120-130 C
+
R1 N R2 R1 N R2
Yields of 50-85%, A:B of 60:40 to 80:20 for R1, R2 = alkyl, Ph, alkenyl
N N N
Et H N
cat.
93%
Problems of regioselectivity can be avoided by using diynes and nitriles or alkynyl nitriles and alkynes. The less sterically hindered orientation of the product pyridine is greatly favored under these conditions. Vollhardt, ACIEE, 1984, 23, 539-556.
Bu N N Bu
There is a strong preference for the nucleophilic carbon of the dienophile to add to C-3 of the triazine. This is reinforced by electron withdrawing substituents at C-3 or C-3, C-5, and C-6, but can be reversed by electron withdrawing substituents at C-3 or C-3 and C-5. The presence of alkyl groups on the dienophile or the use of a morpholino dienophile can degrade the extent of regioselectivity. A convenient method for the generation of 1,2,4-triazines is via a Diels-Alder/Retro Diels-Alder sequence involving a 1,2,4,5-tetrazine and a nitrogen-containing dienophile. This strategy was used by Boger in his synthesis of Streptonigrin. (Boger and Panek, JOC, 1983, 48, 621-623, JACS, 1985, 107, 5745-5754.
4.1%
Me OBn N OMe
TMS
TMS
Moderate to good yields for 5,6,7 membered rings, alkyl, trialkylsilyl, ester substituents on alkyne.
Heteroatoms are tolerated in the linking chain, but N and S can interfere with catalyst turnover. This served as the basis of Vollhardt's synthesis of vitamin B6. Parnell and Vollhardt, Tetrahedron, 1985, 41, 5791-5796.
SnMe3 I
Me O N
I2 99%
Me O N
OH HO Me NH
Kende intermediate
streptonigrin
Vitamin B6 Cl
O'Malley
4. Electrocyclization of polyunsaturated imines or oximes
Reinhoudt and co-workers cyclized unsaturated oximes generated from cyclic nitrones to pyridines in moderate yield. (Reinhoudt et. al., Tetrahedron, 1989, 45, 3131-3138.
R1 R2 NO2 R3 NEt2 R1 O N CONEt2 R3
KOtBu 60-85%
R1 R2
(R3) (R3)
rt, 30-60%
R2
CONEt2
R1= Alkyl or Ph, R2= Ar, R3= Ph or alkenyl Katsumura and co-workers used two distinct electrocyclizations in their approach to the ocular age pigment A2-E. Katsumura et. al. JOC, 2001, 66, 3099-3110.
CO2Et TBSO CHO CO2Et TBSO CHO
1. LHMDS 2. DDQ
TBSO N CO2Et
NH2 N N NH2 R
CHO
NH2 N N N NMe2 R
+
NMe2
NH2 N N N NMe2 Br O Br CN CN R
+
N N O
"a"
NC H2N N N N O