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Spring 1963
MECHANISTIC ASPECTS OF THE SODIUM BOROHYDRIDE REDUCTION OF PYRIDINIUM IONS
PAUL STANLEY ANDERSON
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Recommended Citation ANDERSON, PAUL STANLEY, "MECHANISTIC ASPECTS OF THE SODIUM BOROHYDRIDE REDUCTION OF PYRIDINIUM IONS" (1963). Doctoral Dissertations. 786. https://scholars.unh.edu/dissertation/786
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ANDERSON, Paul Stanley, 1938- MECHANISTIC ASPECTS OF THE SODIUM BOROHYDRIDE REDUCTION OF PYRIDINIUM IONS.
University of New Hampshire, Ph.D., 1963 Chemistry, organic
U^iiversity Microfilms, Inc., Ann Arbor, Michigan
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. MECHANISTIC ASPECTS OP THE
SODIUM BOROHYDRIDE REDUCTION OF PYRIDINIUM IONS
BY
PAUL STANLEY ANDERSON
B. So'i University of Vermont, 1959
A THESIS
Submitted to the University of New Hampshire
In Partial Fulfillment of
The Requirements for the Degree of
Doctor of Philosophy
Graduate School
Department of Chemistry
June, 1963
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. This thesis has been examined ami-approved. i? Ù
/A
i'7, ('-n W( I Date2,
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGMENT
The author would like to express his sincere
a p p re cia tio n to the members of the fa c u lty and s ta f f of
the Department of Chemistry at the University of New
Hampshire for many hours of fruitful discussions and in
struction. de feels particularly fortunate to have had
the opportunity to work under the inspirational and en
thusiastic direction and abidance of his thesis director,
Dr. Robert E. Lyle. He is also indebted to Mrs. Pearl
Libby for the typing of this manuscript.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS
Page
LIST OF TABLES...... v
LIST OF ILLUSTRATIONS...... vi
I. INTRODUCTION...... 1
II. DISCUSSION AND RESULTS .’ ...... 6
1. Preparation of Pyridines and Pyridinium Salts 7 2. Ultraviolet and Visible Spectra of Pyridinium S alts and the E ffe ct of Sodium Borohydride on These S p e c t r a...... 8 3. Reduction ofi}.—Phenylpyridine Methiodide in the Presence of Deuterium O x id e ...... 12 If. Sodium Borohydride Reduction of 1,If.—Dimethyl— 2—phenylpyridinium Iodide ...... 21 5. Gas Chromatographic Analysis of Sodium Boro— hydride Reduction Mixtures ...... 25 6. Catalytic Hydrogenation of Tetrahydropyridines 35 7. Infrared Spectra of Tetrahydropyridines . . 37 8. Preparation and Identification of Dihydro— p y r i d i n e s ...... 38 9. Reactions of Dihydropyridines ...... lt.7 10. Summary ...... 5l
I I I . EXPERIMENTAL...... 53
1. G e n e r a l ...... 53 2. Methods of Preparation of Pyridines .... 54 3. Preparation of Pyridinium Salts ...... 57 if. Method for Following the Sodium Borohydride Reduction of Pyridinium Ions by Ultraviolet Spectroscopy ...... 58 5. Preparation of Tetrahydropyridines ...... 59 6. P reparation of 1—Me thy 1—If-phe nyl—5-d e u t e r o— 1,2,5,6—tetrahydropyridine 61 7. Catalytic Hydrogenation of Tetrahydropyridines 62 8. Preparation of Dihydropyridines ...... 63 9. Reactions of Dihydropyridines ...... 66
IV. BIBLIOGRAPHY...... 87
iv
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OP TABLES
Number Page
I. Ultraviolet Absorption Spectra of Phenyl— p y r i d i n e s ...... 56
II. Infrared Absorption Bands of Phenylpyridines . 56
III. Properties of Pyridinium Salts ...... 71
IV. Ultraviolet Absorption Spectra of Reductions of Pyridinium Ions with Sodium Borohydride . . 73
V. Properties of Tetrahydropyridines ...... 75
VI. Infrared Absorption Bands of Tetrahydropyridines 79
VII. Nuclear Magnetic Resonance Spectra of Tatra— hydropyridines ...... 8o
VIII. Properties of Piperidines ...... 8l
IX. Gas Chromatographic Analysis of Tetrahydro^ pyridines and Corresponding Piperidines .... 83
X. Ultraviolet Absorption Spectra of Dihydro pyridines ...... 84
XI. Nuclear Magnetic Resonance Spectra of Dihydro— p ’r i d i n e s ...... 85
jor Infrared Bands of Dihydropyridines and xteacticn Products ...... 86
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF ILLUSTRATIONS
Figure Page
1. Types of Products Reported from the Reduction of Various Pyridinium Ions ...... 5
2a. Mechanism for the Formation of the 1,2,5,6—Tetra— hydropyrid i n e ...... l8
2b. Acid Catalyzed Exchange Reaction of XXIX .... 18
2c. Mass Spectrum of XXXVIII ...... 19
2d. Mass Spectrum of XXXIX ...... 20
3. Mechanism for the Formation of the 1,2,3,6—Tetra— hydropyridine ...... 2if
if. Mechanism fo r the Formation of P iperidine .... 3^
5. Preparations and Reactions of the 3,S-fDlphenyl- dihydropyridines ...... if 6
6. Preparations and Reaction of the Ethyl 5—Bromo— dihydronicotinates ...... if 6
vi
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. INTRODUCTION
In recent years sodium borohydride has become a
useful synthetic tool for the conversion of pyridinium ions
to partially reduced pyridines. The use of this reducing
agent permits partial reduction of the pyridine ring in high
yield without reduction of ring substituents other than
ketone and aldehyde functions.The fact that this boro
hydride may be used in aqueous solution as well as in a
large number of organic solvents further enhances its general
usefulness»^
The nature of the products obtained in this reduction
has been found to be dependent on the position and type of
ring substituents. Current reviews on this subject are
a v a ila b le . Q in Ferles ' has reported that 1-methyl-, 1,3-dimethyl-,
1,4-dimethyl- and 1,2,6-trimethylpyridinium iodides and bro
mides gave a mixture of piperidine and tetrahydropyridine on
reduction with sodium borohydride in aqueous basic medium.
Walker^^ has reported that 4-&minopyridinium ions gave rise
to only 4-9minopiperidines on reduction with sodium boro
hydride. These are the only reports of the formation of
piperidines in this type of reduction. As will be indicated
later. Walker's work is a special case. The original work of 1 2 Panouse * indicated that only the tetrahydropyridine was ob
tained from the reduction of 1-methyl- and 1,3-dimethylpyri-
- 1-
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 12 dinlum ions, Schenker has reported that all ^-substituted
pyridinium ions are reduced to the 1,2,5»6-tetrahydropyridine
with sodium borohydride, while pyridinium ions with an alkyl
substituent in the 3-position are reduced to a mixture of
1,2,5,6- and l,2,3»6-tetrahydropyridines,
Recently the general synthetic value of this reduc
tion has been illustrated by May^^*^^ and by Huffman^^, May
obtained l,2,5»6-tetrahydropyridines from the sodium boro
hydride reductions of l-methyl-4-ethylpyridinium iodide and
l-methyl-3»4-diethylpyridinium iodide, while Huffman re
duced l-benzyl-3-(2-indoyl)pyridinium bromide to the corres
ponding 1,2,5,6-tetrahydropyridine.
In the case of pyridinium ions containing an electron
withdrawing substituent in the 3-position, a mixture of 1,6»
dihydropyridine and 1,2,5,6-tetrahydropyridine has been ob
served, Schenker^^ has found that 3-cyanopyridlne metho-
bromide was reduced by sodium borohydride to a mixture of
l-methyl-3-cyano-l,6-dihydropyridine and l-raethyl-3-cyano- 17 1,2,5»6-tetrahydropyridine, Kinoshita reported a similar
result for the reduction of the methiodide of ethyl nico-
tinate. The 1,2-dihydronicotinate was also isolated in this
case by running the reduction in concentrated aqueous sodium
hydroxide solution. Apparently in these cases, the 1,6-di-
hydropyridine was stable toward further borohydride reduction
while, under suitable conditions, the 1,2-dihydropyridine was
further reduced to the 1,2,5,6-tetrahydropyridine,
W allenfels^^ and Karrer^*^ have both found th a t sodium
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. borohydride reduction of various 3,5-dicarboethoxy pyridinium
ions produced solely dihydropyridines. 20 Saunders and Gold obtained a mixture of 1-phenyl-
1,4-dihydropyridine and l-phenyl-l,2-dihydropyridine from the
sodium borohydride reduction of 1-phenylpyridinium iodide.
This is the only reliable report in the present literature of
the actual isolation of a 1,4-dihydropyridine from a sodium
borohydride reduction of a pyridinium salt. The 1,4-dihydro-
pyridine product was present in a relative yield of twenty
p ercen t.
Inspection of these data would lead one to believe
that the sodium borohydride preferentially attacked the 2-
or 6-position of the pyridinium ion leading to a 1,2- or 1,6-
dihydropyridine. The reduction might have been expected to
stop at this stage, since further reduction would require the
hydrogenation of a carbon-carbon double bond, a process not
consistent with the known nature of sodium borohydride. How
ever, it would appear that the enamine nature of the dihydro
pyridine system facilitated protonation of the carbon
atom by the solvent (water or alcohol) giving rise to an im-
monium cation. Such a specie would be expected to rapidly 21 reduce with sodium borohydride.
The presence of piperidine as a sodium borohydride
reduction product must then be postulated as arising from
initial formation of a small quantity of 1,4-dlbydropyridine o as postulated by Ferles, Such a specie would be expected to
undergo complete reduction to the piperidine, since it con-
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. tains a double enamine system. It should be noted that the
total yield of piperidine obtained by Walker^^ from the re
duction of 4-aminopyridinium ions is in accord with the above
conclusions, since, a 4“am in o -l, 2 , 5 , 6 -tetrahydropyridine is
an enamine system which would be expected to undergo further
reduction with this metal hydride to the corresponding pipert
d in e.
The work reported here provides proof for the above
postulated mechanism, A study of substituent effects on the
amount of piperidine formed from the sodium borohydride re
duction of various pyridinium ions is also reported. Some
new dihydropyridines are introduced and the chemical and
physical properties of these compounds are discussed. Figure
1 shows the general type of dihydropyridine and tetrahydro
pyridine systems discussed in this work.
I t should be noted th a t many of the above in d icated
results obtained by other workers appeared in the literature
simultaneously or after the report of the work done in this 22 Laboratory,
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a: R' R' R' 1,2- 1,6- 1,4 - pyridinium Ion Dihydropyridine i R' R' R'
1 , 2 , 5 , 6- 1 , 2 , 3 , 6- Tetrahydropyridine P iperidine
R R
R
Pyridinium Ion 1,2,5,6-Tetrahydropyridine
R
R 1,6 1 ,2 ,3 ,6- R Tetrahydropyridine
R
Pyridinium Ion R R
R 1,4 Dihydropyridine Piperidine
Pig. 1. Types of Products Reported from the Reduction of Various Pyridinium Ions. Products depend on the nature of R'
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DISCUSSION AND RESULTS
The sodium borohydride reduction of carbon—nitrogen
double bonds is well established; however, the reduction of 6 an isolated carbon—carbon double bond has not been reported.
Since the sodium borohydride reduction of a number of pyridl—
nium .ions has been shown to give a 1 , 2 , 5 , 6 —tetrahydropyridine
as one of the products or the only product, it would appear
that a carbon—carbon double bond as well as a carbon—nitrogen
double bond was reduced. I t was, th e re fo re , of in te r e s t to
determine the mechanism of this reduction. To this end, a
deuterium tracer technique and spectroscopic methods ware em
ployed .
It was also apparent that other products (dihydro
pyridines and piperidines) could be obtained from this type
of reduction. The reduction of a number of pyridinium ions
was studied to determine the scope of the reduction and to
evaluate the effect of the nature and position of substituents
on the product composition.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Preparation of pyridines and pyridinium salts.—
During the course of this investigation it was necessary to
synthesize a number of pyridines which were not commercially
available. Known synthetic procedures were used in all cases.
3,5—Dimethyl—2—phenylpyridine (I) was prepared from
3,5—<3 ime thylpyrid ine and phenyllithium by the procedure of
Abramovitch. Compound I had not been previously reported
in the literature. 2—Phenylpyridine (II), 3—methyl—2—phenyl—
pyridine (III), and ^-methyl-2-phenylpyridine (IV) are known
compounds which have previously been prepared by phenyllithium
addition to pyridine, 3-methylpyridine and ^^methylpyrldine,
respectively. The same synthetic procedure was employed in
th is work. 25 The procedure of Schmidle and Mansfield was used
for the preparation of I 4.—phenylpyridine (V). Condensation of
D( —methylstyrene, ammonium chloride and formaldehyde gave 6—
methyl—6 —phenyltetrahydro—1,3—oxazine. This material under—
went an acid catalyzed rearrangement to i|—phenyl—1,2,5, 6 —te tr a —
hydropyridine. Compound V was obtained from the purified
tetrahydropyridine by dehydrogenation in nitrobenzene with a
palladium on alumina catalyst. 26 The procedure of Bachman and Micucci was used for
the preparation of 5—bromonicotinic acid (VII). The conversion
of VII to ethyl 5—bromonicotinate (VI) was most successful when
the standard thionyl chloride procedure was used.
The physical properties of these pyridines were in
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8
good agreement with the respective data reported by other
workers. The infrared and ultraviolet absorption spectral
data observed for compounds I — V is reported in TABLES I
and II, All other pyridines employed in this work were com
mercially available. The pyridinium salts were prepared from
the pyridines by standard procedures as indicated in the
Experimental.
Ultraviolet and visible spectra of pyridinium salts
and the effect of sodium borohydride on these spectra.—
Initially the sodium borohydride reduction of a number of
pyridinium ions was studied by the use of ultraviolet and
visible absorption spectroscopy, the reduction being run
directly in the absorption cell of the spectrophotometer.
The results can best be discussed by grouping the pyridinium
ions studied into three classes.
Class I contained 1—methylpyridinium iodide (VIII),
1-methyl pyridinium bromide (IX), 1—isopropylpyridinium iodide
(X), 1—butylpyridinium bromide (XI), 1—benzylpyridinium bro
mide (XII), 1,3—dime thylpyr id inium iodide (X III), 1, ij.—d ime thyl-
pyridinium iodide ( XIV), 1,3,5—trime thyIpyridinium iodide (XV)
and 1 ,2 , 6 —trirne thylpyrid inium iodide (XVI).
Glass II contained 2—phenyl—, 2—phenyl—3-methyl—, 2—
phenyl—If-me thyl—, 2—phenyl-3 ,5—dime thyl— and Ip-phe ny Ipy r i—
dinium iodide, XVII, XVIII, XIX, XX and XXI, re sp e c tiv e ly .
Class III contained the methiodide (XXII), methobro—
mide (XXIII), and methochloride (XXIV) of 3,5—diphenylpyridine
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. and ethyl 5-t>romonicotinate methiodide (XXV).
In methanol Class I pyridinium ions exhibited an ab
sorption maximum in the region of 260 m;i. On addition of
sodium borohydride, the absorption in this region rapidly de
creased in intensity with the simultaneous formation of a new
maximUnj in the 335—350 mju region. The new maximum decayed
rapidly to leave a spectrum which contained only end absorp
tion near 225 mp. Specific data are contained in TABLE IV.
In methanol Class II pyridinium ions exhibited an ab
sorption maximum in the region from 276 to 29k mp. Addition
of sodium borohydride destroyed this maximum and simultaneously
gave ris e to a new maximum near 330 mp. However, the 330 mp
maximum decayed rapidly to leave only weak absorption near
260 mju. Ihis suggested that the final specie formed contained
an iso la te d phe^ i s u b s titu e n t.
Treatment of Class III pyridinium ions with sodium
borohydride gave rise to new absorption maxima which were
stable in the presence of an excess of the metal hydride. Hie
m ethohalides XXII — XXIV have absorption maxima a t 312 and
258 mp. Addition of sodium borohydride gave a spectrum conr-
ta in in g maxima a t 322, 260 and ijJ.5 mp . These maxima remained
at constant intensity until dilute hydrochloric acid was added
to the sample. The acid destroyed these maxima and regener
ated the original spectrum of the methohalide. Compound XXV
exhibited an absorption maximum at 288 mp in methanol. Addi
tion of sodium borohydride to a methanolic solution of XXV
discharged the 288 mp maximum with the simultaneous formation
of stable maxima at 355 mp and 268 mp . Addition of dilute
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 10
hydrochloric acid destroyed these maxima and gave rise to a
new maximum at 281; m p.
The observation of the transient maximum in the 335—
350 mp region during the reduction of Class I and Class II
pyridinium ions is believed to be due to an initially formed
dihydropyridine. The rapid decay of this transient maximum
is believed to correspond to reduction of the dihydropyridine
to a tetrahydropyridine.
It appeared that reduction past the dihydropyridine
stage was dependent on the protcnation of this enamine system
to form an imraonium cation which then underwent further re
duction to the tetrahydropyridine. This hypothesis was tested
by running the reduction in the aprotic solvent N,N-dimethyl-
formamide. Treatment of Class I pyridinium ions with sodium
borohydride in this aprotic medium gave rise to a loss of the
pyridinium ion absorption band with the simultaneous appear
ance of an absorption band near 335 mp. This new band was
stable and did not decay until water or dilute acid was added
to the solution^! Similar results were obtained with IX, XI
and XII when diglyme was used as the solvent medium. The study
of pyridinium iodides in diglyme was not feasible because of
intense charge transfer bands at 292 and 360 mp which obscured
th is region of the spectrum^.® p Û Ko sower has reported that simple 1,1;—dihydropyri-
dines have an ultraviolet absorption maximum in the region
from 270 to 27 6 mp. Thus 2,1;,1;,6—te trame thyl—1,1;—dihydro—
pyridine exhibited an absorption maximum at 270 mp. Since the
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 11
long wave length band observed on treatment of Class I pyrl—
dinlum ions with sodium borohydride was above 300 mp , it
would appear that the specie formed was a 1,2— rather than a
1,1;—d ihyd ropy rid ine .
On treatment with sodium borohydride in N, N—dimethyl—
formamide. Class II pyridinium ions gave rise to a stable
absorption band near 350 mp, as indicated in TABLE IV. This
band did not decay until water or dilute acid was added to
the sample. The maximum observed near 350 mp was interpreted
as resulting from a 1,6—d ihyd ropyrid ine rather than a 1,2— 29 dihydropyridine. Huisgen has reported that 1-methyl—2—
phenyl—1,2—d ihydropyrid ine has its long wavelength ultra
violet absorption band at 285 mp . The fact that the absorp
tion maximum observed on treatment of Class II pyridinium ions
with sodium borohydride was at considerably longer wavelength
would suggest that the dihydropyridine formed had the phenyl
substituent in conjugation with the two remaining ring double
bonds. This would be the 1,6—d ihydropyrid ine. Further evi
dence in support of this assumption will be presented later.
In the case of Class III pyridinium ions, the observed
stable ultraviolet absorption bands produced by treatment of
these ions with sodium borohydride were subsequently shown to
belong to dihydropyridines by actual product isolation.
As a result of the rapid decay of the transient maxi
mum observed on reduction of Class I and II pyridinium ions
in methanol, the exact position of this short lived band was
somewhat in doubt. The reduction in N,N—dimethylformamide.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 12
where the maximum assigned to the dihydropyridine was stable,
revealed the location of this band with much greater accuracy
as indicated in TABLE IV.
Reduction of U.—phenylpyridine methiodide (XXI) in the
presence of deuterium oxide.— Further evidence for^t^,^
presence and fata of intermediate dihydropyridines in the
sodium borohydride reduction of pyridinium ions was obtained
by a study of the reduction of I 4.—phenylpyridine methiodide
(XXI) in the presence of deuterium oxide. Compound XXI-was
chosen as a model system because its expected sodium boro
hydride reduction product, 1—methyl-];—phenyl—1 , 2 ,5 , 6 —te t r a -
hydropyridine (XXXVIII), was a known compound which had been
well characterized^^ The material obtained from the sodium
borohydride reduction of XXI in N,N—dimethylformamide and
water exhibited physical and chemical properties identical
with those reported by McBlvain^^ fo r compound XXXVIII.
Reduction of XXI with sodium borohydride in anhydrous
N, N—d im ethylf ormamide afforded 1-methyl—i;—phenyl— 1 ,2—dihydro—
pyridine in solution. The solution had a distinct yellow
coloration. An ultraviolet spectrum obtained by dilution of
one drop of this solution with anhydrous N,N-dimethylformamide
exhibited an intense absorption band at 350 mp. The band
cj^sappeared upon addition of one drop of methanol or water to
the cell. Addition of deuterium oxide and a second quantity
of sodium borohydride to the original reaction mixture dis
patched the yellow coloration and gave a cloucfy solution. Sub
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 13
sequent dilution of this solution with water precipitated
the amine bora ne of d ante rated 1—me thy 1-i;—phenyl—1,2,5,6-
tetrahydropyridine as a solid crystalline material. That
th is m a te ria l was an amine borane and not an a lk y l borane was
evident from its Infrared spectrum^^, intense bands at 2390
and 2300 cm“^, and the fact that treatment with acid released
three moles of hydrogen per mole of boron containing compound.
Pure l-methyl-i;—phenyl—5-deuter0—1,2,5,6—tetranydropyridine
(XXXIX) was obtained by decomposition of the amine borane with
hydrogen chloride under anhydrous conditions.
The infrared spectrum of the deuterated tetrahydro
pyridine, XXXIX, contained all of the bands found in the spec
trum of the undeuterated tetrahydropyridine, XXXVIII, in
addition to a weak band at 21i;0 cm“"^, indicative of saturated
C—D s tre tc h in g , and a medium band a t 1265 cm”^, in d icativ e of 32 D—G—H scissoring, concerted vibration. The infrared spec
trum of XXXIX differed considerably in the fingerprint region
from the spectrum of XXXVIII, and thus the identity in struc—'
ture of XXXIX and XXXVIII was proven by melting points, melting
points of derivatives and ultraviolet spectra.
A comparison of the proton magnetic resonance spectra
of XXXIX and XXXVIII suggested that a deuterium atom was
located at the 5—position in XXXIX. The spectra were nearly
identical showing a multiplet due to the resonance of the
aromatic hydrogens at 2.3 tau, a doublet (J = 3.5 cps) at
6.95 tau due to the methylene at the 2—position, a triplet
(J = 3*5 cps) at 3.97 tau resulting from the vinyl hydrogen
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Ik
at position 3 , and a sharp peak at 7.66 tau due to the 1-
methyl s u b s titu e n t. In XXXVIII, the methylene groups on the
5— and 6—positions gave a composite peak (half band width
3.8 cps) a t 7 .k3 tau which at higher amplification was re
solved into a multiplet. In the deuterated compound, XXXIX,
this peak (half band width 2.5 cps) could not be resolved,
indicating a less complex splitting pattern. The relative
peak areas were also in agreement with the presence of only
three protons at the 5— and 6—po sitio n s of XXXIX. The fa c t
that the relative peak area of the 2-methylene resonance at
6.95 tau was identical in both XXXIX and XXXVIII strongly
suggested that the deuterium was at the 5—position, since
the 2— and 6—positions are equivalent in the pyridinium ion,
XXI. (These peak positions are given in ppm in TABLE VII).
Further evidence for this positional assignment of the
deuterium was obtained from the rapid, complete exchange of
all deuterium in XXXIX for hydrogen on warming an acidic
aqueous solution of XXXIX for several minutes on a steam cone.
Furthermore, XXXVIII could be partially deuterated at both the
5— and 6—positions on heating in acidic deuterium oxide solu
tion. The infrared spectrum of this material showed a band at
2250 cm""^, indicative of vinyl C—D stretching^^, as well as
the saturated C—D stretching vibration at 211;0 cm""^.^^ This
strongly suggested that the deuterium was indeed located at
the 5—position in XXXIX, for a reasonable mechanism for ex
change from a saturated carbon can be written only for this
a H y lic position.Proton attack at the 3—position of the
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 15
tetrahydropyridine would form a symmetrical, resonance stabi
lized carbonium ion which could eliminate a proton or deuteron,
explaining this rapid exchange of isotopes. This is shown in
Figure 2b.
On standing for two days in a mixture of sodium boro
hydride and 1-methylpyridinium iodide dissolved in anhydrous
N,N—dimethylformamide and deuterium oxide, compound XXXVIII
did not becOTie deuterated as evidenced by ho changes in the
infrared spectrum of the recovered tetrahydropyridine. This
implied that XXXIX had not become deuterated by exchange
after reduction to the tetrahydropyridine had occurred. A
similar control experiment with the amine borane of XXXVIII
gave the same result. This indicated that the amine borane
would not exchange under the reaction conditions of the sodium
borohydride reduction.
The mass spectrum of the deuterated tetrahydropyridine,
XXXIX, exhibited its parent peak at 171; m/e corresponding to
the presence of one deuterium atom par molecule as the proton
magnetic resonance spectrum of XXXIX had already indicated.
The parent peak of XXXVIII appeared at 173 m/e. The appear—
ance of a peak at 115 m/e in the spectrum of XXXVIII and a
corresponding peak at 116 m/e in the spectrum of XXXIX was
interpreted to be indicative of the formation of PhCH(CH 2)2^
during the fragmentation of XXXVIII and the presence of
PhCHCHgCHD* during the fragm entation of XXXIX. The presence
of a peak a t liZ m/e in the spectra of both XXXIX and XXXVIII
was interpreted to be indicative of the formation of
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 16
+ GH2=N=CH2 during the fragmentation of both compounds. These
data also suggested that the deuterium was located at the 5—
p o s itio n in XXXIX and th a t th is compound did not contain
deuterium in the 2— or 6—position, depending on the origin
of the k2 m/e fragm ent.
On the basis of the ultraviolet absorption spectral
studies and the isotopic investigation of the sodium boro
hydride reduction of XXI, the gross mechanism of this reaction
may be written as shown in Figure 2a. The initial borohydride
attack occurred at the 2—position to give a 1, 2—dihydr©pyri
dine (Structure A). This specie was then protonsted by the
solvent to give an immonium cation which underwent subsequent,
rapid reduction to the product. It should be noted that this
work did not distinguish between protonation of the 1-m ethyl—
i;—phenyl—1,2—d ih y d ropy rid ine (Structure A) at the 3—position
to give immonium cation B and protonation at the 5—position
to give immonium cation G or protonation at both positions to
give an equilibrium mixture of B and G.
The protonation of conjugated dienamines should be
comparable to the protonation of the anion from an oi , (9 —
unsaturated acid and therefore predicted by the correlation, 35 "Ingold's Rule”. Since a very weak acid (alcohol or water)
is responsible for the protonation and the subsequent reduc
tion step is too rapid to allow equilibrium to be attained.
Ingold *3 Rule predicts that the product of the sodium boro
hydride reduction of a conjugated dienamine would be formed
from proton attack at the central carbon atom of the dien—
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 17
amine system. Since the final step of the reduction is ex
tremely rapid, the immonium ion formed preferentially in the
protonation step would be the kinetic product rather than
the thermodynamically more sta b le c a tio n .
Ingold's Rule would than predict that protonation of
dienamine A by the weak acid water would occur preferentially
a t the 5—position to give the kinetically favored product,
immonium cation C. Subsequent reduction of this specie would
give the observed product. 36 Johnson has reported that acetic acid protonated
the dienamine, 3—N—pyrrolidylcholestadiene—3,5 at the 5—
position during the sodium borohydride reduction of this com
pound. This would be in accord with Ingold's Rule. Apparently
this protonation selectivity is lost with stronger proton 37 donors. Opitz and Merz have reported that while water and
acetic acid protonated 1—morpholin 0—3, 5 ,5“trimethylcyclohexa—
d ie ne—1,3 at the central position of the dienamine system,
hydrochloric and perchloric acids protonated the dienamine at
the terminal position.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 18
Ph
Ph CH, Ph BHT EgO BH
CH, CH, Ph XXI XXXVIII
CE,'^
B
Fig. 2a. Mechanism fo r the Formation of the 1 ,2 ,5 ,6 - Tetrahydropyridine .
Ph Ph Ph
V C r' OH OH, CH, XXXIX"
Pig. 2b. ' Acid Catalyzed Exchange Reaction of XXXIX.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 19
z i :
- "4 - Z U -
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2 0
: I : : ! ; j i Hj 1^
IzdL : ; t ;
i i
: h.X-
liir 1-f! i r HT-:
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 21
Sodium borohydrlde reduction of 1 .k—dim ethvl—2—
phenvlpyrldlnlum Iodide (X IX )In an effort to gain further
support for the applicability of Ingold's Rule to the fate
of dlhydropyrldlnes In the sodium borohydrlde reduction of
pyrldlnlum Ions, the reduction of XIX was studied In aqueous
medium. Although a dlhydropyrldlne was not Isolated from the
reduction of XIX, it was presumed that the Initially formed
specie was a 1,6—dlhydropyrldlne rather than a 1,2—dihydro—
pyridine. Three points favored this assignment, the sterlc
Interference to hydride attack at the 2—position exerted by
the phenyl substituent, the formation of the 350 mp absorption
band when XIX was reduced with sodium borohydrlde In N,N—
dlmethylformamlde in the absorption cell of the ultraviolet
spectrophotometer, and the fact that reduction of 1,3,5—trl—
methyl—2—phenylpyrldlnlum iodide (XX) gave a 1,6—dlhydropyrl—
dine product which was Isolated.
The gas chromatographic analysis of the product ob
tained from the reduction of XIX Indicated that It was homo
geneous. The ultraviolet spectrum of this product ruled out
the possibilities of a 1,4,5,6- or 1,2,3,4—tetrahydropyrldlne
s tru c tu re , since the spectrum showed only fin e stru c tu re of
low extinction near 260 m^. Indicative of an unconjugated
phenyl substituent, and end absorption below 225 mp.. Indica
tive of the absence of-c vinyl amine type structure. The
position of the double bond was revealed by the proton mag
netic resonance spectrum of the tetrahydropyrldlne. The
spectrum showed a s in g le t at 7.35 ppm due to the resonance
of the aromatic hydrogens, a singlet at 5*45 ppm due to the
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 22
vinyl hydrogen, a quartet at 3.22 ppm attributed to the ben-
zylic hydrogen, a multiplet at 2.95 ppm assigned to the
methylene at the 6—posltlon, a multiplet at 2.65 ppm due to
the methylene at the 3—position, a singlet at 2.05 ppm re
sulting from the resonance of the IMnethyl hydrogens and a
singlet at 1.70 ppm due to the C—methyl hydrogens. The
relative peak areas were In exact agreement with these asslgnr-
ments. The fact that the benzyllc hydrogen was a quartet,
rather than a doublet, strongly suggested that the product was
1, 1|.—dimethyl—2—phenyl—1,2,3, 6—te trahydropyrIdine (XXXIII)
rather than Its 3,4 double bond Isomer. The 3,4 double bond
Isomer would have been expected to have given rise to an un
mistakable doublet for the benzyllc hydrogen.
The result offered further evidence for the applica
bility of Ingold's Rule to the position of protonation of the
dlenamlne system of a dlhydropyrldlne during the sodium boro
hydrlde reduction (see Figure 3)* If It Is assumed that the
1,6—dlhydropyrldlne (Structure D) was Initially formed from
the reduction of XIX, It would appear that D was protonated
at the 3—posltlon to give the Intermediate product of kinetic
control, Immonlum cation E, which underwent rapid subsequent
reduction to the observed product XXXIIl before an equilibrium
state to favor the thermodynamically more stable Immonlum
cation F was established. Thus Intermediate 1,2— or 1,6—dl—
hydropyrldlnes are believed to undergo specific protonation
at the midpoint of the dlenamlne system by the protlc solvent
during the sodium borohydrlde reduction of pyrldlnlum Ions.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 23
The resulting immonlum cation Is believed to undergo Immedi
ate reduction to the tetrahydropyridine product.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 24
BK“ Ph . Vll XIX XXXIII
Fig. 3. Hechanism for the Formation of the 1,2,3,6-Tetra- hydropyridine from the Sodium Borohydride Reduction of 2-Substituted Pyridinium Ions.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 25
Gas chromatographic analysis of sodium borohydrlde 9 reduction mixtures.— In view of the report by Perles that
the sodium borohydrlde reduction of a number of pyridinium
ions gave piperidines as well as tetrahydropyridines as pro
ducts, it was desirable to determine whether or not this was
the case with the reductions studied in this work. For this
purpose, the material obtained from the sodium borohydrlde
reduction of a number of pyridinium ions was analyzed by gas
chromatography and infrared spectroscopy. The procedures
used for the sodium borohydride reductions are indicated in
the Experimental. The data obtained from the gas chromato
graphic analysis of the reduction products are shown in
TABLES V and IX.
Initially the reduction of 1—butyl, 1—benzyl, 1—iso-
propyl, 1,3—dimethyl— and 1,3,5—trimethyIpyridinium halides was
investigated. - The gas chromatographic analysis of the product
mixtures obtained from the reduction of these pyridinium com
pounds indicated the presence of a two component mixture in
each case. The component of longer retention time was sepa
rated from each mixture by careful fractional distillation
with the exception of the mixture obtained from the reduction
of the 1—isopropyl pyridinium iodide. In each case the com
ponent of longer retention time was shown to be the 1,2,5,6—
tetrahydropyrldlne by catalytic hydrogenation, infrared spec
troscopy, ultraviolet spectroscopy and melting points of
derivatives. The fact that these compounds could be hydro
genated to the known piperidines confirmed the presence of
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u n sa tu ratio n . Tha fa c t th a t these compounds did not e x h ib it
ultraviolet absorption bands above 220 mp, with the exception
of the fine structure near 26o mp present in the 1—benzyl—
tetrahydropyrldlne, confirmed the 1,2,5,6—tetrahydropyrldlne
stru c tu re fo r each compound. This conclusion could be reached
on the basis of the report that a number of simple 1.5,6—
tetrahydronyridines have an absorption maximum near 228 mp ? 27 Tha fact that Wenkert has employed proton magnetic resonance
spectroscopy to show that a number of pyridinium ions with an
alkyl substituent at the 3—position are reduced by sodium
borohydride to the 1,2.5,6—tetrahydropyridine gave further
support for the assignment of this structure to the 1,3—di—
methyltetrahydropyridine obtained here. Further evidence for
the tetrahydropyrldlne structure was offered by tha presence
of a strong band near BOO cm""^ in the infrared spectrum of
each of these compounds which was not present in the corres
ponding piperidine. A comparison of the melting point of the
picrate obtained from the fraction assumed to be tetrahydro—
pyridine with that of the piepridine also indicated that these
were different compounds. The melting points of the tetra—
hydropyridine derivatives are given in TABLE V and those of the
corresponding piperidines are shown in TABLE VIII.
Since the fractional distillation of the mixture ob
tained from the reduction of the 1—isopropyl pyridinium io
dide (X) did not give a good separation, a picrate of the crude
material was obtained and subjected to fractional recrystal— 0 lization. This procedure gave a picrate, m.p. 149—151 , which
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 27
0 was identical with the picrate, m.p. 150—151 , obtained from
1—isopropylpiperidine(XII). A second p ic ra te , m.p. 134” 136°,
was also obtained. This was the picrate of 1—isopropyl—1,2,
5,6—tetrahydropyridine(XXVIII).
The component of shorter retention time in each mix
ture of reduction products was shown to be the piperidine
product. It was identical in retention time to the pure
piperidine obtained from the catalytic hydrogenation of the
corresponding 1,2,5,6—tetrahydropyridine. Retention times of
the pure piperidine and the piperidine present in the sodium
borohydride reduction mixture ware also compared by diluting
the mixture with the pure piperidine. The resulting sample
was then chromatographed. The chromatogram obtained in this
way did not exhibit new peaks but rather an increase in the
relative peak area of the peak of shorter retention time.
Infrared spectra of these mixtures were identical with those
of the original sodium borohydride reduction mixtures with
the exception of slight intensity changes in some of the bands.
In contrast to the reduction of the pyridinium ions
indicated above, the reduction of 4—phenylpyridine methiodide
(XXI), If-me thy Ipy rid ine methiodide (XIV) and 4-^@ th y l—2—phenyl-
pyridine methiodide (XIX) gave a single product in each case.
The gas chromatogram of each reduction product exhibited a
single sharp peak. The product obtained frcan the reduction of
XIV was shown to be the 1 ,2 ,5 ,6 —tetrahydropyridine by cataly
tic hydrogenation to the corresponding piperidine. The infra—
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red and ultraviolet spectra of the tetrahydropyrldlne were in
accord with the structural assignment as were the melting
points of its derivatives. The structural assignments to the
products obtained from XXI and XIX have already been discussed.
Since the reduction of XIX appeared to give only a
single tetrah y d ro p y rld ln e, i t became d e sirab le to study the
reduction of 2—phenylpyridine methiodide (XVIII) as a further
check for the possible formation of double bond isomers of the
tetrahydropyrldlne. Gas chromatographic analysis of the
material obtained from the sodium borohydride reduction of
XVII revealed the presence of two products; however, one of
these products was identical in retention time to 1-methyl—2—
phenylpiperidine (XLVIII) which was obtained from the cataly
tic hydrogenation of the sodium borohydride reduction material.
The ultraviolet and proton magnetic resonance spectra of the
other component of the mixture indicated that it was 1-methyl—
2—phenyl—1,2 ,3 ,6 —tetrah y d ro p y rid in e (XXXI). The u ltr a v io le t
absorption spectrum of XXXI showed only fine structure of low
extinction near 26o mp and end absorption below 225 m^j, in
dicative of an unconjugated phenyl substituent. These data
eliminated 1-methyl—2—phenyl—1,4,5,6-tetrahydropyridine as a 39 possible structure, since Buchel has reported that this
compound has an u ltr a v io le t ab sorption band a t 275 m^. The
proton magnetic resonance spectrum of XXXI confirmed the 1,2,
3,6—tetrahydropyridine structure. The spectrum contained a
broad peak at 5.85 ppm due to the vinyl hydrogen, a quartet
a t 3.32 ppm due to the benzylic hydrogen, a multiplet at 3*05
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ppm due to the methylene at the 6—position, a multiplet at
2.43 ppm assigned to the methylene at the 3—position and a
singlet at 2.19 ppm resulting from the hydrogens of the N—
methyl group. The benzyllc hydrogen quartet confirmed the 1,
2,3,6—tetrahydropyrldlne structure.
Further evidence that the other component of the
mixture obtained from the sodium borohydride reduction of
XVII was a p ip erid in e and not a double bond isomer of the
tetrahydropyrldlne was obtained by a comparison of the in
frared spectrum of the original reduction mixture with that
of a mixture prepared by diluting the tetrahydropyrldlne,
XXXI, with the pure piperidine, XLVIII. These spectra were
identical. A gas chromatogram of this prepared mixture was
also identical with that of the original reduction mixture.
The piperidine again exhibited the shorter retention time.
These results led to the question of whether or not
the sodium borohydride reduction of appropriately substituted
pyridinium ions would give sterically homogeneous or steri—
cally inhomogeneous products. For this purpose the reductions
of 1,3,5—trimethyl—2—phenylpyridinium iodide (XX) and 1,3—
dimethyl—2—phenylpyridinium iodide (XVIII) were studied.
The gas chromatographic analysis of the material ob
tained from tha borohydride reduction of XVIII revealed four
products. Two of these were identical in retention time to
the products of the catalytic hydrogenation of this sodium
borohydride reduction mixture and thus were isomeric piperi
dines. The two remaining products were either geometrical
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isomers of 1,3-dimethyl—2—phenyl—1,2,3,6—tetrahydropyridine
(XXXII) or a m ixture of XXXII and i t s 3,4—double bond isomer.
The former alternative is preferred by analogy to the products
obtained from the reduction of 4"^othyl—2—phenyl— and 2—phenyl-
pyridine methiodide, XIX and XVII respectively. The possibility
that one of the products was a 1,4,5,6— or a 1,2,3,4—tetra—
hydropyridine was eliminated by inspection of the ultraviolet
absorption spectrum of the borohydride reduction mixture. This
spectrum showed only fin e stru c tu re of low ex tin ctio n near 260
m^ and end absorption below 220 m}i, indicating the presence of
an unconjugated phenyl substituent and the absence of a vinyl
amine type structure. These data suggested that the sodium
borohydride reduction of the pyridinium ion is non—sterôo-
specific with respect to both tetrahydropyridine and piperidine
formation. The borohydride reduction of XX further supported
this belief.
The gas chromatographic analysis of the material ob
tained from the reduction of 1,3,5—trimethyl—2—phenylpyri—
dinium iodide (XX) with sodium borohydride revealed that it
was a m ixture of five compounds. Three of these compounds
(three shortest retention times) were identical in retention
time to three of the four isomeric piperidines obtained from
the catalytic hydrogenation of 1,3,5—trimethyl—2—phenyl—1,6—
dihydropyridine (XIV). The two remaining peaks in the gas
chromatogram of the metal hydride reduction mixture were
assigned to geometrical isomers of 1,3,5—trimethyl—2—pheny1—
1,2,3,6—tetrahydropyrldlne (XXXIV) rather than to double bond
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 31
Isomers of XXXIV. The ultraviolet spectrum of XXXIV did not
allow for a 1,4,5,6— or 1,2,3,4—tetrahydropyridine, since it
showed only fin e s tru c tu re of low e x tin c tio n near 260 mp. and
end absorption below 225 m^. The presence of a 1,2,5,6—
tetrahydropyrldlne could not be vigorously excluded but would
seem u n lik ely by analogy to the reduction of XIX and XVII.
These data gave further evidence for the non—stereospecific
nature of this type of reduction. A similar conclusion has 9 been reached by Ferles for tne reduction of 1,2,6—trimethyl—
pyridinium iodide.
Further information about the nature of this reduc
tion was obtained by the inspection of the relative yields of
piperidine and tetrahydropyrldlne shown in TABLE V. These
data are summarized hare. Inspection of these data revealed
that the piperidine percentage increased from 5 to 12 to 28
percent as the 1-substituent was varied from a butyl group
(XXXIX) to a benzyl group (XXX) to an isopropyl group (XXVIII).
S ub strates w ith both a 1— and a 3—su b s titu e n t, XXV and XXXII,
had relatively large percentages of piperidine, 30 percent and
52 percent respectively. Substrates with both a 3— and a 5—
substituent had a much lower piperidine content, XXXIV had
l8 percent and XXXVII had 11 percent. As previously mentioned,
substrates with 4—substituents, XXXIII, XXXVI and XXXVIII, had
no detectable piperidine content. The piperidine content in
tha reduction mixture obtained from 1,2,6—trimethylpyridinium
iodide (XVI) was estim ated to be 44 percent by proton magnetic
resonance spectroscopy. This was based on a comparison of the
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 32
integrals of the vinyl hydrogen peak and the Nnnethyl peak.
Although the presence of piperidine in the product
mixtures obtained from sodium borohydride reduction of pyri—
dinium ions may be accounted for by a number of plausible
mechanisms, it would appear reasonable to assume that the
piperidine resulted from an initial borohydride attack at the
4—position of the pyridinium ion rather than at the 2— or 6—
positions. A 1,4—bihydropyridine formed in this way would be
expected to undergo complete reduction to the piperidine,
since it possesses a double enamine system rather than a di—
enamine system. The reduction of the 1,4—dihydropyridine would
then be analogous to the second and third steps postulated for
the reduction of the 1,2-dihydropyridine to the tetrahydropyri—
dine except that the process would occur twice in order to
obtain the piperidine. This mechanism is shown in Figure 4»
The isolation of a small amount of 1,4-dihydropyridine
from the reduction of 3,5—diphenylpyridine methiodide (XXII)
and from the reduction of ethyl 5—bromonicotinate methiodide
(XXV) confirmed the fact that 1,4—dihydropyridines are formed
during the sodium borohydride reduction of pyridinium ions.
If it is assumed that the piperidine was formed
through the 1,4—dihydropyridine, some significance can be
attached to the gas chromatography data. Thus as the steric
interference of the 1—substituent on borohydride attack at
the 2— or 6—positions increased, the relative yield of piperi
dine also increased. The 1—butylpyridinium bromide (XI) gave
5 percent piperidine, 1—benzylpyridinium bromide (XII)gave
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 33
12 percent piperidine and 1—isopropyIpyridinium iodide (X)
gave 28 percent piperidine.
The effect of substituents at other ring positions
on the amount of piperidine formation appeared to be more
complex. Thus 1,3—dimethyl pyridinium iodide (XIII) gave
30 percent piperidine. This, however, may be an unusual
case, since the major unsaturated product was 1,3—dimethy1—
1,2,5,6—tetrahydropyridine(XXXV), indicating that the initial
hydride attack occurred at the more hindered 2—position,
rather than at tha relatively unhindered 6—position. This
curious result has also been observed for the phenyllithium
addition to 3-fnethylpyridine, where the predominant product 23 was 3—methyl—2—phenylpyridine. This may account for the
high percentage of piperidine obtained from the reduction of
XIII, since the 4—position is relatively unhindered as com
pared to the 2—position. In the case of 1,4—dimathy1pyri—
dinium iodide (XIV), where the 4—position is blocked, no trace
of piperidine could be detected. On the other hand, blocking
both the 2— and 6—positions did not prohibit tetrahydropyri-
dine formation completely as evidenced by the product com
position (44 percent piperidine) obtained from the reduction
of 1,2,6—trime thyIpyridinium iodide(XVI). This is interpreted
to mean that attack at the 2— or 6—positions is favored over
attack at the 4—position, electronically as well as statis
t i c a l l y .
In the case of 1,3,5—trimethylpyridinium iodide (XV),
the steric interference to attack at the 4—position and the
equivalent 2— and 6—positions should be in the same order of
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 34
magnitude. The 12 percent piperidine obtained from the
sodium borohydride reduction of XV indicated more than a
statistical preference for hydride attack adjacent to the
n itro g e n .
The data for 2—phenylpyridine methiodide (XVII) gave
a better separation of the statistical and electronic factors.
If it is assumed that the phenyl substituent prevents attack
at the 2—position, then the statistical probability of attack
at the 4“ or 6—position becomes equal. Compound XVII gav.e-
only 8 percent piperidine, indicating a strong electronically
directed preference for hydride attack to occur at the 6—
position. The 4““Sobstituted member of the 2—phenylpyridine
methiodide series, XIX, gave no trace of piperidine, indi
cating again the ability of a 4—substituent to prevent any
detectable amount of piperidine formation.
The sodium borohydride reduction of 1,3,5—trimethyl—
2—phenylpyridinium iodide (XV) gave 18 percent piperidine.
It would appear that attack at either the 4~ or 6—position
would be subject to similar steric interactions, so that the
electronic preference for attack at the 6—position predominated.
In this case protonation of either a 1,6— or 1,4—dihydropyridine
would also be subject to steric interference by the methyl
groups at the 3— and 5—positions. This steric interference
should be of the same order of magnitude in each case.
The reduction of 1,3—dimethyl—2—phenyIpyridinium iodide
(XVIII) was a particularly interesting case, since the piperi
dine products predominated in a 52 percent relative yield.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 35
The buttressing affect of the phenyl substituent adjacent to
two methyl groups may exert a greater steric effect on the
6—position than it would appear. However, it should be noted
that protonation of the 3—position of the 1,6—dihydropyridine
would be seriously hindered by the combined bulk effect of
the 2—phenyl and the 3-methyl substituents. On the other
hand, protonation of the 1,4—dihydropyridine and subsequent
reduction to a 1,4,5,6—tetrahydropyridine would be relatively
unhindered. This specie could then reduce slowly to the
piperidine. A rapid reduction of the 1,4—dihydropyridine
coupled with a relatively slow reduction of the 1,6—dihydro—
pyridine might have permitted some of the latter isomer to
either rearrange or serve as a hydride source for reduction
of other species in the solution. -%at dihydropyridines in
solution may serve as reducing agents has bean postulated by
Lansbury.^^ This presumably would involve the dihydropyri—
dine acting as a source of hydride ion.
It perhaps would be best to state simply that these
data show that piperidine formation can become important as
a result of steric interference to attack by the borohydride
at 2— and/or 6—position. In all the cases studied it would
appear that initial borohydride attack at a position adjacent
to tha nitrogen was strongly electronically favored.
Catalytic hydrogenation of tetrahydropyridines.— Tha
reference samples of piperidines used for the gas chromato
graphic analysis of the sodium borohydride reduction mixtures
ware obtained from the catalytic hydrogenation of these mix—
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 36
BH BH 4 R R
Pyridinium 1 , 4 , 5 ,6- Ion pyridine Tetrahydropyridine
HgO » R
Piperidine
Fig. 4. Mechanism for the Formation of Piperidine from the. Sodium Borohydride Reduction of Pyridinium Ions.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 37
turss or from tha hydrogenation of the pure tetrahydropyri—
dines. Tha physical properties of these piperidines are in
dicated in T^BL3 VIII. The gas chromatographic analysis of
the material obtained from the hydrogenation of 1—isopropyl—,
1—butyl—, 1—benzyl—, 1,3—dimethyl—, 1, l^—d ime thyl j 1-raethyl—2—
phenyl— and l,!^.—dimethyl—2—phenyltetrahydropyridlne indicated
a single product in each case. The gas chromatographic analy
sis of the material obtained from the hydrogenation of the
sodium borohydride reduction mixture obtained from 1,3—dimethyl-
2—phenylpyridinium iodide Indicated the presence of two piperi
dine isomers. The reference sample of 1,3,5—trimethyl—2—
phenylpiperidine(XLIX) was prepared from the catalytic hydro
genation of 1,3,5—trimethyl—2—phenyl—1,6—dihydropyridine (LIV).
The hydrogenation product was shown to be a mixture of four
isomeric piperidines by gas chromatographic analysis. It
should be noted that in all tha examples studied, the piperi
dines always exhibited a shorter retention time than the cor
responding tetrahydropyridines.
Infrared spectra of tetrahydropyridines.- Since in
frared spectroscopy was used as supporting evidence for the
presence of piperidines in the sodium borohydride reduction
m ixtures, some fu rth e r comments on how tetrah y dropyridines
and piperidines can be distinguished by infrared spectroscopy
are presented here.
The infrared spectra of the tetrahydropyridines pre
pared in this study ware quite similar to the corresponding
piperidines in most regions of the spectrum. Since the only
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 36
major structural difference between the two classes of com
pounds is the vinyl hydrogen contained in the tetrahydro—
pyridine, the vinyl C—H out of plane bending vibration would
be expected to be the most characteristic infrared band use
ful in distinguishing between the tetrahydropyridine and its
corresponding piperidine,^ The 1000 to 750 cm~^ region of
the infrared spectrum was, in fact, the only region in which
a c le a r cut d is tin c tio n between the two cla sses of compounds
could be made. The bands shown in column 1 of TABLE VI were
assigned to the vinyl C—H out of plane bending vibration of
tha indicated tetrahydropyridines. This was the strongest
or only band in the 1000—750 cm*“^ region of the tetrahydro—
pyridine spectrum which was not present in the spectrum of
tha corresponding piperidine. Other bands which were found
in the spectra of certain tetrahydropyridines in this region
which did not appear in the spectra of the corresponding
piperidines are shown in columns 2,3 and ij. of TABLE VI. The
spectra of tetrahydropyridines with two cis vinyl hydrogens
normally exhibited a band near 800 cm””^, while the spectra
of tetrahydropyridines with a single vinyl hydrogen usually
contained a band near 825 cm”^.
Preparation and identification of dihydropyridines.
During the course of this investigation it was found that the
reduction of certain 3,5—disubstituted pyridinium ions with
sodium borohydride gave only dihydropyridines as products.
These products were sufficiently stable to permit accurate
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structural assignments to be made and to permit a study of
some of the reactions of this type of compound to be carried
out. That these compounds did not undergo further reduction
to the tetrahydropyridine was interpreted in terms of both an
electronic and a steric resistance of this type of dlenamlne
system to protonation by the solvent medium.
The sodium borohydride reduction of 3,5—diphenylpyri
dine methiodide (XXII) in aqueous N,N—dimethylformamlde gave
an essentially quantitative yield of a mixture composed of
75 percent 1-methyl—3,5—diphenyl—1,2-dihydropyridine (L) and
25 percent of 1-methyl—3,5—diphenyl—l,i|—dlhydropyrldlne (LI).
The relative percentages were determined by proton magnetic
resonance spectroscopy. Compound L was obtained in a pure
state by repeated recrystallization of this mixture from iso-
propanol. A pure sample of LI was obtained from a sodium
dithlonite reduction of XXII in aqueous sodium bicarbonate
solution. The dithlonite reduction of pyridinium ions has
been shown to be specific for the preparation of l,i|.—dihydro- 14-2 p y rid ln e s .
The structural assignments given to L and LI were
based principally on their respective proton magnetic reso
nance spectra. The appearance of a singlet which integrated
for two hydrogens at ppm in the spectrum of L and a
similar singlet at 3.69 ppm in tha spectrum of LI suggested
that L contained a methylene adjacent to the nitrogen while
LI did not. The spectrum of L exhibited two peaks at 6.82
ppm and 7*09 ppm which were conveniently assigned to the
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resonance of two nonequlvalant vinyl protons. Each peak had
an integral which corresponded to one hydrogen. The spec
trum of LI exhibited only a singlet at 6.87 which integrated
for two hydrogens. This indicated that LI had two equiva
lent vinyl hydrogens and therefore must have the I,!*.—dihydro—
pyridine structure. The detailed spectra of L and LI are
given in TABLE XI.
Ultraviolet and visible spectroscopy, techniques
often used to assign structures to dihydropyridines, gave an
ambiguous result with L and LI. The spectra of both L and
LI exhibited a long wavelength band near kOS with a shoulder
near if.25 mp. The spectrum of LI, however, exhibited much more
intense absorption in this region. The ultraviolet spectrum
of L contained bands a t 310 and 257 m p , while tha spectrum
of LI exhibited bands at 297 and 2I4.9 mp with a shoulder at
266 mu. Thus the spectra of L and LI were quite similar. 19 Traber and Karrer have reported that the spectrum
of 1,2, if., 6—tetram e th y l—3 ,5—d ic a rb oe thoxy—1,2—d ihyd ropy rid ine
exhibited maxima a t 290 and 38O mju, while the spectrum of
the corresponding 1, if.—d ihyd ropy rid ine exhibited maxima at 260
and 3if-8 mp. The f a c t th a t the spectra of both L and LI
showed the same long wavelength maximum is interpreted to
mean that extention of conjugation through the nitrogen (the
nitrogen being in some respects similar to an ethylenic bond)
is important in the case of the 1,if.—dihydropyridine, LI.^^
The infrared spectra of L and LI were also quite
similar (see TABLE XII). Tne most useful region of the in-
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frared spectrum for the characterization of dihydropyridines
is the region from 1700 to 1500 cm""^. Dihydropyridines have
strong absorption bands in this region which are not normally
present in the corresponding pyridinium salts or tetrahydro—
pyridines.^ The infrared spectrum of L exhibited three strong
bands a t 1635, 1595, and 1555 cm”^. The spectrum of the 1,4“
d ihydropyrid ine, LI, showed strong bnads at 1685, 1625, and
I6l0 cm”"^. These bands are presumably associated with tha
carbon-carbon double bond stretching frequencies of the di—
hydropyridine system.
The fact that only dihydropyridines were obtained
from the sodium borohydride reduction of XXII illustrated
the ability of the phenyl substituents at the 3“ and 5—posi
tions to prevent further reduction of the dihydropyridine
system. This was most lik e ly both a s te ric and an e le c tro n ic
effect. The ability of bulky substituents at both the 3—
and 5—positions to prevent further reduction of a dihydro—
pyridine was further illustrated by the following example.
The sodium borohydride reduction of ethyl 5—bromo—
nicotinate methiodide (XXV) in aqueous methanol gave, in high
yield, a mixture of 90 percent ethyl 1-methyl—5—bromo—1,6—
dihydronicotinate (LII) and 10 percent ethyl 1-methyl—5—bromo-
1,4—dihydronicotinste (LIII). The relative percentages were
determined by proton magnetic resonance spectroscopy. The
presence of a 1,2—dihydropyridine or a tetrahydropyrldlne was
not detected. This was in contrast to the product composition 17 reported by Kinoshita for the sodium borohydride reduction
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of ethyl nicotinate methiodide. This methiodide was reported
to give rise to both the 1,2— and the 1,6—dihydronicotinates
when the reduction was performed in aqueous sodium hydroxide
solution, while the 1,6—dihydronicotinate and the 1,2,5,6—
tetrahydrcnicotinate were obtained when the reduction was run
in aqueous methanol. It would appear that the 1,2—dihydro—
nicotinate underwent further reduction to the 1,2,5,6—tetra—
hydronicotinate in the methanolic medium while the 1,6—dihydro—
nicotinate isomer was stable toward further reduction in this
medium. This would be in accord with Ingold's Rule, since the
carboethoxy group at the 3—position would block the protona—
tion of the latter isomer at tha central position of its dien—
amine system and consequently prevent its further reduction to
a tetrahydronicotinate. Kinoshita did not report the forma
tion of a 1,4—dihydronicotinate in this work.
The absence of a tetrahydropyrldlne from the reduction
of XXV would then appear to be consistent with the absence of
the 1,2—dlhydropyrldlne, since both the 3- and the 5—positions
are substituted in this case. This might suggest that the
formation of the 1,6>- and 1,4—dihydropyridines, LII and LIII
respectively, was kinetically favored or that the initial
hydride a tta c k on XXV was re v e rsib le and L II and L III were
the thermodynamically more stable isomers. An alternative
explanation would be that the 1,2—dihydropyridine was formed
in significant quantities but would not reduce further to the
tetrahydropyrldlne due to the steric hindrance to protonation
exerted by 5—bromo substituent. This would require that the
initial hydride attack be reversible or that the 1,2—dihydro-
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pyridine be a source of hydride ion for the reduction of
other species in the solution. The existing data did not
distinguish between these possibilities.
The structures of LII and LIII were originally
assigned on the basis of their ultraviolet spectra. The
spectrum of LII exhibited bands at 268 and 355 mp, while the
spectrum of LIII exhibited a single band in this region at
360 my. This was in good agreement with the ultraviolet spec
tra reported by Nelson^^ and by Wallenfels^^ for a large
number of 1,4“ and 1,6—dihydropyridines containing carbonyl 17 substituents at the 3—position. Kinoshita reported that
the spectrum of ethyl 1—methyl—1,6—dihydronicotinate con
tained bands at 263 and 362 mu , while the spectrum of ethyl
1-methyl—1,1;—dihydronicotinate exhibited a single band in this
region a t 363 mu. The spectrum of the 1,2—dihydronicotinate
was reported to have a long wavelength band at 1;25 mp. The
spectra of a number of other 1,2—dihydropyridines have been
reported to have a long wavelength band near 425 mu.^^ Neither
the spectrum of LII nor the spectrum of LIII exhibited absorp
tion bands in the region from 36 O to 750 mp. The l,li—dihydro—
pyridine, LIII, was also prepare-^ from a dithlonite reduction
of XXV.
The proton magnetic resonance spectra of LII and LIII
supported the structural assignments. A singlet appeared in
the spectrum of LII at 3«92 ppm which had an integral cor
responding to two protons. A similar singlet in the spectrum
of LIII appeared at 3.13 ppm. This suggested that LII con—
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tained a methylene group adjacent to the nitrogen while LIU
did not. The spectrum of LII had singlets at 6.1+2 and 6.97
ppm'due to the resonance of the two nonequivalent vinyl pro
tons. The spectrum of LIU exhibited similar peaks at 5*79
and 6.65 ppm. The complete spectra of LII and L IU are given
in TABLB XI.
The infrared spectra of the 1,6—dihydropyridine, LII,
and its 1,L|.—dihyd ropy rid ine isomer, LIU, were typical of di—
hydropyridines but did not clearly oxstinguish between the
two structures. Tae major bands of each spectrum are shown
in TABLE XII. Nelson^^ has reported that a number of l,4-“*
dihydropyridine3 with a carbonyl substituent in the 3—position
exhibited a carbonyl stretching frequency which was shifted
some 60 cm"“^ toward lower frequency from the parent quaternary
salt. Ihis shift was attributed to a loss of carbonyl charac
ter due to a strong electronic interaction between the nitro
gen and the carbonyl substituent through the polarized 2,3—
double bond. The infrared spectra of LII and LIU exhibited
a similar effect. Ihe carbonyl stretching frequency in the
spectrum of the parent salt, XXV, appeared at 1740 cm””^. The
corresponding stretching frequencies in the spectra of LII
and L IU appeared a t 1665 and 1685 cm""^ resp ec tiv e ly . The
spectrum of LII also exhibited bands a t 1635 and 1595 cm“^,
while the spectrum of LIU contained a band at I6l5 cm“*^.
These bands were probably due to the stretching frequencies
of the carbon—carbon double bonds of the dienamine system.
Although the sodium borohydride reduction of 1,3,5—
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trimathyl—2—phenylpyridinlum iodide (XX) and 1,3—dimethy1—
2—phenylpyridinium iodide (XVIII) normally gave a mixture of
piperidines and tetrahydropyridines, it was possible to
partially stop the reduction at the dihydropyridine stage by
running the reduction in 25 percent sodium carbonate solution.
Presumably, the dihydropyridine did not undergo further re
duction due to i t s low s o lu b ility in th is medium.
The reduction of XX in aqueous sodium carbonate solu
tion gave 1,3,5—trim ethyl—2—phenyl—1,6—dihydropyridine (LIV).
The instability of LIV made its purification extremely diffi
cult. Gas chromatographic analysis of the purest sample of
LIV which was obtained indicated that 10 percent of an im
purity was still present. On the basis of retention time,
this was probably 1,3,5—trim ethyl—2—phenyl—1,2,3, 6-tetrahydro—
pyridine (XXXIV). The structure of LIV was assigned on the
basis of its proton magnetic resonance spectrum which showed
a 5 to 1 aromatic to vinyl proton integral and a singlet at
3.65 ppm which in teg rated f o r two hydrogens and was assigned
to the methylene group at the 6—position. Two strong bands
at 1680 and I 636 cm“^ in the infrared spectrum of LIV also
suggested a dihydropyridine structure.
The ultraviolet spectrum of LIV exhibited two absorp
tion bands at 325 and 2iji|. m|i in ether. Addition of dilute
hydrochloric acid shifted the 325 mja band to 276 m 31 w ith a
slight increase in extinction. Since the 276 mpi band was
consistent with a 2—phenyl—1,4,5,6—te trahydropyrid ine struc
ture^^, it appeared that LIV had the 1,6-dihydropyridine
structure .
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Ph. ■Ph V RX 1 CH, CH.
^ X = I, XXII X = Br, XXIII X = Cl, XXIV XX = HBr, SOgCl, CgH-COCl, CE,I Ph ■Ph
CH, X
Fig. 5. Preparations and Reactions of the 3,5-Diphenyl- dihydropyridine8.
COOE Br,Br. COOEt Br OOEt
BH,“ CH,
XXV B ill HBr ^2°4' sU COO'H Br^_X<:^CüOEt
CH, I OIU Br j
XXVI XXV
Fig. 6. Preparations and Reaction of the Ethyl 5-Bro^o- dihydronicotinates.
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The reduction of XVIII in aqueous sodium carbonate
solution save a mixture which contained material believed to
be 1,3—dimethyl—2—phenyl—1,6—dihydropyridine(LV). This com
pound was not well characterized due to its rapid decomposi
tion during attempts to purify it. The infrared spectrum of
the crude material exhibited strong absorption bands at 1670
and 16^.0 cm“^. The ultraviolet spectrum of LV contained an
absorption band at 330 mjx in alcohol which shifted to 268 mju
on acidification of the solution. It was assumed that LV
also had the 1,6—dihydropyridine structure on the basis of
the similarity of its spectral properties to those of LIV.
Reactions of dihydropyridines.— It is a well estab—
lished fact that dihydropyridines are sensitive to oxidatlon^^'^^
Dihydropyridines have been found to act as reducing agents for 4 4 ii5 such compounds as nitrobenzene , hexachloroacetone , and 46 bromoforra. Free radical mechanisms as well as ionic mecha
nisms have been postulated for these reactions.
It was observed that both 1-methyl—3,5—diphenyl—1,2—
dihydropyridine (L) and its 1,4—dihydropyridine isomer, LI,
could be readily reoxidized to the parent pyridinium ion. Thus
treatment of a benzene solution of either L or LI with an
hydrous hydrogen bromide resulted in a vigorous reaction from
which 3,5-diphenylpyridine methobromide (XXIII) precipitated
quantitatively. The identity of the product was proven by
m elting p o in t, in frared and u ltr a v io le t spectra and by a mix
ture melting point with authentic XXIII. The spectra of the
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product ware Identical to those of authentic XXIII and the
mixture melting point showed no depression.
Treatment of the dihydropyridine L with thionyl
chloride in dry benzene gave a quantitative yield of 3,5—
diphenylpyridine m ethochloride (XXIV). The same compound,
XXIV, was obtained from the reaction of L with benzoyl chlo
ride in dry benzene. The only other product which was iso
lated from the latter reaction was benzoic acid. The pyri—
dinium ion product, XXIV, from these two reactions was
identified by its melting point and by the identity of its
ultraviolet and infrared spectra with those of authentic
XXIV prepared from 3,5—diphenylpyridine and methyl chloride.
Methyl iodide also converted dihydropyridine L to 3,5—di
phenyl pyridine methiodide (XXII) which was identical in all
ways with an authentic sample of this methiodide prepared by
treating 3,5—diphenylpyridine with methyl iodide.
An attempt was made to obtain a Diels—Alder adduct
from dihydropyridine L and tetracyanoethylene; however, it
appeared that the dihydropyridine L reduced the highly elec
tron deficient ethylenic double bond of the tetracyanoethy—
lene. The only product which could be isolated from this
reaction was pyridinium salt of 3,5-diphenylpyridine with a
complex anion containing a cyano group. The presence of the
pyridinium ring was evident from the fact that treatment of
this compound with sodium borohydride regenerated dihydro-
pyridine L. The infrared spectrum ôf the pyridinium compound
contained bands at 2200 and 2l 80 cm”^ indicating the presence
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of the cyano groups In the anion. The elemental analysis
indicated that elements other than carbon, hydrogen, and
nitrogen were present. No further attempt was made to idenr-
tify the structure of the anion.
In contrast to dihydropyridines L and LI, ethyl 1—
methyl—5—brom0-1,6—dihydronicotinate (LII) and ethyl 1-methyl—
5—bromo-1,4—dihydronicotInate (LIII) appeared to have strikingly
different chemical properties. Treatment of LIII with anhydrous
hydrogen bromide in dry benzene gave a black tar, while similar
treatment of LII in dry benzene gave a yellow oil which crys
tallized on standing. This material was subsequently identi
fied as nicotinic acid methobromide (XXVI). The proton mag
netic resonance, infrared and ultraviolet spectra of this
material were identical with those of an authentic sample of
XXVI prepared by the hydrolysis of ethyl nicotine te metho—
bromide. A mixture melting point of the methobromide obtained
from the reaction of LII with hydrogen bromide and the metho—
bromide obtained from the hydrolysis reaction showed no de—
pre 3 3 i on.
It would appear that the strong acid, hydrogen bro
mide, protonated the enamine system of LII at the terminal
position to form an immonium cation. Subsequent loss of the
elements of hydrogen and bromine and hydrolysis of the ester
would have given the observed product. Evidence for the pro—
tonation of LII at the 5-position was obtained by running the
reaction with deuterium bromide. Partially deuterated hydrogen
bromide was generated by dropping deuterium oxide into phos
phorous tribromide. The proton magnetic resonance spectrum of
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the product was identical to that of pure XJCVI with the ex
ception of a 50 percent decrease in peak area of the triplet
at 4*0 ppm assigned to the hydrogen at the 5—position in XXVI,
This would suggest that protonation did occur at the 5—
position of the dihydropyridine LII.
A crystalline Diels—Alder adduct (LVI) was obtained
by treatement of a benzene solution of LII with N—phenylmale—
Imide. The infrared spectrum of the adduct exhibited an ester
carbonyl band at 1740 cm*"^. The ultraviolet spectrum of LVI
exhibited a single absorption band at 212 mp (d —6,990).
Ihese spectral data suggested that the add’ict contained a 1,
2,5,6—tetrahydropyridine structure as would be expected. The
elemental analyses were correct for a 1:1 adduct of LII and
N—phenylmale imide.
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SUMMARY
The types of products obtained from the sodium boro—
hydride reduction of a number of pyridinium ions were found
to be dependent on the nature and position of ring substi
tuents. These results were interpreted in terms of steric
and electronic effects. Tie results are summarized below.
1. The reduction of 1—substituted pyridinium ions gave rise
to a mixture of 1,2,5,6—tetrahydropyridine and the cor
responding piperidine. The relative percentage of
piperidine was dependent on the steric bulk of the 1—sub—
s t i t u e n t .
2. The 4—substituted pyridinium ions gave only the tetra—
hydropyridine product.
3. The 2—substituted pyridinium ions were reduced to a mix
ture of 1,2,3,6—tetrahydropyridine and piperidine.
4. Reduction of the methiodides of 3,5-dimethyIpyridina, 3—
methylpyridine and 2,6-dimethylpyridine gave a mixture of
1,2,5,6—tetrahydropyridine and piperidine. The percentage
of p ip erid in e increased in the order th a t the compounds
are listed.
5. Ethyl 5-bromonicotinate methiodide was reduced to a mix
ture of the corresponding 1,6— and 1,4—dihydropyridines.
6. 3,5—diphenylpyridine methiodide was reduced to a mixture
of the corresponding 1,2— and 1,4—dihydropyridines.
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7. The reduction to the tetrahydropyridine occurred through
the 1,2—dihydropyridine, while the reduction to the
piperidine occurred through the 1,4—dihydropyridine.
8. Protonation of dihydropyridines was shown to be impor
tant in further reduction of these species to tetrahydro—
pyridines and piperidines. Protonation of the 1,2—di—
hydropyridine system by weak acids (water, alcohol)
occurred by kinetic control at the central position of
the dienamine system during the reduction to the tetra—
hydropyridine.
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GENERAL
Melting points were determined on a Kofler hot stage
apparatus and are uncorrected.
Infrared spectra were determined on a Perkin-Elmer
Model 137B Infracord Spectrophotometer and on a Perkin-Elmer
Model 21 Infrared Spectrophotometer equipped with sodium
chloride optics. Infrared spectra of liquid samples were
determined neat, as films. Spectra of solid materials were
determined as mulls in Halocarbon oil (from 4000 cm"^ to
1300 cm"^) and in Nujol (from 1300 cm”^ to 600 cm~^) unless
otherwise indicated.
Ultraviolet and visible spectra were determined on
a Perkin-Elmer Model 4000 Spectracord Recording Spectrophoto
meter. Spectra were determined in spectral grade methanol
unless otherwise indicated.
Proton magnetic resonance spectra were determined
w ith a Varian Model A-60 proton resonance spectrom eter.
Solvents and conditions are indicated with each spectrum
re p o rte d .
Elemental analyses were by Schwartzkopf Microanalyti-
c a l L aboratories, Woodside,- New York.
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METHODS OF PREPARATION OF PYRIDINES
3«5~Dlmethyl-2-phenylpyrldine (I).- Phenyllithiim
was prepared from lithium (7 g .) and bromobenzene (78 g ,) in
anhydrous ether under dry nitrogen, A solution of 3,5-di
methyl pyri dine (48 g .) in anhydrous ether (65 m l.) was added
dropwise with stirring to the ethereal phenyllithium solution.
After the addition was completed, the ether was removed by
distillation and simultaneously replaced with dry toluene.
The toluene solution was stirred under nitrogen at reflux
temperature for 8 hours. The cooled reaction mixture was
diluted with water and extracted with several portions of
ether. The combined ether extracts were dried over anhydrous
potassium carbonate, filtered and concentrated under reduced
pressure. The concentrate was distilled under reduced pres
sure to give 42,3 g. (51/0) of I, b.p. 125-127°/l.4 mm.
Anal. Calcd. for C^H^N: C, 85*25; H, 7.10.
Pound: C, 65.07; H, 7.16,
2-Phenylpyridine ( I I ) . - The procedure of Evans and
Allen^^ was used to prepare I I, b .p , 101-103°/0,3 mm. ( l i t ,
134“138°/10 mm.). Treatment of II with a saturated solution
of picric acid in 95/^ ethanol gave a picrate, m.p. 168-170°.
3-Methvl-2-phenylpyridine (III).- This compound was
prepared by the procedure of Abramov!tch et al. (23). Ill,
b .p . 121- 1 2 7 / 0 .5 mm. (lit. 107-119°/0,3 mm,), gave a picrate,
m.p, I 66 -I 67 .
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ij.-Methyl-2-phenylpyrldine (IV),- The procedure of
Abramovitch et al,^^ gave 49>° of IV, b.p, ll5-117°/l.O mm.
(lit, 110-ll5°/3 mm,). Treatment of IV with a saturated
solution of picric acid in 95^ ethanol gave a p ic ra te , m.p,
188-189.5°.
4-Phenylpyridine ( V ) The procedure of Schmidle
and Mansfield^^ was used to prepare V, m.p. 77-78° (lit,
77-78°).
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TABLE I
ULTRAVIOLET ABSORPTION SPECTRA OF PHENYLPYRIDINES
a Compound Maxima (m)a )' ExtInction No.
I 277 235 9700 14600
II 276 244 10000 14600
III 272 234 7500 10100
IV 274 244 11220 14400
V 255 15200
Spectra determined in methanol.
TABLE II
INFRARED ABSORPTION BANDS OF PHENYLPYRIDINES 925-675 cm.“ ^
Compound Band Position in cm. ^ No.
l" 800s 785s 710 s 745s 700s
II" 802m 755s 740s 692 s
III® 795a 785s 745s 695 s
IV® 870 s 830s 7803 738 s 695s
V^ 830s 730s 760s 685s
a b Determined as liquid film. Determined as Nujol mull.
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EthyI-5"brom onlcotlnate (V I).- This compound was 26 prepared by a method sim ila r to th a t of Bachman and Micucci.
Nicotinic acid was converted to its acid chloride hydrochlo
ride on treatment with excess thionyl chloride under reflux*
After distillation of the excess thionyl chloride under re
duced pressure, the acid chloride hydrochloride was mixed
with an equimolar portion of liquid bromine and placed in an
air bath at 150-1?0° for 12 hours. Precipitation of 5-bromo-
nicotinic acid (V II), m.p. 179-181° (lit, 183 ), occurred
upon dilution of the cooled reaction mixture with water and
adjustment of the pH to 3*0, The infrared spectrum showed
bands a t I 68 O, 770, 715 and 69 O cm,"^ (Nujol mull). The acid,
VII, was recrystallized from 95^ ethanol and converted to the
acid chloride by treatment with thionyl chloride. Treatment
of the acid chloride of VII with excess absolute ethanol under
reflux gave ÔOyo of VI, m.p, 40-4-1° ( H t . 38-39°), a f te r re-
crystallization from n-hexane. The infrared spectrum showed
bands at 1740, 765, 745 and 688 cm,"^ (Nujol mull). In
methanol VI had ultraviolet absorption bands at 277 mju
(£■ =3470 ) and 285 m;j (£ =2460).
Preparation of pyridinium salts (See TABLE III).-
(a) A solution of equimolar quantities of the pyridine and
the alkyl halide in acetone was heated under reflux until
precipitation of the salt as an oil or crystalline solid
appeared to be complete. If the salt separated as an oil,
crystallization was effected by removal of the solvent under
reduced pressure and replacement of it with dry ether. The
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salt was recrystallizad from Isopropanol or methanol to give
80—95^ of pure material. (b) Equimolar quantities of the pyridine and the
halide were mixed in a sealed container with no solvent and
allowed to stand in the dark until precipitation of the salt
occurred. The salt was washed with dry ether and recrystal—
lized from isopropanol.
(c) Methobi*omides and ch lo rid es were prepared by
treating a solution of the pyridine in isopropanol with a
slight excess of methyl bromide or methylchloride. The amount
of alkyl halide added was determined by bubbling the gas
through the isopropanol solution on a pan balance.
Method fo r follow ing the sodium borohydride reduc
tion of pyridinium ions by ultraviolet spectroscopy (See
TABLE IV).— The reduction of several pyridinium ions with
sodium borohydride was studied as a function of time by run—
ning the reaction directly in the absorption call of the
ultraviolet spectrophotometer. The spectrum of each pyri—
dinium ion was recorded before and a f te r one drop of a
saturated solution of sodium borohydride in isopropanol had
been added to the pyridinium salt solution in the absorption
cell. The spectrum was repeatedly scanned as rapidly as
possible until addition of excess borohydride produced no
further changes in the observed spectrum. All solutions were
10 molar in pyridinium salt. Solvents employed were metha
nol, N, N-dime thylformamide and diglyme.
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This method permitted the observation of the spectra
of dihydropyridines which were too reactive to be isolated,
as well as the spectra of dihydro— and tetrahydropyridines
which were later isolated. The maximum assigned to the di—
hydropyridine was not stable in methanol, but remained in N,
N-dimethylformamide until a drop of dilute hydrochloric acid
was added to the c e l l .
Preparation of tetrahydropyridines by reduction of
pyridinium salts with sodium borohydride.— Three methods
were used for the preparation of tetrahydropyridines on a
synthetic scale. The methods differ primarily in the solvent
employed and the molar ratio of sodium borohydride to pyridi—
nium s a l t used. Method C re s u lts in the interm ediate iso la
tion of the product as an amine borane. Tabulated data for
specific ccmpounds are given in TABLE V. Certain pyridinium
salts gave a mixture of tetrahydropyridines and piperidines,
as indicated in TABLE V. Where more than one method of pre
paration was employed for the same tetrahydropyridine, the
yield and product composition were nearly identical in each
case unless otherwise indicated.
Method A. To a solution of 0.12 mole of pyridinium
salt in 100 ml. of anhydrous methanol was added, portionwise
with stirring at ice bath temperature, 9.1 g. (0 .2 4 mole)
of sodium borohydride. After the addition was completed, the
reaction was allowed to stir at room temperature for 0.5 hr.
and then carefully acidified with dilute hydrochloric acid.
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The methanol was removed under reduced pressure and the resi
due was neutralized with a saturated aqueous solution of po
tassium carbonate. The product was removed from the solution
by extraction with ether and purified by distillation.
Method 3. To a solution of 0.12 mole of pyridinium
salt and 15 g• of potassium carbonate in 90 ml. of water and
10 ml. of methanol was added, portionwise with stirring at
ice bath temperature, 5*7 g. (0.l5 mole) of sodium borohydride.
The product separated as an o ily la y e r and was taken up in
ether. The ether extract was filtered, dried over anhydrous
potassium carbonate, and concentrated by distillation under
reduced pressure. The product was purified by distillation
Method C. Sodium borohydride (O.Oo mole) was added
portionwise with stirring to a solution of pyridinium salt
(0.06 mole) in i|0 ml. of N,N—dimethylformamide. Water,(10
ml.) and a second portion of sodium borohydride ( 0.06 mole)
were then added. After stirring at room temperature for 0.5
h r., the reaction mixture was diluted with water (250 ml.)
to precipitate the product as the amine borane. The amine
borane was separated by filtration and converted to the tetra—
hydropyridine hydrochloride on treatment with hydrogen chlo
ride in acetone. The base was then obtained by neutralization
of an aqueous solution of the hydrochloride with potassium
carbonate and extraction of the solution with ether. After
removal of the ether under reduced pressure, the base was
purified by either recrystallization or distillation.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 61
Preparation of l-methyl—4—phenyl—5—dautero—1.2.5.6—
tetrahydropyrldlne (XXXIX).— A solution of l5 g. (0.05 mole)
0 of 1-methyl—4—phenylpyridinium iodide, m.p. 165—16? , in 50
ml. of freshly distilled anhydrous N,N—dimethylformamide was
treated with 1.9 g. (0.05 mole) of sodium borohydride, added
portionwise with stirring at ice bath temperature. A yellow
coloration appeared and disappeared upon addition of 5 ml. of
99.5 mole percent deuterium oxide and 2.0 g. of sodium boro—
hydride. The reaction mixture was poured into 250 ml. of
water to precipitate the tetrahydropyrldlne borane, m.p. 119—
121°. The borane was dissolved in acetone and decomposed
with anhydrous hydrogen chloride to the hydrochloride, m.p.
248—250°, of XXXIX. The base was obtained by neutralization
of an aqueous solution of the hydrochloride with excess po
tassium carbonate and extraction of the amine into ether.
Filtration of the ether extract, after drying over anhydrous
potassium carbonate, and removal of the ether under reduced
pressure gave 7.4 g. (85^) of XXXIX, m.p. 38—39°; molecular
weight 174 (mass spectrum); A 245 (9860) (ethanol); n.m.r.
4—phenyl (multiplet) ^ 2.3, 3—hydrogen (triplet)Y 3.97, 2—
methylene (d o u b let)6.95, 1-methyl (singlet) 7.66. The
infrared spectrum of XXXIX exhibited bands at 2140,1275,765
and 735 cm”^ in addition to all of the bands present in the
undeuterated base.
Control experiment with1 -m ethyl—4—bheny1 —1 . 2 . 5 . 6 —
te trahydropyr id ine borane(LVIB..— A solution ofXLI (5 . 0 g .)
and N-methylpyridinium iodide (2 g .) in dry N,N—dimethyl—
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 62
formamide (20 m l.) and 99*5 mole percent deuterium oxide
(5 ml.) was treated with sodium borohydride (2 g.). The
solution was stirred under nitrogen for 2 hours at room
temperature. The base (3.5 g.) was then isolated in the
usual manner. Its infrared spectrum was identical to that
of undeuterated 1-methyl—4—phenyl—1,2,5,6—tetrahydropyridine,
XXXVIII.
Reaction ofLVII with deuterobromic acid.— A solu
tion of XLI (1.5 g.) in 99.5 mole percent deuterium oxide
(10 m l.) was tre a te d w ith deuterium bromide generated by
dropping deuterium oxide into phosphorous tribromide. The
solution was heated under nitrogen on a steam cone for 2 hr.
The base was recovered in the usual manner. The infrared
spectrum (10^ CS2 solution) of the recovered base exhibited
all of the bands present in XXXVIII, plus additional bands
a t 2250, 2190, 2145, 2120, 1275 , 765,735 and 66 O cra“^.
Catalytic hydrogenation of tetrahydropyridines.- A
solution of the tetrahydropyridine (10 g.) in ethyl acetate
(30 ml.) containing one drop of perchloric acid was added
through a dropping funnel to a mixture of platinum oxide
(0.12 g.) and ethyl acetate (10 ml.) under hydrogen. The
mixture was stirred under hydrogen at atmospheric pressure
and room temperature for 4—5 hours. The reaction mixture
was f i lt e r e d and the solvent was removed under reduced
pressure. The piperidine product( 3 ) was obtained in approx
im ately 90 percent yield by distillation. Properties of
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 63
piperidines are shown in TABLE VIII.
Sodium borohydride reduction of 3.5—diphenylpyridine
methiodide (XXII).— Treatment of a solution of XXII (14.5 g. )
in N,N—dimethylformamide (100 ml.) with sodium borohydride
3 .5 g .) added portionwise with stirring and cooling precipi
tated 9.1 3 . (93^) of a mixture of 75^ 1—methyl—3,5—dipheny1—
1,2—dihydropyridine, L, m.p. 85—90°, and 25^ 1-raethyl—3,5—
diphenyl—1,4—dihydropyridine, LI, m.p. 88—94°. Cpmpound L
was purified by recrystallization from an isopropanol—water
mixture. The infrared spectrum of L had strong bands at
1635 , 1595,945 and 878 cm-1.
A nal. Calcd. fo r C]^QH-j_yN: C, 87.45; H, 6.90.
Pound: C, 87.51; H, 7.11.
Preparation of lHnethyl—3. 5—diphenyl—1.4—dihydro—
pyridine (L I ).— Sodium d ith io n ite (13.5 g . ) was added por—
tionwise with stirring to a solution of 3,5—diphenyIpyridine
methiodide (5.0 g.) in water (170 ml.) and methanol (40 m l.).
The reaction was stirred for 3 hours at 35—40°. A yellow
solid precipitated from the solution and was separated by
filtration. Recrystallization of this solid material from
isopropanol gave 3.1 g. (94^) of LI, m.p. 68—94 . The in
frared spectrum of LI had bands a t I 68 O,I63 O,I6 IO and 865
cm-1.
Anal. Calcd. for C, 87.45; H, 6.90
Found: C, 8 7 .30; H, 6.79.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 64
Preparation of ethyl 1-methyl—6 —broino—1. 6 -dlhydro—
nlcotlnate (LII).— A solution of ethyl 5—bromonicotinate
methiodide (19 g.) and potassium carbonate (10 g. ) in water
(150 ml.) was treated with sodium borohydride ( 3 .8 g.) added
portionwise with stirring at ice bath temperature. A lig h t
orange solid precipitated from the solution and was separated
by filtration. Recrystallization of this crude material from
isopropanol gave 10.8 g. ( 88^) of LII, m.p. 58—61°. The in
frared spectrum of L II contained strong bands a t 1665 and 1635
— 1 cm .
Anal. Calcd. for CçHj^2NÛ2 Br: C, 43.92; H, 4.85.
Pound: C, 43.55; H, 5.05.
Preparation of Ethyl 1—methyl-5—bromo—1.4—dihydro—
nicotinate (LIII).— A solution of ethyl 5—bromonicotinate
methiodide (19 g .) and sodium bicarbonate (20 g.) in water
(300 ml.) was treated with 86 . 7 ^ sodium dithionite (26 g.)
added portionwise with stirring. An orange solid precipi
tated and was separated by f i l t r a t i o n . R e c ry sta lliz a tio n of
the crude solid from S0% aqueous isopropanol gave 1 0 .5 g .
(85^) of LIII, m.p. 59—61°. The infrared spectrum of LIII
exibited strong bands at 1685 and I 6 l 5 cm""^.
Anal. Calcd. for C 9H12NO Br: C, 43.92; H, 4 . 88;
N, 5 . 7 0 . Pound: C, 4 4 . H ; H, 5 .H ; N, 5 . 8 9.
Preparation of 1. 3—Dimethyl—2—phenyl—1.6-dihydro—
pyridine (LV).— To a solution of 15.5 g. (0.05 mole) of
3-methyl—2—phenylpyridine methiodide and 20 g. of potassium
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 65
carbonate In water (65 ml.) and methanol (20 m l.) was added
portionwise with stirring at ice bath temperature 2.7 g.
(0.07 mole)of sodium borohydride. A yellow oil separated
and was extracted into ether. The ether extract was dryed
over anhydrous potassium carbonate, filtered, and concen
trated under reduced pressure. Distillation of the yellow
residue under vacuum gave 7.8 g. (84^) of impure LV, b.p.
87—91° at 1.2 mm. The infrared spectrum of LV had bands at l68o and I638 cm”^ (liquid film). The ultraviolet spectrum
of LV had a band at 330 mp ( £. = 3860 ) (e th e r). The com
pound was not s u ff ic ie n tly pure fo r a carbon and hydrogen
ana ly s i s .
Preparation of 1.3.5—Trimethyl—2—phenyl—1.6—dihvdro—
pyridine (LIV).— A solution of 8,5 g. (0.026 mole) of 3,5—
dimethyl—2—phenylpyridine methiodide and 10 g. of sodium car
bonate in water (50 mL) was treated with sodium borohydride
(2.2 g.) added portionwise with stirring at ice bath tempera
tu re . A yellow oil separated from the water layer and was
extracted into ether. Concentration of the ether extract and
distillation of the residue under reduced pressure gave 4*0 g.
{71%) of LIV, b .p . 103—106 ° at 1.0 mm. The infrared spectrum
of LIV had bands a t 1685 and I 638 cm""^ (liquid film). The
ultraviolet absorption spectrum of LIV in ether had maxima at
325 mpi ( £ = 3210) and 244 mp ( t = 8OOO ).
Anal. Calcd. for C, 84*42; H, 8.54.
Pound: C, 83.67 ; H, 8.95*
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 66
Reaction of 1-mathyl—3.5—dlphanvl—1.2—dlhydropyrl—
dine (L) with hydrogen bromide.— A solution of L (1.0 g.)
in freshly distilled tetrahydrofuran (15 ml.) was treated
with excess anhydrous hydrogen bromide. A white solid preci
pitated immediately. Recrystallization of this solid from
isopropanol gave a quantitative yield of 3,5—diphenylpyridine
methobromide, XXIII, m.p. 248—250°. The in frared and u l tr a
violet absorption spectra of this material were identical
with the spectra of an authentic sample of XXIII prepared by
treating 3,5—diphenyIpyridine with methyl bromide. This
material did not depress the melting point of authentic
XXIII on adm ixture.
Anal. Calcd. for G^gH^^NBr: Br, 24.54*
Pound: Br, 24*30.
Reaction of L with methyl iodide.— Me thyl iodide
(10 g.) was added to a solution of L (2.5 g.) in freshly
distilled tetrahydrofuran (25 ml.). On standing for two
days at room temperature, 2.9 g. (8o^) of 3,5-diphenylpyri—
dine methiodide, XXII, m.p. 201—202°, precipitated. The
methiodide was separated by filtration and recrystallized
from methanol. Compound XXII, obtained in this manner, had
ultraviolet and infrared absorption spectra which were iden
tical with the spectra of XXII prepared from 3,5—diphenyl—
pyridine and methyl iodide. The methiodide obtained in this
reaction showed no melting point depression on admixture with
authentic XXII.
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Anal. Calcd. for I, 34*05. Pound:
I, 33*73*
Reaction of L with thionyl chloride.— A solution of
redistilled thionyl chloride (0.48 g.) in freshly distilled
tetrahydrofuran (5 ml.) was added dropwise with stirring to
a solution of L (1.0 g.) in tetrahydrofuran (15 ml.). A
vigorous reaction ensued with the immediate precipitation of
a quantitative yield of 1-methyl—3,5—diphenylpyridinium
ch lo rid e, XXIV, m.p. 225—227°. Compound XXIV, obtained in
this manner, did not depress the melting point of XXIV pre
pared from 3,5—diphenylpyridine and methyl chloride. Both
samples of XXIV had identical ultraviolet and infrared
s p e c tra .
Anal. Calcd. for G]^Q%^NC1 : Cl, 12.61. Pound:
Cl, 12.23.
Reaction of L with benzoyl chloride.— A solution of
1 .4 g * (0.01 mole) of benzoyl chloride in benzene (5 ml.) was
added dropwise to a solution of 2.5 g* (0.01 mole) of L in
benzene (20 ml.). After warming the solution on the steam
bath for several minutes, a white solid precipitated. The
solid was separated by filtration and recrystallized from
isopropanol to give 2.1 g. (75^) of 3,5—diphenylpyridine
methochloride, m.p. 225—227°. The filtrate was concentrated
and extracted with hot water to give 0.36 g. of benzoic acid,
m.p. 122- 124° .
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Reaction of L with tetracyanoethylene»— A so lu tio n
of tetracyanoethylene (0.5l g.) in freshly distilled tetra—
hydrofuran (5 ml.) was added to a solution of L (1.0 g.) in
tetrahydrofuran (25 ml.). The resulting solution had a black
coloration. After standing at room temperature for five days,
the solution was concentrated to a black residue. Several
recrystallizations of this residue from isopropanol gave a
small amount of yellow crystalline material, m.p. 156—158°.
The ultraviolet spectrum of this material showed a shoulder
a t 305 mp^ and a maximum a t 259 m^ . The in frared spectrum of
this compound contained bands at 2200, 2l 60 , 755 and 690 cm”*^.
Treatment with sodium borohydride in methanol converted this
m ateria l to L.
Anal. Calcd. for 76.80; H, 4*53;
N, 18.67. Pound: C, 75.01; H, 4»50; N, 16.12.
Reaction of ethyl 1-methyl—5-bromo—l,6—dihydronico
tina te (LII) with hydrogen bromide.— A solution of LII (2.0 g.)
in anhydrous benzene (20 ml.) was treated with an excess of
hydrogen bromide. A yellow oil separated from the solution.
The benzene layer was decanted and the oily residue was ex
tracted into hot isopropanol. On cooling the isopropanol
so lu tio n , 2.0 g . of a white so lid , m.p. 265—267°, was deposi
ted. This solid material was recrystallized from methanol.
The ultraviolet and infr^ed spectra of this material were
identical with the spectra of nicotinic acid methobromide
(XXVI) obtained by the hydrolysis of ethyl nicotinate metho—
bromide with hydrobromic acid. This material did not depress
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the melting point of authentic XXVI on admixture.
Anal. Calcd. for CyH8BrN02:‘ Br, 36.70; Pound:
Br, 37.10.
spectrum. (20^ DgO) 2.2 ppm (s), l+.O ppm (t)
U-35 ppm (d), 4-55 ppm (s), (ppm from Me^Si).
Reaction of L II with deuterium bromide.— Deuterium
bromide was prepared by dropping 99*5 mole percent deuterium
oxide on phosphorous tribromide. Treatment of a solution of
L II (2.0 g.) in dry benzene (25 ml.) with deuterium bromide
precipitated a light yellow oil which crystallized on stand
ing. Recrystallization of this crude material from methanol
gave 1.7 g. (82^) of partially deuterated nicotinic acid
methobromide, m.p. 265—267°. The proton magnetic resonance
spectrum of this material was identical to that of XXVI w ith
the exception of a fifty percent decrease in the relative
peak area of the 4*0 ppm triplet. The infrared spectrum of
this material contained all the bands of XXIV in addition to
bands at 740, 778 and 832 cm”^.
I^phenylmaleimida adduct of LII.— A solution of LII
(0.7 g.) and N—phenylmaleimide (0.54 g*) in freshly distilled
tetrahydrofuran (25 ml.) was allowed to stand at room tempera
ture for four days. The solution deposited a brown sludge
which was recrystallized several times from isopropanol to give
0.8 g. (66^) of a white crystalline adduct, LVI, m.p. l80—182°.
The infrared spectrum of the adduct had strong bands at 1775,
1740 and 1701 cm'-l. The ultraviolet absorption spectrum of
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LVI exhibited a maximum a t 212 mp ( 6T =6,990).
A nal. Calcd. f o r CigH^gBrNgO^: G, 54*32; H, 4*52;
N, 6 . 67 . Found: C, 54*42; H, 4*61; N, 6 .6 7 .
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TABLE I I I
PROPERTIES OF PYRIDINIUM SALTS H o'!
Type I Type I I I Type IV Compound Type R R» R* ' M.P. No.
VIII I CHj- 116 - 118°
IX® I GHj- 152-I5if.°
X I (C H .lgC E- 119-121°
XI® I CH^ (0:12)3- 90- 95° f
XII® I PhCHg- 87 - 91° f
XVII II H- H- H- 142- 1^4° XVIII II CH3- H-H- 175 - 176 °
XIX I I H- GH3- H- 143- 145°
XX II GH3- H- GH3- 210-211°
XIII III CH3- H- H- 97-100°
XIV III H- GH3- H- 156-158°
XV III CH3- H- GH3- 273 - 274 °
XXI I I I H- Ph~ H- 165-167°
XXII III P h - H- P h - 201-202°
XXIII® I I I P h - H~ P h- 248- 250°
XXIV” I I I Ph~ H- Pli— 225- 227 °
XXV III -GOOEt H- Bi>- 138- 140°
XXVI I I I -COOH H- H- 265-267°
XVI IV GH3- GH3- 230- 232°
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TABLE I l l (co n t.)
Compound Method R ecryst. % Halogen No. of Prep. Solvent Calcd. Found
VIII a h 57.94 57.80
IX c h 45.98 45.21
X a , b h 51.00 49.95
XI a , b h 37.04
XII a , b h 33.20
XVII a h 42.76 42.68
XVIII a h 4 0 .8 4 41.21 XIX a h 4 0 .8 4 40.87
XX a h 38.96 38.49 XIII a h 54.04 XIV a h 5 4 .0 4 54.41 XV a i 51.00 51.23
XXI a h 42.76 42.55
XXII a 1 34.05 33.97
XXIII c i 24.54 24.74 XXIV c h 12.61 13.02
XXV a h 34.14 34.10 XXVI d h 36.70 36.25
XVI b i 51.00 49.26
d Prepared from hydrolysis of ethyl nicotinate methobromide. 8 f S Bromide salt. Salt w| s extremely hydroscopic. Chloride h s a l t . Isopropanol. Methanol.
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TABLE IV
ULTRAVIOLET ABSORPTION SPECTRA OF REDUCTIONS OF PYRIDINIUM IONS WITH S0DIUI4 BOROHYDRIDE
Compound Pyrldlglum Ion NaBH^ Added No. Maxima (mu) E x tin c tio n Me OH" DMF
VIII 353 S h 3910 335 259 4440 265 sh 3190
IX 253 sh 3950 350 335 259 4500 265 sh 3210
X 253 sh 4 2 4 0 355 338 259 5200 265 sh 3800
XI 253 sh 340 338 259 6060 265 sh
XII 260 5870 337 269 sh
XVII 283 8600 3 3 0 350
XVIII 276 8 2 4 0 335 3 5 0
XIX 279 9000 355 350
XX 282 9450 330 3 2 5
XIII 266 4720 330 330 273 sh 3350
XV 271 5200 330 310 278 sh
XXI 294 4240 350 355 267 sh 3190
XXII 312 6 7 8 0 322 (lOOOO)J 258 31780 260 (17000 )° 4 1 5 (13000)° XXIII 312 6230 c 258 30000
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TABLE IV (c o n t. )
Compound Pyrldlglum Ion NaBH^ Added No. Maxima (mu) E x tin ctio n MeOH^ DMF
XXIV 312 5400 0 260 31500
XXV 293 sh 3140 355 ( 6400 ), 286 4140 268 (14000)° 276 sh 3000 261 (12600)°
XXVI 270 6200 355 ( 60001° 265 9 8 0 0 262 (12000)°
XVI 273 8 4 0 0
a Maxima were determined In methanol. ^Maxima were stab le In Q m ethanol. Maxima were the same as observed with XXI. d Extinctions were approximately 4000 u n ie 38 IndIcated.
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TABLE V
PROPERTIES OP TETRAHYDROPYRIDINES
R* R» R" - I j 1 R CH3 in 3 CH3 Type I Type I I Type III Type IV Compound Type R R> R " B.P. No.
XXVII I CH3- 112°
XXVIII I (CH3)2CH- 1 5 2 - 1 5 4 °
XXIX I CH3(CH2)3" 82°/3 0 mm.
XXX I PhCHg- 115° A mm. XXXI II H- H- H- 80- 82° / I . 2 mm.
XXXII I I CH3- H- H- 1 2 7 - 1 3 3 ° /2 7 mm.
XXXIII II H- GHy- H- 85—88° / l mm.
XXXIV I I CH3- H- CH3- 70°/0.3 mm.
XXXV III GH3- H- H- 132- 136 ° XXXVI III H- CH3- H- 129-131°
XXXVII I I I CH3— H- GH3- 87°/l05 mm. XXXVIII III H- P h - H- 42-44° XXXIX I I I H- P h- D- 42-44° XL IV GHj- GH3— 49°/25 mm.
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TABLE V (cont.)
Compound Method Yield P lcrate° Methlodlde° No. of Prep.
XXVII a,b 69 201-203° 268 - 270 ° g g
XXVIII a ,b 73 134-136° 232- 233° 28 72
XXIX a,b 81 106-108° 5 95
XXX b 73 143-145° 157 - 159° 12 88
XXXI b 78 138- 140° 178 - 181° 8 92
XXXII b 80 209- 211° 52 48
XXXIII b,c 83 149- 152° 0 100
XXIV c 77 18 82
XXXV a,b 70 108- 110° 147 - 149° 30 70
XXXVI a ,b 72 144- 146 ° 214- 216 ° 0 100
XXXVII a,b 79 117-119° 185- 187 ° 11 89
XXXVIII c 88 225- 2270 ^ 0 100 „h XXXIX c 88 225- 227 ° 0 100
XL a 64 230- 232° 44^ 56
Melting points of pure tetrahydropyrldlne derivatives. ®Relative percentages of piperidine. ^Relative percentages of tetrahydropyrldlne. Sjiot determined. ^Melting point of hydrobromide. Estimated by nuclear magnetic resonance spectroscopy.
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TABLE V (cont.)
Carbon and Hydrogen Analysis
Compound No. Calcd Pound %c %C iH
XXVII (47)'^
XXVIII 76.80 12.00 76.74 12 . 93^ XXIX (48)j
XXX 83.24- 8.67 83.13 8.83 XXXI 83.24 6.67 83.22 6.87 XXXII 83.42 9.06 83.35 9.32 XXXIII 83.42 9.09 83.13 9.20 XXXIV 83.58 9.45 83.43 9.47
XXXV (49)"^
XXXVI (50)j
XXXVII 76.80 12.00 76.90 12.20
XXXVIII (28) j
XXXIX (2 8) j
XL (51)^
Literature reference, ^Analytical sample contained 28^ piperidine.
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TABLE V (cont.)
ULTRAVIOLET ABSORPTION SPECTRA OF TETRAHYDROPYRIDINES
Compound Maxima (mu) and E x tin c tio n ^ No. ______
XXX 264 (163) 258 (230) 252 (200)
XXXI 264 (258) 258 (314) 252 (266)
XXXII 264 (220) 258 (290) 252 (280)
XXXIII 264 (278) 258 (338) 252 (299)
XXXIV 264 (176) 258 (242) 252 (210)
^Spectra were determined In methanol
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TABLE VI
INFRARED ABSORPTION BANDS OF TETRAHYDROPYRIDINES 1000—750 cm. - 1
- 1 Compound Band P o sitio n in cm. No. 2l
XXVII 800 s
XX/III 793 s 854 m 938 m 992 m XXIX 798 s 812 s
XXX 765 s 810 3
XXXI 787 s
XXXII 860 3
XXXIII 790 s 904 m XXXIV 8o5 3
XXXV 828 s 940 m
XXXVI 824 3 770 m 963 m 990 w
XXXVII 823 8 880 8
XXXVIII 825 3
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TABLE V II
NUCLEAR MAGNETIC RESONANCE SPECTRA OF TETRAHYDROPYRIDINES
Compound PPM (Ma^Sl) I n te g r a l Assignm ent No. a ,c XXXI 5.84 ia) 2 vinyl hydrogens 3.32 (q)* 1 benzylic hydrogen 3.05 (m) 2 C—6 methylene 2.43 (m) 2 C—3 methylene 2.19 (s) 3 N-ine thy 1
XXXIII 7.35 (s) 5 aromatic hydrogen 5.45 (s) 1 vinyl hydrogen 3.22 (q) 1 benzylic hydrogen 2.95 (m) 2 C—6 methylene 2.65 (m) 2 G—3 methylene 2.05 (s) 3 N—methyl 1.70 (s) 3 C—methyl
x x x v iir 7.30 (m) 5 aromatic hydrogens 6.00 (t)® 1 vinyl hydrogen 3.05 (m) 2 C—2 methylene 2.58 (m) 4 C—5, C—6 methylenes 2.33 (s) 3 N-me thyl
^Benzene solvent. ^Deuterochloroform solvent. ^Benzene as Internal standard. Singlet, Quartet. Multiplet. ^ T r i p l e t .
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TABLE V III
PROPERTIES OF PIPERIDINES
Pipe rid ine Compound M.P. of Carbon and Hydrogen Analysis Picrate Calcd. Found %C %H
1—isopropyl XLI 150-151° (52)°
1—butyl XLII 135-137° (4.8)°
1—benzyl XLIII 182-185° (52)°
1,4—d ime thy l XL IV 184-186° (50)°
1,3—d ime th y l XLV 169-170° (49)''
1,4—8 ime th y l— XLVI 175-180° 82.54 10.05 82.84 10.34 2—phenyl
1,3—d ime th y l— XLVII® 148-165° 82.54 10.05 82.43 10.01 2—phenyl
1-me thyl—2— XLVIII 173-175° 82.28 9.71 82.24 9.79 phenyl
1 , 3 , 5 - t r i - XLIX°*° 186-188° 82.76 10.34 82.58 10.20 me th y l—2— phenyl
®Mixture of two iaomera. ^Mixture of four isomers. °Litera- ture reference. °Obtained by catalytic hydrogenation of the d ihydropyrid ine.
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TABLE ■
Compound B.P. Ultraviolet Absorption g No. Maxima (tn^) and E x tin ctio n s
XLI 140- 143° XLII 79 —80° / l 8 mm.
XLIII 68°/0.5 mm. 252 (200) 258 (230) 264 (168)
XL IV 126 - 130°
XLV 127 - 128°
XLVI 73°/O .6 mm. 251 (230) 257 (270) 263 (210)
XLVII 63 —64 ° / 0 . 7 mm. 251 ( 210 ) 257 (255) 263 (190)
XLVIII 55-56°/0 .5 mm. 251 (230) 257 (270) 263 (210)
XL IX 90-92°/ I . 4 mm. 251 (356) 257 (350) 263 (260)
Spectra were determined in methanol.
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TABLE IX
GAS CHROMATOGRAPHIC ANALYSES OF TETRAHYDROPYRIDINES AND CORRESPONDING PIPERIDINES®
Compound Temp. P re ss u re Flow Rate No. of Retention Jimes No. Peaks ( s e c . )
XXVIII 149° 10 1 .4 2 120,132
XLI 149° 10 1 .4 1 120
XXIX 149° 10 1 .4 2 150,162
XLII 149° 10 1 .4 1 147
XXX 179° 12 1 .6 2 276,294
XLIII 179° 12 1 .6 1 276
XXI 179° 12 1 .6 2 234,270
XLVIII 179° 12 1 .6 1 230
XXXII^ 192° 14 1.5 4 147 , 190, 200,249 XLVII 192° 14 1.5 2 147,190 XXXIII 196° 12 1 .6 1 240
XLVI 196° 12 1.6 1 186
XXXLV^ 192° 14 1.5 5 144, 168 , 190, 255,288
XL IX 192° 14 1.5 4 146 , 168 , 198,232
XXV 137 ° 10 1.6 3 84,90,96
XLV 137 ° 10 1.6 1 80
XXXVI 137 ° 10 1.6 1 90
XL IV 137 ° 10 1.6 1 78
XXXVII 149° 10 1 .4 2 81,90 1370 XL 10 1.6 3 108, 120,132
®Two meter, 5^ silicone grease on chromsorb diatocaceous earth column. Carbowax 1500 column (Perkin-Elraer "K"). °See TABLE V for relative percentages.
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TABLE X
ULTRAVIOLET ABSORPTION SPECTRA OF D IHYDROPYRID INES
Compound M ethanol HCl Added No. Maxima (mu) E x tin c tio n Maxima (mu) E x tin c tio n
L 425= 3200 405 4ioo 312 6000 310 6470 258 30000 257 17000
LI 427^ 9600 312 6000 403 16800 256 30000 297 7200 266® - 10400 249 16400
LII 355, 6600 282 10500 281® 7750 268.5, 13000 261.5 12250 218 19400
LIII 360 12000
LIV 325 3210 276 8200 244 6000
LV 330 3860 268 262
â Shoulder.
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TABLE X I
NUCLEAR MACYSTIC RESONANCE SPECTRA OP DIHYDROPYRIDINES
Compound S olvent PPM I n te g r a l Assignment No. (CH^Si)
0 L acetone 2 .4 4 (s) 3 N-me th y l 4 .4 0 (s) 2 C—2 methylene 6.82 (3 ) 1 C—4 hydrogen 7 .0 9 (s) 1 G—6 hydrogen 7.47 (m) 10 aromatic hydrogens
L benzene^ 2.40 (s) 3 N-methyl 4 .1 5 (s) 2 0—2 methylene a LI acetone 3.69 (s) 2 C—4 methylene 6.87 (3 ) 2 vinyl hydrogens 7 .4 4 (m) 10 aromatic hydrogens
LI benzene^ 2 .60 (3 ) 3 N-me th y l 3 .6 2 (3 ) 2 0—4 methylene
LII CCl^^ 1.02 (t) 3 C-me thyl 2.65 (s) 3 N-me thyl 3.92 (s) 2 C—6 methylene 4 .0 5 (q) 2 methylene 6.42 (s ) 1 vinyl hydrogen 6.97 (s) 1 vinyl hydrogen
LIII CGl^ 1.05 (t) 3 C-me th y l 2.81 (s) 3 N-methyl 3.13 (s) 2 C—4 methylene 3.87 (q) 2 methylene 5 .7 9 (s) 1 vinyl hydrogen 6.65 (s ) 1 vinyl hydrogen
b =In te rn a l standard a c e to n e . In te rn a l standard benzene. ° In te rn a l standard chloroform.
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vr\ VAVA VA OO O VA VA VA o O H o x CM fA iH A M O H H M > o H ►> H §o H H MM > > G H H o fc a , 4 Hi Hi Hi Hi %% > > Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 87 BIBLIOGRAPHY 1. J . J . Panouae, Compt. ren d ., 233. 260, 1200 (1951). 2. J . J. Panouse, Bull. Soc. Chlm., D 53 (1953). 3. M. B.Mathews and S. E. Conn, J. Am. Cham. Soc., Zi, 5428 (1953). 4. R. Lyle, E. Perlowski, H. Troscianlec and G. Lyle, J. Org. Chem., 1761 (1955). 5. R. Lyle and G. Gauthier, unpublished results. 6. N. G. Gaylord, Reduction with Complex Metal Hydrides. Interscience Publishers Inc., New York"] 1956, pp. 781 —8o 6 . 7 . K. Schenker, Angew. Chem., 8l (I96 I). 8. E. N. Shaw, Pyridine and Its Derivatives. Vol. II (Edited by E. Klingsburg), pp. 47—55. Interscience, New York (1961). 9. M. Perles, Coll. Czechoslow. Chem. Commun., 479 (1958). 10. M. Perles, ibid.. 2221, 3326 (1959). 11. G. N. Walker et al., J. Org. Chem., 2740 (1961). 12. K. Schenker, Angew. Chem., 22, 638 ( i 960 ). 1 3 . S. Saito and E. L. May, J. Org. Chem., 2%, 245 (1962). 1 4 . J. H. Ager and E. L. May, ib id . . 2%, 948 (1962). 15 . J. W. Huffman, ibid.. 504 (1962). 16. K. Schenker and J. Drue y, Helv. Chim. Acta, 42, I960, 2571 (1959). 1 7 . N. K inoshita, M. Haraana and T. Kawasaki, J . Pharm. Bull. (Japan), 10, 753 (1962). 18. K. Wallenfels and H. Schuly, Ann., 621. 86, 106, 215 (1959). 1 9. W. Traber and P. Karrer, Helv. Chim. Acta, 4 1 , 2066 (1956). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 88 20. M. Saunders and E. H. Gold, J. Org. Chem., 1439 (1962). 21. A. R.Katrltzky, J. Chem. Soc., 2586 (1955). 22. R. E. Lyle, D, A. Nelson, P. S. Anderson, Tetrahedron Letters, l^, 553 (1962). 23. R. A. Abraraovitch, et al., Gan. J. Chem., 761 (I960). 2 4 . J. C. Evans and C. P. H. Allan, Org. Syntheses, Col. Vol. II, 517 (1953). 2 5 . C. J. Schmldle and R. C.Mansfield, J. Am. Chem. Soc., 28, 1702 (1956). 2 6 . G. B. Bachman and D. Micucci, J. An. Cham. Soc., 2 0 , 2381 (1948). 2 7 . E. Wenkert, et al., J. Am. Chem. Soc., 84, 3732 (1962). 2 8. E. M. Kosower and T. S. Sorensen, J. Org. Chem., 22, 3764 (1962). 2 9. R. Grashey and R. Huisgen, B er., _g2, 2641 (1959). 3 0 . S. M. McElvain and J. C. Safranski, J. Am. Chem. Soc., 22, 3134 (1950). 3 1 . E. G. Ashby, J.Am. Chem. Soc., 8I, 4791 (1959). 3 2 . E. J. Corey, J.Am. Chem. Soc., 2Â> 5036 (1956). 33* S. Gristoi, J. Org. Chem., 22, 293 (1962). 3 4 . A. P. Casey, H. H. Beckett and N. A. Armstrong, Tetrahedron, 16, 85 (1961). 35. Ingold, Structure and Mechanism in Organic Chemistry. Cornell University Press, Ithaca, N. Y., 19^3, pp. 554-575. 3 6 . J. A. Marshall and W. S, Johnson, J. Org. Chem., 28, 421, 595 (1963). 3 7 . G. Opita and W. Merz, Ann., 652. 139 (1962). 3 8. H. Weitkamp and P. Korte, Ber., 2896 (1962). 39. K. Buckel and P. Korte, Ber., 25» 2438 (1962). 4 0 . P. T. Landsbury, J. Am. Chem. Soc., 82» 3537 (1961). 4 1 . L. J. Bellamey, Infrared Spectra of Complex M olecules. John Wiley and Sons, Inc., New York, 1958 pp. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 89 42. D. A. Nelson, Ph. D. ‘Ttxesis, University of New Hampshire, (I960). 43. E. A. Braude, et al., J. Chem. Soc., 45 (1946). 44. D. G. Dlttmer, Tetrahedron Letters, 22, 897 (1961). 4 5. D. C. Dittmer and J. M. Kolyer, J. Org. Chem., 56 (1962). 46. P. H. Wastheliuer, J. Am.Chem. Soc., 82, 584 (1961). 47. R. Lukes, Collection Czechoslov. Chem. Commun., 12, 71 (1947). C. A., 4 1 , 4150a (1947). 4 8. R. Paul and S. Tchelitcheff, Bull. Soc. Chim., 21, 982 (1954). 4 9. R. Lukes, et al.. C o llection Czechoslov. Chem. Commun., 12, 463 (1950). C. A., 42, 7572d (1951). 5 0 . M. Perlas, Chem. listy, 2£, 674 (1958). C. A., 22 , 13724 (1958). 5 1 . R. Lukes and J. Jizba, Chem. listy, 4A, 622 (1952). C. A., 41, 9326a (1953). 5 2 . I. Heilbron, Dictionary of Organic Compounds. Vol. IV. Oxford University Press, New York, 1953, p. 217. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.