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The stereochemical course of the nucleophilic displacement of cyanide from alpha-ferrocenyl-alpha-aminonitriles, and model experiments for the synthesis of optically active alpha-ferrocenyl alkyl...

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The stereochemical course of the nucleophilic displacement of cyanide from alpha-ferrocenyl-alpha-aminonitriles, and model experiments for the synthesis of optically active alpha-ferrocenyl alkyl...

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Content THE STEREOCHEMICAL C O U R SE O F THE NUCLEOPHILIC
H
•DISPLACEM ENT OF CYANIDE F R O M a-FERROCENYL-a-AMINONITRILES,
A N D M O D E L EXPERIMENTS FO R THE SYNTHESIS
O F OPTICALLY ACTIVE a-FERROCENYL ALKYLAMINES
by
Salah Amin Zahr
iu
A Thesis Presented to the
FACULTY O F THE G R A D U A TE S C H O O L
In Partial Fulfillment of the
Requirements for the Degree
M ASTER O F SCIENCE
(Chemistry)
January 1973
UMI Number: EP41656
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fi-o)
U N IV E R S IT Y O F S O U T H E R N C A L IF O R N IA
• THE GRADUATE SCHOOL
UNIVERSITY PARK
LOS ANGELES, CALIFORNIA 90007
This thesis, w ritten by
Salah Amin Zahr
under the direction of hiS....Thesis Com m ittee,
and approved by a ll its members, has been p re
sented to and accepted by the D ean of The
Graduate School, in p a rtial fu lfillm e n t of the
requirements fo r the degree of:
? s t e c _ p. f . A y . . ( . Q . b M i ? . try.) j
{ . W k h o
Dean
Date February 1973
c
' l b
2 .1
1
THESIS COMMITTEE
[
To m y parents.
A C K N O W LED G EM EN TS
I wish to thank Professor Ivar K. Ugi for his guidance and sup
port of m y graduate work, and also, I am very grateful to m y parents
for their devotion and encouragement.
i i i
I TABLE O F CO NTENTS
!
i
; I . Introduction and Discussion of the Problem.......................................
i
| A.- Four Component Condensations. (4 CC).,. . .......................................
| B. The Synthesis of a-Acylami.nocarbonamides and Peptide
}
I Derivatives.................... . ......................
I
| C. The Amine Components..........................................................................
| D. Synthesis of Amines from a-Aminonitriles....................................
f
j I I . Results and Discussion of the R esults..............................................
\
I I I I . Experimental S ection... .................................................................
| A. !?Physi.o-chemical Characteristics of Products............................
| B. Formyl ferrocene .........................................................................
1
! C. . NsN-dimethyl-a-iferrocenyTami.nonitrile. .......................
| D. Nr,morpholino-a-'?errocenyT-a-aminohi tri le .....................................
J E. .Attempt to Resolve N,N-dimethyl-a-ferrocenylacetonitri l e . .
| Ob a) With R-(+)-tartaric acid...............................................................
| b) Attempted resolution with d-10-camphor.sulfonic acid...
i c) Attempted resolution with dinap.htoyl tartaric a c id .....
j
| F. Resolution o f: N-morphol ine-a-ferroeenylami.noni tri l e . _____
i
i a) Attempted resolution with tartaric acid...............................
| b) Attempted resolution by d-10-camphor sulfonic a c id .....
i c) Spontaneous resolution., ...............................................
i 1. In absolute alcohol ...... ......................................
i
j 2. Further exploratory experiments. .......... ....................
| 3. Spontaneous resolution with cyclohexane ______
iv
Preparation of a-Ferrocenyl-a-N-morpholino Acetonitrile___
Preparation of N-morpholinp-a-ferrocenylethylamine from
N,N,N-Trimethyl-l-ferrocenylethylammoniumiodide. ................
References
j INTRODUCTION A N D DISCUSSION OF THE PR O B LEM
I
I * 1 ?
;A . Four Component Condensations (4 CC) ’ 5
| Amines 1 and carbonyl compounds 2, such as aldehydes and ketones**,
; /v / -w
Ireact with isonitriles 3 and suitable acids 4 to form a-adducts 5 which
*** A /
J b y spontaneous secondary reactions are converted into stable a-amino
'derivatives 6. The term four-component condensation is used for a mul-
iticomponent reaction according to the following scheme.
I
R^NH-R2 + R 3-C0-R4 + CN-R5 + H X
R 3 .R4
stable a-amino
R1 ' c XN
N./ V / \
acid derivative
C 'R5
j*In this thesis the abbreviation "4 C C " w ill be used. The 4 C C is
also occasionally called "a-amino alkylation of isonitriles and acids"
pr "a-addition of am m onium ions and anions to isonitriles, coupled
with secondary reactions." See also references 1 and 2.
T *It is also possible and advisable to use the condensation product
of the amines and carbonyl compounds, such as aminals, Schiff bases,
1
or enamines. 1 ________
2
The nature of the secondary reaction is largely dependent on the
type of acid component used.
In this 4 C C som e acids, like hydrogen cyanate, hydrogen thio-
i ’
i
[cyanate, and carboxylic acids, behave differently toward secondary
i
| amines than toward primary amines. The a-adducts of these contain
|
! acyl ating moieties and generally can be transformed by secondary re-
j
; actions into stable a-amino acid derivatives only is the a-adduct con-
! tains an acylatable >N H group.
!
I
I As a rule in 4 CC, the isoni.trile component is added to the solu-
i tion of the three other components with stirring and cooling. The prod-
i
: uct can be isolated after the reaction is over* Mostly, the 4 C C prod-
1
|ucts crystallize out, with yields of 80-100%.
The formation of uniform products is accounted for by the fact
[that all the side reactions are reversible, while the main reaction is
; not. The reaction is extremely versatile, since four different start-
i
i
\ ing materials take part.
IB. The Synthesis of a-Acylaminocarbonamldes and Peptide Derivatives.
j The combination of ammonia or primary amines la, aldehydes or ke-
< i* W »
Stones 2, reacts with carboxylic acids, 4a, and isonitriles 3 to form
j XV V -
:the intermediate a-adducts 5a. Then by a cyclic mechanism, a spon-
[ taneous 0 N acyl transfer occurs to yield a-acylaminocarbonamides
j
; 6a.
Scheme I
RX-NH2 + R 3-CO-R4 + R 6-C00H + CN-R5
la 2a 4a ..3a
R 3-C— C=N-R5
at
pi p^
R*-NH f fi l l c
,0 > R -C0-N—-C-CO-NH-R
,6
' N
5a 6a
; Because of the formation of the two carbonamide groups in the
; product 6a, the reaction scheme I has a strong driving force. Be-
<%/
i
| cause of the cyclic mechanism the 0 -> N acyl transfer competes very
| effectively with any possible side reaction of the a-adduct, 5a.
■ A method for peptide synthesis (Scheme II) is provided by the
.stereoselective 4 C C of carboxylic acids according to Scheme I.
i
I Scheme II
B n-NH-P1-C00H + R1*-NH2 + R3-CH0 + CN-P2-C02-Bc
4b lb 2b 3b
R 3
1 * 2
B n-NH-P -CO-N— C — C0-NH-P^-C02-Bc
(1*1
| N-terminally protected amino acids or peptides (4b), suitable op-
!
s tic a lly active amine component (lb ), aldehydes (2b), and a-isocyano
: esters, or a-isocyano acyl peptide esters (3b) can undergo 4 C C to j
! produce peptide derivative 6b. I
> The desired peptide can be obtained only from the product 6b only
i f the R group of the amino component can be replaced by hydrogen
I
; under conditions that w ill not racemize or destroy the peptide.
■ ; i
; j
’ C- The Amine Components. j
i
I
In the synthesis of the tripeptide derivative 6b by 4 C C (Scheme !
I I ) , with ammonia as the amine component, lb (R*=H), the N- and C- j
}
!
terminally protected tripeptide is formed directly; but there are two !
serious drawbacks against ammjonia: |
I
1. I t undergoes 4 C C in lower yield than primary amines because j
with ammonia there are irreversible side reactions, e.g., the Passer-
: ini reaction. a
2. With ammonia, i t is impossible to influence the steric course
i of 4 CC.
! 3 A
Unsymmetrically substituted carbonyl compounds (R -CO-R where
‘ 3 4\
|R / R ) lead to the formation of products with new centers of chiral-
i
;ity . So 4 C C in which chiral components take part lead to a mixture
of diastereoisomers.• The diastereoisomers are formed at equal rates,
4
in equal amounts, in the absence of asymmetric induction. The stereose-
i i
(
le c tiv ity of asymmetrically induced syntheses depends upon the chemical|
5 '
chirality of the chiral reference system; the asymmetric inducing j
j power of an element of chirality is determined by its distance from
i
i the newly formed element of chirality, the chemical properties of the
j reactants, and the reaction conditions.
! The dependence of the ratio of Q p^ to the P- and N- products^3-^
| of stereoselective 4 C C upon all the factors has to be investigated
i
| so as to obtain information needed in.order to synthesize the stereo-
i *
' isomers desired in high yields.
:
i To use the 4 C C approach to the best advantage, an optically ac-
i -
! tive amine, lb, must be used whose asymmetric inducing power is'high
i ~
! 1*
| under conditions where the 4 C C yield is high. Also, the R group
I
I of the inducing optically active primary amine component, lb, must
!
| be replaceable by hydrogen under mild conditions, after the condensa-
i .
I
j tion. So finding the optimum asymmetrically inducing and cleavable
famine component is the main pre-condition for stereoselective 4 C C
; peptide syntheses, and also the conditions under which the amine re-
t
1 acts with high stereoselectivity and yield. Usually a stereoselecti-
jv ity of at least 99% is required for peptide synthesis, but presently
■ 6
! the best results are about 95%.
t
! 7 8 9
j Model reactions were investigated ’ * to find the best amine and
ireaction conditions with both aspects in mind. The results provide a
|
!basis for finding reaction conditions under which either one of the
i
jdiastereomeric products of stereoselective 4 C C is formed in high
j 7 8
|yield, ’ also a criteria for selecting reaction conditions under
iwhich the asymmetric inducing power of optically active amine compo-
jnents can be evaluated and compared with stereoselectivity data from ]
i . |
other stereoselective reactions (e.g .. by_the_s_t.ereo.chemica.l_JJnear____■
C L
free energy relationship). This allows testing of new amine compo
nents by stereoselective reactions which are simple to do and evalu-
1
I ate*, an example is the acylation of primary optically active amines,
i • 10 ^
! lb, by phenyltrifluoromethyl ketene, (Scheme I I I ) . |
I — >
t
i
i Scheme I I I
j. * ■.............
I C6H5(CF3)OC=0 + H2N-R* — C 6H5-CH(CF3)-C0-NHR
I 8 r< lb 9 i
! /V
\ I
i I
i This reaction at -60°C to 0°C in chloroform is a simple pair of
\
I 28
i corresponding reactions. I t is in contrast to 4 C C in which the
! * . . .1
! limiting intrinsic stereoselectivities are hard to determine. An op- I
I tic a lly active primary amine, lb, which shows a high relative power
io f asymmetric induction in this procedure* has, under suitable reac-
£
j tion conditions, shown high potentiality in stereoselective 4 C C pep-
| tide synthesis an amine component (Scheme I I ) .
I Besides the fact that the amine must have a high chemical chiral-
j ity in 4 C C peptide synthesis, i t also must be easy to cleave accord
in g to 5 6, under conditions which do not damage peptides.
| The most promising class of amines appears to be the a-ferrocenyl-
|alkyl amines. Acting as a "steric template" they undergo 4 C C with
|high yields and good stereoselectivity; in addition, their 4 C C prod-
i
ucts cleave easily (6b 7) because of easy formation of ferrocenyl-
' /N i/ ‘
1 1 1 0 I
|alkyl carbonium ion. * In the case of ferrocenylalkyl amines with |
1 n i , !
iplanar chirality, 10, (R f H), the combination of R and R has to !
be found by model reactions like Scheme I I I .
In the stereoselective model 4 C C the products 11 (Scheme IV) are
cleaved by treatment with trifluoroacetic or formic acid: (S,S)-11
Q U
yields (S)-12. This shows the advantage of a-ferrocenylalkyl amines,
10, as cleavable and asymmetrical inducing amine components of stereo-
selective 4 C C peptide synthesis, this also allows one to reassign the
9
absolute configuration of (+)-a-ferrocenylethyl amine as (S)-10a.
Scheme IV
The absolute configuration of 10a is of particular interest since
1
the a-ferrocenylalkyl amines with planar ch irality, 10, (R f H), are
prepared from 11, a derivative of 10a, by stereospecific transformation,
— *
e.g., Scheme V.
Scheme V
96%
14i(R,R)
v N ( C H 3 ).
15-(R,S)
13-(R)
'N(ch3)
H C H3
14-(R,S
n( ch3) 2
15(R, R)
R = C H 3, C 2H5, Si(CH3)3, CH20H, CH(CgH5)0H, C(C6H5)20H
The configuration of the planar element of chirality of 14 is
14
related to the central configuration of 10a in a conclusive manner.
The major product of the lith iatio n of 13(R) is exo-14-(R,R) be-
cause in the cyclic transition state the C-methyl group stays above
9
the plane of the upper ring of the ferrocene system and does not in-
| terfere with i t , while in the case of endo-14-(R,S), a strong repul-
! sive interaction of the C-methyl and ferrocene system takes place.
i
!
| The racemic ferrocene derivatives with planar elements of chiral-
i ity are generally d iffic u lt to resolve into optically active anti-
[
' 13 14 is
I podes, but since the antipodes of 11 are easy to prepare, ’ Scheme
! V provides a wide variety of optically active ferrocene derivatives
; with planar elements of ch irality, including the amine components, 10.
! In the transformation of 14 into amine components 10 and the recovery
A / • -'"W
; after cleavage reaction 6b 7, i t is an advantage of the ferrocene
derivative that optically active a-ferrocenylalkyl compounds 16 can
i
; undergo nucleophilic substitution (Scheme VI) with complete reten-
j tion of the planar element of chirality and configuration of the cen-
ucleof
12,14
12
j tral element of chirality. Such retentive nucleophilic substitu
tions are illustrated in Schemes VII and V III
Scheme VI
Y6
16
i
; W e can interpret Scheme VII by assuming that the nucleophilic
isubstitutions of VII proceed via the chiral stabilized carbonium ion
;18,. which has a high rotational barrier about the C -ferrocenyl bond.*1^
U
10
1 18
/V /
i
| The retentive substitutions of Scheme VII require that 18 is
| formed by "upward" departure of leaving group and an attack "from the
S top" by the nucleophile.
! Scheme VII
[
i
i
i
C-NH
l
t
I
K? Sn(OH) i
i
s
j
11
Similar processes via the stabilized carbonium ion 19 account for
Scheme V I I I . 14
.
I Scheme V III refers to the (R,S) diastereomers, unless otherwise
j specified. The reagents and reaction conditions are:
! A = methyl iodide
' B = sodium methoxide in methanol at 20°
j
; C = reflux in acetone
|
; D = sodium azide in aqueous glyme at 60°
! -
; E = potassium stannite in aqueous glyme at 25
; F = formaldehyde and sodium borohydride in methanol at 0°
i
G = trimethyl am m onium iodide in methanol
j H = hydrogen bromide in methanol at 20°
Cycle Scheme IX is possible i f the amine component, 10, which is
\ available according to Schemes V -V III, permits the required high de-
j
gree of stereoselectivity for the 4 C C peptide synthesis (Scheme I I )
'and i f 10 can be recovered after cleavage (6b-7). Then we have a
j /> - /v> ■
■ 16
|stereoselective 4 C C peptide synthesis according to this cycle.
!D. Synthesis of Amines from a-Aminonitriles.
j The presently available methods for the synthesis of optically ac-
i .
! tive amines of the type 10 rely on stereoselective metallation of 13,
and therefore are confined to synthesis of compounds with R = H, or
■ C H .. j
! J !
!
I The reaction of a-aminonitriles with Grignard reagents seems to
i
jprovide potential basis for a generally applicable synthetic method for
S ch em e VIII
12
R3 R4 R5
1 1 i
— N H -C -C O -N H -C -C O -N H
1
O
I
o
0
1
1
1
i 1 1
H H H
Scheme IX
CN-CCO
o r
— NH-C-COOH
-N H -C -C O -N---- C— C O -N H -C -C O -
t i
H H
“ ‘ ' "" " 14
chiral amines 10, R f H, or CHg, e.g., R = C 2 H, C 2Hg, CgHg, etc.
17
In 1924 Christiaen observed that the cyano group of a-aminoni-
1 .
| trile s can be replaced by the nucleophilic organyl residue of Grignard
1 ■
18
.18
reagents.
WelvaertiU et. a l . studied the steric course of the nucleophilic
substitution of the cyano group of te rt. butyl-4-N,N-dimethylcyclo-
hexyl aminonitrile. They concluded that the nucleophilic substitution
, ch3
N' J Ring I ^
x ch3 — *
i of the cyano group o,f a-aminonitriles by the organyl residue of Grig
nard reagents proceeds via ammonium ions or am monium cyanide ion pairs
R J. C N
r2 ' ^ N rJ
/ R 1
C N
I ' X nl
R
c _
R -
R V / R
R2^' V NR21
R 3 v N R ,,1
r2\*' \ r
As a consequence of this we can expect that this nucleophilic
1
'displacement reaction w ill not preserve the stereochemical features
!of the starting material when applied to an optically active a-amino-
jn itrile , unless a chiral, sufficiently stable, ammonium ion is in-
15
volved, as can be expected for the a-ferrocenyl a-aminonitriles,
e
C M
C - -R1
N nr2
C N 8
Fe
R M qX
Fe
Chiral a-ferrocenylalkyl compounds are well known toundergo S N
1
type reaction via chiral carbonium ion configurational retention (see
above Scheme V I I ) . ^ a*
RESULTS A N D DISCUSSION O F THE RESULTS
, Originally, the following sequence of reactions, Figure 19, was
| planned as a model for the synthesis of ch(i)rjal a-ferrocenylalkyl amine
I j
! by reacting chiral a-ferrocenyl a-aminonitriles with Grignard reagents,
iThis is because the absolute configuration of chiral a-ferrocenylethyl-
! \AC
|dimethyl amine is well established.
i
| The reaction of I I I , a-ferrocenyl-N-dimethyl aminonitrile with
jCHgMgl is known to proceed well according to previous experience.^9*
;19,20
: An attempt was made to prepare the aminonitrile I I I directly from
!ferrocene, following the mechanistic assumption that nucleophilic ad-
Idition of cyanide might take place across the^ C=Ni
jmeier complex (see below), obtained by interaction of dimethyl forma- j
;mide and ferrocene in the presence of phosphoryl chloride. This at- j
.tempt was made by treating the intermediate ( ViIsmeier,complex) with
Ipotassium cyanide.
However, several attempts to effect this reaction to proceed were
iunsuccessful. Other routes may be effective and work should be done
17
Figure 19.
Fe
HN(CH3)2 + NaCN,
NaHSO,
I I
LiAlH
4
Na/NH,
*
Fe
C H 0m0
/ 2 2
C "> H H
x n( ch3) 2
Fe
VI
18
on i t in the future. However, the above cycle of reactions could not
be carried oQf because I I I could not be obtained optically active.
Extensive attempts were made to resolve racemic I I I with a variety of
| chiral acids such as R -(+)-tartaric acid, R-(+)-dibenzoyl tartaric
I acid, (-)-binanphtoyl tartaric acid, Cl-10-camphor sulfonic acid.
i
i All these failed to lead to any optically active I I I (see Experimen-
! tal Section).
! Therefore i t was planned to attempt to generate som e analog of
i
' I I I in an optically active form, and, as will be shown below, reso-
| lution was possible for a-N-morpholine-a-ferrocenyl acetonitrile V III.
C H O
+ NaC N
NaH SO
Fe
/
C H
\
n .
C N
V III
j I t is interesting to note that i t was also not possible to resolve
i
I
jracemic V III with any of the standard acidic resolving agents.
! But, V III is incidentally oiie of the rare racemic compounds
that have a high tendency to undergo spontaneous resolution.
An ordinary crystallization of this compound from cyclohexane or
;ethanol gave an optically active compound.
This is a rare phenomena in chemistry. Few compounds were re-
21
ported to have these characteristics. Anderson and H ill have ob-
P ........ ' 19
j served a spontaneous resolution of atropine sulfate, repeated crystal-
j lization of this dl-Salt from absolute alcohol yielded the d and 1-
i ,, 25 o
| hyoscyamine sulfate with ^ = ± 20 . The atropine sulfate was
; prepared by racemization of 1-hyoscyamine and also by synthesis from
!
\
! synthetic tropic acid and tropine, the spontaneous resolution occurred
| -
| with both samples.
j dl-Histidine monohydrochloride also has been resolved spontane-
22
| ously. Malic acid has been reported to be resolved by crystal!iza-
: tion of inactive am monium molybdomalate; also malic acid has been re-
! solved by innoculation of a conc. solution of the zinc am m onium salt
! 23
: with crystals of the active salt.
In crystallization of methyl ethylallylani1inum2^ iodide from
1 chloroform solution is subject to spontaneous resolution. In this
; case there is a spontaneous interconversion of the enantiomers.
! c ?h r
j p b c H
! h9c- n- ch9- ch=ch9i 0 — —^ h9c- n^ 2 5 + ch9=chch9i 0
■ J I C 2 X J N .r u < L C
C 6H5
> C 6H5
(+)
?2H5
^----- H2C=CH-H2C-N+-CH3I 9
(-)
C6H5
I
I f one enantiomer crystallizes in preference to the other, owing to
-the presence of crystal seeds, the mother liquor will become racemic
after som e, time,,., .dye...to the.equ jlIb r la .above.. __________________
Most of these cases are somewhat different from the case we have,
since we could not collect except one antipode.
Recrystallization from cyclohexane gave optically active crys-
2 5
tals of [a]g = -20°, leaving the mother liquor at -20°, and gave
another crop of crystals with [ a ] p = -25.5°.
In the case of absolute ethanol, better resolution took place,
where high resolution was attained.
i 25
First crystallization yields crystals with [ajg = -32.3
(ethanol), evaporating the mother liquor to one-third volume and lea-
o -,25
ving i t at -20 C overnight yielded crystals of optical rotation [ctjD
-70° (ethanol). Taking the optical rotation of the mother liquor i t
self gave an optical rotation of [ a ] ^ = -60°.
From the fact that racemic V III on crystallization from ethanol
yielded levorotatory crystals as well as levorotatory mother liquor,
one may draw the conclusion that an interconversion of the antipodes
takes place during the process of crystallization. But more studies
should be done in this case and we w ill try to explain this phenomena
in the near future.
The following sequence of reactions was planned for'the chiral
V III in order to establish its absolute configuration (Scheme X, see
below), and also to confirm the assumed reaction mechanism for the
nucleophilic displacement of the cyano group by RM gX.
E/€
(t H3)eN N
H iJiiu Q
£H3/
N e;3 /2L003’2 0-"N ,
£H D 203H'I 1 '
ZH N ZH 3
/K
frHLVH
( - ) s ;
------ 0 * \ 93
i 6 h h o ' i
N O *
EXPERIMENTAL SECTION I
I
I
i ■ ■ •. ■ • ■ • 1
i A. Physio-chemical - Characteristics of Products. i
1 ' !.
; i
! , I
i All melting points were measured on either a Fisher-Johns or ■ ■
j
iThomas.Hoover melting apparatus, and are uncorrected. Infrared spec-
i f
! tra were recorded on a Perkin-^Elmer IR 457 and are calibrated with
t
|
■ reference to polystyrene. Nuclear magnetic resonance spectra were
jrecorded on a Varian A-50 nm r instrument using tetramethyl si lane as
|an internal standard. Optical rotations were measured on a Perkin- |
i !
I Elmer 141 digital polarimeter using a thermostatted 1 decimeter c e ll. i
i . ‘ |
| The thermostatting unit was a Bronwill Scientific circulating thermo- !
I 0 I
js ta t and was. calibrated in each case to At = ± 0.1 C.
1 j
; ' j
i
; I
IB. . Formylferrocene. i
■ ----------------------------------------------------- 5-----------------------• j
! |
' ' [
| The procedure used was a modification of the one reported by Sato j
1 25
|and coworkers ; 29.2 g (0.4 mole) of dimethylformamide was added to ■
5 )
■ S \
|37.2 g (0.2 mole) of ferrocene in 150 m l of dry chloroform and the re- j
i •
! suiting mixture was stirred in an ice bath under nitrogen for 10 min. ;
| j
I 61.2 g (0.2 mole) of phosphoryl chloride was then added dropwise to J
j 1
j the mixture over about a half an hour with stirring,, which was con- j
! j
Itinued for an additional 20 hr. at 55°-60°C. Chloroform was evapora- !
i . i
|ted from the resulting reaction mixture under reduced pressure below !
} j
■ O ‘
j 60 C. The residue was poured into ice and precipitated unreacted ferroj
; cene was filtered out. The filtr a te was carefully neutralized with j
23
sodium carbonate powder and extracted repeatedly with ether. The com
bined extract was dried over unhydrous magnesium sulfate after wash
ing with water. Evaporation under reduced pressure gave crude product
m.p. 120-123°C which was recrystallized* from n-hexane to give reddish
brown crystals, m.p. 124-125°C ( l i t . 124.5). The yield** was 24 g
(56%).
C. N ,N-dimethy1-g-Ferroceny1 aminoni t r i 1e.
26
The procedure used was essentially the sam e as reported by Hauser.
To a stirred solution of 10.4 g (0.1 mole) of sodium bisulfite in
100 m l of water was added 21.6 g (0.1 mole) of formylferrocene in 60 m l
of methanol, followed, after 5 min., by a solution 24 g (0.14 mole) of
25% aq. dimethyl amine in 40 m l of 50% methanol. 4.9 g (0.1 mole) of
sodium cyanide in 20 m l of water was added dropwise with stirring after
the mixture is cooled in an ice .bath. Color changes from red to orange.
50 m l of ether was added and the reaction mixture stirred for 4 hr. at
room temperature. The product is extracted three times with ether and
dried over anhydrous magnesium sulfate. The solvent was removed under
reduced pressure to yield 23.1 g (87%) of the aminonitrile, m.p. 83-86°.
*The crude product could not be recrystallized from dichloromethane 3:
n-hexane 1 as reported. The crude product was completely soluble in
this solvent at room temperature.
**The maxim um yield reported by this procedure was 74% which could not
be realized in this work.
24
The crude product was recrystallized in hexanes to give yellowish .
brown crystals, m.p. 84-85°C. j
!
i
D. N-morpholine-ot-ferrocenyl-a-aminonitri.le. 1
j ' |
i i
: The procedure used in preparing this compound is similar to the I
I ' !
: procedure used for the preparation of N,N-dimethyl- -ferrocenylamino- i
f \
In itr.ile; morpholine was used instf^adof the dimethyl amine. |
| 21.6 g (0.1 mole) of formylferrocene in. 60 m l of methanol was added j
\ ... .
| to a solution of 10.4 g (0.1 mole) of sodium bisulfite in 100 m l of
! water followed after 5 min. by a solution .of 12.2 g (0.14 mole) of
J
j
jmorpholine in 20 ml of 50% methanol. The mixture was cooled in.an
! ice bath and a solution of 4.9 g (0.1 mole) of sodium cyanide in 20 m l
j ■
|of water was added dropwise. 50 m l of ether.was added and the mixture
jstirred for 4 hr. at 55-60°C. j
1
! j
j The product was extracted in ether, dried over anhydrous magnesium j
j ' !
j sulfate. The solvent was evaporated to give 25.4 g ,(81.6%). of the j
!aminonitrile, m.p. 146-148°C. j
i !
j Recrystallization .from cyclohexane (see below) yielded crystals of |
!m.p. 147°C. !
I !
t !
( |
; ■ !
j E. Attempt to Resolve N,N-dimethyl-g-Ferrocenylacetoni.trile . i
i . !
; I
i _ [
j a) 'with R -(+)-tartaric -'Scid. I
i !
(The resolution presented here is a slight improvement of the reso- |
' . 27
|luti,on developed by Hoffmann and modified by KTusacek ). !
j Racemic aminonitrile (26.8,g, 0.1 mole) and R-(+)-tartaric acid |
25
(15 g, Mallinckrodt 2312 AR, dextrorotatory with Levo configuration)
Were dissolved in 40 m l and 27 m l of methanol consecutively at 55-60°.
| The tartaric acid solution was added in one portion to the amino-
jn itrile solution and allowed to cool 2-5° per hour while stirring over-
Wight. N o crystals formed.
! The sam e method was repeated with ethanol as a solvent and no cry-
i
jstals could be obtained.
! b) Attempted resolution with d-10-camphor sulfonic acid.
i
| The same procedure as above was repeated in methanol and ethanol
; ' I
as solvents. Resolution could not be affected. No crystals formed. j
! i
c) Attempted resolution with dinaphtoyl tartaric acid. j
| j
| The sam e method again was applied as above. Crystals formed di- j
t i
jrectly by the addition of binaphtoyl tartaric acid. Attempts were m ade |
f I
;to recrystallize them in order to get a resolution, but failed. i
: i
i
. I
■ F . Resolution of N-morpholint>p>-ferrocenylaminonitrile. j
5 • !
t i
: a) Attempted resolution with tartaric acid. j
; l
(The sam e procedure was used as above). 31.0 g (0.1 mole) of the
jaminonitrile was dissolved in 770 m l of ethanol at 55°. 15 g (0.1 mole)
jof tartaric acid dissolved in 27 m l of ethanol at 55° and added to the
!
(
jaminonitrile in one portion. The temperature was allowed to drop 2-5°
‘ . i
, j
jper hour. The next day, about 22 g of the tartarate salt were collected I
'by suction filtra tio n and the mother liquor set aside for use later. The!
; j
tartarate salt was added to 135 m l of 20% (w/w) aqueous N aO H solution. !
> . i
jThe free aminonitrile was extracted with dichloromethane, washed with i
! i
! ;
saturated salt and dried over K ^C O g and evaporated in vacuo to give J
about 17 g of the free aminonitrile, m.p. 147°. The aminonitrile was
not optically active.
The mother liquor was evaporated into one-third of its volume
and le ft to crystallize. Crystals thajt were collected were also opti
cally inactive.
b) Attempted resolution by d-10-camphor sulfonic acid.
The sam e procedure was applied, but in this case, the salt was
not obtained.
c) Spontaneous resolution.
1. In absolute alcohol.
31.0 g (0.1 mole) of the racemic aminonitrile were dissolved in
770 m l of absolute alcohol at 55°C. The temperature was allowed to
drop 2-3° per hour. 22.0 g of the aminonitrile were collected with
[ajp5 = -32.3° (ethanol). The mother liquor was evaporated into
one-third and let .crystallize, at -20°C. Crystals were collected by
suction filtra tio n , 3.65 g with [a]p5 = -70° (ethanol). Then the op-
25 o
tical rotation of the mother liquor was taken to give [&]p = -54.5
(ethanol).
The optical activity of the crystals decreased by time.
2. Further exploratory experiments.
5 g (0.016 mole) of racemic aminonitrile was dissolved in 105 m l
o n
of absolute alcohol at 55-60°C. Optically active crystals with [ajp
-20° were added and solution was allowed to cool slowly, 2-3° per hour
o 25
making i t go to 0 . 3.5 g were collected by filtra tio n with [a]p =
27
,
3. Spontaneous resolution with cyclohexane.
5 g (0.016 mole) of the racemic,aminonitrile was dissolved in
100 ml of cyclohexane at refluxing temperature. The solution then was j
i |
| allowed to cool to room temperature,and then.was placed in a freezer at
i !
' 0 i ■
| temperature of -20 C. After a few hours, crystals were collected, withj
I _ ,?5 o !
j optical rotation of jaJD = -25.5 . !
j
5
i
! Preparation of a-Ferrocenyl-g-N-morpholino Acetonitrile. j
I i
! 1
i The procedure used is essentially ,the one used by Hauser , except
j
■for a few changes in the purification stage.
! ~ *i25
| 1 g (0.0032 mole) of optically active aminonitrile with Lajggg =
!
i -43.2 dissolved in 30 ml of dry ether was added dropwise to a stirred
» i
I solution of methylmagnesiurn iodide prepared from 0.01 mole each of j
s
I
1 methyl iodide and magnesium .in.20 m l of dry ether. The solution was
\
i
I stirred for one hour and then le ft standing, overnight. The reaction i
mixture was decomposed by 15% am m onium chloride solution, extracted
. .
in dichloromethane and the solvent evaporated. The product was chro- j
matographed through silica gel column with dichloromethane as solvent; j
io.82 g (82%) of the amine was collected with = -42.5°. |
|
j
H. Preparation of N-morp.holino-g-Ferrocenyl ethyl amine from N,N,N- |
Trimethyl -1 -Ferrocenyl ethylammoni umiodide.. i
■ !
i !
i j
! 4 g (0.01 mole) of N,N,N-trimethyl-l-ferrocenylamminiumiodide . I
i I
j [a]p5 = -20.5 dissolved in 50 m l of methanol and 2.34 g (0.03) of i
Imorpholine was added. The mixture was stirred for three hours at j
60t -65°C and then allowed to cool for .a few hours after that. The
reaction product was added to 60 ml of water, and extracted by di-
! chloromethane. The dichloromethane solution was then extracted with
| 15% phosphoric acid. The phosphoric acid extract was made basic by
! addition of NaOH, and extracted in dichloromethane.
i
j The product was chromatographed over silica .gel with 1 chloro-
|form:l methanol as solvent. 1.74 g (60%) was-collected with, [a]gg5
REFERENCES I
I
j
I. Ugi, Angew. Chem . , 74., 9 (1962); Angew. Chem . Iiiternat. Edit. , J
1 _ , 8 (1962). i
I. Ugi, Isonitri.le Chemistry, Academic Press, M ew York, 1971, p. j
145. |
(a) I. Ugi and: A. Steinbruckner, Angew. Chem., 72., 267 (1960); j
(b) I. Ugi and K; Offermann, Chem ; Ber. , £7, 2996 (1964). J
Review articles: J
(a) A. McKenzie, Angew. Chem., 45., 59 (1932); j
(b). E.E. Turner and M.M. Harris; Quart. Rev. (London) , ,l_s @§13^47)^7
I
(c) V. Prelog, Bull. Soc. Chim. France, 987 (1956); [
(d) E.L. Eli e l, Stereochemistry of Carbon Compounds, McGraw-Hill,
New-York, 1962; j
(e) J.J. Klabunowski, Asymmetrische Syntheses, V E B Deutscher Verlagj
der Wissenschaften, Berlin, .1963; j
i
(f) H. Pracejus, Fortseher,; Chem . Forsch. (Berlin)., J3, 493 (1967); j
(g) D.R. Boyd and M.H. McKervey, Quart. Rev. (London), 22., 95 j
(1958); |
(h) J. Mathieu and J. Weill-Raynal, Bull. Soc. Chim., France, 1211 j
i
(1968). |
i
(a) I. Ugi, dahrb. Akad. Wiss. Goettingen; 21 (1965); j
(b) I. Ugi, Z. Naturforsch, B, 20, 405 (1965);
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(e) E. Ruch and A. Schonhdfer, Theor. Chim. Acta, 10, 91 (1968); I
30
(f) E. Ruch, Theor. Chim. Acta, 1 _ 1 _ , 183 (1968);
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Angew. Chem., 82_, 741 (1970); Angew. Chem. Internat. E d it., 9 ^ ,
703 (1970).
6. H. Kleimann and I. Ugi, unpublished results, 1967.
7. H. Herlinger, H. Kleimann, K. Offermann, K. Rucker, and I. Ugi,
Justus Liebigs Ann. Chem., 692 , 94 (1966).
8. I. Ugi and G. Kaufhold, Justus Liebigs Ann. Chem., 709, 11 (1967).
9. D. Marquarding, P. Hoffmann, H. Heitzer, and I. Ugi, J. Amer. Chem .
Soc., 92, 1969 (1970).
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(b) H. Pracejus and A. T ille , Chem. Ber., 9^6, 854 (1965);
(c) H. Pracejus, Fortschr. Chem. Forsch., 8, 493 (1967):
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(b) D.S. Trifan, R. Bacskai, Tetrahedron L e tt., 1 (1960).
(c) D.S. Trifan, R. Bacskai, J. Amer. Chem . Soc., 8£, 5010 (1960);
(d) E.A. H ill, J.H. Richards, J. Amer. Chem . Soc., 83^, 3840 (1961);
(e) J.C. Ware, T.G. Traylor, Tetrahedron L e tt., 1295 (1965);
(f) M. Rosenblum, Chemistry of the Iron Group Metallocenes, Part I ,
John Wiley and Sons, N ew York, 1965, p. 129.
(g) M. Rosenblum and F.W. Abbate in "Advances in Chemistry" series,
No. 62, American Chemical Society, Washington, D.C., 1966, p.
532;
(h) T.G. Traylor and J.C. Ware, J. Amer. Chem . Soc., 89, 2304(4967);4
( i) J. Feinberg and M . Rosenblum, J. Amer. Chem. Soc., 9 1 _ , 4325
»
(1969).
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j and I. Ugi, Angew. Chem., S 2 _ , 77.(1970); Angew. Chem. Internat
| - Edit. ,_9, 64 (197,0).
j (b) G. Gokel and I. Ugi, Angew. Chem., 83_, 178 (1971).
j
113. K. Schlogl, Top. Stereochem. , 1 _ , 39 (196.7).
|
j 14. (a) D. Marquarding, H. Klusacek, G. Gokel, P. Hoffmann, and I. Ugi
Angew. Chem., 82^ 360 (1970);
! (b) D. Marquarding, H. Klusacek, G. Gokel, P. Hoffmann, and I. Ugi
I J. Amer. Chem . Soc., 92, 5389 (1970);
, (c) L. Battelle, R. Bau, G. Gokel, R. Oyakawa, and I. Ugi, J.
I Amer; Chem. Soc., in press.
i
| 15. G. Gokel and I. Ugi, J . Chem . Educ., 49, 294 (1972).
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j
| .17.. A. Christiaen, Bull. Soc. Chim. Belg., 33, 483-90 (1924).
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i
i (1968).
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I. Ugi, Angew. Chem., 82_, 77 (1970).
! >
120. G.W. Gokel, D. Marquarding and I. Ugi, Submitted. to J. Org. Chem .
|21. M . Anderson and A .H ill, J. Chem . Soc., 993 (1928).
l
|22. I. Duschinskyi Chemistry and Industry, J^,(j3342S9 3 . 4 ).
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i Ed, New York, John Wiley and Sons, 1943.
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)
|25. M. Sato, H. Kono, M . Shiga, I. Motoyama and K. Hata, J. Chem . Soc.
32 ’
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i
i
27. D. Marquarding, H. Klusacek, G. Gokel, P. Hoffmann, and I. Ugi, j
J. Amer. Chem . Soc., 92, 5389 (1970). j
28. A.S. Arora and A. Schats, unpublished results. !
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Asset Metadata

Creator Zahr, Salah Amin (author)

Core Title The stereochemical course of the nucleophilic displacement of cyanide from alpha-ferrocenyl-alpha-aminonitriles, and model experiments for the synthesis of optically active alpha-ferrocenyl alkyl...

Degree Master of Science

Degree Program Chemistry

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag chemistry, organic,OAI-PMH Harvest

Language English

Contributor Digitized by ProQuest (provenance)

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c17-796404

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