Synthetic routes to perhydroazulenes; studies with oxygenated models
by Amo Richard DeBernardis
A thesis submitted to the Graduate Faculty in partial fulfillment of the requirements for. the degree of
MASTER OF SCIENCE in Chemistry
Montana State University
© Copyright by Amo Richard DeBernardis (1971)
Abstract:
The research program was initiated to learn whether diazomethane ring expansion might prove a
reasonable method of arriving at perhydroazulenes that are related to some sesquiterpenes. In the
course of the investigation, which involved 4-methyl-cis 3a,4,7,7a-tetrahydrophthalan as a model, it
was concluded that a methyl group can have powerful directive effects; possibly more electronic in
nature than steric. Also, the choice of an oxygen heterocyclic system as a model for the carbocyclic
systems resulted in an analysis of the long range directive effects of oxygen. Additional studies using a
sulfur hetero-atom confirmed the long range hetero-interactions. As part of the study using oxygenated
systems, the sex attractant of the bark beetle, Dendroctonus brevicomis, was prepared by an
unambiguous synthesis. The initial question of the program, that of investigating the use of
diazomethane ring expansion, was answered and evidence shows that the desired product is that
obtained in greater quantity. Overall yields, however, appear to be prohibitive in using this as a
synthetic route. The poor ring expansion may result from electronic and/or steric effects. STATEMENT OF PERMISSION TO COPY
In p re sen tin g th is th e s is in p a rtia l fulfillm ent of the re q u ire m e n ts fo r an
advanced deg ree at M ontana State U n iv ersity , I ag ree th a t the L ib ra ry sh a ll
m ake it fre e ly available fo r insp ectio n .
I fu rth e r agree th a t p e rm issio n fo r
extensive copying of th is th e s is fo r sch o larly p u rp o ses m ay be g ran ted by m y
m a jo r p ro fe s s o r, o r, in h is absen ce, by the D ire c to r of L ib ra r ie s .
It is u n d e r­
stood th a t any copying o r publication of th is th e s is fo r fin an cial gain sh all not
be allow ed w ithout my w ritte n p e rm issio n .
Signature
a
SYNTHETIC ROUTES TO PERHYDROAZULENES
STUDIES WITH OXYGENATED MODELS
by
A. R ich ard D eB ern ard is
A th e s is subm itted to the G raduate F acu lty in p a rtia l
fulfillm ent of the re q u ire m e n ts for. the deg ree
of
MASTER OF SCIENCE
in
C h em istry
Approved:
Head, M ajor D epartm ent
C hairm an, Exam ining Com m itte
MONTANA STATE UNIVERSITY
B ozem an, M ontana
A u g u stj 1971
to
Beau
who h a s su ffered m any lonely hours
ACKNOWLEDGMENT
S everal people have had a m a jo r ro le in m aking th is r e s e a r c h study p o s­
sib le and I would like to take th is opportunity to thank them .
I would e sp e c ia lly like to thank my p a re n ts w ithout w hose help th e com ­
pletion of th is th e sis would not have been p o ssib le .
I would like to acknowledge
the C h em istry D epartm ent of M ontana State U niversity fo r its support in the way
of teach in g a ssis ta n tsh ip s ; and fo r m aking it p o ssib le fo r m e to p a rtic ip a te in
the N orthw est reg io n al m eeting o f the A m erican C hem ical Society (Utah, su m ­
m e r 1969) and to attend the National O rganic Sym posium (Utah, 1969).
F o r its
g e n ero sity in the way of p a rtia l su m m e r su p p o rt in the su m m e r of 1968 and com ­
p le te support during the su m m er of 1970, I would like to thank D r. Roy Huffman,
I
vice p re s id e n t of r e s e a r c h , and the Endowment and R e s e a rc h Foundation of
M ontana State U niversity.
I would like to thank D r. A. P . K rapcho, U niversity
of V erm ont, fo r h is helpful inform atio n .
I a lso thank my fellow re s e a rc h e r ,
M r. R . D. O tz en b e rg e r, fo r h is tim e involved in d iscu ssio n s and in helping to
build la b o ra to ry a p p aratu s.
My sp ec ia l thanks is extended to D r. B rad fo rd P. Mundy fo r his guidance
in th is r e s e a r c h and h is sp e c ia l patien ce w ith my many tan g en ts.
TABLE OF CONTENTS
PAGE
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L ist of T a b le s ....................................................................................................
L is t of F ig u r e s ...................................................... ..
viii
ix
CHAPTER
I
II
I nt r oduct i on. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I*
Synthesis of Alkene System ................................. ..
10
TTT Ring expansion of Alkene .............................................. ..
37
IV
A nalysis of su lfu r-h e te ro a to m . . . . . . . . . . . . . . . . . . . . . . . . . . .
V Synthesis of the se x a t t r actant B rev ico m in ...................... ..
*V1
VII
46
50
E x p e rim e ntal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
Appendix ....................................................... ............ ..............................
77
VIII R eferen c es .............................................................
ABSTRACT
The r e s e a r c h p ro g ram w as in itia te d to le a rn w h eth er d iazom ethane rin g
expansion m ight prove a re a so n a b le m ethod of a rriv in g at p e rh y d roazulenes th a t
a re re la te d to som e se sq u ite rp e n e s. In th e co u rse of the in v estig atio n , which
involved 4 -m e th y l-c is 3 a ,4 , 7 , 7 a-tetrah y d ro p h th alan as a m odel, it w as con­
cluded th a t a m ethyl group can have pow erful d irectiv e effects; possibly m o re
e le c tro n ic in nature than s te r ic . A lso, the choice of an oxygen h etero cy clic
sy ste m as a m odel fo r the carb o cy clic sy ste m s re su lte d in an an aly sis of the
long ran g e d ire c tiv e effects of oxygen. A dditional studies usin g a su lfu r h e te ro ­
atom confirm ed the long ran g e h e te ro -in te ra c tio n s. As p a rt of the study using
oxygenated sy ste m s , the s e x a t t r actant of the b a rk b eetle, D endroctonus b re v ic o m is, w as p re p a re d by an unam biguous sy n th esis. The in itia l question of the
p ro g ra m , th at of in vestigating the use of di azom ethane rin g expansion, was
answ ered and evidence shows th at the d e s ire d product is th a t obtained in g re a te r
quantity. O verall y ie ld s, how ever, ap p ear to be prohibitive in using th is as a
synthetic ro u te . The p oor rin g expansion m ay re s u lt fro m e le c tro n ic a n d /o r
s te r ic e ffe cts.
-v iii-
LIST OF TABLES
TABLE
PAGE
1.
D iborane h y d ratio n of cy clic s y ste m s . . . . . . . . . . . . . . . . . . . . . . .
13
2.
A nalysis of the pinacol re a rra n g e m e n t ............................................... 23
3.
H ydration of 3 -m ethycyclohexene .......................................................
31
4.
H ydration of 4 - M e th y l-c is -3 a ,4 , 7 a ,7 -te tra h y d ro p h th a la n . . . .
34
5.
Ring expansion of the m odel c y c lo h e x a n o n e ............. .......................
41
6.
D ie ls-A ld e r re a c tio n fo r fo rm atio n of 2 -carboxaldehyde-6~
m e th y l-3 , 4 -d eh y d ro -2 H -p y ran . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
-ix -
LIST OF FIGURES
FIGURE
PAGE.
1.
E xam ples of p erhydroazu len e compounds ............................................
I
2.
The c o rre c t s tru c tu re fo r f} - v e tiv o n e ;.........................................
2
3.
Synthesis of A rom adendrene .................
3
4.
Synthesis of /3 -vetivone by K rapcho and Mundy ...........................
4
5.
Synthesis of
5
6.
A pproach to all carbon sy stem . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
7.
A ttem pted cyanide d isplacem en t ...............
7
8.
P roposed sy ste m th a t m ight be of in te re s t to look i n t o ...............
'8
9.
P re p a ra tio n of phthalan (3) ............................. .......................................
10
10.
M echanism of cy clizatio n to the fu r an d eriv ativ e .................
12
11.
The hy d ratio n of 3_ w ith diborane ............................
15
12.
Gas ch ro m ato g ram of hyd ro b o ratio n p ro d u cts . . . . . . . . . . . . . . .
15
13.
D euterium exchange of 2-m ethycyclohexanone ..........................
18
14.
N m r study of duete ra te d sy ste m £ and l £ ................................
19
15.
The Use of D isiam ylborane fo r H ydroboration ...............................
21
16.
P ro p o sed m ech an ism fo r the pinacol re a rra n g e m e n t . . . . . . . . .
24
17.
C arbonium ion stab ility .........................................................
24
18.
M odel of 4 -M e th y l-c is -3 a ,4 ,7 ,7 a -te tra h y d ro p h th a la n .................
26
vetivone by M arsh a ll ........................
-X -
FIGURE
PAGE
19.
The p ro c e s s of o x y m ercu ratio n — d e m e rc u ra tio n .................. ..
27
20.
O xym ercuration of 3 -m e th y lc y c lo h e x e n e ........... ..............................
28
21.
O x y m ercu ratio n of the alkene (3
........................ ....
28
22.
P a s to 1s w ork on H ydration of alkenes ...............................................
29
23.
C onform ational is o m e rs of 3-m ethylqyclohexene ...........................
32
24.
M ethyl group in te ra c tio n s in 3 ,3 -dim ethylcyclohexene ................
32
25.
E ffect of oxygen atom on alkene (_3 ) sy ste m
35
26.
Ring expansion of m ethyl-cyclohexanone ..........................................
37
27.
Ring expansion of the ketone (IQ) ........... ...... .............................
38
28.
Unambiguous sy n th esis of the expansion pro d u ct (25 ) . . . . . . . .
40
29.
C om parison of g as ch ro m ato g ram s of expansion p ro d u c ts . . ; .
42
30.
G as c h ro m ato g ram of product obtained fro m rip g
expansion .........................................................................
44
31.
Synthesis of su lfu r sy ste m alcohols ( 2 9 ) ........................ .................
46
32.
C om parison of alcohol re te n tio n tim e s ..................................... ..
47
33.
N m r co m p ariso n of compounds in c p s . . . . . . . . . . . . . . . . . . . . . . .
49
34.
In te rn a l cy clizatio n w ith m e rc u ric acetate . . . . . . . . . . . . . . . . . .
50
35.
The se x a ttra c t ant brev ico m in . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
36.
S ilv e rs te in 's sy n th esis of b rev ico m in
53
37.
W a sse rm a n ’s sy n th esis of b rev ico m in ...............................
^
........... .....................
........... ..
54
rXL
FIGURE
PAGE
38.
Synthesis of b r e y i c o m i n ......... ....................... ....................................
55
39.
P o ssib le p ro d u cts fro m the D ie ls-A ld e r re a c tio n ......................
57
PART
I
INTRODUCTION
Although te rp e n e s have, in g e n e ra l, occupied a p o sitio n of in te re st to
organic c h em ists based alm ost e n tire ly on in te re stin g sk ele ta l fe a tu re s, and
ability to undergo com plex sk ele ta l reo rg a n iz atio n , in the p a st th e ir p h a rm a lo g ical use has been of little concern .
The sy n th esis of perh y d ro azu len es has
re c e n tly becom e of co n sid erab le in te re s t, due to th e ir p h arm alo g ical activity.
M em bers of th is unique c la s s of sesq u ite rp e n es b e a r in com m on the c h a r a c te r­
is tic rin g sy stem com posed of m utually fused five and seven rin g (figure I).
The positioning of additional m o ieties a re , as a ru le , p red ictab le on sim ple
biogenetic reaso n in g .
H ow ever, non -iso p ren o id s tru c tu re s a re known, and a re
p a rtic u la rly common in the perhydroazulene te rp e n e s.
F ig u re I :
E x am p les of p e rh y d ro a z u le n e co m pounds.
- 2 —
E xam ples of s e v e ra l perhydroazulene sesq u ite rp e n es a re shown in fig u re
I.
The extent of pharm acological and o th e r physiological a c tiv itie s a re well
re p re se n te d in the sesq u iterp en e p arth en in (ii)1 in which both e ffects have been
exhibited.
L actucin (iii)2 and helen alin (iv)^ have also been shown to be active
pharm ac ologic a lly .
The potential of th e se in te re stin g compounds has not been re fle c ted in
abundant sy n th esis.
R e s e a rc h in th is synthetic a re a is exem plified by the not­
able sy n th esis of A rom adendrene by Buchi^ (figure 3), and /3-vetivone by A. P.
K rapcho and B. P. Mundy^ (figure 4) and also the independent sy n th esis of /?vetivone by J . A. M a rsh a ll6 (figure 5) w ith th e se e x am p les, the com plexities of
the sy n th esis can be noted.
In the case of the A rom adendrene syn th esis the
assigned s tru c tu re (vii) w as shown not to a g ree w ith the synthetic product (yi).
The two independent sy n th eses of /3-vetivone gave p ro d u cts w hich w ere not con­
siste n t w ith the iso la ted n a tu ra l p roduct and led to eventual s tru c tu re re a s s ig n ­
m ent.
The c o rre c t s tr u c tu r e , as w as finally d eterm in ed by M a rsh a ll7, is
shown in figure 2.
T hus, in both c a se s it w as only because of the attem pted
sy n th eses th at the assigned s tru c tu re s w ere found to be in c o rre c t.
F ig u re 2 : The c o rre c t s tru c tu re fo r /3 - vetivone.
- 3 -
CH2 =GH-CHO^
(pH
F ig u re 3: S y n th esis of A ro m a d e n d re n e .
I . ) saponified
--------------- >
2 .) CHgNg
C ^O ,
I.) fo rm ic aicd
sodium CHgOgC^=
2' > % ,
pe riodaTe
3.) sodium
m ethoxid
CH3 Og
1.
MeOOC
f i - vet ivone
F ig u re 4:
)NaBH4/M eOH
2.
)TsCl
3. ) NaCN
1.
) a cetic
)MeMgI anhydride
--------------->
2.
1.
) HCl
reduction
----------------- >
--------------------- >
2.
) B F g -e th e ra te
->
D erivative
S y n th esis of /3- v etiv o n e by K rap ch o and Mundy.
^
MeMgI
I .) b ro m ination
deriv ativ e
------------ =»
CuAc
2.) dehydrobrom ination
d isobutylalum inun
nydfide
P -T sC l
pyridine
Pt/E tO H
benzene
chro m ic
converted to the
m e so - de si s opr opy Iide ne dihydro /3 - vetivone
F ig u re 5: S y n th esis of ^ - v etiv o n e by M a rs h a ll.
B - vetivone
ketone
—6 —
In the sy n th esis of "jS-vetivone" by K rapcho and Mundy, many of the
re a c tio n s w ere te ste d on oxygenated m odel sy ste m s.
EliefS has used an oxygen
containing sy stem as a m odel fo r the le s s available carb o cy clic sy stem .
genated m odels have also been used by RickbornO.
Oxy­
The noted su c c e ss with
oxygenated m odels would indicate they can lend insight into p ro b lem s that m ight
be encountered in the carb o cy clic analogs.
The objective of th is r e s e a r c h w as to d esign an efficien t p re p a ra tio n of
(viii) and in vestigate the p o ssible rin g expansion to the perhydroazulene m odel
(ix)
.
T his m odel sy stem would be e asily p re p a re d and p ro b le m s w orked out
(ix)
(viii)
w ith it would m ake the subsequent p re p a ra tio n of the carbon sy stem much e a s ­
ie r , and hopefully provide an e a s ie r ro u te to som e of the p erh y d ro azu len es.
The logical way to approach the all carbon compound would be through a dicyan­
ide as is shown in figure 6.
However, it is not possible to obtain the dicyanide
d ire c tly fro m the ditosylate o r d im esy late (xiii).
-I -
cyclization
CH OTs
F ig u re 6:
A pproach to all carbon sy ste m .
T his can be explained on the b a sis of the s te ric a lly hindered d itosylate system
(figure 7).
A possib le route to the perhydroazulene sk eleto n from the oxygen­
ated sy ste m is delineated in figure 8.
Although th e re a re no d ire c t lite ra tu re
analogies, th e re a re iso la ted exam ples to suggest that once th is basic ring
skeleton (ix) is p re p a re d it would be feasib le to convert it to som e of the ana­
logous sesq u iterp en e like sy ste m s (figure 8).
F ig u re
7:
A ttem p ted cyanide d is p la c e m e n t.
—8 —
(xxiii)
(XXLV)
F ig u re 8 :
P roposed sy ste m th a t m ight be of i n te r e s t.
PROPOSED
RESEARCH
To e s ta b lis h w hether d iazom ethane rin g expansion of 4 -m e th y l-6 -o x o c is -3 a , 4, 7, 7a-hexahydrophthalan to 4 -m eth y l~ cis-2 -o x a-7 -k eto d ex ah y d ro azu Ien e, the oxo-m odel of a perhydroazulene,. would be an efficien t m ethod of p r e ­
p a rin g p erh y d ro azu len es re la te d to the se sq u ite rp e n e s.
The s te r ic and e le c tro n ic
effects of a suitable positioned m ethyl group in d ire c tin g the c o u rse of the r e a c ­
tio n would also be inv estig ated .
PA R T
SYNTHESIS
II
OF ALKENE
SYSTEM
In o rd e r to synthesize the re q u ire d ketone (9) it w as f ir s t n e ce ssa ry to
p re p a re the alkene (3).
The subsequent hydration and oxidation of 3 would then
give the d e sire d ketone (9).
Following p ro c e d u res used p rev io u sly by Mundy
12
the phthalan (3) w as p re p a re d according to fig u re 9„
I
F ig u re 9:
P re p a ra tio n of phthalan (3).
P iperylene and m aleic anhydride w ere refluxed in benzene which con­
tained a tra c e of iodine13.
The c ry sta llin e anhydride 0 w as then reduced to
2 w ith lithium alum inum hydride.
T h ere w e re in te re stin g b y -p ro d u cts form ed
in th is reduction th a t co n sisted of one o r both of two is o m e ric lactones (G) and
0 , as evidenced by in fra re d spectro sco p y .
,
-1 1 -
The form ation of lactones during red u ctio n of anhydrides w ith lithium
alum inum hydride has been w ell e sta b lish e d 14. It has been observ ed that when
the anhydride 4 w as reduced w ith lithium alum inum h y d rid e , the only product
obtained w as the lactone 5.
It w as also noted th at fu rth e r red u ctio n of the
4
5
lacto n es (6) and (7) with lithium alum inum hydride gave a q u antitative yield of
the diol (2).
The m echanism of th is anom alous re a ctio n has re c en tly been r e ­
p o rte d 15.
2
6
The diol w as then converted to the m onotosylate under conditions fo r
which it is known th a t sy ste m s of th is type re a d ily undergo cy clizatio n to the
fu r an d eriv ativ e (figure 10).
The in fra re d and n u clear m agnetic s p e c tra
—12 —
(appendix, page 78) w ere co n sisten t w ith the assigned s tru c tu re fo r the phthalan.
F ig u re 10:
M echanism of cy clizatio n to the fu r an d eriv ativ e.
Having su ccessfu lly p re p a re d 3 in reaso n ab le quantity, it w as n e ce ssa ry to find
a good m ethod fo r the p re p a ra tio n of the ketone (9). T h ere w ere se v e ra l m ethods
available for hydration, the re s u lts of w hich a re d e sc rib e d below.
The c h em is­
tr y of 3 had not been p reviously studied, thus it was unim portant w here one
s ta rte d .
The f i r s t m ethod trie d w as th at of hydroboration.
The lite ra tu re has
evidence of co n siderable w ork done in th is a re a by H. C. B row n16 and D. J .
P a sto 17. The r e s u lts of som e of th is w ork are shown in Table I .
P a s to 1s w ork w ith 3 -m ethylcyclohexene ag reed v ery w ell with that of
B row n18. All of th e se sy ste m s trie d w ere conform ationally inhom ogeneous,
-1 3 -
w h ereas the alkene (3) sy stem w as of a rig id n atu re.
One of o u r in te re s ts in
th is re s e a r c h w as to analyze the effects of the m ethyl group upon the develop­
m ent of a basic perhydroazulene sy stem .
This m ethod of hyd ratio n w ill then
give insight into som e of its e ffe cts.
TABLE
I
D iborane hydration of cyclic sy ste m s
The hydroboration w as c a rrie d out in a s im ila r m an n er as that of B row n19.
In fra re d a n aly sis at th is point indicated the pro d u cts to be the expected alcohols.
H ow ever, when oxidation w as attem pted w ith su lfu ric acid and potassium d ich ­
ro m ate all th at w as re c o v e re d was a decom position product^.
This type of
oxidation was apparently too stro n g and a le s s d ra s tic m ethod w as needed.
A
—14—
v ery good m ethod w as found in the Jo n es o x id a tio n ^ .
It is known that even such
unstable compounds as 8^ can be oxidized w ithout d e stru ctio n of oth er sk eletal
fe a tu re s ^
This oxidation w as c a rrie d out at 25°C, w as v ery sim ple to run,
and gave high y ield s; th u s, m aking it a very acceptable m ethod fo r oxidation.
When it w as c a r rie d out on the alcohols th e re w as an alm o st quantitative yield
of ketone product.
T his w as indicated in the stro n g absorbtion at 1720 cm - * in
the in fra re d sp ec tru m and the alm ost com plete lo ss of the -OH absorbtion.
H
8
The problem of sep a ra tio n and identification tu rn ed out to be som ew hat
m o re difficult.
H ow ever, it w as possible to s e p a ra te the ketones by gas c h ro m a ­
tographic m ethods.
A colum n
6 feet long and 4 m m inside d ia m e te r packed
w ith 20% C arbow ax on 40/60 fire b ric k provided good sep a ra tio n .
The ra tio of
the ketones w as 60/40.
As can be seen in figure 12, one of the peaks has a
r a th e r la rg e shoulder.
T h is, it was fe lt, m ight be a ttrib u ted to the possible
e p im e r th at would re s u lt in ketone (9).
T h is ep im erizatio n would re s u lt in a
th ird ketone which would explain the sh o u ld er.
-1 5 -
BH
3
F ig u re 1 1 :
The hydration of S w ith d ib o ra n e .
Column : 20% C arbow ax on fire b ric k
Length : Six feet
T e m p e ra tu re : 180 C
12,7 m in.
10. 0 m in.
F ig u re
12 : G as c h ro m a to g ra m of h y d ro b o ra tio n p ro d u c ts .
-1 6 -
In o rd e r to positiv ely identify the two ketones and a lso v erify th is e p im e riz a tio n of the hydrogen it w as n e c e s sa ry to obtain pure sam p les of each
ketone.
The logical approach would be w ith p re p a rativ e gas chrom atography.
A g la ss colum n tw elve feet long w ith an inside d ia m e te r of 4 m m was m ade in
our la b o ra to ry .
S eparation and co llectio n of a sam ple of the tw o ketones w as
attem pted by th is m ethod.
S eparation w as achieved; how ever, since the r e ­
covery w as low (50%) and the tim e re q u ire d fo r obtaining m illig ra m sam p les
w as so long, th is m ethod w as felt to be im p ra c tic a l.
A lso, since larg e am ounts
of ketone (10) w ere n e c e s sa ry fo r the rin g expansion a m o re efficien t sep a ra tio n
p ro c e s s w as re q u ire d .
The o th e r m ethod available w as th a t of colum n chrom atography, but it
w as f ir s t n e c e s sa ry to find a m eans fo r se p a ra tio n w ith th in la y e r chrom ato­
graphy.
The support se le c te d w as s ilic a as opposed to alum ina due to p o ssib le
re a c tio n s and re a rra n g e m e n ts of the keto group.
With som e ex p erim en tatio n
the conditions and solvents fo r sep a ra tio n w ere found.
The sep a ra tio n on th in la y e r in d icated th a t it would be n e c e ssa ry to in ­
c re a s e the length of the solid phase to achieve a clean sep a ra tio n .
Since a com ­
m e rc ia l colum n w as not availab le, w ith th e help of M r. O tzen b erg er23 it was
p o ssib le to fashion a suitable one out of g la s s .
The colum n w as 60 cm long and
had a 30 m m inside d ia m e te r and w as w a te r jacketed.
The high volatility of the
-1 7 -
elutant solvents u sed m ade it n e c e ssa ry to cool the colum n to rem ove the heat
g en erate d by ab sorption and deab so rp tio n of the solvents on the solid phase.
W ith th is colum n it w as p o ssib le to se p a ra te one g ra m sam p les of the
ketone m ix tu re .
The gas ch ro m ato g ram of the collected fra c tio n s indicated
e ac h ketone to be uncontam inated w ith the o th er.
E ach fra c tio n gave a 2 , 4 -d in itro h y d razo n e d eriv ativ e and the m elting
ra n g e s w e re c o n sid erab ly differen t (fraction 10: m .p . 164-5, and frac tio n 9:
m . p. 176-7).
In fra re d a n aly sis of fra c tio n s 9 and 10 showed each to contain a stro n g
ab so rp tio n fo r a ketone w ith the carbonyl frequency fo r each ketone being the
sam e (see appendix, page 79).
The n u c lea r m agnetic reso n an ce sp e c tru m of e ac h ketone was c o n sid e r­
ably d ifferen t; how ever, conclusive assig n m en t of s tru c tu re could not be acco m ­
p lish e d at th is point (see appendix, pages 83 and 84).
It w as fe lt th a t if an e p im e riz atio n w as taking place and if one ketone did
have the s tru c tu re of ketone (9) then it should be p o ssib le to em ploy d euterium
exchange as ah analytic m ethod.
T his exchange would be evident in the n u c lea r
m agnetic reso n an ce as a lo s s in the sp littin g of the m ethyl sig n al fo r the com ­
pound having the seco n d ary m ethyl group a to the carbonyl function.
E x p erim en ts on a m odel compound w ere f ir s t attem p ted in o rd e r to
A
—18—
e sta b lis h the ex p erim en tal technique.
A g as ch ro m ato g rap h ically pure sam ple
of 2 -m ethylcyclohexanone w as sele c ted as the m odel.
The n u c lea r m agnetic
reso n an ce sp ec tru m of the deutera te d compound did show a lo ss of the sp littin g
of the m ethyl group at 1.1 6 as w as expected (figure 13).
The ketones (9) and (10) w ere then subjected to the sam e condition fo r
deu teriu m exchange and the n u c lea r m agnetic reso n an ce sp ec tru m of each was
taken (figure 14).
As w as expected th e re w as a lo ss in the sp littin g of the
m ethyl group in one of the ketones (11). The doublet fo r the m ethyl group was
re ta in e d in the o th e r ketone (12).
F ig u re 13:
D e u te riu m exchange of 2 -m eth y c y c lo h e x a n o n e .
-1 9 -
0.0
F ig u re 14 :
N m r study of d u e terate d sy ste m 9 and 10 .
6
—2 0 —
On the b a sis of the info rm atio n and subsequent fu rth e r evaluation of the n u clear
ipagqetic s p e c tra the given s tru c tu re s w ere assig n ed to ketones (10) and (9).
R eturning now tp the quantitative r e s u lts obtained fro m gas ch ro m ato ­
graphy it w as p o ssib le to evaluate hy d ro b o ratio n as a m ethod fo r hydration.
Thq d e s ire d ketone (10) w as not the m a jo r product and at th is point it w as not
p o ssib le to fu rth e r c o n sid e r hydroboration as a m ethod of hydration.
-2 1 -
The use of a m ore hindered hydroborating group provided a second
m ethod fo r hydration.
Tliis m ethod of hydration using d is i am ylborane (b is-3 -
mpthy 1-2-b u ty lb o ran e) has been re p o rte d in the lite ra tu re by Brow n2^.
With a
m uch la r g e r group on the borane it w as fe lt th at th is would hinder attack at the
C -5 carbon.
Inform ation provided in the lite ra tu re shows th at disiam ylborane d ire c ts
predom inantly to the le s s hindered carbon atom .
to be tr u e 25 (see figure 15).
In two ex am p les th is is shown
Some w ork on sim ple cyclic sy ste m s have given
c o n trad icto ry re s u lts and w ill be fu rth e r d iscu ssed at a la te r tim e.
o^ * '
W
H
.
CH0
CH
3x
RBH
/t
5%
F ig u re 15:
A
/
CH1
95%
The Use of D isiam ylborane fo r H ydroboration.
The d isiam ylborane w as p re p a re d in the sam e way as by Brown
.
The
alkene w as then subjected to hy d roboration w ith d isiam ylborane under the sam e
-2 2 —
conditions as w ere u sed in the l i t e r a tu re ^ ? .
Indeed, the re s u lts w e re in good ag reem en t w ith those obtained by Brown
and c o -w o rk e rs.
The use of disiam y lb o ran e did shift the ketone product ra tio
tow ards the expected ketone (10).
product as w as d e sire d .
H ow ever, 10 w as s till not the predom inate
The m ethyl group did seem to play som e ro le in the
d ire c tio n of attack but fu rth e r study w as s till needed to d e term in e how stro n g
o r im p o rtan t it w as.
T h ere is y e t a th ird m ethod fo r hyd ratio n of the alkene (3), the pinacol
re a rra n g e m e n t.
This m ethod was sele c ted la rg e ly because of a c o n cu rren t
study being done on the pinacol re a rra n g e m e n t in our la b o ra to ry .
The pinacol
re a rra n g e m e n t does, how ever, provide a p o tentially easy and quick m ethod fo r
obtaining ketone p ro d u cts from the sy ste m being studied.
The alkene (3) w as
re a d ily converted to the alcohols needed fo r the pinacol re a rra n g e m e n t.
Since
it w as e asy to p re p a re both the cis and tra n s diols fro m the alkene it w as felt
both sy ste m s should be attem pted in the re a rra n g e m e n t.
The c is diol (13) w as
p re p a re d by p o tassiu m perm anganate oxidation of 3^ in good y ie ld s.
P re p a ra tio n
of the tra n s diol (14) sy ste m w as achieved using the p e rfo rm ic acid hydroylation
p ro c e d u re .
The conditions under which the pinacol re a rra n g e m e n t should be c a r rie d
out w ere not w ell e sta b lish e d .
Some re c e n t w ork in th is a re a in our la b o ra to ry
-2 3 -
indicated v a ria tio n s in re a c tio n conditions would change the product ra tio s .
Q ualitative an aly sis of ketone fo rm atio n under v ario u s acid co n cen tratio n s,
using both the cis and tra n s is o m e rs of cyclohexane diol, indicated that the
optim um conditions involved acid co n cen tratio n s of 80% o r g r e a te r .
Table 2
shows the re s u lts of the pinacol re a rra n g e m e n t under v ario u s conditions.
TABLE 2
A nalysis of the pinacol re a rra n g e m e n t.
O v e r­
all
Y ield
40%
Room T em p.
---------------- >
Con. H2SO4
None
None
R eflux
None
Con. H SO.
2 4
15%
T ra c e
85%
59%
-2 4 -
It is e a sily seen fro m Table 2. th a t the re s u lts fro m the pinacol r e a r ­
ran g em en t w e re not v e ry d e sira b le .
T h e re w e re also many side products and
in som e re a c tio n s the s ta rtin g m a te ria ls w e re so decom posed th a t th is m ethod
w as discontinued.
The r e s u lts up to th is point w ere not v e ry encouraging and an evaluation
of the d ata at th is tim e helped to decide the d ire c tio n of ketone re s e a rc h p u r ­
su its.
The effect of the m ethyl group upon the fo rm atio n of 3_ is not a v ery
stro n g one.
In all th r e e 29 of the h y d ratio n s tr ie d th e re w e re n early equal
am ounts of both ketones o r in the case of the pinacol a la r g e r p ercen tag e of 9.
It would a p p ea r th a t the rig id ity of the sy ste m is of little im p o rtan ce.
The h y -
d ro b o ratio n e x p erim en ts seem ed to a g ree v e ry w ell w ith what w as re p o rte d in
the lite ra tu re .
A nalysis of the pinacol re a rra n g e m e n t re s u lts ; even though, they w ere
not s a tisfa c to ry as a synthetic m ethod w e re v e ry in te re stin g .
C onsidering the
m ech an ism of the pinacol re a rra n g e m e n t and the m a jo r p ro d u ct fro m the r e a c ­
tio n s of the diols (13) and (14), it is p o ssib le to d eterm in e w hich carbonium ion
would be the m o re fav o rab le.
FigurelG su g g ests the m ech an ism to explain the
p red o m in ate fo rm atio n of 10.
T his .m echanism would indicate th a t the m o re
stable of the two p o ssib le carbonium ions is 15.
E x p erim en tal re s u lts would
-2 5 -
F ig u re 16 : Proposed m echanism fo r the pinacol re a rra n g e m e n t
also indicate th at a carbonium ion at 0 6 is m o re stable than at C-5 (figure 17).
F ig u re 17:
C arb o n iu m ion sta b ility .
-2 6 -
A plausible explanation of th ese re s u lts would be that the oxygen of the
fu ran rin g is p a rtic ip a tin g to produce an e le c tro n ic effect th a t would stab ilize
th is carbonium ion (figure 18).
F u rth e r in v estig atio n of the sy stem was n e c e s ­
s a ry in o rd e r to determ in e the po ssib le effects of the oxygen, and other r e s e a r c h
F ig u re 18:
Model of 4 -M e th y l-c is -3 a ,4 , 7 , 7 a-tetrah y d ro p h th alan .
in our la b o ra to ry is try in g to evaluate the effects of h e tero ato m s.
O xym ercuration p ro v id es another ro u te fo r alkene hydration.
This
m ethod has been shown to be an effective M arkownikoff hyd ratio n technique.
O xym ercuration is also a very d e sira b le m ethod of hydration because of the
m ild ex p erim en tal conditions involved.
It is very selectiv e in its re a ctiv ity and
w ill not in te rfe re o r re a c t w ith any o th er functional groups^®.
The m echanism fo r o xym ercu ratio n has been under investigation fo r
som e tim e (figure 19).
T h ere has been som e d iscu ssio n as to w hether the m e r ­
c u ric acetate com plexes w ith the pi sy stem of the double bond in the f ir s t step
—27 —
o r if th e re is a disp lacem en t of an acetate ion by one of the carbon c e n te rs of
the double bond.
H ow ever, at th is point the m ech an istic d e tails of the o x y m er-
c u ratio n re a c tio n a re not the focus of the re s e a rc h .
1.
)1^ O -TH F
2.
) KOH
+ Hg-OAc
"'Hg- OAc
KOHZNaBH4
/k r O H
F ig u re 19:
The p ro c e ss of o x y m ercu ratio n — d em ercu ratio n .
If th e re is a s te r ic effect to d isp lacem en t taking place in oxym ercuration
then th is should be e a sily seen in a m odel sy stem .
m ethylcyclohexene.
The m odel of choice w as 3 -
Evidence fro m d isiam ylborane re a c tio n s would suggest that
the c e n te r of h igher e le c tro n density would be at C -2.
T h e re fo re , it would be
p re d ic ted th at fo r oxy m ercu ratio n 3 -m ethylcyclohexanone would be the m ajo r
product.
The o x y m ercu ratio n of 3-m ethylcyclohexene was c a r r ie d out and the p ro ­
ducts w e re analyzed by gas chrom atography.
W ith both p o ssib le ketones a v a il­
able, d e term in atio n of the products was v ery easy .
As expected, the m ajo r
—28 —
product w as 3-m ethylcyclohexanone (figure 20).
F ig u re 20:
This method of hydration was
O xym ercuration of 3-m ethylcyclohexene.
next applied to 3^ If the id ea is c o rre c t th at the bond is p o la riz e d tow ards C -5,
it would be p re d ic te d th a t the m a jo r product of o x y m ercu ratio n would be ketone
(10). When 3. w as subjected to hyd ratio n by o x y m ercu ratio n the m a jo r product
w as the ketone (10) as p re d ic te d (figure 21).
T his m ethod of hydration.
I . ) Hg(OAc)
2 .) oxidation
(3)
(10)
F ig u re 21:
O x y m e rc u ra tio n of th e alkene (3).
(9)
-2 9 -
o x y m ercu ratio n , then p ro v id es a reaso n ab le m eans of obtaining larg e quantities
of the needed ketone (10) and m akes its p u rifica tio n by colum n chrom atography
re la tiv e ly e asy .
B efore proceeding on to the question of rin g expansion th e re was a d e sire
to look fu rth e r into the c h em istry of the compound used as a m odel.
This helped
to c larify som e of the re s u lts obtained in the oth er m ethods u sed fo r hydration.
Investigation of the hydroboration of 3 -m ethycyc lohexene has been m en ­
tioned before as being studied by Brown, who found e sse n tia lly equal addition of
boron to C -I and C - 2 ^ .
P asto in a m o re d etailed an aly sis found that the addi­
tion tra n s to the m ethyl group was favored w ith the o v erall addition again being
e q u a l^ (figure 22 ).
When the compound was subjected to hydroboration with
d isiam ylborane th e re w as no e x trem e d ifferen ce between addition at C -I and C 2; a co n sid erab le d e p a rtu re fro m ex am p les in the acyclic sy ste m s
H
F ig u re 22:
P a s to 's w ork on H y d ratio n of a lk e n e s .
. However,
—30—
when Brown re a c te d 3 ,3 -dim ethylcyclohexene th e re was a s te r ic in teractio n
noted in the p ro d u ct ra tio
OA
.
Since evidence gained fro m th is m odel compound has a stro n g b earin g on
th is re s e a rc h , re -e v a lu a tio n of th e se re a c tio n s was undertaken.
The pinacol
re a rra n g e m e n t w as not u sed due to the la rg e num ber of side p ro d u cts which
m ade the an aly sis of the ketones difficult and u n reliab le.
Table 3.
R esu lts are shown in
Good ag reem en t w as found in e x p erim en t I w ith both Brow n35 and
P a s to rs 35 r e s u lts .
H ow ever, the re s u lts of ex p erim en t 2 w ere not in a g re e ­
m ent w ith those of Brow n but can be well ra tio n a liz ed by a m echanism to be
p roposed la te r .
In all of the c a se s exam ined the m ethyl group has m aintained its ability
to d ire c t addition both in the e le c tro n ic and s te r ic c a s e s .
T his is p a rtic u la rly
evident in the case of ox y m ercu ratio n w here it is evident th a t C-2 is much m o re
capable of displacing the acetate group fro m m e rc u ric a cetate than C - l.
T his
e le c tro n ic effect, in com bination w ith a seem ingly sm all s te r ic effect, can be
nationalized by the concept of ally lie s tr a in 3
in which 3-m eth y l cyclohexene
t alees the p re fe rre d conform ation th at h as the m ethyl group in the axial position.
In th is A ^ ’ 2) conform ation the m ethyl group allow s fo r b o tto m -sid e attack
w hile also reducing s te r ic in te ra c tio n as is p o ssib le in A (figure 23).
-3 1 -
TABLE 3
H ydration of 3-m ethycyclohexene.
METHODS OF HYDRATION
PRODUCT RATIOS
I)
B2H6
54
46
2)
D isiam ylborane
67
33
3)
O xym ercuration
12
88
4)
Pinacol R earran g em en t
No observed ketone
p ro d u cts
-3 2 -
F ig u re 23:
C onform ational is o m e rs of 3-m ethylcyclohexene.
S till, the m ethyl group can p a rtic ip a te in its inductive effect m aking C-2
e le c tro n ic a lly the m ore favorable of the two addition s ite s .
T his argum ent is
co n sisten t w ith B row n's o bservatio n th at 3 ,3 -dim ethylcyclohexene d ire c ts addi­
tio n in predom inantly one d ire c tio n , because in the A ^ '
conform ation, one
m ethyl group s till c re a te s a s te r ic in te ra c tio n (figure 24).
F ig u re 24:
M ethyl group in te ra c tio n s in 3 , 3-dim ethylcyclohexene.
-3 3 -
Re turning now to the alkene (3) sy ste m , fo r which the com bined re s u lts
a re lis te d in Table 4, it is in te re stin g to note th at in two out of the th re e c a se s
the r e s u lts w ere not in ag reem en t w ith those of the sim ple 3 -m ethylcyclohexene
sy ste m .
The m odel would suggest th at the h y d roboration re a c tio n 2 should go
predom inantely in the d ire c tio n of C-5 because th e re would s till be the p o s sib i­
lity of attack fro m the bottom sid e.
In the c ase of o x y m ercu ratio n since the
h ig h er e le c tro n c e n te r should be at the C-6 c e n te r because of the induction of
e le c tro n s fro m the m ethyl group.
is th is tru e .
H ow ever, re s u lts show th at in n eith er case
Why then a re the re s u lts in such d isag ree m e n t w ith the m odel
sy ste m ?
The only p o ssib le elem en t th at could influence th is re a c tio n would be an
in te ra c tio n caused by the oxygen atom .
" s u p ra -a n n u la r" in te r a c tio n ^ ,
T his effect has been r e f e r r e d to as a
if one analyzes the space fillin g model a d ia ­
g ra m m ay be draw n as shown in figure 25.
T his su p ra -a n n u la r effect of the
oxygen c au ses a sh ift in the e le c tro n density about the pi bond.
T h erefo re the
hig h er co n cen tratio n of e le c tro n charge is at C-5 and th is would cause the d is ­
crepancy betw een the m odel and the alkene (3).
The 50 :50 m ix tu re re su ltin g fro m the re a c tio n of 3^ w ith diborane can be
ra tio n a liz e d by a com bination of: I , little s te r ic effect; 2, oxygen p a rtic ip a tio n
which m ight com pensate fo r any sm all s te r ic effect; and 3, the n o n -d iscrim in atio n
TA B LE 4.
H ydration of 4 -M e th y I-c is -3 a , 4, 7a, 7, tetrah y d ro p h th alan .
O
1 . ) H ydration
----------------------- =»
2 . ) Jones oxidation
METHODS OF HYDRATION
PRODUCT RATIOS
I)
D iborane
60
40
2)
D isiam ylborane
38
62
3)
O xym ercuration
18
82
4)
Pinacol R earran g em en t
85
15
—35 —
F ig u re 25:
E ffect of oxygen atom on alkene (3) sy stem .
of the s te ric a lly sm a ll diborane and its re la tiv e ly high re a c tiv ity .
C onsidering
only the s te r ic e ffe c ts, one would expect a slig h t favor of boron attack at C-6
w ith disiam y lb o ran e.
H ow ever, the oxygen p a rticip atio n com plexed with a
"tw ist conform ation" r e s u lts in a slig h t p re fe re n c e of addition at C-5.
In the
re a c tio n of m e rc u ric acetate the m ech an ism would suggest th a t the carbon w ith
the highest e le c tro n density would be the one th at would d isp lace the acetate ion.
The su p ra -a n n u la r in te ra c tio n of the e th e r oxygen, as alread y indicated has
-3 6 -
shifted the e le c tro n density tow ards C -5.
T hus, d isp lacem en t would be by C-5
and the pred o m in ate ketone would be at C -6, w hich was the c a se .
F in ally , it
is also p o ssib le to ra tio n a liz e the re s u lts of the pinacol re a rra n g e m e n t.
T his
re a c tio n p ro c e ed s v ia a carbonium ion m ech an ism and the m odel would suggest
th a t the C-6 carbon would be the m o re stable of the two p o ssib le ions and the
m a jo r p ro d u ct would then be the C-5 ketone (9).
PART in
RING
EXPANSION
OF
ALKENE
The next question involved in the p ro je c t was that encountered in ring
expansion.
The p roposed m ethod was that using diazom ethane to rin g enlarge
the ketone obtained from hydration.
A la rg e amount of the w ork in the lite r a ­
tu re has shown that rin g expansion re s u lts in s e v e ra l p o ssib le pro d u cts depend­
ing on the conditions39 (figure 26).
F ig u re 26:
The diazom ethane re a c tio n with the ketone
Ring expansion of m ethyl-cyclohexanone.
(10) would then re s u lt in two ketone p ro d u cts (figure 27).
It w as fe lt that if one
of th ese ketones could be synthesized by an a lte rn a te m ethod then the id en tifica­
tio n of the p ro d u cts would be e a s ie r .
Ketone (19) w as chosen because it w as
fe lt to be the e a s ie r of the two to sy n th esize.
T his feeling w as in light of p r e ­
vious synthetic w ork by Mundy, and m entioned in the introduction.
The only
difference is in the two sy n th eses in the lack of one m ethyl group in the sta rtin g
—38 —
CE.
CE,
CH,
CE,
O
O
O
2
17
10
F ig u re 27:
m a te ria ls .
18
19
Ring expansion of the ketone (10).
The approach to th is sy n th esis is shown in fig u re 28, startin g with
the alread y available alkene (3).
The alkene (3) w as tre a te d w ith p e rfo rm ic acid, followed by h y d ro ly sis,
to give the tra n s diol (14) in reaso n ab ly good y ield s.
T his diol was then cleaved
w ith sodium bism u th ate, according to the m ethod of Rigby4 0 , to give an u n cy clized aldehyde (20) th at w as im m ediately red u ced with lithium alum inum hydride
to the diol (21).
In fra re d an aly sis of the crude aldehyde did indicate th a t the product w as
uncyclized, and fu rth e r p u rificatio n was not attem pted due to the instability of
th is type of sy stem .
The diol (21) w as then converted to the d ito sy late d eriv ativ e (22).
P u r i­
fication of the uncyclized sy stem w as done at th is point and the in fra re d an aly sis
-3 9 -
proved it to be the expected d ito sy late.
Cyanide d isp lacem en t of the tosylate in
anhydrous dim ethylsulfoxide re s u lte d in the d e sire d dicyanide (23) which was
hydrolyzed to the diacid (24).
The p y ro ly sis of the diacid in the p re se n c e of b ariu m hydroxide and
pow dered iro n yielded the cycloheptanone rin g sy stem (25). In fra re d an aly sis
showed the lo ss of the acid function w ith the re te n tio n of the stro n g carbonyl
peak (appendix, page 81).
Gas chrom atography showed the p ro d u ct to contain
one m a jo r peak th at had a re te n tio n tim e som ew hat lo n g er th an the cyclohexan­
one sy ste m s.
w eight of 168.
The m a ss sp ec tru m of th is sy stem also showed it to have a m a ss
It also fo rm ed a 2,4 -d in itro p h en y lh y d razo n e d eriv ativ e.
The
s im ila rity in the frag m en tatio n p a tte rn of th is compound (25) and the cyclohex­
anones (9) and (10) would suggest th a t indeed 25 is the cyclized compound.
Now having one of the rin g expansion pro d u cts it w as p o ssib le to go
ahead w ith the diazom ethane rin g expansion ex p erim en ts.
P rev io u s w ork r e ­
p o rte d in the lite ra tu re suggest th a t a c a ta ly st is n e c e ssa ry to reduce the am ount
of epoxide fo rm atio n and at the sam e tim e help in the rin g e x p a n s io n ^ .
W ork
w as f ir s t done on a m odel sy ste m to in su re th at expansion w as taking place.
R eaction w ith m ethyl cyclohexanone showed th a t when alum inum chloride w as
u sed in c ataly tic am ounts and the d iazom ethane w as g e n erated in e x c e s s, rin g
expansion did take place (Table 5);
-4 0 -
F ig u re 28 : Unambiguous sy n th esis of the expansion product (25).
T A B L E 5.
Ring expansion of the m odel cyclohexanone.
C atalyst
D iazom ethane
(m ole/m ole)
CHoN9./C«Hin
Type of
CHgN2
addition
(h r.)
T im e
before
w ork-up
Solvent
Expansion
Product
1:1
in d ire c t (a)
none
e th e r
none
BF3
1 :1 0
in d ire c t
none
e th e r
none
BFg
1 :3 0
in d ire c t
18
e th e r
none
BF3
1 :3 0
d ire c t (b)
18
e th e r
none
BF3
1 :3 0
d ire c t
18
ethanol
tra c e
d ire c t
18
ethanol
20%
AlCl3 (c)
H
CO
O
BF3
AlClg (d)
1 :3 0
d ire c t
18 .
ethanol
none
AlClg (e)
1 :3 0
d ire c t
18
ethanol
none
(a) Solution of d iazom ethane p re p a re d and then a p o rtio n w as added to the ketone.
(b) D iazom ethane g en erate d in situ w ith the ketone.
(c) Anhydrous AlClg le ft open to the atm o sp h ere fo r two days.
(d) Anhydrous AICI3 .
(e) U nactivated A lClg.
-4 2 -
A pplication of the rin g expansion to Ij) did indicate that th e re w ere in ­
deed two expansion p ro d u cts.
This was indicated by gas chrom otographic analy­
s is , which indicated that the syn th esized ketone (25) and one of the expansion
products (14) had exactly the sam e re te n tio n tim e s .
(Compounds 1_9 and 25_
have now been e sta b lish e d as the s a m e .) The o th er peak w as felt to be the o th er
expansion p roduct, and had a very s im ila r re te n tio n tim e (figure 29).
The m a ss
18. 5 m in.
1 5 .3 m in
F ig u re 29:
C om parison of gas ch ro m ato g ram s of expansion p ro d u cts.
of the expansion p roducts showed both peaks to have exactly the sam e m /e
-4 3 -
values; w ith the m a ss sp e c tru m of the second peak having the sam e frag m en ta­
tion p a tte rn as th a t of the synthetic ketone (appendix, pages 90 and 91 ). Gas
chrom atographic collection of th ese rin g expanded ketones and the subsequent
in fra re d a n aly sis showed both peaks to contain the stro n g carbonyl and reten tio n
of the te trah y d ro fu ran y l rin g sy ste m .
N uclear m agnetic reso n an ce of the d e­
s ire d ketone showed the product to contain the c o rre c t sp ec tru m fo r the assigned
s tru c tu re (appendix, page 85). It is also in te re stin g to note th at th e re was no
epoxide form ed th at c o rresp o n d ed to the m /e of the proposed epoxide (17). The
m a ss sp ec tru m indicated a compound th at had a m a ss ion of 182, however,
th e re is som e indication th a t th is m ay be an epoxide of the s tru c tu re (26). T his
O
idea is a re s u lt of the g as ch ro m ato g ram which shows th is compound to have a
m uch s h o rte r re te n tio n tim e than the ketones (9) and (10) (figure 30).
The p o s ­
sib ility of the compound being an eight m em b ered ketone sy ste m could be e li­
m inated on the b a sis of a sh o rt re te n tio n tim e .
A high m o le c u lar weight ketone
such as th is should be re ta in e d until a fte r ketones (18) and (19) have come off
the colum n.
The m a ss sp ec tru m (appendix, pages 90 and 91 ) is v ery s im ila r
to th a t of the expanded k eto n es.
The in fra re d sp ectru m shows no carbonyl
—4 4 —
ab so rption which helps to elim in ate the idea of a ketone.
m /e 182
-e-ti m in.
F ig u re 30:
Gas c h ro m ato g ram of product obtained
from rin g expansion.
R esu lts would indicate that the p o ssib le rin g expansion of ketone (10)
would not provide a useful m ean s fo r the p re p a ratio n of the d e sire d cy clo heptanone sy stem .
The d e sire d expansion product was the m ajo r is o m e ric
product, but the o v erall yield of th is ketone was not v e ry high (less than
5%).
Why d o e sn 't the rin g expansion w o rk ?
One m ight suggest that it is
due to the s te r ic lhnderance to attack at the carbonyl carb o n , o r to fu rth e r
su p ra -a n n u la r in te ra ctio n .
A lso, it is not unreasonable to suggest that a
-4 5 -
n e c e s sa ry 1 ,3 in te ra c tio n (eith er C- • •« C, o r C- • - O) in the tra n sitio n sta te
m ight inhibit the re a c tiv ity .
H ow ever, at th is tim e th e re is not enough e v i­
dence to support e ith e r p o ssib ility .
PART
IV
The effects of the oxygen h etero ato m w as of in te re s t because of its d ir ­
ective effects.
A nother heteroato m that w as of in te re s t was the su lfu r atom.
Since the sy n th esis of (28) w as re la tiv e ly e asy , we looked into its effect on
oxym ercuration.
The hydration (figure 31) was c a rrie d only as fa r as the a lco ­
hols (29) because oxidation of the alcohols would have re su lte d in the d estru ctio n
28
F ig u re 31:
Synthesis of su lfu r sy stem alcohols (29).
of the tetrahydrothiophene rin g .
T h erefo re the d irectiv e effect was com pared
by using the alcohols of the oxygen sy stem as stan d ard s.
Gas chrom atographic
re te n tio n tim e s of the alcohols of the su lfu r sy stem w ere s im ila r to those of
-4 7 -
the oxygen sy stem .
As it turned out the su lfu r sy stem alcohols w ere c ry s ta l so
p u rifica tio n and then gas chrom ato g rap h ic an aly sis gave the unam bigious in fo r­
m ation on the alcohol ra tio s (figure 32).
Oxygen sy stem
15 m in.
13 m in.
S u lfu r sy ste m
27 m in.
21 m in.
F ig u re 32:
C om parison of alcohol re te n tio n tim e s .
If one a ssu m e s th at the is o m e r re te n tio n tim e in the gas c h ro m ato ­
grap h of the oxygen sy stem can be co m pared w ith the su lfu r compound, then the
o x y m ercu ratio n of the su lfu r compound would give approxim ately an equal m o la r
ra tio of the alcohols.
—4 8 “
The r e s u lts of the su lfu r sy stem fit v e ry w ell w ith the o th er inform ation.
If one extends the id ea of the e le c tro n s of the oxygen sy ste m to th at of the s u l­
fu r it is found th at the d o rb ita ls of the su lfu r atom Will be influencing the
e le c tro n s of the double bond,
Since th e se oybitals a re a little la rg e r and w ill
encom pass a w id er u re a the d ire c tiv e effect w ill bp d ep rp ased .
At the sam e
tim e it would be expected th a t the re a c tiv ity of the Sulfur pompound would be
slo w er than any o th e rs. T his w as quulitatively observed in th a t the oxygen s y s ­
tem w as com pleted in s e v e ra l m inutes w hile the su lfu r sy ste m w as com pleted
in two h o u rs.
O ther evidence supporting th is id ea w as obtained through a nuc­
le a r m agnetic study of m ethylcyclohexene (30), alkene (3), and the su lfu r
alkene (28). It w as significantly noted th a t th e re w as a sh ift in the alkene p r o ­
tons w ith the in c re a sin g siz e of the h etero ato m s (figure 33).
T his would say
th a t the h e tero ato m is shielding th e se p ro to n s and causing the shift upfield.
At th is tim e we a re not p re p a re d to fully d iscu ss the m echanism or the
ste re o c h e m ic a l consequences of the re a c tiq n .
However, the known su lfu r-
m e rc u ry affinity as evidenced by d en atu ratio n of S-containing p ro te in s, coupled
w ith the reaso n ab le y ield s of alcohol pro d u ct obtained, le a d s to the in te re stin g
problem of what is the ro le of the h etero ato m in influencing chem ical re a c tiv ity .
-4 9 -
5 9 .1
CH
3
30
I
6 .0
»
5 .0
F ig u r e 33 : N m r c o m p a ris o n of com pounds in cp s.
I
1 .0
PART
SYNTHESIS OF
THE
V
SEX ATTRACTANT
BREVICOMIN
As p a rt of the p ro g ram concerned with oxygenated s y ste m s , w ork in our
la b o ra to ry showed th at in the absence of w a te r an in te rn a l hydroxyl group could
p a rtic ip a te in the ox y m ercu ratio n re a c tio n (figure 34).
F ig u re 34:
In tern al cy clizatio n w ith m e rc u ric a ce ta te.
Since 32 b e a rs a s im ila rity to the in sec t sex a t t r a ctan t, brevicom in (34),
we undertook a sim ple sy n th esis of th is im p o rtan t compound (figure 35).
F ig u re 35:
T he s e x a ttr a c ta n t b re v ip o m in .
-5 1 -
T his sex a ttra c ta n t, brey ico m in , is re le a s e ^ by the b a rk beetle, Dendroctonus b re v ic o m is.
T h e re a re m any re a so n s fp r th is In te re s t; the m ajo r
one being th at th is beetle alone is resp o n aib le fo r the d e stru c tio n of the equiva­
le n t of five billion b o ard feet of tim b e r each y e a r ^ ,
about six tim e s the am ount caused by fir e .
T his fig u re re p re se n ts
At the p re s e n t tim e th e re is no
effective control of th e se b e e tle s.
The p ro c e s s through which th e d e stru c tio n tak es place begins with the
attack of a few b a rk b e e tle s upon the tr e e s which; is then followed by a la rg e
secondary invasion w hich eventually k ills the tr e e .
W hile the in itia l b e etles a re
boring into the tr e e to c o n stru c t a nuptial ch am b er, they e x c re te f r a s s , a m ix ­
tu re of fe c al p e lle ts and wood frag m e n ts.
Contained in the f r a s s is an a ttr a c t­
ant w hich c au ses the seco n d ary invasion.
This a ttra c ta n t is produced by the
fem ale and it a ttra c ts the m ale.
A c o n sid erab le am ount of r e s e a r c h w as c a r rie d out to tr y and iso la te the
a ttra c ta n t and c h a ra c te riz e its s tru c tu re in hopes th a t if m ight be used in som e
way to control th e se b e e tle s.
The iden tificatio n of the a ttra c ta n t w as accprnpfished by iso latio n of 2 mg
of the .active compound fro m 1.5 Kg of f r a s s .
S ilv e rste in in 1968
It was id en tified by R. M.
AQ
B rev ico m in h as re c en tly been sy n th esized by two independent m ethods.
—5 2 —
S ily erste in 4^ (figure 36) w as the f ir s t to malce th is compound and it was la te r
Synthesized by H. W0 W asserm an 4^ (figure 37). In both c a s e s the sy n th eses
S-re re la tiv e ly long and involved w ith a few ch em icals th at cau se the expense of
th e se m ethods to be r a th e r high,
It w as fe lt th a t w ith the s im ila ritie s betw een the cyolized compound (32)
and b rev ico m in (34) th a t we m ight be able to approach the sy n th esis of b re v icom in in a le s s expensive way w ith few er s te p s .
Synthetic route shown in fig u re 38.
i
The sy n th esis involved the
O
Il
'C - C H 3
l.)H B r, H2O
)
2 .) HOCH2CH2OH,
-5 3 -
O
O
CK3 _ " c ( d H 2 )2 B r
H2 °
O
H2/ Ni()Ac)2
CH3- " C(CH2 )3-CaCCH2CH3
NaBH,
I
CH3- >
m -ch lo ro p erb en zo ic
---------- ------------------- a
a c id
I
A > 3 - C=CHCH2 CH3
I
I
O
O
CH0 _ r c i C H 2)3- C — CHCH,CH
2— 3
A
CIS
F ig u r e 36: S ilv e r s te in 's s y n th e s is of b re v ic o m in .
—54—
D ecarboxlyation
210° / base w ashed
s e a le d tube
F ig u re 37 : W a s s e r m a n 's s y n th e s is of b re v ic o m in
-5 5 -
CH3x^ O
EtM gBr
36
34
F ig u re 38.
Synthesis of brevicom in
The two s ta rtin g m a te ria ls a c ro lie n and m ethyl vinyl ketone, which
a re both re la tiv e ly inexpensive, would through a D ie ls-A ld er re a ctio n lead
to the pyran d e riv a tiv e (35).
The conditions under which the D iels-A ld er
re a c tio n would re s u lt in the d e sire d p ro d u ct w ere e sta b lish e d a fte r som e
ex p erim en tatio n (Table 6).
by B uchi46.
S ystem s v e ry s im ila r to th e se have been m ade
A nalysis of the product fro m th is re a c tio n by gas chrom atogra
phy showed th re e stro n g peaks.
T hese peaks m ight be attrib u te d to the pos
sib le p ro d u cts shown in figure 39.
T his m ix tu re of aldehydes and ketones
“56-
TABLE
6.
D ie ls-A Id er re a c tio n fo r fo rm atio n of 2 -carb o x ald eh y d e- 6m eth y l- 3 , 4 -d ih y d ro -2 H -p y ran .
A crolein
(g)
5
M ethyl Vinyl
Ketone
(S)
10
5
10
5
' 10
10
Benzene
Solvent
(ml)
15
Tim e
(hr o)
T em p.
(°C)
R esu lts
180
Alcohol
p re sen t
2
180
Low
yield
(0.5 g)
2
180
yield
(2g)
180
yield
(6g)
I
25
25
2
30
5
80
1.5
180
yield
(8g)
30
15
80.
2
180
yield
(18 g)
-5 7 -
was c a r r ie d on to the next step without fu rth e r attem pt at sep a ra tio n .
CH3
F ig u re 39:
P o ssib le p ro d u cts fro m the D ie ls-A ld er reactio n .
The G rig n ard addition to the carb o n y ls w as c a r rie d out and the alcohol
p roducts w ere iso la ted w ithout any com p licatio n s.
Again, gas chrom atography
of th ese alcohols showed th e re to be th re e com ponents.
O xym ercuration in the absence of w ater nicely con v erted the alcohol
product to a cyclic sy ste m .
Gas ch rom atographic co m p ariso n of a known s a m ­
ple of brevicom in (obtained from Jim L otan, U. S. F o re s t S ervice) showed the
product to contain b revicom in.
Separation of a sam ple and the in stru m en tal
a n aly sis of it showed brevicom in to be identical with the sy n th esized compound
(in fra red , n u clear m agnetic reso n an ce, and m a ss sp ectro g rap h y ; appendix,
p ag es 82, 86, and, 92.
The o v erall y ield s at the p re s e n t tim e a re not c o n sid ered to be at the
optim um level but with a little fu rth e r w ork it is felt it can be in c re ase d .
PA R T
VII
EXPERIMENTAL
SECTION
Th,e in fra re d s p e c tra w ere re c o rd e d on a B eckm an IR -S , using polysty­
ren e as the stan d a rd .
NMR s p e c tra w ere re c o rd e d on a V arian A-60 using
TMS as. an in te rn a l stan d a rd and d eu tero ch lo ro fo rm as the solvent.
and boiling points a re u n c o rre c te d and a re in d eg rees c en tig rad e.
The m elting
Gas ch ro m a ­
to g rap h ic analysis w ere p e rfo rm e d on an F & M Model 400 unit, using a hy d ro ­
gen flam p d e te c to r and D isc in te rg ra to r.
A nalytical d ata followed by (*) w ere
kindly obtained fro m P ro fe s s o r K rapcho, and have not been re p o rte d in the
lite r a tu r e .
C is-S -M eth y l-4 -C y clo h ex an e-C is, C is-1 ,2 -D ic arb o x y lic Acid Anhydride (I ) :
In 50 m l of benzene, (52 g, 0.76 m ole) of p iperyline w as dissolved.
mijxtpre was s tir r e d and heated to a gentle reflu x .
added.until a slig h t re d co lo r rem ain ed .
The
A few c ry s ta ls of iodine w ere
To the m ix tu re w as added m aleic an­
hydride (52 g, 0.53 m ole) disso lv ed in 200 m l of benzene, o v er a th re e hour
p e rio d .
A fter the addition had been com pleted the solution w as allowed to reflu x
fo r an additional th re e h o u rs.
duced p re s s u re d istilla tio n .
The e x c e ss benzene was then rem oved by r e ­
The c o n cen trated m ix tu re w as allow ed to re m a in
a t room te m p e ra tu re overnight, a fte r which a solid had fo rm ed .
This crude
m a te ria l w as then filte re d and w ashed w ith cold ethanol, to rem ove the e x ce ss
benzene and iodine.
The re su ltin g w hite c ry s ta ls (51 g, 97%) had a m elting
-5 9 -
range of 61-62° (lit. ^ 7 , 61°).
C is-3 -M eth y l-4 -C y clo h ex e n e-C is, C is-1 ,2 -d im e th a n o l (2):
The anhydride (60.0 g, 0.36 m ole) w as dissolved! in 600 m l of anhydrous
e th e r.
The solution w as added during a five hour p erio d to a refluxing solution
p re p a re d from lithium alum inum hydride (15.2 g, 0.40 m ole) in 600 m l of anhy­
drous e th e r,
When the addition w as com pleted, the m ix tu re w as refluxed fo r
an additional 24 h o u rs.
A fter th is tim e , the re a c tio n m ix tu re w as then cooled,
and sufficient wet e th e r w as added to hydrolyze the alum inum s a lts .
s a tu ra te d aqueous solution of R ochelle s a lts was then added.
A 100 m l
The m ixture was
s tir r e d fo r an additional hour and the s a lts w ere then filte re d fro m the solution.
The e th e r filtra te w as d rie d w ith m agnesium sulfate and co n cen trated at
red u ced p re s s u re (0.5 m m Hg), y ield 33.0 g (59%).
In fra re d a n aly sis showed a stro n g broad peak fo r the -OH and also th a t
no qarbonyl re m a in ed in the product.
4 -M ethyl-c i s -3 a , 4 , 7 , 7 a-te tra h y d ro p h th a la n (3):
In 40 m l of dry pyridine was d isso lv ed the diol (2), (21 g, 0.13 m ole).
T his solution was heated to reflu x while a solution of to sy lq h lo rid e (38 g, 0.2
m ole) In 40 m l of pyridine w as slow ly added.
The re a c tio n m ix tu re was allow ed
to re m a in at reflu x fo r about 12 h o u rs, a fte r which tim e it w as cooled and
poured o v er an ic e -s u lfu ric acid s lu rry .
The product w as e x tra c te d with
-6 0 -
pentane and w as d is tille d to y ield 14 g (73% yield) of a w a te r -c le a r liquid having
a boiling range of 44-48° at 0.2 m m Hg.
The in fra re d sp e c tru m (KBr p late)
showed the c h a ra c te ris tic e th e r linkage of te tra h y d ro fu ran d e riv a tiv e s at 9.2 ju
(1087 c m -1 ).
A n a k Ctt) C alcd. fo r C9H14O:
Found:
C, 78.21; H, 10.21
" C, 78.00; H5 10.14
H ydration of (3) fry H ydroboration:
The alkane (3.49 g, 0.24 m ole) w as d isso lv ed in 15 m l of dry te tra h y d ro ­
fu ran to which sodium borohydride (1.43 g,, 0.37 m ole) w as added.
The re a c tio n
m ix tu re was placed under nitro g en a tm o sp h ere a fte r w hich b o ro n triflu o rid e
e th e ra te (9.3 g, 0.065 m ole) w as slow ly added.
0°.
The re a c tio n w as p erfo rm ed at
H ydrolysis of the boron com plex w as affected by adding 10 m l of w a ter
sa tu ra te d e th e r, followed by 5 m l of w a te r.
A solution of 4M NaOH (10 m l),
followed by 10 m l of 30% hydrogen peroxide com pleted the h y d ro ly sis.
The
re a c tio n m ixture was allow ed to w arm to room te m p e ra tu re and s tir fo r 12
h o u rs.
E x trac tio n w ith e th e r yielded the crude alcohol m ix tu re .
The alcohols
w ere p laced in an E rle n m e y e r fla sk w ith 20 m l of analytical g rad e acetone.
T his fla sk w as placed in a w a ter bath so as to m ain tain the solution at 25°.
To
th is w as added dropw ise the Jones re a g en t; m ade up to 50 m l w ith w a te r, until
an o range-brow n c o lo r re m a in ed .
The m ix tu re was then e x tra c te d th re e tim e s
I
-6 1 -
w ith m ethylene chloride and back e x tra c te d tw ice w ith w a te r.
The m ethylene
chloride w as then d rie d w ith m agnesium sulfate and reduced in volum e, yielding
the ketones (9) and (10) in alm o st quantitative yield.
The ketones could be sep a ra te d on a 6 foot x 6 m m g la ss column packed
w ith 2 OM carbow ax on 30/60 m e sh fire b ric k o r by colum n chrom atography u ti­
lizing a 30 m m x 60 cm w a te r cooled colum n packed w ith s ilic a gel (14 g s ilic a
gel G, 30 m l of HgO, activ ated fo r 45 m inutes) and eluted w ith solvent (chloro­
fo rm : e th e r : pentane : 55 :28 :17).
The identity of £ w as e sta b lish e d by deu­
te riu m exchange, re s u ltin g in the lo s s of the m ethyl doublet.
fe a tu re s could be noted in the in fra re d s p e c tru m s.
No distinguishing
The NMR s p e c tra of the
ketones w ere co n siste n t w ith the assig n ed s tru c tu re s .
The 2 , 4-dinitrophenylhyd razo n es of 0 a n d IOwere p re p a re d :
10 m l. 164-5
and 9 mp. 176-7
Anal: C alcd. fo r C i rHi r N^O e;:
c,
53.89; H, 5.43
Found:
10
c,
53.91; H, 5.31
9
c,
53.92; H, 5.55
D eu teratio n of 2-m ethylcyclohexanone:
A gas chrom ato g rap h ically p u rified sam ple of 2-m ethyl-cyclohexanone
(0.25 g) w as s tir r e d w ith 2 m l of d eu teriu m oxide at room te m p e ra tu re , to
which had been added 500 m g of sodium .
T his re a c tio n m ix tu re was s tir r e d fo r
—62—
24 h o u rs.
The aqueous solution w as e x tra c te d th re e tim e s w ith carb o n te tra c h lo r­
ide and then d rie d ov er sodium su lfate.
The e x tra c ts w ere th en concentrated
to the point at which reso n an ce sp ec tru m could be taken.
The above p ro c e d u re w as also u sed fo r d eu teriu m exchange of the ketones
(9) and (10). The am ount of sodium , how ever, w as red u ced to 250 mg.
P re p a ra tio n of B is - 3 -m e th y l- 2 -butylborane (d isiam y lb o ran e):
In a th re e neck 500 m l flask equipped w ith a co ndenser and dropping fun­
nel, w as placed 80 m l of d ry m onoglym e, 23.1 g (0.33 m ole) of 2-m e th y l- 2 butene in 20 m l of dry monoglym e and 4.7 g (0.125 m ole) of sodium borohydride.
The fla sk w as placed in an ic e -b a th and the sy stem purged and placed under
nitrogen atm o sp h ere.
Then 23.5 g of b o ro n -triflu o rid e e th e ra te was added d ro p -
w ise over a 30 m inute perio d .
The s e m i-so lid re a c tio n m ix tu re w as p e rm itte d to re m a in an additional
15 ho u rs at 0°.
The hydroboration w ith d isiam y lb o ran e of the alkene w as then c a r rie d
out in the u sual m an n er followed by Jones oxidation.
The p ro d u ct was then su b ­
je c te d to gas chrom atographic an aly sis showing the p ro d u cts to be 38% 9 and
62% 10.
-63-
4 -m e th y l-c is -5 , 6 -h y d ro x y -c is-3 a , 4 , 7 a , -hexahydrophthalan (13):
The alkene (3) (4 g, 0.03 m ole) in 42 m l of w ater w as s tir r e d vigorously
and to th is was added a solution of p o tassiu m perm anganate (4.6 g in 100 m l of
w ater) at a ra te so as to m aintain the te m p e ra tu re at 5°.
A fter the addition w as
com pleted the jn ix tu re w as s tir r e d fo r 15 m in u tes and then left to stand at ro o m
te m p e ra tu re overnight.
The w a te r solution w as e x tra c te d th re e tim e s w ith dichlorom ethane and
the co n cen tratio n of th is solution yielded (2.5 g, 50%) of a c ry sta llin e compound
w ith a m elting range of: 92-4°.
The crude product w as re c ry s ta lliz e d fro m ch lo ro fo rm and skelly B. to
give a w hite c ry sta llin e product w ith a m elting range of 99-100°.
The in fra re d
sp e c tru m (potassium brom ide pellet) exhibited a bro ad , stro n g -OH region.
A nal: C alcd. fo r C9H i6O3 :
C, 62.76; H, 9.37
Found:
C, 63.17; H, 8.95
M ass spec, m /e : 172
4 -m e th y l- tr a n s - 5 , 6 -h y d ro x y -c is-3 a , 4, 7 a , -hexahydrophthalan (14):
The alkene (3) (11.1 g, 0.08 m ole) w as added dropw ise to a s tir r e d and
cooled solution of p e rfo rm ic acid (p rep ared fro m 13 g of 31% hydrogen peroxide
and 55 m l of 90% fo rm ic acid).
at 40° during the addition.
The te m p e ra tu re of the m ix tu re was m aintained
T his m ix tu re w as then s tir r e d fo r an additional 20
-6 4 -
hours at room te m p e ra tu re .
The e x ce ss solvent was rem o v ed by vacuum d istilla tio n (w ater a s p ira to r),
w ith slig h t heating.
A solution of sodium hydroxide was added to the rem ain in g
visco u s solution until it w as b a sic .
The b a sic m ix tu re was s tir r e d overnight.
The e n tire m ix tu re w as continuously e x tra c te d with m ethylene chloride
overnight.
The so lid w as filte re d fro m th e solution and ro ta ry evaporation of
solution yielded som e additional p roduct.
The p u re tra n s -g ly c o l (weight 8 g, 70% yield) m e lted at 125-7°.
The in fra re d sp ec tru m (potassium brom ide p ellet) showed a stro n g -OH
s tre tc h at 2.92 /j, (3425 cm~^).
Anal =M C alcd0 fo r C9H16O3 :
C, 62.73; H, 9.36
Found:
C, 62.96; H, 9.58
P ro ce d u re fo r P inacol Re arra n g em en t
In a 250 m l fla sk w ith a re flu x co n d en ser was p laced th e glycol (13)
(4.2 g, 0.02 m ole) in 30 m l of 20% su lfu ric acid.
at .reflux te m p e ra tu re fo r two h o u rs.
20 m l of w a te r.
T his m ix tu re was then s tir r e d
The solution w as cooled and diluted w ith
The aqueous solution w as e x tra c te d th re e tim e s with d ic h lo ro -
m ethane and the com bined e x tra c ts w ere d rie d over sodium carbonate.
R o tary
ev ap o ratio n of the solvent yielded a d a rk brow n oil.
The gas chrom atographic an aly sis of the product showed it to contain no
-6 5 -
significant am ount of ketone pro d u cts.
In a sm all fla sk w as p laced the glycol (13) (0.2 g, 0.001 m ole) and to
th is w as added I m l of co n cen trated su lfu ric acid.
To the m ix tu re was then
added 5 m l of w a te r and then e x tra c te d th re e tim e s with dichlorom ethane.
e x tra c ts w ere d rie d o v er sodium sulfate and co n cen trated .
The
The gas ch ro m ato ­
g rap h ic an aly sis of the product showed a 40% yield of ketones in an 98 :11 ra tio
of £ to 10»
The glycol (14) (0.1 g, 50 m illim o le s) w as placed in a sm a ll flask and to
it w as added I m l of 20% su lfu ric acid.
te m p e ra tu re of 120°.
T h is m ix tu re w as s tir r e d at an oil bath
The m ix tu re w as w orked up in the sam e m anner as the
p revious re a c tio n of th is type.
The gas ch ro m ato g rap h showed only a sm all
am ount of the ketone (9) and s e v e ra l o th er unidentifiable com pounds.
The glycol (14) w as then subjected to the sam e p ro c e d u re as that u sed
fo r the glycol (13) in the p re se n c e of c o n cen trated su lfu ric acid at room te m p ­
e r a tu r e .
Gas ch ro m ato g rap h ic an aly sis of the product obtained from (14)
showed a yield of 59% in ,the ra tio of 85 :15 fo r the ketones (9) and (10) re s p e c ti­
vely.
O xym ercuration
The alkene (3) (13.8 g, 0.1 m ole) w as added to a s tir r e d m ixture of 31 g
of m e rc u ric acetate in 100 m l of w a ter and 100 m l of te tra h y d ro fu ran .
The
-6 6 -
re a c tio n m ix tu re w as s tir r e d until the yellow co lo r had d isap p e a re d and then an
additional five m in u tes.
The flask was p laced in an ice bath and 100 m l of 3M
p o tassiu m hydroxide w as added followed by a solution of 1.9 g of sodium b o ro hydride in 100 pal of SM p o tassiu m hydroxide.
T his m ix tu re was s tir r e d until
a g re y -c o lo re d solution w as obtained and elem en tal m e rc u ry w as observed.
th is tim e 100 m l of a s a tu ra te d solution of sodium chloride w as added.
At
The
m ix tu re w as e x tra c te d th re e tim e s w ith dichlorom ethane and the solution con­
c e n tra te d to yield the crude alcohols.
Gas ch ro m atic an aly sis showed the ra tio s
to be 18% (9) and 82% (10).
H ydration of. 3-m ethylcyclohexane
The hydroboration of 3 -m ethylcyclohexene (30) (0.5 g, 52 m illim o les)
w as c a r r ie d out in the sam e m an n er as th at p ro ced u re fo r the hydroboration of
the alkene (3).
The gas chrom atographic an aly sis of the pro d u cts showed the
ketones (a) and (b) to be in the ra tio of 46 :5 4 . '
The hydroboration, usin g d isiam y lb o ran e, of 3-m ethyl-cyclohexene (30)
(0.5 g, 52 m illim o le s) and using 60 m l of a 0.165 m o la r solution of d isiam y l­
b o ran e, w as accom plished in the sam e m an n er as th at p ro c e d u re used on the
alkene (3).
The gas chro m ato g rap h ic an aly sis of the ketone p ro d u cts showed
a 33 : 67 ra tio of a and b.
The o x y m ercu ratio n of 3 -m ethylcyclohexene was done in the sam e
-6 7 -
m an n er as d e sc rib e d fo r the alkene (3}„ A nalysis by gas ch ro m ato g rap h showed
the ketone ra tio to be 88 :12 fo r a and b re sp ec tiv e ly .
0!-M ethyl-4 -O x a -c y clo p e n ta n e -cis- 1 , 2 -diacetaldehyde (20):
The glycol (2) (3 g, 0.0174 m ole) w as m ixed w ith (6.3 g, 0.023 m ole) of
sodium bism u th ate, 8 m l of w a te r, 15 m l of 33% phosphoric acid and 25 m l of
e th e r.
T his re a c tio n w as p laced in a 100 m l one neck round bottom flask and
s tir r e d at room te m p e ra tu re fo r 16 h o u rs.
phosphate s a lts had tu rn e d g ra y in c o lo r.
At th is tim e , the b ism u th a teThe re a c tio n m ix tu re w as subjected
to vacuum filtra tio n and rin s e d tw ice w ith dichlorom ethane.
The combined
d ichio ro m ethane la y e rs w e re d rie d o v er anhydrous sodium su lfate.
ev ap o ratio n of the solvent yielded 2.5 g ra m s of product.
A sp ira to r
No fu rth e r p u rificatio n
of the product was attem pted due to the known th e rm a l in sta b ility of th is type of
compound.
The in fra re d sp e c tru m (sodium chloride p la te s, neat) showed the c h a r ­
a c te ris tic C -H s tre tc h of the aldehyde group at 3.64 (2740 cm - -*-) and the a ld e ­
hyde group at 5.78 (1725 c m - -*-), also a w eak -OH s tre tc h w as p re se n t.
Q i-M ethyl-O xa-C yclopentane-Cis-1, 2-diethanol (21):
The crude aldehyde (20) (2.5 g) in 25 m l of anhydrous e th e r was added to
a refluxing solution of lithium alum inum hydride (1.0 g) in 50 m l of anhydrous
e th e r.
When the addition of the aldehyde had been com pleted, another 100 m l
—68—
of e th e r was slow ly added to the m ix tu re.
The m ix tu re was then s tir r e d fo r an
additional 14 h o u rs, at reflu x te m p e ra tu re .
The solution w as then cooled and a sm all amount of a s a tu ra te d R ochelle
s a lt solution w as added.
A fter th e solution w as s tir r e d fo r an ho u r, the solution
w as filte re d and the s a lts w ere w ashed w ith dichlorom ethane.
The com bined ■
e x tra c ts w e re re d u c ed in volum e to y ield 1.0 g ra m s of a v isco u s oil.
The in fra re d sp e c tru m of the crude pro d u ct showed a stro n g -OH at
2.98 /j, (3360 cm - 1 ) also two carbonyl ab so rp tio n s w ere p re s e n t 5.82 fi, 5.98 p
(1710, 1670 cm - 1 ).
0'-m e th y l-4 -o x a -c y c lo p e n ta n e -c is -l, 2-d ie th a n o l-d i-p -to luene sulfonate (22):
The crude diol (8.64 g, 0.057 m ole), calcu lated on th e b a sis of p u re diol,
w as d isso lv ed in 40 m l of pyridine and w as added dropw ise to a cooled, s tir r e d
solution of p-toluene sulfonylchloride (19.8 g, 0.104 m ole) in 50 m l of p y rid in e.
The addition w as com pleted in one-half hour and the re a c tio n m ix tu re was
s tir r e d fo r two additional h o u rs.
p yridine solution.
At th is tim e a p re c ip ita te had form ed in the
The pyridine solution w as then kept at 0° overnight.
The cold solution w as then poured into ic e -w a te r re s u ltin g in a heavy o il.
The w a te r w as decanted fro m the oil and c ry sta lliz a tio n w as accom plished by
d issolving the oil in e th e r followed by a sm a ll amount of p etro leu m e th er.
addition of ethanol, c ry s ta ls w ere produced.
Upon
The product w as th en filte re d and
—69 —
w ashed w ith e th e r, yielding 6.1 g (70%) of white to sy I a te ,
w ith a m elting range
of 98-9°.
The in fra re d sp ec tru m (potassium brom ide p ellet) showed two stro n g
peaks c h a ra c te ris tic of SOg s tre tc h e s at 7.43 (1348 cm -1 ) and 8.55 (1170 cm""^)
and th a t of the fu r an rin g at 9.12 (1098 cm -1 ).
A nal. (*); C alcd. fo r CggHggOySg:
S, 13.29
Found:
S, 13.47
a ;-M eth y l-4 -o x a -c y clo p e n ta n e-cis-l, 2 -d ip ro p io n itrile (23):
The to sy late (3.0 g, 0.06 m ole) w as s tir r e d w ith p o tassiu m cyanide (2.4
g, 0.043 m ole) in 35 m l of dim ethysulfoxide at room te m p e ra tu re fo r 13 h o u rs.
The re a c tio n was then heated to 85° and w as m aintained at th is te m p e ra tu re fo r
24 h o u rs.
The dim ethylsulfoxide w as then rem oved by reduced p re s s u re d is tilla ­
tion.
A fter rem o v al of m o st of the solvent, the m ixture w as p o ured into an ic e -
w a ter s lu rry .
This w a te r solution was th en continuously e x tra c te d fo r 13 ho u rs
w ith dichlorom ethane,
R otary evaporation of the solvent yielded a yellow co l­
o red solution.
The crude product w as then d istille d in a high te m p e ra tu re high vacuum
a p p aratu s yielding 1.4 g (47%) product at 180-5° at 0.3 m m Hg.
The in fra re d sp ec tru m showed a stro n g absorption fo r C N at 4.48
-7 0 -
(2240 cm"""*") and th a t fo r the te tra h y d rp fu ran rin g at 9.45 (1058 cm - "*").
Anal. (*): C alcd. fo r C n H 16N2 O: C, 68.81; H, 8.40; N, 14.59
Found:
•
C, 68.91; H, 8.59; N, 14.51
jS -M e th y l-4 -o x a-cy c lo p e n ta n e-c is-l, 2-dipropionic Acid (24):
The d in itrile (1.4 g, 0.0074 m ole) w as refluxed fo r 48 h o u rs with 17.8
m l of an aqueous solution of KOH (33% by weight).
The evolution of am m onia
w as noted as an indication of the re a c tio n o ccu rrin g .
The solution w as then cooled to room te m p e ra tu re and acidified w ith
50% phosphoric acid.
A fter 12 h o u rs, at room te m p e ra tu re , a white c ry s ta l
p re c ip ita te d out and 12 h o u rs la te r a d a rk c ream ed co lo red c ry s ta l p re c ip ita ted .
R e c ry sta lliz a tio n fro m hot w a te r yielded white c ry s ta ls 0.55 g (39%)
w ith a m elting range of 128-30°.
The in fra re d sp ec tru m (potassium brom ide p ellet) showed the c h a ra c ­
te r is tic hydrogen-bonded -OH and a sp lit carbonyl w ith the two peaks at 5.72
(1747 p m -1) and 5.91 (1698 cm - 1 ).
A nal. (*); C alcd. fo r C11Hl 6Os:
C, 57.37; H, 7.87
Found:
C, 57.18; H, 7.86
4 -M e th y l-c is-2 -o x a -6 -k e to d e ca h y d ro a zu le n e (25):
An intim ate m ix tu re of the d iacid (0.55 g, 0.0024 m ole), 0.55 g of iro n
pow der and 0.18 g of B arium hydroxide , w ere p laced in a p ie ce of g lass tubing
-7 1 -
w ith a side a rm leading into a cooled co llectio n tube.
h eated w ith a fre e flam e in an a ir bath.
d is tille d from the m ix tu re.
The m ix tu re .was then
W ater d istille d and then a d ark oil
The d a rk oil w as then re d is tille d at reduced p r e s ­
s u re in a m ic ro d istilla tio n ap p aratu s to y ield a yellow co lo red oil.
The in fra re d sp ec tru m of the product showed a stro n g carbonyl peak at
5.88 (1700 cm - -*-) and the te tra h y d ro fu ra n rin g at 9.40 (1062 cm - l) .
The m a ss
sp ec tru m of the product showed the m /e to be 168 and many s im ila ritie s w ere
found betw een it and the six m e m b e r sy ste m s (10) sp ec tru m (appendix, page 89
Und 91 ).
G eneral p ro ced u re fo r rin g expansion
The g en eratio n of d iazom ethane w as accom plished fro m co m m erically
available N -M eth y l-N -nitroso-p -to lu en esu lfo n am id e (D iazaid, A ldrich).
The
ap p aratu s w as s e t up in a w ell v en tilated hood and all g la ss edges w ere th o r­
oughly fire -p o lish e d , due to the explosive n ature of diazom ethane.
The sy ste m
contained no ground g la ss jo in ts, co rk jo in ts w ere u sed exclusively.
Ip a round bottom two neck d istilla tio n fla sk w as p laced 8.7 m l of 95%
ethanol and 1.5 g of p o tassiu m hydroxide in 2 m l of w a te r.
T his solution w as
heated to 70° w ith s tirrin g and a solution of D iazald (5.3 g) in 40 m l of anhydrous
e th e r w as added dropw ise.
The re su ltin g yellow colored d is tilla te was added
d ire c tly into an E rle n m e y e r fla sk containing the re a c ta n ts .
This was
-7 2 -
accom plighed by fitting the co n d en ser w ith an exten sio n so th a t the diazom ethane
w as introduced below the su rfa ce of the solution.
In the E rle n m e y e r fla sk w as p laced 0.3 g of cyclohexanone in 100 m l of
anhydrous e th e r to which had been added a sm all amount of anhydrous alum inum
ch lo rid e.
The alum inum chloride had been left open to th e a ir approxim ately
two days.
A fter the addition of the diazom ethane had been com pleted the solution
w as d a rk yellow in c o lo r, and w as le ft at room te m p e ra tu re overnight.
end of th is tim e the yellow colo r was no lo n g er p re se n t.
At the
The e th e r solution
w as w ashed th re e tim e s w ith w a te r and th en d rie d o v er m agnesium sulfate.
C oncentration of the e th e r solution and g as ch ro m ato g rap h ic an aly sis of the
p ro d u ct indicated a 25% y ield of cycloheptanone.
T his sam e p ro c e d u re , w as then applied to the ketone (10), using tw ice
the am ount of diazom ethane.
The g as c h ro m ato g ram showed a 9 % yield of the
d e s ire d rin g expansion pro d u ct (18) along w ith a 5 % y ield of the ketone (19).
C is-3 -m e th y l-4 -c y c lo h e x e n e -c is , c is - 1 , 2 -d im eth an o l-d im eth an e-su lfo n ate (26) .
The diol (2) (10 g, 0.06 m ole) in 40 m l of pyridine w as added dropw ise
to a cooled and s tir r e d solution of 29 g (0.25 mole) m eth an esulfonyI chloride in
50 m l of pyridine.
The addition w as com pleted in one hour and the m ix tu re was
allow ed to s tir an additional 12 h o u rs.
The solution w as kept at O0 overnight.
-73-
The cold pyridine solution w as p o u red into ice w a ter and an oil w as ob­
tained.
C ry sta lliz a tio n of the oil fro m m ethanol afforded a white cry stallin e
product (16 g, 85%) w ith a m elting ran g e of 59-60°.
The in fra re d s p e c tra m (potassium brom ide p ellet) showed the c h a r a c te r­
is tic -SOg s tre tc h e s at 7.48 (1338 cm - 1 ) and 8.57 (1170 cm - 1 ).
A nal. (*); C alcd. fo r C n H 2OS2Oe:
C, 42.31; H, 6.46
Found:
C, 42.50; H, 6.44
4 -M e th y l-c is -4 , 4 a , 7, 7a-tetrah y d ro -2 -b en zo th io p h en e (27)
In 200 m l of anhydrous ethanol w as p laced 3 g of sodium .
Hydrogen
sulfide w as then bubbled through th is solution until a sa tu ra te d solution was
achieved.
To the s a tu ra te d solution w as added 15 g (0.048 m ole) of the m e sy ­
la te (26) and the m ix tu re w as heated to reflu x .
p re c ip ita te appeared in the solution.
In one half h o u r a heavy white
A nother 100 m l of ethanol was added at
th is tim e and the solution w as s tir r e d fo r 24 h o u rs.
The e x ce ss ethanol w as d is tille d and w a te r w as added to the re sid u e.
T his aqueous solution w as e x tra c te d th re e tim e s w ith dichlorom ethane and the
com bined e x tra c ts d rie d w ith m agnesium su lfa te. R o tary evaporation of the
splvenl and d istilla tio n at red u ced p re s s u re yielded 7.3 g (96%) of product.
. M ass s p e c tra l a n aly sis showed the m a ss ion to be 154.
In fra re d analy­
s is showed the c h a ra c te ris tic s u lfu r-c a rb o n stre tch in g freq u e n cies to be
-7 4 -
p re s e n t (appendix, page 78)..
A nal: C alcd. fo r
C9H14S:
Found:
C, 70.11; H,
9.08; S, 20.81
C, 70.09; H,
9.44; S, 20.91
(5 o r 6 ~ h y d ro x y )-4 -m e th y l-c is-4 , 4 a , 7, 7 a-tetrah y d ro -2 -b en zo th io p h en e
The su lfu r alkene (27) (0.22 g, 1.4 m oles) w as subjected to o x y m e rc u ra tion (sam e p ro c e d u re as d e sc rib e d fo r the alkene (3), page 65) and the c r y s ta l­
line alcohol (yield 0.19 g, 90%) w ere co m p ared to th o se obtained from alkene
(3) when subjected to oxym ercu ratio n .
The gas ch ro m ato g ram showed the a l­
cohols to be in a 55 :45 ra tio .
A nal: C alcd. fo r
Found:
C 9H16OS:
C, 62.73; H,
9.38
C, 62.96; H,
9.35
2- c arboxaldehyde- 6-m e th y l- 3 , 4 -D ih y d ro -2 H -p y ran (35):
In a bomb w e re p laced 30 g (0.54 m ole) of a cro lien , 15 g (0.21 m ole) of
m ethyl vinyl ketone and 80 m l of benzene.
The bomb was th e n sealed and h eated
to 180° and kept at th is te m p e ra tu re fo r two h o u rs with o ccasio n al m ixing.
The
bomb wgs then slow ly cooled to room te m p e ra tu re and the re a c tio n m ixture r e ­
m oved.
The solution w as co ncen trated by ro ta ry ev ap o ratio n and the product
w as d is tille d at 35-40° (2 m m Hg), y ield 18 g ra m s.
s is of the product showed it to be a m ix tu re .
Gas chrom atographic analy­
M ass sp ec tro g rap h ic an aly sis of
each peak p re s e n t showed the m ix tu re to contain a compound of the c o rre c t m /e
-7 5 -
126 fo r the d e sire d p y ra n d e riv a tiv e .
The in fra re d sp e c tru m showed a stro n g
carbonyl ab sorbtion w ith the absence of -OH.
No attem pt w as m ade to iso la te
the d e s ire d product at th is point.
2-hydroxy p ro p y l-6 -m e th y l-3 , 4-D ih y d ro -2 H -p y ran (36)
The ethylm agnesium brom ide w as p re p a re d by the addition of (5.45 g,
0.05 m ole) ethylbrom ide to a m ix tu re of (1.20 g, 0.05 m ole) m agnesium and 80
m l of anhydrous e th e r (containing a sm all tra c e of Iodine).
The re su ltin g m ix ­
tu re w as s tir r e d u n til no tra c e of m agnesium could be d etected .
The aldehyde
m ix tu re (3 g, 0.023 m ole) w as slowly added to the p re p a re d ethylm agnesium
brom ide (0.05 m ole) and the solution w as then hydrolized w ith w ater.
The s a lts
w e re then disso lv ed by acidificatio n of the solution w ith d ilute hydrochloric
acid.
The acidic solution was e x tra c te d w ith dichlorom eth an e.
C oncentration
of the e x tra c ts and d istilla tio n of the cru d e product yielded 4.0 g ra m s of a a l­
cohol m ix tu re.
The d e sire d alcohol w as not iso la te d but c a r r ie d on to the next
step .
16, 8-D ioxabicyclo [ 3.2.1. ] o ct ane -7 -eth y l - 5 -m e thy I (34)
In 75 m l of dry te tra h y d ro fu ran w as placed (9.6 g, 0.03 m ole) of m e r c u r ­
ic a c e ta te .
This m ix tu re w as s tir r e d w ith the addition of the alcohols (4.0 g,
0.03 m ole) fo r th re e h o u rs at room te m p e ra tu re .
The addition of 30 m l of SM
p o tassiu m hydroxide im p a rte d a yellow color to the solution.
A solution of
-76-
30 m l of SM p o tassiu m hydroxide containing sodium borohydride (0.76 g /4 0 m l
of 3M KOH) w as then added to the cooled yellow re a ctio n m ix tu re re su ltin g in a
g ra y solution.
A s a tu ra te d sodium ch lo rid e solution (30 m l) w as then added
and the m ix tu re w as s tir r e d fo r 10 m in u tes.
then e x tra c te d w ith dichlorom ethane.
The solution w as filte re d and
The e x tra c ts w ere co n cen trated by
ro ta ry evaporation and the prod u ct w as d istille d at 63° (12 m m Hg) yielding
3.5 g ra m s of a m ix tu re.
Gas ch ro m atic an aly sis on a 20% carbow ax 20M c o l­
um n showed the y ield of b rev ico m in to be 9%. Iso latio n of b rev ico m in was
accom plished w ith the sam e type of colum n and w as shown by in fra re d , n u c lea r
m agnetic re so n an c e, m a ss .spectrum and gas ch rom atographic reten tio n tim e
to be id en tical w ith b rev ico m in (appendix, page 92) (brevicom in sam ple obtained
from J im L otan, U. S. F o r e s t S ervice).
.PART
VIII
APPENDIX
WAVENUMBER C M '
5000
4000
3000
25
1500
UOO
1300
1200
Tl
1100
1000
9 00
8 00
700
1000
9 00
800
700
I I III I I I I I
WAVELENGTH IN MICRONS
WAVENUMBER CM'
5000
4 0 00
3000
2!
1500
1400
1300
1200
1100
<I1
OO
I
W AVELENGTH IN M ICRO N S
WAVELENGTH IN M ICRO N S
9
10
11
16
18
20
25
3D__
PERCENT TRANSMISSION
8
PERCENT TRANSMISSION
7.5
OO
0
1
1200
WAVENUMBER CM'
1100
W AVELENGTH IN M ICRO N S
WAVENUMBER C M '
T TTTTTyTTT
I I I I I
T J -T
I I I I I
t T tt T T - y r
I? I I I
; i : ;
WAVENUMBER CM'
T T T T T T ' I P T T T T T - Jn T F y T T T T T T T T J
I
OO
| I I I T jT T T
' n _I_rfT n r T I Trr '1 I'1" 1 1 ! I 1 1 H
8
n
DTTT
WAVELENGTH IN M ICRO N S
T TTTTT
I
"I ' I I
CTTT
M
I
WAVENUMBER CM'
T T T F l i r i I | IIITl 11 IHj IT
2
3
Tl Il
A
I I IT T TTTT J-T
|
5
6
7
8
9
10
11
12
13
14
16
WAVELENGTH IN MICRONS
WAVENUMBER CM'
I
OO
to
I
W AVELENGTH IN M ICRO N S
PfM ( I )
300
I
I L. i_. I
'
j ';
I
PPAA( 6 )
4.0
'
E
' ;
PPM (! )
4.0
5.0
6.0
7.0
8.0
9.0
I
'
I
I
I
I
I
I
I
I
C tf
(X)
— 8
—
•
peak height
100
8
140
150
160
170
180
140
150
160
170
180
peak height
100-
40
50
GO
70
80
90
100
HO
120
130
peak height
-8 9 -
120
130
140
150
IfiO
170
180
130
140
150
IfiO
170
180
peak height
100-
100
HO
-9 0 -
peak height
100 •
120
EO
140
EO
140
EO
IfiO
170
EO
170
EO
peak height
100-
100
HO
EO
IfiO
peak height
—91—
130
150
IfiO
170
ISO
150
100
170
ISO
peak height
120
130
140
—92—
O
peak height
100 -
130
140
350
IfiO
170
180
320
130
140
150
IfiO
170
180
peak height
120
40
50
GO
70
80
90
100
HO
—93 T
REFEREN CES
REFERENCES
I,
W. H erz, H. W atanabe, M. M iyazaki and Y. K ishida5 J . Am0 Chem. S o c .,
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3.
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6.
J . A. M arsh all and P . C 0 Johnson,
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7.
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8.
E. L. E liel and C. P illa r ,
9.
B 0 R ickborn and S. Lwo, O rg0 C hem 0, 30, 2212 (1965).
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10.
A0,G„ A nderson and E. J . F r e e n o r , J . Am. C hem 0 Soc0- , 86, 50378 (1964).
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P riv a te com m unication w ith D r0 B. P. Mundy.
12.
B .P . Mundy, D octoral T h e sis,
13.
R .L . F ra n k , R .D . E m m ick, and R, S0 Johnson,
69, 2313-5 .(1947).
14.
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J 0J 0 B loom field and S. L . L ee, O rg. Chem., 32 , 3919-24 (1967).
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-9 6 -
16.
HoC. B row n and G. Z w eifiel,
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20.
H. C. Brow n ,
page 192.
H y d ro b o ra tio n , W. A. B enjam in, Inc. , New Y ork , 1962,
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R. R. S au ers, and R. A. P a re n t,
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23.
M r. O tz e n b e rg e r, w orking on P h D ., M ontana S ta te U n iv ersity .
24.
H. C. Brow n and G. Zw eifiel, J . Am. Chem. Soc. , 83 , 1241-6 (1961).
25.
H. C. Brow n, H ydroboration, W. A. B enjam in, I n c ., N e w Y b rk , 1962,
pageI 92.
26.
H. C. B row n and G. Z w e ifie l, J . Am. Chem. Soc. , 83_ , 1241-6 (1961)
27.
i b id ., p. 1242.
28.
H. C h ris to l, A. P . K rapcho, and F . P ic tr a s ant,
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29.
The pinacol re a rra n g e m e n t w ill be co n sid ered as a way of getting to the
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N ;S. Z efiron,
31.
H. C. B row n and G. Z w eifiel, J . Am. Chem. Soc. , 83 , 2544
32.
D. J . P asto and F .M . K lein, O rg. Chem. , 33 , 1468 (1968).
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H. C0 Brow n and G. Zw eifiel, J. Am. Chem. Soc. , 83 , 1241
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(7), 527 (1965).
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(1961).
■- 9 7 -
34.
H. C. B row n and G. Zw eifiel, J . Am. Chem . Soc. , 83 , 2544 (1961).
35.
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36.
D. J . P a ste and F .M . K lein, O rg. Chem . , 33 , 1468 (1968).
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F . Johnson, Chem. R ev. , 68_ , 375 (1968).
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C. D. G utsche, J. Am. Chem. Soc. , 71 , 3513, (1949).
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R. M. S ilv erste in ,
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44.
T. E. B e lla s, R. G. B row nbe, and R. M. S ilv erstein , T e tra h e d ro n , 25 ,
5149 (1969).
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3674 (1969).
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G. B achi and J . E Pow ell, J . Am. Chem . Soc. , 92 , 3126 (1970).
47.
R. L . F r a n k , R. D. E m m ick , and R. S. Johnson,
69 , 2313 (1947).
J . Chem. Eduo. , 45:12, 794 (1968).
J . Am. Chem. Soc. ,
MONTANA STATE UNIVERSITY LIBRARIES
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