Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 23
Synthesis and Characterization of
2(2-Tetrahydropyranylthio) methyl cyclopropylamine
Zuhair A. Muhi-Eldeen*, Samira F. Hassan**
Rece ived 2-6-2002 Acce pted 13-6-2004
ABSTRACT
2(2-Tetra hydropyra nylthio) methyl cycloprop yl a mines we re s ynthes ized fro m a llylme rc apta n thro ugh
se veral step s. The struc ture s of the inte rme diates a nd the final p ro duc ts where co nfirme d thro ugh IR,
NMR and elemental a nalysis, these comp ounds ma y be of v alue in the treatme nt o f dis eas es where free
ra dica ls a re implicated in their pa thogensis, s ince the thio and the amino groups o f the synthe sized
co mpounds may a ct a s fre e ra dical sc ave ngers.
الخـــــــــــــــالصة
ــ ة من امينات اـل موع و -2( -2لقد تم تحضير مج ن ثاي را وبي هيدر را ركابتان وذل) تت مي روبيل من الليل كلو ب خالل عدد مثيل ساي ك من
طوات مـراء . من الخ عة تحـت الح ه اش ة تقني واسط هائية ب والن ة طي كبات الوس غناطيسـي (IR)تم تشخيص المر ن الم رني ف اـل -H)وطـي
NMR ) عناصر االولية خيص ال e) وتش le me ntal a nalys e s معالجة . ( ة في ن ذات قيم مكن ان تكو رة م ركبات المحض هذه الم
الل مراض المتسببة من خ طليقة اال ور ال حرر الجذ fre)ت e radic als) . مكن ان كبات م مر هذه ال ي المينو ف وا ع الثايو مي وجود مجا ن ال
راض ور الطليقة والمسببة لألم جذ طة لهذة ال هب ون م .تك
INTRODUCTION
Free ra dicals hav e b ee n implicated in
many dise as es, among these are
athe ro scle ros is, rhe uma to id a rthritis, ca ta ra cts,
ne oplas tic dis eas s, diabe tic retinopa thy,
Parkins on's , Alzheimer inflammatory disea se s
of gas tro-intes tina l tra ct a nd a ging1-5.
Free ra dicals are de fine d a s ato ms or
molec ules tha t co ntain one o r more unp aire d
elec trons and are spe cies that c ause me ta bolic
disturba nce s and ce ll injury b y interacting with
mac ro molecules a nd othe r c ellula r co ns titue nts
such as proteins , lipids , ca rb ohydrates and
DNA res ulting in a variety o f b io lo gical
co nse quenc es , including c ellula r and tis sue
da mage , mutatio n c arc inogens is and ce ll
de ath6. The obs erva tion that 2 -
merca ptoethylamine , 2 –me rc atoprop ylamine ,
disulfide ,
Thioe thers a nd sulfoxid es 7were cap ab le in
protec ting a nimals a gains t fre e
ra dica ls ge nerate d as a re sult of ionizing
ra diatio n promote d o ur interes t to synthe size-
2(2-te trahyd rop yranylthio )
methylc yc lo propyla mine 1 . the thioethe r and
the amino groups in 1 o r the c orre sp ond ing
“s ulfhydryl and amino gro ups in the ir expec te d
major me ta bo lites may ac t co ope ra tive ly a s
free rad ic al sca ve nge rs ”.
The re fo re the se co mpound s may be utilize d
se le ctiv ely to treat one o r mo re of the
previously me ntio ned d is ea se s.
SYNTHETIC MATERIAL
Allylmercaptan , p- to luenesulfonic acid ,
dihyd ropyran e thldiazoce ta te , we re obtained
fro m Aldric h Che mic al Co. (Milwa ukee ,
WI ,US A ) .
Analytical Equipment
Melting p oints were de te rminated by using a
calibrated Thoma s Ho ove r me lting p oint
app aratus .IR s pec tra were re corde d us ing a
Unica m SP - 3 00 sp ectrophotome te r . NMR
spe ctra were obtaine d us ing a Va riant FT80 A
spe ctro meter. Chemica l shifts are re ported as
part p er million downfield fro m
te trame thylsilane as inte rnal standard for
HNMR spe ctra . Eleme ntal mic ro analysis we re
perfo rmed by H.Ma liss a and G.Reute r,FRG.
pyran ( 3) .Allylthiotetrahyro -2
- Allylme rc apta n ( 3,74 g ,1 mo le ) and 200 mg
of p-toluene sulfonic ac id we re plac ed in a
500 ml RB- flas k fitte d with a reflux c ond ens er
and ma gnetic s tirre r . Dihydro pyra n ( 84g , 1
mole ) wa s add ed drop wis e . The reac tion
mixture wa s hea te d on a steam ba th for 1 0
minutes . After he ating fo r 5-10 minutes , a
vigorous exothe rmic rea ctio n s ta rted and
continued d uring the add ition of dihyd ro pyran
. Afte r 1 1/2 hours , refluxing was s to ppe d and
potas sium ca rb ona te ( 1.0 g) w as ad ded . The
mixture wa s stirred a t ro om tempe ra ture for 1
hour , filte re d and fra ctio nally distilled
yielding 80 .2 g .
( 50% ) o f 2- a llylthiotetra hydropyra n ( 3) b .p
. 42 -4 4 ( 0.1 mm )
* Dep ar tme nt o f med ic ina l c hemistry ,Co llag e of Phar macy,Univer sity of Petra , Aman -J ord an;
** De par tme nt o f Ph arma ceu tica l ch emistry, Co llag e of Phar macy,Univer sity of Bagh dad ,
Bagh dad -I ra q
Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 24
Infrared ( nea t , c m-1 ) showed b ands at 308 0
(= CH2, stre tch ); 294 0, 2 860 , 285 0, (CH2,
stretch ); 16 35 ( C = C , s tretc h ) ; 1 180 , 10 80,
104 0, 101 5 (tetrahydropyra nyl group ) a nd 94 0
( S-
CH2 ) Nmr (d- chloroform , δ ) 1.28 - 2.18 (
multip le t , 6 H , (CH2 )3 ); 3.20 ( multiplet ,
2H, S-CH2 ) ; 4.09 a nd 3 .5 ( multiplEt , 2 H ,
OCH2) ; The v inyl protons ap pea r a s
multip le ts o verlapp ing with ( O- CH-S ) at
5.20 ( multiplet , 3H , C=CH2 , O-CH-S ) and
5.82 ( multiplet , 1H , C=CH )
Ana l . Calc ulated :Found for C8 H14 OS : C ,
60.7 5 ;H , 8 .8 6 ; S , 20 .2 5 fo und : C , 60.63 ;
H , 8.85 ; S , 2 0.47 .
allythiotetarhyropyran -Reaction of 2
(3) with ethyl diazoacetate
In a 2 50 ml three - ne cke d flas k provide d
with a reflux conde nse r, dropp ing funne l and
magnetic stirrer wa s plac ed 2-
allythiotetra ahydrop yran
(4 ,1 5.8 g , 0 .1mole ) and 5 0 mg o f cop per
pow der . The mixture was s tirred rap id ly (16 0
- 16 5 C° , o il bath ) a nd the e thyl d ia zo ace ta te
(1 1.4 g , 0 .1 ) was a dde d at suc h rate so a s to
av oid a v igorous re action . After e thyl
diazoac etate ad dition the evo lutio n of nitro ge n
ce ase d . The reac tio n mixture was refluxe d
distillate ( 4 0-60 C° a t 0.2 mm ) . The d is tilla te
was a na lyzed b y ga s liquid p artitio n
chro matgraphy which s hows the p re sence of
se veral prod ucts . Thes e prod ucts were
te ntatively id entified as diethyl ma le ate ,
diethyl fumarate a nd the starting ma te rial .
Other products are
a-
Ethyl α-allyl-α
( 2- etrahydropyranythio) acetate
(5) , b.p . 72-74 C°
at ( 0.01 5) mm , wa s identifie d by infrared and
nmr s pec tra and eleme ntal a nalys is . The
infrared s pe ctrum ( ne at , cm-1 ) s ho wed ba nd s
at 308 0 (C=CH2 stretch ); 2 940 , 286 0 , 2 850 ,
(CH2- stretch ); 17 35 (C=O, s tretch ) ; 164 0
(C=C) ; 10 80 ,105 0 , 1 020 (CH2 ,
te tra hyd ro pyranyl gro up ) , 940 (S- CH2 ).
Nmr (d- c hloroform ,δ ) , 5.78 (multiple t , 1 H ,
HC=C ) ; 5 .2 4 (multiplet , 2H,C =CH2 ); 5.0
(multiplet ,1H,O- CH - S ) ; 4.16 a nd 4.0
(multiplet ,3H ,COOCH2 , α- CHO o f the
(CH2 tetrahydrop yranyl group ) ;3.5
(multiplet , 2H , β - CHO of the
te tra hyd ro pyranyl gro up ,S - CH -COOEt ) ,
2.57 (multip le t , 2 H,CH2 - C=C ) , 1.45 to 2.0
(b ro ad , multiple ,6 H (CH2 )3) ; 1.25 (triplet ,
3H, CH3 )
Ana l . Calculated : Fo und for C12H 2 0 O3S:C ,
59 . 0 1/. ;H , 8.19 ; S , 1 3.11. Fo und :
C,58.24 ;H,8.15 ; S,13 . 45 .
b-
2(2-Tetrahydropyranylthio)methyl-
1-c arboe thoxycyclopropane(4)
5.5g (22.5%), of 4,was obta ined a s a
colorless liquid , b.p.12 0-122 C˚ a t (0.2mm). gas
liquid partition c hromatogra phy on 3.8%
silico n gum rub ber (UC-W98 ) o n chromo so rb -
W(80 -1 00me sh), 4ft 0.25 in gla ss c olumn with
column tempe ra ture 19 0C˚, injec tion pa rt
te mpe ra ture 3 20C˚, d etec to r tempe ra ture
280 C˚, inle t p re ssure of 40 p si and c arrier gas
(N2 ) flow rate of (6 0ml/min) sho wed two
pea ks at 3.2 minutes (8 7%) tra ns -4 and 4 .0
minutes (1 3%) cis- 4.The mixture ha d an
infrared spe ctrum (nea t,c m-1) that showe d
bands a t 29 00, 28 60 (CH2, stretch); 172 0(C=O,
stre tc h); 1 105 , 10 80, 104 0 and 1 015
(tetrahydropyra nyl gro up and cycloprop ane
abs orptio n). NMR(d-chlo ro fo rm ,δ)0.7-
1.2(mulip le t , 2H,CH2 of
cyc lo propa ne ;1 .3 4(triplet, 3 H, CH3); 1.4-
2.15(multip le t 7H(CH2)3, 1 H o f cycloprop ane
α to CH2-S ); 2.58 (d oub le t, 2 H,S -CH2,J-
CH,CH2-S = 6 .5 Hz) 3.3(multiple t, 1H, CH-
cyc lo propa ne α-to COOEt); 3 .5 6(multiplet,
1H,β-CHO of tetra hydropyra nyl group );
3.9(multiplet, 1 H, α-CHO, of
te trahyd rop yrahyl gro up), 4 .1 4(qua rtet,
2H,CH2 of the ester group), 5.0(multiplet,
1H,O-CH-S ).
An a l . C a lc u la te d : F o u n d F o r
C12H20O 3S: C ,5 9 .0 1H ,8 .1 9 ; S ,13 .1 1.
F ound: C,5 8.24;H,8.15 ;S ,1 3.50
2(2-te trahydropyranylthio)
me thylcyclopropylcar boxyhydr -
azide(6)
A s olution of (4 .8 8g,2.0x10-3mole) of 2-(2 -̀
te trahyd rop yranylthio )me thyl-1 -
carbo ethoxyc yclop ro pane 4 and 20 ml of 8 5%
hyd ra zine hydrate was refluxe d fo r 24 ho urs.
The mixture wa s co oled and he ld a t 0°C fo r 24
hours ; no prec ip ita te formed. The exce ss of
hyd ra zine hydrate wa s re mov ed unde r reduced
press ure affording a s emi-s olid tha t fa iled to
crysta llize unde r v ario us conditions. The
unrea cted e ster 4 wa s re mov ed by d is solving
the crud e hyd ra zide in chlo fo rm. The
hyd ra zide 6 was p re cipita ted with a nhydrous
ether. A white s olid wa s obtained in Et2O; this
turned to a se mi-so lid up on remo val o f ethe r.
The hyra zide 6 ha d a n infrared s pe ctrum
(neat,cm-1) that s howe d bands a t 33 00 (NH2 ,
stre tc h ) ;29 20,28 30(CH2,stre tc h)166 0(CONH,
stre tc h); 110 5 , 10 80 ,1 040 and
102 0(te trahydrop yranyl group and
cyc lo propa ne ring). NMR (d-
chloroform,δ)8.17(multip le t,1 H,CONH)
4.97(multip le t,1H,O-CH-S); 4 .0 5 and 3.5 5
(multiplet,2 H,OCH2) ;2 .8 -3 .0 (multip le t , 3 H ,
Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 25
NH2 , CH -c yc lo pro pa ne) ; 2.6 (multiplet , 2 H ,
S-CH2),1.1-1.2(multip le t,7H,(CH2)3 and
1H,CH-of c yclop ro pane α-to CH2-S);0 .8 - 1.0
(multiplet,2H,CH2of c yclop rp ane ).
This s emi-solid hyd ra zide was used witho ut
furthe r purific atio n.
2(2Tetrahydropyranylthio)methylcy
clopropylamin
A solution of (4 .6 4g,2 .0 x10 -2mole ) of 2 - ( 2-
te tra hyd ro pyranylthio )
methylc yc lo propylc arboxyhydrazid e 6 in
100 ml c hloroform wa s chilled to -5 C°(ic e-sa lt
ba th). With ra pid s tirring, 1.2g(2 .0 x1 0-2 mole)
of s od ium nitrite in 5 ml of water, follo wed b y
10ml of 1 0%HCl, were add ed . The rea ctio n
mixture wa s allowed to s ta nd 5 -1 0minute s; the
chlo roform layer was s ep arated a nd the
aq ueo us layer wa s extrac ted once with 20 ml of
chlo roform. The c omb ined chloroform
frac tions were dried (Na2SO4) and filte re d. To
this solution 50 ml of d ry tolue ne wa s add ed.
The c hloroform wa s re move d und er reduce d
pres sure and N2 ev olution co ntinue d
vigo rously while he ating the rema ining to luene
solution under reduce d pre ss ure on stea m
ba th. Afte r N2 e volution c eas ed a da rk b ro wn
so lid ma teria l p re cipita te d (infrared , KBr,
228 0c m-1,N=C=O, 8). F ifteen ml of
25%me thanolic KOH was a dde d to the to luene
co ntaining the s olid is ocyanate and the mixture
was refluxed a t 125 C° fo r 1 8 hours . After
he ating, the red dish b ro wn mixture wa s
extrac te d with to luene, drie d (Na 2S O4)
filte re d. The tolue ne wa s remo ve d under
re duced pres sure . The res id ue was d is tille d
affo rd ing 0 .5 g(26.7%) of cis- and tra ns-
amine 1,b.p. 98 -1 00C° at ( 0.3mm).Gas s iq uid
pa rtition chroma tograp hy (glpc )a na lysis o n
3.8% s ilicon gum rubb er (UC- W-98 ) o n
chro moso rb – W (80 -1 00 mesh), 4ftx0.25 in
glas s c ol tempe ra ture 17 5C°,injuc tio n pa rt
te mpe ra ture 30 0 C°and d etec to r te mperatur
285 C° inlet press ure 40 ps i a nd ca rrie d ga s
(N2 ) flow ra te o f (6 0ml /min) sho wed two
pe aks at 1.28 minute s (8 5%) tra ns -1 and 2 .4 8
minutes (1 5%) c is -1 .
The a mine mixture ha d a n infrared sp ectrum
(nea t,cm-1) tha t s ho wed b and s a t 36 00 -
330 0(broad , NH2,s tre tc h ); 3 000 , 29 30 and
286 0 (CH2,stre tc h) 16 25-15 90(NH,be nding);
110 5,10 80,10 45 and 101 5 (tetrahydropyra nyl
and cyc lo propyl ring). NMR (d-c hloroform, δ )
4.97 (multiplet ,1 H , O-CH-S) ; 4.0 nd
3.5(multip le t,2H,O-CH2); 2 .6 ( multiplet, 2 H ,
S-CH2) 2.3 (multiplet, 1 H , CH , c yclop ro pane
α - to NH2) ; 1 . 2-2
(multiplet,7H,(CH2)3,1H,CH cycloprop ane α-
to CH2S) , 0.7 - 1.1
(multiplet ,2 H ,CH2 ,c yc lo prpane)
Ana l. Calc ulated: Found Fo r
C9H 17OSN:C,57.75 ,;H,9.09 ;N,7 .4 8;S,17.11 .
Found : C , 57 .19 ; H , 8 . 84 ;N,7.03 ;S ,1 8.44.
DISUSSION and SRESULT
The new co mpound 1 wa s prep ared a s dep ic ted
in s che me 1 Allymerca ptan 2 which s erves a s
starting materia l was rea dily converted in 80%
yield to 2-a llylthiotetrahydropyra n 3 through
re action with 2,3-dihyd ro pyran in the pres enc e
of p-toluenes ulfo nic a cid. The IR and NMR
spe ctra were c onsistent with the as signed
structure . Tre atment of 3 with e thyldiazoac etate
affo rd ed a mixture of trans - and cis- 2-(2 -
te trahyd rop yranylthio ) me thyl-1 -
carbo ethoxyc yclop ro pane 4 a nd a s ulfo nium
ylid e re arra nge ment prod uc t
name lyethyl-α-allyl-α (2-te trahyd rop yranylthio )
ace ta te 5 in 81.4% and 1 8.6% yie ld a t 150 -
155 C° re sp ectively 8. Ethyld ia zoa ce ta te rea cts
with allymerca ptan to ge nerate tra ns - and c is -
cyc lo propa ne derivative 4 through c arbene
add ition to the do uble bo nd 9 and with thio ethe r
group to form sulfonium ylid e 10. Such
sulfonium ylide is kno wn to unde rgo Steve n's
re arra nge ment, which de pe nds o n the structure
of the ylide , may e ithe r invo lv e a n antrafac ia l
1,3-sigma trop ic re arra ngeme nt or suprafac ia l
1,5-sigma trop ic rearrangeme nt 11. In our cas e
both 1,3- and 1 ,5 - re arra ngements affo rd ed the
same comp ound 5. The mixture of 4 c ould no t
be se pa ra te d by p hys ic al metho ds a nd was us ed
as a mixture in the
next ste p. Re action of 4 with 8 5% hydrazine
hyd ra te a fforde d the hyd ra zide 6 as a gummy
solid in almo st quantitativ e yield; Attemp ts to
crysta llize this gummy hyd ra zide were
uns uc ces sful. The purity of the c ompo und wa s
determine b y
gas s liq uid partition chro matogra phy (glpc ); the
non-c rystalline hydra zide wa s then sub jucted to
Curtius re arra nge ment. The re arrange ment
proce ede d through the a zide 7 and the
is ocyanate 8 . The intermed ia te a zide 7 wa s
detec ted by its IR s pe ctrum (CON3, 2 15 0 c m
-1).
The iso cya na te 8 c ould b e is olated a s a brown
solid which showe d a n IR a bso rp tion b and a t
228 0 c m-1 (N=C=O). The isoc ya nate 8 wa s
re fluxed with 25% metha no lic KOH to generate
the des ire d trans- a nd cis- cyc lo propyla mine 1
as a mixture in a ra tio of 8 5:15 re sp ective ly.
The IR and NMR s pec tra were co ns is te nt with
the a ss igned structure as discuss ed in the
exp erime ntal part.
Ir aq i J.Pharm.Sc i., Vol.15 (1 ) ,2006 26
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