Preparation of 1-adamantyl ketones: Structure, mechanism of formation and biological activity of potential by-products

Article abstract of DOI:10.1135/cccc20060709

Reactions between adamantane-1-carbonyl chloride and several Grignard reagents as well as interactions with solvents have been examined. Some new and unexpected adamantane derivatives were isolated, fully characterized and their biological activity determined. In particular, an unexpected isochromanone 16 was formed in an S_EAr process, in which a stable hydrocarbon was the leaving group.

Full text of DOI:10.1135/cccc20060709

1-Adamantyl Ketones
709
PREPARATION OF 1-ADAMANTYL KETONES: STRUCTURE,
MECHANISM OF FORMATION AND BIOLOGICAL ACTIVITY
OF POTENTIAL BY-PRODUCTS
a
b
c,
Robert VÍCHA , Marek NEČAS and Milan POTÁČEK *
a
Department of Food Engineering and Chemistry, Faculty of Technology,
Tomas Bata University in Zlín, Náměstí T.G.M. 275, 762 72 Zlín, Czech Republic;
e-mail: rvicha@ft.utb.cz
Department of Inorganic Chemistry, Faculty of Science, Masaryk University Brno,
b
Kotlářská 2, 611 37 Brno, Czech Republic; e-mail: man@chemi.muni.cz
Department of Organic Chemistry, Faculty of Science, Masaryk University Brno,
c
Kotlářská 2, 611 37 Brno, Czech Republic; e-mail: potacek@chemi.muni.cz
Received March 16, 2005
Accepted Jan uary 19, 2006
Reaction s between adam an tan e-1-carbon yl ch loride an d several Grign ard reagen ts as well as
in teraction s with solven ts h ave been exam in ed. Som e n ew an d un expected adam an tan e de-
rivatives were isolated, fully ch aracterized an d th eir biological activity determ in ed. In partic-
ular, an un expected isoch rom an on e 16 was form ed in an SEAr process, in wh ich a stable
h ydrocarbon was th e leavin g group.
Keyw ord s: Adam an tan e; 1-Adam an tyl alkyl/aryl keton es; Acyl ch lorides; Side products; Bio-
logical activity; Grign ard reagen ts.
Various am in es con tain in g th e adam an tan e m oiety h ave sh own biological
activity1. Sin ce th e first discovery of th e an tiviral effect of 1-adam an tyl-
am in e2 in 1964, a n um ber of com poun ds con tain in g th e adam an tan e ske-
leton h ave been described as efficien t an tiviral3,4, an titum or5,6, h ypo-
glycem ic7, an tidepressan t8,9, an tim icrobial10, an d an ticon vulsan t agen ts11.
Several adam an tan e-con tain in g drugs are curren tly bein g used in m odern
m edicin e in th e proph ylaxis an d treatm en t of various viral diseases an d
Parkin son ism 9,12
.
Am on g th ese, 1-(1-adam an tyl)eth an -1-am in e an d sim ilar am in es play an
important role with their unprecedented virostatic effect13,14. 1-(1-Adamantyl)-
alkan -1-am in es, wh ich are usually prepared from appropriate keton es, be-
lon g to th e m ost effective drugs. Establish ed m eth ods for th e preparation of
such keton es (Sch em e 1) are gen erally based on th e reaction of Grign ard re-
agen ts with acyl ch lorides15,16. We h ave recen tly developed a n ew efficien t
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 5, pp. 709–722
© 2006 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20060709

710
Vícha, Nečas, Potáček:
an d fast m eth od for th e preparation of 1-adam an tyl alkyl/aryl keton es us-
in g catalytic am oun ts of AlCl3 an d CuCl 17
.
SCHEME 1
In th is paper, we describe th e side reaction s an d th eir products, th e path -
ways of side products form ation an d th eir biological activity in th e con text
of possible utilization of th is m eth od in drug syn th esis.
Th us, we perform ed reaction s of adam an tan e-1-carbon yl ch loride (1)
with selected Grign ard reagen ts – m eth ylm agn esium iodide (2a), eth yl-
m agn esium brom ide (2b ), propylm agn esium brom ide (2c), isopropyl-
m agn esium brom ide (2d ), ben zylm agn esium brom ide (2e) an d ph en yl-
m agn esium brom ide (2f) – with a focus on th e iden tification of m in or side
products. In teraction s of acyl ch loride 1 with th e solven ts used in th e pres-
en ce of a Lewis acid (Sch em e 2) were studied sim ultan eously.
RESULTS AND DISCUSSION
By th e reaction of acyl ch lorides with Grign ard reagen ts, th e correspon din g
keton es were form ed. Wh en a Grign ard reagen t is used with out an y addi-
tive, its stron g n ucleoph ilic ch aracter gives rise to th e form ation of a ter-
tiary alcoh ol18. If th e Grign ard reagen t h as β-h ydrogen atom s, th e cor-
respon din g secon dary alcoh ols can also arise from th e reduction of th e
form ed keton e with an excess of th e reagen t19,20 an d th e correspon din g
alken e is form ed as its oxidation product. Th e alcoh ols are th e m ain un de-
sirable side products in keton e syn th esis, especially wh en catalytic am oun ts
of m etal h alides are used for in situ tran sm etalation 17. Such procedures are
very sen sitive to th e rate of th e Grign ard reagen t addition in to th e reaction
m ixture, an d an y deviation from its im m ediate optim um con cen tration
leads to th e form ation of th e side products m en tion ed above. Th is problem
could arise in a large scale syn th esis, wh ere h om ogen eity of th e reaction
m ixture durin g th e addition of th e Grign ard reagen t can be sign ifican tly
disturbed. It was som ewh at surprisin g th at in all th e cases wh en a Grign ard
reagen t pron e to causin g reduction was used, 1,2-addition s practically did
n ot occur an d we detected in sign ifican t, if an y, am oun ts of tertiary alco-
h ols 6. On th e oth er h an d, th e reduction s were frequen t, an d we foun d sec-
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 5, pp. 709–722

1-Adamantyl Ketones
711
on dary alcoh ols 4 an d also 1-adam an tylm eth an ol (8), arisin g from th e
reduction of adam an tan e-1-carbon yl ch loride21. Th e in term ediate of th is
tran sform ation , aldeh yde 7, was also detected in all th e cases.
For th e keton e-form in g reaction s in question , an equim olar ratio of acyl
ch loride 1 an d Grign ard reagen t 2 was always used, but th e reduction s as
well as th e 1,2-addition s to carbon yl required two m olecules of 2 per on e
m olecule of alcoh ol. Con sequen tly, som e startin g m aterial 1 m ust h ave re-
m ain ed an d could react with alcoh ols upon bein g left in th e reaction m ix-
ture for a sufficien t period of tim e. Th us, esters 9 an d 10b–10d were also
detected in th e crude products. Even wh en eth ylm agn esium brom ide was
used, ester 10b, wh ich easily crystallized durin g th e work-up procedure, was
th e m ain product. On ly in th e cases wh ere th e structure of 2 did n ot allow
reduction s, 1,2-addition s to carbon yl took place. Th us, in run s a, e an d f
(Table I), th e correspon din g tertiary alcoh ols 6 were detected an d wh en
m eth ylm agn esium iodide was used, th e correspon din g ester 11a was iso-
lated.
SCHEME 2
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712
Vícha, Nečas, Potáček:
Every Grign ard reagen t can beh ave as a base abstractin g an acidic h ydro-
gen an d furn ish in g th e correspon din g h ydrocarbon . Th is beh avior led to
th e form ation of an in terestin g class of com poun ds, especially wh en an
α-h ydrogen was presen t in th e syn th esized keton e. Th e proposed m ech a-
n ism of th is reaction is sh own in Sch em e 3. Th e tran sien tly form ed m agn e-
sium en olate could react with a secon d m olecule of acyl ch loride 1 to yield
1,3-di(1-adam an tyl)propan e-1,3-dion es 12. Th e am oun t of th e dion e
stron gly depen ded on th e structure of Grign ard reagen t 2. Th us, wh en
aliph atic Grign ard reagen t 2 was used in th e reaction , th e dion e am oun t
varied in th e ran ge 0–2%, wh ereas in th e case of ben zylm agn esium brom ide
(2e), wh en th e en olate in term ediate was stabilized by reson an ce, th e
TABLE I
Com position (in %) of crude products determ in ed by GC MS
R in RMgX
Product
CH3 (a)
C2H5 (b)
C3H7 (c)
i-C3H7 (d )
ben zyl (e)
ph en yl (f)
3
4
48.0
–
8.3
9.7
6.6
0.8
0.7
<0.1
2.2
71.7
0.0
<0.1
–
7.0
30.8
5.7
0.0
0.7
1.6
34.0
18.0
0.0
0.0
2.2
–
2.5
13.7
0.0
0.0
1.7
5.1
42.8
33.5
0.0
0.0
0.3
–
32.1
–
88.6
–
5
0.0
13.6
–
0.5
30.0
–
<0.1
8.4
–
6
7
8
–
–
–
9
–
–
–
10
11
12
–
–
–
27.1
2.0
2.2
–
0.0
35.2
0.3
0.5
0.0
–
5b
16
3.1
–
–
Reaction con dition s: In to th e solution of 5.0 m m ol of acyl ch loride 1 in 40 m l of fresh ly
distilled dieth yl eth er, on e equivalen t of a Grign ard reagen t solution in dieth yl eth er was
added in on e portion at 5 °C. Th e reaction m ixture was allowed to warm up to room tem -
perature, an d stirred for 48 h . Com poun ds 3a–3c, 3e, 3f, 4b, 5a–5c, 6a, 6b, 6e, 6f, 7, 8, 9,
10b, 11a, 12e an d 16 were iden tified usin g a stan dard. Oth er com poun ds were iden tified by
m ass spectra.
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1-Adamantyl Ketones
713
am oun t of dion e 12e in creased to 35%. Th e am oun t of th e correspon din g
dion e varied from 0.5 to 2.5% wh en th e catalytic system AlCl3/CuCl was
used for th e syn th esis of keton es 3a, 3b an d 3e. Notably, th ese dion es are
th e m ost un desirable side products in keton e syn th esis because th eir separa-
tion is a difficult task (even in am oun ts lower th an 1%) due to ph ysico-
ch em ical properties sim ilar to th ose of th e keton es. Decreasin g solven t po-
larity can suppress un desirable dion e form ation . Th us, usin g a toluen e–THF
SCHEME 3
m ixture in th e 70:30 volum e ratio in place of THF for th e preparation of
keton e 3a decreased th e am oun t of dion e 12a from 2.5 to 0.4%.
In prin ciple, Lewis acids such as Zn Cl2 or AlCl3 used for tran sm etallation
in keton e syn th esis17 as well as m agn esium (II) h alides form ed in th e reac-
tion are capable of in itiatin g th e cleavage of eth ers used as solven ts22–25
.
Usual experim en tal procedures in clude th e addition of a Grign ard re-
agen t solution in dieth yl eth er or in THF in to th e solution of acyl ch loride
an d a catalyst in THF. Th us, eth yl adam an tan e-1-carboxylate (5b) was
form ed wh en th e Grign ard reagen t was prepared in dieth yl eth er. Th e
am oun t of 5b obviously in creased with in creasin g reaction tim e17. Surpris-
in gly, th e cleavage of dieth yl eth er was preferred wh en a m ixture of dieth yl
eth er an d tetrah ydrofuran was used. However, wh en on ly THF was presen t
as solven t, th e correspon din g product 14 arose (Sch em e 4). In addition , es-
ter 14 reacted with THF to yield 4-(4-ch lorobutoxy)butyl adam an tan e-
1-carboxylate (15), wh ich was isolated in an am oun t of ca. 5% (relative to
14). On th e con trary, wh en 1,4-dioxan e was used, sim ilar products were
n ot detected, alth ough th e an alogous 2-(2-ch loroeth oxy)eth yl adam an tan e-
1-carboxylate seem s to be an acceptable precursor of eth ylen e bis-
(adam an tan e-1-carboxylate) (13), wh ich was th e on ly isolated product.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 5, pp. 709–722

714
Vícha, Nečas, Potáček:
SCHEME 4
Sm all am oun ts of esters 5 cam e from th e alcoh ols con tain ed as im purities
in th e startin g alkyl/aryl h alides used for th e preparation of th e Grign ard
reagen ts. Th ese alcoh ols form ed th e correspon din g m agn esium alkoxides
an d subsequen tly reacted with 1. Air oxygen m ay also attack Grign ard re-
agen ts26,27 to yield alkoxides, but th is was im probable in our case because
all experim en ts were carried out un der argon atm osph ere.
Wh en ben zylm agn esium brom ide was used in th e reaction , an un ex-
pected isoch rom an on e derivative 16 was iden tified in th e reaction m ixture
(Sch em e 5). A probable in term ediate of th is reaction is th e m agn esium
alkoxide of 2-(1-adam an tyl)-1,3-diph en ylpropan -2-ol (6e), wh ich un der-
wen t an in tram olecular cyclization un der th e form ation of 16. Th e on ly
con ceivable carbon yl source seem ed to be an excess of 1. Alth ough th e cor-
respon din g ester in term ediate (Sch em e 5) was n ot detected, we assum e its
form ation an d subsequen t in tram olecular electroph ilic arom atic substitu-
tion with adam an tan e as a leavin g group. Th e presen ce of adam an tan e in
th e reaction m ixture was proved by gas ch rom atograph y with adam an tan e
as a stan dard, an d con firm ed by m ass spectrom etry. Moreover, iso-
ch rom an on e 16 was detected as a product in a separate reaction of alcoh ol
6e with acyl ch loride 1 an d 5 m ole % of AlCl3 in dieth yl eth er at room tem -
perature. To th e best of our kn owledge, th is reaction is th e first described
SEAr substitution wh ere a stable h ydrocarbon is a leavin g group. Th e struc-
ture of 16 was determ in ed by 2D NMR experim en ts an d con firm ed by X-ray
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 5, pp. 709–722

1-Adamantyl Ketones
715
diffraction an alysis. Two distin ct con form ers were presen t in th e asym m et-
ric part of th e un it cell, differin g m ain ly in th e m utual orien tation of th eir
ben zyl an d isoch rom an on e groups. In th e first con form er (Fig. 1, left), th e
least-squares plan es th rough th e arom atic rin gs were in clin ed by 24.0(1)°,
wh ile th e rin gs were alm ost perpen dicular (88.5(1)°) in th e secon d con -
form er. Th e m olecules form ed a layered arran gem en t, exten din g in th e
crystallograph ic ac plan e. In th e b-direction , we th erefore foun d altern atin g
layers of both con form ers, wh ich were well separated from each oth er. De-
tailed study of th e m ech an ism as well as th e scope of th is reaction will be
th e subject of furth er research .
1
16
6e
SCHEME 5
FIG. 1
ORTEP diagram s of two isoch rom an on e 16 con form ers. Each of th em occupies own layer in
crystal. Selected bon d len gth s (in Å), regular an d torsion an gles (in °) for both con form ers are
given : C1–O2 1.345(2), 1.352(2); C1–O28 1.210(2), 1.206(2); O2–C3 1.480(2), 1.471(2);
C3–C11 1.568(2), 1.573(2); C3–C21 1.546(2), 1.546(2); C1–O2–C3 124.7(1), 124.6(1);
O2–C3–C4 111.1(1), 110.6(1); O2–C3–C11 103.8(1), 107.2(1); O2–C3–C11 105.9(1), 103.4(1);
C4–C3–C11 111.2(1), 114.3(1); C4–C3–C21 111.9(1), 109.7(1); C11–C3–C4–C5 –153.1(1),
82.0(2); C1–O2–C3–C11 145.9(2), –95.8(2); C11–C3–C21–C22 177.1(1), –176.1(1)
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 5, pp. 709–722

716
Vícha, Nečas, Potáček:
Fin ally, we tested som e of th e n ew isolated adam an tan e derivatives for
th eir biological activity; th e results are sh own in Table II. Non e of th e
tested com poun ds displayed an tim icrobial activity in th e con cen tration s
used, an d on ly com poun d 6e exh ibited a sligh t cytotoxic effect.
TABLE II
Biological activity tests
Cytotoxicity,
GI50, µM
An tim icrobial activity, MIC, µg m l–1
Strain a
4225
Cell lin eb
Com pd.
3953
4223
4224
3988
3954
3955
K-562
MCF7
6e
9
>100
NTc
>50
>100
NTc
>50
>100
NTc
>50
>100
NTc
>50
>100
NTc
>50
>100
NTc
>50
>100
NTc
>50
>167
>167
>167
>167
NT
144
>167
>167
>167
NT
11a
10b
12e
13
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
NTc
>100
>100
NTc
>100
>100
NTc
>100
>100
NTc
>100
>100
NTc
>100
>100
NTc
>100
>100
NTc
>100
>100
>167
NT
>167
NT
14
15
NT
NT
a
Microbial strain s were obtain ed from Czech Collection of Microorgan ism s (CCM). 3953,
4223, Staph ylococcus aureus; 4224, En th erococcus faecalis; 4225, 3988, 3954, Esch erich ia
b
coli; 3955, Pseudom on as aerugin osa. Cell lin es: K-562, ch ron ic m yelosis; MCF7, carcin om a
c
m am m ae. Com poun ds were n ot soluble in DMSO. NT, n ot tested.
CONCLUSION
Reduction s were th e m ost frequen tly observed side reaction s in th e reac-
tion s of adam an tan e-1-carbon yl ch loride (1) with Grign ard reagen ts. How-
ever, wh en th e structure of th e Grign ard reagen t did n ot allow reduction s,
1,2-addition s to th e carbon yl of th e keton e prim arily form ed occurred. Th e
alcoh ols form ed in th is way could react with acyl ch loride 1 to produce th e
correspon din g esters. Th e startin g acyl ch loride 1 also yielded th e corre-
spon din g aldeh yde 7, alcoh ol 8 an d subsequen tly 1-adam an tylm eth yl
adam an tan e-1-carboxylate (9) in all cases wh ere reduction s could take
place. In som e cases, th e basic n ature of th e Grign ard reagen ts allowed th e
en olization of th e keton es presen t, an d subsequen t substitution of ch lorin e
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 5, pp. 709–722

1-Adamantyl Ketones
717
in 1 to produce substituted 1,3-dion es 12. Th e form ation of th ese un desir-
able side products was suppressed by replacin g up to 70% of THF by tolu-
en e. Acyl ch loride 1 m ay attack oxygen -con tain in g solven ts to yield th e
correspon din g esters. Neverth eless, th is process requires lon g reaction
tim es, an d, con sequen tly, th e form ation of th e esters is n ot a serious com -
plication in th e keton e syn th esis.
EXPERIMENTAL
Gen eral
All reaction s were carried out un der argon atm osph ere. Solven ts were dried by stan dard
m eth ods an d were fresh ly distilled before use. Alkyl/aryl h alides used for th e Grign ard re-
agen t syn th esis were obtain ed from com m ercial sources an d were used with out furth er puri-
fication . Zn Cl2 was purch ased from Fluka an d was dried un der vacuum at 160 °C for 2 h
before use. Stan dard sam ples of alkyl adam an tan e-1-carboxylates28, 1-adam an tylm eth an ol29
1-(1-adam an tyl)eth an -1-ol30, 1-(1-adam an tyl)propan -1-ol30, 2-(1-adam an tyl)propan -2-ol31
,
,
3-(1-adam an tyl)pen tan -3-ol31 an d 1-adam an tyl alkyl/aryl keton es17 were prepared accordin g
to literature procedures. NMR spectra were recorded in CDCl3 on a Bruker AM-300 spectrom -
eter operatin g at 300 MHz for 1H an d 75.5 MHz for 13C, usin g TMS as an in tern al stan dard.
Ch em ical sh ifts are given in ppm (δ-scale), couplin g con stan ts (J) in Hz. IR spectra (ν, cm –1
)
were m easured in KBr pellets on an FTIR ATI Mattson Gen esis Series device. GC MS (EI at
70 eV, ion source at 200 °C) an alyses were run on a GC 8000 Series with detector Trio 1000
(Fison In strum en ts) on a Zebron -5 colum n , 30 m lon g, with h elium carrier gas; m/z values
are given alon g with th eir relative in ten sities (in %). In spectra presen tation s, adam an tyl is
abbreviated to Ad. Th e followin g tem perature program was used: 120 °C (7 m in ), tem pera-
ture in crease 25 °C/m in up to 250 °C. Meltin g poin ts are un corrected. Diffraction data for
com poun d 16 were collected on a Kum a KM-4 four-circle CCD diffractom eter an d corrected
for Loren tz an d polarization effects. Th e structure was solved by direct m eth ods an d refin ed
usin g a SHELXTL program package (SHELXTL, Version 5.10, 1997, Bruker AXS In c., Madison
(WI), USA). Th e h ydrogen atom s were placed in calculated idealized position s an d refin ed as
ridin g. CCDC 256207 con tain s th e supplem en tary crystallograph ic data for th is paper. Th ese
data can be obtain ed free of ch arge via www.ccdc.cam .ac.uk/con ts/retrievin g.h tm l (or from
th e Cam bridge Crystallograph ic Data Cen tre, 12, Un ion Road, Cam bridge, CB2 1EZ, UK; fax:
+44 1223 336033; or deposit@ccdc.cam .ac.uk). Tests for biological activity were perform ed in
th e Laboratory of Growth Regulators, In stitute of Experim en tal Botan y, Academ y of Scien ces
of th e Czech Republic, Olom ouc.
Adam an tan e-1-carbon yl Ch loride (1)
In to a suspen sion of adam an tan e-1-carboxylic acid (25.0 g, 0.126 m ol) in toluen e (32 m l),
SOCl2 (19.6 g, 0.164 m ol) was dropwise added at 70 °C. Th e reaction m ixture was th en
stirred at th is tem perature for 8 h . Excess SOCl2 was th en rem oved as an azeotrope with tol-
uen e. Fin ally, th e m ixture was cooled an d left crystallizin g at –15 °C. Th e pale yellow n ee-
dles obtain ed were filtered off an d dried in th e stream of an in ert gas (yield 22.3 g, 89%,
m .p. 47–48 °C; lit.32 49–51 °C). NMR data were iden tical with th ose reported32
.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 5, pp. 709–722

718
Vícha, Nečas, Potáček:
Grign ard Reagen ts 2a–2f
Grign ard reagen ts were prepared in th e usual way33 usin g th e correspon din g alkyl brom ides
or alkyl ch lorides an d 1.3 m ol excess of m agn esium turn in gs in dieth yl eth er, an d were im -
m ediately used in subsequen t reaction s. Th e con cen tration s of th eir clear solution s were de-
term in ed by acid/base titration 34
.
Reaction of Acyl Ch loride 1 with Grign ard Reagen ts 2. Gen eral Procedure
In to a well-stirred solution of 5.0 m m ol (1.00 g) of acyl ch loride 1 in 40 m l of fresh ly dis-
tilled dieth yl eth er, on e equivalen t of a Grign ard reagen t solution in dieth yl eth er was
added in on e portion at 5 °C. Th e reaction m ixture was allowed to warm up to room tem -
perature, an d stirred for 48 h . After a usual work-up in volvin g quen ch in g with 1 M h ydro-
ch loric acid, an d subsequen t wash in g th e organ ic layer with a saturated K2CO3 solution an d
brin e, th e m ixture was an alyzed by GC MS. Th e crude product was obtain ed by solven t re-
m oval. In som e cases, com poun ds could n ot be isolated by both colum n ch rom atograph y or
crystallization .
Reaction of Acyl Ch loride 1 with Meth ylm agn esium Iodide
A colorless solid (269 m g, 30%) precipitated after th e treatm en t of th e crude product with
dieth yl eth er. Th e product was filtered off, crystallized from aceton e an d iden tified as
2-(1-adam an tyl)propan -2-yl adam an tan e-1-carboxylate (11a ) (m .p. 182–185 °C). For
C
24H36O2 (356.5) calculated: 80.85% C, 10.18% H; foun d: 80.50% C, 10.08% H. 1H NMR:
1.63 s, 6 H (C(CH3)2); 1.67–1.71 overlapped m , 18 H (adam an tan e CH2); 2.03 m , 6 H
(adam an tan e CH). 13C NMR: 19.7 (C(CH3)2), 28.4 (AdCOO C3, C5, C7), 28.8 (Ad C3, C5,
C7), 36.2 (Ad C4, C6, C9), 36.9 (AdCOO C4, C6, C9), 37.4 (Ad C2, C8, C10), 39.4 (AdCOO
C2, C8, C10), 40.3, 42.3 (AdCOO C1), 86.2 (C(CH3)2), 177.3 (COO). IR: 2987–2850 s, 1720 s,
1454 w, 1385 w, 1360 w, 1323 w, 1275 w, 1250 m , 1227 w, 1192 w, 1140 m , 1103 w,
1074 m , 1018 w, 976 w, 868 w, 806 w, 741 w. EI MS: 176 (M+ – Ad – CO2 – 1, 16), 161 (3),
135 (Ad, 100), 119 (12), 107 (10), 105 (12), 93 (42), 91 (49), 79 (81), 77 (48), 67 (30), 65
(20), 55 (29), 53 (32).
Reaction of Acyl Ch loride 1 with Eth ylm agn esium Brom ide
Th e colorless solid obtain ed after solven t rem oval was crystallized from aceton e to yield
610 m g (68%) of 1-(1-adam an tyl)propyl adam an tan e-1-carboxylate (10b) (m .p. 122–124 °C).
For C24H36O2 (356.5) calculated: 80.85% C, 10.18% H; foun d: 80.47% C, 9.89% H. 1H NMR:
0.82 overlapped m , 3 H (CHCH2CH3); 1.54–1.74 overlapped m , 20 H; 1.95–2.03 overlapped
m , 12 H; 4.53 overlapped m ,
1 H
(CHCH2CH3). 13C NMR: 11.0 (CHCH2CH3), 21.1
(CHCH2CH3), 28.3 (AdCOO C3, C5, C7), 28.5 (Ad C3, C5, C7), 36.8 (Ad C1), 36.9 (AdCOO
C4, C6, C9), 37.4 (Ad C4, C6, C9), 38.5 (AdCOO C2, C8, C10), 39.5 (Ad C2, C8, C10), 41.4
(AdCOO C1), 81.7 (CHCH2CH3), 177.7 (COO). IR: 2966–2848 s, 1724 s, 1452 w, 1385 m ,
1342 w, 1321 w, 1269 w, 1236 s, 1184 w, 1103 w, 1072 m , 978 w, 941 w, 897 w, 812 w,
739 w, 675 w, 640 w. EI MS: 221 (M+ – Ad, 1), 181 (7), 176 (M+ – Ad – CO2 – 1, 65), 163
(Ad + CO, 7), 135 (Ad, 100), 93 (11), 91 (9), 79 (20), 77 (5), 67 (7).
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1-Adamantyl Ketones
719
Reaction of Acyl Ch loride 1 with Propylm agn esium Brom ide
Th e colorless solid (250 m g, 29%) precipitated after th e treatm en t of th e crude product with
eth er was filtered off, crystallized from aceton e an d iden tified as 1-adam an tylm eth yl
adam an tan e-1-carboxylate (9) (m .p. 251–252 °C; lit.35 247–250 °C). NMR data were iden tical
with th ose reported35
.
Reaction of Acyl Ch loride 1 with Isopropylm agn esium Brom ide
From th e crude m ixture, com poun d 9 (302 m g, 35%) was isolated after treatm en t with ace-
ton e. A secon d crop (73 m g, 7%) was obtain ed after repeated colum n ch rom atograph y
(h exan e–eth yl acetate, 8:1; silica gel). Th e colorless n eedles (m .p. 35–37 °C) were iden tified
as 1-(1-adam an tyl)-2-m eth ylpropan -1-ol (4d). Spectral data correspon ded to th ose reported36
.
Reaction of Acyl Ch loride 1 with Ph en ylm agn esium Brom ide
Two com poun ds were isolated from th e crude reaction m ixture by repeated colum n ch rom atog-
raph y (ch loroform ; silica gel). Th e first, flat colorless crystals (1.028 g, 85.1%, m .p. 49–51 °C;
lit.37 48–50 °C), was iden tified as 1-adam an tyl ph en yl keton e (3f). NMR data were iden tical
with th ose reported38. Th e oth er com poun d (1-adam an tyl)diph en ylm eth an ol (6f) was iso-
lated as colorless n eedles (120 m g, 7.5% relative to 1, m .p. 126–128 °C; lit.39 127–128 °C).
Spectral data correspon ded to th ose reported40
.
Reaction of Acyl Ch loride 1 with Ben zylm agn esium Brom ide
Th ree com poun ds were isolated from th e crude m ixture by colum n ch rom atograph y (silica
gel; h exan e–eth yl acetate, 8:1).
2-(1-Adamantyl)-1,3-diphenylpropan-2-ol (6e). Com poun d 6e was crystallized from h exan e
givin g 504 m g (28.9% relative to 1) of colorless waxy flat crystals (m .p. 119–122 °C). For
C
25H30O (346.5) calculated: 86.66% C, 8.73% H; foun d: 86.50% C, 8.67% H. 1H NMR:
1.74–1.86 overlapped m , 12 H (Ad CH2); 2.09 m , 3 H (Ad CH); 2.75 d, 2 H, J(CHAHB) = 13.9
(CHAHBPh ); 3.10 d, 2 H, J(CHAHB) = 13.5 (CHAHBPh ); 7.00 m , 4 H (CH2Ph ); 7.20 m , 6 H
(CH2Ph ). 13C NMR: 29.0 (Ad C3, C5, C7), 36.7 (Ad C4, C6, C9), 37.4 (Ad C2, C8, C10), 40.5
(CH2Ph ), 41.4 (Ad C1), 76.8 (C(CH2Ph )2), 126.3 (Ph C4), 128.2 (Ph C3, C5), 131.4 (Ph C2,
C6), 138.7 (Ph C1). IR: 3584 m , 3080 w, 3061 w, 3023 w, 2909 s, 2849 m , 1600 w, 1493 m ,
1452 m , 1345 m , 1085 m , 1031 w, 993 w, 967 w, 817 w, 748 m , 699 s, 604 w, 535 m . EI MS:
345 (M+ – 1, 3), 330 (3), 329 (M+ – OH, 3), 328 (5), 255 (M+ – ben zyl, 96), 237 (M+ – ben zyl –
H2O, 5), 211 (M+ – Ad, 8), 210 (M+ – Ad-1, 14), 193 (11), 163 (M+ – ben zyl – ph en yl, 5), 136
(adam an tan e, 42), 135 (Ad, 100), 119 (13), 118 (9), 115 (9), 107 (32), 105 (17), 93 (60), 92
(25), 91 (ben zyl, 94), 81 (21), 79 (60), 77 (ph en yl, 18), 67 (20), 65 (14), 55 (10).
1,3-Di(1-adamantyl)-2-phenylpropane-1,3-dione (12e). Com poun d 12e was crystallized from
dieth yl eth er givin g 357 m g (34.1% relative to 1) of colorless n eedles (m .p. 185–188 °C). For
C
29H36O2 (416.6) calculated: 83.61% C, 8.71% H; foun d: 83.41% C, 8.66% H. 1H NMR:
1.54–1.84 m , 24 H (Ad CH2); 2.18 m , 6 H (Ad CH); 5.73 s, 1 H (CHPh ); 7.18 m , 2 H (CHPh );
7.20–7.34 m , 3 H (CHPh ). 13C NMR: 28.3 (Ad C3, C5, C7), 36.7 (Ad C4, C6, C9), 39.2 (Ad
C2, C8, C10), 47.7 (Ad C1), 59.6 (CHPh ), 127.6 (Ph C4), 128.7 (Ph C3, C5), 130.1 (Ph C2,
C6), 133.7 (Ph C1), 207.4 (CO). IR: 2903 s, 2849 s, 1715 m , 1677 m , 1495 w, 1453 m , 1343
w, 1279 m , 1237 w, 1144 w, 1104 w, 1010 m , 930 w, 720 m , 698 w, 599 w, 555 w. EI MS:
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720
Vícha, Nečas, Potáček:
416 (M+, 1), 163 (Ad + CO, 17), 135 (Ad, 100), 118 (3), 107 (11), 93 (23), 91 (ben zyl, 14), 79
(20), 77 (ph en yl, 6), 67 (6).
3-(1-Adamantyl)-3-benzylisochromane-1-one (16). Com poun d 16 was crystallized from h ex-
an e to give 15 m g (1.6% relative to 1) of colorless crystals (m .p. 176–179 °C). 1H NMR:
1.71–1.84 m , 12 H (Ad CH2); 2.07 m , 3 H (Ad CH); 2.86 d, 1 H, J(CHAHB) = 13.9 (CHAHBPh );
2.96 d, 1 H, J(CHAHB) = 16.9 (CHCHD); 3.32 d, 1 H, J(CHCHD) = 13.8 (CHAHBPh ); 3.38 d,
1 H, J(CHCHD) = 16.9 (CHCHD); 6.95–7.12 m , 7 H; 7.27–7.32 m , 1 H; 7.76–7.79 m , 1 H.
13C NMR: 28.7 (Ad C3, C5, C7), 29.5 (C4), 36.5 (Ad C4, C6, C9), 37.1 (Ad C2, C8, C10),
40.9 (CH2Ph ), 41.4 (Ad C1), 88.6 (C3), 125.2 (C8a), 126.5 (C6), 126.6 (Ph C4), 127.4 (C5),
128.2 (Ph C3, C5), 129.5 (C8), 131.2 (Ph C2, C6), 133.4 (C7), 136.9 (C4a), 138.7 (Ph C1),
158.8 (C1). IR: 3060 w, 3030 w, 2902 s, 2846 m , 1695 s, 1604 w, 1493 w, 1458 m , 1344 w,
1302 m , 1225 w, 1124 m , 1030 w, 993 w, 748 m , 702 m , 609 w. EI MS: 373 (M+ + 1, 4), 281
(M+ – ben zyl, 78), 236 (M+ – Ad – 1, 10), 135 (Ad, 100), 118 (11), 107 (9), 93 (28), 91 (ben -
zyl, 72), 79 (33), 67 (10).
Reaction of Acyl Ch loride 1 with Tetrah ydrofuran
In a 100-m l flask, Zn Cl2 (110 m g, 0.8 m m ol) was dried by h eatin g to th e m eltin g poin t un -
der vacuum . After coolin g to laboratory tem perature, th e flask was filled with argon an d
50 m l of fresh ly distilled THF was added. Adam an tan e-1-carbon yl ch loride 5 g (25.16 m m ol)
was th en added in on e portion . Th e reaction m ixture was stirred un der reflux for 8 h . Th e
reaction was quen ch ed with 20 m l of 1 M HCl an d th e water layer was extracted th ree tim es
with dieth yl eth er. Th e com bin ed organ ic layers were wash ed twice with a saturated K2CO3
solution , on ce with brin e an d dried over an h ydrous Na2SO4. Th e solven t was rem oved to
obtain 6.47 g (95% yield) of a pale yellow oil. Th e crude product was purified by colum n
ch rom atograph y (silica gel; h exan e–eth yl acetate, 8:1) an d two com poun ds were isolated as
viscous colorless oils.
Th e m ajor product was 4-ch lorobutyl adam an tan e-1-carboxylate (14). For C15H23ClO2
(270.8) calculated: 66.53% C, 8.56% H; foun d: 66.38% C, 8.63% H. 1H NMR: 1.67–1.89 over-
lapped m , 16 H; 2.02 m , 3 H (Ad CH); 3.58 t, 2 H, J = 5.9 (O(CH2)3CH2Cl); 4.09 t, 2 H, J =
5.9 (OCH2(CH2)3Cl). 13C NMR: 26.3 (OCH2CH2(CH2)2Cl), 28.1(Ad C3, C5, C7), 29.4
(O(CH2)2CH2CH2Cl), 36.7 (Ad C4, C6, C9), 39.1 (Ad C2, C8, C10), 40.9 (Ad C1), 44.8
(O(CH2)3CH2Cl), 63.4 (OCH2(CH2)3O), 177.9 (COO). IR: 2907–2852 s, 1725 s, 1563 w, 1453 s,
1345 m , 1324 s, 1268 s, 1234 s, 1184 s, 1104 s, 1077 s, 1004 w, 978 w, 886 w, 740 m , 676 m ,
653 m . EI MS: 271 (M+ + 1, 2), 235 (M+ – Cl, 3), 181 (15), 179 (Ad + CO2, 6), 135 (Ad, 100),
107 (6), 93 (15), 91 (12), 79 (13), 77 (4), 67 (7), 55 (11).
Th e m in or product was 4-(4-ch lorobutoxy)butyl adam an tan e-1-carboxylate (15). For
C
19H31ClO3 (342.9) calculated: 66.55% C, 9.11% H; foun d: 66.62% C, 8.97% H. 1H NMR:
1.60–1.69 overlapped m , 12 H; 1.77–1.81 overlapped m , 8 H; 1.93 m , 3 H (Ad CH); 3.37 m ,
4 H ((CH2)3CH2OCH2(CH2)3); 3.50 t, 2 H, J = 6.6 (O(CH2)3CH2Cl); 3.99 t, 2 H, J = 6.2
(OCH2(CH2)3O). 13C NMR: 25.7 (O(CH2)2CH2CH2O), 26.4 (OCH2CH2(CH2)2O), 27.2
(OCH2CH2(CH2)2Cl), 28.1 (Ad C3, C5, C7), 29.7 (O(CH2)2CH2CH2Cl), 36.7 (Ad C4, C6, C9),
39.0 (Ad C2, C8, C10), 40.9 (Ad C1), 45.1 (OCH2)3CH2Cl), 64.0 (OCH2(CH2)3O), 70.1
(OCH2(CH2)3Cl), 70.5 (O(CH2)3CH2O), 177.9 (COO). IR: 2908–2798 s, 1725 s, 1560 w, 1453 s,
1364 m , 1345 s, 1324 w, 1268 m , 1235 s, 1184 m , 1105 s, 1077 s, 979 w, 963 w, 813 w,
741 w, 676 w, 651 w. EI MS: 343 (M+ + 1, 12), 235 (M+ – OC4H8Cl, 14), 163 (Ad + CO, 100),
135 (adam an tan e, 70), 93 (10), 91 (16), 71 (5), 55 (5).
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1-Adamantyl Ketones
721
Reaction of Acyl Ch loride 1 with Dioxan e
Acyl ch loride 1 (5 g, 25 m m ol) was dissolved in 50 m l (0.59 m ol) of dry dioxan e. A solution
of Zn Cl2 (0.1 g, 0.7 m ol) was th an added, an d th e m ixture was stirred for 48 h . After th is pe-
riod, 20 m l of 1 M HCl were added, an d th e m ixture was stirred for an oth er 15 m in . Th e wa-
ter layer was separated, an d extracted th ree tim es with dieth yl eth er. Th e com bin ed organ ic
ph ases were wash ed several tim es with a 1.6 M K2CO3 solution , an d dried over an h ydrous
Na2SO4. A pale yellow solid was obtain ed after solven t rem oval. Th e rem ain der of th e start-
in g m aterial was recovered from th e alkalin e extracts after acidification as adam an tan e-
1-carboxylic acid.
Th e crude product was crystallized from aceton e to yield 1.42 g (29.2%, m .p. 122–123 °C)
of 2-(1-adam an tan oyloxy)eth yl adam an tan e-1-carboxylate (13). For C24H34O4 (386.5) calcu-
lated: 74.58% C, 8.87% H; foun d: 74.73% C, 8.91% H. 1H NMR: 1.71 m , 12 H (Ad CH2);
1.89 m , 12 H (Ad CH2); 2.16 m , 6 H (Ad CH); 4.24 s, 4 H (O(CH2)2O). 13C NMR: 28.1 (Ad
C3, C5, C7), 36.7 (Ad C4, C6, C9), 39.0 (Ad C2, C8, C10), 40.9 (Ad C1), 62.0 (O(CH2)2O),
177.5 (COO). IR: 2066–2847 s, 1723 s, 1476 w, 1451 m , 1363 w, 1333 m , 1317 w, 1270 w,
1238 s, 1184 m , 1104 s, 1085 s, 999 w, 972 w, 936 w, 894 w, 811 w, 766 w, 741 w, 679 w. EI
MS: 385 (M+ – 1, 18), 251 (M+ – Ad, 19), 250 (M+ – Ad – CO, 32), 207 (M+ – Ad – CO2, 100),
163 (Ad + CO, 12), 136 (adam an tan e, 17), 135 (Ad, 91), 107 (6), 93 (16), 91 (6), 78 (5).
This work was supported by the Ministry of Industry and Trade of the Czech Republic (grant
No. PZ-CH/25). We thank R. Kareš for EI MS measurements.
REFERENCES
1. Aldrich P. A., Hermann E. C., Meier W. E., Paulshock M., Prichard W. W., Snyder J. A.,
Watts J. C.: J. Med. Chem. 1971, 14, 535.
2. Davies W. L., Grunert R. R., Haff R. F., Paulshock J., Walts J. C., Word T. R., Hermann
E. C., Hoffmann C. E.: Science 1964, 144, 862.
3. Oker-Blom N., Anderson A. L.: Eur. J. Cancer 1966, 2, 9.
4. Lundahl K., Schut J., Schlatmann J. L. M. A., Paerels G. B., Peters A.: J. Med. Chem. 1972,
15, 129.
5. Lasek W., Switaj T., Sienko J., Kasprzycka M., Basak G., Miklaszewicz P., Maj M., Nowis D.,
Grzela T., Golab J., Mlynarczuk I., Jalili A., Kaminska B., Dziembowska M., Czajkowski K.,
Nowaczyk M., Gorska A., Kazimierczuk Z.: Cancer Chemother. Pharm. 2002, 50, 213.
6. El-Sherbeny M. A.: Med. Chem. Res. 2002, 11, 74.
7. Gerzon K., Krumkalns E. V., Brindle R. L., Marshall F. J., Root M. A.: J. Med. Chem. 1963,
6, 760.
8. Rogóż Z., Dlaboga M., Dziedzicka-Wasylewska M.: J. Physiol. Pharmacol. 2003, 54, 257.
9. Chakrabarti J. K., Foulis M. J., Hotten T. M., Szinai S. S., Todd A.: J. Med. Chem. 1974,
17, 602.
10. Orzeszko A., Kamińska B., Starościak B.: Farmaco 2002, 57, 619.
11. Ilies M. A., Masereel B., Rolin S., Scozzafava A., Câmpeanu G., Cîmpeanu V., Supuran
C. T.: Bioorg. Med. Chem. 2004, 12, 2717.
12. Spasov A. A., Khamidova T. V., Bugaeva L. I., Morozov I. S.: Khim.-Farm. Zh. 2000, 34, 3.
13. Kato N., Eggers H.: Virology 1969, 37, 632.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 5, pp. 709–722

722
Vícha, Nečas, Potáček:
14. Kiselev O. I., Blinov V. M., Kozeletskaya K. N., Ilenko V. I., Platonov V. G., Chupakhin
O. N., Stukova M. A., Karginov V. A.: Vestn. Ross. Akad. Med. Nauk 1993, 1015.
15. Sasaki T., Simizu K.: Chem. Pharm. Bull. 1984, 4, 1433.
16. Cahiez G., Laboue B.: Tetrahedron Lett. 1992, 33, 4439.
17. Vícha R., Potáček M.: Tetrahedron 2005, 61, 83.
18. Hatano M., Matsumura T., Ishihara K.: Org. Lett. 2005, 7, 573.
19. Tuulmets A., Sassian M.: J. Organomet. Chem. 1999, 586, 145.
20. Ashby E. C., Goel A. B.: J. Am. Chem. Soc. 1981, 103, 4983.
21. Greene J. L., Abraham D., Zook H. D.: J. Org. Chem. 1959, 24, 132.
22. Whitmore F. C., Wheeler W. R.: J. Am. Chem. Soc. 1938, 60, 2899.
23. Alper H., Huang C.-C.: J. Org. Chem. 1973, 38, 64.
24. Ganem B., Small V. R.: J. Org. Chem. 1974, 39, 3728.
25. Green L., Hemeon I., Singer R. D.: Tetrahedron Lett. 2000, 41, 1343.
26. Porter C. W., Steel C.: J. Am. Chem. Soc. 1920, 42, 2650.
27. Goebel M. T., Marvel C. S.: J. Am. Chem. Soc. 1933, 55, 1693.
28. Marchand A. P., Xing D., Bott S. G.: Tetrahedron 1996, 52, 825.
29. Reith B. A., Strating J., Van Leusen A. M.: J. Org. Chem. 1974, 39, 2728.
30. Shiner V. J., Neumann T. E.: Croat. Chem. Acta 1996, 69, 1405.
31. Dua S., Bowie J. H.: J. Chem. Soc., Perkin Trans. 2 1998, 1443.
32. Hoffmann H. M. R., Haase K.: Synthesis 1981, 715.
33. Novakov C. P., Feierman D., Cederbaum A. I., Stoyanovsky D. A.: Chem. Res. Toxicol.
2001, 14, 1239.
34. Gilman H., Wilkinson P. D., Fishel W. P., Meyers C. H.: J. Am. Chem. Soc. 1923, 45, 150.
35. Grava I. Ya., Polis Ya. Yu., Lubak M. Yu., Lieninsh E. E., Shamc V. D., Dipan I. V., Gavars
M. P., Cekacis I. P.: Zh. Org. Khim. 1981, 17, 778.
36. Kraus G. A., Siclovan T. M.: J. Org. Chem. 1994, 59, 922.
37. Lednicer D., Heyd W. E., Emmert D. E., TenBrink R. E., Schurr P. E., Day C. E.: J. Med.
Chem. 1979, 22, 69.
38. Rieke R. D., Hanson M. V., Brown J. D., Nium Q. J.: J. Org. Chem. 1996, 61, 2726.
39. Stetter H., Rauscher E.: Chem. Ber. 1960, 93, 1161.
40. Molle G., Briand S., Bauer P., Dubois J.-E.: Tetrahedron 1984, 40, 5113.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 5, pp. 709–722