Esters and amides of hexanoic acid substituted with tertiary amino group in terminal position and their activity as transdermal permeation enhancers

Article abstract of DOI:10.2298/JSC090527034F

Series of alkyl esters of 6-(diethylamino)-, 6-(pyrrolidin-1-yl)-, 6-(piperidin-1-yl) and 6-(m orpholin-4-yl)hexanoic acids and alky lamides of 6-(dimethylamino)-, 6-(piperidin-1-y l) and 6-(morpholin-4-yl)hexanoic acids, co n-taining 8-12 c arbon ato ms in the alky l chai n, were prepared by m ethods of classical organi c sy nthesis. The appr opriate secondary a mine wa s alky lated with ethyl 6-bromohexanoate to give ester of ω-substituted hexanoic acid, except of ethy l 6-(di methylamino)hexanoate (1), which wa s pr epared by Esch-weiler-Clarke methylation of 6-a minohexanoic acid followe d by direct est erification with ethanol. The resulted esters of ω-substituted hexanoi c aci ds underwent dire ct transest erification with long chain alka nols to y ield the desired amino esters, or they were treated with long-chain alkylamines to prepare secondary a mides of the appropriate heterocy clic hexa noic a cids. These products were in vitro tested on their activity as transdermal permeation enhancers on the strip s of the excised hu man skin with theophylline as the model permeant. The activity was evaluated u sing para meter enh ancement ratio (ER), defined as the ratio between the overall am ount of the per meant pa ssing through the skin with the t ested enha ncer an d that witho ut tested substance. Decyl 6-(pyrrolidin-1-yl)hexanoate (9) with ER = 30 showed the high est activity. The enhancing effect s of the esters were generally better than those of the amides.

Full text of DOI:10.2298/JSC090527034F

J. Serb. Chem. Soc. 75 (5) 595–603 (2010)
JSCS–3990 547:616.032:61
UDC 547.295.2+547.288.2+542.913+
1.778
Original scientific paper
Esters and amides of hexanoic acid substituted with tertiary
amino group in terminal position and their activity as
transdermal permeation enhancers
1
2
3
*
OLDŘICH FARSA , PAVEL DOLEŽAL and ALEXANDR HRABÁLEK
1Institute of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharma-
ceutical Sciences Brno, Palackého 1/3, 612 42 Brno, 2Department of Pharmaceutical
Technology, Faculty of Pharmacy, Charles University, Hradec Králové and
3Department of Inorganic and Organic Chemistry, Faculty of Pharmacy,
Charles University, Hradec Králové, Czech Republic
(Received 27 May 2009, revised 4 January 2010)
Abstract: Series of alkyl esters of 6-(diethylamino)-, 6-(pyrrolidin-1-yl)-, 6-(pi-
peridin-1-yl) and 6-(m orpholin-4-yl)hexanoic acids and alky lamides of 6-(di-
methylamino)-, 6-(piperidin-1-yl) and 6-( morpholin-4-yl)hexanoic acids, con-
taining 8–12 c arbon ato ms in the alky l chai n, were prepared by m ethods of
classical organi c sy nthesis. Th e appr opriate secondary a mine wa s alky lated
with ethyl 6-bromohexanoate to give ester of ω-substituted hexanoic aci d, ex-
cept of ethy l 6-(di methylamino)hexanoate ( 1), which wa s pr epared by Esch -
weiler–Clarke methylation of 6-a minohexanoic acid followe d by direct est e-
rification with ethanol. The resulted esters of ω-substituted hexanoi c aci ds
underwent direct transesterification with long chain alkanols to y ield the de-
sired amino esters, or they were treated with long-chain alkylamines to prepare
secondary a mides of the appropriate heterocy clic hexa noic a cids. These pro -
ducts were in vitro tested on their activity as transdermal permeation enhancers
on the strip s of the excised hu man skin with theophylline as the model per -
meant. The activity was evaluated u sing para meter enh ancement ratio ( ER),
defined as the ratio between the overall am ount of the per meant pa ssing
through the skin with the t ested enha ncer an d that witho ut tested substance.
Decyl 6-(pyrrolidin-1-yl)hexanoate (9) with ER = 30 showed the high est ac-
tivity. The enhancing effect s of the esters were generally better than those of
the amides.
Keywords: transdermal permeation enhancers; ω-amino acid derivatives.
INTRODUCTION
Transdermal permeation enhancers (TPEs ) are speci al pharmaceutical exci-
pients, which enable or facilitate the passage of var ious drugs t hrough the skin
*Corresponding author. E-mail: farsao@vfu.cz
doi: 10.2298/JSC090527034F
595
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

596
FARSA, DOLEŽAL and HRABÁLEK
barrier to the blood circulation, thereby enabling their sy stemic effect. Together
with antimicrobial preservatives and antioxidants, t hey belong to a narrow group
of excipients which c an be chara cterized by their own enu merable a ctivities.
Only a few drugs with high lipophilicit y, such as steroids, nitrates, some opioid
analgesics (f entanyl) an d several alkal oids ( e.g., nicotine or scopolam ine), ar e
capable of penetrating through the skin by themselves. For this reason TPEs con-
stitute important ingredients of transder mal application sy stems, which are po -
pular because of their be nefits and used not only in hum an, but more recently
1
also in veterinary therapy. They can provide steady-state plas ma concentrations
of drugs an d long-term therapy from a si ngle dose, avoid the hepatic first-pass
metabolism a ssociated wit h oral adm inistration and allow easy termination of
drug input. The role of chemical TPEs is to reversibly alter the barrier properties
of the stratum corneum (SC), which is the outerm ost layer of skin, by disruption
2
of the membrane structures or by maximizing drug solubility within the skin.
Compounds used or tested as TPEs constitute a very diverse group of struc-
tures. Various derivatives of amino acids occupy among them a comparatively
important position. Previously, a series of long chain alkyl esters of 6-(dimethyl-
amino)hexanoic acid with a linear alkyl chain having 8 to 12 carbon atom s were
3
prepared. The distance of 5 carbon atoms between the terminal amino group and
the carboxyl as well as the range of lengths of alkyl chains were selected based on
previous experiences. The older results demonstrated that alkyl esters of ω-amino
acids have their optimum transdermal permeation enhancing effect for linear oc -
tyl to dodecyl groups, that branching of an alkyl chain essentially lowers the ac-
4
tivity, and that derivatives of 6-am inohexanoic acid are significantly m ore po-
5
tent than tho se with another num ber of carbon ato ms in the acy l chain. It was
found that these co mpounds showed hi gh enhancement activity of transder mal
permeation of theophylline as a model permeant of “moderate lipophilicity”. The
highest effect was obtained with dodecy l 6-(dim ethylamino)hexanoate (DDAK )
with an enhancement ratio (ER) of nearly 80. Such a significant activity was ra-
tionalized based on the higher basicity of the tertiary am ino group of this com-
3
pound. It is also supposed this increase of activity must be connected with an
essentially higher toxicity due to high stability against enzymatic hydrolysis. For
this reason, this type of structural modification temporarily became of marginal
interest. More recently , the above-menti oned DDAK was shown t o be an effec-
6
tive enhancer of percutane ous permeation of adefovir and h ydrocortisone. Sur-
prisingly, DDAK was demonstrated to be rapidly metabolized by porcine este-
rase with t = 17.2 m in and displa yed low acute toxicit y. It also showed re-
1/2
versibility of action on treated skin expressed as electrical resistance (impedance)
at 120 kHz, which during 3 h after treat ment with DDAK dropped to 20 % of its
7
initial value and after removal of the enhancer slowly increased. These r esults
returned our interest to th e field of enhancers with a tertiary amino group. The
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

6-AMINOHEXANOIC ACIDS DERIVATIVES ENHANCING PERMEATION
597
aim of this preliminary pilot study was to determine the influence of expansion of
the dimethylamino group into either an open diethylamino group or a closed satu-
rated heterocyclic ring, i.e., pyrrolidine, piperidine or morpholine, on permeation
enhancement activity. Simultaneously, the effect of substitution of the ester group
with an amide moiety could also be evaluated.
RESULTS
Synthesis of compounds and determination of their activity
Long-chain alkyl esters of 6-aminohexanoic acids with a tertiary amino
group. Ethyl esters of 6-(diethy lamino)hexanoic, 6-(py rrolidin-1-yl)hexanoic, 6 -
(piperidin-1-yl)hexanoic and 6-(morpholin-4-yl)hexanoic acids were prepared by
direct alky lation of the ap propriate secondar y am ine with eth yl 6-bromohexa-
noate. Their transesterifi cation with an appropriate long-chain alkanol cataly zed
with in situ prepared sodium alcoholate under the sim ultaneous distilling off of
8
the arising et hanol according to Franke et al. led t o octyl to dodecy l esters of
these ω-amino acids (Scheme 1).
Scheme 1. Procedure of the synthesis of alkyl esters and N-alkylamides of 6-(diethyl-
amino)hexanoic, 6-(pyrrolidin-1-yl)hexanoic, 6-(piperidin-1-yl)hexanoic and
6-(morpholin-4-yl)hexanoic acids.
Long chain alkyl amides of 6-(dimethylamino)hexanoic acid. Eschweiler–
–Clarke methylation of 6-aminohexanoic acid with formaldehyde and formic acid
9
according to Fusco et al. (the detail ed description of the rea ction procedure is
3
given in the literature ) gave 6-(dim ethylamino)hexanoic acid, which was d i-
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

598
FARSA, DOLEŽAL and HRABÁLEK
rectly esterified with ethanol. The resulting ethyl-6-(dimethylamino)hexanoate was
heated with an appropriate aminoalkane to yield the corresponding alkylamide of
6-(dimethylamino)hexanoic acid (Scheme 2).
Scheme 2. Procedure of the synthesis of N-alkyl-6-dimethylaminohexanamides (24–28).
Long chain alkyl amides of N,N-disubstituted 6-aminohexanoic acids. Octyl
to do decyl amides of 6-(dieth ylamino)hexanoic, 6-(pyrrolidin-1-yl)hexanoic,
6-(piperidin-1-yl)hexanoic and 6-(morpholin-4-yl)hexanoic acids were synthesized
similarly by heating of th e appropriate aminoalkane with an ω-substituted ethyl
hexanoate under the simultaneous distilling off of the arising ethanol (Scheme 1).
All products were isolated and purifie d either by distillation under reduced
pressure or by crystallization from a suitable system of solvents, or only by sorp-
tion filtration through an alu mina column. The iden tities of all the co mpounds
1
13
were confirmed b y their I R, H- and C-NMR-spectra and by elemental an a-
lysis.
Analytical and spectral data of the synthesized compounds
The complete analytical and spectral data of the synthesized compounds can
be found in the electron ic v ersion o f th e p aper as Suppl ementary material
(http://www.shd.org.rs/JSCS/), from the o ffice of the Serbian Che mical Society
upon request (JSCS@shd.org.rs) or from the corresponding author upon request.
Evaluation of the activity of the synthesized compounds and their results
Testing of the transder mal permeation enhancing activit y was performed in
vitro on strips of excised human skin with theophylline, thought to be a drug of
“middle lipophilicity”, as a model penetrant in the sy stem of liberation cells ac-
10
cording to Franz from a propylene glycol medium. Due to capacity utilization
of the testing workplace, only one or several members of each homologous series
underwent the evaluation procedure. The final results of the testing are presented
as values of the enhance ment ratio (ER), defined simply as the ratio between the
overall amount of the per meant which passed through t he skin with tested en-
hancer and that without the tested substance. These values are given in Table I.
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

6-AMINOHEXANOIC ACIDS DERIVATIVES ENHANCING PERMEATION
599
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

600
FARSA, DOLEŽAL and HRABÁLEK
DISCUSSION
The results of the determ ination of the percutaneous permeation enhancing
activity of the prepared compounds showed that substitution of ester moiety with
the isosteric amide group led to significant activity loss. This fact is probably not
only due to a decrease of the overall li pophilicity of such amides in comparison
to the isosteri c esters, but more to th e presence of an additional hydrogen bond
donor site in the CONH moiety and possibly also to the higher melting points of
the am ides ( e.g., m .p. 48–49 °C for 6-(dim ethylamino)N-dodecyl-hexanamide
(28), while the isosteric d odecyl 6-dimethylaminohexanoate is a liquid at roo m
temperature). These ch anges of the physic ochemical properties could lead to a
higher phase transition temperature of the lip id bilayers of cell membranes of SC
of a skin treated with an appropriate amide in comparison wit h that of a skin
treated with the isosteric ester, partially due to the lower SC uptake of the amidic
13,14
enhancer (co mp.
). In addition, an exchange of the t erminal dimethylamino
group with any other tertiary amino function, either acyclic diethylamino group,
or five- to six-me mbered saturated basic rings, caused a decrease in the activity.
Differences between the enhancing
effect of the esters of
6-(piperidin-1-
yl)hexanoic acid and the isosteric esters of 6-(morpholin-4-yl)hexanoic acid (the
ER values of the dec yl esters 15 and 20 are 5.6 an d 15.0, respectively) suggest
that not only the bulkiness of the basic substituent at the terminal position of the
chain of hexanoic acid itself, bu t also its lipophilicity and/o r the presen ce of
additional hydrogen bond acceptor site (ethereal oxygen of the morpholine ring)
15
could influe nce the activit y (com p. ). However, also the influence of the
different basicity of both heterocyclic substituents cannot be excluded (the pK of
a
N-alkylpiperidines ranges between 9 and 10 , while t he pK of N-alkylmorpho-
a
lines varies from 7 to 8). The overall basicity optimum could be found at a p K
a
slightly u nder 9, which is the value of the m
ost potent 6-(di methylamino)-
hexanoic acid derivative ( pK of 6-(dimethylamino)N-dodecyl-hexanamide (28)
a
11
is 8.8 ). As far as the alk yl chain length is concerned, the alk yls with 10 and 12
carbon atoms of both prep ared esters and amides seem to be more advantageous
than those wi th 8, 9 or 11 carbon atoms, but more data are required for a m ore
concrete statement. In general, the structur al changes realized in this study led to
compounds with reduced activities.
EXPERIMENTAL
General
1
The H- and 13C-NMR spectra were obtained using a V arian Mercury 300 MHz or V a-
rian Gemini 200 MHz FT-NMR spectrometer in deuterated chloroform or dimethyl sulfoxide.
The IR sp ectra were measured on a Nic olet Impact FTIR spectrometer. Melting points wer e
determined on a Boetius apparatus Nagema (Rapido Wägetechnik, Radebeul, Germany) and
are uncorrected. Elemental analyses (C, H, N, O) were perfor med on a Perkin–Elmer 2400
CHNS/O analyzer. All the presented rea ction yields are preparative. Deter mination of trans-
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

6-AMINOHEXANOIC ACIDS DERIVATIVES ENHANCING PERMEATION
601
dermal permeation enhancing activity was pe rformed on the set of cells according to Franz 10
manufactured in the workshops of the Fac ulty of Pharmacy of the Charle s University in Hra-
dec Králové, Czech Republic. The HPLC ana lyses were perf ormed on the c hromatographic
system consisting of the isocr atic pump LCP 4001(Ecom, Prague, Czech Republic), inj ector
LCI 30 (Laboratorni pristroje, Prague, Czech Republic), column LiChroCart 125-4 (LiChros-
pher 100, RP 18, 5 μm, Merck, Darmstadt, Germany), an SP 8440 UV detector (Spectra Phy-
sics) and the integrating software CSW 1.7 (Data Apex, Prague, Czech Republic), the mixture
methanol:water 1:1 was use d as the mobile phase at a flow rate 1 ml/min. The effluent was
monitored at 272 nm. The retention time of theophylline was 2.70±0.02 min.
Synthesis of esters of 6-(diethylamino)hexanoic acid (1, 5–7), 6-(pyrrolidin-1-yl)hexanoic acid
(2,8–11), 6-(piperidin-1-yl)hexanoic acid (3, 12–17) and 6-(morpholin-4-yl)hexanoic acid
(4,18–22)
A mixture of 0.500 mol (112 g) of ethy l 6-bromohexanoate and 1.5 mol of the ap pro-
priate secondary amine was re fluxed under sti rring for 24 h. After cooling, the reaction mix-
ture was diluted with 100 ml of diethyl ether and left in a refrigerator until cry stals of hydro-
bromide of the appropriate se condary a mine form ed. This salt wa s filtered off, the diethy l
ether was evaporated and the residue was distilled under reduced pressure. A reduced pressure
distillation of the reaction mixture after alkylation of pyrrolidine with ethyl 6-bromohexanoate
also gav e a small a mount of 1,6-bis(py rrolidin-1-yl)hexan-1-one (2a) as a by -product, pro-
bably originating by the dire ct a minolysis of ethy l 6-(py rrolidin-1-yl)hexanoate with py r-
rolidine.
A solution of 0.020 mol of (1), (2) (3) or (4) and 0.10 mol of an appropriate alkanol wa s
heated to 90 °C and then 0.010 mol of sodium was dissolved in it. This mixture was heated to
boiling and kept boiling under continuous distilling off of the formed ethanol through a 10 cm
long Vigreux column for 6 h. The unreacted alkanol was then distilled off, the liquid residue
was diluted with 4.0 ml of 0.50 M aqueous acetic acid, and this mixture was vigorously stirred
and then extrac ted with 3 ×20 ml of diethy l ether. The co mbined ethereal ex tracts were drie d
with sodium sulfate, the diethyl ether was evaporated and the pure long-chain alkyl ester was
obtained by distillation of the liquid residue under reduced pressure.
Alkylamides of 6-(dimethylamino)hexanoic acid
A mixture of 20 mmol ethyl 6-(dimethylamino)hexanoate (23), prepared by Eschweiler–
–Clarke reductive methylation followed by direct esterification with ethanol,3 and 22 mmol of
an appropriate aminoalkane, was heated under stirring at 180 °C for 2.5 h. After cooling, the
reaction mixture was di stilled under reduced pressure to re move both unrea cted 23 and al-
kylamine and to isol ate th e desired alky amide ( 24–27). N-Decyl-6-(dimethylamino)hexa-
namide (27), which spontaneously solidified at room temperature after it had been isolated by
distillation, was additionally recrystallized fr om hexane. 6-(dimethylamino)N-dodecyl-hexa-
namide ( 28) co uld not be i solated by distillat ion under redu ced pressure d ue to its to hig h
boiling te mperature, for this reason it wa s isol ated by recrystallizati on of the residue afte r
dodecylamine and 23 had been distilled off.
Alkylamides of 6-(piperidin-1-yl)hexanoic acid and 6-(morpholin-4-yl)hexanoic acid
A mixture of 0.020 mol of 3 or 4 and 0.022 m ol of an alkylamine was heated to a te m-
perature near t o the boiling p oint of the a mine for 4 h, then the mixture was di stilled under
reduced pressure, or it wa s dissolved in hexane and left to crystallize in a refrigerator to give
the corresponding alkylamide.
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

602
FARSA, DOLEŽAL and HRABÁLEK
Evaluation of the activity of the prepared compounds
Testing of tran sdermal permeation enhancing activity of th e prepared compounds wa s
performed by the sa me manner as w as pre viously describ ed for alky l esters of 6-(di me-
thylamino)hexanoic acid.3
CONCLUSIONS
32 novel long-chain alkyl esters and N-alkylamides of 6-aminohexanoic acids
with an acyclic or cyclic tertiary amino group and with alkyl chains in the range
from octy l to dodec yl wer e prepared (com pound 28, 6-(dim ethylamino) N-do-
11,12
decyl-hexanamide, which was previously patented in different contexts,
was
also prepared as a member of the homologous serie s). Thirteen of the prepare d
compounds were tested on their transd ermal permeation enhancement activity in
vitro using excised human skin with theophylline as the model permeant. All the
evaluated substances showed an enhancing effect. The highest activity , characte-
rized by ER = 30 was exhibited by compound 9, i.e., decyl 6-(pyrrolidin-1-yl)-
hexanoate. In general, the esters were more potent than the a mides. Comparison
of the activities of the tested compounds, including the previously prepared alkyl
3
6-(dimethylamino)hexanoates, suggested that increasing bulkiness of the ter-
minal basic substituent leads to a decrease of the act ivity and, in addition, a ba-
sicity optimum exists in region of pK slightly under 9.
a
Acknowledgements. This work was supported by the Research Project MSM0021620822
of the Ministry of Education of the Czech Republic.
И З В О Д
ЕСТРИ И АМИДИ ХЕКСАНСКЕ КИСЕЛИНЕ СУПСТИТУИСАНИ ТЕРЦИЈАРНОМ
АМИНО ГРУПОМ У ТЕРМИНАЛНОМ ПОЛОЖАЈУ И ЊИХОВА АКТИВНОСТ У
ПОВЕЋАЊУ ТРАНСДЕРМАЛНЕ ПРОПУСТЉИВОСТИ
OLDŘICH FARSA1, PAVEL DOLEŽAL2 и ALEXANDR HRABÁLEK3
1Institute of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences
Brno, Palackého 1/3, 612 42 Brno 2Department of Pharmaceutical Technology, Faculty of Pharmacy,
Charles University, Hradec Králové и 3Department of Inorganic and Organic Chemistry, Faculty of
Pharmacy, Charles University, Hradec Králové, Czech Republic
Серија алкил естара 6-(диетиламино)-, 6-(пиролидин-1-ил)-, 6-(пиперидин-1-ил) и 6-(мор-
фолин-4-ил)хексанских киселина и алкиламида 6- (диметиламино)-, 6-( пиперидин-1-ил)
и 6-(морфолин-4-ил)хексанских киселина, који садрже 8–12 угљеникових атома у алкил- ни-
зу, добијена је класичним органским синтезама. Одговарајући секундарни амин алкилован је
етил-6-бромхексаноатом (1) да би се добио естар ω-супституисане хексанске киселине, осим
етил-6-(диметиламино)хексаноата, који је добијен Ешвајлер–Кларковим (Eschweiler–Clarke)
метиловањем праћеним директном естерификацијом са етанолом. Добијени естри ω-супсти-
туисане хексанске киселине подвргнути су директној трансестерификацији са алкохолима
дугачког низа да би се добили жељени амино естри, или су третирани алкиламинима са ду-
гачким низом да би се добили секундарни амиди одговарајућих хетероцикличних хексан-
ских киселина. Активност ових прозвода у повећању трансдермалне пропустљивости тести-
рана је in vitro на узорцима људске коже, са теофилином као моделом пропустљивости. За
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

6-AMINOHEXANOIC ACIDS DERIVATIVES ENHANCING PERMEATION
603
оцену активности коришћен је параметар односа пропустљивости (ЕR), дефинисан као однос
укупне количине супстанце која пролази кроз кожу уз присуство испитиваних једињења и
без њих. Децил-6-(пиролидин-1-ил)хексаноат (9) са ЕR = 30 показао је највећу активност.
Ефекти естара у повећању пропустљивости били су, генерално, бољи него ефекти амида.
(Примљено 27. маја 2009, ревидирано 4. јануара 2010)
REFERENCES
1. B. M. Magnusson, K. A. Walters, M. S. Roberts, Adv. Drug Deliv. Rev. 50 (2001) 205
2. C. H. Purdon, C. G. Azzi, J. Zhang, E. W. Smith, H. I. Maibach, Crit. Rev. Ther. Drug
Carrier Syst. 21 (2004) 97
3. A. Hrabálek, P. Doležal, O. Farsa, Z. Šklubalová, Pharmazie 55 (2000) 759
4. A. Hrabálek, K. Vávrová, P. Doležal, M. Macháček, J. Pharm. Sci. 94 (2005) 1494
5. A. Hrabálek, P. Doležal, M. Roman, M. Macháček, Z. Šklubalová, Pharmazie 49 (1994)
325
6. K. Vávrová, K. Lorencová, J. Novotný, A. Holý, A. Hrabálek, Eur. J. Pharm. Biopharm.
70 (2008) 901
7. J. Novotný, P. Kova říková, M. Novotný, B. Ja nůšová, A. Hrabálek, K. Vávrová, Pharm.
Res. 26 (2009) 811
8. F. Franke, M. Klepel, H. Lehman, C. Schromm, B. Braemer, (Fahlberg List), DD 201371
(1983)
9. R. Fusco, G. Palazzo, S. Chavarelli, D. Bovet, Gazz. Chim. Ital. 79 (1949) 836
10. T. J. Franz, J. Invest. Dermatol. 64 (1975) 190
11. V. Böllert, U. Curtius, G. Fritz, J. Nentwig, (Bayer Leverkusen), DE 1418849 (1969)
12. J. Conrad, H. Schnegelb erger, H.-W. Eckert, F. Saygin, G. Koppensteiner, (Henkel), DE
2355026 (1975)
13. J. Hadgraft, J. Peck, D. G. Williams, W. J. Pugh, G. Allan, Int. J. Pharm. 141 (1996) 17
14. K. M. B. Mackay, A. C. Williams, B. W. Barry, Int. J. Pharm. 228 (2001) 89
15. Y. Song, C. Xiao, R. Mendelsohn, T. Zheng, L. Strekowski, B. Michniak, Pharm. Res. 22
(2005) 1918
16. P. A. Barett, (Wellcome Foundation), GB 682160 (1952)
17. P. Barczynski, Z. Dega-Szafran, E. Dulewicz, M. Petryna, M. Szafran, Pol. J. Chem. 74
(2000) 1149
18. Y. K. Lu, O. Y. Magidson, Zh. Obshch. Khim. 29 (1959) 3299
19. T. Abe, H. Baba, K. Okuhara, H. Fukaya, J. Fluorine Chem. 111 (2001) 115.
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

J. Serb. Chem. Soc. 75 (5) S1–S10 (2010)
JSCS–3990 547:616.032:61
UDC 547.295.2+547.288.2+542.913+
1.778
Supplementary material
SUPPLEMENTARY MATERIAL TO
Esters and amides of hexanoic acid substituted with tertiary
amino group in terminal position and their activity as
transdermal permeation enhancers
1
2
3
*
OLDŘICH FARSA , PAVEL DOLEŽAL and ALEXANDR HRABÁLEK
1Institute of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharma-
ceutical Sciences Brno, Palackého 1/3, 612 42 Brno, 2Department of Pharmaceutical
Technology, Faculty of Pharmacy, Charles University, Hradec Králové and
3Department of Inorganic and Organic Chemistry, Faculty of Pharmacy,
Charles University, Hradec Králové, Czech Republic
J. Serb. Chem. Soc. 75 (5) (2010) 605–613
Ethyl 6-(diethylamino)hexanoate (1). Yield 50 % ; b.p. 104–109 °C at 0.7–
16
–1
0.9 kPa (137–140 °C at 1.86 kPa ). IR (CHCl , cm ): 2973, 2838, 1727, 1466,
3
1
1375, 1300, 1270. H-NMR (300 MHz, CDCl , δ / ppm): 4.13 (2H, q, J = 14.5,
3
7.4 Hz, CH CH O), 2.49 (4H, q, J = 14.0, 6.9 Hz, (CH CH ) N), 2.40 (2H, t, J =
3
2
3
2 2
= 7.2 Hz, CH CO), 2.30 (2H, t, J = 7.5 Hz, NCH acyl), 1.70–1.58 (2H, m, CH
2
2
2
acyl), 1.52 –1.38 (2 H, m, CH acy l), 1.3 6–1.20 (5H, m, CH ac yl + C H CH O),
2
2
3
2
13
1.00 ( 6H, t, J = 6.5 Hz, (C H CH ) N). C-NMR (75 MHz, δ / ppm ): 173.45
3
2 2
(CO), 60.07 (OCH ), 52.70 (CH N acy l), 46.80 ( (CH ) N), 3 4.28 ( CH CO),
2
2
2 2
2
27.22 ( CH CH N), 26.73 ( CH (CH ) CO), 24.95 ( CH CH CO), 14.25
2
2
2
2 2
2
2
(CH CH O) 11.68 ((CH CH ) N).
3
2
3
2 2
Ethyl 6-(pyrrolidin-1-yl)hexanoate (2). Yield 53 %; b.p. 106–112 °C at 0.5–
16
–1
–0.6 kPa (143–146°C at 2.0 kPa ). IR (CHCl , cm ): 2965, 2938, 2880, 2865,
3
1
2800, 1727, 1464, 1375, 1301, 1271. H-NMR (200 MHz, CDCl , δ / ppm): 4.11
3
(2H, q, J = 14.3, 7. 3 Hz, OCH ), 2.55–2.36 (6H, m, (CH ) N), 2.29 (2H, t, J =
2
2 3
= 7.51 Hz, CH CO), 1.82–1.30 (10H, m, 5CH ), 1.24 (3H, t, J = 7.1 Hz, CH ).
2
2
3
13
C-NMR (50 MHz, δ / p pm): 173.67 (CO), 60.10 (OCH ) 56.40 (NCH acyl),
2
2
54.18 ((CH ) N pyrr.), 34.30 (CH CO), 28.65 (CH ), 27.25 (CH ), 24.92 (CH ),
2 2
2
2
2
2
23.43 (CH ), 14.20 (CH ).
2
3
1,6-Bis(pyrrolidin-1-yl)hexan-1-one (2a), a side product. Yield 3 % ; b.p .
178–183 °C at 0.06–0. 08 kPa; Anal. Calcd. for C H N O: C, 70.54; H, 10.99;
14 26
2
N, 11.75; O, 6.71 %. Found: C, 70.61; H, 11.05; N, 11.69; O, 6.80 %. IR (CHCl ,
3
*Corresponding author. E-mail: farsao@vfu.cz
S1
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

S2
FARSA, DOLEŽAL and HRABÁLEK
–1
1
cm ): 2973, 2936, 2879, 2800, 1624, 1448, 1343, 1328, 1294, 1270, 1252. H-
-NMR (200 MHz, CDCl , δ / ppm ): 3.40 (4H, qi, 2 CH ); 2.58–2.37 (6H, m,
3
2
(CH ) N) acyl); 2.24 (2H , t, J = 7.5 Hz, CH CO), 2.00–1.15 (14H, m, 7 CH ).
2 3
2
2
13
C-NMR (50 MHz, δ / ppm): 171.55 (CO), 56.43 (NCH acyl), 54.16 ((CH ) N
2
2 2
pyrr-acyl), 46.50 (CON( CH ) ), 45.48 (CH ), 34.63 ( CH CO), 28.81 (CH ),
2 2
2
2
2
27.55 (CH ), 26.06 (CH ), 24.77 (CH ), 24.33 (CH ), 23.38 (CH ).
2
2
2
2
2
Ethyl 6-(piperidin-1-yl)hexanoate (3). Yield 55 % , b.p. 120 –124 °C at 0.13
17
–1
kPa (114– 115 °C at 0.11 kPa ). IR ( CHCl , cm ): 2938, 2865, 280 0, 17 27,
3
1
1464, 1375, 1271. H-NMR (200 MHz, CDCl , δ / ppm): 4.11 (2H, q, J = 14.3,
3
7.3 Hz, OCH ) 2.43–2.20 (4H, m, NCH + CH CN acyl), 2.3 (4H, 4t, J = 7.0 Hz,
2
2
2
2 CH N piperid.), 1.77–1.30 (12H, m, β+γ CH piperid. + β+γ+δ CH acyl), 1.24
2
2
2
13
(3H, t, J = 7 .1 Hz, C H ). C-NMR (50 MHz, δ / ppm ): 173.6 7 (CO), 60.10
3
(OCH ), 59.35 (NCH acy l), 54. 63 (( CH ) N piperid), 34.3 3 ( CH CO), 27.33
2
2
2 2
2
(NCH CH ), 26.04 (CH ), 25.02 (CH CH CO), 14.20 (CH ).
2
2
2
2
2
3
Ethyl 6-(morpholin-4-yl)hexanoate (4). Yield: 82 %; b.p. 120–123 °C at 0.4
18
19
–1
kPa (140–144 °C at 0.5 3 kPa, 150–153 °C at 0. 53 kPa ). IR ( CHCl , cm ):
3
1
2941, 2863, 1727, 1458, 1375, 1256. H-NMR (300 MHz, CDCl , δ / ppm): 4.11
3
(2H, q, J = 14.4, 7.5 Hz, CH CH O), 3.70 (4H, t, J = 4.7 Hz, O(C H CH ) N),
3
2
2
2 2
2.40 (4H, t, J = 4.4 Hz, O(CH CH ) N), 2.35–2.25 (4H, m, CH CO + NCH
2
2 2
2
13
2
acyl), 1.73–1.41 (6H, m, (3CH ), 0.87 (3H, t, J = 6.7 Hz, CH ). C-NMR (75
2
3
MHz, CDCl , δ / ppm): 173.28 (CO), 66.82 ((CH ) O morph.), 60.04 (CH OCO),
3
2 2
2
58.74 (CH N acyl), 53.64 ((CH ) N morph.), 34.15 (CH CO), 26.93 (CH CH N
2
2 2
2
2
2
acyl), 26.16 (CH (CH ) CO), 24.79 (CH CH CO), 14.21 (CH ).
2
2 2
2
2
3
Octyl 6-(diethylamino)hexanoate (5). Yield 67 %; b.p. 134–138 °C at 0.03 5
kPa; Anal. Calcd. for C H NO : C, 72.19; H, 12 .45; N, 4.6 8; O, 10.68 % .
18 37
2
–1
Found: C, 72.25; H, 12.35; N, 4.59; O, 10.80 %. IR (CHCl , cm ): 2930, 2856,
3
1
1727, 1465, 1378, 1271. H-NMR (300 MHz, CDCl , δ / ppm): 4.04 (2H, t, J =
3
6.9 Hz, OCH ), 2.50 (4H, q, J = 7.1, 14.3 Hz, (CH CH ) N), 2.36 (2H, t, J = 7.7
2
3
2 2
Hz, NCH CH ), 2.29 (2 H, t, J = 7.6 Hz, CH CO), 1.68–1.25 (18H, m, 9 CH ),
2
2
2
2
13
0.99 (6H, t, J = 7.1 Hz, (C H CH ) N), 0.87 (3H, t, J = 6.7 Hz, CH octyl). C-
3
2 2
3
NMR (75 MHz, δ / ppm): 174.12 (CO), 64.66 (OCH ), 52.98 (NCH ), 47.07
2
2
((CH CH ) N), 34.58 (CH CO), 32.01 (CH ), 29.44 (CH CO), 29.41 (CH CO),
3
2 2
2
2
2
2
28.86 ( CH CO), 27.48 (CH CO), 26.94 ( CH CO), 26.16 ( CH CO), 25.23
2
2
2
2
(CH CO), 22.65 (CH CH octyl), 14.32 (CH octyl). 11.87 ((CH CH ) N).
2
2
3
3
3
2 2
Decyl 6-(diethylamino)hexanoate (6). Yield 52 %; b.p. 154–158 °C at 0.018
kPa. Anal. calcd. for C H NO : C, 73.34; H, 12.62; N, 4.28; O, 9.77 %. Found:
20 41
2
–1
C, 73.25; H, 12.54; N, 4. 17; O, 9.6 6 %. IR (CHCl , cm ): 2933, 2859, 1727,
1458, 1378, 1270. H-NMR (300 MHz, CDCl , δ / ppm): 4.05 (2H, t, J = 6.8 Hz,
3
1
3
OCH ), 2.51 (4H, q, J = 7.1, 14.3 Hz, (CH CH ) N), 2.37 (2H , t, J = 7.7 Hz,
2
3
2 2
NCH CH ), 2.29 (2H, t, J = 7.6 Hz, CH CO), 1.69–1.23 (20H, m, 10 CH ), 0.99
2
2
2
2
13
(6H, t, J = 7.1 Hz, (CH CH ) N), 0.87 (3H, t, J = 6.7 Hz, CH decyl). C-NMR
3
2 2
3
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

SUPPLEMENTARY MATERIAL
S3
(75 MHz, δ / ppm ): 173.91 (CO), 64.48 (OCH ), 52.6 9 ( NCH ), 46.80
2
2
((CH CH ) N), 29.31 (C H ), 29.22 ( CH ), 28.59 (CH ), 27.21 (CH ); 26.66
3
2 2
2
2
2
2
(CH ), 25.89 (CH ), 24.96 (CH ), 22.65 (CH ), 14.15 (CH decy l), 11. 59
2
2
2
2
3
((CH CH ) N).
3
2 2
Dodecyl 6-(diethylamino)hexanoate (7). Yield: 52 %; b.p. 162–166 at 0. 02
kPa. Anal. Calcd. for C H NO : C, 74.31; H, 12.76; N, 3.94; O, 9.0 %. Found:
22 45
2
–1
C, 74.27; H, 12.64; N, 4. 02; O, 8.9 2 %. IR (CHCl , cm ): 2931, 2859, 1727,
1465, 1378, 1270. H-NMR (300 MHz, CDCl , δ / ppm): 4.03 (2H, t, J = 6.7 Hz,
3
1
3
OCH ), 2.50 (4H, q, J = 14.3, 7.1 Hz, (CH CH ) N), 2.38 (2H , t, J = 7.6 Hz,
2
3
2 2
NCH CH ), 2.30 (2H, t, J = 7.6 Hz, CH CO), 1.63–1.56 (2H, m, OCH CH ),
2
2
2
2
2
1.49–1.35 (2H, m, CH ), 1.32–1.24 (18H, m, 9 CH ), 0.99 (6H, t, J = 7.1 Hz,
2
2
13
(CH CH ) N), 0.88 (3H, t, J = 6.7 Hz, CH dodecyl). C-NMR (75 MHz, δ /
3
2 2
3
/ ppm): 173.83 (CO), 64.38 (OCH ), 52.69 (NCH ), 46.79 ((CH CH ) N), 34.30
2
2
3
2 2
(CH CO), 29.60 (CH ), 29.59 (CH ), 29.54 (CH ), 29.49 (CH ), 29.31 (CH ), 29.22
2
2
2
2
2
2
(CH ), 28.59 (CH ), 27.21 (CH ), 26.66 (CH ), 25.89 (CH ), 24.96 (CH CH CO),
2
2
2
2
2
2
2
22.65 (CH CH dodecyl), 14.08 (CH dodecyl), 11.59 ((CH CH ) N).
2
3
3
3
2 2
Octyl 6-(pyrrolidin-1-yl)hexanoate (8). Yield: 71 %; b.p. 127–136 °C at 0.03
kPa. Anal. C alcd. for C H NO : C, 72.68; H, 11.86; N, 4.71; O, 10.76 %.
18 35
2
–1
Found: C, 72.56; H, 11.92; N, 4.61; O, 10.82 %. IR (CHCl , cm ): 2930, 2858,
2801, 1724, 1466, 1352, 1270. H-NMR (300 MHz, CDCl , δ / ppm): 4.04 (2H,
3
1
3
t, J = 6.7 Hz, OCH ), 2.51–2.35 (6H, m, (CH ) N pyrr. + NCH acyl), 2.30 (2H,
2
2 2
2
t, J = 7. 5 Hz, CH CO), 1.79–1.73 (4H, m, 2 C H ), 1.69–1.46 (6H, m, 3 CH ),
2
2
2
13
1.40–1.19 (14H, m, 7 CH ), 0.87 (3H, t, J = 6.9 Hz, CH ). C-NMR (75 MHz,
2
3
δ / ppm): 173.59 (CO), 64.40 (OCH ), 56.40 (NCH acyl), 54.20 ((CH ) N pyrr.),
2
2
2 2
34.30 ( CH CO), 31.79 ( CH CH CH ), 29.22 (CH alky l), 29. 20 (CH alky l),
2
2
2
3
2
2
28.80 (OCH CH ), 28.66 (NCH CH acy l), 27.29 ( CH (CH ) CO), 25.9 5
2
2
2
2
2
2 2
(O(CH ) CH ), 24. 99 ( CH CH CO), 23.40 (( CH ) CH N py rr., i.e., 2 βCH
2 2
2
2
2
2 2
2
2
pyrr.), 22.66 (CH CH ), 14.13 (CH ).
2
3
3
Decyl 6-(pyrrolidin-1-yl)hexanoate (9). Yield: 62 %; b.p.150–155 °C at 0.02
kPa. Anal. C alcd. for C H NO : C, 73.79; H, 12.08; N, 4.30; O, 9.83 %.
20 39
2
–1
Found: C, 7 3.67; H, 12. 15; N, 4.21; O, 9.91 % . IR (CHCl , cm ): 2929, 2858,
2800, 1724, 1467, 1353, 1272. H-NMR (300 MHz, CDCl , δ / ppm): 4.07 (2H,
3
1
3
t, J = 6.8 Hz, OCH ), 2.51–2.34 (6H, m, (CH ) N pyrr.+ NCH acyl), 2.29 (2H,
2
2 2
2
t, J = 7. 5 Hz, CH CO), 1.79–1.73 (4H, m, 2 CH ), 1.68–1.45 (6H, m, 3 CH ),
2
2
2
13
1.41–1.16 (16H, m, 8 CH ), 0.87 (3H, t, J = 6.7 Hz, CH ). C-NMR (75 MHz,
2
3
δ / ppm): 173.61 (CO), 64.40 (OCH ), 56.42 (NCH acyl), 54.21((CH ) N pyrr.),
2
2
2 2
34.33 ( CH CO), 31.92 ( CH CH CH ), 29.66 (CH alky l), 29. 62 (CH alky l),
2
2
2
3
2
2
29.57 (CH alky l), 29 .35 (CH alky l), 29.2 9 (CH alky l), 28 .79 (OCH CH ),
2
2
2
2
2
28.68 (NCH CH acy l), 27.31 ( CH (CH ) CO), 2 5.98 (O(CH ) CH2), 25.0 1
2
2
2
2 2
2 2
(CH CH CO), 23.42 (( CH ) CH N pyrr., i.e., 2 βCH pyrr.), 22.73 (CH CH ),
2
2
2 2
2
2
2
3
14.18 (CH ).
3
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

S4
FARSA, DOLEŽAL and HRABÁLEK
Undecyl 6-(pyrrolidin-1-yl)hexanoate (10). Yield: 66 %; b.p. 169–170 °C at
–1
1
0.04 kPa. IR (CHCl , cm ): 2928, 28 56, 280 1, 17 24, 146 6, 13 52, 127 5; H-
3
-NMR (300 MHz, CDCl , δ / ppm ): 4.04 (2H, t, J = 6.8 Hz, OCH ), 2.51–2.35
3
2
(m, 6H, (CH ) N pyrr.+ NCH acyl), 2.29 (2H, t, J = 7.5 Hz, CH CO), 1.81–1.71
2 2
2
2
(4H, m, 2 C H ), 1.69–1.47 (6H, m, 3 CH ); 1.40–1.18 (18H, m, 9 CH ), 0.87
2
2
2
13
(3H, t, J = 6 .6 Hz, C H ). C-NMR (75 MHz, δ / ppm ): 173.5 7 (CO), 64.37
3
(OCH ), 56.40 (NCH acyl); 54.21 ((CH ) N py rr.), 34.30 (CH CO), 31.9 2
2
2
2 2
2
(CH CH CH ); 29.62 (CH alkyl); 29.60 (CH alkyl), 29.55 (CH alkyl), 29.35
2
2
3
2
2
2
(CH alkyl), 29.28 (CH alkyl), 28.81 (OCH CH ), 28.66 (NCH CH acyl), 27.29
2
2
2
2
2
2
(CH (CH ) CO), 25.96 (O(CH
) CH ), 25.0 0 ( CH CH CO), 23.4 1
2
2 2
2 2
2 2 2
((CH ) CH N pyrr., i.e., 2 βCH pyrr.), 22.71 (CH CH ), 14.17 (CH ).
2 2
2
2
2
3
3
Dodecyl 6-(pyrrolidin-1-yl)hexanoate (11). Yield 49 %; b.p. 182 –183 °C at
0.04 kPa. Anal. Calcd. for C H NO : C, 74.73; H, 12.26; N, 3. 96; O, 9.05 %.
22 43
2
–1
Found: C, 7 4.68; H, 12. 35; N, 3.89; O, 9.11 % . IR (CHCl , cm ): 2928, 2856,
3
1
2801, 1724, 1466, 1352, 1275. H-NMR (300 MHz, CDCl , δ / ppm): 4.04 (2H,
3
t, J = 6.8 Hz, OCH ), 2.52–2.37 (6H, m, (CH ) N pyrr. + NCH acyl), 2.30 (2H,
2
2 2
2
t, J = 7. 4 Hz, CH CO), 1.81–1.71 (4H, m, 2 CH ), 1.70–1.46 (6H, m, 3 CH ),
2
2
2
13
1.42–1.17 (20H, m, 10 CH ), 0.87 (3H, t, J = 6.8 Hz, CH ). C-NMR (75 MHz,
2
3
δ / ppm): 173.61 (CO). 64.40 (OCH ), 56.42 (NCH acyl), 54.22 (CH ) N pyrr.),
2
2
2 2
34.33 ( CH CO), 31.95 ( CH CH CH ), 29.69 (CH alky l), 29. 67 (CH alky l),
2
2
2
3
2
2
29.62 (CH alkyl), 29.57 (CH alkyl), 29.39 (CH alkyl), 29.30 (CH alkyl), 28.81
2
2
2
2
(OCH CH ), 28.69 (NCH CH acyl), 27.32 (CH (CH ) CO), 25.98 (O(CH ) CH ),
2
2
2
2
2
2 2
2 2
2
25.02 ( CH CH CO), 23.43 (( CH ) CH N py rr., i.e., 2 βCH p yrr.), 22.74
2
2
2 2
2
2
(CH CH ), 14.19 (CH ).
2
3
3
Octyl 6-(piperidin-1-yl)hexanoate (12). Yield: 62 %; b.p.163 °C at 0.04–0.05
kPa; Anal. Calcd. for C H NO : C, 73.26; H, 11 .97; N, 4.5 0; O, 10.27 % .
19 37
2
–1
Found: C, 73.18; H, 12.05; N, 4.43; O, 10.39 %. IR (CHCl , cm ): 2934, 2858,
1724, 1469, 1456, 1378, 1271, 1258. H-NMR (300 MHz, CDCl3, δ / ppm): 4.04
3
1
(2H, t, J = 6.5 Hz, OCH ), 2.41–2.20 (8H, m, (4 CH ), 1.69–1.37 (12H, m, 6
2
2
13
CH ), 1.36–1.20 (12H, m, 6 CH ), 0.88 (3H, t, J = 6.8 Hz, CH ). C-NMR (75
2
2
3
MHz, CDCl , δ / pp m): 173.61 (CO); 64.39 (OCH ), 59.35 (NCH acyl), 54.63
3
2
2
((CH ) N piperid.), 3 4.33 ( CH CO), 31.81 (CH ); 29. 25 (CH ) 29.22 (CH ),
2 2
2
2
2
2
28.67 (CH ), 27.33 (NCH CH ), 26.68 (CH ); 26.04 (CH ), 25.97 (CH ), 25.02
2
2
2
2
2
2
(CH CH CO), 24.54 (CH ), 22.68 (CH CH ); 14.15 (CH ).
2
2
2
2
3
3
2-Octyl 6-(piperidin-1-yl)hexanoate (13). Yield: 68 %; pale yellow oil. Anal.
Calcd. for C H NO : C, 73.26; H, 11.97; N, 4 .50; O, 10. 27 % . Found: C,
19 37
2
–1
73.21; H, 12 .08; N, 4. 41; O, 10.34 % . IR (CHCl , cm ): 2936, 285 8, 17 25,
1469, 1456, 1378, 1271, 1257. H-NMR (300 MHz, CDCl , δ / ppm): 4.98–4.82
3
1
3
(1H, m, OCH), 2.43–2.20 (8H, m, 4 CH ) 1.69–1.37 (12H, m, 6 CH ), 1.36–1.13
2
2
13
(13H, m, 5 CH + CHCH ), 0.87 (3H, t, J = 6.80 Hz, term inal CH ). C-NMR
2
3
3
(75 MHz, CDCl , δ / ppm) 173.17 (CO), 70.71 (OCH), 59.37 (NCH acyl), 54.63
3
2
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

SUPPLEMENTARY MATERIAL
S5
((CH ) N piperid.), 35.9 6 (OCH CH ), 34.69 ( CH CO), 31.78 (CH ), 29.14
2 2
2
2
2
(CH ), 27.32 (NCH CH ), 26.70 (CH ), 26.04 (CH ), 25.41 (OCHCH CH ),
2
2
2
2
2
2
2
25.10 ( CH CH CO), 24.54 ( CH (CH ) piperid. ), 22.6 2 ( CH CH ), 20.06
2
2
2
2 2
2
3
(OCHCH ), 14.13 (CH CH ).
3
2
3
Nonyl 6-(piperidin-1-yl)hexanoate (14). Yield: 47 %; pale y ellow oil. Anal.
Calcd. for C H NO : C, 73.79; H, 12.08; N, 4.30; O, 9.83 %. Found: C, 73.69;
20 39
2
–1
H, 12.15; N, 4.24; O, 9.94 %. IR (CHCl , cm ): 2934, 2857, 1724, 1468, 1456,
1378, 1271, 1257. H-NMR (300 MHz, CDCl , δ / ppm): 4.03 (2H, t, J = 6.7 Hz,
3
1
3
OCH ), 2.41–2.21 (8H, m, 4 CH ), 1.70–1.18 (26H, m, 13 CH ), 0.86 (3H, t, J =
2
2
2
13
= 6.7 Hz, CH ). C-NMR (75 MHz, CDCl , δ / ppm ): 173.81 (CO), 64. 38
3
3
(OCH ), 59.30 (NCH acyl), 54.57 ((CH ) N p iperid.), 34.25 (CH CO), 31.80
2
2
2 2
2
(CH ), 29.43 (CH ), 29.20 (CH ), 29.19 (CH ), 28.58 (CH2), 27.24 (CH ), 26.56
2
2
2
2
2
(CH ), 25.91 (CH ), 25.88 (CH ), 24.92 ( CH CH CO), 24.42 (CH ), 22.61
2
2
2
2
2
2
(CH CH ), 14.06 (CH ).
2
3
3
Decyl 6-(piperidin-1-yl)hexanoate (15). Yield: 55 % ; pale yellow oil. Anal.
Calcd. for C H NO : C, 74.28; H, 12.17; N, 4.13; O, 9.42 %. Found: C, 74.18;
21 41
2
–1
H, 12.25; N, 4.07; O, 9.5 3 %. IR (CHCl cm ): 2931, 2857, 1724, 1468, 1456,
1378, 1271, 1258. H-NMR (300 MHz, CDCl , δ / ppm): 4.04 (2H, t, J = 6.7 Hz,
3
1
3
OCH ), 2.38–2.30 (4H, m, 2 CH ), 2.26 (2H, t, J = 7.7 Hz, CH CO), 1.67–1.48
2
2
2
(10H, m, 5 CH ), 1.35–1.24 (20H, m, 10 CH ), 0.87 (3H, t, J = 6.7 Hz, CH ).
2
2
3
13
C-NMR (75 MHz, CDCl , δ / ppm): 173.86 (CO), 64.41 (OCH ), 59.36 (NCH
3
2
2
acyl), 54.62 ((CH ) N piperid.), 3 4.29 ( CH CO), 31. 89 (CH ), 29. 62 (CH ),
2 2
2
2
2
29.61 (CH ), 29.55 (CH ), 29.51 (CH ), 29.33 (CH2), 29.24 (CH ); 28.61 (CH ),
2
2
2
2
2
27.27 (CH ), 26.62 (CH ), 25.97 (CH ), 25.91 ( CH ), 24.95 ( CH CH CO),
2
2
2
2
2
2
24.47 (CH ), 22.66 (CH CH ), 14.10 (CH ).
2
2
3
3
Undecyl 6-(piperidin-1-yl)hexanoate (16). Yield 53 %; pale yellow oil. Anal.
Calcd. for C H NO : C, 74.73; H, 12.26; N, 3.96; O, 9.05 %. Found: C, 74.68;
22 43
2
–1
H, 12.35; N, 3.88; O, 9.12 %. IR (CHCl , cm ): 2927. 2856, 1724, 1468, 1457,
1378, 1271, 1258. H-NMR (300 MHz, CDCl , δ / ppm): 4.04 (2H, t, J = 6.7 Hz,
3
1
3
OCH ), 2.40–2.24 (8H, m, 4 CH ), 1.68–1.25 (30H, m, 15 CH ), 0.87 (3H, t, J =
2
2
2
13
= 6.6 Hz, CH ). C-NMR (75 MHz, CDCl , δ / ppm ): 174.11 (CO), 64. 67
3
3
(OCH ), 59.57 (NCH acyl), 54.8 4 ((CH ) N piperid.), 34. 54 (CH CO), 32.14
2
2
2 2
2
(CH ), 31.82 (CH ), 29.84 (CH ); 29.81 (CH ), 29.76 (CH ), 29.57 (CH ), 29.49
2
2
2
2
2
2
(CH ), 28.87 (CH ), 27.52 (CH ), 26.83 (CH ), 26.18 (CH ), 25.20 (CH ), 24.69
2
2
2
2
2
2
(CH ), 22.89 (CH CH ); 14.36 (CH ).
2
2
3
3
Dodecyl 6-(piperidin-1-yl)hexanoate (17). Yield: 7 8 % ; pale yellow oil .
Anal. Calcd. for C H NO : C, 75.15; H, 12.34; N, 3.81; O, 8.70 %. Found: C,
23 45
2
–1
75.08; H, 12.42; N, 3.75; O, 8.79 %. IR (CHCl , cm ): 2930, 2856, 1724, 1468,
1457, 1378, 1271, 1258; H-NMR (300 MHz, CDCl , δ / ppm): 4.05 (2H, t, J =
3
1
3
= 6.7 Hz, OCH ), 2.40–2.24 (8H, m, 4 CH ), 1.69–1.26 (32H, m, 16 CH ), 0.88
2
2
2
13
(3H, t, J = 6.6 Hz, CH ). C-NMR (75 MHz, CDCl , δ / pp m): 173.86 (CO),
3
3
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

S6
FARSA, DOLEŽAL and HRABÁLEK
64.41 (OCH ), 59.36 (NCH acyl), 54.62 ((CH ) N piperid.), 3 4.29 (CH CO),
2
2
2 2
2
31.89 (CH ), 29.62 (CH ), 29.61 (CH ), 29.55 (CH ), 29.51 (CH ), 29.33(CH ),
2
2
2
2
2
2
29.23 (CH ), 28.61 (CH ), 27.27 (NCH CH acyl), 26.62 (CH ), 25.97 (CH ),
2
2
2
2
2
2
25.91 (CH ), 24.95 (CH CH CO), 24.47 (CH ), 22.66 (CH CH ), 14.10 (CH ).
2
2
2
2
2
3
3
Octyl 6-(morpholin-4-yl)hexanoate (18). Yield: 58 %, b.p. 161–163 °C at
0.04–0.05 kP a. Anal. Calcd. for C H NO : C, 68.97; H, 11 .25; N, 4.47; O,
18 35
3
–1
15.31 %. Found: C, 6 9.08; H, 11. 33; N, 4.38; O, 15.39 %. IR (CHCl , cm ):
2930, 2859, 1724, 1468, 1373, 1287, 1258. H-NMR (300 MHz, CDCl , δ / ppm):
3
1
3
4.04 (2H, t, J = 6.7 Hz, OCH alkyl), 3.70 (4H, t, J = 4.6 Hz, O(CH CH ) N),
2
2
2 2
2.41 (4H, t, O(CH CH ) N), 2.30–2. 26 (4H, m, CH CO + NC H acyl), 1.73–
2
2 2
2
2
1.41 (6H, m, 3 CH ), 1.40–1.18 (12H, m, 6 CH ), 0.87 (3H, t, J = 6.8 Hz, CH ).
2
2
3
13
C-
-NMR (75 MHz, CDCl , δ / ppm): 173.53 (CO), 66.93 ((CH ) O morph.), 64.41
3
2 2
(OCH ), 58.86 (NCH acy l), 53.74 (( CH ) N m orph.), 34.28 (CH CO), 31. 79
2
2
2 2
2
(CH CH CH ), 29.23 (CH ), 29.21 (CH ), 28.66 (OCH2CH ), 27.05 (NCH2CH
2
2
3
2
2
2
2
acyl), 26.26 (CH (CH ) CO), 25.95 (O(CH ) CH ), 24.93 (CH CH CO), 22.67
2
2 2
2 2
2
2
2
(CH CH ), 14.15 (CH ).
2
3
3
Nonyl 6-(morpholin-4-yl)hexanoate (19). Yield 56 % ; b.p. 175 –179 °C at
0.04–0.06 kP a. Anal. Calcd. for C H NO : C, 69.68; H, 11 .39; N, 4.28; O,
19 37
3
–1
14.66 %. Found: C, 6 9.78; H, 11. 43; N, 4.19; O, 14.69 %. IR (CHCl , cm ):
2928, 2858 , 1725 , 1467 , 1375 , 1287 , 1259 . H-NMR (300MHz, CDCl , δ /
3
1
3
ppm): 4.15–3.95 (2H, m, OCH ), 3.70 (4H, t, J = 6.8 Hz, O(C H CH ) N), 2.41
2
2
2 2
(4H, t, J = 4.5 Hz, O(CH CH ) N), 2.34–2.24 (4H, m, CH CO + N CH acyl),
2
2 2
2
2
1.70–1.43 (6H, m, 3 CH ), 1.39–1.19 (14H, m, 7 CH ), 0.87 (3H, t, J = 6.8 Hz,
2
2
13
CH ). C-NMR (75 MHz, CDCl , δ / ppm): 173.52 (CO), 66.94 ((CH ) O morph.),
3
3
2 2
64.41 (OCH ), 58. 87 (NC H acy l), 53.75 ((CH ) N m orph.), 34. 28 ( CH CO),
2
2
2 2
2
31.91 (CH CH CH ), 29.55 (CH ), 29.33 (CH ), 29.27 (CH ), 28.66 (OCH CH ),
2
2
3
2
2
2
2
2
27.05 (NCH CH acy l), 26.27 ( CH (CH ) CO), 25.96 (O(CH ) CH ), 24.9 4
2
2
2
2 2
2 2
2
(CH CH CO), 22.71 (CH CH ), 14.17 (CH ).
2
2
2
3
3
Decyl 6-(morpholin-4-yl)hexanoate (20). Yield 48 %; b.p. 150 °C at 0.02
kPa. Anal. C alcd. for C H NO : C, 70.33; H, 11.51; N, 4.10; O, 14.05 %.
20 39
3
–1
Found: C, 70.44; H, 11.63; N, 4.08; O, 14.11 %. IR (CHCl , cm ): 2929, 2857,
1724, 1467, 1375, 1287, 1258. H-NMR (300 MHz, CDCl , δ / ppm): 4.05 (2H,
3
1
3
t, J = 6.7 Hz, OCH ), 3.71 (4H, t, J = 5.0 Hz, O(CH CH ) N), 2.42 (4H, t, J =
2
2
2 2
= 4.5 Hz, O(CH 2CH ) N), 2.35–2.27 (4H, m, CH CO + NCH acyl), 1.72–1.44
2 2
2
2
13
(6H, m, 3 CH ), 1.42–1.17 (16H, m, 8 CH ), 0.87 (3H, t, J = 6.7 Hz, CH ). C-
2
2
3
-NMR (75 MHz, CDCl , δ / ppm): 173.52 (CO), 66.93 ((CH ) O morph.), 64.41
3
2 2
(OCH ), 58.85 (NCH acy l), 53.74 (( CH ) N m orph.), 34.26 (CH CO), 31. 86
2
2
2 2
2
(CH CH CH ), 29. 50 (C H ), 29.44 ( CH ), 29.27 (CH ), 29.25 (CH ), 28.6 6
2
2
3
2
2
2
2
(OCH CH ), 27.04 (N CH CH acy l), 26.26 (CH (CH ) CO), 25. 95
2
2
2
2
2
2 2
(O(CH ) CH ), 24.93 (CH CH CO), 22.69 (CH CH ), 14.16 (CH ).
2 2
2
2
2
2
3
3
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

SUPPLEMENTARY MATERIAL
S7
Undecyl 6-(morpholin-4-yl)hexanoate (21). Yield 43 %; b.p. 180 °C at 0.055
kPa. Anal. C alcd. for C H NO : C, 70.94; H, 11.62; N, 3.94; O, 13.50 %.
21 41
3
–1
Found: C, 71.08; H, 11.73; N, 3.82; O, 13.59 %. IR (CHCl , cm ): 2928, 2857,
1725, 1467, 1375, 1287, 1259. H-NMR (300 MHz, CDCl , δ / ppm): 4.07 (2H,
3
1
3
t, J = 6.8 Hz, OCH ), 3.71 (4H, t, J = 4.9 Hz, O(CH CH ) N), 2.41 (4H, t, J =
2
2
2 2
= 5.7 Hz, O(CH 2CH ) N), 2.35–2.23 (4H, m, CH CO + NCH acyl), 1.73–1.42
2 2
2
2
13
(6H, m, 3 CH ), 1.40–1.15 (18H, m, 9 CH ), 0.86 (3H, t, J = 7.0 Hz, CH ). C-
2
2
3
-NMR (75 MHz, CDCl , δ / ppm): 173.48 (CO), 66.92 ((CH ) O morph.), 64.38
3
2 2
(OCH ), 58.81 (NCH acy l), 53.73 (( CH ) N m orph.), 34.25 (CH CO), 31. 91
2
2
2 2
2
(CH CH CH ), 29.69 (CH ), 29.61 (CH ), 29.52 (CH ), 29.36 (O(CH ) CH ),
2
2
3
2
2
2
2 3
2
29.26 ( CH (CH ) CH ), 28.64 (OCH CH ), 27.03 (NCH CH acy l), 26.22
2
2 2
3
2
2
2
2
(CH (CH ) CO), 25.94 ( O(CH ) CH ), 24.98 (CH CH CO), 22.73 ( CH CH ),
2
2 2
2 2
2
2
2
2
3
14.18 (CH ).
3
Dodecyl 6-(morpholin-4-yl)hexanoate (22). Yield 29 %; b.p. 178–182 °C at
0.03 kPa. Anal. Calcd. for C H NO : C, 71.5; H, 11.73; N, 3.79; O, 12.99 %.
22 43
3
–1
Found: C, 71.58; H, 11.81; N, 3.65; O, 13.09 %. IR (CHCl , cm ): 2927, 2856,
3
1
1724, 1467, 1374, 1287, 1257. H-NMR (300 MHz, CDCl , δ / ppm): 4.05 (2H,
3
t, J = 6.8 Hz, OCH ), 3.71 (4H, t, J = 4.9 Hz, O(CH CH ) N), 2.42 (4H, t, J =
2
2
2 2
= 4.4 Hz, O(CH CH ) N), 2.35–2.27 (4H, m, CH CO + NCH acyl), 1.73–1.43
2
2 2
2
2
13
(6H, m, 3 CH ), 1.41–1.19 (20H, m, 10 CH ), 0.88 (3H, t, J = 6.7 Hz, CH ). C-
2
2
3
-NMR (75 MHz, CDCl , δ / ppm): 173.47 (CO), 66.92 ((CH ) O morph.), 64.38
3
2 2
(OCH ), 58.84 (NCH acy l), 53.7 3 ((CH ) N morph.), 34. 25 ( CH CO), 31.91
2
2
2 2
2
(CH CH CH ), 29. 65 (C H ), 29.64 ( CH ), 29.58 (CH ), 29.54 (CH ), 29.3 6
2
2
3
2
2
2
2
(O(CH ) CH ), 29.26 (CH (CH ) CH ), 28.65 (OCH CH ), 27.03 (NCH CH
2 3
2
2
2 2
3
2
2
2
2
acyl), 26.26 (CH (CH ) CO), 25.94 (O(CH ) CH ), 24.92 (CH CH CO), 22.70
2
2 2
2 2
2
2
2
(CH CH ), 14.16 (CH ).
2
3
3
6-(Dimethylamino)-N-octyl-hexanamide (24). Yield: 77 % ; b. p.: 152 °C at
0.4 kPa. Anal. Calcd. for C H N O: C, 71.06; H, 12.6 7; N, 10.36; O, 5.92 %.
16 34
2
–1
Found: C, 71.12; H, 12 .75; N, 10.54; O, 6.01 % . IR (KBr, cm ): 3449, 2930,
1
2859, 1660, 1518, 1467, 1378. H-NMR (300 MHz, CDCl , δ / ppm): 5.60 (1H,
3
s, CONH), 3.21 (2H, q, J = 7.0, 13.1 Hz, CH ), 2.25–2.12 (10H, m, (CH ) N + 2
2
3 2
CH ), 1.68–1.58 (2H, m, CH ) 1.48–1.41 (4H, m, 2 CH ), 1.36–1.25 (12H, m, 6
2
2
2
13
CH ), 0.88 (3H, t, J = 6.7 Hz, CH octyl). C-NMR (75 MHz, CDCl , δ / ppm):
2
3
3
172.83 (CO), 59.52 ((CH ) NCH ), 45.56 ((CH ) N), 39.46 (CONHCH ), 36.74
3 2
2
3 2
2
(CH ), 31.74 (CH ), 29.65 (CH ), 29.22 (CH ), 29.17 (CH ), 27.38 (CH ), 26.98
2
2
2
2
2
2
(CH ), 26.89 (CH ), 25.60 (CH ), 22.59 (CH ), 14.05 (CH ).
2
2
2
2
3
6-(Dimethylamino)-N-(1-methylheptyl)-hexanamide (25). Yield: 54 %; b.p.:
176–178 °C at 0.6–0.8 kPa. Anal. Calcd. for C H N O: C, 71.06; H, 12.67; N,
16 34
2
–1
10.36; O, 5.92 %. Found: C, 71.10; H, 12.73; N, 10.45; O, 5.87 %. IR (KBr, cm ):
1
3436, 29 31, 2860, 16 56, 1511, 14 66, 1379. H-NMR (300 M Hz, CDCl , δ /
3
/ ppm): 5.31 (1H, d, J = 8.8 Hz, CONH), 4.08–3.88 (1H, m, NHCH(CH )CH ),
3
2
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

S8
FARSA, DOLEŽAL and HRABÁLEK
2.32–2.20 (8H, m, (CH ) N + CH ), 2.15 (2H, t, J = 7.3 Hz, CH CO), 1.73–1.35
3 2
2
2
(16H, m, 8 CH ), 1.11 (3H, d, J = 6.6 Hz, NHCH(CH )CH ), 0.88 (3H, t, J = 6.4
2
3
2
13
Hz, C H terminal). C-NMR (75 MHz, CDCl , δ / pp m): 172 .05 (CO), 59 .57
3
3
((CH ) NCH ), 45.38 (CONHCH), 45.08 ((CH ) N), 37.05 (CONHCH(CH )CH ),
3 2
2
3 2
3
2
36.94 (CH CO), 31.75 (CH ), 29.14 ( CH ), 27.34 ( CH ), 27.00 (CH ), 25.97
2
2
2
2
2
(CH ), 25.67 (CH ), 22.53 (CH ), 21.02 (CONHCH(CH )CH ), 13.97 (CH
2
2
2
3
2
3
terminal).
6-(Dimethylamino)-N-nonyl-hexanamide (26). Yield 59 % ; b.p. 211–212 °C
at 0.7–0.8 kPa. Anal. Calcd. for C H N O: C, 71.77; H, 12.76; N, 9.85; O, 5.62
17 36
2
–1
%. Found: C, 71.70; H, 12.81; N, 9.91; O, 5.55 %. IR (KBr, cm ): 3449, 2930,
2858, 1660, 1518, 1467, 1378. H-NMR (300 MHz, CDCl3, δ / ppm): 5.64 (1H,
1
s, CONH); 3.21 (2H, q, J = 7.0, 13.1 Hz, CH ), 2.24–2.11 (10H, m, (CH ) N + 2
2
3 2
CH ), 1.67–1.57 (2H, m, CH ), 1.50–1.42 (4H, m, 2 CH ), 1.40–1.23 (14H, m, 7
2
2
2
13
CH ), 0.85 (3H, t, J = 6.7 Hz, CH nonyl). C-NMR (75 MHz, CDCl , δ / ppm):
2
3
3
173.10 (CO), 59.78 ((CH ) NCH ); 45.71 ((CH ) N) 39.72 (CONHCH ), 36.98
3 2
2
3 2
2
(CH ), 32.07 (CH ), 29.91 (CH ), 29.73 (CH ), 29.53 (CH ), 29.46 (CH ), 27.64
2
2
2
2
2
2
(CH ), 27.24 (CH ), 27.16 (CH ), 25.87 (CH ), 22.87 (CH ), 14.33 (CH ).
2
2
2
2
2
3
6-(Dimethylamino)-N-decyl-hexanamide (27). Yield 69 %; colorless powder,
m.p. 36–40 °C, b.p. 17 3–175 °C at 0.03 kPa. Anal. Calcd. for C H N O: C,
72.42; H, 12.83; N, 9.38; O, 5.36 %. Found: C, 72.35; H, 12.81; N, 9.45; O, 5.28 %.
18 38
2
–1
1
IR (KBr, cm ): 3449, 2928, 2856, 1660, 1518, 1467, 1378. H-NMR (300 MHz,
CDCl , δ / ppm ): 5.60 (1H, s, (CONH), 3.21 (2H, q, J = 7.0, 13.2 Hz, CH ),
3
2
2.26–2.13 (10H, m, ((CH ) N + 2 CH ), 1.67–1.57 (2H, m, CH ), 1.49–1.40 (4H,
3 2
2
2
13
m, 2 CH ), 1.38–1.21 (16H m, 8 CH ), 0.87 (3H, t, J = 6.7 Hz, CH decyl). C-
2
2
3
-NMR (75 MHz, CDCl , δ / ppm ): 172.82 (CO), 59.51 ((CH ) NCH ) 45.45
3
3 2
2
((CH ) N), 3 9.46 (CONH CH ), 36.74 ( CH CO), 29.05 (CH ), 29.12 (CH ),
3 2
2
2
2
2
29.27 (CH ), 29.48 (CH ), 27.37 (CH ), 26.97 (CH ), 26.90 (CH ), 25.60 (CH ),
2
2
2
2
2
2
22.64 (CH ), 14.09 (CH ).
2
3
6-(Dimethylamino)-N-dodecyl-hexanamide (28). Yield 40 %
; colorless
12
–1
powder, m.p. 48–49 °C (4 8–50 °C). IR (KBr, cm ): 3449, 2927, 2856, 1660,
1
1518, 1467, 1377. H-NMR (300 MHz, CDCl , δ / pp m): 5.57 (1H s, (CONH),
3
3.21 (2H, q, J = 7.0, 1 3.1, CH ), 2.25–2.12 (10H, m, (CH ) N + 2 CH ), 1.68–
2
3 2
2
1.58 (2H, m, CH ), 1.51–1.36 (2H, m, CH ), 1.35–1.23 (22H, m, 11 CH ), 0.86
2
2
2
13
(3H, t, J = 6.6 Hz, CH dodecyl). C-NMR (75 MHz, CDCl , δ / ppm): 172.82
3
3
(CO), 59.51 ((CH ) NCH ), 45.45 ((CH ) N), 39.46 (CONHCH ), 36.74
3 2
2
3 2
2
(CH CO) 31.87 (CH ), 29.65 (CH ), 29.61 (CH ), 29.59 (CH ), 29.58 (CH ),
2
2
2
2
2
2
29.55 (CH ), 29.31 (CH ), 29.27 (CH ), 27.37 (CH ), 26.97 (CH ), 26.90 (CH ),
2
2
2
2
2
2
25.60 (CH ), 22.64 (CH ), 14.09 (CH ).
2
2
3
N-Decyl-6-(piperidin-1-yl)hexanamide (29). Yield: 40 %; colorless powder,
m.p. 36–40 °C. Anal. Calcd. for C H N O: C, 74.5; H, 12.5; N, 8.27; O, 4.73 %.
21 42
2
–1
Found: C, 7 4.39; H, 12. 53; N, 8.38; O, 4.61 % . IR (CHCl , cm ): 3450, 2930,
3
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

SUPPLEMENTARY MATERIAL
S9
1
2856, 1660, 1518, 1468, 1377. H-NMR (300 MHz, CDCl , δ / ppm): 5.51 (1H,
3
s, NH), 3.24 –3.17 (2H, q, CH ), 2.33 ( 4H, s, 2 CH ), 2.25 ( 2H, t, J = 7.7 Hz,
2
2
NCH ), 2.14 (2H, t, J = 7.6 Hz, CH CO), 1.68–1.23 (28H, m, 14 CH ), 0.86 (3H,
2
2
2
13
t, J = 6.6 Hz, CH ). C-NMR (75 MHz, CDCl , δ / ppm ): 172.84 (CO), 59. 34
3
3
(CH (CH CH ) N), 54.6 1 (NCH acy l), 39 .45 (C ONHCH ), 36.74 ( CH CO),
2
2
2 2
2
2
2
31.84 (CONHCH CH ), 29.65 (CH ), 29.50 (CH ), 29.27 (CH ), 27.30 (CH ),
2
2
2
2
2
2
26.89 (CH ), 26.63 (CH ), 25. 95 (C H ), 25.70 ( CH ), 24.44 (CH ), 22. 64
2
2
2
2
2
(CH CH ), 14.08 (CH ).
2
3
3
N-Dodecyl-6-(piperidin-1-yl)hexanamide (30). Yield: 38 %; colorless pow-
der, m.p. 45–49 °C. Anal. Calcd. for C H N O: C, 75.35; H, 12.65; N, 7.64; O,
23 46
2
–1
4.36 %. Found: C, 75.28; H, 12.73; N, 7.74; O, 4.29 %. IR (CHCl , cm ): 3449,
2931, 2856, 1660, 1518, 1468, 1377. H-NMR (300 MHz, CDCl , δ / ppm): 5.50
3
1
3
(1H, s, NH), 3.24 –3.18 (2H, q, CH ), 2.33 (4H, s, 2 CH ), 2.26 (2H, t, J = 7.8
2
2
Hz, NCH ), 2.14 (2H, t, J = 7.6 Hz, CH CO), 1.68–1.24 (32H, m, 16 CH ), 0.86
2
2
2
13
(3H, t, J = 6.7 Hz, CH ). C-NMR (75 MHz, C DCl , δ / pp m): 172.83 (CO),
3
3
59.35 (CH (CH CH ) N), 54.62 (NCH acyl), 39.46 (CONHCH ), 36.76 (CH CO),
2
2
2 2
2
2
2
31.88 (CONHCH CH ), 29.66 (CH ), 29.61 (CH ), 29.60 (CH ), 29.55 (CH ),
2
2
2
2
2
2
29.52 (CH ), 29.31 (CH ), 29.28 (CH ), 27.30 (CH ), 26.90 (CH ), 26.64 (CH ),
2
2
2
2
2
2
25.96 (CH ), 25.70 (CH ), 24.45 (CH ), 22.65 (CH CH ), 14.10 (CH ).
2
2
2
2
3
3
6-(Morpholin-4-yl)-N-octyl-hexanamide (31). Yield 28 % ; b.p. 22 5–230 °C
at 0.2 kPa. A nal. Calcd. for C H N O : C, 69.18; H, 11.61; N, 8.96; O, 10.24
18 36
2 2
–1
%. Found: C , 69.28; H, 1 1.73; N, 9.04; O, 10.2 9 %. IR (CHCl , cm ): 3449,
2930, 28 57, 1660, 15 18, 1467, 14 59, 1373. H-NMR (300 M Hz, CDCl , δ /
3
1
3
/ ppm): 5.58 (1H, s, CONH), 3.72 ( 4H, t, O(CH CH ) N), 3.20 (2H, q, J = 7.2,
2
2 2
12.8 Hz, CH ), 2.39 (4H, t, J = 4.5 Hz, O(CH CH ) N), 2.32 (2H, t, J = 7.7 Hz,
2
2
2 2
NCH acyl), 2.13 (2H, t, J = 7.6 Hz, CH CO), 1.70–1.55 (2H, m, CH CH CO),
2
2
2
2
1.52–1.41 (4H, m, 2 CH ), 1.38–1.25 (12H, m, 6 CH ), 0.88 (3H, t, J = 6.7 Hz,
2
2
13
CH ).
C-NMR (75 MHz, C DCl , δ / ppm): 172.72
(CO), 66.75
CH ) N), 39.44
3
3
(O(CH CH ) N), 58.80 (NCH acy l), 53.54 (O(CH
2
2 2
2
2
2 2
(CONHCH ), 36.55 (CH CO), 31.82 ( CH ), 29.71 (CH ), 29.48 (CH ), 29.28
2
2
2
2
2
(CH ), 27.11 (CH ), 26.86 (CH ), 26.19 (CH ), 25.63 (CH ), 22.60 (CH ), 14.05
2
2
2
2
2
2
(CH ).
3
6-(Morpholin-4-yl)-N-nonyl-hexanamide (32). Yield 41 %; colorless pow-
der, m.p. 41–47 °C, b.p. 201–203 °C at 0.05 kPa. Anal. Calcd. for C H N O :
19 38
2 2
C, 69.89; H, 11.73; N, 8 .58; O, 9.80 %. Found: C, 6 9.95; H, 11 .83; N, 8.64 ; O,
–1
1
9.91 %. IR (CHCl , cm ): 3449, 2930, 2858, 1661, 1518,1467, 1459, 1375. H-
3
-NMR (300 MHz, CDCl , δ / ppm): 5.45 (1H, s, CONH), 3.70 (4H, t, J = 4.7 Hz,
3
O(CH CH ) N), 3.21 (2H , q, J = 7.1, 12.9, CH ), 2.40 ( 4H, t, J = 4.4 Hz,
2
2 2
2
O(CH CH ) N), 2.31 (2H, t, J = 7.7 Hz, NCH acyl), 2.14 (2H, t, J = 7.6 Hz,
2
2 2
2
CH CO), 1.69–1.59 (2H, m, CH CH CO), 1.54–1.44 (4H, m, 2 CH ), 1.37–1.24
2
2
2
2
13
(14H, m, 7 CH ), 0.86 (3H, t, J = 6.7 Hz, CH ). C-NMR (75MHz, CDCl , δ /
2
3
3
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

S10
FARSA, DOLEŽAL and HRABÁLEK
/ ppm ): 172.73 (CO), 6 6.95 (O( CH CH ) N), 5 8.88 (NCH acy l), 53.73
2
2 2
2
(O(CH CH ) N), 39.46 (CONHCH ), 36.73 (CH CO), 31.81 (CH ), 29.65 (CH ),
2
2 2
2
2
2
2
29.47 (CH ), 29.26 (CH ), 29.20 (CH ), 27.11 (CH ), 26.88 (CH ), 26.27 (CH ),
2
2
2
2
2
2
25.65 (CH ), 22.62 (CH CH ), 14.08 (CH ).
2
2
3
3
N-Decyl-6-(morpholin-4-yl)hexanamide (33). Yield 44 %; colorless powder,
m.p. 45–48 °C. Anal. Calcd. for C H N O : C, 70.54; H, 11.84; N, 8.23; O, 9.40
20 40
2 2
–1
%. Foun d: C, 70.6 5; H, 1 1.75; N, 8.14; O, 9.5 1 %. IR (CHCl , cm ): 3449,
2930, 28 57, 1660, 15 18, 1467, 14 59, 1378. H-NMR (300 M Hz, CDCl , δ /
3
1
3
/ ppm): 5.45 (1H, s, CONH), 3.70 (4H, t, J = 4.7 Hz, O(CH CH ) N), 3.21 (2H,
2
2 2
q, J = 7.1, 12 .9 Hz, CH ), 2.40 (4H, t, J = 4.4 Hz, O(CH CH ) N), 2.31 (2H, t,
2
2
2 2
J = 7.7 Hz, NCH acyl), 2.14 (2H, t, J = 7.6 Hz, CH CO), 1.69–1.59 (2H, m,
2
2
CH CH CO), 1.54–1.44 (4H, m, 2 CH ), 1.37–1.24 (14H, m, 7 CH ), 0.86 (3H,
2
2
2
2
13
t, J = 6.7 Hz, C H ). C-NMR (75 MH z, CDCl , δ / pp m): 172.72 (CO), 66.74
3
3
(O(CH CH ) N), 58.76 (NCH acyl), 53.60 (O(CH CH ) N), 39.43 (CONH CH ),
2
2 2
2
2
2 2
2
36.60 ( CH CO), 31.80 (C H ), 29.5 9 ( CH ), 29.47 (CH ), 29.46 (CH ), 29.4 3
2
2
2
2
2
(CH ), 29.22 (CH ), 26.98 (CH ), 26.85 (CH ), 26.05 (CH ), 25.55 (CH ), 22.59
2
2
2
2
2
2
(CH CH ), 14.04 (CH ).
2
3
3
N-Dodecyl-6-(morpholin-4-yl)hexanamide (34). Yield 50 %; colorless pow-
der, m.p. 48–53 °C. Anal. Calcd. for C H N O : C, 71.69; H, 12.03; N, 7.6; O,
22 44
2 2
–1
8.68 %. Found: C, 71.58; H, 11.93; N, 7.54; O, 8.71 %. IR (CHCl , cm ): 3449,
3
1
2930, 2858, 1660, 1518, 1467, 1459, 1376. H-NMR (300 MHz, CDCl , δ / ppm):
3
5.56 (1H, s, CONH), 3.77 (4H, t, J = 4.6 Hz, O(C H CH ) N), 3.22 (2H, q, J =
2
2 2
= 13.2 Hz, 6.6 Hz, CH ), 2.43 (4H, t, J = 7.5 Hz, O(CH CH ) N), 2.34 (2H, t, J =
2
2
2 2
= 4.6 Hz, NCH acyl), 2.17 (2H, t, J = 7.51 Hz, CH CO), 1.65–1.12 (26H, m, 13
2
2
13
CH ), 0.87 (3H, t, J = 6.42, CH ). C-NMR (75 MHz, CDCl , δ / ppm): 172.70
2
3
3
(CO), 66.43 (O(CH CH ) N), 58.65 (NCH acyl), 53.49 (O(CH CH ) N), 39.55
2
2 2
2
2
2 2
(CONHCH ), 36.55 (CH CO), 31.88 ( CH ), 29.69 (CH ), 29.59 (CH ), 29.55
2
2
2
2
2
(CH ), 29.30 (CH ), 29.01 (CH ), 28.93 (CH ), 27.82 (CH ), 26.93 (CH ), 26.56
2
2
2
2
2
2
(CH ), 25.64 (CH ), 25.43 (CH ), 22.64 (CH CH ), 14.03 (CH ).
2
2
2
2
3
3
_________________________________A___v_a__i_l_a_b__l_e___o__n_l_i_n__e___a_t__w___w__w___._s_h__d__._o__r_g__._r_s_/__J_S__C__S_/__________________________________
2010 Copyright (CC) SCS

Copyright of Journal of the Serbian Chemical Society is the property of National Library of Serbia and its
content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for individual use.