A conformational study of cyclohexane-1,3,5-tricarbonitrile derivatives

Article abstract of DOI:10.1002/jccs.200100032

Cyclohexane-1,3,5-tricarbonitrile reached equilibrium having 1,3-cis-1,5-cis and 1,3-cis-1,5-trans isomers in a ratio of 3:7. The cis,cis-isomer preferred the conformation with three equatorial cyano groups, whereas the cis,trans-isomer displayed two cyano groups on equatorial positions and another cyano group on axial position. Condensation of cis,cis-cyclohexane-1,3,5-tricarbonitrile with L-(S)-valinol by the catalysis of ZnCl₂ in refluxing 1,2-dichlorobenzene afforded two isomeric cyclohexane-1,3,5-trioxazolines in favor of the 1,3-cis-1,5-trans isomer. Metalation of cis,cis-cyclohexane-1,3,5-tricarbonitrile, followed by alkylations with dimethyl sulfate, benzyl bromide or allyl bromide, gave the corresponding trialkylation products with predominance of 1,3-cis-1,5-trans isomers. The cis,trans-isomer showed two cyano groups on axial positions and another cyano group on equatorial position, whereas the cis,cis-isomer exhibited three axial cyano groups. Treatment of trimethyl cis,cis-cyclohexane-1,3,5-tricarboxylate with lithium diisopropylamide and dimethyl sulfate afforded mainly the trimethyl ester of Kemp's triacid, which showed three axial carboxylate groups. Two competitive factors, i.e. the steric effect of incoming electrophiles and the dipole-dipole interactions of the cyano or carboxylate groups, might interplay to give different stereoselectivities in these reaction systems.

Full text of DOI:10.1002/jccs.200100032

JournaloftheChineseChemicalSociety, 2001, 48, 193-200
193
A Conformational Study of Cyclohexane-1,3,5-tricarbonitrileDerivatives
Tsung-Hsun Chuang (
) and Jim-Min Fang* (
)
DepartmentofChemistry,NationalTaiwanUniversity,Taipei,Taiwan106,R.O.C.
Cyclohexane-1,3,5-tricarbonitrilereachedequilibriumhaving1,3-cis-1,5-cis and 1,3-cis -1,5-trans iso-
mers in a ra tio of 3:7. The cis,cis-iso mer pre ferred the con for ma tion with three equa to rial cyano groups,
whereas the cis,trans-isomerdisplayedtwocyanogroupsonequatorialpositionsandanothercyanogroupon
axialposition.Condensationofcis ,cis-cyclohexane-1,3,5-tricarbonitrilewithL-(S)-valinolbythecatalysisof
ZnCl2 in refluxing 1,2-dichlorobenzene af forded two iso meric cyc lo hex ane-1,3,5-trioxazolines in favor of
the 1,3-cis-1,5-transiso mer. Metalation of cis ,cis-cyclohexane-1,3,5-tricarbonitrile,followedbyalkylations
with dimethyl sul fate, benzyl bro mide or allyl bro mide, gave the cor re spond ing trialkylation productswith
predominanceof1,3-cis -1,5-transiso mers. Thecis,trans-isomershowedtwocyanogroupsonaxialpositions
and an other cyano group on equa to rial po si tion, whereas the cis,cis-iso mer ex hib ited three ax ial cyano
groups. Treat ment of trimethylcis,cis-cyclohexane-1,3,5-tricarboxylatewithlithiumdiisopropylamideand
dimethyl sul fate af forded mainly the trimethyl es ter of Kemp’s triacid, which showed three ax ial carboxylate
groups.Twocompetitivefactors,i.e.thestericeffectofincomingelectrophilesandthedipole-dipoleinterac-
tions of the cyano or carboxylate groups, might in ter play to give dif fer ent stereoselectivitiesinthesereaction
systems.
INTRODUCTION
Many ef forts have been ex erted on the conformational
acid 2a also ex ists as the con former hav ing three carboxylic
groups on the equa to rial po si tions (Eq. 2). Un like Kemp’s
triacid hav ing three ax ial carboxylic groups, the steric ef fect
by dis po si tions of three ax ial carboxylic groups in2a might
over ride the ef fect of intramolecular hy dro gen bond ing. It is
also known8 that heat ing of cis,cis-cyclohexane-1,3,5-tr-i
carboxylic acid2a at 240 C causes an isomerization to reach
anequilibriumbetween2a and the cis,trans-isomer2b with a
ra tio of 44:56. The cis,trans-isomer 2b ex ists as the con-
former having one axial and two equatorial carboxylic
groups, but not the other way around.
stud ies of sub sti tuted cyclohexanes. Kemp and Petrakis1
have re ported an es pe cially in ter est ing com pound cis,cis-
1,3,5-trimethylcyclohexane-1,3,5-tricarboxylic acid 1a
(Kemp’s triacid), in which all carboxylic groups are ax ial.
Due to this well-defined con for ma tion, Kemp’s acid and its
de riv a tives can be used as the units for mo lec u lar rec og ni-
tion.2-6 For ex am ple, the m-phenylenediamine bis(Kemp’s
triacidimide)isutilizedasabuildingblockformolecularre-
ceptors.2 It can sta bi lize carboxylate-bridged dimetallic cen-
ters to serve as a func tional model of re lated en zymes.3 In cor-
po ra tion of pep tide chains on Kemp’s triacid can gen er ate
collagen-liketriplehelices.4 Kemp’s triacid disubstituted de-
rivatives are employed as metal ion-separating agents.5
Kemp’s triacid can be linked by crown ethers or por phy rins to
func tion as C-cleft agents.6 Use of Kemp’s triacid and its de-
rivativesasabuildingscaffoldforasymmetricsynthesisand
combinatorialsynthesishavebeenrecentlyexplored.7
Theconformationwiththreeaxialcarboxylicgroupsin
Kemp’s triacid is at trib ut able to the sta bi li za tion by intra-
molecularhydrogenbonding. WhenKemp’striacidistreated
withNaOHsolution,12 a suc ces sive ion iza tion makes a flip-
pingofthecyclohexanering. Thisconformationalchangere-
leaseselectrostaticrepulsionandleadstothethermodynami-
cally more sta ble con former with three equa to rial car box-
ylate groups (Eq. 1). Cis,cis-cyclohexane-1,3,5-tricarboxylic
O2C
CO2H
CO2H
CO2H
Me
OH
Me
O2C
CO2
Me
Me
Me
Me
all equatorial CO2
1a (Kemp's triacid)
(1)
all axial CO2H
H
H
H
CO2H
H
H
240 oC
HO2C
HO2C
H
HO2C
HO2C
CO2H
2a/2b = 44:56
(2)
cis-cis
cis-trans
2a
2b
RESULTS AND DISCUSSION
As a con tin u a tion of the above-mentioned stud ies, we

194 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001
Chuang and Fang
pre pared sev eral de riv a tives of 1,3,5-trisubstituted cyclo-
hexanes and ex am ined their con for ma tions. Triacid2a was
treated with thionyl chlo ride to give the triacyl chlo ride 3a
(Scheme I).9 Nucleophilic sub sti tu tion of3a with MeOH or
PhOH yielded the triesters 4a and 5a, respectively.7,9
Ammonolysis of 5a in liq uid NH3 af forded the triamide 6a.9
De hy dra tion of the triamide 6a was car ried out by heat ing
with SOCl2 in DMF to give the trinitrile 7a.9 All the de riv a-
tives 3a-7awere shown to have the sym met ric cis,cis-struc-
tures by NMR anal y ses. No cis,trans-iso mers were found.
At tempts to con vert triacid2adirectlytothecorresponding
trioxazolines by treatments with 2-aminoethanol or 2-
amino-2-methylpropan-1-olundervariousconditionsfailed.
Thecondensationreactionoftrinitrile 7a with L-(S)-valinol
was realized by the catalysis of ZnCl2 in refluxing 1,2-
dichlorobenzene.10,11 How ever, a sig nif i cant isomerization
also oc curred un der such re ac tion con di tions, thus two iso-
meric trioxazolines 8a and 8b were ob tained in a ra tio of 3:7.
The symmetric cis,cis-iso mer 8a (C24H39N3O3) showed 8
peaks in the13C NMR spec trum, whereas thecis,trans-iso mer
8bdis played the 24 car bons as 20 peaks. In the1H NMR spec-
trum of 8a, the H-1, H-3 and H-5 ap peared at H 2.63 as a trip-
let of trip lets with large and small cou pling con stants (J =
12.6 and 3.0 Hz), in di cat ing their ax ial dis po si tions. On the
other hand, the1H NMR spec trum of 8b showed three sig nals
at 2.63, 2.78 and 2.84 cor re spond ing to H-1 (ax ial), H-3
(ax ial) and H-5 (equa to rial), re spec tively, due to the un-
symmetricorientationofthreeoxazolinesubstituents.
ORTEP Draw ing of Com pound 7b
When cis ,cis-trinitrile 7a was treated with t-BuOK in
t-BuOHsolutionatroomtemperatureforaprolongedperiod
(24 h), a mix ture of 7a and the cis,trans-isomer 7b was ob-
tained in a ra tio of 3:7. Sim i lar treat ment of a 1:1 mix ture of
7a and 7b also ended up with the iso meric ra tio of 3:7. The
struc ture of7b was con firmed by an X-ray dif frac tion anal y-
sis, which showed two cyano groups on equa to rial po si tions
and an other cyano group on ax ial po si tion. The 13C NMR
spec trum of7b (C9H9N3) showed only 6 sig nals due to its
sym met ric struc ture. In the 1H NMR spec trum, H-1 and H-3
ontheaxialpositionsappearedat 2.90, whereas H-5 on the
equa to rial po si tion ap peared at a lower field of 3.19. Ac-
cord ing to an MM3 cal cu la tion, the cis,trans-isomer 7b is
more sta ble than the cis,cis-iso mer7a bear ing three equa to-
rial cyano groups by an en ergy dif fer ence of -0.509 kcal
mol-1. This cal cu la tion was in agree ment with the ob served
isomericratioof7a/7b (3:7) at equi lib rium. As the CN group
has a small size, the steric ef fect should be min i mal. How-
ever, the ax ial dis po si tion of one CN group in 7b could re-
lease the di pole-dipole in ter ac tion with the other two CN
groups.12 Thus, the cis,trans-iso mer 7bis ther mo dy nam i-
cally more sta ble than the cis,cis-isomer 7a, which ex erts
larger di pole-dipole re pul sions among the three equa to rial
cyanogroups.Thealternativeconformerof7b with two ax ial
cyano groups was not observed because these two axial
cyano groups would cause se vere di pole-dipole re pul sion.
Sim i lar rea sons could be at trib ut able to the pref er a ble con-
form ers of triacid2b and trioxazoline 8b.
Scheme I
H
Z
H
H
H
H
H
H
H
H
H
Z
NC
Oxz
Oxz
Z
i-v
CN
vi
Oxz
NC
Oxz
H
2a Z = CO2H
3a Z = COCl
7a
vii
8a
+
Oxz
4a Z = CO2Me
5a Z = CO2Ph
6a Z = CONH2
H
H
1
CN
5
H
Oxz
NC
H
8b
3
NC
O
7b
Oxz =
N
Reagents and conditions: i, for 3a: 2a/SOCl , reflux, 12 h; >99%.
2
ii, for 4a: 2a/SOCl /MeOH, rt, 4 h; 96%. iii, for 5a: 3a/PhOH,
2
o
pyridine, CH Cl , 40 C, 12 h; 90%. iv, for 6a: 5a/liquid NH , 40
2
2
3
o
o
C to rt, 15 h; 85%. v, for 7a: 6a/SOCl , DMF, 45 C, 15 h; 65%.
vi, L-valinol, cat. ZnCl , 1,2-dichlorobenzene, reflux, 24 h; 8a, 20%;
2
The electrophilic re ac tions of triester 4a and trinitrile
7a pro ceeded with dif fer ent stereoselectivities (Ta ble 1).
2
8b, 45%. vii, t-BuOK/t-BuOH, rt, 24 h; 7a/7b = 3:7.

Cyclohexane-1,3,5-tricarbonitrileDerivatives
J. Chin. Chem. Soc., Vol. 48, No. 2, 2001 195
Table 1. Electrophilic Reactions of Cyclohexane Triester 4a and Trinitrile 7a
H
H
Z
Z
Z
1
R
5
Z
H
Z
3
Z
H
Z
LDA; RX
Z
R
R
R
Z
R
+
Z
+
Z
Z
R
R
R
Z = CO2Me
4a
trialkylation, cis-cis
trialkylation, cis-trans
dialkylation, cis-trans
10c, 11c
7a Z = CN
9a, 12a, 13a
9b 12b
Reactant
Electrophile
Ratio of Product
Z =
R =
4a
7a
7a
7a
7a
Me2SO4
Me2SO4
PhCH2Br
CH2=CHCH2Br
Ph2PCl
9a/9b = 85:15
10b/10c = 80:20
11b/11c = 41:59
12a/12b = 28:72
13a only
CO2Me
CN
CN
CN
CN
Me
Me
PhCH2
CH2=CHCH2
Ph2P
Triester 4a was treated with LDA (3.3 equiv) in an Et2Osolu-
tion at 0 C, fol lowed by alkylation with ex ces sive amounts
of Me2SO4, to give Kemp’s acid trimethyl es ter 9a and the
cis,trans-iso mer9b in a ra tio of 85:15.2a As 9a was sub jected
to saponification to give Kemp’s triacid1a, its struc ture with
three carboxylate groups on the ax ial po si tions was es tab-
lished. On the other hand, treat ment of the trinitrile 7a with
LDA and Me2SO4 in Et2O/THF so lu tion (v/v, 1:1) at -78 C
gave a trimethylation prod uct 10b with cis,trans-configura-
tion (50% yield). No cis,cis-isomer10a was found, though a
side prod uct 10c (11% yield) re sulted from an in com plete
methylation. A sim i lar alkylation re ac tion of 7a with benzyl
bromidealsogavethetribenzylationproduct11b (24% yield)
and the dimethylation prod uct 11c (35% yield). Using allyl
bro mide as the electrophile, two triallylation prod ucts 12a
and 12b were ob tained in a ra tio of 28:72. The struc tures of
these prod ucts were de ter mined by spec tral meth ods. For ex-
ample,NOEexperimentswereappliedtodeterminetheillus-
tratedconfigurationandconformationof11b.Thus,irradia-
tionoftheaxiallyorientedH-4 (and H-6 ) at 1.64 caused
enhancementsofH-2 (at 1.20)andthetwomethylenesig-
nals of C-1 and C-3 allyl groups (at 2.36).Irradiationofthe
methylenesignal(at 3.04) of C-5 allyl group (on ax ial po si-
tion) caused a 16% en hance ment of the res o nance at 2.47
for H-4 and H-6 . The C2-symmetricnatureofthedialkyla-
tion prod ucts 10c and 11c were in di cated by their13C NMR
spec tra, so that10c and 11c should have the cis,trans-config-
urations. TheirC-5protons, appearingat 3.20 (tt, J = 12.9,
3.0 Hz) and 3.16 (tt, J = 13.2, 3.3 Hz), dis played the char ac-
ter is tic pat terns with large and small cou pling con stants, be-
ing con sis tent with their ax ial dis po si tions in the il lus trated
conformers.
ac tion might in ter play in these electrophilic re ac tions to af-
fect the stereoselectivity.12 The dianionic intermediateB
might re act with a sec ond electrophile to af ford the in ter me-
di ates of cis-an ionC and trans-anion D (Scheme II). The re-
ac tion of C with a third electrophile would give ei ther the
cis,cis-prod uctFvia equa to rial at tack, or the cis,trans-prod-
uct G via ax ial at tack. The cis,cis-prod uctF with three ax ial
CNgroupswouldbethermodynamicallydisfavoredbecause
it ex hib ited se vere di pole-dipole re pul sions. Ex cept for a
bulky electrophile such as Ph2PCl,9 al ky la tions ofC should
occur preferentially from the axial approach to give the
cis,trans-productG such as10b, 11b, and12b(R1 = R2 = R 3).
The trialkylation prod ucts 10b, 11b, and 12b could also be
derivedfromtheequatorialalkylationsofthetrans-an ionD,
which had an ax ial R2 alkyl group to hin der the ax ial ap-
proachofthethirdhalidemolecule.Asimilarrationalecould
be ap plied to the for ma tion of dialkylation prod ucts 10c and
11c, but not other stereoisomers. In al ky la tions of the triester
4a, the trans-anionintermediateJ, hav ing a larger steric ef-
fect be tween the ax ial Me and CO2Me groups, was also less
favorable than the cis-anion intermediate I. As Me and
CO2Me groups were more sterically de mand ing than the CN
group(bycomparisonofI and J with C and D), both I and J
would un dergo alkylation via the equa to rial ap proach of an
Me2SO4 moleculetogive,respectively,the cis ,cis-product9a
and the cis,trans-prod uct9b. As a con se quence, tri methyla-
tion of 4a led to 85% of9a and 15% of 9b.
EXPERIMENTAL
Allreactionsrequiringanhydrousconditionswerecon-
Wespeculatedthatstericeffectanddipole-dipoleinter-
ducted in a flame-dried ap pa ra tus un der an at mo sphere of ar-

196 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001
Chuang and Fang
Scheme II
LiN
LiN
C
C
H
H
R1X
H
LDA
C
C
N
C
NLi
N
C
N
7a
A
N
N
C
N
C
C
N
C
NLi
R1
R2
NLi
+
C
R2X
C
R1
R1
C
NLi
C
R2
N
C
D (trans)
C (cis)
B
LiN
R3X
R3X
N
N
C
N
N
C
N
C
N
N
C
R3
5
C
1
C
1
C
R2
3
1
R1
R1
R1
R3
C
R3
5
N
5
3
3
C
N
R2
R2
F (cis-cis)
G (cis-trans)
H (cis-trans)
OLi
OLi
OMe
CO2Me
CO2Me
CO2Me
Me
i) LDA
ii) 2 Me2SO4
OMe
+
4a
Me
Me
Me
MeO2C
I (cis)
Me2SO4
J (trans)
Me2SO4
CO2Me
CO2Me
CO2Me
Me
CO2H
Me
CO2H
Me
Me
Me
Me
9a (cis-cis)
MeO2C
9b (cis-trans)
gon. Sy ringes and nee dles for the trans fer of re agents were
dried at 120 C and al lowed to cool in a des ic ca tor over P2O5
beforeuse.Ethersweredistilledfromsodiumbenzophenone
ketyl; (chlo ri nated) hy dro car bons, and amines from CaH2.
Re ac tions were mon i tored by TLC us ing pre-coated with a
0.25 mm layer of sil ica con tain ing a flu o res cent in di ca tor
(MerckArt.5544).Columnchromatographywascarriedout
on Kieselgel 60 (40-63 m).Opticalrotationsweremeasured

Cyclohexane-1,3,5-tricarbonitrileDerivatives
J. Chin. Chem. Soc., Vol. 48, No. 2, 2001 197
on a dig i tal polarimeter with a cuvette of 1 cm length. [ ]D
The trinitrile 7a (30 mg, 0.19 mmol) was treated with
t-BuOK (10 mg) in a so lu tion oft-BuOH (0.3 mL) and THF
(2 mL) at room tem per a ture for 24 h. The mix ture was con-
cen trated in vacuo, dis solved in CH2Cl2 (20 mL), washed
with wa ter (15 mL) and brine (15 mL), dried (Na2SO4), and
chromatographed on a silica gel column by elution with
EtOAc/hex ane (1:1) to give the cis ,cis-iso mer7a (8.5 mg,
28%) and thecis,trans-isomer7b (19.5 mg, 65%).
-1
Values are given in 10 deg cm2 g-1. 1H and13CNMRspectra
were re corded on Bruker AC-200 and AM-300 WB spec-
trometers.ChemicalshiftsarereportedrelativetoCHCl3 [
H
7.26, C (cen tral line of t) 77.0]. Cou pling con stants (J) are
given in Hz. The X-ray dif frac tion data were col lected on a
CAD-4 diffractometer. The anal y ses were car ried out on a
microVAX III com puter us ing NRC VAX soft ware.
7a: Solid, mp 174-176 C (lit.9 mp 175 C);
(300
H
cis,cis-Cyclohexane-1,3,5-tricarboxyl trichloride (3a)9
Treat ment ofcis,cis-cyclohexane-1,3,5-tricarboxylic
acid 2a (pur chased from Fluka) with thionyl chlo ride, ac-
cordingtothereportedprocedure,9 gave the triacyl chlo ride
3ain a quan ti ta tive yield. Solid, mp 44-45 C (lit.9 mp 44-46
C); H (200 MHz, CDCl3) 1.67 (3H, dt, J 12.6, 12.6), 2.66
(3H, dt,J 12.6, 3.6) and 2.84 (3H, tt,J 12.6, 3.6); C (50 MHz,
CDCl3) 30.3 (3 CH2), 52.2 (3 CH) and 174.2 (3 C).
MHz, CDCl3) 1.87 (3H, dt, J 12.9, 12.9) and 2.48-2.58 (m,
6H);
(75 MHz, CDCl3) 26.2 (3 CH2), 30.9 (3 CH) and
C
118.4 (3 C); m/z 160 (M+ + 1, 5%), 106 (84) and 54 (100).
7b: Solid, mp 152-154 C; TLC (EtOAc/hex ane (3:7))
Rf 0.20;
(KBr)/cm-1 2245;
(300 MHz, CDCl3) 1.81-
max
H
1.94 (3H, m), 2.30 (2H, br d, J13.8), 2.45 (1H, d,J 13.8), 2.90
(2H, m), 3.19 (1H, m); (75 MHz, CDCl3) 23.9 (2 CH2),
C
25.2 (CH2), 30.0 (2 CH), 30.8 (CH), 118.6 (C) and 119.0 (2
C); m/z 160 (M+ + 1, 8%), 159 (1), 106 (98) and 54 (100)
(Found: M+, 159.0818. C9H9N3 requires 159.0796). The
struc ture of7b was con firmed by an X-ray dif frac tion anal y-
sis.
Crys tal data of com pound7b (C9H9N3, M = 159.08):
monoclinic, space group P21/c, Z = 8, a = 14.359(2), b =
10.237(8), c = 13.124(1) Å, = 111.769(8)o, V = 1791.6(3)
Å3, crys tal size 0.4 0.5 0.6 mm,T = 298 K, re flec tions col-
lected2575,independentreflections2287. Rf = 0.037, Rw =
0.033. Re fine ment method: full-matrix least-squares on F2.
All bond dis tances and bond an gles are as ex pected. These
dataaredepositedwiththeCambridgeCrystallographicData
Center.
Trimethyl cis,cis-cyclohexane-1,3,5-tricarboxylate (4a)7b
Treat ment of the triacid2a with thionyl chlo ride in the
pres ence of MeOH, ac cord ing to the re ported pro ce dure,7b
gave the triester 4a (96% yield). H (200 MHz, CDCl3) 1.47
(3H, dt, J 12.6, 12.6), 2.23 (3H, br d, J 12.6) and 2.39 (3H, dt,
J 12.6, 3.2); C (50 MHz, CDCl3) 30.4 (3 CH2), 41.6 (3 CH),
51.8 (3 Me) and 174.4 (3 C).
Triphenyl cis,cis-cyclohexane-1,3,5-tricarboxylate(5a)9
Treat ment of the triacyl chlo ride 3a with PhOH in the
pres ence of pyridine, ac cord ing to the re ported pro ce dure,9
gave the triester 5a (90% yield). Solid, mp 130-131 C (lit.9
mp 130 C); H (200 MHz, CDCl3) 1.89 (3H, dt, J 12.6, 12.6),
2.67 (3H, br d,J 12.6), 2.78 (3H, td,J 12.6, 3.2), 7.12 (6H, dd,
J 7.6, 1.0), 7.22 (3H, tt, J 7.2, 1.0) and 7.40 (6H, dd, J 7.6,
7.2).
cis,cis-1,3,5-Tris[(S)-4-isopropyl-1,3-oxazolin-2-yl]cyc lo-
hexane (8a) and cis,trans-1,3,5-Tris[(S)-4-isopropyl-1,3-
oxazolin-2-yl]cyclohexane(8b)
A mix ture of trinitrile 7a (290 mg, 1.8 mmol), L-(S)-
valinol (742 mg, 7.2 mmol) and ZnCl2 (30 mg, 0.2 mmol) in
1,2-dichlorobenzene (8 mL) was refluxed at 180 C for 24 h.
Themixturewasconcentrated,andtheresiduewasdissolved
in CH2Cl2 (20 mL). The or ganic phase was washed with wa ter
(2 15 mL) and brine (2 15 mL), dried (Na2SO4), and
chromatographed on a silica gel column by elution with
EtOAc to give the cis ,cis-iso mer8a (151 mg, 20%) and the
cis,trans-isomer8b (337 mg, 45%).
cis,cis-Cyclohexane-1,3,5-tricarboxamide (6a)9
Treat ment of the triester 5a with liq uid am mo nia ac-
cordingtothereportedprocedure9 gave the triester 4a (85%
yield). Solid, mp 287-289 C (lit.9 mp 290 C); H (300 MHz,
CD3OD) 1.45 (3H, dt, J 12.6, 12.6), 2.10 (3H, br d, J 12.6)
and 2.21 (3H, td, J 12.6, 3.3); C (75 MHz, CD3OD) 34.6 (3
CH2), 47.2 (3 CH) and 183.9 (3 C).
cis,cis-Cyclohexane-1,3,5-tricarbonitrile (7a) and
cis,trans-Cyclohexane-1,3,5-tricarbonitrile(7b)
Treat ment of the triamide 6a with thionyl chlo ride ac-
cordingtothereportedprocedure9 gave the trinitrile 7a (65%
yield).
8a: Solid, mp 92-94 C; [ ]26D -65.7 (c 1.3, CHCl3);
TLC (EtOAc) Rf 0.17; max (KBr)/cm-1 1664; H (300 MHz,
CDCl3) 0.76 (9H, d, J 6.9), 0.84 (9H, d, J 6.9), 1.53 (3H, dt, J
12.6, 12.6, H-2 , H-4 and H-6 ), 1.59-1.70 (3H, m), 2.15
(3H, br d, J 12.6, H-2 , H-4 and H-6 ), 2.63 (3H, tt, J 12.6,

198 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001
Chuang and Fang
3.0, H-1 , H-3 and H-5 ), 3.75-3.86 (6H, m, 3 CH2O) and
4.08 (3H, dt, J 7.2, 7.2, 3 CHN); C (75 MHz, CDCl3) 17.6 (3
Me), 18.5 (3 Me), 32.1 (3 CH2), 32.2 (3 CH), 36.3 (3 CH),
69.5 (3 CH2), 71.6 (3 CH) and 168.6 (3 C);m/z 417 (M+, 8%)
and 374 (100) (Found: M+, 417.2988. C24H39N3O3 requires
417.2991).
cis,trans-1,3,5-Trimethylcyclohexane-1,3,5-tricarbonitrile
(10b) and cis,trans-1,3-Dimethylcyclohexane-1,3,5-
tricarbonitrile (10c)
Under an atmosphere of argon, BuLi (4.2 mL, 6.6
mmol, 1.6 M of hex ane so lu tion) was added dropwise to a so-
lu tion ofi-Pr2NH (0.92 mL, 6.6 mmol) in Et2O (30 mL) at 0
C. The mix ture was stirred for 20 min, cooled to -78 C, and
a so lu tion of the trinitrile 7a (318 mg, 2 mmol) in THF (30
mL)/Et2O (15 mL) was added dropwise. After 10 min,
Me2SO4 (0.63 mL, 6.6 mmol) was added dropwise to the re-
sult ing pink so lu tion. The mix ture was warmed, stirred at 25
C for 12 h, and quenched by ad di tion of sat u rated NH4Cl.
Themixturewasconcentratedbyrotaryevaporation,diluted
with CH2Cl2 (40 mL), washed with wa ter (15 mL) and brine
(15 mL), dried (Na2SO4), and chromatographed on a sil ica gel
column by elution with EtOAc/hexane (1:1) to give the
cis,trans-iso mer of trialkylation prod uct10b (201 mg, 50%)
and the dialkylation prod uct10c (41 mg, 11%).
8b: Oil; [ ]26D -40.2 (c 2.9, CHCl3); TLC (EtOAc) Rf
0.22;
(neat)/cm-1 1662; H (300 MHz, CDCl3) 0.77-0.90
max
(18H, m), 1.44-1.73 (6H, m), 2.17 (1H, br d, J 12.9, H-2b),
2.27 (2H, br d, J 12.9, H-4 and H-6 ), 2.63 (1H, tt, J 12.9,
3.3, H-1 ), 2.78 (1H, tt, J 12.9, 3.3, H-3 ), 2.84 (1H, br s,
H-5 ), 3.77-3.91 (6H, m), 4.05-4.15 (3H, m); C (75 MHz,
CDCl3) 17.5 (Me), 17.6 (Me), 17.9 (Me), 18.6 (Me), 18.7
(Me), 18.8 (Me), 30.4 (2 CH2), 32.2 (CH), 32.3 (CH), 32.4
(CH), 32.5 (CH), 32.6 (CH), 32.7 (CH2), 32.8 (CH), 69.3
(CH2), 69.4 (2 CH2), 71.5 (2 CH), 72.0 (CH), 167.7 (C) and
169.4 (2 C); m/z 417 (M+, 45%) and 374 (100) (Found: M+,
417.2986. C24H39N3O3 re quires 417.2991).
10b: Solid, mp 227-229 C; TLC (EtOAc/hex ane (1:1))
Trimethyl cis,cis-1,3,5-trimethylcyclohexane-1,3,5-
tricarboxylate (9a) and Trimethyl cis,trans-1,3,5-
trimethylcyclohexane-1,3,5-tricarboxylate (9b)
Method A. Treat ment of Kemp’s acid (pur chased from
Aldrich)withdiazomethaneaccordingtothereportedproce-
dure7a gave the triester 9ainaquantitativeyield.
Rf 0.28;
(KBr)/cm-1 2233; H (300 MHz, CDCl3) 1.22
max
(1H, d, J 14.4 ), 1.49 (6H, s), 1.70 (2H, d, J 14.4 ), 1.98 (3H,
s), 2.38 (2H, d, J 14.4) and 2.43 (1H, d, J 14.4); C (75 MHz,
CDCl3) 22.7 (Me), 29.1 (2 C), 29.7 (2 Me), 32.5 (C), 43.1 (2
CH2), 43.9 (CH2), 122.3 (2 C) and 123.5 (C); m/z 201 (M+,
1%) and 134 (100) (Found: M+, 201.1259. C12H15N3 requires
201.1266) (Anal. Found: C, 71.45; H, 7.49; N, 21.08.
C12H15N3 re quires C, 71.61; H, 7.51; N, 20.88).
MethodB.Underanatmosphereofargon,asolutionof
the triester 4a (8.8 g, 34.3 mmol) in Et2O (50 mL) was added
dropwise to the freshly pre pared LDA so lu tion (113 mmol) in
Et2O (100 mL) at 0 C. The mix ture was stirred for 2 h, and
Me2SO4 (14 mL, 147 mmol) was added. The mix ture was
warmed, stirred at room tem per a ture for 12 h. The pre cip i-
tates were fil tered off, the fil trate was washed with wa ter (3
50 mL), HCl (20 mL of 1 M so lu tion) and brine (20 mL),
dried (Na2SO4), and chromatographed on a sil ica gel col umn
by elu tion with EtOAc/hex ane (10:1) to give the cis,cis-iso-
mer 9a (6.6 g, 64%) and the cis,trans-isomer9b (1.2 g, 12%).
9a: Solid, mp 80-81 C (lit.7a mp 79-81 C); TLC
(EtOAc/hex ane (10:1)) Rf 0.2; H (200 MHz, CDCl3) 0.86
(3H, d,J 14.8), 1.11 (9H, s), 2.63 (3H, d,J 14.8) and 3.56 (9H,
10c: Solid, mp 249-250 C; TLC (EtOAc/hex ane (1:1))
Rf 0.20;
(KBr)/cm-1 2236; H (300 MHz, CDCl3) 1.20
max
(1H, d, J14.4), 1.45 (2H, t, J12.9), 1.48 (6H, s), 2.32 (1H, d,J
14.4, H-2 ), 2.48 (2H, br d, J 12.9, H-4 , 6 ) and 3.20 (1H, tt,
J 12.9, 3.0, H-5);
(75 MHz, CDCl3) 24.2 (C-5), 28.1
C
(Me-1, 3), 32.0 (C-1, 3), 39.0 (C-4, 6), 43.3 (C-2), 119.1
(CN-5), 120.7 (CN-1, 3); m/z 187 (M+, 1%) and 120 (100)
(Found: M+, 187.1107. C 11H13N3 re quires 187.1109).
cis,trans-1,3,5-Tribenzylcyclohexane-1,3,5-tricarbonitrile
(11b) and cis,trans-1,3-Dibenzylcyclohexane-1,3,5-
tricarbonitrile (11c)
s); (50 MHz, CDCl3) 31.0 (Me), 41.2 (3 CH2), 43.5 (3 C),
51.4 (3 Me) and 176.5 (3 C).
Alkylation of the trinitrile 7a (159 mg, 1 mmol) with
benzyl bro mide (1.2 mL, 10 mmol) in Et2Osolution, byapro-
ce dure sim i lar to that for10b, gave the trialkylation prod ucts
11b(103 mg, 24%) and the dialkylation prod uct 11c (119 mg,
35%).
C
9b: Oil; TLC (EtOAc/hex ane (10:1)) Rf 0.2; max (neat)/
cm-1 1731 and 1715; H (300 MHz, CDCl3) 1.02 (1H, d, J
14.7), 1.04 (3H, s), 1.07 (6H, s), 1.65 (2H, d, J 14.7), 2.07
(2H, d,J 14.7), 2.58 (1H, d,J 14.7), 3.52 (6H, s) and 3.54 (3H,
s); C (75 MHz, CDCl3) 25.7 (Me), 29.5 (2 Me), 40.1 (2 CH2),
41.1 (2 C), 41.7 (C), 41.8 (CH2), 51.5 (2 Me), 51.6 (Me),
177.5 (2 C) and 178.4 (C); m/z 300 (M+, 2%) and 121 (100)
(Found: M+, 300.1583. C15H24O6 re quires 300.1573).
11b: Solid, mp 225-227 C;TLC(EtOAc/hexane(3:7))
Rf 0.25;
(KBr)/cm-1 2235; H (300 MHz, CDCl3) 1.45
max
(1H, d,J 14.4), 1.80 (2H, d, J 14.4), 2.30 (1H, d, J 14.4), 2.45
(2H, d,J 14.4), 2.93 (4H, s), 3.46 (2H, s) and 7.22-7.45 (15H,
m);
(75 MHz, CDCl3) 34.4 (2 C), 38.6 (C), 39.5 (CH2),
C

Cyclohexane-1,3,5-tricarbonitrileDerivatives
J. Chin. Chem. Soc., Vol. 48, No. 2, 2001 199
39.8 (2 CH2), 40.8 (CH2), 48.1 (2 CH2), 121.7 (2 C), 122.5
(C), 127.7 (CH), 128.2 (2 CH), 128.4 (2 CH), 128.7 (4 CH),
130.5 (4 CH), 130.8 (2 CH), 132.4 (2 C) and 134.4 (C); m/z
(FAB) 429 (M+). (Found: M+, 429.2214. C30H27N3 requires
429.2205).
wanUniversity)forhelpfuldiscussions.
Received November 22, 2000.
11c: Solid, mp 262-264 C; TLC (EtOAc/hex ane (3:7))
Key Words
Rf 0.20;
(KBr)/cm-1 2240; H (300 MHz, CDCl3) 1.32
Cyclohexane-1,3,5-tricarbonitrile; Kemp’s triacid;
Cyclohexane-1,3,5-trioxazoline; Alkylation.
max
(1H, d, J 14.4), 1.54 (2H, t,J 13.2), 2.15 (1H, d, J 14.4), 2.38
(2H, br d, J 13.2), 2.89 (4H, s), 3.16 (1H, tt, J 13.2, 3.3) and
7.19-7.37 (10H, m); C (75 MHz, CDCl3) 24.0 (CH), 37.2 (2
C), 37.5 (2 CH2), 40.1 (CH2), 46.9 (2 CH2), 119.3 (C), 119.8
(2 C), 128.2 (2 CH), 128.8 (4 CH), 130.3 (4 CH), 132.4 (2 C);
m/z (FAB) 339 (M+) (Found: M+, 339.1736. C23H21N3 re-
quires 339.1735) (Anal. Found: C, 81.15; H, 6.12; N, 12.48.
C23H21N3 re quires C, 81.38; H, 6.24; N, 12.38).
REFERENCES
1. Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46,
5140.
2. (a) Rebek, Jr., J.; Askew, B.; Killoran, M.; Nemeth, D.;
Lin, F.-T. J. Am. Chem. Soc. 1987, 109, 2426. (b) Rebek,
Jr., J. Science 1987, 235, 1478. (c) Askew, B.; Ballester,
P.; Buhr, C.; Jeong, K. S.; Jones, S.; Parris, K.; Wil liams,
K.; Rebek, Jr., J. J. Am. Chem. Soc. 1989, 111 , 1082.
3. (a) Curran, T. P.; Borysenko, C. W.; Abelleira, S. M.;
Messier, R. J. J. Org. Chem. 1994, 59, 3522. (b) Tanase,
T.; Yun, J. W.; Lippard, S. J. Inorg. Chem. 1995, 34, 4220.
(c) He, C.; Lippard, S. J. J. Am. Chem. Soc. 1998, 120,
105.
cis,cis-1,3,5-Triallylcyclohexane-1,3,5-tricarbonitrile (12a)
and cis,trans-1,3,5-Triallylcyclohexane-1,3,5-
tricarbonitrile (12b)
Alkylation of the trinitrile 7a (159 mg, 1 mmol) with
allyl bro mide (0.52 mL, 6 mmol) in Et2Osolution,byaproce-
dure sim i lar to that for10b, gave the trialkylation prod ucts
12a (42 mg, 15%) and 12b (107 mg, 38%).
12a: Solid, mp > 300 C (dec.); TLC (EtOAc/hex ane
(4:6)) Rf 0.05;
(KBr)/cm-1 2236; H (200 MHz, CDCl3)
max
4. Melacini, G.; Feng, Y.; Good man, M. J. Am. Chem. Soc.
1996, 118, 10725. (b) Good man, M.; Melacini, G.; Feng,
Y. J. Am. Chem. Soc. 1996, 118, 10928.
5. (a) Hirose, T.; Baldwin, B. W.; Uchimaru, T.; Tsuzuki, S.;
Uebayashi, M.; Taira, K. Chem. Lett. 1995, 231. (b)
Baldwin, B. W.; Hirose, T.; Wang, Z.-H.; Uchimaru, T.;
Yliniemel, A. Bull. Chem. Soc. Jpn. 1997, 70, 1895.
6. (a) Liang, Y.; Chang, C. K. TetrahedronLett. 1995, 36,
3817. (b) Jeong, K.-S.; Kim, J. H. Bull. Ko rean Chem.
Soc. 1996, 17, 564.
1.07 (3H, d, J 14.6), 2.36 (6H, d, J 7.4), 2.42 (3H, d, J 14.6),
5.16-5.32 (6H, m), 5.79-5.97 (3H, m); C (50 MHz, CDCl3)
34.6 (3 C), 41.1 (3 CH2), 46.7 (3 CH2), 119.6 (3 C), 121.8 (3
CH2), 129.7 (3 CH);m/z 279 (M+, 1%) and 136 (100) (Found:
M+, 279.1730. C18H21N3 re quires 279.1735).
12b: Solid, mp 103-105 C;TLC(EtOAc/hexane(4:6))
Rf 0.20;
(KBr)/cm-1 2236; H (300 MHz, CDCl3) 1.20
max
(1H, d, J 14.7, H-2 ), 1.64 (2H, d, J 14.4, H-4 and H-6 ),
2.34 (1H, d, J 14.7, H-2 ), 2.36 (4H, d, J 7.5, 1-CH2 and
3-CH2), 2.45 (2H, d, J 14.4, H-4 , and H-6 ), 3.04 (2H, d, J
7.5, 5-CH2), 5.24 (2H, d, J 17.1), 5.32 (2H, d, J 10.2), 5.38
7. (a) Stack, J. G.; Curran, D. P.; Rebek, Jr., J.; Ballester, P.
J. Am. Chem. Soc . 1991, 113, 5918. (b) Stack, J. G.;
Curran, D. P.; Geib, S. V.; Rebek, Jr., J.; Ballester, P. J.
Am. Chem. Soc. 1992, 114, 7007. (c) Kocis, P.; Issakova,
O.; Sepetov, N. F.; Lebl, M. TetrahedronLett. 1995, 36,
6623.
8. Steitz, Jr., A. J. Org. Chem. 1968, 33, 2978.
9. Mayer, H. A.; Stößel, P.; Fawzi, R.; Steimann, M. Chem.
Ber. 1995, 128, 719.
(1H, d, J 10.2), 5.50 (1H, d,J 17.1) and 5.80-5.92 (3H, m);
C
(75 MHz, CDCl3) 32.9 (2 C), 36.8 (C), 37.7 (CH2), 39.3 (2
CH2), 40.6 (CH2), 46.5 (2 CH2), 121.3 (2 C), 122.0 (2 CH2),
122.1 (C), 122.6 (CH2), 129.3 (2 CH), 130.7 (CH); m/z 279
(M+, 7%) and 136 (100) (Found: M+, 279.1735. C18H21N3 re-
quires 279.1735).
10. Bolm, C.; Weickhardt, K.; Zehnder, M.; Glasmacher, D.
Helv. Chim. Acta 1991, 74, 717.
ACKNOWLEDGEMENT
11. For reviews on the preparation and chemistry of
oxazolines, see: (a) Wiley, R. H.; Bennett, Jr., L. L.
We thank the Na tional Sci ence Coun cil for fi nan cial
sup port. We are grate ful to Prof. Bih-Yaw Jin (Na tional Tai-

200 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001
Chuang and Fang
Chem. Rev. 1949, 44, 447. (b) Frump, J. A. Chem. Rev.
1971, 71, 483. (c) Meyer, A. I.; Mihelich, E. D. Angew.
Chem. Int. Ed. Engl. 1976, 15, 270. (d) Reuman, M.;
Meyer, A. I. Tetrahedron 1985, 41, 837.
12. Luján-Upton, H. A.; Okamoto, Y. Chem. Lett. 1997,
1253.