Stereoselective synthesis of 3,6-disubstituted 1,2-diaminocyclohexanes through ring-closing metathesis of 4,5-diamino-1,7-octadiene derivatives

Article abstract of DOI:10.1055/s-2005-918515

3,6-Disubstituted 4,5-di[(S)-1-phenylethylamino]-1,7-octadienes with different configurations at the carbon stereocenters were protected as dihydrochlorides or cyclic phosphorous diamides and then converted into (1R,2R)-3,6-disubstituted 1,2-diaminocycloh

Full text of DOI:10.1055/s-2005-918515

PAPER
285
Stereoselective Synthesis of 3,6-Disubstituted 1,2-Diaminocyclohexanes
through Ring-Closing Metathesis of 4,5-Diamino-1,7-octadiene Derivatives
Stereoselective
S
a
r
3,6-Disu
l
bstitut
a
B
clohexane
s
by
R
o
C
M
Reactio
g
a
Dipartimento di Chimica Organica ’A. Mangini’, Università di Bologna, viale Risorgimento 4, 40136 Bologna, Italy
Dipartimento di Chimica ’G. Ciamician’, Università di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax +39(051)2099456; E-mail: diego.savoia@unibo.it
b
Received 30 June 2005; revised 11 July 2005
In this paper, we describe the results of our efforts to
achieve the RCM reaction of other 3,6-disubstituted-4,5-
diamino-1,7-octadienes 1c-e with defined configurations
of the stereocenters C3 and C6. Configurationally pure
Abstract: 3,6-Disubstituted 4,5-di[(S)-1-phenylethylamino]-1,7-
octadienes with different configurations at the carbon stereocenters
were protected as dihydrochlorides or cyclic phosphorous diamides
and then converted into (1R,2R)-3,6-disubstituted 1,2-diaminocy-
clohexanes through ruthenium-catalyzed ring-closing metathesis compounds 1 are available through double addition of g-
and subsequent hydrogenolysis-hydrogenation steps.
substituted allylzinc reagents to the optically pure di-
imine, derived from glyoxal and (S)-1-phenylethylamine.8
In these reactions, the configuration of the a-amino ste-
reocenters (C4, C5) in products 1 is controlled by the
chiral auxiliary, whereas the relative stereochemistry of
the stereocenters C3 and C6 depends on the E/Z configu-
ration of the C=C bond in the allylic organozinc reagent.
The configuration of all stereocenters in 1 is maintained in
the cyclization, leading to stereochemically defined prod-
ucts 2. Obviously, compounds ent-2 are available starting
from (R)-1-phenylethylamine.
Key words: catalysis, cyclization, diamines, metathesis, ruthenium
The ring-closing metathesis (RCM) of 1,n-dienes has
been widely applied for the construction of nitrogen-con-
taining compounds, for example, natural alkaloids con-
taining the pyrrolidine or piperidine ring1 and amino-
substituted cycloalkenes.2 We have recently reported3a
that the dihydrochloride of (4R,5R)-4,5-diamino-1,7-octa-
diene derivative 1a was converted into the N,N¢-disubsti-
tuted 1,2-diaminocyclohex-4-ene 2a by a RCM reaction
using the first generation Grubbs ruthenium carbene com-
plex 5 as the catalyst (Scheme 1). On the other hand, the
cyclization of the vinyl-substituted diaminodiene 1b was
obtained with moderate diastereoselectivity through for-
mation of the formaldehyde aminal 3, which was then di-
rectly converted into diaminocyclohexene 2b in the
presence of trifluoroacetic acid in refluxing toluene.3b In
contrast, we could not find suitable conditions to achieve
the cyclization of the phenyl-substituted substrate 1c,
even using the second generation ruthenium carbene com-
plex 6.
In particular, we describe a novel procedure for the cy-
clization of diaminodienes 1, which involves the prelimi-
nary preparation of cyclic phosphorous diamides 4 by
reaction with phosphorus trichloride.9,10 The RCM reac-
tion of these intermediates leads to bicyclic phosphorous
diamides 7,11 which are hydrolyzed to give the required
diaminocyclohexenes 2, avoiding their purification by
treatment with a HCl/MeOH solution.
It is noteworthy that the RCM route is an alternative to the
zirconium-promoted and -catalyzed reductive cycliza-
tions of 1,12 which in our study could not be applied to
compound 1e with hydroxy substituents in the allylic po-
sitions.
The importance of compounds 2 stems from their poten-
tial as intermediates, due to the possible transformation of
the alkene function, e.g., hydrogenation to saturated com-
pounds, or other addition reactions, e.g., epoxidation and
dihydroxylation, providing access to ring-substituted de-
rivatives of the prototypical chiral ligand 1,2-diaminocy-
clohexane.4 The new compounds can find application as
novel chiral N,N-ligands for metal species. In fact, the ef-
fect of substituents on the reactivity and stereoselectivity
of salen complexes featuring a substituted cyclohexane
ring has become object of investigation.5 Moreover, poly-
hydroxylated diaminocyclohexenes (diaminoconduritols)
and -cyclohexanes are potentially active as glycosidase
inhibitors6 and can form cytostatic platinum complexes.7
Since it was apparent from the previous results that the
RCM reaction of compounds 1 was strongly affected by
the steric effects of the allylic substituents R, we contin-
ued the investigation on several 3,6-disubstituted com-
pounds 1, aiming to find out suitable protocols for their
cyclization. The results of the RCM reactions carried out
on the dihydrochlorides of diaminodienes 1 or the phos-
phorous diamides 4 are summarized in Table 1.
Compound 1d was prepared as a mixture of the two main
diastereomers (55:45 ratio, not separated), which differed
in the configuration of one allylic stereocenter.
The two ruthenium catalysts 5 and 6 displayed different
activity in the RCM reaction of 1d. As a matter of fact,
working with catalyst 5 on 1d·2HCl in refluxing CH2Cl2
no reaction was observed after six hours (entry 1). On the
other hand, catalyst 6 (5 mol%) under the same conditions
SYNTHESIS 2006, No. 2, pp 0285–0292
x
x
.
x
x
.2
0
0
5
Advanced online publication: 21.12.2005
DOI: 10.1055/s-2005-918515; Art ID: Z12705SS
© Georg Thieme Verlag Stuttgart · New York

286
C. Boga et al.
PAPER
HCHO, PTSA (cat.)
R = CH=CH2
PCl3, Et3N
R
R
R
R
Me
Me
Ph
Me
Ph
Me
Ph
N
O
N
H
DMAP (cat.)
NH HN
P
Ph
1
4
1) HCl
2) 5 or 6 (cat.)
3) NaOH
6 (cat.),
CH2Cl2,
40 °C
Me
Ph
Me
N
N
Ph
3
HCl–
dioxane
R
R
5 (cat.), TFA
R
R
Me
Ph
Me
Me
Ph
Me
N
N
O
MeOH
NH HN
toluene, 110 °C
P
Ph
Ph
H
2
7
a: R = H; b: R = vinyl; c: R = Ph; d: R = Me; e: R = OH; f: R = OEt; g: R = OPh
Cy3P
N
N
Mes
Mes
Cl
Ru CHPh
Cl
Ru CHPh
Cl
PCy3
Cl
5
6
PCy3
Scheme 1
was able to discriminate the two diastereomers of 1d at a ysis) and prevalence of the cis isomer after acidic
high degree: the C1-symmetric diastereomer C1-1d was hydrolysis (entry 6). Better reaction conditions were
quickly consumed and converted into cis-2d, i.e. with the found using CH2Cl2 as the solvent at 40 °C. In this case,
cis relationship of the two methyl substituents (entry 2). cis-2b was isolated in 53% yield after chromatographic
The diaminocyclohexene cis-2d and unreacted C2-sym- separation from minor amounts of the trans diastereomer
metric 1d (C2-1d) were separated by column chromatog- and unreacted 1b (entry 7).
raphy and obtained in 35% and 37% yield, respectively.
Using this route, the separation of the two diastereomers
of 1d, which is tedious and incomplete on a large scale,
can be avoided.
Unfortunately, phosphorous diamide 4c prepared from
phenyl-substituted diaminodiene 1c did not undergo cy-
clization either in CH2Cl2 or in benzene at reflux using
catalyst 6 (entry 8). In contrast, the presence of hydroxy
Furthermore, we found that protection of the diamine substituents was not detrimental to the cyclization of 1e to
moiety as a cyclic phosphorous diamide is convenient for 2e (70% yield) catalyzed by complex 6 under the same
the RCM reaction, being more easily introduced as well as conditions (entry 10), whereas catalyst 5 was inactive (en-
removed than other common diamides. In fact, we pre- try 9). With this regard, it should be underlined that previ-
pared the phosphorous diamide 4d and then observed a ously described syntheses of oxygen-substituted
quick cyclization in the presence of 4 mol% of catalyst 6 cyclohexenes via RCM reactions were generally achieved
in CH2Cl2 at 40 °C (entry 3). After acidic hydrolysis of the through protection of the hydroxy functions in the starting
reaction mixture the desired free diamine 2d was isolated 1,7-dienes, and required high loadings of the catalyst 5
in 92% yield.
(up to 30 mol%), high temperatures and long reaction
times.13 Moreover, isomerization of the allylic alcohol to
methyl ketone was a competitive pathway in reactions cat-
alyzed by 5.13,14
The trans-dimethyl-substituted diastereomer was similar-
ly prepared in good yield starting from C2-1d (entry 4),
that had been recovered from the previous run described
in entry 2.
Either the dihydrochloride or the phosphorous diamide 4f
of the diethoxy-substituted substrate 1f (75:25 mixture of
diastereomers, the prevalent one had C1-symmetry) were
submitted to RCM reactions in refluxing CH2Cl2 (entries
11, 12). Only the phosphorous diamide 4f could be con-
verted in moderate yield into the desired cyclohexene cis-
2f. No successful conversion was achieved in the RCM re-
actions of the C2-symmetric phenoxy-substituted com-
pounds 1g·2HCl and 4g by using catalyst 6 either in
CH2Cl2 at 40 °C or in toluene at 110 °C (entries 13, 14).
The phosphorous diamide 4b with pentadienyl substitu-
ents was prepared from diamine 1b in a similar manner.
We observed that 4b did not undergo cyclization in the
presence of catalyst 5 in refluxing toluene, as diamine 1b
was almost quantitatively recovered after the hydrolysis
step (entry 5). Instead, the RCM reaction of 4b was mod-
erately successful in the presence of catalyst 6 (7 mol%)
in refluxing benzene (3 h), allowing the bicyclic phospho-
rous amide 7b to be obtained in ca. 30% yield (NMR anal-
Synthesis 2006, No. 2, 285–292 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of 3,6-Disubstituted 1,2-Diaminocyclohexanes by RCM Reactions
287
Table 1 Ring-Closing Metathesis of Diaminodiene Derivatives
Entry Diaminodiene
Yield of intermediate
(%)
RCM catalyst,
solvent, temp., time
Yield of product (%)a
Me
Me
NH HN
Ph
Me
Me
1d·2HCl
(100)
1
5 (5 mol%), CH2Cl2, 40 °C, 6 h
6 (5 mol%), CH2Cl2, 40 °C, 3 h
1db
Ph
1d (dr ca. 55:45)
Me
Me
Me
Me
Me
Me
Me
Me
2
3
1d·2HCl
NH HN
NH HN
Ph
Ph
Ph
Ph
cis-2d (35)
C2–1d (37)
Me
Me
Me
Me
Me
Me
Me
Me
6 (4 mol%), CH2Cl2, 40 °C, 4 h;
then HCl-MeOH
1d (dr = 55:45)
NH HN
N
O
N
H
Ph
Ph
P
Ph
Ph
2d (92, cis/trans = 55:45)
4d (87)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
6 (4 mol%), CH2Cl2, 40 °C, 3 h;
then HCl-MeOH
4
5
Me
NH HN
NH HN
N
N
H
Ph
Ph
P
Ph
Ph
Ph
Ph
O
trans-2d (74)
C2-1d
C2-4d (93)
5 (7 mol%), toluene, 110 °C, 6 h;
then HCl-MeOH
1bb
Me
N
Ph
Me
Ph
Me
Me
Ph
N
H
NH HN
P
Ph
O
1b
4b (92)
Me
Me
Ph
6
7
4b
6 (7 mol%), benzene, 80 °C, 3 h
N
O
N
H
P
Ph
7b (30, cis-7b prevalent)c
6 (7 mol%), CH2Cl2, 40 °C, 3 h;
then HCl-MeOH
4b
Me
Ph
Me
Ph
NH HN
cis-2b (53)d
Ph
Me
N
Ph
Me
5 (10 mol%), benzene, 80 °C, 6 h;
Ph
Me
Ph
Me
8
9
or 6 (10 mol%), CH2Cl2, 40 °C, 6 h; 1cb
then HCl-MeOH
N
H
NH HN
P
Ph
Ph
O
Ph
Ph
4c
1c
4c (94%)
HO
Me
OH
Me
1e·2HCl
(100)
5 (5 mol%), CH2Cl2, 40 °C, 3 h
1eb
NH HN
Ph
Ph
1e
Synthesis 2006, No. 2, 285–292 © Thieme Stuttgart · New York

288
C. Boga et al.
PAPER
Table 1 Ring-Closing Metathesis of Diaminodiene Derivatives (continued)
Entry Diaminodiene
Yield of intermediate
(%)
RCM catalyst,
solvent, temp., time
Yield of product (%)a
HO
Me
OH
Me
10
1e·2HCl
6 (7 mol%), CH2Cl2, 40 °C, 4 h
6 (7 mol%), CH2Cl2, 40 °C, 4 h
NH HN
Ph
Ph
2e (70)
EtO
OEt
Me
1f·2HCl
(100)
11
1fa
Me
NH HN
Ph
Ph
1f (C1/C2 = 75:25)
EtO
Me
OEt
Me
EtO
Me
OEt
Me
6 (5 mol%), CH2Cl2, 40 °C, 4 h;
then HCl-MeOH
12
13
14
1f (C1/C2 = 75:25)
NH HN
N
O
N
H
Ph
Ph
P
Ph
Ph
cis-2f (38) d
4f (75)c
PhO
OPh
1g·2HCl
(100)
6 (10 mol%), CH2Cl2, 40 °C, 6 h;
or toluene, 110 °C, 3 h
1gb
Me
Me
NH HN
Ph
Ph
1g
6 (10 mol%), CH2Cl2, 40 °C, 6 h;
PhO
Me
N
OPh
Me
1g
or 6 (10 mol%), toluene, 110 °C, 4 h; 1ga
then HCl-MeOH
N
H
P
Ph
Ph
O
4g (100)
a Yield of product isolated by column chromatography.
b The unreacted starting material was generally recovered in >95% yield.
c Yield determined by 1H NMR spectroscopy of the crude reaction mixture.
d Minor amounts of unreacted 1b or 1f and trans-2b or -2f were not isolated.
From these results, it appears that the RCM reaction of
3,6-disubstituted 4,5-diamino-1,7-octadienes 1 is prefera-
bly accomplished through the cyclic phosphorous di-
1) HCO2NH4,
20% Pd(OH)2/C
EtOH, reflux, 3 h
R
Me
R
Me
R
R
amides 4 by using ruthenium catalyst 6 in CH2Cl2 at
40 °C. The reaction is sensitive to steric effects, being af-
fected by the nature of the substituents and the configura-
tion of the inherent stereocenters. Particularly,
cyclohexenes are more easily formed when the allylic
substituents can assume the relative cis-relationship in the
six-membered carbon ring. Nevertheless, the C2-symmet-
ric hydroxy-substituted diaminodiene 1e can be cyclized
to give substituted cyclohexene trans-2e through the dihy-
drochloride.
NH HN
ClH3N
NH3Cl
2) HCl/dioxane
Ph
Ph
2
8
6
3
2
6
3
6
3
Me
Me
Me
Me
HO
OH
1
1
2
1
2
ClH3N
NH3Cl
ClH3N
NH3Cl
ClH3N
NH3Cl
(1R,2R,3S,6S)-8d,
(1R,2R,3R,6S)-8d,
(1S,2S,3R,4R)-8e,
91%
90%
91%
3
3
6
6
Et
Et
EtO
OEt
Finally, the N-unsubstituted diaminocyclohexanes
(1R,2R,3R,6S)-8d, (1R,2R,3S,6S)-8d, (1S,2S,3R,6R)-8e,
(1R,2R,3R,6S)-8g and (1S,2S,3R,6S)-8f were prepared
from 2d-g by palladium-catalyzed hydrogenation-hy-
drogenolysis in refluxing ethanol (Scheme 2). Particularly
noteworthy is that diethyl-substituted compound 8g de-
rived from the vinyl-substituted precursor 2b.
1
1
2
2
ClH3N
NH3Cl
ClH3N
NH3Cl
(1R,2R,3R,6S)-8g,
(1S,2S,3R,6S)-8f,
94%
55%
Scheme 2
Synthesis 2006, No. 2, 285–292 © Thieme Stuttgart · New York

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Stereoselective Synthesis of 3,6-Disubstituted 1,2-Diaminocyclohexanes by RCM Reactions
289
Anal. Calcd for C24H32N2: C, 82.71; H, 9.25; N, 8.04. Found: C,
82.46; H, 9.29; N, 8.07.
It can be concluded that the RCM reactions of the proper
substrates 1d-g have allowed to prepare new 1,2-diami-
nocyclohexane derivatives, where both the amino groups
are equatorially oriented and the C3,C6 substituents are in
one of the three possible relative orientations: axial-equa-
torial (8d-g), equatorial-equatorial (8d) and axial-axial
(8e). The effect of the relative stereochemistry of the
C3,C6 substituents and their size should now be assessed
in a number of asymmetric reactions, e.g., those catalyzed
by salen complexes.
(1R,4R,5S,6S)-5,6-Bis{[(1S)-1-phenylethyl]amino}cyclohex-2-
ene-1,4-diol (2e)
White powder; mp 120–122 °C.
[a]D25 –11.4 (c 0.63, CHCl3).
IR (KBr): 3318, 3027, 1600, 1324, 1259 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.38 (d, 6 H, J = 6.6 Hz), 1.9–2.9
(broad, 4 H), 2.45 (m, 2 H), 3.81 (q, 2 H, J = 6.6 Hz), 4.06 (m, 2 H),
5.97 (dd, 2 H, J = 1.4, 2.8 Hz), 7.2–7.4 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 25.2, 52.5, 55.1, 62.3, 126.6,
Melting points are uncorrected. Solvents were distilled over the ap-
propriate drying agent under N2 atmosphere before use: THF (sodi-
um benzophenone ketyl, then LiAlH4), CH2Cl2 (P2O5). Optical
rotations were measured on a digital polarimeter in a 1 dm cell and
[a]D values are given in 10–1 deg·cm3·g–1. 1H NMR spectra were re-
corded on a Varian Gemini instrument at 300 MHz or 200 MHz for
127.2, 128.6, 130.5, 145.1.
Anal. Calcd for C22H28N2O2: C, 74.97; H, 8.01; N, 7.95. Found: C,
74.67; H, 8.04; N, 7.92.
Phosphorous Diamides 4; General Procedure
1
samples in CDCl3, which was stored over Mg: H and 13C NMR
To a stirred solution of diaminodiene 1 (2 mmol) in CH2Cl2 (10 mL)
were added Et3N (2.02 g, 20 mmol) and DMAP (10 mg). Freshly
distilled PCl3 (0.55 g, 4 mmol) was added at 0 °C and the mixture
was stirred for 3 h at reflux. After cooling at 0 °C, H2O (10 mL) was
slowly added (Caution!), CH2Cl2 was removed at reduced pressure,
and the organic materials were extracted with Et2O (3 × 10 mL).
The ethereal layers were collected, then Na2SO4 and SiO2 (1 g) were
added, the mixture was stirred for 30 min, then filtered through a
small pad of Celite, and the organic solution was concentrated at re-
duced pressure. The products were used without further purifica-
tion.
chemical shifts are reported in ppm relative to CHCl3, dH = 7.27,
dC = 77.0) and J values are given in Hz. 31P NMR spectra were re-
corded on a Varian Mercury 400 spectrometer at 161.90 MHz;
chemical shifts are referenced to external standard 85% H3PO4. MS
spectra were taken at an ionizing voltage of 70 eV on a Hewlett-
Packard 5970 or 5890 spectrometer with GLC injection. Chromato-
graphic separations were performed on columns of SiO2 (Merck,
230–400 mesh) at medium pressure. The ruthenium catalysts 5 and
6 were purchased from Aldrich. The metathesis reactions were car-
ried out in a flame-dried apparatus under a static atmosphere of dry
Ar.
(4R,5R)-1,3-Bis[(1S)-1-phenylethyl]-4,5-bis(1-vinylprop-2-en-
1-yl)-1,3,2-diazaphospholidine 2-Oxide (4b)
Whitish oil.
[a]D25 +21.6 (c 0.44, CHCl3).
RCM Reactions of Diaminodienes 1 through their Dihydrochlo-
rides; General Procedure
To the stirred solution of diaminodiene 1 (2 mmol) in MeOH (5 mL)
was added HCl (4 M in dioxane, 1 mL). Then the solvent was re-
moved at reduced pressure to leave an off-white solid. This solid
was dissolved in CH2Cl2 (6 mL), complex 6 (5–7 mol%) was added
while Ar was bubbled through the solution (0.5 min), and the solu-
tion was stirred at 40 °C until (almost) complete conversion (TLC
analysis). The cooled reaction mixture was treated with 2 M NaOH
(5 mL) and the organic phase was extracted with CH2Cl2 (3 × 5 mL).
The collected organic layers were dried (CaCl2) and concentrated at
reduced pressure to leave a greyish solid. Pure diaminocyclo-
hexenes were obtained by column chromatography (SiO2, cyclo-
hexane-EtOAc).
IR (neat): 3428, 3077, 2360 (PH), 1635, 1226 (P=O), 1129, 1037,
998, 918, 773, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.73 (d, 3 H, J = 7.3 Hz), 1.78 (d,
3 H, J = 7.3 Hz), 2.55–2.75 (m, 3 H), 2.85–2.95 (m, 1 H), 4.10–4.20
(m, 1 H), 4.25–4.55 (m, 3 H), 4.75–5.25 (m, 7 H), 5.30–5.50 (m, 1
H), 5.50–5.70 (m, 2 H), 7.25–7.45 (m, 8 H), 7.55–7.65 (m, 2 H),
8.04 (d, 1 H, 1JP,H = 609 Hz, PH).
13C NMR (75 MHz, CDCl3): d = 21.42 (d, 3JC,P = 3.6 Hz, CH3), 21.4
3
(d, JC,P = 3.6 Hz, CH3), 51.2 (CHCH=CH2), 51.6 (CHCH=CH2),
55.85 (d, 2JC,P = 7.2 Hz, CHCH3), 56.2 (d, 2JC,P = 6.1 Hz, CHCH3),
59.7 (d, 2JC,P = 9.0 Hz, CHCHN), 62.6 (d, 2JC,P = 7.8 Hz, CHCHN),
116.6 (CH2=), 116.9 (CH2=), 117.6 (CH2=), 117.8 (CH2=), 127.4,
127.5, 127.85, 128.0, 128.35, 128.6 (6 lines for arom. CH), 136.1
(CH=), 136.2 (CH=), 136.9 (CH=), 137.25 (CH=), 142.8 (arom. C),
143.1 (arom. C).
(1R,2R,3R,6S)-3,6-Dimethyl-N,N¢-bis[(1S)-1-phenylethyl]cyclo-
hex-4-ene-1,2-diamine (cis-2d)
This compound was obtained as an oil starting from the (6R,6S)-
mixture of 1d·2HCl through chromatographic separation of unre-
acted C2-1d.
31P NMR (162 MHz, CDCl3): d = 8.9 (dm, 1JP,H = 609 Hz).
[a]D25 –61.5 (c 0.22, CHCl3).
IR (neat): 3340, 3295, 3062, 3023, 1602, 1370 cm–1.
(4R,5R)-4,5-Bis[(1S)-1-methylprop-2-en-1-yl]-1,3-bis[(1S)-1-
phenylethyl]-1,3,2-diazaphospholidine 2-Oxide (C2-4d)
Whitish oil.
[a]D25 –31.2 (c 0.73, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.63 and 1.11 (2 d, 6 H, J = 6.9
Hz), 1.22 and 1.48 (2 d, 6 H, J = 6.6 Hz), 1.27 (s, 1 H) 2.0 (m, 2 H),
2.07 (dd, 1 H, J = 9.9, 8.7 Hz), 2.36 (dd, 1 H, J = 15.3, 5.1 Hz), 2.40
(m, 1 H), 3.68 and 3.81 (2 q, 2 H, J = 6.6 Hz), 5.21 (ddd, 1 H,
J = 9.9, 1.8, 1.5 Hz), 5.46 (ddd, 1 H, J = 9.9, 4.8, 2.4 Hz), 7.1–7.4
(m, 10 H).
IR (neat): 3445, 3065, 3035, 2346 (PH), 1638, 1600, 1228 (P=O),
1130, 1033, 913, 802, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.76 (d, 3 H, J = 7.1 Hz), 0.79 (d,
3 H, J = 7.1 Hz), 1.76 (d, 3 H, J = 7.0 Hz), 1.82 (d, 3 H, J = 7.0 Hz),
2.20–2.49 (m, 2 H), 2.58–2.90 (m, 2 H), 4.12–4.42 (m, 2 H), 4.52–
5.04 (m, 4 H), 5.15–5.34 (m, 1 H), 5.65–5.84 (m, 1 H), 7.23–7.43
(m, 8 H), 7.52–7.60 (m, 2 H), 7.96 (d, 1 H, 1JP,H = 609 Hz, PH).
13C NMR (50 MHz, CDCl3): d = 14.2, 20.2, 24.1, 25.6, 31.1, 41.0,
53.5, 55.7, 56.7, 58.4, 126.7, 127.2, 128.1, 128.3, 130.3, 131.5.
GC-MS: m/z (%) = 105 (100), 214 (65), 110 (51), 120 (17), 348 (2,
M+).
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13C NMR (75 MHz, CDCl3): d = 15.4 (CH3CHCH=), 15.6
(CHCH=CH2), 83.2 (CHCH=CH2), 83.5 (CHCH=CH2), 117.9
(CH2=), 118.0 (CH2=), 118.9 (CH2=, 3 sign. overl.), 119.7 (CH2=),
127.15, 127.2, 127.27, 127.3, 127.3, 127.4, 127.5, 127.5, 127.6,
127.8, 127.9, 128.0, 128.2, 128.2, 128.2, 128.3, 128.23 128.5 (18
lines for arom. CH), 134.6 (CH=), 135.0 (CH=), 135.1 (CH=),
135.38 (CH=), 135.58 (CH=), 135.69 (CH=), 143.10 (arom. C),
143.35 (arom. C), 143.4 (arom. C), 143.4 (arom. C), 143.55 (arom.
C), 143.8 (arom. C).
3
(CH3CHCH=), 21.6 (d, JC,P = 4.7 Hz, CH3CHN), 21.7 (d,
3JC,P = 5.2 Hz, CH3CHN), 38.2 (CHCH=CH2), 38.7 (CHCH=CH2),
2
2
55.0 (d, JC,P = 6.9 Hz, NCHCH3), 55.1 (d, JC,P = 7.6 Hz,
2
2
NCHCH3), 60.1 (d, JC,P = 9.1 Hz, CHCHN), 62.55 (d, JC,P = 8.2
Hz, CHCHN), 115.5 (CH2=), 116.0 (CH2=), 127.3, 127.4, 127.7,
127.9, 128.2, 128.4 (6 lines for arom. CH), 138.3 (CH=), 139.3,
(CH=), 142.35 (arom. C), 142.8 (arom. C).
1
31P NMR (162 MHz, CDCl3): d = 9.9 (dm, 1JP,H = 609 Hz).
31P NMR (162 MHz, CDCl3): d = 12.1 (dm, JP,H = 609 Hz), 11.1
(dm, 1JP,H = 609 Hz), 8.3 (dm, 1JP,H = 604 Hz).
(4R,5R)-1,3-Bis[(1S)-1-phenylethyl]-4,5-bis[(1R)-1-phenylprop-
2-en-1-yl]-1,3,2-diazaphospholidine 2-Oxide (4c)
White solid; mp 210–215 °C (dec.).
[a]D25 +19.2 (c 0.39, CHCl3).
(4S,5S)-4,5-Bis[(1R)-1-phenoxyprop-2-en-1-yl]-1,3-bis[(1S)-1-
phenylethyl]-1,3,2-diazaphospholidine 2-Oxide (4g)
White solid; mp 125–134 °C (dec.).
[a]D25 +1.7 (c 1.8, CHCl3).
IR (KBr): 3429, 3026, 2329 (PH), 1600, 1226 (P=O), 1128, 1035,
988, 933, 900, 770, 701, 635, 542 cm–1.
IR (KBr): 3406, 3070, 3042, 2365 (PH), 1646, 1597, 1228 (P=O),
1118, 1031, 928, 803, 753, 700, 692 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.39 (d, 3 H, J = 7.2 Hz), 1.44 (d,
3 H, J = 7.2 Hz), 2.58–3.05 (m, 5 H), 3.05–3.20 (m, 1 H), 3.80 (d, 1
H, J = 17.3 Hz), 3.95 (d, 1 H, J = 17.3 Hz), 4.69 (dd, 1 H, J = 10.4,
1.8 Hz), 4.77 (dd, 1 H, J = 10.4, 1.8 Hz), 5.50–5.70 (m, 2 H), 7.05–
7.20 (m, 4 H), 7.20–7.45 (m, 14 H), 7.50–7.62 (m, 2 H), 8.30 (d, 1
H, 1JP,H = 602 Hz, PH).
1H NMR (300 MHz, CDCl3): d = 1.72 (d, 3 H, J = 7.0 Hz), 1.79 (d,
3 H, J = 7.0 Hz), 3.28–3.41 (m, 1 H), 3.41–3.55 (m, 1 H), 4.16–4.34
(m, 2 H), 4.38–4.60 (m, 2 H), 4.98–5.30 (m, 4 H), 5.40–5.57 (m, 1
H), 5.60–5.78 (m, 1 H), 6.65 (d, 2 H, J = 8.1 Hz), 6.74 (d, 2 H,
J = 8.1 Hz), 6.88–7.00 (m, 2 H), 7.10–7.30 (m, 10 H), 7.34–7.53 (m,
4 H), 8.06 (d, 1 H, 1JP,H = 613 Hz, PH).
13C NMR (75 MHz, CDCl3): d = 21.2 (d, 3JC,P = 6.0 Hz, CH3), 21.3
3
(d, JC,P = 5.0 Hz, CH3), 53.8 (CHCH=CH2), 54.8 (CHCH=CH2),
13C NMR (75 MHz, CDCl3): d = 20.83 (d, 3JC,P = 4.2 Hz, CH3), 21.3
2
2
3
2
56.0 (d, JC,P = 6.8 Hz, CHCH3), 57.0 (d, JC,P = 5.0 Hz, CHCH3),
61.9 (d, 2JC,P = 9.7 Hz, CHCHN), 65.6 (d, 2JC,P = 7.7 Hz, CHCHN),
117.6 (CH2=), 117.9 (CH2=), 126.75, 126.92, 127.2, 127.4, 127.7,
128.1, 128.35, 128.4, 128.4, 128.6 (10 lines, 2 sign. overl. for arom.
CH), 137.2 (CH=), 137.7 (CH=), 141.4 (arom. C), 141.7 (arom. C),
143.9 (arom. C), 143.95 (arom. C).
(d, JC,P = 4.2 Hz, CH3), 54.6 (d, JC,P = 6.5 Hz, CHCH3), 55.0 (d,
2JC,P = 8.0 Hz, CHCH3), 57.7 (d, 2JC,P = 8.9 Hz, CHCHN), 60.14 (d,
2JC,P = 8.1 Hz, CHCHN), 78.4 (CHCH=CH2), 79.4 (CHCH=CH2),
115.7 (arom. CH), 116.3 (arom. CH), 118.6 (CH2=), 119.0 (CH2=),
121.10, 121.15, 127.3, 127.4, 127.5, 127.5, 128.4, 128.5, 129.2,
129.3 (10 lines for arom. CH), 133.65 (CH=), 134.5 (CH=), 142.35
(arom. C), 142.4 (arom. C), 142.7 (arom. C), 142.7 (arom. C).
31P NMR (162 MHz, CDCl3): d = 7.2 (dm, 1JP,H = 602 Hz).
31P NMR (162 MHz, CDCl3): d = 13.4 (dm, 1JP,H = 613 Hz).
(4S,5S)-4-[(1R)-1-Ethoxyprop-2-en-1-yl]-5-[(1S)-1-ethoxyprop-
2-en-1-yl)-1,3-bis[(1S)-1-phenylethyl]-1,3,2-diazaphospholi-
dine 2-Oxide and (4S,5S)-4,5-Bis[(1S)-1-ethoxyprop-2-en-1-yl)-
1,3-bis[(1S)-1-phenylethyl]-1,3,2-diazaphospholidine 2-Oxide
(4f)
Yellowish oil; dr = 70:30.
[a]D25 –7.0 (c 0.68, CHCl3).
RCM Reactions of Phosphorous Acid Diamides 4; General Pro-
cedure
Preparation of Diaminocyclohexenes 2 through 8
Complex 6 (43 mg, 0.05 mmol) was added to the stirred solution of
phosphorous diamide 4 (2 mmol) in CH2Cl2 (6 mL) while Ar was
bubbled through the solution (0.5 min) at 40 °C. An equal amount
of complex 6 was added after 1.5 h and the mixture was further
stirred at 40 °C for 1.5–2 h. The solvent was removed under reduced
pressure and the residue was dissolved in MeOH (8 mL), then HCl
(4 M in 2 mL dioxane) was added and the mixture was stirred over-
night. The solvent was removed at reduced pressure and the residue
was treated with Et2O (10 mL), H2O (10 mL) and solid NaOH until
pH 11. The organic phase was separated and the aqueous layer was
further extracted with Et2O (3 × 5 mL). The collected organic layers
were dried (Na2SO4) and concentrated at reduced pressure to leave
a yellowish oil. Pure diaminocyclohexene was obtained through
column chromatography (SiO2, cyclohexane-EtOAc).
IR (neat): 3433, 3062, 3028, 2346 (PH), 1640, 1226 (P=O), 1131,
929, 772, 703 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.87 (t, 3 H, J = 7.0 Hz), 0.95 (t,
3 H, J = 7.0 Hz), 1.01 (t, 3 H, J = 7.0 Hz), 1.07 (t, 3 H, J = 7.0 Hz),
1.11 (t, 3 H, J = 7.0 Hz), 1.14 (t, 3 H, J = 7.2 Hz), 1.69 (d, 3 H,
J = 7.3 Hz) 1.70 (d, 3 H, J = 7.0 Hz), 1.71 (d, 3 H, J = 7.1 Hz), 1.72
(d, 3 H, J = 7.2 Hz), 1.76 (d, 3 H, J = 7.0 Hz), 1.78 (d, 3 H, J = 6.5
Hz), 2.40–3.60 (m, 24 H), 4.10–5.90 (m, 24 H), 7.20–7.50 (m, 24
H), 7.50–7.65 (m, 6 H), 7.96 (d, 2 H, 1JP,H = 609 Hz, PH), 8.07 (d,
1 H, 1JP,H = 604 Hz, PH).
Compound 2b was previously described.3b
13C NMR (75 MHz, CDCl3): d = 14.9 (CH3CH2OCH=), 15.0
(CH3CH2OCH=), 15.1 (CH3CH2OCH=), 15.2 (CH3CH2OCH=),
3
(1R,2R,3S,6S)-3,6-Dimethyl-N,N¢-bis[(1S)-1-phenylethyl]cyclo-
hex-4-ene-1,2-diamine (trans-2d)
Yellowish oil.
[a]D25 +64.2 (c 1.74, CHCl3).
IR (neat): 3317, 3082, 3060, 3011, 1602, 1368 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.09 (d, 6 H, J = 5.7 Hz), 1.28 (d,
6 H, J = 6.6 Hz), 1.68 (br m, 2 H), 2.04 (m, 4 H), 3.89 (q, 2 H,
J = 6.6 Hz), 5.21 (s, 2 H), 7.1–7.4 (m, 10 H).
13C NMR (50 MHz, CDCl3): d = 20.5, 24.8, 40.6, 58.1, 62.3, 126.8,
127.1, 128.3, 131.4, 145.8.
15.2 (CH3CH2OCH=), 15.3 (CH3CH2OCH=), 21.2 (d, JC,P = 3.4
3
3
Hz, CH3), 21.2 (d, JC,P = 3.2 Hz, CH3), 21.3 (d, JC,P = 4.3 Hz,
3
3
CH3), 21.4 (d, JC,P = 3.7 Hz, CH3), 21.5 (d, JC,P = 5.5 Hz, CH3),
21.7 (d, 3JC,P = 4.9 Hz, CH3), 55.2 (d, 2JC,P = 6.0 Hz, CHCH3), 55.6
2
2
(d, JC,P = 7.1 Hz, CHCH3), 55.8 (d, JC,P = 7.5 Hz, CHCH3), 55.9
(d, 2JC,P = 6.1 Hz, CHCH3), 56.25 (d, 2JC,P = 7.0 Hz, CHCH3), 56.9
(d, 2JC,P = 5.7 Hz, CHCH3), 57.3 (d, 2JC,P = 8.7 Hz, CHCHN), 56.2
(d, 2JC,P = 9.6 Hz, CHCHN), 58.8 (d, 2JC,P = 9.6 Hz, CHCHN), 60.8
(d, JC,P = 8.2 Hz, CHCHN), 61.35 (d, JC,P = 7.8 Hz, CHCHN),
61.6 (d, JC,P = 8.4 Hz, CHCHN), 63.95 (OCH2), 64.0 (OCH2),
2
2
2
64.15 (OCH2), 64.3 (OCH2), 64.5 (OCH2), 64.5 (OCH2), 81.1
(CHCH=CH2), 81.6 (CHCH=CH2), 82.7 (CHCH=CH2), 82.9
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Stereoselective Synthesis of 3,6-Disubstituted 1,2-Diaminocyclohexanes by RCM Reactions
291
GC-MS: m/z (%) = 105 (100), 214 (63), 110 (50), 120 (17), 348 (3,
(1S,2S,3R,6R)-3,6-Dihydroxycyclohexane-1,2-diaminium
Dichloride (8e)
M+).
Mp 200–210 °C (dec.).
[a]D25 –73.2 (c 0.17, MeOH).
Anal. Calcd for C24H32N2: C, 82.71; H, 9.25; N, 8.04. Found: C,
82.41; H, 9.29; N, 8.01.
IR (KBr): 3364, 2600–3200 (br), 1549, 1205 cm–1.
1H NMR (300 MHz, CD3OD): d = 1.60 (dd, 2 H, J = 9.8, 4.2 Hz),
1.89 (dd, 2 H, J = 9.8, 1.2 Hz), 3.53 (m, 2 H), 4.07 (m, 2 H).
(1S,2S,3R,6S)-3,6-Diethoxy-N,N¢-bis[(1S)-1-phenylethyl]cyclo-
hex-4-ene-1,2-diamine (cis-2f)
Yellowish oil.
[a]D25 –82.7 (c 0.7, CHCl3).
13C NMR (75 MHz, CD3OD): d = 26.2, 53.3, 67.1.
IR (neat): 3301, 3027, 1602, 1369, 1326, 1270, 1088 cm–1.
Anal. Calcd for C6H16Cl2N2O2: C, 32.89; H, 7.36; N, 12.79. Found:
C, 32.75; H, 7.39; N, 12.75.
1H NMR (200 MHz, CDCl3): d = 1.09 and 1.26 (2 t, 6 H, J = 7.0
Hz), 1.32 and 1.44 (2 d, 6 H, J = 6.2 Hz), 2.24 (dd, 2 H, J = 11.4,
3.2 Hz), 2.55 (dd, 2 H, J = 11.4, 8.0 Hz), 3.43 (dq, 1 H, J = 1.8, 8.0
Hz), 3.5–3.75 (m, 4 H), 3.75–3.95 (m, 2 H), 4.17 (q, 1 H, J = 6.6
Hz), 5.79 (dd, 1 H, J = 1.8, 10.4 Hz), 5.90 (ddd, 1 H, J = 1.2, 4.8,
10.4 Hz), 7.1–7.5 (m, 10 H).
13C NMR (50 MHz, CDCl3): d = 15.55, 15.8, 24.9, 25.8, 26.9, 54.0,
54.2, 55.4, 57.1, 64.1, 64.2, 68.5, 125.8, 126.3, 126.9, 127.0, 127.0,
128.1, 128.5, 131.6, 145.3, 146.5.
(1S,2S,3R,6S)-3,6-Diethoxycyclohexane-1,2-diaminium
Dichloride (8f)
The crude compound was isolated as a yellowish solid in 87% yield,
then washed with Et2O-MeOH (8:1) to give a white solid in 55%
yield.
Mp 175–185 °C (dec.).
[a]D25 –14.1 (c 0.27, MeOH).
IR (KBr): 3413, 3143, 2200–2500 (br), 1626, 1107 cm–1.
GC-MS: m/z (%) = 105 (100), 57 (33), 77 (22), 161 (20), 106 (12),
1H NMR (300 MHz, CD3OD): d = 1.27 and 1.29 (2 t, 6 H, J = 6.9
Hz), 1.55 (m, 2 H), 2.12 (m, 1 H), 2.25 (m, 1 H), 3.40–3.65 (m, 4
H), 3.65–3.90 (m, 3 H), 3.93 (s, 1 H).
13C NMR (50 MHz, CD3OD): d = 15.85, 15.9, 23.7, 24.1, 54.7,
55.5, 65.6, 66.0, 74.4, 77.7.
266 (10), 120 (6).
Anal. Calcd for C26H36N2O2: C, 76.43; H, 8.88; N, 6.86. Found: C,
76,74; H, 8.91; N, 6.84.
Preparation of 1,2-Diaminocyclohexanes Dihydrochlorides 8;
General Procedure
Anal. Calcd for C10H24Cl2N2O2: C, 43.64; H, 8.79; N, 10.00. Found:
C, 43 51; H, 8.82; N, 10.15.
A mixture of 1,2-diaminocyclohexene 2 (1 mmol), HCO2NH4
(0.800 g, 12.5 mmol), 20% Pd(OH)2/C (0.100 g) in EtOH (10 mL)
was heated at reflux temperature for 3 h. The cooled mixture was
filtered through a small pad of celite and the organic solution was
treated with HCl (0.5 mL; 4 M in dioxane). The solvents were re-
moved under reduced pressure to leave the diamine dihydrochloride
as a white solid (>95% pure by 1H NMR).
(1R,2R,3R,6S)-3,6-Diethylcyclohexane-1,2-diaminium
Dichloride (8g)
Mp 170–180 °C (dec.).
[a]D25 –3.8 (c 0.44, MeOH).
IR (KBr): 3436, 2500–3400 (br), 1594, 1503 cm–1.
(1R,2R,3R,6S)-3,6-Dimethylcyclohexane-1,2-diaminium
Dichloride (cis-8d)
Mp 200–210 °C (dec.).
[a]D25 –8.4 (c 0.5, MeOH).
IR (KBr): 3420, 2500–3500 (br), 1594, 1566, 1498 cm–1.
1H NMR (300 MHz, CD3OD): d = 1.13 (d, 3 H, J = 7.2 Hz), 1.20 (d,
3 H, J = 6.6 Hz), 1.50 (dt, 1 H, J = 2.7, 12.9 Hz), 1.60–1.90 (m, 4
H), 2.50 (m, 1 H), 3.39 (dd, 1 H, J = 10.5, 11.1 Hz), 3.66 (dd, 1 H,
J = 4.8, 10.5 Hz).
1H NMR (300 MHz, CD3OD): d = 0.88 (t, 6 H, J = 7.0 Hz), 1.1–1.7
(m, 8 H), 1.7–1.8 (m, 1 H), 1.9–2.1 (m, 1 H), 3.26 (dd, 1 H, J = 9.6,
8.0 Hz), 3.49 (dd, 1 H, J = 9.6, 4.8 Hz).
13C NMR (75 MHz, CD3OD): d = 11.0, 11.9, 19.2, 23.6, 25.1, 25.3,
39.6, 42.6, 54.7, 56.6.
Anal. Calcd for C10H24Cl2N2: C, 49.38; H, 9.95; N, 11.52. Found:
C, 49.58; H, 9.99; N, 11.48.
13C NMR (75 MHz, CD3OD): d = 12.9, 18.8, 28.3, 30.9, 33.1, 37.3,
Acknowledgment
56.2, 56.4.
This work was carried out in the field of the FIRB Project: Progetta-
zione, preparazione e valutazione biologica e farmacologica di
nuove molecole organiche quali potenziali farmaci innovativi.
Anal. Calcd for C8H20Cl2N2: C, 44.66; H, 9.37; N, 13.02. Found: C,
44.47; H, 9.40; N, 12.97.
(1R,2R,3S,6S)-3,6-Dimethylcyclohexane-1,2-diaminium
Dichloride (trans-8d)
References
Mp 230–240 °C (dec.).
[a]D25 +7.2 (c 1.3, MeOH).
IR (KBr): 3425, 2500–3400 (br), 1594, 1520 cm–1.
1H NMR (300 MHz, CD3OD): d = 1.18 (d, 6 H, J = 6.0 Hz), 1.34
(m, 2 H), 1.82 (d, 4 H, J = 7.5 Hz), 3.2 (d, 2 H, J = 7.8 Hz).
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44.48; H, 9.41; N, 12.98.
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Synthesis 2006, No. 2, 285–292 © Thieme Stuttgart · New York

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Synthesis 2006, No. 2, 285–292 © Thieme Stuttgart · New York