An efficient synthesis of tetrasubstituted cyclohexyl-1,2-diamines

Article abstract of DOI:10.1016/j.tetlet.2005.01.072

The synthesis of symmetrically tetrasubstituted diamines derived from the (R,R)-cyclohexyl-1,2-diamine is reported. We comment on the efficiency of this sequential substitution approach as a method for the synthesis of tetrasubstituted diamines and discus

Full text of DOI:10.1016/j.tetlet.2005.01.072

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1921–1925
An efficient synthesis of tetrasubstituted cyclohexyl-1,2-diamines
Hitesh Arjan,a Ewan Boyd,b Gregory S. Coumbarides,a Jason Eames,a,* Ray V. H. Jones,b
c
RachelA. Stenson and MichaelJ. Suggate
a
aDepartment of Chemistry, Queen Mary, University of London, Mile End Road, London E1 4NS, UK
bSyngenta, Grangemouth Manufacturing Centre, Earls Road, Grangemouth, Scotland FX3 8XG, UK
cSyngenta, Syngenta, Global Specialist Technology, PO Box A38, Leeds Road, Huddersfield HD2 1FF, UK
Received 29 October 2004; revised 5 January 2005; accepted 14 January 2005
Abstract—The synthesis of symmetrically tetrasubstituted diamines derived from the (R,R)-cyclohexyl-1,2-diamine is reported. We
comment on the efficiency of this sequentialsubstitution approach as a method for the synthesis of tetrasubstituted diamines and
discuss the acceptable substitution pattern for this methodology.
ꢀ 2005 Elsevier Ltd. All rights reserved.
NEt2
NH2
NH2
NMe2
1. Introduction
CH3CHO
HCHO
HCO2H
NaBH3CN
NEt2
NMe2
The synthesis of enantiomerically pure tetrasubstituted
diamines is well documented.1 They have been synthes-
ised by either direct alkylation of the parent chiral di-
amine with an achiral2–18/meso-based electrophile,15,19
or by alkylation of the parent achiral diamine with a chi-
ral electrophile.18 Of these approaches, the more synthet-
(R,R)-1
(R,R)-5; 73%
(R,R)-3; 47-85%
NMe2
Ph
Ph
NMe2
NMe2
Ph
NH2
NH2
HCHO
HCO2H
NMe2
Ph
(R,R)-6
(R,R)-4; 85%
(R,R)-2
ically versatile appears to involve direct alkylation of a
6
chiraldiamine
with an achiral electrophile.2–17 The
Scheme 1. Synthesis of diamines (R,R)-3, (R,R)-4, (R,R)-5 and
(R,R)-6.
majority of these studies have relied on step-
wise2–11,15,17 and in situ reductive amination,8–11,16,19,20
followed by direct alkylation (using simple SN2 dis-
placement methodology)11,13,19 to form the required four
carbon–nitrogen (C–N) single bonds. Using this type of
strategy, the synthesis of symmetrically tetrasubstituted
diamines using a single-step process would appear to
be relatively straightforward. However, it is surprising
From these reports, there appears to be a limited num-
ber that dealdirectyl with the conversion of disubsti-
tuted diamines to tetrasubstituted diamines. The
synthesis of disubstituted diamines such as dimethyl
and dibenzyldiamines 7 and 8 appears to be relatively
simple. Alexakis et al.15 have reported both the dimethy-
lation and dibenzylation of cyclohexyldiamine (R,R)-1
using methyliodide and benzylbromide to give the
dimethyland dibenzydl iamines 7 and 8, respectively, in
low to moderate yields (Scheme 2). Alternatively,
diamines 7 and 8 can be synthesised in higher yields
by reduction of the corresponding bis-dicarbamate
92,3,5,8,10,15 and imine 104–6,10 using a nucleophilic
hydride source (Scheme 2).
to find only
a
limited number of available
methods;8,11,12,14,16,19,21,22 the most common being the
Eschweiler–Clarke methylation23 of cyclohexyldiamine
1
8,16,20 and diphenylethylene diamine 28 using formalde-
hyde and formic acid to give the tetramethylcyclo-
hexyldiamine 3 and tetramethyldiphenylethylenediamine
4 in 47–85% and 85% yields, respectively (Scheme 1).
This type of reductive amination approach has also been
used to synthesise the related tetraethylcyclohexyldi-
amine 511 and tetramethylcyclopentyldiamine 6.11
To overcome the poor nucleophilicity of these secondary
16
*
amines, Alexakis and co-workers have developed an
in situ reductive amination procedure using an aldehyde
Corresponding author. Tel.: +44 207 882 5251; fax: +44 207 882
5251; e-mail: j.eames@qmul.ac.uk
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.072

1922
H. Arjan et al. / Tetrahedron Letters 46 (2005) 1921–1925
Ph
NH
Br
Br
15
NH2
NH2
NHMe
NH2
N
N
PhCH2Br
50%
MeI
Et3N, CH2Cl2
20-30%
NH
Ph
NHMe
NH2
(R,R)-7
(R,R)-8
(R,R)-1
(R,R)-1
(R,R)-1
PhCHO
EtOCOCl
78%15
(R,R)-16
90%4
LiAlH4
92%15
NaBH4
95%4
Br
Br
Ph
O
H
OEt
NH
NH2
NH2
17
N
N
H
H
N
N
Et3N, CH2Cl2
NH
H
O
Ph
OEt
(R,R)-18; 60%
(R,R)-9
(R,R)-10
Br
Br
Scheme 2. Synthesis of diamines (R,R)-7 and (R,R)-8.
N
N
(R)-19
toluene, Et3N
NH2
NH2
(e.g., benzaldehyde 11) and NaBH3CN to introduce the
benzylsubstituents in diamine 12 (Scheme 3). This pro-
cedure appears to be efficient for a wide range of substi-
tuted aldehydes. By comparison, N-alkylation of the
parent diamine 7 has been shown to occur using an
SN2 activated electrophile such as an epoxide (e.g.,
13)19 to give the bis-b-aminoalcohol 14 in moderate
yield (Scheme 3). Finally, double N-alkylation of each
amino group within the diamine (R,R)-1 has been
(R,R)-1
(R,R,R,R)-20; 51%
Scheme 4. Synthesis of diamines (R,R)-16, (R,R)-18 and (R,R,R,R)-20.
Ph
O
Ph
Ph
NH
achieved using achiraland chiraldibromides
15, 17
N
N
Ph
Ph
N
N
Ph
Ph
PhCOCl, Et3N
CH2Cl2
LiAlH4
THF
and 19 to give the tetrasubstituted diamines 16,12,14,24
1812 and 2018 respectively by ensuring that the second
alkylation step was intramolecular (Scheme 4).
NH
Ph
Ph
O
Ph
(R,R)-22; 79%
(R,R)-21; 65%
(R,R)-8
We were interested in extending this methodology
towards the synthesis of novel symmetrically tetra-
substituted diamines in an attempt to gain a better
understanding of these processes. We initially chose to
synthesise the tetrabenzylsubstituted diamine (R,R)-22
Scheme 5. Synthesis of diamine (R,R)-22.
(R,R)-1 using benzyl bromide as the electrophilic benzyl
source. We initially probed the efficiency of N-benzyl-
ation by addition of benzylbromide (4 equiv) to a soul -
tion of cyclohexyldiamine (R,R)-1 in dichloromethane
in the presence of a suitable base (e.g., Et3N, K2CO3
and LiOHÆH2O) (Scheme 6). However, the use of lith-
ium hydroxide monohydrate (LiOHÆH2O: Scheme 6: en-
try 3) was found to be more efficient leading to a higher
yield of the required tetrabenzylcyclohexyldiamine
(R,R)-22 (64%). In addition, the high yield of each alkyl-
ation step (approximately 90%) enabled the efficient sep-
aration of the tetrabenzylcyclohexyldiamine (R,R)-22
from the intermediate mono-, di- and tribenzyldiamines,
25
by reduction of the corresponding bis-amide (R,R)-21
using lithium aluminium hydride in THF (Scheme 5).
The bis-amide (R,R)-21 was synthesised in 65% yield
by addition of benzoylchol ride 25 to a stirred solution of
dibenzyldiamine (R,R)-8 and triethylamine in dichloro-
methane (Scheme 5). Lithium aluminium hydride reduc-
tion of the bis-amide (R,R)-21 gave the required
symmetrically substituted tetrabenzyl diamine (R,R)-22
in 79% yield. This process was moderately efficient giv-
ing access to diamine (R,R)-22 in an overall 38% yield
(over four steps)26 starting from the parent diamine
(R,R)-1 (Schemes 2 and 5). This type of reductive amin-
ation methodology has previously been used in the syn-
thesis of tetramethylcyclohexyldiamine (R,R)-3.8,11,16
With this information at hand, we next chose to investi-
gate the sequentialbenzyaltion of the parent diamine
Ph
Base (4 equiv.)
PhCH2Br (4 equiv.)
N
N
Ph
Ph
NH2
NH2
CH2Cl2
Ph
(R,R)-1
(R,R)-22
Ph
13
OH
OH
PhCHO 11
H
H
O
NHMe
NHMe
N
N
Base
Yield (%)
Entry
N
N
NaBH3CN
Me
Me
Me
Me
28a
AcOH, MeOH, rt
Et3N
1
2
K2CO3
41
Ph
LiOH.H2O
3
64
(R,R)-7
(R,R)-12; 49%
aIn addition 26% of the dibenzylamine (R,R)-8 was also isolated
14; 30%
Scheme 3. Synthesis of diamines (R,R)-12 and 14.
Scheme 6. Synthesis of diamine (R,R)-22.

H. Arjan et al. / Tetrahedron Letters 46 (2005) 1921–1925
1923
Ph
Cl
Ph
Ph
Ph
NH
Cl
LiOH.H2O
LiOH.H2O
N
N
N
Ph
Ph
OMe
MeI
Me
Me
PhCH2Br (2 equiv.)
OMe
MeO
N
24
26
CH2Cl2
CH2Cl2
N
NH
Ph
LiOH.H2O
Bu4NI
26(4 equiv.)
LiOH.H2O
Bu4NI
24 (4 equiv.)
Ph
N
N
(R,R)-8
(R,R)-22; 95%
(R,R)-12; 90%
(R,R)-1
CH2Cl2
CH2Cl2
N
Ph
MeO
OMe
LiOH.H2O
CH2=CHCH2Br
N
N
CH2Cl2
(R,R)-27; 59%
Br
(R,R)-25; 52%
Cl
Ph
(R,R)-23; 96%
NO2
28
Cl
30
NO2
O2N
N
Scheme 7. Synthesis of diamines (R,R)-12, (R,R)-22 and (R,R)-23.
LiOH.H2O
LiOH.H2O
28 (4 equiv.)
Bu4NI
N
N
30 (4 equiv.)
(R,R)-1
CH2Cl2
CH2Cl2
N
O2N
which was found to be particularly problematic when
using triethylamine as the base (Scheme 6: entry 1).
NO2
Alternatively, tetrabenzylcyclohexyldiamine (R,R)-22
can be synthesised in near quantitative yield by direct
benzylation of dibenzylcyclohexyldiamine (R,R)-8 by
addition of 2 equiv of benzylbromide and itlhium
hydroxide monohydrate (Scheme 7). This N-alkylation
process appears to be particularly efficient for a variety
of SN2 active electrophiles like methyl iodide and allyl
bromide giving the corresponding dimethyldibenzyl-
and diallyldibenzylcyclohexyldiamines (R,R)-12 and
(R,R)-23 in 90% and 96% yields respectively (Scheme 7).
(R,R)-31; 40%
(R,R)-29; 56%
Scheme 9. Synthesis of diamines (R,R)-25, (R,R)-27, (R,R)-29 and
(R,R)-31.
24, 26 and 30 and bromide 28 to a solution of cyclo-
hexyldiamine (R,R)-1 and tetrabutylammonium iodide
(Scheme 9). These reactions proceeded smoothly giving
the required symmetrically tetrasubstituted diamines
(R,R)-25, (R,R)-27, (R,R)-29 and (R,R)-31 in moderate
to good yields.
In an attempt to improve the overall yield by limiting
the background substitution reaction between benzyl
bromide and lithium hydroxide, we next investigated
the sequentialaddition of ilthium hydroxide monohy-
drate to a solution of the parent diamine (R,R)-1 and
benzylbromide in dicholromethane. We chose to add
4 equiv of benzylbromide to a stirred soultion of di-
amine (R,R)-1 in dichloromethane, which resulted in the
formation of a precipitate after 1 h. Lithium hydroxide
monohydrate (1 equiv) was added to the resulting solu-
tion and this was stirred for a further 1 h. This proce-
dure was repeated until all 4 equiv of lithium
hydroxide monohydrate had been added. The resulting
solution was stirred for a further 6 h to give the required
tetrabenzylcyclohexyldiamine (R,R)-22 in an improved
77% yield (Scheme 8).
We were next interested in the synthesis of tetraallylsub-
stituted diamine (R,R)-32 as this should allow access to
the tetrapropylcyclohexyldiamine (R,R)-33 through sim-
ple hydrogenation. Sequential addition of 4 equiv of
allyl bromide and lithium hydroxide monohydrate to the
diamine (R,R)-1 gave the tetraallylcyclohexyldiamine
(R,R)-32 in 63% yield. This was easily converted into
the required tetrapropylcyclohexyldiamine (R,R)-33 in
good yield (92%) by hydrogenation at atmospheric pres-
sure using palladium-on-charcoal as the mediator
(Scheme 10). It is worthy of note that this particular
diamine (R,R)-33 cannot be synthesised directly by
addition of propyliodide to the diamine ( R,R)-1 as E2
Our attention next turned towards the synthesis of other
symmetrically tetrasubstituted diamines such as (R,R)-
25, (R,R)-27, (R,R)-29 and (R,R)-31 using our sequential
alkylation method by addition of the benzyl chlorides
LiOH.H2O
CH2=CHCH2Br (4 equiv.)
NH2
NH2
N
N
CH2Cl2
64% by addition of LiOH.H2O (4 equivalents)
77% by sequential addition of LiOH.H2O
(R,R)-1
(R,R)-32; 63%
Ph
LiOH.H2O (4 equiv.)
PhCH2Br (4 equiv.)
N
N
N
Ph
Ph
NH2
NH2
H2, Pd
toluene
N
CH2Cl2
Ph
(R,R)-1
(R,R)-22
(R,R)-33; 92%
Scheme 8. Synthesis of diamine (R,R)-22.
Scheme 10. Synthesis of diamines (R,R)-32 and (R,R)-33.

1924
H. Arjan et al. / Tetrahedron Letters 46 (2005) 1921–1925
Ph
1492 (Ph); mp 122 ꢁC; dH (270 MHz, CDCl3) 7.39 (8H,
LiOH.H2O
PhCH2Br (4 equiv.)
d, J = 5.7 Hz, 8 · CH; Ph), 7.19 (12H, m, 12 · CH;
Ph), 3.76 (4H, d, J = 13.9 Hz, 4 · CH–Ph), 3.35 (4H,
d, J = 13.9 Hz, 4 · CH–Ph), 2.68 (2H, br s, 2 · NCH),
2.08 (2H, m, 2 · CH), 1.72 (2H, m, 2 · CH) and
1.05 (4H, m, 4 · CH); dC (100 MHz, CDCl3) 140.6,
128.9, 127.9, 126.5, 58.2, 53.2, 25.9 and 24.9
(Found MH+, 474.3106. C34H39N2 requires MH+
475.3108).
Ph
Ph
NH2
NH2
Ph
Ph
N
N
Ph
Ph
CH2Cl2
Ph
(R,R)-34; 62%
(R,R)-2
Scheme 11. Synthesis of diamine (R,R)-34.
elimination of propyl iodide appears to be the major
pathway under these reaction conditions.
Acknowledgements
To ensure that this methodology was not solely depen-
dent on the structural nature of the cyclohexyldiamine
(R,R)-1, we additionally chose to convert the (R,R)-
diphenylethylene diamine 2 into the corresponding
tetrabenzyl diphenylethylene diamine (R,R)-34 using
our sequentialaddition procedure ( Scheme 11). This
reaction was efficient and gave the required diamine
(R,R)-34 in 62% yield.
We are gratefulto The RoyalSociety, The University of
London CentralResearch Fund and Syngenta (Grange-
mouth, Scotland) for their financial support and the
EPRSC NationalMass Spectrometry Service (Swansea)
for accurate mass determinations.
References and notes
In conclusion, we report an efficient and practical route
to the synthesis of symmetrically substituted diamines
(R,R)-12, (R,R)-22, (R,R)-23, (R,R)-25, (R,R)-27,
(R,R)-29, (R,R)-31, (R,R)-32, (R,R)-33 and (R,R)-34
using a sequentialsubstitution reaction mediated by lith-
ium hydroxide monohydrate. This single-step process
is particularly efficient and cost-effective since each
diamine is derived from four sequential N-alkylations.
Without the need for reductive methods (and the subse-
quent use of lithium aluminium hydride and/or sodium
borohydride) this methodology appears to be a safer
alternative to reductive amination especially when per-
formed on a larger scale.
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18.0 mmol) was added and three further additions were
performed at hourly intervals until all 4 equiv of lithium
hydroxide monohydrate had been added (3.00 g,
72.0 mmol). The solution was stirred for a further 6 h.
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rated. The aqueous layer was washed with dichloro-
methane (2 · 50 mL) and the combined organic
extracts were dried over chipped sodium hydroxide pel-
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due was purified by flash column chromatography,
initially eluting with light petroleum (40–60 ꢁC)/diethyl
ether (9:1), then diethylether/cholroform (1:1) to
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(R,R)-22 (6.47 g, 77%) as a white crystalline solid; RF
22
D
[(diethylether/cholroform) 1:1] 0.49; ½aꢀ +36.0 (c 0.5,
CHCl3); vmax (film)/cmꢁ1 2854 (CH), 1600 (Ph) and

H. Arjan et al. / Tetrahedron Letters 46 (2005) 1921–1925
1925
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