Synthesis of N,N′-disubstituted cyclic 1,2-diamines derived from (1R,2R)-1,2-diaminocyclohexane

Article abstract of DOI:10.1016/j.tetlet.2005.03.128

The synthesis of N,N′-unsymmetrically tetrasubstituted cyclic 1,2-diamines derived from (1R,2R)-diaminocyclohexane is reported. We comment on the structural nature of these cyclic 1,2-diamines and discuss their characteristic features.

Full text of DOI:10.1016/j.tetlet.2005.03.128

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3473–3478
Synthesis of N,N0-disubstituted cyclic 1,2-diamines derived
from (1R,2R)-1,2-diaminocyclohexane
Ewan Boyd,a Gregory S. Coumbarides,b Jason Eames,b,* Ray V. H. Jones,a
Majid Motevalli,b Rachel A. Stensonc and Michael J. Suggateb
aSyngenta, Grangemouth Manufacturing Centre, Earls Road, Grangemouth FX3 8XG, Scotland, UK
bDepartment of Chemistry, Queen Mary, University of London, Mile End Road, London E1 4NS, UK
cSyngenta, Syngenta, Global Specialist Technology, PO Box A38, Leeds Road, Huddersfield HD2 1FF, UK
Received 13 January 2005; revised 7 March 2005; accepted 17 March 2005
Available online 9 April 2005
Abstract—The synthesis of N,N0-unsymmetrically tetrasubstituted cyclic 1,2-diamines derived from (1R,2R)-diaminocyclohexane is
reported. We comment on the structural nature of these cyclic 1,2-diamines and discuss their characteristic features.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The synthesis of enantiomerically pure symmetrically1
Br
Br
i-Pr
i-Pr
H
H
H
H
5
and unsymmetrically2 N,N0-tetrasubstituted 1,2-diam-
ines like 1 and 2 are well documented (Scheme 1). These
diamines have been synthesised by either direct
alkylation3 or reductive amination2,4 of the parent
1,2-diamine.5 Whereas, reports into the synthesis of
N,N0-tetrasubstituted cyclic 1,2-diamines like 3 are less
common (Scheme 1).6 Periasamy7 has recently reported
an efficient route for the synthesis of a variety of substi-
tuted cyclic diamines (R,R)-6, (R,R)-8 and (R,R)-10
using a series of structurally related dibenzylbromides
5, 7 and 9, and diisopropyldiamine (R,R)-4 (Scheme
2). These different cyclisation pathways appear to be
predictable and clearly allow efficient access to 8-mem-
bered ring diamines, and 18- and 20-membered ring cyc-
lictetraamines in moderate to good yield ( Scheme 2).
N
NH
K2CO3, KI
CH3CN
NH
i-Pr
N
i-Pr
(R,R)-4
(R,R)-6; 80%
Br
H
H
H
7
Br
N
N
N
N
i-Pr
i-Pr
i-Pr
i-Pr
(R,R)-4
K2CO3, KI
CH3CN
H
(R,R)-8; 60%
i-Pr
Br
i-Pr
1
1
R
R
N
R
H
H
H
H
H
Br
H
H
9
N
N
N
R2
R2
N
R2
R2
(R,R)-4
R
R
K2CO3, KI
CH3CN
N
N
N
N
R
N
R1
H
H
1
H
i-Pr
i-Pr
R
1
3
2
(R,R)-10; 34%
Scheme 1.
Scheme 2.
We have recently become interested8 in the synthesis of
symmetically and unsymmetrically N,N0-tetrasubstituted
*
Corresponding author. Tel./fax: +44 2078 825251; e-mail: j.eames@
qmul.ac.uk
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.128

3474
E. Boyd et al. / Tetrahedron Letters 46 (2005) 3473–3478
77%
95%
Ph
H
Ph
PhCH2Br
LiOH.H2O
CH2Cl2
PhCH2Br
LiOH.H2O
CH2Cl2
H
H
H
NH2
NH2
N
N
Ph
Ph
NH
NH
H
Ph
H
Ph
(R,R)-13
(R,R)-12
(R,R)-11
90%
MeI
LiOH.H2O
CH2Cl2
40%
PhCH2Br
LiOH.H2O
CH2Cl2
Ph
Ph
H
Me
H
H
H
N
NH
NH
Me
Me
NH
Me
NH
H
Ph
N
H
Ph
(R,R)-15
(R,R)-14
(R,R)-11
Scheme 3.
diamines like (R,R)-12 and (R,R)-14 by sequential alkyl-
ation of the corresponding parent diamines (R,R)-11,9
(R,R)-13 and (R,R)-15 using benzyl bromide and methyl
iodide as alkylating agents mediated by lithium hydrox-
ide monohydrate (LiOHÆH2O) as the base (Scheme 3).
Br
16
H
H
H
Br
N
N
NH
LiOH.H2O
CH2Cl2
Prompted by Periasamyꢀs report,7 we now disclose an
extension of our methodology towards the synthesis of
nine and 10-membered N,N0-tetrasubstituted cyclic 1,2-
diamines derived from (1R,2R)-diaminocyclohexane 13
using a variety of multi-benzylating agents, including
dibromide 16, dichloride 17 and tetrabromide 18
(Scheme 4).
NH
H
(R,R)-11
(R,R)-19; 7 8%
Scheme 5.
We first probed the dibenzylation of the dibenzyldi-
amine (R,R)-11 using a 1,6-dibromide 16 due to its simi-
larity to the corresponding double benzylation using
2 equiv of benzyl bromide (Schemes 3 and 5). Addition
of the 1,6-dibromide 16 to a stirred solution of di-
benzyldiamine (R,R)-119 and lithium hydroxide mono-
hydrate in dichloromethane gave, after stirring for
12 h, the cyclic 1,2-diamine (R,R)-19 as a single product
in excellent yield (Scheme 5).
Formation of a single homologue (R,R)-19 was con-
firmed by mass spectrometry and its structural nature
was determined by single crystal X-ray diffraction (Fig.
1).10 It is particularly interesting to note, the conform-
ational arrangement of each benzyl substitutent present
within this 1,2-diamine; one benzyl group is positioned
pseudo-axial and the other benzyl substituent is posi-
Figure 1. ORTEP diagram of diamine (R,R)-19.
tioned pseudo-equatorial with respect to the adjacent
1,2-diaminocyclohexane ring. These benzylic positions
are evidently not equivalent and consequently this di-
amine (R,R)-19 is non-C2-symmetricin its crystal phase.
The remaining biphenyl substituent was positioned sim-
ilarly, with one benzylicposition oriented pseudo-axial
and the remaining benzylicposition oriented pseudo-
equatorial. This conformational arrangement induces
axial chirality within the biaryl framework. The confor-
mational preference of this cyclic diamine (R,R)-19
was found to be surprisingly similar to that of related
non-cyclic tetrabenzylsubstituted 1,2-diamines.8,10
H
NH2
NH2
Br
Br
Br
Br
Cl
Cl
Br
Br
H
(R,R)-13
16
17
18
Scheme 4.

E. Boyd et al. / Tetrahedron Letters 46 (2005) 3473–3478
3475
O
O
H
16
Br
16
Br
CH3
N
CH3
NH
H
H
H
H
H
Br
Br
N
N
NH
NH
LiOH.H2O
CH2Cl2
LiOH.H2O
CH2Cl2
NH
N
CH3
H
O
H
O
CH3
(R,R)-15
Scheme 6.
(R,R)-20; 57 %
(R,R)-29
Scheme 8.
(R,R)-30; 40%
We next turned our attention to probing the efficiency of
this ring forming reaction by screening a variety of
structurally related disubstituted diamines (R,R)-15,11
(R,R)-21,12 (R,R)-23,13 (R,R)-25, (R,R)-27 and (R,R)-
29 (Schemes 6–8). Addition of the 1,6-dibromide 16 to
a stirred solution of diamines (R,R)-15, (R,R)-21,
(R,R)-23, (R,R)-25, (R,R)-27 and (R,R)-29 and lithium
hydroxide monohydrate in dichloromethane gave, after
stirring for 12 h, the required cyclic 1,2-diamines
(R,R)-20, (R,R)-22, (R,R)-24, (R,R)-26, (R,R)-28 and
(R,R)-30, respectively, in moderate to good yield
(Schemes 6–8). It appears that the structural nature of
these 1,2-diamines plays little or no role within these
ring-forming processes.
16
Br
H
H
H
N
Br
NH2
NH2
LiOH.H2O
CH2Cl2
N
H
(R,R)-13
(R,R)-31; 63%
Scheme 9.
However, it was found that a secondary diamine was
necessary for cyclic 1,2-diamine formation, as a primary
diamine [e.g., (R,R)-13] was shown to form efficiently
the corresponding C2-symmetrictetrasubstituted dia-
mine (R,R)-31 in good yield (Scheme 9).
unusual 8-membered ring 1,2-diamines (Schemes 10
and 11). Addition of 1,4-dichloride 17 to a stirred solu-
tion of disubstituted diamines (R,R)-11,9 (R,R)-15,11
(R,R)-21,12 (R,R)-23,13 (R,R)-25, (R,R)-27 and (R,R)-
29 and lithium hydroxide monohydrate in dichloro-
methane under our standard reaction conditions, gave
We next chose to investigate the use of a related 1,4-
dichloride 17 in an attempt to synthesise structurally
MeO
MeO
OMe
OMe
16
16
H
H
H
H
H
H
H
H
N
N
N
N
NH
NH
NH
NH
LiOH.H2O
CH2Cl2
LiOH.H2O
CH2Cl2
MeO
O2N
MeO
OMe
OMe
(R,R)-23
(R,R)-21
(R,R)-24; 80%
(R,R)-22; 60%
O2N
NO2
NO2
16
H
16
H
N
H
H
N
NH
NH
LiOH.H2O
CH2Cl2
LiOH.H2O
CH2Cl2
NH
H
NH
H
N
H
N
H
O2N
O2N
NO2
NO2
(R,R)-27
(R,R)-28; 61%
(R,R)-25
(R,R)-26; 55%
Scheme 7.

3476
E. Boyd et al. / Tetrahedron Letters 46 (2005) 3473–3478
Me
N
17
H
LiOH.H2O
CH2Cl2
(R,R)-15
N
H
Me
(R,R)-32; 16%
O
H
17
17
H
N
N
N
N
LiOH.H2O
CH2Cl2
LiOH.H2O
CH2Cl2
(R,R)-29
(R,R)-11
H
O
H
(R,R)-34; 63%
(R,R)-33; 53%
Scheme 10.
MeO
OMe
17
17
N
N
N
N
LiOH.H2O
CH2Cl2
LiOH.H2O
CH2Cl2
(R,R)-23
(R,R)-21
MeO
OMe
(R,R)-36; 85%
(R,R)-35; 33%
O2N
NO2
17
17
N
N
N
N
LiOH.H2O
CH2Cl2
LiOH.H2O
CH2Cl2
(R,R)-27
(R,R)-25
O2N
NO2
(R,R)-38; 34%
(R,R)-37; 59%
Scheme 11.
the required cyclic 1,2-diamines (R,R)-32–38 in moder-
ate to good yield (Schemes 10 and 11).
this tetraamine 40 as the sole product was confirmed
by mass spectrometry and NMR spectroscopy.
We have shown that ring formation is efficient for a
range of structurally diverse disubstituted diamines
(R,R)-11, (R,R)-15, (R,R)-29 and found independently
in line with Periasamyꢀs findings7 that no higher homo-
logues were formed (determined by mass spectrometry).
The use of a secondary diamine was also paramount
for 8-membered ring formation as cyclisation to form
the corresponding symmetrically substituted diamine
(R,R)-39 was evidently preferred for the corresponding
primary diamine (R,R)-13 (Scheme 12).8,14
In conclusion, we report an efficient and practical route
for the synthesis of disubstituted cyclic 1,2-diamines
(R,R)-19, (R,R)-20, (R,R)-22, (R,R)-24, (R,R)-26,
Cl
Cl
17
H
H
H
NH2
NH2
N
N
LiOH.H2O
CH2Cl2
H
However, addition of 1,2,4,5-tetrakis(bromomethyl)-
benzene bromide 18 to a stirred solution of dibenzyl di-
amine (R,R)-11 in dichloromethane under our standard
reaction conditions, gave the unusual cyclic tetraamine
(R,R,R,R)-40 in good yield (Scheme 13). Formation of
(R,R)-13
(R,R)-39; 40%
Scheme 12.

E. Boyd et al. / Tetrahedron Letters 46 (2005) 3473–3478
3477
1 · CHAHBbiaryl), 2.08 (1H, br m, 1 · CH), 1.71 (3H,
br m, 3 · CH) and 0.99 (4H, br m, 4 · CH); dC
(100 MHz, CDCl3) 142.3, 142.2, 141.8, 140.2, 139.2,
136.6, 131.8, 130.7, 128.9, 127.9, 127.8, 127.4, 127.0,
126.9, 126.7, 126.1, 60.0, 54.8, 54.4, 53.4, 50.8, 50.4,
32.3, 26.1, 25.3 and 22.6. (Found M+H+, 473.2951
C34H37N2 requires M+H+ 473.2957.)
18
H
H
H
H
H
H
N
N
N
N
NH
NH
LiOH.H2O
CH2Cl2
(R,R,R,R)-40; 60%
(R,R)-11
Scheme 13.
Acknowledgements
We are grateful to The Royal Society, The University of
London Central Research Fund and Syngenta (Grange-
mouth, Scotland) for their financial support, and the
EPSRC National Mass Spectrometry Service (Swansea)
for accurate mass determinations.
(R,R)-28, (R,R)-30 and (R,R)-32–38 derived from the
corresponding disubstituted diamines (R,R)-11, (R,R)-
15, (R,R)-21, (R,R)-23, (R,R)-25, (R,R)-27 and (R,R)-
29, and dibromide 16 and dichloride 17. Intramolecular
cyclisation to form these cyclic 1,2-diamines is evidently
more preferred than intermolecular cyclisation to form
related tetraamine homologues. However, cyclic tetra-
amines like (R,R,R,R)-40 can be efficiently synthesised
by use of a suitable alkylating agent, 1,2,4,5-tetra-
kis(bromomethyl)benzene bromide 18. The use of a sec-
ondary diamine is paramount for formation of cyclic
1,2-diamines as primary diamines [e.g., (R,R)-13] prefer
to cyclise to form the corresponding symmetrically
substituted diamines (R,R)-31 and (R,R)-39 in good
yield. Previous reports into the synthesis of cyclic amines
and imines derived from (1R,2R) diaminocyclohexane
have utilised related alkylations15 and condensation pro-
cesses involving aldehydes16 and dialdehydes.17
References and notes
1. (a) Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.;
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Representative experimental procedure: (+)-N,N0-Dibenz-
yl-(7R,8R)-dicyclohexano-5,6,7,8,9,10-hexahydro-6,9-
diaza-dibenzo[a,c]cyclodecene 19: 2,20-Bis(bromometh-
yl)-1,10-diphenyl 16 (0.60 g, 1.76 mmol) was added to a
stirred solution of (À)-(R,R)-N,N0-dibenzyldiaminocy-
clohexane 11 (0.20 g, 1.76 mmol) in dichloromethane
(10 mL) at room temperature. Two portions of lithium
hydroxide monohydrate (75 mg, 1.76 mmol) were added
after four and 8 h. The resulting solution was stirred for
12 h. Water (10 mL) was added and the resulting layers
separated. The aqueous layer was washed with dichloro-
methane (2 · 30 mL), and the combined organic extracts
were dried over MgSO4, and concentrated under re-
duced pressure. The residue was purified by flash col-
umn chromatography, initially eluting with light
petroleum (40–60 ꢁC)/diethyl ether (9:1), then light
petroleum (40–60 ꢁC)/diethyl ether (1:1) to give (+)-
N,N0-dibenzyl-(7R,8R)-dicyclohexano-5,6,7,8,9,10-hexa-
hydro-6,9-diaza-dibenzo[a,c]cyclodecene 19 (0.64 g, 78
7. Padmaja, M.; Periasamy, M. Tetrahedron: Asymmetry
2004, 15, 2437.
8. Arjan, H.; Boyd, E.; Coumbarides, G. S.; Eames, J.;
Jones, R. V. H.; Stenson, R. A.; Suggate, M. J. Tetrahe-
dron Lett. 2005, 46, 1921.
9. For further details see Ref. 5a.
%) as a small white needles; Rf [(light petroleum
10. (a) Crystallographicdata has been deposited with the
Cambridge CrystallographicData Centre [reference num-
ber 255736 for (R,R)-19]; (b) Eames, J.; Motevalli, M.;
Suggate, M. J., unpublished results; (c) Suggate, M. J.,
PhD Thesis, University of London, 2005.
11. For further details see Ref. 3c.
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Scopellita, R.; Floriani, C. J. Am. Chem. Soc. 1999, 121,
6158.
22
(40–60 ꢁC)/diethyl ether) 9:1] = 0.38; ½aꢀ +112.2 (c 0.9,
D
CHCl3); mmax (film)/cmÀ1 3055, 2927, 2854, 1596 and
1504; dH (270 MHz, CDCl3) 7.58 (1H, d, J 7.2,
1 · CH; biaryl), 7.34 (4 H, br s, 4 · CH; biaryl), 7.27
(4H, br m, 4 · CH; Ph), 7.19 (2H, br s, 2 · CH; biaryl),
7.13 (6H, br m, 6 · CH; Ph), 7.03 (1H, br d, J 7.2,
2 · CH; biaryl), 4.46 (1H, d, J 12.9, 1 · CHAHBbiaryl),
4.31 (1H, d, J 12.9, 1 · CHAHBbiaryl), 3.68 (2H, dd, J
13.1 and 6.7, 2 CHAHBAr), 3.37 (2H, dd, J 8.9 and
5.7, 2 · CHAHBAr), 3.18 (1H, d, J 12.8 Hz, 1 · CHAHB-
Ar), 2.71 (2H, br m, 2 · CHN), 2.55 (1H, d, J 14.8 Hz,

3478
E. Boyd et al. / Tetrahedron Letters 46 (2005) 3473–3478
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