An efficient method for the preparation of N,N-disubstituted 1,2-diamines

Article abstract of DOI:10.1016/S0040-4039(00)01501-X

C₂-Symmetric 1,2-diamines are useful precursors to numerous reagents used in asymmetric synthesis and catalysis. We report here an efficient protocol for converting the two most commonly used trans-1,2-diamines to N,N-disubstituted derivatives, a transformation that simplifies the preparation of non-C₂-symmetric diamines. Central to the method is the high-yielding conversion of the diamines to the corresponding monoacetylated derivatives via imidazoline intermediates. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01501-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8431–8434
An efficient method for the preparation of
N,N-disubstituted 1,2-diamines
Judith M. Mitchell and Nathaniel S. Finney*
Department of Chemistry and Biochemistry University of California, San Diego, 9500 Gilman Drive, La Jolla,
CA 92093-0358, USA
Received 26 July 2000; accepted 8 September 2000
Abstract
C2-Symmetric 1,2-diamines are useful precursors to numerous reagents used in asymmetric synthesis
and catalysis. We report here an efficient protocol for converting the two most commonly used
trans-1,2-diamines to N,N-disubstituted derivatives, a transformation that simplifies the preparation of
non-C2-symmetric diamines. Central to the method is the high-yielding conversion of the diamines to the
corresponding monoacetylated derivatives via imidazoline intermediates. © 2000 Published by Elsevier
Science Ltd.
C2-Symmetric 1,2-diamines are important precursors to chiral reagents for asymmetric
synthesis and catalysis.1 These diamines have seen widest use in the preparation of C2-symmetric
chiral auxiliaries, such as those shown in Fig. 1, since differentiating the two nitrogen centers
typically requires the use of substoichiometric amounts of a derivatizing agent followed by
separation of the resulting mixture of diamine, monofunctionalized diamine and difunctional-
ized diamine.2,3 We report here an efficient two-step method for preparing monoacylated
derivatives of two common C2-symmetric diamines via imidazoline intermediates (Scheme 1),
and show that these monoacylated diamines can be conveniently transformed to N,N-disubsti-
tuted 1,2-diamines (Scheme 2). We anticipate that the convenience of this method will facilitate
further exploration of non-C2-symmetric diamine derivatives as chiral auxiliaries and ligands.
Ph
Ph
O
O
N
N
O2S NH HN SO2
Ph2P
NH HN
PPh2
tBu
OH HO
tBu
tBu
tBu
Me
Me
Figure 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01501-X

8432
NH2
NH2
N
NHAc
NH2
a
a
b
b
Me
N
H
NH•HCl
OEt
5 90%
from 1
1
3
a.
Me
b. EtOH/H2O, ∆
Ph
Ph
NH2
Ph
Ph
Ph
Ph
NHAc
N
Me
N
H
NH2
NH2
6 83%
2
4 92%
Scheme 1.
NHAc
NH2
NHAc
NH2
a
a
b
NR2
7a 100%
NR2
9a 68%
a. aldehyde, NaBH3CN, AcOH
b. 4M HCl, ∆
5
7b 75%
9b 98%
a series R = CH3
b series R,R =
Ph
Ph
NHAc
NH2
Ph
Ph
NHAc
Ph
Ph
NH2
NR2
b
NR2
6
8a 85%
8b 81%
10a 72%
10b 71%
Scheme 2.
Condensation of (1R,2R)-cyclohexane-1,2-diamine (1) or (1S,2S)-1,2-diphenylethylenediamine
(2) with the Pinner salt derived from acetonitrile conveniently provides the corresponding
imidazolines 3 and 4.4,5 After evaluating acidic and basic hydrolysis conditions, we have found
refluxing a solution of 3 or 4 in neutral ethanol–water mixtures for 12–24 hours to be the best
method for effecting conversion to the corresponding monoacetyl diamines 5 and 6.6,7
The Pinner salt of benzonitrile also performs acceptably for cyclohexanediamine, providing
the corresponding N-benzoyl derivative in good yield after hydrolysis of the phenyl imidazoline.
However, the phenyl imidazoline prepared from diphenylethylenediamine resisted hydrolysis
under all conditions tried. Application of this method to straight-chain diamines such as
ethylenediamine led to significantly lower yields (<50%), presumably because oligomerization
competes with imidazoline formation.
In a representative procedure, dry acetonitrile (1.0 mL, 19.0 mmol, 2.0 equiv.) was dissolved
in dry ethanol (ca. 6 mL). Gaseous HCl was passed through the solution for 1.5 hours, after
which residual solvent was removed under a stream of dry N2. The crude imidate hydrochloride,
obtained as a white solid, was redissolved in dry ethanol and cooled to 0°C under N2.
Cyclohexanediamine (1.1 g, 9.6 mmol, 1 equiv.) was added in one portion and the solution
allowed to stir at room temperature for 8–10 hours. 1 M NaOH (aq., 75 mL) was added, and
the mixture extracted with 5% CH3OH–CH2Cl2 (3×50 mL). The combined organic phases were
1
dried over Na2SO4 and concentrated to afford crude 3 (>95% purity by H NMR). Compound
3 so obtained (1.3 g, 9.6 mmol) was heated to reflux in 1:1 EtOH–H2O for 12 hours,8 whereupon
evaporation of the solvent afforded pure 5 (1.4 g, 8.6 mmol) in a 90% yield for two steps.
The monoacetyl diamines can be converted to N,N-dialkyl derivatives by reductive amina-
tion,9,10 followed by acidic cleavage of the acetamide (Scheme 2). In a typical procedure, 5 (0.6
g, 3.7 mmol, 1 equiv.) and aqueous formaldehyde (37% w/w, 1.5 mL, 18.6 mmol, 5.0 equiv.)

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were combined in CH3CN (20 mL) and stirred for 15 minutes. NaBH3CN (0.5 g, 7.4 mmol, 2.0
equiv.) was added, followed 15 minutes later by AcOH (1 mL). After 2 hours, the reaction
mixture was diluted with 2% CH3OH–CH2Cl2 (50 mL), washed with 1 M NaOH (3×50 mL),
dried over Na2SO4, and concentrated to afford pure 7a as a white solid in quantitative yield (0.7
g, 3.7 mmol). Hydrolysis of 7a to 9a was effected by refluxing for 12 hours in 4 M HCl. After
cooling to ambient temperature, the reaction was made basic by addition of 4 M NaOH (30 mL)
and extracted with 5% CH3OH–CH2Cl2 (3×50 mL). The combined organic fractions were dried
over Na2SO4 and concentrated to afford pure 9a as a colorless oil (0.4 g, 2.5 mmol, 68%).11
In summary, the procedures described provide convenient access to N,N-disubstituted deriva-
tives of the two most widely-used trans-1,2-diamines. This methodology is complementary to
that previously developed,2,3,12 and should prove useful to researchers involved in asymmetric
synthesis and catalysis. We have found the diamine derivatives described here to be convenient
precursors to tridentate ligands such as 11 and 12 (Scheme 3),13 which are the focus of ongoing
study in our laboratories.
tBu
tBu
OH
tBu
tBu
tBu
CHO
NH2
a
b
NH OH
N(Me)2
N
OH
a. EtOH, RT
b. NaBH3CN, AcOH
+
N(CH3)2
N(Me)2
tBu
9a
12
11
Scheme 3.
Acknowledgements
The authors thank the UCSD Academic Senate, the ARCS Foundation (fellowship to
J.M.M.), and the Petroleum Research Fund administered by the American Chemical Society
(33779-G) for support of this research, and the National Science Foundation (CHE-9709183) for
support of the Departmental NMR facilities.
References
1. (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. Engl. 1998, 37, 2580–2627. (b) Bennani, Y. L.;
Hanessian, S. Chem. Rev. 1997, 97, 3161–3195.
2. For representative examples of diamine monofunctionalization, see: (a) Wennemers, H.; Yoon, S. S.; Still, W. C.
J. Org. Chem. 1995, 60, 1108–1109. (b) Xu, D.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron Lett. 1995,
36, 7357–7360. (c) Lopez, J.; Liang, S.; Bu, X. R. Tetrahedron Lett. 1998, 39, 4199–4202. (d) Balsells, J.;
Mejorado, L.; Phillips, M.; Ortega, F.; Aguirre, G.; Somanathan, R.; Walsh, P. J. Tetrahedron: Asymmetry 1998,
9, 4135–4142.
3. Solid-phase synthesis has also been used to differentiate symmetrical diamines. See, among others: (a) Fre´chet, J.
M. Tetrahedron 1981, 37, 663–683. (b) Leznoff, C. C. Acc. Chem. Res. 1978, 11, 327–333.
4. (a) Pinner, A.; Klein, F. Bericht 1877, 10, 1889–1891. For reviews of the synthesis and reactivity of imidates, see:
(b) Roger, R.; Neilson, D. G. Chem. Rev. 1961, 61, 179–210. (c) Zilberman, E. N. Russ. Chem. Rev. 1962, 31,
615–640.
5. Ferm, R. J.; Riebsomer, J. L. Chem. Rev. 1954, 54, 593–613.

8434
6. This is consistent with the currently accepted mechanism of imidate hydrolysis. See: D. G. Nielsen. In The
Chemistry of Amidines and Imidates; Patai, S.; Rapoport, Z., Eds.; Wiley & Sons: New York, 1991; Vol. 2,
Chapter 9.
1
7. All new compounds were fully characterized by H and 13C NMR, IR, and HRMS. Spectroscopic data for select
1
new compounds: 3: H NMR (300 MHz, CDCl3), l: 4.71 (br s, 1H, NH), 2.77–2.88 (m, 2H, H-2, H-7), 2.03–2.07
(m, 2H, H-6), 1.85 (s, 3H, H-1), 1.66–1.69 (m, 2H, H-3), 1.14–1.38 (m, 4H, H-4, H-5). 13C NMR (300 MHz,
CDCl3), l: 165.2, 69.4 (2×C), 30.6, 24.8 (2×C), 16.1 (2×C). FTIR (neat), cm−1: 3414(m), 3156(s), 2937(s), 2860(s),
1600(m), 1464(m), 1227(m). HRMS (EI), m/z: calcd for C8H14N2 (Na+): 161.1886, found: 161.1055. 8a: H NMR
1
(400 MHz, CDCl3), l: 7.24–7.29 (m, 6H, H-7–H-9), 7.01–7.09 (m, 4H, H-6, H-10), 6.33 (d, 1H, J=8.0 Hz, NH),
5.66 (t, 1H, J=7.0 Hz, H-2), 3.51 (d, 1H, J=7.0 Hz, H-3), 2.26 (s, 6H, H-4), 1.87 (s, 3H, H-1). 13C NMR (400
MHz, CDCl3), l: 170.4, 141.9, 137.1, 129.9 (2×C), 129.1 (2×C), 129.0, 128.6 (2×C), 128.08 (2×C), 128.0, 76.0,
54.7, 44.6, 24.7. FTIR (neat), cm−1: 3283(m), 3033(m), 2784(s), 1648(s), 1549(m), 1217(m), 752(s). HRMS (FAB),
1
m/z: calcd for C18H22N2O (Na+): 305.1630, found: 305.1631. 11: H NMR (300 MHz, CDCl3), l: 8.31 (s, 1H,
H-8), 7.35 (d, 1H, J=2.1 Hz, H-9), 7.07 (d, 1H, J=2.4 Hz, H-10), 3.21 (dt, 1H, J1=10 Hz, J2=4.0 Hz, H-7),
2.60–2.70 (m, 1H, H-2), 2.28 (s, 6H, H-1), 1.60–1.90 (m, 4H, H-3, H-6), 1.44 (s, 9H, H-11), 1.20–1.40 (m, 13H,
H-4, H-5, H-12). 13C NMR (400 MHz, CDCl3), l: 165.3, 157.7, 139.9, 136.4, 127.0, 125.8, 117.4, 68.7, 68.0, 40.9,
35.3, 34.9, 34.0, 31.4, 29.33, 25.6, 24.7, 24.1. FTIR (neat), cm−1: 2954(s), 2932(s), 2860(m), 2768(w), 1632(m),
1441(m), 1361(w), 1265(w). HRMS (MALDI-FTMS), m/z: calcd for C23H38N2O (H+): 359.3057, found:
1
359.3061. 12: H NMR (300 MHz, CDCl3), l: 7.22 (d, 1H, J=2.1 Hz, H-9), 6.90 (d, 1H, J=2.4 Hz, H-10), 4.10
(d, 1H, J=13 Hz, H-8), 3.75 (d, 1H, J=13 Hz, H-8%), 2.32–2.42 (m, 2H, H-2, H-7), 2.33 (s, 6H, H-1), 1.70–1.85
(m, 4H, H-3, H-6), 1.42 (s, 9H, H-1), 1.18–1.34 (m, 13H, H-4, H-5, H-12). 13C NMR (400 MHz, CDCl3), l:
153.6, 140.7, 135.8, 123.5, 123.1, 122.5, 66.9, 57.4, 49.9, 40.0, 34.9, 34.3, 31.8, 30.9, 29.8, 25.1, 24.6, 21.5. FTIR
(neat), cm−1: 3274(w), 2951(s), 2934(s), 2861(m), 2829(w), 1599(w), 1480(m), 1458(m), 1238(m), 1103(m). HRMS
(MALDI-FTMS), m/z: calcd for C23H40N2O (H+): 361.3213, found: 361.3202.
8. Hydrolysis of the diphenylethylenediamine imidazoline was carried out in 0.5:1:1 dioxane–EtOH–H2O at 170°C
in a sealed tube.
9. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904.
10. The dialdehyde precursor to the azepine derivatives was prepared by Swern oxidation of the corresponding
commercially available diol: Mancuso, A. J.; Swern, D. A. Synthesis 1981, 165–185.
11. Purification of compounds 8a,b and 10a,b required flash column chromatography, employing CH3OH–CH2Cl2
mixtures as eluent.
12. The procedure described here is, to our knowledge, the most effective for the preparation of these monoacetyl
diamines. While Ref. 2a describes the efficient preparation of the monotrifluoroacetamide of trans-1,2-
diphenylethylenediamine, the lability of trifluoroacyl group limits subsequent transformation.
13. Imine 11 was obtained in 40% yield by combining equimolar amounts of 9a and 3,5-di-tert-butylsalicylaldehyde
in CH3OH, removing the solvent under vacuum, and purifying the residue by chromatography with 5%
CH3OH–CH2Cl2. Amine 12 was obtained in 97% yield by reduction of 11 under the conditions described for 7a
(NaBH3CN–AcOH–CH3CN).
.