Organocatalyzed solvent-free Aza-Henry reaction: A breakthrough in the one-pot synthesis of 1,2-diamines

Article abstract of DOI:10.1021/jo0488762

A nitrogen-containing superbase such as TMG was found to be an effective catalyst for the reaction between N-diphenylphosphinoyl imines and nitroalkanes. Exploiting a protocol that avoids the use of any solvent also during workup procedure, we synthesized

Full text of DOI:10.1021/jo0488762

SCHEME 1
Organocatalyzed Solvent-Free Aza-Henry
Reaction: A Breakthrough in the One-Pot
Synthesis of 1,2-Diamines
Luca Bernardi,* Bianca F. Bonini, Elena Capito`,
Gabriella Dessole, Mauro Comes-Franchini,
Mariafrancesca Fochi, and Alfredo Ricci*
Dipartimento di Chimica Organica “A. Mangini”,
Facolta` di Chimica Industriale, Universita` di Bologna,
viale Risorgimento 4, 40136 Bologna, Italy
important synthetic applications of these compounds
(Scheme 1).7
ricci@ms.fci.unibo.it
Received July 2, 2004
Over the past few years, significant interest has been
focused on the development of new protocols for environ-
mentally benign processes that are both economically and
technologically feasible,8 and an important area of green
chemistry deals with solvent minimization.9 Whereas it
has been found that the nitroaldol reaction can be
performed under solvent-free conditions,10 the application
of this methodology to the aza-Henry reaction appears
to be unexplored. These reactions are in most cases
catalyzed or promoted by metal salts,11 and several
drawbacks lie in the cost and the toxicity of the metal
species and in the use of organic solvents that are often
ecologically harmful. To face these problems, only re-
cently the first general asymmetric organocatalyzed aza-
Henry reactions have been developed by Johnston’s and
Takemoto’s groups.12
Abstract: A nitrogen-containing superbase such as TMG
was found to be an effective catalyst for the reaction between
N-diphenylphosphinoyl imines and nitroalkanes. Exploiting
a protocol that avoids the use of any solvent also during
workup procedure, we synthesized a series of â-nitroamines
in excellent yields and high diastereomeric ratios. These
results, combined with the capability of the indium in
conjunction with Zn as the stoichiometric reducing agent to
perform in aqueous medium reduction of the nitro group
under mild reaction conditions, led us to devise a three-step,
one-pot synthesis of a range of 1,2-diamines, making use of
environmentally friendly procedures in the various steps.
Herein we report a new and significantly simplified
and environmentally friendly approach to the catalytic
aza-Henry reaction using new solvent- and metal-free
conditions.
With the aim of using an organocatalytic approach to
the reaction, we reasoned that an organic base should
be capable of activating the nitroalkane through depro-
tonation, but due to the lack of strong Lewis or Brønsted
acidic sites, it might not give significant interactions with
Among the classical name reactions in organic synthe-
sis, the Henry or nitroaldol reaction1 is easily recogniz-
able as one of the most important tools for carbon-carbon
bond formation and has been used for the synthesis of a
vast array of â-amino alcohols, which are valuable
intermediates for the synthesis of many pharmaceutically
active compounds.2 On the other hand, the 1,2-diamine
structural motif is important in biologically active natural
products, in medicinal chemistry, and more recently as
a core unit in chiral auxiliaries and chiral ligands for use
in asymmetric catalysis.3 In the past few years, this has
prompted significant research to be directed toward the
nitro-Mannich (aza-Henry) reaction, the nucleophilic
addition of nitroalkanes to imines to give â-nitroamine
derivatives.4 The reduction to 1,2-diamines5 and the Nef
reaction to produce R-amino acids6 highlight several
(7) Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151.
(8) Anastas, P. T.; Williamson, T. C. In Green Chemistry, Designing
Chemistry for the Environment; Anastas, P. T., Williamson, T. C., Eds.;
American Chemical Society: Washington, DC, 1996; pp 1-17.
(9) (a) Metzger, J. O. Angew. Chem., Int. Ed. 1998, 37, 2975. (b)
Toda, F. Acc. Chem. Res. 1995, 28, 480. (c) Tanaka, K.; Toda, F. Chem.
Rev. 2000, 100, 1025. (d) Tanaka, K. Solvent-free Organic Synthesis;
Wiley-VCH: Weinheim, 2003. (e) Rothemberg, G.; Downie, A. P.;
Raston, C. L.; Scott, J. L. J. Am. Chem. Soc. 2001, 123, 8701. (f) Loupy,
A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mathe´, D.
Synthesis 1998, 1213. (g) Varma, R. S. Green Chem. 1999, 6, 43.
(10) (a) Rosini, G.; Ballini, R.; Sorrenti, P. Synthesis 1983, 1014.
(b) Kumar, H. M. S.; Subba Reddy, B. V.; Yadav, J. S. Chem. Lett.
1998, 637. (c) Bhattacharya, A.; Purohit, V. C. Org. Proc. Res. Dev.
2003, 7, 254. (d) Ballini, R.; Bosica, G.; Parrini, M. Chem. Lett. 1999,
1105 and references therein.
(11) (a) Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J.
Org. Chem. 1998, 63, 9932. (b) Anderson, J. C.; Peace, S.; Pih, S. Synlett
2000, 850. (c) Yamada, K.-i.; Harwood: S. J.; Gro¨ger, H.; Shibasaki,
M. Angew. Chem., Int. Ed. 1999, 38, 3504. (d) Yamada, K.-i.; Moll, G.;
Shibasaki, M. Synlett 2001, 980. (e) Tsuritani, N.; Yamada, K.-i.;
Yoshikawa, N.; Shibasaki, M. Chem. Lett. 2002, 276. (f) Qian, C.; Gao,
F.; Chen, R. Tetrahedron Lett. 2001, 42, 4673. (g) Knudsen, K. R.;
Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am.
Chem. Soc. 2001, 123, 5843. (h) Nishiwaki, N.; Knudsen, K. R.; Gothelf,
K. V.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992.
(12) (a) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org.
Lett. 2004, 6, 625. (b) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J.
Am. Chem. Soc. 2004, 126, 3418.
(1) (a) Henry, L. Acad. Sci. Ser. C. 1895, 1265. (b) Henry, L. Bull.
Soc. Chim. Fr. 1895, 13, 999.
(2) (a) Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: Oxford, 1991; Vol. 2,
p 321. (b) Luzzio, F. A.
Tetrahedron 2001, 57, 915.
(3) (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580. (b) Michalson, E. T.; Szmuszkovicz, J. Prog. Drug Res.
1989, 33, 135.
(4) Baer, H. H.; Urbas, L. In The Chemistry of the Nitro and Nitroso
Groups; Patai, S., Ed.; Interscience: New York, 1970; , Part 2, p 117.
(5) (a) Morris, M. L.; Sturgess, M. A. Tetrahedron Lett. 1993, 34,
43. (b) Sturgess, M. A.; Yarberry, D. J. Tetrahedron Lett. 1993, 34,
4743. (c) Enders, D.; Wiedemann, J. Synthesis 1996, 1443. (c) Lucet,
D.; Toupet, L.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 1997, 62,
2682. (d) Imagawa, K.; Hata, E.; Yamada, T.; Mukaiyama, T. Chem.
Lett. 1996, 291.
(6) (a) Pinnick, H. W. Org. React. 1990, 38, 655. (b) Ballini, R.;
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10.1021/jo0488762 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/16/2004
8168
J. Org. Chem. 2004, 69, 8168-8171

TABLE 1. Solvent-Free Aza-Henry Reaction of
the imine moiety. Following this working hypothesis, we
decided to focus on the use of N-diphenylphosphinoyl
imines 1 for the development of a solvent-free aza-Henry
reaction, as the diphenylphosphinoyl moiety, easily re-
movable at the end of the synthetic sequence,13 should
also guarantee a sufficient reactivity toward nucleophilic
species.
N-Phosphinoylimines Catalyzed by TMGa
After a brief screening of different organic bases, we
found 1,1,3,3-tetramethylguanidine (TMG) to be particu-
larly effective as a catalyst in the reaction between imine
1a and 1-nitropropane (1.25 equiv) under solvent-free
conditions,14 in line with the previous reports on the
parent Henry reaction.2,15 Use of only 5 mol % TMG
afforded a clean and fast reaction. After dilution with
CH2Cl2, acidic workup to remove the catalyst, and
evaporation of the organic solvent and excess 1-nitropro-
pane, the corresponding nitroamine 2a was obtained in
almost quantitative yield with good diastereoselectivity
(94:6), favoring the anti isomer.16 Heating the reaction
mixture or performing the reaction under ultrasound or
microwave irradiation did not result in any considerable
enhancement in the reaction rate.17
t
yield anti:
b
entry
R
R′
R′′ adduct (h)
%
sync
1
2
3
4
5
6
7
8
9
Ph (1a)
p-ClC6H4 (1b)
CH3CH2
CH3CH2
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
2
96
95
94:6
84:16
95:5
95:5
95:5
H
2
p-(MeO)-C6H4 (1c) CH3CH2
H
24 92
2-furyl (1d)
CH3CH2
CH3CH2
CH3CH2
CH3(CH2)4
PhCH2
H
H
2
2
90
92
2-thienyl (1e)
H
tert-butyl (1f)
H
170 95 >98:2
24 90 >98:2
26 95 >98:2
1a
1a
1a
H
H
H
CH3
1
3
90
96
10 1a
CH3
2j
a Reaction was conducted with 1a-f (0.2 mmol), nitroalkane
(0.25 mmol), and TMG (0.01 mmol) at room temperature. b After
chromatography on silica gel. c Determined by 1H NMR spectros-
copy.
However, for a truly solvent-free process, solvents need
to be avoided also during workup procedure. To this
purpose, we found that the nitroalkane in excess and the
relatively volatile TMG catalyst could be efficiently
removed by Kugelrhor distillation directly from the
reaction mixture (0.1 mBar, 100 °C). This protocol
furnished the â-nitroamine 2a in nearly quantitative
rate (entry 3). Also the sterically crowded imine 1f,
derived from pivalaldehyde, was poorly reactive, the
corresponding nitroamine 2f being produced in high yield
only after prolonged reaction time (entry 6).18 Increasing
the length (entries 7 and 8) or the branching (entry 10)
of the nitroalkane chain had only a slight effect on the
reaction rate. With one exception (entry 2), very good
diastereoselectivities were observed.
1
yield and in a spectroscopically (>95%, H NMR) pure
form. Furthermore, no epimerization at the R-carbon to
the nitro moiety was observed during distillation. Silica
gel chromatography afforded the analytically pure com-
pound 2a.
The scope of the solvent-free aza-Henry reaction was
then investigated varying both the imine and the nitroal-
kane partners (Table 1).
The relative configuration of the aza-Henry adduct 2a
1
was assigned as anti by comparison of the H and 13C
NMR spectra of the free diamine 5 (vide infra) with
literature data.11a The configuration of the other nitro-
amines 2b-h was tentatively given as anti on the basis
1
of the similarities between their H NMR spectra with
the one relative to compound 2a. As a matter of fact, 1H
NMR analysis of adducts 2a-e, which are all present in
both diastereomeric forms, shows the signal relative to
the proton R to the nitro moiety of the minor isomer
invariably shifted downfield with respect to its counter-
part in the major anti isomer. Similarly, the signal of the
amidic proton of the minor isomer of these compounds
always appears shifted upfield with respect to the signal
of the corresponding proton of the major anti isomer.
Furthermore, the two geminal protons of the methylene
moiety are superimposed in the 1H NMR spectrum in the
minor isomer, while the same protons in the major isomer
invariably show two distinct resonances (∆δ ≈ 0.20 ppm).
Although the conversion of some of the â-nitroamines
Aromatic N-diphenylphosphinoyl imines 1a-e and
imine 1f derived from pivalaldehyde were reacted with
1-nitropropane under the optimized reaction conditions
(1.25 equiv of nitroalkane, 5 mol % TMG), all furnishing
nitroamines 2a-f in excellent yields. Unsubstituted
aromatic imine 1a (entry 1) and heteroaromatic imines
1d (entry 4) and 1e (entry 5), as well as imine 1b (entry
2) bearing an electron-withdrawing group, reacted
smoothly under standard conditions with 1-nitropropane
affording after 2 h the expected products in almost
quantitative yields, whereas the presence of an electron-
releasing group in 1c slowed considerably the reaction
(13) (a) Ramage, R.; Atrash, B.; Hopton, D.; Parrott, M. J. J. Chem.
Soc., Perkin Trans. 1 1985, 1217. (b) Ramage, R.; Hopton, D.; Parrott,
M. J. J. Chem. Soc., Perkin Trans. 1 1984, 1357.
(14) ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo-
[4.3.0]non-5-ene (DBN) were equally effective in promoting the reac-
tion.
(15) Simoni, D.; Invidiata, F. P.; Manfredini, S.; Ferroni, R.; Lam-
pronti, I.; Roberti, M.; Pollini, G. P. Tetrahedron Lett. 1997, 38, 2749.
(16) High diastereselectivity observed is not a result of a thermo-
dynamic equilibration in the presence of a strong base such as TMG,
as â-nitroamine 2a with a 55:45 diastereomeric ratio (obtained from a
reaction catalyzed by DABCO) was recovered with the same anti/syn
ratio after several hours in the presence of 5 mol % TMG.
(17) For the sake of comparison with the usual solution-phase
chemistry, we also carried out the reaction in a few organic solvents
such as THF, CH2Cl2, and toluene, observing a remarkable drop in
the rate of the reaction, presumably due to dilution effects.
2 to the corresponding vicinal diamines has already been
11c,d
reported using SmI2, this reducing agent
presents
drawbacks due to high cost and low stability. Therefore,
we planned the development of an alternative, user-
friendly procedure for the reduction of the nitro group.19
In the past few years the reduction of aliphatic and
aromatic nitro compounds by metallic indium has emerged
(18) Other imines derived from enolizable aliphatic aldehydes were
not tested in the reaction due to the lack of methods for the preparation
of these compounds.
(19) Kabalka, G. W.; Varma, R. S. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 8, p 363.
J. Org. Chem, Vol. 69, No. 23, 2004 8169

TABLE 2. One-Pot Synthesis of Vicinal Diamines and
Their Derivatization to Disulfonamidesa
SCHEME 2. Reduction of
N-(2-Nitro-1-phenylbutyl)diphenylphosphinic
Amide (2a) with Metals
as a suitable method, tolerant to a series of functional
groups and performable also in aqueous medium.20
Furthermore, the reduction of a â-nitro-N-diphenylphos-
phinoylamine by Zn metal has already been reported in
a particular case by the group of Shibasaki.11e Hence, we
decided to investigate the possibility of using a metallic
system for the conversion of the aza-Henry adducts 2 into
the corresponding diamines 3 in aqueous solvent. Using
9 mol equiv of metallic indium as the reducing agent,
we were able to convert nitroamine 2a into the corre-
sponding monoprotected 1,2-diamine 3a in 90% yield, in
refluxing THF and using AcOH or a saturated NH4Cl
aqueous solution as a proton source (Scheme 2). Switch-
ing to less expensive metals, Al did not furnish any
reduced product under the same reaction conditions,
whereas powdered Zn was only moderately active, af-
fording a mixture of diamine 3a and hydroxylamine 4
(Scheme 2). Indium(0) therefore appeared to be the metal
of choice for this transformation. However, due to its cost,
the stoichiometric protocol was converted into catalytic
combining a small amount of indium with a less expen-
sive metal. Following this strategy, efficiently applied to
Barbier-type allylations21 and, more recently, to the
reduction of hydroxylamines,22 we performed the reduc-
tion of 2a with Zn as the stoichiometric reducing agent
in the presence of a small amount (25 mol %) of indium.
To our delight, the reduction proceeded smoothly, afford-
ing the corresponding N-protected diamine 3a in very
good yield and with the same diastereomeric ratio of the
starting nitroamine 2a (Scheme 2).
entry
R
R′
product
yieldb
anti:sync
1
2
3
4
5
Ph
CH3
CH3
CH3
CH3
Ph
6a
6b
6c
6e
6h
65%
68%
60%
58%
55%
94/6
84/16
95/5
95/5
>98/2
p-ClC6H4-
p-MeOC6H4-
2-Thienyl
Ph
a Reagents and conditions: (a) nitroalkane (1.25 equiv), TMG
(5 mol %); (b) In (0.25 equiv), Zn (10 equiv), THF/NH4Clsat, ∆, 18
h; (c) 6 M HCl, ∆, 4 h; (d) TsCl (2.2 equiv), Na2CO3 (4.4 equiv),
THF/H2O, 18 h. b Isolated yield over four steps with respect to
imines 1. c Determined by 1H NMR spectroscopy.
the reagents at the appropriate time in the same reaction
vessel. The final free 1,2-diamine 5 could be isolated in
good yield and purity (>90%, 1H NMR) after acidic
hydrolysis aimed at removing the diphenylphosphinoyl
protection at nitrogen (Table 2). The obtainment of the
free 1,2-diamine 5 allowed the assignment of its relative
configuration as anti, by comparison of its H and 13C
1
NMR spectra with literature data.11a Similar reactions
of N-diphenylphosphinoyl imines 1b,c,e,h, performed
according to this one-pot, three-step protocol afforded the
corresponding amines 5b,c,e,h in 60-90% yields, thus
confirming the general character of this procedure. The
diamines were converted into the more stable disulfona-
mides 6a-c,e,h, which were isolated by silica gel chro-
matography and fully characterized.
One of the important directions in sustainable organic
synthesis is the development of one-pot processes, i.e.,
combined reactions without intermediate recovery steps.23
We envisioned that a one-pot protocol from the N-diphe-
nylphosphinoyl imine to the corresponding free diamine
could be devised. We also anticipated that the Kugelrhor
distillation step could be avoided, since excess nitroal-
kane and the TMG catalyst should not interfere with the
subsequent reduction and deprotection steps.24 Indeed,
we were able to carry out the whole synthetic process in
a one-pot fashion in a very effective way, simply adding
In summary, the results presented in this paper
provide a new metal- and solvent-free procedure for the
aza-Henry reaction. The reaction proceeds smoothly for
a range of different imines and nitroalkanes, in the
presence of a catalytic amount of TMG. Furthermore, the
use of solvents is avoided also during workup, as the
adducts can be obtained in a highly spectroscopically pure
form by simply distilling off the catalyst from the crude
reaction mixture. A user-friendly protocol based on the
use of zinc in conjunction with a catalytic amount of
indium in aqueous medium was also developed for the
conversion of nitroamines into the corresponding mono-
protected diamines. Exploiting this reductive protocol, a
range of free 1,2-diamines could be synthesized from the
parent imines in a one-pot, three-step procedure that
furnishes the final compounds in good yield and high
purity.
(20) Pitts, M. R.; Harrison, J. R.; Moody, C. J. J. Chem. Soc., Perkin
Trans. 1 2001, 955 and references therein.
(21) (a) Araki, S.; Jin, S.-J.; Idou, Y.; Butsugan, Y. Bull. Chem. Soc.
Jpn. 1992, 65, 1736. (b) Auge´, J.; Lubin-Germain, N.; Thiaw-Woaye,
A. Tetrahedron Lett. 1999, 40, 9245. (c) Steurer, S.; Podlech, J. Adv.
Synth. Catal. 2001, 343, 251. (d) Lombardo, M.; Girotti, R.; Morganti,
S.; Trombini, C. Org. Lett. 2001, 3, 2981. (e) Gordon, C. M.; Ritchie, C.
Green Chem. 2002, 4, 124.
(22) Cicchi, S.; Bonanni, M.; Cardona, F.; Revuelta, J.; Goti, A. Org.
Lett. 2003, 5, 1773.
Experimental Section
(23) Bruggink, A.; Schoevaart, R.; Kieboom, T. Org. Proc. Res. Dev.
2003, 7, 622.
General Procedure for the Solvent-Free Aza-Henry
Reaction. A nitroalkane (0.25 mmol) was added to a test tube
followed by TMG (1.3 µL, 0.01 mmol) and N-diphenylphosphinoyl
(24) In the one-pot protocol, 10 equiv of zinc should be used instead
of 9 equiv due to the consumption of the reducing agent for excess
1-nitropropane.
8170 J. Org. Chem., Vol. 69, No. 23, 2004

imine 1a-f (0.2 mmol). The resulting white solid was magneti-
cally stirred at room temperature until disappearance of the
starting material (TLC, CHCl3/MeOH 9/1). The residual nitroal-
kane and the TMG catalyst were then removed on a Kugelrhor
apparatus (0.1 mBar, 100 °C), obtaining >95% spectroscopically
pure nitroamines 2a-j as white solids. The nitroamines were
further purified by chromatography on silica gel (CHCl3/MeOH
mixtures).
2.77-2.72 (m, 1Hmaj), 1.58 (br s, 4Hmaj, 4Hmin), 1.50-1.36 (m,
1Hmaj, 1Hmin), 1.28-1.16 (m, 1Hmaj, 1Hmin), 0.98 (t, J ) 7.4 Hz,
3Hmin), 0.93 (t, J ) 7.4 Hz, 3Hmaj); 13C NMR (100 MHz) [anti
isomer] δ 144.7, 128.4, 127.0, 126.8, 60.6, 58.8, 27.3, 10.8; IR
νmax (thin layer, NaCl plate) 3384, 3290 cm-1; ESI-MS m/z 165
(M + H+).
General Procedure for the Synthesis of Bis-4-methyl-
benzensulfonamides 6a-c,e,h. To a stirred solution of crude
diamines 5a-c,e,h in H2O/THF (1/2 v/v, 0.6 mL) were sequen-
tially added Na2CO3 (4.4 equiv) and TsCl (2.2 equiv). After 18 h
of stirring at room temperature, the resulting biphasic mixture
was diluted with Et2O and H2O. The layers were separated, and
the aqueous layer was extracted twice with Et2O. The combined
organic extracts were washed twice with H2O, dried over MgSO4,
filtered, and evaporated under reduced pressure. The crude
products were then purified by chromatography on silica gel
(Hex/AcOEt mixtures).
4-Methyl-N-(2-[(4-methylphenyl)sulfonyl]amino-1-phe-
nylbutyl)benzenesulfonamide (6a). Following the general
procedure for the synthesis of bis-sulfonamides, we obtained
compound 6a as a white solid in 65% yield (61 mg) and in a
94:6 diastereomeric ratio (1H NMR) favoring the anti isomer:
1H NMR (400 MHz, CDCl3) δ 7.78-7.70 (m, 2Hmaj, 2Hmin), 7.56-
7.46 (m, 2Hmaj, 2Hmin), 7.33-7.27 (m, 2Hmaj, 2Hmin), 7.19-7.11
(m, 5Hmaj), 7.10-7.05 (m, 5Hmin), 6.97-6.93 (m, 2Hmaj, 2Hmin),
6.06 (d, J ) 8.5 Hz, 1Hmin), 5.40 (d, J ) 6.5 Hz, 1Hmaj), 4.51 (d,
J ) 8.7 Hz, 1Hmaj), 4.42 (d, J ) 6.8 Hz, 1Hmin), 4.21-4.19 (m,
1Hmin), 4.15 (t, J ) 7.4 Hz, 1Hmaj), 3.43-3.34 (m, 1Hmaj), 3.30-
3.21 (m, 1Hmin), 2.44 (s, 3Hmin), 2.43 (s, 3Hmaj), 2.36 (s, 3Hmaj),
N-(2-Nitro-1-phenylbutyl)diphenylphosphinic Amide
(2a). Following the general procedure for the solvent-free aza-
Henry reaction, we obtained compound 2a as a white solid in
96% yield (76 mg) and in a 94:6 diastereomeric ratio (1H NMR)
favoring the anti isomer: 1H NMR (400 MHz) δ 7.85-7.78 (m,
2Hmaj, 2Hmin), 7.72-7.64 (m, 2Hmaj, 2Hmin), 7.58-7.38 (m, 4Hmaj
,
4Hmin), 7.34-7.26 (m, 5Hmaj, 5Hmin), 7.16-7.12 (m, 2Hmaj), 7.09-
7.06 (m, 2Hmin), 4.80 (ddd, J ) 10.4, 6.6, 3.7 Hz, 1Hmin), 4.64
(ddd, 10.5, 6.6, 4.1m Hz, 1Hmaj), 4.58-4.44 (m, 1Hmaj, 1Hmin),
4.15 (dd, J ) 11.1, 7.3 Hz, 1Hmaj), 3.82 (dd, J ) 11.6, 8.4 Hz,
1Hmin), 2.20-2.05 (m, 1Hmaj), 2.10-1.95 (m, 2Hmin), 1.86-1.74
(m, 1Hmaj), 0.94 (t, J ) 7.2 Hz, 3Hmaj, 3Hmin); 13C NMR (100 MHz)
[anti isomer] δ 138.8, 132.4, 132.3, 132.2, 131.9, 131.2, 131.1,
129.6, 129.0, 128.7, 128.5, 128.4, 128.3, 126.4, 95.4, 95.3, 57.3,
25.2, 10.4; IR νmax (thin layer, NaCl plate) 3376, 1555, 1206 cm-1
;
HRMS m/z calcd for C22H23N2NaO3P+ 417.1338, found 417.1337
(M + Na+). Anal. Calcd for C22H23N2O3P: C, 67.00; H, 5.88; N,
7.10. Found: C, 67.08; H, 5.84; N, 7.16.
General Procedure for the Synthesis of 1,2-Diamines
5a-c,e,h. A nitroalkane (0.25 mmol) was added to a test tube
followed by TMG (1.3 µL, 0.01 mmol) and N-diphenylphosphinoyl
imine 1a-c,e,h (0.2 mmol). The resulting white solid was
magnetically stirred at room temperature for 2-24 h. The tube
was then equipped with a condenser; THF (2 mL) and a
saturated aqueous NH4Cl solution (0.7 mL) were added, followed
by In powder (5.8 mg, 0.05 mmol) and Zn powder (130 mg, 2
mmol). The mixture was heated to reflux with stirring for 18 h
and cooled to room temperature; then, 6 M HCl was added (1.0
mL), and the resulting solution was heated to reflux with
stirring. After 4 h, the reaction mixture was cooled to room
temperature and then H2O (1 mL) was added; the aqueous phase
was washed with EtOAc (3 × 2 mL), basified with solid NaOH
(pH > 12), and then extracted with EtOAc (4 × 4 mL). The
organic extracts were dried over MgSO4, filtered, and evapo-
rated, affording crude amines 5a-c,e,h in very good yields as
pale yellow oils. The purity of the products was judged to be
2.34 (s, 3Hmin), 1.51-1.39 (m, 1Hmaj, 1Hmin), 1.04-0.91 (m, 1Hmaj
,
1Hmin), 0.53 (t, J ) 7.3 Hz, 3Hmaj), 0.50-0.48 (m, 3Hmin); 13C
NMR (100 MHz) [anti isomer] δ 143.6, 143.2, 137.6, 137.2, 136.9,
129.7, 129.3, 128.5, 127.9, 127.3, 127.2, 60.7, 59.1, 29.7, 24.2,
21.5, 21.4; ESI-MS m/z 473 (M + H)+, 495 (M + Na+); IR νmax
(thin layer, NaCl plate) 3380, 1334, 1160 cm-1. Anal. Calcd for
C24H28N2O4S2: C, 60.99; H, 5.97; N, 5.93; Found: C, 61.04; H,
5.92; N, 5.98.
Acknowledgment. We acknowledge financial sup-
port by the National Project “Stereoselezione in Chimica
Organica. Metodologie e Applicazioni” 2003 and by the
RTN project “Design, Analysis and Computation for
Catalytic Organic Reactions” (Contract HPRN-CT-2001-
00172).
1
>90%, according to H NMR analysis of the crude products.
1-Phenyl-1,2-butanediamine (5a).11a Following the general
procedure for the synthesis of 1,2-diamine, we obtained crude
compound 5a as a pale yellow oil in 97% yield (31 mg) in a 94:6
diastereomeric ratio (1H NMR), favoring the anti isomer: 1H
NMR (400 MHz) δ 7.36-7.22 (m, 5Hmaj, 5Hmin), 3.83 (d, J ) 5.9
Hz, 1Hmin), 3.71 (d, J ) 6.2 Hz, 1Hmaj), 2.83-2.77 (m, 1Hmin),
Supporting Information Available: Experimental de-
tails and characterization data for compounds 2b-j, 3a, 5b,
5c, 5e, 5h, 6b, 6c, 6e, and 6h. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO0488762
J. Org. Chem, Vol. 69, No. 23, 2004 8171