The nitro-Mannich reaction and its application to the stereoselective synthesis of 1,2-diamines

Article abstract of DOI:10.1021/jo981700d

The addition of alkyl nitronate anions to PMB imines, derived from benzaldehyde or straight-chain carbaldehydes, in the presence of a Bronsted acid, proceeds in greater than 90% yield with up to 10:1 diastereoselection favoring the anti isomer. The mechanism of this addition reaction is intriguing and is under investigation. The moderately unstable β-nitro amines can be reduced with samarium diodide and the PMB group removed with CAN, in good overall yields, to give sensitive 1,2-diamines without erosion of diastereoselectivity. This protocol represents a new, stereoselective synthesis of certain 1,2-diamines.

Full text of DOI:10.1021/jo981700d

9932
J . Org. Chem. 1998, 63, 9932-9934
Th e Nitr o-Ma n n ich Rea ction a n d Its Ap p lica tion to th e
Ster eoselective Syn th esis of 1,2-Dia m in es†
Harry Adams,‡ J ames C. Anderson,*,‡ Simon Peace,‡ and Andrew M. K. Pennell§
Department of Chemistry, University of Sheffield, Sheffield S3 7HF, U.K., and GlaxoWellcome, Medecines
Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
Received August 20, 1998
The addition of alkyl nitronate anions to PMB imines, derived from benzaldehyde or straight-
chain carbaldehydes, in the presence of a Bronsted acid, proceeds in greater than 90% yield with
up to 10:1 diastereoselection favoring the anti isomer. The mechanism of this addition reaction is
intriguing and is under investigation. The moderately unstable â-nitro amines can be reduced with
samarium diiodide and the PMB group removed with CAN, in good overall yields, to give sensitive
1,2-diamines without erosion of diastereoselectivity. This protocol represents a new, stereoselective
synthesis of certain 1,2-diamines.
The 1,2-diamine structural motif is important in
For our methodology to be as flexible as possible, we
required a method of bringing two nitrogen-containing
fragments together stereoselectively. To maximize the
diastereoselectivity, we believed that we needed a reac-
tion that proceeded through a six-membered, Zimmer-
man-Traxler-like transition state. We concentrated on
transition states 1, which involved the addition of an
R-aza carbanion to an imine. Two possible scenarios
required the addition of metalated hydrazones or nitro-
nate anions to imines via transition states 2 and 3,
respectively.
biologically active natural products,1 in medicinal chem-
istry,2 and more recently in their use as chiral auxiliaries
and chiral ligands in asymmetric catalysis.3 While a
number of intriguing reports have appeared detailing the
stereoselective generation of 1,2-diamines, the diaste-
reoselective synthesis of 1,2-disubstituted 1,2-diamines
to date relies upon the conversion of alkenes via diols
and diazides4 or aziridines,5 aza-pinacol-type coupling of
two imines,6 conversion of enantiomerically pure natu-
rally occurring amino acids,7 the addition of R-nitrogen
carbanions to imines,8 and the use of chiral auxiliaries.9
The scope of these methods is limited due to the vari-
ability in diastereoselection and, where appropriate, the
availability of enantiomerically pure starting materials,
the nature of the chiral auxiliary, or in many cases the
basicity of the reaction conditions.23 Herein, we describe
the nitro-Mannich reaction as part of a mild and general
stereoselective method for the synthesis of 1,2-diamines
that has the potential to produce enantiomerically pure
products.
It is known that tert-butylhydrazones add to ketones
to form R-hydroxy hydrazones.10 Our attempts at the
analogous addition reaction between N-benzylidene-tert-
butyl- or -tert-butyldiphenylmethylhydrazone11 and N-
benzylidenebenzylamine were unsuccessful. However,
deprotonation of nitropropane with n-BuLi followed by
addition of N-benzylidenebenzylamine to the resultant
nitronate ion (1.1 equiv with respect to imine) and
quenching with acetic acid (AcOH) at -78 °C furnished
the â-nitro amine 412 in virtually quantitative yield with
a diastereoselection of greater than 15:1 by 1H NMR
(Scheme 1). As the addition product 4 is analogous to
those obtained from the diastereoselective nitroaldol
studies of Seebach et al.13 the major diastereoisomer was
† This article is dedicated to my friend and colleague Professor
Charles J . M. Stirling on the occasion of his retirement.
‡ University of Sheffield.
§ Glaxo Wellcome.
(1) (a) Pasini, A.; Zunino, F. Angew. Chem., Int. Ed. Engl. 1987, 26,
615-24. (b) Otsuka, M.; Masuda, T.; Haupt, A.; Ohno, M.; Shiraki, T.;
Sugiura, Y.; Maeda, K. J . Am. Chem. Soc. 1990, 112, 838-45.
(2) (a) Michalson, E. T.; Smuszkovicz, J . Prog. Drug. Res. 1989, 33,
135. (b) Reedijk, J . J . Chem. Soc., Chem. Commun. 1996, 801-6.
(3) (a) Blaser, H.-U. Chem. Rev. 1992, 92, 935-52. (b) Soai, K.; Niwa,
S. Ibid. 833-56. (c) J acobsen, E. N. in Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: Weinheim, 1993; p 159. (d) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483-
547.
1
assigned on the basis of a similar H NMR analysis. The
(4) Pini, D.; Iuliano, A.; Rosini, C.; Salvadori, P. Synthesis 1990,
1023-4.
(5) (a) Meguro, M.; Asao, N.; Yamamoto, Y. Tetrahedron Lett. 1994,
35, 7395-8. (b) Leung, W.-H.; Yu, M.-T.; Wu, M.-C.; Yeung, L.-L. Ibid.
1996, 37, 891-2.
(10) Adlington, R. M.; Baldwin, J . E.; Bottaro, J . C.; Perry, M. W.
D. J . Chem. Soc., Chem. Commun. 1983, 1040-1.
(11) Baldwin, J . E.; Adlington, R. M.; Newington, I. M. J . Chem.
Soc., Chem. Commun. 1986, 176-8.
(6) (a) Shimizu, M.; Iida, T.; Fujisawa, T. Chem. Lett. 1995, 609-
10 and references therein. (b) Taniguchi, N.; Uemura, M. Synlett 1997,
51-3.
(12) This class of product is similar to those that can be obtained
by the classic nitro-Mannich reaction [see: Baer, H. H.; Urbas, L. In
The Chemistry of the Nitro and Nitroso Groups, Part 2; Patai, S., Ed.;
(7) Reetz, M. T.; J aeger, R.; Drewlies, R.; Hu¨bel, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 103-6.
Interscience: New York, 1970;
p 117]. However, there are few
(8) (a) Kise, N.; Kashiwagi, K.; Watanabe, M.; Yoshida, J . J . Org.
Chem. 1996, 61, 428-9. (b) Park, Y. S.; Boys, M. L.; Beak, P. J . Am.
Chem. Soc. 1996, 118, 3757-8.
diastereoisomeric examples, and those that we could find combined
N-phenylbenzylimine with either nitroethane (see: Hurd, C. D.; Strong,
J . S. J . Am. Chem. Soc. 1950, 72, 4813-4) or nitropropopane (see:
Kozlov, L. M.; Fink, E. F. Trudy Kazan. Khim. Tekhnol. Inst. im. S.
M. Kirova 1956, 21, 163-6) to yield â-nitro amines both in 35% yield
but gave no comment regarding diastereoselectivity.
(9) (a) Enders, D.; Wiedemann, J . Synthesis 1996, 1443-50. (b)
Alvaro, G.; Grepioni, F.; Savoia, D. J . Org. Chem. 1997, 62, 4180-2
and references therein.
10.1021/jo981700d CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/05/1998

Stereoselective Synthesis of 1,2-Diamines
J . Org. Chem., Vol. 63, No. 26, 1998 9933
Sch em e 1
Sch em e 2
Ta ble 1. Syn th esis of Rep r esen ta tive 1,2-Dia m in es
diastereo-
yielda
of 7 (%)
selectivityb
anti/syn
yieldc
of 8 (%) of 9 (%)
yieldd
entry R1
R2
1
2
3
4
5
6
7
Et
Et
Et
Ph
n-Pn
c-Hex
90
95
95
60
74
95
95
10:1
9:1
2:3
60
66
45
48
96
100
86
Me2 Ph
86
Ph
Et
Et
Ph
CH2OBn
(CH2)3Ph
1:15
3:2
7:1
77
52
100
76
a
b
Crude yield estimated from mass balance and NMR. From
250 MHz 1H NMR (CDCl3). c Isolated yield over two steps with
respect to imine. Isolated yield.
assumption was made that the more highly populated
conformations are those in which there is a hydrogen
bond between the vicinal NH and ON-O groups as in
4-anti and 4-syn. This same analysis was used in the
assignment of future additions (vide infra) and was
supported by a single-crystal X-ray analysis of the cyclic
urea 6 derived from 5.14
d
Entries 1-3 examine which substituents are tolerated
on the aldimine fragment. The success of the n-pentyl-
imine in entry 2 is indicative of the mild reaction
conditions of this method. Although steric hindrance in
the imine partner does not appear to affect the yield of
the coupling, the diastereoselection is drastically dimin-
ished (entry 3). Tertiary nitronate anions are tolerated
(entry 4) and still accomplish a moderate yield for the
three-step synthesis of this particular 1,2-diamine (9, R1
) Me2, R2 ) Ph). The reversal of stereoselectivity with
phenyl nitromethane (entry 5) is curious, but we have
verified this structural assignment by single-crystal X-ray
analysis. An account of this anomaly awaits further
mechanistic studies, which will elucidate a working
transition-state model for these reactions. This addition
product (7, R1 ) Ph, R2 ) Ph) was too unstable to survive
even the mild reducing conditions employed in this
sequence. An imine derived from 2-benzyloxyacetalde-
hyde gave poor diastereoselection (entry 6), but the
corresponding carbon analogue gave the expected level
of stereocontrol (entry 7). At present, the stereoselective
nitro-Mannich reaction seems applicable to the synthesis
of 1,2-diamines from the coupling of nitroalkyl com-
pounds with PMB imines derived from benzaldehyde or
straight-chain carbaldehydes.19 Further studies concern-
ing heteroatom substituents on the nitroalkyl fragment
and imines derived from substituted benzaldehydes are
underway to further define the limitations of this meth-
odology.
To produce the desired 1,2-diamine, we required the
reduction of the alkyl nitro function to a primary alkyl-
amine. Most common descriptions concerning the reduc-
tion of nitro compounds refer to aromatic systems. In
addition, 4 is unstable to chromatography and prolonged
periods in solution due to â-elimination.15 Consequently,
standard reducing systems invariably gave dibenzyl-
amine as the chief reduction product. Fortunately, sa-
marium diiodide gently reduces the nitro function to our
desired primary amine 516 in 62% yield.15b,17 Hydro-
genolysis of the N-benzyl group of 5, to give the naked
1,2-diamine, caused many problems due to other sites
being susceptible to cleavage. It was at this point that
we optimized the reaction conditions using N-(4-meth-
oxybenzyl)imines as the N-4-(methoxybenzyl) (PMB)
group could be easily removed using ceric ammonium
nitrate (CAN).18 The general three-step sequence is
outlined in Scheme 2 with a selection of representative
examples in Table 1.
(13) Seebach, D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E. Helv.
Chim. Acta 1982, 65, 1101-33.
(14) Crystallographic data (excluding structure factors) for structure
6 has been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-101457. Copies of the data
can be obtained free of charge on application to The Director, CCDC,
12 Union Road, Cambridge CB2 1EZ, U.K. (fax: Int. code +(1223) 336-
033; e-mail: deposit@chemcrys.cam.ac.uk).
The addition of a nitronate anion to an imine is
thermodynamically impossible.20 This reaction (Scheme
2) is only made possible by the presence of acetic acid.
(15) (a) Akhtar, M. S.; Sharma, V. L.; Seth, M.; Bhaduri, A. P. Indian
J . Chem. 1988, 27B, 448-51. (b) Sturgess, M. A.; Yarberry, D. J .
Tetrahedron Lett. 1993, 34, 4743-6.
(16) A forefather of this method for the synthesis of 1,2-diamines is
the reduction, with Raney nickel and hydrogen (see Lambert, A.; Rose,
J . D. J . Chem. Soc. 1947, 1511-3), of products produced from the
condensation between primary (see: Senkus, M. J . Am. Chem. Soc.
1946, 68, 10-12) or secondary amines (see: J ohnson, H. G. J . Am.
Chem. Soc. 1946, 68, 12-14 and J ohnson, H. G. Ibid. 1946, 68, 14-
18), formaldehyde, and nitroalkanes. We have found no reports of this
method with other aldehydes, which would produce diastereomeric
products.
(18) Smith, A. B., III; Leahy, J . W.; Noda, I.; Remiszewski, S. W.;
Liverton, N. J .; Zibuck, R. J . Am. Chem. Soc. 1992, 114, 2995-3007.
(19) Nitroamines 4 and 7, protected diamines 5 and 8, and diamines
9 have all been fully characterized except for satisfactory elemental
analyses. We attribute this to the compounds’ sensitivity, but satisfac-
tory elemental analyses were obtained on the di-N-Boc derivatives (see
the Supporting Information).
(20) As ∆G ) -RT ln K and if we approximate K ≈ ∆Ka in this
case, as the change in bond enthalpy is small, and we define pKa’s of
9 for nitropropane and 35 for the aza anion of 4 then at -78 °C we
(17) Kende, A. S.; Mendoza, J . S. Tetrahedron Lett. 1991, 32, 1699-
1702.
find ∆G ≈ +97 kjmol-1
!

9934 J . Org. Chem., Vol. 63, No. 26, 1998
Adams et al.
Whether it is added to the nitronate anion or to the bulk
reaction mixture, the outcome of the reaction is identical.
Control experiments suggest that the diastereoselection
is derived from the addition of the two reaction partners,
not through equilibration to a tertiary nitronate anion
and subsequent protonation.21 Further studies are un-
derway to determine whether a nitronic acid or a proto-
nated imine is a key intermediate to elucidate the mech-
anism of this reaction.22
In summary, we have developed a three-step diaste-
reoselective synthesis of 1,2-diamines that involves the
coupling of alkyl nitro compounds and aldimines in good
overall yields. Mechanistic studies, catalytic studies, and
methods to control the absolute stereochemistry of the
products, to further develop the stereoselective nitro-
Mannich reaction, are underway and will be reported in
due course.
Ack n ow led gm en t. We thank GlaxoWellcome and
the EPSRC for a CASE award (S.P.), Prof. C. J . M.
Stirling and Dr. N. H. Williams of this department for
helpful discussions, Mr. A. J ones and Ms. J . Stanbra
for measuring microanalytical data, and Mr. S. Thorpe
and Mr. N. Lewus for providing mass spectra.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, spectroscopic data, and proton NMR spectra for
compounds 4-9 (32 pages). See any current masthead page
for ordering information.
J O981700D
(22) Nitronic acids can be prepared by the treatment of alkali metal
salts of nitroalkanes with strong mineral acid, although treatment with
weaker acids such as AcOH is believed to give predominantly C-
protonation [see: Nielsen A. T. In The Chemistry of the Nitro and
Nitroso Group, Part 1; Patai, S., Ed.; Wiley Interscience: New York,
1969; pp 349], what may happen in THF at -78 °C is unpredictable.
pKa (propane-nitronic acid) ) 4.6, pKa (nitropropane) ) 9.0 (in water,
see: Nielsen, A. T. above and references therein). pKa (acetic acid) )
4.7 and pKa (N-benzylidenebenzylamine) ∼7 (see: Koehler, K.; Sand-
strom, W.; Cordes, E. H. J . Am. Chem. Soc. 1964, 86, 2413-9. Cordes,
E. H.; J encks, W. P. Ibid. 1963, 85, 2843-8)
(21) Treatment of 7 (R1 ) Et, R2 ) Ph, 10:1 anti/syn) with BuLi (X
equiv) at -78 °C for 5 min and then addition of AcOH (2X equiv)
followed by workup with saturated aqueous NaHCO3 as before gave
the following products by NMR: X ) 1, 16% imine, 65% anti-7, 19%
syn-7; X ) 2, 40% imine, 45% anti-7, 14% syn-7. Control experiment
with no BuLi, but 2 equiv of AcOH at -78 °C followed by workup with
saturated aqueous NaHCO3 as before gave a quantitative recovery of
7 with unaltered diastereomeric excess.
(23) For a recent review see: Lucet, D.; LeGall, T.; Mioskowski, C.
Angew. Chem., Int. Ed. Engl. 1998, 37, 2580-2627.