Efficient N-N bond cleavage of chiral trisubstituted hydrazines with BH3·THF

Article abstract of DOI:10.1055/s-1998-5742

Cleavage of the N-N bond of chiral trisubstituted hydrazines 1 with excess BH₃·THF complex gives the corresponding optically active amines 2 in moderate to excellent yields and with high enantiomeric purity. This racemization and epimerization free cleavage procedure is compatible with functionalities sensitive to reductive cleavage conditions.

Full text of DOI:10.1055/s-1998-5742

1182
LETTERS
SYNLETT
Efficient N-N Bond Cleavage of Chiral Trisubstituted Hydrazines with BH THF
3
Dieter Enders,* René Lochtman, Michaela Meiers, Stephan Müller, Ryszard Lazny
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax: +49 (0)241/8888-127; E-mail: Enders@RWTH-Aachen.de
Received 13 August 1998
Abstract: Cleavage of the N-N bond of chiral trisubstituted hydrazines
1 with excess BH3 THF complex gives the corresponding optically
active amines 2 in moderate to excellent yields and with high
enantiomeric purity. This racemization and epimerization free cleavage
procedure is compatible with functionalities sensitive to reductive
cleavage conditions.
BH3 THF could only be applied to tetrasubstituted hydrazines, with the
cleavage of trisubstituted hydrazines being unsuccessful. Kibayashi et
al.13b-e have also published a similar method for the cleavage of
tetrasubstituted hydrazines.
We now wish to report our method to cleave N-N bonds of a broad
range of differently trisubstituted hydrazines 1 using BH3 THF as
cleavage reagent and giving rise to the optically active amines 3-7
(Figure 1).
Enantiomerically-pure amines are fundamental structures and of great
importance in organic synthesis. We have recently reported an efficient
asymmetric synthesis of optically active amines based on the SAMP/
RAMP-hydrazone methodology.1 Conversion of aldehydes into SAMP/
RAMP-hydrazones and subsequent 1,2-addition of organometallic
compounds leads to the corresponding hydrazines 1.2 Alternatively, β-
acceptor substituted hydrazine derivatives 1 can be synthesized
diastereoselectively via conjugate addition of an enantiopure nitrogen
nucleophile such as SAMP to enoates or 1-alkenyl sulphones. A key
step in all these procedures to prepare optically active amines 2 is the
cleavage of the hydrazine N-N bond.
An efficient asymmetric synthesis of protected (1-ferrocenyl-
alkyl)amines
3
starts
from
commercially
available
ferrocenylcarbaldehyde, which is converted into the SAMP-
hydrazone.14a,b Nucleophilic 1,2-addition of organolithium compounds
to the hydrazone C=N double bond leads to the corresponding
hydrazines. Subsequent N-N bond cleavage of activated hydrazines
using common methods such as lithium in liquid ammonia and
samarium(II) iodide afforded ethylferrocene and vinylferrocene,
respectively. Hydrogenolysis using platinum dioxide as catalyst gave
low yields with significant loss of enantiomeric purity and large
amounts of side-products. The Raney-nickel promoted hydrogenolysis
afforded the protected amines 3, but suffered from the disadvantages
mentioned above. Partial epimerization or racemization could not be
avoided even by varying the hydrogenolysis conditions. In order to
cleave the N-N bond of the hydrazine we employed BH3 THF as
reductive cleavage reagent, which led to amines 3 in good yields (80-89
%) and high enantiomeric excesses (93-95 %). In the same way 1,1′-
bis(1-aminoalkyl)ferrocene derivatives 4 were synthesized.14c The N-N
bond cleavage of the bis-hydrazines via Raney-nickel hydrogenolysis
proceeded only in the methyl case 4a with good yields and
stereoselectivities. Accordingly, cleavage of the hydrazine N-N bond
with BH3 THF afforded the protected amines 4 in good yields (53-69 %)
and stereoselectivities (de = 80-90 %, ee = 90-98 %).
We now wish to report an efficient method using BH3 THF as a
cleavage reagent for trisubstituted hydrazines 1 in order to access the
amines 2, such as (1-ferrocenylalkyl)amines 3, 1,1′-bis(1-amino-alkyl)-
ferrocene derivatives 4, 1,2-diamines 5, β-amino sulphones 6 and BH3-
protected β-amino phosphines 7 (Scheme 1, Figure 1).
Protected C2-symmetrical 1,2-diamines 5 can be prepared in high
diastereo- and enantiomeric excesses by nucleophilic 1,2-addition of
organocerium reagents to the C=N double bond of bis-SAMP-
hydrazones and subsequent reductive N-N bond cleavage of the
corresponding hydrazines.15 Attempts to introduce an activating group
into the 1,2-bis-hydrazines in order to cleave the N-N bond with lithium
in ammonia failed. The cleavage of the N-N bond with Raney-nickel as
well as with platinum dioxide as hydrogenation catalysts was
unsuccesful. In both cases the generated diamines might serve as
chelating ligands for the released heavy metal cations. Consequently,
BH3 THF was used as cleaving reagent which afforded the protected
1,2-diamines 5 in moderate to good yields (22-58 %) and high
diastereomeric and enantiomeric purity (de = 86-96 %, ee = 96-≥98 %).
Scheme 1
Several methods for the cleavage of hydrazine N-N bonds have been
reported in the literature. The reductive cleavage of heteroatom-
heteroatom bonds using samarium (II) iodide is well known.3 Lithium4
and sodium5 in ammonia has been used to cleave hydrazines, which
have been activated by prior conversion to acetyl or benzoyl derivatives.
However, this procedure suffers from occasional undesired cleavage of
the C-N bond instead of the N-N bond. Several groups have also
reported hydrogenolytic N-N bond cleavage methods using platinum
dioxide,6 palladium hydroxide7 or palladium on carbon8,3d as catalysts.
An additional well-known catalytic method is the Raney-nickel
promoted hydrogenolysis of hydrazine N-N bonds.9 In this case the
cleavage reaction is dependent on the activity of the catalyst, which can
be deactivated in several steps due to the preparation procedure.10
Unfortunately, this N-N bond cleavage protocol suffers from harsh
reaction conditions, a tedious preparation, competitive hydrogenation of
aromatic residues and partial racemization and epimerization. Zinc in
acetic acid11 and formic acid12 are other reagents to cleave hydrazine
N-N bonds.
Optically active β-amino sulphones 6 can be prepared by conjugate
addition of the chiral nitrogen nucleophile SAMP to 1-alkenyl
sulphones.16 Subsequent N-N bond cleavage of the resulting β-
hydrazino sulphones 1 leads to enantiomerically pure protected amines
6. The employment of Raney-nickel is not feasible, since the C-S bond
is cleaved under these reaction conditions. Since samarium(II) iodide
and platinum dioxide failed to cleave the N-N bond, BH3 THF was the
cleaving reagent of choice. The protected amines 6 were obtained in
good yields (58-82 %) and excellent enantiomeric excesses (≥96 %). In
this case the chiral auxiliary (SMP) was recycled as the Boc-protected
derivative.
Feuer and Brown13a observed during their investigations to reduce the
carbonyl groups of 1,2-dialkylperhydropyridazine-3,6-diones that a
large excess of BH3 THF resulted in N-N bond cleavage. However,

November 1998
SYNLETT
1183
The BH3 THF N-N bond cleavage of trisubstituted hydrazines 1,
prepared by 1,2-addition of organometallic reagents to α-
phosphinylated SAMP-hydrazones, afforded the BH3-protected β-
amino phosphines 7 in good yields (81-83 %) and diastereoselectivities
(75-78 %).17
was basified with solid KOH (3 and 4) or saturated NaHCO3-solution
(5-7) and extracted with methylene chloride or diethyl ether. The crude
amine was usually protected by reaction with Boc2O, benzyl chloro
formate or acetyl chloride before isolation and characterization.
Acknowledgements: This work was supported by the Deutsche
Forschungsgemeinschaft (Leibniz prize, Sonderforschungsbereich 380)
and the Fonds der Chemischen Industrie. We thank Degussa AG, BASF
AG, Bayer AG and Hoechst AG for the donation of chemicals.
References and Notes
(1
Enders, D. In Asymmetric Synthesis, Morrison, J. D. Ed.;
Academic Press: London, 1984; Vol. 3, p. 275.
Enders, D.; Fey, P.; Kipphardt, H. Org. Synth. 1987, 65, 173; 183.
(2) For a review see: Enders, D.; Reinhold, U. Tetrahedron:
Asymmetry 1997, 8, 1895.
(3) Cleavage with samarium diiodide: a) Natale, N. R. Tetrahedron
Lett. 1982, 23, 5009. b) Souppe, J.; Danon, L.; Namy, J. L.;
Kagan, H. B. J. Organomet. Chem. 1983, 227. c) Namy, J. L.;
Souppe, J.; Collin, J.; Kagan, H. B. J. Org. Chem. 1984, 49, 2045.
d) Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266. e)
Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron
1994, 50, 4399. f) Sturino, C. F.; Fallis, A. G. J. Am. Chem. Soc.
1994, 116, 7447. g) Kadota, J.; Park, J.-Y.; Yamamoto, Y. J. Chem.
Soc., Chem. Comm. 1996, 841.
Figure 1
(4) Cleavage with lithium in ammonia: . a) Rautenstrauch, V.; Delay,
F. Angew. Chem. 1980, 92, 764; Angew. Chem., Int. Ed. Engl.
1980, 19, 726. b) Denmark, S. E.; Nicaise, O.; Edwards, J. J. Org.
Chem. 1990, 55, 6219. c) Enders, D.; Bartzen, D. Liebigs Ann.
Chem. 1991, 569. d) Denmark, S. E.; Nicaise, O. Synlett 1993,
359. e) Brimble, M. A.; Heathcock, C. H. J. Org. Chem. 1993, 58,
5261. f) Enders, D.; Tiebes, J.; DeKimpe, N.; Keppens, M.;
Stevens, C.; Smagghe, G. J. Org. Chem. 1993, 58, 4881. g)
Enders, D.; Schankat, J.; Klatt, M. Synlett 1994, 795. h) Enders,
D.; Meiers, M. Angew. Chem. 1996, 108, 2391; Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2261. i) Enders, D.; Chelain, E.; Raabe,
G.; Bull. Soc. Chim. Fr. 1997, 299.
(5) Cleavage with sodium in ammonia: a) Mellor, J. M.; Smith, N. M.
J. Chem. Soc., Perkin 1 1984, 2927. b) Gilchrist, T. L.; Hughes,
D.; Wasson, R. Tetrahedron Lett. 1987, 28, 1573. c) Enders, D.;
Reinhold, U. Angew. Chem. 1995, 107, 1332; Angew. Chem. Int.
Ed. Engl. 1995, 34, 1219. d) Enders, D.; Reinhold, U. Liebigs
Ann. 1996, 11.
(6) Cleavage by platinum dioxide promoted hydrogenolysis:
Claremon, D. A.; Lumma, P. K.; Phillips, B. T. J. Am. Chem. Soc.
1986, 108, 8265.
In conclusion, an efficient method to cleave N-N bonds of trisubstituted
hydrazines has been reported. The employment of the BH3 THF
complex as reductive cleaving reagent gives the corresponding amines
in good yields and without racemization or epimerization. Further
advantages of this cleavage protocol are the simplicity, generality and
the compatability with reducible functional groups, such as aryl groups,
in the starting hydrazine.
(7) Cleavage by palladium hydroxide promoted hydrogenolysis: a)
Kim, Y. H.; Choi, J. Y. Tetrahedron Lett. 1996, 37, 5543. b) Choi,
J. Y.; Kim, Y. H. Tetrahedron Lett. 1996, 37, 7795.
(8) Cleavage by palladium on carbon promoted hydrogenolysis: a)
Takahashi, H.; Tomita, K.; Noguchi H. Chem. Pharm. Bull. 1981,
29, 3387. b) Takahashi, H.; Suzuki, Y. Chem. Pharm. Bull. 1983,
31, 4295.
(9) Cleavage by Raney-nickel promoted hydrogenolysis: a) Enders,
D.; Schubert, H. Angew. Chem. 1984, 96, 368; Angew. Chem., Int.
Ed. Engl. 1984, 23, 365. b) Egli, M.; Hoesch, L.; Dreiding, A. S.
Helv. Chim. Acta 1985, 68, 220. c) Enders, D.; Schubert, H.;
Nübling, C. Angew. Chem. 1986, 98, 1118; Angew. Chem., Int. Ed.
Engl. 1986, 25, 1109. d) Denmark, S. E.; Weber, T.; Piotrowski J.
Am. Chem. Soc. 1987, 109, 2224. e) Alexakis, A.; Lensen, N.;
General Procedure for the N-N bond cleavage with BH3 THF:19
The hydrazines 1 were dissolved in dry THF (20-50 mL/mmol) and
refluxed with 10 or 20 equivalents of BH3 THF (1.0 m in THF) for 5 to
70 h. The reaction was cooled to -5 °C (3 and 4) or to room temperature
(5-7), acidified with aqueous hydrochloric acid and stirred for 2 h. The
THF was evaporated under reduced pressure and the aqueous solution

1184
LETTERS
SYNLETT
Mangeney, P. Synlett 1991, 625. f) Enders, D.; Tiebes, J. Liebigs
Ann. Chem. 1993, 173. g) Enders, D.; Klatt, M.; Funk, R. Synlett
1993, 226. h) Enders, D.; Funk, R.; Klatt, M.; Raabe, G.;
Hovestreydt, E. R. Angew. Chem. 1993, 105, 418; Angew. Chem.,
Int. Ed. Engl. 1993, 32, 418. i) Baker, W. R.; Condon, S. L. J. Org.
Chem. 1993, 58, 3277. j) Enders, D.; Bettray, W.; Raabe, G.;
Runsink, J. Synthesis 1994, 1322. k) Rossano, L. T.; Lo, Y. S.,
Moore, J. R.; Gale, T. M.; Arnett, J. F.; Anzalone, L.; Lee, Y.-C.;
Meloni, D. J. Tetrahedron Lett. 1995, 36, 4967. l) Enders, D.;
Wahl, H.; Bettray, W. Angew. Chem. 1995, 107, 527; Angew.
Chem., Int. Ed. Engl. 1995, 34, 455. m) Enders, D.; Wiedemann,
J. Synthesis 1996, 1443. n) Solladie-Cavallo, A.; Bonne, F.
Tetrahedron: Asymmetry 1996, 7, 171. o) Thiam, M.; Chastrette,
F. Tetrahedron Lett. 1990, 31, 1429. p) Enders, D.; Nübling, C.;
Schubert, H. Liebigs Ann., Recl. 1997, 1089. q) Enders, D.;
Wiedemann, J. Liebigs Ann., Recl. 1997, 699.
3795. e) Beaudegnies, R.; Ghosez, L. Tetrahedron: Asymmetry
1994, 5, 557. f) Leblanc, Y.; Boudreault, N. J. Org. Chem. 1995,
60, 4268.
(12) Cleavage with formic acid: Enders, D.; Meyer, I. Dissertation,
Technical University of Aachen 1998.
(13) Cleavage with BH3 THF: a) Feuer, H.; Brown Jr., F. J. Org. Chem.
1970, 35, 1468. b) Suzuki, H.; Aoyagi, S.; Kibayashi, C.
Tetrahedron Lett. 1995, 36, 935. c) Suzuki, H.; Aoyagi, S.;
Kibayashi, C. Tetrahedron Lett. 1995, 36, 6709. d) Suzuki, H.;
Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1995, 60, 6114. e)
Yamazaki, N., Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron
Lett. 1996, 37, 6161.
(14) a) Enders, D.; Lochtman, R.; Raabe, G. Synlett 1996, 126. b)
Enders, D.; Lochtman, R. Synlett 1997, 355. c) Enders, D.;
Lochtman, R. Eur. J. Org. Chem. 1998, 689.
(15) Enders, D.; Meiers, M. Eur. J. Org. Chem. 1998, submitted.
(10) a) Mozingo, R. Org. Synth. Coll. 1955, Vol. III, 181. b)
Autorenkollektiv, Organikum, VEB Deutscher Verlag der
Wissenschaften, 16. Edition, Berlin, 1986.
(16) Enders, D.; Müller, S. F.; Raabe, G. Angew. Chem. 1998,
submitted.
(17) Enders, D.; Lazny, R., unpublished results, RWTH Aachen, 1998.
(11) Cleavage with zinc in acetic acid: a) Wieland, H.; Fressel, H.
Chem. Ber. 1911, 44, 898. b) Ames, D. E.; Kucharska, H. Z. J.
Chem. Soc. 1963, 4924. c) Serckx-Poncin, B.; Hesbain-Frisque,
A.-M.; Ghosez, L. Tetrahedron Lett. 1982, 23, 3261. d) Enders,
D.; Demir, A. S.; Puff, H.; Franken, S. Tetrahedron Lett. 1987, 28,
(18) Enders, D.; Berg, T.; Runsink, J.; Raabe, G. Helv. Chim. Acta
1996, 79, 118.
(19) Spectroscopic (IR, NMR, MS) and microanalytical data of these
compounds were in full agreement with their structure.