A practical photochemically induced method for nin bond cleavage of n,n-disubstituted hydrazides

Article abstract of DOI:10.1055/s-0029-1217759

The development of an unprecedented methodology based upon direct photolysis of N,N-disubstituted hydrazides to secure N-N bond cleavage and to trigger the formation of NH-free lactams has been disclosed.

Full text of DOI:10.1055/s-0029-1217759

LETTER
2621
A Practical Photochemically Induced Method for N–N Bond Cleavage of
N,N-Disubstituted Hydrazides
N
–N Bond Cle
t
avage
é
of
N
,N-Dis
p
ubstituted
H
y
drazides ane Lebrun,a,b Axel Couture,*a,b Eric Deniau,a,b Pierre Grandclaudona,b
a
Université des Sciences et Technologies de Lille 1, LCOP, Bâtiment C3(2), 59655 Villeneuve d’Ascq, France
Fax +33(3)20336309; E-mail: axel.couture@univ-lille1.fr
b
CNRS, UMR 8009 ‘Chimie Organique et Macromoléculaire’, 59655 Villeneuve d’Ascq, France
Received 2 July 2009
and co-workers.14 All these reactions have been claimed
to proceed with varying degrees of success and some of
them may be fraught with difficulties associated with the
lack of reactivity, the acidic or basic conditions required
and the use of hazardous reagents, namely hydrogen un-
der pressure even though hydrogenations using in situ
generated hydrogen have been also described.15 And fi-
nally, partial racemization of neighboring stereogenic
centers has been sometime observed upon this ultimate
chemical operation.
Abstract: The development of an unprecedented methodology
based upon direct photolysis of N,N-disubstituted hydrazides to se-
cure N–N bond cleavage and to trigger the formation of NH-free
lactams has been disclosed.
Key words: cleavage, photochemistry, synthetic methods, hy-
drazides, lactams
The cleavage of the nitrogen–nitrogen bond of hydrazine
derivatives and of their N-acyl-protected forms is an area
of current interest in chemistry and the development of
synthetic methodologies to break N–N bonds and trigger
off the formation of the NH free compounds is currently
the object of synthetic endeavour.1 In particular, this
cleavage appears as a key transformation in a variety of
asymmetric syntheses of amines and amino acids which
are important pharmacophores in numerous biologically
active compounds.2 Organic chemists have at their dispos-
al a number of synthetic methods to secure the N–N bond
cleavage of N,N-disubstituted hydrazines but few general
methods have demonstrated broad synthetic utility. Sever-
al reductive methods have been disclosed for this chemi-
cal transformation but they are strongly conditioned by
the structural profile of the molecules, nonaromatic hydra-
zines being more resistant than the aromatized ones.3 The
most widely used technique hinges upon catalytic hydro-
genolysis over Raney nickel,4 platinium-5 or palladium-
based catalysts.6 Alternative methods based upon elec-
troreductive process, electron transfer from metals, for ex-
ample, Na or Li/NH3,7 or by making use of SmI2 with
HMPA as co-solvent8 and diborane9 have also been estab-
lished. Catalytic processes based upon the use of polynu-
clear ruthenium clusters,10 ruthenium-based complexes,11
and tungsten or molybdenium complexes12 have been re-
cently reported. And finally, the N–N bond cleavage of
N,N-disubstituted hydrazines has been incidentally ob-
served upon treatment with naphthol analogues under
simply thermal conditions.13 To circumvent limitations
and difficulties related to the strong reducing conditions
that are incompatible with a number of functionalities or
protecting groups, alternative oxidative methods for the
N–N bond cleavage of N,N-disubstituted hydrazides by
peracids have been recently developed by J. M. Lassaletta
These results prompt us to develop a mild, efficient, and
versatile method for the deamination of hydrazides
through N–N bond cleavage that is based upon the use of
light as an energy source. Although well established in
biochemistry, photochemically removable groups have
been scarcely used in organic synthesis.16 Such groups are
particularly interesting since they do not need acidic, ba-
sic, or metal-assisted activation for cleavage. Indeed pho-
tochemical substrate activation often occurs without
additional reagents and under especially mild conditions
that renders this process particularly appealing in the con-
text of green chemistry.
A number of structurally and constitutionally diverse
models 1a–h were selected for this study and are por-
trayed in Table 1. SAMP-hydrazides 1a–e (entries 1–5)
were favored since this chiral auxiliary ranks high in the
hierarchy of temporary activating agents involved in
asymmetric syntheses of a wide range of amino deriva-
tives.17
Experimentally, a solution of the appropriate hydrazide 1
(0.2 mmol) dissolved in toluene (5 mL) and freshly dis-
tilled n-hexane (200 mL) was purged by bubbling argon
through it for 30 minutes. Photolyses were carried out in
a water-cooled quartz reactor equipped with dry argon in-
let and magnetic stirrer. The solution was placed in a Ray-
onet RPR 208 photochemical reactor containing eight
RUL 2537 Å lamps. Degassing and stirring of the solution
was maintained until complete consumption of the start-
ing material (TLC). To remove traces of tarry material the
solution was passed through a Celite pad that was subse-
quently washed with CH2Cl2 (5 mL). The solvents were
removed and the residual photoproduct was chromatogra-
phied on a silicagel column (Merck, Kieselgel 0.040–
0.063 mm particle size) using ethyl acetate (for 2d,e,h)
and mixtures of ethyl acetate–hexanes (for 2a–c,f,g), as
eluent. A representative series of compounds, which have
SYNLETT 2009, No. 16, pp 2621–2624
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.09.2009
DOI: 10.1055/s-0029-1217759; Art ID: G21309ST
© Georg Thieme Verlag Stuttgart · New York

2622
S. Lebrun et al.
LETTER
been prepared by this technique, are presented in Table 1 expectedly, the photochemically-induced release of the
where it may be seen that this simple procedure affords N(Ph)2 moiety (entries 6, 7) was significantly more diffi-
satisfactory yields of the NH-free lactams 2a–h.
cult than for the structurally diverse cyclized or opened
N,N-dialkyl units (entries 5–8). This synthetic strategy
tolerates the presence of endo- and exocyclic unsaturated
moieties (entries 6, 7) and photolysis of enehydrazides
1c,g was accompanied with partial E/Z photoisomeriza-
tion of the corresponding free NH enelactames 2c,g (en-
tries 3, 7). In the case of diarylated compounds 1f,g
(entries 6, 7) the presence of tetraphenylhydrazine could
be identified in the crude photoproduct so that one can
reasonably assume that the photochemical process in-
volves homolytic N–N bond scission. This mode of cleav-
Examination of Table 1 deserves some comments. Longer
irradiation times were required for N–N bond cleavage of
aromatic hydrazides (entries 1, 2) and constitutionally di-
verse enehydrazides (entries 3, 6, 7) than for saturated an-
alogues (entries 4, 5, 8). The photochemical process
spared the stereochemistry of the stereogenic centers a to
the nitrogen atom embedded in the structurally different
models (entries 1, 2, 4, 5). Thus enantiopure compounds
2a,b,d,e were obtained as single enantiomers by photoly-
sis of the parent diastereopure compounds 1a,b,d,e. Un-
Table 1 Photoproducts 2a–h from N–N Bond Cleavage of Hydrazides 1a–h
Entry
1
Starting hydrazide
1a–h
Photoproduct
2a–h
Irradiation time (h) Yield (%)
OMe
O
O
1a18
2a18
10
10
64
66
NH
Ph
O
N
N
N
Ph
O
OMe
2
1b18
2b18
NH
N
Ph
Ph
OMe
OMe
Ph
3
4
1c19
2c20
8
8
62
69
N
N
N
NH
O
O
Ph
1d19
2d19
NH
N
O
O
OMe
Ph
Ph
5
6
7
1e21
1f22
1g24
2e21
2f23
2g26
6
10
12
71
63
61
NH
O
N
O
N
Ph
Ph
NH
N
N
O
O
O
O
Ph
N
N
NH
Ph
Ph
Ph
Ph
Ph
Me
8
1h27
NH
O
2h21
6
76
N
N
Me
O
Synlett 2009, No. 16, 2621–2624 © Thieme Stuttgart · New York

LETTER
N–N Bond Cleavage of N,N-Disubstituted Hydrazides
2623
(7) (a) Rautenstrauch, V.; Delay, F. Angew. Chem., Int. Ed.
Engl. 1980, 19, 726. (b) Mellor, J. M.; Smith, N. M.
J. Chem. Soc. 1984, 2927.
(8) (a) Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114,
6266. (b) Atkinson, R. S.; Kelly, B. J.; Williams, J.
Tetrahedron 1992, 48, 7713.
(9) (a) Enders, D.; Lochtman, R.; Meiers, M.; Müller, S.; Lazny,
R. Synlett 1998, 1182. (b) Suzuki, H.; Aoyagi, S.;
Kibayashi, C. Tetrahedron Lett. 1994, 35, 6119. (c)Suzuki,
H.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1995, 60, 6114.
(10) (a) Takei, I.; Dohki, K.; Kobayashi, K.; Suzuki, T.; Hidai, M.
Inorg. Chem. 2005, 44, 3768. (b) Martínez, S.; Trepat, E.;
Moreno-Mañas, M.; Sebastian, R. M.; Vallribera, A.; Mata,
I.; Molins, E. ARKIVOC 2007, (iv), 170.
age is a logical consequence of the low energy
requirements of the nitrogen–nitrogen bond.28 Dissipation
of carbonyl excitation energy upon irradiation at 254 nm
is sufficient to induce rupture of the least stable bond in
the vicinity of the chromophore, so that the primary pho-
toreaction is the N–N cleavage. Unfortunately radical re-
combination precludes recovery of the chiral auxiliary
(entries 1–5).
In summary a mild, efficient, and conceptually new syn-
thetic method that enriches the repertoire of the synthetic
approaches to the cleavage of N–N bond of N,N-disubsti-
tuted hydrazides has been disclosed. In practice, this
methodology that hinges upon a photo-induced nonoxida-
tive N–N bond cleavage giving rise to secondary amides
is advantageous over traditional methods since it tolerates
the presence of functionalities sensitive to reducing con-
ditions and is compatible for substrates equipped with ste-
reogenic centers. We also believe that this strategy could
be applied for the deamination of a variety of substrates
and might find wide application in preparation of many
valuable aminated compounds.
(11) Nakajima, Y.; Suzuki, H. Organometallics 2003, 22, 959.
(12) Schrock, R.; Glassman, T. E.; Vale, M. G. J. Am. Chem. Soc.
1991, 113, 725.
(13) Tang, Q.; Zhang, C.; Luo, M. J. Am. Chem. Soc. 2008, 130,
5840.
(14) (a) Fernández, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.;
Martín-Zamora, E. Angew. Chem. Int. Ed. 2002, 41, 831.
(b) Fernández, R.; Ferrete, A.; Llera, J. M.; Magriz, A.;
Martín-Zamora, E.; Díez, E.; Lassaletta, J. M. Chem. Eur. J.
2004, 10, 737; and references cited therein.
(15) (a) Lunn, G.; Sansone, E. B.; Keefer, L. K. Synthesis 1985,
1104. (b) Alonso, F.; Radivoy, G.; Yus, M. Tetrahedron
2000, 56, 8673. (c) Alonso, F.; Candela, P.; Gómez, C.; Yus,
M. Adv. Synth. Catal. 2003, 345, 275.
Acknowledgment
We are grateful to the Centre National de la Recherche Scientifique
(CNRS) and the Région Nord-Pas-de-Calais (Programme PRIM)
for financial support.
(16) Hoffmann, N. Chem. Rev. 2008, 108, 1052.
(17) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253.
(18) Deniau, E.; Enders, D.; Couture, A.; Grandclaudon, P.
Tetrahedron: Asymmetry 2003, 14, 2253.
(19) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P.
Tetrahedron: Asymmetry 2003, 14, 2625.
(20) Tsolomitis, G.; Tsolomitis, A. Heterocycl. Commun. 2006,
12, 93.
(21) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Org.
Lett. 2007, 9, 2473.
(22) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P.
Synthesis 2006, 3490.
References and Notes
(1) Selected examples for N–N bond cleavage in hydrazines:
(a) Hinman, R. L. J. Org. Chem. 1957, 22, 148. (b) Feuer,
H.; Brown, F. Jr. J. Org. Chem. 1970, 35, 1468.
(c) Denmark, S. E.; Nicaise, O.; Edwards, J. P. J. Org. Chem.
1990, 55, 6219. (d) Alonso, F.; Radivoy, G.; Yus, M.
Tetrahedron 2000, 56, 8673. (e) Fernandez, R.; Ferrete, A.;
Lassaletta, J. M.; Llera, J. M.; Monge, A. Angew. Chem. Int.
Ed. 2000, 39, 2893. (f) Friestad, G. K.; Ding, H. Angew.
Chem. Int. Ed. 2001, 40, 4491. (g) Enders, D.; Funabiki, K.
Org. Lett. 2001, 3, 1575. (h) Sapountzis, I.; Knochel, P.
Angew. Chem. Int. Ed. 2004, 43, 897. (i) Ding, H.; Friestad,
G. K. Org. Lett. 2004, 6, 637. (j) Sinha, P.; Kofink, C. C.;
Knochel, P. Org. Lett. 2006, 8, 3741.
(23) Koltunov, K. Y.; Prakash, G. K. S.; Rasul, G.; Olah, G. A.
Eur. J. Org. Chem. 2006, 4861.
(24) 2-Diphenylamino-3-[1-phenylmeth-(E)-ylidene]-2,3-
dihydroisoindol-1-one (1g) was prepared from 2-diphenyl-
amino-isoindole-1,3-dione25 and benzylmagnesium bromide
following a reported procedure.19
Analytical Data
(2) (a) Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron
2001, 57, 7785. (b) Kienle, M.; Dubbaka, S. R.; Brade, K.;
Knochel, P. Eur. J. Org. Chem. 2007, 4166.
(3) Gilchrist, T. L. In Comprehensive Organic Synthesis, Vol.
8; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
388.
(4) (a) Enders, D.; Schubert, H. Angew. Chem., Int. Ed. Engl.
1984, 23, 365. (b) Egli, M.; Hoesch, L.; Dreiding, A. S.
Helv. Chim. Acta 1985, 68, 220. (c) Denmark, S. E.; Weber,
T.; Piotrowski, D. W. J. Am. Chem. Soc. 1987, 109, 2224.
(d) Thiam, M.; Chastrette, F. Tetrahedron Lett. 1990, 31,
1429. (e) Alexakis, A.; Lensen, N.; Mangeney, P. Synlett
1991, 625. (f) Baker, W. R.; Condon, S. L. J. Org. Chem.
1993, 58, 3277. (g) A. Solladié-Cavallo, A.; Bonne, F.
Tetrahedron: Asymmetry 1996, 7, 171.
Mp 225–226 °C. 1H NMR (300 MHz, CDCl3): d = 6.93 (s, 1
H, CH=), 7.05 (t, J = 7.0 Hz, 2 H, Harom), 7.20–7.51 (m, 15
H, Harom), 7.55 (d, J = 7.6 Hz, 1 H, Harom), 7.91 (d, J = 7.5
Hz, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): d = 111.7,
119.5 (4 × CH), 123.3, 123.5 (2 × CH), 124.0, 128.0, 128.5,
128.7 (2 × CH), 129.4 (4 × CH), 129.5 (2 × CH), 129.7,
133.1, 132.5, 133.7, 134.6, 144.6 (2 × C), 164.5 (CO) ppm.
Anal. Calcd for C27H20N2O: C, 83.48; H, 5.19; N, 7.21.
Found: C, 83.62; H, 5.12; N, 7.00.
(25) Nam, H.; Kang, D. H.; Kim, J. K.; Park, S. Y. Chem. Lett.
2000, 11, 1298.
(26) Uozumi, Y.; Mori, E.; Mori, M.; Shibasaki, M.
J. Organomet. Chem. 1990, 399, 93.
(27) 1-Dimethylamino-6-phenylpiperidin-2-one (1h) was
prepared from benzaldehyde hydrazone [N,N-dimethyl-N¢-
(1-phenylmethylidene)hydrazine] following a previously
described synthetic sequence:21 addition of allyllithium,
amidation with acryloyl chloride, RCM, hydrogenation
(Pd/C).
(5) Claremon, D. A.; Lumma, P. K.; Phillips, B. T. J. Am. Chem.
Soc. 1986, 108, 8265.
(6) (a) Takahashi, H.; Tomika, K.; Noguchi, H. Chem. Pharm.
Bull. 1981, 29, 3387. (b) Kim, Y. H.; Choi, J. Y.
Tetrahedron Lett. 1996, 37, 5543.
Synlett 2009, No. 16, 2621–2624 © Thieme Stuttgart · New York

2624
S. Lebrun et al.
Analytical Data
LETTER
Anal. Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83.
Found: C, 71.71; H, 8.49; N, 13.09.
(28) (a) Pitzer, K. S. J. Am. Chem. Soc. 1948, 70, 2140.
(b) Jaffé, H. H.; Orchin, M. Theory and Applications of
Ultraviolet Spectroscopy; John Wiley and Sons: New York,
1962, 180.
Colorless oil. 1H NMR (300 MHz, CDCl3): d = 1.54–1.88
(m, 3 H), 2.04–2.11 (m, 1 H), 2.47–2.55 (m, 1 H), 2.75 (s, 6
H, 2 × CH3), 4.65 (t, J = 5.4 Hz, 1 H), 7.25–7.31 (m, 5 H,
H
arom) ppm. 13C NMR (75 MHz, CDCl3): d = 16.9, 32.8,
34.0, 64.8, 126.9, 127.3, 128.3, 142.4, 170.7 (CO) ppm.
Synlett 2009, No. 16, 2621–2624 © Thieme Stuttgart · New York