Trifluoroacetyl-Activated Nitrogen-Nitrogen Bond Cleavage of Hydrazines by Samarium(II) Iodide

Article abstract of DOI:10.1021/ol036480r

(Matrix presented) Trifluoroacetyl derivatives of hydrazines undergo clean and efficient reductive cleavage of the N-N bond with Sml₂ in the presence of MeOH. After N-trifluoroacetylation, acyl-, aryl-, and alkyl-substituted hydrazines are redu

Full text of DOI:10.1021/ol036480r

ORGANIC
LETTERS
2004
Vol. 6, No. 4
637-640
Trifluoroacetyl-Activated
Nitrogen−Nitrogen Bond Cleavage of
Hydrazines by Samarium(II) Iodide
Hui Ding and Gregory K. Friestad*
Department of Chemistry, UniVersity of Vermont, Burlington, Vermont 05405
gregory.friestad@uVm.edu
Received December 20, 2003
ABSTRACT
Trifluoroacetyl derivatives of hydrazines undergo clean and efficient reductive cleavage of the N−N bond with SmI2 in the presence of MeOH.
After N-trifluoroacetylation, acyl-, aryl-, and alkyl-substituted hydrazines are reductively cleaved by this method to afford trifluoroacetamides
in yields ranging from 70 to 96%. These conditions accommodate alkene functionality, avoid racemization, and furnish chiral amines bearing
a readily removable TFA protecting group.
Chiral R-branched amines are ubiquitous components of
biologically active compounds and are versatile building
blocks for medicinal chemistry and natural product synthesis.
Among approaches to asymmetric amine synthesis, addition
of carbon-centered radicals1 and organometallic or hydride
reagents2 to hydrazones potentially provides straightforward
access to chiral amines.3 The advantages of hydrazones over
imines include a favorable equilibrium in their formation
(even in aqueous media), ease of purification and handling,
and resistance to tautomerization.
We required a general method for N-N bond cleavage,
compatible with alkene functionality, to facilitate access to
enantiopure homoallylic amines via allylsilane addition to
chiral N-acylhydrazones.2b Recently, cleavage of the N-N
bond in hydrazines has been achieved by oxidation with
magnesium monoperoxyphthalate.4 More commonly, reduc-
tion has been employed, using hydrogenolysis5 (H2 with Pd-
C, Pd(OH)2, PtO2, Pt, or Raney nickel catalysts), dissolving
metal reduction,6 hydroboration,7 or other methods.8 Reduc-
tive cleavage with samarium(II) iodide9 (SmI2), with various
additives, has gained prominence in many recent studies.10,11
Our experimental work became focused on samarium(II)
iodide because of its compatibility with alkene functionality
and the operational simplicity of the experimental procedures
(e.g., rapid reaction at ambient temperature and pressure). It
has previously been found that an activating acyl group on
one of the nitrogens may be needed to promote reaction with
SmI2 or other one-electron reductants.6,8,10,11 Accordingly,
we found dramatically different results upon direct treatment
of 1a2b or 22b with SmI2 and HMPA in THF (eq 1). The free
amine 1a gave no reaction, but the corresponding N-benzoyl
derivative 2 underwent rapid, quantitative N-N bond cleav-
(1) (a) Friestad, G. K.; Shen, Y.; Ruggles, E. L. Angew. Chem., Int. Ed.
2003, 42, 5061-5063. (b) Friestad, G. K.; Jiang, T.; Fioroni, G. M.
Tetrahedron: Asymmetry 2003, 14, 2853-2856. (c) Friestad, G. K.; Qin,
J. J. Am. Chem. Soc. 2001, 123, 9922-9923. (d) Friestad, G. K.; Qin, J. J.
Am. Chem. Soc. 2000, 123, 8329-8330. (e) Friestad, G. K.; Massari, S. E.
Org. Lett. 2000, 2, 4237-4240. (f) Friestad, G. K. Org. Lett. 1999, 1, 1499-
1501.
(2) (a) Qin, J.; Friestad, G. K. Tetrahedron 2003, 59, 6393-6340. (b)
Friestad, G. K.; Ding, H. Angew. Chem., Int. Ed. 2001, 39, 4491-4493.
(3) (a) Reviews: Friestad, G. K. Tetrahedron 2001, 57, 5461-5456.
Bloch, R. Chem. ReV. 1998, 98, 1407-1438. Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry 1997, 8, 1895-1946. For recent applications of
hydrazones as addition acceptors in asymmetric synthesis of amines, see:
(b) Hamada, T.; Manabe, K.; Kobayashi, S. Angew. Chem., Int. Ed. 2003,
42, 3927-3930. Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J.
Am. Chem. Soc. 2003, 125, 6610-6611. (c) Berger, R.; Rabbat, P. M. A.;
Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596-9597. (d) Funabiki,
K.; Nagamori, M.; Matsui, M.; Enders, D. Synthesis 2002, 2585-2588. (e)
Kobayashi, S.; Hirabayashi, R. J. Am. Chem. Soc. 1999, 121, 6942-6943.
(4) Ferna´ndez, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.; Monge,
A. Angew. Chem., Int. Ed. 2000, 39, 2893-2897.
10.1021/ol036480r CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/27/2004

age under these conditions. Unfortunately, hydrolysis of the
resulting benzamide required harsh conditions that ultimately
caused decomposition. From this it was concluded that
general applications in multifunctional synthetic schemes
would require a more readily removable acyl activating
group.
Previously, we had attempted to exploit carbamate derivatives
(eq 2, R ) methoxycarbonyl or benzyloxycarbonyl) to meet
these requirements.12 However, on the same substrate for
which benzoyl activation had enabled quantitative N-N
cleavage, these carbamate derivatives underwent no reaction
at all (eq 2), a dramatic illustration of the unusual N-N bond
activation properties of the benzoyl group. This chemical
behavior toward SmI2 is consistent with activating effects
previously documented by electroreductive measurements,
which showed increased potentials proportional to the
number of benzoyl substituents.8a
We sought an acyl group that could combine N-N bond
activation with wide acceptance as a protecting group.
(5) For examples of hydrogenolysis with various catalysts, see the
following. (a) Pd/C: Chandrasekhar, S.; Reddy, C. R.; Rao, R. J. Synlett
2001, 1561-1562. Clive, D. L. J.; Zhang, J.; Subedi, R.; Bouetard, V.;
Hiebert, S.; Ewanuk, R. J. Org. Chem. 2001, 66, 1233-1241. Bataille, P.;
Paterne, M.; Brown, E. Tetrahedron: Asymmetry 1998, 9, 2181-2192. (b)
Pd(OH)2: Kim, Y. H.; Choi, J. Y. Tetrahedron Lett. 1996, 37, 5543-5546.
(c) PtO2: Genari, C.; Colombo, L.; Bertolini, G. J. Am. Chem. Soc. 1986,
108, 6394-6395. Claremon, D. A.; Lumma, P. K.; Phillips, B. T. J. Am.
Chem. Soc. 1986, 108, 8265-8266. Guerra, F. M.; Mish, M. R.; Carreira,
E. M. Org. Lett. 2000, 2, 4265-4267. (d) Raney Ni: Hinman, R. L. J.
Org. Chem. 1957, 22, 148-150. Enders, D.; Schubert, H.; Nu¨bling, C.
Angew. Chem., Int. Ed. Engl. 1986, 25, 1109-1110. Evans, D. A.; Britton,
T. C.; Dorow, R. L.; Dellaria, J. F. J. Am. Chem. Soc. 1986, 108, 6397-
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Nicaise, O.; Denmark, S. E. Bull. Soc. Chim. Fr. 1997, 134, 395-398.
Hsieh, Y.-T.; Lee, G.-H.; Wang, Y.; Luh, T. Y. J. Org. Chem. 1998, 63,
1484-1490. Martin, S. F.; Hom, R. K. Tetrahedron Lett. 1999, 40, 2887-
2890. Breuil-Desvergnes, V.; Compain, P.; Vate`le, J.-M.; Gore´, J. Tetra-
hedron Lett. 1999, 40, 5009-5012. Ghelfi, F.; Parsons, A. F. J. Org. Chem.
2000, 65, 6249-6253. (e) Pt: Perez Luna, A.; Ceschi, M.-A.; Bonin, M.;
Micouin, L.; Husson, H.-P.; Gougeon, S.; Estenne-Bouhtou, G.; Marabout,
B.; Sevrin, M.; George, P. J. Org. Chem. 2002, 67, 3522-3524.
(6) (a) Mellor, J. M.; Smith, N. M. J. Chem. Soc., Perkin Trans. 1 1984,
2927-2931. (b) Denmark, S. E.; Nicaise, O.; Edwards, J. P. J. Org. Chem.
1990, 55, 6219-6223. (c) Enders, D.; Tiebes, J.; De Kimpe, N.; Kappens,
M.; Stevens, C.; Smagghe, G. J. Org. Chem. 1993, 58, 4881-4884. (d)
Brimble, M. A.; Heathcock, C. H. J. Org. Chem. 1993, 58, 5261-5263.
(e) Enders, D.; Leriverend, C. Tetrahedron: Asymmetry 1997, 8, 2787-
2792. (f) Enders, D.; D´ıez, E.; Ferna´ndez, R.; Mart´ın-Zamora, E.; Mun˜oz,
J. M.; Pappalardo, R. R.; Lassaletta, J. M. J. Org. Chem. 1999, 64, 6329-
6336. (g) Koohang, A.; Stanchina, C. L.; Coates, R. M. Tetrahedron 1999,
55, 9669-9686. (h) Alonso, F.; Radivoy, G.; Yus, M. Tetrahedron 2000,
56, 8673-8678. (i) Wasserman, H. H.; Matsuyama, H.; Robinson, R. P.
Tetrahedron 2002, 58, 7177-7190.
A key inference, suggesting an alternative to the benzoyl
group, was drawn from a recent kinetic analysis of ketone
reductions by SmI2. In these elegant studies, Flowers showed
that ortho fluorine substituents gave dramatically enhanced
rates of reduction of aryl ketones by SmI2.13 A chelation
model (Figure 1a) was advanced to explain the enhanced
Figure 1. (a) Chelation model proposed by Flowers, and supported
by rigorous analysis of activation parameters, to explain increased
reduction rates of 2′-fluoroacetophenone by SmI2. [SmII] represents
samarium(II) species with undetermined ratios of iodide and THF
ligands. (b) Our hypothesis: trifluoroacetyl group should facilitate
reductive cleavage of the N-N bond of hydrazines.
(7) Feuer, H.; Brown, F., Jr. J. Org. Chem. 1970, 35, 1468-1471. Enders,
D.; Lochtman, R.; Meiers, M.; Muller, S.; Lazny, R. Synlett 1998, 1182-
1184. Enders, D.; Thiebes, C. Synlett 2000, 1745-1748. Yamazaki, N.;
Kibayashi, C. Tetrahedron Lett. 1997, 38, 4623-4626. Also see refs 1a
and 1c.
(8) (a) For an electrochemical method, see: Chauveau, A.; Martens, T.;
Bonin, M.; Micouin, L.; Husson, H.-P. Synthesis 2002, 1885-1890. Horner,
L.; Jordan, M. Liebigs Ann. Chem. 1978, 1505-1517. (b) For use of
phosphoryl isothiocyanate, see: Overman, L. E.; Rogers, B. N.; Tellew, J.
E.; Trenkle, W. C. J. Am. Chem. Soc. 1997, 119, 7159-7160.
reducing power of SmI2 under these circumstances. A similar
chelated structure can be envisioned involving the trifluo-
roacetyl (TFA) moiety (Figure 1b). From this we were led
to the hypothesis that TFA might facilitate the N-N bond
cleavage process.14 Importantly, TFA is a popular amine-
(9) Souppe, J.; Danon, L.; Namy, J. L.; Kagan, H. B. J. Organomet.
Chem. 1983, 250, 227-236.
(10) For a review: Williams, D. B. G.; Blan, K.; Caddy, J. Org. Prep.
Proc. Int. 2001, 33, 565-602. For examples with various additives, see:
(a) MeOH or t-BuOH: Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992,
114, 6266-6267. Atkinson, S. R.; Kelly, B. J.; Williams, J. Tetrahedron
1992, 48, 7713-7730. Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford,
N. Tetrahedron 1994, 50, 4399-4428. Also see refs 3e and 8b. (b) EtOH:
ref 3b. (c) HMPA: Sturino, C. F.; Fallis, A. G. J. Am. Chem. Soc. 1994,
116, 7447-7448. Park, J.-Y.; Kadota, I.; Yamamoto, Y. J. Org. Chem.
1999, 64, 4901-4908. Kadota, I.; Park, J. Y.; Yamamoto, Y. J. Chem.
Soc., Chem. Commun. 1996, 841-842. (d) DMPU: Enders, D.; Funabiki,
K. Org. Lett. 2001, 3, 1575-1577.
(12) Qin, J. Ph.D. Dissertation, University of Vermont, Burlington,
Vermont, 2003.
(13) Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2002, 124, 6357-
6361.
(14) (a) Trifluoroacetamides have been employed in N-N bond cleavage
with Li/NH3 or Al/Hg. See refs 6a and 6e. (b) Trifluoroacetyl protection
has been exploited during N-O bond cleavage. However, acetamides and
carbamates were also effective in these studies, in contrast to eq 2. See:
Keck, G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett. 1995, 36,
7419-7422. Keck, G. E.; McHardy, S. F.; Murry, J. A. J. Org. Chem.
1999, 64, 4465-4476. Keck, G. E.; Wager, T. T.; McHardy, S. F.
Tetrahedron 1999, 55, 11755-11772.
(11) For a general review of the use of SmI2 as a reductant, see:
Molander, G. A. In Organic Reactions; Paquette, L., Ed.; Wiley: New York,
1994; Vol. 46, pp 211-367.
638
Org. Lett., Vol. 6, No. 4, 2004

Scheme 1
Table 1. Effect of Additives on N-N Bond Cleavage after
Acylation of 1a (Scheme 1)
entry
hydrazine
additive
products (yield, %)
1
2
3
4
5
6
2
2
2
3a
3a
3a
HMPA
MeOH
none
HMPA
MeOH
none
4 (96), 6a (93)
4 (94), 6a (94)
4 (68), 6a (82)
5a (83), 6a (47)
5a (95), 6a (93)
5a (67), 6a (nd)
protecting group and is easily hydrolyzed. Here we report
that N-trifluoroacetylation activates the SmI2-mediated N-N
bond cleavage process, enabling smooth conversion of a
variety of trisubstituted hydrazines to TFA-protected amines.
To compare the effects of trifluoroacetyl and benzoyl
groups in N-N bond activation, these two acylated com-
pounds were prepared by lithiation of 1a2b and reaction with
trifluoroacetic anhydride (TFAA) or benzoic anhydride,
respectively (Scheme 1). The N-benzoyl hydrazine 22b was
exposed to SmI2 to afford benzamide 42b in high yield, in
the presence of either HMPA or MeOH as an additive.
Meanwhile, the oxazolidinone 6a was recovered in high yield
in each case. When the N-TFA hydrazine 3a was treated
with samarium(II) iodide for 30 min at room temperature in
the presence of HMPA (entry 4), the reaction gave a good
yield of trifluoroacetamide 5a.15 Replacing HMPA with
MeOH, which probably worked as a proton source, gave
superior results (entry 5), particularly with respect to recovery
of 6a. In the absence of additive, however, yields decreased
(entries 3 and 616) due to some side reactions. Thus, optimal
conditions17 for studies of the scope of the TFA-activated
N-N cleavage called for use of MeOH as an additive.
For exploration of the reaction scope, a series of hydrazines
with varying substitution patterns were available from our
previous studies of allylsilane additions (1a, 1b)2b and radical
additions (1c, 1d)1a,c to N-acylhydrazones or prepared by
NaBH3CN reduction18 (1e-h; see Supporting Information)
of the corresponding hydrazones.
Cleavage of the N-N bond of various types of hydrazines
occurred with good yields (Table 2). Upon conversion to
their TFA derivatives, N-acylhydrazines (entries 1, 2, and
4-6) were cleaved by SmI2 to afford the corresponding
trifluoroacetamides 5a-d15 or 5e14b in excellent yields (91-
96%), although 1c was an exception (entry 3, 70%).
Trisubstituted hydrazines bearing N,N-diaryl (1g) or N,N-
dialkyl substitution (1h) also were cleaved to afford 5e in
good yields (82%) although a longer reaction time (2 h) was
required. It is worth noting that the steric hindrance of
R-branched hydrazines 1c and 1d did not impede the N-N
bond cleavage.
Table 2. Examples of Trifluoroacetyl-Activated Hydrazine N-N Bond Cleavage
a 3,4-Dimethoxyphenyl. b Yield not determined.
Org. Lett., Vol. 6, No. 4, 2004
639

Importantly, the enantiomeric purities of chiral hydrazines
are unchanged by N-N bond cleavage according to the
method described in Table 2. For example, trifluoroacet-
amides 5b and 5d were obtained without detectable racem-
ization according to chiral HPLC analysis.19
ease of removal, effectively avoided the degradation that had
been observed during hydrolysis of the related benzamide
as described above (eq 1).
Furthermore, as expected from ample precedent, removal
of the TFA protecting group from 5b was achieved in high
yield under mild conditions (eq 3). The TFA group, with its
(15) Structures of new compounds 1b, 1e, 1f, 5a-d, and 7 are consistent
with combustion analyses and spectroscopic data (1H and 13C NMR, IR,
MS) provided in Supporting Information.
(16) In addition to the lower yield of 5a, oxazolidinone 6a was
contaminated in this case by a complex mixture of byproducts. Complete
consumption of starting material occurred.
In summary, we have found that the trifluoroacetyl
substituent enables clean and efficient reductive cleavage of
the N-N bond of various hydrazines using SmI2 in the
presence of MeOH. These conditions are compatible with
alkene functionality, and thus offer an important complement
to hydrogenolysis or hydroboration. Furthermore, the method
furnishes chiral amines that bear a convenient TFA protecting
group to facilitate subsequent synthetic applications.
(17) (a) Representative Experimental Procedure. To a solution of 1b
(79 mg, 0.206 mmol) in THF (2.0 mL) under N2 at -78 °C was added
n-BuLi (1.6 M in hexanes, 140 µL, 0.224 mmol) at -78 °C. After 40 min,
trifluoroacetic anhydride (50 µL, 0.353 mmol) was added at -78 °C. The
mixture was allowed to warm to ambient termperature overnight. Concen-
tration and flash chromatography (4:1 hexanes/ethyl acetate) gave 3b (80
mg, 81%) as a pale yellow oil. To a solution of 3b (48 mg, 0.1 mmol) in
MeOH (0.2 mL) under N2 was added SmI2 (2.6 mL, 0.3 M in THF)
dropwise. After 30 min, the dark blue solution was opened to air, and the
color changed to yellow. Concentration and flash chromatography gave 5b
(27.5 mg, 91%) and 6a (15 mg, 85%). (b) The concentration of SmI2 was
assumed on the basis of the preparation; the actual concentration is likely
somewhat lower. Use of a freshly titrated SmI2 solution (0.10 M) showed
that a 3:1 molar ratio of SmI2:3d was sufficient to achieve complete
conversion (93% yield).
Acknowledgment. We thank NIH (RO1-GM67187) and
Vermont NSF EPSCoR for generous support.
Supporting Information Available: Characterization
data for 1b, 1e, 1f, 5a-d, and 7. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) Grehn, L.; Ragnarsson, U. Tetrahedron 1999, 55, 4843-4852.
(19) Compound 5b was enantiomerically pure as judged by HPLC
comparison with a racemic sample (see Supporting Information). A
nonracemic sample of 1d (50.4% ee), prepared according to a procedure
reported in ref 2b, gave 5d of the same enantiomeric purity.
OL036480R
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Org. Lett., Vol. 6, No. 4, 2004