The reactions of hydrazines with α-lactams. Regiochemistry of hydrazine addition and subsequent ring closure to N-aminohydantoins or 1,2,4-triazine- 3,6-diones

Full text of DOI:10.1021/jo981650c

9128
J . Org. Chem. 1998, 63, 9128-9130
Sch em e 1
Th e Rea ction s of Hyd r a zin es w ith
r-La cta m s. Regioch em istr y of Hyd r a zin e
Ad d ition a n d Su bsequ en t Rin g Closu r e to
N-Am in oh yd a n toin s or
1,2,4-Tr ia zin e-3,6-d ion es
Robert V. Hoffman,*,† Madhava M. Reddy,†
Curtis M. Klumas,† and Francisco Cervantes-Lee‡
Department of Chemistry and Biochemistry, North
Horseshoe Drive, New Mexico State University,
Las Cruces, New Mexico 88003-8001, and Department of
Chemistry, University of Texas at El Paso,
El Paso, Texas 79968
Although both heterocycles can be accessed via the
chemistry outlined in Scheme 1, it is necessary to
understand the factors which control the cyclization of 3
to either 4 or 5, and to do so requires a reliable method
for the assignment of structures. A combination of NMR
and IR spectroscopy and X-ray structure determination
has been used to determine the regiochemistry of trap-
ping of the R-lactam 2 by hydrazine nucleophiles to
produce 3 and to identify factors which control the
cyclization of 3 to either 4 or 5.
Received August 13, 1998
In tr od u ction
We recently reported that R-lactams 2 derived from
N-mesyloxymalonamides 1 react with hydrazine deriva-
tives to produce azapeptide analogues 3 which subse-
quently undergo cyclization to 1,2,4-triazine-3,6-diones
4 (Scheme 1).1 The assignment of the triazine structure
to 4 was based on reports in the literature of similar
cyclizations which gave the six-membered ring products.2
There were also some reports in the literature that some
compounds originally assigned as 1,2,4-triazine-3,6-di-
ones were actually 3-aminohydantoins 5.3 The primary
means for distinguishing these two structural isomers
has been IR spectroscopy. The IR assignments were first
developed from a series of analogues3a and later cor-
roborated by synthesis.4 One difficulty in the assign-
ments is that 4 can be converted to 5 under several
reaction conditions.3a
Resu lts a n d Discu ssion
As reported previously, reaction of 1,1-dibenzylhydra-
zine and 1a gave the open-chain product 3a which did
not undergo ring closure under the reaction conditions.1
Treatment of 3a with sodium hydride in THF gave
cyclization as evidenced by disappearance of the ethoxy
1
group protons in the H NMR and the appearance of IR
bands at 1780 and 1724 cm-1. Because there is only one
possible mode of cyclization, 3-(N,N-dibenzylamino)-
hydantoin 5a must be the product structure (eq 1).
The heterocyclic core of 4 has potential utility as a
scaffold for the construction of â-turn mimics.1 Since the
hydantoin core of 5 is biologically active in a variety of
contexts,5 5 itself is also of potential biological interest.
† New Mexico State University.
‡ University of Texas at El Paso. (Direct inquiries about X-ray
structure determinations to this author.)
Reaction of 1a with 1,2-dibenzylhydrazine gave the
open-chain analogue 3b which was cyclized to the triaz-
inedione 4a , again the only cyclization product possible.
In this case, the loss of the ethoxy group protons in the
NMR and the ester carbonyl group at 1730 in the IR was
accompanied by the appearance of an IR band at 1680
cm-1 and no other bands in the carbonyl region above
1700 cm-1. The carbonyl carbons of 4a gave two signals
at δ 155.7 and 167.8. These signals could be assigned
from their splitting patterns of the nondecoupled 13C
NMR spectrum. The signal at δ 167 was a broadened
triplet (J C-H ) 60 Hz) from vicinal splitting of the amide
carbonyl carbon by the protons at C-5. The signal at δ
155 was a broadened multiplet without resolved split-
tings (J C-H < 20 Hz) from vicinal splitting of the urea
(1) Hoffman, R. V.; Nayyar, N. K. J . Org. Chem. 1995, 60, 5992.
(2) (a) Lindenmann, A.; Kahn, N. H.; Hofmann, K. J . Am. Chem.
Soc. 1952, 74, 476. (b) Milne, H. B., S. L.; Bayer, R. P.; Fish, D. W. J .
Am. Chem. Soc. 1960, 82, 4582. (c) Baudet, P.; Calin, M. Helv. Chim.
Acta 1972, 52, 282. (d) Kraatz, U.; Wamhoff, H.; Korte, F. Leibigs Ann.
Chem. 1972, 758, 177.
(3) (a) Gut, J .; Novacek, A.; Fiedler, P. Collect. Czech. Chem.
Commun. 1968, 33, 2087. (b) Wright, G. C.; Michels, J . G.; Spencer,
C. F. J . Med. Chem. 1969, 16, 379. (c) Schwan, T. J .; Sanford, T. J . J .
Heterocycl. Chem. 1979, 16, 1655. (d) Lalezari, I.; Stein, C. A. J .
Heterocycl. Chem. 1984, 21, 5. (e) Lalezari, I. J . Heterocycl. Chem. 1985,
22, 741.
(4) Schwan, T. J . J . Heterocycl. Chem. 1983, 20, 547.
(5) (a) Marton, J .; Enisz, J .; Hosztafi, S.; Timar, T. J . Agric. Food
Chem. 1993, 41, 148. (b) Dressman, B. A.; Spangle, L. A.; Kaldor, S.
W. Tetrahedron Lett. 1996, 37, 937. (c) DeWitt, S. H.; Kiely, J . S.;
Stankovic, C. J .; Schroeder, M. C.; Cody, D. M. R.; Pavia, M. R. Proc.
Natl. Acad. Sci. 1995, 90, 6909.
10.1021/jo981650c CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/05/1998

Notes
J . Org. Chem., Vol. 63, No. 24, 1998 9129
carbonyl group by the N-methyl and N-benzyl protons
on the flanking nitrogens. Thus the amide resonance is
at a lower field than the urea carbonyl group in triazine
4a (eq 2).
assigned as a 1,2,4-triazine-3,6-dione.1 On the basis of
the IR absorptions, this product must be hydantoin 5b,
which was confirmed by an X-ray crystal structure.
These results allow the structures of hydrazine-trap-
ping products to be assigned confidently by their IR
spectra. From present and previous results,1 it can be
generalized that monosubstituted hydrazines with bulky
or conjugating groups (Scheme 1, R2 ) H, R3 ) Ar, tert-
alkyl) react regiospecifically at the terminal nitrogen to
give 1-acylated-2-substituted products 3, which cyclize
preferentially to N-aminohydantoin products 5. Simple
monoalkylhydrazines (Scheme 1, R2 ) alkyl, R3 ) H)
react regiospecifically at the internal nitrogen to give
1-acylated 1-alkylhydrazimes, which cyclize to 1,2,4-
triazine-3,6-diones 4. Moreover, 1,2-disubstituted hy-
drazines can give only 4, while 1,1-disubstituted hydra-
zines can give only 5. The synthesis of particular
heterocycles by the application of this chemistry can now
be pursued with confidence.
Reaction of 1a with benzylhydrazine was reported to
give a cyclic product whose IR spectrum had a carbonyl
absorption at 1680 cm-1 and thus could be assigned as a
1,2,4-triazine-3,6-dione.1 Examination of the undecou-
pled 13C spectrum permits the structure to be assigned
specifically as 4b because the amide carbonyl group at δ
163.5 is a clean triplet (J C-H ) 55 Hz), while the urea
carbonyl carbon is a broad multiplet at δ 154.8. Thus,
trapping of the R-lactam by benzylhydrazine takes place
on the internal nitrogen to give 3c, which can only cyclize
to triazinedione 4b (eq 3).
Exp er im en ta l Section
General experimental procedures have been described previ-
ously.1 Compounds 1a , 1b, 3a , 4b, and 5b were prepared as
previously described.1 1,2-Dibenzyl hydrazine was prepared by
a literature procedure.6 IR spectra were taken either as KBr
disks (solids) or as neat films (oils). NMR spectra were recorded
in CDCl3.
P r ep a r a tion of 5a . Azaurea 3a 1 (500 mg, 1.41 mmol) was
added to a suspension of NaH (36 mg, 1.41 mmol) in THF (10
mL) at 0 °C under a blanket of nitrogen. The reaction mixture
was stirred for 1 h at 0 °C and then stirred at room temperature
for 3 h. The solvent was removed under reduced pressure and
ethyl acetate (65 mL), and then water (5 mL) was added to the
residue. The layers were separated, and the organic layer was
dried (MgSO4) and evaporated by rotary evaporation to give 5a
These experiments are consistent with the IR assign-
ments made by Schwann,4 who found that 1,2,4-triazine-
3,6-diones have IR bands near 1680 cm-1. In contrast,
N-aminohydantoins are characterized by a band in the
vicinity of 1780 cm-1 and a second, stronger carbonyl
1
(320 mg, 74%): H NMR δ 2.69 (s, 3H), 3.32 (s, 2H), 4.27 (ABq,
4H, J ) 12 Hz), 7.1 and 7.38 (m, 10H); IR 1780, 1724 cm-1
.
Noteworthy is that the ethoxy group protons are absent, indicat-
ing cyclization has occurred.
absorption at about 1730 cm-1
.
P r ep a r a tion of 3b. A solution of Hunig’s base (2.38 g, 18.38
mmol) in CH2Cl2 (15 mL) was added by syringe pump over 7 h
to a mixture of 1a (2 g, 8.36 mmol) and 1,2-diphenylhydrazine‚
HCl in CH2Cl2 (25 mL). The mixture was stirred for an
additional 8 h at room temperature. The solvent was removed
by rotary evaporation, and EtOAc (60 mL) was added to the
residue. The solution was washed with water (4 × 20 mL) and
brine (20 mL), dried (MgSO4), and filtered through a 1 in. pad
of silica gel. The solvent was removed to give a yellow oil (2.92
g, 97%). The crude product was purified by flash chromatog-
raphy (hexane/ethyl acetate, 6:4) to give 3b as a golden oil (2.0
g, 67%): 1H NMR δ 1.22 (t, 3H, J ) 7 Hz), 2.04 (s, 1H), 3.05 (s,
3H), 3.85 (s, 2H), 4.03 (s, 2H), 4.31 (q, 2H, J ) 7 Hz), 4.53 (s,
2H), 7.29-7.34 (m, 10H).
Reaction of N-cyclohexyl hydroxamate derivative 1b
with benzylhydrazine gave a cyclized product with IR
absorptions at 1693 and 1656 cm-1. On the basis of the
above spectral correlations, the structure is assigned as
triazine 4c (eq 4). This was proven to be the case by an
X-ray crystal structure, which confirms both the nucleo-
philic trapping by the internal nitrogen of the benzylhy-
drazine and the lack of IR absorptions above 1700 cm-1
for the 1,2,4-triazine-3,6-dione cyclization product.
P r ep a r a tion of 4a . Azaurea 3b (500 mg, 1.41 mmol) was
added to a suspension of NaH (36 mg, 1.41 mmol) in THF (10
mL) at 0 °C under a blanket of nitrogen. The reaction mixture
was stirred for 1 h at 0 °C and then stirred at rt for 3 h. The
solvent was removed under reduced pressure and ethyl acetate
(65 mL), and then water (5 mL) was added to the residue. The
layers were separated, and the organic layer was dried (MgSO4)
and evaporated by rotary evaporation to give 4a . Purification
In contrast, reaction of 1c with tert-butylhydrazine1
gave a cyclic product that had IR absorptions at 1780
and 1724 cm-1 (eq 5). This product was originally
(6) Rosini, G.; Medici, A.; Soverini, M. Synthesis 1979, 789.

9130 J . Org. Chem., Vol. 63, No. 24, 1998
Notes
by flash chromatography (hexane/ethyl acetate, 6:4) gave 4a (300
mg, 69%) as a clear oil: 1H NMR δ 2.83 (s, 3H), 3.34 (s, 2H),
165.0; IR (KBr) 3391, 1693, 1656 cm-1
C16H21N3O2: C, 66.87; H, 7.31; N, 14.63. Found: C, 66.86; H,
7.59; N, 14.65.
.
Anal. Calcd for
4.61 (s, 2H), 4.79 (s, 2H), 7.11-7.29 (m, 10H); IR 1680 cm-1 13C
;
NMR δ 29.6, 49.8, 58.3, 76.7, 127.5, 127.6, 128.2, 128.3, 129.0,
129.1, 129.5, 136.5, 155.7, 167.8. With the proton decoupler
turned off, the 13C signal at δ 167.8 was a broadened triplet (J
) 60 Hz), while the signal at δ 155.7 was a broadened multiplet
(J < 20 Hz). This establishes that the former signal corresponds
to the amide carbonyl group and the latter signal is that of the
urea carbonyl group.
Slow evaporation of a CH2Cl2 solution of 4c gave crystals
suitable for X-ray crystallography.
P r ep a r a tion of 5b. Compound 5b was prepared from 1c
and tert-butylhydrazine as described previously.1 Slow evapora-
tion of a CH2Cl2 solution of 5b gave crystals suitable for X-ray
crystallography.
P r ep a r a tion of 4c. A solution of mesylate 1b7 (765 mg, 2.5
mmol) in THF (15 mL) was added dropwise to a suspension of
NaH (66 mg, 2.75 mmol) in THF (15 mL) at 0 °C. After the
addition was complete, benzylhydrazine (306 mg, 2.5 mmol) in
THF (15 mL) was added dropwise over a period of 20 min. The
reaction mixture was stirred at 0 °C for 1 h and then at rt for
10 h. The solvent was evaporated, and the residue was taken
up in ethyl acetate (50 mL), washed with brine (10 mL), dried
(MgSO4), and evaporated. The crude product was purified by
flash chromatography (hexanes/ethyl acetate, 3:2) to give 4c (203
Ack n ow led gm en t. This work was supported by
Selectide Corporation, a Division of Hoechst Marion
Roussell, with additional funding from the National
Science Foundation (CHE 9520431). The authors thank
Dr. Marcel Patek of Selectide Corporation for very
helpful discussions.
1
Su p p or tin g In for m a tion Ava ila ble: The H NMR spec-
tra of 3b and 5a and the 13C NMR spectrum of 4a which
establish purity for these compounds, and the ORTEP struc-
tures and X-ray data for 4c and 5b (17 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
1
mg, 71%): mp 130-131 °C; H NMR δ 1.0-1.9 (br s, 10H), 3.6
(s, 2H), 4.0-4.2 (m, 1H), 4.7 (s, 2H), 7.3 (s, 5H), 9.1 (br s, 1H);
13C NMR δ 25.9, 30.1, 44.4, 51.7, 54.2, 128.6, 128.9, 135.9, 155.4,
(7) Prepared by the reported procedure: Hoffman, R. V.; Nayyar,
N. K. J . Org. Chem. 1995, 59, 3530 and Hoffman, R. V.; Nayyar, N.
K.; Chen, W. J . Org. Chem. 1995, 60, 4121 from ethyl malonyl chloride
and N-cyclohexylhydroxylamine (Aldrich).
J O981650C