Petasis boronic acid-Mannich reactions of substituted hydrazines: Synthesis of α-hydrazinocarboxylic acids

Article abstract of DOI:10.1016/S0040-4039(02)01511-3

N-1-(Carbamate protected)-N-2-(alkyl or aryl substituted) hydrazines can serve as amine substrates for the Petasis boronic acid-Mannich reaction, providing a practical synthetic route for the preparation of α-hydrazinocarboxylic acids. The scope and limitations of this method have been examined.

Full text of DOI:10.1016/S0040-4039(02)01511-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6845–6847
Petasis boronic acid–Mannich reactions of substituted
hydrazines: synthesis of a-hydrazinocarboxylic acids†
David E. Portlock,a,* Dinabandhu Naskar,b Laura Westa and Min Lia
aCombinatorial Chemistry Section, Procter & Gamble Pharmaceuticals, Health Care Research Center,
8700 Mason Montgomery Road, Mason, OH 45040, USA
bChembiotek Research International, Block BN, Sector-V, Salt Lake City, Calcutta 700 091, India
Received 9 May 2002; revised 17 July 2002; accepted 18 July 2002
Abstract—N-1-(Carbamate protected)-N-2-(alkyl or aryl substituted) hydrazines can serve as amine substrates for the Petasis
boronic acid–Mannich reaction, providing a practical synthetic route for the preparation of a-hydrazinocarboxylic acids. The
scope and limitations of this method have been examined. © 2002 Published by Elsevier Science Ltd.
as antibiotics,9 protease inhibitors,10 antivirals,11 and
chiral a-amino acids.12 In this letter, we report a mild,
practical, and novel method for the synthesis of a-
hydrazinocarboxylic acids using the Petasis boronic
acid–Mannich reaction.
The Petasis boronic acid–Mannich reaction is a practi-
cal method for the preparation of a-amino acids.1,2
Furthermore, it has been used for the synthesis of
combinatorial libraries, because a wide variety of
amines and aryl boronic acids can be readily condensed
in a multi parallel fashion on solid supports.3 Indeed,
the Petasis boronic acid–Mannich reaction is ideally
suited for combinatorial chemistry because: (1) it is a
multi-component condensation;4 (2) an increasing vari-
ety of boronic acids and amines are commercially avail-
able, and (3) it proceeds at ambient temperature in a
wide range of solvents. The reaction is most efficient
with alkenyl and electron-rich aromatic boronic acids,
secondary amines, and sterically hindered primary
amines, although anilines, unprotected amino acids,
and peptides can also participate.1a,b Due to our inter-
ests in a-hydrazinocarboxylic acids as building blocks
for the synthesis of combinatorial libraries of heterocy-
cles for drug discovery,5 we have investigated the scope
and limitations of using substituted hydrazines as
amine components in the Petasis boronic acid–Mannich
reaction. To our knowledge hydrazines have not previ-
ously been studied as substrates for this reaction.1–3
Substituted hydrazines were prepared by two methods
(Scheme 1). Various aldehydes were condensed with
BocNHNH2 and the resulting hydrazones 1 were
reduced either by catalytic hydrogenation or NaBH3CN
to provide a series of Boc-protected alkyl substituted
hydrazines 3 (R1=t-BuO; R2=alkyl).13 Alternatively,
commercially available heteroaryl- or phenylhydrazines
2 (Y=H, NO2) were regioselectively protected to
provide N-1-Boc-N-2-(substituted aryl)-hydrazines 3
(R1=t-BuO; R2=aryl).14
a
BocNHN CHR
BocNHNH2
1
b
R2
H
Methods for the preparation of a-hydrazinocarboxylic
acids have received considerable attention due to their
wide utility as building blocks for the synthesis of
b-turn,6 g-turn,7 and a-helix8 peptidomimetics, as well
R1
N
N
c
H2NNH
Y
H
O
3
2
Scheme 1. General routes to alkyl and phenyl substituted
hydrazines. Reagents and conditions: (a) RCHO, abs. EtOH;
(b) H2, 10% Pd–C, abs. EtOH or NaBH3CN, p-TsOH, THF;
(c) (Boc)2O, Et2O.
* Corresponding author. E-mail: portlockde@pg.com
This paper is dedicated to the memory of Professor Henry Rapo-
port, who (over many years) provided valuable insight and practical
advice to our combinatorial chemistry projects.
†
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01511-3

6846
D. E. Portlock et al. / Tetrahedron Letters 43 (2002) 6845–6847
A variety of these substrates 3 were then subjected to
standard Petasis boronic acid–Mannich reaction con-
ditions, i.e. 1 equiv. each of 3, glyoxylic acid mono-
hydrate, and an organoboronic acid stirred at
ambient temperature in CH2Cl2 for 48 h (Table 1).15
When R1=t-BuO and R2=alkyl (4a–g), these reac-
tions proceeded in satisfactory yields ranging from 60
to 99% after purification by flash chromatography. In
the examples explored, yields did not vary appreciably
due to variation of the arylboronic acid (4a–c and
4d–e). Remarkably, when R1=t-BuO and R2=
phenyl, 4h was obtained in 99% yield. In this case,
the reacting nitrogen atom is a poor nucleophile,
because it is aniline-like and further deactivated
inductively by the adjacent carbamate group. How-
ever, 4-nitrophenyl substituted hydrazine 3j, which is
further deactivated by an electron withdrawing substi-
tutent, produced 4j in only modest yield (LC-MS,
34%). Similarly, 3k failed to give any of the desired
product, 4k (LC-MS).
Table 1. Petasis boronic acid–Mannich reactions of substituted hydrazines

D. E. Portlock et al. / Tetrahedron Letters 43 (2002) 6845–6847
6847
Since building blocks of structure 4 (R2=H) were of
interest to us for combinatorial library production,5 we
wondered if they could be prepared from the unsubsti-
tuted hydrazine, 3 (R1=t-BuO; R2=H). However,
when BocNHNH2 was subjected to the same Petasis
boronic acid–Mannich reaction conditions, a complex
mixture of products was obtained (LC-MS). Neverthe-
less, the desired product 4l could be prepared in 71%
yield by first pre-forming the presumed intermediate,
BocNHNꢀCHCO2H and then adding an aryl boronic
acid in CH2Cl2 at ambient temperature. Furthermore,
4l could also be obtained by catalytic debenzylation of
4g. Using this protective group strategy, 4l was
obtained (H2 balloon, 10% Pd–C, abs. EtOH) in 71%
yield after purification by flash chromatography. As
expected, the Boc group in 3 could be replaced by a
CBZ, e.g. 4m was obtained cleanly in 60% yield. And
finally, the commercially available semicarbazide 3n
was examined. Although the expected product 4n was
obtained, the yield was poor (LC-MS, 20%) and formed
as a complex mixture of products.
7. Ferguson, M. D.; Meara, J. P.; Nakanishi, H.; Lee, M.
S.; Kahn, M. Tetrahedron Lett. 1997, 38, 6961.
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In summary, we have demonstrated that N-1-(carba-
mate protected)-N-2-(alkyl or aryl substituted) hydrazi-
nes can serve as amine substrates for the Petasis
boronic acid–Mannich reaction providing a practical
synthetic route for the preparation of a-hydrazinocar-
boxylic acids. Further studies related to the utility of
products 4 as intermediate building blocks for a tandem
Petasis-Ugi multicomponent condensation have been
disclosed16 and complete experimental details will be
reported in due course.
12. (a) Oguz, U.; Guilbeau, G. G.; McLaughlin, M. L.
Tetrahedron Lett. 2002, 43, 2873; (b) Burk, M. J.; Mar-
tinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron 1994,
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References
15. General procedure for the Petasis boronic acid–Mannich
reaction of substituted hydrazines 3 to prepare a-hydrazi-
noacids 4: to a stirred mixture of glyoxylic acid monohy-
drate (0.41 g, 4.4 mmol) in CH2Cl2 (23 mL) was added
N-1-Boc-N-2-(cyclohexylmethyl)-hydrazine (1.0 g, 4.4
mmol) followed by 4-methoxyphenylboronic acid (0.67 g,
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temperature for 48 h and after this time, the CH2Cl2 was
removed under reduced pressure. The residue was
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purified
by
chromatography
(silica
gel,
40%
EtOAc:hexanes) to give 1.75 g (99%) of 4a as a hydro-
scopic white solid: Rf=0.18 (50% EtOAc:hexanes); ana-
lytical HPLC: Polaris C18 column (4.6×250 mm, 3
micron particle size), mobile phase 0.1% aqueous phos-
phoric acid/CH3CN linear gradient over 30 min, 1 mL/
min, one peak detected by ELS and UV at 215 nm,
tR=18.4 min; H NMR (CDCl3, 300 MHz): l 0.75–1.80
(m, 11H), 1.40 (s, 9H), 2.40–2.65 (m, 2H), 3.84 (s, 3H),
4.57 (s, 1H), 5.2 (br s, 1H), 6.93 (d, 2H), 7.21 (d, 2H); C
NMR (CDCl3, 75 MHz): l 26.21, 26.29, 26.76, 28.40,
31.43, 31.67, 35.86, 55.57, 72.60, 72.89, 82.21, 114.42,
131.31, 131.76, 157.26, 160.19, 172.69; LCMS (ELSD):
393 (M+H+).
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