Convenient synthesis of monobenzylated hydrazides via aqueous zinc-mediated addition reactions

Article abstract of DOI:10.1080/00397911.2013.851245

Addition of substituted benzyl bromides to dialkyl azodicarboxylates under aqueous zinc-mediated addition conditions occurs readily to afford monobenzylated hydrazides in good to excellent yields. The reaction is tolerant of a variety of substituents on the benzyl bromide ring. Several dialkyl azodicarboxylates were successfully tested under the reaction conditions. The limitations of the reaction are also addressed.

Full text of DOI:10.1080/00397911.2013.851245

Synthetic Communications®, 44: 1128–1136, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.851245
CONVENIENT SYNTHESIS OF MONOBENZYLATED
HYDRAZIDESVIA AQUEOUS ZINC-MEDIATED
ADDITION REACTIONS
Gary W. Breton
Department of Chemistry, Berry College, Mount Berry, Georgia, USA
GRAPHICAL ABSTRACT
Abstract Addition of substituted benzyl bromides to dialkyl azodicarboxylates under
aqueous zinc-mediated addition conditions occurs readily to afford monobenzylated
hydrazides in good to excellent yields. The reaction is tolerant of a variety of substituents on
the benzyl bromide ring. Several dialkyl azodicarboxylates were successfully tested under the
reaction conditions. The limitations of the reaction are also addressed.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Aqueous; azodicarboxylate; hydrazide; zinc
INTRODUCTION
The aqueous zinc-mediated addition reaction of allyl halides to appropriate
electrophiles (e.g., aldehydes, ketones, activated imines, nitroalkenes) has proven to
be a convenient and powerful method in organic synthesis (Scheme 1).[1] Conducting
such reactions under aqueous conditions rather than the typical anhydrous conditions
required by most organometallic reactions has the obvious advantage of simplify-
ing reaction setup (i.e., no prior drying of reagents, solvents, and reaction glassware
is necessary) but also requires less organic solvent, thereby generating less chemical
waste.[1] Although first discovered in 1978, advances in these metal-mediated aqueous
Received September 2, 2013.
Address correspondence to Gary W. Breton, Department of Chemistry, Berry College, Mount
Berry, GA 30101, USA. E-mail: gbreton@berry.edu
1128

CONVENIENT SYNTHESIS OF MONOBENZYLATED HYDRAZIDES
1129
Scheme 1. General aqueous aqueous Zn°-mediated addition reactions of allyl bromide with aldehydes
and ketones.
Scheme 2. Typical result from aqueous Zn°-mediated addition reactions of benzyl bromide with aldehydes
and ketones.
reactions continue even today.[1,2] Curiously, however, while allyl halides react readily
under these conditions, benzyl halides are poor substrates, preferring to undergo
net protonation and or Wurtz-type coupling rather than addition to electrophiles
(Scheme 2).[3] A few recent advances have been made in the utilization of benzyl
halides in such reactions, but these require the addition of expensive and/or toxic
cocatalysts to promote reactivity.[3a,4]
Our recently reported studies on the synthesis of 2,3-dihydro-1H-indazoles
(3) required the selective formation of monobenzylated hydrazides 2a (Scheme 3).[5]
We were frustrated by the tendency of di-tert-butyl hydrazodiformate (1) to form
bisalkylated hydrazides 2b (Fig. 1) rather than the desired monoalkylated hydrazides
Scheme 3. Synthetic route for 2,3-dihydro-1H-indazoles (3).
Figure 1. Structure of undesired bisalkylated hydrazides.

1130
G. W. BRETON
2a even though we utilized reaction conditions previously optimized by Rasmussen
for its monoalkylation.[6] Others have struggled with similar problems of competing
overalkylation in the reactions of hydrazines and their hydrazide derivatives.[6,7]
Preformation of the hydrazide monoanion of 1 prior to the SN2 step has been
suggested to favor monoalkylation over bisalkylation,[7b,8] but this solution is appar-
ently not global.[8d] Given the importance of monoalkylated hydrazides in organic
synthesis,[6,7,9] it is not surprising that the pursuit of methods to synthesize these
compounds is still under active investigation.[6–10]
A few examples of the synthesis of monobenzylated hydrazides via the addition
of benzyl organometallics to dialkyl azodicarboxylates have been reported.[11] However,
these studies were all conducted under typical anhydrous conditions. Furthermore, we
could find no studies that investigated the scope of the reaction. It would be beneficial
if these reactions were amenable to being conducted under the aqueous zinc-mediated
conditions discussed above. Upon investigation, we are delighted to report that benzyl
substrates can be successfully added to dialkyl azodicarboxylates under aqueous zinc-
mediated conditions to afford the desired monobenzylated hydrazides in good to excel-
lent yields despite their previously reported reluctance to react under similar conditions.[3]
DISCUSSION
To initially test for reactivity, 1mmol of benzyl bromide in 2 mL of tetrahy-
drofuran (THF) was added to a stirring mixture of 1 equivalent each of Zn metal and
di-tert-butyl azodicarboxylate (4) in 1 mL of saturated aqueous NH4Cl (Scheme 4).
After 3h the reaction mixture was filtered to remove zinc salts that had formed.
Analysis of the crude reaction mixture by 1H NMR spectroscopy revealed an approx-
imate 50/50 mixture of monoalkylated hydrazide 5a and starting benzyl bromide. In
addition to remaining 4 there was also hydrazide 1, apparently formed from direct
reduction of 4 by the zinc metal. A control reaction demonstrated that 4 does indeed
react quantitatively with zinc metal under the reaction conditions in the absence of
benzyl bromide to form 1. To counteract this competing reaction, the amounts of
4 and zinc were increased. A 1:2:2 reaction mixture of benzyl bromide, 4, and zinc
under identical reaction conditions afforded a 3:1 mixture of 5a to benzyl bromide,
suggesting that most, but not all, of the starting benzyl bromide was able to compete
with 4in its reaction with zinc. Finally, increasing the amount of zinc to 3 equivalents
(overall 1:2:3 ratio of benzyl bromide–4–zinc) resulted in complete consumption of
starting material and addition product 5a was afforded in 91% isolated yield (see
Table 1). Given this success, a series of benzyl bromides was subjected to identical
reaction conditions (method A). The results are compiled in Table 1. In general, good
Scheme 4. Reaction of benzyl bromide with 4 and Zn° under aqueous Zn-mediated conditions.

CONVENIENT SYNTHESIS OF MONOBENZYLATED HYDRAZIDES
1131
Table 1. Aqueous Zn°-mediated addition reaction of substituted benzyl bromides to di-tert-butyl
azodicarboxylate (4)
Yield (%)
Entry
1
Substrate
Product
Method Aa
91
Method Bb
92
5a
2
3
5b
5c
88
74
4
5
6
5d
5e
5f
86
86
79
7
8
5g
5h
99
74
9
5i
5j
NDc
81
10
74
(Continued )

1132
G. W. BRETON
Table 1. Continued
Yield, %
Entry
11
Substrate
Product
Method Aa
Method Bb
79
5k
77
12
13
5l
NDc,d
5m
28e
a1:2:3 mixture of benzyl bromide–4–Zn°.
b2:1:2 mixture of benzyl bromide–4–Zn°.
cNone detected.
dOnly dimerized product was observed.
eConducted in aqueous K2HPO4 rather than NH4Cl.
to excellent yields of the anticipated monobenzylated hydrazides were obtained. The
reaction was tolerant of the presence of a variety of substituents on the aromatic
ring including alkyl groups (entries 2 and 3), various halogens (entries 4–6), the meth-
oxy group (entry 7), and the carbomethoxy group (entry 8). The presence of a nitro
group (entry 9), however, suppressed the reaction. In addition to the starting mate-
rial, several minor products were observed as well as hydrazide 1, but no evidence for
formation of any appreciable amount of product 5i was observed from the 1H NMR
spectrum of the crude reaction mixture or by thin-layer chromatographic (TLC)
analysis.
Although reaction was successful with 3-carbomethoxybenzyl bromide (entry 8)
employing method A, we found it difficult to cleanly separate the hydrazide product
5h from by-product 1 using column chromatography. Therefore, an alternative method
was developed to limit the formation of 1. According to this method (method B) an
excess of substituted benzyl bromide (2mmol) was added to a single equivalent of 4in
the presence of Zn (2mmol). The lesser amount of hydrazide 1 by-product formed
by this method allowed for much easier purification of the desired addition products.
We tested this method on a few other substrates and observed comparable results to
those using method A (entries 1, 10, and 11).
The secondary bromide (1-bromoethyl)benzene also underwent reaction suc-
cessfully (entry 11) to afford 5k. The major by-product observed was the dimeric
compound 2,3-diphenylbutane. In contrast, bromodiphenylmethane (entry 12) failed
to yield any of the desired hydrazide product 5l. The only product observed resulted
from dimerization of the bromide to form 1,1,2,2-tetraphenylethane. We attempted

CONVENIENT SYNTHESIS OF MONOBENZYLATED HYDRAZIDES
1133
Scheme 5. Aqueous Zn°-mediated addition of benzyl bromide to other dialkyl azodicarboxylates.
to minimize the dimerization process by slow addition (via syringe pump) of a THF
solution of the bromide to a stirring mixture of 4 and Zn° in saturated aqueous
NH4Cl without success. Similarly, slow addition of a premixed THF solution of the
bromide and 4 to the Zn° did not afford the addition product. Perhaps because of
its large tert-butyl groups, 4 is simply too sterically hindered of an electrophile to
accept such a sterically hindered intermediate generated from this particular benzyl
bromide.
3-Bromomethylpyridine (used as the HBr salt) was unreactive under the reac-
tion conditions of method A (96% of starting 4 was accounted for as a 6:1 mixture of
1 to unreacted 4). We suspected that the acidic aqueous ammonium chloride condi-
tions were responsible. We tried conducting the reaction under basic conditions pre-
viously developed by Bieber et al. (1.5g K2PO4/1.5 mL water/THF)[3a] but observed
only trace amounts of product 5m. Addition of a catalytic amount of AgNO3 to
enhance reactivity (also according to the Bieber procedure)[3a] resulted in complete
consumption of the pyridine substrate and isolation of 5m in a poor 28% yield. The
1
major by-product (by H NMR analysis of the crude reaction mixture) appeared to
be 3-methylpyridine, resulting from protonation of the radical anion.
In addition to azodicarboxylate 4, the reaction was also successful (method A,
Scheme 5) using the electrophiles diethyl azodicarboxylate (to afford 6, 68% yield), diiso-
propyl azodicarboxylate (7, 97% yield), and dibenzyl azodicarboxylate (8, 71% yield).
All of these reactions were significantly faster (<30min for loss of the characteristic
yellow color of the azodicarboxylate) than the corresponding reactions with 4, conceiv-
ably due to the lesser amount of steric hindrance from their respective CO2R groups.
Finally, allyl bromide was also subjected to the reaction conditions (method B,
Scheme 6) to afford addition product 9in 56% yield. Although only moderate, this
yield compares favorably to the reported yield (50%) obtained by direct allylation of
1 where bisalkylation effectively competes.[7d]
Scheme 6. Aqueous Zn°-mediated addition of allyl bromide to 4.

1134
G. W. BRETON
EXPERIMENTAL
Column chromatography was conducted on silica gel (234–400mesh) using
compound-appropriate mixtures of hexanes and EtOAc as eluent. Thin-layer chro-
matography was performed on precoated silica-gel plates (250mm) and visualized by
ultraviolet light and/or by visualization with I2 vapor. The I2 vapor was especially
helpful for visualizing the reduced unsubstituted hydrazides. 1H and 13C NMR spec-
tra were obtained on a 400-MHz NMR spectrometer unless otherwise specified, and
were generally collected at 60°C to simplify the spectra which are terribly complicated
at room temperature due to conformational restrictions. Chemical shifts are reported
in units of parts per million downfield from tetramethylsillene (TMS). Elemental
analyses were performed by a commercial laboratory. High-resolution mass spec-
tral (HRMS) analysis was performed via gas chromatography (GC)–MS (TOF EI).
Diethyl azodicarboylate (DEAD) was synthesized via N-bromosuccinimide (NBS)
oxidation of the corresponding commercially available hydrazide and purified by
column chromatography immediately prior to use.[12] All other chemicals and solvents
were obtained from commercial sources and used without further purification.
General Procedure: Method A
To 0.195g (3mmol) of Zn metal in 1mL saturated aqueous NH4Cl solution
was added 0.46g (2mmol) of 4. Stirring was begun and a solution of the appropriate
benzyl bromide (1mmol) in 2mL of THF was added via pipette. The reaction vessel
was capped and the mixture allowed to stir until the yellow color of 4 was discharged
(generally ~3h). The reaction mixture was filtered through a plug of glass wool into
a centrifuge tube. The organic layer was removed. The aqueous layer was washed
2×2mL of THF. The combined organic layers were dried over Na2SO4, filtered, and
concentrated. Column chromatography on SiO2 using appropriate mixtures of ethyl
acetate and hexanes provided the desired compounds.
General Procedure: Method B
To 0.13g (2mmol) of Zn metal in 1mL saturated aqueous NH4Cl solution was
added 0.23g (1mmol) of 4. Stirring was begun and a solution of the appropriate
benzyl bromide (2mmol) in 2mL of THF was added via pipette. The reaction vessel
was capped and the mixture allowed to stir until the yellow color of 4 was discharged
(generally ~3h). The reaction mixture was filtered through a plug of glass wool into
a centrifuge tube. The organic layer was removed. The aqueous layer was washed
2×2mL of THF. The combined organic layers were dried over Na2SO4, filtered, and
concentrated. Column chromatography on SiO2 using appropriate mixtures of ethyl
acetate and hexanes provided the desired compounds.
N-Benzyl-N’-[(tert-butoxy)carbonyl] (tert-butoxy)
carbohydrazide (5a)[6,11b–d]
According to method A, from 0.171g (1mmol) of benzyl bromide was obtained
0.291g (91% yield) of 5a as a white solid: mp 101.8–103.0°C (lit.[11b] 102–104°C); 1H

CONVENIENT SYNTHESIS OF MONOBENZYLATED HYDRAZIDES
1135
NMR (CDCl3, 60°C) δ 7.29–7.25 (m, 5H), 6.33 (br s, 1H), 4.60 (br s, 2H), 1.47 (s, 9H),
1.42 (s, 9H); 13C NMR (CDCl3, 60°C) δ 155.3, 155.1, 137.3, 128.5(2C), 127.5, 81.3,
81.0, 53.7(br), 28.3, 28.2.
FUNDING
This material is based upon work supported by the National Science Foundation
under CHE-1125616. We also thank the Berry College Faculty Development Grant
program for support of this research.
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR spectra for all synthesized
compounds can be found via the Supplementary Content section of this article’s
Web page.
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