Acyl hydrazines as precursors to acyl radicals

Article abstract of DOI:10.1016/S0040-4020(02)00490-8

The use of acyl hydrazines (hydrazides) as precursors for the stoichiometric generation of acyl radicals is explored. Two classes of substrates are examined: unsubstituted acyl hydrazines and acyl hydrazines substituted with a leaving group (2-nitrobenzenesulfonyl or 'nosyl'). Both types are successfully converted to acyl radicals, and are then trapped by nitroxide radicals to give acyloxyamine products. Cyclization reactions are demonstrated for both classes of substrates. A low temperature modification of the McFayden-Stevens reaction is also developed.

Full text of DOI:10.1016/S0040-4020(02)00490-8

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 5513±5523
Acyl hydrazines as precursors to acyl radicals
Rebecca Braslau,p Marc O. Anderson, Frank Rivera, Armando Jimenez, Terra Haddad
and Jonathan R. Axon
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
Received 11 April 2002; accepted 7 May 2002
AbstractÐThe use of acyl hydrazines (hydrazides) as precursors for the stoichiometric generation of acyl radicals is explored. Two classes
of substrates are examined: unsubstituted acyl hydrazines and acyl hydrazines substituted with a leaving group(2-nitrobenzenesulfonyl or
`nosyl'). Both types are successfully converted to acyl radicals, and are then trapped by nitroxide radicals to give acyloxyamine products.
Cyclization reactions are demonstrated for both classes of substrates. A low temperature modi®cation of the McFayden±Stevens reaction is
also developed. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
groups has been reviewed.12 Two distinct categories of
carbohydrazines are considered in this discussion: unsubsti-
tuted (R±NHNH2) and those substituted with a leaving
The use of acyl radical methodology as a tool for the
formation of carbon±carbon bonds, and particularly in the
construction of carbon ring systems has been an important
development in modern synthetic organic chemistry.1
Today a number of successful methods of generating acyl
radicals have been developed, and have been utilized in
organic synthesis. The most widely studied method is the
stannane reduction of selenoesters,2 based on a radical chain
mechanism. Likewise, carbonylation of organohalides in a
tin-mediated chain sequence has been developed by Ryu.3
These methods suffer from toxicity and disposal issues
associated with the use of organotin reagents and their
resulting waste products. A number of techniques have
been developed to circumvent these problems, including
the use of tris(trimethylsilyl)silane,4 water soluble tin
hydride reagents,5 ¯uorous tin hydride reagents,6 and solid
phase tin hydride reagents.7 Other methods of generating
acyl radicals have also been developed that avoid the use
of organotin reagents altogether. Examples of these methods
are the oxidation of aryl diazonium-tethered thioesters8 and
the photolysis of substrates such as thioxanthates,9 acyl
cobalt salen species,10 and telluroesters.11
group(R±NHNH±X or R±NX±NH ).
2
The oxidative conversion of unsubstituted alkyl hydrazines
to alkyl radicals was ®rst demonstrated by Corey et al. in a
strategy for preparing hindered optically active amines
derived from borneol.13 This method of generating radicals
has been used extensively in our laboratory to study stereo-
selective trapping of nitroxides at prochiral carbon
centers,14 and has also been used in the synthesis of
initiators for nitroxide-mediated `living' free-radical poly-
merization.15 Alkyl hydrazines substituted with leaving
groups have also been shown to be precursors to alkyl
radicals: Myers et al. have demonstrated that alkyl hydra-
zines substituted with a 2-nitrobenzenesulfonyl (`nosyl' or
`Ns') groupspontaneously degrade to alkyl radicals.
16
The
mechanism for the generation of alkyl radicals from unsub-
stituted and nosyl-substituted alkyl hydrazines involves the
initial formation of a reactive alkyl diazene17 intermediate
(R±NvN±H) followed by degradation with loss of nitrogen
to afford the carbon radical. There is evidence that acyl
radicals generated from acyl hydrazines may play a part in
the enzyme-mediated mechanism of action of isoniazid, a
widely utilized antituberculosis drug.18
The alkyl or acyl hydrazine functional groupis character-
ized by an N±N single bond connected to an alkyl carbon
atom or a carbonyl group, respectively. Acyl hydrazines are
also known as hydrazides, and the general class of carbon-
substituted hydrazines are also referred to as carbo-
hydrazines. Much is known about the structure and
reactivity of carbohydrazines, and this class of functional
Herein the generation and utilization of acyl radicals from
acyl hydrazine precursors is explored. Acyl hydrazines are
attractive precursors to acyl radicals as they can be prepared
easily from inexpensive reagents, and often exist as stable
crystalline species. Reported here are results in the genera-
tion of acyl radicals from unsubstituted acyl hydrazines and
from nosyl-substituted acyl hydrazines. Direct trapping of
the acyl radicals is ®rst demonstrated, followed by examples
of cyclization reactions.
Keywords: acyl hydrazines; acyl radicals; McFayden±Stevens reaction.
Corresponding author. Tel.: 11-831-459-3087; fax: 11-831-459-2935;
e-mail: braslau@chemistry.ucsc.edu
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00490-8

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R. Braslau et al. / Tetrahedron 58 (2002) 5513±5523
Scheme 1.
2. Results and discussion
lead oxide in the presence of the persistent nitroxide radical
TEMPO (6) to afford acyloxyamine product 7. This result
demonstrated that unsubstituted acyl hydrazines could
indeed be converted to acyl radicals, and spawned the
examination of other substrates. Thus, methyl cyclohexyl-
acetate (8) was cleanly converted to the corresponding
unsubstituted acyl hydrazine (9) using the ester hydrazin-
olysis method, and was then treated with lead oxide and
TEMPO to generate the trapped product (10) in excellent
yield. Next, Cbz-protected valine (11) was converted to the
corresponding Boc-protected acyl hydrazine (12), and was
then deprotected to afford the unsubstituted acyl hydrazine
(13). This compound was reacted with lead oxide and
TEMPO to generate product 14. Multiple chromatographic
separations were required to obtain a pure sample, contri-
buting to the low yield of this example. Lastly, commer-
cially available adipic dihydrazide (15) was subjected to the
same conditions to yield the diacyloxyamine product (16),
albeit in low isolated yield.
2.1. Acyl radicals from unsubstituted acyl hydrazines
The ®rst task at hand was the preparation of unsubstituted
acyl hydrazine substrates. The most commonly reported
method in the literature is the direct hydrazinolysis of
methyl esters. For example, methyl benzoate (1) was reacted
with hydrazine monohydrate to generate benzhydrazide (2)
(Scheme 1). This method is unattractive due to the toxicity
and explosiveness of hydrazine, and because a large excess
is generally required. The use of hydrazine can be circum-
vented by using a two-stepprotocol
19
in which an acyl
group is coupled with Boc-protected hydrazine (tert-butyl-
carbazate 3), followed by deprotection. The alternative
sequence is illustrated by the coupling of this reagent with
benzoic acid (4) to generate Boc-protected acyl hydrazine 5,
which is then deprotected with tri¯uoroacetic acid (TFA) to
yield benzhydrazide (2).
Having demonstrated the simple trapping of acyl radicals
derived from unsubstituted acyl hydrazines, more syntheti-
cally interesting acyl radical cyclization reactions were
then explored. The ®rst substrate examined was derived
from 2-allylbenzoic acid11c (17), and sets the stage for a
The generation of acyl radicals from benzhydrazide and
other simple unsubstituted acyl hydrazines was then investi-
gated (Scheme 2). The conditions employed were based on
those utilized in the generation of alkyl radicals from alkyl
hydrazines.13±15 Thus benzhydrazide (2) was treated with
Scheme 2.

R. Braslau et al. / Tetrahedron 58 (2002) 5513±5523
5515
Scheme 3.
5-exo-trig radical cyclization. This material was prepared in
a few steps by ortho-lithiation and alkylation20 of a phenyl
dimethyloxazoline precursor. The acid (17) was coupled to
Boc-protected hydrazine (3) and then deprotected to afford
the desired unsubstituted acyl hydrazine (18) (Scheme 3).
Treatment of this substrate with lead oxide and TEMPO (6)
followed by silica gel puri®cation led to the isolation of two
products: cyclized a,b-unsaturated ketone 19 and the
undesired directly trapped product 20. Compound 19 is
derived from alkoxyamine product 21, through silica-
catalyzed elimination during puri®cation.
the clean isolation of a,b-unsaturated ketone product 26.
The use of the nitroxide trapTEMPOL instead of less
polar TEMPO was signi®cant, as the latter was found to
co-ellute with the eliminated product during the chromato-
graphic puri®cation. The optimization strategy developed
for this cyclization substrate 23 was then extended for the
prototypical acyl radical trapping reaction and found effec-
tive: when applied to benzhydrazide (2), the acyloxyamine
product (7) was isolated in signi®cantly higher yield (73%)
than that previously obtained (45%).
The next cyclization substrate examined was derived from
2-(2-methallyloxy)-benzoic acid (27), also available from
methyl salicylate.11c This was converted to the acyl chloride,
coupled with Boc-protected hydrazine (3) and deprotected
to give the corresponding unsubstituted acyl hydrazine
substrate (28) (Scheme 5). Attempts at effecting cyclization
of this substrate with lead oxide were unsuccessful, and led
only to isolation of unreacted starting material. This could
not be readily explained, but when other oxidants were
screened, potassium ferricyanide was found to be satisfac-
tory. Thus, treatment of the substrate with potassium ferri-
cyanide and TEMPOL (24) was carried out. The crude
reaction mixture was then treated with sodium l-ascorbate
to reduce residual paramagnetic TEMPOL,21 and the desired
cyclized product (29) was then isolated, in addition to the
product of direct acyl radical trapping (30). Interestingly,
cyclization seems to have occurred exclusively in the 6-exo-
trig mode on the hindered ole®n: no evidence for the
The second substrate examined was derived from
2-allyloxybenzoic acid (22), which can be readily prepared
in two steps from methyl salicylate,11c and was chosen as a
precursor for 6-exo-trig cyclization. Through the standard
sequence, the acid was coupled to Boc-protected hydrazine
(3) and deprotected to yield substrate 23 (Scheme 4).
Considerable effort was made to optimize the cyclization
conditions for this substrate. It was found that slow addition
of the substrate to a sonicated suspension of lead oxide and
nitroxide trap(in this case TEMPOL, 24) gave the greatest
yield of cyclized product. The reasoning behind the use of
these conditions will be addressed in the mechanistic discus-
sion. After carrying out the cyclization, product 25 could not
easily be separated from residual paramagnetic nitroxide,
and this prevented 1H NMR analysis. It was then discovered
that the crude reaction mixture could be heated in the
presence of silica gel to force elimination, allowing for
Scheme 4.

5516
R. Braslau et al. / Tetrahedron 58 (2002) 5513±5523
Scheme 5.
1
7-endo-trig product could be detected by H NMR after
treatment with sodium l-ascorbate. This is consistent with
results obtained in the acyl radical cyclization of analogous
selenoester,2 aryl tethered thioester,8 and telluroester11
substrates. Attempts to cyclize an acyl radical onto a
tethered aryl trapusing 2-hpenoxy benzhydrazide gave
only a trace of the desired product under these oxidative
conditions.
Instead, sonication was performed to enhance interactions
between the substrate (or acyl diazene) and the hetero-
geneous oxidizing agent.
Another problematic side reaction is the formation of the
acyl radical-nitroxide direct-trapped byproduct in the cycli-
zation studies. The extremely fast rate constants with which
nitroxides trapcarbon radicals 25 makes it not surprising that
direct-trapped material is generated in signi®cant quantity.
The use of a slower trap(diphenyl disul®de) was brie¯y
investigated in a cyclization attempt with substrate 22.
Unfortunately the reaction produced a complicated mixture
with only trace formation of the desired cyclized product,
and recovery of the majority of the disul®de trapunreacted.
This suggests that the nitroxide may be involved in the
oxidative conversion of the acyl diazene to the acyl radical
(Scheme 6, step b). This proposal is consistent with studies
on alkyl diazenes, particularly kinetic evidence from Myers
et al. on nosyl-substituted alkyl hydrazines which suggest
that nitroxides accelerate the degradation of alkyl diazenes
to alkyl radicals.16b
The oxidative generation of acyl radicals from unsubstituted
acyl hydrazines is proposed to proceed through the mechan-
ism shown in Scheme 6. The initial stepproceeds via an
overall two-electron oxidation of the substrate to generate
an acyl diazene intermediate (stepa). This intermediate can
react via two different pathways. In the ®rst, a one-electron
oxidation occurs followed by loss of proton (step b) and
liberation of dinitrogen (stepc) to generate the acyl radical.
In the second pathway, another equivalent of starting
material can react through nucleophilic acyl substitution
to generate a 1,2-diacylhydrazine byproduct (step d).22
The addition of nucleophiles to acyl diazenes is a known
reaction, and has been used in peptide synthesis.23 The
formation of the undesired 1,2-diacylhydrazine is particu-
larly problematic as it consumes 2 equiv. of starting
material. Two strategies for decreasing the occurrence of
this side reaction were devised: (a) slow introduction of
the substrate to minimize its concentration during the course
of the reaction, and (b) increasing the rate of the oxidation
events so that stepb is enhanced over stepd to minimize the
formation of 1,2-diacylhydrazine. The ®rst strategy is easily
implemented by syringe pump addition of the substrate. The
second strategy could be pursued by the use of stronger
oxidizing agents. However, this is complicated by the fact
that nitroxides can be oxidized to oxoammonium species.24
2.2. Acyl radicals from nosyl-substituted acyl hydrazines
The second method that was explored for the generation of
acyl radicals utilizes acyl hydrazine substrates substituted
with a leaving group. A key difference between the uses of
unsubstituted acyl hydrazines and substituted acyl hydra-
zines lies in the mechanism for formation of the acyl
diazene intermediate. In the case of the former, the substrate
is oxidized in a two-electron manner to generate the acyl
diazene. This contrasts with the latter, in which the substrate
undergoes elimination to arrive at the same intermediate.
Scheme 6.

R. Braslau et al. / Tetrahedron 58 (2002) 5513±5523
5517
Scheme 7.
Methodology has been previously developed that utilizes
substituted acyl hydrazines outside of the context of radical
chemistry. The McFayden±Stevens reaction converts
toluenesulfonyl (`tosyl')-substituted acyl hydrazines to
aldehydes by brief thermolysis in the presence of base
(Scheme 7).26 This reaction effects a one-stepreduction of
carboxylic acid derivatives to aldehydes, and has been used
as an alternative to hydride reducing agents such as diiso-
butylaluminum hydride (DIBAL) in natural products
synthesis.27,28 The McFayden±Stevens reaction most likely
occurs through an acyl diazene intermediate,26c although a
mechanism for the transformation of the diazene to the
aldehyde has not been ®rmly established.
instead of tosyl was explored (Scheme 8). Benzhydrazide
(2) was allowed to react with 2-nitrobenzenesulfonyl
chloride (31) to generate the corresponding nosyl-substi-
tuted acyl hydrazine (32). In contrast with nosyl-substituted
alkyl hydrazines, which degrade readily even at low
temperature,16 nosyl-substituted acyl hydrazines are surpris-
ingly stable. To test the thermal stability of species 32, it
was dissolved in DMSO-d6 and thermolyzed to 1708C with-
1
out decomposition noted by H NMR. This compound was
then examined in the context of the normal McFayden±
Stevens reaction. It was found that nosyl-substituted acyl
hydrazine 32 could be converted to benzaldehyde by treat-
ment with potassium carbonate at 808C for 2.5 h, a much
lower temperature than the traditional McFayden±Stevens
reaction. The product was then isolated as the 2,4-dinitro-
phenylhydrazone (33).
The ability to access acyl diazene intermediates by base
catalyzed elimination might provide an alternative route to
the generation of acyl radicals. However, the high tempera-
tures employed in the traditional McFayden±Stevens
reaction are unattractive in developing new methodology.
Thus, two goals were established: (a) the development of
lower temperature conditions for the McFayden±Stevens
reaction, and (b) modi®cation of these conditions to give
access to acyl radical intermediates that could either be
trapped or cyclized.
The next goal was to modify these new conditions in a way
that would give access to an acyl radical intermediate
(Scheme 9). Assuming that an acyl diazene is formed tran-
siently, the use of oxidizing conditions should allow the
transformation of this intermediate to the desired acyl radi-
cal (see Scheme 6). Thus the newly developed McFayden±
Stevens conditions were modi®ed further by the addition of
an oxidizing agent and a nitroxide radical trap. When
applied to substrate 32, these conditions produced the
desired outcome: formation of acyloxyamine product 34
via a presumed acyl radical intermediate.
The ®rst goal was pursued by selecting a better leaving
groupthan the tosyl groupnormally used in the McFayden±
Stevens reaction. In work by Myers et al. on generating
alkyl diazenes (and alkyl radicals) from substituted alkyl
hydrazines,16 the nosyl groupwas found to be a highly
effective choice. Indeed, precedent shows that electron-
withdrawing aryl substituents accelerate the elimination of
arylsulfonyl-substituted hydrazines.29 Thus, a variant of the
McFayden±Stevens reaction utilizing the nosyl group
Having demonstrated the generation and simple trapping of
acyl radicals derived from nosyl±substituted acyl hydra-
zines, the ®nal objective was to use these conditions in the
context of acyl radical cyclization (Scheme 10). Two of the
previously utilized cyclization substrates were examined. In
Scheme 8.
Scheme 9.

5518
R. Braslau et al. / Tetrahedron 58 (2002) 5513±5523
Scheme 10.
the ®rst case, compound 23 was cleanly transformed to the
corresponding nosyl-substituted acyl hydrazine 35. The
cyclization of this substrate was attempted several times
without success using the previously established conditions.
It was suspected that the desired cyclized product 25 may
have formed, but then immediately degraded under the
reaction conditions. This is not unreasonable since a variety
of reaction pathways can be envisioned for such a
compound in re¯uxing alkali solution (e.g. base-catalyzed
aldol chemistry). The next logical stepwas to utilize a
substrate in which the product does not bear an a-hydrogen
atom, to prevent enolization or elimination reactions of the
product. Thus, unsubstituted acyl hydrazine 28 was
converted to nosyl-substituted species 36, and then
subjected to the acyl radical generating conditions. The
desired product 29 could be isolated cleanly, although the
isolated yield was low. Very little (,3%) of the direct-
trapped product (30) was isolated in this reaction. Unfortu-
nately, attempts to optimize the yield of this reaction, or to
characterize any side products were not successful.
Solvents for radical trapping experiments were degassed
by passing argon through them for at least 15 min prior
to use. Tetrahydrofuran (THF) was freshly distilled from
sodium/benzophenone ketyl. Sonication was carried out
in a Fisher FS-14 cleaning bath. Slow reagent addition
was performed using a Sage Instruments syringe pump
(model 355) with gas tight Hamilton syringes. Analyti-
cal thin layer chromatography (TLC) was carried out
using plastic plates coated with silica gel 60 F254. The
developed plates were visualized using short wave UV
light (254 nm), and were typically stained in an iodine/
silica chamber and/or using a staining dip(e.g. p-anisal-
dehyde or phosphomolybdic acid) followed by heating
with a heat gun. Flash column chromatography was
performed using Universal Scienti®c Inc. Silica Gel
63-200. NMR spectra were recorded on either a Bruker
ACF dual probe 250 MHz or a Varian 500 MHz spec-
trometer with tetramethylsilane as an internal standard
for proton and the CDCl3 triplet as an internal standard
for carbon. The following abbreviations are used to
describe peak splitting when appropriate: brˆbroad,
sˆsinglet, dˆdoublet, qˆquartet, mˆmultiplet. IR spec-
tra were recorded in CDCl3 solution on a Perkin±Elmer
1600 FTIR spectrometer. High-resolution mass spectro-
scopy was obtained using FAB, CI, or EI on one of
three systems: (a) a Finnegan 4000 spectrometer with
the Super Incos Data System at the University of
Illinois, (b) a VG ZAB-SE reverse geometry spectro-
meter with a VG 11/250 data system at the University
of Illinois, or (c) a Mariner spectrometer from Applied
Biosystems with TOF detection at the University of
California at Santa Cruz. Melting points are
uncorrected.
3. Conclusion
In summary, a new method for the generation of acyl radi-
cals has been developed that utilizes either unsubstituted
acyl hydrazines or nosyl-substituted acyl hydrazines. With
both classes of substrates, the simple generation of acyl
radicals was demonstrated initially, followed by application
to cyclization reactions. This method differs from seleno-
ester, telluroester and carbonylation methodology, in that
the acyl radical is generated in a stoichiometric fashion,
and is trapped by a nitroxide rather than participating in a
radical chain reaction. The use of lead oxide as oxidant was
chosen for convenience in most cases, although the more
environmentally friendly potassium ferricyanide was also
demonstrated to be effective. In the development of these
4.1.1. Benzoic hydrazide (2) by hydrazinolysis of methyl
benzoate. General method A. To a solution of methyl
benzoate (1) (0.2 ml, 1.6 mmol) in methanol (1.1 ml) was
added hydrazine monohydrate (0.32 ml, 6.4 mmol), and the
solution was re¯uxed for 6 h. TLC showed consumption of
the ester starting material and formation of the product.
Solvent was removed in vacuo and the residue was taken
upin EtOAc (20 ml). This was washed with saturated aq.
NaCl (20 ml) and then dried over MgSO4. Solvent was
removed in vacuo to afford a white crystalline solid (mp
conditions,
a
lower-temperature variation of the
McFayden±Stevens reaction was also developed.
4. Experimental
4.1. General
1
109±1138C) (0.193 g, 89%). H NMR (500 MHz, CDCl3):
d 4.11 (bs, 2H), 7.34 (bs, 1H), 7.46 (dt, 2H, Jˆ1.5, 9 Hz),
All reactions were carried out under an atmosphere of argon.

R. Braslau et al. / Tetrahedron 58 (2002) 5513±5523
5519
7.54 (dt, 1H, Jˆ1.5, 9 Hz), 7.75 (dd, 2H, Jˆ1.5, 9 Hz). The
spectroscopic data of this compound matches that of the
commercial material.
Rfˆ0.34. IR (CDCl3): 3450, 1671 cm21
.
1H NMR
(250 MHz, CDCl3): d 0.90±1.29 (m, 6H), 1.68±1.82 (m,
5H), 2.00 (d, 2H, Jˆ7.5 Hz), 3.91 (bs, 2H), 6.65 (bs, 1H).
13C NMR (63 MHz, CDCl3, APT): d 26.1 (CH2), 33.2
(CH2), 35.2 (CH), 42.6 (CH2), 173.3 (Cquat). LRMS (electro-
spray 1): found [M11]ˆ157.
4.1.2. Benzoic hydrazide (2) by a two step coupling
sequence from benzoic acid. General method B. To a
solution of benzoic acid (4) (0.185 g, 1.51 mmol) in
CH2Cl2 (15 ml) was added tert-butyl carbazate (3)
(0.204 g, 1.54 mmol) followed by 1-(3-dimethylaminopro-
pyl)-3-ethylcarbodiimide hydrochloride (aka EDCI or
WSC-HCl) (0.297 g, 1.55 mmol), and the mixture was
allowed to stir at rt overnight. TLC showed consumption
of benzoic acid and formation of the product. CH2Cl2 was
then added (15 ml) and the organic solution was washed
sequentially with saturated aq. NaHCO3 (3£15 ml) followed
by saturated aq. NaCl (15 ml), and then dried over MgSO4.
Removal of solvent in vacuo yielded benzoic [N-(tert-
butoxycarbonyl)]-hydrazide (5) as a white crystalline solid
(mp144±146 8C) (0.329 g, 92%). This material was used in
the next stepwithout further puri®cation or characterization.
4.1.5. (2,2,6,6-Tetramethyl-1-piperidinyloxy)-cyclohexyl-
acetate (10). General method C (unoptimized). A suspen-
sion of cyclohexylacetic hydrazide (9) in degassed toluene
(0.3 ml) was added slowly by syringe to a stirred suspension
of TEMPO (6) (0.048 g) and PbO2 (0.297 g, 1.25 mmol) in
degassed toluene (0.3 ml), and then the trace contents of the
syringe were washed in with additional degassed toluene
(0.3 ml). The suspension was allowed to stir at rt overnight,
and then the product was ®ltered through celite with
CH2Cl2, and solvent was removed in vacuo to yield the
product as a slightly amber oil (0.081 g, 93%). TLC: 4:1
hexane/EtOAc, UV, I2, PMA stain, Rfˆ0.77 (white by
PMA). IR (CDCl3): 1752 cm21 1H NMR (250 MHz,
.
CDCl3): d 0.97±1.90 (m, 29H), 2.31 (d, 2H, Jˆ6.5 Hz).
13C NMR (63 MHz, CDCl3, APT): d 17.2 (CH2), 20.7
(CH3), 26.2 (CH2), 26.3 (CH2), 32.2 (CH3), 33.4 (CH2),
34.8 (CH), 39.1 (CH2), 40.9 (CH2), 60.0 (Cquat), 172.7
(Cquat). HRMS calcd for C17H31NO2 [M1H]ˆ282.2433,
found [M1H]ˆ282.2433.
Solid benzoic [N-(tert-butoxycarbonyl)]-hydrazide (5)
(0.133 g, 0.56 mmol) was cooled to 08C and tri¯uoroacetic
acid was carefully added (1 ml). The mixture was allowed to
stir from 08C to rt, over 1 h. TLC showed consumption of
the Boc-protected acyl hydrazine and formation of the
product. Aq. saturated NaHCO3 was added (5 ml) and the
product was extracted with CH2Cl2 (3£10 ml). The organic
layer was dried over MgSO4, and then removal of solvent in
vacuo yielded the product as a white crystalline material:
mp110±112 8C (0.040 g, 53%). The spectroscopic data of
this product matches that of the commercially available
material.
4.1.6. N-Carbobenzyloxy-l-valine hydrazide (13). Using
general method B, N-carbobenzyloxy-l-valine (0.250 g,
0.995 mmol) was converted to the title compound as a
white wax-like solid (0.096 g; 58% yield ®rst step, 94%
1
yield second step). H NMR (250 MHz, CDCl3): d 0.83 (t,
6H, Jˆ5 Hz), 1.93±1.82 (m, 1H), 2.50 (s, 3H), 3.34 (s, 3H),
3.73 (t, 1H, Jˆ7.5 Hz), 4.23 (d, 2H), 5.01 (s, 2H), 7.4±7.22
(m, 9H), 9.13 (br s, 1H). The spectroscopic data of this
compound matches the literature.30
4.1.3. (2,2,6,6-Tetramethyl-1-piperidinyloxy)-benzoate
(7), using optimized conditions shown in Scheme 4. A
mixture of benzhydrazide (2) (0.066 g, 0.485 mmol) in
degassed toluene (1.6 ml) was prepared and a few drops
of methanol was added to aid in solubility. This was then
added slowly by syringe to a sonicated suspension of PbO2
(0.541 g, 1.941 mmol) and 2,2,6,6-tetramethylpiperidinyl-
oxy radical (TEMPO) (0.083 g, 0.534 mmol) in degassed
toluene (1.6 ml), over a period of 30 min, and then the
trace contents of the syringe were washed in with additional
degassed toluene (1.6 ml). The suspension was allowed to
sonicate an additional 30 min, and was then allowed to stir
at rt overnight. The suspension was ®ltered through celite
with CH2Cl2, and solvent was removed in vacuo to yield the
product as a slightly yellow oil (0.092 g, 73%). TLC: 1:3
hexane/EtOAc, UV, I2, ninhydrin stain, Rfˆ0.34. IR
4.1.7.
N-(Carbobenzyloxy)-O-(2,2,6,6-tetramethyl-1-
piperidinyl)-l-valine (14). Using general method C,
N-carbobenzyloxy-l-valine hydrazide (13) (67 mg,
0.254 mmol) was converted to the crude product (42 mg,
43% yield). This was further puri®ed by preparative TLC
(4:1 hexane/EtOAc) to yield the title compound (0.009 g,
9%). TLC: 4:1 hexane/EtOAc, UV, Rfˆ0.5. IR (CDCl3):
.
1H NMR (500 MHz,
1758.5, 1721.2, 1224.9 cm21
CDCl3): d 0.96 (d, 6H, Jˆ7 Hz), 1.06 (d, 6H, Jˆ6.5 Hz),
1.16 (br s, 6H), 1.76±1.37 (m, 6H), 2.28±2.21 (m, 1H), 4.40
(dd, 2H, Jˆ5, 10 Hz), 5.14 (s, 2H), 5.28 (d, 1H, Jˆ10 Hz),
7.39±7.30 (m, 5H). 13C NMR (125 MHz, CDCl3, APT): d
17.0 (CH2), 17.3 (CH3), 19.8 (CH3), 20.6 (CH3), 20.8 (CH3),
31.2 (CH), 32.1 (CH2), 39.2 (CH3), 39.4 (CH3), 58.5 (CH),
60.3 (Cquat), 60.6 (Cquat), 67.1 (CH2), 128.2 (CH), 128.3
(CH), 128.6 (CH), 136.4 (Cquat), 156.4 (Cquat), 171.9
(Cquat). HRMS calcd for C22H34N2O4 [M1H]ˆ391.2597,
found [M1H]ˆ391.2600.
1
(CDCl3): 1744 cm21. H NMR (250 MHz, CDCl3): d 1.12
(s, 6H), 1.27 (s, 6H), 1.74±1.55 (m, 6H), 7.48 (t, Jˆ7.5 Hz),
7.57 (t, Jˆ7.5 Hz), 8.1 (d, Jˆ5 Hz). 13C NMR (125 MHz,
CDCl3, APT): d 17.1 (CH2), 21.0 (CH3), 32.1 (CH3), 39.2
(CH2), 60.5 (Cquat), 128.7 (CH), 129.7 (CH), 129.9 (Cquat),
132.9 (CH), 166.5 (Cquat). HRMS calcd for C16H23NO2
[M1H]ˆ262.1807, found [M1H]ˆ262.1795.
4.1.8. Bis-(2,2,6,6-tetramethyl-1-piperidinyloxy)-adipate
(16). Using general method C, adipic dihydrazide (15)
(239 mg, 1.37 mmol) was converted to the title compound
as a slightly amber solid material (99 mg, 17% yield). IR
4.1.4. Cyclohexylacetic hydrazide (9). Using general
method A, methyl cyclohexylacetate (8) (1.0 ml,
6.09 mmol) was converted to the title compound as a
white crystalline material (mp118±120 8C) (0.428 g,
45%). TLC: 1:3 hexane/EtOAc, I2, ninhydrin stain,
1
(CDCl3): 2975.3, 2940.8, 2232.2, 1753.8 cm21. H NMR
(500 MHz, CDCl3): d 1.06 (s, 12H), 1.15 (s, 12H), 1.75±
1.38 (m, 12H), 1.78 (br s, 4H), 2.40 (br s, 4H). 13C NMR

5520
R. Braslau et al. / Tetrahedron 58 (2002) 5513±5523
(125 MHz, CDCl3, APT): d 17.1 (CH2), 20.7 (CH3), 25.0
(CH2), 31.1 (CH3), 32.8 (CH2), 39.1 (CH2), 60.0 (Cquat),
172.9 (Cquat).
cating suspension of lead oxide (0.856 g, 3.58 mmol) in
degassed toluene (30 ml) over a period of 2 h. The trace
contents of the syringe were then washed in with additional
degassed toluene (6 ml). The suspension was allowed to stir
at rt overnight. Silica was added (0.026 g) and the reaction
mixture was heated to 1008C for 6 h. The product mixture
was ®ltered through celite with CH2Cl2, and solvent was
removed in vacuo to yield the crude product, which was
then puri®ed by ¯ash column chromatography (10:1 hexane/
EtOAc) to afford the eliminated product (0.046 g, 48%). 1H
NMR (250 MHz, CDCl3): d 4.99 (s, 2H), 5.56 (s, 1H), 6.30
(s, 1H), 6.99±7.07 (m, 2H), 7.47 (t, 1H, Jˆ8.5 Hz), 7.99 (d,
1H, Jˆ7.8 Hz). 13C NMR (63 MHz, CDCl3): d 71.2, 118.0,
121.9, 122.1, 122.2, 127.9, 136.0, 139.0, 161.9, 181.9. The
spectroscopic data of this compound matches the
literature.11c
4.1.9. 2-Allylbenzhydrazide (18). Using general method B,
2-allylbenzoic acid11c (17) was converted to the title
compound (66% over two steps) as white crystalline solid:
mp104±105 8C. TLC: 1:3 hexane/EtOAc, UV, I2, ninhydrin
stain, Rfˆ0.2 (red by ninhydrin). IR (CDCl3): 2950, 1794,
1
1670, 1476 cm21. H NMR (250 MHz, CDCl3): d 3.47 (d,
Jˆ6.3 Hz), 4.26 (bs, 2H), 4.91±5.03 (m, 2H), 5.83±5.99 (m,
1H), 7.14±7.36 (m, 4H), 7.7 (bs, 1H). 13C NMR (63 MHz,
CDCl3): d 37.4 (CH2), 116.1 (CH2), 126.3 (CH), 127.4
(CH), 130.5 (CH), 134.0 (Cquat), 137.3 (CH), 138.2 (Cquat),
170.6 (Cquat). HRMS calcd for C10H12N2O [M]ˆ176.0950,
found [M]ˆ176.0921.
4.1.10. 2-Methylene-1-indanone (19). To a suspension of
2-allylbenzhydrazide (18) (0.053 g, 0.301 mmol) in
degassed toluene (30 ml) was added a few drops of tert-
butanol to form a homogenous solution. TEMPO (6) was
added (0.057 g, 0.365 mmol) followed by lead oxide
(0.295 g, 1.234 mmol), and the reaction was allowed to
stir at rt overnight. The product mixture was ®ltered through
celite with CH2Cl2, and puri®ed by preparative TLC (10:1
hexane/EtOAc) to yield the eliminated product, 2-methyl-
ene-1-indanone (19) (0.011 g, 25%) as slightly yellow oil.
1H NMR (250 MHz, CDCl3): d 3.77 (s, 2H), 5.65 (s, 1H),
6.37 (s, 1H), 7.38±7.64 (m, 3H), 7.87 (d, 1H, Jˆ7.5 Hz).
The spectroscopic data of this compound matches the
literature.11c
4.1.13. 2-(2-Methallyloxy)-benzoic hydrazide (28). To a
solution of 2-(2-methallyloxy)-benzoic acid11c (27)
(1.981 g, 10.30 mmol) in toluene (34 ml) was added oxalyl
chloride (9 ml, 103 mmol, 10 equiv.) and DMF (three
drops). The solution was allowed to stir 1 h, and then
solvent was removed in vacuo to afford the crude acid
chloride. The acid chloride was then dissolved in CH2Cl2
(34 ml) and cooled to 08C. To this mixture was added
DMAP (1.384 g, 10.96 mmol) followed by tert-butyl carba-
zate (3) (1.449 g, 10.96 mmol), and the solution was then
allowed to stir at rt overnight. Solvent was removed in
vacuo and the crude residue was then taken upin EtOAc
(50 ml) and washed sequentially with 10% aq. HCl
(2£50 ml) and 5% aq. NaHCO3 (50 ml). The organic solu-
tion was dried over MgSO4 and solvent was removed to
yield the Boc-protected acyl hydrazine as white solid (mp
108±1098C) (2.924 g, 93%). This compound was used in
the next stepwithout further characterization.
Also isolated by preparative TLC was the undesired direct-
trapped product (2,2,6,6-tetramethyl-1-piperidinyloxy)-2-
allylbenzoate (20) (0.014 g, 15%). IR (CDCl3):
1
1730 cm21. H NMR (250 MHz, CDCl3): d 0.90 (s, 6H),
1.14 (s, 6H), 1.46±1.77 (m, 6H), 3.75 (d, 2H, Jˆ6.3 Hz),
4.96±5.07 (m, 2H), 5.96±6.02 (m, 1H), 7.25±7.40 (m, 2H),
7.44±7.47 (m, 1H), 7.84±7.88 (m, 1H). 13C NMR (63 MHz,
CDCl3): d 14.2, 17.0, 20.9, 32.0, 38.1, 39.2, 60.3, 115.7,
125.8, 126.0, 129.7, 131.0, 131.8, 137.4, 141.9, 177.0.
Using the TFA-deprotection step described in general
method B, 2-(2-methallyloxy)-benzoic [N-(tert-butoxy-
carbonyl)]-hydrazide (2.957 g, 9.65 mmol) was converted
to the title compound (28) as white crystals: mp78±80 8C
(1.926 g, 97% after recrystallization with EtOAc/hexane).
1
IR (CDCl3): 3155, 1794, 1654 cm21. H NMR (500 MHz,
4.1.11. 2-Allyloxybenzoic hydrazide (23). Using general
method B, 2-allyloxybenzoic acid11c (22) (1.129 g,
6.33 mmol) was converted to the crude title compound as
a slightly amber oil. This was crystallized with EtOAc/
hexane in two batches to yield the product as white crystals:
mp54±56 8C (1.181 g, 73% overall yield, 2 steps). TLC: 1:1
hexane/EtOAc, UV, I2, Rfˆ0.1. IR (CDCl3): 3421, 1794,
CDCl3): d 1.76 (s, 3H), 4.65 (s, 2H), 4.97 (s, 1H), 5.06 (s,
1H), 7.05±7.08 (m, 1H), 7.14 (d, 1H, Jˆ9 Hz), 7.49±7.52
(m, 1H), 7.67±7.70 (m, 1H), 10.05 (bs, 1H), 10.62 (bs, 1H).
13C NMR (125 MHz, CDCl3): d 19.0, 71.4, 112.7, 113.5,
120.5, 120.7, 130.2, 133.1, 140.2, 156.0, 164.7. HRMS
calcd for C11H14N2O2 [M1H]ˆ207.1134, found
[M1H]ˆ207.1136.
1
1653, 1480 cm21. H NMR (250 MHz, CDCl3): d 4.17
(bs, 2H), 4.63 (d, 2H, Jˆ5 Hz), 5.34±5.41 (m, 2H), 5.97±
6.02 (m, 1H), 6.98±7.06 (m, 2H), 7.34±7.41 (m, 1H), 8.14
(d, 1H, Jˆ7.5 Hz), 8.9 (bs, 1H). 13C NMR (63 MHz, CDCl3,
APT): d 69.8 (CH2), 112.6 (CH2), 119.2 (CH), 120.2 (Cquat),
121.5 (CH), 132.0 (CH), 132.1 (CH), 132.8 (CH), 156.4
(Cquat), 166.4 (Cquat). HRMS calcd for C10H12N2O2
[M]ˆ192.0899, found [M]ˆ192.0896.
4.1.14. 3-[(4-Hydroxy-2,2,6,6-tetramethyl-1-piperidinyl-
oxy)methyl]-3-methylchromanone (29). A solution of
2-(2-methallyloxy)-benzoic hydrazide (28) (0.075 g,
0.36 mmol) in degassed toluene (1 ml1trace DMSO for
solubility) was prepared and this was added slowly by
syringe pump to a sonicating suspension of potassium ferri-
cyanide (0.916 g, 3.83 mmol) and TEMPOL (24) (0.069 g,
0.400 mmol) in degassed 6:1 toluene/H2O (18 ml), over a
period of 2 h. Trace contents of the syringe were then
washed in with approximately 1 ml of additional degassed
toluene. The suspension was allowed to stir at rt overnight
and then H2O was added (20 ml) and the crude product
mixture was extracted with CH2Cl2 (3£20 ml). Solvent
4.1.12. 3-Methylenechroman-4-one (26). A solution of
2-allyloxybenzoic hydrazide (23) (0.114 g, 0.593 mmol)
and 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy radical
(TEMPOL) (24) (0.104 g, 0.604 mmol) in degassed toluene
(6 ml) was prepared and added slowly by syringe to a soni-

R. Braslau et al. / Tetrahedron 58 (2002) 5513±5523
5521
was removed in vacuo, and a suspension of sodium l-ascor-
bate (0.144 g, 0.727 mmol) in anhydrous MeOH (3.8 ml)
was added and allowed to stir for 30 min. Solvent was
removed again, and then the cyclized product (29) was
isolated by ¯ash column chromatography (2:1 hexane/
EtOAc) as a colorless oil (0.027 g, 21%). IR (CDCl3):
orange solid. The solid was vacuum ®ltered, taken upin
EtOAc, dried over MgSO4, and solvent was removed in
vacuo to yield the hydrazone as an orange crystalline solid
(0.079 g, 80%): mp230±233 8C, lit 2378C. 1H NMR
(250 MHz, DMSO-d6): d 7.48±7.54 (m, 3H), 7.78±7.82
(m, 2H), 8.10 (d, 1H, Jˆ11 Hz), 8.37 (dt, 1H, Jˆ3,
11 Hz), 8.71 (s, 1H), 8.86 (d, 1H, Jˆ3 Hz), 11.67 (bs,
1H). The spectroscopic data of this compound matches
authentically prepared hydrazone from benzaldehyde.
2978, 1686, 1607, 1479 cm21
.
1H NMR (500 MHz,
CDCl3): d 1.05 (s, 3H), 1.14 (s, 3H), 1.17 (s, 3H), 1.21 (s,
3H), 1.26 (s, 3H), 1.43 (t, 2H, Jˆ12 Hz), 1.63 (bs, 1H), 1.76
(dd, 2H, Jˆ4, 12.5 Hz), 3.76 (d, 1H, Jˆ9 Hz), 3.91 (m, 1H),
4.09 (d, 1H, Jˆ9 Hz), 4.24 (d, 1H, Jˆ12 Hz), 4.58 (d, 1H,
Jˆ12 Hz), 6.96 (d, 1H, Jˆ8 Hz), 7.02 (dt, 1H, Jˆ1, 8 Hz),
7.47 (dt, 1H, Jˆ1, 8 Hz), 7.91 (dd, 1H, Jˆ1, 8 Hz). 13C
NMR (125 MHz, CDCl3): d 16.7, 21.2, 33.0, 46.0, 48.5,
60.6, 63.2, 73.8, 117.8, 120.4, 121.6, 127.8, 135.8, 161.5,
195.0. HRMS calcd for C20H29NO4 [M1H]ˆ348.2175,
found [M1H]ˆ348.2189.
4.1.17. (4-Hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy)-
benzoate (34). A solution of benzoic [N-(2-nitrobenzene-
sulfonyl)]-hydrazide (32) (0.070 g, 0.218 mmol) and
TEMPOL (24) (0.043 g, 0.249 mmol) in THF (1 ml) was
prepared, and this was added slowly by syringe pump to a
re¯uxing (808C) suspension of freshly activated K2CO3
(0.372 g, 2.69 mmol) and potassium ferricyanide (0.717 g,
2.18 mmol) in degassed 95% EtOH (3.5 ml), over a period
of 1 h. Trace contents of the syringe were washed in with
approximately 1 ml of additional degassed 95% EtOH, and
the suspension was allowed to continue re¯uxing for an
additional hour. H2O was then added (20 ml) and the
product was extracted with CH2Cl2 (3£20 ml). The organic
layer was washed with saturated aq. NaCl (40 ml), dried
over MgSO4, and solvent was removed in vacuo to yield
the product as a slightly amber-colored oil (0.052 g, 87%).
IR (CDCl3): 2944, 1747 cm21. 1H NMR (500 MHz, CDCl3):
d 1.15 (s, 3H), 1.32 (s, 3H), 1.78 (t, 2H, Jˆ12 Hz), 1.95 (dt,
2H, Jˆ4, 12 Hz), 4.10 (m, 1H), 7.46 (t, 2H, Jˆ7.5 Hz), 7.57
(t, 1H, Jˆ7.5 Hz), 8.05 (d, 2H, Jˆ7.5 Hz). 13C NMR
(125 MHz, CDCl3): d 21.9, 32.1, 47.7, 60.8, 63.1, 128.6,
129.5, 129.7, 133.1, 166.4. HRMS calcd for C16H23NO3
[M1H]ˆ278.1751, found [M1H]ˆ278.1781.
Also isolated was the direct-trapped product (30) (0.033 g,
1
26%). IR (CDCl3): 2979, 1734 cm21. H NMR (500 MHz,
CDCl3): d 1.17 (s, 6H), 1.21 (s, 6H), 1.77±1.82 (m, 5H),
1.86±1.88 (m, 2H), 3.99 (m, 1H), 4.53 (s, 2H), 4.98 (s, 1H),
5.14 (s, 1H), 6.92±6.98 (m, 2H), 7.38±7.42 (m, 1H), 7.72 (d,
1H, 7.5). 13C NMR (125 MHz, CDCl3): d 19.5, 21.7, 32.1,
47.8, 60.7, 63.3, 72.2, 113.2, 120.3, 120.7, 131.0, 132.9,
140.3, 157.6, 167.0. HRMS calcd for C20H29NO4
[M1H]ˆ348.2175, found [M1H]ˆ348.2122.
4.1.15. Benzoic [N0-(2-nitrobenzenesulfonyl)]-hydrazide
(32). General method D. To a solution of benzhydrazide
(2) (0.136 g, 1.0 mmol) in THF (3.3 ml) was added
NaHCO3 (0.848 g, 10.1 mmol) and 2-nitrobenzenesulfonyl
chloride (31) (0.211 g, 0.95 mmol) and DMF (0.039 g,
0.53 mmol, 0.5 equiv.). This suspension was stirred at rt
overnight. Next, H2O was added (10 ml), and the product
was extracted with CH2Cl2 (2£10 ml). The organic product
layer was washed with 10% aq. HCl (10 ml), dried over
MgSO4, and then solvent was removed in vacuo to yield a
yellowish solid (0.303 g, 99%). This material was recrystal-
lized using CH2Cl2/hexane to yield the ®nal product as a
white crystalline solid: mp156±158 8C (0.239 g, 78%).
TLC: 1:1 hexane/EtOAc, UV, I2, Rfˆ0.5. IR (CDCl3):
.
1H NMR (500 MHz,
4.1.18. 2-(2-Methallyloxy)-benzoic [N0-(2-nitrobenzene-
sulfonyl)]-hydrazide (36). Using general method E, 2-(2-
methallyloxy)-benzoic hydrazide (28) (0.498 g, 2.41 mmol)
was converted to the title compound as a slightly tan solid
material: mp108±110 8C (0.513 g, 61% after recrystalliza-
tion from CH2Cl2/hexane in two batches). IR (CDCl3):
3382, 1665, 1602, 1544, 1480, 1400 cm21 1H NMR
.
(500 MHz, CDCl3): d 1.95 (s, 3H), 4.67 (s, 2H), 5.16 (s,
1H), 5.18 (s, 1H), 7.01 (m, 2H), 7.46 (dt, 1H, Jˆ2, 9 Hz),
7.64 (t, 1H, Jˆ8 Hz), 7.76 (dt, 1H, Jˆ1, 8 Hz), 7.84 (d, 1H,
Jˆ5 Hz), 8.04 (t, 2H, Jˆ13 Hz), 8.73 (d, 1H, Jˆ7 Hz), 9.84
(d, 1H, Jˆ7 Hz). 13C NMR (125 MHz, CDCl3): d 19.6,
73.3, 112.9, 115.2, 118.4, 121.7, 126.4, 131.9, 132.4,
132.6, 133.0, 134.3, 134.5, 139.3, 147.9, 157.0, 164.4.
HRMS calcd for C17H17N3O6S [M1H]ˆ392.0917, found
[M1H]ˆ392.0934.
3155, 1794, 1475, 1383 cm21
MeOH-d4): d 7.41 (t, 2H, Jˆ7.5 Hz), 7.52 (t, 1H,
Jˆ7.5 Hz), 7.68±7.73 (m, 3H), 7.79 (dt, 1H, Jˆ1.5,
10 Hz), 7.90 (dd, 1H, Jˆ1.5, 8 Hz), 8.11 (dd, 1H, Jˆ1.5,
8 Hz). 13C NMR (125 MHz, MeOH-d4): d 124.9 (CH),
127.2 (CH), 128.2 (CH), 131.2 (CH), 131.5 (Cquat), 132.0
(CH), 132.1 (CH), 134.3 (CH), 148.1 (Cquat), 167.5 (Cquat).
HRMS calcd for C13H11N3O5S [M1H]ˆ322.0498, found
[M1H]ˆ322.0500.
4.1.19. 3-[(4-Hydroxy-2,2,6,6-tetramethyl-1-piperidinyl-
oxy)methyl]-3-methylchromanone (29) by cyclization of
compound 36. A solution of 2-(2-methallyloxy)-benzoic
[N0-(2-nitrobenzenesulfonyl)]-hydrazide (36) (0.104 g,
0.266 mmol) and TEMPOL (24) (0.050 g, 0.293 mmol) in
THF (1 ml) was added slowly by syringe pump to a re¯ux-
ing (808C) suspension of freshly activated K2CO3 (0.368 g,
2.66 mmol) and potassium ferricyanide (0.875 g,
2.66 mmol) in degassed 95% EtOH (13 ml, 0.02 M), over
a period of 2 h. Trace contents of the syringe were washed in
with approximately 1 ml of additional degassed 95% EtOH,
and the suspension was allowed to continue re¯uxing for an
4.1.16. Benzaldehyde 2,4-dinitrophenylhydrazone (33):
low temperature McFayden±Stevens reaction condi-
tions.
A suspension of benzoic [N-(2-nitrobenzene-
sulfonyl)]-hydrazide (32) (0.112 g, 0.349 mmol) and
freshly activated K2CO3 (0.372 g, 3.49 mmol) in 95%
EtOH (3.5 ml) was heated at 808C for 2.5 h. TLC showed
only a trace presence of starting material. The reaction
mixture was then ®ltered, and then added to a solution of
2,4-dinitrophenylhydrazine (0.172 g, 0.872 mmol) in 10%
aq. HCl (8.7 ml), resulting in the immediate deposition of
benzaldehyde 2,4-dinitrophenylhydrazone (33) as a yellow-

5522
R. Braslau et al. / Tetrahedron 58 (2002) 5513±5523
D. M. J. Chem. Soc., Perkin Trans. 1 1990, 2721±2728.
(c) Patel, F. F.; Pattenden, G.; Thompson, D. M. J. Chem.
Soc., Perkin Trans. 1 1990, 2729±2734. (d) Gill, G. B.;
Pattenden, G.; Reynolds, S. J. Tetrahedron Lett. 1989, 30,
3229±3232.
hour. The majority of the solvent was then removed in
vacuo. H2O was then added (20 ml) and the product was
extracted with CH2Cl2 (3£20 ml). The organic product layer
was washed with saturated aq. NaCl (40 ml), dried over
MgSO4, and solvent was removed in vacuo to yield the
crude product as a slightly amber-colored oil. The cyclized
product (29) was isolated by ¯ash column chromatography
(2:1 hexane/EtOAc) as a colorless oil (0.027 g, 29%). Also
isolated was direct-trapped product (30) (0.003 g, 3%). The
spectroscopic properties of these compounds match those of
the compounds isolated previously.
11. (a) Chen, C.; Crich, D.; Papadatos, A. J. Am. Chem. Soc. 1992,
114, 8313±8314. (b) Chen, C.; Crich, D. Tetrahedron Lett.
1993, 34, 1545±1548. (c) Crich, D.; Chen, C.; Hwang, J.-T.;
Yuan, H.; Papadatos, A.; Walter, R. I. J. Am. Chem. Soc. 1994,
116, 8937±8951.
12. (a) Overberger, C. G.; Anselme, J.-P.; Lombardino, J. G.
Organic Compounds with Nitrogen±Nitrogen Bonds; The
Ronald: New York, 1966. (b) Smith, P. A. S. Derivatives of
Hydrazine and Other Hydronitrogens Having N±N Bonds;
The Benjamin/Cummings Publishing: London, 1983.
13. (a) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25,
491±494. (b) Corey, E. J.; Gross, A. W. J. Org. Chem.
1985, 50, 5391±5393.
Acknowledgements
We would like to thank the National Science Foundation
(CHE 9527647 and CHE 0078852) for ®nancial support.
Frank Rivera and Armando Jimenez also gratefully
acknowledge support from the National Institute of Health
program `Bridges to the Future' (GM 51765).
14. (a) Braslau, R.; Burrill, L. C.; Mahal, L. K.; Wedeking, T.
Angew. Chem., Int. Ed. Engl. 1997, 36, 237±238. (b) Naik,
N.; Braslau, R. Tetrahedron 1998, 54, 667±696. (c) Braslau,
R.; Naik, N.; Zipse, H. J. Am. Chem. Soc. 2000, 122, 8421±
8434.
References
15. (a) Braslau, R.; Burrill, L. C.; Siano, M.; Naik, N.; Howden,
R. K.; Mahal, L. K. Macromolecules 1997, 30, 6445±6450.
(b) Benoit, D.; Chaplinski, V.; Braslau, R.; Hawker, C. J.
J. Am. Chem. Soc. 1999, 121, 3904±3920.
1. Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem.
Rev. 1999, 99, 1991±2069.
2. (a) Schwartz, C. E.; Curran, D. P. J. Am. Chem. Soc. 1990,
112, 9272. (b) Boger, D. L.; Mathvink, R. J. J. Org. Chem.
1992, 57, 1429±1443. (c) Crich, D.; Fortt, S. M. Tetrahedron
1989, 45, 6581±6598. (d) Crich, D.; Eustace, A.; Fortt, S. M.;
Ritchie, T. J. Tetrahedron 1990, 46, 2135±2148.
16. (a) Myers, A. G.; Movassaghi, M.; Zheng, B. J. Am. Chem.
Soc. 1997, 119, 8572±8573. (b) Myers, A. G.; Movassaghi,
M.; Zheng, B. Tetrahedron Lett. 1997, 38, 6569±6572.
17. (a) Kosower, E. M. Acc. Chem. Res. 1971, 4, 193±198.
(b) Tsuji, T.; Kosower, E. M. J. Am. Chem. Soc. 1971, 93,
1993±1999.
3. Ryu, I.; Kusano, K.; Ogawa, A.; Kambe, N.; Sonoda, N. J. Am.
Chem. Soc. 1990, 112, 1295±1297.
18. (a) Johnsson, K.; Schultz, P. G. J. Am. Chem. Soc. 1994, 116,
7425±7426. (b) Rozwarski, D. A.; Grant, G. A.; Barton,
D. H. R.; Jacobs, Jr, W. R.; Sacchettini, J. C. Science 1998,
279, 98±102.
4. (a) Chatgilialoglu, C.; Griler, D.; Lesage, M. J. Org. Chem.
1988, 53, 3641±3642. (b) Chatgilialoglu, C. Acc. Chem. Res.
1992, 25, 188±194. (c) Giese, B.; Kopping, C.; Chatgilialoglu,
C. Tetrahedron Lett. 1989, 30, 681±684.
19. Gordon, M. S.; Krause, J. G.; Linnemanmohr, M. A.; Parchue,
R. R. Synthesis (Stuttgart) 1980, 244±245.
5. (a) Light, J.; Breslow, R. Tetrahedron Lett. 1990, 31, 2957±
2958. (b) Rai, R.; Collum, D. B. Tetrahedron Lett. 1994, 31,
2957±6224.
20. (a) Padwa, A.; Ku, A. J. Am. Chem. Soc. 1978, 100, 2181±
2190. (b) Meyers, A. I.; Temple, D. L.; Haidukewych, D.;
Mihelich, E. D. J. Org. Chem. 1974, 39, 2787±2793.
(c) Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40,
3158±3159. (d) Gschwend, H. W.; Hamdan, A.
J. Org. Chem. 1975, 40, 2008±2009.
6. (a) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118,
2531±2533. (b) Hadida, S.; Super, M. S.; Beckman, E. J.;
Curran, D. P. J. Am. Chem. Soc. 1997, 119, 7406±7407.
(c) Horner, J. H.; Martinez, E. N.; Newcomb, M.; Hadida,
S.; Curran, D. P. Tetrahedron Lett. 1997, 38, 2783±2786.
(d) Curran, D. P.; Hadida, S.; Kim, S. Y.; Luo, Z. Y. J. Am.
Chem. Soc. 1999, 121, 6607±6615. (e) Curran, D. P. Pure
Appl. Chem. 2000, 72, 1649±1653. (f) Curran, D. P.; Lee,
Y. Z. Green Chem. 2001, 3, G3±G7.
21. Anderson, J. E.; Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 2
1992, 7, 1027±1031.
22. (a) Fahr, E.; Lund, H. Angew. Chem., Int. Ed. Engl. 1966, 5,
372±384. (b) Back, T. G.; Collins, S.; Kerr, R. G.
J. Org. Chem. 1981, 46, 1564±1570. (c) Lerch, U.; Moffatt,
J. G. J. Org. Chem. 1971, 36, 3861.
7. (a) Gerigk, U.; Gerlach, M.; Neurmann, W. P.; Vieler, R.;
Weintritt, V. Synthesis 1990, 448±452. (b) Gerlach, M.;
È
23. Wolman, Y.; Gallop, P. M.; Patchornik, A.; Beyer, A. J. Am.
Chem. Soc. 1962, 84, 1889.
Jordens, F.; Kuhn, H.; Neumann, W. P.; Peterseim, M.
J. Org. Chem. 1991, 56, 5971±5972. (c) Dumartin, G.; Ruel,
G.; Kharboutli, J.; Delmond, B.; Connil, M.-F.; Jousseaume,
B.; Pereyre, M. Synlett 1994, 952±954. (d) Junggebauer, J.;
Neumann, W. P. Tetrahedron 1997, 53, 1301±1310.
(e) Dumartin, G.; Pourcel, M.; Delmond, B.; Donard, O.;
Pereyre, M. Tetrahedron Lett. 1998, 39, 4663±4666.
24. (a) Abdulla, R. F. Aldrichim. Acta 1988, 21, 31. (b) Lorimer, J.
P.; Mason, T. J. Chem. Soc. Rev. 1987, 16, 239±274.
(c) Lindley, J.; Mason, T. J. Chem. Soc. Rev. 1987, 16,
275±311. (d) Boudjouk, P. J. Chem. Educ. 1986, 63, 427±
429. (e) Einhorn, C.; Einhorn, J.; Luche, J. L. Synthesis
(Stuttgart) 1989, 787±813. (f) Einhorn, C.; Einhorn, J.;
Dickens, M.; Luche, J. Tetrahedron Lett. 1990, 31, 4129±
4130.
8. Crich, D.; Hao, X. J. Org. Chem. 1997, 62, 5982±5988.
9. Delduc, P.; Tailhan, C.; Zard, S. Z. J. Chem. Soc., Chem.
Commun. 1988, 308±310.
10. (a) Pattenden, G. Chem. Soc. Rev. 1988, 17, 361±382.
(b) Coveney, D. J.; Patel, V. F.; Pattenden, G.; Thompson,
25. (a) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1976, 8, 13±19.
(b) Bowry, V. W. U.; Ingold, K. J. Am. Chem. Soc. 1992, 114,

R. Braslau et al. / Tetrahedron 58 (2002) 5513±5523
5523
4992±4996. (c) Chateauneuf, J.; Lusztyk, J.; Ingold, K. U.
J. Org. Chem. 1988, 53, 1629±1632. (d) Arends, I. W. C.
E.; Mulder, P.; Clark, K. B.; Wayner, D. D. M. J. Phys.
Chem. 1995, 99, 8182±8189.
27. Manna, R. K.; Jaisankar, P.; Giri, V. S. Synth. Commun. 1998,
28, 9±16.
28. Boger, D. L.; Patel, M. J. Org. Chem. 1988, 53, 1405±1415.
29. HuÈnig, S.; MuÈller, H. R.; Thier, W. Angew. Chem., Int. Ed.
Engl. 1965, 4, 271±382.
26. (a) McFayden, J. S.; Stevens, T. S. J. Chem. Soc. 1936,
584. (b) Babad, H.; Herbert, W.; Stiles, A. W.
Tetrahedron Lett. 1966, 7, 2927±2931. (c) Matin, S. B.;
Craig, J. C.; Chan, R. P. K. J. Org. Chem. 1974, 39,
2285±2289. (d) Cacchi, S.; Paolucci, G. Gazz. Chim.
Ital. 1974, 104, 221±224.
30. (a) Faessler, A.; Bold, G.; Capraro, H.-G.; Cozens, R.; Mestan,
J.; Poncioni, B.; Roesel, J.; Tintelnot-Blomley, M.; Lang, M.
J. Med. Chem. 1996, 39 (16), 3203±3216. (b) Bindewald, R.;
Danho, W.; Buellesbach, E.; Bodanszky, M.; Zahn, H. Int. J.
Pept. Protein Res. 1984, 23 (4), 376±383.