Studies on the synthesis of amidoximes from nitroalkanes

Article abstract of DOI:10.1016/j.tet.2011.09.147

The reaction of primary nitroalkanes with magnesium or lithium amides provides a convenient, one-step synthesis of substituted amidoximes.

Full text of DOI:10.1016/j.tet.2011.09.147

Tetrahedron 67 (2011) 10208e10211
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Studies on the synthesis of amidoximes from nitroalkanes
*
Gabriella Sanguineti, Hoang V. Le, Bruce Ganem
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of primary nitroalkanes with magnesium or lithium amides provides a convenient, one-step
synthesis of substituted amidoximes.
Received 1 September 2011
Received in revised form 29 September 2011
Accepted 30 September 2011
Available online 6 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
This paper is dedicated to Gilbert Stork, an
inspiring teacher and research mentor, on
the occasion of his ninetieth birthday
Keywords:
Amidoxime
Nitroalkane
Nitronate
Thiohydroximate
1. Introduction
R1
R1
base
acid HO
O
O
O2N
R1
N
As part of our ongoing effort to expand the repertoire of syn-
thetically useful multicomponent reactions (MCRs), we recently
disclosed a new synthesis of substituted indoles from nitroalkanes
and arylhydrazines in the presence of base.1 The success of the
method relied on transforming the derived nitronate anion 2
(Scheme 1) either to the monoprotonated aci-nitro species 3 or to
the di-protonated iminium species 4, with subsequent hydrazine
addition and N/N interchange to produce arylhydrazone 5.
This indole synthesis was inspired by two early patents
reporting successful nucleophilic additions of thiols to nitronates
leading to thiohydroximate esters 9 (Scheme 2).2 Although no
mechanism was proposed in the patents, one likely sequence of
transformations is depicted in Scheme 2.3
We wondered whether the analogous reaction of nitronates
with primary or secondary amines, either alone or in the presence
of a thiol or some other catalyst, would afford the corresponding
amidoximes 10. Such amidoximes are of considerable medicinal
interest. Besides being involved in the biosynthesis of NO, they
display potent pharmacological activity as anticoagulants, platelet
inhibitors, antimicrobial agents and matrix metalloprotease in-
hibitors.4 We now report our systematic study of this
N
(1 equiv)
O
1
2
3
nitronate
aci-nitro
form
R1
R1
HO
HO
strong
acid
ArNH-N
N
Fischer
indole
5
4
Nef reaction
intermediate
Scheme 1. Nitro to indole conversion.
transformation, as well as the scope and generality of organo-
lithium and magnesium-mediated conversion of nitroalkanes into
amidoximes 10.
2. Results and discussion
Using 1-nitropropane as a model nitroalkane, we successfully
prepared the corresponding thiohydroximate ester 9 (R1¼CH3,
R¼Ph) using thiophenol according to published conditions
(NaOCH3eCH3OH, reflux).2 Given that 9 is an oximino analogue of
a thioester, we expected it to react smoothly with an amine nu-
cleophile to furnish the corresponding amidoxime 10. However, the
reaction of 9 with aniline (CH3OH, reflux) was extremely sluggish,
* Corresponding author. Tel.: þ1 607 255 7360; e-mail address: bg18@cornell.edu
(B. Ganem).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.147

G. Sanguineti et al. / Tetrahedron 67 (2011) 10208e10211
10209
Table 2
R1
R1
SR
O
O
O
Effect of metallating agent on the synthesis of N-alkylpropionamidoximes
RSH
N
N
Amine
Yield w/EtMgCl (%)
Method A
Yield w/n-BuLi (%)
HO
2
6
Method B
n-Butylamine
Cyclohexylamine
tert-Butylamine
Pyrrolidine
28
32
32
46
59
47
19
26
R1
SR
R1
SR
R1
SR
O
O=N
HO N
N
HO
7
8
9
Data in Table 2 indicate that, perhaps not surprisingly, the yield
of amidoxime was affected by steric factors in the primary amines.
More interestingly, however, the data suggest that n-butyllithium
was the preferred reagent for preparing N-(primary alkyl) or
N-(secondary alkyl) amidoximes. Metallation using Grignard re-
agents was preferred in making amidoximes from tert-butylamine
or pyrrolidine.
R1
NR2R3
HO N
10
Scheme 2. Proposed mechanism of nitroalkane to thiohydroximate conversion.
Having tested the effects of various metallating agents and of
amine structure, the amidoxime synthesis was further applied to
several different nitroalkanes in order to expand its scope and gen-
erality. Insodoing,theuseofadditionalaminecomponents, including
unsaturated amines and anilines, was also explored. Fig. 1 below
depicts the structures of the various new amidoximes that were
synthesized from nitromethane, nitroethane and 1-nitropropane.
Each structure in the figure also indicates the optimal method of
preparation, and the yield obtained.
and afforded a complex mixture of products. Besides obtaining the
hoped-for propionamidoxime 10 (R1¼CH3, R2¼H, R3¼Ph), we also
identified the corresponding N,N0-diphenylpropionamidine. Both
products were formed in low yield. Control experiments estab-
lished that the amidine was derived from 10.5,6
Taken together, the surprisingly low reactivity of thiohydrox-
imates and the unexpected susceptibility of amidoximes to further
nucleophilic addition by amines indicated that the thiohydrox-
imate pathway from nitroalkanes would not likely afford a viable
route to amidoximes. We decided to explore instead the direct
reaction of 1-nitropropane with nucleophilic amines. After nu-
merous attempts, however, we were unable to identify conditions
under which a primary or secondary amine (n-butylamine, aniline,
pyrrolidine) would react with 1-nitropropane either neat or in
a protic (methanol) or aprotic (DMSO) solvent, even at elevated
temperatures, to form detectable quantities of the corresponding
amidoxime.
We next considered the possibility of boosting the nucleophi-
licity of the amine component by metallation. A little-cited 1988
Russian report describes the reaction of nitromethane and nitro-
ethane with magnesium tert-butylamide (2.5 equiv, prepared using
EtMgBr and tert-butylamine at rt in THF) to afford the corre-
sponding N-tert-butylformamidoxime and N-tert-butylacetami-
doxime in 40 and 45% yields, respectively.7
In applying the published procedure to various combinations of
nitroalkanes and amines we observed that EtMgCl metallated the
amine component only sluggishly at rt. Therefore, to ensure com-
plete consumption of the Grignard reagent, the amine was added to
EtMgCl in THF at reflux with continued heating until gas evolution
ceased prior to adding the nitroalkane.
H3C
H3C
H3C
N OH
N OH
N OH
C6H11NH
n-BuNH
t-BuNH
10c
10a
10b
(B, 47%)
(B, 59%)
(A, 32%)
H3C
H3C
BnNH
10e
H3C
PhNH
N OH
N OH
N OH
N
10f
10d
(B, 44%)
(B, 56%)
(A, 46%)
H3C
H3C
H
N OH
N OH
N OH
N
CH2=CHCH2NH
t-BuNH
10g
10h
10i
(A, 41%)
(A, 40%)
(A, 26%)
H3C
NH
To ascertain whether the yield of amidoxime could be improved
using different metallated amines, we studied the reaction of 1-
nitropropane and n-butylamine using various metallating agents.
The results are shown in Table 1.
As indicated in Table 1, promising results were obtained in this
pilot study using lithium amides. We therefore undertook a side-
by-side comparison of magnesiated (method A) versus lithiated
(method B) amides in the synthesis of amidoximes derived from
various primary and secondary amines. Those data are summarized
in Table 2.
N OH
10j
CF3
NC
Fig. 1. Examples of amidoximes prepared from nitroalkanes.
(B, 68%)
Despite the strongly basic conditions involved, the method
generally affords amidoximes, although in moderate yields. At-
tempts to prepare amidoxime 10i from allylamine were un-
successful using method B, probably because of polylithiation,
which has been reported to be THF-catalyzed.8 However, by
switching to method A, 10i could be synthesized in low yield.
The amidoxime synthesis seemed to work best using anilines, as
indicated by the formation of amidoximes 10f and 10j. Besides
being notable for its yield (68%), the successful preparation of 10j
establishes that the method tolerates the presence of some reactive
(trifluoromethyl, nitrile) functionality in the amine component.
Table 1
Yields of N-(n-butyl)propionamidoxime from 1-nitropropane using various metal-
lating agents
Base
% Yield
EtMgCl
EtMgCl/cat. CuCl
n-BuLi
28
27
58
27
NaH

10210
G. Sanguineti et al. / Tetrahedron 67 (2011) 10208e10211
In summary, we have investigated the effect of metallating
mixture was saturated with sodium chloride and extracted with
ethyl ether (4ꢂ10 mL). The combined ether layers werewashed with
brine, dried (MgSO4), filtered and concentrated in vacuo to afford the
desired amidoxime.
agent and amine substitution pattern in the condensation of
nitronate anions with amide anions to produce amidoximes, an
important family of medicinally active compounds. Two generally
useful sets of conditions were developed and applied to the prep-
aration of a representative family of amidoximes. The results we
report establish a useful new dimension to the chemistry of pri-
mary nitroalkanes, which are already important building blocks in
organic synthesis.
3.3.1. Amidoxime 10a. The product was obtained as an orange oil
(86 mg, 59%), and 1H NMR and IR matched literature values:9 1
H
NMR (400 MHz, CDCl3)
d 8.52 (br, 1H), 5.14 (br s, 1H), 3.10 (m, 2H),
2.23 (q, J¼7.5 Hz, 2H), 1.49 (m, 2H), 1.36 (m, 2H), 1.14 (t, J¼7.5 Hz,
3H), 0.93 (t, J¼7.5 Hz, 3H). 13C NMR (400 MHz, CDCl3)
d 156.3, 41.8,
3. Experimental section
3.1. General
33.1, 22.2, 19.9, 13.8, 10.9. IR (neat) 3233 (br), 2959 (s), 2933 (s),
2873 (s), 1645 (s).
3.3.2. Amidoxime 10b. The product was obtained as a yellow solid
1H NMR and 13C NMR spectra were taken on a Varian Mercury-
300 or a Varian Inova-400 spectrometer using CDCl3 with 0.05% v/v
(46 mg, 32%): 1H NMR (400 MHz, CDCl3)
d 8.24 (br, 1H), 5.30 (br s,
1H), 2.40 (q, J¼7.5 Hz, 2H), 1.33 (s, 9H), 1.16 (t, J¼7.5 Hz, 3H). 13C
TMS or DMSO-d6 as solvents, recorded in
d
(ppm), and referenced to
NMR (400 MHz, CDCl3) d 156.2, 50.6, 31.5, 23.7, 11.0. IR (CH2Cl2)
TMS (0.00 ppm for 1H NMR and 77.16 ppm for 13C NMR) or DMSO-
d6 (2.50 ppm for 1H NMR and 39.52 ppm for 13C NMR). IR spectra
were obtained using a Thermo Nicolet Avatar 370DTGS FT-IR
spectrometer and recorded in wavenumbers (cmꢀ1). Melting
points were measured using a Thomas Hoover Uni-melt Capillary
Melting Point Apparatus or a Mel-Temp Apparatus. Mass spectra
were measured at the Life Sciences Core Laboratories Center using
ABI/MDS Sciex 4000 Q Trap. Chemicals were obtained from Aldrich,
Acros, Aensar, Fisher, or Matrix Scientific, and used as received
unless otherwise specified.
3241 (br), 2974 (s), 2939 (m), 2877 (m), 1633 (s). ESI-MS (CH3OH)
144.9 (MþH), 167.2 (MþNa), 183.2 (MþK).
3.3.3. Amidoxime 10c. The product was obtained as an orange solid
(80.7 mg, 47%): 1H NMR (400 MHz, CDCl3)
d 8.39 (br, 1H), 5.13 (br d,
J¼9.7 Hz, 1H), 3.13 (m, 1H), 2.24 (q, J¼7.5 Hz, 2H), 1.88 (m, 2H), 1.75
(m, 2H), 1.60 (m, 2H), 1.37e1.15 (m, 2H), 1.14 (t, J¼7.5 Hz, 3H). 13C
NMR (400 MHz, CDCl3)
d 155.5, 50.6, 35.3, 25.4, 25.2, 22.2, 11.3. IR
(CH2Cl2) 3207 (br), 2932(s), 2853 (s), 1641 (s). ESI-MS (CH3OH)
171.2 (MþH), 193.2 (MþNa), 209.2 (MþK).
3.2. General procedure for the synthesis of amidoximes using
ethylmagnesium chloride (method A)
3.3.4. Amidoxime 10d. The product was obtained as an orange solid
(65 mg, 46%): 1H NMR (400 MHz, CDCl3)
d 8.89 (br, 1H), 3.26 (m,
4H), 2.53 (q, J¼7.6 Hz, 2H), 1.86 (m, 4H), 1.17 (t, J¼7.6 Hz, 3H). 13C
A solution of ethylmagnesium chloride (2 mL of 2 M solution in
THF, 4 mmol) in dry THF (2 mL) in a nitrogen-flushed 2-neck 50 mL
RBF fitted with a condenser and septum was brought to reflux, and
the amine (4 mmol, freshly distilled over sodium hydride) was
added neat dropwise. The resulting solution was stirred at reflux
until the evolution of ethane gas was complete. The oil bath was
lowered, and nitroalkane (1 mmol, freshly distilled over sodium
hydride) was added dropwise. The septum was replaced with
a glass stopper, and the resulting solution was brought to reflux for
3 h. The reaction solution was cooled to 0 ꢁC and acidified to pH 2
with 3 M aqueous HCl. The bulk of THF was removed in vacuo and
the residual aqueous phase was washed with ethyl ether (4ꢂ5 mL),
cooled to 0 ꢁC and then basified to pH 10 using 3 M NaOH. The
resulting viscous suspension was saturated with sodium chloride
and extracted with ethyl ether (4ꢂ 10 mL; caution: emulsions may
form). The combined ether layers were washed with brine, dried
(MgSO4), filtered and concentrated in vacuo to afford the desired
amidoxime.
NMR (400 MHz, CDCl3) d 160.8, 46.4, 25.0, 19.6, 10.7. IR (CH2Cl2)
3207 (br), 2967(s), 2874 (s), 1628 (s). ESI-MS (CH3OH) 143.04
(MþH), 165.1 (MþNa), 181.2 (MþK).
3.3.5. Amidoxime 10e. The crude product was obtained as a yellow
oil, of which a portion was purified by silica gel flash column
chromatography (ethyl acetate, Rf¼0.30) to afford a yellow oil
(69 mg, calculated total yield 44%): 1H NMR (400 MHz, CDCl3)
d 9.47
(br, 1H), 7.43e7.04 (m, 5H), 5.62 (br s, 1H), 4.31 (d, J¼5.1 Hz, 2H),
2.21 (q, J¼7.5 Hz, 2H), 1.11 (t, J¼7.5 Hz, 3H). 13C NMR (400 MHz,
CDCl3)
d 156.1, 139.4, 128.7, 127.3, 126.8, 45.9, 22.1, 10.9. IR (neat)
3206 (br), 3085 (s), 3061 (s), 3028 (s), 2974 (s), 2935 (s), 2874 (s),
1646 (s). ESI-MS (CH3OH) 179.1 (MþH).
3.3.6. Amidoxime 10f. The product was purified by silica gel flash
column chromatography (1:1 ethyl acetate/hexane, Rf¼0.30) to
afford a yellow solid (92 mg, 56%): 1H NMR (400 MHz, CDCl3)
d 9.79
(br, 1H), 7.30 (m, 2H), 7.18e6.99 (m, 3H), 2.39 (q, J¼7.5 Hz, 2H), 1.02
(t, J¼7.5 Hz, 3H). 13C NMR (400 MHz, CDCl3)
d 154.2, 139.0, 129.2,
124.6, 124.2, 22.6, 10.8. IR (CH2Cl2) 3187 (br), 2978 (m), 2939 (m),
3.3. General procedure for the synthesis of amidoximes using
n-butyllithium (method B)
2877 (m), 1641 (s), 1598 (s). ESI-MS (CH3OH) 165.0 (MþH).
A solution of amine (4 mmol, freshly distilled over sodium hy-
dride) in dry THF (1.5 mL) in a nitrogen-flushed 2-neck 50 mL RBF
fitted with a condenser and septum was cooled to ꢀ78 ꢁC, then
n-butyllithium (2.5 mL of 1.6 M solution in hexanes, 4 mmol) was
added. After warming the reaction mixture to rt and then back to
0 ꢁC, nitroalkane (1 mmol, freshlydistilled over sodium hydride) was
added dropwise. The septum was replaced with a glass stopper, and
the resulting suspension was brought to reflux for 3 h, (note: the stir
bar was agitated to dislodge any solids sticking to the walls of the
flask). The reaction suspensionwas cooled to 0 ꢁC and acidified to pH
2 with 3 M HCl. The bulk of THF was removed in vacuo and the re-
sidual aqueous phase was washed with ethyl ether (4ꢂ5 mL), cooled
to 0 ꢁC and then basified to pH 10 using 3 M NaOH. The resulting
3.3.7. Amidoxime 10g. The product was obtained as a light yellow
solid (47 mg, 41%, mp 73e75 ꢁC): 1H NMR and 13C NMR matched
with literature7 values: 1H NMR (400 MHz, CDCl3)
d 9.29 (br, 1H),
6.85 (d, J¼11.1 Hz, 1H), 5.17 (br d, J¼11.1 Hz, 1H), 1.25 (s, 9H). 13C
NMR (400 MHz, CDCl3)
d 142.6, 50.0, 30.6.
3.3.8. Amidoxime 10h. The product was obtained as an orange solid
(50.7 mg, 40%): 1H NMR matched with literature10 values: 1H NMR
(400 MHz, CDCl3)
d
8.88 (br, 1H), 3.25 (m, 5H), 2.06 (s, 3H), 1.86 (m,
156.6, 46.7, 25.0, 11.9.
5H). 13C NMR (400 MHz, CDCl3)
d
3.3.9. Amidoxime 10i. The product was obtained as a yellow solid
(29.4 mg, 26%): 1H NMR (300 MHz, CDCl3)
9.59 (br, 1H), 5.86 (m,
d

G. Sanguineti et al. / Tetrahedron 67 (2011) 10208e10211
10211
1H), 5.42 (br s, 1H), 5.17 (m, 2H), 3.75 (s, 2H), 1.85 (s, 3H). 13C NMR
(300 MHz, CDCl3) 152.9, 135.8, 115.6, 44.8, 14.7. IR (CH2Cl2) 3241
provided by NSF (CHE 7904825; PGM 8018643) and NIH
(RR02002).
d
(br), 3081(m), 2928 (m), 2859 (m), 1651 (s). ESI-MS (CH3OH) 115.12
(MþH).
References and notes
3.3.10. Amidoxime 10j. The crude product was obtained as a yellow
solid, of which a portion was purified by trituration with CH2Cl2
(2ꢂ2 mL) to afford a yellow solid (143 mg, calculated total yield
1. Simoneau, C. A.; Strohl, A. M.; Ganem, B. Tetrahedron Lett. 2007, 48, 1809.
2. (a) Copenhaver, J. W. U.S. Patent 2,786,865, 1957; Chem. Abstr. 1957, 51, 77105;
(b) Buchanan, J. B. U.S. Patent 3,787,470, 1974; Chem. Abstr. 1974, 80, 82059.
3. Keller, T. H.; Yelland, L. J.; Benn, M. H. Can. J. Chem. 1984, 62, 437.
4. Reviews: (a) Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas, K. E.; Varella,
E. A.; Nicolaides, D. N. Curr. Pharm. Des. 2008, 14, 1001; (b) Nicolaides, D. N.;
Varella, E. A. Suppl. B In The Chemistry of Acid Derivatives; Patai, S., Ed.; John
Wiley: New York, 1992; Vol. 2, p 875.
5. While amidines have been prepared by reductive deoxygenation of amidox-
imes,6 to our knowledge the transformation of 10 into N,N0-diphenylpropio-
namidine appears to be the first example of an amidoxime-to-amidine
transformation by nucleophilic addition and elimination of NH2OH.
6. (a) Mull, R. P.; Mizzoni, R. H.; Dapero, M. R.; Egbert, M. E. J. Med. Chem. 1962, 5,
651; (b) Nadrah, K.; Dolenc, M. S. Synlett 2007, 1257.
68%, mp 160.5e162 ꢁC). 1H NMR (300 MHz, DMSO-d6)
d 9.85 (s, 1H),
9.12 (s, 1H), 8.16 (d, J¼2.0 Hz, 1H), 7.91 (d, J¼8.6 Hz, 1H), 7.78 (dd,
J1¼8.6 Hz, J2¼2.0 Hz, 1H), 2.02 (s, 3H). 13C NMR (300 MHz, DMSO-
d6)
d
151.3, 145.9, 136.0, 131.6 (q, J¼31.8 Hz), 124.6, 120.9, 119.8,
116.5, 114.5 (q, J¼5.3 Hz), 13.9. IR (CHCl3) 3356 (s), 3320 (m), 3249
(m), 3105 (m), 2228 (s), 1612 (s), 1544 (s). ESI-MS (CH3OH) 244.08
(MþH).
7. Apasov, E. T.; Kalinin, A. V.; Strelenko, Y. A.; Tartakovskii, V. A. Izv. Akad. Nauk
SSSR, Ser. Khim. 1988, 2873.
Acknowledgements
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Funding was provided by the NIH (GM 008500 Training Grant
Support for HVL). Support of the Cornell NMR Facility has been
10. Bushey, D. F.; Hoover, F. C. J. Org. Chem. 1980, 45, 4198.