Ring expansions of acyloxy nitroso compounds

Article abstract of DOI:10.1016/j.tetlet.2015.09.002

Treatment of cyclopentanone and cyclobutanone-derived oximes with lead(IV) tetraacetate gives the bright blue acyloxy nitroso compounds, which upon basic hydrolysis yields the ring expansion product cyclic hydroxamic acids in 12-81% yield. Reactions of substituted cyclopentanones provide ring expanded products where the -NOH group regioselectively inserts to the more substituted position and gives a better yield compared to the treatment of the same ketone with a basic solution of Piloty's acid. Reaction of phosphines with acyloxy nitroso compounds generally generates a ring-expanded Beckmann rearrangement product that can be hydrolyzed to the corresponding lactam. Acyloxy nitroso compounds that undergo rapid hydrolysis to HNO do not show this ring expansion reactivity. These results further demonstrate the versatility of acyloxy nitroso compound to yield structurally complex materials.

Full text of DOI:10.1016/j.tetlet.2015.09.002

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ring expansions of acyloxy nitroso compounds
Mallinath B. Hadimani, Rajeswari Mukherjee, Ranjan Banerjee, Mai E. Shoman, Omar M. Aly,
⇑
S. Bruce King
Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of cyclopentanone and cyclobutanone-derived oximes with lead(IV) tetraacetate gives the
bright blue acyloxy nitroso compounds, which upon basic hydrolysis yields the ring expansion product
cyclic hydroxamic acids in 12–81% yield. Reactions of substituted cyclopentanones provide ring
expanded products where the –NOH group regioselectively inserts to the more substituted position
and gives a better yield compared to the treatment of the same ketone with a basic solution of Piloty’s
acid. Reaction of phosphines with acyloxy nitroso compounds generally generates a ring-expanded
Beckmann rearrangement product that can be hydrolyzed to the corresponding lactam. Acyloxy nitroso
compounds that undergo rapid hydrolysis to HNO do not show this ring expansion reactivity. These
results further demonstrate the versatility of acyloxy nitroso compound to yield structurally complex
materials.
Received 15 July 2015
Revised 24 August 2015
Accepted 2 September 2015
Available online xxxx
Keywords:
Acyloxy nitroso compounds
Cyclic hydroxamic acids
Ring expansion
Organic phosphines
HNO donors
Ó 2015 Elsevier Ltd. All rights reserved.
Introduction
ketones forms cyclic hydroxamic acids through the intermediacy
of the same
hydrolysis of 1-nitroso cyclopentyl acetate (2a) yields
a
-hydroxy C-nitroso species.21 However, the basic
The chemical properties of nitroxyl (HNO) biologically
distinguish it from other nitrogen oxides including nitric oxide
(NO).1–4 Nitroxyl readily dimerizes to ultimately form nitrous
oxide (N2O) and condenses with protein thiols to generate
disulfides and sulfinamides that mediate much of HNO’s distinct
biology.3–5 This electrophilic reactivity demands the use of HNO
donors in fundamental studies and such donors form potential
therapeutics for congestive heart failure, cancer, alcoholism, and
hemolytic disorders.6–13 Angeli’s salt (Na2N2O3) and Piloty’s acid
(PhSO2NHOH, N-hydroxy benzenesulfonamide) represent the most
widely used HNO donors but numerous structurally and mechanis-
tically diverse HNO donors have appeared, including acyloxy
nitroso compounds.14–19 While stable acyloxy nitroso compounds
react as N–O heterodienophiles,20 relatively little work describing
their synthetic potential has appeared and we report two distinct
ring expansions of acyloxy nitroso compounds.
a
six-membered ring cyclic hydroxamic acid (3a, 25% yield) with
little N2O (evidence of HNO) formation suggesting a strain-based
ring expansion.21 Given this common
a-hydroxy C-nitroso
intermediate, we pursued the idea that other small (4–5)
membered ring acyloxy nitroso compounds would rearrange to
cyclic hydroxamic acids under basic conditions.
Condensation of a series of four and five-membered ring
ketones (4a–g) with hydroxylamine gives the corresponding oxi-
mes (5a–g) in good yield (Scheme 2).
Treatment of these oximes with lead(IV) tetraacetate gives the
bright blue acyloxy nitroso compounds (2a–g), which were quickly
purified by passage through a short silica column and used without
further purification. Slow addition of a methanol solution of 2a–g
to a 2 M NaOH solution a 0 °C followed by work up generally
produces the corresponding cyclic hydroxamic acid (3a–g) in good
yield (12–81%, Scheme 2, Table 1).
As shown in Table 1, basic hydrolysis of 2a yields 3a in 25%
yield.20 Under these conditions, acyloxy nitroso compound (2a)
disappears and both ketone (4a) and oxime (5a) form as by-products.
Similar treatment of the acyloxy nitroso compound derived
from 2-methyl cyclopentanone (2b) gives the ring expanded cyclic
hydroxamic acid (3b) in 77% yield. This result demonstrates two
important features of this process: (1) the N-insertion occurs to
the more hindered side of the ketone as shown by NMR chemical
shift/splitting and integration analysis and (2) the yield vastly
Expansion to cyclic hydroxamic acids
Earlier work shows that 1-nitrosocyclohexyl acetate (1) hydro-
lyzes to an unstable a-hydroxy C-nitroso species that decomposes
to cyclohexanone and HNO (Scheme 1).21 The reaction of Piloty’s
acid under basic conditions with four and five-membered ring
⇑
Corresponding author. Tel.: +1 336 758 5774; fax: +1 336 758 4656.
E-mail address: kingsb@wfu.edu (S.B. King).
http://dx.doi.org/10.1016/j.tetlet.2015.09.002
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Hadimani, M. B.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.09.002

2
M. B. Hadimani et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
O
N
O
N
O
The ring expansion products (3a–g) from the corresponding ketones (4a–g)
O
O
OAc
H2O
KOH/ CH3OH-H2O
KOH/ CH3OH-H2O
Entry Starting ketone
Acyloxy nitroso
compound (2)
Product (3)
%
yield
+
N2O
(4)
1
O
AcO NO
AcO NO
AcO NO
O
OH
N
a
25
77
O
O
N
N
OAc
OH
O
H2O
O
O
N
OH
N
b
2a
3a
Scheme 1. Pathways of acyloxy nitroso compound hydrolysis.
O
O
OH
N
N
c
71
improves from the direct treatment of the ketone with basic solu-
tions of Piloty’s acid (77% vs 5%).21 Examination of the crude reac-
tion mixture by NMR spectroscopy shows the formation of only a
single regioisomer. The yield improvement likely results from the
lack of a requirement to generate the N-anion of Piloty’s acid under
O
AcO NO
AcO NO
O
N
OH
d
12
63
67
O
O
O
OH
e
these reaction conditions in the presence of acidic ketone a-hydro-
gens. Other substituted acyloxy nitroso compounds (2c–f)
smoothly rearrange to form the more hindered cyclic hydroxamic
acids (3c–f). Single crystal X-ray crystallographic analysis clearly
defines the structure of 3c and 3e and confirms that rearrangement
occurs to the most hindered side (Fig. 1). Exposure of the cyclobu-
tanone-derived acyloxy nitroso compound (2g) to basic conditions
yields the five-membered ring hydroxamic acid (3g) in 81% yield
(Scheme 2, Table 1).
O
AcO NO
Ph
OH
Ph
Ph
N
O
f
O
OAc
NO
OH
N
g
81
Ph
Ph
Ph
Scheme 1 depicts a likely mechanism for these transformations.
Basic hydrolysis of the acetate group would give the unstable
release HNO,14,16,27 the reaction of acyloxy nitroso compounds
and triaryl phosphines was explored.
a-hydroxy C-nitroso species that undergoes ring expansion to the
cyclic hydroxamic acid as previously demonstrated suggesting that
the electrophilic nitroso group coupled with the strain within the
smaller rings induces rearrangement to the cyclic hydroxamic
acid.21 These results show this pathway operates in four and five
membered ring acyloxy nitroso compounds but not in the larger
non-strained six membered ring compound. The reaction of
substituted acyloxy nitroso compounds-derived from substituted
cyclopentanones affords ring expanded products where the –NOH
group regioselectively inserts to the more substituted position
similar to other well-known ring expansion rearrangements
(Baeyer–Villiger).21 This methodology provides a direct and rapid
method to generate structurally diverse cyclic hydroxamic acids
from four and five membered ring ketones that are not easily
accessible other methods (including the reaction of N-hydroxyben-
zenesulfonamide with the ketone under basic conditions).22
Treatment
of
1-nitrosocyclohexyl
acetate
(1)
with
triphenylphosphine (TPP) in benzene or toluene at room temperature
results in an exothermic reaction with the disappearance of the
deep blue color. After 60 min, analysis of the reaction mixture by
31P NMR spectroscopy and mass spectrometry shows the genera-
tion of triphenyl phosphine oxide (d = 26.09 ppm, m/z = 279.1,
95% yield, Scheme 3), which was identical to a standard. In
addition to phosphine oxide, a seven membered ring Beckmann
rearrangement product (6, Scheme 3) forms in 55% yield that
was identified by GC–MS (m/z = 156) and both 1D and 2D NMR
spectroscopy (Supporting information). Acid-catalyzed hydrolysis
of 6 (1 M HCl) yields caprolactam (7, Scheme 3), which was also
identical to a known standard by both MS and NMR analysis.
The reaction of 1 with TPP was monitored using UV–Vis
spectrometry following the disappearance of the absorbance at
667 nm corresponding to the nitroso group (Table 2). Incubation
of 1 with TPP in benzene or toluene at room temperature shows
an exponential decrease of 1 over time and the rate shows a linear
dependence on the concentration of phosphine (Table 2) suggest-
ing a bimolecular reaction. Under pseudo-first order conditions
(10 equiv of TPP) an observed rate constant of k = 3.5 minÀ1 with
a half-life of t1/2 = 0.2 min is observed (Table 2). As expected, these
results reveal that phosphines react faster with most acyloxy
nitroso compounds than these compounds hydrolyze to HNO
(for 1, t1/2 = 800 min, pH 7.6 1:1 Tris buffer/MeOH).27
Phosphine-mediated Beckmann rearrangement
During the investigation of acyloxy nitroso compounds as
potential HNO donors, our group also examined the reactions of
phosphines as new HNO traps through their formation of unique
aza-ylide products.23,24 Phosphines react as nucleophiles with a
variety of electrophilic nitroso compounds (C-nitroso, S-nitroso,
and H-NO) to yield numerous products depending on the structure
of the phosphine and the nitroso substrate.25,26 Given the known
reactivity and the potential of acyloxy nitroso compounds to
HO
O
O
N
O
n
N
O
O
NH2OH. HCl
Pb(OAc)4
NaOH / MeOH
OH
N
n
n
n
4
5
2
n = 1, 2
3
Scheme 2. Conversion of ketones to cyclic hydroxamic acids via acyloxy nitroso compounds.
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M. B. Hadimani et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Figure 1. X-ray crystallography data for hydroxamic acids 3c and 3e.
O
O
N
O
N
O
Ph3P, Benzne
rt
O
O
1M HCl
H2O
O
HN
O
N
O
10
1
7
6
+ Ph3P=O
O
O
O
+
Ph3P=O
Scheme 3. Reaction of 1-nitrosocyclohexyl acetate (1) with TPP.
OH
N
O
N
O
11
Table 2
Kinetics of the reaction of compound 1 with TPP in benzene
O
1
Entry Compound TPP
(equiv)
Observed rate constant (kobs
,
t1/2
(min)
minÀ1
)
Scheme 5. Reaction of NCA and NCP with TPP.
1
2
3
4
1
1
1
1
1
2
5
0.09
0.18
0.5
8
3.7
1.4
0.2
electrophilic phosphonium ion adduct (8, Scheme 4). Beckman
rearrangement of this phosphonium ion results in ring expansion
to 9 with the formation of triphenyl phosphine oxide (Scheme 4).
Addition of acetate to 9 gives 6 and hydrolysis produces caprolactam
(7, Scheme 4). Such a mechanism finds direct precedence in a
similar ring expansion during the reaction of 1-chloro-1-nitrosocy-
clohexane during its reaction with triphenyl phosphine.28
Treatment of 1-nitrosocyclohexyl pivalate (10) with TPP in ben-
zene also gives triphenyl phosphine oxide and the corresponding
pivalate ester (11, Scheme 5). 1H and 13C NMR spectroscopy both
confirm the structure of 11. Further support of Scheme 4 as a
plausible rearrangement mechanism comes from the treatment
of 1 with triphenyl phosphine in the presence of excess pivalic
acid, which also yields 11 suggesting the trapping of 9 by the free
carboxylic acid.
Addition of 1-nitroscyclohexyl trifluoroacetate (12, Scheme 6),
an acyloxy nitroso compound that rapidly hydrolyzes to HNO
(t1/2 = 121 ms),5 to a solution of TXPTS (tris(2,4-dimethyl-5-sul-
fophenyl)phosphine trisodium salt) in 1:1 acetonitrile/Tris buffer
(0.1 M, pH 7.6) gives the corresponding phosphine oxide and aza-
ylide. GC–MS analysis also reveals the formation of cyclohexanone
from the reaction that further supports hydrolysis of 12 to HNO.
These results suggest that 12 rapidly hydrolyzes to HNO, which
is trapped as the aza-ylide by TXPTS as previously described.26
10
3.5
O
O
N
O
Ph3P, Benzne
rt
H2O
O
O
HN
+
Ph3P=O
+
O
N
7
1
6
Ph3P
O
N
CH3COO-
N
O
Ph3P
O
O
N
N
CH3COO-
9b
9a
Ph3P=O
8
Scheme 4. Proposed mechanism for the reaction of 1-nitrosocyclohexyl acetate (1)
with TPP.
Scheme 4 shows the proposed mechanism for the conversion of
1 to caprolactam upon reaction with triphenyl phosphine.
Addition of the phosphine to the nitroso oxygen atom
with simultaneous loss of the acetate group would yield the
Please cite this article in press as: Hadimani, M. B.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.09.002

4
M. B. Hadimani et al. / Tetrahedron Letters xxx (2015) xxx–xxx
CF3
O
O
O
Supplementary data
N
O
TXPTS
O
+
NH
+
R3P
R3P
Supplementary data (experimental details of the synthetic
procedures and characterization data for all compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.09.002.
CH3CN:Buffer (1:1)
12
Scheme 6. Reaction of 12 with TXPTS in 1:1 acetonitrile/Tris buffer (0.1 M, pH 7.6).
References and notes
Overall, these results show that acyloxy nitroso compounds
directly react with phosphines to yield ring expanded products
unless they first hydrolyze to HNO, which then reacts with the
phosphine to give the expected products.
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In summary, this work shows that acyloxy nitroso compounds
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nitroso compounds-derived from four and five membered ring
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Author contributions
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The manuscript was written through contributions of all
authors. M.B.H., R.M., R.B., and M.E.S. performed all the experi-
ments. S.B.K. and O.M.A. wrote and edited the manuscript. All
authors have given approval to the final version of the manuscript.
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Furdui, C. M.; King, S. B. ACS Chem. Biol. 2010, 5, 405–414.
24. Reisz, J. A.; Zink, C. N.; King, S. B. J. Am. Chem. Soc. 2011, 133, 11675–11685.
25. Reisz, J. A.; Klorig, E. B.; Wright, M. W.; King, S. B. Org. Lett. 2009, 11, 2719–
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Acknowledgements
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This project was supported by the National Institutes of Health
(HL62198, S.B.K.). We acknowledge the financial support of an
Egyptian Government studentship to Mai E. Shoman through the
Channel system between Minia University, Egypt and Wake Forest
University. Dr. Cynthia Day (Wake Forest University) performed
the X-ray crystallographic studies.
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Please cite this article in press as: Hadimani, M. B.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.09.002