Solid-phase supported nitrosocarbonyl intermediates: Old scope and new limitations in the organic synthesis

Article abstract of DOI:10.1016/j.tetlet.2017.07.026

Nitrosocarbonyl intermediates on solid polystyrenic support are generated at room temperature by the mild oxidation of resin-bound stable nitrile oxides. They undergo one-pot ene reactions with tetramethyl- and trimethyl-ethylene and other highly substitu

Full text of DOI:10.1016/j.tetlet.2017.07.026

Accepted Manuscript
Solid-phase supported nitrosocarbonyl intermediates: old scope and new limi-
tations in the organic synthesis
Bhupendra Prasad Joshi, Misal Giuseppe Memeo, Paolo Quadrelli
PII:
S0040-4039(17)30872-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.026
TETL 49108
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
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5 July 2017
6 July 2017
Please cite this article as: Joshi, B.P., Memeo, M.G., Quadrelli, P., Solid-phase supported nitrosocarbonyl
intermediates: old scope and new limitations in the organic synthesis, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.07.026
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Graphical Abstract
Solid-phase supported nitrosocarbonyl intermediates: Leave this area blank for abstract info.
old scope and new limitations in the organic synthesis.
Bhupendra Prasad Joshi, Misal Giuseppe Memeo and Paolo Quadrelli*
O
O
O
MeO
O
O
H
W'
W'
N
N
N
OH
O
Transesterification
Reaction
OH
Ene
Reaction
Y: 21-27% O
O
O

1
Tetrahedron Letters
journal homepage: www.els evier.com
Solid-phase supported nitrosocarbonyl intermediates: old scope and new limitations in
the organic synthesis
Bhupendra Prasad Joshi,a Misal Giuseppe Memeob and Paolo Quadrellib∗
a Institute of Himalayan Bioresources Technology, C.S.I.R., Palampur (H.P.) – 176061, India.
b Dipartimento di Chimica, Università degli Studi di Pavia, Viale Taramelli 12, 27100 – Pavia, Italy.
ARTICLE INFO
ABSTRACT
Article history:
Received
Nitrosocarbonyl intermediates on solid polystyrenic support are generated at room temperature
by the mild oxidation of resin-bound stable nitrile oxides. They undergo one-pot ene reactions
with tetramethyl- and trimethyl-ethylene and other highly substituted olefins. Less substituted
ethylenes as well as cyclohexene and cyclopentene are heavily disfavoured and nitrosocarbonyls
on solid phase undergo fast dimerization and/or decomposition pathways. These outcome
strongly limit the SP applications in organic synthesis, although applicable to structurally
specific N-alkenyl hydroxamic acids.
Received in revised form
Accepted
Available online
Keywords:
Nitrosocarbonyl intermediates
Solid Phase Synthesis
Nitrile oxides
2009 Elsevier Ltd. All rights reserved.
Ene reactions
Hetero Diels-Alder cycloaddition
The Solid Phase (SP) synthesis of small molecules is the
subject of extensive research activities,1 since it represent one of
the largely applied ways to generate small libraries suitable for
combinatorial chemistry. Applications of these methodologies
and other high throughput synthetic technologies often help the
search of core structures of pharmaceuticals agents or represent
useful approaches towards synthetic intermediates.2 Our
traditional research interests in nucleoside chemistry prompted us
in furtherly investigating SP approaches to these relevant
compounds by means of 1,3-dipolar cycloaddition and
acylnitroso intermediates chemistry.
The 1,3-dipolar cycloaddition reactions are an example of one
of the most powerful tools to prepare families of heterocyclic
compounds whose importance in the medicinal chemistry field
has been proven by the increasing attention in literature.3 Some
methods have been suggested to perform 1,3-dipolar
cycloadditions on SP4 and, among these, the chemistry of nitrile
oxides5 found applications in the syntheses of isoxazolines and
isoxazolidines or other related compounds, even if limited to few
examples.
reactions through the site-site isolation induced by the solid
support. The longer half-life of nitrile oxides (up to 24 h) allowed
studying possible applications for preparing heterocyclic
compounds with a wide range of dipolarophiles or for other
synthetic elaborations.6 The most intriguing transformation is the
conversion of SP supported nitrile oxides into nitrosocarbonyl
intermediates 3 by the mild oxidation with N-methylmorpholine
N-oxide (NMO).7 By application of the well-established solution
chemistry,6 properly tuned up for the case at hand, these fleeting
intermediates could be generated for the first time on SP and
instantly trapped with suitable dienes affording the resin-bound
Hetero Diels-Alder (HDA) cycloadducts 4, isolated upon
cleavage in moderate yields (20-30%).8
CHO
O
O
DIC/DMAP
+
O
W'
SP
OH
DCM, r.t., 48h
W'
CHO
COOH
W-OH
1
(i) NH2OH
(ii) NCS
(iii) Et3N
O
O
O
We have demonstrated that a stable aromatic nitrile oxide can
be prepared on SP upon coupling the 4-carboxybenzaldehyde to a
Wang resing W-OH and converting the resin-bound aldehyde 1
into the stable 1,3-dipole 2 following the previously established
protocols (Scheme 1).6
The stability of the nitrile oxide 2 is secured by overtaking the
well-known tendency of these dipoles to undergo dimerization
———
NMO
DCM
O
O
O
W'
W'
W'
N
O
N
_
+
C=N-O
O
O
O
4
3
2
Scheme 1. SP supported nitrile oxide, conversion into
nitrosocarbonyl and HDA cycloaddition reaction.
∗ Corresponding author. Tel. +39 0382 987315; Fax. +39 0382 987323; e-mail: paolo.quadrelli@unipv.it

2
Tetrahedron Letters
Although extremely unstable9 other than highly reactive,
indicates the site of the attachment to the nitrosocarbonyl
nitrogen atom N in the product formation). The resulting
suspension was vigorously shacked for
temperature. After this period of time, the resins were filtered and
carefully washed with DCM, MeOH, DCM and finally dried
under vacuum overnight.
nitrosocarbonyl intermediates can behave as “Super-Enophiles”
and we have reported that ene adducts can be successfully
obtained by trapping the nitrosocarbonyl intermediates generated
by the mild oxidation of nitrile oxides with a number of olefins in
a convenient one-pot procedure at room temperature.10
2 days at room
On pursuing our studies on the applications of SP synthesis,
we completed the outline on the nitrosocarbonyls on SP and wish
to report here the results concerning the SP ene reactions of these
fleeting intermediates and the discussion about the limitations of
the proposed methodology. The results of these investigations
would help the understanding of potential applications of
nitrosocarbonyl SP chemistry to the synthesis of nucleoside
In details, the oxidizing agent is added as first to the
suspension, followed (after 1 minute) by the olefin of choice with
the aim to prevent the 1,3-dipolar cycloaddition between the
supported nitrile oxide moiety and the olefins. This precaution
was adopted of course in particular for the less substituted
alkenes which are known to act as dipolarophiles, preferentially.
The presence of the supported ene adducts 5 on the resins was
verified through the FT-IR (Diffuse Reflectance, DR) and the
gel-phase 13C-NMR spectra, at first.11 The FT-IR spectra did not
give significative indications; it can be deducted, from the
ubiquitous presence of large band between 2500-3500 cm-1, the
occurrence of the OH group absorption for some of the tested
alkenes (olefins a-e). The gel-phase 13C-NMR spectra of the
adducts 5a-d showed, besides the typical signals attributable to
the resin bulk, some diagnostic signals depending on the type of
the ene partner, which are gathered in the Table 1. On the other
hand, the spectra of the presumed adducts 5e-k were less
promising. Having in mind the previously reported results on ene
reactions of nitrosocarbonyls,6,10,12 the choice of the olefins to
perform this study on SP included a selection of the more
substituted along with those alkenes which gave the ene adducts
as the major product with respect to the competing 1,3-dipolar
cycloadduct as well as some examples of double or single
substituted olefins. From the analyses of the 13C-NMR spectra the
signals attributable to the ene adducts could be detected just in
products 5a-d. Repeated experiments conducted on different
resin batches confirmed the above results.
O
O
O
NMO
DCM
O
O
H
O
W'
W'
W'
r.t., 48h
N
N
O
OH
C=N-O
O
O
2
3
5
MeOH/THF (1:3)
Et3N, KCN
∆, 2h
O
W-OH
+
MeO
N
OH
O
6
analogues, a typical research activity pursued by our group.
Scheme 2. SP supported nitrile oxide, conversion into
nitrosocarbonyl and HDA cycloaddition reaction.
Wang resin [p-benzyloxybenzyl alcohol polystyrene (PS)
resin, loading 1.00 mmol/g from Novabiochem; W-OH]
supported nitrile oxide 2, (Scheme 2) freshly prepared according
to the reported procedure,6 was swollen in dichloromethane
(DCM) and an excess (5 equivs.) of selected olefins a-k (see
Table 1) was added along with 2 equivs. of NMO (the dot
Table 1. Olefins, diagnostic 13C-NMR signals of the supported ene adducts 5, yields of cleaved adducts 6 and 1H-NMR signals
of the aliphatic moieties of the adducts 6 produced via the reaction path sketched in the Scheme 2.
Entry
Olefins
5
Diagnostic 13C-NMR signals of
supported ene adducts 5 (δ,
CDCl3)
Cleaved
adducts 6,
yields %
1H-NMR signals for the aliphatica moieties
of adducts 6 (δ,CDCl3)
1
a
14.1; 20.9; 60.3; 171.5
27
1.49 (s, 6H, CH3); 1.75 (s, 3H, CH3-C=);
3.97 (s, 3H, CH3O); 4.85 and 4.89 (b, 2H,
CH2=).
2
b
13.5; 20.5; 59.1; 191.5
25
1.30 (d, 3H, CH3); 1.73 (s, 3H, CH3-C=);
3.97 (s, 3H, CH3O); 4.90 and 5.00 (bs, 2H,
CH2=); 5.04 (q, 1H, CH).
3
4
5
c
13.3; 53.3; 115.1; 191.6
21
23
1.25 (d, 3H, CH3); 1.82 (s, 3H, CH3); 1.88
(d, 3H, CH3-CH=); 3.88 (s, 3H, CH3O);
5.45 (s, 1H, CH=); 5.48 (q, 1H, CH).
d
1.10 (t, 3H, CH3); 1.53 (q, 2H, CH2); 1.88
(s, 3H, CH3-C=); 3.89 (s, 3H, CH3O); 5.50
(s, 2H, CH=); 5.48 (q, 1H, CH).
13.4; 13.8; 30.8; 54.2; 191.4
No reaction
aThe aromatic signals are generally found between 7.6 and 8.1 δ.

3
The gel-phase 13C-NMR spectra of resins 5(a-d) were
compared with the reference spectra of the ene adducts obtained
from independent syntheses with the same olefins and
nitrosocarbonyl benzene. No signals attributable to the ene
products were found in the cases of resins 5e-k.[6,10]
8a,b are obtained in nice keeping with other studies on the
HNO generation.14 Upon cleavage under transesterification
conditions the terephtalates 9a,b are isolated.
These results are somewhat dissimilar with those obtained in
the case of HDA cycloadditions where the products yields were
good and in the cases of other ene reactions performed with
aromatic nitroso Ar(Het)-NO derivatives.15 However, it must be
noted that in some and specific cases, the ene reaction was
proved to behave in an excellent way; it is the case of the Rink
amide resin where a pyridine-nitroso moiety was linked to solid
support. This resin-bound compound sequestered a single
component from crude plant seed extracts via chemo- and
regioselective ene reaction.15,16
The final confirm of the presence of the supported ene
compounds 5 came from the cleavage which was conducted
through transesterification reaction (Scheme 2) according to the
well-established protocol, already reported for the HDA
cycloadducts.6
The resins 5 were allowed to swell in a MeOH/THF (1:3)
mixture in the presence of an excess (10 equivs.) Et3N and 2
equivs. of KCN. After refluxing for 2-3 hrs monitoring the
reactions by TLC, the resins were filtered and washed with THF,
MeOH, DCM and dried under vacuum to be submitted to recycle.
The concentrated organic phases were taken up with DCM, then
washed with water and dried. Upon evaporation of the solvent,
the crude mixtures were purified through column
chromatography or preparative TLC. Only the pure adducts 6a-e
were isolated in moderate yields as a result of repeated
independent experiments (Table 1). The structures were
attributed upon their spectroscopic data and the most significative
1H-NMR signals corresponding to the aliphatic moieties are
reported in the Table 1.
For sake of completeness and to find some elucidations on
these opposite reaction outcomes, competition experiments were
done both in solution and on SP by generating the
nitrosocarbonyl intermediate through oxidation with NMO in the
/
tetramethyl-ethylene or 1,3-cyclohexadiene tetramethyl-
presence of equimolecular amounts of cyclopentadiene
/
ethylene (Scheme 4). The results obtained in classical solution
chemistry display a neat preference toward only the HDA
cycloaddition path since cycloadducts 12a,b were obtained in
83% yields after purification. No signals attributable to the ene
adduct 13 were found even in the crude mixtures. Identical
results gave the experiments run on SP. The resins were
identified as the cycloadducts to dienes 4a,b and from the
analysis of the gel-phase 13C-NMR no signals were attributed to
ene adduct 5a. Standard cleavage gave the HDA cycloadducts
14a,b in fair yields, confirming the given results.7
The cleavage outcome confirmed that the highly substituted
olefins are able to capture the supported nitrosocarbonyl
affording the corresponding ene adducts in fair yields. On the
other hand, the less substituted alkenes as well as simple cyclic
olefins failed. More complex cyclic alkenes were also tested but
unsuccessfully. Three competitive reactions, namely the desired
ene addition, the fast dimerization/decomposition of
nitrosocarbonyls and in some cases the undesired 1,3-dipolar
cycloaddition of the nitrile oxide precursor, may account for the
low yields observed on SP with respect to the classical solution
phase synthesis. Moreover, further difficulties arise in order to
drive the reaction towards a single pathway since the ene reaction
rate is lower than the dimerization/decomposition or
cycloaddition paths, and this fact is also stressed by the SP
environment which requires excess of reagents to push up both
reaction rates and yields. Generally, from the cleavage solutions,
abundant and complex mixtures of products were collected,
mainly mono- and dimethyl-terephtalate (average 50%) whose
structures are related to the decomposition of the nitrosocarbonyl
moiety (Scheme 3).6,8,12
Solution chemistry
(
)
n
Ph
O
O
HO
(
)
n
NMO, DCM
r.t., 48h
Ph-C=N-OH
N
COPh
COPh
Cl
N
N
O
2 equivs.; ratio = 1:1
10
11
12
13
n
1
2
4
a
b
12
a
SP chemistry
b
O
O
O
(
)
O
n
O
O
W'
W'
(
)
W'
n
N
N
N
O
O
OH
5 equivs.; ratio = 1:1
O
O
O
3
4
5a
MeOH/THF (1:3)
Et3N, KCN
∆, 2h
MeOOC
Y (%)
14a 25
14b 21
(
)
n
N
O
14a,b
O
Scheme 4. Competition experiments on SP between and HDA
cycloaddition and ene reaction.
_
O
O
O
+
+
NH2R3
N
O
r.t., 48h
O
O
+
[ NO ]
W'
+
W'
We can affirm that the low yields of the cleaved ene adducts 6
from highly substituted olefins can be related to the very low rate
of the ene pathway when these fleeting intermediates are
supported on Wang resins. Time consumes the supported
O
N
O
O
O
NMO
Excess
3
7
ROH (R = H, Me)
nitrosocarbonyl
intermediate
that
enters
the
O
COOMe
dimerization/decomposition routes, mainly preferred to the 1,3-
dipolar cycloaddition. However, these results also testify the
efficiency of the oxidation of nitrile oxides to nitrosocarbonyls
on the resins. We cannot exclude a different outcome on other
solid supports; but these tests were not conducted.
MeOH/THF (1:3)
O
W'
OR
Et3N, KCN
∆, 2h
O
O
OR
9a,b
8a,b
Recently, we described a ene-based approach to nucleoside
analogues by preparing a cyclopentene-substituted heterobase of
type 14. In our mind, we were interested in functionalizing the
cyclopentene moiety with the solid supported nitrosocarbonyl 3
with the aim to obtain the SP derivative 15 (Scheme 5).
Scheme 3. SP supported nitrosocarbonyl decomposition
pathway.
We believe that the excess NMO can destroy the
nitrosocarbonyl through addition to the carbonyl group and loss
of NO (or nitric oxide).8,13 Typically, such a large amount of
oxidant has never been used in solution chemistry. In the
presence of methanol (or water due to humidity) the acid/ester
We made a single test on this idea. However, as expected, the
experiment failed and no signals corresponding to the supported

4
Tetrahedron
compound 15 were detected on the resin in a gel-phase 13C
Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233-
1251. (f) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S.
P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401. (g)
Seneci, P. Solid-Phase Synthesis and Combinatorial Technologies,
Wiley, J. and Sons, New York, 2000.
N
O
N
3. (a) For synthetic applications of nitrile oxides see: Jager, V.;
Colinas, P. A. Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Product, Padwa, A.
and Pearson, W. H. Ed.; Wiley, J. and Sons, Eds., Hoboken (NJ):
2003, pp. 361-472. (b) Booth, S.; Hermkens, P. H. H.; Ottenheijm,
H. C. J.; Rees, D. C. Tetrahedron 1998, 54, 15385-15443 and
references therein. (c) Zaragoza Dörwald, F. Organic Synthesis on
Solid Phase, Wiley-VCH, Weinheim, 2000, pp. 369-372. (d)
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Samuelson, R. E.; Kurth, M. J. Chem. Rev. 2001, 101, 137-202. (f)
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(b) Lorsbach, B. A.; Miller, R. B.; Kurth, M. J. J. Org. Chem.
1996, 61, 8716-8717. (c) Kurth, M. J.; Randall, L. A. A.;
Takenuchi, K. J. Org. Chem. 1996, 61, 8755-8761. (d)
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6803.
Ene
reaction
O
O
W'
+
N
O
O
W'
O
N
14
3
15
OH
O
Transesterification
N
O
MeO
N
OH
16
O
NMR spectrum.
Scheme 5. SP supported nitrosocarbonyl functionalization
strategy to nucleoside analogues.
5. (a) Beebe, X.; Schore, N. E.; Kurth, M. J. J. Am. Chem. Soc. 1992,
114, 10061-10062. (b) Beebe, X.; Schore, N. E.; Kurth, M. J. J.
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In case of success, the latter compound would have been
cleaved from the solid support by transesterification to furnish
the final product 16.17 Unfortunately the reactivity of
cyclopentene in SP ene reaction is completely unsatisfactory and
these preliminar but fundamental tests shed a strong light on the
limitations of the applied model of synthesis of an hypothetical
library of nucleoside analogues.
TetrahedronLett. 2000, 41, 5617-5622. (f) Shankar, B. B.; Yang,
D. Y.; Girton, S.; Ganguly, A. K. Tetrahedron Lett. 1988, 39,
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P. Eur. J. Org. Chem. 2002, 1175-1183.
In conclusion, even though the method cannot be proposed to
prepare extended libraries of N-alkenyl hydroxamic acids on SP
or to be used in the derivatization of olefins for other synthetic
purposes, it discloses the limitations due to the high instability of
nitrosocarbonyl intermediates. The SP environment is unable to
prolong the life-time of nitrosocarbonyls in spite of the site-site
isolation which in theory could prevent their dimerization but not
decomposition by other reagents, especially when used in large
excess. Reasonably nitrosocarbonyls undergo a rapid cleavage to
the benzoyl radicals and nitric oxide,13,15 analogous to the
photochemical cleavage of α-hydroxy ketones18 or in Norrish
Type I processes.19 The mild conditions under which the
reactions were performed could made the protocol suitable for
the C-N bond formation on SP. However, only a limited range of
highly substituted olefins can be employed and in high
concentrations. These are the strong limitations of the protocol.
The synthetic elaboration towards amides20 through the easy
deoxygenation of the N-alkenyl hydroxamic acids seems to be
the only synthetic application of the protocol and needs further
investigations and developments to make the methodology
applicable, at least in some cases.
7. Quadrelli, P.; Mella, M.; Gamba Invernizzi, A.; Caramella, P.
Tetrahedron 1999, 55, 10497-10510.
8. For synthetic applications on nitroso compounds see: Memeo, M.
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9. Cohen, A. D.; Zeng, B.-B.; King, S. B.; Toscano, J. P. J. Am.
Chem. Soc. 2003, 125, 1444-1445.
10. Quadrelli, P.; Mella, M.; Caramella, P. Tetrahedron Lett. 1998,
39, 3233-3236.
11. Look, G. C.; Holmes, C. P.; Chinn, P.; Gallop, M. A. J. Org.
Chem. 1994, 59, 758-761.
12. Quadrelli, P.; Mella, M.; Caramella, P. Tetrahedron Lett. 1999,
40, 797-800 and unpublished results.
13. Memeo, M. G.; Dondi, D.; Mannucci, B.; Corana, F.; Quadrelli, P.
Tetrahedron 2013, 69, 7387-7394.
14. (a) Guthrie, D. A.; Kim, N. Y.; Siegler, M. A.; Moore, C. D.;
Toscano, J. P. J. Am. Chem. Soc. 2012, 134, 1962-1965. (b)
Adachi, Y.; Nakagawa, H.; Matsuo, K.; Suzuki, T. S.; Miyata, N.
Chem. Commun. 2008, 5149-5151.
15. (a) Krchnak, V.; Zajfcek, J.; Miller, P. A.; Miller, M. J. J. Org.
Chem. 2011, 76, 10249-10253. (b) Krchnak, V.; Waring, K. R.;
Noll, B. C.; Moellmann, U.; Dahse, H.-M.; Miller, M. J. J. Org.
Chem. 2008, 73, 4559-4567.
16. Krchnak, V.; Moellmann, U.; Dahse, H.-M.; Miller, M. J. J.
Comb. Chem. 2008, 10, 104-111.
17. Scagnelli, L.; Memeo, M. G.; Carosso, S.; Bovio, B.; Quadrelli, P.
Eur. J. Org. Chem. 2013, 3835-3846.
Acknowledgments
Financial support by University of Pavia and MIUR (PRIN
2011, CUP: F11J12000210001). Thanks are due to the University
of Pavia - C.I.C.O.P.S. for a research grant for B.P.J.
18. (a) Colley, C. S.; Grills, D. C.; Beslay, N. A.; Jockusch, S.;
Matousek, P.; Parker, A. W.; Towrie, M.; Turro, N. J.; Gill, P. M.
W.; George, M. W. J. Am. Chem. Soc. 2002, 124, 14952-14958.
(b) Ward, H. R. Free Radicals Kochi, J. K., Ed.; Wiley, J. and
Sons, New York, 1973; pp. 264-265.
References and notes
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449-472. (b) Franzen, R. G. J. Comb. Chem. 2000, 2, 195-214. (c)
Dolle, R. E.; Nelson, K. H. J. Comb. Chem. 1999, 1, 235-282. (d)
Van Maarseveen, J. H. Comb. Chem. High Throughput Screening
1998, 1, 185-214. (e) Gallop, M. A.; Barrett, R. W.; Dower, W. J.;

5
Supplementary Material
Experimental procedures and 13C NMR spectra of the Wang
resin solid-supported ene adducts 5a-d.

6
Tetrahedron
ꢀ Nitrosocarbonyls on solid polystyrenic
support are generated by oxidation of nitrile
oxides.
ꢀ They undergo one-pot ene reactions with
highly substituted olefins.
ꢀ Less substituted ethylenes are disfavoured
and nitrosocarbonyls fast dimerization
occurred.
ꢀ These outcome strongly limit SP
applications, although applicable to N-
alkenyl hydroxamic acids.