Synthesis of N,N,O-Trisubstituted Hydroxylamines by Stepwise Reduction and Substitution of O-Acyl N,N-Disubstituted Hydroxylamines

Article abstract of DOI:10.1021/acs.orglett.6b00556

Diverse N,N,O-trisubstituted hydroxylamines, an under-represented group in compound collections, are readily prepared by partial reduction of N-acyloxy secondary amines with diisobutylaluminum hydride followed by acetylation and reduction of the so-formed O-acyl-N,N-disubstituted hydroxylamines with triethylsilane and boron trifluoride etherate. Use of carbon nucleophiles in the last step, including allyltributylstannane, silyl enol ethers, and 2-methylfuran, gives N,N,O-trisubstituted hydroxylamines with branching α- to the O-substituent. N,N-Disubstiuted hydroxylamines are conveniently prepared by reaction of secondary amines with dibenzoyl peroxide followed by diisobutylaluminum hydride reduction.

Full text of DOI:10.1021/acs.orglett.6b00556

Letter
pubs.acs.org/OrgLett
Synthesis of N,N,O‑Trisubstituted Hydroxylamines by Stepwise
Reduction and Substitution of O‑Acyl N,N‑Disubstituted
Hydroxylamines
Sandeep Dhanju and David Crich*
Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
*
S Supporting Information
ABSTRACT: Diverse N,N,O-trisubstituted hydroxylamines, an
under-represented group in compound collections, are readily
prepared by partial reduction of N-acyloxy secondary amines with
diisobutylaluminum hydride followed by acetylation and reduction of
the so-formed O-acyl-N,N-disubstituted hydroxylamines with triethylsilane and boron trifluoride etherate. Use of carbon
nucleophiles in the last step, including allyltributylstannane, silyl enol ethers, and 2-methylfuran, gives N,N,O-trisubstituted
hydroxylamines with branching α- to the O-substituent. N,N-Disubstiuted hydroxylamines are conveniently prepared by reaction
of secondary amines with dibenzoyl peroxide followed by diisobutylaluminum hydride reduction.
he hydroxylamine moiety is an interesting functional
hydroxylamine moiety is found in biologically active natural
T
group with the potential to enrich compound collections,
products and their analogues, such as the anticancer
1
22,23
in which it is currently under-represented, by increasing the
calicheamicins and esperamicins,
tRNA synthase inhibitor SB-219383, and a recent selective
the potent bacterial
3
3
2
24
fraction of sp -hybridized atoms (Fsp ) without the synthetic
complication of an additional stereogenic center. This is
25
inhibitor of human neuraminidase isoenzymes.
because the low basicity of the hydroxylamine function (pK
Before the broader application of trisubstituted hydroxyl-
amines can be investigated, improved methods for their
synthesis are required. Thus, while several methods exist for
a
3
,4
hydroxylamine in water = 5.93) and the modest barrier to
−
1
5−8
inversion (∼15 kcal·mol )
together ensure that at
26,27
physiological pH the pyramidal nitrogen is not protonated in
aqueous solution and undergoes rapid inversion of config-
uration. As such, hydroxylamines carrying two different
nitrogen substituents can be considered as surrogates of chiral
alcohols and ethers that avoid the need for asymmetric
synthesis. Indeed, we have recently prepared and evaluated as
β-(1→3)-glucan mimetics a series of mono-, di-, and trimeric
N-alkoxyimino sugars in which the hydroxylamine nitrogen
replaces the anomeric carbon and eliminates the need for
the preparation of acyclic hydroxylamines,
only a relatively
limited number of methods are available for the synthesis
8
,9,27−31
N,N,O-trisubstituted systems,
other than by the 2,3-
Meisenheimer rearrangement of allylic tertiary amine N-oxides
with its inherent limitation to the formation of the O-allylated
32−36
hydroylamines.
In particular, the O-alkylation of N,N-
disubstituted hydroxylamines to give N,N,O-trisubstituted
26
systems is only described with simple, potent electrophiles.
We considered the latter problem as analogous to the synthesis
9
of ethers from alcohols, for which a number of creative
diastereoselective glycosidic bond formation. On the other
37,38
methods have been devised recently,
and focused on the
hand, the low basicity of the N-alkoxyimino sugars and of
oxazines, unlike their N-alkyl counterparts, render them poor
analogues of glycosyl oxocarbenium ions and correspondingly
development of methods based on the reduction of O-acyl-
N,N-disubstituted hydroxylamines to the trisubstituted hydrox-
ylamines without concomitant reductive cleavage of the N−O
bond (Scheme 1). We report here on the reduction of this
concept to practice and on the synthesis of a number of
diversely trisubstituted hydroxylamines.
8
,10
poor glycosidase inhibitors.
The paucity of hydroxylamines in compound collections is
due in part to current criteria for compound selection, which
with a view to limiting false positives in biochemical screens,
exclude molecules containing heteroatom−heteroatom bonds
Synthesis of N,N-disubstituted hydroxylamines for acylation
39
11−13
was best achieved by adaptation of the Ganem protocol for
the formation of N-(benzoyloxy)amines followed by diisobu-
tylaluminum hydride (DIBAL) reduction (Table 1). Alter-
natively, aza-Michael addition of a secondary amine to
acrylonitrile, followed by N-oxide formation and Cope
on the grounds of their weakness and electrophilicity.
In
particular, N-aryl- and N-heteroarylhydroxylamines are geno-
toxic because of their ability to form adducts with nucleic acid
bases following activation by O-acetylation or O-sulfona-
1
4−18
19
tion.
However, with computed and experimentally
40
2
0
elimination, also was found to be effective (Scheme 2). O-
Acylhydroxylamines were synthesized (Table 2) from N,N-
derived N−O bond dissociation energies ranging from 55
−1
to 65 kcal·mol depending on substituent pattern, and lacking
the ability to undergo activation by acylation or sulfation,
trisubstituted hydroxylamines are neither particularly thermally
Received: February 27, 2016
2
1
unstable nor electrophilic. Although not common, the
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of Trisubstituted Hydroxylamines from
Table 3. Synthesis of Trisubstituted Hydroxylamines
N-Acyloxyamines
Table 1. Synthesis of N,N-Disubstituted Hydroxylamines
a
Stirring with (BzO) (1.1 equiv) and K HPO (1.5 equiv) in DMF at
2
2
4
b
rt for 1−22 h. Stirring with DIBAL (2.5 equiv) in CH Cl at 0 °C for
1
2
2
5 min.
Scheme 2. Alternative Synthesis of N-(Acyloxy)amines
Exemplified for N-4-(Phenylbutyroyl)pyrrolidine
Table 2. Synthesis of N-(Acyloxy)amines
a
(
i) DIBAL (1.25−2 equiv), CH Cl , −78 °C, time; (ii) Ac O (6
2
2
2
b
equiv), Py (3 equiv), DMAP (2 equiv), CH Cl , −78 to 0 °C. Et SiH
2
2
3
(
2.5−5 equiv), BF ·OEt (2.5−6.25 equiv), CH Cl , −78 °C to rt.
3
2
2
2
c
d e
Not isolated. Yield over two steps. 2-Np = 2-naphthalenyl.
1
4−18
acylation or sulfation,
it is noteworthy that the
nucleophilic attack on the more highly substituted O-
acylhydroxylamines by DIBAL reported in Table 1 takes
place at the carbonyl group and leaves the N−O bond intact.
Selective reduction of the carbonyl group in hydroxamic acid
derivatives, i.e., N-acylhydroxylamines, has also been de-
a
R CO H (1.25−2.5 equiv), DCC (1.25−2.5 equiv), DMAP (0.2
3
2
b
equiv), CH Cl , RT, 0.5−30 h. 2-Np = 2-naphthalenyl.
27
2
2
scribed.
Adapting Rychnovsky’s protocol for the synthesis of ethers
37
disubstituted hydroxylamines and the corresponding carboxylic
acids with the aid of dicyclohexyl carbodiimide (DCC) and 4-
from esters, the O-acylhydroxylamines were then reduced
with diisobutylaluminum hydride (DIBAL) at −78 °C and the
intermediate aluminum alkoxides trapped in situ with acetic
anhydride in the presence of pyridine and DMAP followed by
warming to 0 °C to give a diverse range of O-(α-acetoxyalkyl)
41
(dimethylamino)pyridine (DMAP). In view of the mecha-
nism for the genotoxicity of N-aryl- and N-heteroarylhydroxyl-
amines, which are rendered electrophilic at nitrogen by O-
B
DOI: 10.1021/acs.orglett.6b00556
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 4. Synthesis of Trisubstituted Hydroxylamines with Concomitant CC Bond Formation
a
b
c
(
i) DIBAL (2 equiv), CH Cl , −78 °C; (ii) Py (3 equiv), DMAP (2 equiv), Ac O (6 equiv), CH Cl , −78 to 0 °C. Not isolated. Two steps.
2
2
2
2
2
45−49
N,N-dialkylhydroxylamines 5 in good to excellent yield (Table
). In particular, it is noteworthy that the reaction is compatible
literature methods for C-glycoside formation
reductive allylation of α-acetoxy ethers,
and for the
DIBAL-mediated
50,51
3
with alkyl and aryl groups in both the N- and O-substituents
and is tolerant of branching at the α- and β-positions of the acyl
groups undergoing reduction (Table 3, 6g, 6h). Treatment of
the O-(α-acetoxyalkyl)hydroxylamines with triethylsilane and
boron trifluoride ethereate in dichloromethane at −78 °C
followed by warming to 0 °C gave the anticipated O-alkyl-N,N-
dialkylhydroxylamines in good yield (Table 3). As some O-(α-
acetoxyarylmethyl)hydroxylamines were found to be relatively
unstable, the final reduction with Et SiH and BF ·OEt was best
reductive acetylation of 2a and 2b was followed by treatment of
the intermediate O-(α-acetoxybenzyl)hydroxylamines 5a and
5b with allyltributylstannane in the presence of BF ·OEt
3
2
between −78 and 0 °C to give the trisubstituted hydroxyl-
amines 7a and 7b in 82% and 54% isolated yields, respectively,
for the two step protocol (Table 4, entries 1 and 2). The
reductive allylation could also be conducted in high yield with
the isolated and sterically hindered O-(α-acetoxyalkyl)-
hydroxylamines 2g (Table 4, entry 3). A silyl enol ether also
proved to be a satisfactory nucleophile (Table 4, entry 4) for
capture of the intermediate aminoxocarbenium ion (Table 4,
3
3
2
conducted without isolation, when good overall yield of the
hydroxylamines was obtained for the two-step process (Table 3,
52
6a, 6b, 6m). Monitoring by thin-layer chromatography revealed
entry 4) as observed previously with glycosyl and simple
acyclic oxocarbenium ions derived from the corresponding
the actual temperature of the Lewis acid mediated reduction of
the O-(α-acetoxyalkyl) hydroxylamines by triethylsilane to be
substrate dependent, reflecting the stability of the presumed
intermediate aminoxocarbenium ions. The β-(2-naphthyloxy)-
ethyl system 6l provides an extreme example of the effect of
substituent on reduction, requiring stirring with multiple
equivalents of silane and Lewis acid at room temperature
over 7 days in order to achieve a 38% isolated yield of
hydroxylamine. The relative slowness of this particular
reduction reflects the destabilizing influence of alkoxy groups
on oxocarbenium ion like intermediates such as is widely
53
acetates. Finally, 2-methylfuran was also found to be a suitable
nucleophile enabling the synthesis of the complex hydroxyl-
amines 7e and 7f in moderate yield (Table 4, entries 5 and 6).
Overall, a straightforward method for the synthesis of N,N,O-
trisubstituted hydroxylamines has been developed on the basis
of the acylation and subsequent two-step reduction of N,N-
disubstituted hydroxylamines, which themselves are readily
accessible by the reaction of secondary amines with dibenzoyl
peroxide followed by reductive deacylation. Replacement of the
hydride source in the reductive deacetoxylation of the
intermediate O-(α-acetoxyalkyl)hydroxylamines by suitable
carbon nucleophiles enables the formation of trisubstituted
hydroxylamines branched α- to the oxygen atom. These
methods, which proceed via the intermediacy of amino-
42−44
appreciated in carbohydrate chemistry.
The scope of the hydroxylamine-forming process was further
expanded by the replacement of triethylsilane in the final
reduction by other suitable nucleophiles. Thus, adapting
C
DOI: 10.1021/acs.orglett.6b00556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
xocarbenium ions, considerably extend the range of fully
substituted hydroxylamines currently available and should
permit the wider application of this underutilized functional
group in medicinal chemistry.
(24) Berge, J. M.; Copley, R. C. B.; Eggleston, D. S.; Hamprecht, D.
W.; Jarvest, R. L.; Mensah, L. M.; O’Hanlon, P. J.; Pope, A. J. Bioorg.
Med. Chem. Lett. 2000, 10, 1811.
(
25) Zhang, Y.; Albohy, A.; Zou, Y.; Smutova, V.; Pshezhetsky, A. V.;
Cairo, C. W. J. Med. Chem. 2013, 56, 2948.
26) Melman, A. In The Chemistry of Hydroxylamines, Oximes, and
(
ASSOCIATED CONTENT
Supporting Information
■
Hydroxamic Acids, Part 1; Rappoport, Z., Liebman, J. F., Eds.; Wiley:
Chichester, 2009; p 117.
*
S
(27) Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Angew. Chem.,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00556.
Int. Ed. 2010, 49, 6369.
(
(
28) Malik, G.; Guinchard, X.; Crich, D. Org. Lett. 2012, 14, 596.
29) Sun, L.; Li, P.; Amankulor, N.; Tang, W.; Landry, D. W.; Zhao,
1
Full experimental details, characterization data, and H
K. J. Org. Chem. 1998, 63, 6472.
(30) Elboray, E. E.; Gao, C.; Grigg, R. Tetrahedron 2012, 68, 3103.
and 13C NMR spectra for all new compounds (PDF)
(31) Barnes, K. L.; Chen, K.; Catalano, V. J.; Jeffrey, C. S. Org. Chem.
Front. 2015, 2, 497.
(32) Reetz, M. T.; Lauterbach, E. H. Tetrahedron Lett. 1991, 32,
4481.
AUTHOR INFORMATION
Corresponding Author
■
*
(33) Enders, D.; Kempen, H. Synlett 1994, 969.
E-mail: dcrich@chem.wayne.edu.
(34) Davies, S. G.; Smyth, G. D. J. Chem. Soc., Perkin Trans. 1 1996,
Notes
2
467.
The authors declare no competing financial interest.
(35) Bao, H.; Qi, X.; Tambar, U. K. Synlett 2011, 1789.
(36) Theodorou, A.; Limnios, D.; Kokotos, C. G. Chem. - Eur. J.
2
(
(
015, 21, 5238.
REFERENCES
■
37) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191.
38) Vo, C.-V. T.; Mitchell, T. A.; Bode, J. W. J. Am. Chem. Soc. 2011,
(
1) Axerio-Cilies, P.; Castaneda, I. P.; Mirza, A.; Reynisson, J. Eur. J.
Med. Chem. 2009, 44, 1128.
2) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
752.
3) Mollin, J.; Kasparek, F.; Lasovsky, J. Chem. Zvesti 1975, 29, 39.
4) Bartmess, J. E. In Chemistry of Hydroxylamines, Oximes and
Hydroxamic Acids; Rappoport, Z., Liebman, J. F., Eds.; Wiley:
Chichester, 2011; Vol. 2, p 115.
5) Riddell, F. G.; Turner, E. S.; Boyd, A. Tetrahedron 1979, 35, 259.
6) Hassan, A.; Wazeer, M. I. M.; Perzanowski, H. P.; Ali, S. A. J.
Chem. Soc., Perkin Trans. 2 1997, 411.
7) Raban, M.; Kost, D. Tetrahedron 1984, 40, 3345.
8) Malik, G.; Ferry, A.; Guinchard, X.; Cresteil, T.; Crich, D. Chem. -
Eur. J. 2013, 19, 2168.
9) Ferry, A.; Malik, G.; Guinchard, X.; Vetvicka, V.; Crich, D. J. Am.
Chem. Soc. 2014, 136, 14852.
10) Bach, P.; Bols, M. Tetrahedron Lett. 1999, 40, 3461.
11) Rishton, G. M. Drug Discovery Today 2003, 8, 86.
12) Sink, R.; Gobec, S.; Pecar, S.; Zega, A. Curr. Med. Chem. 2010,
1
33, 14082.
(
6
(
(
(
(
39) Biloski, A. J.; Ganem, B. Synthesis 1983, 537.
40) O’Neil, I. A.; Cleator, E.; Tapolczay, D. J. Tetrahedron Lett.
2
(
5
(
3
(
001, 42, 8247.
41) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
22.
42) Overend, W. G.; Rees, C. W.; Sequeira, J. S. J. Chem. Soc. 1962,
429.
43) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.;
Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
44) Martin, A.; Arda, A.; Desire, J.; Martin-Mingot, A.; Probst, N.;
Sinay, P.; Jimenez-Barbero, J.; Thibaudeau, S.; Bleriot, Y. Nat. Chem.
016, 8, 186.
45) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
976.
(
(
(
(
(
́
́
̈
́
́
2
(
4
(
(
(
(
1
(
(
1
(
5
(
(
(
46) Kozikowski, A. P. Tetrahedron Lett. 1982, 23, 2281.
47) Danishefsky, S. J.; Kerwin, J. F. J. Org. Chem. 1982, 47, 3803.
48) Keck, G. E.; Enholm, E. J.; Kachensky, D. F. Tetrahedron Lett.
7, 4231.
1
984, 25, 1867.
13) Bruns, R. F.; Watson, I. A. J. Med. Chem. 2012, 55, 9763.
14) Fan, L.; Schut, H. A. J.; Snyderwine, E. G. Carcinogenesis 1995,
(
(
49) Giannis, A.; Sandhoff, K. Tetrahedron Lett. 1985, 26, 1479.
50) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61,
6, 775.
15) Sadrieh, N.; Davis, C. D.; Snyderwine, E. G. Cancer Res. 1996,
6, 2683.
16) Williams, J. A.; Stone, E. M.; Fakis, G.; Johnson, N.; Cordell, J.
A.; Meinl, W.; Glatt, H.; Sim, E.; Phillips, D. H. Pharmacogenetics 2001,
1, 373.
17) Benigni, R.; Giuliani, A.; Franke, R.; Gruska, A. Chem. Rev. 2000,
00, 3697.
18) Novak, M.; Chakraborty, M. In Chemistry of Hydroxylamines,
8
(
7
(
1
(
317.
51) Kadota, I.; Uyehara, H.; Yamamoto, Y. Tetrahedron 2004, 60,
361.
52) Ogawa, T.; Pernet, A. G.; Hanessian, S. Tetrahedron Lett. 1973,
4, 3543.
53) Rychnovsky, S. D.; Cossrow, J. Org. Lett. 2003, 5, 2367.
(
1
(
1
(
Oximes and Hydroxamic Acids; Rappoport, Z., Liebman, J. F., Eds.;
Wiley: Chichester, 2011; Vol. 2, p 577.
(
19) Yu, B.; Reynisson, J. Eur. J. Med. Chem. 2011, 46, 5833.
(
20) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic
Compounds; CRC Press: Boca Raton, 2003.
(
21) Ashani, Y.; Silman, I. In The Chemistry of Hydroxylamines,
Oximes, and Hydroxamic Acids, Part 1; Rappoport, Z., Liebman, J. F.,
Eds.; Wiley: Chichester, 2009; p 609.
(
22) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel,
M. M.; Morton, G. O.; McGahren, W. J.; Borders, D. B. J. Am. Chem.
Soc. 1987, 109, 3466.
(
23) Golik, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi,
M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. J. Am. Chem.
Soc. 1987, 109, 3462.
D
DOI: 10.1021/acs.orglett.6b00556
Org. Lett. XXXX, XXX, XXX−XXX