(2-Nitrophenyl)acetyl: A new, selectively removable hydroxyl protecting group

Article abstract of DOI:10.1021/ol100562f

Figure presented The utility of the (2-nitrophenyl)acetyl (NPAc) group for the protection of hydroxyl functions is reported. (2-Nitrophenyl)acetates are readily prepared starting from the commercially available, inexpensive (2-nitrophenyl)acetic acid, and these esters are stable under a series of common carbohydrate transformations. The NPAc group can be removed selectively using Zn and NH₄Cl without affecting a series of common protecting groups. This new protecting group is orthogonal with the commonly used tert-butyldimethylsilyl, levulinoyl, 9-fluorenylmethoxycarbonyl, naphthylmethyl, and p-methoxybenzyl groups.

Full text of DOI:10.1021/ol100562f

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2076-2079
(2-Nitrophenyl)acetyl: A New, Selectively
Removable Hydroxyl Protecting Group
Katalin Daragics and Pe´ter Fu¨gedi*
Department of Carbohydrate Chemistry, Chemical Research Center, Hungarian
Academy of Sciences, Pusztaszeri u´t 59-67, H-1025 Budapest, Hungary
pfugedi@chemres.hu
Received March 8, 2010
ABSTRACT
The utility of the (2-nitrophenyl)acetyl (NPAc) group for the protection of hydroxyl functions is reported. (2-Nitrophenyl)acetates are readily
prepared starting from the commercially available, inexpensive (2-nitrophenyl)acetic acid, and these esters are stable under a series of common
carbohydrate transformations. The NPAc group can be removed selectively using Zn and NH4Cl without affecting a series of common protecting
groups. This new protecting group is orthogonal with the commonly used tert-butyldimethylsilyl, levulinoyl, 9-fluorenylmethoxycarbonyl,
naphthylmethyl, and p-methoxybenzyl groups.
The chemistry of multifunctional organic compounds relies
heavily on extensive use of protecting groups. The protecting
groups should be easily introduced using readily available,
inexpensive chemicals, they should be stable to a wide range
of reaction conditions, as well as during workup and
purification, and, additionally, they should be removable
selectively, under mild conditions without causing any other
undesired chemical transformation. Although an enormous
number of protecting groups are reported,1 only a small set
of these groups is used routinely, as many of the reported
protecting groups only partly meet the above criteria. The
concept of orthogonal protection,2 in which any of a set of
different protecting groups can be removed selectively without
affecting the others, is particularly attractive in the carbohydrate
field, as a strategy leading to “standardized intermediates”3 for
oligosaccharide synthesis. For hydroxyl groups, only a few sets
of orthogonal protecting groups are reported, each consisting
of only 2-3 individual groups.4 There is still a continuous need
for additional, new protecting groups in synthetic carbohydrate
chemistry, in particular for protecting groups that are orthogonal
to the commonly used ones.
Assisted cleavage is a very useful concept for developing
new protecting groups. In assisted cleavage, the protecting
groups have extra functionality and deprotection is initiated
by chemical transformation of this auxiliary function. The
modification of the auxiliary function results in a readily
cleavable form or, frequently, in spontaneous deprotection.
A variety of protecting groups have been introduced recently
on the basis of this principle including, among others, the
4-acetoxy-2,2-dimethylbutyryl,5 the 2-(chloroacetoxymeth-
yl)benzoyl,6 the 2-(chloroacetoxyethyl)benzoyl,7 the 3-(2′-
benzyloxyphenyl)-3,3-dimethylpropanoyl,8 the 2-(allyloxy)-
phenylacetyl,4d and the 2-(prenyloxymethyl)benzoyl,9 as well
(4) (a) Wong, C.-H.; Ye, X.-S.; Zhang, Z. J. Am. Chem. Soc. 1998,
120, 7137–7138. (b) Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.; Schmidt,
W.; Kunz, H. Angew. Chem., Int. Ed. 1998, 37, 2503–2505. (c) Zhu, T.;
Boons, G.-J. Tetrahedron: Asymmetry 2000, 11, 199–205. (d) Arranz, E.;
Boons, G.-J. Tetrahedron Lett. 2001, 42, 6469–6471. (e) Haller, M. F.;
Boons, G.-J. Eur. J. Org. Chem. 2002, 2033–2038. (f) Prabhu, A.; Venot,
A.; Boons, G.-J. Org. Lett. 2003, 5, 4975–4978. (g) Tanaka, H.; Amaya,
T.; Takahashi, T. Tetrahedron Lett. 2003, 44, 3053–3057. (h) Fan, R.-H.;
Achkar, J.; Herna´ndez-Torres, J. M.; Wei, A. Org. Lett. 2005, 7, 5095–
5098. (i) Reina, J. J.; Rojo, J. Tetrahedron Lett. 2006, 47, 2475–2478. (j)
Tatai, J.; Fu¨gedi, P. Tetrahedron 2008, 64, 9865–9873.
(1) (a) Wuts, P. G. M.; Greene, T. W. Greene’s ProtectiVe Groups in
Organic Synthesis; John Wiley & Sons: New York, 2007. (b) Kocienski,
P. J. Protecting Groups; Georg Thieme Verlag: Stuttgart and New York,
1994.
(2) Schelhaas, M.; Waldmann, H. Angew. Chem., Int. Ed. Engl. 1996,
35, 2056–2083.
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3417–3421.
(3) (a) Slife, C. W.; Nashed, M. A.; Anderson, L. Carbohydr. Res. 1981,
93, 219–230. (b) Nashed, M. A.; Chowdhary, M. S.; Anderson, L.
Carbohydr. Res. 1982, 102, 99–110. (c) Nashed, M. A.; Anderson, L. J. Am.
Chem. Soc. 1982, 104, 7282–7286.
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(7) Ziegler, T.; Pantkowski, G. Tetrahedron Lett. 1995, 36, 5727–5730.
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10.1021/ol100562f  2010 American Chemical Society
Published on Web 04/02/2010

as the 4-azidobutyryl,10 the 2-(azidomethyl)benzoyl,11 and
the 2-(azidomethyl)phenylacetyl12 groups. Despite some of
the attractive features of these protecting groups, they contain
functional groups such as acetyl, chloroacetyl, benzyl, allyl,
prenyl, and azido, which are used themselves as protecting
or masking groups. This prevents selective deprotection of
these groups in the presence of the above functionalities.
The nitro group seems to be a more attractive auxiliary group
for this purpose,13 as it eliminates the above problems, and
as a very large number of methods are known for its
reduction to the highly nucleophilic amino group,14 which
then assists in the cleavage of the protecting group. In
addition, a number of nitro compounds are available com-
mercially, providing readily available starting materials for
protecting groups. Thus, (2-nitrophenyl)acetic acid is an
inexpensive, commercially available compound, and reduc-
tion of (2-nitrophenyl)acetates (1) leads to esters of (2-
aminophenyl)acetic acid (2). Cyclization of 2 to the indoli-
none 3 is known to occur readily in a fast process releasing
the corresponding alcohol (4) (Scheme 1).15
previously unreported crystalline anhydride (5b), or the acid
(5c) itself in carbodiimide-promoted acylations (Scheme 2).
Scheme 2. Introduction of the (2-Nitrophenyl)acetyl Group
Alternatively, the Mitsunobu reaction was also used with the
free acid, and it showed a remarkable regioselectivity toward
the primary hydroxyl. In each case, the corresponding esters
(7, 9) were isolated in almost quantitative yields.
The (2-nitrophenyl)acetyl group was found to be stable
under a series of common carbohydrate transformations,
including acylations, acetalations, reductive acetal openings
(BH3·THF-TMSOTf),17 and glycosylations.18
Scheme 1. Reductive Deprotection of (2-Nitrophenyl)acetates
Different reductive conditions were investigated and found
to be applicable to the removal of the (2-nitrophenyl)acetyl
group (Table 1).
We now report the (2-nitrophenyl)acetyl (NPAc) as a new
hydroxyl protecting group, which can be removed selectively
via assisted cleavage after reduction of the nitro group to an
amine.
Table 1. Reductive Removal of the NPAc Protecting Group of 7
Introduction of the (2-nitrophenyl)acetyl group to different
carbohydrate derivatives was readily accomplished by con-
ventional methods, using the acid chloride16 (5a), the
(9) Vatele, J.-M. Tetrahedron Lett. 2005, 46, 2299–2301.
(10) (a) Kusumoto, S.; Sakai, K.; Shiba, T. Bull. Chem. Soc. Jpn. 1986,
59, 1296–1298. (b) Velarde, S.; Urbina, J.; Pena, M. R. J. Org. Chem. 1996,
61, 9541–9545.
(11) (a) Wada, T.; Ohkubo, A.; Mochizuki, A.; Sekine, M. Tetrahedron
Lett. 2001, 42, 1069–1072. (b) Love, K. R.; Andrade, R. B.; Seeberger,
P. H. J. Org. Chem. 2001, 66, 8165–8176.
entry
cleavage conditions
reaction time (h)
yield (%)
1
2
3
4
5
6
H2, Pd/C, EtOH, rt
Zn, NH4Cl, MeOH, rt
NH4Cl, MeOH, rt
Zn, MeOH, rt
In, NH4Cl, MeOH, rt
Al, NH4Cl, MeOH, rt
1
2
168
168
24
31
93
-
50
82
75
(12) Xu, J.; Guo, Z. Carbohydr. Res. 2002, 337, 87–91.
(13) Some of the previously reported protecting groups having a nitro
auxiliary function, involve (a) the 4-methyl-4-nitropentanoyl group for
hydroxyl and amine protection, see: Ho, T.-L. Synth. Commun. 1980, 10,
469–472. (b) the 2,2-dimethyl-2-(o-nitrophenyl)acetyl group for amine
protection, see: Jiang, Y. Y.; Zhao, J.; Hu, L. Q. Tetrahedron Lett. 2002,
43, 4589–4592. (c) the 3-(4-tert-butyl-2,6-dinitrophenyl)-2,2-dimethylpro-
pionyl group for amine protection, see: Johnson, F.; Habus, I.; Gentles,
R. G.; Shibutani, S.; Lee, H. C.; Iden, C. R.; Rieger, R. J. Am. Chem. Soc.
1992, 114, 4923–4924. For the use of related groups in prodrug activation
by bioreduction, see: (d) Hu, L. Q.; Liu, B.; Hacking, D. R. Bioorg. Med.
Chem. Lett. 2000, 10, 797–800. (e) Liu, B.; Hu, L. Q. Bioorg. Med. Chem.
2003, 11, 3889–3899.
120
Catalytic hydrogenation using palladium on carbon pro-
ceeded readily, the reaction mixture, however, contained, in
(14) (a) Hudlicky, M. Reductions in Organic Chemistry; Ellis Horwood:
Chichester, England, 1984. (b) Ono, N. The Nitro Group in Organic
Synthesis, Wiley-VCH: New York, 2001.
(16) (a) Peet, N. P.; Sunder, S. J. Heterocycl. Chem. 1983, 20, 1355–
1357. (b) Moody, C. J.; Rahimtoola, K. F. J. Chem. Soc., Perkin Trans. 1
1990, 673–679. (c) Alazard, J.-P.; Terrier, C.; Mary, A.; Thal, C.
Tetrahedron 1994, 50, 6287–6298. (d) Taga, M.; Ohtsuka, H.; Inoue, I.;
Kawaguchi, T.; Nomura, S.; Yamada, K.; Date, T.; Hiramatsu, H.; Sato,
Y. Heterocycles 1996, 42, 251–263.
(15) For reaction kinetics data and mechanistic details on the cyclization
of (2-nitrophenyl)acetates and propionates, see: (a) Fife, T. H.; Duddy, N. W.
J. Am. Chem. Soc. 1983, 105, 74–79. (b) Kirby, A. J.; Mujahid, T. G.;
Camilleri, P. J. Chem. Soc., Perkin Trans. 2 1979, 1610–1616.
(17) Daragics, K.; Fu¨gedi, P. Tetrahedron Lett. 2009, 50, 2914–2916.
Org. Lett., Vol. 12, No. 9, 2010
2077

addition to 6, its (2-aminophenyl)acetyl derivative, which
could be converted to 6 by heating in ethanol. In contrast to
the above two-stage removal of the NPAc group, deprotec-
tion using Zn and NH4Cl could be accomplished in one step,
the (2-aminophenyl)acetyl derivative has not accumulated
during the reaction.19 The reaction with Zn alone was
sluggish, and NH4Cl alone failed to give any reaction. In
combination with NH4Cl, zinc could be replaced with other
metals, such as In and Al to effect the same transformation.
From the reagent combinations tested, Zn-NH4Cl was
selected for further investigations and a series of hexopyra-
noside derivatives were reacted in MeOH (Table 2). In all
cases, the reactions afforded the corresponding hydroxy
products in high yields.
benzyl (entry 2a), allyl (entry 6), 1-naphthylmethyl (1NAP)
(entry 7), and tert-butyldimethylsilyl ethers (entry 5); ben-
zylidene (entries 3 and 6) and isopropylidene (see Table 1)
acetals, and acyl groups, including acetyl (entries 1c and 5),
benzoyl (entries 1b and 2a), levulinoyl (entry 4), Fmoc (entry
2b), and benzyloxycarbonyl (entry 4) groups. Furthermore, the
reactions could be performed on both O- and S-glycosides, and,
importantly, the azido group also remained intact (entry 7).
The orthogonality of the (2-nitrophenyl)acetyl group
against some of the common protecting groups was tested
on compound 24 (Table 3).
Table 3. Orthogonality of the NPAc Group with Common
Protecting Groups
Table 2. Compatibility of NPAc Removal with Common
Protecting Groups Using Zn and NH4Cl
yield
(%)
yield of
26 (%)
entry
substrate
product
a
1
2
3
4
24a R ) TBDMS 25a R ) TBDMS 81 Bu4NF
78
81
87
78
24b R ) Fmoc
24c R ) Lev
24d R ) Bz
25b R ) Fmoc
25c R ) Lev
25d R ) Bz
73 Et3N
78 H2NNH2
91 NaOMe
a Catalyst used.
Not only was the NPAc group selectively removed leaving
the TBDMS, Fmoc and Lev groups intact, but any of these
groups could also be cleaved with the appropriate reagents
without affecting the (2-nitrophenyl)acetyl residue. In the
case of compound 24 having the NPAc group at O-2, even
selective removal of benzoyl group (entry 4) could be
accomplished.20
Furthermore, the (2-nitrophenyl)acetyl group was also found
to be orthogonal with the 1-naphthylmethyl group (Scheme 3).
1
Scheme 3
.
Orthogonality of the NPAc and NAP Groups
a In addition to 11c, 22% of the acetyl migrated product, methyl 6-O-
acetyl-2,3-di-O-benzyl-R-D-glucopyranoside, has also been isolated.
In case of the chloroacetyl group (Scheme 4), though
selective removal of the ClAc group could be cleanly
The reaction is compatible with most of the common
protecting groups, such as benzyl (entries 1-7), 4-methoxy-
(18) For examples of the above transformations in the presence of the
NPAc group see the Supporting Information.
2078
Org. Lett., Vol. 12, No. 9, 2010

accomplished, removal of the NPAc group was accompanied
by partial loss of the chloroacetyl group.
Scheme 5
.
NPAc as a Participating Neighboring Group in
Glycosylations
Scheme 4. Selective Removal of the NPAc and ClAc Groups
a In addition to 31, 13% of the dechloroacetylated derivative of 31 was
also isolated.
The utility of the (2-nitrophenyl)acetyl group for oligosac-
charide synthesis is illustrated in Scheme 5.
Me2S2-Tf2O-promoted glycosylation21 of 11a with the
thioglycoside 14 afforded the ꢀ-(1f6)-linked disaccharide
33 in excellent yield. Selective removal of the NPAc group
afforded the 2′-hydroxy derivative (34), further glycosylation
of 34 with 14 gave the trisaccharide 35 suitable for further
chain elongation.
The results indicate that the (2-nitrophenyl)acetyl group
is an effective participating neighboring group, which leads
to the selective formation of 1,2-trans glycosides in glyco-
sylations.
complished in the presence of the most common carbohy-
drate protecting groups. The NPAc group is orthogonal with
TBDMS, Fmoc, Lev, NAP, and MPM protecting groups.
Due to its advantegous properties, such as low cost, ease of
introduction, selective removal, orthogonality with a series
of common protecting groups, the (2-nitrophenyl)acetyl
group is anticipated to become a valuable tool for the
protection of hydroxyl groups.
In conclusion, we have introduced the (2-nitrophenyl)-
acetyl group as a new, selectively removable hydroxyl
protecting group. Preparation of NPAc esters can easily be
performed by a variety of methods. The NPAc group is stable
under most of the common carbohydrate transformations. It
can be removed by different reductive methods. Selective
removal of the NPAc group with Zn-NH4Cl can be ac-
Acknowledgment. We are grateful to Dr. Pa´l Szabo´
(Chemical Research Center, Hungarian Academy of Sci-
ences) and Dr. Izabella Lois (Chemical Research Center,
Hungarian Academy of Sciences) for their assistance in
recording the MS and NMR spectra, respectively. The skillful
technical assistance of Ms. Katalin T. Palcsu (Chemical
Research Center, Hungarian Academy of Sciences) is grate-
fully acknowledged.
(19) Interestingly, compound 3 could not be detected in deprotections
of the NPAc group with Zn and NH4Cl. We assume that a Zn complex of
(2-aminophenyl)acetic acid is formed. For ready formation of Zn complexes
of amino acids, see: Rombach, M.; Gelinsky, M.; Vahrenkamp, H. Inorg.
Chim. Acta 2002, 334, 25–33, and references therein.
Supporting Information Available: Experimental pro-
cedures, characterization data and copies of NMR spectra
of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(20) Isolated acyl groups at O-2 of hexopyranosides are known to be
relatively resistant to Zemple´n deacylation. See: (a) Fu¨gedi, P.; Lipta´k, A.;
Na´na´si, P.; Szejtli, J. Carbohydr. Res. 1982, 104, 55–67. (b) Szurmai, Z.;
Lipta´k, A.; Snatzke, G. Carbohydr. Res. 1990, 200, 201–208.
(21) Tatai, J.; Fu¨gedi, P. Org. Lett. 2007, 9, 4647–4650.
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