2,2-Dimethyl-2-(o-nitrophenyl)acetyl (DMNA) as an assisted cleavage protecting group for amines

Article abstract of DOI:10.1016/S0040-4039(02)00891-2

2,2-Dimethyl-2-(o-nitrophenyl)acetyl group (DMNA) was explored as an assisted cleavage protecting group for amines and a one-step deprotection condition was developed for its efficient removal using hydrogenation in the presence of Pd-C or PtO₂ catalyst and 10% HOAc in MeOH. DMNA was found to be especially useful for the synthesis of gem-diamino compounds using Hofmann rearrangement.

Full text of DOI:10.1016/S0040-4039(02)00891-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4589–4592
2,2-Dimethyl-2-(o-nitrophenyl)acetyl (DMNA) as an assisted
cleavage protecting group for amines
Yongying Jiang, Jun Zhao and Longqin Hu*
Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey,
160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA
Received 6 April 2002; revised 7 May 2002; accepted 9 May 2002
Abstract—2,2-Dimethyl-2-(o-nitrophenyl)acetyl group (DMNA) was explored as an assisted cleavage protecting group for amines
and a one-step deprotection condition was developed for its efficient removal using hydrogenation in the presence of Pd–C or
PtO2 catalyst and 10% HOAc in MeOH. DMNA was found to be especially useful for the synthesis of gem-diamino compounds
using Hofmann rearrangement. © 2002 Elsevier Science Ltd. All rights reserved.
Amines often need to be protected in organic transfor-
mations such as peptide coupling reactions. The most
commonly used protecting groups are carbamoyl
groups like Z, Fmoc, and Boc.1 These carbamoyl pro-
tecting groups work well under most circumstances.
However, there are cases where carbamoyl protecting
groups cannot be used and other protecting groups
have to be sought to protect amines in a more stable
form such as an amide.
ally proceeds under acidic conditions such as alcoholic
HCl2 or through a copper(II)-catalyzed hydrolysis of
the benzamide.4 In the case of 3-(4-tert-butyl-2,6-dini-
trophenyl)-2,2-dimethylpropionamide, deprotection was
accomplished in a one-step process using Ti3+ ion in an
aqueous buffer of pH 7.0.5 The availability of these
mild conditions for the reduction of nitro group makes
it possible to selectively remove these protecting groups
in the presence of various other functional groups. The
enhanced UV absorption and lipophilicity of nitro-
phenyl group also facilitate the separation and purifica-
tion of the highly polar amino compounds they protect.
In addition, o-nitrophenyl amides are easily prepared
and stable to most reaction conditions. Besides their
application as protecting groups, they have also been
used as a promoiety in prodrug design.6,7
o-Nitrophenyl amides I such as o-nitrophenoxyac-
etamide, 3-(o-nitrophenyl)propionamide, o-nitrobenz-
amide, and 3-(4-tert-butyl-2,6-dinitrophenyl)-2,2-di-
methylpropionamide have been explored as assisted
cleavage protecting groups for amines (Scheme 1).1
Deprotection can be accomplished by reduction of the
nitro group and the resulting amine II is sufficiently
nucleophilic to undergo a facile intramolecular cycliza-
tion reaction releasing the free amine IV. The first step
of nitro reduction could be accomplished using zinc and
ammonium chloride,2 hydrogen transfer reduction
using cyclohexene or sodium phosphinate,3 or hydro-
genation using PtO2.4 The second cyclization step usu-
In our efforts to synthesize reductively activated pro-
drugs of FUDR, we found that 2,2-dimethyl-2-(o-
aminophenyl)acetates cyclize very quickly with half
lives in the order of seconds.7 The two methyl groups
attached to the a-position of the carbonyl were intro-
duced to restrict the rotational freedom (the conforma-
tion) of the molecule and thus facilitate the attack on
the ester carbonyl by the nucleophilic amine. The corre-
sponding 2,2-dimethyl-2-(o-aminophenyl) acetamides
were found to be sufficiently stable and could be iso-
lated by flash column chromatography. Similar to other
o-aminophenyl amides, the intramolecular cyclization
reaction of 2,2-dimethyl-2-(o-aminophenyl) acetamides
was promoted by the presence of acid leading to the
cleavage of the amide bonds and the release of the free
amines. Here, we describe the development of 2,2-
H
N
NH2
HN
NO2
HN
R
O
R
[H]
R
NH2
IV
+
O
O
I
II
III
Scheme 1.
* Corresponding author. Tel.: +1-732-445-5291; fax: +1-732-445-6312;
e-mail: longhu@rci.rutgers.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00891-2

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Y. Jiang et al. / Tetrahedron Letters 43 (2002) 4589–4592
Table 1. Effect of acid used on the yield of cyclization of
d6 im6 ethyl-2-(o-n6 itrophenyl)a6 cetyl group (DMNA) as an
2a
assisted cleavage protecting group for amines and its
application in the synthesis of gem-diamino
compounds.
Acid
Equiv.
3 (%)b
4 (%)b
5 (%)b
TFA
HCl
TsOH
HOAc
1.5
1.5
1.5
5.0
70
75
76
85
89
80
82
91
10
8
DMNA protecting group can be easily introduced in
high yield using the corresponding acyl chloride or
other typical peptide coupling methods. In this commu-
nication, we focused mainly on the optimization of the
deprotection conditions: the reduction and the subse-
quent cyclization release process. Na-DMNA-phenyl-
alanine methyl amide (1) was used as a model com-
pound to work out the deprotection conditions. Hydro-
genation using 5% Pd–C in methanol was found to
efficiently reduce compound 1 to the corresponding
amine 2 as shown in Scheme 1. Under the neutral
hydrogenation condition, no significant cyclization was
observed.8
8
B2c
a Experiments carried out with 0.05 M solution of compound 2.
b Isolated yields unless otherwise noted.
c Estimated based on HPLC.
was subjected to hydrogenation in the presence of 10%
acetic acid in methanol, H-Phe-NH-CH3 (3) was iso-
lated in 97% yield, which is significantly higher than the
two-step deprotection process described above. Under
this one-step deprotection condition, two cyclized prod-
ucts were isolated: 3,3-dimethyl-1,3-dihydroindol-2-one
(4) in 33% yield and 1-hydroxy-3,3-dimethyl-1,3-dihy-
droindol-2-one (8) in 57% yield. The formation of
hydroxy lactam 8 in higher yield suggests that the
intermediate in the reduction of nitro group, hydroxyl-
amine 6, preferentially undergoes the desired cyclization
reaction.2 Because of its higher nucleophilicity, the
cyclization of the hydroxylamine intermediate 6 is
expected to be faster, thus decreasing the formation of
the corresponding amine intermediate 7, which in turn
reduces the formation of the dehydration side product 8
and improves the efficiency of deprotection.
We then examined the effects of four different acids
(HCl, TFA, TsOH, and HOAc) on the cyclization
release process of the amino compound 2. The cycliza-
tion reaction was very fast under acidic conditions; it
was completed within 30 min after the acid was added
but the amount of acid used was found to be critical
with 1.5 equiv. required for the three stronger acids
(HCl, TsOH, TFA) and at least 5 equiv. needed for the
weaker HOAc. The product composition was similar
for the acids tested with phenylalanine methyl amide
(3) isolated in moderate yields (70–85%) and 3,3-
dimethyl-1,3-dihydroindol-2-one (4) as the other major
product in 80–90% yield (Scheme 2 and Table 1). In
addition, a dehydration product, Na-(3,3-dimethyl-3H-
indole-2-yl)phenylalanine methyl amide (5) was
observed using LC–MS and characterized using NMR
after isolation.9 Although only observed as a minor
product (510%), the dehydrated compound 5 was
more significant for the three stronger acids than for
HOAc (Table 1). Since HOAc is a mild acid and is
tolerated by many other functional groups, we consider
it to be the reagent of choice for the deprotection.
The above one-step deprotection condition was used to
deprotect a number of other Na-DMNA-protected
amino acid derivatives and dipeptides.10 As shown in
Table 2, the corresponding amines were obtained in
high yields (80–97%) using our one-step deprotection
procedure as compared to moderate yields (42–85%)
reported using other deprotection methods.1 In addi-
tion, our one-step deprotection of DMNA is simple and
more selective. Under this mild acidic condition, Boc
(13“20) and tert-butyl ester (14“21) were not
affected. However, benzyl ester (12“19) was reduc-
tively cleaved while Z (14) and benzyl ether (15) were
partially cleaved. Selectivity can be achieved in the
latter case when the more selective PtO2 catalyst was
used (14“21 and 15“22). This is consistent with the
Having accomplished the deprotection of DMNA in a
two-step sequence, we decided to explore a one-step
deprotection process using hydrogenation in the pres-
ence of dilute HOAc (Scheme 3). When compound 1
H
NO2
NH2
O
Ph
Ph
O
Ph
O
Ph
O
N
O
N
H2
H
N
HA
H
N
H
N
H
N
O
+
CH3
+
5% Pd-C
CH3OH
(Table 1)
N
H
N
H
H2N
N
H
CH3
CH3
CH3
O
(100%)
2
5
1
3
4
Scheme 2.
OH
NH
NH2
O
OH
Ph
Ph
H2, 10% Pd-C
10% HOAc/CH3OH
N
O
H
N
H
1
3
+
4
+
N
N
H
N
H
O
CH3
CH3
( 97%)
(33%)
O
O
(57%)
8
7
6
Scheme 3.

Y. Jiang et al. / Tetrahedron Letters 43 (2002) 4589–4592
4591
Table 2. Deprotection of DMNA-protected amino acids and peptides using the one-step deprotection process10
Entry
Na-DMNA-protected AA or peptides
Catalyst
AA or peptidesb
Yield (%)c
Yield 4+8% (8/4)c
1
2
3
4
5
6
7
8
Na-DMNA-Phe-NHMe (1)
Na-DMNA-Phe-Gly-NH2 (9)
Na-DMNA-Val-Gly-NH2 (10)
Na-DMNA-Ser-OCH3 (11)
10% Pd–C
10% Pd–C
10% Pd–C
10% Pd–C
10% Pd–C
10% Pd–C
H-Phe-NHMe (3)
97
88
94
86
85
80
81
94
91 (1.7/1)
91 (1.7/1)
93 (0.9/1)
89 (1.5/1)
95 (1.2/1)
88 (1/1)
H-Phe-Gly-NH2 (16)
H-Val-Gly-NH2 (17)
H-Ser-OCH3 (18)
Na-DMNA-Ile-OBzl (12)
H-Ile-OH (19)
Na-DMNA-Lys(Boc)-OCH3 (13)
Na-DMNA-Lys(Z)-OBut (14)
Na-Boc-Phe-gHse(OBzl)-DMNA (15)
H-Lys(Boc)-OCH3 (20)
H-Lys(Z)-OBut (21)
Na-Boc-Phe-gHse(OBzl)-H (22)
a
PtO2
92 (4.7/1)
98 (8.8/1)
a
PtO2
a The Z or Bzl protecting group was partially cleaved if 10% Pd–C is used as the catalyst.
b All compounds were confirmed by NMR and LC–MS.
c Isolated yields.
OBzl
OBzl
Boc-Phe-OBt
OBzl
O
OBzl
NO2
O
NO2
O
NO2
O
O
H
BTI
H2, PtO2
H
N
NH2
N
DIEA
ACN:H2O (1:1)
( 90%)
10% HOAc/MeOH
(94%)
N
H
N
H
NH2
N
H
N
H
Boc
H2N
N
H
Boc
(81%)
O
Ph
Ph
23
24
15
22
Scheme 4.
fact that PtO2 is more selective and it causes more
hydrogenation than hydrogenolysis.11 It should also be
noted that the ratio of the hydroxy lactam 8 to lactam
4 isolated were increased to around 5:1 or better when
PtO2 was used as a catalyst. As expected, the DMNA
protecting group is stable to conditions used to remove
Boc or Fmoc.12
BTI-mediated Hofmann rearrangement reaction, where
the common carbamoyl protecting groups like Z and
Boc could not be used.
Acknowledgements
We gratefully acknowledge the financial support of a
pilot project grant from the Gallo Prostate Cancer
Center of the Cancer Institute of New Jersey.
In addition to its convenient and mild deprotection
conditions, DMNA protection of amines in the form of
stable amides would find specific applications in cases
where carbamoyl protecting groups such as Z and Boc
are not suitable. One such example is the bis(trifluoro-
acetoxy)iodobenzene (BTI)-mediated Hofmann rear-
rangement of terminal a-amino acid amides we
attempted recently. BTI-mediated Hofmann rearrange-
ment is the most widely used method for the synthesis
of peptide analogues containing a retro-inverso peptide
bond isostere.13 The monocarbamoyl (Z or Boc) pro-
tected gem-diamines lacked sufficient stability under the
Hofmann rearrangement conditions.13,14 However,
References
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley: New York, 1999; pp.
494–564.
2. Panetia, C. A. J. Org. Chem. 1969, 34, 2773–2775.
3. Entwistle, I. D. Tetrahedron Lett. 1979, 20, 555–558.
4. Koul, A. K.; Bachhawat, J. M.; Prashad, B.;
Ramegowda, N. S.; Mathur, A. K.; Mathur, N. K.
Tetrahedron 1973, 29, 625–628.
when DMNA-protected
subjected to BTI-mediated Hofmann rearrangement,
Na-DMNA-
-gHse(OBzl)-NH2 (24) was easily
D
-Hse(OBzl) amide (23) was
5. Johnson, F.; Habus, I.; Gentles, R. G. J. Am. Chem. Soc.
1992, 114, 4923–4924.
D
6. Sykes, B. M.; Atwell, G. J.; Denny, W. A.; McLennan,
D. J.; O’Connor, C. J. J. Chem. Soc., Perkin Trans. 2
1995, 337–342.
7. Hu, L; Liu, B.; Hacking, D. R. Bioorg. Med. Chem. Lett.
2000, 10, 797–800.
obtained in 90% yield (Scheme 4), and DMNA was
successfully removed, after Boc-Phe-OH coupling, by
the procedure described above to give Na-Boc-Phe-
gHse(OBzl)-NH2 (22).15 This example demonstrated the
usefulness of DMNA in the synthesis of peptide
analogs containing the retro-inverso peptide bond
isostere.
8. Typical procedure: To a solution of Na-DMNA-phenyl-
alanine methyl amide (1, 1 mmol) in methanol (20 mL)
was added catalytic amount of 5% Pd–C. H2 was intro-
duced using a balloon and maintained for 30 min. The
Pd–C catalyst was removed by filtration through Celite
545 and the filtrate was concentrated in vacuo below
20°C. The product was dried in vacuo and gave Na-(2,2-
dimethyl-2-(o-aminophenyl)acetyl) phenylalanine methyl
amide (2) in quantitative yield.
In conclusion, we explored the use of 2,2-dimethyl-2-(o-
nitrophenyl) acetyl group (DMNA) as an assisted
cleavage protecting group and developed a one-step
process for its efficient deprotection. We have shown
that DMNA is especially useful as a protecting group
for the synthesis of gem-diamino compounds using

4592
Y. Jiang et al. / Tetrahedron Letters 43 (2002) 4589–4592
15. Spectroscopic data for Na-DMNA-
9. Spectroscopic data for Na-(3,3-dimethyl-3H-indole-2-
D
-gHse(OBzl)-H (24):
yl)phenylalanine methyl amide (5): 1H NMR (CD3OD,
200 MHz): l ppm 7.32–6.89 (10H, m, Ar), 4.70 (1H, dd,
J=5.8 Hz, 9.2 Hz, CH), 3.28 (1H, dd, J=5.8 Hz, 13.8
Hz, Phe-CH2), 3.05 (1H, J=9.2 Hz, 13.8 Hz, Phe-CH2),
2.75 (3H, s, N-CH3), 1.36 (3H, s, CH3), 1.16 (3H, s,
CH3); 13C NMR (CD3OD, 200 MHz): 136.6, 128.5,
127.4, 126.8, 125.8, 120.9, 120.0, 114.3, 56.9, 37.3, 24.5,
23.3, 22.7; LC–MS (ESI): 322.0 (MH+).
1H NMR (CD3OD, 200 MHz) l ppm 7.93–7.29 (m, 9H,
Ar), 5.19 (t, 1H, J=6.6 Hz, CH), 4.95 (s, 2H, Bzl-CH2),
3.66 (t, 2H, J=6 Hz, CH2-O), 2.20 (dd, 2H, J=6.6 Hz, 6
Hz, CH2), 1.65 (s, 3H, CH3), 1.64 (s, 3H, CH3); 13C
NMR (CD3OD, 200 MHz): 177.3, 148.5, 137.6, 137.3,
128.2, 127.6, 127.3, 127.0, 124.7, 72.4, 64.6, 56.8, 30.9,
25.9, 25.7; LC–MS (ESI): 372.23 (MH+), 743.42 (2M+1).
Spectroscopic data for Na-Boc-Phe-gHse(OBzl)-DMNA
10. Typical procedure: Na-DMNA-amino acid or dipeptide
(1 mmol) in 10% HOAc in methanol (20 mL) was added
a catalytic amount of 10% Pd–C or PtO2. H2 was intro-
duced using a balloon and maintained for 30 min. The
catalyst was removed by filtration through Celite 545 and
the filtrate was concentrated and the product was isolated
either by flash column chromatography with an initial
ethyl acetate wash to remove all side products followed
by methanol to elute the desired product or by a cationic
exchange column eluted with 1% TEA in methanol.
11. Burke, S. D.; Danheiser, R. L. Handbook of Reagents for
Organic Synthesis. Oxidizing and Reducing Agents; Wiley:
New York, 1999; pp. 294–299.
12. No change was observed by TLC and HPLC when
Na-DMNA-phenylalanine methyl amide (1) was treated
with 50% TFA in CH2Cl2 or neat TFA for 30 min or 20%
piperidine in DMF for 48 h.
13. Fletcher, M. D.; Campbell, M. M. Chem. Rev. 1998, 98,
763–795.
1
(15): H NMR (CDCl3, 200 MHz): l ppm 7.24–7.84 (m,
14H, Ar), 5.05 (m, 1H, CH), 4.44 (s, 2H, Bzl-CH2), 4.36
(m, 1H, Phe-CH), 3.62–3.47 (m, 2H, CH2-O), 3.25 (dd,
1H, J=13.6 Hz, 5.2 Hz, Phe-CH2), 3.0 (dd, 1H, J=13.6
Hz, 8.6 Hz, Phe-CH2), 2.20 (m, 2H, CH2), 1.59 (s, 3H,
CH3), 1.54 (s, 3H, CH3), 1.38 (s, 9H, Boc); 13C NMR
(CDCl3, 200 MHz): 175.5, 171.6, 155.4, 149.3, 139.2,
137.9, 137.1, 133.2, 129.6, 128.7, 128.6, 128.1, 128.0,
126.8, 125.6, 79.9, 73.4, 66.5, 57.3, 55.8, 47.0, 38.2, 32.4,
28.4, 27.7, 27.4, LC–MS (ESI): 619 (MH+).
Spectroscopic data for Na-Boc-Phe-gHse(OBzl)-H·HCl
(22): 1H NMR (CD3OD, 200 MHz): l ppm 7.36–7.23 (m,
5H, Ar), 5.30 (m, 1H, CH), 4.53 (s, 2H, Bzl-CH2), 4.35
(dd, 1H, J=9.2 Hz, 6 Hz, Phe-CH), 3.6 (m, 2H, CH2-O),
3.1 (dd, 1H, J=13.6 Hz, 9.2 Hz, Phe-CH2), 2.8 (d, 2H,
Phe-CH2), 2.2 (m, 2H, CH2), 1.35 (s, 9H, Boc); 13C NMR
(CD3OD, 200 MHz): 173.4, 155.8, 137.4, 136.6, 128.7,
128.5, 127.6, 127.5, 127.0, 126.9, 125.9, 78.9, 72.3, 64.2,
55.7, 55.4, 31.2, 26.7; LC–MS (ESI): 411 (MH+−17),
428.18 (MH+), 450.1 (M+Na).
14. Pallai, P. V.; Richman, S.; Struthers, R. S.; Goodman,
M. Int. J. Pept. Protein Res. 1983, 21, 84–92.