Mild and efficient deprotection of the amine protecting p-methoxyphenyl (PMP) group

Article abstract of DOI:10.1016/j.tetlet.2006.09.044

Mild and efficient procedures for deprotection of the amine nitrogen protecting p-methoxyphenyl (PMP) group are described. Periodic acid and trichloroisocyanuric acid (TCCA) were found to be particularly effective in realizing amine liberation using 1 and 0.5 equiv of the oxidant, respectively. Extension of the periodic acid-mediated conditions to simultaneous alcohol oxidation by combination with a catalytic amount of sodium dichromate led to smooth conversion of PMP-protected Mannich products into the corresponding β-amino acids in a one-pot procedure.

Full text of DOI:10.1016/j.tetlet.2006.09.044

Tetrahedron Letters 47 (2006) 8109–8113
Mild and efficient deprotection of the amine protecting
p-methoxyphenyl (PMP) group
a
a
b
Jorge M. M. Verkade, Lieke J. C. van Hemert, Peter J. L. M. Quaedflieg,
b
a
a,
*
Paul L. Alsters, Floris L. van Delft and Floris P. J. T. Rutjes
a
Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, NL-6525 ED Nijmegen, The Netherlands
b
DSM Pharmaceutical Products—Advanced Synthesis, Catalysis and Development, PO Box 18, NL-6160 MD Geleen,
The Netherlands
Received 16 August 2006; revised 25 August 2006; accepted 8 September 2006
Available online 29 September 2006
Abstract—Mild and efficient procedures for deprotection of the amine nitrogen protecting p-methoxyphenyl (PMP) group are
described. Periodic acid and trichloroisocyanuric acid (TCCA) were found to be particularly effective in realizing amine liberation
using 1 and 0.5 equiv of the oxidant, respectively. Extension of the periodic acid-mediated conditions to simultaneous alcohol
oxidation by combination with a catalytic amount of sodium dichromate led to smooth conversion of PMP-protected Mannich
products into the corresponding b-amino acids in a one-pot procedure.
ꢀ
2006 Elsevier Ltd. All rights reserved.
With the advent of new catalytic strategies to produce
enantiopure products, p-anisidine stands out as the
OMe
oxidation
O
O
1
R
H O
NH
R1
R
R
2
N
N
O
starting material of choice for a variety of processes that
involve imine intermediates. In particular, asymmetric
Mannich reactions catalyzed by L- or D-proline proceed
smoothly using p-anisidine-derived Schiff bases of alde-
1
1
R
R
1
(R = H, alkyl)
2
3
benzoquinone
Scheme 1. Deprotection of PMP-protected amines.
2
hydes and ketones. Other applications involve the
(
asymmetric) reduction of p-methoxyphenyl (PMP)-pro-
ates. Currently, most reports describe oxidative removal
with ceric ammonium nitrate (CAN) at low pH, but
appear to neglect the serious disadvantages associated
with this procedure. Usually, a large excess of CAN
3
tected imines, the involvement of p-anisidine in a three-
component reaction to form N-PMP-protected amino
acid amides, and application in asymmetric Diels–
7
4
5
Alder reactions.
(4–5 equiv) is required, the reaction has a laborious
work-up procedure involving column chromatography,
CAN is expensive, and highly toxic. Some of these
disadvantages also apply to phenyl iodoacetate
Furthermore, a Cu-catalyzed procedure for introduction
of the PMP-group as a protecting group for amino func-
tions has been described. Obviously, all of these strate-
gies at one point require liberation of the desired amine
by oxidative deprotection of the p-methoxyphenyl func-
tion (Scheme 1). The inevitable deprotection of the PMP
group was identified by us as a crucial and important
drawback for scale-up and commercial application of
any type of methodology involving N-PMP intermedi-
6
(
PhI(OAc) ), which has also been reported as a depro-
2
8
tecting agent. In recognition of these drawbacks, the
Mioskowski group—in a search for better deprotection
methods—recently reported an electrochemical proce-
9
dure for the oxidative removal of the PMP substituent.
However, electrochemical reactions are poorly amenable
to scale up, requiring special production equipment.
Based on these arguments, we set out to develop a new
methodology that can be applied broadly for deprotec-
tion of the PMP-group with cheap reagents and benefi-
cial atom economy for potential large scale application
in an industrial setting. We decided that the readily
Keywords: p-Methoxyphenyl (PMP) deprotection; b-Amino acids;
Asymmetric Mannich reactions; Organocatalysis; Oxidative
deprotection.
*
Corresponding author. Tel.: +31 24 365 3202; fax: +31 24 365
393; e-mail: F.Rutjes@science.ru.nl
3
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.044

8110
J. M. M. Verkade et al. / Tetrahedron Letters 47 (2006) 8109–8113
accessible reduced Mannich product 410 would be a
useful starting point to search for oxidation reagents
that might be effective in realizing PMP deprotection.
Initially, an HPLC assay was adopted that allowed us
to determine the conversion in time (after 8 and 20 h)
of PMP-protected amine 4 into the corresponding free
amine 5 upon treatment with varying amounts (1 or
This is in agreement with a mechanism involving initial
formation of the benzoquinone-derived iminium ion 2,
which under the reaction conditions hydrolyzes to the
desired free amine 3 (Scheme 1). The apparently illogical
decrease in yield upon going from 1 to 4 equiv of TCCA
(entries 8 and 9) can be explained by overoxidation of
the liberated amino alcohol in the latter case. Periodic
acid shows a relatively low conversion after 8 h, but very
good conversion after 24 h (entry 11), while additional
equivalents of oxidant yielded no improvement (entry
12). Other halogen-containing oxidants have also been
tested under these acidic conditions such as the hyperva-
lent Dess–Martin reagent (entries 5 and 6), hypochlo-
rous acid (entries 13 and 14), and a series of
electrophilic halide reagents (entries 15–25). Without
exception, in all cases conversion of 4 into 5 was
observed, but with reduced effect compared to TCCA
and periodic acid. Finally, several inorganic oxidants
were applied, but appeared unsuccessful for this trans-
formation (entries 26–30).
4
equiv) of oxidant. As can be seen from Table 1,
CAN and PhI(OAc) in the presence of 1 equiv of sulfu-
2
ric acid were indeed effective in deprotecting, albeit with
moderate conversions. We were, however, pleasantly
surprised to find that under these acidic conditions,
readily available and cheap oxidants such as trichloro-
isocyanuric acid (TCCA) and periodic acid (H IO )
5
6
were capable of deprotecting the PMP group effectively
entries 7–12). The data show that the addition of a
(
strong protic acid is crucial in the deprotection reac-
tions, since without the acid the oxidants do not give
any conversion of the starting material at all (entries 7
and 10).
Table 1. Deprotection of PMP-protected amine 4 using various oxidants
OMe
O
HN
a
NH
2
HO
Ph
HO
Ph
Me
Me
O
4
5
a
a
Entry
Equivalent
Oxidant
Conversion to 5
at t = 8 h (%)
Conversion to 5
at t = 20 h (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
4
1
4
1
4
1
1
4
4
1
4
1
4
1
1
4
1
4
1
4
1
4
1
4
4
4
4
4
4
CAN
CAN
PhI(OAc)
PhI(OAc)
DM
35
71
54
59
47
58
<5
79
36
34
42
47
64
48
67
<5
82
0
2
2
DM
b
b
TCCA
TCCA
TCCA
b
b
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
H
5
H
5
H
5
IO
IO
IO
6
6
6
<5
<5
20
32
40
65
58
41
81
77
75
57
80
50
50
53
55
<5
81
75
41
81
60
59
62
79
55
59
78
—
—
17
21
—
—
—
—
—
HOCl
HOCl
PBP
NCS
NCS
NBS
NBS
NIS
NIS
Br
Br
2
2
I
I
2
2
2 2
H O
c
KMnO
NaBO Æ4H
Na CO Æ1.5H
Cr
4
15
3
2
O
0
0
0
2
3
2 2
O
K
2
2 7
O
Conditions: (a) 1 or 4 equiv oxidant, 1 equiv H
2
SO
4 2
, 5 mol % benzoic acid (internal standard), MeCN/H O 1:1, rt.
a
Conversions were determined using HPLC (Inertsil ODS-3 column) on crude samples from the reaction mixture.
b
c
2 4
Carried out without the addition of H SO .
Several by-products were detected by HPLC. (DM = Dess–Martin periodinane, PBP = pyridinium bromide perbromide, NCS = N-chloro-
succinimide, NBS = N-bromosuccinimide, NIS = N-iodosuccinimide.)

J. M. M. Verkade et al. / Tetrahedron Letters 47 (2006) 8109–8113
8111
To verify the results of our initial screening, we per-
formed a series of preparative scale experiments on the
initial substrate 4 as well as on the PMP-protected
amines 6–11 with TCCA and periodic acid (Table 2).
In the case of TCCA, 0.5 equiv appeared optimal since
only two of the three chlorine substituents are involved
good yield, but proceeded poorly with periodic acid
which led us to conclude that for these conditions a sub-
stituent at the benzylic a-position is desired (entries 1
and 2). Indeed, PMP-protected a-methylbenzylamine 7
gave excellent yields of the desired product 13 with both
oxidants (entries 3 and 4). N-PMP-protected 4-phenyl-
butan-2-amine 8 underwent deprotection with similar effi-
ciency to give 4-phenylbutan-2-amine (14, entries 5 and
6). Deprotection of the reduced Mannich adducts 4 and
9, 10 also proceeded readily to furnish the correspond-
ing amines in excellent yields (entries 7–12). Finally,
1
1
in the oxidation, whereas one equivalent of periodic
acid was required. As can be judged from Table 2, the
corresponding free amines 5, 12–17 were formed with
satisfactory results.1
2,13
Subjection of PMP-protected
benzylamine 6 to TCCA provided the free amine 12 in
Table 2. Preparative scale N-PMP deprotections
a
Entry
n-PMP amine
Oxidant
T (ꢁC)
t (h)
Product (yield %)
PMP
HN
NH2
1
2
6
6
TCCA
H IO
5 6
21
21
16
16
12 (73)
12 (<5)
PMP
HN
NH2
Me
Me
3
4
7
7
TCCA
IO
21
21
16
16
13 (99)
13 (89)
H
5
6
PMP
NH
NH2
Me
Me
5
6
8
8
TCCA
IO
21
21
16
16
14 (73)
14 (80)
H
5
6
PMP
HO
NH2
HO HN
Me
Me
7
8
4
4
TCCA
IO
21
21
16
16
5 (80)
5 (99)
H
5
6
PMP
HO
NH2
HO HN
Me
Me
NO2
NO2
9
0
9
9
TCCA
IO
21
21
16
16
15 (99)
15 (95)
1
H
5
6
PMP
HO
Me
NH2
HO HN
Me
1
1
1
2
10
10
TCCA
IO
21
21
16
16
16 (81)
16 (95)
H
5
6
Me
PMP
HO
NHMe
HO
N
Me
Me
NO2
NO2
1
1
3
4
11
11
TCCA
IO
90
90
0.1
1.5
17 (77)
17 (66)
H
5
6
Conditions: 1 equiv H
Isolated yield of HCl salt after aqueous work-up (>95% pure according to HPLC).
2
SO
4
, 1 equiv H
5
IO
6
or 0.5 equiv TCCA, MeCN/H
2
O 1:1, 21 or 90 ꢁC.
a

8112
J. M. M. Verkade et al. / Tetrahedron Letters 47 (2006) 8109–8113
tertiary amine 11 was subjected to the same conditions,
but showed minimal conversion in both cases. However,
upon heating to 90 ꢁC the same oxidative cleavage took
place resulting in the secondary amine 17 in a reasonable
yield with both TCCA and periodic acid (entries 13 and
b-amino acids. Studies to elucidate the exact mechanism
of the oxidation process and to determine the scope and
limitations of these deprotection conditions are cur-
rently ongoing.
1
4). It may be expected that the yield could be further
increased by optimization of the reaction conditions. It
must be noted that our PMP removal procedure is
accompanied by a straightforward and practical work-
up, which sharply contrasts with the laborious CAN
chromatography protocol. In all cases, after completion
of the reaction, work-up involved washing the aqueous
mixture with CH Cl (to remove benzoquinone) before
adjustment to pH 10.5 and extraction with ethyl acetate.
Upon acidification of the organic layer with a solution
of HCl in ethyl acetate and subsequent concentration,
the deprotected amines were obtained in high purity
Acknowledgements
M. Willems is acknowledged for a practical contribu-
tion. This work forms part of the Ultimate Chiral Tech-
nology project supported in part with funds provided by
SNN (Cooperation Northern Netherlands) and EFRO
(European Fund for Regional Development).
2
2
References and notes
(
>95% according to HPLC) as the corresponding HCl
1
. For general reviews, see, for example: (a) List, B. Chem.
Commun. 2006, 819–824; (b) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138–5175.
. For reviews, see: (a) Marques, M. M. B. Angew. Chem.,
Int. Ed. 2006, 45, 348–352; (b) C o´ rdova, A. Acc. Chem.
Res. 2004, 37, 102–112.
salts.
The deprotection sequence was further extended in the
2
1
4
synthesis of two b-amino acids via a one-pot deprotec-
tion oxidation sequence (Scheme 2). First, the Mannich
adducts 4 and 9 were treated with the periodic acid
deprotection conditions and after completion, a cata-
lytic amount of sodium dichromate and an additional
3. For racemic methods, see, for example: (a) Menche, D.;
Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.; Rudolph, S.
Org. Lett. 2006, 8, 741–744; For asymmetric reductive
amination, see, for example: (b) Storer, R. I.; Carrera, D.
E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006,
5
equiv of periodic acid were added to the aqueous solu-
tion, resulting in oxidation of the alcohol to the carbox-
ylic acid function. The crude mixture was purified
using ion exchange chromatography to yield the corre-
1
28, 84–86; (c) Hoffmann, S.; Majeed Seayad, A.; List, B.
1
5
Angew. Chem., Int. Ed. 2005, 44, 7424–7427.
. Cannella, R.; Clerici, A.; Panzeri, W.; Pastori, N.; Punta,
C.; Porta, O. J. Am. Chem. Soc. 2006, 128, 5358–5359.
4
1
6
sponding b-amino acids 18 and 19 in good yields.
Given the vast number of 1,3-aminoalcohols that are
accessible via asymmetric Mannich reaction, the latter
pathway represents an easy and efficient entry into a
large variety of b-amino acids.
5. Sund e´ n, H.; Ibrahem, I.; Eriksson, L.; C o´ rdova, A.
Angew. Chem., Int. Ed. 2005, 44, 4877–4880.
6. Lu, Z.; Twieg, R. J. Tetrahedron Lett. 2005, 46, 2997–
3
001.
7
. (a) Sakai, T.; Korenaga, T.; Washio, N.; Nishio, Y.;
Minami, S.; Ema, T. Bull. Chem. Soc. Jpn. 2004, 77, 1001–
In conclusion, the extensive use of the p-methoxyphenyl
1
007; (b) Hata, S.; Iguchi, I.; Iwasawa, T.; Yamada, K.;
(
PMP) group in asymmetric organocatalysis requires
Tomioka, K. Org. Lett. 2004, 6, 1721–1723; (c) Overman,
L. E.; Owen, C. E.; Pavan, M. P. Org. Lett. 2003, 5, 1809–
easy and scalable deprotection procedures in order to
render these processes economically viable. We have
developed novel, mild and efficient oxidative cleavage
conditions involving a series of electrophilic halide
reagents, which are effective if the deprotection is carried
out at low pH. Periodic acid and trichloroisocyanuric
acid (TCCA) were identified as being particularly effec-
tive for N-deprotection, requiring only 1 and 0.5 equiv,
respectively, to give a high yield of the desired amine.
The periodic acid-mediated conditions were used in
combination with a catalytic amount of sodium dichro-
mate—added to the same pot after completion of the
deprotection—to convert asymmetric Mannich prod-
ucts, in a one-pot procedure, into the corresponding
1
2
812; (d) Chi, Y.; Zhou, Y.-G.; Zhang, X. J. Org. Chem.
003, 68, 4120–4122; (e) Fustero, S.; Garcia Soler, J.;
Bartolom e´ , A.; Sanchez-Rosello, M. Org. Lett. 2003, 5,
2707–2710; (f) Fustero, S.; Bartolom e´ , A.; Sanz-Cervera,
J. F.; Sanchez-Rosello, M.; Soler, J. G.; Ramirez de
Arellano, C.; Fuentes, A. S. Org. Lett. 2003, 5, 2523–2526;
(
g) C o´ rdova, A. Synlett 2003, 1651–1654.
8
9
. (a) Janey, J. M.; Hsiao, Y.; Armstrong, J. D., III. J. Org.
Chem. 2006, 71, 390–392; (b) Ibrahem, I.; Casas, J.;
C o´ rdova, A. Angew. Chem., Int. Ed. 2004, 43, 6528–6531;
(
c) C o´ rdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.;
Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842–1843;
d) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper,
(
M. L. J. Am. Chem. Soc. 2001, 123, 10409–10410.
. De Lamo Marin, S.; Martens, T.; Mioskowski, C.; Royer,
J. J. Org. Chem. 2005, 70, 10592–10595.
1
0. C o´ rdova, A. Chem. Eur. J. 2004, 10, 1987–1997.
11. Quaedflieg, P. J. L. M.; Alsters, P. L.; Pojarliev, P.; Jary,
PMP
1
) H IO6 (1 equiv)
HO HN
Me
5
NH2
H SO (1 equiv)
W. G. WO Patent 2005040149, 2005; Chem. Abstr. 2005,
2
4
HO C
H O, MeCN
2
2
1
42, 430492.
Me
12. All new compounds were appropriately characterized with
2
) Na Cr O (5 mol %)
X
2
2
7
X
1
13
H IO (5 equiv)
FTIR, H and C NMR and high resolution mass data.
5
6
1
3. Representative procedure for deprotection using TCCA: To
4
9
(X = H)
(X = NO2)
18 (X = H): 85%
a solution of 7 (0.25 g, 1.1 mmol) in MeCN/H O (20 mL,
19 (X = NO ): 95%
2
2
1
:1) were added TCCA (0.26 g, 0.55 mmol) and 1 M
Scheme 2. Formation of b-amino acids.
aqueous H SO (1.1 mL). The mixture was stirred for 16 h
2
4

J. M. M. Verkade et al. / Tetrahedron Letters 47 (2006) 8109–8113
8113
at rt and then washed with CH
2
Cl
2
(3 · 100 mL). The
15. Schmieder-van de Vondervoort, L.; Bouttemy, S.; Padron,
J. M.; le Bras, J.; Muzart, J.; Alsters, P. L. Synlett 2002,
243–246.
16. Representative experimental procedure for b-amino acid
formation: To a solution of the amine (1.9 mmol) in
resulting aqueous phase was subsequently brought to
pH 10.5 through addition of 5 M aqueous KOH and
extracted with EtOAc (4 · 100 mL). The combined
organic layers were brought to pH 1 via addition of
EtOAc/HCl, dried (MgSO
the HCl salt of 13. Spectral data of 13ÆHCl: H NMR
400 MHz, D O): d 1.65 (d, J = 6.9 Hz, 3H), 4.55 (q,
4
), and concentrated to afford
MeCN/H
2 2 4
O (20 mL, 1:1) were added 1 M aqueous H SO
1
(1.9 mmol) and H IO (0.42 g, 1.9 mmol. The reaction
5
6
(
2
mixture was stirred at ambient temperature for 16 h.
Subsequently, Na Cr Æ2H O (27 mg, 0.092 mmol) was
added, followed by H IO (2.1 g, 0.92 mmol) and the
1
3
J = 6.2 Hz, 1H), 7.49 (m, 5H); C NMR (100 MHz,
2
2
O
7
2
À1
D O): d 19.5, 51.2, 126.7, 129.4, 129.4, 137.9; IR m (cm ):
2
5
6
2
972, 2879, 1609, 1513, 1084, 1032, 763, 696, 537, HRMS
mixture was stirred for an additional 16 h. After comple-
tion, the reaction mixture was washed with CH Cl
2
(ESI) calcd for C 12N (M+) 122.0970, found 122.0981.
Representative procedure for deprotection using periodic
acid: To a solution of 7 (0.25 g, 1.1 mmol) in MeCN/H O
8
H
2
(3 · 50 mL) and purified by ion exchange chromatography
2
(DOWEX 50W · 8) to give the corresponding b-amino
1
(
20 mL, 1:1) were added H
5
IO
(1.1 mL). The mixture was stirred for
6 h at rt and washed with CH Cl (3 · 100 mL). The
6
(0.25 g, 1.1 mmol) and
acid as a white solid. Spectral data: Compound 18:
H
1
1
2 4
M aqueous H SO
NMR (300 MHz, D
2
O): d 1.27 (d, J = 6.8 Hz, 3H), 3.01
1
3
2
2
(
(
m, 1H), 4.47 (d, J = 8.1 Hz, 1H), 7.47 (m, 5H); C NMR
resulting aqueous phase was subsequently brought to
pH 10.5 through addition of 5 M aqueous KOH and
extracted with EtOAc (4 · 100 mL). The combined
organic layers were brought to pH 1 via addition of
EtOAc/HCl, dried (MgSO ) and concentrated to afford
the HCl salt of 13.
75 MHz, D O): d 13.5, 45.4, 57.1, 126.7, 128.6, 128.8,
2
À1
1
1
34.8, 179.5; IR m (cm ): 2972, 1559, 1454, 1401, 1368,
208, 1107, 1065, 1032, 755, 700; HRMS (ESI) calcd for
C H NO Na 224.0663, found: 224.0666. Compound 19:
1
0
12
2
2
1
4
H NMR (300 MHz, D O): d 1.27 (d, J = 6.9 Hz, 3H), 2.98
2
(
8
m, 1H), 4.59 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H),
13
1
4. For a general entry into the synthesis of b-amino acids,
see, for example: Enantioselective Synthesis of b-Amino
Acids; 2nd ed.; Juaristi, E. E., Soloshonok, V. A., Eds.,
Wiley & Sons: Hoboken, 2005; pp 195–213.
2
.33 (d, J = 8.4 Hz, 2H); C NMR (75 MHz, D O): d
1
79.4, 147.4, 142.2, 128.0, 123.7, 56.5, 45.7, 13.4; IR m
À1
(
cm ): 2969, 1737, 1365, 1229, 1216, 735, 668, 611; HRMS
(
12 2 4
ESI) calcd for C10H N O Na 247.0695, found: 247.0716.