Mild non-transition metal catalyzed deprotection of N-allyloxycarbonyl amines

Article abstract of DOI:10.1016/j.tetlet.2005.04.064

A synthesis of methyl (2S)-2-amino-4-oxo-2,4-diphenylbutanoate has been achieved via a novel one-pot non-transition metal mediated deprotection of the N-allyloxycarbonyl amine using iodine in wet acetonitrile. The applicability of this transformation has been demonstrated by deprotecting a variety of N-allyloxycarbonyl amines, α-aminomethyl esters and simple N-allyloxycarbonyl alkyl amines. Deprotection occurs in high yield (82-93%) without erosion of the optical purity of the chiral substrates.

Full text of DOI:10.1016/j.tetlet.2005.04.064

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4403–4405
Mild non-transition metal catalyzed deprotection of
N-allyloxycarbonyl amines
Ronald H. Szumigala, Jr.,a,* Ekama Onofiok,b Sandor Karady,a
Joseph D. Armstrong, IIIa and Ross A. Millera,*
aDepartment of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
bThe University of California-Davis Medical School, Davis, CA 95616, USA
Received 22 March 2005; accepted 14 April 2005
Available online 5 May 2005
Abstract—A synthesis of methyl (2S)-2-amino-4-oxo-2,4-diphenylbutanoate has been achieved via a novel one-pot non-transition
metal mediated deprotection of the N-allyloxycarbonyl amine using iodine in wet acetonitrile. The applicability of this transform-
ation has been demonstrated by deprotecting a variety of N-allyloxycarbonyl amines, a-aminomethyl esters and simple N-allyloxy-
carbonyl alkyl amines. Deprotection occurs in high yield (82–93%) without erosion of the optical purity of the chiral substrates.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Protection of the highly reactive amino functionality as
a carbamate (Alloc, BOC, Cbz, FMOC, etc.) is common
I
I2
O
R
O
R
practice in organic chemistry, especially in the total syn-
theses of biologically active compounds, combinatorial
chemistry, and solid phase peptide methodology. In par-
ticular, the N-allyloxycarbonyl, or Alloc, moiety has
seen increasingly widespread use in the recent past due
to its ready availability, ease of installation, high stabil-
ity under the range of pHÕs, temperatures and nucleo-
philic, oxidative, and reducing reaction conditions.
Removal has typically been achieved chemoselectively
under mild conditions using transition metal catalysts.1,2
There are, however, drawbacks associated with these
heavy metal-based deprotections, namely, the high cost
of reagents, competitive allylamine formation, and diffi-
culty of removing trace quantities of the metal, espe-
cially if it is in the last step of a manufacturing
synthesis. Therefore, alternative methods of Alloc
deprotection that do not use heavy metals were sought,
but to the best of our knowledge they do not exist. In
this letter, we would like to report a novel one-pot, high
yielding, oxidative N-Alloc deprotection protocol of
simple amines and a-aminomethyl esters via iodocycli-
zation in acetonitrile/water (Scheme 1).
∗
∗
O
MeCN
H2O
O
O
N
H
O
N
H
O
O
1
R
∗
O
H2N
I
O
2
+
I
O
R
∗
O
O
N
O
O
O
3
O
Scheme 1. Proposed mechanism of iodine deprotection.
required (Scheme 2) and we opted to pursue 9 by the
alkylation of an oxazolidinone precursor that should
occur with high diastereoselectivity.3 Carbamate, rather
than carboxamide, protection of the nitrogen was neces-
sary since carbamates give better yields and diastereo-
meric ratios of cis:trans oxazolidinone isomers than do
amides.4 Although we could prepare the ethyl carba-
mate derivative and alkylate it in high yield and
selectivity, we were unsuccessful at the removal of the
During the course of our research, enantiopure methyl
(2S)-2-amino-4-oxo-2,4-diphenylbutanoate (9) was
*
Corresponding authors. E-mail: ross_miller@merck.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.064

4404
R. H. Szumigala, Jr. et al. / Tetrahedron Letters 46 (2005) 4403–4405
in 74% yield when 5 was reacted with benzaldehyde
Ph
Ph
a
b
dimethyl acetal.9 Fortuitously, the trans-isomer proved
highly crystalline and was isolated from a 1:1 mixture
of toluene/heptane to provide 6a in 60% yield and
>99% purity as assayed by HPLC. Alkylation of 6a with
2-bromoacetophenone at À70 ꢁC gave 7 in 90% yield
with >97% diastereoexcess.10 Hydrolysis of 7 (4 N
LiOH/MeOH) followed by esterification at ambient
temperature (MeI/NaHCO3) in dry DMF furnished Alloc-
protected quaternary amino methyl-ester 8b in 90% over-
all yield for the two steps after silica gel chromatography.
A one pot methanolysis/deprotection of 7 was attempted
in methanol with iodine, but only resulted in iodoetheri-
fication and diiodination of the allyl double bond.11
Alloc
N
H
CO2H
Ph
H2N
CO2H
Ph
4
5
Alloc
Ph
Alloc
N
N
+
O
O
O
O
O
6b
Ph
6a
c
O
O
Ph
Ph
Ph
Ph
d,
f
Alloc
Ph
N
Alloc
N
H
CO2R
O
Following the original deprotection conditions of Fra-
ser-Reid,12 <15% yield of productwas observed afetr
24 h when 8b was reacted with iodine (3 equiv) in a 1:1
mixture of THF/water. When the reaction was run in
4:1 methanol/water, a mixture of the desired product 9
(22%), iodoetherification product (LCMS analysis), car-
boxylic acid 8a (42%), as well as unreacted starting
material 8b were all observed. While a simple change
in solvent to 4:1 acetonitrile/water minimized hydrolysis
and improved the yield of the reaction to 48%, a mixture
of iodohydrin side products was also observed. We
sought to minimize iodohydrin formation by lowering
the pH of the reaction mixture, however, the addition
of acid had no effect on either the rate or yield of the
reaction.13 Upon optimization of the water content
(3 equiv), an 87% yield of 9 was realized after 48 h at
ambient temperature. Heating this reaction (40–60 ꢁC)
increased the reaction rate, but had deleterious effects
on the yield of amine formation.
7
8a: R = H
e
8b: R = Me
O
Ph
Ph
H2N
CO2Me
9
Scheme 2. Synthesis of methyl (2S)-2-amino-4-oxo-2,4-diphenylbut-
anoate 9. Reagents and conditions: (a) Alloc-Cl, 5 N NaOH, THF,
0 ꢁC, 15 min, 99%; (b) PhCH(OMe)2, PhSO3H, toluene, 85 ꢁC,
200 Torr, 2–4 h; (c) LiHMDS, TMEDA, THF, À70 ꢁC, 15 min, then
2-bromoacetophenone, À70 ꢁC to rt, 30 min, 90%; (d) 4 N aq LiOH/
MeOH, 16 h; (e) MeI, NaHCO3, DMF, 1 h, 90% for two steps; (f) I2,
H2O, MeCN, rt, 48 h, 87%.
carbamate even under forcing acidic or basic conditions.
Therefore, we prepared the Alloc derivative with the
expectation of milder removal after the alkylation using
heavy metal-based conditions. Due to the problems
associated with heavy metals, such as the expense and
toxicity, we also desired to find an alternative procedure
to remove the Alloc group. We expected that reaction of
positive halogens would induce cyclization of the Alloc
group followed by a hydrolysis to give the free amine
and a neutral iodocarbonate 3. The neutral carbonate
3 would be easily separated from the basic amine extrac-
tively (Scheme 1). Analogous halocyclization deprotec-
tion methodology has been used by Fraser-Reid5 to
remove pentenamide protecting groups, but has not
been extended to carbamates to the best of our knowl-
edge. Also, a 1,2 iodoetherification of the 3-methylbut-
2-en-1-yl-carbamate (Preoc) group followed by zinc
The scope and limitations of this transformation
was determined by the deprotection of several N-allyl-
oxycarbonyl-amino-methyl-esters and simple N-Alloc-
amines.14 As seen in Table 1, a variety of functional
groups is well tolerated under our reaction conditions.
Alkyl substituted amino-esters (examples 1 and 2), as well
as phenyl and benzyl substituted compounds (examples
3–5), were deprotected in relatively high yields (82–
92%). Iodination of phenyl rings, including electron rich
aryl substituents, was not observed in our hands. A sim-
ple alkyl amine was also examined (example 6) and found
to undergo the desired reaction in high yield (93%). Ero-
sion of optical purity was monitored in each case by chi-
ral SFC and found not to occur to any measurable extent.
`
reduction has been recently reported by Vatele, although
in that paper, only simple addition of iodine and meth-
anol across the double bond was observed.6 C–N bond
cleavage did not occur until treatment of the b-meth-
oxyiodide with excess zinc.
The by-product of the deprotection, 4-iodomethyl-1,3-
dioxolan-2-one (3), is a synthetically useful intermediate
for various B-adrenergic blockers and antibacterial
cephalosporin compounds.15 We monitored the produc-
tion of 3 by HPLC and chiral SFC to determine if any
transfer of chirality from the substrate to the allyloxy
moiety took place. Although 3 was examined from all
deprotections, enantiomerically enriched iodo-carbon-
ate has not been observed.
(2R)-{[(allyloxy)carbonyl]amino}(phenyl)acetic acid (5)
was prepared in near quantitative yield from R-(-)-2-phe-
nylglycine (4) by the slow addition (1 h) of allyl chloro-
formate (1 equiv) to 4 in THF/5 N NaOH at0 ꢁC.7
Upon acidification with 37% HCl and toluene extraction,
5 was obtained in 99% yield and >99% purity as assayed
by HPLC and used directly in the oxazolidinone synthe-
sis. Slight modification of the Karady protocol3a affor-
ded a 15:1 mixture of trans:cis oxazolidinone isomers8
In conclusion, a high-yielding non-transition metal cat-
alyzed Alloc liberation protocol has been developed
and demonstrated on a variety of substrates. Minimiza-

R. H. Szumigala, Jr. et al. / Tetrahedron Letters 46 (2005) 4403–4405
4405
Table 1. Iodocyclization deprotection of Alloc-carbamates in wet
acetonitrilea,b
References and notes
1. Guibe, F. Tetrahedron 1998, 54, 2967–3042.
2. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New
York, 1999.
3. (a) Karady, S.; Amato, J. S.; Weinstock, L. M. Tetrahe-
dron Lett. 1984, 25, 4337–4340; (b) Seebach, D.; Fadel, A.
Helv. Chim. Acta 1985, 68, 1243–1250; (c) Smith, A. B.,
III; Benowitz, A. B.; Favor, D. A.; Sprengeler, P. A.;
Hirschmann, R. Tetrahedron Lett. 1997, 38, 3809–3812;
(d) Ma, D.; Ding, K.; Tian, H.; Wang, B.; Cheng, D.
Tetrahedron: Asymmetry 2002, 13, 961–969.
´
Entry Substrate
Product
Yield
(%)
1
86c
Alloc
N
H
CO2Me
H2N
CO2Me
2
87c
89
Alloc
N
H
CO2Me
CO2Me
H2N
CO2Me
CO2Me
Ph
Ph
H2N
4. OÕDonnell, M. J.; Fang, Z.; Ma, X.; Huffman, J. C.
Heterocycles 1997, 46, 617–630.
5. Debenham, J.; Rodebaugh, R.; Fraser-Reid, B. Liebigs
Annalen/Recueil 1997, 5, 791–802.
3
Alloc
N
H
Ph
Ph
`
6. Vatele, J. Tetrahedron Lett. 2003, 44, 9127–9129.
4
92
Alloc
7. The use of other solvents (DCM, toluene) required
elevated temperatures (23–50 ꢁC) for the reaction to go
to completion, and resulted in lower yields (88–95%).
8. The major isomer was determined to have trans config-
uration by NOE experiments.
N
H
CO2Me
H2N
HO
CO2Me
HO
5
82
9. To an 85 ꢁC slurry of 5 and PhSO3H (2 mol%) in toluene
(7.5 mL/g vs 5) was added benzaldehyde dimethyl acetal
(1.5 equiv) as a solution in toluene, slowly over 2 h. A
mixture of methanol and toluene was distilled off over the
course of the reaction under slight vacuum (200 Torr) to
minimize esterification of the carbamate starting material.
Toluene was continually added through the distillation to
maintain the approximate starting volume.
Alloc
N
H
CO2Me
H2N
CO2Me
Alloc
H2N
N
6
93
H
O
O
O
O
Ph
7d
85e
Ph
10. The de was determined at methyl ester 8b via SFC
(Chiralcel OF column).
11.
Alloc
N
H
CO2Me
H2N
CO2Me
O
Ph
Ph
a Productyields have notbeen optimized.
b Yields were determined by HPLC analysis versus
O
MeO
a
standard
O
N
O
I
prepared from commercially available authentic material unless
otherwise noted.
c Yields were determined by HPLC analysis of the rederivatized Alloc-
protected amine versus a standard prepared from synthetically
available material.
d The deprotection was performed at ambient temperature.
e Yields were determined by HPLC analysis versus a standard prepared
from synthetically available material.
O
Ph
and
O
Ph
Ph
O
I
O
N
O
I
O
Ph
were identified by LCMS of the crude reaction mixture of
7 with iodine in MeOH.
12. Debenham, J. S.; Madsen, R.; Roberts, C.; Fraser-Reid,
B. J. Am. Chem. Soc. 1995, 117, 3302–3303.
13. In a simplified system, water acidified to pH 1, 2, 3, and
5 by aqueous HCl was used in the iodocyclization
deprotection of Alloc-phenylglycine methyl ester. The
reaction was monitored by HPLC over 24 h. No
noticeable differences were observed between the
reactions.
tion of iodohydrin formation by optimization of the
water content proved key to maximizing the reaction
yield. While optical purity of the substrates was not af-
fected by the deprotection, no transfer of chirality to the
iodocarbonate leaving group occurred.
Acknowledgements
14. Typical procedure: To a solution of N-Alloc-amine or N-
Alloc-amino-methyl ester (1.0 g) in dry acetonitrile
(12 mL) at room temperature was added water (3 equiv)
followed by iodine (3 equiv). The reaction mixture was
heated to 60 ꢁC and aged for 8–16 h. After such time, the
reaction was cooled to 10 ꢁC, quenched with a 20%
solution of sodium sulfite, and extracted with CH2Cl2
(3 · 15 mL). The organic and aqueous layers were quan-
titatively assayed by HPLC for product.
15. (a) Olivero, A. G.; Cassel, J. M.; Poulsen, J. R. PCT Int.
Appl. WO 93/22451, 1993; (b) Nagano, N.; Hara, R.;
Murakami, Y.; Nakano, K.; Kouda, A.; Maeda, T.;
Shibanuma, T.; Yamazaki, A.; Matsui, H. Eur. Pat. Appl.
84308969.9, 1985.
The authors thank Mr. Robert Reamer for NOE exper-
iments on compounds 6a and 6b, Ms. Mirlinda Biba for
chiral SFC analysis, and Dr. Thomas J. Novak for
HRMS analysis.
Supplementary data
Detailed experimental procedures for the preparation of
9, as well as characterization data, is available free of
charge via the Internet at http://pubs.acs.org. Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2005.04.064.