An efficient synthesis of ortho-N-Boc-arylmethyl ketone derivatives

Article abstract of DOI:10.1016/S0040-4039(03)01597-1

A new and efficient method for the preparation of ortho-N-Boc-arylmethyl ketone derivatives is reported. The reaction involves the intermediacy of a 4-methylene-3,1-benzoaxin-2-one moiety which smoothly converts to the target compounds under acidic conditions. The ortho-N-Boc-arylmethyl ketone derivatives can be formed in a one-pot reaction or alternatively the 4-methylene-3,1-benzoaxin-2-ones can be isolated and subsequently transformed into the desired products.

Full text of DOI:10.1016/S0040-4039(03)01597-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6429–6432
An efficient synthesis of ortho-N-Boc-arylmethyl ketone
derivatives
Pierre-Emmanuel Broutin, Peter Hilty and Andrew W. Thomas*
F. Hoffmann-La Roche AG, Pharmaceuticals Division, Discovery Chemistry, Basel CH 4070, Switzerland
Received 10 May 2003; revised 26 June 2003; accepted 26 June 2003
Abstract—A new and efficient method for the preparation of ortho-N-Boc-arylmethyl ketone derivatives is reported. The reaction
involves the intermediacy of a 4-methylene-3,1-benzoaxin-2-one moiety which smoothly converts to the target compounds under
acidic conditions. The ortho-N-Boc-arylmethyl ketone derivatives can be formed in a one-pot reaction or alternatively the
4-methylene-3,1-benzoaxin-2-ones can be isolated and subsequently transformed into the desired products.
© 2003 Elsevier Ltd. All rights reserved.
An efficient synthesis of N-Boc-acetophenone 1, as a
key strategic intermediate in a synthetic sequence, was
sought.1 However, when attempting the N-Boc-protec-
tion of ortho-aminoacetophenone 2 under standard
conditions we were initially surprised to find that the
desired product 1 was not formed and instead 4-methyl-
ene-3,1-benzoaxin-2-one 3 was isolated in 46% yield
(Scheme 1).
new mild method for preparation of compounds of type
3. Since two equivalents of Boc2O are required in the
transformation it was found that adding each equiva-
lent portion-wise with either catalytic (10 mol%) or 1
equivalent of DMAP both offered acceptable reaction
times and yields even at room temperature. At elevated
temperatures the reactions were complete within a few
minutes but the reaction yield was compromised
somewhat.
The outcome of this reaction was undesired and was
also found to be general for a small array of products
3a–d (Table 1). However, encouraged by the fact that
we had discovered a novel access to this scarcely stud-
ied heterocyclic ring-system we briefly investigated this
A mechanism for the formation of the observed prod-
ucts 3 is proposed whereby the reaction proceeds
through the bis-N-Boc derivative 4. This infers enolisa-
tion of the methyl ketone 5 and intramolecular cyclisa-
tion via oxygen with concomitant loss of t-BuOH to
afford the 4-methylene-3,1-benzoaxin-2-one 3 (Fig. 1).
This new route to 4-methylene-3,1-benzoaxin-2-ones 3
complements the known routes to molecules of such
type which have been prepared from 62 and 73 in
moderate to good yields using phosgene and
acylisocyanates as the ‘CO’ source, respectively (Fig. 2).
All reactions were closely monitored by HPLC-MS
which showed nearly quantitative formation of the
4-methylene-3,1-benzoaxin-2-ones 3. Therefore we were
frustrated and puzzled by the differences in the yields
obtained after a silica-gel chromatographic purification
step (Table 1). In closely examining the fractions col-
lected post-purification we observed small amounts of a
relatively non-polar product that appeared to form only
during the chromatographic step. MS-analysis revealed
this to be the desired N-Boc-acetophenone 1 and its
formation was speculated to be due to decomposition
Scheme 1. Formation of 4-methylene-3,1-benzoaxin-2-one;
Reagents and conditions: (a) Boc2O (1 equiv.), DMAP (10
mol%), CH2Cl2, rt, 1 h, silica gel chromatography, 46%.
Keywords: 4-methylene-3,1-benzoaxin-2-one; polymer supported
reagents; ortho-N-Boc-acetophenone; protecting groups.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01597-1

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P.-E. Broutin et al. / Tetrahedron Letters 44 (2003) 6429–6432
Table 1. Formation of 4-methylene-3,1-benzoaxin-2-ones 3a–d
Compound
R
R
Boc2O (equiv.)
DMAP (equiv.) Temperature (°C)
Reaction time (min)
Yield (%)
Conv.
Isol.
3a
3a
3a
3b
3b
3c
3c
3c
3d
H
H
H
OMe
OMe
H
H
H
OMe
OMe
1.0
2.0
2×1.0
2.0
2.0
0.1
0.1
1.0
0.1
1.0
1.0
2.0
0.1
1.0
25
25
25
25
25
25
25
40
25
60
60
30
60
30
30
30
10
30
46
80
82
80
86
99
80
65
99
40
65
46
65
56
85
50
50
81
OCH2O OCH2O 2.0
OCH2O OCH2O 2.0
OCH2O OCH2O 2.0
Cl
Cl
2.0
fonic acid) offered much better yields and in shorter
reaction times (Table 2). In addition the use of silica-gel
or polymer supported acids to catalyse the decomposi-
tion of 3 into 1 required no further purification of the
products after simple filtration and evaporation of sol-
vent therefore offering an improved access to the
desired N-Boc-acetophenones 1.
The growing acceptance of polymer supported
reagents4 as standard reagents in organic synthesis
encouraged us to design a one-pot method to allow
direct access to the desired N-Boc-acetophenones 1
without chromatographic purification. Our initial
attempt to employ polymer supported DMAP followed
by filtration and evaporation of the reaction solvent
afforded the 4-methylene-3,1-benzoaxin-2-one 3c in
good yield (75%). Subsequent reaction of 3c without
purification using A-15 in CH2Cl2 yielded the desired
product 1c in 60% yield.
Figure 1. Proposed mechanism for the formation of 3.
A one-pot reaction was also possible and in the step-
wise addition of the reagents [polymer supported
DMAP, Boc2O then after formation of the intermediate
3c (monitored by TLC and HPLC-MS)] followed by
addition of A-15 to the reaction mixture allowed the
isolation of the desired product 1c in 72% yield. A
further development of the one-pot method was also
possible where all reagents were added at the same
time. In this case the reaction needed excess of reagents
and extended reaction time but, pleasingly, the desired
product 1c was isolated in 56% yield without any
purification steps involved (Scheme 3).
Figure 2. Reagents and conditions: (a) COCl2, collidine, tolu-
ene, 0°C, 96%; (b) PhCONꢀCꢀO, CH2Cl2, rt, 30%.
of 3 under the slightly acidic conditions of the silica gel
column. Upon testing this hypothesis by (a) stirring the
crude reaction mixture in a 1N HCl in THF solution
and (b) performing a time-delayed TLC by leaving a
‘TLC-spot’ on the silica gel TLC-plate for 2 h before
‘running the TLC’, we observed the near-complete con-
version of 4-methylene-3,1-benzoaxin-2-ones 3 into 1
when monitored by TLC and HPLC-MS.
In conclusion a new efficient method for the prepara-
tion of ortho-N-Boc-arylmethyl ketone derivatives has
been developed which involves the intermediacy of
4-methylene-3,1-benzoaxin-2-ones which smoothly con-
vert into the target compounds under acidic conditions.
This serendipitous discovery prompted performing
these reactions on a preparative scale and, pleasingly,
yields up to 95% were recorded for this transformation
when screening a small range of acids (Scheme 2).
Silica gel allowed the product to be isolated in good
yields albeit with extended reaction times but notably
Amberlyst-15 (a strongly acidic polymer supported sul-
Scheme 2. Reagents and conditions: (a) see Table 2.

P.-E. Broutin et al. / Tetrahedron Letters 44 (2003) 6429–6432
Table 2. Acid mediated transformation of 3 to 1
6431
1(b) To a solution of 8-methylene-6-oxo-8H-1,3,7-tri-
oxa-5-aza-cyclopenta[b]naphthalene-5-carboxylic acid
tert-butyl ester 3c (1.0 g, 3.3 mmol) in CH2Cl2 (100
mL) was added silica gel (100 g) and the reaction
mixture shaken in a rotary shaker for 24 h. The reac-
tion mixture was then filtered, washed with CH2Cl2 (20
mL) and the combined organic fractions were evapo-
rated to afford (6-acetyl-benzo[1,3]dioxol-5-yl)-car-
bamic acid tert-butyl ester 1c (0.55 g, 60%) as a white
Adduct
Acid (100
wt%)
Product
Reaction
time (h)
Yield (%)
3a
3a
3a
3b
3b
3c
3c
3d
3d
SiO2
1a
1a
1a
1b
1b
1c
1c
1d
1d
48
2
2
24
1
24
1
41
75
58
65
95
60
75
73
70
A-15
HCl (1N)
SiO2
A-15
SiO2
A-15
SiO2
A-15
1
solid; H NMR (CDCl3, 300 MHz) l 11.4 (1H, br s),
8.10 (1H, s), 7.20 (1H, s), 5.98 (2H, s), 2.57 (3H, s), 1.51
(9H, s); m/e (EI) 279.2 (M, 45%), 179.2 (100).
24
1
Following a similar method to 1(a) using DMAP (10
mol%) provided 4-methylene-2-oxo-4H-benzo[d][1,3]-
oxazine-1-carboxylic acid tert-butyl ester 3a (0.95 g,
1
65%) which was isolated as a white solid; H NMR
(CDCl3, 300 MHz) l 7.50 (1H, d), 7.35 (1H, t), 7.15
(2H, m), 4.95 (2H, m), 1.60 (9H, s); m/e (EI) 261.2 (M,
4%), 161.1 (100).
Following a similar method as 1(b) using A-15 (1.0 g)
provided (2-acetyl-phenyl)-carbamic acid tert-butyl
ester 1a (0.58 g, 75%) which was isolated as a white
1
solid; H NMR (CDCl3, 300 MHz) l 10.9 (1H, br s),
8.45 (1H, d), 7.87 (1H, dd), 7.51 (1H, t), 7.02 (1H, t),
2.63 (3H, s), 1.51 (9H, s); m/e (EI) 235.2 (M, 40%),
179.2 (60), 135.2 (100).
Scheme 3. Reagents and conditions: (a) PS-DMAP (2 equiv.),
Boc2O (2 equiv.), CH2Cl2, rt, 90 min, 75%; (b) A-15 (100
wt%), CH2Cl2, rt, 1 h, 60%; (c) PS-DMAP (2 equiv.), Boc2O
(2 equiv.), CH2Cl2, rt, 90 min then A-15 (100 wt%), CH2Cl2,
rt, 1 h, 72%; (d) PS-DMAP (4 equiv.), Boc2O (2 equiv.), A-15
(100 wt%), CH2Cl2, rt, 12 h, 56%.
Polymer supported DMAP and A-15 method
To a solution of 6%-amino-3%,4%-(methylenedioxy) ace-
tophenone 2c (1.0 g, 5.6 mmol) in CH2Cl2 (10 mL) at
room temperature under an Argon-flow was added
Boc2O (2.4 g, 11.2 mmol) followed by polymer sup-
ported DMAP (3.74 g, 11.2 mmol) with the immediate
evolution of gas in the reaction mixture and the reac-
tion mixture shaken in a rotary shaker for 1.5 h. The
reaction mixture was then filtered, washed with CH2Cl2
(10 mL) and the combined organic fractions were evap-
orated to afford 8-methylene-6-oxo-8H-1,3,7-trioxa-5-
aza-cyclopenta[b]naphthalene-5-carboxylic acid tert-
butyl ester 3c (1.28 g, 75%) as a white solid. The solid
was then dissolved in CH2Cl2 (10 mL) and A-15 (1.3 g)
added and the reaction mixture shaken in a rotary
shaker for 1 h. The reaction mixture was then filtered,
washed with CH2Cl2 (10 mL) and the combined organic
fractions were evaporated to afford (6-acetyl-
benzo[1,3]dioxol-5-yl)-carbamic acid tert-butyl ester 1c
(0.71 g, 60%) as a white solid. Data as above.
This method was found to be applicable to the iterative
parallel synthesis of a diverse array of N-Boc-acetophe-
none derivatives and further use of these synthetic
intermediates within chemistry programmes will be
reported in due course.
Typical experimental procedures and data for representa-
tive examples
Standard methods for cyclisation to 4-methylene-3,1-
benzoaxin-2-ones 3 and conversion to ortho-N-Boc-ace-
tophenone 1 derivatives
1(a) To a solution of 6%-amino-3%,4%-(methylenedioxy)
acetophenone 2c (1.0 g, 5.6 mmol) in CH2Cl2 (10 mL)
at room temperature under an Argon-flow was added
Boc2O (2.4 g, 11.2 mmol) followed by DMAP (0.7 g,
5.6 mmol) with immediate ‘bubbling’ in the reaction
mixture. After 30 min, the reaction mixture was washed
with HCl (1N, 2×10 mL), and the organic layer, sepa-
rated, dried and evaporated to leave a light yellow oil.
Purification by chromatography on silica gel eluting
with diethyl ether:hexane (1:1) afforded 8-methylene-6-
oxo-8H-1,3,7-trioxa-5-aza-cyclopenta[b]naphthalene-5-
carboxylic acid tert-butyl ester 3c (1.45 g, 85%) as a
white solid; 1H NMR (CDCl3, 300 MHz) l 6.88 (1H, s),
6.80 (1H, s), 4.78 (2H, m) and 1.61 (9H, s); m/e (EI)
305.2 (M, 7%), 205.2 (100).
One-pot method with polymer supported DMAP and
A-15
To a solution of 6%-amino-3%,4%-(methylenedioxy) ace-
tophenone 2c (0.1 g, 0.36 mmol) in CH2Cl2 (2 mL) at
room temperature under an Argon-flow was added
Boc2O (0.16 g, 0.72 mmol) followed by polymer sup-
ported DMAP (82 mg, 2.88 mmol) and A-15 (0.1 g)
and the reaction mixture shaken in a rotary shaker for
12 h. The reaction mixture was then filtered, washed
with CH2Cl2 (2 mL) and the combined organic
fractions were evaporated to afford (6-acetyl-

6432
P.-E. Broutin et al. / Tetrahedron Letters 44 (2003) 6429–6432
benzo[1,3]dioxol-5-yl)-carbamic acid tert-butyl ester 1c
(0.06 g, 56%) as a white solid. Data as above.
Terefenko, E. A.; Slavin, J. Tetrahedron Lett. 2001, 42,
2097; (b) Chandrasekhar, S.; Narsihmulu, Ch. Tetrahedron
Lett. 2000, 41, 7969.
Acknowledgements
We thank Dr. Alex Alanine for support of this work
and Dr. Matthias Nettekoven for helpful comments
during the preparation of the manuscript.
2. Visser, C. M.; Kellogg, R. M. Bioorg. Chem. 1977, 6, 79.
3. Molina, P.; Conesa, C.; Alias, A.; Arques, A.; Velasco, M.
D. Tetrahedron 1993, 49, 7599.
4. Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1
2000, 3815.
References
1. Two other methods for the preparation of ortho-N-Boc-
acetophenone have been reported: (a) Zwang, P.;