Radical-based methodology for efficient generation of acyclic N-acylimines

Article abstract of DOI:10.1016/S0040-4039(00)01683-X

α-Methoxybenzamides 11, which are convenient precursors of acyclic N-acylimines, can be cleanly generated in high yields via a free radical process starting from an o-aminobenzamide 16 derived from an N-t-butyl or N-cumyl secondary amine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01683-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9199–9204
Radical-based methodology for efficient generation of
acyclic N-acylimines
Wenchun Chao and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 12 September 2000; accepted 25 September 2000
Abstract
a-Methoxybenzamides 11, which are convenient precursors of acyclic N-acylimines, can be cleanly
generated in high yields via a free radical process starting from an o-aminobenzamide 16 derived from an
N-t-butyl or N-cumyl secondary amine. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: radicals and radical reactions; amides; nitrogen heterocycles; allylation; Diels–Alder reactions.
We have recently reported a new strategy for preparation of a-methoxybenzamides, which are
very useful N-acyliminium ion precursors,1,2 based upon some observations made many years
ago by Turpin and Hey,3 and followed up by Cohen and coworkers4,5 in some insightful
mechanistic investigations. As shown in Scheme 1, we developed a simple one-pot method to
convert o-aminobenzamides 1, which are very easily prepared by the reaction of amines with
isatoic anhydride,6 to a-methoxybenzamides 6. The overall process involves as key steps an in
situ diazotization of 1 to give 2, [1,5]-hydrogen atom translocation in aryl radical 3, followed by
oxidation of the new radical 4 by Cu+2 to the N-acyliminium species 5. Subsequent in situ
trapping of unstable intermediate 5 by solvent gives the a-methoxybenzamide 6. We have also
spent considerable time investigating the regioselectivity of this procedure in cases involving
unsymmetrical o-aminobenzamides of cyclic secondary amines.2 To briefly summarize these
results, oxidations of unsymmetrical o-aminobenzamide derivatives of pyrrolidines and piperi-
dines generally show good regioselectivity for methylene over methine oxidation, particularly
when the a-substituent R in 1 is large. We have rationalized the observed regioselectivity of this
process based upon a hypothesis involving amide rotamer populations of the intermediate aryl
radical (cf. 3).2,5
* Corresponding author. Tel: (814) 863-0189; fax: (814) 863-8403; e-mail: smw@chem.psu.edu
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01683-X

9200
+
N2
R
R HCl
NaNO2
H
R
N
NH2
N
N
-N2
O
O
O
Cu+1
5% CuCl
MeOH
3
2
1
1,5-H atom
transfer
MeO
R
R
R
Cu+2
N
MeOH
N
N
H
+
O
O
O
6 (major regioisomer)
4
5
Scheme 1.
One limitation of the methodology is that an o-aminobenzamide 7 of a primary amine does
not undergo the desired radical oxidation process upon diazotization in the presence of CuCl,
but rather forms a stable triazine 8 (Eq. (1)). In order to solve this problem, and to extend the
scope and utility of this chemistry, we have begun to investigate acyclic systems of type 9a/b
(Scheme 2). The strategy here is to have group ‘X’ on nitrogen be easily removable, thereby making
these systems equivalent to effecting the oxidation chemistry with a primary amine derivative.
Moreover, since the hypothesis is that amide rotamer populations control the regioselectivity of
the process, we expected that having a large, bulky ‘X’ group would bias the system towards
rotamer 9a, a critical feature which should lead to efficient oxidation to ultimately afford the
desired a-methoxybenzamides 11, precursors to acyclic N-acylimines. It should be noted that little
good methodology is available for preparation of N-acylimines derived from simple aldehydes,
and even fewer methods are known which produce such species from ketones.7
O
O
NaNO2
Bu
HCl, MeOH
N
N
NHBu
NH2
(1)
CuCl
N
7
8
Some initial feasibility experiments were conducted with the O-alkyl hydroxamic acid
derivatives 9a/b (X=Ot-Bu and OMe, R=pentyl), which upon exposure to our standard
diazotization/oxidation conditions2 afforded complex mixtures containing low to moderate
yields of reduction products 13 as the only identifiable compounds (Scheme 2). It is probable
that 13 arises via hydrogen atom abstraction from solvent by intermediate aryl radical rotamer
12, which is incapable of a 1,5-hydrogen atom migration. We were pleased to find, however, that
if the ‘X’ substituent on nitrogen is changed to t-butyl or cumyl,8 oxidation in fact leads to the
desired a-methoxybenzamides 11 in excellent yields, presumably via amide rotamer 10. In this
communication we describe the development of this chemistry into a practical synthetic method.
The substrates for these studies were prepared starting from the appropriate t-butyl or cumyl
amine derivative 14,8,9 which was first acylated with o-nitrobenzoyl chloride to afford amides 15

9201
R
R
R
X
X
X
MeO
N
HCl
N
NH2
N
NaNO2
O
O
O
10% CuCl
MeOH
11
9a
3 Å MS
0-18 oC
10
X=t-Bu, cumyl
R
O
R
O
R
X
X
X
NH2
HCl
NaNO2
N
N
N
O
10% CuCl
MeOH
12
13
9b
X=Ot-Bu, OMe; R=pentyl
Scheme 2.
(Scheme 3). In these systems, the rather bulky acyclic amines did not acylate well with isatoic
anhydride.6 Reduction of the nitro group then afforded the o-aminobenzamide substrates 16 in
good overall yields. We have developed a standard set of oxidation conditions10 which have been
tested with a number of these o-aminobenzamides 16 to generate a-methoxybenzamides like 11
(cf. Scheme 2), and the results are listed in Table 1. As can be seen, product yields are high in
all the cases involving oxidation at a methylene carbon. However, the methine system shown in
entry 9 led to the corresponding enamide rather than the methoxy compound, but only in
moderate yield. It is not clear what the problem is in this case, but since as noted above
N-acylimines derived from simple ketones are not readily available,1 we intend to investigate
such systems further.
o-nitrobenzoyl
chloride
NEt3, CH2Cl2
NaBH4
Cu(acac)2
i-PrOH/EtOH
O
O
R
R
R'
N
R
N
R"
R'
R"
R'
R"
N
H
NO2
15
NH2
16
14
R = Me, Ph
Scheme 3.
We have also tried a few reactions of the N-acylimines generated from some of the oxidation
products in Table 1. Thus, a-methoxybenzamide 17 reacts with allyltrimethylsilane at room
temperature in the presence of boron trifluoride etherate to afford allylation product 18 with
concomitant cleavage of the N-t-butyl group (Scheme 4). Similarly, allylation of substrate 19
(anisole used as a cation scavenger) and the corresponding N-cumyl system 20 led to the
N-dealkylated product 21 in good yields.
In addition, a-methoxybenzamides 22a and 22b are good substrates for hetero Diels–Alder
cycloadditions.11 Treatment of 22a with boron trifluoride etherate/methanesulfonic acid
overnight leads to a stereospecific [4+2]-cyclization11 via the corresponding N-acyliminium
intermediate 23 to afford bicyclic oxazine 24, which is identical to the compound which we have

9202
Table 1
Conversion of N-alkyl-o-aminobenzamides to a-methoxybenzamides9
entry
1
o-aminobenzamide
reaction time
1.5 h
product
O
yield (%)
93
O
t-Bu
t-Bu
N
N
NH2
MeO
O
O
t-Bu
t-Bu
N
N
2
3
94
82
1.5 h
2.0 h
NH2
MeO
O
O
t-Bu
t-Bu
N
N
C4H9
C4H9
NH2
MeO
O
N
O
t-Bu
t-Bu
N
4
5
1.5 h
3.5 h
91
99
NH2
MeO
O
O
t-Bu
Ph
t-Bu
N
N
Ph
NH2
MeO
O
O
t-Bu
N
t-Bu
Ph
N
N
94
3.0 h
6
NH2
Ph
MeO
O
O
Ph
N
Ph
Ph
92
92
47
7
8
3.0 h
3.5 h
NH2
Ph
MeO
O
O
Ph
Ph
N
N
NH2
MeO
O
O
t-Bu
t-Bu
N
N
3.0 h
9
NH2

9203
O
O
TMS
BF3-Et2O
CH2Cl2, rt
18-21 h
H
R
N
Ph
N
Ph
R'
R'
MeO
17 R = t-Bu, R' = H
19 R = t-Bu, R' = Ph
20 R = CMe2Ph, R' = Ph
18 (R' = H, 87%)
21 (R' = Ph, 81%, anisole added)
21 (R' = Ph, 81%)
Scheme 4.
previously prepared11 (Scheme 5). It is not clear here whether cleavage of the N-t-butyl group
precedes the cycloaddition (i.e. X=BF3 or H in imine 23) or occurs afterwards. The N-cumyl
system 22b also successfully cyclizes to the same product 24.
BF3-Et2O
Me
MeSO3H
CH2Cl2, rt
~18 h
H
H
Me
O
Me
O
O
N
X
Ph
N
X
Ph
+
N
Ph
MeO
24 X = t-Bu (75%)
23
22a X = t-Bu
22b X = CMe2Ph
X = CMe2Ph (61%)
Scheme 5.
In summary, we have developed a simple, high yielding new route to produce a-methoxyben-
zamides, which are stable, storable precursors to N-acylimines formally derived from simple
aldehydes and ketones. We are currently investigating extensions and applications of this
methodology to alkaloid total synthesis.
Acknowledgements
We are grateful to the National Institutes of Health (CA-32299) for financial support of this
research.
References
1. For reviews of the chemistry of N-acylimines, see: (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367. (b) Hiemstra, H.; Speckamp, W. N. In The Alkaloids; Brossi, A., Ed. N-Acyliminium ions as intermediates
in alkaloid synthesis. 1988; Vol. 32, p. 271. (c) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds. Additions to N-acyl iminium ions. Pergamon: Oxford, 1991; Vol. 2, p.
1047. (d) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2-1, 56, 3817.
2. (a) Han, G.; McIntosh, M. C.; Weinreb, S. M. Tetrahedron Lett. 1994, 35, 5813. (b) Han, G.; LaPorte, M. G.;
McIntosh, M. C.; Weinreb, S. M.; Parvez, M. J. Org. Chem. 1996, 61, 9483. (c) Han, G. Ph.D. Thesis, The
Pennsylvania State University, 1997. (d) LaPorte, M. G. Ph.D. Thesis, The Pennsylvania State University, 2-1.
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J. Am. Chem. Soc. 1968, 90, 6866.

9204
5. See also: (a) Snieckus, V.; Cuevas, J.-C.; Sloan, C. P.; Liu, H.; Curran, D. P. J. Am. Chem. Soc. 1990, 112, 896.
(b) Curran, D. P.; Liu, H. J. Chem. Soc., Perkin Trans. 1 1994, 1377 and references cited therein. Interestingly,
the translocated radicals in our system (cf. 4) do not cylize back onto the aromatic ring as observed by Curran,
presumably because Cu-promoted oxidation to the N-acylimine is faster.
6. Coppola, G. M. Synthesis 1980, 505.
7. See for example: Johnson, A. P.; Luke, R. W. A.; Steele, R. W.; Boa, A. N. J. Chem. Soc., Perkin Trans. 1 1996,
883. Johnson, A. P.; Luke, R. W. A.; Boa, A. N. J. Chem. Soc., Perkin Trans. 1 1996, 895. Al-Talib, M.; Zaki,
M.; Hehl, S.; Stumpf, R.; Fischer, H.; Jochims, J. C. Synthesis 1996, 1115.
8. The secondary cumyl systems were prepared from cumyl amine by straightforward procedures. Popielarz, R.;
Arnold, D. R. J. Am. Chem. Soc. 1990, 112, 3068; Kamer, P. C. J.; Nolte, R. J. M.; Drenth, W. J. Am. Chem.
Soc. 1988, 110, 6818. See also: Metallinos, C.; Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1, 1183. We thank
Professor Snieckus and Costa Metallinos for providing useful information on preparation of cumyl amine.
9. The secondary t-butyl amines used to prepare the substrates in entries 1 and 5 of Table 1 are commercially
available. Others were prepared by routine chemistry.
10. Experimental procedure for oxidation of o-aminobenzamides 16: The o-aminobenzamide (1.0 equiv.) and NaNO2
(1.5 equiv.) were dissolved in dry methanol (0.07 M solution) in a clean two-necked flask (free of contamination
with copper). To this solution at 0°C was added dropwise 1.0 M methanolic HCl (5.6 equiv.) over 10 min and
the mixture was stirred at this temperature for an additional 50 min until the starting material was converted to
,
the diazonium salt (determined by TLC). Powdered molecular sieves (3 A, loaded in a flask connected by a
ground glass joint, predried over a flame in vacuo for 20 min) were quickly added and the mixture was stirred
for 10 min. Anhydrous cuprous chloride (0.1 equiv.) was then added and the mixture was stirred at 12–18°C for
1.5 h. The mixture was filtered through Celite and the pad was rinsed with methanol. The filtrate was neutralized
with NaOMe (7.0 equiv.) and the methanol was removed under reduced pressure. The residue was purified by
flash chromatography on activated neutral alumina (to which 5% water was added) eluting with 14:1 hexanes/
ethyl acetate to afford the a-methoxybenzamide.
11. Scola, P. M.; Weinreb, S. M. J. Org. Chem. 1986, 51, 3248.
.
.