Exploratory synthetic studies of the α-methoxylation of amides via cuprous ion-promoted decomposition of o-diazobenzamides

Article abstract of DOI:10.1021/jo961529a

A convenient nonelectrochemical amide oxidation method has been developed. The process involves a cuprous ion-promoted decomposition of o-diazobenzamides like 4, generated in situ from the corresponding o-aminobenzamides, to give N-acyliminium ion intermediate 9 via a 1,5-H-atom transfer, followed by metal-catalyzed oxidation of the resulting α-amidyl radical. The transformation produces α-methoxybenzamides 15 in good yields. An attempt was made to apply this oxidation method to a total synthesis of the alkaloid (-)-anisomycin (16). Scalemic o-aminobenzamide pyrrolidine derivatives 18a/18b underwent oxidation to give α-methoxylated amide substrates 19a/19b, respectively, in good yields. However, alkylation of the N-acyliminium intermediate 20 with (p-methoxybenzyl)magnesium chloride gave the undesired anti-compounds 22a/22b as the major products. The amide oxidation exhibits good regioselectivity with many unsymmetrical 2-substituted piperidine and pyrrolidine systems. In general, it appears that the larger the C-2 substituent, the greater the methylene/methine H-atom abstraction ratio. A mechanistic rationale for this selectivity is suggested based upon amide rotamer populations. An extension of this methodology can be used to conduct two sequential amide oxidations using readily prepared 2-amino-6-nitrobenzamides such as 68 and 69.

Full text of DOI:10.1021/jo961529a

J . Org. Chem. 1996, 61, 9483-9493
9483
Exp lor a tor y Syn th etic Stu d ies of th e r-Meth oxyla tion of Am id es
via Cu p r ou s Ion -P r om oted Decom p osition of o-Dia zoben za m id es†
Gyoonhee Han, Matthew G. LaPorte, Mathias C. McIntosh, and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
Masood Parvez‡
Department of Chemistry, University of Calgary, 2500 University Drive, N.W.,
Calgary, Alberta, T2N 1N4, Canada
Received August 6, 1996X
A convenient nonelectrochemical amide oxidation method has been developed. The process involves
a cuprous ion-promoted decomposition of o-diazobenzamides like 4, generated in situ from the
corresponding o-aminobenzamides, to give N-acyliminium ion intermediate 9 via a 1,5-H-atom
transfer, followed by metal-catalyzed oxidation of the resulting R-amidyl radical. The transformation
produces R-methoxybenzamides 15 in good yields. An attempt was made to apply this oxidation
method to a total synthesis of the alkaloid (-)-anisomycin (16). Scalemic o-aminobenzamide
pyrrolidine derivatives 18a /18b underwent oxidation to give R-methoxylated amide substrates 19a /
19b, respectively, in good yields. However, alkylation of the N-acyliminium intermediate 20 with
(p-methoxybenzyl)magnesium chloride gave the undesired anti-compounds 22a /22b as the major
products. The amide oxidation exhibits good regioselectivity with many unsymmetrical 2-substituted
piperidine and pyrrolidine systems. In general, it appears that the larger the C-2 substituent, the
greater the methylene/methine H-atom abstraction ratio. A mechanistic rationale for this selectivity
is suggested based upon amide rotamer populations. An extension of this methodology can be
used to conduct two sequential amide oxidations using readily prepared 2-amino-6-nitrobenzamides
such as 68 and 69.
Sch em e 1
In tr od u ction
During the course of our recent work on total synthesis
of the Amaryllidaceae alkaloid lycoricidine and its con-
geners,1 we explored an approach to the tricyclic ring
system of the natural products using an intramolecular
Meerwein arylation as the key strategic step.2,3 However,
exposure of the simple model o-aminobenzamide 1 to the
usual Meerwein arylation conditions2 did not produce any
of the desired tricycle 2 (Scheme 1) but rather chroma-
tography of the complex reaction mixture led to isolation
of only the N-hydroxymethyl amide 3, albeit in low yield.
A search of the literature indicated that this transforma-
tion is not unprecedented. In fact, over four decades ago
Hey and Turpin found that an o-diazobenzamide 4
prepared from a secondary amine can be dealkylated to
a benzamide 7 upon treatment with copper powder under
aqueous conditions (Scheme 2).4 In a series of elegant
papers, Cohen and co-workers subsequently established
that this transformation is catalyzed by Cu+1 ion and
provided strong evidence for the free radical mechanism
shown in Scheme 2.5 The proposed reaction sequence
involves initial reduction of the diazonium salt by Cu+1
leading to evolution of nitrogen and formation of an aryl
radical 5, along with Cu+2 ion.2c Radical 5 then under-
Sch em e 2
† Dedicated to Professor Richard W. Franck on the occasion of his
60th birthday.
‡ Author to be contacted regarding X-ray structure determination.
X Abstract published in Advance ACS Abstracts, December 15, 1996.
(1) McIntosh, M. C.; Weinreb, S. M. J . Org. Chem. 1993, 58, 4823.
(2) For reviews of the Meerwein arylation, see: (a) Rondestvedt, C.
S., J r. Org. React. 1960, 11, 189. (b) Rondestvedt, C. S., J r. Ibid. 1976,
24, 225. (c) Galli, C. Chem. Rev. 1988, 88, 765.
(3) See also: Murphy, J . A.; Rasheed, F.; Roome, S. J .; Lewis, N. J .
Chem. Soc., Chem. Commun. 1996, 737 and references cited therein.
(4) Hey, D. H.; Turpin, D. G. J . Chem. Soc. 1954, 2471. See also,
Hey, D. H.; Rees, C. W.; Todd, A. R. J . Chem. Soc. (C) 1967, 1518 and
references cited therein.
goes a 1,5-hydrogen atom transfer to generate R-amidyl
radical 6, which is oxidized by cupric ion to the N-
(5) (a) Lewin, A. H.; Dinwoodie, A. H.; Cohen, T. Tetrahedron 1966,
22, 1527. (b) Cohen, T.; McMullen, C. H.; Smith, K. J . Am. Chem. Soc.
1968, 90, 6866. (c) Cohen, T.; Smith, K. W.; Swendloff, M. D. Ibid.
1971, 93, 4303. For a related free radical process involving sulfon-
amides, see: Pines, S. H.; Purick, R. M.; Reamer, R. A.; Gal, G. J .
Org. Chem. 1978, 43, 1337.
S0022-3263(96)01529-0 CCC: $12.00 © 1996 American Chemical Society

9484 J . Org. Chem., Vol. 61, No. 26, 1996
Han et al.
Sch em e 3
acyliminium species 9. Such imines are highly electro-
philic and are prone to hydrolysis via a “methylol” such
as 8 (R′′ ) H) to afford the dealkylated product 7.6
N-Acyliminium compounds 9 are now well established
as important synthons in organic chemistry.7,8 The most
common method presently used for generating these
intermediates is by elimination of R-alkoxy amides of type
8 (R′′ ) Me, Et, etc.). Although it is now possible to
prepare precursors 8 directly from the component amides
and aldehydes,9 a very simple route to these species
involves electrochemical anodic oxidation of carbamates
and related N-acyl derivatives 10 of amines (eq 1). This
latter procedure to R-alkoxy carbamates 11 has been
widely investigated by Shono and co-workers and has
been used extensively in alkaloid total synthesis.8a
Ta ble 1. Con ver sion of Sym m etr ica l Secon d a r y Am in es
to r-Meth oxyben za m id es
A very attractive aspect of the amide oxidation meth-
odology is that it allows functionalization of a generally
stable and often readily available starting material.10 It
occurred to us that the Hey/Turpin/Cohen chemistry
outlined in Scheme 2 might provide a convenient alter-
native to the Shono electrochemical amide oxidation
procedure in eq 1 and in this paper are described our
feasibility studies toward this objective.11
Resu lts a n d Discu ssion
A. Develop m en t of Meth od ology w ith Sym m etr i-
ca l System s. Initial studies were directed at developing
an experimentally simple and convenient two-step pro-
tocol for amide oxidations. It is well known that a
secondary amine 13 can be converted in high isolated
yield into an o-aminobenzamide derivative 14 using
commercially available isatoic anhydride (12)12 (Scheme
3). In certain cases involving less basic and/or hindered
amines an alternative two-step procedure has been used
(vide infra). It is possible to combine the diazotization
step with the Hey/Turpin/Cohen sequence to produce an
R-alkoxybenzamide 15 from the o-aminobenzamide. Thus,
treatment of 14 with sodium nitrite and dry HCl in
methanol containing about 5% cuprous chloride for
varying lengths of time at room temperature yields
products 15 in good yields. A number of examples of this
sequence are shown in Table 1.
(6) “Methylol” derivatives of formaldehyde such as 3 or of other
electrophilic aldehydes are often isolable. cf . Zaugg, H. E.; Martin,
W. B. Org. React. 1965, 14, 52.
(7) See for example: Weinreb, S. M.; Scola, P. M. Chem. Rev. 1989,
89, 1525. Zaugg, H. E. Synthesis 1970, 49 and 181. Weinreb, S. M.
Acc. Chem. Res. 1985, 18, 16. Hiemstra, H.; Speckamp, W. N. Additions
to N-Acyl Iminium Ions. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon: Oxford, 1991; Vol. 2, p 1047.
(8) (a) Shono, T. Top. Curr. Chem. 1988, 148, 131. Shono, T.
Electroorganic Chemistry as
a New Tool in Organic Synthesis”;
Springer: Heidelberg, 1984, and references cited therein. (b) Mitzlaff,
M.; Warning, K.; J ensen, H. Liebigs Ann. Chem. 1978, 1713.
(9) J ohnson, A. P.; Luke, R. W. A.; Steele, R. W.; Boa, A. N. J . Chem.
Soc., Perkin Trans. 1 1996, 883. J ohnson, A. P.; Luke, R. W. A.; Boa,
A. N. Ibid. 1996, 895 and references cited therein.
(10) See also: Magnus, P.; Hulme, C.; Weber, W. J . Am. Chem. Soc.
1994, 116, 4501.
(11) For preliminary accounts of portions of this work, see: (a) Han,
G.; McIntosh, M. C.; Weinreb, S. M. Tetrahedron Lett. 1994, 35, 5813.
(b) Weinreb, S. M. J . Heterocycl. Chem. 1996, 33, 1437.
(12) Venuti, M. C. Synthesis 1982, 266. Coppola, G. M. Ibid. 1980,
505. Staiger, R. P.; Wagner, E. C. J . Org. Chem. 1953, 18, 1427.
In the case of the pyrrolidine-derived system, ring
opening of R-methoxybenzamide 15a tends to occur,
particularly if extended reaction times are used.8 There-
fore, the amido acetal 15a ' can be isolated in good yield
if the oxidation step is conducted for two days. The six-
and seven-membered ring systems do not show quite as
great a propensity for in situ acetal formation but do form

Cuprous Ion-Promoted R-Methoxylation of Amides
J . Org. Chem., Vol. 61, No. 26, 1996 9485
Sch em e 4
analogous products, although more slowly. The acyclic
system 14f is prone to dealkylation unless care is taken
to exclude traces of water. However, in the presence of
4 Å molecular sieves, R-methoxybenzamide 15f is pro-
duced in high yield. It might be noted that acyclic
R-alkoxyamides like 15f generally appear to be hydro-
lytically sensitive and tend to decompose easily under the
conditions used in this methodology. This dealkylation
also appears to be an occasional problem in the electro-
chemical procedure.8
In view of the successful development of the funda-
mental oxidation methodology with symmetrical systems,
we decided to next investigate an application of this
procedure to a total synthesis of (-)-anisomycin (16),13
an alkaloid produced by a Streptomyces species.14 This
Sch em e 5
compound has antibiotic activity against both pathogenic
protozoa and some fungi, and has been used clinically
for treatment of tricomonas vaginitis and amoebic dys-
entery.15 Although there are over a dozen existing
syntheses of this alkaloid,16 both in racemic form and of
the (-)- and (+)-enantiomers, it appeared that our
methodology might provide a very direct new entry to
anisomycin.
The substrates utilized in our study were the known
C2-symmetric pyrrolidine derivatives 17a 17 and 17b.16b,18
Both are readily available in enantiomerically pure form
from L-tartaric acid via a short sequence of steps. The
N-benzylamines 17a /17b can be converted into o-amino-
benzamide derivatives 18a /18b, respectively, in two steps
in good overall yields by hydrogenation followed by the
isatoic anhydride procedure (Scheme 4). Application of
the above amide oxidation methodology to 18a /18b
provided the desired R-methoxybenzamides 19a /19b,
respectively. Due to the homotopicity of the methylene
carbons flanking the nitrogen in 18a /18b because of the
C2-symmetry of the system, it is of no significance which
methylene group is oxidized.
in refluxing ether afforded an excellent yield of a 1/18
mixture of alkylated pyrrolidines 21a and 22a . We
presume that addition to an iminium complex 20 (R )
Me) occurs first and that the N-benzoyl group contained
in the initial product is removed by excess organometallic.
However, the major product of the addition was shown
to be the undesired anti compound 22a by comparison
of its spectral and optical rotation data with that previ-
ously reported.21
It was our intention at this stage to effect a stereo-
selective chelation-controlled addition of (p-methoxy-
benzyl)magnesium chloride to 19a /b via the correspond-
ing N-acyliminium ion 20 (Scheme 5).19 Treatment of
methyl ether series 19a with excess Grignard reagent20
With the hope that a MOM protecting group would be
a more effective syn-director than methyl, R-methoxy-
benzamide 19b was treated with excess Grignard reagent
under identical conditions. In this case a high yield of a
1/65 mixture of 21b/22b was obtained, with the undesired
anti isomer being formed in even greater proportion than
in the methyl ether series. Since this result was rather
unexpected, and because we had available only tiny
amounts of the known syn isomer,16b it was decided to
chemically correlate the previously unknown anti isomer
22b with the methyl-protected series in order to unam-
biguously establish stereochemistry. Therefore, pyrroli-
dine 22b was hydrolyzed using the procedure described
for the syn isomer to yield diol 2322 (Scheme 6). This
compound was then converted to the benzyl carbamate
and O-dimethylated, yielding diether 24. Finally, car-
bamate removal yielded pyrrolidine 22a identical to an
authentic sample.21
(13) Wong, C. M. Can. J . Chem. 1968, 46, 1101 and references cited
therein.
(14) Sobin, B. A.; Tanner, F. W., J r. J . Am. Chem. Soc. 1954, 76,
4053.
(15) Korzybski, T.; Kowszyk-Gindifer, Z.; Kurytowiicz, W. Antibiot-
ics; American Society of Microbiology: Washington, D.C. 1978; Vol. 1,
p 343.
(16) For lead references, see: (a) Tokuda, M.; Fujita, H.; Miyamoto,
T.; Suginome, H. Tetrahedron 1993, 49, 2413. (b) Ballini, R.; Marcan-
toni, E.; Petrini, M. J . Org. Chem. 1992, 57, 1316. (c) Shi, Z.-C.; Lin,
G.-Q. Tetrahedron:Asymmetry 1995, 6, 2907. (d) Yoda, H.; Nakajima,
T.; Yamazaki, H.; Takabe, K. Heterocycles 1995, 41, 2423. (e) Kang, S.
H.; Choi, H. J . Chem. Soc., Chem. Commun. 1996, 1521.
(17) Seebach, D.; Kalinowski, H.-O.; Bastani, B.; Crass, G.; Daum,
H.; Dorr, H.; Du Preez, N. P.; Ehrig, V.; Langer, W.; Nussler, C.; Oei,
H.-A.; Schmidt, M. Helv. Chim. Acta 1977, 60, 301.
(18) Iida, H.; Yamazaki, N.; Kibayashi, C. J . Org. Chem. 1986, 51,
1069. Cicchi, S.; Hold, I.; Brandi, A. Ibid. 1993, 58, 5274.
(19) Kleinman, E. F.; Volkmann, R. A. Reactions of Allyl and
Propargyl/Allenic Organometallics with Imines and Iminium Ions. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
Oxford, 1991; Vol. 2, p 975.
(20) Treatment of R-methoxybenzamides 19a /b with approximately
1 equiv of Grignard reagent gave no reaction.
(21) Felner, I.; Schenker, K. Helv. Chim. Acta 1970, 53, 754.
(22) Oida, S.; Ohki, E. Chem. Pharm. Bull. 1969, 17, 1405.

9486 J . Org. Chem., Vol. 61, No. 26, 1996
Han et al.
Ta ble 2. P r od u cts of Oxid a tion of th e
Sch em e 6
o-Am in oben za m id e of 2-Meth ylp ip er id in e
Recently, Petrini and co-workers16b,23 reported that the
closely related cyclic nitrone 25 reacts with (p-methoxy-
benzyl)magnesium chloride to afford a 2/3 mixture of
syn/ anti adducts 26 and 27 (eq 2). However, in the
presence of MgBr2 etherate in CH2Cl2 the selectivity
reversed, now giving a 7/3 mixture of 26/27. When we
Piperidine derivatives with larger substituents at C-2
were then examined to see if the regioselectivity could
be improved. Thus, the 2-propyl and 2-allyl systems 34
and 36, respectively, were oxidized (eqs 3, 4). In each
case, the transformation was highly regioselective and
only the products from methylene hydrogen atom trans-
fer were isolated (cf. Scheme 2).
conducted the Grignard addition to R-methoxybenzamide
19a in the presence of MgBr2 etherate, a 1/12 mixture of
syn/ anti adducts 21a /22a was formed, but in only 42%
yield. Similar Grignard addition to MOM-protected
system 19b led to a 1/8 mixture of syn/ anti products 21b/
22b, again in a poor 32% yield. Thus, although the
proportions of the desired syn products increased some-
what, overall product yields were disappointingly low. As
a result of these experiments, we have not pursued this
route to anisomycin.
B. Un sym m etr ica l System s. Since the scope and
utility of this new methodology would be greatly ex-
panded if the procedure showed good regioselectivity with
unsymmetrical systems, we decided to next survey the
amide oxidation chemistry in a series of 2-substituted
piperidine derivatives. Therefore, N-acylation of 2-meth-
ylpiperidine was effected with isatoic anhydride to afford
o-aminobenzamide 28. Using our standard reaction
conditions, oxidations were conducted with amide 28 at
a number of temperatures to produce mixtures of prod-
ucts 29-33 (Table 2). The initially formed R-methoxy-
benzamides in this study, as well as those in some of the
cases discussed below, are transformed in situ to a variety
of related products, and no attempts were made to
maximize the formation of any particular type of func-
tionalized product. As can be seen from Table 2, the total
isolated yield of products, as well as a low 2/1 methylene/
methine regioselectivity for the reaction of 28, remains
essentially constant at all temperatures (vide infra).
Only minor variations of the ratios of the products 29-
33 were seen.
A substrate derived from 2-(trimethylsilyl)piperidine
(38)24 (eq 5) was also studied. In this particular example
it proved more efficient to prepare the o-aminobenzamide
39 via a two-step procedure using 2-nitrobenzoyl chloride
for the initial N-acylation, followed by nitro group reduc-
tion. Oxidation of o-aminobenzamide 39 once again only
led to product 40 resulting from methylene hydrogen
atom migration.
One additional piperidine derivative which was exam-
ined was 2-methoxymethyl compound 41. Exposure of
(23) See also Giovannini, R.; Marcantoni, E.; Petrini, M. J . Org.
Chem. 1995, 60, 5706.
(24) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.

Cuprous Ion-Promoted R-Methoxylation of Amides
J . Org. Chem., Vol. 61, No. 26, 1996 9487
Sch em e 7
this o-aminobenzamide to our standard conditions af-
forded a mixture of oxidation products 42-44 (eq 6). In
this case, the methylene/methine ratio is only 1.3/1, a low
regioselectivity which was rather surprising (vide infra).
The pyrrolidine analogue 54 of 2-(methoxymethyl)-
piperidine derivative 41 showed much greater regio-
selectivity. Therefore, oxidation of o-aminobenzamide 54
afforded products 55-58 in the isolated yields indicated
(eq 10). The ratio of methylene/methine oxidation in this
substrate is thus 14.2/1 (vs 1.3/1 for 41).
We have also examined an analogous series of unsym-
metrical 2-substituted pyrrolidines. Thus, the amide 45
derived from 2-methylpyrrolidine upon oxidation pro-
duced a mixture of 46-49 in the isolated yields shown
in eq 7. The regioselectivity with 45 is better than that
Although the regioselectivity in the piperidine and
pyrrolidine examples described here are somewhat vari-
able, in most cases the process shows very good selectivity
comparable to that of the Shono electrochemical oxida-
tion. These studies indicate that the methodology has
significant synthetic potential in the oxidation of unsym-
metrical systems.
Three additional examples of unsymmetrical amide
substrates have been investigated. The tetrahydroiso-
quinoline-derived compound 59 was oxidized to yield a
mixture of 60 and 61 (eq 11). There appears to be a slight
preference here for benzyl methylene hydrogen atom
transfer (ratio 1.7/1). The tetrahydroquinoline o-amino-
found for the 2-methylpiperidine compound 28 (7.3/1 vs
2.2/1, methylene/methine). In addition, the propyl- and
allyl-substituted systems 50 and 52, respectively, have
been studied. In both cases, only the R-methoxybenz-
amides 51 and 53 derived from methylene hydrogen atom
transfer could be isolated (eqs 8, 9).
benzamide 6225 yielded a small amount of the desired
R-methoxyamide 63, but the Pschorr cyclization product

9488 J . Org. Chem., Vol. 61, No. 26, 1996
Han et al.
6426 was produced in a major amount (eq 12). Finally,
the indoline system 65 led only to phenol 66 (eq 13).
F igu r e 1.
C. Sequ en tia l Am id e Oxid a tion s. As a further
extension of the methodology, we have examined the
feasibility of conducting a series of two sequential oxida-
tions. Commercially available 5-nitroisatoic anhydride
(67), which is the reagent used for this purpose, was
converted to the 2-amino-6-nitrobenzamides 68 and 69
with piperidine and pyrrolidine, respectively (Scheme 7).
Exposure of these compounds to the standard oxidation
conditions led to good yields of the R-methoxy o-nitro-
benzamides 70 and 71. These R-alkoxy amides could be
efficiently alkylated with allyltrimethylsilane in the
presence of titanium tetrachloride to afford 72 and 73.7,8
Both the olefin and nitro groups in 72/73 were then
reduced by catalytic hydrogenation to yield 2-propyl
o-aminobenzamides 34/50. Also, selective reduction of
the nitro functionality in 72/73 could be effected with zinc
dust to give 2-allyl o-aminobenzamides 36/52. As de-
scribed above in eqs 3, 4, 8, and 9, substrates 34, 50, 36,
and 52 all undergo subsequent regioselective oxidations
to afford the corresponding R-methoxybenzamides.
D. Mech a n istic Discu ssion . In recent years, nu-
merous examples of the synthetic uses of 1,5-hydrogen
atom transfers in radical reactions have appeared.27
Most commonly these so called “radical-translocation”
reactions27b involve subsequent trapping of the newly
formed carbon-centered radical either inter- or intra-
molecularly by species such as olefins or chain transfer
reagents. A possible alternative fate for the translocated
radical is reduction to a carbanion, and an example of
this process has recently appeared.28 The chemistry
described above involves a third alternative, i.e. oxidation
of the translocated radical to a carbonium ion.
Sch em e 8
it was postulated based upon deuterium labeling studies
that amide rotation between radicals 74 and 75 is slow
relative to 1,5-hydrogen atom transfer producing R-
amidyl radicals 76 and 77, respectively (Figure 1). Later
work by Grimshaw et al. confirmed this hypothesis.29 In
addition, more recently obtained rate data on amide
rotation30 and aryl radical lifetimes31 support these
conclusions.
The synthetic consequences of the process outlined in
Figure 1 is nicely exemplified by work reported by
Snieckus, Curran, and co-workers.27a,b For example, it
was found that rotamer populations of o-iodobenzamides
such as 78 and 79 (Scheme 8), as determined by NMR,
correlate well with yields of radical cyclization products
like 81. Thus, radical 80 derived from rotamer 79 leads
to the cyclization product 81, whereas the translocated
radical produced from amide rotamer 78 leads to a
complex, unidentifiable mixture of products.27b
We believe that the regiochemistry in our amide
oxidation protocol is probably also determined by rotamer
populations. Examination of the o-aminobenzamide of
2-(methoxymethyl)piperidine (41) was undertaken by
X-ray crystallography since this particular substrate led
to apparently anomalous regiochemical results upon
oxidation (vide supra). The structure and conformation
of this amide is shown in the ORTEP plot in Figure 2.32
The primary question which arises in the work outlined
here is the origin of the regioselectivity in the oxidations
of unsymmetrical o-aminobenzamides. In the Cohen
studies5 of the Hey/Turpin amide dealkylation reaction,4
(25) o-Aminobenzamides 62 and 65 were prepared from the corre-
sponding amines using the two-step N-acylation/NO2-reduction pro-
cedure described for 2-(trimethylsilyl)piperidine (38) (eq 5).26
(26) Nagarajan, K.; Pillai, P. M.; Bhute, R. S. Indian J . Chem. 1969,
7, 848.
(27) (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. (c) Curran, D. P.; Yu, H.; Liu,
H. Tetrahedron 1994, 50, 7343. (d) Denenmark, D.; Hoffmann, P.;
Winkler, T.; Waldner, A.; De Mesmaeker, A. Synlett 1991, 621. (e)
Undheim, K.; Williams, L. J . Chem. Soc., Chem. Commun. 1994, 883.
(f) Beaulieu, F.; Arora, J .; Veith, U.; Taylor, N. J .; Chapell, B. J .;
Snieckus, V. J . Am. Chem. Soc. 1996, 118, 8727, and references cited
therein.
(29) Grimshaw, J .; Haslett, R. J .; Trocha-Grimshaw, J . J . Chem.
Soc., Perkin Trans. 1 1977, 2448.
(30) See for example: Stewart, W. E.; Siddall, T. H. Chem. Rev.
1970, 70, 517. Oki, M. Top. Stereochem. 1983, 14, 1.
(31) Scaiano, J . C.; Stewart, L. C. J . Am. Chem. Soc. 1983, 105, 3609.
(32) The authors have deposited X-ray data with the Cambridge
Crystallographic Data Centre. The coordinates can be obtained, on
request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK.
(28) Murakami, M.; Hayashi, M.; Ito, Y. J . Org. Chem. 1992, 57,
793.

Cuprous Ion-Promoted R-Methoxylation of Amides
J . Org. Chem., Vol. 61, No. 26, 1996 9489
F igu r e 3.
2-methylpiperidine 28 was examined. Compound 28
showed a 1.9/1 methylene/methine ratio with the ruthe-
nium catalyst (vs 2.2/1 with CuCl). Simlarly, 2-(methoxy-
methyl)pyrrolidine 54, which gave a 14.2 methylene/
methine selectivity with copper, showed a reduced 11/1
selectivity with the ruthenium catalyst. As a control
here, 2-methylpyrrolidine 45 showed a 4.7/1 methylene/
methine regioselectivity with ruthenium (vs 7.3/1 with
CuCl). Thus there seems to be a loss in methylene
selectivity in all four cases examined using catalytic
ruthenium, but since these changes are rather small, we
are uncertain at present as to the significance of these
results, and to whether there is any effect of the metal
other than acting as a redox reagent.
F igu r e 2. ORTEP plot of o-aminobenzamide 41.
Interestingly, there is no hydrogen bonding between the
amide carbonyl oxygen and the o-amino group, which are
in an anti relationship. The amide rotamer found here
would lead exclusively to methylene hydrogen atom
abstraction rather than the 1.3/1 methylene/methine
ratio observed. However, there are a number of inter-
mediates between the o-aminobenzamide starting mate-
rial 41 and the aryl radical and there is no simple way
of knowing which radical precursor determines the final
rotamer population. Thus o-aminobenzamide substrate
conformation may in fact have no relationship to the
oxidation regiochemistry.
We also examined the simple N-benzoyl derivatives of
the three 2-substituted piperidines shown in Figure 3
since amide oxidation of the corresponding o-amino-
benzamides of these amines give varying regioselectivi-
ties (vide supra). However, proton NMR analysis of the
benzamides 82/83 in CD3OD at temperatures from -50
°C to 0 °C showed 1/1 amide rotamer populations in all
cases. Therefore, it appears that these unsubstituted
benzamides are probably not good model systems to
investigate what is occurring in the oxidation process. It
might also be noted that ortho-substituted benzamide
rotamer populations do not appear to be temperature
dependent,33 and therefore the invariance of the oxidation
of the 2-methylpiperidine derivative 28 to reaction tem-
perature is not surprising (Table 2).
From inspection of our results, it would appear that
in the unsymmetrical piperidine and pyrrolidine oxida-
tions the larger the C-2 substituent the greater the
tendency for methylene vs methine 1,5-hydrogen atom
transfer, perhaps as a result of a steric bias for rotamer
74 over 75 (Figure 1). However, the fact that the
2-(methoxymethyl)piperidine derivative 41 shows virtu-
ally no regioselectivity is not in accord with this supposi-
tion. A possible alternative explanation for this one
seemingly odd result is that there may be some type of
copper chelation with 41, thus altering the regiochemical
results compared to the sterically similar compounds 34
and 36.
Con clu sion
An efficient two-step preparative method has been
developed for converting a secondary amine34 to an
R-methoxybenzamide. The methodology shows good re-
gioselectivity with many unsymmetrical R-substituted
pyrrolidines and piperidines, although further studies are
needed to more fully delineate the mechanistic origin of
this selectivity. We are continuing to investigate the
scope and limitations of the chemistry outlined here and
are applying the protocol to alkaloid total synthesis.11b
Exp er im en ta l Section
Gen er a l. Chemicals were purchased from Aldrich Chemi-
cal Co. except for 5-nitroisatoic anhydride and 2-methyl-
pyrrolidine which were obtained from Pfaltz and Bauer, and
Alfa, respectively. Reactions were run under an atmosphere
of argon. Flash chromatography was performed using EM
Sciences silica gel 60. Preparative TLC was done with EM
silica gel 60 PF254. Melting points are uncorrected. Combus-
tion analyses were carried out by Atlantic Microlab.
Gen er a l P r oced u r e for Syn t h esis of o-Am in ob en z-
a m id es. To a solution of isatoic anhydride (12, ∼30 mmol)
(or 5-nitroisatoic anhydride (67)) in DMF (0.5 M solution) was
added the amine (1.1 equiv) in the presence of DMAP (0.1
equiv) at 0 °C. After 2-3 h at 0 °C the reaction mixture was
warmed to rt, stirred for 20-24 h, diluted with water (100 mL),
and extracted with ethyl acetate (50 mL × 3). The combined
organic layer was washed with brine (50 mL × 2), dried over
MgSO4, and concentrated. The crude product was purified by
flash column chromatography (ethyl acetate/hexanes, 1/1-2/
1). Compounds 14a -c and 14f have been previously pre-
pared.12
In an attempt to test this hypothesis, we explored the
possibility of using a different metal as the oxidation
catalyst. It was found that RuCl2(PPh3)3 functions as an
effective catalyst in quantities similar to CuCl, producing
comparable yields of oxidation products. Interestingly,
oxidation of 2-(methoxymethyl)piperidine system 41 us-
ing the ruthenium complex gave a slightly reversed
regioselectivity with a methine/methylene ratio of 1.2/1
(vs 1.3/1 methylene/methine for CuCl). As a control, the
(34) Application of the procedure to the o-aminobenzamide i derived
from a primary amine led to heterocycle ii in 98% yield.35
(35) cf. LeBlanc, R. J .; Vaughn, K. Can. J . Chem. 1972, 50, 2544.
Hasspacher, K.; Ohnacker, G. US Patent 3,316,262 (Chem. Abstr. 1967,
67, 64445q).
(33) Lewin, A. H.; Frucht, M. Org. Magn. Reson. 1975, 7, 206.

9490 J . Org. Chem., Vol. 61, No. 26, 1996
Han et al.
1
14d (mixture of diastereomers, colorless oil, 98%): IR (neat)
equiv), CuCl (2 mol%) (1.5 h): (IR (film) 1650 cm-1; H NMR
1
3445, 3351, 1634 cm-1; H NMR (200 MHz/CDCl3) δ 7.17 (dt,
(200 MHz/CDCl3) δ 7.55-7.34 (m, 5H), 5.72 and 4.66 (rotam-
ers, br s, 1H), 3.61 and 3.22 (rotamers, br t, 2H), 3.40 and 2.97
(rotamers, 2s, 3H), 2.16-1.52 (m, 4H); EIMS m/z (relative
intensity) 205 (M+, 2), 105 (100), 77 (40); HRMS (C12H15NO2)
calcd 205.1103, found 205.1088.
J ) 7.9, 1.4 Hz, 1H), 7.05 (dt, J ) 7.9, 1.4 Hz, 1H), 6.75-6.70
(m, 2H), 4.29 (rotamers, br s, 3H), 4.02 (br s, 1H), 3.57-3.50
(rotamers, m, 2H), 2.62 (br t, 2H), 1.11 (d, J ) 6.1 Hz, 6H);
EIMS m/ z (relative intensity) 234 (M+, 19), 120 (o-NH2PhCO+,
100); HRMS (C13H18N2O2) calcd 234.1368, found 234.1366.
14e (white solid, 85%): mp 72-73.5 °C; IR (film) 3470, 3383,
Am id o a ceta l 15a ′ (pale yellow oil; 82%) (2 d): IR (film)
3326, 1643 cm-1; H NMR (200 MHz/CDCl3) δ 7.76 (dd, J )
1
1
1626 cm-1; H NMR (200 MHz/CDCl3) δ 7.18-7.06 (m, 2H),
7.7, 1.9 Hz, 2H), 7.49-7.38 (m, 3H), 6.45 (br s, 1H), 4.38 (t, J
) 5.1 Hz, 1H), 3.44 (q, J ) 2.9 Hz, 2H), 3.30 (s, 6H), 1.69-
1.04 (m, 4H); 13C NMR (75 MHz/CDCl3) δ 167.2, 130.8, 129.8,
128.0, 126.7, 104.1, 52.6, 39.4, 29.7, 24.1; CIMS m/z (relative
intensity) 238 (MH+, 6), 206 (M+ - OMe, 100), 105 (PhCO+,
51); HRMS (C13H18NO3) calcd 236.1287, found 236.1273.
r-Meth oxyben za m id e 15b (colorless oil; 69%) (1.5 h): IR
6.74-6.66 (m, 2H), 4.14 (br s, 2H), 3.62 (br s, 2H), 3.39 (br s,
2H), 1.95-1.36 (m, 8H); EIMS m/ z (relative intensity) 218
(M+, 34), 120 (o-NH2PhCO+, 100); HRMS (C13H18N2O) calcd
218.1419, found 218.1414.
2-Meth ylpiper idin e o-am in oben zam ide (28) (white solid,
49%): mp 91-94 °C; 1H NMR (200 MHz/CDCl3) δ 7.14 (d, J )
7.2 Hz, 1H), 7.05 (d, J ) 8.1 Hz, 1H), 6.74-6.67 (m, 2H), 4.55
(rotamers, br s, 1H), 4.15 (br s, 2H), 4.07 (rotamers, br s, 1H),
2.95 (rotamers, t, J ) 13.1 Hz, 1H), 1.65-1.43 (m, 6H), 1.18
(d, J ) 6.9 Hz, 3H). Anal. Calcd for C13H18N2O: C, 71.52; H,
8.31; N, 12.84. Found: C, 71.40; H, 8.29; N, 12.77.
(film) 1644 cm-1; H NMR (200 MHz/CDCl3) δ 7.40 (m, 5H),
1
6.40 and 4.86 (rotamers, br s, 1H), 3.39 and 3.06 (rotamers,
br s, 3H), 3.24 and 2.97 (rotamers, br t, 2H), 1.36-2.00 (m,
6H); CIMS m/ z (relative intensity) 220 (MH+, 8), 188 (M+
-
OMe, 100), 105 (PhCO+, 45); HRMS (C13H17NO2) calcd 219.1259,
found 219.1260.
2-(Meth oxym eth yl)p ip er id in e o-a m in oben za m id e (41)
(white solid, 67%): recrystallized from Et2O/hexanes, mp 106-
107 °C; 1H NMR (200 MHz/CDCl3) δ 7.20-7.05 (m, 2H), 6.73-
6.61 (m, 2H), 4.32 (br s, 2H), 3.72 (t, J ) 14 Hz, 2H), 3.45-
3.20 (m, 4H), 3.15-2.90 (m, 2H), 1.70-1.45 (m, 6H); CIMS m/ z
(relative intensity) 249 (MH+, 100), 217 (M+ - OMe, 5), 203
(M+ - C2H5O, 40), 120 (o-NH2PhCO+, 70).
Am id o a ceta l 15b′ (colorless oil, 49%) (3 d): IR (film) 3324,
1634 cm-1; 1H NMR (300 MHz/CDCl3) δ 7.72 (dd, J ) 7.0, 1.6
Hz, 2H), 7.38-7.25 (m, 3H), 7.04 (br s, 1H), 4.24 (t, J ) 5.6
Hz, 1H), 3.28 (q, J ) 7.0 Hz, 2H), 3.21 (s, 6H), 1.55-1.46 (m,
6H); 13C NMR (75 MHz/CDCl3) δ 167.2, 130.7, 129.8, 127.9,
126.7, 104.1, 52.3, 39.5, 31.8, 28.9, 21.6; CIMS m/ z (relative
intensity) 252 (MH+, 7), 220 (M+ - OMe, 100), 105 (PhCO+,
15); HRMS (C14H20NO3) calcd 250.1443 (M+ - H), found
250.1459.
2-Meth ylp yr r olid in e o-a m in oben za m id e (45) (tan solid,
68%): mp 79-82 °C; IR (CDCl3) 1614 cm-1 1H NMR (200
;
MHz/CDCl3) δ 7.18-7.09 (m, 2H), 6.70-6.64 (m, 2H), 4.54 (br
s, 2H), 4.26 (br s, 1H), 3.48 (br s, 2H), 2.13-1.49 (m, 3H), 1.23-
1.16 (m, 4H); EIMS m/ z (relative intensity) 204 (M+, 28), 120
(o-NH2PhCO+, 100), 84 (C5H10N, 54); HRMS (C12H16N2O) calcd
204.1263, found 204.1267.
r-Meth oxyben za m id e 15c (light yellow oil, 68%) (27 h):
IR (film) 1644 cm-1; 1H NMR (200 MHz/CDCl3) δ 7.44 (m, 5H),
5.70 and 4.70 (rotamers, br s, 1H), 3.57 and 3.54 (rotamers, s,
3H), 4.30-3.04 (m, 6H); EIMS m/ z (relative intensity) 221
(M+, 7), 190 (M+ - OMe, 8), 116 (M+ - PhCO, 9), 105 (PhCO+,
100); HRMS (C12H15NO3) calcd 221.1052, found 221.1048.
r-Meth oxyben za m id e 15d (light yellow oil, 71%) (3 d): IR
(CDCl3) 1633 cm-1; 1H NMR (200 MHz/CDCl3) δ 7.40 (m, 5H),
5.50 and 4.47 (rotamers, s, 1H), 4.43 and 3.14 (rotamers, d, J
) 2.1 Hz, 1H), 3.70 and 3.54 (rotamers, m, 2H), 3.53 and 3.06
(rotamers, two s, 3H), 3.26 and 2.84 (rotamers, t, J ) 2.1 Hz,
1H), 1.35 (t, J ) 5.6 Hz, 3H), 1.12 and 1.05 (rotamers, d, J )
5.6 Hz, 3H); EIMS m/ z (relative intensity) 249 (M+, 8), 218
(M+ - OMe, 2), 144 (M+ - PhCO, 12), 105 (PhCO+, 100);
HRMS (C14H19NO3) calcd 249.1365, found 249.1366.
r-Meth oxyben za m id e 15e (pale yellow solid, 73%): mp
2-(Meth oxym eth yl)pyr r olidin e o-am in oben zam ide (54)
(colorless oil, 82%): IR (CCl4) 3476, 3366, 1628 cm-1; 1H NMR
(200 MHz/CDCl3) δ 7.22-7.10 (m, 2H), 6.72-6.65 (m, 2H), 4.49
(br s, 2H), 4.38 (br s, 2H), 3.47-3.32 (m, 3H), 2.06-1.81 (m,
4H); CIMS m/ z (relative intensity) 235 (MH+, 100).
Tetr a h yd r oisoqu in olin e o-a m in oben za m id e (59) (light
yellow oil, 98%): IR (neat) 3454, 3353, 1614 cm-1 1H NMR
;
(200 MHz/CDCl3) δ 7.22-7.06 (m, 6H), 6.78-6.69 (m, 2H), 4.76
(br s, 2H), 4.36 (br s, 2H), 3.79 (br s, 2H), 2.89 (t, J ) 6.1 Hz,
2H); CIMS m/ z (relative intensity) 253 (MH+, 100); EIMS m/ z
(relative intensity) 252 (M+) HRMS (C16H16N2O) calcd 252.1263,
found 252.1262.
57-59 °C (2 h): IR (CDCl3) 1626 cm-1; H NMR (200 MHz/
1
P ip er id in e 2-a m in o-6-n itr oben za m id e (68) (yellow solid,
91%): (from 5-nitroisatoic anhydride): recrystallized from
benzene/hexanes, mp 163-164 °C; IR (CH2Cl2) 3495, 3377,
CDCl3) δ 7.47-7.34 (m, 5H), 5.94 and 4.83 (rotamers, t, J )
7.1 Hz, 1H), 4.24 (dt, J ) 13.7, 3.3 Hz, 1H), 3.38 and 3.03
(rotamers, s, 3H), 2.28-2.14 (m, 1H), 1.92-1.35 (m, 8H); CIMS
m/ z (relative intensity) 234 (MH+, 16), 202 (M+ - OMe, 81),
128 (M+ - PhCO, 17), 105 (PhCO+, 100); HRMS (C14H19NO2)
calcd 233.1416, found 233.1413.
1
1619, 1325 cm-1; H NMR (200 MHz/CDCl3) δ 8.10-8.06 (m,
2H), 6.70 (dd, J ) 9.5, 2.0 Hz, 1H), 5.21 (br s, 2H), 3.56 (br s,
4H), 1.65-1.58 (m, 6H); CIMS m/ z (relative intensity) 250
(MH+, 100). Anal. Calcd for C12H15N3O3: C, 57.82; H, 6.07;
N, 16.86. Found: C, 57.90; H, 6.09; N, 16.93.
r-Meth oxyben za m id e 15f (yellow oil, 86%), 4 Å molecular
sieves were used (1 h): 1H NMR (300 MHz/CDCl3) δ 7.38-
7.27 (m, 5H), 4.82 and 3.65 (rotamers, 2bs, 1H), 3.35-3.26 (m,
2H), 3.04 (br s, 3H) 1.40-1.38 (d, J ) 6.0 Hz, 3H), 1.32-1.27
(m, 3H); 13C NMR (75 MHz/CDCl3) δ 171.8, 136.8, 129.4, 128.5,
126.6, 86.3, 54.5, 34.1, 20.1, 14.3; CIMS m/ z (relative intensity)
208 (MH+, 20), 176 (M+ - OMe, 100), 105 (PhCO+, 20).
Am id o a ceta l 29 (yellow oil): 1H NMR (300 MHz/CDCl3)
δ 7.75 (d, J ) 7.7 Hz, 2H), 7.52-7.36 (m, 3H), 5.96 (br d, J )
7.7 Hz, 1H), 4.32 (t, J ) 5.5 Hz, 1H), 4.26-4.13 (m, 1H), 3.27
(s, 6H), 1.59-1.36 (m, 6H), 1.19 (d, J ) 6.7 Hz, 3H); EIMS
m/ z (relative intensity) 234 (M+ - OMe, 4), 105 (PhCO+, 100).
Am id o k eton e 30 (light yellow solid): mp 72-73.5 °C; IR
P yr r olid in e 2-a m in o-6-n itr oben za m id e (69) (tan solid,
73%): (from 5-nitroisatoic anhydride, CH3CN was used as
solvent): recrystallized from ethyl acetate/hexanes, mp 215-
216 °C; 1H NMR (200 MHz/CDCl3) δ 8.24 (d, J ) 2.6 Hz, 1H),
8.06 (dd, J ) 9.1, 2.6 Hz, 1H) 6.67 (d, J ) 9.1 Hz, 1H), 5.64
(br s, 2H), 3.60 (br s, 4H), 1.94 (br s, 4H); CIMS m/ z (relative
intensity) 236 (MH+, 100), 165 (M+ - C4H8N, 5). Anal. Calcd
for C11H13N3O3: C, 56.16; H, 5.57; N, 17.86. Found: C, 56.26;
H, 5.58; N, 17.95.
St a n d a r d Con d it ion s for Syn t h esis of r-Met h oxy-
ben za m id es. To a solution of the o-aminobenzamide (1-3
mmol) in MeOH (0.05 M solution) was added NaNO2 (2 equiv)
and CuCl (5 mol %). Methanolic HCl (3%, 3 equiv) was added
over 5-10 min, and the reaction mixture was stirred at rt for
the time indicated. The reaction mixture was diluted with
saturated NaHCO3 solution, and methanol was removed by
rotary evaporation. The residue was extracted with ethyl
acetate (30 mL × 3), washed with saturated NaCl solution,
dried over MgSO4, and concentrated. The crude product was
purified by preparative TLC (ethyl acetate/hexanes, 1/2-1/1).
r-Meth oxyben za m id e 15a (colorless oil; 43%), slightly
modified conditions were used: NaNO2 (3 equiv), HCl (3.3
(CDCl3) 1714, 1655 cm-1 1H NMR (300 MHz/CDCl3) δ 7.79
;
(dd, J ) 7.9, 1.4 Hz, 2H), 7.52-7.40 (m, 3H), 6.38 (br s, 1H),
3.45 (q, J ) 6.5 Hz, 2H), 2.52 (t, J ) 6.5 Hz, 2H), 2.16 (s, 3H),
1.73-1.61 (m, 4H); 13C NMR (75 MHz/CDCl3) δ 167.4, 134.6,
131.2, 128.3, 126.8, 42.8, 39.4, 29.9, 28.7, 20.5; EIMS m/ z
(relative intensity) 219 (M+, 5), 114 (M+ - PhCO, 4), 105
(PhCO+, 100). Anal. Calcd for C13H17NO2: C, 71.20; H, 7.81;
N, 6.39. Found: C, 71.12; H, 7.85; N, 6.47.
Am id o a ld eh yd e 31 (yellow solid): mp 76-77 °C; IR
(CDCl3) 1726, 1660 cm-1; 1H NMR (200 MHz/CDCl3) δ 9.87 (t,

Cuprous Ion-Promoted R-Methoxylation of Amides
J . Org. Chem., Vol. 61, No. 26, 1996 9491
J ) 1.4 Hz, 1H), 7.88 (dd, J ) 7.7, 1.9 Hz, 2H), 7.56-7.47 (m,
3H), 6.34 (d, J ) 7.3 Hz, 1H), 4.31-4.27 (m, 1H), 2.56 (t, J )
7.2 Hz, 2H), 1.81-1.55 (m, 4H), 1.30 (d, J ) 6.7 Hz, 3H); 13C
NMR (75 MHz/CDCl3) δ 202.3, 167.1, 134.7, 131.3, 128.5,
126.8, 45.4, 43.5, 36.2, 21.0, 18.4; EIMS m/ z (relative intensity)
219 (M+, 4), 105 (PhCO+, 100). Anal. Calcd for C13H17NO2:
C, 71.20; H, 7.81; N, 6.39. Found: C, 71.13; H, 7.84; N, 6.44.
7.78-7.72 (m, 1H), 7.53-7.38 (m, 4H), 6.12 (br s, 1H), 4.30-
4.00 (m, 1H), 2.56 (q, J ) 6.4 Hz, 2H), 1.88 (q, J ) 6.8 Hz,
2H), 1.23 (d, J ) 6.6 Hz, 3H); EIMS m/ z (relative intensity)
205 (M+, 2), 105 (PhCO+, 100), 77 (C6H5+, 37).
Am id o a ceta l 48 (yellow oil, 4%): 1H NMR (200 MHz/
CDCl3) δ 7.78-7.73 (m, 1H), 7.49-7.37 (m, 4H), 6.11 (br s,
1H), 4.35 (t, J ) 4.8 Hz, 1H), 4.20-3.95 (m, 1H), 3.30 (d, J )
4.4 Hz, 6H), 1.70-1.50 (m, 4H), 1.21 (d, J ) 6.6 Hz, 3H); CIMS
m/ z (relative intensity) 251 (MH+, 2), 220 (M+ - OMe, 100),
105 (PhCO+, 20).
1
En a m id e 32 (colorless oil): IR (neat) 1633 cm-1; H NMR
(200 MHz/CDCl3) δ 7.35 (m, 5H), 5.94 and 4.75 (rotamers, br
s, 1H), 4.90 and 3.89 (rotamers, br s, 1H), 3.41 (br s, 1H), 3.01
(br s, 2H), 2.22-1.28 (m, 5H); EIMS m/ z (relative intensity)
201 (M+, 4), 105 (PhCO+,100); HRMS (C13H15NO) calcd
201.1154, found 201.1164.
Am id o k eton e 49 (yellow oil, 9%): IR (neat) 3325, 1714,
1
1644 cm -1; H NMR (300 MHz/CDCl3) δ 7.80-7.77 (m, 2H),
7.53-7.41 (m, 3H), 6.57 (br s, 1H), 3.48 (q, J ) 5.7 Hz, 2H),
2.62 (t, J ) 6.6 Hz, 2H), 2.18 (s, 3H), 1.93 (q, J ) 6.6 Hz, 2H);
13C NMR (75 MHz/CDCl3) δ 209.4, 167.4, 134.5, 131.4, 128.6,
126.8, 41.4, 39.9, 30.1, 23.0; CIMS m/ z (relative intensity) 206
(MH+, 100), 105 (PhCO+, 20).
En a m id e 33 (colorless oil): 1H NMR (200 MHz/CDCl3) δ
7.57 (d, J ) 6.5 Hz, 2H), 7.44 (m, 3H), 5.06 (br t, 1H), 3.62 (t,
J ) 5.3 Hz, 2H), 1.76-1.50 (m, 7H); EIMS m/ z (relative
intensity) 201 (M+, 100), 105 (PhCO+, 55).
r-Meth oxyben za m id e 35 (yellow oil, 71%), slightly modi-
fied conditions were used: NaNO2 (2.7 equiv), HCl (15.3 equiv),
CuCl (20 mol%) (2 d): IR (film) 1633 cm-1; 1H NMR (300 MHz/
CDCl3) δ 7.31-7.21 (m, 2H), 6.91-6.83 (m, 3H), 4.83, 4.50,
3.45 (rotamers, br s, 1H), 3.74 (br s, 3H), 2.98-2.79 (rotamers,
two br s, 1H), 1.59-1.20 (br s, 10H), 0.87 (br s, 3H); 13C NMR
(75 MHz/CDCl3, 50 °C) δ 159.7, 129.4, 128.9, 126.5, 118.7,
114.9, 112.2, 55.3, 32.1. 28.5, 26.1, 19.4, 19.1, 13.9; EIMS m/ z
(relative intensity) 261 (M+, 21), 218 (M+ - C3H7, 57), 135
(100); HRMS (C16H23NO2) calcd 261.1729, found 261.1734.
r-Meth oxyben za m id e 37 (pale yellow oil, 86%), slightly
modified conditions were used: NaNO2 (2.2 equiv), HCl (6.3
r-Meth oxyben za m id e 51 (yellow oil, 71%), slightly modi-
fied conditions were used: NaNO2 (2.4 equiv), HCl (7.5 equiv),
CuCl (7 mol %) (3 h): IR (film) 1633 cm-1; 1H NMR (200 MHz/
CDCl3) δ 7.52-7.20 (m, 4H), 7.05-6.85 (m, 1H), 4.25 (br s,
1H), 3.76 (br s, 3H), 3.45-3.25 (m, 1H), 2.20-1.50 (m, 4H),
1.45-1.00 (m, 4H), 0.95-0.80 (m, 3H); EIMS m/ z (relative
intensity) 247 (M+, 2), 174 (M+ - C3H7, 20), 135 (100); HRMS
(C15H21NO2) calcd 247.1572, found 247.1565.
r-Meth oxyben za m id e 53 (yellow oil, 71%); slightly modi-
fied conditions were used: NaNO2 (3.0 equiv), HCl (11.9 equiv),
CuCl (5 mol %) (1 d): 1H NMR (200 MHz/CDCl3) δ 7.40-7.15
(m, 1H), 7.10-6.85 (m, 4H), 6.00-5.75 (m, 1H), 5.20-4.80 (m,
2H), 4.30 (br s, 1H), 3.78 (s, 3H), 3.38 (t, J ) 12 Hz, 1H), 2.75-
2.55 (m, 1H), 2.50-2.25 (m, 1H), 2.00-1.65 (m, 4H); CIMS m/ z
(relative intensity) 246 (MH+, 100), 204 (M+ - OMe, 30), 135
(40), 105 (PhCO+, 5).
1
equiv), CuCl (10 mol%) (2 d): IR (film) 1633 cm-1); H NMR
(200 MHz/CDCl3) δ 7.38-7.22 (m, 3H), 6.90-6.86 (m, 2H), 5.72
(br s, 1H), 5.09-4.80 (m, 3H), 3.76 (br s, 3H), 2.93 (br s, 1H),
2.50-2.35 and 2.35-2.15 (rotamers, 2m, 2H), 1.59 (br s, 6H);
CIMS m/ z (relative intensity) 260 (MH+,100), 218 (M+ - C3H5,
42), 105 (PhCO+, 10); HRMS (C16H21NO2) calcd 259.1572,
found 259.1567.
r-Meth oxyben za m id e 55 (colorless oil, 61%) (1.5 h): 1H
NMR (300 MHz/CDCl3) δ 7.63-7.39 (m, 5H), 4.78 and 4.47
(rotamers, br s, 1H), 3.57 and 3.00 (rotamers, br s, 2H), 3.37
(s, 4H), 3.15 and 2.77 (rotamers, s, 3H), 2.18-1.83 (m, 4H);
EIMS m/ z (relative intensity) 249 (M+, 2), 218 (M+ - OMe,
5), 105 (PhCO+, 100).
Am id o a ld eh yd e 40 (yellow oil, 67%) (1 h): IR (CDCl3)
1
3437, 1724, 1652 cm-1; H NMR (200 MHz/CDCl3) δ 9.79 (s,
1H), 7.78-7.73 (m, 2H), 7.51-7.41 (m, 3H), 5.85 (br d, J ) 10
Hz, 1H), 3.80-3.45 (m, 1H), 2.53-2.41 (m, 2H), 1.79-1.41 (m,
4H), 0.023 (s, 9H); CIMS m/ z 278 (MH+, 100), 262 (M+ - Me,
20), 249 (M+ - CHO+, 20), 105 (PhCO+, 10); HRMS (C15H23N2-
OSi) calcd 277.1498, found 277.1479.
Am id o a ld eh yd e 56 (colorless oil, 18%): 1H NMR (300
MHz/CDCl3) δ 9.79 (br t, 1H), 7.77 (d, J ) 6.8 Hz, 2H), 7.52-
7.32 (m, 3H), 6.55 (br d, J ) 7.9 Hz, 1H), 4.29 (m, 1H), 3.49
(d, J ) 3.2 Hz, 2H), 3.36 (s, 3H), 2.14-1.89 (m, 4H); EIMS
m/ z (relative intensity) 235 (M+, 1), 190 (M+ - C2H5O, 13),
105 (PhCO+, 100).
r-Meth oxyben za m id e 42 (colorless oil, 33%), slightly
modified conditions were used: NaNO2 (2.1 equiv), HCl (9.1
1
equiv), CuCl (18 mol%) (1 h): IR (film) 1644 cm-1; H NMR
En a m id e 57 (colorless oil, 6%): 1H NMR (200 MHz/CDCl3)
δ 7.56-7.28 (m, 5H), 4.87 and 4.43 (rotomers, br s, 1H), 3.67-
3.22 (m, 4H), 3.49 (s, 3H), 2.36-2.02 (m, 2H); EIMS m/ z
(relative intensity) 217 (M+, 1), 105 (PhCO+, 100).
(300 MHz/CDCl3) δ 7.39 (s, 5H), 5.91, 4.86 (rotamers, br s, 1H),
3.95, 3.75 (rotamers, m, 1H), 3.59-3.53 (m, 2H), 3.46-3.37
(m, 3H), 3.18 (br s, 1H), 3.01 (br s, 2H), 2.04-1.85 (m, 3H),
1.76-1.50 (m, 3H); CIMS m/ z (relative intensity) 264 (MH+,
5), 232 (M+ - OMe, 100), 218 (M+ - C2H5O, 5), 105 (PhCO+,
10); HRMS (C15H21NO3) calcd 263.1521, found 263.1518.
Am id o a ld eh yd e 43 (yellow oil, 12%): IR (neat) 3507, 3319,
2932, 1722, 1640 cm-1; 1H NMR (200 MHz/CDCl3) δ 9.76 (t, J
) 1 Hz, 1H), 7.81-7.73 (m, 2H), 7.52-7.48 (m, 3H), 6.46 (m,
1H), 4.29 (m, 1H), 3.50 (t, J ) 2 Hz, 2H), 3.36 (s, 3H), 2.57-
2.49 (m, 2H), 1.80-1.51 (m, 4H); EIMS m/ z (relative intensity)
249 (M+, 7), 218 (M+ - OMe, 10), 204 (M+ - C2H5O, 12), 105
(PhCO+, 100).
Am id o k eton e 58 (colorless oil, 6%): IR (film) 3314, 1725,
1
1642 cm-1; H NMR (300 MHz/CDCl3) δ 7.77 (d, J ) 7.6 Hz,
2H), 7.51-7.40 (m, 3H), 6.55 (br s, 1H), 4.24 (s, 2H), 3.48 (q,
J ) 6.3 Hz, 2H), 3.39 (s, 3H), 2.60 (t, J ) 6.7 Hz, 2H), 1.95 (m,
2H); EIMS m/ z (relative intensity) 235 (M+, 2), 190 (M+
-
C2H5O, 10), 105 (PhCO+, 100); HRMS (C13H17NO3) calcd
235.1208, found, 235.1211.
r-Meth oxyben za m id e 60 (colorless oil, 37%) (1.5 h): 1H
NMR (300 MHz/CDCl3) δ 7.47 (s, 5H), 7.30-7.17 (m, 4H), 5.30
and 4.53 (rotamers, br s, 1H), 5.22 and 4.42 (rotamers, br d,
2H), 4.53 and 3.62 (rotamers, br s, 1H), 3.50 and 3.15
(rotamers, br s, 3H), 3.24 and 3.01 (rotamers, br d, 2H); EIMS
m/ z (relative intensity) 267 (M+, 0.4), 236 (M+ - OMe, 9), 105
(PhCO+, 100).
Am id o k eton e 44 (yellow oil, 34%): IR (neat) 3334, 3063,
2934, 1731, 1650 cm-1; 1H NMR (300 MHz/CDCl3) δ 7.79-7.77
(m, 2H), 7.48-7.39 (m, 3H), 6.50 (br s, 1H), 4.00 (s, 2H), 3.46-
3.40 (m, 5H), 2.51 (t, J ) 6.7 Hz, 2H), 1.71-1.60 (m, 4H); 13
C
Am id o a ld eh yd e 61 (colorless oil, 61%): 1H NMR (300
MHz/CDCl3) δ 10.17 (s, 1H), 7.71 (d, J ) 8.1 Hz, 2H), 7.44-
7.35 (m, 7H), 6.84 (br s, 1H), 3.70 (q, J ) 6.5 Hz, 2H), 3.35 (t,
J ) 6.9 Hz, 2H); EIMS m/ z (relative intensity) 253 (M+, 5),
148 (M+ - PhCO, 5), 105 (PhCO+, 100).
2-Meth oxytetr a h yd r oqu in olin e ben za m id e (63) (white
solid, 13%) (15 min): mp 95-98 °C; IR (CDCl3) 1643 cm-1; 1H
NMR (200 MHz/CDCl3) δ 7.38-7.17 (m, 6H), 7.03 (t, J ) 7.4
Hz, 1H), 6.87 (t, J ) 7.5 Hz, 1H), 6.62 (d, J ) 8.0 Hz, 1H),
6.03-5.99 (m, 1H), 3.41 (s, 3H), 2.90-2.78 (m, 2H), 2.41-2.34
(m, 1H), 2.10-2.05 (m, 1H); CIMS m/ z (relative intensity) 267
(M+, 20), 236 (M+ - OMe, 100), 105 (PhCO+, 50); HRMS
(C17H17NO2) calcd 267.1259, found 267.1265.
NMR (75 MHz/CDCl3) δ 208.6, 167.5, 134.6, 131.3, 128.5,
126.8, 77.6, 59.3, 39.4, 38.0, 28.9, 20.0; EIMS m/ z (relative
intensity) 249 (M+, 6), 204 (M+ - C2H5O, 1), 105 (PhCO+, 100),
77 (C6H5+, 32); HRMS (C14H19NO3) calcd 249.1365, found
249.1350.
r-Meth oxyben za m id e 46 (yellow oil, 44%) (1 h): 1H NMR
(200 MHz/CDCl3) δ 7.62-7.37 (m, 5H), 4.69 (br s, 1H), 4.45-
4.30 and 4.15 (rotamers, m, 1H), 3.25-3.02 (br s, 2H), 2.76
(br s, 1H), 2.30-1.45 (m, 4H), 1.36-1.22 (m, 3H); CIMS m/ z
(relative intensity) 220 (MH+, 20) 188 (M+ - OMe, 100), 105
(PhCO+, 25) .
Am id o a ld eh yd e 47 (yellow oil, 18%): IR (neat) 3318, 1819,
1719, 1637 cm-1 1H NMR (200 MHz/CDCl3) δ 9.83 (s, 1H),
;

9492 J . Org. Chem., Vol. 61, No. 26, 1996
Han et al.
2-Meth oxyp ip er id in e o-n itr oben za m id e (70) (yellow oil,
benzamide (19a : 0.11 g, 0.4 mmol; 19b: 0.46 g, 1.4 mmol) in
ether (for 19a , 12 mL; for 19b, 40 mL) was added p-
(methoxybenzyl)magnesium chloride (1 M in THF) (for 19a ,
2.93 mL, 2.93 mmol; for 19b, 7 mL, 7 mmol). After being
refluxed for 15 h, the reaction was quenched with NH4Cl and
brine (1/1, 20 mL). The reaction mixture was extracted with
ethyl acetate (50 mL × 3), dried over MgSO4, and evaporated.
The residue was purified by flash column chromatography (for
21a , 22a MeOH/ethyl acetate, 1/3; for 21b, 22b, MeOH/ethyl
acetate, 1/5) to give a yellow oil (21a , 5 mg, 5%; 22a , 91 mg,
87%) (21b, 6 mg, 1%; 22b, 0.387 g, 89%).
72%) (15 min): IR (CDCl3) 1634 cm-1 1H NMR (200 MHz/
;
CDCl3) δ 8.22-8.18 (m, 2H), 7.70-7.53 (m, 2H), 5.78, 4.67
(rotamers, br s, 1H), 4.31, 3.29, 3.01 (rotamers, br s, 5H), 1.93-
1.51 (m, 6H); 13C NMR (75 MHz/CDCl3) δ 168.8, 148.0, 137.8,
132.8, 129.8, 124.5, 122.0, 85.5, 79.9 (rotamers), 55.2, 54.2
(rotamers) 43.0, 37.5 (rotamers), 30.1, 25.8, 24.8 (rotamers),
18.4; EIMS m/ z (relative intensity) 264 (M+, 9), 233 (M+
-
OMe, 17) 150 (o-NO2PhCO+, 100); HRMS (C13H16N2O4) calcd
264.1110, found, 264.1090.
2-Meth oxyp yr r olid in e o-n itr oben za m id e (71) (yellow
oil, 65%) (50 min): IR (CDCl3) 1636 cm-1; 1H NMR (200 MHz/
CDCl3) δ 8.64 (s, 1H), 8.41-8.30 (m, 1H), 8.00 (m, 1H), 7.64
(t, J ) 8.0 Hz, 1H), 5.71, 4.64 (rotamers, m, 1H), 3.78-3.51
and 3.46 (rotamers, m, 2H), 3.11 (s, 3H), 2.16-1.66 (m, 4H);
CIMS m/ z (relative intensity) 251 (MH+, 50), 219 (M+ - OMe,
100), 150 (o-NO2PhCO+, 10); HRMS (C14H14N2O4) calcd
250.0953, found 250.0941.
P r ep a r a tion of N-Acylp yr r olid in es 18a a n d 18b. To a
solution of the N-benzylpyrrolidine (17a , 1.54 g, 6.97 mmol;
17b, 4.65 g, 16.55 mmol) in MeOH (for 17a , 140 mL; for 17b,
250 mL) was added Pd(OH)2 on carbon (for 17a , 0.3 g; for 17b,
0.5 g). The reaction mixture was hydrogenated under 1 atm
of H2 at rt for 3 h. The catalyst was removed by filtration
through a Celite pad, and the filtrate was evaporated to give
the crude amine which was used for the next step without
further purification.
To a solution of isatoic anhydride (for 18a , 1.14 g, 7.0 mmol;
for 18b, 2.7 g, 16.6 mmol) in DMF (for 18a , 4 mL; for 18b, 17
mL) was added the above crude pyrrolidine in DMF (3 mL) at
0 °C in the presence of DMAP (for 18a , 84 mg; for 18b, 0.5 g).
The reaction mixture was allowed to warm to rt, stirred for
15 h, diluted with brine (10 mL), and extracted with ethyl
acetate (30 mL × 3). The organic extract was washed with
brine (30 mL), dried over MgSO4, and evaporated. The residue
was purified by column chromatography (for 18a , ethyl
acetate; for 18b, ethyl acetate/hexanes, 1/1) to give the
N-acylpyrrolidine (18a , light yellow solid, recrystallized from
ethyl acetate/hexanes, mp 105-106 °C, 1.2 g, 68%; 18b, a light
yellow oil, 4.4 g, 86%).
21a : 1H NMR (300 MHz/CDCl3) δ 7.15 (d, J ) 8.6 Hz, 2H),
6.82 (d, J ) 8.6 Hz, 2H), 3.79 (s, 3H), 3.46-3.22 (m, 3H), 3.36
(s, 3H), 3.31 (s, 3H), 2.86-2.78 (m, 2H), 2.52 (br s, 1H); [R]D
)
-39.1° (c ) 0.64, CDCl3), lit.21 [R]D ) -63° (c ) 0.979, CDCl3).
21b: 1H NMR (300 MHz/CDCl3) δ 7.17 (d, J ) 8.6 Hz, 2H),
6.84 (d, J ) 8.6 Hz, 2H), 4.76 (d, J ) 6.8 Hz, 1H), 4.71-4.60
(m, 3H), 4.21 (dd, J ) 3.2, 2.0 Hz, 1H), 3.87 (d, J ) 4.6, 1.3
Hz, 1H), 3.79 (s, 3H), 3.51-3.43 (m, 2H), 3.39 (s, 3H), 3.33 (s,
3H), 2.90-2.82 (m, 1H).
22a : IR (film) 3338 cm-1; 1H NMR (300 MHz/CDCl3) δ 7.15
(d, J ) 8.6 Hz, 2H), 6.83 (d, J ) 8.6 Hz, 2H), 3.78 (s, 3H), 3.69
(dt, J ) 4.8, 1.9 Hz, 1H), 3.38 (d, J ) 3.9 Hz, 1H), 3.34 (s, 3H),
3.26 (s, 3H), 3.14-2.93 (m, 3H), 2.87 (dd, J ) 13.6, 6.3 Hz,
1H), 2.75 (dd, J ) 13.6, 6.3 Hz, 1H), 2.39 (br s, 1H); 13C NMR
(75 MHz/CDCl3) δ 157.9, 131.0, 129.7, 113.6, 89.6, 85.8, 65.4,
57.1, 56.4, 54.9, 50.2, 38.7; 13C DEPT NMR (75 MHz/CDCl3) δ
129.7 (CH), 113.6 (CH), 89.6 (CH3), 85.8 (CH3), 65.4 (CH3), 57.1
(CH), 56.4 (CH), 54.9 (CH), 50.2 (CH2), 38.7 (CH2); [R]D ) +6.3°
(c ) 1.50, CDCl3), lit.21 [R]D ) +4° (c ) 1.7, CDCl3); HRMS
(C14H21NO3) calcd 251.1521, found 251.1525.
22b: IR (film) 3339 cm-1; 1H NMR (300 MHz/CDCl3) δ 7.14
(d, J ) 8.4 Hz, 2H), 6.82 (d, J ) 8.5 Hz, 2H), 4.70-4.60 (m,
3H), 4.47 (d, J ) 6.7 Hz, 1H), 4.06 (dt, J ) 3.5, 1.4 Hz, 1H),
3.77 (dd, J ) 4.6, 1.3 Hz, 1H), 3.75 (s, 3H), 3.35 (s, 3H), 3.29
(s, 3H), 3.18-3.11 (m, 1H), 3.02 (d, J ) 3.5Hz, 2H), 2.87 (dd,
J ) 13.6, 6.2 Hz, 1H), 2.77 (dd, J ) 13.6, 8.0 Hz, 1H), 2.02 (br
s, 1H); 13C NMR (75 MHz/CDCl3) δ 158.0, 130. 9, 130.3, 129.9,
113.8, 95.6, 95.1, 85.6, 81.1, 66.1, 55.3, 55.1, 51.3, 38.7.
Meth od B. The procedure in method A was used except
MgBr2 etherate (1 equiv) was added before the addition of the
Grignard reagent, and CH2Cl2 was used as solvent to give 21a ,
3.5%, 21b, 3.3% / 22a , 28%, 22b, 39%.
18a : 1H NMR (200 MHz/CDCl3) δ 7.24-7.05 (m, 2H), 6.75-
6.55 (m, 2H), 4.68 (br s, 2H), 3.94-3.45 (m, 6H), 3.35 (br s,
6H); CIMS m/ z (relative intensity) 251 (MH+, 100), 120 (o-
NH2PhCO+, 37). Anal. Calcd for C13H18N2O3: C, 62.38; H,
7.25; N, 11.19. Found: C, 62.49; H, 7.25; N, 11.22.
P r ep a r a tion of Diol 23. Pyrrolidine 22b (0.15 g, 0.48
mmol) was refluxed in a mixture of MeOH/5 N HCl (1/1, 10
mL) for 22 h. The solution was then concentrated, made
alkaline with Na2CO3, and extracted with CHCl3 (2 × 20 mL).
The aqueous phase was allowed to stand overnight at 5 °C,
and the light yellow solid was collected by filtration. The crude
product was purified by recrystallization from acetone/hexanes
to give diol 23 as a white solid (48 mg, 45%): mp 125-128 °C
1
18b: IR (film) 3456, 3355, 1621 cm-1; H NMR (200 MHz/
CDCl3) δ 7.22-7.05 (m, 2H), 6.71-6.58 (m, 2H), 4.65 (br s,
6H), 4.13 (br s, 2H), 3.97-3.44 (m, 4H), 3.38 (br s, 6H); CIMS
m/ z (relative intensity) 311 (MH+, 100), 279 (M+ - OMe, 19),
248 (M+ - 2OMe, 3); HRMS (C15H22N2O5) calcd 310.1529,
found, 310.1552.
(lit.22
mp 130-131.5 °C).
P r ep a r a tion of r-Meth oxyben za m id es 19a a n d 19b. To
a solution of the amine (18a : 0.69 g, 2.77 mmol; 18b: 0.35 g,
1.13 mmol) and NaNO2 (for 19a , 0.35 g, 5.54 mmol; for 19b,
156 mg, 2.3 mmol) in MeOH (for 19a , 50 mL; for 19b, 22 mL)
were added 3% methanolic HCl (for 19a , 15.8 mL, 13.9 mmol;
for 19b, 3.8 mL, 3.4 mmol) and CuCl (for 19a , 14 mg; for 19b,
6 mg). After being stirred for 2 h at rt, the reaction mixture
was diluted with NaHCO3 solution (30 mL), and the solvent
was removed by rotary evaporation. The residue was ex-
tracted with ethyl acetate (30 mL), washed with brine (30 mL),
dried over MgSO4, and evaporated. The residue was purified
by flash column chromatography (for 19a , ethyl acetate/
hexanes, 1/1; for 19b, ethyl acetate/hexanes, 2/1) to give a
colorless oil (19a , 0.50 g, 68%; 19b, 0.26 g, 73%).
Con ver sion of Am in o Diol 23 to Eth er Ca r ba m a te 24.
To a solution of amino diol 23 (22 mg, 0.1 mmol) in aqueous
Na2CO3 solution (44 M, 2 mL) and CH2Cl2 (2 mL) was added
benzyl chloroformate (44 M in CH2Cl2, 2 mL) . After being
stirred for 2 h, the reaction mixture was extracted with CH2Cl2
(30 mL × 3). The extract was dried over MgSO4 and
evaporated, and the residue was purified by preparative TLC
(ethyl acetate/hexanes, 3/1) to give the carbamate diol as a
colorless oil (13 mg, 40%): 1H NMR (300 MHz/CDCl3) δ 7.48-
7.40 (m, 5H), 7.18 (br d, 1H), 7.04 (br d, 1H), 6.92 (br d, 2H),
5.15 (s, 2H), 4.14 (br s, 1H), 4.04-3.81 (m, 3H), 3.74 (s, 3H),
3.35 (dd, J ) 7.1, 2.9 Hz, 1H), 3.15 (br d, 1H), 2.98 (dd, J )
9.2, 6.7 Hz, 1H), 2.24 (br d, 1H), 1.93 (br s, 1H).
1
19a : H NMR (200 MHz/CDCl3) δ 7.51-7.30 (m, 5H), 5.74
To a solution of the above diol (13 mg, 0.036 mmol) in THF
(5 mL) was added NaH (2 mg, 95%, 0.08 mmol) and MeI in
THF (0.4 v/v%, 1 mL) at 0 °C. After being stirred for 1 h at 0
°C and then for 40 min at rt and refluxed for 2 h, the reaction
mixture was diluted with NH4Cl solution (10 mL) and ex-
tracted with ethyl acetate (20 mL × 3). The extract was dried
over MgSO4 and evaporated. The residue was purified by
preparative TLC (ethyl acetate/hexanes, 1/3) to give dimethyl
ether carbamate 24 as a colorless oil (12 mg, 87%): 1H NMR
(300 MHz/CDCl3) δ 7.46-7.28 (m, 5H), 7.20 (d, J ) 7.5 Hz,
1H), 7.04 (d, J ) 7.5 Hz, 1H), 6.83 (dd, J ) 10.0, 4.6 Hz, 2H),
and 4.70 (br d, 1H), 4.16-3.01 (m, 13H); EIMS m/ z (relative
intensity) 265 (M+, 4), 234 (M+ - OMe, 13), 105 (PhCO+, 100).
19b: IR (neat) 3061, 1658 cm-1; 1H NMR (300 MHz/CDCl3)
δ 7.56-7.36 (m, 5H), 5.49 and 4.89 (br d, 1H), 4.75-4.49 (m,
4H), 4.40-3.82 (m, 3H), 3.58-3.05 (m, 10H); EIMS m/ z
(relative intensity) 325 (M+, 3), 294 (M+ - OMe, 2), 263 (M+
- 2OMe, 1), 105 (PhCO+, 100); HRMS (C16H23NO6) calcd
325.1525, found 325.1524.
P r ep a r a tion of Gr ign a r d Ad d ition P r od u cts 21a , 21b,
22a a n d 22b, Meth od A. To a solution of the R-methoxy-

Cuprous Ion-Promoted R-Methoxylation of Amides
J . Org. Chem., Vol. 61, No. 26, 1996 9493
5.25-5.09 (m, 2H), 3.98 and 3.67 (rotamers, m, 1H), 3.80 (br
s, 5H), 3.54 (s, 2H), 3.41 (s, 3H), 3.28 and 3.08 (rotamers, m,
1H), 3.03 (d, J ) 6.7 Hz, 3H), 2.73 (q, J ) 12.1 Hz, 1H).
Hyd r ogen olysis of Ben zyl Ca r ba m a te 24. A solution of
benzyl carbamate 24 (12 mg, 0.031 mmol) in EtOH (3 mL) was
hydrogenated for 0.5 h in the presence of 10% Pd/C (12 mg) at
1 atm of H2. The catalyst was removed by filtration through
a Celite pad and concentrated in vacuo to give the amine 22a
as a light yellow oil (6 mg, 77%): 1H NMR (300 MHz/CDCl3)
δ 7.16 (d, J ) 8.6 Hz, 2H), 6.84 (d, J ) 8.6 Hz, 2H), 3.79 (s,
3H), 3.71 (dt, J ) 4.8, 1.9 Hz, 1H), 3.38 (d, J ) 3.9 Hz, 1H),
3.35 (s, 3H), 3.28 (s, 3H), 3.14-2.93 (m, 3H), 2.86 (dd, J )
13.6, 6.3 Hz, 1H), 2.78 (dd, J ) 13.6, 6.3 Hz, 1H), 2.39 (br s,
1H); 13C NMR (75 MHz/CDCl3) δ 157.9, 131.2, 130.0, 113.9,
89.9, 86.1, 65.6, 57.3, 56.7, 55.2, 50.4, 38.9.
acetate (15 mL) followed by evaporation of the filtrate.
Purification of the residue was done by flash column chroma-
tography eluting with ethyl acetate/hexanes (1/1-3/1).
2-P r op ylp ip er id in e o-a m in oben za m id e (34) (yellow oil,
88%): 1H NMR (300 MHz/CDCl3) δ 7.08 (t, J ) 4.5 Hz, 1H),
6.60 (t, J ) 7.6 Hz, 3H), 4.84, 4.51 (rotamers, br s, 1H), 3.75
(br s, 2H), 3.51, 2.96, 2.76 (rotamers, br s, 2H), 1.59 (br s, 6H),
1.41, 1.18, 1.11 (3br s, 7H); EIMS m/ z (relative intensity) 246
(M+, 16), 203 (M+ - C3H7, 33), 120 (o-NH2PhCO+, 100).
2-P r op ylp yr r olid in e o-a m in oben za m id e (50) (yellow oil,
92%): 1H NMR (200 MHz/CDCl3) δ 7.18-7.10 (t, J ) 7.9 Hz,
1H), 6.85-6.66 (m, 3H), 4.25 (br s, 1H), 3.75-3.50 (m, 2H),
3.40-3.34 (t, J ) 5.6 Hz, 2H), 2.05-1.50 (m, 4H), 1.40-1.25
(m, 4H), 0.95-0.75 (m, 3H); EIMS m/ z (relative intensity) 232
(M+, 20), 189 (M+ - C3H7, 19), 120 (o-NH2PhCO+, 100).
Syn t h esis of 2-(Tr im et h ylsilyl)p ip er id in e o-Am in o-
ben za m id e (39). To a solution of 2-(trimethylsilyl)piperidine
(38,24 75 mg, 0.48 mmol) in 10.0 mL of CH2Cl2 and triethyl-
amine (1.0 mL) was added o-nitrobenzoyl chloride (121 mg,
0.65 mmol) in 2.0 mL of CH2Cl2 at 0 °C. The reaction mixture
was warmed to rt, stirred for 18 h and extracted with 5% HCl
(10 mL × 2). The organic layer was washed with satd NaHCO3
(10 mL × 2), dried with MgSO4, and concentrated. The residue
was purified by flash column chromatography (ethyl acetate/
hexanes, 1/1) to give 2-(trimethylsilyl)piperidine o-nitrobenz-
amide (yellow oil, 93 mg, 63%): 1H NMR (200 MHz/CDCl3) δ
8.18 (d, J ) 8.2 Hz, 1H), 7.69 (t, J ) 7.4 Hz, 1H), 7.54 (t, J )
6.8 Hz, 1H), 7.40-7.30 (m, 1H), 4.32, 3.96 (rotamers, 2br s,
1H), 3.27-3.05 (m, 2H), 1.89-1.47 (m, 6H), 0.14 (s, 9H); EIMS
m/ z (relative intensity) 306 (M+, 2), 291 (M+ - Me, 100), 150
(o-NO2COPh+, 39).
Gen er a l P r oced u r e for Zin c Red u ction of Allyl o-
Nitr oben zam ides. The allyl o-nitrobenzamide (0.2-2.5 mmol)
in ethyl acetate/Et2O (1/1, 0.08 M) was treated with Zn dust
(5 equiv) and glacial acetic acid. After 1 d at rt, the mixture
was filtered through Celite, and the pad was washed with ethyl
acetate (25 mL), followed by concentration of the filtrate. The
residue was partitioned between ethyl acetate (3 × 25 mL)
and H2O (25 mL). The combined organics were washed with
brine, dried with MgSO4, and concentrated in vacuo. The
crude oil was purified by flash column chromatography, eluting
with ethyl acetate/hexanes (2/1).
2-Allylp ip er id in e o-a m in ob en za m id e (36) (yellow oil,
88%): IR (film) 3443, 3346, 1614 cm-1 1H NMR (200 MHz/
;
CDCl3) δ 7.18-7.10 (t, J ) 7.8 Hz, 1H), 6.79-6.61 (m, 3H),
5.76 (br s, 1H), 5.08-4.99 (m, 3H), 3.79 (br s, 2H), 2.92 (br s,
2H), 2.43-2.35 (m, 1H), 2.35-2.15 (m, 1H), 1.70-1.40 (br s,
6H); CIMS m/ z (relative intensity) 245 (MH+, 100) 203 (M+
- C3H5, 40), 120 (o-NH2PhCO+, 20); HRMS (C15H20N2O) calcd
244.1576, found 244.1573.
A solution of the above o-nitrobenzamide (63 mg, 0.21 mmol)
in MeOH (10.0 mL) was hydrogenated for 1.5 h in the presence
of 10% Pd/C (52 mg) at 1 atm of H2. The catalyst was removed
by filtration through
a Celite pad, and the filtrate was
2-Allylp yr r olid in e o-a m in oben za m id e (52) (yellow oil,
concentrated. The residue was purified by flash column
chromatography (ethyl acetate/hexanes, 1/2) to give amide 39
86%): IR (film) 3437, 3345, 1614 cm-1 1H NMR (200 MHz/
;
as a yellow oil (56 mg, 97%): IR (film) 3458, 3346, 1614 cm-1
1H NMR (200 MHz/CDCl3) δ 7.17-7.02 (m, 2H), 6.73-6.66 (m,
2H), 4.20 (br s, 2H), 4.10 (br s, 1H), 3.59 (m, 1H), 3.13 (m,
1H), 1.78-1.41 (m, 6H), 0.97 (s, 9H); CIMS m/ z (relative
intensity) 277 (MH+, 100), 261 (M+ - Me, 30), 203 (M+ - TMS,
2), 120 (o-NH2PhCO+, 20); HRMS (C15H24N2OSi) calcd 276.1658,
found 276.1647.
Gen er a l P r oced u r e for Allyla tion of r-Meth oxyben z-
a m id es. To a solution of the R-methoxybenzamide (0.2-8
mmol) in CH2Cl2 (0.05 M) at -78 °C was added TiCl4 (2 equiv,
1.0 M in CH2Cl2) followed by allyltrimethylsilane (2 equiv).
The reaction mixture was allowed to warm to rt overnight,
neutralized with saturated NaHCO3 (10 mL), and extracted
with CH2Cl2 (25 mL × 3). The combined organic layer was
washed with brine (50 mL × 2), dried over MgSO4, and
concentrated. The crude product was purified by flash column
chromatography (ethyl acetate/hexanes, 1/1-2/1).
;
CDCl3) δ 7.20-7.10 (t, J ) 6 Hz, 1 Hz), 6.85-6.65 (m, 3H),
5.95-5.70 (m, 1H), 5.15-4.85 (m, 2H), 4.32 (br s, 1H), 3.85-
3.60 (br s, 2H), 3.45-3.30 (m, 2H), 2.75-2.55 (m, 1H), 2.45-
2.20 (m, 1H), 2.00-1.60 (m, 4H); EIMS m/ z (relative intensity)
230 (M+, 13), 189 (M+ - C3H5, 24), 120 (o-NH2PhCO+, 100);
HRMS (C14H18N2O) calcd 230.1419, found 230.1436.
Gen er a l Oxid a tion P r oced u r e Usin g Ru Cl2(P P h 3)3 a s
Ca ta lyst. To a solution of the o-aminobenzamide (0.4-0.9
mmol) in MeOH (0.07 M) were added NaNO2 (2 equiv) and
RuCl2(PPh3)3 (6 mol%). Methanolic HCl (3%, 3-4 equiv) was
added over 5-10 min, and the reaction mixture was stirred
at rt for the time indicated. The reaction mixture was diluted
with saturated NaHCO3 solution and concentrated in vacuo.
The residue was extracted with ethyl acetate (20 mL × 3),
washed with brine, dried over MgSO4, and concentrated. The
crude product was purified by preparative TLC (ethyl acetate/
hexanes, 1/2-1/1).
2-Allylp ip er id in e o-n itr oben za m id e (72) (yellow oil,
79%) (20 h): 1H NMR (300 MHz/CDCl3) δ 8.09-8.06 (m, 2H),
7.57-7.44 (m, 2H), 5.67, 5.39, 4.41, 3.64 (rotamers, br s, 1H),
4.95-4.92 (m, 3H), 3.25, 2.99, 2.79 (rotamers, br s, 2H), 2.50-
2.40, 2.19 (rotamers, m, 2H), 1.54-1.34 (rotamers, br s, 6H);
13C NMR (75 MHz/CDCl3) δ 167.6, 147.5, 138.1, 134.5, 116.6
(rotamers), 133.6, 117.7 (rotamers), 132.2, 129.2, 123.4, 121.4,
54.3, 36.9 (rotamers) 47.3, 42.9 (rotamers), 34.0, 28.1, 27.1,
25.5 (rotamers), 18.3; CIMS m/ z (relative intensity) 275 (MH+,
90), 233 (M+ - C3H5, 100), 150 (o-NO2PhCO+, 20).
2-Allylp yr r olid in e o-n itr oben za m id e (73) (yellow oil,
85%) (2 d): 1H NMR (200 MHz/CDCl3) δ 8.35-8.20 (t, J ) 14
Hz, 2H), 7.90-7.75 (d, J ) 10 Hz, 1H), 7.65-7.50 (t, J ) 8
Hz, 1H), 5.90-5.55 (m, 1H), 5.50-4.70 (m, 2H) 4.40-4.20 (br
s, 1H), 3.95-3.10 (m, 2H), 2.70-2.55 (m, 1H), 2.45-2.20 (m,
1H), 2.10-1.60 (m, 4H); CIMS m/ z (relative intensity) 261
(MH+, 100), 219 (M+ - C3H5, 50), 150 (o-NO2PhCO+, 20).
Gen er a l P r oced u r e for Hyd r ogen a tion of Allyl-Su b-
stitu ted o-Nitr oben za m id es. The allyl benzamide (0.5-4.7
mmol) in dry methanol (0.05 M) was reduced in the presence
of Pd/C (10%) under 1 atm of H2 for 22 h. The solution was
filtered through Celite, and the pad was rinsed with ethyl
Rea ction of o-a m in oben za m id e 41 (1 h): 42 (19%), 43
(15%), 44 (42%).
Rea ction of o-a m in oben za m id e 45 (1 h): 46 (33%), 47
(11%), 48 (3%), 49 (10%).
Rea ction of o-a m in oben za m id e 28 (5 min): 30 (24%), 31
(23%), 32 (37%), 33 (7%).
Rea ction of o-a m in oben za m id e 54 (1 h): 55 (46%), 56
(18%), 57 (10%), 58 (7%).
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM-32299) for support of this
research.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra for new compounds (52 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O961529A