Synthesis of modified Weinreb amides: N-tert-butoxy-N-methylamides as effective acylating agents

Article abstract of DOI:10.1016/j.tetlet.2004.07.106

An efficient preparation of N-methyl-O-tert-butylhydroxylamine hydrochloride has been settled, which allowed the synthesis of modified Weinreb amides. Nucleophilic addition of organolithium and Grignard reagents on these N-tert-butoxy-N-methylamides afforded efficiently the corresponding ketones and reduction with DIBAL furnished the corresponding aldehydes in good yields up to 97%.

Full text of DOI:10.1016/j.tetlet.2004.07.106

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7107–7110
Synthesis of modified Weinreb amides:
N-tert-butoxy-N-methylamides as effective acylating agents
*
*
ˆ
Olivier Labeeuw, Phannarath Phansavath and Jean-Pierre Genet
` ´ ´
Laboratoire de Synthese Selective Organique et Produits Naturels, UMR CNRS 7573, Ecole Nationale Superieure
de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Received 1 June 2004; revised 21 July 2004; accepted 23 July 2004
Available online 12 August 2004
Abstract—An efficient preparation of N-methyl-O-tert-butylhydroxylamine hydrochloride has been settled, which allowed the syn-
thesis of modified Weinreb amides. Nucleophilic addition of organolithium and Grignard reagents on these N-tert-butoxy-N-meth-
ylamides afforded efficiently the corresponding ketones and reduction with DIBAL furnished the corresponding aldehydes in good
yields up to 97%.
Ó 2004 Elsevier Ltd. All rights reserved.
N-Methoxy-N-methylamides1 (commonly named Wein-
reb amides) are important carbonyl equivalents, which
nC8H17
H
have been extensively used for the preparation of ke-
tones and their synthetic utility has been widely demon-
strated.2–4 In the course of our studies on the synthesis
of (À)-isoavenaciolide,5 a naturally occurring secondary
metabolite exhibiting antifungal activity,6 we needed
b-hydroxy ketone 2, which could result from nucleo-
philic addition of n-octyllithium on Weinreb amide 1
(Scheme 1).
OH
O
O
O
BnO
OMe
BnO
O
N
N
Me
Me
1
4
1. nC8H17Li (2.2 to 4 eq.)
THF or Et2O
H+
H2C O
-78˚C to -40˚C
2. H+
However, whatever the conditions (various solvents,
temperatures or number of equivalents of n-octyllith-
ium), the desired ketone 2 was obtained in only 5–24%
yield. The main product of the reaction was N-methyl-
amide 3 (36–63% yield). Formation of 3 results from
decomposition of intermediate 4 via an E2 elimination
reaction, which generates formaldehyde as demon-
strated earlier by Graham and Scholz7 when treating
(N-methyl-N-methoxy)methoxyacetamide with lithium
diisopropylamide. Similar observations have also been
reported in the literature.8
OH
O
OH
O
BnO
+
BnO
H
nC8H17
N
Me
2 (5-24%)
3 (36-63%)
Scheme 1.
drawback when working on elaborated compounds.
For that purpose, we chose to replace the N-methoxy
group with a N-tert-butoxy group as in amides 5
(Scheme 2).
We were thus interested in designing a modified Weinreb
amide whose structure would avoid this competitive
decomposition reaction, which may be
a major
To examine the usefulness of these new Weinreb amides,
we had first to set up a convenient route to N-methyl-O-
tert-butylhydroxylamine hydrochloride 6, whose reac-
tion with acid chlorides, esters or carboxylic acids 7
Keywords: N-Methyl-O-tert-butylhydroxylamide; Acylation; Alde-
hydes; Ketones; Weinreb amides.
*
Corresponding authors. Tel.: +33 1 44276743; fax: +33 1 44071062;
e-mail: genet@ext.jussieu.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.106

7108
O. Labeeuw et al. / Tetrahedron Letters 45 (2004) 7107–7110
O
O
a
HCl
H
OH
Cbz
OH
b
Cbz
O
c
HCl
H
O
+
O
N
N
N
6
N
R
N
R
X
Me
Me
Me
Me
Me
7 (X= Cl,OR1,OH)
5
6
13
15
14
Scheme 2.
Scheme 4. Reagents and conditions: (a) benzylchloroformate,
NaHCO3, CH2Cl2, 0°C, 0.5h, then rt, 15h, 93%; (b) AcOt-Bu, HClO4,
dioxane, rt, 19h, 97%; (c) H2, Pd/C, MeOH, HCl (MeOH), rt, 24h,
95%.
O
O
a
b
e
N O
H2N O
HCl
HCl
N OH
subsequent treatment with tert-butyl acetate and per-
chloric acid led quantitatively to N-O-tert-butylcarba-
mate 15.13 Finally, hydrogenolysis of the carbamate
moiety using Pd/C in HCl/MeOH furnished 614 in quan-
titative yield. Thus, N-methyl-O-tert-butylhydroxylam-
ine hydrochloride 6 was readily prepared in three steps
and 86% overall yield from N-methylhydroxylamine
hydrochloride 13.
O
O
9
10
8
c
d
alloc
O
alloc
O
H
O
N
H
N
N
Me
Me
11
12
6
Having to hand an efficient and large-scale synthesis of
6, we were able to examine the utility of this new amine.
Thus, treatment of commercially available acid chlo-
rides 16–18 with 6 in the presence of pyridine afforded
amides 19–21 in good yields (Scheme 5). We then stud-
ied the nucleophilic addition of organolithium and Grig-
nard reagents on these new Weinreb amides as well as
reduction reactions with diisobutylaluminium hydride
(Table 1).
Scheme 3. Reagents and conditions: (a) AcOt-Bu, HClO4, dioxane, rt,
40h, 99%; (b) H2N–NH2ÆH2O, EtOH, n, 45min then HCl, 82%; (c)
allylchloroformate, pyridine, CH2Cl2, rt, 1h; (d) NaH, MeI, DMF, rt,
15h, 78% (two steps); (e) Pd(OAc)2 (2.5mol%), TPPTS (12.5mol%),
NaBH4, H2O/MeOH, rt, 1h, then HCl, 60–70%.
would easily afford the desired amides 5. Our initial syn-
thesis of 6 started with N-hydroxyphthalimide 8, which
was treated with tert-butyl acetate and perchloric acid
in dioxane9 to afford tert-butoxyphthalimide 9 in 99%
yield (Scheme 3). Deprotection of the amine using
hydrazine in EtOH and acidification with HCl then fur-
nished O-tert-butylhydroxylamine hydrochloride 10 in
82% yield. Subsequent protection of the amine using
allylchloroformate, followed by N-methylation readily
afforded compound 12 in 78% overall yield. Finally,
N-methyl-O-tert-butylhydroxylamine hydrochloride 6
was obtained after alloc deprotection in the presence
of Pd(OAc)2, TPPTS and sodium borohydride10,11 and
subsequent treatment with HCl.
Thus, addition of methylmagnesium bromide on amide
19 afforded acetophenone in 92% yield, comparable to
the yield observed with the corresponding N-methoxy-
N-methylamide1 (entry 1). Reaction of 19 with either
n-butyllithium or lithium phenylacetylide proceeded
likewise with good yields (entries 2 and 3). Reduction
of amides 19–21 with DIBAL cleanly afforded the corre-
sponding aldehydes in 70–83% yield (entries 4–6). Final-
ly, addition of methylmagnesium bromide on amide 21
led to the corresponding ketone in 97% yield (entry 7).
The above results illustrate the usefulness of these new
Weinreb amides since all reactions proceeded in good
yields, comparable to those obtained with the corre-
sponding N-methoxy-N-methylamides (entries 1, 3, 4,
and 7), and slightly higher in some cases (entries 2 ,5,
and 6).
As this first route to N-methyl-O-tert-butylhydroxylam-
ine hydrochloride 6 was a little lengthy, we devised a
more straightforward synthesis starting from commer-
cially available N-methylhydroxylamine hydrochloride
13 (Scheme 4).
We next studied the nucleophilic addition of n-octyllith-
ium on N-tert-butoxy-N-methyl amide 22, an intermedi-
ate in our synthesis of (À)-isoavenaciolide (Scheme 6).
The reaction afforded the expected ketone 2 with a
Protection of 13 using benzylchloroformate afforded the
corresponding carbamate 1412 in 93% yield and
O
O
O
6, Pyr., CH2Cl2
1. R1M
O
R
N
R1
0˚C to rt, 1 h
2. H+
R
Cl
R
Me
16 : R = Ph
17 : R =
19, 92%
20, 99%
21, 93%
Ph
18 : R = nC17H35
Scheme 5.

O. Labeeuw et al. / Tetrahedron Letters 45 (2004) 7107–7110
Table 1. Addition of R1M to amides 19–21
7109
Entry
1
Amide
R1Ma
Equiv
1.1
T (°C)
t (h)
Product
Yield (%)
O
19
MeMgBr
0
1
92 (93)b
Ph
Ph
Ph
Me
O
O
2
19
n-BuLi
2
0
1
91 (84)
nBu
3
4
5
6
7
19
19
20
21
21
1.5
1.5
1.1
1.5
2
rt
1
91 (90)
70 (71)
80 (76)
83 (71)
97 (94)
Ph
Li
Ph
DIBALc
DIBALc
DIBALc
MeMgBr
À78
1.5
1.5
2
PhCHO
CHO
À78
Ph
À50 to À30
n-C17H35CHO
O
0
1
nC17H35
Me
a All reactions were carried out in THF on a 1mmol scale.
b Yields in brackets are those reported in the literature1 for the corresponding N-methoxy-N-methylamides.
c Reduction of amides 19–21 with DIBAL were carried out at low temperature to prevent the formation of the corresponding amines.
References and notes
OH
O
OH
O
1. nC8H17Li (2.5 eq.)
THF, -5˚C, 1 h
2. H+
BnO
O
BnO
N
nC8H17
1. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815–3818.
Me
2. For a review, see: Singh, J.; Satyamurthi, N.; Aidhen, I. S.
J. Prakt. Chem. 2000, 342, 340–347.
3. For a review, see: Mentzel, M.; Hoffmann, H. M. R. J.
Prakt. Chem. 1997, 339, 517–524.
22
2 (72%)
OH
O
4. For a review, see: Sibi, M. P. Org. Prep. Proced. Int. 1993,
25, 15–40.
5. Labeeuw, O.; Blanc, D.; Phansavath, P.; Ratoveloma-
BnO
+
N
O
H
ˆ
nana-Vidal, V.; Genet, J.-P. Eur. J. Org. Chem., 2004,
2352–2358.
23 (14%)
6. Aldridge, D. C.; Turner, W. B. J. Chem. Soc. C, 1971,
2431–2432.
Scheme 6.
7. Graham, S. L.; Scholz, T. H. Tetrahedron Lett. 1990, 31,
6269–6272.
8. For selected examples: (a) Keck, G. E.; McHardy, S. F.;
Murry, J. A. Tetrahedron Lett. 1993, 34, 6215–6218; (b)
Anderson, J. C.; Flaherty, A.; Swarbrick, M. E. J. Org.
Chem. 2000, 65, 9152–9156; (c) Selvamurugan, V.; Aidhen,
I. S. Tetrahedron 2001, 57, 6065–6069; (d) Selnick, H. G.;
Bourgeois, M. L.; Butcher, J. W.; Radzilowsli, E. M.
Tetrahedron Lett. 1993, 34, 2043–2046; (e) Sibi, M. P.;
Sharma, R.; Paulson, K. L. Tetrahedron Lett. 1992, 33,
1941–1944; (f) Romo, D.; Johnson, D. D.; Plamondon, L.;
Miwa, T.; Schreiber, S. L. J. Org. Chem. 1992, 57,
5060–5063; (g) Birbeck, A. A.; Enders, D. Tetrahedron
Lett. 1998, 39, 7823–7826; (h) Alberola, A.; Ortega, A. G.;
Sada¨ba, M. L.; San˜udo, C. Tetrahedron 1999, 55,
6555–6566; (i) Tius, M. A.; Bush-Petersen, J. Synlett
1997, 531–532.
significantly improved 72% yield compared to the results
obtained with N-methoxy-N-methyl amide 1 (5–24%, see
Scheme 1), although a rearrangement product 23, easily
separable by flash chromatography, was also formed in
this reaction (14% yield).15
In summary, an efficient route to N-methyl-O-tert-but-
ylhydroxylamine hydrochloride 6 was devised, which al-
lowed the preparation of the corresponding modified
Weinreb amides. Nucleophilic addition of organoli-
thium and Grignard reagents on these new N-tert-but-
oxy-N-methylamides readily afforded the corres-
ponding ketones and hydride reduction with DIBAL
delivered the corresponding aldehydes in good yields
up to 97%. As demonstrated in the case of our synthesis
of (À)-isoavenaciolide, the replacement of the N-meth-
oxy group by a N-tert-butoxy group in Weinreb amides
could be of synthetic value in organic synthesis.
9. Chimiak, A.; Kolasa, T. Rocz. Chem. 1974, 48, 139–142.
10. This procedure takes advantage of water soluble palla-
ˆ
dium(0) catalysts developed in our laboratory: Genet,
J.-P.; Blart, E.; Savignac, M.; Lemeune, S.; Paris, J.-M.
Tetrahedron Lett. 1993, 34, 4189–4192, and the use of
sodium borohydride as allyl scavenger: Beugelmans, R.;

7110
O. Labeeuw et al. / Tetrahedron Letters 45 (2004) 7107–7110
Neuville, S. K. E.; Bois-Choussy, M.; Chastanet, J.; Zhu,
J. Tetrahedron Lett. 1995, 36, 3129–3132.
11. For a review on Pd(0)-catalyzed reactions in aqueous
37.4, 85.1. MS (DCI/NH3): m/z = 104 [M + H]+, 121
[M + NH4]+.
15. (a) For the formation of compound 23, the following
mechanism can be postulated:
ˆ
medium, see: Genet, J.-P.; Savignac, M. J. Organomet.
Chem. 1999, 576, 305–317.
12. Characteristic data for compound 14: Rf 0.25 (cyclohex-
ane/AcOEt: 7:3). IR (film): 3293 (broad), 3068, 3042, 2935,
1701 (broad)cmÀ1. 1H NMR (CDCl3, 200MHz): d 3.21 (s,
3H), 5.15 (s, 2H), 7.30–7.40 (m, 5H). 13C NMR (CDCl3,
50MHz): d 38.1, 68.1, 128.1, 128.4, 128.6, 158.1. MS
(DCI/NH3): m/z = 181 [M + H]+, 199 [M + NH4]+. Anal.
Calcd for C9H11NO3: C 59.66, H 6.12, N 7.73, found C
59.49, H 6.15, N 7.71.
O
O
O
O
BnO
O
BnO
N
N
CH2
OtBu
13. Characteristic data for compound 15: Rf 0.66 (cyclohex-
ane/AcOEt: 7:3). IR (film): 3032, 2971, 2930, 1742,
OH
O
Hyd.
BnO
1706cmÀ1
.
1H NMR (CDCl3, 300MHz):
d
1.24
N
H
O
(s, 9H), 3.19 (s, 3H), 5.16 (s, 2H), 7.30–7.40 (m, 5H).
13C NMR (CDCl3, 75MHz): d 27.2, 41.2, 67.9, 82.0,
128.2,128.5, 136.2, 160.1. MS (DCI/NH3): m/z = 238
[M + H]+, 255 [M + NH4]+. Anal. Calcd for C13H19NO3:
C 65.80, H 8.07, N 5.90, found C 65.76, H 8.07, N
5.97.
23
For similar rearrangements, see: Pepper, A. G.; Procter,
G.; Voyle, M. Chem. Commun. 2002, 9, 1066–1067; (b)
Desai, M. C.; Doty, J. L.; Brighty, S. K. E. Tetrahedron
Lett. 1993, 34, 961–962.
14. Characteristic data for compound 6: IR (KBr): 2981, 2884,
2684, 2489cmÀ1. 1H NMR (CD3OD, 200MHz): d 1.44 (s,
9H), 2.98 (s, 3H). 13C NMR (CD3OD, 50MHz): d 26.7,