Novel sequential process from N-methoxyamides and vinyl grignard reagents: New synthesis of β-aminoketones

Full text of DOI:10.1021/jo0057497

J . Org. Chem. 2001, 66, 3613-3616
3613
Sch em e 1
Novel Sequ en tia l P r ocess fr om
N-Meth oxya m id es a n d Vin yl Gr ign a r d
Rea gen ts: New Syn th esis of
â-Am in ok eton es
Arthur Gomtsyan,* Robert J . Koenig, and
Chih-Hung Lee
Abbott Laboratories, Neurological and Urological Diseases
Research, Abbott Park, Illinois 60064
Sch em e 2
arthur.r.gomtsyan@abbott.com
Received November 29, 2000
â-Aminoketones and corresponding γ-amino alcohols
are useful synthetic intermediates. They have been used
in the synthesis of natural products1 and are structural
fragments of a number of pharmaceutically important
compounds and drugs most prominent of which are
Prozac2 and Lipitor.3 Classical methods for the synthesis
of â-aminoketones include Mannich reaction4 of methyl
ketones with amine and paraformaldehyde, the utiliza-
tion of â-haloalkyl ketones in alkylation reactions, and
vinyl ketones in 1,4-conjugate addition reactions with
amines.5
Our attempt to prepare vinylphenyl ketone from corre-
sponding Weinreb amide and vinylmagnesium bromide
resulted in desired product along with â-(N-methoxy-N-
methyl)aminoethylphenyl ketone. However, the first
report on such side-reaction was published by Wuts and
co-workers6 who found that the desired enone from the
reaction of Weinreb amide of leucine derivative with
vinylmagnesium bromide was contaminated with â-
aminoketone. This side-reaction was so prevalent that
authors abandoned that particular approach to their
target molecule. Similar observation has been made by
Wickberg and co-workers7 who characterized unstable
â-aminoketone intermediates in their synthesis of 1,4-
diketones from Weinreb amides and methylcyclopro-
penyllithium. Utilizing these observations we described
in our preliminary communication8 a direct synthesis of
â-aminoketones from amides. In that procedure the
amino function in the starting amide would become
amino function in the â-aminoketone. However, reactivity
of amides was variable with Weinreb amides providing
the highest yield and shortest reaction time. Now we are
able to report that Weinreb amides can serve as common
starting materials for the efficient synthesis of a variety
of â-aminoketones. In this expansion of the scope of our
original procedure, Weinreb amides undergo sequential
transformation consisting of nucleophilic substitution
with different vinyl-Grignard reagents followed by Michael
type reactions with a number of amines.
The sequence is outlined in Scheme 1 for the repre-
sentative example of N-methyl-N-methoxybenzamide 1a .
The net result of the process is “insertion of ethylene”
into amide. Table 1 illustrates many applications of the
reported methodology. Its versatility is demonstrated by
changing a nature of all three components of the sequen-
tial process, i.e., starting amide, vinyl nucleophile and
N-nucleophile. Thus, aromatic amides 1a and 1c and
aliphatic amides 1b and 1d can be successfully employed
as starting substrates. No significant racemization was
observed when the optically active derivative of alanine
1b used as a starting material (entry 5). The Mosher
ester 14 prepared from 6 (Scheme 2) was compared with
a similar Mosher ester synthesized from racemic amino-
ketone rac-6 which in turn was obtained from racemic
1
amide rac-1b. H NMR spectrum of Mosher ester from
chiral series contained two singlets for N-Me group and
two doublets for C-Me group with a ratio ∼2.5:1 indicat-
ing a presence of two major diastereomers. One ad-
ditional singlet and doublet with less than 5% intensity
were also present. Racemic series provided Mosher ester
as a mixture of four diastereomers with a ratio ∼1:2.5:
1:2.5, as four peak sets were found for N-Me and C-Me
groups. Comparison of two 1H NMR spectra revealed that
minor racemization may have occurred and it accounts
for <5%.
On the reagent side, in addition to unsubstituted
vinylmagnesium bromide (entries 1-5, 9-11), 1- and
2-substituted vinyl reagents (entries 6-8, 12) also ef-
fectively participate in the reaction. For example, the
R-methyl-â-aminoketones 7, 8, 13, and the â-methyl-â-
aminoketone are available by this approach. Reduction
of the last product by NaBH4 to the stable â-amino
alcohol 9 was used to prevent â-elimination of the ketone
during chromatography on silica gel. The reaction of
optically active 1b with isopropenylmagnesium bromide
and morpholine provided the ketone 13 as a ∼2:1 mixture
of diastereomers differing in the configuration of the
newly created chiral center.
(1) For selected applications of â-aminoketones in the synthesis of
natural products and biologically active compounds, see: (a) Ogata,
M.; Matsumoto, H.; Kida, S.; Shimizu, S.; Tawara, K.; Kawamura, Y.
J . Med. Chem. 1987, 30, 1497. (b) Takahashi, K.; Shimizu, S.; Ogata,
M. Synth. Commun. 1987, 17, 809. (c) Buchi, G.; Gould, S. J .; Naf, F.
J . Am. Chem. Soc. 1971, 93, 2492.
(2) For representative syntheses, see: (a) Devine, P. N.; Heid, R.
M., J r.; Tschaen, D. M. Tetrahedron 1997, 53, 6739. (b) Corey, E. J .;
Reichard, G. A. Tetrahedron Lett. 1989, 30, 5207. (c) Gao, Y.; Sharpless,
K. B. J . Org. Chem. 1988, 53, 4081.
(3) Graul, A.; Castaner, J . Drugs Future 1997, 22, 956.
(4) Tramontini, M. Synthesis 1973, 703.
(5) Perlmutter, P. Conjugate Addition Reactions in Organic Syn-
thesis; Pergamon Press: New York, 1992; p 114.
(6) Wuts, P. G. M.; Putt, S. R.; Ritter, A. R. J . Org. Chem. 1988, 53,
4503.
The third component of the sequential procedure, the
N-nucleophile, also can be varied as exemplified with
amines (entries 1-9, 12) and hydrazines (entries 10, 11).
(7) Bergman, R.; Nilsson, B.; Wickberg, B. Tetrahedron Lett. 1990,
31, 2783.
(8) Gomtsyan, A. Org. Lett. 2000, 2, 11.
10.1021/jo0057497 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/26/2001

3614 J . Org. Chem., Vol. 66, No. 10, 2001
Ta ble 1. On e-P ot Syn th esis of â-Am in ok eton es a n d P yr a zolin es fr om Wein r eb Am id es
Notes
a
1.1 equiv of Grignard reagent and 1.5 equiv of amine were used in standard procedure unless stated otherwise. b2.5 equiv of the
Grignard reagent was used. 2.5 equiv of amine was used. dYield is based on two steps including reduction of ketone to 9 by NaBH4 in
c
MeOH at 0 °C.
Sch em e 3
In the latter case pyrazoline products 11 and 12 are
obtained9 as a result of three consecutive transforma-
tions: nucleophilic substitution, 1,4-conjugate addition,
and intramolecular cyclization leading to a hydrazone
formation (Scheme 3). Thus, synthesis of pyrazolines is
achieved by creating three new bonds in a single step.
With regard to amines, secondary ones are better rea-
gents than primary amines (entry 4) since 1,4-conjugate
addition products with primary amines undergo further
(9) For common methods for the synthesis of pyrazolines, see:
J arboe, C. H. In Heterocyclic Compounds: Pyrazoles, Pyrazolines,
Pyrazolidines, Imidazoles and Condensed Rings; Wiley: R. H., Ed; J .
additions giving rise to side products.
The mechanism of the reported transformation (Scheme
Wiley & Sons: NewYork, 1967; pp 177-206.
4) may involve the conversion of tetrahedral intermediate

Notes
J . Org. Chem., Vol. 66, No. 10, 2001 3615
Sch em e 4
Sch em e 5
i10 to the final â-aminoketone through possible pathways
a or b. Consequently, intermediates ii and iii can be
envisioned.
variety of amides, vinyl Grignard reagents and N-
nucleophiles. Application of the methodology in medicinal
chemistry for parallel and solid-phase syntheses14 can
also be anticipated.
The crossover experiment (Scheme 5) ruled out ir-
reversible formation of ii. Indeed, the hypothetical eno-
late ii formed from tetrahedral intermediate i and
N-benzylmethylamine could not be affected by the second
amine, piperidine, and could only hydrolyze to â-benzyl-
methylaminoketone. Because both aminoketones 15 and
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under an
atmosphere of dry nitrogen. Commercially available anhydrous
tetrahydrofuran was used without prior distillation. NMR
spectra were obtained in CDCl3 at 300 or 400 MHz for 1H and
75 or 100 MHz for 13C.
1
16 were found in the reaction mixture (LC-MS and H
NMR), it is most likely that our sequential reaction
proceeds through the pathway b where vinyl ketone iii
that forms from i after addition of water undergoes
Michael type reaction with amine.
Gen er a l P r oced u r e for th e Syn th esis of 2-13. To a
solution of starting amide (2.0 mmol) in dry THF (20 mL) at 0
°C was added a 1 M solution of vinylmagnesium bromide (2.2
mmol) in THF within 1 min. After 10 min the mixture was
allowed to attain ambient temperature and was stirred for 1 h.
This mixture was treated with amine (3.0 mmol) followed by
water (3 mL). The mixture was stirred for 20 min, diluted with
ethyl acetate, and washed twice with water. The organic layer
was separated, concentrated, and chromatographed on SiO2
(EtOAc-hexane) to afford â-aminoketones or pyrazolines.
3-P ip er id in op r op iop h en on e 2. 1H NMR δ 7.91 (m, 2H),
7.58-7.42 (m, 3H), 3.21 (t, J ) 8.5 Hz, 2H), 2.82 (t, J ) 8.5 Hz,
2H), 2.49 (m, 4H), 1.60 (m, 4H), 1.43 (m, 2H); 13C NMR 198.8,
136.7, 132.7, 128.2, 127.7, 54.3, 53.6, 36.1, 25.7, 24.0; MS m/z
218 (M + H). Anal. Calcd for C14H19NO‚0.5H2O: C 74.30; H 8.91;
N 6.19. Found: C 74.06; H 8.52; N 5.85.
All N-nucleophiles in the last step must compete with
N-methyl-N-methoxyamine (or corresponding magne-
sium amide) that forms along with iii in the process of
decomposition of tetrahedral intermediate i. It is inter-
esting to note that generally no product arising from
addition of N-methyl-N-methoxyamine to the ketone iii
was observed. The only exception was the reaction
between amide 1b, vinylmagnesium bromide, and di-
benzylamine (entry 9) when 9% of N-methyl-N-meth-
oxyamine analogue of the major product 10 was also
isolated.
3-(N-Met h yl-N-m et h oxyet h yla m in o)p r op iop h en on e 3.
1H NMR δ 7.98 (m, 2H), 7.55 (m, 1H), 7.48 (m, 2H), 3.51 (t, J )
6.0 Hz, 2H), 3.37 (s, 3H), 3.22 (t, J ) 8.5 Hz, 2H), 2.92 (t, J )
8.5 Hz, 2H), 2.67 (t, J ) 6.0 Hz, 2H), 2.37 (s, 3H); 13C NMR 199.0,
136.6, 132.8, 128.3, 127.7, 70.1, 58.5, 56.5, 52.4, 42.3, 36.1; MS
m/z 222 (M + H); HRMS calcd for C13H19NO2 222.1494 (M +
H), found 222.1496.
In summary, we have discovered a new mild and
efficient sequential transformation11 for the facile and
rapid preparation of â-aminoketones or their deriva-
tives,12 e.g., pyrazolines, utilizing readily available and
stable Weinreb amides13 as common starting materials.
The reaction proceeds in good to excellent yields for a
1
3-(N-Meth yl-N-ben zyla m in o)p r op iop h en on e 4. H NMR
δ 7.92 (m, 2H), 7.52 (m, 1H), 7.43 (m, 2H), 7.30-7.20 (m, 5H),
3. 54 (s, 2H), 3.18 (t, J ) 8.0 Hz, 2H), 2.89 (t, J ) 8.0 Hz, 2H),
2.24 (s, 3H); 13C NMR 199.3, 138.7, 136.8, 132.9, 128.8, 128.5,
128.1, 127.9, 126.9, 62.3, 52.4, 42.1, 36.8; MS m/z 254 (M + H).
Anal Calcd for C17H19NO‚0.03H2O: (253.88) C 80.43; H 7.57; N
5.52. Found: C 80.04; H 7.47; N 5.32.
3-Ben zyla m in op r op iop h en on e 5. 1H NMR δ 7.92 (m, 2H),
5.55 (m, 1H), 7.45 (m, 2H), 7.39-7.20 (m, 5H), 3.83 (s, 2H), 3.23
(t, J ) 8.0 Hz, 2H), 3.05 (t, J ) 8.0 Hz, 2H), 1.90 (broad s, 1H);
MS m/z 240 (M + H).
(10) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(b) Sibi, M. P. Org. Prep. Proceed. Intl. 1993, 25, 15.
(11) For
a discussion of sequential transformations in organic
chemistry, see: (a) Hall, N. Science 1994, 266, 32. (b) Tietze, L. F.;
Modi, A. Med. Res. Rev. 2000, 20, 304. (c) Tietze, L. F. Chem Rev. 1996,
96, 115. (d) Bunce, R. A. Tetrahedron 1995, 48, 13103. (e) Tietze, L.
F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (f) Posner,
G. H. Chem. Rev. 1986, 86, 831.
(12) The advantage of this one-pot procedure over two-step alterna-
tive can be shown by comparison of our synthesis of 4 (89% yield) with
Ely Lilly’s two-step Mannich-Michael approach to 4 (64-70% yield
and use of 10 equiv of amine). Pedregal Tercero, C. ES2101650, 1997;
Chem Abstr. 1998, 128, 114779c.
(13) (a) Raghuram, T.; Vijaysaradhi, S.; Singh, I.; Singh, J . Synth.
Commun. 1999, 29, 3215. (b) Aidhen, I. S.; Ahuja, J . R. Tetrahedron
Lett. 1992, 33, 5431. (c) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron
Lett. 1997, 38, 2685. (d) Handa, S.; Gibson, C. L. Tetrahedron
Asymmetry 1996, 7, 1281.
(14) For solid-phase Weinreb amides, see: (a) Salvino, J . M.; Mervic,
M.; Mason, H. J .; Kiesow, T.; Teager, D.; Airey, J .; Labaudiniere, R. J .
Org. Chem. 1999, 64, 1823. (b) Fehrentz, J .-A.; Paris, M.; Heitz, A.;
Velek, J .; Winternitz, F.; Martinez, J . J . Org. Chem. 1997, 62, 6792.
(c) Dinh, T. Q.; Armstrong, R. W. Tetrahedron Lett. 1996, 37, 1161.

3616 J . Org. Chem., Vol. 66, No. 10, 2001
Notes
(R)-2-(N-ter t-Bu toxyca r bon yl)a m in o-5-(N-m eth yl-N-ben -
zyla m in o)-3-p en ta n on e 6. [R]D +6.2° (c 1.90; CH2Cl2); 1H NMR
δ 7.28 (m, 5H), 5.46 (broad s, 1H), 4.31 (m, 1H), 3.50 (s, 2H),
2.71 (m, 4H), 2.19 (s, 3H), 1.44 (s, 9H), 1.31 (d, J ) 6.0 Hz, 3H);
13C NMR 208.5, 138.4, 128.7, 128.0, 125.879.3, 62.1, 55.0, 51.8,
41.7, 37.0, 28.1, 17.3; MS m/z 321 (M + H); HRMS calcd for
126.8, 58.2, 48.4, 41.8, 29.4; MS m/z 268 (M + H); HRMS calcd
for C18H21NO 268.1701 (M + H), found 268.1704.
1-Meth yl-3-p h en yl-4,5-d ih yd r op yr a zole 11. 1H NMR δ
7.61 (m, 2H), 7.35-7.23 (m, 3H), 3.13 (t, J ) 8.3 Hz, 2H), 2.94
(t, J ) 8.3 Hz, 2H), 3.90 (s, 3H); 13C NMR 151.5, 132.8, 128.3,
128.2, 125.6, 56.0, 43.3, 33.2; MS m/z 161 (M + H). Anal. Calcd
for C10H12N2: (160.22) C 74.97; H 7.55; N 17.48. Found: C 75.17;
H 7.65; N 17.21.
C
18H28N2O3 321.2178 (M + H), found 321.2178.
2-Meth yl-3-m or p h olin op r op iop h en on e 7. 1H NMR δ 7.95
(m, 2H), 7.54 (m, 1H), 7.46 (m, 2H), 3.73 (m, 1H), 3.59 (m, 4H),
2.86 (dd, J ) 8.0 and 13.5 Hz, 1H), 2.45-2.38 (m, 5H), 1.20 (d,
J ) 8.5 Hz, 3H); 13C NMR 203.8, 137.0, 132.9, 128.4, 128.1, 66.9,
62.0, 53.9, 38.3, 16.1; MS m/z 234 (M + H). Anal. Calcd for
C14H19NO2: (233.31) C 72.07; H 8.21; N 6.00. Found: C 71.84;
H 8.01; N 5.92.
1-Ben zyl-3-m eth yl-4,5-d ih yd r op yr a zole 12. 1H NMR δ
7.39-7.20 (m, 5H), 4.10 (s, 2H), 2.88 (t, J ) 10.0 Hz, 2H), 2.50
(t, J ) 10.0 Hz, 2H), 1.94 (s, 3H); 13C NMR 152.4, 137.6, 128.6,
128.0, 126.8, 61.0, 53.7, 36.7, 15.9; MS m/z 175 (M + H). Anal.
Calcd for C11H14N2: (174.24) C 75.82, H 8.10, N 16.08. Found:
C 75.56, H 8.19, N 15.96.
3-P ip er id in o-2-m et h yl-1-[3-(6-ch lor op yr id yl)]-1-p r op a -
n on e 8. 1H NMR δ 8.96 (d, J ) 2.5 Hz, 1H), 8.20 (dd, J ) 2.5
and 9.0 Hz, 1H), 7.43 (d, J ) 9.0 Hz, 1H), 3.67 (m, 1H), 2.80
(dd, J ) 9.0 and 13.0 Hz, 1H), 2.48-2.28 (m, 5H), 1.50-1.30
(m, 6H), 1.18 (d, J ) 9.0 Hz, 3H); 13C NMR 202.0, 154.9, 149.8,
138.0, 131.1, 124.0, 62.6, 54.8, 39.3, 25.8, 24.0, 15.6; MS m/z 267
(M + H). Anal. Calcd for C14H19N2ClO: (266.77) C 63.03, H 7.18,
10.50. Found: C 62.78, H 7.03, N 10.41.
(R)-2-(N-ter t-Bu t oxyca r b on yla m in o)-5-m or p h olin o-4-
m eth yl-3-p en ta n on e 13. 1H NMR δ 4.40 (m, 1H), 3.67 (m, 4H),
3.18-2.96 (m, 1H), 2.75-2.20 (m, 6H), 1.46 and 1.44 (2s, 9H),
1.31 (m, 3H), 1.08 and 1.04 (2D, J ) 7 Hz, 3H); MS m/z 301 (M
+ H); HRMS calcd for C15H28N2O4 301.2127 (M + H), found
301.2140.
N-Met h yl-N-m et h oxy-2-[(ter t-b u t oxyca r b on yl)a m in o]-
p r op a n a m id e (r a c-1b) was synthesized according to the pro-
cedure6 described for the synthesis of Boc-leucine Weinreb
amide. Boc-DL-alanine (1.9 g, 10.0 mmol), N,O-dimethylhydroxyl-
amine hydrochloride salt (1.2 g, 12.3 mmol), and triethylamine
(2.8 mL, 20.1 mmol) were mixed in dry CH2Cl2 (30 mL), and
DEPC (diethyl phosphorocyanidate) (3.0 mL, 19.8 mmol) was
then added, causing a slight exothermic reaction. The reaction
mixture was stirred at ambient temperature overnight and then
was poured into water and extracted with CH2Cl2 (3 × 30 mL).
The combined organic extracts were washed with saturated
NaHCO3 solution and dried over MgSO4. The solvent was
removed in vacuo, affording the crude product as a greasy yellow
solid. Purification by flash chromatography (EtOAc-hexanes,
2:3) afforded the desired product as a white solid, 2.11 g (96%).
1H NMR δ 5.25 (broad d, 1H), 4.69 (m, 1H), 3.77 (s, 3H), 3.20 (s,
3H), 1.44 (s, 9H), 1.31 (d, J ) 7 Hz). MS m/z 233 (M + H).
3-(N-Met h yl-N-b en zyla m in o)-3-m et h yl-1-p h en ylp r op a -
n ol 9. To a solution of benzamide 1 (1. 09 g, 6.6 mmol) in dry
THF (60 mL) at 0 °C was added a 0.5 M solution of 1-propenyl-
magnesium bromide (15 mL, 7.3 mmol) in THF within 1 min.
After 10 min, the mixture was allowed to attain ambient
temperature and was stirred for 1 h. This mixture was treated
with N-benzylmethylamine (1.60 g, 13.2 mmol) followed by water
(8 mL). The mixture was stirred for 20 min, diluted with ethyl
acetate, and washed twice with water. Organic layer was
separated, concentrated, and dissolved in MeOH (50 mL). To
this solution was added NaBH4 (0.50 g, 13.2 mmol) at 0 °C and
resulting mixture stirred at ambient temperature for 2 h. The
mixture was quenched with water, concentrated under vacuo,
and diluted with ethyl acetate. After washing with 1 N HCl and
water, the organic layer was separated, concentrated, and
chromatographed on SiO2 (EtOAc-hexane) to afford 9 (1.00 g,
56%). 1H NMR δ 7.60 (broad s, 1H), 7.41-7.20 (m, 5H), 4.86
(dd, J ) 1.5 and 10.5 Hz, 1H), 3.75 (d, J ) 12.0 Hz, 1H), 3.58 (d,
J ) 12.0 Hz, 1H), 3.27 (m, 1H), 2.22 (s, 3H), 1.86 (ddd, J ) 10.5,
14.5 and 21.0 Hz, 1H), 1.50 (ddd, J ) 1.5, 4.5 and 14.5 Hz, 1H),
1.02 (d, J ) 7.5 Hz, 3H); 13C NMR 145.1, 138.1, 129.0, 128.5,
128.1, 127.3, 126.8, 125.4, 75.6, 58.9, 58.6, 41.7, 34.9, 11.9; MS
m/z (M + H) 270. Anal. Calcd for C18H23NO‚0.1H2O: (171.13) C
79.72, H 8.62, 5.16. Found: C 79.45, H 8.23, N 4.80.
Ack n ow led gm en t. Authors thank Professor Peter
Beak for helpful and stimulating discussions, and Dr.
Tom Pagano, Adam Huffman, David Whittern, and J an
Waters for excellent NMR support.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
1
NMR spectra for 2-13 and H NMR spectra for Mosher esters
14 from chiral and racemic series. This material is available
4-Diben zyla m in o-2-bu ta n on e 10. 1H NMR δ 7.30-7.13 (m,
10H), 3.53 (broad s, 4H), 2.78 (t, J ) 8.0 Hz, 2H), 2.59 (t, J )
8.0 Hz, 2H), 1.98 (s, 3H); 13C NMR 207.8, 139.1, 128.7, 128.1,
free of charge via the Internet at http://pubs.acs.org.
J O0057497