Improved syntheses of α-BOC-aminoketones from α-BOC-amino-Weinreb amides using a pre-deprotonation protocol

Article abstract of DOI:10.1016/S0040-4039(02)02031-2

A general procedure was developed to prepare α-BOC-aminoketones in good yields from α-BOC-amino Weinreb amides containing an exchangeable amino proton. By first deprotonating this amino group using 1 equiv. of a simple alkyl Grignard base, only a stoichio

Full text of DOI:10.1016/S0040-4039(02)02031-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8223–8226
Improved syntheses of a-BOC-aminoketones from
a-BOC-amino-Weinreb amides using a pre-deprotonation
protocol
Jinchu Liu,* Norihiro Ikemoto,* Daniel Petrillo and Joseph D. Armstrong, III
Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 20 August 2002; revised 17 September 2002; accepted 18 September 2002
Abstract—A general procedure was developed to prepare a-BOC-aminoketones in good yields from a-BOC-amino Weinreb
amides containing an exchangeable amino proton. By first deprotonating this amino group using 1 equiv. of a simple alkyl
Grignard base, only a stoichiometric amount, rather than a large excess, of the nucleophile was needed to prepare the ketone. This
procedure is therefore more economical to run and the purification is easier. © 2002 Elsevier Science Ltd. All rights reserved.
Weinreb amides (N-methoxy-N-methylamides) are use-
ful precursors to ketones. When they are allowed to
react with Grignard or organolithium reagents, stable,
metal-chelated tetrahedral intermediates are formed,
which resist further nucleophilic attack. Formation of
alcohol side products is therefore minimized.1 Weinreb
amides that contain an a-BOC-amino group have been
used to access a-BOC-aminoketones, which are inter-
mediates in the syntheses of many drugs and biologi-
cally active compounds.2
was required because the deprotonation of the
exchangeable amino proton of 2 was faster than the
nucleophilic attack at the Weinreb amide functional
group. Thus, when only 1.2 equiv. of reagent 3 was
used, only a trace amount of 1 was isolated, along with
recovered 2 and 3-methoxypyridine by-product.
For scale-up work, the use of excess Grignard reagent 3
was impractical. First, this reagent was not commer-
cially available and had to be prepared from expensive
3,5-dibromopyridine in two steps. Second, this made
purification of 1 difficult due to the formation of large
amounts of 3-methoxypyridine by-product.
We recently required multi-kg quantities of the a-BOC-
aminoketone 1 (Fig. 1), an intermediate to an HIV
protease drug candidate. This intermediate was pre-
pared initially by reacting the Weinreb amide 2 with >2
equiv. of Grignard reagent 3 (Scheme 1). Excess reagent
It was reasoned that pre-deprotonation of the amino
group using an inexpensive base whose by-product is
easily removed, followed by the addition of a stoichio-
metric amount of nucleophile 3, should avoid these
problems. Thus, by first adding a little less than 1
Table 1. Comparison of bases
Figure 1.
Entry
Base
Yield (%)
1
2
3
4
i-PrMgCl
MeMgCl
n-BuLi
96
99
32
44
Scheme 1.
s-BuLi
* Corresponding authors.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02031-2

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J. Liu et al. / Tetrahedron Letters 43 (2002) 8223–8226
equiv. of i-PrMgCl/THF, followed by 1.0 to 1.25 equiv.
of Grignard reagent 3, a good yield of BOC-amino-
A literature search revealed that aminoketones are pre-
pared typically using excess amounts of nucleophiles
when an exchangeable amino proton is present in their
BOC- or CBZ-protected amino-Weinreb amide precur-
sors.2–5 Some of these Grignard or organolithium
reagents are neither commercially available nor trivial
to prepare.3a,c,d,5,6 Furthermore, the purification was
difficult in many cases, especially when the desired
ketone
1 was obtained with much less of 3-
methoxypyridine by-product. After work-up, the a-
BOC-aminoketone 1 was crystallized out of the organic
solution with good purity, thus eliminating the chro-
matographic purification. Multi-kg quantities of 1 were
prepared successfully using this procedure.
Table 2. Preparation of a-Boc-aminoketonesa

J. Liu et al. / Tetrahedron Letters 43 (2002) 8223–8226
8225
product is unstable to chromatography.5b,7 Thus, fur-
ther study and development of our pre-deprotonation
protocol appeared warranted.
with i-PrMgCl followed by addition of s-BuLi/hexane
as the nucleophile, a poor yield (20%) of the corre-
sponding ketone was isolated after 1 day at room
temperature. Therefore, the reactivity of Weinreb
amides appears to be restricted to primary alkyl
reagents. In fact, our survey of the literature did not
uncover any examples in which a Weinreb amide was
reacted successfully with a secondary alkyl nucleophile.
The choice of base was studied first, using the conver-
sion of 2 to the phenylketone 4 as a test reaction (Table
1). The four bases shown were chosen because they are
readily available and have by-products that are volatile
and easily removed. The Grignard reagents, MeMgCl/
THF and i-PrMgCl/THF, gave high yields of 4 when
0.98 equiv. were added first to the Weinreb amide 2 at
<−5°C, followed by 1.2 equiv. of phenyl Grignard. The
lithium bases, n-BuLi/hexane and s-BuLi/hexane, on
the other hand, gave poor yields and more unidentified
impurities under the same reaction conditions. Adding
1 equiv. of MgBr2–Et2O to the reaction mixture
between the s-BuLi and the phenyl Grignard charges
did not improve the yield. It was subsequently found
that the Weinreb amide 2 is unstable to the lithium
bases even at −15 to −10°C, while it is completely stable
in the presence of Grignard bases. Thus, after base
addition followed by work-up, the Weinreb amide 2
was recovered in 99% yield using i-PrMgCl/THF but
only in 54% yield with n-BuLi/hexane.
In summary, a pre-deprotonation strategy was applied
to Weinreb amides containing an exchangeable amino
group. It was demonstrated that primary alkyl, aryl and
alkynyl nucleophiles could be added to afford the cor-
responding ketones in high yields. There was very little
waste since only a small excess of these nucleophiles
was used. By minimizing the formation of their by-
products, purification of the desired ketones was made
easier. This simple procedure is an improvement over
the procedures that are typically reported in the litera-
ture that employ a large excess of nucleophiles and
should see general utility in cases when exchangeable
protons are present in the molecules.
Acknowledgements
Using either MeMgCl/THF or i-PrMgCl/THF as the
base, we then studied the reactivities of several lithium
and magnesium nucleophiles with BOC-glycine Wein-
reb amide 2, as well as its a-methyl and isopropyl
derivatives (Table 2). Slightly less than 1 equiv. of base
was added to the Weinreb amide, followed by 1.1 to
1.26 equiv. of nucleophile. The reaction was followed
by HPLC or TLC, and when most of the Weinreb
amide had been converted, the reaction was worked up
and the desired ketone was purified.8 Some organo-
lithium reagents that are unstable (entries 3 and 9) were
generated at low temperature following published pro-
cedures.6a,9 For these examples, a pre-cooled solution of
the deprotonated Weinreb amide was added to a solu-
tion of these reagents (−60°C), and the resulting mix-
ture was allowed to warm slowly to room temperature
over several hours.
The authors thank Ms. Jennifer Chilenski for %ee
determinations and Dr. Peter Dormer for NMR spec-
trum discussion.
References
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With these procedures, a variety of ketones were pre-
pared readily in good to excellent yields using aryl,
alkynyl and primary alkyl nucleophiles. These yields are
as good as those reported for the corresponding reac-
tions using excess nucleophilic reagents.2g,6 Purification
was comparatively easier, because less by-products were
produced. With our pre-deprotonation protocol, ketone
intermediates were prepared containing functional
groups that can be elaborated to more complex target
structures (entries 2, 3, 4, and 9). Furthermore, the
method can be applied to chiral Weinreb amides
(entries 10 and 11) to provide optically pure ketones
(>99% ee) without racemization.10
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the Weinreb amide 2 (Table 2), while secondary alkyl
nucleophiles did not. After treating 2 with 2.3 equiv. of
i-PrMgCl/THF at room temperature for three days, the
Weinreb amide 2 was recovered in 48% yield with no
desired isopropylketone. After pre-deprotonation of 2

8226
J. Liu et al. / Tetrahedron Letters 43 (2002) 8223–8226
Iwasawa, H.; Shiroshi, S. Chem. Pharm. Bull. 1988, 36,
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to the resulting slurry was charged 4.9 mL of 2.0 M
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afford a clear solution. After cooling to <−10°C, 6.3 mL
of 2.0 M PhMgCl/THF (12.6 mmol) was added at
<−5°C. The cooling bath was removed, and the mixture was
allowed to warm to rt over 30 min. After a 4 h age at rt,
the reaction was complete. The mixture was cooled over
an ice bath and 23 mL of 1.0N HCl was added slowly at
<20°C, followed by 25 mL of EtOAc. The aqueous layer
was cut, and the organic layer was washed with 25 mL of
water and dried over anhydrous Na2SO4. Evaporation of
the solvent afforded 2.70 g oil, which solidified on stand-
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3341; (f) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shi-
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EtOAc), 2.25
g
of BOC-aminoacetophenone was
obtained as a white crystalline solid in 96% yield.
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Brunet, M.; Duceppe, J.-S.; Malenfant, E.; Moss, N. J.
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10. The optical purity was determined by chiral HPLC:
Chiralcel OJ (25 cm×4.6 mm), 1% EtOH/heptane, 1.5
mL/min, 20°C, 254 nm.
8. Typical procedure for preparation of BOC-a-aminoketone:
BOC-glycine Weinreb amide 2 (2.18 g, 10.0 mmol) was
dissolved in 20 mL of dry THF, degassed and inerted