A practical one-pot process for α-amino aryl ketone synthesis

Article abstract of DOI:10.1016/j.tetlet.2005.09.183

An efficient, convenient, high-yielding synthesis of α-amino aryl ketones is described, involving the one-pot deprotonation-transmetallation- arylation of a Weinreb amide while retaining chirality of the original amide.

Full text of DOI:10.1016/j.tetlet.2005.09.183

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8587–8589
A practical one-pot process for a-amino aryl ketone synthesis
Karen Conrad,* Yi Hsiao and Ross Miller
Department of Process Research, Merck Research Laboratories, Merck & Co. Inc., Rahway, NJ 07065, USA
Received 1 August 2005; revised 28 September 2005; accepted 29 September 2005
Available online 18 October 2005
Abstract—An efficient, convenient, high-yielding synthesis of a-amino aryl ketones is described, involving the one-pot deprotona-
tion–transmetallation–arylation of a Weinreb amide while retaining chirality of the original amide.
ꢀ 2005 Elsevier Ltd. All rights reserved.
a-Amino ketones are important building blocks for
many biologically active compounds. There are many
different synthetic routes to a-amino ketones reported
in the literature,1 and Weinreb amide arylation/alkyl-
ation via Grignard addition is one of the most utilized
methods.1d,e
of the moisture-sensitive Grignard reagent at sub-zero
temperature not only lowers the productivity but also
can lessen the robustness of the process.
Recently, during the investigation of the synthesis of an
a-Cbz-amino ketone (1), we surprisingly discovered that
the widely accepted Weinreb amide pre-deprotonation
step is not necessary. In contrast to alkylation reagents
where transmetallation is faster than the deprotonation,
we theorized that the deprotonation would not only be
faster than the Grignard addition to the Weinreb amide5
but also the transmetallation of the bromide. In fact, the
reaction proceeded smoothly when i-PrMgCl (2.5 equiv)
was directly added into a mixture of Weinreb amide
(2) and 3,5-bis (trifluoromethyl)bromobenzene (3) at
À10 ꢁC. (Scheme 1) After aging at roomtemperature
overnight, the desired product was obtained at 92%
HPLC assay yield and 99% ee. Fromthese results, it
was obvious that the rate of deprotonation dominated
at first stage of the reaction. To confirmthese results,
the addition of isopropylmagnesium chloride to a solu-
tion of the Weinreb amide (2) and the bromide was fol-
lowed by HPLC. The appearance of the debrominated
In general, to prepare an a-amino ketone by this met-
hod, the Weinreb amide is derived from a N-protected
amino acid (Boc or Cbz)1d,e and the Grignard reagent
is prepared fromthe corresponding halide using Mg
metal or i-PrMgCl.2,3 The N-protected Weinreb amide
contains one exchangeable proton and excess base is
required for the deprotonation, which is normally
accomplished by using an extra equivalent of the pre-
pared Grignard4 or i-PrMgCl.5 Therefore, the reaction
involves a two-pot process; the deprotonation of the
Weinreb amide and the Grignard formation performed
in two separate vessels, followed by transferring the
Grignard into the deprotonated N-protected Weinreb
amide solution. This method is useful for small scale
synthesis to kilogramscale, however, the requirement
of two anhydrous reaction vessels as well as a transfer
O
F3C
NHCbz
Br
F3C
NHCbz
O
1.
i
-PrMgCl, rt age
O
+
N
2. H+
CF3
CF3
1
2
3
Scheme 1.
Keywords: a-Amino aryl ketone synthesis; Weinreb amide; Grignard arylation.
*
Corresponding author. Tel.: +1 732 594 5129; fax: +1 732 594 1499; e-mail: karen_conrad@merck.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.183

8588
K. Conrad et al. / Tetrahedron Letters 46(2005) 8587–8589
1,3-bis(trifluoromethyl)benzene (resulting from the
quenched aryl grignard) does not occur until at least
0.95 equiv of the Grignard has been added. Thus, the
Weinreb amide is deprotonated first, then the aryl Grig-
nard is generated in situ using KnochelÕs procedure.2
8, 4-methoxybromobenzene, and 4-bromotoluene. How-
ever, simply changing the bromide to the corresponding
iodide will allow the reaction to proceed, as with iodo-
benzene 9, methoxyiodobenzene 10–11, and iodotoluene
12–14. Thiazole 15 will also transmetallate at the same
position as 2-bromothiazole 16 and produce ketone
product at an acceptable yield, due to the acidic nature
of the hydrogen at the 2-position.
The major side reaction is the addition of the isopropyl-
magesium chloride directly to the Weinreb amide, form-
ing the isopropyl adduct. This by-product was
controlled at <4–5%, and can be easily removed during
the crystallization. We have also found that the typical
acid quench at the end of the reaction causes the race-
merization of the product. However, a reverse quench
using HCl can minimize this problem, resulting in crude
ketone 1 of 95% ee, and a crystallization fromheptane
upgraded the ee to 99%. Using our new one-pot proto-
col, this reaction was successfully operated on multi-
There also appears to be a substitution effect on the
Grignard reactivity. o-Substituted aryl halides have a
lower yield than the m- or p-substituted analogs. For
example, 3,5-difluoro-1-bromobenzene 5 has a higher
yield than 2,5-difluoro-1-bromobenzene 4. Similarly, 2-
iodotoluene 14 has a lower yield than 3- or 4-iodotolu-
ene (12 and 13). However, this trend is opposite with
the iodomethoxybenzenes 10 and 11. o-Methoxyiodo-
benzene has the higher yield, possibly through the co-
ordination of the oxygen with the Mg metal to form
a more stable intermediate.6b,7
10
kilogramscale.
With these encouraging results, a variety of other aryl
halides were examined to determine the scope of the
reaction (see Table 1).
The % ee was determined by chiral HPLC assay of the
isolated ketone compared to an authentic sample of
the racemic ketone, synthesized using the same chemis-
try as previously described. As previously discussed,
the % ee of the ketone product is dependant on the acid
quench, as well as the isolation. With optimization of
both procedures for the individual substrates, we would
expect the % ee to improve for these examples.
The reaction works very well with aryl bromides
containing electron-withdrawing groups,6 as shown in
entries 3–6, and 15–17. As previously mentioned, the
main side reaction is the formation of the isopropyl
adduct of the Weinreb amide. We have found that the
amount of this adduct generated is dependent on the
rate of transmetallation. If the aryl Grignard forms
quickly, little to no adduct is produced. On the other
hand, if the aryl Grignard forms slowly or not at all,
the adduct formation can become a competitive reac-
tion. Transmetallation does not occur or occurs very
slowly when there are electron-donating groups or no
substituents on the aryl bromide, as with bromobenzene
We have also examined the use of a morpholine amide
in our reaction (Scheme 2), as the N,O-dimethylhydr-
oxylamine used to synthesize Weinreb amide can be pro-
hibitively expensive for scale-up.8 Morpholine amide9
performs similarly in our one-pot reaction. However,
the yields are approximately 5–10% lower under the
Table 1. Grignard reaction of 2 with aryl halides
O
O
O
O
NHCbz
NHCbz
NHCbz
Ar
X
+
N
Ar
+
5
2
4
Entry
Halide
Assay yield, %a
Ketone 4
Adduct 5
ee %b
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3,5-Bis(trifluoromethyl)bromobenzene
1-Bromo-2,5-difluorobenzene
1-Bromo-3,5-difluorobenzene
3-Bromopyridine
3-Bromo-5-methoxypyridine
Bromobenzene
Iodobenzene
3-Iodoanisole
2-Iodoanisole
4-Iodotoluene
93.7
86.6
98.7
79.1
97.1
0
90.5
84.3
92.9
84.7
96.6
83.6
83.4
90.7
88.7
4.0
7.7
1.3
3.3
3.3
>90
0
1.2
0.4
0.6
1.4
9.7
0
99
89
91
90
88
0
99
96
99
98
97
91
94
94
82
3-Iodotoluene
2-Iodotoluene
Thiazole
2-Bromothiazole
0
15.7
4-Bromobenzonitrile
a Assay yield of a-amino ketone product determined by HPLC using purified standards of desired products.
b ee determined by chiral HPLC assay of product compared to authentic sample of racemic ketone using Chiralpak AD-H (250 · 4.6 mm) column.

K. Conrad et al. / Tetrahedron Letters 46(2005) 8587–8589
F3C Br
8589
O
O
F3C
NHCbz
NHCbz
CF3
N
O
1.
i
-PrMgCl, rt age
2. H+
CF3
Scheme 2.
C.; Prasad, J. V. N. V.; Rich, D. H. Tetrahedron Lett.
1993, 34, 5217; (f) Seki, M.; Matsumoto, K. Tetrahedron
Lett. 1996, 37, 3165; (g) Satoh, Y.; Moliterni, J. Synlett
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Iwasawa, H.; Shiroshi, S. Chem. Pharm. Bull. 1988, 36,
3341; (j) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shiroshi,
S. Chem. Pharm. Bull. 1988, 36, 3296.
same experimental conditions (1.25 equiv bromide,
2.5 equiv i-PrMgCl in THF, age at ambient temp), and
we have found that the completed unquenched reaction
is unstable with extended age time.
In conclusion, we have discovered a novel one-pot
process for a-amino ketone synthesis via the arylation
of Weinreb amides, which require no pre-deprotonation
of the Weinreb amide, dramaticaly simplifies the opera-
tion, and increases the productivity. The procedure
clearly demonstrates that the Knochel magnesiztions
are kinetically slower than deprotonations in contrast
to organolithiumtransmetallations.
5. Liu, J.; Ikemoto, N.; Petrillo, D.; Armstrong, J. D.
Tetrahedron Lett. 2002, 43, 8223.
6. (a) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P.
Angew. Chem., Int. Ed. 2000, 39, 4414; (b) Knochel, P.;
Dohle, W.; Gommermann, N.; Florian, F. K.; Kopp, F.;
Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed.
2003, 42, 4302; (c) Oshima, K.; Inoue, A.; Kitagawa, K.;
Shinokubo, H. J. Org. Chem. 2001, 66, 4333.
7. Schlosser, M.; Katsoulos, G.; Takagishi, S. Synlett 1991,
731.
Acknowledgment
8. Tillyer, R.; Frey, L. F.; Tschaen, D. M.; Dolling, U.-H.
Synlett 1996, 225.
9. (a) Williams, M. J.; Jobson, R. B.; Yasuda, N.; Marche-
sini, G.; Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron
Lett. 1995, 36, 5461; (b) Sengupta, S.; Mondal, S.; Das, D.
Tetrahedron Lett. 1999, 40, 4107.
We thank Ms. Mirlinda Biba for assistance with chiral
HPLC analysis, HRMS.
Supplementary data
10. Typical experimental procedure: Weinreb amide 2 (10.0 g,
37.4 mmol) and 3,5-bis(trifluoromethyl)bromobenzene 3
(13.75 g, 46.9 mmol) were dissolved in 40 ml THF, and the
solution was degassed (Kf < 500 ppm). The solution was
cooled using an acetone/dry ice bath (2 precipitates out of
solution at À10 ꢁC), and i-PrMgCl in THF (40 ml, 2 M,
80 mmol) was slowly added to the reaction so that the
internal temperature 6À5 ꢁC. At the end of the addition,
the external cooling was removed, and the reaction was
aged at ambient temperature overnight (reaction usually
completes within 6 h). HCl (5 N, 23 ml) was charged to a
separate vessel and cooled to 0 ꢁC, and the reaction
mixture was then charged so that the internal temperature
was 65 ꢁC. MTBE (20 ml) was added, mixed, and the
layers separated. The pH of the aqueous layer was 4.1
(typical range 3.7–4.4). The MTBE layer was then washed
with water (20 ml) and saturated aq NaCl (20 ml), and
then concentrated via vacuumdistillation to approxi-
mately 20 ml at 26–28 in. Hg and internal temperature of
25–30 ꢁC. Heptane (100 ml) was added, and the solution
was distilled to 65 ml, with the internal temperature 45–
60 ꢁC and 26–28 in. Hg. The solution was slowly cooled to
35 ꢁC, and then seeded (approx. 1 wt %). The slurry was
then slowly cooled to 10 ꢁC over 2.5 h. The solids were
filtered, washed with 20 ml cold heptane, and the cake was
dried on the filter, 69% isolated yield, >99% ee. The
experimental procedure as described for 1 through the satd
aq NaCl wash was used for the remainder of the examples.
The MTBE was then evaporated and the residue chro-
matographed on silica gel, eluting with hexanes/ethyl
acetate. The purified product was then used as a standard
to determine reaction yield by HPLC.
Full characterization of compounds and experimental
details. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2005.09.183.
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