Dihalomethylation of N-protected phenylalanine esters

Article abstract of DOI:10.1016/S0040-4039(01)01253-9

Dihalomethylation of several N-protected amino acid esters gave N-protected α-aminoalkyl-α′-dihalomethylketones, which are useful intermediates for the synthesis of erythro β-amino-α-hydroxycarboxylic acids, in good yield. The dihalomethylketones were successfully converted to N-protected α-aminoalkyl-α′-halomethylketones by selective catalytic hydrogenation.

Full text of DOI:10.1016/S0040-4039(01)01253-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6337–6340
Dihalomethylation of N-protected phenylalanine esters
Tomoyuki Onishi, Yasuyuki Otake, Naoko Hirose, Takashi Nakano, Takayoshi Torii,
Masakazu Nakazawa and Kunisuke Izawa*
AminoScience Laboratories, Ajinomoto Co. Inc., 1-1 Suzuki-cho, Kawasaki 210-8681, Japan
Received 18 May 2001; revised 5 July 2001; accepted 13 July 2001
Abstract—Dihalomethylation of several N-protected amino acid esters gave N-protected a-aminoalkyl-a%-dihalomethylketones,
which are useful intermediates for the synthesis of erythro b-amino-a-hydroxycarboxylic acids, in good yield. The dihalomethylke-
tones were successfully converted to N-protected a-aminoalkyl-a%-halomethylketones by selective catalytic hydrogenation. © 2001
Elsevier Science Ltd. All rights reserved.
We previously described practical methods for the syn-
thesis of a-aminoalkyl-a%-chloromethylketone deriva-
tives via the chloromethylation of N-protected
3-oxazolidin-5-ones or N-imine-protected amino acid
esters.1,2 Based on our results, we concluded that during
the chloromethylation, the amino group should be pro-
tected by an appropriate N-protecting group without
leaving a hydrogen atom unprotected. As an extension
of the study, we turned our attention to the reaction of
N-protected amino acid esters with dihalomethyl-
lithium, which can be conveniently generated in situ
from dihalomethane and base.3,4 In this paper, we
report the dihalomethylation of several kinds of N-pro-
tected amino acid esters and its application to the
synthesis of N-protected a-aminoalkyl-a%-halomethyl-
ketones.
First, the reaction of dichloromethyllithium5 and N-
diphenylmethylene-protected amino acid ester 1,6,7
which has been used in studies of chloromethylation,
was investigated.8,9 Due to the slower generation of
dichloromethyllithium compared to that of chloro-
methyllithium, the addition of n-butyllithium in hexane
to a solution of ester 1 and CH2Cl2 in THF did not
give the desired dichloromethylketone (procedure B,
Table 1). However, since dichloromethyllithium is rela-
tively stable10 and can be kept in ethereal solution at
−78°C,8 the addition of ester 1 to a solution of
Table 1. Comparison between dihalomethylation and chloromethylation of compound 1
O
O
O
XCH2Cl
nBuLi
Ph
N
Ph
N
Cl
Ph
N
Cl
or
OMe
Ph
Ph
Cl
Ph
Ph
Ph
Ph
2 (X=Cl)
3 (X=Br)
1
XCH2Cl
n-BuLi
Procedure
Conditions
Yield (%)
2
3
CH2Cl2 (2.5 equiv.)
CH2Cl2 (2.5 equiv.)
2 equiv.
2 equiv.
A
B
THF–Et2O, −78°C
THF–Et2O, −78°C
96
Trace
–
–
BrCH2Cl (1.3 equiv.)
BrCH2Cl (1.3 equiv.)
1.3 equiv.
1.3 equiv.
A
B
THF, −78°C
THF, −78°C
–
–
0
Quant.
Procedure A: Ester 1 was added to a solution of dichloromethyllithium (or chloromethyllithium).
Procedure B: n-Butyllithium was added to a solution of ester 1 and dichloromethane (or bromochloromethane).
* Corresponding author. Fax: +81-44-211-7610; e-mail: kunisuke izawa@ajinomoto.com
–
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01253-9

6338
T. Onishi et al. / Tetrahedron Letters 42 (2001) 6337–6340
dichloromethyllithium in Et2O–THF successfully gave
the desired dichloromethylketone 2 in high yield11
(procedure A) and with high optical purity (98% e.e.
after hydrolysis).12 This result is in contrast to the
case of chloromethylation, since chloromethyllithium
is quite unstable and could not be stored even at
−78°C.10
The results are summarized in Table 2. Using the
same procedure as above, the addition of N-Boc-pro-
tected amino acid ester 6 to an Et2O–THF solution
of dichloromethyllithium, which was generated in situ
from CH2Cl2 and n-BuLi, directly gave N-carbamate-
protected a-aminoalkyl-a%-dichloromethylketone 7 in
54% yield without racemization (procedure A).
Abstraction of the proton of NH in the carbamate
contributes to the full retention of stereochemistry.
The yield was nicely increased to 67% when LDA
was used as a base.15 Interestingly, in the case of
N-carbamate-protected amino acid esters, the addition
of base (n-BuLi or LDA) to a solution of ester and
CH2Cl2 also gave the desired product (procedure B).
Using procedure B, dichloromethylation could be per-
formed at −20°C, which is a much higher tempera-
ture.16 Furthermore, we examined the dibromo-
methylation of ester 6. The addition of ester 6 to a
THF solution of dibromomethyllithium,17 generated
in situ from CH2Br2 and LDA, gave the desired
dibromomethylketone 8 in 46% yield.18 Compound 8
could also be obtained using procedure B. In the case
of dibromomethylation, accompanying formation of
bromomethylketone 919 was observed. Impurity 9
would be given by lithium–bromine exchange after
the addition of dibromomethyllithium to 6.20,21 The
In an attempt to obtain various N-protected a-
aminoalkyl-a%-dichloromethylketones, the dichloro-
methylation of N-benzylidene-protected amino acid
ester 413 followed by hydrolysis with hydrochloric
acid was also examined and gave unprotected a-
aminoalkyl-a%-dichloromethylketone 5 as a HCl salt in
32% yield with modest optical purity (66% e.e.)
(Scheme 1).14 The instability of compound 5 under
acidic conditions may decrease the yield. Partial
racemization is probably due to the abstraction of the
a-proton by dichloromethyllithium, which is more
basic than chloromethyllithium.
As mentioned above, compound 5 is not a stable
enough intermediate for preparation of several kinds
of N-protected a-aminoalkyl-a%-dichloromethylketones.
This prompted us to examine direct dihalomethylation
of N-carbamate-protected amino acid esters, which
are not suitable substrates for the chloromethylation.1
O
O
CH2Cl2 (2.5 eq.)
HCl aq.
THF
HCl H2N
Ph
Cl
Ph
N
OMe
nBuLi (2 eq.)
THF-Et2O, -78oC
Cl
Ph
4
5
32% (66% e.e.)
Scheme 1.
Table 2. Dihalomethylation of compound 6
O
O
O
CH2X2
BocHN
BocHN
X
BocHN
X
+
OMe
Base
Ph
X
Ph
Ph
6
7 (X=Cl)
8 (X=Br)
9 (X=Br)
CH2X2
Base
Procedure
Temp. (°C)
Reaction yield (%)
Isolated yield (%)
7
8
9
6
CH2Cl2 (4 equiv.)
CH2Cl2 (2.3 equiv.)
CH2Cl2 (4 equiv.)
CH2Cl2 (2.5 equiv.)
n-BuLi (4 equiv.)
LDA (2.3 equiv.)
n-BuLi (4 equiv.)
LDA (2.5 equiv.)
A
A
B
B
−78
−78
−78
−20
60
79
62
58
–
–
–
–
–
–
–
–
1
10
3
54
67
52
46
24
CH2Br2 (2.5 equiv.)
CH2Br2 (2.5 equiv.)
LDA (2.5 equiv.)
LDA (2.5 equiv.)
A
B
−78
−78
–
–
53
55
8
12
27
33
46
31
Procedure A: Ester 6 was added to a solution of dihalomethyllithium.
Procedure B: The base was added to a solution of ester 6 and dihalomethane.

T. Onishi et al. / Tetrahedron Letters 42 (2001) 6337–6340
Table 3. Selective catalytic hydrogenation of dihalomethylketone
6339
H2 (1 atm)
Catalyst
O
O
O
BocHN
Ph
BocHN
Ph
X
BocHN
Ph
X
+
Me
Additive
MeOH, rt
X
7 (X=Cl)
8 (X=Br)
10 (X=Cl)
9 (X=Br)
11
X
Catalyst
Additive
Time (h)
Yield (%)
Product
11
Cl
Cl
Cl
10% Pd/C
10% Pd/C
5% Pd/BaSO4
Nothing
Nothing
Et3N
1
17
3
66
Trace
64
4
0
6
Br
Br
10% Pd/C
5% Pd/BaSO4
Nothing
Et3N
2
2.5
40
71
50
6
Yield was determined by HPLC.
obtained dihalomethylketones 7 and 8 could be con-
verted to erythro b-amino-a-hydroxycarboxylic acids by
stereoselective hydrolysis, which was recently reported
by the Kaneka group (Scheme 2).22,23
verted to halomethylketones via selective catalytic
hydrogenation using Lindlar catalyst in the presence of
triethylamine.
References
Next, to obtain N-protected a-aminoalkyl-a%-
halomethylketones from dihalomethylketones, the
selective catalytic hydrogenation of N-protected a-
aminoalkyl-a%-dihalomethylketones was studied (Table
3). Hydrogenation of dichloromethylketone 7 using
10% Pd/C as a catalyst gave chloromethylketone 102 in
66% yield. However, prolonging the reaction time
caused cleavage of Boc group due to the generation of
HCl. Hydrogenation of dibromomethylketone 8 only
1. Onishi, T.; Hirose, N.; Nakano, T.; Nakazawa, M.;
Izawa, K. Tetrahedron Lett. 2001, 42, 5883.
2. Onishi, T.; Nakano, T.; Hirose, N.; Nakazawa, M.;
Izawa, K. Tetrahedron Lett. 2001, 42, 5887.
3. Koebrich, G.; Flory, K.; Drischel, W. Angew. Chem., Int.
Ed. Engl. 1964, 3, 513.
4. Taguchi, H.; Yamamoto, H.; Nozaki, H. J. Am. Chem.
a
mixture of bromomethylketone 919 and
Soc. 1974, 96, 6510.
gave
methylketone 11.24 To our delight, the selective hydro-
genation of compounds 7 and 8 proceeded nicely using
5% Pd/BaSO4 (Lindlar catalyst) in the presence of
triethylamine, which is essential for acceleration of the
reaction. Under these conditions, chloromethylketone
10 and bromomethylketone 9 were obtained in respec-
tive yields of 64 and 71% with good selectivity.25
5. Albizati, K. F. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: New
York, 1995; Vol. 3, pp. 1723–1725.
6. O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47,
2663.
7. Polt, R.; Peterson, M. A. Tetrahedron Lett. 1990, 31,
4985.
8. Bacquet, C.; Villieras, J.; Normant, J.-F.; Normant, H.
C. R. Acad. Sci. Paris Ser. C 1974, 278, 929.
9. Barluenga, J.; Baragana, B.; Alonso, A.; Concellon, J. M.
J. Chem. Soc., Chem. Commun. 1994, 969.
10. Koebrich, G.; Fischer, R. H. Tetrahedron 1968, 24, 4343.
11. A solution of dichloromethane (2.5 equiv.) in anhydrous
THF was added to a solution of n-butyllithium (2 equiv.)
in hexane–Et2O–THF at −78°C. After stirring for 10 min
at −78°C, a solution of ester 1 was added dropwise. After
stirring for 2 h at −78°C, saturated NH4Cl aqueous
solution was added. The product was extracted to give 2
as a pale yellow oil. 1H NMR (CDCl3) l 3.12 (dd, J=4.6,
13.2 Hz, 1H), 3.20 (dd, J=8.4, 13.2 Hz, 1H), 4.56 (dd,
J=4.6, 8.4 Hz, 1H), 6.52 (d, J=9.9 Hz, 2H), 6.53 (s, 1H),
6.96–7.05 (m, 2H), 7.15–7.47 (m, 9H), 7.61 (d, J=9.1 Hz,
2H).
In conclusion, the dihalomethylation of several N-pro-
tected amino acid esters was investigated. In contrast to
chloromethylation, direct dihalomethylation of N-car-
bamate-protected amino acid esters afforded N-carba-
mate-protected a-aminoalkyl-a%-dihalomethylketones,
which are useful intermediates for the synthesis of
erythro b-amino-a-hydroxycarboxylic acids, in good
yield. The resultant dihalomethylketones could be con-
O
OH
CO2H
NaOH
BocHN
Ph
X
BocHN
Ph
H2O-toluene
60oC
X
7 (X=Cl)
8 (X=Br)
83% (68% d.e.) (X=Cl)
84% (60% d.e.) (X=Br)
12. A solution of dichloromethylketone 2 in THF was treated
with an excess of 2 mol/l HCl at rt for 1.5 h. Enantiomer
purity was determined as 98% e.e. by HPLC using a
Crownpak CR(+) column.
Scheme 2.

6340
T. Onishi et al. / Tetrahedron Letters 42 (2001) 6337–6340
13. Dondoni, A.; Perrone, D. Tetrahedron Lett. 1992, 33,
7259.
THF was added to a solution of lithium diisopropyl-
amide (2.5 equiv.) in heptane–ethylbenzene–THF at
−78°C. After stirring for 10 min at −78°C, a solution of
ester 6 was added dropwise. After stirring for 1 h at
−78°C, 1 mol/l HCl was added. The product was
extracted and purified by crystallization from ethyl ace-
tate to give 8 as a white solid. The reaction yield was
determined by HPLC using an Inertsil ODS-2 column.
14. A solution of dichloromethane (2.5 equiv.) in anhydrous
THF was added to a solution of n-butyllithium in hex-
ane–Et2O–THF at −78°C. After stirring for 10 min at
−78°C, a solution of ester 4 was added dropwise. After
stirring for 2 h at −78°C, an excess of 2 mol/l HCl aq.
was added. Yield was determined by HPLC using an
Inertsil ODS-2 column. Enantiomer purity was deter-
mined by HPLC using a Crownpak CR(+) column.
15. A solution of dichloromethane (2.3 equiv.) in anhydrous
THF was added to a solution of lithium diisopropyl-
amide (2.3 equiv.) in heptane–ethylbenzene–THF at
−78°C. After stirring for 10 min at −78°C, a solution of
ester 6 was added dropwise (procedure A). After stirring
for 1 h at −78°C, 1 mol/l HCl was added. The product
was extracted and purified by crystallization from ethyl
acetate to give 7 as a white solid. The reaction yield was
determined by HPLC using an Inertsil ODS-2 column.
Enantiomer purity was determined by HPLC using a
Chiralcel OD-H column. [h]2D0=−52.7° (c 2.25, CH2Cl2);
1H NMR (CDCl3) l 1.40 (s, 9H), 3.01 (dd, J=7.9, 13.8
Hz, 1H), 3.22 (dd, J=5.7, 13.8 Hz, 1H), 4.62–5.00 (m,
2H), 6.08 (s, 1H), 7.17–7.22 (m, 2H), 7.22–7.36 (m, 3H).
16. A solution of ester 6 and dichloromethane (2.5 equiv.) in
anhydrous THF was cooled to −20°C, and lithium diiso-
propylamide (2.5 equiv.) in heptane–ethylbenzene–THF
was added dropwise (procedure B). After stirring for 1 h
at −20°C, 2 mol/l HCl was added.
1
[h]2D0=−40.6° (c 2.0, CH2Cl2); H NMR (CDCl3) l 1.41
(s, 9H), 3.04 (dd, J=7.3, 13.8 Hz, 1H), 3.20 (dd, J=6.2,
13.8 Hz, 1H), 4.64–5.05 (m, 2H), 6.00 (s, 1H), 7.17–7.37
(m, 5H).
19. Raddaz, P.; Jonczyk, A.; Minck, K.-O.; Schmitges, C. J.;
Sombroek, J. J. Med. Chem. 1991, 34, 3267.
20. Kowalski, C. J.; Haque, M. S. J. Org. Chem. 1985, 50,
5140.
21. Chen, P.; Cheng, P. T. W.; Spergel, S. H.; Zahler, R.;
Wang, X.; Thottathil, J.; Barrish, J. C.; Polniaszek, R. P.
Tetrahedron Lett. 1997, 38, 3175.
22. Matsumoto, S.; Matsuo, K.; Sugawa, T.; Moroshima, T.;
Inoue, K. US Patent 6,020,518, 2000.
23. Matsumoto, S.; Matsuo, K.; Moroshima, T.; Sugawa, T.;
Inoue, K.; Takahashi, S. The 74th Spring Annual Meet-
ing of The Chemical Society of Japan 1998, 1, D5, 44,
962. Similar results were obtained in our experiments.
24. Kawai, M.; Boparai, A. S.; Bernatowicz, M. S.; Rich, D.
H. J. Org. Chem. 1983, 48, 1876.
25. A catalytic amount of 5% Pd/BaSO4 was added to a
mixture of dihalomethylketone 7 (or 8) and triethylamine.
After stirring for 3 h under a H2 atmosphere, insoluble
material was filtered off. The reaction yield was deter-
mined by HPLC using an Inertsil ODS-2 column.
17. Albizati, K. F. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: New
York, 1995; Vol. 3, pp. 1569–1573.
18. A solution of dibromomethane (2.3 equiv.) in anhydrous
.