New reaction conditions using trifluoroethanol for the E-I Hofmann rearrangement

Article abstract of DOI:10.1039/a904126e

The Hofmann rearrangement of -protected glutamine esters to N²-protected (2S)-4-[(2,2,2-trifluoroethoxy)carbonyIamino]-2-aminobutyric acid esters was successfully achieved by an electrochemical method using a trifluoroethanol (TFE)-MeCN solvent system where the TFE may play an important role in controlling the basicity caused by electrochemically generated bases.

Full text of DOI:10.1039/a904126e

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New reaction conditions using trifluoroethanol for the E-I
Hofmann rearrangement
a
b
b
b
Yoshihiro Matsumura,* Yuki Satoh, Kimihiro Shirai, Osamu Onomura and
Toshihide Maki
b
a
Institute for Fundamental Research of Organic Chemistry, Kyushu University, 6-10-1
Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan. E-mail: matumura@ms.ifoc.kyushu-u.ac.jp
Faculty of Pharmaceutical Sciences, Nagasaki University, 1-14 Bunkyo-machi,
b
Nagasaki 852-8131, Japan
Received (in Cambridge) 24th May 1999, Accepted 11th June 1999
2
2
The Hofmann rearrangement of N -protected glutamine esters to N -protected (2S)-4-[(2,2,2-trifluoroethoxy)-
carbonylamino]-2-aminobutyric acid esters was successfully achieved by an electrochemical method using a
trifluoroethanol (TFE)–MeCN solvent system where the TFE may play an important role in controlling the
basicity caused by electrochemically generated bases.
2 EGB
+
H2
Introduction
Br–
EGB
H+
EGBH+
It is worthwhile to investigate new reaction conditions that
make it possible to achieve the Hofmann rearrangement (for
example, the transformation of carboxamides 1 to methyl carb-
amates 2) under non-basic conditions since the Hofmann
rearrangement is in general carried out under strongly basic
2
EGBH+
+
2e
[
Br]+
EGB EGBH+
–
2e
–
RCONH2 RCONHBr
RCON-Br
RN=C=O
5
cathode
1
1
3
4
anode
conditions, and thus is not generally applicable to substrates
MeOH
which are unstable under such basic conditions. Recently sev-
eral modified methods for the Hofmann rearrangement have
appeared which can be carried out under non-basic conditions
but all of them use more than an equimolar amount of an
RNHCO2Me
2
Fig. 1
2
expensive or hazardous oxidizing reagent. On the other hand,
we have reported an electrochemical method (the E-I Hofmann
rearrangement) which uses a catalytic amount of bromide ion
in MeOH as solvent or in a mixed solvent consisting of MeOH
Results and discussion
2
(
2S)-N -Boc-Protected glutamine methyl ester 6a is highly
3
and MeCN (Scheme 1).
unstable under basic conditions. In fact, the E-I Hofmann
rearrangement of (2S)-N -Boc-protected glutamine methyl
ester 6a in MeOH containing bromide ions resulted in the
formation of the desired product 7a in low yield (Scheme 2).
2
2e Br–
3
–
RCONH2
RNHCO2Me
MeOH / MeCN
2
1
Scheme 1
NHBoc
i
NHBoc
CO Me
NHBoc
One of the advantages of the E-I Hofmann rearrangement is
its non-basic nature since the quantity of electrochemically
generated base (EGB) is theoretically equal to the quantity
CO2Me
6a + NH
+
2
O
NH2
O
4
N
H
O
CO2Me
of protons generated in the rearrangement of 1 to 2 through
N-brominated intermediates 3, N-bromo anions 4, and iso-
6a
7a
8a
cyanates 5 as schematically represented in Fig. 1. Hence, onϩe
2.2 F mol–1
at 60˚C
at ambient temp.
0% 28% (>99.9%ee) 14%(25%ee)
equivalent of EGB plays the role of trapping the proton H
2.9 F mol–1 20% 26% (>99.9%ee) 10%(47%ee)
ϩ
removed in the reaction of 1 with anodically generated [Br]
ϩ
and the other EGB equivalent abstracts the proton H from 3
Scheme 2 Reagents and conditions: i, Et NBr, MeOH–MeCN, Pt
4
to give 4.
electrodes.
Accordingly, the reaction conditions for the E-I Hofmann
rearrangement are neutral taken as a whole throughout the
electrolysis, but a small amount of EGB may survive for a
short time. Hence, if the substrate 1 and/or the rearranged
product 2 are unstable under weakly basic conditions, the E-I
Hofmann rearrangement may result in an unsatisfactory result.
The by-product 8a might be generated by a base-catalyzed
cyclization of 6a. Furthermore, the fact that 6a was unstable
under basic conditions was shown by the reaction of 6a with
sodium methoxide in MeOH even at a low temperature for a
short time to give a mixture of recovered 6a (46%, ~100% ee),
8a (30%, 89% ee) and 9a (18%, 86% ee) which was formed

-Glutamine esters are carboxamides unstable under such con-
6
ditions, however the Hofmann rearranged products from
through 8a (Scheme 3).
5

-glutamine are important in organic synthesis.
Because of the importance of the Hofmann rearranged
products from -glutamine in organic synthesis, there have been
several attempts at the Hofmann rearrangement of -glutamine
We report herein new reaction conditions that allow us
to efficiently achieve the E-I Hofmann rearrangement of
-glutamine esters without a loss of their optical purity.
2c,7

derivatives, however it has not been possible to start from
J. Chem. Soc., Perkin Trans. 1, 1999, 2057–2060 2057

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NHBoc
+
NHBoc
The application of these new reaction conditions to other
carboxamides such as asparagine esters, which are more
unstable to base than glutamine esters, is under investigation.
i
6a
6a
+
CONH2
OMe
O
N
O
O
H
8a
Experimental
9a
4
6%
30%
(89%ee)
18%
Electrochemical reactions were carried out by using a DC
Power Supply (GP 050-2) from Takasago Seisakusho, Inc.
HPLC analyses were achieved by using an LC-10AT VP and
an SPD-10A VP from Shimadzu Seisakusho Inc. Specific
(
>99.9%ee)
(86%ee)
Scheme 3 Reagents and conditions: i, NaOMe (0.5 equiv. with respect
to 6a), MeOH, 0 ЊC, 15 min.
rotations, [α] , were measured with using a Jasco DIP-1000 and
D
Ϫ1
2
Ϫ1
1
glutamine esters. This may be due to the instability of such
esters under basic conditions as shown in Scheme 3.
are given in units of 10 deg cm g . H NMR spectra were
measured on a Varian Gemini 200 or 300 spectrometer with
TMS as an internal standard. IR spectra were obtained on a
Shimadzu FTIR-8100A. Elemental analyses were carried at the
Center for Instrumental Analysis, Nagasaki University. Mass
spectra were obtained on a JEOL JMS-DX 303 instrument.
We report herein new reaction conditions for the E-I Hofmann
2
rearrangement in which N -protected glutamine methyl esters
6
a,b can be converted to the desired carbamates 10a,b in good
yields without any loss of the optical purity. The key point in our
method was the use of 2,2,2-trifluoroethanol (TFE) as a co-
solvent. Namely, the E-I Hofmann rearrangement of 6a,b in
TFE–MeCN as solvent gave 10a,b in good yield with ~100% ee,
12
13
14
8
15
16
Since materials 6a, 6b and products 8a, 8b, 9a, 11 are
known compounds, their elemental analyses were not carried
out.
8
although a small amount of 8b was produced in the case of 6b
(
Scheme 4). The use of MeOH containing an acid such as acetic
2
N -Boc-L-Glutamine methyl ester 6a
acid instead of TFE did not afford any rearranged products.
A solution of di-tert-butyl dicarbonate in THF was added to a
solution of -glutamine (20 mmol) in 1 M sodium hydroxide by
means of an addition funnel and cooling with ice–water. After
stirring at rt for 5 h, the reaction mixture was acidified to pH
NHP
NHP
NHP
i
CO2Me
NH2
6a or 6b
+
+
NH
CO2Me
2
–3 by slow addition of 1 M KHSO , and then extracted with
4
O
O
N
H
O
CO2CH2CF3
ethyl acetate. The extract was dried over MgSO , and the sol-
4
2
vent was evaporated in vacuo to give N -Boc--glutamine. To a
6a,b
2
a; P=Boc
b; P=Cbz
8a,b
solution of N -Boc-glutamine in DMF was added K CO (24
10a,b
2
3
mmol). Methyl iodide (30 mmol) was then added to the mixture
and the resulting solution was stirred at rt for 6 h. The mixture
was extracted with ethyl acetate. The extract was dried over
2.1 F mol–1 6a 0% 8a 0%
at 60˚C
at ambient temp. 3.2 F mol–1 6a 0% 8a 0%
2.1 F mol–1 6b 0% 8b 15%
at 60˚C
10a 80% (>99.9%ee)
10a 61% (>99.9%ee)
10b 75% (>99.9%ee)
MgSO , and the solvent was evaporated in vacuo. The residue
4
was subjected to column chromatography (silica gel) with
n-hexane–ethyl acetate to give pure 6a in 60% overall yield. Mp
Scheme 4 Reagents and conditions: i, Et NBr, TFE–MeCN, Pt
4
20
electrodes.
86–89 ЊC; [α] Ϫ24.9 (c 0.99, MeOH) (uncorrected); δ (200
D
H
MHz, CDCl ) 1.45 (s, 9H), 1.80–2.03 (m, 1H), 2.21–2.39 (m,
3
The advantage of the E-I Hofmann rearrangement carried
out under the new reaction conditions was clearly demon-
strated by the fact that the reaction of 6a with bromine and
sodium methoxide (reaction conditions in the conventional
Hofmann rearrangement) or the reaction of 6a with bromine
and NaH in TFE–MeCN did not afford any of the desired
3H), 3.75 (s, 3H), 4.26–4.41 (m, 1H), 5.30 (br d, J = 8.0 Hz, 1H),
Ϫ1
5.35–5.56 (br s, 1H), 6.05–6.23 (br s, 1H); νmax (KBr)/cm 3352,
2979, 1740, 1671, 1528, 1165.
2
N -Cbz-L-Glutamine methyl ester 6b
9
A solution of Cbz-Cl in THF was added to a solution of
rearranged product 7a or 10a (Scheme 5), and the E-I

-glutamine (20 mmol) in 1 M sodium hydroxide by means of
an addition funnel and cooling with ice–water. After stirring at
rt for 5 h, the reaction mixture was acidified to pH 2–3 by slow
NHBoc
NHBoc
i
addition of 1 M KHSO , and then extracted with ethyl acetate.
4
6
a
+
+
NH
CO2Me
CO2Me
The extracts were dried over MgSO , and the solvent was evap-
4
O
OMe
2
CO2Me
orated in vacuo to give N -Cbz--glutamine. To a solution of
11
2
N -Cbz--glutamine in DMF was added K CO (24 mmol).
2
3
6a
8%
43%
7a
Methyl iodide (30 mmol) was added to the mixture and the
resulting solution was stirred at rt for 6 h. The mixture was
extracted with ethyl acetate. The extract was dried over MgSO4,
and the solvent was evaporated in vacuo. The residue was
subjected to column chromatography (silica gel) with n-hexane–
ethyl acetate to give pure 6b in 60% overall yield. Mp 135–
0%
ii
6a
+
10a
0%
0%
Scheme 5 Reagents and conditions: i, Br (2 equiv. with respect to 6a),
NaOMe (5 equiv. to 6a), MeOH, reflux temp., 30 min; ii, Br (2 equiv.
with respect to 6a), NaH (5 equiv. with respect to 6a), TFE (5 equiv.)–
MeCN, reflux temp., 30 min.
2
2
6
137 ЊC; [α]
Ϫ21.2 (c 1.02, MeOH) (uncorrected); δ (200 MHz,
2
D
H
CDCl ) 1.87–2.09 (m, 1H), 2.15–2.39 (m, 3H), 3.76 (s, 3H),
3
4
.30–4.48 (m, 1H), 5.11 (s, 1H), 5.19–5.40 (br s, 1H), 5.61 (br d,
J = 7.4 Hz, 1H), 5.70–5.97 (br s, 1H), 7.36 (s, 5H); ν (KBr)/
cm 3156, 2984, 1794, 1717, 1682, 1562, 1096.
max
Hofmann rearrangement of 6a in MeOH–MeCN as solvent
gave 7a in a low yield (Scheme 2).
Ϫ1
Thus, we have for the first time succeeded in achieving the
Hofmann rearrangement of N -protected glutamine esters 6a,b
E-I Hofmann Rearrangement: typical procedure
2
by using a TFE–MeCN solvent system. TFE may play an
important role in controlling the basicity which occurs for a
short time by EGB on (or in the vicinity of) the cathode. TFE is
A solution of 6a (1.2 mmol) and Et NBr (0.6 mmol) in MeCN
4
(6 mL) containing MeOH (6 mmol) was charged in a one-
compartment cell equipped with platinum plate anode and
cathode (1 cm × 2 cm), and a constant current (100 mA) was
10,11
known to be more acidic than MeOH.
2
058 J. Chem. Soc., Perkin Trans. 1, 1999, 2057–2060

View Article Online
passed through the cell at ambient temperature (30–40 ЊC) until
solvent was evaporated in vacuo to give a residue which con-
Ϫ1
2
.9 F mol of electricity was passed. After the removal of
tained 6a, 8a and 9a. The yields of 6a, 8a and 9a were deter-
1
MeCN, the residue was extracted with ethyl acetate. The extract
mined by integral intensity of the H NMR spectrum.
was dried over MgSO , and the solvent was evaporated in vacuo
4
to give a mixture of 7a, 8a and recovered 6a, which was sub-
jected to column chromatography (silica gel) with n-hexane–
ethyl acetate to give pure 7a, 8a and recovered 6a. The ees of 6a,
Methyl (4S)-4-tert-butoxycarbonylamino-4-carbamoylbutyr-
ate 9a. Mp 130–132 ЊC; [α]D Ϫ6.2 (c 0.44, MeOH) (uncor-
rected), 86% ee (Chiralcel OD (0.46 cm id × 75 cm), n-hexane–
22
7
a, and 8a were determined by chiral HPLC.
ethanol 6:1, detected at 210 nm, retention times (t ): (R) = 14
r
min, (S) = 15 min); δH (200 MHz, CDCl ) 1.44 (s, 9H), 1.84–
3
Methyl (2S)-2-tert-butoxycarbonylamino-4-methoxycarbonyl-
aminobutyrate 7a. Oil (Found: C, 49.5; H, 7.5; N, 9.6%; M ,
2.03 (m, 1H), 2.04–2.26 (m, 1H), 2.35–2.62 (m, 1H), 3.36–3.50
(m, 1H), 3.70 (s, 3H), 4.12–4.31 (m, 1H), 5.37–5.52 (br s, 1H),
ϩ
Ϫ1
2
2
90.1475. C H N O requires C, 49.65; H, 7.64; N, 9.65%; M,
5.79–5.98 (br s, 1H), 6.42–6.60 (br s, 1H); νmax (KBr)/cm 3056,
1
2
22
2
6
2
0
90.1477); [α] Ϫ19.3 (c 1.44, MeOH) (uncorrected), >99.9% ee
2988, 1735, 1696, 1595, 1422, 1273.
D
(
Chiralpak AS (0.46 cm id × 25 cm), n-hexane–ethanol 9:1,
detected at 210 nm, retention times (t ): (R) = 7.8 min, (S) = 8.5
Reaction of 6a with Br : typical procedure
r
2
min); δH (300 MHz, CDCl ) 1.38 (s, 9H), 1.53–1.64 (m, 1H),
3
To a solution of NaOMe (5 mmol) in MeOH (12 ml) was added
1
.92–2.05 (m, 1H), 2.93–3.04 (m, 1H), 3.36–3.50 (m, 1H), 3.60
Br (1.0 mmol) at 0 ЊC. The resulting solution was stirred at 0 ЊC
2
(
5
s, 3H), 3.67 (s, 3H), 4.23–4.38 (m, 1H), 5.13–5.28 (br s, 1H),
.36–5.49 (br s, 1H); νmax (neat)/cm 3347, 2978, 1740, 1539,
for 10 min. 6a (1 mmol) was added to the mixture and the
resulting reaction mixture was immediately refluxed for 30 min.
After the removal of MeOH, aqueous Na S O was added to
Ϫ1
1
167.
2
2
3
the residue, and the organic portion was extracted with ethyl
(
3S)-3-tert-Butoxycarbonylamino-2,6-dioxopiperidine 8a. Mp
ϩ
acetate. The extract was dried on MgSO , and the solvent was
4
1
2
(
96–200 ЊC (Found: M , 228.1135. C H N O requires M,
10 16 2 4
25
evaporated in vacuo to give a mixture of 11 and recovered 6a,
which was subjected to column chromatography (silica gel) with
n-hexane–ethyl acetate to give pure 11 and recovered 6a.
28.1109); [α] Ϫ55.5 (c 1.05, MeOH) (uncorrected), 89% ee
D
Chiralpak AS (0.46 cm id × 25 cm), n-hexane–ethanol 6:1,
detected at 210 nm, retention times (t ): (R) = 22 min, (S) = 28
r
min); δH (300 MHz, CDCl ) 1.47 (s, 9H), 1.73–1.98 (m, 1H),
2
3
Dimethyl (2S)-N -Boc-glutamate 11. δH (200 MHz, CDCl3)
2
5
3
.33–2.60 (m, 1H), 2.60–2.86 (m, 2H), 4.29–4.40 (m, 1H), 5.34–
.47 (br d, J = 5.4 Hz, 1H), 8.39–8.48 (br s, 1H); νmax (KBr)/cm
357, 3235, 1725, 1690, 1534, 1358, 1190.
1
4
.43 (s, 9H), 1.90–2.50 (m, 5H), 3.68 (s, 3H), 3.74 (s, 3H), 4.20–
.40 (m, 1H), 5.37–5.52 (m, 1H).
Ϫ1
Methyl (2S)-2-tert-butoxycarbonylamino-4-[(2,2,2-trifluoro-
Acknowledgements
One of the authors (Y. M.) is grateful for a Grant-in-Aid
for Scientific Research on Priority Areas (No. 283, “Inno-
vative Synthetic Reaction”), and Scientific Research (B)
ethoxy)carbonylamino]butyrate 10a. Mp 215–217 ЊC (Found: C,
ϩ
4
4
3.8; H, 5.8; N, 7.8%; M , 358.1356. C H F N O requires C,
1
3
21
3
2
2
6
2
3.58; H, 5.91; N, 7.82%; M, 358.1351); [α]D Ϫ22.0 (c 1.11,
MeOH) (uncorrected), >99.9% ee (Chiralpak AD (0.46 cm
id × 75 cm), n-hexane–ethanol 15:1, detected at 210 nm, reten-
(
No. 09450335) from the Ministry of Education, Science and
Culture, Japan.
tion times (t ): (R) = 11.5 min, (S) = 12.7 min); δH (200 MHz,
r
CDCl ) 1.45 (s, 9H), 1.62–1.81 (m, 1H), 2.00–2.20 (m, 1H),
3
3
.02–3.22 (m, 1H), 3.47–3.61 (m, 1H), 3.76 (s, 3H), 4.30–4.55
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Ϫ1
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4
9.1; H, 4.85; N, 7.2%; M , 392.1194. C H F N O requires C,
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19
3
2
6
1
8
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r
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3
1
2
5
H), 3.30–3.53 (m, 1H), 3.67 (s, 3H), 4.28–4.47 (m, 3H), 5.04 (s,
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8
(
3S)-3-Benzyloxycarbonylamino-2,6-dioxopiperidine 8b. [α]D
Ϫ16.0 (c 1.01, MeOH) (uncorrected), 24% ee (Chiralcel OD
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nm, retention times (t ): (S) = 26 min, (R) = 31 min); δ (200
(
r
H
MHz, CDCl ) 1.75–2.00 (m, 1H), 2.35–2.85 (m, 3H), 4.25–4.45
m, 1H), 5.14 (s, 2H), 5.70 (br d, J = 6 Hz, 1H), 7.36 (s, 5H), 8.40
3
(
(
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8
9
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NaOMe (0.5 mmol) at 0 ЊC. The resulting solution was stirred
at 0 ЊC for 15 min, and then aqueous NH Cl was added to the
mixture. After the removal of MeOH, the residue was extracted
with ethyl acetate. The extract was dried over MgSO , and the
(
Ϫ)-asparagine under basic conditions has been reported: J. S.
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4
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J. Chem. Soc., Perkin Trans. 1, 1999, 2057–2060
2059

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1
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