An efficient process for the bromolactamization of unsaturated acids

Article abstract of DOI:10.1016/j.tetlet.2007.08.113

Bromolactamization of the N-Boc derivatives of unsaturated amides using N-bromosuccinimide and lithium t-butoxide in tetrahydrofuran occurs smoothly to give excellent yields of bromo N-Boc α-lactams, which are valuable as synthetic intermediates.

Full text of DOI:10.1016/j.tetlet.2007.08.113

Tetrahedron Letters 48 (2007) 7567–7570
An efficient process for the bromolactamization of unsaturated acids
Ying-Yeung Yeung and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, United States
Received 22 August 2007; revised 29 August 2007; accepted 30 August 2007
Available online 5 September 2007
Abstract—Bromolactamization of the N-Boc derivatives of unsaturated amides using N-bromosuccinimide and lithium t-butoxide in
tetrahydrofuran occurs smoothly to give excellent yields of bromo N-Boc a-lactams, which are valuable as synthetic intermediates.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Recently, we have reported an efficient and enantioselec-
tive synthesis of the antiflu agent oseltamivir phosphate
(Tamiflu).1 One of the key steps in that process is the
Knapp iodolactamization of amide 1 to form c-lactam
2.2,3 One drawback in that sequence for large-scale pro-
duction stems from the use of trimethylsilyl triflate
(TMSOTf), an expensive and moisture sensitive reagent.
Herein we report a different and more practical process
for lactamization.
(ClCO)2
t-BuOH
NH2
NHBoc
N
C O
O
O
O
1
5
4
BocNHLi
OMe
NHBoc
O
O
5
6
I
I
1. TMSOTf, Et3N, pentane
2. I2, Et2O/THF, 2 h, 84%
NH2
N
HN
O
O
Boc
O
Table 1. Protection of amide
3
1
2
O
O
R
1. (COCl)2, (CH2Cl)2, 70 °C, 2 h
2. t-BuOH, 40 °C
O
R
NH2
NHBoc
AcHN
Entry Substrate
Product
Time (h) Yield (%)
OEt
=
H2PO4
H3N
O
NH2
NHBoc
Tamiflu
1
1
83
O
1
O
In our synthesis of oseltamivir iodolactam 2 was trans-
formed into the N-t-butoxycarbonyl (Boc) derivative 3
which greatly facilitates the remaining six steps in
the synthesis. For this reason we investigated a more
direct route to the N-Boc protected lactam 3 and the
use of N-Boc-imides for halolactamization. Amide 1
was transformed into the corresponding isocyanate (4)
which upon reaction with t-butyl alcohol gave the N-
Boc-imide 5.4 Three examples of this process are shown
in Table 1.
5
NHBoc
2
3
NH2
2
4
78
71
O
O
7
O
O
NHBoc
NH2
*
Corresponding author. Tel.: +1 617 495 4033; fax: +1 617 495
0376; e-mail: corey@chemistry.harvard.edu
9
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.113

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Y.-Y. Yeung, E. J. Corey / Tetrahedron Letters 48 (2007) 7567–7570
Table 2.
O
O
t-BuOC(O)NH2, t-BuOLi,
THF
R
OR
Product
R
NHBoc
Entry
1
Substrate
Temperature (ꢁC)
Time (h)
8
Yield (%)
83
NHBoc
OMe
À20 to 23
O
5
O
6
2a
3a
4a
0–23
0–23
0–23
12
12
12
64
68
86
O
NHBoc
O
OCH2CF3
10
O
O
NHBoc
OCH2CF3
11
O
O
NHBoc
OCH2CF3
12
a 2 equiv t-BuOLi was used.
Alternatively, the reaction of ester 6 with the lithio
derivative of t-butylcarbamate5 provided Boc-imide 5
directly. Examples of this route are shown in Table 2.
reagent since the major product was found to be the
vicinal dibromide 14 (X = Br) (Table 3, entries 4 and
5). Iodine on the other hand did provide the trans-iodo
lactam (13, X = I). However, the best conditions were
those outlined in entry 7 which involved t-BuOLi as
the base and N-bromosuccinimide (NBS) as the bromi-
nating agent and afforded the desired bromolactam 13
(X = Br) in 94% yield. When these conditions were
applied to a number of other unsaturated N-Boc imides
the expected bromolactams were obtained in the yields
shown in Table 4. The process was highly efficient
A representative procedure for the synthesis of 5 by the
process outlined in Table 2 is given herein.6
A number of conditions were screened for the halolacta-
mization of Boc-imide 5 using the lithio derivative of the
imide and various halogenating agents. The results are
summarized in Table 3. Bromine was not a satisfactory
Table 3.
X
X
1. Base
NHBoc
NHBoc
X
2. X-Hal
BocN
O
5
O
O
13
14
Entrya
Base
X-Hal
Solvent
Temperature (ꢁC), time (h)
Yield (13, 14) (%)
1
2
3
4
5
6
7
n-BuLi
n-BuLi
n-BuLi
n-BuLi
t-BuOLi
t-BuOLi
t-BuOLi
I2
THF
THF
THF
Et2O
Et2O
THF
THF
0–23, 12
À20, 1.5
À20, 4
60b, 0
66, 15
72, 0
0, 91
0, 95
72, 27
94, 0
Br2
NBS
Br2
Br2
Br2
NBS
À20, 4
À20, 4
À20 to 0, 2
À20 to 0, 2
a For entry 1, X = I, for entries 2–8, X = Br.
b 30% starting material was recovered.

Y.-Y. Yeung, E. J. Corey / Tetrahedron Letters 48 (2007) 7567–7570
Table 4. Bromolactamization of Boc-imides
7569
Entry
Substrate
Product
Temp (ꢁC)
Time (h)
4
Yield (%)
Br
1
À20 to 0
92
NHBoc
BocN
O
O
7
16
O
O
NHBoc
9
NBoc
2
3
4
À20 to 0
À20 to 0
À20 to 23
4
4
93
84
Br
17
Br
BocN
O
NHBoc
O
10
18
O
O
NBoc
NHBoc
12
54a
Br
11
19
O
O
NBoc
NHBoc
5
À20 to 0
8
73
Br
12
20
a 39% of starting material was recovered.
Br
for the formation of c-lactams (Table 4, entries 1–3)
but somewhat less so for d-lactams (Table 4, entries 4
and 5).7
DBU, THF, reflux,
18 h, 87%
ref.1
2
BocN
BocN
O
O
The use of sodium hydride as base, as has been chosen
in the one case reported earlier,3a afforded greatly infe-
rior results for the bromolactamization of N-Boc-
imides as compared with t-BuOLi as base, in our
experience.
13
15
There are some other examples that indicate the utility
of the halolactamization process to effect asymmetric
induction. For example, diastereoselective iodolacta-
mization of chiral substrates such as 21 which contain
a chiral controller group occurs with good stereo-
control.8
Treatment of the N-Boc bromolactam 13 with 1,8-diaz-
abicycloundecene (DBU) in THF at reflux for 18 h
provided the unsaturated lactam 15 (87% yield), a key
intermediate for the synthesis of oseltamivir.1 The new
bromolactamization process described herein is both
more practical and convenient than the Knapp protocol
employed by us originally.1 The operational effective-
ness of the new method and also the route to oseltamivir
that we have developed has been substantiated by the
successful preparation of oseltamivir by Harvard junior
undergraduates in a one-semester course in intermediate
organic synthesis (under the guidance of Dr. Ahmindra
Jain).
O
H
O
O
O
N
N
O
N
H
N
O
H
H
H
I
Me
22
Me
21
Et
Et

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Y.-Y. Yeung, E. J. Corey / Tetrahedron Letters 48 (2007) 7567–7570
combined organic extracts were washed with brine (3 mL),
References and notes
dried (MgSO4), filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography (n-
hexane–EtOAc, 5:1) to give the desired Boc-imide 5 (84 mg,
75%) as a colorless solid.
1. Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc.
2006, 128, 6310.
2. Knapp, S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006.
3. For some other applications of halolactamization, see: (a)
Boeckman, R. K., Jr.; Connell, B. T. J. Am. Chem. Soc.
1995, 117, 12368; (b) Fujita, M.; Kitagawa, O.; Suzuki, T.;
Taguchi, T. J. Org. Chem. 1997, 62, 7330; Review on lactam
formation: (c) Robin, S.; Rousseau, G. Tetrahedron 1998,
54, 13681–13736.
7. Representative procedure for the preparation of 4-bromo-7-
oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl
ester (13): To a solution of Boc-imide 5 (0.25 mmol) in
THF (1.5 mL) was added dropwise a solution of t-BuOLi
(1.0 M in THF, 0.25 mL, 0.25 mmol) at À20 ꢁC over
10 min. After stirring for an additional 20 min, the solution
was shielded from light and NBS (52 mg, 0.27 mmol) in
THF (0.5 mL) was added dropwise over 30 min. The
resulting solution was allowed to warm to 0 ꢁC. After 2 h
at 0 ꢁC, the reaction mixture was treated with saturated
NaHSO3 (1 mL). The organic layer was separated and the
aqueous layer was extracted with Et2O (3 · 3 mL). The
combined organic extracts were washed with water (1 mL),
dried (MgSO4), filtered, and concentrated and in vacuo.
The residue was purified by flash column chromatography
(n-hexane–EtOAc, 5:1) to give the desired lactam 13 (72 mg,
94%) as a colorless solid.
´
´
´
4. Martın, A.; Perez-Martin, I.; Suarez, E. Org. Lett. 2005, 7,
2027.
5. Love, B.; Kormendy, M. F. J. Org. Chem. 1963, 28,
3421.
6. Procedure for the preparation of N-boc-imide 5: To a
solution of ester 6 (70 mg, 0.5 mmol) and tert-butylcarba-
mate (59 mg, 0.5 mmol) in THF (2 mL) was added t-BuOLi
(1.0 M in THF, 1.0 mL, 1.0 mmol) at À20 ꢁC over 30 min.
The solution was allowed to warm to 23 ꢁC, stirred at that
temperature for 8 h, and treated with saturated aqueous
NH4Cl (3 mL). The organic layer was separated and the
aqueous layer was extracted with Et2O (3 · 5 mL). The
8. Shen, M.; Li, C. J. Org. Chem. 2004, 69, 7906–7909.