Radical carboazidation of alkenes: An efficient tool for the preparation of pyrrolidinone derivatives

Article abstract of DOI:10.1002/1521-3773(20020916)41:18<3460::AID-ANIE3460>3.0.CO;2-6

A one-pot intermolecular radical carboazidation of alkenes is reported. The utility of the reaction is demonstrated by the development of a three-component preparation of pyrrolidinones, pyrrolizidinones [Eq. (a)], and indolizidinones starting from benzen

Full text of DOI:10.1002/1521-3773(20020916)41:18<3460::AID-ANIE3460>3.0.CO;2-6

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Experimental Section
Radical Carboazidation of Alkenes: An
Efficient Tool for the Preparation of
Pyrrolidinone Derivatives**
The procedure for the asymmetric alder±ene reaction of 1b catalyzed by
[
4]
rhodium (2b):
.01 mmol) and (S)-BINAP (13.8 mg, 0.022 mmol) were dissolved in
freshly distilled 1,2-dichloroethane (2 mL), then freshly prepared 1b
37.2 mg, 0.2 mmol) was added to the solution at room temperature under
nitrogen. After the mixture had been stirred for 1 min, AgSbF (0.04 mmol)
2
In a dried Schlenk tube, [{Rh(cod)Cl} ] (4.9 mg,
0
Philippe Renaud,* Cyril Ollivier, and
Philippe Panchaud
(
6
was added, and the reaction was complete within 5 min. The reaction
mixture was directly subjected to column chromatography. Compound 2b
The use of free radical reactions in multistep synthesis has
steadily increased over the last years, mainly because of their
compatibility with a large number of functional groups and
their high potential for performing sequential transforma-
tions.[ Recently, we developed a novel method that allows
(
35.8 mg, 96% yield, > 99.9% ee) was obtained. The ee value was
determined by GC with chiral select 1000 at 1508C. [a]
D
¼ 23.85 (c ¼ 0.5,
1
CHCl
3
); H NMR (400 MHz, CDCl
3
): d ¼ 7.33±7.29 (m, 2H), 7.22±7.18 (m,
1H), 7.12±7.10 (m, 2H), 6.24( s, 1H), 5.70±5.65 (m, 1H), 5.2±5.16 (m, 2H),
4.77 (d, J ¼ 14.0 Hz, 1H), 4.64 (d, J ¼ 14.0 Hz, 1H), 4.15 (t, J ¼ 7.7 Hz, 1H),
.60±3.48 ppm (m, 2H); 13C NMR (90 MHz, CDCl
3 ): d ¼ 144.1, 137.6, 137.1,
128.9, 128.3, 127.1, 122.5, 118.1, 72.8, 70.7, 51.1 ppm.
1]
the efficient formation of carbon±nitrogen bonds by reaction
3
of radicals with sulfonyl azides.[
2,3]
Since sulfonyl azides
possess an electrophilic character, this azidation process is
particularly efficient with nucleophilic radicals and does not
occur with ambiphilic or electrophilic radicals. For instance,
the cyclization depicted in Scheme 1 can be performed by
Received: April 15, 2002 [Z19091]
[
[
1] a) H. M. R. Hoffmann, Angew. Chem. 1969, 81, 597; Angew. Chem. Int.
Ed. Engl. 1969, 8, 556; b) D. F. Taber, Intramolecular Diels-Alder and
Alder Ene Reactions, Springer, Berlin, 1984, p. 61 ± 94.
2] a) B. M. Trost, Acc. Chem. Res. 1990, 23, 34; b) B. M. Trost, M. J.
Krische, Synlett 1998, 1; c) B. M. Trost, Chem. Eur. J. 1998, 4, 2405;
d) B. M. Trost, D. Toste, J. Am. Chem. Soc. 2000, 122, 714; e) S. J. Sturla,
N. M. Kabalaeui, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 1976,
and reference therein; f) D. Llerena, C. Aubert, M. Malacria, Tetrahe-
dron Lett. 1996, 37, 7027; g) M. E. Kraft, A. M. Wilson, O. A. Dasse, L.
Bonaga, Y. Y. Cheung, Z. Fu, B. Shao, J. L. Scott, Tetrahedron Lett.
1
1
998, 39, 5911; h) Y. Takayama, Y. Gao, F. Sato, Angew. Chem. 1997,
09, 890 ± 892; Angew. Chem. Int. Ed. Engl. 1997, 36, 851 ± 853.
Scheme 1. Radical cyclization±azidation process. a) PhSO
Bu Sn)
(1.5 equiv), tBuON¼NOtBu (3 mol%), benzene.
2 3
N (3 equiv),
(
3
2
[
3] a) B. M. Trost, D. C. Lee, F. Rise, Tetrahedron Lett. 1989, 30, 651;
b) B. M. Trost, B. A. Czeskis, Tetrahedron Lett. 1994, 35, 211; c) A.
Goeke, M. Sawamura, R. Kuwano, Y. Ito, Angew. Chem. 1996, 108, 686;
Angew. Chem. Int. Ed. Engl. 1996, 35, 662; d) M. Hatano, M. Terada, K.
Mikami, Angew. Chem. 2001, 113, 255 ± 259; Angew. Chem. Int. Ed.
mixing all the reagents at once under relatively concentrated
conditions (0.5m substrate) without the formation of even
traces of noncyclized products.
2
001, 40, 249 ± 252.
This observation let us speculate that the reaction could
also be accomplished in intermolecular processes. Here we
report our first results on the intermolecular addition of
radicals to unactivated alkenes followed by azidation. This
reaction sequence represents a formal carboazidation of
alkenes, and it is the key process for an efficient three-
component synthesis of pyrrolidinone, pyrrolizidinone, and
indolizidinone derivatives.
[
4] a) P. Cao, B. Wang, X. Zhang, J. Am. Chem. Soc. 2000, 122, 6490 ± 6491;
b) P. Cao, X. Zhang, Angew. Chem. 2000, 112, 4270 ± 4272; Angew.
Chem. Int. Ed. 2000, 39, 4104 ± 4106.
[
[
5] Z. Zhang, H. Qian, J. Longmire, X. Zhang, J. Org. Chem. 2000, 65,
6
223 ± 6226.
6] Using [{Rh(BINAP)Cl}
2
6
] as catalyst precursor and AgSbF as additive,
the reaction of 1a yielded 2a in less than 5% conversion within 20 min
at room temperature. This was consistent with the low reactivity
observed in ref. [4b].
[
7] Compared with our earlier system, [{Rh(dppb)Cl}
2
]
and
In a first series of experiments, we tested the feasibility of
the reaction starting from terminal alkenes and different
radical precursors that are known to be efficient in radical
atom or group transfer reactions (Scheme 2, see also Ta-
ble 1).[ A one-pot procedure similar to that used for intra-
molecular reactions gave promising results: The radical
precursors are treated with phenylsulfonyl azide (3 equiv),
[
{Rh(dppbo)Cl} ] were effective catalytic precursors for the Alder±
2
[
4]
ene reaction. This clearly indicates the differences between our
previous catalyst and the new catalytic system.
4]
[
*] Prof. P. Renaud, P. Panchaud
University of Berne
Department of Chemistry and Biochemistry
Freiestrasse 3, 3000 Berne 9 (Switzerland)
Fax : (þ 41)31-631-3426
E-mail: philippe.renaud@ioc.unibe.ch
C. Ollivier
University of Fribourg
Department of Chemistry
1
700 Fribourg (Switzerland)
[
**] Part of the projected Ph.D. thesis of P. Panchaud. This work was
supported by the Swiss National Science Foundation (grant 21-
6
7106.01).
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Angew. Chem. Int. Ed. 2002, 41, No. 18

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olefins substituted at both carbon atoms give low yields in
atom transfer processes with iodoacetate derivatives.[ We
tested the reaction with dimethyl cyclohex-4-ene-1,2-dicar-
boxylate, and observed only traces of the desired azide.[
Interestingly, norbornene, a more reactive 1,2-disubstituted
alkene, reacts cleanly with ethyl iodoacetate to afford the
azide 8 in 74% yield as a 85:15 exo:endo mixture of isomers
7]
8]
Scheme 2. Reaction of terminal alkenes with various radical precursors.
a) PhSO (3 equiv), (Bu Sn)
(1.5 equiv), tBuON¼NOtBu (3±21 mol%),
benzene.
2
N
3
3
2
(
Scheme 3).
Table 1. Radical carboazidation of terminal alkenes according to Scheme 2.[a]
From a mechanistic point of view,
the reaction is expected to occur in
a stepwise manner involving car-
bon±carbon bond formation by an
atom or group transfer reaction
followed by an azidation process
(Scheme 4, path A). This mecha-
nism is supported by the detection
of the intermediate product of
iodine or dithiocarbonate transfer.
However, in the case of diethyl
bromomalonate, diethyl phenylse-
lenomalonate, and bromotrichloro-
methane, the products of bromine
and phenylselanyl transfer are not
efficiently converted into azides.[
R1
R , R
2
3
Product
Yield [%]
Entry
X
1
2
3
4
5
6
7
8
9
I
I
I
Br
EtOOCCH
EtOOCCH
EtOOCCH
EtOOCCH
EtOOCCH
EtOOCCH
2
2
2
2
2
2
C
6
H
13, H
1
2
3
1
1
4
5
6
6
6
7
79
89
77
66
70
80
75[
46
50[
76
(CH
(CH
2
)
)
5
2
3
OTBDMS, H
C
C
6
H
H
13, H
13, H
SiMe
13, H
13, H
13, H
13, H
SC(S)OEt
SC(S)OEt
I
Br
SePh
SC(S)OEt
Br
6
CH
2
3
, H
b]
(EtOOC)(Me)CH
C
C
C
C
6
H
6
H
6
H
6
H
[
c]
(COOEt)
(COOEt)
(COOEt)
2
2
2
CH
CH
CH
d]
1
1
0
1
40[
e]
Cl
3
C
(CH
2
)
5
[
a] See the Experimental Section for the reaction conditions. [b] 1:1 Mixture of diastereomers. [c] 26% of
Br transfer. [d] 34% of PhSe transfer. [e] 36% of Br transfer. TBDMS ¼ tert-butyldimethylsilyl.
2,9]
terminal olefins (2 equiv), hexabutyldistannane (1.5 equiv),
and di-tert-butylhyponitrite (DTBHN, 3±21 mol%) as initia-
tor in refluxing benzene.[ Slow addition of the benzenesul-
fonyl azide is not necessary because this electrophilic reagent
does not react with the initial ambiphilic or electrophilic
5]
radicals, such as enolate radicals and the trichloromethyl
radical.
2 3
Scheme 3. Reaction of norbornene with ethyl iodoacetate. a) PhSO N
(3 equiv), (Bu
3
Sn)
2
(1.5 equiv), tBuON¼NOtBu (6 mol%), benzene.
Reactions of 1-octene, methylenecyclohexane, and silylated
-pentene-1-ol with ethyl iodoacetate give the expected azides
R3
5
R3
1, 2, and 3 in good yields (Table 1, entries 1±3). Reactions of
R2
R1
(–R1
X
X
)
R3
R2
R1
R1
R1
ethyl bromoacetate and ethyl 2-ethoxythiocarbonylsulfanyle-
thanoate with 1-octene (entries 4, 5) furnish the azide 1 in 66
and 70% yield, respectively.[ Reaction of the same dithio-
carbonate with allyltrimethylsilane delivers the addition±azi-
dation product 4 in 80% yield (entry 6). As expected, other
enolate radicals react with similar efficiency, as demonstrated
by the reaction of ethyl 2-iodopropionate with 1-octene,
affording 5 in 75% yield (entry 7). The reaction of the
malonyl radical, generated from either diethyl bromomalo-
nate or diethyl phenylselenomalonate, with 1-octene gives the
carboazidation product 6 in only 46 or 50% yield, respectively
R2
path A
X = I, SCSOEt)
(
product of atom
transfer
6]
PhSO2N3
–PhSO2 )
path B
(X = Br, SePh)
Bu3Sn
(
(–Bu3SnX)
PhSO2N3
R3
N3
R3
R1
R1
R2
R2
(–PhSO2
R1
)
(
entries 8, 9). The products of bromine atom and phenyl-
(Bu3Sn)2
X
R1
PhSO2
Bu Sn
3
seleno group transfer were identified as the major side
products. Interestingly, when the malonyl radical is generated
from diethyl ethoxythiocarbonylsulfanylmalonate, the car-
boazidation product 6 is obtained in higher yield (76%,
entry 10). Finally, the use of bromotrichloromethane, a
reagent known to be very efficient for bromine atom transfer
reactions, was investigated. Reaction with methylenecyclo-
hexane furnishes the azide 7 in 40% yield (entry 11). In this
last example, the only identified side product was again the
product of bromine atom transfer.
(
–Bu3SnSO2Ph)
3
(–Bu SnX)
Scheme 4. Proposed mechanism for the radical carboazidation process.
Therefore, the observed azides are presumably issued from a
direct mechanism of radical addition±azidation (path B). The
rate of azidation of the intermediate radical competes with the
rate of bromine atom and phenylseleno group transfer.[
Path A contributes only marginally to the formation of the
azide due to the inefficient azidation of the intermediate
alkylbromide and selenide.
10,11]
By analogy to iodine atom transfer, we were expecting that
the radical addition±azidation process would be limited to
terminal alkenes. Indeed, Curran and co-workers showed that
The radical carboazidation of alkenes with 2-iodoesters can
be coupled with the reduction of azides to afford 3-amino
Angew. Chem. Int. Ed. 2002, 41, No. 18
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esters that spontaneously cyclize to pyrrolidinones
celite. The solvent was removed under reduced pressure, and the crude
product was purified by flash chromatography (CH Cl /MeOH).
2
2
(
Scheme 5). For example, 5-hexylpyrrolidinone (9) is pre-
pared in 67% overall yield from 1-octene and ethyl iodoace-
tate. The intermediate 3-azidoester is reduced with indium in
Received: April 24, 2002 [Z19158]
[
1] General reviews on radical reactions: Radicals in Organic Synthesis
(
Eds.: P. Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001; B. Giese,
O
Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds,
Pergamon, Oxford, 1988; D. P. Curran in Comprehensive Organic
Synthesis, Vol. 4 (Eds.: B. M. Trost, I. Fleming, M. F. Semmelhack),
Pergamon, Oxford, 1991, p. 715 and 779; W. B. Motherwell, D. Crich,
Free Radical Chain Reactions in Organic Synthesis, Academic Press,
London, 1992; J. Fossey, D. Lefort, J. Sorba, Free Radicals in Organic
Synthesis, Wiley, Chichester, 1995; C. Chatgilialoglu, P. Renaud in
General Aspects of the Chemistry of Radicals (Ed.: Z. B. Alfassi),
Wiley, Chichester, 1999, p. 501.
a,b
I
+
C6H13
nC6H13
EtO
67%
N
H
O
9
O
(
)n
a,b
Br
I
+
( )n
R
EtO
N
R
O
[2] C. Ollivier, P. Renaud, J. Am. Chem. Soc. 2001, 123, 4717.
[
3] Early examples of intermolecular radical aminations: V. F. Patel, G.
Pattenden, Tetrahedron Lett. 1987, 28, 1451; A. Ghosez, T. Gˆbel, B.
Giese, Chem. Ber. 1988, 121, 1807; A. Veit, B. Giese, Synlett 1990, 166;
D. H. R. Barton, J. Cs. Jaszberenyi, E. A. Theodorakis, J. H. Reibens-
pies, J. Am. Chem. Soc. 1993, 115, 8050; review: C. Ollivier, P. Renaud
in Radicals in Organic Synthesis, Vol. 2 (Eds.: P. Renaud, M. P. Sibi),
Wiley-VCH, Weinheim, 2001, p. 93.
1
1
1
1
0 n = 1, R = H: a) 77% b) 82%
1 n = 1, R = Me: a) 72% b) 84%*
2 n = 2, R = H: a) 74% b) 72%
3 n = 2, R = Me: a) 69% b) 83%*
*
1:1 mixture of diastereomers
Scheme 5. Two-step preparation of mono- and bicyclic lactams from
terminal alkenes. a) PhSO (3 equiv), (Bu Sn)
(1.5 equiv), tBuON¼
NOtBu (3±21 mol%), refluxing benzene. b) 1. Indium 1 equiv), NH Cl
1 equiv), refluxing EtOH. 2. Et N (5 equiv), refluxing EtOH.
2
N
3
3
2
[
4] Review: J. Byers in Radicals in Organic Synthesis, Vol. 1 (Eds.: P.
Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001, p. 72.
4
(
3
[
5] DTBHN decomposes with a half-life of 29 min at 658C to give tert-
butoxyl radicals and nitrogen. It is a stable solid that is easily prepared
from tert-butyl bromide and commercially available sodium hyponi-
trite (Aldrich): H. Kiefer, T. G. Traylor, Tetrahedron Lett. 1966, 7,
ethanol.[12] Spontaneous cyclization to 9 is observed, but it is
slow. The lactamization process can be promoted by adding
triethylamine and by heating the crude reaction mixture
under reflux. Starting from 5-bromopent-1-ene and 6-bromo-
hex-1-ene, the reduction of the azide initiates a double
cyclization leading to pyrrolizidinones 10 and 11 as well as
indolizidinones 12 and 13 (Scheme 5). It is interesting to note
that, even in the presence of primary bromides, the carboa-
zidation process with iodoesters proceeds in good yields.
In conclusion, a one-pot intermolecular radical addition±
azidation procedure has been developed. Remarkably, this
reaction is efficient with nonactivated terminal alkenes and
takes advantage of the radical atom or group transfer
processes. In order to illustrate the utility of the reaction,
the preparation of pyrrolidinones, pyrrolizidinones, and
indolizidinones starting from phenylsulfonyl azide, terminal
alkenes, and 2-iodoesters was developed. This reaction is
expected to be of great importance for the total synthesis of
alkaloids. Such applications are currently underway in our
laboratory and will be reported in due course.
6
163; G. D. Mendenhall, Tetrahedron Lett. 1983, 24, 451. For further
preparation details, see J. T. Banks, J. C. Scaiano, W. Adam, R. S.
Oestrich, J. Am. Chem. Soc. 1993, 115, 2473. The generation of
trialkylstannyl radicals by reaction of tert-butoxyl radicals with
hexaalklydistannanes has been reported and used for an ESR study
of tin radicals: J. Cooper, A. Hudson, R. A. Jackson, J. Chem. Soc.
Perkin Trans. 2 1973, 1056.
[
6] General reviews on the use of dithiocarbonates in radical reactions:
S. Z. Zard in Radicals in Organic Synthesis, Vol. 1 (Eds.: P. Renaud,
M. P. Sibi), Wiley-VCH, Weinheim, 2001, p. 90; S. Z. Zard, Angew.
Chem. 1997, 109, 724; Angew. Chem. Int. Ed. Engl. 1997, 36, 672.
7] D. P. Curran, M. H. Chen, E. Spletzer, C. M. Seong, C. T. Chang, J.
Am. Chem. Soc. 1989, 111, 8872.
[
[
8] The use of Lewis acid to promote iodine atom transfer to 1,2-
disubstituted alkenes has been reported and may offer a solution for
this reaction: C. L. Mero, N. A. Porter, J. Am. Chem. Soc. 1999, 121,
5
155.
[
9] The bromide resulting from the atom transfer process between
bromotrichloromethane and methylenecyclohexane gave the azide 12
in only 33% yield upon reaction for 10 h in refluxing benzene with
PhSO
2
N
3
(3 equiv), Bu
6
Sn
2
(1.5 equiv), and tBuONNOtBu
(
50 mol%).
[
[
[
10] For the rate of bromine atom transfers, see D. P. Curran, E. Bosch, J.
Kaplan, M. Newcomb, J. Org. Chem. 1989, 54, 1826.
11] For the rate of phenylseleno group transfers, see D. P. Curran, A. A.
Martin-Esker, S. B. Ko, M. Newcomb, J. Org. Chem. 1993, 58, 4691.
12] G. V. Reddy, G. V. Rao, D. S. Iyengar, Tetrahedron Lett. 1999, 40, 3937.
Experimental Section
Carboazidation reaction: DTBHN (5 mg, 0.03 mmol) was added every 2 h
to a solution of ethyl 2-iodoacetate (214 mg, 1.0 mmol), benzenesulfonyl
azide (550 mg, 3.0 mmol), olefin (2.0 mmol), and Bu
.5 mmol) in dry benzene (2.0 mL) at reflux under N . The reaction was
monitored by thin-layer chromatography. Upon completion of the reaction
4±12 h), the solvent was removed under reduced pressure and the crude
product was filtered through silica gel. Elution with hexane allowed the
removal of unchanged Bu Sn , and then elution with hexane/Et O gave a
crude product that was purified by flash chromatography (hexane/Et O).
Reductive lactamization: Indium powder (230 mg, 2.0 mmol) and NH Cl
107 mg, 2.0 mmol) were added to a solution of the azide (2.0 mmol) in dry
ethanol (6.0 mL). The reaction mixture was stirred under reflux for 2 h.
Then Et N (1.4 mL, 10.0 mmol) was added, and the reaction mixture was
6 2
Sn (0.76 mL,
1
2
(
6
2
2
2
4
(
3
stirred under reflux for 4 h. The cooled reaction mixture was diluted with
EtOAc (10 mL), stirred for 10 min, and filtered through a short pad of
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