Facile generation and synthetic utility of nitrogen-centered aziridinyl radicals

Article abstract of DOI:10.1055/s-2007-990960

Nitrogen-centered aziridinyl radicals can be generated through homolysis of N-haloaziridines, which can be easily produced upon treatment of NH aziridines with N-bromo- or N-iodosuccinimide. This methodology allows synthesis of a variety of β-haloaziridin

Full text of DOI:10.1055/s-2007-990960

2912
LETTER
Facile Generation and Synthetic Utility of Nitrogen-Centered Aziridinyl
Radicals
N
itrogen-Centered
i
A
zirid
a
inyl Radica
o
ls yang Yang, Andrei K. Yudin*
Department of Chemistry, The University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada
Fax +1(416)9467676; E-mail: ayudin@chem.utoronto.ca
Received 25 May 2007
cations of functionalized aziridines has led to an investi-
gation of the utility of nitrogen-centered aziridinyl
radicals in the synthesis of heterocyclic derivatives.
Abstract: Nitrogen-centered aziridinyl radicals can be generated
through homolysis of N-haloaziridines, which can be easily pro-
duced upon treatment of NH aziridines with N-bromo- or N-iodo-
succinimide. This methodology allows synthesis of a variety of
b-haloaziridines in moderate to good yields. Further transformation
into piperazine scaffolds can be achieved via nucleophilic substitu-
tion at the b-position and aziridine ring opening initiated by oxalyl
chloride.
In the course of our study, we have found that methyl azir-
idine-2-carboxylate, when treated with styrene in the pres-
ence of N-bromosuccinimide (NBS), did not furnish the
expected primary bromide product 1, affording instead the
unexpected anti-Markovnikov product 2 (Scheme 1).
Key words: N-aziridinyl radicals, b-haloaziridines, nucleophilic
substitution, aziridine ring opening, piperazine synthesis
Table 1 Optimization of Haloamination of Styrene with Aziridine
Carboxylate 2a
Aziridines are valuable three-membered-ring systems in
modern synthetic chemistry.1 Based on their ring strain,
various manipulations of aziridine-containing com-
pounds, including nucleophilic ring opening2 and cy-
cloaddition,3 have been extensively explored. The use of
aziridines as highly versatile and readily available radical
precursors has received an increased attention over the
past few years.4
Entry Halogen Solvent
source
Temp
Additive Yield
(%)
1
2
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NIS
CH2Cl2
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
–
20
15
trace
10
12
8
–
3
hexane
toluene
DME
–
4
–
Either carbon- or nitrogen-centered radicals can be gener-
ated from aziridines. The carbon-centered aziridinyl radi-
cals were first reported by Yamanaka et al. in the 1970s,5
but the synthetic applications of these species were not de-
veloped until Ziegler reported an intramolecular radical
cyclization of chiral aziridinyl radicals onto indole rings
in 1994.6 Later, this method was successfully utilized in
the synthesis of FR-900482, a mitomycin-like antitumor
agent.7
5
–
6
DCE
–
7
DME–H2O (4:1) r.t.
–
–
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
r.t.
–
–
9
r.t.
–
40
50
80
90
10
NIS
0 °C to r.t.
0 °C to r.t
0 °C to r.t
–
Although much effort has been devoted to carbon-cen-
tered aziridinyl radicals, nitrogen-centered aziridinyl rad- 11
NBS
4 Å MS
4 Å MS
icals have not been extensively studied. The basic
physical and chemical properties of the nitrogen-centered
12
NIS
aziridinyl radicals were examined in the 1970s by the a All reactions were carried out with 1 equiv of aziridine carboxylate
Danen and Ingold groups.8 Our interest in synthetic appli-
(0.2 M), 1 equiv of styrene, and 1.2 equiv of NXS for 12 h.
COOMe
Br
N
NBS
H
N
NBS
N
COOMe
Br
+
COOMe
2
1
anti-Markovnikov product
not observed
Scheme 1 NBS-promoted haloamination of styrene with aziridine
SYNLETT 2007, No. 18, pp 2912–2918
x
x
.x
x
.2
0
0
7
Advanced online publication: 19.10.2007
DOI: 10.1055/s-2007-990960; Art ID: S04007ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Nitrogen-Centered Aziridinyl Radicals
2913
Encouraged by this result, a systematic study was under- A radical, rather than cationic, mechanism appears to op-
taken to optimize the reaction conditions. Different sol- erate in this process. Homolysis of the N–X bond of the
vents, halogen sources, reaction temperatures, and intermediate 10, which can be isolated from the reaction
additives were investigated in order to obtain the optimal system after stirring the NXS reagent with an aziridine in
condition for the anti-Markovnikov product 2. The results dichloromethane for five minutes, leads to the nitrogen-
are summarized in Table 1. Dichloromethane is superior centered radical 11. Compound 11 then attacks the double
to other solvent systems, such as THF, hexane, toluene, bond of the olefin. The resulting intermediate 12 gives rise
DME, DCE, and DME–H2O. Better yields were achieved to anti-Markovnikov product 13 (Scheme 2).
by lowering the reaction temperature to 0 °C and using
4 Å molecular sieves. N-Iodosuccinimide (NIS) was the
Interestingly, a reversal in regioselectivity was observed
in entry 5. This is attributed to a competition between the
superior reagent for the reaction, although NBS also af-
cationic and radical pathways. The olefins with functional
forded good yields. We applied the optimized protocol to
groups that destabilize the carbocationic intermediates
various styrenes, and the results are shown in Table 2.9
more than the corresponding radicals are likely to afford
Table 2 NXS-Facilitated Haloamination of Olefins with Aziridinesa
Entry
1
Aziridine
Olefin
NXS
NBS
Product
Yield (%, dr)
Br
H
N
N
N
N
80
(1:1)
COOMe
COOMe
COOMe
COOMe
2
3
I
H
N
90
(1:1)
2
3
4
NIS
NIS
NIS
COOMe
COOMe
COOMe
I
H
N
96
(1:1)
Br
Br
4
5
I
H
N
N
80
(1:1)
COOMe
COOMe
I
N
H
N
53
(1:1)
5
NIS
COOMe
MeO
MeO
6
I
N
H
N
60
(1:1)
COOMe
6
7
8
NIS
NIS
NIS
O2N
COOMe
COOMe
COOMe
O2N
7
I
H
N
N
65
(1:1)
COOMe
COOMe
NC
NC
8
I
H
N
N
70
(1:1)
Cl
Cl
9
a All reactions were carried out using 1 equiv of aziridine (0.2 M), 1 equiv of olefin, 1.2 equiv of NXS, and 4 Å MS in anhyd CH2Cl2 for 12 h.
Synlett 2007, No. 18, 2912–2918 © Thieme Stuttgart · New York

2914
X. Yang, A. K. Yudin
LETTER
X
N
NXS
H
N
homolysis
N
COOMe
COOMe
COOMe
11
10
X
X
N
N
COOMe
COOMe
13
anti-Markovnikov product
12
Scheme 2 Proposed mechanism of NXS-facilitated haloamination of olefin with aziridine
free-radical adducts, while olefins with the functional product was obtained. The difference in reactivity be-
groups, which stabilize the carbocationic intermediates, tween aziridine and piperidine lies in the different stability
give the product with reversed selectivity. When it comes of the corresponding N-halo species. When treated with
to aliphatic alkenes, neither the cationic pathway nor NXS, piperidine can readily eliminate HX to form an
radical pathway appears to be strongly favored, leading to unstable imine, while aziridine is reluctant to go through
a mixture of both free-radical and cationic products.
this process due to the kinetic barrier for the formation of
a highly strained azirine species. The long lifetime of the
N-haloaziridine intermediate facilitates homolysis and
subsequent attack on the olefin (Scheme 3).
To verify the predominant radical pathway, we carried out
the reaction in the presence of galvinoxyl, a well-known
radical scavenger used in exploring reactions with N-chlo-
rosuccinimide.10 No product was detected after 12 To further evaluate reactivity of the radical adducts, we
hours.11 The effect of light was also investigated. It was subjected them to treatment with different nucleophiles
found that the reaction proceeded smoothly in the dark, including alcohols, amines, thiols, and salts. The results
giving rise to anti-Markovnikov product.
are shown in Table 3.12
Furthermore, in order to compare the reactivity of aziri-
dines with other secondary amines, piperidine was sub-
jected to the reaction. After 12 hours, no olefin addition
Table 3 Nucleophilic Substitution of b-Haloaziridinesa
Entry b-Haloaziridine
Nucleophile
Additive Product
Yield (%, dr)
N3
Br
I
80
(1:1)
N
N
1
2
NaN3
–
14
COOMe
COOMe
COOMe
COOMe
Br
I
N
75
(1:3)
HN
–
15
H2N
N
Br
Br
I
I
NH2
N
N
3
4
–
–
unisolable products
–
COOMe
NHBn
N
78
(1:1)
NH2
16
17
COOMe
COOMe
I
HN
55
(1:1)
N
N
5
–
COOMe
H2N
COOMe
NC
NC
Synlett 2007, No. 18, 2912–2918 © Thieme Stuttgart · New York

LETTER
Nitrogen-Centered Aziridinyl Radicals
2915
Table 3 Nucleophilic Substitution of b-Haloaziridinesa (continued)
Entry b-Haloaziridine
Nucleophile
Additive Product
Yield (%, dr)
I
O
N
N
O
COOMe
50
(1:1)
6
–
18
NC
N
N
H
COOMe
NC
I
NHBn
70
(1:1)
NH2
N
N
7
8
–
–
–
–
19
20
COOMe
COOMe
I
N
N
N
N
N
NaOAc
80
–
COOMe
COOMe
COOMe
COOMe
COOMe
I
SH
9
unisolable products
no reaction
I
I
10
11b
–
HO
OMe
N
30
(5:1)
MeOH
AgNO3 21
AgNO3 22
COOMe
COOMe
Br
Br
I
ONO2
N
OH
40
(4:1)
12b
13b
N
N
COOMe
COOMe
Br
Br
I
36
(1:1)
O
AgOTf 23
HO
N
Br
I
COOMe
COOMe
Br
OH
N
COOMe
COOMe
20
(1:1)
O
14b
15b
AgOTf 24
N
Br
I
OH
N
AgOTf
no product isolated
–
a Unless noted, reactions were carried out with 1 equiv of b-haloaziridine (0.05 M) and 10 equiv of nucleophile in DMF at r.t. for 12 h.
b Reactions were carried out with 1 equiv of b-haloaziridine, 1.0 equiv of alcohol, 1.2 equiv of K2CO3, and 1.0 equiv of Ag salt in anhyd CH2Cl2
at r.t. for 30 min.
The substitution product was detected for entry 3. How- the starting b-haloaziridine was completely consumed af-
ever, when the reaction mixture was subjected to column ter three hours, however, intractable product was formed.
chromatography, the product decomposed. For entry 8, The crude NMR of the reaction mixture showed that the
the elimination pathway dominated the reaction, since that aziridine ring was opened, which indicates that the start-
the acetate anion is still a good leaving group. For entry 9, ing material also underwent ring-opening process under
Synlett 2007, No. 18, 2912–2918 © Thieme Stuttgart · New York

2916
X. Yang, A. K. Yudin
LETTER
R
NXS
I
– HX
N
H
N
X
N
N
AgX
X
c
COOMe
a
R
N
d
b
X
COOMe
H
N
NXS
N
N
25
×
– HX
X = NO3 or OTf
azirine
Scheme 4 The formation of aziridineaziridinium ion
Scheme 3 Different reactivity between piperidine and aziridine
atives of biological importance starting from these func-
tionalized building blocks.
the reaction condition. For entry 10, the nucleophilicity of
allyl alcohol was too low to react with the b-iodoaziridine.
After stirring at room temperature for 12 hours, no reac-
tion was detected and the starting material was recovered.
It has been reported that the aziridine ring opening can be
initiated by the acylation of aziridine nitrogen to produce
an activated aziridinium species. Acetyl chloride,15 phos-
gene,16 and methyl chloroformate17 have been investigat-
ed in this chemistry. We envisioned a route to compound
26, which contains a piperazine core similar to selective
brain serotonin (5HT2A) antagonists (Scheme 5).18
Silver salts were explored as additives. The substitution
product was afforded when b-iodoaziridine was treated
with 1.0 equivalent of silver nitrate in methanol. How-
ever, when we changed the nucleophile to 3-phenylprop-
2-yn-1-ol and decreased its amount to 10 equivalents, the
benzylic position was attacked by the nitrate anion, rather
than the alcohol (entry 12, Table 3). To avoid the compe-
tition between the alcohol and the counterion of the silver
salt, silver triflate was employed. Although substitution
products were obtained, none of the isolated yields were
satisfactory, ranging from 20% to 40%. For propargyl
alcohol, no product was isolated, although the starting
aziridine was completely consumed (Table 3, entry 15).
The reaction of oxalyl chloride with aziridine 19 provided
a mixture of the piperazine product 29 through the aziri-
dinium intermediate 27 and recovered starting material
19. The recovered starting material might have been
formed upon basic workup of the quaternary ammonium
salt 28 which originated from the ring opening of aziridine
by in situ generated HCl (Scheme 6). We varied bases,
reaction solvents, and reaction temperature to obtain the
optimal conditions for the piperazine product. It was
found that treatment of aziridine 19 with 2.0 equivalents
of K2CO3 and 2.2 equivalents of oxalyl chloride in aceto-
nitrile at 60 °C provided the best result (Table 4).
In the absence of nucleophiles, once silver triflate was
added to the reaction system, silver iodide precipitate
formed almost immediately. We suspect that the aziri-
dineaziridinium intermediate 25 (azoniaspiro[2.2]pentane
cation), has been formed (Scheme 4). The latter can
conceivably lead to a number of products in subsequent
reactions.
Table 4 Optimization of Aziridine Ring Opening Initiated by
Oxalyl Chloride
Entry
Base
K2CO3
K2CO3
K2CO3
Et3N
NaH
Solvent
MeCN
MeCN
MeCN
CH2Cl2
THF
Temp
r.t.
Yield (%)
The existence of aziridineaziridinium ions have been pos-
tulated to account for some experimental observations in
analytical studies.13 According to the computational re-
sults,14 aziridineaziridinium ions possess ring strain simi-
lar to that of a protonated aziridine, and are prone to ring-
opening process from either side.
1
2
3
4
5
6
60
95
80
65
90
10
60 °C
80 °C
r.t.
Based on our NXS-promoted coupling reaction and the
protocol for substitution of primary amines, a variety of
functionalized aziridines have been synthesized. We then
proceeded to investigate the synthesis of piperazine deriv-
r.t.
–
MeCN
60 °C
R2
R2
N
R1
R1
O
O
N
O
O
NHR2
reduction
Cl
Cl
N
N
N
COOMe
R1
Cl
COOMe
HO
O
R2
O
N
Cl
26
N
R1
COOMe
Scheme 5 Synthesis of piperazine derivatives
Synlett 2007, No. 18, 2912–2918 © Thieme Stuttgart · New York

LETTER
Nitrogen-Centered Aziridinyl Radicals
2917
Cl
Bn
N
O
O
O
O
MeOOC
NH2+Cl–
NHBn
N
base
Cl
Cl
+
19
COOMe
N
Bn
N
Cl
H2+Cl–
19
COOMe
28
O
29
R2
O
N
N
COOMe
27
Scheme 6 Aziridine ring opening initiated by oxalyl chloride
(5) Yamanaka, H.; Kikui, J.; Teramura, K. J. Org. Chem. 1976,
41, 3794.
(6) Ziegler, F. E.; Belema, M. J. Org. Chem. 1994, 59, 7962.
(7) (a) Ziegler, F. E.; Berlin, M. Y. Tetrahedron Lett. 1998, 39,
2455. (b) Ziegler, F. E.; Belema, M. J. Org. Chem. 1997, 62,
1083.
The diketopiperazine product 29 was subsequently
reduced by LiAlH4 or BH3·SMe2 in 40% and 20% yields,
respectively.19 Further transformation was easily achieved
by hydrogenation followed by alkylation or acylation at
nitrogen (Scheme 7).
(8) (a) Maeda, Y.; Ingold, K. U. J. Am. Chem. Soc. 1979, 101,
837. (b) Danen, W. C.; Kensler, T. T. Tetrahedron Lett.
1971, 25, 2247.
(9) Typical Procedure for the NXS-Facilitated N-Aziridinyl
Radical Reaction with Olefins
Bn
Bn
N
N
O
N
In a flame-dried Schlenk flask, equipped with septum,
magnetic stir bar, and nitrogen inlet, were placed NIS (235
mg, 1.33 mmol), powdered 4 Å MS (200 mg), anhyd CH2Cl2
(10 mL) under nitrogen atmosphere at 0 °C. After 10 min,
aziridine-2-carboxylate methyl ester (100 mL, 1.11 mmol)
was added via syringe. After 30 min, when TLC showed no
aziridine remaining, 2-bromostyrene (138 mL, 1.11 mmol)
was added via syringe. The reaction mixture was allowed to
warm up to r.t. and stirred for 8 h. When TLC showed no
methyl 1-iodoaziridine-2-carboxylate remaining, the
reaction mixture was filtered and concentrated in vacuo, the
residue oil was subjected to chromatography on silica gel,
eluted with hexane–EtOAc (60:40), to give the product as
light yellow oil.
N
O
COOMe
Cl
29
HO
30
Scheme 7 Reduction of diketopiperazine. Reagents and conditions:
a) LiAlH4 (12 equiv), THF, 60 °C, 40%; b) BH3·SMe2 (9 equiv), THF,
70 °C, 20%.
In conclusion, a synthetic potential of nitrogen-centered
aziridinyl radicals has been evaluated. Nitrogen-centered
aziridinyl radicals can be generated upon treatment of
aziridines with readily available reagents such as N-bro-
mosuccinimide and N-iodosuccinimide. This approach
was successfully applied to the synthesis of a series of
b-haloaziridines in moderate to high yields. The function-
alization of the b-haloaziridines was achieved by nucleo-
philic attack of a variety of nucleophiles at the b-position.
Further transformation of the substitution products to pip-
erazine derivatives has been reported.
Methyl 1-[2-(2-Bromophenyl)-2-iodoethyl]aziridine-2-
carboxylate (4)
Yield 96%. First diastereomer: 1H NMR (400 MHz, CDCl3):
d = 7.58–7.56 (m, 1 H), 7.51–7.49 (m, 1 H), 7.33–7.29 (m, 1
H), 7.13–7.09 (m, 1 H), 5.77–5.74 (t, J = 6.8 Hz, 1 H), 3.68
(s, 3 H), 3.18–3.13 (m, 1 H), 2.91–2.86 (m, 1 H), 2.31–2.30
(d, J = 3.2 Hz, 1 H), 2.03–2.00 (m, 1 H), 1.86–1.84 (d,
J = 6.8 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 170.7,
140.7, 133.5, 130.1, 129.7, 128.4, 122.9, 77.6, 77.2, 76.9,
67.7, 52.4, 37.3, 34.5, 27.5. Second diastereomer: 1H NMR
(400 MHz, CDCl3): d = 7.59–7.57 (m, 1 H), 7.51–7.49 (m, 1
H), 7.32–7.28 (m, 1 H), 7.12–7.08 (m, 1 H), 5.76–5.72 (t,
J = 7.2 Hz, 1 H), 3.72 (s, 3 H), 3.19–3.14 (m, 1 H), 2.91–2.86
(m, 1 H), 2.34–2.32 (m, 1 H), 2.34–2.31 (m, 1 H), 2.20–2.19
(d, J = 2.8 Hz, 1 H), 1.67–1.66 (d, J = 6.4 Hz, 1 H). 13C NMR
(100 MHz, CDCl3): d = 170.8, 140.7, 133.4, 130.1, 130.0,
128.4, 122.9, 67.7, 52.5, 38.3, 33.8, 27.5.
Acknowledgment
We thank NSERC, CFI, ORDCF, and Amgen for financial support.
References and Notes
(10) (a) Hirashita, T.; Tanaka, J.; Hayashi, A.; Araki, S.
Tetrahedron Lett. 2005, 46, 289. (b) Albeniz, A. C.;
Espinet, P.; Lopez-Fernandez, R.; Sen, A. J. Am. Chem. Soc.
2002, 124, 11278. (c) Matyjaszewski, K. Macromolecules
1998, 31, 4710. (d) Digiacomo, P. M.; Kuivila, H. G. J.
Organomet. Chem. 1973, 63, 251.
(1) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K.,
Ed.; John Wiley and Sons: New York, 2006.
(2) Hu, X. E. Tetrahedron 2004, 60, 2701.
(3) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765.
(4) For recent reviews, see: (a) Gansäuer, A.; Lauterbach, T.;
Narayan, S. Angew. Chem. Int. Ed. 2003, 42, 5556. (b) Li,
J. J. Tetrahedron 2001, 57, 1.
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2918
X. Yang, A. K. Yudin
LETTER
(11) In a flame-dried Schlenk flask, equipped with septum,
magnetic stir bar, and nitrogen inlet, were placed NIS (1.2
equiv), powdered 4 Å MS (180 mg/mol aziridine), anhyd
CH2Cl2 (0.11 mmol/mL) under nitrogen atmosphere at 0 °C.
Aziridine-2-carboxylate methyl ester (1.0 equiv) was added
via syringe. After 30 min, when TLC showed no aziridine
remaining, galvinoxyl (1.0 equiv) was added, followed by
the addition of styrene. The reaction mixture was allowed to
warm up to r.t. and stirred for 8 h. A control experiment was
set up at the same time to compare the effect of the radical
trap. After 8 h, the control experiment in the absence of
galvinoxyl proceeded smoothly and the anti-Markovnikov
product was afforded, while no desired product was formed
in the presence of galvinoxyl.
(13) (a) Audier, L.; Azzaro, M.; Cambon, A.; Guedj, R. Bull. Soc.
Chim. Fr. 1968, 1013. (b) Audier, L.; Azzaro, M.; Cambon,
A.; Guedj, R. Bull. Soc. Chim. Fr. 1968, 1021.
(14) Martinez, A.; Elguero, J.; Mo, O.; Yanez, M. J. Mol. Struct.
(Theochem) 1994, 309, 45.
(15) Lee, K.-D.; Suh, J.-M.; Park, J.-H.; Ha, H.-J.; Choi, H. G.;
Park, S. P.; Chang, J. W.; Lee, W. K.; Dong, Y.; Yun, H.
Tetrahedron 2001, 57, 8267.
(16) Park, C. S.; Kim, M. S.; Sim, T. B.; Pyun, D. K.; Lee, C. H.;
Choi, D.; Lee, W. K. J. Org. Chem. 2003, 68, 43.
(17) Sim, T. B.; Kang, S. H.; Lee, K. S.; Lee, W. K. J. Org. Chem.
2003, 68, 104.
(18) Fink, D. M.; Smith, H. K. Aventis Pharma Inc. (USA)
WO2006086705, 2006.
(12) Typical Procedure for the Nucleophilic Substitution of
b-Haloaziridines with Amines
(19) Procedure for the Synthesis of 30
In a 5 mL Schlenk tube, equipped with septum and magnetic
stir bar, were placed 19 (0.1 mmol), K2CO3 (0.22 mmol), and
anhyd MeCN (1 mL). Oxalyl chloride was added via syringe
and the solution was stirred at 60 °C for 2 h. When TLC
showed no starting material remaining, the solution was
filtered and the filtrated was washed with H2O. The organic
layer was dried over anhyd Na2SO4 and filtered. The filtrated
was concentrated in vacuo and the light brown residue was
directly used in the next step without purification.
Reduction with LiAlH4
To a mixture of 4 (50 mg, 0.122 mmol) and DMF (2.5 mL)
was added allylamine (91.5 mL, 12.2 mmol) at r.t. and the
mixture stirred for 12 h. When TLC showed no 4 remaining,
H2O (4 mL) and Et2O (2 mL) were added, the layers were
then separated. The ether layer was washed with H2O
followed by drying over Na2SO4. The solvent was removed
in vacuo and the oily residue was subjected to
chromatography on alumina, eluted with hexane–EtOAc
(80:20), to give the product 15 as light yellow oil.
Methyl 1-[2-Allylamino-2-(2-bromophen-yl)ethyl]azir-
idine-2-carboxylate (15)
To a suspension of 300 mg LiAlH4 (7.91 mmol) in 40 mL
THF, 264 mg crude product of diketopiperazine 29 (0.66
mmol) dissolved in 5 mL THF was added. The mixture was
stirred at 60 °C for 12 h. After cooling to 0 °C, H2O (0.4 mL),
15% NaOH (0.4 mL), and H2O (0.4 mL) were added
dropwise while stirring. The mixture was filtered and the
filtrate was concentrated in vacuo. The residue was
subjected to silica gel chromatography, eluted with CH2Cl2–
MeOH (90:10). Yield 40%.
Yield 75%. 1H NMR (400 MHz, CDCl3): d = 7.63–7.62 (m,
1 H), 7.52–7.49 (m, 1 H), 7.32–7.28 (m, 1 H), 7.13–7.09 (m,
1 H), 5.92–5.84 (m, 1 H), 5.19–5.06 (m, 2 H), 4.34–4.31 (m,
1 H), 3.71 (s, 3 H), 3.12–3.07 (m, 2 H), 2.76–2.71 (m, 2 H),
2.22–2.16 (m, 1 H), 2.03–2.00 (m, 1 H), 1.73–1.71 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 171.36, 140.20, 136.91,
133.02, 129.02, 127.91, 127.89, 124.12, 116.00, 65.72,
60.72, 52.37, 50.11, 38.13, 34.16.
Reduction with BH3·SMe2
Typical Procedure for the Nucleophilic Substitution of
b-Haloamines with Alcohols Facilitated by Silver Salts
To a mixture of 4 (100 mg, 0.302 mmol), allyl alcohol (205
mL, 0.302 mmol), K2CO3 (50.0 mg, 0.362 mmol), and anhyd
CH2Cl2 (10 mL), was added AgOTf (77.6 mg, 0.302 mmol)
at r.t. and the mixture was stirred for 30 min. When TLC
showed no 4 remaining, the mixture was filtered and
concentrated in vacuo. The oily residue was subjected to
chromatography on silica gel, eluted with hexane–EtOAc
(70:30), to give the product 23 as light yellow oil.
To a solution of crude product of diketopiperazine 29 in
anhyd THF (10 mL/mmol) under reflux was added dropwise
9 equiv of a 2 M solution of BH3·SMe2 in THF. The mixture
was refluxed for 7 h, the solvent was evaporated under
reduced pressure, and 4 equiv of a 0.2–0.4 M HCl solution
were added. The mixture was stirred for 30 min at 100 °C,
and then it was cooled to 0 °C, and 6 equiv of a 0.2–0.4 M
solution of NaOH were added. Then, the mixture was stirred
for a further 90 min. The aqueous mixture was saturated with
solid K2CO3 and extracted with CH2Cl2 (3–4 times, 5 mL/
mmol), and the combined organic extracts were dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was
subjected to silica gel chromatography, eluted with CH2Cl2–
MeOH (90:10). Yield 20%.
3-(4-Benzyl-3-phenylpiperazin-1-yl)propan-1-ol (30)
Yield 40%. 1H NMR (400 MHz, CDCl3): d = 7.50–7.19 (m,
10 H), 3.82–3.77 (m, 3 H), 3.03–2.78 (m, 4 H), 2.64–2.57
(m, 2 H), 2.42–2.11 (m, 2 H), 0.89–0.87 (m, 2 H). 13C NMR
(100 MHz, CDCl3): d = 141.9, 139.1, 129.0, 128.9, 128.8,
128.4, 128.2, 127.9, 127.0, 67.6, 64.9, 62.3, 59.1, 53.6, 51.9,
27.2, 9.7.
Methyl 1-[2-(Allyloxy)-2-(2-bromophenyl)ethyl]azir-
idine-2-carboxylate (23)
Yield 36%. 1H NMR (400 MHz, CDCl3): d = 7.53–7.47 (m,
4 H), 7.45–7.32 (m, 2 H), 7.16–7.12 (m, 2 H), 5.92–5.86 (m,
2 H), 5.30–5.24 (m, 2 H), 5.18–5.15 (d, J = 10.4 Hz, 2 H),
3.99–3.83 (m, 4 H), 3.72 (s, 6 H), 3.00–2.98 (m, 1 H), 2.69–
2.67 (m, 1 H), 2.50–2.45 (m, 1 H), 2.27–2.26 (m, 2 H), 2.15–
2.13 (m, 1 H), 2.13–2.08 (m, 1 H), 2.08–2.04 (m, 1 H), 1.80–
1.78 (d, J = 6.8 Hz, 1 H), 1.59–1.57 (d, J = 6.4 Hz, 1 H). 13
NMR (100 MHz, CDCl3): d = 171.5, 139.4, 134.8, 134.7,
133.0, 129.5, 129.4, 128.3, 128.3, 127.9, 123.1, 123.1,
C
117.1, 117.0, (79.9, 79.62), (70.5, 70.3), (65.3, 65.2), (52.3,
52.2), (39.1, 36.7), (35.4, 32.8).
Synlett 2007, No. 18, 2912–2918 © Thieme Stuttgart · New York

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