Template-induced enantioselectivity in the reductive radical cyclization of 3-(3-iodopropoxy)propenoic acid derivatives depending on the binding motif

Article abstract of DOI:10.1055/s-2008-1067024

Different binding motifs HXC=O have been screened in the enantioselective radical cyclization of various linear derivatives of 3-(3-iodopropoxy)propenoic acid. The reactions were performed in the presence of an enantiomerically pure, chiral 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-one derivative, which acts as a hydrogen-binding template. The cyclized products were obtained in good to excellent yields (66-88%). Enantioselectivities up to 59% ee were achieved. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067024

PAPER
1559
Template-Induced Enantioselectivity in the Reductive Radical Cyclization of
3-(3-Iodopropoxy)propenoic Acid Derivatives Depending on the Binding Motif
Radical
C
ycliz
e
ation of 3-(
t
3-Iodo
e
propoxy)pr
r
openoic
Acid
D
K
erivatives apitán, Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
Received 14 February 2008
O
2
β
initiator
Abstract: Different binding motifs HXC=O have been screened in
the enantioselective radical cyclization of various linear derivatives
of 3-(3-iodopropoxy)propenoic acid. The reactions were performed
in the presence of an enantiomerically pure, chiral 1,5,7-trimethyl-
3-azabicyclo[3.3.1]nonan-2-one derivative, which acts as a hydro-
gen-binding template. The cyclized products were obtained in good
to excellent yields (66–88%). Enantioselectivities up to 59% ee
were achieved.
HX
HX
O
I
O
Bu3SnH, toluene
O
1a–g
2a–g
O
HX
O
Key words: cyclizations, enantioselectivity, lactams, radical reac-
3a–g
tions, supramolecular chemistry
Scheme 1 Radical cyclization of various derivatives 1 of 3-(3-iodo-
propoxy)propenoic acid via radical intermediates 3 to the correspon-
ding tetrahydrofurans 2
Enantioselective radical reactions have received consider-
able attention in recent years.1,2 Among these reactions,
conjugate addition reactions are particularly useful as they
often allow for the concomitant formation of a carbon–
carbon bond and a new stereogenic center.3 Enantioselec-
tive radical-cyclization reactions4 of acrylates are rare.5,6
In the single example (up to 48% ee) reported to date,5 a
chiral Lewis acid was employed to control the conforma-
tion of the acrylate and to provide an efficient enantioface
differentiation. A 5-exo-trig cyclization of chiral b-alkoxy-
vinyl sulfoxides has been reported for the construction of
tetrahydrofurans with good diastereoselectivity.7
the fragment HXC=O (depicted as € in Figure 1) binds
by two hydrogen bonds to the template.
The starting materials 1 for the radical cyclization were
prepared from methyl propiolate (4) and 3-chloropro-
panol via intermediate ester 5 (Scheme 2). Saponification
led to 3-(3-chloropropoxy)propenoic acid (6), which was
used as starting material for amide 1a and benzimidazol-
one 1d (Table 1). They were generated via the respective
chloro derivative by a Finkelstein reaction (Method A).
While amide formation (product 1a) was facile with gas-
eous ammonia, benzimidazolone was deprotonated (NaH,
DMF) prior to acylation (product 1d). The Finkelstein re-
action could also be used to convert 3-(3-chloropro-
poxy)propenoic acid (6) into the title compound 1b, from
which the derivatives 1c, 1e–g were synthesized via the
corresponding 3-(3-iodopropoxy)propenoyl chloride
(Method B). Detailed reactions conditions are provided in
the experimental section.
In this study, we conducted 5-exo-trig radical cyclization
reactions with various derivatives 1 of the title compound,
3-(3-iodopropoxy)propenoic acid. These compounds re-
act in the presence of tributyltin hydride and an appropri-
ate initiator to give the corresponding tetrahydrofurans 2
(Scheme 1). The former b-carbon atom of the acrylic acid
derivative is converted into a stereogenic center at C-2 of
the tetrahydrofuran, with the radical addition step (inter-
mediates 3) being stereoselectivity determining. In earlier
work,8 we have shown that a radical cyclization reaction
in the presence of a chiral template can proceed enantiose-
lectively if binding of the substrate to the template is fea-
sible by hydrogen bonding.9 Quinolones have been shown
to exhibit a very effective binding motif for this coordina-
tion, often allowing high enantioselectivities.10,11 Other
binding motifs have not yet been extensively studied.
Since a modification ‘HX’ of the acrylic acid at the termi-
nal carboxy group was considered to be facile, we specu-
lated that we could use this specific cyclization to identify
viable binding motifs for association. In an ideal scenario,
Racemic products 2 were smoothly obtained in all cases
by treating the corresponding precursors 1 with tributyltin
hydride and an initiator, yields ranging between 74 and
94% (Table 1). Except for the reaction of 1c to 2c, which
required AIBN as the initiator in refluxing benzene, all re-
actions were conducted in toluene at ambient temperature
using triethylborane as the initiator. Separation of enantio-
mers by chiral HPLC (Daicel Chiralpak AD-H) was pos-
sible in all cases. This fact facilitated the assessment of the
enantiomeric excess (ee) for reactions which were con-
ducted in the presence of template 7 (Figure 1). In the lat-
ter set of reactions, the radical cyclization was performed
at –78 °C in toluene employing 2.5 equivalents of the
complexing reagent 7.
SYNTHESIS 2008, No. 10, pp 1559–1564
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1067024; Art ID: Z04608SS
© Georg Thieme Verlag Stuttgart · New York
The yields remained very good in most cases, entry 7 be-
ing the exception, and the products 2 were obtained in

1560
P. Kapitán, T. Bach
PAPER
HO
Et3N, CH2Cl2
45%
Cl
O
MeOOC
Cl
O
O
Cl
4
5
NaOH, H2O
76%
6: Y = Cl
1b: Y = I
NaI, acetone
97%
HOOC
O
Y
1. (COCl)2, CH2Cl2
2. HXH, CH2Cl2 or DMF
3. NaI, acetone
1. (COCl)2, CH2Cl2
2. HXH, CH2Cl2 or MeCN
6
1b
1a,c–g
Method A
Method B
cf. Table 1
Scheme 2 Preparation of substrates 1 from 3-(3-chloropropoxy)propenoic acid (6) via intermediate product 5
Table 1 Reaction Conditions, Yields and Enantioselectivities in the Radical Cyclization Reaction of Substrates 1a–g
Entry HX
Methoda
Substrate Initiatorc (equiv) Template 7 (equiv) Temp Product Yieldd ee (%)
Yieldb (%)
(°C)
(%)
1
2
3
A
71
1a
1b
1c
Et3B (0.25)
Et3B (0.25)
–
2.5
25
–78
2a
2b
2c
83
87
–
20
H2N
HO
–
–
Et3B (0.25)
Et3B (0.25)
–
2.5
25
–78
94
70
–
31
B
63
AIBN (0.20)
Et3B (0.25)
–
2.5
80
–78
90
83
–
<5
O
N
H2N
H
4
5
A
41
1d
1e
Et3B (0.25)
Et3B (0.25)
–
2.5
25
–78
2d
2e
85
86
–
37
H
N
N
O
B
36
Et3B (0.25)
Et3B (0.25)
UV (300 nm)
–
2.5
2.5
25
–78
–75
74
73
80
–
59
55
NH
N
O
6
7
B
78
1f
Et3B (0.25)
Et3B (0.25)
–
2.5
25
–78
2f
84
88
–
5
H
N
N
B
79
1g
Et3B (0.25)
Et3B (0.25)
–
2.5
25
–78
2g
74
66
–
24
H
N
Ph
N
H
a Preparation according to Method A or B, as specified in Scheme 2.
b Yield of isolated product 1a,c–g.
c Radical reactions were conducted at a substrate concentration of 15 mM in toluene as the solvent (see experimental section).
d Yield of isolated product 2a–g.
template 7 occurs and that the binding persists in the rad-
ical cyclization process via intermediates 3.
α
N
H
N
H
O
β
O
N
O
N
In addition, the enantioselective reaction course also indi-
cates that there is a conformational preference with regard
to rotation around the CO–Ca bond (Figure 1). Linear
amides are constrained by the geometrical properties of
the amide bond, in particular by the almost perfect planar-
ity around the C–N bond, which shows partial double
bond character. One would consequently expect an s-
trans conformation to be preferred for the CO–Ca bond
due to 1,3-allylic strain. The expectation is substantiated
by recent calculations conducted on acrylamide.12 As a
consequence of the preferred s-trans conformation, the
I
O
O
7
7•1
Figure 1 Complexation of template 7 with substrates 1a–g
enantiomerically enriched form. Remarkably, the simple
binding motifs carboxylic amide (H2NCO) and carboxylic
acid (HOCO) accounted for significant ee values, indicat-
ing that a binding of substrates 1a and 1b (entries 1, 2) to
Synthesis 2008, No. 10, 1559–1564 © Thieme Stuttgart · New York

PAPER
Radical Cyclization of 3-(3-Iodopropoxy)propenoic Acid Derivatives
1561
ed with an Agilent 5973 or a Finnigan MAT 8200 mass spectrome-
ter. The unstable iodo compounds 1, for some of which MS (EI)
and/or HRMS data could not be obtained, were not stored but used
immediately after preparation.
major enantiomer of the radical cyclization should be
formed by Si-face attack at carbon atom Cb (Figure 1). We
considered hydrazides as carboxylic acid derivatives
which could possibly exhibit an increased preference for
the s-trans conformation, but the results recorded with the
hydrazine derivates, e.g. with 1f and 1g, were disappoint-
ing (Table 1, entries 6, 7). The linear urea 1c (entry 3) was
equally unsuited for achieving high enantiomeric excess-
es. It was also the only substrate in which the cyclization
could not be induced by triethylborane in the absence of
template 7; AIBN was required for initiation at elevated
temperature. Interestingly, the triethylborane-initiated cy-
clization did work in the presence of template 7 at –78 °C
but, as already mentioned, the enantiomeric excess of
product 2c was very low. In contrast, the cyclic ureas 1d
and 1e (entries 4 and 5) delivered relatively high enantio-
selectivities given the distance between the binding motif
and the reaction center at Cb. Indeed, binding to the tem-
plate presumably occurs via two hydrogen bonds at the
lactam part of the urea, which is four bonds away from the
prostereogenic carbon atom Cb. Due to this distance, the
tetrahydronaphthalene backbone is apparently no longer
capable of completely shielding one of the two enan-
tiotopic faces around Cb. The possibility that the polar ini-
tiator triethylborane is responsible for a decreased
enantioselectivity was ruled out by initiating the cycliza-
tion of 1e to 2e with UV light. The enantiomeric excess re-
corded with this protocol (55% ee) was, in fact, slightly
lower than the ee obtained in the triethylborane case (59%
ee, entry 5).
3-Chloropropyl 3-(3-Chloropropoxy)propenoate (5)
Et3N (3 mL) was added to a stirred soln of methyl propiolate (4; 5.0
g, 59.5 mmol) and 3-chloropropanol (15 mL) in CH2Cl2 (60 mL) at
0 °C. After an exothermic reaction, the solution was stirred at rt for
2 h, then washed with 1 N HCl (20 mL) and H2O (20 mL), and dried
(Na2SO4). Kugelrohr distillation (135 °C/0.2 mbar) gave 5.
Yield: 6.1 g (45%); Rf = 0.25 (Et2O–pentane, 1:3).
IR (neat): 2962 (w), 2880 (w), 1707 (s), 1620 (s), 1440 (s), 1329
(m), 1285 (m), 1207 (m), 1116 (vs), 1038 (m) cm–1.
1H NMR (360 MHz, CDCl3): d = 2.13 (virt. quin, J @ 6.5 Hz, 2 H,
2¢¢-H), 2.18 (virt. quin, J @ 6.5 Hz, 2 H, 2¢-H), 3.62–3.69 (2 × t,
J = 6.5 Hz, 4 H, 3¢-H, 3¢¢-H), 4.03 (t, J = 5.8 Hz, 2 H, 1¢¢-H), 4.28 (t,
J = 5.8 Hz, 2 H, 1¢-H), 5.24 (d, J = 12.6 Hz, 1 H, 2-H), 7.61 (d,
J = 12.6 Hz, 1 H, 3-H).
13C NMR (90 MHz, CDCl3): d = 32.1 (t), 32.2 (t), 41.2 (t), 41.7 (t),
61.0 (t), 67.6 (t), 97.0 (d), 162.7 (d), 167.9 (s).
MS (EI, 70 eV): m/z (%) = 240/242 (3/1) [M+], 205/207 (14/5), 177/
179 (15/5), 147/149 (100/33), 101 (21), 71 (89).
HRMS (EI): m/z calcd for C9H14Cl2O3: 240.0320/242.0291; found:
240.0310/242.0292.
3-(3-Chloropropoxy)propenoic Acid (6)
A mixture of ester 5 (6.0 g, 25.0 mmol) in 0.5 N aq NaOH (115 mL)
was stirred at 40 °C for 24 h. The aqueous layer was washed with
Et2O (2 × 25 mL), then acidified with 6 N HCl and extracted with
CH2Cl2 (3 × 15 mL). The combined CH2Cl2 extracts were dried
(Na2SO4) and the solvent was removed to afford 6 as white crystals.
Yield: 3.1 g (76%); mp 93 °C; Rf = 0.62 (CH2Cl2–MeOH, 10:1).
In summary, the results indicate that the association to
template 7 increases for acrylic acid derivatives in the or-
der hydrazide < amide < acid < cyclic urea. The as yet in-
complete enantioselectivity in the case of ureas 1d and 1e
is most likely due to the insufficient face differentiation
exerted by the tetrahydronaphthalene shield of template 7.
To prove this assumption and to employ the urea binding
motif in a general fashion, further experiments will be di-
rected at the synthesis of templates with even more ex-
tended shields. Studies along these lines are underway in
our laboratories and will be reported in due course.
IR (KBr): 3421 (br), 3100 (m), 3087 (m), 2962 (m), 2927 (m), 2897
(m), 1700 (vs), 1610 (vs), 1466 (m), 1306 (s), 1208 (vs), 731 (s)
cm–1.
1H NMR (360 MHz, CDCl3): d = 2.17 (virt. quin, J @ 6.1 Hz, 2 H,
2¢-H), 3.66 (t, J = 6.1 Hz, 2 H, 3¢-H), 4.04 (t, J = 5.8 Hz, 2 H, 1¢-H),
5.22 (d, J = 12.6 Hz, 1 H, 2-H), 7.67 (d, J = 12.6 Hz, 1 H, 3-H),
11.05 (br s, 1 H, OH).
13C NMR (90 MHz, CDCl3): d = 31.6 (t), 40.7 (t), 67.5 (t), 96.3 (d),
164.0 (d), 173.4 (s).
MS (EI, 70 eV): m/z (%) = 164/166 (20/7) [M+], 146/148 (3/1), 101
(25), 88 (50), 76 (30), 70 (56), 55 (6), 49 (13), 41 (100).
HRMS (EI): m/z calcd for C6H9ClO3: 164.0240; found: 164.0240.
All reactions involving water-sensitive chemicals were carried out
in flame-dried glassware with magnetic stirring under argon. Anhy-
drous Et3N and CH2Cl2 were distilled from CaH2 prior to use. Com-
mon solvents (Et2O, pentane, EtOAc, CH2Cl2, MeOH) were
distilled prior to use. All other solvents and reagents were used as
received. TLC was performed on glass plates (0.25 mm silica gel
60, F254); detection was by coloration with ceric ammonium molyb-
date or phosphomolybdic acid. Column chromatography was per-
formed on silica gel 60 (230–400 mesh; ca. 50 g for 1 g of material
to be separated) with the eluent mixture indicated. 1H and 13C NMR
spectra were recorded on Bruker AV-250 and AV-360 instruments
at 303 K. Chemical shifts are reported relative to tetramethylsilane
as internal standard. Apparent multiplets which occur as a result of
accidental equality of coupling constants of magnetically nonequiv-
alent protons are marked as virtual (virt.). The multiplicities of the
13C NMR signals were determined by DEPT experiments and stan-
dard two-dimensional NMR experiments. IR spectra were recorded
with a Perkin-Elmer 1600 instrument and mass spectra were record-
3-(3-Iodopropoxy)propenamide (1a)
Oxalyl chloride (170 mL, 3.2 equiv) was added to a soln of acid 6
(100 mg, 0.61 mmol) in CH2Cl2 (2 mL), and the mixture was heated
for 1 h under reflux. The mixture was concentrated under reduced
pressure to afford crude 3-(3-chloropropoxy)propenoyl chloride.
Ammonia was introduced over 5 min to a soln of this acid chloride
in CH2Cl2 (5 mL) at –15 °C. The solvent was removed and the crude
product was purified by column chromatography (CH2Cl2–MeOH,
200:1 → 50:1). The resulting amide (72 mg, 0.44 mmol) and NaI
(166 mg, 2.5 equiv) were heated in acetone (15 mL) under reflux for
48 h. The acetone was removed, the residue was suspended in H2O
(10 mL) and the product was extracted with CH2Cl2 (3 × 15 mL).
The combined extracts were dried (Na2SO4) and the solvent was re-
moved to give 1a as white crystals.
Yield: 111 mg (71%); mp 138–140 °C; Rf = 0.56 (CH2Cl2–MeOH,
10:1).
Synthesis 2008, No. 10, 1559–1564 © Thieme Stuttgart · New York

1562
P. Kapitán, T. Bach
PAPER
1-[3-(3-Iodopropoxy)propenoyl]-1,3-dihydro-2H-benzimid-
IR (KBr): 3345 (br), 3080 (w), 2947 (m), 2924 (m), 2874 (m), 1676
(s), 1593 (vs), 1419 (m), 1330 (m), 1203 (s), 1128 (s), 1025 (m), 825
(m) cm–1.
1H NMR (360 MHz, DMSO-d6): d = 2.09 (virt. quin, J @ 6.6 Hz, 2
H, 2¢-H), 3.20 (t, J = 6.7 Hz, 2 H, 3¢-H), 3.82 (t, J = 5.9 Hz, 2 H, 1¢-
H), 5.28 (d, J = 12.4 Hz, 1 H, 2-H), 5.74 (br s, 1 H, NH), 6.50 (br s,
1 H, NH), 7.39 (d, J = 12.4 Hz, 1 H, 3-H).
13C NMR (90 MHz, DMSO-d6): d = 3.4 (t), 32.0 (t), 69.8 (t), 99.7
(d), 158.1 (d), 167.3 (s).
MS (EI, 70 eV): m/z (%) = 255 (1) [M+], 239 (2), 184 (12), 169 (18),
128 (15), 98 (28), 41 (100).
azol-2-one (1d)
NaH (60% in oil, 35 mg) was washed with pentane (2 × 2 mL) and
suspended in DMF (2 mL). Benzimidazolone (122 mg, 0.91 mmol)
was added at r.t. and the mixture was stirred for 30 min. 3-(3-Chlo-
ropropoxy)propenoyl chloride (0.91 mmol), prepared as described
above (see 1a), in DMF (2 mL) was added dropwise and the solu-
tion was stirred for 24 h at r.t. After workup, the product was sepa-
rated by column chromatography (EtOAc–pentane, 1:4 → 1:2) to
give white crystals (104 mg, 41%) of 1-[3-(3-chloropropoxy)prope-
noyl]-1,3-dihydro-2H-benzimidazol-2-one. This compound (104
mg, 0.37 mmol) and NaI (277 mg, 5 equiv) were stirred in acetone
(5 mL) for 48 h under reflux. The solvent was removed, the residue
was suspended in H2O (10 mL) and the product was extracted with
CH2Cl2 (3 × 15 mL). The combined extracts were dried (Na2SO4)
and the solvent was removed to give 1d as white crystals.
HRMS (EI) : m/z [M+ – NH2] calcd for C6H8IO2: 238.9569; found:
238.9569.
3-(3-Iodopropoxy)propenoic Acid (1b)
Yield: 140 mg (41%); mp 158–160 °C; Rf = 0.78 (EtOAc–pentane,
1:1).
Acid 6 (500 mg, 3.04 mmol) and NaI (900 mg, 2 equiv) were heated
in acetone (15 mL) under reflux for 48 h. The solvent was removed,
the residue was suspended in H2O (10 mL) and the product was ex-
tracted with CH2Cl2 (3 × 15 mL). The combined extracts were dried
(Na2SO4) and the solvent was removed to give 1b as yellowish crys-
tals.
IR (neat): 3088 (w), 3069 (w), 2971 (m), 2938 (m), 2875 (m), 1678
(s), 1610 (s), 1421 (m), 1334 (m), 1300 (m), 1212 (s), 1164 (s), 941
(m), 824 (m) cm–1.
1H NMR (360 MHz, CDCl3): d = 2.28 (virt. quin, J @ 6.1 Hz, 2 H,
2¢¢-H), 3.25 (t, J = 6.5 Hz, 2 H, 3¢¢-H), 4.12 (t, J = 6.1 Hz, 2 H, 1¢¢-
H), 7.04–7.12 (m, 4 H, 2¢-H, 3 × HAr), 7.96 (d, J = 12.2 Hz, 1 H, 3¢-
H), 8.22 (d, J = 7.2 Hz, 1 H, HAr), 8.86 (br s, 1 H, NH).
13C NMR (90 MHz, CDCl3): d = 1.2 (t), 32.4 (t), 70.9 (t), 98.6 (d),
109.0 (d), 116.3 (d), 122.8 (d), 124.4 (s), 127.6 (d), 128.0 (s), 153.4
(s), 164.6 (d), 166.0 (s).
Yield: 750 mg (97%); mp 118–119 °C; Rf = 0.62 (CH2Cl2–MeOH,
10:1).
IR (KBr): 3442 (br), 3080 (w), 2924 (m), 2852 (m), 1677 (s), 1618
(vs), 1416 (m), 1332 (m), 1219 (s), 1181 (s), 1158 (s) cm–1.
1H NMR (250 MHz, CDCl3): d = 2.20 (virt. quin, J @ 6.0 Hz, 2 H,
2¢-H), 3.27 (t, J = 6.7 Hz, 2 H, 3¢-H), 3.97 (t, J = 6.0 Hz, 2 H, 1¢-H),
5.23 (d, J = 12.7 Hz, 1 H, 2-H), 7.66 (d, J = 12.7 Hz, 1 H, 3-H), 11.0
(br s, 1 H, OH).
13C NMR (63 MHz, CDCl3): d = 1.1 (t), 32.3 (t), 70.5 (t), 96.3 (d),
164.0 (d), 173.3 (s).
MS (EI, 70 eV): m/z (%) = 256 (1) [M+], 239 (1), 169 (21), 141 (5),
129 (12), 111 (7), 99 (13), 83 (31), 71 (10), 55 (6), 41 (100).
MS (EI, 70 eV): m/z (%) = 372 (37) [M+], 239 (100), 169 (81), 134
(30), 106 (12), 71 (25), 41 (68).
HRMS (EI): m/z calcd for C13H13IN2O3: 371.9971; found:
371.9965.
1-[3-(3-Iodopropoxy)propenoyl]tetrahydropyrimidin-2(1H)-
one (1e)
HRMS (EI): m/z calcd for C6H9IO3: 255.9596; found: 255.9599.
Oxalyl chloride (0.11 mL, 3.3 equiv) was added to a soln of acid 1b
(100 mg, 0.39 mmol) in CH2Cl2 (4 mL) and the mixture was heated
under reflux for 1 h. Then, the mixture was concentrated under re-
duced pressure. The resulting acid chloride was dissolved in MeCN
(2 mL) and added dropwise to a suspension of pulverized trimeth-
yleneurea (78 mg, 2 equiv) in MeCN (8 mL) under reflux. After 30
min under reflux, the MeCN was removed and the product was pu-
rified by column chromatography (CH2Cl2–MeOH, 200:1 → 100:1)
to give 1e as a viscous oil.
N-[3-(3-Iodopropoxy)propenoyl]urea (1c)
Oxalyl chloride (0.22 mL, 3.3 equiv) was added to a soln of acid 1b
(200 mg, 0.78 mmol) in CH2Cl2 (4 mL) and the mixture was heated
under reflux for 1 h. Then, the mixture was concentrated under re-
duced pressure. The resulting acid chloride was dissolved in MeCN
(2 mL) and added dropwise to a suspension of pulverized urea (55
mg, 1.2 equiv) in MeCN (8 mL) under reflux. After 30 min under
reflux, the solution was cooled to 0 °C, and the precipitated product
was collected by filtration and washed with Et2O (2 × 10 mL) to af-
ford 1c as white crystals.
Yield: 47 mg (36%); Rf = 0.70 (CH2Cl2–MeOH, 10:1).
IR (neat): 3263 (m), 2952 (w), 2875 (w), 1687 (s), 1644 (s), 1586
(m), 1479 (m), 1343 (s), 1300 (s), 1187 (m), 1145 (s), 1038 (m)
cm–1.
Yield: 145 mg (63%); mp 175–178 °C; Rf = 0.55 (CH2Cl2–MeOH,
10:1).
1H NMR (360 MHz, CDCl3): d = 1.95–2.00 (m, 2 H, 5-H), 2.21
(virt. quin, J @ 6.1 Hz, 2 H, 2¢¢-H), 3.28 (t, J = 6.8 Hz, 2 H, 3¢¢-H),
3.36 (dt, J = 2.6, 6.1 Hz, 2 H, 4-H), 3.81–3.85 (m, 2 H, 6-H), 3.97
(t, J = 6.1 Hz, 2 H, 1¢¢-H), 5.38 (br s, 1 H, NH), 6.75 (d, J = 12.2 Hz,
1 H, 2¢-H), 7.70 (d, J = 12.2 Hz, 1 H, 3¢-H).
13C NMR (90 MHz, CDCl3): d = 1.5 (t), 21.8 (t), 32.5 (t), 40.8 (t),
41.4 (t), 70.0 (t), 101.2 (d), 161.9 (d), 168.6 (s); one signal missing.
IR (neat): 3370 (m), 3311 (m), 3210 (m), 2962 (w), 1697 (s), 1668
(s), 1591 (s), 1396 (m), 1247 (m), 1154 (s), 1101 (s), 956 (m), 800
(s) cm–1.
1H NMR (360 MHz, DMSO-d6): d = 2.12 (virt. quin, J @ 6.8 Hz, 2
H, 2¢-H), 3.28 (t, J = 6.8 Hz, 2 H, 3¢-H), 3.94 (t, J = 6.1 Hz, 2 H, 1¢-
H), 5.55 (d, J = 12.6 Hz, 1 H, 2¢¢-H), 7.12 (br s, 1 H, NH2), 7.59 (d,
J = 12.6 Hz, 1 H, 3¢¢-H), 7.86 (br s, 1 H, NH2), 9.88 (br s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 284 (15), 256 (20), 211 (9) [M+ – I], 172
(61), 155 (25), 127 (43), 100 (100), 84 (60), 56 (91).
13C NMR (90 MHz, DMSO-d6): d = 3.1 (t), 32.0 (t), 71.0 (t), 98.8
(d), 154.2 (s), 161.6 (d), 167.2 (s).
MS (EI, 70 eV): m/z (%) = 299 (1) [M + H+], 173 (2), 146 (6), 103
(44), 87 (45), 75 (31), 60 (21), 44 (100).
1-[3-(3-Iodopropoxy)propenoyl]pyrazolidine (1f)
Et3N (166 mL, 3 equiv) was added to a mixture of pyrazolidine di-
hydrochloride (84 mg, 1.5 equiv) in CH2Cl2 (5 mL). To this solu-
tion, 3-(3-iodopropoxy)propenoyl chloride (0.39 mmol), prepared
as described above (see 1e), dissolved in CH2Cl2 (2 mL) was added
Synthesis 2008, No. 10, 1559–1564 © Thieme Stuttgart · New York

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Radical Cyclization of 3-(3-Iodopropoxy)propenoic Acid Derivatives
1563
and the mixture was stirred for 30 min at r.t. The mixture was con-
centrated and the product was purified by column chromatography
(CH2Cl2–MeOH, 200:1 → 100:1) to give 1f as an unstable yellow-
ish oil.
1H NMR (360 MHz, CDCl3): d = 1.53–1.62 (m, 1 H, 4¢-HA), 1.90–
1.98 (m, 2 H, 3¢-HA, 4¢-HB), 2.08–2.18 (m, 1 H, 3¢-HB), 2.54 (dd, J =
15.6, 5.7 Hz, 1 H, 2-HA), 2.63 (dd, J = 15.6, 7.2 Hz, 1 H, 2-HB),
3.77–3.82 (m, 1 H, 5¢-HA), 3.89–3.95 (m, 1 H, 5¢-HB), 4.24–4.32
(m, 1 H, 2¢-H), 8.90 (br s, 1 H, OH).
Yield: 94 mg (78%); Rf = 0.70 (CH2Cl2–MeOH, 10:1).
13C NMR (90 MHz, CDCl3): d = 25.5 (t), 31.2 (t), 40.3 (t), 68.0 (t),
75.0 (d), 176.3 (s).
IR (neat): 3214 (w), 2938 (w), 2880 (w), 1639 (s), 1580 (s), 1450
(m), 1421 (m), 1319 (m), 1188 (s), 1125 (m), 1033 (m), 965 (m),
819 (m) cm–1.
1H NMR (360 MHz, CDCl3): d = 2.06 (virt. quin, J @ 7.3 Hz, 2 H,
4-H), 2.18 (virt. quin, J @ 5.9 Hz, 2 H, 2¢¢-H), 3.01 (t, J = 5.7 Hz, 2
H, 3-H), 3.25 (t, J = 6.7 Hz, 2 H, 3¢¢-H), 3.56 (t, J = 7.6 Hz, 2 H, 5-
H), 3.90 (t, J = 5.8 Hz, 2 H, 1¢¢-H), 4.08 (br s, 1 H, NH), 6.07 (br s,
1 H, 2¢-H), 7.52 (d, J = 12.5 Hz, 1 H, 3¢-H).
N-(Tetrahydrofuran-2-ylacetyl)urea (2c)
Yield: 83%; mp 151–155 °C; Rf = 0.45 (CH2Cl2–MeOH, 10:1).
IR (neat): 3380 (m), 3224 (w), 3152 (w), 2972 (w), 2871 (w), 1702
(vs), 1586 (s), 1503 (m), 1391 (s), 1198 (s), 1106 (m), 1067 (s), 829
(m) cm–1.
1H NMR (360 MHz, CDCl3): d = 1.41–1.51 (m, 1 H, 4¢-HA), 1.76–
1.86 (m, 2 H, 3¢-HA, 4¢-HB), 1.92–2.01 (m, 1 H, 3¢-HB), 2.42 (dd, J =
14.5, 5.5 Hz, 1 H, 2-HA), 3.25 (dd, J = 14.5, 7.7 Hz, 1 H, 2-HB),
3.56–3.61 (m, 1 H, 5¢-HA), 3.70–3.76 (m, 1 H, 5¢-HB), 4.07–4.14 (m,
1 H, 2¢-H), 7.19 (br s, 1 H, NH2), 7.74 (br s, 1 H, NH2), 10.09 (br s,
1 H, NH).
13C NMR (90 MHz, CDCl3): d = 24.9 (t), 30.6 (t), 42.0 (t), 66.8 (t),
74.9 (d), 153.7 (s), 172.6 (s).
MS (EI, 70 eV): m/z (%) = 171 (1) [M+ – H], 144 (18), 129 (68), 102
(18), 84 (21), 71 (62), 60 (75), 44 (100).
13C NMR (90 MHz, CDCl3): d = 1.7 (t), 27.4 (t), 32.5 (t), 44.1 (t),
47.8 (t), 69.9 (t), 97.2 (d), 159.8 (d), 167.0 (s).
3-(3-Iodopropoxy)propenoic Acid N¢-Phenylhydrazide (1g)
3-(3-Iodopropoxy)propenoyl chloride (0.39 mmol), prepared as de-
scribed above (see 1e), was dissolved in CH2Cl2 (2 mL) and added
dropwise to a soln of phenylhydrazine (108 mg, 2 equiv) in CH2Cl2
(10 mL). The mixture was stirred for 30 min at r.t., then concentrat-
ed, and the product was purified by column chromatography
(EtOAc–pentane, 1:2) to give 1g as an unstable yellowish oil.
Yield: 106 mg (79%); Rf = 0.85 (CH2Cl2–MeOH, 10:1).
HRMS (EI): m/z calcd for C7H12N2O3: 172.0848; found: 172.0848.
IR (neat): 3224 (w), 3045 (w), 3016 (w), 2938 (m), 2880 (m), 1648
(s), 1596 (s), 1494 (s), 1391 (m), 1314 (m), 1193 (s), 1111 (m), 965
(m), 815 (m) cm–1.
1H NMR (360 MHz, CDCl3): d = 2.09 (virt. quin, J @ 6.6 Hz, 2 H,
2¢-H), 3.20 (t, J = 6.6 Hz, 2 H, 3¢-H), 3.80 (t, J = 5.8 Hz, 2 H, 1¢-H),
4.74 (br s, 1 H, NH), 5.40 (br d, J = 12.2 Hz, 1 H, 2-H), 6.84 (br s,
1 H, NH), 7.21–7.43 (m, 5 H, HAr), 7.56 (d, J = 12.2 Hz, 1 H, 3-H).
1-(Tetrahydrofuran-2-ylacetyl)-1,3-dihydro-2H-benzimidazol-
2-one (2d)
Yield: 86%; mp 118–120 °C; [a]D25 –7.4 (c 0.31, MeOH); 37% ee;
Rf = 0.65 (EtOAc–pentane, 1:1).
IR (KBr): 3205 (w), 3064 (w), 2957 (m), 2928 (m), 2856 (m), 1730
(s), 1701 (s), 1479 (m), 1319 (m), 1276 (m), 1149 (m), 1096 (m),
1047 (m), 960 (m), 756 (s) cm–1.
1H NMR (360 MHz, CDCl3): d = 1.65–1.73 (m, 1 H, 4¢¢-HA), 1.90–
2.02 (m, 2 H, 3¢¢-HA, 4¢¢-HB), 2.20–2.25 (m, 1 H, 3¢¢-HB), 3.34 (dd,
J = 16.8, 5.0 Hz, 1 H, 2¢-HA), 3.49 (dd, J = 16.8, 7.7 Hz, 1 H, 2¢-HB),
3.78–3.84 (m, 1 H, 5¢¢-HA), 3.90–3.96 (m, 1 H, 5¢¢-HB), 4.48–4.55
(m, 1 H, 2¢¢-H), 7.02 (ddd, J = 7.4, 1.5, 0.6 Hz, 1 H, 4-H), 7.13 (dt,
J = 7.7, 1.5 Hz, 1 H, 5-H), 7.18 (dt, J = 7.6, 1.5 Hz, 1 H, 6-H), 8.20
(ddd, J = 7.8, 1.5, 0.6 Hz, 1 H, 7-H), 8.48 (br s, 1 H, NH).
13C NMR (90 MHz, CDCl3): d = 25.6 (t), 31.6 (t), 43.4 (t), 68.1 (t),
74.7 (d), 109.0 (d), 116.2 (d), 122.8 (d), 124.7 (d), 127.4 (s), 127.7
(s), 153.1 (s), 171.3 (s).
MS (EI, 70 eV): m/z (%) = 246 (7) [M+], 134 (100), 106 (10), 71
(15).
13C NMR (90 MHz, CDCl3): d = 1.4 (t), 32.4 (t), 70.6 (t), 97.0 (d),
126.5 (d), 127.4 (d), 129.1 (d), 129.2 (s), 160.4 (d), 167.3 (s).
Enantioselective Radical Cyclization; General Procedure
A soln of the iodide 1a–g (1.0 equiv) and template 7 (2.5 equiv) in
toluene (15 mM) was cooled to –78 °C under argon. Bu3SnH (2.0
equiv), Et3B (0.25 equiv) and air (1 mL) were then added by sy-
ringe. The solution was stirred for 1 h (TLC control) at –78 °C and
subsequently concentrated. Product and template 7 were separated
by column chromatography with the indicated solvents (Rf). Enan-
tiomeric excesses were obtained by chiral HPLC (Daicel Chiralpak
AD-H) and are listed in Table 1. Specific rotations refer to enantio-
merically enriched products with the given ee.
(Tetrahydrofuran-2-yl)acetamide (2a)
Yield: 87%; Rf = 0.52 (CH2Cl2–MeOH, 10:1).
HRMS (EI): m/z calcd for C13H14N2O3: 246.1005; found: 246.1004.
1-(Tetrahydrofuran-2-ylacetyl)tetrahydropyrimidin-2(1H)-one
(2e)
IR (KBr): 3382 (br), 3198 (br), 2970 (m), 2873 (m), 1666 (s), 1414
(m), 1262 (w), 1206 (w), 1183 (w), 1063 (m) cm–1.
Yield: 73%; mp 76–77 °C; [a]D25 –5.0 (c 0.32, MeOH); 59% ee;
Rf = 0.55 (CH2Cl2–MeOH, 10:1).
1H NMR (360 MHz, CDCl3): d = 1.48–1.58 (m, 1 H, 4¢-HA), 1.84–
1.95 (m, 2 H, 3¢-HA, 4¢-HB), 2.02–2.10 (m, 1 H, 3¢-HB), 2.40 (dd, J =
15.3, 7.6 Hz, 1 H, 2-HA), 2.46 (dd, J = 15.3, 4.5 Hz, 1 H, 2-HB),
3.73–3.79 (m, 1 H, 5¢-HA), 3.86–3.93 (m, 1 H, 5¢-HB), 4.09–4.16 (m,
1 H, 2¢-H), 5.74 (br s, 1 H, NH2), 6.49 (br s, 1 H, NH2).
IR (KBr): 3229 (w), 3108 (w), 2967 (w), 2938 (w), 2890 (w), 2846
(w), 1697 (s), 1673 (s), 1484 (m), 1421 (m), 1305 (m), 1227 (m),
1159 (m), 1057 (m), 1023 (m) cm–1.
1H NMR (360 MHz, CDCl3): d = 1.50–1.60 (m, 1 H, 4¢¢-HA), 1.83–
1.97 (m, 4 H, 3¢¢-HA, 4¢¢-HB, 5-H), 2.04–2.13 (m, 1 H, 3¢¢-HB), 3.17
(dd, J = 16.8, 5.2 Hz, 1 H, 2¢-HA), 3.25 (dd, J = 16.8, 7.5 Hz, 1 H,
2¢-HB), 3.32 (dt, J = 6.0, 2.6 Hz, 2 H, 4-H), 3.67–3.78 (m, 2 H, 6-H),
3.82–3.90 (m, 2 H, 5¢¢-H), 4.33–4.41 (m, 1 H, 2¢¢-H), 5.38 (br s, 1
H, NH).
13C NMR (90 MHz, CDCl3): d = 25.4 (t), 31.3 (t), 41.8 (t), 68.0 (t),
75.5 (d), 173.7 (s).
MS (EI, 70 eV): m/z (%) = 129 (3) [M+], 114 (3), 101 (65), 86 (100),
71 (92), 59 (81), 56 (15), 43 (88).
HRMS (EI): m/z calcd for C6H11NO2: 129.0790; found: 129.0789.
13C NMR (90 MHz, CDCl3): d = 21.7 (t), 25.6 (t), 31.4 (t), 40.7 (t),
41.5 (t), 44.8 (t), 67.9 (t), 75.4 (d), 154.3 (s), 173.7 (s).
(Tetrahydrofuran-2-yl)acetic Acid (2b)13
Yield: 70%.
Synthesis 2008, No. 10, 1559–1564 © Thieme Stuttgart · New York

1564
P. Kapitán, T. Bach
PAPER
MS (EI, 70 eV): m/z (%) = 212 (6) [M+], 195 (2), 184 (58), 169 (45),
153 (15), 142 (39), 127 (5), 111 (12), 101 (100), 85 (35), 71 (61), 56
(25), 43 (41).
References
(1) For reviews, see: (a) Zimmerman, J.; Sibi, M. P. Top. Curr.
Chem. 2006, 263, 107. (b) Sibi, M. P.; Manyem, S.;
Zimmerman, J. Chem. Rev. 2003, 103, 3263. (c) Bar, G.;
Parsons, A. Chem. Soc. Rev. 2003, 32, 251. (d) Sibi, M. P.;
Rheault, T. R. In Radicals in Organic Synthesis, Vol. 1;
Renaud, P.; Sibi, M. P., Eds.; VCH: Weinheim, 2001, 461–
478. (e) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32,
163.
HRMS (EI): m/z calcd for C10H16N2O3: 212.1161; found: 212.1159.
1-(Tetrahydrofuran-2-ylacetyl)pyrazolidine (2f)
Yield: 88%; Rf = 0.60 (CH2Cl2–MeOH, 10:1).
IR (neat): 3462 (w), 2957 (w), 2875 (w), 1639 (s), 1596 (m), 1450
(s), 1431 (s), 1280 (w), 1062 (s), 1018 (m), 927 (m), 839 (m) cm–1.
(2) For a recent organocatalytic approach, see: (a) Sibi, M. P.;
Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124.
(b) Beeson, T. D.; Mastrachhio, A.; Hong, J.-B.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582.
(3) For a review, see: Srikanth, G. S. C.; Castle, S. L.
Tetrahedron 2005, 61, 10377.
(4) For a review, see: Miyabe, H.; Takemoto, Y. Chem. Eur. J.
2007, 13, 7280.
(5) Nishida, M.; Hayashi, H.; Nishida, A.; Kawahara, N. Chem.
Commun. 1996, 579.
1H NMR (360 MHz, CDCl3): d = 1.54–1.64 (m, 1 H, 4¢¢-HA), 1.80–
2.10 (m, 5 H, 3¢¢-H, 4-H, 4¢¢-HB), 2.66 (dd, J = 14.1, 5.3 Hz, 1 H, 2¢-
HA), 2.91–3.06 (m, 3 H, 2¢-HB, 3-H), 3.48–3.56 (m, 2 H, 5-H), 3.69–
3.75 (m, 1 H, 5¢¢-HA), 3.82–3.89 (m, 1 H, 5¢¢-HB), 4.23–4.30 (m, 1
H, 2¢¢-H).
13C NMR (90 MHz, CDCl3): d = 25.5 (t), 27.5 (t), 31.4 (t), 40.1 (t),
43.9 (t), 48.0 (t), 67.8 (t), 76.5 (d), 171.1 (s).
MS (EI, 70 eV): m/z (%) = 182 (13) [M+ – 2 H], 154 (20), 139 (25),
112 (29), 70 (100), 43 (36).
(6) For diastereoselective acrylate additions, see, for example:
(a) Nishida, N.; Ueyama, E.; Hayashi, H.; Ohtake, Y.;
Yamaura, Y.; Yanaginuma, E.; Yonemitsu, O.; Nishida, A.;
Kawahara, N. J. Am. Chem. Soc. 1994, 116, 6455.
(b) Enholm, E. J.; Cottone, J. S.; Allais, R. Org. Lett. 2001,
3, 145. (c) Enholm, E. J.; Cottone, J. S. Org. Lett. 2001, 3,
3959.
(7) (a) Zahouily, M.; Journet, M.; Malacria, M. Synlett 1994,
366. (b) Keum, G.; Kang, S. B.; Kim, Y.; Lee, E. Org. Lett.
2004, 6, 1895.
(8) Dressel, M.; Bach, T. Org. Lett. 2006, 8, 3145.
(9) For other work related to hydrogen-bond-mediated
enantioselectivity in radical reactions, see: Cho, D. H.; Jang,
D. O. Chem. Commun. 2006, 5045.
(10) For radical reactions, see: (a) Aechtner, T.; Dressel, M.;
Bach, T. Angew. Chem. Int. Ed. 2004, 43, 5849.
(b) Dressel, M.; Aechtner, T.; Bach, T. Synthesis 2006, 2206.
(11) For selected applications in photochemical reactions, see:
(a) Bach, T.; Bergmann, H.; Harms, K. Angew. Chem. Int.
Ed. 2000, 39, 2302. (b) Bach, T.; Bergmann, H. J. Am.
Chem. Soc. 2000, 122, 11525. (c) Bach, T.; Bergmann, H.;
Harms, K. Org. Lett. 2001, 3, 601. (d) Bach, T.; Bergmann,
H.; Grosch, B.; Harms, K. J. Am. Chem. Soc. 2002, 124,
7982. (e) Grosch, B.; Orlebar, C. N.; Herdtweck, E.;
Kaneda, M.; Wada, T.; Inoue, Y.; Bach, T. Chem. Eur. J.
2004, 10, 2179.
HRMS (EI): m/z calcd for C9H14N2O2: 182.1055; found: 182.1055.
(Tetrahydrofuran-2-yl)acetic Acid N¢-Phenylhydrazide (2g)
Yield: 66%; mp 112–115 °C; [a]D25 +4.6 (c 0.24, MeOH); 24% ee;
Rf = 0.78 (CH2Cl2–MeOH, 10:1).
IR (neat): 3321 (m), 3257 (m), 3045 (w), 3030 (w), 2951 (m), 2923
(m), 2868 (m), 1643 (vs), 1599 (s), 1550 (m), 1491 (s), 1437 (m),
1259 (m), 1058 (m), 974 (m), 752 (s) cm–1.
1H NMR (360 MHz, CDCl3): d = 1.52–1.62 (m, 1 H, 4¢-HA), 1.85–
2.98 (m, 2 H, 3¢-HA, 4¢-HB), 2.04–2.13 (m, 1 H, 3¢-HB), 2.49 (dd, J =
15.1, 8.2 Hz, 1 H, 2-HA), 2.55 (dd, J = 15.1, 3.8 Hz, 1 H, 2-HB),
3.78–3.84 (m, 1 H, 5¢-HA), 3.92–3.98 (m, 1 H, 5¢-HB), 4.15–4.22 (m,
1 H, 2¢-H), 5.28 (br s, 1 H, NH), 6.82–6.90 (m, 3 H, HAr), 7.19–7.23
(m, 2 H, HAr), 8.31 (br s, 1 H, NH).
13C NMR (90 MHz, CDCl3): d = 25.5 (t), 31.4 (t), 40.8 (t), 68.2 (t),
75.4 (d), 113.5 (d), 120.9 (d), 129.1 (d), 148.0 (s), 171.0 (s).
MS (EI, 70 eV): m/z (%) = 220 (33) [M+], 161 (10), 108 (100), 77
(14), 71 (64), 43 (31).
HRMS (EI): m/z calcd for C12H16N2O2: 220.1212; found: 220.1211.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(Schwerpunktprogramm 1179 Organokatalyse), by the Alexander
von Humboldt Foundation (Research Scholarship to P.K.) and by
the Fonds der Chemischen Industrie.
(12) Aparicio-Martínez, S.; Hall, K. R.; Balbuena, P. B. J. Phys.
Chem. A 2006, 110, 9183.
(13) Patrick, T. B.; Wu, T.-T. J. Org. Chem. 1978, 43, 1506.
Synthesis 2008, No. 10, 1559–1564 © Thieme Stuttgart · New York