Intramolecular diamination and alkoxyamination of alkenes with N-sulfonyl ureas employing N-iodosuccinimide

Article abstract of DOI:10.1016/j.tet.2010.03.082

Reaction of N-δ-alkenyl-N′-sulfonyl urea 1 with N-iodosuccinimde (NIS; 2 equiv) and a catalytic amount of AgOTf (20 mol %) at room temperature led to intramolecular alkoxyamination to form bicyclic isourea 2a in 95% isolated yield. In comparison, reaction

Full text of DOI:10.1016/j.tet.2010.03.082

Tetrahedron 66 (2010) 4827–4831
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Intramolecular diamination and alkoxyamination of alkenes with N-sulfonyl ureas
employing N-iodosuccinimide
*
Hao Li, Ross A. Widenhoefer
French Family Science Center, Duke University, Durham, NC 27708–0346, United States
a r t i c l e i n f o
a b s t r a c t
Reaction of N-d
-alkenyl-N0-sulfonyl urea 1 with N-iodosuccinimde (NIS; 2 equiv) and a catalytic amount
Article history:
Received 9 February 2010
Received in revised form 21 March 2010
Accepted 22 March 2010
of AgOTf (20 mol %) at room temperature led to intramolecular alkoxyamination to form bicyclic isourea
2a in 95% isolated yield. In comparison, reaction of 1 with NIS and sodium bicarbonate (1 equiv) at room
temperature led to isolation of bicyclic imidazolidin-2-one 2b in 91% yield. These NIS-mediated
alkoxyamination and diamination protocols were effective for a range of N-d
-alkenyl-N0-sulfonyl ureas
Available online 27 March 2010
to form the corresponding heterobicyclic compounds in good yield with high chemoselectivity and good
to excellent diastereoselectivity.
Ó 2010 Published by Elsevier Ltd.
1. Introduction
Similarly, Mun˜iz has reported the IPy2BF4-mediated diamination
of alkenes with N-sulfonyl ureas to form bicyclic imidazolidin-2-
Vicinal diamines,1 vicinal amino alcohols,2 and related de-
rivatives are component of a number of naturally occurring and
biologically active molecules and find employment as synthetic
intermediates, chiral ligands, and chiral auxiliaries. A particularly
attractive route to the synthesis of vicinal diamines and amino al-
cohols is through the direct difunctionalization of alkenes. Early
approaches to alkene difunctionalization by Backva¨ll,3 Barluenga,4
Sharpless,5 and others6 employed stoichiometric amounts of
a heavy metal complex or salt. The hydroxyamination of alkenes
was subsequently rendered catalytic in osmium7 and eventually,
both catalytic and enantioselective.8 There has been renewed in-
terest in the direct difunctionalization of alkenes9 and recent efforts
in this area have led to the development of effective processes for
the copper-mediated diamination of alkenes with sulfamides,10,11
the Pd(II)-12,13 or Ni(II)-catalyzed14 diamination of alkenes with
ureas, sulfamides, or guanidines in the presence of a stoichiometric
oxidant, the palladium-catalyzed oxidative aminoacetoxylation of
alkenes,15 and the Pd(0)- or Cu(I)-catalyzed diamination of alkenes
with di-tert-butyldiaziridinone and related reagents.16
one derivatives, although high reaction temperature (120 ꢀC) was
required to achieve optimal yield.18 In the course of our in-
vestigation of a potential gold(I)-catalyzed route to the difunc-
tionalization of alkenes with N-sulfonyl ureas, we instead
discovered a pair of complementary procedures for the selective,
room temperature intramolecular diamination and alkoxyamina-
tion of alkenes with N-sulfonyl ureas mediated by N-iodosuccini-
mide (NIS). Herein we provide an account of our results in this area.
2. Results and discussion
As part of our ongoing interest in the development of gold(I)-
catalyzed processes for the hydroamination of unactivated al-
kenes,19 we recently reported the room temperature intramolecular
hydroamination of N-d- and N-3-alkenyl ureas catalyzed by a gold(I)
N-heterocyclic carbene complex.20 We noted with interest recent
reports that described the utilization of N-iodosuccinimide (NIS) in
conjunction with gold(I)-catalysis for the iodofunctionalization of
alkynes and allenes.21 On the basis of these precedents, we envi-
sioned a gold(I)-catalyzed, NIS-mediated pathway for the oxidative
A pair of recent reports have demonstrated that the difunc-
tionalization of alkenes with N-sulfonyl ureas can be realized with
hypervalent iodine or iodonium reagents in the absence of transi-
tion metal catalysts. Michael has reported the intramolecular
alkoxyamination of alkenes with N-sulfonyl ureas mediated by
PhI]O in the presence of a strong Lewis or Brønsted acid.17
difunctionalization of an N-d-alkenyl urea involving electrophilic
trapping of the initially formed gold alkyl species I with NIS to form
the alkyl iodide II followed by intramolecular halide displacement
by the pendant urea (Scheme 1).22
In apparent support of the pathway outlined in Scheme 1, re-
action of 1-(2,2-diphenylpent-4-enyl)-3-tosylurea (1) with NIS
(2 equiv) and a catalytic 1:1 mixture of (IPr)AuCl [IPr¼1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidine] and AgOTf (5 mol %) in tol-
uene for 24 h at room temperature led to isolation of isourea 2a in
* Corresponding author. E-mail address: rwidenho@chem.duke.edu (R.A.
Widenhoefer).
0040-4020/$ – see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.03.082

4828
H. Li, R.A. Widenhoefer / Tetrahedron 66 (2010) 4827–4831
O
O
O
NHR
(L)Au+
O
NR
O
N
NHR
N
NHR
NIS
NH
or
N
N
NR
II
I
Au
I
Scheme 1.
82% yield (Table 1, entry 1). However, subsequent control experi-
ments revealed that silver, but not gold, was required for the effi-
cient conversion of 1 to 2a. In the absence of metal catalyst, reaction
of 1 with NIS (2 equiv) at room temperature was sluggish (w30%
conversion in 24 h) and formed bicyclic imidazolidin-2-one 2b as
the exclusive product (Table 1, entry 2). In contrast, treatment of 1
with NIS (2 equiv) and a catalytic amount of AgOTf (5 mol %) in
toluene at room temperature for 14 h led to complete consumption
of 1 with isolation of isourea 2a in 95% yield as the exclusive (>98%
of the crude reaction mixture) product (Table 1, entry 3). Silver
presumably facilitates the initial C–N formation through activation
of NIS23 and facilitates C–O bond formation in preference to C–N
bond formation in the second ring-closing step by enhancing the
electrophilicity of an alkyl iodide intermediate analogous to II,
leading to preferential attack by the hard oxygen nucleophile.24
1–6). N-
group at the
d
Alkenyl ureas 9-11 that possessed a single alkyl or phenyl
-position of the alkenyl chain also underwent intra-
b
molecular alkoxyamination and diamination to form the corre-
sponding heterocycles 12–14 in >70% isolated yield with up to 9:1
dr with predominant formation of the diastereomer possessing
a trans arrangement of the exocyclic hydrocarbyl group and
bridgehead hydrogen atom (Table 2, entries 7–12). N-d-Alkenyl
urea 15 that possessed a methyl substituent at the internal olefinic
carbon atom underwent intramolecular alkoxyamination and dia-
mination to form heterocycles 16 in good yield (Table 2, entries 13
and 14). N-d-Alkenyl ureas 17 and 18 that possessed a methyl or
phenyl substituent at the terminal olefinic carbon atom underwent
intramolecular alkoxyamination to form heterocycles 19a and 20a,
respectively in >70% yield with selective formation of the dia-
stereomer possessing a cis arrangement of the exocyclic alkyl group
and bridgehead hydrogen atom (Table 2, entries 15 and 16). N-d-
Alkenyl ureas 17 and 18 also underwent NIS-mediated diamination
to form bicyclic imidazolidin-2-ones 19b and 20b, respectively,
albeit with diminished yield and/or diastereoselectivity relative to
Table 1
Effect of metal and additives on the reaction of 1 with NIS
O
NHTs
alkoxyamination (Table 2, entries 17 and 18). The N-u-alkenyl urea
NTs
O
NIS (2 equiv)
additives
toluene, 25 °C
21 underwent efficient NIS-mediated alkoxyamination to form
isourea 22a in 83% yield (Table 2, entry 19), but failed to undergo
efficient diamination. In contrast, the N-allylaniline derived urea 23
underwent effective diamination to form imidazolidin-2-one 24b
in 82% yield (Table 2, entry 20), but failed to undergo effective
alkoxyamination.
NH
+
Ph
Ph
N
Ph
Ph
N
O
NTs
Ph
Ph
1
2a
2b
Entry
Additive
Time (h)
2a (%)a
2b (%)a
1
2
3
4
(IPr)AuCI/AgOTf (5 mol %)
None
AgOTf (20 mol %)
NaHCO3 (1 equiv)
24
24
14
2
82
d
d
30
db
91
3. Summary
95
dc
We have developed an effective method for the intramolecular
diamination of N-alkenyl ureas with NIS catalyzed by AgOTf to form
bicyclic imidazolidin-2-ones and for the intramolecular alkoxy-
amination of N-alkenyl urea with NIS in the presence of a sodium
bicarbonate or triethylamine. These processes are characterized by
high chemoselectivity, good yield and in many cases, excellent
diastereoselectivity.
a
Isolated yield of >95% purity.
Compound 2b constituted <5% of the crude reaction mixture.
Compound 2a constituted <5% of the crude reaction mixture
b
c
The presence of a metal-free reaction pathway for the conver-
sion of 1 to imidazolidin-2-one 2b was, in retrospect, not surprising
as C–N bond formation in the electrophilic cyclization of un-
saturated carboxamide derivatives has been demonstrated.25 One
approach to the realization of selective C–N bond formation in
these transformations is through employment of base in conjunc-
tion with an acidic carboxamide derivative such as an N-sulfonyl
carboxamide.26 We therefore considered that employment of
a base in the reaction of 1 with NIS might facilitate the C–N bond
forming processes in the conversion of 1 to 2b. This was indeed
found to be the case, and reaction of 1 with NIS in the presence of
sodium bicarbonate (1 equiv) at room temperature for 2 h led to
formation of a >95:5 mixture of 2b and 2a, from which 2b was
isolated in 91% yield (Table 1, entry 4).
Having identified efficient routes to the selective conversion of 1
to either 2a or 2b, we probed the scope and generality of the NIS-
mediated intramolecular alkoxyamination and diamination of al-
kenes with N-tosylureas (Table 2). N-
possessed gem-dialkyl substitution at the
chain and the unsubstituted N- -alkenyl urea 5 underwent efficient
4. Experimental
4.1. General methods
Catalytic reactions were performed in sealed glass tubes under
an atmosphere of dry nitrogen unless noted otherwise. NMR
spectra were obtained on a Varian spectrometer operating at
400 MHz for 1H NMR and 100 MHz for 13C NMR in CDCl3 unless
noted otherwise. IR spectra were obtained on a Bomen MB-100 FT
IR spectrometer. Gas chromatography was performed on a Hewlett-
Packard 5890 gas chromatograph equipped with a 25 m poly-
dimethylsiloxane capillary column. Flash column chromatography
was performed employing 200–400 mesh silica gel (EM). Thin layer
chromatography (TLC) was performed on silica gel 60 F254. Ele-
mental analyses were performed by Complete Analysis Laborato-
ries (Parsippany, NJ). p-Toluenesulfonyl isocyanate (Acros) was used
as received. Tosylureas 1,18 3–5,18 9,16 15,18 17,18 18,18 and 2311 and p-
nitrophenylurea 2127 were synthesized employing published
procedures.
d
-Alkenyl ureas 3 and 4 that
b
-position of the alkenyl
d
intramolecular alkoxyamination and diamination to form the cor-
responding heterocycles 6–8 in >85% isolated yield (Table 2, entries

H. Li, R.A. Widenhoefer / Tetrahedron 66 (2010) 4827–4831
4829
Table 2
Intramolecular alkoxyamination and diamination of g- and d C
-alkenyl ureas mediated by NIS (2 equiv) in toluene at 25 ꢀ
Entry
Substrate
NHTs
NH
Additivea
Time (h)
Isourea product
Yieldb
Urea product
Yieldb
O
NTs
O
N
R
R
N
R
R
O
NTs
R
R
1
2
3
4
5
6
R¼Me (3)
A
A
A
B
C
B
2
2
3
1
1
3
6a
7a
8a
94%
93%
86%
R¼–(CH2)5– (4)
R¼H (5)
R¼Me (3)
4b
7b
8b
97%
85%
93%
R¼–(CH2)5– (4)
R¼H (5)
O
NHTs
NTs
O
O
N
H
N
H
NH
R
R
NTs
R
7
8
9
10
11
12
R¼Ph (9)
A
B
A
B
A
B
2
3
2
1
1
2
12a
13a
14a
72% (5:1)
94% (9:1)
82% (4:1)
R¼i-Pr (10)
R¼Et (11)
R¼Ph (9)
12b
13b
14b
92% (8:1)
88% (9:1)
82% (5:1)
R¼i-Pr (10)
R¼Et (11)
O
NHTs
NH
NTs
O
N
N
O
NTs
Me
Me
16a
Me
16b
13
14
A
B
1
1
95%
88%
O
NHTs
NH
NTs
O
O
Me
Me
N
H
Me
Me
N
H
NTs
Me
Me
R
R
R
15
16
17
18
R¼Me (17)
R¼Ph (18)
R¼Me (17)
R¼Ph (18)
A
A
B
B
24
3
2
19a
20a
72% (>20:1)
83% (>20:1)
19b
20b
84% (4.5:1)
69% (>20:1)
3
O
NHAr
NH
NAr
O
Ph
Ph
N
A
B
24
16
83%
Ph
Ph
21 (Ar = 4-C6H4NO2)
22a
19
O
NHTs
NH
O
N
82%
NTs
24b
23
20
a
Additives: A¼AgOTf (20 mol %); B¼NaHCO3 (1 equiv); C¼NEt3 (1 equiv).
b
Isolated yields of >95% purity. Diastereomeric purity shown in parentheses.
4.2. Synthesis of N-alkenyl ureas
(m, 1H), 0.845 (d, J¼7.0 Hz, 3H), 0.843 (d, J¼7.0 Hz, 3H). 13C{1H}
NMR:
d 152.4, 144.6, 136.95, 136.92, 129.8, 126.9, 116.5, 44.0, 41.1,
4.2.1. 1-(2-Isopropyl-4-pentenyl)-3-tosylurea (10). p-Toluenesulfonyl
isocyanate (0.21 mL, 1.4 mmol) was added to a solution of 2-iso-
propyl-4-pentenylamine11 (0.3 g,1.4 mmol) in CH2Cl2 (10 mL) at 0 ꢀC
and the resulting mixture was stirred overnight at room tempera-
ture. The solvent was evaporated under vacuum and the resulting
oily residue was chromatographed to give 10 in 87% yield. TLC
33.4, 28.3, 21.6, 19.5, 19.1. IR (neat, cmꢁ1): 3343, 2958, 1656, 1553,
1464, 1346,1163, 891, 664. Anal. calcd (found) for C27H28N2O: H, 7.46
(7.43); C, 59.23 (59.25).
4.2.2. 1-(2-Ethyl-4-pentenyl)-3-tosylurea (11). Reaction of 2-ethyl-
4-pentenylamine28 with p-toluenesulfonyl isocyanate employing
a procedure similar to that used to synthesize 10 gave 11 in 82%
(hexanes–EtOAc¼1:1): Rf¼0.4. 1H NMR:
d 9.57 (s, 1H), 7.75 (d,
J¼8.0 Hz, 2H), 7.27 (d, J¼8.0 Hz, 2H), 6.53 (t, J¼6.0 Hz, 1H), 5.69 (tdd,
J¼6.5, 10.5, 17 Hz, 1H), 5.03–4.98 (m, 2H), 3.17 (m, 2H), 2.41 (s, 3H),
2.08 (td, J¼5.5,14 Hz,1H),1.84 (td, J¼8.0,14 Hz,1H),1.59 (m,1H),1.38
yield. TLC (hexanes–EtOAc¼3:1): Rf¼0.7. 1H NMR:
d 9.54 (s, 1H),
7.76 (d, J¼8.0 Hz, 2H), 7.24 (d, J¼8.0 Hz, 2H), 6.51 (t, J¼5.6 Hz, 1H),
5.66 (m, 1H), 4.98 (d, J¼5.2 Hz, 1H), 4.95 (s, 1H), 3.12 (t, J¼5.2 Hz,

4830
H. Li, R.A. Widenhoefer / Tetrahedron 66 (2010) 4827–4831
1H), 2.38 (s, 3H), 1.94 (m, 2H), 1.48 (septet, J¼6.8 Hz, 1H), 1.20
4.4. Syntheses of bicyclic ureas
(pentet, J¼6.8 Hz, 2H), 0.82 (t, J¼7.2 Hz, 3H). 13C{1H} NMR:
d 152.4,
144.4, 136.7, 135.9, 129.6, 126.9, 116.5, 42.6, 39.1, 35.5, 23.7, 21.4,
10.8. IR (neat, cmꢁ1): 3336, 3100, 1654, 1547, 1347, 1162, 1089, 893,
813, 664. Anal. calcd (found) for C27H28N2O: H, 7.14 (7.21); C, 58.04
(58.05).
4.4.1. Synthesis of compound 2b. A suspension of 1 (43 mg,
0.10 mmol), NIS (45 mg, 0.20 mmol), and NaHCO3 (8.4 mg,
0.10 mmol) in toluene (1.0 mL) was stirred at room temperature for
2 h. The crude reaction mixture was loaded directly onto a silica gel
column and chromatographed (SiO2; hexanes–EtOAc¼3:1) to give
2b (40 mg, 91%). TLC (hexanes–EtOAc¼3:1): Rf¼0.4. 1H NMR:
d 7.92
4.3. Synthesis of bicyclic isoureas
(d, J¼8.0 Hz, 2H), 7.34 (d, J¼8.0 Hz, 2H), 7.31–7.12 (m, 10H), 4.10–
4.07 (m, 2H), 3.93 (tt, J¼5.5, 10 Hz, 1H), 3.88 (d, J¼11.5 Hz, 1H), 3.65
(dd, J¼5.5, 9.5 Hz, 1H), 2.57 (dd, J¼5.0, 11.5 Hz, 1H), 2.47 (s, 3H), 2.26
4.3.1. Compound 2a17. A suspension of 1 (43 mg, 0.10 mmol), NIS
(45 mg, 0.20 mmol), and AgOTf (1.3 mg, 4.7ꢂ10ꢁ3 mmol) in tolu-
ene (1.0 mL) was stirred for 14 h at room temperature. The crude
reaction mixture was loaded directly onto a silica gel column and
chromatographed (hexanes–EtOAc¼1:1) to give 2 (42 mg, 95%).
(dd, J¼9.5, 12.0 Hz, 1H). 13C{1H} NMR:
d 156.3, 145.5, 145.3, 144.8,
135.0, 129.7, 128.6, 128.1, 126.8, 126.78, 126.5, 56.9, 56.2, 54.1, 48.0,
43.7, 21.7.
Remaining imidizolidin-2-ones were synthesized employing
procedures similar to that used to synthesize 2b. The 1H and 13C
NMR spectra of known compounds 6b–8b,18 16b,18 19b,17 20b,18
and 24b12 were identical to reported spectra.
TLC (hexanes–EtOAc¼1:1): Rf¼0.3. 1H NMR:
d
7.85 (d, J¼8.5 Hz,
2H), 7.32–7.14 (m, 12H), 4.70 (t, J¼9.0 Hz, 1H), 4.35 (dd, J¼7.0,
9.0 Hz, 1H), 4.31 (d, J¼11.0 Hz, 1H), 4.16 (m, 1H), 3.90 (d, J¼11.0 Hz,
1H), 2.59 (dd, J¼5.0, 11.5 Hz, 1H), 2.41 (dd, J¼10.0, 11.0 Hz, 1H), 2.40
(s, 3H). 13C{1H} NMR:
d
160.5, 144.9, 144.6, 142.5, 139.4, 129.2,
4.4.2. Compound 12b. TLC (hexanes–EtOAc¼3:1): Rf¼0.3. 1H NMR:
128.7, 128.6, 127.2, 127.1, 126.9, 126.7, 126.4, 73.3, 58.7, 58.2, 57.2,
43.1, 21.6.
Remaining bicyclic isoureas were synthesized employing pro-
cedures similar to that used to synthesize 2a. The 1H and 13C NMR
spectra of known compounds 6a–8a,17 12a,18 19a,18 and 20a18 were
identical to reported spectra.
d
7.92 (d, J¼10.0 Hz, 2H), 7.32 (d, J¼10.0 Hz, 2H), .26–7.17 (m, 3H),
7.06 (d, J¼8.5 Hz, 1H), 4.02 (dd, J¼10.0, 12.0 Hz, 1H), 3.90–3.81 (m,
2H), 3.53–3.44 (m, 3H), 2.42 (s, 3H), 2.34 (m, 1H), 1.47 (dd, J¼13.0,
28.5 Hz, 1H). 13C{1H} NMR:
d 156.4, 144.9, 141.0, 135.1, 129.7, 128.7,
128.0, 127.0, 126.9, 56.4, 52.0, 46.9, 45.5, 40.1, 21.7. IR (neat, cmꢁ1):
2963, 1725, 1359, 1166, 1091, 759, 702, 662. Anal. Calcd (found) for
C20H22N4O5S: H, 5.15 (4.96); C, 55.80 (55.67).
4.3.2. Compound 13a. TLC (hexanes–EtOAc¼1:1): Rf¼0.2. 1H NMR:
d
7.77 (d, J¼8.4 Hz, 2H), 7.17 (d, J¼8.4 Hz, 2H), 4.58 (dd, J¼8.0,
4.4.3. Compound 13b. TLC (hexanes–EtOAc¼1:1): Rf¼0.7. 1H NMR:
9.2 Hz,1H), 4.26 (dd, J¼5.2, 9.2 Hz,1H), 4.01 (tdd, J¼5.6, 8.0.10.8 Hz,
1H), 3.33 (dd, J¼8.8, 11.2 Hz, 1H), 3.18 (dd, J¼8.8, 11.2 Hz, 1H), 2.33
(s, 3H), 2.12–2.02 (m, 2H), 1.48 (septet of doublets, J¼6.4, 8.8 Hz,
1H), 1.12 (q, J¼10.8 Hz, 1H), 0.82 (d, J¼6.8 Hz, 3H). 13C{1H} NMR:
d
7.84 (d, J¼8.5 Hz, 2H), 7.25 (d, J¼8.5 Hz, 2H), 3.90 (dd, J¼9.0,
11.0 Hz, 1H), 3.66 (m, 2H), 3.10 (dd, J¼3.0, 9.0 Hz, 2H), 2.36 (s, 3H),
1.92 (m, 2H), 1.36 (tdd, J¼6.5, 9.0, 13.5 Hz, 1H), 0.95 (q, J¼11.5 Hz,
1H), 0.78 (d, J¼7.0 Hz, 6H). 13C{1H} NMR:
d 156.2, 144.7, 135.1, 129.6,
d
160.4, 142.4, 139.9, 129.1, 129.0, 127.03, 126.99, 72.9, 60.9, 60.8,
127.9, 56.1, 49.3, 47.9, 47.1, 36.2, 32.5, 21.6, 21.2, 21.1. IR (neat, cmꢁ1):
2964, 1726, 1387, 1356, 1168, 1095, 821, 662. Anal. Calcd (found) for
C13H15N3O3: H, 6.88 (6.92); C, 59.60 (59.51).
50.6, 49.4, 36.1, 32.4, 21.5, 21.2. IR (neat, cmꢁ1): 2956, 1596, 1426,
1277, 1147, 857, 682, 614. Anal. Calcd (found) for C20H22N4O5S: H,
6.88 (6.86); C, 59.60 (59.50).
4.4.4. Compound 14b. TLC (hexanes–EtOAc¼3:1): Rf¼0.7. 1H NMR:
4.3.3. Compound 14a. TLC (hexanes–EtOAc¼1:1): Rf¼0.3. 1H NMR:
d
7.89 (d, J¼8.0 Hz, 2H), 7.30 (d, J¼8.0 Hz, 2H), 3.95 (dd, J¼8.5, 9.5 Hz,
d
7.79 (d, J¼8.0 Hz, 2H), 7.20 (d, J¼8.0 Hz, 2H), 4.62 (t, J¼9.2, 1H),
1H), 3.70 (m, 1H), 3.18 (dd, J¼8.5, 11.5 Hz, 1H), 3.08 (dd, J¼8.0,
11.5 Hz, 1H), 2.41 (s, 3H), 2.22–2.14 (m, 1H), 2.11–2.06 (m, 1H), 1.33
(m, 2H), 0.98 (q, J¼10.5, 1H), 0.84 (t, J¼8.0 Hz, 3H). 13C{1H} NMR:
4.28 (dd, J¼6.0, 9.2 Hz, 1H), 4.06 (m, 1H), 3.37 (dd, J¼8.8, 10.8 Hz,
1H), 3.16 (dd, J¼8.8, 10.8 Hz, 1H), 2.36 (s, 3H), 2.30 (m, 1H), 2.13 (td,
J¼5.6, 11.6 Hz, 1H), 1.38 (pentet, J¼7.2 Hz, 2H), 1.11 (q, J¼10.8 Hz,
d
156.4, 144.8, 135.1, 129.7,128.0, 55.9, 50.4, 47.3, 42.1, 37.6, 27.1, 21.7,
1H), 0.86 (t, J¼7.2 Hz, 3H). 13C{1H} NMR:
d
160.5, 142.3, 139.8, 129.0,
12.6. IR (neat, cmꢁ1): 2962, 1726, 1358, 1165, 1092, 757, 662. Anal.
Calcd (found) for C20H22N4O5S: H, 5.15 (4.96); C, 55.80 (55.67).
126.9, 73.1, 60.6, 51.6, 43.4, 37.4, 26.8, 21.4, 12.5. IR (neat, cmꢁ1):
2961, 1585, 1440, 1284, 1152, 1080, 859, 823, 666, 613. Anal. Calcd
(found) for C20H22N4O5S: H, 5.15 (4.96); C, 55.80 (55.67).
4.5. Assignment of product relative configuration
4.3.4. Compound 16a. TLC (hexanes–EtOAc¼1:1): Rf¼0.3. 1H NMR:
The relative configuration of 13b was established by the pres-
ence of a strong cross peak relating tertiary proton Ha to bridgehead
proton Hb in the 1H–1H NOESY spectrum. The relative configura-
tions of compounds 12b, 14b, and 12a–14a were assigned based on
analogy to 13b. The relative configurations of compounds 19a, 19b,
20a, and 20b were assigned from the published spectra.17,18
d
7.79 (d, J¼8.4 Hz, 2H), 7.20 (d, J¼8.4 Hz, 2H), [4.29, 4.25, ABq,
J¼8.8 Hz, 2H], 3.77 (d, J¼12.4 Hz, 1H), 2.81 (d, J¼12.4 Hz, 1H), 2.36
(s, 3H), [1.67, 1.58, ABq, J¼13.2 Hz, 2H], 1.47–1.27 (m, 8H), 1.32 (s,
3H), 1.15–1.03 (m, 2H). 13C{1H} NMR:
d 161.5, 142.2, 139.8, 128.9,
126.9, 81.1, 66.2, 56.4, 50.2, 45.9, 37.5, 36.5, 26.8, 25.3, 23.8, 22.9,
21.5. IR (neat, cmꢁ1): 2925, 1595, 1311, 1156, 816, 663. Anal. Calcd
(found) for C20H22N4O5S: H, 5.15 (4.96); C, 55.80 (55.67).
O
i-Pr
Ha
N
13b
NTs
4.3.5. Compound 22a. TLC (hexanes–EtOAc¼3:1): Rf¼0.6. 1H NMR:
d
8.13 (d, J¼8.0 Hz, 2H), 7.38 (d, J¼8.0 Hz, 2H), 7.31–7.18 (m, 10H),
Hb
4.90 (br d, J¼14.0, 1H), 4.56 (m, 1H), 3.79 (m, 2H), 3.05 (dd, J¼1.2,
14.0 Hz, 1H), 2.75 (br d, J¼13.6 Hz, 1H), 2.37 (dt, J¼2.8, 13.6 Hz, 1H),
1.91 (qd, J¼2.8, 13.2 Hz, 1H), 1.25 (br q, J¼13 Hz, 1H). 13C{1H} NMR:
NOE
d
155.0, 152.6, 146.5, 143.8, 142.0, 128.6, 128.5, 127.7, 126.7, 126.5,
Acknowledgements
126.3, 124.7, 123.8, 71.5, 55.1, 50.0, 46.0, 33.8, 26.1. IR (neat, cmꢁ1):
1648, 1567, 1495, 1316, 1265, 1002, 859, 697. HRMS calcd (found) for
C25H23N3O3 (Mþ): 413.1739 (413.1756).
Acknowledgement made to the NIH (GM-080422) for support of
this research.

H. Li, R.A. Widenhoefer / Tetrahedron 66 (2010) 4827–4831
4831
18. Mun˜iz, K.; Ho¨velmann, C. H.; Campos-Go´ mez, E.; Barluenga, J.; Gonza´lez, J. M.;
Streuff, J.; Nieger, M. Chem. Asian J. 2008, 3, 776–788.
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