Intramolecular aza-[4+3] cycloaddition reactions of α- halohydroxamates

Article abstract of DOI:10.1055/s-0033-1338883

Polyheterocyclic scaffolds were prepared by intramolecular aza-[4+3] cycloaddition reactions of aza-oxyallylic cations with cyclic dienes. The aza-oxyallylic cation was generated in situ by the dehydrohalogenation of α-halohydroxamates. The highly functionalized heterocyclic products undergo a variety of reactions that provide useful scaffolds for target-directed synthesis, including macrocyclic furans and polyhydroxylated azepanes. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338883

PAPER
▌1825
paper
Intramolecular Aza-[4+3] Cycloaddition Reactions of α-Halohydroxamates
Intramolecular Cycloaddition Reactions of Aza-Oxyallylic Cations
Arjun Acharya, John A. Eickhoff, Christopher S. Jeffrey*
Department of Chemistry, University of Nevada, Reno, 1664 N. Virginia St. Mail Stop 0216, Reno, NV 89557, USA
Fax +1(775)7846804; E-mail: cjeffrey@unr.edu
Received: 22.04.2013; Accepted: 06.05.2013
This article is dedicated in honor of Professor Scott Denmark’s 60th birthday.
Intramolecular variants of the [4+3] cycloaddition of oxy-
Abstract: Polyheterocyclic scaffolds were prepared by intramolec-
allylic cations with dienes are established as powerful
ular aza-[4+3] cycloaddition reactions of aza-oxyallylic cations
methods for target-directed synthesis.5 Like the all-carbon
[4+3] cycloadditions, we envisioned that analogous aza-
with cyclic dienes. The aza-oxyallylic cation was generated in situ
by the dehydrohalogenation of α-halohydroxamates. The highly
functionalized heterocyclic products undergo a variety of reactions [4+3] methods would provide access to new classes of
that provide useful scaffolds for target-directed synthesis, including
macrocyclic furans and polyhydroxylated azepanes.
polyheterocyclic scaffolds for target-directed synthesis
and drug discovery (Scheme 1, B). Herein, we report our
Key words: cycloaddition, nitrogen, azasugars, heterocycles, mac-
rocycles
investigation of the intramolecular aza-[4+3] cycloaddi-
tion and its application to the synthesis of various polyhet-
erocyclic scaffolds.
The intramolecular cycloaddition of oxyallylic cations
has been categorized based upon the connectivity of the
diene and dienophilic reactants.5f,j Type I [4+3]-cycload-
dition reactions are the most commonly explored type and
are characterized by the tethering of diene and dienophilic
reactants through their termini. Two possible modes of
type I cycloaddition reactions are available when consid-
ering the aza-[4+3] cycloaddition and are differentiated
by whether the diene is tethered through the nitrogen or
carbon terminus of the eventual aza-allylic cation. The
type I′ aza-[4+3]-cycloaddition reaction, whereby the di-
ene and dienophilic components are tethered through the
N–O bond, was the subject of our initial studies (Scheme
1, B).
Polyheterocyclic compounds are an important class of
small molecules used in drug discovery and natural prod-
uct synthesis.1 Our group has reported an efficient method
for the synthesis of caprolactams and diazepanones using
an aza-[4+3] cycloaddition of a transient aza-oxyallylic
cation with a diene (Scheme 1, A).2 The aza-allylic cation
was formed in situ via dehydrohalogenation of α-halo
benzylhydroxylamines or N-chlorourea derivatives. The
oxygen donor group was essential for the success of this
reaction, and was computationally identified to stabilize
the proposed intermediate.2a,3,4
A. Established: the intermolecular [4+3] cycloaddition of aza-oxyallyl cations
Difficulties associated with the incorporation and stability
of haloketones into the cycloaddition precursors have lim-
ited the number of examples of all-carbon intramolecular
[4+3] cycloaddition triggered by dehydrohalogenation.6
In order to circumvent problems associated with incorpo-
rating this reactive and labile functional group, we have
designed our approach such that a late stage amide cou-
ples with α-haloacid halides and a diene-tethered hydrox-
ylamine 8. To establish the feasibility of this strategy, the
hydroxylamine 8 was synthesized from 2-furanpropanol
(7) in two steps (Scheme 2). Acylation of the hydroxyl-
amine with 2-bromo-2-propanoyl bromide provided the
cycloaddition precursor 9 for our initial studies.
O
O
O
R2
OBn
R2
X
– HX
[4+3]
A
R1
R2
OBn
R1
N
OBn
N
H
N
A
R1
1
2
3
an aza-oxyallyl cation
B. This work: the intramolecular [4+3] cycloaddition of aza-oxyallyl cations
O
O
O
O
R2
X
R1
O
R2
O
O
O
N
N
[4+3]
R2
R1
H
N
R1
– HX
O
Treatment of the α-haloamide 9 under the Föhlisch condi-
tions (Et3N, CF3CH2OH)7 provided the tricyclic product
10, representing the first example of a type I′ intramolec-
ular aza-[4+3]-cycloaddition reaction.7 Further attempts
at optimization of this reaction provided variable results,
predominantly due to the competitive elimination or sol-
volysis of the haloamide functional group.2a
4
5
6
Scheme 1 The concept for the intramolecular aza-[4+3]-cycloaddi-
tion reaction of aza-oxyallylic cations
SYNTHESIS 2013, 45, 1825–1836
Advanced online publication: 12.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338883; Art ID: SS-2013-C0307-OP
© Georg Thieme Verlag Stuttgart · New York

1826
A. Acharya et al.
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Table 1 Evaluation of Effect of Reaction Conditions for the Cyclo-
adduct Product 10
H2N
O
1) N-hydroxyphthalimide
O
HO
Ph3P, DEAD
O
O
O
O
O
Et
2) NH2NH2⋅H2O
Et
Et
Br
O
O
O
N
N
O
O
N
conditions
H
+
7
8
see Table 1
9
endo-10
exo-10
O
Entry
Conditionsa
Concn (M)
Time Yield (%)b
(dr, endo/exo)c
O
O
Et
O
Et
Br
Et3N, CF3CH2OH
0 °C
O
N
O
N
H
1
2
3
4
Et3N, TFE
Et3N, TFE
Na2CO3, TFE
0.025 M
0.25 M
0.25 M
0.25 M
2 d
46 (3:1)
40 h
4 d
68 (3:1)
49 (2.5:1)
68 (2:1)
10
9
Scheme 2 The first example of an intramolecular aza-[4+3] cycload-
dition of α-halohydroxamates with an appended furan
Et3N, LiClO4,
Et2O, reflux
2 d
5
Et3N, HFIP
0.25 M
10 d
84 (2.1:1)
Overall, the best results were obtained when conducting
the reaction at 0.25 M using triethylamine as the base (Ta-
a All reactions were conducted by adding the base to a solution of the
substrate in the specified solvent at 0 °C. After the addition, the mix-
ble 1, entry 2). Running the reaction at concentrations ture was allowed to warm to r.t. until complete consumption of start-
ing material; TFE: CF3CH2OH; HFIP: (CF3)2CHOH.
lower than 0.25 M did not improve the yield of the cyclo-
adduct and resulted in slow reaction rates (entry 1). Our
b Reaction yields represent the combined yield of both the isolated
diastereoisomeric cycloadducts.
previous studies of the intermolecular aza-[4+3]-cycload-
dition reaction demonstrated that sodium carbonate was
an effective base. However, in the intramolecular case, the
use of sodium carbonate slowed the reaction rate (entry 3).
Reaction of the halohydroxamate with LiClO4 and trieth-
ylamine in anhydrous diethyl ether provided good yield of
the cycloadduct 10 with diminished diastereoselectivity
(entry 4).8
c Diastereoisomeric ratio (dr) was determined via crude 1H NMR
analysis of the mixture after workup.
with the diastereoselectivity observed for other type I in-
tramolecular [4+3]-cycloaddition reactions of haloke-
tones with furans (entries 2, 3, 6, 7, and 9, 10). With
respect to the diene reactant, N-Boc-pyrrole containing
substrates underwent the cycloaddition in good yield and
better diastereoselectivity compared with the furan sub-
strates (entries 5–7). A 5-methyl-substituted furan sub-
strate provided the tricyclic product in good yield (entry
10). Interestingly, the incorporation of a fused aryl group
in the 6-atom tether provided the cycloadduct (entries 8,
9) with excellent diastereoselectivity (entry 9). The rigid-
ity of the unsaturated system likely reduces the degrees of
freedom in the side-chain resulting in the enhanced yield
and diastereoselectivity. Finally, the effect of a side-chain
stereogenic center on the diastereoselectivity of the cyclo-
addition reaction was studied. As shown, methyl substitu-
tion at the benzylic position had little effect on the
diastereoselectivity of the reaction, resulting in only a
~2:1 ratio of diastereoisomers under a variety of condi-
tions (entry 11).
The scope of the aza-[4+3]-cycloaddition reaction of six-
atom tethered substrates was evaluated with respect to di-
ene, α-hydroxamate substitution, and tether substitution
(Table 2). The cycloaddition precursors for these studies
were easily prepared in three to five steps by homologa-
tion of various 2-substituted furan or pyrrole alcohols or
by direct installation of the tethering unit from the parent
heterocycle (see Supporting Information for details). In all
cases, reactions under the standard conditions provided
the cycloadducts in fair to good yield. The use of hexa-
fluoroisopropanol (HFIP) as the solvent improved the
overall yield of reactions of α,α′-dialkylhaloamide sub-
strates (Table 2, entries 2, 4, 5, 11) by minimizing the
competitive solvolysis with trifluoroethanol.2a,9 Unlike
the intermolecular analogues of this reaction, the mono-
substituted haloamides provided only marginal diastereo-
selectivity for the endo-cycloadduct, which is consistent
Synthesis 2013, 45, 1825–1836
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Intramolecular Cycloaddition Reactions of Aza-Oxyallylic Cations
1827
Table 2 Evaluation of the Substrate Scope for the Intramolecular Aza-[4+3] Reactions of 6-Atom-Tethered Halogenated Hydroxamates with
Various Dienes
Entry
Substrate
Reaction conditionsa
Product
Yield (%)b (dr, endo/exo)c
Br
H
O
N
O
O
1
TFE, Et3N, 3 h
47
N
O
O
O
Cl
Cl
O
H
O
N
Cl
Et
H
O
O
TFE, Et3N, 48 h
HPIP, Et3N, 72 h
68 (1:1)
79 (2.5:1)
N
2
3
4
5
O
O
Br
O
H
N
Et
O
O
N
see Table 1
see Table 1
O
O
O
Br
O
H
N
O
O
N
Et3N, HFIP, 20 h
74
O
O
O
Br
H
N
Boc
O
Et3N, TFE, 5 h
Et3N, HFIP, 24 h
Na2CO3, TFE, 20 h
45
85
56
O
O
N
O
N
Boc
N
Cl
Cl
O
H
Boc
O
O
N
Cl
Et
H
Et3N, TFE, 40 h
Et3N, HFIP, 65 h
Na2CO3, TFE, 72 h
66 (4:1)
61 (5:1)
60 (4.8:1)
O
Boc
N
O
O
6
7
N
N
N
Br
H
Boc
N
Et
Et3N, TFE, 18 h
Et3N, HFIP, 12 d
Na2CO3, TFE, 40 h
48 (4:1)
57 (3:1)
49 (4.1:1)
O
Boc
N
N
O
Br
O
O
HN
O
O
N
O
8
Et3N, HFIP, 3 h
71
O
Br
Et
O
O
Et
HN
O
O
N
O
Et3N, TFE, 12 h
Et3N, HFIP, 13 d
63 ( 19:1)
69 ( 19:1)
9
O
© Georg Thieme Verlag Stuttgart · New York
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A. Acharya et al.
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Table 2 Evaluation of the Substrate Scope for the Intramolecular Aza-[4+3] Reactions of 6-Atom-Tethered Halogenated Hydroxamates with
Various Dienes (continued)
Entry
Substrate
Reaction conditionsa
Product
Yield (%)b (dr, endo/exo)c
Br
O
H
Et
N
Et
Et3N, TFE, 18 h
Et3N, HFIP, 14 d
67 (2.2:1)
75 (3:1)
O
O
O
10
N
N
O
O
O
Br
O
H
N
Et3N, TFE, 16 h
Et3N, HFIP, 20 h
Na2CO3, TFE, 30 h
65 (2.6:1; α/β)
95 (2:1; α/β)
60 (2.4:1; α/β)
O
O
11
O
O
a All reactions were conducted by adding the base to a solution of the substrate in the specified solvent at 0 °C. After the addition, the mixture
was allowed to warm to r.t. until complete consumption of the starting material. HFIP = (CF3)2CHOH; TFE = CF3CH2OH.
b Reaction yields represent the combined yield of both isolated diastereoisomeric cycloadducts.
c Diastereoisomeric ratio (dr) was determined via crude 1H NMR analysis of the mixture after workup.
Shortening the tether length to a five-atom tether provided methacrylamide. Extension of the tether from 6 to 7 atoms
better yields of the cycloadduct when compared with the provided the corresponding 1,2-oxazepane products in
six-atom tethered analogues with diminished diastereose- good yield in all cases (entries 5–7). Again, the diastereo-
lectivity (Table 3, entries 2–4). Interestingly, the ethyl- selectivity in these examples remained close to identical
substituted substrate with the five-atom tether demon- to the six-membered analogues. Further extension to an
strated a preference for the exo-cycloadduct (entry 4) The eight-atom tether provided exclusive formation of a mac-
attempted cycloaddition reactions of a 2-furylmethanol rocyclic product, which was the subject of our following
tethered amide failed to close the strained four-membered investigations (entry 8).
oxazetidine and instead resulted in only elimination to the
Table 3 Evaluation of the Effect of Variable Tether Length on the Yield of the Intramolecular Aza-[4+3] Reactions of Halohydroxamates
Entry
Substrate
Reaction conditionsa
Product
Yield (%)b (dr, endo/exo)c
O
O
O
O
1
Et3N, HFIP, reflux, 2 d
n.d.
O
O
N
N
Br
Br
H
H
H
O
N
O
O
N
2
3
4
5
Et3N, HFIP, 1 h
Et3N, HFIP, 30 h
82
O
O
O
Cl
O
H
N
Cl
Et
Cl
Et
O
O
N
91 (3:2)
O
O
O
Br
O
H
N
Et3N, TFE, 16 h
Et3N, HFIP, 12 d
Na2CO3, TFE, 30 h
85 (1:2.8)
83 (1:2.3)
75 (1:2.5)
O
O
N
O
O
O
O
O
O
O
N
H
Et3N, TFE, 1 h
Et3N, HFIP, 1 h
30
51
Br
N
O
O
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Intramolecular Cycloaddition Reactions of Aza-Oxyallylic Cations
1829
Table 3 Evaluation of the Effect of Variable Tether Length on the Yield of the Intramolecular Aza-[4+3] Reactions of Halohydroxamates (continued)
Entry
6
Substrate
Reaction conditionsa
Et3N, HFIP, 36 h
Product
Yield (%)b (dr, endo/exo)c
O
O
Cl
Cl
O
O
N
H
O
N
91 (1:1.1)
O
Cl
O
O
O
O
Et
Et
N
H
O
Br
7
8
Et3N,TFE, 18 h
N
67 (1:1.5)
O
O
O
O
N
NH
O
H
Br
Et3N, HFIP, 18 h
50
O
O
a All reactions were conducted by adding the base to a solution of the substrate in the specified solvent at 0 °C. After the addition, the mixture
was allowed to warm to r.t. until complete consumption of starting material; n.d.: not detected.
b Reaction yields represent the combined yield of both isolated diastereoisomeric cycloadducts.
c Diastereoisomeric ratio (dr) was determined via crude 1H NMR analysis of the mixture after workup.
Isolation of the interesting macrocyclic product led us to
consider two mechanistic pathways for the formation of
O
O
Et
Et
O
aza-[4+3]
O
N
n
the heterocylophane 13b: (1) direct electrophilic aromatic
substitution at the electrophilic carbon atom of the aza-
oxyallylic cation or (2) the [4+3] cycloaddition to provide
12b followed by rearrangement to the furan 13b. Given
the exclusive selectivity for the 2,5-disubstituted macro-
cyclic product 13b, we propose that the macrocyclic prod-
uct is the result of the stepwise process that proceeds
through 12b. Indeed, isolation of the cycloadduct 12a and
treatment with acid provided quantitative conversion to
the heterocyclophane 13a in support of this two-step path-
way (Scheme 3). Further investigations of the scope of
this formal heteromacrocyclization are under way.
H
N
O
Br
O
n
11a, n = 1
11b, n = 2
12a, n = 1
12b, n = 2
13a
direct
electrophilic
aromatic
substitution
quant yield for
O
O
Et
O
NH
aromatization
O
N
n
O
H
O
n
Et
13a, n = 1
13b, n = 2
The heterocyclic products formed via the intramolecular
aza-[4+3] cycloaddition provide highly functionalized
building blocks for organic synthesis. The array of orthog-
onal functional groups present in the tricyclic product pro-
vides ample opportunities for the synthesis of biologically
active classes of heterocycles, including nucleoside mim-
Scheme 3 Preliminary mechanistic studies of the origin of the mac-
rocyclic products 13a and 13b (n = 1, 2)
ics and polyhydroxylated azepanes.10 The alkene moiety benium ion and aromatization. Reductive opening of the
underwent diastereoselective oxidation from the concave caprolactam 14 using lithium aluminum hydride occurred
face of the [3.2.1]-azabiocyclooctane ring of 14 providing in good yield to provide the cyclic oxime 19. The presence
the epoxide 15 and diol 16 in good yield (Scheme 4). Cat- of the aldehyde in 19 suggests that half reduction occurs
alytic hydrogenation of the alkene 14 using palladium on to form a stable tetrahedral intermediate that opens to the
carbon selectively provided the saturated heterocycle 17 aldehyde upon workup. Protection of the dihydroxylated
without cleavage of the weak N–O bond. Attempted derivative 16 and treatment of the ketal 20 with Mo(CO)6
cleavage of the 1,2-hydroxazine of the lactam 14 using provided the lactam 21 in excellent yield, demonstrating
Mo(CO)6 provided the furan 18 in excellent yield.11 For- that the N–O bond in the [3.2.1]-bicyclo product can be
mation of the furan 18 presumably proceeds via Lewis cleaved in the absence of the dihydrofuran moiety
acid catalyzed rupture of the aminal moiety to an oxocar- (Scheme 4).
© Georg Thieme Verlag Stuttgart · New York
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A. Acharya et al.
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O
O
O
N
Mo(CO)6
O
O
OsO4, NMO
MeCN–H2O (9:1)
N
H2N
O
reflux, 12 h
O
MeCN–H2O–acetone (1:1:2)
r.t.,16 h
OH
O
14
18
97%
HO
OH
16
LiAlH4
THF
92%
0 °C
O
O
N
O
O
N
O
H
OH
O
O
N
O
O
15
93%
19
68%
17
86%
O
O
O
OMe
MeO
NH
N
OH
O
O
Mo(CO)6
16
CSA, CH2Cl2, 2 h
MeCN–H2O (9:1)
reflux, 4 h
O
O
O
O
20
97%
21
88%
Scheme 4 Examples of derivatization reactions of the [3.2.1]-azabicyclononane 14
6700 FT-IR with a diamond ATR and data are reported as cm–1.
High-resolution mass spectra were obtained using an Agilent 6230
TOF LC/MS with an (atmospheric pressure photoionization (APPI)
or electrospray (ESI) source with purine and HP-0921 as an internal
calibrants.
In conclusion, intramolecular [4+3] cycloaddition reac-
tions of α-halohydroxamates and cyclic aromatic dienes
have been established as methods for the construction of
polyheterocyclic caprolactams. Substrates containing fu-
ran and pyrrole dienes, a variety of α-substituents, and
variable tether lengths provided the cycloadducts in fair to
good yield. Attempts to close an eight-membered hydrox-
azocene 12b resulted in the formation of a macrocyclic fu-
ran 13b. The [3.2.1]-azabicyclononane core could be
converted to a variety of highly substituted heterocyclic
products, including macrocycles, polyhydroxylated cap-
rolactams, and oxazines.
[4+3]-Cycloaddition Reactions; General Procedure
To a solution of haloamide (1 equiv) in TFE or HFIP (0.25 M with
respect to haloamide) was added Et3N or Na2CO3 (2 equiv) at 0 °C.
The solution was allowed to warm to r.t. and the reaction was mon-
itored to completion by TLC (3:1 or 2:1 hexanes–EtOAc). After the
reaction was complete, the volatiles were removed under reduced
pressure, and the residue was purified by flash column chromatog-
raphy (9:1 to 3:1, hexanes–EtOAc) to provide the respective cyclo-
adduct.
(±)-(1S,9S,Z)-8,8-Dimethyl-5,12-dioxa-6-azatricyc-
lo[7.2.1.01,6]dodec-10-en-7-one (Table 2, entry 1)
Prepared in 47% yield (33 mg, 0.16 mmol) as a white solid from
1-[O-3-(2-furyl)propyloxyamino]-2-bromo-2-methylpropan-1-one
(100 mg, 0.34 mmol) via the general procedure; mp 115.1–
116.6 °C; Rf = 0.22 (1:1 hexanes–EtOAc).
All reactions were carried out under an atmosphere of N2 in oven-
dried glassware with magnetic stirring, unless otherwise specified.
CH2Cl2 was purified by passage through a bed of activated alumina.
All other reagents and solvents were purchased from Sigma-Aldrich
Chemical Company and used without any further purification. TLC
information was recorded on Silicycle glass 60 F254 plates and de-
veloped by staining with KMnO4 or ceric ammonium molybdate
(CAM). Purification of reaction products was carried out by flash
chromatography using Silicycle Siliaflash® P60 (230–400 mesh).
1H NMR spectra were measured on Varian 400 (400 MHz), Varian
MR400 (400 MHz), or Varian 500 (500 MHz) spectrometers and
are reported in ppm. Standard abbreviations were used to denote
signal multiplicities; coupling constant(s) are in Hz. TMS was used
as an internal standard (TMS at 0.00 ppm) in CDCl3. 13C NMR
spectra were recorded on V400 or V500 spectrometer and reported
in ppm using solvent as an internal standard (CDCl3 at 77.16 ppm
and CD3OD at 49.86 ppm). IR spectra were recorded on a Nicolet
FT-IR (ATR, neat): 3080, 2945, 2870, 1676, 1456, 1445, 1385,
1357, 1331, 1316, 1304, 1279, 1261, 1224, 1176, 1104, 1062 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.77 (d, J = 5.9 Hz, 1 H), 6.47
(ddd, J = 5.9, 2.0, 0.9 Hz, 1 H), 4.48 (d, J = 2.0 Hz, 1 H), 4.21
(dddd, J = 11.6, 4.6, 4.6, 1.7 Hz, 1 H), 3.92 (ddd, J = 11.7, 2.3, 2.3
Hz, 1 H), 2.04 (m, 3 H), 1.88 (m, 1 H), 1.50 (s, 3 H), 1.07 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 175.0, 136.2, 134.9, 97.3, 86.3,
70.5, 49.9, 29.1, 26.8, 23.6, 20.1.
HRMS (ESI): m/z calcd for C11H15NO3 + Na (M + Na)+: 232.0944;
found: 232.0946.
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Intramolecular Cycloaddition Reactions of Aza-Oxyallylic Cations
1831
(±)-(1S,8S,9S,Z)-8-Chloro-5,12-dioxa-6-azatricyclo[7.2.1.01,6]do-
dec-10-en-7-one and (±)-(1S,8R,9S,Z)-8-Chloro-5,12-dioxa-6-
azatricyclo[7.2.1.01,6]dodec-10-en-7-one (Table 2, entry 2)
Prepared in 38% yield (32 mg, 0.15 mmol) as a white solid from 1-
[O-3-(2-furyl)propyloxyamino]-2,2-dichloroethan-1-one (100 mg,
0.40 mmol) via the general procedure.
(dd, J = 8.6, 6.2 Hz, 1 H), 2.16–1.97 (m, 4 H), 1.95–1.83 (m, 2 H),
1.08 (t, J = 7.5 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.4, 135.2, 134.8, 97.3, 80.1,
70.6, 53.3, 28.9, 25.0, 23.7, 11.9.
HRMS (ESI): m/z calcd for C11H15NO3 + Na (M + Na)+: 232.0944;
found: 232.0933.
endo-Diastereoisomer
(±)-(1S,9S,Z)-5,12-Dioxa-4-azatetracyclo[7.2.1.52,2.04,9]hepta-
dec-10-en-3-one (Table 2, entry 4)
Prepared in 74% yield (55 mg, 0.22 mmol) as a white solid from
(±)-[O-3-(2-furyl)propyloxyamino](1-bromocyclohexyl)formalde-
hyde (100 mg, 0.30 mmol) via the general procedure; mp 139.4–
141.2 °C; Rf = 0.33 (1:1 hexanes–EtOAc).
Mp >116 °C (dec.); Rf = 0.32 (1:1 hexanes–EtOAc).
FT-IR (ATR, neat): 3098, 2967, 2937, 2919, 2855, 1701, 1591,
1435, 1358, 1348, 1338, 1279, 1261, 1226, 1190, 1147, 1096 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.87 (d, J = 6.0 Hz, 1 H), 6.57 (dd,
J = 6.0, 1.9 Hz, 1 H), 5.14 (dd, J = 5.1, 1.9 Hz, 1 H), 4.85 (d, J = 5.1
Hz, 1 H), 4.29–4.22 (m, 1 H), 3.96 (ddd J = 12.2, 2.6, 2.6 Hz, 1 H),
2.14–1.89 (m, 4 H).
13C NMR (126 MHz, CDCl3): δ = 164.8, 137.8, 133.1, 98.2, 81.3,
70.8, 57.8, 28.8, 23.3.
HRMS (ESI): m/z calcd for C9H10ClO3 + Na (M + Na)+: 240.0215;
found: 240.0198.
FT-IR (ATR, neat): 3091, 2936, 2849, 1678, 1595, 1453, 1355,
1324, 1290, 1275, 1262, 1222, 1206, 1185, 1146, 1103, 1089 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.76 (d, J = 6.0 Hz, 1 H), 6.47 (dd,
J = 5.9, 2.1 Hz, 1 H), 4.94 (d, J = 2.1 Hz, 1 H), 4.20 (dddd, J = 11.7,
4.6, 4.6, 1.6 Hz, 1 H), 3.91 (ddd, J = 11.7, 2.2, 2.2 Hz, 1 H), 2.14–
1.74 (m, 8 H), 1.67–1.56 (m, 3 H), 1.49–1.23 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 175.1, 136.3, 134.8, 97.1, 82.1,
70.4, 53.8, 33.9, 29.1, 29.0, 25.4, 23.7, 21.5, 21.3.
exo-Diastereoisomer
Mp 115.3–116.8 °C; Rf = 0.21 (1:1 hexanes–EtOAc).
HRMS (ESI): m/z calcd for C14H20NO3 (M + H)+: 250.1438; found:
250.1438.
FT-IR (ATR, neat): 3095, 2992, 2963, 2922, 2856, 1683, 1591,
1440, 1361, 1346, 1330, 1289, 1262, 1236, 1211, 1195, 1145, 1094
cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.94 (d, J = 5.8 Hz, 1 H), 6.42
(ddd, J = 5.9, 2.1, 1.0 Hz, 1 H), 5.02 (d, J = 2.2 Hz, 1 H), 4.25
(dddd, J = 11.6, 3.4, 3.4, 1.7 Hz, 1 H), 4.17 (d, J = 1.1 Hz, 1 H), 4.01
(ddd, J = 11.6, 2.6, 2.6 Hz, 1 H), 2.24 (ddd, J = 3.9, 5.3, 5.3 Hz, 1
H), 2.15–1.91 (m, 4 H).
tert-Butyl (±)-(1R,9S,Z)-8,8-Dimethyl-7-oxo-5-oxa-6,12-diaza-
tricyclo[7.2.1.01,6]dodec-10-ene-12-carboxylate (Table 2, entry
5)
Prepared in 85% yield (67 mg, 0.38 mmol) as a white solid from
tert-butyl
2-{3-[N-2-bromo-2-methylpropionyl(aminooxy)]pro-
pyl}-1H-pyrrole-1-carboxylate (100 mg, 0.26 mmol) via the gener-
al procedure; mp 130.9–131.8 °C; Rf = 0.36 (4:6 hexanes–EtOAc).
13C NMR (126 MHz, CDCl3): δ = 164.4, 138.8, 131.6, 97.6, 82.9,
70.8, 56.3, 28.4, 23.4.
HRMS (ESI): m/z calcd for C9H10ClO3 + Na (M + Na)+: 240.0215;
found: 240.0212.
FT-IR (ATR, neat): 2994, 2975, 2932, 2863, 1703, 1683, 1603,
1468, 1461, 1441, 1385, 1375, 1366, 1351, 1341, 1331, 1306, 1283,
1253, 1272, 1219, 1233, 1196, 1168, 1148, 1111, 1082 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.77 (d, J = 6.1 Hz, 1 H), 6.43 (dd,
J = 6.0, 2.7 Hz, 1 H), 4.56 (d, J = 2.7 Hz, 1 H), 4.23 (dddd, J = 11.4,
4.5, 2.7, 1.8 Hz, 1 H), 4.07 (ddd, J = 11.1, 3.4, 3.2 Hz, 1 H), 3.42
(ddd, J = 13.2, 5.2, 5.0 Hz, 1 H), 2.07 (dddd, J = 13.9, 3.9, 3.9, 1.7
Hz, 1 H), 2.03 (ddd, J = 14.0, 3.9, 3.9, 1.7 Hz, 1 H), 2.01–1.88 (m,
2 H), 1.49 (s, 9 H), 1.41 (s, 3 H), 1.13 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 177.2, 150.6, 139.0, 134.6, 82.4,
81.1, 70.5, 66.6, 51.3, 28.3, 26.7, 26.2, 22.9, 21.9.
HRMS (ESI): m/z calcd for C16H25N2O4 (M + H)+: 309.1809; found:
309.1823.
(±)-(1S,8S,9S,Z)-8-Ethyl-5,12-dioxa-6-azatricyclo[7.2.1.01,6]do-
dec-10-en-7-one and (±)-(1S,8R,9S,Z)-8-Ethyl-5,12-dioxa-6-
azatricyclo[7.2.1.01,6]dodec-10-en-7-one (Table 2, entry 3)
Prepared in 68% yield (48 mg, 0.23 mmol) as a white solid from
(±)-1-[O-3-(2-furyl)propyloxyamino]-2-bromobutan-1-one (100
mg, 0.34 mmol) via the general procedure.
endo-Diastereoisomer
Mp 119.5–121.6 °C; Rf = 0.27 (1:1 hexanes–EtOAc).
FT-IR (ATR, neat): 3089, 2985, 2963, 2936, 2883, 2867, 2360,
2337, 2163, 1682, 1591, 1474, 1463, 1450, 1430, 1388, 1356, 1320,
1296, 1281, 1266, 1241, 1222, 1200, 1144, 1119, 1096 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.77 (d, J = 6.0 Hz, 1 H), 6.42
(ddd, J = 6.0, 1.9, 0.9 Hz, 1 H), 4.99 (dd, J = 5.0, 1.9 Hz, 1 H), 4.22
(dddd, J = 11.7, 4.7, 4.7, 1.5 Hz, 1 H), 3.93 (ddd, J = 11.8, 2.4, 2.4
Hz, 1 H), 3.04 (dt, J = 9.9, 5.1 Hz, 1 H), 2.15–1.95 (m, 4 H), 1.24–
1.15 (m, 2 H), 1.04 (t, J = 7.5 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 171.4, 136.7, 133.8, 97.3, 80.5,
70.6, 52.5, 29.3, 23.7, 19.3, 12.1.
HRMS (ESI): m/z calcd for C11H16NO3 (M + H)+: 210.1125; found:
210.1128.
tert-Butyl (±)-(1R,8S,9S,Z)-8-Chloro-7-oxo-5-oxa-6,12-diazatri-
cyclo[7.2.1.01,6]dodec-10-ene-12-carboxylate and tert-Butyl
(±)-(1R,8R,9S,Z)-8-Chloro-7-oxo-5-oxa-6,12-diazatricyc-
lo[7.2.1.01,6]dodec-10-ene-12-carboxylate (Table 2, entry 6)
Prepared in 61% yield (55 mg, 0.18 mmol) as a white solid from
tert-butyl 2-{3-[N-2,2-dichloroacetyl(aminooxy)]propyl}-1H-pyr-
role-1-carboxylate (100 mg, 0.29 mmol) via the general procedure.
endo-Diastereoisomer
Mp 141.1–144.0 °C; Rf = 0.6 (4:6 hexanes–EtOAc).
FT-IR (ATR, neat): 3088, 2981, 2948, 2968, 2912, 2864, 1701,
1603, 1481, 1449, 1337, 1311, 1280, 1293, 1252, 1206, 1157, 1108,
1070 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.81 (d, J = 6.2 Hz, 1 H), 6.46 (dd,
J = 6.2, 2.7 Hz, 1 H), 4.93 (dd, J = 4.7, 2.7 Hz, 1 H), 4.88 (d, J = 4.7
Hz, 1 H), 4.25 (dddd, J = 11.6, 4.2, 2.1, 2.1 Hz, 1 H), 4.04 (dd,
J = 11.5, 2.6, 2.6 Hz, 1 H), 3.50 (br s, 1 H), 2.05–1.88 (m, 3 H), 1.52
(s, 9 H).
exo-Diastereoisomer
Mp 108.4–110.9 °C; Rf = 0.20 (1:1 hexanes–EtOAc).
FT-IR (ATR, neat): 3083, 2963, 2933, 2867, 1686, 1590, 1553,
1442, 1358, 1321, 1286, 1272, 1234, 1145, 1199, 1094 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.71 (d, J = 5.9 Hz, 1 H), 6.43 (dd,
J = 5.9, 2.1 Hz, 1 H), 4.79 (d, J = 2.2 Hz, 1 H), 4.22 (dddd, J = 11.7,
4.6, 4.6, 1.7 Hz, 1 H), 3.94 (ddd, J = 11.8, 2.4, 2.4 Hz, 1 H), 2.36
13C NMR (126 MHz, CDCl3): δ = 166.9, 151.4, 140.2, 131.3, 82.8,
82.5, 70.6, 63.7, 58.8, 28.3, 25.9, 22.8.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1825–1836

1832
A. Acharya et al.
PAPER
HRMS (ESI): m/z calcd for C14H19ClN2O4 + Na (M + Na)+:
337.0926; found: 337.0948.
1H NMR (500 MHz, CDCl3): δ = 7.41–7.35 (m, 3 H), 7.14–7.12 (m,
1 H), 6.70 (d, J = 6.0 Hz, 1 H), 6.43 (dd, J = 5.7, 1.9 Hz, 1 H), 5.30
(dd, J = 14.3, 0.6 Hz, 1 H), 5.00 (d, J = 14.4 Hz, 1 H), 4.70 (d,
J = 1.9 Hz, 1 H), 1.53 (s, 3 H), 1.15 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 174.0, 138.9, 134.7, 134.0, 131.0,
128.8, 127.7, 126.1, 124.0, 95.8, 87.3, 71.6, 49.6, 26.9, 20.0.
exo-Diastereoisomer
Mp >138 °C (dec.); Rf = 0.40 (4:6 hexanes–EtOAc).
FT-IR (ATR, neat): 3090, 3005, 2980, 2932, 2868, 1713, 1695,
1523, 1477, 1454, 1444, 1383, 1368, 1355, 1343, 1329, 1313, 1282,
1246, 1267, 1190, 1214, 1156, 1170, 1111, 1083 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.90 (d, J = 6.0 Hz, 1 H), 6.34 (dd,
J = 6.0, 2.8 Hz, 1 H), 5.10 (dd, J = 2.8, 1.2 Hz, 1 H), 4.25 (d, J = 1.3
Hz, 1 H), 4.26–4.21 (m, 1 H), 4.16–4.10 (m, 1 H), 3.61 (dt, J = 15.5,
9.5 Hz, 1 H), 2.00 (m, 3 H), 1.51 (s, 9 H).
HRMS (ESI): m/z calcd for C15H15NO3 + Na (M + Na)+: 280.0944;
found: 280.0954.
(±)-(1S,12S,13S,14Z)-12-Ethyl-9,16-dioxa-10-azatetracyc-
lo[11.2.1.01,10.02,7]hexadeca-2(7),3,5,14-tetraen-11-one (Table 2,
entry 9)
Prepared in 63% yield (48 mg, 0.18 mmol) as a light brown oil from
(±)-1-{O-[o-(2-furyl)phenyl]methyloxyamino}-2-bromobutan-1-
one (100 mg, 0.29 mmol) via the general procedure; Rf = 0.54 (4:6
hexanes–EtOAc).
13C NMR (126 MHz, CDCl3): δ = 167.0, 150.6, 141.9, 130.7, 82.2,
81.9, 70.6, 63.5, 57.8, 28.2, 25.0, 22.7.
HRMS (ESI): m/z calcd for C14H19ClN2O4 + Na (M + Na)+:
337.0926; found: 337.0937.
FT-IR (ATR, neat): 3215, 3071, 2966, 2931, 2876, 2851, 1689,
1590, 1496, 1456, 1360, 1331, 1279, 1249, 1219, 1202, 1158, 1118,
1102, 1072 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.46–7.35 (m, 3 H), 7.15–7.10 (m,
1 H), 6.64 (d, J = 5.7 Hz, 1 H), 6.56 (dd, J = 5.7, 1.9 Hz, 1 H), 5.30
(d, J = 14.3 Hz, 1 H), 5.02 (d, J = 1.9 Hz, 1 H), 5.00 (d, J = 14.3 Hz,
1 H), 2.44 (ddd, J = 8.7, 6.0, 0.8 Hz, 1 H), 2.06 (ddq, J = 13.6, 7.6,
6.0 Hz, 1 H), 1.92 (ddq, 13.7, 8.8, 7.4 Hz, 1 H), 1.10 (t, J = 7.5 Hz,
1 H).
tert-Butyl (±)-(1R,8S,9S,Z)-8-Ethyl-7-oxo-5-oxa-6,12-diazatri-
cyclo[7.2.1.01,6]dodec-10-ene-12-carboxylate and tert-Butyl
(±)-(1R,8R,9S,Z)-8-Ethyl-7-oxo-5-oxa-6,12-diazatricyc-
lo[7.2.1.01,6]dodec-10-ene-12-carboxylate (Table 2, entry 7)
Prepared in 57% yield (46 mg, 0.15 mmol) as a white solid from
tert-butyl
2-{3-[N-2-bromobutyryl(aminooxy)]propyl}-1H-pyr-
role-1-carboxylate (100 mg, 0.26 mmol) via the general procedure.
endo-Diastereoisomer
Mp 131.1–134.3 °C; Rf = 0.48 (4:6 hexanes–EtOAc).
13C NMR (101 MHz, CDCl3): δ = 170.5, 138.0, 134.6, 133.8, 130.7,
129.0, 127.8, 126.2, 124.1, 95.8, 80.9, 76.7, 71.5, 52.8, 25.1, 12.0.
HRMS (ESI): m/z calcd for C15H15NO3 + Na (M + Na)+: 280.0944;
FT-IR (ATR, neat): 3088, 2974, 2860, 1739, 1707, 1694, 1454,
1346, 1289, 1245, 1163, 1102 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.72 (d, J = 6.2 Hz, 1 H), 6.29 (dd,
J = 6.2, 2.7 Hz, 1 H), 4.72 (dd, J = 4.4, 2.8 Hz, 1 H), 4.21 (dddd,
J = 11.5, 4.0, 1.9, 1.9 Hz, 1 H), 4.02 (ddd, J = 11.6, 2.5, 2.5 Hz, 1
H), 3.6 (br s, 1 H), 3.00 (dt, J = 10.1, 4.4 Hz, 1 H), 2.11 (dddd,
J = 15.4, 7.7, 4.7, 4.7 Hz, 1 H), 2.05–1.83 (m, 4 H), 1.51 (s, 9 H),
1.30–1.16 (m, 2 H), 1.03 (t, J = 7.5 Hz, 3 H).
found: 280.0966.
(±)-(1S,8S,9R,Z)-8-Ethyl-9-methyl-5,12-dioxa-6-azatricyc-
lo[7.2.1.01,6]dodec-10-en-7-one and (±)-(1S,8R,9R,Z)-8-Ethyl-9-
methyl-5,12-dioxa-6-azatricyclo[7.2.1.01,6]dodec-10-en-7-one
(Table 2, entry 10)
Prepared in 67% yield (44 mg, 0.22 mmol) as a white solid from
(±)-1-[O-3-(5-methyl-2-furyl)propyloxyamino]-2-bromobutan-1-
one (100 mg, 0.33 mmol) via the general procedure.
13C NMR (101 MHz, CDCl3): δ = 173.5, 152.0, 139.0, 131.7, 81.9,
81.5, 70.4, 61.0, 52.6, 28.4, 26.2, 23.2, 20.1, 11.8.
HRMS (ESI): m/z calcd for C16H24N2O4 + Na (M + Na)+: 331.1628;
found: 331.1632.
endo-Diastereoisomer
Mp 94.8–97.1 °C; Rf = 0.46 (3:7 hexanes–EtOAc).
FT-IR (ATR, neat): 3089, 2965, 2947, 2932, 2879, 2854, 1743,
1684, 1596, 1530, 1502, 1460, 1445, 1377, 1355, 1338, 1317, 1303,
1277, 1252, 1231, 1209, 1194, 1163, 1133, 1096 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.63 (d, J = 5.8 Hz, 1 H), 6.20 (d,
J = 5.8 Hz, 1 H), 4.21 (dddd, J = 11.6, 4.0, 4.0, 1.2 Hz, 1 H), 3.92
(ddd, J = 11.7, 2.5, 2.5 Hz, 1 H), 2.79 (dd, J = 7.0, 3.7 Hz, 1 H),
2.07–1.95 (m, 4 H), 1.90–1.84 (m, 1 H), 1.78–1.68 (m, 1 H), 1.52
(s, 3 H), 1.04 (t, J = 7.5 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 172.3, 137.6, 135.6, 97.1, 87.8,
70.5, 58.3, 29.8, 23.6, 21.9, 19.2, 14.0.
HRMS (ESI): m/z calcd for C12H17NO3 + Na (M + Na)+: 246.1101;
found: 246.1112.
exo-Diastereoisomer
Mp 127.5–129.9 °C; Rf = 0.35 (4:6 hexanes–EtOAc).
FT-IR (ATR, neat): 2978, 2938, 2881, 1682, 1700, 1443, 1456,
1476, 1379, 1367, 1362, 1352, 1344, 1326, 1303, 1284, 1269, 1248,
1171, 1152, 1114, 1075 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.69 (d, J = 6.0 Hz, 1 H), 6.36 (dd,
J = 6.0, 2.8 Hz, 1 H), 4.84 (d, J = 2.8 Hz, 1 H), 4.25–4.19 (m, 1 H),
4.05 (ddd, J = 11.1, 3.3, 3.3 Hz, 1 H), 3.47 (td J = 12.7, 4.7 Hz, 1
H), 2.43 (dd, J = 10.0, 5.3 Hz, 1 H), 2.07–1.90 (m, 5 H), 1.73 (ddq,
J = 14.5, 10.0, 7.3 Hz, 1 H), 1.50 (s, 9 H), 1.11 (t, J = 7.4 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 173.8, 150.9, 137.7, 134.3, 82.3,
81.3, 70.6, 59.3, 55.0, 28.3, 26.0, 24.4, 23.0, 12.3.
HRMS (ESI): m/z calcd for C16H24N2O4 (M + Na)+: 331.1628;
found: 331.1634.
exo-Diastereoisomer
Mp 95.2–98.4 °C; Rf = 0.3 (3:7 hexanes–EtOAc).
FT-IR (ATR, neat): 3091, 2968, 2926, 2870, 2857, 1743, 1668,
1598, 1446, 1381, 1360, 1293, 1274, 1261, 1246, 1226, 1217, 1189,
1159, 1137, 1099 cm–1.
(±)-(1S,13S,14Z)-12,12-Dimethyl-9,16-dioxa-10-azatetracyc-
lo[11.2.1.01,10.02,7]hexadeca-2(7),3,5,14-tetraen-11-one (Table 2,
entry 8)
1H NMR (500 MHz, CDCl3): δ = 6.64 (d, J = 5.7 Hz, 1 H), 6.24 (d,
J = 5.7 Hz, 1 H), 4.21 (br dd, J = 12.0, 5 Hz, 1 H), 3.92 (ddd,
J = 11.6, 2.1, 2.1 Hz, 1 H), 2.39 (dd, J = 8.7, 5.1 Hz, 1 H), 2.10–1.77
(m, 6 H), 1.42 (s, 3 H), 1.08 (t, J = 7.5 Hz, 3 H).
Prepared in 71% yield (54 mg, 0.20 mmol) as a white solid from
1-{O-[o-(2-furyl)phenyl]methyloxyamino}-2-bromo-2-methylpro-
pan-1-one (100 mg, 0.29 mmol) via the general procedure; mp
151.2–152.6 °C; Rf = 0.36 (4:6 hexanes–EtOAc).
13C NMR (126 MHz, CDCl3): δ = 172.7, 139.8, 134.8, 97.7, 86.2,
70.4, 56.2, 29.2, 23.7, 21.7, 18.7, 12.3.
FT-IR (ATR, neat): 3095, 2994, 2979, 2963, 2938, 2907, 2865,
1681, 1493, 1471, 1382, 1363, 1336, 1287, 1269, 1204, 1183, 1125,
1102, 1068 cm–1.
Synthesis 2013, 45, 1825–1836
© Georg Thieme Verlag Stuttgart · New York

PAPER
Intramolecular Cycloaddition Reactions of Aza-Oxyallylic Cations
1833
HRMS (ESI): m/z calcd for C12H17NO3 + Na (M + Na)+: 246.1101;
found: 246.1121.
endo-Diastereoisomer
Mp 134.2–137.3 °C; Rf = 0.67 (2:8 hexanes–EtOAc).
FT-IR (ATR, neat): 3115, 3010, 2966, 2901, 1678, 1601, 1469,
1431, 1378, 1334, 1323, 1307, 1291, 1205, 1248, 1225, 1147, 1108,
1077 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.57 (d, J = 5.7 Hz, 1 H), 6.53 (dd,
J = 5.7, 2.0 Hz, 1 H), 5.14 (d, J = 2.0 Hz, 1 H), 4.34–4.26 (m, 2 H),
4.22 (s, 1 H), 2.78–2.74 (m, 2 H).
(±)-(1S,2S,9R,Z)-2,8,8,9-Tetramethyl-5,12-dioxa-6-azatricyc-
lo[7.2.1.01,6]dodec-10-en-7-one and (±)-(1S,2R,9R,Z)-2,8,8,9-
Tetramethyl-5,12-dioxa-6-azatricyclo[7.2.1.01,6]dodec-10-en-7-
one (Table 2, entry 11)
Prepared in 91% yield (66 mg, 0.30 mmol) as a white solid from
(±)-1-[O-3-(5-methyl-2-furyl)butyloxyamino]-2-bromo-2-methyl-
propan-1-one (100 mg, 0.33 mmol) via the general procedure.
13C NMR (101 MHz, CDCl3): δ = 160.1, 136.0, 134.1, 100.0, 81.3,
69.6, 54.0, 34.5.
(±)-(1S,2S,9R,Z)-2,8,8,9-Tetramethyl-5,12-dioxa-6-azatricyc-
lo[7.2.1.01,6]dodec-10-en-7-one
Mp 123.9–126.8 °C; Rf = 0.54 (4:6 hexanes–EtOAc).
HRMS (ESI): m/z calcd for C8H8ClNO3 + Na (M + Na)+: 224.0085;
found: 224.0072.
FT-IR (ATR, neat): 3091, 2973, 2940, 2869, 1678, 1598, 1468,
1440, 1368, 1286, 1327, 1255, 1227, 1155, 1120 cm–1.
exo-Diastereoisomer
Mp 132.8–133.6 °C; Rf = 0.58 (2:8 hexanes–EtOAc).
1H NMR (500 MHz, CDCl3): δ = 6.59 (d, J = 5.9 Hz, 1 H), 6.28 (dd,
J = 6.0, 0.9 Hz, 1 H), 4.17 (ddd, J = 11.6, 4.7, 1.5 Hz, 1 H), 3.96
(ddd, J = 14.0, 11.8, 4.7, 2.3 Hz, 1 H), 2.26–2.12 (m, 1 H), 1.62
(ddd, J = 13.3, 4.3, 2.0 Hz, 1 H), 1.87–1.80 (m, 1 H), 1.78–1.65 (m,
1 H), 1.40 (d, J = 1.1 Hz, 6 H), 1.10 (s, 3 H), 0.98 (d, J = 6.8 Hz, 3
H).
13C NMR (126 MHz, CDCl3): δ = 176.4, 139.6, 133.5, 101.0, 88.8,
70.3, 52.7, 33.8, 32.2, 23.3, 20.16, 16.4, 14.9.
HRMS (ESI): m/z calcd for C13H19NO3 + Na (M + Na)+: 260.1257;
found: 260.1260.
FT-IR (ATR, neat): 3081, 2979, 2894, 1662, 1595, 1472, 1436,
1371, 1362, 1332, 1319, 1305, 1287, 1225, 1210, 1148, 1112, 1085
cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.68 (dd, J = 5.7, 1.9 Hz, 1 H),
6.54 (d, J = 5.7 Hz, 1 H), 5.18 (dd, J = 6.1, 2.0 Hz, 1 H), 4.65 (d,
J = 6.1 Hz, 1 H), 4.32 (ddd, J = 8.4, 7.5, 3.2 Hz, 1 H), 4.21 (ddd,
J = 9.6, 8.4, 6.4 Hz, 1 H), 2.77 (ddd, J = 13.5, 9.6, 7.5 Hz, 1 H), 2.67
(ddd, J = 13.6, 6.4, 3.2 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 159.7, 137.77, 132.7, 99.9, 86.1,
69.5, 55.3, 34.0.
(±)-(1S,2R,9R,Z)-2,8,8,9-Tetramethyl-5,12-dioxa-6-azatricyc-
lo[7.2.1.01,6]dodec-10-en-7-one
Mp 120.0–124.1 °C; Rf = 0.54 (4:6 hexanes–EtOAc).
HRMS (ESI): m/z calcd for C8H8ClNO3 + Na (M + Na)+: 224.0085;
found: 224.0092.
FT-IR (ATR, neat): 2972, 2938, 2875, 2360, 2340, 1677, 1465,
1439, 1369, 1328, 1289, 1255, 1121 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.70 (d, J = 5.8 Hz, 1 H), 6.27 (d,
J = 5.8 Hz, 1 H), 4.20–4.15 (m, 1 H), 4.04–4.00 (m, 1 H), 2.25–2.14
(m, 2 H), 1.38 (s, 6 H), 1.09 (s, 3 H), 1.09 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 177.2, 139.0, 136.6, 99.4, 88.9,
65.8, 53.4, 52.6, 52.6, 31.1, 30.4, 23.2, 16.6, 12.5.
(±)-(1S,7R,8S,Z)-7-Ethyl-4,11-dioxa-5-azatricyclo[6.2.1.01,5]un-
dec-9-en-6-one and (1S,7S,8S,Z)-7-Ethyl-4,11-dioxa-5-azatricy-
clo[6.2.1.01,5]undec-9-en-6-one (Table 3, entry 4)
Prepared in 85% yield (63 mg, 0.32 mmol) as a white solid from
(±)-1-[O-2-(2-furyl)ethyloxyamino]-2-bromobutan-1-one (100 mg,
0.36 mmol) via the general procedure.
endo-Diastereoisomer
Mp 108.9–111.2 °C, Rf = 0.37 (2:8 hexanes–EtOAc).
HRMS (ESI): m/z calcd for C13H19NO3 + Na (M + Na)+: 260.1257;
found: 260.1283.
FT-IR (ATR, neat): 3080, 2963, 2877, 2340, 2360, 1662, 1463,
1436, 1364, 1229, 1148, 1115 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.51 (dd, J = 5.7, 2.0 Hz, 1 H),
6.36 (d, J = 5.7 Hz, 1 H), 4.82 (d, J = 2.0 Hz, 1 H), 4.23 (ddd,
J = 8.4, 7.3, 3.7 Hz, 1 H), 4.17 (ddd, J = 8.3, 7.4, 3.8 Hz, 1 H), 2.71
(ddd, J = 13.2, 9.5, 7.5 Hz, 1 H), 2.64 (ddd, J = 13.1, 6.5, 3.7 Hz, 1
H), 2.29 (dd, J = 8.4, 4.1 Hz, 1 H), 2.05 (dddd, J = 14.8, 7.6, 7.6,
7.6, 4.0 Hz, 2 H), 1.93–1.83 (m, 2 H), 1.05 (t, J = 7.5 Hz, 4 H).
(±)-(1S,8S,Z)-7,7-Dimethyl-4,11-dioxa-5-azatricyc-
lo[6.2.1.01,5]undec-9-en-6-one (Table 3, entry 2)
Prepared in 82% yield (57 mg, 0.29 mmol) as a white solid from
(±)-1-[O-2-(2-furyl)ethyloxyamino]-2-bromo-2-methylpropan-1-
one (100 mg, 0.36 mmol) via the general procedure; mp 110.9–
112.1 °C; Rf = 0.44 (2:8 hexanes–EtOAc).
FT-IR (ATR, neat): 3081, 2979, 2894, 1662, 1595, 1472, 1460,
1436, 1390, 1371, 1362, 1332, 1319, 1305, 1287, 1225, 1210, 1148,
1183, 1112, 1085 cm–1.
13C NMR (126 MHz, CDCl3): δ = 167.1, 136.0, 134.2, 99.3, 81.7,
68.9, 48.8, 34.7, 23.90, 11.3.
1H NMR (500 MHz, CDCl3): δ = 6.51 (dd, J = 5.7, 2.0 Hz, 1 H),
6.44 (d, J = 5.7 Hz, 1 H), 4.56 (d, J = 2.0 Hz, 1 H), 4.25 (ddd,
J = 8.3, 7.3, 6.7 Hz, 1 H), 4.18 (ddd, J = 8.6, 8.3, 6.7 Hz, 1 H), 2.69
(ddd, J = 13.2, 9.0, 7.4 Hz, 1 H), 2.64 (ddd, J = 13.2, 6.6, 3.8 Hz, 1
H), 1.46 (s, 3 H), 1.12 (s, 3 H).
exo-Diastereoisomer
Mp 106.1–110.3 °C; Rf = 0.37.
FT-IR (ATR, neat): 3078, 2963, 2935, 2877, 1664, 1595, 1464,
1436, 1364, 1340, 1326, 1308, 1295, 1228, 1148, 1083, 1049, 1028
cm–1.
13C NMR (101 MHz, CDCl3): δ = 170.1, 135.3, 134.7, 99.1, 88.0,
68.9, 47.3, 34.6, 27.1, 20.5.
HRMS (ESI): m/z calcd for C10H13NO3 + Na (M + Na)+: 218.0788;
found: 218.0807.
1H NMR (400 MHz, CDCl3): δ = 6.53 (dd, J = 5.8, 2.0 Hz, 1 H),
6.43 (d, J = 5.8 Hz, 1 H), 5.01 (dd J = 6.3, 1.9 Hz, 1 H), 4.23 (m, 1
H), 4.17 (m, 1 H), 2.94 (ddd, J = 11.1, 6.2, 2.94 Hz, 1 H), 2.71 (m,
1 H), 1.92 (m, 1 H), 1.38 (m, 1 H), 1.04 (t, J = 7.5 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 168.6, 135.4, 134.4, 105.0, 99.5,
80.9, 69.0, 51.0, 35.1, 21.5, 12.2.
(±)-(1S,7S,8S,Z)-7-Chloro-4,11-dioxa-5-azatricyc-
lo[6.2.1.01,5]undec-9-en-6-one and (±)-(1S,7R,8S,Z)-7-Chloro-
4,11-dioxa-5-azatricyclo[6.2.1.01,5]undec-9-en-6-one (Table 3,
entry 3)
HRMS (ESI): m/z calcd for C10H14NO3 (M + H)+: 196.0968; found:
196.0960.
Prepared in 91% yield (84 mg, 0.38 mmol) as a white solid from 1-
[O-2-(2-furyl)ethyloxyamino]-2,2-dichloroethan-1-one (100 mg,
0.42 mmol) via the general procedure.
© Georg Thieme Verlag Stuttgart · New York
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A. Acharya et al.
PAPER
(±)-(1S,10S,Z)-9,9-Dimethyl-6,13-dioxa-7-azatricyc-
lo[8.2.1.01,7]tridec-11-en-8-one (Table 3, entry 5)
Prepared in 51% yield (37 mg, 0.17 mmol) from (±)-1-[O-4-(2-fu-
ryl)butyloxyamino]-2-bromo-2-methylpropan-1-one (100 mg, 0.33
mmol) via the general procedure; white solid; mp 96.1–98.7 °C;
Rf = 0.38 (4:6 hexanes–EtOAc).
FT-IR (ATR, neat): 3080, 2935, 2875, 1678, 1594, 1452, 1439,
1380, 1346, 1304, 1276, 1261, 1220, 1201, 1147, 1130, 1111, 1076
cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.47 (d, J = 5.8 Hz, 1 H), 6.32 (dd,
J = 5.8, 1.7 Hz, 1 H), 4.98 (dd, J = 5.3, 1.7 Hz, 1 H), 4.33 (ddd,
J = 11.9, 3.5, 3.5 Hz, 1 H), 3.80 (ddd, J = 12.4, 8.8, 5.9 Hz, 1 H),
2.96 (ddd, J = 10.4, 5.1, 5.1 Hz, 1 H), 2.26 (ddd, J = 15.0, 11.0, 1.6
Hz, 1 H), 2.13 (ddd, J = 15.1, 7.2, 1.6 Hz, 1 H), 2.08–1.91 (m, 2 H),
1.89–1.84 (m, 1 H), 1.81–1.76 (m, 2 H), 1.27–1.15 (m, 1 H), 1.03 (t,
J = 7.5 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 168.9, 139.1, 132.7, 100.93, 81.4,
78.4, 51.0, 34.5, 31.3, 21.1, 19.4, 12.1.
HRMS (ESI): m/z calcd for C12H17NO3 + Na (M + Na)+: 246.1101;
found: 246.1108.
FT-IR (ATR, neat): 3097, 3086, 2984, 2974, 2958, 2928, 2866,
1672, 1596, 1506, 1472, 1449, 1436,1383, 1373, 1359, 1343, 1329,
1290, 1281, 1262, 1221, 1202, 1144, 1117, 1077 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.47 (dt, J = 5.8, 0.6 Hz, 1 H), 6.36
(dd, J = 5.8, 1.8 Hz, 1 H), 4.49 (d, J = 1.8 Hz, 1 H), 4.33 (dddd,
J = 12.5, 4.2, 3.5, 1.3 Hz, 1 H), 3.79–3.72 (m, 1 H), 2.26 (ddd,
J = 15.1, 11.3, 1.1 Hz, 1 H), 2.12 (dddd, J = 15.2, 7.4, 1.3, 0.6 Hz,
1 H), 2.05–1.92 (m, 1 H), 1.92–1.83 (m, 1 H), 1.83–1.76 (m, 2 H),
1.49 (s, 3 H), 1.05 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 172.8, 138.6, 133.7, 101.2, 87.6,
78.4, 48.2, 34.5, 31.3, 27.2, 21.7, 19.5.
exo-Diastereoisomer
Mp 75.2–76.9 °C; Rf = 0.42 (4:6 hexanes–EtOAc).
HRMS (ESI): m/z calcd for C12H18NO3 (M + H)+: 224.1281; found:
224.1279.
FT-IR (ATR, neat): 3082, 2963, 2932, 2874, 1662, 1595, 1456,
1439, 1381, 1346, 1331, 1304, 1277, 1245, 1222, 1202, 1145, 1128,
1075 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.40 (d, J = 5.8 Hz, 1 H), 6.31 (dd,
J = 5.7, 1.9 Hz, 1 H), 4.80 (d, J = 1.9 Hz, 1 H), 4.36 (dddd, J = 12.6,
3.7, 3.7, 1.3 Hz, 1 H), 3.78–3.71 (m, 1 H), 2.28 (ddd, J = 15.5, 11.2,
1.5 Hz, 1 H), 2.25 (dd, J = 8.6, 5.0 Hz, 2 H), 2.15 (ddd, J = 15.1, 7.2,
1.5 Hz, 2 H), 2.04–1.90 (m, 4 H), 1.81 (ddd, J = 9.9, 4.6, 4.2 Hz, 3
H), 1.09 (t, J = 7.5 Hz, 3 H).
(±)-(1S,9S,10S,Z)-9-Chloro-6,13-dioxa-7-azatricyc-
lo[8.2.1.01,7]tridec-11-en-8-one and (±)-(1S,9R,10S,Z)-9-Chloro-
6,13-dioxa-7-azatricyclo[8.2.1.01,7]tridec-11-en-8-one (Table 3,
entry 6)
Prepared in 38% yield (32 mg, 0.14 mmol) as a white sticky liquid
from
1-[O-4-(2-furyl)butyloxyamino]-2,2-dichloroethan-1-one
(100 mg, 0.38 mmol) via the general procedure.
13C NMR (101 MHz, CDCl3): δ = 169.4, 137.5, 133.9, 101.1, 81.2,
78.6, 51.01, 34.40, 31.40, 25.09, 21.71, 11.75.
HRMS (ESI): m/z calcd for C12H17NO3 + Na (M + Na)+: 246.1101;
found: 246.1105.
endo-Diastereoisomer
Rf = 0.58 (4:6 hexanes–EtOAc).
1H NMR (500 MHz, CDCl3): δ = 6.56 (d, J = 5.8 Hz, 1 H), 6.48 (dd,
J = 5.8, 1.8 Hz, 1 H), 5.14 (dd, J = 5.4, 1.8 Hz, 1 H), 4.76 (d, J = 5.4
Hz, 1 H), 4.38 (ddd, J = 12.6, 3.2, 1.2 Hz, 1 H), 3.86–3.22 (m, 1 H),
2.28 (ddd, J = 15.3, 10.7, 1.8 Hz, 1 H), 2.17 (ddd, J = 15.4, 6.8, 2.2
Hz, 1 H), 1.99–1.79 (m, 4 H).
13C NMR (126 MHz, CDCl3): δ = 163.2, 139.8, 132.3, 102.2, 82.0,
78.8, 56.2, 34.2, 31.2, 21.5.
(±)-2-Ethyl-5,14-dioxa-4-azabicyclo[9.2.1]tetradeca-1(13),11-
dien-3-one (Table 3, entry 8; 13b)
Prepared in 50% yield (38 mg, 0.0.16 mmol) as a white solid from
1-[O-5-(2-furyl)pentyloxyamino]-2-bromobutan-1-one (100 mg,
0.31 mmol) via the general procedure; mp 122.2–124.5 °C;
Rf = 0.52 (2:8 hexanes–EtOAc).
HRMS (ESI): m/z calcd for C10H12ClNO3 + Na (M + Na)+:
252.0398; found: 252.0401.
FT-IR (ATR, neat): 3176, 3022, 2960, 2922, 2864, 2353, 2322,
1686, 1655, 1552, 1457, 1225, 1189, 1072 cm–1.
exo-Diastereoisomer
1H NMR (500 MHz, CDCl3): δ = 7.91 (s, 1 H), 6.11 (d, J = 3.0 Hz,
1 H), 5.95 (d, J = 3.1 Hz, 1 H), 4.00 (br s, 1 H), 3.84 (br s, 1 H), 3.45
(br s, 1 H), 2.67 (ddd, J = 21.5, 8.0, 4.0 Hz, 2 H), 2.15–1.97 (m, 1
H), 1.87 (m, 1 H), 1.77–1.76 (m, 1 H), 1.64–1.60 (m, 1 H), 1.48–
1.45 (m, 2 H), 1.26–1.19 (m, 2 H), 1.03 (t, J = 7.4 Hz, 3 H).
Rf = 0.46 (4:6 hexanes–EtOAc).
FT-IR (ATR, neat; characterized as a mixture): 2938, 2864, 1693,
1595, 1439, 1380, 1346, 1327, 1283, 1270, 1249, 1221, 1201, 1143,
1125, 1078 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.62 (d, J = 5.7 Hz, 1 H), 6.31 (dd,
J = 5.7, 2.0 Hz, 1 H), 5.03 (d, J = 2.0 Hz, 1 H), 4.40 (dddd, J = 12.5,
6.8, 1.7, 1.7 Hz, 1 H), 4.13 (s, 1 H), 3.85 (m, 1 H), 2.30 (ddd,
J = 15.2, 11.0, 1.8 Hz, 1 H), 2.21 (m, 1 H), 2.13–2.00 (m, 1 H),
1.98–1.79 (m, 3 H).
13C NMR (126 MHz, CD3OD): δ = 171.5, 157.5, 153.6, 109.0,
107.9, 48.1, 28.9, 27.0, 26.7, 26.5, 22.2, 13.07, 13.1.
HRMS (ESI): m/z calcd for C13H20NO3 (M + H)+: 238.1438; found:
238.1436.
13C NMR (101 MHz, CDCl3): δ = 163.1, 141.2, 130.5, 101.8, 84.4,
79.0, 56.0, 33.8, 31.2, 21.6.
(±)-(1S,11S,Z)-2-Ethyl-5,14-dioxa-4-azabicyclo[9.2.1]tetradec-
12-en-3-one (13a)
To a solution of (±)-(1S,9S,10S,Z)-9-ethyl-6.13-dioxa-7-azatricyc-
lo[8.2.1.01,7]tridec-11-en-8-one (8.0 mg, 0.04 mmol) in CDCl3 (0.4
mL) was added pyridinium p-toluenesulfonate (10 mg, 0.04 mmol)
and the NMR tube was tightly sealed. The reaction mixture was
heated at 75 °C and monitored to completion by NMR analysis. The
volatiles were removed under reduced pressure and the residue was
purified by flash column chromatography (1:9 to 4:1 hexanes–
EtOAc) to provide 13b with quantitative yield (8.0 mg, 0.04 mmol)
as a white solid; mp 157.4–158.5 °C; Rf = 0.54 (4:6 hexanes–
EtOAc).
HRMS (ESI): m/z calcd for C10H12ClNO3 + Na (M + Na)+:
252.0398; found: 252.0402.
(±)-(1S,9S,10S,Z)-9-Ethyl-6,13-dioxa-7-azatricyc-
lo[8.2.1.01,7]tridec-11-en-8-one and (±)-(1S,9R,10S,Z)-9-Ethyl-
6,13-dioxa-7-azatricyclo[8.2.1.01,7]tridec-11-en-8-one (Table 3,
entry 7)
Prepared in 67% yield (49 mg, 0.22 mmol) as a white solid from 1-
[O-4-(2-furyl)butyloxyamino]-2-bromobutan-1-one (100 mg, 0.33
mmol) via the general procedure.
FT-IR (ATR, neat): 3157, 2952, 2929, 2881, 1657, 1612, 1545,
1492, 1467, 1448, 1376, 1261, 1158, 1088 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.78 (s, 1 H), 6.14 (d, J = 3.0 Hz,
1 H), 5.97 (d, J = 2.9 Hz, 1 H), 3.78 (t, J = 7.2 Hz, 2 H), 3.06 (br s,
endo-Diastereoisomer
Mp 78.5–81.2 °C; Rf = 0.56 (3:7 hexanes–EtOAc).
Synthesis 2013, 45, 1825–1836
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Intramolecular Cycloaddition Reactions of Aza-Oxyallylic Cations
1835
1 H), 2.76–2.64 (m, 2 H), 2.43 (br s, 1 H), 2.21–2.08 (m, 1 H), 2.07–
1.96 (m, 1 H), 1.94–1.72 (m, 3 H), 1.02 (t, J = 7.4 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 174.6, 155.1, 150.0, 108.0, 106.3,
77.91, 46.9, 27.4, 26.8, 26.0, 21.6, 12.1.
HRMS (ESI): m/z calcd for C12H17NO3 + Na (M + Na)+: 246.1101;
found: 246.1079.
The mixture was passed through a Celite bed and washed with EtO-
Ac (20 mL). The collected filtrate was concentrated under reduced
pressure. Purification by flash column chromatography (4:1 to 3:2
hexanes–EtOAc) afforded the product 17 in 86% yield as a white
solid (21 mg, 0.20 mmol); mp 57.1–59.7 °C; Rf = 0.60 (1:1 hex-
anes–EtOAc).
FT-IR (ATR, neat): 2957, 2982, 2937, 2865, 1679, 1459, 1447,
1387, 1358, 1311, 1290, 1273, 1249, 1214, 1194, 1155, 1126, 1080
cm–1.
(±)-(1S,9R,10S,12S)-8,8-Dimethyl-5,11,13-trioxa-6-azatetracyc-
lo[7.3.1.01,6.010,12]tridecan-7-one (15)
To a solution of 14 (50 mg, 0.24 mmol) in CH2Cl2 (2 mL) was added
m-CPBA (82 mg, 0.48 mmol) and the reaction mixture was stirred
for 3 d. The complete consumption of 14 was confirmed by TLC
(1:1 hexanes–EtOAc). The white precipitate was filtered, the filtrate
was washed with aq NaHCO3 (5 mL) and brine (5 mL), and then the
organic layer was dried (Na2SO4). The volatiles were removed un-
der reduced pressure and purified by flash column chromatography
(4:1 to 3:2 hexanes–EtOAc) to afford the product 15 in 93% yield
as a white solid (50.2 mg, 0.22 mmol); mp 177.1–179.6 °C;
Rf = 0.57 (1:1 hexanes–EtOAc).
1H NMR (500 MHz, CDCl3): δ = 4.20 (dddd, J = 11.4, 4.6, 4.6, 1.7
Hz, 1 H), 4.07 (dd, J = 7.9, 1.5 Hz, 1 H), 3.85 (ddd, J = 11.6, 2.7 Hz,
1 H), 2.61 (ddd, J = 9.5, 3.8, 3.8 Hz, 1 H), 2.17–2.08 (m, 1 H), 2.02–
1.78 (m, 2 H), 1.67 (ddd, J = 12.3, 5.9 Hz, 1 H), 1.40 (s, 1 H), 1.10
(s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 173.2, 97.0, 83.0, 71.1, 46.9, 33.3,
31.0, 27.1, 24.5, 23.7, 20.2.
HRMS (ESI): m/z calcd for C11H17NO3 + K (M + K)+: 250.0840;
found: 250.0856.
FT-IR (ATR, neat): 3062, 2980, 2928, 2868, 2361, 2339, 1675,
1492, 1474, 1438, 1396, 1386, 1366, 1349, 1321, 1280, 1266, 1237,
1217, 1175, 1160, 1149, 1129, 1097 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.24 (dddd, J = 11.6, 4.6, 4.6, 1.6
Hz, 1 H), 4.12 (d, J = 3.0 Hz, 1 H), 4.0 (s, 1 H), 3.88 (ddd, J = 11.7,
11.7, 2.2 Hz, 1 H), 3.71 (d, J = 3.0 Hz, 1 H), 2.17–2.13 (m, 1 H),
2.11–1.98 (m, 2 H), 1.93–1.88 (m, 1 H), 1.42 (s, 3 H), 1.21 (s, 3 H).
(±)-2-[5-(3-Hydroxypropyl)-2-furyl]-2-methylpropionamide
(18)
Prepared in 96% yield (61 mg, 0.23 mmol) as a white solid from 14
(50 mg, 0.24 mmol) via general procedure E (Supporting Informa-
tion); mp 90.2–92.9 °C; Rf = 0.50 (2:8 hexanes–EtOAc).
FT-IR (ATR, neat): 3391, 3286, 3190, 2985, 2937, 2891, 1651,
1619, 1557, 1478, 1463, 1446, 1400, 1366, 1344, 1324, 1256, 1237,
1215, 1179 cm–1.
13C NMR (126 MHz, CDCl3): δ = 173.4, 92.2, 79.5, 70.8, 54.2, 51.3,
46.3, 26.8, 26.0, 23.0, 19.3.
HRMS (ESI): m/z calcd for C11H15NO4 + Na (M + Na)+: 248.0893;
found: 248.0888.
1H NMR (500 MHz, CDCl3): δ = 6.11 (d, J = 3.2 Hz, 1 H), 6.02–
5.92 (m, 1 H), 5.58 (s, 1 H), 5.33 (s, 1 H), 3.70 (t, J = 6.2 Hz, 2 H),
2.73 (t, J = 7.4 Hz, 2 H), 1.95–1.83 (m, 2 H), 1.53 (s, 7 H).
13C NMR (126 MHz, CDCl3): δ = 177.7, 156.3, 155.4, 106.4, 105.7,
62.0, 43.5, 31.0, 24.6, 24.5.
HRMS (ESI): m/z calcd for C11H17NO3 + Na (M + Na)+: 234.1101;
found: 234.1093.
(±)-(1S,9R,10S,11S)-10,11-Dihydroxy-8,8-dimethyl-5.12-dioxa-
6-azatricyclo[7.2.1.01,6]dodecan-7-one (16)
To a solution 14 (100 mg, 0.48 mmol) in MeCN–H2O–acetone (1
mL:1 mL:2 mL) was added NMO (112 mg, 0.98 mmol) and OsO4
(0.65 mL, 1% in H2O), and the mixture was stirred at r.t. for over-
night. The complete consumption of 14 was confirmed by TLC (1:1
hexanes–EtOAc). To the reaction mixture was added NaHSO3 (0.50
g) and stirred for 1 h. The mixture was filtered and the filtrate was
neutralized to pH 7 with aq 1 N H2SO4 and the solvents were re-
moved by rotary evaporation and the pH was further adjusted to 2.
The solution was extracted with EtOAc (100 mL), the organic layer
dried (Na2SO4), and concentrated under rotary vapor to obtain prod-
uct 16 in 92% yield as a pale yellow crystalline solid (107 mg, 0.44
mmol); mp 151.2–153.3 °C; Rf = 0.5 (1:9 MeOH–CHCl3).
(Z)-3-Hydroxy-2,2-dimethyl-5-(3,4,5,6-tetrahydropyrid-2-
yl)penten-4-al (19)
To a solution 14 (50 mg, 0.24 mmol) in anhyd Et2O (1.5 mL) was
added a solution of LiAlH4 (2 M solution in THF, 0.12 mL, 0.26
mmol) at 0 °C and the reaction at room temperature was stirred for
1 h. The complete consumption of 14 was confirmed by TLC (1:1
hexanes–EtOAc). The crude product was purified by flash column
chromatography (3:2 to 1:1 hexanes–EtOAc) to provide the product
19 in 68% yield as a pale yellow oil (34 mg, 0.16 mmol); Rf = 0.45
(1:1 hexanes–EtOAc).
FT-IR (ATR, neat): 3364, 2964, 2948, 2925, 2874, 2852, 1650,
1453, 1441, 1387, 1362, 1333, 1314, 1282, 1269, 1238, 1223, 1157,
1124, 1092 cm–1.
FT-IR (ATR, neat): 3327, 2971, 2928, 1717, 1465, 1364, 1053
cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.94 (dd, J = 11.8, 7.2 Hz, 1 H),
5.86 (ddt, J = 11.8, 1.2, 0.6, 0.6 Hz, 1 H), 4.48 (d, J = 7.2 Hz, 1 H),
4.09–4.04 (m, 1 H), 3.99–3.94 (m, 1 H), 2.27 (ddd, J = 11.8, 1.2, 0.6
Hz, 2 H), 2.05–1.85 (m, 2 H), 1.14 (s, 3 H), 1.10 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 206.2, 154.8, 135.4, 128.5, 71.0,
65.8, 49.6, 23.85, 19.1, 18.9, 16.9.
1H NMR (500 MHz, CDCl3): δ = 4.43 (t, J = 6.1 Hz, 1 H), 4.36 (t,
J = 6.5 Hz, 1 H), 4.18 (dddd, J = 11.3, 4.7, 4.7, 1.6 Hz, 1 H), 3.87
(s, 1 H), 3.85 (ddd, J = 12.0, 2.3 Hz, 1 H), 3.44 (d, J = 6.8 Hz, 1 H),
3.26 (d, J = 6.0 Hz, 1 H), 2.41–2.37 (m, 1 H), 1.98 (dddd, J = 12.4,
4.5, 4.5, 3.4 Hz, 1 H), 1.87 (dd, J = 13.0, 4.5 Hz, 1 H), 1.80 (dtd,
J = 11.5, 4.2, 2.1 Hz, 1 H), 1.40 (s, 3 H), 1.20 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 171.6, 98.2, 89.9, 72.1, 71.2, 71.1,
44.7, 27.0, 25.5, 22.7, 19.8.
HRMS (ESI): m/z calcd for C11H18NO5 (M + H)+: 244.1179; found:
244.1161.
HRMS (ESI): m/z calcd for C11H18NO3 (M + H)+: 212.1281; found:
212.1302.
(±)-(1S,9R,10S,14S)-8,8,12,12-Tetramethyl-5,11,13,15-tetroxa-
6-azatetracyclo[7.5.1.01,6.010,14]pentadecan-7-one (20)
To a solution 16 (80 mg, 0.33 mmol) in CH2Cl2 (1 mL) were added
camphorsulfonic acid (1 mg, 2 mol%) and 2,2-dimethoxypropane
(0.06 mL, 0.49 mmol) and the mixture was stirred at r.t. for 2 h. The
complete consumption of 16 was confirmed by TLC (1:1 hexanes–
EtOAc). To the reaction mixture was added sat. aq NaHCO3 (1 mL)
and extracted with Et2O (3 × 20 mL). The combined extracts were
washed with brine (30 mL), dried (MgSO4), and concentrated under
(±)-(1S,9S,Z)-8,8-Dimethyl-5,12-dioxa-6-azatricyc-
lo[7.2.1.01,6]dodec-10-en-7-one (17)
To a solution of 14 (50 mg, 0.24 mmol) in EtOAc (2 mL) was added
10% Pd/C (15 mg) and evacuated with house vacuum (water aspi-
rator) and flushed with H2 gas through a balloon. The reaction mix-
ture was stirred under H2 gas balloon at r.t. for 5 h. The complete
consumption of 14 was confirmed by TLC (1:1 hexanes–EtOAc).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1825–1836

1836
A. Acharya et al.
PAPER
reduced pressure to obtain product 20 in 97% yield as a white solid
(102 mg, 0.32 mmol); mp 188.0–192.0 °C; Rf = 0.68 (1:9 MeOH–
CHCl3).
(2) (a) Jeffrey, C. S.; Barnes, K. L.; Eickhoff, J. A.; Carson, C.
R. J. Am. Chem. Soc. 2011, 133, 7688. (b) Jeffrey, C. S.;
Anumandla, D.; Carson, C. R. Org. Lett. 2012, 14, 5764.
(3) For a review on the reactivity and synthetic applications of
stabilized nitrenium ions, see: Kikugawa, Y. Heterocycles
2009, 78, 571; and references cited therein.
FT-IR (ATR, neat): 2987, 2960, 2942, 2873, 1680, 1475, 1456,
1444, 1389, 1359, 1325, 1379, 1295, 1277, 1266, 1233, 1208, 1255,
1093, 1167, 1147 cm–1.
(4) For examples of recent applications of stabilized nitrenium
ions in organic synthesis, see: (a) Wardrop, D. J.; Bowen, E.
G.; Forslund, R. E.; Sussman, A. D.; Weerasekera, S. L.
J. Am. Chem. Soc. 2009, 132, 1188. (b) Bowen, E. G.;
Wardrop, D. J. Org. Lett. 2010, 12, 5330. (c) Wardrop, D. J.;
Bowen, E. G. Org. Lett. 2011, 13, 2376. (d) Wardrop, D. J.;
Yermolina, M. V.; Bowen, E. G. Synthesis 2012, 44, 1199.
(5) (a) Lohse, A. G.; Hsung, R. P. Chem. Eur. J. 2011, 17, 3812.
(b) Harmata, M. Chem. Commun. 2010, 8904. (c) Harmata,
M. Chem. Commun. 2010, 8886. (d) Huan, J.; Hsung, R. P.
ChemTracts 2005, 18, 207. (e) Harmata, M. Adv. Synth.
Catal. 2006, 348, 2297. (f) Harmata, M. Acc. Chem. Res.
2001, 34, 595. (g) Cha, J. K.; Oh, J. Curr. Org. Chem. 1998,
2, 217. (h) Harmata, M. In Advances in Cycloaddition; Vol.
4; Lautens, M., Ed.; JAI Press: Greenwich (CT, USA), 1997,
41–86. (i) West, F. G. In Advances in Cycloaddition; Vol. 4;
Lautens, M., Ed.; JAI Press: Greenwich (CT, USA), 1997,
1–40. (j) Harmata, M. Tetrahedron 1997, 53, 6235.
(k) Padwa, A.; Schoffstall, A. In Advances in Cycloaddition;
Vol. 2; Curran, D. P., Ed.; JAI Press: Greenwich (CT, USA),
1990, 1–89. (l) Harmata, M. Recent Res. Dev. Org. Chem.
1997, 1, 523. (m) Rigby, J. H.; Pigge, F. C. Org. React.
1997, 51, 351. (n) Mann, J. Tetrahedron 1986, 42, 4611.
(o) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984,
23, 1. (p) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl.
1973, 12, 819.
1H NMR (500 MHz, CDCl3): δ = 7.27 (s, 1 H), 4.80 (d, J = 7.2 Hz,
1 H), 4.79 (d, J = 7.2 Hz, 1 H), 4.20 (dddd, J = 11.5, 4.6, 1.6, 1.6 Hz,
1 H), 3.95 (s, 1 H), 3.84 (td, J = 11.6, 2.6 Hz, 1 H), 2.34–2.32 (m, 1
H), 2.32–2.30 (m, 1 H), 1.99–1.84 (m, 1 H), 1.82–1.77 (m, 1 H),
1.49 (s, 3 H), 1.42 (s, 3 H), 1.33 (s, 3 H), 1.20 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 171.6, 112.9, 97.1, 87.2, 80.7,
80.1, 70.9, 44.1, 27.2, 26.0, 25.3, 25.1, 22.8, 19.8.
HRMS (ESI): m/z calcd for C14H21NO5 + Na (M + Na)+: 306.1312;
found: 306.1308.
(±)-(1R,2S,6S,7S)-7-(3-Hydroxypropyl)-4,4,10,10-tetramethyl-
3,5,11-trioxa-8-azatricyclo[5.3.1.02,6]undecan-9-one (21)
Prepared in 88% yield (46 mg, 0.16 mmol) as a white solid from 20
(52 mg, 0.18 mmol) via general procedure E (Supporting Informa-
tion); mp 167.7–170.0 °C; Rf = 0.50 (1: 9 MeOH–CHCl3).
FT-IR (ATR, neat): 3380, 3199, 3084, 2982, 2957, 2937, 2869,
1644, 1451, 1402, 1476, 1369, 1317, 1273, 1342, 1231, 1192, 1154,
1104, 1081 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.76 (s, 1 H), 4.84 (d, J = 5.6 Hz,
1 H), 4.48 (d, J = 5.6 Hz, 1 H), 3.98 (s, 1 H), 3.70 (t, J = 8.2 Hz, 2
H), 2.84 (s, 1 H), 2.06 (m, 1 H), 1.94 (m, 1 H), 1.86–1.73 (m, 2 H),
1.48 (s, 3 H), 1.35 (s, 3 H), 1.31 (s, 3 H), 1.18 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 176.0, 112.8, 93.4, 88.2, 86.0,
79.8, 61.9, 40.8, 28.0, 27.2, 26.2, 25.6, 25.2, 19.6.
HRMS (ESI): m/z calcd for C14H23NO5 + Na (M + Na)+: 308.1468;
found: 308.1478.
(6) (a) Föhlisch, B.; Herter, R. Chem. Ber. 1984, 117, 2580.
(b) Grainger, R. S.; Owoare, R. B.; Tisselli, P.; Steed, J. W.
J. Org. Chem. 2003, 68. 7899.
(7) Föhlisch, B.; Gehrlach, E.; Herter, R. Angew. Chem., Int. Ed.
Engl. 1982, 21, 137.
Acknowledgment
(8) Herter, R.; Föhlisch, B. Synthesis 1982, 976.
This work was supported through an ACS-PRF grant (51442–
DNI1) and through startup funding from the University of Nevada,
Reno.
(9) Hexafluoroisopropanol improves the yield of reactions
proceeding through reactive oxyallyl cationic intermediates,
see: (a) Harmata, M.; Huang, C.; Rooshenas, P.; Schreiner,
P. R. Angew. Chem. Int. Ed. 2008, 47, 8696. (b) Myers, A.
G.; Barbay, J. K. Org. Lett. 2001, 3, 425.
(10) For a review on the synthesis and biological activity of
polyhydroxylated aza-heterocycles, see: Wardrop, D. J.;
Waidyarachchi, S. L. Nat. Prod. Rep. 2010, 27, 1431; and
references cited therein.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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Synthesis 2013, 45, 1825–1836
© Georg Thieme Verlag Stuttgart · New York