General Approach to Nitrogen-Bridged Bicyclic Frameworks by Rh-Catalyzed Formal Carbenoid Insertion into an Amide C-N Bond

Article abstract of DOI:10.1021/acs.joc.5b01954

Various nitrogen-bridged bicyclic skeletons are found in bioactive natural products and pharmaceuticals. The development of a new reaction to construct these molecular frameworks has attracted considerable attention in synthetic organic chemistry. We deve

Full text of DOI:10.1021/acs.joc.5b01954

Article
pubs.acs.org/joc
General Approach to Nitrogen-Bridged Bicyclic Frameworks by
Rh-Catalyzed Formal Carbenoid Insertion into an Amide C−N Bond
Shingo Harada, Masato Kono, Tomoyuki Nozaki, Yasuhiro Menjo, Tetsuhiro Nemoto,*
and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
S
* Supporting Information
ABSTRACT: Various nitrogen-bridged bicyclic skeletons are
found in bioactive natural products and pharmaceuticals. The
development of a new reaction to construct these molecular
frameworks has attracted considerable attention in synthetic
organic chemistry. We developed a novel synthetic method
for obtaining a wide variety of nitrogen-bridged bicyclic com-
pounds with a catalytic process, Rh-catalyzed formal carbenoid
insertion into an amide C−N bond. Using 0.1−0.4 mol %
Rh2(NHCOtBu)4 catalyst, various azabicyclo[X.Y.Z]alkane derivatives were obtained in good to excellent yield, successfully
demonstrating the broad substrate scope of the developed process. Experimental and computational studies to elucidate the
reaction mechanism revealed that the formal insertion reaction of a carbenoid into an amide C−N bond proceeded via the
formation of Rh-associated N-ylides, followed by an acyl group-selective Stevens [1,2]-shift through a concerted addition/
elimination process on the sp2-hybridized carbon.
derivatives.3 The present reaction sequence is equivalent to
INTRODUCTION
Nitrogen-bridged bicyclic skeletons are ubiquitous structures in
■
formal carbenoid insertion into a C−N single bond. Stevens
[1,2]-shifts generally proceed through diradical intermediates.4
biologically active alkaloids, and various azabicyclic skeletons
are found in this class of natural products (Figure 1).1 The
Therefore, this transformation is the preferred process for
benzylic ylides. On the other hand, the metal carbenoid-
mediated N-ylide formation−Stevens rearrangement cascade
using amides as substrates has very limited applications,5 in part
because of the competitive formation of an O-ylide
intermediate via the reaction of the carbonyl oxygen with a
metal carbenoid.6,7 Detailed investigation of the reactivity of
N-ylides generated from amide or urea derivatives in the pres-
ence of a Rh catalyst by Padwa and co-workers indicated that
α-diazo esters containing an amide in the γ-position react with a
Rh(II) dimer complex, producing a transition metal-mediated
equilibrium mixture of the N-ylide and O-ylide intermediates
(Scheme 1a).5a O-Ylides efficiently react with dipolarophiles to
give the corresponding cycloaddition adducts. N-Ylides are
formed as thermodynamically more stable intermediates in the
absence of dipolarophiles and undergo sigmatropic rearrange-
ment or fragmentation reactions. When the tetrahydroisoqui-
nolyl amide derivative 1 was treated with a catalytic amount of
Rh2(OCOMe)4, a Stevens [1,2]-shift of the most reactive
benzylic substituent proceeded preferentially from the corre-
sponding N-ylide intermediate to give the product with an
isoindolobenzazepine ring system, leading to formal carbenoid
insertion into a benzylic C−N bond (Scheme 1b).5b
Figure 1. Bioactive natural products with a nitrogen-bridged bicyclic
skeleton.
development of a new reaction to construct these molecular
frameworks has attracted considerable attention in synthetic
organic chemistry because such reactions can be utilized as
pivotal transformations in complex molecule synthesis. In addi-
tion, these azabicyclic frameworks are attractive scaffolds for
drug discovery because of their potentially diverse bioactivities.2
Extensive efforts are therefore focused on this research topic.
The reaction of amines with a metal carbenoid provides
the corresponding N-ylide intermediates, generally followed
by a Stevens [1,2]-shift to give substituent-rearranged amine
In the course of our synthetic studies aimed at (−)-agelastatin
A,8 we investigated the construction of the tricyclic framework
Received: August 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
to investigate the present Rh-catalyzed skeletal rearrangement
process. Herein, we report the first formal carbenoid insertion
into an amide C−N bond using a Rh(II) dimer complex, which
was successfully applied to the construction of diverse nitrogen-
bridged bicyclic frameworks. Experimental and computational
studies performed to elucidate the reaction mechanism are also
described.
Scheme 1. An Example of a Precedent Metal Carbenoid-
Mediated N-Ylide Formation−Stevens Rearrangement
Cascade Using Amide Substrates
RESULTS AND DISCUSSION
■
Optimization of the Reaction Conditions. The reaction
conditions were optimized using compound 6a as a model sub-
strate (Table 1). On the basis of the unexpected findings shown
in Scheme 2, a solution of 6a and 2 mol % Rh2(OCOMe)4 in
1,4-dioxane was stirred for 2 h at room temperature, affording
the desired product 7a in 38% yield (entry 1). We first screened
the source of metal catalysts. When the reaction was performed
using Rh(I) or Rh(III) complexes, the desired product 7a was
not obtained (entries 2 and 3). The use of other metal com-
plexes, such as Fe(acac)3,10 Cu(OTf)2,11 and (2,4-tBu2C6H4O)3-
PAuSbF6,12 also gave unsatisfactory results (entries 4−6). Thus,
we examined the reaction in detail using Rh(II) dimer com-
plexes. Compared with the results obtained using Rh2-
(carboxylate)4 complexes (entries 1 and 7−9), the target skeletal
rearrangement proceeded more efficiently using 2 mol %
Rh2(NHCOMe)4 complex, and compound 7a was obtained in
74% yield (entry 10).13 Screening of other Rh2(carboxamidate)4
complexes revealed that the electronic and structural properties
of the carboxamidate ligands affected the catalytic activity. The
best result (92% yield) was obtained when the reaction was
catalyzed by Rh2(NHCOtBu)4, which was prepared from
Rh2(OCOMe)4 and pivalamide using a protocol analogous to
that used to prepare Rh2(carboxamidate)4.13b Compared with
the reactions using Rh(II) dimer complexes bearing primary
carboxamidate ligands (entries 10−12), there was a significant
decrease in the yield when Rh2(caprolactamate)4 was utilized as
the catalyst, suggesting that hydrogen in the carboxamidate ligands
has an important role in promoting the reaction (entry 13).
Solvent effect studies revealed that the use of a mixed solvent
(1:1 1,4-dioxane/CH2Cl2) gave more satisfactory results (95%
yield) (entry 15). The yield was further improved when the
reaction was performed at 40 °C (98% yield) (entry 16), and
0.4 mol % catalyst was sufficient to promote this skeletal re-
arrangement process without any decrease in the yield (entry 17).
Scope and Limitations of the Developed Rh Catalysis.
Having identified the optimal reaction conditions, we next
examined the scope of the insertion reaction with respect to
the substrate. The substrate generality of the synthesis of
9-azabicyclo[4.2.1]nonane derivatives is summarized in
Scheme 3. When compound 6b possessing a quaternary carbon
center at the α-position of the amide group was utilized as a
substrate, the reaction proceeded smoothly in the presence of
0.4 mol % Rh2(NHCOtBu)4, affording compound 7b in 94%
yield. β-Substituted lactams 6c and 6d, as well as a benzo-fused
lactam 6e, were also suitable substrates for this reaction, and the
corresponding azabicyclic compounds 7c−e were produced
in 70−85% yield. In addition, compound 7f bearing a
tetrasubstituted carbon center at the ring junction could be
synthesized in 85% yield. Substrates possessing an N-benzyl
group (6g) and an N-butyl group (6h) could also be applied to
this reaction, providing compounds 7g and 7h in 96 and 90%
yield, respectively.
via Rh-catalyzed C−H insertion of functionalized pyrrole
derivative 3. The reaction was performed using 2 mol %
Rh2(OCOMe)4 in 1,4-dioxane at room temperature. Although
the desired transformation did not proceed, an unexpected
product with an azabicyclo[3.2.2]nonane framework 4 was
isolated as a major product (13% yield) (Scheme 2a). The
Scheme 2. Formation of an Unexpected Product with an
Azabicyclic Framework
product structure indicated that Rh carbenoid-mediated N-ylide
formation occurred preferentially over the conventional five-
membered ring formation through Rh-catalyzed C−H
insertion, and after the formation of N-ylide intermediate 5,
the Stevens [1,2]-shift of the acyl group occurred selectively
even in the presence of a p-methoxybenzyl group on the amide
nitrogen.9 The observed transformation is an unexplored
reaction in the field of metal carbenoid chemistry, formal
carbenoid insertion into an amide C−N bond. We hypothe-
sized that establishing a practical catalyst system for this
transformation would provide general access to nitrogen-
bridged bicyclic skeletons (Scheme 2b). This background led us
To demonstrate the practicality of this catalytic synthetic
method, we performed the experiments shown in Scheme 4.
B
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 1. Optimization of the Reaction Conditions
entry
X (mol %)
catalyst
solvent
1,4-dioxane
concn (M)
temp
rt
yield (%)
1
2
2
Rh2(OCOMe)4
Rh(acac)(ethylene)2
RhCl3(H2O)3
0.004
0.004
0.004
0.004
0.004
0.004
0.004
0.004
0.004
0.004
0.004
0.004
0.004
0.004
0.004
0.004
0.020
38
0
2
1,4-dioxane
1,4-dioxane
PhCl
rt
3
2
rt
0
4
20
20
10
2
Fe(acac)3/NaBArF
Cu(OTf)2
100 °C
100 °C
100 °C
rt
0
5
PhCl
trace
0
6
(ArO)3PAuSbF6
Rh2(OCOCPh3)4
Rh2(S-PTPA)4
PhCl
7
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH2Cl2
26
27
0
8
2
rt
9
2
Rh2(OCOCF3)4
Rh2(NHCOMe)4
Rh2(NHCOCF3)4
Rh2(NHCOtBu)4
Rh2(caprolactamate)4
Rh2(NHCOtBu)4
Rh2(NHCOtBu)4
Rh2(NHCOtBu)4
Rh2(NHCOtBu)4
rt
10
11
12
13
14
2
rt
74
55
92
38
88
95
98
98
2
rt
2
rt
2
rt
2
rt
a
15
2
1,4-dioxane/CH2Cl2
1,4-dioxane/CH2Cl2
1,4-dioxane/CH2Cl2
rt
a
16
a
2
40 °C
40 °C
17
0.4
a
In 1:1 (v/v) 1,4-dioxane/CH2Cl2. S-PTPA is N-phthaloyl-(S)-phenylalaninate. Ar is 2,4-tBu2C6H4. BArF is B[C6H3(CF3)2]4.
Scheme 3. Synthesis of 9-Azabicyclo[4.2.1]nonane
Derivatives
Scheme 4. Demonstration of the Practicality
a
H atoms have been omitted for the sake of clarity.
It is noteworthy that this catalysis could be performed on a
gram scale (1.5 g of 6a) using 0.1 mol % catalyst in 0.08 M
solvent, producing compound 7a in 90% yield. Slow addition of
the diazo substrate using a syringe pump was not required for
this catalysis, making the process more accessible. Optically
active diazo substrate (−)-6a with a 98% ee was prepared and
treated under the optimized conditions. Product (+)-7a was
obtained in 98% yield without a noticeable loss of optical
purity, demonstrating its applicability to asymmetric synthesis
of azabicyclic compounds.14 Discrimination of the two ketones
in 7a was further explored. Reduction of the ketones in 7a with
DIBAL-H proceeded in a highly diastereoselective manner
(>95:5), providing compound 8 in 80% yield. The structure of
8 was confirmed by X-ray crystallography. Subsequent acylation
of 8 with isobutyric anhydride at −78 °C proceeded site-
selectively to afford monoacylated compound 9 in 75% yield.
To evaluate the substrate generality of the developed process,
synthesis of other nitrogen-bridged bicyclic compounds with
azabicyclo[X.Y.1]alkane skeletons was further investigated
(Scheme 5). When ethylene-tethered-type diazocarbonyl
compound 6i was used as a substrate, benzo-fused
8-azabicyclo[3.2.1]octane 7i was obtained in 90% yield.
Azabicyclo[3.2.1]octanes with a methyl group at the α-position
of ketones 7j and 7k were also accessible without epimerization
of the stereogenic center (65 and 96% yield, respectively).
Similarly, compound 6l bearing a tetrasubstituted carbon center
at the benzylic carbon was a suitable substrate, affording
azabicyclo[3.2.1]octane derivative 7l in 77% yield.
10-Azabicyclo[4.3.1]decanes 7m and 7n and 9-azabicyclo[3.3.1]-
nonane 7o were also accessible from the corresponding
C
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 5. Synthesis of Azabicyclo[X.Y.1]alkanes
Scheme 6. Synthesis of Azabicyclo[X.Y.2]alkanes
a
Products were obtained as a single diastereomer unless otherwise
noted. dr is the diastereomeric ratio.
a
Isolated yield determined by silica gel column chromatography.
b
Estimated yield determined by 1H NMR using Ph3CH as an internal
diazocarbonyl compounds 6m−o under the same reaction
conditions (7m, 82% yield; 7n, 68% yield; 7o, 67% yield).
Furthermore, when ε-caprolactam derivatives 6p and 6q were
utilized as the substrates, the Rh-catalyzed skeletal rearrange-
ment occurred in a diastereoselective manner,15 affording
10-azabicyclo[5.2.1]decane 7p and 11-azabicyclo[5.3.1]-
undecane 7q in 77 and 80% yield, respectively.
c
standard. H atoms have been omitted for the sake of clarity.
Scheme 7. Experiments To Elucidate the Reaction
Mechanism
Synthesis of azabicyclo[X.Y.2]alkanes was next examined
using substrates bearing a diazocarbonyl substituent at the
β-position of the amide nitrogen (Scheme 6). The optimized
conditions for the synthesis of azabicyclo[X.Y.1] skeletons were
also effective for this purpose. Using indole and pyrrole-fused
substrates 6r and 3, the corresponding 6-azabicyclo[3.2.2]-
nonanes 7r and 4 were obtained in 69 and 85% yield,
respectively. Although the reaction of γ-lactam derivative 6s
also proceeded smoothly under the same reaction conditions,
the corresponding 2-azabicyclo[2.2.2]octane 7s was isolated in
only 27% yield because of the gradual decomposition of 7s
during the silica gel column purification. Therefore, after the
construction of the 2-azabicyclo[2.2.2]octane core using the
developed skeletal rearrangement, DIBAL-H was directly added
to the reaction mixture to give diol 10 in 74% yield with
excellent diastereoselectivity. The relative configuration of 10
was confirmed by X-ray crystallography after it had been
converted into an N-Boc diacetate derivative 11.
a
b
From Scheme 3 for comparison. H atoms have been omitted for the
sake of clarity.
a model system (Scheme 7). When the reaction was performed
under optimal conditions, 7d was obtained in 82% yield,
accompanied by the formation of 12 in 17% yield. Similar
results were obtained using Rh2(NHCOMe)4 as a catalyst. On
the other hand, the use of Rh2(OCOMe)4 affected the product
compositions. In addition to 7d (25% yield) and 12 (16%
yield), compound 13, the product presumably formed by the
Stevens [1,2]-shift of the PMB group involving a radical pair
intermediate,4 was isolated in 13% yield. The product com-
positions were affected by the structure of the Rh(II) dimer
Mechanistic Investigation into the Developed Rh
Catalysis. During studies of the substrate scope, we observed
the formation of [1,4]-PMB transfer products16 such as 12 in
some entries, which most likely occurred because of a
dissociation−recombination mechanism from the N-ylide
intermediate.4 To gain insight into the reaction mechanism,
product compositions were analyzed using the reaction of 6d as
D
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
complex, strongly indicating the intermediacy of the Rh-
associated N-ylide.17 Moreover, as shown in Table 1,
remarkable differences in the catalyst activity were observed
between Rh(II) dimer complexes with primary carboxamidate
ligands and those with secondary carboxamidate ligands,
suggesting that the amide hydrogen was involved in the
transition state of the N → C acyl transfer step. These
experimental findings led us to propose the transition state
model shown in Figure 2 for Rh-catalyzed formal carbenoid
the amide in the energy-minimized structure is approximately
2.3 Å, indicating the existence of a hydrogen bonding
interaction.22 Nucleophilic attack of the nitrogen atom on the
carbenoid carbon gives Rh-associated N-ylide 15, which was
calculated to be 10 kcal/mol more stable than complex 14.
Subsequent N → C acyl transfer was initiated by nucleophilic
attack of the carbon associated with Rh metal, providing
transition state 16. The calculated structure indicated that
hydrogen bond networks (2.2 and 2.4 Å) stabilized the
transition state.23 The activation energy was reasonably low
(17 kcal/mol), supporting the reaction pathway via model 16.
Intrinsic reaction coordinate analysis24 demonstrated that this
step is a nonsynchronous concerted process,25 suggesting the
direct production of 17 from 16. In addition, the postulated
zwitterionic intermediate 18 was calculated to be a highly
unstable complex, leading us to conclude that the [1,2]-acyl
transfer proceeded via a concerted addition/elimination process
on the sp2 carbon.26 Dissociation of the Rh(II) dimer complex
easily occurred from 17, affording the final product 19. Both
the nucleophilicity of the carbon associated with a Rh metal
and the hydrogen bond donating activity of the hydrogen in
the carboxamidate ligands were affected by the substituent in
the carbonyl group of the carboxamidate ligands. Apposite
balance of these properties would realize the efficient
promotion of the formal carbenoid insertion into an amide
C−N bond via a selective Stevens [1,2]-shift of the acyl groups.
Figure 2. Proposed transition state model.
insertion into an amide C−N bond, where the Stevens [1,2]-
shift of the acyl group is facilitated by a hydrogen bonding
interaction between the amide carbonyl group and the
hydrogen in the carboxamidate ligand.
To test the validity of our transition state model, density
functional theory calculations were performed using a
structurally simplified model (Scheme 8).18 The geometry of
the proposed structures was calculated at the RB3LYP level
with the LANL2DZ basis set for Rh and the 6-31G* basis
set for C, H, N, and O.19,20 Computational analyses of the
generation of Rh carbenoids from diazo compounds have been
well-investigated by the Nakamura group.20 Thus, we began our
calculations from Rh carbenoid 14.21 The distance between the
oxygen atom of the carbonyl group and the hydrogen atom of
CONCLUSION
■
We developed a novel synthetic method for obtaining a wide
variety of nitrogen-bridged bicyclic compounds with Rh-
catalyzed formal carbenoid insertion into an amide C−N
bond. Using 0.1−0.4 mol % Rh2(NHCOtBu)4 catalyst, various
azabicyclo[X.Y.Z]alkane derivatives were obtained in good to
excellent yield, successfully demonstrating the broad substrate
a
Scheme 8. Energy Profile Calculated at the RB3LYP/LANL2DZ and 6-31G(d) Level of Theory
a
H atoms of the C−H bonds have been omitted for the sake of clarity.
E
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3.75 (d, J = 13.2 Hz, 1H), 3.81 (s, 3H), 3.82 (m, 1H), 3.89 (d, J =
13.2 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 21.2, 27.3, 40.5, 40.9, 47.5, 55.2, 58.6,
58.7, 81.4, 114.0, 129.5, 130.1, 159.1, 206.8, 211.8; IR (ATR) ν 2961,
2912, 1753, 1696, 1511, 1244 cm−1; HRMS (ESI-TOF) [M + Na]+
generality of the developed process. Experimental and
computational studies to elucidate the reaction mechanism
revealed that the formal insertion reaction of a carbenoid into
an amide C−N bond proceeded via the formation of Rh-
associated N-ylides, followed by an acyl group-selective Stevens
[1,2]-shift through a concerted addition/elimination process on
the sp2 carbon. The developed method provides a general
approach to nitrogen-bridged bicyclic frameworks and can be
applied to the synthesis of complex natural products and phar-
maceutical agents.
+
calcd for C17H21NNaO3 m/z 310.1414, found m/z 310.1417.
9-(4-Methoxybenzyl)-9-azaspiro[bicyclo[4.2.1]nonane-3,1′-cyclo-
pentane]-5,7-dione (7d). Prepared according to general procedure
A and isolated as a colorless oil (82% yield, 53.6 mg): Rf = 0.6
EXPERIMENTAL SECTION
■
1
General Information. Analytical thin layer chromatography was
performed on Kieselgel 60F254, 0.25 mm thickness plates. Column
chromatography was performed with silica gel 60 N (spherical, neutral
63-210 mesh). Reactions were conducted in dry solvent. Other
reagents were purified by the usual methods.
(n-hexane/EtOAc, 3/2); H NMR (400 MHz, CDCl3) δ 1.19−1.68
(m, 9H), 2.16 (d, J = 12.8 Hz, 1H), 2.24−2.35 (m, 2H), 2.67 (m, 1H),
3.34 (d, J = 12.8 Hz, 1H), 3.68 (s, 1H), 3.73 (d, J = 13.2 Hz, 1H), 3.80
(s, 3H), 3.81 (m, 1H), 3.84 (d, J = 13.2 Hz, 1H), 6.86 (d, J = 8.8 Hz,
2H), 7.26 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.3,
25.0, 36.6, 38.7, 42.9, 43.9, 47.3, 49.7, 55.2, 59.1 (2C), 81.8, 114.0,
129.5, 130.2, 159.1, 206.0, 211.7; IR (ATR) ν 2951, 1751, 1693, 1510,
General Procedure A for the Insertion Reaction. To a stirred
solution of Rh2(NHCOtBu)4 (0.48 mg, 0.8 μmol) in 1,4-dioxane
(5 mL) and CH2Cl2 (3 mL) was added a solution of α-diazocarbonyl
compound 6 (0.2 mmol) in CH2Cl2 (2 mL) over 3 min at 40 °C. After
being stirred for 2 h at 40 °C, the reaction mixture was concentrated
under reduced pressure and purified by flash chromatography on silica
gel to afford nitrogen-bridged compound 7.
+
1244 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for C20H26NO3 m/z
328.1907, found m/z 328.1889.
Characterization of Products 7a−s, 4, and 10−13.
3,4-Benzo-9-(4-methoxybenzyl)-9-azabicyclo[4.2.1]nonane-2,8-
dione (7e). Prepared according to general procedure A and isolated as
a colorless oil (70% yield, 45 mg): Rf = 0.7 (n-hexane/EtOAc, 3/2);
1H NMR (400 MHz, CDCl3) δ 2.41 (d, J = 18.4 Hz, 1H), 2.81−2.89
9-(4-Methoxybenzyl)-9-azabicyclo[4.2.1]nonane-2,8-dione (7a).
Prepared according to general procedure A and isolated as white
powder (98% yield, 53.3 mg): mp 79−81 °C; Rf = 0.7 (n-hexane/
EtOAc, 2/3); 1H NMR (400 MHz, CDCl3) δ 1.44 (m, 1H), 1.73 (m,
1H), 1.81 (m, 1H), 2.10 (m, 1H), 2.24 (d, J = 18.0 Hz, 1H), 2.44 (dd,
J = 15.6, 6.0 Hz, 1H), 2.73 (dd, J = 18.0, 8.8 Hz, 1H), 2.88 (ddd, J =
15.6, 14.0, 2.4 Hz, 1H), 3.74 (s, 1H), 3.79 (s, 3H), 3.81 (m, 1H), 3.84
(d, J = 13.2 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 6.86 (d, J = 8.4 Hz,
2H), 7.24 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 18.2,
34.7, 40.1, 42.4, 52.2, 57.1, 57.8, 80.5, 114.0, 129.5, 129.9, 159.1, 206.9,
210.9; IR (ATR) ν 2930, 1751, 1697, 1610, 1510, 1240, 1173, 1134,
1096, 1031, 814 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for
(m, 2H), 3.81 (s, 3H), 3.87−3.97 (m, 3H), 4.03 (s, 1H), 4.06 (d, J =
13.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 7.2 Hz, 1H), 7.28
(d, J = 8.4 Hz, 2H), 7.29 (m, 1H), 7.39 (dd, J = 7.6, 7.6 Hz, 1H), 7.72
(d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 40.3, 42.5, 52.3,
55.1, 55.3, 77.6, 113.9, 127.2, 128.6, 129.8, 130.7, 132.0, 132.7, 135.8,
137.7, 159.1, 200.2, 210.1; IR (ATR) ν 2927, 2835, 1752, 1672, 1610,
1510, 1243 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for
+
C20H19NNaO3 m/z 344.1257, found m/z 344.1266.
+
C16H20NO3 m/z 274.1438, found m/z 274.1439.
9-(4-Methoxybenzyl)-6-methyl-9-azabicyclo[4.2.1]nonane-2,8-
dione (7f). Prepared according to general procedure A and isolated
as white powder (85% yield, 48.6 mg): mp 99−101 °C; Rf = 0.6
1
(n-hexane/EtOAc/MeOH, 8/8/1); H NMR (400 MHz, CDCl3) δ
1.50 (s, 3H), 1.57 (m, 1H), 1.80 (m, 1H), 1.89 (m, 1H), 2.09 (m, 1H),
2.46 (m, 1H), 2.55 (s, 2H), 2.65 (dd, J = 16.8, 5.2 Hz, 1H), 3.68 (d,
J = 13.6 Hz, 1H), 3.78 (s, 3H), 3.81 (s, 1H), 4.17 (d, J = 13.6 Hz, 1H),
6.83 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 19.2, 27.0, 38.9, 44.1, 47.3, 50.4, 55.2, 61.4, 78.9,
113.8, 129.2, 129.8, 158.8, 207.5, 208.6; IR (ATR) ν 2930, 1752, 1696,
1611, 1510, 1457, 1242, 1171, 1032, 814 cm−1; HRMS (ESI-TOF)
9-(4-Methoxybenzyl)-3,3-dimethyl-9-azabicyclo[4.2.1]nonane-
2,8-dione (7b). Prepared according to general procedure A and
isolated as a colorless oil (94% yield, 56.3 mg): Rf = 0.7 (n-hexane/
1
EtOAc, 3/2); H NMR (400 MHz, CDCl3) δ 1.05 (s, 3H), 1.46 (s,
3H), 1.49−1.66 (m, 3H), 2.21 (d, J = 18.4 Hz, 1H), 2.26 (m, 1H),
2.68 (dd, J = 18.4, 8.4 Hz, 1H), 3.67−3.86 (m, 4H), 3.80 (s, 3H), 6.85
(d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 24.8, 28.9, 31.3, 32.2, 38.8, 46.7, 55.2, 57.7, 59.1, 81.8, 113.9,
129.6, 130.1, 159.0, 208.7, 213.1. IR (ATR) ν 2934, 1749, 1693, 1511,
+
[M + Na]+ calcd for C17H21NNaO3 m/z 310.1414, found m/z
310.1413.
+
1245 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for C18H23NNaO3
m/z 324.1570, found m/z 324.1564.
9-Benzyl-9-azabicyclo[4.2.1]nonane-2,8-dione (7g). Prepared ac-
cording to general procedure A and isolated as a colorless oil (96%
yield, 46.9 mg): Rf = 0.2 (n-hexane/EtOAc, 3/1); 1H NMR
(400 MHz, CDCl3) δ 1.46 (m, 1H), 1.73 (m, 1H), 1.82 (m, 1H),
2.12 (m, 1H), 2.26 (d, J = 18.4 Hz, 1H), 2.46 (dd, J = 15.6, 6 Hz, 1H),
2.76 (dd, J = 18.4, 8.4 Hz, 1H), 2.91 (m, 1H), 3.76 (s, 1H), 3.81 (m,
1H), 3.92 (d, J = 14 Hz, 1H), 3.98 (d, J = 14 Hz, 1H), 7.25−7.36 (m,
5 H); 13C NMR (100 MHz, CDCl3) δ 18.1, 34.6, 40.1, 42.4, 57.7, 57.9,
80.6, 127.5, 128.2, 128.5, 137.9, 206.9, 210.8; IR (ATR) ν 2928, 1752,
rac-(1S,4S,6R)-9-(4-Methoxybenzyl)-4-methyl-9-azabicyclo-
[4.2.1]nonane-2,8-dione (7c). Prepared according to general
procedure A and isolated as a colorless oil (85% yield, 49 mg): Rf =
0.7 (n-hexane/EtOAc, 3/2); H NMR (400 MHz, CDCl3) δ 0.92 (d,
J = 6.8 Hz, 3H), 1.59 (m, 1H), 2.21−2.35 (m, 4H), 2.71 (dd, J =
18.8, 9.6 Hz, 1H), 3.38 (dd, J = 13.2, 2.8 Hz, 1H), 3.70 (s, 1H),
1
F
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1697, 1495, 1455, 1409, 1322, 1239, 1133, 1078 cm−1; HRMS (ESI-
61.4 mg): mp 80−81 °C; Rf = 0.7 (n-hexane/EtOAc, 3/2); H NMR
(400 MHz, CDCl3) δ 0.80 (d, J = 6.8 Hz, 3H), 3.06 (qd, J = 6.8, 6.4
Hz, 1H), 3.77 (d, J = 13.2 Hz, 1H), 3.80 (s, 3H), 3.90 (d, J = 13.2 Hz,
1H), 4.02 (s, 1H), 4.40 (d, J = 6.4 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H),
7.11 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.2 Hz, 1H), 7.43 (dd, J = 7.6,
7.6 Hz, 1H), 7.61 (dd, J = 7.6, 7.2 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 11.3, 46.5, 52.1, 55.2, 64.2, 78.5,
113.9, 126.6, 128.4, 128.6, 128.9, 130.0, 130.6, 135.1, 139.7, 159.1,
190.1, 210.3; IR (ATR) ν 2969, 2934, 1758, 1689, 1611, 1601, 1512,
+
TOF) [2M + Na]+ calcd for C30H34N2NaO4 m/z 509.2411, found
m/z 509.2418.
9-Butyl-9-azabicyclo[4.2.1]nonane-2,8-dione (7h). Prepared ac-
cording to general procedure A and isolated as a pale yellow oil (90%
yield, 37.7 mg): Rf = 0.6 (n-hexane/EtOAc/MeOH, 8/8/1); 1H NMR
(400 MHz, CDCl3) δ 0.92 (t, J = 7.2 Hz, 3H), 1.32−1.51 (m, 5H),
1.73−1.80 (m, 2H), 2.12 (m, 1H), 2.27 (d, J = 18.0 Hz, 1H), 2.45 (dd,
J = 16.0, 5.6 Hz, 1H), 2.64−2.84 (m, 4H), 3.77 (s, 1H), 3.82 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 13.8, 18.0, 20.1, 30.7, 34.1, 40.8, 42.5,
52.3, 58.4, 80.4, 207.8, 211.0; IR (ATR) ν 3649, 2928, 1753, 1698,
1457, 1410, 1313, 1238, 1137, 1084 cm−1; HRMS (ESI-TOF) [2M +
+
1243 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for C20H20NO3 m/z
322.1438, found m/z 322.1445.
+
Na]+ calcd for C24H38N2NaO4 m/z 441.2724, found m/z 441.2725.
cis-3,4-Benzo-8-(4-methoxybenzyl)-5-methyl-8-azabicyclo[3.2.1]-
octane-2,7-dione (7l). Prepared according to general procedure A and
isolated as a pale yellow oil (77% yield, 49.2 mg): Rf = 0.7 (n-hexane/
EtOAc, 3/2); 1H NMR (400 MHz, CDCl3) δ 1.92 (s, 3H), 2.55 (d, J =
17.2 Hz, 1H), 2.80 (d, J = 17.2 Hz, 1H), 3.44 (d, J = 13.2 Hz, 1H),
3.79 (s, 3H), 3.86 (s, 1H), 3.96 (d, J = 13.2 Hz, 1H), 6.84 (d, J =
8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.43
(dd, J = 7.6, 7.6 Hz, 1H), 7.66 (dd, J = 7.6, 7.6 Hz, 1H), 7.98 (d, J =
7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.3, 48.1, 51.0, 55.2,
62.7, 78.1, 113.9, 125.4, 126.3, 128.3, 129.1, 129.9, 130.1, 135.9, 144.7,
159.0, 190.9, 206.5; IR (ATR) ν 2974, 2834, 1760, 1688, 1598, 1512,
(+)-(1S,6R)-9-(4-Methoxybenzyl)-9-azabicyclo[4.2.1]nonane-2,8-
dione [(+)-7a]. Prepared according to general procedure A and
isolated as white powder (98% yield, 53.7 mg): mp 94−96 °C;
[α]23 + 213.7° (c 1, CHCl3). The enantiomeric excess was
D
determined to be 98% after reduction to 8.
+
1250 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for C20H20NO3 m/z
322.1438, found m/z 322.1427.
3,4-Benzo-8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane-2,7-
dione (7i). Prepared according to general procedure A and isolated as
a pale yellow oil (90% yield, 52.1 mg): Rf = 0.7 (n-hexane/EtOAc,
3/2); 1H NMR (400 MHz, CDCl3) δ 2.39 (d, J = 17.6 Hz, 1H), 3.00
(dd, J = 17.6, 6.8 Hz, 1H), 3.74 (d, J = 13.2 Hz, 1H), 3.80 (s, 3H), 3.87
(d, J = 13.2 Hz, 1H), 3.96 (s, 1H), 4.52 (d, J = 6.8 Hz, 1H), 6.85 (d,
J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 7.2 Hz, 1H),
7.44 (dd, J = 7.2, 7.2 Hz, 1H), 7.61 (dd, J = 7.2, 7.2 Hz, 1H), 7.96 (d,
J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 43.0, 52.5, 55.2, 59.7,
78.5, 113.9, 126.4, 126.5, 128.5, 128.6, 129.9, 130.0, 135.6, 142.7,
159.1, 189.9, 207.6; IR (ATR) ν 2958, 2835, 1759, 1691, 1512, 1244,
10-(4-Methoxybenzyl)-10-azabicyclo[4.3.1]decane-2,9-dione
(7m). Prepared according to general procedure A and isolated as white
powder (82% yield, 47 mg): mp 89−90 °C dec; Rf = 0.5 (n-hexane/
1
EtOAc, 3/2); H NMR (400 MHz, CDCl3) δ 1.55−1.76 (m, 3H),
1.85−2.00 (m, 2H), 2.11 (m, 1H), 2.30−2.49 (m, 3H), 3.12 (m, 1H),
3.31 (m, 1H), 3.63 (s, 1H), 3.80 (s, 3H), 3.82 (d, J = 13.2 Hz, 1H),
3.89 (d, J = 13.2 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 20.0, 22.7, 31.7, 34.6, 42.1, 54.7,
55.2, 59.7, 76.7, 113.9, 129.4, 129.9, 159.1, 206.0, 208.7; IR (ATR)
ν 2935, 1728, 1697, 1610, 1510, 1242, 1031 cm−1; HRMS (ESI-TOF)
+
701 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for C19H18NO3 m/z
308.1281, found m/z 308.1285.
+
[M + Na]+ calcd for C17H21NNaO3 m/z 310.1414, found m/z
310.1418.
rac-(1S,5R,6R)-3,4-Benzo-8-(4-methoxybenzyl)-6-methyl-8-
azabicyclo[3.2.1]octane-2,7-dione (7j). Prepared according to
general procedure A and isolated as a pale yellow oil (65% yield,
10-(4-Methoxybenzyl)-10-azaspiro[bicyclo[4.3.1]decane-3,1′-cy-
clopentane]-5,7-dione (7n). Prepared according to general procedure
A and isolated as a colorless oil (68% yield, 46 mg): Rf = 0.3
1
41.9 mg): Rf = 0.7 (n-hexane/EtOAc, 3/2); H NMR (400 MHz,
CDCl3) δ 1.45 (d, J = 7.2 Hz, 3H), 2.47 (q, J = 7.6 Hz, 1H), 3.73 (d,
J = 13.2 Hz, 1H), 3.81 (s, 3H), 3.90 (d, J = 13.2 Hz, 1H), 3.98 (s, 1H),
4.06 (s, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.15
(d, J = 7.2 Hz, 1H), 7.43 (dd, J = 7.6, 7.6 Hz, 1H), 7.61 (dd, J = 7.6,
7.2 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
16.5, 48.7, 51.7, 55.2, 65.8, 78.6, 113.9, 126.3, 126.6, 128.4, 128.9,
129.8 (2C), 135.8, 142.4, 159.0, 190.4, 209.9; IR (ATR) ν 2972, 2934,
1758, 1687, 1601, 1512, 1246 cm−1; HRMS (ESI-TOF) [M + H]+
1
(n-hexane/EtOAc, 4/1); H NMR (400 MHz, CDCl3) δ 1.38 (m,
1H), 1.62−2.04 (m, 10H), 2.16 (d, J = 11.2 Hz, 1H), 2.39−2.60 (m,
3H), 3.12 (d, J = 11.2 Hz, 1H), 3.26 (m, 1H), 3.43 (s, 1H), 3.74 (d, J =
12.8 Hz, 1H), 3.80 (s, 3H), 3.89 (d, J = 12.8 Hz, 1H), 6.86 (d, J =
8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
22.8, 23.4, 25.5, 34.3, 39.8, 40.7, 42.1, 43.0, 51.8, 53.5, 55.2, 57.8, 75.9,
113.9, 129.3, 130.3, 159.1, 206.6, 208.8; IR (ATR) ν 2951, 2872, 1727,
1699, 1512, 1247 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for
+
calcd for C20H20NO3 m/z 322.1438, found m/z 322.1448.
+
C21H27NNaO3 m/z 364.1883, found m/z 364.1880.
rac-(1S,5R,6S)-3,4-Benzo-8-(4-methoxybenzyl)-6-methyl-8-
azabicyclo[3.2.1]octane-2,7-dione (7k). Prepared according to
general procedure A and isolated as pale yellow powder (96% yield,
3,4-Benzo-9-(4-methoxybenzyl)-9-azabicyclo[3.3.1]nonane-2,8-
dione (7o). Prepared according to general procedure A and isolated
as a pale yellow oil (67% yield, 43.1 mg): Rf = 0.6 (n-hexane/EtOAc,
G
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
3/2); H NMR (400 MHz, CDCl3) δ 2.08 (m, 1H), 2.33 (m, 1H),
3.72 (d, J = 13.2 Hz, 1H), 3.80 (s, 3H), 3.93 (d, J = 13.2 Hz, 1H), 4.21
(s, 1H), 5.33 (m, 1H), 6.86 (d, J = 8.0 Hz, 2H), 7.18−7.47 (m, 6H),
7.74 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 41.3, 48.2,
55.0, 55.2, 58.3, 79.2, 109.6, 110.4, 113.9, 121.6, 123.8, 126.47, 126.51,
128.4, 130.2, 134.4, 137.7, 159.1, 184.7, 202.0; IR (ATR) ν 2919,
1729, 1658, 1512, 1354, 1327, 1243, 1168, 1031 cm−1; HRMS
2.50 (m, 1H), 2.67 (m, 1H), 3.75 (s, 2H), 3.80 (s, 3H), 3.97 (s, 1H),
4.16 (m, 1H), 6.84 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.26
(d, J = 7.6 Hz, 1H), 7.46 (dd, J = 7.6, 7.6 Hz, 1H), 7.65 (dd, J = 7.6,
7.6 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
31.1, 34.9, 54.9, 55.3, 57.0, 78.6, 113.9, 126.3, 127.4, 128.1, 128.7,
130.0, 130.3, 135.4, 141.6, 159.2, 192.1, 201.1; IR (ATR) ν 2947,
2835, 1724, 1681, 1512, 1246 cm−1; HRMS (ESI-TOF) [M + H]+
+
(ESI-TOF) [M + Na]+ calcd for C22H20N2NaO3 m/z 383.1366,
found m/z 383.1373.
+
calcd for C20H20NO3 m/z 322.1438, found m/z 322.1447.
rac-(5S,8S)-2,3-Dibromo-10-(4-methoxybenzyl)-5H-8,5-
(epiminomethano)pyrrolo[1,2-a]azepine-7,9(6H,8H)-dione (4). Pre-
pared according to general procedure A and isolated as pale yellow
powder (85% yield, 79.7 mg): mp 137−138 °C dec; Rf = 0.6
cis-10-(4-Methoxybenzyl)-10-azabicyclo[5.2.1]decane-2,9-dione
(7p). Prepared according to general procedure A and isolated as pale
yellow powder (77% yield, 44 mg): mp 111−113 °C; Rf = 0.7
1
(n-hexane/EtOAc, 3/2); H NMR (400 MHz, CDCl3) δ 2.73 (m,
1
(n-hexane/EtOAc, 2/3); H NMR (400 MHz, CDCl3) δ 1.01 (m,
1H), 2.88 (d, J = 12.0 Hz, 1H), 2.94 (dd, J = 18.0, 3.2 Hz, 1H), 3.59
(d, J = 12.0, 5.6 Hz, 1H), 3.68 (d, J = 13.2 Hz, 1H), 3.80 (s, 3H), 3.89
(d, J = 13.2 Hz, 1H), 4.11 (s, 1H), 5.30 (m, 1H), 6.87 (d, J = 8.8 Hz,
2H), 7.20 (s, 1H), 7.21 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 40.5, 53.2, 54.6, 55.3, 58.3, 79.1, 102.8, 112.1, 114.0, 119.6,
128.2, 130.2, 132.0, 159.3, 180.2, 200.8; IR (ATR) ν 2917, 2836, 1733,
1652, 1513, 1378, 1331, 1245 cm−1; HRMS (ESI-TOF) [M + Na]+
1H), 1.46 (m, 1H), 1.60−2.10 (m, 6H), 2.65 (dd, J = 18.0, 7.6 Hz,
1H), 3.42 (m, 1H), 3.43 (s, 1H), 3.53 (m, 1H), 3.73 (d, J = 13.2 Hz,
1H), 3.82 (s, 3H), 3.93 (d, J = 13.2 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H),
7.32 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 22.3, 30.8,
35.8, 39.1, 39.3, 55.2, 59.4, 60.3, 77.2, 114.0, 130.1, 130.4, 159.2, 209.9,
211.1; IR (ATR) ν 2929, 2855, 1757, 1698, 1611, 1512, 1247,
+
1032 cm−1; HRMS (ESI-TOF) [2M + Na]+ calcd for C34H42N2NaO6
+
calcd for C18H16Br2N2NaO3 m/z 488.9420, found m/z 488.9431.
m/z 597.2935, found m/z 597.2944.
2-(4-Methoxybenzyl)-2-azabicyclo[2.2.2]octane-6,7-dione (7s).
Prepared according to general procedure A (27% yield, 14.1 mg):
1H NMR (400 MHz, CDCl3) δ 2.35 (dd, J = 18.0, 1.2 Hz, 2H), 2.48
(dd, J = 18.0, 3.2 Hz, 2H), 2.65 (m, 1H), 2.93 (dd, J = 1.2, 1.2 Hz,
2H), 3.40 (s, 1H), 3.65 (d, J = 3.2 Hz, 2H), 3.80 (s, 3H), 6.85 (d, J =
8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
28.0, 42.6, 53.7, 55.2, 59.7, 74.7, 113.8, 129.5, 130.1, 159.0, 203.6; IR
(ATR) ν 2919, 1740, 1715, 1611, 1511, 1245, 1173, 1077, 1031 cm−1;
cis-11-(4-Methoxybenzyl)-11-azabicyclo[5.3.1]undecane-2,10-
dione (cis-7q). Prepared according to general procedure A and
isolated as a colorless oil (80% yield, 89:11 dr, 42.6 mg). Major
1
diastereomer: Rf = 0.5 (n-hexane/EtOAc, 4/1); H NMR (400 MHz,
CD3CN, 50 °C) δ 1.38−2.22 (m, 9H), 2.48−2.64 (m, 2H), 2.93−3.02
(m, 2H), 3.36 (s, 1H), 3.82 (s, 3H), 3.84 (d, J = 13.2 Hz, 1H), 3.88 (d,
J = 13.2 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, CD3CN, 50 °C) δ 25.6, 28.1, 31.8, 32.9, 35.8,
40.6, 56.1, 58.0, 60.1, 78.2, 115.0, 131.9 (2C), 160.5, 209.5, 215.5; IR
(ATR) ν 2930, 1720, 1698, 1610, 1510, 1244, 1154, 1032 cm−1;
+
HRMS (ESI-TOF) [M + H]+ calcd for C15H18NO3 m/z 260.1281,
found m/z 260.1269.
+
HRMS (ESI-TOF) [2M + Na]+ calcd for C36H46N2NaO6 m/z
625.3248, found m/z 625.3240.
(1s,4r,6R,7S)-2-(4-Methoxybenzyl)-2-azabicyclo[2.2.2]octane-6,7-
diol (10). To a solution of Rh2(NHCOtBu)4 (0.48 mg, 0.8 μmol) in
CH2Cl2 (8 mL) was added 6s (57.5 mg, 0.20 mmol) in CH2Cl2 (2.0 mL)
over 3 min at room temperature. After being stirred for 30 min, the
reaction mixture was cooled to −78 °C, and DIBAL-H (1.02 M in
hexane, 0.78 mL, 0.80 mmol) was added. After the mixture had been
stirred for 1 h at −78 °C, the reaction was quenched with a 2 M
aqueous Rochelle salt solution and the mixture was extracted with
AcOEt, washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The crude residue was purified by flash
chromatography on silica gel (CHCl3/MeOH, 15/1 to 5/1) to afford
10 as pale yellow powder (74% yield, 38.8 mg): mp 79−81 °C;
1H NMR (400 MHz, CDCl3) δ 1.44 (d, J = 12.8 Hz, 2H), 1.82−1.91
(m, 3H), 2.79 (s, 1H), 2.85 (s, 2H), 3.86 (s, 3H), 3.90 (m, 2H), 4.01
(s, 2H), 6.86 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 26.3, 36.3, 55.1, 55.2, 61.6, 61.8, 68.5, 113.8,
129.8, 131.6, 158.7; IR (ATR) ν 3395, 2930, 1611, 1512, 1245, 1177,
1035, 1006, 831 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for
trans-11-(4-Methoxybenzyl)-11-azabicyclo[5.3.1]undecane-2,10-
dione (trans-7q). Prepared according to general procedure A and
isolated as colorless blocks (80% yield, 89:11 dr, 5.4 mg): mp 111−
1
113 °C. Minor diastereomer: Rf = 0.4 (n-hexane/EtOAc, 4/1); H
NMR (400 MHz, CDCl3) δ 1.36 (m, 1H), 1.61 (m, 1H), 1.84−2.31
(m, 7H), 2.51−2.67 (m, 3H), 3.02 (m, 1H), 3.39 (d, J = 13.2 Hz, 1H),
3.49 (s, 1H), 3.81 (s, 3H), 3.85 (d, J = 13.2 Hz, 1H), 6.89 (d, J =
8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
23.8, 26.1, 26.9, 27.0, 38.7, 44.4, 48.4, 55.3, 58.3, 79.6, 114.0, 129.1,
130.6, 159.1, 207.0, 211.6; IR (ATR) ν 2939, 1723, 1697, 1512,
+
1246 cm−1; HRMS (ESI-TOF) [2M + Na]+ calcd for C36H46N2NaO6
m/z 625.3248, found m/z 625.3254.
+
C15H22NO3 m/z 264.1594, found m/z 264.1592.
rac-(6S,9S)-12-(4-Methoxybenzyl)-6H-9,6-(epiminomethano)-
azepino[1,2-a]indole-8,10(7H,9H)-dione (7r). Prepared according to
general procedure A and isolated as yellow powder (69% yield,
49.6 mg): mp 168−169 °C dec; Rf = 0.5 (n-hexane/EtOAc, 3/2);
1H NMR (400 MHz, CDCl3) δ 2.82 (m, 1H), 2.91 (d, J = 12.0 Hz,
(1s,4r,6R,7S)-2-(4-Methoxybenzyl)-2-azabicyclo[2.2.2]octane-6,7-
diyl Diacetate (s1). To a stirred solution of 10 (75.6 mg, 0.29 mmol),
DMAP (3.7 mg, 0.03 mmol), and triethylamine (0.09 mL, 0.64 mmol)
in THF (5.8 mL) was added acetic anhydryde (0.06 mL, 0.64 mmol)
at 0 °C. After the mixture had been stirred for 1 h at room
temperature, the reaction was quenched with saturated aqueous
1H), 3.07 (dd, J = 13.2, 3.2 Hz, 1H), 3.69 (d, J = 12.0, 5.6 Hz, 1H),
H
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
NaHCO3 and the mixture was extracted with AcOEt, washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
The crude residue was purified by flash chromatography on silica gel
(hexane/AcOEt, 3/1) to afford s1 as a colorless oil (93% yield,
(31.5 mL) and CH2Cl2 (25 mL) was added 6a (1.5 g, 5.0 mmol) in
CH2Cl2 (6 mL) over 5 min at 40 °C. After being stirred for 2 h at
40 °C, the reaction mixture was concentrated under reduced pressure
and purified by flash chromatography on silica gel (n-hexane/EtOAc,
3/1) to afford 7a in 90% yield (1.22 g, 4.5 mmol).
1
92.2 mg): H NMR (400 MHz, CDCl3) δ 1.56−1.59 (m, 2H), 1.90−
2.03 (m, 3H), 2.11 (s, 6H), 2.87 (s, 2H), 3.02 (dd, J = 2.4, 2.4 Hz,
1H), 3.80 (s, 3H), 3.86 (s, 2H), 4.85 (ddd, J = 9.6, 2.8, 2.8 Hz, 2H),
6.84 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.4, 26.2, 32.6, 54.8, 55.2, 55.3, 60.5, 71.9,
113.4, 129.4, 132.0, 158.5, 170.5; IR (ATR) ν 2935, 1735, 1611, 1510,
1440, 1364, 1239, 1170, 1024, 832 cm−1; HRMS (ESI-TOF) [M + Na]+
calcd for C19H25NNaO5+ m/z 370.1625, found m/z 370.1625.
Recognition of Diketone (Scheme 4).
rac-(1S,2R,6R,8S)-9-(4-Methoxybenzyl)-9-azabicyclo[4.2.1]nonane-
2,8-diol (8). To a stirred solution of 7a (55 mg, 0.2 mmol) in THF
(1.3 mL) was added 1.0 M DIBAL-H in hexane (0.8 mL, 0.8 mmol)
at −78 °C. After the mixture had been stirred at −78 °C for 1 h, 0.2 M
potassium sodium (+)-tartrate (aqueous) was added and stirring was
continued at room temperature for an additional 1 h. The reaction
mixture was filtered through Celite, extracted with EtOAc, washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure. The crude residue was purified by flash chromatography on
silica gel (n-hexane/EtOAc/MeOH, 36/12/1) to afford 8 in 80% yield
(>95:5 dr, 44.4 mg, 0.16 mmol) as white powder: mp 99−101 °C;
Rf = 0.4 (n-hexane/EtOAc/MeOH, 8/8/1); 1H NMR (400 MHz, CDCl3)
δ 1.36−1.46 (m, 1H), 1.57 (m, 1H), 1.70−1.80 (m, 2H), 1.87 (m,
1H), 1.94−2.02 (m, 2H), 2.72 (m, 1H), 3.21 (m, 1H), 3.36 (dd,
J = 6.8, 4.4 Hz, 1H), 3.68 (d, J = 13.2 Hz, 1H), 3.74 (d, J = 13.2 Hz,
1H), 3.78 (s, 3H), 3.86 (m, 1H), 3.96 (br s, 1H), 4.05 (br s, 1H), 4.69
(m, 1H), 6.83 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 20.7, 33.7, 34.2, 43.1, 55.2, 57.7, 58.6, 65.6, 74.0,
75.9, 113.5, 129.1, 132.5, 158.5; IR (ATR) ν 3339, 2923, 1611, 1510,
1458, 1243, 1168, 1026, 822 cm−1; HRMS (ESI-TOF) [2M + Na]+
(1s,4r,6R,7S)-2-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.2]octane-
6,7-diyl Diacetate (11). A solution of s1 (92.2 mg, 0.27 mmol), Boc2O
(471.4 mg, 2.16 mmol), and 20% Pd(OH)2/C (20.3 mg) in EtOH
(9 mL) was stirred under a H2 atmosphere. After 13 h, the reaction
mixture was filtered through a short pad of Celite and concentrated
in vacuo. The obtained residue was purified by flash chromatography
on silica gel (hexane/AcOEt, 2/1) to afford 11 as a white powder
(99% yield, 83.2 mg): mp 103−105 °C; 1H NMR (400 MHz, CDCl3,
major rotamer) δ 1.43−1.52 (m, 11H), 2.00−2.11 (m, 9H), 3.35−3.39
(m, 2H), 4.36 (dd, J = 2.8, 2.8 Hz, 1H), 4.85−4.90 (m, 2H); 13C NMR
(100 MHz, CDCl3, major rotamer) δ 21.0, 25.4, 28.5, 32.0, 48.0, 50.6,
68.9, 79.4, 156.0, 170.3; IR (ATR) ν 1737, 1687, 1410, 1363, 1227,
1175, 1114, 1023, 907 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for
+
C16H25NNaO6 m/z 350.1574, found m/z 350.1565.
The structure of 11 could be confirmed by X-ray diffraction analysis
(CCDC number 1404663)
+
calcd for C32H46N2NaO6 m/z 577.3248, found m/z 577.3251.
The structure of 8 could be confirmed by X-ray diffraction analysis
(CCDC number 1034017)
2′-(4-Methoxybenzyloxy)-8′,8a′-dihydro-1′H-spiro[cyclopentane-
1,7′-indolizin]-5′(6′H)-one (12). Prepared according to general
procedure A using Rh2(OCOMe)4, instead of Rh2(NHCOtBu)4, and
isolated as colorless blocks in 16% yield: mp 120−121 °C; Rf = 0.3
rac-(1R,5R,6S,7S)-5-Hydroxy-9-(4-methoxybenzyl)-9-azabicyclo-
[4.2.1]nonan-7-yl Isobutyrate (9). To a stirred solution of 8 (55.5 mg,
0.2 mmol), DMAP (2.4 mg, 0.02 mmol), and Et3N (0.033 mL,
0.24 mmol) in CH2Cl2 (5 mL) was added (iPrCO)2O (0.093 mL,
0.56 mmol) at −78 °C. After the mixture had been stirred at −78 °C
for 5 h, H2O was added and the reaction mixture was extracted with
EtOAc, washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The crude residue was purified by flash
chromatography on silica gel (CHCl3/CH3CN, 20/1) to afford 9 in
75% yield (52.1 mg, 0.15 mmol) as a pale yellow oil: Rf = 0.4 (CHCl3/
1
(n-hexane/EtOAc, 1/2); H NMR (400 MHz, CDCl3) δ 1.46−1.90
(m, 10H), 2.18 (d, J = 17.6 Hz, 1H), 2.36 (d, J = 17.6 Hz, 1H), 2.59−
2.71 (m, 2H), 3.81 (s, 3H), 4.13 (m, 1H), 4.72 (d, J = 10.8 Hz, 1H),
4.75 (d, J = 10.8 Hz, 1H), 6.38 (s, 1H), 6.90 (d, J = 8.0 Hz, 2H), 7.29
(d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 23.6, 23.9, 36.7,
38.1, 39.6, 41.2, 41.7, 43.0, 55.3, 55.8, 72.2, 102.1, 114.0, 127.9, 129.6,
150.3, 159.7, 164.7; IR (ATR) ν 3111, 2927, 1653, 1616, 1516, 1468,
+
1247, 1173 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for C20H26NO3
m/z 328.1907, found m/z 328.1916.
The structure of 12 could be confirmed by X-ray diffraction analysis
(CCDC number 1035392)
1
CH3CN, 20/1); H NMR (400 MHz, CDCl3) δ 1.17 (d, J = 6.0 Hz,
3H), 1.19 (d, J = 7.2 Hz, 3H), 1.34−1.52 (m, 2H), 1.72−1.87 (m,
3H), 1.93 (m, 1H), 2.02 (m, 1H), 2.46−2.60 (m, 2H), 2.99 (m, 1H),
3.27 (m, 1H), 3.52 (m, 1H), 3.72 (d, J = 13.2 Hz, 1H), 3.76−3.86 (m,
5H), 5.38 (m, 1H), 6.84 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 18.8, 19.1, 21.0, 33.5, 34.0, 34.2, 40.7,
55.2, 57.8, 58.1, 65.5, 75.5, 75.9, 113.6, 129.1, 132.1, 158.6, 176.2; IR
(ATR) ν 3483, 2929, 1727, 1611, 1510, 1467, 1242, 1160, 1035,
3′-(4-Methoxybenzyl)dihydro-1′H-spiro[cyclopentane-1,7′-indoli-
zine]-2′,5′(3′H,6′H)-dione (13). Prepared according to general
procedure A using Rh2(OCOMe)4, instead of Rh2(NHCOtBu)4, and
isolated as a colorless oil in 9% yield: Rf = 0.3 (n-hexane/EtOAc, 1/2);
1H NMR (400 MHz, CDCl3) δ 1.22−1.75 (m, 10H), 2.10−2.28 (m,
+
822 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for C20H30NO4 m/z
348.2169, found m/z 348.2166.
Synthesis and Characterization of Rh2(NHCOtBu)4. Dirho-
dium Tetrapivalamidate. The mixture of Rh2(OAc)4 (100 mg,
0.23 mmol) and H2NCOtBu (300 mg, 3 mmol) in chlorobenzene
(10 mL) was heated to reflux for 12 h, and then the solvent was
distilled off by heating at a rate such that ∼5 mL of the solvent was
removed per hour. After 2 h, chlorobenzene (10 mL) was added to the
mixture, and the solvent was distilled off at the same rate for 2 h. This
process was repeated one additional time, and the residue was purified
by flash chromatography on silica gel (EtOAc/CH2Cl2, 2/3) to afford
the titled compound in 74% yield (102 mg, 0.17 mmol) as black
powder: mp >300 °C; Rf = 0.2 (CH2Cl2/EtOAc, 1/1); 1H NMR
(400 MHz, CDCl3) δ 1.07 (s, 36H), 4.81 (br s, 4H); 13C NMR
3H), 2.46 (d, J = 14.4 Hz, 1H), 2.86 (m, 1H), 3.20 (dd, J = 14.0,
2.8 Hz, 1H), 3.29 (dd, J = 14.0, 5.6 Hz, 1H), 3.77 (s, 3H), 4.50 (m,
1H), 6.78 (d, J = 7.6 Hz, 2H), 7.07 (d, J = 7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 23.7, 24.3, 34.4, 35.9, 40.8, 41.0, 41.1, 44.0, 45.0,
53.4, 55.3, 63.3, 114.0, 128.6, 130.9, 158.7, 168.8, 212.6; IR (ATR) ν
2945, 2863, 1756, 1638, 1512, 1456, 1249 cm−1; HRMS (ESI-TOF)
+
[M + Na]+ calcd for C20H25NNaO3 m/z 350.1727, found m/z
350.1733.
Procedure for the Insertion Reaction on a Gram Scale. To a
stirred solution of Rh2(NHCOtBu)4 (3.0 mg, 5 μmol) in 1,4-dioxane
I
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(100 MHz, DMF-d7, 50 °C) δ 27.9, 39.4, 180.7; IR (ATR) ν 3352,
2961, 2863, 1570, 1485, 1447, 1356, 1258, 1170 cm−1; HRMS (ESI-
TOF) [M + H]+ calcd for C20H41N4O4Rh2+ m/z 607.1232, found m/z
607.1239.
cis-2-[1-(4-Methoxybenzyl)-4-methyl-6-oxopiperidin-2-yl]acetic
Acid (s3c). Prepared according to general procedure B and isolated as
white powder (30% yield, two steps): mp 157−160 °C; Rf = 0.2
1
(EtOAc); H NMR (400 MHz, CD3OD) δ 0.99 (d, J = 6.8 Hz, 3H),
1.25−1.46 (m, 2H), 1.84 (m, 1H), 2.04−2.11 (m, 2H), 2.40 (dd, J =
15.6, 8.4 Hz, 1H), 2.44 (m, 1H), 2.71 (dd, J = 15.6, 4.0 Hz, 1H), 3.71
(m, 1H), 3.74 (s, 3H), 4.26 (d, J = 15.6 Hz, 1H), 5.04 (d, J = 15.6 Hz,
1H), 6.87 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CD3OD) δ 21.3, 27.6, 38.4, 39.9, 41.7, 47.0, 54.4, 55.7,
115.1, 129.9, 130.4, 160.5, 174.0 (2C); IR (ATR) ν 3286, 2952, 2912,
1712, 1602, 1577, 1514, 1252, 1201 cm−1; HRMS (ESI-TOF) [M +
Synthesis and Characterization of Substrates. General
Procedure B for Preparing Carboxylic Compound s3.
+
Na]+ calcd for C16H21NNaO4 m/z 314.1363, found m/z 314.1371.
2-[8-(4-Methoxybenzyl)-9-oxo-8-azaspiro[4.5]decan-7-yl]acetic
Acid (s3d). Prepared according to general procedure B and isolated as
white powder (51% yield, two steps): mp 164−166 °C; Rf = 0.2
(EtOAc); 1H NMR (400 MHz, CDCl3) δ 1.29−1.92 (m, 10H), 2.32−
2.45 (m, 2H), 2.49 (dd, J = 15.6, 8.4 Hz, 1H), 2.72 (dd, J = 15.6,
3.2 Hz, 1H), 3.65 (m, 1H), 3.79 (s, 3H), 4.09 (d, J = 14.8 Hz, 1H),
5.28 (d, J = 14.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 23.9, 24.6, 35.0, 38.7, 40.0, 40.1,
40.2, 44.5, 45.9, 50.8, 55.2, 114.0, 128.8, 129.2, 158.9, 171.6, 174.3; IR
(ATR) ν 2945, 2860, 1720, 1610, 1513, 1246 cm−1; HRMS (ESI-
To a stirred solution of s2 in CH2Cl2 was added DIBAL-H (1.0 M
solution in n-hexane, 1.5 equiv) at −78 °C. After the mixture had been
stirred at −78 °C for 1 h, 0.2 M potassium sodium (+)-tartrate
(aqueous) was added and stirring was continued at room temperature
for 1 h. The reaction mixture was filtered through Celite, extracted
with EtOAc, washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was used for the next reaction
without further purification. To a stirred suspension of NaH (2 equiv,
60% dispersion in mineral oil) in THF was added triethylphospho-
noacetate (1.8 equiv) at 0 °C, and the mixture was stirred at 0 °C for
30 min. Hydroxylactam was added to the reaction mixture, and the
whole was stirred at room temperature for 12 h. NaOH (aqueous,
10%) was added, and stirring was continued at room temperature for
12 h. The reaction mixture was acidified with 6 N aqueous HCl,
extracted with EtOAc, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography on silica gel to afford s3.
+
TOF) [M + H]+ calcd for C19H26NO4 m/z 332.1856, found m/z
332.1851.
2-[2-(4-Methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-
yl]acetic Acid (s3e). Prepared according to general procedure B and
isolated as white powder (51% yield, two steps): mp 147−148 °C;
1
Rf = 0.3 (n-hexane/EtOAc, 1/1); H NMR (400 MHz, CDCl3) δ
2.44−2.55 (m, 2H), 2.80 (dd, J = 16.4, 1.6 Hz, 1H), 3.20 (dd, J = 16.4,
5.6 Hz, 1H), 3.79 (s, 3H), 4.05 (d, J = 14.8 Hz, 1H), 4.06 (m, 1H),
5.37 (d, J = 14.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 7.6 Hz,
1H), 7.28 (d, J = 8.4 Hz, 2H), 7.36 (dd, J = 7.6, 7.6 Hz, 1H), 7.43 (dd,
J = 8.0, 7.6 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 32.3, 36.0, 48.3, 51.3, 55.2, 114.1, 127.4, 128.1, 128.3, 128.6,
129.4, 129.5, 132.3, 135.4, 159.1, 164.0, 175.3; IR (ATR) ν 3080,
2951, 1723, 1619, 1510, 1471, 1244 cm−1; HRMS (ESI-TOF) [M +
2-[1-(4-Methoxybenzyl)-6-oxopiperidin-2-yl]acetic Acid (s3a).
Prepared according to general procedure B and isolated as white
powder (69% yield, two steps): mp 168−170 °C; Rf = 0.4 (CHCl3/
1
MeOH, 5/1); H NMR (400 MHz, CDCl3) δ 1.70−1.95 (m, 4H),
2.45−2.60 (m, 3H), 2.69 (dd, J = 16, 3.6 Hz, 1H), 3.78 (s, 3H), 3.86
(m, 1H), 3.94 (d, J = 14.8 Hz, 1H), 5.21 (d, J = 14.8 Hz, 1H), 6.83 (d,
J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 9.70 (br s, 1H); 13C NMR
(100 MHz, CDCl3) δ 16.5, 26.9, 31.2, 37.3, 47.5, 52.2, 55.2, 114.0,
128.8, 129.2, 158.9, 171.3, 174.0; IR (ATR) ν 2951, 1713, 1581, 1511,
1413, 1355, 1243, 1176, 1032, 909 cm−1; HRMS (ESI-TOF) [2M +
+
Na]+ calcd for C19H19NNaO4 m/z 348.1206, found m/z 348.1200.
+
Na]+ calcd for C30H38N2NaO8 m/z 577.2520, found m/z 577.2530.
2-(1-Benzyl-6-oxopiperidin-2-yl)acetic Acid (s3g). Prepared ac-
cording to general procedure B and isolated as white powder (37%
yield, two steps): mp 124−126 °C; Rf = 0.5 (n-hexane/EtOAc/
1
MeOH, 8/8/1); H NMR (400 MHz, CDCl3) δ 1.75−1.95 (m, 4H),
2.45−2.60 (m, 3H), 2.70 (dd, J = 16 Hz, 1H), 3.85 (m, 1H), 4.03 (d,
J = 15.2 Hz, 1H), 5.26 (d, J = 15.2 Hz, 1H), 7.22−7.33 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 16.5, 26.8, 31.1, 37.3, 48.1, 52.6, 127.4,
127.7, 128.6, 136.6, 171.5, 173.9; IR (ATR) ν 2946, 1719, 1590,
1485, 1452, 1413, 1254, 1188, 1072, 960 cm−1; HRMS (ESI-TOF)
2-[1-(4-Methoxybenzyl)-5,5-dimethyl-6-oxopiperidin-2-yl]acetic
Acid (s3b). Prepared according to general procedure B and isolated as
white powder (50% yield, two steps): mp 161−162 °C; Rf = 0.2
1
(EtOAc); H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 1.26 (s, 3H),
+
[M + Na]+ calcd for C14H17NNaO3 m/z 270.1101, found m/z
1.54−1.92 (m, 4H), 2.56 (dd, J = 15.6, 10.0 Hz, 1H), 2.71 (dd, J =
15.6, 3.2 Hz, 1H), 3.78 (s, 3H), 3.80 (m, 1H), 3.84 (d, J = 14.8 Hz, 1H),
5.21 (d, J = 14.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 23.6, 27.8, 27.9, 31.7, 37.4, 38.2,
47.6, 52.7, 55.2, 114.0, 129.0, 129.5, 158.9, 175.1, 176.8; IR (ATR)
ν 2924, 1723, 1579, 1511, 1172 cm−1; HRMS (ESI-TOF) [M + Na]+
calcd for C17H23NNaO4+ m/z 328.1519, found m/z 328.1527.
270.1094.
2-(1-Butyl-6-oxopiperidin-2-yl)acetic Acid (s3h). Prepared accord-
ing to general procedure B and isolated as white powder (32% yield,
1
two steps): mp 86−88 °C; Rf = 0.5 (CHCl3/MeOH, 5/1); H NMR
(400 MHz, CDCl3) δ 0.92 (t, J = 7.2 Hz, 3H), 1.24−1.39 (m, 2H),
1.47−1.63 (m, 2H), 1.74−1.88 (m, 4H), 2.35−2.60 (m, 3H),
J
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2.68−2.82 (m, 2H), 3.83−3.92 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 13.8, 16.6, 20.2, 26.9, 29.5, 31.3, 37.6, 45.6, 53.2, 170.7,
174.3; IR (ATR) ν 2956, 1721, 1589, 1487, 1415, 1353, 1297, 1249,
1193, 1087 cm−1; HRMS (ESI-TOF) [2M + Na]+ calcd for
2.66−2.77 (m, 2H), 2.95 (dd, J = 9.6, 6.0 Hz, 1H), 3.47 (dd, J = 10.4,
8.0 Hz, 1H), 3.80 (s, 3H), 4.38 (s, 2H), 6.86 (d, J = 8.4 Hz, 2H), 7.16
(d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 27.7, 37.2, 38.3,
46.0, 51.8, 55.3, 114.1, 128.1, 129.5, 159.1, 173.7, 175.4; IR (ATR)
ν 2923, 1719, 1684, 1637, 1513, 1420, 1246, 1175, 1032, 847 cm−1;
+
C22H38N2NaO6 m/z 449.2622, found m/z 449.2622.
+
HRMS (ESI-TOF) [M + Na]+ calcd for C14H17NNaO4 m/z
2-[2-(4-Methoxybenzyl)-3-oxoisoindolin-1-yl]acetic acid (s3i) was
prepared by a reported procedure.27
286.1050, found m/z 286.1056.
General Procedure C for Preparing Diazocarbonyl Compound 6.
2-[2-(4-Methoxybenzyl)-1-methyl-3-oxoisoindolin-1-yl]acetic
Acid (s3l). To a stirred solution of 2-(4-methoxybenzyl)isoindoline-
1,3-dione (2.4 g, 9 mmol) in THF (100 mL) was added MeLi
(10.8 mmol, 1.1 M solution in Et2O). After the mixture had been
stirred at −78 °C for 0.5 h, the reaction was quenched with saturated
aqueous NH4Cl, and the solvent was removed under reduced pressure.
The reaction mixture was extracted with CH2Cl2, washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. The
residue was used for the next reaction without further purification. To
a stirred suspension of NaH (900 mg, 22.5 mmol, 60% dispersion in
mineral oil) in THF was added triethylphosphonoacetate (3.6 mL,
18 mmol) at room temperature, and the mixture was stirred for
30 min. The residue was added to the reaction mixture, and the whole
was stirred at 130 °C for 5 h. NaOH (aqueous, 10%) was added, and
stirring was continued at 50 °C for 12 h. The reaction mixture was
acidified with 6 N aqueous HCl, extracted with CH2Cl2, washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
The crude residue was purified by flash chromatography on silica
gel to afford s3l as a colorless gum (383 mg, 13% yield, three steps):
Rf = 0.3 (EtOAc); 1H NMR (400 MHz, CDCl3) δ 1.37 (s, 3H), 2.82
(d, J = 14.8 Hz, 1H), 2.88 (d, J = 14.8 Hz, 1H), 3.75 (s, 3H), 4.44
(d, J = 15.6 Hz, 1H), 4.94 (d, J = 15.6 Hz, 1H), 6.78 (d, J = 8.8 Hz,
2H), 7.26 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.42 (dd,
J = 7.6, 7.6 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H), 7.75 (d, J =
7.6 Hz, 1H), 9.12 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 25.8,
42.2, 42.5, 55.2, 64.0, 113.8, 121.1, 123.8, 128.5, 129.2, 129.9, 130.7,
131.9, 148.9, 158.8, 168.8, 172.2; IR (ATR) ν 3368, 2932, 1726,
1647, 1613, 1513, 1246 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for
To a stirred solution of the carboxylic acid in CH2Cl2 was added
(COCl)2 (1.3 equiv) at 0 °C, and the mixture was stirred for 1 h at
room temperature. The reaction mixture was concentrated under
reduced pressure to give crude acid chloride. The residue was
dissolved in CH3CN, and TMSCHN2 (2.0 M solution in Et2O,
3 equiv) was added to the solution at 0 °C. After being stirred for 1 h,
the reaction mixture was concentrated under reduced pressure and
purified by flash chromatography on silica gel to afford
α-diazocarbonyl compound 6.
6-(3-Diazo-2-oxopropyl)-1-(4-methoxybenzyl)piperidin-2-one
(6a). Prepared according to general procedure C and isolated as yellow
powder (87% yield, two steps): mp 83−85 °C; Rf = 0.2 (n-hexane/
1
EtOAc/MeOH, 8/8/1); H NMR (400 MHz, CDCl3) δ 1.72−1.90
(m, 4H), 2.38−2.54 (m, 3H), 2.64 (dd, J = 15.2, 3.2 Hz, 1H), 3.79 (s,
3H), 3.92−3.98 (m, 1H), 4.00 (d, J = 14.8 Hz, 1H), 5.10 (d, J =
14.8 Hz, 1H), 5.19 (s, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.19 (d, J =
8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 17.1, 27.2, 31.7, 43.6,
47.5, 52.3, 55.2, 55.5, 113.9, 129.2, 129.5, 158.9, 170.0, 191.6; IR
(ATR) ν 2949, 2099, 1624, 1510, 1462, 1359, 1242, 1174, 1031, 969,
+
814 cm−1; HRMS (ESI-TOF) [2M + Na]+ calcd for C32H38N6NaO6
m/z 625.2745, found m/z 625.2748.
+
C19H20NO4 m/z 326.1385, found m/z 326.1391.
6-(3-Diazo-2-oxopropyl)-1-(4-methoxybenzyl)-3,3-dimethylpiper-
idin-2-one (6b). Prepared according to general procedure C and
isolated as a colorless oil (74% yield, two steps): Rf = 0.3 (n-hexane/
EtOAc, 1/1); 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 1.26
(s, 3H), 1.57−2.04 (m, 4H), 2.46−2.65 (m, 2H), 3.79 (s, 3H), 3.89
(d, J = 14.4 Hz, 1H), 3.90 (m, 1H), 5.11 (d, J = 14.4 Hz, 1H), 5.21 (s,
1H), 6.84 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 23.8, 27.9, 28.0, 32.0, 38.1, 43.7, 47.6, 52.8,
55.2, 55.5, 113.9, 129.0, 129.8, 158.8, 176.3, 191.7; IR (ATR) ν 3067,
2955, 2100, 1624, 1510, 1374, 1245 cm−1; HRMS (ESI-TOF)
2-[1-(4-Methoxybenzyl)-5-oxopyrrolidin-3-yl]acetic Acid (s3s). To
a solution of (E)-methyl 4-[(4-methoxybenzyl)amino]but-2-enoate28
(15 mmol) and triethyamine (5.0 mL, 36 mmol) in CH2Cl2 (75 mL)
was added methyl malonyl chloride (1.9 mL, 18 mmol) at 0 °C, and
the resulting mixture was stirred for 1 h at room temperature. The
reaction was quenched with saturated aqueous NaHCO3, and the
mixture was extracted with CH2Cl2, dried over Na2SO4, and
concentrated under reduced pressure to afford the crude residue.
To a stirred solution of NaH (60% in oil, 272 mg, 6.8 mmol) in
THF (30 mL) was added the crude residue at −78 °C, and the
reaction mixture was stirred for 1 h at room temperature. Aqueous
NaOH (2 M) was added, and stirring was continued for 1 h at room
temperature. The reaction was quenched with 1 N aqueous HCl, and
the mixture was extracted with AcOEt, washed with brine, dried over
Na2SO4, and concentrated under reduced pressure.
+
[M + Na]+ calcd for C18H23N3NaO3 m/z 352.1632, found m/z
352.1626.
cis-6-(3-Diazo-2-oxopropyl)-1-(4-methoxybenzyl)-4-methylpiper-
idin-2-one (6c). Prepared according to general procedure C and
isolated as a colorless oil (73% yield, two steps): Rf = 0.2 (n-hexane/
EtOAc, 1/1); 1H NMR (400 MHz, CDCl3) δ 0.98 (d, J = 4.8 Hz, 3H),
1.24 (m, 1H), 1.80−2.26 (m, 4H), 2.53−2.77 (m, 2H), 3.80 (s, 3H),
3.83 (m, 1H), 4.35 (d, J = 15.6 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H),
5.07 (s, 1H), 6.84 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 21.1, 26.5, 37.9, 41.1, 46.1, 46.6, 53.4,
55.2, 55.6, 114.0, 128.6, 129.6, 158.7, 171.3, 191.4; IR (ATR) ν 3087,
2953, 2104, 1630, 1512, 1368, 1245 cm−1; HRMS (ESI-TOF)
A solution of the crude residue in 1,4-dioxane (34 mL) was refluxed
for 15 h. After cooling to room temperature, the reaction mixture was
concentrated under reduced pressure, and the crude mixture was
purified by flash chromatography on silica gel (hexane/AcOEt/MeOH,
8/8/1 to 1/1/1) to afford s3s as white powder (38%, 1.5 g): mp 107−
1
108 °C; H NMR (400 MHz, CDCl3) δ 2.20 (dd, J = 15.6, 5.6 Hz,
1H), 2.43 (dd, J = 16.4, 7.6 Hz, 1H), 2.50 (dd, J = 16.8, 6.0 Hz, 1H),
K
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
+
[M + Na]+ calcd for C17H21N3NaO3 m/z 338.1475, found m/z
338.1467.
3-(3-Diazo-2-oxopropyl)-2-(4-methoxybenzyl)isoindolin-1-one
(6i). Prepared according to general procedure C and isolated as a pale
yellow oil (61% yield, two steps): Rf = 0.4 (n-hexane/EtOAc, 2/3); 1H
NMR (400 MHz, CDCl3) δ 2.54 (dd, J = 7.2, 16.0 Hz, 1H), 2.80 (dd,
J = 5.2, 16.0 Hz, 1H), 3.78 (s, 3H), 4.43 (d, J = 17.2 Hz, 1H), 4.97 (m,
1H), 5.00 (s, 1H), 5.02 (d, J = 17.2 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H),
7.22 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.48 (dd, J = 7.2, 7.2
Hz, 1H), 7.53 (dd, J = 7.2, 7.2 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 43.6, 44.0, 55.2, 55.7, 56.0, 114.0, 122.5,
123.8, 128.5, 129.2 (2C), 131.7 (2C), 145.1, 159.0, 168.3, 190.7; IR
(ATR) ν 3457, 2931, 2101, 1674, 1611, 1510, 1408, 1373, 1330,
1243 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for C19H18N3O3+ m/z
336.1343, found m/z 336.1347.
9-(3-Diazo-2-oxopropyl)-8-(4-methoxybenzyl)-8-azaspiro[4.5]-
decan-7-one (6d). Prepared according to general procedure C and
isolated as a colorless oil (73% yield, two steps): Rf = 0.3 (n-hexane/
1
EtOAc, 1/2); H NMR (400 MHz, CDCl3) δ 1.31−1.68 (m, 9H),
1.85 (m, 1H), 2.25−2.43 (m, 3H), 2.75 (m, 1H), 3.80 (s, 3H), 3.80
(m, 1H), 4.24 (d, J = 14.8 Hz, 1H), 5.02 (d, J = 14.8 Hz, 1H), 5.10 (s,
1H), 6.85 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 23.8, 24.4, 34.9, 40.1, 40.3, 40.5, 44.7, 45.6, 46.3,
51.5, 55.2, 55.5, 113.9, 129.0, 129.3, 158.7, 170.9, 191.4; IR (ATR)
ν 2950, 2102, 1624, 1511, 1355, 1243 cm−1; HRMS (ESI-TOF)
+
[M + Na]+ calcd for C20H25N3NaO3 m/z 378.1788, found m/z
378.1786.
3-(3-Diazo-2-oxopropyl)-2-(4-methoxybenzyl)-3,4-dihydroisoqui-
nolin-1-one (6e). Prepared according to general procedure C and
isolated as a pale yellow oil (79% yield, two steps): Rf = 0.3 (n-hexane/
rac-(S)-3-[(R)-4-Diazo-3-oxobutan-2-yl]-2-(4-methoxybenzyl)-
isoindolin-1-one (6j). Prepared according to general procedure C
using 2-[2-(4-methoxybenzyl)-3-oxoisoindolin-1-yl]propanoic acid
prepared according to general procedure B using triethyl 2-
phosphonopropionate, instead of triethylphosphonoacetate, and
isolated as a colorless oil (75% yield, 2:1 dr, two steps): Rf = 0.4
1
EtOAc, 1/1); H NMR (400 MHz, CDCl3) δ 2.36−2.42 (m, 2H),
2.75 (m, 1H), 3.18 (dd, J = 16.0, 5.6 Hz, 1H), 3.79 (s, 3H), 4.07
(d, J = 14.4 Hz, 1H), 4.17 (m, 1H), 5.09 (s, 1H), 5.18 (d, J =
14.4 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.28
(d, J = 8.0 Hz, 2H), 7.37 (dd, J = 7.6, 7.2 Hz, 1H), 7.43 (dd, J = 7.6,
7.2 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 32.5, 42.2, 48.2, 51.4, 55.2, 55.5, 114.0, 127.2, 127.9, 128.2, 129.0,
129.5, 129.7, 132.0, 135.7, 159.0, 163.5, 191.6; IR (ATR) ν 3067,
2952, 2101, 1635, 1510, 1371, 1243 cm−1; HRMS (ESI-TOF) [M +
1
(n-hexane/EtOAc, 1/1); H NMR (400 MHz, CDCl3) δ 0.61 (d, J =
7.2 Hz, 3H), 3.09 (m, 1H), 3.79 (s, 3H), 4.16 (d, J = 17.2 Hz, 1H),
4.92 (m, 1H), 5.23 (d, J = 17.2 Hz, 1H), 5.27 (s, 1H), 6.86 (d, J = 8.8
Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.46−7.50
(m, 2H), 7.88 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
8.7, 43.5, 43.9, 55.0, 55.2, 60.0, 114.2, 123.7 (2C), 128.4, 128.6, 129.4,
131.5, 132.6, 142.1, 159.1, 168.6, 194.7; IR (ATR) ν 3080, 2934, 2104,
1681, 1612, 1512, 1361, 1245 cm−1; HRMS (ESI-TOF) [M + H]+
+
Na]+ calcd for C20H19N3NaO3 m/z 372.1319, found m/z 372.1322.
+
calcd for C20H20N3O3 m/z 350.1499, found m/z 350.1492.
6-(3-Diazo-2-oxopropyl)-1-benzylpiperidin-2-one (6g). Prepared
according to general procedure C and isolated as yellow powder (85%
yield, two steps): mp 87−89 °C; Rf = 0.2 (n-hexane/EtOAc/MeOH,
1
rac-(S)-3-[(S)-4-Diazo-3-oxobutan-2-yl]-2-(4-methoxybenzyl)-
isoindolin-1-one (6k). Prepared according to general procedure C
using 2-[2-(4-methoxybenzyl)-3-oxoisoindolin-1-yl]propanoic acid
prepared according to general procedure B using triethyl 2-phos-
phonopropionate, instead of triethylphosphonoacetate, and isolated as
white powder (75% yield, 2:1 dr, two steps): mp 150−151 °C dec;
Rf = 0.4 (n-hexane/EtOAc, 1/1); 1H NMR (400 MHz, CDCl3) δ 0.83 (d,
J = 7.6 Hz, 3H), 3.00 (m, 1H), 3.76 (s, 3H), 4.17 (d, J = 17.2 Hz, 1H),
4.94 (m, 1H), 5.21 (d, J = 17.2 Hz, 1H), 5.22 (s, 1H), 6.82 (d, J =
8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.46 (dd,
J = 7.2, 7.2 Hz, 1H), 7.52 (dd, J = 7.2, 7.2 Hz, 1H), 7.88 (d, J = 7.2 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 9.3, 44.1, 47.0, 54.7, 55.2, 60.2,
113.8, 121.9, 123.8, 128.5, 129.1, 129.5, 131.8, 132.4, 144.1, 158.9,
169.2, 194.4; IR (ATR) ν 3076, 2933, 2108, 1678, 1623, 1512, 1375,
1245 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for C20H20N3O3+ m/z
350.1499, found m/z 350.1500.
8/8/1); H NMR (400 MHz, CDCl3) δ 1.72−1.93 (m, 4H), 2.40−
2.55 (m, 3H), 2.63 (dd, J = 15.2, 3.2 Hz, 1H), 3.95 (m, 1H), 4.10 (d,
J = 15.2 Hz, 1H), 5.13 (d, J = 15.2 Hz, 1H), 5.19 (s, 1H), 7.22−7.34
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 17.1, 27.3, 31.7, 43.6, 48.2,
52.6, 55.5, 127.3, 127.7, 128.5, 137.3, 170.1, 191.5; IR (ATR) ν 2948,
2097, 1622, 1495, 1450, 1414, 1328, 1136, 1071, 967 cm−1; HRMS
+
(ESI-TOF) [2M + Na]+ calcd for C30H34N6NaO4 m/z 565.2534,
found m/z 565.2543.
1-Butyl-6-(3-diazo-2-oxopropyl)piperidin-2-one (6h). Prepared
according to general procedure C and isolated as a yellow oil (74%
yield, two steps): Rf = 0.2 (n-hexane/EtOAc/MeOH, 8/8/1); 1H
NMR (400 MHz, CDCl3) δ 0.92 (t, J = 7.2 Hz, 3H), 1.25−1.37 (m,
2H), 1.47−1.60 (m, 2H), 1.72−1.90 (m, 4H), 2.30−2.53 (m, 3H),
2.62−2.73 (m, 2H), 3.84−3.91 (m, 1H), 3.97−4.01 (m, 1H), 5.30 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 13.9, 17.0, 20.2, 27.1, 29.6, 31.7,
43.7, 45.3, 52.9, 55.7, 169.6, 191.7; IR (ATR) ν 3486, 2954, 2099,
1618, 1474, 1415, 1362, 1296, 1136, 1083 cm−1; HRMS (ESI-TOF)
3-(3-Diazo-2-oxopropyl)-2-(4-methoxybenzyl)-3-methylisoindo-
lin-1-one (6l). Prepared according to general procedure C and isolated as
a colorless oil (30% yield, two steps): Rf = 0.3 (n-hexane/EtOAc,
+
[2M + Na]+ calcd for C24H38N6NaO4 m/z 497.2847, found m/z
497.2855.
L
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1/1); 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 3H), 2.71 (d, J = 14.8 Hz,
1H), 2.83 (d, J = 14.8 Hz, 1H), 3.77 (s, 3H), 4.55 (s, 1H), 4.63 (d, J =
16.0 Hz, 1H), 4.84 (d, J = 16.0 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 7.32
(d, J = 8.8 Hz, 2H), 7.42 (d, J = 7.2 Hz, 1H), 7.48 (dd, J = 7.2, 7.2 Hz,
1H), 7.55 (dd, J = 7.2, 7.2 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 26.0, 42.5, 48.3, 55.2, 55.8, 64.4, 113.8,
121.2, 123.9, 128.5, 129.4, 130.3, 131.0, 131.8, 149.0, 158.8, 168.0,
189.6; IR (ATR) ν 3074, 2972, 2932, 2100, 1676, 1633, 1511, 1365,
1244 cm−1; HRMS (ESI-TOF) [M + H]+ calcd for C20H20N3O3+ m/z
350.1499, found m/z 350.1501.
3-(4-Diazo-3-oxobutyl)-2-(4-methoxybenzyl)isoindolin-1-one
(6o). Prepared according to general procedure D and isolated as a pale
yellow oil (74% yield, three steps): Rf = 0.4 (n-hexane/EtOAc, 1/1);
1H NMR (400 MHz, CDCl3) δ 1.68−1.84 (m, 2H), 2.29−2.45 (m,
2H), 3.78 (s, 3H), 4.13 (d, J = 17.2 Hz, 1H), 4.52 (m, 1H), 4.87 (s,
1H), 5.20 (d, J = 17.2 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 7.25 (d, J =
8.4 Hz, 2H), 7.34 (d, J = 7.2 Hz, 1H), 7.48 (dd, J = 7.2, 7.2 Hz, 1H),
7.54 (dd, J = 7.2, 7.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 24.5, 32.7, 43.2, 54.4, 55.2, 57.7, 114.0, 122.2,
123.7, 128.3, 129.0, 129.5, 131.7, 132.4, 144.0, 159.0, 168.4, 193.2; IR
(ATR) ν 2925, 2104, 1684, 1649, 1512, 1246 cm−1; HRMS (ESI-
TOF) [M + Na]+ calcd for C20H19N3NaO3+ m/z 372.1319, found m/z
372.1317.
General Procedure D. To a stirred solution of 6 in dioxane and
H2O (9/1) was added CF3COOAg (20 mol %), and the whole was
stirred at room temperature for 12 h. EtOAc, toluene, and H2O were
successively added to the reaction mixture, and the aqueous layer was
extracted with a 10% NaOH solution. The combined aqueous layer
was acidified with a 10% HCl solution; the organic layer was extracted
with EtOAc, and the combined organic layer was dried over Na2SO4
and concentrated. The residue was used for the next reaction without
further purification. To a stirred solution of the carboxylic acid in
CH2Cl2 was added (COCl)2 (1.3 equiv) at 0 °C, and the mixture was
stirred at room temperature for 1 h. The reaction mixture was
concentrated under reduced pressure to give crude acid chloride. The
residue was dissolved in CH3CN, and TMSCHN2 (2.0 M solution in
Et2O, 3 equiv) was added to the solution at 0 °C. After being stirred
for 1 h, the reaction mixture was concentrated under reduced pres-
sure and purified by flash chromatography on silica gel to afford
α-diazocarbonyl compounds 6m, 6n, and 6o.
N-(4-Methoxybenzyl)-5-oxohexanamide (s4). To a stirred sol-
ution of 1-(4-methoxybenzyl)-piperidine-2,6-dione (933 mg, 4 mmol)
in THF (200 mL) was added MeLi (8.8 mmol, 1.1 M solution in
Et2O). After being stirred at −78 °C for 1 h, the reaction mixture was
quenched with saturated aqueous NaHCO3, and the solvent was
removed under reduced pressure. The reaction mixture was extracted
with CH2Cl2, washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The crude residue was purified by flash
chromatography on silica gel (n-hexane/EtOAc/MeOH, 12/8/1) to
afford s4 (837 mg, 84%) as white powder: mp 107−109 °C; Rf =
1
0.3 (n-hexane/EtOAc/MeOH, 8/8/1); H NMR (400 MHz, CDCl3)
δ 1.89 (tt, J = 6.8 Hz, 2H), 2.11 (s, 3H), 2.21 (t, J = 6.8 Hz, 2H),
2.50 (t, J = 6.8 Hz, 2H), 3.79 (s, 3H), 4.34 (d, J = 5.6 Hz, 2H), 6.01
(br s, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 19.5, 29.8, 35.1, 42.3, 42.8, 55.1,
113.9, 129.0, 130.3, 158.8, 172.1, 208.5; IR (ATR) ν 3299, 1701, 1637,
1545, 1511, 1303, 1246, 1160, 1027, 819 cm−1; HRMS (ESI-TOF)
+
[2M + Na]+ calcd for C28H38N2NaO6 m/z 521.2622, found m/z
521.2621.
6-(4-Diazo-3-oxobutyl)-1-(4-methoxybenzyl)piperidin-2-one
(6m). Prepared according to general procedure D and isolated as a
1
pale yellow oil (72% yield, three steps): Rf = 0.3 (EtOAc); H NMR
(400 MHz, CDCl3) δ 1.66−2.44 (m, 10H), 3.30 (m, 1H), 3.78 (s,
3H), 3.91 (d, J = 14.4 Hz, 1H), 5.27 (s, 1H), 5.30 (d, J = 14.4 Hz, 1H),
6.84 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 16.9, 25.8, 26.5, 31.7, 36.3, 46.4, 54.0, 54.4, 55.0,
113.6, 129.0, 129.5, 158.5, 169.9, 193.2; IR (ATR) ν 2952, 2100, 1617,
1510, 1352, 1242 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for
6-(3-Diazo-2-oxopropyl)-1-(4-methoxybenzyl)-6-methylpiperi-
din-2-one (6f). To a stirred suspension of NaH (2 equiv, 60%
dispersion in mineral oil) in THF was added triethylphosphonoacetate
(1.8 equiv) at 0 °C, and the mixture was stirred at 0 °C for 30 min. s4
(499 mg, 2 mmol) was added and the mixture stirred in refluxing THF
for 35.5 h. After the mixture had cooled to room temperature, NaOH
(aqueous, 10%) was added, and stirring was continued at room
temperature for 2 h. The reaction mixture was acidified with 6 N
aqueous HCl, extracted with EtOAc, washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was
used for the next reaction without further purification. To a stirred
solution of the crude carboxylic acid in CH2Cl2 was added (COCl)2
(1.3 equiv) at 0 °C, and the mixture was stirred at room temperature
for 1 h. The reaction mixture was concentrated under reduced pressure
to give crude acid chloride. The residue was dissolved in CH3CN, and
TMSCHN2 (2.0 M solution in Et2O, 3 equiv) was added to the
solution at 0 °C. After being stirred for 1 h, the reaction mixture was
concentrated under reduced pressure and purified by flash
chromatography on silica gel (n-hexane/EtOAc/MeOH, 16/8/1) to
afford 6f as a yellow oil (13% yield, three steps): Rf = 0.3 (n-hexane/
EtOAc/MeOH, 8/8/1); 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 3H),
1.72−1.90 (m, 3H), 2.18 (m, 1H), 2.48−2.56 (m, 4H), 3.77 (s, 3H),
4.50 (d, J = 15.6 Hz, 1H), 4.67 (d, J = 15.6 Hz, 1H), 5.20 (s, 1H),
6.81 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 16.9, 27.0, 32.2, 35.0, 44.7, 49.1, 55.2, 56.6,
59.6, 113.7, 128.1, 131.2, 158.3, 171.1, 191.2; IR (ATR) ν 2948, 2098,
1616, 1510, 1441, 1352, 1242, 1174, 1031 cm−1; HRMS (ESI-TOF)
+
C17H21N3NaO3 m/z 338.1475, found m/z 338.1473.
9-(4-Diazo-3-oxobutyl)-8-(4-methoxybenzyl)-8-azaspiro[4.5]-
decan-7-one (6n). Prepared according to general procedure D and
isolated as a colorless oil (68% yield, three steps): Rf = 0.3 (n-hexane/
1
EtOAc, 1/2); H NMR (400 MHz, CDCl3) δ 1.24−1.68 (m, 10H),
1.92−1.97 (m, 2H), 2.24−2.49 (m, 4H), 3.35 (m, 1H), 3.79 (s, 3H),
3.96 (d, J = 14.4 Hz, 1H), 5.18 (s, 1H), 5.37 (d, J = 14.4 Hz, 1H), 6.84
(d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 23.7, 24.6, 27.6, 34.4, 34.6, 39.4, 40.1, 40.2, 44.7, 45.0, 52.0,
54.5, 55.1, 113.8, 129.1, 129.4, 158.7, 171.1, 193.6; IR (ATR) ν 2945,
2861, 2100, 1624, 1510, 1344, 1242 cm−1; HRMS (ESI-TOF) [M +
+
Na]+ calcd for C21H27N3NaO3 m/z 392.1945, found m/z 392.1953.
M
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
+
[M + Na]+ calcd for C17H21N3NaO3 m/z 338.1475, found m/z
338.1470.
to the stirred solution was added (COCl)2 (0.11 mL, 1.3 mmol) at
0 °C. The whole was stirred at room temperature for 10 min and
concentrated. The residue was dissolved in MeCN (4.5 mL), and to
the stirred solution was added TMSCHN2 (342 mg, 3 mmol) in Et2O
(1.5 mL) at 0 °C. The whole was stirred for 1 h and concentrated. The
residue was purified by column chromatography (n-hexane/EtOAc/
MeOH, 3/7/0 to 0/9/1) to give 6p (69% yield, 242 mg, three steps)
as a colorless oil: Rf = 0.3 (n-hexane/EtOAc, 2/3); 1H NMR
(400 MHz, CDCl3) δ 1.38−1.80 (m, 6H), 2.44−2.78 (m, 4H), 3.78 (s,
3H), 3.87 (m, 1H), 4.17 (d, J = 14.8 Hz, 1H), 4.92 (d, J = 14.8 Hz,
1H), 5.21 (s, 1H), 6.84 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 23.0, 24.2, 32.0, 37.8, 42.6, 50.5, 53.6,
55.0, 55.3, 113.7, 129.5, 130.0, 158.7, 174.9, 191.3; IR (ATR) ν 2932,
2099, 1611, 1510, 1367, 1244 cm−1; HRMS (ESI-TOF) [M + Na]+
7-[2-(tert-Butyldimethylsilyloxy)ethyl]azepan-2-one (s6). To a
stirred solution of s529 (600 mg, 3.3 mmol) in THF (30 mL) was
added LiBH4 (215 mg, 9.8 mmol) at 0 °C, and the whole was allowed
to warm to room temperature. After 13 h, MeOH, H2O, and saturated
aqueous NH4Cl were successively added to the mixture; the organic
layer was extracted with EtOAc, and the combined organic layer was
dried over Na2SO4 and concentrated. The residue was dissolved in
DMF (5 mL), and to the stirred solution were added imidazole
(449 mg, 6.6 mmol) and TBSCl (648 mg, 4.3 mmol) at 0 °C. The
whole was stirred at room temperature for 1 h, and saturated aqueous
NH4Cl was added to the mixture. The organic layer was extracted with
EtOAc, and the combined organic layers were dried over Na2SO4.
Concentration and column chromatography (n-hexane/EtOAc, 6/5 to
3/7) gave s6 (433 mg, 49%, two steps) as a colorless oil: Rf = 0.6
+
calcd for C17H21N3NaO3 m/z 338.1475, found m/z 338.1477.
7-(4-Diazo-3-oxobutyl)-1-(4-methoxybenzyl)azepan-2-one (6q).
1
Prepared according to general procedure D and isolated as a colorless
(EtOAc); H NMR (400 MHz, CDCl3) δ 0.07 (s, 6H), 0.91 (s, 9H),
1
oil (76% yield, three steps): Rf = 0.5 (EtOAc); H NMR (400 MHz,
1.36−2.04 (m, 8H), 2.45 (m, 2H), 3.53 (m, 1H), 3.68−3.79 (m, 2H),
6.14 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ −5.6, −5.5, 18.1,
23.2, 25.8, 29.7, 35.6, 36.8, 38.4, 51.8, 60.0, 177.6; IR (ATR) ν 3221,
2927, 2855, 1660, 1441, 1100, 831 cm−1; HRMS (ESI-TOF) [2M +
CDCl3) δ 1.38−2.31 (m, 10H), 2.55 (ddd, J = 14.4, 12.4, 2.4 Hz, 1H),
2.69 (ddd, J = 14.4, 6.8, 2.0 Hz, 1H), 3.43 (m, 1H), 3.79 (s, 3H), 4.09
(d, J = 14.4 Hz, 1H), 4.96 (d, J = 14.4 Hz, 1H), 5.14 (s, 1H), 6.84 (d,
J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 23.2, 23.7, 26.5, 31.6, 37.4, 37.7, 51.1, 54.4, 55.2, 56.8 113.7,
129.8, 130.3, 158.8, 175.2, 193.5; IR (ATR) ν 2931, 2098, 1610, 1510,
1356, 1243, 1173, 1031 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for
+
H]+ calcd for C28H59N2O4Si2 m/z 543.4008, found m/z 543.4017.
+
C18H23N3NaO3 m/z 352.1632, found m/z 352.1639.
7-(2-Hydroxyethyl)-1-(4-methoxybenzyl)azepan-2-one (s7). To a
stirred solution of s6 (409 mg, 1.5 mmol) and tetrabutylammonium
iodide (111 mg, 0.30 mmol) in THF (15 mL) was added NaH
(79 mg, 2.0 mmol, 60% dispersion in mineral oil) at 0 °C. After 0.5 h,
PMBCl (0.25 mL, 1.8 mmol) was added to the mixture, and the whole
was stirred at 50 °C for 3 h. Tetrabutylammonium fluoride (1.6 g,
6.0 mmol) in THF (6 mL) was added to the reaction mixture, and the
whole was stirred at 35 °C for 4 h. Saturated aqueous NH4Cl was
added to the mixture; the organic layer was extracted with EtOAc, and
the combined organic layers were dried over Na2SO4. Concentration
and column chromatography (EtOAc) gave s7 (310 mg, 74%) as a
colorless oil: Rf = 0.3 (EtOAc); 1H NMR (400 MHz, CDCl3) δ 1.29−
2.05 (m, 9H), 2.53 (ddd, J = 14.4, 12.8, 1.6 Hz, 1H), 2.68 (ddd, J =
12.8, 6.8, 1.6 Hz, 1H), 3.59 (t, J = 6.0 Hz, 2H), 3.69 (m, 1H), 3.79 (s,
3H), 4.10 (d, J = 14.4 Hz, 1H), 5.02 (d, J = 14.4 Hz, 1H), 6.83 (d, J =
8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
23.4, 24.0, 31.9, 34.3, 37.8, 51.1, 53.8, 55.2, 59.4, 113.7, 129.7, 130.4,
158.8, 175.5; IR (ATR) ν 3386, 2928, 1606, 1511, 1245, 1034 cm−1;
General Procedure E. To a solution of (E)-methyl 4-[(4-
methoxybenzyl)amino]but-2-enoate and carboxylic acid (1.1 equiv)
in DMF (0.5 M) were added EDC·HCl (1.2 equiv) and HOBt
(0.3 equiv), and the reaction mixture was stirred for 2 h at room
temperature. The reaction was quenched with H2O, and the mixture
was extracted with EtOAc, washed with H2O and brine, dried over
Na2SO4, and concentrated under reduced pressure to afford the crude
residue that could be utilized in the next step without further
purification.
To a solution of the crude residue in DMF (0.5 M) was added
K2CO3 (10 mol %), and the mixture was stirred for 30 min at room
temperature. Then H2O was added, and the reaction mixture was
extracted with EtOAc, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography on silica gel to afford cyclized ester.
+
HRMS (ESI-TOF) [2M + Na]+ calcd for C32H46N2NaO6 m/z
577.3248, found m/z 577.3242.
Methyl 2-[2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo-
[1,2-a]pyrazin-4-yl]acetate (s8a). Prepared according to general
procedure E and isolated as a white solid (77% yield, 82.9 mg, two
1
steps): mp 101−102 °C; Rf = 0.2 (n-hexane/EtOAc, 1/1); H NMR
7-(3-Diazo-2-oxopropyl)-1-(4-methoxybenzyl)azepan-2-one (6p).
To a stirred solution of s7 (277 mg, 1.0 mmol) in acetone (10 mL)
was added Jones reagent (2.0 mL, 2.5 M) at 0 °C, and the whole was
(400 MHz, CDCl3) δ 2.52 (dd, J = 16.8, 7.6 Hz, 1H), 2.60 (dd, J =
16.8, 6.0 Hz, 1H), 3.35 (dd, J = 13.2, 2.8 Hz, 1H), 3.58 (s, 3H), 3.79
(s, 3H), 3.80 (dd, J = 13.2, 4.0 Hz, 1H), 4.27 (d, J = 14.0 Hz, 1H), 4.58
(dddd, J = 7.6, 6.0, 4.0, 2.8 Hz, 1H), 5.00 (d, J = 14.0 Hz, 1H), 6.21
(dd, J = 4.0, 2.4 Hz, 1H), 6.73 (dd, J = 2.4, 1.6 Hz, 1H), 6.86 (d, J =
8.4 Hz, 2H), 6.96 (dd, J = 4.0, 1.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 37.5, 48.2, 48.3, 50.2, 51.9, 55.2,
110.3, 114.0, 122.0, 123.7, 128.9, 129.9, 130.0, 159.0, 159.1, 170.6; IR
i
stirred for 0.5 h. PrOH, EtOAc, toluene, and H2O were successively
added to the reaction mixture, and the aqueous layer was extracted
with a 10% NaOH solution. The combined aqueous layer was acidified
with a 10% HCl solution; the organic layer was extracted with EtOAc,
and the combined organic layer was dried over Na2SO4 and
concentrated. The residue was dissolved in CH2Cl2 (1.0 mL), and
N
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(ATR) ν 2952, 1732, 1634, 1544, 1510, 1433, 1328, 1302, 1242,
residue was purified by flash chromatography on silica gel to afford the
α-diazocarbonyl compound.
+
1173 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for C18H20N2NaO4
m/z 351.1315, found m/z 351.1323.
4-(3-Diazo-2-oxopropyl)-2-(4-methoxybenzyl)-3,4-
dihydropyrazino[1,2-a]indol-1(2H)-one (6r). Prepared according to
general procedure F and isolated as brown blocks (14% yield, 180.9
mg, three steps): mp 104−106 °C; Rf = 0.2 (n-hexane/EtOAc/MeOH,
M e t h y l 2 - [ 2 - ( 4 - M e t h o x y b e n z y l ) - 1 - o x o - 1 , 2 , 3 , 4 -
tetrahydropyrazino[1,2-a]indol-4-yl]acetate (s8b). Prepared accord-
ing to general procedure E and isolated as a colorless oil (59% yield,
1
200.8 mg, two steps): Rf = 0.4 (n-hexane/EtOAc, 1/1); H NMR
1
8/8/1); H NMR (400 MHz, CDCl3) δ 2.40 (m, 2H), 3.51 (d, J =
(400 MHz, CDCl3) δ 2.48 (dd, J = 16.8, 5.2 Hz, 1H), 2.53 (dd, J =
16.8, 8.4 Hz, 1H), 3.50 (s, 3H), 3.56 (d, J = 13.2 Hz, 1H), 3.79 (s,
3H), 3.94 (dd, J = 13.2, 4.0 Hz, 1H), 4.25 (d, J = 14.4 Hz, 1H), 4.88
(m, 1H), 5.16 (d, J = 14.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 2H), 7.16 (m,
1H), 7.27−7.34 (m, 5H), 7.71 (dd, J = 7.6, 0.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 35.3, 47.1, 47.8, 48.5, 51.8, 55.2, 107.0, 109.4,
114.1, 120.9, 122.8, 124.7, 127.6, 128.1, 128.5, 130.1, 135.1, 159.2,
159.5, 170.7; IR (ATR) ν 2951, 1731, 1645, 1610, 1547, 1510, 1433,
1328, 1302, 1242, 1173 cm−1; HRMS (ESI-TOF) [M + Na]+ calcd for
13.2 Hz, 1H), 3.78 (s, 3H), 3.92 (dd, J = 13.2, 3.6 Hz, 1H), 4.08 (d, J =
14.4 Hz, 1H), 4.58 (s, 1H), 5.00 (m, 1H), 5.27 (d, J = 14.4 Hz, 1H),
6.88 (d, J = 8.4 Hz, 2H), 7.14 (m, 1H), 7.26−7.29 (m, 5H), 7.69 (d,
J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 41.3, 47.1, 47.9, 48.4,
55.2, 55.4, 106.9, 109.6, 114.0, 120.9, 122.7, 124.7, 127.5, 128.1, 128.9,
130.4, 135.1, 159.3, 159.4, 190.8; IR (ATR) ν 2933, 2101, 1633, 1546,
1509, 1430, 1350, 1316, 1239, 1173 cm−1; HRMS (ESI-TOF) [M +
+
Na]+ calcd for C22H20N4NaO3 m/z 411.1428, found m/z 411.1433.
+
C22H22N2NaO4 m/z 401.1472, found m/z 401.1477.
6,7-Dibromo-4-(3-diazo-2-oxopropyl)-2-(4-methoxybenzyl)-3,4-
dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (3). Prepared according to
general procedure F and isolated as a pale yellow oil (67% yield,
63 mg, three steps): Rf = 0.4 (n-hexane/EtOAc, 3/2); 1H NMR
(400 MHz, CDCl3) δ 2.40 (m, 2H), 3.51 (dd, J = 13.2, 0.8 Hz, 1H),
3.79 (s, 3H), 3.83 (dd, J = 13.2, 3.6 Hz, 1H), 3.99 (d, J = 14.0 Hz, 1H),
4.69 (s, 1H), 4.74 (m, 1H), 5.15 (d, J = 14.0 Hz, 1H), 6.87 (d, J =
8.8 Hz, 2H), 7.00 (s, 1H), 7.25 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 41.0, 46.9, 48.3, 50.0, 55.25, 55.31, 101.0, 105.3,
114.1, 116.0, 125.3, 128.7, 130.4, 157.0, 159.4, 190.0; IR (ATR)
ν 2933, 2105, 1639, 1512, 1377, 1327, 1245 cm−1; HRMS (ESI-TOF)
Methyl 2-[6,7-Dibromo-2-(4-methoxybenzyl)-1-oxo-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazin-4-yl]acetate (s8c). To a stirred
solution of s8a (781.7 mg, 2.38 mmol) in MeOH (4.3 mL) and
THF (4.3 mL) was added 1.3-dibromo-5,5-dimethylhydrantoine
(408.9 mg, 1.43 mmol) at −40 °C, and the mixture was stirred for
1 h. The reaction was quenched with saturated aqueous NaSO3,
extracted with EtOAc, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography using silica gel to afford s8c as a white solid
(14% yield, 162.7 mg): mp 106−107 °C; Rf = 0.5 (n-hexane/EtOAc,
1
1/1); H NMR (400 MHz, CDCl3) δ 2.38−2.56 (m, 2H), 3.52 (m,
+
[M + Na]+ calcd for C18H16Br2N4NaO3 m/z 516.9481, found m/z
1H), 3.53 (s, 3H), 3.80 (s, 3H), 3.82 (m, 1H), 4.12 (d, J = 14.0 Hz,
1H), 4.59 (m, 1H), 5.07 (d, J = 14.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H),
7.01 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
35.2, 46.9, 48.2, 48.8, 51.8, 55.2, 103.7, 112.8, 114.1, 114.7, 124.9,
128.6, 130.1, 158.1, 159.1, 170.1; IR (ATR) ν 2952, 1731, 1644, 1543,
1511, 1468, 1428, 1370, 1324, 1241 cm−1; HRMS (ESI-TOF) [M +
516.9486.
4-(3-Diazo-2-oxopropyl)-1-(4-methoxybenzyl)pyrrolidin-2-one
(6s). Prepared according to general procedure C and isolated as a
brown oil (65%, two steps): 1H NMR (400 MHz, CDCl3) δ 2.12 (dd,
J = 16.8, 7.2 Hz, 1H), 2.30−2.50 (m, 2H), 2.64 (dd, J = 16.8, 8.8 Hz,
1H), 2.78 (m, 1H), 2.91 (dd, J = 9.6, 6.0 Hz, 1H), 3.46 (dd, J = 10.0,
8.8 Hz, 1H), 3.79 (s, 3H), 4.34 (d, J = 14.8 Hz, 1H), 4.38 (d, J = 14.8,
1H), 5.24 (s, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 27.9, 37.3, 44.9, 45.9, 51.8, 55.0, 55.3,
+
Na]+ calcd for C18H18Br2N2NaO4 m/z 506.9526, found m/z
506.9515.
114.0, 128.4, 129.5, 159.1, 173.3, 192.3; IR (ATR) ν 2015, 1682, 1637,
General Procedure F. A solution of ester s8 in a 1/1 MeOH/1 N
aqueous NaOH mixture (0.1 M) was stirred for 21 h at room
temperature, and the reaction mixture was acidified with 1 N aqueous
HCl, extracted with EtOAc, washed with brine, dried over Na2SO4,
and concentrated under reduced pressure to afford crude carboxylic
acid.
1513, 1442, 1355, 1246, 1176, 1032 cm−1; HRMS (ESI-TOF) [M +
+
Na]+ calcd for C15H17N3NaO3 m/z 310.1162, found m/z 310.1165.
Preparation of (−)-6a.
To a stirred solution of the crude carboxylic acid in CH2Cl2 was
added (COCl)2 (1.3 equiv) at room temperature, and the mixture was
stirred for 10 min. The reaction mixture was concentrated under
reduced pressure to give crude acid chloride. The residue was
dissolved in CH3CN (0.2 M), and TMSCHN2 (2.0 M solution in
Et2O, 3 equiv) was added to the solution at 0 °C. After the mixture
had been stirred for 1 h, saturated aqueous NaHCO3 was added and
the reaction mixture was extracted with Et2O, washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The crude
(R)-3-{2-[(R)-1-(4-Methoxybenzyl)-6-oxopiperidin-2-yl]acetyl}-4-
phenyloxazolidin-2-one [(−)-s9]. A solution of s3a (554.6 mg,
2 mmol), (R)-4-phenyl-2-oxazolidinone (326 mg, 2 mmol), DMAP
(122 mg, 1 mmol), and N-ethyl-N′-[3-(dimethylamino)propyl]-
carbodiimide (EDC) HCl salt (460 mg, 2.4 mmol) in CH2Cl2
(10 mL) was stirred at room temperature for 36 h. The reaction
O
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mixture was concentrated under reduced pressure and purified by flash
chromatography on silica gel (n-hexane/EtOAc/MeOH, 16/8/1) to
afford s9 as a colorless gum (39% yield, 330.9 mg). The absolute
configuration of the piperidinone ring was determined by converting it
to s10: Rf = 0.3 (n-hexane/EtOAc/MeOH, 8/8/1); 1H NMR
(400 MHz, CDCl3) δ 1.59 (m, 1H), 1.64−1.80 (m, 2H), 1.92 (m,
1H), 2.42 (m, 1H), 2.53 (m, 1H), 3.08 (dd, J = 16.4, 8.4 Hz, 1H), 3.37
(dd, J = 16.4, 4.4 Hz, 1H), 3.79 (s, 3H), 3.98 (m, 1H), 4.18 (d, J =
14.8 Hz, 1H), 4.26 (dd, J = 9.2, 3.6 Hz, 1H), 4.63 (dd, J = 9.2, 8.4 Hz,
1H), 4.94 (d, J = 14.8 Hz, 1H), 5.28 (dd, J = 8.4, 3.6 Hz, 1H), 6.83 (d,
J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.25 (dd, J = 7.6, 0.8 Hz,
2H), 7.31−7.41 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 17.1, 27.6,
31.6, 38.9, 47.8, 52.0, 55.2, 57.6, 69.9, 113.8, 125.8, 128.9, 129.2 (2C),
129.7, 138.7, 153.4, 158.7, 169.9, 170.0; IR (ATR) ν 2946, 1775, 1700,
1631, 1511, 1458, 1382, 1324, 1243, 1199, 1039 cm−1; HRMS
X-ray crystallographic data (CIF)
X-ray crystallographic data (CIF)
X-ray crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: tnemoto@faculty.chiba-u.jp.
*E-mail: yk4710h@yahoo.co.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant Number
26860008.
■
+
(ESI-TOF) [M + H]+ calcd for C24H27N2O5 m/z 423.1914, found
m/z 423.1915; [α]20 − 79.0° (c 1.0, CHCl3)
D
REFERENCES
■
(1) (a) Cordell, G. A.; Quinn-Beattie, M. L.; Farnsworth, N. R.
Phytother. Res. 2001, 15, 183. (b) Wonnacott, S.; Gallagher, T. Mar.
Drugs 2006, 4, 228. (c) Edwankar, C. R.; Edwankar, R. V.; Deschamps,
J. R.; Cook, J. M. Angew. Chem., Int. Ed. 2012, 51, 11762. (d) Zaima,
K.; Koga, I.; Iwasawa, N.; Hosoya, T.; Hirasawa, Y.; Kaneda, T.; Ismail,
I. S.; Lajis, N. H.; Morita, H. J. Nat. Med. 2013, 67, 9. (e) Jadhav, A.;
Liang, W.; Papageorgiou, P. C.; Shoker, A.; Kanthan, S. C.; Balsevich,
J.; Levy, A. S.; Heximer, S.; Backx, P. H.; Gopalakrishnan, V. J.
Pharmacol. Exp. Ther. 2013, 345, 383. (f) Zhang, Z.-J.; Yang, J.; He, J.;
Wu, X.-D.; Shao, L.-D.; Li, Y.; Huang, S.-X.; Li, R.-T.; Zhao, Q.-S.
Tetrahedron Lett. 2014, 55, 6490. (g) Edwankar, R. V.; Edwankar, C.
R.; Deschamps, J. R.; Cook, J. M. J. Org. Chem. 2014, 79, 10030.
(h) Beatty, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2014, 136,
10270.
(2) (a) Neuss, N.; Neuss, M. N. In The Alkaloids; Brossi, A., Suffness,
M., Eds.; Academic Press: San Diego, 1990; Vol. 37, p 229. (b) The
Alkaloids. Antitumor Bisindole Alkaloids from Catharanthus roseus (L.);
Brossi, A., Suffness, M., Eds.; Academic Press: San Diego, 1990; Vol.
37. (c) Ishikawa, H.; Colby, D. A.; Boger, D. L. J. Am. Chem. Soc. 2008,
130, 420. (d) Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.;
Kakei, H.; Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009,
131, 4904. (e) Jadhav, A.; Liang, W.; Papageorgiou, P. C.; Shoker, A.;
Kanthan, S. C.; Balsevich, J.; Levy, A. S.; Heximer, S.; Backx, P. H.;
Gopalakrishnan, V. J. Pharmacol. Exp. Ther. 2013, 345, 383.
(3) (a) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1993, 115, 1177.
(b) Vanecko, J. A.; Wan, H.; West, F. G. Tetrahedron 2006, 62, 1043.
(c) Sharma, A.; Guenee, L.; Naubron, J.-V.; Lacour, J. Angew. Chem.,
Int. Ed. 2011, 50, 3677.
(R)-6-(3-Diazo-2-oxopropyl)-1-(4-methoxybenzyl)piperidin-2-one
[(−)-6a]. To a stirred solution of s9 (659.2 mg, 1.56 mmol) in THF
(6.2 mL) were added LiOH (93.4 mg, 3.9 mmol) and 30% aqueous
H2O2 (0.35 mL, 3.1 mmol) in H2O (1.7 mL) at 0 °C. After the
mixture had been stirred for 1 h at 0 °C, saturated aqueous NaHCO3
was added to the reaction mixture, and the aqueous layer was washed
with EtOAc. The aqueous layer was acidified with 1 N aqueous HCl,
extracted with EtOAc, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to afford crude (R)-s3a.
(R)-s3a was converted to (−)-6a according to general procedure C
and isolated as yellow powder (37% yield, 174.3 mg, three steps): mp
101−103 °C; [α]23 − 34.0° (c 1, CHCl3). The enantiomeric excess
D
was determined to be 98% by analytical chiral HPLC. Nineteen min,
21 min (OJ-H column, 85/15 n-hexane/iPrOH, 1 mL/min, 254 nm).
Determination of the Absolute Configuration and Enantiomeric
Excess.
(R)-2-(6-Oxopiperidin-2-yl)acetic Acid [(−)-s10]. A solution of (R)-
s3a (49.6 mg, 0.18 mmol) in trifluoroacetic acid was refluxed for 12 h,
and the reaction mixture was concentrated under reduced pressure.
The residue was dissolved in CH2Cl2 and basified with saturated
aqueous NaHCO3, and the aqueous layer was washed with CH2Cl2.
The aqueous layer was acidified with 6 N aqueous HCl, washed with
CH2Cl2, concentrated under reduced pressure, and extracted with
CHCl3. The extract was filtered through Celite and washed with Et2O
to afford (−)-s10 as colorless powder (78% yield, 21.1 mg, two steps):
(4) (a) Sweeney, J. B. Chem. Soc. Rev. 2009, 38, 1027. (b) Stewart, C.;
McDonald, R.; West, F. G. Org. Lett. 2011, 13, 720 See also refs 3a 3b.
(5) (a) Padwa, A.; Snyder, J. P.; Curtis, E. A.; Sheehan, S. M.;
Worsencroft, K. J.; Kappe, C. O. J. Am. Chem. Soc. 2000, 122, 8155.
(b) Padwa, A.; Beall, L. S.; Eidell, C. K.; Worsencroft, K. J. J. Org.
Chem. 2001, 66, 2414.
mp 117−119 °C; [α]24 − 21.2° (c 0.5, EtOH). (S)-2-(6-
D
Oxopiperidin-2-yl)acetic acid [(+)-s10}: [α]D + 17.8° (c 1, EtOH).30
(6) (a) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263.
(b) Padwa, A.; Hasegawa, T.; Liu, B.; Zhang, Z. J. Org. Chem. 2000, 65,
7124. (c) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072. (d) Jung, D. J.;
Jeon, H. J.; Kim, J. H.; Kim, Y.; Lee, S.-g. Org. Lett. 2014, 16, 2208.
(7) For O-ylide formation of imide derivatives, see: (a) England, D.
B.; Padwa, A. Org. Lett. 2007, 9, 3249. (b) England, D. B.; Padwa, A. J.
Org. Chem. 2008, 73, 2792. (c) Li, H.; Bonderoff, S. A.; Cheng, B.;
Padwa, A. J. Org. Chem. 2014, 79, 392. (d) Padwa, A.; Zou, Y.; Cheng,
B.; Li, H.; Downer-Riley, N.; Straub, C. S. J. Org. Chem. 2014, 79,
3173.
(8) Menjo, Y.; Hamajima, A.; Sasaki, N.; Hamada, Y. Org. Lett. 2011,
13, 5744.
(9) Bond dissociation energies of amide C−N bonds are higher than
those of benzylic C−N bonds and comparable to those of stable C−H
or C−C bonds. For example, HC(O)−NH2, Bn−NH2, CH3−H, and
CH3−CH3 bond energies are 422, 307, 439, and 377 kJ/mol,
(1S,2R,6R,8S)-9-(4-Methoxybenzyl)-9-azabicyclo[4.2.1]nonane-
2,8-diol [(−)-8]. Prepared via the same procedure for the synthesis of 8
and isolated as white powder: mp 74−76 °C; [α]20 − 14.1° (c 1,
D
CHCl3). The enantiomeric excess was determined to be 98% by
analytical chiral HPLC. Eighteen min, 21 min (AD-H column, 95/5
n-hexane/iPrOH, 1 mL/min, 254 nm).
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01954.
Computational details and charts of spectra (PDF)
P
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
respectively. See: Luo, Y. R. Comprehensive Handbook of Chemical Bond
Energies; CRC Press: Boca Raton, FL, 2007.
(10) Shen, J.-J.; Zhu, S.-F.; Cai, Y.; Xu, H.; Xie, X.-L.; Zhou, Q.-L.
(27) Dudash, J.; Rybczynski, P.; Urbanski, M.; Xiang, A.; Zeck, R.;
Zhang, X.; Zhang, Y. U.S. Patent Appl. US 20070099930 A1
20070503, 2007.
(28) Coleman, R. S.; Felpin, F.-X.; Chen, W. J. Org. Chem. 2004, 69,
7309.
(29) DeVita, R. J.; Goulet, M. T.; Wyvratt, M. J.; Fisher, M. H.; Lo, J.-
L.; Yang, Y.-T.; Cheng, K.; Smith, R. G. Bioorg. Med. Chem. Lett. 1999,
9, 2621.
Angew. Chem., Int. Ed. 2014, 53, 13188.
(11) (a) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.; Zhou, Q.-L. J. Am.
Chem. Soc. 2007, 129, 5834. (b) Slattery, C. N.; Maguire, A. R.
Tetrahedron Lett. 2013, 54, 2799.
(12) (a) Yu, Z.; Ma, B.; Chen, M.; Wu, H.-H.; Liu, L.; Zhang, J. J. Am.
Chem. Soc. 2014, 136, 6904. (b) Xi, Y.; Su, Y.; Yu, Z.; Dong, B.;
McClain, E. J.; Lan, Y.; Shi, X. Angew. Chem., Int. Ed. 2014, 53, 9817.
(13) Use of Rh2(NRCOR′)4. See: (a) Doyle, M. P.; Bagheri, V.;
Wandless, T. J.; Harn, N. K.; Brinker, D. A.; Eagle, C. T.; Loh, K.-L. J.
Am. Chem. Soc. 1990, 112, 1906. (b) Doyle, M. P.; Winchester, W. R.;
Hoorn, J. A. A.; Lynch, V.; Simonsen, S. H.; Ghosh, R. J. Am. Chem.
Soc. 1993, 115, 9968.
(30) Polniaszek, R. P.; Belmont, S. E.; Alvarez, R. J. Org. Chem. 1990,
55, 215.
(14) Racemic 7a was obtained when chiral Rh(II) dimer complex
Rh2(S-PTPA)4 was used as a catalyst (Table 1, entry 8), indicating that
a kinetic resolution did not ocurr during the developed process.
(15) Examples of trans-bicyclo[5.2.1],[5.3.1]alkane: Winkler, J. D.;
Hong, B. C.; Hey, J. P.; Williard, P. G. J. Am. Chem. Soc. 1991, 113,
8839.
(16) Clark, J. S.; Whitlock, G.; Jiang, S.; Onyia, N. Chem. Commun.
2003, 2578.
(17) Clark, J. S.; Hansen, K. E. Chem. - Eur. J. 2014, 20, 5454.
(18) The calculations were performed with SPARTAN ’14 packages.
(19) See the Supporting Information for details.
(20) This level of theory was previously used in Rh-catalyzed
insertions: Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem.
Soc. 2002, 124, 7181.
(21) Orientations of the carboxamidate ligands were assigned a (2,2-
cis) geometry, based on the following reports: (a) Ahsan, M. Q.;
Bernal, I.; Bear, J. L. Inorg. Chem. 1986, 25, 260. (b) Welch, C. J.; Tu,
Q.; Wang, T.; Raab, C.; Wang, P.; Jia, X.; Bu, X.; Bykowski, D.;
Hohenstaufen, B.; Doyle, M. P. Adv. Synth. Catal. 2006, 348, 821 See
also ref 13b.
(22) To the best of our knowledge, rhodium catalysts working as a
hydrogen bond donor have not been reported. On the other hand,
rhodium catalysts working as a hydrogen bond acceptor have been
well-documented. See: (a) Anada, M.; Washio, T.; Shimada, N.;
Kitagaki, S.; Nakajima, M.; Shiro, M.; Hashimoto, S. Angew. Chem., Int.
Ed. 2004, 43, 2665. (b) Briones, J. F.; Hansen, J. H.; Hardcastle, K.;
Autschbach, J.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 17211.
(c) Goto, T.; Takeda, K.; Shimada, N.; Nambu, H.; Anada, M.; Shiro,
M.; Ando, K.; Hashimoto, S. Angew. Chem., Int. Ed. 2011, 50, 6803.
(d) Xu, X.; Doyle, M. P. Inorg. Chem. 2011, 50, 7610. (e) Watanabe,
Y.; Washio, T.; Krishnamurthi, J.; Anada, M.; Hashimoto, S. Chem.
Commun. 2012, 48, 6969. (f) Li, Z.; Boyarskikh, V.; Hansen, J. H.;
Autschbach, J.; Musaev, D. G.; Davies, H. M. L. J. Am. Chem. Soc.
2012, 134, 15497. (g) Xu, X.; Wang, X.; Liu, Y.; Doyle, M. P. J. Org.
Chem. 2014, 79, 12185.
(23) Acyl transfer controlled by hydrogen bonds. See: (a) Oh, S. H.;
Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E.
Angew. Chem., Int. Ed. 2008, 47, 7872. (b) Peschiulli, A.; Procuranti,
B.; O’Connor, C. J.; Connon, S. J. Nat. Chem. 2010, 2, 380.
(c) Binanzer, M.; Hsieh, S.-Y.; Bode, J. W. J. Am. Chem. Soc. 2011, 133,
19698. (d) Mittal, N.; Lippert, K. M.; De, C. K.; Klauber, E. G.; Emge,
T. J.; Schreiner, P. R.; Seidel, D. J. Am. Chem. Soc. 2015, 137, 5748.
Our examples: (e) Harada, S.; Kuwano, S.; Yamaoka, Y.; Yamada, K.;
Takasu, K. Angew. Chem., Int. Ed. 2013, 52, 10227. (f) Kuwano, S.;
Harada, S.; Kang, B.; Oriez, R.; Yamaoka, Y.; Takasu, K.; Yamada, K. J.
Am. Chem. Soc. 2013, 135, 11485.
(24) Fukui, K. Acc. Chem. Res. 1981, 14, 363.
(25) Woodward−Hoffmann rules cannot be applied to this process,
which does not consist of normal pericyclic reactions: (a) Woodward,
R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 781.
(b) Jaber, D. M.; Burgin, R. N.; Helper, M.; Zavalij, P. Y.; Doyle, M. P.
Org. Lett. 2012, 14, 1676 and references cited therein.
(26) Allen, S. E.; Hsieh, S.-Y.; Gutierrez, O.; Bode, J. W.; Kozlowski,
M. C. J. Am. Chem. Soc. 2014, 136, 11783 and references cited therein.
Q
DOI: 10.1021/acs.joc.5b01954
J. Org. Chem. XXXX, XXX, XXX−XXX