Polycyclic Ring Formation Using Bis-diazolactams for Cascade Stitching

Article abstract of DOI:10.1021/acs.joc.6b02663

The chemoselective reaction of donor/acceptor (D/A) and acceptor/acceptor (A/A) diazo moieties in the same molecule was examined using 3-diazo-1-(ethyl 2-diazomalonyl)indolin-2-one under rhodium(II) catalysis. The metallo carbenoid derived from the D/A diazo group is preferentially formed and undergoes selective CH, NH, and OH insertion reactions, cyclopropanation, cyclopropenation, sulfur ylide formation/2,3-sigmatropic rearrangement, as well as nitrogen ylide formation followed by azetidine ring expansion. The initial reaction can be paired with a subsequent tandem cascade sequence involving dipole formation/cycloaddition in either an intra- or intermolecular sense to generate polycyclic N-heterocycles in one pot, with the formation up to three new rings in a single operation. Excellent diastereoselectivity was observed in the intramolecular cycloaddition reaction producing 5 to 7-membered rings.

Full text of DOI:10.1021/acs.joc.6b02663

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Article
Polycyclic Ring Formation Using Bis-Diazolactams for Cascade Stitching
Sara Anne Bonderoff, and Albert Padwa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02663 • Publication Date (Web): 15 Dec 2016
Downloaded from http://pubs.acs.org on December 19, 2016
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Polycyclic Ring Formation Using
Bis-Diazolactams for Cascade Stitching
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Sara A. Bonderoff and Albert Padwa∗
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
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TOC Graphic
Ph
Ph
N2
Rh2(OPiv)4
PhH, Δ
.
TsOH H2O
O
H
N
N
N
O
H
N2
O
Ph
O
CO2Et
O
HO
OEt
CO2Et
O
Abstract: The chemoselective reaction of donor/acceptor (D/A) and acceptor/acceptor
(A/A) diazo moieties in the same molecule was examined using 3-diazo-1-(ethyl 2-
diazomalonyl)indolin-2-one under rhodium(II) catalysis. The metallo carbenoid derived
from the D/A diazo group is preferentially formed and undergoes selective CH, NH and
OH insertion reactions, cyclopropanation, cyclopropenation, sulfur ylide formation/2,3-
sigmatropic rearrangement, as well as nitrogen ylide formation followed by azetidine ring
expansion. The initial reaction can be paired with a subsequent tandem cascade sequence
involving dipole formation/cycloaddition in either an intra- or intermolecular sense to
generate polycyclic N-heterocycles in one pot, with the formation up to three new rings in
a single operation. Excellent diastereoselectivity was observed in the intramolecular
cycloaddition reaction producing 5 to 7-membered rings.
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Introduction
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The total synthesis of alkaloids is an enduring pursuit of organic chemists. These
naturally occurring molecules are biologically and structurally intriguing, and they provide
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both inspiration and a proving ground for development of new reactions. A strategy used in
our research group for assembling polycyclic congested natural alkaloids has been to employ
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the Rh(II)-catalyzed cascade reactions of functionalized diazo compounds. Tandem
catalyzed reactions are often designed to exploit both catalyst and reagent selectivity so as to
enforce the correct sequence of constituent reactions to produce the desired overall
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transformation. By this means, cascade chemistry allows for a rapid increase in molecular
complexity in a single synthetic step from carefully designed substrates, maximizing bond
formations per operation. Over the years we have successfully applied a tandem Rh(II)-
catalyzed dipole formation/dipolar cycloaddition strategy to construct complex nitrogen
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heterocyles in a single operation. For example, a synthesis of the pentacyclic alkaloid (±)-
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aspidophytine 4 was carried out by making use of the domino dipole cascade sequence. The
Scheme 1
O
O
N
N
+
CO2t-Bu
O
-
Rh(II)
O
CO2t-Bu
N
MeO
N
O
N2
Me
O
CO2Me
OMe
Me
MeO
MeO
O
MeO
1
2
O
N
N
O
O
MeO
MeO
MeO
CO2t-Bu
O
steps
N
MeO
N
O
H
H
Me
Me
CO2Me
3
(±)-Aspidophytine; 4
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key sequence of reactions involved a 1,3-dipolar cycloaddition of the ‘push-pull’ dipole 2
derived from lactam 1 across the indole π-system. The exo-cycloadduct 3 was the exclusive
product formed from the Rh(II)-catalyzed reaction of diazo ketoester 1. A three-step
sequence was then used to reductively open up the oxabicyclic ring system and remove both
the ester and OH groups. Subsequent functional group manipulations allowed for the high-
yielding conversion of compound 3 into (±)-aspidophytine 4 (Scheme 1).
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In order to enhance the versatility of this approach, we sought to introduce a second
diazo moiety within the starting material so as to increase the complexity of the Rh(II)-
cascade reaction. This could result in the formation of two of the rings of a contiguously
fused core in a single step starting from a bis-diazo compound and a bifunctionalized reaction
partner. A plethora of possibilities exist for the cascade sequence. Variation of functionality
at the tethered reactive site is certainly plausible. Ring size of the final product could also be
controlled by simply changing the tether length. Prior to our foray into the cycloaddition
chemistry of differentially substituted bis-diazo compounds, we recognized that there were a
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few isolated examples reported in the literature that were related to this proposition. For
example, Moody and Miller studied the OH insertion reaction of methanol with phosphono-
diazoesters such as 5 to give 6, and noted the selectivity for insertion to take place at the
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monosubstituted diazo site, leaving the phosphono-diazoester moiety intact (Scheme 2). In
2009, Muthusamy and Srinivasan probed the formal CH insertion chemistry of a bis-
Scheme 2
O
N2
O
N2
Rh(II)
H
O
O
O
P(OEt)2
O
O
P(OEt)2
MeOH
N2
O
OMe
O
O
6
5
H
N2
N
N
Rh(II)
Rh(II)
N
PhH, reflux
N
O
N
O
O
N
O
H
N2
N2
O
O
O
O
Me
Me
O
Me
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diazolactam with a N-allyl substituted indole and reported an interesting example of insertion
into the aromatic framework (7 8) followed by intramolecular cycloaddition (8 9) across
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the tethered π-bond.
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In an earlier communication, we disclosed a preliminary study of the
cyclopropanation reactions of bis-diazolactams containing both donor-acceptor (D/A) and
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acceptor-acceptor (A/A) substituted diazo groups.
We noted complete selectivity for
reaction at the D/A flanked diazo site (Scheme 3). This was followed by intramolecular
cycloaddition across the neighboring π-bond via the 1,3-dipole formed by reaction of the
Scheme 3
R2
R2
N2
( )n
Rh2(OPiv)4
PhH, Δ
Rh2(OPiv)4
PhH, rt
( )n
H
O
O
N
N
N
N2
O
N2
( )n
R2
O
O
O
OR1
(3 equiv.)
73%
CO2R1
12; n = 1
OR1
O
10
O
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Rh(II)-catalyst with the second diazo group. Herein we report a more detailed description of
some cyclopropanations, XH-insertions, Stevens [1,2]-shift of ammonium ylides, and 2,3-
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sigmatropic rearrangement of sulfonium ylides of several bis-diazolactam systems that we
also studied and which produced complex polycyclic structures in a single operation.
Results and Discussion
The question of whether it is possible to carry out a number of well-known Rh(II)-
catalyzed transformations of a bis-diazolactam is interesting in itself, as there are not many
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examples of this type of reaction in the literature. We initiated our studies by first
examining the Rh(II)-catalyzed chemistry of 3-diazo-1-(ethyl 2-diazomalonyl)-indolin-2-one
(13) for several reasons. First, it is already known that bis-diazo containing substrates are
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prone to undergo ring formation through a metathesis reaction at the diazo carbons.
By
positioning the D/A diazo moiety in a ring having a 1,3-relationship to the other diazo group,
ring formation is not geometrically feasible. Moreover, D/A–carbenoids are more easily
formed under Rh(II) catalysis than A-carbenoids and they exhibit a substantial difference in
13
reactivity and selectivity in the ensuing chemistry. Thus, we anticipated that the D/A diazo
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site of 13 should react with the rhodium(II) catalyst much more rapidly than the A/A diazo
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site, thereby enabling selective reaction of the D/A diazo moiety while the A/A diazo
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group was expected to remain intact. The 3-diazoindolin-2-one system had been studied
previously and was found to perform well using a variety of metallocarbenoid induced
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reactions. Bis-Diazolactam 13 was easily prepared in 74% yield by acylation of the known
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3-diazoindolin-2-one with ethyl 2-diazomalonyl chloride, providing 13 in 74% yield
(Scheme 4).
Scheme 4
N2
O
O
N2
Cl
OEt
O
N2
N
O
N2
NaH, THF, 0oC
74%
N
O
H
OEt
O
13
We began our studies by examining the Rh(II)-catalyzed cyclopropanation of 13 with
styrene (Scheme 5). A solution of bis-diazolactam 13 was added over 1h to a
dichloromethane solution containing one equivalent of styrene and a catalytic amount of
Rh2(OPiv)4. The reaction was conducted at 0°C in order to promote selective decomposition
of the more reactive D/A diazo without impacting on the A/A diazo group. Pleasingly,
cyclopropane 14 was produced in 93% yield, without any observation of products derived
from decomposition at the A/A diazo site. The stereochemical assignment of 14 was based
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on literature precedent, and was corroborated by the observation that the chemical shift of
the proton at the 4-position of the indolinone ring is located at 5.92 ppm, indicative of
anisotropic shielding by the cis phenyl substituent. Vinyl acetate, an electron deficient
cyclopropanation substrate, also underwent the desired reaction in excellent yield as
evidenced by 1H-NMR analysis of the crude reaction mixture. However, the isolated yield of
15 corresponded to only 53% due to its instability to chromatographic purification. The
Rh(II)-catalyzed reaction of 13 with cyclopentene afforded compound 16 in 68% yield by
NMR spectroscopy analysis but could only be isolated in 43% yield. Cyclopropenation
using an alkyne also occurred, although this somewhat more difficult transformation required
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that the reaction be performed at room temperature rather than 0 °C.
Thus,
cyclopropenation of 13 with 1-pentyne at ambient temperature furnished compound 17 in
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Scheme 5
R1
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R2
N2
9
R1 R2
O
Rh(II)
O
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+
N
N
N2
N2
O
O
OEt
13
O
OEt
O
Ph
OAc
O
O
O
N
N
N
O
N2
N2
N2
O
O
OEt
OEt
OEt
O
O
O
16; 43% (68% NMR)
14; 93%
15; 53% (90% NMR)
O
Me
O
O
N
N
N2
N2
O
O
OEt
OEt
O
O
17; 56%
18; 57%
CHO
H
O
O
O
N
N
N2
N2
O
O
OEt
OEt
O
O
20; 87%
19
56% yield, again with no apparent reaction at the A/A diazo location despite the increase in
temperature. The reaction of 13 with 2-trimethylsiloxy-1,5-hexadiene gave indolinone 18 in
57% isolated yield by a cyclopropanation/ring opening sequence. We also examined the
Rh(II) catalyzed reaction of 13 with furan which afforded 20 in 87% yield. Presumably this
reaction also proceeds via an initial cyclopropanation reaction to give 19 as a transient
intermediate which was rapidly transformed into 20, a reorganization known to occur with
20
related systems.
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We next investigated the possibility that the D/A carbenoid derived from 13 would
undergo both CH and XH insertion chemistry (Scheme 6). Indeed CH insertion occurred
smoothly with anisole and N-methylindole, furnishing compounds 21 and 22 in 76% and
96% yield. In the case of anisole, this electron-rich aromatic compound was employed as the
solvent. Reaction of 13 with N-methylindole proceeded more readily and only three
equivalents of the indole was necessary. When N-allyl pyrrole was used, the catalyst loading
was raised to 1 mol %, and the temperature was increased to reflux in benzene in order to
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Scheme 6
N2
H
R
Rh(II)
H R
O
O
N
N
N2
CO2Et
N2
CO2Et
O
O
13
OMe
Me
N
O
O
O
N
N
N2
N
N2
CO2Et
22; 96%
N2
CO2Et
O
O
CO2Et
O
25; 54%
21; 76%
N
N
O
O
N
N
N2
N2
54% (5.8:1)
O
O
CO2Et
CO2Et
23
24
Ph
N
O
O
O
N
N
N2
N2
O
O
CO2Et
CO2Et
27; 46%
26; 45%
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effect complete diazo decomposition. We believe this to be the result of an interaction of the
pyrrole with the catalyst in an inhibitory manner. In this case, a 5.8:1- mixture of 23 and 24
was isolated in 54% yield. Although CH insertion reactions with tetrahydrofuran and
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cyclohexene failed to occur, bis-diazolactam 13 reacted readily with 1,4-cyclohexadiene, to
afford the CH-insertion product 25 in 54% yield. Although XH insertion reactions can
possibly suffer from catalyst quenching by the heteroatom, we had previously found that OH
insertion with 13 and 3-butene-1-ol gave 26 in 45% yield, and NH-insertion took place with
22
N-(1-pentene-5-yl)aniline to give 27 in 46% yield.
In contrast to the above observations, the Rh(II)-catalyzed reaction of 13 with allyl
sulfide resulted first in sulfonium ylide formation and this was followed by a [2,3]-
sigmatropic rearrangement to give compound 28 in 82% yield (Scheme 7). An elevated
temperature (80°C) was required in order to effect decomposition of the bis-diazolactam 13
in the presence of allyl sulfide. Electron rich substrates are known to inhibit Rh(II)-
23
catalysis, and the interaction of the sulfur atom with the catalyst could explain the observed
temperature effect. Although the A/A-diazo moiety might have been expected to decompose
23
in the presence of Rh2(OAc)4 at this temperature, compound 28 proved to be stable within
the time frame required to consume the starting bis-diazolactam 13.
Scheme 7
N2
S
S
2
O
O
N
Rh2(OAc)4
N2
CO2Et
N
N2
CO2Et
PhH, reflux
82%
O
O
13
28
After demonstrating that selective cyclopropanation, cyclopropenation, CH and XH
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insertion, as well as Doyle like reactions of bis-diazolactam 13 proceeds by selective D/A-
diazo decomposition, we next examined the dipole formation-cycloaddition pathway at the
A/A-diazo site. The previously synthesized diazo-cyclopropane 14 was treated with
Rh2(OPiv)4 in the presence of three equivalents of dimethyl acetylenedicarboxylate (DMAD)
in benzene at reflux temperature. Under these conditions, cycloadduct 29 was isolated in
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59% yield (Scheme 8). The intramolecular dipole/cycloaddition cascade of compound 28
provided cycloadduct 30 in 80% yield. It is notable that the reaction conditions employed for
the formation of 30 are identical to those used for the synthesis of 28, but required prolonged
heating (36h) relative to the more facile formation of 28 (1h). Indoles 22 and 23 are devoid
of a substituent group at the C–3 carbon of the indolinone ring, and therefore there is a
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possibility that proton elimination can become competitive with cycloaddition once dipole
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formation occurs.
Indeed, in the case using compound 22, intermolecular dipolar
cycloaddition of the resulting 1,3-dipole with DMAD did not occur. Instead, proton transfer
Scheme 8
Ph
Ph
Rh2(OPiv)4
DMAD
CO2Me
CO2Me
CO2Et
O
N
N
O
N2
CO2Et
PhH, reflux
59%
O
O
14
29
S
S
Rh2(OAc)4
O
H
N
N
O
N2
PhH, reflux
80%
O
O
CO2Et
CO2Et
28
30
Me
N
Me
N
Rh2(OPiv)4
DMAD
O
N
O
N2
PhH, reflux
99%
N
O
22
CO2Et
CO2Et
O
31
N
Rh2(OPiv)4
DMAD
N
H
O
H
N
N2
PhH, reflux
79%
N
O
O
O
CO2Et
CO2Et
23
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of the transient dipole gave the 2,3-dihydrooxazole ring of compound 31 in near quantitative
yield. On the other hand, when diazolactam 23 was heated in the presence of the Rh(II)-
catalyst, intramolecular dipolar cycloaddition was found to be much faster than proton
transfer and cycloadduct 32 was isolated in 79% yield.
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At this stage of our studies, we attempted to induce a one-pot multicomponent
cyclopropanation/cycloaddition cascade reaction. We were pleased to find that cycloadduct
29 could be obtained in 70% yield from the reaction of bis-diazolactam 13 with a slight
excess of styrene and in the presence of three equivalents of DMAD in refluxing benzene
(Scheme 9). Changing the acetylenic dipolarophile to the less reactive methyl propiolate,
afforded the analogous cycloadduct 30 in 53% yield. In this particular case, the Rh(II)-
catalyzed reaction was conducted at an elevated temperature where decomposition of both
the diazo groups occur. It is not crystal clear whether selective reaction of the D/A-diazo
moiety occurs prior to reaction of the A/A-diazo group at the elevated temperatures
employed, though this is most probable.
Scheme 9
Ph
N2
CO2Me
Ph
O
N
N
O
R
CO2Me
Rh2(OPiv)4
PhH, reflux
all in one pot
R
N2
O
O
CO2Et
CO2Et
29: R=CO2Me; 70%
33: R=H; 53%
13
With this issue in mind, we decided to examine the reaction of bis-diazolactam 13
with 2-phenyl-1,5-hexadiene (34) in order to provide some confirmation of the ordering of
events in Scheme 9. If the dipole is formed first, it should not result in a bimolecular
cycloaddition reaction because the simple terminal alkene is not suitably activated for a
dipolar intermolecular cycloaddition reaction, although it can undergo an intramolecular one.
When a disubstituted alkene such as 34 is to be employed as the trapping partner, it would be
expected that two different stereoisomers would be formed from the cyclopropanation
reaction. With 2-phenyl-1,5-hexadiene (34) as the reaction partner, the size difference
between the phenyl and butenyl groups should first lead to preferential formation of the
cyclopropane where the butenyl group is oriented adjacent to the incipient dipole (i.e.
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compound 35, vide infra). This geometrical arrangement would allow for a subsequent
intramolecular cycloaddition in the second step of the cascade. With the other stereoisomer
(i.e. compound 36, vide infra), the butenyl group will be oriented away from the incipient
dipole, and therefore cannot be a part of the tether for a successful cycloaddition step. What
we actually observed was that when the bis-diazolactam 13 was allowed to react with diene
34 using Rh2(OPiv)4 in refluxing benzene, the only product formed as a single diastereomer
was cycloadduct 37 isolated in 73% isolated yield (Scheme 10). The relative stereochemistry
of 37 was determined by X-ray crystallographic analysis. The formation of cycloadduct 37
seemingly requires an initial cyclopropanation reaction to produce a cyclopropane with a
tethered π-bond correctly oriented and thus the dipolar cycloaddition step must follow after
cyclopropanation for these types of cascade reactions.
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45
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Scheme 10
Ph
N2
Rh2(OPiv)4
PhH, Δ
O
N
N
H
N2
O
Ph
O
O
34
OEt
CO2Et
O
(3 equiv.)
79%
13
37
Interestingly, when the Rh(II)-catalyzed reaction of 13 with diene 34 was carried out
at 0oC, the two expected diastereomeric cyclopropanes (i.e. 35 and 36) were formed with a
combined yield of 84% in a 2.2:1 ratio and cycloadduct 37 was not detected in the reaction
mixture (Scheme 11). The stereochemistry assignment was based on the upfield shift of the
proton at the 4-position of the indolinone ring for diastereomer 35 (δ 5.50) due to anisotropic
shielding by the cis phenyl group. As expected, diastereomer 35 afforded cycloadduct 37 in
88% yield when heated in refluxing benzene in the presence of the Rh(II) catalyst. What was
surprising was that the other diastereomer 36 also produced 37 in a comparable yield when
treated under identical conditions.
Scheme 11
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Ph
N2
Rh2(OPiv)4
Ph
O
PhH, 0oC
+
O
O
N
N2
N
N
N2
N2
Ph
O
O
O
34
OEt
10
11
12
13
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18
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36
37
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O
OEt
OEt
O
O
84% (2.2:1 d.r.)
35
36
13
Rh2(OPiv)4
PhH, reflux
Ph
N
H
O
O
CO2Et
37
At first glance it would seem as though the diastereoselectivity of the initial
cyclopropanation step involved in the formation of cycloadduct 37 is not important to the
outcome of the cycloaddition reaction. The fact that the cis diasteromer 36 also produced 37
can best be explained by a thermal isomerization about the cyclopropane ring prior to
25
cycloaddition step. Furthermore, when the minor diastereomer 36 is treated with the Rh(II)
catalyst and 10 equivalents of DMAD at 50°C in benzene, bimolecular cycloaddition with
the acetylenic dipolarophile occurred to give 38 as the exclusive product as evidenced by
NMR but was only obtained in 50% isolated yield (Scheme 12). In contrast, diastereomer 35
underwent intramolecular cycloaddition with the tethered π-bond at a faster rate than the
bimolecular reaction with DMAD.
This observation provides strong support that
cyclopropane isomerization for 36 is necessary for the subsequent intramolecular
cycloaddition, and that it occurs at a slower rate than the bimolecular cycloaddition with
DMAD. We also noted that the bridging oxabicyclic ring in adduct 37 was easily cleaved in
the presence of catalytic acid to give alcohol 39 in 74% yield.
Scheme 12
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Ph
5
6
7
8
9
O
N
N2
O
Ph
OEt
10
11
12
13
14
15
16
17
18
19
20
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35
36
37
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O
35
from 35: 88%
from 36: 85%
from 35 with
10 equiv. DMAD,
50οC: 76% (NMR)
13
DCM, 0οC
84% (2.2:1 35:36)
37
Rh2(OPiv)4
PhH, Δ
Ph
O
N
N2
.
O
10 % TsOH H2O
OEt
O
PhH, rt, 1h
74%
36
Rh2(OPiv)4
DMAD (10 equiv.)
PhH, 50°C
50 %
Ph
H
Ph
N
CO2Me
CO2Et
O
HO
39
N
O
CO2Me
O
CO2Et
38
We next conducted a survey of some additional tandem cycloaddition reactions of the
bis-diazolactam 13 (Scheme 13). When 13 was treated with o-divinylbenzene in the
presence of the Rh(II) catalyst at 80oC, cycloadduct 40 was formed in 41% yield. As was
discussed above, epimerization about the initially formed mixture of cyclopropanes is most
likely involved in the subsequent production of 40. Insertion of the carbenoid into an XH
group (X=O or N) was also compatible with the tandem process. Thus, OH insertion into
allyl alcohol afforded the 5-membered ring ether 41 in 68% yield. The NH insertion reaction
with N-(1-buten-4-yl)aniline was found to be similarly efficient and produced cycloadduct 42
in 69% yield. Sufonium ylide formation followed by a [2,3]-rearrangement/cycloaddition
reaction was carried out as a 1-pot sequence, with 30 being formed in 77% yield, as
compared to an overall yield of 65% when the cycloaddition was performed after isolation of
the intermediate sulfide 28. Azetidines are known to react with both A and A/A diazo
compounds to afford pyrrolidines as ring expansion products via a transient ammonium
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ylide. Pleasingly, the reaction of methyl N-allyl-azetidine-3-carboxylate with the D/A diazo
group in 13 proceeded smoothly to give a 2:1-mixture of hexacyclic amines 43 and 44 in a
combined yield of 63%. The stereochemistry of the minor diastereomer 44 was confirmed
by X–ray crystallographic analysis.
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12
13
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17
18
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36
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40
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45
46
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Scheme 13
H
Rh2(OPiv)4
PhH, reflux
N
H
O
O
41%
CO2Et
40
H
Rh2(OPiv)4
PhH, reflux
X
N
H
O
N2
HX
O
CO2Et
O
N
N2
41; X=O; 68%
42; X=NPh; 69%
O
OEt
13
O
Rh2(OAc)4
PhH, reflux
S
S
N
H
2
O
77%
O
CO2Et
30
Rh2(OAc)4
PhH, reflux
MeO2C
MeO2C
N
N
O
+
CO2Me
N
H
H
N
N
O
O
O
CO2Et
CO2Et
63% (2:1)
43
44
Having characterized the major reactions of the D/A, A/A bis(diazo) system 13, we became
interested in exploring whether a related insertion/cycloaddition sequence would occur with
other bis(diazo)lactams and chose piperidone 45 for this study. As was the case with bis-
diazolactam 13, the diazo groups are geometrically precluded from an intramolecular
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methathesis reaction. However, in contrast to 13, the diazo functionality contained within the
piperidone lactam ring of 45 does possess hydrogens alpha to the carbenoid site and this
might result in a rapid deprotonation of the metallocarbene intermediate. To probe this
possibility, bis(diazo)lactam 45 was easily synthesized from 3-diazo-2-piperidone in 80%
yield (Scheme 14) and its subsequent chemistry was examined. In order to minimize the
chance of deprotonation, we paired bis(diazo)lactam 45 with 3-buten-1-ol since OH insertion
reactions with this alcohol was expected to be very facile. The Rh(II)-catlayzed OH insertion
using 45 was carried out at –40°C and the expected insertion product 46 was formed in 60%
isolated yield. When 46 was further subjected to the Rh(II)-catalyst in refluxing benzene, a
smooth cycloaddition reaction occurred to form tetracycle 47 in 89% yield. This compound
was obtained as a single diastereomer, in congruence with the reactions observed with
bis(diazo)lactam 13. There was no evidence of any eliminative quenching of the dipole
intermediate. Since compound 46 was unstable toward chromatographic purification, we
sought to perform the overall transformation of 45 to 47 as a one-pot tandem sequence.
However, it was necessary to carry out the cascade reaction in two stages, since the OH
insertion reaction of 45 is incompatible with the elevated temperature required to effect the
dipolar cycloaddition. After completion of the OH insertion step as evidenced by TLC
analysis, benzene was added to the reaction mixture, and the solution was heated to reflux in
the presence of the catalyst to effect the dipole formation/cycloaddition cascade, producing
47 in 89% yield by NMR analysis.
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36
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45
46
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Scheme 14
H
O
Rh2(OPiv)4
HO
N2
O
Rh2(OPiv)4
N
O
N
O
N
H
O
PhH, reflux
89%
N2
N2
O
O
DCM, −40oC
O
CO2Et
CO2Et
CO2Et
47
52% (80% NMR)
46
45
In summary, we have investigated the tandem cascade chemistry of two different
bis(diazo)lactams with a variety of reaction partners. These unique molecules undergo
preferential reaction at the cyclic D/A or A-diazo site under Rh(II) catalysis, and the ensuing
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transient metallocarbenoid undergoes CH, NH and OH insertion reactions, cyclopropanation,
cyclopropenation, sulfur ylide formation/2,3-sigmatropic rearrangement, as well as nitrogen
ylide formation followed by azetidine ring expansion. This initial reaction can be paired with
a subsequent tandem cascade sequence involving dipole formation/cycloaddition in either an
intra- or intermolecular sense to generate polycyclic N-heterocycles in one pot, with the
formation up to three new rings in a single operation. Excellent diastereoselectivity was
observed in the intramolecular cycloaddition reaction producing 5 to 7-membered rings. In
the case of the cyclopropanation/ cycloaddition sequence with aryl alkenes,
stereoconvergence due to a cyclopropane epimerization during the dipole formation step
yields the cycloadducts as single diastereomers.
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Experimental Section
General Procedures. Melting points are uncorrected. Mass spectra were determined at
an ionizing voltage of 70eV. The mass analyzer type used for the HRMS measurements was
TOF with electrospray as the ionization method. Unless otherwise noted, all reactions were
performed in flame-dried glassware under an atmosphere of either dry nitrogen or argon.
All solvents were distilled prior to use. Solutions were evaporated under reduced pressure
with a rotary evaporator and the residue was chromatographed on a silica gel column
(0.04-0.062 mm) using an ethyl acetate/hexane mixture as the eluent. All solids were
recrystallized from ethyl acetate/hexane for analytical data. Yields refer to isolated,
spectroscopically pure compounds.
2-Phenyl-1'-(ethyl diazomalonyl)spiro[cyclopropane-1,3'-indolin]-2'-one (14). A catalytic
amount (0.3 mg) of Rh2(OPiv)4, dichloromethane (1.0 mL) and styrene (11.5 µL, 0.1 mmol)
was cooled in an ice/water bath, and a solution of 1-(ethyl diazomalonyl)-3-diazoindolin-2-
16
one (13) (30 mg, 0.1 mmol) in dichloromethane (1.0 mL) was added over 1h via a syringe
pump. The resulting pale yellow solution was concentrated under reduced pressure and
purified by flash column chromatography to give 35 mg (93%) of the titled compound 14 as
a white solid, mp 48–51 °C; IR (KBr) 2983, 2931, 2137, 1724, 1659, 1604, 1481, and 1465
cm–1; 1H-NMR (400 MHz, CDCl3) δ 1.29 (t, 3H, J = 7.1 Hz), 2.04 (dd, 1H, J= 8.2, 4.8 Hz),
2.26 (dd, 1H, J= 9.2,4.7 Hz), 3.34 (t, 1H, J= 8.7 Hz), 4.28 (q, 2H, J= 7.1 Hz), 5.92 (d, 1H, J
= 7.6 Hz), 6.75 (t, 1H, J = 7.5 Hz), 7.13 (t, 1H, J= 7.9 Hz), 7.16–7.19 (m, 2H), 7.22–7.30 (m,
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3H), and 7.62 (d, 1H, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3) δ 14.6, 23.9, 33.9, 38.4,
62.2, 72.5, 113.7, 120.9, 124.1, 126.9, 127.1, 128.0, 128.7, 130.3, 134.3, 139.6, 160.5, 160.8,
and 175.4; HRMS calcd for [C21H17N3O4+H+]: 376.1292; found: 376.1295.
2-Acetoxy-1'-(ethyl diazomalonyl)spiro[cyclopropane-1,3'-indolin]-2'-one (15 ) was
prepared in a similar manner to give 48 mg (53%) of 15 as a thick oil; IR (film) 2984, 2141,
1755, 1702, 1661, 1610, and 1466 cm–1; 1H-NMR (400 MHz, CDCl3) δ 1.29 (t, 3H, J = 7.1
Hz), 1.95 (dd, 1H, J = 6.4, 5.5 Hz), 2.03 (s, 3H), 2.19 (t, 1H, J = 6.8 Hz), 4.25–4.34 (m, 2H),
4.71 (dd, 1H, J= 7.0, 5.4 Hz), 6.98 (d, 1H, J= 7.4 Hz), 7.14 (t, 1H, J = 7.1 Hz), 7.31 (t, 1H, J
= 7.7 Hz), and 7.69 (d, 1H, J = 8.1 Hz); 13C-NMR (100 MHz, CDCl3) δ 14.6, 20.6, 22.3,
32.9, 61.0, 62.3, 72.3, 114.5, 120.7, 124.6, 125.3, 128.0, 140.1, 160.1, 160.8, 170.1, and
173.5; HRMS calcd for [C17H15N3O6+H+]: 358.1039; found: 358.1038.
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59
60
3'-Spiro[bicyclo[3.1.0]heptane-6,3'-indolin]-2'-one (16). This compound was prepared in a
similar manner to give 49 mg (43%) of 16 as a white solid; mp 100-101°C; IR (KBr) 2958,
2876, 2134, 1727, 1658, 1607, and 1463 cm–1; 1H-NMR (400 MHz, CDCl3) δ 1.29 (t, 3H, J =
7.2 Hz), 1.89–2.11 (m, 3H), 2.21–2.32 (m, 3H), 2.52–2.57 (m, 2H), 4.27 (q, 2H, J = 7.2 Hz),
6.89 (d, 1H, J = 7.5 Hz), 7.17 (t, 1H, J = 7.4 Hz), 7.31 (t, 1H, J = 8.0 Hz), and 7.75 (d, 1H, J
= 8.1 Hz); 13C-NMR (100 MHz,CDCl3) δ 14.5, 24.8, 29.0, 40.9, 62.1, 114.3, , 121.9, 124.2,
126.4, 126.9, 140.5, 160.8, and 174.5; HRMS calcd for [C18H17N3O4+H+]: 340.1292, found:
340.1293.
2-Propyl-1'-(ethyl diazomalonyl)spiro[cyclopropene-1,3'-indolin]-2'-one (17). To a
mixture containing dichloromethane (1.0 mL), 1-pentyne (30 µL, 0.30 mmol) and a catalytic
amount of Rh2(OAc)4 (0.2 mg) was added a solution of bis-diazolactam 13 (30 mg, 0.1
mmol) in dichloromethane (1.0 mL) via a syringe pump over 3 h at rt. The resulting yellow
solution was concentrated under reduced pressure and purified by flash column chromate-
graphy to give the titled compound 17 (56%) as a yellow gum; IR (neat) 3126, 2964, 2873,
2132, 1727, 1652, 1608, and 1462 cm–1; 1H-NMR (400MHz, CDCl3) δ 0.98 (t, J = 7.4 Hz,
3H), 1.29 (t, J= 7.2 Hz, 3H), 1.61 (sextet, J = 7.4 Hz, 2H), 2.54 (t, J= 7.3 Hz, 2H), 4.34–4.21
(m, 2H), 6.43 (s, 1H), 6.88 (d, J= 7.5 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.8 Hz,
1H), and 7.69 (d, J = 8.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ 13.9, 14.5, 20.6, 26.1,
34.4, 62.0, 72.2, 92.3, 114.2, 114.5, 119.8, 124.6, 127.3, 131.4, 138.9, 160.6, 160.9, and
177.1; HRMS calcd for [C18H17N3O4+Na+]: 362.1111; found; 362.1112.
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1-(Ethyl diazomalonyl)-3-(5-hexen-2-one-1-yl)indolin-2-one (18). A sample of 2-
5
6
27
trimethylsiloxy-1,5-hexadiene (46 mg, 0.3 mmol), benzene (1.0 mL), and 0.3 mg of
7
8
9
Rh2(OPiv)4 was heated to reflux and then a solution of 13 (30 mg, 0.10 mmol) in benzene
(1.0 mL) was added over a 1h period via syringe at 80oC. The solution was concentrated
under reduced pressure and purified by flash column chromatography to give 19 mg (57 %)
of the titled compound 18 as a pale yellow oil: IR (film) 3079, 2981, 2909, 2141, 1718, 1661,
1608, 1481, and 1465 cm–1; 1H-NMR (400 MHz, CDCl3) δ 1.31 (t, J= 7.2 Hz, 1H), 1.31 (t,
J= 7.2 Hz, 1H), 2.37–2.30 (m, 2H), 2.59–2.53 (m, 2H), 3.01 (dd, J= 18.3, 7.7 Hz, 1H), 3.24
10
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45
46
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(dd, J= 18.3, 3.7 Hz, 1H), 4.03 (dd, J= 7.6, 3.5 Hz, 1H), 4.29 (ABX3, 2H, ΔδAB = 0.02, JAB
=
10.5Hz, JAX = JBX = 7.4 Hz), 5.05–4.96 (m, 2H), 5.77 (ddt, J = 16.8, 10.6, 6.6 Hz, 1H), 7.14
(ABX, 2H, ΔδAB = 0.06, JAB = 7.2 Hz, JAX = 0, JBX = 7.4 Hz), 7.29 (t, J= 7.6 Hz, 1H), and
7.61 (d, J= 8.1 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ 14.5, 27.8, 41.7, 41.9, 43.9, 62.2,
72.6, 114.1, 115.9, 124.0, 125.0, 128.2, 128.6, 136.8, 140.1, 160.2, 160.7, 176.6, and 206.5;
MS calcd for [C19H19N3O5+H+]: 370.1403; found; 370.1407.
1-(Ethyl diazomalonyl)-3-((2Z)-2-butenalidene)indolin-2-one (20) was prepared according
to the general procedure described above and was obtained as a thick oil in 87 % yield; IR
(film) 3057, 2982, 2854, 2138, 1724, 1667, 1598, and 1462 cm–1; 1H-NMR (400 MHz,
CDCl3) δ 1.29 (t, J= 7.1 Hz, 3H), 4.29 (q, J = 7.1 Hz, 2H), 6.34 (dd, J= 11.1, 8.1 Hz, 1H),
7.22 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.8 Hz,
1H), 7.79 (dd, J = 13.1, 11.2 Hz, 1H), 8.09 (d, J= 13.3 Hz, 1H), and 10.46 (d, J= 8.0 Hz, 1H);
13C-NMR (100 MHz, CDCl3) δ 14.5, 62.3, 72.8, 114.8, 121.9, 124.9, 125.2, 127.9, 130.7,
131.6, 135.1, 138.1, 140.9, 160.3, 160.5, 166.2, and 189.9; HRMS calcd for
[C17H13N3O5+H+]: 340.0928; found: 340.0929.
1-(Ethyl 2-diazomalonyl)-3-(4-methoxyphenyl)indolin-2-one (21). To a mixture
containing a catalytic amount (0.3 mg) of Rh2(OPiv)4, and anisole (1.0 mL) was added a
solution of bis-diazolactam 13 (30 mg, 0.10 mmol) in anisole (1.0 mL) over 1 h via a syringe
pump. The solution was concentrated under reduced pressure to give a thick oil which was
purified by flash column chromatography to afford 29 mg (76%) of 21 as a pale yellow gum;
IR (film) 2981, 2837, 2139, 1754, 1725, 1652, 1608, and 1511 cm–1; 1H-NMR (400 MHz,
CDCl3) δ 1.17 (t, 3H, J = 7.1Hz), 3.78 (s, 3H), 4.16 (ABX3, 2H, ΔδAB = 0.06, JAB = 10.7 Hz,
JAX = JBX = 7.1Hz), 4.73 (s, 1H), 6.84–6.89 (m, 4H), 7.09–7.37 (m, 1H), and 7.67 (d, 1H, J =
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8.0 Hz); 13C-NMR (100 MHz, CDCl3) δ 14.4, 52.0, 55.5, 62.2, 114.3, 114.6, 125.3, 125.4,
128.0, 128.6, 128.8, 130.0, 140.2, 159.6, 160.6, 160.7, and 175.0; HRMS calcd for
[C20H17N3O5+H+]: 380.1241; found: 380.1240.
1-(Ethyl 2-diazomalonyl)-3-(indole-3-yl)indolin-2-one (22) was prepared in a similar
manner (39 mg, 96%) and obtained as a white solid, mp 70-71°C; IR (KBr) 3053, 2981,
2137, 1725, 1606, and 1478 cm–1; 1H-NMR (600 MHz, CDCl3) δ 1.16 (t, 3H, J= 7.1Hz), 3.75
(s, 3H), 4.12 (ABX3, 2H, ΔδAB = 0.03, JAB = 10.7 Hz, JAX = JBX = 7.1 Hz), 5.08 (s, 1H), 6.99
(s, 1H), 7.04 (t, 1H, J= 7.5 Hz), 7.13 (t, 1H, J= 7.5 Hz), 7.19–7.25 (m, 2H), 7.26–7.31 (m,
2H), 7.35 (t, 1H, J = 7.8 Hz), and 7.73 (d, 1H, J = 8.2 Hz); 13C-NMR (150 MHz, CDCl3) δ
14.3, 33.1, 45.1, 62.1, 108.8, 109.7, 114.3, 119.5, 119.8, 122.4, 125.2, 126.9, 128.3, 128.6,
128.7, 137.5, 140.0, 160.7, 160.8, and 175.2; HRMS calcd for [C22H18N4O4+H+]: 403.1401;
found: 403.1404.
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1-(Ethyl 2-diazomalonyl)-3-(N-allylpyrrole-2-yl)indolin-2-one (23) and 1-(Ethyl 2-
diazomalonyl)-3-(N-allylpyrrole-3-yl)indolin-2-one (24). A mixture of N-allylpyrrole (13
mg, 0.12 mmol), benzene (1.0 mL), and a catalytic amount (0.5 mg) of Rh2(OPiv)4 was
heated to reflux and then a solution of 13 (30 mg, 0.10 mmol) in benzene (1.0 mL) was
added via a syringe pump. The solution was subjected to flash column chromatography to
give 18 mg (47%) of 23, followed by 2.5 mg (7%) of 24 as clear oils; Compound 23:
IR(neat) 2981, 2138, 1752, 1726, 1699, 1607, 1480, and 1463 cm–1; 1H-NMR (400 MHz,
CDCl3) δ 1.17 (t, 3H, J = 7.1 Hz), 4.15 (ABX3, 2H, ΔδAB = 0.08, JAB = 10.7 Hz, JAX = JBX
=
7.1 Hz), 4.52 (d, 1H, J= 16.6 Hz), 4.76 (dd, 1H, J= 16.6, 5.6 Hz), 4.92 (s, 1H), 4.99 (d, 1H, J
= 17.3 Hz), 5.18 (d, 1H, J = 10.2 Hz), 5.91 (s, 1H), 5.91–6.02 (m, 1H), 6.08 (t, 1H, J = 3.2
Hz), 6.69–6.70 (m, 1H), 7.19 (t, 1H, J = 7.5 Hz), 7.27 (d, 1H, J = 7.5 Hz), 7.36 (t, 1H, J= 7.9
Hz), and 7.65 (d, 1H, J = 8.1 Hz); 13C-NMR (100 MHz, CDCl3) δ 14.4, 45.1, 50.1, 62.3,
107.8, 109.5, 114.2, 117.1, 123.1, 125.2, 125.5 125.6, 127.1, 129.0, 134.6, 140.1, 160.6, and
160.8, 173.6
Compound 24: IR (film) 2982, 2924, 2140, 1756, 1729, 1656, 1607, 1479, and 1464
cm–1; 1H-NMR (600 MHz, CDCl3) δ 1.22 (t, 3H, J = 7.1Hz), 4.22 (ABX3, 2H, ΔδAB = 0.05,
JAB = 10.8 Hz, JAX = JBX = 7.1 Hz), 4.42 (d, 2H, J = 5.9 Hz), 4.75 (s, 1H), 5.14 (d, 1H, J =
17.0 Hz), 5.19 (d, 1H, J = 10.2 Hz), 5.91–5.98 (m, 1H), 6.07–6.08 (m, 1H), 6.58–6.59 (m,
1H), 6.60–6.62 (m, 1H), 7.18 (t, 1H, J = 7.6 Hz), 7.30–7.34 (m, 1H), and 7.66 (d, 1H, J= 8.0
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Hz); 13C-NMR (100 MHz, CDCl3) δ 14.4, 25.9, 52.5, 62.2, 108.3, 114.2, 117.5, 118.1, 119.8,
121.6, 125.0, 125.2, 128.4, 129.1, 134.2, 140.0, 160.7, 160.8, and 175.5.
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3-(1,4-Cyclohexadien-3-yl)-1-(ethyl 2-diazomalonyl)indolin-2-one (25). To a mixture of
Rh2(OPiv)4 (1 mg, 0.002 mmol), dichloromethane (1.0 mL), and 1,4-cyclohexadiene (95 µL,
1.0 mmol) was added a solution of 13 (30 mg, 0.10 mmol) in benzene (1.0 mL) over 1h via a
syringe pump. After heating at reflux for 3h the solution was concentrated under reduced
pressure to give19 mg (54%) of the titled compound 25 as a white solid, mp 81–83°C; IR
(KBr) 3021, 2982, 2817, 2136, 1724, 1656, 1607, 1479, and 1464 cm–1; 1H-NMR (600 MHz,
CDCl3) δ 1.32 (t, 3H, J = 7.1 Hz), 2.49–2.65 (m, 2H), 3.68 (d, 1H, J = 3.5 Hz) 3.69–3.74 (m,
1H), 4.30 (ABX3, 2H, ΔδAB = 0.02, JAB = 10.8Hz, JAX = JBX = 7.1 Hz), 5.45–5.50 (m, 1H),
5.66–5.71 (m, 1H), 5.72–5.76 (m, 1H), 5.93–5.97 (m, 1H), 7.10 (td, 1H, J = 7.6, 0.8 Hz, 1H),
7.28 (t, 1H, J = 7.5 Hz,), 7.37 (d, 1H, J = 7.5 Hz), and 7.59 (d, 1H, J= 8.0 Hz); (150 MHz,
CDCl3) δ 14.5, 26.5, 38.7, 50.7, 62.2, 114.0, 123.8, 124.6, 124.7, 126.1, 127.0, 127.6, 128.1,
128.4, 140.3, 160.4, 160.6, and 175.5; HRMS calcd for [C19H17N3O4+H+]: 352.1292; found;
352.1293.
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3-Allyl-3-allylthio-1-(ethyl 2-diazomalonyl)indolin-2-one (28). A mixture of Rh2(OAc)4
(0.9 mg, 0.002 mmol), benzene (1.0 mL), and allyl sufide (14 µL, 0.1 mmol) was heated to
reflux and then a solution of 13 (30 mg, 0.10 mmol) in benzene (1.0 mL) was added via a
syringe pump. After being heated for an additional 1h the solution was concentrated under
reduced pressure and purified by flash column chromatography to give 32 mg (82%) of the
titled compound 28 as a colorless gum; IR (film) 2981, 2136, 1727, 1703, 1659, 1604, 1478,
and 1465 cm–1; 1H-NMR (600 MHz, CDCl3) δ 1.32 (t, 3H, J= 7.1Hz), 2.84 (ABX, 2H, ΔδAB
= 0.05, JAB = 13.9 Hz, JAX = 7.8 Hz, JBX = 6.6 Hz), 3.08 (dd, 1H, J= 12.9, 6.4 Hz), 3.20 (dd,
1H, J = 12.9, 8.0 Hz), 4.31 (q, 2H, J= 7.1 Hz), 4.93–4.98 (m, 2H), 5.02 (d, 1H, J = 10.0 Hz),
5.06 (d, 1H, J= 16.9 Hz), 5.53 (ddt, 1H, J = 17.1, 10.0, 7.3 Hz), 5.67 (dddd, 1H, J = 16.7,
10.0, 7.9, 6.4 Hz), 7.22 (t, 1H, J = 7.5 Hz), 7.33 (td, 1H, J = 7.8, 1.2 Hz), 7.37 (d, 1H, J = 7.5
Hz), and 7.62 (d, 1H, J = 8.1 Hz); 13C-NMR (100 MHz, CDCl3) δ 14.6, 32.8, 40.9, 55.1,
62.2, 114.6, 118.6, 120.7, 124.6, 125.4, 128.3, 129.5, 130.8, 133.2, 139.0, 159.9, 160.5, and
175.3; HRMS calcd for [C19H19N3O4S+H+]: 386.1169, found: 386.1170.
(2aS,2a1R,4R,10bS)-Ethyl 10b-allyl-5-oxo-2,2a,3,4,5,10b-hexahydro-2a1,4-epoxybenzo[b]
thieno[4,3,2-hi]indolizine-4-carboxylate (30). A mixture of Rh2(OAc)4 (0.9 mg, 0.002
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mmol), benzene (1.0 mL), allyl sufide (14 µL, 0.10 mmol) and bis-diazolactam 13 (30 mg,
0.10 mmol) was heated at reflux for 14 h. The mixture was concentrated under reduced
pressure and purified by flash column chromatography to give 28 mg (80%) of the titled
compound 30 as a white solid, mp 113–114°C; IR (KBr) 2980, 1728, 1640, 1604, 1475, and
1444 cm–1; 1H-NMR (400 MHz, CDCl3) δ 1.39 (3H, J= 7.2 Hz), 2.21 (dd, 1H, J = 12.8, 4.2
Hz), 2.51 (dd, 1H, J = 12.8, 7.2 Hz), 2.80 (ABX, 2H, ΔδAB = 0.10, JAB = 14.0 Hz, JAX = 6.7
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Hz, JBX = 7.7 Hz), 2.91–3.05 (m, 3H), 4.41 (ABX3, 2H, ΔδAB = 0.06, JAB = 10.8 Hz, JAX
=
JBX = 7.2 Hz), 5.04 (d, 1H, J= 17.1 Hz), 5.11 (d, 1H, J= 10.0 Hz), 5.90 (ddt, 1H, J= 17.1,
10.0, 7.2 Hz), 7.13 (t, 1H, J= 7.6 Hz), 7.25 (d, 1H, J = 7.6 Hz), 7.30 (t, 1H, J = 7.6 Hz), and
7.39 (d, 1H, J = 7.8 Hz); 13C-NMR (100 MHz, CDCl3) δ 14.4, 33.6, 35.9, 42.2, 54.0, 57.1,
62.7, 94.9, 113.9, 114.1, 120.2, 125.4, 126.7, 129.5, 132.8, 132.9, 138.4, 162.0, and 164.6;
HRMS calcd for [C19H19NO4S+H+]: 358.1108, found: 358.1104.
Ethyl 3-oxo-9-(1-methylindol-3-yl)-2,3-dihydrooxazolo[3,2-a]indole-2-carboxylate (31).
A mixture of 1-(ethyl 2-diazomalonyl)-3-(indole-3-yl)indolin-2-one (22) (25 mg, 0.062
mmol), benzene (1.2 mL), DMAD (23 µL, 0.19 mmol) and Rh2(OPiv)4 (0.2 mg) was heated
at reflux for 1h. The solution was allowed to cool, concentrated under reduced pressure and
purified by flash column chromatography to give 23 mg (99%) of the titled compound 31 as
a pale pink solid, mp 200-201°C; IR (KBr) 2924, 1752, 1727, 1668, 1611, 1537, and 1458
cm–1; 1H-NMR (400 MHz, CDCl3) δ 1.40 (t, 3H, J = 7.1 Hz), 3.88 (s, 1H), 4.34–4.47 (m,
2H), 5.62 (s, 1H), 7.19 (t, 1H, J = 7.2 Hz), 7.27–7.41 (m, 5H), 7.63 (d, 1H, J = 7.7 Hz), 7.89
(d, 1H, J = 7.8 Hz), and 7.92 (d, 1H, J = 8.1 Hz); 13C-NMR (100 MHz, CDCl3) δ 14.3, 33.2,
63.6, 84.7, 88.1, 104.4, 109.6, 113.6, 119.8, 120.2, 121.1, 122.4, 123.0, 125.7, 126.0, 127.0,
127.2, 135.3, 137.1, 150.8, 159.5, and 163.7; HRMS calcd for [C22H18N2O4+H+]: 375.1339,
found: 375.1336.
(5aR,5a1R,7R,13bR)-Ethyl 8-oxo-5,5a,6,7,8,13b-hexahydro-5a1,7-epoxyindolo[3,2,1-ij]-
pyrrolo[1,2-g][1,6]naphthyridine-7-carboxylate (32). A mixture containing 1-(ethyl 2-
diazomalonyl)-3-(N-allylpyrrole-2-yl)indolin-2-one (23) (18 mg, 0.048 mmol), benzene (1.0
mL) and Rh2(OAc)4 (2 mg) was heated at reflux for 12h. The mixture was allowed to cool to
rt , concentrated under reduced pressure and purified by flash column to give 13 mg (79%) of
the titled compound 32 as a white solid, mp 167-168°C; IR (KBr) 2982, 1732, 1605, 1479,
1464, and 1394 cm–1; 1H-NMR (400 MHz, CDCl3) δ 1.39 (t, 3H, J = 7.2Hz), 2.09 (dd, 1H, J
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= 13.0, 3.8 Hz), 2.64 (dd, 1H, J = 13.0, 8.0 Hz), 2.71–2.80 (m, 1H), 3.78 (t, 1H, J = 12.2 Hz),
4.21 (dd, 1H, J = 12.4, 5.3 Hz), 4.36–4.48 (m, 2H), 5.00 (s, 1H), 6.19 (t, 1H, J = 3.2 Hz),
6.39 (s, 1H), 6.62 (s, 1H), 7.18 (t, 1H, J = 7.6 Hz), 7.30 (t, 1H, J = 7.7 Hz), 7.41 (d, 1H, J =
7.8 Hz), and 7.60 (d, 1H, J = 7.6 Hz); 13C-NMR (100MHz, CDCl3) δ 14.4, 30.9, 39.3, 41.7,
47.8, 62.9, 89.9, 102.9, 106.4, 108.6, 113.8, 120.1, 124.9, 125.4, 126.6, 129.2, 132.8, 136.1,
164.9, and 165.4; HRMS calcd for [C20H18N2O4+H+]: 351.1339; found: 351.1338.
(1'S,2'R)-7-Ethyl 8,9-dimethyl 6-oxo-2'-phenyl-6,7-dihydrospiro[7,9a-epoxypyrido[1,2-
a]indole-10,1'-cyclopropane]-7,8,9-tricarboxylate (29). A mixture containing Rh2(OPiv)4
(0.3 mg), benzene (1.0 mL), styrene (35 µL, 0.30 mmol), DMAD (35 µL, 0.30 mmol), and
13 (30 mg, 0.10 mmol) was heated to reflux for 1 h. Concentration under reduced pressure
followed by flash column chromatography gave 37 mg (75%) of the titled product 29 as an
off-white solid, mp 66–68°C; IR (KBr) 2986, 2952, 2277, 1724, 1602, 1550, and 1441 cm–1;
1H-NMR (400 MHz, CDCl3) δ 1.37 (t, 3H, J = 7.1 Hz) 1.99–2.05 (m, 1H), 2.10–2.15 (m,
1H), 3.29 (dd, 1H, J = 9.4, 7.3 Hz), 3.77 (s, 3H), 3.91 (s, 3H), 4.31–4.42 (m, 2H), 6.84 (d,
1H, J = 7.7 Hz), 6.89–6.95 (m, 2H), 7.00–7.05 (m, 1H), 7.07–7.13 (m, 4H), and 7.46 (dd, 1H,
J = 7.7, 1.4 Hz); 13C-NMR (150 MHz, CDCl3) δ 14.3, 20.6, 30.3, 30.7, 52.4, 53.2, 62.0,
115.2, 123.2, 125.5, 126.16, 126.18, 126.8, 127.9, 128.0, 129.1, 130.5, 133.4, 134.7, 136.1,
139.3, 157.2, 161.5, 163.3, and 163.8; HRMS calcd for [C27H23NO8+H+]: 490.1496; found:
490.1495.
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(1'S,2'R)-7-Ethyl 9-methyl 6-oxo-2'-phenyl-6,7-dihydrospiro[7,9a-epoxypyrido[1,2a]-
indole-10,1'-cyclopropane]-7,9-dicarboxylate (33). A mixture containing a catalytic
amount of Rh2(OPiv)4 (0.3 mg), benzene (1.0 mL), styrene (13 µL, 0.11 mmol), methyl
propiolate (27 µL, 0.3 mmol) and 13 (30 mg, 0.10 mmol) was heated at reflux for 4 h. The
solution was concentrated under reduced pressure and purified by flash column
chromatography to give 23 mg (53%) of the titled compound 33 as a colorless oil; IR (neat)
2983, 2279, 1717, 1597, and 1538 cm–1; 1H-NMR (400MHz, CDCl3) δ 1.38 (t, 3H, J= 7.7
Hz), 2.03 (dd, 1H, J= 9.3, 6.0 Hz, 1H), 2.12 (t, 1H, J= 6.7 Hz), 3.32 (dd, 1H, J = 9.3, 7.3 Hz),
3.80 (s, 3H), 4.32–4.40 (m, 2H), 6.83 (dd, 1H, J= 7.7, 1.3 Hz), 6.93–6.97 (m, 2H), 7.07–7.13
(m, 4H), 7.37 (s, 1H), 7.53 (dd, 1H, J = 7.6, 1.7 Hz); 13C-NMR (100MHz, CDCl3) δ 14.5,
20.7, 30.5, 30.7, 52.0, 61.5, 116.4, 119.2, 123.1, 125.5, 125.9, 126.6, 127.8, 128.0, 128.9,
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131.3, 133.5, 134.6, 136.4, 142.5, 158.3, 162.7, and 164.1 HRMS calcd for [C25H21NO6+H+]:
432.1442, found: 432.1438.
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trans-2-(1-Buten-4-yl)-2-phenyl-1'-(ethyl diazomalonyl)spiro[cyclopropane-1,3'-
indolin]-2'-one (35) and cis-2-(1-Buten-4-yl)-2-phenyl-1'-(ethyl diazomalonyl)spiro-
[cyclopropane-1,3'-indolin]-2'-one (36). These compounds were prepared by using the
general procedure described above and purified by flash column chromatography give 174
mg (61%) of the trans isomer 35 as a colorless gum and 71 mg (23%) of the cis isomer as a
white solid. Compound 35: IR (film) 3059, 2979, 2135, 1724, 1660, 1607, and 1480 cm–1;
1H-NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J= 7.2 Hz), 1.94–2.08 (m, 3H), 2.14 (d, 1H, J=
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4.9 Hz), 2.20 (d, 1H, J = 4.9 Hz), 2.44–2.57 (m, 1H), 4.29 (ABX3, 2H, ΔδAB = 0.08, JAB
=
10.7 Hz, JAX = JBX = 7.1 Hz), 4.90–4.99 (m, 2H), 5.50 (d, 1H, J= 7.7 Hz), 5.72–5.84 (m, 1H),
6.66 (t, 1H, J= 7.7 Hz), 6.75–6.83 (m, 1H), 7.10 (t,1H, J= 7.7 Hz), 7.08–7.18 (m, 1H), 7.23–
7.30 (m, 1H), 7.44–7.37 (m, 2H), and 7.62 (d, 1H, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3)
δ 14.6, 30.8, 31.6, 31.8, 32.1, 36.8, 49.1, 62.1, 72.1, 113.2, 115.0, 121.7, 123.5, 126.7, 127.8,
128.2, 128.5, 128.7, 129.7, 131.8, 138.3, 138.7, 139.0, 160.7, 160.8, and 174.7; HRMS calcd
for [C25H23N3O4+H+]: 430.1761; found: 430.1760.
Compound 36: mp 120-121°C; IR (KBr) 3059, 2979, 2925, 2136, 1733, 1698, 1661,
1606, and 1480 cm–1; 1H-NMR (400 MHz, CDCl3) δ 1.22 (t, 3H, J = 7.1 Hz), 1.81–1.91 (m,
1H), 1.93 (d, 1H, J = 5.1 Hz), 1.95–2.10 (m, 3H), 2.48 (d, 1H, J = 5.1 Hz), 4.13–4.26 (m,
2H), 4.89–4.97 (m, 2H), 5.67–5.79 (m, 1H), 7.16–7.22 (m, 3H), 7.24–7.36 (m, 5H), and 7.70
(d, 1H, J = 8.2 Hz); 13C-NMR (100MHz, CDCl3) δ 14.5, 29.8, 31.4, 35.3, 38.2, 48.2, 61.9,
114.5, 115.5, 122.0, 124.1, 127.4, 127.5, 127.6, 128.5, 129.9, 137.8, 138.8, 140.1, 160.0,
160.6, and 172.6; HRMS calcd for [C25H23N3O4+H+]: 430.1761; found: 430.1762.
(2aS,2a1R,4R,10bS,11aR)-Ethyl 5-oxo-11a-phenyl-1,2,2a,3,4,5,11,11a-octahydro-2a1,4-
epoxycyclopropa[d]pyrido[1,2,3-lm]carbazole-4-carboxylate (37). A mixture of 2-phenyl-
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1,5-hexadiene (106 mg, 0.67 mmol), benzene (1.7 mL), a catalytic amount (0.5 mg) of
Rh2(OPiv)4 and bis-diazolactam 13 (50 mg, 0.17 mmol) was heated at reflux for 1 h. The
solution was concentrated under reduced pressure and purified by flash column
chromatography to give 54 mg (79%) of the titled compound 37 as a white solid, mp 141–
143 °C; IR (KBr) 3055, 2934, 2855, 1745, 1604, 1478, and 1460 cm–1; 1H-NMR (400 MHz,
CDCl3) δ 1.36 (t, 3H, J = 7.1 Hz), 1.26–1.39 (m, 1H), 1.67 (d, 1H, J = 6.0 Hz), 1.80–1.89 (m,
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1H), 1.95 (dd, 1H, J = 13.0, 3.7 Hz), 2.02 (d, 1H, J = 6.0 Hz), 1.99–2.09 (m, 1H), 2.24–2.32
(m, 1H), 2.38 (ddd, 1H, J = 14.5, 3.9, 2.6 Hz), 2.64 (dd, 1H, J = 13.0, 8.0 Hz), 4.38 (ABX3,
2H, ΔδAB = 0.04, JAB = 11.0 Hz, JAX = JBX = 7.1 Hz), 5.62 (d, 1H, J = 7.7 Hz), 6.67 (app t,
1H, J = 7.7 Hz), 7.20–7.30 (m, 3H), and 7.39 (d, 1H, J = 7.9 Hz); 13C-NMR (100 MHz,
CDCl3) δ 14.5, 18.5, 25.0, 31.4, 33.4, 33.9, 34.6, 40.2, 62.6, 87.2, 102.7, 112.9, 123.1, 123.8,
127.3, 128.7, 130.5, 132.4, 140.0, 141.7, 165.7, and 170.8; HRMS (EI, M+H) calcd for
[C25H23NO4+H+]: 402.1700; found: 402.1701.
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(1'S,2'S,7R,9aS)-7-Ethyl 8,9-dimethyl 2'-(but-3-en-1-yl)-6-oxo-2'-phenyl-6,7-
dihydrospiro[7,9a-epoxypyrido[1,2-a]indole-10,1'-cyclopropane]-7,8,9-tricarboxylate
(38). A mixture of cis-2-(1-buten-4-yl)-2-phenyl-1'-(ethyl diazomalonyl)spiro[cyclopropane-
1,3'-indolin]-2'-one (36) (18 mg, 0.042 mmol), benzene (0.84 mL), DMAD (52 µL, 0.42
mmol) and Rh2(OPiv)4 (0.1 mg) was heated at 50°C for 3 h. The solution was allowed to
cool, concentrated under reduced pressure and purified by flash column chromatography to
give 14 mg (50%) of the titled compound 38 as a colorless oil; IR (film) 2951, 2261, 1722,
1603, 1547, and 1440 cm–1; 1H-NMR (600 MHz, CDCl3) δ 0.92–0.99 (m, 1H), 1.31 (t, 3H, J
= 7.1 Hz), 1.68 (d, 1H, J = 6.2 Hz), 1.83–1.94 (m, 2H), 2.47–2.55 (m, 2H), 3.76 (s, 3H), 3.77
(s, 3H), 4.19–4.30 (m, 2H), 4.77–4.82 (m, 2H), 5.57–5.65 (m, 1H), 7.08–7.15 (m, 2H), 7.16–
7.26 (m, 4H), 7.41 (d, 2H, J = 7.7 Hz), and 7.77 (d, 1H, J= 7.5 Hz); 13C-NMR (150 MHz,
CDCl3, 50°C) δ 14.3, 25.3, 31.6, 33.5, 29.8, 52.2, 52.9, 61.6, 114.9, 116.4, 124.4, 125.5,
126.2, 127.1, 127.2, 128.2, 129.2, 129.5, 132.9, 133.3, 134.5, 138.4,139.4,157.0, 161.6, and
163.6; HRMS calcd for [C31H29NO8+Na+]: 566.1785; found: 566.1790.
(4aS,6R)-Ethyl 6-hydroxy-7-oxo-2-phenyl-1,4,4a,5,6,7-hexahydrobenzo[b]cyclohepta-
[hi]indolizine-6-carboxylate (39). To a solution of compound 37 (54 mg, 0.13 mmol) in
benzene (2.7 mL) was added TsOH·H2O (2.5 mg, 0.013 mmol). The solution was allowed to
stir at rt for 1 h and then quenched by the addition of a saturated aqueous sodium
bicarbonate. The aqueous layer was extracted with dichloromethane and the combined
extracts were washed with water then brine, dried over anhydrous magnesium sulfate,
filtered, and concentrated under reduced pressure. Purification by flash column
chromatography gave 45 mg (74%) of the titled compound 39 as a white solid; mp 66–68°C;
IR (KBr) 3550–3300, 2928, 2853, 1739, 1694, 1621, 1460, and 1383 cm–1; 1H-NMR (400
MHz, CDCl3) δ 1.24–1.29 (m, 4H), 2.15 (t, 1H, J = 13.5 Hz), 2.46–2.59 (m, 2H), 2.66–2.76
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(m, 1H), 3.25–3.36 (m, 1H), 3.95 (ABq, 2H, ΔδAB = 0.10, JAB = 19.0 Hz), 4.22–4.32 (m, 2H),
4.41 (s, 1H), 6.23–6.29 (m, 1H), 7.22–7.44 (m, 7H), 7.47–7.54 (m, 1H), and 8.40–8.48 (m,
1H); 13C-NMR (100 MHz, CDCl3) δ 14.3, 27.9, 31.3, 32.8, 39.3, 63.0, 76.5, 114.8, 116.7,
118.1, 124.9, 125.3, 126.3, 127.4, 128.7, 131.2, 134.1, 136.8, 141.9, 143.8, 168.0, and 170.4;
HRMS calcd for [C25H23NO4+Na+]: 424.1519; found: 424.1518.
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(2R,41R,8bS,9aS,13bR)-Ethyl 3-oxo-1,2,3,9,9a,13b-hexahydro-2,41-epoxybenzo[b]cyclo-
propa[d]pyrido[1,2,3-lm]carbazole-2-carboxylate (40). This compound was prepared
using the standard Rh(II)-catalyzed procedure and was purified by flash column
chromatography to give 27 mg (41%) of 40 as a white solid, mp 94-95°C; IR (KBr) 2983,
2254, 1732, 1607, 1485, and 1411 cm–1; 1H-NMR (600 MHz, CDCl3) δ 1.36 ( t, 3H, J = 7.1
Hz), 1.60–1.67 (m, 2H), 2.61 (dd, 1H, J= 12.7, 4.7 Hz), 2.73 (dd, 1H, J= 8.9, 6.0 Hz), 2.99
(dd, 1H, J = 12.7, 8.5 Hz), 3.58 (dd, 1H, J = 8.2, 4.8 Hz), 4.38 (ABX3, 2H, ΔδAB = 0.03, JAB
= 10.7 Hz, JAX = JBX = 7.1 Hz), 6.93 (d, 1H, J = 7.6 Hz), 7.10–7.14 (m, 2H), 7.21–7.30 (m,
3H), 7.43–7.46 (m, 1H), and 7.48 (d, 1H, J = 7.9 Hz); 13C-NMR (150 MHz, CDCl3) δ 14.4,
23.0, 24.5, 26.5, 34.2, 43.9, 62.7, 89.9, 102.9, 113.6, 120.5, 125.1, 127.4, 127.5, 128.3, 130.0,
134.8, 135.1, 135.4, 137.0, 165.2, and 166.7; HRMS calcd for [C23H19NO4+H+]: 374.1387;
found: 374.1390.
(2aR,2a1R,4R,10bS)-Ethyl 5-oxo-2,2a,3,4,5,10b-hexahydro-2a1,4-epoxybenzo[b]furo-
[4,3,2-hi]indolizine-4-carboxylate (41). This compound was prepared using the standard
procedure and after purification of the reaction mixture by flash column chromatography
gave 70 mg (68%) of 41 as a pale yellow oil; IR (film) 2984, 2871, 1731, 1607, 1468, and
1411 cm–1; 1H-NMR (400 MHz, CDCl3) δ 1.39 (t, 3H, J = 7.2 Hz), 2.27 (dd, 1H, J = 12.6,
5.8 Hz), 2.55 (dd, 1H, J = 12.6, 8.2 Hz, 1H), 2.61–2.71 (m, 1H), 3.67 (dd, 1H, J= 11.6, 8.3
Hz), 3.67 (dd, 1H, J = 11.6, 8.3 Hz, 1H), 4.18 (t, 1H, J = 7.7 Hz), 4.42 (q, 2H, J = 7.2 Hz),
5.56 (s, 1H), 7.19 (td, 1H, J = 1.8 Hz), 7.37–7.44 (m, 2H), and 7.49 (d, 1H, J = 7.6 Hz); 13C-
NMR (100 MHz, CDCl3) δ 14.4, 31.5, 50.4, 62.9, 71.7, 74.5, 97.3, 111.8, 114.7, 125.6,
128.1, 131.0, 132.2, 135.5, 161.7, and 164.4; HRMS calcd for [C16H15NO5+H+]: 302.1023;
found: 302.1022.
(2aR,2a1R,4R,10bS)-ethyl-5-oxo-1-phenyl-2,2a,3,4,5,10b-hexahydro-1H-2a1,4-
epoxybenzo[b]pyrrolo[4,3,2-hi]indolizine-4-carboxylate (42). A catalytic amount (0.6
mg) of Rh2(OPiv)4, benzene (1.0 mL), and N-allylaniline (13 mg, 0.10 mmol), were
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added sequentially to a 10 mL flask with a sidearm, which was stoppered with a septum,
equipped with a condenser. The resulting solution was heated at reflux, and a solution of
bis-diazo compound 1 (30 mg, 0.10 mmol) in benzene (1.0 mL) was added through the
sidearm over a 1h period using a syringe pump. Stirring was continued at this
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temperature for an additional 3 h and the solution was then concentrated under reduced
pressure. Purification by flash column chromatography gave 27 mg (69%) of the titled
compound 42 as an off-white solid, mp 196-198°C; IR (film) 2982, 2845, 1728, 1602,
1502, and 1466 cm-1; 1H-NMR (600 MHz, CDCl3) δ 1.40 (t, 3H, J = 7.2 Hz), 2.36 (dd,
1H, J = 12.7 and 5.5 Hz), 2.61 (dd, 1H, J = 12.7 and 8.2 Hz), 2.80-2.86 (m, 1H), 3.09
(dd, 1H, J = 11.1 and 9.0 Hz), 3.97 (t, 1H, J = 8.1 Hz), 4.42 (q, 2H, J= 7.2 Hz), 6.85-6.92
(m, 3H), 7.15 (t, 1H, J = 7.6 Hz), 7.34 (t, 2H, J = 7.7 Hz), 7.34 (t, 1H, J = 7.8 Hz), and
7.63 (d, 1H, J = 7.7 Hz); 13C-NMR (150 MHz, CDCl3) δ 14.4, 33.0, 46.2, 53.0, 60.2,
62.8, 96.2, 108.8, 113.1, 114.7, 118.7, 125.7, 127.9, 129.9, 130.4, 134.6, 135.3, 148.1,
161.8, and 164.5; HRMS calcd for [C22H20N2O4+H+]: 377.1496; found: 377.1501.
(1R,5aR,5a1R,7R,13bS)-7-Ethyl 1-methyl 8-oxo-1,2,3,5,5a,6,7,8-octahydro-5a1,7-epoxy-
benzo[b]pyrrolizino[2,1-hi]indolizine-1,7-dicarboxylate (43) and (1S,5aR,5a1R,7R,13bS)-
7-ethyl 1-methyl 8-oxo-1,2,3,5,5a,6,7,8-octahydro-5a1,7-epoxybenzo[b]-pyrrolizino[2,1-
hi]indolizine-1,7-dicarboxylate (44). A mixture of methyl N-allylazetidine-2-carboxylate
(39 mg, 0.25 mmol), benzene (2.5 mL), and Rh2(OAc)4 was heated to reflux, and a solution
of 13 (75 mg, 0.25 mmol) in benzene (2.5 mL) was added over 1h via a syringe pump, and
heating was continued for an additional 3h. The brown solution was concentrated under
reduced pressure and purified by flash column chromatography to give 43 mg (43%) of 43
and 21 mg (20%) of 44.
Compound 43 was obtained as a yellow oil from the above reaction; IR (film) 2950,
1729, 1605, 1469, and 1410 cm–1; 1H-NMR (600 MHz, CDCl3) δ 1.41 (t, 3H, J= 7.1Hz),
2.27–2.35 (m, 2H), 2.49–2.54 (m, 2H), 2.60–2.67 (m, 1H), 2.70–2.77 (m, 1H), 2.89 (dt, 1H, J
= 10.9, 6.8 Hz), 3.20 (s, 3H), 3.43 (dd, 1H, J = 8.1, 6.7 Hz), 3.56 (t, 1H, J = 7.6 Hz), 3.53 (dt,
1H, J = 10.9, 6.3 Hz), 4.43 (q, 2H, J = 7.1 Hz), 7.11 (t, 1H, J = 7.7 Hz), 7.27–7.32 (m, 2H),
and 7.38 (d, 1H, J = 7.7 Hz); 13C-NMR (100MHz, CDCl3) δ 14.4, 30.5, 33.7, 46.6, 49.9,
51.8, 53.8, 59.0, 62.7, 74.5, 95.9, 108.6, 114.1, 125.5, 126.3, 130.1, 134.4, 136.8, 161.8,
164.7, and 171.9; HRMS calcd for [C21H22N2O6+H+]: 399.1551; found: 399.1554.
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Compound 44 was also obtained (21 mg, 20%) from the above reaction as an off-white
solid; mp 180–182°C; IR (KBr) 2950, 1722, 1606, 1472, and 1411 cm–1; 1H-NMR (600
MHz, CDCl3) δ 1.35 (t, 3H, J= 7.2 Hz), 2.18–2.26 (m, 2H), 2.34–2.47 (m, 2H), 2.55–2.63
(m, 2H), 3.15 (dd, 1H, J= 12.4, 6.7 Hz), 3.21–3.27 (m, 2H), 3.36 (dd, 1H, J= 6.0, 3.9 Hz),
3.62 (s, 3H), 4.36 (ABX3, 2H, ΔδAB = 0.07, JAB = 10.8 Hz, JAB = JBX = 7.2 Hz), 7.21 (t, 1H,
7.7 Hz), 7.35 (t, 1H, J= 8.0 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.42 (d, 1H, J = 7.8 Hz); 13C-NMR
(100MHz, CDCl3) δ 14.4, 30.5, 33.7, 46.6, 49.9, 51.8, 53.8, 59.0, 63.0, 74.5, 95.9, 108.6,
114.1, 125.5, 126.3, 130.1, 134.4, 136.8, 161.8, 164.7, and 171.9; HRMS calcd for
[C21H22N2O6+H+]: 399.1551; found: 399.1553.
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3-Diazo-1-(ethyl diazomalonyl)-2-piperidone (45). A sample of 3-diazo-2-piperidone
(300 mg, 2.40 mmol) was dissolved in 12 mL dry THF. The solution was cooled in an
ice/water bath, and 192 mg (4.8 mmol) of sodium hydride (60 % dispersion in mineral oil)
was added and the resulting suspension was allowed to stir for 10 min. Ethyl diazomalonyl
chloride1 (640 mg, 3.6 mmol) was added via syringe, and the mixture was allowed to stir for
30 min at rt. Water was added and the aqueous layer was extracted with ethyl acetate. The
combined extracts were washed with water then brine, dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. Flash column chromatography of the
resulting residue gave 509 mg (80 %) of the titled compound 45 as a bright yellow solid, mp
60–61°C; IR (KBr) 2981, 2127, 2085, 1723, 1698, and 1637 cm–1; 1H-NMR (400 MHz,
CDCl3) δ 1.28 (t, J = 7.0 Hz, 3H), 2.02–1.94 (m, 2H), 2.80 (t, J = 6.7 Hz, 2H), 3.70–3.64 (m,
2H), and 4.24 (q, J = 7.0 Hz, 2H); 13C-NMR (100MHz, CDCl3) δ 14.4, 21.2, 22.0, 44.9, 58.1,
61.8, 72.3, 161.4, 163.9, 166.0; HRMS calcd for [C10H11N5O4+H+]: 266.0884; found
266.0885.
3-(3-buten-1-oxy)-1-(ethyl 2-diazomalonyl)-2-piperidone (46). A mixture of Rh2(OPiv)4
(0.2 mg), dichloromethane (0.75 mL), 3-buten-1-ol (6.5 µL, 0.075 mmol) and 20 mg (0.075
mmol) of 45 was stirred for 1h at rt . The mixture was concentrated under reduced pressure
and purified by flash column chromatography to give 12 mg (52%) of the titled compound 46
as a pale yellow oil; IR (neat) 2956, 2131, 1715, and 1651 cm–1; 1H-NMR (400 MHz, CDCl3)
δ 1.25 (t, 3H, J = 7.1 Hz), 1.81–2.04 (m, 3H), 2.17–2.25 (m, 1H), 2.36 (q, 2H, J= 6.9 Hz),
3.49–3.58 (m, 2H), 3.68–3.76 (m, 1H), 3.92 (dt, 1H, J = 9.3, 6.8 Hz), 4.06 (dd, 1H, J = 10.2,
6.2 Hz), 4.13–4.74 (m, 2H), 5.01 (d, 1H, J = 10.2 Hz), 5.08 (dq, 1H, J= 17.1, 1.6 Hz), and
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5.82 (ddt, 1H, J = 17.1, 10.2, 6.7 Hz); 13C-NMR (100MHz, CDCl3) δ 14.5, 21.3, 29.7, 34.5,
46.7, 61.7, 70.9 72.0, 77.8, 116.6, 135.3, 161.1, 165.5, and 174.9.
(3aS,3a1R,5R,10aS)-ethyl 6-oxodecahydro-3a1,5-epoxypyrano[2,3,4-ij]quinolizine-5-
carboxylate (47). A sample of the above diazo-2-piperidone 46 (23 mg, 0.074 mmol),
benzene (1.5 mL), and Rh2(OAc)4 (0.3 mg) was heated at reflux for 1h. The solution was
allowed to cool to rt and then concentrated under reduced pressure. Recrystallization of the
residue from ethyl acetate and hexane provide 19 mg (89%) of the titled compound 47 as a
white solid, mp 149–150°C; IR (KBr) 2951, 2872, 1747, 1716, and 1097 cm–1; 1H-NMR
(400 MHz, CDCl3) δ 1.35 (t, 3H, J = 7.1 Hz), 1.58–1.77 (m, 2H), 1.79–2.00 (m, 5H), 2.24–
2.33 (m, 2H), 2.65 (td, 1H, J= 13.0, 3.4 Hz), 3.63–3.73 (m, 2H), 3.77 (dd, 1H, J= 13.4, 4.6
Hz), 4.26 (dd, 1H, J= 11.0, 6.6 Hz), and 4.30–4.43 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ
14.4, 22.1, 24.9, 31.9, 35.9, 36.1, 38.7, 59.9, 62.5, 70.5, 86.1, 91.7, 165.8, and 169.8; HRMS
calcd for [C14H19NO5+H+]: 282.1336; found: 282.1335.
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Acknowledgments. We greatly appreciate financial support provided by the National
Science Foundation (CHE-1057350), the Camille and Henry Dreyfus foundation (SI-14-
008) and the Emory Emeritus foundation for an Alfred B. Heilbrun Jr. award.
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Supporting Information Available: H and C-NMR data of various key compounds.
This material is available free of charge via the Internet at http://pubs.acs.org.
Crystallographic information for 37 (CIF)
Crystallographic information for 44 (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: chemap@emory.edu
E-mail: sara.bonderoff@gilead.com
Notes:
The authors declare no competing financial interest.
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Saxton, J. E., Ed.; Wiley: Chichester, 1994, Chapter 1. (c) Toyota, M. Ihara, M.
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