Intramolecular cycloaddition reactions of furo[3,4- b ]indoles for alkaloid synthesis

Article abstract of DOI:10.1021/jo500331j

Model studies dealing with the Cu(II)- or Rh(II)-catalyzed carbenoid cyclization/cycloaddition cascade of several α-diazo indolo amido esters have been carried out as an approach to the alkaloid scandine. The Cu(II)-catalyzed reaction of an α-diazo indolo diester that contains a tethered oxa-pentenyl side chain was found to give rise to a reactive benzo[c]furan which undergoes a subsequent [4 + 2]-cycloaddition across the tethered π-bond. The reaction proceeds by the initial generation of a copper carbenoid intermediate which cyclizes onto the adjacent carbonyl group to give a reactive benzo[c]furan which in certain cases can be isolated. Disappointingly, the analogous reaction with the related amido indolo ester failed to take place, even when the tethered π-bond contained an electron-withdrawing carbomethoxy group. It would seem that the geometric requirements for the intramolecular cycloaddition of the furo[3,4-b]indole system with the tethered π-bond imposes distinct restrictions upon the bond angles of the reacting centers to prevent the cycloaddition reaction from occurring. However, the incorporation of another carbonyl group on the nitrogen atom of the tethered alkenyl diazo amido indolo ester seemingly provides better orbital overlap between the reacting π-systems and allows the desired cycloaddition reaction to occur.

Full text of DOI:10.1021/jo500331j

Article
pubs.acs.org/joc
Intramolecular Cycloaddition Reactions of Furo[3,4‑b]indoles for
Alkaloid Synthesis
Albert Padwa,*,† Yan Zou,† Bo Cheng,† Hao Li,† Nadale Downer-Riley,‡ and Christopher S. Straub†
†Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States
‡Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica
S
* Supporting Information
ABSTRACT: Model studies dealing with the Cu(II)- or Rh(II)-catalyzed carbenoid cyclization/cycloaddition cascade of several
α-diazo indolo amido esters have been carried out as an approach to the alkaloid scandine. The Cu(II)-catalyzed reaction of an
α-diazo indolo diester that contains a tethered oxa-pentenyl side chain was found to give rise to a reactive benzo[c]furan which
undergoes a subsequent [4 + 2]-cycloaddition across the tethered π-bond. The reaction proceeds by the initial generation of a
copper carbenoid intermediate which cyclizes onto the adjacent carbonyl group to give a reactive benzo[c]furan which in certain
cases can be isolated. Disappointingly, the analogous reaction with the related amido indolo ester failed to take place, even when
the tethered π-bond contained an electron-withdrawing carbomethoxy group. It would seem that the geometric requirements for
the intramolecular cycloaddition of the furo[3,4-b]indole system with the tethered π-bond imposes distinct restrictions upon the
bond angles of the reacting centers to prevent the cycloaddition reaction from occurring. However, the incorporation of another
carbonyl group on the nitrogen atom of the tethered alkenyl diazo amido indolo ester seemingly provides better orbital overlap
between the reacting π-systems and allows the desired cycloaddition reaction to occur.
of the aspidosperma alkaloid dehydrotabersonine (3).12,13 Based
on this biotransformation, we designed a total synthesis toward
scandine (1) from diol 2 as outlined in Scheme 2. It is proposed
that diol 2 could be prepared from the pentacyclic imine 4 by a
reductive opening of its oxabicyclic ring followed by a hydro-
xylation reaction. An intramolecular metal-catalyzed carbenoid
cyclization/cycloaddition reaction of pentacycle 5 should give
INTRODUCTION
■
Nitrogen-containing natural products are abundant in nature and
exhibit diverse and important biological properties.1 Accordingly,
novel strategies for the stereoselective synthesis of azapolycyclic
systems such the Melodinus alkaloids2−4 continue to receive
considerable attention in the field of synthetic organic chemistry.
Although methods of preparing the melodinus alkaloids vary
widely,5−10 approaches that employ cycloaddition chemistry are
particularly attractive given the rapid introduction of molecular
Scheme 2
complexity within a single chemical operation.11 Scandine (1) is
one of the key members of the Melodinus alkaloid family and
was isolated from Melodinus scandens in 1969.12 The highly
functionalized C ring of scandine with its four stereocenters
(three of which are quaternary) presents a significant synthetic
challenge (Scheme 1).5−10 The congested cyclopentane core of
scandine (1) is thought to arise by means of a rearrangement of
diol 2 by expansion of the B ring and contraction of the C ring.12
Diol 2 is believed to be the result of an oxidative rearrangement
Scheme 1
Received: February 11, 2014
Published: March 11, 2014
© 2014 American Chemical Society
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access to imine 4. Spiro[indole-3,3′-pyrrolidin]-2′-one 6 was
envisioned to arise from indole diester 7 via some standard
alkylation chemistry.
RESULTS AND DISCUSSION
■
For our initial investigations into the tandem process, we chose
to examine the metallo-catalyzed behavior of α-diazo diester 15
which contains a tethered oxapentenyl side chain (i.e., R = H).
Under a variety of experimental conditions and using several
different Rh(II) catalysts with an assortment of ligand groups,
we could not isolate any characterizable product. We were
concerned that a competing C−H insertion of the rhodium
carbenoid might be a problem with this system because of the
propensity of C−H bonds proximate to ether oxygens to insert
into rhodium carbenoids.21a Consequently, we turned our
attention to the use of copper catalysts. The critical role played
by the choice of the transition-metal catalyst used in carbene
transfer processes is well-known.21a We found that when
Cu(acacF6)2 hydrate21b was used as the catalyst (toluene reflux)
with diazoester 15, tetrahydrochromene 17 was obtained as the
sole product in 66% yield (Scheme 5). The Cu(II)-catalyzed
In 1976, Hamaguchi and Ibata reported the first example of
a related carbenoid cascade sequence (i.e., 5 to 4).14 These
workers found that 1-methoxybenzo[c]furans (i.e., 9) were
generated as transient intermediates in the Cu(acac)2-catalyzed
decomposition of methyl diazomethylbenzoate derivatives (8).
These highly reactive species were readily trapped with a variety
of added dienophiles such as N-phenylmaleimide to afford
bimolecular Diels−Alder cycloadducts of type 10 (Scheme 3).15
Scheme 3
Scheme 5
Since the original report, quite a number of examples of this
versatile reaction have been described in the literature.16,17 In
certain cases, the suspected benzo[c]furan 9 was isolated and
characterized.16b In a series of publications, Friedrichsen and co-
workers reported on the use of an intramolecular cycloaddition
variant of the Hamaguchi−Ibata reaction as a method to prepare
a number of annulated hydroquinolines.17 His team found
that the metal-catalyzed cyclization/cycloaddition reaction of
α-diazo-esters of type 11 worked smoothly with thiopheno,
isoxazolo, and indolo c-annulated furans to produce a variety
of polycyclic ring systems (Scheme 4). The tethered X group
Scheme 4
reaction (toluene reflux) of the closely related α-diazo diester 16
(R = C2H5) was also studied and found to afford dihydronaph-
thalen-1(2H)-one 18, but in only 30% yield as the only
identifiable product. When the Cu(II)-catalyzed reaction of 16
was carried out at a lower temperature (i.e., refluxing benzene),
benzo[c]furan 19 could be isolated in modest yield. Obviously,
the first step involves generation of a copper carbenoid
intermediate which, after an intramolecular cyclization with the
adjacent carbonyl group, yields the reactive benzo[c]furan 19 (R
= C2H5). Further heating of 19 in toluene at 110 °C gave 18. This
reaction can be rationalized by a [4 + 2]-cycloaddition of 19 with
the tethered alkenyl π-bond in refluxing toluene to give 21 as a
transient intermediate which reacts further with some water
derived perhaps from the Cu(acacF6) hydrate catalyst to produce
18. We assume that a related cyclization reaction occurs with 15
to also afford a benzo[c]furan intermediate analogous to 19,
corresponded to carbon, oxygen, or an amino-containing atom.
Over a period of years, our research group has also made
extensive use of the metal-catalyzed reaction of α-diazo carbonyl
compounds to generate carbonyl ylide dipoles which underwent
a smooth intramolecular [3 + 2]-cycloaddition reaction.18,19
With our continuing interest in the total synthesis of pentacyclic
alkaloids,20 we wondered whether an intermediate related to 5
(Scheme 2) might undergo the Hamaguchi−Ibata reaction and
thus be effectively employed for a scandine synthesis. With this in
mind, we set out to examine a number of related model systems
to probe whether this sequence of reactions could be employed
for an eventual synthesis of scandine.
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which then undergoes a subsequent Diels−Alder cycloaddition
to produce 20 as a transient species. Loss of the now available
bridgehead hydrogen from cycloadduct 20 leads to the formation
of 17.
Scheme 7
Having established the facility with which the cyclization/
cycloaddition cascade occurs with the simple aromatic systems of
type 15/16, we turned our attention to the indolo systems which
would eventually be needed for a scandine synthesis. Our first
efforts in this direction required the preparation of indole diester
7. We envisioned that diester 7 could be readily synthesized from
phenylhydrazine and dimethyl-1,3-acetone-dicarboxylate (22)
via a Fischer indole reaction sequence (Scheme 6) as previously
Scheme 6
Scheme 8
reported by Joule and co-workers for related 1,3-dicarbonyl
phenylhydrazine derivatives.22 We found, however, that only
pyrazol-3-one 24 was formed under the conditions described by
Joule. Thus, condensing phenylhydrazine and dimethyl-1,3-
acetonedicarboxylate (22) in the presence of a catalytic amount
of acetic acid in ether first gave the ene-hydrazone 23 which was
subsequently transformed into pyrazol-3-one 24 by treatment
with small quantities of acid. Although 23 could be isolated and
purified, when it was subjected to various acidic conditions the
desired indole diester 7 was not produced. Instead, only the
formation of 24 was observed under these conditions.
In a previous report, Yamanaka and co-workers described the
formation of various 3-acyl-substituted indoles by a palladium-
catalyzed cyclization of β-(2-halophenyl)amino substituted α,β-
unsaturated ketones and esters.23 Using this protocol, we found
that the desired indole diester 7 could be prepared in a two-
step procedure starting from the condensation of 2-iodoaniline
and dimethyl-1,3-acetone-dicarboxylate (22). The resulting
unsaturated ester 26 was subsequently cyclized to the required
indole diester 7 by a palladium catalyzed reaction. The sub-
sequent coupling of 7 with di-tert-butyl dicarbonate proceeded
uneventfully to give amide 27 in 94% yield (Scheme 7).
rhodium(II) acetate as the catalyst. Thus, exposure of 28 to
5 mol % of Rh2(OAc)4 in benzene at 80 °C in the presence of an
equivalent amount of DMAD afforded the expected Diels−Alder
adduct 29 derived from a transient furo[3,4-b]indole inter-
mediate (Scheme 8). A related sequence of reactions also
occurred when the isomeric diazoacetic ester 31 was treated
with either Cu(acacF6) or Rh2(OAc)4 and DMAD under similar
experimental conditions to give cycloadduct 32. The above
findings are also consistent with the initial formation of a
transient furo[3,4-b]indole intermediate which is subsequently
trapped with the added dienophile.
In order to establish whether an intramolecular cycloaddition
reaction will occur with the furo[3,4-b]indole system, we next
investigated the metal-catalyzed reaction of diazoacetic ester 37.
Compound 37 was easily prepared from the known indole acid
3325 as outlined in Scheme 9. Most satisfactorily, the reaction of
37 with Cu(acacF6)2 in refluxing toluene gave dihydropyrano-
carbazole 38 in 64% yield (Scheme 9). The formation of 38
The substituted diazoacetic ester 28 was then readily prepared
from 27 using the Regitz diazo-transfer methodology.24 In
contrast with the results encountered with α-diazo diesters 15
and 16, the carbenoid induced cyclization/cycloaddition reaction
also worked reasonably well using either Cu(acacF6) or
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In this case it was possible to actually isolate the initially formed
furo[3,4-b]indole 42 in 54% yield (Scheme 10).
Scheme 9
Since α-diazoacetic ester 41 underwent the desired cyclization
when exposed to the copper catalyst producing an isolable
benzo[c]furan derivative (i.e., 42), we embarked on a further
study of this type of reaction employing the closely related amide
44 as a key substrate. Our hope was to assemble the penta-
cyclic skeleton (i.e., 47) of scandine should the intramolecular
cyclization/cycloaddition cascade proceed in the desired manner
(Scheme 11). Ideally, cycloadduct 45 would be formed from
Scheme 11
Scheme 10
diazo amido ester 44 and would then be used to prepare 47 via
mesylate 46. Unfortunately, the Cu(II) reaction of 44 was quite
messy, and no signs of any cycloadduct could be detected in
the crude reaction. Similar results were obtained using several
Rh(II) catalysts or varying the nature of the solvent. Although
the conformational approach of the tethered π-bond to the
benzo[c]furan intermediate seemed quite feasible based on
Dreiding molecular models, only decomposition of the starting
material and unspecified side reactions were observed.26.
This disappointing result led us to examine whether an intra-
molecular cyclization/cycloaddition cascade would occur with
the isomeric diazo amido ester 50. To this end, indole 49 was
prepared from 48 as outlined in Scheme 12. Standard diazo
Scheme 12
is perfectly consistent with the intramolecular trapping of a
furo[3,4-b]indole intermediate with the tethered alkenyl group
on the neighboring ester group. A subsequent ring-opening of
the transient 1,4-oxido cycloadduct and elimination of water
results in the observed product.
The exact role of the metal catalyst in these reactions is
unclear, but increasing the reactivity of the metallo carbenoid
could influence the reaction in several ways. Although carbonyl
ylide formation will be more rapid when Rh(II) catalysts are
employed, we believe that the higher yields of cyclized products
from the Cu(II)-catalyzed reactions result from stabilization of
the metal-bound ylide intermediates, which in turn suppress
competitive reactions such as C−H insertions. With the
knowledge that the Cu(II)-catalyzed reaction of 37 results in
a facile intramolecular cyclization/cycloaddition cascade, we
subsquently investigated the Cu(II)-catalyzed behavior of the
isomeric diazoacetic ester 41 which represents a more
appropriate model system for an eventual synthesis of scandine.
transfer of 49 gave 50 which was then subjected to thermolysis
with the Cu(II) catalyst in refluxing toluene. This reaction,
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however, gave rise to only a very poor yield (i.e., 2%) of the
expected cyclic compound 51. Several different Rh(II) catalysts
were also employed but no improvement in the yield of 51
was seen.26.
effect an intramolecular cycloaddition across the more activated
π-bond were unsuccessful with both 53 and 56. No signs of the
expected cycloadducts 54 and 57 could be detected in the crude
reaction mixture. Only decomposition of the starting materials
and a rather messy mixture of uncharacterizable products was
observed. The negative results obtained with diazo-amido esters
53 and 56 demonstrate that the attachment of an electron-
withdrawing group on the tethered alkene is still insufficiently
beneficial in promoting the intramolecular cascade reaction of
these systems.
The lack of reactivity of the above diazoamido esters does not
seem to be related to electronic factors associated with FMO
considerations. Consequently, an alternative explanation was
sought in terms of relative strain in the transition state. The geo-
metric requirements for the intramolecular [4 + 2]-cycloaddition
of the furo[3,4-b]indole system with the tethered π-bond imposes
distinct restrictions upon the bond angles of the reacting centers.
One possibility to provide a more favorable pathway for the
cycloaddition would be to place another sp2 center on the
tethered side chain. We hoped that this would provide better
overlap between the reacting π-systems and thus facilitate the
internal cycloaddition. It should be noted that dramatic rate
enhancing effects originating from placement of a carbonyl group
on the tethered alkene for intramolecular [4 + 2]-cycloadditions
have previously been reported in the literature.29
The negative results encountered with diazo-amido esters 44
and 50 stand in marked contrast with the cascade process that
readily took place with diazoesters 15 and 16. As was pointed
out in a previous report by Friedrichsen,27 furo[3,4-b]indoles
are much less chemically reactive than the corresponding
benzo[c]furans. This reactivity difference can be explained in
terms of the thermodynamic parameters of the cycloaddition. By
using quantum chemical methods, the data obtained showed that
the [4 + 2]-cycloaddition of 4H-furo[3,4-b]indole with ethylene
or acetylene is significantly less exothermic than the analogous
reactions with benzo[c]furan. If the product from the benzo[c]-
furan system (A) is more stable relative to the furo[3,4-b]indole
product (B), the relative energy profiles are given qualitatively by
Figure 1. We believe that this energy difference in the products
Should the key cyclization/cycloaddition cascade sequence
work with an imido substituted diazo ester, we envisioned that
this methodology could be used not only for a synthesis of
scandine but also for the formation of the A−D rings of the
pentacyclic aspidosperma family of alkaloids. The preparation
of an appropriately functionalized indole 62 and its Rh(II)- or
Cu(II)-catalyzed cyclization to give 63 would form the basis for
further studies on the synthesis of aspidosperma alkaloids such as
vindoline and aspidophytine (Scheme 14). Access to the starting
Figure 1. Possible reaction profiles.
mirrors an energy differential between the transition states
thereby accounting for the reactivity difference between the two
heterocyclic systems.
Scheme 14
Since the furan ring generally shows low reactivity toward
unactivated dienophiles as a consequence of a large HOMO−
LUMO energy gap,28 we thought that we might be able to
promote the cycloaddition of the diazo-amido system by
incorporating an electron-withdrawing group on the tethered
π-bond. With this in mind, diazo-amido esters 53 and 56 were
prepared and their behavior under the Cu(II)-catalyzed condi-
tions was examined (Scheme 13). However, all of our attempts to
Scheme 13
material necessary to prepare this model system was straightfor-
ward. Indole 58 was prepared in large quantities via a four step
literature procedure.30 Conversion of 58 to amide 59 followed
by acylation with 6031 afforded imide 61 in high overall yield.
Diazo transfer using p-nitrobenzenesulfonyl azide (pNBSA)32 and
DBU as a base afforded diazoester 62 in 78% yield (Scheme 15).
Slow addition of 62 to a suspension of either Cu(acacF6)2 or
Rh2(OAc)4 in benzene at 100 °C furnished the furo[3,4-b]indole
intermediate 64, which immediately underwent cycloaddition
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a
system provides a clue for an eventual synthesis of scandine and
some related aspidosperma alkaloids. We are continuing toexplore
the scope, generality, and synthetic applications of the intra-
molecular cycloaddition of furo[3,4-b]indoles and will report
additional findings at a later date.
Scheme 15
EXPERIMENTAL SECTION
■
General Procedures. Melting points are uncorrected. Mass spectra
were determined at an ionizing voltage of 70 eV. The mass analyzer
type used for the HRMS measurenments 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 unless specified
otherwise. All solids were recrystallized from ethyl acetate/hexane for
analytical data. Yields refer to isolated, spectroscopically pure
compounds.
a
Reagents: (a) (COCl)2, MeNH2, 81%; (b) PhH, Et3N, 82%; (c)
pNBSA, DBU, 78%.
Pent-4-en-1-yl 2-(2-methoxy-2-oxoethyl)benzoate. A mixture
of hex-5-en-1-ol (260 mg, 2.3 mmol), DCC (480 mg, 2.3 mmol),
and CuCl (3 mg, 0. 03 mmol) was stirred at 0 °C under argon for 16 h.
The solution was then diluted with hexane and filtered through a layer
of Celite. The organic phase was collected and concentrated under
reduced pressure to give 0.7 g of (Z)-pent-4-en-1-yl N,N′-dicyclohex-
ylcarbamimidate as a pale yellow oil which was used directly in the next
step without any purification.
with the tethered π-bond to form the oxobridged intermediate
63. This compound could not be easily purified, but, rather,
was taken up in wet ethyl acetate and heated briefly. When the
solution was cooled, a pale yellow oil was isolated and the
structure of this compound was assigned as diol 66 based on its
spectroscopic properties and comparison to similar structures in
the literature.33 This product is the result of a nitrogen assisted
opening of the oxobridge in cycloadduct 63 followed by addition
of water to quench the iminium ion 65 (Scheme 16).
A solution of 2-(2-methoxy-2-oxoethyl)benzoic acid34 (187 mg, 0.96
mmol) and the above carbamimidate (310 mg, 1.06 mmol) in toluene
(5 mL) was heated at 80 °C in a sealed tube for 18 h. After being cooled
to rt, the mixture was filtered through a short pad of Celite with EtOAc.
The solvent was removed under reduced pressure, and the residue was
purified by silica gel chromatography to give 235 mg (93%) of the titled
compound as a colorless oil: IR (thin film) 2951, 1739, 1714, 1262,
1165, 1079 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.85 (quint, 2H, J =
7.2 Hz), 2.20 (q, 2H, J = 7.2 Hz), 3.69 (s, 3H), 4.02 (s, 2H), 4.29 (t, 2H,
J = 6.6 Hz), 5.03 (dd, 1H, J = 10.2 and 1.8 Hz), 5.07 (dd, 1H, J = 16.8 and
1.8 Hz), 5.81−5.87 (m, 1H), 7.26 (d, 1H, J = 7.8 Hz), 7.37 (td, 1H, J =
7.8 and 1.2 Hz), 7.49 (td, 1H, J = 7.8 and 1.2 Hz), 8.02 (dd, 1H, J = 7.8
and 1.2 Hz); 13C NMR (150 MHz, CDCl3) δ 27.6, 30.1, 40.4, 51.9, 64.4,
115.3, 127.4, 129.8, 130.9, 132.2, 132.3, 135.8, 137.4, 167.0, 171.9;
HRMS calcd for [C15H18O4 + H+] 263.1283, found 263.1277.
Pent-4-en-1-yl 2-(1-Diazo-2-methoxy-2-oxoethyl)benzoate
(15). To a sample of the above diester (250 mg, 0.95 mmol) in
CH3CN (5 mL) at 0 °C under argon was added DBU (0.21 mL,
1.40 mmol). After the mixture was stirred for 10 min at 0 °C, TsN3
(0.22 mL, 1.43 mmol) was added, and the solution was stirred for an
additional 16 h at rt. The mixture was quenched with a phosphate buffer
solution (10 mL, pH = 7.0) and extracted with CH2Cl2. The combined
organic phase was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
Scheme 16
to give 210 mg (76%) of the titled compound 15 as a yellow oil: IR (thin
1
film) 2092, 1705, 1435, 1292, 1246 cm− ; 1H NMR (600 MHz, CDCl3)
δ 1.85 (p, 2H, J = 6.6 Hz), 2.20 (q, 2H, J = 7.2 Hz), 3.80 (s, 3H), 4.30
(t, 2H, J = 6.6 Hz), 5.01 (d, 1H, J = 10.2 Hz), 5.07 (dd, 1H, J = 17.4 and
1.8 Hz), 5.80−5.87 (m, 1H), 7.39 (t, 1H, J = 7.8 Hz), 7.50 (d, 1H, J = 7.8
Hz), 7.55 (td, 1H, J = 7.8 and 1.2 Hz), 7.99 (d, 1H, J = 7.8 Hz); 13C
NMR (150 MHz, CDCl3) δ 27.8, 29.7, 30.1, 52.1, 64.8, 115.4, 126.0,
128.0, 129.5, 130.9, 131.1, 132.1, 137.3, 166.2, 166.5; HRMS calcd for
[C15H16N2O4 + Na+] 311.1008, found 311.1002.
Methyl 6-Hydroxy-3,4,5,6-tetrahydro-2H-benzo[h]-
chromene-6-carboxylate (17). A solution of the above compound
15 (45 mg, 0.16 mmol) in toluene (3 mL) was slowly added dropwise
to a suspension of Cu(acacF6) hydrate (15 mg, 0.03 mmol) in toluene
(3 mL) at reflux under argon. After the addition was complete, the
mixture was heated for 3 h at 110 °C, cooled to rt, and filtered through a
layer of Celite using EtOAc. The organic phase was concentrated under
reduced pressure, and the residue was purified by flash chromatography
to give 27 mg (66%) of the titled compound 17 as a colorless oil: IR
In conclusion, an intramolecular tandem cyclization/
cycloaddition reaction of an α-diazo indolo imido ester was used
to assemble a heavily functionalized azapolycyclic ring system from
easily available starting materials. The success with the model
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(thin film) 3466, 2952, 2924, 1729, 1436, 1253, 1153, 1093 cm−1; H
NMR (600 MHz, CDCl3) δ 1.94−2.02 (m, 2H), 2.11−2.21 (m, 2H),
2.58 (d, 1H, J = 16.8 Hz), 2.93 (d, 1H, J = 16.8 Hz), 3.54 (s, 1H), 3.80 (s,
3H), 4.16 (t, 2H, J = 4.8 Hz), 7.14 (d, 1H, J = 7.8 Hz), 7.21 (t, 1H, J = 7.8
Hz), 7.32 (t, 1H, J = 7.8 Hz), 7.55 (d, 1H, J = 7.8 Hz); 13C NMR (150
MHz, CDCl3) δ 22.7, 25.2, 39.2, 53.2, 66.0, 74.7, 104.0, 121.4, 124.7,
127.4, 128.7, 131.0, 134.3, 143.4, 176.1; HRMS calcd for [C15H16O4 +
H+] 261.1127, found 261.1122.
4-Methylenehexyl 2-(2-Methoxy-2-oxoethyl)benzoate. A
mixture of 4-methylene-1-hexanol (280 mg 2.45 mmol), DCC (506 mg,
2.45 mmol), and CuCl (3 mg, 0. 03 mmol) was stirred at 0 °C under argon
for 16 h. The solution was then diluted with hexane and filtered through
a layer of Celite. The organic phase was collected and concentrated
under reduced pressure to give 0.66 g of (Z)-4-methylenehexyl N,N′-
dicyclohexylcarbamimidate as a pale yellow oil which was used directly in
the next step without any purification. A solution of 2-(2-methoxy-2-
oxoethyl)benzoic acid (133 mg, 0.69 mmol) and the above imidate
(220 mg, 0.69 mmol) in toluene (3 mL) was heated at 80 °C in a sealed
tube for 18 h. After being cooled to rt, the mixture was filtered through a
short pad of Celite with EtOAc. The solvent was removed under reduced
pressure, and the residue was purified by silica gel chromatography to give
phase was collected and concentrated under reduced pressure. The
residue was purified by preparative chromatography to give 10 mg
(30%) of the titled compound 18 as a clear oil: IR (thin film) 3456, 2955,
1
1
1735, 1676, 1250, 1141 cm−1; H NMR (400 MHz, CDCl3) δ 0.89
(t, 3H, J = 7.2 Hz), 1.63−1.90 (m, 6H), 2.19 (d, 1H, J = 14.8 Hz), 2.65
(d, 1H, J = 14.8 Hz), 3.45−3.60 (m, 2H), 3.78 (s, 3H), 4.34 (s, 1H), 7.19
(d, 1H, J = 7.6 Hz), 7.46 (t, 1H, J = 7.8 Hz), 7.57 (td, 1H, J = 7.6 and 1.2
Hz), 8.03 (dd, 1H, J = 7.6 and 0.8 Hz); 13C NMR (100 MHz, CDCl3) δ
8.4, 26.5, 27.3, 32.5, 39.1, 47.1, 53.8, 62.9, 73.6, 126.7, 127.7, 129.3,
131.0, 134.0, 140.3, 176.7, 201.1; HRMS calcd for [C17H22O5 + H+]
307.1545, found 307.1542.
Compound 18 was also obtained in 30% yield by heating a sample of
isobenzofuran 19 in toluene in the presence of Cu(acacF6) hydrate at
reflux for 3 h.
(E)-Dimethyl 3-((2-Iodophenyl)amino)pent-2-enedioate (26).
A solution of 2-iodoaniline (10.95 g, 50.0 mmol), dimethyl-1,3-
acetonedicarboxylate (22) (8.7 g, 50.0 mmol), and TsOH·H2O (0.95g,
5.0 mmol) in benzene (50 mL) was heated under reflux for 3 h using a
Dean−Stark apparatus for the azeotropic removal of water. The solution
was cooled to rt, and the mixture was partitioned between EtOAc and
H2O. The aqueous phase was extracted with EtOAc, and the combined
organic phase was dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography to
give 11.8 g (63%) of the titled compound 26 as a pale yellow oil: IR (thin
film) 2949, 1738, 1660, 1610, 1579, 1256, 1159, 1047, 1016 cm−1; 1H
NMR (600 MHz, CDCl3) δ 3.19 (s, 2H), 3.59 (s, 3H), 3.70 (s, 3H), 4.86
(s, 1 H), 6.93 (t, 1H, J = 7.8 Hz), 7.18 (d, 1H, J = 7.8 Hz), 7.31 (t, 1H, J =
7.8 Hz), 7.86 (d, 1H, J = 7.8 Hz), 10.1 (s, 1H); 13C NMR (150 MHz,
CDCl3) δ 38.3, 50.6, 52.3, 88.5, 98.3, 127.2, 127.8, 128.9, 139.5, 140.5,
153.6, 168.8, 170.3; HRMS calcd for [C13H14INO4 + H+] 376.0046,
found 376.0040.
Methyl 2-(2-Methoxy-2-oxoethyl)-1H-indole-3-carboxylate
(7). A solution of the above compound 26 (3.66 g, 9.8 mmol), Et3N
(1.63 mL, 1.18 g, 11.7 mmol), and Pd(OAc)2 (0.11 g, 0.5 mmol) in
DMF (3 mL) was heated in a sealed tube at 100 °C for 3 h. The solution
was cooled to rt, and the mixture was partitioned between EtOAc and
H2O. The aqueous phase was extracted with EtOAc, and the combined
organic phase was dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography to
give 1.47 g (61%) of the titled compound 7:22 IR (thin film) 3322, 1735,
1692, 1671, 1458, 1204, 1086 cm−1; 1H NMR (600 MHz, CDCl3) δ 3.81
(s, 3H), 3.94 (s, 3H), 4.39 (s, 2H), 7.23−7.25 (m, 2H), 7.37−7.40 (m,
1H), 8.09−8.11 (m, 1H), 9.74 (s, 1H); 13C NMR (150 MHz, CDCl3) δ
32.2, 50.9, 52.4, 105.0, 111.2, 121.3, 121.8, 122.8, 126.2, 134.7, 138.7,
166.1, 171.2; HRMS calcd for [C13H13NO4 + H+] 248.0923, found
248.0919.
1-tert-Butyl 3-Methyl 2-(2-methoxy-2-oxoethyl)-1H-indole-
1,3-dicarboxylate (27). The above NH-indole 7 (200 mg, 0.81 mmol),
TEA (135 μL, 0.97 mmol), and DMAP (15 mg, 0.12 mmol) were
dissolved in 10 mL of CH3CN, and the solution was cooled to 0 °C. To
this solution was added di-tert-butyl dicarbonate (424 mg, 1.94 mmol),
and the reaction mixture was stirred at 0 °C for 1.5 h. The mixture was
quenched with 5 mL of H2O and extracted with EtOAc. The combined
organic layers were washed with brine, dried over MgSO4, and filtered.
The filtrate was concentrated under reduced pressure, and the crude
residue was subjected to silica gel chromatography to give 263 mg (94%)
of the titled compound 27 as a white solid: mp 110−111 °C; IR (film)
2952, 1738, 1704, 1586, 1566, 1477, 1455, 1435, 1370, 1357, 1315, 1282,
1253, 1198, 1171, 1144, 1118, 1012 cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.68 (s, 9H), 3.72 (s, 3H), 3.97 (s, 3H), 4.75 (s, 2H), 7.40−7.30 (m,
2H), 8.20−8.06 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 33.9, 52.3,
86.0, 112.0, 115.5,122.0 124.0, 125.1, 126.8, 135.8, 140.8, 150.1, 165.8, 170.5.
1-tert-Butyl 3-Methyl 2-(1-diazo-2-methoxy-2-oxoethyl)-1H-
indole-1,3-dicarboxylate (28). The above indole 27 (150 mg,
0.43 mmol) and TsN3 (128 mg, 0.65 mmol) were dissolved in 3 mL of
CH3CN, and the solution was cooled to 0 °C. To this solution was
added DBU (97 μL, 0.65 mmol) and the mixture was stirred at rt for
12 h. The solution was quenched with 3 mL of H2O and extracted
with EtOAc. The combined organic layers were washed with brine, dried
over MgSO4, and filtered. The filtrate was concentrated under reduced
165 mg (83%) of the titled compound as a colorless oil: IR (thin film)
1
1
2963, 1741, 1715, 1262, 1212, 1165, 1138, 1079 cm− ; H NMR (600
MHz, CDCl3) δ 1.04 (t, 3H, J = 7.5 Hz), 1.89 (p, 2H, J = 7.2 Hz), 2.05
(q, 2H, J = 7.2 Hz), 2.16 (t, 2H, J = 7.2 Hz), 3.68 (s, 3H), 4.02 (s, 2H), 4.28
(t, 2H, J = 6.6 Hz), 4.75 (d, 2H, J = 9.6 Hz), 7.25 (d, 1H, J = 7.8 Hz), 7.36
(td, 1H, J = 7.8 and 1.2 Hz), 7.47 (td, 1H, J = 7.8 and 1.2 Hz) , 8.02 (dd, 1H,
J = 7.8 and 1.8 Hz); 13C NMR (150 MHz, CDCl3) δ 12.2, 26.6, 28.6, 32.4,
40.3, 51.8, 64.6, 108.2, 127.3, 129.8, 130.8, 132.2, 132.2, 135.8, 149.9, 167.0,
171.8; HRMS calcd for [C17H22O4 + H+] 291.1596, found 291.1592.
4-Methylenehexyl 2-(1-Diazo-2-methoxy-2-oxoethyl)-
benzoate (16). To a solution of the above diester (87 mg, 0.30 mmol)
in CH3CN (3 mL) at 0 °C under argon was added DBU (0.13 mL,
0.87 mmol). After being stirred for 15 min at 0 °C, TsN3 (0.13 mL,
0.85 mmol) was added, and the mixture was stirred for 20 min at 0 °C and
then for 16 h at rt. The reaction mixture was quenched with a phosphate
buffer solution (10 mL, pH = 7.0) and extracted with CH2Cl2. The
combined organic phase was dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash chromatography
to give 67 mg (71%) of the titled compound 16 as a yellow oil: IR (thin
1
1
film) 2961, 2090, 1703, 1291, 1242, 1191 cm− ; H NMR (600 MHz,
CDCl3) δ 1.03 (t, 3H, J = 7.5 Hz), 1.89 (p, 2H, J = 7.2 Hz), 2.05 (q, 2H, J =
7.2 Hz), 2.16 (t, 2H, J = 7.8 Hz), 3.80 (s, 3H), 4.30 (t, 2H, J = 5.0 Hz), 4.75
(d, 2H, J = 11.4 Hz), 7.39 (t, 1H, J = 7.8 Hz), 7.49 (d, 1H, J = 7.8 Hz), 7.54
(t, 1H, J = 7.8 Hz), 7.99 (d, 1H, J = 7.8 Hz); 13C NMR (150 MHz, CDCl3)
δ 12.2, 26.7, 28.6, 32.4, 52.1, 65.1, 108.2, 126.0, 128.0, 129.5, 129.7, 130.9,
131.1, 132.0, 150.0, 166.2, 166.4; HRMS calcd for [C17H20N2O4 + H+]
317.1501, found 317.1497.
Methyl 3-((4-Methylenehexyl)oxy)isobenzofuran-1-carboxy-
late (19). A solution of the above diazo compound 16 (20 mg,
0.06 mmol) in toluene (2 mL) was added dropwise to a suspension of
Cu(acacF6) hydrate (6 mg, 0.012 mmol) in toluene (2 mL) at 80 °C
under argon for 1 h. After being cooled to rt, the reaction mixture was
filtered through a short silica pad with EtOAc. The organic phase was
collected and concentrated under reduced pressure. The residue was
purified by preparative chromatography to give 5 mg of the titled
compound 19 (28%) as clear oil: IR (thin film) 2960, 2924, 1735, 1705,
1286, 1205 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.04 (t, 3H, J = 7.8
Hz), 1.89 (p, 2H, J = 7.2 Hz), 2.04 (q, 2H, J = 7.2 Hz), 2.14 (q, 2H,
J = 7.8 Hz), 3.87 (s, 3H), 4.30 (t, 2H, J = 6.6 Hz), 4.74 (s, 1H), 4.77 (d,
1H, J = 0.6 Hz), 7.55 (dd, 1H, J = 7.2 and 1.2 Hz), 7.62 (td, 1H, J =
7.8 and 1.2 Hz), 7.67 (td, 1H, J = 7.8 and 1.2 Hz), 8.02 (dd, 1H, J = 7.8
and 1.2 Hz); HRMS calcd for [C17H20O4 + H+] 289.1439, found
289.1436.
Methyl 3-Ethyl-1-hydroxy-3-(3-hydroxypropyl)-4-oxo-
1,2,3,4-tetrahydronaphthalene-1-carboxylate (18). A solution
of diazo compound 16 (37 mg, 0.12 mmol) in toluene (3 mL) was added
dropwise to a suspension of Cu(acacF6) hydrate (11 mg, 0.02 mmol) in
toluene (3 mL) at reflux for 3 h. After being cooled to rt, the reaction
mixture was filtered through a short silica pad with EtOAc. The organic
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pressure, and the crude residue was subjected to silica gel chromato-
graphy to give 97 mg (60%) of the titled compound 28 as a yellow solid:
mp 92−94 °C; IR (film) 2981, 2953, 2111, 1744, 1701, 1557, 1478,
1454, 1435, 1394, 1370, 1352, 1315, 1279, 1257, 1192, 1144, 1117,
δ 1.89 (dq, 2H, J = 8.8 and 6.7 Hz), 2.30−2.19 (m, 2H), 3.71 (s, 3H),
4.20 (s, 2H), 4.37 (t, 2H, J = 6.6 Hz), 5.07−5.01 (m, 1H), 5.10 (dq, 1H,
J = 17.2 and 1.7 Hz), 5.86 (ddt, 1H, J = 16.9, 10.2, and 6.6 Hz), 7.18 (t,
1H, J = 17.2 Hz), 7.34 (t, 1H, J = 17.2 Hz), 7.40 (dq, 1H, J = 8.3 and 0.9
Hz), 7.66 (d, 1H, J = 8.0 Hz), 8.93 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 28.1, 30.3, 30.7, 52.3, 64.7, 112.1, 115.7, 115.8, 120.7, 120.9,
124.55, 125.9, 128.1, 135.9, 137.5, 162.2, 171.9.
1
1062, 1010 cm−1; H NMR (400 MHz, CDCl3) δ 1.66 (s, 9H), 3.81
(d, 3H, J = 15.6 Hz), 4.00 (s, 3H), 7.48−7.32 (m, 2H), 8.18 (brs, 2H);
13C NMR (100 MHz, CDCl3) δ 28.1, 52.1, 52.5, 85.8, 112.5, 115.3,
1-tert-Butyl-2-pent-4-enyl 3-((Methoxycarbonyl)methyl)-1H-
indole-1,2-dicarboxylate (36). A solution of the above indole 35
(200 mg, 1 equiv), DMAP (0.15 mmol, 1 equiv), and TEA (1.2 equiv) in
CH3CN (8 mL) was cooled to 0 °C. To this mixture was added t-Boc2O
(2.4 equiv), and the reaction mixture was stirred at 0 °C for 1 h. The
mixture was quenched with H2O (5 mL) and extracted with EtOAc.
The combined organic layer was washed with brine, dried over MgSO4,
and filtered. The filtrate was concentrated under reduced pressure, and
the crude residue was subjected to silica gel chromatography to give the
titled compound 36 in 86% yield as a light yellow liquid: IR (film) 2025,
1736, 1641, 1592, 1568, 1451, 1405, 1356, 1332, 1277, 1240, 1209 cm−1;
1H NMR (400 MHz, CDCl3) δ 1.26−1.18 (m, 9H), 1.45 (dd, 2H, J = 9.7
and 5.0 Hz), 1.85−1.72 (m, 2H), 3.27 (dd, 3H, J = 2.9 and 1.3 Hz), 3.51
(d, 2H, J = 2.8 Hz), 3.94 (td, 2H, J = 6.9 and 2.8 Hz), 4.61 (d, 1H, J = 10.3
Hz), 4.73−4.63 (m, 1H), 5.42 (dd, 1H, J = 17.4 and 8.6 Hz), 6.92−6.87
(m, 1H), 7.07−6.97 (m, 1H), 7.18 (d, 1H, J = 8.3 Hz), 7.66 (dd, 1H, J =
8.6 and 2.7 Hz); 13C NMR (100 MHz, CDCl3) δ 28.0, 28.1, 30.3, 30.4,
52.5, 65.2, 84.9, 115.3, 115.7, 119.3, 120.4, 123.5, 127.2, 128.5, 128.7,
136.8, 137.5, 149.4, 162.4, 170.8.
1-tert-Butyl-2-pent-4-enyl-3-((Methoxycarbonyl)-
diazomethyl)-1H-indole-1,2-dicarboxylate (37). A sample of the
above indole 36 (70 mg, 0.17 mmol) and TsN3 (52 mg, 0.26 mmol)
were dissolved in 1.1 mL of CH3CN under argon, and the reaction
mixture was cooled to 0 °C. To this mixture was added DBU (39 μL,
0.26 mmol), and the solution was stirred at 0 °C for 10 min and then at rt
for 15 h. The mixture was quenched with 2 mL of H2O and extracted
with EtOAc. The combined organic layer was washed with brine,
dried over MgSO4, and filtered. The filtrate was concentrated under
reduced pressure, and the crude residue was subjected to silica gel
chromatography to give 49 mg (66%) of the titled compound 37 as a
yellow oil: IR (film) 2979, 2102, 1735, 1563, 1450, 1395, 1356, 1328,
1224, 1151, 1110 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.65 (s, 9H),
1.91−1.83 (m, 2H), 2.25−2.16 (m, 2H), 3.83 (s, 3H), 4.37 (td, 2H, J =
6.8 and 0.9 Hz), 5.02 (ddt, 1H, J = 10.2, 2.0, and 1.2 Hz), 5.08 (dq, 1H,
J = 17.1 and 1.6 Hz), 5.83 (ddtd, 1H, J = 16.8, 10.2, 6.6, and 0.9 Hz), 7.32
(ddd, 1H, J = 8.1, 7.2, and 1.0 Hz), 7.46 (ddt, 1H, J = 8.4, 7.2, and
1.1 Hz), 7.58−7.53 (m, 1H), 8.09 (dd, 1H, J = 8.5 and 0.9 Hz); 13C
NMR (150 MHz, CDCl3) δ 27.8, 28.0, 28.1, 30.1, 52.5, 65.6, 85.4, 110.9,
115.19, 115.7, 121.4, 123.7, 127.4, 127.5, 128.4, 136.7, 137.4, 149.1, 161.9.
11-tert-Butyl 6-Methyl 3,4-Dihydropyrano[2,3-a]carbazole-
6,11(2H)-dicarboxylate (38). A 6.2 mg (0.013 mmol) sample of
copper hexafluoroacetylacetonate hydrate was suspended in 2 mL of
degassed toluene and heated to reflux. To this mixture was added a
solution of the above diazo compound 37 (27 mg, 0.063 mmol) in 2 mL
of degassed toluene over a period of 1 h, and the mixture was heated at
reflux for 45 min. After cooling to rt, the mixture was filtered through a
pad of Celite and rinsed with EtOAc. The filtrate was concentrated
under reduced pressure, and the crude residue was subjected to silica gel
chromatography to give 15 mg (64%) of the titled compound 38 as
a light yellow solid: mp 120−122 °C; IR (film) 2928, 2184, 1719, 1615,
1563, 1502, 1453, 1433, 1393, 1355, 1324, 1298, 1274, 1231, 1203,
1157, 1136, 1094, 1059, 1043, 1022, 1002 cm−1; 1H NMR (600 MHz,
CDCl3) δ 1.63 (s, 9H), 2.15 (pent, 2H, J = 5.4 Hz), 2.99 (t, 3H, J = 6.4
Hz), 4.01 (s, 3H), 4.37 (t, 2H, J = 5.4 Hz), 7.34 (dt, 1H, J = 8.2 and 1.2
Hz), 7.49 (dt, 1H, J = 8.3 and 1.3 Hz), 7.76 (d, 1H, J = 1.2 Hz), 8.08 (d,
1H, J = 8.2 Hz), 8.82 (d, 1H, J = 8.2 Hz); 13C NMR (150 MHz, CDCl3)
δ 22.4, 25.0, 28.1, 52.2, 67.0, 83.5, 113.4, 116.8, 119.4, 122.7, 124.5,
125.3, 125.9, 127.6, 128.9, 129.1, 141.0, 147.5, 150.8, 167.9; HRMS
calcd for [C22H23NO5 + H+] 382.1654, found 382.1649.
122.3, 124.2, 126.3, 126.0, 127.1, 129.0, 129.4, 137.0, 149.3, 164.4.
9-tert-Butyl 11,12,13-Trimethyl-(1R,11R)-1-methoxy-14-oxa-
9-azatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),3,5,7,12-pen-
taene-9,11,12,13-tetracarboxylate (29). A sample of the above
diazo compound 28 (31 mg, 0.083 mmol) and DMAD were taken up
in 8 mL of benzene. To this solution was added Rh2(OAc)4 (1.8 mg,
0.0042 mmol), and the reaction mixture was heated at 80 °C for 100 min.
After being cooled to rt, the mixture was concentrated under reduced
pressure and the crude residue was subjected to silica gel chromatography
to give 10 mg (25%) of the title compound 29 as a yellow solid: mp 176−
178 °C; IR (film) 2953, 1741, 1690, 1602, 1533, 1434, 1410, 1369, 1350,
1
1312, 1283, 1241, 1214, 1150, 1093, 1047, 1020 cm−1; H NMR (600
MHz, CDCl3) δ 1.67 (s, 9H), 3.86 (s, 6H), 3.89 (s, 3H), 4.07 (s, 3H),
7.38 (td, 1H, J = 7.2 and 1.2 Hz), 7.55 (td, 1H, J = 7.2 and 1.8 Hz), 8.13
(d, 1H, J = 8.4 Hz), 8.17 (d, 1H, J = 8.4 Hz); 13C NMR (100 MHz,
CDCl3) δ 27.8, 52.6, 53.9, 62.8, 72.8, 86.1, 114.1, 115.3, 123.5, 124.0,
124.9, 128.3, 130.0, 130.9, 140.4, 148.5, 159.8, 164.7, 165.7, 179.5;
HRMS calcd for [C24H25NO10 + H+] 488.1557, found 488.1556.
1-tert-Butyl 2-Methyl-3-((methoxycarbonyl)diazomethyl)-
1H-indole-1,2-dicarboxylate (31). To a solution containing
1-tert-butyl 2-methyl 3-(2-methoxy-2-oxoethyl)-1H-indole-1,2-dicar-
boxylate (30)35 (50 mg, 0.14 mmol) and 4-acetylamidobenzenesulfonyl
azide (42 mg, 0.17 mmol) in 0.5 mL of CH3CN under argon was added
DBU (30 μL, 0.20 mmol). The reaction mixture was stirred at rt for 15 h,
and then the mixture was quenched with 1 mL of H2O and extracted
with EtOAc. The combined organic layers were washed with brine, dried
over MgSO4, and filtered. The filtrate was concentrated under reduced
pressure, and the crude residue was subjected to silica gel chromato-
graphy to give 32 mg (64%) of the titled compound 31 as a yellow solid:
mp 58−60 °C; IR (film) 2981, 2953, 2100, 1733, 1562, 1435, 1394,
1354, 1318, 1272, 1226, 1151, 1107, 1068 cm−1; 1H NMR (400 MHz,
CDCl3) δ 1.63 (s, 9H), 3.83 (s, 3H), 3.95 (s, 2H), 7.32 (ddd, 1H, J = 8.1,
7.2, and 1.0 Hz), 7.46 (ddd, 1H, J = 8.5, 7.2, and 1.3 Hz), 7.55 (ddd, 1H,
J = 7.9, 1.1, and 0.6 Hz), 8.11 (dt, 1H, J = 8.5 and 0.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 28.3, 52.5, 52.9, 85.4, 111.3, 115.2, 120.9, 121.4,
123.8, 127.3, 127.6, 127.8, 136.8, 149.1, 162.4.
9-tert-Butyl 1,12,13-Trimethyl (1R,11R)-11-Methoxy-14-oxa-
9-azatetracyclo[9.2.1.02,10.03,8]tetradeca-2(10),3,5,7,12-pen-
taene-1,9,12,13-tetracarboxylate (32). The above diazo compound
31 (31 mg, 0.083 mmol) and 1.2 equiv of DMAD were dissolved in
8 mL of benzene. To this solution was added Rh2(OAc)4 (1.8 mg,
0.0042 mmol), and the mixture was heated at 80 °C for 100 min. After
being cooled to rt, the reaction mixture was concentrated under reduced
pressure, and the crude residue was subjected to silica gel chromato-
graphy to give 11 mg (27%) of the titled compound 32 as a yellow oil:
IR (film) 2952, 1925, 2850, 1736, 1676, 1604, 1541, 1433, 1371, 1317,
1222 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.68 (s, 9H), 3.81 (s, 6H),
3.86 (s, 3H), 3.98 (s, 3H), 7.52−7.34 (m, 2H), 7.73 (dd, 1H, J = 8.1 and
0.9 Hz), 8.18 (d, 1H, J = 8.1 Hz); 13C NMR (100 MHz, CDCl3) δ 27.8,
52.6, 54.0, 63.4, 86.7, 112.8, 115.9, 116.1, 122.5, 123.8, 125.3, 127.4,
138.3, 141.2, 148.9, 155.5, 164.5, 165.5, 182.9; HRMS calcd for
[C24H25NO10 + H+] 488.1557, found 488.1554.
Pent-4-enyl 3-((Methoxycarbonyl)methyl)-1H-indole-2-car-
boxylate (35). A solution of 3-((methoxycarbonyl)methyl)-1H-
indole-2-carboxylic acid (33)25 (200 mg, 0.858 mmol) and 1,3-
dicyclohexyl-2-(pent-4-enyl)isourea (34) (276 mg, 0.943 mmol) in
toluene (6.6 mL) was heated under argon at 70 °C for 16 h. The reaction
mixture was cooled to rt, filtered through a pad of Celite, and rinsed with
EtOAc. The filtrate was concentrated under reduced pressure, and the
crude residue was subjected to silica gel chromatography to give the
titled compound 35 (213 mg, 83%) as a light yellow solid: mp 55−
56 °C; IR (film) 3333, 1951, 1732, 1683, 1640, 1620, 1578, 1552, 1435,
1392, 1326, 1238, 1165, 1128, 1097 cm−1; 1H NMR (400 MHz, CDCl3)
Pent-4-enyl 2-((Methoxycarbonyl)methyl)-1H-indole-3-car-
boxylate (39). A solution of 2-(2-methoxy-2-oxoethyl)-1H-indole-3-
carboxylic acid36 (21 mg, 0.09 mmol) and (Z)-pent-4-en-1-yl N,N′-
dicyclohexylcarbamimidate (29 mg, 0.10 mmol) in toluene (1 mL) was
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heated at 80 °C in a sealed tube for 18 h. After being cooled to rt, the
reaction mixture was filtered through a short pad of Celite with EtOAc.
The solvent was removed under reduced pressure, and the residue was
purified by silica gel chromatography to give the titled compound 39
(21 mg, 78%) as a colorless oil: IR (thin film) 3323, 2852, 1736, 1689,
1668, 1457, 1201, 1085 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.93 (p,
2H, J = 7.2 Hz), 2.75 (q, 2H, J = 7.2 Hz), 3.78 (s, 3H), 4.36 (s, 2H), 4.37
(t, 2H, J = 7.2 Hz), 5.03 (dd, 1H, J = 10.2 and 1.2 Hz), 5.10 (dt, 1H, J =
16.8 and 1.8 Hz), 5.85−5.92 (m, 1H), 7.21−7.26 (m, 2H), 7.35 (dd, 1H,
J = 6.6 and 1.2 Hz), 8.11 (dd, 1H, J = 7.2 and 1.8 Hz), 9.80 (s, 1H); 13C
NMR (150 MHz, CDCl3) δ 28.10, 30.3, 32.2, 52.4, 63.2, 105.2, 111.2,
115.3, 121.4, 121.8, 122.8, 126.3, 134.7, 137.5, 138.6, 165.7, 171.2.
1-tert-Butyl 3-Pent-4-enyl 2-((Methoxycarbonyl)methyl)-1H-
indole-1,3-dicarboxylate (40). To a solution of the above compound
39 (21 mg, 0.07 mmol) in CH3CN (2 mL) at 0 °C were added DMAP
(1.5 mg, 0.01 mmol), Et3N (1.3 mL, 0.01 mmol), and t-Boc2O (38 mg,
0.17 mmol). After being stirred for 1.5 h at 0 °C, the reaction mixture
was quenched with a saturated NH4Cl solution (2 mL). The mixture
was then partitioned between CH2Cl2 and H2O. The organic phase
was collected, and the aqueous phase was extracted with CH2Cl2.
The combined organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by silica
gel chromatography to give 24 mg of the titled compound 40 (86%) as a
colorless oil: IR (thin film) 2979, 1738, 1700, 1454, 1280, 1195, 1144,
1116 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.67 (s, 9H), 1.93 (p, 2H,
J = 7.2 Hz), 2.25 (q, 2H, J = 7.2 Hz), 3.71 (s, 3H), 4.38 (t, 2H, J = 6.6
Hz), 4.75 (s, 2H), 5.03 (dd, 1H, J = 9.6 and 1.2 Hz), 5.10 (dd, 1H, J =
17.4 and 1.2 Hz), 5.83−5.90 (m, 1H), 7.30−7.36 (m, 2H), 8.11 (dd, 1H,
J = 7.8 and 1.8 Hz), 8.14 (dd, 1H, J = 7.2 and 1.8 Hz); 13C NMR (150
MHz, CDCl3) δ 27.9, 28.0, 30.3, 33.7, 52.07, 63.9, 85.7, 111.9, 115.3,
115.5, 121.8, 123.8, 124.8, 126.7, 135.6, 137.4, 140.5, 149.8, 165.1, 170.2.
1-tert-Butyl 3-Pent-4-enyl 2-((Methoxycarbonyl)-
diazomethyl)-1H-indole-1,3-dicarboxylate (41). A sample of
DBU (42 mL, 0.28 mmol) was added to a solution of 40 (66 mg,
0.16 mmol) in CH3CN (3 mL) at 0 °C under argon. After the mixture
was stirred for 15 min at 0 °C, TsN3 (101 mL, 0.66 mmol) was added to
the solution, and the mixture was stirred for an additional 16 h at rt.
The mixture was quenched with a phosphate buffer solution (10 mL,
pH = 7.0) and extracted with CH2Cl2. The combined organic phase was
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography to give 31 mg (44%)
of the titled compound 41 as a yellow oil: IR (thin film) 2111, 1744,
1701, 1478, 1317, 1280, 1257, 1192, 1146, 1117 cm−1; 1H NMR (600
MHz, CDCl3) δ 1.65 (s, 9H), 1.93 (p, 2H, J = 7.2 Hz), 2.40 (q, 2H, J =
7.2 Hz), 3.71−3.86 (m, 3H), 4.40 (t, 2H, J = 6.6 Hz), 5.02 (dd, 2H, J =
10.2 and 1.2 Hz), 5.08 (dd, 2H, J = 16.8 and 1.2 Hz), 5.82−5.89 (m, 1H),
7.35 (t, 1H, J = 7.2 Hz), 7.40 (t, 1H, J = 7.2 Hz), 8.18 (d, 1H, J = 15.6
Hz); 13C NMR (150 MHz, CDCl3) δ 27.9, 28.0, 30.2, 52.1, 64.2, 85.4,
113.0, 115.1, 115.5, 122.1, 124.0. 125.8, 126.3, 127.8, 128.9, 129.8, 136.7,
137.3, 149.1, 163.7, 165.3.
were added N,N-diisopropylethylamine (0.14 mL, 0.8 mmol), N-(2-
((tert-butyldimethylsilyl)oxy)ethyl)pent-4-en-1-amine (29 mg, 0.12 mmol),
hydroxybenzotriazole (18 mg, 0.13 mmol), and 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (23 mg, 0.12 mmol). After being
stirred overnight for 18 h, the mixture was diluted with EtOAc, and the
organic phase was washed with 1 M HCl, a saturated NaHCO3 solution,
and then brine. The organic layers were collected, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by silica
gel chromatography to afford 35 mg (97%) of methyl 2-(3-((2-((tert-
butyldimethyl-silyl)oxy)ethyl)(pent-4-en-1-yl)carbamoyl)-1H-indol-2-
yl)acetate as a colorless oil which was immediately converted into the
corresponding t-Boc indole derivative as outlined below.
To a solution of the above compound (35 mg, 0.08 mmol) in CH3CN
(3 mL) at 0 °C were added 4-(dimethylamino)pyridine (1.4 mg, 0.01
mmol), Et3N (13 mL, 0.09 mmol), and t-Boc2O (42 mg, 0.19 mmol).
After being stirred for 1.5 h at 0 °C, the mixture was quenched with a
saturated NH4Cl solution and then extracted with CH2Cl2. The organic
phase was dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography to
give 42 mg of the titled compound 43 (97%) as a colorless oil which
consisted of a 3:2 mixture of rotamers: IR (thin film) 2952, 2930, 1739,
1631, 1456, 1371, 1357, 1328, 1171, 1120 cm−1; 1H NMR (600 MHz,
CDCl3) δ −0.09 (s, 2H), −0.08 (s, 2H), 0.10 (s, 3H), 0.11 (s, 3H), 0.81
(s, 6H), 0.93 (s, 9H), 1.48−1.58 (m, 2H), 1.65 (s, 15H), 1.74−1.68 (m,
3.7H), 2.15−2.19 (m, 1H), 3.34−3.57 (m, 6.7H), 3.67 (s, 3H), 3.69 (s,
2H), 3.83−3.97 (m, 3.3H), 4.03−4.18 (m, 3.3H), 4.83−4.87 (m, 2H),
5.01 (d, 0.67H, J = 9.6 Hz), 5.08 (d, 0.67H, J = 16.8 Hz), 5.56−5.63 (m,
1H), 5.84−5.91 (m, 0.67H), 7.23 (t, 1.7H, J = 7.2 Hz), 7.31 (t, 1.7H, J =
7.2 Hz), 7.37 (d, 0.7H, J = 7.8 Hz), 7.47 (d, 1H, J = 7.8 Hz), 8.09−8.11
(m, 1.7H); 13C NMR (150 MHz, CDCl3) δ 18.1, 18.2, 27.0, 27.9, 28.0,
29.7, 30.5, 31.3, 34.0, 45.9, 47.1, 50.0, 50.8, 52.0, 61.3, 62.6, 84.9, 115.0,
115.2, 115.8, 115.9, 118.8, 118.9, 119.1, 119.5, 123.2, 123.3, 124.7, 124.8,
126.3, 126.5, 131.7, 131.9, 135.4, 137.3, 137.8, 150.1, 150.2, 166.2, 166.3,
170.1, 170.2.
Treatment of 43 with TsN3 using the standard reaction conditions for
the introduction of a diazo group followed by a subsequent thermolysis
of the labile diazo ester 44 with Cu(acacF6) hydrate produced no
characterizable products. There was no indication of the presence of
an intramolecular cycloadduct in the crude reaction mixture which
consisted of a multitude of products.
Methyl 2-(2-(N-Methyl-N-(pent-4-enyl)carbamoyl)-1H-indol-
3-yl)acetate (48). A mixture of 3-(2-methoxy-2-oxoethyl)-1H-indole-
2-carboxylic acid (200 mg, 1 equiv), N-methylpent-4-en-1-amine hydro-
chloride salt (1.5 equiv), EDCI (2 equiv), and BtOH (2.5 equiv) was
taken up in 3.4 mL of THF. To the solution was added DIPEA (6 equiv)
dropwise, and the resulting mixture was stirred at rt for 20 h. The solvent
was removed under reduced pressure, and the crude residue was
subjected to silica gel chromatography to give the titled indole 48 as
a pale yellow solid in 73% yield: mp 81−82 °C; IR (film) 3223, 3059,
2930, 1736, 1608, 1559, 1488, 1433, 1403, 1342, 1312, 1259, 1192,
1164, 1077, 1008 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.74 (t, 2H, J =
7.6 Hz), 2.14−1.96 (m, 3H), 3.10 (s, 3H), 3.54 (t, 2H, J = 7.6 Hz), 3.69
(s, 3H), 3.85 (s, 2H), 4.98 (d, 1H, J = 10.4 Hz), 5.03 (d, 1H, J = 17.5 Hz),
5.90−5.70 (m, 1H), 7.17 (ddd, 1H, J = 8.0, 7.0, and 1.0 Hz), 7.30−7.26
(m, 1H), 7.35 (d, 1H, J = 8.0 Hz), 7.61 (d, 1H, J = 7.6 Hz), 8.48 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 26.7, 31.0, 52.3, 109.0, 111.8, 115.6,
Methyl 1-(Pent-4-en-1-yloxy)-1H,3H,4H-furo[3,4-b]indole-3-
carboxylate (42). A solution of the above diazo compound 41 (29 mg,
0.068 mmol) in toluene (2 mL) was added dropwise to a suspension of
Cu(acacF6) hydrate (6.5 mg, 0.014 mmol) in toluene (2 mL) at 135 °C
under argon. The mixture was stirred for 1 h at 135 °C, cooled to rt, and
filtered through a short pad of silica with EtOAc. The organic phase was
collected and concentrated under reduced pressure, and the residue was
purified by preparative chromatography to give 11 mg (54%) of 42 as a
colorless oil: IR (thin film) 1813, 1760, 1719, 1454, 1354, 1217, 1178,
1086 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.89 (p, 2H, J = 7.2 Hz), 2.21
(q, 2H, J = 7.2 Hz), 3.86 (s, 3H), 4.35 (t, 2H, J = 6.6 Hz), 5.03 (dd, 1H,
J = 10.2 and 1.2 Hz), 5.09 (dd, 1H, J = 17.4 and 1.2 Hz), 5.82−5.89 (m,
1H), 6.09 (s, 1H), 7.45−7.48(m, 2H), 7.98(t, 1H, J = 4.5 Hz), 8.15 (t, 1H, J
= 4.8 Hz); 13C NMR (100 MHz, CDCl3) δ 27.9, 53.8, 64.4, 76.0, 106.5,
112.9, 115.6, 122.4, 125.6, 125.7, 130.1, 131.0, 137.2, 140.8, 148.2, 162.6,
164.3; HRMS calcd for [C17H17NO4 + H+] 300.1236, found 300.1237.
tert-Butyl 3-((2-((tert-Butyldimethylsilyl)oxy)ethyl)(pent-4-
en-1-yl)carbamoyl)-2-(2-methoxy-2-oxoethyl)-1H-indole-1-
carboxylate (43). To a solution of 2-(2-methoxy-2-oxoethyl)-1H-
indole-3-carboxylic acid (19 mg, 0.08 mmol) in CH2Cl2 (2 mL) at rt
120.0, 120.6, 124.0, 127.6, 129.1, 135.8, 137.6, 165.2, 171.8.
tert-Butyl 2-(N-Methyl-N-(pent-4-enyl)carbamoyl)-3-
((methoxycarbonyl)methyl)-1H-indole-1-carboxylate (49). The
above indole 48 (200 mg, 1 equiv), DMAP (0.15 mmol, 1 equiv), and
TEA (1.2 equiv) were dissolved in CH3CN (8 mL), and the solution
was cooled to 0 °C. To this mixture was added t-Boc2O (2.4 equiv), and
the mixture was stirred at 0 °C for 1 h. The reaction was then quenched
with H2O and extracted with EtOAc. The combined organic layers
were washed with brine, dried over MgSO4, and filtered. The filtrate
was concentrated under reduced pressure, and the crude residue was
subjected to silica gel chromatography to give the corresponding t-Boc-
protected indole 49 in 99% yield as a colorless liquid and was obtained as
a 1.7:1-mixture of rotamers: IR (film) 2978, 2931, 1732, 1639, 1575,
1477, 1450, 1343, 1409, 1358, 1326, 1254, 1231, 1143, 1111, 1081,
3181
dx.doi.org/10.1021/jo500331j | J. Org. Chem. 2014, 79, 3173−3184

The Journal of Organic Chemistry
Article
1021 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.63 (s, 9H), 1.89 (t, 1H, J =
7.5 Hz), 2.06 (m, 1H), 2.19 (q, 1H, J = 7.8 Hz), 2.88 (s, 3H), 3.06 (dt,
1H, J = 13.6 and 7.3 Hz), 3.13 (m, 1H), 3.19 (td, 1H, J = 9.3 and 6.1 Hz),
3.68 (s, 3H), 4.97−4.82 (m, 1H), 5.02−5.09 (m, 1H), 5.66 (m, 1H),
5.88 (m, 2H), 7.31−7.28 (m, 1H), 7.37 (m, 1H), 7.59−7.50 (m, 1H),
8.16 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 26.2, 27.0, 28.1, 28.2,
30.1, 30.5, 30.8, 31.2, 32.3, 36.1, 46.9, 50.4, 52.3, 84.7, 84.8, 112.8, 113.2,
115.3, 115.5, 115.7, 119.1, 119.7, 123.4, 125.6, 129.1, 131.1, 131.8, 135.3,
135.6, 137.2, 140.0, 149.1, 149.2, 163.9, 164.0, 170.9, 171.0.
26.6, 29.2, 31.9, 47.6, 52.0, 52.2, 52.4, 110.6, 111.6, 119.6, 120.8, 122.4,
125.5, 132.6, 135.0, 139.8, 167.6, 168.2, 171.0.
The above NH-indole (200 mg, 1 equiv), DMAP (0.15 mmol), and
TEA (1.2 equiv) were dissolved in CH3CN (8 mL), and the solution
was cooled to 0 °C. To this mixture was added t-Boc2O (2.4 equiv), and
the mixture was stirred at 0 °C for 1 h. The reaction was then quenched
with H2O and extracted with EtOAc. The combined organic layers
were washed with brine, dried over MgSO4, and filtered. The filtrate
was concentrated under reduced pressure, and the crude residue was
subjected to silica gel chromatography to give the corresponding t-Boc-
protected indole 52 in 73% yield as a colorless liquid which was obtained
as a 1.3:1 mixture of rotamers: IR (film) 2925, 2852, 1735, 1629, 1395,
1370, 1326, 1200, 1151, 1120 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.63
(s, 9H), 1.73−1.88 (m, 2H), 1.96−2.05 (m, 1H), 2.38−2.42 (m, 1H),
2.91 (s, 2H), 3.11 (s, 1H), 3.22−3.50 (m, 2H), 3.61−3.75 (m, 6H),
4.02−4.15 (m, 2H), 5.36 (s, 0.4H), 5.65 (s, 0.6H), 6.02 (s, 0.4H, 6.20 (s,
0.6H), 7.21−7.25 (m, 1H), 7.28−7.32 (m, 1H), 7.37 (d, 1H, J = 8.0 Hz),
8.08 (d, 1H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 26.3, 26.4, 28.2,
28.8, 29.6, 32.7, 34.1, 34.2, 36.8, 47.0, 50.8, 52.1, 52.3, 85.2, 116.1, 119.1,
119.5, 123.5, 125.0, 125.4, 125.8, 126.4, 126.6, 132.1, 132.4, 135.6, 139.6,
139.8, 150.3, 166.5, 166.6, 167.7, 170.6.
11-tert-Butyl 6-Methyl 1,2,3,4-Tetrahydro-1-methylpyrido-
[2,3-a]carbazole-6,11-dicarboxylate (51). A 100 mg sample of
the above t-Boc indole 49 and TsN3 (2 equiv) were dissolved in 1.1 mL
of CH3CN under argon and the reaction mixture was cooled to 0 °C.
To this mixture was added DBU (39 μL, 0.26 mmol), and the solution
was stirred at 0 °C for 10 min and then at rt for 15 h. The mixture was
quenched with 2 mL of H2O and extracted with EtOAc. The combined
organic layer was washed with brine, dried over MgSO4, and filtered.
The filtrate was concentrated under reduced pressure, and the crude
residue was subjected to silica gel chromatography to give tert-butyl 2-
(N-methyl-N-(pent-4-enyl)carbamoyl)-3-((methoxycarbonyl)-
diazomethyl)-1H-indole-1-carboxylate (50) in 51% yield as a 1.4:1 mixture
of rotamers and was used without further purification in the next step:
1H NMR (400 MHz, CDCl3) δ 1.63 (s, 9H), 1.81−1.79 (m, 1H),
1.93−1.87 (m, 1H), 2.16 (q, 1H, J = 7.6 Hz), 2.89 (s, 1.8H), 3.11−3.02
(m, 1H), 3.12 (s, 1.2H), 3.19 (t, 1H, J = 7.8 Hz), 3.75−3.60 (m, 0.4H),
3.81 (s, 3H), 4.08−4.00 (m, 0.6H), 4.94−4.85 (m, 0.8H), 5.12−5.01 (m,
1.2H), 5.70−5.59 (m, 0.4H), 5.92−5.82 (m, 0.6H), 7.31 (t, 1H, J = 7.6
Hz), 7.42−7.37 (m, 1H), 7.49 (d, 1H, J = 8.4 Hz), 8.21−8.16 (m, 1H).
A sample of copper hexafluoroacetylacetonate hydrate (3.7 mg,
0.0075 mmol) was suspended in 1.3 mL of degassed toluene, and the
mixture was heated at reflux. To this mixture was added a solution of
diazo compound 50 (17 mg, 0.038 mmol) in 1.3 mL of degassed toluene
over a period of 1 h, and heating was continued for 45 min. After being
cooled to rt, the mixture was filtered through a pad of Celite and rinsed
with EtOAc. The filtrate was concentrated under reduced pressure,
and the crude residue was subjected to silica gel chromatography to give
0.3 mg (2%) of a light yellow foam whose structure was assigned as
compound 51 on the basis of its NMR spectrum: 1H NMR (400 MHz,
CDCl3) δ 1.62 (s, 9H), 2.06 (br, 2H), 2.86 (t, 2H, J = 6.0 Hz), 2.97 (d,
3H, J = 0.8 Hz), 3.43 (br, 2H), 3.97 (d, 3H, J = 1.2 Hz), 7.32 (t, 1H, J =
8.0 Hz), 7.43 (t, 1H, J = 7.8 Hz), 7.68 (s, 1H), 8.12 (d, 1H, J = 8.0 Hz)
and 8.86 (d, 1H, J = 8.4 Hz).
Treatment of 52 with TsN3 using the standard reaction conditions for
the introduction of a diazo group followed by a subsequent thermolysis
of the labile diazo ester 53 with Cu(acacF6) hydrate produced no
characterizable products. There was no indication of the presence of
an intramolecular cycloadduct such as 54 in the crude reaction mixture
which consisted of a multitude of products.
tert-Butyl 3-(2-Methoxy-2-oxoethyl)-2-[(5-methoxy-4-meth-
ylidene-5-oxopentyl)(methyl)carbamoyl]-1H-indole-1-carbox-
ylate (55). A mixture of 3-((methoxycarbonyl)-methyl)-1H-indole-2-
carboxylic acid (200 mg, 1 equiv), methyl 5-(methylamino)-2-
methylenepentanoate hydrochloride salt (1.5 equiv), EDCI (2 equiv),
and BtOH (2.5 equiv) was taken up in 3.4 mL of THF. To this solution
was added DIPEA (6 equiv) dropwise, and the resulting mixture was
stirred at rt for 20 h. The solvent was removed under reduced pressure,
and the crude residue was subjected to silica gel chromatography to give
methyl 5-[1-[3-(2-methoxy-2-oxoethyl)-1H-indol-2-yl]-N-methylfor-
mamido]-2-methylidenepentanoate as a yellow oil in 87% yield: IR
(film) 3219, 2949, 1716, 1608, 1557, 1488, 1434, 1311, 1193, 1146,
1113 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.84 (q, 2H, J = 7.4 Hz), 2.32
(s, 2H), 3.09 (s, 3H), 3.56 (t, 2H, J = 7.2 Hz), 3.69 (s, 3H), 3.77 (s, 3H),
3.87 (s, 2H), 5.59 (s, 1H), 6.15 (s, 1H), 7.16 (ddd, 1H, J = 7.8, 7.2, 1.0
Hz), 7.27 (d, 1H, J = 8.0, 1.2 Hz), 7.39 (dt, 1H, J = 8.0, 0.9 Hz), 7.60 (dt,
1H, J = 8.0, 0.9 Hz), 8.77 (s, 1H).
The above NH-indole (200 mg, 1 equiv), DMAP (0.15 mmol), and
TEA (1.2 equiv) were dissolved in CH3CN (8 mL), and the solution was
cooled to 0 °C. To this mixture was added t-Boc2O (2.4 equiv), and
the mixture was stirred at 0 °C for 1 h. The reaction was then quenched
with H2O and extracted with EtOAc. The combined organic layers
were washed with brine, dried over MgSO4, and filtered. The filtrate
was concentrated under reduced pressure, and the crude residue was
subjected to silica gel chromatography to give the corresponding t-Boc-
protected indole 55 in 83% yield as a colorless liquid which was obtained
as a 1.8:1-mixture of rotamers: IR (film) 2950, 1732, 1641, 1477, 1450,
1435, 1359, 1327, 1255, 1151, 1120 cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.56−1.63 (m, 9H), 1.65−1.75 (m, 1H), 1.80−1.91 (m, 1H), 2.06−
2.16 (m, 0.4H), 2.43 (t, 1H, J = 7.6 Hz), 2.86 (s, 2H), 3.12 (s, 2H), 3.13−
3.26 (m, 0.6H), 3.62−3.71 (m, 6H), 3.78 (s, 2H), 3.96−4.14 (m, 0.4H),
5.44 (s, 0.3H), 5.68 (s, 0.5H), 6.05 (s, 0.3H), 6.22 (s, 0.5H), 7.22−7.30
(m, 1H), 7.35−7.39 (m, 1H), 7.51 (t, 1H, J = 8.2 Hz), 8.12 (dd, 1H, J =
12.0, 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 26.0, 26.8, 28.3, 29.2,
29.5, 30.2, 30.4, 32.3, 36.1, 46.8, 50.5, 52.0, 52.3, 84.8, 84.9, 112.9, 113.3,
115.8, 115.9, 119.6, 119.8, 123.5, 125.5, 125.6, 129.1, 131.8, 135.4, 135.6,
139.5, 139.9, 149.2, 1634.0, 164.2, 167.7, 171.0, 171.1.
tert-Butyl 2-(2-Methoxy-2-oxoethyl)-3-[(5-methoxy-4-meth-
ylidene-5-oxopentyl)(methyl)carbamoyl]-1H-indole-1-carbox-
ylate (52). A 35 mg sample (0.28 mmol) of the known 1-methyl-3-
methylenepiperidin-2-one37 was suspended in 6 N HCl (1.7 mL), and
the solution was heated at reflux for 48 h. After the mixture was cooled to
rt, MeOH (2 mL) was added, and the mixture was saturated with HCl
gas and then heated at reflux for 24 h. The solution was concentrated
under reduced pressure to give 24 mg (44%) of methyl 5-(methylamino)-
2-methylenepentanoate hydrochloride salt as a viscous yellow oil which
was used in the next step without any purification: IR (film) 3418, 2950,
1
2778, 1716, 1632, 1695, 1455, 1440, 1298, 1168 cm−1; H NMR (400
MHz, CD3OD) δ 1.94 (brs, 2H), 2.46 (brs, 2H), 2.74 (s, 3H), 3.50−3.79
(m, 5H), 5.78 (s, 1H), 6.24 (s, 1H), 7.10 (m, 2H), 7.25 (m, 1H), 7.40 (m,
1H); 13C NMR (100 MHz, CD3OD) δ 26.4, 30.0, 34.8, 45.9, 52.9, 127.4,
140.1, 168.4.
A mixture of 2-(2-methoxy-2-oxoethyl)-1H-indole-3-carboxylic acid
(200 mg, 1 equiv), the above amine salt (1.5 equiv), EDCI (2 equiv), and
BtOH (2.5 equiv) was taken up in 3.4 mL of THF. To this solution was
added DIPEA (6 equiv) dropwise, and the resulting mixture was stirred
at rt for 20 h. The solvent was removed under reduced pressure, and the
crude residue was subjected to silica gel chromatography to give methyl
5-[1-[2-(2-methoxy-2-oxoethyl)-1H-indol-3-yl]-N-methylformamido]-
2-methylidenepentanoate as a yellow oil in 41% yield: IR (film) 3175,
2950, 2927, 1741, 1721, 1698, 1557, 1495, 1456, 1402, 1199, 1167 cm−1;
1H NMR (400 MHz, CDCl3) δ 1.62−1.82 (m, 2H), 1.95−2.20 (m, 3H),
3.04 (s, 3H), 3.55 (brs, 2H), 3.65−3.71 (m, 6H), 3.88 (d, 2H, J = 4.4
Hz), 5.57 (brs, 1H), 6.17 (brs, 1H), 7.09−7.14 (m, 2H), 7.24−7.25 (m,
1H), 7.38−7.42 (m, 1H), 9.62 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
Treatment of 55 with TsN3 using the standard reaction conditions for
the introduction of a diazo group followed by a subsequent thermolysis
of the labile diazo ester 56 with Cu(acacF6) hydrate produced no
characterizable products. There was no indication of the presence of an
intramolecular cycloadduct such as 57 in the crude reaction mixture
which consisted of a multitude of products.
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Article
2-[3-[(1-Diazo-2-methoxycarbonylmethyl-1-methyl-1H-in-
dole-3-carbonyl)methylamino]-3-oxo-propyl]acrylic Acid
Methyl Ester (62). To a solution of 0.24 g (1.0 mmol) of
2-methoxycarbonylmethyl-1-methyl-1H-indole-3-carboxylic acid
(58)30 in 10 mL of dry CH2Cl2 containing 2 drops of dry DMF was
added 0.13 g (1.1 mmol) of oxalyl chloride. The solution was stirred at rt
for 30 min and concentrated under reduced pressure, and an additional
10 mL portion of CH2Cl2 was added followed by a 2.0 M solution of
methyl amine in THF (3.3 mmol). The mixture was stirred at rt for 1 h,
poured into water, and extracted with CHCl3. The organic layers
were combined, dried over MgSO4, and filtered, and the solvent was
removed under reduced pressure. The residue was subjected to silica gel
chromatography to give 0.2 g (81%) of (1-methyl-3-methyl-carbamoyl-
1H-indol-2-yl)acetic acid methyl ester (59) as a white solid: mp 124−
126 °C; IR (film) 1736, 1628, 1551, 1472, 1403 cm−1; 1H NMR (300
MHz, CDCl3) δ 2.98 (m, 3H), 3.59 (s, 3H), 3.69 (s, 3H), 4.24 (s, 2H),
6.39 (brs, 1H), 7.13−7.28 (m, 3H), 7.74 (d, 1H, J = 7.2 Hz); 13C NMR
(75 MHz, CDCl3) δ 26.4, 29.8, 31.2, 52.5, 109.5, 109.7, 119.2,
121.1, 122.2, 124.7, 136.1, 136.5, 166.2, 170.3; HRMS calcd for
[C14H16N2O3 + H+] 261.1239, found 261.1242.
A mixture of 0.98 g (3.8 mmol) of the above compound, 1.0 g
(5.6 mmol) of 4-methoxycarbonylpent-4-enoyl chloride (60),31 3.5 g of
powdered molecular sieves (4 Å, <5 μm), and 30 mL of CH2Cl2 was
stirred for 18 h at rt. The reaction mixture was filtered through a pad of
Celite, and the filtrate was washed with an aqueous NaHCO3 solution.
The organic layer was dried over MgSO4 and filtered, and the solvent
was removed under reduced pressure. The resulting crude oil was
subjected to silica gel chromatography to give 1.23 g (82%) of 2-[3-[(2-
methoxycarbonylmethyl-1-methyl-1H-indole-3-carbonyl)methylamino]-
3-oxopropyl]acrylic acid methyl ester (61) as a pale yellow oil: IR (neat)
1741, 1719, 1661, 1532, 1474, 1439 cm−1; 1H NMR (300 MHz, CDCl3) δ
2.65 (t, 2H, J = 7.5 Hz), 2.82 (t, 2H, J = 7.5 Hz), 3.24 (s, 3H), 3.67 (s, 3H),
3.74 (s, 3H), 3.77 (s, 3H), 4.25 (s, 2H), 5.53 (d, 1H, J = 1.2 Hz), 6.14 (d,
1H, J = 1.2 Hz), 7.22−7.49 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 28.1,
30.5, 31.5, 33.8, 35.7, 52.0, 52.8, 110.3, 110.4, 119.9, 122.7, 123.3, 124.7,
125.8, 136.7, 139.3, 140.6, 167.3, 169.3, 170.5, 175.1; HRMS calcd for
[C21H24N2O6 + H+] 401.1713, found 401.1716.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chemap@emory.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We greatly appreciate financial support provided by the National
Science Foundation (CHE-1057350) and the Emory Emeritus
foundation for an Alfred B. Heilbrun Jr. award.
REFERENCES
■
(1) (a) Dake, D. Tetrahedron 2006, 62, 3467. (b) Confalone, P. N. J.
Heterocycl. Chem. 1990, 27, 31. (c) de Meijere, A.; Kozhushkov, S. I.;
Khlebnikov, A. F. Top. Curr. Chem. 2000, 207, 89. (d) Padwa, A. Chem.
Soc. Rev. 2009, 38, 3072. (e) Nair, V.; Suja, T. D. Tetrahedron 2007, 63,
12247. (f) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765.
(2) Saxton, J. E. In The Akaloids; Cordell, G. A., Ed.; Academic Press:
New York, 1998; Vol. 51, pp 2−197.
(3) Daudon, M.; Mehri, H.; Plat, M. M.; Hagaman, E. W.; Schell, F. M.;
Wenkert, E. J. Org. Chem. 1975, 40, 2838.
(4) Szabo, L. F. ARKIVOC 2007, 7, 280.
́
(5) (a) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Org.
Chem. 1989, 54, 1236. (b) Overman, L. E.; Robertson, G. M.;
Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598.
(6) Hayashi, Y.; Inagaki, F.; Mukai, C. Org. Lett. 2011, 13, 1778.
(7) Zhang, H.; Curran, D. P. J. Am. Chem. Soc. 2011, 133, 10376.
(8) (a) Selig, P.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 5082.
(b) Selig, P.; Herdtweck, E.; Bach, T. Chem.Eur. J. 2009, 15, 3509.
(9) Denmark, S. E.; Cottell, J. J. Adv. Synth. Catal. 2006, 348, 2397.
(10) Goldberg, A. F. G.; Stoltz, B. M. Org. Lett. 2011, 13, 4474.
(11) (a) Chiacchio, U.; Padwa, A.; Romeo, G. Curr. Org. Chem. 2009,
13, 422. (b) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. 1993, 32,
131. (c) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993.
(d) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134. (e) Bur, S. K.; Padwa, A. Adv. Heterocycl. Chem. 2007, 94,
1. (f) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341. (g) Ho, T. L.
Tandem Organic Reactions; John Wiley: New York, 1992.
(12) (a) Bernauer, K.; Enplert, G.; Vetter, W.; Weiss, E. Helv. Chim.
Acta 1969, 52, 1886. (b) Daudon, M.; Mehri, H.; Plat, M. M.; Hagaman,
E. W.; Schell, F. M.; Wenkert, E. J. Org. Chem. 1975, 40, 2838.
(c) Daudon, M.; Mehri, M. H.; Plat, M. M.; Hagaman, E.; Wenkert, E. J .
Org. Chem. 1976, 41, 3275. (d) Hugel, G.; Levy, J. J. Org. Chem. 1986, 51,
1594.
To a solution containing 0.5 g (1.3 mmol) of the above compound 61
and 0.37 g (1.6 mmol) of 4-nitrobenzenesulfonyl azide32 in 20 mL of
CH3CN at 0 °C under Ar was added 0.21 g (1.4 mmol) of DBU. The
solution was stirred at 0 °C for 1 h, the solvent was removed under
reduced pressure, and the residue was subjected to flash silica gel
chromatography to give 0.41 g (78%) of 62 as an orange oil which was
used in the next step without further purification: 1H NMR (400 MHz,
CDCl3) δ 2.66 (t, 2H, J = 7.2 Hz), 2.81 (t, 2H, J = 7.2 Hz), 3.21 (s, 3H),
3.68 (s, 3H), 3.77 (s, 3H), 3.86 (s, 3H), 5.55 (d, 1H, J = 1.2 Hz), 6.15
(d, 1H, J = 1.2 Hz), 7.27−7.59 (m, 4H).
6,11c-Dihydroxy-1,7-dimethyl-2-oxo-1,2,3,4,5,6,7,11c-
octahydropyrido[3,2-c]carbazole-4a,6-dicarboxylic Acid Di-
methyl Ester (66). To a suspension of 10 mg of Rh2(OAc)4 in
10 mL of benzene at 100 °C was slowly added a solution of 0.21 g
(0.49 mmol) of diazoindole 62 in 3 mL of benzene. The mixture was
heated for 1.5 h, the solvent was removed under reduced pressure, and
the residue was dissolved in 10 mL of EtOAc. The solution was allowed
to cool to rt, and the resulting solid was filtered to give 0.09 g (47%) of
66 as a pale yellow oil: IR (Nujol) 1742, 1731, 1621, 1461, 1378 cm−1;
1H NMR (400 MHz, DMSO) δ 1.81−1.99 (m, 1H), 2.19 (d, 1H, J =
13.6 Hz), 2.25−2.36 (m, 2H), 2.64−2.70 (m, 1H), 2.78−2.81 (brd, 1H),
2.81 (s, 3H), 3.31 (s, 3H), 3.70 (s, 3H), 3.93 (s, 3H), 6.23 (s, 1H), 6.74
(s, 1H), 7.12 (t, 1H, J = 7.6 Hz), 7.23 (t, 1H, J = 7.6 Hz), 7.49 (d, 1H, J =
7.6 Hz), 7.60 (d, 1H, J = 7.6 Hz); 13C NMR (100 MHz, DMSO) δ 25.1,
29.8, 32.4, 33.4, 41.6, 51.4, 52.5, 54.5, 72.0, 84.3, 109.8, 112.5, 119.4,
121.5, 121.8, 123.8, 136.9, 137.8, 171.2, 171.8, 172.1; HRMS calcd for
[C21H24N2O7 + H+] 417.1662, found 417.1656.
(13) Guo, L.-W.; Zhou, Y.-L. Phytochemistry 1993, 34, 563.
(14) Hamaguchi, M.; T. Ibata, T. Chem. Lett. 1976, 287.
(15) For a review on isobenzofurans, see: Rodrigo, R. Tetrahedron
1988, 44, 2093.
(16) (a) Bernabe, P.; Castedo, L.; Dominguez, D. Tetrahedron Lett.
1998, 39, 9785. (b) Sarkar, T. K.; Ghosh, S. K.; Nandy, S. K.; Chow, T. J.
Tetrahedron Lett. 1999, 40, 397. (c) Baily, J. H.; Coulter, C. V.; Pratt, A.
J.; Robinson, W. T. J. Chem. Soc., Perkin Trans. 1 1995, 589.
(17) (a) Friedrichsen, W.; Konig, B.-M.; Hildebrandt, K.;
̈
Debaerdemaeker, T. Heterocycles 1986, 24, 302. (b) Konig, B.-M.;
̈
Friedrichsen, W. Tetrahedron Lett. 1987, 28, 4279. (c) Hildebrandt, K.;
Friedrichsen, W. Heterocycles 1989, 29, 1243. (d) Schoning, A.;
̈
Friedrichsen, W. Z. Naturforsch Sect. B 1989, 44, 825. (e) Aßmann, L.;
Debaerdemaeker, T.; Friedrichsen, W. Tetrahedron Lett. 1991, 32, 1161.
(f) Nagel, J.; Friedrichsen, W.; Debaerdemaeker, T. Z. Naturforsch., Sect.
B 1993, 48, 213.
(18) (a) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263.
(b) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223. (c) Padwa,
A. Top. Curr. Chem. 1997, 189, 121. (d) Doyle, M. P.; McKervey, M. A.;
Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; John Wiley and Sons: New York, 1998. (e) Padwa, A. Helv.
Chim. Acta 2005, 88, 1357. (f) Padwa, A.; Marino, J. P., Jr.; Osterhout,
M. H. J. Org. Chem. 1995, 60, 2704. (g) Padwa, A.; Marino, J. P., Jr.;
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR data of various key compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Article
Osterhout, M. H.; Price, A. T.; Semones, M. A. J. Org. Chem. 1994, 59,
5518. (h) Hertzog, D. L.; Nadler, W. R.; Osterhout, M. H.; Price, A. T.;
Padwa, A. J. Org. Chem. 1994, 59, 1418.
(19) (a) England, D. B.; Padwa, A. Org. Lett. 2007, 9, 3249.
(b) England, D. B.; Padwa, A. J. Org. Chem. 2008, 73, 2792.
(20) Li, G.; Padwa, A. Org. Lett. 2011, 13, 3767.
(21) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; John Wiley and
Sons: New York, 1998. (b) Saba, A. Synthesis 1984, 268.
(22) Mills, K.; Khawaja, I. K. A.; Al-Saleh, F. S.; Joule, J. A. J. Chem. Soc.,
Perkin Trans. 1 1981, 636.
(23) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis
1990, 215.
(24) Regitz, M. Chem. Ber. 1965, 98, 1210.
(25) Robinson, J. R.; Good, N. E. Can. J. Chem. 1957, 35, 1578.
(26) It should be noted that, unlike the negative results encountered
with the furo[3,4-b]indole system, the structurally simpler and more
reactive 1-aminobenzo[c]furan system did undergo the sought-after
intramolecular [4 + 2]-cycloaddition reaction; see: (a) Peters, O.;
Friedrichsen, W. Tetrahedron Lett. 1995, 36, 8581. (b) Sarkar, T. K.;
Basak, S.; Ghosh, S. K. Tetrahedron Lett. 2000, 41, 759.
(27) Peters, O.; Friedrichsen, W. Heterocycl. Commun. 1996, 2, 203.
(28) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
(29) For examples, see: (a) Oppolzer, W.; Frostl, W. Helv. Chim. Acta
̈
1975, 58, 590. (b) Oppolzer, W.; Frostl, W.; Weber, H. P. Helv. Chim.
̈
Acta 1975, 58, 593. (c) Oppolzer, W.; Flaskamp, E. Helv. Chim. Acta
1977, 60, 204. (d) White, J. D.; Demnitz, F. W. J.; Oda, H.; Hassler, C.;
Snyder, J. P. Org. Lett. 2000, 2, 3313. (e) Turner, C. I.; Williamson, R.
M.; Paddon-Row, M. N. J. Org. Chem. 2001, 66, 3963. (f) Tantillo, D. J.;
Houk, K. N.; Jung, M. E. J. Org. Chem. 2001, 66, 1938. (g) Weingarten,
M. D.; Prein, M.; Price, A. T.; Snyder, J. P.; Padwa, A. J. Org. Chem. 1997,
62, 2001. (h) Padwa, A.; Bur, S.; Lynch, S. M. Org. Lett. 2002, 4, 473.
(i) Padwa, A.; Ginn, J. D.; Bur, S. K.; Eidell, C. K.; Lynch, S. M. J. Org.
Chem. 2002, 67, 3412.
(30) (a) Bahadur, G. A.; Bailey, A. S.; Middleton, N. W.; Peach, J. M. J.
Chem. Soc., Perkin Trans. 1 1980, 1688. (b) Karrick, G. L.; Peet, N. P. J.
Heterocycl. Chem. 1986, 23, 1055.
(31) (a) Foote, C. S.; Kwon, B. M. J. Org. Chem. 1989, 54, 3878.
(b) Padwa, A.; Hennig, R.; Kappe, C. O.; Reger, T. S. J. Org. Chem. 1998,
63, 1144.
(32) Sundberg, R. J.; Pearce, B. C. J. Org. Chem. 1985, 50, 425.
(33) Kam, T. S.; Yoganathan, K.; Wei, C. Tetrahedron Lett. 1996, 37,
3603.
(34) (a) Banerjee, A.; Adak, M. M.; Das, S.; Banerjee, S.; Sengupta, S. J.
Indian Chem. Soc. 1987, 64, 34. (b) Ram, N.; Charles, I. Tetrahedron
1997, 53, 7335.
(35) Tokuyama, H.; Kaburagi, Y.; Chen, X.; Fukuyama, T. Synthesis
2000, 429.
(36) Bevk, D.; Svete, J.; Stanovnik, B. J. Heterocycl. Chem. 2005, 42,
1413.
(37) Loreto, M. A.; Migliorini, A.; Tardella, P. A.; Gambacorta, A. Eur.
J. Org. Chem. 2007, 2365.
3184
dx.doi.org/10.1021/jo500331j | J. Org. Chem. 2014, 79, 3173−3184