Access to Spirocyclized Oxindoles and Indolenines via Palladium-Catalyzed Cascade Reactions of Propargyl Carbonates with 2-Oxotryptamines and Tryptamines

Article abstract of DOI:10.1021/acs.joc.5b00277

(Chemical Equation Presented). Reported here are methods for the direct construction of a range of spirocyclized oxindoles and indolenines in good to excellent yields. Specifically, we report the palladium-catalyzed reactions of oxindoles and indoles, both functioning as bis-nucleophiles, with propargyl carbonates to afford spirocyclic products having an exocyclic double bond on the newly formed ring. The reaction proceeds through a process wherein the first nucleophilic unit on the oxindole or indole reacts with an allenyl-palladium species, formed from oxidative addition of Pd(0) to propargyl carbonates, to generate a π-allyl palladium intermediate that then reacts further with the second nucleophilic component of the oxindole or indole. The cascade process forges two bonds en route to spirocyclized oxindole and indolenine products. The use of chiral phosphines renders the cyclization sequence enantioselective, providing spirocyclic products with modest to good enantioselectivities.

Full text of DOI:10.1021/acs.joc.5b00277

Article
pubs.acs.org/joc
Access to Spirocyclized Oxindoles and Indolenines via Palladium-
Catalyzed Cascade Reactions of Propargyl Carbonates with
2‑Oxotryptamines and Tryptamines
Antoinette E. Nibbs, Thomas D. Montgomery, Ye Zhu, and Viresh H. Rawal*
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue Chicago, Illinois 60637, United States
S
* Supporting Information
ABSTRACT: Reported here are methods for the direct construction of a range of spirocyclized oxindoles and indolenines in
good to excellent yields. Specifically, we report the palladium-catalyzed reactions of oxindoles and indoles, both functioning as
bis-nucleophiles, with propargyl carbonates to afford spirocyclic products having an exocyclic double bond on the newly formed
ring. The reaction proceeds through a process wherein the first nucleophilic unit on the oxindole or indole reacts with an allenyl-
palladium species, formed from oxidative addition of Pd(0) to propargyl carbonates, to generate a π-allyl palladium intermediate
that then reacts further with the second nucleophilic component of the oxindole or indole. The cascade process forges two bonds
en route to spirocyclized oxindole and indolenine products. The use of chiral phosphines renders the cyclization sequence
enantioselective, providing spirocyclic products with modest to good enantioselectivities.
INTRODUCTION
■
Natural products hold a great fascination for synthetic organic
chemists. The intricate connectivity of the different atoms in a
natural product, even a simple one, can inspire the conception of
diverse strategies for its synthesis, with individual steps either
grounded on established precedents or guided by reactivity
principles. Given the subtle interplay between structure and
reactivity, particularly in a complex setting, it is often the case that
methods shown to be effective in one substrate can fail
completely in another seemingly similar substrate. While a
source of frustration, these failures serve as beacons to point out
the limitations of available methodology and thereby spur the
development of new solutions to the challenges at hand. In this
way, a complex molecule synthesis exercise can have an impact
well beyond what may be anticipated upon conception of a
project. We describe below the results of a methodology study
that had its origins precisely as described above, motivated by
difficulties encountered with a simple allylation reaction during a
total synthesis program.
Over the years, our research group has pursued the synthesis of
several families of monoterpene indole alkaloids such as
strychnine (1), vindoline (2), geissoschizine (3), and strictamine
(4) (Figure 1). A route that was conceived to strictamine
Figure 1. Indole-alkaloid natural products.
Received: February 5, 2015
© XXXX American Chemical Society
A
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capitalized on palladium-catalyzed C−C bond-forming pro-
cesses, such as the Heck or enolate alkenylation reaction. Both
transformations were selected for their ability to maintain the
defined stereochemistry of an alkenyl chain during the bond-
forming step.1 In one of the approaches explored, the Heck
cyclization precursor was expected to be prepared from methyl
ketone iii, which in turn would originate from iv, the product of
β-allylation of a tryptoline precursor (Scheme 1).2
Scheme 1. Retrosynthesis of 4
The regioselectivity of alkylation in simple indoles (i.e., N-− vs
C-3-alkylation) was known to be controllable through judicious
selection of reactants and reaction conditions, in line with the
hard−soft acid−base (HSAB) heuristic used to predict such
selectivity in ambident reactants.3 When appropriate conditions
were examined for the β-allylation of simple 3-substituted
indoles, the results were variable and quite poor for 2,3-
disubstituted indole derivatives such as β-carbolines. This
limitation in available methodology provided an opportunity to
explore alternate methods for the desired β-allylation, and
initiated our studies of palladium catalysis as an effective means
to functionalize indole derivatives.
In 2006, when we began our study of palladium-catalyzed β-
allylation of indoles, there were few reports of this process, with
most giving primarily, or only, N-allylation.4 The one exception
was the pioneering work of Bandini and Umani-Ronchi, who
reported selective β-allylation of β-unsubstituted indoles.5 With
2,3-disubstituted indoles required for our planned synthesis, the
published methods gave the β-allylation products in only modest
or low yields and so motivated the development of a palladium-
catalyzed decarboxylative β-allylation of 2,3-disubstituted indoles
(Figure 2, eq a).6 The mild reaction conditions and broad
functional group tolerance of the allylation chemistry that we
developed then inspired the examination of the corresponding β-
benzylation reaction of indoles (eq b).7,8 More recently, we
reported a useful variant of these two reactions, wherein the N-
alloc and N-Cbz indoles are transformed to the C-3-allyl and C-3-
benzyl indolenine derivatives, respectively (eq c).9 Success with
allylation and benzylation of indole substrates set the stage for
the investigation of the analogous propargylation reac-
tion.7b,10−12 In contrast to the first two processes, the
palladium-catalyzed propargylation did not give the expected
propargylated indole derivative (eq d). Unlike the intermediates
formed from the oxidative addition of palladium to allyl and
benzyl carbonates, which are capable of reacting with one
nucleophile, the intermediate from propargyl carbonate has the
capacity to react twice with nucleophiles. With this in mind, we
examined the reaction of indolic substrates having in place a
Figure 2. Pd-catalyzed β-functionalization of indoles.
second nucleophilic group and obtained spirocyclized products
arising from reaction with both nucleophilic units (eq e).13,14
We report here the results of further studies on the palladium-
catalyzed reaction of propargyl carbonates with indole bis-
nucleophiles, in addition to new studies with oxindole bis-
nucleophiles. The reactions are high-yielding and furnish the
desired spirocyclic products under mild conditions and at low
catalyst loadings. Also described are the results of a study of
enantioselective spirocyclization of propargyl carbonates with
oxindole and indole substrates in the presence of chiral
phosphine ligands.
RESULTS AND DISCUSSION
■
Since tryptamine derivatives were competent bis-nucleophiles
for the spirocyclization reaction, we hypothesized that 2-
oxotryptamine derivatives would perform comparably, possibly
better. We were pleased to find that the optimized reaction
conditions used for indole substrates also worked well for
oxindole 6a and produced the spirooxindole 7a in 83% yield,
although requiring a significantly longer reaction time (Table 1,
entry 1).15 The reaction conditions originally employed for the
attempted propargylation of 2,3-dimethylindole gave an
appreciably faster reaction rate with oxindole 6a (entry 2). By
changing the ligand to dppb, we noted a major improvement in
rate, with the reaction proceeding to completion after only 40
min at ambient temperature (97%, entry 3). As seen previously,13
B
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a
Table 1. Optimization of Oxindole Spirocyclization
b
entry
[Pd]
ligand
solvent
5a (equiv)
time (h)
yield
1
2
3
4
5
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd(OAc)2
Xantphos
DPEphos
dppb
CH2Cl2
THF
1.3
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
1.5
1.5
18
83
83
97
0
0.75
0.75
0.75
4
c
THF
none
THF
PPh3
THF
0
d
6
dppb
THF
0.75
0.5
0.75
0.75
0.33
2
10
84
92
0
7
8
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
dppb
CH2Cl2
EtOAc
THF
dppb
e
9
dppb
10
dppb
THF
98
98
95
f
c
c
11
dppb
dppb
THF
g
12
THF
6
a
b
Reaction conditions: [Pd] (5.0 mol %), ligand (5.5 mol %), 6a (0.1 M in solvent), N2 atmosphere, 23 °C. NMR yield calculated using 1,3,5-
c
d
e
trimethoxybenzene as an internal standard; see Experimental Section for details. Isolated yield for a single run. dppb (11 mol %). Reaction run
under ambient atmosphere. [Pd] (2.0 mol %), dppb (2.2 mol %). [Pd] (1.0 mol %), dppb (1.1 mol %).
f
g
the reaction did not proceed in the absence of a phosphine ligand
(entry 4), nor when monodentate ligands were employed (entry
5). Other palladium sources were examined and offered no
significant improvement (entry 6). We found polar aprotic
solvents (entries 3, 7, and 8) to be superior to either nonpolar or
protic solvents. Use of excess propargyl carbonate 5a led to a
significant reduction in reaction time, giving full conversion to
the product after 20 min (entry 10). Importantly, the
spirocyclization proceeded in high yields even with reduced
catalyst loadings (entries 11 and 12). In order to have common
conditions for a range of substrates, 5 mol % of the palladium
catalyst was used for examining the substrate scope.
containing substitution at the 1- and/or 3-positions was
synthesized and subjected to the reaction conditions.
Figure 3. Substituted propargyl carbonates.
With optimized conditions in hand, we proceeded to survey
the substrate scope for the oxindole spirocyclization. Our studies
initially focused on the N10-Ts oxindoles (Table 2, entries 1−3)
with the N1-methyl and N1-benzyl substrates both giving the
desired product in excellent yield (entries 1, 2). Interestingly,
oxindole substrates lacking a substituent at N1 reacted
significantly slower, though still gave the expected cyclized
product in near-quantitative yield (entry 3). Tryptophan-derived
oxindole 6d gave spirooxindole 7d in good yield as a mixture of
diastereomers (entry 4), and 2-propylamine oxindole 6e gave the
corresponding seven-membered spirocycle (entry 5). However,
the reaction of oxindole carbamate 6f under the optimized
reaction conditions produced a significant quantity of oligomeric
products. The problem was minimized by using a dilute reaction
concentration, elevated temperature, and slow addition of the
oxindole to the reaction mixture,16 which increased the yield of
the cyclized product from 18% to 68% (entry 6). Under similar
reaction conditions, N10-Ph acetamide 6g provided spirocycle 7g
in good yield (entry 7). Interestingly, the N10-Me acetamide 6h
provided the isomeric eneamide 7h in good yield (entry 8). As
expected, phenol 6i formed the tetracyclic product 7i in excellent
yield (entry 9).
Under the optimized reaction conditions, the substituted
propargyl carbonates 5b−5d produced the expected spirocyclic
products as inseparable mixtures of regioisomers or olefin
isomers. A notable exception was the geminal-dimethyl
substituted carbonate 5e, which afforded spirooxindole 7j in
excellent yield and with minimal formation of the isomeric
addition product (Scheme 2).
A brief evaluation of the carbonate substrate scope was carried
using substituted propargyl carbonates 5b−5g and tryptamine
sulfonamide 8a. Methyl-substituted propargyl carbonates 5b or
5d gave complex mixtures of stereoisomers, and trisubstituted
propargyl carbonate 5e gave no product, even on heating to 40
°C for 72 h. The phenyl-substituted propargyl carbonate 5c gave
Scheme 2. Selective Spirocyclization Reaction Using
Trisubstituted Propargyl Carbonate 5e
In order to further explore the scope of these spirocyclization
reactions, we also examined the reaction of substituted propargyl
carbonates (Figure 3). A series of tert-butyl propargyl carbonates
C
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a
Table 2. Substrate Scope for Oxindole Spirocyclization
a
b
Reaction conditions: oxindole 6 (0.2 mmol), 5a (1.5 equiv), Pd2(dba)3·CHCl3 (2.5 mol %), dppb (5.5 mol %), 6 (0.1 M in THF), 23 °C. Isolated
c
d
yield for a single run. Diastereomer ratio determined by 1H NMR. Isolated as 48% and 30%. Solution of 6f (0.2 mmol) in THF (1 mL) at 50 °C
added by syringe pump over 1 h.
the product as a single constitutional isomer, as a 4:1 mixture of
diastereomers. Interestingly, the isomeric propargyl carbonate 5f
yielded the same product, with comparable diastereoselectivity
(Scheme 3). These results suggest the involvement of a common
reaction intermediate that is converted into spiroindolenine 9a
with near-identical diastereoselectivity (see Scheme 4). Finally,
when disubstituted propargyl carbonate 5g was used, the
reaction generated spiroindolenine 9b as a single product in
moderate yield and with excellent diastereoselectivity (32% yield,
18:1 dr).
proposed in analogy with mechanisms presented for related Pd-
catalyzed reactions (Figure 4).10,17 Decarboxylative oxidative
addition of Pd(0) to the propargyl carbonate generates a tert-
butoxide anion and Pd-allene I.18 The tert-butoxide anion may
serve as the endogenous base that deprotonates oxindole 6.
Given the similarity in their pKa values,17c−e,19 deprotonation at
C-3 (to give enolate II) or N10 (to give amide anion VI) are both
feasible, and the two anions are expected to be in dynamic
equilibrium. At this point, nucleophilic addition by enolate II
would generate palladium carbene III,11a−c,20 whereas amide
anion VI would give palladium carbene VII. Subsequent
protonation would form the corresponding Pd-π-allyl species
Although we have not studied the mechanism of this reaction,
a reasonable catalytic cycle for these spirocyclizations can be
D
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Scheme 3. Reaction of Substituted Propargyl Carbonates with Tryptamine Sulfonamide 8a
Scheme 4. Mechanistic Rationale for the Stereoconvergent Synthesis of 9a
Figure 4. Reaction catalytic cycles.
IV or VIII, respectively. Intramolecular allylation of IV by N10
would give spirooxindole V, whereas the same process on VIII
would occur at C3 to give IX.10a,21 Both processes give rise to
Pd(0), thereby enabling continuation of the catalytic cycle.
E
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The suggested mechanistic scheme accounts for the formation
of isomeric spirooxindoles, depending on the withdrawing group
present on the N10 nitrogen. A strong electron-withdrawing
group such as tosyl on the side-chain nitrogen would render the
resulting anion less nucleophilic, thus favoring initial addition of
the oxindole enolate to the allenyl palladium species (Figure 4,
species III). On the other hand, with a less powerful withdrawing
group such as carbomethoxy, the resulting nitrogen-based anion
would be more nucleophilic and give initial C−N bond
formation (Figure 4, species VII). We have not been able to
correlate more precisely the product outcome with the nature of
the side chain and its pKa,22 presumably because other factors
such as relative nucleophilicity and steric considerations also play
an important role in determining the product outcome.
Table 3. Investigation of Chiral Phosphine Ligands for the
Indole Spirocyclization
a
The reaction of tryptamine sulfonamide 8a with substituted
propargyl carbonate 5c or 5f to give nearly the same
diastereomeric ratio of spiro product 9a (Scheme 3) can be
understood as follows. The reaction of the two propargyl
carbonates with Pd(0) would give Pd-allenyl species that are
constitutional isomers (Scheme 4). Subsequent addition of the
sulfonamide nucleophile would form two isomeric Pd-
carbenoids that on protonation would produce isomeric σ-allyl
intermediates, capable of interconversion through a common π-
allyl species 10. In order for 5c and 5f to generate the same
product, the rate of the interconversion must be faster than the
rate of C−C bond formation.
A natural progression of the Pd-catalyzed allylation,
benzylation, and spirocyclization reactions is to render the
processes enantioselective. Toward this end we examined a
focused collection of chiral phosphine ligands for the
spirocyclization reactions of indole substrates (Table 3).7b (R)-
BINAP gave the spiroindolenine product 11a in good yield but
low, albeit promising, enantioselectivity (entry 1). Modifying the
quantity of chiral ligand or reaction temperature or utilizing a
more hindered phosphine (entries 2−4) gave only minor
improvements to the selectivity. Use of a monodentate ligand
gave no conversion to product (entry 5). Employment of
BIPHEP-type ligands improved the enantioselectivity and yield
modestly (entry 6). Encouragingly, switching the aryl substituent
on the ligand from phenyl to furyl improved the results
measurably (entry 7). An even greater increase in enantiose-
lectivity was observed using the bulkier 4-Me-furyl ligand (41%
ee, entry 8). Unfortunately, the use of benzofuran-substituted
BIPHEP did not enhance selectivity (entry 9). The most
promising selectivities were observed for 2-aryl tryptamine
sulfonamide substrates. When paired with L2, 2-phenylindole-
nine 11b was formed with 53% ee (entry 10). The
dimethoxyphenyl indolenine 11c was formed with 66% ee
under the same reaction conditions, and in higher yield (entry
11). Finally, use of the bulkier ligand L3 with dimethoxy-
phenylindole 8c produced indolenine 11c with 77% ee (entry
12).
A brief examination of the enantioselective spirocyclization of
oxindole substrates has proven less fruitful (Scheme 5). A
number of chiral phosphine ligands were examined for the
reaction, but most did not afford the product at ambient
temperature. The cyclization did proceed at elevated temper-
atures and with an extended reaction time (20 h), but gave the
product in just 8% yield and with 32% ee. It is interesting to note
that, despite the ease of the racemic spirocyclization reactions of
oxindoles with propargyl carbonates (ambient temperature,
generally less than 30 min), rendering these reactions highly
enantioselective has, to date, proven difficult.
a
Reaction conditions: [Pd] (5 mol %), phosphine ligand (5.5 mol %),
b
5a (1.3 equiv), 8 (0.04 M in CH2Cl2). Isolated yield for a single run.
c
d
Determined by chiral stationary phase HPLC. (R)-BINAP (10 mol
%).
Scheme 5. Investigation of Chiral Phosphine Ligands for the
Oxindole Spirocyclization
CONCLUSION
■
Inspired by methodology needs arising from a natural product
total synthesis project, we have investigated and developed mild
methods for the C-3 functionalization of oxindoles and indoles.
In the present study, we focused on the palladium-catalyzed
decarboxylative spirocyclization reactions of 2-oxotryptamine
derivatives possessing two nucleophilic sites, which afforded
intricate, spirocyclized products. The transformation involves the
reaction of propargyl carbonate with Pd(0) to generate a Pd-
allenyl species that reacts with the first nucleophilic unit on the
oxindole substrate to generate, after protonation, a π-allyl
palladium intermediate, which then reacts further with the
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material, the reaction mixture was concentrated in vacuo. The residue
was dissolved in CH2Cl2 and washed with water. The aqueous phase was
extracted with CH2Cl2, and the combined organic layers were washed
with brine. The organic layer was dried with anh. MgSO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography to give the desired product.
But-2-yn-1-yl tert-butyl Carbonate (5b). Prepared according to
Method B using 2-butyn-1-ol (1.9 mL, 25 mmol), 60% w/w NaH (1.43
g, 35.7 mmol), Boc2O (5.2 g, 23.8 mmol), and THF (250 mL) for 16 h.
Purified by filtration over a short plug of SiO2 and the method by Basel
and Hassner25 (for the destruction of excess Boc2O) to afford 5b (1.08 g,
63%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 4.63 (q, J = 2.4
Hz, 2H), 1.85 (t, J = 2.4 Hz, 3H), 1.49 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 152.9, 83.4, 82.4, 72.8, 55.0, 27.6, 3.4; HRMS (ESI) calcd for
(C9H14O3Na)+ [M + Na]+: 193.0835, found: 193.0837.
second nucleophilic component. The cascade process forges two
bonds (C−C and C−N) en route to spirocyclized oxindole
products. Depending on the nature of the nitrogen nucleophile,
either the C−C or the C−N bond is formed first, thereby giving
with high selectivity 3′- or 2′-methylene spirocyclic products,
respectively. Substituted propargyl carbonates were examined
and found to react successfully with oxindole and indole
substrates, in some cases giving a single product. The
enantioselective variant of these spirocyclization reactions was
also examined for tryptamine substrates and provided the
corresponding spirocyclic products with modest to good
enantioselectivities.
EXPERIMENTAL SECTION
tert-Butyl (3-Phenylprop-2-yn-1-yl) Carbonate (5c). Step 1:
Prepared according to procedure by Panteleev and co-workers.26
Pd(PPh3)2Cl2 (35 mg, 50 μmol) and CuI (19 mg, 0.1 mmol) were
suspended in NEt3 (20 mL, 0.275 M) under a positive pressure of
nitrogen. To this suspension was added iodobenzene (560 μL, 5.0
mmol) and propargyl alcohol (320 μL, 5.5 mmol). The reaction was
stirred for 16 h at ambient temperature. Any precipitate matter was
removed by filtration through a plug of Celite, which was then washed
with NEt3 (2 × 10 mL). The reaction mixture was passed through a plug
of silica and concentrated in vacuo. This residue was used without further
purification. Step 2: Prepared according to Method B using 60% w/w
NaH (320 mg, 8.0 mmol) in THF (15 mL), the unpurified Sonogashira
product (5.0 mmol) as a solution in THF (10 mL), and Boc2O (982 mg,
4.5 mmol) in THF (25 mL). Purified by flash column chromatography
(10% EtOAc/Hexanes) to afford 5c (929 mg, 73% over both steps) as a
red/brown liquid. Analytical data (1H NMR, 13C NMR, and HRMS)
■
General Information. Reactions were run in oven-dried glassware
under a N2 atmosphere. Reactions were monitored by TLC on silica gel
60 Å F254 plates, visualized by UV florescence quenching (254 nm), I2/
SiO2, PMA, Seebach’s stain, or Hanessian’s staining solution. Flash
column chromatography (EtOAc/Hexanes or MeOH/CH2Cl2) was
performed with silica gel (40−63 μm). NMR spectra were measured at
500 MHz for 1H spectra and 125 MHz for 13C spectra. 1H spectra were
calibrated from internal standard TMS (δ 0.0) or solvent resonance
(CHCl3: 7.26, DMSO: 2.5). 13C spectra were calibrated from solvent
resonance (CHCl3: 77.0, DMSO: 39.52). NMR data are reported as
chemical shift (parts per million, ppm), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, p = pentet, m = multiplet, br = broad
signal), coupling constant (Hz), and integration. High-resolution mass
spectral analysis was measured on TOF LC/MS (positive electrospray
ionization). Enantiomeric excess was determined by chiral HPLC
analysis using an HPLC instrument with a Chiralcel OD-H or ChiralPak
AD-H or AS-H column (250 mm × 10 mm, 4.6 μm particle size, 1.0 mL/
min flow rate) equipped with a guard column, employing a mixture of
isopropanol and hexanes. Melting points were measured using a
capillary melting point apparatus.
match those reported in the literature.27
provided to demonstrate purity.
A
1H NMR spectrum is
tert-Butyl (2-Methylbut-3-yn-2-yl) Carbonate (5d). Prepared
according to Method B using 2-methyl-3-butyn-ol (1.02 mL, 10.5
mmol), 60% w/w NaH (0.62 g, 15.5 mmol), Boc2O (2.18 g, 10.0 mmol),
and THF (100 mL) for 16 h. Purified by filtration over a short plug of
Methylene chloride (CH2Cl2), tetrahydrofuran (THF), toluene, and
dimethylformamide (DMF) were purified by passage over activated
alumina, using a solvent purification system. All other solvents were
purchased from commercial suppliers and used as received. Pd2(dba)3·
CHCl3 and Pd(OAc)2 were purchased from commercial suppliers and
used as received. Xantphos, DPEphos, dppb, (R,R)-DACH, PPh3, (R)-
T-BINAP, QUINAP, and (R)-BINAP were purchased from commercial
suppliers and used as received. BIPHEP ligands L1, L2, L3, and L4 were
prepared according to previously published procedures.7b tert-Butyl
prop-2-yn-1-yl carbonate, 4-methyl-N-(2-(2-methyl-1H-indol-3-yl)-
ethyl)benzenesulfonamide, 4-methyl-N-(2-(2-phenyl-1H-indol-3-yl)-
ethyl)benzenesulfonamide, and N-(2-(2-(3,4-dimethoxyphenyl)-1H-
indol-3-yl)ethyl)-4-methylbenzenesulfonamide were prepared accord-
ing to previously published procedures.13 Unless otherwise noted,
tryptamine, propargyl alcohols, and all other materials were purchased
from commercial suppliers and used as received.
1
SiO2 to afford 5d (1.05 g, 57%) as a colorless liquid. H NMR (500
MHz, CDCl3) δ 2.56 (s, 1H), 1.69 (s, 6H), 1.49 (s, 9H); 13C NMR (125
MHz, CDCl3) 151.13, 84.22, 81.86, 72.56, 72.33, 28.66, (×2) 27.60
(×3); HRMS (ESI) calcd for (C10H17O3)+ [M + H]+: 185.1172, found:
185.1169.
tert-Butyl (2-Methyl-4-phenylbut-3-yn-2-yl) Carbonate (5e).
Step 1: Prepared according to a procedure by Li and co-workers.28 To a
125 mL flame-dried round bottom flask (RBF) were added HNEt2 (125
mL), PhBr (7.6 mL, 60 mmol), 2-methyl-3-butyn-2-ol (4.9 mL, 50
mmol), PPh3 (197 mg, 0.75 mmol), CuI (95 mg, 0.5 mmol), and
Pd(OAc)2 (56 mg, 0.25 mmol). The mixture was sparged with N2 for 30
min, and then the RBF was fitted with a reflux condenser and sparged for
an additional 5 min. The reaction was allowed to reflux for 22 h. After
cooling to ambient temperature, the mixture was concentrated in vacuo.
Purified by flash column chromatography (10% EtOAc/Hexanes) to
afford the Sonogashira product (6.98 g, 87%) as a tan solid. Analytical
data (1H and 13C NMR) match those reported in the literature.28 1H
NMR spectrum is provided to demonstrate purity. Step 2: Prepared
according to Method B using Sonogashira product (1.76 g, 11 mmol),
60% w/w NaH (840 mg, 21 mmol), Boc2O (2.29 g, 10.5 mmol), and
THF (110 mL). Purified by flash column chromatography (10%
EtOAc/Hexanes) and the method by Basel and Hassner25 (for the
destruction of excess Boc2O) to afford 5e (1.67 g, 61%) as a light yellow
solid. Mp: 46−47 °C; 1H NMR (500 MHz, CDCl3): δ 7.45−7.40 (m,
2H), 7.33−7.27 (m, 3H), 1.78 (s, 6H), 1.51 (s, 9H); 13C NMR (125
MHz, CDCl3): δ 151.3, 131.6 (×2), 128.2, 128.1 (×2), 122.6, 89.9, 84.0,
81.8, 73.7, 28.9 (×2), 27.7 (×3); HRMS (ESI) calcd for (C16H20O3Na)+
[M + Na]+: 283.1305, found: 283.1294.
General Procedure for tert-Butyl Propargyl Carbonates.
Method A: Prepared according to Chalasani and co-workers.23 To a
solution of propargyl alcohol in anh. CH2Cl2 maintained under a
positive pressure of nitrogen were added N(i-Pr)2Et and DMAP. The
reaction mixture was cooled to 0 °C, and di-tert-butyl dicarbonate was
added either portionwise over two min or dropwise as a solution in
CH2Cl2. The reaction mixture was slowly warmed to ambient
temperature (23 °C) over 3 h. The reaction mixture was diluted with
CH2Cl2 and washed with water, 10% aq. HCl, sat. aq. NaHCO3, and
brine. The organic layer was then dried over anh. MgSO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography to give the desired product. Method B: Prepared
according to Stambask and co-workers.24 To a suspension of 60% w/w
̌
tert-Butyl (1-Phenylprop-2-yn-1-yl) Carbonate (5f). Prepared
according to Method A using 1-phenylprop-2-yn-1-ol (920 μL, 7.57
mmol), Boc2O (2.2 g, 9.9 mmol), N(i-Pr)2Et (3.3 mL, 18.9 mmol),
DMAP (93 mg, 0.76 mmol), and CH2Cl2 (640 μL). Purified by flash
column chromatography (10% EtOAc/Hexanes) to afford 5f (1.54 g,
NaH in THF maintained under a positive pressure of nitrogen was
added the propargyl alcohol. This mixture was allowed to stir at ambient
temperature for 30 min and was then cooled to 0 °C. To this mixture was
added a solution of Boc2O in THF over 1 h, and the mixture was allowed
to warm to ambient temperature. After consumption of the starting
G
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Article
88%) as a red/brown liquid. Analytical data (1H NMR, 13C NMR,
HRMS) match those reported in the literature.27 A 1H NMR spectrum is
provided to demonstrate purity.
on standing. Analytical data (1H and 13C NMR) match those reported in
the literature.33 A 1H NMR spectrum is provided to demonstrate purity.
Preparation of C-3-Alkyl Sulfonamides. To a solution of
tryptamine (5 mmol) in anh. CH2Cl2 (8 mL) maintained under a
positive pressure of nitrogen was added NEt3 (10.0 mmol) and cooled to
0 °C. To the stirred solution was added tosyl or mesyl chloride (5.5
mmol) in one portion, and the reaction was allowed to slowly warm to
ambient temperature. The reaction was allowed to stir an additional 12
h. The solution was then diluted with CH2Cl2 (10 mL), washed with
10% aq. HCl (2 × 10 mL), aq. NaHCO3 (15 mL), and brine. The
organic layer was passed through a plug of silica, which was washed with
CH2Cl2 (3 × 15 mL). The combined organic portions were dried over
anh. MgSO4 or anh. Na2SO4 and concentrated in vacuo. The residue was
purified by flash column chromatography to give the desired products.
N-(2-(1H-Indol-3-yl)ethyl)-4-methylbenzenesulfonamide (SI-
3). Prepared according to the general procedure using tryptamine (2.4 g,
15 mmol), CH2Cl2 (24 mL), Et3N (2.3 mL, 16.5 mmol), and TsCl (3.43
g, 18 mmol) for 16 h at 0 → rt. Purified by flash column chromatography
(5% MeOH/CH2Cl2) to afford SI-3 (4.13 g, 88%) as a pale orange solid.
Analytical data (1H and 13C NMR) match those reported in the
literature.34 A 1H NMR spectrum is provided to demonstrate purity.
4-Methyl-N-(2-(1-methyl-1H-indol-3-yl)ethyl)benzene-
sulfonamide (SI-4). Prepared according to the general procedure using
tryptamine SI-1 (310 mg, 1.63 mmol), CH2Cl2 (8.2 mL), NEt3 (450 μL,
3.3 mmol), and TsCl (370 mg, 2.0 mmol) for 12 h at ambient
temperature. Purified by flash column chromatography (20% EtOAc/
Hexanes) to afford SI-4 (1.01 g, 62% over two steps) as a yellow oil.
Analytical data (1H NMR, 13C NMR, HRMS) match those reported in
the literature.35 A 1H NMR spectrum is provided to demonstrate purity.
N-(2-(1-Benzyl-1H-indol-3-yl)ethyl)-4-methylbenzene-
sulfonamide (SI-5). Step 1: Prepared according to a procedure by
Feng and co-workers.36 To a 250 mL RBF were added tryptamine (4.81
g, 30 mmol), phthalic anhydride (4.58 g, 30.9 mmol), and toluene (176
mL). The RBF was fitted with a reflux condenser and brought to reflux.
After 13 h, the reaction mixture was cooled and concentrated in vacuo.
Purified by trituration from CH2Cl2 and Hexanes to afford tryptamine
phthalimide (7.77 g, 89%) as a light-yellow solid after three triturations.
Analytical data (1H, 13C NMR) match those reported in the literature.36
A 1H NMR spectrum is provided to demonstrate purity. HRMS (ESI)
calcd for (C18H15N2O2) + [M + H]+: 291.1128, found: 291.1129. Step 2:
Prepared according to Zhai and co-workers.37 To a suspension of 60%
w/w NaH (488 mg, 12.2 mmol) in DMF (87 mL) was added a solution
of tryptamine phthalimide (2.61 g, 6.12 mmol) in DMF (44 mL). Benzyl
bromide (2.5 mL, 20.8 mmol) was added to the mixture, which was then
heated at 60 °C for 14.5 h. At this point, TLC indicated incomplete
consumption of starting material, so additional NaH (488 mg, 12.2
mmol) was added. After an additional 2 h, the reaction was cooled to
ambient temperature. The mixture was poured over NaHCO3, into
EtOAc, washed five times with water, once with brine, and dried over
anh. Na2SO4. The orange-sherbert-colored solid was used without
further purification. Step 3: The protected tryptamine (6.12 mmol) was
dissolved in EtOH (100 mL) and heated to 70 °C. After 10 min, 50−
60% hydrazine hydrate (1.9 mL) was added. After 18.5 h, the mixture
was cooled to ambient temperature and filtered through a cotton plug.
The filtrate was diluted with 1.0 M aq. NaOH and extracted three times
with 4:1 CHCl3/i-PrOH and dried over anh. Na2SO4. The solvent was
concentrated to afford a light yellow oil, which was used without further
purification. Step 4: Prepared according to the general procedure using
unpurified tryptamine precursor (6.12 mmol), CH2Cl2 (9.9 mL), NEt3
(938 μL, 6.73 mmol), and TsCl (1.4 g, 7.34 mmol) for 17.5 h at ambient
temperature. Purified by flash column chromatography (30 → 40%
EtOAc/Hexanes) to afford SI-5 (2.05 g, 83% over two steps) as an off-
white solid. Mp: 118 °C; 1H NMR (500 MHz, CDCl3): δ 7.62 (d, J = 8.3
Hz, 2H), 7.42 (d, J = 7.9 Hz, 1H), 7.34−7.28 (m, 2H), 7.28−7.24 (m,
2H), 7.20 (d, J = 8.1 Hz, 2H), 7.19−7.16 (m, 1H), 7.10 (d, J = 6.8 Hz,
2H), 7.05 (ddd, J = 7.8, 7.0, 1.0 Hz, 1H), 6.86 (s, 1H), 5.25 (s, 2H), 4.33
(t, J = 6.1 Hz, 1H), 3.28 (q, J = 6.5 Hz, 2H), 2.92 (t, J = 6.6 Hz, 2H), 2.39
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 143.0, 137.3, 136.8, 136.6,
129.4 (×2), 128.5 (×2), 127.5, 127.4, 126.8 (×2), 126.7 (×2), 126.4,
tert-Butyl (4-Phenylbut-3-yn-2-yl) Carbonate (5g). Prepared
according to Method A using 4-phenyl-3-butyn-2-ol (1.11 mL, 7.6
mmol), Boc2O (2.2 g, 9.9 mmol), N(i-Pr)2Et (3.3 mL, 18.9 mmol),
DMAP (93 mg, 0.76 mmol), and CH2Cl2 (0.64 mL) for 16 h. Purified by
filtration over a short plug of SiO2 to afford 5g (2.01 g, 99%) as a pale
1
yellow liquid. H NMR (500 MHz, CDCl3): δ 7.46−7.41 (m, 2H),
7.33−7.27 (m, 3H), 5.50 (q, J = 6.7 Hz, 1H), 1.62 (d, J = 6.7 Hz, 3H),
1.51 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 152.3, 131.6, 128.3, 128.0
(×2), 122.1, 87.0, 84.8, 82.2, 63.4, 27.6, 27.5 (×3), 21.3; HRMS (ESI)
calcd for (C15H18O3Na)+ [M + Na]+: 269.1148, found: 269.1152.
Preparation of N1-Alkyl Tryptamines and Tryptamine
Derivatives: 2-(1-Methyl-1H-indol-3-yl)ethanamine (SI-1).
Step1: Prepared according to Feldman and co-workers.29 To a 250
mL RBF were added tryptamine (3.52 g, 22 mmol), 1,4-dioxane (18.3
mL), and Et3N (6.13 mL, 44 mmol). A solution of Boc2O (4.37 g, 20
mmol) in 1,4-dioxane (18.3 mL) was added dropwise via addition funnel
over 10 min. After 18 h, the mixture was poured into a separatory funnel,
diluted with CH2Cl2, and washed three times with 1.0 M aq. HCl. The
organic layer was backextracted once with CH2Cl2, and the combined
organic layers were washed once with brine, dried over anh. Na2SO4, and
concentrated in vacuo. The dark red-brown residue was used without
further purification. Step 2: Prepared according to Song and co-
workers.30 To a 250 mL RBF containing unpurified Boc-tryptamine
were added CH2Cl2 (110 mL), TBAHSO4 (1.49 g, 4.39 mmol),
powdered NaOH (10.6 g, 26.5 mmol), and MeI (2.74 mL, 44 mmol).
The mixture was stirred for 15 h, then diluted with water, and stirred
vigorously for 30 min. The organic layer was separated, washed three
times with water, and backextracted once with CH2Cl2. The combined
organic layers were washed once with brine, dried over anh. Na2SO4, and
concentrated in vacuo. Purified by flash column chromatography (20%
EtOAc/Hexanes) to remove most of the TBAHSO4. The resulting
residue was used without further purification. Step 3: Prepared
according to a modified procedure by Song and co-workers.30 To a
500 mL RBF containing N-methyl Boc tryptamine was added CH2Cl2
(100 mL). This solution was cooled with an ice/water bath, and a
solution of 50/50 v/v TFA/CH2Cl2 (15.3 mL) was added dropwise over
30 min via an addition funnel. The reaction mixture was stirred for 10
min at 0 °C, then the ice/water bath was removed, and the reaction
mixture was allowed to warm to ambient temperature. After 16.5 h, the
reaction mixture was cooled with an ice/water bath and slowly
neutralized with sat. aq. NaHCO3. The resulting mixture was poured
into a separatory funnel, and the organic layer was separated. The
aqueous layer was extracted twice with CH2Cl2, washed once with brine,
dried over Na2SO4, and concentrated in vacuo to afford SI-1 (2.82 g,
82%) as a dark-brown solid foam. Analytical data (1H and 13C NMR)
match those reported in the literature.31
provided to demonstrate purity.
A
1H NMR spectrum is
Methyl (2-(1H-Indol-3-yl)ethyl)carbamate (SI-2). Step 1:
Prepared according to a procedure by Fong and Copp.32 To a mixture
of tryptamine (3.20 g, 20 mmol) in EtOAc (40 mL) were added 1.0 M
NaOH (25 mL) and methyl chloroformate (2 mL, 26 mmol). After 14 h
at ambient temperature (23 °C), the reaction mixture was poured into a
separatory funnel. The organic layer was separated, washed once with
water, dried over anh. Na2SO4, and concentrated in vacuo. The residue
was used without further purification. Step 2: Prepared according to
Method B with tryptamine carbamate (20 mmol), CH2Cl2 (100 mL),
TBAHSO4 (1.36 g, 4 mmol), powdered NaOH (9.6 g, 400 mmol), and
MeI (2.5 mL, 40 mmol) at ambient temperature for 19 h. Afterwards,
analysis by TLC indicated that the reaction had not gone to completion.
Additional powdered NaOH (9.6 g, 400 mmol) was added. TLC after an
additional 9 h indicated that the reaction had gone to completion. The
reaction mixture was diluted with water and poured into a separatory
funnel. The organic layer was separated and washed twice with 1.0 M
HCl. The organic layer was washed once with brine and dried over anh.
Na2SO4. Purified by flash column chromatography (3 → 4% MeOH/
CH2Cl2) to afford SI-2 (2.65 g, 57%) as a red-orange oil that solidified
H
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121.7, 119.0, 118.6, 110.7, 109.7, 49.7, 43.1, 25.3, 21.3; HRMS (ESI)
calcd for (C24H25N2O2S)+ [M + H]+: 405.1631, found: 405.1624.
Methyl 3-(1H-Indol-3-yl)-2-(4-methylphenylsulfonamido)-
propanoate (SI-6). Prepared according to the general procedure
using (L)-tryptophan methyl ester hydrochloride (2.0 g, 7.9 mmol),
CH2Cl2 (15.7 mL), Et3N (3.3 mL, 23.6 mmol), and TsCl (1.65 g, 8.6
mmol) for 12 h at ambient temperature. Purified by flash column
chromatography (20% EtOAc/Hexanes) to afford SI-6 (2.05 g, 70%) as
a white powder. Analytical data (1H NMR, 13C NMR, HRMS) match
those reported in the literature.38 A 1H NMR spectrum is provided to
demonstrate purity.
2-(1-Methyl-1H-indol-3-yl)-N-phenylacetamide (SI-8). Pre-
pared according to the general procedure using 1-methyl-3-indoleacetic
acid (1.89 g, 10 mmol), CH2Cl2 (33 mL), NEt3 (3.1 mL, 22 mmol),
EDCI (2.3 g, 12 mmol), and aniline (1 mL, 11 mmol) for 15 h at
ambient temperature. Purified by flash column chromatography (0 →
2% MeOH/CH2Cl2) to afford SI-8 (1.20 g, 45%) as a tan solid.
Analytical data (1H and 13C NMR) match those reported in the
literature.41 A 1H NMR spectrum is provided to demonstrate purity.
N-Methyl-2-(1-methyl-1H-indol-3-yl)acetamide (SI-9). Pre-
pared according to the general procedure using 1-methyl-3-indoleacetic
acid (1.89 g, 10 mmol), CH2Cl2 (33 mL), NEt3 (3.1 mL, 22 mmol),
EDCI (2.3 g, 12 mmol), and MeNH2 (5.5 mL, 2.0 M in THF) for 18 h at
ambient temperature. Purified by flash column chromatography (5 →
30% MeOH/CH2Cl2) to afford SI-9 (1.06 g, 52%) as an orange-brown
solid. Analytical data (1H NMR, 13C NMR, HRMS) match those
4-Methyl-N-(3-(1-methyl-1H-indol-3-yl)propyl)benzene-
sulfonamide (SI-7). Step 1: Prepared according to a modified
procedure by Kuehne and co-workers.39 To a 20 mL Ace Glass pressure
tube was added indole (4.69 g, 40 mmol), acrylonitrile (4.4 mL, 66.8
mmol), Cu(OAc)2 (80 mg, 0.4 mmol), B(OH)3 (25 mg, 0.4 mmol), and
toluene (2.9 mL). The vessel was sealed and heated to 135 °C behind a
blast shield. After 48 h, the reaction was cooled to ambient temperature.
The reaction mixture was poured into a separatory funnel and diluted
with water, and the aqueous layer was extracted three times with
CH2Cl2. The combined organic layers were dried over anh. Na2SO4.
Purified by flash column chromatography (10 → 20% EtOAc/Hexanes)
to afford the nitrile (4.24 g, 62%) as an off-white solid. Analytical data
(1H NMR, 13C NMR, HRMS) matched those reported in the
reported in the literature.42
demonstrate purity.
A
1H NMR spectrum is provided to
General Procedure for Indole Oxidation. To a solution of
tryptamine in DMSO at ambient temperature (23 °C) was added 12.1
M HCl dropwise. After the oxidation was completed, the reaction
mixture was neutralized with sat. aq. NaHCO3 and extracted with
CH2Cl2. The combined organic layers were washed with water and brine
and dried over anh. MgSO4 or anh. Na2SO4. The organic extract was
then concentrated in vacuo. The residue was purified by flash column
chromatography to give the desired products.
literature.40 A H NMR spectrum is provided to demonstrate purity.
1
Step 2: Prepared according to a modified procedure by Kuehne and co-
workers.39 To a 200 mL RBF fitted with a reflux condenser under a
positive pressure of nitrogen was added lithium aluminum hydride (25.9
mL of 1.0 M solution in THF, 25.9 mmol) followed by cooling to 0 °C. A
solution of the nitrile (2.0 g, 11.8 mmol) in THF (35.6 mL) was added
to the cooled reaction flask dropwise via cannula over 10 min. The
reaction flask was then warmed to room temperature, heated to reflux
using an oil bath, and allowed to reflux for 5 h. The reaction mixture was
then allowed to cool to room temperature and was worked up using the
Fieser method. The resulting residue was purified by flash column
chromatography (5% MeOH/CH2Cl2) to afford the amine (1.05 g, 51%
yield) as a yellow oil. The oil was used without further purification. Step
3: Prepared according to a modified procedure by Meijere and co-
workers.31 To a solution of the crude amine (0.42 g, 2.4 mmol) in DMF
(6 mL) 60% w/w NaH (116 mg, 2.9 mmol) was added portionwise over
5 min. This was allowed to stir at ambient temperature for 30 min under
a positive pressure of nitrogen. To the stirring solution was added a
solution of MeI (0.18 mL, 2.9 mmol) in DMF (6 mL) dropwise over 15
min. The resulting solution was allowed to stir for an additional 18 h.
The reaction solution was poured into water and diluted with CH2Cl2.
The organic layer was separated and washed 5 times with H2O, once
with brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by flash column chromatography (10% EtOAc/Hexanes)
to afford the alkylated homotryptamine (0.31 g, 68%) as a pale-yellow
oil. Step 4: Prepared according to the general procedure using the
homotryptamine precursor (0.23 g, 1.2 mmol), CH2Cl2 (2.4 mL), Et3N
(0.2 mL, 1.44 mmol), and TsCl (0.27 g, 1.44 mmol) for 18 h at ambient
temperature. Purified by flash column chromatography (20% EtOAc/
4-Methyl-N-(2-(1-methyl-2-oxoindolin-3-yl)ethyl)benzene-
sulfonamide (6a). Prepared according to the general procedure using
sulfonamide SI-4 (320 mg, 1.0 mmol), DMSO (1.7 mL 24.3 mmol), and
12.1 M HCl (3.4 mL, 41.6 mmol) at ambient temperature. Methanol (1
mL) was added to keep solids solubilized. Purified by flash column
chromatography (30% EtOAc/Hexanes) to afford 6a (170 mg, 55%) as
a white solid. Mp: 132−133 °C; 1H NMR (500 MHz, CDCl3): δ 7.74 (d,
J = 8.2 Hz, 2H), 7.33−7.27 (m, 3H), 7.17 (d, J = 7.3 Hz, 1H), 7.07 (t, J =
7.7 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 5.52 (br s, 1H), 3.45 (dd, J = 8.8,
5.1 Hz, 1H), 3.26 (ddd, J = 12.8, 7.1, 5.6 Hz, 1H), 3.22−3.11 (m, 1H),
3.19 (s, 3H), 2.42 (s, 3H), 2.25−2.16 (m, 1H), 1.91 (dddd, J = 14.3, 8.8,
7.1, 5.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 177.8, 143.9, 143.1,
137.2, 129.6, 128.2 (×2), 128.2, 127.0 (×2), 123.6, 122.7, 108.2, 43.5,
40.9, 30.3, 26.2, 21.4.; HRMS (ESI) calcd for (C18H21N2O3S)+ [M +
H]+: 345.1267, found: 345.1253.
N-(2-(1-Benzyl-2-oxoindolin-3-yl)ethyl)-4-methylbenzene-
sulfonamide (6b). Prepared according to the general procedure using
sulfonamide SI-5 (331 mg, 0.82 mmol), DMSO (291 μL, 4.09 mmol),
and 12.1 M HCl (676 μL, 8.18 mmol) at ambient temperature for 24 h.
Analysis by TLC indicated the reaction was not yet complete, so
additional DMSO (291 μL, 4.09 mmol) and 12.1 M HCl (676 μL, 8.18
mmol) were added to the reaction mixture, which was stirred for an
additional 10 h. Purified by flash column chromatography (40% EtOAc/
Hexanes) to afford 6b (279 mg, 81%) as an off-white solid. Mp: 118 °C;
1H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 8.2 Hz, 2H), 7.36−7.23 (m,
7H), 7.22−7.13 (m, 2H), 7.03 (td, J = 7.6, 1.0 Hz, 1H), 6.76−6.68 (m,
1H), 5.57−5.46 (m, 1H), 4.91 (d, J = 15.7 Hz, 1H), 4.85 (d, J = 15.6 Hz,
1H), 3.55 (dd, J = 8.7, 5.1 Hz, 1H), 3.37−3.25 (m, 1H), 3.20 (ddt, J =
12.8, 7.1, 5.7 Hz, 1H), 2.42 (s, 3H), 2.25 (ddt, J = 14.4, 7.1, 5.5 Hz, 1H),
1.95 (dddd, J = 14.0, 8.5, 7.0, 5.7 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ 177.8, 143.0, 142.9, 137.1, 135.6, 129.5 (×2), 128.6 (×2),
128.1, 128.0, 127.5, 127.1 (×2), 126.9 (×2), 123.8, 122.6, 109.1, 43.6,
43.2, 40.6, 30.5, 21.3; HRMS (ESI) calcd for (C24H22N2O2SNa)+ [M −
H2O + Na]+: 425.1300, found: 425.1300.
1
Hexanes) to afford SI-7 (0.23 g, 59%) as a yellow oil. H NMR (500
MHz, CDCl3): δ 7.70 (d, J = 8.2 Hz, 2H), 7.46 (dd, J = 7.9, 1.1 Hz, 1H),
7.31−7.24 (m, 3H), 7.21 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.07 (ddt, J =
8.0, 7.0, 1.1 Hz, 1H), 6.76 (s, 1H), 4.41 (br s, 1H), 3.72 (s, 3H), 3.01 (q, J
= 6.6 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H), 2.41 (s, 3H), 1.85 (m, 2H); 13C
NMR (125 MHz, CDCl3): δ 143.2, 137.0, 129.6 (×2), 127.6, 127.1
(×3), 126.4, 121.5, 118.7, 118.6, 113.3, 109.2, 42.8, 32.5, 29.9, 21.9, 21.5;
HRMS (ESI) calcd for (C19H23N2O2S)+ [M + H]+: 343.1475, found:
343.1475.
Preparation of Indole 3-Acetamides. To a 100 mL RBF was
added indole acetic acid and CH2Cl2. Et3N was added, followed by
EDCI. The mixture was allowed to stir for a few minutes, and then the
amine was added. Upon consumption of starting material, the reaction
was diluted with water. The mixture was poured into a separatory funnel
and washed with 1.0 M NaOH several times and brine and dried over
anh. Na2SO4. The residue was purified by flash column chromatography
to give the desired products.
4-Methyl-N-(2-(2-oxoindolin-3-yl)ethyl)benzenesulfonamide
(6c). Prepared according to the general procedure using sulfonamide SI-
3 (1.12 g, 3.56 mmol), DMSO (909 μL, 12.8 mmol), and 12.1 M HCl
(1.06 mL, 12.8 mmol) at ambient temperature for 22 h. Purified by flash
column chromatography (10% MeOH/CH2Cl2) to afford 6c (768 g,
1
65%) as a light purple solid. Mp 160−161 °C; H NMR (500 MHz,
DMSO-d6): δ 10.39 (s, 1H), 7.69 (s, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.39
(d, J = 8.1 Hz, 2H), 7.16 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 6.93
(t, J = 7.5 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 3.43 (t, J = 6.7 Hz, 1H), 3.35
(br s, 1 H), 2.93−2.81 (m, 2H), 2.38 (s, 3H), 1.91 (ddt, J = 13.3, 8.8, 6.7
Hz, 1H), 1.81 (ddt, J = 13.3, 8.5, 6.4 Hz, 1H); 13C NMR (125 MHz,
I
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Article
DMSO-d6): δ 178.5, 142.6, 142.5, 137.5, 129.6 (×2), 129.1, 127.7, 126.4
(×2), 123.8, 121.2, 109.2, 42.5, 40.0, 30.3, 20.9; HRMS (ESI) calcd for
(C17H18N2O3S)+ [M + H]+: 331.1111, found: 331.1094.
2.91−2.83 (m, 1H), 2.87 (d, J = 4.7 Hz, 3 H), 2.58 (dd, J = 15.5, 6.8 Hz,
1H); 13C NMR (125 MHz, CDCl3): δ 177.6, 170.7, 143.8, 128.4, 128.1,
124.1, 122.6, 108.0, 42.2, 37.0, 26.3, 26.2; HRMS (ESI) calcd for
(C12H15N2O2)+ [M + H]+: 219.1128, found: 219.1129.
Methyl 3-(1-Methyl-2-oxoindolin-3-yl)-2-(4-methylphenyl-
sulfonamido)propanoate (6d). Prepared according to the general
procedure using sulfonamide SI-6 (1.9 g, 5.0 mmol), DMSO (8.5 mL,
120 mmol), and 12.1 M HCl (17 mL, 205 mmol) at ambient
temperature for 12 h. Purified by flash column chromatography (30%
EtOAc/Hexanes) to afford 6d (1.3 g, 66%) as a white solid. Mp: 97−98
°C; 1H NMR (500 MHz, CDCl3) δ 8.72 (br s, min), 8.59 (br s, maj),
7.78 (d, J = 8.2 Hz, maj), 7.64 (d, J = 8.2 Hz, min), 7.33 (d, J = 7.5 Hz,
min), 7.30 (d, J = 8.0 Hz, maj), 7.23 (d, J = 6.7 Hz, 2H), 7.20 (d, J = 7.0
Hz, 2H), 7.08−7.02 (m, 2H), 6.90 (d, J = 7.8 Hz, maj), 6.87 (d, J = 7.7
Hz, min), 6.41 (d, J = 10.1 Hz, min), 6.15 (d, J = 8.8 Hz, maj), 4.30 (td, J
= 9.1, 5.0 Hz, maj), 4.22 (td, J = 9.9, 4.2 Hz, min), 3.72−3.66 (m, 1H),
3.62 (dd, J = 7.9, 3.3 Hz, 1H), 3.46 (s, maj), 3.43 (s, min), 2.41 (s, maj),
2.38 (s, min), 2.33 (ddd, J = 14.4, 9.2, 3.7 Hz, maj), 2.19 (ddd, J = 14.1,
8.2, 4.9 Hz, min); 13C NMR (125 MHz, CDCl3) δ 171.7, 171.4, 143.6,
143.3, 141.8, 141.3, 137.0, 136.7, 129.6, 129.4, 128.8, 128.3, 128.2, 127.3,
127.1, 124.4, 123.8, 122.6, 122.4, 110.3, 110.1, 53.9, 53.7, 52.4, 52.3,
42.7, 42.2, 34.1, 32.4, 21.5, 21.4; HRMS (ESI) calcd for
(C19H21N2O5S)+ [M + H]+: 389.1166, found: 389.1159.
4-Methyl-N-(3-(1-methyl-2-oxoindolin-3-yl)propyl)benzene-
sulfonamide (6e). Prepared according to the general procedure using
unpurified tryptamine SI-7 (0.23 g, 0.67 mmol), DMSO (1.2 mL, 16.1
mmol), and 12.1 M HCl (2.3 mL, 27.5 mmol) at ambient temperature
for 12 h. Purified by flash column chromatography (50% EtOAc/
Hexanes) to afford 6e (0.16 g, 68%) as a brown solid. Mp: 129−130 °C;
1H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 8.2 Hz, 2H), 7.35−7.24 (m,
3H), 7.17 (d, J = 7.5 Hz, 1H), 7.04 (td, J = 7.5, 1.0 Hz, 1H), 6.81 (d, J =
7.8 Hz, 1H), 4.85 (t, J = 6.2 Hz, 1H), 3.42 (t, J = 6.0 Hz, 1H), 3.16 (s,
3H), 2.99−2.84 (m, 2H), 2.42 (s, 3H), 2.02−1.84 (m, 2H), 1.61−1.49
(m, 2H); 13C NMR (125 MHz, CDCl3): δ 177.6, 144.2, 143.2, 137.0,
129.6 (×2), 128.5, 128.0, 127.0 (×2), 123.7, 122.5, 108.0, 44.7, 42.9,
27.3, 26.1, 25.8, 21.5; HRMS (ESI) calcd for (C19H23N2O3S)+ [M +
H]+: 359.1424, found: 359.1408.
3-(2-Hydroxyphenyl)-1-methylindolin-2-one (6i). Step 1: Pre-
pared according to a procedure by Basavaiah and co-workers.43 To a 250
mL RBF was added isatin (2.94 g, 20 mmol), Na2CO3 (5.30 g, 50
mmol), acetone (100 mL), and Me2SO4 (2.85 mL, 30 mmol). The RBF
was fitted with a reflux condenser and heated at reflux for 42.5 h. After
cooling to ambient temperature, the bright-orange suspension was
vacuum-filtered and the filtrate was concentrated. Purified by flash
column chromatography (0 → 2.5% EtOAc/Hexanes) to afford methyl
isatin (2.92 g) as a bright red-orange oil that consisted of a mixture of
product and some Me2SO4. The residue was used without further
purification. Step 2: The 100 mL RBF containing the aforementioned
methyl isatin was purged with N2, and anh. CH2Cl2 (20 mL) and
cyclohexenone (1.94 mL, 20 mmol) were added. The mixture was
cooled with an ice/water bath, and TiCl4 (20 mL, 1.0 M in CH2Cl2) was
added. The reaction was allowed to warm to ambient temperature. After
3.5 h, the reaction mixture was cooled with an ice/water bath and
quenched with water, extracted three times with CH2Cl2, and dried over
anh. Na2SO4, The combined organic layers were reduced in vacuo.
Purified by flash column chromatography (5% MeOH/CH2Cl2) to
afford the hydroxyoxindole (1.68 g, 33% over two steps) as a light-yellow
solid foam. A 1H NMR spectrum is provided to demonstrate purity. Step
3: To a 100 mL RBF containing the hydroxyoxindole (852 mg, 3.31
mmol) was added 1,2-dichloroethane (3.3 mL) and 48% aq. HBr (1.9
mL). The reaction mixture was refluxed for 15.5 h and then cooled to
ambient temperature. The reaction mixture was diluted with water and
extracted three times with CH2Cl2, and the combined organic layers
were dried over anh. Na2SO4 and concentrated in vacuo. Purified by flash
column chromatography (50−75% EtOAc/Hexanes) to afford 6i (551
mg, 70%) as an off-white solid. Analytical data (1H and 13C NMR)
match those reported in the literature.43
provided to demonstrate purity.
A
1H NMR spectrum is
General Procedure for the Calculation of NMR Yields. The
crude reaction mixture was concentrated in vacuo, and the residue was
dissolved in an appropriate deuterated solvent (1 mL). To this solution
was added 1,3,5-trimethoxybenzene (0.33 equiv), followed by stirring
until all solids were completely dissolved. An aliquot was removed and
subjected to 1H NMR analysis (d1 relaxation time is set to 5) wherein
the integration value of the 1,3,5-trimethoxybenzene signal at δ 6.08 (s,
3H) was compared to the integration values of several peaks
corresponding to the desired product. With this information the
NMR yield was determined by using the following equations:
Methyl (2-(1-Methyl-2-oxoindolin-3-yl)ethyl)carbamate (6f).
Prepared according to the general procedure using tryptamine SI-2
(1.43 g, 6.16 mmol), DMSO (2.2 mL, 30.8 mmol), and 12.1 M HCl (5.1
mL, 61.6 mmol) at ambient temperature for 21 h. Purified by flash
column chromatography (40 → 50% EtOAc/Hexanes), followed by
trituration with CH2Cl2/Et2O to afford 6f (515 mg, 34%) as a light gray
1
powder. Mp: 98 °C; H NMR (500 MHz, CDCl3): δ 7.34−7.27 (m,
2H), 7.08 (td, J = 7.5, 1.0 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 5.27 (br s,
1H), 3.65 (s, 3H), 3.48 (t, J = 6.7 Hz, 1H), 3.46−3.34 (m, 2H), 3.21 (s,
3H), 2.25−2.16 (m, 1H), 2.03 (dt, J = 14.0, 7.1 Hz, 1H); 13C NMR (125
MHz, CDCl3): δ 177.7, 157.0, 144.0, 128.5, 128.0, 123.8, 122.6, 108.0,
51.9, 43.4, 38.5, 30.6, 26.1; HRMS (ESI) calcd for (C13H17N2O3)+ [M
+H]+: 249.1234, found: 249.1232.
P
NMR yield =
SM
2-(1-Methyl-2-oxoindolin-3-yl)-N-phenylacetamide (6g). Pre-
pared according to the general procedure using tryptamine SI-8 (1.02 g,
3.86 mmol), DMSO (1.4 mL, 19.3 mmol), and 12.1 M HCl (3.2 mL,
38.6 mmol) at ambient temperature for 16 h. Purified by flash column
chromatography (2.5% MeOH/CH2Cl2) to afford 6g (849 mg, 79%) as
a straw-colored solid. Mp: 58−59 °C; 1H NMR (500 MHz, CDCl3): δ
9.06 (br s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.40−7.29 (m, 4H), 7.16−7.06
(m, 2H), 6.87 (d, J = 7.7 Hz, 1H), 3.96 (t, J = 6.7 Hz, 1H), 3.27 (s, 3H),
3.05 (dd, J = 15.8, 7.8 Hz, 1H), 2.79 (dd, J = 15.7, 5.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3): δ 177.9, 168.6, 143.7, 138.1, 128.9 (×2), 128.3,
128.1, 124.2, 124.1, 123.0, 119.9 (×2), 108.2, 42.2, 38.4, 26; HRMS
(ESI) calcd for (C17H14N2ONa)+ [M−H2O+Na]+: 285.1004, found:
285.1015.
3x
y
P =
* mmol of (1, 3, 5‐trimethoxybenzene)
P = calculated mmol of product; SM = mmol of starting material; x = a
normalized average of three aromatic signals corresponding to the
product; and y = integration value of 1,3,5-trimethoxybenzene peak at δ
6.08.
General Procedure for the Pd-Catalyzed Spirocyclization of
Oxindole-Based Bis-nucleophiles. Oxindole substrate 6 (0.20
mmol), Pd2(dba)3·CHCl3 (5 mg, 5.0 μmol, 5 mol % Pd), and dppb
(5 mg, 11 μmol) were added to an oven-dried 16 × 100 borosilicate test
tube. The test tube was covered with a rubber septum and sealed with
Teflon tape or parafilm. The test tube was purged with N2, anhydrous
THF (2 mL) was added, and the mixture was maintained under a
positive pressure of nitrogen. The reaction was either heated or
maintained at ambient temperature (23 °C) as indicated. After 15 min
the propargyl tert-butyl carbonate 5 (0.30 mmol) was added to the
reaction mixture. After consumption of starting material as judged by
TLC, the reaction mixture was filtered through a pipet plug of Celite and
concentrated. The residue was purified by flash column chromatography
to give the desired products.
N-Methyl-2-(1-methyl-2-oxoindolin-3-yl)acetamide (6h). Pre-
pared according to the general procedure using indole acetamide SI-9
(1.06 g, 5.24 mmol), DMSO (1.9 mL, 26.2 mmol), and 12.1 M HCl (4.4
mL, 52.4 mmol) at ambient temperature for 26.5 h. Purified by flash
column chromatography (5 → 10% MeOH/CH2Cl2) to afford 6h (589
1
mg, 52%) as a pale-yellow powder. Mp: 157−158 °C; H NMR (500
MHz, CDCl3): 7.30 (t, J = 7.5 Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.84 (d, J
= 7.7 Hz, 1H), 6.52 (br s, 1H), 3.87 (t, J = 6.8 Hz, 1H), 3.23 (s, 3H),
J
DOI: 10.1021/acs.joc.5b00277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1-Methyl-3′-methylene-1′-tosylspiro[indoline-3,4′-piperi-
din]-2-one (7a). Prepared according to the general procedure using
oxindole 6a (69 mg, 0.20 mmol), propargyl carbonate 5a (47 mg, 0.30
mmol), Pd2(dba)3·CHCl3 (2 mg, 2 μmol), dppb (2 mg, 4.4 μmol), and
anh. THF (2 mL) at ambient temperature for 20 min. Purified by flash
column chromatography (30% EtOAc/Hexanes) to afford 7a (75 mg,
98%) as a white solid. Mp: 194 °C; 1H NMR (500 MHz, CDCl3): δ 7.72
(d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.31 (ddd, J = 8.1, 6.9, 2.1
Hz, 1H), 7.14−7.06 (m, 2H), 6.84 (d, J = 7.8 Hz, 1H), 5.06 (s, 1H), 4.55
(s, 1H), 4.28 (dd, J = 12.8, 1.7 Hz, 1H), 3.88 (d, J = 12.7 Hz, 1H), 3.79
(dq, J = 9.8, 2.4 Hz, 1H), 3.42 (td, J = 12.4, 2.9 Hz, 1H), 3.10 (s, 3H),
2.46 (s, 3H), 2.19 (td, J = 13.2, 4.8 Hz, 1H), 1.78 (dt, J = 13.7, 2.7 Hz,
1H); 13C NMR (125 MHz, CDCl3): δ176.7, 143.5, 143.2, 139.3, 133.7,
130.5, 129.7 (×2), 128.5, 127.7 (×2), 124.3, 122.7, 114.2, 108.3, 51.1,
49.6, 41.6, 34.0, 26.0, 21.5; HRMS (ESI): Mass calcd for
(C21H23N2O3S)+ [M + H]+: 383.1424; found: 383.1429.
1-Benzyl-3′-methylene-1′-tosylspiro[indoline-3,4′-piperi-
din]-2-one (7b). Prepared according to the general procedure using
oxindole 6b (84 mg, 0.20 mmol), propargyl carbonate 5a (47 mg, 0.30
mmol), Pd2(dba)3·CHCl3 (5 mg, 5 μmol), dppb (5 mg, 11 μmol), and
anh. THF (2 mL) at ambient temperature for 30 min. Purified by flash
column chromatography (20 → 30% EtOAc/Hexanes) to afford 7b (85
mg, 92%) as a white solid foam. Mp: 158−159 °C; 1H NMR (500 MHz,
CDCl3): δ 7.73 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.31−7.21
(m, 3H), 7.18 (td, J = 7.6, 1.6 Hz, 1H), 7.16−7.12 (m, 2H), 7.12−7.04
(m, 2H), 6.71 (d, J = 7.8 Hz, 1H), 5.10 (s, 1H), 4.83 (d, J = 15.8 Hz, 1H),
4.74 (d, J = 15.8 Hz, 1H), 4.59 (s, 1H), 4.32 (dd, J = 12.8, 1.6 Hz, 1H),
3.91 (d, J = 12.7 Hz, 1H), 3.83 (ddt, J = 11.9, 4.6, 2.2 Hz, 1H), 3.46 (td, J
= 12.3, 2.8 Hz, 1H), 2.45 (s, 3H), 2.25 (ddd, J = 13.9, 12.7, 4.9 Hz, 1H),
1.85 (dt, J = 13.8, 2.7 Hz, 1H); 13C NMR (125 MHz, CDCl3): 176.8,
143.6, 142.3, 139.4, 135.5, 133.6, 130.5, 129.7 (×2), 128.7 (×2), 128.4,
127.7 (×2), 127.5, 126.7 (×2), 124.4, 122.8, 114.5, 109.3, 51.0, 49.7,
43.1, 41.7, 34.0, 21.5; HRMS (ESI): Mass calcd for (C27H26N2O3SNa)+
[M + Na]+: 481.1556; found: 481.1557.
3′-Methylene-1′-tosylspiro[indoline-3,4′-piperidin]-2-one
(7c). Prepared according to the general procedure using oxindole 6c (66
mg, 0.20 mmol), propargyl carbonate 5a (47 mg, 0.30 mmol),
Pd2(dba)3·CHCl3 (5 mg, 5 μmol), dppb (5 mg, 11 μmol), and anh.
THF (2 mL) at ambient temperature for 14 h. Purified by flash column
chromatography (30% EtOAc/Hexanes) to afford 7c (70 mg, 95%) as a
white solid. Mp: 205−207 °C; 1H NMR (500 MHz, CDCl3): 7.75 (br s,
1H), 7.73 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 7.24 (tt, J = 7.5,
1.3 Hz, 1H), 7.11−7.02 (m, 2H), 6.83 (d, J = 7.7 Hz, 1H), 5.08 (s, 1H),
4.59 (s, 1H), 4.28 (dd, J = 12.9, 1.5 Hz, 1H), 3.88 (dd, J = 12.9, 1.4 Hz,
1H), 3.82−3.73 (m, 1H), 3.42 (td, J = 12.4, 2.9 Hz, 1H), 2.47 (s, 3H),
2.20−2.10 (m, 1H), 1.83 (dt, J = 13.8, 2.8 Hz, 1H); 13C NMR (125
MHz, CDCl3): 178.7, 143.6, 140.3, 139.1, 133.9, 131.2, 129.7 (×2),
128.5, 127.8 (×2), 124.8, 122.8, 114.6, 109.8, 51.4, 49.6, 41.6, 34.0, 21.6;
HRMS (ESI): Mass calcd for (C20H21N2O3S)+ [M + H]+: 369.1267;
found: 369.1266.
1H), 5.04 (s, 1H), 4.89 (d, J = 6.2 Hz, 1H), 4.59 (d, J = 14.9 Hz, 1H),
4.51 (s, 1H), 4.38 (d, J = 15.0 Hz, 1H), 3.67 (s, 3H), 2.52−2.48 (m, 1H),
2.48 (s, 3H), 2.17 (dd, J = 14.2, 7.2 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ 178.6, 169.9, 143.4, 140.6, 138.6, 137.5, 130.7, 129.5 (×2),
128.8, 127.6 (×2), 124.6, 122.7, 114.2, 110.0, 53.3, 52.3, 51.2, 46.0, 34.4,
21.5; HRMS (ESI): Mass calcd for (C22H23N2O5S)+ [M + H]+:
427.1322; found: 427.1324.
1′-Methyl-3-methylene-1-tosylspiro[azepane-4,3′-indolin]-
2′-one (7e). Prepared according to the general procedure using
oxindole 6e (61 mg, 0.17 mmol), propargyl carbonate 5a (41 mg, 0.26
mmol), Pd2(dba)3·CHCl3 (4 mg, 4.3 μmol), dppb (4 mg, 9.4 μmol), and
anh. THF (1.7 mL) at ambient temperature for 20 min. Purified by flash
column chromatography (30% EtOAc/Hexanes) to afford 7e (53 mg,
78%) as a white solid. Mp: 161 °C; 1H NMR (500 MHz, CDCl3): δ 7.73
(d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 7.7 Hz, 1H), 7.16
(d, J = 7.2 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 5.25
(s, 1H), 4.61 (s, 1H), 4.42 (dd, J = 14.0, 1.5 Hz, 1H), 3.92 (d, J = 13.9 Hz,
1H), 3.90−3.82 (m, 1H), 3.17 (s, 3H), 2.97 (ddd, J = 12.5, 8.4, 3.6 Hz,
1H), 2.46 (s, 3H), 2.16−2.07 (m, 2H), 2.04−1.91 (m, 1H), 1.85−1.74
(m, 1H); 13C NMR (125 MHz, CDCl3): δ 178.6, 144.1, 143.2, 142.9,
136.3, 133.8, 129.7 (×2), 128.1, 127.3 (×2), 124.3, 122.8, 119.9, 108.2,
55.3, 51.9, 48.9, 35.0, 26.3, 24.4, 21.5; HRMS (ESI): Mass calcd for
(C22H25N2O3S) + [M + H]+: 397.1580; found: 397.1592.
Methyl 1-Methyl-2′-methylene-2-oxospiro[indoline-3,4′-pi-
peridine]-1′-carboxylate (7f). To a 50 mL RBF were added
Pd2(dba)3·CHCl3 (5 mg, 5 μmol) and dppb (5 mg, 11 μmol). The
flask was purged with N2, and anh. THF (20 mL) was added. After 5
min, propargyl carbonate 5a (47 mg, 0.30 mmol) was added and then
stirred at ambient temperature for 5 min. After heating to 50 °C for 15
min, a solution of oxindole 6f (50 mg, 0.20 mmol) in THF (1 mL) was
added dropwise via syringe pump over 1 h. After 15 h, the reaction was
cooled to ambient temperature, filtered over a Celite pipet plug, and
concentrated in vacuo. Purified by flash column chromatography (40%
EtOAc/Hexanes) to afford 7f (39 mg, 68%) as an amber residue.
NOTE: The exocyclic olefin product slowly isomerizes to an endocyclic
olefin product at ambient temperature; purified 7f is stored at −78 °C to
1
slow/halt this process. Analytical data for 7f: H NMR (500 MHz,
CDCl3): δ 7.37 (d, J = 7.4 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.05 (t, J =
7.5 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 5.20 (s, 1H), 4.93 (s, 1H), 4.22 (dt,
J = 13.4, 5.2 Hz, 1H), 3.78 (s, 3H), 3.67 (ddd, J = 13.6, 9.8, 3.7 Hz, 1H),
3.23 (s, 3H), 2.73 (d, J = 13.6 Hz, 1H), 2.23 (d, J = 13.6 Hz, 1H), 2.12
(ddd, J = 14.0, 9.7, 4.5 Hz, 1H), 1.67 (dt, J = 13.7, 4.8 Hz, 1H); 13C NMR
(125 MHz, CDCl3): δ 178.6, 155.2, 142.7, 139.1, 132.8, 128.1, 123.9,
122.3, 109.3, 108.1, 52.8, 46.7, 41.2, 39.3, 32.0, 26.3; HRMS (ESI): Mass
calcd for (C16H19N2O3) + [M + H]+: 287.1390; found: 287.1392.
1-Methyl-5′-methylene-1′-phenylspiro[indoline-3,4′-piperi-
dine]-2,2′-dione (7g). To a 50 mL RBF were added oxindole 6g (56
mg, 0.20 mmol), Pd2(dba)3·CHCl3 (5 mg, 5 μmol), and dppb (5 mg, 11
μmol). The flask was purged with N2, and anh. THF (20 mL) was added.
The flask was immediately immersed in a 50 °C oil bath. After heating
for 15 min, propargyl carbonate 5a (47 mg, 0.30 mmol) was added in
one portion. After 30 min, the reaction mixture was cooled to ambient
temperature, filtered over a Celite pipet plug, and concentrated in vacuo.
Purified by flash column chromatography (50 → 70% EtOAc/Hexanes)
to afford 7g (49 mg, 77%) as an off-white solid foam. Mp: 63−64 °C;
NOTE: The exocyclic olefin product slowly isomerizes to the endocyclic
olefin product at ambient temperature; purified 7g is stored at −78 °C to
slow/halt this process. 1H NMR (500 MHz, CDCl3): δ 7.50−7.40 (m,
4H), 7.36 (t, J = 7.7 Hz, 1H), 7.34−7.28 (m, 1H), 7.28−7.23 (m, 1H),
7.14 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 5.14 (s, 1H), 4.83 (d, J =
14.5 Hz, 1H), 4.79 (s, 1H), 4.35 (d, J = 14.5 Hz, 1H), 3.26 (s, 3H), 2.96
(d, J = 16.3 Hz, 1H), 2.79 (d, J = 16.3 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ 176.1, 167.6, 143.1, 142.1, 139.5, 130.6, 129.2 (×2), 128.8,
127.0, 126.0 (×2), 123.9, 123.1, 113.2, 108.6, 55.2, 52.4, 40.5, 26.4;
Methyl 5′-Methylene-2-oxo-1′-tosylspiro[indoline-3,4′-pi-
peridine]-2′-carboxylate (7d). Prepared according to the general
procedure using oxindole 6d (78 mg, 0.20 mmol), propargyl carbonate
5a (47 mg, 0.30 mmol), Pd2(dba)3·CHCl3 (5 mg, 5 μmol), dppb (5 mg,
11 μmol), and anh. THF (2 mL) at ambient temperature for 8 h. Purified
by flash column chromatography (5 → 50% EtOAc/Hexanes) to afford
diastereomer 7d major (41 mg, 48%) as a white solid, mp: 213−214 °C,
and diastereomer 7d minor (25 mg, 30%) as a white solid. Mp: 213−
214 °C; 7d major: 1H NMR (500 MHz, CDCl3): δ 8.56 (br s, 1H), 7.83
(d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.30−7.20 (m, 1H), 7.10 (d,
J = 7.9 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 5.06 (s,
1H), 4.72−4.65 (m, 1H), 4.63 (s, 1H), 4.24 (d, J = 13.5 Hz, 1H), 4.13 (d,
J = 13.5 Hz, 1H), 3.77 (s, 3H), 2.49−2.44 (m, 1H), 2.46 (s, 3H), 2.20
(ddd, J = 14.1, 4.6, 1.9 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 178.8,
171.4, 143.8, 140.3, 138.4, 134.5, 131.2, 129.6 (×2), 128.7, 128.3 (×2),
124.6, 122.8, 115.1, 110.2, 54.9, 52.6, 51.4, 48.9, 36.1, 21.6; HRMS
+
HRMS (ESI): Mass calcd for (C20H19N2O2) [M + H]+: 319.1441;
found: 319.1437.
+
(ESI): Mass calcd for (C22H23N2O5S) [M + H]+: 427.1322; found:
1,1′-Dimethyl-2′-methylenespiro[indoline-3,4′-piperidine]-
2,6′-dione (7h). To a 50 mL RBF were added oxindole 6h (44 mg, 0.20
mmol), Pd2(dba)3·CHCl3 (5 mg, 5 μmol), and dppb (5 mg, 11 μmol).
The flask was purged with N2, and anh. THF (20 mL) was added. The
427.1327. 7d minor: 1H NMR (500 MHz, CDCl3): δ 8.14 (br s, 1H),
7.82 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 7.24 (td, J = 7.8, 1.3 Hz,
1H), 7.04 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 7.4 Hz,
K
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flask was immediately immersed in a 50 °C oil bath. After heating for 15
min, propargyl carbonate 5a (47 mg, 0.30 mmol) was added in one
portion. After 30 min, the reaction mixture was cooled to ambient
temperature, filtered over a Celite pipet plug, and concentrated in vacuo.
Purified by flash column chromatography (0 → 5% MeOH/CH2Cl2) to
afford 7h (37 mg, 73%) as an amber residue that slowly crystallized on
standing. Mp: 139−140 °C; 1H NMR (500 MHz, CDCl3): 7.32 (td, J =
7.7, 1.3 Hz, 1H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 6.96 (dd, J = 7.5, 1.2 Hz,
1H), 6.90 (d, J = 7.8 Hz, 1H), 4.52 (t, J = 1.7 Hz, 1H), 4.20 (t, J = 1.6 Hz,
1H), 3.34 (s, 3H), 3.25 (s, 3H), 3.05 (d, J = 17.4 Hz, 1H), 3.03 (dt, J =
14.5, 1.8 Hz, 1H), 2.49 (dd, J = 17.3, 2.8 Hz, 1H), 2.41 (dd, J = 14.6, 2.9
Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 177.0, 167.0, 142.6, 141.6,
130.7, 128.7, 123.2, 122.8, 108.4, 94.5, 45.0, 39.1, 37.2, 29.6, 26.4;
Hz, 1H), 3.43 (s, 1H), 2.53 (s, 3H), 2.19 (td, J = 13.3, 5.1 Hz, 1H), 1.91
(d, J = 0.9 Hz, 3H), 1.14 (ddd, J = 13.4, 3.2, 2.2 Hz, 1H). 13C NMR
analytical data and HRMS data match those reported below.
2-Methyl-2′-methylene-3′-phenyl-1′-tosylspiro[indole-3,4′-
piperidine] (9a). Prepared according to the general procedure using
sulfonamide 8a (66 mg, 0.20 mmol), propargyl carbonate 5f (60 mg,
0.26 mmol), Pd2(dba)3·CHCl3 (5 mg, 5.0 μmol), Xantphos (6 mg, 11.0
μmol), and anh. CH2Cl2 (5 mL) at 23 °C for 18 h. Purified by flash
column chromatography (20% EtOAc/Hexanes) to afford 9a (51 mg,
1
57%, 4.3:1 dr) as an off-white solid. Mp: 78−80 °C; H NMR (500
MHz, CDCl3) (major): 7.92−7.86 (m, 2H), 7.70 (dd, J = 7.5, 1.0 Hz,
1H), 7.49−7.43 (m, 3H), 7.41 (td, J = 7.7, 1.1 Hz, 1H), 7.24 (t, J = 7.2
Hz, 1H), 7.09−7.00 (m, 2H), 6.95 (t, J = 7.6 Hz, 2H), 6.29 (br s, 2H),
5.51 (d, J = 1.7 Hz, 1H), 4.60 (d, J = 1.9 Hz, 1H), 4.53 (ddd, J = 14.5, 5.2,
2.0 Hz, 1H), 3.90 (ddd, J = 14.6, 13.3, 3.1 Hz, 1H), 3.43 (s, 1H), 2.52 (s,
3H), 2.19 (td, J = 13.3, 5.2 Hz, 1H), 1.91 (s, 3H), 1.71 (dt, J = 14.4, 4.0
Hz, 1H), 1.14 (dt, J = 13.3, 2.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ
183.2, 155.0, 154.9, 144.0, 143.9, 142.1, 139.6, 138.0, 135.2, 129.8, 129.6,
129.5, 128.7, 128.6, 128.3, 128.1, 128.0, 127.8, 127.6, 127.3, 127.2, 125.1,
124.7, 124.5, 121.0, 120.8, 120.0, 116.5, 60.8, 53.4, 51.5, 43.1, 43.1, 32.2,
32.2, 31.5, 29.7, 22.0, 21.6, 15.6; HRMS (ESI): Mass calcd for
(C27H27N2O2S)+ [M + H]+: 443.1788; found: 443.1789.
+
HRMS (ESI): Mass calcd for (C15H17N2O2) [M + H]+: 257.1285;
found: 257.1277.
1′-Methyl-3-methylenespiro[chroman-4,3′-indolin]-2′-one
(7i). Prepared according to the general procedure using oxindole 6i (48
mg, 0.20 mmol), propargyl carbonate 5a (47 mg, 0.30 mmol),
Pd2(dba)3·CHCl3 (5 mg, 5 μmol), dppb (5 mg, 11 μmol), and anh.
THF (2 mL) at ambient temperature for 20 min. Purified by flash
column chromatography (10 → 30% EtOAc/Hexanes) to afford 7i (52
mg, 95%) as a pale-yellow powder. Mp: 97−98 °C; 1H NMR (500 MHz,
CDCl3): δ 7.37 (td, J = 7.7, 1.3 Hz, 1H), 7.14 (ddd, J = 8.6, 7.2, 1.6 Hz,
1H), 7.10 (td, J = 7.5, 1.0 Hz, 1H), 7.02 (dd, J = 7.4, 1.3 Hz, 1H), 6.95
(td, J = 8.3, 1.0 Hz, 2H), 6.73 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 6.41 (dd, J =
7.8, 1.7 Hz, 1H), 5.35 (dd, J = 11.9, 1.3 Hz, 1H), 5.17 (d, J = 1.3 Hz, 1H),
4.68 (d, J = 12.0 Hz, 1H), 4.65 (s, 1H), 3.25 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 176.7, 155.6, 144.5, 139.3, 132.3, 128.8, 128.7, 127.9,
125.5, 123.3, 121.8, 121.1, 117.4, 113.6, 108.2, 68.4, 55.5, 26.6; HRMS
2′-Benzylidene-1,3′-dimethyl-1′-tosylspiro[indoline-3,4′-pi-
peridin]-2-one (9b). Prepared according to the general procedure
using sulfonamide 8a (66 mg, 0.20 mmol), propargyl carbonate 5g (64
mg, 0.26 mmol), Pd2(dba)3·CHCl3 (5 mg, 5.0 μmol), Xantphos (6 mg,
11.0 μmol), triethylamine (30 mg, 0.3 mmol), and anh. CH2Cl2 (5 mL)
at 40 °C for 24 h. Purified by flash column chromatography (20%
EtOAc/Hexanes) to afford 9b (29.4 mg, 32%, 18:1 dr) as a pale-yellow
oil. 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 8.3 Hz, min), 7.55 (d, J =
7.6 Hz, 1H, maj), 7.52 (d, J = 8.3 Hz, 2H, maj), 7.40 (dd, J = 7.5, 2.0 Hz,
2H, maj), 7.34 (d, J = 7.4 Hz, 1H, maj), 7.33−7.29 (m, 1H, maj), 7.26−
7.22 (m, J = 1.4 Hz, 2H, maj), 7.20 (d, J = 7.8 Hz, min), 7.11 (d, J = 8.4
Hz, 2H, maj), 7.05 (t, J = 7.5 Hz, 1H, maj), 6.96 (t, J = 7.5 Hz, min), 6.70
(d, J = 7.4 Hz, min), 6.48 (d, J = 7.7 Hz, min), 6.26 (s, 1H, maj), 5.45 (d, J
= 7.0 Hz, min), 4.35 (dd, J = 5.0, 15.0 Hz, min), 4.28 (dd, J = 14.7, 3.5
Hz, 1H, maj), 3.79−3.71 (m, 1H, maj), 3.09−2.97 (m, 1H, maj), 2.65 (s,
min), 2.57 (s, min), 2.42−2.32 (m, 1H, maj), 2.37 (s, 3H, maj), 2.15 (s,
3H, maj), 1.77 (dd, J = 6.9, 2.0 Hz, min), 1.13 (d, J = 13.3 Hz, 1H, maj),
0.53 (d, J = 6.7 Hz, 3H, maj); 13C NMR (126 MHz, CDCl3) δ 184.22,
155.03, 143.53, 139.24, 137.16, 136.40, 135.05, 129.29 (×2), 129.00
(×2), 128.63, 128.29 (×2), 128.25, 127.83 (×2), 127.58, 124.73, 123.82,
120.54, 63.00, 44.23, 38.88, 30.86, 21.45, 15.37, 11.94; HRMS (ESI):
Mass calcd for (C28H29N2O2S)+ [M + H]+: 457.1944; found: 457.1947.
General Procedure for the Enantioselective Pd-Catalyzed
Spirocyclization of Indole-Based Bis-nucleophiles. Tryptamine
sulfonamide 813 (0.20 mmol), Pd2(dba)3·CHCl3 (5 mg, 5.0 μmol, 5 mol
% Pd), and chiral ligand (11 μmol) were added to an oven-dried 16 ×
100 borosilicate test tube. The test tube was covered with a rubber
septum and sealed with Teflon tape or parafilm. The test tube was
purged with N2, anhydrous CH2Cl2 (5 mL) was added, and the mixture
was maintained under a positive pressure of nitrogen. After 15 min, tert-
butyl propargyl carbonate 5a (0.26 mmol) was added to the reaction
mixture. After consumption of starting material as judged by TLC, the
reaction was filtered through a pipet plug of Celite and concentrated.
The residue was purified by flash column chromatography to give the
desired products.
+
(ESI): Mass calcd for (C18H16NO2) [M + H]+: 278.1176; found:
278.1165.
1-Methyl-2′-phenyl-3′-(propan-2-ylidene)-1′-tosylspiro-
[indoline-3,4′-piperidin]-2-one (7j). Prepared according to the
general procedure using oxindole 6a (69 mg, 0.20 mmol), propargyl
carbonate 5e (78 mg, 0.30 mmol, as a 0.30 M solution in THF),
Pd2(dba)3·CHCl3 (5 mg, 5 μmol), dppb (5 mg, 11 μmol), and anh. THF
(2 mL) at 50 °C for 30 min. Purified by flash column chromatography
(20 → 25% EtOAc/Hexanes) to afford 7j (92 mg, 95%) as an
amorphous bright orange-yellow solid foam. 1H NMR (500 MHz,
CDCl3): δ 7.53 (t, J = 7.1 Hz, 3H), 7.44−7.37 (m, 2H), 7.36−7.29 (m,
4H), 7.19 (d, J = 8.1 Hz, 2H), 7.08 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.8 Hz,
1H), 4.14−4.07 (m, 1H), 3.16 (s, 3H), 2.64−2.53 (m, 2H), 2.45−2.39
(m, 2H), 2.36 (s, 3H), 1.53 (s, 3H), 0.97 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 177.5, 144.1, 142.9, 136.8, 131.4 (×2), 129.4 (×2), 129.0,
128.4, 128.2 (×2), 127.9, 126.9 (×2), 124.8, 123.2, 122.3, 107.9, 94.3,
82.7, 55.5, 39.9, 38.6, 32.0, 26.0, 24.6, 23.8, 21.3; HRMS (ESI): Mass
calcd for (C29H31N2O3S) + [M + H]+: 487.2050; found: 487.2052.
General Procedure for the Pd-Catalyzed Spirocyclization of
Indole-Based Bis-nucleophiles. Tryptamine sulfonamide 8 (0.20
mmol), Pd2(dba)3·CHCl3 (5 mg, 5.0 μmol, 5 mol % Pd), and Xantphos
(6 mg, 11 μmol) were added to an oven-dried 16 × 100 borosilicate test
tube. The test tube was covered with a rubber septum and sealed with
Teflon tape or parafilm. The test tube was purged with N2, anhydrous
CH2Cl2 (5 mL) was added, and the mixture was maintained under a
positive pressure of nitrogen. After 15 min, tert-butyl propargyl
carbonate 5 (0.26 mmol) was added to the reaction mixture. After
consumption of starting material as judged by TLC, the reaction was
filtered through a pipet plug of Celite and concentrated. The residue was
purified by flash column chromatography to give the desired products.
2-Methyl-2′-methylene-3′-phenyl-1′-tosylspiro[indole-3,4′-
piperidine] (9a). Prepared according to the general procedure using
sulfonamide 8a (66 mg, 0.20 mmol), propargyl carbonate 5c (60 mg,
0.26 mmol), Pd2(dba)3·CHCl3 (5 mg, 5.0 μmol), Xantphos (6 mg, 11.0
μmol), and anh. CH2Cl2 (5 mL) at 23 °C for 24 h. Purified by flash
column chromatography (20% EtOAc/Hexanes) to afford 9a (59 mg,
70%, 4:1 dr) as an off-white solid. Mp: 78−80 °C; 1H NMR (500 MHz,
CDCl3) (major): 7.94−7.85 (m, 2H), 7.70 (d, J = 7.4 Hz, 1H), 7.53−
7.43 (m, 3H), 7.41 (td, J = 7.6, 1.1 Hz, 1H), 7.27−7.20 (m, 1H), 7.10−
7.01 (m, 2H), 6.95 (t, J = 7.7 Hz, 2H), 6.29 (br s, 2H), 5.50 (d, J = 1.7 Hz,
1H), 4.53 (ddd, J = 14.6, 5.2, 2.0 Hz, 1H), 3.90 (ddd, J = 14.7, 13.4, 3.1
2-Methyl-2′-methylene-1′-tosylspiro[indole-3,4′-piperidine]
(11a). Prepared according to the general procedure using tryptamine 8a
(66 mg, 0.20 mmol), propargyl carbonate 5a (41 mg, 0.26 mmol),
Pd2(dba)3·CHCl3 (5 mg, 5 μmol), 2,2′-Bis(di-2-(4-methylfuranyl)-
phosphino)-6,6′-dimethoxy-1,1′-biphenyl (6 mg, 11 μmol), and
CH2Cl2 (5 mL) at ambient temperature for 16 h. Purified by flash
column chromatography (20% EtOAc/Hexanes) to afford 11a (51 mg,
69%, 41% ee) as a white solid. Analytical data (1H NMR, 13C NMR, and
HRMS) match those previously reported in the literature.13 A 1H NMR
spectrum is provided to demonstrate purity. The enantiomeric ratio was
measured by HPLC (Chiralpak AD-H, 25% i-PrOH/Hexanes, 1 mL/
min, Rt1 = 10.30, Rt2 = 16.4).
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2′-Methylene-2-phenyl-1′-tosylspiro[indole-3,4′-piperidine]
(11b). Prepared according to the general procedure using tryptamine 8b
(39 mg, 0.10 mmol), propargyl carbonate 5a (20 mg, 0.13 mmol),
Pd2(dba)3·CHCl3 (3 mg, 2.5 μmol), 2,2′-Bis(di-2-furanylphosphino)-
6,6′-dimethoxy-1,1′-biphenyl (3 mg, 5.5 μmol), and anh. CH2Cl2 (2.5
mL) at ambient temperature for 18 h. Purified by flash column
chromatography (20% EtOAc/Hexanes) to afford 11b (30 mg, 70%,
53% ee) as a white solid. Analytical data (1H NMR,13C NMR, and
HRMS) match those previously reported in the literature.13 A 1H NMR
spectrum is provided to demonstrate purity. The enantiomeric ratio was
measured by HPLC (Chiralcel OD-H, 2.5% i-PrOH/Hexanes, 1 mL/
min, Rt1 = 34.8, Rt2 = 38.2).
2-(3,4-Dimethoxyphenyl)-2′-methylene-1′-tosylspiro-
[indole-3,4′-piperidine] (11c). Prepared according to the general
procedure using tryptamine 8c (45 mg, 0.10 mmol), propargyl
carbonate 5a (20 mg, 0.13 mmol), Pd2(dba)3·CHCl3 (3 mg, 2.5
μmol), 2,2′-Bis(di-2-(4-methylfuranyl)phosphino)-6,6′-dimethoxy-
1,1′-biphenyl (3 mg, 5.5 μmol), and anh. CH2Cl2 (2.5 mL) at ambient
temperature for 24 h. Purified by flash column chromatography (20%
EtOAc/Hexanes) to afford 11c (36 mg, 73%, 77% ee) as a white solid.
Analytical data (1H NMR, 13C NMR, and HRMS) match those
previously reported in the literature.13 A 1H NMR spectrum is provided
to demonstrate purity. The enantiomeric ratio was measured by HPLC
(Chiralcel AD-H, 10% i-PrOH/Hexanes, 1 mL/min, Rt1 = 24.3, Rt2 =
57.4).
1-Methyl-3′-methylene-1′-tosylspiro[indoline-3,4′-piperi-
din]-2-one (7a*). Prepared according to a modification of the general
procedure using oxindole 6a (69 mg, 0.20 mmol), propargyl carbonate
5a (47 mg, 0.30 mmol), Pd2(dba)3·CHCl3 (5 mg, 5.0 μmol), (R,R)-
DACH-phenyl (7 mg, 11 μmol), and anh. THF (2 mL) at 40 °C for 4 h,
followed by heating to 60 °C for 16 h. Purified by flash column
chromatography (25% EtOAc/Hexanes) to afford 7a* (6 mg, 8%, 32%
ee) as a white solid. Analytical data (1H NMR, 13C NMR, and HRMS)
match those reported in this document for 7a. A 1H NMR spectrum is
provided to demonstrate purity. The enantiomeric ratio was measured
by HPLC (Chiralpak AS-H, 10% i-PrOH/Hexanes, 1 mL/min, Rt1 =
22.8, Rt2 = 26.0).
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR, HRMS, and melting point ranges of new
compounds, 2-D NMR for 9b, and pKa table. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: vrawal@uchicago.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the National Institutes of Health
(R01GM069990) is gratefully acknowledged.
■
REFERENCES
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