A Phosphorus(III)-Mediated (4+1)-Cycloaddition of 1,2-Dicarbonyls and Aza-o-Quinone Methides to Access 2,3-Dihydroindoles

Article abstract of DOI:10.1002/hlca.201900192

A (4+1)-cycloaddition is reported between 1,2-dicarbonyls and aza-o-quinone methide precursors to access 2,3-dihydroindoles bearing a tetra-substituted carbon center. The utilization of dioxyphospholenes as carbene surrogates provided dihydroindoles in 20–90 % yield, wherein the electronic nature of the dioxyphospholene impacts its role in the reaction.

Full text of DOI:10.1002/hlca.201900192

DOI: 10.1002/hlca.201900192
FULL PAPER
A Phosphorus(III)-Mediated (4+1)-Cycloaddition of 1,2-Dicarbonyls
and Aza-o-Quinone Methides to Access 2,3-Dihydroindoles
Kaitlyn E. Eckert,a Antonio J. Lepore,a and Brandon L. Ashfeld*a
a
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, United States,
e-mail: bashfeld@nd.edu
A (4+1)-cycloaddition is reported between 1,2-dicarbonyls and aza-o-quinone methide precursors to access
2,3-dihydroindoles bearing a tetra-substituted carbon center. The utilization of dioxyphospholenes as carbene
surrogates provided dihydroindoles in 20–90% yield, wherein the electronic nature of the dioxyphospholene
impacts its role in the reaction.
Keywords: cycloaddition, aza-o-quinone methides, dihydroindoles, Kukhtin–Ramirez reaction, 1,2-dicarbonyls.
Introduction
Despite the number of elegant approaches for the
construction of heterocyclic frameworks, the selective
and convergent assembly of highly substituted nitro-
gen-containing ring scaffolds remains a significant
challenge in pharmaceutical drug development.[1–5]
The prevalence of these subunits in designed small
molecules and natural products exhibiting promising
anticancer and anti-bacterial properties further illus-
trates the need for efficient, convergent approaches to
these motifs.[6–8] Dipolar cycloadditions, specifically
Scheme 1. Cycloaddition construction of N-heterocycles.
the (3+2) assembly of an azomethine ylide and an
electron deficient alkene, constitutes a powerful tool
in the construction of pyrrolidine derivatives (Sche-
me 1,a). However, the potential complications due to scaffolds, we were motivated to evaluate this strategy
the inherent reactivity and lack of chemoselectivity toward C2-disubstituted dihydroindoles (Scheme 1,b).
associated with 1,3-dipoles, combined with the struc-
While the transition metal-catalyzed decomposition
tural requirements (i.e., electron withdrawing substitu- of diazo compounds can serve as a versatile source of
ents) for both components, led us to consider C1 synthons, we sought a metal-free alternative to our
alternative disconnects.[9–16] One complementary ap- previously
reported
Rh-catalyzed
(4+1)-
proach involves the (4+1)-cycloaddition between a cycloadditions.[17,18] For this study, we chose to utilize
1,3-heterodiene and a disubstituted, biphilic C1 sub- a Kukhtin–Ramirez-like redox neutral condensation to
unit to construct the pyrrolidine core. Given our exploit the biphilic nature of oxyphosphonium eno-
previous success in the (4+1) assembly of heterocyclic lates as C1 subunits.[19–24] Recent work by Radosevich,
He, and our own group have demonstrated the
versatility of this approach in providing direct access
to CÀ C and CÀ X bonds.[25–29]
Inspired by Scheidt and coworkers elegant enantio-
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/hlca.201900192
selective assembly of benzopiperidinones employing
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Scheme 2. Selected quinone methides in (4+n)-cycloadditions.
an NHC-catalyzed [4+2]-cycloaddition of in situ gen- dihydroindole 4a in 58% yield (Scheme 3). Likewise,
erated aza-o-quinone methides (aza-o-QM) and ali- the (4+1)-cycloaddition between N-methyl isatin (3a)
phatic carboxylic acids (Scheme 2,a), and building on and 1a under comparable reaction conditions pro-
our previous work toward dihydrobenzofurans (Sche- vided spirooxindole 5a in 32% yield. Encouraged by
me 2,b), we speculated that aza-o-QMs could serve as these initial results, we turned our attention toward
1,3-heterodienes in the construction of 2,3-dihydroin- optimizing formation of dihydroindole cycloadducts 4
doles employing readily accessible oxyphosphonium and 5 and gaining mechanistic insight into the
enolates as C1 synthons.[25,27,30–38] Herein, we report phosphorus(III)-mediated (4+1)-cycloaddition.
the successful development of a phosphorus(III)-medi-
Although an initial survey of solvent effects
ated redox construction of 2,3-dihydroindoles result- employing either polar or non-polar aprotic solvents
ing from the addition of 2-amino benzyl halides to 1,2- (e.g., PhMe, THF, DMF, etc.) on the cycloaddition of 1a
dicarbonyls (Scheme 2,c). The resulting (4+1)-cyclo- and 2a revealed only minor variations in yield and
addition represents a complementary method for conversion, we noted that conducting the reaction in
heterocycle assembly and adds to the growing CH2Cl2 provided reproducible results with superior
ensemble of synthetic methods based on Kukhtin– yields of 4a. In general, a survey of amine and
i
Ramirez-like reactivity.
inorganic bases (e.g., Pr2NEt, Li2CO3, Cs2CO3) resulted
Results and Discussion
Our initial foray into dihydroindole construction began
by examining the net (4+1)-cycloaddition employing
a biphilic oxyphosphonium enolate as a C1 synthon
and a 1,4-dipole aza-o-QM. Employing conditions
comparable to those forged by Scheidt and coworkers,
presumptive aza-o-QM generation by treatment of
benzyl chloride 1a with Cs2CO3 followed by exposure
to the oxyphosphonium enolate derived from methyl
benzoyl formate (2a) and P(NMe2)3 led to formation of
Scheme 3. Initial findings.
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in only modest changes to 40–44% of the yield of 4a converted to the α-chloro ester through phosphine
(Table 1, Entries 1 and 2). Likewise, employing benzyl oxide displacement. Based on this mechanistic hypoth-
bromide 1b as the aza-o-QM precursor under con- esis, we surmised that by employing a strong,
ditions comparable to that illustrated in Scheme 3 exogenous base in a polar, aprotic solvent, we could
failed to improve the yield of 4a in comparison to reduce the formation of α-chloro ester 6 and epoxide
benzyl chloride 1a (Table 1, Entry 3). A similar outcome 7. To that end, pre-treatment of 1a with NaH followed
was observed when the corresponding sulfonates by 1.2 equiv. each of 2a and P(NMe2)3 provided 4a in
(e.g., X=MeSO3, TsSO3) were employed. Interestingly, 57% yield and chloroester 6 in a 19:1 ratio favoring
treatment of benzyl chloride 1a and 2a with P(NMe2)3 the desired cycloadduct (Table 1, Entry 6). Increasing
in the absence of an exogenous base provided 4a in the amount of 2a and P(NMe2)3 to 2.0 equiv. each
50% yield (Table 1, Entry 4). Speculating that the subsequently increased the yield of 4a to 95% and
intermediate oxyphosphonium enolate derived from effectively eliminated formation of 6 (Table 1, Entry 7).
the addition of P(NMe2)3 to 2a acts as an effective, The byproduct distribution observed in Entries 5–7
soluble organic base for aza-o-QM generation, we would seem to suggest that the oxyphosphonium
anticipated that increasing the equivalents of α-keto enolate can act as an effective base or nucleophile in
ester 2a and P(NMe2)3 relative to 1a should improve initiating the (4+1)-cycloaddition. While the yield of
the yield of 4a. Gratifyingly, the addition of two 4a in Entry 7 when employing NaH was modestly
equivalents of 2a and P(NMe2)3 to 1a provided 4a in improved compared to the absence of base, the
90% yield by NMR in which the intermediate oxy- 2.0 equiv. of 1a required led us to proceed with the
phosphonium enolate was distributed unequally be- operationally simpler conditions depicted in Entry 5.
tween 4a, α-chloro ester 6, and epoxide 7 in a 10:10:1
To probe the viability of a mechanism that
proceeds through an acyl aniline deprotonation by the
ratio (Table 1, Entry 5).[39,40]
While epoxide 7 is a common self-condensation oxyphosphonium enolate derived from 2a, we sub-
product in Kukhtin–Ramirez-like functionalizations, the jected deuterium labeled 1a and α-keto ester 2a to
formation of α-chloro ester 6 presumably arises from the optimized reaction conditions in Table 1, Entry 5,
the addition of HCl across the oxyphosphonium and evaluated the amount of deuterium incorporation
enolate intermediate in a fashion commensurate with in the resulting α-chloro ester 6 (Scheme 4). Exposure
Radosevich’s 2015 study.[25] The formation of 4a and 6 of 1a–d to two equivalents of 2a and P(NMe2)3
in a 1:1 ratio supports a mechanism wherein the resulted in an 85% yield of cycloadduct 4a and 82%
presumptive aza-o-QM intermediate arises from a 1,4- yield of α-chloro ester 6d with 50% d-incorporation.
elimination of the benzyl chloride in 1a by a sacrificial While the relative acidity of the α-proton in 6 likely
equivalent of oxyphosphonium enolate that is then contributed to the modest level of d-incorporation,
Table 1. Optimized Formation of Dihydroindole 4a[a]
Entry
1
Base
Equivalents
of 2a
NMR Yield
4a/6/7
of 4a [%][b]
1
2
3
3
1a
1a
1b
1b
1a
1a
1a
1a
iPr2NEt
Li2CO3
Cs2CO3
Cs2CO3
–
–
NaH
NaH
1.2
1.2
1.2
1.2
1.2
2.0
1.2
2.0
40
44
40
40
50
90
57
95
1:0:0
1:0:0
1:0:0
1:0:0
4
1:0:0
5
10:10:1
19:1:11
1:0:1
6[c]
7[c]
[a]
[b]
Conditions: 1 (0.2 mmol), 2a and P(NMe2)3 employed in equimolar amounts, base (0.4 mmol), in CH2Cl2 (0.3 M). Employing
[c]
10 mol-% trimethoxybenzene as an internal standard at 500 MHz. Modified standard conditions included NaH (0.22 mmol) and
1,2-F2C6H4 (0.3 M) as solvent.
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consistent with the higher pKa of α-aryl formyl
enolates in comparison to the corresponding enolate
derived from N-alkyl oxindoles and the intermediary
acidity of the N-acyl aniline 1.[41]
During these initial experiments we determined
that self-condensation of 3a occurred prior to con-
sumption of 1a as the reaction warmed to room
temperature, and at a seemingly faster rate than what
we observed with 2a. However, when the reaction was
Scheme 4. Deuterium incorporation in 6-d.
°
°
this would seem to support the viability of a allowed to warm from À 78 C to À 60 C, and main-
mechanism involving an initial oxyphosphonium eno- tained at this temperature for 15 h, a 54% yield of 5a
late deprotonation of the N-acyl aniline derivative.
was obtained (Table 2, Entry 5). This finding is consis-
We next turned our attention toward evaluating tent with previous studies on Kukhtin-Ramirez-like
the (4+1)-cycloaddition employing isatin derivatives reactivity wherein self-condensation of the 1,2-
as C1 synthons. Interestingly, employing isatin 3a dicarbonyl is retarded at lower temperatures.[39]
under the optimized reaction conditions employed in Increasing the amount of Cs2CO3, P(NMe2)3, and 3a
our optimization study for α-keto ester 2a, failed to from 1.2 to 2.0 further improved the yield of
provide the corresponding spirooxindole 5a (Table 2, dihydroindole 5a to 77% (Table 2, Entry 6). Having
Entry 1). Likewise, the addition of either NEt3 or KOtBu identified an optimal set of conditions for the (4+1)-
yielded solely the epoxide resulting from self-conden- cycloadditions employing 1,2-dicarbonyls 2a and 3a,
sation of 3a and decomposition of the aza-o-QM we turned our attention toward ascertaining the
precursor 1a. However, upon addition of 10 mol-% architectural limitations in the assembly of dihydroin-
Cs2CO3 gave 5a in 37% yield (Table 2, Entry 2). doles 4 and 5.
Increasing the amount of Cs2CO3 to a full equivalent
In general, and quite distinct from our findings
did not significantly impact the yield of 5a, and related to the corresponding (4+1)-cycloadditions
comparable results were obtained with K2CO3 (Table 2, through o-quinone methides, the adducts derived
Entries 3 and 4). Given that an exogenous base is from various aniline derivatives were obtained in
required when employing isatin 3a, whereas the consistently modest yields. Additionally, the incorpo-
oxyphosphonium enolate derived from formate 2a is ration of specific functional groups ultimately inhibited
sufficient to provide the corresponding cycloadduct product formation. For example, treatment of N-acyl
4a in good yield illustrates the impact subtle structural anilines bearing halogen substituents at C(4) or C(5)
changes in the starting materials can have on the with either 2a or 3a under those optimal conditions
reaction outcome. Additionally, this observation is identified in Table 1 resulted in either exclusive
epoxide formation or an intractable mixture of prod-
ucts. However, the presence of a methyl or methoxy
substituent at C(5) in anilines 1c and 1d enabled
Table 2. Employing N-Me Isatin as a C1 Synthon.[a]
formation of the corresponding cycloadducts 4b and
4c respectively, albeit in modest yields (Scheme 5).
Employing N-methyl isatin 3a led to dihydroindoles 5b
and 5c in significantly decreased yields (Scheme 6).
While methyl substitution at C(6) of 1a provided
dihydroindole 5d in 51% yield, the presence of a C(6)-
methoxy group decreased the yield of the cyclo-
Entry
Base
Equivalents
of Base
Ratio 3a/1a
Yield [%]
1
2
3
–
–
2.0
1.2
1.2
1.2
1.2
2.0
0
37
30
28
54
77
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
0.1
1.2
1.2
1.2
2.0
4
5[b]
6[b]
[a]
Conditions: 1a (0.2 mmol), 3a (0.24 mmol), P(NMe2)3
[b]
(0.24 mmol), base (0.24 mmol), in CH2Cl2 (0.2 M). Reaction
°
°
temperature: À 78 C to À 60 C.
Scheme 5. Dihydroindole construction.
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Scheme 6. Spiropyrrolidine oxindole assembly.
adduct. Interestingly, the N-Boc group on aniline 1a
proved critical as we observed no cycloadduct
formation from the corresponding N-Ts, -Bn, -Ac, or
-Cbz derivatives. Additionally, stereoelectronic varia-
tions of formate 2 or isatin 3 through the presence of Scheme 7. Rh-Catalyzed C(3)-amino oxindole synthesis.
aryl electron-withdrawing or electron-donating sub-
stituents resulted in trace product formation with self-
condensation of the corresponding oxyphosphonium pathways en route to dihydroindole formation
enolates as the major reaction pathway.
(Scheme 8). Addition of P(NMe2)3 to formate 1a leads
Based on our recent efforts in the C(3)-functionali- to an equilibrium between dioxaphospholene 11a and
zation of oxindoles employing diazooxindoles in a (4+ oxyphosphonium enolate 11b, of which the enolate is
1)-cycloaddition, we sought to evaluate the compara-
tive efficacy of a Rh(II)-metallocarbene as the C1
synthon with 2-amino benzyl chlorides.[42–44] Interest-
ingly, treatment of aza-o-QM precursor 1a with
diazooxindole 8 in the presence of Rh2(OAc)4 and
K2CO3 yielded only recovered starting material. How-
ever, employing N-methyl aniline 1g resulted in
formation of C(3)-amino oxindole 9b in 95% yield
(Scheme 7)1. Likewise, the addition of N-bromobenzyl
diazooxindole 8b to aniline 1g provided oxindole 9c
in 57% yield. While aniline addition to the electrophilic
metallocarbene sets the stage for an intramolecular
benzylation, the combination of a slow rhodium
enolate C-alkylation and facile protonation precluded
spirooxindole formation. The importance of the metal
counterion was further illustrated by the quantitative
yield achieved in the formation of spirooxindole 10
upon treatment of amino oxindole 9b with NaH at
°
50 C for 12 h.
Based on our current and previous findings, as well
as those reported by Ramirez,[19–22] Scheidt,[32]
Radosevich,[25,27,31,34–38] and Xiao,[33] our working mech-
anistic hypothesis addresses two possible competing
1 This structure was verified using single X-ray crystallog-
raphy on the N-4-bromobenzyl diazooxindole derivative.
Scheme 8. Potential competing reaction mechanisms.
See Supporting Information for details.
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the presumptive reactive constitutional isomer. tetramethylsilane (TMS). Coupling constants are reported
Whether facilitated by an exogenous base or oxy- in Hertz [Hz]. Spectral splitting patterns are designated
phosphonium enolate 11b as shown, subsequent as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
deprotonation of the aniline NÀ H initiates an elimina- comp m, complex multiplet; app, apparent; and br. s,
tion of the benzyl chloride to provide aza-o-QM 12 broad singlet. IR Spectra were obtained using a Thermo
(path A). The Michael addition of a second equivalent Electron Nicolet 380 FT-IR using a silica (Si) crystal in an
of 11b followed by an intramolecular displacement of attenuated total resonance (ATR) tower and reported as
(Me2N)3P=O provides the corresponding dihydroindole wavenumber [cmÀ 1]. High- and Low-resolution electro-
4a. Alternatively, formation of the crucial C(2)À C(3) spray ionization (ESI) measurements were made with a
bond in dihydroindoles 4 and 5 could arise from a Bruker MicroTOF II mass spectrometer. Analytical thin
direct displacement of the benzyl chloride in 1 by layer chromatography (TLC) was performed using EMD
oxyphosphonium enolate 11b to yield the 250 micron 60 F254 silica gel plates, visualized with UV
phosphonium chloride 14 (path B). Subsequent ring light and stained with p-anisaldehyde. Flash column
closure yields the cycloadduct in a fashion comparable chromatography was performed according to Still’s
to that illustrated by path A. While a mechanism procedure[45] using EMD 40–63 μm 60 Å silica gel.
proceeding through an aza-o-QM intermediate is Known compounds 1 were synthesized according to
consistent with our previous work toward the con- literature procedures.[32]
struction of dihydrobenzofurans,[30] a direct benzyl
chloride substitution mechanism cannot be ruled out.
General Procedure for the Synthesis of 2,
3-Dihydroindoles (4)
P(NMe2)3 (0.4 mmol) was added dropwise to a solution
Conclusions
°
of 2 (0.4 mmol) in CH2Cl2 (2 mL) at À 78 C. The resulting
In conclusion, we have developed a convergent, (4+ solution was stirred for 10 min followed by the addition
1)-cycloaddition for the synthesis of C(2)-disubstituted of 1 (0.2 mmol). The reaction mixture was allowed to
dihydroindoles employing 2-amino benzyl chlorides warm to room temperature over 15 h then concentrated
with 1,2-dicarbonyls in a phosphoramide-mediated under reduced pressure. The residue was purified by
redox annulation. This method provides the corre- flash column chromatography eluting with a solvent
sponding 5-membered N-heterocycles and highlights gradient of hexanes/AcOEt (20:1 to 10:1) to afford the
the delicate balance of basicity and nucleophilicity of title compound 4.
the versatile, intermediary oxyphosphonium enolates.
Studies focused on resolving the curious influence of
1-tert-Butyl 2-Methyl 2-Phenyl-2,3-dihydro-1H-
various benzyl chloride and 1,2-dicarbonyl substitution indole-1,2-dicarboxylate (4a). Dihydroindole 4a was
on the outcome of this cycloaddition and the compet- synthesized on a 0.2 mmol scale to provide 46 mg (90%)
ing mechanistic scenarios en route to dihydroindole of the title compound as a colorless oil: IR (neat): 2978,
1
assembly are currently underway and will be reported 2953, 2929, 1751, 1705, 1371. H-NMR (500 MHz, CDCl3):
in due course.
7.47 (d, J=7.6, 2 H); 7.31 (t, J=7.0, 2 H); 7.27–7.24 (m, 2
H); 7.04 (d, J=6.7, 1 H); 6.97 (t, J=6.8, 1 H); 3.86 (d, J=
16.2, 1 H); 3.80 (s, 3 H) 3.39 (d, J=16.2, 1 H); 1.56 (br., 2
H); 1.27 (br., 7 H). 13C-NMR (125 MHz): 172.6; 129.1; 129.0;
128.4; 128.2; 128.0; 127.6; 127.5; 126.7; 124.4; 123.2;
115.2; 77.4; 76.0; 52.9; 29.9; 28.2. HR-ESI-TOF-MS:
Experimental Section
General Experimental Procedures
Solvents and reagents were reagent grade and used 254.1194 ([M+H]+, C16H15NO2+; calc. 254.1176).
without further purification unless noted otherwise. 1,2-
Difluorobenzene and 1,4-dioxane were passed through a
1-tert-Butyl 2-Methyl 5-Methyl-2-phenyl-2,3-dihy-
column of activated alumina stored over molecular dro-1H-indole-1,2-dicarboxylate (4b). Dihydroindole
sieves under argon. All reactions were carried out in 4b was synthesized on a 0.3 mmol scale to provide
flame-dried glassware under an argon or nitrogen 41 mg (37%) of the title compound as a colorless oil: IR
1
atmosphere unless otherwise specified. H-NMR spectra (neat): 2978, 2927, 2850, 1750, 1704, 1492, 1367, 1228,
1
were obtained at either 400, or 500 MHz. 13C-NMR were 1147. H-NMR (500 MHz, CDCl3): 7.92 (br., 1 H); 7.46 (d,
obtained at 125 or 150 MHz. Chemical shifts are reported J=6.6, 2 H); 7.31 (t, J=7.1, 2 H); 7.26 (t, J=8.1, 1 H); 7.05
in parts per million ([ppm], δ), and referenced from (d, J=7.8, 1 H); 6.86 (s, 1 H); 3.84 (d, J=16.2, 1 H); 3.79 (s,
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3 H); 3.35 (d, J=16.0, 1 H); 2.27 (s, 3 H); 1.60 (br., 2 H); oxindole 5b was synthesized on a 0.2 mmol scale to
1.26 (br., 7 H). 13C-NMR (100 MHz): 172.2 (2 C); 132.3; provide 14 mg (20%) of the title compound as a yellow
129.2; 128.7; 128.3; 127.8; 127.6; 127.0; 126.3; 124.7; oil: IR (neat): 2957, 2921, 2851, 1724, 1709, 1614, 1491,
1
114.5; 81.5; 73.0; 52.5; 46.2; 27.8; 20.7. HR-ESI-TOF-MS: 1470, 1366, 1149, 1086, 752, 734. H-NMR (400 MHz,
368.1871 ([M+H]+, C22H26NO4+; calc. 368.1856).
CDCl3): 7.84 (d, J=8.2, 1 H); 7.31 (t, J=7.6, 1 H); 7.10 (d,
J=7.6, 1 H); 7.06 (d, J=7.9, 1 H); 6.99 (t, J=7.6, 1 H); 6.96
1-tert-Butyl 2-Methyl 5-Methoxy-2-phenyl-2,3-di- (s, 1 H); 6.83 (d, J=7.6, 1 H); 3.60 (d, J=16.1, 1 H); 3.24 (s,
hydro-1H-indole-1,2-dicarboxylate (4c). Dihydroindole 3 H); 3.16 (d, J=16.1, 1 H); 2.32 (s, 3 H); 1.11 (s, 9 H). 13C-
4c was synthesized on a 0.3 mmol scale to provide NMR (100 MHz): 176.6; 151.0; 142.7; 141.0; 132.6; 132.4;
31 mg (58%) of the title compound as a colorless oil: IR 129.0; 128.4; 127.0; 125.0; 123.1; 121.7; 114.6; 107.9; 81.2;
(neat): 3064, 2922, 2850, 1751, 1702, 1490, 1377, 1256, 68.7; 41.4; 27.8; 26.5; 20.9. HR-ESI-TOF-MS: 387.1685 ([M+
1136. 1H-NMR (500 MHz, CDCl3): 7.95 (d, J=6.2, 1 H); 7.46 Na]+, C22H24N2NaO3+; calc. 387.1679).
(br., 2 H); 7.31 (t, J=6.5, 2 H); 7.26 (t, J=4.8, 1 H); 6.78 (d,
J=8.0, 1 H); 6.62 (d, J=2.5, 1 H); 3.84 (d, J=16.1, 1 H);
tert-Butyl 5-Methoxy-1’-methyl-2’-oxo-1’,2’-dihy-
3.80 (s, 3 H); 3.75 (s, 3 H); 3.36 (d, J=16.0, 1 H); 1.60 (br., 2 dro-2,3’-spirobi[indole]-1(3H)-carboxylate (5c). Spiro-
H); 1.26 (br., 7 H). 13C-NMR (100 MHz): 172.3; 160.3; 156.0; pyrrolidine oxindole 5c was synthesized on a 0.06 mmol
141.4; 136.3; 127.8; 127.3; 126.5 (2 C); 115.5; 112.7; 110.6; scale to provide 7 mg (31%) of the title compound as a
81.4; 73.2; 55.7; 52.7; 46.4; 28.0. HR-ESI-TOF-MS: 384.1783 yellow oil: IR (neat): 3055, 2927, 1726, 1704, 1612, 1490,
1
([M+H]+, C22H26NO5+; calc. 384.1805).
1470, 1374, 1323, 1256, 1141, 1125, 1088, 1013. H-NMR
(500 MHz, CDCl3): 7.87 (d, J=8.9, 1 H); 7.31 (t, J=7.6, 1
H); 7.10 (d, J=7.5, 1 H); 7.00 (t, J=7.5, 1 H); 6.83 (d, J=
7.9, 1 H); 6.78 (dd, J=6.6, 2.3, 1 H); 6.73 (s, 1 H); 3.79 (s, 3
H); 3.62 (d, J=16.2, 1 H); 3.24 (s, 3 H); 3.16 (d, J=16.2, 1
General Procedure for the Synthesis of Spiropyrrolidine
Oxindoles (5)
P(NMe2)3 (0.4 mmol) was added dropwise to a mixture of H); 1.11 (s, 9 H). 13C-NMR (125 MHz): 176.8; 156.2; 132.8;
1 (0.2 mmol) and Cs2CO3 (0.4 mmol) in CH2Cl2 (0.5 mL). 129.3; 129.0; 128.5; 125.5; 124.0; 123.3; 121.9; 115.6;
°
The mixture was cooled to À 78 C and a solution of 3 112.9; 111.1; 108.2; 81.3; 69.0; 56.0; 41.8; 28.0; 26.7. HR-
(0.4 mmol) in CH2Cl2 (0.5 mL) was added dropwise. The ESI-TOF-MS: 403.1621 ([M+Na]+, C22H24N2NaO4+; calc.
°
reaction was allowed to warm slowly to À 60 C by 407.1628).
removal of the dry ice/acetone bath, stirred for 15 h at
°
À 60 C, then filtered through a pad of Celite and
tert-Butyl 1’,6-Dimethyl-2’-oxo-1’,2’-dihydro-2,3’-
concentrated under reduced pressure. The resulting spirobi[indole]-1(3H)-carboxylate (5d). Spiropyrrolidine
residue was purified by flash chromatography eluting oxindole 5d was synthesized on a 0.14 mmol scale to
with CH2Cl2/hexanes/AcOEt (12:7:1) to afford the title provide 26 mg (51%) of the title compound as a yellow
compound 5.
oil: IR (neat): 2978, 2926, 1706, 1612, 1498, 1471, 1427,
1366, 1313, 1249, 1147, 1128, 1084. H-NMR (500 MHz,
1
tert-Butyl 1’-Methyl-2’-oxo-1’,2’-dihydro-2,3’-spiro- CDCl3): 7.84 (s, 1 H); 7.30 (t, J=7.5, 1 H); 7.10 (d, J=7.5, 1
bi[indole]-1(3H)-carboxylate (5a). Spiropyrrolidine oxin- H); 7.00–6.98 (m, 2 H); 6.84–6.82 (m, 2 H); 3.59 (d, J=
dole 5a was synthesized on a 0.2 mmol scale to provide 15.9, 1 H); 3.24 (s, 3 H); 3.15 (d, J=15.9, 1 H); 2.36 (s, 3 H);
54 mg (77%) of the title compound as a yellow oil: IR 1.12 (s, 9 H). 13C-NMR (125 MHz): 176.8; 151.3; 143.6;
(neat): 3054, 2978, 2934, 1708, 1613, 1482, 1470, 1375, 142.9; 138.2; 132.8; 129.3; 124.2; 123.8; 123.3; 121.9;
1
1351, 1315, 1240. H-NMR (500 MHz, CDCl3): 7.98 (d, J= 115.9; 110.1; 108.2; 81.6; 69.2; 41.4; 28.0; 26.7; 21.9. HR-
8.1, 1 H); 7.31 (t, J=7.7, 1 H); 7.25 (t, J=7.7, 1 H); 7.14 (d, ESI-TOF-MS: 387.1684 ([M+Na]+, C22H24N2NaO3+; calc.
J=7.3, 1 H); 7.10 (d, J=7.3, 1 H); 7.01–6.98 (m, 2 H); 6.84 387.1679).
(d, J=7.8, 1 H); 3.64 (d, J=16.1, 1 H); 3.25 (s, 3 H); 3.20 (d,
J=16.1, 1 H) 1.12 (s, 9 H). 13C-NMR (125 MHz): 176.8;
tert-Butyl 6-Methoxy-1’-methyl-2’-oxo-1’,2’-dihy-
151.2; 143.5; 142.9; 132.7; 129.3; 128.2; 124.6; 123.3; dro-2,3’-spirobi[indole]-1(3H)-carboxylate (5e). Spiro-
123.1; 121.9; 115.2; 110.1; 108.2; 81.6; 68.9; 41.7; 28.0; pyrrolidine oxindole 5e was synthesized on a 0.06 mmol
26.7.
HR-ESI-TOF-MS:
373.1505
([M+Na]+, scale to provide 7 mg (27%) of the title compound as a
C21H22N2NaO3+; calc. 373.1523).
yellow oil: IR (neat): 3057, 2931, 1707, 1612, 1497, 1470,
1
1448, 1376, 1321, 1249, 1162, 1086. H-NMR (500 MHz,
tert-Butyl 1’,5-Dimethyl-2’-oxo-1’,2’-dihydro-2,3’- CDCl3): 7.66 (d, J=2.0, 1 H); 7.31 (t, J=7.9, 1 H); 7.12 (d,
spirobi[indole]-1(3H)-carboxylate (5b). Spiropyrrolidine J=7.2, 1 H); 7.00 (d, J=8.2, 1 H); 7.00 (t, J=7.2, 1 H); 6.83
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(d, J=7.8, 1 H); 6.57 (dd, J=8.2, 2.3, 1 H); 3.84 (s, 3 H); chromatography eluting with a solvent gradient of
3.56 (d, J=16.0, 1 H); 3.24 (s, 3 H); 3.13 (d, J=16.0, 1 H); hexanes/AcOEt (3:1) to afford 25 mg (95%) of 9b as an
1.11 (s, 9 H). 13C-NMR (125 MHz): 176.5; 160.1; 151.0; orange oil: IR (neat): 2925, 2855, 2652, 1739, 1610, 1470,
1
144.5; 142.6; 132.5; 129.1; 124.6; 123.1; 121.6; 118.6; 1368, 1328, 1092, 756. H-NMR (500 MHz, CDCl3): 7.59
109.5; 108.0; 101.0; 81.4; 69.5; 55.6; 40.8; 27.7; 26.5. HR- (dd, J=8.1, 1.1, 1 H); 7.47 (dd, J=7.6, 1.6, 1 H); 7.38 (d,
ESI-TOF-MS: 407.1625 ([M+Na]+, C22H24N2NaO4+; calc. J=7.4, 1 H); 7.36–7.30 (m, 2 H); 7.15 (t, J=7.5, 1.2, 1 H);
407.1628).
7.08 (tt, J=7.6, 0.9, 1 H); 6.84 (d, J=7.8, 1 H); 5.04 (d, J=
11.1, 1 H); 5.02 (s, 1 H); 4.95 (d, J=11.1, 1 H); 3.23 (s, 3 H);
tert-Butyl [2-(Chloromethyl)phenyl](2H)carbamate 2.57 (s, 3 H). 13C-NMR (125 MHz): 175.0; 150.7; 143.8;
(1a-d). A mixture of 1a (100 mg, 0.4 mmol) and Cs2CO3 132.1; 131.4; 129.3; 129.0; 125.4; 124.8; 124.4; 123.7;
(269 mg, 0.8 mmol) in CH2Cl2 (2 mL) was stirred for 122.6; 108.0; 66.0; 42.9; 36.3; 26.0. HR-ESI-TOF-MS:
5 min, followed then by the addition of D2O (2 mL) and 265.1321 ([M+HÀ HCl]+, C17H17N2O+; calc. 265.1335).
stirred for an additional 20 min. The mixture was trans-
ferred to a separatory funnel and extracted with CH2Cl2
1-[(4-Bromophenyl)methyl]-3-diazo-1,3-dihydro-
(3×5 mL). The resulting organic fractions were dried 2H-indol-2-one (8b). Diazo oxindole (100 mg, 0.6 mmol),
(Na2SO4) and concentrated under reduced pressure to K2CO3 (104 mg, 0.8 mmol), and p-bromobenzyl bromide
afford 68 mg (68%) of 1a–d as a white solid: IR (neat): (173 mg, 0.7 mmol) were added sequentially to a flame-
2979, 2933, 2534, 1809, 1724, 1496, 1377, 1368, 1249, dried vial and dissolved in DMF (0.6 mL). After stirring for
1166, 1118, 1055, 735. 1H-NMR (400 MHz, CDCl3): 7.85 (d, 15 h at room temperature, the mixture was diluted with
J=8.0, 1 H); 7.35 (td, J=7.6, 1.6, 1 H); 7.26 (dd, J=7.6, Et2O (20 mL) and washed with H2O (3×60 mL), dried
1.5, 1 H); 7.06 (td, J=7.5, 1.0, 1 H); 4.61 (s, 2 H); 1.54 (s, 9 (Na2SO4), filtered, and concentrated under reduced
H). 13C-NMR (125 MHz): 153.2; 147.0; 137.2; 130.3; 130.2; pressure. The residue was purified by flash chromatog-
124.2; 122.8; 81.1; 44.4; 28.5; 27.6. HR-ESI-TOF-MS: raphy eluting with hexanes/AcOEt (4:1) to afford 109 mg
°
241.0857 ([M+H]+, C12H16NO2Cl+; calc. 241.0870).
(53%) of 8b as a red solid: M.p. 98–100 C. IR (neat):
3057, 2927, 2857, 2087, 1676, 1608, 1467, 1397, 1377,
1
Methyl Chloro(phenyl)(2H)acetate (6-d). P(NMe2)3 1338, 1167, 1011. H-NMR (500 MHz, CDCl3): 7.41 (dt, J=
(41 mg, 0.24 mmol) was added dropwise to a solution of 8.5, 2.5, 2 H); 7.19–7.18 (m, 1 H); 7.16 (dt, J=8.6, 2.4, 2 H);
°
2a (41 mg, 0.24 mmol) in CH2Cl2 (2 mL) at À 78 C. The 7.09 (dt, J=7.6, 1.5, 1 H); 7.07 (dt, J=7.6, 1.5, 1 H); 6.78–
resulting solution was stirred for 10 min followed by the 6.76 (m, 1 H); 4.95 (s, 2 H). 13C-NMR (125 MHz): 167.0;
addition of 1a–d (30 mg, 0.12 mmol). The mixture was 135.3; 133.6; 132.1; 129.3; 125.7; 122.6; 121.9; 118.6;
allowed to warm to room temperature over 15 h, then 117.0; 109.6; 43.9; 30.0. HR-ESI-TOF-MS: 328.0052 ([M+
concentrated under reduced pressure. The residue was H]+, C15H11BrN3O+; calc. 328.0080).
purified by flash column chromatography eluting with a
solvent gradient of hexanes/AcOEt (20:1 to 10:1) to
1-[(4-Bromophenyl)methyl]-3-{[2-(chloromethyl)
provide 18 mg (83%) of 6–d as a clear oil and 36 mg phenyl](methyl)amino}-1,3-dihydro-2H-indol-2-one
(85%) of 4a as a clear oil. Spectral data for 6–d agree (9c). To a flame-dried 2-dram vial was added 1g
with literature sources:[46] IR (neat): 3031, 2954, 2924, (15.6 mg, 0.1 mmol) and Rh2(OAc)4 (1.4 mg, 0.003 mmol)
1
2853, 1754, 1455, 1436, 1281, 1162, 1006, 728, 695. H- sequentially, and the mixture dissolved in PhMe (0.5 mL).
NMR (500 MHz, CDCl3): 7.51–7.48 (m, 2 H); 7.40–7.37 (m, A solution of 8b (65.6 mg, 0.2 mmol) in PhMe (0.5 mL)
3 H); 5.37 (s, 0.5 H); 3.78 (s, 3 H). 13C-NMR (100 MHz): was added through slow addition with a syringe pump
168.9; 135.7; 129.3; 128.9; 127.9; 59.0; 53.4.
over 1 h at room temperature. After stirring for an
additional 1 h at room temperature, the mixture was
concentrated under reduced pressure. The residue was
3-{[2-(Chloromethyl)phenyl](methyl)amino}-1-
methyl-1,3-dihydro-2H-indol-2-one (9b). Compound purified by flash chromatography eluting with a solvent
1g (15.6 mg, 0.1 mmol), K2CO3 (13.8 mg, 0.1 mmol), and gradient of hexanes/AcOEt (3:1) to afford 24 mg (57%) of
Rh2(OAc)4 (1.4 mg, 0.003 mmol) were added sequentially 9c as an orange oil (CCDC #1895498). IR (neat): 3066,
to a flame-dried vial and constituted in PhMe (0.5 mL). A 3029, 2924, 2853, 1738, 1613, 1488, 1469, 1350, 1176,
solution of 8 (20.8 mg, 0.12 mmol) in PhMe (0.5 mL) was 1011, 754. 1H-NMR (500 MHz, CDCl3): 7.60 (dd, J=8.1, 1.1,
added to the mixture through slow addition with a 1 H); 7.48 (dd, J=7.6, 1.7, 1 H); 7.43–7.41 (m, 3 H); 7.34
°
syringe pump over 1 h at 50 C. The mixture was then (ddd, J=8.0, 7.4, 1.7, 1 H); 7.23 (tt, J=7.8, 1.2, 1 H); 7.20–
cooled to room temperature and concentrated under 7.15 (m, 3 H); 7.07 (td, J=7.6, 1.0, 1 H); 6.70 (d, J=7.8, 1
reduced pressure. The residue was purified by flash H); 5.09 (s, 1 H); 5.03 (d, J=11.1, 1 H); 4.97 (d, J=11.1, 1
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Helv. Chim. Acta 2019, 102, e1900192
[3] S. A. Ruider, S. Muller, E. M. Carreira, ‘Ring Expansion of 3-
H); 4.94 (d, J=15.7, 1 H); 4.79 (d, J=15.7, 1 H); 2.62 (s, 3
H). 13C-NMR (125 MHz): 175.5; 150.9; 143.0; 135.1; 132.7;
132.2; 131.8; 129.7; 129.4; 125.9; 125.4; 125.1; 124.3;
123.2; 121.9; 109.3; 66.3; 43.4; 43.2; 37.0. HR-ESI-TOF-MS:
419.0759 ([M+HÀ HCl]+, C23H20BrN2O+; calc. 419.0735).
Oxetanone-Derived Spirocycles: Facile Synthesis of Satu-
rated Nitrogen Heterocycles’, Angew. Chem. Int. Ed. 2013,
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1,1’-Dimethyl-1,3-dihydro-2,3’-spirobi[indol]-
2’(1’H)-one (10). NaH (2.3 mg, 0.06 mmol) was added to
a stirring solution of 9b (16.5 mg, 0.05 mmol) in DMF
°
(0.25 mL) at room temperature. After stirring at 50 C for
12 h, water (ca. 0.5 mL) was added. The resulting mixture
was extracted with AcOEt (3×5 mL), and the combined
organic layers were dried (MgSO4) and concentrated
under reduced pressure. The residue was purified by
flash chromatography eluting with hexanes/AcOEt (3:1)
to give 13 mg (>99%) of 10 as an orange oil. IR (neat):
2923, 2852, 1719, 1608, 1485, 1468, 1370, 1345, 1091,
1
744. H-NMR (500 MHz, CDCl3): 7.33 (td, J=7.8, 1.3, 1 H);
7.17–7.12 (m, 2 H); 7.07 (dd, J=7.2, 0.7, 1 H); 7.00 (td, J=
7.6, 1.0, 1 H); 6.87 (d, J=7.8, 1 H); 6.72 (td, J=7.5, 0.9, 1
H); 6.47 (d, J=7.8, 1 H); 3.53 (d, J=15.6, 1 H); 3.25 (s, 3
H); 3.19 (d, J=15.6, 1 H); 2.46 (s, 3 H). 13C-NMR
(150 MHz): 177.0; 151.9; 143.1; 129.5; 129.3; 127.9; 126.9;
124.1; 123.5; 123.0; 118.1; 108.4; 106.7; 73.9; 40.8; 30.7;
29.7; 24.6 (trace diazo dimer). HR-ESI-TOF-MS: 265.1352
([M+H]+, C17H17N2O+; calc. 265.1335).
[11] J.-J. Feng, T.-Y. Lin, C.-Z. Zhu, H. Wang, H.-H. Wu, J. Zhang,
‘The Divergent Synthesis of Nitrogen Heterocycles by
Rhodium(I)-Catalyzed Intermolecular Cycloadditions of
Vinyl Aziridines and Alkynes’, J. Am. Chem. Soc. 2016, 138,
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Acknowledgements
[12] H. Shang, Y. Wang, Y. Tian, J. Feng, Y. Tang, ‘The Divergent
Synthesis of Nitrogen Heterocycles by Rhodium(II)-Cata-
lyzed Cycloadditions of 1-Sulfonyl 1,2,3-Triazoles with 1,3-
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This work was supported by the National Science
Foundation (CAREER CHE-1056242 and 1665440).
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Author Contribution Statement
K. Eckert and A. Lepore conducted the experiments and
analyzed the data. Prof. B. Ashfeld conceived and
designed the experiments. K. Eckert and Prof. B. Ashfeld
prepared the manuscript.
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Received August 2, 2019
Accepted October 7, 2019
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