Key words
indoles - cyclobutanones - Brønsted acids - tandem reactions - catalysis
Due to the extremely high number of natural bioactive compounds containing an indole
unit,[1] a wide number of chemoselective syntheses and functionalizations of this heterocycle
have been exploited.[2] In particular, many investigations were focused on the identification of new and
specific therapeutic agents for the treatment of several human diseases such as glaucoma,[3] hypertension,[4] depression,[5] Alzheimer’s disease,[6] cardiovascular diseases,[7] and viral infections.[8] A number of strained cyclobutyl- and cyclopropylindole derivatives have aroused
significant interest, not only for their pharmacological properties but, above all,
for their usefulness in drug–receptor affinity studies. Indeed, the affinity of lead
compounds can be studied by performing radioligand binding assays using constrained
molecular architectures that, by reducing the rotations around certain bonds, clarify
the way in which these molecules interact with biological targets.[9] Examples include compound 4991W93, a 5HT1B/1D receptor and partial agonist with
potential for the treatment and prophylaxis of migraine,[10] the inhibition of leukotriene production,[11] CRTH2 antagonists[12] and estrogen receptor modulators[13] (Scheme [1, a]). Despite their biological activity, direct insertion of a cyclobutane unit on
the indole skeleton is limited to a few multistep approaches, generally requiring
the preparation of prefunctionalized substrates (Scheme [1, b]).[9c]
[10]
[14]
Scheme 1 (a) Representative bioactive cyclobutyl-indole drugs. (b) Strategies for the insertion
of a cyclobutanone unit on indoles.
In this context, a versatile one-pot catalytic and chemoselective procedure would
represent a significant advance for drug design and synthesis. We recently reported
the preparation of indole cyclopropylcarbaldehydes 3 through a tandem acid-catalyzed addition/ring-contraction reaction of 2-hydroxycyclobutanone
(1) and indole (2a) (Scheme [2, a]).[15] Continuing our studies in this research field,[16] we discovered that functionalized aldehyde 3a furnished the corresponding indolylcyclobutanone derivative 4a on treatment with PTSA at 50 °C (Scheme [2, b]).
Scheme 2 (a) Acid-catalyzed synthesis of indole cyclopropylcarbaldehyde 3a. (b) The C3–C4 ring expansion of aldehyde 3a to give cyclobutanone 4a. (c) A catalytic one-pot synthesis of indolyl cyclobutanone derivative 4a.
This observation inspired us to develop a two-step, one-pot synthesis of cyclobutanone
indoles 4 following the general procedure shown in Scheme [2, c]. To explore the feasibility of this process, a series of experiments was performed
to identify the best reaction conditions. A summary of the results is reported in
Table [1] (see also Table S1 in the Supporting Information). We first examined the reaction
between 2-hydroxycyclobutanone (1) and indole (2a) in the presence of TsOH (10 mol%) under neat conditions and isolated the desired
product 4a in only 18% yield after 24 hours (entry 1). The reaction carried out in toluene at
40 °C gave the product 4a in an improved 48% yield (entry 2), and this increased to 58% when the reaction was
performed at 50 °C (entry 3). Increasing the temperature to 60 °C did not lead to
any further improvement in the yield of 4a (entry 4). Furthermore, no significant benefits were obtained from the use of 3 Å
molecular sieves or other anhydrous reaction conditions. Finally, a catalyst screen
using recyclable NR-50 (Nafion resin 50), AR-15 (Amberlyst resin 15) and AR-35 (Amberlyst
resin 35) (entries 5, 6 and 7) showed that the optimum yield of 4a (96%) was obtained when using AR-15 (10 mol% loading) at 50 °C in toluene.
Table 1 Initial Screening Studiesa
|
|
Entry
|
Catalyst (mol%)
|
Solvent
|
Temp (°C)
|
Ratio of 3a/4a
b
|
Conv. (%)c
|
Yield (%)d
|
|
1
|
TsOH (10)
|
neat
|
40
|
2:1
|
21
|
18
|
|
2
|
TsOH (10)
|
toluene
|
40
|
1:1
|
50
|
48
|
|
3
|
TsOH (10)
|
toluene
|
50
|
1:3
|
63
|
58
|
|
4
|
TsOH (10)
|
toluene
|
60
|
1:16
|
60
|
54
|
|
5
|
NR-50 (10)
|
toluene
|
50
|
1:22
|
96
|
94
|
|
6
|
AR-15 (10)
|
toluene
|
50
|
1:28
|
97
|
96
|
|
7
|
AR-35 (10)
|
toluene
|
50
|
1:28
|
93
|
90
|
a Reaction conditions: 1 (50 mg, 0.58 mmol), 2a (1.0 equiv), acid catalyst [Nafion resin 50 (NR-50), Amberlyst resin 15 (AR-15) or
Amberlyst resin 35 (AR-35): 10 mol%], solvent (1.5 mL), 8–24 h, 40–50 °C.
b The 3a:4a ratio was determined by 1H NMR analysis.
c The conversion into 4a was determined by 1H NMR analysis.
d Yield of isolated product 4a after flash chromatography.
With optimized reaction conditions in hand, we next studied the scope of this one-pot,
two-step procedure using substituted indoles 2a–v (Scheme [3]). Good functional group tolerance was observed for indoles 2, allowing access to a variety of cyclobutanone adducts 4. Indoles 2a–d furnished the corresponding adducts 4a–d in good to high yields (73–96%). Satisfactory results were achieved by reacting 2-hydroxycyclobutanone
(1) with N-substituted indoles 2e–i, affording the cyclobutanones 4e–i in 89–94% yields.[17] The 2- and 3-alkyl/aryl indoles 2j–q gave good conversions and yields of the corresponding indolyl ketones 4j–p, with 4q being recovered as a 50.50 mixture of diastereoisomers (90% yield), probably due
to epimerization at C2 of the cyclobutanone moiety during the chromatographic purification
step. On the other hand, reactions of 1 with indoles 2r–v, bearing electron-withdrawing groups at the C4 or C5 positions, did not occur as
desired. In these cases, cyclopropyl carbaldehydes 3r–v were isolated as unique reaction products in yields of 74–90%.
Scheme 3 Exploration of the substrate scope
Further experiments carried out with N-benzylpyrrole afforded the corresponding cyclopropanes 3w/3w′ (as an 80:20 mixture of regioisomers) in 68% overall yield. The reaction of 1 with 3,5-dimethoxyphenol yielded the cyclobutanone 4x in 86% yield.
The results obtained during this study allowed us to put forward a plausible mechanism
for the acid-catalyzed one-pot addition of a cyclobutanone to the indole skeleton
(Scheme [4]). In our hypothesis, the protonation of cyclobutanone 1 promotes indole nucleophilic attack leading to the formation of the adduct I.[15]
[16a]
[b] At room temperature, this intermediate undergoes a rapid C4–C3 ring contraction
via carbocationic species II, mainly affording the cyclopropyl carbaldehydes 3.[16] At higher temperatures (50 °C), the establishment of an equilibrium between the
three-membered-ring species 3 and the cyclobutane carbocationic intermediate II leads to the formation of derivatives 4.[18]
[19] However, this process is favored by the presence of electron-donating groups on
the heterocyclic system. On the other hand, reactions carried out with indoles bearing
electron-withdrawing groups (e.g., 2r–v) destabilize the carbocationic species II and promote the C4–C3 ring contraction as a preferential stabilization process.[19]
[20]
Scheme 4 Proposed reaction mechanism for the synthesis of cyclobutanones 4 and cyclopropyl carbaldehydes 3 under acid-catalyzed conditions
In summary, a new one-pot catalytic functionalization of indoles has been established
under mild conditions. This method provides a straightforward access to diverse indolyl
cyclobutanone compounds in good to excellent yields, underlining a broad substrate
scope and some limitations related to the presence of electron-withdrawing groups.
This two-step, one-pot process has been studied by using a recyclable polystyrene-based
ion exchange resin. Further studies aimed toward adapting this reaction to a continuous-flow
process are currently underway in our laboratories.
Diphenyl phosphate, Amberlyst 15, Amberlyst 35 and indoles 2a,d,i,l,q,r were purchased from Sigma-Aldrich and used without further purification. Indoles
2b,c,m,s were purchased from TCI and used without further purification. Unless noted otherwise,
all experiments were carried out in a 5 mL vial closed with a screw cap and equipped
with a magnetic stir bar. Analytical thin-layer chromatography was performed using
0.25 mm Aldrich silica gel 60-F plates. Flash chromatography was performed using Merck
silica gel (70–200 mesh). Yields refer to chromatographically and spectroscopically
pure materials. Melting points were determined with a Büchi M-560 apparatus. Infrared
spectra were recorded on FT-IR Bruker Equinox-55 or Thermo Fisher Scientific Nicolet
IS50 FTIR spectrophotometers and are reported in wavenumbers (cm–1). 1H and 13C NMR spectra were obtained on Bruker DRX 600 (1H, 600 MHz; 13C, 150 MHz) or Varian 500 (1H, 500 MHz; 13C, 126 MHz) spectrometers at 27 °C using CDCl3 (internal reference = 7.26 ppm) as the solvent. 13C NMR were recorded at 126 MHz (internal reference = 77.00 ppm) using CDCl3 as the solvent. Chemical shifts (δ) are given in ppm. Coupling constants (J) are reported in Hz. Low-resolution mass spectrometry was performed using an Agilent-HP
GC-MS (EI, 70 eV). High-resolution mass spectrometry (HRMS) was performed in fast
atom bombardment (FAB+) ionization mode (ESI) using Bruker micrOTF-Q II and/or Agilent
Q-TOF 6520 instruments.
Cyclobutyl Indoles 4; General Procedure
Cyclobutyl Indoles 4; General Procedure
In a 5 mL glass vial, a mixture of 2-hydroxycyclobutanone (1a) (100 mg, 1.1 mmol), indole 2a–v (1.0 mmol), Amberlyst 15 (10 mol%) and toluene (3.0 mL) was stirred at 50 °C. After
completion of the reaction, the crude product was loaded on a silica gel column and
purified by flash chromatography using hexanes/diethyl ether (10:1 to 3:1) as the
eluent.
2-(1H-Indol-3-yl)cyclobutanone (4a)
2-(1H-Indol-3-yl)cyclobutanone (4a)
Yield: 117 mg (96%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.97 (s, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.29 (d, J = 8.1 Hz, 1 H), 7.17–7.11 (m, 1 H), 7.08 (d, J = 1.4 Hz, 1 H), 7.06 (td, J = 7.6, 1.0 Hz, 1 H), 4.68 (tdd, J = 7.9, 2.5, 1.2 Hz, 1 H), 3.31–3.14 (m, 1 H), 3.07 (dddd, J = 17.6, 9.7, 4.9, 2.7 Hz, 1 H), 2.55 (qd, J = 10.6, 4.9 Hz, 1 H), 2.14 (ddt, J = 11.0, 9.6, 8.1 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 208.8, 136.3, 126.3, 122.4, 121.1, 119.7, 119.0, 112.0, 111.2, 57.0, 45.1,
18.3.
All analytical data were in good accordance with reported data.[16]
2-(5-Methyl-1H-indol-3-yl)cyclobutanone (4b)
2-(5-Methyl-1H-indol-3-yl)cyclobutanone (4b)
Yield: 187 mg (94%); colorless oil.
FTIR (film): 2994, 1788, 1612, 1454, 1228, 1129, 1011 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.33 (s, 1 H), 7.25 (d, J = 10.0 Hz, 1 H), 7.11 (d, J = 1.4 Hz, 1 H), 7.03 (d, J = 8.3 Hz, 1 H), 4.80–4.60 (m, 1 H), 3.32–3.23 (m, 1 H), 3.13 (dddd, J = 17.6, 9.6, 4.9, 2.7 Hz, 1 H), 2.61 (ddd, J = 21.4, 10.6, 4.9 Hz, 1 H), 2.45 (s, 3 H), 2.29–2.13 (m, 1 H).
13C NMR (126 MHz, CDCl3): δ = 208.8, 136.3, 126.3, 122.4, 121.1, 119.7, 119.0, 112.0, 111.2, 57.0, 45.1,
18.3.
HRMS (ESI): m/z [M + Na]+ calcd for C13H13NNaO: 222.0895; found: 222.0898.
2-(7-Methoxy-1H-indol-3-yl)cyclobutanone (4c)
2-(7-Methoxy-1H-indol-3-yl)cyclobutanone (4c)
Yield: 185 mg (86%); green oil.
FTIR (film): 2998, 1789, 1614, 1460, 1221, 1129, 1009 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.12 (s, 1 H), 7.08 (s, 1 H), 7.00 (d, J = 7.0 Hz, 1 H), 6.87 (d, J = 7.0 Hz, 1 H), 6.59 (dd, J = 6.5, 3.5 Hz, 1 H), 4.90 (t, J = 6.5 Hz, 1 H), 3.80 (s, 3 H), 2.72–2.67 (m, 1 H), 2.40–2.37 (m, 1 H), 2.08–2.01
(m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 210.9, 154.4, 131.3, 128.3, 124.8, 116.5, 112.6, 112.1, 100.6, 55.9, 40.8,
29.1, 19.0.
HRMS (ESI): m/z [M + Na]+ calcd for C13H13NNaO2: 238.0844; found: 238.0851.
2-(5-Fluoro-1H-indol-3-yl)cyclobutanone (4d)
2-(5-Fluoro-1H-indol-3-yl)cyclobutanone (4d)
Yield: 148 mg (73%); yellow oil.
FTIR (film): 2986, 1790, 1463, 1227, 1145, 986 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.97 (br s, 1 H), 7.22–7.19 (m, 1 H), 7.12 (td, J = 9.8, 2.1 Hz, 2 H), 6.88 (td, J = 9.1, 2.3 Hz, 1 H), 4.62 (t, J = 9.2 Hz, 1 H), 3.30–3.12 (m, 1 H), 3.14–2.93 (m, 1 H), 2.55 (qd, J = 10.7, 5.0 Hz, 1 H), 2.17–2.00 (m, 1 H).
13C NMR (126 MHz, CDCl3): δ = 208.7, 129.7, 122.9, 111.9 (d, J = 1.8 Hz), 111.8, 110.9 (d, J = 1.9 Hz), 110.7, 104.1 (d, J = 1.8 Hz), 104.0, 56.8, 45.1, 18.2.
HRMS (ESI): m/z [M + Na]+ calcd for C12H10FNNaO: 226.0644; found: 226.0651.
2-(1-Methyl-1H-indol-3-yl)cyclobutanone (4e)
2-(1-Methyl-1H-indol-3-yl)cyclobutanone (4e)
Yield: 183 mg (92%); orange oil.
All analytical data were in good accordance with reported data.[15]
2-(1-Benzyl-1H-indol-3-yl)cyclobutanone (4f)
2-(1-Benzyl-1H-indol-3-yl)cyclobutanone (4f)
Yield: 258 mg (94%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.49 (d, J = 7.9 Hz, 1 H), 7.22 (dd, J = 11.7, 4.2 Hz, 3 H), 7.18 (d, J = 8.4 Hz, 2 H), 7.06–7.03 (m, 3 H), 7.00 (s, 1 H), 5.18 (s, 2 H), 4.67 (td, J = 8.4, 2.0 Hz, 1 H), 3.29–3.12 (m, 1 H), 3.04 (dddd, J = 17.5, 9.6, 4.9, 2.7 Hz, 1 H), 2.53 (qd, J = 10.6, 4.9 Hz, 1 H), 2.22–1.95 (m, 1 H).
13C NMR (126 MHz, CDCl3): δ = 202.1, 137.3, 136.7, 128.7, 127.6, 126.8, 125.2, 122.1, 119.7, 119.4, 119.2,
111.0, 109.8, 57.0, 50.0, 45.1, 18.4.
All analytical data were in good accordance with reported data.[16]
2-[1-(3-Methoxybenzyl)-1H-indol-3-yl]cyclobutanone (4g)
2-[1-(3-Methoxybenzyl)-1H-indol-3-yl]cyclobutanone (4g)
Yield: 283 mg (93%); colorless oil.
FTIR (film): 2984, 1789, 1458, 1227, 1144, 908 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.49 (d, J = 7.9 Hz, 1 H), 7.18 (s, 1 H), 7.15–7.08 (m, 2 H), 7.03 (dd, J = 11.0, 3.9 Hz, 1 H), 7.00 (s, 1 H), 6.71 (dd, J = 8.2, 2.4 Hz, 1 H), 6.63 (d, J = 7.6 Hz, 1 H), 6.59 (s, 1 H), 5.15 (s, 2 H), 4.74–4.57 (m, 1 H), 3.66 (s, 3 H),
3.19 (dddd, J = 18.0, 10.7, 8.3, 2.5 Hz, 1 H), 3.04 (dddd, J = 17.5, 9.6, 4.9, 2.7 Hz, 1 H), 2.53 (qd, J = 10.7, 4.9 Hz, 1 H), 2.12 (dtd, J = 10.9, 9.6, 8.2 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 208.9, 159.9, 138.9, 136.8, 129.8, 127.0, 125.2, 122.1, 119.4, 119.2, 119.1,
112.7, 112.7, 111.0, 109.8, 57.0, 55.1, 49.9, 45.0, 18.4.
HRMS (ESI): m/z [M + Na]+ calcd for C20H19NNaO2: 328.1313; found: 328.1314.
2-[1-(Naphthalen-2-ylmethyl)-1H-indol-3-yl]cyclobutanone (4h)
2-[1-(Naphthalen-2-ylmethyl)-1H-indol-3-yl]cyclobutanone (4h)
Yield: 295 mg (91%); brown solid; mp 76 °C.
FTIR (film): 2952, 1790, 1612, 1463, 1352, 1200, 1072 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.77 (m, 3 H), 7.61–7.55 (m, 2 H), 7.48–7.40 (m, 2 H), 7.29 (d, J = 8.1 Hz, 1 H), 7.26–7.21 (m, 1 H), 7.20–7.14 (m, 1 H), 7.13–7.08 (m, 2 H), 5.39
(s, 2 H), 4.80–4.67 (m, 1 H), 3.25 (dddd, J = 17.8, 10.6, 8.3, 2.5 Hz, 1 H), 3.11 (dddd, J = 17.5, 9.6, 4.9, 2.7 Hz, 1 H), 2.60 (qd, J = 10.6, 4.9 Hz, 1 H), 2.19 (ddt, J = 10.9, 9.6, 8.2 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 208.8, 136.9, 134.7, 133.3, 132.8, 128.6, 127.8, 127.6, 127.1, 126.3, 126.0,
125.6, 125.2, 124.8, 122.1, 119.4, 119.3, 111.1, 109.8, 57.0, 50.2, 45.0, 18.4.
HRMS (ESI): m/z [M + Na]+ calcd for C23H19NNaO: 348.1364; found: 348.1371.
2-(1-Benzyl-5-chloro-1H-indol-3-yl)cyclobutanone (4i)
2-(1-Benzyl-5-chloro-1H-indol-3-yl)cyclobutanone (4i)
Yield: 275 mg (89%); yellow oil.
FTIR (film): 3073, 1783, 1441, 1224, 1018, 990 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.44 (d, J = 1.3 Hz, 1 H), 7.20 (dd, J = 10.6, 7.1 Hz, 3 H), 7.05 (t, J = 7.8 Hz, 2 H), 7.04–6.99 (m, 3 H), 5.14 (s, 2 H), 4.59 (td, J = 8.1, 2.2 Hz, 1 H), 3.19 (dddd, J = 18.9, 10.6, 8.4, 2.4 Hz, 1 H), 3.09–2.92 (m, 1 H), 2.52 (qd, J = 10.7, 4.9 Hz, 1 H), 2.07 (tt, J = 10.8, 8.3 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 208.4, 137.0, 135.3, 129.3, 128.9, 128.2, 127.9, 127.1, 126.9, 126.7, 125.4,
122.6, 118.9, 111.0, 110.9, 56.8, 50.4, 45.3, 18.5.
HRMS (ESI): m/z [M + Na]+ calcd for C19H16ClNNaO: 332.0818; found: 332.0821.
2-(2-Methyl-1H-indol-3-yl)cyclobutanone (4j)
2-(2-Methyl-1H-indol-3-yl)cyclobutanone (4j)
Yield: 173 mg (87%); yellow oil.
FTIR (film) : 2989, 1788, 1457, 1231, 1144 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.83 (br s, 1 H), 7.33 (d, J = 7.8 Hz, 1 H), 7.25 (d, J = 6.5 Hz, 1 H), 7.10 (t, J = 7.1 Hz, 1 H), 7.08–7.01 (m, 1 H), 4.67 (ddt, J = 10.7, 8.6, 2.2 Hz, 1 H), 3.28 (dddd, J = 19.3, 10.5, 8.7, 2.0 Hz, 1 H), 3.23–3.12 (m, 1 H), 2.52 (qd, J = 10.8, 4.8 Hz, 1 H), 2.40–2.34 (m, 1 H), 2.33 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 210.1, 135.3, 131.9, 127.3, 121.3, 119.5, 118.1, 110.4, 107.2, 57.0, 45.0,
18.3, 12.1.
HRMS (ESI): m/z [M + Na]+ calcd for C13H13NNaO: 222.0895; found: 222.0899.
2-(2-Phenyl-1H-indol-3-yl)cyclobutanone (4k)
2-(2-Phenyl-1H-indol-3-yl)cyclobutanone (4k)
Yield: 219 mg (84%); colorless oil.
FTIR (film): 3054, 2989, 1789, 1623, 1456, 1227, 1112, 1024 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.06 (br s, 1 H), 7.38–7.34 (m, 5 H), 7.31–7.29 (m, 1 H), 7.17–7.16 (m, 1 H),
7.14–7.13 (m, 1 H), 7.06–7.03 (m, 1 H), 4.87–4.66 (m, 1 H), 3.31–3.02 (m, 2 H), 2.52–2.30
(m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 201.8, 136.1, 129.8, 129.1, 129.0, 123.0, 122.8, 120.4, 120.2, 119.5, 119.0,
111.2, 111.1, 57.5, 45.1, 18.3.
HRMS (ESI): m/z [M + Na]+ calcd for C18H15NNaO: 284.1051; found: 284.1053.
2-[2-(p-Tolyl)-1H-indol-3-yl]cyclobutanone (4l)
2-[2-(p-Tolyl)-1H-indol-3-yl]cyclobutanone (4l)
Yield: 250 mg (91%); colorless oil.
FTIR (film): 3007, 1790, 1502, 1460, 1134, 1028 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.07 (br s, 1 H), 7.44 (d, J = 7.9 Hz, 1 H), 7.39 (d, J = 8.1 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 2 H), 7.21–7.17 (m, 1 H), 7.13–7.09 (m, 1 H), 4.90–4.71 (m, 1 H), 3.35–3.12
(m, 2 H), 2.55–2.45 (m, 2 H), 2.42 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 209.9, 138.2, 136.2, 135.9, 129.6, 128.4, 127.7, 127.4, 122.3, 120.0, 119.3,
111.1, 107.6, 57.6, 45.0, 21.2, 18.3.
HRMS (ESI): m/z [M + Na]+ calcd for C19H17NNaO: 298.1208; found: 298.1211.
2-(3-Methyl-1H-indol-2-yl)cyclobutanone (4m)
2-(3-Methyl-1H-indol-2-yl)cyclobutanone (4m)
Yield: 189 mg (95%); yellow oil.
FTIR (film): 3390, 3053, 2919, 1789, 1704, 1612, 1462, 1386, 1238 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.49 (dd, J = 7.9, 3.5 Hz, 1 H), 7.13 (dd, J = 7.8, 2.3 Hz, 2 H), 7.05 (ddd, J = 7.9, 5.6, 2.4 Hz, 1 H), 6.83 (d, J = 0.8 Hz, 1 H), 5.67–5.45 (m, 1 H), 3.11–3.03 (m, 1 H), 2.99–2.91 (m, 1 H), 2.66
(d, J = 3.0 Hz, 1 H), 2.62 (ddd, J = 21.5, 10.9, 4.4 Hz, 1 H), 2.22 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 203.6, 135.8, 128.9, 122.8, 121.9, 119.4, 119.2, 112.2, 109.1, 68.5, 41.8,
20.2, 9.5.
HRMS (ESI): m/z [M + Na]+ calcd for C13H13NNaO: 222.0895; found: 222.0901.
3-[2-(2-Oxocyclobutyl)-1H-indol-3-yl]propionic Acid Methyl Ester (4n)
3-[2-(2-Oxocyclobutyl)-1H-indol-3-yl]propionic Acid Methyl Ester (4n)
Yield: 211 mg (78%); colorless oil.
FTIR (film): 3418, 2973, 2881, 1781, 1721, 1622, 1462, 1397, 1087, 912 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.50 (d, J = 7.9 Hz, 1 H), 7.13–7.10 (m, 2 H), 7.05 (ddd, J = 7.9, 5.9, 2.1 Hz, 1 H), 6.86 (s, 1 H), 5.54 (ddd, J = 10.5, 4.1, 2.1 Hz, 1 H), 3.59 (s, 3 H), 3.11–3.01 (m, 1 H), 2.99 (t, J = 7.8 Hz, 2 H), 2.97–2.90 (m, 1 H), 2.60 (t, J = 7.8 Hz, 2 H), 2.59–2.56 (m, 1 H), 2.26–2.18 (m, 1 H).
13C NMR (151 MHz, CDCl3): δ = 203.2, 173.6, 135.8, 127.8, 122.7, 122.0, 119.6, 119.0, 115.2, 109.3, 68.4,
51.5, 41.8, 34.5, 20.4, 20.0.
HRMS (ESI): m/z [M + Na]+ calcd for C16H17NNaO3: 294.1106; found: 294.1112.
N,N-Diethyl-3-[2-(2-oxocyclobutyl)-1H-indol-3-yl]propionamide (4o)
N,N-Diethyl-3-[2-(2-oxocyclobutyl)-1H-indol-3-yl]propionamide (4o)
Yield: 230 mg (74%); yellow oil.
FTIR (film): 3412, 2977, 2889, 1781, 1627, 1460, 1298, 1089, 1086 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.52 (d, J = 7.9 Hz, 1 H), 7.14–7.07 (m, 2 H), 7.04 (ddd, J = 8.0, 4.9, 3.1 Hz, 1 H), 6.87 (s, 1 H), 5.55 (ddd, J = 10.4, 3.9, 2.0 Hz, 1 H), 3.30 (dd, J = 14.0, 7.0 Hz, 2 H), 3.12 (dd, J = 14.2, 7.1 Hz, 2 H), 3.08–3.04 (m, 1 H), 3.02 (dd, J = 9.0, 6.9 Hz, 2 H), 2.93 (dddd, J = 14.9, 12.3, 7.4, 5.3 Hz, 1 H), 2.63–2.59 (m, 1 H), 2.60–2.57 (m, 2 H), 2.23 (dt,
J = 20.0, 9.9 Hz, 1 H), 1.02 (t, J = 7.0 Hz, 3 H), 0.99 (t, J = 7.1 Hz, 3 H).
13C NMR (151 MHz, CDCl3): δ = 203.3, 171.7, 135.7, 127.9, 122.8, 121.9, 119.5, 119.0, 115.9, 109.3, 68.4,
41.8, 41.7, 40.1, 33.6, 20.8, 19.9, 14.1, 12.9.
HRMS (ESI): m/z [M + Na]+ calcd for C19H24N2NaO2: 335.1735; found: 335.1737.
2-[3-(2-Nitro-1-phenylethyl)-1H-indol-2-yl]cyclobutanone (4p)
2-[3-(2-Nitro-1-phenylethyl)-1H-indol-2-yl]cyclobutanone (4p)
Yield: 304 mg (91%); colorless oil.
FTIR (film): 2919, 1701, 1456, 1225, 1153, 907, 738 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.36 (dd, J = 18.2, 8.0 Hz, 1 H), 7.28–7.22 (m, 5 H), 7.14 (t, J = 4.1 Hz, 2 H), 7.06–6.98 (m, 1 H), 6.92 (d, J = 27.1 Hz, 1 H), 5.59 (dt, J = 17.0, 5.3 Hz, 1 H), 5.09 (td, J = 7.9, 4.5 Hz, 1 H), 4.97 (ddd, J = 12.6, 7.3, 5.3 Hz, 1 H), 4.86 (ddd, J = 17.8, 12.5, 8.6 Hz, 1 H), 3.20–3.15 (m, 1 H), 2.98–2.95 (m, 1 H), 2.67–2.65 (m,
1 H), 2.28–24 (m, 1 H).
13C NMR (126 MHz, CDCl3): δ = 202.7, 138.9, 134.4, 128.9, 127.7, 125.2, 124.3, 123.2, 122.9, 121.1, 118.9,
114.0, 109.4, 84.8, 79.4, 68.6, 27.5, 21.4.
HRMS (ESI): m/z [M + Na]+ calcd for C20H18N2NaO3: 357.1215; found: 357.1221.
2-[5-Methyl-3-(2-nitro-1-phenylethyl)-1H-indol-2-yl]cyclobutanone (4q)
2-[5-Methyl-3-(2-nitro-1-phenylethyl)-1H-indol-2-yl]cyclobutanone (4q)
Obtained as a 55:45 mixture of diastereoisomers.
Yield: 313 mg (90%); colorless oil.
FTIR (film): 3013, 2980, 2232, 1789, 1785, 1644, 1470, 1229, 1148, 1012 cm–1.
Isomer A
1H NMR (500 MHz, CDCl3): δ = 7.25–7.24 (m, 4 H), 7.20–7.17 (m, 3 H), 7.00 (m, 1 H), 6.97–6.95 (s, 1 H),
5.53 (d, J = 8.2 Hz, 1 H), 5.07–5.03 (m, 1 H), 4.99–4.91 (m, 1 H), 4.90–4.80 (m, 1 H), 3.17–3.04
(m, 1 H), 3.03–2.91 (m, 1 H), 2.67–2.55 (m, 1 H), 2.31 (s, 3 H), 2.27–2.21 (m, 1 H).
13C NMR (126 MHz, CDCl3): δ = 202.6, 138.9, 134.4, 129.7, 129.0, 128.9, 127.7, 127.5, 124.3, 122.9, 118.8,
114.0, 109.4, 79.4, 68.6, 28.5, 27.5, 21.3, 20.0.
HRMS (ESI): m/z [M + Na]+ calcd for C21H20N2NaO3: 371.1372; found: 371.1379.
Isomer B)
1H NMR (500 MHz, CDCl3): δ = 7.25–7.23 (m, 4 H), 7.19–7.17 (m, 2 H), 7.13–7.12 (m, 1 H), 7.02 (d, J = 4.5 Hz, 1 H), 6.82 (s, 1 H), 6.66–6.23 (m, 1 H), 5.07–5.04 (m, 1 H), 4.99–4.90
(m, 1 H), 4.89–4.80 (m, 1 H), 3.07–3.06 (m, 1 H), 2.98–2.95 (m, 1 H), 2.76–2.74 (m,
1 H), 2.32 (s, 3 H), 2.27–2.19 (m, 1 H).
13C NMR (126 MHz, CDCl3): δ = 202.7, 138.9, 134.4, 129.7, 129.0, 128.9, 127.7, 125.2, 122.9, 121.1, 118.9,
114.0, 109.4, 84.9, 68.7, 41.9, 28.4, 21.4, 20.1.
HRMS (ESI): m/z [M + Na]+ calcd for C21H20N2NaO3: 371.1372; found: 371.1377.
1-(5-Nitro-1H-indol-3-yl)cyclopropanecarbaldehyde (3r)
1-(5-Nitro-1H-indol-3-yl)cyclopropanecarbaldehyde (3r)
Yield: 170 mg (74%); yellow solid.
All analytical data were in good accordance with reported data.[16]
3-(1-Formylcyclopropyl)-1H-indole-4-carbonitrile (3s)
3-(1-Formylcyclopropyl)-1H-indole-4-carbonitrile (3s)
Yield: 170 mg (81%); colorless oil.
All analytical data were in good accordance with reported data.[16]
3-(1-Formylcyclopropyl)-1H-indole-5-carboxylic Acid Methyl Ester (3t)
3-(1-Formylcyclopropyl)-1H-indole-5-carboxylic Acid Methyl Ester (3t)
Yield: 218 mg (90%); colorless oil.
FTIR (film): 3472, 2961, 1785, 1711, 1620, 1437, 1261, 1096 cm–1.
1H NMR (600 MHz, CDCl3): δ = 9.25 (s, 1 H), 8.30 (s, 1 H), 8.25 (s, 1 H), 7.86 (dd, J = 8.6, 1.6 Hz, 1 H), 7.30 (d, J = 8.6 Hz, 1 H), 7.10 (d, J = 2.1 Hz, 1 H), 3.86 (s, 3 H), 1.61 (q, J = 4.0 Hz, 2 H), 1.35 (q, J = 4.1 Hz, 2 H).
13C NMR (151 MHz, CDCl3): δ = 201.1, 168.0, 138.8, 127.4, 125.4, 123.9, 122.1, 121.9, 114.8, 111.1, 51.8,
28.7, 15.8.
HRMS (ESI): m/z [M + Na]+ calcd for C14H13NNaO3: 266.0793; found: 266.0798.
3-(1-Formylcyclopropyl)-1H-indole-4-carboxylic Acid Methyl Ester (3u)
3-(1-Formylcyclopropyl)-1H-indole-4-carboxylic Acid Methyl Ester (3u)
Yield: 199 mg (82%); colorless oil.
All analytical data were in good accordance with reported data.[16]
3-(1-Formylcyclopropyl)-1H-indole-5-carbaldehyde (3v)
3-(1-Formylcyclopropyl)-1H-indole-5-carbaldehyde (3v)
Yield: 155 mg (73%); colorless oil.
FTIR (film): 3348, 2960, 1726, 1665, 1611, 1258, 1094 cm–1.
1H NMR (600 MHz, CD3OD): δ = 9.94 (s, 1 H), 9.17 (s, 1 H), 8.09 (d, J = 1.0 Hz, 1 H), 7.72 (dd, J = 8.5, 1.5 Hz, 1 H), 7.50 (d, J = 8.5 Hz, 1 H), 7.33 (s, 1 H), 1.70 (q, J = 3.8 Hz, 2 H), 1.48–1.43 (m, 2 H).
13C NMR (151 MHz, CD3OD): δ = 203.0, 194.6, 141.9, 130.4, 129.2, 128.0, 125.7, 122.9, 115.6, 113.3, 30.0,
15.8.
HRMS (ESI): m/z [M + Na]+ calcd for C13H11NNaO2: 236.0687; found: 236.0688.
1-(1-Benzyl-1H-pyrrol-2-yl)cyclopropanecarbaldehyde (3w)
1-(1-Benzyl-1H-pyrrol-2-yl)cyclopropanecarbaldehyde (3w)
Obtained as an 80:20 mixture of regioisomers.
Yield: 153 mg (68%); colorless oil.
FTIR (film): 2998, 2982, 1728, 1660, 1224, 1048, 1002, 980 cm–1.
1H NMR (600 MHz, CDCl3): δ (major regioisomer) = 8.97 (s, 1 H), 7.23 (dt, J = 12.1, 2.9 Hz, 2 H), 7.19-7.18
(m, 2H), 6.88 (d, J = 1.8 Hz, 1 H), 6.67–6.59 (m, 1 H), 6.11–6.07 (m, 1 H), 6.03 (dt,
J = 12.9, 6.4 Hz, 1 H), 4.98 (s, 2 H), 1.39 (q, J =3.9 Hz, 2 H), 1.17 (q, J = 4.0
Hz, 2 H).
13C NMR (151 MHz, CDCl3): δ (major regioisomer) = 200.2, 137.9, 129.4, 128.7, 127.6, 126.9, 122.9, 110.5,
107.3, 50.9, 29.5, 16.8.
HRMS (ESI): m/z [M + Na]+ calcd for C15H15NNaO: 248.1051; found: 248.1063.
2-(2-Hydroxy-4,6-dimethoxyphenyl)cyclobutanone (4x)
2-(2-Hydroxy-4,6-dimethoxyphenyl)cyclobutanone (4x)
Yield: 190 mg (86%); colorless oil.
FTIR (film): 3412, 3023, 2988, 1787, 1462, 1228, 1144, 1021 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.31 (s, 1 H), 6.07–5.96 (m, 1 H), 5.92 (d, J = 2.3 Hz, 1 H), 4.74 (dd, J = 10.7, 8.3 Hz, 1 H), 3.74 (s, 3 H), 3.71 (s, 3 H), 3.16–3.02 (m, 2 H), 2.47–2.31
(m, 1 H), 2.20 (dq, J = 10.5, 8.5 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 213.2, 160.2, 159.1, 155.2, 105.2, 94.1, 91.3, 55.5, 55.2, 55.1, 44.1, 18.0.
HRMS (ESI): m/z [M + Na]+ calcd for C12H14NaO4: 245.0790; found: 245.0799.
