A Route to 2-Substituted 3-Cyanopyrroles: Synthesis of Danaidal and Suffrutine A

Article abstract of DOI:10.1021/acs.joc.6b01298

The title compounds were prepared in a two-step sequence from 4,4-dimethoxybutyronitrile and the respective esters by Claisen condensation and subsequent Paal-Knorr pyrrole synthesis. The sequence could be performed as a one-pot procedure delivering the pyrroles in yields of 47-72% over two steps (13 examples). Intramolecular variants of the method were applied to the total synthesis of danaidal and suffrutine A from the respective trityl-protected ω-amino alkanoates.

Full text of DOI:10.1021/acs.joc.6b01298

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Note
A Route to 2-Substituted 3-Cyanopyrroles:
Synthesis of Danaidal and Suffrutine A
Johannes M. Wiest, and Thorsten Bach
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01298 • Publication Date (Web): 22 Jun 2016
Downloaded from http://pubs.acs.org on June 27, 2016
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A Route to 2-Substituted 3-Cyanopyrroles: Synthesis of
Danaidal and Suffrutine A
Johannes M. Wiest, Thorsten Bach*
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Department Chemie and Catalysis Research Center (CRC), Technische Universität München,
Lichtenbergstr. 4, 85747 Garching, Germany
Corresponding Author
*Email: thorsten.bach@ch.tum.de
ABSTRACT
The title compounds were prepared in a twoꢀstep sequence from 4,4ꢀdimethoxybutyronitrile and
the respective esters by Claisen condensation and subsequent PaalꢀKnorr pyrrole synthesis. The
sequence could be performed as oneꢀpot procedure delivering the pyrroles in yields of 47ꢀ72%
over two steps (13 examples). Intramolecular variants of the method were applied to the total
synthesis of danaidal and suffrutine A from the respective tritylꢀprotected ωꢀamino alkanoates.
In 1932, Strain reported the first synthesis of a monoꢀ2ꢀsubstituted 3ꢀcyanopyrrole from
cyanoacetone, ammonia, and 1,2ꢀdichloroethyl methyl ether.1 Like some previously synthesized
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compounds of this class, which contained additional substituents in 4ꢀ and 5ꢀposition,2 the
compound was found to behave neither like a typical pyrrole nor like a typical nitrile. Indeed, the
conjugation of the cyano group renders 3ꢀcyanopyrroles remarkably stable towards oxidation and
they have played an important role in pyrrole chemistry as testified by several reports on their
synthesis.3,4 We became interested in the compound class in connection with our work on the Pdꢀ
catalyzed alkylation of 2ꢀphenylpyrroles.5 It was found that the respective 3ꢀcyanopyrroles such
as 1a can be selectively monoalkylated upon Pd catalysis delivering products such as 1b and 1c
in good yields (Scheme 1). The pyrrole ring serves as directing group which allows for selective
palladation in orthoꢀposition of the benzene ring. The remarkable fact that a single but no double
alkylation was observed is due to the substituent in 3ꢀposition, which avoids rotation around the
phenylꢀpyrrol bond after the first alkylation has occurred.
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SCHEME 1. PdꢀCatalyzed Alkylation of 3ꢀCyanoꢀ2ꢀphenylpyrrole (1a).
Although the synthesis of compound 1a was feasible by known procedures3bꢀc,3h we found the
published procedures on the synthesis of 2ꢀsubstituted 3ꢀcyanopyrroles less concise and less
general than desirable for the preparation of this compound class. We therefore searched for an
alternative to their synthesis and found a convenient oneꢀpot procedure, which allows the
introduction of the pyrrole C2 carbon atom and the 2ꢀsubstituent from the respective alkanoate.
The results are disclosed in this manuscript and applications to the synthesis of danaidal6,7 and to
the first synthesis of suffrutine A8 are described.
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Inspired by a patent publication, according to which Nꢀhydroxypyrroles were prepared from the
Claisen condensation products of halogenated benzoates and 4,4ꢀdimethoxybutyronitrile (three
examples),9 we considered a disconnection of pyrroles 1 in the spirit of a PaalꢀKnorr synthesis
leading to γꢀketoaldehyde 2 or a derivative thereof (Scheme 2). Following a Claisen
disconnection, 4,4ꢀdimethoxybutyronitrile (3) emerged as a precursor for the cyano group at C3
and for carbon atoms C3ꢀC5 within the pyrrole ring.
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SCHEME 2. Retrosynthetic Analysis Leading via a Putative 1,4ꢀDicarbonyl Compound 2 to
Nitrile 3 as Starting Material
Initial studies towards the Claisen condensation of nitrile 3 and an alkanoate were performed with
methyl benzoate (4a) and revealed that sodium hydride (3 equiv.) is a suitable base for this
transformation. The choice of solvent was crucial for the success of the reaction and 1,2ꢀ
dimethoxyethane (DME) was found to be the superior choice. Apolar solvents such as toluene did
not produce the desired condensation product while DME enabled the formation of product 5
within five hours at reflux employing an equimolar ratio of 3 and 4a (Scheme 3). Gratifyingly,
the desired PaalꢀKnorr condensation to product 1a could be induced by heating intermediate 5 in
a solution of ammonium acetate (20 equiv.) in acetic acid for 20 hours at 120 °C. Aldehyde 2 was
not detected as an intermediate but its cyclic enol acetal 6 could be isolated if the reaction was
stopped after one hour. The isolated acetal 6 underwent the conversion to pyrrole 1a if subjected
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to the reaction conditions of the PaalꢀKnorr reaction and is thus a likely intermediate in the
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conversion 5 → 1a.
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S
CHEME 3. Optimization of the Twoꢀstep Protocol for the Synthesis of Pyrrole 1a from Methyl
Benzoate (4a) via Intermediates 5 and 6.
It was found that the conversion of 4a to 1a could be performed in one reaction flask without
purification of intermediate 5. Once TLC analysis indicated full conversion in the first step, the
solvent was removed under reduced pressure and the second set of reagents was added. The
reaction mixture was kept at 120 °C until the formation of pyrrole 1a was complete. Following
this precedence several other pyrroles 1 were prepared from 4,4ꢀdimethoxybutyronitrile (3) and
the respective esters (Table 1). The choice of ester (methyl vs. ethyl) was determined by its
commercial availability and volatility. All aryl esters which were tested (entries 2ꢀ6) gave
moderate to good yields (54ꢀ70%) in the oneꢀpot protocol. In the aliphatic series (entries 7ꢀ13),
alkanoates with a primary or secondary alkyl group R reacted smoothly while the reaction of
methyl pivaloate (entry 11) turned out to be sluggish. The conversion in the Claisen condensation
could be improved if the reaction was performed in the higher boiling solvent diethoxyethane
(DEE) but the overall yield remained moderate (47%).
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T
ABLE 1. Formation of 2ꢀSubstituted 3ꢀCyanopyrroles 1 by Claisen Condensation and
5
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Subsequent Cyclization
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yieldb
[%]
entry
R
R1 t1 [h]a t2 [h]a product
1
2
Me
Me
5
20
19
64
1a
1d
20
66
3
4
5
Me
Me
Me
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64
70
69
1e
1f
1g
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7
Me
Me
18
6
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60
54
65
1h
1i
8
9
Me
Et
Me
Me
Et
12
21
5
16
21
68
65
54
47
1j
1k
1l
10
11
iBu
tBu
18
Me
17c
120
1m
12
13
Et
14
17
20
13
72
54
1n
1o
Me
a Reaction time in the individual step until full conversion was reached. b Yield after two reaction steps. c The
reaction was performed in 1,2ꢀdiethoxyethane (DEE) as the solvent.
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Preliminary studies revealed that the method could also be applied to the synthesis of Nꢀ
substituted pyrroles. When the primary Claisen product 5 (Scheme 2) was treated with benzyl
amine instead of ammonium acetate, product 7 was obtained in 40% yield (Figure 1). Based on
this observation, an easy access to the heterocyclic core of danaidal (8) and suffrutine A [(E,E)ꢀ9]
seemed feasible if the PaalꢀKnorr reaction step was performed intramolecularly.10
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O
NC
OHC
O
N
N
N
7
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9
(E,E)-
F
IGURE 1. Structures of pyrrole 7, of danaidal (9), and of suffrutine A [(E,E)ꢀ9]
The required ωꢀamino alkanoates 10 for the synthesis of the indolizine and pyrrolizine ring were
chosen to be protected as Nꢀtrityl (Tr) derivatives and were readily available from the respective
amino acids.11 As in the synthesis of pyrroles 1, the reaction could be performed as a oneꢀpot
process. Trityl removal was facilitated under the acidic conditions of the second reaction step and
delivered the free ammonium salts, which readily cyclized to products 11 (Scheme 4). The
pheromone danaidal (8) was easily available from 3ꢀcyanoꢀ2,3ꢀdihydroꢀ1Hꢀpyrrolizine (11a)
upon reduction with diisobutylaluminium hydride (DibalꢀH) at 0 °C in CH2Cl2 (87%).
S
CHEME 4. Synthesis of the Pyrrole Fragments of Danaidal and Suffrutine A
NC
1. 3, NaH, reflux (DME)
O
2. 120 °C (HOAc)
TrHN
R1
O
n
N
n
10a n = 1 R1 = Et
10b n = 2 R1 = Me
84%
68%
11a
11b
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While danaidal has been a frequent synthetic target7 the indolizidine alkaloids suffrutine A and
suffrutine B have just recently been described and their total synthesis has not yet been reported.
The compounds were isolated from the roots of Flueggea suffruticosa and were shown to
promote Neuroꢀ2a cell differentiation.8 The compounds were found to be interconvertible upon
irradiation with light. In our synthetic approach to the suffrutines, nitrile 11b was treated with
methyl lithium to generate methyl ketone 12 in a yield of 77% (Scheme 5).12 HornerꢀWadsworthꢀ
Emmons reaction with diethyl cyanomethylphosphonate delivered quantitatively nitrile 13, which
was obtained as a mixture of (E)ꢀ and (Z)ꢀisomers. The compounds were separable at this stage
but were prone to rapid E/Zꢀisomerization upon storage. The diastereomeric mixture was reduced
with DibalꢀH to aldehyde 14, which was obtained as an E/Zꢀmixture with similar composition
(E/Z = 80/20) as the nitrile. In this instance, a separation by column chromatography could not be
achieved, which is why aldehyde 14 was taken as an E/Zꢀmixture into the Knoevenagel
condensation with 2ꢀcoumaranone.
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S
CHEME 5. Synthesis of Suffrutine A and its Diastereoisomers (9) from 5,6,7,8ꢀ
Tetrahydroindolizine 11b.
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Product 9 was obtained as a mixture of four diastereoisomers in a ratio of 41/32/15/12. The major
components could be separated in the dark and suffrutine A could be obtained cleanly as the
respective isomer (E,E)ꢀ9. All analytical data of this compound were identical to the reported
data of the natural product.8 The second isolated major component exhibits a different
configuration at the double bond between the benzofuranꢀ2(3H)ꢀone carbon atom C3’ and carbon
atom C1 of the butenylidene bridge and it could be identified as (Z,E)ꢀ9, suffrutine B, although its
spectra were not a clean as the spectra of suffrutine A. The minor components could not be
separated but there is evidence (same molecular mass, similar UV/vis spectra) for them to be
isomers of suffrutines A and B and they are tentatively assigned the structure (E,Z)ꢀ9 and (Z,Z)ꢀ9.
Upon standing at day light, isomerization of suffrutines A and B was observed, which was not
only a mutual interconversion but indicated also the formation of compounds (E,Z)ꢀ9 and (Z,Z)ꢀ9
(see Supporting Information for further details).
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CONCLUSION
In summary, a concise route to 2ꢀsubstituted 3ꢀcyanopyrroles was developed, which can
potentially be expanded to the synthesis of Nꢀsubstituted pyrroles. The cyano group can be
further elaborated as shown in the total syntheses of danaidal and suffrutine A. The method
employs 4,4ꢀdimethoxybutyronitrile as a C4ꢀbuilding block and leaves consequently the 4ꢀ and
the 5ꢀposition of the pyrrole unsubstituted and it is therefore envisaged to serve as a useful entry
to 2,3ꢀdisubstituted pyrroles.
EXPERIMENTAL SECTION
General Methods:
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Air and moisture sensitive reactions were carried out in ovenꢀdried glassware sealed with rubber
septa under a positive pressure of dry argon. Dry tetrahydrofuran (THF), dichloromethane
(CH2Cl2) and diethyl ether (Et2O) were obtained from a solvent purification system. Other dry
solvents, e.g. methanol (MeOH), were obtained in the highest purity available stored over
molecular sieves and were used without further purification. Analytical thin layer
chromatography (TLC) was performed on silica gel 60 (F254) glass plates. The TLC plates were
visualized by either ultraviolet (UV) light (λ = 254 nm) or treatment with cerium ammonium
molybdate (CAM) stain followed by gentle heating. Purification of products was accomplished
by flash chromatography on silica gel 60 (230ꢀ400 mesh). All solvents for chromatography, e.g.
ethyl acetate (EtOAc), were distilled prior to use. NMR spectra were measured on either a 300, or
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1
a 400 or a 500 MHz nuclear magnetic resonance spectrometer. The H NMR spectra were
13
calibrated against the residual solvent peak of chloroform (7.26 ppm), and the C{1H} NMR
spectra were calibrated against the central peak of CDCl3 (77.16 ppm). Data for 1H NMR spectra
were reported as follows: chemical shift in parts per million (ppm), peak shape, coupling constant
in Hertz (Hz), and integration. Apparent multiplicity which occurs as a result of accidental
equality of coupling constants to those of magnetically nonꢀequivalent protons are marked as
virtual (virt.); broad signals are marked as broad (br.). Infrared spectra were recorded by
attenuated total reflection (ATR) technique and are reported as wave numbers ṽ (cm–1). Mass
spectra were measured with a mass selective quadrupole detector (EI, 70 eV) or with an ion trap
mass spectrometer (ESI). HRMS data were determined at a doubleꢀfocussing magnetic sector
instrument (EI, 70 eV) or at a linear ion trap with a Fourier transform ion cyclotron resonance
detector (ESI). All measured melting points (mp) are uncorrected.
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General Procedure for the Synthesis of Pyrroles 1: NaH (300 mg, 7.50 mmol, 60% suspension
in mineral oil, 3.0 equiv) was suspended in 1,2ꢀdimethoxyethane (10 mL). 4,4ꢀ
Dimethoxybutyronitrile (323 mg, 330 µL, 2.50 mmol, 1.0 equiv) was added and the reaction
mixture heated to 90 °C. The appropriate ester (2.50 mmol, 1.0 equiv) was added via syringe and
the heterogeneous solution refluxed under argon atmosphere until all starting material was
consumed. The reaction mixture was cooled to room temperature, quenched with methanol, and
all volatiles were removed under reduced pressure. NH4OAc (3.86 g, 50.0 mmol, 20 equiv) and
HOAc (10 mL) were added to the crude material and the mixture heated to 120 °C until full
conversion was reached. The reaction mixture was diluted with EtOAc (150 mL) and neutralized
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with 2
M aqueous NaOH solution. The organic layer was washed with brine (50 mL), separated,
dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. Purification
by flash chromatography (SiO2, solvent, detection mode) gave the respective 3ꢀcyanopyrroles.
2-Benzoyl-4,4-dimethoxybutanenitrile (5)
NaH (400 mg, 10.0 mmol, 60% suspension in mineral oil, 2.0 equiv) was suspended in 1,2ꢀ
dimethoxyethane (20 mL). 4,4ꢀDimethoxybutyronitrile (776 mg, 782 µL, 6.00 mmol, 1.2 equiv)
was added and the reaction mixture heated to 90 °C. Methyl benzoate (681 mg, 625 µL,
5.00 mmol, 1.0 equiv) was added via syringe and the heterogeneous solution refluxed under
argon atmosphere for 5 h. The reaction mixture was cooled to room temperature, quenched with
methanol, and all volatiles were removed under reduced pressure. The crude material was taken
up in CH2Cl2 (150 mL) and washed with 0.01
M aq. HCl solution (150 mL) and brine (50 mL).
The organic layer was separated, dried over Na2SO4, filtered and all volatiles were removed in
vacuo. Purification by flash chromatography (SiO2, pentane/Et2O 4:1 to 3:1, UV) gave the
product as a colorless liquid (980 mg, 4.20 mmol, 84%). TLC (pentane/Et2O 3:1): Rf = 0.18
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[UV]. H NMR (500 MHz, CDCl3, 298 K) δ = 2.25 (ddd, J = 14.1 Hz, J = 8.5, 4.3 Hz, 1H),
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2.38 (ddd, J = 14.1 Hz, 3J = 6.5, 5.9 Hz, 1H), 3.34 (s, 3H), 3.43 (s, 3H), 4.54 (dd, J = 8.5, 5.9
7
8
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3
Hz, 1H), 4.57 (dd, J = 6.5, 4.3 Hz, 1H), 7.50ꢀ7.57 (m, 2H), 7.62ꢀ7.69 (m, 1H), 7.96ꢀ8.02 (m,
2H). 13C{1H} NMR (126 MHz, CDCl3, 298 K) δ = 32.9 (t), 35.2 (d), 54.1 (q), 54.9 (q), 102.3 (d),
117.3 (s), 129.0 (d), 129.2 (d), 134.0 (s), 134.7 (d), 190.3 (s). IR (ATR): ṽ = 2940, 2835, 2249,
1696, 1449, 1231, 1126, 1074, 978, 697. MS (EI, 70 eV): m/z (%) = 201 (19), 170 (11), 105
(100), 77 (38). HRMS (EI, 70 eV): calcd for C13H14O3N+ [(M–H)+] = 232.0968; found =
232.0962.
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5-Methoxy-2-phenyl-4,5-dihydrofuran-3-carbonitrile (6)
2ꢀBenzoylꢀ4,4ꢀdimethoxybutanenitrile (300 mg, 1.28 mmol, 1.0 equiv) was dissolved in acetic
acid (2.0 mL) and stirred at 120 °C for 1 h. Acetic acid was removed under reduced pressure and
the crude was taken up in CH2Cl2 (100 mL) and washed with saturated, aqueous Na2CO3 solution
(100 mL) and brine (50 mL). The organic layer was separated, dried over Na2SO4, filtered and all
volatiles removed under reduced pressure. Purification by flash chromatography (SiO2,
pentane/Et2O 4:1, UV) gave the product (230 mg, 1.14 mmol, 89%) as a colorless liquid. TLC
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2
(pentane/Et2O 3:1): Rf = 0.44 [UV]. H NMR (500 MHz, CDCl3, 298 K) δ = 2.90 (dd, J =
3
2
3
3
16.1 Hz, J = 2.6 Hz, 1H), 3.26 (dd, J = 16.1 Hz, J = 7.2 Hz, 1H), 3.56 (s, 3H), 5.66 (dd, J =
7.2, 2.6 Hz, 1H), 7.40ꢀ7.55 (m, 3H), 7.91ꢀ8.02 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3,
298 K) δ = 38.5 (t), 56.2 (q), 79.3 (s), 106.5 (d), 117.3 (s), 127.2 (d), 128.1 (s), 128.8 (d), 131.5
(d), 165.3 (s). IR (ATR): ṽ = 2937, 2207, 1623, 1355, 1219, 1091, 1072, 1009, 973, 890, 769,
689. MS (EI, 70 eV): m/z (%) = 201 (100), 170 (23), 140 (23), 105 (58), 77 (36). HRMS (EI, 70
+
eV): calcd for C12H11NO2 [M+] = 201.0784; found = 201.0782.
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2-Phenyl-1H-pyrrole-3-carbonitrile (1a)
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Route A. 5ꢀMethoxyꢀ2ꢀphenylꢀ4,5ꢀdihydrofuranꢀ3ꢀcarbonitrile (70.0 mg, 340 µmol, 1.0 equiv)
was dissolved in acetic acid (1 mL). NH4OAc (536 mg, 6.95 mmol, 20.0 equiv) was added and
the solution stirred at 120 °C for 20 h. The reaction mixture was diluted with EtOAc (20 mL) and
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neutralized with 2
M aqueous NaOH solution (20 mL). The organic layer was washed with brine
(10 mL), separated, dried over Na2SO4, filtered and the solvent evaporated under reduced
pressure. Purification by flash chromatography (SiO2, pentane/Et2O 2:1, UV) gave the product
(49.0 mg, 291 µmol, 86%) as a colorless solid. Route B. Synthesized from methyl benzoate
(341 mg, 316 µL, 2.50 mmol) according to the general procedure (Reaction times: 5 h and 20 h).
Purification by flash chromatography (SiO2, pentane/Et2O 3:1 to 2:1, UV) gave the product as a
colorless solid (271 mg, 1.61 mmol, 64%). TLC (pentane/Et2O 2:1): Rf = 0.22 [UV]. mp: 145ꢀ
147 °C. 1H NMR (400 MHz, CDCl3, 298 K) δ = 6.56 (virt. t, 3J ≈ 4J = 2.8 Hz, 1H), 6.83 (dd, 3J =
2.9, 2.7 Hz, 1H), 7.35ꢀ7.42 (m, 1H), 7.43ꢀ7.52 (m, 2H), 7.65ꢀ7.75 (m, 2H), 8.73 (br. s, 1H).
13C{1H} NMR (101 MHz, CDCl3, 298 K) δ = 90.5 (s), 114.0 (d), 117.6 (s), 119.1 (d), 125.9 (d),
128.9 (d), 129.4 (d), 129.9 (s), 139.1 (s). The spectral data matched those reported in the
literature.3b
2-(3,4-Dimethoxyphenyl)-1H-pyrrole-3-carbonitrile (1d)
Synthesized from methyl 3,4ꢀdimethoxybenzoate (341 mg, 2.50 mmol) according to the general
procedure (Reaction times: 20 h and 19 h). Purification by flash chromatography (SiO2, 3% Et2O
in CH2Cl2, UV) gave the product as a colorless solid (377 mg, 1.65 mmol, 66%). TLC (SiO2): Rf
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= 0.24 (3% Et2O in CH2Cl2) [UV]. mp: 135ꢀ137 °C. H NMR (300 MHz, CDCl3, 298 K): δ =
3.92 (s, 3H), 3.95 (s, 3H), 6.54 (dd, 3J = 3.1 Hz, 4J = 2.6 Hz, 1H), 6.78 (dd, 3J = 3.1, 2.6 Hz, 1H),
6.94 (d, 3J = 8.4 Hz, 1H), 7.17 (dd, 3J = 8.4 Hz, 4J = 2.2 Hz, 1H), 7.30 (d, 4J = 2.2 Hz, 1H), 8.61
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(br. s, 1H). C{1H} NMR (75 MHz, CDCl3, 298 K): δ = 56.2 (q), 56.2 (q), 89.7 (s), 109.5 (d),
111.8 (d), 113.7 (d), 117.9 (s), 118.4 (d), 118.6 (d), 122.9 (s), 139.4 (s), 149.6 (s), 149.7 (s). IR
(ATR): ṽ = 3322, 2215, 1516, 1468, 1255, 1229, 1146, 1023, 694. MS (EI, 70 eV): m/z (%) = 228
+
(100), 213 (48), 185 (55), 142 (22). HRMS (EI): calcd for C13H12N2O2 [M+] = 228.0893; found
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= 228.0896.
2-(Thiophen-3-yl)-1H-pyrrole-3-carbonitrile (1e)
Synthesized from methyl thiopheneꢀ3ꢀcarboxylate (586 mg, 0.50 mL 4.12 mmol) according to the
general procedure (Reaction times: 14 h in 15 mL DME and 16 h in 15 mL HOAc). Purification
by flash chromatography (SiO2, CH2Cl2, UV) gave the product as a red solid (456 mg,
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1.65 mmol, 64%). TLC (pentane/Et2O 1:1): Rf = 0.30 [UV]. mp: 124ꢀ126 °C. H NMR (500
MHz, CDCl3, 298 K): δ = 6.51 (virt. t, 3J ≈ 4J = 2.8 Hz, 1H), 6.77 (virt. t, 3J ≈ 2.8 Hz, 1H), 7.44
(dd, 3J = 5.1 Hz, 4J = 2.8 Hz, 1H), 7.46 (dd, 3J = 5.1 Hz, 4J = 1.5 Hz, 1H), 7.69 (dd, 4J = 2.8, 1.5
Hz, 1H), 8.65 (s, 1H). C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 90.0 (s), 113.3 (d), 117.7
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(s), 118.5 (d), 121.9 (d), 124.9 (d), 127.4 (d), 130.8 (s), 135.2 (s). IR (ATR): ṽ = 3289, 3116,
2212, 860, 785, 684. MS (EI, 70 eV): m/z (%) = 174 (100), 147 (14). HRMS (EI): calcd for
C9H6N2S+ [M+] = 174.0246; found = 174.0246.
2-(Furan-2-yl)-1H-pyrrole-3-carbonitrile (1f)
Synthesized from methyl 2ꢀfuroate (315 mg, 267 µL, 2.50 mmol) according to the general
procedure (Reaction times: 16 h and 14 h). Purification by flash chromatography (SiO2, dryꢀ
loaded, pentane/Et2O 3:1 to 2:1, UV) gave the product as a colorless solid (275 mg, 1.74 mmol,
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70%). TLC (pentane/Et2O 3:1): Rf = 0.17 [UV]. mp: 86ꢀ88 °C. H NMR (500 MHz, CDCl3,
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298 K): δ = 6.49 (virt. t, J ≈ J = 2.9 Hz, 1H), 6.53 (dd, J = 3.5, 1.8 Hz, 1H), 6.77 (virt. t, J =
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2.8 Hz, 1H), 6.97 (dd, 3J = 3.5 Hz, 4J = 0.7 Hz, 1H), 7.43 (dd, 3J = 1.8 Hz, 4J = 0.7 Hz, 1H), 8.88
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(s, 1H). C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 88.6 (s), 107.6 (d), 112.4 (d), 113.0 (d),
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116.8 (s), 118.7 (d), 130.8 (s), 142.0 (d), 144.6 (s). IR (ATR): ṽ = 3261, 3166, 2221, 1434, 995,
733. MS (EI, 70 eV): m/z (%) = 158 (100), 129 (65), 103 (18). HRMS (EI): calcd for C9H6N2O+
[M+] = 158.0475; found = 158.0465.
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2-(Pyridin-3-yl)-1H-pyrrole-3-carbonitrile (1g)
Synthesized from methyl nicotinate (378 mg, 341 µL, 2.50 mmol) according to the general
procedure (Reaction times: 20 h and 20 h). Purification by flash chromatography (SiO2, EtOAc,
UV) gave the product as a colorless solid (292 mg, 1.74 mmol, 69%). TLC (EtOAc): Rf = 0.31
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[UV]. mp: 163ꢀ165 °C. H NMR (500 MHz, CDCl3, 298 K): δ = 6.62 (virt. t, J ≈ J = 2.8 Hz,
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1H), 6.92 (virt. t, 3J = 2.8 Hz, 1H), 7.43 (ddd, J = 8.1, 4.8 Hz, 5J = 0.9 Hz, 1H), 8.15 (ddd, J =
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8.0 Hz, 4J = 2.4, 1.6 Hz, 1H), 8.61 (dd, J = 4.8 Hz, 4J = 1.6 Hz, 1H), 8.87 (dd, 4J = 2.4, 0.8 Hz,
1H), 9.37 (br. s, 1H). 13C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 91.9 (s), 114.4 (d), 117.0 (s),
120.4 (d), 124.3 (d), 126.4 (s), 133.9 (d), 135.4 (s), 146.4 (d), 149.5 (d). IR (ATR): ṽ = 3106,
2216, 1496, 1471, 808, 733, 685. MS (EI, 70 eV): m/z (%) = 169 (100), 142 (18), 129 (10).
+
HRMS (EI): calcd for C10H7N3 [M+] = 169.0634; found = 169.0635.
2-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrrole-3-carbonitrile (1h)
Synthesized from methyl benzo[d][1,3]dioxoleꢀ5ꢀcarboxylate (2.00 g, 11.1 mmol) according to
the general procedure (Reaction times: 18 h in 60 mL DME and 17 h in 10 mL HOAc).
Purification by flash chromatography (SiO2, pentane/Et2O 1:1, UV) gave the product as a pale
orange solid (1.27 g, 5.98 mmol, 54%). TLC (pentane/Et2O 1:1): Rf = 0.18 [UV]. mp: 166ꢀ168
°C. 1H NMR (500 MHz, CDCl3, 298 K): δ = 6.03 (s, 2H), 6.53 (virt. t, 3J ≈ 4J = 2.8 Hz, 1H), 6.78
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(dd, 3J = 3.1, 2.6 Hz, 1H), 6.88ꢀ6.92 (m, 1H), 7.11ꢀ7.17 (m, 2H), 8.51 (br. s, 1H). 13C{1H} NMR
(126 MHz, CDCl3, 298 K): δ = 89.9 (s), 101.6 (t), 106.5 (d), 109.1 (d), 113.6 (d), 117.5 (s), 118.5
(d), 120.1 (d), 123.8 (s), 139.0 (s), 148.2 (s), 148.5 (s). IR (ATR): ṽ = 3282, 2213, 1506, 1465,
1240, 1040, 807, 681. MS (EI, 70 eV): m/z (%) = 212 (100), 154 (15), 127 (15). HRMS (EI):
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calcd for C12H8N2O2 [M+] = 212.0580; found = 212.0571.
2-(4-Bromophenyl)-1H-pyrrole-3-carbonitrile (1i)
Synthesized from methyl 4ꢀbromobenzoate (538 mg, 2.50 mmol) according to the general
procedure (Reaction times: 6 h and 60 h). Purification by flash chromatography (SiO2, dryꢀ
loaded, pentane/Et2O 2:1 to 1:1, UV) gave the product as a pale red solid (398 mg, 1.62 mmol,
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65%). TLC (pentane/Et2O 3:2): Rf = 0.16 [UV]. mp: 177ꢀ179 °C. H NMR (500 MHz, CDCl3,
298 K): δ = 6.57 (virt. t, 3J ≈ 4J = 2.8 Hz, 1H), 6.85 (virt. t, 3J = 2.9 Hz, 1H), 7.54ꢀ7.58 (m, 2H),
7.58ꢀ7.63 (m, 2H), 8.67 (br. s, 1H). 13C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 91.0 (s), 114.2
(d), 117.3 (s), 119.5 (d), 123.1 (s), 127.4 (d), 128.7 (s), 132.7 (d), 137.8 (s). IR (ATR): ṽ (cmꢀ1) =
3262, 2220, 1495, 1448, 897, 821, 707, 681. MS (EI, 70 eV): m/z (%) = 248 (99), 246 (100), 167
(32), 140 (41). HRMS (EI): calcd for C11H7 BrN2 [M+] = 245.9787; found = 245.9789.
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2-Ethyl-1H-pyrrole-3-carbonitrile (1j)
Synthesized from methyl propionate (220 mg, 240 µL, 2.50 mmol) according to the general
procedure (Reaction times: 12 h and 16 h). Purification by flash chromatography (SiO2,
pentane/Et2O 3:1 to 1:1, UV) gave the product as a colorless solid (205 mg, 1.71 mmol, 68%).
TLC (pentane/Et2O 4:1): Rf = 0.16 [UV]. mp: 47ꢀ49 °C. 1H NMR (500 MHz, CDCl3, 298 K): δ =
1.30 (t, 3J = 7.6 Hz, 3H), 2.81 (q, 3J = 7.6 Hz, 2H), 6.36 (virt. t, 3J ≈ 4J =2.8 Hz, 1H), 6.62 (dd, 3J
= 3.1, 2.5 Hz, 1H), 8.39 (br. s, 1H). 13C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 13.7 (q), 20.3
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(t), 90.2 (s), 111.6 (d), 117.3 (d), 117.3 (s), 143.2 (s). IR (ATR): ṽ = 3287, 2974, 2216, 1463, 731.
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MS (EI, 70 eV): m/z (%) = 120 (41), 105 (100), 78 (12). HRMS (EI): calcd for C7H8N2 [M+] =
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120.0682; found = 120.0683.
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2-Methyl-1H-pyrrole-3-carbonitrile (1k)
Synthesized from methyl acetate (240 mg, 258 µL, 3.25 mmol, 1.5 equiv) according to the
general procedure (Reaction times: 7 h, then another 3 equiv of ester were added and the reaction
mixture refluxed for another 14 h; 21 h for the cyclization). Purification by flash chromatography
(SiO2, pentane/Et2O 2:1 to 1:1, UV) gave the product as a colorless solid (173 mg, 1.63 mmol,
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65%). TLC (pentane/Et2O 3:1): Rf = 0.10 [UV]. mp: 128ꢀ130 °C. H NMR (500 MHz, CDCl3,
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298 K): δ = 2.42 (s, 3H), 6.35 (virt. t, J ≈ J = 2.9 Hz, 1H), 6.62 (virt. t, J = 2.8 Hz, 1H), 8.43
(br. s, 1H). 13C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 12.3 (q), 91.4 (s), 111.5 (d), 117.3 (s),
117.5 (d), 137.4 (s). IR (ATR): ṽ = 3262, 2219, 1459, 1375, 1097, 899, 740. MS (EI, 70 eV): m/z
(%) = 106 (58), 105 (100). HRMS (EI): calcd for C6H6N2 [M+] = 106.0525; found = 106.0532.
+
The spectral data matched those reported in the literature.3d
2-Isobutyl-1H-pyrrole-3-carbonitrile (1l)
Synthesized from ethyl isovalerate (326 mg, 377 µL, 2.50 mmol) according to the general
procedure (Reaction times: 5 h and 18 h). Purification by flash chromatography (SiO2,
pentane/Et2O 3:1, UV) gave the product as a colorless oil (200 mg, 1.36 mmol, 54%). TLC
(pentane/Et2O 3:1): Rf = 0.25 [UV]. 1H NMR (500 MHz, CDCl3, 298 K): δ = 0.95 (d, 3J = 6.7 Hz,
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6H), 1.98 (virt. nonet, J = 6.7 Hz, 1H), 2.63 (d, J = 7.3 Hz, 2H), 6.37 (virt. t, J ≈ 4J = 2.9 Hz,
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1H), 6.63 (dd, J = 2.5 Hz, 1H), 8.29 (br. s, 1H). C{1H} NMR (126 MHz, CDCl3, 298 K): δ =
22.3 (q), 29.5 (d), 36.0 (t), 91.6 (s), 111.5 (d), 117.4 (d), 117.5 (s), 141.1 (s). IR (ATR): ṽ = 3284,
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2959, 2218, 1459, 724. MS (EI, 70 eV): m/z (%) = 148 (26), 106 (60), 105 (100). HRMS (EI):
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calcd for C9H12N2 [M+] = 148.0995; found = 148.0998.
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2-(tert-Butyl)-1H-pyrrole-3-carbonitrile (1m)
Synthesized from methyl pivalate (445 mg, 509 µL, 3.00 mmol, 1.20 equiv) according to the
general procedure (Reaction times: 17 h in diethoxyethane and 119 h). Purification by flash
chromatography (SiO2, pentane/Et2O 4:1 to 3:1, UV) gave the product as a pale red solid
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(174 mg, 1.18 mmol, 47%). TLC (pentane/Et2O 3:1): Rf = 0.18 [UV]. mp: 63ꢀ65 °C. H NMR
(500 MHz, CDCl3, 298 K): δ = 1.45 (s, 9H), 6.40 (virt. t, 3J ≈ 4J = 2.9 Hz, 1H), 6.58 (virt. t, 3J =
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2.9 Hz, 1H), 8.42 (br. s, 1H). C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 29.8 (q), 32.9 (s),
88.2 (s), 113.3 (d), 116.0 (d), 118.2 (s), 149.1 (s). IR (ATR): ṽ (cmꢀ1) = 3270, 2966, 2220, 1452,
1085, 897, 698. MS (EI, 70 eV): m/z (%) = 148 (27), 133 (100), 105 (19). HRMS (EI): calcd for
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C9H12N2 [M+] = 148.0995; found = 148.0996.
2-Cyclopropyl-1H-pyrrole-3-carbonitrile (1n)
Synthesized from ethyl cyclopropanecarboxylate (428 mg, 446 µL, 3.75 mmol, 1.5 equiv)
according to the general procedure (Reaction times: 14 h and 20 h). Purification by flash
chromatography (SiO2, pentane/Et2O 2:1 to 1:1, UV) gave the product as an almost colorless
solid (237 mg, 1.79 mmol, 72%). TLC (pentane/Et2O 4:1): Rf = 0.08 [UV]. mp: 71ꢀ73 °C.
1H NMR (500 MHz, CDCl3, 298 K): δ = 0.83ꢀ0ꢀ94 (m, 2H), 0.96ꢀ1.09 (m, 2H), 1.99 (tt, 3J = 8.5,
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5.2 Hz, 1H), 6.33 (virt. t, J ≈ J = 2.9 Hz, 1H), 6.57 (virt. t, J = 2.7 Hz, 1H), 8.25 (br. s, 1H).
13C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 6.9 (t), 8.0 (d), 90.7 (s), 111.9 (d), 117.0 (d), 117.3
(s), 142.5 (s). IR (ATR): ṽ = 3261, 2223, 1577, 1464, 1339, 1046, 876, 732. MS (EI, 70 eV): m/z
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(%) = 132 (100), 131 (79), 105 (79). HRMS (EI): calcd for C8H8N2 [M+] = 132.0682; found =
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2-(3-Methoxypropyl)-1H-pyrrole-3-carbonitrile (1o)
Synthesized from methyl 4ꢀmethoxybutyrate (341 µL, 331 mg, 2.50 mmol) according to the
general procedure (Reaction times: 17 h and 14 h). Purification by flash chromatography (SiO2,
pentane/Et2O 1:1, UV) gave the product as a colorless oil (223 mg, 1.36 mmol, 54%). TLC
(pentane/Et2O 1:1): Rf = 0.16 [UV]. 1H NMR (500 MHz, CDCl3, 298 K): δ = 1.93 (m, 2H), 2.90
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(m, 2H), 3.41 (s, 3H), 3.47 (t, J = 5.6 Hz, 2H), 6.33 (t, 3J ≈ 4J = 2.8 Hz, 1H), 6.61 (dd, 3J = 3.1,
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2.4 Hz, 1H), 9.34 (br. s, 1H). C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 24.4 (t), 28.4 (t),
58.9 (q), 72.5 (t), 90.6 (s), 111.2 (d), 117.5 (s), 117.5 (d), 141.4 (s). IR (ATR): ṽ (cmꢀ1) = 3280,
2928, 2873, 2217, 1458, 1116, 731. MS (EI, 70 eV): m/z (%) = 164 (24), 132 (100), 131 (56),
105 (89). HRMS (EI): calcd for C9H12N2O+ [M+] = 164.0944; found = 164.0944.
1-Benzyl-2-phenyl-1H-pyrrole-3-carbonitrile (7)
Synthesized from methyl benzoate (340 mg, 2.50 mmol) according to the general procedure
(Reaction times: 14 h and 20 h) using benzyl amine (5.46 mL, 5.36 g, 50.0 mmol, 20.0 equiv)
instead of NH4OAc. Purification by flash chromatography (SiO2, pentane/Et2O 10:1 to 6:1, UV)
gave the product as an almost colorless solid (269 mg, 1.04 mmol, 42%). TLC (pentane/Et2O
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3:1): Rf = 0.33 [UV]. mp: 89ꢀ91 °C. H NMR (500 MHz, CDCl3, 298 K): δ = 5.09 (s, 2H), 6.55
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(d, J = 3.1 Hz, 1H), 6.68 (d, J = 3.1 Hz, 1H), 6.98 (m, 2H), 7.27ꢀ7.34 (m, 3H), 7.37ꢀ7.41 (m,
2H), 7.41ꢀ7.48 (m, 3H).13C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 51.3 (t), 92.8 (s), 112.4
(d), 117.4 (s), 122.9 (d), 126.7 (d), 128.1 (d), 129.0 (d), 129.1 (d), 129.2 (s, Cꢀ1’), 129.3 (d, Cꢀ4’),
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129.7 (d), 136.9 (s), 141.8 (s). IR (ATR): ṽ (cmꢀ1) = 3031, 2219, 1497, 1482, 1454, 1429, 766,
730, 697. MS (EI, 70 eV): m/z (%) = 258 (50) [M+], 91 (100). HRMS (EI): calculated for
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+
C18H14N2 [M+] = 258.1152; found = 258.1152.
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Ethyl 4-(tritylamino)butanoate (10a)
Ethylꢀ4ꢀaminobutyrate hydrochloride (1.68 g, 10.0 mmol, 1.02 equiv) was dissolved in dry
CHCl3 (30.0 mL) and neutralized with NEt3 (2.02 g, 2.77 mL, 20.0 mmol, 2.04 equiv). Trityl
chloride (2.73 g, 9.80 mmol, 1.00 equiv) was added and the reaction mixture stirred at 70 °C for
5 h. The solution was diluted with CH2Cl2 and washed with H2O and brine. The organic layer was
separated, dried over Na2SO4, filtered and all volatiles were removed under reduced pressure.
Purification by flash chromatography (SiO2, dryꢀloaded, pentane Et2O 15:1 to 9:1, UV) gave the
product as a colorless oil (3.24 g, 8.67 mmol, 87%). TLC (pentane/Et2O 9:1): Rf = 0.26 [UV].
1H NMR (500 MHz, CDCl3, 298 K): δ = 1.23 (t, 3J = 7.1 Hz, 3H), 1.48 (br. s), 1.81 (virt. quintet,
3
3
3
3
3J ≈ J = 7.1 Hz, 2H), 2.15 (t, J = 6.8 Hz, 2H), 2.43 (t, J = 7.4 Hz, 2H), 4.12 (q, J = 7.1 Hz,
2H), 7.15ꢀ7.20 (m, 3H), 7.25ꢀ7.28 (m, 6H), 7.41ꢀ7.51 (m, 6H). 13C{1H} NMR (126 MHz, CDCl3,
298 K): δ = 14.4 (q), 26.2 (t), 32.6 (t), 43.1 (t), 60.5 (t), 70.9 (s), 126.3 (d), 127.9 (d), 128.7 (d),
146.2 (s), 173.9 (s). IR (ATR): ṽ = 3059, 2979, 1731, 1447, 1183, 1157, 769, 746, 706. MS (EI,
70 eV): m/z (%) = 373 (1), 296 (100), 258 (57), 243 (91), 165 (48). HRMS (EI): calcd for
+
C25H27NO2 [M+] = 373.2036; found = 373.2027.
2,3-Dihydro-1H-pyrrolizine-7-carbonitrile (11a)
NaH (300 mg, 7.50 mmol, 60% suspension in mineral oil, 3.0 equiv) was suspended in 1,2ꢀ
dimethoxyethane (10 mL). 4,4ꢀdimethoxybutyronitrile (323 mg, 330 µL, 2.50 mmol, 1.0 equiv)
was added and the reaction mixture heated to 90°C. Ethyl 4ꢀ(tritylamino)butanoate (3.75 mmol,
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1.5 equiv) in dimethoxyethane (5 mL) was added via syringe and the heterogeneous solution
refluxed under argon atmosphere for 40 h. The reaction mixture was cooled to room temperature,
quenched with methanol, and all volatiles were removed under reduced pressure. HOAc (10 mL)
was added to the crude material and the solution heated to 120 °C for 1.5 h. The reaction mixture
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was diluted with CH2Cl2 (150 mL) and neutralized with 2
M aqueous NaOH solution (150 mL).
The organic layer was washed with brine (50 mL), separated, dried over Na2SO4, filtered and the
solvent evaporated under reduced pressure. Purification by flash chromatography (SiO2,
pentane/Et2O 3:1, UV) gave the product as a colorless solid (295 mg, 2.23 mmol, 84%). TLC
(pentane/Et2O 3:1): Rf = 0.14 [UV]. mp: 58ꢀ60 °C. 1H NMR (500 MHz, CDCl3, 298 K): δ = 2.57
3
3
3
3
(virt. quintet, J = 7.3 Hz, 2H), 2.98 (t, J = 7.4 Hz, 2H), 3.99 (t, J = 7.2 Hz, 2H), 6.42 (d, J =
3
13
2.9 Hz, 1H), 6.55 (d, J = 2.9 Hz, 1H). C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 24.5 (t),
27.3 (t), 47.5 (t), 84.3 (s), 115.3 (d), 115.8 (d), 117.5 (s), 145.4 (s). IR (ATR): ṽ = 3132, 3112,
2962, 2216, 1507, 1299, 744. MS (EI, 70 eV): m/z (%) = 132 (65), 131 (100), 105 (19). HRMS
+
(EI): calcd for C8H8N2 [M+] = 132.0682; found = 132.0678. The spectral data matched those
reported in the literature.12
Danaidal (2,3-Dihydro-1H-pyrrolizine-7-carbaldehyde) (8)
2,3ꢀDihydroꢀ1Hꢀpyrrolizineꢀ7ꢀcarbonitrile (53 mg, 400 µmol, 1.0 equiv) was dissolved in dry
CH2Cl2 (6.0 mL) under an argon atmosphere. DibalꢀH (1
M in CH2Cl2, 600 µL, 600µmol,
1.5 equiv) was added dropwise at 0 °C and the reaction mixture stirred at 0 °C for 1 h. Saturated
aqueous Rochelle salt solution (5 mL) was added at 0 °C and the solution vigorously stirred at
room temperature for 2 h. H2O was added and the aqueous layer extracted with CH2Cl2 twice.
The combined organic layers were washed with brine, separated, dired over Na2SO4, filtered and
the solvent evaporated under reduced pressure. Purification by flash chromatography (SiO2,
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pentane/Et2O 1:1 to 1:2 UV) gave Danaidal as a colorless solid (47 mg, 348 µmol, 87%). TLC
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(pentane/Et2O 1:1): Rf = 0.16 [UV]. mp: 59ꢀ61 °C. 1H NMR (500 MHz, CDCl3, 298 K): δ = 2.59
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9
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3
3
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(virt. quintet, J = 7.3 Hz, 2H), 3.09 (t, J = 7.4 Hz, 2H), 3.98 (t, J = 7.2 Hz, 2H), 6.60 (d, J =
3.0 Hz, 1H), 6.63 (d, 3J = 3.0 Hz, 1H), 9.72 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3, 298 K): δ
= 24.6 (t), 27.3 (t), 46.8 (t), 112.9 (d), 116.4 (d), 117.7 (s), 146.0 (s), 185.1 (d). IR (ATR): ṽ =
1660, 1543, 1506, 1435, 1292, 1125. MS (EI, 70 eV): m/z (%) = 135 (100), 134 (96), 106 (44).
HRMS (EI): calculated for C8H9NO+ [M+] = 135.0679; found = 135.0673. CHN: Anal. calcd for
C8H9NO = C 71.09, H 6.71, N 10.36; found = C 70.77, H 6.72, N 10.10.
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Methyl 5-(tritylamino)valerate (10a)
5ꢀAminovaleric acid (3.34 g, 28.5 mmol, 1.0 equiv) was dissolved in dry MeOH (25.0 mL).
SOCl2 (8.48 g, 5.18 mL, 71.2 mmol, 2.5 equiv) was added at 0 °C and the reaction mixture was
allowed to warm to room temperature overnight. All volatiles were carefully removed under
reduced pressure and the crude solid was taken up in dry CH2Cl2 (25 mL) and neutralized with
NEt3 (6.92 g, 9.47 mL, 68.4 mmol, 2.4 equiv). Trityl chloride (8.74 g, 31.4 mmol, 1.1 equiv) was
added and the reaction mixture was stirred at room temperature for 3 h. H2O (100 mL) was added
and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 × 100 mL) and
the combined organic layer was dried over Na2SO4, filtered and the solvent evaporated under
reduced pressure. Purification by flash chromatography (SiO2, pentane/Et2O 19:1 to 9:1, UV)
gave the product as a colorless solid (9.71 g, 26.0 mmol, 91%). TLC (pentane/Et2O 19:1): Rf =
1
0.10 [UV]. mp: 88ꢀ90 °C. H NMR (500 MHz, CDCl3, 298 K): δ = 1.50 (br. s, 1H), 1.51 (virt.
quintet, 3J = 7.3 Hz, 2H), 1.67 (virt. quintet, 3J = 7.5 Hz, 2H), 2.12 (t, 3J = 7.0 Hz, 2H), 2.28 (t, 3J
= 7.5 Hz, 2H), 3.65 (s, 3H), 7.14ꢀ7.22 (m, 3H), 7.23ꢀ7.30 (m, 6H), 7.43ꢀ7.50 (m, 6H).
13C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 22.9 (t), 30.5 (t), 34.2 (t), 43.3 (t), 51.7 (q), 71.0
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(s), 126.3 (d), 127.9 (d), 128.7 (d), 146.3 (s), 174.3 (s). IR (ATR): ṽ = 2948, 1737, 1448, 1203,
706. MS (EI, 70 eV): m/z (%) = 373 (1), 296 (100), 258 (50), 243 (90), 165 (59). HRMS (EI):
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+
calcd for C25H27NO2 [M+] = 373.2036; found = 373.2027.
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5,6,7,8-Tetrahydroindolizine-1-carbonitrile (11b)
NaH (850 mg, 21.3 mmol, 60% suspension in mineral oil, 3.0 equiv) was suspended in 1,2ꢀ
dimethoxyethane (30 mL). 4,4ꢀDimethoxybutyronitrile (1.19 g, 1.20 mL, 8.50 mmol, 1.2 equiv)
was added and the reaction mixture heated to 90°C. Methyl 5ꢀ(tritylamino)valerate (7.08 mmol,
1.0 equiv) in dimethoxyethane (10 mL) was added via syringe and the heterogeneous solution
refluxed under argon atmosphere for 9 h. The reaction mixture was cooled to room temperature,
quenched with methanol, and all volatiles were removed under reduced pressure. HOAc (40 mL)
was added to the crude material and the solution heated to 120 °C for 2 h. The reaction mixture
was diluted with CH2Cl2 (150 mL) and neutralized with 4
M aqueous NaOH solution (200 mL).
The organic layer was washed with brine (50 mL), separated, dried over Na2SO4, filtered and the
solvent evaporated under reduced pressure. Purification by flash chromatography (SiO2,
pentane/Et2O 5:1 to 1:1, UV) gave the product as a pale yellow liquid (701 mg, 4.79 mmol,
1
68%). TLC (pentane/Et2O 5:1): Rf = 0.18 [UV]. H NMR (500 MHz, CDCl3, 298 K): δ = 1.83ꢀ
1.91 (m, 2H), 1.93ꢀ2.02 (m, 2H), 2.88 (t, 3J = 6.4 Hz, 2H), 3.92 (t, 3J = 6.0 Hz, 2H), 6.35 (d, 3J =
3
13
3.0 Hz, 1H), 6.55 (d, J = 3.0 Hz, 1H). C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 20.2 (t),
22.4 (t), 23.1 (t), 45.7 (t), 88.8 (s), 111.0 (d), 117.4 (s), 120.0, (d), 138.4 (s). IR (ATR): ṽ = 2952,
2211, 1505, 1347, 1205, 718. MS (EI, 70 eV): m/z (%) = 146 (66), 145 (100), 118 (48). HRMS
+
(EI): calcd for C9H10N2 [M+] = 146.0838; found = 146.0835. The spectral data matched those
reported in the literature.3b
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1-(5,6,7,8-Tetrahydroindolizin-1-yl)ethan-1-one (12)
5,6,7,8ꢀTetrahydroindolizineꢀ1ꢀcarbonitrile (219 mg, 1.50 mmol, 1.0 equiv) was dissolved in dry
THF (20 mL) and the solution was cooled to 0 °C. Under argon atmosphere MeLi (1.73 mL,
1.3
M
in Et2O, 2.25 mmol, 1.5 equiv) was added dropwise and the reaction mixture was stirred at
aqueous HCl solution (3 mL) and
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0 °C for 1 h. The reaction was stopped by the addition of 2
M
allowed to warm to room temperature overnight (vigorous stirring). The solution was neutralized
with aqueous, saturated NaHCO3 solution and the aqueous layer was extracted with EtOAc
(100 mL). The organic layer was washed with brine (20 mL), separated, dried over Na2SO4,
filtered and all volatiles were removed under reduced pressure. Purification by flash
chromatography (SiO2, pentane/Et2O 2:1 to 1:1, UV) gave the product as a pale yellow liquid
1
(189 mg, 1.16 mmol, 77%). TLC (pentane/Et2O 1:1): Rf = 0.39 [UV]. H NMR (500 MHz,
CDCl3, 298 K): δ = 1.80ꢀ1.87 (m, 2H), 1.91ꢀ1.98 (m, 2H), 2.37 (s, 3H), 3.10 (t, 3J = 6.5 Hz, 2H),
3.93 (t, 3J = 6.0 Hz, 2H), 6.44 (d, 3J = 3.1 Hz, 1H), 6.55 (d, 3J = 3.1 Hz, 1H). 13C{1H} NMR (126
MHz, CDCl3, 298 K): δ = 20.2 (t), 23.0 (t), 24.5 (t), 28.3 (q), 45.8 (t), 110.2 (d), 119.3 (d), 120.1
(s), 136.5 (s), 194.5 (s). IR (ATR): ṽ = 2946, 1647, 1535, 1502, 1318, 1227, 1154, 924. MS (EI,
70 eV): m/z (%) = 163 (47), 148 (100), 120 (25). HRMS (EI): calcd for C10H13NO+ [M+] =
163.0992; found = 163.0990. The spectral data matched those reported in the literature.13
3-(5,6,7,8-Tetrahydroindolizin-1-yl)but-2-enenitrile (13)
Diethyl cyanomethylphosphonate (886 mg, 809 µL, 5.00 mmol, 10 equiv) was added to a stirred
suspension of NaH (200 mg, 60% in mineral oil, 5.00 mmol, 10 equiv) in dry toluene (10 mL)
under argon atmosphere. The gelꢀlike solution was heated to 110 °C and dry DMF (1 mL) was
added to obtain a clear solution. 1ꢀ(5,6,7,8ꢀTetrahydroindolizinꢀ1ꢀyl)ethanꢀ1ꢀone (82.0 mg,
500 µmol, 1.0 equiv) in dry toluene (2 mL) was added dropwise and the reaction mixture stirred
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at 110 °C for 15 h. The reaction mixture was cooled to room temperature and H2O (50 mL) was
added. The aqueous layer was extracted with EtOAc (50 mL) and the organic layer was
separated, washed with brine, dried over Na2SO4, filtered and all volatiles removed under
reduced pressure. Purification by flash chromatography (SiO2, pentane/Et2O 2:1 to 1:1, UV) gave
the product as a colorless oil (93.0 mg, 500 µmol, 99%), which was obtained as a mixture of E/Z
isomers (ratio E/Z ≈ 4:1). The isomers can be separated by careful flash chromatography (SiO2,
pentane/Et2O 3:1 to 2:1, UV) to get pure samples (isomerization occurs within a day at room
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temperature/daylight). E-isomer: TLC (pentane/Et2O 2:1): Rf = 0.41 [UV]. H NMR (500 MHz,
4
CDCl3, 298 K): δ = 1.84ꢀ1.91 (m, 2H), 1.92ꢀ2.00 (m, 2H), 2.23 (d, J = 0.9 Hz, 3H), 2.84 (t, 3J =
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6.4 Hz, 2H), 3.95 (t, J = 6.0 Hz, 2H), 5.12 (q, J = 0.9 Hz, 1H), 6.27 (d, J = 3.0 Hz, 1H), 6.53
3
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(d, J = 3.0 Hz, 1H). C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 21.0 (t), 21.5 (q), 22.9 (t),
24.9 (t), 46.0 (t), 88.0 (d), 107.8 (d), 118.5 (s), 119.6 (s), 120.2 (d), 129.8 (s), 155.7 (s). IR
(ATR): ṽ = 2949, 2200, 1584, 1498, 1322, 1157, 717. MS (EI, 70 eV): m/z (%) = 186 (100), 185
+
(85), 171 (67), 158 (28), 120 (19). HRMS (EI): calcd for C12H14N2 [M+] = 186.1152; found =
1
186.1146. Z-isomer: TLC (pentane/Et2O 2:1): Rf = 0.50 [UV]. H NMR (500 MHz, CDCl3, 298
K): δ = 1.84ꢀ1.91 (m, 2H), 1.92ꢀ2.00 (m, 2H), 2.18 (d, 4J = 1.4 Hz, 3H), 2.82 (t, 3J = 6.4 Hz, 2H),
3.96 (t, 3J = 6.2 Hz, 2H), 5.08 (q, 4J = 1.4 Hz, 1H), 6.44 (d, 3J = 3.0 Hz, 1H), 6.54 (d, 3J = 3.0 Hz,
13
1H). C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 21.2 (t), 23.2 (t), 25.7 (t), 29.8 (q), 45.9 (t),
90.5 (d), 108.2 (d), 118.0 (s), 119.5 (s), 120.0 (d), 129.9 (s), 156.7 (s).
3-(5,6,7,8-Tetrahydroindolizin-1-yl)but-2-enal (14)
3ꢀ(5,6,7,8ꢀTetrahydroindolizinꢀ1ꢀyl)butꢀ2ꢀenenitrile (93.0 mg, 500 µmol, 1.0 equiv) was
dissolved in dry CH2Cl2 (7.5 mL) and cooled to 0 °C. DibalꢀH (800 µL, 1
M in CH2Cl2,
800 µmol, 1.6 equiv) was added and the reaction mixture stirred at 0 °C for 2 h. The solution was
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quenched with aqueous, saturated Rochelle salt (Na/K tartrate) solution (6 mL) and vigorously
stirred at room temperature overnight. H2O was added and the layers separated. The aqueous
layer was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered
and the solvent was evaporated under reduced pressure. Purification by flash chromatography
(SiO2, pentane/Et2O 2:1, UV) gave the product as a pale yellow oil (48.0 mg, 254 µmol, 51%),
which was obtained as a mixture of E/Z isomers (ratio E/Z ≈ 4:1). A separation of the isomers
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could not be achieved. E-isomer: TLC (pentane/Et2O 2:1): Rf = 0.18 [CAM]. H NMR (500
4
3
MHz, CDCl3, 298 K): δ = 1.82ꢀ1.90 (m, 2H), 1.93ꢀ1.99 (m), 2.48 (d, J = 1.2 Hz), 2.91 (t, J =
6.4 Hz), 3.96 (t, 3J = 6.1 Hz), 6.10 (dq, 3J = 8.3 Hz, 4J = 1.2 Hz), 6.38 (d, 3J = 3.0 Hz), 6.56 (d, 3J
= 3.0 Hz), 10.07 (d, 3J = 8.3 Hz). 13C{1H} NMR (126 MHz, CDCl3, 298 K): δ = 17.4 (q), 21.0 (t),
22.9 (t), 25.5 (t), 46.1 (t), 108.2 (d), 120.1 (s), 120.4 (d), 123.4 (d), 131.2 (s), 155.3 (s), 191.2 (d).
IR (ATR): ṽ = 2946, 1642, 1590, 1495, 1321, 1152. MS (EI, 70 eV): m/z (%) = 189 (100), 172
(56), 160 (79), 146 (37), 120 (89). HRMS (EI): calcd for C12H15NO+ [M+] = 189.1148; found =
1
189.1149. Z-isomer: TLC (pentane/Et2O 2:1): Rf = 0.18 [CAM]. H NMR (500 MHz, CDCl3,
298 K): δ = 1.76ꢀ1.82 (m, 2H), 1.94ꢀ1.99 (m, 2H), 2.21 (d, 4J = 1.3 Hz, 3H), 2.65 (t, 3J = 6.3 Hz,
2H), 3.97 (t, 3J = 6.3 Hz, 2H), 5.95 (dq, 3J = 8.1 Hz, 4J = 1.3 Hz), 6.18 (d, 3J = 2.9 Hz, 1H), 6.57
3
3
13
(d, J = 2.9 Hz, 2H), 9.47 (d, J = 8.1 Hz, 1H). C{1H} NMR (126 MHz, CDCl3, 298 K): δ =
21.3 (t), 23.4 (t), 23.8 (t), 26.5 (q), 45.8 (t), 109.4 (d), 118.1 (s), 120.2 (d), 126.3 (d), 130.1 (s),
158.0 (s), 194.2 (d).
Suffrutine
A
(
(E)-3-((E)-3-(5,6,7,8-tetrahydroindolizin-1-yl)but-2-en-1-ylidene)benzo-
furan-2(3H)-one) ((E,E)-9) and B ((Z)-3-((E)-3-(5,6,7,8-tetrahydroindolizin-1-yl)but-2-en-1-
ylidene)benzofuran-2(3H)-one) ((Z,E)-9)
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3ꢀ(5,6,7,8ꢀTetrahydroindolizinꢀ1ꢀyl)butꢀ2ꢀenal (18.9 mg, 100 µmol, 1.0 equiv), 2ꢀcourmaranone
(20.1 mg, 150 µmol, 1.5 equiv) and piperidine (1.70 mg, 2.00 µL, 20.0 mmol, 0.2 equiv) were
dissolved in dry toluene (2.0 mL) under an argon atmosphere. The yellow solution was heated to
110 °C for 1 h. The solvent was removed under reduced pressure and the crude purified by flash
chromatography (SiO2, pentane/Et2O 4:1 to 3:1, Vis) gave the product as a red semisolid
(19.0 mg, 62.2 mmol, 62%), which consists of 4 isomers (E/E : Z/E : E/Z : Z/Z 41:32:15:12). The
isomers can be separated by flash chromatography in the dark (SiO2, pentane/Et2O, Vis) to give
analytically pure samples (Suffrutine A and B are very sensitive towards visible light;
isomerization occurs readily). E,E-isomer (Suffrutine A): TLC (pentane/Et2O 2:1): Rf = 0.36
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[Vis]. 1H NMR (500 MHz, CDCl3, 298 K): δ = 1.91ꢀ1.97 (m, 2H), 1.99ꢀ2.06 (m, 2H), 2.41 (d, J
= 1.2 Hz, 3H), 3.07 (t, 3J = 6.3 Hz, 2H), 4.01 (t, 3J = 6.0 Hz, 2H), 6.42 (d, 3J = 3.1 Hz, 1H), 6.59
(d, 3J = 3.1 Hz, 1H), 7.01 (dq, 3J = 13.0 Hz, 4J = 1.2 Hz, 1H), 7.12 (d, 3J = 7.9 Hz, 1H), 7.15 (virt.
td, 3J ≈ 3J =7.6 Hz, 4J = 1.1 Hz, 1H), 7.26 (virt. td, 3J ≈ 3J =7.8 Hz, 4J = 1.3 Hz, 1H), 7.60 (dd, 3J
= 7.5 Hz, 4J = 1.4 Hz, 1H), 7.89 (d, 3J = 13.0 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3, 298 K):
δ = 17.8 (q), 21.2 (t), 23.0 (t), 25.7 (t), 46.2 (t), 108.5 (d), 110.8 (d), 115.2 (s), 118.3 (d), 120.6
(d), 122.2 (d), 123.7 (d), 124.6 (s), 128.2 (d), 130.5 (s), 137.5 (d), 150.6 (s), 153.1 (s), 170.4 (s).
UVꢀVis (MeCN): λmax = 458 nm. Z,E-isomer (Suffrutine B): TLC (pentane/Et2O 2:1): Rf = 0.56
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[Vis]. 1H NMR (500 MHz, CDCl3, 298 K): δ = 1.90ꢀ1.96 (m, 2H), 1.96ꢀ2.02 (m, 2H), 2.39 (d, J
= 1.0 Hz, 3H), 3.11 (t, 3J = 6.2 Hz, 2H), 3.98 (t, 3J = 6.0 Hz, 2H), 6.41 (d, 3J = 3.1 Hz, 1H), 6.57
(d, 3J = 3.1 Hz, 1H), 7.07 (d, 3J = 8.0 Hz, 1H), 7.11 (virt. td, 3J ≈ 3J = 7.6 Hz, 4J = 1.0 Hz), 7.21
(virt. td, 3J ≈ 3J = 7.8 Hz, 4J = 1.3 Hz, 1H), 7.46 (dd, 3J = 7.6 Hz, 4J = 1.3 Hz, 1H), 7.79 (d, 3J =
12.7 Hz, 1H), 7.86 (dq, 3J = 12.7 Hz, 4J = 1.0 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3, 298 K):
δ = 17.1 (q), 21.2 (t), 22.9 (t), 25.7 (t), 46.3 (t), 108.5 (d), 110.5 (d), 113.9 (s), 118.6 (d), 119.0
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(d), 120.2 (d), 122.0 (s), 123.4 (d), 126.1 (s), 127.8 (d), 131.3 (s), 136.7 (d), 148.7 (s), 152.2 (s),
168.0 (s). UVꢀVis (MeCN): λmax = 467 nm.
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ACKNOWLEDGEMENT
This work was supported by the Fonds der Chemischen Industrie (Kekulé scholarship to J.M.W.)
and the Deutsche Forschungsgemeinschaft (DFG, Ba 1372/19ꢀ1).
SUPPORTING INFORMATION
1H and 13C{1H} NMR spectra for all compounds, NMR comparison of danaidal and suffrutines A
and B with literature data, UV/vis spectra of compounds 9
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