Synthesis of Substituted 1-Alkylidenephthalanes via Lithium-Promoted 5-exo-dig Cyclization

Article abstract of DOI:10.1002/ejoc.201800205

A one-pot synthesis of 1-alkylidenephthalanes from 3-(2-bromophenyl)propyne derivatives has been developed. 3-(2-Bromophenyl)propynal acetals 9 and corresponding orthoester 19 were treated successively with n-butyllithium and various aldehydes and ketones at low temperature to obtain 1-alkylidenephthalanes 10 and 20 with various functional groups at the exocyclic methylene moiety. Halogen-metal exchange, nucleophilic addition to various carbonyl compounds, regioselective 5-exo-dig cyclization of the respective intermediate lithium alcoholate and hydrolysis represent the key steps in this Domino reaction. A two-step mechanism involving at first a synchronous cyclization to form a vinyllithium intermediate and then a methoxide elimination leading to the respective 1-methoxy allenes is suggested based on DFT-calculations.

Full text of DOI:10.1002/ejoc.201800205

A Journal of
Accepted Article
Title: Synthesis of substituted 1-alkylidenephthalanes via lithium
promoted 5-exo-dig cyclization
Authors: Bernhard Wünsch, Paul Bunse, and Ernst-Ulrich Würthwein
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800205
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800205
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10.1002/ejoc.201800205
European Journal of Organic Chemistry
1
Synthesis of substituted 1-alkylidenephthalanes via
lithium promoted 5-exo-dig cyclization
Paul Bunsea, Ernst-Ulrich Würthweinb, Bernhard Wünscha,c*
a Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-
Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
Tel.: +49-251-8333311; Fax: +49-251-8332144; E-mail: wuensch@uni-muenster.de
Homepage: https://www.uni-muenster.de/Chemie.pz/forschen/ag/wuensch/
b Organisch-Chemisches Institut der Westfälischen Wilhelms-Universität Münster and
Center for Multiscale Theory and Computation (CMTC), Corrensstraße 40, D-48149
Münster, Germany.
c
Cells-in-Motion Cluster of Excellence (EXC 1003 – CiM), Westfälische Wilhelms-
Universität Münster, Germany.
Abstract: A one-pot synthesis of substituted 1-alkylidenephthalanes from 3-(2-
bromophenyl)propyne derivatives has been developed. 3-(2-Bromophenyl)propynal
acetals 9 and corresponding orthoesters 19 were treated successively with
n-butyllithium and various aldehydes and ketones at low temperature to obtain
1-alkylidenephthalanes 10 and 20 with various functional groups at the exocyclic
methylene moiety. Halogen-metal exchange, nucleophilic addition to various carbonyl
compounds, regioselective 5-exo-dig cyclization of the respective intermediate lithium
alcoholate and hydrolysis represent the key steps in this Domino reaction. A two-step
mechanism involving at first a synchronous cyclization to form a vinyl lithium
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intermediate and then a methanolate elimination leading to the respective 1-methoxy
allenes is suggested based on DFT-calculations.
Key words; alkylidenephthalanes; phenylpropynal acetals; orthoesters; DFT
calculations; 5-exo-dig cyclization, Domino reaction
Introduction
1,3-Dihydro-2-benzofuran, also known as phthalane, is frequently found as core
structure in functional organic molecules, natural products and pharmacologically
active compounds. For example, the pH indicator phenolphthalein synthesized first by
Adolf von Baeyer in 1871 contains the 2-benzofuran-1(3H)-one ring system
(phthalide), which is crucial for its pH sensitivity.[1] The phthalane containing natural
product pestacin (1) isolated from Pestalotiopsis microspora shows antifungal and
strong antioxidative properties.[2] Paecilospirone (2), a spirocyclic phthalane isolated
from marine fungus Paecilomyces species, represents a potential antimitotic agent.[3]
The phthalanes 3 with a spirocyclic connected piperidine ring represent potent and
selective σ1 receptor ligands.[4][5] The 18F-labeled 2-fluoroethyl derivative fluspidine (3a:
n = 2, R = Bn) is currently investigated as PET tracer in clinical studies.[6–8] The
aminopropyl substituted phthalane citalopram (4) is a selective serotonin reuptake
inhibitor, which is used in more than 65 countries for the treatment of major depression
and anxiety disorders. In 2012, 1-alkylidenephthalanes 5 were found to have moderate
antibacterial and antidepressant effect.[9][10] (Figure 1)
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Figure 1. Natural products 1 and 2 and pharmacologically active compounds 3 - 5 with
phthalane scaffold.
1-Alkylidenephthalanes 5 can be synthesized by cyclization of functionalized
2-ethynylbenzyl alcohols. According to Baldwin’s rules both 5-exo-dig and 6-endo-dig
cyclization reactions are favored leading to 1-alkylidenephthalanes (1-alkylidene-2-
benzofurans) and/or 1H-2-benzopyrans.[11] A large variety of catalysts enables the
regioselective synthesis of 1-alkylidenephthalanes.[10,12–14] A one-step transformation
of silylated 2-ethynylbenzyl alcohols into 1-alkylidenephthalanes has also been
reported.[15] Another method is the Michael addition of 2-iodobenzyl alcohols to
activated alkynes, followed by intramolecular Heck reaction.[16] The additional
activating functional group at the original alkyne (e.g. a C=O-moiety) allows further
modifications. Another method to obtain 1-alkylidenephthalanes with a C=O-moiety in
the sidechain uses the Sonogashira reaction of 2-ethynylbenzyl alcohol with various
aryl iodides under CO pressure.[17]
In our research devoted to novel receptor ligands, we became interested in variously
substituted phthalanes. Therefore, a novel method for the synthesis of
1-alkylidenephthalanes with additional functional groups at the exocyclic double bond,
such as hydroxymethyl, formyl or alkoxycarbonyl should be developed.
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Results and Discussion
At first, propynal dimethyl acetal 9a was synthesized in three steps from 1-bromo-
2-iodobenzene (6) comprising a Sonogashira reaction[18] with propargyl alcohol,
oxidation with TEMPO and (diacetoxyiodo)benzene[19] and acetalization with methanol.
The diethyl acetal 9b was prepared by Sonogashira reaction of 1-bromo-2-
iodobenzene (6) with propynal diethyl acetal, which are both commercially available
Furthermore, the cyclic acetal 9c was synthesized by transacetalization of diethyl
acetal 9b with 2,2-dimethylpropane-1,3-diol. (Scheme 1)
Scheme 1. Synthesis of 3-(2-bromophenyl)propynal acetals 9a-c. Reagents and
reaction conditions: (a) HC≡CCH2OH, PdCl2(PPh3)2, CuI, Et3N, THF, rt, 15 h; (b)
TEMPO, PhI(OAc)2, CH2Cl2, rt, 4.5 h; (c) CH(OCH3)3, Amberlyst® 15, MeOH, 75 °C,
2.5 h, microwave; (d) HC≡CCH(OEt)2, PdCl2(PPh3)2, CuI, Et3N, THF, rt, 20 h; (e)
(CH3)2C(CH2OH)2, Amberlyst® 15, toluene, 60 °C, 5.5 h, reduced pressure.
The next step in the synthesis of phthalanes should be the generation of benzylic
alcohols 11 by reaction of aryl bromides 9 with n-BuLi and aldehydes or ketones.
Unexpectedly, successive treatment of 9a with n-BuLi and cyclohexanone at -78 °C
provided the aldehyde 10a instead of the expected benzylic alcohol 11a after aqueous
work-up and purification by flash chromatography. (Scheme 2) Instead of simple
hydroxyalkylation, a Domino reaction comprising of halolgen-metal exchange,
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nucleophilic addition to cyclohexanone. cyclization of the intermediate alcoholate, and
formal hydrolysis had occurred.
Scheme 2. One-step transformation of acetal 9a into aldehyde 10a.
In order to understand the reaction mechanism leading to the unexpected direct
formation of the aldehyde 10a, DFT calculations (TPSS/def2-TZVP including GD3BJ
dispersion interaction and the polarizable continuum model (PCM) for THF)[20–22] were
performed for the 5-exo-dig-cyclization as key step of the reaction. Starting point of the
reaction is the lithium alcoholate 12a, which was formed upon addition of the aryllithium
intermediate to cyclohexanone. The Gibbs free energies of the lithium alcoholate 12a,
whose lithium counterion was solvated by two molecules of THF, of the corresponding
intermediates (Z)- and (E)-13a, the lithium coordinated allene 14a and the related
transition states were calculated.
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Scheme 3. Calculated reaction mechanism for the formation of 14a starting from
alcoholate 12a; Gibbs free energies [298 K, kcal/mol].
Stepwise shortening of the alcoholate-O – alkynyl-C-distance of 12a led over a tiny
barrier (only 2.2 kcal/mol) in a slightly exothermic reaction (-3.6 kcal/mol) to the
vinyllithium compound (E)-13a. The isomeric form (Z)-13a is lower in energy
(-6.7 kcal/mol). Elongation of one of the methoxy C-O bonds in (E)-13a as reaction
coordinate led via the transition state TS (E)-13a-14a (2.0 kcal/mol) to the allene 14a,
representing the global minimum of this part of the energy surface (-10.9 kcal/mol).
(Scheme 3) Thus, from the data obtained compounds 13a may be considered to be
kinetic reaction products, which will be interconverted into the thermodynamic product
14a depending on the temperature applied. Both products 13a and 14a will give the
aldehyde 10a upon hydrolysis.
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A comparable reaction was already observed for -lithioalk-2-ynyl methyl ethers
affording alkenylidinecycloalkanes.[23] Lavoisier-Gallo and Rodriguez were able to
perform an intramolecular SN2' reaction of potassium 6-bromohex-4-ynolats leading to
2-vinylidenetetrahydrofurans by elimination of bromide.[24] Patil et al. demonstrated
with their synthesis of 1-(2-alkoxyvinylidne)-2-benzopyrans the general stability of the
1,3-dialkoxyallene structure.[25] The base catalyzed cyclization of pent-4-yn-1-ol
derivatives to afford 2-methylenetetrahydrofurans can be regarded as related
transformation. This transformation was used for the synthesis of various
furans.[12,14,26–28]
Scheme 4. Reaction of 9b with n-BuLi and cyclohexanone and subsequent trapping
with ClSi(CH3)3 to form 15b confirms the existence of the alcoholate of 11b
corresponding to 12a in Scheme 3 as intermediate of the transformation.
In order to support the calculated reaction mechanism, various experiments were
conducted. The formation of the intermediate alcoholate 12b (diethyl acetal) was
confirmed by trapping it with ClSiMe3 affording the silyl ether 15b. After aqueous work-
up and flash chromatography, the tertiary alcohol 11b was isolated as sole product in
24 % yield. (Scheme 4)
Careful aqueous work-up of the reaction of diethyl acetal 9b with cyclohexanone and
1
subsequent analysis of the crude product by H NMR spectroscopy revealed the
presence of acetal 10o and aldehyde 10a in the ratio of 4 : 1. (Scheme 5) A second 1H
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NMR spectrum of the same sample recorded after storage in DMSO-d6 for 10 h
showed further transformation of acetal 10o into aldehyde 10a (ratio 10o : 10a = 1 : 1).
It is assumed that water in the NMR solvent DMSO-d6 was responsible for the further
hydrolysis of diethyl acetal 10o to yield aldehyde 10a. Probably the vinylogous
orthoester structure in 10o is responsible for its facile hydrolysis.
Scheme 5. 1-Alkylidenephthalanes 10o and 10a observed after aqueous work-up.
In a further experiment, cyclohexanone was added to lithiated 9b at -80 °C. Then, THF
was removed in vacuo at room temperature, the residue was dissolved in THF-d8 and
NMR spectra were recorded. Finally, the same experiment was conducted in THF-d8
at -80 °C and the NMR spectra were recorded immediately after addition of
cyclohexanone. Both experiments showed the formation of diethyl acetal 10o as the
1
major product, which obviously represents the first identifiable intermediate. The H
NMR spectrum confirmed unequivocally the structure of the acetal 10o displaying two
characteristic duplets at 5.04 ppm and 5.50 ppm originating from adjacent protons of
the diethoxyethylidene ((EtO)2CH-CH=) side chain.
In order to investigate the scope and limitations of this novel transformation the
dimethyl acetal 9a, the diethyl acetal 9b and the cyclic acetal 9c were reacted with
n-BuLi and subsequently with various ketones and aldehydes to provide a large series
of substituted 1-alkylidenephthalanes 10. The results are summarized in Table 1.
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Table
1.
One-pot
transformation
of
acetals
9a-c
into
substituted
1-alkylidenephthalanes 10.
yield
compd.
9a
R
R1
R2
(CH2)5
R3
Product
10a
10b
10c
10a
10b
10d
10e
10f
(E)/(Z)a
5:95
(%)
Me
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
42
9a
Me
Me
H
Ph
76b
40b
62
59
69
53
52
15
68
43
24
54
45
32
-
5:95
9a
Me
t-Bu
5:95
9b
9b
9b
9b
9b
9b
9b
9b
9b
9b
9c
Et
(CH2)5
10:90
10:90
10:90
10:90
10:90
5:95
Et
Me
Me
Me
Ph
Me
Et
Et
n-Bu
Et
(CH2)4
Et
H
H
H
H
H
Ph
t-Bu
10g
10c
10h
10i
Et
Et
5:95
i-Pr
5:95
Et
i-Bu
5:95
Et
cyclohexyl
10j
10:90
<1:>99
<1:>99
-
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
CH2C(CH3)2CH2
(CH2)5
CH(OCH2)2C(CH3)2
CH(OCH2)2C(CH3)2
CH(OCH2)2C(CH3)2
CH(OCH2)2C(CH3)2
10k
10l
9c
Me
H
Ph
Ph
9c
10m
10n
9c
H
t-Bu
-
-
a The ratio of (E) : (Z)-configured diastereomers was determined from 1H NMR spectra
of purified products.
b Transformation was performed at -90 °C.
Since diethyl acetal 9b was accessible in only one reaction step from commercially
available compounds, it represented the preferred starting material in this study. Both
dimethyl acetal 9a and diethyl acetal 9b resulted in the direct formation of the
aldehydes 10a-j. However, the cyclic acetal of 9c was not cleaved, but was retained in
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the produced 1-alkylidenephthalanes 10k+l. Reactions with aldehydes appear to give
lower yields than reactions with ketones with exception of pivalaldehyde providing the
aldehyde 10c in 68 % yield. Unexpectedly, transformations with benzaldehyde
afforded either low yields of aldehyde 10g (15 %) or failed to give acetal 10m.
EtO OEt
(a),(b)
58 %
(e)
(c),(d)
79 %
EtO OEt
H3C
EtO OEt
OEt
OEt
EtO OEt
OEt
OEt
47 %
Br
19
16
17
18
Scheme 6: Synthesis of orthoester 19. Reagents and reaction conditions. (a) Br2,
pyridine, 0 °C, 2 h; (b) KOtBu, DMSO, rt, 6 h; (c) Br2, CH2Cl2, 0 °C, 1 h; (d) KOH, 18-
crown-6, heptane, 98 °C, 18 h; (e) C6H4BrI, PdCl2(PPh3)2, CuI, Et3N, THF, rt, 15 h;
In addition to various acetals, the orthoester 19 was included into the study. Orthoester
19 was obtained by Sonogashira reaction of 1-bromo-2-iodobenzene (6) with triethyl
orthopropynoate (18). The alkyne 18 was prepared from triethyl orthopropanoate (16)
by alternate bromination and HBr elimination via orthoacrylate 17.[29][30] (Scheme 6)
Table 2. Reaction of orthoester 19 with various ketones and aldehydes to afford
ethoxycarbonyl substituted 1-alkylidenephthalanes 20.
O
1. n-BuLi, THF
-78 °C, 15 min
EtO OEt
OEt
OEt
O
2. R1R2C=O
-78 °C - r.t., 16 h
3. H2O
1R2
Br
R
19
20a-d
R1
R2
product
20a
yield (%)
(E)/(Z)a
<1:>99
10:90
<1:>99
-
(CH2)5
47
47
50
-
Me
H
Ph
t-Bu
Ph
20b
20c
H
20d
a The ratio of (E) : (Z)-configured diastereomers was determined from 1H NMR spectra
of purified products.
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Treatment of orthoester 19 with n-BuLi and various aldehydes and ketones led to the
ethoxycarbonyl substituted 1-alkylidenephthalanes 20a-c. (Table 2) Again the
aromatic aldehyde benzaldehyde failed to give the phenyl substituted derivative 20d.
Gas phase DFT calculations (without solvating THF molecules) for the reaction of the
lithiated trimethyl orthoester (in analogy of 12a) resulted in a one-step reaction with a
barrier of 9.1 kcal/mol and direct formation of the corresponding allene species
(-7.3 kcal/mol). (see Supporting Information)
1
According to H NMR spectra, the formed aldehydes 10a-j, acetals 10k-l and esters
20a-c exist as mixtures of (Z)- and (E)-configured diastereomers. Usually, the ratio
(Z) : (E) is in the range of 90 : 10 to 95 : 5. For the cyclic acetals 10k and 10l as well
as the esters 20a and 20c signals for the minor (E)-configured diastereomer could not
be detected in the 1H and 13C NMR spectra.
Conclusion
Herein, a novel method is reported for the synthesis of variously substituted
1-alkylidenephthalanes 10 and 20 bearing an additional carbonyl moiety at the
exocyclic double bond. Starting from 1-bromo-2-iodobenzene (6) allowed the synthesis
of 1-alkylidenephthalanes 10 with a formyl moiety in only two reaction steps via
propynal diethyl acetal 9b. 1-Alkylidenephthalanes 20 with an ethoxycarbonyl moiety
at the double bond were obtained by reaction of orthoester 19 with aldehydes and
ketones. The key step is a Domino reaction comprising a halogen-metal exchange,
nucleophilic addition to various carbonyl compounds, 5-exo-dig cyclization of resulting
alcoholates and formal hydrolysis. DFT calculations resulted in a two-step reaction
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mechanism starting from intermediate alcoholate 12 producing a vinyl lithium
compound 13 in the first step and formation of allene 14 in the second step by
methanolate elimination
Experimental Section
Chemistry, General Methods
Oxygen and moisture sensitive reactions were carried out under nitrogen, dried with
silica gel with moisture indicator (orange gel, VWR, Darmstadt, Germany) and in dry
glassware (Schlenk flask or Schlenk tube). Temperatures were controlled with dry
ice/acetone (-78 °C), ice/water (0 °C), Cryostat (Julabo TC100E-F, Seelbach,
Germany), magnetic stirrer MR 3001 K (Heidolph, Schwalbach, Germany) or RCT CL
(IKA, Staufen, Germany), together with temperature controller EKT HeiCon (Heidolph)
or VT-5 (VWR) and PEG or silicone bath. All solvents were of analytical or technical
grade quality. Demineralized water was used. CH2Cl2 was distilled from CaH2; THF
was distilled from sodium/benzophenone; MeOH was distilled from magnesium
methanolate. Thin layer chromatography (tlc): tlc silica gel 60 F254 on aluminum sheets
(VWR). Flash chromatography (fc): Silica gel 60, 40–63 µm (VWR); parentheses
include: diameter of the column (d), length of the stationary phase (l), fraction size (V)
and eluent. Automated flash chromatography: IsoleraTM Spektra One (Biotage®);
parentheses include: cartridge size, flow rate, eluent, fractions size was always 20 mL.
Melting point: Melting point system MP50 (Mettler Toledo, Gießen, Germany), open
capillary, uncorrected. MS: MicroTOFQII mass spectrometer (Bruker Daltonics,
Bremen, Germany); deviations of the found exact masses from the calculated exact
masses were 5 mDa or less; the data were analyzed with DataAnalysis® (Bruker
Daltonics). NMR: NMR spectra were recorded in deuterated solvents on Agilent DD2
400 MHz and 600 MHz spectrometers (Agilent, Santa Clara CA, USA); chemical shifts
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(δ) are reported in parts per million (ppm) against the reference substance
tetramethylsilane and calculated using the solvent residual peak of the undeuterated
solvent; coupling constants are given with 0.5 Hz resolution; assignment of 1H and 13C
NMR signals was supported by 2-D NMR techniques where necessary.IR: FT/IR IR
Affinity®-1 spectrometer (Shimadzu, Düsseldorf, Germany) using ATR technique.
HPLC method for the determination of the purity
Pump: LPG-3400SD, degasser: DG-1210, autosampler: ACC-3000T, UV-detector:
VWD-3400RS, interface: DIONEX UltiMate 3000, data acquisition: Chromeleon 7
(equipment and software from Thermo Fisher Scientific, Lauenstadt, Germany);
column: LiChrospher® 60 RP-select B (5 µm), LiChroCART® 250-4 mm cartridge; flow
rate: 1.0 mL/min; injection volume: 5.0 µL; detection at λ = 210 nm; solvents: A:
demineralized water with 0.05 % (V/V) trifluoroacetic acid, B: CH3CN with 0.05 % (V/V)
trifluoroacetic acid; gradient elution (% A): 0 - 4 min: 90 %; 4 - 29 min: gradient from
90 % to 0 %; 29 - 31 min: 0 %; 31 - 31.5 min: gradient from 0 % to 90 %; 31.5 - 40 min:
90 %.
Synthetic procedures
2-(3H-Spiro[[2]benzofuran-1,1'-cyclohexan]-3-yliden)acetaldehyde (10a)
Method A: Diethyl acetal 9b (430 mg, 1.52 mmol, 1.0 eq) was dissolved in THF (35 mL)
and the solution was cooled to -78 °C. A solution of n-butyllithium in n-hexane (2.5 M,
0.73 mL, 1.82 mmol, 1.2 eq) was added dropwise and the solution was stirred for
15 min at -78 °C. A solution of cyclohexanone (0.28 mL, 2.73 mmol, 1.8 eq) in absolute
THF (3 mL) was added dropwise within 15 min. Afterwards, the reaction mixture was
warmed up to rt within 16 h. H2O was added and the reaction mixture was stirred for
further 10 min. The aqueous layer was extracted with CH2Cl2 (3 x). Brine was added
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after the first extraction step to afford better phase separation. The combined organic
layers were dried (Na2SO4) and the solvents were removed in vacuo. The residue was
purified by twofold flash column chromatography (1. 100 g cartridge, cyclohexane:ethyl
acetate = 9:1, 2. 50 g cartridge, CH2Cl2:ethyl acetate = 95:5). The product was isolated
as red resin, yield 214 mg (62 %).
Method B: As described in method A, dimethyl acetal 9a (231 mg, 0.91 mmol, 1.0 eq)
was reacted with a solution of n-butyllithium in n-hexane (2.5 M, 0.44 mL, 1.09 mmol,
1.2 eq) and cyclohexanone (0.11 mL, 1.09 mmol, 1.2 eq) in THF (15 mL). The residue
was purified by threefold flash column chromatography (1. 100 g cartridge,
cyclohexane:ethyl acetate = 95:5 → 90:10, 2. 50 g cartridge, cyclohexane:ethyl
acetate = 90:10, 3. 25 g cartridge, CH2Cl2:ethyl acetate = 95:5). The product was
isolated as red resin, yield 87.8 mg (42 %).
1
Rf = 0.33 (CH2Cl2:ethyl acetate = 9:1); H NMR (600 MHz, CD2Cl2): δ [ppm] = 1.75 -
1.91 (m, 10H, (CH2)5), 5.66 (d, J = 8.5 Hz, 0.9H, C=CH), 5.84 (d, J = 8.1 Hz, 0.1H,
C=CH*), 7.34 (dt, J = 7.6/0.8 Hz, 1H, 7-Harom.), 7.45 (td, J = 7.7/1.0 Hz, 1H, 5-Harom.),
7.55 (td, J = 7.5/1.0 Hz, 1H, 6-Harom.), 7.63 (dt, J = 7.7/0.9 Hz, 0.9H, 4-Harom.), 8.22 (d,
J = 8.0 Hz, 0.1H, 4-Harom.*), 10.17 (d, J = 8.5 Hz, 0.9H, CHO*), 10.32 (d, J = 8.1 Hz,
0.1H, CHO); 13C NMR (151 MHz, CD2Cl2): δ [ppm] = 23.1 (2C, CH2), 25.4 (1C, CH2),
36.9 (2C, CH2), 94.2 (1C, C-1), 98.5 (1C, C=CH), 121.6 (1C, C-7arom.), 123.2 (0.9C,
C-4arom.), 126.4 (0.1C, C-4arom.*), 129.3 (1C, C-5arom.), 132.0 (1C, C-3aarom.), 132.8 (1C,
C-6arom.), 150.3 (1C, C-7aarom.), 171.5 (1C, C=CH), 187.6 (0.1C, CHO*), 189.3 (0.9C,
CHO). Compound 10a was isolated as a mixture of (Z)- and (E)-isomers. In the NMR
spectra a ratio of 90:10 is observed. Signals for the (E)-isomer are marked with an
asterisk. HPLC (method A): tR = 22.2 min, purity 96.8 %; IR: ෤ [cm-1] = 2932, 2859 (C-
Haliph.), 1647 (CH=O), 1620 (C=Calkene), 1466 (CH2 deform.), 1053 (C-O-C), 806 (=C-
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alkene), 764 (=C-Harom. deform.); Exact Mass (APCI): m/z = 229.1219 (calcd. 229.1223
H
for C15H17O2 [MH]+).
2-(3-tert-Butyl-2-benzofuran-1(3H)-yliden)acetaldehyde (10c)
Method A: Diethyl acetal 9b (242 mg, 0.85 mmol, 1.0 eq) was dissolved in THF (15 mL)
and the solution was cooled to -78 °C. A solution of n-butyllithium in n-hexane (2.5 M,
0.41 mL, 1.03 mmol, 1.2 eq) was added dropwise and the solution was stirred for
15 min at -78 °C. A solution of 2,2-dimethylpropanal (0.09 mL, 0.85 mmol, 1.0 eq) in
THF (2 mL) was added dropwise within 14 min. Afterwards, the reaction mixture was
warmed up to rt within 22 h. H2O was added and the reaction mixture was stirred for
further 10 min. The aqueous layer was extracted with CH2Cl2 (3 x). Brine was added
after the first extraction step to afford better phase separation. The combined organic
layers were dried (Na2SO4) and the solvents were removed in vacuo. The residue was
purified by flash column chromatography (100 g cartridge, CH2Cl2:ethyl
acetate = 95:5). The product was isolated as yellow solid, mp 106 °C, yield 126 mg
(68 %).
Method B: As described in method A, dimethyl acetal 9a (192 mg, 0.75 mmol, 1.0 eq)
was reacted as in method A described with a solution of n-butyllithium in n-hexane
(2.5 M, 0.36 mL, 0.90 mmol, 1.2 eq) and 2,2-dimethylpropanal (0.15 mL, 1.35 mmol,
1.8 eq) in THF (25 mL) at -90 °C. The residue was purified by flash column
chromatography (100 g cartridge, CH2Cl2:ethyl acetate = 95:5). The product was
isolated as yellow solid, yield 65.4 mg (40 %).
Rf = 0.43 (CH2Cl2:ethyl acetate = 9:1); 1H NMR (400 MHz, CD2Cl2): δ [ppm] = 1.00 (s,
0.45H, C(CH3)3*), 1.03 (s, 8.55H, C(CH3)3), 5.28 (s, 0.05H, ArCHO*), 5.38 (s, 0.95H,
ArCHO), 5.66 (d, J = 8.5 Hz, 0.95H, C=CH), 5.86 (d, J = 8.2 Hz, 0.05H, C=CH*), 7.45
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- 7.58 (m, 3H, 4-Harom., 5-Harom., 6-Harom.), 7.66 (d, J = 7.6 Hz, 0.95H, 7-Harom.), 8.27 (d,
J = 7.8 Hz, 0.05H, 7-Harom.*), 10.17 (d, J = 8.5 Hz, 0.95H, CHO), 10.32 (d, J = 8.1 Hz,
0.05H, CHO*); 13C NMR (101 MHz, CD2Cl2): δ [ppm] = 25.7 (3C, C(CH3)3), 37.2 (1C,
C(CH3)3), 94.2 (0.05C, ArCHO*), 96.0 (0.95C, ArCHO), 97.9 (0.95C, C=CH), 104.6
(0.05C, C=CH*), 123.0 (0.95C, C-7arom.), 123.7 (1C, C-4arom.), 126.2 (0.05C, C-7arom.*),
129.4 (1C, C-6arom.), 132.4 (1C, C-5arom.), 133.8 (1C, C-7aarom.), 143.5 (0.95C, C-
3aarom.), 146.0 (0.05C, C-3aarom.*), 172.7 (0.95C, C=CH), 174.1 (0.05C, C=CH*), 187.7
(0.05C, CHO*), 189.0 (0.95C, CHO). Compound 10c was isolated as a mixture of (Z)-
and (E)-isomers. In the NMR spectra a ratio of 95:5 is observed. Signals for the (E)-
isomer are marked with an asterisk. HPLC (method A): tR = 21.6 min, purity 97.6 %;
IR: ෤ [cm-1] = 2967, 2955, 2870 (C-Haliph.), 1643 (CH=O), 1624 (C=Calkene), 1389 (CH3
deform.), 1026 (C-O-C), 837 (=C-Halkene), 775 (=C-Harom. deform.); Exact Mass (APCI):
m/z = 217.1229 (calcd. 217.1223 for C14H17O2 [MH]+).
(Z)-3-[(5,5-Dimethyl-1,3-dioxan-2-yl)methylen]-3H-spiro[[2]-benzofuran-1,1'-
cyclohexane] (10k)
Cyclic acetal 9c (180 mg, 0.61 mmol, 1.0 eq) was dissolved in THF (20 mL) and the
solution was cooled to -78 °C. A solution of n-butyllithium in n-hexane (2.5 M, 0.29 mL,
0.73 mmol, 1.2 eq) was added dropwise and the solution was stirred for 15 min at -
78 °C. A solution of cyclohexanone (0.11 mL, 1.10 mmol, 1.8 eq) in THF (3.5 mL) was
added dropwise via syringe pump (10 mL/h). Afterwards, the reaction mixture was
warmed up to rt within 16 h. H2O was added and the reaction mixture was stirred for
further 15 min. The aqueous layer was extracted with CH2Cl2 (3 x). Brine was added
after the first extraction step to afford better phase separation. The combined organic
layers were dried (Na2SO4) and the solvents were removed in vacuo. The residue was
purified by twofold flash column chromatography (1. 100 g cartridge,
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cyclohexane:Et3N = 98:2, 2. 100 g cartridge, cyclohexane:ethyl acetate = 95:5). The
product was isolated as yellow resin, yield 85.5 mg (45 %). Rf = 0.29
(cyclohexane:ethyl acetate = 9:1); 1H NMR (600 MHz, Acetone-d6): δ [ppm] = 0.75 (s,
3H, CH3), 1.19 (s, 3H, CH3), 1.63 - 1.86 (m, 10H, (CH2)5), 3.55 (d, J = 10.9 Hz, 2H,
C(CHAHB)2)), 3.59 (d, J = 10.5 Hz, 2H, C(CHAHB)2)), 5.07 (d, J = 7.5 Hz, 1H, C=CH),
5.50 (d, J = 7.5 Hz, 1H, CH(OCH2)2), 7.33 - 7.42 (m, 3H, 5-Harom., 6-Harom., 7-Harom.),
7.56 - 7.60 (m, 1H, 4-Harom.); 13C NMR (151 MHz, Acetone-d6): δ [ppm] = 22.0 (1C,
CH3), 23.2 (2C, CH2), 23.3 (1C, CH3), 25.5 (1C, CH2), 30.4 (1C, C(CH3)2), 37.3 (2C,
CH2), 77.7 (2C, CH(OCH2)2), 90.0 (1C, C-1), 93.8 (1C, C=CH), 98.6 (1C, CH(OCH2)2),
121.3 (1C, C-4arom.), 121.7 (1C, C-7arom.), 129.0 (1C, C-5arom.), 130.2 (1C, C-6arom.),
133.5 (1C, C-3aarom.), 149.0 (1C, C-7aarom.), 156.5 (1C, C=CH); HPLC (method A): tR =
22.3 min, purity 91.2 %; IR: ෤ [cm-1] = 3044 (=C-Harom.), 2936, 2851 (C-Haliph.), 1690
(C=Calkene), 1462 (CH2 deform.), 1393 (CH3 deform.), 1088 (C-O-C), 1061 (C-O-C),
791 (=C-Halkene), 752 (=C-Harom. deform.); Exact Mass (APCI): m/z = 315.1966 (calcd.
315.1955 for C20H27O3 [MH]+).
Ethyl (Z)-2-(spiro[[2]benzofuran-1,1'-cyclohexan]-3-yliden)acetate (20a)
Orthoester 19 (144 mg, 0.44 mmol, 1.0 eq) was dissolved in THF (25 mL) and the
solution was cooled to -78 °C. A solution of n-butyllithium in n-hexane (2.5 M, 0.21 mL,
0.53 mmol, 1.2 eq) was added dropwise and the solution was stirred for 15 min at -
78 °C. A solution of cyclohexanone (0.08 mL, 0.79 mmol, 1.8 eq) in THF (2 mL) was
added dropwise via syringe pump (10 mL/h). Afterwards, the reaction mixture was
warmed up rt within 17 h. H2O was added and the reaction mixture was stirred for
further 10 min. The aqueous layer was extracted with CH2Cl2 (3 x). Brine was added
after the first extraction step to afford better phase separation. The combined organic
layers were dried (Na2SO4) and the solvents were removed in vacuo. The residue was
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purified by flash column chromatography (50 g cartridge, cyclohexane:ethyl
acetate = 9:1). The product was isolated as yellow resin, yield 56.1 mg (47 %).
Rf = 0.30. (cyclohexane:ethyl acetate = 8:2); 1H NMR (600 MHz, DMSO-d6): δ [ppm] =
1.23 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.42 (m, 1H, (CH2)5), 1.58 (d, J = 13.3 Hz, 2H,
(CH2)5), 1.69 - 1.83 (m, 5H, (CH2)5), 1.90 (td, J = 13.3/5.3 Hz, 2H, (CH2)5), 4.07 (q, J =
7.1 Hz, 2H, OCH2CH3), 5.56 (s, 1H, C=CH), 7.44 (ddd, J = 8.0/6.1/2.2 Hz, 1H, 5-Harom.),
7.51 - 7.58 (m, 2H, 6-Harom., 7-Harom.), 7.85 (d, J = 7.8 Hz, 1H, 4-Harom.); 13C NMR
(151 MHz, DMSO-d6): δ [ppm] = 14.4 (1C, OCH2CH3), 22.0 (2C, CH2), 24.2 (1C, CH2),
35.8 (2C, CH2), 58.5 (1C, OCH2CH3), 85.0 (1C, C=CH), 92.5 (1C, C-1), 121.2 (1C, C-
7arom.), 122.1 (1C, C-4arom.), 128.8 (1C, C-5arom.), 131.6 (1C, C-6arom.), 131.7 (1C, C-
3aarom.), 149.2 (1C, C-7aarom.), 165.2 (1C, CO2Et), 165.7 (1C, C=CH); HPLC (method
A): tR = 23.7 min, purity 94.8 %; IR: ෤ [cm-1] = 2978, 2932, 2859 (C-Haliph.), 1701 (C=O),
1636 (C=Calkene), 1466 (CH2 deform.), 1369 (CH3 deform.), 1146 (CO-O-CH2CH3),
1069 (C-O-C), 802 (=C-Halkene), 768 (=C-Harom. deform.); Exact Mass (ESI): m/z =
273.1488 (calcd. 273.1485 for C17H21O3 [MH]+).
Ethyl (Z)-2-[3-(tert-butyl)-2-benzofuran-1(3H)-yliden]acetate (20c)
Orthoester 19 (219 mg, 0.67 mmol, 1.0 eq) was dissolved in THF (25 mL) and the
solution was cooled to -78 °C. A solution of n-butyllithium in n-hexane (2.5 M, 0.32 mL,
0.80 mmol, 1.2 eq) was added dropwise and the solution was stirred for 15 min at -
78 °C. A solution of 2,2-dimethylpropanal (0.13 mL, 1.20 mmol, 1.8 eq) in THF (2 mL)
was added dropwise via syringe pump (10 mL/h). Afterwards, the reaction mixture was
warmed up rt within 19 h. H2O was added and the reaction mixture was stirred for
further 10 min. The aqueous layer was extracted with CH2Cl2 (3 x). Brine was added
after the first extraction step to afford better phase separation. The combined organic
layers were dried (Na2SO4) and the solvents were removed in vacuo. The residue was
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19
purified by flash column chromatography (100 g cartridge, cyclohexane:ethyl
acetate = 9:1). The product was isolated as yellow resin, yield 86.3 mg (50 %).
Rf = 0.22 (cyclohexane:ethyl acetate = 8:2); 1H NMR (600 MHz, DMSO-d6): δ [ppm] =
0.94 (s, 9H, C(CH3)3), 1.22 (t, J = 7.1 Hz, 3H, OCH2CH3), 4.02 - 4.14 (m, 2H,
OCH2CH3), 5.47 (s, 1H, ArCHO), 5.56 (s, 1H, C=CH), 7.44 - 7.52 (m, 1H, 6-Harom.),
7.54 - 7.58 (m, 2H, 4-Harom., 5-Harom.), 7.89 (d, J = 7.8 Hz, 1H, 7-Harom.); 13C NMR
(151 MHz, DMSO-d6): δ [ppm] = 14.4 (1C, OCH2CH3), 24.9 (3C, C(CH3)3), 36.0 (1C,
C(CH3)3), 58.5 (1C, OCH2CH3), 84.2 (1C, C=CH), 94.0 (1C, ArCHO), 121.9 (1C, C-
7arom.), 123.1 (1C, C-4arom.), 128.7 (1C, C-6arom.), 131.1 (1C, C-5arom.), 133.6 (1C, C-
7aarom.), 142.4 (1C, C-3aarom.), 165.1 (1C, CO2Et), 166.9 (1C, C=CH); HPLC (method
A): tR = 23.1 min, purity 96.0 %; IR: ෤ [cm-1] = 2959, 2936, 2901, 2870 (C-Haliph.), 1705
(C=O), 1639 (C=Calkene), 1466 (CH2 deform.), 1366 (CH3 deform.), 1142 (CO-O-
CH2CH3), 1072 (C-O-C), 806 (=C-Halkene), 768 (=C-Harom. deform.); Exact Mass (APCI):
m/z = 261.1491 (calcd. 261.1485 for C16H21O3 [MH]+).
Supporting Information Available
Supporting Information includes the Experimental procedures and spectroscopic data
1
of all compounds and additional information for DFT calculations. Additionally, all H
and 13C NMR spectra are included.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft (DFG) which is
gratefully acknowledged. We also thank Mrs. Sharon Reuter for technical support.
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Graphical Abstract
Text for Graphical Abstract
The 1-alkylidenephthalane scaffold is found in several biological active compounds. In
order to synthesize 1-alkylidenephthalanes a Domino reaction was developed using 2-
alkynyl substituted bromobenzenes. Successive bromine/lithium exchange,
nucleophilic addition at aldehydes or ketones 5-exo-dig cyclization and hydrolysis
resulted in aldehydes or esters in high yield. The 5-ex-dig cyclization key step was
theoretically analyzed by DFT calculations.
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