Convergent Strategy to Dizocilpine MK-801 and Derivatives

Article abstract of DOI:10.1021/acs.joc.8b00305

A convergent total synthesis of MK-801 has been achieved. Key synthetic transformations include a multicomponent Barbier-type reaction to construct the α-branched amine, a selective Heck α-coupling tactic to generate the exocyclic alkene skeleton, and a late-stage intramolecular hydroamination reaction between the exocyclic alkene and the secondary protected amine. The efficacy of this method was demonstrated by the synthesis of two news analogues substituted on the aromatic rings.

Full text of DOI:10.1021/acs.joc.8b00305

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Note
Convergent strategy to dizocilpine MK-801 and derivatives
Kasireddy Harsha Vardhan Reddy, Expédite Yen-Pon, Sylvia
Cohen-Kaminsky, Samir Messaoudi, and Mouad Alami
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 28 Feb 2018
Downloaded from http://pubs.acs.org on February 28, 2018
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The Journal of Organic Chemistry
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Convergent strategy to dizocilpine MK-801 and
derivatives
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K. Harsha Vardhan Reddy,a# Expédite Yen-Pon,a# Sylvia Cohen-Kaminsky,b,c Samir
Messaoudi,*a Mouad Alami*a
a Univ. Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de
Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry, F-92296, France.
b Inserm UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, F-92350, France.
c
Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, F-94270,
France.
samir.messaoudi@u-psud.fr, mouad.alami@u-psud.fr
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
A convergent total synthesis of MK-801 has been achieved. Key synthetic transformations
include multi-component Barbier-type reaction to construct the α-branched amine, a selective
Heck α-coupling tactic to generate the exocyclic alkene skeleton, and a late-stage intramolecular
hydroamination reaction between the exocyclic alkene and the secondary protected amine. The
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efficacy of this method was demonstrated by the synthesis of two news analogues substituted on
the aromatic rings.
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MK-801 is an original nortropane derivative whose core is fused with two benzene rings. One of
its two isomers, the (+)-MK-801,1 also called Dizocilpine, is a highly potent non-competitive
antagonist of the N-methyl- D-aspartate (NMDA) receptor which acts by binding to a site
located within the NMDA associated ion channel and thus prevents Ca2+ flux. This biological
property gives it potential as drug to treat CNS disorders, confirmed by its well-known use as
anticonvulsant. The therapeutic potency combined with the synthetic challenge triggered several
groups attention. The principal syntheses developed are summarized in Scheme 1. via a catalytic
Reissert-type reaction starting from the 1-methylisoquinoline using an aluminium-BINOL
complex. Ivy Carroll and co-workers3 described a rapid synthesis of the racemic version of MK-
801 based on a 1,3-dipolar cycloaddition between the betaine, generated in situ from the 4-
hydroxy-1-methylisoquinoline, and a benzyne ring. The first partner could be prepared via a
four-step route described by the same group. Molander et al.4 developed a synthetic pathway
involving an original lanthanide-promoted intramolecular hydroamination reaction from the
commercially available dibenzosuberone. Merck lab5 approach consisted on the 1,2-addition of a
Grignard on the dibenzosuberenone followed by a base-induced intramolecular cyclization and a
final hydroxyl removal. Recently, Chen et al.6 depicted a five-step synthetic route starting from
the dibenzosuberenone with a key Lewis acid-catalyzed cyclization and a final magnesium
desulfonylation. Although all these strategies are efficient, their main limitation is the
introduction of substituents on both aromatic rings which limits the pharmacomodulation of
these parts of the molecules. Our group took up the challenge to develop a new pathway to
synthesize this pharmaceutical agent and various analogues via a key multicomponent Barbier-
type reaction that could tolerate a great diversity of modulations (Scheme 1).
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SCHEME 1.
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The retrosynthetic approach we envisioned is depicted in Scheme 2. The nitrogen bridged core
of Dizocilpine could be obtained by an hydroamination reaction between the exocyclic alkene
and the secondary protected amine of compound A which could be obtained through an
intramolecular selective -Heck reaction. The major milestone of our strategy was to obtain the
pre-organized vinyl/halide containing moiety B starting from the easily accessible 2-
vinylbenzaldehyde,7 the commercially available benzylamine and 2-bromobenzylbromide.
Herein we report our preliminary results of this study.
SCHEME 2. Retrosynthesis
Multicomponent reactions are very seducing for the synthesis of highly complex molecules
because of the multiple bond formation usually achieved in one step.8 Wu et al.9 and later Le
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Gall et al,10 developped an efficient zinc-promoted Barbier-like reaction that allows the access
to -branched amines involving three partners: benzaldehyde, cyclic or alicyclic amine and
benzylbromide. As their methodology seems to tolerate a wide range of substituents we decided
to apply this three components strategy to our building blocks. Wu’s methodology only led to 1a
with a low yield of 18% (Table 1, entry 1). Le Gall’s method instead provided the desired
compound with an improved yield of 41% (Table 1, entry 2). A small modification of these
conditions, i.e. an increase of benzylamine equivalents pleasingly rose the yield up to 49%.
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TABLE 1. Synthesis of 1a through zinc-promoted Barbier-like reactiona
Entry SM1 (equiv) SM2 (equiv) SM3(equiv) Solvent Time (h) Yield (%)b
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2
3
1
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3
THF
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18
41
49
1.1
1
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2.5
2.2
MeCN
MeCN
1.4
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a Conditions: Under inert atmosphere, a suspension of zinc dust (3 equiv.), trifluoroacetic acid
(0.3 equiv.) and benzyl bromide (0.4 equiv.) in dry acetonitrile was stirred 5min at room
temperature. Then, benzylamine (1.4 equiv.), vinylbenzaldehyde (1 equiv.) and 2-bromobenzyl
bromide (2.2 equiv.) were added to the solution and the reaction mixture was stirred at room
temperature for 1 h. bYield of isolated product.
The next step consists in the formation of a 7-membered ring compound 3a through an
intramolecular -Heck reaction. To prevent the formation of an indoline side-product during this
step, it was necessary to protect the nitrogen atom through a carbamate group (2a obtained in
85% yield, Table 2). This last could result from a Buchwald coupling during the palladium-
catalyzed C-C bond formation.
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TABLE 2. Synthesis of 7-membered ring compound 3a through an intramolecular -Heck
reaction
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Entry
Pd (mol%)
Base (equiv)
Solvent
MeCN
DMSO
DMSO
Time (h)
Yield (%)b
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Pd(PPh3)4 (50)
Pd(PPh3)4 (10)
Pd(PPh3)4 (20)
1.2
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90
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a Under inert atmosphere, to compound 2a (1 equiv.) and K2CO3 (x equiv.) in the solvent was
added Pd (x mol%) and was stirred for the suitable time. Yield of isolated product. heated at
85°C.
b
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To favor the formation of the exocyclic alkene, we then optimized the Heck reaction (Table
2). Based on the conditions described by Danishefsky et al.11 to generate the exocyclic Taxol
alkene, the first catalytic system used consisted in Pd(PPh3)4 (0.5 equiv) in MeCN at 85°C.
Despite the high catalyst loading (0.5 equiv), only 10% of 3a has been obtained. Changing the
solvent from MeCN to DMSO, in order to carry out the reaction at higher temperature, resulted
in a major improvement with 68% yield (Table 2, entry 3). With 0.2 equivalent of Pd(PPh3)4 and
3 equivalents of K2CO3 as the base the reaction proceeded with an excellent yield of 90% in
only 2 hours.
As reported in Table 3, the deprotection of the amine did not occur as smoothly as we
thought in classical acidic condition, i.e. 20% (v/v) TFA in DCM. In these conditions we
observed, in a significant amount, a by-product resulting from the elimination of the
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benzylamine moiety. We then turned our attention to milder conditions as the one reported by
Qu et al.12 Indeed, they described the use of water, at elevated temperature, as an efficient
reagent to remove the Boc protecting group from a large variety of amine. Applying this
attractive method to compound 3a was vain since only the starting material was recovered.
Treatment of 3a with sodium carbonate (1.2 equiv) in a mixture of water and DME as depicted
by Guillaumet et al.,13 was not successful in our case. Eventually, using dry HCl in solution in
dioxane followed by a quick basic treatment with potassium carbonate gave 4a with 89%
yield.14
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TABLE 3. Boc deprotection of 3aa
Entry
Reagent
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H2O
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Time (h)
Yield (%)a
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rt
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0
/
100 °C
100 °C
rt
Na2CO3
HCl/Dioxane
H2O/DME
/
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0
89
With pure compound 4a in hand, we then focused on the final cyclization/deprotection
reaction sequence. The hydroamination reaction has been widely studied and a rapid
optimization, based on Ackermann et al.’s work15 on TiCl4-catalyzed hydroamination of
vinylarene, resulted in the bridged-protected compound. This intermediate directly without any
purification, underwent an hydrogenation catalyzed by 10% palladium on carbon with
ammonium formate as hydrogene source.16 This reaction required high catalyst loading (0.5
equiv) but afforded the targeted (±)-MK-801 (compound 5a) with 50% yield over two steps
(Scheme 3).
SCHEME 3. TiCl4-catalyzed hydroamination
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To demonstrate the robustness of our strategy, we explored the possibility to extend it to other
substrates such as 5-methyl-2-vinylbenzaldehyde and 2-bromo-1-(bromomethyl)-4-
methoxybenzene. To the best of our knowledge, only few examples of modified MK-801 are
described in the litterature.5,17 With our methodology, for both substrates, the sequence MCR-
protection-Heck coupling-deprotection resulted in the desired compounds 4b and 4c with a
satisfying yield of respectively 46% and 23% over 4 steps (Scheme 4). In the case of compound
4b, it appeared that hydrogenation with Pearlman’s catalyst gave a better result that the former
method with HCOONH4 and Pd/C, providing compound 5b with 51% over 2 steps. For
compound 4c, the sequence previously described allowed to afford compound 5c with 47% yield
over the two steps.
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SCHEME 4. Synthesis of substituted MK-801 through the described strategy
Conclusion
In conclusion, we successfully developed an original and practical synthesis of Dizocilpine
and two of its analogues. This method could tolerate more modifications and presents the
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advantage of requiring simple and commercially available starting material over the one
existing. Efforts are now in progress to synthesis a large library of MK-801 analogues through
this strategy to study their biological activity as antagonist of the N-methyl- D-aspartate
(NMDA) receptor.
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Experimental Section
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General Information. All reactions were conducted under argon atmosphere. Solvents:
cyclohexane, dichloromethane, 1,4-dioxane, ethyl acetate and methanol for extraction and
chromatography were technical grade. THF was distilled over Na/benzophenone
1
Instrumentation. These compounds were all identified by usual physical methods, e.g., H
NMR, 13C NMR (J-MOD), IR, HR-MS (ESI). 1H and 13C NMR spectra were measured in CDCl3
1
with a Bruker Avance-300. H chemical shifts are reported in ppm from an internal standard
TMS or of residual chloroform (7.26 ppm) or methanol (3.32 ppm). The following abbreviations
are used: m (multiplet), s (singlet), d (doublet), t (triplet), dd (doublet of doublets), dt (doublet of
triplets), ddd (doublet of doublet of doublets). 13C chemical shift are reported in ppm from
central peak of deuteriochloroform (77.16 ppm) or deuteriomethanol (49.00 ppm). IR spectra
were measured on a Bruker Vector 22 spectrophotometer and are reported in wave numbers (cm-
1). The angels of rotation were measured on a Perkin Elmer Polarimeter 341 and denoted as
specific rotations: [α]D. High resolution mass spectra (HR-MS) were recorded on a Bruker
MicroTOF spectrometer, using ESI with methanol as the carrier solvent. Nominal and exact m/z
values are reported in Daltons. Melting points were recorded on a Büchi B-450 apparatus and
are uncorrected. Analytical TLC was performed on Merck precoated silica gel 60F plates. Merck
silica gel 60 (0.015-0.040 mm) was used for column chromatography. Flash chromatography
was performed on silica gel 60 (0.040-0.063 mm) at medium pressure (200 mbar). Compounds
were visualized under a UVP Mineralight UVGL-58 lamp (254 nm) and with vanillin/Δ or
phosphomolybdic acid/Δ. Unless otherwise noted, other materials are obtained from commercial
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Page 10 of 21
suppliers and were used without further purification.
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Typical procedure for the MCR2:
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A suspension of zinc dust (3 equiv.), trifluoroacetic acid (0.3 equiv.) and benzyl bromide (0.4
equiv.) in dry acetonitrile was stirred 5min at room temperature. Then, benzylamine (1.4
equiv.), vinylbenzaldehyde (1 equiv.) and 2-bromobenzyl bromide (2.2 equiv.) were added to the
solution and the reaction mixture was stirred at room temperature for 1 h (exothermic reaction).
After completion of reaction, the resulting solution was poured to a saturated aqueous NH4Cl
solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and
evaporated to dryness and the desired compound was purified by column chromatography.
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N-benzyl-2-(2-bromophenyl)-1-(2-vinylphenyl)ethanamine (1a)
Following the general procedure for MCR compound 1a was obtained starting from
benzylamine (1.71 g, 16 mmol), 2-vinylbenzaldehyde (1.45 g, 11 mmol) and 2-bromobenzyl
bromide. Light yellow oil (2.11 g, 5.3 mmol, 49%); TLC: R f 0.28 (c-hexane/EtOAc 90/10); IR
(neat): ν (cm-1) 628, 660, 696, 749, 773, 912, 986, 1024, 1112, 1158, 1205, 1361, 1440, 1469,
1
1495, 1567, 1625, 3026, 3062; H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 7.7 Hz, 1H), 7.64 –
7.54 (m, 1H), 7.53 – 6.89 (m, 12H), 5.52 (dd, J = 17.3, 1.2 Hz, 1H), 5.24 (dd, J = 10.9, 1.2 Hz,
1H), 4.51 (t, J = 7.0 Hz, 1H), 3.77 (d, J = 13.5 Hz, 1H), 3.59 (d, J = 13.5 Hz, 1H), 3.22 (dd, J =
13
13.4, 7.8 Hz, 1H), 3.10 (dd, J = 13.4, 6.3 Hz, 1H), 1.80 (s, 1H). C NMR (75 MHz, CDCl3) δ
140.6 (C), 140.5(C), 138.2(C), 137.8(C), 134.7(CH), 132.8(CH), 131.8(CH), 128.3(2CH),
128.1(2CH), 128.0(2CH), 127.2(CH), 127.1(CH), 126.8(CH), 126.3(CH), 125.1(C),
116.0(CH2), 57.2(CH), 51.5(CH2), 44.5(CH2); HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C23H2279BrN 392.1015, found: 392.1018. and m/z: (M+H)+ calcd for C23H2281BrN 394.0993,
found: 394.0995.
N-benzyl-2-(2-bromophenyl)-1-(5-methyl-2-vinylphenyl)ethanamine (1b)
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Following the general procedure for MCR, compound 1b was obtained starting from
benzylamine (0.4 mL, 3.66 mmol), 5-methyl-2-vinylbenzaldehyde (297 mg, 2 mmol) and 2-
bromobenzyl bromide (1.19 g, 4.76 mmol). Colorless oil (512 mg, 1.26 mmol, 61%); TLC : R f
0.2 (c-hexane / EtOAc 20/1); IR (neat): ν (cm-1) 630, 660, 697, 749, 823, 909, 986, 1025, 1120,
1158, 1199, 1357, 1411, 1439, 1469, 1566, 1609, 1734, 2922, 3027, 3062; 1H NMR (300 MHz,
CDCl3) δ 7.62 (d, J = 6.6 Hz, 1H), 7.50 – 7.00 (m, 12H), 5.53 (d, J = 17.2 Hz, 1H), 5.22 (d, J =
11.1 Hz, 1H), 4.60 – 4.45 (m, 1H), 3.81 (d, J = 13.5 Hz, 1H), 3.62 (d, J = 13.5 Hz, 1H), 3.41 –
3.00 (m, 2H), 2.51 (s, 3H), 1.83 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 140.7(C), 140.3(C),
138.2(C), 137.7(C), 134.8(C), 134.4(CH), 132.8(CH), 131.8(CH), 128.3(2CH), 128.1(CH),
127.9(2CH), 127.2(2CH), 127.2(CH), 126.7(CH), 126.1(CH), 125.0(C), 115.1(CH2), 57.0(CH),
51.5(CH2), 44.5(CH2), 21.5(CH3); HRMS (ESI-TOF) m/z: (M+H)+ calcd for C24H2479BrN
406.1170, found: 406.1173 and m/z: (M+H)+ calcd for C24H2481BrN 408.1150, found:
408.1164.
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N-benzyl-2-(2-bromo-5-methoxyphenyl)-1-(2-vinylphenyl) ethanamine (1c)
Following the general procedure for MCR compound 1c was obtained starting from
benzylamine (1.71 g, 16 mmol), 2-vinylbenzaldehyde (1.45 g, 11 mmol) and 1-bromo-2-
(bromomethyl)-4-methoxybenzene (7.0 g, 25 mmol). Colorless oil (2.2 g, 5.39 mmol, 49%)
TLC: R f 0.44 (c-hexane/EtOAc 80/20); IR (neat): ν (cm-1) 644, 698, 733, 763, 774, 801, 856,
874, 912, 986, 1015, 1047, 1057, 1116, 1133, 1240, 1278, 1313, 1414, 1440, 1464, 1478,
1572,`1595, 2834, 2933, 3026, 3061; 1H NMR (300 MHz, CDCl3) δ 7.67 – 7.62 (m, 1H), 7.42 –
7.30 (m, 3H), 7.30 – 7.13 (m, 7H), 6.95 (dd, J = 17.3, 10.9 Hz, 1H), 6.59 (dd, J = 8.7, 3.1 Hz,
1H), 6.40 (d, J = 3.1 Hz, 1H), 5.41 (dd, J = 17.2, 1.6 Hz, 1H), 5.12 (dd, J = 11.0, 1.6 Hz, 1H),
4.39 (t, J = 7.1 Hz, 1H), 3.67 (d, J = 13.3 Hz, 1H), 3.55 (d, J = 10.3 Hz, 4H), 3.10 (dd, J = 13.3,
7.6 Hz, 1H), 2.93 (dd, J = 13.3, 6.5 Hz, 1H), 1.73 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
158.6(C), 140.6(C), 140.4(C), 138.9(C), 137.9(C), 134.6(CH), 133.2(CH), 128.3(2CH),
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128.1(CH), 128.0(2CH), 127.1(CH), 126.8(2CH), 126.3(CH), 116.8(CH), 116.0(CH2),
115.5(C), 114.4(CH2), 57.2(CH), 55.4(CH3), 51.5(CH2), 44.7(CH2); HRMS (ESI-TOF) m/z:
(M+H)+ calcd for C24H24 79BrNO 422.1120, found: 422.1116 and m/z: (M+H)+ calcd. for
C24H2481BrNO 424.1099, found: 424.1095.
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Typical procedure for Boc protection
A solution of compound 1 (1 equiv.) and Boc2O (1.5 equiv.) in THF was stirred at 60oC for 12
h. The mixture was then quenched with saturated NaHCO3 solution and extracted with CH2Cl2.
The combined organic fractions were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The crude residue was purified by flash chromatography.
Tert-butyl benzyl (2-(2-bromophenyl)-1-(2-vinylphenyl) ethyl)carbamate(2a)
Following the general procedure for Boc protection, compound 2a was obtained starting from
compound 1a (392 mg, 1 mmol), Boc2O (327 mg, 1.5 mmol), THF (2 mL). White solid (418
mg, 0.85 mmol, 85%); mp: 85-87°C; TLC : R f 0.71(c-hexane/EtOAc 80/20); IR (neat): ν (cm-
1) 630, 661, 695, 731, 750, 781, 823, 868, 914, 930, 951, 964, 983, 1027, 1074, 1123, 1145,
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1160, 1222, 1252, 1277, 1324, 1361, 1401, 1428, 1470, 1570, 1679, 2928, 2969, 3032; H
NMR (300 MHz, CDCl3) δ 7.53 (d, J = 7.9 Hz, 1H), 7.50-7.44 (m, 1H), 7.36 (s, 1H), 7.31-7.13
(m, 5H), 7.1-7.05 (m, 4H), 6.90 (br s, 2H), 5.98 (s, 1H), 5.46 (d, J = 17.1 Hz, 1H), 5.23 (d, J =
10.2 Hz, 1H), 4.34 (d, J = 15.5 Hz, 1H), 4.20 (d, J = 15.4 Hz, 1H), 3.33 (d, J = 7.1 Hz, 2H), 1.22
(s, 9H). 13C NMR (75 MHz, CDCl3) δ 155.3(C), 139.3(C), 138.9(C), 138.2(C), 136.9(C),
134.8(CH), 132.8(CH), 131.6(CH), 128.2(CH), 127.8(3CH), 127.7(2CH), 127.4(1CH),
126.6(CH), 126.5(CH), 126.3(CH), 125.5(CH2), 116.4(CH2), 79.8(C), 54.6(CH), 38.4(CH2),
28.2(3CH3); HRMS (ESI-TOF) m/z: (M+H)+ calcd for C28H3079BrNO2 492.1538, found:
492.1545, and m/z: (M+H)+ calcd for C28H3081BrNO2 494.1518, found: 494.1536.
Tert-butyl benzyl (2-(2-bromophenyl)-1-(5-methyl-2-vinylphenyl)ethyl)carbamate(2b)
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The Journal of Organic Chemistry
Following the general procedure for Boc protection, compound 2b was obtained starting from
compound 1b (510 mg, 1.25 mmol ), Boc2O (360 mg, 1.65 mmol), THF (6 mL). Colorless oil
(602 mg, 1.19 mmol, 79%), TLC : R f 0.28 (c-hexane/EtOAc 20/1); IR (neat): ν (cm-1) 662,
698, 751, 825, 844, 868, 910, 967, 1028, 1059, 1115, 1160, 1212, 1252, 1321, 1369, 1397,
1432, 1455, 1474, 1495, 1688, 1755, 1811, 2932, 2982; 1H NMR (300 MHz, CDCl3) δ 7.57 (d,
J = 7.5 Hz, 1H), 7.45 – 6.84 (m, 12H), 5.95 (s, 1H), 5.43 (d, J = 16.7 Hz, 1H), 5.18 (d, J = 13.1
Hz, 1H), 4.26 (dd, J = 41.6, 26.7 Hz, 2H), 3.32 (s, 2H), 2.36 (d, J = 36.6 Hz, 3H), 1.21 (s, 9H).
13C NMR (75 MHz, CDCl3) δ 155.2(C), 139.3(C), 138.2(C), 137.2(C), 136.6(C), 135.9(C),
134.5(2CH), 132.7(2CH), 131.6(CH), 128.7(2CH), 128.1(CH), 127.6(2CH), 127.3(2CH),
126.3(2CH), 125.4(CH2), 115.4(CH2), 79.6(C), 54.4(CH), 38.1(CH2), 28.1(3CH3), 21.4(CH3).
HRMS (ESI-TOF) m/z: (M+Na)+ calcd for C29H32BrNO2Na 528.1514, found: 528.1506.
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Tert-butyl benzyl (2-(2-bromo-5-methoxyphenyl)-1-(2-vinylphenyl) ethyl) carbamate (2c)
Following the general procedure for Boc protection, compound 2c was obtained (starting from
compound 1c (422 mg, 1 mmol), Boc2O (327 mg, 1.5 mmol), THF (2 mL) White solid (418 mg,
0.8 mmol, 80%); mp: 67-69°C; TLC : R f 0.52 (c-hexane/EtOAc 80/20); IR (neat): ν (cm-1);
680, 696, 729, 750, 802, 826, 865, 903, 921, 942, 973, 991, 1009, 1023, 1060, 1113, 1132,
1163, 1219, 1254, 1278, 1301, 1326, 1363, 1403, 1424, 1456, 1474, 1572, 1599, 1673, 2834,
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2930, 2969, 3010; H NMR (300 MHz, CDCl3) δ 7.57 – 6.90 (m, 12H), 6.80 – 6.62 (m, 1H),
6.00 (s, 1H), 5.57 (t, J = 28.0 Hz, 1H), 5.31 (t, J = 14.1 Hz, 1H), 4.31 (q, J = 15.5 Hz, 2H), 3.73
(s, 3H), 3.45 – 3.16 (m, 2H), 1.29 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 158.8(C), 155.3(C),
139.3(C), 139.1(C), 138.8(C), 136.8(C), 134.7(CH), 133.1(CH), 128.1(2CH), 127.8(2CH),
127.6(2CH), 127.0(CH), 126.5(CH), 126.4(2CH), 116.8(CH), 116.3(CH2), 115.8(C),
114.3(CH2), 79.7(C), 55.53(OCH3), 54.6 (CH), 38.2 (CH2), 28.1(3CH3). HRMS (ESI-TOF) m/z:
(M+Na)+ calcd for C29H3279BrNO3Na 544.1463, found: 544.1467 and m/z: (M+Na)+ calcd for
C24H1581BrNO3Na 546.1443, found: 546.1457.
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Typical procedure for Heck coupling3
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A sealed tube was equipped with a septum and purged with argon. The tube was charged with
compound 2 (1 equiv.), K2CO3 (3 equiv.), Pd(PPh3)4 (0.2 equiv.) and dry DMSO. The resulting
mixture was flushed with argon and was stirred for 2 h at 150 °C. The resulting slurry was
allowed to cool to room temperature, diluted with EtOAc and washed with a large amount of
brine solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The
crude was purified by flash chromatography.
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Tert-butylbenzyl
carbamate (3a)
(5-methylene-10,
11-dihydro-5H-dibenzo
[a,d][7]annulen-10-yl)
Following the general procedure for Heck coupling, compound 3a was obtained starting from
compound 2a (492 mg, 1.0 mmol), K2CO3 (414 mg, 3.0 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol),
DMSO (5 mL). Compound 3a was isolated as a mixture of rotamers. White solid (370 mg, 0.9
mmol, 90%); mp: 127-129°C; TLC: R f 0.41 (c-hexane/EtOAc 80/20); IR (neat): ν (cm-1) 663,
697, 710, 740, 752, 769, 784, 858, 876, 902, 959, 1033, 1060, 1106, 1125, 1154, 1166, 1210,
1252, 1271, 1298, 1314, 1364, 1396, 1460, 1485, 1626, 1683, 2933, 2976; 1H NMR (300 MHz,
CDCl3) δ 7.50 – 7.07 (m, 13H), 5.91 (br s, 0.4H), 5.67 (br s, 1H), 5.36 (m, 1.2H), 4.5 (m, 0.5H),
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4.01 (m, 1H), 3.53 (m, 0.6H), 3.1 (m, 0.5H), 2.75 (sl, 0.4H) 1.50 (s, 9H). C NMR (75 MHz,
CDCl3) δ 156.1(C), 151.8(C), 144.2(C), 140.4(C), 136.4(C), 135.5(C), 135.1(C), 129.5(CH),
128.2(CH), 128.0(CH), 128.0(CH), 127.0(2CH), 127.0(2CH), 126.7(2CH), 126.4(CH),
117.0(CH2), 80.3(C), 58.4(CH), 38.2(CH2), 37.6(CH2), 28.6(3CH3). HRMS (ESI-TOF) m/z:
(M+Na)+ calcd for C28H29NO2Na 434.2096, found: 434.2089.
Tert-butyl
benzyl(8-methyl-5-methylene-10,11-dihydro-5H-dibenzo[a,d][7]annulen-10-
yl)carbamate (3b)
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The Journal of Organic Chemistry
Following the general procedure for Heck coupling, compound 3b was obtained starting from
compound 2b (192 mg, 0.38 mmol), K2CO3 (173.5 mg, 1.25 mmol), Pd(PPh3)4 (45 mg, 0.03
mmol), DMSO (0.9 mL). Compound 3b was isolated as a mixture of rotamers. Colorless oil
(160 mg, 0.37 mmol, 98%), TLC: Rf 0.42 (c-hexane/EtOAc 20/1); 1H NMR (300 MHz, CDCl3)
δ 7.43 – 6.84 (m, 13H), 5.84 (br s, 0.5H), 5.62 (br s, 0.5H), 5.28 (m, 1H), 4.36 (m, 0.6H), 3.92
(br s, 1H), 3.5 (m, 0.7H), 3.11 (m, 0.5H), 2.2 (s, 3H) 1.50 (s, 9H). 13C NMR (75 MHz, CDCl3) δ
156.4(C), 151.7(C), 144.5(C), 140.3(C), 137.8(C), 135.7(C), 135.0(C), 129.6(CH), 129.4(CH),
128.6(CH), 128.0(2CH), 127.0(2CH), 126.6(2CH), 116.5(CH2), 80.2(C), 58.4(CH), 48.6 (CH2),
38.1(CH2), 37.3(CH2), 28.6(3CH3). IR (neat): ν (cm-1)1042, 1053, 1078, 1228, 1253, 1381,
1407, 1452, 1964, 2208, 2340, 2362, 2902, 2970, 2988; HRMS (ESI-TOF) m/z: (M+Na)+ calcd
for C29H31NO2Na 448.2252, found: 448.2254.
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Tert-butyl benzyl(2-methoxy-5-methylene-10,11-dihydro-5H-dibenzo[a,d][7]annulen-10-
yl)carbamate (3c)
Following the general procedure for Heck coupling, compound 3c was obtained starting from
compound 2c (522 mg, 1 mmol), K2CO3 (414 mg, 3 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol),
DMSO (5 mL). Compound 3a was isolated as a mixture of rotamers. White solid (371 mg, 0.8
mmol, 84%); mp: 46-48°C; TLC : R f 0.26 (c-hexane/EtOAc 90/10); IR (neat): ν (cm-1) 621,
643, 706, 741, 774, 792, 815, 858, 872, 894, 910, 935, 963, 1028, 1077, 1090, 1116, 1157,
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NMR (300 MHz, CDCl3) δ 7.32 – 6.94 (m, 12H), 6.75-6.55 (m, 1.7H), 6.4 (br s, 0.4H), 5.65 (br
s, 0.4H), 5.48 (s, 1H), 5.15 (s, 1H), 4.32 (m, 0.5H), 3.94 (m, 1H), 3.94-3.58 (m, 4H), 3.37 (m,
0.7H), 2.93 (m, 0.5H), 1.34 (br s, 9H). 13C NMR (75 MHz, CDCl3) δ 159.5(C), 156.3(C),
151.3(C), 140.3(C), 136.7(C), 136.3(C), 131.1(CH), 129.4(2CH), 128.6(CH), 128.0(2CH),
127.8(CH), 127.0(2CH), 127.0(CH), 126.5(CH), 116.7(CH2), 114.2(CH), 112.4(CH),
111.8(CH), 80.2(C), 58.4(CH), 48.6(CH), 38.5(CH2), 37.9(CH2), 28.5(3CH3). HRMS (ESI-
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TOF) m/z: (M+H)+ calcd for C29H32NO3 442.2382, found: 442.2381.
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Typical procedure for the amine deprotection: 4
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Under an inert atmosphere, at 0 °C, HCl (80 equiv., 4M in dioxane) was added compound 3 (1
equiv.). The mixture was then stirred at room temperature for 5h. The solvent was removed by
rotary evaporation and the crude reaction was used directly to the next step without any
purification. Dry THF and K2CO3 (2 equiv.) were added to the residue and the stirring was
maintained for 2h at room temperature. The resulting suspension was filtered through a celite
pad and rinsed with EtOAc. The filtrate was concentrated in vacuo and the crude was purified by
silica gel chromatography.
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N-benzyl-5-methylene-10,11-dihydro-5H-dibenzo[a,d][7]annulen-10-amine(4a)
Following the general procedure for the amine deprotection, compound 4a was obtained starting
from compound 3a (411 mg, 1.0 mmol). White solid (277 mg, 0.89 mmol, 89%); mp: 264-
266°C; TLC: Rf 0.25(c-hexane/EtOAc 90/10); IR (neat): ν (cm-1) 697, 727, 753, 779, 904, 975,
1028, 1037, 1073, 1093, 1118, 1158, 1202, 1254, 1269, 1328, 1452, 1486, 1601, 1616, 1668,
1695, 1723, 2920, 3026, 3062; 1H NMR (300 MHz, CDCl3) δ 7.44 – 7.33 (m, 4H), 7.37 – 7.13
(m, 9H), 5.45 (dd, J = 14.3, 1.6 Hz, 2H), 4.25 (dd, J = 7.4, 3.2 Hz, 1H), 3.76 (s, 2H), 3.41 – 3.26
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 151.8(C), 140.7(C), 140.2(C), 139.8 (C), 135.1(2C),
130.6(CH), 128.5(2CH), 128.4(CH), 128.4(CH), 128.3(CH), 127.9(CH), 127.9(CH), 127.2(CH),
127.1(CH), 126.6(CH), 117.4(CH2), 58.5(CH), 51.4(CH2), 39.2(CH2); HRMS (ESI-TOF) m/z:
(M+H)+ calcd for C23H21N 312.1728, found: 312.1723.
N-benzyl-8-methyl-5-methylene-10,11-dihydro-5H-dibenzo[a,d][7]annulen-10-amine(4b)
Following the general procedure for the amine deprotection, compound 4b was obtained
starting from compound 3b (300 mg, 0.7 mmol). Yellowish oil (180 mg, 0.55 mmol, 78%);
TLC : R 0.17 (c-hexane/EtOAc 80/20); IR (neat): ν (cm-1)804, 880, 1045, 1088, 1274,
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1326, 1380, 1408, 1453, 2361, 2901, 2974; 1H NMR (300 MHz, CDCl3) δ 7.45 – 7.07 (m,
12H), 5.46 (d, J = 9.1 Hz, 2H), 4.23 (dd, J = 7.3, 3.1 Hz, 1H), 3.84 (s, 2H), 3.44 – 3.28 (m, 2H),
2.41 (s, 3H), 1.79 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 151.6(C), 140.6(C), 140.4(C),
139.9(C), 137.7(C), 137.6(C), 135.1(C), 130.5(CH), 128.7(CH), 128.4(2CH), 128.4(2CH),
128.2(CH), 127.8(CH), 127.7(CH), 127.0(CH), 126.5(CH), 117.1(CH2), 58.6(CH), 51.5(CH2),
39.2(CH2), 21.0(CH3); HRMS (ESI-TOF) m/z: (M+H)+ calcd for C24H23N 326.1909, found:
326.1918.
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N-benzyl-2-methoxy-5-methylene-10,11-dihydro-5H-dibenzo[a,d][7]annulen-10-amine(4c)
Following the general procedure for the amine deprotection, compound 4c was obtained starting
from compound 3c (441.6mg, 1.0 mmol). White solid (239 mg, 0.7 mmol, 70%); mp: 264-
266°C; TLC : R f 0.35 (c-hexane/EtOAc:80/20); IR (neat): ν (cm-1) 634, 650, 667, 697, 717,
731, 750, 761, 783, 801, 824, 847, 865, 881, 902, 919, 944, 973, 944, 973, 1016, 1041, 1068,
1081, 1101, 1124, 1231, 1270, 1306,1323,1343,1375, 1409, 1434, 1460, 1499, 1604, 1650,
1698, 2327, 2341, 2361, 2902, 2989; 1H NMR (300 MHz, CDCl3) δ 7.39 – 7.18 (m, 10H), 6.73
(dd, J = 8.5, 2.7 Hz, 1H), 6.67 (d, J = 2.7 Hz, 1H), 5.39 (dd, J = 26.2, 1.8 Hz, 2H), 4.21 (dd, J =
7.5, 3.4 Hz, 1H), 3.76 (s, 5H), 3.36 – 3.18 (m, 2H), 1.83 (s, 1H).13C NMR (75 MHz, CDCl3) δ
159.3(C), 151.2(C), 141.2(C), 140.6(C), 140.0(C), 136.6(C), 132.4(C), 129.6(CH), 128.5(2CH),
128.4(2CH), 128.2(CH), 127.8(CH), 127.4(CH), 127.2(CH), 127.0(CH), 116.5(CH2), 115.7(C),
112.2(CH), 58.6(CH), 55.4(CH), 51.6(CH3), 40.1(CH2); HRMS (ESI-TOF) m/z: (M+H)+ calcd
for C24H23NO 342.1858, found: 342.1865.
Typical procedure for the cyclization/hydrogenation5:
A sealed tube was charged with dry toluene, compound 4 (1 equiv.) and TiCl4 (0.2 equiv.). The
tube was flushed with argon, and the resulting mixture was stirred for 3 days at 150oC. After
completion of the reaction, the solvent was evaporated under reduced pressure. The crude
reaction was used directly to the next step without any purification. 10% Pd/C (0.5 equiv.),
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anhydrous ammonium formate (15 equiv.) and dry methanol were added in a single portion
under nitrogen. The resulting reaction mixture was stirred at reflux temperature. After
completion of reaction, the catalyst was removed by filtration through a celite pad and rinsed
with chloroform. The filtrate was evaporated under reduced pressure and the resulting crude was
purified by flash chromatography.
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5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (5a)
Following the general procedure for cyclization/hydrogenation, compound 5a was obtained
starting from compound 4a (312 mg, 1.0 mmol). Colorless oil (110 mg, 0.50 mmol, 50%) TLC:
R f 0.24 (MeOH/DCM, 5/95); IR (neat): ν (cm-1)631, 691, 713, 725, 741, 754, 772, 799, 844,
1014, 1032, 1048, 1061, 1095, 1117, 1202, 1244, 1296, 1344, 1375, 1423, 1458, 1488, 1731,
2928, 2961, 3065; 1H NMR (300 MHz, CDCl3) δ 7.31 – 7.24 (m, 2H), 7.14 – 7.03 (m, 5H), 6.96
– 6.92 (m, 1H), 4.70 (d, J = 5.6 Hz, 1H), 3.45 (dd, J = 16.8, 5.7 Hz, 1H), 2.73 (d, J = 16.8 Hz,
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1H), 2.54 (s, 1H), 1.92 (s, 3H); C NMR (75 MHz, CDCl3) δ 152.2(C), 144.7(C), 144.4(C),
132.4(C), 130.3(CH), 127.2(CH), 127.1(CH), 126.7(CH), 125.8(CH), 121.7(CH), 121.5(CH),
118.7(CH), 64.3(C), 58.5(CH), 34.6(CH2), 20.2(CH3); HRMS (ESI-TOF) m/z: (M+H)+ calcd
for C16H15N 222.1283, found: 222.1275.
2-methoxy-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (5c)
Following the general procedure for cyclization/hydrogenation, compound 5c was obtained
starting from compound 4c (341 mg, 1.0 mmol). Colorless oil (118 mg, 0.47 mmol, 47%);
TLC : R f 0.17 (MeOH/DCM, 3/97 ); IR (neat): ν (cm-1) 651, 695, 732, 760, 799, 817, 842,
895, 980, 1030, 1069, 1143, 1193, 1253, 1273, 1311, 1342, 1377, 1407, 1455, 1496, 1576,
1606, 2360, 2901, 2970, 2988; 1H NMR (300 MHz, CDCl3) δ 7.43 – 6.96 (m, 6H), 6.61 (d, J =
3 Hz, 1H), 6.49 (s, 1H), 4.87 (s, 1H), 4.71 (d, J = 2.1 Hz, 1H), 3.68 (s, 3H), 3.45 (dd, J = 16.8,
5.0 Hz, 1H), 2.72 (d, J = 17.1 Hz, 1H), 1.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.9, 151.7,
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143.6, 136.2, 133.5, 127.3, 127.1, 126.8, 122.6, 121.8, 118.5, 115.5, 111.2, 64.1, 58.2, 55.2,
34.6,19.9. HRMS (ESI-TOF) m/z: (M+H)+ calcd for C17H17NO 252.1388, found: 252.1385.
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5,8-dimethyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (5b)
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In a sealed tube, under argon, to a solution of N-benzyl-8-methyl-5-methylene-10,11-dihydro-
5H-dibenzo[a,d][7]annulen-10-amine (144 mg, 0.44 mmol) in dry toluene (1 mL) was added
TiCl4 (0.09 mL, 0.09 mmol, 1M in DCM) was added. The resulting mixture was stirred for 3
days at 150 oC. After completion of the reaction, solvent was evaporated under reduced pressure.
The crude reaction was used directly to the next step without any purification. 10~15%
Pd(OH)2/C (200 mg, 0.16 mmol, 50% in H2O) was added to the crude solubilized in dry
methanol (4 mL). The mixture was stirred under hydrogen atmosphere for 8h. After completion
of reaction, the catalyst was removed by filtration through a celite pad, which was then rinsed
with DCM. The filtrate was evaporated to dryness and purified by flash chromatography to
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afford
the
desired
product
5,8-dimethyl-10,11-dihydro-5H-5,10-
epiminodibenzo[a,d][7]annulene as a yellowish oil (40.4 mg, 0.17 mmol, 51%); TLC : R f 0.31
(DCM/MeOH, 95:5); IR (neat): ν (cm-1) 630, 665, 711, 742, 773, 810, 836, 853, 880, 904, 929,
966, 989, 1034, 1070, 1103, 1117, 1229, 1266, 1293, 1321, 1341, 1375, 1425, 1451, 1484,
1
1615, 1713, 2854, 2921, 2968 H NMR (300 MHz, CDCl3) δ 7.18 – 7.14 (m, 1H), 7.04 – 6.97
(m, 3H), 6.88 – 6.83 (m, 3H), 4.62 (d, J = 5.6 Hz, 1H), 3.54 – 3.35 (m, 3H), 2.65 (d, J = 16.9
Hz, 1H), 2.21 (s, 3H), 1.84 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 148.9(C), 144.2(C), 144.0(C),
136.7(C), 132.1(C), 130.3(CH), 127.8(CH), 125.9(CH), 122.6(CH), 121.5(CH), 118.5(CH),
64.3(C), 58.4(CH3), 34.4(CH2), 21.4(CH), 20.0(CH3). HRMS (ESI-TOF) m/z: (M+H)+ calcd
for C17H17N 236.1439, found: 236.1436.
Supporting Information Available: Spectroscopic data of all compounds. This material is
available free of charge via the the Internet at http://pubs.acs.org.
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Acknowledgment.
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Authors acknowledge support of this project by CNRS, University Paris Sud and by La Ligue
Contre le Cancer through an Equipe Labellisée 2014 grant. This work was funded by LabEx
LERMIT (Laboratory of Excellence in Research on Medication and Innovative Therapeutics)
under the “Investment for the Future” program ANR-11-IDEX-0003-01 within the ANR-10-
LABX-0033 (to S.C-K. and M.A), and Agence Nationale de la Recherche (ANR) “Biomedical
Innovation” program 2014(DS0404) within ANR-14-CE16-0016 (to S.C-K.)
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