Improved synthesis for the rodenticides, diphenacoum and brodifacoum

Article abstract of DOI:10.1039/a607269k

An improved synthesis of the 3-[3-(p-substituted phenyl)-1,2,3,4-tetrahydro-1-napththyl]-4-hydroxycoumarins, diphenacoum and brodifacoum, is described. The process is primarily based on the formation of one of the crucial bonds in the carbon backbone using organocopper methodology, and on the coupling of the 4-hydroxycoumarin moiety to the 3-biphenyl tetralin unit under strongly acidic conditions.

Full text of DOI:10.1039/a607269k

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Improved synthesis for the rodenticides, diphenacoum and
brodifacoum
Pieter S. van Heerden, Barend C. B. Bezuidenhoudt and Daneel Ferreira *
Department of Chemistry, University of the Orange Free State, PO Box 339, Bloemfontein,
9300 South Africa
An improved synthesis of the 3-[3-(p-substituted phenyl)-1,2,3,4-tetrahydro-1-napththyl]-4-
hydroxycoumarins, diphenacoum and brodifacoum, is described. The process is primarily based on the
formation of one of the crucial bonds in the carbon backbone using organocopper methodology, and on
the coupling of the 4-hydroxycoumarin moiety to the 3-biphenyl tetralin unit under strongly acidic
conditions.
Herein, we report on a new protocol for the synthesis of
Introduction
diphenacoum and brodifacoum from low-cost, commercially
available starting materials and involving organocopper chem-
istry6,7 to form one of the crucial bonds in their carbon frame-
works. This method represents an improvement of existing pro-
cesses leading to a two-fold increase in overall yield with a
decrease in the number of steps from 8 and/or 9 to 5 and 6
respectively for diphenacoum and brodifacoum.
The 3-[3-(p-substituted phenyl)-1,2,3,4-tetrahydro-1-naphthyl]-
4-hydroxycoumarins, diphenacoum 1 and brodifacoum 2, show
outstanding activity against both Warfarin-sensitive and
Warfarin-resistant rats, and are now used commercially as
rodenticides. Owing to their anticoagulant properties these may
also be used at extremely low concentrations in humans suffer-
ing from circulatory diseases. The total syntheses of these
commercially important anticoagulants have been the topic of
several reports over the last two decades.1–5 Although some
progress has been made to overcome the detrimental effect of
stilbene formation in the Shadbolt and Woodward synthesis,
the overall yields of both compounds are still very low (10–
20%).5
Results and discussion
In order to establish an overall improvement of the existing
syntheses of diphenacoum and brodifacoum, we have opted for
the retrosynthetic sequence outlined in Scheme 1. Since 1,4-
Michael additions can be accomplished in excellent yields via
Scheme 1
J. Chem. Soc., Perkin Trans. 1, 1997
1141

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organocopper reagents, the butanoate esters 8 and 9 could
either be synthesized through the organocopper-mediated 1,4-
addition of biphenyl 17 and bromobiphenyl 18 units to ester 19,
or via transfer of a benzyl group 25 to α,β-enoates 6 and 7.
Acid-catalysed cyclization and subsequent condensation with
4-hydroxycoumarin 16, would then give diphenacoum 1 and
brodifacoum 2. Owing to the successful conjugate addition of
aryl based organocuprates to 1,4-Michael acceptors,8,9 initial
attempts to synthesize esters 8 and 9 were focused on the former
approach. The unreported ethyl 4-phenylcrotonate 19 was
prepared in good yield (81%) and selectivity (E :Z 7:1) by
a standard Wittig reaction between (carbethoxy)triphenyl-
phosphonium chloride and phenylacetaldehyde.
Conjugate addition of conventional Gilman reagents to α,β-
unsaturated esters has met with limited success due to com-
petitive reaction at the carbonyl centre. However, Yamamoto’s
Lewis acid-activated reagent 10 and Lipshutz’s higher order
cyanocuprate8 represent viable alternatives for inducing 1,4-
addition to enoates. In order to test the feasibility of our
approach a variety of model conjugate addition reactions of
cuprates [Bu2Cu(CN)Li2, BuCu–BF3, Bu2CuLi–BF3] to enoate
19 was evaluated. Analysis of the 1H NMR spectra of the reac-
tion mixtures indicated in each case the exclusive formation of
polyene-like material with no evidence of the formation of any
addition product. Formation of these polyenes of types 21 and
22 presumably resulted from 1,2-addition followed by abstrac-
tion of the relatively acidic benzylic and homo-allylic protons in
the adduct of type 20 by the cuprate (Scheme 2). Although
yields, respectively. Our organocopper methodology was then
successfully applied to the synthesis of butanoates 8 and 9 by
treating enoates 6 and 7 with the BnCu–TMEDA complex in
the presence of TMSCl leading to good yields (81–84%) and
regioselectivities (only 1,4-addition) in both cases. Transform-
ation of butanoates 8 and 9 into the tetralones 10 and 11 was
initially approached via the Kim–Lee protocol5 involving cycli-
zation of the butanoic acid analogue of 9 with polyphosphoric
acid in toluene. Although the desired conversions were achieved
in both cases, these reactions were not sufficiently high yielding
(68–71%) and alternative methods were investigated. The use of
AlCl3 in dry toluene at 90 ЊC effectively catalysed the Friedel–
Crafts type cyclization of butanoates 8 and 9 into the tetralones
10 and 11 in good yields (88 and 86%, respectively). Although
this cyclization could give rise to either 3-(p-substituted phenyl)-
3,4-dihydronapthalen-1(2H)-ones, e.g. 10, or 6-(p-substituted
phenyl)-3-benzylindan-1-ones, it has been shown that six-
membered rings are formed in preference to five-membered
rings.15 Such a formation of a six-membered ring was con-
firmed by the carbonyl stretching bands at ca. 1680 cmϪ1 in the
IR spectra of tetralones 10 and 11 in contrast to the expected
absorption for substituted indanones at ca. 1720 cmϪ1 16
. Thus,
we have efficiently synthesized the tetralone derivatives 10 and
11 which are the key intermediates in the synthesis of diphen-
acoum 1 and brodifacoum 2.
In the Shadbolt–Woodward synthesis, access to 1 and 2 is
feasible by condensation of 4-hydroxycoumarin 16 and the cor-
responding 1-bromotetralin derivatives 14 and 15. Owing to
steric hindrance, forcing conditions (140 ЊC) were required to
establish coupling. In our hands this procedure, however, led to
preferential dehydrohalogenation of 14 and 15, giving only
poor yields (~20–30%) of diphenacoum 1 and broadifacoum 2
(Scheme 4).
Upon reduction of tetralones 10 and 11 with either sodium
boranuide or aluminium isopropoxide, Shadbolt and Wood-
ward reported products with cis and trans relative stereo-
chemistry respectively.1 Since a 1,3-cis orientation would facili-
tate a possible SN 2 coupling mechanism through minimization
of the steric effect caused by the bulky biphenyl substituents,
ketones 10 and 11 were thus treated with NaBH4–EtOH–THF
yielding the corresponding cis benzyl alcohols 12 (98%, 90% de)
and 13 (97%, 90% de). The relative stereochemistry of 12 and
13 was established by 1H NMR spectroscopy. Following previ-
ous suggestions,17,18 the observed NOE (2.69 and 2.48%,
respectively for 12 and 13) between H-1 and H-3 in both
1,2,3,4-tetrahydro-3-biphenyl-4-yl-1-naphthols for the first time
confirmed the 1,3-cis relationship of the hydroxy and biphenyl
groups. The alicyclic rings are held in half-chair conformations
with both substituents occupying pseudo-equatorial orienta-
tions (Fig. 1). Owing to the bulkiness of the biphenyl substitu-
ents, the observed diastereoselectivity presumably resulted by
attack of the sodium boranuide from the less hindered face of
the carbonyl functionality.
Subsequent in situ bromination (PBr3) of alcohols 12 and
13 afforded tetrahydronapththyl halides 14 and 15 in good
yields. In principle, deprotonation of 4-hydroxycoumarin 16
followed by addition of the corresponding bromotetralin elec-
trophile, e.g. 14, should lead to the target α-alkylated products
1 and 2. These base-catalysed couplings would require lower
temperatures, hence inhibiting dehydrotetralin formation and
leading to increased yields. However, even the mild deproton-
ation (lutidine–THF or K2CO3–acetone) of coumarin 16 at
room temperature and subsequent treatment with either 14 or
15, resulted in the preferential formation of the unwanted
products of dehydrohalogenation. Such a propensity of the
bromotetralins to dehydrohalogenation under basic conditions
prompted investigation of alternative acid-catalysed coup-
lings. The following variation of the Shadbolt–Woodward
procedure was found to be superior in terms of product yield
and reproducibility of the reaction. Separate treatment of a
Scheme 2
contrary to the usual mode of action of organocopper reagents,
literature precedent 11 for cuprates acting as bases does exist.
These complications prompted recourse to the alternative
approach which required the introduction of a benzyl group to
the β-position of the biphenyl esters 6 and 7. Our recent dem-
onstration of the highly successful conjugate addition 6,7 of the
benzyl copper reagent, BnCu–TMEDA, to cinnamic esters,
indicated that the corresponding additions of the biphenyl
unsaturated esters 6 and 7 would proceed in an analogous fash-
ion to give rise to butanoates 8 and 9.
Initial attempts to synthesize the commercially unavailable
carbaldehyde 5 via bromination [thallium() acetate–Br2]12 of
biphenylcarbaldehyde
4
and formylation [N-phenyl-N-
methylformamide–POCl3]13 of bromobiphenyl were unsuccess-
ful, presumably due to low reactivity of the substrates. Careful
lithiation of dibromobiphenyl 3 at low temperature, followed by
treatment of the intermediate anion with N,N-dimethyl-
formamide (DMF)14 afforded 4Ј-bromobiphenylcarbaldehyde
5 (95%) (Scheme 3). With both precursors 4 and 5 available,
separate Wittig condensation with (carbethoxy)triphenylphos-
phonium chloride in DMF and sodium methoxide at room
temperature, gave the biphenyl esters 6 and 7 in 92 and 87%
1142
J. Chem. Soc., Perkin Trans. 1, 1997

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Scheme 3 Reagents and conditions: i, BuLi, THF, Ϫ78 ЊC, then DMF, Ϫ78→0 ЊC; ii, Ph3PϩCH2CO2EtClϪ, NaOMe, DMF; iii, PhCH2Cu–TMEDA,
TMSCl, THF, Ϫ78→Ϫ30 ЊC; iv, AlCl3, toluene, 90 ЊC; v, NaBH4, EtOH–THF, RT; vi, NaBH4, EtOH–THF, RT, then PBr3, DCM, 0 ЊC;
vii, 4-hydroxycoumarin, HCl(g), 160 ЊC
mixture of 14 or 15 and 16 under an HCl atmosphere at
160 ЊC for 30 min gave approximately equal quantities of the
cis and trans isomers [RF 0.13 and 0.26 on silica in hexane–
benzene–acetone (6:3:1)] of anticoagulants 1 (80%) and 2
(77%), together with minor quantities of the elimination arte-
facts 23 and 24. Owing to the success of this condensation, it
was expected that coupling between 4-hydroxycoumarin 16
and alcohols 12 and 13 would also be feasible under strongly
acidic conditions at elevated temperatures. Such an approach
would reduce the number of steps and result in an economic-
ally more favourable process. Thus by analogy, condensation
of 16 and alcohols 12 and 13 provided a trans/cis mixture
spicuously absent when H-1 of the corresponding trans-isomers
was irradiated.
The coupling reaction presumably occurs according to the
sequence outlined in Scheme 5. Since an almost 1:1 ratio of
diastereoisomeric compounds 1 and 2 was obtained, it appears
that initial dehydration is followed by random SN 1-attack on
carbocation 26 by 4-hydroxycoumarin 16. In addition, the
coupling is driven to completion by the reversible regeneration
of carbocation 26 from the elimination by-products 23 and 24.
The slight selectivity may be attributed to the steric effect
caused by the biphenyl unit, leading to predominant formation
of the trans-isomers (Scheme 5).
of tetrahydronaphthylcoumarins 1 (trans:cis 3:2) and
2
We have thus developed a viable total synthesis of the anti-
coagulants diphenacoum 1 and brodifacoum 2 with a marked
increase in overall yield to 54 and 43% compared to those
of existing processes. Besides limiting the number of steps to
five and six this protocol also has the potential to address
the stereoselective synthesis of these compounds, a process
which is currently being pursued and will be the subject of an
impending publication.
(trans:cis 5:4) in 78 and 74% yields, respectively (Scheme 3).
The relative stereochemistry of the trans/cis isomers of diphen-
acoum 1 and brodifacoum 2 was again assigned by a series of
NOE experiments (Scheme 5). Irradiation of the C-1 benzylic
protons in the corresponding cis-isomers caused a substantial
NOE enhancement (2.13 and 2.30%, respectively) of the C-3
benzylic signals at δ 3.04. Similar NOE enhancement was con-
J. Chem. Soc., Perkin Trans. 1, 1997
1143

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Scheme 4
Scheme 5
4Ј-Bromobiphenyl-4-carbaldehyde 5
To a solution of 4,4Ј-dibromobiphenyl 3 (2 g, 6.41 mmol) in dry
THF (20 ml) under argon at Ϫ78 ЊC butyllithium (1.63  solu-
tion in hexanes; 3.93 ml, 6.41 mmol, 1 equiv.) was added drop-
wise with stirring. After 15 min DMF (20 ml) was added to the
mixture, the temperature of which was allowed to rise to room
temperature, while stirring was continued for 2 h. The mixture
was diluted with water (50 ml) and extracted with ether (3 × 50
ml). The combined extracts were dried (Na2SO4) and evapor-
ated and flash chromatography (hexane–acetone 9:1) of the
residue gave the carbaldehyde 5 as a white powder (1.6 g, 95%);
mp 158 ЊC; RF 0.26 (hexane–acetone 9:1); m/z 260 and 262
(Mϩ, 77%), 262 (74), 261 (55), 259 (46), 153 (16), 152 (100), 151
(23), 150 (12), 126 (10), 76 (23) and 75 (12) (Found: Mϩ,
259.9838 and 261.9816. C13H9OBr requires Mϩ, 259.9837 and
Fig. 1
Experimental
1H NMR spectra were recorded at ambient temperatures on a
Bruker AM-300 spectrometer for solutions in CDCl3 or C6D6.
IR spectra were recorded on a Unicam SP 100 spectro-
photometer, using 0.1 cm sodium chloride solution cells. High
and low resolution mass spectra were obtained on a Kratos
MS-80 mass spectrometer. Melting points were measured on a
Reichert hot-stage apparatus and are uncorrected. Flash col-
umn chromatography was on Merck Kieselgel 60 (230–400
mesh) under a positive pressure by means of compressed nitro-
gen. Thin layer chromatography (TLC) was carried out on
Merck Kieselgel 60 F254 plates with visualization by UV light
and/or formaldehyde–sulfuric acid spray. Reagents and solv-
ents were purified by standard procedures.19 CuI was freshly
prepared 20 and purified 21 under an argon atmosphere. All other
chemicals were used as purchased. Experiments were per-
formed under anhydrous conditions in an Ar atmosphere,
unless specified to the contrary, using oven-dried apparatus and
employing standard techniques for handling air-sensitive
materials. Ether refers to diethyl ether.
261.9817); νmax(liquid film)/cmϪ1 1707 (C᎐O), 3022, 1428 and
᎐
750; δH (CDCl3) 10.06 (1 H, s, CHO), 7.96 (2 H, d, J 8.5, H-2,6),
7.72 (2 H, d, J 8.5, H-3,5), 7.62 (2 H, d, J 8.5, H-3Ј,5Ј) and
7.50 (2 H, d, J 8.5, H-2Ј,6Ј).
(E)-Ethyl 4Ј-phenylcinnamate 6
A suspension of sodium methoxide (1.3 g, 23.85 mmol, 2.3
equiv.) in dry DMF (100 ml) was added to
(carboxyethyl)triphenylphosphonium chloride (4.6 g, 12.14
mmol, 1.1 equiv.) [prepared by stirring triphenylphosphine
(21.67 g, 82.6 mmol) and ethyl chloroacetate (10 g, 81.6 mmol)
in dry benzene (50 ml) at room temperature] and the mixture
1144
J. Chem. Soc., Perkin Trans. 1, 1997

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was stirred at room temperature for 12 h. It was then treated
with a solution of carbaldehyde 4 (2 g, 10.99 mmol) in dry
DMF (50 ml), added dropwise over a period of 1 h. Stirring
was continued for 48 h, after which the mixture was diluted
with water (150 ml) and extracted with ether (3 × 150 ml). The
combined extracts were successively washed with water (50
ml), 0.1  hydrochloric acid (2 × 100 ml), water (50 ml), dried
(Na2SO4) and evaporated. Flash chromatography (hexane–
acetone, 9:1) of the residue gave the cinnamate 6 as a white
solid (2.6 g, 92%); mp 89 ЊC (lit.,22 87 ЊC); RF 0.34 (hexane–
acetone, 9:1); m/z 252 (Mϩ, 100%), 224 (10), 208 (11), 207 (61),
182 (49), 181 (56), 180 (39), 179 (27), 178 (65), 165 (20), 154
(13), 153 (25), 152 (58) and 151 (20); νmax(liquid film)/cmϪ1
ml) and TMEDA (4 ml, 23.93 mmol, 2.2 equiv.) followed by
addition of BnMgCl (1.17  solution in THF; 19 ml, 21.75
mmol, 2 equiv.) was allowed to react with ethyl 4-(4Ј-
bromophenyl)cinnamate 7 (3.6 g, 10.88 mmol in 55 ml of THF)
in the presence of TMSCl (54.38 mmol; 7.1 ml, 5 equiv.) to give
the butanoate 9 as a white solid (3.7 g, 81%); mp 49 ЊC; RF 0.54
(hexane–acetone, 9:1); m/z 422 and 424 (Mϩ, 10%), 423 (10),
333 (70), 332 (68), 290 (98), 289 (100), 253 (40), 211 (42), 179
(70), 178 (85), 165 (35), 152 (32), 91 (73) and 65 (28) (Found:
Mϩ, 422.0878 and 424.0863. C24H23O2Br requires Mϩ, 422.0881
and 424.0862); νmax(liquid film)/cmϪ1 1728 (C᎐O), 1524, 1248
᎐
and 930; δH (CDCl3) 7.53 (2 H, d, J 8.5, H-3Љ,5Љ), 7.45 (2 H, d, J
8.5, H-2Љ,6Љ), 7.43 (2 H, d, J 8.5, H-3Ј,5Ј), 7.26–7.05 (7 H, m,
Ph), 3.99 (2 H, q, J 7, OCH2CH3), 3.52–3.42 (1 H, m, H-3), 2.96
(1 H, dd, J 14 and 7.5) and 2.91 (1 H, dd, J 14 and 8) (4-CH2),
2.69 (1 H, dd, J 16 and 7) and 2.62 (1 H, dd, J 16 and 8.5) (2-
CH2) and 1.12 (3 H, t, J 7, OCH2CH3).
1713 (C᎐O), 2938, 1314 and 1035; δ (CDCl ) 7.72 (1 H, d, J
᎐
H
3
15.5, H-3), 7.64–7.56 (6 H, m, Ph), 7.48–7.35 (3 H, m, Ph),
6.48 (1 H, d, J 15.5, H-2), 4.28 (2 H, q, J 7, OCH2CH3) and
1.35 (3 H, t, J 7, OCH2CH3).
(E)-Ethyl 4Ј-(4Љ-bromophenyl)cinnamate 7
3-(Biphenyl-4Ј-yl)-1,2,3,4-tetrahydronaphthalen-1-one 10
The cinnamate 7 was prepared by treating a suspension of
sodium methoxide (3.2 g, 59.63 mmol, 2.3 equiv.) and (carboxy-
ethyl)triphenylphosphonium chloride (7.9 g, 21.1 mmol, 1.1
equiv.) in dry DMF (200 ml) with 4Ј-bromobiphenyl-4-carb-
aldehyde 5 (5.0 g, 19.2 mmol) in dry DMF (200 ml) as was
described for compound 6. Flash chromatography (hexane–
acetone, 9:1) afforded the target molecule 7 as a white solid (5.5
g, 87%); mp 79 ЊC; RF 0.54; m/z 330 and 302 (Mϩ, 100%), 332
(99), 304 (12), 302 (12), 287 (47), 286 (10), 285 (48), 260 (29),
259 (15), 258 (34), 206 (20), 179 (13), 178 (71), 177 (14), 176
(27), 152 (31), 151 (19), 89 (14), 88 (12) and 76 (21) (Found: Mϩ,
330.0254 and 332.0235. C17H15O2Br requires Mϩ, 330.0255 and
Anhydrous AlCl3 (240 mg, 1.79 mmol, 3 equiv.) was added to a
solution of the butanoate 8 (200 mg, 0.581 mmol) in dry tolu-
ene (4 ml). The mixture was kept at 90 ЊC for 16 h after which it
was treated with 3  hydrochloric acid (3 ml), concentrated by
solvent removal under reduced pressure and extracted with
ethyl acetate (2 × 20 ml). The combined extracts were washed
with water (20 ml), dried (Na2SO4) and evaporated to dryness
to yield the tetralone 10 as a white solid (0.152 g, 88%) follow-
ing preparative TLC (hexane–acetone, 9:1); mp 95 ЊC (lit.,1 92–
94 ЊC); RF 0.3; νmax(liquid film)/cmϪ1 1683 (C᎐O), 2260, 1386
᎐
and 897; δH (CDCl3) 8.09 (1 H, dd, J 8 and 1.5, H-8), 7.62–7.28
(12 H, m, Ph), 3.57–3.46 (1 H, m, H-3), 3.31–3.18 (2 H, m,
4-CH2), 3.02 [1 H, ddd, J 14, 4 and 2, H-2(eq)] and 2.87 [1 H,
dd, J 16.5 and 12.5, H-2(ax)].
332.0233); νmax(liquid film)/cmϪ1 1713 (C᎐O), 3016, 1524 and
᎐
1245; δH (CDCl3) 7.76 (1 H, d, J 15.5, H-3), 7.62–7.56 (6 H, m,
Ph), 7.47 (2 H, d, J 8.5, H-2Ј,6Ј), 6.48 (1 H, d, J 15.5, H-2), 4.28
(2 H, q, J 7, OCH2CH3), 1.35 (3 H, t, J 7, OCH2CH3).
3-(4Љ-Bromobiphenyl-4Ј-yl)-1,2,3,4-tetrahydronaphthalen-1-one
11
Ethyl 3-(biphenyl-4Ј-yl)-4-phenylbutanoate 8
Treatment of the butanoate 9 (200 mg, 0.4728 mmol) with
AlCl3 (190 mg, 1.43 mmol, 3 equiv.) in dry toluene (4 ml) as
described above, gave the tetralone 11 (153 mg, 86%); mp
153 ЊC (lit.,1 156–158 ЊC); RF 0.29 (hexane–acetone, 9:1);
A mixture of CuI (8.4 g, 44.2 mmol, 2 equiv.) and dry THF (160
ml) in a round-bottom flask was sealed with a rubber septum,
flushed with argon and dry TMEDA (8 ml, 48.6 mmol, 2.2
equiv.) was added. After the mixture had been stirred at room
temperature for 10 min the flask was cooled to Ϫ78 ЊC and the
benzyl Grignard reagent (1.17  solution in THF; 38 ml, 44.2
mmol, 2 equiv.) was added to it. The mixture was then stirred at
Ϫ78 ЊC for 15 min after which a solution of chlorotrimethyl-
silane (14.2 ml, 110.5 mmol, 5 equiv.) and the enoate 6 (5.6 g,
22.1 mmol), in dry THF (110 ml), was injected into it via a
syringe with continued stirring; during this operation the tem-
perature of the mixture was allowed to rise to Ϫ30 ЊC. After 24
h the cold reaction mixture was poured into a separatory funnel
containing saturated aqueous NH4Cl–NH4OH (3:2; 100 ml)
and extracted twice with ether (200 ml). The combined extracts
were then washed with water (200 ml), dried (Na2SO4) and
evaporated to dryness. Flash chromatography (hexane–acetone,
9:1) of the residue gave butanoate 8 as a white solid (6.3 g,
84%); mp 67 ЊC; RF 0.34 (hexane–acetone, 9:1); m/z 344 (Mϩ,
27%), 299 (8), 256 (9), 254 (18), 253 (84), 252 (11), 212 (16), 211
(100), 183 (11), 181 (28), 180 (34), 179 (18), 178 (20), 167 (18),
166 (11), 165 (17), 149 (15), 91 (17) and 88 (10) (Found; Mϩ,
344.1762. C24H24O2 requires Mϩ, 344.1776); νmax(liquid film)/
νmax(liquid film)/cmϪ1 1689 (C᎐O), 1605, 1488 and 906;
᎐
δH (CDCl3) 8.09 (1 H, dd, J 8 and 1.5, H-8), 7.62–7.28 (11 H,
m, Ph), 3.57–3.46 (1 H, m, H-3), 3.31–3.18 (2 H, m, 4-CH2),
3.02 [1 H, ddd, J 16.5, 4 and 2, H-2(eq)] and 2.86 [1 H, dd,
J 16.5 and 12.5, H-2(ax)].
3-(Biphenyl-4Ј-yl)-1,2,3,4-tetrahydronaphthalen-1-ol (mixture of
cis,trans isomers) 12
Sodium boranuide (51 mg, 1.342 mmol, 4 equiv.) was added to
a solution of the ketone 10 (100 mg, 0.3355 mmol) in EtOH–
THF (1:1 mixture; 5 ml). The mixture was stirred for 4 h after
which the excess of boranuide was destroyed by the addition of
acetone prior to removal of the solvents in vacuo and the add-
ition of water (5 ml). The mixture was extracted with ether
(3 × 10 ml) and the combined extracts were dried (Na2SO4), and
evaporated to yield a white solid (98 mg, 98%); RF 0.37
(hexane–benzene–acetone, 6:3:1); δH (CDCl3) 7.67–7.08 (13 H,
m, Ph), 5.05–4.95 [1 H, m, H-1 (cis,trans)], 3.48–3.36 [1 H, m,
H-3 (trans)], 3.2–2.9 [3 H, m, 2-CH2 (cis,trans), 4-CH (cis)],
2.57–2.49 [1 H, m, H-3 (cis)], 2.38–2.30 (1 H, m) and 2.19–2.09
(1 H, m) [4-CH2 (trans)], 2.04–1.91 [1 H, m, 4-CH (cis)] and 2.0–
1.8 (br s, OH).
cmϪ1 1731 (C᎐O), 2938, 1491 and 1146; δ (CDCl ) 7.59–7.04
᎐
H
3
(14 H, m, Ph), 3.99 (2 H, q, J 7, OCH2CH3), 3.51–3.41 (1 H, m,
H-3), 2.97 (1 H, dd, J 14 and 7) and 2.91 (1 H, dd, J 14 and 8)
(4-CH2), 2.7 (1 H, dd, J 15.5 and 6.5) and 2.63 (1 H, dd, J 15.5
and 8) (2-CH2) and 1.11 (3 H, t, J 7, OCH2CH3).
3-(4Љ-Bromobiphenyl-4Ј-yl)-1,2,3,4-tetrahydronaphthalen-1-ol
(mixture of cis,trans isomers) 13
Similar treatment of the bromo ketone 11 (100 mg, 0.2652
mmol) with sodium boranuide (40 mg, 1.061 mmol, 4 equiv.)
in EtOH–THF (1:1; 5 ml) gave the product 13 as a white solid
(97 mg, 97%); RF 0.38 (hexane–benzene–acetone, 6:3:1);
δH (CDCl3) 7.67–7.10 (12 H, m, Ph), 5.05–4.95 [1 H, m, H-1
Ethyl 3-(4Љ-bromobiphenyl-4Ј-yl)-4-phenylbutanoate 9
In a reaction similar to that for the preparation of the
butanoate 8, the BnCu–TMEDA complex [prepared by dissolv-
ing CuI (4.2 g, 21.72 mmol, 2 equiv.) in a mixture of THF (80
J. Chem. Soc., Perkin Trans. 1, 1997
1145

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(cis,trans)], 3.48–3.36 [1 H, m, H-3 (trans)], 3.2–2.9 [3 H, m,
2-CH2 (cis,trans), 4-CH (cis)], 2.57–2.49 [1 H, m, H-3 (cis)],
2.38–2.30 (1 H, m) and 2.19–2.09 (1 H, m) [4-CH2 (trans)],
2.04–1.91 [1 H, m, 4-CH (cis)] and 2.0–1.8 (br s, OH).
(1 H, br s, H-1Ј), 2.85–2.65 (4 H, br s) and 2.4–2.3 (1 H, br s)
(2Ј-CH2, H-3Ј, 4Ј-CH2).
Acknowledgements
3-[3Ј-(Biphenyl-4Љ-yl)-1Ј,2Ј,3Ј,4Ј-tetrahydro-1Ј-naphthyl]-4-
hydroxychromen-2-one 1 (diphenacoum)
Financial support by the Foundation for Research Develop-
ment, Pretoria and the ‘Sentrale Navorsingsfonds’ of this Uni-
versity is gratefully acknowledged.
A mixture of the 4-hydroxycoumarin 16 (106 mg, 0.6532 mmol,
2 equiv.) and the tetralol 12 (98 mg, 0.3266 mmol) under an
HCl(g) atmosphere was heated at 160 ЊC for 30 min. Flash
chromatography (hexane–benzene–acetone, 6:3:1) of the mix-
ture afforded the title compound 1 (0.115 g, 78%; trans:cis,
3:2); trans-isomer: mp 213 ЊC (lit.,1 215–217 ЊC, mixture of
isomers); RF 0.26 (hexane–benzene–acetone, 6:3:1); νmax(liquid
References
1 R. S. Shadbolt and D. R. Woodward, J. Chem. Soc., Perkin Trans. 1,
1976, 1190.
2 M. R. T. Hadler and R. S. Shadbolt, G. P., 2424806, 1975.
3 M. R. T. Hadler and R. S. Shadbolt, USP, 3957824, 1976.
4 M. R. T. Hadler and R. S. Shadbolt, USP, 4035505, 1977.
5 I. O. Kim and S. G. Lee, UKP, 2210040, 1989.
6
film)/cmϪ1 1698 (C᎐O), 3022, 1425 and 1035; δ (C D ) 7.63
᎐
H
6
6
(1 H, dd, J 8 and 1.5, H-5), 7.52–7.48 (2 H, m, Ph), 7.4 (2 H, d,
J 8, Ph), 7.26–6.72 (12 H, m, Ph), 6.17 (br s, OH), 4.84 (1 H, dd,
J 6 and 2.5, H-1Ј), 3.10–2.99 (1 H, m, H-3Ј), 2.88–2.79 (1 H, m)
and 2.68–2.58 (1 H, m) (4Ј-CH2), 2.53–2.45 (1 H, m) and
2.18–2.06 (1 H, m) (2Ј-CH2); cis-isomer: mp 216 ЊC (lit.,1
215–217 ЊC, mixture of isomers); RF 0.13 (hexane–benzene–
acetone, 6:3:1); νmax(liquid film)/cmϪ1 1698 (C᎐O), 3022, 1425
᎐
and 1035; δH (C6D6) 7.72–7.62 (br s, OH), 7.54 (2 H, dd, J 8
and 1.5, H-5), 7.47 (2 H, d, J 8, Ph), 7.29–6.77 (13 H, m, Ph),
5.02–4.92 (1 H, br s, H-1Ј), 2.85–2.65 (4 H, br s) and 2.4–2.3
(1 H, br s) (2Ј-CH2, H-3Ј, 4Ј-CH2).
3-[3Ј-(4ٞ-Bromobiphenyl-4Љ-yl)-1Ј,2Ј,3Ј,4Ј-tetrahydro-1Ј-
naphthyl]-4-hydroxychromen-2-one 2 (brodifacoum)
A condensation similar to that described above between the
tetralol 13 (100 mg, 0.2638 mmol) and 4-hydroxycoumarin 16
(86 mg, 0.5276 mmol, 2 equiv.) at 160 ЊC for 30 min gave the
title compound 2 (0.103 g, 74%, trans:cis, 11:9); trans-isomer:
mp 224 ЊC (lit.,1 228–230 ЊC, mixture of isomers); RF 0.26
(hexane–benzene–acetone, 6:3:1); νmax(liquid film)/cmϪ1 1695
(C᎐O), 3016, 1422 and 1035; δ (C D ) 7.63 (1 H, dd, J 8 and
᎐
H
6
6
1.5, H-5Ј), 7.49 (1 H, dd, J 8 and 1.5, Ph), 7.39 (1 H, d, J 8,
Ph), 7.32 (2 H, d, J 8, H-3ٞ,5ٞ), 7.26–6.70 (11 H, m, Ph), 4.86–
4.81 (1 H, br s, H-1Ј), 3.10–2.99 (1 H, m, H-3Ј), 2.88–2.79 (1 H,
m) and 2.68–2.58 (1 H, m) (4Ј-CH2), 2.53–2.45 (1 H, m) and
2.18–2.06 (1 H, m) (2Ј-CH2); cis-isomer: mp 227 ЊC (lit.,1 228–
230 ЊC, mixture of isomers); RF 0.13 (hexane–benzene–acetone,
6:3:1); νmax(liquid film)/cmϪ1 1695 (C᎐O), 3016, 1422 and
᎐
1035; δH (C6D6) 7.66–7.63 (br s, OH), 7.54 (1 H, dd, J 8 and 1.5,
H-5Ј), 7.48 (1 H, d, J 8, Ph), 7.37–6.76 (14 H, m, Ph), 5.02–4.92
1146
J. Chem. Soc., Perkin Trans. 1, 1997