Weinreb amide based building blocks for convenient access to 1,1-diarylethenes and isocombretastatin analogues

Article abstract of DOI:10.1016/j.tetlet.2011.03.072

A successful strategy based on the synthetic equivalent containing Weinreb amide functionality for the convenient access to 1,1-diarylethenes in general and for the isocombretastatin analogues in particular has been developed from the commercially available glyoxalic acid. The convenience with which the structural variations can be made in assembling the aryl residues shows generality associated with the developed strategy. The intermediates also provide access to 1,2,2-triarylethanones, represented by the synthesis of advanced intermediate of tamoxifen.

Full text of DOI:10.1016/j.tetlet.2011.03.072

Tetrahedron Letters 52 (2011) 2683–2686
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Weinreb amide based building blocks for convenient access
to 1,1-diarylethenes and isocombretastatin analogues
⇑
Sivaraman Balasubramaniam, Harikrishna Kommidi, Indrapal Singh Aidhen
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A successful strategy based on the synthetic equivalent containing Weinreb amide functionality for the
convenient access to 1,1-diarylethenes in general and for the isocombretastatin analogues in particular
has been developed from the commercially available glyoxalic acid. The convenience with which the
structural variations can be made in assembling the aryl residues shows generality associated with
the developed strategy. The intermediates also provide access to 1,2,2-triarylethanones, represented by
the synthesis of advanced intermediate of tamoxifen.
Received 10 February 2011
Revised 10 March 2011
Accepted 15 March 2011
Available online 22 March 2011
Keywords:
Weinreb amide
Ó 2011 Elsevier Ltd. All rights reserved.
Grignard addition
1,1-Diarylethenes
Isocombretastatin analogues
Combretastatin 1, naturally occurring stilbenoids strongly inhi-
bit tubulin polymerization through binding to the colchicine site of
tubulin1 and have received much attention due to their simple
structures. The structure–activity relationships (SARs) have re-
vealed that Z-stilbene compounds display remarkable anticancer
activities over the E-isomers thus making the cis-orientation of
the two aromatic rings as one of the prerequisite for pronounced
biological activity.2 However, propensity of combretastatins and
other Z-stilbene analogues to isomerize, either during storage or
administration has initiated extensive search for cis-restricted ana-
logues.3 The structure–activity relationship studies revealing that
the replacing 1,2-ethylene bridge by 1,1-ethylene bridge between
the two aryl rings resulted in the retention of the biological activity
which has led to the emergence of a new synthetic analogue called
isocombretastain 2.4 It was further observed that the trimethoxy
phenyl ring is the most essential component for the activity asso-
ciated with isocombretastain 2 (Fig. 1).5,6 Freedom to vary aryl ring
B in isocombretastain has opened up wide possibility towards sev-
eral isocombretastain analogues 3.5,6 With the emergence of iso-
combretastatin 2 and its analogues 3 as promising class of
compounds, under the broad heading of 1,1-diarylethenes, syn-
thetic efforts towards them become necessary and justified. At
present juncture three routes are available in the literature for
their synthesis. These routes are based on palladium catalysed Bar-
luenga coupling of N-tosylhydrazone derived from acetophenone
with aryltriflates,7 Wittig olefination of di-aryl ketones5,6 and
dehydration in 1,1-diarylethanols as tertiary alcohols.6
The importance of isocombretastatin 2 and our continued inter-
est in developing and using the synthetic equivalents based on the
Weinreb amide (WA) functionality,8,9 attracted our attention. In
the conceived strategy for 3 as analogues of 2, the two aryl residues
were envisaged to be delivered as nucleophilic component, due to
Bridge
R
MeO
MeO
Bridge
B
Bridge
B
A
MeO
MeO
OH
MeO
MeO
A
A
B
R
OMe
OMe
OH
OMe
OMe
OMe
Combretastatin
CA-4: R= H
CA-1: R= OH
3
1
2 isocombretastatin
Figure 1. Structure of combretastain, isocombretastatin and novel isocombretastatin analogues.
⇑
Corresponding author. Fax: +91 44 22574202.
E-mail address: isingh@iitm.ac.in (I.S. Aidhen).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.072

2684
S. Balasubramaniam et al. / Tetrahedron Letters 52 (2011) 2683–2686
R1S
Ar1
SR2
Ar2
(70%), 8y (78%) and 8z (50%), respectively. Attempts were made to
SR2 Me
N
O
increase the yield of 8z by varying the reaction temperature and
also the mode of addition of the reactants. Much to our delight,
better yield of 68% was obtained by adding phenylmagnesium bro-
mide generated in THF to the solution of 4z in THF at ꢀ25 to
R1S
Ar1
Ar2
Ar1
Ar2
OMe
O
4
OH
6
7
5
: R1 = R2 = Et
x
y
ꢀ30 °C. The anticipated pronounced acidity of the
a-proton in
: R , R2 = -(CH2)2-
z: R1, R2 = -(CH2)3-
1
the ketones 8x–z made the subsequent addition of the second aryl-
magnesium halide onto the ketones challenging and interesting.
This was in the context that the Grignard reagent could either
act as a base or as a nucleophile. Initial attempts involving addition
of 2.5 equiv of p-methoxyphenylmagnesium bromide solution in
THF to a solution containing 8x, 8y and 8z in THF separately at
ꢀ5 to 0 °C revealed only 40–50% consumption of the ketones on
TLC. Substantial amounts of unreacted ketones were also observed
on TLC, even after 2 h of reaction period, indicating possible trap-
ping of the ketones as enolates, which refused any further reaction
with the available organometallics. The mild acidic work-up with
saturated ammonium chloride solution afforded the corresponding
tertiary alcohols 9x, 9y and 9z in 40–50% yields. However, to our
satisfaction, the reverse addition comprising of addition of the ke-
tones 8x, 8y and 8z independently to a solution of p-methoxyphe-
nylmagnesium bromide (2.5 equiv) in THF at temperature ranging
from 15 to 20 °C furnished the corresponding alcohols 9x, 9y and
9z in 76%, 80% and 78%, respectively, along with much reduced
quantities (10–15%) of ketones (Scheme 1).
Figure 2. New building blocks for the synthesis of a,
a0-diarylacetaldehyde and 1,1-
diarylethenes.
R1S
O
SR2
R1S
SR2
M
R1S
O
SR2
a
b
Me
N
OMe
MeO
c
4
8
x: R1 = R2 = Et
9: M = OH
10
y: R1, R2 = -(CH2)2-
: M =H
: R , R2 = -(CH2)3-
1
z
Scheme 1. Reagents and conditions: (a) For 4x and 4y: PhMgBr (2.5 equiv), THF, 0–
5 °C, 2 h, for 4z (reverse addition): PhMgBr (2.5 equiv), THF, ꢀ30 to ꢀ25 °C, 2 h, (8x:
70%; 8y: 78%; 8z: 68%); (b) p-OMePhMgBr (2.5 equiv), THF, 15–20 °C, 2 h, (9x: 76%;
9y: 80%; 9z: 78%); (c) triethylsilane (5 equiv), TFA (2.0 equiv), DCM (10 V), 0–5 °C,
2 h, 80% for 10y and 10z.
The recovery of ketones is not deleterious as they can be used in
the fresh batch of the same reaction to obtain the alcohols 9x–z or
with other arylmagnesium bromides. Having successfully obtained
the alcohols 9x-z, our next aim was to subject these alcohols to
deoxygenation and hydrolysis of the thioacetal moiety to arrive
convenient availability of ArMgX. Towards the needed electrophilic
synthetic equivalent representing the two carbons in ethylene
bridge, we banked on potential and promise of WA-based synthetic
equivalents. The increasing confidence in the use of WA function-
ality in industry on kilogram scale10 further justified its exploration
for a strategy towards synthesis of isocombretastatin analogues.
Glyoxalic acid derived WA-building blocks 4x–z were envisaged
for quick assembling of the aryl residues and subsequent transfor-
mation of the tertiary alcohol 5 to the targeted 1,1-diarylethenes 7
at a,
a0-diarylacetaldehyde 11. Tertiary alcohol 9x failed to furnish
the deoxygenated thioacetal 10x under Et3SiH/TFA conditions.
Even with the change in Lewis acid component (BF3Et2O, SnCl2)
and reaction conditions, TLC showed only degradation. We focused
our attention in evaluating the alcohols 9y and 9z towards the
same deoxygenation protocol. Indeed alcohols 9y and 9z under-
went clean deoxygenation with Et3SiH/TFA conditions at 0–5 °C
affording the corresponding alkanes 10y and 10z each in good
yields (80%). The attempted hydrolysis of the thioacetal moiety
in 10y and 10z also had contrasting behaviour. The compound
10y did not undergo hydrolysis and gave only the starting material
back under variety of thioketal de-protecting protocols available in
literature,13 whereas the compound 10z underwent clean hydroly-
sis using HgCl2/HgO in CH3CN/H2O mixture at 70 °C to yield 11.
This sharp contrasting behaviour between 10y and 10z raised some
doubts on the structural aspect of the compound 10y. Single crystal
X-ray diffraction data14 of the compound 10y, confirmed the struc-
through the intermediacy of
Incidently the present objective also had an inbuilt additional
a,
a0-diarylacetaldehydes 6 (Fig. 2).
incentive of paving a way for a new, simple and convenient route
for
important.11
a, 6 which are synthetically very
a0-diarylacetaldehydes
Glyoxalic acid as starting material furnished multi-gram quan-
tities of the proposed building blocks 4x–z in two simple steps.12
As a representative example and in an attempt to implement the
proposed strategy for 1,1-diarylethenes, the compounds 4x, 4y
and 4z were independently added to the preformed phenylmagne-
sium bromide in THF at 0–5 °C. Clean reaction ensued in each case
furnishing the corresponding ketones in good to modest yields, 8x
ture assigned to it. The
a,
a0-diarylacetaldehyde 11 obtained
M
SR2
R1S
O
b
a
MeO
MeO
MeO
12a
: M =OH
c
13a: M = OMs
10
11
y: R1, R2 = -(CH2)2-
z: R1, R2 = -(CH2)3-
d
MeO
7a
10y
Scheme 2. Reagents and conditions: (a) HgCl2 (3.0 equiv), HgO (3.0 equiv), ACN/H2O (3:1, 10 V), 70 °C, 3 h; (b) NaBH4 (1.1 equiv), MeOH (5 V), 0 °C, 1 h, 75% (2 steps); (c) (i)
MsCl (1.25 equiv), TEA (2.1 equiv), DCM (10 V), rt, 8 h; (ii) DBU (3.0 equiv), DCM (10 V), rt, 10 h, 70% (2 steps).

S. Balasubramaniam et al. / Tetrahedron Letters 52 (2011) 2683–2686
2685
Table 1
1,1-Diaryl ethenes 7a–c and isocombretastatin analogues 3a–d
HgCl2, HgO
AcN:H2O
70 oC, 2 h
OH
Ar2
Ar2MgBr
MsCl, TEA
DCM, 8 h
Ar1MgBr
S
S
15 oC, THF, 2h
S
S
Ar1
Ar2
Ar1
4z
Ar1
-25 o
C
H
Et3SiH
TFA, 0 oC, 2 h
DBU, DCM
10 h
THF, 2h
Ar2
NaBH4, MeOH
0 oC, 1 h
Ar1
O
14
7/3
12
10z, 15
Entry
1
Aryl ketone 14 (yield)
Dithiane 10Z, 15 (yield for 2 steps)
Alcohol 12 (yield for 2 steps)
12a (75%)
1,1-Diaryl ethenes 7/3 (yield for 2 steps)
OMe
S
S
S
)
S
7a (70%)
O
14a, (62%)
MeO
10
z, (63%
S
S
S
S
S
S
2
3
12b (74%)
12c (70%)
7b (66%)
7c (65%)
O
O
14b, (65%)
F
15b, (62%)
OMe
S
S
S
MeO
OMe
14c, (63%)
15c, (60%)
S
OMe
OMe
4
5
12d (70%)
12e (68%)
3a (64%)
3b (65%)
MeO
OMe
15d, (64%)
OMe
OMe
S
S
S
OMe
OMe
S
OMe
F
O
OMe
15e, (62%)
14d, (62%)
S
S
OMe
OMe
6
7
12f (72%)
12g (70%)
3c (68%)
3d (66%)
OMe
OMe
15f, (63%)
S
S
OMe
OMe
OMe
15g, (61%)
through the hydrolysis of 10z was passed through small filtration
column of silica-gel and subjected to reduction with NaBH4 imme-
diately. The primary alcohol 12a obtained in quantitative yield was
converted to the mesylate 13a and subjected to elimination reac-
tion under DBU conditions to furnish 1,1-diarylethenes 7a
(Scheme 2).
Having realized that amongst the three WA-based building
blocks 4x–z, proposed for arriving at 1,1-diarylethenes through a
new strategy, 4z was the most promising one. Further, successful
addition of various arylmagnesium bromide demonstrated the
generality associated with the developed new strategy to arrive
at 7, 1,1-diarylethenes class of compounds (Table 1). For the tar-
geted synthesis of isocombretastatin analogues, addition of 3,4,5-
trimethoxyarylmagnesium bromide, generated from 3,4,5-tri-
methoxybromo benzene which can be prepared in two steps from
commercially available 2,6-dimethoxy phenol using a literature
procedure,15 onto WA functionality 4z as one of the arylmagne-
sium bromide becomes imperative as this aryl residue is most cru-
cial for the biological activity. Successful formation of 3a, 3b, 3c
and 3d (Table 1) as isocombretastatin analogues, illustrates the
useful application of developed strategy for 1,1-diarylethene class
of compounds. All compounds exhibited satisfactory spectral and
analytical details.
Interestingly, a,
a0-diarylacetaldehyde 11 also served as a valu-
able intermediate for the synthesis of 1,2,2-triarylethanone 16,16
an advanced precursor for tamoxifen 17 which is a therapeutically

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S. Balasubramaniam et al. / Tetrahedron Letters 52 (2011) 2683–2686
OH
O
b
a
11
H
NMe2
OMe
OMe
O
17
16
18 [de 1:1]
Tamoxifen
Scheme 3. Reagents and conditions: (a) PhMgBr (1.2 equiv), THF, 0 °C, 1 h, 75%; (b) PCC (2.0 equiv), DCM (10 V), rt, 1 h, 80%.
2. (a) Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Schmidt, J. M.;
Hogan, F. J. Med. Chem. 1995, 38, 1666; (b) Pettit, G. R.; Toki, B. E.; Herald, D. L.;
Boyd, M. R.; Hamel, E.; Pettit, R. K.; Chapuis, J. C. J. Med. Chem. 1998, 41, 1688.
3. Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.; Genazzani, A. J. Med.
Chem. 2006, 49, 3033. and references cited therein.
4. Messaoudi, S.; Tréguier, B.; Hamze, A.; Provot, O.; Jean-Francois Peyrat, J.-F.; De
Losada, J. R.; Liu, J.-M.; Bignon, J.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.;
Brion, J.-D.; Alami, M. J. Med. Chem. 2009, 52, 4538.
5. Alvarez, R.; Alvarez, C.; Mollinedo, F.; Sierra, B. G.; Medarde, M.; Peláez, R.
Bioorg. Med. Chem. 2009, 17, 6422.
6. Hamze, A.; Giraud, A.; Messaoudi, S.; Provot, O.; Peyrat, J.-P.; Bignon, J.; Jian-
Miao Liu, J.-M.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Jean-Daniel Brion, J.-
D.; Alami, M. Chem. Med. Chem. 2009, 4, 1912.
used drug for the treatment of oestrogen dependent breast cancer
(Scheme 3). Addition of preformed phenylmagnesium bromide
onto the aldehyde 11 yielded the alcohol 18 in 75% (1:1 de). This
alcohol 18 upon oxidation under PCC (Pyridinium chlorochromate)
condition yielded the triaryl ethanone 16 in good yields of 80%. Gi-
ven the fact that 1,2,2-triarylethanones constitutes an important
class of compounds, this achievement further illustrates the poten-
tial of our new building block 4z for other synthetic endeavours.
In conclusion, amongst the building blocks 4x, 4y and 4z con-
ceived for the synthesis of 1,1-diarylethenes in general and iso-
combretastatin analogues in particular, 4z was found to be the
most useful. The developed strategy demonstrates the versatility
factor in assembling the aryl residues on the ethylene bridge. All
the reactions and conditions en-route synthesis of target molecule
are simple, good yielding and amenable for scale-up.
7. Tréguier, B.; Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M. Tetrahedron Lett. 2009,
50, 6549.
8. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815; For reviews on
Weinreb amide chemistry see: (a) Siva-raman, B.; Aidhen, I. S. Synthesis 2008,
3707; (b) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000, 342, 340;
(c) Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339, 517; (d) Sibi, M. P.
Org. Prep. Proc. Int. 1993, 25, 15.
9. (a) Sivaraman, B.; Aidhen, I. S. Eur. J. Org. Chem. 2010, 4991; (b) Harikrishna, K.;
Sivaraman, B.; Aidhen, I. S. Tetrahedron 2010, 66, 3723; (c) Sivaraman, B.;
Senthilmurugan, A.; Aidhen, I. S. Synlett 2007, 2841.
Acknowledgements
10. Urban, F. J.; Jasys, V. J. Org. Process Res. Dev. 2004, 8, 169.
The authors thank DST-New Delhi for the funding towards
400 MHz NMR machine to the Department of Chemistry, IIT-Ma-
dras under the IRHPA scheme and ESI-MS facility under the FIST
program. B.S.R. and K.H.K. are thankful to CSIR for a Fellowship.
11. (a) Sharma, A.; Sharma, N.; Kumar, R.; Sharma, U. K.; Sinha, A. K. Chem.
Commun. 2009, 5299; (b) Sørensen, U. S.; Bleisch, T. J.; Kingston, A. E.; Wright,
R. A.; Johnson, B. G.; Schoepp, D. D.; Ornstein, P. L. Bioorg. Med. Chem. 2003, 11,
197; (c) Pettit, G. R.; Lippert, J. W., III; Herald, D. L. J. Org. Chem. 2000, 65, 7438.
12. Synthesis of the compounds 4y and 4z and its usefulness for the synthesis of
mono-protected
a-diketones have been demonstrated by us earlier, see:
Sivaraman, B.; Aidhen, I. S. Synlett 2007, 959.
Supplementary data
13. For a review on reagents for the preparation and cleavage of 1,3-dithiolanes,
see: Banerjee, A. K.; Laya, M. S. Russ. Chem. Rev. 2000, 69, 947.
14. Crystal data for the dithiolane alkane 10y: Formula: C17 H18 O S2; unit cell
parameters: a = 9.4654 (4), b = 16.2625 (7), c = 10.1330 (4), b = 99.751 (2);
space group: P2(1)/c; CCDC number 810679.
15. Percec, V.; Holerca, M. N.; Nummelin, S.; Morrison, J. J.; Glodde, M.; Smidrkal, J.;
Peterca, M.; Rosen, B. M.; Uchida, S.; Balaguruswamy, V. S. K.; Sesinkowska, M.;
Heiney, P. A. Chem. Eur. J. 2006, 12, 6216.
Supplementary data (containing experimental procedure, spec-
tral details and 1H and 13C spectra for selected compounds is avail-
able) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.03.072.
16. (a) Churruca, F.; SanMartin, R.; Tellitu, I.; Domínguez, E. Org. Lett. 2002, 4, 1591.
and references cited therein; (b) Barluenga, J.; Escribano, M.; Moriel, P.; Aznar,
F.; Valdés, C. Chem. Eur. J. 2009, 15, 13291.
References and notes
1. Lin, C. M.; Ho, H. H.; Pettit, G. R.; Hamel, E. Biochemistry 1989, 28, 6984.