Synthesis and atropisomerism of 2,2′-ortho disubstituted biphenyls

Article abstract of DOI:10.1016/j.tetlet.2010.09.010

The role of substitution on the aromatic rings for the synthesis of 2:2 disubstituted biphenyls has been investigated. Atropisomerism involved in the above ring system has been studied using NMR spectroscopy. The outcome of inter and intramolecular Heck r

Full text of DOI:10.1016/j.tetlet.2010.09.010

Tetrahedron Letters 51 (2010) 6213–6215
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Tetrahedron Letters
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Synthesis and atropisomerism of 2,20-ortho disubstituted biphenyls
C. H. Wang a, , J. Reilly a, N. Brand a, S. Schwartz a, S. Alluri a, T. M. Chan b, A. V. Buevich b, A. K. Ganguly a,
⇑
⇑
a Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA
b Merck Research Laboratories, Kenilworth, NJ 07033-1300, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2010
Revised 1 September 2010
Accepted 3 September 2010
Available online 15 September 2010
The role of substitution on the aromatic rings for the synthesis of 2:2 disubstituted biphenyls has been
investigated. Atropisomerism involved in the above ring system has been studied using NMR spectros-
copy. The outcome of inter and intramolecular Heck reaction is discussed.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Radical cyclization
Atropisomerism
1. Introduction
Br
Recently1 we reported a novel synthesis of ortho–ortho disub-
stituted biphenyls represented by structure 1. Thus when com-
pound 2 was treated with TBTH in refluxing toluene solution it
yielded 1 as the major product along with a minor component 3
(Scheme 1). Intrigued by the complexity of the structure repre-
sented by compound 3 and the possibility of it being a novel phar-
macophore in drug discovery, we reinvestigated the above reaction
to determine whether we could change the proportion of 1 and 3 in
the above reaction either by changing the substrate or the reaction
condition. Thus we investigated the substitution effects on ring A
and B. In this Letter, we wish to report our findings and also dis-
close the outcome of the inter/intra molecular Heck reaction2 used
during the synthesis. We also wish to record atropisomerism
amongst a class of compounds reported in this Letter.
B
HN
O
A
N
2
H
H
H
N
NH
O
H
+
O
HN
N
H
3 (17.6%)
1 (70.6%)
Scheme 1.
Wethen investigatedthe effectof substitutions on ring B. Synthe-
sis of 2 involves addition of cinnamyl bromide in the presence of in-
dium to the imine 14. To prepare the B ring-substituted derivatives
represented by structures 15 and 16 (see Scheme 3), we needed a
good procedure for the preparation of substituted cinnamyl bro-
mides which proved to be unsatisfactory following several litera-
ture7 procedures for their synthesis. Perhaps the substituted
cinnamyl bromides were not very stable. We therefore studied
whether we could prepare 15 and 16 starting with 17. We were
aware that the outcome of this reaction could be complicated by
the competition involving intramolecular Heck reaction8 of 17 to
yield 18 and intermolecular Heck reaction9 when the reaction was
carried out in the presence of bromo substituted benzenes. To our
surprise the major product in the above reaction was the outcome
of the intermolecular reaction pathway. Thus compound 17 yielded
2 as the major product along with compound 18 (5%) as a minor
2. Present study
To study the effect of the substitution on ring A, we prepared3 8
and 9 starting with appropriately substituted isatins 4 and 5 and
following the sequence of steps4,5 involving 6 and 7 (see Scheme
2). Radical induced cyclization6 of 8 yielded 10 and 11. Similarly
9 yielded 12 and 13. From the yields obtained in these cases it ap-
pears that there is a trend of aromatic substitution effect in the
outcome of the radical reaction described above, however no gen-
eralization about it can be made with the limited number of exam-
ples studied.
⇑
Corresponding authors. Tel.: +1 201 216 5540; fax: +1 201 216 8240.
E-mail address: akganguly1@aol.com (A.K. Ganguly).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.010

6214
C. H. Wang et al. / Tetrahedron Letters 51 (2010) 6213–6215
H
In, NaI
Cinnamyl
bromide
H
H
Br
N
O
R
HN
R
2-bromoaniline
R
NH
N
Br
R
O
R
+
O
THF
TBTH,
AIBN
O
EtOH
reflux
N
H
HN
O
N
N
N
O
H
H
H
10 R = OCF3 (17.6%)
12 R = F (16%)
8 R = OCF3 (17.2%)
9 R = F (47%)
2 R = H (50%)
6 R = OCF3
7 R = F
14 R = H
11 R = OCF3 (41.2%)
13 R = F (42%)
4 R = OCF3
5 R = F
Scheme 2.
R1
R2
R1
R2
Br
Br
Dioxane:H2O
(3:1)
Pd(OAc)2
P(Ph)3, TEA
Br
HN
HN
HN
Pd(OAc)2
P(Ph)3, TEA
Dioxane:H2O
O
O
O
N
N
H
(3:1)
N
H
H
2
R1 = R2 = H (23.6%)
15 R1 = OCH3 ; R2 = H (25%)
TBTH
AIBN
17
18 (13.1%)
16 R1 = H ; R2 = OCH3 (26.7%)
H
H
N
H
R1
R2
R1
NH
+
R2
O
HN
N
O
19 R1 = OCH3 ; R2 = H (19%)
21 R1 = H ; R2 = OCH3 (24.4%)
20 R1 = OCH3 ; R2 = H (26.8%)
22 R1 = H ; R2 = OCH3 (48.7%)
H
Scheme 3.
R
N
N
O
N
N
R'
R'
O
23: R= R'= H
24: R= R'=-CH2-CH=CH2
26: R= -CH2-CH=CH2 ; R'=H
25: R'= -CH2-CH=CH2
30: R'= CH3
27: R= -CH2-CH=CH2 ; R'= CH3
28: R= -CH2-CH=CH2 ; R'= CH2Ph
29: R= -CH2-CH=CH2 ; R'= CH2Ph
31: R'= CH2Ph
32: R'= CH2Ph
Scheme 5.
closing metathesis without much success till we found out that the
treatment12 of 23 with allyl bromide in DMF solution without any
base yielded exclusively 26. This appears to be a general reaction
and could be very useful for the preparation of mono-substituted
anilines. Further work is in progress to determine the scope of this
reaction and will be published at a future date. Treatment of 26 in
DMF solution and methyl iodide in the presence of cesium carbonate
yielded 27 (77%). Similarly 26 when treated13 in DMF solution with
benzyl bromide and sodium iodide yielded 28 (50.9%) and 29
(23.5%). Structure elucidation of 28 and 29 was carried out by NMR
spectroscopy. 1D and 2D homonuclear COSY and NOESY and heter-
onuclear HSQC, HSQCTOCSY and HMBC experiments were per-
formed on a Varian INOVA 600 MHz spectrometer in CDCl3 at
25 °C. MMX force field calculations of 28 (29) structure (PCModel
software14) predicted the lowest energy conformations with a
boat-like eight-membered ring structure and the H3 proton in either
axial or equatorial orientation. Long-range NOE’s between the H3
and H15, between the H12 and H23 and between the H6 and H25
protons in 28 (shown as red arrows in Scheme 4) proved that the
Scheme 4.
component. We repeated the reaction of 17 with para-methoxy and
meta-methoxy bromobenzenes and obtained 16 and 15 also in mod-
est yield, respectively. Radical cyclization of 15 yielded 19 and 20
whereas 16 yielded 21 and 22. It would appear that para electron-
donating substitution has the desired effect for the formation of
the ring system represented by the structure 22.
In our earlier publication1, we also reported the conversion of 17
to 23usingradicalcyclizationprocess. Compound23whentreated10
in DMF solution with allyl bromide and cesium carbonate yielded
only the diallyl compound 24 (see Scheme 5) which underwent
ring-closing metathesis11 to yield 25, which was found to decom-
pose on standing at room temperature. We presumed that the allyl
group on the non-basic nitrogen atom contributed towards the
instability of the molecule. We tried a variety of reaction conditions
to selectively allylate the basic nitrogen which is needed for the ring-

C. H. Wang et al. / Tetrahedron Letters 51 (2010) 6213–6215
6215
3. NMR spectra were recorded with 400 MHz and/or 600 MHz spectrometers
using CDCl3 as solvent with TMS as an internal standard unless otherwise
stated. NMR and high resolution mass spectra of all the compounds described
in this letter were consistent with the assigned structures. Assignments were
further confirmed using 2D NMR and NOE experiments. The figures in
parenthesis in all the schemes represent yields in the reactions. It should be
noted that the yields reported in this letter are not optimised. The purity of the
compounds was established using various chromatographic techniques.
Compounds 10, 11, 15, 18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, and
32 were not crystalline. All other compounds described in the Letter were
crystalline. Crystals were obtained from DCM–hexane for compounds 2, 8, 9,
16, and 23 and from THF–hexane for compounds 12 and 13. The melting points
of compounds 2, 8, 9, 12, 13, 16, and 23 were 163–165, 139–141, 214–216,
108–110 (decomposes), >235, 199–200, and 179–181 °C, respectively.
4. Preparation of imine 6. A solution of 5-(trifluoro-methoxy)isatin (500 mg,
2.77 mmol) and 2-bromoaniline (372 mg, 2.77 mmol) in ethanol was refluxed
for 6 h. The mixture was evaporated to dryness and the product used for the
next step without purification.
5. Preparation of 8. To a solution of 6 (800 mg, 2.08 mmol) in DMF, indium
(238.6 mg, 2.08 mmol) and sodium iodide (467 mg, 3.12 mmol) were added. To
the stirred reaction mixture cinnamyl bromide (0.41 mL, 3.12 mmol) was
added dropwise. After completion of the reaction it was filtered and evaporated
to dryness. The crude reaction mixture was extracted with DCM, the organic
layer washed with water, dried over anhydrous sodium sulfate, filtered and
evaporated, followed by column chromatography to yield compound 8.
6. Example of radical cyclisation: Preparation of 10 and 11. To a solution of 8
(170 mg, 0.34 mmol) in toluene (30 mL), AIBN (11.1 mg, 0.07 mmol)) was
added. TBTH (0.10 mL, 0.37 mmol) was then added dropwise to the reaction
mixture which was then heated for 1 h at 110 °C at which point another
0.2 equiv of AIBN and 1.1 equiv of TBTH were added. The mixture was
evaporated to dryness followed by extraction with DCM. The organic layer was
washed with water, dried over anhydrous sodium sulfate and after evaporation
purified by column chromatography to obtain pure products.
7. (a) Firouzabadi, H.; Iranpoor, N.; Ebrahimzadeh, F. Tetrahedron Lett. 2006, 47,
1771–1775; (b) Yadav, V. K.; Babu, K. G. Tetrahedron 2003, 59, 9111–9116; (c)
Hajipour, A. R.; Falahatia, A. R.; Ruoho, A. E. Tetrahedron Lett. 2006, 47, 4191–
4196.
8. Example of intramolecular Heck reaction: Preparation of 18. To a solution of 17
(200 mg, 0.58 mmol) in CH3CN (9 mL) and water (3 mL), Pd(OAc)2 (6.54 mg,
0.03 mmol), PPh3(15.3 mg, 0.06 mmol) and triethylamine (0.10 mL, 2.56 mmol)
were added. The reaction mixture was refluxed for 24 h and then evaporated to
dryness, extracted with DCM and the organic layer washed with water, dried
over anhydrous sodium sulfate, filtered, evaporated, followed by column
chromatography to yield pure product.
9. Example of intermolecular Heck reaction: Preparation of 2. To a solution of 17
(300 mg, 0.87 mmol) in CH3CN (24 mL) and water (8 mL), Pd(OAc)2 (9.8 mg,
0.05 mmol) and PPh3(25.2 mg, 0.09 mmol) were added. The reaction mixture
was stirred under nitrogen to which triethylamine (0.14 mL, 0.96 mmol) and
bromobenzene (0.325 mL, 2.56 mmol) were added dropwise. The mixture was
refluxed for 2 days, evaporated to dryness and extracted with DCM. The organic
layer was washed with water, dried over anhydrous sodium sulfate, filtered,
evaporated, followed by column chromatography to yield compound 2.
10. Preparation of 24. To a solution of 23 (100 mg, 0.38 mmol) in DMF, cesium
carbonate (246.8 mg, 0.76 mmol), sodium iodide (114 mg, 0.76 mg), and allyl
bromide (0.08 mL, 0.84 mmol) were added. The reaction was refluxed for 3 h.
The mixture was filtered, evaporated to dryness and extracted with DCM.
Compound 24 was obtained using column chromatography of the crude
reaction mixture.
11. Example of ring closing metathesis: Preparation of 31. To a solution of 28
(127.9 mg, 0.32 mmol) in DCM, 1st generation Grubbs catalyst (13.3 mg,
0.02 mmol) was added. The reaction was refluxed for 2 h. The reaction mixture
was diluted with DCM and washed with water. The organic layer was dried
over anhydrous sodium sulfate, filtered, evaporated, and the crude product was
chromatographed to yield compound 31.
12. Preparation of 26. To a solution of 23 (300 mg, 1.14 mmol) in DMF, sodium
iodide (204.1 mg, 1.36 mmol) and allyl bromide (0.118 mL, 1.36 mmol) were
added. The reaction mixture was stirred at room temperature for one day. It
was evaporated to dryness and the residue extracted with DCM. The organic
layer was dried over anhydrous sodium sulfate, filtered and evaporated to
dryness. Purification by column chromatography yielded compound 26.
13. Preparation of 28 (29). To a solution of 26 (250 mg, 0.82 mmol) in DMF (7 mL),
cesium carbonate (321.1 mg, 0.99 mmol), sodium iodide (147.7 mg,
0.986 mmol), and benzyl bromide (0.12 mL, 0.99 mmol) were added. The
reaction mixture was stirred at room temperature over night, filtered,
evaporated and chromatographed to yield 28 (29).
Scheme 6.
H3 proton occupies an axial orientation relative to the eight-mem-
bered ring plane. In turn an equatorial orientation of the H3 proton
in 29 was confirmed by NOE’s between the H3 and H6 and between
the H15 and H25 protons. We have observed a slow overnight tran-
sition of 29 to 28 at 65 °C in toluene-d8. Since the rate of isomeriza-
tion was very slow even at 65 °C, 28 and 29 can be classified as
atropisomers. Atropoisomers are stereoisomers with a significantly
restricted rotation about a single bond which allows isolation of two
isomers (rotamers).15 Atropoisomersim is frequently observed in
biphenyl systems that have bulky substituents in ortho positions.15
In 28 and 29 a restricted rotation about the C10–C11 sp2–sp2 single
bond is caused by a rigid four-atom linker which connects two ortho
positions of the biphenyl subunit. Isomerization of 28 and 29 atrop-
isomers is a complex multistep process which we are currently
investigating. Results of this study will be published in the future.
Ring-closing metathesis11 of 27 yielded 30 (67%). Similarly 28
under ring-closing metathesis condition yielded 31 (75.8%) and
29 yielded 32(72%). Unlike 25 compounds 30, 31 and 32 were sta-
ble at room temperature.
Similar to 28 and 29, structure elucidation of 31 and 32 was car-
ried out by 1D and 2D NMR spectroscopy. Initially conformations
of 31 and 32 were generated from corresponding 3D structures
of 28 and 29. Then energy-minimized conformations of 31 and
32 were verified by long-range NOE’s. Thus, NOE’s between the
H3 and H15 and between the H6 and H25 protons in 31 (shown
as red arrows in Scheme 6) were consistent with predicted confor-
mation with an axial H3 proton, whereas NOE’s between the H15
and H25 and between the H3 and H6 protons in 32 were consistent
with the conformation in which the H3 proton occupies an equato-
rial orientation relative to the eight-membered ring.
Acknowledgements
We wish to thank Schering-Plough Research Institute (presently
Merck Research Laboratories), for generous financial assistance.
Three of us (J.R., N.B. and S.S.) would also like to thank Stevens Insti-
tute of Technology for the award of undergraduate fellowships.
References and notes
14. PCModel v. 8.5 Serena Software, Bloomington IN 47402-3076.
15. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds;
John Wiley and Sons, 1994. pp 1142–1145.
1. Wang, C. H.; Alluri, S.; Ganguly, A. K. Tetrahedron Lett. 2009, 50, 1879–1881.
2. (a) Rayabarapu, D. K.; Zhou, A.; Jeon, K. O.; Samarakoon, T.; Rolfe, A.; Siddiqui,
H.; Hanson, P. R. Tetrahedron 2009, 65, 3180–3188; (b) Majumdar, K. C.;
Chattopadhyay, B.; Ray, K. Tetrahedron Lett. 2007, 48, 7633–7636.