Acid-catalyzed ether rearrangement: Total synthesis of isomimosifoliol and (±)-dihydromimosifoliol

Article abstract of DOI:10.1080/00397911.2011.567882

An acid-catalyzed rearrangement of benzyl phenyl ethers to diphenylmethane derivatives, followed by salt formation and Hofmann elimination, is a simple method for the syntheses of isomimosifoliol and dihydromimosifoliol.

Full text of DOI:10.1080/00397911.2011.567882

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Acid-Catalyzed Ether Rearrangement:
Total Synthesis of Isomimosifoliol and
(±)-Dihydromimosifoliol
Veera Reddy Arava a , Sashibhushan Malreddy a & Sreenivasulu Reddy
Thummala b
a Research and Development Laboratories, Suven Life Sciences Ltd.,
Hyderabad, India
b Department of Chemistry, S. K. University, Anantapur, India
Accepted author version posted online: 02 Jan 2012.Version of
record first published: 20 Aug 2012.
To cite this article: Veera Reddy Arava , Sashibhushan Malreddy & Sreenivasulu Reddy Thummala
(2012): Acid-Catalyzed Ether Rearrangement: Total Synthesis of Isomimosifoliol and (±)-
Dihydromimosifoliol, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:24, 3545-3552
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Synthetic Communications1, 42: 3545–3552, 2012
Copyright # Suven Life Sciences Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.567882
ACID-CATALYZED ETHER REARRANGEMENT: TOTAL
SYNTHESIS OF ISOMIMOSIFOLIOL AND
(ꢀ)-DIHYDROMIMOSIFOLIOL
Veera Reddy Arava,1 Sashibhushan Malreddy,1 and
Sreenivasulu Reddy Thummala2
1Research and Development Laboratories, Suven Life Sciences Ltd.,
Hyderabad, India
2Department of Chemistry, S. K. University, Anantapur, India
GRAPHICAL ABSTRACT
Abstract An acid-catalyzed rearrangement of benzyl phenyl ethers to diphenylmethane deri-
vatives, followed by salt formation and Hofmann elimination, is a simple method for the
syntheses of isomimosifoliol and dihydromimosifoliol.
Keywords Benzyl phenyl ethers; ether rearrangement; Hofmann elimination; tetraalkyl-
ammonium salts
INTRODUCTION
(þ)-Mimosifoliol (1) was recently isolated by Wall et al.[1] from the root of
Aeschynomene mimosifolia Vatke (Leguminosae) along with (þ)-mimosifolenone
(2). Mimosifoliol (1) demonstrated weak activity in a DNA strand scission assay.
A concentration of 25 mg=ml of 1 was approximately equal in activity to 0.1 mg=ml
of bleomycin sulfate. Despite its activity in the assay, (þ)-mimosifoliol (1) proved
to be inactive against several human cancer cell lines. We herein report a total syn-
thesis of isomimosifoliol in a new route developed by our group.
We have recently observed a novel acid-catalyzed rearrangement on ethers
during the investigation of duloxetine[2] as shown in Scheme 1.
Using this novel rearrangement as a key step, we have synthesized tolterodine
in good yields[3] as shown in Scheme 2.
Received December 18, 2010.
Address correspondence to Veera Reddy Arava, R&D Laboratories, Suven Life Sciences Ltd.,
#18, Phase-III, Jeedimetla, Hyderabad 500 055, India. E-mail: reddyvenis@rediffmail.com
3545

3546
V. R. ARAVA, S. MALREDDY, AND S. R. THUMMALA
Scheme 1. Novel ether rearrangement in duloxetine.
Scheme 2. Key rearrangement step in tolterodine.
Scheme 3. Pettus strategy.
The first synthesis of mimosifoliol by Pettus used o-quinone methide intermedi-
ate strategy with protection and deportation of the phenolic group[4] as shown in
Scheme 3.
The second synthesis by Toste et al. utilized rhenium-catalyzed aromatic
propargylation as a key step without protection of phenols[5] as shown in Scheme 4.

ISOMIMOSIFOLIOL AND (ꢀ)-DIHYDROMIMOSIFOLIOL
3547
Scheme 4. Toste methodology.
RESULTS AND DISCUSSION
In our quest to develop a general methodology for derivatives and analogs of
mimosifoliol (1), we adopted our recent acid-catalyzed rearrangement method[2] as
shown in Scheme 1.
Mannich adduct of acetophenone was reduced with sodium borohydride to
give alcohol (3). Alcohol was reacted with 2,5-dimethoxy fluorobenzene to give an
ether product (4). The ether (4) was rearranged in perchloric acid to give phenols
5a and 5b. The compounds 4, 5a, and 5b were characterized by their spectral data
and microelemental analysis. Compounds 5a and 5b were reacted with methyl iodide
to give quaternary salts 6a and 6b as shown in Scheme 5.
The salt (6a) was characterized by its characteristic spectral data. The quatern-
ary salt was subjected to Hofmann elimination conditions to get mimosifoliol (1) as
shown in Scheme 6.
During Hofmann elimination with butyl lithium, it was observed that
along with a minor dl-mimosifoliol, a major isomimosifoliol (7) was also formed.
Isomimosifoliol (7) was characterized thoroughly and also converted into
(ꢀ)-dihydromimosifoliol (8) by hydrogenation. Both compounds were characterized
by spectral data and microelemental analysis.
During the rearrangement of ether (4), the o-isomer (5b) was also formed (20%)
along with the p-isomer (5a) (45%). The product 5b was reacted with methyl iodide
and the formed salt 6b was subjected to Hofmann elimination under 1,8-diazabicyclo
[5.4.0]under-7-ese (DBU)=toluene-isopropyl alcohol (IPA) reflux conditions to give
5,8-dimethoxy-4-phenyl-chroman (or dl-cyclomimosifoliol) (9) as shown in
Scheme 7, which has been characterized thoroughly.
EXPERIMENTAL
1H and 13C NMR spectra were recorded using a Bruker 400 spectrophotometer
(400 and 100 MHz respectively) with tetramethylsilane (TMS) as internal standard.

3548
V. R. ARAVA, S. MALREDDY, AND S. R. THUMMALA
Scheme 5. Preparation of diphenyl quaternary ammonium derivatives 6a and 6b.
Scheme 6. Hofmann elimination product of 6a.
Scheme 7. Hofmann elimination product of 6b.

ISOMIMOSIFOLIOL AND (ꢀ)-DIHYDROMIMOSIFOLIOL
3549
Infrared (IR) spectra were recorded on a Perkin-Elmer spectrophotometer as KBr
pellets or neat. Analytical thin-layer chromatography (TLC) was conducted on
E-Merck 60F254 aluminum-backed silica-gel plates (0.2 mm). Developed plates were
visualized using ultraviolet (UV) light or iodine chamber. High-performance liquid
chromatographic (HPLC) spectra were recorded on a Shimadzu 2010 instrument.
Preparation of 3-Dimethylamino-1-phenyl-propan-1-ol (3)
3-Dimethylamino-1-phenyl propan-1-one hydrochloride (70.0 g, 0.328 mol)
was dissolved in methanol (350.0 mL) and cooled to 10–15 ꢁC. Sodium borohydride
solution [12.48 g, 0.329 mol (sodium borohydride dissolved in 130.0 mL of 10% aque-
ous NaOH solution)] was added over 30 min and the reaction mass was stirred for 3
h. Reaction progress was monitored by TLC, and after completion of the reaction,
solvent was evaporated under vacuum below 60 ꢁC to get the crude alcohol. The
crude product was dissolved in ethyl acetate and washed with water (2 ꢂ 500.0 mL).
The organic layer was dried over anhydrous sodium sulfate, and concentration of
solvent under vacuum gave a colorless liquid (54.0 g, yield: 92%).
1
IR (neat, cmꢃ1): 3747, 3350, 2824, 1463, 515; H NMR (400 MHz, CDCl3): d
7.39 (m, 4H), 7.24 (t, 1H, J ¼ 7.08 Hz), 5.26 (s, 1H), 4.94 (q, 1H, J ¼ 4.12 Hz), 2.63
(m, 1H), 2.43 (m, 1H), 2.29 (s, 6H), 1.84 (m, 2H); 13C NMR (100 MHz, CDCl3): d
145.09, 128.09, 126.76, 125.49, 75.49, 58.24, 45.23, 34.55; ESI-MS (þVe mode):
m=z (%) ¼ 181.03 [M þ 2]; Purity by HPLC: 99.92%.
Preparation of [3-(2,5-Dimethoxy-
phenoxy)3-phenylpropyl]dimethylamine (4)
Sodium hydride (15.64 g, 60%, 0.391 mol) was added to a solution of
3-dimethylamino-1-phenyl propan-1-ol (50.0 g, 0.279 mol) in dimethyl sulfoxide
(250.0 mL) and stirred for 30 min at rt. 2,5-Dimethoxy-1-fluorobenzene (52.34 g,
0.335 mol) was added to the reaction mass, heated to 135–140 ꢁC, and stirred for
4 h. Reaction progress was monitored by TLC, and after completion of the reaction,
the mass was cooled to rt. Water (300.0 mL) was added, and the product was
extracted into toluene (2 ꢂ 250.0 mL). The toluene layer was washed with saturated
brine solution (2 ꢂ 100.0 mL) followed by water (100.0 mL). The toluene layer was
dried over anhydrous sodium sulfate and concentrated under vacuum at <70 ꢁC
to get the crude product (87.5 g). The obtained crude was dissolved in ethyl acetate
(200.0 mL) and 30.0 g of 85% o-phosphoric acid was added drop wise at (25–30 ꢁC).
After the addition, the reaction mixture was stirred for 30 min, cooled to 10–15 ꢁC,
and stirred for 1 h. The slurry was then filtered and the solids were washed with
50.0 mL of cold ethyl acetate (10–15 ꢁC). The solid was stirred in a mixture of
50.0 mL dichloromethane and 100.0 mL of water at 25–30 ꢁC, and 90.0 mL of 30%
aqueous ammonium hydroxide solution was added. The reaction mixture was stirred
for 10 min at 25–30 ꢁC, and the layers were separated. The organic layer was washed
with water (50.0 mL ꢂ 2) and dried over anhydrous sodium sulfate. The solution was
concentrated at 35–40 ꢁC to get solid material (55.0 g, yield: 63%).
IR (KBr, cmꢃ1): 3433, 2946, 1690, 1878, 1609, 1509, 1460, 1231, 1162, 762;
1H NMR (400 MHz, CDCl3): d 7.39 (d, 2H, J ¼ 7.3 Hz), 7.31 (t, 2H, J ¼ 7.3 Hz),

3550
V. R. ARAVA, S. MALREDDY, AND S. R. THUMMALA
7.25 (t, 2H, J ¼ 7.22 Hz), 6.78 (d, 1H, J ¼ 8.7 Hz), 6.39 (d, 1H, J ¼ 2.7 Hz), 6.35 (dd,
1H, J1 ¼ 8.6, J2 ¼ 2.8 Hz), 5.24 (t, 1H, J ¼ 5.6 Hz), 3.83 (s, 3H), 3.50 (s, 3H), 2.46
(t, 2H, J ¼ 7.2 Hz), 2.30 (m, 1H), 2.23 (s, 6H), 2.03 (m, 1H); 13C NMR (100 MHz,
CDCl3): d 153.93, 148.66, 144.32, 141.72, 128.42, 127.47, 126.03, 113.27, 104.26,
104.15, 56.93, 55.75, 55.32, 45.39, 36.40; ESI-MS (þVe mode): m=z (%) ¼ 316.3
[M þ 1]; DSC: 57.62 ꢁC; Purity by HPLC: 99.95%. Anal. calcd. for C19H25NO3
(315.40): C, 72.35; H, 7.99; N, 4.44. Found: C, 72.0961; H, 7.8667; N, 4.7088.
Preparation of 4-(3-Dimethylamino-1-phenyl-propyl)2,5-
dimethoxy-phenol (5)
To a solution of [3-(2,5-dimethoxy-phenoxy)3-phenyl-propyl]-dimethylamine 4
(60.0 g, 0.19 mol) in dichloromethane (400.0 mL) was added 100.0 mL of perchloric
acid (71–73%) at 0–5 ꢁC. The reaction mixture was stirred for 3 h at 0–5 ꢁC, and
the reaction progress was monitored by TLC. After the staring material disappeared
ice water was added to the reaction mixture and basified (pH 9–10) with aqueous
ammonium hydroxide solution. The reaction mixture was stirred for 30 min, and
the layers were separated. The aqueous layer was extracted with dichloromethane
(2 ꢂ 100.0 mL). Combined organic layers were washed with water (2 ꢂ 100.0 mL)
and dried over anhydrous sodium sulfate. The solvent was evaporated at 40 ꢁC to
get 40.0 g of crude material. The crude product mixture was separated using column
chromatography. Three compounds, para-isomer (5a, 45%), ortho-isomer (5b, 22%),
and 2,5-dimethoxy phenol (5.0 g, 10%), were isolated and characterized as follows.
Para-isomer (5a). IR (KBr, cmꢃ1): 2830, 2477, 1587, 1466, 1199, 1041, 787;
1H NMR (400 MHz, CDCl3): d 10.09 (s, 1H), 7.26 (m, 5H), 6.72 (s, 1H), 6.50
(s, 1H), 4.35 (t, 1H, J ¼ 7.6 Hz), 3.77 (s, 3H), 3.69 (s, 3H), 2.27 (m, 2H), 2.19
(s, 6H), 2.14 (m, 2H); 13C NMR (100 MHz, CDCl3): d 151.43, 144.98, 144.75,
140.67, 128.09, 127.77, 125.70, 123.67, 111.03, 99.94, 45.21, 40.90, 32.69; ESI-MS
(þVe mode): m=z (%) ¼ 316.30 [M þ 1]; DSC: 139.03 ꢁC; Purity by HPLC: >99%.
Anal. calcd. for C19H25NO3 (315.40): C, 72.35; H, 7.99; N, 4.44. Found: C,
71.9882; H, 8.2287; N, 4.9499.
Ortho-isomer (5b). IR (KBr, cmꢃ1): 2936, 2860, 2775, 1597, 1480, 1359,
1
1244, 1151, 1094, 701; H NMR (400 MHz, CDCl3): d 11.0 (s, 1H), 7.26 (m, 5H),
6.70 (d, 1H, J ¼ 8.7 Hz), 6.26 (d, 1H, J ¼ 7.8 Hz), 4.55 (t, 1H, J ¼ 9.0 Hz), 3.86
(s, 3H), 3.20 (s, 3H), 2.43 (m, 4H), 2.37 (s, 6H); 13C NMR (100 MHz, CDCl3): d
151.43, 144.97, 144.67, 140.60, 128.09, 127.77, 125.69, 123.74, 111.00, 99.86, 58.16,
56.47, 56.02, 45.35, 40.90, 32.75; ESI-MS (þVe mode): m=z (%) ¼ 316.30 [M þ 1];
DSC: 118.31 ꢁC; Purity by HPLC: >95%. Anal. calcd. for C19H25NO3 (315.40): C,
72.35; H, 7.99; N, 4.44. Found: C, 72.1818; H, 8.1739; N, 4.6845.
Quaternary Salt Preparation of 4-(3-Dimethylamino-
1-phenyl-propyl)-2,5-dimethoxy-phenol with Methyl Iodide (6a)
To a solution of 4-(3-dimethylamino-1-phenyl-propyl)-2,5-dimethoxy-phenol
5a (8.0 g, 0.025 mol) in dichloromethane (100.0 mL) was added methyl iodide
(4.50 g, 0.0317 mol). The reaction mixture was stirred for 1 h at rt, and the reaction

ISOMIMOSIFOLIOL AND (ꢀ)-DIHYDROMIMOSIFOLIOL
3551
progress was monitored by TLC. After the disappearance of starting material,
the salt was filtered from the reaction mixture, and the cake was washed with
dichloromethane (20.0 mL) to get a white compound (10.62 g, yield: 92%).
IR (KBr) (cmꢃ1): 3231, 1521, 1452, 1209, 730, 481; 1H NMR (400 MHz,
CDCl3): d 8.96 (s, 1H), 7.33 (m, 4H), 7.17 (t, 1H, J ¼ 7.1 Hz), 6.94 (s, 1H), 6.45
(s, 1H), 4.22 (t, 1H, J ¼ 7.6 Hz), 3.72 (s, 3H), 3.64 (s, 3H), 3.18 (m, 2H), 3.0
(s, 9H), 2.5 (m, 2H); 13C NMR (100 MHz, CDCl3): d 151.29, 146.36, 144.49,
141.91, 128.69, 127.90, 126.48, 121.03, 113.21, 101.15, 64.96, 57.34, 56.52, 52.61,
27.39; ESI-MS (þVe mode): m=z (%) ¼ 330.02 [M ꢃ I]. Melting point:
262.2–263.5 ꢁC.
Preparation of Isomimosifoliol (7)
The quaternary salt 6a (6.0 g, 0.013 mol) was suspended in tetrahydrofuran
(THF), and the reaction mass was cooled to 0–5 ꢁC. n-Butyl lithium in hexane
(1.6 M, 36.0 mL) was added over a period of 15 min at 0–5 ꢁC, and slowly the reac-
tion mixture temperature was raised to 25–30 ꢁC over a period of 1 h. It was stirred
for 1 h at rt, and the reaction progress was monitored by TLC. After the starting
material disappeared, ice water was added to the reaction mixture. The product
was extracted with ethyl acetate (4 ꢂ 25.0 mL) and dried over anhydrous sodium sul-
fate. The combined organic layer was concentrated at 60 ꢁC to get a light yellow
material (4.0 g).
GC-MS of crude sample shows 31% of mimosifoliol 1 and 35% of isomimosi-
foliol 7.
Pure product was isolated from the crude mixture by column chromatography
eluting with hexane and ethyl acetate (9:1) and recrystallized two times with methy-
lenechloride and hexane mixture as solvent to get pure isomimosifoliol 7. (We could
not isolate mimosifoliol in pure form; it always was mixture of 1 and 7).
IR (KBr, cmꢃ1): 3519, 2938, 2914, 2840, 2025, 1630, 1598, 1509, 1416, 1296,
1
1216, 1037, 655; H NMR (400 MHz, CDCl3): d 7.27 (m, 5H), 6.66 (s, 1H), 6.58
(s, 1H), 6.29 (q, 1H, J ¼ 6.8 Hz), 5.65 (s, 1H), 3.81 (s, 3H), 3.65 (s, 3H), 1.68
(d, 3H, J ¼ 6.8 Hz); 13C NMR (100 MHz, CDCl3): d 151.81, 145.39, 142.14,
140.31, 138.30, 127.95, 126.38, 126.10, 124.93, 119.38, 113.95, 99.84, 56.53, 56.25,
15.63; ESI-MS (þVe mode): m=z (%) ¼ 271.32 [M þ 1]; melting point:
101.2–104.4 ꢁC; GC-MS: 99.28%. Anal. calcd. for C17H18O3 (270.32): C, 75.53; H,
6.71. Found: C, 75.6458; H, 6.8322.
Preparation of Dihydromimosifoliol (8)
To a solution of isomimosifoliol 7 (75.0 mg, 0.277 mmol) in methanol was
added 5% Pd=C (wet, 10.0 mg) in an autoclave. It was hydrogenated at 50 psi for
2 h at 35–40 ꢁC. The reaction progress was monitored by TLC. After the starting
material disappeared, the reaction mass was cooled to rt, filtered through a celite
bed, and concentrated under vacuum at <60 ꢁC to get the crude product. The pro-
duct was separated by column chromatography and after bulb-to-bulb distillation
gave an off-white solid (47.5 mg, yield: 63%).

3552
V. R. ARAVA, S. MALREDDY, AND S. R. THUMMALA
REFERENCES
1. Fullas, F.; Kornberg, L. J.; Wani, M. C.; Wall, M. E.; Farnsworth, N. R.; Chagwedera,
T. E.; Kingharm, A. D. J. Nat. Prod. 1996, 59, 190–192.
2. Reddy, A. V.; Rao, S. B. U.; Reddy, B. S. Ind. J. Chem. 2007, 46B, 1695–1698.
3. Reddy, A. V.; Reddy, B. S.; Malreddy, S.; Golla, N. Synth. Commun. 2011, 41, 1565–1571.
4. (a) Tuttle, K.; Rodringnez, A. A.; Pettus, T. R. R. Synlett. 2003, 2234–2236; (b) Selenski,
C.; Pettus, T. R. R. J. Org. Chem. 2004, 69, 9196–9203; (c) Selenski, C.; Mejorado, L. H.;
Pettus, T. R. R. Synlett 2004, 1101–1103.
5. Kennedy-Smith, J. J.; Young, L. A.; Toste, F. D. Org. Lett. 2004, 6, 1325–1327.