Synthesis of the potassium channel opener (3S,4R)-3,4-dihydro-4-(2,3- dihydro-2-methyl-3-oxo-pyridazin-6-yl)oxy-3-hydroxy-6-(3-hydroxyphenyl) sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran

Article abstract of DOI:10.1080/00397910701557531

The preparation of the potassium channel opener (3S,4R)-3,4-dihydro-4-(2,3- dihydro-2-methyl-3-oxo-pyridazin-6-yl)oxy-3-hydroxy-6-(3-hydroxyphenyl) sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (1) as a single enantiomer is reported. Considerable improvement

Full text of DOI:10.1080/00397910701557531

This article was downloaded by: [Stony Brook University]
On: 28 October 2014, At: 11:33
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of the Potassium Channel Opener
(3S,4R)‐3,4‐Dihydro‐4‐(2,3‐dihydro‐2‐methyl‐3‐ox
Javier Magano a , Allison Acciacca a , Vladimir Beylin a , Julie Spence a ,
Peter Dunn b & Mike Hughes b
a Pfizer Global Research and Development , Michigan, USA
b Pfizer Global Research and Development , Sandwich, United Kingdom
Published online: 05 Oct 2007.
To cite this article: Javier Magano , Allison Acciacca , Vladimir Beylin , Julie Spence ,
Peter Dunn & Mike Hughes (2007) Synthesis of the Potassium Channel Opener
(3S,4R)‐3,4‐Dihydro‐4‐(2,3‐dihydro‐2‐methyl‐3‐oxo‐pyridazin‐6‐Yl)oxy‐3‐hydroxy‐6‐(3‐hydroxyphenyl)sulphonyl‐2,2,3
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
37:20, 3569-3578, DOI: 10.1080/00397910701557531
To link to this article: http://dx.doi.org/10.1080/00397910701557531
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 37: 3569–3578, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701557531
Synthesis of the Potassium Channel Opener
(3S,4R)-3,4-Dihydro-4-(2,3-dihydro-2-
methyl-3-oxo-pyridazin-6-Yl)oxy-3-
hydroxy-6-(3-hydroxyphenyl)sulphonyl-
2,2,3-trimethyl-2H-benzo[b]pyran
Javier Magano, Allison Acciacca, Vladimir Beylin, and
Julie Spence
Pfizer Global Research and Development, Michigan, USA
Peter Dunn and Mike Hughes
Pfizer Global Research and Development, Sandwich, United Kingdom
Abstract: The preparation of the potassium channel opener (3S,4R)-3,4-dihydro-4-
(2,3-dihydro-2-methyl-3-oxo-pyridazin-6-yl)oxy-3-hydroxy-6-(3-hydroxyphenyl)sul-
phonyl-2,2,3-trimethyl-2H-benzo[b]pyran (1) as a single enantiomer is reported. Con-
siderable improvements have been implemented with respect to the original synthesis
that allow for the preparation of multigram quantities of the final target compound. The
optimized synthesis consists of a six-step linear sequence whose key step is an asym-
metric epoxidation protocol through the use of Jacobsen’s (S,S)-(þ)-N,N0-bis(3,5-di-
tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride catalyst.
Keywords: asymmetric epoxidation, 6-(hydroxyphenyl)sulphonylbenzo[b]pyran,
potassium channel opener, smooth muscle relaxant activity
Received in the USA March 30, 2007
Address correspondence to Javier Magano, Pfizer Global Research and Develop-
ment, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. E-mail: javier.magano@
pfizer.com
3569

3570
J. Magano et al.
INTRODUCTION
6-(Hydroxyphenyl)sulphonylbenzo[b]pyran derivatives display smooth muscle
relaxant activity by a mechanism that involves potassium channel opening.[1]
They are therefore used in the treatment of conditions related to the altered
tone and/or motility of smooth muscle, which can occur in the lung, bladder,
gut, uterus, and cardiovascular system. Such conditions include chronic obstruc-
tive airways disease, asthma, urinary incontinence, irritable bowel syndrome,
diverticular disease, oesophageal achalasia, and hypertension. Additionally,
this family of compounds may be useful in the treatment of peripheral
vascular disease, congestive heart failure, pulmonary hypertension, myocardial
and cerebral ischaemia, angina, male pattern baldness, cardiac arrhythmia,
skeletal muscle fatigue/paralysis (myotonic muscular dystrophy), glaucoma,
epilepsy, tinnitus, vertigo, and dysmenorrhoea.
DISCUSSION
Compound 1 is a potent potassium channel opener that was developed in our
laboratories and whose original synthesis is shown in Scheme 1. Friedel–Craft
Scheme 1. Original synthesis of compound 1.

Potassium Channel Opener Benzopyran
3571
acylation of 4-bromoanisole (2) with propionyl chloride (3) in the presence of
AlCl3 in refluxing CH2Cl2 for 3 days afforded hydroxyketone 4, which was
converted to chromanone 5 in a mixture of acetone/xylenes with piperidine
as base. This reaction was very sluggish and did not go to completion even
after several days at reflux. Acetone/N,N-dimethylformamide (DMF)/piper-
idine at 808C gave complete conversion after 2 days with yields around 90%.
Chromanone 5 was then reduced with NaBH4 in methanol and, after
quenching with water and extracting the resulting alcohol 6 from the
aqueous phase with toluene, it was treated with p-toluenesulfonic acid to
give alkene 7 in quantitative yield. The coupling of 7 with 3-methoxythiophe-
nol (8) in the presence of Pd(Ph3P)4 and NaOt-Bu in degassed ethanol at reflux
provided methylether 9.[2] Demethylation was effected with LiI in 2,4,6-
collidine at 1608C to give phenol 10.[3] Reprotection of the hydroxy group
with tert-butyldimethylsilyl chloride (TBDMSCl) followed by asymmetric
epoxidation using Jacobsen’s catalyst (S,S)-(þ)-N,N0-bis(3,5-di-tert-butylsali-
cylidene)-1,2-cyclohexanediaminomanganese(III) chloride and 4-methylpyri-
dine-N-oxide in a biphasic mixture of aqueous NaClO and CH2Cl2 gave
epoxisulfone 13.[4] The reaction of 13 with 3 equivalents of 1-methyl-3,6-
(1H,2H)-pyridazinedione (14) in refluxing isopropyl alcohol (IPA) for 48 h
afforded crude 1.[5] Purification by flash chromatography and recrystallization
from pentane/ethanol gave compound 1 as a white solid.
The synthesis consisted of nine linear steps with a 16% overall yield. Sig-
nificantly, there was no need for purification of the intermediates, which was a
major advantage for any future scale-up work. On the other hand, the disad-
vantages of this route were that all the intermediates, except for 4 and 13,
were high-boiling oils, which made their purification by distillation difficult
or impossible, and second, the last step required extensive purification.
An additional concern was methylether 9 deprotection, which, in some
cases, gave incomplete conversion even after the addition of a very large
excess of LiI.
A small-scale laboratory study of the chemistry revealed that a shorter or
more convergent synthesis was necessary to viably scaleup the chemistry and
that there was a need to simplify the purification process for the last step. To
accomplish this, we first turned our attention to the synthesis of chromene 7. A
review of the literature revealed that chromenes such as 7 had either an ester or
a keto group at the 3-position,[6] but the examples with alkyl groups were
scarce, and their preparation required several steps.[7] However, one article
was finally found where it was reported that the synthesis of 3-alkyl
chromenes could be performed in one step starting from salicylaldehydes
and chlorobutanes in the presence of ZnCl2.[8]
The new synthetic route (Scheme 2) started with the reaction between
5-bromosalicylaldehyde (15) and 2-chloro-2-methylbutane (16) in the
presence of ZnCl2 in refluxing CHCl3 to give bromochromene 7 in 100%
yield by mass and 90% purity by gas chromatography (GC) analysis.
Attempts to distill this intermediate at high vacuum resulted in considerable

3572
J. Magano et al.
Scheme 2. Improved synthetic route for the preparation of 1.
decomposition. Crude 7 was then treated as before with 3-methoxythiophenol
(8) in the presence of Pd(Ph3P)4 and NaOt-Bu in refluxing ethanol. This gave
rise to a crude methylether 9 that showed purity satisfactory for use without
any further manipulations in the next step.
The harsh reaction conditions employed to demethylate 9 and the cost of
LiI (up to 6 equivalents used) forced us to look for an alternative methodology.
Attempts to accomplish this transformation through the use of AlCl3/EtSH,[9]
BBr3,[10] or Cl3MeSi/NaI[11] failed, giving either decomposition or incom-
plete reaction. However, it was discovered that a combination of either NaH
or KOt-Bu and EtSH in refluxing N,N-dimethylformamide (DMF) for 1 h
gave complete conversion to 10 in good yield and purity. Crude phenol 10
was reprotected with TBDMSCl/imidazole in DMF to give intermediate 11,
which was purified at this point by passing it through a short silica-gel pad
to remove some highly polar impurities. Alkene 11 was then asymmetrically
epoxidized, and the sulfide group oxidized to the sulfone following the pre-
viously tested method. The use of commercial bleach had no detrimental
effect on the enantiomeric excess of the epoxidation and was considerably
cheaper. Also, the use of 4-methylpyridine-N-oxide was crucial to obtain
high enantioselectivity (.99% ee), because the enantiomeric excess when
the far less expensive N-methylmorpholine-N-oxide was employed dropped
to the upper 80s. When the reaction was run with the unprotected phenol or
with the TMS-protected phenol, decomposition was observed.

Potassium Channel Opener Benzopyran
3573
Figure 1. Silyl protected impurity.
The last step required 36 h at reflux in IPA and 3 equivalents of 1-methyl-
3,6-(1H,2H)-pyridazinedione (14) to consume the starting material. During
previous runs, a less-polar impurity was detected by both thin-layer chromato-
graphy (TLC) and high performance liquid chromatography (HPLC) analysis
(5–10%). This impurity was characterized as compound 17 (Fig. 1).
Because of the limited commercial availability of 1-methyl-3,6-(1H,2H)-
pyridazinedione material and its high cost, we prepared it in our laboratories.
A typical experimental procedure is as follows: to a solution of maleic
anhydride (210 g, 2.14 mol) in glacial acetic acid (1 L) cooled in an ice-water
bath (partial freezing may occur), methylhydrazine (114 mL, 2.14 mol) is
added dropwise while the internal temperature is held below 208C. After
15 min, the cooling bath is removed, and the mixture is allowed to warm to
ambient temperature. After 1 h, the solvent is removed under vacuum to give
a white solid, which is slurried in 500 mL of acetone for 1 h, filtered, washed
with cold acetone (2 ꢀ 250 mL), and placed in a vacuum oven at 608C for 2
days to give 233 g (86%) of 1-methyl-3,6-(1H,2H)-pyridazinedione as a
1
white solid. Mp ¼ 210–2128C. H NMR (CDCl3, 400 MHz): d 3.40 (s, 3H),
6.82 (d, J ¼ 9.7 Hz, 1H), 6.99 (d, J ¼ 9.7 Hz, 1H).
Other conditions that we tried for this last step (Cs2CO3/toluene/reflux,
KOt-Bu/t-BuOH/reflux, K2CO3/DMF/1008C, NaOH/DMF/758C) gave no
reaction and/or partial decomposition.
We found that the addition of 1 equivalent of tetrabutylammonium
fluoride as a 1 M solution in THF completed the deprotection. Crude 1 was
subsequently purified by column chromatography and recrystallized from
ethanol to give the desired product in 35% yield with chemical and optical
purities (ee) better than 96% and 99% respectively. Attempts to purify 1 by
alternative methods were unsuccessful because of the impurities produced
during the last two steps of the synthesis.
CONCLUSION
In conclusion, a shorter synthetic route has been successfully developed for
compound 1. The scalability of this experimental protocol has been corroborated

3574
J. Magano et al.
by the preparation of multigram quantities of material through the implemen-
tation of numerous improvements with respect to the original synthesis.
EXPERIMENTAL
All reagents and solvents were used as received. 5-Bromosalicylaldehyde, etha-
nethiol, 4-phenylpyridine-N-oxide, Jacobsen’s catalyst, and 1 M solution of tet-
rabutylammonium fluoride in THF were purchased from Aldrich Chemical Co.
2-Chloro-2-methylbutane was purchased from TCI America. Zinc chloride,
sodium tert-butoxide, tert-butyldimethylsilyl chloride (TBDMSCl), and
imidazole were purchased from Lancaster. Tetrakis(triphenylphosphine)palla-
dium(0) was purchased from either Aldrich Chemical Co. or Strem. 3-Methox-
ybenzenethiol was purchased from Oakwood Products, Inc. Chloroform,
N,N-dimethylformamide, dichloromethane, triethylamine, and isopropyl alcohol
(IPA) were purchased from Mallinckrodt. Bleach was purchased from Chlorox
Professional Products Company. Ethanol was purchased from Aaper. Silica gel
was purchased from EM Science.
1H NMR spectra were recorded on a Varian-Gemini-400 in either CDCl3
or d6-DMSO as both solvent and internal standard.
HPLC analyses to determine chemical purity were performed with a
YMC Pack Pro C18 column with 60:40 20-mM ammonium formate (pH
5.0)–acetonitrile as mobile phase. Chiral HPLC analysis were performed
with a Chiralpak AD column (250 ꢀ 4.6 mm, 10 m) with 800:200:1:0.5
hexanes–IPA–TFA–diethylamine as mobile phase.
Positive and negative ion atmospheric pressure chemical ionization
(APCI) mass spectra were obtained on a Micromass Platform LC mass
spectrometer.
Melting points were determined with a Thomas Hoover melt-temp
apparatus and are uncorrected.
Synthesis of Chromene 7
A mixture of ZnCl2(141.2 g, 1.03 mol), 5-bromosalicylaldehyde (15)
(208.6 g, 1.03 mol), and 2-chloro-2-methylbutane (16) (153 mL, 1.24 mol)
in chloroform (1.5 L) was refluxed for 10 h under a nitrogen atmosphere.
After cooling to 208C, water (1 L) was added, and the two layers were
separated. The aqueous layer was extracted with chloroform (2 ꢀ 200 mL),
and the combined organic extracts were washed with brine (100 mL) and
dried over MgSO4. The solvent was removed to give 262.4 g (GC purity:
90% a/a) of chromene 7as a very thick, dark purple oil, which was used in
1
the next step without any further purification. H NMR (400 MHz, CDCl3)
d 1.39 (s, 6H), 1.83 (s, 3H), 6.01 (s, 1H), 7.01 (d, J ¼ 2.4 Hz, 1H), 7.12
(dd, J ¼ 8.6 Hz, J ¼ 2.4 Hz, 1H). MS m/z ¼ 254 (M þ H)þ.

Potassium Channel Opener Benzopyran
Synthesis of Methyl Ether 9
3575
Chromene 7(262.1 g, 1.03 mol), 3-methoxythiophenol (8) (174.0 g, 1.24 mol),
and Pd(Ph3P)4(23.9 g, 20.7 mmol) were dissolved in degassed, absolute
ethanol (2 L) under a nitrogen atmosphere. The mixture was cooled in an
ice-water bath, and NaOt-Bu (332.0 g, 3.45 mol) was added in small
portions over 30 min while the temperature inside of the flask was held
below 258C. The resulting mixture was refluxed for 18 h and then cooled to
208C. Water (1 L) was added, and some of the solvent was removed under
vacuum. The aqueous residue was extracted with hexanes (3 ꢀ 1 L), and
the combined organic extracts were dried over MgSO4. The solvent was
removed under vacuum to give 215.4 g (HPLC purity: 82% a/a) of methyl
ether 9as a dark green oil, which was used in the next step without any
1
further purification. H NMR (400 MHz, CDCl3) d 1.43 (s, 6H), 1.83 (s,
3 H), 6.04 (s, 1H), 6.65–6.77 (m, 4H), 7.06–7.21 (m, 3H). MS m/z ¼ 313
(M þ H)þ.
Synthesis of Phenol 10
To a suspension of NaH (128.1 g, 3.19 mol) in dry DMF (1, 100 mL) under a
nitrogen atmosphere, a solution of ethanethiol (220 ml, 2.97 mol) in dry DMF
(620 mL) was added. The ice bath was removed, and after 10 m, a solution of
methyl ether 9(344.3 g, 1.10 mol) in dry DMF (400 mL) was added in one
portion. The resulting mixture was refluxed for 1 h and then allowed to cool
to 208C. Water (2 L) was added, and the reaction was neutralized to pH 1
with 1 N HCl. The aqueous layer was extracted with tert-butyl methyl ether
(3 ꢀ 1 L), and the combined organic extracts were washed with brine and
dried over MgSO4. The solvent was removed to give 132.7 g of phenol
10as a brown oil (HPLC purity: 72% a/a). The crude was used without any
1
further purification in the next step. H NMR (400 MHz, CDCl3) d 1.20
(s, 3H), 1.43 (s, 3H), 1.83 (s, 3H), 6.03 (s, 1H), 6.57–6.60 (m, 3H), 7.05–
7.20 (m, 3H). MS m/z ¼ 299 (M þ H)þ.
Synthesis of TBDMS-Protected Phenol 11
A solution of phenol 10 (278.1 g, 931 mmol) in dry DMF (830 mL) under a
nitrogen atmosphere was cooled in an ice-water bath. Imidazole (146.0 g,
2.14 mol) was added, followed by TBDMSCl (147 g, 987 mmol) in small
portions. The cooling bath was removed, and the mixture was stirred at
room temperature for 72 h. Water (1 L) was added, and the aqueous layer
was extracted with hexanes (3 ꢀ 1 L). The combined organic extracts were
dried over MgSO4, and the solvent was removed under vacuum to give a
dark brown oil, which was chromatographed on silica gel (hexanes/

3576
J. Magano et al.
CH2Cl22/1as mobile phase) to give 296.6 g (77% for two steps; HPLC purity:
1
92% a/a) of 11as a yellow oil. H NMR (400 MHz, CDCl3) d 0.00 (s, 6H),
0.81 (s, 12H), 1.31 (s, 6H), 1.71 (s, 3H), 5.92 (s, 1H), 6.47–6.49 (m, 2H),
6.64–6.67 (m, 2H), 7.06-7.14 (m, 1H). MS m/z ¼ 413 (M þ H)þ.
Synthesis of Epoxide 13
Alkene 11(225.0 g, 545 mmol), (S,S)-Jacobsen’s catalyst [(S,S)-(þ)-N,
N0-bis(3, 5-di-tert-butylsalicylidene)-1, 2-cyclohexanediaminomanganese(III)
chloride, 25.3 g, 40 mmol] and 4-methylmorpholine-N-oxide (24.3 g,
142 mmol) were dissolved in CH2Cl2 (1.3 L), and the flask was cooled in
an ice-water bath. Commercial bleach (NaClO content: 6.15%; 7.75 L) was
added over 1.5 h while the internal temperature was held below 208C. The
cooling bath was removed, and the dark brown mixture was allowed to
reach ambient temperature and vigorously stirred at this temperature for
18 h. The resulting thick emulsion was filtered through-celitew, and the two
layers were separated. The aqueous layer was extracted with CH2Cl2
(3 ꢀ 1 L), and the combined organic extracts were washed with brine and
dried over MgSO4. The solvent was removed to give 215.9 g of epoxide 13
as a brown solid (HPLC purity: 89% a/a) that was used in the next step
without any further purification. 1H NMR (400 MHz, CDCl3) d 0.00
(s, 6H), 0.77 (s, 12H), 1.07 (s, 3H), 1.31 (s, 3H), 1.35 (s, 3H), 3.51 (s, 1H),
6.67 (d, J ¼ 8.6 Hz, 1H), 6.77–6.81 (m, 1H), 7.12–7.17 (m, 2H), 7.26–
7.29 (m, 1H), 7.57 (dd, J ¼ 2.4 Hz, J ¼ 8.5 Hz, 1H), 7.69 (d, J ¼ 2.4 Hz,
1H). MS m/z ¼ 461 (M þ H)þ.
Synthesis of 1
Epoxide 13 (92.9 g, 202 mmol), 1-methyl-3,6-(1H,2H)-pyridazinedione (14)
(76.4 g, 605 mmol), and triethylamine (85 ml, 605 mmol) were dissolved in
isopropyl alcohol (550 mL), and the mixture was refluxed for 28 h and then
cooled to 208C. Thin-layer chromatographic (TLC) analysis (ethyl acetate/
methanol 95/5) showed complete consumption of the starting material and
a spot corresponding to the tert-butyldimethylsilyl-protected intermediate
17. Tetrabutylammonium fluoride solution (1 M) in THF (200 mL) was
added, and the mixture was stirred at room temperature for 30 min to
complete the removal of the TBDMS protecting group. The solvent was
removed under vacuum to give a dark brown oil which was dissolved in
ethyl acetate (2 L), washed with water (1 ꢀ 1.5 L, 3 ꢀ 500 mL), and brine,
and dried over MgSO4. The solvent was removed to give a dark brown
solid, which was purified by chromatography on silica gel (acetonitrile/
methanol, gradient elution) to give 57.6 g of a beige solid. This solid was
dissolved in ethanol (500 mL), filtered to remove some insoluble material,

Potassium Channel Opener Benzopyran
3577
and concentrated to a final volume of about 200 mL. The solution was placed
in a freezer at 258C for 20 h and the solid thus obtained was filtered, washed
with cold ethanol (2 ꢀ 20 mL), and dried under vacuum at 208C and 17 torr to
1
give 33.5 g (35% yield) of 1 as an off-white solid. H NMR (400 MHz, d6-
DMSO) d 0.99 (t, J ¼ 7.1 Hz, 3H), 1.15 (s, 3H), 1.28 (s, 3H), 1.34 (s, 3H),
3.35–3.40 (m, 2H), 3.54 (s, 3H), 4.31 (t, J ¼ 5.1 Hz, 1H), 5.35 (s, 1H),
5.74 (s, 1H), 6.92–7.00 (m, 3H), 7.12-7.13 (m, 1H), 7.19–7.34 (m, 3H),
7.68 (dd, J ¼ 2.5 Hz, J ¼ 8.8 Hz, 1H), 7.76 (d, J ¼ 2.2 Hz, 1H), 10.19
(s, 1H). MS m/z ¼ 473 (M þ H)þ. Anal. calcd. for C23H24N2O7S: C, 58.46;
H, 5.12; N, 5.93; S, 6.79. Found: C, 58.09; H, 5.10; N, 5.93; S, 6.86. Mp:
138–1658C. HPLC chemical purity: 97.9%; HPLC optical purity: .99.5%
(ee).
ACKNOWLEDGMENTS
The authors thank their colleagues in the Analytical Research and Develop-
ment Group for their work to develop methods to determine the chemical
and optical purities. Also, we thank Michael H. Chen for useful discussions
during the implementation of this project, Ji Zhang for providing us with
the experimental procedure for the preparation of 1-methyl-3,6-(1H,2H)-pyr-
idazinedione, and Daniel T. Belmont, Jerry D. Clark, and D. Keith Anderson
for reviewing this manuscript, all of them from the RAPI Group in Ann Arbor.
REFERENCES
1. Mackenzie, A. R.; Monagham, S. M. Preparation of benzopyrans as smooth muscle
relaxants WO 95/04730; CAN 122:265247; File date, July 18, 1994.
2. Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza, R.; DeVries, P.; Leitza, S.;
Reilly, E. B.; Okasinski, J. F.; Fesik, S. W.; von Geldem, T. W. Novel
p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/
intracellular adhesion molecule-1 interaction, 2: Mechanism of inhibition and
structure-based improvement of pharmaceutical properties. J. Med. Chem. 2001,
44, 1202.
3. Harrison, I. T. Cleavage of alkyl aryl ethers with lithium iodide. J. Chem. Soc.,
Chem. Comm. 1969, 616.
4. Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. Highly enantiose-
lective epoxidation catalysts derived from 1,2-diaminocyclohexane. J. Am. Chem.
Soc. 1991, 113, 7063.
5. Cho, H.; Katoh, S.; Sayama, S.; Murakami, K.; Nakanishi, H.; Kajimoto, Y.;
Ueno, H.; Kawasaki, H.; Aisaka, K.; Uchida, I. Synthesis and selective coronary
vasodilatory activity of 3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-
3-ol derivatives: Novel potassium channel openers. J. Med. Chem. 1996, 39, 3797.
6. (a) Ravichandran, S. A new approach to the synthesis of chromenes derivatives.
Synth. Commun. 2001, 31, 1233; (b) Kawase, Y.; Yamaguchi, S. A new

3578
J. Magano et al.
preparative method for 2,2-dimethyl-2H-chromenes. Bull. Chem. Soc. Jpn. 1982,
55, 1153.
7. (a) Mali, R.; Joshi, P. Useful syntheses of prenylated coumarins and pyrano-3-aryl-
coumarins. Synth. Commun. 2001, 31, 2753; (b) Coterill, W. D.; Livingstone, R.;
O’Donnell, P. A. Reactions of 2,2,4-trimethyl-2H-benzo[b]pyran and 2,2,4-
trimethyl-2H-naphtho[1,2-b]pyran with bromine. J. Chem. Res. Miniprint 1993,
11, 3001; (c) Aukrust, I.; Noushabadi, M.; Skatteboel, L. A general synthesis of
chromenes. Pol. J. Chem. 1994, 68, 2167.
8. Pommier, H. P.; Baril, J.; Gruda, I.; Leblanc, R. M. Synthesis of long-chain cou-
marines and 2H-chromenes. Spectral and monolayer properties. Can. J. Chem.
1979, 57, 1377.
9. Grese, T. A.; Pennington, L. D.; Sluka, J. P.; Adrian, M. D.; Cole, H. W.;
Fuson, T. R.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Shetler, P. K.;
Short, L. L.; Venugopalan, M.; Yang, N. N.; Sato, M.; Glasebrook, A. L.;
Bryant, H. U. Synthesis and pharmacology of conformationally restricted raloxi-
fene analogues: Highly potent selective estrogen receptor modulators. J. Med.
Chem. 1998, 41, 1272.
10. Grieco, P. A.; Nishizawa, M.; Oguri, T.; Burke, S. D.; Marinovic, N. Sesquiterpene
lactones: Total synthesis of (+)-vernolepin and (+)-vernomenin. J. Am. Chem.
Soc. 1977, 99, 5773.
11. Olah, G. A.; Husain, A.; Gupta, B. G. B.; Narang, S. C. Synthetic methods and
reactions, 96: Trichloromethylsilane/sodium iodide, a new regioselective
reagent for ether cleavage. Angew. Chem. Int. Ed. 1981, 8, 690.