Synthesis of 3,3-dimethyl-4-chromanones: Improved procedures without ring opening

Article abstract of DOI:10.1080/00397910500383543

A procedure for the 3,3-dimethylation of 4-chromanones under basic conditions was improved; the by-product from chromanone ring opening was isolated and its structure was determined. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500383543

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Synthesis of 3,3‐Dimethyl‐4‐chromanones:
Improved Procedures Without Ring Opening
Ayako Yamashita a , Emily B. Norton a , Cilien Hanna a , Jaechul Shim a
Edward J. Salaski a , Dahui Zhou a & Tarek S. Mansour a
,
a Chemical and Screening Sciences, Wyeth Research, Pearl River , New York,
USA
Published online: 19 Aug 2006.
To cite this article: Ayako Yamashita , Emily B. Norton , Cilien Hanna , Jaechul Shim , Edward J. Salaski ,
Dahui Zhou & Tarek S. Mansour (2006) Synthesis of 3,3‐Dimethyl‐4‐chromanones: Improved Procedures
Without Ring Opening, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:4, 465-472, DOI: 10.1080/00397910500383543
To link to this article: http://dx.doi.org/10.1080/00397910500383543
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Synthetic Communicationsw, 36: 465–472, 2005
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500383543
Synthesis of 3,3-Dimethyl-4-chromanones:
Improved Procedures Without
Ring Opening
Ayako Yamashita, Emily B. Norton, Cilien Hanna,
Jaechul Shim, Edward J. Salaski, Dahui Zhou,
and Tarek S. Mansour
Chemical and Screening Sciences, Wyeth Research,
Pearl River, New York, USA
Abstract: A procedure for the 3,3-dimethylation of 4-chromanones under basic con-
ditions was improved; the by-product from chromanone ring opening was isolated
and its structure was determined.
Keywords: 4-Chromanones, dimerization, dimethylation, potassium tert-butoxide,
ring opening
The synthesis of 3,3-dialkylated 4-chromanones by direct alkylation is
rendered difficult by its tendency to undergo ring opening to a phenolate
anion under basic conditions.[1] Recorded attempts to achieve direct
dialkylation[2] have mostly led to monoalkylation, and efforts to achieve
further alkylation of a monoalkylated product usually result in low yields or
in ring opening to a phenol. The problems associated with ring opening of
4-chromanones under basic conditions have been well-documented,[3] but,
to our knowledge, there has been no determination of the structure of the
product(s) formed from the phenolate anion expected from ring opening. It
has been suggested that the phenolate anion would “polymerize” to multiple
structures (dimer, trimer, etc.), which proved difficult to characterize.[4] In
Received in the USA April 1, 2005
Address correspondence to Ayako Yamashita, (current address), Department of
Chemistry, Columbia University, New York, NY 10027, USA. E-mail: ay2122@
columbia.edu
465

466
A. Yamashita et al.
1950, Padfield and Tomlinson reported that treatment of 4-chromanone (1a)
with sodium ethoxide in hot ethanol produced a mixture of at least two
products, which appeared to be a dimer and a trimer, formed by the self-
condensation of 4-chromanone.[5] These products were reportedly too
difficult to separate for purification and were not characterized. Because of
these problems, 3,3-substituted-4-chromanone derivatives have usually been
prepared by cyclization from various salicylic acid derivatives.[6]
We wished to develop a method for the efficient dimethylation of
various 4-chromanones at the 3 position. Specifically, the synthesis of 3,3-
dimethyl-4-chromanone (3a) and 6-fluoro-3,3-dimethyl-4-chromanone (3b)
from 4-chromanone (1a) and 6-fluoro-4-chromanone (1b), respectively, was
our immediate goal because 3a and 4a have been claimed as key intermediates
in the synthesis of some agents for the treatment of depression.[7] We now
report our finding that the use of potassium tert-butoxide[8] at low tempera-
tures (2788C) overcomes the problems associated with ring opening to give
the desired 3,3-dimethyl-4-chromanones 3, in almost quantitative yields. In
addition, we were able to isolate a self-condensation product 4 and
determine its structure by X-ray analysis. (Crystals of 4b suitable for X-ray
were obtained as colorless prisms by recrystallization from methanol. The
supplementary publication number for the X-ray for 4b is CCDC 267463.
The crystallographic data for 4b analyzed by X-ray have been deposited
with Cambridge Crystallographic Data Center, 12 Union Road, Cambridge
CB2 1EW, UK.)
Dialkylation of 4-chromanones was initially studied with 6-fluoro-4-
chromanone (1b) using various bases, solvents, and temperatures
(Scheme 1), and the results are shown in Table 1. Treatment of 1b with
lithium diisopropylamide (LDA) (1.3 mole eq.) in THF at 2788C, followed
by addition of iodomethane (8.5 mol eq.) gave the mono-methylated product
2b as a major product (54% yield) along with at least three minor
by-products (Entry 1). One of the by-products appeared to be the desired
3,3-dimethylated product 3b, which was detected by mass spectroscopy, but
was difficult to isolate in pure form. Treatment of 2b with LDA
(1.2 mol eq.) and an excess of iodomethane gave 3b in 50% yield (Entry 2).
By using lithium hexamethyldisilazide (LHMDS) (2.1 mol eq.) as a base
with iodomethane (2.1 mol eq.) in THF at 2788C, only 2b was obtained in
34% yield (Entry 3). Other bases that were examined, such as NaH and
potassium hexamethyldisilazide (KHMDS), gave complex mixtures of
Scheme 1. Dimethylation of chromanones.

Synthesis of 3,3-Dimethyl-4-chromanones
467

468
A. Yamashita et al.
products, including formation of 2b and/or 3b, which were detected by mass
spectroscopy (Entries 4, 5).
In view of the fact that potassium enolates are more reactive toward alky-
lation than lithium or sodium enolates,[8] potassium tert-butoxide was used as
a base for dimethylation of 1b. Thus, when 1b was treated with an excess of
potassium tert-butoxide (5 mol eq.) and iodomethane (10 mol eq.) at 08C, 3b
was obtained in 35% yield along with a single by-product (4b, a white solid,
10% yield, Entry 6). Although the yield of 3b was not high, this was the first
successful dialkylation reaction of 1b under basic conditions. The by-product
4b showed the correct molecular weight (MW 388) for a dimer [ESI/MS
(m/z) spectrum], but its 1H NMR spectrum was not conclusive for a
dimeric structure. The X-ray analysis of 4b revealed its structure to be the
self-condensation product shown in Fig. 1. An analogous self-condensation
product (4a, 29%) accompanied the dimethylated product (3a, 59%) under
the conditions described for the dimethylation of 1b (Entry 7). To our
knowledge, this is the first determination of the structure of the base-
catalyzed self-condensation product from 4-chromanones.
Figure 1. Ortep diagram of 4b.

Synthesis of 3,3-Dimethyl-4-chromanones
469
A plausible pathway for the dimer formation is outlined for 4b
(Scheme 2). Treatment of 1b with iodomethane in the presence of
potassium tert-butoxide should generate the mono-methylated product 2b,
which would be converted to its anion 5b in the presence of excess base.
Ring opening to form the phenolate intermediate can compete with the
second methylation, depending on the base and temperature, thus forming
an intermediate enone 6b. Alkylation of 6 with the anion 5 would generate
an intermediate 7b, which undergoes a second methylation to produce 4b.
We were eventually able to devise conditions that suppressed dimer
formation and gave the desired dimethylation of 4-chromanones in quantitat-
ive yield. Thus, potassium tert-butoxide was added in portions to a mixture of
1b and iodomethane in THF, while keeping the reaction temperature at
2788C. The desired product 3b was isolated in essentially quantitative
yield (Entry 9). Alternatively, a cooled (2788C) mixture of 1a and iodo-
methane was introduced to a solution of potassium tert-butoxide in THF, at
2788C. This inverse addition method also produced 3a in quantitative yield
(Entry 10). Similarly, dimethylation of 1b gave 3b in 98% yield (Entry 11).
In summary, we developed a highly efficient procedure for the
3,3-dimethylation of 4-chromanones under basic conditions. The structure
of a by-product formed under other than optimal base conditions dimethyla-
tion was also established. Our method is not only suitable for the synthesis
of 3,3-dialkyl-4-chromanone derivatives in practically quantitative yield but
is also applicable to large-scale preparations (see Experimental).
EXPERIMENTAL
Reaction of 6-Fluoro-2,3-dihydro-4H-chromen-4-one (1b) with
Iodomethane in the Presence of Potassium tert-Butoxide at 08C
A solution of 1b (60 g, 0.36 mol) and iodomethane (225 mL, 3.61 mol) in
anhydrous THF (1000 mL) was cooled at 08C. Potassium tert-butoxide
Scheme 2. Plausible pathway to dimer.

470
A. Yamashita et al.
(202.63 g, 1.81 mol) was added portionwise to this solution with stirring.
During the process of addition, the temperature of the reaction mixture
was kept at 08C to avoid exothermic reaction. White precipitate
developed, and the mixture became very viscous. The cooling bath was
removed, and the resulting mixture was heated at 608C for 6 h, then at
reflux for 1 h. The mixture was cooled and stirred at room temperature
for 15 h and then poured into methanol. The mixture was concentrated in
vacuo, and the residue was dissolved in water. The aqueous layer was
extracted with diethyl ether, and the extracts were combined. The residue
(68 g, orange oil) was chromatographed (silica gel, elution by 10% ethyl
acetate in hexanes), to give 24.25 g (35%) of 6-fluoro-3,3-dimethyl-2,3-
dihydro-4H-chromen-4-one (3b) as a yellow solid. MS (ES) m/z: 195.1
1
(M þ H). H NMR (d, CDCl3): 1.21 (6H, s), 4.14 (2H, s), 6.94 (1H, dd,
J ¼ 4.2, 9.00 Hz), 7.15–7.23 (1H, m), 7.54 (1H, dd, J ¼ 3.21, 9.00 Hz).
Analysis for C11H11FO2: calcd.: C, 68.03; H, 5.71. Found: C, 67.77;
H, 5.99.
Further elution gave 13.9 g (10%) of 6-fluoro-3-[3-(5-fluoro-2-methoxy-
phenyl)-2,2-dimethyl-3-oxopropyl]-3-methyl-2,3-dihydro-4H-chromen-4-one
(4b) as white solid. The structure was determined by X-ray analysis. MS (ES)
1
m/z: 389.1 (M þ H). H NMR (d, CDCl3): 1.06 (3H, s), 1.13 (3H, s), 1.17
(3H, s), 2.06 (1H, d, J ¼ 11.1 Hz), 2.28 (1H, d, J ¼11.1 Hz), 3.65 (3H, s),
4.16 (1H, d, J ¼ 8.7 Hz), 4.38 (1H, d, J ¼ 8.7 Hz), 7.02–7.22 (4H, m),
7.44–7.50 (2H, m). Analysis for C22H22F2O4: calcd.: C, 68.03; H, 5.71.
Found: C, 67.99; H, 5.98.
Reaction of 1b with Methyl Iodide in the Presence of Potassium
tert-Butoxide at 2788C
A solution of 1b (38.8 g, 0.235 mol) and iodomethane (52 mL, 0.835 mol) in
THF (300 mL) was added to a solution of potassium tert-butoxide (104 g,
0.93 mol) in anhydrous THF (1000 mL), cooled at 2788C (bath tempera-
ture), under nitrogen atmosphere. During this process, the temperature of
the reaction mixture was kept at 2788C to avoid exothermic reaction.
White precipitate was formed, and the reaction mixture became supernatant.
Upon completing addition, TLC analysis indicated that most of the starting
material was consumed. An additional amount (30 mL, 0.48 mol) of iodo-
methane was added all at once. The resulting white slurry was allowed
to warm to room temperature over a period of 15 h and was filtered
through a celite cake. The filtrate was concentrated in vacuo to give
44.8 g (98.3%) of 3b. Analytical HPLC (4.6 ꢁ 150 mm ODS3 Prodigy
C18 column eluted with 10–100% acetonitrile in water containing 0.02%
trifluoroacetic acid over 20 min): 97.6% at 14.8 min.

Synthesis of 3,3-Dimethyl-4-chromanones
471
Reaction of 2,3-Dihydro-4H-chromen-4-one (1a) with Methyl Iodide
in the Presence of Potassium tert-Butoxide at 08C
Following the procedure described for the first reaction, 1a (8.0 g, 0.054 mol)
was treated with iodomethane (17 mL, 0.27 mol) in the presence of potassium
tert-butoxide (30 g, 0.27 mol) in anhydrous THF (150 mL) under nitrogen
atmosphere. After workup, the residue was chromatographed (silica gel,
elution by CH2Cl2) to give 5.62 g (59.1%) of 3,3-dimethyl-2,3-dihydro-4H-
chromen-4-one (3a) as a clear pale yellow oil. MS (ES) m/z: 177.1
1
(M þ H). IR cm21: 1685, 1605, 1580, 1475. H NMR (d, CDCl3): 1.21
(6H, s), 4.13 (2H, s), 6.96 (1H, dd, J ¼ 0.6, 6.3 Hz), 7.03 (1H, ddd), 7.47
(1H, ddd) 7.91 (1H, dd, J ¼ 1.2, 7.5 Hz). Analysis for C11H12O2: calcd.: C,
74.98; H, 6.86. Found: C, 74.70; H, 7.13.
Further elution by CH2Cl2 gave 2.8 g (29.4%) of 3-[3-(2-methoxy-
phenyl)-2,2-dimethyl-3-oxopropyl]-3-methyl-2,3-dihydro-4H-chromen-4-one
(4a) as a white solid. MS (ES) m/z: 353.1 (M þ H). IR cm21: 1680, 1600,
1
1580, 1475. H NMR (d, CDCl3): 1.03 (3H, s), 1.12 (3H, s), 1.16 (3H, s),
2.12 (1H, d, J ¼ 11.1 Hz), 2.25 (1H, d, J ¼ 11.1 Hz), 3.64 (3H, s), 4.14 (1H,
d, J ¼ 8.7 Hz), 4.39 (1H, d, J ¼ 8.7 Hz), 6.98–7.12 (5H, m), 7.32–7.42 (1H,
m), 7.57–7.58 (1H, m), 7.74–7.77 (1H, m). Analysis for C22H24O4: calcd.: C,
74.98; H, 6.86. Found: C, 74.94; H, 7.08.
Reaction of 1a with Iodomethane in the Presence of Potassium
tert-Butoxide at 2788C
Following the procedure described for the second reaction, 1a (25 g,
0.169 mol) was treated with iodomethane (53 mL, 0.95 mol) in the presence
of potassium tert-butoxide (30 g, 0.27 mol) in anhydrous THF (1000 mL) at
2788C under nitrogen atmosphere. After workup, the residue was chromato-
graphed (silica gel, elution by CH2Cl2) to give 30 g (quantitative yield) of 3a.
1
Physical properties [MS (ES), H NMR, TLC] of the product were same as
described earlier.
ACKNOWLEDGMENTS
Authors thank the Discovery Analytical Chemistry Department, Wyeth
Research, Pearl River, New York, and Princeton, New Jersey, for their analyti-
cal support. Authors thank Douglas Ho, director, Small Molecule X-ray
Facility, Department of Chemistry, Princeton University, Princeton,
New Jersey, and Jerauld Skotnicki for useful discussions and suggestions
during this project.

472
A. Yamashita et al.
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