Synthesis of C4-C5 cycloalkyl-fused and C6-modified chromans via ortho-quinone methides

Article abstract of DOI:10.1002/asia.201403356

Starting from 3,5-dimethoxybenzaldehyde, some functionalized 2,3,4-trisubstituted tricyclic 4,5-cycloalkyl-fused and 6-modified chromans could be prepared via ortho-quinone methides (o-QMs)/hetero-Diels-Alder (HDA) reactions of the appropriate precursors.

Full text of DOI:10.1002/asia.201403356

DOI: 10.1002/asia.201403356
Full Paper
Cycloaddition
Synthesis of C4ÀC5 Cycloalkyl-Fused and C6-Modified Chromans
via ortho-Quinone Methides
Kassrin Tangdenpaisal,[a] Kanokpish Chuayboonsong,[b] Patchaya Sukjarean,[b]
Varisa Katesampao,[b] Nok Noiphrom,[a] Somsak Ruchirawat,[a, b, c] and
Poonsakdi Ploypradith*[a, b, c]
Abstract: Starting from 3,5-dimethoxybenzaldehyde, some
functionalized 2,3,4-trisubstituted tricyclic 4,5-cycloalkyl-
fused and 6-modified chromans could be prepared via
ortho-quinone methides (o-QMs)/hetero-Diels–Alder (HDA)
reactions of the appropriate precursors. The bromide at C6
served as a handle for introducing other substituents
through palladium-catalyzed cross-coupling reactions and
other functional-group transformations. Moderate to high
yields (up to 80%) and diastereoselectivities (up to >99:1)
could be obtained under [PtCl4] catalysis. The preferred endo
transition state during the cycloaddition reaction played an
important role in governing the stereochemical outcomes at
C2ÀC3ÀC4. The configurationally fixed E geometry of the bi-
cyclic o-QMs influenced the cycloaddition reactions to favor
the C2ÀC4 cis relationship.
Introduction
Chroman or benzopyran are important cores of flavanoids that
have been shown to exhibit a wide range of interesting bio-
logical activities, such as anticancer, antibacterial, antioxidant,
and anxiolytic.[1] Our research group has been involved in the
chemistry of ortho-quinone methides (o-QMs),[2,3] which, upon
reacting with the appropriate dienophiles, provide the corre-
sponding chromans in good yields and diastereoselectivity. Re-
cently, we reported both acid- and platinum(IV)-catalyzed gen-
eration of o-QMs and their intermolecular as well as intramo-
lecular [4+2] cycloaddition reactions, or the hetero-Diels–Alder
(HDA) reaction, to give the chroman systems.[4,5]
As shown in Figure 1, the core structure of rubriflordilacto-
ne A (1)[6] is an example of a C4ÀC5 cyclopentyl-fused chroman
isolated from the stems and leaves of Schisandra rubriflora.
Compound 1 exhibits weak anti-HIV-1 activity. In addition,
some sesquiterpenoids from the rhizomes of Ligularia virgau-
rea (2 and 3; Figure 1)[7] represent C4ÀC5 cyclohexyl-fused hy-
Figure 1. 4,5-Cycloalkyl-fused chromans (1–3) and C6-arylchromenone (4).
drochromene systems, whereas the gem-difluoromethylenated
biflavonoid (4) features a C6-arylated chromenone core.[8] We
anticipated that these different chroman-related cores could
be prepared by using our developed o-QM/cycloaddition
chemistry.
[a] K. Tangdenpaisal, N. Noiphrom, Prof. Dr. S. Ruchirawat, Dr. P. Ploypradith
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute
54 Kamphaeng Phet 6 Road, Laksi, Bangkok 10210 (Thailand)
E-mail: poonsakdi@cri.or.th
[b] K. Chuayboonsong, P. Sukjarean, V. Katesampao, Prof. Dr. S. Ruchirawat,
Dr. P. Ploypradith
Results and Discussion
Program in Chemical Biology, Chulabhorn Graduate Institute
54 Kamphaeng Phet 6 Road, Laksi, Bangkok 10210 (Thailand)
C6-Modifications through Palladium-Catalyzed Cross-Cou-
pling Reactions
[c] Prof. Dr. S. Ruchirawat, Dr. P. Ploypradith
Centre of Excellence on Environmental Health and Toxicology
Commission on Higher Education (CHE)
Strategically, it is possible to perform C6 modifications either
before or after the formation of the chroman core. Modifica-
tions on the chroman core would be considered more efficient
Ministry of Education (Thailand)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403356.
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because they could be performed on the same intermediate at
a later stage (a divergent approach).
Table 1. C6-Arylated chromans obtained by Suzuki reactions.
From our previous studies, the presence of the bromine
atom appeared to be beneficial for the generation of o-QMs as
well as their HDA reactions.[4] Thus, we first investigated the
feasibility of performing C6 modification through palladium-
catalyzed Suzuki cross-coupling reactions[9–11] with phenyl bor-
onic acid derivative as a model. As shown in Scheme 1, by
using our developed chemistry, bromobenzaldehyde 5 and 6-
Entry Ar
Yield [%][a]
Suzuki[b] Acetate[c] Chroman[d] Overall
1
2
8a (99)
8b (85)
9a (73)
9b (71)
7 (56)
41
50
10b (82)
3
4
8c (87)
8d (87)
9c (86)
9d (72)
10c (51)
10d (82)
38
51
5
6
8e (89)
8 f (45)
9e (59)
9 f (58)
10e (56)
10 f (51)
29
13
Scheme 1. Model reaction for C6 modification through Suzuki reactions.
MOM=methoxymethyl, DMAP=4-dimethylaminopryidine.
7
8
8g (78)
8h (92)
9g (94)
9h (68)
10g (81)
10h (0)
59
0
bromo-2-phenylchroman 6 could be prepared from 2-hydroxy-
4-methoxybenzaldehyde as the starting material. After some
experimentation to optimize the conditions, it was found that
performing the Suzuki reaction at the aldehyde stage provided
the corresponding chroman 7 in better overall yield (41%;
Scheme 1, route B) than that obtained at the chroman stage
(17%; Scheme 1, route A) over the same number of steps.
Thus, the presence of the electron-withdrawing aldehyde sub-
stituent on the aromatic ring of 5 facilitates the Suzuki reac-
tion.
[a] Yields of products isolated. [b] [Pd(PPh3)4] (5 mol%), boronic acids
(1.2 equiv), and K2CO3 (2 equiv) were employed in PhMe/EtOH/H2O (3:3:2)
at reflux for 22 h. [c] The yields were evaluated over two steps of NaBH4
reduction and acetylation. [d] [PtCl4] (10 mol%) and styrene (10 equiv)
were used.
For C6 modifications at the chroman stage, we anticipated
that lithium–bromine exchange of the bromochroman 6 could
generate the corresponding C6-aryl anion, which would further
react with various electrophiles, as shown in Table 2.
Having established the optimized conditions and found
a suitable route to introduce the phenyl group at C6, we em-
ployed such an approach to introduce other aromatic substitu-
ents, as summarized in Table 1.
It should be noted that the duration of lithium–bromine ex-
change is critical and should not exceed 5 min. Prolonging the
reaction time of exchange, even at À788C, led to the forma-
The Suzuki reactions of aldehyde 5 with various boronic
acids were successfully performed to give the corresponding
products 8a–g in moderate to excellent yields (45–99%). An
electron-withdrawing group (NO2)-containing boronic acid
gave product 8 f in a moderate yield of 45%. Subsequent bor-
ohydride reduction followed by acetylation gave benzyl ace-
tates 9a–g in good yields (58–94%) over two steps. Finally, the
o-QM/HDA reactions of benzyl acetates 9a–g under [PtCl4] cat-
alysis with styrene gave the desired C6-arylated 2-phenylchro-
mans 7 and 10b–g in good yields (51–82%). Benzyl acetate
9h, with a furan ring, did not give the corresponding chroman
product 10h (Table 1, entry 8). Decomposition of 9h under the
reaction conditions was observed and less than 10% of 9h
could be recovered. Overall, 6-arylated chromans 7 and 10b–g
could be formed from bromobenzaldehyde 5 in 13–59% yield
over 4 steps.
Table 2. Lithium–bromine exchange of 6 and its reactions with electro-
philes.
Entry
E
R
Product
Yield [%][a]
1
2
3
MeOCOCl
Me2NCHO
Me2NSO2Cl
MeOCO
HCO
Me2NSO2
11
12
13
53
55
37[b]
[a] Yields of products isolated. [b] At À408C, only the debrominated by-
product was observed. The yield of this reaction was calculated from the
1H NMR spectrum of the purified fractions that contained the desired
product along with the debrominated product.
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tion of the debrominated byproduct (with H replacing Br) as
the major product, presumably arising from C2ÀC6 intermolec-
ular proton transfer, which could occur prior to the addition of
electrophiles.[12] As summarized in Table 2, the C6-aryl anion
could react with methyl chloroformate, N,N-dimethylforma-
mide (DMF), or sulfamoyl chloride to give the C6-functionalized
products 11–13 in moderate yields (37–55%). In all cases,
about 10–20% of the debrominated byproduct was also ob-
tained. However, if the temperature of the reaction was raised
to À408C after adding electrophiles at À788C, only the debro-
minated byproduct was obtained. This observation suggested
that the rate of the C2ÀC6 intermolecular proton-transfer pro-
cess was faster than the addition of the C6-aryl anion to the
electrophile at À408C. Attempts to react the aryl anion with
different aromatic aldehydes at À788C, as well as at other tem-
peratures, however, failed to give the corresponding alcohol
products. Only the formation of the debrominated byproduct
was observed.[13]
cores of 1–3 by means of our o-QM methodology, we also
wish to investigate the effects of joining these substituents, R
and R1, as an additional five- or six-membered ring on the plat-
inum(IV)-catalyzed HDA reactions with appropriately activated
and functionalized dienophiles. The presence of this five- or
six-membered ring would essentially lock the corresponding
bicyclic o-QM (F) into the E conformation, which should pro-
vide the chroman product (G) with good to excellent 2,4-cis
diastereoselectivity.
As shown in Scheme 3, retrosynthetic analysis revealed that
the tricyclic C4ÀC5 cycloalkyl-fused chroman core 14 could be
envisioned to arise from the HDA reactions of the appropriate
C4ÀC5 Cycloalkyl-Fused Chromans via (E)-o-QMs
We next investigated the generation of configurationally fixed
(E)-o-QMs from the appropriate precursors under platinum(IV)
catalysis. Previously, it was reported that (E)-o-QM (A) was the
preferred conformer over (Z)-o-QM (B) if the substituent R1
ortho to the olefin moiety of the o-QM containing an R group
was smaller than the carbonyl moiety (Scheme 2).[14] Moreover,
such preferred E configuration of the o-QM is expected to pro-
vide the corresponding 2,4-cis chroman (D) with high diaste-
reoselectivity over the 2,4-trans chroman (E) owing to the pref-
erence for the endo transition state of the ensuing HDA reac-
tions with dienophiles.
Scheme 3. Retrosynthetic analysis of 14.
o-QM precursor, which, in turn, could come from the 1-inda-
none or 1-tetralone derivative (15), depending on the ring size.
The aromatic fused cyclopentanone and cyclohexanone would
be installed through a sequence of reactions involving the
Wittig-type reaction followed by hydrogenation and intramo-
lecular Friedel–Crafts-type acylation of 3,5-dimethoxybenzalde-
hyde (16). The o-QM/cycloaddition partner 17 would come
from the Wittig-type reaction of the appropriate aldehyde 18.
The synthesis of indanone 19 employed 16 as a starting ma-
terial. As shown in Scheme 4, aldehyde 16 could be either con-
verted into indanone 19 directly through a three-step process,
involving a Knoevenagel reaction with malonic acid, to give
the corresponding (E)-cinnamic acid derivative in a yield of
Thus, together with devising a synthetic method for the
preparation of the tricyclic C4ÀC5 cycloalkyl-fused chroman
Scheme 2. Preference for the E-configured o-QMs, leading to the 2,4-cis-
chroman product and bicyclic o-QMs locked in the E configuration.
Scheme 4. Synthesis of indanone and tetralone o-QM precursors 20 and 22.
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94%. Subsequent hydrogenation of the resulting olefin,[15] fol-
lowed by [SnCl4]-mediated Friedel–Crafts-type acylation/cycli-
zation,[15] gave 19 in yields of 84 and 75%, respectively
(Scheme 4, Method A). Alternatively, aldehyde 16 could be first
quantitatively converted into the corresponding cinnamate
ester through Wittig olefination. Ensuing hydrogenation fol-
lowed by saponification gave the acid. Subsequent [SnCl4]-
mediated Friedel–Crafts-type acylation/cyclization then gave
19 in a yield of 99% over 3 steps (Scheme 4, Method B). Over-
all, method A in Scheme 4 gave 19 in a yield of 59% over
3 steps, whereas method B gave 19 in a superior yield of 98%
over 4 steps.
tate 24, on the other hand, could not be purified and was
used in the subsequent o-QM/HDA reaction directly. Upon re-
acting with styrene (10 equiv) in the presence of [PtCl4]
(10 mol%), compound 23 gave 25 as a 6:1 mixture of C2ÀC4
diastereomers in a moderate yield of 53%.[18] On the other
hand, compound 22 gave 26 as a 3:1 mixture of C2ÀC4 diaste-
reomers in a yield of 35% over 3 steps.[18]
Owing to the more stable nature and better yields of indanyl
acetate 23, the five-membered ring series was further investi-
gated for the platinum(IV)-catalyzed HDA reaction with cinna-
mate 27 (2 equiv). The temperature and reaction time were
then optimized, and the results are summarized in Table 3.
Indanone 19 was then subjected to selective ortho-demethy-
lation by using BCl3; this proceeded smoothly in a yield of
98%.[16] Subsequent bromination by using molecular bromine
in CH2Cl2 also proceeded quantitatively prior to MOM protec-
tion of the phenol to give 20 in a yield of 86%. During the
bromination reaction, it is critical to maintain a temperature of
08C, slowly add neat molecular bromine (at the rate of ca.
0.02 mLminÀ1), and keep the reaction time to a minimum (typi-
cally 1–1.5 h). It should be noted that conducting the reaction
at higher temperatures, prolonging the reaction time, adding
Br2 as a solution, or using solvents other than CH2Cl2 gave
poor results. Overall, starting from 16, the indanone o-QM pre-
cursor 20 could be obtained in a yield of up to 82% over
7 steps.
Table 3. Optimization of the reaction conditions for 23 and 27.
Entry
Conditions[a]
Yield of 28 [%][b]
1
2
3[c]
RT, 2 h
20
52
À408C to RT, 18 h
i) À208C, 3 h
ii) À108C to 08C, 18 h
iii) RT, 3 h
0
20
80
4
5
À208C to RT, 18 h
08C to RT, 18 h
By using a similar strategy, starting from 16, tetralone 21
was prepared through a Wittig-type reaction[17] (39% yield), hy-
drogenation (97% yield), and Friedel–Crafts-type acylation/cyc-
lization (86% yield). Attempts to perform the Wittig-type reac-
tion by using the phosphonium salt derived from the corre-
sponding ethyl ester instead of the carboxylic acid failed. With
tetralone 21 in hand, a three-step reaction sequence of selec-
tive ortho-demethylation (68%), bromination (89%), and MOM
protection (44%) provided the corresponding tetralone o-QM
precursor 22 in a yield of 9% over 6 steps.
Both compounds 20 and 22 were then converted into the
corresponding acetates 23 and 24, respectively, as shown in
Scheme 5, through borohydride reduction and acetylation.
Acetate 24 was less stable than indanyl acetate 23, which
could be isolated in a yield of 81% after chromatography. Ace-
[a] Two equivalents of 28 were used. [b] Yields of products isolated.
[c] Starting material 23 was completely recovered.
It should be noted that the reaction between 23 and 27 is
best carried out from 08C to RT over 18 h, with the best yield
of 80%. Any attempts to lower the temperature gave lower
yields (0–52%) of the C4ÀC5 cyclopentyl-fused 2-arylchroman
28. In addition, in all cases (except entry 3 in Table 3, for which
there was no reaction), product 28 was obtained with excel-
lent diastereocontrol as a single diastereomer (>99:1) at the
C2ÀC3ÀC4 ring junctions.
Next, we investigated the scope of cinnamates 29a–i
(2 equiv) as dienophiles under the optimized reaction condi-
tions (Table 4). With 4-benzyloxy group, 4-benzyloxycinnamate
29a gave chroman 30a in a yield of 69%, which was slightly
lower than the yield obtained from 4-methoxycinnamate 27
(Table 4, entry 1). Both the number and position of the me-
thoxy groups on the aromatic ring are critical (Table 4, en-
tries 2–9). The reaction of 29 f gave chroman 30 f in a good
yield of 64% (Table 4, entry 6), whereas only moderate yields
of 38 and 45% of 30d[19] and 30e, respectively, were obtained
from 29d and 29e, respectively (Table 4, entries 4 and 5). In
contrast, no chromans 30b and 30c were obtained from the
reactions with 29b and 29c, respectively (Table 4, entries 2
and 3). Starting material 23 was completely consumed in both
cases, whereas yields of over 80% for 29b and 29c were re-
covered unchanged. Cinnamate 29g, with 4-Br replacing the
4-OMe group of 29c, provided the corresponding chroman
30g in a low yield of 13% (Table 4, entry 7). For cinnamates
29h and 29i, which contain three methoxy groups on the aro-
Scheme 5. Benzyl acetates 23 and 24 and their o-QM/HDA reactions.
DCM=dichloromethane.
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Table 4. Scope of the cinnamate esters 29 as dienophiles.
Entry
1
Cinnamate
Ar[a]
Chroman
Yield [%][b]
69
29a
30a
2
29b
30b
0[c]
3
4
5
6
7
29c
29d
29e
29 f
29g
30c
30d
30e
30 f
30g
0[c]
Scheme 6. Dienophiles 31–35 and HDA reactions of 23 with indole acrylate
36 and cinnamate 38 to give the products 37 and 39, respectively.
38
with our previous findings.[5] For acrylate 38, both methoxy
groups are not in conjugation with the acrylate moiety, which
means that the olefin is not sufficiently reactive as a dienophile
for the HDA reaction.
45
The effect of modifying the methylene carbon of the indanyl
system adjacent to the reactive configurationally fixed (E)-o-
QM was further investigated. To this end, indanone 20 was
subjected to dimethylation via the corresponding enolate
(Scheme 7). Following reduction and acetylation, compound
40 was obtained in a yield of 54% over 3 steps. Acetate 40
smoothly underwent the o-QM/HDA reaction with 27 to give
the corresponding chroman 41 in 60% yield.
64
13
8
9
29h
30h
30i
22
43
29i[d]
[a] Two equivalents of 29a–i were used. [b] Yields of products isolated.
[c] Compound 23 was completely consumed, but the reactions gave only
mixtures of unidentifiable byproducts, presumably from the decomposi-
tion of 23; >80% of 29b and 29c were recovered. [d] The corresponding
methyl ester was used.
matic ring, only low to moderate yields (22–43%) of the corre-
sponding products 30h and 30i could be obtained (Table 4,
entries 8 and 9). It is interesting to note that other cinnamates
31–33, which did not contain an electron-donating group, as
well as cyclohexyl acrylate 34 (Scheme 6), gave no desired
chroman products, as expected. In addition, even coumarin 35,
which contained a methoxy group at a position similar to that
in cinnamate 27, did not give the corresponding coumarin
chroman. In all cases, compounds 31–35 were virtually fully re-
covered.
Scheme 7. Modified indane 40, its chroman adduct 41, and C6-debrominat-
ed product 42 obtained from 28 through hydrogenolysis.
Debromination of 28 could be effectively performed
through palladium-catalyzed hydrogenolysis to give 42 in
a yield of 97% (Scheme 7).
Upon reacting with 36, benzyl acetate 23 did not give 2-(3’-
indolyl)-3-carboxyethylchroman, which was the expected prod-
uct; instead, acetate 23 gave 37 in moderate to good yields
(52–80%), depending on the amount of 36.[20] In addition, ace-
tate 23 also reacted with 38 to give arylated indane 39, in-
stead of the chroman. The formation of both diarylmethane-
type compounds 37 and 39 through the nucleophilic addition
of the electron-rich aromatic moiety to the o-QM is consistent
Conclusion
C6 modifications of the chroman core could be performed
either at the aldehyde stage or at the chroman stage, depend-
ing on the type of modification, by exploiting the bromine
atom at C6 as a handle. Palladium-catalyzed Suzuki reactions
were more effectively performed at the aldehyde stage, ulti-
mately giving the 6-arylated 2-phenylchromans in good overall
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cated by TLC (typically 20 h). The reaction mixture was cooled to
room temperature. Water and EtOAc were added and the two
phases were separated. The aqueous layer was extracted twice
with EtOAc and the combined organic phases were washed once
with brine, dried over Na2SO4, filtered, and concentrated under re-
duced pressure to give a crude product, which was further purified
by preparative thin-layer chromatography (PTLC; 30% EtOAc/hex-
anes) to give the product.
yields (up to 59%) over six steps starting from 2-hydroxy-4-me-
thoxybenzaldehyde. On the other hand, lithium–bromine ex-
change of 2-phenylchroman 6 provided the corresponding C6-
aryl anion, which could react with some electrophiles to give
the products in moderate to good yields (up to 55%).
The C4ÀC5 cyclopentyl-/cyclohexyl-fused 2-aryl-3-carboxy-
ethylchromans could be prepared via the configurationally
fixed (E)-o-QM. The presence of the five- or six-membered ring
at C4ÀC5 provided rigidity and forced the o-QMs to assume
the E configuration, which governed the outcome of the ensu-
ing endo-selective HDA reactions with various cinnamates to
give the corresponding chroman products with exclusive trans
relationships at both C2ÀC3 and C3ÀC4. Both the position and
number of electron-donating groups on the cinnamate were
crucial. For the five-membered ring series, the indane o-QM
precursor 23 could be prepared in a good overall yield of 66%
over 9 steps from 16. Including the final step of (E)-o-QM gen-
eration/HDA reaction (up to 80% yield), the C4ÀC5 cyclopen-
tyl-fused chromans could be prepared in moderate to good
yields (up to 53%) over 10 steps. In contrast, the C4ÀC5 cyclo-
hexyl-fused series were more challenging owing to some
lower-yielding steps and low stability of the o-QM precursor
24.
Compound 7
The product was obtained as a colorless oil (0.04 g, 0.13 mmol,
41% from 5 over 3 steps and 0.02 g, 0.065 mmol, 24% from 6).
1H NMR (300 MHz, CDCl3): d=2.06–2.25 (m, 2H), 2.73–2.80 (m, 1H),
2.92–3.00 (m, 1H), 3.75 (s, 3H), 5.07 (dd, J=10.1, 2.4 Hz, 1H), 6.57
(s, 1H), 7.03 (s, 1H), 7.24–7.51 ppm (m, 12H); 13C NMR (75 MHz,
CDCl3): d=24.3, 30.1, 55.6, 78.0, 100.1, 113.5, 123.3, 126.0, 126.4,
127.9, 128.5, 129.4, 131.3, 138.3, 141.5, 155.2, 155.7 ppm; IR (UATR):
n˜max =2926, 1618, 1583, 1484, 1264 cmÀ1; LRMS (EI): m/z (%): 316
(100) [M]+, 225 (13), 212 (27), 184 (10); HRMS (TOF): m/z calcd for
C22H21O2 [M+H]+: 317.1536; found: 317.1530.
Compound 8a
Synthetic applications of the developed method toward the
total synthesis of some complex natural products and non-nat-
ural medicinally important compounds are currently being pur-
sued in our laboratory and will be reported in due course.
The product was obtained as a yellow oil (0.098 g, 0.360 mmol,
99%). H NMR (300 MHz, CDCl3): d=3.56 (s, 3H), 3.88 (s, 3H), 5.35
1
(s, 2H), 6.81 (s, 1H), 7.31 (t, J=7.2 Hz, 1H), 7.39 (t, J=7.3 Hz, 2H),
7.47 (dd, J=8.2 Hz, 2H), 7.84 (s, 1H), 10.38 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3): d=55.8, 56.5, 94.9, 97.8, 118.9, 125.1, 127.1, 128.0,
129.3, 130.5, 136.8, 161.1, 162.6, 188.1 ppm; IR (UATR): n˜max =2922,
1671, 1599, 1484, 1285 cmÀ1; LRMS (EI): m/z (%): 272 (100) [M]+,
227 (41), 226 (77), 212 (21), 139 (22), 128 (17); HRMS (TOF): m/z
calcd for C16H17O4 [M+H]+: 273.1121; found: 273.1115.
Experimental Section
General
Unless otherwise noted, reactions were run in oven-dried round-
bottomed flasks. Tetrahydrofuran (THF) was distilled from sodium
benzophenone ketyl or purified by the solvent purification system
(Innovative Technology); DCM was also purified by the solvent pu-
rification system (Innovative Technology) prior to use. All other
compounds were used as received from the suppliers. The crude
reaction mixtures were concentrated under reduced pressure by
removing organic solvents on a rotary evaporator. Column chroma-
tography was performed by using silica gel 60 (particle size 0.06–
0.2 mm; 70–230 mesh ASTM). Analytical TLC was performed with
silica gel 60 F254 aluminum sheets. Chemical shifts for 1H NMR
spectra were reported in ppm (d) downfield from tetramethylsilane
(TMS). Splitting patterns are described as singlet (s), doublet (d),
triplet (t), quartet (q), multiplet (m), broad (br), and doublet of dou-
blets (dd). Resonances for IR spectra are reported in wavenumbers
(cmÀ1). Low-resolution (LR) mass spectra were obtained by using
either electron ionization (EI) or time-of-flight (TOF) methods,
whereas high resolution (HR) mass spectra were obtained by using
the TOF method. Melting points are uncorrected.
Compound 8b
The product was obtained as a yellow solid (0.095 g, 0.310 mmol,
85%). M.p. (EtOAc/hexanes) 87.2–88.98C; H NMR (300 MHz, CDCl3):
1
d=3.58 (s, 3H), 3.85 (s, 3H), 5.36 (s, 2H), 6.80 (s, 1H), 7.24–7.32 (m,
3H), 7.41–7.46 (m, 1H), 7.71 (s, 1H), 10.37 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3): d=55.7, 56.3, 94.6, 97.3, 118.3, 122.8, 126.2, 128.6,
129.0, 130.6, 131.4, 133.8, 135.9, 161.5, 162.8, 187.8 ppm; IR (UATR):
n˜max =2925, 1672, 1605, 1573, 1449, 1261 cmÀ1; LRMS (EI): m/z (%):
308 (32) [C16H1537ClO4]+, 306 (100) [C16H1535ClO4]+, 260 (88), 246
(58), 155 (47), 127 (43), 75 (24), 57 (45); HRMS (TOF): m/z calcd for
C16H1635ClO4 [M+H]+ and C16H1637ClO4 [M+H]+: 307.0731, 309.0708;
found: 307.0738, 309.0705.
Compound 8c
The product was obtained as a colorless oil (0.105 g, 0.318 mmol,
1
87%). H NMR (300 MHz, CDCl3): d=3.58 (s, 3H), 3.64 (s, 3H), 3.84
(s, 3H), 3.89 (s, 3H), 5.36 (s, 2H), 6.792 (dd, J=7.6, 1.5 Hz, 1H),
6.793 (s, 1H), 6.94 (dd, J=8.2, 1.5 Hz, 1H), 7.03–7.11 (m, 1H), 7.74
(s, 1H), 10.37 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=55.8, 55.9,
56.6, 60.6, 94.9, 97.5, 112.0, 118.6, 122.2, 123.2, 123.6, 130.9, 131.4,
147.2, 152.6, 161.4, 163.3, 188.2 ppm; IR (UATR): n˜max =2937, 1675,
1244 cmÀ1; LRMS (EI): m/z (%): 332 (100) [M]+, 286 (63); HRMS
(TOF): m/z calcd for C18H20NaO6 [M+Na]+: 355.1152; found:
355.1164.
General Procedure for the Suzuki Cross-Coupling Reaction
K2CO3 (2.0 equiv), boronic acid derivatives (1.2 equiv), and H2O
(6 mL mmolÀ1 of starting material) were added to a stirred solution
of aryl bromide (1.0 equiv), in toluene/EtOH (1:1, 10 mLmmolÀ1 of
starting material). The reaction mixture was stirred vigorously and
[Pd(PPh3)4] (5 mol%) was added, and the reaction mixture was
heated at reflux until all starting material was consumed, as indi-
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Compound 8d
General Procedure for Borohydride Reduction/Acetylation
The product was obtained as a yellow solid (0.106 g, 0.318 mmol,
87%). M.p. (EtOAc/hexanes) 109.9–111.88C; 1H NMR (300 MHz,
CDCl3): d=3.56 (s, 3H), 3.74 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 5.34
(s, 2H), 6.50–6.55 (m, 2H), 6.78 (s, 1H), 7.07–7.13 (m, 1H), 7.24 (s,
1H), 10.36 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=55.3, 55.6,
55.9, 56.5, 94.9, 97.7, 98.8, 104.2, 118.66, 118.72, 122.0, 127.4, 131.7,
158.0, 160.5, 161.1, 163.5, 188.3 ppm; IR (UATR): n˜max =2941, 1599,
1151 cmÀ1; LRMS (EI): m/z (%): 332 (100) [M]+, 286 (76); HRMS
(TOF): m/z calcd for C18H20NaO6 [M+Na]+: 355.1152; found:
355.1168.
NaBH4 (1.5 equiv) was added to a solution of the MOM-protected
benzaldehyde (1.0 equiv) in EtOH (10 mLmmolÀ1) at 08C, and the
reaction was warmed up and stirred at room temperature for 2 h.
The resulting mixture was concentrated under reduced pressure.
Water and EtOAc were added and the two phases were separated.
The aqueous layer was extracted with EtOAc and the combined or-
ganic phases were washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure to give a crude product,
which was used in the acetylation step without further purification.
A solution of the benzyl alcohol (1.0 equiv) in DCM (10 mLmmolÀ1
)
was cooled in an ice bath for 10 min before DMAP (1.5 equiv) and
Et3N (1.5 equiv) were added. Ac2O (1.5 equiv) was then slowly
added by means of a syringe to the mixture and then the resulting
mixture was warmed to room temperature and stirred until com-
plete consumption of the starting material, as indicated by TLC
(normally 3–4 h). Water and DCM were added and the two phases
were separated. The aqueous layer was extracted with DCM and
the combined organic phases were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure to give
the crude benzyl acetate product, which was further purified by
column chromatography on silica gel (30% EtOAc/hexanes) to give
the desired product.
Compound 8e
The product was obtained as a white solid (0.108 g, 0.325 mmol,
89%). M.p. (EtOAc/hexanes) 87.2–88.98C; H NMR (300 MHz, CDCl3):
1
d=3.57 (s, 3H), 3.90 (s, 6H), 3.91 (s, 3H), 5.35 (s, 2H), 6.81 (s, 1H),
6.91 (d, J=8.4 Hz, 1H), 7.01 (d, J=1.8 Hz, 1H), 7.00–7.06 (m, 2H),
7.82 (s, 1H), 10.38 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=55.8,
56.4, 94.8, 97.7, 110.7, 112.6, 118.8, 121.7, 124.8, 129.4, 130.1, 148.1,
148.3, 160.8, 162.5, 188.1 ppm; IR (UATR): n˜max =2931, 1676, 1598,
1452, 1251 cmÀ1; LRMS (EI): m/z (%): 332 (100) [M]+, 286 (99),
272 (39), 216 (17), 127 (16); HRMS (TOF): m/z calcd for C18H21O6
[M+H]+: 333.1332; found: 333.1328.
Compound 9a
Compound 8 f
Benzaldehyde 8a (0.10 g, 0.37 mmol) was converted into the corre-
sponding benzyl acetate, which was obtained as colorless oil
(0.086 g, 0.27 mmol, 73%). 1H NMR (300 MHz, CDCl3): d=2.07 (s,
3H), 3.52 (s, 3H), 3.81 (s, 3H), 5.15 (s, 2H), 5.26 (s, 2H), 6.82 (s, 1H),
7.29 (t, J=7.2 Hz, 2H), 7.39 (t, J=7.3 Hz, 2H), 7.49 ppm (d, J=
7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=21.0, 55.7, 56.1, 61.5,
94.6, 98.7, 116.9, 124.1, 126.6, 127.9, 129.4, 132.6, 137.8, 155.9,
157.5, 171.0 ppm; IR (UATR): n˜max =2956, 2833, 1733, 1614,
1488 cmÀ1; LRMS (EI): m/z (%): 316 (6) [M]+, 213 (21), 212 (100),
184 (25), 141 (10), 115 (8); HRMS (TOF): m/z calcd for C18H20O5 [M]+:
316.1305; found: 316.1313.
The product was obtained as a yellow solid (0.025 g, 0.082 mmol,
45%). M.p. (EtOAc/hexanes) 118.5–119.28C; 1H NMR (300 MHz,
CDCl3): d=3.58 (s, 3H), 3.92 (s, 3H), 5.38 (s, 2H), 6.86 (s, 1H), 7.56
(t, J=6.7 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 8.17 (dd, J=
8.2, 1.5 Hz, 1H), 8.38 (s, 1H), 10.39 ppm (s, 1H); 13C NMR (75 MHz,
CDCl3): d=56.0, 56.5, 94.8, 97.9, 119.0, 121.8, 122.4, 124.3, 128.9,
130.4, 135.2, 138.4, 147.9, 161.7, 162.4, 187.8 ppm; IR (UATR): n˜max
=
2925, 1672, 1601, 1527, 1347 cmÀ1; LRMS (EI): m/z (%): 317 (41)
[M]+, 149 (66), 81 (39), 71 (64), 69 (97), 55 (69); HRMS (TOF): m/z
calcd for C16H16NO6 [M+H]+: 318.0972; found: 318.0969.
Compound 8g
Compound 9b
The product was obtained as a white solid (0.092 g, 0.285 mmol,
78%). M.p. (EtOAc/hexanes) 131.8–133.08C; 1H NMR (300 MHz,
CDCl3): d=3.59 (s, 3H), 3.74 (s, 3H), 5.38 (s, 2H), 6.86 (s, 1H), 7.34–
7.40 (m, 2H), 7.41–7.54 (m 3H), 7.82 (s, 1H), 7.82–7.89 (m. 2H),
10.42 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=55.8, 56.6, 94.9,
97.6, 118.8, 123.9, 125.3, 125.6, 125.7, 126.0, 127.6, 128.0, 128.2,
Benzaldehyde 8b (0.081 g, 0.264 mmol) was converted into the
corresponding benzyl acetate, which was obtained as a colorless
1
oil (0.066 g, 0.187 mmol, 71%). H NMR (300 MHz, CDCl3): d=2.07
(s, 3H), 3.53 (s, 3H), 3.78 (s,3H), 5.15 (s, 2H), 5.27 (s, 2H), 6.81 (s,
1H), 7.17 (s, 1H), 7.22–7.30 (m, 3H), 7.40–7.46 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=21.0, 55.8, 56.2, 61.5, 94.7, 98.4, 116.5,
121.8, 126.4, 128.4, 129.3, 131.9, 132.5, 134.1, 137.0, 156.5, 157.9,
171.0 ppm; IR (UATR): n˜max =2956, 1735, 1139, 1000 cmÀ1; LRMS
(EI): m/z (%): 352 (5) [C18H1937ClO5]+, 350 (4) [C18H1935ClO5]+, 248
(35), 246 (100); HRMS (TOF): m/z calcd for C18H1935ClNaO5 [M+Na]+,
C18H1937ClNaO5 [M+Na]+: 373.0813, 375.0789; found: 373.0816,
375.0798.
131.7, 132.1, 133.4, 135.2, 161.5, 163.5, 181.2 ppm; IR (UATR): n˜max
=
2939, 1676, 1601, 1141 cmÀ1; LRMS (EI): m/z (%): 322 (100) [M]+,
276 (54), 84 (48); HRMS (TOF): m/z calcd for C20H19O4 [M+H]+:
323.1278; found: 323.1282.
Compound 8h
The product was obtained as a yellow solid (0.087 g, 0.336 mmol,
92%). M.p. (EtOAc/hexanes) 102.9–103.78C; 1H NMR (300 MHz,
CDCl3): d=3.54 (s, 3H), 3.98 (s, 3H), 5.31 (s, 2H), 6.46 (dd, J=3.3,
1.8 Hz, 1H), 6.78 (s, 1H), 6.81 (d, J=3.3 Hz, 1H), 7.45 (d, J=1.8 Hz,
1H), 8.32 (s, 1H), 10.36 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=
55.9, 56.5, 94.9, 97.8, 109.1, 111.4, 114.9, 118.9, 126.3, 141.2, 148.9,
160.4, 161.1, 188.1 ppm; IR (UATR): n˜max =2941, 2860, 1668, 1607,
1572, 1388 cmÀ1; LRMS (EI): m/z (%): 262 (73) [M]+, 232 (21), 216
(100), 202 (18), 173 (10), 102 (10), 89 (12); HRMS (TOF): m/z calcd
for C14H15O5 [M+H]+: 263.0914; found: 263.0907.
Compound 9c
Benzaldehyde 8c (0.077 g, 0.232 mmol) was converted into the
corresponding benzyl acetate, which was obtained as a pale
yellow oil (0.075 g, 0.200 mmol, 86%). 1H NMR (300 MHz, CDCl3):
d=2.06 (s, 3H), 3.53 (s, 3H), 3.65 (s, 3H), 3.78 (s, 3H), 3.89 (s, 3H),
5.13 (s, 2H), 5.26 (s, 2H), 6.80 (s, 1H), 6.84 (dd, J=7.6, 1.5 Hz, 1H),
6.92 (dd, J=8.2, 1.5 Hz, 1H), 7.03–7.10 (m, 1H), 7.21 ppm (s, 1H);
13C NMR (75 MHz, CDCl3): d=21.0, 55.73, 55.75, 56.1, 60.5, 61.6,
94.7, 98.3, 111.6, 116.3, 120.8, 123.3, 123.5, 132.2, 132.7, 147.1,
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152.6, 157.9, 171.0 ppm; IR (neat): n˜max =2937, 1734, 1468, 1217,
1006 cmÀ1; LRMS (EI): m/z (%): 376 (17) [M]+, 272 (100); HRMS
(TOF): m/z calcd for C20H24NaO7 [M+Na]+: 399.1414; found:
399.1428.
Compound 9h
Benzaldehyde 8h (0.082 g, 0.313 mmol) was converted into the
corresponding benzyl acetate, which was obtained as a white solid
(0.065 g, 0.213 mmol, 68%). M.p. (EtOAc/hexanes) 46.1–48.38C;
1H NMR (300 MHz, CDCl3): d=2.09 (s,3H), 3.50 (s, 3H), 3.93 (s, 3H),
5.15 (s, 2H), 5.24 (s, 2H), 6.46 (dd, J=3.1, 1.8 Hz, 1H), 6.78 (s, 1H),
6.81 (dd, J=3.1, 0.7 Hz, 1H), 7.43 (dd, J=1.8, 0.7 Hz, 1H), 7.80 ppm
(s, 1H); 13C NMR (75 MHz, CDCl3): d=21.0, 55.6, 56.1, 61.6, 94.6,
98.4, 108.4, 111.5, 113.9, 117.0, 128.0, 140.7, 149.8, 155.5, 156.5,
171.0 ppm; n˜max =2939, 1735, 1218 cmÀ1; LRMS (EI): m/z (%):
306 (16) [M]+, 202 (100); HRMS (TOF): m/z calcd for C16H18NaO6
[M+H]+: 329.0996; found: 329.1001.
Compound 9d
Benzaldehyde 8d (0.100 g, 0.301 mmol) was converted into the
corresponding benzyl acetate, which was obtained as a colorless
1
oil (0.084 g, 0.217 mmol, 72%). H NMR (300 MHz, CDCl3): d=2.06
(s, 3H), 3.52 (s, 3H), 3.76 (s, 3H), 3.77 (s, 3H), 3.84 (s, 3H), 5.13 (s,
2H), 5.25 (s, 2H), 6.53–6.56 (m, 2H), 6.80 (s, 1H), 7.11–7.16 (m, 1H),
7.20 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=21.1, 55.3, 55.6,
55.9, 56.1, 61.7, 94.7, 98.7, 98.8, 104.2, 116.3, 119.6, 120.8, 131.9,
133.3, 155.8, 158.0, 158.3, 160.2, 171.1 ppm; IR (neat): n˜max =2939,
1733, 1607, 1496, 1207 cmÀ1; LRMS (EI): m/z (%): 376 (22) [M]+, 272
(100); HRMS (TOF): m/z calcd for C20H24NaO7 [M+Na]+: 399.1414;
found: 399.1413.
General Procedure for the [PtCl4]-Mediated Generation of
o-QM and HDA Reaction
Styrene (10 equiv) was added to a stirred solution of benzyl ace-
tate (1.0 equiv) in DCM (10 mLmmolÀ1) at room temperature. The
resulting mixture was stirred at 08C for 10 min and then [PtCl4]
(10 mol%) was added. The reaction mixture was stirred until the
starting material was consumed, as indicated by TLC (typically 3–
4 h). At that time, the reaction mixture was filtered to remove
[PtCl4], which was washed with excess CH2Cl2. The filtrate was then
concentrated under reduced pressure to give a crude product mix-
ture, which was further purified by column chromatography on
silica gel (10% EtOAc/hexanes) to give the desired product.
Compound 9e
Benzaldehyde 8e (0.05 g, 0.15 mmol) was converted into the corre-
sponding benzyl acetate, which was obtained as a colorless oil
(0.033 g, 0.089 mmol, 59%). 1H NMR (300 MHz, CDCl3): d=2.07 (s,
3H), 3.52 (s, 3H), 3.81 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 5.15 (s, 2H),
5.26 (s, 2H), 6.81 (s, 1H), 6.91 (d, J=9 Hz, 1H), 7.03 (d, J=6.9 Hz,
2H), 7.28 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=20.9, 55.7, 56.0,
61.5, 94.5, 98.6, 110.7, 112.8, 116.7, 121.5, 123.8, 130.4, 132.3, 147.8,
148.2, 155.6, 157.4, 170.9 ppm; IR (UATR): n˜max =2993, 1733, 1612,
1588, 1499 cmÀ1; LRMS (EI): m/z (%): 376 (13) [M]+, 273 (22), 272
(100), 241 (21), 71 (10), 57 (15); HRMS (TOF): m/z calcd for C20H24O7
[M]+: 376.1516; found: 376.1521.
Compound 10b
Acetate 9b (0.021 g, 0.057 mmol) underwent the o-QM/HDA reac-
tion to give the product as a colorless oil (0.017 g, 0.046 mmol,
82%). 1H NMR (300 MHz, CDCl3): d=2.04–2.27 (m, 2H), 2.71–2.82
(m, 1H), 2.90–3.04 (m, 1H), 3.73 (s, 3H), 5.01 (dd, J=10.1, 2.6 Hz,
1H), 6.59 (s, 1H), 6.91 (s, 1H), 7.21–7.48 ppm (m, 9H); 13C NMR
(75 MHz, CDCl3): d=24.4, 30.1, 55.7, 78.1, 99.9, 113.1, 121.2, 126.1,
126.3, 127.9, 128.2, 128.56, 128.63, 129.2, 131.4, 132.0, 134.3, 137.6,
141.6, 155.8, 156.1 ppm; n˜max =2929, 1619, 1444, 1141 cmÀ1; LRMS
(EI): m/z (%): 352 (3) [C22H1937ClO2]+, 350 (6) [C22H1935ClO2]+, 86 (35),
84 (100); HRMS (TOF): m/z calcd for C22H2035ClO2 [M+H]+,
C22H2037ClO2 [M+H]+: 351.1146, 353.1125; found: 351.1144,
353.1127.
Compound 9 f
Benzaldehyde 8 f (0.11 g, 0.33 mmol) was converted into the corre-
sponding benzyl acetate, which was obtained as a yellow oil
(0.07 g, 0.19. mmol, 58%). 1H NMR (300 MHz, CDCl3): d=2.09 (s,
3H), 3.53 (s, 3H), 3.84 (s, 3H), 5.16 (s, 2H), 5.29 (s, 2H), 6.85 (s, 1H),
7.33 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 8.14 (dd,
J=8.2 Hz, 1H), 8.38 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=21.0,
55.8, 56.2, 61.3, 94.5, 117.3, 121.4, 123.2, 124.3, 128.7, 132.3, 135.4,
139.5, 148.0, 156.8, 157.5, 171.0 ppm; IR (UATR): n˜max =2938, 1734,
1614, 1508, 1346 cmÀ1; LRMS (EI): m/z (%): 361 (8) [M]+, 258 (20),
257 (100), 229 (30), 69 (16), 57 (10); HRMS (TOF): m/z calcd for
C18H19NO7 [M]+: 361.1156; found: 361.1157.
Compound 10c
Acetate 9c (0.021 g, 0.057 mmol) underwent the o-QM/HDA reac-
tion to give the product as a pale yellow oil (0.011 g, 0.029 mmol,
51%). 1H NMR (300 MHz, CDCl3): d=2.03–2.26 (m, 2H), 2.69–2.81
(m, 1H), 2.89–3.03 (m, 1H), 3.66 (s, 3H), 3.73 (s, 3H), 3.89 (s, 3H),
5.07 (dd, J=10.0, 2.6 Hz, 1H), 6.56 (s, 1H), 6.86 (dd, J=7.6, 1.6 Hz,
1H), 6.90 (dd, J=8.2, 1.6 Hz, 1H), 6.95 (s, 1H), 7.02–7.10 (m, 1H),
7.29–7.50 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d=55.8, 55.9,
56.6, 60.6, 94.9, 97.5, 112.0, 118.6, 122.2, 123.2, 123.6, 130.9, 131.4,
147.2, 152.6, 161.4, 163.3, 188.2 ppm; IR (UATR): n˜max =2931, 1466,
1099, 699 cmÀ1; LRMS (EI): m/z (%): 376 (100) [M]+; HRMS (TOF):
m/z calcd for C24H25O4 [M+H]+: 377.1747; found: 377.1757.
Compound 9g
Benzaldehyde 8g (0.080 g, 0.248 mmol) was converted into the
corresponding benzyl acetate, which was obtained as a colorless
1
oil (0.086 g, 0.233 mmol, 94%). H NMR (300 MHz, CDCl3): d=3.58
(s, 3H), 3.64 (s, 3H), 3.84 (s, 3H), 3.89 (s, 3H), 5.36 (s, 2H), 6.792
(dd, J=7.6, 1.5 Hz, 1H), 6.793 (s, 1H), 6.94 (dd, J=8.2, 1.5 Hz, 1H),
7.03–7.11 (m, 1H), 7.74 (s, 1H), 10.37 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3): d=55.8, 55.9, 56.6, 60.6, 94.9, 97.5, 112.0, 118.6,
122.2, 123.2, 123.6, 130.9, 131.4, 147.2, 152.6, 161.4, 163.3,
188.2 ppm; IR (neat): n˜max =2955, 1735, 1503, 1216, 778 cmÀ1; LRMS
(EI): m/z (%): 366 (31) [M]+, 262 (100); HRMS (TOF): m/z calcd for
C22H22NaO5 [M+Na]+: 389.1359; found: 389.1347.
Compound 10d
Acetate 9d (0.021 g, 0.057 mmol) underwent the o-QM/HDA reac-
tion to give the product as a white solid (0.018 g, 0.047 mmol,
82%). M.p. (EtOAc/hexanes) 59.6–61.28C; H NMR (300 MHz, CDCl3):
d=2.02–2.25 (m, 2H), 2.70–2.81 (m, 1H), 2.89–3.03 (m, 1H), 3.72 (s,
3H), 3.77 (s, 3H), 3.84 (s, 3H), 5.04 (dd, J=10.0, 2.6 Hz, 1H), 6.50–
6.56 (m, 3H), 6.94 (s, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.29–7.48 ppm
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(m, 5H); 13C NMR (75 MHz, CDCl3): d=24.5, 30.3, 55.3, 55.7, 55.8,
Compound 11
78.1, 98.9, 100.1, 104.2, 113.1, 120.0, 120.3, 126.1, 127.9, 128.5,
Chroman 6 (0.02 g, 0.06 mmol) underwent lithium–bromine ex-
change followed by the reaction with methyl chloroformate
(0.02 mL, 0.25 mmol) to give the product as a yellow oil (0.01 g,
0.03 mmol, 53%). 1H NMR (300 MHz, CDCl3): d=2.10–2.27 (m,2H),
2.71–2.88 (m, 1H), 2.90–2.97 (m, 1H), 3.90 (s, 6H), 5.10 (dd, J=10.0,
2.5 Hz, 1H), 6.51 (s, 1H), 7.26–7.41 (m, 5H), 7.67 ppm (s, 1H);
13C NMR (75 MHz, CDCl3): d=24.1, 29.7, 51.7, 56.1, 78.5, 100.5,
111.9, 113.5, 126.0, 128.1, 128.6, 133.7, 140.9, 159.6, 166.3 ppm; IR
(UATR): n˜max =2921, 2850, 1722, 1572, 1279, 1143 cmÀ1; LRMS (EI):
m/z (%): 298 (100) [M]+, 239 (70); HRMS (TOF): m/z calcd for
C18H19O4 [M+H]+: 299.1278; found: 299.1275.
131.9, 132.0, 141.8, 155.0, 156.5, 158.1, 160.0 ppm; IR (UATR): n˜max
=
2929, 1608, 1582, 1489, 1140 cmÀ1; LRMS (EI): m/z (%): 376 (86)
[M]+, 178 (100); HRMS (TOF): m/z calcd for C24H25O4 [M+H]+:
377.1747; found: 377.1763.
Compound 10e
Acetate 9e (0.025 g, 0.066 mmol) underwent the o-QM/HDA reac-
tion to give the product as a colorless oil (0.014 g, 0.037 mmol,
56%). 1H NMR (300 MHz, CDCl3): d=2.04–2.26 (m, 2H), 2.73–2.81
(m, 1H), 2.91–3.02 (m, 1H), 3.77 (s, 3H), 3.90 (s, 3H), 3.91 (s, 3H),
5.08 (dd, J=10.0, 2.4 Hz, 1H), 6.57 (s, 1H), 6.90 (d, J=8.7 Hz, 1H),
7.04 (d, J=9.6 Hz, 3H), 7.33–7.46 ppm (m, 5H); 13C NMR (75 MHz,
CDCl3): d=24.2, 30.0, 55.5, 55.7, 77.9, 100.0, 110.7, 112.8, 113.4,
121.5, 123.0, 125.9, 127.8, 128.4, 131.0, 141.4, 147.6, 148.2, 154.8,
Compound 12
Chroman 6 (0.022 g, 0.07 mmol) underwent lithium–bromine ex-
change followed by the reaction with DMF (0.02 mL, 0.28 mmol) to
155.6 ppm; IR (UATR): n˜max =2931, 1607, 1583, 1492, 1443 cmÀ1
;
1
give the product as a yellow oil (0.01 g, 0.04 mmol, 55%). H NMR
LRMS (EI): m/z (%): 376 (19) [M]+, 270 (70), 166 (100), 138 (26), 91
(39), 55 (16); HRMS (TOF): m/z calcd for C24H25O4 [M+H]+:
377.1747; found: 377.1742.
(300 MHz, CDCl3): d=2.11–2.29 (m, 2H), 2.73–2.81 (m, 1H), 2.87–
2.98 (m, 1H), 3.86 (s, 3H), 5.13 (dd, J=10.1, 2.6 Hz, 1H), 6.48 (s,
1H), 7.32–7.44 (m, 5H), 7.62 (s, 1H), 10.29 ppm (m, 1H); 13C NMR
(75 MHz, CDCl3): d=24.0, 29.6, 55.7, 78.8, 99.7, 114.5, 118.8, 125.9,
128.2, 128.6, 130.2, 140.7, 161.7, 162.0, 188.5 ppm; IR (UATR): n˜max
=
Compound 10 f
3031, 2924, 1669, 1611, 1276, 1114 cmÀ1; LRMS (EI): m/z (%): 268
(65) [M]+, 239 (32), 149 (100); HRMS (TOF): m/z calcd for C17H17O3
[M+H]+: 269.1172; found: 269.1180.
Acetate 9 f (0.031 g, 0.086 mmol) underwent the o-QM/HDA reac-
tion to give the product as a yellow oil (0.016 g, 0.044 mmol, 51%).
1H NMR (300 MHz, CDCl3): d=1.98–2.22 (m, 2H), 2.68–2.76 (m, 1H),
2.85–2.96 (m, 1H), 3.71 (s, 3H), 5.03 (dd, J=9.9, 2.4 Hz, 1H), 6.52 (s,
1H), 7.00 (s, 1H), 7.27–7.39 (m, 5H), 7.45 (t, J=7.9 Hz, 1H), 7.77 (d,
J=8.4 Hz, 1H), 8.05 (dd, J=8.2, 1.2 Hz, 1H), 8.31 ppm (s, 1H);
13C NMR (75 MHz, CDCl3): d=24.1, 29.8, 55.6, 78.1, 100.1, 114.0,
120.6, 121.1, 124.1, 125.9, 127.9, 128.5, 128.6, 131.1, 135.4, 140.0,
141.1, 148.0, 155.6, 156.1 ppm; IR (UATR): n˜max =3026, 2924, 1734,
1618, 1448 cmÀ1; LRMS (EI): m/z (%): 361 (9) [M]+, 167 (14), 149
(45), 83 (42), 69 (82), 55 (61); HRMS (TOF): m/z calcd for C22H20NO4
[M+H]+: 362.1386; found: 362.1376.
Compound 13
Chroman 6 (0.024 g, 0.07 mmol) underwent lithium–bromine ex-
change followed by the reaction with N,N-dimethylsulfamoyl chlo-
ride (0.03 mL, 0.31 mmol) to give the product as a yellow oil
1
(0.014 g, 0.04 mmol, 37%). H NMR (300 MHz, CDCl3): d=2.03–2.22
(m, 3H), 2.67–2.74 (m, 2H), 2.84–2.95 (m, 2H), 3.76 (s, 1H, minor),
3.83 (s, 3H), 5.01–5.06 (m, 2H), 6.47–6.50 (m, 1H), 6.51 (s, 1H), 6.98
(d, J=4.5 Hz, 1H, minor), 7.07 (s, 1H), 7.31–7.44 ppm (m, 8H); IR
(UATR): n˜max =3749, 3031, 2927, 1614, 1500, 1443, 1152 cmÀ1; LRMS
(EI): m/z (%): 347 (0.47) [M]+, 274 (100), 239 (97).
Compound 10g
Acetate 9g (0.021 g, 0.057 mmol) underwent the o-QM/HDA reac-
tion to give the product as a colorless oil (0.017 g, 0.046 mmol,
81%). 1H NMR (300 MHz, CDCl3): d=2.09–2.30 (m, 2H), 2.71–2.83
(m 1H), 2.91–3.09 (m, 1H), 3.64 (s, 3H), 5.12 (ddd, J=9.9, 7.2,
2.7 Hz, 1H), 6.63 (s,1H), 6.99 (s, 1H), 7.30–7.54 (m, 9H), 7.63–7.70
(m, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.86 ppm (d, J=7.9 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=55.8, 55.9, 56.6, 60.6, 94.9, 97.5, 112.0,
118.6, 122.2, 123.2, 123.6, 130.9, 131.4, 147.2, 152.6, 161.4, 163.3,
188.2 ppm; IR (UATR): n˜max =2928, 1616, 1494, 1142 cmÀ1; LRMS
(EI): m/z (%): 366 (100) [M]+; HRMS (TOF): m/z calcd for C26H23O2
[M+H]+: 367.1693; found: 367.1698.
Compound 19
Method A: For the synthesis of (E)-3,5-dimethoxycinnamic acid,
a
solution of 16 (1.08 g, 6.52 mmol), malonic acid (3.39 g,
32.6 mmol), dry pyridine (10.5 mL, 131 mmol), and piperidine
(2.60 mL, 26.1 mmol) was heated on a boiling water bath for 4 h.
The reaction mixture was cooled and poured into cold water
(50 mL) and carefully acidified with dilute HCl (1:1) with stirring.
Upon filtration, 3,5-dimethoxycinnamic acid was obtained as
a white solid (1.28 g, 6.15 mmol, 94%). M.p. (EtOAc/hexanes) 170–
1718C; 1H NMR (400 MHz, CDCl3): d=3.82 (s, 6H), 6.40 (d, J=
15.9 Hz, 1H), 6.52 (t, J=2.2 Hz, 1H), 6.69 (d, J=2.2 Hz, 2H),
7.69 ppm (d, J=15.9 Hz, 1H); 13C NMR (100 MHz, CDCl3 +MeOH):
d=55.2, 102.4, 105.9, 118.6, 136.2, 145.2, 160.8, 169.0 ppm; IR
(UATR): n˜max =2926, 2835, 1682, 1633, 1433 cmÀ1; LRMS (EI): m/z
(%): 208 (25) [M]+, 149 (47), 97 (30), 83 (38), 71 (60), 69 (72), 57
(100); HRMS (TOF): m/z calcd for C11H11O4 [MÀH]+: 207.0662;
found: 207.0656.
General Procedure for Lithium–Bromine Exchange of Chroman
6 and Its Reactions with Electrophiles
n-BuLi (2.0m, 2.0 equiv) was added to a solution of 6 (1.0 equiv) in
THF (10 mLmmolÀ1
)
at À788C. After 5 min, the electrophile
(4.0 equiv) was added neat by means of a syringe at À788C and
the reaction mixture was allowed to stir for 1 h. Water and EtOAc
were added and the two phases were separated. The aqueous
layer was extracted with EtOAc and the combined organic phases
were washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure to give a crude product, which was
further purified by PTLC with 5–10% EtOAc/hexanes as the eluent.
For the synthesis of 3-(3’,5’-dimethoxyphenyl)propionic acid from
(E)-3,5-dimethoxycinnamic acid, palladium on activated charcoal
(0.12 g, 0.12 mmol) was added to a solution of 3,5-dimethoxycin-
namic acid (0.26 g, 1.23 mmol) in EtOAc (12 mL). The resulting mix-
ture was stirred at room temperature under a hydrogen atmos-
phere until complete consumption of the starting material, as indi-
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cated by TLC (1–2 h). The palladium catalyst was removed by filtra-
tion through Celite and the filtrate was concentrated under re-
duced pressure to give a crude product, which was further purified
by PTLC (50% EtOAc/hexanes) to give the propionic acid product
as a white solid (0.22 g, 1.05 mmol, 84%). M.p. (EtOAc/hexanes)
2 h. EtOH was removed under reduced pressure and water (50 mL)
and Et2O (50 mL) were added to the resulting crude product. The
two phases were separated; the aqueous phase was later acidified
to pHꢀ4. EtOAc (50 mL) was added and the two phases were sep-
arated. The aqueous layer was extracted with EtOAc (3ꢁ50 mL)
and the combined organic phases were washed with brine, dried
over Na2SO4 (50 mL), and concentrated under reduced pressure to
give the crude product (2.86 g), which was used in the next step
without further purification.
1
57–588C; H NMR (400 MHz, CDCl3): d=2.67 (t, J=7.8 Hz, 2H), 2.67
(t, J=7.8 Hz, 2H), 3.78 (s, 6H), 6.35 (s, 1H), 6.39 (s, 2H), 11.33 ppm
(brs, 1H); 13C NMR (100 MHz, CDCl3): d=30.8, 35.4, 55.2, 98.3,
106.3, 142.5, 160.9, 179.3 ppm; IR (UATR): n˜max =2993, 1705, 1594,
1460, 1429 cmÀ1; LRMS (EI): m/z (%): 210 (48) [M]+, 165 (100), 57
(24), 55 (24); HRMS (TOF): m/z calcd for C11H13O4 [MÀH]+:
209.0819; found: 209.0819.
Oxalyl chloride (1.71 mL, 20.3 mmol) and DMF (2–3 drops) were
added to a solution of the propionic acid (2.86 g) in toluene
(135 mL), and the resulting mixture was stirred for 3.5 h at room
temperature. The reaction mixture was evaporated under reduced
pressure. The residue was dissolved in DCM (135 mL), and a solu-
tion of SnCl4 in DCM (1.0m, 13.5 mL, 13.5 mmol) was added over
20 min with ice cooling. After being stirred for 2 h, the reaction
mixture was quenched with water (50 mL) and the resulting mix-
ture was extracted with DCM (3ꢁ50 mL). The organic layer was
dried over Na2SO4 and evaporated under reduced pressure to give
a crude product, which was further purified by column chromatog-
raphy (80% EtOAc/hexanes) to give the desired product indanone
19 as a light yellow solid (2.60 g, 13.5 mmol, 99%).
For the synthesis of 19 from 3-(3’,5’-dimethoxyphenyl)propionic
acid, oxalyl chloride (0.60 mL, 6.72 mmol) and DMF (2–3 drops)
were added to a solution of propionic acid (0.94 g, 4.47 mmol) in
toluene (20 mL), and the resulting mixture was stirred for 3.5 h at
room temperature. The reaction mixture was evaporated under re-
duced pressure. The residue was dissolved in DCM (20 mL), and
a solution of SnCl4 in DCM (1.0m, 5.00 mL, 4.92 mmol) was added
over 20 min with ice cooling. After being stirred for 2 h, the reac-
tion mixture was quenched with water (20 mL) and the resulting
mixture was extracted with DCM (3ꢁ20 mL). The organic layer was
dried over Na2SO4 and evaporated under reduced pressure to give
a crude product, which was further purified by column chromatog-
raphy (80% EtOAc/hexanes) to give the desired product indanone
19 as a light yellow solid (0.65 g, 3.38 mmol, 75%). M.p. (EtOAc/
Compound 20
For the synthesis of 7-hydroxy-5-methoxy-1-indanone, BCl3
(7.38 mL, 1m in DCM, 7.38 mmol) was added to a solution of 5,7-
dimethoxy-1-indanone (19; 0.71 g, 3.69 mmol) in DCM (20 mL)
with ice cooling. The resulting mixture was stirred at 08C until
complete consumption of the starting material, as indicated by
TLC (3 h). The reaction mixture was quenched with water and the
resulting mixture was extracted with DCM (3ꢁ20 mL). The com-
bined organic phases were washed with brine (20 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure to give
a crude product, which was further purified by column chromatog-
raphy on silica gel (10% EtOAc/hexanes) to give the demethylated
product as a light yellow solid (0.64 g, 3.62 mmol, 98%). M.p.
(EtOAc/hexanes) 98–1008C; 1H NMR (400 MHz, CDCl3): d=2.67 (t,
J=5.8 Hz, 2H), 3.03 (t, J=5.8 Hz, 2H), 3.84 (s, 6H), 6.28 (s, 1H), 6.46
(s, 1H), 9.17 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=26.0, 36.2,
55.8, 99.1, 103.6, 117.1, 157.1, 159.0, 168.0, 207.8 ppm; IR (UATR):
n˜max =3273, 2926, 1664, 1634, 1494 cmÀ1; LRMS (EI): m/z (%): 178
(100) [M]+, 177 (44), 149 (38), 83 (23), 71 (33), 70 (21), 69 (51), 57
(51), 55 (37); HRMS (TOF): m/z calcd for C10H11O3 [M+H]+:
179.0702; found: 179.0710.
1
hexanes) 96–978C; H NMR (300 MHz, CDCl3): d=2.64 (t, J=5.6 Hz,
2H), 3.00 (t, J=5.6 Hz, 2H), 4.08 (s, 6H), 6.19 (s, 1H), 6.39 ppm (s,
1H); 13C NMR (75 MHz, CDCl3): d=25.8, 36.1, 55.4, 55.8, 100.4,
105.1, 116.1, 157.9, 158.9, 166.7, 207.9 ppm; IR (UATR): n˜max =3113,
1625, 1480, 1334 cmÀ1
;
LRMS (EI): m/z (%): 164 (100)
[C11H12O3ÀC2H4]+, 163 (74), 136 (26), 69 (25); HRMS (TOF): m/z
calcd for C11H13O3 [M+H]+: 193.0859; found: 193.0858.
Method B: (Carbethoxymethylene)triphenylphosphorane (13.6 g,
39.1 mmol) was added to a solution of 16 (5.00 g, 30.1 mmol) in
DCM (60 mL) at 08C. The mixture was allowed to stir and slowly
warmed up to room temperature then stirred for 18 h. The reac-
tion mixture was quenched with water and the resulting mixture
was extracted with DCM (3ꢁ40 mL) and the combined organic
phases were washed with brine (30 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure to give a crude product,
which was further purified by column chromatography on silica
gel (20% EtOAc/hexanes) to give the product as a white solid
(7.10 g, 30.1 mmol, 100%). M.p. (EtOAc/hexanes) 45.3–48.08C;
1H NMR (300 MHz, CDCl3): d=1.34 (t, J=7.1 Hz, 3H), 3.81 (s, 3H),
4.26 (s, 3H), 4.26 (q, J=7.1 Hz, 2H), 6.40 (d, J=16 Hz, 1H), 6.49 (t,
J=2.2 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 7.60 ppm (d, J=16 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=14.3, 55.4, 60.5, 102.5, 105.9, 118.8,
136.3, 144.6, 161.0, 166.8 ppm; IR (UATR): n˜max =2939, 1709, 1639,
1590, 1152 cmÀ1; LRMS (EI): m/z (%): 236 (100) [M]+, 191 (62), 164
(58); HRMS (TOF): m/z calcd for C13H17O4 [M+H]+: 237.1121; found:
237.1122
For the synthesis of 4-bromo-7-hydroxy-5-methoxy-1-indanone
from 7-hydroxy-5-methoxy-1-indanone, neat bromine (0.56 mL,
11.2 mmol) was added by means of a syringe to a solution of the
demethylated product (2.00 g, 11.2 mmol) in DCM (110 mL) with
ice cooling and the reaction was stirred at 08C for 1.5 h. Water
(50 mL) and DCM (50 mL) were added and the two phases were
separated. The aqueous layer was extracted with DCM (3ꢁ50 mL)
and the combined organic phases were washed with a saturated
solution of Na2S2O5 (30 mL) and brine (30 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure to give the
crude product, which was further purified by recrystallization
(DCM) to give the desired product as a light yellow solid (2.88 g,
11.2 mmol, 99%). M.p. (DCM) 173–1758C; 1H NMR (300 MHz,
CDCl3): d=2.63 (t, J=5.8 Hz, 2H), 2.91 (t, J=5.8 Hz, 2H), 3.86 (s,
3H), 6.27 (s, 1H), 9.08 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=
27.4, 36.1, 56.9, 98.1, 99.6, 117.7, 155.6, 158.2, 163.2, 207.7 ppm; IR
(UATR): n˜max =3359, 2922, 1678, 1610, 1471, 1363 cmÀ1; LRMS (EI):
m/z (%): 258 (97) [C10H981BrO3]+, 256 (100) [C10H979BrO3]+, 147 (25),
Palladium on activated charcoal was added to a solution of the
ethyl cinnamate ester (3.20 g, 13.6 mmol) in EtOAc (135 mL). The
resulting mixture was stirred at room temperature under a hydro-
gen atmosphere until complete consumption of the starting mate-
rial, as indicated by TLC (1–2 h). The palladium catalyst was re-
moved by filtration through Celite and the filtrate was concentrat-
ed under reduced pressure to give a crude product (3.25 g), which
was used in the next step without further purification.
KOH (5% in EtOH, 50 mL) was added to a solution of the ethyl
ester (3.25 g) and the mixture was stirred at room temperature for
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Full Paper
77 (26), 69 (29); HRMS (TOF): m/z calcd for C10H1079BrO3 [M+H]+,
C10H1081BrO3 [M+H]+: 256.9807, 258.9787; found: 256.9799,
258.9784.
(%): 224 (6) [M]+, 165 (25), 152 (23), 149 (43), 112 (26), 97 (32), 85
(29), 83 (39), 71 (68), 70 (40), 69 (59), 57 (100), 55 (66); HRMS (TOF):
m/z calcd for C12H15O4 [MÀH]+: 223.0975; found: 223.0969.
NaH (55% dispersion, 0.11 g, 2.36 mmol) was added to a solution
of 4-bromo-7-hydroxy-5-methoxy-1-indanone (0.30 g, 1.18 mmol)
in THF (12 mL) at 08C under an argon atmosphere, and the reac-
tion was stirred at that temperature for 1 h. Then, MOMCl (0.18 mL,
2.36 mmol) was added neat by means of a syringe. The resulting
mixture was warmed up and stirred at room temperature until
complete consumption of the starting material, as indicated by
TLC (normally 2–3 h). Water (10 mL) and EtOAc (10 mL) were
added and the two phases were separated. The aqueous layer was
extracted with EtOAc (2ꢁ10 mL) and the combined organic phases
were washed with water (4ꢁ10 mL) and brine (10 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure to give
a crude product, which was further purified by column chromatog-
raphy on silica gel (40% EtOAc/hexanes) to give the desired prod-
uct 20 as a yellow solid (0.31 g, 1.02 mmol, 86%). M.p. (EtOAc/hex-
anes) 122–1238C; 1H NMR (300 MHz, CDCl3): d=2.66 (t, J=6.0,
6.3 Hz, 2H), 2.96 (t, J=6.0 Hz, 2H), 3.52 (s, 3H), 3.97 (s, 3H), 5.34 (s,
2H), 6.69 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=26.9, 36.7, 56.4,
56.6, 94.9, 98.3, 101.6, 120.6, 155.9, 157.9, 161.7, 202.4 ppm;
Following a procedure similar to that used to prepare compound
19, 4-(3,5-dimethoxyphenyl)butanoic acid (0.55 g, 2.46 mmol) un-
derwent the SnCl4-mediated Friedel–Crafts cyclization to give the
desired product 21 as a light yellow solid (0.44 g, 2.13 mmol, 87%).
1
M.p. (EtOAc/hexanes) 61–628C; H NMR (300 MHz, CDCl3): d=1.98–
2.06 (m, 2H), 2.56 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3 Hz, 2H) 3.85 (s,
3H), 3.88 (s, 3H), 6.32 ppm (d, J=3.6 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=22.84, 31.6, 40.8, 55.4, 56.0, 97.2, 104.6, 109.3, 149.3,
162.6, 163.8, 196.2 ppm; IR (UATR): n˜max =2939, 2840, 1667, 1596,
1455 cmÀ1; LRMS (EI): m/z (%): 206 (13) [M]+, 178 (26), 166 (67),
149 (39), 97 (32), 95 (26), 91 (39), 85 (28), 83 (38), 71 (58), 70 (32),
69 (72), 57 (100), 56 (28), 55 (71); HRMS (TOF): m/z calcd for
C12H15O3 [M+H]+: 207.1015; found: 207.1009.
Compound 22
BCl3 in DCM (1.0m; 2.78 mL, 2.78 mmol) was added slowly by
means of a dropping funnel to a solution of tetralone 21 (0.44 g,
2.13 mmol) in DCM (20 mL) at À788C over 20 min. The reaction
was stirred at À788C to room temperature for 18 h. Water (20 mL)
and DCM (20 mL) were added and the two phases were separated.
The aqueous layer was extracted with DCM (3ꢁ20 mL) and the
combined organic phases were washed with a saturated solution
of Na2S2O5 (10 mL) and brine (10 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure to give the crude prod-
uct, which was further purified by column chromatography (10%
EtOAc/hexanes) to give the demethylated product as a light brown
solid (0.28 g, 1.46 mmol, 69%). M.p. (EtOAc/hexanes) 69–708C;
1H NMR (300 MHz, CDCl3): d=2.01–2.09 (m, 2H), 2.60 (t, J=6.5 Hz,
2H), 2.83 (t, J=6.5 Hz, 2H) 3.81 (s, 3H), 6.25 (d, J=2.7 Hz, 2H),
12.87 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=22.8, 30.0, 38.4,
IR (UATR): n˜max =2933, 1702, 1590, 1473, 1440, 1214 cmÀ1
;
LRMS (EI): m/z (%): 287 (48) [C12H1481BrO4ÀCH3]+, 285 (51)
[C12H1479BrO4ÀCH3]+, 271 (35), 269 (66), 267 (32), 243 (69), 242 (78),
241 (100), 162 (41), 161 (37), 89 (47), 77(59), 69 (54), 63 (32), 57
(49), 55 (52), 51 (34); HRMS (TOF): m/z calcd for C12H1479BrO4
[M+H]+, C12H1481BrO4 [M+H]+: 301.0070, 303.0049; found:
301.0064, 303.0048.
Compound 21
For the synthesis of (E)-4-(3’,5’-dimethoxyphenyl)but-3-enoic acid,
NaH (55% dispersion, 0.47 g, 10.4 mmol) was added portionwise to
55.4, 98.9, 106.7, 112.6, 147.1, 165.8, 203.0 ppm; IR (UATR): n˜max
=
a
solution of (2-carboxyethyl)triphenylphosphonium bromide
2943, 1620, 1492, 1432, 1385 cmÀ1; LRMS (EI): m/z (%): 192 (63)
[M]+, 164 (100), 71 (29), 69 (37), 57 (53), 55 (45); HRMS (TOF): m/z
calcd for C11H13O3 [M+H]+: 193.0859; found: 193.0867.
(2.59 g, 6.25 mmol) in dry THF (20 mL) at 08C. The mixture was
then allowed to warm to room temperature and stirred for 2 h.
Then, a solution of 16 (0.69 g, 4.16 mmol) in THF (20 mL) was
added at 08C. The mixture was warmed to room temperature and
stirred for 14 h. A solution of NaOH (10% w/v, 10 mL) was added,
and the resulting solution was washed with toluene (5ꢁ10 mL)
and diethyl ether (2ꢁ10 mL). The aqueous phase was acidified
with concentrated HCl and extracted with DCM (3ꢁ10 mL). The
combined extracts were washed with dilute HCl (10 mL), dried, and
evaporated to give a brown oil. Chromatography (50% EtOAc/hex-
anes) gave the butenoic acid product as a yellow solid (0.36 g,
1.62 mmol, 39%). M.p. (EtOAc/hexanes) 53–548C; 1H NMR
(300 MHz, CDCl3): d=2.67 (t, J=5.8 Hz, 2H), 3.03 (t, J=5.8 Hz, 2H),
3.28 (d, J=6.9 Hz, 2H), 3.79 (s, 6H), 6.22–6.48 (m, 3H), 6.53 ppm (d,
J=1.8 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=37.9, 55.4, 100.1,
104.4, 121.4, 134.0, 138.7, 160.9, 177.6 ppm; IR (UATR): n˜max =2939,
2838, 1698, 1591, 1301 cmÀ1; LRMS (EI): m/z (%): 222 (68) [M]+, 182
(100), 177 (75), 161 (27), 149 (51), 135 (27), 109 (26), 91 (28), 79
(20), 77 (30), 71 (30), 69 (41), 63 (24), 57 (49), 55 (46), 51 (24); HRMS
(TOF): m/z calcd for C12H15O4 [M+H]+: 223.0964; found: 223.0972.
Following a procedure similar to that used to prepare 4-bromo-7-
hydroxy-5-methoxy-1-indanone, the demethylated tetralone prod-
uct (0.28 g, 1.46 mmol) was brominated to give the corresponding
product as a yellow solid (0.35 g, 1.30 mmol, 89%). M.p. (DCM)
117–1188C; 1H NMR (300 MHz, CDCl3): d=2.05–2.14 (m, 2H), 2.63
(t, J=6.5 Hz, 2H), 2.98 (t, J=6.5 Hz, 2H), 3.93 (s, 3H), 6.38 (s, 1H),
13.11 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=22.0, 30.6, 37.8,
56.6, 98.4, 103.1, 112.3, 145.2, 161.8, 164.9, 203.2 ppm; IR (UATR):
n˜max =2936, 2874, 1631, 1602, 1439, 1386 cmÀ1; LRMS (EI): m/z (%):
272 (14) [C11H1181BrO3]+, 270 (15) [C11H1179BrO3]+, 167 (22), 149 (77),
97 (27), 85 (26), 83 (34), 81 (23), 71 (62), 70 (32), 69 (62), 57 (100),
56 (24), 55 (72); HRMS (TOF): m/z calcd for C11H1279BrO3 [M+H]+,
C11H1281BrO3 [M+H]+: 270.9964, 272.9944; found: 270.9975,
272.9948.
Following a procedure similar to that used for the MOM protection
to prepare 20, the brominated tetralone (0.21 g, 0.77 mmol) was
converted into the corresponding MOM ether tetralone 22 as
a brown solid (0.11 g, 0.34 mmol, 44%). M.p. (EtOAc/hexanes) 106–
(E)-4-(3’,5’-Dimethoxyphenyl)but-3-enoic acid (0.53 g, 2.39 mmol)
was hydrogenated to give 4-(3,5-dimethoxyphenyl)butanoic acid
as a light yellow solid (0.52 g, 2.32 mmol, 97%). M.p. (DCM) 64–
658C; 1H NMR (300 MHz, CDCl3) d 1.88–1.98 (m, 2H), 2.30 (t, J=
7.5 Hz, 2H), 2.58 (t, J=7.5 Hz, 2H), 3.78 (s, 6H), 6.31 (d, J=2.1 Hz,
1H), 6.35 ppm (d, J=2.1 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=
26.1, 33.4, 35.3, 55.2, 98.0, 106.5, 143.7, 160.6, 160.8, 178.3 ppm; IR
(UATR): n˜max =2938, 1703, 1595, 1460, 1428 cmÀ1; LRMS (EI): m/z
1
1088C; H NMR (300 MHz, CDCl3): d=2.02–2.11 (m, 2H), 2.56 (t, J=
6.5 Hz, 2H), 3.00 (t, J=6.5 Hz, 2H), 3.53 (s, 3H), 3.94 (s, 3H), 5.26 (s,
2H), 6.71 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=22.0, 31.5, 40.0,
56.4, 56.5, 95.7, 99.2, 105.9, 118.3, 146.4, 159.1, 159.6, 195.9 ppm; IR
(UATR): n˜max =2947, 1627, 1464, 1437, 1382, 1356 cmÀ1; LRMS (EI):
m/z
(%):
272
(86)
[C13H1581BrO4ÀC2H4O]+,
270
(84)
[C13H1579BrO4ÀC2H4O]+, 244 (57), 242 (57), 149 (37), 135 (34), 97
Chem. Asian J. 2015, 00, 0 – 0
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(41), 85 (38), 83 (49), 77 (30), 71 (63), 70 (38), 69 (83), 57 (100), 56
(31), 55 (82); HRMS (TOF): m/z calcd for C13H1679BrO4 [M+H]+,
C13H1681BrO4 [M+H]+: 315.0226, 317.0206; found: 315.0222,
317.0197.
78.9, 98.0 (minor), 98.3, 116.8, 124.9 (minor), 126.0, 127.1 (minor),
128.0, 128.4 (minor), 128.5, 136.9, 141.5, 142.6 (minor), 153.8,
155.0 ppm; LRMS (EI): m/z (%): 360 (54) [C19H1981BrO2]+, 358 (57)
[C19H1979BrO2]+, 256 (87), 254 (92), 175 (100), 115 (53), 104 (44), 103
(37), 91 (55), 78 (25), 77 (28); HRMS (TOF): m/z calcd for
C19H2079BrO2 [M+H]+, C19H2081BrO2 [M+H]+: 359.0641, 361.0621;
found: 359.0636, 361.0623.
Compound 23
Following the general procedure for the borohydride reduction/
acetylation (with the reduction requiring 18 h), indanone 20
(0.300 g, 0.958 mmol) was converted into the corresponding indan-
yl acetate 23 as a white solid (0.277 g, 0.778 mmol, 81% over two
steps).
Compound 28
Following the general procedure for the [PtCl4]-mediated genera-
tion of the o-QM/HDA reaction, indanyl acetate 23 (0.020 g,
0.056 mmol) reacted with cinnamate 27 (0.023 g, 0.112 mmol) for
18 h to give 28 as a white solid (0.020 g, 0.045 mmol, 80%). M.p.
Note: During purification by chromatography on silica gel with
20% EtOAc/hexanes, it is critical that Et3N (1% v/v) is included to
prevent decomposition of the product. It is also important to
ensure complete removal of Et3N in vacuo because its presence,
even in trace amounts, interferes with the subsequent [PtCl4]-medi-
ated reaction. M.p. (EtOAc/hexanes) 102.6–103.88C; 1H NMR
(300 MHz, CDCl3): d=2.03 (s, 3H), 2.06–2.17 (m, 1H), 2.37–2.53 (m,
1H), 2.90 (ddd, J=2.9, 9.0, 17.1 Hz, 1H), 3.01–3.16 (m, 1H), 3.46 (s,
3H), 3.89 (s, 3H), 5.18 (s, 2H), 6.39 (dd, J=1.7, 6.9 Hz, 1H),
6.60 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=21.2, 31.9, 32.6,
56.0, 76.5, 94.3, 98.0, 100.7, 122.3, 148.5, 153.9, 157.9, 170.6 ppm;
IR (UATR): n˜max =2943, 1734, 1222, 1149 cmÀ1; LRMS (EI): m/z (%):
346 (4) [C14H1781BrO5]+, 344 (4) [C14H1779BrO5]+, 242 (97), 240 (100);
HRMS (TOF): m/z calcd for C14H1779BrNaO5 [M+Na]+, C14H1781BrNaO5
[M+Na]+: 367.0152, 369.0132; found: 367.0169, 369.0148.
1
(CH2Cl2/hexanes) 105.2–106.18C; H NMR (300 MHz, CDCl3): d=0.98
(t, J=7.1 Hz, 3H), 1.68–1.84 (m, 1H), 2.34–2.43 (m, 1H), 2.59 (appar-
ent t, J=10.4 Hz, 1H), 2.85–3.04 (m, 2H), 3.59 (dt, J=10.4, 6.4 Hz,
1H), 3.81 (s, 3H), 3.82 (s, 3H), 3.95 (q, J=7.1 Hz, 2H), 5.09 (d, J=
10.4 Hz, 1H), 6.30 (s, 1H), 6.95 (d, J=8.7 Hz, 2H), 7.31 ppm (d, J=
8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=14.0, 33.3, 43.2, 51.9,
55.3, 56.6, 60.7, 81.0, 97.2, 99.4, 113.9 (2C), 120.5, 128.9 (2C), 129.8,
145.6, 151.6, 156.5, 160.0, 172.1 ppm; IR (UATR): n˜max =2928, 1728,
1248, 1150 cmÀ1; LRMS (EI): m/z (%): 448 (11) [C22H2381BrO5]+, 446
(11) [C22H2379BrO5]+, 242 (20), 240 (20), 206 (80), 161 (63), 149 (100);
HRMS (TOF): m/z calcd for C22H2379BrNaO5 [M+Na]+, C22H2381BrNaO5
[M+Na]+: 469.0621, 471.0604; found: 469.0609, 471.0594.
Compound 30a
Compound 25
Following the general procedure for the [PtCl4]-mediated genera-
tion of o-QM/HDA reaction, indanyl acetate 23 (0.020 g,
0.056 mmol) reacted with cinnamate 29a (0.032 g, 0.112 mmol) for
18 h to give 30a as a white solid (0.020 g, 0.039 mmol, 69%). M.p.
Following the general procedure for the [PtCl4]-mediated genera-
tion of o-QM and HDA reaction, the indanyl acetate 23 (0.04 g,
0.11 mmol) was converted into the product 25 as a dark yellow
solid of a 6:1 mixture of inseparable diastereomers (0.021 g,
1
(CH2Cl2/hexanes) 109.4–111.88C; H NMR (300 MHz, CDCl3): d=0.95
1
(t, J=7.1 Hz, 3H), 1.66–1.85 (m, 1H), 2.31–2.45 (m, 1H), 2.58 (appar-
ent t, J=10.4 Hz, 1H), 2.82–3.05 (m, 2H), 3.58 (dt, J=10.4, 6.4 Hz,
1H), 3.82 (s, 3H), 3.94 (q, J=7.1 Hz, 2H), 5.075 (s, 2H), 5.083 (d, J=
10.4 Hz, 1H), 6.30 (s, 1H), 6.96 (d, J=8.7 Hz, 2H), 7.31 (d, J=8.7 Hz,
2H), 7.33–7.46 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d=14.0,
33.3, 33.9, 43.2, 51.9, 56.6, 60.7, 70.0, 81.0, 97.2, 99.4, 114.9 (2C),
120.5, 127.4 (2C), 128.0, 128.6 (2C), 128.9 (2C), 130.1, 136.8, 145.6,
151.5, 156.5, 159.1, 172.1 ppm; IR (UATR): n˜max =2936, 1728, 1589,
1148 cmÀ1; LRMS (EI): m/z (%): 524 (6) [C28H2781BrO5]+, 522 (6)
[C28H2779BrO5]+, 91 (100); HRMS (TOF): m/z calcd for C28H2879BrNaO5
[M+Na]+, C28H2881BrNaO5 [M+Na]+: 523.1115, 525.1099; found:
523.1114, 525.1110.
0.06 mmol, 53%). H NMR (300 MHz, CDCl3): d=1.59–1.67 (m, 2H),
1.74–1.86 (m, 2H, minor), 2.30–2.45 (m, 2H), 2.63–2.72 (m, 1H,
minor), 2.79–2.96 (m, 2H), 3.30–3.42 (m, 1H), 3.83 (s, 3H), 3.88 (s,
3H, minor), 5.10 (dd, J=2.1 Hz, 1H), 5.64 (d, J=3.0 Hz, 1H, minor),
6.31 (s, 1H), 6.40 (s, 1H, minor), 7.22–7.41 ppm (m, 5H); 13C NMR
(75 MHz, CDCl3): d=32.64 (minor), 33.61 (minor), 34.1, 34.2 (minor),
34.5 (minor), 34.6, 37.3, 39.3, 56.6, 80.2, 97.2 (minor), 97.4, 122.3,
122.6 (minor), 124.8, 126.3, 127.1 (minor), 128.2 (minor), 128.4
(minor), 128.6, 141.0, 142.0 (minor), 145.7, 152.2, 156.3 ppm; LRMS
(EI): m/z (%): 346 (52) [C18H1781BrO2]+, 344 (53) [C18H1779BrO2]+, 242
(95), 240 (99), 161 (100), 149 (32), 133 (40), 104 (58), 103 (56), 102
(33), 91 (80), 90 (31), 89 (34), 78 (37), 77 (60), 71 (38), 69 (59), 57
(63), 55 (49); HRMS (TOF): m/z calcd for C18H1879BrO2 [M+H]+,
C18H1881BrO2 [M+H]+: 345.0484, 347.0464; found: 345.0473;
347.0463.
Compound 30d[19]
Following the general procedure for the [PtCl4]-mediated genera-
tion of the o-QM/HDA reaction, indanyl acetate 23 (0.020 g,
0.056 mmol) reacted with cinnamate 29d (0.026 g, 0.112 mmol) for
18 h to give 30d as a pale yellow solid (0.010 g, 0.021 mmol, 38%).
Compound 26
Following the general procedure for the borohydride reduction/
acetylation and [PtCl4]-mediated generation of o-QM and HDA re-
action, the tetralone 22 (0.04 g, 0.11 mmol) was converted into the
chroman 26 as a white solid of a 3:1 mixture of inseparable diaste-
1
M.p. (EtOAc/hexanes) 113.7–116.08C; H NMR (300 MHz, CDCl3): d=
0.99 (t, J=7.1 Hz, 3H), 1.68–1.84 (m, 1H), 2.34–2.46 (m, 1H), 2.81
(apparent t, J=10.5 Hz, 1H), 2.85–3.05 (m. 2H), 3.59 (dt, J=10.5,
6.5 Hz, 1H), 3.81 (s, 3H), 3.83 (s, 3H), 3.95 (q, J=7.1 Hz, 2H), 5.48
(d, J=10.5 Hz, 1H), 6.28 (s, 1H), 7.05 (d, J=1.6 Hz, 1H), 7.12 (dd,
J=8.1, 1.6 Hz, 1H), 7.21 ppm (d, J=8.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=13.9, 14.4 (minor), 30.6 (minor), 33.2 (minor), 33.4, 33.9,
35.0, 43.1, 43.4, 50.1, 55.6 (minor), 55.8, 56.45, 56.54 (minor), 56.6,
60.4 (minor), 60.5, 74.1 (minor), 76.1, 96.8 (minor), 97.3, 99.3, 111.1
(minor), 112.1 (minor), 112.7, 113.4 (minor), 114.6, 115.1, 120.7,
126.7, 129.9 (minor), 145.2 (minor), 145.6, 151.7, 151.9, 153.5
1
reomers (0.014 g, 0.04 mmol, 35%). H NMR (400 MHz, CDCl3): d=
1.18–1.30 (m, 2H), 1.71–1.83 (m, 2H, minor), 1.94–2.01 (m, 1H),
2.04–2.12 (m, 1H, minor), 2.15–2.22 (m, 1H), 2.27–2.35 (m, 1H,
minor), 2.60–2.69 (m, 2H), 2.88–3.02 (m, 3H), 3.83 (s, 3H), 3.88 (s,
3H, minor), 5.19 (dd, J=2.3 Hz, 1H), 5.57 (d, J=3.8 Hz, 1H, minor),
6.39 (s, 1H), 6.48 (s, 1H, minor), 7.31–7.44 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): d=22.5 (minor), 22.7, 26.9 (minor), 28.7 (minor),
29.0, 29.6 (minor), 30.6, 34.0, 34.4 (minor), 37.4, 56.2, 75.9 (minor),
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(minor), 153.7, 156.3, 171.2 (minor), 171.8 ppm; IR (UATR): n˜max
=
Compound 30h
2954, 1731, 1590, 1149 cmÀ1
; LRMS (EI): m/z (%): 478 (17)
Following the general procedure for the [PtCl4]-mediated genera-
tion of the o-QM/HDA reaction, indanyl acetate 23 (0.020 g,
0.056 mmol) reacted with cinnamate 29h (0.030 g, 0.112 mmol) for
18 h to give 30h as a white solid (0.006 g, 0.012 mmol, 22%). M.p.
[C23H2581BrO6]+, 476 (16) [C23H2579BrO6]+, 236 (100); HRMS (TOF):
m/z calcd for C23H2679BrNaO6 [M+Na]+, C23H3681BrNaO6 [M+Na]+:
477.0907, 479.0890; found: 477.0901, 479.0901.
1
(EtOAc/hexanes) 114.4–116.78C; H NMR (300 MHz, CDCl3): d=0.98
(t, J=7.1 Hz, 3H), 1.70–1.88 (m, 1H), 2.33–2.47 (m, 1H), 2.90 (appar-
ent t, J=10.5 Hz, 1H), 2.91–3.06 (m, 2H), 3.59 (dt, J=10.5, 6.2 Hz,
1H), 3.81 (s, 3H), 3.865 (s, 3H), 3.872 (s, 3H), 3.91 (s, 3H), 3.97 (dq,
J=7.1, 3.0 Hz, 2H), 5.37 (d, J=10.5 Hz, 1H), 6.27 (s, 1H), 6.68 (d,
J=8.7 Hz, 1H), 7.03 ppm (d, J=8.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=14.0, 33.4, 33.9, 43.3, 49.8, 56.0, 56.6, 60.5, 60.7, 61.5,
77.1, 97.3, 99.3, 107.3, 120.7, 123.5, 123.6, 142.4, 145.6, 151.6, 152.8,
154.4, 156.5, 172.1 ppm; IR (neat): n˜max =2940, 1730, 1466,
1150 cmÀ1; LRMS (EI): m/z (%): 508 (4) [C24H2781BrO7]+, 506 (4)
[C24H2779BrO7]+, 81 (100); HRMS (TOF): m/z calcd for C24H2779BrNaO7
[M+Na]+, C24H2781BrNaO7 [M+Na]+: 529.0832, 531.0816; found:
529.0833, 531.0832.
Compound 30e
Following the general procedure for the [PtCl4]-mediated genera-
tion of the o-QM/HDA reaction, indanyl acetate 23 (0.020 g,
0.056 mmol) reacted with cinnamate 29e (0.026 g, 0.112 mmol) for
18 h to give 30e as a pale yellow solid (0.012 g, 0.025 mmol, 45%).
1
M.p. (EtOAc/hexanes) 134.7–136.38C; H NMR (300 MHz, CDCl3): d=
0.99 (t, J=7.1 Hz, 3H), 1.69–1.85 (m, 1H), 2.35–2.44 (m, 1H), 2.61 (t,
J=10.5, 1H), 2.86–3.08 (m 2H), 3.59 (dt, J=10.5, 6.4 Hz, 1H), 3.83
(s, 3H), 3.89 (s, 6H), 3.96 (q, J=7.1 Hz, 2H), 5.09 (d, J=10.5 Hz,
1H), 6.32 (s, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.91 (d, J=1.9 Hz, 1H),
6.95 ppm (dd, J=8.2, 1.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=
14.0, 33.4, 33.9, 43.2, 51.9, 55.93, 55.95, 56.6, 60.7, 81.3, 97.3, 99.5,
110.4, 110.9, 120.3, 120.5, 130.2, 145.6, 149.0, 140.5, 151.5, 156.6,
172.1 ppm; IR (UATR): n˜max =2937, 1728, 1261, 1149 cmÀ1; LRMS
(EI): m/z (%): 478 (6) [C23H2581BrO6]+, 476 (6) [C23H2579BrO6]+, 236
(100); HRMS (TOF): m/z calcd for C23H2579BrNaO6 [M+Na]+,
C23H2581BrNaO6 [M+Na]+: 499.0728, 501.0710; found: 499.0729,
501.0699.
Compound 30i
Following the general procedure for the [PtCl4]-mediated genera-
tion of the o-QM/HDA reaction, indanyl acetate 23 (0.020 g,
0.056 mmol) reacted with cinnamate 29i (0.030 g, 0.112 mmol) for
18 h to give 30i as a white solid (0.012 g, 0.024 mmol, 43%). M.p.
(EtOAc/hexanes) 142.8–145.68C; 1H NMR (300 MHz, CDCl3): d=
1.68–1.85 (m, 1H), 2.34–2.46 (m, 1H), 2.62 (apparent t, J=10.4 Hz,
1H), 2.86–3.07 (m 2H), 3.52 (s, 3H), 3.58 (dt, J=10.4, 6.6 Hz, 1H),
3.84 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 5.09 (d, J=10.3 Hz, 1H), 6.34
(s, 1H), 6.60 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): d=33.4, 33.8,
43.2, 51.8, 51.9, 56.1, 60.8, 81.4, 97.2, 99.7, 104.3, 120.3, 133.3,
138.3, 145.7, 151.3, 153.3, 156.6, 172.6 ppm; IR (UATR): n˜max =2927,
1734, 1592, 1464, 1152, 1125 cmÀ1; LRMS (EI): m/z (%): 494 (0.91)
[C23H2581BrO7]+, 492 (0.96) [C23H2579BrO7]+, 149 (100), 69 (92); HRMS
(TOF): m/z calcd for C23H2679BrNaO7 [M+Na]+, C23H2681BrNaO7
[M+Na]+: 493.0856, 495.0839; found: 493.0871, 495.0858.
Compound 30 f
Following the general procedure for the [PtCl4]-mediated genera-
tion of o-QM/HDA reaction, indanyl acetate 23 (0.020 g,
0.056 mmol) reacted with cinnamate 29 f (0.025 g, 0.112 mmol) for
18 h to give 30 f as a white solid (0.017 g, 0.036 mmol, 64%). M.p.
1
(EtOAc/hexanes) 124.1–126.38C; H NMR (300 MHz, CDCl3): d=1.03
(t, J=7.1 Hz, 3H), 1.67–1.84 (m, 1H), 2.33–2.44 (m, 1H), 2.55 (appar-
ent t, J=10.4 Hz, 1H), 2.85–3.05 (m 2H), 3.57 (dt, J=10.4, 6.5 Hz,
1H), 3.82 (s, 3H), 3.99 (q, J=7.1 Hz, 2H), 5.06 (d, J=10.4 Hz, 1H),
5.95–5.98 (m, 2H), 6.30 (s, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.83–
6.89 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=14.0, 33.3, 33.9,
43.1, 52.0, 56.6, 60.7, 81.2, 97.2, 99.5, 101.2, 107.7, 108.1, 120.4,
121.5, 131.6, 145.6, 147.8, 148.0, 151.4, 156.6, 172.0 ppm; IR (UATR):
n˜max =2958, 1728, 1441, 1248, 1151 cmÀ1; LRMS (EI): m/z (%): 462
(8) [C22H2181BrO6]+, 460 (8) [C22H2179BrO6]+, 416 (10), 414 (10), 220
(100); HRMS (TOF): m/z calcd for C22H2279BrO6 [M+H]+, C22H2281BrO6
[M+H]+: 461.0594, 463.0577; found: 461.0581, 463.0545.
Compound 37
Following the general procedure for the [PtCl4]-mediated genera-
tion of the o-QM/HDA reaction, indanyl acetate 23 (0.020 g,
0.056 mmol) reacted with indole cinnamate 36 (0.026 g,
0.112 mmol or 0.063 g, 0.28 mmol) for 18 h to give 37 as a yellow
solid (0.014 g, 0.029 mmol, 52% or 0.021 g, 0.045 mmol, 80%). M.p.
1
(EtOAc/hexanes) 216.2–218.58C; H NMR (300 MHz, CDCl3): 1.37 (t,
J=7.1 Hz, 3H), 2.25 (s, 3H), 2.24–2.41 (m, 1H), 2.54–2.66 (m, 1H),
2.97–3.11 (m, 1H), 3.26 (ddd, J=16.7, 9.3, 2.2 Hz, 1H), 3.86 (s, 3H),
3.88 (s, 3H), 4.31 (q, J=7.1 Hz, 2H), 4.59 (s, 1H), 4.97 (t, J=8.8 Hz,
1H), 6.25 (s, 1H), 6.34 (d, J=16.2 Hz, 1H), 6.95–7.02 (m, 1H), 7.13–
7.20 (m, 1H), 7.26–7.38 (m, 2H), 7.93 ppm (d, J=16.2 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=14.3, 31.5, 34.2, 34.3, 40.8, 56.5, 60.8,
99.1, 99.6, 109.9, 118.8, 120.4, 122.36, 122.44, 120.8, 122.8, 124.6,
Compound 30g
Following the general procedure for the [PtCl4]-mediated genera-
tion of the o-QM/HDA reaction, indanyl acetate 23 (0.020 g,
0.056 mmol) reacted with cinnamate 29g (0.032 g, 0.112 mmol) for
18 h to give 30g as a white solid (0.004 g, 0.0073 mmol, 13%).
1
M.p. (EtOAc/hexanes) 145.8–148.08C; H NMR (300 MHz, CDCl3): d=
125.6, 131.8, 138.3, 146.5, 152.6, 156.5, 166.6 ppm; IR (UATR): n˜max
=
0.99 (t, J=7.1 3H), 1.68–1.85 (m, 1H), 2.34–2.46 (m, 1H), 2.81 (ap-
parent t, J=10.5 Hz, 1H), 2.85–3.05 (m, 2H), 3.59 (dt, J=10.5,
6.3 Hz, 1H), 3.81 (s, 3H), 3.83 (s, 3H), 3.95 (q, J=7.1 Hz, 2H), 5.48
(d, J=10.5 Hz, 1H), 6.28 (s, 1H), 7.05 (d, J=1.7 Hz, 1H), 7.12 (dd,
J=8.1, 1.7 Hz, 1H), 7.21 ppm (d, J=8.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=13.9, 33.4, 33.9, 43.1, 49.9, 56.0, 56.6, 60.7, 75.7, 97.2,
99.5, 114.9, 120.6, 123.6, 123.8, 125.0, 130.4, 145.7, 151.5, 156.5,
3421, 2937, 1713, 1465, 1188 cmÀ1; HRMS (TOF): m/z calcd for
C24H2579BrNO4 [M+H]+, C24H2581BrNO4 [M+H]+: 470.0961, 472.0944;
found: 470.0944, 472.0938.
Compound 39
158.3, 171.7 ppm; IR (UATR): n˜max =2935, 1732, 1591, 1151 cmÀ1
;
Following the general procedure for the [PtCl4]-mediated genera-
tion of o-QM/HDA reaction, indanyl acetate 23 (0.020 g,
0.056 mmol) reacted with cinnamate 38 (0.026 g, 0.112 mmol) for
18 h to give 39 as a pale yellow solid (0.013 g, 0.028 mmol, 50%).
HRMS (TOF): m/z calcd for C22H2379Br2O5 [M+H]+, C22H2379Br81BrO5
[M+H]+, C22H2381Br2O5 [M+H]+: 524.9907, 526.9888, 528.9872;
found: 524.9892, 526.9894, 528.9878.
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M.p. (EtOAc/hexanes) 168.2–170.98C; H NMR (300 MHz, CDCl3): d=
2H); 13C NMR (75 MHz, CDCl3): d=13.9, 22.2, 27.0, 46.3, 47.1, 49.7,
52.3, 55.3, 56.5, 60.6, 81.0, 97.2, 99.8, 113.9 (2C), 119.3, 128.9 (2C),
129.5, 144.1, 152.1, 156.2, 160.0, 172.3 ppm; IR (UATR): n˜max =2957,
1729, 1248, 1148 cmÀ1; LRMS (EI): m/z (%): 476 (2) [C24H2781BrO5]+,
474 (12) [C24H2779BrO5]+, 403 (31), 401 (34), 149 (100); HRMS (TOF):
m/z calcd for C24H2879BrO5 [M+H]+, C24H2881BrO5 [M+H]+: 475.1115,
477.1098; found: 475.1101, 477.1106.
2.24–2.36 (m, 1H), 2.38–2.54 (m, 1H), 3.00 (ddd, J=16.5, 9.9,
3.8 Hz, 1H), 3.21–3.36 (m, 1H), 3.80 (s, 3H), 3.84 (brs, 6H), 4.27 (q,
J=7.1 Hz, 2H), 5.08 (dd, J=9.9, 3.8 Hz, 1H), 5.88 (brs, 1H), 6.22 (s,
1H), 6.40 (d, J=15.9 Hz, 1H), 6.75 (s, 2H), 7.61 ppm (d, J=15.9 Hz,
1H); 13C NMR (75 MHz, CDCl3): d=14.3, 29.7, 35.6, 38.0, 56.1, 56.4,
60.6, 98.3, 98.7, 104.5, 118.5, 121.8, 123.1, 134.4, 144.2, 147.3, 152.0,
155.9, 166.8 ppm; IR (UATR): n˜max =3421, 2936, 1707, 1575,
1109 cmÀ1; LRMS (EI): m/z (%): 478 (19) [C23H2581BrO6]+, 476 (18)
[C23H2579BrO6]+, 236 (100); HRMS (TOF): m/z calcd for
C23H2679BrNaO6 [M+Na]+, C23H2681BrNaO6 [M+Na]+: 477.0907,
479.0890; found: 477.0917, 479.0914.
Compound 42
NaOAc (0.012 g, 0.145 mmol) and Pd/C (0.020 g, 0.019 mmol) was
added to a stirred solution of ester 28 (0.028 g, 0.063 mmol) in
EtOAc (0.5 mL) at room temperature. The reaction mixture was
stirred for 2 h under a hydrogen atmosphere, and then filtered
through a short pad of Celite. The solvent was removed to give
product 42 as a pale yellow solid (0.022 g, 0.061 mmol, 97%). M.p.
Compound 40
NaH (55% dispersion, 0.033 g, 0.75 mmol) and MeI (0.05 mL,
0.75 mmol) were sequentially added to a stirred solution of inda-
none 20 (0.094 g, 0.30 mmol) in DMF (1.5 mL) at 08C. The resulting
mixture was stirred at RT for 18 h and then quenched with water
(2 mL). The aqueous layer was extracted with EtOAc (3ꢁ2 mL). The
combined organic layers were washed with water (7ꢁ5 mL) and
brine (5 mL), dried over Na2SO4, and filtered. The filtrate was
evaporated (aspirator then in vacuo) to give a crude product,
which was used for the next step without further purification.
1
(CH2Cl2/hexanes) 107.2–110.58C; H NMR (300 MHz, CDCl3): d=0.98
(t, J=7.1 Hz, 3H), 1.63–1.81 (m, 1H), 2.31–2.43 (m, 1H), 2.57 (appar-
ent t, J=10.4 Hz, 1H), 2.76 (dd, J=14.9, 8.0 Hz, 1H), 2.85–3.06 (m,
1H), 3.49 (dt, J=10.4, 6.3 Hz, 1H), 3.75 (s, 3H), 3.80 (s, 3H), 3.94 (q,
J=7.1 Hz, 2H), 5.10 (d, J=10.4 Hz, 1H), 6.26 (d, J=1.6 Hz, 1H),
6.46 (s, 1H), 6.89 (d, J=8.7 Hz, 2H), 7.32 ppm (d, J=8.7 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=14.0, 32.6, 34.3, 42.2, 52,1, 55.3, 55.6,
60.5, 80.8, 97.4, 103.4, 113.8 (2C), 119.9, 128.9 (2C), 130.2, 145.4,
152.6, 159.9, 161.1, 172.4 ppm; IR (UATR): n˜max =2954, 1728, 1600,
1249, 1135 cmÀ1; LRMS (EI): m/z (%): 368 (14) [M]+, 295 (40), 149
(100), 57 (37); HRMS (TOF): m/z calcd for C22H25O5 [M+H]+:
369.1697; found: 369.1697.
NaBH4 (0.039 g, 0.75 mmol) was added to a mixture of the dime-
thylated indanone in EtOH (3 mL) and the mixture was stirred at
RT for 18 h. The solvent was removed under reduced pressure and
the residue dissolved in EtOAc (5 mL). The organic layer was
washed with water (3ꢁ5 mL) and brine (5 mL), dried over Na2SO4,
and filtered. The filtrate was evaporated (aspirator then in vacuo)
to give a crude benzyl alcohol, which was used for the next step
without further purification.
Acknowledgements
Financial support from the Thailand Research Fund (TRF;
BRG5580010) for P.P. is gratefully acknowledged.
DMAP (0.055 g, 0.45 mmol), Et3N (0.063 mL, 0.45 mmol), and acetic
anhydride (0.045 mL, 0.45 mmol) were sequentially added to a solu-
tion of the corresponding alcohol in CH2Cl2 (3 mL) at 08C. The reac-
tion mixture was stirred at RT for 18 h and then quenched with
water (3 mL). The aqueous layer was extracted with CH2Cl2 (3ꢁ
3 mL). The combined organic layers were washed with water (3ꢁ
5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate
was evaporated (aspirator then in vacuo) to give a crude product,
which was purified by column chromatography (0–30% EtOAc/
hexanes) to give the desired indanyl acetate 40 as a brown oil
(0.062 g, 0.16 mmol, 54% over three steps). 1H NMR (300 MHz,
CDCl3): d=1.12 (s,3H), 1.14 (s, 3H), 2.03 (s, 3H), 2.68 (d, J=16.6 Hz,
1H), 2.91 (d, J=16.6 Hz, 1H), 3.45 (s, 3H), 3.88 (s, 3H), 5.13–5.20
(m, 2H), 6.08 (s, 1H), 6.58 ppm (s, 1H); 13C NMR (75 MHz, CDCl3):
d=21.0, 22.4, 27.8, 42.5, 47.6, 56.0, 56.6, 81.7, 94.4, 98.0, 101.0,
122.2, 147.6, 154.4, 157.7, 170.5 ppm; IR (UATR): n˜max =2959, 1732,
1231, 1150 cmÀ1; LRMS (EI): m/z (%): 374 (3) [C16H2181BrO5]+, 372 (3)
[C16H2179BrO5]+, 270 (99), 268 (100), 189(23), 174(27); HRMS (TOF):
m/z calcd for C16H2179BrNaO5 [M+Na]+, C16H2181BrNaO5 [M+Na]+:
395.0465, 397.0446; found: 395.0469, 397.0451.
Keywords: asymmetric
synthesis
·
cycloaddition
·
heterocycles · heterogeneous catalysis · platinum
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(EtOAc/hexanes) 118.1–120.68C; H NMR (300 MHz, CDCl3): d=0.90
(s, 3H), 1.00 (t, J=7.1 Hz, 3H), 1.23 (s, 3H), 2.61 (d, J=15.7 Hz, 1H),
2.69 (dd, J=11.1, 9.9 Hz, 1H), 2.92 (d, J=15.9 Hz, 1H), 3.45 (d, J=
11.1 Hz, 1H), 3.81 (s, 6H), 3.94 (q, J=7.1 Hz, 2H), 5.04 (d, J=9.9 Hz,
1H), 6.29 (s, 1H), 6.90 (d, J=8.7 Hz, 2H), 7.30 ppm (d, J=8.7 Hz,
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products were isolated to ascertain the intermediacy of the proposed
C2-benzylic anion as a result of the proton transfer.
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(OMe) or -withdrawing groups (Cl, OCF3, and NO2) were employed.
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tion conditions were investigated: A) À788C for 1 h; B) À408C for 1 h;
C) À788C with slow warming to room temperature, at which time the
reaction was quenched; and D) À408C with slow warming to room
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product with only <10% of the desired products.
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due to the presence of the carbonyl group of the indanone/tetralone
system, which facilitates the coordination/complexation of BCl3 to the
methyl group at the ortho position over that at the para position. In ad-
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gave inconsistent or irreproducible results.
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only decomposition of 23 was detected.
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Received: November 29, 2014
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FULL PAPER
Cycloaddition
Kassrin Tangdenpaisal,
Kanokpish Chuayboonsong,
Patchaya Sukjarean, Varisa Katesampao,
Nok Noiphrom, Somsak Ruchirawat,
Poonsakdi Ploypradith*
Minor adjustments: C4ÀC5-Cycloalkyl-
fused and C6-modified 2-arylchromans
can be prepared through hetero-Diels–
Alder reactions of the appropriate
ortho-quinone methides, starting from
simple hydroxyl-/methoxy-disubstituted
benzaldehydes (see scheme).
&& – &&
Synthesis of C4ÀC5 Cycloalkyl-Fused
and C6-Modified Chromans via ortho-
Quinone Methides
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