Synthesis of substituted tropones by sequential Rh-catalyzed [5+2] cycloaddition and elimination

Article abstract of DOI:10.1016/j.tet.2015.04.039

Abstract Highly substituted tropones are prepared from cycloheptatrienes derived from Rh-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and propargylic alcohols. The intermolecular [5+2] cycloaddition is highly regioselective for a v

Full text of DOI:10.1016/j.tet.2015.04.039

Tetrahedron xxx (2015) 1e6
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted tropones by sequential Rh-catalyzed [5þ2]
cycloaddition and elimination
a
a
,
b
,
, Ka Yang , Weiping Tang a
a
,c,
*
*
Wangze Song , Bao-min Xi
a
School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705-2222, USA
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou,
b
Guangdong Province 510515, PR China
c
Department of Chemistry, University of Wisconsin, Madison, WI 53706, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly substituted tropones are prepared from cycloheptatrienes derived from Rh-catalyzed in-
Received 13 March 2015
Received in revised form 11 April 2015
Accepted 13 April 2015
Available online xxx
termolecular [5þ2] cycloaddition of 3-acyloxy-1,4-enynes and propargylic alcohols. The intermolecular
[
5þ2] cycloaddition is highly regioselective for a variety of propargylic alcohols. Elimination of the cy-
cloaddition products afforded various substituted tropones.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Tropone
Cycloaddition
Rhodium
1,4-Enynes
Alkynes
1. Introduction
Tropone 1 and its derivatives such as tropolone 2 are non-
benzenoid seven-membered aromatic compounds. The structures
1
of tropones were first proposed 1940s. To date, over two hundred
2
of naturally occurring tropone derivatives have been identified.
They have broad pharmacological activities ranging from anti-
bacterial, anti-fungal, anti-tumor to anti-viral activities.3 Many of
them have complex structural architectures, such as tropone-
Fig. 1. Tropones, tropolones and tropone-containing natural products.
4
containing natural products hainanolidol 3 and harringtonolide
5
5
ion 6 and alkene (Scheme 1). Although we were able to assemble
4
(Fig. 1).
the carbon skeleton of 4 very efficiently, it took us a number of steps
to remove the extra oxygen bridge in 7 for the formation of tropone
in target 4. Clearly, the development of new types of [5þ2] cyclo-
additions is highly desirable.
Numerous methods have been developed for the synthesis of
6
tropones and their derivatives. Many of them were recently
7
reviewed by us in the context of natural product synthesis. How-
ever, efficient synthesis of highly substituted tropones is a still
We have recently reported intra- and intermolecular12 Rh-
catalyzed [5þ2] cycloadditions for the synthesis of highly
substituted cycloheptatrienes by using 3-acyloxy-1,4-enyne as
11
8
challenging problem. For example, only the parent non-
substituted tropone was used as the substrate in many of the cy-
cloaddition methods involving tropones including some very re-
13
9
a novel 5-carbon component (Scheme 2). The high degree of
unsaturation and the enol ester functionality in cycloaddition
product 9 are ideally set up for the synthesis of substituted tropone
cent reports. We have recently completed the first total synthesis
10
of harringtonolide 4 via a [5þ2] cycloaddition of oxidopyrylium
1
0. We herein report our efforts along this direction for the first
time.
Efforts for the conversion of cycloheptatriene product 9 directly
to tropones by oxidation were fruitless. Although we were able to
*
Corresponding authors. Tel.: þ86 20 6164 8549; fax: þ86 20 6164 8533 (B.X.);
tel.: þ1 608 890 1846; fax: þ1 608 262 5345 (W.T.); e-mail addresses: xibaomin@
sohu.com (B.-min Xi), wtang@pharmacy.wisc.edu (W. Tang).
http://dx.doi.org/10.1016/j.tet.2015.04.039
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
W. Song et al. / Tetrahedron xxx (2015) 1e6
Scheme 1. Total synthesis of (ꢀ)-harringtonolide.
Scheme 2. Rh-catalyzed intermolecular [5þ2] cycloaddition and formation of
tropones.
remove the ester group in 9 by reduction or hydrolysis, we could
not convert the hydrolyzed products to tropones by oxidative re-
agents. During the development of the intermolecular [5þ2] cy-
cloadditions,12 we learned that high regioselectivity could be
observed when propargylic alcohols 12 were employed as the
substrates (Scheme 3). With the hydroxyl group handle in product
13, we thought we might be able to prepare tropones by elimina-
tion reaction instead of oxidation reaction.
Previously, we mainly used the pivalate ester of 3-hydroxy-1,4-
enyne as the 5-carbon component for Rh-catalyzed [5þ2] cyclo-
additions.12 It generally provided higher yields of the product
compared to other esters such as acetate or benzoate. We imagine
that the acetate in 13 or 14 can be easily hydrolyzed under milder
conditions. We first examined the scope of the Rh-catalyzed [5þ2]
cycloaddition using 3-acyloxy-1,4-enyne 11a and 11b with a variety
of propargylic alcohols. Ester 11a was prepared in just one step
12
from commercially available 3-methyl-1-penten-4-yn-3-ol. Ester
1
3
1b is available in three steps from commercially available 1-octyn-
-ol.
Product 13a was prepared as a single isomer (Scheme 3) in the
14
Scheme 3. Synthesis of substituted cycloheptatrienes.
presence of Wilkinson’s catalyst. The same condition worked for
most of the terminal alkynes. The addition of electron-poor phos-
phine can improve the yield for products 13c and 13h. When in-
ternal alkynes are employed, much better yields were obtained for
potassium carbonate in methanol to complete both elimination and
hydrolysis in one step. However, the yield was much lower using
the two step sequence.
We then examined the scope of the three-step sequence. A va-
riety of disubstituted tropones could be prepared from the corre-
sponding cycloheptatrienes. Tropones 16d and 16f were obtained
in lower yields from substrates bearing a benzylic or a tertiary al-
cohol, respectively. The TBS-protected primary alcohol in substrate
0
products 13i and 13j/13j under condition b. High regioselectivity
was observed for product 13i, while a ratio of 2:1 was obtained for
0
1
products 13j and 13j . The R group can be methyl or other alkyl
1
groups, such as n-pentyl in 14. When R was switched phenyl
group, the acetate substrate isomerized to conjugated 1,3-enyne
15
15
under the reaction condition.
We next examined the possibility of synthesizing tropones by
eliminating the hydroxyl group in products 13 and 14. We envi-
sioned that conversion of allylic alcohols 13 or 14 to mesylate 17
followed by based-mediated elimination should yield tetraene in-
termediate 18, which could be hydrolyzed to aromatic tropone
product 16 via enol intermediate 19 (Scheme 4). Indeed, a three-
step sequence converted 13a to tropone 16a in a 61% isolated
yield. We also tried to treat mesylate intermediate 17a with
1
3h can be tolerated and tropone 16h was prepared in a 56% iso-
lated yield. Trisubstituted tropone 16i was prepared from the cor-
responding alcohol 13i in a 63% isolated yield. Trisubstituted
0
tropones 16j and 16j could be isolated in 47% and 24% yields, re-
0
spectively, from a mixture of non-separable alcohols 13j and 13j .
Cycloheptatriene 14 was also converted to tropone 20 under the
same condition.
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W. Song et al. / Tetrahedron xxx (2015) 1e6
3
Scheme 5. Amination and cycloaddition of substituted tropones.
2. Experimental section
Esters 11a and 11b were prepared from the corresponding al-
cohols by esterification reactions following our previously reported
12,14
procedures.
2.1. General procedures for the Rh-catalyzed intermolecular
[
5D2] cycloaddition
Method A: To a flask containing 1,4-enyne (1 mmol) and alkyne
(
2 mmol) was added RhCl(PPh
3
)
3
(5 mol %) and chloroform (0.4 M).
ꢁ
The flask was flushed with argon and allowed to stir at 65 C. The
reaction was monitored by TLC until the 1,4-enyne was completely
consumed (approximately 12 h). The solvent was evaporated and
the resulting residue was purified via flash chromatography on
silica gel using ethyl acetate and hexanes to yield [5þ2] cycload-
dition products.
Method B: To a flask containing 1,4-enyne (1 mmol) and alkyne
2 mmol) was added [Rh(COD)Cl] (5 mol %), tris[4-(trifluoromethyl)
2
Scheme 4. Synthesis of substituted tropones.
(
phenyl] phosphine (30 mol %) and chloroform (0.4 M). The flask was
ꢁ
flushed with argon and allowed to stir at 65 C. The reaction was
monitored by TLC until the 1,4-enyne was completely consumed
We further functionalized tropone products 16b, 16d, and 16e to
(approximately 12 h). The solvent was evaporated and the resulting
amino-tropones 21 (Scheme 5). The amino group was introduced to
0
residue was purified via flash chromatography on silica gel using
ethyl acetate and hexanes to yield [5þ2] cycloaddition products.
the
a
-position of tropones by treating them with hydrazine fol-
3
a
lowing literature procedures. Since the a-position is blocked by
methyl substituent, regioselectivity is not a concern for the ami-
nation reaction.
2.2. 4-(1-Hydroxyethyl)-7-methylcyclohepta-1,3,6-trien-1-yl
acetate (13a)
We also explored the [4þ2] cycloaddition between tropone 16b
and anhydride 22. Under thermal conditions, cycloaddition product
Oil. Method A, 66% yield. 1H NMR (500Mz, CDCl
) d 6.22 (d,
3
2
3 was obtained in high regio- and diastereoselectivity. The less
substituted diene in tropone 16b selectively reacted with the
dienophile and afforded only the endo-product.
J¼6.5 Hz, 1H), 6.07 (d, J¼6.5 Hz, 1H), 5.25 (t, J¼7.5 Hz, 1H), 4.44 (q,
J¼6.5 Hz, 1H), 2.58e2.54 (m, 1H), 2.28e2.24 (m, 1H), 2.21 (s, 3H),
1
3
In summary, we have developed an efficient sequence to convert
products derived from Rh-catalyzed [5þ2] cycloaddition of 3-
acyloxy-1,4-enynes and alkynes to substituted tropones. High
regioselectivity was observed for all terminal alkynes in the Rh-
catalyzed [5þ2] cycloaddition. For internal alkynes, high regiose-
lectivity could also be obtained when there were two electronically
differentiated substituents on the two termini of the internal al-
kynes. Various di- and tri-substituted tropones were synthesized
efficiently from the cycloheptatriene cycloaddition product by
a three-step mesylation, elimination and hydrolysis sequence.
1.78 (s, 3H), 1.31 (d, J¼8.5 Hz, 3H); C NMR (100Mz, CDCl
3
) d 169.6,
151.9, 142.1, 130.8, 120.8, 119.5, 117.5, 71.1, 27.9, 23.6, 21.0, 17.9. IR
ꢂ1
(film): 2926, 1730, 1637, 1440, 1370, 1218, 1056, 830 cm . HRMS
(ESI) m/z calcd. For C12
H
16
O
3
(MþNa)þ 231.0997, found 231.0993.
2.3. 4-(1-Hydroxyhexyl)-7-methylcyclohepta-1,3,6-trien-1-yl
acetate (13b)
Oil. Method A, 71% yield. 1H NMR (500Mz, CDCl
J¼6.5 Hz,1H), 6.02 (d, J¼6.5 Hz,1H), 5.22 (t, J¼7.0 Hz,1H), 4.22e4.19
3
) d 6.22 (d,
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4
W. Song et al. / Tetrahedron xxx (2015) 1e6
(
3
m, 1H), 2.58e2.54 (m, 1H), 2.24e2.20 (m, 1H), 2.20 (s, 3H), 1.78 (s,
HRMS (ESI) m/z calcd. For C16
287.1615.
H
24
O
3
(MþNa)þ 287.1617, found
H), 1.72 (s, 1H), 1.57e1.53 (m, 2H), 1.35e1.24 (m, 6H), 0.87 (t,
13
J¼7.0 Hz, 3H); C NMR (100Mz, CDCl
3
) d 169.6, 151.8, 141.0, 130.7,
1
20.8, 119.4, 118.5, 75.5, 37.0, 31.9, 27.7, 25.7, 22.7, 21.0, 17.9, 14.2. IR
2.9. 4-(2-((tert-Butyldimethylsilyl)oxy)-1-hydroxyethyl)-7-
methylcyclohepta-1,3,6-trien-1-yl acetate (13h)
ꢂ1
(film): 2930, 1728, 1637, 1370, 1210, 1062, 834, 777 cm . HRMS
(
ESI) m/z calcd. For C16
24
H O
3
(MþNa)þ 287.1623, found 287.1618.
Oil. Method B, 90% yield. 1H NMR (500Mz, CDCl
) d 6.26 (d,
3
J¼6.5 Hz, 1H), 6.14 (d, J¼6.5 Hz, 1H), 5.21 (t, J¼7.0 Hz, 1H), 4.30 (d,
2
.4. 4-(1-Hydroxy-3-phenylpropyl)-7-methylcyclohepta-1,3,6-
J¼8.5 Hz, 1H), 3.63 (dd, J¼10.0, 3.5 Hz, 1H), 3.39 (dd, J¼10.0, 8.5 Hz,
trien-1-yl acetate (13c)
1
H), 2.76 (d, J¼2.5 Hz,1H), 2.59e2.55 (m,1H), 2.21 (s, 3H), 2.17e2.13
13
1
(m, 1H), 1.78 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H); C NMR (125Mz,
CDCl 169.6, 152.1, 135.6, 131.0, 119.8, 119.7, 119.6, 75.2, 67.3, 28.0,
Oil. Method A, 55% yield. Method B, 69% yield. H NMR (400Mz,
3
) d
CDCl
1
2
3
)
d
7.30e7.26 (m, 2H), 7.20e7.16 (m, 3H), 6.22 (d, J¼6.4 Hz,
2
6.1, 21.0, 18.5, 17.9, ꢂ5.0, ꢂ5.1. IR (film): 2970, 2858, 2349, 1738,
H), 6.05 (d, J¼6.4 Hz, 1H), 5.24 (t, J¼6.0 Hz, 1H), 4.25e4.23 (m, 1H),
ꢂ1
1436, 1374, 1110, 1060, 834 cm . HRMS (ESI) m/z calcd. For
.70e2.62 (m, 2H), 2.60e2.57 (m, 1H), 2.24e2.19 (m, 4H), 1.91e1.84
þ
1
3
C18H30O Si (MþNa) 361.1805, found 361.1802.
(
1
7
m, 2H), 1.79 (s, 3H), 1.67 (s, 1H); C NMR (100Mz, CDCl
52.0, 142.0, 140.5, 130.9, 128.68, 128.66, 126.1, 120.8, 119.4, 118.8,
4.8, 39.7, 32.4, 27.7, 21.0, 17.9. IR (film): 3027, 2923, 1749, 1637,
3
)
d
169.6,
4
2.10. 4-(Hydroxymethyl)-3,7-dimethylcyclohepta-1,3,6-trien-
ꢂ1
1-yl acetate (13i)
1454, 1369, 1213, 1120, 1056, 833 cm . HRMS (ESI) m/z calcd. For
þ
C
H
19 22
O
3
(MþNa) 321.1461, found 321.1461.
1
Oil. Method B, 76% yield. H NMR (500Mz, CDCl
3
) d 6.18 (s, 1H),
5
2
d
.40 (t, J¼9.0 Hz,1H), 4.23 (s, 2H), 2.44 (d, J¼7.5 Hz, 2H), 2.20 (s, 3H),
2
.5. 4-(Hydroxy(phenyl)methyl)-7-methylcyclohepta-1,3,6-
13
.06e2.01 (m,1H),1.87 (s, 3H),1.76 (s, 3H); C NMR (100Mz, CDCl
3
)
trien-1-yl acetate (13d)
169.5, 151.0, 130.2, 129.9, 127.4, 124.7, 122.3, 62.8, 30.4, 20.9, 17.8,
1
17.6. IR (film): 3405, 2950, 1752, 1637, 1321, 1131, 1061, 1016,
Oil. Method A, 68% yield. H NMR (400Mz, CDCl
3
) d 7.38e7.25
ꢂ1
(MþNa)þ 231.0991,
873 cm . HRMS (ESI) m/z calcd. For C12
H
16
O
3
(
(
(
1
1
m, 5H), 6.25 (s, 2H), 5.34 (s, 1H), 5.00 (t, J¼7.2 Hz, 1H), 2.41e2.36
13
found 231.0989.
m, 1H), 2.28e2.23 (m, 1H), 2.18 (s, 3H), 1.73 (s, 3H); C NMR
100Mz, CDCl 169.6, 152.0, 142.4, 140.3, 130.7, 128.6, 128.0, 126.9,
21.7, 119.3, 119.1, 77.1, 28.5, 21.0, 17.9. IR (film): 2935, 1750, 1632,
3
) d
2.11. 3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(hydrox-
ꢂ1
ymethyl)-7-methylcyclohepta-1,3,6-trien-1-yl acetate (13j and
441, 1142, 1060, 924, 770, 697 cm . HRMS (ESI) m/z calcd. For
0
þ
13j )
C
17
18
H O
3
(MþNa) 293.1154, found 293.1151.
1
Oil. Method B, 79% yield (2:1) mixture. Major H NMR (500Mz,
2
1
.6. 4-(1-Hydroxy-2,2-dimethylpropyl)-7-methylcyclohepta-
,3,6-trien-1-yl acetate (13e)
CDCl
3
)
d
6.29 (s, 1H), 5.34 (t, J¼7.5 Hz, 1H), 4.36e4.34 (m, 2H),
4
0
.30e4.26 (m, 2H), 2.40 (s, 2H), 2.20 (s, 3H),1.77 (s, 3H), 0.89 (s, 9H),
.08 (s, 6H); Major C NMR (100Mz, CDCl ) d 169.5, 151.7, 131.8,
3
13
Oil. Method A, 73% yield. 1H NMR (500Mz, CDCl
3
) d 6.22 (d,
1
30.2, 122.3, 120.1, 63.7, 63.5, 31.7, 26.0, 21.0, 18.5, 17.6, ꢂ5.0. IR
J¼6.5 Hz, 1H), 6.00 (d, J¼6.5 Hz, 1H), 5.26 (t, J¼7.5 Hz, 1H), 3.97 (s,
ꢂ1
film): 2930, 2858, 1728, 1472, 1370, 1135, 1062, 834 cm . HRMS
(
(
1
0
1
2
H), 2.68e2.64 (m, 1H), 2.20e2.16 (m, 4H), 1.80 (s, 3H), 1.70 (s, 1H),
.93 (s, 9H); 13C NMR (125Mz, CDCl
169.6, 151.7, 139.0, 131.0,
21.1, 120.4, 119.5, 83.6, 36.0, 26.5, 25.6, 25.5, 21.0, 17.9. IR (film):
Si (MþNa)þ 361.1805, found 361.1808.
30 4
ESI) m/z calcd. For C18H O
3
) d
2.12. 4-(Hydroxymethyl)-7-pentylcyclohepta-1,3,6-trien-1-yl
ꢂ1
981, 2874, 2341, 1747, 1637, 1480, 1266, 1005, 896. cm . HRMS
acetate (14)
(
ESI) m/z calcd. For C15
22
H O
3
(MþNa)þ 273.1461, found 273.1460.
Oil. Method A, 62% yield. 1H NMR (500Mz, CDCl
) d 6.26 (d,
3
2
.7. 4-(2-Hydroxypropan-2-yl)-7-methylcyclohepta-1,3,6-
J¼6.0 Hz, 1H), 6.06 (d, J¼6.5 Hz, 1H), 5.28 (t, J¼7.0 Hz, 1H), 4.24 (s,
trien-1-yl acetate (13f)
2
1
H), 2.42 (d, J¼7.5 Hz, 2H), 2.19 (s, 3H), 2.08 (t, J¼8.0 Hz, 2H), 1.68 (s,
H),1.38e1.32 (m, 2H),1.29e1.24 (m, 2H),1.20e1.16 (m, 2H), 0.85 (t,
Oil. Method A, 62% yield. 1H NMR (400Mz, CDCl
3
) d 6.25 (d,
13
J¼7.5 Hz, 3H); C NMR (125Mz, CDCl
3
) d 169.7, 151.6, 137.9, 135.5,
J¼6.8 Hz, 1H), 6.17 (d, J¼6.4 Hz, 1H), 5.26 (t, J¼7.2 Hz, 1H), 2.42 (d,
1
20.24, 120.15, 118.3, 66.2, 32.2, 31.7, 29.1, 29.0, 22.6, 21.0, 14.2. IR
13
J¼7.6 Hz, 2H), 2.21 (s, 3H),1.78 (s, 3H),1.41 (s, 6H); C NMR (100Mz,
CDCl 169.7, 151.4, 145.4, 130.6, 120.9, 119.7, 115.5, 73.0, 30.0, 29.9,
ꢂ1
film): 3431, 2928, 1750, 1436, 1364, 1122, 1020, 928 cm . HRMS
(
(
3
)
d
22 3
ESI) m/z calcd. For C15H O
(MþNa)þ 273.1467, found 273.1471.
2
1
2
1.0, 17.8. IR (film): 3450, 2979, 1740, 1637, 1438, 1367, 1215, 1115,
062, 957. cm . HRMS (ESI) m/z calcd. For C13H O
ꢂ1
(MþNa)þ
18 3
2.13. General procedures for the synthesis of tropones from
45.1148, found 245.1153.
cycloheptatrienes
2
.8. 4-(1-Hydroxy-2-methylpentyl)-7-methylcyclohepta-
To a solution of the cycloheptatriene substrate (0.2 mmol) in dry
1
,3,6-trien-1-yl acetate (13g)
dichloromethane (4 mL) was added triethylamine (85
m
L) and MsCl
ꢁ
(31
m
L) at ꢂ78 C. The reaction was warmed to room temperature
1
Oil. Method A, 64% yield (dr 1:1). H NMR (500Mz, CDCl
3
)
d
6.23
and stirred for 1 h. The solution was quenched with saturated
aqueous NaHCO (10 mL) solution and extracted with dichloro-
methane (3ꢃ10 mL). The combined organic layers were washed
with brine, dried with Na SO , concentrated under vacuum to give
the crude mesylation product.
To a solution of the crude mesylation product in dry THF (4 mL)
was added DBU (44 L) at room temperature. After stirring at this
(
1
1
dd, J¼9.0, 6.0 Hz, 1H), 6.02 (dd, J¼15.0, 6.0 Hz, 1H), 5.23e5.21 (m,
3
H), 4.01 (dd, J¼45.5, 6.0 Hz, 1H), 2.48e2.44 (m, 1H), 2.30e2.27 (m,
H), 2.21 (s, 3H), 1.78 (s, 3H), 1.67e1.65 (m, 1H), 1.34e1.25 (m, 4H),
2
4
1
3
1
.10e1.07 (m, 1H), 0.92e0.85 (m, 5H), 0.79 (d, J¼7.0 Hz, 1H);
C
3
NMR (100Mz, CDCl ) d 169.6, 166.6, 151.8, 151.6, 140.3, 140.2, 130.9,
130.8, 121.0, 120.7, 119.8, 119.5, 119.4, 119.1, 80.4, 79.2, 37.6, 37.3,
m
3
6.1, 34.2, 27.9, 21.0, 20.5, 20.4, 17.907, 17.899, 16.7, 14.6, 14.5, 14.3. IR
temperature for 10e30 min, it was concentrated to give the crude
tetraene product. To a solution of this crude product in MeOH
ꢂ1
(film): 3426, 2922, 1727, 1456, 1371, 1216, 1123, 1037, 924 cm
.
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W. Song et al. / Tetrahedron xxx (2015) 1e6
5
(
4 mL) was added K
2
CO
3
(13 mg) at room temperature. After stir-
2.25 (s, 3H), 2.25e2.20 (m, 1H), 1.72e1.67 (m, 1H), 1.41e1.25 (m,
13
ring at this temperature for 5e10 min, the product was concen-
trated under vacuum. The residue was purified by flash
chromatography on silica gel using ethyl acetate and hexanes to
give the final tropone product.
3H), 1.19e1.13 (m, 1H), 0.90e0.85 (m, 6H); C NMR (100Mz, CDCl
3
)
d
187.2, 150.2, 147.1, 139.2, 139.0, 135.7, 133.0, 47.6, 39.1, 34.5, 22.7,
20.3, 19.4, 14.5. IR (film): 2455, 2360, 2254, 1737, 1625, 1565, 1421,
ꢂ1
20O (MþNa)þ
1230, 1095, 904. cm . HRMS (ESI) m/z calcd. For C14
2
H
27.1406, found 227.1409.
2
.14. 5-Ethyl-2-methylcyclohepta-2,4,6-trienone (16a)
2
.21. 5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-
1
Oil. 18 mg, 61% yield. H NMR (500Mz, CDCl
3
)
d
7.25 (d, J¼9.5 Hz,
methylcyclohepta-2,4,6-trienone (16h)
1
(
1
2
H), 7.04 (s, 2H), 6.78 (d, J¼9.5 Hz, 1H), 2.55 (q, J¼7.5 Hz, 2H), 2.25
13
1
s, 3H), 1.21 (t, J¼7.5 Hz, 3H); C NMR (100Mz, CDCl
3
)
d
187.2, 150.1,
Oil. 32 mg, 56% yield. H NMR (500Mz, CDCl
3
)
d
7.27 (d, J¼9.5 Hz,
49.4, 139.6, 138.5,136.0,131.2, 33.0, 22.7, 15.3. IR (film): 3417, 3055,
1H), 7.19e7.03 (m, 2H), 6.83 (d, J¼9.0 Hz, 1H), 3.83 (t, J¼6.0 Hz, 2H),
ꢂ1
13
854, 1728, 1573, 1266, 1080, 957 cm . HRMS (ESI) m/z calcd. For
2.71 (t, J¼6.5 Hz, 2H), 2.28 (s, 3H), 0.86 (s, 9H), 0.01 (s, 6H); C NMR
þ
C
10
H
12O (MþNa) 171.0780, found 171.0779.
3
(100Mz, CDCl ) d 187.1, 150.7, 145.0, 139.20, 139.18, 135.6, 133.4,
6
3.6, 43.1, 26.1, 22.7, 18.5, ꢂ5.2. IR (film): 2953, 2895, 1730, 1631,
ꢂ1
2
.15. 5-Hexyl-2-methylcyclohepta-2,4,6-trienone (16b)
1577, 1374, 1254, 1095. cm . HRMS (ESI) m/z calcd. For C16H O Si
26 2
(
MþNa)þ 301.1594, found 301.1597.
1
Oil. 28 mg, 67% yield. H NMR (500Mz, CDCl
3
)
d
7.24 (d, J¼9.0 Hz,
1
3
H), 7.03 (s, 2H), 6.76 (d, J¼9.0 Hz,1H), 2.49 (t, J¼7.5 Hz, 2H), 2.25 (s,
2.22. 2,5,6-Trimethylcyclohepta-2,4,6-trienone (16i)
13
H), 1.57e1.55 (m, 2H), 1.34e1.27 (m, 6H), 0.88 (t, J¼7.0 Hz, 3H);
187.2, 150.1, 148.2, 139.5, 138.7, 135.9, 132.0,
0.0, 31.8, 31.0, 29.0, 22.8, 22.7, 14.3. IR (film): 3040, 2925, 1737,
C
1
NMR (100Mz, CDCl
3
)
d
Oil. 19 mg, 63% yield. H NMR (500Mz, CDCl
3
)
d
7.14e7.11 (m,
13
4
1
C
2H), 6.81 (d, J¼9.5 Hz, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H);
C
ꢂ1
581, 1664, 1360, 1220, 962 cm . HRMS (ESI) m/z calcd. For
NMR (100Mz, CDCl 186.3, 149.0, 147.1, 144.1, 140.2, 134.9, 132.1,
3
) d
þ
14
H
20O (MþNa) 227.1412, found 227.1416.
26.0, 25.5, 22.1. IR (film): 2923, 2855, 1738, 1566, 1372, 1216, 950,
8
149.0960, found 149.0966.
ꢂ1
12O (MþH)þ
94, 713 cm . HRMS (ESI) m/z calcd. For C10
H
2
.16. 2-Methyl-5-(3-phenylpropyl)cyclohepta-2,4,6-trienone
(
16c)
2
.23. 6-(((tert-Butyldimethylsilyl)oxy)methyl)-2,5-
1
Oil. 29 mg, 60% yield. H NMR (400Mz, CDCl
3
)
d
7.31e7.29 (m,
dimethylcyclohepta-2,4,6-trienone (16j)
2
H), 7.24e7.21 (m, 2H), 7.19e7.16 (m, 2H), 7.02 (s, 2H), 6.76 (d,
1
J¼9.2 Hz, 1H), 2.66 (t, J¼7.6 Hz, 2H), 2.53 (t, J¼9.5 Hz, 2H), 2.27 (s,
Oil. 27 mg, 47% yield. H NMR (500Mz, CDCl
3
)
d
7.28 (d, J¼9.5 Hz,
1
3
3
H), 1.96e1.88 (m, 2H); C NMR (100Mz, CDCl
3
)
d
187.2, 150.4,
1H), 7.14 (d, J¼10.0 Hz, 1H), 7.07 (s, 1H), 4.53 (s, 2H), 2.25 (s, 6H),
13
147.5, 141.7, 139.6, 138.5, 135.7, 132.2, 128.7, 128.6, 126.3, 39.4, 35.4,
3
0.94 (s, 9H), 0.11 (s, 6H); C NMR (100Mz, CDCl ) d 186.5, 150.0,
3
7
2
2.5, 22.7. IR (film): 3053, 2927, 2858, 1730, 1573, 1456, 1265, 1097,
145.3, 145.0, 140.8, 134.9, 129.1, 65.2, 26.15, 26.11, 23.2, 22.3, 18.6,
ꢂ1
18O (MþH)þ
ꢂ1
33, 700 cm . HRMS (ESI) m/z calcd. For C17
H
ꢂ5.1. IR (film): 3055, 2955, 1729, 1626, 1265, 1063, 1017, 838. cm
.
39.1430, found 239.1436.
HRMS (ESI) m/z calcd. For C16
H
26
O
2
Si (MþNa)þ 301.1594, found
301.1600.
2
.17. 5-Benzyl-2-methylcyclohepta-2,4,6-trienone (16d)
2
.24. 5-(((tert-Butyldimethylsilyl)oxy)methyl)-2,6-
1
0
Oil. 21 mg, 51% yield. H NMR (500Mz, CDCl
3
)
d
7.33e7.30 (m,
dimethylcyclohepta-2,4,6-trienone (16j )
3
H), 7.26e7.24 (m, 1H), 7.17e7.15 (m, 2H), 6.99 (s, 2H), 6.81 (d,
13
1
J¼9.0 Hz, 1H), 3.85 (s, 2H), 2.25 (s, 3H); C NMR (100Mz, CDCl
3
)
Oil. 13 mg, 24% yield. H NMR (500Mz, CDCl
3
)
d
7.36 (s, 1H), 7.14
d
187.1, 150.6, 146.0, 139.5, 139.1, 138.5, 135.6, 132.7, 129.2, 129.1,
(d, J¼9.0 Hz, 1H), 6.77 (d, J¼9.5 Hz, 1H), 4.53 (s, 2H), 2.24 (s, 6H),
13
127.1, 45.5, 22.7. IR (film): 3055, 2987, 2361, 1726, 1575, 1422, 1265,
3
0.93 (s, 9H), 0.11 (s, 6H); C NMR (100Mz, CDCl ) d 187.1, 149.4,
ꢂ1
14O (MþNa)þ 233.0937,
8
96. cm . HRMS (ESI) m/z calcd. For C15
H
147.8, 142.0, 136.5, 134.8, 132.9, 66.5, 26.1, 22.7, 22.1, 18.6, ꢂ5.0. IR
ꢂ1
found 233.0945.
(film): 3055, 2954, 2858, 1738, 1625, 1265, 1177, 1060, 940. cm
.
HRMS (ESI) m/z calcd. For C16
H
26
O
2
Si (MþNa)þ 301.1594, found
2
.18. 2-Methyl-5-neopentylcyclohepta-2,4,6-trienone (16e)
301.1601.
1
Oil. 28 mg, 72% yield. H NMR (500Mz, CDCl
3
)
d
7.26 (d, J¼9.0 Hz,
2.25. 5-Methyl-2-pentylcyclohepta-2,4,6-trienone (20)
1
(
1
1
H), 7.00 (s, 2H), 6.72 (d, J¼9.5 Hz,1H), 2.41 (s, 2H), 2.27 (s, 3H), 0.93
187.2, 150.5, 145.5, 140.5, 138.3,
35.4, 134.3, 53.6, 32.8, 29.6, 22.7. IR (film): 3060, 2964, 1730, 1587,
s, 9H); 13C NMR (100Mz, CDCl
d
Oil. 23 mg, 60% yield. H NMR (400Mz, CDCl
1
d
7.12 (d, J¼9.2 Hz,
3
)
3
)
1H), 6.99 (s, 2H), 6.80 (d, J¼9.2 Hz, 1H), 2.62e2,58 (m, 2H), 2.30 (s,
ꢂ1
13
403, 1264, 1080, 1026 cm . HRMS (ESI) m/z calcd. For C13
MþNa) 213.1255, found 213.1259.
H
18
O
3H), 1.56e1.50 (m, 2H), 1.36e1.31 (m, 4H), 0.88 (t, J¼6.8 Hz, 3H);
C
þ
(
NMR (100Mz, CDCl 186.8, 153.9, 143.3, 139.7, 139.0, 135.3, 132.3,
3
) d
3
5.4, 32.0, 28.8, 25.8, 22.8, 14.2. IR (film): 2955, 2925, 1729, 1633,
ꢂ1
2
.19. 5-Isopropyl-2-methylcyclohepta-2,4,6-trienone (16f)
1574, 1462, 1190, 1040, 844. cm . HRMS (ESI) m/z calcd. For
C
13
H
18O (MþNa)þ 213.1249, found 213.1256.
Oil. 14 mg, 42% yield. All spectra data are in accordance with
literature.16
2.26. General procedures for the amination of tropones
To a solution of -methyl-tropone (0.1 mmol) in EtOH (0.5 mL)
2
.20. 2-Methyl-5-(2-methylpentyl)cyclohepta-2,4,6-trienone
a
(
16g)
was added 65% hydrazine monohydrate (0.12 mL). The solution was
allowed to stir at 60 C until all starting material was consumed by
monitoring the reaction by TLC (w2h). The reaction was concen-
trated under vacuum and then taken up in EtOAc (4 mL) and
ꢁ
1
Oil. 31 mg, 75% yield. H NMR (400Mz, CDCl
H), 7.05e6.98 (m, 2H), 6.73 (d, J¼9.2 Hz, 1H), 2.55e2.51 (m, 1H),
3
)
d
7.24 (d, J¼9.2 Hz,
1
Please cite this article in press as: Song, W.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.039

6
W. Song et al. / Tetrahedron xxx (2015) 1e6
washed with H
with brine, dried over Na
vacuum. The crude residue was purified by flash column chroma-
tography on silica gel using ethyl acetate and hexanes to provide
2
O (3ꢃ4 mL). The organic layer was then washed
SO , filtered and concentrated under
J¼7.2, 2.0 Hz, 1H), 3.60e3.58 (m, 1H), 3.53 (dd, J¼7.2, 1.2 Hz, 1H),
2.12e2.08 (m, 2H), 1.76 (s, 3H), 1.37e1.33 (m, 2H), 1.30e1.23 (m,
2
4
13
3
6H), 0.87 (t, J¼9.6 Hz, 3H); C NMR (125Mz, CDCl ) d 193.4, 171.0,
152.5, 144.2, 137.7, 118.1, 53.9, 47.9, 43.1, 42.2, 36.7, 31.7, 28.9, 26.8,
the desired
a
-amino-tropones.
22.8, 18.4, 14.3. IR (film): 3055, 2930, 2359, 1785, 1674, 1265, 1076,
ꢂ1
(MþNa)þ
928, 832 cm . HRMS (ESI) m/z calcd. For C18
H
22
O
4
2
.27. 2-Amino-4-hexyl-7-methylcyclohepta-2,4,6-trienone
325.1410, found 325.1424.
(
21a)
Acknowledgements
1
Oil. 17 mg, 79% yield. H NMR (500Mz, CDCl
3
)
d
7.37 (d, J¼9.5 Hz,
1
(
H), 6.80 (s, 1H), 6.57 (d, J¼10.0 Hz, 1H), 5.80 (br s, 2H), 2.54e2.51
W. T. thanks University of Wisconsin and National Institute of
Health (R01GM088285) for funding. B.-m. Xi thanks Southern
Medical University for funding.
m, 2H), 2.40 (s, 3H), 1.62e1.57 (m, 2H), 1.35e1.25 (m, 6H), 0.89 (t,
13
J¼6.5 Hz, 3H); C NMR (125Mz, CDCl
3
) d 175.2, 154.1, 150.5, 139.0,
1
3
37.5, 123.9, 115.3, 41.2, 32.1, 31.9, 29.1, 23.4, 22.8, 14.3. IR (film):
ꢂ1
055, 2987,1730,1530,1422,1265, 839. cm . HRMS (ESI) m/z calcd.
þ
Supplementary data
For C14
H
21NO (MþNa) 242.1515, found 242.1584.
Supplementary data (NMR spectra for all new compounds.) re-
lated to this article can be found at http://dx.doi.org/10.1016/
j.tet.2015.04.039.
2
.28. 2-Amino-4-benzyl-7-methylcyclohepta-2,4,6-trienone
(
21b)
Oil. 19 mg, 85% yield. 1H NMR (500Mz, CDCl
) d 7.39 (d,
3
J¼10.0 Hz, 1H), 7.32e7.29 (m, 2H), 7.24e7.22 (m, 1H), 7.18 (d,
References and notes
J¼7.0 Hz, 2H), 6.76 (s, 1H), 6.62 (d, J¼10.0 Hz, 1H), 5.76 (br s, 2H),
13
1. (a) Dewar, M. J. S. Nature 1945, 155, 50; (b) Dewar, M. J. S. Nature 1945, 155, 141.
3
3
.90 (s, 2H), 2.39 (s, 3H); C NMR (125Mz, CDCl ) d 175.5, 153.9,
2. (a) Zhao, J. Curr. Med. Chem. 2007, 14, 2597; (b) Bentley, R. Nat. Prod. Rep. 2008,
1
48.0, 140.3, 139.5, 137.4, 129.1, 128.9, 126.9, 124.5, 115.3, 46.5, 23.4.
25, 118.
ꢂ1
IR (film): 3319, 3282, 2382, 1728, 1609, 1521, 1276, 969, 740. cm
HRMS (ESI) m/z calcd. For C15
.
3. (a) Ononye, S. N.; VanHeyst, M. D.; Oblak, E. Z.; Zhou, W.; Ammar, M.; Anderson,
A. C.; Wright, D. L. ACS Med. Chem. Lett. 2013, 4, 757; (b) Day, J. A.; Cohen, S. M. J.
Med. Chem. 2013, 56, 7997; (c) Hirsch, D. R.; Cox, G.; D’Erasmo, M. P.; Shakya, T.;
Meck, C.; Mohd, N.; Wright, G. D.; Murelli, R. P. Bioorg. Med. Chem. Lett. 2014, 24,
H
15NO (MþNa)þ 248.1045, found
2
48.1048.
4943.
4
5
6
. Frey, B.; Wells, A. P.; Rogers, D. H.; Mander, L. N. J. Am. Chem. Soc. 1998, 120, 1914.
. Zhang, M.; Liu, N.; Tang, W. J. Am. Chem. Soc. 2013, 135, 12434.
. (a) Graening, T.; Schmalz, H. G. Angew. Chem., Int. Ed. 2004, 43, 3230; (b) Bat-
tiste, M. A.; Pelphrey, P. M.; Wright, D. L. Chem.dEur. J. 2006, 12, 3438; (c)
Abdelkafi, H.; Nay, B. Nat. Prod. Rep. 2012, 29, 845; (d) Meck, C.; D’Erasmo, M. P.;
Hirsch, D. R.; Murelli, R. P. Med. Chem. Comm. 2014, 5, 842.
2
.29. 2-Amino-4-(tert-butyl)-7-methylcyclohepta-2,4,6-
trienone (21c)
Oil. 16 mg, 79% yield. 1H NMR (500Mz, CDCl
) d 7.37 (d,
3
J¼10.0 Hz, 1H), 6.76 (s, 1H), 6.52 (d, J¼10.0 Hz, 1H), 5.79 (br s, 2H),
7. Liu, N.; Song, W.; Schienebeck, C. M.; Zhang, M.; Tang, W. Tetrahedron 2014, 70,
13
2
.46 (s, 2H), 2.41 (s, 3H), 0.94 (s, 9H); C NMR (125Mz, CDCl
3
)
9281.
d
175.2, 153.3, 147.3, 139.2, 136.8, 126.0, 117.3, 54.8, 32.8, 29.8, 23.4.
8. (a) Meck, C.; Mohd, N.; Murelli, R. P. Org. Lett. 2012, 14, 5988; (b) Williams, Y. D.;
Meck, C.; Mohd, N.; Murelli, R. P. J. Org. Chem. 2013, 78, 11707.
IR (film): 3419, 3281, 2952, 1730, 1605, 1524, 1424, 1363, 1163, 962,
8
found 228.1365.
9
. (a) Houk, K. N.; Woodward, R. B. J. Am. Chem. Soc. 1970, 92, 4145; (b) Houk, K. N.;
Luskus, L. J.; Bhacca, N. S. J. Am. Chem. Soc. 1970, 92, 6392; (c) Noble, W. J. L.;
Ojosipe, B. A. J. Am. Chem. Soc. 1975, 97, 5939; (d) Trost, B. M.; Seoane, P. R. J. Am.
Chem. Soc. 1987, 109, 615; (e) Machiguchi, T.; Hasegawa, T.; Ishii, Y.; Yamabe, S.;
Minato, T. J. Am. Chem. Soc. 1993, 115, 11536; (f) Nair, V.; Poonoth, M.; Vellalath,
S.; Suresh, E.; Thirumalai, R. J. Org. Chem. 2006, 71, 8964; (g) Trost, B. M.;
McDougall, P. J.; Hartmann, O.; Wathen, P. T. J. Am. Chem. Soc. 2008, 130, 14960;
ꢂ1
19NO (MþNa)þ 228.1358,
29 cm . HRMS (ESI) m/z calcd. For C13
H
2
.30. Procedure for the synthesis of 23 via [4D2]
cycloaddition
(h) Li, P.; Yamamoto, H. J. Am. Chem. Soc. 2009, 131, 16628; (i) Xie, M.; Liu, X.;
Wu, X.; Cai, Y.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2013, 52, 5604; (j) Liu, H.;
Wu, Y.; Zhao, Y.; Li, Z.; Zhang, L.; Yang, W.; Jiang, H.; Jing, C.; Yu, H.; Wang, B.;
Xiao, Y.; Guo, H. J. Am. Chem. Soc. 2014, 136, 2625; (k) Teng, H.-L.; Yao, L.; Wang,
C.-J. J. Am. Chem. Soc. 2014, 136, 4075.
0. (a) Pellissier, H. Adv. Synth. Catal. 2011, 353, 189; (b) Ylijoki, K. E. O.; Stryker, J. M.
Chem. Rev. 2013, 113, 2244.
11. (a) Shu, X.-Z.; Huang, S.; Shu, D.; Guzei, I. A.; Tang, W. Angew. Chem., Int. Ed.
2011, 50, 8153; (b) Shu, X.-Z.; Schienebeck, C. M.; Song, W.; Guzei, I. A.; Tang, W.
Angew. Chem., Int. Ed. 2013, 52, 13601.
To a solution of tropone 16b (0.06 mmol) in xylene (0.3 mL) was
added furan-2,5-dione (29.5 mg). The solution was allowed to stir
ꢁ
at 120 C overnight. The reaction was concentrated under vacuum
1
and purified by flash column chromatography on silica gel using
ethyl acetate and hexanes to provide the desired cycloaddition
product in 65% yield.
1
2. Shu, X.-Z.; Li, X.; Shu, D.; Huang, S.; Schienebeck, C. M.; Zhou, X.; Robichaux, P.
J.; Tang, W. J. Am. Chem. Soc. 2012, 134, 5211.
2
.31. 9-Hexyl-6-methyl-3a,4,8,8a-tetrahydro-1H-4,8-
ethenocyclohepta[c]furan-1,3,5-trione (23)
13. Schienebeck, C. M.; Li, X.; Shu, X.-Z.; Tang, W. Pure Appl. Chem. 2014, 86, 409.
1
4. Schienebeck, C. M.; Song, W.; Smits, A. M.; Tang, W. Synthesis 2015, 47, 1076.
5. Bychkova, N. A.; Zotchik, N. V.; Motorina, Z. N.; Rubtsov, I. A. Zh. Obshch. Khim.
985, 55, 1111.
16. Kato, M.; Yamamoto, S.; Nomura, S.; Miwa, T. Bull. Chem. Soc. Jpn. 1990, 63, 64.
1
1
Oil.12 mg, 65% yield. H NMR (400Mz, CDCl
3
)
d
6.98 (d, J¼6.8 Hz,
1
1
H), 5.79 (d, J¼6.0 Hz, 1H), 3.99 (dd, J¼6.0, 1.2 Hz, 1H), 3.69 (dd,
Please cite this article in press as: Song, W.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.039