Catalytic Chemo- and Regioselective Coupling of 1,3-Dicarbonyls with N-Heterocyclic Nucleophiles

Article abstract of DOI:10.1021/acs.joc.6b00731

The development of a decarboxylative palladium-catalyzed coupling of 1,3-dicarbonyl compounds with indole, pyrrole, imidazole, and pyrazole nucleophiles via an allylic linker under neutral conditions is disclosed. This process enables the installation of an all-carbon quaternary center and new C-C and C-N bonds in a single operation. Despite the weakly acidic nature of N-heterocycles, the reactions proceed with good efficiency and complete regio- and chemoselectivity.

Full text of DOI:10.1021/acs.joc.6b00731

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Article
Catalytic Chemo- and Regioselective Coupling of
1,3-Dicarbonyls with N-Heterocyclic Nucleophiles
Miles Kenny, Daniel James Kitson, and Vilius Franckevicius
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 May 2016
Downloaded from http://pubs.acs.org on May 23, 2016
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Catalytic Chemo- and Regioselective Coupling of 1,3-Dicarbonyls with N-Heterocyclic
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Nucleophiles
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Miles Kenny, Daniel J. Kitson and Vilius Franckevičius*
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Department of Chemistry, Lancaster University, Lancaster LA1 4YB, U.K.
E-mail: v.franckevicius@lancaster.ac.uk
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TOC Graphic.
O
R
2
O
R
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
O
O
O
R
O
R
N
+
R1
R2
R1
N
H
toluene, 120 °C, 2 h
R3
40 examples
(19-99% yield)
R3
R
propargyl enol carbonates
of1,3-dicarbonyls
indoles and
pyrroles
complete regioselectivity
and chemoselectivity
Abstract.
The development of a decarboxylative palladium-catalyzed coupling of 1,3-dicarbonyl compounds
with indole, pyrrole, imidazole and pyrazole nucleophiles via an allylic linker under neutral
conditions is disclosed. This process enables the installation of an all-carbon quaternary center and
new C–C and C–N bonds in a single operation. Despite the weakly acidic nature of N-heterocycles,
the reactions proceed with good efficiency and complete regio- and chemoselectivity.
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Introduction.
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Scheme 1. Reactivity of η3-π-Propargylpalladium(II) Intermediates with Nucleophiles
6
7
8
A. η3-π-Propargylpalladium(II) intermediate:
B. Selectivity issues.
reactivity with soft nucleophiles.
O
2
1
Pd(II)Ln
X
X
O
OMe
9
5
XH
YH
LnPd(0)
one pot
CO2 + MeO
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Cross-coupling (regioselectivity):
Pd(II)Ln
+ X
X
Y
2
Pd(II)Ln
η3-π-propargylpalladium(II)
Y
X
X
7
6
4
Homo-coupling (chemoselectivity):
XH + MeO
X
Y
Pd(II)Ln
MeOH
X
Y
XH
5
8
3
X
C. Control of regioselectivity in the coupling of 1,3-dicarbonyls with nucleophiles.
2
O
O
via
R
O
LnPd(0)
YH
PdLn
O
O
O
O
Y
R1
O
R1
R2
R3
chemo- and
regioselective
11
R1
R2
10
−CO2
R3
R3
9
Previous work:
This work:
R
O
O
YH =
HO
YH =
YH =
R
R4
R5
R
N
R6
H
H
indoles and pyrroles
(pKa >20)
1,3-dicarbonyls
(pKa 13–16)
phenols
(pKa 12–20)
R
2
2
2 R4
O
R6
O
O
O
R
R
R
O
O
O
O
O
N
R1
R1
R1
R
R3
R3
R5
R3
R
12
13
14
Since the seminal report of the palladium-catalyzed allylic alkylation reaction of nucleophiles with
allylic electrophiles,1 this process has undergone revolutionary expansion to a range of new
asymmetric C–C and C–heteroatom bond-formation methodologies.2 The analogous propargylic
electrophiles can also be used but the transformation to products involving nucleophiles and
palladium(0) is distinct and more complex.3 Typically, this process commences with the formation
of η3-π-propargylpalladium(II) intermediate 2 through oxidative addition of palladium(0) to 1 (A,
Scheme 1).4 At this point, hard nucleophiles, such as organometallic reagents, tend to undergo
either propargylation or allenylation.5 However, if the nucleophile HX is relatively acidic and can,
therefore, give rise to a stabilized anion, enolates of 1,3-dicarbonyl compounds and phenolate
anions being examples, then addition of the nucleophile to the central carbon atom of the η3-π-
propargylpalladium(II) motif 2 takes place.6 The resulting putative palladacyclobutene intermediate
37 is then protonated by a second equivalent of the nucleophile HX, generating η3-π-
allylpalladium(II) complex 4. In the final stage, an allylic alkylation process affords product 5.8 The
overall transformation is the union of two molecules of the nucleophile via an allylic linker in 5 in a
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single operation. The utility of this reaction can be greatly enhanced by being able to couple two
different nucleophiles selectively (B, Scheme 1). However, for this to be a viable process, the
following conditions must be met: the order of addition of the two nucleophiles must be controlled,
resulting in the correct regioselectivity of cross-coupling (6 versus 7), and the undesired homo-
coupling of both nucleophiles must be prevented (5 and 8). To date, attempts to meet these criteria
in the coupling of two different nucleophiles in an intermolecular sense have proven difficult.9
Instead, control of regio- and chemoselectivity is imparted by tethering at least two of the reacting
components in a cyclization process, thus favoring the intramolecular reaction pathway over all
others.10
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Seeking to control the selectivity of the intermolecular coupling of two nucleophiles, we became
inspired by recent developments of the palladium-catalyzed decarboxylative allylic alkylation
reaction for the synthesis of congested all-carbon quaternary centers.11 This approach
regiospecifically generates a latent enolate from allylic enol carbonates or esters that can be
associated with the palladium metal complex after decarboxylation.12 We postulated that, if the
analogous propargyl enol carbonate of type 9 were to undergo similar decarboxylation under
palladium catalysis (C, Scheme 1), and if the resulting enolate remained associated with the π-
propargylpalladium(II) motif following decarboxylation (10), then the addition of the enolate to the
central carbon atom of the π-propargyl unit in 10 should take place faster than that of the external
nucleophile owing to the intramolecular nature of the reaction. In this way, both regio- and
chemoselectivity could be controlled in the formation of product 11. Indeed, we have found this to
be the case in the coupling of 1,3-dicarbonyls with phenols to generate structures of type 12.13
Subsequently, we reported the coupling of two different 1,3-dicarbonyl compounds (13),14 the
regioselectivity of which can be controlled by judiciously adding one of the nucleophiles as the
propargyl enol carbonate.
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Because the accepted reaction mechanism involves protonation of palladacyclobutene intermediate
3, the acidity of the external nucleophile is expected to be important; phenols (pKa 12–20 in
DMSO)15 and 1,3-dicarbonyl compounds (pKa 13–16 in DMSO)16 are relatively acidic and, hence,
are readily incorporated without the need for acid or base additives. However, the use of less acidic
N-heterocyclic nucleophiles, such as pyrroles and indoles (pKa 23 and 21 in DMSO, respectively),17
in this coupling reaction is more challenging. In this report, we disclose the development of a regio-
and chemoselective palladium-catalyzed decarboxylative coupling reaction of 1,3-dicarbonyl
compounds with weakly acidic N-heterocyclic nucleophiles under neutral conditions. This one-pot
process installs new C–C and C–N bonds and an all-carbon quaternary center in a single step, and
proceeds with full regiocontrol and chemoselectivity.
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Results and Discussion.
Table 1. Optimization of the Reaction Conditionsa
O
Pd2(dba)3 (5 mol %)
ligand (10 mol %)
O
O
O
O
O
O
O
N
N
+
solvent, temperature
2 h
N
H
15a
17a
18 (not observed)
16a
entry
ligand
dppe
solvent
T (°C) regioselectivity
(17a:18)b,c
17a:16ab
yieldd
(%)
—
1
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
80
80
80
80
—
no reaction
1:4.7
e
2
PPh3
>19:1
>19:1
>19:1
>19:1
—
13
3
DPEphos
dppf
1:2.3
27
4
1:2.1
28
5
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
1,4-dioxane 80
1:2.0
32
6
DMF
80
80
80
80
80
complex mixture
1:3.5
n.d.
11
7
MeCN
THF
>19:1
>19:1
>19:1
>19:1
8
1:1.8
24
9
CH2Cl2
toluene
1:1.9
35
10
1:0.8
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9
11
Xantphos
toluene
120
>19:1
>19:1
1:0.7
55
12
Xantphos
xylene
150
1:0.8
32
aAll reactions were performed with 0.24 mmol of 15a and 16a; concn = 0.16 M. bDetermined by 1H NMR analysis of
the crude product mixtures. cIn all cases, no homo-coupling of 15a or 16a (chemoselectivity) was observed. dYield of
isolated 17a. e[Pd(PPh3)4] was used in place of [Pd2(dba)3]. n.d. = not determined.
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16
17
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19
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PPh2
PPh2
Fe
O
Ph2P
O
PPh2
PPh2
PPh2
PPh2
PPh2
Xantphos
dppf
dppe
DPEphos
In the first instance, we tested the reactivity of propargylic carbonate 15a derived from a 1,3-
diketone and indole (16a) in the presence of a source of palladium(0) and a phosphine ligand in 1,4-
dioxane as the solvent at 80 °C (Table 1). With the exception of dppe (entry 1), palladium
tetrakis(triphenylphosphine) (entry 2), as well as large-bite-angle bidentate ligands, that is,
DPEphos, dppf and Xantphos (entries 3–5), all afforded the desired coupled product 17a. The
reaction with Xantphos as the ligand afforded the highest yield of 17a (entry 5), but the reaction
efficiency was relatively low with significant quantities of unreacted indole (16a) being observed in
the crude product mixtures. This result was perhaps not surprising given the lower acidity of indole
(16a) as compared to phenols and 1,3-dicarbonyls. Remarkably, however, no formation of
regioisomer 18 nor homo-coupled products of 15a or 16a was observed. With Xantphos as the
chosen ligand, a solvent screen (entries 6–10) led to a small increase in the yield of 17a when the
reaction was run in toluene (entry 10). Pleasingly, the yield of 17a was improved to 55% by
elevating the reaction temperature to 120 °C (entry 11), conditions where smaller quantities of
unreacted indole (16a) were detected. The reaction at a higher temperature of 150 °C in xylene as
the solvent did not result in an improvement of the yield of 17a (entry 12). It should be noted that
only N-alkylation of indole (16a) took place with no C-alkylated products being observed. This
result is in contrast to the previously reported C-allylation of indoles.18 Similarly, reactions of
indoles with propargylic compounds also follow the C-alkylation pathway,19 albeit most likely due
to the intramolecular arrangement of the reacting centers.
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Scheme 2. Control of Regio- and Chemoselectivity
3
4
5
6
7
8
O
O
A. Use of Propargyl Carbamate of Indole.
O
O
N
O
O
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
18 (desired)
N
+
O
O
O
toluene, 120 °C, 2 h
O
19
20
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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21 (isolated, 88%)
B. Intermolecular Coupling Reaction.
O
O
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
O
complex mixture
and
poor mass recovery
+
+
OMe
O
N
toluene, 120 °C, 2 h
H
1
20
16a
Having established that the use of enol carbonate 15a in the presence of indole (16a) affords the
predicted regioisomer 17a with complete selectivity, we sought to investigate whether the opposite
regioisomer 18 could be accessed by utilizing a propargyl carbamate of indole (19) (A, Scheme 2).
Surprisingly, the only process that took place was the homo-coupling of 1,3-diketone 20 to 21. It is
likely that the anion of indole, formed by decarboxylation of 19, is basic enough to generate a
nucleophilic enolate of 1,3-diketone 20, which then reacts preferentially. A purely intermolecular
coupling reaction between carbonate 1, 1,3-diketone 20 and indole (16a) led to poor mass recovery
of a complex mixture of products (B, Scheme 2). These results highlight the requirement for a
propargyl enol carbonate as the coupling partner if high levels of selectivity are to be obtained.
Table 2. Indole Scopea–d
O
R1
O
R2 Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
R1
O
O
O
O
R2
N
+
toluene, 120 °C, 2 h
N
H
17
15a
16
CO2Me
CN
O
O
O
O
O
O
N
17a
N
N
17c
>19:1 (55%)
17b
>19:1 (70%)
>19:1 (55%)
EtO2C
O
O
O
O
O
O
N
N
Cl
17e
>19:1 (52%)
17d
>19:1 (59%)
CCDC 1443121
O
O
O
O
N
N
N
OMe
NO2
O2N
17f
>19:1 (62%)
17g
>19:1 (62%)
17h
>19:1 (27%)
O
O
O
O
N
N
N
17i
>19:1 (73%)
17j
>19:1 (53%)
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aAll reactions were performed with 0.24 mmol of 15a and 16; concn = 0.16 M. bRegioselectivity determined by 1H
NMR analysis of the crude product mixtures. cIn all cases, no homo-coupling of 15a or 16 (chemoselectivity) was
observed. dYields of isolated 17 are shown.
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9
10
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13
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15
16
17
18
19
20
21
22
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In the next stage of this study, a range of indoles were screened under the optimized reaction
conditions (Table 2). All substrates were found to react with complete chemo- and regioselectivity.
In addition to unsubstituted indole product 17a, the presence of electron-withdrawing substituents at
the 3-position afforded 17b in a higher yield, presumably due to the higher acidity of the indole NH
proton. However, the yield of 17c, containing a 3-nitrile substituent, was similar to that of
unsubstituted 17a (55%). An electron-withdrawing ester side-chain in the 2-position gave 17d, the
structure of which was confirmed by X-ray crystallography,20 thus unequivocally proving the
regioselectivity of the reaction. The presence of electron-withdrawing substitution on the benzene
ring also gave rise to products 17e–g in moderate to good yields. These results were in contrast to
substitution with an electron-donating methoxy group, whereby a lower yield of product 17h was
obtained and larger quantities of unreacted indole 16h were observed in the crude product mixture.
It is likely that the decreased acidity of indole 16h is responsible for its reduced reactivity. Finally,
analogs of indole, namely 7-azaindole (16i) and carbazole (16j), gave rise to products 17i and 17j in
73% and 53% yield, respectively.
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Table 3. Pyrrole Scopea–d
3
4
5
6
7
8
9
O
R1
O
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
O
R1
O
O
O
N
+
N
H
toluene, 120 °C, 2 h
15a
22
23
O
O
O
O
N
N
CO2Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CCDC 1443120
23a
>19:1 (21%)
23b
>19:1 (81%)
O
O
CO2Me
MeO2C
O
O
O
O
O
O
O
O
N
N
N
N
CO2Me
CO2Me
23f
>19:1 (60%)
23c
>19:1 (42%)
23d
>19:1 (41%)
23e
>19:1 (57%)
Ph
N
n-Bu
O
CHO
O
O
O
O
O
O
N
N
CO2Me
CO2Me
CO2Me
23g
>19:1 (95%)
23h
>19:1 (58%)
23i
>19:1 (59%)
aAll reactions were performed with 0.24 mmol of 15a and 22; concn = 0.16 M. bRegioselectivity determined by 1H
NMR analysis of the crude product mixtures. cIn all cases, no homo-coupling of 15a or 22 (chemoselectivity) was
observed. dYields of isolated 23 are shown.
To the best of our knowledge, there are no reports of palladium-catalyzed reactions of pyrroles with
propargylic compounds. Therefore, encouraged by the desired reactivity of indoles in the reaction,
the coupling of pyrroles 22 as N-heterocyclic nucleophiles with a 1,3-diketone was explored (Table
3). To our surprise, the reaction with unsubstituted pyrrole (22a) was found to be less efficient than
that with indole (16a) and significant quantities of unreacted pyrrole (22a) were present in the crude
product mixture. In spite of this, 23a was formed with complete regio- and chemoselectivity and no
C-alkylation took place. The introduction of an electron-withdrawing group in the 2-position of
pyrrole 22b significantly enhanced its reactivity and 23b was isolated in excellent yield. The sense
of the regioselectivity of the reaction was confirmed by the X-ray crystal structure of 23b.20 The
introduction of electron-withdrawing substituents in the 3-position paved the way to 23c and 23d in
moderate yields. Further decoration of the pyrrole motif with two carbonyl side chains afforded
products 23e–h in good to excellent yields. A mix of electron-donating and withdrawing
substituents was also effective (23i).
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Table 4. 1,3-Dicarbonyl Scopea–d
3
4
MeO2C
O
CO2Me
2
2
5
6
7
8
O
O
R
R
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
O
O
O
O
N
O
16b
H
N
N
R1
R1
R2
R1
+
or
CO2Me
or
toluene, 120 °C, 2 h
R3
R3
R3
CO2Me
15
25
24
N
H
22b
9
CO2Me
CO2Me
O
O
O
O
O
O
O
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
N
N
CO2Me
CO2Me
CO2Me
23b
>19:1 (81%)
25b
>19:1 (55%)
25a
>19:1 (66%)
24a
>19:1 (72%)
17b
>19:1 (70%)
CO2Me
CO2Me
O
O
O
O
O
O
O
O
O
N
N
N
N
N
Ph
Ph
CO2Me
CO2Me
CO2Me
Me
Me
25d
>19:1 (55%)
Me
>19:1 (83%)
EtO2C
O
24b
>19:1 (71%)
25c
>19:1 (60%)
25e
>19:1 (74%)
24c
CO2Me
CO2Me
O
O
OEt
N
O
O
O
Ph
Ph
Me
N
O
N
N
N
CO2Me
CO2Me
CO2Me
>19:1 (55%)
O
25h
24e
>19:1 (56%)
25g
>19:1 (72%)
25f
>19:1 (85%)
O
24d
>19:1 (56%)
O
EtO2C
CO2Me
CO2Me
O
O
OEt
O
OMe
O
OEt
O
O
O
O
O
Me
N
N
N
N
N
EtO
BocN
O
CO2Me
CO2Me
CO2Me
Me
25j
>19:1 (61%)
O
24g
>19:1 (81%)
25k
>19:1 (56%)
24f
>19:1 (54%)
25i
>19:1 (99%)
aAll reactions were performed with 0.24 mmol of 15 and 16b or 22b; concn = 0.16 M. bRegioselectivity determined by
1H NMR analysis of the crude product mixtures. cIn all cases, no homo-coupling of 15 or 16b or 22b (chemoselectivity)
was observed. dYields of isolated 24 and 25 are shown.
Having demonstrated the desired reactivity of a set of indole and pyrrole substrates in the reaction,
attention was focused on other 1,3-dicarbonyl compounds and the efficiency and selectivity with
which they can be coupled with N-heterocycles (Table 4). In the case of indole 16b as the coupling
partner, cyclohexanone-based systems provided products 24a and 24b in good yields and complete
selectivity. Similarly, the use of propargyl enol carbonates derived from linear and cyclic 1,3-
diketones readily generated products 24c–f. We were pleased to discover that a ß-ketoester also
underwent the desired coupling to give 24g in 81% yield. In the coupling reaction of pyrrole 22b
with a set of propargyl enol carbonates 15, cyclohexanone-based and linear 1,3-diketones provided
compounds 25a–e in moderate to good yields. Similarly, products 25f and 25g, containing cyclic
1,3-diketones, were isolated in high yield. ß-Ketoesters were also readily incorporated, with 25h
and 25i being isolated in 55% and 99% yield, respectively, with complete selectivity. Finally, it was
encouraging to discover that malonates and ß-amidoesters were successfully transformed into
desired products 25j and 25k in 61% and 56% yields, respectively.
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Table 5. N-Heterocycle Scopea–d
3
4
5
O
O
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
O
R1
N
O
O
O
R1
R2
+
N
H
R2
toluene, 120 °C, 2 h
6
7
8
9
15a
26
27
O
O
O
O
N
N
N
O
N
O
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
27c
>19:1 (51%)
27b
>19:1 (42%)
27a
>19:1 (49%)
O
O
O
O
O
N
N
27d
(complex mixture)
27e
(complex mixture)
aAll reactions were performed with 0.24 mmol of 15a and 26; concn = 0.16 M. bRegioselectivity determined by 1H
NMR analysis of the crude product mixtures. cIn all cases, no homo-coupling of 15a or 26 (chemoselectivity) was
observed. dYields of isolated 27 are shown.
In addition to indoles and pyrroles, we found that the analogous aromatic N-heterocyles, containing
two nitrogen atoms, such as imidazole (26a), benzimidazole (26b) and pyrazole (26c), all afforded
coupled products 27a–c in moderate yields with complete chemo- and regioselectivity.
Unfortunately, saturated cyclic amines morpholine (26d) and pyrrolidine (26e), which are
significantly less acidic than their aromatic counterparts, failed to invoke the desired reactivity (27d
and 27e), and only complex mixtures of product were obtained.
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The Journal of Organic Chemistry
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Scheme 3. Mechanistic Study
3
4
A. Enolate Crossover.
96% D
(D)H
O
O
O
5
N
O
O
O
6
7
CO2Me
H(D)
D
CO2Me
1 eq
[D]-23b: 84% D
(74%)
N
H
[D]-15a
0.5 eq
22b
8
9
O
O
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
toluene, 120 °C, 2 h
O
O
O
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CO2Me
15b
25b: non-D only
(62%)
0.5 eq
B. Symmetrical π-Allylpalladium(II) Intermediate.
48% D
(D)H
O
96% D O
O
CO2Me
1 eq
N
N
O
O
O
H
22b
CO2Me
D
H(D)
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
toluene, 120 °C, 2 h
48% D
[D]-25b (58%)
[D]-15b
1 eq
68% D
27% D
O
(D)H
O
CO2Me
N
O
O
O
O
D
[D]-22b 1 eq
N
CO2Me
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
toluene, 120 °C, 2 h
H(D)
15b
23% D
[D]-25b (63%)
1 eq
O
68% D
96% D
O
75% D
D
CO2Me
N
O
O
O
O
D
[D]-22b 1 eq
N
D
CO2Me
82% D
[D2]-25b (65%)
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
toluene, 120 °C, 2 h
D
[D]-15b
1 eq
C. Competition Experiment: Effect of Acidity.
CO2Me
O
O
O
MeO2C
O
O
O
N
16b
1 eq
15a
N
H
17b (65%)
1 eq
O
O
Pd2(dba)3 (5 mol %)
Xantphos (10 mol %)
toluene, 120 °C, 2 h
N
16a
1 eq
N
H
17a (not formed)
To gain a better understanding of the mechanism of the reaction and the origin of regioselectivity,
an enolate crossover experiment was conducted (A, Scheme 3). Two structurally similar propargyl
enol carbonates [D]-15a and 15b were reacted with pyrrole 22b and the products isolated. 1H NMR
spectroscopy indicated 84% deuterium incorporation in [D]-23b and no deuteration of 25b. This
observation illustrates that there is no enolate crossover in the reaction, suggesting that the η3-π-
propargylpalladium(II) complex is tightly bound to the enolate following the decarboxylation step.
The reaction of [D]-15b with pyrrole 22b resulted in the scrambling of the deuterium label between
the vinylic and allylic positions in [D]-25b (B, Scheme 3). Deuterium scrambling across the allyl
group also took place when non-deuterated carbonate 15b was coupled with deuterated pyrrole [D]-
22b. These results were further confirmed by the incorporation of two deuterium labels in near-
equal amounts at the vinylic and allylic positions in [D2]-25b when [D]-15b was coupled with [D]-
22b. It is, therefore, feasible to conclude that a deprotonation step of the nitrogen nucleophile and a
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symmetrical π-allylpalladium(II) intermediate are implicated in the mechanism. Finally, a
4
5
6
7
8
9
competition experiment between indole 16b, containing an ester side-chain in the 3-position, and an
unsubstituted indole (16a) was performed (C, Scheme 3). Whilst each of these substrates takes part
in individual reactions with carbonate 15a, the reaction of the mixture of the two resulted solely in
the formation of product 17b, not 17a. Given that substituted 16b is more acidic than 16a, it can be
postulated that the rate of deprotonation of 16b and, therefore, the rate of nucleophilic addition, is
faster than that of 16a. This conclusion is corroborated by the fact that reactions with more acidic
indoles and pyrroles generally give rise to higher yields of product.
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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32
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Proposed Reaction Mechanism
O
O
O
N
O
O
O
CO2Me
23b
15b
Pd(0)Ln
CO2
Pd(II)Ln
O
CO2Me
Pd(II)Ln
N
O
O
O
28
30
O
O
Pd(II)Ln
CO2Me
N
H
29
22b
In light of the above results and the observation that complete regio- and chemoselectivity was
observed in the coupling reactions, a feasible mechanism commences with oxidative addition of
palladium(0) to propargyl enol carbonate 15b and decarboxylation (Scheme 4). The resulting η3-π-
propargylpalladium(II) motif is likely to be tightly associated with the intermediate enolate in 28,
preventing enolate crossover from taking place. It is, therefore, likely that an inner-sphere addition
mechanism of the enolate to the central carbon atom of the η3-π-propargylpalladium(II) unit
operates, ensuring complete regioselectivity of the reaction. The resulting transient
palladacyclobutene intermediate 2921 is then protonated by N-heterocycle 22b. The ensuing
symmetrical η3-π-allylpalladium(II) complex 30 finally undergoes N-alkylation and affords product
23b with the concomitant regeneration of the palladium(0) catalyst.
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In conclusion, we have developed a decarboxylative palladium-catalyzed coupling reaction of 1,3-
dicarbonyl compounds with only weakly acidic N-heterocycles under neutral conditions, which
generates new C–C and C–N bonds and an all-carbon quaternary center in a single step. The broad
scope of this transformation has been demonstrated through the successful coupling of a variety of
1,3-dicarbonyl compounds with a range of indole, pyrrole, imidazole and pyrazole substrates. In all
cases, the reactions proceed with complete chemo- and regioselectivity, which is efficiently
controlled by judiciously utilizing a propagyl enol carbonate as one of the coupling partners.
Mechanistic studies indicate that the association of the palladium metal with the enolate following
decarboxylation is likely to be responsible for the high levels of regiocontrol. Access to
enantioenriched products forms the focus of our current work in the area.
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60
Experimental Section.
1. General Information. All commercially available starting materials were used as received
without further purification. Solvents were of reagent grade and dried prior to use. Petrol refers to
the fraction of petroleum ether that boils between 40 °C and 60 °C. All reactions were performed
under an argon atmosphere in oven dry glassware. Reactions were monitored by thin layer
chromatography using pre-coated silica gel plates with a fluorescent indicator (254 nm) and
visualized by UV light (254 nm) or by staining with potassium permanganate or aqueous acidic
ammonium molybdate(IV) solutions. Flash column chromatography was carried out using Fisher
silica gel (60 Å particle size, 230–400 mesh). NMR spectra were recorded on either 400 or 300
MHz instruments (1H NMR at 400 and 300 MHz, respectively, and 13C{1H} NMR at 100 and 75
MHz, respectively) in CDCl3. Residual solvent CHCl3 was referenced at 7.26 ppm for 1H NMR
spectra and the central resonance of CDCl3 was referenced to 77.0 ppm for 13C{1H} NMR spectra.
IR spectra were recorded on an FTIR spectrometer as a neat film. High resolution mass
spectrometry data were recorded using electron spray ionization on an LCMS-IT-TOF mass
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spectrometer. Melting points were uncorrected. Structures of 17d and 23b were solved by single
4
5
crystal X-ray diffraction.
6
7
8
9
The syntheses of all propargyl enol carbonates 15, including [D]-15a, as well as methyl propargyl
carbonate 1, are reported in the literature,13-14 with the exception of propargyl esters 15j and 15k,
the procedures for which are reported below. Indole propargyl carbamate 19 was prepared by a
procedure different to that used in the literature.22 The following pyrroles were synthesized via
precedented methods: 22c,23 22e,24 22f,25 22g,25 22h,26 and 22i.25 All other N-heterocycles were
obtained from commercial sources.
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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46
47
48
49
50
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55
56
57
58
59
60
2. Synthesis of Propargyl Esters and Carbamates
O
O
O
O
EtO
OEt
EtO
OEt
Me
O
Me
O
15j
1,1-Diethyl 1-prop-2-ynyl ethane-1,1,1-tricarboxylate (15j). To a solution of diethyl methyl
malonate (425 µL, 2.5 mmol) in THF (20 mL) was added potassium tert-butoxide (313 mg, 3.13
mmol) and the mixture was stirred at room temperature for 10 minutes. Propargyl chloroformate
(270 µL, 3.12 mmol) was added dropwise and the solution was stirred at room temperature for 90
minutes. The reaction was quenched with aq. HCl (1 N, 20 mL) and extracted with EtOAc (3 x 20
mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and
concentrated in vacuo. Flash column chromatography [Petrol:EtOAc 9:1] afforded 15j (300 mg,
47%) as a colorless oil. RF 0.66 [Petrol:EtOAc 4:1]; νmax (film)/cm−1 3280, 2963, 1731; δH (400
MHz, CDCl3) 4.73 (d, J = 2.5 Hz, 2H), 4.22 (q, J = 7.1 Hz, 4H), 2.47 (t, J = 2.5 Hz, 1H), 1.69 (s,
3H), 1.24 (t, J = 7.2 Hz, 6H); δC (100 MHz, CDCl3) 167.2, 166.9, 76.5, 75.4, 62.3, 61.7, 53.3, 18.6,
13.7; HRMS (ESI): m/z calcd for C12H16O6 [M+Na]+ 297.0839, found 279.0818.
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9
O
O
OMe
O
O
O
BocN
BocN
OMe
O
15k
31
1-tert-Butyl 3-methyl 3-prop-2-ynyl 2-oxopiperidine-1,3,3-tricarboxylate (15k). A suspension of
sodium hydride (60 wt%, 48.5 mg, 1.2 mmol) in THF (10 mL) was cooled to 0 °C. A solution of 31
(300 mg, 1.1 mmol), prepared via a literature procedure,27 in THF (5 mL) was added dropwise and
the mixture was stirred at 0 °C for 10 minutes. Propargyl chloroformate (117 µL, 1.2 mmol) was
added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction was
quenched with aq. HCl (1 N, 20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic
fractions were washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. Flash column
chromatography [Petrol:EtOAc 9:1] afforded 15k (211 mg, 57%) as a yellow oil. RF 0.17
[Petrol:EtOAc 4:1]; νmax (film)/cm−1 3270, 2980, 1716; δH (400 MHz, CDCl3) 4.80 (dd, J = 5.7, 2.5
Hz, 2H), 3.83 (s, 3H), 3.65 (t, J = 6.4 Hz, 2H), 2.56-2.51 (m, 2H), 2.48 (t, J = 2.3 Hz, 1H), 1.90-
1.80 (m, 2H), 1.52 (s, 9H); δC (100 MHz, CDCl3) 167.4, 166.6, 165.1, 152.6, 83.7, 76.5, 75.6, 65.6,
53.7, 53.5, 45.3, 28.1, 27.9, 19.4; HRMS (ESI): m/z calcd for C16H21NO7 [M+Na]+ 362.1210, found
362.1216.
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19
20
21
22
23
24
25
26
27
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48
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60
Prop-2-ynyl 1H-indole-1-carboxylate (19). A suspension of sodium hydride (60 wt%, 110 mg, 2.75
mmol) in THF 15 mL) was cooled to 0 °C. A solution of indole (296 mg, 2.5 mmol) in THF (5 mL)
was added dropwise and the mixture was stirred at 0 °C for 10 minutes. Propargyl chloroformate
(268 µL, 2.75 mmol) was added dropwise and the mixture was stirred at room temperature for 1
hour. The reaction was quenched with aq. HCl (1 N, 20 mL) and extracted with EtOAc (3 x 20 mL).
The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated
in vacuo. Flash column chromatography [Petrol:EtOAc 9:1] afforded 19 (130 mg, 26%) as a
red/brown solid. RF 0.35 [Petrol:EtOAc 4:1]; m.p. 48-51 °C; νmax (film)/cm−1 3281, 2137, 1712,
1604; δH (300 MHz, CDCl3) 8.21 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 3.8 Hz, 1H), 7.57-7.55 (m, 1H),
7.39-7.32 (m, 1H), 7.30-7.22 (m, 1H), 6.62 (dd, J = 3.8, 0.7 Hz, 1H), 5.02 (d, J = 2.5 Hz, 2H), 2.59
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(t, J = 2.5 Hz, 1H); δC (75 MHz, CDCl3) 150.2, 135.3, 130.5, 125.4, 124.7, 123.3, 121.1, 115.2,
4
5
108.7, 76.9, 76.0, 54.3. Data matches literature values.22
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2. Palladium-Catalyzed Coupling of 1,3-Dicarbonyls with N-Heterocycles
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15
16
17
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19
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22
23
24
25
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General procedure. Carbonate 15 (0.24 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), Xantphos (13.9
mg, 0.024 mmol) and indole 16 or pyrrole 22 or N-heterocycle 26 (0.24 mmol) were added to a
dried tube under argon. The tube was fitted with a septum and purged further with argon. Toluene
(1.5 mL) was added and the sealed tube was added to an oil bath pre-heated to 120 °C. The mixture
was stirred at 120 °C for 2 hours, then allowed to cool to room temperature and concentrated in
vacuo. Purification by flash column chromatography afforded coupled products 17 (Table 2), 23
(Table 3), 24 (Table 4), 25 (Table 4), and 27 (Table 5).
2,2'-(Prop-2-ene-1,2-diyl)bis(2-acetylcyclohexan-1-one) (21). Flash column chromatography
[Petrol:EtOAc 9:1-4:1] afforded homo-coupled 21 (34 mg, 88%) as a 1.2:1 mixture of
diastereoisomers rather than the desired cross-coupled product 18. RF 0.32 [Petrol:EtOAc 4:1]; m.p.
123-126 °C; νmax (film)/cm−1 2931, 2848, 1697; δH (400 MHz, CDCl3) 5.03-4.99 (m, 1H), 4.93-4.89
(m, 1H), 2.57-2.48 (m, 3H), 2.44-2.36 (m, 3H), 2.32-2.24 (m, 1H), 2.23 (s), 2.20 (s) and 2.19 (s)
(6H), 2.15-2.07 (m, 1H), 2.01-1.84 (m, 2H), 1.83-1.57 (m, 8H); δC (75 MHz, CDCl3) 210.0, 209.9,
209.8, 209.6, 209.1, 209.1, 208.3, 207.9, 140.6, 140.3, 117.3, 117.0, 73.9, 73.8, 67.0, 66.9, 41.3,
41.1, 41.0, 41.0, 37.1, 36.6, 36.2, 35.3, 33.3, 33.1, 27.5, 27.4, 27.2, 27.1, 26.7, 26.6, 26.5, 26.3, 21.9,
21.8, 21.8, 21.7; HRMS (ESI): m/z calcd for C19H26O4 [M+H]+ 319.1904, found 319.1906.
2-(3-(1H-Indol-1-yl)prop-1-en-2-yl)-2-acetylcyclohexanone (17a). Flash column chromatography
[Petrol:EtOAc 19:1-9:1] afforded 17a (27 mg, 55%) as a yellow solid. RF 0.52 [Petrol:EtOAc 4:1];
m.p. 94-96 °C; νmax (film)/cm−1 3386, 3089, 3056, 2946, 2858, 1709, 1694, 1652, 1610, 1511; δH
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(400 MHz, CDCl3) 7.63 (dt, J = 8.1, 1.1 Hz, 1H), 7.36 (dq, J = 8.1, 0.8 Hz, 1H), 7.23-7.17 (m, 1H),
7.13-7.07 (m, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.54 (dd, J = 3.1, 0.9 Hz, 1H), 4.99-4.98 (m, 1H), 4.85-
4.79 (m, 1H), 4.63-4.57 (m, 2H), 2.55 (dd, J = 8.0, 5.9 Hz, 2H), 2.48-2.41 (m, 1H), 2.22 (s, 3H),
2.12-2.02 (m, 1H), 2.01-1.91 (m, 1H), 1.90-1.75 (m, 2H), 1.73-1.65 (m, 1H); δC (100 MHz, CDCl3)
208.8, 206.8, 142.3, 136.3, 128.6, 128.3, 121.8, 120.8, 119.5, 115.8, 109.7, 101.8, 72.2, 48.3, 41.1,
33.3, 27.0, 26.3, 22.0; HRMS (ESI): m/z calcd for C19H21NO2 [M+H]+ 296.1645, found 296.1650.
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Methyl 1-(2-(1-acetyl-2-oxocyclohexyl)allyl)-1H-indole-3-carboxylate (17b). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 17b (59 mg, 70%) as a pale yellow solid. RF 0.20
[Petrol:EtOAc 4:1]; m.p. 108-110 °C; νmax (film)/cm−1 2950, 1692, 1528; δH (400 MHz, CDCl3)
8.20-8.15 (m, 1H), 7.78 (s, 1H), 7.46-7.41 (m, 1H), 7.32-7.24 (m, 2H), 5.02 (q, J = 0.6 Hz, 1H),
4.92-4.85 (m, 1H), 4.61-4.54 (m, 2H), 3.91 (s, 3H), 2.63-2.53 (m, 2H), 2.53-2.44 (m, 1H), 2.23 (s,
3H), 2.10-1.95 (m, 2H), 1.93-1.83 (m, 1H), 1.82-1.73 (m, 1H), 1.72-1.64 (m, 1H); δC (100 MHz,
CDCl3) 208.6, 206.8, 165.3, 141.5, 136.8, 135.0, 126.4, 123.1, 122.0, 121.6, 115.8, 110.5, 107.7,
72.2, 51.0, 48.9, 41.1, 33.6, 27.0, 26.2, 22.1; HRMS (ESI): m/z calcd for C21H23NO4 [M+H]+
354.1700, found 354.1683.
1-(2-(1-Acetyl-2-oxocyclohexyl)allyl)-1H-indole-3-carbonitrile (17c). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 17c (43 mg, 55%) as a yellow solid. RF 0.20
[Petrol:EtOAc 4:1]; m.p. 96-99 °C; νmax (film)/cm−1 3121, 2942, 2214, 1697, 1645; δH (400 MHz,
CDCl3) 7.76-7.73 (m, 1H), 7.60 (s, 1H), 7.51-7.47 (m, 1H), 7.36-7.31 (m, 1H), 7.30-7.24 (m, 1H),
5.06 (br s, 1H), 4.94-4.87 (m, 1H), 4.60-4.53 (m, 2H), 2.64-2.46 (m, 3H), 2.22 (s, 3H), 2.07-1.97 (m,
2H), 1.94-1.85 (m, 1H), 1.82-1.72 (m, 1H), 1.71-1.63 (m, 1H); δC (100 MHz, CDCl3) 208.5, 206.7,
141.3, 135.7, 135.6, 127.6, 124.2, 122.3, 119.8, 115.9, 115.7, 111.1, 86.4, 72.2, 49.1, 41.1, 33.7,
27.0, 26.2, 22.1; HRMS (ESI): m/z calcd for C20H20N2O2 [M+H]+ 321.1598, found 321.1591.
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Ethyl 1-(2-(1-acetyl-2-oxocyclohexyl)allyl)-1H-indole-2-carboxylate (17d). Flash column
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chromatography [Petrol:EtOAc 9:1-4:1] afforded 17d (52 mg, 59%) as a pale yellow solid. RF 0.45
[Petrol:EtOAc 4:1]; m.p. 102-104 °C; νmax (film)/cm−1 2957, 1697, 1649; δH (300 MHz, CDCl3)
7.70-7.63 (m, 2H), 7.41-7.33 (m, 2H), 7.16 (ddd, J = 8.1, 7.0, 0.8 Hz, 1H), 5.24-5.08 (m, 2H), 4.88
(t, J = 1.6 Hz, 1H), 4.38-4.28 (m, 2H), 4.20 (t, J = 1.2 Hz, 1H), 2.67-2.59 (m, 2H), 2.52-2.42 (m,
1H), 2.36 (s, 3H), 2.28-2.16 (m, 1H), 2.02-1.90 (m, 2H), 1.90-1.80 (m, 1H), 1.78-1.64 (m, 1H), 1.38
(t, J = 7.1 Hz, 3H); δC (75 MHz, CDCl3) 209.3, 207.9, 161.7, 142.2, 139.5, 127.2, 125.7, 125.5,
122.3, 120.9, 113.4, 111.4, 110.8, 72.0, 60.4, 46.7, 41.0, 33.4, 27.3, 26.6, 22.0, 14.3; HRMS (ESI):
m/z calcd for C22H25NO4 [M+H]+ 368.1856, found 368.1847.
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2-Acetyl-2-(3-(5-chloro-1H-indol-1-yl)prop-1-en-2-yl)cyclohexan-1-one (17e). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 17e (41 mg, 52%) as a brown solid. RF 0.45
[Petrol:EtOAc 4:1]; m.p. 113-115 °C; νmax (film)/cm−1 2948, 1701, 1643; δH (300 MHz, CDCl3)
7.57 (d, J = 2.1 Hz, 1H), 7.30 (dt, J = 8.8, 0.8 Hz, 1H), 7.15 (dd, J = 8.7, 2.0 Hz, 1H), 7.06 (d, J =
3.2 Hz, 1H), 6.46 (dd, J = 3.2, 0.9 Hz, 1H), 5.00-4.98 (m, 1H), 4.86-4.77 (m, 1H), 4.59-4.49 (m,
2H), 2.59-2.51 (m, 2H), 2.45 (dddd, J = 14.4, 8.3, 5.5, 2.2 Hz, 1H), 2.20 (s, 3H), 2.08-1.93 (m, 2H),
1.91-1.74 (m, 2H), 1.72-1.63 (m, 1H); δC (100 MHz, CDCl3) 208.7, 206.8, 142.2, 134.7, 129.9,
129.4, 125.3, 122.1, 120.2, 115.7, 110.9, 101.5, 72.2, 48.7, 41.1, 33.5, 27.0, 26.3, 22.1; HRMS
(ESI): m/z calcd for C19H20NO2Cl [M+H]+ 330.1255, found 330.1257.
Acetyl-2-(3-(7-nitro-1H-indol-1-yl)prop-1-en-2-yl)cyclohexanone (17f). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 17f (51 mg, 62%) as a brown solid. RF 0.63
[Petrol:EtOAc 4:1]; m.p. 125-128 °C; νmax (film)/cm−1 2948, 1714, 1694, 1504; δH (400 MHz,
CDCl3) 7.88 (dd, J = 7.8, 1.0 Hz, 1H), 7.82 (dd, J = 7.9, 1.1 Hz, 1H), 7.27 (d, J = 3.4 Hz, 1H), 7.14
(t, J = 7.9 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H), 4.97-4.91 (m, 1H), 4.88-4.81 (m, 2H), 4.31-4.29 (m,
1H), 2.55 (dd, J = 8.0, 5.9 Hz, 2H), 2.50-2.42 (m, 1H), 2.24 (s, 3H), 2.09-2.00 (m, 1H), 1.99-1.84
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(m, 2H), 1.82-1.73 (m, 1H), 1.70-1.62 (m, 1H); δC (100 MHz, CDCl3) 208.7, 207.3, 142.6, 136.8,
133.8, 133.6, 127.4, 127.0, 120.2, 118.7, 114.7, 103.7, 72.1, 51.8, 41.0, 33.3, 27.1, 26.5, 22.0;
HRMS (ESI): m/z calcd for C19H20N2O4 [M+H]+ 341.1496, found 341.1500.
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Acetyl-2-(3-(5-nitro-1H-indol-1-yl)prop-1-en-2-yl)cyclohexanone (17g). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 17g (51 mg, 62%) as an orange solid. RF 0.22
[Petrol:EtOAc 4:1]; m.p. 120-122 °C; νmax (film)/cm−1 2927, 2111, 1709, 1694, 1511; δH (400 MHz,
CDCl3) 8.57 (d, J = 2.1 Hz, 1H), 8.11 (dd, J = 8.1, 2.1 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.21 (d, J
= 3.2 Hz, 1H), 6.70 (d, J = 3.2 Hz, 1H), 5.05-5.03 (m, 1H), 4.90 (dt, J = 17.4, 1.5 Hz, 1H), 4.57 (dt,
J = 17.5, 1.6 Hz, 1H), 4.54 (s, 1H), 2.65-2.45 (m, 3H), 2.22 (s, 3H), 2.10-1.96 (m, 2H), 1.95-1.85
(m, 1H), 1.83-1.62 (m, 2H); δC (100 MHz, CDCl3) 208.6, 206.8, 141.8, 141.8, 139.2, 131.8, 127.6,
118.1, 117.6, 115.6, 110.0, 104.5, 72.2, 48.9, 41.1, 33.6, 27.0, 26.2, 22.1; HRMS (ESI): m/z calcd
for C19H20N2O4 [M+H]+ 341.1496, found 341.1485.
2-Acetyl-2-(3-(5-methoxy-1H-indol-1-yl)prop-1-en-2-yl)cyclohexanone (17h). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 17h (21 mg, 27%) as a red oil. RF 0.25
[Petrol:EtOAc 4:1]; νmax (film)/cm−1 3121, 2942, 2214, 1697, 1645; δH (300 MHz, CDCl3) 7.27-
7.23 (m, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.02 (d, J = 3.0 Hz, 1H), 6.87 (dd, J = 8.9, 2.5 Hz, 1H), 6.44
(dd, J = 3.1, 0.8 Hz, 1H), 4.98 (t, J = 1.3 Hz, 1H), 4.78 (dt, J = 17.6, 1.6 Hz, 1H), 4.63 (t, J = 1.6 Hz,
1H), 4.55 (dt, J = 17.6, 1.6 Hz, 1H), 3.85 (s, 3H), 2.56 (t, J = 6.7 Hz, 2H), 2.48-2.39 (m, 1H), 2.20
(s, 3H), 2.11-2.00 (m, 1H), 2.00-1.91 (m, 1H), 1.90-1.77 (m, 2H), 1.73-1.64 (m, 1H); δC (75 MHz,
CDCl3) 208.8, 206.8, 154.1, 142.5, 131.7, 129.2, 128.9, 115.9, 112.1, 110.6, 102.5, 101.4, 72.3,
55.8, 48.7, 41.1, 33.4, 27.0, 26.4, 22.1; HRMS (ESI): m/z calcd for C20H23NO3 [M+H]+ 326.1751,
found 326.1747.
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2-(3-(1H-Pyrrolo[2,3-b]pyridin-1-yl)prop-1-en-2-yl)-2-acetylcyclohexanone (17i). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 17i (52 mg, 73%) as a brown solid. RF 0.20
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[Petrol:EtOAc 4:1]; m.p. 60-62 °C; νmax (film)/cm−1 2931, 1709, 1695, 1511; δH (400 MHz, CDCl3)
8.26 (dd, J = 4.8, 1.6 Hz, 1H), 7.88 (dd, J = 7.9, 1.6 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 7.03 (dd, J =
7.8, 4.6 Hz, 1H), 6.48 (d, J = 3.6 Hz, 1H), 4.97 (t, J = 1.3 Hz, 1H), 4.84 (t, J = 1.4 Hz, 2H), 4.68 (t,
J = 1.6 Hz, 1H), 2.65-2.48 (m, 2H), 2.45-2.35 (m, 1H), 2.27 (s, 3H), 2.21-2.11 (m, 1H), 1.95-1.74
(m, 3H), 1.73-1.64 (m, 1H); δC (100 MHz, CDCl3) 209.1, 207.2, 147.6, 143.1, 142.9, 128.7, 128.6,
120.2, 116.1, 115.8, 100.0, 72.4, 45.9, 41.0, 32.9, 27.1, 26.8, 21.8; HRMS (ESI): m/z calcd for
C18H20N2O2 [M+H]+ 297.1598, found 297.1588.
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2-(3-(9H-Carbazol-9-yl)prop-1-en-2-yl)-2-acetylcyclohexanone (17j). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 17j (44 mg, 53%) as an orange solid. RF 0.30
[Petrol:EtOAc 4:1]; m.p. 105-107 °C; νmax (film)/cm−1 2942, 1701, 1645; δH (400 MHz, CDCl3)
8.11 (dt, J = 7.8, 0.8 Hz, 2H), 7.46 (dd, J = 7.0, 1.1 Hz, 2H), 7.40 (dt, J = 8.2, 0.8 Hz, 2H), 7.25 (dd,
J = 7.2, 1.2 Hz, 2H), 4.99 (dt, J = 18.3, 1.7 Hz, 1H), 4.92 (t, J = 1.4 Hz, 1H), 4.71 (dt, J = 18.3, 1.9
Hz, 1H), 4.50 (t, J = 1.9 Hz, 1H), 2.68-2.60 (m, 2H), 2.56-2.48 (m, 1H), 2.35 (s, 3H), 2.26-2.16 (m,
1H), 2.07-1.90 (m, 2H), 1.89-1.81 (m, 1H), 1.80-1.69 (m, 1H); δC (100 MHz, CDCl3) 208.9, 207.3,
140.6, 140.2, 126.0, 122.9, 120.3, 119.3, 114.9, 108.9, 72.2, 45.1, 41.2, 33.6, 27.2, 26.5, 22.3;
HRMS (ESI): m/z calcd for C23H23NO2 [M+H]+ 346.1802, found 346.1795.
2-(3-(1H-Pyrrol-1-yl)prop-1-en-2-yl)-2-acetylcyclohexanone (23a). Flash column chromatography
[Petrol:EtOAc 19:1-4:1] afforded 23a (12.5 mg, 21%) as a black solid. RF 0.56 [Petrol:EtOAc 4:1];
m.p. 114-116 °C; νmax (film)/cm−1 3386, 3099, 3056, 2944, 2858, 1695, 1511; δH (400 MHz,
CDCl3) 6.59 (t, J = 2.1 Hz, 2H), 6.14 (t, J = 2.3 Hz, 2H), 5.07 (t, J = 1.0 Hz, 1H), 4.92 (t, J = 1.5 Hz,
1H), 4.55 (dt, J = 16.5, 1.2 Hz, 1H), 4.36 (dt, J = 16.5, 1.2 Hz, 1H), 2.50 (dd, J = 8.0, 6.2 Hz, 2H),
2.42-2.35 (m, 1H), 2.11 (s, 3H), 2.03-1.88 (m, 2H), 1.83-1.70 (m, 2H), 1.68-1.61 (m, 1H); δC (100
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HRMS (ESI): m/z calcd for C15H19NO2 [M+H]+ 246.1489, found 246.1491.
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Methyl 1-(2-(1-acetyl-2-oxocyclohexyl)allyl)-1H-pyrrole-2-carboxylate (23b). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 23b (59 mg, 81%) as a yellow solid. RF 0.43
[Petrol:EtOAc 4:1]; m.p. 104-106 °C; νmax (film)/cm−1 2946, 1716, 1692, 1643; δH (300 MHz,
CDCl3) 6.96 (dd, J = 4.1, 1.9 Hz, 1H), 6.89 (dd, J = 2.5, 1.8 Hz, 1H), 6.18 (dd, J = 3.9, 2.6 Hz, 1H),
5.01-4.91 (m, 2H), 4.86 (dt, J = 16.7, 1.5 Hz, 1H), 4.40 (t, J = 1.7 Hz, 1H), 3.76 (s, 3H), 2.64-2.47
(m, 2H), 2.44-2.35 (m, 1H), 2.26 (s, 3H), 2.17-2.07 (m, 1H), 1.96-1.78 (m, 3H), 1.75-1.62 (m, 1H);
δC (75 MHz, CDCl3) 209.0, 207.3, 161.2, 143.9, 129.8, 121.9, 118.1, 114.2, 108.6, 72.1, 51.0, 50.2,
41.0, 33.1, 27.2, 26.7, 21.8; HRMS (ESI): m/z calcd for C17H21NO4 [M+Na]+ 326.1363, found
326.1348.
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Methyl 1-(2-(1-acetyl-2-oxocyclohexyl)allyl)-1H-pyrrole-3-carboxylate (23c). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 23c (30.5 mg, 42%) as a dark yellow solid. RF
0.09 [Petrol:EtOAc 4:1]; m.p. 74-76 °C; νmax (film)/cm−1 2952, 1712, 1694; δH (400 MHz, CDCl3)
7.23 (t, J = 2.0 Hz, 1H), 6.57-6.52 (m, 2H), 5.11 (br s, 1H), 4.93-4.90 (m, 1H), 4.56 (dt, J = 16.5,
1.3 Hz, 1H), 4.31 (dt, J = 16.3, 1.1 Hz, 1H), 3.77 (s, 3H), 2.55-2.36 (m, 3H), 2.10 (s, 3H), 1.99-1.90
(m, 2H), 1.84-1.76 (m, 1H), 1.75-1.68 (m, 1H), 1.65-1.57 (m, 1H); δC (100 MHz, CDCl3) 208.5,
206.7, 165.1, 143.1, 126.7, 122.7, 117.1, 116.1, 110.2, 72.3, 52.0, 50.9, 41.0, 33.3, 26.9, 26.1, 21.9;
HRMS (ESI): m/z calcd for C17H21NO4 [M+Na]+ 326.1363, found 326.1348.
1-(2-(1-Acetyl-2-oxocyclohexyl)allyl)-1,5,6,7-tetrahydro-4H-indol-4-one (23d). Flash column
chromatography [Petrol:EtOAc 9:1-1:1] afforded 23d (31 mg, 41%) as a dark orange oil. RF 0.10
[Petrol:EtOAc 4:1]; νmax (film)/cm−1 2939, 1697, 1647; δH (400 MHz, CDCl3) 6.57 (d, J = 3.2 Hz,
1H), 6.51 (d, J = 3.2 Hz, 1H), 5.09 (br s, 1H), 4.63-4.60 (m, 1H), 4.53 (dt, J = 17.5, 1.8 Hz, 1H),
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4.24 (dt, J = 17.4, 1.5 Hz, 1H), 2.69 (t, J = 6.2 Hz, 2H), 2.55-2.44 (m, 4H), 2.18 (s, 3H), 2.15-2.10
(m, 2H), 2.07-1.98 (m, 2H), 1.93-1.83 (m, 1H), 1.81-1.72 (m, 2H), 1.70-1.62 (m, 1H); δC (75 MHz,
CDCl3) 208.5, 206.7, 194.4, 144.2, 142.4, 122.9, 120.9, 115.7, 105.9, 72.0, 48.9, 41.0, 37.7, 33.5,
26.9, 26.1, 23.7, 22.0, 21.4; HRMS (ESI): m/z calcd for C19H23NO3 [M+Na]+ 336.1570, found
336.1551.
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Dimethyl 1-(2-(1-acetyl-2-oxocyclohexyl)allyl)-1H-pyrrole-2,5-dicarboxylate (23e). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 23e (49 mg, 57%) as a dark orange solid. RF 0.29
[Petrol:EtOAc 4:1]; m.p. 144-146 °C; νmax (film)/cm−1 2946, 1727, 1699; δH (300 MHz, CDCl3)
6.96 (s, 2H), 5.61 (dt, J = 17.0, 2.0 Hz, 1H), 5.43 (dt, J = 16.9, 1.6 Hz, 1H), 4.84 (t, J = 1.8 Hz, 1H),
4.16 (t, J = 1.9 Hz, 1H), 3.82 (s, 6H), 2.81-2.65 (m, 1H), 2.45-2.33 (m, 1H), 2.28 (s, 3H), 2.31-2.26
(m, 2H), 2.09-1.89 (m, 2H), 1.86-1.70 (m, 2H); δC (75 MHz, CDCl3) 209.4, 206.6, 160.6, 144.1,
127.6, 117.0, 113.9, 72.2, 51.7, 47.9, 40.9, 32.5, 27.6, 27.1, 21.5; HRMS (ESI): m/z calcd for
C19H23NO6 [M+Na]+ 384.1418, found 384.1406.
Methyl 1-(2-(1-acetyl-2-oxocyclohexyl)allyl)-4-(3-methylbutanoyl)-1H-pyrrole-2-carboxylate (23f).
Flash column chromatography [Petrol:EtOAc 9:1-4:1] afforded 23f (56 mg, 60%) as a light yellow
solid. RF 0.56 [Petrol:EtOAc 4:1]; m.p. 75-78 °C; νmax (film)/cm−1 3188, 2953, 1697, 1636; δH (400
MHz, CDCl3) 7.47 (d, J = 1.8 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 5.00-4.97 (m, 1H), 4.94-4.92 (m,
2H), 4.44-4.41 (m, 1H), 3.78 (s, 3H), 2.60 (d, J = 7.0 Hz, 2H), 2.56 (dd, J = 8.2, 6.3 Hz, 2H), 2.49-
2.39 (m, 1H), 2.29-2.19 (m, 4H), 2.13-2.04 (m, 1H), 2.00-1.85 (m, 2H), 1.85-1.75 (m, 1H), 1.71-
1.61 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H); δC (100 MHz, CDCl3) 208.8, 207.2, 195.2, 160.8, 143.2,
132.4, 125.3, 123.2, 117.7, 114.1, 72.0, 51.4, 50.8, 48.5, 41.0, 33.3, 27.1, 26.5, 25.4, 22.7, 22.7,
21.9; HRMS (ESI): m/z calcd for C22H29NO5 [M+Na]+ 410.1938, found 410.1923.
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Methyl 1-(2-(1-acetyl-2-oxocyclohexyl)allyl)-4-benzoyl-1H-pyrrole-2-carboxylate (23g). Flash
column chromatography [Petrol:EtOAc 9:1-4:1] afforded 23g (93 mg, 95%) as a red oil. RF 0.22
[Petrol:EtOAc 4:1]; νmax (film)/cm−1 2950, 1701, 1638; δH (400 MHz, CDCl3) 7.84-7.79 (m, 2H),
7.54 (tt, J = 7.3, 2.3 Hz, 1H), 7.51-7.45 (m, 3H), 7.43 (d, J = 2.1 Hz, 1H), 5.01-4.96 (m, 3H), 4.49-
4.46 (m, 1H), 3.79 (s, 3H), 2.55 (dd, J = 7.8, 6.3 Hz, 2H), 2.49-2.40 (m, 1H), 2.27 (s, 3H), 2.14-2.04
(m, 1H), 1.99-1.85 (m, 2H), 1.84-1.75 (m, 1H), 1.71-1.63 (m, 1H); δC (100 MHz, CDCl3) 208.7,
207.1, 189.0, 160.8, 143.2, 138.9, 134.4, 131.9, 128.9, 128.3, 123.5, 123.2, 119.5, 114.1, 72.0, 51.4,
50.0, 41.0, 33.3, 27.1, 26.5, 21.9; HRMS (ESI): m/z calcd for C24H25NO5 [M+Na]+ 430.1625, found
430.1609.
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Methyl 1-(2-(1-acetyl-2-oxocyclohexyl)allyl)-4-formyl-1H-pyrrole-2-carboxylate (23h). Flash
column chromatography [Petrol:EtOAc 9:1-4:1] afforded 23h (46 mg, 58%) as an orange solid. RF
0.19 [Petrol:EtOAc 4:1]; m.p. 96-99 °C; νmax (film)/cm−1 2953, 1720, 1697, 1668, 1518; δH (400
MHz, CDCl3) 9.76 (s, 1H), 7.01 (d, J = 4.2 Hz, 1H), 6.97 (d, J = 4.4 Hz, 1H), 5.51 (dt, J = 17.3, 2.2
Hz, 1H), 5.37 (dt, J = 17.3, 2.0 Hz, 1H), 4.89-4.87 (m, 1H), 4.21-4.18 (m, 1H), 3.84 (s, 3H), 2.74-
2.66 (m, 1H), 2.47-2.40 (m, 1H), 2.30 (s, 3H), 2.36-2.21 (m, 2H), 2.08-1.97 (m, 1H), 1.95-1.83 (m,
1H), 1.87-1.78 (m, 1H), 1.78-1.68 (m, 1H); δC (100 MHz, CDCl3) 209.2, 206.8, 181.0, 160.6, 143.7,
135.3, 129.0, 121.3, 117.5, 113.8, 72.1, 51.9, 48.1, 40.9, 32.7, 27.4, 27.0, 21.5; HRMS (ESI): m/z
calcd for C18H21NO5 [M+K]+ 370.1051, found 370.1062.
Methyl-1-(2-(1-acetyl-2-oxocyclohexyl)allyl)-4-butyl-1H-pyrrole-2-carboxylate (23i). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 23i (51 mg, 59%) as a yellow oil. RF 0.51
[Petrol:EtOAc 4:1]; νmax (film)/cm−1 2927, 1697; δH (400 MHz, CDCl3) 6.79 (d, J = 1.9 Hz, 1H),
6.68 (d, J = 1.9 Hz, 1H), 4.94-4.86 (m, 2H), 4.82-4.75 (m, 1H), 4.43 (t, J = 2.2 Hz, 1H), 3.76 (s,
3H), 2.66-2.48 (m, 2H), 2.42 (t, J = 8.1 Hz, 2H), 2.45-2.34 (m, 1H), 2.27 (s, 3H), 2.17-2.08 (m, 1H),
1.96-1.78 (m, 3H), 1.74-1.59 (m, 1H), 1.52 (quintet, J = 7.7 Hz, 2H), 1.33 (sextet, J = 7.7 Hz, 2H),
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117.7, 114.2, 72.1, 50.9, 50.0, 41.0, 33.0, 33.0, 27.2, 26.8, 26.2, 22.7, 21.8, 13.9; HRMS (ESI): m/z
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calcd for C21H29NO4 [M+Na]+ 382.1989, found 382.1993.
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Methyl-1-(2-(2-acetyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)allyl)-1H-indole-3-carboxylate
(24a). Flash column chromatography [Petrol:EtOAc 9:1-4:1] afforded 24a (69 mg, 72%) as a
yellow solid. RF 0.24 [Petrol:EtOAc 4:1]; m.p. 149-152 °C; νmax (film)/cm−1 2946, 1697, 1533; δH
(400 MHz, CDCl3) 8.17-8.12 (m, 1H), 8.04 (dd, J = 8.1, 1.3 Hz, 1H), 7.76 (s, 1H), 7.51 (td, J = 7.5,
1.4 Hz, 1H), 7.42-7.38 (m, 1H), 7.33 (td, J = 8.0, 1.2 Hz, 1H), 7.29-7.22 (m, 3H), 4.97 (q, J = 1.3
Hz, 1H), 4.83 (t, J = 1.5 Hz, 2H), 4.63-4.61 (m, 1H), 3.89 (s, 3H), 3.11-2.96 (m, 2H), 2.70 (ddd, J =
14.3, 7.3, 6.1 Hz, 1H), 2.43 (ddd, J = 14.0, 7.0, 5.1 Hz, 1H), 2.31 (s, 3H); δC (100 MHz, CDCl3)
204.7, 195.7, 165.3, 142.8, 140.7, 136.8, 134.9, 134.3, 131.8, 128.8, 128.0, 127.1, 126.4, 123.2,
122.1, 121.6, 116.5, 110.4, 107.8, 68.5, 51.0, 49.2, 29.8, 27.7, 25.9; HRMS (ESI): m/z calcd for
C25H23NO4 [M+H]+ 402.1700, found 402.1681.
Methyl-1-(2-(1-isobutyryl-2-oxocyclohexyl)allyl)-1H-indole-3-carboxylate (24b). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 24b (65 mg, 71%) as a pale yellow solid. RF 0.20
[Petrol:EtOAc 4:1]; m.p. 81-83 °C; νmax (film)/cm−1 2950, 1758, 1723, 1684; δH (300 MHz, CDCl3)
8.17-8.10 (m, 1H), 7.74 (s, 1H), 7.49-7.42 (m, 1H), 7.30-7.20 (m, 2H), 4.94 (br s, 1H), 4.75 (dt, J =
17.6, 1.5 Hz, 1H), 4.62 (dt, J = 17.5, 1.6 Hz, 1H), 4.50 (br s, 1H), 3.88 (s, 3H), 3.01 (heptet, J = 6.7
Hz, 1H), 2.51 (t, J = 6.5 Hz, 2H), 2.47-2.38 (m, 1H), 2.12-1.99 (m, 1H), 1.98-1.68 (m, 4H), 1.16 (d,
J = 6.5 Hz, 3H), 1.11 (d, J = 6.7 Hz, 3H); δC (75 MHz, CDCl3) 213.1, 209.0, 165.4, 141.2, 138.0,
135.0, 126.4, 123.2, 122.1, 121.6, 115.9, 110.7, 107.8, 72.6, 51.0, 49.1, 41.3, 37.2, 32.9, 26.7, 22.1,
21.3, 20.6; HRMS (ESI): m/z calcd for C23H27NO4 [M+H]+ 382.2013, found 382.2007.
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Methyl 1-(3-benzoyl-3-methyl-2-methylene-4-oxopentyl)-1H-indole-3-carboxylate (24c). Flash
column chromatography [Petrol:EtOAc 9:1-4:1] afforded 24c (78 mg, 83%) as an orange oil. RF
0.24 [Petrol:EtOAc 4:1]; νmax (film)/cm−1 2948, 1697, 1677, 1533; δH (400 MHz, CDCl3) 8.21-8.13
(m, 1H), 7.92-7.85 (m, 2H), 7.78 (s, 1H), 7.59 (tt, J = 7.6, 1.4 Hz, 1H), 7.50-7.45 (m, 2H), 7.43-
7.38 (m, 1H), 7.30-7.23 (m, 2H), 5.12 (q, J = 1.2 Hz, 1H), 4.94 (dt, J = 17.9, 1.8 Hz, 1H), 4.81 (dt, J
= 17.4, 1.7 Hz, 1H), 4.58-4.55 (m, 1H), 3.91 (s, 3H), 2.25 (s, 3H), 1.81 (s, 3H); δC (100 MHz,
CDCl3) 206.1, 199.6, 165.4, 143.7, 136.8, 135.5, 135.1, 133.4, 129.2, 128.7, 126.4, 123.1, 122.0,
121.6, 115.0, 110.5, 107.7, 68.5, 51.0, 49.2, 27.6, 21.2; HRMS (ESI): m/z calcd for C24H23NO4
[M+H]+ 390.1670, found 390.1675.
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Methyl 1-(3,3-diacetyl-5-ethoxy-2-methylene-5-oxopentyl)-1H-indole-3-carboxylate (24d). Flash
column chromatography [Petrol:EtOAc 9:1-4:1] afforded 24d (54 mg, 56%) as an orange solid. RF
0.10 [Petrol:EtOAc 4:1]; m.p. 104-107 °C; νmax (film)/cm−1 2935, 1716, 1692, 1531; δH (400 MHz,
CDCl3) 8.22-8.15 (m, 1H), 7.76 (s, 1H), 7.33-7.23 (m, 3H), 4.97 (q, J = 1.4 Hz, 1H), 4.89 (t, J = 1.7
Hz, 2H), 4.53 (q, J = 1.9 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.22 (s, 2H), 2.29 (s, 6H),
1.30 (t, J = 7.3 Hz, 3H); δC (100 MHz, CDCl3) 203.6, 170.8, 165.3, 141.7, 136.6, 134.8, 126.4,
123.2, 122.1, 121.8, 117.0, 110.0, 108.0, 72.3, 61.5, 51.0, 48.7, 39.6, 27.6, 14.0; HRMS (ESI): m/z
calcd for C22H25NO6 [M+Na]+ 422.1574, found 422.1580.
Methyl-1-(2-(1,3-dioxo-2-phenyl-2,3-dihydro-1H-inden-2-yl)allyl)-1H-indole-3-carboxylate (24e).
Flash column chromatography [Petrol:EtOAc 9:1-4:1] afforded 24e (59 mg, 56%) as a dark orange
oil. RF 0.40 [Petrol:EtOAc 4:1]; νmax (film)/cm−1 2946, 1697; δH (300 MHz, CDCl3) 8.10-8.05 (m,
1H), 8.00-7.95 (m, 2H), 7.87-7.81 (m, 2H), 7.65 (s, 1H), 7.52-7.47 (m, 2H), 7.42-7.34 (m, 3H),
7.24-7.18 (m, 3H), 5.08-5.06 (m, 1H), 4.85 (t, J = 1.6 Hz, 2H), 4.74-4.71 (m, 1H), 3.88 (s, 3H); δC
(75 MHz, CDCl3) 198.4, 165.2, 141.3, 140.7, 136.6, 136.3, 135.1, 134.4, 129.1, 128.4, 128.2, 126.4,
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C28H21NO4 [M+H]+ 436.1543, found 436.1534.
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Methyl 1-(2-(1-methyl-2,6-dioxocyclohexyl)allyl)-1H-indole-3-carboxylate (24f). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 24f (44 mg, 54%) as a yellow oil. RF 0.12
[Petrol:EtOAc 4:1]; νmax (film)/cm−1 2946, 1692, 1533; δH (300 MHz, CDCl3) 8.19-8.11 (m, 1H),
7.72 (s, 1H), 7.29-7.21 (m, 3H), 4.97 (q, J = 1.1 Hz, 1H), 4.62 (q, J = 1.9 Hz, 1H), 4.55 (t, J = 1.3
Hz, 2H), 3.88 (s, 3H), 2.69-2.57 (m, 4H), 2.00-1.84 (m, 2H), 1.50 (s, 3H); δC (75 MHz, CDCl3)
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207.5, 165.2, 142.3, 136.6, 135.0, 126.4, 123.2, 122.2, 121.7, 115.7, 110.2, 108.0, 70.2, 51.0, 48.5,
38.3, 19.9, 17.4; HRMS (ESI): m/z calcd for C20H21NO4 [M+H]+ 340.1543, found 340.1537.
Methyl 1-(2-(1-(ethoxycarbonyl)-2-oxocyclopentyl)allyl)-1H-indole-3-carboxylate (24g). Flash
column chromatography [Petrol:EtOAc 9:1-4:1] afforded 24g (72 mg, 81%) as a red oil. RF 0.19
[Petrol:EtOAc 4:1]; νmax (film)/cm−1 2940, 1695, 1533; δH (400 MHz, CDCl3) 8.20-8.11 (m, 1H),
7.78 (s, 1H), 7.38-7.32 (m, 1H), 7.27-7.21 (m, 2H), 5.09 (br s, 1H), 5.02 (dt, J = 17.4, 1.5 Hz, 1H),
4.86 (dt, J = 17.2, 1.5 Hz, 1H), 4.56-4.54 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.58-2.43
(m, 2H), 2.39-2.27 (m, 2H), 2.05-1.88 (m, 2H), 1.26 (t, J = 6.8 Hz, 3H); δC (100 MHz, CDCl3)
211.7, 170.2, 165.4, 139.3, 136.8, 135.1, 126.5, 123.0, 122.0, 121.5, 114.9, 110.5, 107.5, 64.4, 62.2,
50.9, 48.7, 37.9, 33.7, 19.5, 14.0; HRMS (ESI): m/z calcd for C21H23NO5 [M+H]+ 370.1649, found
370.1629.
Methyl-1-(2-(2-acetyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)allyl)-1H-pyrrole-2-carboxylate
(25a). Flash column chromatography [Petrol:EtOAc 9:1-4:1] afforded 25a (56 mg, 66%) as a pale
yellow solid. RF 0.60 [Petrol:EtOAc 4:1]; m.p. 92-95 °C; νmax (film)/cm−1 2939, 1694; δH (300 MHz,
CDCl3) 8.06 (dd, J = 7.9, 1.3 Hz, 1H), 7.48 (td, J = 7.5, 1.5 Hz, 1H), 7.32 (tt, J = 8.0, 0.6 Hz, 1H),
7.24 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 4.1, 2.0 Hz, 1H), 6.88 (dd, J = 2.5, 1.8 Hz, 1H), 6.18 (dd, J =
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4.0, 2.7 Hz, 1H), 5.26 (dt, J = 17.2, 1.8 Hz, 1H), 4.89-4.81 (m, 2H), 4.38-4.36 (m, 1H), 3.76 (s, 3H),
3.14 (ddd, J = 17.0, 9.9, 4.9 Hz, 1H), 3.01 (ddd, J = 17.5, 5.9, 4.7 Hz, 1H), 2.72-2.61 (m, 1H), 2.48
(ddd, J = 14.2, 6.5, 4.6 Hz, 1H), 2.37 (s, 3H); δC (75 MHz, CDCl3) 205.8, 195.9, 161.2, 143.5,
143.3, 133.9, 132.1, 129.7, 128.8, 127.9, 126.9, 122.0, 118.2, 115.0, 108.8, 68.7, 51.1, 50.3, 29.4,
28.1, 25.7; HRMS (ESI): m/z calcd for C21H21NO4 [M+K]+ 390.1102, found 390.1105.
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Methyl 1-(2-(1-isobutyryl-2-oxocyclohexyl)allyl)-1H-pyrrole-2-carboxylate (25b). Flash column
chromatography [Petrol:EtOAc 9:1] afforded 25b (44 mg, 55%) as an orange oil. RF 0.70
[Petrol:EtOAc 4:1]; νmax (film)/cm−1 2946, 1697; δH (300 MHz, CDCl3) 6.97 (dd, J = 4.0, 1.8 Hz,
1H), 6.91 (dd, J = 2.5, 1.9 Hz, 1H), 6.18 (dd, J = 3.9, 2.6 Hz, 1H), 5.12 (dt, J = 17.1, 1.9 Hz, 1H),
4.88-4.85 (m, 1H), 4.69 (d, J = 17.0, 1.5 Hz, 1H), 4.42 (t, J = 1.9 Hz, 1H), 3.77 (s, 3H), 3.02 (heptet,
J = 6.3 Hz, 1H), 2.74-2.64 (m, 1H), 2.47-2.39 (m, 1H), 2.36-2.27 (m, 1H), 2.26-2.17 (m, 1H), 2.01-
1.89 (m, 2H), 1.86-1.73 (m, 2H), 1.14 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H); δC (75 MHz,
CDCl3) 213.2, 209.8, 161.3, 143.3, 129.7, 122.0, 118.1, 114.8, 108.7, 72.8, 51.0, 50.2, 41.1, 37.4,
32.4, 26.9, 21.5, 20.9; HRMS (ESI): m/z calcd for C19H25NO4 [M+Na]+ 354.1676, found 354.1660.
Methyl 1-(3-acetyl-3-methyl-2-methylene-4-oxopentyl)-1H-pyrrole-3-carboxylate (25c). Flash
column chromatography [Petrol:EtOAc 9:1-4:1] afforded 25c (40 mg, 60%) as a yellow solid. RF
0.22 [Petrol:EtOAc 4:1]; m.p. 58-61 °C; νmax (film)/cm−1 2991, 1716, 1692, 1531; δH (400 MHz,
CDCl3) 6.96 (dd, J = 4.0, 1.8 Hz, 1H), 6.86 (dd, J = 2.5, 1.8 Hz, 1H), 6.18 (dd, J = 3.9, 2.5 Hz, 1H),
4.95-4.92 (m, 1H), 4.89 (t, J = 1.6 Hz, 2H), 4.38 (td, J = 1.9, 0.6 Hz, 1H), 3.76 (s, 3H), 2.23 (s, 6H),
1.64 (s, 3H); δC (100 MHz, CDCl3) 206.9, 161.2, 144.3, 129.7, 121.8, 118.2, 113.9, 108.6, 70.1,
51.0, 50.0, 27.0, 18.4; HRMS (ESI): m/z calcd for C15H19NO4 [M+Na]+ 300.1206, found 300.1192.
Methyl-1-(3-benzoyl-3-methyl-2-methylene-4-oxopentyl)-1H-pyrrole-2-carboxylate (25d). Flash
column chromatography [Petrol:EtOAc 19:1-9:1] afforded 25d (45 mg, 55%) as a pale yellow solid.
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RF 0.75 [Petrol:EtOAc 4:1]; m.p. 91-93 °C; νmax (film)/cm−1 2948, 1707, 1654; δH (300 MHz,
CDCl3) 7.97-7.92 (m, 2H), 7.53 (tt, J = 7.5, 2.1 Hz, 1H), 7.46-7.38 (m, 2H), 6.98 (dd, J = 4.1, 1.9
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Hz, 1H), 6.86 (dd, J = 2.5, 1.9 Hz, 1H), 6.19 (dd, J = 3.9, 2.6 Hz, 1H), 5.28-5.19 (m, 1H), 4.99-4.90
(m, 2H), 4.38-4.35 (m, 1H), 3.78 (s, 3H), 2.25 (s, 3H), 1.78 (s, 3H); δC (75 MHz, CDCl3) 206.0,
200.2, 161.2, 145.5, 135.3, 132.9, 129.8, 129.7, 128.3, 121.9, 118.1, 114.4, 108.6, 68.7, 51.0, 50.2,
27.3, 20.4; HRMS (ESI): m/z calcd for C20H21NO4 [M+Na]+ 362.1363, found 362.1339.
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Methyl 1-(3,3-diacetyl-5-ethoxy-2-methylene-5-oxopentyl)-1H-pyrrole-2-carboxylate (25e). Flash
column chromatography [Petrol:EtOAc 9:1-4:1] afforded 25e (62 mg, 74%) as a red oil. RF 0.15
[Petrol:EtOAc 4:1]; νmax (film)/cm−1 2952, 1733, 1701, 1533; δH (400 MHz, CDCl3) 6.97 (dd, J =
4.0, 1.8 Hz, 1H), 6.76 (dd, J = 2.6, 1.8 Hz, 1H), 6.19 (dd, J = 4.0, 2.6 Hz, 1H), 4.99 (q, J = 1.7 Hz,
1H), 4.88 (t, J = 1.9 Hz, 2H), 4.36-4.34 (m, 1H), 4.16 (q, J = 7.3 Hz, 2H), 3.76 (s, 3H), 3.20 (s, 2H),
2.31 (s, 6H), 1.27 (t, J = 7.2 Hz, 3H); δC (100 MHz, CDCl3) 204.5, 170.8, 161.1, 142.7, 129.3,
121.7, 118.3, 115.3, 108.8, 71.5, 61.1, 51.0, 50.0, 37.4, 27.8, 14.0; HRMS (ESI): m/z calcd for
C18H23NO6 [M+Na]+ 372.1418, found 372.1416.
Methyl-1-(2-(1,3-dioxo-2-phenyl-2,3-dihydro-1H-inden-2-yl)allyl)-1H-pyrrole-2-carboxylate (25f).
Flash column chromatography [Petrol:EtOAc 9:1-4:1] afforded 25f (79 mg, 85%) as an orange oil.
RF 0.40 [Petrol:EtOAc 4:1]; νmax (film)/cm−1 2948, 1699, 1593; δH (300 MHz, CDCl3) 8.06-8.01 (m,
2H), 7.89-7.83 (m, 2H), 7.49-7.44 (m, 2H), 7.40-7.30 (m, 3H), 6.87 (dd, J = 4.0, 1.9 Hz, 1H), 6.67
(dd, J = 2.6, 1.9 Hz, 1H), 6.07 (dd, J = 3.9, 2.6 Hz, 1H), 5.07 (t, J = 1.5 Hz, 2H), 5.02 (t, J = 1.5 Hz,
1H), 4.59 (t, J = 1.8 Hz, 1H), 3.75 (s, 3H); δC (75 MHz, CDCl3) 198.4, 161.0, 143.5, 141.0, 136.1,
134.6, 129.3, 128.9, 128.4, 128.2, 124.0, 122.4, 118.1, 116.6, 108.6, 67.1, 51.0, 50.3; HRMS (ESI):
m/z calcd for C24H19NO4 [M+Na]+ 408.1206, found 408.1186.
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The Journal of Organic Chemistry
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Methyl-1-(2-(1-methyl-2,6-dioxocyclohexyl)allyl)-1H-pyrrole-2-carboxylate (25g). Flash column
chromatography [Petrol:EtOAc 9:1-4:1] afforded 25g (50 mg, 72%) as a yellow solid. RF 0.41
[Petrol:EtOAc 4:1]; m.p. 84-87 °C; νmax (film)/cm−1 2939, 1725, 1690; δH (400 MHz, CDCl3) 6.96
(dd, J = 4.0, 1.8 Hz, 1H), 6.73 (dd, J = 2.6, 1.8 Hz, 1H), 6.17 (dd, J = 4.0, 2.6 Hz, 1H), 4.79 (t, J =
1.8 Hz, 2H), 4.77-4.75 (m, 1H), 4.21 (dt, J = 2.7, 0.8 Hz, 1H), 3.77 (s, 3H), 3.03-2.94 (m, 2H),
2.62-2.53 (m, 2H), 2.28-2.18 (m, 1H), 1.81-1.68 (m, 1H), 1.42 (s, 3H); δC (100 MHz, CDCl3) 207.7,
161.1, 145.7, 129.4, 121.9, 118.3, 112.4, 108.8, 71.3, 51.1, 49.7, 38.7, 18.2, 17.6; HRMS (ESI): m/z
calcd for C16H19NO4 [M+Na]+ 312.1206, found 312.1204.
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Methyl 1-(2-(1-(ethoxycarbonyl)-2-oxocyclopentyl)allyl)-1H-pyrrole-2-carboxylate (25h). Flash
column chromatography [Petrol:EtOAc 9:1-4:1] afforded 25h (42 mg, 55%) as an orange oil. RF
0.35 [Petrol:EtOAc 4:1]; νmax (film)/cm−1 2978, 1750, 1701; δH (400 MHz, CDCl3) 6.95 (dd, J = 4.0,
1.7 Hz, 1H), 6.85 (d, J = 2.8, 2.1 Hz, 1H), 6.16 (dd, J = 4.1, 2.7 Hz, 1H), 5.20 (dt, J = 16.9, 1.4 Hz,
1H), 4.99-4.95 (m, 2H), 4.34 (t, J = 1.6 Hz, 1H), 4.21-4.12 (m, 2H), 3.76 (s, 3H), 2.64-2.54 (m, 1H),
2.46-2.35 (m, 3H), 2.05-1.93 (m, 2H), 1.29 (t, J = 7.3 Hz, 3H); δC (100 MHz, CDCl3) 212.1, 170.0,
161.2, 142.0, 129.7, 121.9, 118.1, 113.1, 108.4, 65.1, 61.9, 50.9, 50.1, 37.8, 33.3, 19.4, 14.0; HRMS
(ESI): m/z calcd for C17H21NO5 [M+Na]+ 342.1312, found 342.1284.
Methyl 1-(2-(3-acetyl-2-oxotetrahydrofuran-3-yl)allyl)-1H-pyrrole-2-carboxylate (25i). Flash
column chromatography [Petrol:EtOAc 9:1-4:1] afforded 25i (69 mg, 99%) as a brown oil. RF 0.67
[Petrol:EtOAc 2:1]; νmax (film)/cm−1 2922, 1761, 1701, 1533; δH (400 MHz, CDCl3) 6.98 (dd, J =
4.0, 1.8 Hz, 1H), 6.81 (dd, J = 2.6, 1.9 Hz, 1H), 6.19 (dd, J = 3.9, 2.6 Hz, 1H), 5.23 (dt, J = 2.5, 0.9
Hz, 1H), 5.06 (dt, J = 17.0, 1.8 Hz, 1H), 4.83 (dt, J = 16.9, 1.7 Hz, 1H), 4.48-4.45 (m, 1H), 4.30
(ddd, J = 13.1, 7.9, 5.2 Hz, 1H), 4.25-4.18 (m, 1H), 3.76 (s, 3H), 3.04 (ddd, J = 13.2, 7.2, 5.3 Hz,
1H), 2.53-2.45 (m, 1H), 2.41 (s, 3H); δC (100 MHz, CDCl3) 200.6, 173.0, 161.2, 141.5, 129.6,
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