Palladium-catalyzed annulation of allenes with indole-2-carboxylic acid derivatives: Synthesis of Indolo[2,3-c]pyrane-1-ones via Ar-I Reactivity or C-H functionalization

Article abstract of DOI:10.1021/jo301149s

Two methodologies, one involving Ar-I reactivity and the other through C-H functionalization, for the formation of indolo[2,3-c]pyrane-1-ones via the corresponding allenes, are presented. A highly efficient approach to indolo[2,3-c]pyrane-1-one derivatives through the Pd-catalyzed regioselective annulation of allenes with 3-iodo-1-alkylindole-2-carboxylic acids is described. This method is fairly general for a wide range of allenes affording the respective indolo[2,3-c]pyrane-1-ones in good to excellent yields. In addition, a Pd(II)-catalyzed oxidative coupling of indole-2-caboxylic acid derivatives with allenes via direct C-H functionalization to afford the corresponding indolo[2,3-c]pyrane-1-ones in moderate to good yields has been developed.

Full text of DOI:10.1021/jo301149s

Article
pubs.acs.org/joc
Palladium-Catalyzed Annulation of Allenes with Indole-2-carboxylic
Acid Derivatives: Synthesis of Indolo[2,3‑c]pyrane-1-ones via Ar−I
Reactivity or C−H Functionalization
R. Rama Suresh and K. C. Kumara Swamy*
School of Chemistry, University of Hyderabad, Hyderabad 500 046, A. P., India
S
* Supporting Information
ABSTRACT: Two methodologies, one involving Ar−I reac-
tivity and the other through C−H functionalization, for the
formation of indolo[2,3-c]pyrane-1-ones via the corresponding
allenes, are presented. A highly efficient approach to indolo[2,3-
c]pyrane-1-one derivatives through the Pd-catalyzed regiose-
lective annulation of allenes with 3-iodo-1-alkylindole-2-
carboxylic acids is described. This method is fairly general for
a wide range of allenes affording the respective indolo[2,3-
c]pyrane-1-ones in good to excellent yields. In addition, a
Pd(II)-catalyzed oxidative coupling of indole-2-caboxylic acid
derivatives with allenes via direct C−H functionalization to
afford the corresponding indolo[2,3-c]pyrane-1-ones in mod-
erate to good yields has been developed.
Alternatively, we visualized that the indolo[2,3-c]pyrane-1-ones
can be presumably constructed by the Pd-catalyzed annulation
of allenes with indole-2-carboxylic acid derivatives by C−H
functionalization. Moreover, the transition-metal-catalyzed
direct C−H functionalization of indole derivatives for the
arylation/alkenylation at either the C(2)- or C(3)-position of
indole and oxidative annulations with internal alkynes that lead
to fused heterocyclic compounds have been successfully
achieved.11,12 Although rhodium-catalyzed annulation of allene
via C−H activation is known,13 Pd-catalyzed oxidative
annulations of indole-2-caboxylic acids with allenes via direct
C−H functionalization to produce the corresponding indolo-
[2,3-c]pyrane-1-ones (lactones) has not been established yet. In
this paper, we describe the reactions of allenes with 3-iodo-
indole-2-carboxylic acid derivatives and our initial results on the
direct annulations of allenes with indole-2-carboxylic acid
derivatives by C−H activation under palladium catalysis.
INTRODUCTION
■
Allenes are versatile synthons and can be used as precursors for
a variety of biologically important heterocycles such as
furanones, γ- and δ-lactones, functionalized dihydrofurans,
benzofurans, imidazoles, chromenes, and many more.1 In
particular, transition-metal-catalyzed2 or organocatalyzed3
reactions of allenes for C−C or C−Het (Het = a heteroatom)
bond formation has emerged as a prominent area in organic
synthesis. Allenylphosphonates (phosphorylated allenes) and
allenylphosphine oxides can also be employed as useful
precursors in organic synthesis.4,5 We have recently reported
the synthesis of phosphono-benzofurans, phosphono-inden-
ones, and phosphono-isocoumarins by the palladium-catalyzed
reactions of allenylphosphonates.6 Since indole derivatives have
a wide range of biological activity,7 we considered the
palladium-catalyzed reactions of allenes with indole-2-carbox-
ylic acid derivatives that may lead to indolo[2,3-c]pyrane-1-
ones as a worthwhile study. The efficacy of indolo[2,3-c]pyrano
[also termed as pyrano[3,4-b]indoles] scaffolds as inhibitors for
hepatitis C virus NS5B polymerase has been studied
extensively.8 It is also noteworthy that the indolo[2,3-
c]pyrane-1-one derivatives are good precursors for the synthesis
of pharmaceutically valuable β-carbolines.9,10 In the literature,
very few methods have been reported for the synthesis of
indolo[2,3-c]pyrane-1-ones, including a copper(I) catalyzed
cyclization of iodo-indole-2-carboxylic acids with terminal
alkynes9a and gold(III) chloride catalyzed cycloisomerization
of 3-ethynyl-indole-2-carboxylic acid.9c However, the former
protocol has the drawback of using stoichiometric amount of
the copper reagent at high reaction temperature (120 °C) with
average to good yields, while the latter method is expensive.
RESULTS AND DISCUSSION
■
The allene precursors shown in the Chart 1 were prepared by
standard methods.14−17 We shall first discuss the Pd-catalyzed
cyclization using iodo-indole carboxylic acids; this will be
followed by reactions using free indole-carboxylic acids that
involve C−H activation.
(i) Pd-Catalyzed Annulation of Allenes with 3-Iodo-1-
alkyl-indole-2-carboxylic Acids. We first treated the allene
(OCH2CMe2CH2O)P(O)C(Ph)CCH2 (1) with 1-meth-
Received: June 4, 2012
Published: July 24, 2012
© 2012 American Chemical Society
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allene to alkyne when P(o-tol)3 was used.6a Similar to allene 6,
the other precursor 10 also led to vinylphosphonate 32 (Table
1, see Figure S3 in Supporting Information for X-ray structure).
The allenylphosphine oxides 11−14 with 21a behaved similarly
and afforded the cyclized products 33−36 in good yield. The
broader applicability of this system is also evidenced by the
isolation of indolo[2,3-c]pyrane-1-ones 37 and 38 by using the
allenoate 15. Furthermore, this chemistry was extendable to the
sulfonyl substituted allenes 16 and 17 (leading to compounds
39 and 40) and aryl substituted allene 20 (leading to pyrano-
indole 41).18 These data are also presented in Table 1. In the
reactions leading to 39 and 40 though the yield was better
when K2CO3 was used in place of CsF. The important feature
of this work is that essentially one product is formed
regioselectively.
Chart 1. Allene Precursors Used in the Present Study
In the 13C NMR spectrum of 28, the carbon attached to
phosphorus shows a doublet at δ 123.6 [1J(P−C) = 180.0 Hz].
The large value of 1J(P−C) is consistent with the sp2
hybridized carbon being connected to phosphorus as
depicted.14 The major isomer is assigned a (Z) configuration
based on X-ray data for compounds 29/32. For further
confirmation of the stereochemistry, we have determined the X-
ray structure of 37 (Supporting Information, Figure S4). As
regards products 28 and 39, the phosphonyl product 28 is
vinylic (with respect to phosphorus), whereas the correspond-
ing the sulfonyl substituted pyranone product 39 is allylic (with
respect to sulfur). Hence, in order to doubly make sure of our
assignment, compound 39 was characterized by single crystal
X-ray crystallography (Supporting Information, Figure S5).
Formation of pyranoindole derivatives can be rationalized by
the pathway shown in Scheme 3.6a The arylpalladium complex I
upon reacting with the allene gives the π-allyl palladium
complex II through the insertion reaction at the β-carbon of
allene. Elimination of HI (by the base) and the palladium
moiety leads to species III. The cyclization then occurs to
provide the compound IV; rearrangement (proton shift)
leading to V may occur depending on the substituents present.
Thus, the reaction of allenes 1−17 and 20 with 1-alkyl-iodo-
indole-2-carboxylic acid afforded β,γ-cyclization products (with
respect to phosphorus) most likely due to the stabilization of
allylic carbocation III by alkyl (or -H) groups at the γ-
position.19
yl-3-iodo-indole-2-carboxylic acid (21a) in the presence of
Pd(OAc)2 (5 mol %) and CsF (2.0 equiv) in PEG-400 (5.0
mL).6b Under these conditions, the desired product could not
be observed (31P NMR). When the reaction was conducted in
the presence of Pd(OAc)2 (5 mol %), P(o-tol)3 (15 mol %),
and CsF (2.0 equiv) in DMF as the solvent for 14 h, the
corresponding indolo[2,3-c]pyrane-1-one (22) was obtained in
94% isolated yield (Scheme 1); the cyclization occurred even in
the absence of P(o-tol)3, but the yield was lower (78%
isolated). Changing the base from CsF to K2CO3 and in the
presence of the phosphine [Pd(OAc)2 (5 mol %)/P(o-tol)3 (15
mol %)/K2CO3 (2.0 equiv)], compound 22 was obtained in
73% isolated yield. Thus CsF as a base worked better here. The
structure of compound 22 was confirmed by X-ray crystallog-
raphy (Figure S1 in Supporting Information); the P-C(Ph)−C
distance of 1.527(3) Å clearly shows that the double bond that
was initially present at this position in the allene is now a single
bond as depicted in Scheme 1, confirming that a proton shift
also has occurred. With these conditions in hand, we then
explored the scope of this catalytic system for the synthesis of
pyrano-indole derivatives 23−29 (Scheme 2a); in the reaction
using allenes 6 and 9, the products obtained were vinyl-
phosphonates 28 and 29. The X-ray structure of 29 is
determined; on this basis, compound 28 was assigned a similar
configuration. The phosphono-allene was completely con-
sumed in this reaction, suggesting that the reaction is
quantitative with respect to the allene. In the case of allenes
7 and 8 with a terminal CH2 or CH(Me) group, the
reactions leading to 30 and 31 (cf. Scheme 2b) were conducted
in the absence of P(o-tol)3 because of the isomerization of
(ii) Pd-Catalyzed Annulation of Allenes with 1-Alkyl-
indole-2-carboxylic Acids via C−H Functionalization. As
a part of our investigations on allenes, the oxidative coupling of
indole-2-carboxylic acids 42a−d with allenes 9, 10, 13−15, and
18−20 by Pd catalysis via C−H functionalization has also been
explored (Scheme 4a); the pyranoindoles thus obtained were
29, 32, 35−37, 41, and 43−49. For this purpose, we first
established reaction conditions for the oxidative annulation of
allene 18 with the indole-2-carboxylic acid 42a (Scheme 4b).
Scheme 1. Reaction of Allene 1 with 3-Iodo-1-methylindole-2-carboxylic Acid (21a) Leading to Phosphono-indolopyranone 22
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Scheme 2. Synthesis of Phosphono-indolo[2,3-c]pyrane-1-ones 23−31
We were pleased to discover that the reaction was feasible for
the formation of 44 as the major product. However, at least
three other isomeric products in minor quantities (GC−MS
evidence) are also formed.20 Hence, the principal challenge in
optimization centered upon increasing the yield of 44 at the
expense of the other isomers. Initially, the reaction was
conducted in the presence of Pd(OAc)2, stochiometric
Cu(OAc)2 as the oxidant, and LiOAc as the base [a catalytic
system recently employed by Miura10e] in dimethyl acetamide
(DMA) as the solvent at 120 °C/12 h (Table 2, entry 1).
Under these conditions, the yield of compound 44 after
isolation was 39% along with traces of isomers. When the
catalyst was changed to PdCl2, the yield of 44 (entry 2) was
lower. No increase in the yield was observed by changing the
oxidant from Cu(OAc)2 to Ag2CO3 (entry 3). Quite pleasingly
though, the yield (after isolation) and selectivity of 44 was
dramatically increased to 67% using Pd(OAc)2 in conjunction
with stochiometric Ag2CO3 as the oxidant/base and CH3CN as
the solvent (entry 4). Screening of other palladium salts/
oxidants/solvents led to the formation of 44 in only modest
yield/selectivity (entries 5−11). Thus, Pd(OAc)2 as the
catalyst, Ag2CO3 as the oxidant/base, CH3CN as the solvent,
80 °C as the reaction temperature, and 12−14 h reaction time
were selected as optimal conditions. The results, leading to
compounds 29, 32, 35−37, 41, and 43−49 are shown in Table
3.
(b) While the allenylphosphonates 9 and 10 afforded single
isomers [(Z)-29 or (Z)-32], allenylphosphine oxides 13
and 14 led to (Z + E) isomeric products 35 and 36, with
the major isomer having (Z) configuration. All of these
are also (β,γ)-cyclized products.
(c) The allenoate 15 also afforded (β,γ)-cyclized products 37
and 43 in the ratio 1:3; compound 37 probably results
from isomerization of 43.21
(d) Reaction of the aryl allenes (18−20) with 1-methyl-
indole-2-carboxylic acids 42a−d using the above
conditions readily afforded the indolopyranones [44−
49 and 41; Table 3]. The structure for the cyclized
product pyranoindole 47 is established by X-ray
crystallography (Supporting Information, Figure S6).
The point to be noted here is that 44−49 derived from
allenes 18 and 19 are (α,β)-cyclized, whereas product 41
derived from the allene 20 is (β,γ)-cyclized.22 Such
greater reactivity of the CMe2 end as in 20 has been
observed before.6a
(e) The reaction was not feasible in the case of α-aryl
allenylphosphonate 1, probably due to steric factors;
hence reaction using similar allenes 2−6 and 11 was not
attempted. As mentioned elsewhere, phosphorus allenes
7 and 12 rearrange to give alkynes in the presence of a
base.6a
A possible pathway based on the literature reports12d−f,h is
proposed in Scheme 5. Initially, exchange of an acetate group in
Pd(OAc)2 by the indole carboxylate leads to a species with the
liberation of AcOH without undergoing decarboxylation (at the
indole residue) in the presence of silver salts.23 Then this
species undergoes carbo-palladation at the C(3)-position,
forming a palladacycle intermediate VI that subsequently
inserts into allenes to produce allylic palladium(II) inter-
mediates VII or VII′. Subsequent reductive elimination
generates the lactones as well as Pd(0) species; the latter is
The salient features of cyclization involving this C−H
functionalization are summarized below:
(a) The phosphorus based allenes 9, 10, 13, and 14 with 1-
methyl-indole-2-carboxylic acid 42a afforded the [β,γ]
products 29, 32, 35, and 36 (Table 3). Compound 29 is
the same as that obtained using 9 and 3-iodo-1-methyl-
indole-2-carboxylic acid; the configuration is (Z) at the
exocyclic double bond.
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Table 1. Details of the Synthesis of Pyranoindoles 32−41
Scheme 3. Proposed Pathway for the Annulation Reaction
reoxidized to the Pd(II) species by silver or copper salts. While
the oxidative coupling of 1-methyl-indole-2-carboxylic acids
with allenes 9, 10, 13−15, and 20 led to β,γ-cyclization
products, that of allenes 18 and 19 occurred at the β,α-site
(with respect to phenyl or p-tolyl group) is observed in the
case. The reason for this preference is not clear at the moment.
SUMMARY
■
In summary, the present study gives an illuminating account of
comparison between C−H functionalization and Ar−I
reactivity in the formation of indolo[2,3-c]pyrane-1-ones. We
have described the Pd-catalyzed regioselective cyclization
reactions of allenylphosphonates/allenylphosphine oxides,
allenoate EtO2CCHCCH2, and allenylsulfones [4-Cl-
C6H4−S(O)2CRCCH2] with 3-iodo-indole-2-carboxylic
acids that led to indolo[2,3-c]pyrane-1-ones (pyranoindoles)
in high yields essentially as single isomers. This is a new route
for indolo[2,3-c]pyrane-1-ones from allenes. More importantly,
the Pd-catalyzed oxidative annulation of allenes via direct C−H
functionalization with 1-alkyl-indole-2-carboxylic acid deriva-
tives at the C3-position affording corresponding indolo
pyranones in moderate to good yields has been demonstrated.
The formation of lactones without undergoing decarboxylation
of indole-2-carboxylic acids is notable. The present method
highlights the synthesis in good yields of various phosphono-
indolo[2,3-c]pyrane-1-ones that are not readily available by
conventional synthetic routes.
EXPERIMENTAL SECTION
■
General Comments. Solvents were dried according to known
methods as appropriate.24 1H, 13C, and 31P NMR spectra (1H, 400
MHz or 500 MHz; 13C, 100 or 125 MHz; and 31P, 162 or 202 MHz)
were recorded using a 400 or 500 MHz spectrometer in CDCl3 (unless
stated otherwise) with shifts referenced to SiMe4 (δ = 0) or 85%
H3PO4 (δ = 0). IR spectra were recorded on an FTIR
spectrophotometer. Melting points were determined by using a local
hot-stage melting point apparatus and are uncorrected. Elemental
analyses were carried out on a CHN analyzer. Mass spectra were
recorded using GC−MS/LC−MS equipment. HRMS was recorded
using an ESI-TOF analyzer. The allenylphosphonates/phosphine
oxides 1−14,14 allenoate 15,16 allenylsulfones 16 and 17,17a and
phenyl-substituted allenes 18−2017b were prepared by literature
procedures.
a
The combined yield of the E + Z isomers was essentially quantitative
(31P NMR). The major isomer is assigned Z configuration on the basis
of the X-ray structures of compounds 29/32. Here, the reaction was
complete within 10 h. In these cases, the reaction conditions were
b
c
similar to (i) except that K2CO3 was used in place of CsF.
d
Assignment of stereochemistry is based on the structure of (A)
mentioned in ref 18.
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Scheme 4. Formation of Pyranoindoles by C−H Functionalization of Indole Carboxylic Acids
Table 2. Optimization of Reaction Conditions for the Annulation of Phenylallene 18 with Indole Carboxylic Acid 42a Leading
a
to Product 44
b
entry
Pd source
Pd(OAc)2
oxidant
base
solvent
temp (°C)
(%)yield of 44
c
1
Cu(OAc)2
Cu(OAc)2
Ag2CO3
LiOAc
LiOAc
DMA
120
120
120
80
39
c
2
PdCl2
DMA
21
3
Pd(OAc)2
Pd(OAc)2
PdCl2
DMA
28
c
4
Ag2CO3
Ag2CO3
CH3CN
CH3CN
CH3CN
CH3CN
DMF
67
c
5
90
42
c
6
Pd(OAc)2
PdCl2
Cu(OAc)2
Cu(OAc)2
Ag2CO3
LiOAc
LiOAc
90
22
c
7
80
29
8
Pd(OAc)2
PdCl2
120
120
120
120
29
c
9
Ag2CO3
DMF
19
10
11
PdCl2
Ag2CO3
DMA
51
c
PdCl2(CH3CN)2
Ag2CO3
DMA
53
a
Reaction conditions: indole-2-carboxylic acid (0.25 mmol), phenylallene (0.375 mmol), catalyst (10 mol %), oxidant Cu(OAc)2 (0.5 mmol) or
b
Ag2CO3 (0.375 mmol), base (0.5 mmol), solvent (5 mL); 10−16 h (reaction time is not optimized). Isolated yield based on the amount of 42a
after column chromatography; 42a was completely consumed. A mixture of products was obtained (GC−MS).
c
1
(i) General Procedures for the Synthesis of 3-Iodo-1-
methylindole-2-carboxylic Acid (21a), 1-Benzyl-3-iodo-indole-
2-carboxylic Acid (21b), and Indole Carboxylic Acids 42a−d.
(a) To a stirred solution of 3-iodo-indole-2-ethylcarboxylate (1.0
equiv) in dimethylformamide (DMF, 0.3 M with respect to iodo
compound) at rt were added tetrabutylammonium bromide (TBAB)
(10 mol %) and K2CO3 (2.0 equiv). To this was added iodomethane
(5 equiv) or benzyl chloride (2.0 equiv), and the round-bottomed flask
(RBF) was sealed with a glass stopper. The contents were stirred at rt
for 12 h. After the completion of the reaction (TLC), the mixture was
diluted with dichloromethane (DCM), washed with brine, dried over
Na2SO4, and filtered, and the solvent was removed by rotary
evaporator. The crude product was purified by column chromatog-
raphy (hexane/EtOAc; 9:1) to get the 1-benzyl or 1-methyl-3-iodo-
indole-2-ethylcarboxylate pure product in 96% or 88% yield,
respectively.
(b) The 1-benzyl or 3-iodo-1-methylindole-2-ethylcarboxylate as
obtained in (a) was dissolved in EtOH (0.3 M), and the contents were
heated under reflux before addition of KOH (3.0 equiv) in water (0.15
M). This mixture was heated again under reflux for 16 h, the solvent
was removed by rotary evaporator, and the crude material was
extracted with ethyl acetate. The organic layer (EtOAc) was dried with
anhydrous Na2SO4, and the solvent was removed by rotary evaporator
to get the carboxylic acid (21a or 21b) in 91−90% yield.
1265, 928 cm−1. H NMR (400 MHz, CDCl3): δ 4.12 (s, 3H), 7.19−
7.27 (m, 1H), 7.42−7.73 (m, 3H). 13C NMR (100 MHz, CDCl3): δ
31.8, 110.4, 110.7, 112.5, 120.8, 122.9, 124.3, 125.7, 126.9, 167.2. LC−
MS: m/z 302 [M + H]+. Anal. Calcd for C10H8INO2: C, 39.89; H,
2.68; N, 4.65. Found: C, 39.95; H, 2.62; N, 4.61.
(ii) General Procedure for the Preparation of Indolo[2,3-
c]pyrane-1-ones (22−41). Into an oven-dried 25 mL round-
bottomed flask were added Pd(OAc)2 (5.0 mol %), P(o-tol)3 (15
mol %), 3-iodo-1-methylindole-2-carboxylic acid 21a or 21b (0.55
mmol), CsF (or K2CO3) (1.0 mmol), and DMF (5.0 mL), and the
mixture was kept stirring at rt for 5 min. After that, allene (0.5 mmol)
was added. The RBF was flushed with N2 and sealed. Then the
contents were heated at 80 °C with stirring for 14 h. After the
completion of the reaction (TLC), the mixture was cooled to rt,
diluted with ethyl acetate (30 mL), washed with brine (3 × 10 mL),
dried over anhydrous Na2SO4, and filtered, and the solvent was
removed by rotary evaporator. The crude products were purified by
column chromatography (hexane/EtOAc; 1:1.5) to get the pure
products in 54−94% yield. Compounds 22−38 were prepared by this
method, by using 0.55 mol of the indole carboxylic acid, unless stated
otherwise.
Compound 22. Yield: 0.205 g (94%; white solid). Mp: 222−224
°C. IR (KBr): 2965, 1696, 1476, 1262, 1020, 874, 799 cm−1; 1H NMR
(400 MHz, CDCl3): δ 0.79 (s, 3H), 0.99 (s, 3H), 3.68−3.77 (m, 2H),
4.23−4.28 (m, 5H), 5.16 (d, J = 26.8 Hz, 1H), 7.18−7.58 (m, 8H),
7.90 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 21.4, 21.5, 31.5, 32.7 (d, J = 6.5 Hz), 43.3 (d, J =
136.6 Hz), 75.9 (d, J = 6.8 Hz), 76.0 (d, J = 6.6 Hz), 110.9, 112.8 (d, J
= 3.3 Hz), 120.3, 121.3, 122.2, 122.6, 123.5 (d, J = 14.5 Hz), 127.5,
128.1 (d, J = 3.3 Hz), 128.9 (d, J = 2.8 Hz), 129.7 (d, J = 5.8 Hz),
The acids 42a−d were also prepared by the hydrolysis of the
corresponding ethyl esters which were obtained by the above
procedure. These are known.25
Compound 21a. Yield: 1.89 g (90%; using 7.00 mmol of 3-iodo-1-
methyl-indole-2-ethylcarboxylate). Mp: 174−176 °C (white solid),
lit.26 (177−178 °C). IR (KBr): 3058, 2924, 2591, 1672, 1501, 1350,
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Table 3. Reaction of Allenes 9, 10, 13−15, and 18−20 with 42a−d via C−H Functionalization: Formation of Indolopyranones
a b
,
29, 32, 35−37, 41, and 43−49
a
Reaction conditions: for entries 1−4, indole-2-carboxylic acid (0.55 mmol), allene (0.5 mmol), Pd(OAc)2 (10 mol %), Ag2CO3 (0.75 mmol),
b
CH3CN (5 mL), 12 h. For entries 5−12, 0.5 mmol of indole-2-carboxylic acid and 0.75 mmol of allene were used. Isolated yield based on the
c
amount of the allene for entries 1−4 and indole-2-carboxylic acid (42a) for entries 5−12. The combined yield of the E + Z isomers was essentially
d
quantitative (31P NMR); isomer ratio was ∼3:7. The major isomer is assigned (Z) configuration on the basis of the compounds 29/32. The
reaction was complete but the yield of isolated pure compound 43 is lower because of the closeness in Rf values of 37 and 43. Total isolated yield of
e
the unseparated products 37 + 43 was >58%. For pure compound 37 (X-ray), see Table 1. Based on GC−MS data.
133.8 (d, J = 7.7 Hz), 141.1, 143.0 (d, J = 7.3 Hz), 157.0. 31P NMR
(162 MHz, CDCl3): δ 18.8. HRMS (ESI) calcd for C24H24NO5P (M +
H)+ 438.1392l, found 438.1392. This compound was crystallized from
DCM containing traces of hexane.
J = 6.5 Hz), 76.0 (d, J = 6.8 Hz), 110.9, 113.0 (d, J = 2.9 Hz), 120.4,
121.3, 122.3, 122.7, 123.6 (d, J = 14.4 Hz), 127.4, 129.60 (d, J = 6.0
Hz), 129.64 (d, J = 2.6 Hz), 130.6 (d, J = 7.6 Hz), 137.9 (d, J = 3.4
Hz), 141.1, 143.0 (d, J = 7.3 Hz), 157.0. 31P NMR (162 MHz,
CDCl3): δ 18.9. LC−MS: m/z 452 [M + H]+. Anal. Calcd for
C25H26NO5P: C, 66.51; H, 5.80; N, 3.10. Found: C, 66.45; H, 5.85; N,
3.18.
Compound 23. Yield: 0.052 g (77%; white solid; using 0.15 mmol
of allene 2). Mp: 216−218 °C. IR (KBr): 2967, 1711, 1512, 1474,
1
1277, 1061, 831 cm−1. H NMR (500 MHz, CDCl3): δ 0.85 (s, 3H),
Compound 24. Yield: 0.200 g (86%; white solid). Mp: 230−232
°C. IR (KBr): 3058, 2955, 1719, 1613, 1510, 1246, 1051, 735 cm−1.
1H NMR (500 MHz): δ 0.85 (s, 3H), 1.00 (s, 3H), 3.67−3.79 (m,
5H), 4.23−4.28 (m, 5H), 5.10 (d, J = 33.0 Hz, 1H), 6.87−6.89 (m,
1.00 (s, 3H), 2.30 (s, 3H), 3.67−3.77 (m, 2H), 4.23−4.27 (m, 5H),
5.12 (d, J = 26.5 Hz, 1H), 7.16−7.23 (m, 3H), 7.43−7.51 (m, 4H),
7.92 (d, J = 8.0 Hz, 1H), 8.02 (br, 1H). 13C NMR (125 MHz, CDCl3):
δ 21.1, 21.5, 31.5, 32.7 (d, J = 6.2 Hz), 42.8 (d, J = 137.0 Hz), 75.9 (d,
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Anal. Calcd for C30H28NO5P: C, 70.17; H, 5.50; N, 2.73. Found: C,
70.08; H, 5.56; N, 2.81.
Scheme 5. Possible Pathway for the Formation of
Pyranoindoles (Lactones)
Compound 28. Yield: 0.158 g (84%; white solid). Mp: 140−146
1
°C. IR (KBr): 2924, 1715, 1609, 1507, 1252, 1055, 785 cm−1. H
NMR (500 MHz, CDCl3): δ 1.01 (s, 3H), 1.26 (s, 3H), 2.34 (d, J =
15.0 Hz, 3H), 3.88 (dd, J ≈ 17.0 Hz, J ≈ 11.0 Hz, 2H), 4.14 (s, 3H),
4.41 (dd, J ≈ 11.0 Hz, J ≈ 6.0 Hz, 2H), 5.55 (s, 2H), 7.28−7.47 (m,
3H), 7.66 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 20.0
(d, J = 8.4 Hz), 21.5, 22.2, 31.3, 32.7 (d, J = 5.5 Hz), 71.6 (d, J = 7.6
Hz), 74.8 (d, J = 5.9 Hz), 77.3, 120.2, 120.4, 122.5 (d, J = 180.0 Hz),
121.9, 122.2, 123.7, 124.1, 126.2, 139.7, 140.0 (d, J = 15.5 Hz), 160.0.
31P NMR (202 MHz, CDCl3): δ 15.9. HRMS (ESI) calcd for
C19H22NO5P (M + Na)+ 398.1134, found 398.1134.
Compound 29. Yield: 0.158 g (81%; white solid). Mp: 118−122
1
°C. IR (KBr): 2965, 2884, 1715, 1586, 1269, 1059, 745 cm−1. H
NMR (400 MHz, CDCl3): 1.14 (s, 6H), 2.01 (s, 6H), 3.96 (dd→t, J ≈
12.0 Hz, 2H), 4.19 (s, 3H), 4.26 (dd→t, J ≈ 10.0 Hz, 2H), 6.42 (d, J =
8.0 Hz, 1H), 7.37−7.54 (m, 3H), 8.00 (d, J = 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3): 21.6, 21.7, 29.0, 31.7, 32.7 (d, J = 5.3 Hz), 75.6,
75.7, 88.5 (d, J = 5.8 Hz), 106.4 (d, J = 194.7 Hz), 111.6, 118.7 (d, J =
24.5 Hz), 121.7, 122.3, 123.3, 124.0, 126.8, 140.7, 155.5 (d, J = 7.2
Hz), 158.5. 31P NMR (162 MHz, CDCl3): δ 12.2. HRMS (ESI) calcd
for C20H24NO5P (M + H)+ 389.1392, found 389.1392. This
compound was crystallized from ethyl acetate containing traces of
hexane.
Compound 30. Yield: 0.133 g (74%; white solid). Mp: 216−218
°C. IR (KBr): 3081, 2971, 1705, 1607, 1476, 1267, 1065, 735 cm−1.
1H NMR (400 MHz, CDCl3): δ 0.89 (s, 3H), 0.93(s, 3H), 3.51 (d, J =
20.4 Hz, 2H), 3.67 (dd, J = 16.6 Hz, J ≈ 11.0 Hz, 2H), 4.20−4.23 (m,
5H), 7.28−7.33 (m, 2H), 7.48−7.56 (m, 2H), 8.12 (d, J = 8.4 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 21.3, 21.6, 25.6 (d, J = 141.0
Hz), 31.4, 32.6 (d, J = 6.0 Hz), 75.10, 75.14, 108.5 (d, J = 11.0 Hz),
110.7, 120.9, 121.40, 121.45, 123.1, 123.8 (d, J = 4.0 Hz), 127.8, 141.2,
141.6 (d, J = 11.0 Hz), 157.0. 31P NMR (162 MHz, CDCl3): δ 21.3.
HRMS (ESI) calcd for C18H20NO5P (M + Na)+ 384.0977, found
384.0977.
Compound 31. Yield: 0.158 g (84%; white solid). Mp: 250−252
°C. IR (KBr): 2959, 2888, 1710, 1611, 1474, 1266, 1057, 806 cm−1.
1H NMR (400 MHz, CDCl3): 0.84 (s, 3H), 0.87 (s, 3H), 2.41 (d, J =
4.4 Hz, 3H), 3.55 (d, J = 14.8 Hz, 2H), 3.59 (dd, J = J ≈ 11.4 Hz, 2H),
4.19−4.21 (m, 5H), 7.25−7.28 (m, 1H), 7.45−7.53 (m, 2H), 8.13 (d, J
= 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): 17.0, 21.2, 21.4, 25.9 (d,
J = 141.0 Hz), 31.3, 32.5 (d, J = 5.8 Hz), 74.80, 74.82, 104.1 (d, J = 11.2
Hz), 110.5, 120.5, 120.7, 120.9, 123.4, 125.3, 127.5, 141.4, 150.8 (d, J
= 10.0 Hz), 157.2. 31P NMR (162 MHz, CDCl3). HRMS (ESI) calcd
for C19H22NO5P (M + Na)+ 398.1134, found 398.1134.
2H), 7.19−7.23 (m, 1H), 7.44−7.51 (m, 4H), 7.89 (d, J = 8.0 Hz,
1H), 8.02 (br, 1H). 13C NMR (125 MHz): δ 21.5, 31.5, 32.7 (d, J =
6.4 Hz), 42.3 (d, J = 137.6 Hz), 55.3, 75.8 (d, J = 6.8 Hz), 75.9 (d, J =
6.7 Hz), 110.9, 133.0 (d, J = 2.7 Hz), 114.3 (d, J = 2.7 Hz), 120.3,
121.3, 122.2, 122.7, 123.5 (d, J = 14.5 Hz), 125.4 (d, J = 14.5 Hz),
127.4, 130.8 (d, J = 5.7 Hz), 141.1, 142.8 (d, J = 7.1 Hz), 157.0, 159.4
(d, J = 3.3 Hz). 31P NMR (202 MHz, CDCl3): δ 19.1. LC−MS: m/z
467 [M]+. Anal. Calcd for C25H26NO6P: C, 64.24; H, 5.61; N, 3.00.
Found: C, 64.41; H, 5.56; N, 3.07.
Compound 25. Yield: 0.159 g (68%; white solid; using 0.15 mmol
of allene 2). Mp: 212−216 °C. IR (KBr): 2957, 1715, 1617, 1489,
1339, 1285, 1057, 785 cm−1. 1H NMR (400 MHz, CDCl3): δ 0.87 (s,
3H), 0.98 (s, 3H), 3.70−3.82 (m, 2H), 4.23−4.32 (m, 5H), 5.12 (d, J
= 26.8 Hz, 1H), 7.19−7.23 (m, 1H), 7.32−7.34 (m, 2H), 7.46−7.52
(m, 4H), 7.82 (d, J = 8.0 Hz, 1H), 8.01 (br, 1H). 13C NMR (100
MHz, CDCl3): δ 21.4, 21.6, 31.5, 32.8 (d, J = 5.9 Hz), 42.5 (d, J =
137.1 Hz), 75.7 (d, J = 6.6 Hz), 75.8 (d, J = 6.6 Hz), 111.0, 112.4,
120.2, 121.4, 122.2, 122.3, 123.1 (d, J = 14.1 Hz), 127.6, 129.1 (d, J =
2.7 Hz), 131.0 (d, J = 5.8 Hz), 132.4 (d, J = 7.4 Hz), 134.1 (d, J = 4.2
Hz), 141.1, 143.1 (d, J = 7.1 Hz), 156.8. 31P NMR (162 MHz,
CDCl3): δ 18.6. LC−MS: m/z 471 and 473 [M]+. Anal. Calcd for
C24H23ClNO5P: C, 61.09; H, 4.91; N, 2.97. Found: C, 61.22; H, 4.98;
N, 2.91.
Compound 26. Yield: 0.198 g (81%; brown solid). Mp: 278−280
1
°C. IR (KBr): 3104, 1725, 1609, 1470, 1238, 1061, 743 cm−1. H
NMR (400 MHz, CDCl3): δ 0.72 (s, 3H), 0.90 (s, 3H), 3.37−3.55 (m,
2H), 4.15−4.24 (m, 5H), 6.00 (d, J = 26.0 Hz, 1H), 7.05−7.09 (m,
1H), 7.44−7.55 (m, 5H), 7.71−8.00 (m, 5H), 8.15 (d, J = 7.6 Hz,
1H). 13C NMR (125 MHz, CDCl3): δ 21.3, 31.4, 32.5 (d, J = 6.5 Hz),
39.3 (d, J = 139.9 Hz), 75.6 (d, J = 3.0 Hz,), 75.7 (d, J = 2.9 Hz),
110.8, 113.6 (d, J = 5.6 Hz), 120.5, 121.2, 121.8, 122.8, 123.2, 123.5
(d, J = 10.1 Hz), 125.4 (d, J = 2.6 Hz), 125.9, 126.8, 127.4, 127.8 (d, J
= 6.4 Hz), 129.0 (d, J = 2.2 Hz), 129.3, 130.2 (d, J = 4.9 Hz), 131.6 (d,
J = 8.5 Hz), 134.3, 141.0, 144.1 (d, J = 7.6 Hz), 156.8. 31P NMR (202
MHz, CDCl3): δ 20.1. LC−MS: m/z 487 [M]+. Anal. Calcd for
C28H26NO5P: C, 68.99; H, 5.38; N, 2.87. Found: C, 68.79; H, 5.31; N,
2.95.
Compound 32. Yield: 0.14 g (65%; white solid). Mp: 198−200 °C.
1
IR (KBr): 2932, 1713, 1609, 1485, 1273, 1057, 822 cm−1. H NMR
(400 MHz, CDCl3): δ 0.75 (s, 3H), 1.15 (s, 3H), 1.67−2.12 (m, 10H),
3.58−3.69 (m, 4H), 4.16 (s, 3H), 5.92 (d, J = 9.6 Hz, 1H), 7.33−7.45
(m, 3H), 8.54 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3):
20.7, 21.7, 21.8, 25.2, 31.4, 32.3 (d, J = 7.0 Hz), 35.5, 76.6, 77.2, 88.1
(d, J = 21.0 Hz), 109.2 (d, J = 179.0 Hz), 110.2, 117.7 (d, J = 9.0 Hz),
122.3, 123.4, 123.8, 124.7, 126.6, 139.7, 152.2, 159.2. 31P NMR (162
MHz, CDCl3): δ 11.0. LC−MS: m/z 429 [M]+. Anal. Calcd for
C23H28NO5P: C, 64.33; H, 6.57; N, 3.26. Found: C, 64.48; H, 6.65; N,
3.18. This compound was crystallized from DCM containing traces of
hexane.
Compound 33. Yield: 0.158 g (64%; white solid). Mp: 288−292
°C. IR (KBr): 3056, 1701, 1599, 1476, 1206, 1036, 739, 511 cm−1. 1H
NMR (500 MHz, CDCl3): δ 4.20 (s, 3H), 5.32 (d, J = 11.0 Hz, 1H),
7.17−7.18 (m, 3H), 7.25−7.29 (m, 2H), 7.36−7.53 (m, 11H), 7.83−
7.87 (m, 2H), 8.06 (d, J = 8.5 Hz, 1H), 8.48 (s, 1H). 13C NMR (125
MHz, CDCl3): δ 31.5, 45.5 (d, J = 64.1 Hz), 111.1, 114.9 (d, J = 3.5
Hz), 120.5, 121.4, 122.30, 122.31, 123.4 (d, J = 10.1 Hz), 127.5, 127.6
(d, J = 2.6 Hz), 128.3, 128.4, 129.0 (d, J = 11.3 Hz), 130.3 (d, J = 4.6
Hz), 131.2 (d, J = 8.4 Hz), 131.4 (d, J = 9.0 Hz), 131.9 (d, J = 2.8 Hz),
132.0 (d, J = 2.5 Hz), 132.2 (d, J = 57.1 Hz), 132.6, 133.1 (d, J = 5.8
Hz), 141.1, 143.8 (d, J = 7.8 Hz), 157.0. 31P NMR (202 MHz,
Compound 27. Yield: 0.163 g (79%; white solid; using 0.4 mmol of
allene 1). Mp: 224−228 °C. IR (KBr): 3058, 2971, 1717, 1613, 1462,
1
1277, 1059, 741 cm−1. H NMR (500 MHz, CDCl3): δ 0.79 (s, 3H),
0.99 (s, 3H), 3.68−3.77 (m, 2H), 4.24−4.28 (m, 2H), 5.19 (d, J = 27.0
Hz, 1H), 5.90 (d, J = 16.0 Hz, 1H), 6.04 (d, J = 16.0 Hz, 1H), 7.18−
7.27 (m, 7H), 7.36−7.44 (m, 4H), 7.58−7.59 (m, 2H), 7.93 (d, J = 8.5
Hz, 1H), 8.07 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 21.4, 21.5,
32.7 (d, J = 6.4 Hz), 43.4 (d, J = 136.5 Hz), 48.1, 75.9 (d, J = 6.8 Hz),
76.0 (d, J = 6.6 Hz), 111.7, 112.8 (d, J = 3.3 Hz), 120.8, 121.5, 121.9,
122.7, 124.1 (d, J = 14.0 Hz), 127.1, 127.6 (d, J = 3.1 Hz), 128.1 (d, J
= 3.1 Hz), 128.8, 128.9 (d, J = 2.6 Hz), 129.80, 129.81, 129.8 (d, J = 5.9
Hz), 133.8 (d, J = 7.5 Hz), 137.3, 140.7, 143.4 (d, J = 7.3 Hz), 156.7.
31P NMR (162 MHz, CDCl3): δ 18.7. LC−MS: m/z 514 [M + H]+.
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CDCl3): δ 32.3. HRMS (ESI) m/z: calcd for C31H24NO3P (M + H)+
490.1572, found 490.1572.
122.0, 122.4, 127.7, 129.1, 129.5, 129.7, 130.2, 130.60, 130.64, 136.4,
140.9, 141.1, 143.1, 156.4. LC−MS: m/z 464 and 466 [M]+. Anal.
Calcd for C25H18ClNO4S: C, 64.72; H, 3.91; N, 3.02. Found: C, 64.82;
H, 3.85; N, 3.12.
Compound 34. Yield: 0.191 g (92%; brown solid). Mp: 248−252
°C. IR (KBr): 2948, 1707, 1435, 1331, 1183, 1030, 847, 735 cm−1. 1H
NMR (500 MHz, CDCl3): δ 3.90 (d, J = 12.5 Hz, 2H), 4.16 (s, 3H),
7.07 (d, J = 4.0 Hz, 1H), 7.21−7.24 (m, 1H), 7.42−7.55 (m, 8H),
7.78−7.82 (m, 4H), 8.05 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz,
CDCl3): δ 30.0 (d, J = 67.8 Hz), 31.3, 108.6 (d, J = 8.1 Hz), 110.7,
121.0, 121.2, 121.6, 122.9, 124.2 (d, J = 4.5 Hz), 127.5, 128.8, 128.9,
131.10, 131.14, 131.7, 132.2 (d, J = 2.3 Hz), 132.4, 141.1, 141.7 (d, J =
8.0 Hz), 156.9. 31P NMR (202 MHz, CDCl3): δ 29.1. HRMS (ESI)
calcd for C25H20NO3P (M + H)+ 414.1181, found 414.1181.
Compound 35. Yield: 0.140 g (63%; white solid). Mp: 156−160
°C. IR (KBr): 3058, 2988, 1715, 1563, 1485, 1254, 1094, 721 cm−1.
1H NMR (400 MHz, CDCl3): δ 1.99 (s, 6H), 4.19 (s, 3H), 6.89 (d, J =
15.6 Hz, 1H), 7.25−7.27 (m, 1H), 7.50−7.56 (m, 8H), 7.70−7.84 (m,
5H). There was also a minor isomer: δ 1.69, 4.01, 6.45(d) [other peaks
were buried in the signals due to the major isomer]. 13C NMR (100
MHz, CDCl3): δ 29.8, 31.7, 89.1, 111.5, 113.7 (d, J = 103.3 Hz), 121.5,
122.4, 123.2, 126.6, 128.9 (d, J = 12.0 Hz), 130.9 (d, J = 9.7 Hz),
131.8, 135.1, 136.1, 140.7, 154.3, 158.7. 31P NMR (162 MHz, CDCl3):
δ 20.7 [major, ca. 75%], 18.7 [minor, ca. 25%]. LC−MS: m/z 441
[M]+. Anal. Calcd for C27H24NO3P: C, 73.46; H, 5.48; N, 3.17. Found:
C, 73.56; H, 5.41; N, 3.22.
Compound 36. Yield: 0.130 g (54%; white solid). Mp: 210−212
°C. IR (KBr): 2926, 1707, 1561, 1437, 1350, 1267, 1098, 828 cm−1.
1H NMR (400 MHz, CDCl3): δ 1.56−1.98 (m, 8H), 2.75−2.82 (m,
2H), 4.18 (s, 3H), 6.84 (d, J = 15.6 Hz, 1H), 7.46−7.56 (m, 9H), 7.68
(d, J = 8.4 Hz, 1H), 7.81−7.86 (m, 4H). 13C NMR (100 MHz,
CDCl3): δ 21.5, 24.0, 31.6, 37.1, 89.9 (d, J = 3.0 Hz), 111.5, 113.5 (d, J
= 104.0 Hz), 119.4 (d, J = 19.0 Hz), 121.5, 121.7, 122.5, 123.1, 123.5,
126.5, 128.1 (d, J = 12.0 Hz), 128.8 (d, J = 12.0 Hz), 130.7, 131.0 (d, J
= 10.0 Hz), 131.3, 131.7, 135.2, 136.3, 140.7, 155.0, 158.5. 31P NMR
(162 MHz, CDCl3): δ 21.5. LC−MS: m/z 481 [M]+. Anal. Calcd for
C30H28NO3P: C, 74.83; H, 5.86; N, 2.91. Found: C, 74.65; H, 5.81; N,
2.99.
Compound 41. Yield: 0.114 g (72%; white solid; using 0.5 mmol of
21a and 0.6 mmol of allene 20). Mp: 134−138 °C. IR (KBr): 3058,
1
2984, 1701, 1509, 1483, 1267, 1090, 747 cm−1. H NMR (400 MHz,
CDCl3): 1.75 (s, 6H), 4.16 (s, 3H), 6.36 (d, J = 8.4 Hz, 1H), 6.74−
6.78 (m, 1H), 6.85 (s, 1H), 7.21−7.55 (m, 7H). 13C NMR (100 MHz,
CDCl3): 27.7, 31.4, 87.7, 110.3, 119.6, 120.6, 122.1, 124.0, 124.5,
125.3, 125.7, 127.5, 128.4, 129.5, 133.6, 137.6, 140.1, 160.4. HRMS
(ESI) calcd for C21H19NO2 (M + H)+ 318.1496, found 318.1494.
(iii) Pd-Catalyzed Annulation of Allenes with 1-Alkyl-indole-
2-carboxylic Acids via C−H Functionalization: Synthesis of
compounds 29, 32, 35−37, 41, and 43−49. Standardization of
Reaction Conditions. An oven-dried 10 mL RBF was charged with the
Pd(II) complex (10 mol %), oxidant [Ag2CO3 or Cu(OAc)2; 0.375−
0.500 mmol], 1-methyl-indole-2-carboxylic acid 42a (0.25 mmol), and
the base [LiOAc, CsF or K2CO3]. The RBF was evacuated for 5 min
and filled with N2. To this was added solvent [CH3CN, DMF, or
dimethyl acetamide; 2.5 mL], and the contents were stirred at rt for 5
min. After this, allene 18 (0.375 mmol) was added via a micropipet.
The RBF was flushed with N2 and sealed. The contents were stirred in
preheated oil bath (80−120 °C) for the indicated period of time. After
the completion of the reaction (GC−MS), the mixture was cooled to
rt, diluted with ethyl acetate (15 mL), washed with brine (3 × 5 mL),
dried over Na2SO4, and filtered, and the solvent was removed from the
filtrate. The crude product was purified by column chromatography
(silica gel, ethyl acetate−hexane) to get the pure product (44). Other
details are presented in Table 2.
Standardized Procedure for the Preparation of Compounds 29,
32, 35−37, 41, and 43−49. In an oven-dried 25 mL RBF was taken
silver carbonate (0.75 mmol) and dried in vacuo while heating with a
hot air gun for 0.5 h. After cooling (5 min), Pd(OAc)2 (10 mol %), 1-
alkylindole-2-carboxylic acid (0.5−0.55 mmol), and CH3CN (5.0 mL)
were added. The mixture was kept stirring at rt for 5 min. After that,
allene (0.50−0.75 mmol) was added, and the RBF was sealed with a
stopper. The resulting mixture was heated with stirring at 80 °C (oil
bath) for 10−12 h. After the completion of the reaction (GC−
MS)/31P NMR), the solvent was removed by rotary evaporator and
the mixture subjected to flash chromatography (silica gel, ethyl
acetate/hexane 1:19) to obtain the pure products in 43−68% yield.
Compounds 29, 32, 35−37, 41, and 43−49 were prepared by this
procedure.
Compound 37. Yield: 0.116 g (81%; white solid; using 0.5 mmol of
21a and 0.6 mmol of allene 15). Mp: 106−110 °C. IR (KBr): 3083,
1
1730, 1707, 1624, 1478, 1275, 1017, 737 cm−1. H NMR (400 MHz,
CDCl3): 1.23 (t, J ≈ 7.0 Hz, 3H), 3.80 (s, 2H), 4.16−4.21 (m, 5H),
7.24−7.28 (m, 2H), 7.45−7.53 (m, 2H), 7.91 (d, J = 8.0 Hz, 1H). 13C
NMR (100 MHz, CDCl3): 14.2, 31.3, 34.5, 61.5, 110.8, 111.0, 120.8,
121.3, 121.5, 122.4, 124.0, 127.6, 141.1, 141.3, 157.2, 170.5. HRMS
(ESI) calcd for C16H15NO4 (M + H)+ 286.1001, found 286.1001. This
compound was crystallized from DCM containing traces of hexane.
Compound 38. Yield: 0.090 g (83%; white solid; using 0.3 mmol of
21b and 0.36 mmol of allene 15). Mp: 220−222 °C. IR (KBr): 3034,
Compound 43. Yield: total yield 62%. Combined yield (37 + 43):
0.089 g [47%; using 15 (0.75 mmol) and 42a (0.50 mmol)] Isolated
yield for 43: 0.022 g (15%; white solid). Mp: 120−122 °C. IR (KBr):
2961, 1717, 1697, 1601, 1489, 1262, 1030 cm−1. 1H NMR (400 MHz,
CDCl3): δ 1.36 (t, J ≈ 7.6 Hz, 3H), 4.19 (s, 3H), 4.26 (q, J = 7.2 Hz,
2H), 5.90 (d, J = 2.4 Hz, 2H), 6.57 (dd→t, J ≈ 2.2 Hz, 1H), 7.38−7.40
(m, 1H), 7.52−7.53 (m, 2H), 8.03 (d, J = 8.0 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 14.5, 31.8, 60.5, 70.7, 111.4, 118.3, 121.7, 122.3,
123.3, 124.1, 127.0, 140.4, 143.4, 159.0, 166.4. HRMS (ESI) calcd for
C16H15NO4 (M + Na)+ 308.0899, found 308.0895.
1
2980, 1730, 1707, 1622, 1495, 1277, 1022, 741 cm−1. H NMR (400
MHz, CDCl3): 1.25 (t, J = 7.2 Hz, 3H), 3.85 (s, 2H), 4.65 (q, J = 7.2
Hz, 2H), 5.98 (s, 2H), 7.20−7.30 (m, 7H), 7.46−7.51 (m, 2H), 7.97
(d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): 14.2, 34.5, 48.0,
61.6, 111.1, 111.7, 121.3, 121.6, 122.6, 124.7, 126.5, 127.1, 127.6,
127.9, 128.8, 137.4, 140.7, 141.7, 157.0, 170.5. LC−MS: m/z 361
[M]+. Anal. Calcd for C22H19NO4: C, 73.12; H, 5.30; N, 3.88. Found:
C, 73.32; H, 5.38; N, 3.81.
Compound 39. Yield: 0.170 g (85%; white solid). Mp: 204−208
°C. IR (KBr): 3117, 1721, 1707, 1615, 1476, 1314, 1146, 1024 cm−1.
1H NMR (500 MHz, CDCl3): δ 1.80 (d, J = 9.0 Hz, 3H), 4.24 (s, 3H),
5.09−5.10 (br, 1H), 7.24−7.39 (m, 4H), 7.49−7.59 (m, 2H), 7.69−
7.72 (m, 2H), 8.00 (d, J = 8.0 Hz, 1H). 13C NMR (125 MHz, CDCl3):
δ 14.9, 31.5, 59.1, 111.1, 112.5, 120.4, 121.3, 121.6, 122.8, 123.0, 127.9,
129.3, 131.1, 134.7, 141.0, 141.3, 143.0, 156.5. LC−MS: m/z 402 and
404 [M]+. HRMS (ESI) calcd for C20H16ClNO4S (M + Na)+
424.0387, found 424.0387. This compound was crystallized from
DCM contianing traces of hexane.
Compound 44. Yield: 0.098 g (68%; white solid; using 0.5 mmol of
42a and 0.75 mmol of 18). Mp: 154−156 °C. IR (KBr): 3036, 2932,
1
1701, 1480, 1308, 1096, 733 cm−1. H NMR (400 MHz, CDCl3): δ
4.11 (s, 3H), 5.16 (s, 1H), 5.94 (s, 1H), 6.19 (s, 1H), 7.27−7.36 (m,
4H), 7.43−7.49 (m, 4H), 7.95 (d, J = 8.0 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 31.4, 85.1, 111.0, 113.2, 120.6, 122.0, 122.7, 126.7,
127.3, 128.3, 128.5, 128.7, 129.0, 130.3, 136.6, 138.0, 140.6, 159.7.
HRMS (ESI) calcd for C19H15NO2 (M + Na)+ 312.1001, found
312.1001.
Compound 45. Yield: 0.094 g (62%; white solid; using 0.5 mmol of
42c and 0.75 mmol of 18). Mp: 130−134 °C. IR (KBr): 2924, 1707,
Compound 40. Yield: 0.152 g (66%; brown solid). Mp: 156−160
1
1466, 1231, 1092, 905, 735 cm−1. H NMR (400 MHz, CDCl3): δ
1
°C. IR (KBr): 3063, 2924, 1609, 1476, 1319, 1148, 702 cm−1. H
1.43 (t, J = 7.2 Hz, 3H), 4.65 (m, 2H), 5.14 (s, 1H), 5.93 (s, 1H), 6.19
(s, 1H), 7.27−7.49 (m, 8H), 7.96 (d, J = 8.4 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 15.5, 39.7, 85.1, 111.0, 113.1, 120.8, 122.0, 122.1,
NMR (500 MHz, CDCl3): δ 4.21 (s, 3H), 5.03 (s, 1H), 7.16−7.56 (m,
10H), 7.68−7.70 (m, 2H), 7.85 (d, J = 8.4 Hz, 1H), 8.27 (br, 1H). 13C
NMR (125 MHz, CDCl3): δ 31.5, 69.1, 111.1, 111.3, 120.0, 121.7,
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Article
122.2, 126.6, 127.3, 128.5, 128.7, 136.8, 138.0, 139.6, 159.4. HRMS
(ESI) calcd for C20H17NO2 (M + H)+ 304.1339, found 304.1337.
Compound 46. Yield: 0.103 g (62%; white solid; using 0.5 mmol of
42c and 0.75 mmol of 18). Mp: 94−98 °C. IR (KBr): 2955, 1713,
47: C21H19NO3, M = 333.39, monoclinic, space group P2(1)/c, a =
13.0768(16), b = 16.069(2), c = 8.6435(9) Å, β = 105.021(13)°, V =
1754.3(4) Å3, Z = 4, μ = 0.084 mm−1, data/restraints/parameters:
3093/1/230, R indices (I > 2σ(I)): R1 = 0.0583, wR2 (all data) =
0.1277. CCDC no. 8844803.
1
1522, 1471, 1341, 1184, 698 cm−1. H NMR (400 MHz, CDCl3): δ
A: C38 H30 N2 O4, M = 578.64, monoclinic, space group C2/c, a =
24.956(5), b = 8.9926(8), c = 16.635(3) Å, β = 129.57(3)°, V =
2877.8(9) Å3, Z = 4, μ = 0.087 mm−1, data/restraints/parameters:
2404/0/200, R indices (I > 2σ(I)): R1 = 0.0566, wR2 (all data) =
0.1302. CCDC no. 8844804.
0.93 (t, J = 7.2 Hz, 3H), 1.34−1.38 (m, 2H), 1.78−1.82 (m, 2H),
4.60−4.63 (m, 2H), 5.17 (d, J = 1.6 Hz, 1H), 5.94 (d, J = 1.2 Hz, 1H),
6.19 (s, 1H), 7.27−7.50 (m, 8H), 7.96 (d, J = 8.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 13.9, 20.1, 32.5, 44.5, 85.1, 111.3, 113.1, 120.6,
121.9, 122.05, 122.09, 122.3, 126.5, 127.2, 128.5, 128.6, 136.8, 138.1,
139.9, 159.5. HRMS (ESI) calcd for C22H21NO2 (M + H)+ 332.1652,
found 332.1650.
Compound 47. Yield: 0.072 g (43%; white solid; using 0.5 mmol of
42d and 0.75 mmol of 18). Mp: 100−104 °C. IR (KBr): 2975, 1703,
1464, 1337, 1196, 1096, 999, 749 cm−1. 1H NMR (400 MHz, CDCl3):
δ 1.11 (t, J ∼ 7.0 Hz, 3H), 3.46−3.54 (m, 2H), 5.23 (s, 1H), 5.99 (s,
1H), 6.03−6.10 (m, 2H), 6.20 (s, 1H), 7.31−7.39 (m, 4H), 7.47−7.67
(m, 4H), 7.95 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
15.0, 64.1, 73.5, 85.0, 112.4, 114.4, 121.9, 122.2, 122.5, 122.7, 127.2,
128.5, 128.7, 136.5, 137.8, 140.4, 159.5. HRMS (ESI) calcd for
C21H19NO3 (M + Na)+ 356.1263, found 356.1263. It was crystallized
from chloroform at 30 °C.
ASSOCIATED CONTENT
■
S
* Supporting Information
More experimental data, additional molecular drawings, CIF
1
files, copies of H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kckssc@uohyd.ernet.in; kckssc@yahoo.com.
■
Notes
Compound 48. Yield: 0.096 g (63%; white solid; using 0.5 mmol of
42a and 0.75 mmol of 19). Mp: 126−130 °C. IR (KBr): 2955, 1703,
The authors declare no competing financial interest.
1
1478, 1308, 1229, 1200, 1090, 808, 735 cm−1. H NMR (400 MHz,
CDCl3): δ 2.34 (s, 3H), 4.11 (s, 3H), 5.17 (s, 1H), 5.93 (s, 1H), 6.16
(s, 1H), 7.15−7.17 (m, 2H), 7.27−7.30 (m, 1H), 7.35−7.37 (m, 2H),
7.42−7.49 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 21.2, 31.4, 85.1, 111.0, 113.1, 120.6, 121.96, 122.00, 122.7,
126.6, 127.2, 129.2, 129.3, 135.1, 136.6, 138.5, 140.6, 159.8. HRMS
(ESI) calcd for C20H17NO2 (M + H)+ 304.1339, found 304.1337.
Compound 49. Yield: 0.112 g (65%; white solid; using 0.5 mmol of
42c and 0.75 mmol of 19). Mp: 100−104 °C. IR (KBr): 2955, 1705,
520, 1472, 1237, 1190, 1098, 741 cm−1. 1H NMR (500 MHz, CDCl3):
δ 0.94 (t, J = 7.5 Hz, 3H), 1.35−1.37 (m, 2H), 1.79−1.82 (m, 2H),
2.36 (s, 3H), 4.60−4.63 (m, 2H), 5.17 (s, 1H), 5.92 (s, 1H), 6.17 (s,
1H), 7.17−7.28 (m, 3H), 7.36−7.38 (m, 2H), 7.46−7.47 (m, 2H),
7.96 (d, J = 8.0 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 20.1,
21.2, 32.5, 44.5, 85.1, 111.3, 112.9, 120.7, 121.9, 122.1, 122.2, 122.4,
126.4, 127.2, 129.3, 135.2, 137.0, 138.4, 139.9, 159.5. HRMS (ESI)
calcd for C23H23NO2 (M + H)+ 346.1809, found 346.1807.
(iv) X-ray Data. X-ray data for compounds 22, 29, 32, 37, 39, 47,
and A were collected using Mo Kα (λ = 0.71073 Å) radiation. The
structures were solved and refined by standard methods.27 CCDC
numbers are CCDC 8844798−884804.
ACKNOWLEDGMENTS
■
We thank DST (New Delhi) for financial support and Single
Crystal X-ray Diffractometer Facility and UGC (New Delhi)
for equipment under UPE and CAS programs. R.R.S. thanks
the Council of Scientific and Industrial Research (CSIR, New
Delhi) for a fellowship. K.C.K.S. thanks DST for a J.C. Bose
fellowship. We also thank Dr. P. Raghavaiah and Mr. T. R. N.
Prasad for technical help with respect to compounds C and D.
REFERENCES
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29: C20H24NO5P, M = 389.37, monoclinic, space group P2(1)/c, a
= 13.8122(6), b = 13.1379(4), c = 11.7893(6) Å, β = 112.165(6)°, V =
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0.1046. CCDC no. 8844799.
32: C23H28NO5P, M = 429.43, monoclinic, space group P2(1)/c, a
= 7.1222(9), b = 17.729(2), c = 16.957(2) Å, β = 93.189°, V =
2137.9(5) Å3, Z = 4, μ = 0.164 mm−1, data/restraints/parameters:
3772/0/274, R indices (I > 2σ(I)): R1 = 0.1213, wR2 (all data) =
0.2163. CCDC no. 8844800.
37: C16H15NO4, M = 285.29, monoclinic, space group P2(1)/c, a =
13.362(3), b = 13.883(3), c = 7.8491(17) Å, β = 103.842(3)°, V =
1413.7(6) Å3, Z = 4, μ = 0.097 mm−1, data/restraints/parameters:
2484/0/193, R indices (I > 2σ(I)): R1 = 0.0501, wR2 (all data) =
0.1351. CCDC no. 8844801.
39: C H C NO S, M = 486.79, triclinic, space group Pi, a =
̅
21 18 l3
4
9.1437(8), b = 9.3147(7), c = 12.7844(16) Å, α= 92.975(8)°, β =
95.650(9)°, γ= 91.661(6)°, V = 1081.48(18) Å3, Z = 4, μ = 0.549
mm−1, data/restraints/parameters: 3802/0/274, R indices (I > 2σ(I)):
R1 = 0.0536, wR2 (all data) =. 0.1581. CCDC no. 8844802.
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6967
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(C) [Mp: 148−150 °C. IR (KBr): 2932, 1711, 1480, 1211, 1109,
1053, 982 cm−1. 1H NMR (400 MHz, CDCl3): δ 4.13 (s, 3H), 4.87 (d,
J ≈ 12.20 Hz, 1H), 5.02 (d, J ≈ 12.2 Hz, 1H), 5.51 (s, 1H), 5.87 and
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122.0, 122.2, 126.7, 128.2, 128.3, 128.6, 134.1, 136.4, 140.5, 158.7.
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fluorene) (m/z 300) that we could isolate did not contain the allene
residue (1H NMR, partial X-ray structure), we did not proceed further.
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(20) The other three possible isomers are shown below:
(21) Interestingly, when Cu(OAc)2 (0.75 mmol) + LiOAc (1.0
mmol) was used in place of Ag2CO3, with the reaction time being 8 h;
0.75 mmol of the allenoate, only compound 37 was preferentially
formed.
(22) Compound 41 was obtained with 64% isolated yield from 0.5
mmol of 42a and 0.75 mmol of 20.
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