Simple synthesis of amides and weinreb amides Using PPh3 or PolymerSupported PPh3 and Iodine

Article abstract of DOI:10.1002/ejoc.200901420

The combination of PPh₃/I₂ has been shown to be effective for the conversion of a range of carboxylic acids into secondary, tertiary, and Weinreb amides. Simplification of the procedure was possible with the use of polymer-supported PPh₃/ I₂. Weinreb amides produced with the use of polymer-supported PPh₃ could be filtered through a short silica gel plug and used in further transformations. Thus, the use of polymer-supported PPh₃ offers potential applicability to diversityoriented reactions. Formal total syntheses of apocynin and pratosine, as well as syntheses of anhydrolychorinone and hippadine, have been achieved through the use of this amide-forming method. An attempt has been made to gain insight into this reaction.

Full text of DOI:10.1002/ejoc.200901420

FULL PAPER
DOI: 10.1002/ejoc.200901420
Simple Synthesis of Amides and Weinreb Amides Using PPh3 or Polymer-
Supported PPh3 and Iodine
Amit Kumar,[a] Hari Kiran Akula,[a] and Mahesh K. Lakshman*[a]
Keywords: Amides / Phosphanes / Supported reagents / Iodine / Synthetic methods
The combination of PPh3/I2 has been shown to be effective
for the conversion of a range of carboxylic acids into second-
ary, tertiary, and Weinreb amides. Simplification of the pro-
cedure was possible with the use of polymer-supported PPh3/
I2. Weinreb amides produced with the use of polymer-sup-
ported PPh3 could be filtered through a short silica gel plug
and used in further transformations. Thus, the use of poly-
mer-supported PPh3 offers potential applicability to diversity-
oriented reactions. Formal total syntheses of apocynin and
pratosine, as well as syntheses of anhydrolychorinone and
hippadine, have been achieved through the use of this
amide-forming method. An attempt has been made to gain
insight into this reaction.
to ketones, the formal synthesis of two natural products,
and the total synthesis of two others, where amide forma-
tion is a key step.
Introduction
Besides being a ubiquitous functionality, the amide link-
age is prominent in functional group interconversions dur-
ing multistep syntheses. This is reflected in a substantial
amount of literature that continues to emanate on new
methods for formation of the amide bond.[1,2] Halophos-
phonium salts derived from PPh3/I2 and [(R2N)3]P/I2 have
recently found applications in the activation of the amide
linkages of hypoxanthine nucleosides for further transfor-
mations,[3–7] and dehydration of oximes by PPh3/I2 has been
reported.[8] Direct activation of tautomerizable heterocycles
for C–C bond-forming reactions by PyBroP has recently
been demonstrated.[9] Thus, halophosphonium compounds
enjoy wide applications in organic transformations. In the
area of amide-bond formation, the combination of PPh3
with halogen sources such as NCS,[10] NBS,[11] Br2,[12]
BrCCl3,[13] CCl4,[13,14] CBr4,[14] and trichloroisocyanuric
acid[15] have all been explored. In addition, polymer-sup-
ported PPh3 (Pol–Ph3P) has been utilized for amidation in
Results and Discussion
By using 31P{1H} NMR spectroscopy, we previously ob-
served that upon mixing PPh3 and I2 in a 1:1 ratio a new
species is produced, presumably (Ph3P+–I)I–. This entity
was capable of reacting with the amide group of hypo-
xanthine nucleosides.[5] Therefore, our first question was
whether such a species could react with carboxylic acids as
well. Since BroP and PyBroP are well-known reagents for
amidation,[18] this appeared feasible. For the reaction to oc-
cur, deprotonation of the carboxylic acid would be neces-
sary and iPr2NEt was selected for this purpose. The overall
reaction is depicted in Scheme 1. Here, either an acyl phos-
phonium species or an acyl iodide (produced by substitu-
tion of Ph3PO with iodide) could undergo reaction with the
amine, producing the amide.
[16]
combination with CCl4 and Cl3CCN.[17]
To our surprise, the combination of PPh3 and I2 for the
generation of the amide linkage seems to have remained
unstudied. The simplicity in handling these reagents, and
the fact that they are inexpensive, renders them particularly
attractive for this purpose. In this paper we have explored
the utility of this reagent combination, as well as Pol–Ph3P,
for the synthesis of various amides and synthetically versa-
tile Weinreb amides. We have applied this method en route
[a] Department of Chemistry, The City College and The City Uni-
versity of New York,
160 Convent Avenue, New York, NY 10031-9198, U.S.A
Fax: +1-212-650-6107
E-mail: lakshman@sci.ccny.cuny.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901420.
Scheme 1. A plausible mechanism for the amidation reaction.
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A. Kumar, H. K. Akula, M. K. Lakshman
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With this rationale we set about exploring the general tion of the highly hindered tert-butylamine with benzoic
versatility of the method by using a range of carboxylic ac- acid proceeded well (Table 1, Entry 13). α-Methoxyphen-
ids and amines. The results from this analysis are presented ylacetic acid reacted reasonably with both tert-butylamine
in Table 1.
and benzylamine (Table 1, Entries 14 and 15). Acceptable
Results from Table 1 indicate that (Ph3P+–I)I– is suitably reactions of 3-chloropropanoic acid with benzylamine
effective for the conversion of several carboxylic acids into (Table 1, Entry 16) and trans-3-hexenoic acid with piper-
the corresponding amides, and at a 1:1:1:1:1.5 stoichiome- idine (Table 1, Entry 17) were observed.
try of PPh3/I2/carboxylic acid/amine/iPr2NEt, primary and
Although many reactions gave moderate to good product
secondary amines react well. Substitution α to the amine yields under the above-mentioned stoichiometry, some reac-
does not hinder the reaction (Table 1, Entries 5 and 9). Re- tions could be improved with the use of 2 molar equivalents
action of an o-substituted arylamine proceeded in accept- each of PPh3 and I2 (Table 1, Entries 10, 12, 14–17). Also of
able yield (Table 1, Entry 10). 3-Furoic acid reacted ef- interest is the fact that N-methoxy-N-methyl (Weinreb[34]
)
ficiently, without complication (Table 1, Entry 11). Reac- amides could also be prepared by this route (Table 1, En-
Table 1. Amide and Weinreb amide synthesis using PPh3/I2.[a]
[a] Reactions were conducted by using 1 mmol each of PPh3, I2, carboxylic acid, amine, and 1.5 mmol of iPr2NEt in 4 mL of CH2Cl2,
unless noted otherwise. [b] Yield obtained by using 2 equiv. each of PPh3 and I2, and 1.5 equiv. of o-toluidine. [c] Yield obtained by using
2 equiv. each of PPh3 and I2. [d] 2.5 equiv. of iPr2NEt was used.
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Simple Synthesis of Amides and Weinreb Amides
tries 18 and 19). Owing to the synthetic versatility of Wein- indicated earlier, Pol–PPh3 has been used for amid-
reb amides, methods for their facile preparation are of con- ation,[16,17] and PPh3/CBr4 has been used in Weinreb amide
tinued interest.[35–39]
synthesis.[40] However, to the best of our knowledge, Pol–
Because Ph3PO is a byproduct in this reaction, we next PPh3 has not been used in combination with I2. Our results
considered facilitating its easy removal. For this, polymer- with Pol–PPh3/I2 are shown in Table 2.
Results from Table 2 indicate that the use of (Pol–Ph3P+–
I)I– is just about as effective as solution chemistry and that
this combination can be used for the synthesis of Weinreb
amides as well. The operational simplicity is exemplified by
the fact that the Weinreb amides obtained could be simply
filtered through a short silica gel plug and then subjected to
reactions with organometallics (Scheme 2, yields were not
optimized but examples are to demonstrate utility for high-
throughput synthesis). Thus, (E)-N-methoxy-N-methylbenz-
amide could be converted into benzophenone and n-but-
ylphenyl ketone, whereas N-methoxy-N-methyl-3-phenyl-
acrylamide was converted into chalcone and (E)-1-phenyl-
1-hepten-3-one.
supported PPh3 (Pol–PPh3) offered a simple solution. As
Table 2. Use of Pol–PPh3/I2 for the synthesis of amides and Wein-
reb amides.[a]
Next, we considered evaluating the use of the described
methodology for the synthesis of natural products where a
key step is amide formation. The first compound selected
was apocynin (acetovanillin), which possesses interesting
physiological activities. For example, it has been shown to
have vasodialatory properties possibly through inhibition of
Rho kinase activity,[43] antimetastatic activity against hu-
man lung cancer cells,[44] and inhibition of cartilage damage
caused by inflammation.[45] This compound has previously
been prepared by Grignard addition to vanillin acetate fol-
lowed by oxidation with DDQ,[46a] and by Yb(OTf)3-medi-
ated Friedel–Crafts reaction/demethylation of aryl methyl
ethers.[46b] As shown in Scheme 3, our formal synthesis of
apocynin involved the conversion of veratric acid (1) into
the corresponding Weinreb amide 2 by using 2 equiv. each
of PPh3 and I2, 1 equiv. each of carboxylic acid and Me-
(MeO)NH·HCl, and 2.5 equiv. of iPr2NEt (69% yield). Ad-
dition of MeMgBr to 2 then yielded 3Ј,4Ј-dimethoxyace-
tophenone (3, 97% yield). The conversion of 3 into apocy-
nin by selective demethylation by using NaSEt is known in
the literature.[47]
The second formal synthesis was that of pratosine, which
belongs to the family of Amaryllidaceae alkaloids, and sev-
eral members of this family possess high biological activity
(e.g. reversible inhibition of fertility in male rats[48a] and
antitumor activity[48b]). N-Acylindoline 4 has previously
been prepared by a Pd-catalyzed amidation.[49] In our ap-
proach, starting from veratric acid (1), amide 4 was synthe-
[a] Reactions were conducted by using 1 mmol each of Pol–PPh3
(2.28 mmol/g loading), I2, carboxylic acid, amine, and 1.5 mmol of
iPr2NEt in 4 mL of CH2Cl2, unless noted otherwise. [b] Yield ob-
tained by using 2 equiv. each of Pol–PPh3 and I2. [c] 2.5 equiv. of
iPr2NEt was used.
Scheme 2. Synthesis of ketones from Weinreb amides obtained through the use of Pol–PPh3/I2, followed by filtration through a silica gel
plug.
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A. Kumar, H. K. Akula, M. K. Lakshman
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products in CDCl3 matched those in the literature, only six
aromatic protons have been reported for each,[49] and this
corresponded to our observations. We wanted to ensure
that no undesired electrophilic reactions had occurred on
the aromatic ring in our cases. Therefore, we sought ad-
1
ditional data. When the H NMR spectra of 4 and 6 were
obtained in C6D6, an additional broad downfield proton
resonance was observed in each case (ca. δ = 8.1 ppm, see
spectra in the Supporting Information). Further, in the case
of 4, four distinct methoxy group resonances could be ob-
served at δ = 3.31, 3.30, 3.28, and 3.27 ppm. Heating the
C6D6 solutions to 70 °C resulted in a significant sharpening
of the broad, downfield aromatic resonances in 4 and 6. In
the case of 4, coalescence of the methoxy group resonances
to two major ones was also seen. The COSY spectra for 4
and 6 in C6D6 at 70 °C are fully consistent with their respec-
tive structures, and in each case long-range coupling of the
benzylic CH2 group to the ortho aromatic proton was ob-
served (see data in the Supporting Information).
Some of these properties are likely due to restricted rota-
tion induced by the amide linkage. Although, this in itself
is not surprising, it does raise a question about the effi-
ciency of the cyclization reaction by hypervalent iodine rea-
gents (e.g., 6 Ǟ anhydrolychorinone), which are conducted
at subambient temperatures. That is, in such cases an unfa-
vorably disposed rotamer could potentially influence the
yield of the cyclization step.
Scheme 3. Formal total syntheses of apocynin and pratosine.
sized by using of 1 equiv. each of PPh3/I2/carboxylic acid/
indoline and 1.5 equiv. of iPr2NEt (83% yield). Conversion
of 4 to pratosine has been reported.[49]
As a third example to showcase the amidation step, we
completed the synthesis of anhydrolychorinone and hippad-
ine (Scheme 4). Here again lynchpin N-acyl amide 6 was
previously synthesized by Pd-catalyzed amidation.[49] We
conducted amide formation by using 1 equiv. each of PPh3/
I2/piperonylic acid/indoline and 1.5 equiv. iPr2NEt, or with
the use of Pol–PPh3 in place of PPh3 under otherwise iden-
tical conditions. Consistent with the results in Tables 1 and
2, yields from both methods were comparable: 70% from
solution chemistry and 74% with Pol–PPh3. Further con-
versions were conducted as reported.[49] Oxidation of 6 to
anhydrolychorinone proceeded in 23% yield by using PhI-
(OCOCF3)2 and BF3·Et2O (83% reported in the litera-
ture[49]), and DDQ olefination proceeded in 78% yield
(80% reported in the literature[49]) to yield hippadine.
Attempts at Understanding the Reaction Intermediates
As shown in Scheme 1, an acyl phosphonium species
and/or an acyl iodide could be potential intermediates in
this amidation. Acyl phosphonium intermediates have been
invoked previously in the synthesis of esters, amides, and
acyl azides.[10,14,40,50] On the other hand, acyl chlorides and
acyl bromides have been prepared by reaction of acids with
PPh3/Cl3CCN[51] and PPh3/Br3CCO2Et,[52] respectively.
Thus, we questioned whether acyl phosphonium intermedi-
ates could be directly observed by 31P{1H} NMR spec-
troscopy.
A solution of PPh3 in CD2Cl2 at room temperature pro-
duced a sharp singlet at δ = –5.0 ppm. Addition of I2
(1 equiv.) led to rapid disappearance of the phosphane sig-
nal and appearance of a new resonance at δ = –18.4 ppm,
presumably due to the formation of (Ph3P+–I)I–.[5] Addition
of PhCO2H to this mixture led to no observable change
in the 31P resonance. However, upon addition of iPr2NEt
(1.5 equiv.), a new resonance was produced at δ = 30.1 ppm.
Finally, addition of pyrrolidine (1 equiv.) to this mixture led
to a very small upfield shift of the resonance (δ =
28.9 ppm). A similar result was obtained by using morph-
oline. Thus, it was not possible to establish exactly what
type of intermediate is involved.
Scheme 4. Syntheses of anhydrolychorinone and hippadine.
Therefore, in a second line of experimentation we ex-
During the course of our investigations we encountered posed 3,5-dinitrobenzoic acid to the Pol–PPh3/I2/iPr2NEt
some unusual 1H NMR spectroscopic characteristics of combination in the absence of pyrrolidine. After 1 h, the
amides 4 and 6. Although the 1H NMR spectra of our polymer was filtered, pyrrolidine was added to the filtrate,
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Simple Synthesis of Amides and Weinreb Amides
gel column (EtOAc/hexanes). Any deviations from this procedure
are noted in Table 1.
and the reaction was continued for an additional 1 h. The
amide from this reaction was isolated in 11% yield, which
is very low compared to that in Entry 3 in Table 2 (65%
yield in a reaction time of 1 h). One possible explanation
for the diminished yield could be the loss of the carboxylic
acid as a polymer-bound acyl phosphonium species. Had
acyl iodide been produced rapidly in the reaction, this
should have remained in solution, leading to a better out-
come. On the basis of this experiment, it is conceivable that
the amidation reaction described herein proceeds largely via
the intermediacy of an acyl phosphonium species, at least
when Pol–PPh3 is utilized.
Synthesis of Amides by Using Pol–PPh3/I2: To a stirring solution of
I2 (1.0 mmol) in dry CH2Cl2 (5 mL) at 0 °C was added Pol–PPh3
(1.0 mmol). The reaction mixture was flushed with nitrogen gas
and allowed to stir at 0 °C for 5 min. At this temperature, the car-
boxylic acid (1.0 mmol) was added followed by the dropwise ad-
dition of iPr2NEt (1.5 mmol) and the appropriate amine
(1.0 mmol). The reaction mixture was slowly brought to room tem-
perature and allowed to stir until no starting material could be seen
on TLC (see Table 2 for reaction times). The reaction mixture was
filtered and evaporated to dryness. The crude product was purified
through a short silica gel plug (EtOAc/hexanes). Any deviations
from this procedure are noted in Table 2.
Synthesis of Weinreb Amides by Using Pol–PPh3/I2: To a stirring
solution of I2 (1.0 mmol) in dry CH2Cl2 (5 mL) at 0 °C was added
Pol–PPh3 (1.0 mmol). The reaction mixture was flushed with nitro-
gen gas and allowed to stir at 0 °C for 5 min. At this temperature,
the carboxylic acid (1.0 mmol) was added followed by the dropwise
addition of iPr2NEt (2.5 mmol) and N,O-dimethylhydroxylamine
hydrochloride (1.0 mmol). The reaction mixture was slowly brought
to room temperature and allowed to stir until no starting material
could be seen on TLC (see Table 2 for reaction times). The reaction
mixture was filtered and evaporated to dryness. The crude product
was purified through a short silica gel plug (EtOAc/hexanes).
Conclusions
In summary, we have demonstrated that the combination
of PPh3/I2 or Pol–PPh3/I2 can be effectively utilized for the
synthesis of a wide range of amides. The advantage of the
PPh3/I2 combination is that the reagents are cheap and
easy-to-handle, and the reactions are straightforward to
conduct. In addition, the synthetically valuable N-methoxy-
N-methyl (Weinreb) amides can also be synthesized by
using this mild conversion, and simple purification allows
for their rapid use in further transformations. The useful-
ness of this procedure has been demonstrated through the
formal total synthesis of two natural products, apocynin
and pratosine, as well as to the total synthesis of anhydroly-
chorinone and hippadine, where amide formation is an im-
portant step. No problems were evident in any of the cases
reported.
N-(3,5-Dinitrobenzoyl)pyrrolidine: Purification of the crude product
obtained by the procedure described above on a silica gel column
(60% EtOAc in hexanes) afforded the title compound (84.3 mg,
83%) as a yellow foam. Rf (40% EtOAc in hexanes) = 0.35. 1H
NMR (500 MHz, CDCl3, ambient temperature): δ = 9.13 (s, 1 H,
Ar-H), 8.76 (s, 2 H, Ar-H), 3.74 (t, 3JH,H = 6.6 Hz, 2 H, pyrrolidin-
3
yl-H), 3.52 (t, JH,H = 6.6 Hz, 2 H, pyrrolidinyl-H), 2.09–2.01 (m,
4 H, pyrrolidinyl-H) ppm. 13C NMR (125 MHz, CDCl3, ambient
temperature): δ = 164.3, 148.3, 140.3, 127.5, 119.6, 49.5, 46.8, 26.4,
24.2 ppm. HRMS: calcd. for C11H12N3O5 [M + H]+ 266.0771;
found 266.0774.
Experimental Section
3Ј,4Ј-Dimethoxyacetophenone (3)
General Experimental Considerations: Thin-layer chromatography
was performed on 200 µm silica gel plates and column chromato-
graphic purifications were performed on 200–300 mesh silica gel.
CH2Cl2 and iPr2NEt were distilled from CaH2, and THF was dis-
tilled from LiAlH4 and freshly distilled from Na prior to use. All
other reagents were obtained from commercial sources and were
used without further purification. Pol–PPh3 (PS-triphenylphos-
phane, 2.28 mmol/g) was obtained from Biotage. 1H NMR spectra
were recorded at 500 MHz and are referenced to the residual pro-
tonated solvent. 31P{1H} NMR spectra were recorded at 202 MHz
and are referenced to 85% H3PO4 as external standard. Some rep-
resentative synthetic procedures are given below.
Step1 – Preparation of Weinreb Amide 2: In a clean, dry, 10-mL
round-bottomed flask equipped with a stirring bar were placed
PPh3 (526.0 mg, 2.0 mmol) and I2 (507.6 mg, 2.0 mmol) in dry
CH2Cl2 (6 mL). The reaction mixture was flushed with nitrogen
gas and allowed to stir at 0 °C for 5 min. At this temperature, verat-
ric acid (182.1 mg, 1.0 mmol) was added, followed by the dropwise
addition of iPr2NEt (434 µL, 2.5 mmol) and N,O-dimethylhydrox-
ylamine hydrochloride (97.5 mg, 1.0 mmol). The reaction mixture
was slowly brought to room temperature and allowed to stir for
1 h. The reaction mixture was diluted with water and extracted with
CH2Cl2. The organic layer was dried with anhydrous Na2SO4 and
evaporated under reduced pressure to afford the crude product.
Chromatographic purification on a silica gel column (40% EtOAc
in hexanes) afforded 2 (155.2 mg, 69%) as a viscous liquid. Rf (40%
Synthesis of Amides by Using PPh3/I2: In a clean, dry, 10-mL
round-bottomed flask equipped with a stirring bar were placed
PPh3 (1.0 mmol) and I2 (1.0 mmol) in dry CH2Cl2 (4 mL). The re-
action mixture was flushed with nitrogen gas and allowed to stir at
0 °C for 5 min. At this temperature, the carboxylic acid (1.0 mmol)
was added, followed by the dropwise addition of iPr2NEt
(1.5 mmol) and the appropriate amine (1.0 mmol). The reaction
mixture was slowly brought to room temperature and allowed to
stir until no starting material could be seen on TLC (see Table 1
for reaction times). The reaction mixture was diluted with water
and extracted with CH2Cl2. The organic layer was dried with anhy-
drous Na2SO4 and evaporated under reduced pressure to afford the
crude product, which was purified by chromatography on a silica
1
EtOAc in hexanes) = 0.55. H NMR (500 MHz, CDCl3, ambient
3
temperature): δ = 7.33 (d, JH,H = 8.4 Hz, 1 H, Ar-H), 7.22 (s, 1
H, Ar-H), 6.68 (d, 3JH,H = 8.4 Hz, 1 H, Ar-H), 3.86 (s, 3 H, OMe),
3.85 (s, 3 H, OMe), 3.52 (s, 3 H, N-OMe), 3.30 (s, 3 H, N-Me)
ppm.
Step 2 – Addition of MeMgBr to 2: In a clean, dry, 10-mL round-
bottomed flask equipped with a stirring bar was placed 2
(125.0 mg, 0.554 mmol) in dry THF (5.0 mL) under nitrogen gas,
and the mixture was cooled to –10 °C. At this temperature,
MeMgBr (554 µL, 1.66 mmol) was added dropwise, with stirring.
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A. Kumar, H. K. Akula, M. K. Lakshman
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The reaction mixture was slowly brought to 0 °C and allowed to
stir for 1 h. The reaction was quenched with saturated aqueous
NH4Cl (5 mL) and extracted with EtOAc (20 mL). The organic
layer was separated, dried with Na2SO4, and concentrated. Chro-
matographic purification on a silica gel column (35% EtOAc in
hexanes) afforded 3 (96.2 mg, 97%) as a colorless, viscous liquid.
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1
Rf (40% EtOAc in hexanes) = 0.62. H NMR (500 MHz, CDCl3):
3
δ = 7.49 (d, JH,H = 8.3 Hz, 1 H, Ar-H), 7.44 (s, 1 H, Ar-H), 6.81
3
(d, JH,H = 8.3 Hz, 1 H, Ar-H), 3.86 (s, 3 H, OMe), 3.85 (s, 3 H,
OMe), 2.48 (s, 3 H, COCH3) ppm. This compound is commercially
available.
N-(3,4-Dimethoxybenzoyl)indoline (4):[49] 1H NMR (500 MHz,
3
CDCl3, ambient temperature): δ = 7.21 (d, JH,H = 7.4 Hz, 1 H,
3
Ar-H), 7.16 (dd, JH,H = 1.8, 8.2 Hz, 1 H, Ar-H), 7.14 (s, 1 H, Ar-
3
H), 7.11 (br. s, 1 H, Ar-H), 7.00 (t, JH,H = 7.1 Hz, 1 H, Ar-H),
3
3
6.89 (d, JH,H = 8.2 Hz, 1 H, Ar-H), 3.66 (t, JH,H = 8.3 Hz, 2 H,
3
NCH2), 3.41 (s, 3 H, OCH3), 3.38 (s, 3 H, OCH3), 2.51 (t, JH,H
=
8.3 Hz, 2 H, CH2) ppm. 1H NMR (500 MHz, C6D6, 70 °C): δ =
7.94 (br. s, 1 H, Ar-H), 7.09 (s, 1 H, Ar-H), 7.04 (d, 3JH,H = 7.8 Hz,
3
3
1 H, Ar-H), 7.00 (t, JH,H = 7.8 Hz, 1 H, Ar-H), 6.91 (d, JH,H
=
3
7.3 Hz, 1 H, Ar-H), 6.83 (t, JH,H = 7.3 Hz, 1 H, Ar-H), 3.66 (t,
3JH,H = 8.3 Hz, 2 H, NCH2), 3.41 (s, 3 H, OCH3), 3.38 (s, 3 H,
3
OCH3), 2.51 (t, JH,H = 8.3 Hz, 2 H, CH2) ppm.
N-(Piperonoyl)indoline (6):[49] To a stirring solution of I2 (253.8 mg,
1.0 mmol) in dry CH2Cl2 (5 mL) at 0 °C was added Pol–PPh3
(438.0 mg, 1.0 mmol). The reaction mixture was flushed with nitro-
gen gas and allowed to stir at 0 °C for 5 min. At this temperature,
piperonylic acid (166.1 mg, 1.0 mmol) was added, followed by the
dropwise addition of iPr2NEt (260.0 µL, 1.5 mmol) and indoline
(112 µL, 1.0 mmol). The reaction mixture was slowly brought to
room temperature and allowed to stir for 2 h. The mixture was
filtered and evaporated to dryness. Chromatographic purification
on a silica gel column (30% EtOAc in hexanes) afforded 6
(199.2 mg, 74%) as a colorless solid. Rf (40% EtOAc in hexanes)
= 0.60. 1H NMR (500 MHz, CDCl3, ambient temperature): δ =
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3
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(t, JH,H = 7.4 Hz, 1 H, Ar-H), 6.85 (d, JH,H = 8.0 Hz, 1 H, Ar-
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3
H), 6.03 (s, 2 H, OCH2), 4.10 (t, JH,H = 7.9 Hz, 2 H, indolinyl-
H), 3.11 (t, JH,H = 7.9 Hz, 2 H, indolinyl-H) ppm. 1H NMR
3
(500 MHz, C6D6, 70 °C): δ = 7.93 (br. s, 1 H, Ar-H), 6.99 (t, 3JH,H
= 8.0 Hz, 1 H, Ar-H), 6.96 (s, 1 H, Ar-H), 6.89 (d, 3JH,H = 7.8 Hz,
3
3
1 H, Ar-H), 6.82 (t, JH,H = 7.3 Hz, 1 H, Ar-H), 6.51 (d, JH,H
7.8 Hz, 1 H, Ar-H), 5.29 (s, 2 H, OCH2), 3.51 (t, JH,H = 8.0 Hz,
2 H, NCH2), 2.45 (t, JH,H = 8.0 Hz, 2 H, CH2) ppm.
=
3
3
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR spectra of all amides and Weinreb
amides shown in Tables 1 and 2; 13C NMR spectrum of N-(3,5-
1
dinitro)benzoylpyrrolidine; H NMR spectra of 3, 4, 6, anhydroly-
1
chorinonine and hippadine; H–1H COSY spectra of 4 and 6.
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Partial support of this work by the National Science Foundation
(NSF) (Grant CHE-0640417), the National Institutes of Health
(NIH) (Grant 5S06 GM008168-30), and a PSC CUNY award to
M. K. L. is acknowledged. Mr. Tom Melninkaitis and Mr. Scott
Klepfer (Biotage) are thanked for a sample of Pol–PPh3 (PS-tri-
phenylphosphane) used in this work, and Dr. Padmanava Pradhan
is thanked for his assistance with some NMR experiments. Infra-
structural support was provided by Research Centers at Minority
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Published Online: April 7, 2010
Eur. J. Org. Chem. 2010, 2709–2715
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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