On the phenyliodine(III)-bis(trifluoroacetate)-mediated olefin amidohydroxylation reaction

Article abstract of DOI:10.1002/ejoc.200600782

When appropriately substituted amides are treated with PIFA in a non-nudeophilic solvent like trifluoroethanol, a stable N-acylnitrenium ion is generated. If under such conditions a C=C double bond is present in the molecule, an intramolecular cyclization

Full text of DOI:10.1002/ejoc.200600782

FULL PAPER
DOI: 10.1002/ejoc.200600782
On the Phenyliodine(III)-Bis(trifluoroacetate)-Mediated Olefin
Amidohydroxylation Reaction
Imanol Tellitu,*[a] Andrea Urrejola,[a] Sonia Serna,[b] Isabel Moreno,[a] M. Teresa Herrero,[a]
Esther Domínguez,*[a] Raul SanMartin,[a] and Arkaitz Correa[a]
Keywords: Hypervalent iodine / Pyrrolidines / N-Acylnitrenium / PIFA / Cyclization
When appropriately substituted amides are treated with PIFA
in a non-nucleophilic solvent like trifluoroethanol, a stable
N-acylnitrenium ion is generated. If under such conditions a
fered to conclude that, according to our assumption, an ionic
mechanism rather than a radical one must be considered.
Additionally, a study of the scope of this cyclization protocol
C=C double bond is present in the molecule, an intramolecu- is conducted using substrates with different substituents
lar cyclization process takes place in an exo mode with ad-
ditional generation of a hydroxy group at the terminal posi-
tion of the original olefin moiety to render a series of pyrrol-
idine and piperidine derivatives. In this paper, proofs are of-
either on the amidic nitrogen or all along the carbon chain.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
associated to them. And, secondly, in spite of the growing
amount of novel applications shown by the specialized lit-
erature, there is still much reactivity of the IIII or IV reagents
to be discovered.[6] In this context, our group started a re-
search program directed to expand the applicability of
phenyliodine(III) bis(trifluoroacetate) (PIFA), one of the
most active members of this family of compounds, in het-
erocyclic chemistry. Originally, we drew our attention to the
PIFA-promoted intramolecular aromatic amidation reac-
tion (see Figure 1), which turned out to be an efficient and
productive way to form series of quinoline and benzodi-
azepine derivatives of general type 3.[7] From the mechan-
istic point of view, it is suggested that when the mildly oxi-
dant IIII reagent reacts with N-methoxy-substituted amides
of type 1, N-acylnitrenium intermediates 2 are generated.[8]
Finally, in the presence of nucleophilic species (i.e. arene or
heteroaromatic rings), the so-obtained electrophilic inter-
mediates are trapped intramolecularly to form new C–N
linkages.[9]
Introduction
The formation of C–N bonds is one of the fundamental
issues in organic synthesis. Displacements by nitrogen con-
taining nucleophiles,[1] Curtius or Beckmann rearrange-
ments of carbonyl compounds,[2] nucleophilic attack to un-
saturated C–N bonds, and reductive amination of aldehydes
and ketones compiles the majority of the most popular pro-
cedures developed to carry out this task. Nevertheless, the
amination at non-oxygenated carbon positions without the
formation of by-products is an unusual transformation.[3]
In this context, amination of double C–C bonds encom-
passes an attractive approach with atom economy, although
it requires activation of either the double bond or the nitro-
gen functionality as a result of electrostatic repulsion be-
tween both groups. Besides, the 2+2 addition of the amine
and the olefin is considered to be a forbidden process due
to the large energy difference between the π(C=C) and the
σ(N–H) orbitals.[4]
The use of hypervalent iodine reagents has gained over
the last years an increasing number of adepts among the
organic synthetic chemists for several reasons.[5] Firstly, we
can benefit from the clean transformations usually
achieved, the mild conditions required, and the low toxicity
[a] Departamento de Química Orgánica II, Facultad de Ciencia y
Tecnología, Universidad del País Vasco – Euskal Herriko
Unibertsitatea (UPV/EHU)
Figure 1. Intramolecular reaction of (hetero)aromatic rings with N-
acylnitrenium ions generated by PIFA.
P. O. Box 644, 48080 Bilbao, Spain
Fax: +34-94-601-2748
E-mail: imanol.tellitu@ehu.es
In order to enrich this strategy in the field of heterocyclic
synthesis, we envisioned that olefin residues might play a
similar role as the nucleophilic partner of the reaction. In
fact, we have recently found that when ortho-substituted vi-
[b] Planta Piloto de Química Fina, Universidad de Alcalá de
Henares,
28871 Alcalá de Henares, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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nyl or allyl benzamides are treated with PIFA, isoindolin- application of the cyclization conditions followed by treat-
ones and isoquinolinones are obtained, respectively, prov- ment with the complex BH3·SMe2, as a convenient reducing
ing the certainty of our assumption.[10] At the same time agent, rendered nicely the 5-hydroxymethylpyrrolidine de-
this research was being conducted, a beautiful contribution rivative 6a as a pure and stable product. This selected pro-
by the group of Nicolaou on the IBX [1-hydroxy-1,2-benz- tocol was then applied to the series of amides 5b–g.
iodoxol-3(1H)-one 1-oxide] mediated olefin amidation to
form δ-lactames, cyclic carbamates, 1,2-hydroxyamines, and
amino sugars from the corresponding N-arylamides was
published.[11] In that work, and contrarily to our own re-
sults, they also tested the action of PIFA on N-phenyl-4-
pentenamide (5b, in this paper) with unproductive results.
Alerted by this apparent contradiction with our initial
promising results, we considered that a deeper study on the
PIFA-mediated olefin amidohydroxylation reaction was re-
quired. In this paper we now explore the mechanistic in-
sights, as well as the scope and applicability, of the pre-
sented reaction.
Results and Discussion
The first issues we had to address in our investigation
Scheme 2. PIFA-mediated cyclization of linear unsaturated amides
were referred to the nature of the N-substituent and the 5a–f. Reagents and conditions: i) PIFA, CF3CH2OH, –20 °C;
ii) BH3·SMe2, THF, 0 °C Ǟ room temperature (80% for 6a; 82%
for 6b; 70% for 6c; 83% for 6d).
tolerable length of the carbon chain in such a way that the
preparation of β-lactam, pyrrolidine, and piperidine skel-
etons could be at hand assuming a selective exo cyclization
Thus, as shown in Scheme 2, it was found that pyrrol-
mode for each case. Therefore, aromatic amides 5a–e were
idine 6a and piperidine 6c were obtained in good overall
prepared in satisfactory yields from unsaturated carboxylic
yields through 5-exo-trig and 6-exo-trig cyclization modes,
acids 4a–c, as shown in Scheme 1, by previous activation as
respectively.[16] Conversely, an analogous 4-exo-trig process
acyl chlorides followed by treatment with the corresponding
was not favored and the formation of the desired β-lactam
amines.[12] Additionally, aliphatic amides 5f,g were also pre-
could not be detected. Instead, compound 6eЈ was ob-
pared for comparative studies.[13]
tained, which can be considered as an evidence of the gener-
ation of an intermediate species (see intermediate C in
Scheme 3) with a positive charge delocalized on the aro-
matic ring.[17] On the other hand, the need for an amide
substituent of aromatic nature was corroborated by the for-
mation of N-phenyl, N-para-methoxyphenyl, or N-naph-
thyl-substituted heterocycles 6a–d, along with the formation
of lactone 6fЈ (instead of the expected pyrrolidine) when
Scheme 1. Preparation of linear unsaturated amides 5a–g. Reagents
and conditions: i) (a) (COCl)2, CH2Cl2, room temperature; (b)
RNH2, pyridine, CH2Cl2, room temperature (87% for 5a; 82% for
5b; 98% for 5c; 80% for 5d; 72% for 5e; 78% for 5f; 64% for 5g).
starting from the N-alkyl-substituted precursors 5f,g.
An explanation for these divergent results could be pro-
posed by inspection of the mechanistic insights of this IIII
-
mediated amidohydroxylation. As it has been mentioned
The search for the optimal cyclization conditions was above, although substrate 5a resulted to be inert when
conducted using amide 5a as a model compound by varying dichloromethane was employed as solvent, the solution
the solvent, temperature, and the presence of additives. took a deep blue coloration that lasted for longer than 24
Thus, complete recovery of the starting material was at- hours after addition of PIFA. Consequently, the generation
tained when amide 5a was submitted to the action of PIFA of radical species was searched by EPR spectroscopy[18]
in CH2Cl2 as solvent under different temperatures. This re- and, as expected, a triplet with aN value of 0.8 mT was ob-
sult did not change neither when TiCl4 was used addition- served, which is in good agreement with the presence of a
ally nor when the reaction was run in the presence of nitrogen-centered radical of type B (Figure 2),[19] which re-
BF3·OEt2.[14] In the latter case, a complex mixture of poly- sults to be unproductive in this reaction.
meric nature was isolated. Fortunately, the selection of tri-
Thus, in the absence of radical species when the reaction
fluoroethanol as the solvent, in the absence of additives, takes place in trifluoroethanol, and considering the key im-
was crucial for a clean transformation of the starting mate- portance of the aryl group in the success of this reaction, we
rial. However, the putative product A obtained (see suggest that the mechanism for the intramolecular PIFA-
Scheme 2) could not be purified and fully characterized due mediated olefin amidohydroxylation can be described as
to its high instability.[15] Notwithstanding, it was found that follows (see Scheme 3).[20] Once the acyl-nitrenium ion C,
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PIFA-Mediated Olefin Amidohydroxylation Reaction
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diate E either suffers migration to the more stable interme-
diate F, which is attacked by a trifluoroacetate group deliv-
ered by PIFA to form the heterocyclic core G, or it goes
directly to G. This labile trifluoroester is hydrolyzed during
the basic work up (Na2CO3, H2O) to render, after borane
reduction, the pyrrolidine or piperidine derivatives 6a–d.
From the mechanistic proposal it also seems reasonable
that a bicycle intermediate of type E derived from buten-
amide 5e would be too strained to exist, which explains its
apparent unfeasibility to render a cyclic derivative of β-lac-
tamic nature under the explored conditions. On the other
hand, the cyclohexyl or methyl groups in amides 5f,g,
respectively, do not allow an extended delocalization of the
positive charge, which precludes the formation of the corre-
sponding intermediate C. Consequently, instead of pyrrol-
idine formation, the reaction takes place through an alter-
native pathway, which includes olefin activation instead of
nitrogen oxidation, leading to lactone 6fЈ, as it is proposed
in Scheme 4.[21]
Scheme 3. Proposed mechanism for the intramolecular olefin ami-
dohydroxylation.
Scheme 4. Proposed mechanism for the transformation of amides
5f,g into lactone 6fЈ.
In order to explore the suitability of the presented cycli-
zation for the access to a wide range of differently substi-
tuted pyrrolidine derivatives, a series of amides 8a–k was
prepared from the required precursors following different
routes. Thus, while carboxylic acids 7a,b,d,k could be pur-
chased from different sources, carboxylic acids 7c,e–j were
prepared by known procedures including Claisen rearrange-
ment of the corresponding allylic alcohols, allylic alkylation
of the related acetic acids,[22] or alkylation of diethyl malon-
ate with 2,3-dibromopropene followed by decarboxylation
as for 8h.[23] Finally, their transformation into amides 8a–k
was carried out by classical methods.[24]
Next, the cyclization protocol (one-pot treatment with
PIFA followed by reduction with borane) was applied to the
series of amides 8a–k prepared (see Table 1). After careful
optimization of the particular reaction conditions for each
case, the formation of pyrrolidines 9a–c,f,g was achieved in
Figure 2. EPR spectrum of the amidyl radical B.
generated from 5a–d by the action of PIFA, is formed and moderate to good yields. In particular, the generation of
intramolecularly trapped by the olefin fragment in an exo a quaternary carbon center (see 9c) was not problematic.
mode, a primary carbocation D is formed and stabilized by Conversely, we can suggest no reason for the fact that
the adjacent aryl group in a neighboring group participa- amides 8d, and 8,i,j suffered from complete degradation,
tion. Now, it could be suggested that the resulting interme- without detection of heterocycle formation, considering
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Table 1. PIFA-mediated cyclization of γ,δ-unsaturated amides 8a–k.
[a] R = OH, carboxylic acids 7; R = NHPMP, amides 8. [b] Isolated yield after purification by flash chromatography. [c] A complex
mixture of products was obtained. [d] Amide 8g was directly prepared from the corresponding commercially available methyl ester (see
supporting information). [e] Stereochemical elucidation has been possible only with 8g. Major diastereoisomer is represented.
that they would go, respectively, through more favored sec-
ondary and benzylic carbocations of type D. In a similar
way, the deactivation of the nucleophilic character of the
olefin by the bromine atom in substrate 8h can also explain
that the expected pyrrolidine 9h was not formed. It must be
pointed out that, contrary to 9g (dr = 5.6:1) and 9k (dr
= 100:0), pyrrolidines 9a,b,f were obtained as inseparable
mixture of diastereoisomers in variable proportions.[25] On
the other hand, amide 8k rendered the expected bicycle 9k,
along with its unsaturated derivative 11, as a single dia-
stereoisomer. This latter result, although synthetically use-
less, is quite coherent with our mechanistic proposal as ex-
pressed in Scheme 5. If we assumed the formation of the
putative intermediate J (see F in Scheme 3), a nucleophilic
attack, or deprotonation followed by elimination processes
would render, respectively, cyclopenta[b]pyrroles 9k and 11.
Scheme 5. Proposed mechanism for the formation of bicycles 9k
and 11.
In addition, the unique behavior of amide 8e was evi-
denced by its transformation into the conjugated dienamide
10.[26] In this particular case, we presume that, due to the
electronically enriched olefin, activation of the double bond tertiary allylic carbocation N, which suffers deprotonation
by the hypervalent iodine reagent, instead of nitrogen oxi- to render the final compound.
dation, is the favored process (see Scheme 6). An internal
In an attempt to modify the electronic character around
nucleophilic attack in iodonium salt K, followed by elimi- the double bond, we considered that application of the cy-
nation of iodobenzene and a reopening process, leaves a clization conditions on 4-aryl-substituted amides 8l–o would
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and reduction steps leave an equilibrium mixture of the cy-
clic amino alcohol S and linear amino ketone T giving rise
to the final amino alcohols 12a–d due to the excess of the
employed reducing agent.[27] Considering the ability of the
aryl ring to stabilize the newly created positive charge and,
hence, to migrate through the formation of phenonium ion
Q, the whole process should be more favored with electron-
enriched rings.[28] In fact, the so-obtained yields for each
particular aryl ring can be used to support the mechanistic
proposal.
Scheme 6. Proposed mechanism for the formation of diene 10.
be of interest. A Suzuki coupling process between amide
8h and the corresponding boronic acids was the selected
approach to prepare this series of amides, as it is expressed
in Scheme 7. Contrary to our expectations, treatment of
amides 8l–o with PIFA in trifluoroethanol as solvent did
not render the desired pyrrolidine derivatives of type 9. In-
stead, linear amino alcohols 12a–d were obtained in all
cases, which were identified after extensive spectroscopic
and mass spectrometric analyses. An explanation for this
unusual result can be proposed as indicated in Scheme 8.
We suggest that an aryl migration can take place from the
Scheme 8. Proposed mechanism for the transformation of amides
8l–o into amino alcohols 12a–d.
initial cyclic intermediate
P (see intermediate D in
In conclusion, the powerful potential of the hypervalent
iodine reagent PIFA in organic synthesis, which includes
its ability to generate N-acylnitrenium ions from adequately
substituted amides, has been employed satisfactorily in the
preparation of a series of pyrrolidine and piperidine deriva-
tives from the corresponding γ,δ- and δ,ω-unsaturated
amides. A mechanistic study of the PIFA mediated olefin
amidohydroxylation reaction has been conducted to dem-
onstrate that a radical pathway can be ruled out. The mild
conditions that the cyclization reaction under study requires
will probably find prompt applications in the synthesis of a
number of nitrogen containing heterocycles of higher com-
plexity. Finally, the treatment of 4-aryl-substituted amides
under the described reaction conditions represents a new
entry to the synthesis of linear and highly functionalized
amino alcohols.
Scheme 3) through formation of a phenonium ion of type
Q, which reacts with a trifluoroacetate group delivered by
PIFA to render the trifluoroester R. Additional hydrolysis
Experimental Section
Scheme 7. Synthesis and reactivity of 4-aryl-substituted γ,δ-unsatu-
rated amides 8l–o. Preparation of amino alcohols 12a–d. Reagents
and conditions: i) ArB(OH)2, Pd(PPh3)4, K2CO3, DMF/H2O, 50 °C
(63% for 8l; 63% for 8m; 52% for 8n; 61% for 8o); ii) PIFA,
CF3CH2OH, 0 °C; (iii) BH3·SMe2, THF, 0 °C Ǟ room temperature
(37% for 8l; 65% for 8m; 83% for 8n; 20% for 8o).
Typical Procedure for the PIFA-Mediated Cyclization of Unsatu-
rated Amides 5a–f and 8a–k. Synthesis of 2-(Hydroxymethyl)-N-(4-
methoxyphenyl)pyrrolidine (6a): A solution of PIFA (438 mg,
1.02 mmol) in 10 mL of CF3CH2OH was added onto a cold
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(–20 °C) solution of amide 5a (139 mg, 0.68 mmol) in 7 mL of the
same solvent, and the mixture was stirred until total consumption
of the starting material (tlc, 80 min). Then, 10 mL of Na2CO3 (aq.
10%) were added and the aqueous phase was extracted with
CH2Cl2 (3ϫ15 mL). The combined organic extracts were washed
with a saturated solution of NaCl (15 mL), dried with Na2SO4,
filtered, and the solvent was removed under vacuum. Without any
further purification, the resulting residue was dissolved in THF
(4 mL), cooled to 0 °C, and BH3·SMe2 (3.4 mL, 2  in THF,
6.8 mmol) was added dropwise. The reaction mixture was stirred
at room temperature until total consumption of the starting mate-
rial (tlc, 10 h). Then, MeOH was added slowly and the stirring was
continued for 15 min. The solvent was removed under vacuum, and
treatment with MeOH was repeated twice more. The final residue
was purified by column chromatography (EtOAc/MeOH, 96:4) to
afford pyrrolidine 6a as a pale brown oil (113 mg, 80%). 1H NMR
(250 MHz, CDCl3, 20 °C): δ = 1.38–1.54 (m, 2 H), 1.56–1.75 (m, 2
H), 2.93–3.08 (m, 2 H), 3.40 (dd, J = 11.1, 7.5, Hz 1 H), 3.52 (br.
s, 1 H), 3.59 (dd, J = 11.1, 2.8 Hz, 1 H), 3.63–3.73 (m, 4 H), 6.60
(d, J = 9.1 Hz, 2 H), 6.77 (d, J = 9.1 Hz, 2 H) ppm. 13C NMR
(62.9 MHz, CDCl3, 20 °C): δ = 25.8, 30.8, 45.3, 55.7, 66.7, 71.9,
N-(2-Hydroxy-4-methoxyphenyl)-3-butenamide (6eЈ): According to
the typical procedure (in the absence of treatment with borane),
amide 6eЈ (56 mg) was obtained from amide 5e (191 mg, 1 mmol)
in 27% yield as a yellowish solid after purification by column
chromatography (hexanes/EtOAc, 1:1). 1H NMR (250 MHz,
CDCl3, 20 °C): δ = 3.18 (d, J = 7.1 Hz, 2 H), 3.71 (s, 3 H), 5.25–
5.32 (m, 2 H), 5.88–6.05 (m, 1 H), 6.38 (dd, J = 8.7, 2.8 Hz, 1 H),
6.51 (d, J = 2.8 Hz, 1 H), 7.02 (d, J = 8.7 Hz, 1 H), 8.07 (br. s, 1
H), 9.09 (br. s, 1 H) ppm. 13C NMR (62.9 MHz, CDCl3, 20 °C): δ
= 41.3, 55.3, 103.9, 106.3, 118.8, 120.8, 122.9, 130.3, 149.6, 158.6,
170.7 ppm. IR (KBr): ν = 3500–3150, 1651, 1607, 1530 cm–1. MS
˜
(EI): m/z (%) = 207 (25) [M+], 139 (100), 124 (59). HRMS calcd.
for C11H12NO2 (M+ – OH) 190.0868, found 190.0858.
5-(Hydroxymethyl)-4,5-dihydrofuran-2-one (6fЈ): According to the
typical procedure (in the absence of treatment with borane), fu-
ranone 6fЈ (55 mg) was obtained from amide 5f (181 mg, 1 mmol)
in 47% yield (or from amide 5g in 35% yield) as colorless oil after
purification by column chromatography (EtOAc/MeOH, 95:5). All
spectroscopic data was in agreement with the literature.[29]
2-(Hydroxymethyl)-N-(4-methoxyphenyl)-4-methylpyrrolidine (9a):
According to the typical procedure, pyrrolidine 9a was obtained
from amide 8a (219 mg, 1 mmol) carrying out the reaction at 0 °C.
The final residue was purified by column chromatography (EtOAc)
to afford pyrrolidine 9a as a pale brown oil (119 mg, 54%). Mixture
114.8, 142.2, 152.4 ppm. IR (film): ν = 3500–3000, 1508 cm–1. MS
˜
(EI): m/z (%) = 225 (21) [M+ + 18], 207 (1) [M+], 136 (100). HRMS
calcd. for C12H17NO2 207.1259, found 207.1269.
2-(Hydroxymethyl)-N-phenylpyrrolidine (6b): According to the typi-
cal procedure, pyrrolidine 6b (145 mg) was obtained from amide 5b
(175 mg, 1 mmol) in 82% yield as a brown oil after purification by
column chromatography (CH2Cl2/EtOAc, 3:7). 1H NMR
(250 MHz, CDCl3, 20 °C): δ = 1.42–1.76 (m, 4 H), 3.02–3.08 (m, 2
H), 3.38 (dd, J = 11.5, 7.5 Hz, 1 H), 3.42 (br. s, 1 H), 3.53–3.71
(m, 2 H), 6.60 (d, J = 7.5 Hz, 2 H), 6.71 (t, J = 7.5 Hz, 1 H), 7.16
(t, J = 7.5 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3, 20 °C): δ
= 25.6, 30.6, 43.9, 66.6, 71.9, 113.0, 117.5, 129.2, 148.2 ppm. IR
1
of diastereoisomers: 1.4:1. H NMR (250 MHz, CDCl3, 20 °C): δ
= 0.97–1.00 (m, 2ϫ3 H), 1.25–1.30 (m, 2ϫ1 H), 1.42–1.47 (m,
2ϫ1 H), 1.90–1.95 (m, 2ϫ1 H), 2.84–3.01 (m, 2ϫ2 H), 3.35–3.43
(m, 2ϫ3 H), 3.73–3.90 (m, 2ϫ4 H), 6.61–6.64 (m, 2ϫ2 H), 6.67
(d, J = 8.7 Hz, 2ϫ2 H) ppm. 13C NMR (62.9 MHz, CDCl3, 20 °C):
δ = 18.7, 18.9, 29.5, 30.6, 38.1, 38.9, 51.2, 52.5, 55.6, 66.7, 67.2,
69.7, 70.3, 114.6, 114.7, 115.0, 142.1, 142.3, 152.2, 152.4 ppm. IR:
ν = 500–3150, 1512 cm–1. MS (EI): m/z (%) = 239 (12) [M+ + 18],
˜
221 (1) [M+], 136 (100), 108 (10). HRMS calcd. for
(film): ν = 3550–3100, 1506 cm–1. MS (EI): m/z (%) = 195 (15) [M+
˜
C13H19NO2·H2O (M+ + H2O) 239.1521, found 239.1518.
+ 18], 177 (1) [M+], 106 (100). HRMS calcd. for C11H15NO
177.1154, found 177.1153.
2-(Hydroxymethyl)-N-(4-methoxyphenyl)-3-methylpyrrolidine (9b):
According to the typical procedure, pyrrolidine 9b was obtained
from amide 8b (219 mg, 1 mmol), carrying out the reaction at 0 °C.
The final residue was purified by column chromatography (EtOAc)
to afford pyrrolidine 9a as a pale brown oil (115 mg, 52%). Mixture
2-(Hydroxymethyl)-N-(4-methoxyphenyl)piperidine (6c): According
to the typical procedure, piperidine 6c (155 mg) was obtained from
amide 5c (219 mg, 1 mmol) in 70% yield as a brown solid after
purification by column chromatography (EtOAc) followed by
crystallization from pentane. M.p. 42–44 °C (n-pentane). 1H NMR
(250 MHz, CDCl3, 20 °C): δ = 1.45–1.62 (m, 6 H), 2.86 (br. s, 1
H), 3.04–3.09 (m, 2 H), 3.41 (dd, J = 10.7, 7.3 Hz, 1 H), 3.59–3.74
(m, 5 H), 6.58 (d, J = 9.1 Hz, 2 H), 6.77 (d, J = 9.1 Hz, 2 H) ppm.
13C NMR (62.9 MHz, CDCl3, 20 °C): δ = 23.0, 29.3, 32.6, 44.8,
1
of diastereoisomers: 2.3:1. H NMR (250 MHz, CDCl3, 20 °C): δ
= 0.90–0.94 (m, 2ϫ3 H), 1.63–1.82 (m, 2ϫ3 H), 2.98–3.16 (m,
2ϫ2 H), 3.49–3.73 (m, 2ϫ7 H), 6.59–6.62 (m, 2ϫ2 H), 6.76–6.79
(m, 2ϫ2 H) ppm. 13C NMR (62.9 MHz, CDCl3, 20 °C): δ = 14.5,
16.0, 29.7, 33.0, 33.8, 34.5, 43.1, 43.3, 55.7, 62.5, 64.7, 75.2, 76.0,
114.8, 115.0, 142.2, 152.4, 152.5 ppm. IR: ν = 500–3150, 1514 cm–1.
˜
55.7, 66.6, 76.5, 114.2, 114.8, 142.5, 152.0 ppm. IR (KBr): ν =
˜
MS (EI): m/z (%) = 239 (8) [M+ + 18], 221 (2) [M+], 136 (100), 108
(15). HRMS calcd. for C13H19NO2·H2O (M+ + H2O) 239.1521,
found 239.1522.
3500–3150, 1513 cm–1. MS (EI): m/z (%) = 239 (10) [M+ + 18], 201
(28), 199 (82), 136 (100), 108 (27). HRMS calcd. for
C13H19NO2·H2O (M+ + H2O) 239.1521, found 239.1537.
2-(Hydroxymethyl)-N-(1Ј-naphthyl)pyrrolidine (6d): According to
the typical procedure, pyrrolidine 6d (188 mg) was obtained from
amide 5d (225 mg, 1 mmol) in 83% yield as brownish oil after puri-
fication by column chromatography (EtOAc). 1H NMR (250 MHz,
CDCl3, 20 °C): δ = 1.56–1.61 (m, 2 H), 1.80–1.90 (m, 2 H), 3.25–
3.29 (m, 2 H), 3.42–3.46 (m, 1 H), 3.61–3.65 (m, 1 H), 3.74–3.75
2-(Hydroxymethyl)-N-(4-methoxyphenyl)-2-methylpyrrolidine (9c):
According to the typical procedure, pyrrolidine 9c was obtained
from amide 8c (219 mg, 1 mmol) carrying out the reaction at room
temperature. The final residue was purified by column chromatog-
raphy (hexanes/EtOAc, 6:4) to afford pyrrolidine 9c as a pale brown
oil (162 mg, 74%). 1H NMR (250 MHz, CDCl3, 20 °C): δ = 1.16
(m, 1 H), 6.60–6.61 (m, 1 H), 7.23–7.24 (m, 1 H), 7.32–7.36 (m, 1 (s, 3 H), 1.55–1.73 (m, 4 H), 2.65 (br. s, 1 H), 3.09–3.12 (m, 2 H),
H), 7.40–7.45 (m, 2 H), 7.77–7.81 (m, 2 H) ppm. 13C NMR
(62.9 MHz, CDCl3, 20 °C): δ = 25.3, 30.6, 44.0, 66.6, 71.9, 104.4,
117.3, 119.9, 123.4, 124.6, 125.7, 126.5, 128.6, 134.2, 143.4 ppm.
3.43 (t, J = 10.7 Hz, 2 H), 3.74 (s, 3 H), 6.60 (d, J = 8.9 Hz, 2 H),
6.78 (d, J = 8.9 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3,
20 °C): δ = 23.2, 23.8, 36.1, 45.7, 55.7, 69.8, 72.5, 114.6, 114.8,
IR (KBr): ν = 3500–3150 cm–1. MS (EI): m/z (%) = 245 (73) [M+
142.3, 152.3 ppm. IR: ν = 400–3100, 1513 cm–1. MS (EI): m/z (%)
˜
˜
+ 18], 157 (13), 156 (100), 129 (29), 115 (10). HRMS calcd. for
C15H17NO 227.1314, found 227.1310.
= 239 (66) [M+ + 18], 136 (100). HRMS calcd. for C13H19NO2·H2O
(M+ + H2O) 239.1521, found 239.1520.
442
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 437–444

PIFA-Mediated Olefin Amidohydroxylation Reaction
FULL PAPER
N-(4-Methoxyphenyl)-5-methylhexa-2,4-dienamide (10): According
to the typical procedure, amide 10 was obtained from amide 8e
(233 mg, 1 mmol) carrying out the reaction at 0 °C without further
reduction. The final residue was purified by column chromatog-
raphy (EtOAc) to afford amide 10 as a brownish liquid (176 mg,
152.2 ppm. IR: ν = 450–3100, 1508 cm–1. MS (EI): m/z (%) = 285
˜
(7) [M+], 176 (99), 136 (100), 91 (84). HRMS calcd. for C18H23NO2
285.1729, found 285.1724.
1-(p-Methoxyphenyl)-5-(p-methoxyphenylamino)-2-pentanol (12b):
According to the typical procedure, alcohol 12b was obtained from
amide 8m (311 mg, 1 mmol) carrying out the reaction at 0 °C. The
final residue was purified by column chromatography (EtOAc) to
afford alcohol 12b as a pale brown solid (205 mg, 65%). M.p. 88–
90 °C (hexanes). 1H NMR (250 MHz, CDCl3, 20 °C): δ = 1.53–
1.82 (m, 4 H), 2.60–264 (m, 1 H), 2.75–2.79 (m, 1 H), 3.09–3.12
(m, 2 H), 3.75 (s, 3 H), 3.80 (s, 3 H), 6.59 (d, J = 7.8 Hz, 2 H),
6.78 (d, J = 7.8 Hz, 2 H), 6.86 (d, J = 7.4 Hz, 2 H), 7.13 (d, J =
7.4 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3, 20 °C): δ = 26.1,
34.3, 43.2, 55.2, 55.8, 72.5, 114.0, 114.4, 114.9, 130.3, 130.3, 142.4,
1
76%). H NMR (250 MHz, CDCl3, 20 °C): δ = 1.84 (s, 3 H), 1.89
(s, 3 H), 3.78 (s, 3 H), 5.58 (d, J = 11.4 Hz, 1 H), 6.76 (d, J =
11.4 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 2 H), 7.29 (s, NH), 7.34 (d, J =
11.4 Hz, 1 H), 7.47 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR (62.9 MHz,
CDCl3, 20 °C): δ = 18.1, 26.7, 55.4, 114.6, 117.7, 121.6, 121.8,
131.2, 138.0, 145.4, 156.2, 164.9 ppm. IR: ν = 514 cm–1. MS (EI):
˜
m/z (%) = 231 (25) [M+], 123 (100), 108 (36). HRMS calcd. for
C14H17NO2 231.1259, found 231.1262.
4-tert-Butyl-2-(hydroxymethyl)-N-(4-methoxyphenyl)pyrrolidine
(9g): According to the typical procedure, pyrrolidine 9g (110 mg)
was obtained from amide 8g (261 mg, 1 mmol) in 42% yield as a
brown oil after purification by column chromatography (hexanes/
EtOAc, 4:6). Mixture of diastereoisomers: 5.6:1. 1H NMR
(250 MHz, CDCl3, 20 °C): δ = 0.93 (s, 9 H), 1.22–1.31 (m, 1 H),
1.47–1.52 (m, 1 H), 1.62–1.70 (m, 1 H), 2.70–2.76 (m, 1 H), 3.18–
3.22 (m, 1 H), 3.38–3.44 (m, 1 H), 3.50–3.55 (m, 1 H), 3.70–3.80
(m, 4 H), 3.92 (br. s, 1 H), 6.63 (d, J = 8.8 Hz, 1 H), 6.77 (d, J =
8.8 Hz, 1 H) ppm. 13C NMR (62.9 MHz, CDCl3, 20 °C): δ = 27.6,
33.0, 33.2, 44.2, 47.6, 55.6, 66.6, 70.3, 114.7, 115.3, 142.3,
152.2, 158.3 ppm. IR: ν = 450–3100, 1514 cm–1. MS (EI): m/z (%)
˜
= 315 (3) [M+], 176 (100), 136 (48), 121 (88). HRMS calcd. for
C19H25NO3 315.1834, found 315.1815.
1-(3,4-Dimethoxyphenyl)-5-(p-methoxyphenylamino)-2-pentanol
(12c): According to the typical procedure, alcohol 12c was obtained
from amide 8n (341 mg, 1 mmol) carrying out the reaction at 0 °C.
The final residue was purified by column chromatography (EtOAc)
to afford alcohol 12c as a pale brown solid (286 mg, 83%). M.p.
65–68 °C (hexanes). 1H NMR (250 MHz, CDCl3, 20 °C): δ = 1.54–
1.83 (m, 4 H), 2.59–2.63 (m, 1 H), 2.76–2.80 (m, 1 H), 3.11–3.15
(m, 2 H), 3.74 (s, 3 H), 3.80–3.87 (m, 1 H), 3.87 (s, 6 H), 6.60 (d,
J = 8.7 Hz, 2 H), 6.74–6.83 (m, 5 H) ppm. 13C NMR (62.9 MHz,
CDCl3, 20 °C): δ = 26.2, 34.6, 44.0, 45.7, 56.0, 56.1, 56.2, 72.7,
111.5, 112.7, 115.0, 115.1, 121.5, 131.0, 142.2, 147.9, 149.2,
152.6 ppm. IR (film): ν = 3500–3150, 1513 cm–1. MS (EI): m/z (%)
˜
= 263 (6) [M+], 232 (46), 136 (100), 108 (31), 57 (47). HRMS calcd.
for C16H25NO2 263.1883, found 263.1885.
When the reaction was carried out on amide 8k (231 mg, 1 mmol)
according to the typical procedure at –20 °C, compounds 11
(71 mg, 33% yield) and 9k (28 mg, 12% yield) were obtained and
purified by column chromatography (EtOAc).
152.7 ppm. IR: ν = 450–3100, 1514 cm–1. MS (EI): m/z (%) = 186
˜
(9), 176 (100), 151 (15), 136 (15). HRMS calcd. for C20H27NO4
345.1940, found 345.1935.
(3aR,6aR)-N-(4-Methoxyphenyl)-1,2,3,3a,4,6a-hexahydrocyclo-
penta[b]pyrrole (11): M.p. 90–92 °C (hexanes). 1H NMR (250 MHz,
CDCl3, 20 °C): δ = 1.72–1.79 (m, 1 H), 1.90–1.97 (m, 1 H), 2.10–
2.22 (m, 3 H), 2.40–2.45 (m, 1 H), 3.10–3.20 (m, 2 H), 3.74 (s, 3
H), 4.62–4.64 (m, 1 H), 5.91–5.93 (m, 1 H), 6.02–6.04 (m, 1 H),
6.62 (d, J = 8.7 Hz, 2 H), 6.78 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR
(62.9 MHz, CDCl3, 20 °C): δ = 29.1, 37.0, 41.2, 44.7, 55.7, 76.3,
1-(p-Fluorophenyl)-5-(4-methoxyphenylamino)-2-pentanol (12d): Ac-
cording to the typical procedure, alcohol 12d was obtained from
amide 8o (299 mg, 1 mmol) carrying out the reaction at 0 °C. The
final residue was purified by column chromatography (EtOAc) to
afford alcohol 12d as a pale brown solid (61 mg, 20%). M.p. 73–
76 °C (hexanes). 1H NMR (250 MHz, CDCl3, 20 °C): δ = 1.52–
1.82 (m, 4 H), 2.64–2.69 (m, 1 H), 2.77–2.81 (m, 1 H), 3.09–3.12
(m, 2 H), 3.75 (s, 3 H), 3.80–3.84 (m, 1 H), 6.60 (d, J = 8.8 Hz, 2
H), 6.78 (d, J = 8.8 Hz, 2 H), 7.00 (d, J = 8.5 Hz, 2 H), 7.17 (dd,
J = 8.5, 5.5 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3, 20 °C):
δ = 26.1, 34.5, 43.3, 45.2, 55.8, 72.4, 114.6, 114.9, 115.2 (d, J =
21.1 Hz), 115.4 (d, J = 21.1 Hz), 130.7 (d, J = 7.3 Hz), 130.8 (d, J
= 7.3 Hz), 134.1 (d, J = 2.7 Hz), 134.1 (d, J = 2.7 Hz), 142.3, 152.4,
114.4, 114.8, 133.1, 135.5, 142.5, 152.1 ppm. IR: ν = 367,
˜
1507 cm–1. MS (EI): m/z (%) = 233 (100) [M+ + 18], 215 (59) [M+],
200 (59), 136 (65), 77 (60). HRMS calcd. for C14H17NO 215.1310,
found 215.1313.
(3aR,6R,6aR)-N-(4-Methoxyphenyl)-octahydrocyclopenta[b]pyrrol-
6-ol (9k): 1H NMR (250 MHz, CDCl3, 20 °C): δ = 1.42–1.53 (m, 2
H), 1.80–1.86 (m, 1 H), 1.87–1.95 (m, 1 H), 2.11–2.25 (m, 2 H),
2.43 (br. s, OH), 3.08–3.13 (m, 1 H), 3.14–3.21 (m, 1 H), 3.75 (s, 3
H), 3.94–3.95 (m, 1 H), 4.10–4.12 (m, 1 H), 6.64 (d, J = 9.0 Hz, 2
H), 6.79 (d, J = 9.0 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3,
20 °C): δ = 27.6, 29.2, 31.6, 40.4, 44.6, 55.8, 79.0, 79.6, 114.9, 114.9,
160.7 (d, J = 252.7 Hz), 162.6 (d, J = 252.7 Hz) ppm. IR: ν = 450–
˜
3100, 1514 cm–1. MS (EI): m/z (%) = 303 (4) [M+], 176 (100), 136
(26), 109 (21). HRMS calcd. for C18H22NO2F 303.1635, found
303.1644.
142.1, 152.6 ppm. IR: ν = 450–3100, 2931, 1507 cm–1. MS (EI): m/z
˜
Supporting Information (see also the footnote on the first page of
this article): Experimental details for amides 5a–g and 8a–o, and
1H NMR and 13C NMR spectra of all new compounds.
(%) = 251 (62) [M+ + 18], 233 (39) [M+], 136 (100), 108 (49).
HRMS calcd. for C14H19NO2 233.1416, found 233.1414.
5-(p-Methoxyphenylamino)-1-phenyl-2-pentanol (12a): According to
the typical procedure, alcohol 12a was obtained from amide 8l
(281 mg, 1 mmol) carrying out the reaction at 0 °C. The final resi-
due was purified by column chromatography (EtOAc) to afford
alcohol 12a as a pale brown solid (105 mg, 37%). M.p. 57–59 °C.
Acknowledgments
Financial support from the University of the Basque Country (9/
1H NMR (250 MHz, CDCl3, 20 °C): δ = 1.55–1.83 (m, 4 H), 2.67– UPV 41.310-13656/2001) and the Spanish Ministry of Science and
2.71 (m, 1 H), 2.81–2.85 (m, 1 H), 3.09–3.13 (m, 2 H), 3.75 (s, 3
Technology (MCYT BQU 2001-0313 and MEC CTQ2004-03706/
H), 6.60 (d, J = 8.9 Hz, 2 H), 6.78 (d, J = 8.9 Hz, 2 H), 7.25–7.29 BQU) is gratefully acknowledged. A. C. and S. S. thank the Basque
(m, 6 H) ppm. 13C NMR (62.9 MHz, CDCl3, 20 °C): δ = 26.1,
34.4, 44.2, 55.8, 72.4, 114.5, 114.9, 126.5, 128.6, 129.4, 138.4, 142.4,
Government for predoctoral scholarships. We finally thank Dr. L.
Lezama (UPV/EHU) for his assistance in the EPR studies.
Eur. J. Org. Chem. 2007, 437–444
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
443

I. Tellitu, E. Domínguez et al.
FULL PAPER
Due to the similar theoretical chemical shifts and multiplicities
that both 6a and its putative isomer 6aЈ would afford in 1H
and 13C NMR, an additional HMBC experiment was carried
out to confirm the identity of pyrrolidine 6a and, hence, to
exclude the formation of 6aЈ.
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[6] The celebration of specialized conferences reflects the develop-
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also observed in the reaction of a related compound of type 8b
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Nicolaou, Y.-L. Zhong, P. S. Baran, Angew. Chem. Int. Ed.
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1
and isolated signals in H NMR spectroscopy.
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[15] It resulted to be unstable on standing, in the presence of SiO2,
and it also resulted in complete degradation when attempts to
prepare different derivatives (O-acetylation, O-tosylation, O-
benzylation, and O-silylation) were carried out.
[16]
Received: September 6, 2006
Published Online: November 21, 2006
444
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Eur. J. Org. Chem. 2007, 437–444