Developing the scope of o→c aryl migrations: Exploring amide substrates as potential precursors for asymmetric reactions

Article abstract of DOI:10.1002/ejoc.201301716

A new and mild method for the production of diasteromerically enriched α-aryl carbonyl compounds has been achieved. Although only modest diastereoselectivies are observed, they demonstrate the potential of the method for further optimisation. It also appears that reactions that proceed through a five-membered spirocyclic transition state rearrange, whereas those proceeding through a six-membered transition state do not, but stop at the diaryl ether stage.

Full text of DOI:10.1002/ejoc.201301716

FULL PAPER
DOI: 10.1002/ejoc.201301716
Developing the Scope of OǞC Aryl Migrations: Exploring Amide Substrates
as Potential Precursors for Asymmetric Reactions
Dana Ameen[a] and Timothy J. Snape*[a]
Keywords: Synthetic methods / Asymmetric synthesis / Rearrangement / Amides
A new and mild method for the production of diasteromer-
ically enriched α-aryl carbonyl compounds has been
achieved. Although only modest diastereoselectivies are ob-
served, they demonstrate the potential of the method for fur-
ther optimisation. It also appears that reactions that proceed
through a five-membered spirocyclic transition state re-
arrange, whereas those proceeding through a six-membered
transition state do not, but stop at the diaryl ether stage.
Introduction
α-Arylated carbonyl compounds are commonly occur-
ring motifs in synthetic intermediates and biologically inter-
esting molecules, and they arise in a number of important
therapeutic areas, such as: antiarrhythmics; antimuscarin-
ics; phosphodiesterase inhibitors; and cannabinoid receptor
ligands.[1] Despite their importance however, the synthesis
of such compounds is still synthetically challenging.[2] Con-
sequently, they remain of great interest to both academia
and the pharmaceutical industry, especially if methods can
be developed to prepare this motif under mild reaction con-
ditions and in enantiomerically pure form.
Such requirements inspired us to consider whether the
Truce–Smiles rearrangement[3] could be developed to meet
these needs, especially because wide-ranging substrates have
recently been successful in this rearrangement reaction un-
der relatively mild conditions,[4–7] but also because such a
mild, scalable method, amenable to asymmetric induction,
has yet to be developed.
Scheme 1. The Truce–Smiles rearrangement reaction on ester sub-
Erickson and McKennon demonstrated that, under typi-
cal rearrangement conditions [NaH, tetrahydrofuran
(THF), T Ն 0 °C], ester precursors (e.g. 1) rearrange
through intramolecular nucleophilic attack of the enolate
onto the electrophilic proximal diaryl ether to generate an
α-aryl compound, but the products readily cyclise, followed
by tautomerisation in certain cases, giving achiral products
(e.g. 3); so even if asymmetry was induced in the reaction
(i.e. in 2), it would be lost upon cyclisation and isomeris-
ation to 3, Scheme 1.[8] Moreover, owing to the facile C–O
bond rotation in esters, chiral auxiliaries cannot be incorpo-
rated to develop a simple asymmetric variant.
strates and amide analogues (4) studied herein.
To the best of our knowledge, amide enolates (i.e. gener-
ated from 4, n = 1 or 2, Scheme 1) have not been studied as
precursors in the Truce–Smiles rearrangement, and because
such compounds can be rendered enantiomerically pure,
through auxiliary formation, aided by the associated restric-
ted C–N bond rotation,[9–11] it was speculated that the scope
of such OǞC aryl migrations could be further developed
and extended, first to achiral amide substrates to determine
their potential, followed by further advances to exploit
them as precursors for new asymmetric reactions based on
this rearrangement. Furthermore, because cyclisation is not
as likely with amide substrates, loss of any induced stereo-
chemistry should be minimal through this mechanism.
[a] School of Pharmacy and Biomedical Sciences, University of
Central Lancashire,
Preston, PR1 2HE, U.K.
E-mail: tjsnape@uclan.ac.uk
http://www.timsnape.co.uk/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301716.
Eur. J. Org. Chem. 2014, 1925–1934
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1925

D. Ameen, T. J. Snape
FULL PAPER
As can be seen, no rearrangement reaction occurred with
precursors based on propanamide structures, Table 1; only
diaryl ether products 7a–7e were isolated. Even when the
reaction temperature was increased to 100 °C (results not
shown), no rearrangement was observed at all, with either
pyrrolidyl derivative 5b or dibenzyl derivative 5e; only di-
aryl ethers 7b and 7e were isolated, again in quantitative
yields. Similarly, leaving the reactions for 3 days at room
temperature resulted in the same products being formed.
Such reactions proceed through a spirocyclic intermedi-
ate,[14] wherein the Meisenheimer complex is stabilised by
the presence of the electron-withdrawing nitro group at the
ortho position. However, despite precedent for 4-,[5]
5-,[6–8,15–19] and 6-membered[4,20,21] transition states in this
type of rearrangement, the rearranged products have not
been observed with compounds based on propanamide
structures (5) in our hands. In addition, trying to force the
reaction conditions to rearrange pure, isolated diaryl ethers
7b and 7e, met with failure, despite varying the solvent [di-
methyl sulfoxide (DMSO), dimethylformamide (DMF),
THF and CH2Cl2], base (K2CO3, CsOH, NaH, NaOMe)
and temperature (room temp. to 100 °C).
Results and Discussion
Based on previous work,[12] this study began by examin-
ing rearrangement precursors, which it was anticipated
would proceed through a six-membered transition state,
with the potential to make the rearrangement asymmetric
by incorporating enantiomerically pure amides into the re-
action, e.g. with (–)-bis[(S)-1-phenylethyl]amine (8),
(2R,5R)-(–)-trans-2,5-dimethylpyrrolidine (9, R = H) or
(2S,5S)-(+)-2,5-bis(methoxymethyl)pyrrolidine (9,
R =
OMe) (Scheme 2, see Box 2),[13] thus generating enantio-
pure rearrangement precursors. Table 1 outlines the prelimi-
nary results obtained with achiral amides as test cases.
Based on these results, under the assumption that the
rearrangement reaction was failing because of the relatively
high pKa of the α-protons of amide 7, either when formed
in situ or from isolated material, attention was turned to
acetamide-based substrates 10 (Scheme 3), wherein the α-
protons of the amide are also benzylic and should therefore
more readily be abstracted to form the desired amide enol-
ate with K2CO3 prior to its intramolecular attack onto
proximal diaryl ether 11, formed in situ.
Table 2 demonstrates that, as with the propanamide de-
rivatives, diaryl ether 11 is still the major isolated product.
Nevertheless, with acetamide derivatives 10, desired re-
arranged diaryl ether 12 and rearranged-only 13 products
are also produced in modest yields. The amide enolate is
evidently more easily formed in this case, rendering the re-
arrangement more likely to occur, this time through a five-
membered cyclic transition-state (Scheme 4).
Scheme 2. Attempted Truce–Smiles rearrangement reactions with
propanamide substrates (5a–5e,[10] see Box 1); see Table 1 for the
reaction conditions. Box 2 shows three commercially available
amines with which to potentially make the reaction asymmetric.
Table 1. Reaction of propanamide substrates 5 with 6.[a]
[b]
Entry
Rearrangement precursor
Product
Yield [%]
1
2
3
4
5
5a
5b
5c
5d
5e
7a
7b
7c
7d
7e
90
92
87
90
92
Although all starting material 10 was consumed in these
reactions, a mixture of the three possible products was usu-
ally formed (Table 2) with only 1.05 equiv. of 6. As must be
the case here, diaryl ether 11 rearranges intramolecularly to
13 faster than 6 reacts intermolecularly with 10. As such,
13 and 10 exist together during the reaction; reaction of 10
[a] Reaction conditions:
(2.5 equiv.), DMSO (0.1 m), 60 °C, 24 h. [b] Isolated yields.
5 (1.0 equiv.), 6 (1.05 equiv.), K2CO3
Scheme 3. Truce–Smiles rearrangement reaction with acetamide substrates 10a–10e[10]. See Table 2 for the reaction conditions.
1926 Eur. J. Org. Chem. 2014, 1925–1934
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Developing the Scope of OǞC Aryl Migrations
Table 2. Reaction of acetamide substrates 10 with 6.[a]
rearrangement reaction of 11 to 13 proceeds in other sol-
vents (CH2Cl2, DMF, PhMe and THF), and with alterna-
tive bases (CsOH, NaH and NaOMe) as well, although
such reactions were only studied by crude NMR, unlike the
reaction/rearrangement of 10 to 11/12/13 that only works
in polar aprotic solvents such as DMSO and DMF. In order
to facilitate the future development of an asymmetric vari-
ant, attempts were made to force the reaction by increasing
the molar equivalents of 1-fluoro-2-nitrobenzene (6), in-
creasing the reaction temperature and changing base in the
expectation that the complete formation of rearranged
products 12 or 13 would occur (Table 3).
Entry Rearrangement precursor
1
Product
Yield [%][b]
11a
12a
13a
68
21
10
2
3
10a
10b
10c
10d
10e
4
5
6
11b
12b
13b
61
0
33
7
8
9
11c
12c
13c
54
24
21
10
11
12
11d
12d
13d
45
6
45
Table 3. Optimisation of the reaction between 10b and 6.[a]
13
14
15
11e
12e
13e
40
23
37
Entry
6
Base
(equiv.) (equiv.)
Temp. Product ratio[b]
[°C]
11b
12b
13b
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
5.0
5.0
5.0
5.0
10.0
10.0
10.0
10.0
K2CO3 (2.5)
25
60
100
60
25
60
100
60
25
60
100
60
80
58
49
40
97
70
62
71
100
100
100
54
20
42
51
55
3
30
38
29
0
0
0
0
5
0
0
0
0
0
0
0
0
K2CO3 (2.5)
K2CO3 (2.5)
NaH (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
NaH (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
NaH (2.5)
9
10
11
12
0
0
46
[a] Reaction conditions: All reactions were carried out with 10b
(1.0 equiv.), in DMSO (0.1 m) for 24 h. [b] Ratios based integration
of diagnostic signals with 1H NMR spectroscopy relating to the
newly generated CH of rearranged products 12b and 13b, and the
CH2 of diaryl ether 11b.
Unexpectedly, when the number of molar equivalents of
6 was increased from 2.0 to 5.0 and to 10.0 equiv. the
amount of diaryl ether 11b also increased, at all tempera-
tures studied (25, 60 and 100 °C), rather than an increase
in the ratio of rearranged products 12b and 13b, as was
expected. It seems as though increasing the equivalents of
the electrophile halted the reaction at the diaryl ether 11b
stage. One possible explanation for this occurrence could be
the stabilisation of the electron-rich enolate of diaryl ether
11b formed during the first stage of the reaction, by certain
counterions, rendering it unable to react further.
[c]
[a] Reaction conditions: 6 (1.05 equiv.), 10 (1.0 equiv.), K2CO3
(2.5 equiv.), DMSO (0.1 m), 60 °C, 24 h. [b] Isolated yields. [c] X-
ray crystal structure of 13e.[22,23]
Based on the assumption that the stability of the enolate
appeared to be affected by the presence of excess 6, the
effects of a stronger base and alternative counterion were
examined; Table 3 outlines the results of replacing K2CO3
with NaH. As can be seen, increasing the number of equiva-
lents of 6 with NaH as base, at 60 °C, results in an irrevers-
ible deprotonation, leading to an increase in the amount of
rearranged diaryl ether 12b formed relative to 11b, which
peaks with 10 equiv., in which an increase in the total re-
Scheme 4. Proposed mechanism for the successful rearrangement
reaction through a five-membered transition state and intermedi-
ate.
ultimately giving 11 and/or 13, and reaction of 13 giving arranged products increased from zero (with K2CO3) to
12. It was also demonstrated that isolated diaryl ethers (i.e. 46% (with NaH). Possibly, the smaller counterion (Na+)
11), rearrange cleanly to 13 under standard rearrangement and irreversible deprotonation enables the formation of a
conditions (K2CO3, DMSO) in good yield (50% isolated tighter ion pair thus favouring the rearrangement, whereas
yield, 100% based on recovered starting material). Ad- the more dissociated ion pair with K+ is stabilised by the
ditionally, attempts at reaction optimisation show that the excess electrophile.
Eur. J. Org. Chem. 2014, 1925–1934
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1927

D. Ameen, T. J. Snape
FULL PAPER
Scheme 5. Reaction between enantiomerically pure amide 17 and 6, showing the diastereoisomeric rearranged products produced. Com-
pound 20 outlines a suggested mechanism through which the partial diastereoselectivity was achieved.
To test the reaction conditions, and ascertain the level of
asymmetry induced during the rearrangement, enantio-
merically pure substrate 17 was prepared from the reaction
of (2S,5S)-(+)-2,5-bis(methoxymethyl)pyrrolidine (9, R =
OMe) with 2-coumaranone at reflux temperatures in tolu-
ene;[10] the product was isolated in excellent yield (99%).
Subjecting 17 to typical rearrangement reaction conditions
[6 (1.05 equiv.), K2CO3 (2.5 equiv.), DMSO (0.1 m), room
temp., 24 h] resulted in diastereoisomeric mixtures of re-
arranged products 18 (10%) and 19 (45%; Scheme 5).
1
There is a diagnostic H NMR spectroscopic signal for
the CH proton for amides 12a–12e and 13a–13e, in which,
for all cases with compound 12, the newly formed CH reso-
nates furthest downfield at values greater than 6.0 ppm
(presumably the result of an additional electron-deficient
ring in these structures), whereas four out of the five amides
incorporating the structure of compound 13, resonate at
upfield values of less than 6.0 ppm, such that their average
values can be summarised as 6.29Ϯ0.15 (for 12a–12e, in
which the error is Ϯstandard deviation) and 5.77Ϯ0.42 (for
13a–13e see the Exp. Section). As such, this diagnostic fea-
ture enabled us to both determine the identity of rearranged
products 18 and/or 19 formed in the asymmetric reaction,
and determine the diastereoisomeric ratios obtained for
each [i.e. (S,S,S)-18:(R,S,S)-18 and (S,S,S)-19:(R,S,S)-19].
Figure 1 outlines the diagnostic section of the 1H NMR
spectrum of the crude reaction mixture from the reaction
shown in Scheme 5.
1
Figure 1. Diagnostic section of the H NMR spectrum of the dia-
stereoisomers of 18 (6.29 and 6.18 ppm) and 19 (5.99 and
5.92 ppm) as determined from the CH signal of the α-proton to the
amide.
By using these diagnostic signals it can be calculated that tial may exist in this mild method for generating enantio-
the presence of the enantiopure auxiliary resulted in re- enriched chiral centres with chiral auxiliaries through an
arranged products with a dr = 1.6:1 (18) and dr = 1:1.6 aryl-migration rearrangement reaction. Moreover, it is also
(19). Furthermore, when the rearrangement reaction was possible that the dr induced during the reaction is actually
1
carried out on the chiral analogue of 17 possessing chiral higher than that observed in the crude H NMR spectrum
auxiliary trans-dimethylpyrrolidine (9, R = H), the ratios because the rearranged products are prone to racemisation
were dr = 1.7:1 and dr = 1:1.9, respectively, for the analo- owing to the increased acidity of the CH proton on mi-
gous products. Although these diastereoisomeric ratios are gration of the aromatic ring [pKa of phenol: ca. 18.0
relatively low, they are not optimised, and therefore poten- (DMSO) and pKa of 1,1-diphenylcarbonyls: Ն18.75
1928
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Developing the Scope of OǞC Aryl Migrations
(DMSO)];[24] in an effort to ascertain whether the dr ob-
served was kinetic or thermodynamic, a rearrangement re-
action of isolated 21 was performed in which aliquots were
taken and quenched every hour, and an NMR analysis per-
formed. The results indicated an initial dr of 1:1 (after 1 h),
which changed to 1.35:1 (after 4 h), and then surprisingly
swapped to 1:1.54 (after 5 h), a ratio that did not change
further over the course of the reaction (7 h). Moreover,
attempts to optimise the dr were attempted by subjecting
(TLC) was performed with plastic-backed TLC plates coated with
silica G/UV254, in a variety of solvents. The plates were visualised
by UV light (254 nm), p-anisaldehyde solution or KMnO4 solution.
Flash column chromatography was conducted with Davisil silica
60 Å (40–63 μm) under bellows pressure. Low-resolution mass
spectra were recorded with a Thermo FinniganLCQ Advantage
MAX with electron spray ionisation (ESI), and high-resolution
mass spectra were recorded by the EPSRC National Mass Spec-
trometry Service, UK. 1H and 13C NMR spectra were recorded
with a BrukerAvanceDPX 300 (300 MHz) or a Bruker 400
21 to a range of rearrangement conditions [solvent (DMSO, (400 MHz) spectrometer. All chemical shifts (δ) are quoted relative
to a calibration reference of the residual protic solvent; CHCl3 (δH
= 7.26, s) or [D6]DMSO (δH = 2.50, pent) was used as the internal
standard in 1H NMR spectra, and 13C NMR shifts were referenced
with CDCl3 (δC = 77.16, t) or [D6]DMSO (δH = 39.5, m) with
broad band decoupling. Melting points were measured on a Stu-
art® SMP10 melting point apparatus. [α]D was measured with JA-
SCO P-2000 polarimeter and IR spectra were recorded with a NIC-
OLET iS10 instrument.
DMF, THF, PhMe, CHCl3 and CH2Cl2), base (K2CO3,
CsOH, NaH, NaOMe)], but the same (thermodynamic) ra-
tio of about 1:1.6 was obtained in all cases. These results
prompted us to propose that the rearrangement is not as
simple as first presumed, but that the known role of the
product and starting phenols (i.e. 17 and 19) to act as
enantiopure Brønsted acids (as has been shown in the
asymmetric protonation of amide enolates),[10] may be play-
ing a part; an effect that needs further investigation.
This proposed limitation of in situ epimerisation could
potentially be mitigated through the preparation of quater-
nary centres. To this end, diaryl ether 21 was α-acylated
with methyl chloroformate prior to its attempted rearrange-
ment reaction, upon which, if successful, a non-epimeris-
able quaternary carbon centre would be formed. Surpris-
ingly, a diastereoisomeric ratio of 11:1 (83% de) was
achieved in the 1,3-dicarbonyl product, indicating that the
chiral auxiliary is capable of inducing diastereoselectivity
in these substrates. Unfortunately, attempts to produce a
quaternary carbon centre through aryl migration of this
1,3-dicarbonyl compound, under standard rearrangement
conditions, resulted in failure, possibly owing to competing
ester hydrolysis consuming base, or the newly introduced
group imparting increased steric hindrance that cannot be
overcome. Nevertheless, that a major diastereoisomer of the
1,3-dicarbonyl had indeed been produced was confirmed
when, subject to the rearrangement reaction conditions, it
was shown to epimerise to 54% de by crude NMR spec-
troscopy.
Procedure for the Synthesis of 2-Coumaranone: To a solution of 2-
hydroxyphenyl acetic acid (5 g, 32.9 mmol) in toluene (70 mL) was
added p-toluenesulfonic acid (0.62 g, 3.28 mmol). The resulting
solution was stirred at 110 °C under Dean–Stark conditions for 6 h,
after which it was cooled, washed with satd. aq. NaHCO3 (3ϫ
30 mL), brine (30 mL) and extracted with ethyl acetate (2ϫ
30 mL). The combined organic layers were washed with distilled
water (30 mL), dried (MgSO4), filtered and the solvent evaporated
in vacuo to afford 2-coumaranone (4.23 g, 96%) as yellow crystals.
Rf (30% EtOAc in petroleum ether): 0.76, m.p. 51–53 °C (EtOAc/
petroleum ether) [(ref.[25] m.p. 49–51 °C) (toluene)]. IR (neat): ν
˜
max
= 1794 (C=O stretching), 1051 (C–O stretching) cm–1. 1H NMR
(CDCl3, 300 MHz): δH = 3.77 (s, 2 H), 7.12–7.21 (m, 2 H), 7.29–
7.36 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 33.13 (CH2),
110.91, 123.16, 124.22, 124.76 (CH), 129.01, 154.81, 174.24
(C) ppm. MS (APCI): m/z (%) = 134 (100) [M + H]+.
General Procedure for the Synthesis of Amides 5 and 10: To a solu-
tion of 2-coumaranone (1 equiv.) in toluene (0.1 m) was added the
amine (1.5 equiv.). The resulting solution was stirred at 110 °C for
4–6 h, after which it was cooled, acidified (1 m HCl to pH ≈ 1–2),
and extracted with ethyl acetate (2ϫ 30 mL). The combined or-
ganic layers were washed with distilled water (2ϫ 30 mL) and brine
(30 mL), dried (MgSO4), filtered and the solvent evaporated in
vacuo to afford the pure amide directly or after flash column
chromatography.
Conclusions
N,N-Diethyl-3-(2-hydroxyphenyl)propionamide (5a):[26] The solvent
was evaporated in vacuo to afford the title compound as a pale
yellow solid (100%). Rf (30% EtOAc in petroleum ether): 0.41, m.p.
In preliminary efforts to produce an asymmetric Truce–
Smiles rearrangement reaction – a new and potentially mild
method to produce enantiomerically enriched α-aryl carb-
onyl compounds – we have demonstrated modest success in
the application of the rearrangement reaction to new amide
substrates. It has also been demonstrated that amide pre-
128–130 °C (EtOAc/petroleum ether). IR (neat): νmax = 1613 (C=O
˜
1
stretching), 3175 (OH stretching), 1071 (C–O stretching) cm–1. H
NMR (CDCl3, 300 MHz): δH = 1.08 (t, J = 4.5 Hz, 3 H), 1.11 (t,
J = 4.5 Hz, 3 H), 2.71 (t, J = 6.0 Hz, 2 H), 2.94 (t, J = 6.0 Hz, 2
cursors that proceed through a five-membered spirocyclic H), 3.26 (q, J = 9.0 Hz, 2 H), 3.36 (q, J = 9.0 Hz, 2 H), 6.81 (td,
J = 3.0, J = 9.0 Hz, 1 H), 6.91 (dd, J = 3.0, J = 9.0 Hz, 1 H), 7.04
(dd, J = 1.0, J = 8.0 Hz, 1 H), 7.11 (td, J = 1.0, J = 8.0 Hz, 1 H),
9.76 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 13.02, 13.88
(CH3), 24.90, 35.04, 40.95, 42.09 (CH2), 118.13, 120.08, 128.05,
128.48 (CH), 130.70, 155.69, 173.13 (C) ppm. MS (APCI): m/z (%)
= 222 (100) [M + H]+.
transition state rearrange, whereas those proceeding
through a six-membered transition state do not, but stop at
the diaryl ether stage. Optimisation of the rearrangement
reaction conditions and chiral amine auxiliary continue, the
results of which will be reported in due course.
Pyrrolidyl-2-(2-hydroxyphenyl)propanamide (5b): After aqueous
work-up the solvent was evaporated in vacuo to afford the title
compound as colourless crystals (100%). Rf (50% EtOAc in petro-
leum ether): 0.51, m.p. 151–153 °C (EtOAc/toluene). IR (neat):
Experimental Section
General Information: Commercially available reagents were used as
received without purification. Analytical thin layer chromatography
Eur. J. Org. Chem. 2014, 1925–1934
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1929

D. Ameen, T. J. Snape
FULL PAPER
ν
= 1622 (C=O stretching), 1039 (C–N stretching), 3283 (OH
H), 10.47 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 13.05,
˜
max
stretching) cm–1. 1H NMR (CDCl3, 300 MHz): δH = 1.78–1.98 (m, 14.94 (CH3), 37.06, 41.47, 43.67 (CH2), 118.41, 119.97 (CH),
4 H), 2.66 (t, J = 6.0 Hz, 2 H), 2.94 (t, J = 6.0 Hz, 2 H), 3.33 (t, J 121.31 (C), 129.15, 130.54 (CH), 157.43, 172.83 (C) ppm. MS
= 7.5 Hz, 2 H), 3.45 (t, J = 6.0 Hz, 2 H), 6.82 (t, J = 6.0 Hz, 1 H), (APCI): m/z (%) = 208 (100) [M + H]+. HRMS (FAB): calcd. for
6.92 (dd, J = 1.0, J = 8.0 Hz, 1 H), 7.04–7.12 (m, 2 H), 9.90 (s, 1 C12H17NO2 [M + H]+ 208.1332; found 208.1332.
H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 24.40, 24.44, 26.05,
2-(2-Hydroxyphenyl)-1-(pyrrolidin-1-yl)ethanone (10b): After aque-
ous work-up the solvent was evaporated in vacuo to afford the title
compound as colourless crystals (89%). Rf (20% EtOAc in tolu-
ene): 0.42, m.p. 120–122 °C (EtOAc/petroleum ether). IR (neat):
36.74, 46.31, 46.66 (CH2), 118.32, 120.12, 128.09, 128.62 (CH),
130.73, 155.70, 172.42 (C) ppm. MS (APCI): m/z (%) = 220 (100)
[M + H]+. HRMS (FAB): calcd. for C13H17NO2 [M + H]+
220.1332; found 220.1332.
ν
= 1610 (C=O stretching), 2959 (OH stretching), 1094 (C–O
˜
max
stretching) cm–1. H NMR (CDCl3, 300 MHz): δH = 1.89 (pent, J
= 6.0 Hz, 2 H), 2.01 (pent, J = 6.0 Hz, 2 H), 3.48 (t, J = 7.5 Hz, 2
H), 3.68 (t, J = 6.0 Hz, 2 H), 3.70 (s, 2 H), 6.81 (td, J = 1.0, J =
8.0 Hz, 1 H), 6.99 (dd, J = 1.5, J = 8.0 Hz, 1 H), 7.03 (dd, J = 1.0,
J = 8.0 Hz, 1 H), 7.19 (td, J = 1.0, J = 8.0 Hz, 1 H), 10.37 (s, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 24.53, 26.12, 39.03,
46.34, 47.77 (CH2), 118.44, 119.99, 121.06, 129.17 (CH), 130.56,
157.35, 171.60 (C) ppm. MS (APCI): m/z (%) = 206 (100) [M +
H]+. HRMS (FAB): calcd. for C12H15NO2 [M + H]+ 206.1176;
found 206.1176.
1
3-(2-Hydroxyphenyl)-1-(1-piperidyl)propan-1-one (5c): Flash col-
umn chromatography (SiO2; 50% EtOAc in petroleum ether) af-
forded the title compound as colourless crystals (78%). Rf (30%
EtOAc in petroleum ether): 0.46, m.p. 130–132 °C (EtOAc/petro-
leum ether). IR (neat): ν
= 1619 (C=O stretching), 3278 (OH
˜
max
stretching), 1013 (C–O stretching) cm–1. 1H NMR (CDCl3,
300 MHz): δH = 1.55–1.62 (m, 6 H), 2.71 (t, J = 4.5 Hz, 2 H), 2.94
(t, J = 4.5 Hz, 2 H), 3.34 (t, J = 4.5 Hz, 2 H), 3.55 (t, J = 4.5 Hz,
2 H), 6.82 (t, J = 6.0 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1 H), 7.5 (d, J
= 9.0 Hz, 1 H), 7.11 (t, J = 7.5 Hz, 1 H), 9.87 (s, 1 H) ppm. 13C
NMR (CDCl3, 75 MHz): δC = 24.39, 24.82, 25.51, 26.21, 35.25,
43.39, 46.45, (CH2), 118.14, 120.12, 128.06 (CH), 128.55 (C),
130.77 (CH), 155.69, 172.00 (C) ppm. MS (APCI): m/z (%) = 234
(100) [M + H]+. HRMS (FAB): calcd. for C14H19NO2 [M + H]+
234.1489; found 234.1489.
2-(2-Hydroxyphenyl)-1-(piperidin-1-yl)ethanone (10c): Flash column
chromatography (SiO2; 50% EtOAc in petroleum ether) afforded
the title compound as a yellow crystals (98%). Rf (30% EtOAc in
petroleum ether): 0.48, m.p. 107–109 °C (EtOAc/petroleum ether).
IR (neat): ν
= 1616 (C=O stretching), 3166 (OH stretching),
˜
max
3-(2-Hydroxyphenyl)-1-morpholinopropan-1-one (5d): Flash column
chromatography (SiO2; 20% EtOAc in petroleum ether) afforded
the title compound as a colourless solid (82%). Rf (30% EtOAc in
petroleum ether): 0.29, m.p. 129–131 °C (EtOAc/petroleum ether).
1039 (C–O stretching) cm–1. 1H NMR (CDCl3, 300 MHz): δH
=
1.52–1.63 (m, 6 H), 3.55 (t, J = 6.0 Hz, 2 H), 3.61 (t, J = 6.0 Hz,
2 H), 3.73 (s, 2 H), 6.81 (t, J = 7.5 Hz, 1 H), 6.95 (d, J = 9.0 Hz,
1 H), 7.03 (d, J = 9.0 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 9.87 (s,
1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 24.25, 25.36, 26.52,
36.41, 43.45, 48.16, (CH2), 117.99, 120.03 (CH), 121.11 (C), 128.91,
130.18 (CH), 157.03, 171.17 (C) ppm. MS (APCI): m/z (%) = 220
(100) [M + H]+. HRMS (FAB): calcd. for C13H17NO2 [M + H]+
220.1332; found 220.1331.
IR (neat): ν
= 1618 (C=O stretching), 2974 (OH stretching),
˜
max
1035 (C–O stretching) cm–1. 1H NMR (CDCl3, 300 MHz): δH
=
2.71 (t, J = 6.0 Hz, 2 H), 2.96 (t, J = 6.0 Hz, 2 H), 3.42 (t, J =
6.0 Hz, 2 H), 3.62 (m, 6 H), 6.84 (t, J = 5.5 Hz, 1 H), 6.92 (d, J =
9.0 Hz, 1 H), 7.05 (d, J = 9.0 Hz, 1 H), 7.13 (td, J = 1.0, J = 8.0 Hz,
1 H), 9.43 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 24.59,
35.11, 42.48, 45.73, 66.34, 66.76 (CH2), 118.11, 120.34, 128.14
(CH), 128.21 (C), 130.76 (CH), 155.45, 172.64 (C) ppm. MS
(APCI): m/z (%) = 236 (100) [M + H]+. HRMS (FAB): calcd. for
C13H17NO3 [M + H]+ 236.1283; found 236.1283.
2-(2-Hydroxyphenyl)-1-morpholinoethanone (10d): Flash column
chromatography (SiO2; 50% EtOAc in petroleum ether) afforded
the title compound as a lemon-yellow crystalline solid (81%). Rf
(30% EtOAc in petroleum ether): 0.34, m.p. 123–125 °C (EtOAc/
petroleum ether). IR (neat): ν
= 1615 (C=O stretching), 2931
˜
max
N,N-Dibenzyl-3-(2-hydroxyphenyl)propanamide (5e): After aqueous
work-up the solvent was evaporated in vacuo to afford the title
compound as a colourless solid (92%). Rf (10% EtOAc in toluene):
(OH stretching), 1092 (C–O stretching) cm–1. 1H NMR (CDCl3,
300 MHz): δH = 3.65–3.68 (m, 8 H), 3.74 (s, 2 H), 6.83 (td, J = 1.5,
J = 8.0 Hz, 1 H), 6.99 (t, J = 6.0 Hz, 2 H), 7.19 (td, J = 1.5, J =
8.0 Hz, 1 H), 9.56 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC
= 36.31, 42.59, 47.29, 66.51, 66.65 (CH2), 118.32, 120.36 (CH),
120.62 (C), 129.9, 130.17 (CH), 165.95, 171.71 (C) ppm. MS
(APCI): m/z (%) = 222 (100) [M + H]+. HRMS (FAB): calcd. for
C12H15NO3 [M + H]+ 222.1125; found 222.1125.
0.63, m.p. 148–150 °C (EtOAc/toluene). IR (neat): ν
= 1613
˜
max
(C=O stretching), 3181 (O–H stretching), 1142 (C–O stretch-
1
ing) cm–1. H NMR (CDCl3, 300 MHz): δH = 2.82 (t, J = 6.0 Hz,
2 H), 3.01 (t, J = 6.0 Hz, 2 H), 4.41 (s, 2 H), 4.58 (s, 2 H), 6.82 (td,
J = 1.0, J = 8.0 Hz, 1 H), 6.96–7.01 (m, 4 H), 7.13–7.20 (m, 3 H),
7.27–7.30 (m, 6 H), 9.31 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz):
δC = 25.00, 35.11, 48.98, 49.97 (CH2), 118.19, 120.40, 126.37,
127.78, 127.90 (CH), 128.10 (C), 128.15, 128.50, 128.82, 129.17,
130.75 (CH), 135.48, 136.63, 155.37, 174.99 (C) ppm. MS (APCI):
m/z (%) = 346 (100) [M + H]+. HRMS (FAB): calcd. for
C23H23NO2 [M + H]+ 346.1802; found 346.1807.
N,N-Dibenzyl-2-(2-hydroxyphenyl)acetamide (10e): After aqueous
work-up the solvent was evaporated in vacuo to afford the title
compound as yellow crystals (91%). Rf (20% EtOAc in petroleum
ether): 0.66, m.p. 139–141 °C (toluene). IR (neat): ν
= 1613
˜
max
(C=O stretching), 3064 (O–H stretching), 1477 (C–O stretch-
ing) cm–1. 1H NMR (CDCl3, 300 MHz): δH = 3.81 (s, 2 H), 4.63
(s, 2 H), 4.64 (s, 2 H), 6.68–6.76 (m, 2 H), 7.02 (dd, J = 1.5, J =
8.0 Hz, 1 H), 7.14–7.21 (m, 5 H), 7.26–7.41 (m, 6 H), 10.07 (s, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 37.18, 49.33, 51.26,
(CH2), 118.33, 120.14 (CH), 120.99 (C), 126.52, 127.91, 128.15,
N,N-Diethyl-2-(2-hydroxyphenyl)acetamide (10a): Flash column
chromatography (SiO2; 15% EtOAc in petroleum ether) afforded
the title compound as an off-white solid (96%). Rf (30% EtOAc in
petroleum ether): 0.54, m.p. 88–90 °C (EtOAc/petroleum ether). IR
(neat): ν
= 1618 (C=O stretching), 3173 (OH stretching), 1090
˜
max
(C–O stretching) cm–1. H NMR (CDCl3, 300 MHz): δH = 1.13 (t, 128.42, 128.90, 129.23, 129.28, 130.70 (CH), 135.70, 136.28, 157.06,
1
J = 7.5 Hz, 3 H), 1.29 (t, J = 6.0 Hz, 3 H), 3.39 (q, J = 6.0 Hz, 2
H), 3.50 (q, J = 7.5 Hz, 2 H), 3.71 (s, 2 H), 6.82 (td, J = 1.5, J =
174.45 (C) ppm. MS (APCI): m/z (%) = 332 (100) [M + H]+.
HRMS (FAB): calcd. for C22H21 NO2 [M + H]+ 332.1651; found
8.0 Hz, 1 H), 6.97–7.04 (m, 2 H), 7.19 (td, J = 3.0, J = 9.0 Hz, 1 332.1645.
1930
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1925–1934

Developing the Scope of OǞC Aryl Migrations
General Procedure for the Rearrangement Reactions: To a solution
of the amide (5a–5e, 10a–10e) (1 equiv.) in dimethyl sulfoxide
(0.1 m) was added potassium carbonate (2.5 equiv.) and the re-
sulting solution was stirred at room temperature for 30 min. 1-
Fluoro-2-nitrobenzene (1.05 equiv.) was added and the reaction
stirred for 24 h at 60 °C. After being stirred, the mixture was acidi-
fied with hydrochloric acid solution (1 m, 30 mL). The product was
extracted with ethyl acetate (2ϫ 30 mL) and the combined organic
layers were washed with distilled water (2ϫ 20 mL), brine (10 mL),
dried (MgSO4), filtered and the solvent evaporated in vacuo to af-
ford the crude residue which was purified by flash column
chromatography.
1023 (C–O stretching), 1582, 1349 (N–O stretching) cm–1. 1H NMR
(CDCl3, 300 MHz): δH = 2.72 (t, J = 7.5 Hz, 2 H), 2.94 (t, J =
7.5 Hz, 2 H), 3.42 (t, J = 7.5 Hz, 2 H), 3.53 (t, J = 7.5 Hz, 2 H),
3.61 (t, J = 7.5 Hz, 4 H), 6.89 (dd, J = 1.5, J = 8.0 Hz, 2 H), 7.15–
7.28 (m, 3 H), 7.36 (dd, J = 1.5, J = 8.0 Hz, 1 H), 7.47 (t, J =
8.0 Hz, 1 H), 7.97 (dd, J = 1.5, J = 8.0 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δC = 26.72, 32.75, 41.73, 45.73, 66.36, 66.58
(CH2), 118.69, 118.96, 122.66, 125.15, 125.75, 128.06, 131.50 (CH),
132.37 (C), 134.31 (CH), 140.35, 150.45, 152.90, 170.71, (C) ppm.
MS (APCI): m/z (%) = 357 (100) [M + H]+. HRMS (FAB): calcd.
for C19H20N2O5 [M + H]+ 357.1445; found 357.1444.
3-[2-(2-Nitrophenoxy)phenyl]-N,N-dibenzylpropanamide (7e): After
aqueous work-up the solvent was evaporated in vacuo to afford the
title compound as a yellow oil (100%). Rf (10% EtOAc in toluene):
N,N-Diethyl-2-[2-(2-nitrophenoxy)phenyl]propanamide (7a): After
aqueous work-up the solvent was evaporated in vacuo to afford the
title compound as a yellow oil (90%). IR (neat): νmax = 1631 (C=O
0.46. IR (neat): ν
= 1644 (C=O stretching), 1101 (C–O stretch-
˜
˜
max
stretching), 1098 (C–O stretching), 1524, 1349 (N–O stretch-
ing), 1524, 1347 (N–O stretching) cm–1. 1H NMR (CDCl3,
1
ing) cm–1. H NMR (CDCl3, 300 MHz): δH = 0.95–1.01 (m, 6 H), 300 MHz): δH = 2.82 (t, J = 7.5 Hz, 2 H), 3.06 (t, J = 7.5 Hz, 2
2.59 (t, J = 7.5 Hz, 2 H), 2.87 (t, J = 7.5 Hz, 2 H), 3.15 (q, J = H), 4.42 (s, 2 H), 4.57 (s, 2 H), 6.78 (dd, J = 1.0, J = 9.0 Hz, 1 H),
7.5 Hz, 2 H), 3.24 (q, J = 7.5 Hz, 2 H), 6.79 (t, J = 7.5 Hz, 2 H),
7.02–7.15 (m, 3 H), 7.27 (d, J = 6.0 Hz, 1 H), 7.38 (t, J = 7.5 Hz,
6.82 (dd, J = 1.0, J = 9.0 Hz, 1 H), 7.05 (d, J = 9.0 Hz, 2 H), 7.11–
7.15 (m, 4 H), 7.20 (dd, J = 1.5, J = 9.0 Hz, 1 H), 7.23–7.31 (m, 6
1 H), 7.85 (d, J = 9.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): H), 7.34–7.39 (m, 2 H), 7.91 (dd, J = 1.5, J = 8.0 Hz, 1 H) ppm.
δC = 12.92, 14.01 (CH3), 26.69, 33.14, 39.96, 41.75 (CH2), 118.72,
119.05, 122.54, 125.13, 125.74, 127.89, 131.46 (CH), 132.93 (C),
134.29 (CH), 140.33, 150.74, 152.95, 171.08 (C) ppm. MS (APCI):
13C NMR (CDCl3, 75 MHz): δC = 26.95, 33.43, 48.23, 49.90 (CH2),
119.05, 119.33, 122.74, 125.37, 125.04, 126.51, 127.42, 127.54,
128.19, 128.27, 128.68, 128.94, 131.83, 132.93 (CH), 134.41, 136.52,
m/z (%) = 343 (100) [M + H]+. HRMS (FAB): calcd. for 137.38, 140.63, 150.98, 153.31, 172.92 (C) ppm. MS (APCI): m/z
C19H22NO2 [M + H]+ 343.1652; found 343.1646.
(%) = 467 (100) [M + H]+. HRMS (FAB): calcd. for C29H26N2O4
[M + H]+ 467.1965; found 467.1973.
3-[2-(2-Nitrophenoxy)phenyl]-1-(pyrrolidin-1-yl)propan-1-one (7b):
Flash column chromatography (SiO2; 100% petroleum ether) af-
forded the title compound as a yellow oil (92%). Rf (30% EtOAc
N,N-Diethyl-2-[2-(2-nitrophenoxy)phenyl]acetamide (11a): Flash
column chromatography (SiO2; 100% EtOAc in toluene) afforded
the title compound as a yellow oil (74%). Rf (50% EtOAc in tolu-
in petroleum ether): 0.32. IR (neat): νmax = 1604 (C=O stretching),
˜
1039 (C–N stretching), 1100 (C–O stretching), 1523, 1344 (N–O ene): 0.73. IR (neat): ν
= 1638 (C=O stretching), 1098 (C–O
˜
max
stretching) cm–1. H NMR (CDCl3, 300 MHz): δH = 1.80 (tt, J =
6.0 Hz, 2 H), 1.88 (tt, J = 6.0 Hz, 2 H), 2.65 (t, J = 9.0 Hz, 2 H),
2.95 (t, J = 7.5 Hz, 2 H), 3.34 (t, J = 7.5 Hz, 2 H), 3.42 (t, J =
stretching), 1526, 1368 (N–O stretching) cm–1. 1H NMR (CDCl3,
300 MHz): δH = 0.97 (t, J = 7.5 Hz, 3 H), 1.09 (t, J = 7.5 Hz, 3
H), 3.52 (m, 4 H), 3.71 (s, 2 H), 6.90–6.98 (m, 2 H), 7.15–7.29 (m,
1
6.0 Hz, 2 H), 6.90 (dd, J = 3.0, J = 6.0 Hz, 1 H), 6.90 (dd, J = 3.0, 3 H), 7.39–7.48 (m, 2 H), 7.90 (dd, J = 1.5, J = 8.0 Hz, 1 H) ppm.
J = 6.0 Hz, 1 H), 7.15 (td, J = 1.5, J = 8.0 Hz, 2 H), 7.12–7.20 (dd,
J = 1.5, J = 8.0 Hz, 1 H), 7.38 (dd, J = 1.5, J = 8.0 Hz, 1 H), 7.46
(td, J = 1.5, J = 8.0 Hz, 1 H), 7.97 (dd, J = J = 1.5, J = 8.0 Hz, 1
13C NMR (CDCl3, 75 MHz): δC = 12.74, 14.02 (CH3), 34.25, 40.31,
42.33 (CH2), 119.12, 119.34, 123.60, 125.11, 125.39 (CH), 127.90
(C), 128.33, 131.49, 134.21 (CH), 140.44, 150.60, 152.73, 169.37
H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 24.52, 26.20, 26.49, (C) ppm. MS (APCI): m/z (%) = 329 (100) [M + H]+. HRMS
35.02, 45.74, 46.56 (CH2), 118.81, 119.52, 122.65, 125.49, 126.06,
128.14, 131.81, 133.40 (CH), 134.48, 140.58, 151.16, 153.13, 170.84
(C) ppm. MS (APCI): m/z (%) = 341 (100) [M + H]+. HRMS
(FAB): calcd. for C19H22N2O4 [M + H]+ 341.1496; found 341.1503.
(FAB): calcd. for C18H20N2O4 [M + H]+ 329.1496; found 329.1495.
(2-{2-(Diethylamino)-1-[2-(2-nitrophenoxy)phenyl]-2-oxoethyl}phen-
yl)azinic Acid (12a): Flash column chromatography (SiO2; 15%
EtOAc in toluene) afforded the title compound as a lemon-yellow
solid (21%). Rf (50% EtOAc in toluene): 0.82, m.p. 124–126 °C
2-[2-(2-Nitrophenoxy)phenyl]-1-(1-piperidyl)propanone (7c): After
aqueous work-up the solvent was evaporated in vacuo to afford the
title compound as a yellow oil (87%). Rf (30% EtOAc in petroleum
(EtOAc in toluene). IR (neat): νmax = 1639 (C=O stretching), 1091
˜
(C–O stretching), 1520, 1346 (N–O stretching) cm–1 1H NMR
.
ether): 0.36. IR (neat): ν
= 1631 (C=O stretching), 1098 (C–O
(CDCl3, 300 MHz): δH = 1.12 (t, J = 7.5 Hz, 3 H), 1.17 (t, J =
7.5 Hz, 3 H), 3.24–3.57 (m, 4 H), 6.27 (s, 1 H), 6.63 (d, J = 9.0 Hz,
1 H), 6.87 (d, J = 9 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.24–7.37
˜
max
stretching), 1583, 1348 (N–O stretching) cm–1. 1H NMR (CDCl3,
300 MHz): δH = 1.55–1.67 (m, 6 H), 2.77 (t, J = 7.5 Hz, 2 H), 3.01
(t, J = 7.5 Hz, 2 H), 3.42 (t, J = 6.0 Hz, 2 H), 3.60 (t, J = 6.0 Hz, (m, 5 H), 7.44–7.52 (m, 2 H), 7.86 (d, J = 9.0 Hz, 1 H), 7.95 (d, J
2 H), 6.79 (d, J = 6.0 Hz, 2 H), 7.22–7.34 (m, 3 H), 7.45 (d, J = = 9.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 12.69,
6.0 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 1 H), 8.04 (d, J = 6.0 Hz, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 24.39, 25.44, 26.18, 124.63, 125.08, 126.04, 127.74, 129.33, 129.51, 130.59, 132.30,
26.76, 33.32, 42.52, 46.42 (CH2), 118.63, 119.17, 122.53, 125.22, 132.74 (CH), 134.16, 134.40, 140.88, 148.93, 149.93, 153.08, 169.43
13.66 (CH3), 40.73, 42.45 (CH2), 44.44, 118.49, 120.08, 123.65,
125.77, 127.94, 131.42 (CH), 132.93 (C), 134.29 (CH), 140.32, (C) ppm. MS (APCI): m/z (%) = 450 (100) [M + H]+. HRMS
150.75, 152.89, 170.24 (C) ppm. MS (APCI): m/z (%) = 355 (100)
[M + H]+. HRMS (FAB): calcd. for C20H22N2O4 [M + H]+
355.1652; found 355.1646.
(FAB): calcd. for C24H23N3O6 [M + H]+ 450.1654; found 450.1660.
{2-[2-(Diethylamino)-1-(2-hydroxyphenyl)-2-oxoethyl]phenyl}azinic
Acid (13a): Flash column chromatography (SiO2; 15% EtOAc in
2-[2-(2-Nitrophenoxy)phenyl]-1-(1-morpholino)propanone
(7d): toluene) afforded the title compound as a yellow solid (10%). Rf
Flash column chromatography (SiO2; 50% petroleum ether) af-
(50% EtOAc in toluene): 0.62, m.p. 161–163 °C (EtOAc in toluene).
forded the title compound as a yellow oil (90%). Rf (30% EtOAc
IR (neat): νmax = 1616 (C=O stretching), 1590, 1376 (N–O stretch-
˜
1
in petroleum ether): 0.36. IR (neat): νmax = 1639 (C=O stretching),
ing) cm–1. H NMR ([D6]DMSO, 300 MHz): δH = 0.09–0.17 (m, 6
˜
Eur. J. Org. Chem. 2014, 1925–1934
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1931

D. Ameen, T. J. Snape
FULL PAPER
H), 2.22–2.47 (m, 4 H), 5.09 (s, 1 H), 5.99–6.08 (m, 3 H), 6.15 (d, = 1642 (C=O stretching), 1068 (C–O stretching), 1584, 1350 (N–O
J = 6.0 Hz, 1 H), 6.33 (t, J = 7.5 Hz, 1 H), 6.61 (t, J = 7.5 Hz, 1 stretching) cm–1. 1H NMR (CDCl3, 300 MHz): δH = 1.48–1.57 (m,
H), 6.71 (t, J = 7.5 Hz, 1 H), 7.09 (d, J = 9.0 Hz, 1 H), 8.96 (s, 1 4 H), 1.65–1.7 (m, 2 H), 3.52 (t, J = 6.0 Hz, 2 H), 3.61 (t, J =
H) ppm. 13C N: δ = MR ([D6]DMSO, 75 MHz): 12.30, 13.08
6.0 Hz, 2 H), 3.86 (s, 2 H), 7.03 (t, J = 9.0 Hz, 2 H), 7.29 (d, J =
(CH3), 39.38, 41.09 (CH2), 43.40, 115.22, 119.28 (CH), 123.42, 6.0 Hz, 1 H), 7.34–7.41 (m, 2 H), 7.53–7.62 (m, 2 H), 8.04 (dd, J
123.81 (C), 127.43, 128.49, 128.74, 131.18, 132.47, 134.57 (CH),
= 1.5, J = 8.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC
24.37, 25.45, 26.16, 34.24, 42.88, 46.99 (CH2), 119.28, 119.35,
=
149.00, 154.29, 169.04 (C) ppm. MS (APCI): m/z (%) = 329 (100)
[M + H]+. HRMS (FAB): calcd. for C18H20N2O4 [M + H]+ 122.72, 125.23, 125.52, 128.40, 131.31, 134.25 (CH), 127.70, 140.55,
329.1496; found 329.1497.
150.65, 152.55, 168.54 (C) ppm. MS (APCI): m/z (%) = 341 (100)
[M + H]+. HRMS (FAB): calcd. for C19H20N2O4 [M + H]+
341.1496; found 341.1498.
2-[2-(2-Nitrophenoxy)phenyl]-1-(pyrrolidin-1-yl)ethanone (11b):
Flash column chromatography (SiO2; 100% petroleum ether) af-
forded the title compound as yellow oil (90%). Rf (30% EtOAc in
2-[2-(2-Nitrophenoxy)phenyl]-2-(2-nitrophenyl)-1-(1-piperidyl)eth-
petroleum ether): 0.39. IR (neat): ν
= 1636 (C=O stretching),
anone (12c): Flash column chromatography (SiO2; 10% EtOAc in
˜
max
1247 (C–N stretching), 1098 (C–O stretching), 1522, 1345 (N–O toluene) afforded the title compound as a lemon-yellow oil (24%).
stretching) cm–1. 1H NMR (CDCl3, 300 MHz): δH = 1.69–1.92 (m, R (50% EtOAc in toluene): 0.63. IR (neat): ν
= 1639 (C=O
˜
f
max
4 H), 3.31 (t, J = 6.0 Hz, 2 H), 3.43 (t, J = 7.5 Hz, 2 H), 3.67 (s, 2
H), 6.90 (dd, J = 1.5, J = 8.0 Hz, 1 H), 6.95 (dd, J = 1.5, J =
8.0 Hz, 1 H), 7.13–7.26 (m, 3 H), 7.41 (dd, J = 1.5, J = 8.0 Hz, 1
H), 7.45 (dd, J = 1.5, J = 8.0 Hz, 1 H), 7.92 (dd, J = 1.5, J =
8.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 24.43, 26.15,
stretching), 1094 (C–O stretching), 1521, 1346 (N–O stretch-
1
ing) cm–1. H NMR (CDCl3, 300 MHz): δH = 1.48–1.60 (m, 6 H),
3.29–3.36 (m, 1 H), 3.51–3.57 (m, 2 H), 3.68–3.74 (m, 1 H), 6.32
(s, 1 H), 6.60 (d, J = 9.0 Hz, 1 H), 6.88 (d, J = 9.0 Hz, 1 H), 7.09–
7.37 (m, 6 H), 7.47 (t, J = 6.0 Hz, 2 H), 7.85 (d, J = 9.0 Hz, 1 H),
35.89, 45.93, 46.89 (CH2), 119.49, 119.56, 122.68, 125.41, 125.51 7.90 (d, J = 6.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC
=
(CH), 127.84 (C), 128.60, 132.01, 134.35 (CH), 140.64, 150.92,
24.55, 25.67, 25.86, 43.42, 47.03 (CH2), 44.32, 118.68, 119.89,
123.57, 124.65, 125.08, 125.95, 127.67 (CH), 128.84 (C), 129.51,
153.09, 168.74 (C) ppm. MS (APCI): m/z (%) = 327 (100) [M +
H]+. HRMS (FAB): calcd. for C18H18N2O4 [M + H]+ 327.1339; 130.86, 132.11, 132.80, 134.08 (CH), 134.55, 140.69, 148.70, 149.26,
found 327.1343.
152.82, 168.49 (C) ppm. MS (APCI): m/z (%) = 462 (100) [M +
H]+. HRMS (FAB): calcd. for C25H23N3O6 [M + H]+ 462.1660;
found 462.1654.
2-[2-(2-Nitrophenoxy)phenyl]-2-(2-nitrophenyl)-1-(pyrrolidin-1-yl)eth-
anone (12b): Flash column chromatography (SiO2; 10% EtOAc in
toluene) afforded the title compound as a yellow solid (19%). Rf
(30% EtOAc in toluene): 0.46, m.p. 160–162 °C (EtOAc in toluene).
2-(2-Hydroxyphenyl)-2-(2-nitrophenyl)-1-(1-piperidyl)ethanone
(13c): Flash column chromatography (SiO2; 10% EtOAc in tolu-
ene) afforded the title compound as a colourless solid (21%). Rf
IR (neat): ν
= 1638 (C=O stretching), 1187 (C–O stretching),
˜
max
1234 (C–N stretching),1518, 1341 (N–O stretching) cm–1. 1H NMR (50% EtOAc in toluene): 0.81, m.p. 177–179 °C. IR (neat): ν
=
˜
max
(CDCl3, 300 MHz): δH = 1.77–1.95 (m, 4 H), 3.18–3.25 (m, 1 H),
3.35–3.44 (m, 1 H), 3.49–3.55 (m, 1 H), 3.58–3.66 (m, 2 H), 6.08
(s, 1 H), 6.55 (dd, J = 1.0, J = 8.0 Hz, 1 H), 6.80 (dd, J = 1.0, J =
8.0 Hz, 1 H), 7.06 (td, J = 1.0, J = 8.0 Hz, 1 H), 7.14–7.29 (m, 5
H), 7.39–7.46 (m, 2 H), 7.77 (d, J = 8.0 Hz, 1 H) 7.84 (dd, J = 1.0,
J = 8.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 24.45,
26.81 (CH2), 45.88 (CH), 46.31, 46.46 (CH2), 118.63, 119.80,
1618 (C=O stretching), 1596, 1352 (N–O stretching), 3177 (H–O
stretching) cm–1. 1H NMR (CDCl3, 300 MHz): δH = 1.44–1.75 (m,
6 H), 3.44–3.51 (m, 1 H), 3.56–3.65 (m, 3 H), 5.96 (s, 1 H), 6.88–
6.92 (m, 2 H), 7.11 (d, J = 7.5 Hz, 1 H), 7.17 (d, J = 7.5 Hz, 1 H),
7.25 (t, J = 7.5 Hz, 1 H), 7.39 (t, J = 7.5 Hz, 1 H), 7.46 (t, J =
7.5 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR ([D6]-
DMSO, 75 MHz): δC = 24.45, 25.64, 25.73, 43.86, 47.51 (CH2),
123.47, 124.63, 125.21, 125.95, 127.81, 129.07, 129.43, 130.53, 49.45, 118.16, 120.70 (CH), 121.39 (C), 125.06, 128.08, 129.99,
132.23, 132.91 (CH), 133.91, 134.10, 140.74, 148.99, 149.46, 153.27,
131.46, 131.51, 133.30, (CH), 133.62, 148.82, 156.24, 170.32
168.53 (C) ppm. MS (APCI): m/z (%) = 448 (100) [M + H]+.
(C) ppm. MS (APCI): m/z (%) = 341 (100) [M + H]+. HRMS
HRMS (FAB): calcd. for C24H21N3O6 [M + H]+ 448.1503; found (FAB): calcd. for C19H20N2O4 [M + H]+ 341.1496; found 341.1499.
448.1495.
2-[2-(2-Nitrophenoxy)phenyl]-1-morpholinoethanone (11d): Flash
2-(2-Hydroxyphenyl)-2-(2-nitrophenyl)-1-(pyrrolidin-1-yl)ethanone
(13b): Flash column chromatography (SiO2; 16% EtOAc in tolu-
ene) afforded the title compound as a colourless solid (33%). Rf
(30% EtOAc in toluene): 0.67, m.p. 189–191 °C (EtOAc in toluene).
column chromatography (SiO2; 40% EtOAc in toluene) afforded
the title compound as a lemon-yellow oil (45%). Rf (50% EtOAc
in toluene): 0.37. IR (neat): νmax = 1642 (C=O stretching), 1068 (C–
˜
O stretching), 1584, 1350 (N–O stretching) cm–1. 1H NMR (CDCl3,
300 MHz): δH = 3.47–352 (m, 8 H), 3.71 (s, 2 H), 6.89 (m, 2 H),
7.12–7.18 (m, 2 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.38–7.47 (m, 2 H),
IR (neat): νmax = 1615 (C=O stretching), 1584, 1345 (N–O stretch-
˜
ing), 2951 (H–O stretching) cm–1. 1H NMR (CDCl3, 300 MHz): δH
= 1.81–1.97 (m, 3 H), 2.03–2.10 (m,1 H), 3.38–3.62 (m, 3 H), 3.87–
3.94 (m, 1 H), 5.64 (s, 1 H), 6.92–6.99 (m, 2 H), 7.15 (t, J = 7.5 Hz,
2 H), 7.28 (t, J = 7.5 Hz, 1 H), 7.40–7.50 (m, 2 H), 7.99 (d, J =
7.5 Hz, 1 H), 8.74 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC
7.89 (d, J = 9.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz), δC
=
34.09, 42.25, 46.37, 66.64, 66.79 (CH2), 119.27, 119.53, 123.05,
125.44, 125.74 (CH), 127.09 (C), 128.79, 131.46, 134.41 (CH),
140.75, 150.55, 152.62, 169.20, (C) ppm. MS (APCI): m/z (%) =
= 24.44, 26.14, 25.87, 25.90 (CH2), 46.68, 119.04 (CH), 120.27 (C), 343 (100) [M + H]+. HRMS (FAB): calcd. for C18H18N2O5 [M +
120.67, 125.22 (CH), 120.27 (C), 128.40, 130.36, 131.21, 132.20,
133.44 (CH), 132.39, 148.88, 157.25, 170.60 (C) ppm. MS (APCI):
m/z (%) = 327 (100) [M + H]+. HRMS (FAB): calcd. for
C18H18N2O4 [M + H]+ 327.1339; found 327.1343.
H]+ 343.1288; found 343.1288.
2-[2-(2-Nitrophenoxy)phenyl]-1-morpholino-2-(2-nitrophenyl)eth-
anone (12d): Flash column chromatography (SiO2; 30% EtOAc in
toluene) afforded the title compound as a sticky orange oil (6%).
2-[2-(2-Nitrophenoxy)phenyl]-1-(1-piperidyl)ethanone (11c): Flash
column chromatography (SiO2; 10% EtOAc in toluene) afforded
the title compound as a lemon-yellow solid (54%). Rf (50% EtOAc
R (50% EtOAc in toluene): 0.48. IR (neat): ν
= 1645 (C=O
˜
f
max
stretching), 1111 (C–O stretching), 1522, 1347 (N–O stretch-
1
ing) cm–1. H NMR (CDCl3, 300 MHz): δH = 3.35–3.45 (m, 2 H),
in toluene): 0.55, m.p. 74–76 °C (EtOAc in toluene). IR (neat): ν
3.62–3.79 (m, 6 H), 6.31 (s, 1 H), 6.61 (d, J = 8.0 Hz, 1 H), 6.85
˜
max
1932
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1925–1934

Developing the Scope of OǞC Aryl Migrations
(d, J = 8.0 Hz, 1 H), 7.11–7.18 (m, 2 H), 7.23–7.37 (m, 4 H), 7.45– NMR (CDCl3, 300 MHz): δH = 4.21 (d, J = 15.0 Hz, 1 H, HA/B),
7.50 (m, 2 H), 7.90 (t, J = 9.0 Hz, 2 H) ppm. 13C NMR (CDCl3, 4.53 (d, J = 15.0 Hz, 1 H, HC/D), 4.73 (d, J = 15.0 Hz, 1 H, HD/C),
75 MHz): δC = 42.82 (CH2), 44.44 (CH), 46.47, 66.59, 66.95 (CH2),
4.88 (d, J = 15.0 Hz, 1 H, HB/A), 6.15 (s, 1 H), 6.82 (t, J = 7.5 Hz,
118.38, 120.41, 123.97, 124.93, 125.18, 126.18, 127.98, 129.85, 1 H), 6.94 (m, 3 H), 7.01 (d, J = 6.0 Hz, 1 H), 7.14 (m, 2 H), 7.24–
130.89, 132.02, 133.06, 134.16 (CH), 134.40, 140.88, 148.93, 149.93,
7.31 (m, 4 H), 7.44 (t, J = 7.5 Hz, 1 H), 7.53 (t, J = 7.5 Hz, 1 H),
7.79 (s, 1 H), 8.01 (d, J = 6.0 Hz, 1 H) ppm. 13C NMR (CDCl3,
153.08, 169.43 (C) ppm. MS (APCI): m/z (%) = 464 (100) [M +
H]+. HRMS (FAB): calcd. for C24H22N3O7 [M + H]+ 464.1452; 75 MHz): δC = 48.35 (CH2), 49.36 (CH), 50.90 (CH2), 118.21,
found 464.1455.
121.00 (CH), 121.51, 125.20, 127.63, 127.69, 127.88, 128.35, 128.68,
128.86, 130.19, 131.48 (CH), 131.82 (C), 133.00 (CH), 133.31,
135.17, 136.30, 148.97, 155.85, 172.98 (C) ppm. MS (APCI): m/z
(%) = 451 (100) [M – H]+. HRMS (FAB): calcd. for C28H24N2O4
[M + H]+ 453.1809; found 453.1805.
2-(2-Hydroxyphenyl)-1-morpholino-2-(2-nitrophenyl)ethanone (13d):
Flash column chromatography (SiO2; 10% EtOAc in toluene) af-
forded the title compound as a yellow solid (45%). Rf (50% EtOAc
in toluene): 0.22, m.p. 157–159 °C. IR (neat): ν
= 1619 (C=O
˜
max
stretching), 1112 (C–O stretching), 1515, 1343 (N–O stretch-
1-[(2S,5S)-2,5-Bis(methoxymethyl)pyrrolidin-1-yl]-2-(2-hydroxy-
phenyl)ethanone (17): Flash column chromatography (SiO2; 60%
EtOAc in petroleum ether) to afford the title compound as yellow
sticky oil (99%). Rf (30% EtOAc in petroleum ether): 0.42. [α]589
1
ing) cm–1. H NMR (CDCl3, 300 MHz): δH = 3.08–3.18 (m, 2 H),
3.35–3.57 (m, 6 H), 5.99 (s, 1 H), 6.88–6.92 (m, 3 H), 7.04 (d, J =
6.0 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H),
7.56 (t, J = 7.5 Hz, 1 H), 7.99 (d, J = 9.0 Hz, 1 H), 9.86 (s, 1
H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δC = 41.95, 45.55,
65.30, 65.88 (CH2), 43.39, 115.42, 119.41 (CH), 122.50 (C), 124.08,
127.63, 128.83, 128.98, 131.06, 132.83, (CH), 134.50, 148.73,
154.15, 168.78 (C) ppm. MS (APCI): m/z (%) = 343 (100) [M + H]
+. HRMS (FAB): calcd. for C18H18N2O5 [M + H]+ 343.1289; found
343.1288.
= –53.43 (ethanol, c = 0.46 g/100 mL). IR (neat): νmax = 1618 (C=O
˜
1
stretching), 2929 (OH stretching), 1040 (C–O stretching) cm–1. H
NMR (CDCl3, 300 MHz): δH = 1.88–2.01 (m, 3 H), 2.12–2.21 (m,
1 H), 2.25–3.54 [m, 10 H includes 2ϫ (s, 3 H) at 3.24 and 3.37],
3.73 (d, J = 14.0 Hz, 1 H, HA/B), 3.82 (d, J = 14.0 Hz, 1 H, HB/A),
4.20–4.27 (m, 2 H), 6.81 (t, J = 6.0 Hz, 1 H), 6.97 (d, J = 8.0 Hz,
1 H), 7.03 (d, J = 7.0 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 1 H) ppm. 13C
NMR (CDCl3, 75 MHz): δC = 25.81, 27.54, 39.53 (CH2), 57.69,
(CH), 59.15 (CH3), 59.41 (CH), 71.29, 74.79 (CH2), 118.49, 119.95
(CH), 121.62 (C), 129.18, 130.08 (CH), 157.23, 173.46 (C) ppm.
MS (APCI): m/z (%) = 294 (100) [M + H]+. HRMS (FAB): calcd.
for C16H23NO4 [M + H]+ 294.1700; found 294.1702.
2-[2-(2-Nitrophenoxy)phenyl]-N,N-dibenzylacetamide (11e): Flash
column chromatography (SiO2; 10% EtOAc in petroleum ether)
afforded the title compound as a yellow oil (40%). Rf (30% EtOAc
in petroleum ether): 0.49. IR (neat): νmax = 1644 (C=O stretching),
˜
1079 (C–O stretching), 1523, 1349 (N–O stretching) cm–1. 1H NMR
(CDCl3, 300 MHz): δH = 3.90 (s, 2 H), 4.55 (s, 2 H), 4.59 (s, 2 H),
6.88 (dd, J = 1.5, J = 8.0 Hz, 1 H), 7.07 (dd, J = 1.5, J = 8.0 Hz,
1 H), 7.12–7.15 (m, 3 H), 7.18–7.36 (m, 10 H), 7.45 (dd, J = 1.5, J
= 8.0 Hz, 1 H), 7.50 (dd, J = 1.5, J = 8.0 Hz, 1 H), 7.97 (dd, J =
1-[(2S,5S)-2,5-Bis(methoxymethyl)pyrrolidin-1-yl]-2-[2-(2-nitrophen-
oxy)phenyl]-2-(2-nitrophenyl)ethanone (18): Flash column
chromatography (SiO2; 35% EtOAc in petroleum ether) to afford
the title compound as a lemon-yellow sticky oil (10%). Rf (60%
EtOAc in petroleum ether): 0.65. [α]589 = –62.85 (ethanol, c = 0.
1.5, J = 8.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC
=
34.80, 48.65, 50.38 (CH2), 118.83, 120.41, 123.04, 125.08, 125.67,
126.53, 127.41, 127.64, 128.34, 128.61, 128.76, 128.98, 131.99,
134.46 (CH), 136.43, 137.29, 141.00, 150.76, 153.65, 171.19
(C) ppm. MS (APCI): m/z (%) = 453 (100) [M + H]+. HRMS
(FAB): calcd. for C28H24N2O4 [M + H]+ 453.1809; found 453.1810.
24 g/100 mL). IR (neat): ν
= 1639 (C=O stretching), 1109 (C–
˜
max
O stretching), 1524, 1348 (N–O stretching) cm–1. 1H NMR (CDCl3,
300 MHz): δH = 0.75–0.79 (m, 1 H), 1.73–1.92 (m, 8 H), 2.83 (s, 3
H), 2.95–3.09 [m, 5 H, includes (s, 3 H) at 3.09], 3.18 (s, 3 H), 3.21–
3.27 [m, 6 H, includes (s, 3 H) at 3.23], 3.36 (dd, J = 9.0 Hz, 1 H),
3.52 (td, J = 6.0, J = 9.0 Hz, 3 H), 3.71–3.73 (m, 1 H), 4.08–4.15
(m, 1 H), 4.16–4.20 (m, 2 H), 6.07 (s, 1 H), 6.18 (s, 1 H), 6.48 (d,
J = 8.0 Hz, 1 H), 6.75 (t, J = 9.0 Hz, 3 H), 7.00–7.40 (m, 15 H),
7.65 (d, J = 9.0 Hz, 1 H), 7.81 (dd, J = 1.0, J = 8.0 Hz, 3 H) ppm.
13C NMR (CDCl3, 75 MHz): δC = 2 = 5.49, 25.58, 27.48, 27.73
(CH2), 45.61, 46.20, 57.82, 57.89 (CH3), 58.59, 58.75, 58.81, 58.90
(CH), 70.60, 70.71, 73.76,73.79 (CH2), 117.97, 118.88, 119.76,
120.72, 123.32, 123.82, 124.51, 124.68, 124.75, 125.04, 125.81,
127.78, 128.01, 129.10, 129.25 (CH), 129.42 (C), 130.20, 130.40
(CH), 130.66 (C), 132.15,132.57, 132.80, 132.89 (CH), 133.74,
133.94 (C), 134.09, 134.27 (CH), 140.85, 141.39, 149.05, 149.36,
149.62, 152.98, 153.75, 168.92, 169.50 (C) ppm. MS (APCI): m/z
(%) = 536 (100) [M + H]+. HRMS (FAB): calcd. for C28H29N3O8
[M + H]+ 536.2027; found 536.2015.
2-[2-(2-Nitrophenoxy)phenyl]-N,N-dibenzyl-2-(2-nitrophenyl)acet-
amide (12e): Flash column chromatography (SiO2; 20% EtOAc in
petroleum ether) afforded the title compound as orange crystals
(54%). Rf (30% EtOAc in petroleum ether): 0.44, m.p. 170–172 °C
(EtOAc in petroleum ether). IR (neat): ν
= 1647 (C=O stretch-
˜
max
ing) cm–1. 1H NMR (CDCl3, 300 MHz): δH = 4.39 (d, J = 15.0 Hz,
1 H, HA/B), 4.52 (d, J = 15.0 Hz, 1 H, HC/D), 4.64 (d, J = 15.0 Hz,
1 H, HD/C), 4.88 (d, J = 15.0 Hz, 1 H, HB/A), 6.45 (dd, J = 3.0, J
= 9.0 Hz, 1 H), 6.51 (s, 1 H), 6.75 (dd, J = 1.0, J = 8.0 Hz, 1 H),
6.94–6.98 (m, 2 H), 7.11 (td, J = 3.0, J = 9.0 Hz, 1 H), 7.16–7.38
(m, 13 H), 7.50 (d, J = 6.0 Hz, 2 H), 7.88 (dt, J = 3.0, J = 9.0 Hz,
2 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 44.27 (CH), 48.44
50.68 (CH2), 118.59, 120.21 123.65, 124.84, 124.93, 125.95, 127.45,
127.48, 127.96, 128.59, 128.65, 128.74, 129.63, 130.95, 132.33,
132.95, 134.10 (CH), 135.73, 136.91, 140.96, 148.89, 149.29, 153.25,
171.08 (C) ppm. MS (APCI): m/z (%) = 574 (100) [M + H]+.
HRMS (FAB): calcd. for C34H27N3O6 [M + H]+ 574.1973; found
574.1963.
1-[(2S,5S)-2,5-Bis(methoxymethyl)pyrrolidin-1-yl]-2-(2-hydroxy-
phenyl)-2-(2-nitrophenyl)ethanone (19): Flash column chromatog-
raphy (SiO2; 35% EtOAc in petroleum ether) to afford the title
compound as a yellow solid (45%). Rf (60% EtOAc in petroleum
N,N-Dibenzyl-2-(2-hydroxyphenyl)-2-(2-nitrophenyl)acetamide
(13e): Flash column chromatography (SiO2; 25% EtOAc in petro-
leum ether) afforded the title compound as a colourless solid
ether): 0.73, m.p. 126–128 °C (EtOAc in petroleum ether). [α]589
=
–75.76 (ethanol, c = 0.5 g/100 mL). IR (neat): ν = 1620 (C=O
˜
max
stretching), 1113 (C–O stretching), 1524, 1356 (N–O stretching),
(37%). Rf (30% EtOAc in petroleum ether): 0.60, m.p. 195–197 °C 3243 (O–H stretching) cm–1. 1H NMR (CDCl3, 300 MHz): δH
=
(EtOAc in petroleum ether). IR (neat): ν
= 1618 (C=O stretch-
0.62–0.66 (m, 1 H), 1.58–1.63 (m, 4 H), 1.69–1.76 (m, 2 H), 1.92–
1.98 (m, 1 H), 2.78 (s, 3 H), 2.93 (d, J = 3.0 Hz, 1 H), 2.99 (s, 3
˜
max
ing), 1599, 1344 (N–O stretching), 3267 (H–O stretching) cm–1. 1H
Eur. J. Org. Chem. 2014, 1925–1934
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1933

D. Ameen, T. J. Snape
FULL PAPER
H), 3.02 (s, 3 H), 3.08 (s, 3 H), 3.13 (d, J = 9.0 Hz, 1 H), 3.22 (t,
J = 9.0 Hz, 1 H), 3.39 (td, J = 2.0, J = 9.0 Hz, 2 H), 3.51–3.59 (m,
9.0 Hz, 1 H), 7.30 (d, J = 9.0 Hz, 1 H), 7.37 (t, J = 9.0 Hz, 2 H),
7.48 (d, J = 9.0 Hz, 1 H), 7.53 (d, J = 9.0 Hz, 1 H), 7.90 (d, J =
2 H), 3.99–4.06 (m, 2 H), 5.73 (s, 1 H), 5.81 (s, 1 H), 6.43 (d, J = 9.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 25.47, 27.76
7.5 Hz, 1 H), 6.60–6.63 (m, 2 H), 6.85 (d, J = 7.5 Hz, 1 H), 6.88
(m, 3 H), 6.95–7.12 (m, 5 H), 7.60 (d, J = 7.5 Hz, 1 H), 7.66 (d, J
(CH2), 45.58, 55.55, 58.21 (CH3), 58.30, 58.63, 58.88 (CH), 70.58,
73.80, (CH2), 122.71, 124.23, 126.57, 128.06, 129.11, 130.05 (CH),
= 7.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 25.23, 131.12 (C), 133.18, 133.26 (CH), 133.96, 148.73, 153.30, 168.55
27.04, 27.30 (CH2), 46.90, 47.33, 57.21, 57.68 (CH3), 58.06, 58.26,
58.47, 58.57 (CH), 70.26, 70.40, 73.11 (CH2), 116.01, 116.19,
119.77, 119.95 (CH), 122.86, 122.95 (C), 124.29, 124.32, 127.43,
127.68, 129.14,129.24, 129.42, 129.82, 131.68, 131.84, 132.66,
132.75 (CH), 133.85, 133.94, 148.86, 149.12, 154.75, 154.85, 171.02,
171.25 (C) ppm. MS (APCI): m/z (%) = 415 (100) [M + H]+.
HRMS (FAB): calcd. for C22H26N2O6 [M + H]+ 415.1864; found
415.1861.
(C) ppm. MS (APCI): m/z (%) = 471 [M – H]+, (40), 457 (100) [M –
CH3]+.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra.
Acknowledgments
The authors would like to thank Hawler Medical University, Kurd-
istan, Iraq for financial support (to D. A.). Further the EPSRC
National X-ray Crystallography Service and the EPSRC National
Mass Spectrometry Facility (NMSF) are thanked for support.
1-[(2S,5S)-2,5-Dimethylpyrrolidin-1-yl]-2-(2-hydroxyphenyl)eth-
anone: Flash column chromatography (SiO2; 5% EtOAc in toluene)
afforded the title compound as a colourless solid (73%). Rf (20%
EtOAc in toluene): 0.56, m.p. 142–144 °C (EtOAc in toluene).
[α]589 = –69.8 (ethanol, c = 0.2 g/100 mL). IR (neat): ν
= 1560
˜
max
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(C=O stretching), 2965 (OH stretching), 1035 (C–O stretch-
1
ing) cm–1. H NMR (CDCl3, 300 MHz): δH = 1.15 (d, J = 6.0 Hz,
3 H), 1.31 (d, J = 6.0 Hz, 3 H), 1.57–1.61 (m, 1 H), 1.66–1.71 (m,
1 H), 2.07–2.29 (m, 2 H), 3.67 (d, J = 15.0 Hz, 1 H, HA/B), 3.73 (d,
J = 15.0 Hz, 1 H, HB/A), 4.21–4.28 (m, 2 H), 6.80 (t, J = 7.5 Hz, 1
H), 6.97–7.03 (m, 2 H), 7.17 (t, J = 7.5 Hz, 1 H), 11.01 (s, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δC = 19.02, 22.56 (CH3),
29.20, 30.84, 39.32 (CH2), 53.99, 55.04 (CH), 118.54, 119.77 (CH),
121.62 (C), 129.14, 130.73 (CH), 157.55, 172.18 (C) ppm. MS
(APCI): m/z (%) = 234 (100) [M + H]+.
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1-[(2S,5S)-2,5-Bis(methoxymethyl)pyrrolidin-1-yl]-2-[2-(2-nitrophen-
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40% EtOAc in petroleum ether) to afford the title compound as
lemon-yellow sticky oil (45%). Rf (60% EtOAc in petroleum ether):
0.50. IR (neat): ν
= 1639 (C=O stretching), 1107 (C–O stretch-
˜
max
ing), 1583, 1350 (N–O stretching) cm–1. 1H NMR (CDCl3,
300 MHz): δH = 1.83–1.98 (m, 4 H), 2.97 (t, J = 6.0 Hz, 1 H), 3.18
(s, 3 H), 3.20–3.41 [m, 6 H, includes (s, 3 H) at 3.29], 3.64 (d, J =
15.0 Hz, 1 H, HA/B), 3.94 (d, J = 15.0 Hz, 1 H, HB/A), 4.08–4.14
(m, 2 H), 6.89 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 7.15–
7.26 (m, 3 H), 7.37 (dd, J = 1.0, J = 8.0 Hz, 1 H), 7.46 (td, J =
1.0, J = 8.0 Hz, 1 H), 7.90 (dd, J = 1.0, J = 8.0 Hz, 1 H) ppm. 13C
NMR (CDCl3, 75 MHz): δC = 25.34, 27.09, 36.54 (CH2), 57.07,
57.93 (CH3), 58.79, 59.09 (CH), 70.88, 74.20 (CH2), 119.109,
119.67, 122.71, 125.21, 125.49 (CH), 128.18 (C), 128.52, 132.21,
134.26 (CH), 140.84, 150.82, 153.21, 169.80 (C) ppm. MS (APCI):
m/z (%) = 415 (100) [M + H]+. HRMS (FAB): calcd. for
C22H26N2O6 [M + H]+ 415.1864; found 415.1861.
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Received: November 14, 2013
Methyl 3-[(2S,5S)-2,5-Bis(methoxymethyl)pyrrolidin-1-yl]-2-[2-(2-
nitrophenoxy)phenyl]-3-oxopropanoate: Flash column chromatog-
raphy (SiO2; 36% EtOAc in petroleum ether) to afford the title
compound as a lemon-yellow powder (57%). Rf (60% EtOAc in
petroleum ether): 0.63, m.p. 191–193᭺C (EtOAc/petroleum
ether). IR (neat): ν
= 1766 (C=O stretching, ester), 1646 (C=O
˜
max
stretching), 1113 (C–O stretching), 1521, 1340 (N–O stretch-
1
ing) cm–1. H NMR (CDCl3, 300 MHz): δH = 1.87–2.08 (m, 3 H),
2.13–2.25 (m, 1 H), 2.94–3.00 [m, 5 H, includes (s, 3 H) at 2.94],
3.25–3.32 [m, 4 H, includes (s, 3 H) at 3.28], 3.61–3.76 [m, 4 H,
includes (s, 3 H) at 3.65], 4.22–4.28 (m, 1 H), 4.31–4.35 (m, 1 H),
5.97 (s, 1 H), 6.19 (s, 1 H), 7.17 (d, J = 7.83 Hz, 1 H), 7.24 (d, J =
Published Online: January 15, 2014
1934
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Eur. J. Org. Chem. 2014, 1925–1934