Memory of chirality of tertiary aromatic amide: Application to the asymmetric synthesis of (S)-α-methylDOPA

Article abstract of DOI:10.1021/jo301588t

We describe an original asymmetric synthesis of (S)-α-methylDOPA proceeding by the concept of memory of chirality, the only source of chirality being the starting d-alanine. The initial chirality of the amino acid is temporarily transferred to a dynamic axial chirality of a tertiary aromatic amide. The (S)-α-methylDOPA hydrochloride is obtained after four steps with 98% ee.

Full text of DOI:10.1021/jo301588t

Note
pubs.acs.org/joc
Memory of Chirality of Tertiary Aromatic Amide: Application to the
Asymmetric Synthesis of (S)‑α-MethylDOPA
Thi Thoa Mai, Baby Viswambharan, Didier Gori, Cyrille Kouklovsky, and Valerie Alezra*
́
Laboratoire de Chimie des Proced
Naturelles, ICMMO, UMR 8182, CNRS, Bat
́
es
́
et Substances Naturelles, Univ Paris-Sud, Laboratoire de Chimie des Proced
́ ́
es et Substances
̂
410, Orsay F-91405, France
S
* Supporting Information
ABSTRACT: We describe an original asymmetric synthesis of
(S)-α-methylDOPA proceeding by the concept of memory of
chirality, the only source of chirality being the starting D-
alanine. The initial chirality of the amino acid is temporarily
transferred to a dynamic axial chirality of a tertiary aromatic
amide. The (S)-α-methylDOPA hydrochloride is obtained
after four steps with 98% ee.
substantial amount of quaternary α-amino acids possess
Scheme 1. Strategy for the (S)-α-MethylDOPA Synthesis
A
interesting biological activity,1 and thus, many asymmetric
syntheses have been described so far for these compounds.2
The asymmetry can be introduced through a chiral auxiliary or
a chiral catalyst, but few methods benefit from the chirality of a
natural tertiary α-amino acid used as starting material. Among
the self-regeneration of stereocenters developed by Seebach,3
methods based on memory of chirality4 have recently been
explored. Almost all of these methods have been applied to the
synthesis of (S)-α-methylDOPA, a well-known quaternary
amino acid, used in the treatment of hypertension. Several total
asymmetric syntheses have thus already been described, some
of them using a chiral auxiliary,5 other using a chiral catalyst6 or
simply resolution of a racemic intermediate7 or application of
the self-regeneration of stereocenters.8 According to the
concept of Memory of Chirality, the strategy could be to
start from a chiral tertiary amino acid, either alanine or DOPA,
and to perform an alkylation. This strategy has been applied by
Kawabata starting from L-DOPA and led to a (S)-α-
methylDOPA derivative with 80% ee.9 We have been interested
for a few years in the development of new methods to
synthesize nonproteinogenic amino acids,10 in particular,
quaternary α-amino acids by memory of chirality.11 We have
applied this original methodology to model substrates, and we
wanted to extend this efficiently to the total synthesis of a
biologically active compound, such as (S)-α-methylDOPA. In
this paper, we describe a four-step asymmetric total synthesis of
(S)-α-methylDOPA hydrochloride, starting from D-alanine.
The reaction we developed according to the concept of
memory of chirality was based on the dynamic axial chirality of
tertiary aromatic amides.12 The strategy, applied to the
synthesis of (S)-α-methylDOPA, is depicted below (Scheme
1): initial central chirality of the starting natural α-amino acid
should temporarily be transferred to a tertiary aromatic amide
(in our case, a naphthoyl amide), and induce an axial chirality;
this retained axial chirality should then lead to stereoselective
deprotonation/alkylation, even though the initial central
chirality is lost during deprotonation. As we previously
observed11a that alkylation occurs always with retention of
configuration, we thus planned to start from D-alanine to obtain
the (S)-α-methylDOPA.
The first step, preparation of oxazolidinone 1, was achieved
as previously described.11a Compound 1 was obtained with
50% yield without racemization (Scheme 2).
For the second step, deprotonation/alkylation, our previous
studies had shown that for alanine derivative the best solvent
was THF, without the presence of toluene (removed from the
commercial solution of KHMDS). We tried to optimize the
reaction by changing the base, the leaving group of the
Received: July 26, 2012
Published: September 5, 2012
© 2012 American Chemical Society
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dx.doi.org/10.1021/jo301588t | J. Org. Chem. 2012, 77, 8797−8801

The Journal of Organic Chemistry
Note
Scheme 2. Synthesis of Oxazolidinone 1
Table 2. Direct Hydrolysis of Compound 2
entry
1
conditions
results
HBr (47%), 130 °C, overnight
mixture including Pictet−
electrophile, and the reaction time. The results obtained are
gathered in Table 1.
Spengler cyclization
2
3
4
5
6
7
HCl 6 N, 135 °C, 5 days
2 recovered (org layer) +
mixture (aq layer)
a
(i) concd HCl, AcOH, reflux, 2 h; (ii)
TMSCHN2, MeOH, THF, 0.5 h
no reaction, 2 recovered
Table 1. Alkylation of Oxazolidinone 1
(i) concd HCl, AcOH, reflux, 24 h; (ii) degradation
TMSCHN2, MeOH, THF, 0.5 h
CsOH (5 equiv), EtOH, H2O, sealed
oxazolidinone hydrolysis
(compound 4)
tube, 95 °C, 2 h, then H+
CsOH (5 equiv), EtOH, H2O, sealed
oxazolidinone hydrolysis
(compound 4)
tube, 95 °C, 24 h, then H+
6 N HCl, AcOH (3 equiv), PhOH (3
equiv), 110 °C, 7 h
no reaction, 2 recovered
b
c
t1/t2
(min)
conv
yield
(%)
b
entry
base
X
(%)
ee (%)
major product in the aqueous layer was a tetrahydroisoquino-
leine arising from Pictet−Spengler cyclization on the acetone−
iminium intermediate.14 We tried also various other conditions
(entries 3, 4, and 7), but either no reaction occurred or
degradation was observed. Basic hydrolysis led only to
hydrolysis of the oxazolidinone ring (entries 5 and 6).
d
1
2
3
4
5
6
7
8
9
KHMDS
NaHMDS
KHMDS
Br
Br
Br
Br
Br
I
3/10
3/10
1/10
0/10
3/10
1/10
1/2
100
85
81 (98 )
82
e
f
72
f
100
95
80
g
f
KHMDS
82
h
KHMDS
100
100
100
0
79
84
f
KHMDS
KHMDS
KHMDS
KHMDS
61
To avoid the Pictet−Spengler reaction, we then decided to
first hydrolyze the oxazolidinone ring. This was achieved under
basic conditions with 92% yield. Hydrolysis of the amide and
the acetal were then studied (Table 3). Use of iodhydric acid
led to degradation products (entry 1).15,5a Application of
reductive conditions, with the Schwartz reagent,16,10a gave
access to the expected methyl ester but with a low yield (entry
2). We observed degradation when the reaction was heated
under acidic conditions at high temperature for a prolonged
time (entries 3 and 8). Performing the reaction in a sealed tube
in the presence of acetic acid17 (or formic acid) improved the
reaction, but the catechol function was not deprotected (entries
4−7, 9, and 10). Full deprotection was ensured by addition of
phenol (entries 11−13).6a We have thus found two different
conditions to obtain either compound 3 or compound 5.18 In
the best conditions (entry 13) the expected chlorhydrate of
(S)-α-methylDOPA was obtained in 92% yield. This was also
performed on the compound with 98% ee. Measurement of the
optical rotation confirmed that the final compound possess the
(S) absolute configuration.6a The free base could be released
after heating in propylene oxide (yield = 86%), but the
compound was photosensitive.
To conclude, we have performed an original four-step
synthesis of (S)-α-methylDOPA with 81% enantiomeric excess
and 24% overall yield according to the principle of Memory of
Chirality (the ee of the product was enhanced to 98% by
recrystallization). The only source of chirality is the starting D-
alanine, despite this initial chiral center is temporarily destroyed
during the alkylation reaction. We have thus shown that the
methodology we previously developed is easily applied to the
total synthesis of a biologically active compound.
f
I
56
Cl
Cl
3/10
3/180
0
a
General procedure: KHMDS (1.5 equiv, 0.5 M in THF) diluted in
DME (3 equiv) at −78 °C was added via canula to a solution of 1 in
THF (1.2 mL) at −78 °C (0.32 mmol); after t1 (min), electrophile (5
equiv) diluted in THF (1.2 mL) was rapidly added and after t2 (min)
at −78 °C, the reaction was quenched with acetic acid. Determined
by HPLC using a chiral stationary phase. After purification by
b
c
d
e
chromatography. ee after recrystallization (yield = 69%). Commer-
f
cial solution in THF (C = 2 M). Determined on the crude material.
g
In situ reaction: a mixture of DME, THF, base, and electrophile was
h
directly canulated on compound 1. Reaction on 1.77 mmol of
compound 1.
Replacing KHMDS by NaHMDS (entry 2) induced a lower
enantiomeric excess, and reducing the deprotonation time
(entries 3 and 4) did not improve the results. Surprisingly,
going from piperonyl bromide13 to piperonyl iodide was
deleterious for the enantiomeric excess. This could be related to
the unexpected results we observed for the reaction of valine
oxazolidinone enolate with benzyl iodide:11b in that case, the
results (yield and enantiomeric excess) were not reproducible,
perhaps due to competitive single electron transfer reaction or
to degradation of the electrophile. Thus, the best results were
obtained when KHMDS was used as a base and piperonyl
bromide as the electrophile. Recrystallization from ethyl acetate
by pentane diffusion led to compound 2 with 98% ee and 69%
yield (in that case, the mother liquor was enantioenriched and
isolated).
The next step was deprotection, and our first experiments
were performed directly on compound 2 (Table 2). We first
tried the previously optimized conditions that are heating in
concentrated HBr or HCl (entries 1 and 2). In those cases, the
EXPERIMENTAL SECTION
General Information. Unless otherwise stated, all reactions were
conducted in oven-dried glassware under an atmosphere of dry argon
■
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dx.doi.org/10.1021/jo301588t | J. Org. Chem. 2012, 77, 8797−8801

The Journal of Organic Chemistry
Note
Table 3. Basic Hydrolysis of Compound 2, Followed by Hydrolysis of Compound 4
entry
conditions
results (yield, %)
1
2
HI (47%), reflux, 24 h
degradation
(i) TMSCHN2, MeOH, THF; (ii) Cp2ZrHCl, CH2Cl2, −20 °C
concd HCl, AcOH, reflux, 24 h
methyl ester of 5 (31)
3
degradation
4
concd HCl, AcOH, EtOH, sealed tube, 95 °C, 4 h
concd HCl, AcOH, 1,4-dioxane, sealed tube, 95 °C, 2 h
concd HCl, AcOH, 1,4-dioxane, sealed tube, 95 °C, 5 h
concd HCl, AcOH, THF, sealed tube, 95 °C, 4 h
6 N HCl, AcOH, 1,4-dioxane, reflux, 15 h
mixture of ethyl esters of 3 and 5 (80)
5
traces of 5
6
5 (86)
7
5 + THF degradation
8
5 (24) + compound 4 + degradation
9
concd HCl, HCO2H, 1,4-dioxane, sealed tube, 95 °C, 4 h
6 N HCl, AcOH, 1,4-dioxane, sealed tube, 95 °C, 5 h
6 N HCl, AcOH (3 equiv), PhOH (3 equiv), 110 °C, 15 h
6 N HCl, AcOH (3 equiv), PhOH (3 equiv), 120 °C, 16 h
6 N HCl, AcOH (3 equiv), PhOH (3 equiv), sealed tube, 115 °C, 4 h
5 (75)
5 (54)
3 (74)
3 (91)
3 (92)
10
11
12
13
gas. THF was double distilled, first over sodium/benzophenone and
then over LiAlH4/triphenylmethane under argon. Acetone was
purchased with water <50 ppm. All other reagents were used as
received. Potassium bis(trimethylsilyl)amide was purchased as a
toluene solution (0.5 or 0.7 M). Flash chromatography was performed
on Kieselgel 60 (35−70 μm) silica gel. Infrared spectra were recorded
(S)-3-(1-Naphthoyl)-4-(benzo[d][1,3]dioxol-5-ylmethyl)-
2,2,4-trimethyloxazolidin-5-one (2). To a stirred solution of
starting N-(1-naphthoyl)-oxazolidinone (1) (91 mg, 0.321 mmol) in
THF (1.2 mL) at −78 °C was added by canulation a −78 °C
precooled solution of potassium bis(trimethylsilyl)amide in THF (680
μL, 0.482 mmol, c = 0.7 M, 1.5 equiv) and 1,2-dimethoxyethane (100
μL; 0.963 mmol, 3 equiv). The mixture was stirred 3 min at −78 °C.
Then a solution of piperonyl bromide (345 mg, 1.606 mmol, 5 equiv)
in THF (1.2 mL) was injected rapidly, and stirring was maintained for
10 min at −78 °C. Acetic acid (0.7 mL) was finally added, and the
resultant mixture was diluted in diethyl ether (10 mL) and then
washed with a saturated sodium hydrogen carbonate solution (10 mL).
The organic layer was dried with magnesium sulfate, filtered, and then
concentrated to give the crude alkylated oxazolidinone, which was then
purified by flash column chromatography on silica gel (cyclohexane/
EtOAc 80/20) to yield oxazolidinone 2 in 82% yield as a white solid
with 81% enantiomeric excess (ee = 98% after crystallization from
EtOAc and pentane by diffusion, the mother liquor was isolated in
69% yield).
1
as thin films on NaCl plates using an FT-IR spectrophotometer. H
NMR were measured at 250, 300, or 360 MHz using CDCl3 or D2O as
solvent. Chemical shifts are reported in δ units to 0.01 ppm precision
with coupling constants reported to 0.1 Hz precision using residual
solvent as an internal reference. Multiplicities are reported as follows: s
= singlet, d = doublet, t = triplet, m = multiplet, bs = broad singlet. 13C
NMR were measured at 62.5, 75, or 90 MHz using CDCl3, D2O as
solvent. Chemical shifts are reported in δ units to 0.1 ppm precision
using residual solvent as an internal reference. The mass analyzer type
used for the HRMS measurements is a quadrupole-TOF. The HPLC
instrument is principally composed of gradient pump, Peltier effect
column oven and Diodes array detector. All enantiomerics excesses
were determinated by normal-phase HPLC analyses with column
Chiralpak AD-H (250 mm × 4.6 mm i.d.); part. size: 5 μm.
HPLC analysis: Chiralpak AD-H, hexane/ethanol: 90/10, 1 mL/
(R)-3-(1-Naphthoyl)-2,2,4-trimethyloxazolidin-5-one (1). To
a stirred suspension of sodium D-alaninate (1.59 g, 14.38 mmol) and
oven-activated 4 Å molecular sieves in extra-dry acetone (40 mL) at 0
°C under argon atmosphere was slowly added a solution of
trimethylaluminium in toluene (7.19 mL, 14.38 mmol). The mixture
was stirred for 5 min at 0 °C and 15 h at room temperature. Then, 1-
naphthoyl chloride (2.16 mL, 14.38 mmol) was added, and the
reaction mixture was stirred for 2 h. The final mixture was filtered
through Celite, and molecular sieves were washed with ether (2 × 20
mL). Solvents were evaporated, and the resulting solid was dried under
high vacuum for 1 h and then purified by flash column
chromatography on silica gel (cyclohexane/EtOAc: 80/20 with 1%
triethylamine) to give the oxazolidinone 1 in 50% yield as white solid.
HPLC analysis: Chiralpak AD-H, hexane/ethanol 95/05, 1 mL/
min, T = 25 °C, λ = 281 nm; retention times of racemic mixture: 28.4
min and 31.3 min. (R). 1H NMR (360 MHz, 300 K, CDCl3) (δ, ppm):
0.96 (s, 3H), 2.01 (s, 3H), 2.06 (s, 3H) 4.18 (bs, 1H), 7.44−7.58 (m,
4H), 7.80−7.93 (m, 3H). 13C NMR (90 MHz, 300 K, CDCl3) (δ,
ppm): 20.2, 26.3, 27.7, 54.0, 98.5, 124.2, 125.1, 126.9, 128.0, 128.9,
130.5, 133.7, 167.8, 171.6. IR (cm−1): 665, 787, 969, 1057, 1131, 1265,
1378, 1409, 1593, 1650, 1790, 2937, 2985, 3057. Mp (R): 130−132
°C. HRMS (electrospray, Na+): calcd for C17H17NO3Na 306.1106,
min, T = 25 °C, λ = 222 nm; retention times of racemic mixture: 11.9
1
min and 14.5 min. (S). H NMR (250 MHz, 300 K, CDCl3) two
conformers major = M, minor = m; ratio M:m = 10:2.3 (δ, ppm): 0.52
(s, 3Hm), 0.68 (s, 3HM), 1.00 (s, 3HM), 1.48 (s, 3Hm), 1.95 (s,
3Hm), 2.01 (s, 3HM) 3.19 (d, J = 14.4 Hz, 1HM), 3.33 (d, J = 14.4
Hz, 1Hm), 3.95 (d, J = 14.4 Hz, 1HM), 4.01 (d, J = 14.4 Hz, 1Hm),
5.97 (m, 2HM + m), 6.81−6.89 (m, 3HM + m), 7.20 (d, J = 7.8 Hz,
1HM), 7.30−7.34 (m, 1Hm), 7.38−7.55 (m, 3HM + 4Hm), 7.74 (d, J
= 7.8 Hz, 1HM), 7.85 (m, 2HM + m). 13C NMR (75.5 MHz, 300 K,
CDCl3): (δ, ppm): 23.9m, 24.1M, 28.5m, 28.8M, 30.1M, 30.8m,
40.9M, 42.7m, 68.1M + m, 96.5m, 96.6M, 101.2M + m, 108.5m,
108.6M, 110.8M, 111.1m, 123.5M, 123.7m, 124.3M + m, 124.8M,
125.0M, 125.9m, 126.1m, 126.8M, 127.0m, 127.5M+m, 128.5m,
128.7M, 130.0M + m, 130.4M, 130.5m, 130.7M + m, 133.5M + m,
134.2M, 134.8m,147.2M + m, 148.1M + m, 168.6M, 168.9m, 174.0M,
174.5m. IR (cm−1): 665, 732, 781, 1038, 1085, 1250, 1361, 1373, 1404,
1445, 1489, 1504, 1637, 1788, 2924, 2982. Mp (S, ee = 98%): 127−
129 °C. HRMS (electrospray, Na+): calcd for C25H23NO5Na
440.1468, found 440.1456. Optical rotation (product with ee =
98%): [α]22.5 = +64.8 (c = 1.00, CH2Cl2).
(S)-2-(1-NDaphthamido)-3-(benzo[d][1,3]dioxol-5-yl)-2-meth-
ylpropanoic Acid (4). To a solution of 2 (100 mg, 0.24 mmol, ee =
98%) in a 1/1 mixture of water (3 mL) and THF (3 mL) was added
NaOH (36 equiv, 8.6 mmol, 344.8 mg) and the resulting solution
found 306.1091. Optical rotation (product with ee >99%): [α]23
−202.6 (c = 1.00, CH2Cl2)
=
D
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The Journal of Organic Chemistry
Note
refluxed for 24 h. After complete consumption of starting
oxazolidinone by TLC, the solution was allowed to cool and washed
with ether. The aqueous layer was acidified with 2N HCl and then
extracted with dichloromethane, dried over MgSO4, filtered, and
evaporated to give the crude (S)-2-(1-naphthamido)-3-(benzo[d]-
[1,3]dioxol-5-yl)-2-methylpropanoic acid (4) (83 mg, ee = 98%, 92%
ACKNOWLEDGMENTS
■
We thank the Marie Curie Cofund program for a RBUCE-UP
(Research Based University Chairs of Excellence of Paris)
fellowship (postdoctoral fellowship to B.V.) and the ANR
(Agence Nationale de la Recherche; ANR grant PEPSI no.
ANR-08-JCJC0099, doctoral grant to T.T.M.) for financial
support.
1
yield). H NMR (360 MHz, 300 K, CDCl3) (δ, ppm): 1.77 (s, 3H),
3.37 (d, J = 13.8 Hz, 1H), 3.56 (d, J = 13.8 Hz, 1H), 5.87 (s, 2H),
6.63−6.72 (m, 4H), 7.38 (t, J = 15.2 Hz, 1H), 7.45−7.52 (m, 3H),
7.80−7.83 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 8.01 (bs, 1H), 8.22−8.25
(m, 1H). 13C NMR (90 MHz, 300 K, CDCl3) (δ, ppm): 23.3, 41.0,
61.8, 101.1, 108.4, 110.6, 123.5, 124.8, 125.3, 125.5, 126.6, 127.4,
128.5, 129.8, 130.2, 131.1, 133.8, 133.9, 146.8, 147.7, 167.8, 177.9. IR
(cm−1): 666, 1040, 1073, 1098, 1249, 1443, 1489, 1517, 1591, 1637,
1647, 1654, 1717, 2927, 3368, 3583. HRMS (electrospray, Na+): calcd
for C22H19NO5Na 400.1161, found 400.1142. Optical rotation
REFERENCES
■
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D
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dioxol-5-yl)-2-methylpropanoic acid (4) (70 mg, 0.185 mmol), phenol
(52.3 mg, 0.556 mmol, 3 equiv), acetic acid (32 μL, 0.556 mmol, 3
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(3,4-dihydroxyphenyl)-2-methylpropanoic acid as its hydrochloride
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1
salt as a pale orange solid (43 mg, 92% yield). H NMR (360 MHz,
300 K, D2O) (δ, ppm): 1.55 (s, 3H), 2.89 (d, J = 15.3 Hz, 1H), 3.18
(d, J = 15.3 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.70 (s, 1H), 6.82 (d, J
= 8.1 Hz, 1H). 13C NMR (90 MHz, 300 K, D2O) (δ, ppm): 21.5, 41.5,
60.9, 116.4, 117.5, 122.4, 125.5, 143.7, 144.0, 173.8. HRMS
(electrospray, H+): calcd for C10H14NO4 212.0917, found 212.0926.
Optical rotation (product with ee = 98%): [α]20D = −2.9 (c = 1.00, 0.1
M HCl)
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(S)-2-Amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic
Acid. (S)-2-Amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
hydrochloride (3) (65 mg, 0.26 mmol) was refluxed with propylene
oxide (0.5 mL) in ethanol (1 mL) for 3 h. The resulting white
precipitate was then filtered and washed once with ethanol to give the
1
α- methylDOPA in 86% yield (46 mg). H NMR (360 MHz, 300 K,
CDCl3) (δ, ppm): 1.52 (s, 3H), 2.83 (d, J = 14.7 Hz, 1H), 3.18 (d, J =
14.7 Hz, 1H), 6.68 (dd, J = 8.3 Hz, 2.3 Hz, 1H), 6.70 (d, J = 2.3 Hz,
1H), 6.87 (d, J = 8.3 Hz, 1H).
(S)-2-Amino-3-(benzo[d][1,3]dioxol-5-yl)-2-methylpropanoic
Acid Hydrochloride (5). (S)-2-(1-Naphthamido)-3-(benzo[d][1,3]-
dioxol-5-yl)-2-methylpropanoic acid (4) (40 mg, 0.106 mmol), acetic
acid (0.5 mL), and concd HCl (1.2 mL) in 1 mL of 1,4-dioxane were
heated to 95 °C in a sealed tube covered with a foil for 5 h. The
solution was partitioned with ethyl acetate (5 mL) and water (5 mL),
and the aqueous layer was washed with ethyl acetate (2 × 5 mL), and
the aqueous phase was concentrated to yield (S)-2-amino-3-(benzo-
[d][1,3]dioxol-5-yl)-2-methylpropanoic acid as its hydrochloride salt
as a white solid (22 mg, 86% yield). 1H NMR (250 MHz, 300 K, D2O)
(δ, ppm): 1.56 (s, 3H), 2.96 (d, J = 14.5 Hz, 1H), 3.25 (d, J = 14.5 Hz,
1H), 5.9 (s, 2H), 6.72 (d, J = 7.5 Hz, 1H), 6.74 (s, 1H), 6.85 (d, J =
7.5 Hz, 1H). 13C NMR (62.9 MHz, 300 K, D2O) (δ, ppm): 21.8, 42.1,
61.4, 101.3, 108.8, 110.2, 123.6, 127.2, 146.9, 147.5, 174.6. HRMS
(electrospray, H+): calcd for C11H14NO4 224.0917, found 224.0916.
Alezra, V. Angew. Chem., Int. Ed. 2012, 51, 4981−4984. (b) Bouiller
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(12) (a) Betson, M. S.; Clayden, J.; Helliwell, M.; Johnson, P.; Wah
Lai, L.; Pink, J. H.; Stimson, C. C.; Vassiliou, N.; Westlund, N.; Yasin,
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(13) Piperonyl halides were prepared starting from piperonyl alcohol.
Piperonyl chloride with SOCl2, see: Porcal, W.; Merlino, A.; Boiani,
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M.; Gerpe, A.; Gonzalez, M.; Cerecetto, H. Org. Process Res. Dev. 2008,
12, 156−162. Piperonyl bromide with PBr3, see: Angle, S. R.; Choi, I.;
Tham, F. S. J. Org. Chem. 2008, 73, 6268−6278. Piperonyl iodide with
PPh3/iodine, following: Alvarez-Manzaneda, E. J.; Chahboun, R.;
Cabrera Torres, E.; Alvarez, E.; Alvarez-Manzaneda, R.; Haidoura, A.;
Ramos Lopez, J. M. Tetrahedron Lett. 2005, 46, 3755−3759.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: valerie.alezra@u-psud.fr.
Notes
The authors declare no competing financial interest.
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The Journal of Organic Chemistry
Note
(14) This type of cyclization was also observed during hydrolysis by
Kawabata.9
(15) Orena, M.; Porzi, G.; Sandri, S. J. Org. Chem. 1992, 57, 6536−
6541.
(16) Spletstoser, J. T.; White, J. M.; Rao Tunoori, A.; Georg, G. I. J.
Am. Chem. Soc. 2007, 129, 3408−3419.
(17) (a) Reinhold, D. F.; Firestone, R. A.; Gaines, W. A.; Chemerda,
J. M.; Sletzinger, M. J. Org. Chem. 1968, 33, 1209−1213. (b) Seebach,
D.; Gees, T.; Schuler, F. Liebigs Ann. Chem. 1993, 785−799.
(18) This compound has already been described: Lu, T.-J.; Lin, C.-K.
J. Org. Chem. 2011, 76, 1621−1633.
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