Synthesis and resolution of planar-chiral derivatives of 4- (dimethylamino)pyridine

Article abstract of DOI:10.1002/adsc.200700219

A safer and more efficient method for the synthesis of planar-chiral 4-(dimethylamino)pyridine (DMAP) derivatives has been developed. Racemic mixtures of the complexes can be resolved via classical resolution with commercially available tartaric acids.

Full text of DOI:10.1002/adsc.200700219

UPDATES
DOI: 10.1002/adsc.200700219
Synthesis and Resolution of Planar-Chiral Derivatives of
-(Dimethylamino)pyridine
4
a
a
a
a,
Ryan P. Wurz, Elaine C. Lee, J. Craig Ruble, and Gregory C. Fu *
a
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Fax : (+1)-617-324-3611; e-mail: gcf@mit.edu
Received: May 1, 2007
Supporting information for thisarticle isavailable on the WWW under http://a sc .wiley-vch.de/home/.
Abstract: A safer and more efficient method for
the synthesis of planar-chiral 4-(dimethylamino)pyr-
idine (DMAP) derivativeshasbeen developed.
Racemic mixturesof the complexescan be re so lved
via classical resolution with commercially available
tartaric acids.
Keywords: asymmetric catalysis; asymmetric syn-
thesis; heterocycles; homogeneous catalysis
Introduction
During the past decade, we have established that
planar-chiral derivativesof 4-(dimethylamino)pyridine
(
DMAP) and 4-(pyrrolidino)pyridine (PPY) serve as
effective enantioselective catalysts for a wide variety
[
1,2]
of transformations [e.g., Eqs. (1–3)].
To build these
complexes, we adopted the modular approach illus-
trated in Scheme 1, which involves a one-pot assem-
bly from FeCl , a cyclopentadienyllithium, and a het-
2
erocycle.
Scheme 1.
Our initial route to the bicyclic DMAP derivatives
(
2
XÀH) required six steps from commercially available
,3-cyclopentenopyridine and proceeded in ~5% intermediate in the original preparation, 4-nitro-2,3-
[4]
overall yield. The racemic planar-chiral DMAP deriv- cyclopentenopyridine N-oxide, can decompose vio-
atives 1 and 2 were then synthesized as in Scheme 1, lently at >1008C. Asa con es quence, we developed
and they were resolved via HPLC on a chiral station- an alternative nine-step synthesis of the bicyclic pyri-
[3]
[5]
ary phase. However, it waslater determined that an
dinesthat began with adipoyl chloride.
Because
access to catalysts 1 and 2 wasimpeded by the length
of the route and the reliance upon HPLC to separate
the enantiomers, we sought an improved process. In
this report, we describe: 1) streamlined, “low-tech”
preparationsof the heterocyclic frameworks(X ÀH),
and 2) classical resolutions of the racemic iron com-
plexes.
Adv. Synth. Catal. 2007, 349, 2345 – 2352
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2345

Ryan P. Wurz et al.
UPDATES
[
12]
Results and Discussion
(9). The relative simplicity and low cost of the re-
agents that are used in this synthetic sequence are
noteworthy (Scheme 2). The heterocycles( 9) can then
Our new route (Scheme 2) commenceswith a two-
step procedure that effects 4-chlorination of the pyri- be complexed to iron in good yield [Eqs. (4) and (5)].
[
6]
dine ring of 2,3-cyclopentenopyridine. Thus, treat-
[
7]
ment of 3 with H O /AcOH and then POCl fur-
2
2
3
nishes target compound 5 in good overall yield (83%
for two steps). The selective chlorination of 4 in the
para position is noteworthy, since reactions of pyri-
dine N-oxideswith POCl
para selective. Next, the pyridine nitrogen of 5 is
are typically not highly
3
[8]
oxidized in almost quantitative yield (H O and cata-
2
2
[9]
lytic MeReO3; 96%), thereby setting the stage for
amination of the 4 position and oxidation of the fused
five-membered ring. This three-step sequence has
been conducted on a large scale (>100 g) without
[
10]
chromatographic purification of any intermediate.
Pyridine N-oxide 6 is well-suited for the synthesis
of a variety of derivatives via substitution of the
halide. For our purposes, we need to effect displace-
ment of the chloride with pyrrolidine and dimethyla-
mine, which can be accomplished simply by heating 6
[
11]
in the presence of aqueous base (92% yield). Treat-
Asindicated above, for our early ts udieswe ob-
ment of the resulting 4-aminopyridines (7) with Ac O tained enantiopure 1 and 2 from the racemic catalysts
2
furnishes the desired acetates (8), which undergo via preparative HPLC on a chiral stationary phase. In
elimination under acidic conditionsto afford the
target bicyclic pyridinesasmixturesof olefin i so mers
order to provide wider access to these complexes, we
have now developed classical resolutions with tartaric
acid derivatives that furnish the catalysts in >99% ee.
In the case of 1, di-p-toluoyltartaric acid isthe re so lv-
ing agent of choice [Eq. (6)], whereas, for 2, diben-
zoyltartaric acid hasproved to be the mo ts efficient
[
Eq. (7)].
Conclusions
We have developed a new route to enantiopure
planar-chiral DMAP derivatives that addresses sever-
al drawbacks associated with earlier approaches. Spe-
cifically, a potentially hazardousintermediate is
avoided, improved yieldsare obtained, and prepara-
tive chiral HPLC is unnecessary.
Scheme 2.
2346
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2345 – 2352

Synthesis and Resolution of Planar-Chiral Derivatives of 4-(Dimethylamino)pyridine
UPDATES
Experimental Section
4-Chloro-6,7-dihydro-1,5-pyrindane (4-Chloro-6,7-
dihydro-5H-cyclopenta[b]pyridine; 5)
General Remarks
Under argon, POCl (234 g, 142 mL, 1.52 mol) wasadded
3
Unless otherwise specified, reactions were performed in the
air with no precautionsto exclude mo it su re. Analytical
HPLC analyses were carried out on an Agilent Technologies
slowly (dropwise over 30 min) to a 08C solution of 2,3-cyclo-
pentenopyridine N-oxide (4; 103 g, 0.76 mol) in anhydrous
1,2-dichloroethane (500 mL) in a 2-L flask that was placed
in an ice bath. The reaction mixture, which turned orange-
brown, was ts irred for 1 h at room temperature ( note: this
procedure should be adhered to, in order to avoid a substan-
tial exotherm). The reaction vessel was then fitted with a
condenser and slowly heated to reflux for 2 h. Next, the re-
action mixture wasallowed to cool to room temperature,
1100 Seriesin st rument with Daicel Chiralpakꢁ or Regiscol-
umnsin hexane/ s2 -propanol or hexane/ sC H 2Cl2 mixtures;
data are reported asfollow s: column type, eluent, flow rate,
and retention time (t ). Low-resolution mass spectrometric
r
measurements were performed on an Agilent Technologies
LC/MSC SL Multimode (ES/APCI) instrument using a
Zorbax Eclipse (Agilent) XDB-C18 column (5 mm particle
size, 4.6”150 mm).
and the solvent and the excess POCl were removed on a
3
rotary evaporator, leading to a viscous brown oil. The flask
wasplaced in an ice bath, and sm all piecesof ice were cau-
tiously added (~50 g; note: if too much ice isadded initially,
then a substantial exotherm will result). The mixture was
then treated with a solution of 6 N NaOH (~500 mL) via a
dropping funnel (ice wasadded, in order to keep the reac-
tion at ~58C) until pH 7. The mixture wastran fs erred to a
separatory funnel and extracted with diethyl ether (6”
350 mL), and the combined extractswere dried over
Materials
2
,3-Cyclopentenopyridine (6,7-dihydro-5H-cyclopenta[b]pyr-
[13]
idine) [Kinbester Co., Limited (China);>98% ] wasu es d
asreceived. FeCl 2 (Strem) wasground with a mortar and
pestle in a glovebox, prior to use. Other reagents and sol-
ventswere obtained from Strem or Aldrich and u se d asre-
ceived.
MgSO , filtered, and concentrated on a rotary evaporator,
4
affording a dark-orange oil; yield: 102 g (87%).
Thismaterial wasjudged to be 94% pure by
1
H NMR
spectroscopy, and it was used in the next step without fur-
1
ther purification. R =0.17 (20% EtOAc:hexanes); H NMR
2
,3-Cyclopentenopyridine N-Oxide (6,7-Dihydro-5H-
f
[7]
(400 MHz, CDCl ): d=8.24 (d, J=5.5 Hz, 1H), 7.07 (d, J=
3
cyclopenta[b]pyridine 1-Oxide; 4)
5
.4 Hz, 1H), 3.10 (t, J=7.8 Hz, 2H), 3.01 (t, J=7.6 Hz, 2H),
1
3
Glacial acetic acid (500 mL) wasadded over ~2 min (to con-
trol the exotherm) to a 2-liter flask that contained 2,3-cyclo-
pentenopyridine (100 g, 0.84 mol). Then, an aqueous os lu-
tion of H O (30%; 90 mL, 0.87 mol) wasadded, and the
2.12–2.20 (m, 2H); C NMR (100 MHz, CDCl ): d=167.1,
3
148.4, 140.5, 135.6, 121.2, 34.9, 29.8, 21.9; IR (film): v=2959,
À1
1583, 1558, 1458, 1390, 903, 817 cm ; LR-MS (ES/APCI):
+
2
2
calcd. for C H ClN [M+H ]: 154.6; found: 154.1.
8
8
flask was fitted with a reflux condenser capped with a
septum and a needle (vent). The reaction mixture was
heated to 808C behind a blast shield (as a precaution; no ac-
cidentshave occurred). After st irring at 80 8C for 6 h, the so-
lution wastreated with additional aqueousH 2O2 (90 mL,
4
-Chloro-6,7-dihydro-1,5-pyrindane N-Oxide (4-
Chloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-
Oxide; 6)
0.87 mol) and stirred for 18 h at 808C. Then, the reaction
mixture wasallowed to cool to room temperature, and the
acetic/peracetic acid wasremoved on a rotary evaporator.
The resulting pale-yellow residue was cooled in an ice bath
MeReO (500 mg, 2.01 mmol, 0.31 mol%) wasadded to a
solution of 4-chloro-6,7-dihydro-1,5-pyrindane (5; 100 g, 0.65
3
mol) in CH Cl (200 mL) in a 2-L round-bottomed flask. To
2
2
and then carefully treated with aqueousK 2CO (100 g in
this stirred solution was added an aqueous solution of H O2
3
2
2
~
2
50 mL of distilled water) until the solution reached pH
(30%; 130 mL, 1.26 mol; in one portion). The flask was
then capped with a septum and a needle (vent), and the
mixture wasallowed to ts ir at room temperature for 25 h
(the reaction mixture turned orange, and then bright yellow
10. The mixture wasthen extracted with CHCl (4”
3
50 mL), dried over anhydrousMgSO , filtered, and concen-
4
trated on a rotary evaporator. The product crystallized as a
white solid, which was rinsed with methyl tert-butyl ether
as the reaction progressed). Next, the excess H O2 was
2
(
2”200 mL). The washings were concentrated on a rotary
quenched by the addition of small portions of activated
evaporator, which led to the precipitation of additional N-
oxide 4. This precipitated solid was washed with methyl tert-
butyl ether (3”30 mL) and then combined with the initial
batch of product. Compound 4 wasdried under vacuum
overnight to afford a free-flowing, white crystalline solid;
MnO powder (10–20 mg), which resulted in the rapid evo-
2
lution of O2. After the effervescence had subsided
(~30 min), the dark-green reaction mixture wastreated with
brine (200 mL) and extracted with CH Cl (4”200 mL). The
2
2
combined organic extractswere dried over MgSO 4 and fil-
tered through a pad of celite. Removal of the solvent on a
rotary evaporator resulted in the formation of olive-green
crystals, which were dried under vacuum overnight; yield:
106 g (96%).
1
yield: 108 g (95%); mp 121–1238C; H NMR (400 MHz,
CDCl ): d=8.04 (d, J=6.2, 0.8 Hz, 1H), 7.13 (d, J=6.2 Hz,
3
1
7
H), 7.05–7.11 (m, 1H), 3.17 (t, J=7.7 Hz, 2H), 3.02 (t, J=
.7 Hz, 2H), 2.14–2.22 (m, 2H); C NMR (100 MHz,
13
1
CDCl ): d=153.3, 142.4, 137.4, 124.0, 122.7, 31.7, 29.7, 22.2;
The product wasjudged to be 92% pure by H NMR
3
IR (film): v=3391, 2957, 1602, 1441, 1260, 1063, 1011,
spectroscopy, and it was used in the next step without fur-
À1
+
8
1
00 cm ; LR-MS (ES/APCI): calcd. for C H NO [M+Na ]:
58.2, found: 158.1.
ther purification; mp 110–1138C; R =0.16 (acetone);
8
9
f
1
H NMR (400 MHz, CDCl ): d=7.99 (d, J=6.8 Hz, 1H),
3
Adv. Synth. Catal. 2007, 349, 2345 – 2352
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2347

Ryan P. Wurz et al.
UPDATES
1
7
7
.09 (d, J=6.8 Hz, 1H), 3.24 (t, J=7.8 Hz, 2H), 3.07 (d, J=
wasjudged to be 95% pure by
H NMR spectroscopy;
1
3
1
.7 Hz, 2H), 2.19–2.27 (m, 2H);
C NMR (75 MHz,
yield: 38.7 g (92%); mp 150–1568C; H NMR (400 MHz,
CDCl ): d=154.4, 140.7, 139.4, 127.0, 125.1, 31.8, 31.2, 21.8;
CDCl ): d=7.90 (d, J=7.2 Hz, 1H), 6.40 (d, J=7.2 Hz, 1H),
3
3
IR (film): v=3406, 3077, 2962, 1662, 1437, 1311, 1264, 1236,
3.16 (t, J=7.8 Hz, 2H), 3.11 (t, J=7.4 Hz, 2H), 2.96 (s, 6H),
À1
13
1
014, 825, 726 cm ; LR-MS (ES/APCI): calcd. for
2.13 (pent. J=7.5 Hz, 2H); C NMR (100 MHz, CDCl ):
3
+
C H ClNO [M+H ]: 170.6; found: 170.0.
d=153.7, 147.9, 137.3, 126.4, 109.3, 41.4, 33.1, 29.7, 22.6; IR
8
8
(
7
film): v=3379, 2957, 1621, 1509, 1434, 1236, 976, 816,
À1
35 cm ; LR-MS (ES/APCI): calcd, for C H N O [M+
4-Pyrrolidino-6,7-dihydro-1,5-pyrindane N-Oxide (7a)
10 14
2
+
H ]: 179.2; found: 179.2.
Pyrrolidine (189 g, 221 mL, 2.65 mol) wasadded ls owly (to
avoid an exotherm) to a solution of 4-chloro-6,7-dihydro-
1
,5-pyrindane N-oxide (6; 90.0 g, 0.53 mol) and K CO
4-Pyrrolidino-7-acetoxy-6,7-dihydro-1,5-pyrindane–
2
3
(
89.4 g, 0.54 mol) in distilled water (300 mL) in a 2-L round- Acetic Acid Adduct (8a)
bottomed flask. The flask was fitted with a reflux condenser,
and the mixture washeated, with ts irring, under air at 90–
In a 1-L flask, a mixture of acetic anhydride (200 g, 185 mL,
[7]
1
.96 mol) and distilled water (2.1 mL, 117 mmol) was
958C for 17 h. Then, the reaction mixture wascooled to
stirred at room temperature for 10 min under nitrogen. The
flask was then cooled in an ice bath, and 4-pyrrolidino-6,7-
dihydro-1,5-pyrindane N-oxide (7a; 50.0 g, 0.24 mol) was
added slowly via a glass funnel over 15 min (to prevent an
exotherm). The flask was purged with nitrogen, and the mix-
ture was stirred at room temperature for 1 h. The flask was
then fitted with a reflux condenser, and the reaction mixture
washeated to 80 8C with stirring under nitrogen for 25 h.
The solvent was removed on a rotary evaporator from the
resulting dark-brown reaction mixture, leading to a brown
solid. This solid was dissolved in the minimum amount of
CH Cl (~100 mL), and the solution was passed through a 7-
room temperature, and the solvent was removed on a rotary
evaporator, furnishing a black solid. Toluene (100 mL) was
added in order to azeotropically remove the remaining
water. The product wasextracted from the black so lid with
1
:1 acetone:CH Cl (6”300 mL). The dark-purple extracts
2 2
were combined, dried over anhydrousNa SO , filtered, and
2
4
concentrated on a rotary evaporator. The resulting purple-
black solid was dissolved in warm acetone (120 mL; 40–
508C), and then methyl tert-butyl ether (600 mL) was
added. This os lution washeated to 70 8C for 10 min, and
then it wascooled in an ice bath, leading to the precipitation
of N-oxide 7a. The product wascollected by filtration,
washed with methyl tert-butyl ether (300 mL) to remove a
purple impurity and then dried under vacuum overnight, af-
fording a gray, free-flowing solid; yield: 100 g (92%).
2
2
cm pad of silica gel on a 2-L sintered coarse glass frit. The
silica gel was rinsed with 30:70 EtOAc:hexane (1 L),
3
0:60:10 EtOAc:hexane:Et N (~1.5 L), and 60:30:10 EtOA-
3
1
c:hexane: Et N (5 L), collecting 1-L “fractions”. The solvent
3
The product wasjudged to be >99% pure by H NMR
1
wasremoved on a rotary evaporator from the appropriate
fractions (as judged by TLC). The resulting beige solid was
suspended in methyl tert-butyl ether (150 mL) and filtered
through a Buechner funnel. The solid was rinsed with addi-
tional portionsof methyl tert-butyl ether (2”50 mL; the
product is somewhat soluble in this solvent, so large vol-
umes should not be used), resulting in a free-flowing,
cream-colored solid. The desired product was dried under
spectroscopy; m.p. 80–838C; H NMR (400 MHz, CDCl ):
3
d=7.84 (d, J=7.1 Hz, 1H), 6.20 (d, J=7.1 Hz, 1H), 3.47–
3
2
.50 (m, 4H), 3.27 (t, J=7.5 Hz, 2H), 3.15 (t, J=7.8 Hz,
H), 2.06–2.14 (m, 2H), 1.97–2.02 (m, 4H); C NMR
13
(
100 MHz, CDCl ); d=153.7, 145.2, 137.4, 122.8, 107.7, 49.5,
3
3
1
3.1, 29.9, 25.6, 22.3; IR (film): v=3375, 2963, 1624, 1495,
À1
457, 1230, 982 cm ; LR-MS (ES/APCI): calcd. for
+
C H N O [M+H ]: 205.3; found: 205.1.
12
16
2
1
vacuum overnight (98–99% pure according to H NMR
spectroscopy; acetic acid adduct); yield: 43.5 g (58%); mp
4
-(Dimethylamino)-6,7-dihydro-1,5-pyrindane N-
1
1
19–1208C; R =0.51 (9:1 EtOAc:Et N);
H NMR
f
3
Oxide (7b)
(
400 MHz, CDCl ): d=11.38 (br s, 1H), 8.17 (d, J=6.0 Hz,
3
1
3
2
5
1
H), 6.28 (d, J=6.0 Hz, 1H), 6.05 (dd, J=7.5, 5.1 Hz, 1H),
.54–3.58 (m, 4H), 3.33–3.42 (m, 1H), 3.11–3.18 (m, 1H),
.50–2.59 (m, 1H), 2.13 (s, 3H), 2.07 (s, 3H), 1.95–2.02 (m,
With stirring, 4-chloro-6,7-dihydro-1,5-pyrindane N-oxide
(
6; 40.0 g, 236 mmol) was dissolved in a solution of Me NH
2
in water (40 wt%; 100 mL, 790 mmol) in a 500-mL round-
bottomed flask. The solution was transferred to a 250-mL
stainless steel Parr apparatus (due to the volatility of
Me NH) using additional Me NH solution (80 mL,
1
3
H); C NMR (100 MHz, CDCl ): d=175.6, 171.1, 158.7,
3
52.0, 147.3, 120.4, 107.2, 49.3, 30.5, 29.4, 25.6, 22.0, 21.3; IR
À1
(
film): v=2976, 2871, 1736, 1606, 1515, 1372, 1243, 834 cm ;
2
2
+
LR-MS (ES/APCI): calcd. for C H N O [M+H ]: 247.3;
found: 247.1.
1
4
18
2
2
632 mmol) in order to ensure quantitative transfer. The Parr
apparatuswas se aled and heated to 75 8C in an oil bath with
stirring for 24 h (behind a blast shield, as a precaution).
Next, the Parr apparatuswascooled in an ice bath, and the
reaction mixture waspoured into an Erlenmeyer fl ak s.
K CO (39.8 g, 241 mmol) wasadded, and the mixture was
4
-(Dimethylamino)-7-acetoxy-6,7-dihydro-1,5-
pyrindane–Acetic Acid Adduct (8b)
2
3
stirred for 30 min. The solution was transferred to a 1-L
round-bottomed flask, and the solvent was removed on a
rotary evaporator, leading to a black solid. The product was
extracted from the solid with 1:1 acetone:CH Cl (6”
Acetic anhydride (149 g, 138 mL, 1.46 mol) wasadded to a
1-L flask (in a 08C ice bath) that contained 4-(dimethyla-
mino)-6,7-dihydro-1,5-pyrindane N-oxide (7b; 26.0 g, 0.146
mol). Distilled water (1.25 mL, 69.4 mmol) wasadded, and
the solution was stirred at 08C for 30 min. The flask was
then fitted with a reflux condenser and heated to 75–808C
for 24 h under nitrogen. Next, the dark-brown reaction mix-
[7]
2
2
200 mL). The dark-purple extractswere combined, dried
over anhydrousNa SO , filtered, and concentrated on a
2
4
rotary evaporator, providing a black crystalline solid that
2348
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2345 – 2352

Synthesis and Resolution of Planar-Chiral Derivatives of 4-(Dimethylamino)pyridine
UPDATES
ture wasconcentrated on a rotary evaporator, leading to a
brown solid, which was dissolved in the minimum amount of
CH Cl (~50 mL) and passed through a pad of silica gel,
4-(Dimethylamino)pyrindine (N,N-Dimethyl-7H-
cyclopenta[b]pyridin-4-amine; 9b)
2
2
4
-(Dimethylamino)-7-acetoxy-6,7-dihydro-1,5-pyrindane
acetic acid adduct (8b; 20.0 g, 71.3 mmol) wasadded in one
portion to concentrated H SO (44 mL) in an ice bath. The
eluting with 2:3 EtOAc:hexane (500 mL) and then 45:45:10
EtOAc:hexane:Et N (800 mL). The desired product was
3
dried under vacuum overnight (tan solid; 98–99% pure ac-
2
4
1
mixture wa st si rred for 10 min at 0 8C, and then it was
heated to 60–658C in an oil bath for 75 min. Next, the reac-
tion mixture wascooled in an ice bath, and ice wasadded.
The reaction wasthen ls owly quenched over 15 min by the
dropwise addition of NaOH (6 N solution; ~350 mL) until
pH ~12 (heavy white precipitate formed). The reaction mix-
ture wasextracted with EtOAc (6”200 mL), and the organ-
cording to H NMR spectroscopy; acetic acid adduct); yield:
3
0.4 g (74%); m.p. 62–678C; R =0.53 (9:1 EtOAc:Et N);
f
3
1
H NMR (400 MHz, CDCl ): d=11.03 (br s, 1H), 8.22 (d,
3
J=5.9 Hz, 1H), 6.43 (d, J=5.9 Hz, 1H), 6.05 (dd, J=7.4,
5
1
.2 Hz, 1H), 3.16–3.22 (m, 1H), 3.05 (s, 6H), 3.00–3.05 (m,
H), 2.52–2.58 (m, 1H), 2.14 (s, 3H), 2.07 (s, 3H), 1.97–2.03
13
(m, 1H); C NMR (100 MHz, CDCl ): d=174.9, 170.9,
3
ic extractswere dried over Na 2SO [Et N (15 mL) was
159.8, 155.0, 148.1, 122.3, 108.0, 41.2, 30.7, 29.7, 21.8, 21.2;
4
3
added, since the product is stabilized by the presence of a
weak base], filtered, and concentrated on a rotary evapora-
tor. The resulting yellow residue was purified by column
IR (film): v=3383, 2945, 1733, 1587, 1509, 1439, 1371, 1243,
À1
1
024, 962, 816 cm ; LR-MS (ES/APCI): calcd. for
+
C H N O [M+H ]: 221.3; found: 221.1.
12
16
2
2
chromatography, eluting with 45:45:10 EtOAc:hexane:Et N
3
(
(
~
1.0 L), which yielded a yellow-green crystalline solid
judged to be >99% pure by H NMR spectroscopy;
85:15 mixture of olefin isomers); yield: 9.04 g (79%).
Note: This compound is somewhat sensitive, and it is best
4
-Pyrrolidinopyrindine [4-(Pyrrolidin-1-yl)-7H-
1
cyclopenta[b]pyridine; 9a]
4-Pyrrolidino-7-acetoxy-6,7-dihydro-1,5-pyrindane
acetic
acid adduct (8a; 20.0 g, 65.9 mmol) wa sl so wly added in
small portions (to avoid an exotherm) to a flask that con-
tained concentrated H SO (35 mL; in a 08C ice bath). The
to use it immediately. Alternatively, it can be stored in a
freezer under an inert atmosphere for several weeks without
noticeable degradation; mp 59–638C (mix of isomers); R =
2
4
f
1
flask was capped under air with a septum and a needle
vent), and then it washeated to 60–65 8C in an oil bath for
0 min. Next, the reaction mixture wascooled in an ice
bath, and ice wasadded. A oslution of NaOH (6 N;
240 mL) wasadded lso wly over 30–40 min until pH ~12
heavy white precipitate formed). The reaction mixture was
extracted with EtOAc (3”300 mL) and CH Cl (3”
0.39 (9:1 EtOAc:Et N); H NMR (400 MHz, CDCl ): (major
3 3
(
8
isomer) d=8.18 (d, J=5.9 Hz, 1H), 6.93–6.96 (m 1H), 6.76–
6.78 (m, 1H), 6.35 (d, J=5.9 Hz, 1H), 3.63 (s, 2H), 3.14 (s,
6H); (minor isomer) d=8.10 (d, J=5.9 Hz, 1H), 7.14 (dt,
J=8.1, 1.9 Hz, 1H), 6.46 (d, J=5.9 Hz, 1H), 6.42 (dt, J=
~
(
1
3
6.1, 2.1 Hz, 1H), 3.43 (s, 2H), 3.11 (s, 6H); C NMR
(100 MHz, CDCl ): (major isomer) d=165.2, 152.6, 148.8,
2
2
3
2
50 mL), and the organic extractswere dried over Na SO
137.0, 134.2, 120.1, 105.5, 41.4, 39.6; (minor isomer) d=
167.1, 150.8, 146.3, 130.4, 129.4, 123.9, 106.8, 42.2, 40.9; IR
(film): v=2885, 1691, 1589, 1570, 1386, 1373, 1189, 1029,
2
4
[Et N (15 mL) was added, since the product is stabilized by
3
the presence of a weak base], filtered, and concentrated on
a rotary evaporator. The resulting brown residue was puri-
fied by column chromatography, eluting with 45:45:10
EtOAc:hexane:Et N (200 mL) and then 90:10 EtOAc:Et N
À1
+
801 cm ; LR-MS (ES/APCI): calcd. for C10
H N [M+H ]:
12 2
161.2; found: 161.1.
3
3
(
600 mL). The product, a yellow-green crystalline solid, was
1
4
-Pyrrolidinopyrindinyl-pentamethylcyclopentadienyl-
judged to be>98% pure by H NMR spectroscopy (~60:40
mixture of olefin isomers); yield:10.1 g (83%).
Note: This compound is somewhat sensitive, and it is best
to use it immediately. Alternatively, it can be stored in a
freezer under an inert atmosphere for several weeks without
noticeable degradation; mp 84–868C (mix of isomers); R =
0
CDCl ): (major isomer) d=8.17 (d, J=5.9 Hz, 1H), 6.98 (dt,
J=5.7, 1.8 Hz, 1H), 6.80 (dt, J=5.7, 2.0 Hz, 1H), 6.26 (d,
J=5.9 Hz, 1H), 3.74–3.78 (m, 2H), 3.60–3.66 (m, 4H), 2.00–
iron (1)
A
solution of n-BuLi (1.6M in hexanes; 24.1 mL,
3
8.6 mmol) wasadded dropwi se over 2 min to a so lution of
pentamethylcyclopentadiene (5.26 g, 38.6 mmol) in anhy-
drousTHF (200 mL) in a 0 8C ice bath under nitrogen. The
resulting white suspension was stirred for 1 h at 08C.
Separately, anhydrousTHF (80 mL) wasadded to pow-
f
1
.27 (45:45:10 EtOAc:hexanes:Et N); H NMR (400 MHz,
3
3
dered FeCl (4.90 g, 38.6 mmol) in a 2-L round-bottomed
2
flask. The mixture was sonicated for 1 h, resulting in a fine
suspension. Next, the mixture was cooled to 08C, and the
solution that contained the Cp*Li was added by cannula
2
7
6
2
.11 (m, 4H); (minor isomer) d=8.10 (d, J=5.9 Hz, 1H),
.22 (dt, J=6.1, 2.0 Hz, 1H), 6.37 (dt, J=6.2, 2.1 Hz, 1H),
.34 (d, J=5.9 Hz, 1H), 3.60–3.66 (m, 4H), 3.46–3.48 (m,
over 10 min to the suspension of FeCl , leading to a homo-
2
1
3
geneous green solution, which was stirred at 08C for 2.5 h.
In a 250-mL round-bottomed flask, a 08C solution of 4-
pyrrolidinopyrindine (6.54 g, 35.1 mmol) in anhydrousTHF
H), 2.00–2.11 (m, 4H); C NMR (100 MHz, CDCl ):
3
(
major isomer) d=164.6, 149.4, 148.5, 136.9, 134.1, 118.7,
1
1
2
8
04.7, 48.6, 38.9, 25.5; (minor isomer) d=166.9, 147.0, 146.0,
30.6, 128.1, 121.7, 105.7, 49.5, 40.8, 25.7; IR (film): v=3367,
969, 2868, 1693, 1591, 1570, 1484, 1395, 1357, 1059, 900,
(
2
80 mL) wastreated with n-BuLi (1.6M solution in hexanes;
2.4 mL, 35.8 mmol; dropwise addition), and the resulting
À1
dark yellow-brown solution was stirred at 08C for an addi-
tional 1.5 h. This os lution wasthen added by cannula over
00, 708 cm ; LR-MS (ES/APCI): calcd. for C H N [M+
1
2
14
2
+
H ]: 187.3; found: 187.1.
1
5 min to the 08C solution of Cp*FeCl, resulting in a dark-
purple solution. This mixture was stirred for 18 h, during
which time it wasallowed to sl owly warm to room tempera-
ture. Next, the reaction mixture waspoured onto a column
Adv. Synth. Catal. 2007, 349, 2345 – 2352
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2349

Ryan P. Wurz et al.
UPDATES
of silica gel, eluting first with 65:30:5 hexane:EtOAc:Et N
dropwise over 5 min to a stirred solution of enantioenriched
1 (the solid from the first crystallization; 5.84 g, 15.5 mmol,
94% ee) in anhydrousCH Cl (58 mL) in a 500-mL flask
3
(
600 mL) and then with 90:10 EtOAc:Et N (1.5 L). The
3
purple fractionswere collected, and the os lventswere re-
2
2
moved on a rotary evaporator, thereby providing racemic 1
in >99% purity asjudged by H NMR spectroscopy; yield:
under nitrogen. The resulting dark-purple suspension was
stirred at room temperature for 14 h under nitrogen, and
then it was allowed to stand for 1–3 h. The suspension was
filtered, and the purple solid was “worked-up” as described
for the first crystallization: yield: 5.23 g (37%, based on the
starting amount of racemic 1). HPLC analysis revealed
>99% enantiomeric excess of the slow-eluting enantiomer
on chiral HPLC, (À)-(S)-configuration.
1
12.0 g (91%).
This reaction has also been conducted on a larger scale:
4
1
-pyrrolidinopyrindine: 10.0 g, 53.7 mmol; product yield:
1
7.8 g (88%); mp 116–1208C; H NMR (400 MHz, CDCl ):
3
d=8.21 (d, J=5.1 Hz, 1H), 5.59 (d, J=5.2 Hz, 1H), 4.54
(
(
(
dd, J=2.7, 1.1 Hz, 1H), 4.35 (dd, J=2.8, 1.1 Hz, 1H), 3.74
t, J=2.8 Hz, 1H), 3.57 (br s, 4H), 2.07–2.10 (m, 4H), 1.65
Recrystallization of the filtrate from the first crystalliza-
tion: A solution of di-p-toluoyl-l-tartaric acid (2.90 g,
7.51 mmol) in nitrogen-purged EtOAc (125 mL) wasadded
dropwise over 5 min to a stirred solution of enantioenriched
13
s, 15H); C NMR (75 MHz, CDCl ): d=156.3, 156.3, 152.1,
3
111.3, 93.8, 78.4, 74.4, 73.2, 67.1, 64.0, 49.3 , 25.7 (br), 9.9;
IR (KBr): v=2966, 2902, 2865, 1538, 1487, 1380, 1338, 1021,
À1
9
[
07, 730 cm ; LR-MS (ES/APCI): calcd. for C H FeN
1
(the filtrate from the first crystallization; 6.65 g,
17.7 mmol, 70% ee) in anhydrousCH Cl (63 mL) in a 500-
2
2
28
2
+
M+H ]: 377.3; found: 377.2; anal. calcd. for C H FeN : C
22 28 2
2
2
7
0.22, H 7.50, N 7.44; found: C 70.02, H 7.54, N 7.44.
mL flask under nitrogen. Within a few minutes, a dark-
purple suspension had formed. This mixture was stirred at
room temperature for 14 h under nitrogen, and then it was
allowed to stand for 1–3 h. The suspension was filtered, and
the purple solid was “worked-up” as described for the first
crystallization: yield: 5.25 g (38% based on the starting
amount of racemic 1). HPLC analysis revealed >99% enan-
tiomeric excess of the fast-eluting enantiomer on chiral
Classical Resolution of 4-Pyrrolidinopyrindinyl-
pentamethylcyclopentadienyliron (1)
First crystallization: Under nitrogen, a solution of di-p-tol-
uoyl-d-tartaric acid (3.59 g, 9.30 mmol) in nitrogen-purged
EtOAc (270 mL) was added dropwise over 5 min to a stirred
solution of pure, racemic 4-pyrrolidinopyrindinyl-pentame-
thylcyclopentadienyliron (1; 14.0 g, 37.2 mmol) in anhydrous
CH Cl (135 mL) in a 1-L flask. The resulting dark-purple
HPLC, (+)-(R) configuration.
20
D
(
À)-(S)-1: [a] : À2,2808 (c 0.00046, CHCl ); mp 155–
3
1
608C (decomp.; >99% ee).
2
2
suspension was stirred at room temperature for 14 h under
nitrogen, and then it wasallowed to ts and for 1–3 h. Next,
the suspension was filtered, and the solid was rinsed with
hexanes(120 mL). The filtrate wasconcentrated and then
purified by passage through a column of silica gel (the
column should be loaded using 100% EtOAc), washing first
with EtOAc to remove tracesof degradation products
4
-(Dimethylamino)pyrindinyl-pentaphenylcyclopenta-
dienyliron (2)
A
solution of n-BuLi (1.6M in hexanes; 5.45 mL,
8.73 mmol) wasadded dropwi es over 2 min to a mixture of
pentaphenylcyclopentadiene (3.90 g, 8.72 mmol) suspended
in anhydrousTHF (86 mL) under nitrogen. The os lution,
which wasinitially homogeneousand yellow, wasallowed to
stir for 2 h, at which time it was red-orange.
Separately, anhydrousTHF (40 mL) wasadded to pow-
dered FeCl2 (1.07 g, 8.44 mmol) in a 500-mL round-bot-
tomed flask. The mixture was sonicated for 30 min, yielding
a fine suspension. The solution that contained the pentaphe-
nylcyclopentadienyl anion wasthen added by cannula over
(
yellow-brown bands) and then with 90:10 EtOAc:Et N
3
(
~500 mL) to elute catalyst 1 asa blood-red os lution. The
appropriate fractionswere collected and concentrated on a
rotary evaporator. HPLC analysis revealed an enantiomeric
excess of 70% (6.65 g, 48%; fast-eluting enantiomer on
chiral HPLC, [(+)-(R) configuration]. Daicel OD column,
flow: 1.0 mL/min, eluent: 50:50:0.4 2-propanol:hexa-
ne:Et NH. t (+)-(R): 4.67 min; (À)-(S): 11.22 min.
2
r
The purple solid from the filter cake was dissolved in
CH Cl (100 mL), and the solution was treated with a small
2 min to the suspension of FeCl , resulting in a beige solu-
tion. The reaction mixture was st irred at room temperature
for 2 h.
2
2
2
amount of Et N (15 mL) and passed through a column of
3
silica gel, eluting with 90:10 EtOAc:Et N (~500 mL). The
A solution of n-BuLi (1.6M solution in hexanes; 4.54 mL,
7.27 mmol) wasadded dropwi se over 2 min to a so lution of
4-(dimethylamino)pyrindine (1.17 g, 7.27 mmol) in anhy-
drousTHF (35 mL) at 0 8C in a 250-mL round-bottomed
flask. The resulting dark yellow-brown solution was stirred
at 08C for 1.5 h. Then, this os lution wasadded by cannula
over 2 min to the solution of C Ph FeCl (at room tempera-
ture), resulting in a brown solution. The reaction mixture
washeated to 60 8C for 3.5 h. Next, the reaction mixture was
poured onto a column of silica gel, which was eluted with
3
bright-red fractionswere collected. HPLC analy si srevealed
an enantiomeric excess of 94% (5.84 g, 42%; slow-eluting
enantiomer on chiral HPLC, [(À)-(S) configuration].
Note: Column chromatography of catalyst 1 can be per-
formed in the air. However, solutions of catalyst 1 that are
exposed to air for extended periods of time (i.e., hours) will
decompose slightly, leading to the formation of a polar com-
pound that leavesa brown band on the top of si lica gel col-
umns.
5
5
Recrystallization of the solid from the first crystallization:
Calculation of the required amount of resolving agent:
mmol of resolving agent=(mmol of catalyst 1)”0.5”[frac-
tion of the major enantiomer (e.g., 0.97 for 94% ee)].
45:45:10 EtOAc:hexane:Et N (200 mL). The resulting solu-
3
tion wasconcentrated to a dark-purple os lid on a rotary
evaporator, and thiscrude material waspurified by column
chromatography, first eluting with CH Cl (400 mL) to
2
2
A
solution of di-p-toluoyl-D-tartaric acid (2.90 g,
remove the excess C Ph H and then with 90:10 CH Cl :Et N
5 5 2 2 3
7.50 mmol) in nitrogen-purged EtOAc (102 mL) wasadded
(400 mL), which provided the catalyst as a tight purple
2350
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2345 – 2352

Synthesis and Resolution of Planar-Chiral Derivatives of 4-(Dimethylamino)pyridine
UPDATES
band. The purple fractionswere collected and concentrated
mmol of resolving agent=(mmol of catalyst 2)”[fraction of
the major enantiomer (e.g., 0.99 for 98% ee)].
A mixture of enantioenriched 2 (the solid from the first
on a rotary evaporator to afford the title compound in
1
>
99% purity asjudged by H NMR spectroscopy (purple
powder; yield: 4.51 g, 93%).
crystallization; 4.18 g, 6.33 mmol; 98% ee) and CH Cl2
2
This reaction has also been conducted on a larger scale:
(96 mL) in a 500-mL flask under air was sonicated until all
of catalyst 2 had dissolved (~10 min). Next, the solution was
diluted with THF (41 mL), and then a solution of anhydrous
dibenzoyl-l-tartaric acid (2.24 g, 6.25 mmol) in THF
(46 mL; this solution was filtered before use) was added
dropwise via pipette over 10 min to the stirred solution of 2.
The resulting dark-purple mixture was sonicated for ~5 min,
leading to the formation of a large amount of a purple pre-
cipitate. The mixture was ts irred for ~20 min, during which
time it became less viscous. The flask was purged with nitro-
gen for 2–3 min, and then it was stoppered with a septum
and allowed to stir for 20 h. Next, the mixture was allowed
to stand without stirring for 3 h, and then it was filtered.
The purple solid was “worked-up” as described for the first
crystallization. HPLC analysis revealed an enantiomeric
excess >99% [3.17 g, 28% (based on the starting amount of
racemic 2); slow-eluting enantiomer on chiral HPLC, (À)-
(S) configuration].
4
-(dimethylamino)pyrindine: 2.50 g, 15.6 mmol; product
1
yield: 8.15 g (79%); mp 238–2418C; H NMR (400 MHz,
CDCl ): d=8.17 (d, J=5.2 Hz, 1H), 7.13–7.16 (m, 5H),
3
7
1
2
1
6
1
.05–7.12 (m, 10H), 6.94–6.96 (m, 10H), 5.87 (d, J=5.2 Hz,
H), 5.11 (br s, 1H), 4.92–4.94 (m, 1H), 4.28–4.30 (m, 1H),
13
.94 (br s, 6H); C NMR (75 MHz, CDCl ): d=158.6, 153.9,
3
35.3, 132.6, 127.1, 126.2, 113.4, 99.5, 86.0, 77.9, 77.7, 69.6,
6.1, 41.7; IR (film): v=3055, 2952, 1537, 1502, 1351, 1075,
À1
027, 741, 700 cm ; LR-MS (ES/APCI): calcd. for
+
C H FeN [M+H ]: 661.6; found: 661.2; anal. calcd. for
45
36
2
C H FeN : C 81.81, H 5.49, N 4.24; found: C 81.62, H 5.49,
45
36
2
N 4.41.
Classical Resolution of 4-(Dimethylamino)pyrindinyl-
pentaphenylcyclopentadienyliron (2)
Recrystallization of the filtrate from the first crystalliza-
tion: A mixture of enantioenriched 2 (the filtrate from the
First crystallization: In the air, a suspension of racemic 4-(di-
methylamino)pyrindinyl-pentaphenylcyclopentadienyliron
first crystallization; 7.44 g, 11.3 mmol; 52% ee) and CH Cl2
2
(
2; 11.5 g, 17.4 mmol) and CH Cl (200 mL) in a 500-mL
2 2
(
170 mL) in a 500-mL flask was sonicated until all of the
flask was sonicated for ~10 min until all of catalyst 2 had
dissolved. Next, the solution was diluted with THF (79 mL),
and then a solution of anhydrous dibenzoyl-l-tartaric acid
catalyst had dissolved (~10 min). Next, the solution was di-
luted with THF (74 mL), and a solution of dibenzoyl-d-tar-
taric acid monohydrate (3.22 g, 8.58 mmol) in THF (74 mL;
this solution was filtered before use) was added dropwise
via pipette over 10 min to the stirred solution of 2. The re-
sulting dark-purple mixture was sonicated for ~6 min. Next,
while stirring the mixture, the flask was purged with nitro-
gen for 2–3 min. Stirring wascontinued overnight (20 h),
leading to a slurry. The mixture was allowed to stand with-
out stirring for 1 h, and then it was filtered through a sin-
tered glass frit. The purple solid was rinsed with hexanes
[14]
[15]
(
3.12 g, 8.70 mmol)
wise by pipette over 10 min to the stirred solution of catalyst
. The resulting dark-purple solution was sonicated for
6 min. The flask was then fitted with a septum, and the
in THF (79 mL)
wasadded drop-
2
~
flask was vigorously stirred and purged with nitrogen until a
purple suspension formed. This suspension was stirred for
0 h, and then it was allowed to stand for 1.5 h without stir-
ring. Next, the mixture wasfiltered, and the purple os lid
that wascollected wasrin es d with hexanes(100 mL). The
material in the filtrate was purified by passing it through a
column of silica gel, rinsing first with EtOAc to remove
tracesof degradation products(yellow or brown) and then
2
(
(
100 mL) and then suspended in CH Cl (100 mL). Et N
~10 mL) wasadded until the os lution washomogeneou.s
2 2 3
The solution was passed through a column of silica gel, elut-
ing with 95:5 EtOAc:Et N (~900 mL). The dark-purple frac-
3
with 90:10 EtOAc:Et N (~1.0 L) to elute the catalyst as a
3
tionswere collected and concentrated on a rotary evapora-
tor. HPLC analysis revealed an enantiomeric excess of
dark-purple band. The highly colored fractionswere collect-
ed and concentrated on a rotary evaporator. HPLC analysis
revealed an enantiomeric excess of 52% [7.44 g, 65%; fast-
eluting enantiomer on chiral HPLC, (+)-(R) configuration];
RegisWhelk O column, flow: 0.9 mL/min, eluent: 60:40:0.4
CH Cl :hexanes:Et NH. t (+)-(R): 4.6 min; (À)-(S): 5.5 min.
>
99% [5.07 g, 44% (based on the starting amount of race-
mic 2); fast-eluting enantiomer on chiral HPLC, (+)-(R)
20
D
configuration]. (+)-(R)-2: [a] : +9408 (c 0.00024, CHCl );
3
mp 280–2818C (decomp.; >99% ee).
2
2
2
r
The purple solid from the filter cake was dissolved in
CH Cl2 (44 mL) and Et N (4.5 mL). Thi so slution was
2
3
passed through a column of silica gel, eluting with 90:10 Acknowledgements
EtOAc:Et N (~800 mL). The dark-purple fractionswere
3
collected and concentrated on a rotary evaporator. HPLC
analysis revealed an enantiomeric excess of 98% [4.18 g,
Support has been provided by the NIH (National Institute of
General Medical Sciences: R01-GM57034), Merck, Novartis,
and NSERC ofCanada (postdoctoral ef llowship to R.P.W.).
We thank Dr. Jens P. Hildebrand and Jonathan E. Wilson for
preliminary studies.
3
6%; slow-eluting enantiomer on chiral HPLC, (À)-(S) con-
figuration].
Notes: 1) Column chromatography of catalyst 2 can be
performed in the air with essentially no concern for decom-
position. 2) The equivalents of the resolving agent that are
used for the resolution of catalyst 2 isdouble that u es d in
the resolution of catalyst 1.
Recrystallization of the solid from the first crystallization:
Calculation of the required amount of resolving agent:
Adv. Synth. Catal. 2007, 349, 2345 – 2352
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2351

Ryan P. Wurz et al.
UPDATES
References
[7] M. M. Robison, J. Am. Chem. Soc. 1958, 80, 6254–
6
257.
[1] For reviews, see: a) G. C. Fu, Acc. Chem. Res. 2004, 37,
[8] For example, the reaction of pyridine N-oxide with
5
4
42–547; b) G. C. Fu, Acc. Chem. Res. 2000, 33, 412–
20.
POCl proceedswith 70:30 se lectivity favoring the for-
3
mation of 2-chloropyridine (H. Yamanaka, T. Araki, T.
Sakamoto, Chem. Pharm. Bull. 1988, 36, 2244–2247).
We observe almost none (<5%) of the 2-chloropyri-
dine.
[
2] For recent work, see: a) E. C. Lee, K. M. McCauley,
G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 977–979;
b) F. O. Arp, G. C. Fu, J. Am. Chem. Soc. 2006, 128,
1
4264–14265; c) E. Bappert, P. Mueller, G. C. Fu,
[
9] C. Coperet, H. Adolfsson, T.-A. V. Khuong, A. K.
Chem. Commun. 2006, 2604–2606; d) E. C. Lee, B. L.
Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem.
Soc. 2005, 127, 11586–11587; e) C. Schaefer, G. C. Fu,
Angew. Chem. Int. Ed. 2005, 44, 4606–4608; f) S. L.
Wiskur, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 6176–
Yudin, K. B. Sharpless, J. Org. Chem. 1998, 63, 1740–
1
741. In the presence of H O /AcOH, the oxidation
2 2
wasrelatively sl ow.
[
10] We have been able to synthesize compound 6 from 2,3-
cyclopentenopyridine in two, rather than three, steps.
However, these shorter routes are less practical than
the sequence illustrated in Scheme 2.
6
177; g) A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc.
2
005, 127, 5604–5607; h) A. H. Mermerian, G. C. Fu,
Angew. Chem. Int. Ed. 2005, 44, 949–952.
[
[
11] E. Ochiai, J. Org. Chem. 1953, 18, 534–551.
[
3] a) J. C. Ruble, G. C. Fu, J. Org. Chem. 1996, 61, 7230–
12] For a precedent with the parent compound (i.e., with-
7
231; b) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998,
[7].
out a 4-dialkylamino group), see Ref.
1
20, 11532–11533.
[
[
[
13] Purchase price (September 2006): $ 900/kg (including
airborne delivery).
14] Either anhydrousdibenzoyl- l-tartaric acid or itsmono-
hydrate can be employed.
15] Because the solution was somewhat cloudy, it was fil-
tered before it wasu se d.
[
4] We thank Dr. ThomasRoper of GlaxoSmithKline for
pointing out this possibility and Mr. Roy Flanagan of
GlaxoSmithKline for conducting calorimetry studies.
5] J. C. Ruble, Ph. D. Thesis, Massachusetts Institute of
Technology, 1999.
6] In part because it is a subunit of pharmaceuticals such
asCefpirome/Cefrom, 2,3-cyclopentenopyridine ispro-
duced on a large scale.
[
[
2352
asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2345 – 2352