Reactivity Enhancement for Chiral Dirhodium(II) Tetrakis (Carboxamidates)

Article abstract of DOI:10.1002/1615-4169(20010129)343:1<112::AID-ADSC112>3.0.CO;2-M

Difluorinated ligands from azetidinone-4-carboxylates and pyrrolidinone-5-carboxylate have been prepared, substituted onto dirhodium(II), and the reactivities and selectivities of the resulting catalysts have been examined. The fluorinated catalysts exhibit enhanced reactivity towards diazo decomposition but diminished enantioselectivities for cyclopropanation. Selectivity for ylide formation and rearrangement or Si-H insertion is enhanced or similar to that with unfluorinated analogues.

Full text of DOI:10.1002/1615-4169(20010129)343:1<112::AID-ADSC112>3.0.CO;2-M

FULL PAPER
Reactivity Enhancement for Chiral Dirhodium(II)
Tetrakis(Carboxamidates)
Michael P. Doyle,*a Wenhao Hu,a Iain M. Phillips,a Christopher J. Moody,*b
Adrian G. Pepper,b Alexandra M. Z. Slawinc
a Department of Chemistry, University of Arizona, Tucson, Arizona 85721, U.S.A
Fax: +1 5 20/6 26-48 15; e-mail: mdoyle@u.arizona.edu
b School of Chemistry, University of Exeter, Exeter EX4 4QD, United Kingdom
Fax: +44 13 92 26 34 34; e-mail: C.J.Moody@exeter.ac.uk
c Department of Chemistry, University of St Andrews, St Andrews KY16 9ST, United Kingdom
Received July 27, 2000; Accepted October 15, 2000
Keywords: chiral cat-
alysts; fluorinated li-
gands; cyclopropana-
tion; ylides; rhodium
Abstract: Difluorinated ligands from azetidinone-4- cyclopropanation. Selec-
carboxylates and pyrrolidinone-5-carboxylate have tivity for ylide formation
been prepared, substituted onto dirhodium(II), and and rearrangement or Si±
the reactivities and selectivities of the resulting cat- H insertion is enhanced or
alysts have been examined. The fluorinated cata- similar to that with unfluorinated analogues.
lysts exhibit enhanced reactivity towards diazo de-
composition but diminished enantioselectivities for
Introduction
Results and Discussion
The enhancement of catalyst effectiveness through li-
gand modification is a time-honored approach. This
has been especially true for the development of chiral
dirhodium(II) catalysts for metal carbene transforma-
tions.[1] Dirhodium(II) compounds with chiral carbox-
amidate ligands are highly effective towards diazo de-
composition of diazoacetates and diazoacetamides.[2]
However, these catalysts are generally unreactive to-
wards vinyldiazoacetates[3] and diazomalonates,[4] and
alternative reactions or thermal processes occur in-
stead of catalytic diazo decomposition.[1]
Enantiomerically pure 3,3-difluoro-2-oxaazetidine-4-
carboxylates were prepared from d-mannitol (1) by
the sequence of synthetic steps that is described in
Scheme 1. Thus oxidative cleavage of the acetone ke-
tal of d-mannitol,[7] followed by imine formation, af-
forded 3 which was then treated with zinc dust and
ethyl bromodifluoroacetate[8] to produce 4 as a mix-
ture of diastereoisomers whose ratio was dependent
on R1 (Bn, syn/anti = 4.7; p-MeOC6H4CH2, syn/anti =
4.0; Ph2CH, syn/anti = 2.0). Chromatographic separa-
tion of the syn-isomer, alcoholysis, oxidation,[9] and es-
By substitution of fluorine for hydrogen on the car- terification produced the azetidin-2-one product 5 that
bon position alpha to the carboxamide carbonyl, one was deprotected[10] to afford the desired ligand. The
could expect increased reactivity while retaining key to this synthesis was the success of the Reformats-
nearly the same selectivity as the unsubstituted par- ky reaction (step d), for which the only deficiency was
ent carboxamide. Fluorine substitution does influ- the stereoisomer ratio with imines whose R1 substitu-
ence significantly the reactivity of dirhodium(II) car- ent was removable at a later stage. With these consid-
boxylates.[5,6] We describe here the synthesis of erations the p-methoxybenzyl group was determined
difluoroazetidinones and a difluoropyrrolidinone li- to be optimal for the construction of 5 (R1 = H).
gand for dirhodium(II) and the reactivities and selec- Although several esters of 5 (R1 = H) were prepared,
tivities drawn from the corresponding catalysts in only two (R = iBu and cHex) were converted by the
their applications with diazocarbonyl compounds.
standard procedure[11] to dirhodium(II) tetrakis(car-
boxamidates) 6. In spite of extensive efforts, we were
not able to prepare crystals suitable for X-ray structur-
al analysis.
112
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Adv. Synth. Catal. 2001, 343, No. 1

FULL PAPER
Table 1. Reaction of allyl iodide with ethyl diazoacetate[a]
Catalyst
Product
11 : 12 11
12
cis-12
yield %[b]
% ee cis : trans % ee
Rh2(OAc)4
75
36
46
45
41
44
90 : 10
±
45 : 55
50 : 50
50 : 50
50 : 50
43 : 57
37 : 63
±
Rh2(4S-IBAZ)4
Rh2(4R-dFIBAZ)4
Rh2(4R-dFCHAZ)4
Rh2(5S-dFMEPY)4
Rh2(5S-MEPY)4
37 : 63 26
62 : 38 52
59 : 41 47
89 : 11 30
66
39
45
28
44
76 : 24
0
[a] Reaction performed in refluxing CH2Cl2 with 1.0 mol % of
catalyst and 10 equiv of allyl iodide.
[b] Weight yield after chromatography.
come is also seen in more traditional reactions. For
example, with ethyl diazoacetate and styrene (Eq. 1)
6 was less selective diastereoselectively and enantio-
selectively than its non-fluorinated counterparts
(8).[14]
Scheme 1. a: Me2C(OMe)2, pTsOH (46%). b: NaIO4/
CH2Cl2±H2O. c: R1NH2/MgSO4/CH2Cl2. d: Zn/THF/TMSCl/
BrCF2COOEt (61% from 2). e: CH2Cl2/TFA/MeOH/PhMe. f:
Me2CO±H2O (3 : 1)/NaIO4/KMnO4/HOAc. g: iBuOH/pTsOH/
Dean-Stark trap (57% from 4). h: CAN/ MeCN±H2O (2 : 1)
with R1 = p-MeOC6H4CH2 (69%). i: Rh2(OAc)4/PhCl (65%
with R2 = iBu, 73% with R2 = cHex)
ꢀ1†
However, in ylide formation and [2,3]-sigmatropic re-
arrangement with allyl iodide and ethyl diazoacetate
(Eq. 2),[15] a transformation that was only moderately
successful (12±15% yield of 11, up to 39% ee) with
other chiral dirhodium(II) carboxamidates, moderate
yields and significantly higher % ee values were
achieved for 11 with fluorinated catalysts 6 (Table 1),
and these results suggest that there may be further
advantages for these catalysts in ylide transforma-
tions.
To ascertain that the fluorinated ligand did confer
higher reactivity to the associated catalyst,[12] we se-
lected the intramolecular cyclopropanation reaction
of 2-methyl-2-propen-1-yl phenyldiazoacetate (7)[13]
by both Rh2(4R-dFIBAZ)4 (6 a, R2 = iBu) and its hydro-
gen-substituted analogue 8a (Scheme 2). Separately,
these two catalysts gave the cyclopropane product 9
in good yield, modest % ee values, but opposite con-
figuration. With equal amounts of the two catalysts
and under exactly the same reaction conditions, how-
ever, (1S,5R)-9 was the major enantiomer (43% ee),
indicating that 6 a is at least eight times more reactive
towards diazo decomposition of 7 than is 8 a.
ꢀ2†
In addition, 6 is effective for diazo decomposition of
RCN2COOEt (R = CF3 and COOEt) in refluxing di-
chloromethane, but enantiomeric excesses of cyclo-
propanation are less than 40%.
We have also prepared the fluorinated analogue of
Rh2(5S-MEPY)4 through modification with signif-
cantly higher yield of a recently published procedure
for the preparation of ligand 13.[16] In this case we
were able to ibtain crystals suitable for X-ray struc-
tural analysis. The structure of 14 b is shown in Fig-
ure 1; the new catalyst possesses the same (cis-2,2)
geometry as Rh2(5S-MEPY)4. Reaction with phenyl
diazoacetate 7 occurred within minutes at room tem-
perature in dichloromethane using 14 b even though
there was no reaction with 14 a under the same con-
ditions. However, as found with 6 in comparison with
8, enantiocontrol was low (6% ee for 9 catalyzed by
14 b). Comparable results for ylide reactions were
more promising (Table 1), both in chemoselectivity
for iodonium ylide formation and in enantioselectiv-
ity for 11.
Scheme 2.
Lower % ee values for the reactions of 7 catalyzed by
6 a compared to 8 a are a result of the higher reactiv-
ity of the intermediate metal carbene, and this out-
Adv. Synth. Catal. 2001, 343, 112±117
113

asc.wiley-vch.de
Experimental Section
General Experimental Details
The tetrahydrofuran used was distilled prior to use from so-
dium and benzophenone; all other solvents were used with-
out further purification. 1H NMR and 13C NMR spectra were
obtained as solutions in CDCl3, and chemical shifts are re-
ported in parts per million (ppm, d) downfield from the inter-
nal standard, Me4Si (TMS), using either an AM-250, DRX-
400, DRX-500, or DRX-600 NMR spectrometer. Optical rota-
tions were measured using a JASCO DIP-1000 digital polari-
meter. N-Fluorobenzenesulfonimide was recrystallized
from ethyl acetate : hexanes prior to use.
1,2 : 5,6-Diisopropylidene-D-mannitol (2)
A mixture of powdered d-mannitol (28 g, 0.154 mol), p-to-
luenesulfonic acid (0.5 g) and 2,2-dimethoxypropane
(46 mL, 0.375 mol) in dry Me2SO (50 mL) was stirred at
room temperature under nitrogen. Within 1 hour the sus-
pended solids had dissolved, and after 16 hours the reaction
solution was poured into 150 mL of 3% NaHCO3. The mix-
ture was extracted with ethyl acetate (3 ´ 200 mL), and the
extracts were concentrated under reduced pressure until a
solid mass occurred. Hexanes (300 mL) was added, and the
mixture was dissolved under refluxing conditions. The solu-
tion was allowed to cool slowly overnight. The resulting
crystalline material was collected by filtration and then
washed with 100 mL of cold ether/hexanes (1 : 20) and dried
to give the diacetonide; yield: 18 g (0.07 mol, 46%); 1H NMR
(250 MHz, CDCl3): d = 4.23±4.05 (m, 1-H, 4 H), 3.97 (dd,
J = 8.1, 5.6 Hz, 2 H), 3.74 (t, J = 6.2 Hz, 2 H), 2.63 (br s, 2 H),
1.41 (s, 6 H), 1.35 (s, 6 H); 13C NMR (62.5 MHz, CDCl3):
d = 109.4, 76.3, 71.2, 66.7, 26.7, 25.2.
Figure 1. X-Ray crystal structure of dirhodium(II) tetra-
kis[mcthyl 3,3-difluoro-2-oxopyrrolidine-(5S)-carboxylate]
(bis ethyl acetate complex) 14 b
A comparison of results for Si±H insertion with 14[17]
describes a similar outcome, Eq. (3). Reaction times
are an order of magnitude less with Rh2(5S-
dFMEPY)4 than with Rh2(5S-MEPY)4, but enantiocon-
trol is diminished (38% ee for 15 with 14 b versus 58%
ee for 15 with 14 a). However, when tri(isobutyl)si-
lane is used in place of phenyldimethylsilane, enan-
tiomeric excesses for the Si-H insertion products are
comparable (58% ee with 14 b and 56% with Rh2(5R-
MEPY)4).
(4R)-1-(4'-Methoxylbenzyl)-3,3-difluoro-4-(1'R-1',2'-O-
isopropylideneethyl)azetidin-2-one (4)
To a stirred solution of 2 (5.0 g, 19.0 mmol) in CH2Cl2
(50 mL) was added sodium periodate (8.1 g, 38.0 mmol) fol-
lowed by addition of saturated sodium hydrogen carbonate
(2.0 mL). The mixture was stirred at room temperature for
2 hours. Magnesium sulfate (3 g) was added and stirring
was continued for 20 min. The slurry was filtered through a
plug of celite to give a CH2Cl2 solution of crude 2,3-O-isopro-
pylidene-d-glyceraldehye (3).[7] To the above solution was
added anhydrous magnesium sulfate (10 g) then p-methox-
ybenzylamine (4.69 g, 34 mmol) during 30 min. After an ad-
ditional 30 min the resulting slurry was filtered, and the fil-
trate was washed with CH2Cl2 (2 ´ 20 mL). Imine that was
recovered after the solvent evaporated was subjected to the
Reformatsky reaction according to the literature proce-
dure,[8] and the resulting product was fully characterized.
The syn to anti ratio was determined by 1H NMR, and the
syn-lactam 4 was isolated; yield: 7.6 g (23.2 mmol, 61%);
[a]2D5 = ±93.8 (c 1.5, CH2Cl2); 1H NMR (250 MHz, CDCl3):
d = 7.26±7.21 (comp, 2 H), 6.90±6.71 (comp, 2 H), 4.85 (d,
J = 14.7 Hz, 1 H), 4.27±4.16 (comp, 3 H), 3.38 (s, 3 H), 3.76±
3.68 (comp, 2 H), 1.38 (s, 3 H), 1.35 (s, 3 H); 13C NMR
(62.5 MHz, CDCl3): d = 159.9, 130.1, 126.1, 119.9 (t,
JF,C = 292 Hz), 114.1, 110.5, 74.8, 66.3 (t, JF,C = 23.7 Hz), 66.1,
55.3, 44.8 (t, JF,C = 2.8 Hz), 26.5, 24.9.
ꢀ3†
Conclusion
Overall, the fluorinated analogues of Rh2(IBAZ)4 and
Rh2(MEPY)4 do exhibit enhanced reactivity for diazo
decomposition. However, and to our surprise, these
catalysts show significantly diminished selectivity in
cyclopropanation reactions, which may be attributed
to an earlier transition state. In contrast, selectivity in
and for ylide transformations appear to benefit from
this increased reactivity, and in Si±H insertion reac-
tions the influence may be minimal. Additional inves-
tigations are warranted.
114
Adv. Synth. Catal. 2001, 343, 112±117

FULL PAPER
(4R)-1-(4'-Methoxylbenzyl)-3,3-difluoro-4-(isobutyloxy-
carbonyl)azetidin-2-one
Dirhodium(II) Tetrakis[2-methyl-l-propyl 2-oxa-3,3-di-
fluoroazetidine-4(R)-carboxylate] (6 a)
A solution of c-lactam 4 (7.6 g, 23.2 mmol) in 166 mL of
6 : 3 : 1 CH2Cl2/TFA/CH3OH (100 : 50 : 16 mL) was stirred at
room temperature for 1 h (step e, Scheme 1). The solvent
was evaporated under vacuum, and to the residue was
added toluene (50 mL) which was evaporated to remove
residual TFA. The residue was dried thoroughly under
vacuum, then a mixture of 320 mL of 3 : 1 acetone/H2O
(240 : 80 mL) was added to dissolve the residue, then NaIO4
(9.93 g, 46.4 mmol) was added (step f, Scheme 1). The mix-
ture was stirred at room temperature for 2 hours. KMnO4
(10.6 g, 93.6 mmol) was added, followed by acetic acid
(10 mL). The resulting red mixture was stirred at room tem-
perature for 3 h then filtered, and the filter cake was washed
with acetone until the acetone eluent was colorless. The
aqueous eluent was extracted with ethyl acetate
(2 ´ 200 mL). The resulting organic layer was washed with
brine (50 mL), dried over anhydrous MgSO4, and the solvent
was evaporated under reduced pressure to give crude acid.
To the crude acid was added benzene (150 mL), 2-methyl-1-
propanol (20 mL) and p-toluenesulfonic acid (0.43 g). The
resulting solution was refluxed (step g, Scheme 1) until
water was no longer evolved in a Dean-Stark apparatus. Sol-
vent was evaporated and the residue was subjected to col-
umn chromatography on silica gel (hexanes:ethyl acet-
ate = 20 : 1) to afford product as a colorless viscous oil; yield:
4.3 g (13.2 mmol, 57%); [a]2D9 = +37.4 (c 0.4, CH3CN); 1H NMR
(500 MHz, CDCl3): d = 7.15 (d, J = 8.5 Hz, 2 H), 6.89 (d,
J = 8.5 Hz, 2 H), 4.93 (d, J = 15.0 Hz, 1 H), 4.25 (dd, JF,H = 6.8,
2.5 Hz, 1 H), 4.22 (dd, J = 15.0, 1.8 Hz, 1 H), 4.05 (dd, J = 10.5,
7.6 Hz, 1 H), 3.98 (dd, J = 10.5, 7.6 Hz, 1 H), 3.82 (s, 3 H), 2.01±
1.91 (m, 1 H), 0.96 (d, J = 6.6 Hz, 6 H); 13C NMR (125 MHz,
CDCl3): d = 164.8, 159.8, 159.3 (t, JF,C = 30 Hz), 130.0, 126.1,
124.7, 119.5 (t, JF,C = 292 Hz), 114.6, 72.4, 64.0 (t,
JF,C = 25.3 Hz), 55.3, 44.7, 27.6, 18.8.
Prepared and purified in 65% overall yield by standard
methods;[11, 13, 14] [a]D25 = +250.8 (c 0.43, MeCN); anal. found:
C, 38.3; H, 4.1; N, 6.9, calcd. for C32H40N4O12F8Rh2 ´ CH3CN
C, 38.1; H, 4.1; N, 6.5; 1H NMR (250 MHz, CDCl3): d = 4.91±
4.89 (m, 2 H), 4.43±4.41 (m, 2 H), 4.10±3.92 (m, 8 H), 2.02±
1.86 (m, 4 H), 0.96 (d, J = 6.6 Hz, 12 H), 0.92 (d, J = 6.8 Hz,
12 H); 13C NMR (62.5 MHz, CDCl3): d = 168.2, 167.2, 72.2,
72.1, 66.4, 66.1, 52.7, 27.7, 27.5, 18.7; MS (FAB): m/z 1031
([MH]+, 100%); HRMS (FAB) for (C32H40N4O12F8Rh2H)+, m/z
calcd. 1031.0703, found 1031.0712.
2,2-Dimethyl-7-fluoro-8-oxo-1-aza-3-oxabicyclo[3.3.0]-
octane
Prepared by a modification to the method reported by Cow-
ard and Konas.[16] To a cooled stirred solution of diisopropyl-
amine (5.4 mL, 41.9 mmol) in dry THF (30 mL) at ±78 °C, n-
butyllithium in hexanes (14.2 mL, 35.5 mmol) was added via
a syringe pump over a 1 h period and the resulting mixture
stirred for 1 h. A solution of (5S)-2,2-dimethyl-8-oxo-1-aza-
3-oxabicyclo-[3.3.0]octane[18] (5.00 g, 32.3 mmol) in dry
THF (20 mL) was added over a 1 h period to the LDA mix-
ture during which time an orange color developed. After
2 h, N-fluorobenzenesulfonimide (11.2 g, 35.5 mmol) in dry
THF (30 mL) was added dropwise over a 1 h period, and the
reaction mixture was stirred for a further 1 h. The reaction
mixture was then quenched with aqueous saturated ammo-
nium chloride (20 mL) and allowed to warm to room tem-
perature, then THF was removed under reduced pressure.
The resulting aqueous solution was extracted with dichloro-
methane (3 ´ 50 mL), the organic layers were combined and
dried (MgSO4), and the solvent was removed under vacuum
to yield a yellow oil which was subjected to silica gel column
chromatography [EtOAc : hexanes (3 : 2) as eluent]. The title
compound was isolated as a yellow oil which was a mixture
of diastereoisomers; yield: 5.22 g (94%); 1H NMR (600 MHz,
CDCl3) syn-isomer: ꢀ = 5.31 (ddd, J = 52, 10, 8 Hz, 1 H), 4.19
(dd, J = 16, 6 Hz, 1 H), 3.93±3.98 (m, 1 H), 3.50 (dd, J = 9,
9 Hz, 1 H), 2.79 (ddd, J = 13, 8, 6 Hz, 1 H), 1.87±1.96 (m, 1 H),
1.71 (s, 3 H), 1.48 (s, 3 H); anti-isomer: d = 5.08 (dd, J = 52,
6 Hz, 1 H), 4.46 (m, 1 H), 4.15 (dd, J = 8, 6 Hz, 1 H), 3.42 (dd,
J = 9, 9 Hz, 1 H), 2.42 (ddd, J = 21, 15, 6 Hz, 1 H), 1.96±2.06
(m, 1 H), 1.66 (s, 3 H), 1.52 (s, 3 H).
2-Methyl-1-propyl 3,3-Difluoro-2-oxaazetidine-(4R)-car-
boxylate (5 a)
To the above N-protected azetidinone (2.7 g, 8.3 mmol) was
added 75 mL of 2 : 1 CH3CN/H2O (50 : 25 mL). The resulting
solution was cooled to 0 °C under an ice-water bath. Ceric
ammonium nitrate (18.1 g, 33.2 mmol) was added to the
mixture which was stirred at the same temperature for
1 h.[10] The solution was allowed to warm to room tempera-
ture, and stirring was continued for another 3 h. The reac-
tion mixture was extracted with ethyl acetate (2 ´ 200 mL).
The combined organic layer was washed with water
(30 mL) and brine (50 mL), dried over anhydrous MgSO4,
and the solvent was evaporated under reduced pressure.
The residue was subjected to column chromatography on si-
lica gel (hexanes:ethyl acetate = 10 : 1) to afford product as a
colorless oil; yield: 1.18 g (5.7 mmol, 69%); [a]2D5 = +26.6
(c 5.0, CH3CN); 1H NMR (250 MHz, CDCl3): d = 7.40 (br s,
1 H), 4.60 (dd, JF,H = 6.5, 3.5 Hz, 1 H), 4.09 (dd, J = 10.5,
6.9 Hz, 1 H), 3.98 (dd, J = 10.5, 6.6 Hz, 1 H), 2.01±1.91 (m,
1 H), 0.93 (d, J = 6.8 Hz, 6 H); 13C NMR (62.5 MHz, CDCl3):
d = 165.6, 160.3, 120.9 (t, JF,C = 292 Hz), 72.7, 62.2 (t,
JF,C = 24.8 Hz), 27.6, 18.7; MS(FAB): m/z 208 (MH)+.
(5S)-2,2-Dimethyl-7,7-difluoro-8-oxo-1-aza-3-oxabicy-
clo[3.3.0]octane
Prepared as described for the monofluorination procedure
using the 2,2-dimethyl-7-fluoro-8-oxo-1-aza-3-oxabicy-
clo[3.3.0]octane (4.95 g, 28.6 mmol), column chromatogra-
phy [chloroform : EtOAc (4 : 1) as eluent] afforded the title
compound as a white solid; yield: 4.37 g (80%) mp 35±37 °C
(from ethyl acetate/light petroleum); [a]2D8 = +89.2 (c 0.85,
CHCl3); IR (film): m = 1732 cm±1; 1H NMR (500 MHz, CDCl3):
d = 4.26 (dd, J = 9, 6 Hz, 1 H), 4.13 (m, 1 H), 3.47 (dd, J = 9,
9 Hz, 1 H), 2.77 (ddd, J = 15, 15, 6 Hz, 1 H), 2.13 (dddd,
J = 27, 15, 13, 8 Hz, 1 H), 1.68 (s, 3 H), 1.54 (s, 3 H); 13C NMR
(100 MHz; CDC13): d 159.8 (dd, JC,F = 33.0, 28.4 Hz), 121.2
(dd, JC,F = 256.9, 251.6 Hz), 92.4, 69.8, 54.0, 35.1 (dd,
JC,F = 24.7, 21.7 Hz), 26.3, 23.3; 19F NMR (376 MHz; CDCl3,
C6F6 external standard): d = 59.77 (dd, JF,F = 264.4 Hz,
JH,F = 12.9 Hz), 58.44 (ddd, JF,F = 264.0 Hz, JH,F = 26.8,
14.4 Hz); MS (CI, NH3): m/z 192 ([MH]+, 100%).
Adv. Synth. Catal. 2001, 343, 112±117
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(5S)-3,3-Difluoro-5-(hydroxymethyl)-2-pyrrolidinone
To a solution of the (5S)-2,2-dimethyl-7,7-difluoro-8-oxo-1-
aza-3-oxabicyclo[3.3.0]octane (1.91 g, 10.0 mmol) in a 1 : 1
mixture of dioxane and water (60 mL), Amberlite IR-120
(H+) resin (1.91 g) was added, and the reaction mixture was
heated at reflux for 4 h. After cooling to room temperature,
the Amberlite resin was removed via filtration, washed with
water (25 mL) and the solvent was removed under reduced
pressure to give the crude product which was purified by si-
lica gel chromatography [dichloromethane:methanol (5 : 1)
as eluent]. The title compound was isolated as a white crys-
talline solid; yield: 1.38 g (91%); mp 144±145 °C (from
methanol/dichloromethane); [a]2D1 = +30.6 (c 1.01 in MeOH);
anal. found: C, 39.5, H; 4.5; N, 9.1; C5H7F2NO2 requires C,
39.7; H, 4.7; N, 9.3%; IR (KBr): m = 3379, 3238, 1730 cm±1; 1H
NMR (600 MHz, CD3OD): d = 3.74±3.80 (m, 1 H), 3.60 (dd,
J = 11, 4 Hz, 1 H), 3.48 (dd, J = 11, 5 Hz, 1 H), 2.59±2.66 (m,
1 H), 2.31±2.40 (m, 1 H); 13C NMR (100 MHz, DMSO-d6):
d = 165.1 (dd, JC,F = 30.2, 30.2 Hz), 119.4 (dd, JC,F = 247.4,
245.7 Hz), 63.2, 50.2, 32.6 (dd, JC,F = 22.0, 21.9 Hz); 19F NMR
(376 MHz, DMSO-d6, C6F6 external standard): d = 60.75±
59.96 (br m), 59.23 (ddd, JF,F = 265.5 Hz, JH,F = 16.1, 2.3 Hz);
MS (CI, NH3): m/z 169 ([M+NH4]+, 100%).
5.8%; IR (KBr): m = 3448 (OH), 2960, 2924, 2852, 1749,
1653 cm±1
1H NMR (500 MHz, CDCl3): d = 4.28±4.30 (m, 2
;
H), 4.14±4.16 (m, 2 H), 3.81 (s, 6 H), 3.73 (s, 6 H), 2.53±2.72,
(m, 6 H), 2.30 (ddd, 29, 15, 4.5 Hz, 2 H); 13C NMR (100 MHz,
DMSO-d6): d = 178.2 (dd, JC,F = 27.8, 27.7 Hz), 177.6 (dd,
JC,F = 27.5, 27.5 Hz), 173.2, 172.6, 118.6 (dd, JC,F = 247.9,
245.4 Hz), 118.5 (dd, JC,F = 249.5, 246.6 Hz), 58.5, 58.0, 52.5,
52.0, 36.3 (dd, JC,F = 24.5, 23.9 Hz), 35.5 (dd, JC,F = 23.9,
23.3 Hz); 19F NMR (376 MHz, DMSO-d6, C6F6 external stan-
dard): d = 66.14 (dddd, JF,F = 256.3 Hz, JH,F = 21.6, 18.6,
4.1 Hz), 64.47 (ddd, JF,F = 256.6 Hz, JH,F = 19.3, 4.7 Hz), 63.69
(ddd, J = 17.7, 15.2, 2.7 Hz); MS (FAB): m/z 917.7; HRMS
(FAB) for [C24H24N4O12F8Rh2]+, m/z calcd. 917.9373, found
917.9377.
Crystallography
Dirhodium(II)tetrakis[methyl-3,3-difluoro-2-oxopyrroli-
dine-(5S)-carboxylate] 14 b crystallized as two forms, one
with two ethyl acetate axial ligands and one with one ethyl
acetate and one water as axial ligands together with 1.5 mo-
lecules of solvent water. C60H77F16N8O32.5Rh4, M = 2145.94;
orthorhombic, P21212121, a = 12.8943(4), b = 14.0120(3),
c = 50.7866(13) A, V = 9175.9(4) A , qcalcd. 1.553 gcm±1, Z = 4,
46519 reflections measured, 13128 independent (Rint
0.1055), to yield R = 0.0575. Data has been deposited at the
Cambridge Crystallographic Data Centre.
Ê
Ê 3
Methyl
(5S)-3,3-Difluoro-2-oxopyrrolidine-5-carboxy-
late (13)
Freshly prepared Jones reagent was added in portions to a
solution of (5S)-3,3-difluoro-5-(hydroxymethyl)-2-pyrrolidi-
none (0.48 g, 3.20 mmol) in wet acetone (25 mL), and the re-
action was monitored by TLC. Upon complete consumption
of starting material, 2-propanol (10 mL) was added carefully
and the reaction mixture was stirred for 1 h. The reaction
mixture was diluted with water (40 mL), and the organic sol-
vents were removed in vacuo. The aqueous residue was ad-
justed to pH 3.0 with NaHCO3 and continuously extracted
with ethyl acetate for 2 days. The organic phase was concen-
trated under vacuum and the crude acid residue taken up in
ether (100 mL). To this solution was added a freshly pre-
pared solution of diazomethane in ether in portions, and
upon complete consumption of intermediate acid, as judged
by TLC, the reaction was quenched by addition of acetic acid
(2 mL). The reaction mixture was concentrated in vacuo to
give the crude product. Flash chromatography (30 : 5 : 65,
ethyl acetate/methanol/light petroleum) gave the title
compound as an off-white oil; yield: 0.47 g (83%);
[a]2D5 = +1.5 (c 1.02 in CHCl3); IR (film): m = 3282 (NH), 2958,
Acknowledgments
Support for this research by the National Science Foundation
and the National Institutes of Health (Grant GM 46503) to
M.P.D. is gratefully acknowledged. We also acknowledge sup-
port from The Leverhulme Trust to C.J.M.
References
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([C6H11N2O3F2+NH4]+,
100%);
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(CI)
for
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Prepared and purified in 65% overall yield by standard
methods:[11, 13, 14] mp > 275 °C (from ethyl acetate/hexane);
[a]2D4 = ±326.8 (c 0.12, CH3CN); anal. found: C, 30.3; H, 2.8; N
5.5, C24H24F8N4O12Rh2 ´ 2 H2O requires C, 30.2; H, 3.0; N,
116
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117