Supporting Information for
The Development of the First Catalyzed Reaction of Ketenes and Imines: Catalytic,
Asymmetric Synthesis of -Lactams
Andrew E. Taggi, Ahmed M. Hafez, Harald Wack, Brandon Young, Dana Ferraris,
and Thomas Lectka*
Department of Chemistry, Johns Hopkins University, 3400 North Charles Street, Baltimore,
Maryland, 21218
General. Unless otherwise stated, all reactions were carried out under strictly anhydrous, air-free
conditions. All solvents were dried and distilled by standard methods. Unless otherwise
mentioned, all acid chlorides were purchased directly or made from their corresponding acid and
purified before use. Catalysts 4c,1 4d,2 4e,1 4h,3 4i,4 4j,5 imine 5a,6 N,O-acetal 77 and
phenyldiazoketone 108 were prepared according to literature procedure. Products 6a-d, 6g-i9, and
6e10 were previously characterized. All additional reagents used were commercially available
from Aldrich and Acros Chemicals. For photochemical reactions, a Southern New England Ultra
Violet Company Rayonet Photo Mini-Reactor (8 x 4W bulbs) was employed. For React IR
experiments an ASI Applied Systems ReactIR™ 1000 was used. 1H and 13C NMR spectra were
acquired on a Varian Unity Plus 400 MHz instrument in CDCl3. The 1H (400 MHz) and 13C (101
MHz) chemical shifts are given in parts per million (δ) with respect to internal TMS standard or
residual solvent peaks. FTIR spectra were recorded on a Bruker Vector 22 spectrometer and
optical rotations were recorded on a Perkin Elmer 120 polarimeter at room temperature.
1
Brunner, H.; Bügler, J. J. Bull. Soc. Chim. Belg. 1997, 106, 77-84.
2
Stenberg, V. I.; Travecedo, E. F.; J. Org. Chem. 1970, 12, 4131-4136.
3
Cassebaum, H.; Uhlig, K. J. Prakt. Chem. 1973, 315, 1057-1066.
4
Glick, J. J. Am. Chem. Soc. 1942, 64, 564-567.
5
Soundararajan, R.; Balasubramanian, T. R. Tetrahedron Lett. 1984, 48, 5555-5558.
6
Tschaen, D. H.; Turos, E.; Weinreb, S. M. J. Org. Chem. 1984, 49, 5058-5064.
7
Ferraris, D.; Dudding, T.; Young, B.; Drury, W. J., III; Lectka, T. J. Org. Chem. 1999, 64, 21682169.
Allen, A. D.; Fenwick, M. F.; Henry-Riyad, H.; Tidwell, T. T. J. Org. Chem. 2001, 66,
5759-5765. Instead of radial chromatography, products were column chromatographed
through a plug of silica. No decomposition was observed.
8
9
Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III; Lectka, T. J. Am. Chem.
Soc. 2000, 122, 7831-7832.
10
Taggi, A. E.; Wack, H.; Hafez, A. M.; France, S. Org. Lett. 2002, 4, 627-629.
S1
Enantiomeric ratios were obtained using a Regis Technologies (R,R)-Whelk-01 chiral analytical
HPLC column.
General Procedure for the Synthesis of -lactams 6 Using BEMP. One fritted, jacketed
column (2 cm wide) was loaded under nitrogen with BEMP resin 3a (85 mg, 0.20 mmol) and
connected to a 3-neck round bottom flask loaded with benzoylquinine 4a (6 mg, 0.013 mmol).
The column was flushed with THF under nitrogen. The BEMP column was cooled to -78° C
with a dry ice/acetone mixture and the flask was placed in a -78° C dry ice/acetone bath. A
solution of benzyloxyacetyl chloride 1i (24 mg, 0.13 mmol) in THF (1 mL) was added to the top
column allowed to drip by gravity through the BEMP resin and into the flask loaded with the
catalyst. A solution of α-imino ester 5a (33 mg, 0.13 mmol, 1.0 eq) in THF (1 mL) was added to
the flask. The reaction was allowed to warm to room temperature over 5 h. The THF was
removed in vacuo and the residue was subjected to column chromatography (15 %
EtOAc/hexanes) on a short plug of silica gel (1.0 cm x 5 cm) to give 6i (62%, 32 mg).
General Procedure for the Synthesis of -lactams 6 using K2CO3. To a dual reaction/filtration
flask were added two stir bars, one on each side. One side of the flask was charged with excess
K2CO3 (-325 mesh, 179 mg, 1.30 mmol) and 5 mol % benzoylquinine 4a (3 mg, 0.007 mmol).
The other side of the vessel was also loaded with 5 mol % of 4a (3 mg, 0.007 mmol). Toluene (3
ml) was added to the side of the vessel charged with carbonate and 1 mL of toluene was added to
the other side containing only 4a. The apparatus was cooled to 0° C so that the fritted disc was
completely submerged in an ice/water bath. Benzyloxyacetyl chloride 1i (24 mg, 0.13 mmol, in 1
mL of toluene) was added dropwise to the potassium carbonate mixture. The ketene was allowed
to form for 12 hours at 0° C. After 12 h, the apparatus was canted to allow the solution of ketene
to flow through the fritted disc into the other side of the vessel while filtering off any solid
byproducts. α-Imino ester 5a (33 mg, 0.13 mmol) was added to the ketene solution. The reaction
was allowed to warm to room temperature over 12 h. The toluene was removed in vacuo and the
residue was dissolved in chloroform (10 mL). The chloroform solution was washed (3 x 5 mL)
with 1.0 M HCl. The organic layer was dried with MgSO4, filtered through Celite, and
concentrated. The residue was subjected to column chromatography (15% EtOAc/hexanes) on
silica gel to give 6i (56%, 29 mg).
General Procedure for the Synthesis of -lactams 6 using Sodium Hydride.11 To a suspension
of NaH (0.062 g, 2.58 mmol), benzoylquinine 4a (0.055 g, 0.13 mmol) and 15-crown-5 (0.028 g,
0.13 mmol) in toluene (5 mL) at 0° C12 was added benzyloxyacetyl chloride 1i (0.522 g, 2.83
mmol) in toluene (1 mL) over 3 min. The mixture was then stirred vigorously for 7 h. A solution
of 5a (0.330 g, 1.29 mmol) in toluene (9 mL) was then added through a syringe pump over 1 h
(0.16 mL/min) and the reaction was warmed to room temperature over 6 h. The reaction was
then quenched with 1M HCl (3 mL) and washed three times with 10% Na2CO3 (10 mL). The
combined aqueous layers were back extracted twice with Et 2O (10 mL) and the combined organic
layers were then dried over MgSO 4, filtered and concentrated. The crude product was purified on
a short plug of silica (15% EtOAc/hexanes) to yield 6i (60%, 0.312 g).
11
While this procedure can be used on a small scale similar to the above methods, it was designed
to run on a much larger scale.
12
The optimal procedure for the formation of the corresponding ketene from acid chloride 1i was
0° C for 1 h. Other less stable ketenes such as 2e need to be formed at -78° C for 1 h. For details
see ref 44.
S2
3-Phenoxypropionyl Chloride (1f). Phenoxypropionic acid (2.0 g, 12.0 mmol) was dissolved in
40 mL CH 2Cl2 with two drops of DMF and cooled to 0° C. Oxalyl chloride (1.90 g, 15.0 mmol)
was slowly added by syringe over 15 min. The reaction was allowed to warm to room
temperature over night and then the solvent was removed under reduced pressure. The crude oil
was slowly distilled under high vacuum into a receiving flask at -78° C (without water cooling in
the distillation head condencer) to yield pure phenoxypropionicacetyl chloride 1f (white solid,
1.56 g, 85%).
Azidoacetyl Chloride (1k). Sodium azide (2.0 g, 30.8 mmol) was dissolved in 15 mL distilled
H2O and cooled to 0° C. Bromoacetic acid (2.14 g, 15.4 mmol) was then added over 10 min and
the reaction was allowed to slowly warm to room temperature over night. The reaction was
acidified to a pH of 1 and extracted three times with 20 mL diethyl ether. The organics were
combined, dried over MgSO4 and concentrated. The crude mixture was then dissolved in 50 mL
of CH 2Cl2 with two drops of DMF and cooled to 0° C. Oxalyl chloride (2.44 g, 19.3 mmol) was
slowly added by syringe over 15 min. The reaction was allowed to warm overnight to room
temperature and then the solvent was removed under reduced pressure. The crude oil was
distilled under high vacuum at room temperature into a receiving flask at -78° C to yield pure
azidoacetyl chloride 1k as a colorless oil (1.56 g, 85%). All data were consistent with literature
precedent.13
General Procedure for the Synthesis for Ketenes 2a and 2b. Diphenylacetyl chloride 1b (4.0
g, 17.3 mmol) was dissolved in 35 mL dry diethyl ether in a 50 mL flask. The solution was
cooled to 0 °C and freshly distilled triethylamine (1.76 g, 17.3 mmol) was added dropwise over 5
min. The reaction instantly turns bright yellow with a large amount of white precipitate. The
reaction was stirred for 1 h and then the salts were removed with a plug of dry celite on a sintered
glass frit, under nitrogen. The filter was washed with an additional 5 mL diethyl ether. The ether
was removed under high vacuum and the crude residue was kept under vacuum for an additional
30 min. The crude residue was then distilled under high vacuum into a flask at –78 °C (bp ≈ 94
°C) to yield diphenylketene 2b (85%, 2.86 g).
Preparation of Bis(ethoxycarbonyl)ketene 2p.14 Ethylchlorooxoacetate (1.36 mL, 11.6 mmol)
was slowly added over 10 min via syringe to a 100 mL round bottom flask containing
ethyldiazoacetate (1.84 mL, 17 mmol), which was cooled and kept at 0 °C. The yellow solution
was allowed to stir for 15 min before freshly distilled xylenes (50 mL), and a catalytic amount of
Pt-strips (roughly 5 mg, which were recycled) were added. The mixture was refluxed for 90 min
before the solvent was distilled off under high vacuum (dry-ice acetone cooled receiving flask) to
minimize heating of the product. The ketene was then fractionally distilled and the clear and
colorless middle fraction was collected to yield approximately 1.5 mL of product. The ketene
was stored at –30 °C for an unlimited amount of time without any detection of decomposition
products.
General Procedure for the Synthesis of Catalysts 4a, 4b and 4f. Quinine (5.0 g, 15.4 mmol)
was dissolved in 50 mL of THF and triethylamine (7.8 g, 77.0 mmol) and cooled to 0° C.
Benzoyl chloride (3.25 g, 23.1 mmol) was added by syringe over 5 min and the reaction was
13
Dyke, J. M.; Groves, A. P.; Morris, A.; Ogden, J. S.; Dias, A. A.; Oliveira, A. M. S.; Costa, M.
L.; Barros, M. T.; Cabral, M. H.; Moutinho, A. M. C. J. Am. Chem. Soc. 1997, 119, 6883-6887.
14
Staudinger, H.; Hirzel, H.; Ber. Dtsch. Chem. Ges. 1916, 49, 3522.
S3
allowed to warm to room temperature over night. The THF was removed under reduced pressure
and the crude residue was dissolved in 70 mL CH2Cl2 and then washed three times with 20 mL
25% (w/w) NaOH solution. The combined aqueous fractions were back extracted with 30 mL
CH2Cl2, the organic layers were combined, dried over MgSO4, filtered and concentrated. The
crude residue was purified on a short plug of silica with 95.5% EtOAc/0.5% triethylamine to
yield a white solid (foam). The solid was recrystallized from boiling Et2O/hexanes to yield
benzoylquinine 4a (6.21 g, 94%). All data was consistent with literature precedent.15
Benzoyl-epi-quinine (4e).1 Quinine (1.0 g, 3.08 mmol), nitrobenzoic acid (0.54 g, 3.23 mmol)
and triphenylphosphine (0.89 g, 3.39 mmol) were dissolved in 20 mL THF. The materials
dissolved and then a white precipitate rapidly formed. Diisopropyl azodicarboxylate (DIAD, 0.69
g, 3.39 mmol) was added dropwise over five min. The reaction became heterogeneous and was
stirred for 2 h then extracted three times with 20 mL 1M HCl, then neutralized with K2CO3, and
extracted with diethyl ether. The organics were combined, dried over MgSO4 and concentrated.
The crude oil was then stirred for three h in 20% (w/w) NaOH to remove the nitrobenzoyl group.
The reaction was neutralized with 1M HCl and extracted 3 times with 25 mL CH2Cl2. The
combined organics were dried over MgSO4 and concentrated to yield crude epi-quinine. The
crude residue was then subjected to above general acylation conditions to form benzoyl-epiquinine (4e).
Determination of the absolute configuration of 6. The absolute configuration of 6a,9 6c,9 and
6j were determined using single crystal X-ray diffraction. The absolute configuration of 6i was
determined through derivitization to a known compound.9 The stereochemistry was inferred to be
consistent for the remaining products 6.
Ts
O
N
EtOOC
OPh
6f
Cis-(3R,4R)-1-p-toluenesulfonyl-3-phenoxymethyl-4-ethoxycarbonylazetidinone (6f). White
crystalline solid recrystallized from Et 2O/hexanes (major diastereomer): mp = 103-105° C; [α]D =
+10.7° (c = 0.010, CHCl3); 1H NMR (CDCl3) δ 8.00 (d, 2H), 7.39 (d, 2H), 7.20 (t, 2H), 6.94 (t,
1H), 6.68 (d, 2H), 4.87 (d, 1H), 4.23 (m, 2H), 3.99 (m, 3H), 2.48 (s, 3H), 1.06 (t, 3H) ppm; 13C
NMR (CDCl 3) δ 166.9, 162.3, 145.6, 135.9, 129.9, 129.6, 128.2, 121.9, 114.3, 62.4, 61.6, 55.8,
53.3, 29.9, 22.0, 14.1 ppm; IR (CHCl3) 3156, 3020, 2964, 2929, 1796, 1743, 1638, 1600, 1523,
1476, 1425, 1381, 1335, 1217, 1172 cm-1. HPLC (5% i-PrOH/ 1% HOAc/hexanes, 1.0 mL/min)
(R,R) = 28.1, (R,S) = 19.8, (S,R) = 35.8, (S,S) = 43.7 min. Anal Calcd for C20H21NO6S C, 59.5;
H, 5.25; N, 3.47. Found C, 59.7; H, 5.24; N, 3.49.
Ts
O
N
EtOOC
6j
Cis-(3R,4R)-1-p-toluenesulfonyl-3-vinyl-4-ethoxycarbonylazetidinone (6j). White crystalline
solid recrystallized from Et2O/hexanes (major diastereomer): mp = 188-189° C; [α]D = +38.3° (c
= 0.010, CHCl 3); 1H NMR (CDCl3) δ 7.95 (d, 2H), 7.37 (d, 2H), 5.57 (m, 1H), 5.34 (dd, 2H) 4.80
(d, 1H) 4.19 (m, 3H), 2.46 (s, 3H), 1.23 (t, 3H) ppm; 13C NMR (CDCl3) δ 166.8, 162.4, 145.6,
15
Pracejus, H.; Maetje, H. J. Prakt. Chem. 1964, 24, 195-205.
S4
135.4, 129.8, 128.0, 125.3, 123.7, 62.1, 57.6, 56.1 21.8, 14.2 ppm; IR (CHCl3) 2253, 1796, 1750,
1641, 1465, 1378 cm-1. HPLC (5% i-PrOH/ 1% HOAc/hexanes, 1.0 mL/min) (R,R) = 32.5, (R,S)
= 29.7, (S,R) = 35.0, (S,S) = 38.8 min. Anal Calcd for C15H17NO5S C, 55.7; H, 5.30; N, 4.33.
Found C, 55.4; H, 5.31; N, 4.34. Absolute stereochemistry confirmed by single-crystal X-ray
diffraction.16
Ts
O
N
EtOOC
N3
6k
Cis-(3R,4R)-1-p-toluenesulfonyl-3-azido-4-ethoxycarbonylazetidinone (6k). Colorless oil:
[α]D = +8.2° (c = 0.010, CHCl3); 1H NMR (CDCl3) δ 7.92 (d, 2H), 7.36 (d, 2H), 4.98 (d, 1H),
4.86 (d, 1H), 4.23 (q, 2H), 2.44 (s, 3H), 1.24 (t, 3H) ppm; 13C NMR (CDCl3) δ 166.2, 159.0,
146.2, 135.1, 129.1 128.0, 61.9, 56.3, 55.9, 23.3, 14.2 ppm; IR (CHCl 3) 2961, 2927, 2856, 2348,
1710, 1462, 1375 cm-1. HPLC (10% CH2Cl2/ 1% HOAc/hexanes, 1.0 mL/min) (R,R) = 19.7,
(R,S) = 26.9, (S,R) = 31.3, (S,S) = 22.2 min. Anal Calcd for C13H14N4O5S C, 46.1; H, 4.17; N,
16.6. Found C, 46.2; H, 4.19; N, 16.3.
Ts
O
N
EtOOC
Br
6l
Cis-(3R,4R)-1-p-toluenesulfonyl-3-bromo-4-ethoxycarbonylazetidinone (6l). White crystalline
solid recrystallized from Et2O/hexanes (major diastereomer): mp = 123-125° C; [α]D = +47.5° (c
= 0.010, CHCl 3); 1H NMR (CDCl 3) δ 7.94 (d, 2H), 7.38 (d, 2H), 5.19 (d, 1H), 5.05 (d, 1H), 4.25
(q, 2H). 2.44 (s, 3H), 1.23 (t, 3H) ppm; 13C NMR (CDCl3) δ 165.3, 158.3, 146.0, 134.5, 129.8,
128.1, 62.5, 58.7, 43.2, 21.7, 14.0 ppm; IR (CHCl3) 3020, 1802, 1746, 1523, 1476, 1425, 1372,
1217 cm-1. HPLC (10% CH2Cl2/ 1% HOAc/hexanes, 1.0 mL/min) (R,R) = 34.9, (R,S) = 23.8,
(S,R) = 25.8, (S,S) = 40.9 min. Anal Calcd for C13H14BrNO5S C, 41.5; H, 3.75; N, 3.72. Found
C, 41.5; H, 3.77; N, 3.71.
Determination of Rate Constant. Phenylacetyl chloride (0.33 M), proton sponge (0.33 M), and
10 mol% benzoylquinine 6a (0.07 M) were mixed together in 5 mL of toluene at -78° C.
Addition of α-imino ester 2a (0.13 M) to each of the solutions followed. The reaction mixtures
were quenched with methanol at 1, 3, 9, 12 min. β-Lactam 1c was isolated and massed from each
solution. The observed rate of reaction k’ was determined to be 1.6 x 10-1 min -1 as derived from
rate = -d[6a]/dt = k’[6a] = k[1a][4a]. Factoring out the concentrations of BQ and phenylacetyl
chloride, the rate constant k was 7.0 min-1 M-1.
16
See attached data for more information.
S5
Catalytic Beta-Lactam Forming Reaction
2.5
y = 0.1623x + 0.1871
2
2
R = 0.9769
1.5
1
0.5
0
0
5
Time (min)
10
15
Computational Analysis of 9 and model-2p. Calculations performed using Schrödinger Inc.
Titan v. 1.0.5 at B3LYP/6-31G*. Adducts 9 were found to have an energy of –897.158 hartrees.
Model-2p was found to have an energy of –567.831 hartrees. The calculated carbonyl stretch
was 2177 cm-1 which correlated well with the observed for stretch for 2p at 2155 cm-1.
OMe
OMe
N
N
H
O
O
O
N
K>1
+
H
O
N
O
EtO2C
4a
CO 2Et
O
CO 2Et
CO 2Et
2p
4a-2p adduct
IR-Studies of adduct 4a-2p. A stock solution of 2p (0.1 g, 0.54 mmol) in 10 mL of THF was
prepared. Benzoylquinine 4a (0.5-2 mol equivalents) was weighed into individual vials and each
dissolved into 1 mL of the stock solution respectively (including one vial containing 1 equivalent
of 4a in 1 mL of THF serving as background). The vials were capped and shaken until the
contents were completely solubilized to yield yellow solutions of 4a-2p adducts. These solutions
were used in conjunction with a liquid IR-cell at room temperature. Results are illustrated in
Figures 9 and the included full IR spectrum.
General Procedure for the ReactIR experiments. Diphenylacetylchloride (50 mg, 0.216 mmol)
was dissolved in 1 mL of toluene and added into the side arm of the React IR cell containing a
toluene (5 mL) solution of proton sponge 3b (46 mg, 0.216 mmol), benzoylquinine 4a (9 mg,
0.0216 mmol). The latter solution was used for the background spectrum to avoid interference.
The desired bands (2100 cm -1, 1810 cm-1) were monitored over 2 h at room temperature. After 30
min the ketene stretch did not increase further as an equilibrium state was established.
O
Ph
N2
10
O
Ts
hν, Rayonet
10 mol% BQ,
23˚ C
H
Ph
2c
O
N
1 equiv. 5a
EtOOC
Ph
6c
Photolysis of 10. Phenyldiazoketone 10 (18 mg, 0.12 mmol), imino ester 5a (47 mg, 0.18 mmol)
and benzoylquinine 4a (5 mg, 0.012 mmol) were weighed into a long, narrow quartz vessel
equipped with a stir bar and dissolved in 15 mL of THF. This was placed into the Rayonet reactor
and photolyzed for 90 min. The solvent was removed under reduced pressure and the crude
S6
mixture was subjected to column chromatography (15% EtOAc/hexanes) on a plug of silica gel
(1.0 cm x 5 cm) yielding 24 mg of 6c (52% yield, dr 5/1, ee 93%).
Full IR spectrum of adduct 4a-2p.
S7