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DOI: 10.1055/s-0029-1218342
Organocatalytic Stereoselective Aziridination of Imines via Ammonium Ylides
Publication History
Publication Date:
05 November 2009 (online)
Abstract
Tertiary amine catalyzed reaction of imines with phenacyl bromide derivatives expeditiously affords functionalized aziridines in high yields and stereoselectivities in a one-pot process. Advantageously, the protocol precludes the preparation and isolation of ylides and their precursors in a separate step as they are formed in situ.
Key words
aziridines - imines - nitrogen heterocycles - organocatalysis - stereoselective reaction - ylides
Aziridines are fascinating synthetic targets not only as key components of a range of natural and non-natural molecules, [¹] [²] but also as versatile building blocks in synthesis. [³] Whereas the inherent ring strain in aziridines leads to difficulties in their synthesis, functionalization, and modification, it is advantageous for their bioactivity and synthetic applications involving alkylation and selective ring-opening reactions, respectively. [4] The importance of aziridines is reflected in the enormous effort with varying degree of success and limitations that has been devoted to their synthesis. [5-7]
The development of methodology for stereocontrolled formation of carbon-nitrogen bond is one of the challenging research topics. Several reports are available on the application of sulfur ylides to stereocontrolled aziridination of imines. [7] Surprisingly, the literature records no example of such aziridination employing a nitrogen ylide. [8] [9] This remarkable gap and elegant work of Gaunt and co-workers on ammonium ylide promoted cyclo-propanation [¹0] along with our continued quest for the development of novel cyclization reactions [¹¹] prompted us to investigate whether organocatalytic aziridination of imines could be feasible via ammonium ylides, and we report herein the first successful results (Scheme [¹] ).
Scheme 1 One-pot aziridination of imines 1
An ammonium ylide based reaction becomes an attractive target for a general stereoselective aziridination process owing to the vast range of commercially available tertiary amines including the chiral ones. Advantageously, the present process does not require ylides or their precursors to be prepared and isolated in a separate step as they are generated in situ, and the process is catalytic in the ylidic species. In the case of sulfur ylides there are only two reports available where the ylide and its precursor are generated in situ. [7f] [g]
Initially, we tried aziridination of imine 1 (R = Ph) with a stoichiometric amount of phenacyl bromide 2 (Ar = Ph), and a base (Na2CO3, NaOH, or Et3N), but the reaction was unsuccessful. Then, attracted by the chemistry of ammonium ylides, we performed the reaction with salt 4a and a base followed by imine 1a, which delighted us by affording the desired aziridine 3a in varying yields depending upon the reaction conditions employed (Table [¹] ). The best result in terms of the yield and diastereoselectivity was obtained with Na2CO3 in MeCN at 80 ˚C (Table [¹] , entry 1). The temperature appears crucial because the reaction did not take place appreciably even after stirring for 24 hours at room temperature.
In order to expeditiously synthesize 3 and to avoid the preparation of ylide precursor 4a in a separate step, we examined the possibility of a one-pot aziridination process. Thus, a mixture of phenacyl bromide 2 (Ar = Ph; 1 mmol), DABCO (1 mmol), imine 1a (1 mmol), and Na2CO3 (1.5 mmol) in MeCN was stirred at 80 ˚C. After 19 hours, aziridine 3a was isolated in 85% yield with 94% trans selectivity. This one-pot aziridination reaction offers significant advantages as it precludes the necessity to generate and isolate the ylide precursors 4 in a separate step.
In the above one-pot process, a phenacyl bromide 2 undergoes SN2 displacement with the tertiary amine 7 to form a quaternary ammonium salt 4. Deprotonation with Na2CO3 forms the ylide 5, which undergoes addition to imine 1 to form 6. Finally, 3-exo-tet cyclization of 6 delivers aziridine 3 and regenerates amine 7 (Scheme [²] ). This plausible mechanism suggests that the amine 7 is released at the end of the reaction when the aziridine ring is formed, thus it should be possible to use the amine in a catalytic amount. Accordingly, we carried out one-pot organocatalytic aziridination reaction, which worked well. Thus, stirring a mixture of phenacyl bromide 2 (1 mmol), imine 1 (1 mmol), sodium carbonate (1.5 mmol), and DABCO (0.2 mmol) in acetonitrile (5 mL) at 80 ˚C for 19 hours produced aziridine 3 in 85% yield (Table [²] ). [¹²]
Scheme 2 A plausible mechanism and the catalytic cycle of aziridination of imines 1
The general utility of the present organocatalytic aziridination process was demonstrated across a range of substituted N-tosyl imines 1 and phenacyl bromides 2. The results are summarized in Table [²] ; both electron-withdrawing substituents are tolerated to afford the corresponding products 3 in consistently good yields (78-94%) and trans diastereoselectivities (89-97%). However, the present synthetic protocol is not satisfactorily applicable to unactivated aldimines such as N-benzylideneaniline and to N-tosyl ketimines, for example, acetophenone-derived N-tosyl imine.
The observed diastereoselectivity in the formation of aziridines may be tentatively explained by comparing the two intermediates 8 and 9 bearing charged groups anti to each other. The intermediate 8 leading to cis-aziridines is more congested as it possesses three sterically demanding gauche interactions (Scheme [³] ). Thus, trans-aziridines are selectively formed through the sterically less congested intermediate 9. The trans diastereoselectivity of aziridines 3 was assigned on the basis of J values (J = 4.09-4.12 Hz) of 2-H and 3-H, which are lower than those for the cis-aziridines (J = 9.6-9.8 Hz). This is in conformity with the earlier observations for trans-aziridines reported in the literature. [¹³]
| Entry |
Aziridine 3
| Time (h)a | Yield (%)b,c of trans-3 | trans/cis d | |||||||||||||||
| R | Ar | ||||||||||||||||||
| 1 | Ph | Ph | 19 | 85 | 94:6 | ||||||||||||||
| 2 | 4-OMeC6H4 | Ph | 21 | 83 | 92:8 | ||||||||||||||
| 3 | 4-NO2C6H4 | Ph | 24 | 82 | 90:10 | ||||||||||||||
| 4 | n-Bu | Ph | 24 | 78 | 90:10 | ||||||||||||||
| 5 | Ph | 4-ClC6H4 | 19 | 86 | 92:8 | ||||||||||||||
| 6 | 4-OMeC6H4 | 4-ClC6H4 | 19 | 87 | 95:5 | ||||||||||||||
| 7 | 4-NO2C6H4 | 4-ClC6H4 | 20 | 84 | 94:6 | ||||||||||||||
| 8 | n-Bu | 4-ClC6H4 | 24 | 79 | 89:11 | ||||||||||||||
| 9 | Ph | 4-OMeC6H4 | 21 | 80 | 92:8 | ||||||||||||||
| 10 | 4-OMeC6H4 | 4-OMeC6H4 | 23 | 82 | 90:10 | ||||||||||||||
| 11 | 4-NO2C6H4 | 4-OMeC6H4 | 24 | 78 | 89:11 | ||||||||||||||
| 12 | n-Bu | 4-OMeC6H4 | 24 | 78 | 90:10 | ||||||||||||||
| 13 | Ph | 4-NO2C6H4 | 20 | 92 | 91:9 | ||||||||||||||
| 14 | 4-OMeC6H4 | 4-NO2C6H4 | 19 | 90 | 93:7 | ||||||||||||||
| 15 | 4-NO2C6H4 | 4-NO2C6H4 | 21 | 83 | 92:8 | ||||||||||||||
| 16 | n-Bu | 4-NO2C6H4 | 23 | 81 | 91:9 | ||||||||||||||
|
| |||||||||||||||||||
|
a The reaction
mixture was stirred at 80 ˚C. b Yield of isolated and purified trans-aziridine 3. c All compounds gave C, H, and N analyses within ±0.37% and satisfactory spectral [¹H NMR, ¹³C NMR, and (EI)] data. See supporting information for details. d As determined by ¹H NMR integration of cis and trans isomers in the crude product. | |||||||||||||||||||
Scheme 3 A rationale for the trans diastereoselectivity of aziridination
Furthermore, strong NOEs were observed between 2-H/3-H of cis-aziridines (absent in the case of trans isomers), which conclusively prove their cis stereochemistry.
As regards the choice of a tertiary amine 7 for the formation of salt 4, DABCO (1,4-diazobicyclo[2.2.2]octane) was preferred over triethylamine to minimize the propensity for Stevens rearrangement because ring expansion to a seven-membered ring should be less favorable. [¹4] However, use of quinuclidine in place of DABCO did not affect the yield of 3a. Moreover, DABCO was model tertiary amine to mimic the core structure of the cinchona alkaloids because they may be used as a chiral catalyst.
Figure 1
In a pilot work on a one-pot enantioselective aziridination reaction, we stirred a mixture of phenacyl bromide 2a (1 mmol), imine 1a (1 mmol), sodium carbonate (1.5 mmol) and tertiary amine 7a (0.2 mmol) at 80 ˚C for 19 hours to afford aziridine trans-3a in 78% yield with an enantiomeric ratio (e.r.) of 96:4 (92% ee) as determined by chiral HPLC. [¹5] The absolute configuration of trans-3a (92% ee) was determined to be 2S,3R (Figure [¹] ) by comparing the determined specific rotation [α]²4 D +5.62 (c = 0.95, CHCl3) with the reported one [α]²4 D +5.70 (c = 1.00, CHCl3). [¹6] Currently, we are exploring the range of N-tosyl imines, phenacyl halides, and other chiral tertiary bases to develop a general and ammonium ylide based catalytic enantioselective aziridination reaction.
In summary, we have developed the first organocatalytic aziridination of N-tosyl imines with phenacyl bromide derivatives to afford chemically and pharmaceutically relevant aziridines in high yields and trans diastereoselectivities in a one-pot process. The reaction is catalyzed by a tertiary amine and proceeds via an ammonium ylide intermediate. We have also demonstrated that this reaction can be made enantioselective by utilizing a chiral tertiary amine as the catalyst. Advantageously, the present protocol precludes the necessity to prepare and isolate ylides or their precursors in a separate step as they are generated in situ.
Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
- Supporting Information for this article is available online:
- Supporting Information
Acknowledgment
We sincerely thank SAIF, CDRI, Lucknow, for providing microanalyses and spectra. R. K. and Garima are grateful to the CSIR, New Delhi, for the award of a fellowship.
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References and Notes
General Procedure
for the One-Pot Synthesis of Aziridines 3: A mixture of phenacyl
bromide 2 (1 mmol), DABCO (0.2 mmol), imine 1 (1 mmol), and Na2CO3 (1.5 mmol)
in MeCN (5 mL) was stirred at 80 ˚C for 19-24
h (Table
[²]
). After
completion of the reaction (monitored by TLC), it was quenched with
aq HCl (1 M) and extracted with EtOAc (3 × 10 mL). The
combined organic phases were washed with a sat. aq solution of NaHCO3,
dried over MgSO4, and concentrated under reduced pressure.
The crude product thus obtained was purified by silica gel column chromatography
using EtOAc-n-hexane (2:8) as
eluent to afford analytically pure sample of 3 (Table
[²]
). Characterization
Data of Representative Compounds:
Product
3 (Table 2, entry 2): ¹H NMR (400 MHz,
CDCl3): δ = 8.03 (d, J = 8.6
Hz, 2 H), 7.42-7.61 (m, 3 H), 7.20-7.23 (m, 4
H), 7.10 (d, J = 8.4 Hz, 2 H),
6.75 (d, J = 8.4 Hz, 2 H), 4.51
(d, J = 4.1 Hz, 1 H), 4.28 (d, J = 4.1 Hz, 1 H), 3.72 (s, 3
H), 2.36 (s, 3 H). ¹³C NMR (100 MHz,
CDCl3): δ = 190.03, 160.30, 144.12,
136.29, 135.63, 132.63, 129.90, 129.23, 129.00, 128.61, 127.35,
127.21, 113.90, 55.60, 49.99, 47.04, 21.24. IR (KBr): 3051, 2847,
1685, 1602, 1583, 1514, 1456, 1331, 1151, 843, 741 cm-¹.
EIMS: m/z = 407 [M+].
Anal. Calcd for C23H21NO4S: C,
67.79; H, 5.19; N, 3.44. Found: C, 67.99; H, 5.45; N, 3.21. Product 3 (Table 2, entry 6): ¹H NMR
(400 MHz, CDCl3): δ = 8.05 (d, J = 8.5 Hz, 2 H), 7.85 (d, J = 8.9 Hz, 2 H), 7.44 (d, J = 8.9 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H), 7.12 (d, J = 8.3 Hz, 2 H), 6.78 (d, J = 8.3 Hz, 2 H), 4.54 (d, J = 4.1 Hz, 1 H), 4.30 (d, J = 4.1 Hz, 1 H), 3.72 (s, 3
H), 2.37 (s, 3 H). ¹³C NMR (100 MHz,
CDCl3): δ = 190.06, 160.60, 138.00,
136.66, 133.33, 130.00, 129.28, 129.10, 128.64, 127.38, 127.25,
114.20, 114.16, 55.80, 50.03, 47.09, 21.28. IR (KBr): 3049, 2842,
1687, 1603, 1584, 1516, 1448, 1336, 1146, 848 cm-¹.
EIMS: m/z = 441 [M+].
Anal. Calcd for C23H20ClNO4S: C,
62.51; H, 4.56; N, 3.17. Found: C, 62.74; H, 4.29; N, 2.84. Product 3 (Table 2, entry 10): ¹H NMR
(400 MHz, CDCl3): δ = 8.01 (d, J = 8.6 Hz, 2 H), 7.70 (d, J = 8.4 Hz, 2 H), 7.20 (d, J = 8.6 Hz, 2 H), 7.08 (d, J = 8.5 Hz, 2 H), 6.75 (d, J = 8.4 Hz, 2 H), 6.73 (d, J = 8.5 Hz, 2 H), 4.50 (d, J = 4.1 Hz, 1 H), 4.28 (d, J = 4.1 Hz, 1 H), 3.72 (s, 3
H), 3.70 (s, 3 H), 2.35 (s, 3 H). ¹³C
NMR (100 MHz, CDCl3): δ = 190.00, 162.60,
160.00, 144.08, 136.25, 130.40, 129.10, 129.00, 128.50, 127.31,
127.18, 114.30, 113.30, 55.80, 55.10, 49.95, 47.00, 21.20. IR (KBr):
3057, 2847, 1677, 1602, 1577, 1514, 1457, 1334, 1148, 842 cm-¹.
EIMS: m/z = 437 [M+].
Anal. Calcd for C24H23NO5S: C,
65.89; H, 5.30; N, 3.20. Found: C, 65.62; H, 5.55; N, 2.87. Product 3 (Table 2, entry 14): ¹H
NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 8.8 Hz, 2 H), 8.10 (d, J = 8.8 Hz, 2 H), 8.06 (d, J = 8.5 Hz, 2 H), 7.26 (d, J = 8.5 Hz, 2 H), 7.14 (d, J = 8.2 Hz, 2 H), 6.80 (d, J = 8.2 Hz, 2 H), 4.56 (d, J = 4.1 Hz, 1 H), 4.32 (d, J = 4.1 Hz, 1 H), 3.72 (s, 3
H), 2.39 (s, 3 H). ¹³C NMR (100 MHz,
CDCl3): δ = 190.08, 170.00, 149.00,
144.19, 141.20, 136.36, 130.04, 129.90, 129.10, 127.41, 127.29,
123.00, 114.6, 56.01, 50.06, 47.12, 21.30. IR (KBr): 3064, 2853, 1683,
1603, 1584, 1512, 1453, 1338, 1150, 854 cm-¹.
EIMS: m/z = 452 [M+].
Anal. Calcd for C23H20N2O6S:
C, 61.05; H, 4.46; N, 6.19. Found: C, 61.37; H, 4.19; N, 6.47.
Chiral HPLC: enantiomeric excess (ee)
was determined by using a Chiracel OD 25 cm, 4.6 mm internal diameter column,
hexane-i-PrOH (88:12), flow:
1 mL min-¹, 30 ˚C,
λ = 250
nm. The enantiomers had retention times (t
R)
of 22.4 min (major) and 24.2 min (minor).
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References and Notes
General Procedure
for the One-Pot Synthesis of Aziridines 3: A mixture of phenacyl
bromide 2 (1 mmol), DABCO (0.2 mmol), imine 1 (1 mmol), and Na2CO3 (1.5 mmol)
in MeCN (5 mL) was stirred at 80 ˚C for 19-24
h (Table
[²]
). After
completion of the reaction (monitored by TLC), it was quenched with
aq HCl (1 M) and extracted with EtOAc (3 × 10 mL). The
combined organic phases were washed with a sat. aq solution of NaHCO3,
dried over MgSO4, and concentrated under reduced pressure.
The crude product thus obtained was purified by silica gel column chromatography
using EtOAc-n-hexane (2:8) as
eluent to afford analytically pure sample of 3 (Table
[²]
). Characterization
Data of Representative Compounds:
Product
3 (Table 2, entry 2): ¹H NMR (400 MHz,
CDCl3): δ = 8.03 (d, J = 8.6
Hz, 2 H), 7.42-7.61 (m, 3 H), 7.20-7.23 (m, 4
H), 7.10 (d, J = 8.4 Hz, 2 H),
6.75 (d, J = 8.4 Hz, 2 H), 4.51
(d, J = 4.1 Hz, 1 H), 4.28 (d, J = 4.1 Hz, 1 H), 3.72 (s, 3
H), 2.36 (s, 3 H). ¹³C NMR (100 MHz,
CDCl3): δ = 190.03, 160.30, 144.12,
136.29, 135.63, 132.63, 129.90, 129.23, 129.00, 128.61, 127.35,
127.21, 113.90, 55.60, 49.99, 47.04, 21.24. IR (KBr): 3051, 2847,
1685, 1602, 1583, 1514, 1456, 1331, 1151, 843, 741 cm-¹.
EIMS: m/z = 407 [M+].
Anal. Calcd for C23H21NO4S: C,
67.79; H, 5.19; N, 3.44. Found: C, 67.99; H, 5.45; N, 3.21. Product 3 (Table 2, entry 6): ¹H NMR
(400 MHz, CDCl3): δ = 8.05 (d, J = 8.5 Hz, 2 H), 7.85 (d, J = 8.9 Hz, 2 H), 7.44 (d, J = 8.9 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H), 7.12 (d, J = 8.3 Hz, 2 H), 6.78 (d, J = 8.3 Hz, 2 H), 4.54 (d, J = 4.1 Hz, 1 H), 4.30 (d, J = 4.1 Hz, 1 H), 3.72 (s, 3
H), 2.37 (s, 3 H). ¹³C NMR (100 MHz,
CDCl3): δ = 190.06, 160.60, 138.00,
136.66, 133.33, 130.00, 129.28, 129.10, 128.64, 127.38, 127.25,
114.20, 114.16, 55.80, 50.03, 47.09, 21.28. IR (KBr): 3049, 2842,
1687, 1603, 1584, 1516, 1448, 1336, 1146, 848 cm-¹.
EIMS: m/z = 441 [M+].
Anal. Calcd for C23H20ClNO4S: C,
62.51; H, 4.56; N, 3.17. Found: C, 62.74; H, 4.29; N, 2.84. Product 3 (Table 2, entry 10): ¹H NMR
(400 MHz, CDCl3): δ = 8.01 (d, J = 8.6 Hz, 2 H), 7.70 (d, J = 8.4 Hz, 2 H), 7.20 (d, J = 8.6 Hz, 2 H), 7.08 (d, J = 8.5 Hz, 2 H), 6.75 (d, J = 8.4 Hz, 2 H), 6.73 (d, J = 8.5 Hz, 2 H), 4.50 (d, J = 4.1 Hz, 1 H), 4.28 (d, J = 4.1 Hz, 1 H), 3.72 (s, 3
H), 3.70 (s, 3 H), 2.35 (s, 3 H). ¹³C
NMR (100 MHz, CDCl3): δ = 190.00, 162.60,
160.00, 144.08, 136.25, 130.40, 129.10, 129.00, 128.50, 127.31,
127.18, 114.30, 113.30, 55.80, 55.10, 49.95, 47.00, 21.20. IR (KBr):
3057, 2847, 1677, 1602, 1577, 1514, 1457, 1334, 1148, 842 cm-¹.
EIMS: m/z = 437 [M+].
Anal. Calcd for C24H23NO5S: C,
65.89; H, 5.30; N, 3.20. Found: C, 65.62; H, 5.55; N, 2.87. Product 3 (Table 2, entry 14): ¹H
NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 8.8 Hz, 2 H), 8.10 (d, J = 8.8 Hz, 2 H), 8.06 (d, J = 8.5 Hz, 2 H), 7.26 (d, J = 8.5 Hz, 2 H), 7.14 (d, J = 8.2 Hz, 2 H), 6.80 (d, J = 8.2 Hz, 2 H), 4.56 (d, J = 4.1 Hz, 1 H), 4.32 (d, J = 4.1 Hz, 1 H), 3.72 (s, 3
H), 2.39 (s, 3 H). ¹³C NMR (100 MHz,
CDCl3): δ = 190.08, 170.00, 149.00,
144.19, 141.20, 136.36, 130.04, 129.90, 129.10, 127.41, 127.29,
123.00, 114.6, 56.01, 50.06, 47.12, 21.30. IR (KBr): 3064, 2853, 1683,
1603, 1584, 1512, 1453, 1338, 1150, 854 cm-¹.
EIMS: m/z = 452 [M+].
Anal. Calcd for C23H20N2O6S:
C, 61.05; H, 4.46; N, 6.19. Found: C, 61.37; H, 4.19; N, 6.47.
Chiral HPLC: enantiomeric excess (ee)
was determined by using a Chiracel OD 25 cm, 4.6 mm internal diameter column,
hexane-i-PrOH (88:12), flow:
1 mL min-¹, 30 ˚C,
λ = 250
nm. The enantiomers had retention times (t
R)
of 22.4 min (major) and 24.2 min (minor).
Scheme 1 One-pot aziridination of imines 1
Scheme 2 A plausible mechanism and the catalytic cycle of aziridination of imines 1
Scheme 3 A rationale for the trans diastereoselectivity of aziridination
Figure 1