Synthetic route to chiral tetrahydroquinoxalines via ring-opening of activated aziridines

Article abstract of DOI:10.1021/ol2023906

A highly regio- and stereoselective route for the synthesis of racemic and nonracemic tetrahydroquinoxalines via the S_N2-type ring-opening of activated aziridines with 2-bromoanilines followed by the Pd-catalyzed intramolecular C-N bond formati

Full text of DOI:10.1021/ol2023906

ORGANIC
LETTERS
2011
Vol. 13, No. 22
5972–5975
Synthetic Route to Chiral
Tetrahydroquinoxalines via
Ring-Opening of Activated Aziridines
Manas K. Ghorai,* Ashis K. Sahoo, and Sarvesh Kumar
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
mkghorai@iitk.ac.in
Received September 4, 2011
ABSTRACT
A highly regio- and stereoselective route for the synthesis of racemic and nonracemic tetrahydroquinoxalines via the SN2-type ring-opening of
activated aziridines with 2-bromoanilines followed by the Pd-catalyzed intramolecular CꢀN bond formation is described.
The 1,2,3,4-tetrahydroquinoxaline motif is present in
numerous biologically active and pharmacologically impor-
tant compounds.1 Several racemic as well as chiral 1,2,3,4-
tetrahydroquinoxalines have been found to exhibit a diverse
range of biological activities; e.g., compounds 1, 2, and 3
have found applications as potent cholesteryl ester transfer
protein inhibitors,1a vasopressin V2 receptor antagonists,1b
and prostaglandin D2 receptor antagonists,1c respectively
(Figure 1). Although several reports are available for the
construction of 1,2,3,4-tetrahydroquinoxalines,2 efficient
routes for the enantioselective synthesis of such compounds
are limited.3 The most common approach for the synthesis
of chiral tetrahydroquinoxalines is based on the asymmetric
hydrogenation of quinoxalines.4
(3) (a) Massacret, M.; Lhoste, P.; Sinou, D. Eur. J. Org. Chem. 1999, 129.
(b) Kim, J. C.; Choi, H. G.; Kim, M. S.; Ha, H.-J.; Lee, W. K. Tetrahedron
2010, 66, 8108. (c) Li, J.-L.; Han, B.; Jiang, K.; Du, W.; Chen, Y.-C. Bioorg.
Med. Chem. Lett. 2009, 19, 3952. (d) Abraham, C. J.; Paull, D. H.; Scerba,
M. T.; Grebinski, J. W.; Lectka, T. J. Am. Chem. Soc. 2006, 128, 13370.
(e) Samanta, K.; Panda, G. Org. Biomol. Chem. 2010, 8, 2823.
(4) (a) Chen, Q.-A.; Wang, D.-S.; Zhou, Y.-G.; Duan, Y.; Fan, H.-J.;
Yang, Y.; Zhang, Z. J. Am. Chem. Soc. 2011, 133, 6126. (b) Cartigny, D.;
^
Nagano, T.; Ayad, T.; Genet, J.-P.; Ohshima, T.; Mashima, K.;
ꢀ ꢁ
Ratovelomanana-Vidal, V. Adv. Synth. Catal. 2010, 352, 1886. (c) Mrsic,
N.; Jerphagnon, T.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. Adv.
Synth. Catal. 2009, 351, 2549. (d) Rueping, M.; Tato, F.; Schoepke, F. R.
Chem.;Eur. J. 2010, 16, 2688. (e) Tang, W.; Xu, L.; Fan, Q.-H.; Wang,
J.; Fan, B.; Zhou, Z.; Lam, K.; Chan, A. S. C. Angew. Chem., Int. Ed.
2009, 48, 9135. (f) Wang, D.-W.; Wang, D.-S.; Chen, Q.-A.; Zhou, Y.-G.
Chem.;Eur. J. 2010, 16, 1133.
(1) (a) Eary, C. T.; Jones, Z. S.; Groneberg, R. D.; Burgess, L. E.;
Mareska, D. A.; Drew, M. D.; Blake, J. F.; Laird, E. R.; Balachari, D.;
O’Sullivan, M.; Allen, A.; Marsh, V. Bioorg. Med. Chem. Lett. 2007, 17,
2608. (b) Ohtake, Y.; Naito, A.; Hasegawa, H.; Kawano, K.; Marizono, D.;
Taniguchi, M.; Tanaka, Y.; Matsukawa, H.; Naito, K.; Oguma, T.;
EzureY.; Tsuriya, Y. Bioorg. Med. Chem. 1999, 7, 1247. (c) Torisu, K.;
Kobayashi, K.; Iwahashi, M.; Nakai, Y.; Onoda, T.; Sugimoto, I.;
Okada, Y.; Matsumoto, R.; Nanbu, F.; Ohuchida, S.; Nakai, H.; Toda,
M. Bioorg. Med. Chem. 2004, 12, 5361. (d) Sikorski, J. A. J. Med. Chem.
2006, 49, 1. (e) Jacobsen, E. J.; Stelzer, L. S.; Belonga, K. L.; Carter,
D. B.; Im, W. B.; Sethy, V. H.; Tang, A. H.; Von-Voigtlander, P. F.;
Petke, J. D. J. Med. Chem. 1996, 39, 3820. (f) Barrows, T. H.; Farina,
P. R.; Chrzanowski, R. L.; Benkovic, P. A.; Benkovic, S. J. J. Am. Chem.
Soc. 1976, 98, 3678.
(2) (a) Meris-or, E.; Conrad, J.; Klaiber, I.; Mika, S.; Beifuss, U.
Angew. Chem., Int. Ed. 2007, 46, 3353. (b) Yang, S.-C.; Liu, P.-C.; Feng,
W.-H. Tetrahedron Lett. 2004, 45, 4951. (c) Mukhopadhyay, R.; Kundu,
N. G. Synlett 2001, 1143. (d) Nair, V.; Dhanya, R.; Rajesh, C.;
Bhadbhade, M. M.; Manoj, K. Org. Lett. 2004, 6, 4743. (e) Majumdar,
K. C.; Ray, K.; Ponra, S. Tetrahedron Lett. 2010, 51, 5437. (f) Bunce,
R. A.; Herron, D. M.; Hale, L. Y. J. Heterocycl. Chem. 2003, 40, 1031.
(5) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805. (c) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem.
1999, 576, 125. (d) Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.;
Blackmond, D. G.; Strieter, E.; Buchwald, S. L. J. Am. Chem. Soc. 2006,
128, 3584. (e) Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett.
2005, 7, 3965. (f) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2008, 130, 13552. (g) Shen, Q.; Ogata, T.;
Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586. (h) Zheng, Z.; Alper,
H. Org. Lett. 2008, 10, 4903. (i) Stauffer, S. R.; Lee, S.; Stambuli, J. P.;
Hauck, S. I.; Hartwig, J. F. Org. Lett. 2000, 2, 1423. (j) Brain, C. T.; Steer,
J. T. J. Org. Chem. 2003, 68, 6814. (k) Lebedev, A. Y.; Khartulyari, A. S.;
Voskoboynikov, A. Z. J. Org. Chem. 2005, 70, 596. (l) Takenaka, K.;
ꢁ
Itoh, N.; Sasai, H. Org. Lett. 2009, 11, 1483. (m) Hernandez, S.; Moreno,
I.; SanMartin, R.; Herrero, M. T.; Domınguez, E. Org. Biomol. Chem.
2011, 9, 2251. (n) Erb, W.; Neuville, L.; Zhu, J. J. Org. Chem. 2009, 74,
3109. (o) Willis, M. C.; Snell, R. H.; Fletcher, A. J.; Woodward, R. L.
Org. Lett. 2006, 8, 5089. (p) Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2007, 9,
3279. (q) Nakhla, J. S.; Schultz, D. M.; Wolfe, J. S. Tetrahedron 2009,
65, 6549.
ꢀꢁ
ꢁ
(g) Krchnak, V.; Smith, J.; Vagner, J. Tetrahedron Lett. 2001, 42, 2443.
(h) Bunce, R. A.; Herron, D. M.; Ackerman, M. L. J. Org. Chem. 2000,
65, 2847. (i) Renaud, T.; Hurvois, J.-P.; Uriac, P. Eur. J. Org. Chem.
2001, 987. (j) Zheng, L. Y.; Bai, X. Chin. Chem. Lett. 2006, 17, 165.
r
10.1021/ol2023906
Published on Web 10/17/2011
2011 American Chemical Society

Different heteroatomic and C-nucleophiles have been used
for the ring-opening of aziridines,6ꢀ8 and a number of
examples of aziridine-mediated heterocycle syntheses have
also been reported.9
Recently, we have reported the Lewis acid (LA)-mediated
ring-opening of racemic and enantiopure 2-aryl-N-tosyla-
ziridines by a number of nucleophiles to generate racemic
and nonracemic products in high enantiomeric excess.10 We
have demonstrated that the LA-mediated nucleophilic ring-
opening of 2-aryl-N-tosylaziridines does proceed through
an SN2-type pathway instead of a stable 1,3-dipolar inter-
mediate as invoked earlier.
Figure 1. Selected biologically active 1,2,3,4-tetrahydro-
quinoxalines.
In continuation of our research activities in this area, we
have developed a simple strategy for the synthesis of
1,2,3,4-tetrahydroquinoxalines with excellent yields (up
to 85%) and enantiomeric excess (ee) (up to >99%) via
the regio- and stereoselective ring-opening of aziridines by
2-bromo anilines followed by palladium-catalyzed intra-
molecular CꢀN cyclization. We report herein our pre-
liminary results as a communication.
Palladium-catalyzed amination reactions made a large
contribution in organic synthesis for the construction of
CarylꢀN bonds.5 We envisioned that substituted 1,2,3,4-
tetrahydroquinoxalines could easily be accessed by the
ring-opening of aziridines with 2-bromo anilines followed
by Pd-catalyzed intramolecular CꢀN bond formation.
(6) (a) Minakata, S.; Okada, Y.; Komastu, M. Org. Lett. 2005, 7,
3509. (b) Couty, F.; Evano, G.; Prim, D. Tetrahedron Lett. 2005, 46,
2253. (c) Hu, X. E. Tetrahedron 2004, 60, 2701 and references therein.
Scheme 1. Regioselective Ring-Opening of 1a with 2-Bromo-
aniline 2a
ꢁ
(d) Forbeck, E. M.; Evans, C. D.; Gilleran, J. A.; Li, P.; Joullie, M. M.
ꢁ
ꢁ
J. Am. Chem. Soc. 2007, 129, 14463. (e) Ochoa-Teran, A.; Concellon,
ꢁ
J. M.; Rivero, I. A. ARKIVOC 2009, No. ii, 288. (f) Concellοn, J. M.;
Bernad, P. L.; Suarez, J. R. J. Org. Chem. 2005, 70, 9411. (g) Minakata,
ꢁ
S.; Hotta, T.; Oderaotoshi, Y.; Komatsu, M. J. Org. Chem. 2006, 71,
ꢁ
7471. (h) Joullie, M. M.; Kelley, B. T. Org. Lett. 2010, 12, 4244. (i) De
Rycke, N.; David, O.; Couty, F. Org. Lett. 2011, 13, 1836. (j) D’hooghe,
M.; Kenis, S.; Vervisch, K.; Lategan, C.; Smith, P. J.; Chibale, K.; De
Kimpe, N. Eur. J. Med. Chem. 2011, 46, 579. (k) Yadav, J. S.; Satheesh,
ꢁ
G.; Murthy, C. V. S. R. Org. Lett. 2010, 12, 2544. (l) Concellοn, J. M.;
Rodriguez-Solla, H.; Amo, V.; Diaz, P. J. Org. Chem. 2010, 75, 2407. (m)
Zeng, F.; Alper, H. Org. Lett. 2010, 12, 5567. (n) Karikomi, M.;
D’hooghe, M.; Verniest, G.; De Kimpe, N. Org. Biomol. Chem. 2008,
6, 1902. (o) Catak, S.; D’hooghe, M.; De Kimpe, N.; Waroquier, M;
Speybroeck, V. V. J. Org. Chem. 2010, 75, 885. (p) Singh, G. S.;
D’hooghe, M.; De Kimpe, N. Chem. Rev. 2007, 107, 2080. (q) Bhadra,
S.; Adak, L.; Samanta, S.; Islam, A. K. M. M.; Mukherjee, M.; Ranu,
B. C. J. Org. Chem. 2010, 75, 8533. (r) Bera, M.; Pratihar, S.; Roy, S.
J. Org. Chem. 2011, 76, 1475. (s) D’hooghe, M.; Rottiers, M.; Kerkaert, I.;
De Kimpe, N. Tetrahedron 2005, 61, 8746. (t) D’hooghe, M.; Waterinckx,
A.; Vanlangendonck, T.; De Kimpe, N. Tetrahedron 2006, 62, 2295.
(7) (a) Minakata, S.; Murakami, Y.; Satake, M.; Hidaka, I.; Okada,
Y.; Komatsu, M. Org. Biomol. Chem. 2009, 7, 641. (b) Ding, C.-H.; Dai,
L.-X.; Hou, X.-L. Tetrahedron 2005, 61, 9586. (c) D’hooghe, M.; De
Kimpe, N. Chem. Commun. 2007, 1275. (d) D’hooghe, M.; Kerkaert, I.;
Rottiers, M.; De Kimpe, N. Tetrahedron 2005, 60, 3637.
First, we explored the ring-opening of racemic 2-phenyl-
N-tosylaziridine (1a) with 2-bromo aniline (2a) under vary-
ing reaction conditions to afford the corresponding racemic
ring-opened product 3a (Scheme 1). When 1a was treated
with 2-bromo aniline (2a) in the presence of Cu(OTf)2 as the
LA in DCM medium, 3a was produced in 80% yield
(Scheme 1) within 2 h. The reaction was found to be suc-
cessful with other LAs (Zn(OTf)2, Sc(OTf)3, and Yb(OTf)3)
and under solvent free conditions.11 Interestingly, the best
yield of 3a was obtained when 4 equiv of 2-bromoaniline 2a
were used in the absence of any LA and organic solvent.
(Scheme 1; see Table S1, Supporting Information).
Next, we evaluated the palladium-catalyzed cyclization
of 3a to form the product 4a under diverse reaction
conditions, and the results are shown in Table 1. Initially,
we used 10 mol % of palladium catalyst, 20 mol % of the
ligand (PPh3), and K2CO3 as the base (Scheme 2, Table 1,
entry 2). K2CO3 was found tobe a better base than Cs2CO3
(Table 1, entry 1 vs 2), and toluene was a better solvent
than DMF (Table 1, entry 2 vs 3). When we reduced the
amount of catalyst (5 mol %) and ligand (10 mol %) to
(8) (a) Blyumin, E. V.; Gallon, H. J.; Yudin, A. K. Org. Lett. 2007, 9,
4677. (b) Moss, T. A.; Fenwick, D. R.; Dixon, D. J. J. Am. Chem. Soc.
~
2008, 130, 10076. (c) Paixao, M. W.; Nielsen, M.; Jacobsen, C. B.;
Jørgensen, K. A. Org. Biomol. Chem. 2008, 6, 3467. (d) Enders, D.;
Janeck, C. F.; Raabe, G. Eur. J. Org. Chem. 2000, 3337. (e) Xu, Y; Lin,
L.; Kanai, M.; Matsunaga, S; Shibasaki, M. J. Am. Chem. Soc. 2011,
133, 5791.
(9) For some recent examples of aziridine mediated heterocycle
€ €
synthesis, see: (a) Kiss, L.; Mangelinckx, S.; Fulop, F.; De Kimpe, N.
Org. Lett. 2007, 9, 4399. (b) Ghorai, M. K.; Nanaji, Y.; Yadav, A. K.
Org. Lett. 2011, 13, 4256. (c) Du, X.; Yang, S.; Yang, J.; Liu, Y.
Chem.;Eur. J. 2011, 17, 4981. (d) Wu, Y.-C.; Zhu, J. Org. Lett. 2009,
11, 5558. (e) Baktharaman, S.; Afagh, A.; Vandersteen, A.; Yudin, A. K.
Org. Lett. 2010, 12, 240. (f) Prasad, D. J. C.; Sekar, G. Org. Biomol.
ꢁ
Chem. 2009, 7, 5091. (g) Bisol, T. B.; Bortoluzzi, A. J.; Sa, M. M. J. Org.
Chem. 2011, 76, 948. (h) Wang, J.-Y.; Guo, X.-F.; Wang, D.-X.; Huang,
Z.-T.; Wang, M.-X. J. Org. Chem. 2008, 73, 1979. (i) Wang,L.;Liu,Q.-B.;
Wang, D.-S.; Li, X.; Han, X.-W.; Xiao, W.-J.; Zhou, Y.-G. Org. Lett.
2009, 11, 1119. (j) Hong, D.; Lin, X.; Zhu, Y.; Lei, M.; Wang, Y. Org.
Lett. 2009, 11, 5678. (k) Rao, R. K.; Naidu, A. B.; Sekar, G. Org. Lett.
2009, 11, 1923. (l) D’hooghe, M.; Aelterman, W.; De Kimpe, N. Org.
Biomol. Chem. 2009, 7, 135. (m) Brabandt, W. V.; Dejaegher, Y.;
Landeghem, R. V.; De Kimpe, N. Org. Lett. 2006, 8, 1101. (n)
(10) (a) Ghorai, M. K.; Tiwari, D. P. J. Org. Chem. 2010, 75, 6173.
(b) Ghorai, M. K.; Kumar, A.; Tiwari, D. P. J. Org. Chem. 2010, 75, 137.
(c) Ghorai, M. K.; Shukla, D.; Das, K. J. Org. Chem. 2009, 74, 7013.
(d) Ghorai, M. K.; Das, K.; Shukla, D. J. Org. Chem. 2007, 72, 5859.
(e) Ghorai, M. K.; Kumar, A.; Das, K. Org. Lett. 2007, 9, 5441.
(f) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48,
4373. (g) Ghorai, M. K.; Ghosh, K. Tetrahedron Lett. 2007, 48, 3191.
(h) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2009, 50, 1105.
(11) See the Supporting Information for details.
ꢀ
ꢀ
ꢀ
Zukauskaite, A.; Mangelinckx, S.; Buinauskaite, V.; Sackus, A.; De
Kimpe, N. Amino Acids 2011, 41, 541.
Org. Lett., Vol. 13, No. 22, 2011
5973

Scheme 2. Pd-Catalyzed CꢀN Cyclization of 3a
Scheme 3. Synthesis of 1,2,3,4-Tetrahydroquinoxalines 4aꢀf
Table 1. Optimization of Reaction Conditions for the Forma-
tion of 4a
Pd(OAc)2 (mol %), ligand (mol %), base
4a
yield (%)a
entry
(2 equiv), solvent, temp (°C), time (h)
Table 2. Regioselective Ring-Opening of 1 and Pd-Catalyzed
Intramolecular CꢀN Cyclization of 3aꢀfa
1
(10), BINAP (20), Cs2CO3, toluene, 120, 2
(10), BINAP (20), K2CO3, toluene, 120, 2
(10), BINAP (20), K2CO3, DMF, 120, 2
(5), BINAP (10), K2CO3, toluene, 120, 3
(5), BINAP (10), K3PO4, toluene, 120, 2
(5), BINAP (10), NaH, toluene, 120, 15
(5), BINAP (10), KOt-Bu, toluene, 120, 15
(5), BINAP (10), K2CO3, CH3CN, 80, 15
(5), BINAP (10), K2CO3, THF, 60, 15
(5), DPPF (10), K2CO3, toluene, 120 , 2
(5), Xantphos (10), K2CO3, toluene, 120, 2
(5), PPh3 (10), K2CO3, toluene, 120, 4
(5), PPh3 (10), NaOt-Bu, toluene, 120, 15
(5), PPh3 (10), K3PO4, toluene, 120, 15
(5), PPh3 (10), K2CO3, DMF, 120, 15
Pd(PPh3)4 (5), K2CO3, toluene, 120, 15
62
71
46
61
54
34
nr
nr
nr
60
73
85
nr
10
nr
nr
2
entry
1 (Ar)
2 (R) 3 yield (%)b time (h) 4 yield (%)b
3
4
1
2
3
4
5
6
1a (Ph)
2a (H)
2b (Me)
2c (F)
3a, 85
3b, 80
3c, 79
3d, 84
3e, 82
3f, 81
4
4a, 85
4b, 81
4c, 80
4d, 77
4e, 76
4f, 72
5
1a(Ph)
1a (Ph)
6
6
7
7
1b (4-ClC6H4) 2a (H)
1b (4-ClC6H4) 2b (Me)
1b (4-ClC6H4) 2c (F)
4
8
4.5
4
9
10
11
12
13
14
15
16b
a All reactions were carried out with 3aꢀf (1.0 mmol), Pd(OAc)2
(5 mol %), PPh3 (10 mmol %), and K2CO3 (2 equiv) in toluene (8 mL)
under argon for 4ꢀ7 h under refluxed conditions at 120 °C. b Yields of
isolated products (%).
in toluene (Table 1, entry 12). Further attempts to improve
the yield of 4a by changing the base or palladium source
were not successful (Table 1, entries 13ꢀ16). 4a was
characterized by analytical data. The structure of 4a was
further confirmed by X-ray crystallographic analysis
(Figure 2).
a Yields of isolated products.
To generalize this approach and study the substrate
scope, several N-[(2-aryl-2-(2-bromoarylamino)ethyl]-4-
methylbenzenesulfonamides 3aꢀf were prepared from
aziridines 1aꢀb and bromoanilines 2aꢀc. Compounds
3aꢀf were cyclized under optimized conditions (Pd(OAc)2
(5 mol %), PPh3 (10 mol %), K2CO3 (2 equiv), toluene,
120 °C) to afford the corresponding tetrahydroquinoxa-
lines 4aꢀf in excellent yields (Scheme 3, Table 2).
Bicyclic N-tosylcyclohexene and cyclopentene aziridines
(5aꢀb) underwent ring-opening smoothly with a number
of 2-bromoanilines (Table 3, entries 1ꢀ5) and the resulting
ring-opened products 6aꢀecould be successfully transformed
to cyclohexa- and cyclopenta-annulated tetrahydroquino-
xalines 7aꢀe (Scheme 4, Table 3, entries 1ꢀ5). The struc-
ture of compounds 7a and 7d were confirmed by single
crystal X-ray analysis.11
Next, we studied ring-opening of chiral aziridine (R)-1a
with 2-bromoanilines 2, and the best ee (>99%) was
obtained when 4 equiv of 2-bromoanilines were used in
the absence of any LA or solvent (Table 4). Using our
protocol, compounds 8 were cyclized to the corresponding
tetrahydroquinoxalines 9 in excellent ee (Table 5).
A probable mechanism for the formation of chiral
tetrahydroquinoxalines 9aꢀc is described in Figure 3.
Figure 2. Diamond diagram of compound 4a.
half, the desired product 4a was obtained with a slightly
reduced yield (Table 1, entry 4 vs 2). Replacing K2CO3 with
K3PO4 or NaH provided 4a in moderate yield (Table 1,
entries 5ꢀ6). No reaction was observed when tBuOK was
used as a base, toluene was replaced with THF, or CH3CN
was used as the solvent (Table 1, entries 7ꢀ9). Replacing
2,2 -bis(diphenylphosphino)-1,1 -binaphthyl (BINAP)
and 1,1 -bis(diphenylphosphino)ferrocene (DPPF) provided
4a in 60% yield (Table 1, entry 10); however, use of 4,5-bis
(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS)
as the ligand furnished 4a in an improved yield of 71%
(Table1, entry11). ThebestresultwasobtainedusingPPh3
5974
Org. Lett., Vol. 13, No. 22, 2011

Table 5. Synthesis of Chiral 1,2,3,4-Tetrahydroquinoxalines 9
Scheme 4. Synthesis of Cyclopenta [b]- and Cyclohexa [c]-Fused
Tetrahydroquinoxalines 7aꢀe
entry
R
8
yield 8 (%)a ee 8 (%)b
9
yield 9 (%)a ee 9 (%)b
1
2
3
H
8a
85
80
79
>99
>99
98
9a
9b
9c
85
79
62
>99
>99
98
Me 8b
8c
F
Table 3. Regioselective Ring-Opening of 5 and Pd-Catalyzed
Intramolecular CꢀN Cyclization of 6aꢀea
a Yield of isolated products. b ee was determined using Chiralpak
AD-H and AS-H columns.
entry
5 (n)
2 (R)
6 yield (%)b time (h) 7 yield (%)b
1
2
3
4
5
5a (0) 2a (H)
5a (0) 2b (Me)
5b (1) 2a (H)
5b (1) 2b (Me)
5b (1) 2c (F)
6a, 72
6b, 70
6c, 74
6d, 71
6e, 73
8
8
7a, 78
7b, 73
7c, 80
7d, 76
7e, 76
10
8
8
a All reactions were carried out with 6aꢀe (1.0 mmol), Pd(OAc)2
(5 mol %), PPh3 (10 mmol %), and K2CO3 (2 equiv) in toluene (8 mL)
under argon for 8ꢀ10 h refluxed at 120 °C, b Yields of isolated products.
Table 4. Enantioselective Ring-Opening of Chiral Aziridine (R)-1a
equiv
entry 2a
LA
time
(h)
yield
8a (%)a
ee
8ab
(mol %)
solvent
Figure 3. Proposed reaction mechanism.
1
2
3
1
4
4
Cu(OTf)2 (30) CH2Cl2
Cu(OTf)2 (30)
neat
2
80
78
86
0
98
2
followed by Pd catalyzed intramolecular CꢀN bond for-
mation. This method allows the use of a wide range of
aziridines and 2-bromo anilines to construct tetrahydro-
quinoxalines in excellent yields and enantioselectivities.
Further work is in progress.
0.5
>99
a Yields of isolated products. b ee was determined using a Chiralpak
AD-H column.
SN2-type ring-opening of chiral aziridine (R)-1a by 2-bro-
moanilines generates the corresponding bromoamines 8,
whichundergoPd-catalyzed intramolecularCꢀN coupling
to produce the corresponding tetrahydroquinoxalines
9aꢀc.
Acknowledgment. M.K.G. isgrateful toDST, India, for
financial support. A.K.S. and S.K. thank CSIR India for
research fellowships.
In conclusion, we have developed a simple and practical
protocol for the synthesis of racemic and nonracemic
substituted and fused tetrahydroquinoxalines. The reac-
tion proceeds through a solvent and catalyst free SN2-type
ring-opening of N-activated aziridines with 2-bromo anilines
Supporting Information Available. General procedures,
1
X-ray crystallographic data of 4a, copies of H and 13C
spectra for all compounds, and HPLC chromatograms
for ee determination. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 22, 2011
5975