Catalytic enantioselective Friedlaender condensations: Facile access to quinolines with remote stereogenic centers

Article abstract of DOI:10.1021/ol1023932

Enamine catalysis enables the first catalytic enantioselective Friedlaender reaction. The desymmetrization of 4-substituted cyclohexanones upon reaction with o-aminobenzaldehydes allows for the synthesis of quinolines with remote stereogenic centers. Thes

Full text of DOI:10.1021/ol1023932

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5064-5067
Catalytic Enantioselective Friedla¨nder
Condensations: Facile Access to
Quinolines with Remote Stereogenic
Centers
Le Li and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New
Jersey, Piscataway, New Jersey 08854, United States
seidel@rutchem.rutgers.edu
Received October 4, 2010
ABSTRACT
Enamine catalysis enables the first catalytic enantioselective Friedla¨nder reaction. The desymmetrization of 4-substituted cyclohexanones
upon reaction with o-aminobenzaldehydes allows for the synthesis of quinolines with remote stereogenic centers. These heterocycles, which
are obtained with high levels of enantioselectivity, serve as precursors for chiral tacrine analogues.
Tacrine (1, R ) R′ ) H) and its derivatives (Scheme 1)
have shown efficacy in the treatment of cognitive disorders
Scheme 1. Retrosynthesis of Chiral Tacrine Analogues
such as Alzheimer’s disease.1 Tacrine’s mode of action
is attributed to its potent acetylcholinesterase inhibitor
activities,1b,c and compounds 1 are also known to inhibit
other enzymes including butylcholinesterase1e and monoam-
ine oxidase.1d In addition, other pharmacological uses of
tacrine, such as blockage of potassium channels and inhibi-
tion of neuronal monoamine uptake processes, have been
reported.1g Given their important functions in medicinal
chemistry, the synthesis and evaluation of new tacrine
analogues continues to be of significant interest.
We envisioned that chiral nonracemic tacrine derivatives
1 may be derived from their corresponding quinolines 4. The
asymmetric synthesis of these quinolines, which are interest-
ing compounds in their own right, would be most conve-
niently accomplished via catalytic enantioselective Fried-
la¨nder condensations of o-aminobenzaldehydes 3 and ketones
2.2 Here we report the first successful realization of such a
process.
(1) (a) Albert, A.; Gledhill, W. J. J. Soc. Chem. Ind., London 1945, 64,
169. (b) Shaw, F. H.; Bentley, G. Aust. J. Exp. Biol. Med. Sci. 1953, 31,
573. (c) Heilbronn, E. Acta Chem. Scand. 1961, 15, 1386. (d) Kaul, P. N.
J. Pharm. Pharmacol. 1962, 14, 243. (e) Maayani, S.; Weinstein, H.; Ben-
Zvi, N.; Cohen, S.; Sokolovsky, M. Biochem. Pharmacol. 1974, 23, 1263.
(f) Summers, W. K.; Majovski, L. V.; Marsh, G. M.; Tachik i, K.; Kling,
A. N. Engl. J. Med. 1986, 315, 1241. (g) Drukarch, B.; Leysen, J. E.; Stoof,
J. C. Life Sci. 1988, 42, 1011. (h) Dinesen, J.; Jacobsen, J. P.; Hansen,
F. P.; Petersen, E. B.; Eggert, H. J. Med. Chem. 1990, 33, 93. (i) Pirrung,
M. C.; Chau, J. H.-L.; Chen, J. Chem. Biol. 1995, 2, 621. (j) McKenna,
M. T.; Proctor, G. R.; Young, L. C.; Harvey, A. L. J. Med. Chem. 1997,
40, 3516. (k) Bencharit, S.; Morton, C. L.; Hyatt, J. L.; Kuhn, P.; Danks,
M. K.; Potter, P. M.; Redinbo, M. R. Chem. Biol. 2003, 10, 341. (l) Carlier,
P. R.; Anderson, T. D.; Wong, D. M.; Hsu, D. C.; Hartsel, J.; Ma, M.;
Wong, E. A.; Choudhury, R.; Lam, P. C.-H.; Totrov, M. M.; Bollmquist,
J. R. Chem. Biol. Interact. 2008, 175, 368.
(2) (a) Friedla¨nder, P. Berichte 1882, 15, 2572. (b) Manske, R. H. F.;
Kulka, M. Org. React. 1953, 7, 59. (c) Cheng, C. C.; Yan, S. J. Org. React.
1982, 28, 37. (d) Marco-Contelles, J.; Pe´rez-Mayoral, E.; Samadi, A.;
Carreiras, M. C.; Soriano, E. Chem. ReV. 2009, 109, 2652.
10.1021/ol1023932  2010 American Chemical Society
Published on Web 10/11/2010

Since the renaissance of enamine catalysis in the early
2000s, this organocatalytic mode of activation has been
developed into a powerful synthetic tool for the preparation
of valuable chiral building blocks.3,4 Enamine catalysis
provides a mild and general solution for the in situ
transformation of aldehydes and ketones into their corre-
sponding enolate equivalents. In the past decade, a number
of reactions were developed that employ this strategy,
including aldol reactions,5 Mannich reactions,6 Michael
additions,7 and others.8 However, relatively few studies have
focused on reactions that involve the desymmetrization of
prochiral ketones,9 one of the prerequisites for the targeted
Friedla¨nder condensation. Whereas enamines are considered
to be important intermediates in the classical Friedla¨nder
process, relatively harsh reaction conditions are typically
required.10 Interestingly, proline has recently been used as
a catalyst in the Friedla¨nder synthesis of achiral quinolines.11
However, this reaction appears to be limited to the use of
highly activated amino-trifluoromethylketones while simul-
taneously requiring mild heating.
From the outset of our study, it was clear that several
challenges would have to be addressed. First, compared to
the relatively electron-poor benzaldehydes that have been
used predominantly in enamine-catalyzed asymmetric aldol
reactions, the corresponding o-aminobenzaldehydes are ap-
preciably more electron-rich and thus represent less reactive
electrophiles. Second, it was not clear if it would be possible
to conduct the necessary elimination step of the Friedla¨nder
sequence under mild enough conditions that would simul-
taneously allow for a highly enantioselective process. In
addition, it is well-known that o-aminobenzaldehydes tend
to self-condense, even under mild conditions.12
With these considerations in mind, we opted to investigate
the reaction of commercially available and relatively electron
poor 3,5-dibromoaminobenzaldehyde (3a) with 4-phenylcy-
clohexanone (2a). Among the readily available organocata-
lysts tested, only amino acids gave acceptable rates and
selectivities.13 As summarized in Table 1, proline derivatives
provided the best results. trans-4-Hydroxyproline (7a) gave
rise to a slightly higher ee as compared to proline itself.
Given the poor solubility of proline and trans-4-hydroxy-
proline in nonpolar solvents, more soluble silicon protected
trans-4-hydroxyproline derivatives were prepared.14 Gratify-
ingly, the reactivity and selectivity of these catalysts proved
to be very similar to that of unmodified trans-4-hydroxypro-
line.
(3) For selected reviews on organo/enamine catalysis, see: (a) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) Jarvo, E. R.;
Miller, S. J. Tetrahedron 2002, 58, 2481. (c) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138. (d) List, B. Acc. Chem. Res. 2004, 37, 548.
(e) Dotz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37,
580. (f) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis: From
Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH:
Weinheim, Germany, 2005. (g) List, B. Chem. Commun. 2006, 819. (h)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107,
5471. (i) Pellissier, H. Tetrehedron 2007, 63, 9267. (j) Gaunt, M. J.;
Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug DiscoVery Today 2007,
12, 8. (k) Dalko, P. I. EnantioselectiVe Organocatalysis: Reactions and
Experimental Procedures; Wiley-VCH: Wenheim, Germany, 2007. (l)
Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46,
1570. (m) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638.
(n) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem.,
Int. Ed. 2008, 47, 6138. (o) MacMillan, D. W. C. Nature 2008, 455, 304.
(p) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. ReV. 2009, 38, 2178. (q)
Pihko, P. M.; Majander, I.; Erkkila¨, A. Top. Curr. Chem. 2010, 291, 29
.
(4) For selected key contributions to enamine chemistry, see: (a)
Knoevenagel, E. Chem. Ber. 1898, 31, 2596. (b) Stork, G.; Brizzolara, A.;
Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc. 1963, 85,
207. (c) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971,
10, 496. (d) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (e)
Stork, G.; Saccomano, N. A. Tetrahedron Lett. 1987, 28, 2087. (f) Agami,
C.; Platzer, N.; Sevestre, H. Bull. Chim. Soc. Fr. 1987, 2, 358. (g) List, B.;
Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. (h)
List, B. J. Am. Chem. Soc. 2000, 122, 9336. (i) Sakthivel, K.; Notz, W.;
Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260. (j) Northup,
A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798. (k) Tang,
Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu,
Y.-D. J. Am. Chem. Soc. 2003, 125, 5262
.
(5) For selected reviews on aldol reactions, see: (a) Co´rdova, A.; Zou,
W.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem.sEur. J. 2006, 12,
5383. (b) Guillena, G.; Na´jera, C.; Ramo´n, D. J. Tetrahedron: Asymmetry
2007, 18, 2249. (c) Trost, B. M.; Brindle, C. S. Chem. Soc. ReV. 2010, 39,
1600.
To improve the rate and selectivity of the reaction, catalyst
7b was tested in a broad range of solvents (Table 2).15
Several interesting observations were made in the course of
this study. Apolar solvents containing aromatic rings such
(6) For selected reviews on Mannich reactions, see: (a) Ting, A.; Schaus,
S. E. Eur. J. Org. Chem. 2007, 5797. (b) Verkade, J. M. M.; van Hemert,
L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. ReV. 2008,
37, 29.
(7) For selected reviews on Michael reactions, see: (a) Sulzer-Mosse´,
S.; Alexakis, A. Chem. Commun. 2007, 3123. (b) Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 1701. (c) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis
2007, 2065. (d) Almas¸i, D.; Alonso, D. A.; Na´jera, C. Tetrahedron:
Asymmetry 2007, 18, 299.
(10) Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.;
McWilliams, J. C.; Reider, P. J.; Sager, J. W.; Volante, R. P. J. Org. Chem.
2003, 68, 467. See also ref 2.
(8) For selected examples of other reactions, see: (a) Janey, M. J. Angew.
Chem., Int. Ed. 2005, 44, 4292. (b) Marigo, M.; Jørgensen, K. A. Chem.
Commun. 2006, 2001. (c) Guillena, G.; Ramo´n, D. J. Tetrahedron:
Asymmetry 2006, 17, 1465. (d) Merino, P.; Marque´s-Lo´pez, E.; Tejero, T.;
Herrera, R. P. Synthesis 2010, 1. (e) Albrecht, L.; Albrecht, A.; Krawczyk,
H.; Jørgensen, K. A. Chem.sEur. J. 2010, 16, 28. (f) Vilaivan, T.;
Bhanthumnavin, W. Molecules 2010, 15, 917.
(11) Jiang, B.; Dong, J.-J.; Jin, Y.; Du, X.-L.; Xu, M. Eur. J. Org. Chem.
2008, 2693.
(12) For examples, see: (a) Jircitano, A. J.; Sommerer, S. O.; Shelley,
J. J.; Westcott, B. L., Jr.; Suh, I.-H. Acta Crystallogr. 1994, C50, 445. (b)
Kolchinski, A. G. Coord. Chem. ReV. 1998, 174, 207, and references cited
therein.
(13) For a review of primary amino acid catalysis, see: Xu, L.-W.; Lu,
Y. Org. Biomol. Chem. 2008, 6, 2047. Other catalysts such as diarylprolinol,
diarylprolinol silyl ether, and proline amide gave inferior results.
(14) For selected previous uses of these catalysts, see: (a) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.; Shoji, M.; Hashizume,
D.; Koshino, H. AdV. Synth. Catal. 2004, 346, 1435. (b) Enders, D.; Grondal,
C.; Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed. 2005, 44, 4079. (c)
Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji,
M. Angew. Chem., Int. Ed. 2006, 45, 958. (d) Enders, D.; Grondal, C.;
Vrettou, M. Synthesis 2006, 3597. (e) Aratake, S.; Itoh, T.; Okano, T.;
Nagae, N.; Sumiya, T.; Shoji, M.; Hayashi, Y. Chem.sEur. J. 2007, 13,
10246. (f) Han, R.-G.; Wang, Y.; Li, Y.-Y.; Xu, P.-F. AdV. Synth. Catal.
2008, 350, 1474. (g) Hayashi, Y.; Aratake, S.; Imai, Y.; Hibino, K.; Chen,
Q.-Y.; Yamaguchi, J.; Uchimaru, T. Chem. Asian J. 2008, 3, 225. (h) Xu,
L.-W.; Li, L.; Shi, Z.-H. AdV. Synth. Catal. 2010, 352, 243.
(9) For enamine-catalyzed desymmetrizations, see: (a) Ramachary, D. B.;
Barbas, C. F., III. Org. Lett. 2005, 7, 1577. (b) Itagaki, N.; Kimura, M.;
Sugahara, T.; Iwabuchi, Y. Org. Lett. 2005, 7, 4185. (c) Jiang, J.; He, L.;
Luo, S.-W.; Cun, L.-F.; Gong, L.-Z. Chem. Commun. 2007, 736. (d)
Rodr´ıguez, B.; Bruckmann, A.; Bolm, C. Chem.sEur. J. 2007, 13, 4710.
(e) Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. J. J. Am. Chem. Soc.
2008, 130, 404. (f) Zhou, J.; Wakchaure, V.; Kraft, P.; List, B. Angew.
Chem., Int. Ed. 2008, 47, 7656. (g) Diaba, F.; Bonjoch, J. Org. Biomol.
Chem. 2009, 7, 2517. (h) Companyo´, X.; Valero, G.; Crovetto, L.; Moyano,
A.; Rios, R. Chem.sEur. J. 2009, 15, 6564. (i) Chen, J.-R.; Lai, Y.-Y.;
Lu, H.-H.; Wang, X.-F.; Xiao, W.-J. Tetrahedron 2009, 65, 9238. (j) El-
Hamdouni, N.; Companyo´, X.; Rios, R.; Moyano, A. Chem.sEur. J. 2010,
16, 1142. (k) Zhang, L.; Cui, L.; Li, X.; Li, J.; Luo, S.; Cheng, J.-P.
Chem.sEur. J. 2010, 16, 2045.
Org. Lett., Vol. 12, No. 21, 2010
5065

Table 1. Evaluation of Catalystsa
Table 2. Evaluation of Solventsa
entry
solvent
DMSO
time (h)
yield (%)b
ee (%)
1
2
3
4
5
6
7
8
16
24
36
48
48
36
82
80
83
78
75
78
65
65
65
45
67
65
65
78
80
80
75
65
79
79
81
82
82
81
79
79
83
76
87
87
82
86
76
83
90
93
DMF
MeCN
EtOAc
THF
dioxane
CHCl3
CH2Cl2
CCl4
cyclohexane
PhMe
xylenes
PhCF3
anisole
NMI
72c
72c
72c
72c
72c
72c
72c
72c
10
9
10
11
12
13
14
15
16
17d
18e
entry
catalyst
time (d)
yield (%)b
ee (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
7a
7b
7c
8
3
3
3
3
3
3
3c
3
3
1
2
1
1
1
1
1
3c
73
75
74
75
70
70
ND
65
65
83
68
78
82
83
75
80
<5
66
72
70
66
70
47
62
50
47
74
67
79
78
76
-67
66
pyridine
pyridine
pyridine
12
72
96c
a Reactions were performed at rt on a 0.2 mmol scale in anhydrous
solvent (0.2 M) with 3 equiv of cyclohexanone. Reactions were run to full
conversion as judged by TLC analysis. The ee’s were determined by HPLC
analysis. b Isolated yields. c The reaction was incomplete. d The reaction
was run at -20 °C. e The reaction was run at -35 °C.
9
10
11
12
13
14
15
16
17
Table 3. Scope of Cyclohexanonesa
9
10
ND
a Reactions were performed at rt on a 0.2 mmol scale in anhydrous
DMSO (0.2 M) with 3.0 equiv of cyclohexanone. Reactions were run to
full conversion as judged by TLC analysis. The ee’s were determined by
HPLC analysis. b Isolated yields. c The reaction was incomplete.
entry
R
product methodc yield (%)b ee (%)
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
A
A
A
A
76
60
75
73
60
62
85
80
81
82
80
92
92
93
92
90
91
94
93
94
91
95
as toluene and xylenes gave rise to high selectivities but
reactions were very slow (incomplete in 3 days at rt). On
the other hand, more polar solvents gave rise to faster
reaction rates, albeit at the expense of selectivity. A closer
inspection revealed that solvent polarity alone does not
directly correlate with reaction rate.16 Rather, the presence
of basic sites on the solvent appeared to be a factor that
significantly impacts reaction rate.17 These collective obser-
vations led us to evaluate pyridine as a reaction medium since
it combines apparently favorable attributes of other solvents.
Indeed, a reaction conducted in pyridine went to completion
in only 12 h while giving rise to product 4a with 83% ee
(Table 2, entry 16). This increase in reactivity allowed for
the reaction to be performed at a lower temperature. At -20
°C, product 4a was recovered with 90% ee (entry 17).
Ultimately, a toluene/pyridine solvent mixture was found to
provide the best compromise between selectivity and yield.
Further optimization also enabled the reduction of catalyst
loading to 10 mol %.
4-OH-Ph
4-MeO-Ph
3-MeO-Ph
4-CF3-Ph
Me
Et
i-Pr
n-Pr
t-Bu
A
Bd
Bd
B
9
10
11
B
B
B
4j
4k
n-pentyl
a Reactions were performed at -25 °C on a 0.5 mmol scale in anhydrous
solvent for 72 h. The ee’s were determined by HPLC analysis. b Isolated
yields. c Method A: 2 equiv of cyclohexanone and solvent (0.5 M). Method
B: 2 equiv of cyclohexanone and solvent (0.2 M). d 5 equiv of cyclohexanone
was used.
To illustrate the scope of this methodology, different
4-substituted cyclohexanones were tested under the optimized
conditions (Table 3). A number of aliphatic and aromatic
functional groups with different electronic properties were
5066
Org. Lett., Vol. 12, No. 21, 2010

4-n-Pr- and 4-Ph-substituted cyclohexanones. Due to their
attenuated reactivity, more electron-rich o-aminobenzal-
dehydes required slightly higher reaction temperatures.
Satisfactory yields and ee’s were obtained for these
substrates.
Table 4. Scope of Amino Benzaldehydesa
With the chiral quinoline products in hand, a facile
sequence was developed to access the corresponding
tacrine analogues. Following the straightforward sequence
outlined in Scheme 2, the highly enantioenriched tacrine
entry
R
R′
product methodc yield (%)b ee (%)
1d
2d
3d
4d
5
6
7
8
9
n-Pr
Ph
H
H
11a
11b
11c
11d
11e
11f
A
B
A
B
A
B
A
B
A
B
62
60
73
60
70
60
88
81
77
70
87
87
87
87
90
92
90
90
93
92
n-Pr 4-Cl
Ph 4-Cl
n-Pr 4-CF3
Ph 4-CF3
n-Pr 4-CO2Me
Ph 4-CO2Me
n-Pr 3,5-Cl2
Ph 3,5-Cl2
Scheme 2. Synthesis of an Enantioenriched Tacrine Analogue
11g
11h
11i
10
11j
a Reactions were performed at -25 °C on a 0.5 mmol scale in anhydrous
solvent for 72 h. The ee’s were determined by HPLC analysis. b Isolated
yields. c Method A: 5 equiv of cyclohexanones and solvent (0.2 M). Method
B: 2 equiv of cyclohexanones and solvent (0.5 M). d Reactions were
performed at -5 °C.
readily accommodated. Generally, quinoline products were
obtained in good yields and with excellent levels of
selectivity. As summarized in Table 4, a number of
o-aminobenzaldehydes were evaluated in combination with
derivative 14 was obtained in good yield and without loss
of ee.
In conclusion, we have reported the first catalytic enan-
tioselective Friedla¨nder reaction. Enamine catalysis allowed
for the efficient desymmetrization of 4-substituted cyclo-
hexanones in reactions with o-aminobenzaldehydes. Quino-
lines with remote stereogenic centers were obtained in
generally good yields and with good to excellent levels of
enantioselectivity. Furthermore, a chiral quinoline was
converted into a highly enantioenriched tacrine derivative.
Our discovery of interesting solvent effects, in particular the
rate acceleration observed with pyridine, may have implica-
tions for other enamine-catalyzed reactions.
(15) For additive effects in proline catalysis, see: (a) Peelen, T. J.; Chi,
Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598. (b) Zhou, Y.;
Shan, Z. J. Org. Chem. 2006, 71, 9510. (c) Pihko, P. M.; Laurikainen, K. M.;
Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006, 62, 317. (d) Gu,
Q.; Wang, X.-F.; Wang, L.; Wu, X.-Y.; Zhou, Q.-L. Tetrahedron:
Asymmetry 2006, 17, 1537. (e) Zotova, N.; Franzke, A.; Armstrong, A.;
Blackmond, D. G. J. Am. Chem. Soc. 2007, 129, 15100. (f) Guizzetti, S.;
Benaglia, M.; Raimondi, L.; Celentano, G. Org. Lett. 2007, 9, 1247. (g)
Ma, G.-N.; Zhang, Y.-P.; Shi, M. Synthesis 2007, 197. (h) Amedjkouh, M.
Tetrahedron: Asymmetry 2007, 18, 390. (i) Seebach, D.; Beck, A. K.;
Badine, D. M.; Limbach, M.; Eschenmoser, A.; Treasurywala, A. M.; Hobi,
R.; Prikoszovich, W.; Linder, B. HelV. Chim. Acta 2007, 90, 425. (j) Zotova,
N.; Moran, A.; Armstrong, A.; Blackmond, D. G. AdV. Synth. Catal. 2009,
351, 2765. (k) Zotova, N.; Broadbelt, L. J.; Armstrong, A.; Blackmond,
¨
D. G. Bioorg. Med. Chem. Lett. 2009, 19, 3934. (l) Reis, O.; Eymur, S.;
Acknowledgment. Financial support from Rutgers, The
State University of New Jersey is gratefully acknowledged.
We thank Dr. Tom Emge (Rutgers University) for crystal-
lographic analysis.
Reis, B.; Demir, A. S. Chem. Commun. 2009, 1088. (m) Poe, S. L.; Bogdan,
A. R.; Mason, B. P.; Steinbacher, J. L.; Opalka, S. M.; McQuade, D. T. J.
Org. Chem. 2009, 74, 1574. (n) Wang, J.; Lei, M.; Li, Q.; Ge, Z.; Wang,
X.; Li, R. Tetrahedron 2009, 65, 4826. (o) Wang, J.; Wang, X.; Ge, Z.;
Cheng, T.; Li, R. Chem. Commun. 2010, 46, 1751. (p) Demir, A. S.; Eymur,
S. Tetrahedron: Asymmetry 2010, 21, 405. (q) Blackmond, D. G.; Moran,
A.; Hughes, M.; Armstrong, A. J. Am. Chem. Soc. 2010, 132, 7598.
(16) For instance, the reaction in dichloromethane (dielectric constant
) 9.1) took substantially longer to go to completion as compared to the
corresponding reaction in dioxane (dielectric constant ) 2.2), while giving
rise to a similar level of enantioselectivity.
Supporting Information Available: Experimental pro-
cedures, characterization data, and X-ray crystal structure
of 4d. This material is available free of charge via the Internet
at http://pubs.acs.org.
(17) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Angew. Chem., Int.
Ed. 2010, 49, 4997.
OL1023932
Org. Lett., Vol. 12, No. 21, 2010
5067