A new catalyst for the asymmetric Henry reaction: Synthesis of β-nitroethanols in high enantiomeric excess

Article abstract of DOI:10.1021/ol3030023

A new chiral tetrahydrosalen ligand has been designed and synthesized from cis-2,5-diaminobicyclo[2.2.2]octane. The complex generated in situ by the interaction of the ligand with (CuOTf)₂·C₆H ₅CH₃ was an efficient catalyst for the asymmetric Henry reaction, producing nitroaldol products in high yield and good stereoselectivity. Henry reactions catalyzed by this tetrahydrosalen-Cu(I) complex led to syntheses of β-adrenergic blocking agents (S)-toliprolol, (S)-moprolol, and (S)-propanolol.

Full text of DOI:10.1021/ol3030023

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A New Catalyst for the Asymmetric Henry
Reaction: Synthesis of β‑Nitroethanols in
High Enantiomeric Excess
James D. White* and Subrata Shaw
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331,
United States
James.white@oregonstate.edu
Received November 5, 2012
ABSTRACT
A new chiral tetrahydrosalen ligand has been designed and synthesized from cis-2,5-diaminobicyclo[2.2.2]octane. The complex generated in situ
by the interaction of the ligand with (CuOTf)2 C6H5CH3 was an efficient catalyst for the asymmetric Henry reaction, producing nitroaldol products
3
in high yield and good stereoselectivity. Henry reactions catalyzed by this tetrahydrosalen-Cu(I) complex led to syntheses of β-adrenergic
blocking agents (S)-toliprolol, (S)-moprolol, and (S)-propanolol.
The base-catalyzed reaction of an aldehyde with a
nitroalkane (“nitroaldol condensation”) that was discov-
ered by Henry more than a century ago1 continues to
attract synthetic interest for its versatility and operational
simplicity.2 In its general form (eq 1), the nitroaldol or
Henry reaction positions hydroxyl and nitro groups in a
vicinal relationship that provides a template for acquiring
valued chemical entities including pharmaceuticals.3
showed that the chromium(II) complex of 1 is an efficient
catalyst for the hetero-DielsꢀAlder reaction of aldehydes
with a Danishefsky diene and for the NozakiꢀHiyamaꢀ
Kishi reaction of allyl bromide with aromatic aldehydes.5
Introduction of stereoselectivity into the Henry reaction
has received much recent attention,4 but there remains a
need for efficient catalyst systems which deliver the nitro-
ethanol product in high enantiomeric excess with certain
substrate classes. We have previously reported the synthe-
sis of a new salen ligand (1) based on the chiral scaffold
cis-2,5-diaminobicyclo[2.2.2]octane (Figure 1), and we
Figure 1. Salen ligand based on a cis 2,5-diaminobicyclo-
[2.2.2]octane scaffold.
It is known that the Henry reaction can be catalyzed by
copper(II) salts.4g,h,p,x The stable copper(II)-salen complex
2,5 prepared by treatment of 1 with copper(II) acetate in
methanol (Scheme 1), was therefore investigated as a
catalyst for the Henry reaction of p-nitrobenzaldehyde
(1) (a) Henry, L. C.R. Acad. Sci. Ser. C 1895, 1265. (b) Henry, L. Bull.
Soc. Chim. Fr. 1895, 13, 999.
(2) Luzzio, F. A. Tetrahedron 2001, 57, 915.
(3) Rosini, G.; Ballini, R. Synthesis 1988, 833.
r
10.1021/ol3030023
XXXX American Chemical Society

Scheme 1. Synthesis of Copper(II) Complex (þ)-2 and
Tetrahydrosalen Ligand (þ)-5 From (þ)-1
Scheme 2. Asymmetric Henry Reaction Catalyzed by Copper-
(II)-Salen Complex (þ)-2
reaction leading to racemic 4 overwhelmed asymmetric
induction from (þ)-5 (Table 1, entry 1). However, when
the toluene complex of copper(I) triflate6 was used at
1 mol % with ligand (þ)-5 at 10 mol % in dry methanol
(entry 5), a marked increase in the enantiomeric excess of
(R)-4 was observed. The optimum reaction temperature
was found to be 40 °C. When the same conditions were
applied to the Henry reaction of p-chlorobenzaldehyde
with nitromethane an improved yield and enantiomeric
excess of product 6 was observed (Table 1, entry 6); 2,6-
dichlorobenzaldehyde as a substrate (entry 7) raised these
figures further.
Guided by favorable results (entries 5ꢀ7) in Table 1, we
next examined a broad portfolio of aromatic aldehydes
(Table 2, entries 1ꢀ13) in their reaction with nitromethane
catalyzed by the copper(I) complex of (þ)-5. In every case,
nitro alcohol 7 was obtained in >90% enantiomeric excess
(3) with nitromethane under conditions that were intended
to optimize chemical yield and enantioselectivity (Scheme 2).
Initial results were not encouraging, however. Although
20 mol % of (R,R) complex 2 in a methanol/dichloro-
methane solvent pair at elevated temperature was found
to give an acceptable yield of (R)-1-(4-nitrophenyl)-2-
nitroethanol (4), the level of asymmetric induction was poor.
By contrast, reduction of (þ)-1 to diamine (þ)-5, with
sodium borohydride (Scheme 1), followed by complexation
with copper(II) triflate led to a more promising outcome in
the Henry reaction of aryl aldehydes with nitromethane.
First results with p-nitrobenzaldehyde (3) and nitro-
methane using ligand (þ)-5 at 20 mol % and copper(II)
triflate at 5 mol % as the metal source indicated that while
the chemical yield of 4 was acceptable, the background
Table 1. Asymmetric Henry Reaction of Aromatic Aldehydes
with Nitromethane: Effect of Varying Metal Ion Source,
Cu/(þ)-5 Ratio, Catalyst Loading, and Reaction Temperaturea
(4) (a) Sasai, H.; S-uzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418. (b) Sasai, H.; Tokunga, T.; Watanabe, S.;
Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388.
(c) Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki,
M. Chem.;Eur. J. 1996, 2, 1368. (d) Davis, A. V.; Driffield, M.; Smith,
D. K. Org. Lett. 2001, 3, 3075. (e) Trost, B. M.; Yeh, V. S. C.; Ito, H.;
Bremeyer, N. Org. Lett. 2002, 4, 2621. (f) Trost, B. M.; Yeh, V. S. C.
Angew. Chem., Int. Ed. 2002, 41, 861. (g) Risgard, T.; Gothelf, K. V.;
Jorgensen, K. A. Org. Biomol. Chem. 2003, 1, 153. (h) Evans, D. A.;
Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2003, 125, 12692. (i) Ooi, T.; Doda, K.; Maruoka, K. J. Am.
Chem. Soc. 2003, 125, 2054. (j) Zhong, Y. W.; Tian, P.; Lin, G. Q.
Tetrahedron: Asymmetry 2004, 15, 771. (k) Borah, J. C.; Gogoi, S.;
Boruwa, J.; Kalita, B.; Barua, N. C. Tetrahedron Lett. 2004, 45, 3689.
(l) Zubia, A.; Cossio, F. P.; Morao, L. A.; Rieumont, M.; Lopez, X.
J. Am. Chem. Soc. 2004, 126, 5243. (m) Palomo, C.; Oiarbide, M.;
Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442. (n) Palomo, C.;
Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44, 3881. (o) Li, H.;
Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732. (p) Arai, T.;
Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9, 3595. (q) Gruber-
Khadjawi, M.; Purkharthofer, T.; Skranc, W.; Griengl, H. Adv. Synth.
Catal. 2007, 349, 1445. (r) Handa, S.; Nagawa, S.; Sohtome, Y.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2008, 47, 3230.
(s) Toussaint, A.; Pfaltz, A. Eur. J. Chem. 2008, 4591. (t) Kim, H. Y.; Oh,
K. Org. Lett. 2009, 11, 5682. (u) Breuning, M.; Hein, D.; Steiner, M.;
Gessner, V. H.; Strohmann, C. Chem.;Eur. J. 2009, 15, 12764. (v) Ji,
Y. Q.; Qi, G.; Judeh, Z. M. A. Eur. J. Org. Chem. 2011, 4892. (w) Jin, W.;
Li, X.; Wan, B. J. Org. Chem. 2011, 76, 484. (x) Chougnet, A.; Zhang, G.;
Liu, K.; Hausinger, D.; Kagi, A.; Allmendinger, T.; Woggon, W. D.
Adv. Synth. Catal. 2011, 353, 1797.
product 4 or
6
ligand
loading
(mol %)
metal salt
(mol %)
temp t yield ee
(°C) (h) [%]b [%]c
entry
1
Ar
4-NO2C6H4
20
10
Cu(OTf)2
(5)
20 30 4, 68
7
2
4-NO2C6H4
Cu(OTf)2
(2.5)
20 30 4, 55
28
26
43
79
3d 4-NO2C6H4
10 (CuOTf)2 C6H5CH3 20 24 4, 49
3
(5)
4
5
6
7
4-NO2C6H4
4-NO2C6H4
4-CIC6H4
10 (CuOTf)2 C6H5CH3 40 15 4, 85
3
(2.5)
10 (CuOTf)2 C6H5CH3 40 20 4, 64
3
(1)
10 (CuOTf)2 C6H5CH3 40 16 6a, 76 83
3
(1)
2,6-CI2C6H3 10 (CuOTf)2 C6H5CH3 40 20 6b, 89 94
3
(1)
a Reactions were carried out on 0.2 mmol scale with 0.6 mL of
nitromethane. b Yield of isolated product. c Determined by HPLC using
a Daicel Chiralcel AD or OD column. d No molecular sieves added.
(5) White, J. D.; Shaw, S. Org. Lett. 2011, 13, 2488.
B
Org. Lett., Vol. XX, No. XX, XXXX

Access to these structures began with oxidative cleavage
of allyl aryl ethers 11ꢀ1310 to give unstable aldehydes
14ꢀ16 which were reacted with nitromethane under the
conditions specified in Table 2 (Scheme 3). The results of
reactions of14ꢀ16withnitromethaneare shownin Table3
and confirm that ligand 5 is an efficient catalyst for con-
version of these aldehydes to nitro alcohols. Catalytic
hydrogenation of 17ꢀ19 led quantitatively to the corre-
sponding amino alcohols which were condensed in situ
with acetone. A second catalytic hydrogenation produced
8, 9, and 10.11 In this manner, a simple sequence in which
the final three steps are carried out in a single pot leads
from inexpensive starting materials (m-cresol, guaiacol,
and 1-naphthol) to important commercial drugs in good
overall yield and high enantiopurity.
Table 2. Asymmetric Synthesis of β-Nitro Alchohols under Opti-
mized Conditions: Structural Effects on Yield and Enantioselectivitya
product 7
t
yield
[%]b
ee
[%]c
entry
R
(h)
1
Ph
20
24
60
18
24
24
22
12
24
24
18
24
20
42
51
18
48
7a, 90
7b, 95
7c, 81
7d, 94
7e, 96
7f, 97
7g, 93
7h, 93
7i, 99
7j, 87
7k, 98
7l, 87
7m, 98
7n, 90
7o, 89
7p, 83
7q, 95
92
96
91
96
96
92
96
95
95
98
93
94
95
94
95
93
97
2
3-CH3C6H4
2-MeOC6H4
3-MeOC6H4
4-CF3C6H4
2-(OH)C6H4
3
4
5
6
7
3,5-(OMe)2C6H3
2,4-(NO2)2C6H3
3-(4-MeOC7H6O)-4-(NO2)C6H3
2-(OH)-3-(Br)-5-(Me3C)C6H2
1-naphthyl
Scheme 3. Syntheses of (S)-Toliprolol (8), (S)-Moprolol (9), and
(S)-Propanolol (10)
8
9
10
11
12
13
14
15
16
17
2-furyl
3-furyl
cyclohexyl
Me3C
CH3CHdC(CH3) (E)
PhCHdC(CH3) (E)
a Reactions were carried out on 0.2 mmol scale with 0.6 mL of
nitromethane. b Yield is based on allyl ethers 11ꢀ13. c Determined by
HPLC using a Daicel Chiralcel OD column.
and in good yield. Aliphatic aldehydes (entries 14ꢀ15) as
well as R,β-unsaturated aldehydes (entries 16ꢀ17) also
gave a high yield and enantiomeric excess of 7.
The asymmetric Henry reaction is well suited to prep-
aration of the vicinal amino alcohol motif that charac-
terizes blocking agents of the β-adrenergic receptor such as
toliprolol (8),7 moprolol (9),8 and propanolol (10).9 Each
of these drugs features a 1-aryloxy-3-isopropylamino-2-
propanol template with the active enantiomer having an
(S) configuration (Figure 2).
Table 3. Asymmetric Henry Reaction of Aldehydes 14ꢀ16 with
Nitromethane Catalyzed by (þ)-5a
aldehyde
yield
[%]b
ee
[%]c
entry
(Ar)
product
1
2
3
14 (3-CH3C6H4)
15 (2-CH3OC6H4)
16 (1-naphthyl)
17
18
19
90
93
90
96
94
97
a Reactions were carried out on 0.2 mmol scale with 0.6 mL of
nitromethane. b Yield is based on allyl ethers 11ꢀ13. c Determined by
HPLC using a Daicel Chiralcel OD column.
Diastereoselectivity associated with higher order nitro-
alkanes in the asymmetric Henry reaction has been studied
by Shibasaki4b,r and by Jorgensen.4g Inour hands, reaction
of benzaldehyde and 1-naphthaldehyde with nitropropane
in the presence of (þ)-5 and a copper(I) triflate toluene
(8) Lunsford, C. D.; Mays, R. P.; Richman, J. A.; Murphey, R. S.
J. Am. Chem. Soc. 1960, 82, 1166.
Figure 2. β-Adrenergic receptor blocking agents.
(9) Dukes, M.; Smith, L. H. J. Med. Chem. 1971, 14, 326.
(10) Allyl ethers 11ꢀ13 were obtained by reaction of the parent
phenol with allyl bromide and potassium carbonate in acetone at rt.
(11) Sasai, H.; Itoh, N.; Suzuki, T.; Shibasaki, M. Tetrahedron Lett.
1993, 34, 855.
(6) Dines, M. B.; Bird, P. H. J. Chem. Soc., Chem. Commun. 1973, 12.
(7) Howe, R.; Rao, B. S. J. Med. Chem. 1968, 11, 1118.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Asymmetric Addition of 1-Nitropropane to
Benzaldehyde and 1-Naphthaldehyde Catalyzed by
a
(þ)-5/(CuOTf)2 C6H5CH3
3
product 21
t
dr
yield
[%]c
ee
[%]d
Figure 3. Proposed transition state for the asymmetric henry
reaction of aldehydes with nitromethane and 1-nitropropane
entry
R
(h)
syn/antib
catalyzed by a (þ)-5/(CuOTf)2 C6H5CH3 complex.
3
1
2
Ph
1-naphthyl
24
28
>20:1
>50:1
21a, 96
21b, 93
97
98
a Reactions were carried out on 0.2 mmol scale with 0.6 mL of
nitropropane. b Determined by 1H NMR analysis. c Combined yields of
syn and anti isomers. d Determined by HPLC using a Daicel Chiralcel
OD-H or AS-H column.
Scheme 4. Proposed Catalytic Cycle for the Formation of 7
and 21
complex under the conditions specified in Table 2 gave a
syn/anti ratio strongly favoring the syn product 21 which
was formed in high enantiomeric excess (Table 4).
It is clear from the results in Tables 2 and 3 that there is a
strong preference for (1R,2R,4R,5R) ligand (þ)-5 to give
nitroaldol products 7 of an (R) configuration in the reac-
tion of aldehydes with nitromethane. This stipulates that
attack by nitromethane occurs predominantly at the si face
of the carbonyl group; a transition state rationalizing this
outcome is proposed in Figure 3. In this model, reactants
are coordinated to copper(I) complex 20 in a quadrant
under the bicyclic scaffold (right, front) with CꢀC bond
formation taking place from the less sterically encumbered
direction.12 It is likely that organization of transition state
20 is assisted by a NꢀH hydrogen bond with the nitronate
since complex (þ)-2 in which this hydrogen bond is absent
leads to lower enantioselectivity. The results in Table 4
imply that the copper complexed nitronate of nitropro-
pane in transition state 22 has a (Z) configuration with
attack occurring at the si face of the aldehyde carbonyl as
shown in Figure 3.
In summary, an efficient catalyst based on a copper(I)
complex of tetrahydrosalen (þ)-5 has been developed for
the asymmetric Henry reaction. It was shown that high
yields, diastereoselectivity, and enantioselectivity of β-nitro
alcohols can be obtained with this catalyst.
A catalytic cycle that would incorporate transition states
20 and 22 is proposed in Scheme 4. Initial ligand exchange
of tetrahydrosalen (þ)-5 for toluene would give copper(I)
triflate complex 23. Progression of 23 via copper(I) com-
plexes 24 and 25 would complete the catalytic cycle while
generating 7 or 21.
Acknowledgment. We are grateful to Oregon State Uni-
versity Colleges of Pharmacy and Science for funds to
purchase a 500 MHz NMR spectrometer.
Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds.
This material is available free of charge via Internet at
http://pubs.acs.org.
(12) A 180° rotation of the aldehyde in 20 (which would lead to an re
face attack by nitromethane) is disfavored by a steric clash of the
aldehyde hydrogen with a tert-butyl substituent on the opposing benze-
noid ring of the salen ligand.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX