Reductive intramolecular Henry reactions induced by Stryker's reagent

Article abstract of DOI:10.1055/s-2004-836044

Conjugate reductions of nitroalkenes by Stryker's reagent are ensued by intramolecular aldol reactions to produce β-nitroalcohols in good yield, constituting the first examples of reductive Henry reactions.

Full text of DOI:10.1055/s-2004-836044

LETTER
55
Reductive Intramolecular Henry Reactions Induced by Stryker’s Reagent
R
eductive Intramolecula
i
r
Henr
n
y Reactions g Ki Chung, Pauline Chiu*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. China
Fax +86(852)28571586; E-mail: pchiu@hku.hk
Received 1 September 2004
to react with a tethered ketone to afford a cyclized aldol
product.17,18 In the event, the reaction of nitroalkene 2a
with 1.5 hydride equivalents of 1 at room temperature was
complete in minutes to give a 78% yield of reductively cy-
clized products. Further investigation of the reaction con-
ditions revealed that the reductive aldol cyclization of 2a
was extremely facile and could be accomplished within
one hour at –40 °C.19 Two fused-ring isomers were
formed in a ratio of 5:1. The major isomer was the cis-
decalin product c-3a, obtained as a mixture of epimers at
the nitro group. The minor product was the trans-fused
decalin t-3a. Reductive Henry aldol reactions of various
substrates under these reaction conditions are summarized
in Table 1. In all of these cases, tandem conjugate reduc-
tion proceeded smoothly followed by an intramolecular
Henry reaction to give nitroalcohol products with good
yields. These are the first examples of reductive Henry re-
actions. Intramolecular cyclizations to form both six-
membered (Table 1, entries 1–3) and five-membered
rings (Table 1, entries 4 and 5) were successful.
Abstract: Conjugate reductions of nitroalkenes by Stryker’s re-
agent are ensued by intramolecular aldol reactions to produce b-ni-
troalcohols in good yield, constituting the first examples of
reductive Henry reactions.
Key words: nitro-aldol reactions, reductions, tandem reactions,
copper, nitroalkenes
The Henry reaction is the well known aldol condensation
of nitroalkanes with carbonyl compounds and is a classi-
cal carbon-carbon bond-forming reaction.1–4 The b-ni-
troalcohols thus produced can undergo a range of
chemical transformations for the synthesis of b-aminoal-
cohols, a-hydroxyketones, nitroalkenes and other synthet-
ic intermediates.5–7 Various reagents have been found to
promote these condensations, including quaternary am-
monium salts, organic and inorganic bases. While existing
nitroaldol and other methodologies readily provide ni-
troalkenes as electrophilic substrates for further reactions,
e. g. Michael additions, their use as nucleophilic reagents
is often preceded by conversion to nitroalkanes, an impor-
tant transformation for which a number of reductive reac-
tion conditions have been developed.8–11 Recently, an
asymmetric reduction of nitroalkenes has also been real-
ized.12
Compared with the reductive aldol cyclizations of enone
substrates induced by 1 (Equation 1),13a the diastereose-
lectivities of the analogous reductive nitroaldol reactions
are not as high. Although the reductive reactions were
quenched at –40 °C with aqueous NH4Cl or with pre-
cooled 1:1 HOAc–THF, mixtures of diastereomers as well
as epimers at the stereocenter a to the nitro group were ob-
tained. The copper counterion provided by 1 did not pro-
vide any additional selectivity over the traditional base-
induced Henry aldol reactions, which are also not as selec-
tive as their enolate aldol corollaries.
We have been engaged in studies to induce a conjugate re-
duction of nitroalkenes in tandem with a nitroaldol reac-
tion in one operation. These studies were undertaken in
the context of recent developments in the conjugate reduc-
tion of enones to generate enolates for tandem aldol reac-
tions.13,14 However, no examples of the analogous Henry
reaction using nitroalkenes has appeared in the literature.
This reaction may be complicated by concomitant reac-
tions of the nitro group and the electrophile with reducing
agents and bases.12,15 Herein we report the results of our
studies.
O
O
O
HO
H
2 equiv 1, –40 °C
PhCH3, 1 h,
72%
Nitroalkenone substrates 2a–e were prepared by base-in-
duced Henry reactions of aldehydes with simple nitroal-
kanes and subsequent dehydration. Although ketones are
generally poor electrophiles for the Henry reaction, it has
been shown that the intramolecular reaction proceeds sat-
isfactorily.16 Our approach to the reductive Henry reaction
is to engage the nitronate obtained upon conjugate reduc-
tion of a nitroalkene by Stryker’s reagent [Ph3PCuH]6 (1),
Equation 113a
The lack of selectivity is generally attributed to the revers-
ibility of the nitroaldol reaction and the acidity of the a-
proton.6,20 That this reaction is reversible is evidenced by
the fact that the diastereomeric ratio of products t-3b and
c-3b from the reductive cyclization of 2b was found to de-
teriorate from 7:1 (Table 1, entry 2) to 4:1 when the reac-
tion time was extended to 24 hours at –40 °C. Any
epimerizations of the a-protons at these low temperatures
would be attributed to the intermediate aldol alkoxides,
SYNLETT 2005, No. 1, pp 0055–0058
0
5.
0
1.
2
0
0
5
Advanced online publication: 29.11.2004
DOI: 10.1055/s-2004-836044; Art ID: U24404ST
© Georg Thieme Verlag Stuttgart · New York

56
W. K. Chung, P. Chiu
LETTER
Table 1 Reductive Nitroaldol Cyclizations Induced by 1
Table 2 Reductive Nitroaldol Cyclizations Induced by 1
Entry Substrate
Product
Entry
Substrate
Product
(yield,a ratio b-NO2:a-NO2)
(yield,a ratio of epimers)
O
NO2
NO2
NO2
HO
HO
HO
NO2
1
O
H
2a
3f (75%, 5:1)b
c-3a (66%, 1:1)
t-3a (13%)
1
O
NO2
NO2
NO2
O
HO
HO
NO2
2f ratio = 2.5:1
2
X
Y
H
H
2b
4f X, Y = H, NO2 (7%)
t-3b (54%)
c-3b (8%)
O
NO2
HO
NO2
HO
NO2
3
2c
3c (77%, 2:1)
H
O
O
NO2
3g (52%, 2:1)c
HO
NO2
2
NO2
4
O
X
Y
H
2g
2d
3d (74%, 1:2)
O
NO2
HO
4g X, Y = H, NO2 (23%)
5g X, Y = O (8%)
NO2
5
NO2
HO
3e (75%, 3:1)b
2e
a Isolated product yields.
b Inseparable diastereomeric mixture, stereochemistry not deter-
mined.
O
3h (25%, 1:1)
3
O
NO2
2h ratio = 2:1
X
Y
since Stryker’s reagent 1 is typically regarded to be a rel-
atively non-basic reagent. However, we have found that at
higher temperatures, e. g. room temperature, and over a
long reaction time, 1 was able to induce the Henry aldol
reaction of nitroalkane substrate 4b to give the same prod-
ucts as in the reductive cyclization of 2b in a different ra-
tio (Equation 2).21
4h X, Y = H, NO2 (22%)
5h X, Y = O (27%)
O
O
4
5
X Y
NO2
2i ratio = 1.2:1
4i X, Y = H, NO2 (47%)
5i X, Y = O (33%)
NO2
NO2
O
HO
HO
NO2
1.5 equiv 1
+
O
O
r.t., 8 h
PhCH3
82%
X
Y
H
t-3b
H
c-3b
4b
NO2
1:1
4j X, Y = H, NO2 (39%)
5j X, Y = O (33%)
2j
Equation 2
a Isolated product yields.
b Relative stereochemistry not determined.
c Inseparable diastereomeric mixture, stereochemistry not deter-
mined.
Nitroalkene substrates having additional substitution at
the nitro group were also prepared and subjected to reduc-
tion to explore the scope of the reaction (Table 2). The
products resulting from these substrates could not be
epimerized at the a-stereocenter by deprotonation, al-
though the retro-aldol reaction is still possible. Such sub-
strates were found to undergo both conjugate reduction
and cyclization much more sluggishly than those in
Table 1. Treatment of 2f with 1 at –40 °C for 3 hours re-
turned only unreacted starting materials. When the reac-
Synlett 2005, No. 1, 55–58 © Thieme Stuttgart · New York

LETTER
Reductive Intramolecular Henry Reactions
57
(7) Perekalin, V. V.; Lipina, E. S.; Berestovitskaya, V. M.;
tion temperature was raised to ambient temperatures,
reductive Henry cyclization occurred to give a 75% yield
of 3f as a 5:1 mixture of diastereomers. It was found that
additional substituents on the nitroalkene still provided
acceptable to good yields of cyclized aldol products
(Table 2, entries 1 and 2), and hindered ketones also un-
derwent intramolecular reductive cyclization with unen-
cumbered nitroalkenes (Table 1, entries 2, 4). However,
when both of the reaction sites were highly substituted, re-
duction was possible but cyclization failed to occur
(Table 2, entries 4 and 5). With increasing steric hin-
drance surrounding the reaction sites, simple reduction
nitroalkane products 4f–j were isolated and became the
predominant products (Table 2, entries 4 and 5). Also iso-
lated were diketones 5g–j, which were likely to be derived
from Nef reactions of the copper nitronate intermediates
of 4f–j during workup.
Efremov, D. A. Nitroalkene: Conjugated Nitro Compounds;
Wiley: Chichester, 1994.
(8) (a) Urrutia, A.; Rodriguez, J. G. Tetrahedron Lett. 1998, 39,
4143. (b) Lee, W. Y.; Jang, S. Y.; Chae, W. K.; Park, O. S.
Synth. Commun. 1993, 23, 3037.
(9) A case of nitroalkenes reacting directly as the nucleophilic
component: Ono, N.; Hamamoto, I.; Kamimura, A.; Kaji,
A.; Tamura, R. Synthesis 1987, 258.
(10) A tandem conjugate addition Michael reaction: Yasuhara,
T.; Nishimura, K.; Yamashita, M.; Fukuyama, N.; Yamada,
K.; Muraoka, O.; Tomioka, K. Org. Lett. 2003, 5, 1123.
(11) Torii, S.; Inokuchi, T.; Oi, R.; Kondo, K.; Kobayashi, T. J.
Org. Chem. 1986, 51, 254.
(12) Czekelius, C.; Carreira, E. M. Angew. Chem. Int. Ed. 2003,
42, 4793.
(13) (a) Chiu, P.; Szeto, C. P.; Geng, Z.; Cheng, K. F. Org. Lett.
2001, 3, 1901. (b) Chiu, P.; Leung, S. K. Chem. Commun.
2004, 2308.
(14) (a) Chiu, P.; Szeto, C. P.; Geng, Z.; Cheng, K. F.
Tetrahedron Lett. 2001, 42, 4091. (b) Chiu, P.; Chen, B.;
Cheng, K. F. Tetrahedron Lett. 1998, 39, 9229.
(15) Ranu, B. C.; Chakraborty, R. Tetrahedron 1992, 48, 5317.
(16) Weller, T.; Seebach, D.; Davis, R. E.; Laird, B. B. Helv.
Chim. Acta 1981, 64, 736.
(17) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am.
Chem. Soc. 1988, 110, 291.
(18) Stryker’s reagent is commercially available and can also be
prepared: (a) Brestensky, D. M.; Huseland, D. E.;
McGettigan, C.; Stryker, J. M. Tetrahedron Lett. 1988, 29,
3749. (b) Chiu, P.; Li, Z. N.; Fung, C. M. Tetrahedron Lett.
2003, 44, 455.
(19) Typical Experiment Procedure: Compound 1 (1.5 hydride
equiv) was transferred to a dry flask inside a dry box.
Toluene (2 mL) was added and the resulting red solution was
cooled to –40 °C. Nitroalkene 2a (0.6 mmol) in 2 mL toluene
was added to 1 via cannula. After 1 h, the reaction was
quenched by adding 2 mL sat. aq NH4Cl and stirred for 2 h
open to air. The resultant mixture was filtered through a
silica gel pad and concentrated in vacuo. Flash
The reductive nitroaldol intermediate before quenching is
a putative copper nitronate. If copper were able to stabi-
lize the nitronate, a subsequent Nef reaction may be
favored, leading to a one-pot reductive Henry–Nef reac-
tion.22 However, subjecting the reduction mixture to the
Nef conditions was found to be plagued by many side re-
actions, including the retro-aldol reaction. After workup,
nitroalcohols such as t-3b could be transformed in a sepa-
rate reaction into a-hydroxyketone 623 via a Nef reaction
with a concomitant retro-aldol reaction (Equation 3).
In summary, we have accomplished the first reductive
Henry aldol reactions using Stryker’s reagent 1.
O
NO2
HO
HO
1) 2 M NaOH, MeOH
2) iced cooled KMnO4
45%
H
H
chromatography of the residue (5% EtOAc in hexane)
afforded c-3a (two isomers) and t-3a as colorless oils.
c-3a (b-NO2): Rf = 0.66 (20% EtOAc in hexane). IR
(CH2Cl2): 3551, 2943, 2873, 1606, 1546, 1453, 1378 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.17 (dd, J = 12.9, 3.7 Hz,
1 H), 2.92 (s, 1 H), 2.41 (qd, J = 13.0, 4.6 Hz, 1 H), 2.01–
1.94 (m, 1 H), 1.88 (td, J = 13.8, 4.9 Hz, 1 H), 1.79 (td,
J = 13.9, 4.4 Hz, 1 H), 1.75–1.64 (m, 3 H), 1.64–1.55 (m, 3
H), 1.55–1.43 (m, 1 H), 1.35 (dt, J = 14.0, 3.1 Hz, 1 H),
1.17–1.10 (m, 2 H), 1.08 (s, 3 H). 13C NMR (125 MHz,
CDCl3): d = 87.3, 73.6, 39.0, 34.8, 32.9, 31.9, 27.3, 23.2,
22.1, 20.8, 19.7. MS (EI, 20 eV): m/z (%) = 213 (2) [M+],
196 (1), 167 (7), 149 (100). HRMS (EI): m/z calcd for
C11H19NO3 [M+]: 213.1365; found: 213.1353.
t-3b
6
Equation 3
Acknowledgment
Miss Lihong Hu and Dr. G. H. Chen of the Department of Chemi-
stry at The University of Hong Kong are thanked for their help in
performing the computations. This work was supported by the
University of Hong Kong and by the Research Grants Council of
Hong Kong, SAR, P. R. China (Project HKU 7102/ 02P). WKC
thanks the University of Hong Kong for a conference travel grant.
c-3a (a-NO2): Rf = 0.57 (20% EtOAc in hexane). IR
(CH2Cl2): 3563, 2937, 2869, 1606, 1545, 1453, 1370 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.73 (dd, J = 12.0, 5.3 Hz,
1 H), 2.77 (s, 1 H), 2.10 (m, 1 H), 2.06 (qd, J = 13.4, 5.0 Hz,
1 H), 1.96 (td, J = 13.7, 4.6 Hz, 1 H), 1.87–1.53 (m, 6 H),
1.49–1.38 (m, 2 H), 1.22–1.12 (m, 2 H), 1.09 (dm, J = 13.7
Hz, 1 H), 1.08 (s, 3 H). 13C NMR (100 MHz, CDCl3): d =
90.8, 74.7, 39.2, 36.3, 32.3, 27.5, 27.2, 22.4, 21.1, 21.0, 19.3.
MS (EI, 20 eV): m/z (%) = 196 (0.2) [M+ – OH], 167 (17),
149 (100). HRMS (EI): m/z calcd for C11H18NO2 [M+ – OH]:
196.1338; found: 196.1326.
References
(1) Henry, L. Compt. Rend. 1895, 120, 1265.
(2) Rosini, G. In Comprehensive Organic Synthesis, Vol. 2;
Trost, B. M., Ed.; Pergamon: New York, 1992.
(3) Luzzio, F. A. Tetrahedron 2001, 57, 915.
(4) Recent developments in the Henry reaction: Evans, D. A.;
Siedel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey,
C. W. J. Am. Chem. Soc. 2003, 125, 12692.
(5) Shvekhgeimer, M. C. A. Russ. Chem. Rev. 1998, 67, 35.
(6) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001.
t-3a: Rf = 0.71 (20% EtOAc in hexane). IR (CH2Cl2): 3559,
2948, 2869, 1542, 1483, 1446, 1373 cm–1. 1H NMR (500
Synlett 2005, No. 1, 55–58 © Thieme Stuttgart · New York

58
W. K. Chung, P. Chiu
LETTER
(21) The different ratios of diastereomeric products obtained
MHz, CDCl3): d = 4.68 (dd, J = 12.8, 4.1 Hz, 1 H), 2.60 (s,
1 H), 2.47 (qd, J = 12.6, 7.1 Hz, 1 H), 2.01–1.96 (m, 1 H),
1.91–1.78 (m, 2 H), 1.78–1.73 (m, 1 H), 1.73–1.66 (m, 2 H),
1.66–1.60 (m, 1 H), 1.59–1.46 (m, 3 H), 1.25–1.20 (m, 1 H),
1.07–1.03 (m, 1 H), 1.03 (s, 3 H), 0.98 (dt, J = 13.1, 3.3 Hz,
1 H). 13C NMR (125 MHz, CDCl3): d = 90.0, 73.0, 38.2,
34.9, 32.9, 29.6, 27.2, 20.6, 20.3, 19.5, 19.1. MS (EI, 20 eV):
m/z (%) = 196 (0.2) [M+ – OH], 167 (8), 149 (100). HRMS
(EI): m/z calcd for C11H18NO2 [M+ – OH]: 196.1338; found:
196.1302. The relative stereochemistries of c-3a (b-NO2), c-
3a (a-NO2), t-3a (b-NO2), and all other cyclized compounds
3 were determined by 2-D NOE spectral correlations.
under the two reaction conditions (Table 1, entry 2 and
Equation 2) implies that t-3b is the kinetic product and that
the thermodynamic energies of c-3b and t-3b are
comparable. That t-3b is the kinetic product was further
confirmed by being the only product isolated when the
reduction of 2b at –40 °C was quenched after 15 min. The
optimized configurations of t-3b and c-3b by DFT
calculations using the B3LYP/6-31G (d) model showed that
t-3b was thermodynamically more stable than c-3b by 2.1
kcal/mol.
(22) Pinnick, H. W. Org. React. 1990, 38, 655.
(23) Shono, T.; Kise, N.; Fujimoto, T.; Tomimaga, N.; Morita, H.
J. Org. Chem. 1992, 57, 7175.
(20) Seebach, D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E.
Helv. Chim. Acta 1982, 65, 1101.
Synlett 2005, No. 1, 55–58 © Thieme Stuttgart · New York