Tandem Hass-Bender/Henry reaction for the synthesis of dimethylnitro alcohols from benzylic halides

Article abstract of DOI:10.1016/j.tetlet.2005.05.021

Dimethylnitro alcohols are constructed in a one-pot process from benzylic halides and 2-nitropropane. The use of tetrabutylammonium fluoride (TBAF) as the promoter is essential for this tandem Hass-Bender/Henry reaction to proceed.

Full text of DOI:10.1016/j.tetlet.2005.05.021

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4535–4538
Tandem Hass–Bender/Henry reaction for the synthesis of
dimethylnitro alcohols from benzylic halides
Thomas A. Klein and Jeffrey M. Schkeryantz*
Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 4 May 2005; accepted 6 May 2005
Available online 24 May 2005
Abstract—Dimethylnitro alcohols are constructed in a one-pot process from benzylic halides and 2-nitropropane. The use of tetra-
butylammonium fluoride (TBAF) as the promoter is essential for this tandem Hass–Bender/Henry reaction to proceed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Nitro alcohols exemplified by structure 3 (Scheme 1)
constitute an important class of intermediates for the
preparation of a number of biologically relevant organic
molecules. For example, they are an ideal source of
amino alcohols, amino ketones, aziridines and amines.1
hyde) are equivalent. Therefore, we reasoned that cou-
pling these two processes would produce the desired
hydroxynitro compounds directly from benzylic halides.
Since both reactions are dependent on a base to proceed,
we anticipated that choosing the appropriate base to
promote both the Hass–Bender oxidation and the Henry
reaction would be the crucial factor in the overall suc-
cess of this transformation.
Molecules of this type can be synthesized from alde-
hydes and nitronate anions, a conversion termed the
Henry or nitroaldol reaction.2 We wish to report the
convenient synthesis of molecules of this general struc-
ture, not from benzaldehydes, but from benzylic halides
and the anion of 2-nitropropane. The overall transfor-
mation consists of a one-pot Hass–Bender oxidation fol-
lowed by a Henry reaction.
Table 1 shows the outcome of screening various promo-
ters (1.5 equiv) with 2-chlorobenzyl bromide in the pres-
ence of excess 2-nitropropane. The bases NH4OAc, LiF
and CsF (entries 1-3) afforded little, if any reaction.
However, the tertiary amine bases, DBU, HunigÕs base
and HMPP4 (entries 4, 5, and 6) afforded, in addition
to unchanged 2-chlorobenzyl bromide, a mixture of
aldehyde and desired nitroalcohol but with the aldehyde
intermediate predominating. Fortunately, we found that
the use of tetrabutylammonium fluoride (TBAF) (entry
7) promoted both the Hass–Bender oxidation as well as
the Henry reaction to provide the desired product in
93% yield after chromatography.5 The reaction did not
proceed under slightly acidic conditions or without the
aid of a promoter as shown in entries 10 and 11. Only
the starting benzylic bromide was isolated in these cases.
Stronger bases such as sodium hydride or sodium eth-
oxide promoted the Hass–Bender oxidation, however,
under these conditions the Henry product was not
observed (entries 8 and 9).
The Hass–Bender oxidation consists of the reaction of a
substituted nitronate anion with an activated halide to
produce a carbonyl compound.3 The mechanism for this
reaction is believed to be the displacement of the halide
or leaving group by the nitronate oxygen to afford the
O-alkylated nitronate. The carbonyl compound is then
produced by expulsion of acetoneoxime from the inter-
mediate O-alkylated nitronate (Scheme 1).
The Hass–Bender oxidation and the Henry reaction can
both share 2-nitropropane as a common component. In
addition, the product of the Hass–Bender oxidation and
the starting material for the Henry reaction (i.e., alde-
A possible explanation for the essential role of TBAF
resides in the observation that nitro-alcohols with struc-
ture 3 revert to the aldehyde 1 when exposed to strong
bases such as sodium hydride or sodium ethoxide.6 It
Keywords: Hass–Bender reaction; Henry reaction; Tandem reaction;
TBAF.
*
Corresponding author. Tel.: +1 317 433 5175; fax: +1 317 276
7600; e-mail: schkeryantz_jeffrey@lilly.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.021

4536
T. A. Klein, J. M. Schkeryantz / Tetrahedron Letters 46 (2005) 4535–4538
Hass-Bender oxidation
LG
-O
O-
CHO
+
OH
+
N
N
O
N
+
O-
H
1
LG = leaving group
Henry Reaction
CHO
OH
promoter
NO2
NO2
+
1
2
3
Scheme 1. Tandem Hass–Bender/Henry reaction.
Table 1. The effect of various promoters on the ratio of products 7 and
8
of p-chloro benzyl bromide gave compound 10 in
essentially the same yield (77%) illustrating that the
steric environment associated with ortho-substitution
is tolerated. 3-Methyl benzylbromide 11 produced the
dimethylnitro compound 12 in 85% yield while the
2,3-difluoro benzyl bromide 13 gave 14 in 89% yield.
Benzylic chlorides 20 and 26 also proved to be viable
in the transformation supplying 21 and 27 in 46% and
91% yield, respectively. A number of different functional
groups were well tolerated, including the nitro substitu-
ent (entry 6), the ether functionality (entry 9), the readily
oxidized thioether (entry 10), aromatic halides (entries 2,
3, and 5) as well as the ester functional group (entries 8
and 12).
OH
NO2
CHO
Br
promoter
+
Cl
2-nitropropane
Cl
Cl
7
6
8
Entry
Promoter
Ratio of 7:8
1
NH4OAc
LiF
CsF
No reaction
No reaction
No reaction
3:1
2
3
4
HunigÕs base
¨
DBU
5
2:1
1.5:1
6
HMPP
TBAF
NaH
7
1:15
>100:1
Entries 12 and 13 illustrate the methodology is applica-
ble to heteroaromatic substrates. Thus methyl 5-(chloro-
methyl)-2-furoate 26 and 3-(bromomethyl)pyridine
hydrobromide 28 furnished the desired products in
excellent yields. However, the pyridine hydrobromide
(entry 13) required the use of an extra equivalent of
TBAF for the reaction to proceed, presumably to gener-
ate the free base in situ.8 In general, the yields for the
benzylic halides substituted with electron withdrawing
substituents tended to be higher than those containing
electron donating groups (compare entries 6 and 8 with
9, 10, and 11). This is probably a reflection of the nitro-
aldol (Henry) portion of the reaction sequence since in
all cases the benzylic halide was consumed and the only
isolated by-product was the corresponding aldehyde
ensuing from the Hass–Bender oxidation. Attempts to
drive the reaction to completion in these cases by manip-
ulating the stoichiometry of the nitro-propane and/or
TBAF had little or no effect.
8
9
NaOEt
Acetic acid
None
>100:1
No reaction
No reaction
10
11
DBU = 1,8-diazabicyclo[5.4.0]undec-7ene; HMPP = 1,3,4,6,7,8-hexa-
hydro-1-methyl-2H-pyrimido[1,2-A]pyrimidine; TBAF = tetrabutyl-
ammonium fluoride.
seems that the stronger bases promote the Hass–Bender
oxidation but not the Henry reaction, in fact they seem
to favor the retro-Henry. The tertiary amine bases, on
the other hand, allow for the Hass–Bender reaction to
proceed but are not basic enough to drive the Henry
reaction to completion. Apparently, the TBAF solution
is unique in that it possesses an intermediate basicity
that is strong enough to promote the Hass–Bender oxi-
dation but moderate enough so that the retro-Henry is
not favored.7
To define the scope of this transformation we examined
the reactions of a variety of benzyl halides (1.0 equiv)
with 2-nitropropane (3.0 equiv) in the presence of TBAF
(1.5 equiv). The results of these experiments are summa-
rized in Table 2.
The non-benzylic, but nonetheless activated halide, aceto-
phenone methylbromide (entry 14) produced the desired
product 31 in moderate 40% yield. Entry 15 demon-
strates that a non-activated halide is a feasible substrate
for this transformation, producing the expected dimeth-
ylnitro alcohol in 73% yield.
The reaction of benzyl bromide with 2-nitropropane and
1.5 equiv of TBAF afforded the dimethyl nitro product 5
in 69% yield. o-Chloro benzyl bromide provided the
desired product 8 in 76% isolated yield while the use
The reactions involving p-nitrobenzylbromide and p-
nitrobenzylchloride deserve further comment. Reacting
p-nitrobenzylchloride with 2-nitropropane in the pres-

T. A. Klein, J. M. Schkeryantz / Tetrahedron Letters 46 (2005) 4535–4538
Table 2. Scope of the TBAF promoted Hass–Bender/Henry reaction
4537
OH
O2N
NO2
2-nitropropane
Entry Alkyl
halide
Product
Yield
(%)
Br
TBAF
94%
O2N
O2N
15
OH
17
Br
Br
NO2
NO2
1
69
76
77
85
O2N
NO2
2-nitropropane
2
5
Cl
OH
Cl
TBAF
85%
34
16
2
Cl
6
Scheme 2. Hass–Bender/Henry versus formal SN2 reaction.
8
OH
Br
NO2
NO2
ence of strong bases such as sodium hydride or sodium
ethoxide is reported to afford the product of formal di-
rect SN2 displacement 34 without prior oxidation to
the aldehyde in the Hass–Bender sense (Scheme 2). An
SRN1 mechanism has been invoked to account for this
transformation.9
3
Cl
Cl
9
10
OH
Me
Br
Me
4
11
12
When p-nitrobenzylbromide 15 was reacted with 2-
nitropropane in the presence of TBAF the Hass–Bender/
Henry reaction product 17 was isolated in very high
yield (see entry 6).10 However, we found that when p-
nitrobenzylchloride was subjected to our reaction condi-
tions compound 34 was indeed produced in 85% with
only 8% of the desired compound 17 being formed
(entry 7).
F
F
OH
F
F
NO2
Br
5
89
14
13
OH
NO2
X=Br 15
X=Cl 16
X
6
7
94
8
O2N
O2N
17
Kornblum has described the leaving group importance
in partitioning between the Hass–Bender oxidation
and an SRN1 reaction.9a,11 Thus under the conditions
described here an SRN1 mechanism can compete with,
and even take precedence over the Hass–Bender oxida-
tion/Henry reaction sequence to produce products such
as 34 as long as the benzylic chloride is electron deficient
enough to enter into the SRN1 manifold.12,13
OH
Br
NO2
8
84
46
57
63
91
MeO2C
MeO2C
19
18
OH
O
Cl
NO2
O
O
9
O
20
21
OH
In summary, we have demonstrated a tandem Hass–
Bender oxidation/Henry reaction sequence as a facile
entry into dimethylnitro alcohols from a variety of
benzylic halides and 2-nitropropane. The use of TBAF
as the promoter is essential for the tandem sequence to
proceed. Although not explored to its fullest extent, this
methodology may also be applicable to non-benzylic ha-
lides based on the results in entries 14 and 15. Further
exploration of nitroalkanes other than 2-nitropropane
in this transformation is underway in our laboratory.
Br
NO2
10
11
12
MeS
MeS
23
22
OH
Br
NO2
Ph
Ph
24
25
OH
O
MeO2C
Cl
O
NO2
MeO2C
26
27
Acknowledgments
OH
Br
NO2
13
14
15
84
40
73
We acknowledge the members of Eli Lilly & CompanyÕs
analytical laboratory for help in full characterization of
the final dimethylnitro alcohols disclosed in this letter.
N
28
·HBr
N
29
O
O
Br
NO2
OH
References and notes
30
31
OH
1. (a) Colvin, E. W.; Beck, A. K.; Seebach, D. Helv. Chim.
Acta 1981, 64, 2264; (b) Hurd, C. D.; Nilson, M. E. J. Org.
Chem. 1955, 20, 927; (c) Rosini, G.; Ballini, R. Synthesis
1983, 543; (d) Baumberger, F.; Vasella, A. Helv. Chim.
Acta 1983, 66, 2210.
Br
NO2
32
33

4538
T. A. Klein, J. M. Schkeryantz / Tetrahedron Letters 46 (2005) 4535–4538
2. (a) Henry, L. C.R. Hebd. Seances Acad. Sci. 1895, 120,
7. TBAF was purchased from Aldrich and used as received.
No attempt was made to quantify or remove water in the
TBAF solution.
1265; (b) Rosini, G. In Comprehensive Organic Synthesis;
Trost, B. M., Heathcock, C. H., Eds.; Pergamon Press:
New York, 1991; Vol. 2, pp 321–340.
8. For an example of an in situ generation of the free base of
this compound see: Wittenberger, S. J.; Baker, W. R.;
Donner, B. G. Tetrahedron 1993, 49, 1547–1556.
9. (a) Kornblum, N.; Swiger, R. T.; Earl, G. W.; Pinnick, H.
W.; Stuchel, F. W. J. Am. Chem. Soc. 1970, 92, 5513; (b)
Kornblum, N. Angew. Chem., Int. Ed. Engl. 1975, 14, 734–
744; (c) Burt, B. L.; Freeman, D. J.; Gray, P. B.; Norris,
R. K.; Randles, D. Tetrahedron Lett. 1977, 35, 3063–3066;
(d) Kim, J. K.; Bunnett, J. F. J. Am. Chem. Soc. 1970, 92,
7463–7464.
10. For a report which describes the direct SN2 displacement
of benzylic bromides with an alkylnitroacetate to provide
compounds related to 34 see: Gogte, V. N.; Natu, A. A.;
Pore, V. S. Synth. Commun. 1987, 17, 1421–1429.
11. The subsequent Henry reaction was not observed under
the conditions reported by Kornblum.
12. An excellent discussion describing the criteria for entering
the SRN1 reaction manifold is located in the following: (a)
Kornblum, N. Angew. Chem., Int. Ed. Engl. 1975, 14, 734–
744; (b) Beraud, V.; Perfetti, P.; Pfister, C.; Kaafarani, M.;
Vanelle, P.; Crozet, M. P. Tetrahedron 1998, 54, 4923–
4934; (c) Costentin, C.; Hapiot, P.; Medebielle, M.;
Saveant, J.-M. J. Am. Chem. Soc. 2000, 122, 5623–5635.
13. The importance in the nature of the leaving group has
been reported: (a) Kerber, R. C.; Urry, G. W.; Kornblum,
N. J. Am. Chem. Soc. 1965, 87, 4520; (b) Kornblum, N.;
Pink, P.; Yorka, K. J. Am. Chem. Soc. 1961, 83,
2779.
3. Hass, H. B.; Bender, M. L. J. Am. Chem. Soc. 1949, 71,
1767.
4. HMPP has previously been used as a base in the Henry
reaction; see: Simoni, D.; Invidiata, F. P.; Manfrenidi, S.;
Ferroni, R.; Lampronti, I.; Roberti, M.; Pollini, G. P.
Tetrahedron Lett. 1997, 38, 2749.
5. Procedure for the preparation of compound 8: To a stirred
solution of 2-chlorobenzylbromide (0.25 g, 1.22 mmol) in
2 mL of 2-nitropropane is added a 1.0 M solution of
TBAF in THF (1.8 mL, 1.8 mmol, 1.5 equiv). The reaction
mixture is stirred for 12 h and partitioned between ethyl
acetate and saturated aqueous NH4Cl. The layers are
separated and the aqueous layer is extracted with ethyl
acetate (2 · 25 mL). The combined organic layers are
washed with water (2 · 25 mL), brine (25 mL) dried
(Na2SO4), filtered and concentrated in vacuo. Silica gel
chromatography (5–10% EtOAc/Hex) provided 0.26 g
(93%) of the desired compound 8. 1H NMR (400 MHz,
CDCl3) d 7.45 (d, J = 7.6 Hz, 1H), 7.22 (m, 3H), 5.82 (s,
1H), 2.72 (br s, 1H), 1.50 (s, 3H), 1.41 (s, 3H) ppm. 13C
NMR (75 MHz, CDCl3) d 136.3, 133.5, 129.8, 129.7,
129.3, 127.0, 93.1, 72.9, 24.4, 18.8 ppm. Anal. Calcd for
C10H12ClNO3: C 52.30, H 5.27, N 6.10; Found: C 52.16, H
5.22, N 6.05.
6. For example, attempts to silylate compound 8 using
sodium hydride and TBSCl in CH2Cl2 provided a quan-
titative conversion to the corresponding aldehyde.