2-Quinolinecarboxaldehyde: an unusual partner in the Henry reaction and subsequent elimination

Article abstract of DOI:10.1016/j.tetlet.2008.07.044

2-Quinolinecarboxaldehyde participates in a standard Henry reaction when combined with a nitroalkane and catalytic amounts of base. However, water is not readily eliminated from the resulting β-nitro alcohol intermediate to form the expected nitroalkene. Instead, the elimination of nitrous acid is observed furnishing an unexpected ketone product.

Full text of DOI:10.1016/j.tetlet.2008.07.044

Tetrahedron Letters 49 (2008) 5511–5514
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Tetrahedron Letters
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2-Quinolinecarboxaldehyde: an unusual partner in the Henry reaction
and subsequent elimination
*
Ashley Nomland, Ivory D. Hills
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Quinolinecarboxaldehyde participates in a standard Henry reaction when combined with a nitroalkane
and catalytic amounts of base. However, water is not readily eliminated from the resulting b-nitro alcohol
intermediate to form the expected nitroalkene. Instead, the elimination of nitrous acid is observed
furnishing an unexpected ketone product.
Received 30 May 2008
Revised 1 July 2008
Accepted 7 July 2008
Available online 11 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Nitroalkenes are useful intermediates in organic synthesis and
can generally be prepared from the dehydration of a b-nitro alco-
hol, which in turn can be synthesized from the aldol-like reaction
of a nitroalkane and an aldehyde, also known as the Henry reaction
(Scheme 1).1 The Henry reaction is known to be catalyzed by both
bases and acids, and the subsequent formal elimination of water
can be induced thermally or promoted by the addition of other
reagents, such as dicyclohexylcarbodiimide (DCC) or methane-
sulfonyl chloride (MsCl).2
During our ongoing synthetic efforts in drug discovery, we
sought to utilize the nitroalkene intermediate to access primary
and secondary carbinamines.3 Toward that end, we employed the
microwave-mediated method described by Texier-Boullet and
coworkers, which allows for the rapid isolation of nitroalkenes.4
Using this protocol, we isolated nitroalkenes derived from simple
cyclic aldehydes in a straightforward manner. However, when
2-quinolinecarboxaldehyde was used, an unexpected methyl ketone
product was isolated instead of the expected nitroalkene (Scheme
2). This unprecedented transformation piqued our interest; herein
we present the results from our preliminary efforts to explore the
scope and gain some understanding of this reaction.
approximately 10 min under microwave heating.5 These condi-
tions were employed when we made our initial observation of a
ketone product instead of a nitroalkene; however, analysis of these
reactions by LC–MS showed the presence of multiple species, and
the isolated yield was quite variable. We attribute these erratic
outcomes to the lack of solvent and the viscous nature of the reac-
tions. An additional complication was the occasional observation
by LC–MS of Mannich-type products that appeared to incorporate
the piperidine catalyst to form b-nitro amines. These observations
prompted us to explore conditions utilizing solvents, in order to
facilitate efficient mass transport; furthermore, we chose to
employ 1,1,3,3-tetramethylguanidine (TMG) instead of piperidine,
since it is also known to catalyze the Henry reaction and is unlikely
to form Mannich-type products.6
We monitored our initial optimization reactions by LC–MS and
observed that in general these reactions very cleanly and rapidly
(minutes) show consumption of aldehyde to generate a b-nitro
alcohol intermediate, which is followed by slow (hours) formation
of the final ketone products (Table 1). The b-nitro alcohol inter-
mediate appears to form easily in all of the solvents we examined;
however, only in the less polar solvents of dichloroethane and
toluene did the intermediate readily disappear to afford the ketone
product (entries 1–5).7 Additional catalyst did not seem to lead
to a more efficient reaction (entries 6 and 7). However, the
The method by Texier-Boullet and coworkers calls for the disso-
lution of the aldehyde in the nitroalkane with no additional solvent
and use of piperidine as the catalyst. The reaction is then stirred for
O
OH
Catalytic
Base
NO2
Me
elimination
NO2
NO2
R
R
H
R
Henry
Reaction
β-nitro alcohol
intermediate
Scheme 1. Standard Henry reaction followed by dehydration.
* Corresponding author. Tel.: +1 215 652 4756; fax: +1 215 652 3971.
E-mail address: ivory_hills@merck.com (I. D. Hills).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.044

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A. Nomland, I. D. Hills / Tetrahedron Letters 49 (2008) 5511–5514
N
NO2
not observed
OH
catalytic
base
O
N
NO2
N
H
nitromethane
solvent
β-nitro alcohol
O
N
intermediate
microwave
heating
Me
observed
Scheme 2. Expected versus unexpected elimination products of a b-nitroalcohol derived from 2-quinolinecarboxaldehyde.
Table 1
transformation is sensitive to concentration and a dilute reaction
performed at 0.1 M did not proceed past intermediate formation
(entries 8 and 9), while conducting the reaction at 2.0 M led to
the highest HPLC yields (entries 10 and 11).
Optimization of the reaction conditions
O
O
catalytic
TMG
NO2
N
N
H
Me
Me
Next we chose to examine the scope of nitroalkanes that can be
employed in this unique transformation. We were pleased to dis-
cover that when 2-quinolinecarboxaldehyde and nitromethane
are combined in the presence of 10% TMG in 2.0 M toluene, the de-
sired methyl ketone can be isolated in 45% and 60% yield at 50 and
110 °C, respectively (Table 2, entries 1 and 2).8 Both nitroethane
and nitropropane can be utilized to furnish the ethyl (63% yield)
and propyl (37% yield) ketones (entries 3 and 4). Secondary nitro-
alkanes react more sluggishly and 2-nitropropane affords the
i-propyl ketone in only 19% yield, while similarly nitrocyclo-
pentane leads to only 16% isolated yield of the corresponding
ketone (entries 5 and 6).
50 °C
6 hours
Entry
Solvent
Concn (M)
Catalyst loading (%)
Yielda (%)
1
2
3
4
5
6
7
8
9
Toluene
Dichloroethane
Methanol
Ethyl acetate
Acetonitrile
Toluene
Dichloroethane
Toluene
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.1
2.0
2.0
10
10
10
10
10
20
20
10
10
10
10
21
21
0b
0b
0b
22
21
0b
0b
37
30
Dichloroethane
Toluene
Dichloroethane
10
11
We were curious to verify whether or not this unexpected
transformation was indeed uniquely effective for 2-quinolinecar-
boxaldehyde. Employing our optimized reaction conditions with
2-napthaldehyde and 3-quinolinecarboxaldehyde did not lead to
a
Average of two HPLC yields based on a calibrated internal standard.
No product was observed by HPLC; however, significant nitro alcohol inter-
b
mediate was observed.
Table 2
Scope of nitroalkanes in ketone formation
O
O
NO2
R
N
N
10% TMG
H
R
toluene
2.0 M
Entry
Nitroalkane
Temperature (°C)
Product
Yielda (%)
O
O
O
O
NO2
Me
N
N
N
N
1
2
50
110
45
60
Me
NO2
Me
3
4
5
110
110
110
63
37
19
Me
NO2
Me
Me
NO2
Me
Me
Me
NO2
Me
O
N
6
110
16
a
Average of two isolated yields.

A. Nomland, I. D. Hills / Tetrahedron Letters 49 (2008) 5511–5514
5513
O
O
10% TMG
NO2
2.0 M toluene X
H
Me
Me
110 ºC
X
X
X = C or N
No ketone formation.
O
O
10% TMG
N
N
H
Me
2.0 M toluene
110 ºC
15% isolated yield
Scheme 3. Structural analogues of 2-quinolinecarboxaldehyde do not lead to a ketone product (top); 2-pyridinecarboxaldehyde does furnish a ketone product (bottom).
Loss of
H2O
Loss of
HNO2
O
H
HO
H
X
NO2
NO2
N
Me
H
H
H
X = N
X = C
Scheme 4. Substrate-dependent elimination leading to different types of products.
O
O
HO
Loss of
HBr
H
Br
NO2
10% TMG
N
N
NO2
Br
N
H
H
No Loss
of HNO2
NO2
2.0 M toluene
110 °C
40% NMR yield
Scheme 5. Use of bromonitromethane to access a nitromethyl ketone.
any analytical evidence (LC–MS or NMR) of methyl ketone forma-
tion (Scheme 3, top); however, when 2-pyridinecarboxaldehyde
was employed, 2-acetylpyridine was isolated, albeit in low yield
(Scheme 3, bottom).9
Thus after the putative formation of a mesylate leaving group, 2-ni-
tro-vinylquinoline can be smoothly generated in 60% yield
(Scheme 6).
In summary we have shown that 2-quinolinecarboxaldehyde
can smoothly undergo the standard Henry reaction with a variety
of nitroalkanes. However, instead of the typical loss of water to
yield nitroalkenes, an apparent loss of nitrous acid is observed, fur-
nishing ketone products. We do not believe that HNO2 elimination
is a particularly facile process and it is clearly not the preferred
path when a substrate capable of eliminating HBr is employed.
While the standard elimination of water is not readily observed,
the addition of MsCl allows for the formation of the expected
2-nitro-vinylquinoline. We continue to study the mechanistic
aspects of this unique transformation as well as try to extend this
reaction to an aldehyde substrate other than 2-quiniolinecarbox-
aldehyde. We hope to report the results of these investigations in
due course.
With these observations in hand, it is apparent that the sub-
strate-dependent formation of either nitroalkenes or ketones from
a b-nitro alcohol can be explained by two different elimination
reactions (Scheme 4). Thus the standard dehydration reaction
yields the expected nitroalkene; however, the formal elimination
of nitrous acid ultimately furnishes the ketone. While we do not
fully understand the role of the nitrogen atom in the 2-quinoline
scaffold, clearly it facilitates the loss of HNO2 over that of H2O.10
We were intrigued by this apparent reversal in elimination
propensity between water and nitrous acid; however, we do not
believe that the presence of the quinoline nitrogen confers
excellent elimination ability to HNO2. When we examined
bromonitromethane under our reaction conditions, we observed
the formation of a nitromethyl ketone and were unable to acquire
any evidence of HNO2 elimination (Scheme 5). We believe this
compound to be derived from the elimination of HBr from the
standard b-nitro alcohol intermediate. Finally, we have been able
to direct the b-nitro alcohol intermediate derived from 2-quinoline-
carboxaldehyde and nitromethane toward the nitroalkene product
by inducing the formal elimination of water by addition of MsCl.2c,d
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.044.
References and notes
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Angew. Chem., Int. Ed. 2004, 43, 5442–5444; (d) Boruwa, J.; Gogoi, N.; Saikia, P.
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O
N
NO2
1. 10% TMG
NO2
Me
N
H
2. MsCl
toluene
60% isolated yield
Scheme 6. Reaction with MsCl leads to nitroalkene formation.

5514
A. Nomland, I. D. Hills / Tetrahedron Letters 49 (2008) 5511–5514
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7. The reactions performed with more polar solvents such as methanol, ethyl
acetate, and acetonitrile do furnish product after approximately 24 h of
heating.
8. 2-Quinolinecarboxaldehyde (200 mg, 1.27 mmol, 1.00 equiv) and the
corresponding nitroalkane (3.82 mmol, 3.00 equiv) were combined in toluene
0.127 mmol, 10.0%) was added and an immediate color change was observed.
The vial was sealed and the reaction mixture heated with stirring at either
50 °C or 110 °C until no starting material or intermediate was observed by LC–
MS. The reaction mixture was cooled to room temperature, quenched with
sodium bicarbonate, and extracted with dichloromethane. The organic layer
was dried with sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was dissolved in dichloromethane and purified by
column chromatography (80% hexanes/20% ethyl acetate) or (80%
dichloromethane/20% ethyl acetate).
9. Nitroalkene product was not observed (LC–MS and NMR) in any of these
reactions.
10. It has been suggested that elimination of nitrous acid can only occur when
acidic protons are present, beta to the nitro group. For other examples of HNO2
loss in synthetic chemistry, see: (a) Ballini, R.; Bosica, G.; Fiorini, D.; Righi, P.
Synthesis 2002, 681–685; (b) Ballini, R.; Bosica, G.; Fiorini, D.; Gil, M. V.;
Palmieri, A. Synthesis 2004, 605–609.
(636 lL, 2.00 M) in a microwave vial containing a teflon coated magnetic stir