Direct aldol and tandem Mannich reactions in room temperature ammonia solutions

Article abstract of DOI:10.1016/j.tetlet.2005.10.050

An economical, simple, and efficient direct aldol reaction via the double activation of both aldehydes and ketones by ammonia has been developed. An unprecedented tandem Mannich reaction was observed when hydroxybenzaldehydes, pyrrole-2-carboxyaldehyde, a

Full text of DOI:10.1016/j.tetlet.2005.10.050

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8685–8689
Direct aldol and tandem Mannich reactions in room
temperature ammonia solutions
Lichun Feng, Lijin Xu, Kimhung Lam, Zhongyuan Zhou,
C. W. Yip* and Albert S. C. Chan*
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis
and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Received 4 August 2005; revised 13 October 2005; accepted 14 October 2005
Abstract—An economical, simple, and efficient direct aldol reaction via the double activation of both aldehydes and ketones by
ammonia has been developed. An unprecedented tandem Mannich reaction was observed when hydroxybenzaldehydes, pyrrole-
2-carboxyaldehyde, and indole-3-carboxyaldehyde were employed to afford 2,2-dimethyl-6-aryl-4-pyrilidinones in moderate to good
yields.
Ó 2005 Elsevier Ltd. All rights reserved.
The aldol reaction is one of the most powerful transfor-
mations for new carbon–carbon bond formation. The
wide presence of aldol adducts in both natural products
and organic synthesis has intrigued a variety of synthetic
approaches, ranging from the reaction between alde-
hydes and preformed enolates to the direct aldol reac-
tion between aldehydes and unmodified ketones.1,2 In
terms of atom economy,3 the direct aldol reaction is
most desirable since no atom is wasted during the cou-
pling. Recently, amino acid (such as L-proline) and
amine acid complexes4 have been demonstrated to be
efficient catalysts for the asymmetric direct aldol reac-
tion. It is widely accepted that the reaction proceeded
via the double activation of both the donor and accep-
tor. As a versatile and low cost nitrogen source, ammo-
nia has been widely employed in the organic synthesis,
particularly in the multi-component reactions, such as
a-aminoalkylation and a-aminoallylation of carbonyl
compounds.5 To the best of our knowledge, there is
no report on the direct aldol reaction carried out in
ammonia solution. We envision that ammonia may
function as an activator for both aldehydes and unmodi-
fied ketones and thus promote the direct aldol reaction
between aldehydes and unmodified ketones. In this
study, we have demonstrated that ammonia is indeed
an effective activator for the direct aldol reaction
between aldehydes and unmodified ketones in MeOH
solution. Besides, we also have discovered an efficient
and unprecedented ammonia participated multi-compo-
nent construction of 2,2-dimethyl-6-aryl-4-pyrilidinonesy.
To investigate the role of ammonia in the direct aldol
reaction, we chose the reaction between benzaldehyde
and acetone as a model reaction for study. Commer-
cially available 7 N ammonia in MeOH was chosen as
ammonia source. Acetone (10 mmol) and benzaldehyde
(1 mmol) were added to the solution of 7 N ammonia in
MeOH (1 mL) in DMSO (2.5 mL) at room temperature
and the solution was stirred for 16 h. After normal
work-up and silica gel chromatography,6 the desired
aldol product was obtained in 45% yield. From the
crude 1H NMRspectrum, the ratio of four possible
products was found to be I–II–III–IV = 10:1:2.6:0
(Eq. 1, Table 1, entry 1). A preliminary solvent screening
revealed that MeOH was the best solvent that favored
the direct aldol reaction, giving the aldol adduct in very
high ratio (Table 1, entry 2). Efforts to lower the amount
of ammonia by using 100 lL of 7 N ammonia in MeOH
(about 0.7 mmol) led to the incompletion of the reaction
(about 25% conversion). It was also found that excess of
acetone (10 equiv) was crucial for the formation of the
aldol adduct. It was noteworthy that the reaction carried
out in 2.5 mL H2O also afforded the aldol adduct in a
relatively high ratio (Table 1, entry 3). The presence of
Keywords: Tandem; Aldol reaction; Mannich reaction; Ammonia
solutions.
*
Corresponding authors. Tel.: +852 27665222; e-mail addresses:
bccwyip@polyu.edu.hk; bcachan@polyu.edu.hk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.050

8686
L. Feng et al. / Tetrahedron Letters 46 (2005) 8685–8689
Table 1. Direct aldol reaction of benzaldehyde and acetone under different conditions
Ammonia
solution
Ph
HN
O
Ph
O
OH
O
O
O
PhCHO +
+
+
+
HN
r.t. 16 h
Ph
Ph
ð1Þ
Ph
III
I
II
IV
Entry
Ammonia source
Solvent
Ratios of I–II–III–IVa
1
2
3
4
5
6
7 N NH3 in MeOH 1 mL
7 N NH3 in MeOH 1 mL
7 N NH3 in MeOH 1 mL
7 N NH3 in MeOH 1 mL
25% NH4OH 0.5 mL
Ammonia gas
2.5 mL DMSO
2.5 mL MeOH
2.5 mL H2O
2.5 mL CH2Cl2
2.5 mL H2O
Neat
10:1:2.6:0b
42:3:1:0
30:0:1:3.2b
24:6:2:1b
23:0:1:5
8:6:1:2c
a Determined based on the integration of crude 1H NMR.
b The reaction cannot proceed completely within the specified time, about 5–10% benzaldehyde was observed from the crude NMRspectrum.
c Ammonia gas was bubbled into the mixture of benzaldehyde (1 mmol) and acetone (10 mmol) for 5 min, and then reacted at room temperature for
16 h.
water resulted in the increase of the condensation prod-
uct and the incompletion of the reaction. NH4OH solu-
tion was also studied and the same trend was observed
as shown in entry 3 (Table 1, entry 5). Considering the
factors of economy and operational simplicity, neat con-
dition was studied as well. Unfortunately, no selectivity
between I and II was observed (Table 1, entry 6).
With these interesting results in hand, we next studied
the scope of the reaction by using different aldehydes
and the results are summarized in Table 2.11 The reac-
tion worked smoothly for benzaldehyde derivatives with
both electron-withdrawing and electron-donating func-
tional groups (entries 2–8) and heteroaromatic alde-
hydes (entries 11 and 12) to afford the corresponding
Table 2. Direct aldol reaction of different aldehydes and acetone
2N NH3 in MeOH (3.5 mL)
r.t. 16 h
OH O
O
RCHO
+
ð2Þ
R
Entry
1
Aldehydes
Products
OH
Yield (%)a
O
70
76
CHO
1a
1b
OH
O
2
3
4
5
Cl
CHO
Cl
OH
O
CHO
O2N
80
83
75
O2N
O2N
1c
OH
O
CHO
O2N
Br
1d
OH
O
Br
F
CHO
1e
OH
O
6
77
CHO
F
1f

L. Feng et al. / Tetrahedron Letters 46 (2005) 8685–8689
8687
Table 2 (continued)
Entry
Aldehydes
Products
Yield (%)a
60
OH
O
CHO
OMe
7
8
9
OMe
1g
OMe OH
O
OMe
CHO
45
76
MeO
MeO
MeO
OMe
OH
1h
O
CHO
1i
O
CHO
HO
10
73
1j
11
12
76
80
48
O
N
O
CHO
CHO
OH O 1k
N
OH
OH
O
1l
O
OH
OH
13
Cl3C
Cl3C
1m
a Isolated yield.
aldol products in moderate to high yields. Besides, naph-
thaldehyde and anthracenecarboxyaldehyde also exhi-
bited high reactivity (entries 9 and 10). Chloral, which
existed in the form of hydrate also afforded the desired
aldol product in 48% yield. The reaction was also
extended to 2-butanone and 3-pentanone with moderate
regio- and diastereoselectivities (Scheme 1).
It is worth noting that 2,2-dimethyl-6-aryl-4-pyrilidi-
nones were formed as major products instead of the
desired aldol adducts when benzaldehyde derivatives
with a hydroxy group at ortho or para position were
employed in the above direct aldol reaction (Table 3,
entries 1–3).11 This provided an efficient and unprece-
dented synthetic route toward 2,2-dimethyl-6-aryl-4-
2N NH3 in MeOH
O
O
OH
Ph
O
OH
Ph
3.5 mL
+
+
PhCHO
r.t. 16 h, 65%
Regioselectivity: 64
:
36
syn:anti
=
60:40
2N NH3 in MeOH
O
O
OH
Ph
3.5 mL
+
PhCHO
r.t. 16 h, 70%
syn:anti
= 64:36
Scheme 1.

8688
L. Feng et al. / Tetrahedron Letters 46 (2005) 8685–8689
Table 3. Tandem Mannich reactions between aldehydes and acetone
Entry
1
Aldehyde
Product
OH
Yield (%)a
85
O
OH
2a
CHO
HN
O
2
3
80
75
CHO
HO
HO
2b
HN
OH
CHO
OH
O
2c
HN
MeO
MeO
O
CHO
4
45b
N
H
N
H
2d
N
H
O
50b
N
H
2e
5
N
CHO
HN
H
a Isolated yield.
b The reaction was slow under the reaction condition, about 70% conversion was observed within 2 days.
pyrilidinones, which were difficult to achieve using other
methods.7 In addition to hydroxybenzaldehydes, indole-
3-carboxyaldehyde and pyrrole-2-carboxyaldehyde also
showed the same activity although relatively lower yields
were obtained in these cases (Table 3, entries 4 and 5).
amino-hydroxy intermediates can either react with en-
amine derived from acetone and ammonia via pathway
I to afford the aldol adducts9 or form imines, which will
react with enamine derived from acetone via pathway II
to produce the tandem Mannich products (Fig. 1). As
for hydroxybenzaldehydes, pyrrole-2-carboxyaldehyde
and indole-3-carboxyaldehyde, the presence of proton
on either oxygen or nitrogen may favor the formation
of imines and consequently pathway II. To test the spe-
cial role of ammonia in this reaction, we conducted the
Although the precise reaction mechanism is still unclear,
we speculate that the reaction might proceed through
gem-amino-hydroxy intermediates of aldehydes formed
from aldehydes and ammonia in methanol.8 The gem-
NH2
H
OH
H
N
_
OH O
NH3
+ H2O
- NH3
OH
N
H
H
R
H
N
R
R
NH2
R
HO
_
Pathway I
H2O
O
NH2
NH2
H
H
H
N
N
N
R
NH
R
NH2
_
R
NH2
R
H2O
Pathway II
+ H2O
HN
R
HN
_
O
NH3
R
NH
Figure 1. Proposed reaction pathway for the ammonia promoted direct aldol and tandem Mannich reaction.

L. Feng et al. / Tetrahedron Letters 46 (2005) 8685–8689
8689
Yamamoto, H. Acc. Chem. Res. 2004, 37, 570–579; (f)
Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res.
2004, 37, 580–591.
reaction of benzaldehyde and acetone in 2 N solution of
MeNH2 in MeOH (3.5 mL) and no desired aldol adduct
or tandem Mannich product was obtained. This might
be due to the difficulty in forming the gem-amino-hydr-
oxy intermediate.
5. (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210; (b) Reeve, W.; Fine, L. W. J. Org. Chem. 1964,
29, 1148–1150; (c) Ugi, I.; Steinbrucker, C. Chem. Ber.
¨
1961, 94, 734–742; (d) Natchev, I. A. Tetrahedron 1988,
44, 1511–1522; (e) Do¨mling, A.; Ugi, I. Angew. Chem., Int.
Ed. 2000, 39, 3168–3210; (f) Sugiura, M.; Hirano, K.;
Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 7182–7183;
(g) Kobayashi, S.; Hirano, K.; Sugiura, M. Chem.
Commun. 2005, 104–106.
To summarize, we have developed an economical, sim-
ple, and efficient direct aldol reaction via the double acti-
vation of both aldehydes and ketones by ammonia.
Under the same condition, an unprecedented tandem
Mannich reaction was observed when hydroxybenzalde-
hydes, pyrrole-2-carboxyaldehyde, and indole-3-carb-
oxyaldehyde were employed to afford 2,2-dimethyl-6-
aryl-4-pyrilidinones. Since the racemic aldols can be
kinetically resolved using enzymes,10 the combination
of this approach with the enzyme catalyzed kinetic reso-
lution may provide an economical process for the prep-
aration of enantiomerically pure b-hydroxy ketones.
The study on the mechanism as well as the expansion
of the scope of the reaction is in progress.
6. Part of the aldol adducts existed in the form of imine or
enamine in the presence of excess ammonia, which was
transformed into the aldol adducts after silica gel
chromatography.
7. (a) Balasubramanian, M.; Padma, N. Tetrahedron 1963,
19, 2135–2143; (b) Davis, F. A.; Chao, B.; Rao, A. Org.
Lett. 2001, 3, 3169–3171.
8. Formation of gem-amino-hydroxy intermediate has been
observed by in situ 13C and 15N NMR. It can persist even
at 298 K. Xu, T.; Zhang, J.; Haw, J. F. J. Am. Chem. Soc.
1995, 117, 3171–3178.
9. Janda has reported a nornicotine catalyzed aqueous aldol
reaction in which a mechanism was proposed based on
the activation of aldehyde by the intermolecular hydro-
gen bond between water and aldehyde. Dickerson, T. J.;
Lovell, T.; Meijler, M. M.; Noodleeman, L.; Janda, K.
D. J. Org. Chem. 2004, 69, 6603–6609. The fact that
chloral hydrate can react with acetone in ammonia
solution may exclude the direct activation of aldehyde by
ammonia and support the gem-amino-hydroxy interme-
diate pathway.
Acknowledgments
We thank the University Grants Committee of Hong
Kong (Area of Excellence Scheme, AOE P/10-01) and
the Hong Kong Polytechnic University Area of Strategic
Development Fund for financial support of this study.
´
10. Edin, M.; Ba¨ckvall, J. E.; Cordova, A. Tetrahedron
References and notes
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11. General procedure for the direct aldol and tandem
Mannich reaction: To a 3.5 mL of 2 N ammonia solution
in methanol (prepared by diluting 1 mL of 7 N ammonia
solution in MeOH with 2.5 mL MeOH) was added
acetone (10 mmol, 735 lL), followed by 9-anthraldenyde
(1 mmol, 206 mg) at room temperature. The resulting
mixture was allowed to stir at ambient temperature for
16 h. The solvent was removed in vacuo and the residue
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1
colorless oily material in 73% yield (192.7 mg). H NMR
(500 MHz, CDCl3): d = 8.47 (s, 1H), 8.17 (s, 1H), 7.79 (d,
J = 8.5 Hz, 2H), 7.33–7.27 (m, 4H), 6.6–6.58 (m, 1H), 3.49
(dd, J = 10.5, 18.0 Hz, 2H), 2.66 (dd, J = 3.0, 18.0 Hz,
1H), 2.02 (s, 3H); 13C NMR(125 MHz, CDCl 3):
d = 209.3, 134.2, 133.1, 131.9, 129.6, 129.5, 129.4, 128.5,
127.3, 126.1, 125.9, 125.1, 123.7, 66.6, 50.7, 31.0; MS (EI):
m/z (relative intensity, %) = 264 (M+, 6), 246 (17), 203
(100), 178 (43), 76 (10); HR-MS: calcd for C18H16O2:
264.1150; found: 264.1155.
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