α-aminoallylation of aldehydes in aqueous ammonia

Article abstract of DOI:10.1039/b415264f

α-Aminoallylation of aldehydes in aqueous ammonia has been developed; commercial aqueous ammonia was successfully used, and this method does not require anhydrous conditions thus leading to easy and practical operations.

Full text of DOI:10.1039/b415264f

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a-Aminoallylation of aldehydes in aqueous ammonia
Shu¯ Kobayashi,* Keiichi Hirano and Masaharu Sugiura
Received (in Cambridge, UK) 1st October 2004, Accepted 10th November 2004
First published as an Advance Article on the web 26th November 2004
DOI: 10.1039/b415264f
carried out for 6–12 h in the presence of 10 mol% of DBSA (entries
a-Aminoallylation of aldehydes in aqueous ammonia has been
developed; commercial aqueous ammonia was successfully
used, and this method does not require anhydrous conditions
thus leading to easy and practical operations.
15 and 16). It should be noted that the result was further improved
compared to that under the reported conditions (NH3/EtOH)4
(entry 17).
With the conditions using DBSA, a-aminoallylation of various
aldehydes in aqueous ammonia was examined (Table 2).{ It was
found that reactions of benzaldehyde (1b) and its para-substituted
derivatives 1c–d showed moderate chemoselectivities (entries 1–3).
It was unexpected to find that aromatic aldehydes, which exhibited
high selectivity under the reported conditions,4 provided lower
chemoselectivity than 3-phenylpropanal (1a). On the other
hand, salicylaldehyde (1e), heteroaromatic aldehydes 1f–1l, and
cinnamaldehyde (1m) provided the corresponding amines in high
Although ammonia is a readily available nitrogen source, it has
been barely utilized in C–N/C–C bond-forming reactions such as
the Mannich reaction.1 Especially, use of aqueous ammonia has
often been avoided despite its advantages in terms of handling and
safety.2 This might be due to its incompatibility with water-
sensitive, hydrophobic reagents and substrates.3 We have recently
found that aldehydes 1 react with ammonia and allylboronates 2
under mild conditions to afford homoallylic primary amines 3 with
high chemoselectivity (amine 3 vs. alcohol 4) (Scheme 1).4 In this
process, liquid ammonia was employed to saturate the solvent with
ammonia, which was crucial to attain high chemoselectivity.
Although aqueous ammonia could be used as an ammonia source
in an organic solvent such as ethanol, the chemoselectivity was
decreased. Meanwhile, organic reactions only in water have
recently attracted a great deal of attention, not only because of
environmental friendliness and easy handling, but also because of
the unique reactivities and selectivities often observed.5 In this
context, we have been interested in the development of
a-aminoallylation in aqueous ammonia, and herein report a
solution of this issue.
Table 1 a-Aminoallylation of 3-phenylpropanal (1a) with
allylboronate 2aa
Yield (%)b
At the outset, a-aminoallylation of 3-phenylpropanal (1a) as a
probe was examined. Reactions were conducted with an aldehyde
(0.5 mmol) and allylboronate 2a (0.6 mmol) in 25% aqueous
ammonia (1 mL) in the absence or presence of an additive at rt
(Table 1). While the chemoselectivity was much lower without any
additives (entry 1), it was found that acidic and anionic surfactant
molecules (DBSA and lauric acid as well as SDS and SDBS) were
effective as additives (entries 2–9).6 Among these additives, DBSA
was the best. It was suggested that both the acidic and
hydrophobic parts of DBSA played an important role, since
toluenesulfonic acid showed much lower activity (entry 10). With
DBSA, further optimization of reaction conditions was performed
(entries 11–16); the best result was obtained when reactions were
Entry Additive (mol%)
3a
4a
1
2
3
4
5
6
7
None
DBSAc (10)
34
72
67
56
72
44
32
39
6
19
9
7
21
14
Lauric acid (10)
SDSd (10)
SDBSe (10)
CTABf (10)
3-(Dodecyldimethylammonio)propane-
sufonate (10)
8
9
Triton X-100g (10)
PEG-400#h (10)
TsOH (10)
33
44
25
69
65
42
72
12
28
8
7
4
4
6
3
4
10
11
12
13
14
15
16
17j
DBSA (5)
DBSA (20)
DBSA (50)
DBSA (10) (4 h)
DBSA (10) (6 h)
DBSA (10) (12 h)
– (in NH3/EtOH)
86 (79i)
84
78
3
a
Reactions were performed using aldehyde 1a (0.5 mmol),
allylboronate 2a (0.6 mmol), and an additive (10 mol%) in 25%
b
aqueous ammonia at rt for 2h. Determined by 1H NMR analysis
using 1,2,4,5-tetramethylbenzene as an internal standard.
c
d
e
Dodecylbenzenesulfonic acid. Sodium dodecyl sulfate. Sodium
f
dodecylbenzenesulfonate.
Polyethylene glycol tert-octylphenyl ether. Polyethylene glycol
Cetyltrimethylammonium
bromide.
g
h
Scheme 1 a-Aminoallylation of aldehydes using ammonia.
i
(MW ca. 400). Isolated yield. Conducted in ammonia-saturated
j
ethanol (ref 4).
*skobayas@mol.f.u-tokyo.ac.jp
104 | Chem. Commun., 2005, 104–106
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Table 2 a-Aminoallylation of aldehydes 1 with 2a in aqueous
ammonia using DBSAa
Yield (%)
Entry
R (1)
Time/h
3b
4c
1
2
3
4
5
6
7
8
9
Ph (1b)
6
6
6
6
6
2
2
6
2
2
2
2
6
2
6
61 (3b)
60 (3c)
60 (3d)
75 (3e)
88 (3f)
85 (3g)
83 (3h)
60 (3i)
95 (3j)
53 (3k)
93 (3l)
78 (3m)
68 (3n)
49 (3o)
2 (3p)
15 (4b)
8 (4c)
17 (4d)
0 (4e)
0 (4f)
0 (4g)
0 (4h)
15 (4i)
0 (4j)
2 (4k)
4 (4l)
15 (4m)
trace (4n)
6 (4o)
p-NO2C6H4 (1c)
p-MeOC6H4 (1d)
o-HOC6H4 (1e)
2-Pyridyl (1f)
3-Pyridyl (1g)
4-Pyridyl (1h)
2-Thienyl (1i)
3-Thienyl (1j)
2-Furyl (1k)
Scheme 2 a-Aminocrotylation of aldehyde 1f in aqueous ammonia.
ammonia. Several effective conditions such as use of DBSA as an
additive were found. It should be noted that the use of commercial
aqueous ammonia makes the reaction easy and practical.
This work was partially supported by CREST, SORST, and
ERATO, Japan Science and Technology Agency (JST) and a
Grant-in-Aid for Scientific Research from Japan Society of the
Promotion of Science.
10
11
12
13
14
15
a
3-Furyl (1l)
(E)-PhCHLCH (1m)
c-C6H11 (1n)
n-C5H11 (1o)
n-C9H19 (1p)
52 (4p)
Reactions were performed using aldehyde
1
(0.5 mmol),
allylboronate 2a (0.6 mmol), and DBSA (10 mol%) in 25% aqueous
b
c
ammonia at rt for 2h. Isolated yields. Determined by 1H NMR
analysis using 1,2,4,5-tetramethylbenzene as an internal standard.
Shu¯ Kobayashi,* Keiichi Hirano and Masaharu Sugiura
Graduate School of Pharmaceutical Sciences, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
E-mail: skobayas@mol.f.u-tokyo.ac.jp; Fax: 81 3 5684 0634;
Tel: 81 3 5841 4790
yields with high chemoselectivities in most cases (entries 4–12).
Interestingly, 3-furaldehyde (1l) or 3-thiophenecarboxaldehyde (1j)
showed much better reactivity than their 2-substituted analogues.
As for reactions of aliphatic aldehydes, cyclohexanecarboxalde-
hyde (1n) and n-hexanal (1o) gave amines 3n–o in moderate yields
with good chemoselectivity (entries 13 and 14), whereas n-decanal
(1p), a highly hydrophobic linear aldehyde, reversed chemoselec-
tivity to give alcohol 4p as the major product. This suggested that
hydrophobicity of aldehydes is one of the key factors determining
chemoselectivity in this reaction. Although chemoselectivities were
not perfect in several cases, it is noted that the simple acid–base
extraction enables easy isolation of 3.7
Notes and references
{ General procedure of a-aminoallylation of aldehydes using DBSA in
aqueous ammonia: A mixture of allylboronate 2 (0.6 mmol) and
dodecylbenzenesulfonic acid (DBSA) (10 mol%) in 25 wt% aqueous
ammonia (1 mL, ca. 30 equiv.) was stirred at rt for 30 min. To the
suspension was added aldehyde 1 (0.5 mmol), and the mixture was stirred
vigorously at rt for the indicated time. The mixture was acidified with 3 N
hydrochloric acid and extracted with dichloromethane (3 6 20 mL); the
combined organic phases afforded crude alcohol 4. The aqueous layer was
basified with 6 N sodium hydroxide and extracted with dichloromethane
(3 6 20 mL). The combined organic phases were dried over Na2CO3,
filtered, concentrated in vacuo, and purified by preparative TLC (hexane/
isopropylamine) to give amine 3.
While DBSA was found to play an important role in the present
reaction, the reaction of 1a was found to work well in 25%
aqueous ammonia and THF (1/1) without DBSA at rt for 2 h
leading to almost the same result as the DBSA system (3a: 79%,
4a: 12%). Two liquid phases were observed in this system, and a
turbid mixture similar to that observed in the DBSA system was
formed with vigorous stirring. However, these conditions exhibited
low substrate generality, indicating a strong dependence on
aldehyde structure.
1 For reviews: (a) R. Jeyaraman, in Synthetic Reagents, ed. J. S. Pizey and
E. Horwood, Wiley, New York, 1983, vol. 5, pp. 9–83; (b) F. F. Blicke,
Org. React., 1942, 1, 303; (c) G. Hellmann and H. Opitz, in
a-Aminoalkylierung, Verlag Chemie, Weinheim, 1961; (d) A. Do¨mling
and I. Ugi, Angew. Chem. Int. Ed., 2000, 39, 3168.
2 For examples on the use of aqueous ammonia in C–N/C–C bonds-
forming reactions, see: (a) D. Landini, F. Montanari and F. Rolla,
Synthesis, 1979, 26; (b) I. A. Natchev, Tetrahedron, 1988, 44, 1511; (c)
P. A. Coghlan and C. J. Easton, J. Chem. Soc., Perkin Trans. 1, 1999,
2659; (d) for examples on the use of ammonium salts in water, see:
P. A. Grieco, S. D. Larsen and W. F. Fobare, Tetrahedron Lett., 1986,
27, 1975; (e) R. Bossio, S. Marcaccini and R. Pepino, Liebigs Ann.
Chem., 1990, 935.
Next, a-aminocrotylation in aqueous ammonia was investigated.
Whereas 3-phenylpropanal (1a) and benzaldehyde (1b) afforded
the corresponding amines in moderate yields,8 2-pyridinecarbox-
aldehyde (1f) exhibited high reactivity to give amine 5f in high yield
with high chemo- and diastereoselectivity (Scheme 2). In these
cases, high stereospecificity (Z to syn and E to anti) was observed.
In conclusion, we have demonstrated that a-aminoallylation of
aldehydes with allylboronates proceeded smoothly in aqueous
3 A water-soluble rhodium catalyst was employed for reductive amination
of aromatic aldehydes using aqueous ammonia. Highly selective
formation of primary amines was attained under these conditions:
T. Gross, A. M. Seayad, M. Ahmad and M. Beller, Org. Lett., 2002, 4,
2055.
4 M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc., 2004, 126,
7182.
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5 For reviews: (a) Organic Synthesis in Water, ed. P. A. Grieco, Blackie
Academic and Professional, London, 1998; (b) C.-J. Li and T.-H. Chan,
Organic Reactions in Aqueous Media, Wiley, New York, 1997; (c) see
also, D. Sinou, Adv. Synth. Catal., 2002, 344, 221; (d) U. M. Lindstro¨m,
Chem. Rev., 2002, 102, 2751; (e) K. Manabe and S. Kobayashi, Chem.
Eur. J., 2002, 8, 4094.
K. Manabe, S. Iimura, X-M. Sun and S. Kobayashi, J. Am. Chem. Soc.,
2002, 124, 11971.
7 The lower yields compared with those in the previous protocol4 could be
ascribed to an adverse effect of excess water on the equilibrium between
ammonia/aldehydes and water/imines.
8 Yields of a-aminocrotylated products: 1a with (E)-2a (43%),
1a with (Z)-2a (36%), 1b with (E)-2a (30%), and 1b with (Z)-2a
(24%).
6 Examples from our group on the use of DBSA in water, see: (a)
K. Manabe, Y. Mori and S. Kobayashi, Synlett, 1999, 9, 1401; (b)
106 | Chem. Commun., 2005, 104–106
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