Radical hydroxyalkylation of C-H bond adjacent to nitrogen of tertiary amides, ureas, and amines

Article abstract of DOI:10.1021/ja053855q

Tertiary amides, ureas, and amines undergo direct intermolecular addition to aldehydes under the Et₃B/air conditions, thereby providing a unique and simple means for the radical sp³ C-H transformation of nitrogen-containing molecules. Copyright

Full text of DOI:10.1021/ja053855q

Published on Web 07/30/2005
Radical Hydroxyalkylation of C-H Bond Adjacent to Nitrogen of Tertiary
Amides, Ureas, and Amines
Takehiko Yoshimitsu,* Yoshimasa Arano, and Hiroto Nagaoka*
Meiji Pharmaceutical UniVersity, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
Received June 12, 2005; E-mail: takey@my-pharm.ac.jp
Scheme 1. Radical R-C-H Hydroxyalkylation of Nitrogen
Compounds
R-Hydroxyalkylated nitrogen compounds often serve as a rich
source of biologically and synthetically important substances.1
Therefore, novel chemical transformations that provide rapid access
to these functional motifs are of great significance in pharmaceutical
and fine chemical research.
We have recently reported the radical hydroxyalkylation of ethers
and an acetal with aldehydes, which proceeded via hydrogen
abstraction from the C-H bond R to oxygen by using Et3B/air2a,d
or Et3B/TBHP.2b,c In this context, we became interested in the
possibility of the direct R-amino sp3 C-H hydroxyalkylation that
would serve as a new mode for obtaining R-hydroxyalkylated
nitrogen compounds.3,4 Our idea stemmed from the following
insights. First, the relatively small dissociation energy of the C-H
bond adjacent to the nitrogen atom5 would enable the selective
abstraction of the R-hydrogen with radical species generated from
Et3B/air.6 Second, the resultant nucleophilic R-aminoalkyl radicals7
would undergo irreversible addition to aldehydes with the aid of
the oxophilic and Lewis acidic Et3B as an oxyradical scavenger.
In this communication, we show that several tertiary amides,
ureas, and amines undergo direct intermolecular addition to
aldehydes under the Et3B/air conditions, thereby providing a unique
and simple means for the radical sp3 C-H transformation of
nitrogen-containing molecules (Scheme 1).8
In our initial investigation of the feasibility of R-amino C-H
hydroxyalkylation, 1-methyl-2-pyrrolidinone (1) was selected as the
substrate. When γ-lactam 1 was subjected to the hydroxyalkylation
under the Et3B/air conditions, N-CH2 alkylation products 3/4 and
N-CH3 alkylation product 5 were produced (Table 1). The regio-
selectivity of the reaction favoring N-CH2 alkylation rather than
N-CH3 alkylation indicates that hydrogen abstraction occurs
predominantly from the weaker C-H bond; compared to the less-
substituted carbon center, the more highly substituted carbon center
is susceptible to hydrogen abstraction due to the release of steric
strain as well as the hyperconjugative stabilization of the incipient
R-aminoalkyl radical. The amounts of C-H substrate and Et3B
influenced the efficiency of the reaction (entries 6 and 7); when
the reaction was carried out with a relatively small amount of 1,
the amounts of ethyl adduct 6 and reduction byproduct 7 were
increased, and the reaction time was prolonged (entry 6). The
prolonged reaction time (42 h) was also necessary for obtaining a
reasonable yield when 3 equiv of Et3B was used (entry 7). Although
the reaction proceeded under the open-air condition without air
admission, it was significantly decelerated (entry 8); 41 h was
required for completing the reaction under the open-air condition,
in contrast to 14 h for the continuous air-admission condition (ca.
30 mL/h‚mmol aldehyde).
Table 1. Hydroxyalkylation of 1-Methyl-2-pyrrolidinone (1)
yield (%)a,b
time
entry
R
(h)
3/4 (dr 3:4)
5
6
7
1
2
3
4
5
6
7
8
4-MeOC6H4 2a
Ph 2b
3,4-methylenedioxyphenyl 2c 14 62 (77:23)
2-BrC6H4 2d
C12H25 2e
4-MeOC6H4 2a
4-MeOC6H4 2a
4-MeOC6H4 2a
14 68 (68:32)
16 62 (67:33)
7
6
trace
4
no
3
9
6
9
nog
8
12c 54 (42:58)
13
22c 50 (50:50) no no no
42d 54 (69:31)
42e 65 (69:31)
41f 68 (69:31)
6
7
7
11
1
5
6
no
no
a The reaction was carried out using 1-methyl-2-pyrrolidinone (1) (35
equiv relative to aldehyde) and Et3B (6 equiv) with continuous air admission
(ca. 30 mL/h‚mmol aldehyde). b Isolated yield based on aldehyde. c 70 equiv
of 1 was used. d 17 equiv of 1 was used. e 3 equiv of Et3B was used. f The
reaction was carried out under open-air conditions. g Not obtained.
derivatives as 1,3-dimethyl-2-imidazolidinone (8) and 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (9) provided R-alkylated
compounds 16 (75%) and 17 (8%), and 18 (72%) and 19 (11%),
respectively (entries 1 and 2). 1-Methylpyrrolidine (10) and
triethylamine (11) were also efficiently transformed into alkylation
products (entries 3 and 4).9 The hydroxyalkylation of N,N-
diethylaniline (12), an aromatic tertiary amine, gave phenyl-
protected â-amino alcohol 23 in 65% yield (dr 83:17). Interestingly,
the hydroxyalkylation of 4-methylmorpholine (13) was found to
selectively take place at the position R to nitrogen; the regioselec-
tivity in this case indicates that the C-H bond adjacent to nitrogen
is more susceptible to hydrogen abstraction than that adjacent to
the ethereal oxygen, although the C-H bonds R to nitrogen and
oxygen have similar dissociation energies.5d In general, undesirable
side reactions, such as ethyl radical addition and aldehyde reduction,
occurred only modestly in the above conditions (see Supporting
Information). 3-Methyl-2-oxazolidinone (14) and acyclic N,N-
dimethylacetamide (15) were found to be somewhat poor substrates
for the present hydroxyalkylation reaction (43 and 40% yields, en-
tries 7 and 8). The reason for the low yield in the reaction of 14 is
unclear, whereas the inefficient conversion of 15 may be attributed
to thermochemical factors that retard the hydrogen abstraction at
the N-CH3 sites, where radical stabilization is less available.
One plausible mechanism of this reaction, which is analogous
to that proposed for ether hydroxyalkylation,2b,d is shown in Scheme
These results prompted us to apply this radical C-H transforma-
tion to various nitrogen compounds. Table 2 shows that, under the
Et3B/air conditions, tertiary ureas and amines were also hydroxy-
alkylated with 4-methoxybenzaldehyde (2a) to afford alkylation
products in good yields. Thus, the hydroxyalkylation of such urea
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J. AM. CHEM. SOC. 2005, 127, 11610-11611
10.1021/ja053855q CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope
nitrogen atom by using Et3B/air. The present C-H transformation
features the direct generation of R-aminoalkyl radicals from the
C-H substrates, which may potentially serve as an alternative to
the homolysis of C-X (X ) SR, SeR) bonds, the radical
translocation, and the single electron transfer (SET) processes. It
should be noted that this radical reaction enables the rapid
construction of contiguous stereocenters functionalized with het-
eroatoms, which is not readily achieved by other C-H function-
alization methods. Studies on the scope of this reaction are
underway with focus on the application to evolutional organic
synthesis.
Acknowledgment. This work is dedicated to the memory of
Professor Satoru Masamune. We thank Mr. Atsushi Kishida and
Dr. Kazuhiko Takatori for X-ray crystallographic analysis.
Supporting Information Available: Experimental procedures,
1
characterization data, and H/13C NMR spectra of hydroxyalkylation
products. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
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Chem. 2003, 68, 7548-7550. (d) Yoshimitsu, T.; Arano, Y.; Nagaoka,
H. J. Org. Chem. 2005, 70, 2342-2345.
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161. (b) Kim, S. S.; Mah, Y. J.; Kim, A. R. Tetrahedron Lett. 2001, 42,
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a C-H substrate (35 equiv) and Et3B (6 equiv) were used except entry
8. b Isolated yield based on aldehyde. c Stereochemistry of major product
has yet to be determined. d 70 equiv of 15 was used.
Scheme 2. Plausible Mechanism of Radical C-H
Hydroxyalkylation of Nitrogen Compounds
(7) Reviews of R-aminoalkyl radical chemistry: (a) Aurrecoechea, J. M.;
Suero, R. ARKIVOC 2004, 10-35. (b) Hart, D. In Radicals in Organic
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10941.
(9) The hydroxyalkylation of 1-methylpiperidine provided alkylation products
in ca. 60% yield (dr 58:42; regioisomeric ratio ca. 5.5:1). Further studies
on the substrate scope will be reported in due course.
(10) The coordination of Et3B with aldehyde in path b remains a matter of
speculation. However, the formation of 4-methoxybenzyl alcohol from
4-methoxybenzaldehyde in some cases under the Et3B/air conditions
possibly indicates the intermediacy of the “ate” complex of Et3B with
aldehyde that is capable of â-hydride transfer. Studies aimed at elucidating
the details are ongoing.
2. An ethyl radical generated from Et3B/air abstracts the R-hydrogen
of the nitrogen compound to produce nucleophilic R-aminoalkyl
radicals. Then, the R-aminoalkyl radicals irreversibly undergo
addition to aldehyde via two possible pathways that involve the
rapid capture of oxyradicals with Et3B (path a) and/or the
precoordination of aldehyde with Et3B followed by the addition of
R-aminoalkyl radicals (path b).10
In conclusion, we have devised a new radical alkylation reaction
that occurs via the selective abstraction of the hydrogen R to the
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