A general, Bronsted acid-catalyzed hetero-Michael addition of nitrogen, oxygen, and sulfur nucleophiles

Article abstract of DOI:10.1021/ol034596h

(Matrix presented) Strong Bronsted acids such as bis(trifluoromethanesulfon)imide catalyze the hetero-Michael addition of carbamates, alcohols, and thiols to α,β-unsaturated ketones, alkylidene malonates, and acrylimides. Scope, reaction rates, and yields are superior to comparable Lewis acid-catalyzed processes.

Full text of DOI:10.1021/ol034596h

ORGANIC
LETTERS
2
003
Vol. 5, No. 12
141-2144
A General, Brønsted Acid-Catalyzed
Hetero-Michael Addition of Nitrogen,
Oxygen, and Sulfur Nucleophiles
2
Tobias C. Wabnitz and Jonathan B. Spencer*
Cambridge UniVersity Chemical Laboratory, Lensfield Road,
Cambridge CB2 1EW, United Kingdom
jbs20@cam.ac.uk
Received April 6, 2003
ABSTRACT
Strong Brønsted acids such as bis(trifluoromethanesulfon)imide catalyze the hetero-Michael addition of carbamates, alcohols, and thiols to
r,â-unsaturated ketones, alkylidene malonates, and acrylimides. Scope, reaction rates, and yields are superior to comparable Lewis acid-
catalyzed processes.
â-Amino and â-oxy carbonyl functionalities are ubiquitous
motifs in natural products such as alkaloids and polyketides.
unsaturated carbonyl compounds with amine or alcohol
derivatives. This pathway is particularly important for other
1
4
â-Amino carbonyl compounds are also important intermedi-
ates for the synthesis of amino alcohols, diamines, and
â-amino acid derivatives, many of which serve as powerful
antibiotics or other drugs.2
heteronucleophiles such as thiols where Mannich- or aldol-
analogous reactions do not exist.
The development of new synthetic strategies continues to
attract attention as there are drawbacks to many of the
existing methodologies. Mannich reactions often suffer from
harsh conditions and long reaction times and aldol reactions
generally call for stoichiometric amounts of base to form
preactivated enolates. In contrast, hetero-Michael reactions
normally only require catalytic amounts of a strong base or
a Lewis acid to activate either the nucleophile or the acceptor
The reactions of enolates either with imines (Mannich
reaction) or with carbonyl compounds (aldol reaction) are
established methods for the synthesis of these moieties
3
through carbon-carbon bond formation (Scheme 1).
Scheme 1. Syntheses of â-Heteroatom Carbonyl Compounds
(
2) (a) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 117. (b)
EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.; John Wiley
Sons: New York, 1997. (c) Sewald, N. Amino Acids 1996, 11, 397. (d)
&
Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983. (e) Devine, P.
N.; Heid, R. M., Jr.; Tschaen, D. M. Tetrahedron 1997, 53, 6739.
(3) (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (b) Arend,
M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (c)
Tramontini, M.; Angiolini, L. Tetrahedron 1990, 46, 1791. (d) Heathcock,
C. H.; Kim, B. M.; Williams, S. F.; Masamune, S.; Paterson, I.; Gennari,
C. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon:
Oxford, UK, 1991; Vol. 2. (e) Mukaiyama, T. Org. React. 1982, 28, 203.
(f) Paterson, I.; Cowden, C. Org. React. 1997, 51, 1.
Alternatively, aza- or oxa-Michael additions can be used
to create carbon-heteroatom bonds by reaction of R,â-
(4) (a) Jung, M. E. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, p 30. (b) Sibi, M.
P.; Manyem, S. Tetrahedron 2000, 56, 8033. (c) Krause, N.; Hoffmann-
R o¨ der, A. Synthesis 2001, 171. (d) Berkessel, A. In Houben-Weyl: Methods
of Organic Chemistry; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, Germany, 1995;
Vol. E21e, p 4818.
(
1) Reviews: (a) Misra, M.; Luthra, R.; Singh, K. L.; Sushil, K. In
ComprehensiVe Natural Products Chemistry; Barton, D. H. R., Nakanishi,
K., Meth-Cohn, O., Eds.; Pergamon: Oxford, UK, 1999; Vol. 4, p 25. (b)
Staunton, J.; Wilkinson, B. Top. Curr. Chem. 1998, 195, 49.
1
0.1021/ol034596h CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/10/2003

Table 1. Acid Catalysts in the Aza-Michael Addition of 1a
and 2
Table 2. Aza-Michael Addition of 2 to R,â-Unsaturated
Carbonyl Compounds
run
acid
time
yield/%
1
2
3
4
5
6
7
8
9
(CF3SO2)2NH
CF3SO3H
HBF4‚OMe2
HBF4 aq
p-TsOH
p-TsOH‚H2O
H2SO4
CH3SO3H
HCl
10 min
10 min
10 min
2 h
24 h
72 h
72 h
72 h
72 h
72 h
98
91
86
92
98
99
93
47
trace
trace
-
1
1
0
1
CF3CO2H
CH3CO2H
72 h
component. To the latter end, lanthanide triflates, FeCl
3
,
InCl , CeCl /NaI, Bi(NO , platinum group metal complexes,
3
3
3 3
)
and other Lewis acids have been used successfully in aza-
5
Michael additions and asymmetric variants involving chiral
Lewis acids have been reported.6 Similarly, numerous
examples exist of base-mediated oxa-Michael additions and
7
Lewis acid catalysis has been achieved with Pd or Zn salts.
a
With most weak nucleophiles such as carbamates or
alcohols, intramolecular hetero-Michael additions are far
more prominent than intermolecular applications. Recently,
this problem was addressed by Kobayashi et al. and our
group when it was discovered that catalytic amounts of Pd-
Reaction at room temperature.
acceptors by protonation of the carbonyl group (pK ca. -5
a
for R,â-unsaturated ketones) should be feasible in the
presence of weakly basic nucleophiles, with leveling effects
limiting efficiency for more basic Michael donors. Although
some acid mediated, mostly intramolecular aza- and oxa-
Michael reactions have been described, no universal method
for acid-catalyzed hetero-Michael additions has been re-
ported.
Initial studies were carried out using benzyl carbamate
2
CbzNH , 2) and 1-phenyl-2-penten-1-one (1a) as a model
system (Table 1). While carboxylic acids or hydrochloric
acid were not effective (runs 9-11), catalysis could be
achieved with strong acids such as bis(trifluoromethane-
8
9
10
(
CH
3
CN)
2
Cl
2
, Cu(OTf)
2
, or noble metal chlorides such
could be used in a mild,
as PtCl
4
, AuCl, ReCl
5
, and RhCl
3
intermolecular aza-Michael reaction of carbamates and R,â-
unsaturated ketones.
11
In our search toward an economical, environmentally
friendly route to â-amino and â-oxy carbonyl compounds,
we became intrigued by the idea of dispensing with metal
catalysts or strong bases altogether and using catalytic
amounts of cheap, readily available and nontoxic Brønsted
acids instead. We reasoned that activation of Michael
(
sulfon)imide (Tf
tetrafluoroboric acid (run 3). Compared to reaction times
observed with Pd(CH CN) Cl (24 h) or Cu(OTf) (3 h), the
rate acceleration induced by these Brønsted acid catalysts
was dramatic. Weaker sulfonic acids (runs 5-8) and aqueous
or hydrated acids (runs 4, 6) could be used as well, but
reaction rates were significantly reduced.
Rapid conversion was observed when the reaction was
carried out in dichloromethane, acetonitrile, or nitromethane.
Solvents with weakly basic oxygen functionalities such as
2
NH, run 1), triflic acid (TfOH, run 2), or
(
5) For representative examples, see: (a) Matsubara, S.; Yoshioka, M.;
Utimoto, K. Chem. Lett. 1994, 827. (b) P e´ rez, M.; Pleixats, R. Tetrahedron
995, 51, 8355. (c) Cardillo, G.; Gentilucci, L.; Gianotti, M.; Perciaccante,
1
3
2
2
2
P.; Tolomelli, A. J. Org. Chem. 2001, 66, 8657. (d) Nakama, K.; Seki, S.;
Kanemasa, S. Tetrahedron Lett. 2001, 42, 6719. (e) Loh, T.-P.; Wei, L.-L.
Synlett 1998, 975. (f) Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.;
Sambri, L.; Torregiani, E. J. Org. Chem. 2001, 66, 9052. (g) Kawatsura,
M.; Hartwig, J. F. Organometallics 2001, 20, 1960. (h) Srivastava, N.; Banik,
B. K. J. Org. Chem. 2003, 68, 2109.
(
6) (a) Falborg, L.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1996,
823. (b) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959.
c) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. J. Chem. Soc., Chem.
2
(
Commun. 2001, 1240. (d) Nakama, K.; Seki, S.; Kanemasa, S. Tetrahedron
Lett. 2002, 43, 829. (e) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J.
Am. Chem. Soc. 1998, 120, 6615.
(
7) (a) Miller, K. J.; Kitagawa, T. T.; Abu-Omar, M. M. Organometallics
(11) (a) Darvesh, S.; Grant, A. S.; MaGee, D. I.; Valenta, Z. Can. J.
Chem. 1989, 67, 2237. (b) Bland, D.; Chambournier, G.; Dragan, V.; Hart,
D. J. Tetrahedron 1999, 55, 8953. (c) McAlpine, I. J.; Armstrong, R. W.
Tetrahedron Lett. 2000, 41, 1849. (d) Williams, D. R.; Barner, B. A.
Tetrahedron Lett. 1983, 24, 427. (e) Newman, M. S.; Waltcher, I.; Ginsberg,
H. F. J. Org. Chem. 1952, 17, 962 (intermolecular). (f) Hoffman, A. J.
Am. Chem. Soc. 1927, 49, 530 (intermolecular).
2
001, 20, 4403. (b) Hosokawa, T.; Sinohara, T.; Ooka, Y.; Murahashi, S.-
I. Chem. Lett. 1989, 2001. (c) Dheilly, L.; Lievre, C.; Frechou, C.; Demailly,
G. Tetrahedron Lett. 1993, 34, 5895.
(
(
(
8) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25.
9) Wabnitz, T. C.; Spencer, J. B. Tetrahedron Lett. 2002, 43, 3891.
10) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319.
2142
Org. Lett., Vol. 5, No. 12, 2003

Table 3. Hetero-Michael Addition of R,â-Unsaturated Ketones with Alcohols and Aniline
a
CH3OH as solvent. b 8 equiv of 5. c HBF4‚OMe2 as catalyst, see ref 16.
THF, ether, or acetone interfered with protonation equilibria
and gave little or no conversion. Poor solubility limited the
malonate decarboxylation or selective imide hydrolysis.
Although benzyl carbamate protected amine moieties are
known to be sensitive to cleavage in acidic media, low H
+
use of less polar solvents such as toluene. Tf
2
NH was chosen
as a standard catalyst, as it is one of the strongest known
acids12 and has been shown to be a superior catalyst in
condensation reactions, alkyne hydrations, Friedel-Crafts
acylations, conjugated allylations, and polymerization reac-
tions under mild conditions.13
concentrations and the use of nonaqueous solvents com-
pletely suppressed this pathway and decomposition products
could not be detected in any case.
In contrast to our transition metal catalysts, Tf NH also
2
efficiently mediates oxa-Michael additions (Table 3). Simple
alcohols such as methanol were suitable nucleophiles (run
Having established the remarkable catalytic activity of
Tf NH in the conjugate addition of 2 to â-monosubstituted
2
1
) and good yields were obtained with the synthetically more
enones 1a and 1b (Table 2), we focused our investigations
on substrates that had reacted only sluggishly in the presence
of metal catalysts. Enones bearing additional R- or â-sub-
stituents such as 1c, 1d, and 1e could be converted readily
with use of acid catalysts, and a good, thermodynamically
controlled diastereoselectivity was obtained for the addition
to 1e.14 It was also possible to extend the scope of the
reaction to acceptors other than R,â-unsaturated ketones.
Good yields were obtained when the alkylidene malonate
16
useful benzyl alcohols 5-7 (runs 2-6). Both 1- and
2
-naphthylmethanol were similarly effective (runs 7-8),
17
which allows the introduction of the NAP protecting group.
Alcohols are considerably less reactive than carbamates,
hence only poor yields were obtained with acceptors other
than terminal or â-monosubstituted enones. Aryl alcohols
could not be employed due to the competitive interference
of Friedel-Crafts-type reactions, but aniline, the more
nucleophilic nitrogen analogue, furnished the addition prod-
uct in excellent yield (run 9).
15
1
f and the acrylimides 1g and 1h were used. This pathway
offers a possible route to â-amino acid derivatives, e.g. via
Further experiments revealed that the same concept could
be applied successfully to thiols, which constitute another
class of weakly basic nucleophiles and are normally activated
(12) Koppel, I. A.; Taft, R. W.; Anvia, F.; Zhu, S.-Z.; Hu, L.-Q.; Sung,
K.-S.; DesMarteau, D. D.; Yagupolskii, L. M.; Yagupolskii, Y. L.; Ignat’ev,
N. V.; Kondratenko, N.; Volkonskii, A. Y.; Vlasov, V.; Notario, R.; Maria,
P.-C. J. Am. Chem. Soc. 1994, 116, 3047.
1
8,19
by deprotonation.
In addition, thiols are notoriously
difficult to use in the presence of Lewis acidic metals due
to their strong tendency to poison these catalysts, although
(
13) (a) Isihara, K.; Kubota, M.; Yamamoto, H. Synlett 1996, 1045. (b)
Tsuchimoto, T.; Joya, T.; Shirakawa, E.; Kawakami, Y. Synlett 2000, 1777.
c) Cossy, J.; Lutz, F.; Alauze, V.; Meyer, C. Synlett 2002, 45. (d) Kuhnert,
(
20
recent advances have been made.
N.; Peverley, J.; Robertson, J. Tetrahedron Lett. 1998, 39, 3215. (e)
Desmurs, J.-R.; Ghosez, L.; Martins, J.; Deforth, T.; Mignani, G. J.
Organomet. Chem. 2002, 646, 171.
Both benzenethiol (18) and benzyl mercaptan (19) were
effective in this reaction (Table 4). Benzyl sulfides, which
(
14) All aza- and oxa-Michael additions studied were reversible at room
temperature and -20 °C.
15) High conversions were also observed with alkylidene derivatives
(
(16) In run 5, lower yields and diether formation of 6 were observed
with Tf2NH as a catalyst.
(17) Gaunt, M. J.; Boschetti, C. E.; Yu, J.; Spencer, J. B. Tetrahedron
Lett. 1999, 40, 1803.
of Meldrum’s acid at -20 °C in CD3CN, but products rapidly reverted to
the starting materials via retro-Michael addition at room temperature, even
in the absence of a catalyst.
Org. Lett., Vol. 5, No. 12, 2003
2143

These examples demonstrate that Brønsted acid catalysis
can be superior to metal ion catalysis when weakly basic
nucleophiles are used in the hetero-Michael reaction. In
addition, Brønsted acids are not only advantageous in terms
of reactivity, but also regarding waste disposal and cost. The
procedure described herein complements our previous re-
search on the catalytic aza-Michael addition as mild transition
Table 4. Hetero-Michael Addition with Sulfur Nucleophiles
3 2 2
metal catalysts such as Pd(CH CN) Cl gave better results
when reactive, but highly acid-labile substrates such as
2
-cyclohexenone were used.
In summary, the first general, Brønsted acid-catalyzed
hetero-Michael addition has been developed. This easy and
economical process can be used for the construction of Cbz-,
naphthylmethyl-, or benzyl-protected â-amino, â-oxy, or
â-thio carbonyl compounds. Further refinements and ap-
plications of this procedure are now in progress and will be
reported shortly.
a
Acknowledgment. We thank Drs. Christian Stark and Jin-
Quan Yu for helpful discussion. Financial support (T.C.W.)
by the Fonds der Chemischen Industrie, the Studienstiftung
des deutschen Volkes, and St. John’s College, Cambridge,
is gratefully acknowledged.
Reaction in CH3CN, 60 min.
are standard functionalities in organic synthesis for the
protection of thiols,21 could be synthesized by reaction of
1
9 with terminal, disubstituted and trisubstituted enones in
Supporting Information Available: Experimental pro-
cedure and characterization data of all reaction products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
excellent yields and reaction times (runs 2-4).
(
18) Review: Mikolajczyk, M.; Drabowicz, J.; Kielbasinsksi, P. In
Houben-Weyl: Methods of Organic Chemistry; Helmchen, G., Hoffmann,
R. W., Mulzer, J., Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart,
Germany, 1995; Vol. E21e, p 5017. For more recent examples, including
enantioselective syntheses, see: (a) Sundarajan, G.; Prabagaran, N. Org.
Lett. 2001, 3, 389. (b) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K.
J. Am. Chem. Soc. 1997, 119, 12974. (c) Tomioka, K.; Muraoka, A.; Kanai,
M. J. Org. Chem. 1995, 60, 6188. (d) Tomioka, K.; Okuda, M.; Nishimura,
K.; Manabe, S.; Kanai, M.; Nagaoka, Y.; Koga, K. Tetrahedron Lett. 1998,
OL034596H
(19) It has been noted more than 50 years ago that HCl accelerates the
addition of dodecanethiol to mesityl oxide: (a) Stephens, J. R.; Hydock, J.
J.; Kleinholz, M. P. J. Am. Chem. Soc. 1951, 73, 4050. (b) Posner, T. Chem.
Ber. 1902, 35, 799.
3
9, 2141. (e) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem.
(20) Kondo, T.; Mitsudo, T.-a. Chem. ReV. 2000, 100, 3205.
(21) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; Wiley-Interscience: New York, 1999; p 457.
Soc. 1998, 120, 4043. (f) Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T.
Tetrahedron 1997, 53, 2421.
2144
Org. Lett., Vol. 5, No. 12, 2003