Ortho alkylation of aromatic ketimine with functionalized alkene by Rh(I) catalyst

Article abstract of DOI:10.1021/ol048095n

(Chemical Equation Presented) The reaction of the imine of aromatic ketones with functionalized alkenes was performed under a catalytic amount of (PPh ₃)₃RhCl, and corresponding ortho-alkylated ketones were obtained after hydrolysis.

Full text of DOI:10.1021/ol048095n

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4687-4690
Ortho Alkylation of Aromatic Ketimine
with Functionalized Alkene by Rh(I)
Catalyst
Sung-Gon Lim, Jeong-Ae Ahn, and Chul-Ho Jun*
Center for BioactiVe Molecular Hybrid (CBMH), Department of Chemistry,
Yonsei UniVersity, Seoul 120-749, Korea
junch@yonsei.ac.kr
Received September 17, 2004
ABSTRACT
The reaction of the imine of aromatic ketones with functionalized alkenes was performed under a catalytic amount of (PPh3)3RhCl, and
corresponding ortho-alkylated ketones were obtained after hydrolysis. A variety of functional groups in the alkene were tolerated in this ortho
alkylation. This procedure expands the scope of ortho alkylation to the direct ortho functionalization of aromatic ketones.
The activation of unreactive bonds in organic molecules is
one of the current interests in organometallic chemistry.1 In
particular, the catalytic C-H bond activation using transition
metal complexes has been focused on by many synthetic
organic chemists because it is one of the better ways of
avoiding many environmental problems that can occur in
industrial organic synthesis.2 Since direct ortho alkylation
of aromatic ketone compounds, known as Murai’s reaction,
was first devised using RuH2(CO)(PPh3)3 in 1993,3 tremen-
dous developments have been achieved in this field.4,5
But one of the drawbacks has been a limited use of olefin
substrates, because olefin-bearing functional groups could
not be applied to this reaction. Recently, we have developed
new procedures for ortho alkylation and ortho alkenylation
using a ketimine of an aromatic ketone with various alkenes6
and alkynes.7 However, functionalized olefins have been
rarely applied to this ortho alkylation.
During the course of our studies on ortho alkylation, we
found that our strategy tolerated various functional groups
in olefin substrates. In this communication, we report the
ortho alkylation of aromatic ketimine with functionalized
olefins.
Among many olefin substrates bearing functional groups,
acrylate and acrylamide exhibited good reactivities for ortho
alkylation.
For example, when the reaction of benzylimine 1a and
methyl acrylate (2a) was carried out in the presence of
(5) For ortho alkylation, see: (a) Tremont, S. J.; Rahman, H. U. J. Am.
Chem. Soc. 1984, 106, 5759. (b) McCallum, J. S.; Gasdaska, J. R.;
Liebeskind, L. S. Tetrahedron Lett. 1989, 30, 4085. (c) Lewis, L. N.; Smith,
J. F. J. Am. Chem. Soc. 1986, 108, 2728. (d) Grigg, R.; Savic, V.
Tetrahedron Lett. 1997, 38, 5737. (e) Busch, S.; Leitner, W. Chem. Commun.
1999, 2305. (f) Lim, Y.-G.; Han, J.-S.; Yang, S.-S.; Chun, J. H. Tetrahedron
Lett. 2001, 42, 4853. (g) Harris, P. W. R.; Woodgate, P. D. J. Organomet.
Chem. 1997, 530, 211. (h) Guo, H.; Tapsak, M. A.; Weber, W. P. Polym.
Bull. 1995, 34, 49. (i) Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc.
1999, 121, 6616. (j) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2001, 123, 9692. (k) Ahrendt, K. A.; Bergman, R.
G.; Ellman, J. A. Ogr. Lett. 2003, 5, 1301. (l) Thalji, R. K.; Ellman, J. A.;
Bergman, R. G. J. Am. Chem. Soc. 2004, 126, 7192.
(1) Kakiuchi, F.; Murai, S. In ActiVation of UnreactiVe Bonds and
Organic Synthesis; Murai, S., Ed.; Springer: Berlin, German, 1999.
(2) For recent reviews, see: (a) Kakiuchi, F.; Chatani, N. AdV. Synth.
Catal. 2003, 345, 1077. (b) Ritleng, V.; Sirlins, C.; Pfeffer, M. Chem. ReV.
2002, 102, 1731. (c) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698.
(3) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Nature 1993, 366, 529.
(4) For Murai’s ortho alkylation, see: (a) Kakiuchi, F.; Sekine, S.;
Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N.; Murai, S. Bull. Chem.
Soc. Jpn. 1995, 68, 62. (b) Murai, S.; Chatani, N.; Kakiuchi, F. Pure Appl.
Chem. 1997, 69, 589. (c) Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S.
Bull. Chem. Soc. Jpn. 1997, 70, 3117. (d) Sonoda, M.; Kakiuchi, F.;
Kamatani, A.; Chatani, N.; Murai, S. Chem. Lett. 1996, 109. (e) Kakiuchi,
F.; Yamauchi, M.; Chatani, N.; Murai, S. Chem. Lett. 1996, 111.
(6) (a) Jun, C.-H.; Moon, C. W.; Hong, J.-B.; Lim, S.-G.; Chung, K.-
Y.; Kim, Y.-H. Chem. Eur. J. 2002, 8, 485. (b) Jun, C.-H.; Hong, J.-B.;
Kim, Y.-H.; Chung, K.-Y. Angew. Chem., Int. Ed. 2000, 39, 3440.
(7) Lim, S.-G.; Lee, J. H.; Moon, C. W.; Hong, J.-B.; Jun, C.-H. Org.
Lett. 2003, 5, 2759.
10.1021/ol048095n CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/12/2004

Scheme 1. Proposed Mechanism for Ortho Alkylation of
Ketimine 1a with 2
Table 1. Rh(I)-Catalyzed Ortho Alkylation of Aromatic
Ketimine 1 with Functionalized Olefins 2a
group to generate a five-membered ring metallacycle inter-
mediate 5. Subsequently, coordination of the functionalized
olefin 2 to 5 and a hydride insertion in 6 affords 7.2 Reductive
elimination of 7 leads to the ortho-alkylated ketimine 8,
which is hydrolyzed by acidic water to give 4.
Branched acrylate 2d, involving a branched vinyl group,
and N,N-dimethylacrylamide (2e) showed also good reactiv-
ity (entries 4 and 5), whereas phenyl vinyl sulfone (2f) and
acrylonitrile (2g) appeared to give only moderate reactivities
to produce ortho-alkylated aromatic ketone bearing γ-sul-
fonyl and γ-nitrile groups, respectively (entries 6 and 7).
When the reactivities of the aromatic ketimines having
different alkyl substituents (R1) were compared, electron-
withdrawing groups such as the tri-fluoromethyl group on
the phenyl ring showed a better result than electron-donating
groups such as the methoxy group under mild conditions
(entries 10 and 12). In comparing the alkyl group (R2) to
the imine group by increasing the length of the alkyl chain
as methyl, ethyl, and n-pentyl, the yield of the ortho-alkylated
products decreases to 94, 65, and 48% (entries 1, 13, 14).
Regarding the reactivity of functionalized olefins in this
reaction, functionalized olefins are much more reactive than
nonfunctionalized olefins. A competitive reaction of N,N-
dimethylacrylamide (2e) and 1-hexene (2l) with 1a was
a Reagent and conditions: (1) 1 (1.0 equiv), 2 (1.2 equiv), 3 (5 mol %),
toluene, 150 °C, 2 h. (2) 1 N HCl, room temperature, 12 h. b Isolated yield.
GC yields are given in parentheses. c 2.0 Equiv of 2 and 10 mol % 3 were
used. d Reaction was carried out at 100 °C for 30 min.
Table 2. Competitive Reaction of Rh(I)-Catalyzed Ortho
Alkylation of Ketimine 1a with 2e and 2l
(PPh3)3RhCl (3) in toluene at 150 °C for 2 h, ortho-alkylated
acetophenone 4a was isolated in a 94% yield after hydrolysis
(Table 1. entry 1).8 Other functionalized olefins were also
applied in this reaction, and representative examples were
tabulated in Table 1. The reaction of alkyl acrylate 2b-c
with 1a led to the corresponding ortho-alkylated ketone in
very high yields (entries 2 and 3).
entry 1a (equiv) 2e (equiv) 2l (equiv) ratio of 4e/4l yield (%)a
1
2
3
1.0
1.0
1.0
1.2
1.2
1.2
1.2
3.0
5.0
90/10
72/28
62/38
73 (100)
67 (100)
69 (100)
The reaction mechanism is shown in Scheme 1. The Rh-
(I) complex 3 reacts with the ortho-C-H bond in the phenyl
a Isolated yield. GC yields are given in parentheses.
(8) For Rh(I)-catalyzed conjugate addition reactions of acrylates with
arylsilanediols, see: Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169.
4688
Org. Lett., Vol. 6, No. 25, 2004

Scheme 2. 1,4-Addition of 1a to 2m with or without 3
Scheme 3. Ortho Alkylation of 1a with Methyl Crotonate (2o)
performed as shown in Table 2. With a 1/1 ratio of 2e/2l,
ortho-alkylated products, 4e and 4l, were obtained in a 90/
10 ratio in 73% isolated yields (entry 1), informing us that
the functionalized olefin 2e had a much higher reactivity than
nonfunctionalized olefin 2l. Even with a large excess of 2l
compared to 2e (1.2/5.0 of 2e/2l), a 62/38 ratio of 4e/4l was
obtained in high yield (entry 3).
1f and 2a was carried out under the previous reaction
conditions, 2-alkylated 1-acetylnaphthalene 4q11 was isolated
in 82% yield along with a 10% yield of a 1,4-addition
product 4r, as shown in Scheme 4. 8-Alkylated 1-acetyl-
A dramatic driving force of ortho alkylation reaction with
these functionalized olefins compared with the nonfunction-
alized olefin might be a formation of the stable five-
membered ring metallacyclic intermediate 7. To confirm this
hypothesis, N-methylmaleimide (2m), a functionalized olefin,
which could not form the intermediate 7, was applied in this
reaction, as shown in Scheme 2.
Scheme 4. Rh(I)-Catalyzed Ortho Alkylation of Ketimine 1f
with Methyl Acrylate (2a)
From the reaction of 2m with 1a, the expected ortho-
alkylated product 4m was not obtained. Instead, the 1,4-
addition product 4n was isolated in high yield with or without
3. This is because intermediate 7 is important for driving
the reaction of functionalized olefins.
naphthalene 4s was not observed in product mixtures.12 This
is because the formation of the five-membered metallacyclic
complex 11 is more favorable than that of the six-membered
ring complex 12.
The reaction of methyl crotonate (2o) with 1a gave an
unexpected ortho-linear alkylated product 4p, not the ortho-
branched alkylated 4o (Scheme 3). The linear alkyl complex
10 is generated through the isomerization of methyl crotonate
in 9 to methyl 3-butenoate. This type of isomerization can
be seen in some organotransition metal catalytic reactions.10
Reductive elimination and hydrolysis of the resulting ketimine
affords 4p.
Benzylimine of 1-acetylnaphthalene, 1f, is an interesting
substrate since there are two active sites, 2- and 8-position
of naphthalene, for ortho alkylation. When the reaction of
Of the catalysts tested, Wilkinson’s complex (3) showed
that ortho alkylation with functionalized olefin produced the
(9) For homoenolate complexes of Rh(III) binding through the carbonyl
oxygen, see: Hauptman, E.; Sabo-Etienne, S.; White, P. S.; Brookhart, M.;
Garner, M. J.; Fagan, P. J.; Calabrese, J. C. J. Am. Chem. Soc. 1994, 116,
8038.
(10) (a) Jun, C.-H.; Hwang, D.-C.; Na, S.-J. Chem. Commun. 1998, 1405.
(b) Reger, D. L.; Garza, D. G.; Baxter, J. C. Organometallics 1990, 9, 873.
(11) Ortho-alkylated ketimine 4q was characterized by 1H NMR and
COSY spectroscopic analysis; see Supporting Information.
(12) Trace amount (less than 4%) of the unidentified compound was
determined by GCD.
Org. Lett., Vol. 6, No. 25, 2004
4689

yield of 8e was observed compared to the reaction without
13 at the lower temperature: with the addition of 13, a 64%
yield of 8e was obtained at 100 °C, but without 13, only a
10% yield of 8e was observed. At 110 °C, the yield of 8e
was maximized and decreased gradually above that temper-
ature. The reason for the high reactivity of the metal catalyst
was likely the addition of 13, which creates a vacant
coordination site as in 14. This allows a facile coordination
of the functionalized olefins giving 15. However, at high
temperatures, the catalyst might well be decomposed.
In conclusion, ortho alkylation of aromatic benzylimine
has been achieved with olefins bearing various functional
groups. Some of these olefins are more reactive than those
having no functional groups. Wilkinson’s complex showed
the best catalytic activity, and additional (C6H5)4BNa allowed
the reaction to proceed smoothly under mild conditions.
Further applications of these ortho alkylation reactions with
functionalized olefins are under study.
Figure 1. GC yield of 8e by Rh(I)-catalyzed ortho alkylation of
1a with 2e without (C6H5)4BNa (13, 9) and with 5 mol % 13 ())
under different temperatures.
Acknowledgment. This work was supported by the
National Research Laboratory (NRL) (2000-N-NL-01-C-271)
Program administered by the Ministry of Science and
Technology and CBMH.
best catalytic activity. As the reaction temperature increases,
the reactivity of the catalyst 3 also increases as shown in
Figure 1. The yield of the product 8e dramatically increased
from 100 °C up to 130 °C and increased moderately from
130 °C up to 150 °C. In contrast, when 5 mol % (C6H5)4-
BNa (13) was added to this reaction mixture, a much higher
Supporting Information Available: Full experimental
details and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL048095N
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Org. Lett., Vol. 6, No. 25, 2004