Palladium-catalyzed domino cyclization (5-exo/3-exo), ring- expansion by palladium rearrangement, and aromatization: An expedient synthesis of 4-arylnicotinates from Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1002/adsc.201300211

Various 4-arylnicotinate derivatives were synthesized via a palladium-catalyzed cascade reaction of N-(2-bromoallyl)-N-cinnamyltosylamides in a one-pot procedure in good yields. The reaction involves a domino 5-exo/3-exo carbopalladation, ring-expansion b

Full text of DOI:10.1002/adsc.201300211

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DOI: 10.1002/adsc.201300211
Palladium-Catalyzed Domino Cyclization (5-exo/3-exo), Ring-
Expansion by Palladium Rearrangement, and Aromatization: An
Expedient Synthesis of 4-Arylnicotinates from Morita–Baylis–
Hillman Adducts
Ko Hoon Kim,a Se Hee Kim,a Hyun Ju Lee,a and Jae Nyoung Kima,*
a
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Korea
Fax : (+82)-62-530-3389; e-mail: kimjn@chonnam.ac.kr
Received: March 9, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300211.
Abstract: Various 4-arylnicotinate derivatives were
synthesized via a palladium-catalyzed cascade reac-
tion of N-(2-bromoallyl)-N-cinnamyltosylamides in
a one-pot procedure in good yields. The reaction in-
volves a domino 5-exo/3-exo carbopalladation, ring-
expansion by palladium rearrangement, and an aro-
matization process.
portant natural substances and their usefulness as syn-
thetic intermediates in organic synthesis.[1] Especially,
the synthesis of functionalized pyridines with a carbox-
ylic acid moiety at the 3-position (nicotinic acid deriv-
atives) has received much attention due to their bio-
logical importance.[2] The Morita–Baylis–Hillman
(MBH) adducts have been used for the synthesis of
various biologically important substances and synthet-
ic intermediates.[3] Various efficient protocols for the
synthesis of pyridine and quinoline derivatives from
the MBH adducts have also been developed by us
and other groups.[4]
Keywords: 4-arylnicotinates; Morita–Baylis–Hill-
man adducts; palladium; palladium rearrangement;
pyridines
In 2008, we reported the synthesis of 6-oxacyclo-
propa[a]indenes via a palladium-catalyzed sequential
3
À
5-exo carbopalladation and C
(sp ) H activation from
Polysubstituted pyridines are an important class of modified MBH adduct bearing a 2-bromoaryl moiety,
compounds due to their abundance in biologically im- as shown in Scheme 1.[5a] The alkylpalladium inter-
Scheme 1. Synthetic rationale of methyl nicotinate 2a.
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Ko Hoon Kim et al.
Table 1. A brief optimization of reaction conditions.[a]
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mediate does not have a suitable b-hydrogen atom
and activates the proton near to the oxygen atom of
the dihydrobenzofuran ring to form a cyclopropane
ring. Later, we observed a similar 5-exo carbopallada-
tion of modified MBH adducts in their palladium-cat-
alyzed domino reactions.[5b,c] In 1992, the 2010 Nobel
prize laureate Negishi and his co-workers rationalized
that palladium-catalyzed cyclizations of 2-halo-1,6-
dienes occur as sequences of 5-exo/3-exo carbopalla-
dations with subsequent palladium rearrangement of
the cyclopropylcarbinyl-palladium intermediate in
which the b-H elimination is suppressed.[6a] Later,
such a domino 5-exo/3-exo carbopalladation accompa-
nying a palladium rearrangement process was studied
by many research groups including those of Steven-
Entry Base
Solvent
Time [h] 2a [%] 3a [%]
1
2
3
4
5
6
Et3N[b]
DMF[d]
DMF
20
3
3
3
3
0
0
<5
10
65
12
54[g]
72[g]
76[h]
74[h]
0
Et3N[b]
Et3N[b]
K2CO3
DMF[e]
DMF
[c]
[c]
Cs2CO3[c] DMF
Cs2CO3
CH3CN[f] 10
70[h]
[a]
Conditions: substrate 1a (0.5 mmol), PdACHTUNGTRENNUNG(OAc)2
son,[6b] de Meijere,[6c–e] and Ahn.[6f] Similar n-exo
ACTHNUTRGNE(UNG n=6
(5 mol%), PPh3 (10 mol%), 1208C.
2.0 equiv.
2.5 equiv.
At 708C.
NaI (1.0 equiv.) was added.
Reflux.
3a’ was isolated in 4%.
[b]
[c]
[d]
[e]
[f]
or 4)/3-exo carbopalladation and palladium rearrange-
ments have also been reported.[7] Such a tandem 5-
exo/3-exo cyclization accompanying ring-expansion
process was also observed in a radical reaction of
a propargyl ether of an MBH adduct[8a] and bis-vinyl
ethers.[8b] In these respects, we envisioned that 3,4,5-
trisubstituted pyridine derivative 2a could be synthe-
sized from 1a via a palladium-catalyzed domino cycli-
zation (5-exo/3-exo), ring-expansion by palladium re-
arrangement, and an aromatization process, as shown
in Scheme 1.
[g]
[h]
Trace amount of 3a’ was observed but not isolated.
The starting material 1a was prepared readily from
the MBH adduct of benzaldehyde and methyl acry-
late by a simple three-step process, that is a sequential
bromination, substitution with tosylamide, and 2-bro-
moallylation (see the Supporting Information). With
1a in our hand, a brief screening of the reaction con-
ditions was carried out for the synthesis of methyl nic-
otinate 2a, and the results are summarized in Table 1.
When we carried out the reaction in the presence of
Et3N (entries 1–3), 1,4,5,6-tetrahydropyridine 3a was
produced as a major product along with a trace
amount of 1,2,5,6-tetrahydropyridine 3a’ (<4%).[6a]
The reaction in the presence of K2CO3 afforded a low
Scheme 2. A plausible reaction mechanism.
yield of 2a (10%), but the major product was still 3a stabilization effect might facilitate the 5-exo/3-exo
(entry 4). In order to facilitate the elimination of p- cascade carbopalladations. The intermediate II has no
toluenesulfinic acid from 3a or 3a’, we examined the b-hydrogen atom, thus a concomitant palladium rear-
reaction with Cs2CO3 (entry 5), and 2a was obtained rangement/ring expansion proceeded to form a piperi-
in good yield (65%). The reaction in refluxing dine intermediate III. A subsequent syn b-H elimina-
CH3CN was not efficient even in the presence of tion of III could occur in either direction; however,
Cs2CO3 for a long time (entry 6).
1,4,5,6-tetrahydropyridine 3a[10] was formed as
The mechanism for the formation of 2a could be a major product along with a trace amount (<4%) of
proposed in detail, as shown in Scheme 2. An oxida- 1,2,5,6-tetrahydropyridine 3a’.[11] The reason for the
À
tive addition of the C Br bond of 1a to Pd(0) and selective formation of 3a is not clear at this stage;
a subsequent 5-exo carbopalladation gave an alkylpal- however, the ratio of 3a/3a’ might be dependent on
À
ladium intermediate I. Because the intermediate I has the dihedral angles between the C Pd bond and two
no suitable b-hydrogen atom that can be eliminated, C H bonds. A subsequent elimination of TsH from
a
À
sequential 3-exo carbopalladation occurred to 3a/3a’ and double bond isomerization furnished 2a.
afford an alkylpalladium intermediate II. The pres-
Encouraged by these successful results, N-(2-bro-
ence of an ester group can stabilize both alkylpalladi- moallyl)-N-cinnamyltosylamides 1b–l were prepared
um intermediates I and II by chelation,[7a,9] and this from the corresponding MBH adducts (see the Sup-
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Palladium-Catalyzed Domino Cyclization (5-exo/3-exo), Ring-Expansion by Palladium Rearrangement
Table 2. Synthesis of various 4-arylnicotinates.
to good yields (41–75%) in a one-pot procedure
under the optimized palladium-catalyzed reaction
conditions.
As a next experiment, we examined the reaction of
n-pentyl derivative 1m in order to prepare 4-pentylni-
cotinate 2m, as shown in Scheme 3. However, the re-
action of 1m under the optimized condition using
Cs2CO3 in DMF showed the formation of 3m/3m’ in
low yield along with many intractable side products.
The reaction of 1m under the influence of Et3N af-
forded 3m (70%) along with a low yield of 3m’
(13%). A desired 4-pentylnicotinate 2m was not
formed during the reaction at all. Thus the conversion
of 3m to 2m was examined under various conditions;
however, we failed to obtain 2m even under condi-
tions employing an excess amount DBU (5.0 equiv.)
in refluxing toluene (vide infra). The proton at the 4-
position of 3m is less acidic than those of the corre-
sponding 4-aryl derivatives producing 2a–l, and this
might be the reason for the failure. It is noteworthy
that the 3-exo carbopalladation/palladium rearrange-
ment process occurred at the intermediate stage I-m
to give 3m/3m’ preferentially rather than the b-H
elimination to form 3-hex-1-enylpyrrolidine derivative
4.
In order to synthesize 4-styrylnicotinate 2n we ex-
amined the reaction of 1n, as shown in Scheme 4. The
one-pot synthesis of 2n was carried out under the op-
timized condition in the presence of Cs2CO3; howev-
er, the yield of 2n was moderate (47%). Thus we ex-
amined a two-step process, the synthesis of tetrahy-
dropyridine and the following aromatization. The tet-
rahydropyridine 3n was obtained in good yield (72%)
along with 3n’ (11%) when we carried out the reac-
tion in the presence of Et3N. The intermediate 3n
could be converted to 2n under the influence of DBU
(5.0 equiv.) in refluxing toluene in good yield (64%).
However, the overall yield of 2n using a two-step pro-
porting Information), and examined the synthesis of cess was similar to that of the one-pot reaction. A
4-arylnicotinates. As summarized in Table 2, various consecutive 4-exo carbopalladation at the intermedi-
4-arylnicotinates 2b–l were synthesized in moderate ate stage II-n to a tricyclic compound 5 cannot occur
Scheme 3. Attempted synthesis of 4-pentylnicotinate 2m.
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(3%). The tetrahydropyridine 3o could be converted
to 2o in good yield (71%) by treatment with Cs2CO3
in DMF at 1208C for 3 h. However, a trial for the
conversion of methylene derivative 3a to hexylidene
derivative 6 by a CM reaction with 1-hexene failed in
the presence of a second generation Grubbs cata-
lyst.[12]
2-Arylnicotinate 2p could also be synthesized from
N-(2-bromoallyl)-substituted aza-MBH adduct 1o, as
shown in Scheme 6. The synthesis of 1,2,5,6-tetrahy-
dropyridine 3p’ was reported by us a few years ago.[4d]
At that time, the aromatization of 3p’ afforded only
a low yield of 2p (22%). Thus we reexamined a one-
pot synthesis of 2p from 1o in the presence of Cs2CO3
in DMF. At the early stage of the reaction compound
3p’ was formed as a major product along with a trace
amount of 2p; however, a prolonged heating of the
reaction mixture caused a severe decomposition of
3p’ without an increase of 2p. To our delight, the aro-
matization of 3p’ was efficiently conducted with DBU
to produce 2p in moderate yield (59%), as for the
conversion of 3n to 2n (vide supra, Scheme 4). It is in-
teresting to note that 3p’ has been formed as the sole
product, as compared to the formation of 3a and 3a’
in a mixture from 1a (vide supra, Scheme 2). As
shown in Scheme 6, the first 5-exo carbopalladation
might occur selectively towards the re-face of the
double bond of 1o to form the intermediate IV, pre-
Scheme 4. Synthesis of 4-styrylnicotinate 2n.
because the alkylpalladium and styryl moieties are sumably due to the electronic repulsion between the
positioned in a trans-relationship. ester and N-sulfonyl groups. The intermediate IV was
In order to synthesize 5-arylmethyl- or 5-alkylnico- converted to VI, and a subsequent syn b-H elimina-
tinates, we examined a palladium-catalyzed Heck re- tion produced 3p’.
action of 3a and cross-metathesis (CM) reaction, as
As a next examination, we carried out the reaction
shown in Scheme 5. The Heck reaction of 3a with 2- of 1p bearing a nitrile group instead of an ester, as
bromonaphthalene was carried out under the influ- shown in Scheme 7. A severe decomposition was ob-
ence of K2CO3, because compound 3a could be con- served under the conditions employing Cs2CO3 in
verted into 2a in the presence of Cs2CO3. In this way, DMF at 1208C, while the use of Et3N at low tempera-
a tetrahydropyridine 3o was obtained in good yield ture (908C) showed very sluggish reactivity. Only
(78%) along with a trace amount of pyridine 2o a low yield of tetrahydropyridine 3q (22%) was ob-
Scheme 5. Heck reaction of 3a and an extension of side chain.
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Palladium-Catalyzed Domino Cyclization (5-exo/3-exo), Ring-Expansion by Palladium Rearrangement
Scheme 6. Synthesis of 2-phenylnicotinate 2p.
Scheme 7. The importance of a directing group.
tained along with a tosylamide derivative (24%) DBU in toluene, and 2r could be obtained in moder-
when we carried out the reaction under the influence ate yield (64%).
of Et3N at 1208C. As we noted above, the ester
As a last entry, we examined the synthesis of 5-al-
moiety of 1a might facilitate 5-exo carbopalladation kylnicotinate 2s, as shown in Scheme 9. As noted
by stabilizing the alkylpalladium intermediate I; how- above in Scheme 5, an attempted synthesis of 5-alkyl-
ever, such a directing and/or stabilizing effect is not nicotinate using the cross-metathesis protocol failed.
present in the corresponding intermediate I-p for the Thus, we prepared compound 1r with 1,2-dibromo-
nitrile derivative, and this would be the reason for the
low yield of 3q.
In order to obtain 3-acetylpyridine 2r the reaction
of an acetyl derivative 1q was examined, as shown in
Scheme 8. Initially, we examined a one-pot synthesis
of 2r in the presence of Cs2CO3 in DMF at 1208C;
however, we failed to obtain 2r in a reasonable yield.
Monitoring of the reaction progress showed a rapid
formation of tetrahydropyridine 3r as a major product
along with a trace amount of 2r. However, the
amount of 2r was not increased even after a prolonged
heating. Thus, we prepared 3r in the presence of Et3N
and examined the aromatization of 3r to 2r. As in the
case of the styryl derivative (Scheme 4) an aromatiza-
tion of 3r to 2r was carried out in the presence of Scheme 8. Synthesis of 3-acetylpyridine 2r.
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Acknowledgements
This research was supported by Basic Science Research Pro-
gram through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (2012R1A1B3000541). Spectroscopic data were
obtained from the Korea Basic Science Institute, Gwangju
branch.
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Typical Experimental Procedure for the Pd-Catalyzed
Synthesis of Methyl 4-Phenyl-5-methylnicotinate (2a)
A mixture of 1a (232 mg, 0.5 mmol), PdACTHNURTGNENG(U OAc)2 (6 mg,
5 mol%), PPh3 (13 mg, 10 mol%) and Cs2CO3 (408 mg,
2.5 equiv.) in DMF (1.5 mL) was heated to 1208C for 3 h.
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and extracted with diethyl ether. The organic solvent was re-
moved by evaporation, and the residue was purified by flash
column chromatography (hexanes/ether, 3:1) to afford 2a as
a pale yellow solid; yield: 125 mg (65%); mp 48–498C; IR
(KBr): n=1734, 1303, 1148 cmÀ1
;
1H NMR (CDCl3,
300 MHz): d=2.11 (s, 3H), 3.62 (s, 3H), 7.15–7.17 (m, 2H),
7.36–7.48 (m, 3H), 8.62 (br s, 1H), 8.92 (br s, 1H); 13C NMR
(CDCl3, 75 MHz): d=17.27, 52.07, 126.39, 127.59, 127.77,
128.23, 132.11, 137.44, 148.39, 149.69, 153.26, 166.84; ESI-
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6
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[7] For the similar palladium-catalyzed domino n-exoACTHNUTRGNEUNG(n=6
or 4)/3-exo carbopalladations and a following palladium
rearrangement, see: a) V. H. Rawal, C. Michoud, J.
Org. Chem. 1993, 58, 5583–5584; b) M.-L. Bennasar, E.
Zulaica, D. Sole, T. Roca, D. Garcia-Diaz, S. Alonso, J.
Org. Chem. 2009, 74, 8359–8368; c) M.-L. Bennasar, E.
Zulaica, D. Sole, S. Alonso, Tetrahedron 2012, 68,
4641–4648; d) A. Innitzer, L. Brecker, J. Mulzer, Org.
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[8] a) S. Gowrisankar, K. Y. Lee, T. H. Kim, J. N. Kim, Tet-
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K. A. Davies, J. E. Wulff, J. Org. Chem. 2012, 77, 8634–
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[12] For the similar CM reaction, see: a) I. C. Stewart, C. J.
Douglas, R. H. Grubbs, Org. Lett. 2008, 10, 441–444;
b) R. Raju, L. J. Allen, T. Le, C. D. Taylor, A. R.
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8 Palladium-Catalyzed Domino Cyclization (5-exo/3-exo),
Ring-Expansion by Palladium Rearrangement, and
Aromatization: An Expedient Synthesis of 4-
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