Preparation and Suzuki-Miyaura coupling reactions of tetrahydropyridine-2- boronic acid pinacol esters

Article abstract of DOI:10.1021/jo050995+

A study on the conversion of lactam-derived vinyl triflates and phosphates into the corresponding vinyl boronates was carried out. While δ-valerolactam-derived vinyl triflates were successfully converted into 1,4,5,6-tetrahydropyridine-2-boronic acid pinacol ester derivatives by Pd-catalyzed coupling reaction with both bis(pinacolato)diboron and pinacolborane, pyrrolidinone and ε-caprolactam derivatives either did not react or were readily reduced. The δ-valerolactam-derived vinyl boronates are thermally stable compounds that efficiently coupled, under Pd catalysis, with structurally diverse aryl and heteroaryl bromides and triflates, vinyl iodides and bromides, and aromatic acid chlorides, to give the corresponding 2-substituted piperidines in good to excellent yields. The number of electrophiles that can virtually be coupled with these new boronic esters makes them very useful reagents for the synthesis of N-heterocyclic compounds.

Full text of DOI:10.1021/jo050995+

Preparation and Suzuki-Miyaura Coupling Reactions of
Tetrahydropyridine-2-boronic Acid Pinacol Esters
Ernesto G. Occhiato,* Fabrizio Lo Galbo, and Antonio Guarna
Dipartimento di Chimica Organica “U. Schiff”, Polo Scientifico - Universita` di Firenze, Via della
Lastruccia 13, 50019 Sesto Fiorentino, Italy
ernesto.occhiato@unifi.it
Received May 19, 2005
A study on the conversion of lactam-derived vinyl triflates and phosphates into the corresponding
vinyl boronates was carried out. While δ-valerolactam-derived vinyl triflates were successfully
converted into 1,4,5,6-tetrahydropyridine-2-boronic acid pinacol ester derivatives by Pd-catalyzed
coupling reaction with both bis(pinacolato)diboron and pinacolborane, pyrrolidinone and ꢀ-capro-
lactam derivatives either did not react or were readily reduced. The δ-valerolactam-derived vinyl
boronates are thermally stable compounds that efficiently coupled, under Pd catalysis, with
structurally diverse aryl and heteroaryl bromides and triflates, vinyl iodides and bromides, and
aromatic acid chlorides, to give the corresponding 2-substituted piperidines in good to excellent
yields. The number of electrophiles that can virtually be coupled with these new boronic esters
makes them very useful reagents for the synthesis of N-heterocyclic compounds.
Introduction
(Scheme 1) have frequently be used as key intermediates
in the synthesis of heterocyclic compounds through
diverse palladium-catalyzed coupling reactions.6,7 The
Boronic acids and esters have emerged as two of the
most useful classes of organoboron compounds in organic
synthesis, particularly in Pd-catalyzed cross-coupling
reactions with organic halides and triflates (the Suzuki-
Miyaura reaction).1 Over the past few years, in particu-
lar, there has been an increased availability of heteroar-
omatic boronic acids and esters.2 By contrast, there are
only a few examples of preparation of nonaromatic
heterocyclic boronic acids (or esters) to be employed in
metal-catalyzed reactions for the formation of new C-C
bonds.2b,3 Among a number of methods for the prepara-
tion of boronic esters, the Pd-catalyzed borylation of
alkenyl halides and triflates by bis(pinacolato)diboron4
or pinacolborane5 has recently been reported. Vinyl
triflates and phosphates 2 obtained from lactams 1
(3) (a) Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2003, 31, 9308. (b)
Deligny, M.; Larreaux, F.; Toupet, L.; Carboni, B. Adv. Synth. Catal.
2003, 345, 1215. (c) Hercouet, A.; Neu, A.; Peyronel, J.-F.; Carboni, B.
Synlett. 2002, 829. (d) Kalai, T.; Balog, M.; Jeko, J.; Hubbell, W. L.;
Hideg, K. Synthesis 2002, 2365. (e) Suginome, M.; Omari, Y.; Ito, Y.
J. Am. Chem. Soc. 2001, 123, 4601. (f) Eastwood, P. R. Tetrahedron
Lett. 2000, 41, 3705. (g) Colin, S.; Vysse-Ludot, L.; Lecouvre, J.-P.;
Maddaluno, J. J. Chem. Soc., Perkin Trans. 1 2000, 24, 4505. (h)
Fernandez, E.; Maeda, K.; Hooper, M. W.; Brown, J. M. Chem Eur. J.
2000, 10, 1840. (i) Brown, H. C.; Murali, D.; Singaram, B. J. Orga-
nomet. Chem. 1999, 581, 116. (j) Jeanfavre, D. D.; Woska, J. R.;
Pargellis, C. A.; Kennedy, C. A.; Prendergast, J.; Stearns, C.; Reilly,
P. L.; Barton, R. W.; Bormann, B.-J. Biochem. Pharmacol. 1996, 52,
1757. (k) Brown, H. C.; Gupta, A. K.; Prasad, V. J. V. N.; Srebnik, M.
J. Org. Chem. 1988, 53, 1391.
(4) (a) Ishiyama, T.; Takagi, J.; Kamon, A.; Miyaura, N. J. Orga-
nomet. Chem. 2003, 687, 284. (b) Takagi, J.; Kamon, A.; Ishiyama, T.;
Miyaura, N. Synlett 2002, 1880. (c) Takagi, J.; Takahashi, K.; Ish-
iyama, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124, 8001. (d)
Ishiyama, T.; Itoh, Y.; Takahiro, K.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447. (e) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem.
1995, 60, 7508.
* Tel: +39-055-4573480. Fax: +39-055-4573531.
(1) (a) Suzuki, A. J. Organomet. Chem. 2002, 653, 83. (b) Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron, 2002, 58, 9633. (c) Miyaura,
N. Top. Curr. Chem. 2002, 219, 11. (d) Suzuki, A. J. Organomet. Chem.
1999, 576, 147. (e) Suzuki, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim,
Germany, 1998; Chapter 2. (f) Miyaura, N.; Suzuki, A. Chem. Rev.
1995, 95, 2457-2483.
(5) (a) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org.
Chem. 2000, 65, 164. (b) Murata, M.; Oyama, T.; Watanabe, S.;
Masuda, Y. Synthesis 2000, 778. (c) Murata, M.; Watanabe, S.; Masuda,
Y. J. Org. Chem. 1997, 62, 6458.
(6) For a review on the chemistry and synthetic applications of
lactam-derived vinyl triflates and phosphates, see: Occhiato, E. G.
Mini-Rev. Org. Chem. 2004, 1, 149.
(2) For two reviews, see: (a) Tyrrel, E.; Brookes, P. Synthesis
2003, 469. (b) Chinchilla, R.; Na´jera, C.; Yus, M. Chem. Rev. 2004,
104, 2667.
10.1021/jo050995+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/28/2005
7324
J. Org. Chem. 2005, 70, 7324-7330

TABLE 1. Pd-Catalyzed Borylation of Lactam-Derived
SCHEME 1
Vinyl Triflates 2a-c
time
4
5
entry substrate
R
conditions
(h) (%)a (%)b
1
2a
Cbz 5% (Ph3P)2PdCl2,
3
7
39b
85
6
8
2 M Na2CO3, 3 (1.5 equiv),
THF, 50 °C
2
3% (Ph3P)2PdCl2, 6% Ph3P,
K2CO3 (1.5 equiv), 3
(1.5 equiv), dioxane, 90 °C
3
4
2b
2c
Boc as in entry 2
Ts as in entry 2
5
5
81
82
<5
<5
scope of vinyl triflates 2 would certainly be expanded if
an umpolung of these electrophiles is realized by R-bo-
rylation of the heterocycle (Scheme 1), thus producing a
new class of nonaromatic heterocyclic boronates 4 po-
tentially useful for Suzuki-Miyaura cross-coupling reac-
tions. The overall procedure should, in principle, be of
wider applicability than the direct use of the lactam-
derived vinyl triflates because of the vast availability of
the electrophiles (e.g., alkenyl and aryl halides, triflates,
acid chlorides, etc.) that can be used as partners in metal-
catalyzed coupling reactions. Moreover, boronates 4
should hopefully be compounds of greater stability than
the corresponding triflates, which instead, depending on
the ring size and substitution pattern, are often prone
to rapid degradation.6 With this in mind, we first evalu-
ated the feasibility of the transformation of various
lactam-derived vinyl triflates and phosphates into the
corresponding boronates. The heterocycle ring size, the
electron-withdrawing group on the N atom, and the leav-
ing group in 2 were the parameters we decided to modify
to this end. This was followed by a study on the Pd-
catalyzed coupling reactions of boronates 4 with diverse
electrophiles to assess the scope of these new reagents
in the synthesis of R-substituted N-heterocycles.8
a Isolated yield after chromatography. b Conversion determined
by 1H NMR analysis of the crude reaction mixture.
by the Pd-catalyzed coupling with commercial bis(pina-
colato)diboron 3,10 a reagent successfully employed for
the preparation of boronates from diverse vinyl triflates.4
The best protocol (entry 2) was that which uses (Ph3P)2-
PdCl2 (3%) as a catalyst, in the presence of Ph3P and with
finely powdered K2CO3 as a base, in anhydrous dioxane
at 90 °C.4a The reaction was complete in 7 h, furnishing
vinyl boronate 4a in 85% yield after chromatographic
purification. Although K2CO3, if compared to weaker
bases, is reported to induce further coupling between the
boronate and the triflate during the borylation reaction,4a
in situ coupling of 2a with boronate 4a to give dimer 5a11
was almost completely suppressed (about 8% by 1H NMR
analysis of the crude reaction mixture) by employing 1.5
equiv of bis(pinacolato)diboron. The same procedure,
when applied to N-Ts and N-Boc vinyl triflates 2b and
2c, provided boronates 4b and 4c in 81 and 82% yield,
respectively, after chromatography.
Compared to pinacolborane, bis(pinacolato)diboron 3
is quite an expensive reagent; moreover, only one of its
two dioxaborolanyl fragments is transmetalated to form
the boronate.4e Therefore, we evaluated the use of pina-
colborane for the preparation of 4a-c (Table 2), although
with this reagent the reduction of the triflates to tet-
rahydropyridines 712 is a possible concurrent reaction.
In analogy to the work of Baudoin, who employed
sterically hindered phosphine ligands for the borylation
of ortho-substituted phenyl halides,13 we initially used
tricyclohexylphosphine and Buchwald’s phosphine 814
(Figure 1) as ligands, as reported in entries 2-4. How-
ever, we only observed the formation of a modest amount
of 4a in the presence of Cy3P, the main reaction pathway
being the reduction to 7a, whereas with Buchwald’s
Results and Discussion
The conversion of N-Cbz vinyl triflate 2a7j,9 into the
corresponding boronate 4a (Table 1) was first realized
(7) For the most recent applications, see: (a) Fenster, M. D. B.; Dake,
G. R. Chem. Eur. J. 2005, 11, 639. (b) Occhiato, E. G.; Prandi, C.;
Ferrali, A.; Guarna, A. J. Org. Chem. 2005, 70, 4542. (c) Dake, G. R.;
Fenster, M. D. B.; Hurley, P. B.; Patrick, B. O. J. Org. Chem. 2004,
69, 5668. (d) Easton. L. P.; Dake, G. R. Can. J. Chem. 2004, 82, 139.
(e) Prandi, C.; Ferrali, A.; Guarna, A.; Venturello, P.; Occhiato, E. G.
J. Org. Chem. 2004, 69, 7705. (f) Fenster, M. D. B.; Dake, G. R. Org.
Lett. 2003, 5, 4313. (g) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna,
A.; Venturello, P. J. Org. Chem. 2003, 68, 9728. (h) Toyooka, N.;
Fukutome, A.; Nemoto, H.; Daly, J. W.; Spande, T. F.; Martin Garraffo,
H.; Kaneko, T. Org. Lett. 2002, 4, 1715. (i) Xu, Z.; Kozlowski, M. C. J.
Org. Chem. 2002, 67, 3072. (j) Occhiato, E. G.; Trabocchi, A.; Guarna,
A. J. Org. Chem. 2001, 66, 2459. (k) Lepifre, F.; Clavier, S.; Bouyssou,
P.; Coudert, G. Tetrahedron 2001, 57, 6969. (l) Fenster, M. D. B.;
Patrick, B. O.; Dake, G. R. Org. Lett. 2001, 3, 2109. (m) Coe, J. W.
Org. Lett. 2000, 2, 4205. (n) Bamford, S. J.; Luker, T.; Speckamp, W.
N.; Hiemstra, H. Org. Lett. 2000, 2, 1157. (o) Lindstro¨m, S.; Ripa, L.;
Hallberg, A. Org. Lett. 2000, 2, 2291. (p) Ha, J. D.; Cha, J. K. J. Am.
Chem. Soc. 1999, 121, 10012.
(10) Bis(pinacolato)diboron 3 can also be prepared according to the
procedure reported in: Abu Ali, H. A.; Goldberg, I.; Srebnik, M. Eur.
J. Inorg. Chem. 2002, 73.
(11) 1H NMR (200 MHz, CDCl3) spectrum of 5a: δ 7.35-7.25 (m,
10 H), 5.33 (br t, 2 H), 5.07 (s, 4 H), 3.50-3.10 (m, 4 H), 2.10-1.95 (m,
4 H), 1.75-1.50 (m, 4 H).
(12) For the synthesis of 7a (R ) Cbz), see: Okitsu, O.; Suzuki, R.;
Kobayashi, S. J. Org. Chem. 2001, 66, 809.
(13) Baudoin, O.; Gue´nard, D.; Gue´ritte, F. J. Org. Chem. 2000, 65,
9268.
(14) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999,
38, 2413. (b) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 9550.
(8) Part of this work has been disclosed in: Ferrali, A.; Guarna, A.;
Lo Galbo, F.; Occhiato, E. G. Tetrahedron Lett. 2004, 45, 5271.
(9) Lactam-derived vinyl triflates 2a-c are best prepared by treat-
ment of the corresponding lactams with KHMDS at -78 °C in THF,
followed by the addition of PhNTf2 (see Supporting Information).
J. Org. Chem, Vol. 70, No. 18, 2005 7325

Occhiato et al.
TABLE 2. Pd-Catalyzed Borylation of Lactam-Derived
Vinyl Triflates 2a-ca
FIGURE 2. Possible mechanism of borylation with pinacolbo-
rane.
T
4
7
entry substrate
R
catalyst
(°C) (%)b (%)b
SCHEME 2a
1
2
2a
Cbz 3% (Ph3P)PdCl2
3% Pd(OAc)2, 12% Cy3P
3% Pd2(dba)3, 12% Cy3P
3% Pd(OAc)2, 12% 8
3% (dppf)PdCl2
50
0
26
81
70
86
52
50 19
50 21
90 14
3
4
5
20
0
6
50 83 (71)c 17
7
90 66
34
15
57
8
3% (dppf)PdCl2, 12% Ph3As 50 85
3% (dppf)PdCl2, 12% Ph3As 90 43
a Key: 3 (1.5 equiv), 3% (Ph3P)2PdCl2, 6% Ph3P, K2CO3 (1.5
equiv), dioxane, 90 °C, 5 h.
9
10
11
12
2b
2c
Boc 3% (dppf)PdCl2
Ts 3% (dppf)PdCl2
3% (dppf)PdCl2
50 67 (60)c 33
50
0
<10
90 95 (83)c
5
boryl moiety to the R-Pd-OTf complex to generate the
R-Pd-B(OR′)2 intermediate turns out to be significant
only when the temperature is increased (entries 6 and
8), although the reduction process becomes again not
marginal if the reaction is carried out at 90 °C (entries 7
and 9).
a Conditions: 6 (1.5 equiv), Et3N (3 equiv), dioxane, 2 h.
b Conversion determined by 1H NMR analysis of the crude reaction
mixture. c Isolated yield after chromatography.
Interestingly, N-Ts derivative 2c proved to be less
reactive than 2a,b toward both the borylation and
reduction reactions: conversion to 4c was observed only
at 90 °C (entry 12), whereas at lower temperature only
less than 10% (by 1H NMR) of the substrate was reduced
to 7c (entry 11).
As already observed in other cases,5,13 pinacolborane
showed a greater reactivity than bis(pinacolato)diboron
toward lactam-derived vinyl triflates 2a-c, as the bory-
lations with the former reagent were complete in 2 h at
50-90 °C. To further lower the cost of these transforma-
tions, we considered the possibility of using lactam-
derived vinyl phosphates in place of the triflates, which
are similarly prepared by trapping the lactam-derived
potassium enolate with the very cheap diphenyl phos-
phoryl chloride.6,7k,16 We tried a series of conditions with
N-Cbz derivative 2d (Scheme 2), but the reductive
process was predominant under various conditions in the
presence of pinacolborane. Although a certain conversion
to boronate 4a (63%) was observed by carrying out the
reaction with bis(pinacolato)diboron (1.5 equiv) in the
presence of 3% (Ph3P)2PdCl2 in dioxane at 90 °C (Scheme
2), the results obtained with vinyl triflate 2a are superior.
Disappointingly, while the δ-valerolactam derivatives
2a-c were successfully converted into boronates by Pd-
catalyzed coupling reaction with both bis(pinacolato)-
diboron and pinacolborane, pyrrolidinone and ꢀ-capro-
lactam derivatives 9a-c either did not react or were
readily reduced to 11 (Scheme 3) under the optimized
conditions reported above for the six-membered deriva-
tives. In particular, 9a7g (R ) Ts, X ) Tf) decomposed
during the reaction, and 9b16 [R ) CO2Ph, X ) P(O)-
(OPh)2] did not react with bis(pinacolato)diboron. Phos-
phate 9b was completely reduced to pyrroline 11b with
FIGURE 1. Structures of the Herrmann catalyst and Buch-
wald’s phosphine 8.
ligand the reaction occurred at 90 °C, yielding, again,
mainly 7a (entry 4). The highest yields of 4a-c (up to
83%, after chromatography) were obtained when the
couplings were performed in the presence of 3% (dppf)-
PdCl2 as a catalyst and Et3N (3 equiv) as a base, in
dioxane at 50 °C (entries 6 and 10) or 90 °C (entry 12).5a
The presence of Ph3As as an additional ligand appears
to be unnecessary in these reactions (compare entries 6
and 8), as instead reported by Masuda for the transfor-
mation of cyclic alkenyl triflates into the corresponding
boronates with pinacolborane.5b When the reaction was
carried out at room temperature (entry 5), only the
partial reduction of the substrate to 7a (52%) was
observed. This reduction process must be Pd-catalyzed
because the starting material (2a) was recovered unre-
acted after 4 h of heating without the catalyst under the
conditions of entry 6. The transmetalation of the hydride
from pinacolborane, which occurred at room temperature
to form a R-Pd-H species (which in turn undergoes
reductive elimination delivering R-H, i.e., 7a), is re-
markable on the basis of the low nucleophilicity of this
hydride. However, quaternization of the B atom by Et3N
(Figure 2) could play a role in this.15 The transfer of the
(15) Masuda has proposed a mechanism for the borylation in which
Et3N deprotonates pinacolborane forming a boryl anion that then is
transferred to the R-Pd-OTf complex to form the R-Pd-B(OR′)2
intermediate. Please see ref 5a.
(16) Nicolaou, K. C.; Shi, G.-Q.; Namoto, K.; Bernal, F. Chem.
Commun. 1998, 1757.
7326 J. Org. Chem., Vol. 70, No. 18, 2005

SCHEME 3
With aryl triflates (entries 11 and 12), the highest
yields were instead obtained under aqueous conditions,
which provided phenyl and naphthyl derivatives 12 and
16 in 82 and 81% yield, respectively, after chromatogra-
phy. As expected boronate 4a does not undergo hydrolysis
to the corresponding boronic acid under these aqueous
conditions, as we recovered the boronate unaltered when
a THF solution of 4a was heated at 50 °C for 2 h in the
presence of the aqueous base.
The coupling reactions with heteroaryl bromides (Table
4) were generally slower than with aryl bromides and
in some cases did not reach completion even after pro-
longed heating, as in the case of 2-bromopyridine (entry
1). In one case only, conditions employing the pallada-
cycle as the catalyst were superior (entry 3), allowing for
the synthesis of 2-thienyl derivative 24 in 81% yield.
3-Bromofuran reacted only under aqueous conditions
(entry 5) as did various alkenyl halides and triflates
(Table 5, entries 1-4) to give 2-(1-alkenyl)-substituted
piperidines, which are useful dienes in Diels-Alder
reactions.20
The coupling of boronic acids or boronates with acid
chlorides has been described in a few cases.21 We at-
tempted several of the reported reaction conditions21 in
order to couple vinyl boronate 4a with aromatic acid
chlorides. The coupling reaction with benzoyl chloride,
carried out under various anhydrous conditions [for
example, with (Ph3P)2PdCl2 in dioxane and K2CO3 as a
base or in toluene with K3PO4; with (Ph3P)4Pd in toluene
and Cs2CO3 as a base],21a,c did not occur at all, unless
1-2 equiv of water was added. In this case, a low
conversion was observed after prolonged heating. An
appreciable conversion to the desired product 31 was
observed under Bumagin’s conditions (Table 5, entry
5),21d although the highest yield was obtained when we
moved to our standard aqueous conditions (entry 6).
Reasonably, the quaternization of the boron atom by
an HO- ion [or the coordination of the latter to the
acyl-Pd(II) complex]22 is needed to render the trans-
metalation step possible, which is further accelerated
by increasing the concentration (4 M) of the aqueous
base. However, only electron-rich benzoyl chlorides,
as in entry 7, reacted under these conditions to give
the coupling products without undergoing hydrolysis,
and the protocol was inapplicable to aliphatic acid
chlorides.
pinacolborane. Similar results were obtained with the
seven-membered derivative 9c.7j These results are in-
deed not surprising given the thermal instability of
pyrrolidinone- and ꢀ-caprolactam-derived vinyl triflates,
which decompose on standing or during the coupling
reaction.6,7j,17
In contrast to aromatic 2-pyridylboronic esters and,
generally, to boronic acids and esters adjacent to a
heteroatom, which are reported to be highly susceptible
to hydrolytic protodeboronation,18 1,4,5,6-tetrahydro-2-
pyridylboronic ester derivatives 4a-c are compounds
indefinitely stable at room temperature that can be
purified by chromatography on silica gel. An initial study
of reaction conditions for the coupling of 4a with bro-
mobenzene resulted in three optimized protocols: one
employs 2 mol % Herrmann catalyst19 (Figure 1) in
anhydrous toluene at 110 °C with K2CO3 as a base; using
this procedure, a certain amount of 3,4-dihydro-2H-
pyridine 7a (16% by 1H NMR analysis of the crude
reaction mixture) was formed. The second procedure
employs the Pd(OAc)2 (10 mol %)/Ph3P (20 mol %)
catalytic system in the presence of K3PO4‚H2O (2 equiv)
as a base in dioxane at 100 °C. The third protocol employs
aqueous conditions [5% (Ph3P)2PdCl2, 2 M Na2CO3 (aq),
THF, 50 °C]. All of the three procedures were applied to
a series of commercial electron-rich and electron-deficient
aryl bromides, and the best result for each substrate is
reported in Table 3. Good to excellent yields were
obtained with all of the bromoarenes (entries 1-10). Only
2-bromoacetophenone did not react at all under any of
the conditions, presumably because of steric impediment.
It is interesting to note that we always observed the
formation of 7a as a secondary product when we used
the Herrmann catalyst, to an extent exclusively depend-
ent on the nature of the aryl bromide: for example, with
2-bromotoluene, the amount of this byproduct produced
after 4 h at 110 °C was higher (42% by 1H NMR analysis
of the crude reaction mixture) than that produced with
4-methoxybromobenzene (20%) after 8 h at the same
temperature. Also, the reaction of 4a with bromobenzene
took place at lower temperature (90 °C) with the Her-
rmann catalyst; however, it was much slower (15%
conversion after 3.5 h), and in practice, the ratio between
12 and byproduct 7a did not change.
Conclusion
In conclusion, we have demonstrated that δ-valero-
lactam-derived vinyl triflates can be converted into
the corresponding tetrahydropyridine-2-boronic acid pi-
nacol ester derivatives, which results in an umpolung.
Conditions were optimized for the Pd-catalyzed boryla-
tion carried out with both bis(pinacolato)diboron and
pinacolborane. Instead, this was not possible for pyrro-
(17) For example, see: (a) Boren, B.; Hirschi, J. S.; Reibenspies, J.
H.; Tallant, M. D.; Singleton, D. A. Sulikowski, G. A. J. Org. Chem.
2003, 68, 8991. (b) Luker, T.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron Lett. 1996, 37, 8257. (c) Foti, C. J.; Comins, D. L. J. Org.
Chem. 1995, 60, 2656.
(18) (a) Fuller, A. A.; Hester, H. R.; Salo, E. V.; Stevens, E. P.
Tetrahedron Lett. 2003, 44, 2935 and references therein. (b) Ishiyama,
T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57, 9813 and references
therein.
(19) This palladacycle was prepared according to the procedure
reported in: Herrmann, W. A.; Brossmer, K. o¨.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl.
1995, 34, 1844.
(20) (a) Occhiato, E. G.; Trabocchi, A.; Guarna, A. Org. Lett. 2000,
2, 1241. (b) Jiang, J.; De Vita, R. J.; Doss, G. A.; Goulet, M. T.; Wyvratt,
M. J. J. Am. Chem. Soc. 1999, 121, 593. (c) Ha, J. D.; Kang, C. H.;
Belmore, K. A.; Cha, J. K. J. Org. Chem. 1998, 63, 3810.
(21) (a) Urawa, Y.; Ogura, K. Tetrahedron Lett. 2003, 44, 271. (b)
Chen, H.; Deng, M.-Z. Org. Lett. 2000, 2, 1649. (c) Haddach, M.;
McCarthy, J. R. Tetrahedron Lett. 1999, 40, 3109. (d) Bumagin, N. A.;
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(22) Miyaura, N. J. Organomet. Chem. 2002, 653, 54.
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Occhiato et al.
TABLE 3. Pd-Catalyzed Cross-Coupling Reaction of 4a-c with Arylbromides and Aryltriflatesa
a Reactions carried out with 1.5 equiv of RX and stopped when TLC showed total consumption of 4. b Isolated yield after chromatography.
c Method A: 10% Pd(OAc)2, 20% Ph3P, K3PO4‚H2O (2 equiv), dioxane. d Method B: 2% Herrmann catalyst, K2CO3 (2 equiv), toluene.
e Method C: 5% (Ph3P)2PdCl2, 2 M Na2CO3-THF (volume ratio 1.5:2).
lidinone and ꢀ-caprolactam derivatives, which did not
react or were reduced during the Pd-catalyzed coupl-
ing reactions. These δ-valerolactam-derived vinyl bor-
onates efficiently coupled under Pd catalysis with
aryl and heteroaryl bromides and triflates, alkenyl tri-
flates and halides, and aromatic acid chlorides to give
the corresponding 2-substituted piperidines, which are
useful intermediates in organic synthesis. The overall
methodology has two advantages compared to the direct
use of the lactam-derived vinyl triflates in coupling
processes: first, these vinyl boronates are indefinitely
stable on standing. Second, the procedure is of wide
applicability due to the vast range of commercially
available electrophiles for the cross-coupling reactions.
The conversion of the lactam-derived vinyl boronates into
the corresponding boronic acids and trifluoroborates is
7328 J. Org. Chem., Vol. 70, No. 18, 2005

TABLE 4. Pd-Catalyzed Cross-Coupling Reaction of 4a with Heteroarylbromidesa
a Reactions carried out with 1.5 equiv of RBr and stopped when TLC showed complete consumption of 4a. b Isolated yield after
chromatography. c Method A: 10% Pd(OAc)2, 20% Ph3P, K3PO4‚H2O (2 equiv), dioxane. d Conversion determined by 1H NMR analysis of
the crude reaction mixture. e Method B: 2% Herrmann catalyst, K2CO3 (2 equiv), toluene. f Method C: 5% (Ph3P)2PdCl2, 2 M Na2CO3-
THF (volume ratio 1.5:2).
TABLE 5. Other Pd-Catalyzed Cross-Coupling Reactions of 4aa
a Reactions carried out with 1.5 equiv of RX and stopped when TLC showed complete consumption of 4. b Isolated yield after
chromatography. c Method C: 5% (Ph3P)2PdCl2, 2 M Na2CO3, THF. d Method D: 0.1 M PdCl2, 1.63 M Na2CO3, acetone-water (volume
ratio 3:1). e Performed with 4 M Na2CO3 and 2 equiv of acid chloride. f Performed with 2 equiv of acid chloride.
currently under study in our laboratory to further extend
their application to other metal-catalyzed C-C bond
forming reactions such as the 1,2- and 1,4-addition to
carbonyl compounds and the addition to alkenes and
alkynes. The results of these studies will be reported in
due course.
J. Org. Chem, Vol. 70, No. 18, 2005 7329

Occhiato et al.
Method C. To a stirred solution of 4a (52 mg, 0.15 mmol)
in THF (2 mL) were added, under a nitrogen atmosphere, 2
M Na2CO3(aq) (1.5 mL), (Ph3P)2PdCl2 (5.3 mg, 7.5 µmol), and
phenyl trifluoromethanesulfonate (51 mg, 0.23 mmol). The
mixture was heated to 50 °C, left under stirring for 1.5 h, and,
after cooling, diluted with water (10 mL) and extracted with
Et2O (3 × 10 mL). The organic phase was dried for 30 min
over K2CO3 and concentrated in vacuo. The crude oil was
chromatographed (EtOAc-petroleum ether, 1:8, 1% Et3N, Rf
0.42), affording pure 12 (36 mg, 82%) as a colorless oil: 1H
NMR (200 MHz, CDCl3) δ 7.29-7.18 (m, 8 H), 6.79 (m, 2 H),
5.42 (t, J ) 4.0 Hz, 1 H), 4.93 (s, 2 H), 3.83-3.76 (m, 2 H),
2.35-2.23 (m, 2 H), 1.97-1.83 (m, 2 H).
Experimental Section
Procedures for the Preparation of Boronate 4a:
Method A. N-Cbz triflate 2a (780 mg, 2.14 mmol) was
dissolved in anhydrous dioxane (14 mL) in a two-necked flask
under a nitrogen atmosphere. To the solution were added, in
the following order, bis(pinacolato)diboron 3 (816 mg, 3.21
mmol), (Ph3P)2PdCl2 (46 mg, 0.066 mmol), Ph3P (34 mg, 0.13
mmol), and anhydrous K2CO3 (444 mg, 3.21 mmol). The
mixture was heated with an oil bath to 90 °C and left under
stirring for 7 h, after which time the reaction was complete
(by TLC). After cooling to room temperature, the mixture was
diluted with Et2O (60 mL) and washed with water (3 × 40
mL). The organic phase was dried over Na2SO4, filtered, and
concentrated. The crude oil was chromatographed (EtOAc-
petroleum ether, 1:8, Rf 0.20), affording pure 4a (623 mg, 85%)
as a white solid.
Method B. N-Cbz triflate 2a (183 mg, 0.5 mmol) was
dissolved in anhydrous dioxane (2.5 mL) in a Schlenk flask
under a nitrogen atmosphere. To the solution were added, in
the following order, (dppf)PdCl2 (11 mg, 0.015 mmol), pina-
colborane 6 (109 µL, 0.75 mmol), and Et3N (206 µL, 1.5 mmol).
The mixture was heated with an oil bath to 50 °C and left
under stirring for 2 h, after which time the reaction was
complete (by TLC). After cooling to room temperature, the
mixture was diluted with Et2O (15 mL) and washed with water
(3 × 5 mL). The organic phase was dried over Na2SO4, filtered,
and concentrated. The crude oil was chromatographed (EtOAc-
petroleum ether, 1:8, Rf 0.20), affording pure 4a (122 mg, 71%)
as a white solid: mp 65-66 °C; 1H NMR (200 MHz, CDCl3) δ
7.35-7.20 (m, 5 H), 5.28 (br s, 1 H), 5.20 (s, 2 H), 3.59-3.50
(m, 2 H), 2.09-2.02 (m, 2 H), 1.81-1.66 (m, 2 H), 1.31 (s, 12
H); 13C NMR (50.33 MHz, CDCl3) δ 155.6 (s), 135.5 (s), 133.0
(br), 128.2 (d, 2 C), 127.9 (d, 2 C), 127.6 (d), 114.5 (d), 82.8 (s,
2 C), 68.2 (t), 41.5 (t), 24.6 (q, 4 C), 21.7 (t), 21.2 (t); MS m/z
(%) 343 (M+, 0.1), 194 (20), 152 (31), 91 (100). Anal. Calcd for
C19H26BNO4: C, 66.49; H, 7.64; N, 4.08. Found: C, 66.84; H,
7.74; N, 4.01.
6-(4-Methoxyphenyl)-3,4-dihydro-2H-pyridine-1-car-
boxylic Acid Benzyl Ester (18): Method B. Herrmann
catalyst (1.4 mg, 1.5 µmol) and boronate 4a (52 mg, 0.15 mmol)
were dissolved in anhydrous toluene (2 mL) in a Schlenk flask
under a nitrogen atmosphere. To the solution was added
4-bromoanisole (28 µL, 0.23 mmol), followed by anhydrous K2-
CO3 (41.4 mg, 0.30 mmol), and the resulting mixture was
heated at 110 °C. After 8 h, the reaction was complete (by
TLC), and the mixture was diluted with Et2O (15 mL), washed
with water (30 mL), and dried over Na2SO4. Evaporation of
the solvent and chromatography (EtOAc-petroleum ether, 1:8,
Rf 0.36) gave pure 18 (35 mg, 73%) as a colorless oil: 1H NMR
(200 MHz, CDCl3) δ 7.22-7.18 (m, 5 H), 6.82-6.76 (m, 4 H),
5.32 (t, J ) 3.7 Hz, 1 H), 4.92 (s, 2 H), 3.79 (s, 3 H), 3.78-3.73
(m, 2 H), 2.30-2.23 (m, 2 H), 1.92-1.83 (m, 2 H); 13C NMR
(50.33 MHz, CDCl3) δ 158.8 (s), 152.8 (s), 139.3 (s), 135.8 (s),
132.1 (d), 128.0 (d, 2 C), 127.5 (d, 2 C), 126.1 (d, 2 C), 115.6
(s), 114.8 (d), 113.4 (d, 2 C), 67.4 (t), 55.2 (q), 45.2 (t), 23.6 (t),
23.5 (t); MS m/z (%) 323 (M+, 16), 91 (100). Anal. Calcd for
C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.21; H, 6.49;
N, 4.38.
Acknowledgment. We thank MIUR and University
of Florence for financial support. Dr. Alessandro Ferrali
is acknowledged for carrying out some experiments. Mr.
Maurizio Passaponti and Mrs. Brunella Innocenti are
acknowledged for their technical support. Ente Cassa
di Risparmio di Firenze is acknowledged for granting a
400 MHz NMR spectrometer.
Typical Coupling Procedures. 6-Phenyl-3,4-dihydro-
2H-pyridine-1-carboxylic Acid Benzyl Ester (12):7j Method
A. Pd(OAc)2 (3.4 mg, 15 µmol), Ph3P (8 mg, 30 µmol), and
boronate 4a (52 mg, 0.15 mmol) were dissolved in anhydrous
dioxane (1.5 mL) in a Schlenk flask under a nitrogen atmo-
sphere. To the solution was added bromobenzene (24 µL, 0.23
mmol), followed by K3PO4‚H2O (69 mg, 0.30 mmol), and the
resulting mixture was heated at 100 °C. After 1.5 h, the
reaction was complete (by TLC) and the mixture was diluted
with Et2O (15 mL) and washed with water (30 mL). The
organic phase was dried over Na2SO4, filtered, and concen-
trated. The crude oil was chromatographed (EtOAc-petroleum
ether, 1:8, 1% Et3N, Rf 0.42), affording pure 12 (39 mg, 88%)
as a colorless oil.
Supporting Information Available: Full experimental
details and compound characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
JO050995+
7330 J. Org. Chem., Vol. 70, No. 18, 2005