A lactam-derived vinyl boronate as a stable and crystalline reagent for the synthesis of 2-substituted piperidines by Pd-catalyzed coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2004.05.015

A δ-valerolactam-derived vinyl triflate has been converted into the corresponding vinyl boronate by Pd-catalyzed coupling with bis(pinacolato) diboron, which results in an umpolung. This boronate efficiently couples under Pd catalysis with aryl and hetero

Full text of DOI:10.1016/j.tetlet.2004.05.015

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5271–5274
A lactam-derived vinyl boronate as a stable and
crystalline reagent for the synthesis of 2-substituted
piperidines by Pd-catalyzed coupling reactions
Alessandro Ferrali, Antonio Guarna, Fabrizio Lo Galbo and Ernesto G. Occhiato*
Dipartimento di Chimica Organica ‘U. Schiff ’, Universit ꢀa di Firenze, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy
Received 8 April 2004;revised 4 May 2004;accepted 5 May 2004
Abstract—A d-valerolactam-derived vinyl triflate has been converted into the corresponding vinyl boronate by Pd-catalyzed cou-
pling with bis(pinacolato)diboron, which results in an umpolung. This boronate efficiently couples under Pd catalysis with aryl and
heteroaryl bromides to give the corresponding 2-substituted piperidines in excellent yields.
ꢀ
2004 Elsevier Ltd. All rights reserved.
1
Lactam-derived vinyl triflates have found several
applications in the last decade as key intermediates in
the synthesis of heterocyclic compounds. Palladium-
catalyzed coupling reactions with nucleophiles such as
organoboron, organotin, and organozinc derivatives, as
well as carbonylations and Sonogashira couplings, in
particular, have been used for the preparation of an
with the advantage of avoiding the use of toxic tin
5
compounds. The overall procedure should, in principle,
be of wide scope due to the availability of the electro-
philes (e.g. vinyl and aryl halides and triflates, acyl
halides) that are to be used as coupling partners. With
this in mind, we first evaluated the feasibility of the
transformation of lactam-derived vinyl triflate
2
1;2
array of useful a-substituted N-heterocycles. A further
expansion of the synthetic applications of these elec-
trophiles arises from procedures that allow the dis-
placement of the triflate group by a metal such as tin or
lithium. This, in practice, results in an umpolung and it
has been first reported by Hiemstra and co-workers and
4
successively exploited for the synthesis of fasicularin.
We wondered if such an umpolung, followed by metal-
catalyzed coupling reactions with various electrophiles,
could also be realized by a-borylation of the heterocycle,
(Scheme 1) into the corresponding boronate 4, and then
we focused on the Pd-catalyzed coupling of 4 with
bromo(hetero)arenes for the synthesis of 2-aryl- and
2-heteroaryl substituted piperidines that are of great
interest as intermediates in medicinal chemistry.
3
6
Because commercial bis(pinacolato)diboron 3 has suc-
cessfully been employed for the preparation of air and
7
water stable boronates from diverse vinyl triflates,
8
we attempted the conversion of vinyl triflate 2 into
O
O
B
B
KHMDS, PhNTf2
THF, -78°C
O
O
3
Cbz
N
+
O
N
O
ref. 2a
N
Cbz
2
OTf
(Ph3P)2PdCl2,
Ph P, K CO ,
dioxane, 90 °C
N
B
N
Cbz
5
Cbz
3
2
3
Cbz O
4
1
Scheme 1.
Keywords: Boronates;Lactams;Triflates;Palladium;Coupling;Piperidines.
*
Corresponding author. Tel.: +39-055-4573480;fax: +39-055-4573531;e-mail: ernesto.occhiato@unifi.it
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.015

5272
A. Ferrali et al. / Tetrahedron Letters 45 (2004) 5271–5274
boronate 4 by experimenting all of the reported coupling
7
o-tol
o-tol
conditions with 3. The only suitable protocol was that
which uses 1.5 equiv of bis(pinacolato)diboron, in
O
Pd
O
P
Pd
anhydrous dioxane, under (Ph
in the presence of Ph P and with fine powdered K
3
P)
2
PdCl
2
(3%) catalysis,
CO
P
O
O
3
2
3
o-tol o-tol
7a
as a base at 90 ꢁC. The reaction was complete in 7 h
and vinyl boronate 4 was obtained in 85% yield after
8
9
chromatographic purification. Under these conditions,
in situ coupling of 2 with boronate 4 to give dimer 5
10
Figure 1.
1
was almost completely suppressed (less than 8% by H
NMR analysis of the crude reaction mixture). Boronate
4 is a white solid compound, indefinitely stable at room
temperature.
11
Pd(0)
+
R Br
O
N
B
N
Cbz
R
An initial survey of the reaction conditions for the
coupling of 4 with bromoarenes was carried out using
bromobenzene as the electrophile (Scheme 2 and Table
Cbz O
9-20
4
1
).
Scheme 3.
Low yields with aqueous bases (entries 4–5) were mainly
due to degradation of the starting material. The
Pd(OAc) /Ph P catalytic system, in the presence of hy-
heteroaryl bromides (Scheme 3 and Table 2). Data
obtained by using Herrmann catalyst 8 are reported
whenever better or comparable yields were obtained
under the conditions of method A. Despite the
advantage of using a low mol % of catalyst, with this
procedure we always observed the formation of the
a-unsubstituted N-Cbz 3,4-dihydro-2H-pyridine 7 as a
secondary product, to an extent exclusively depending
on the nature of the aryl bromide: for example with 2-
bromotoluene as the electrophile the extent of formation
of this by-product after 4 h at 110 ꢁC was higher (42% by
2
3
drated K
Ph P) Pd under the same conditions (entry 1). Two
were the best protocols: one employs Herrmann catalyst
3 4
PO as a base (entry 6), proved superior to
(
3
4
1
2
8
(1 mol %, Fig. 1) in anhydrous toluene at 110 ꢁC
13
(entry 8) with K
procedure, a certain amount of 3,4-dihydro-2H-pyridine
2 3
CO as a base (method A); using this
1
7
(16% by H NMR analysis of the crude reaction
mixture) was formed;the second procedure employs the
Pd(OAc) (10 mol %)/Ph P (20 mol %) catalytic system
in the presence of K PO ÆH O (2 equiv) as a base in
dioxane at 100 ꢁC (entry 7, method B). 5 mol % or less
of the catalyst can be used with the latter procedure but
longer reaction times are required to consume the
starting material (entry 6).
1
H NMR analysis of the crude reaction mixture) than
2
3
with 4-methoxybromobenzene (20%) after 8 h at the
same temperature. Moreover, with 2-bromotoluene,
changing the catalyst from palladacycle 8 (1%) to
3
4
2
14
(Ph P) Pd (5%) under the conditions of method A, re-
3 4
sulted in a clean, although incomplete after 7 h, reaction
to give 9, suggesting that the H-transfer to the a-position
of the heterocycle to give 7 occurs in the presence of
Both procedures were applied to a series of commercial
electron-rich and electron-deficient aryl bromides and
15
catalyst 8 only. Good to excellent yields were obtained
with all of the bromoarenes (entries 1–8). Only 2-
bromoacetophenone (entry 5) did not react at all either
after 2 h under conditions of method B and 7 h by
method A, presumably because of steric impediment.
Pd(0)
+
Ph Br
+
O
N
Cbz
N
B
N
Cbz
Cbz O
The coupling reactions with heteroaryl bromides (entries
9–12) under conditions B were slower and in some cases
did not reach completion even after prolonged heating,
as with 2-bromopyridine (entry 9). In one case only,
6
7
4
Scheme 2.
a
Table 1. Pd-catalyzed cross-coupling of 4 with bromobenzene
b
Entry
Conditions
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
6% (Ph
5% (Ph
5% (Ph
5% (Ph
5% (Ph
3
3
3
3
3
P)
P)
P)
P)
P)
4
4
4
2
2
Pd, K
Pd, K
Pd, K
3
2
3
PO
CO
PO
4
ÆH
2
O (2 equiv), dioxane, 90 ꢁC
5
55
61
66
43
37
71
88
75
3
(2 equiv), toluene, 110 ꢁC
ÆH O (2 equiv), toluene, 110 ꢁC
5
4
2
5
PdCl
PdCl
2
, 2 M KOH, dioxane, 80 ꢁC
, 2 M KOH, dioxane, 50 ꢁC
1
2
2
5% Pd(OAc)
10% Pd(OAc)
1% 8, K CO
2
, 10% Ph
, 20% Ph
(2 equiv), toluene, 110 ꢁC
3
P, K
3
PO
4
ÆH
2
O (2 equiv), dioxane, 100 ꢁC
5.5
1.5
4
2
3
P, K
3
PO
4
ÆH
2
O (2 equiv), dioxane, 100 ꢁC
2
3
a
Reactions were carried out on 52 mg of 4 (0.15 mmol) with 1.5 equiv of PhBr and stopped after 5 h or when TLC showed complete
consumption of 4.
Isolated yield after chromatography.
b

A. Ferrali et al. / Tetrahedron Letters 45 (2004) 5271–5274
5273
a
Table 2. Pd-catalyzed cross-coupling of 4 with aryl and heteroaryl bromides
b
c
Entry
R–Br
Conditions
Time (h)
Product
Yield (%)
87
Me
Br
Me
Br
1
B
2.5
9
N
Cbz
2
3
B
B
2
2
10
11
91
93
N
Cbz
MeO
MeO
Br
Br
OMe
N
Cbz
d
4
5
6
A
8
7/2
2
N
Cbz
12
13
14
73
0
OMe
COCH3
Br
A/B
B
N
Cbz
COCH3
H3COC
Br
Br
COCH3
89
N
Cbz
7
B
2
N
15
87
H COC
3
Cbz
COCH3
NO2
Br
8
9
B
B
1.5
5
N
Cbz
16
17
83
45
O N
2
N
N
Cbz
N
N
Br
Br
1
1
0
1
B
4
7
N
Cbz
18
19
77
81
N
S
d
A
Br
N
Cbz
S
Br
12
B
2
N
20
62
S
Cbz
S
a
Reactions were carried out on 52 mg of 4 (0.15 mmol) and stopped when TLC showed complete consumption of 4.
b
Conditions A: 1% Herrmann catalyst 8, K
RBr (1.5 equiv), K PO ÆH O (2 equiv), dioxane, 100 ꢁC.
Isolated yield after chromatography. All new compounds gave satisfactory NMR and elemental analysis.
2
CO
3
2 3
(2 equiv), RBr (1.5 equiv), toluene, 110 ꢁC. Conditions B: 10% Pd(OAc) , 20% Ph P,
3
4
2
c
d
2
mol % catalyst.
conditions A using palladacycle 8 were superior (entry
1
1
umpolung. This boronate efficiently couples under Pd
catalysis with aryl and heteroaryl bromides to give the
corresponding 2-substituted piperidines. The overall
methodology is of wide applicability due to the vast
range of commercially available aryl and heteroaryl
bromides. Ongoing studies aim at expanding the scope
of the reaction to different classes of electrophiles.
1) which allowed the synthesis of 2-thienyl derivative
9 in 81% yield.
In conclusion, we have demonstrated that d-valerolac-
tam-derived vinyl triflate 2 can be converted into the
corresponding vinyl boronate 4, which results in an

5274
A. Ferrali et al. / Tetrahedron Letters 45 (2004) 5271–5274
Acknowledgements
3.21 mmol). The mixture was heated with an oil bath to
0 ꢁ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 Et O (60 mL)
and washed with water (3 · 40 mL). The organic phase was
dried over Na SO , filtered and concentrated. The crude
oil was chromatographed (SiO , EtOAc–petroleum ether,
9
MIUR, University of Florence and COFIN 2002–2004
are acknowledged for financial support.
2
2
4
References and notes
2
1
f
:8, R 0.20) obtaining pure 4 (623 mg, 85%) as a white
1
1
2
. For a review on the chemistry of lactam-derived vinyl
triflates see: Occhiato, E. G. Mini-Rev. Org. Chem. 2004,
solid: mp ¼ 65–66 ꢁC; H NMR (200 MHz, CDCl ) d
7.35–7.20 (m, 5H), 5.28 (br s, 1H), 5.20 (s, 2H), 3.59–3.50
3
1, 149.
(m, 2H), 2.09–2.02 (m, 2H), 1.81–1.66 (m, 2H), 1.31 (s,
1
3
. For the most recent applications see: (a) Occhiato, E. G.;
Prandi, C.;Ferrali, A.;Guarna, A.;Venturello, P. J. Org.
Chem. 2003, 68, 9728;(b) Occhiato, E. G.;Prandi, C.;
Ferrali, A.;Guarna, A.;Deagostino, A.;Venturello, P.
J. Org. Chem. 2002, 67, 7144;(c) Toyooka, N.;Fukutome,
A.;Nemoto, H.;Daly, J. W.;Spande, T. F.;Martin
Garraffo, H.;Kaneko, T. Org. Lett. 2002, 4, 1715;(d) Xu,
Z.;Kozlowski, M. C. J. Org. Chem. 2002, 67, 3072;(e)
Occhiato, E. G.;Trabocchi, A.;Guarna, A. J. Org. Chem.
3
12H); C NMR (50.33 MHz, CDCl ) d 155.6 (s), 135.5 (s),
133.0 (br), 128.2 (d, 2C), 127.9 (d, 2C), 127.6 (d), 114.5 (d),
82.8 (s, 2C), 68.2 (t), 41.5 (t), 24.6 (q, 4C), 21.7 (t), 21.2 (t);
þ
MS m=z (%) 343 (M , 0.1), 194 (20), 152 (31), 91 (100).
Elemental analysis calcd C, 66.49;H, 7.64;N, 4.08. Found
C, 66.84;H, 7.74;N, 4.01.
1
10. H NMR (200 MHz, CDCl
(m, 10H), 5.33 (br t, 2H), 5.07 (s, 4H), 3.50–3.10 (br m,
3
) spectrum of 5: d 7.35–7.25
4H), 2.10–1.95 (br m, 4H), 1.75–1.50 (br m, 4H).
2
001, 66, 2459;(f) Fenster, M. D. B.;Patrick, B. O.;Dake,
11. Attempts at preparing the corresponding vinyl boronate
from the N-Ts pyrrolidinone-derived vinyl triflate were
hampered by the ready decomposition of this intermediate
under the coupling conditions.
G. R. Org. Lett. 2001, 3, 2109;(g) Occhiato, E. G.;
Trabocchi, A.;Guarna, A. Org. Lett. 2000, 2, 1241;(h)
Coe, J. W. Org. Lett. 2000, 2, 4205;(i) Bamford, S. J.;
Luker, T.;Speckamp, W. N.;Hiemstra, H.
000, 2, 1157;(j) Lindstr o€ m, S.;Ripa, L.;Hallberg, A.
Org. Lett. 2000, 2, 2291.
. Luker, T.;Hiemstra, H.;Speckamp, W. N. J. Org. Chem.
997, 62, 8131.
. Fenster, M. D. B.;Dake, G. R. Org. Lett. 2003, 5, 4313.
. Very recently the nucleophilic addition of lactam-derived
vinyl triflates to electrophiles such as aldehydes, mediated
by nickel(II) and chromium(II) salts, has been reported:
Easton, L. P.;Dake, G. R. Can. J. Chem. 2004, 82, 139.
. 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.
Org. Lett.
12. This palladacycle was prepared according to the procedure
€
reported in: Herrmann, W. A.;Brossmer, K. O.;Rei-
2
singer, C.-P.;Priermeier, T.;Beller, M.;Fischer, H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1844.
13. General procedure A: catalyst 8 (1.4 mg, 1.5 lmol) and
boronate 4 (52 mg, 0.15 mmol) were dissolved in anhy-
drous toluene (2 mL) in a Schlenk flask under nitrogen
atmosphere. To the solution was added bromobenzene
3
1
4
5
2 3
(24 lL, 0.225 mmol), followed by anhydrous K CO
(41.4 mg, 0.30 mmol) and the resulting mixture was heated
at 110 ꢁC. After 4 h the reaction was complete (by TLC)
6
7
2
and the mixture was diluted with Et O (15 mL), washed
with water (30 mL), and dried over Na
2
SO
, EtOAc–petro-
¼ 0.39) gave pure 6 (33 mg, 75%) as a
4
. Evaporation
. For example see: (a) Ishiyama, T.;Tagaki, J.;Kamon, A.;
Miyaura, N. J. Organomet. Chem. 2003, 687, 284;(b)
Takagi, J.;Kamon, A.;Ishiyama, T.;Miyaura, N. Synlett
of the solvent and chromatography (SiO
2
2
e
leum ether, 1:8, R
f
colorless oil.
2002, 1880;(c) Takagi, J.;Takahashi, K.;Ishiyama, T.;
2 3
14. General procedure B: Pd(OAc) (3.4 mg, 15 lmol), Ph P
Miyaura, N. J. Am. Chem. Soc. 2002, 124, 8001–8006;(d)
Eastwood, P. R. Tetrahedron Lett. 2000, 41, 3705;(e)
Ishiyama, T.;Itoh, Y.;Takahiro, K.;Miyaura, N.
Tetrahedron Lett. 1997, 38, 3447.
(8 mg, 30 lmol) and boronate 4 (52 mg, 0.15 mmol) were
dissolved in anhydrous dioxane (1.5 mL) in a Schlenk flask
under nitrogen atmosphere. To the solution was added
bromobenzene (24 lL, 0.225 mmol), followed by
8
. Lactam-derived vinyl triflate 2 is best prepared by treat-
ment of the lactam 1 with KHMDS at )78 ꢁC in THF,
K
3
PO
4
2
ÆH O (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
Et
Na
followed by the addition of PhNTf
procedure reported in Ref. 2a.
2
according to a
2
O (15 mL), washed with water (30 mL), and dried over
SO . Evaporation of the solvent and chromatography
9
. Preparation of 4: N-Cbz triflate 2 (780 mg, 2.14 mmol) was
dissolved in anhydrous dioxane (14 mL) in a two-necked
flask under nitrogen atmosphere. To the solution were
added, in the order, bis(pinacolato)diboron 3 (816 mg,
2
4
2
e
as above gave pure 6 (39 mg, 88%) as a colorless oil.
15. The reaction takes also place at lower temperature (90 ꢁC)
with the Herrmann catalyst, although it is much slower
(15% conversion after 3.5 h) and, in practice, the ratio
between 9 and by-product 7 does not change.
3
(
.21 mmol), (Ph
3
P)
2
PdCl
2
(46 mg, 0.066 mmol), Ph
34 mg, 0.13 mmol), and anhydrous K CO (444 mg,
3
P
2
3