Cobalt-Catalyzed Cross-Coupling of 3- and 4-Iodopiperidines with Grignard Reagents

Article abstract of DOI:10.1002/chem.201501543

A cobalt-catalyzed cross-coupling between 3- and 4-iodopiperidines and Grignard reagents is disclosed. The reaction is an efficient, cheap, chemoselective, and flexible way to functionalize piperidines. This coupling was used as the key step to realize a short synthesis of (±)-preclamol. Some mechanistic investigations were conducted that highlight the formation of radical intermediates. Scaffold synthesis: A cobalt-catalyzed cross-coupling between iodopiperidines and Grignard reagents is reported (see scheme; PG=protecting group). A large variety of 3- and 4-substituted piperidines were synthesized and the method was applied to a short synthesis of (±)-preclamol. This work constitutes one of the rare examples of cross-couplings involving 3-halogeno piperidines.

Full text of DOI:10.1002/chem.201501543

DOI: 10.1002/chem.201501543
Full Paper
&
Synthetic Methods
Cobalt-Catalyzed Cross-Coupling of 3- and 4-Iodopiperidines with
Grignard Reagents
Laurine Gonnard, Amandine GuØrinot,* and Janine Cossy*[a]
Abstract: A cobalt-catalyzed cross-coupling between 3- and
4-iodopiperidines and Grignard reagents is disclosed. The re-
action is an efficient, cheap, chemoselective, and flexible
way to functionalize piperidines. This coupling was used as
the key step to realize a short synthesis of (Æ)-preclamol.
Some mechanistic investigations were conducted that high-
light the formation of radical intermediates.
Introduction
have been dedicated to the synthesis of substituted piperi-
dines.[6] Among them, the direct functionalization of the piperi-
dine ring through modular metal-catalyzed cross-couplings ap-
peared as a powerful strategy to generate molecular diversity
from halogeno derivatives.[7] Therefore, numerous metal-cata-
lyzed reactions, including Suzuki,[8] Negishi,[9,10] Kumada,[11]
Hiyama,[12] Heck,[13] and Sonogashira[14] cross-couplings, have
been developed to access 4-alkyl, 4-alkenyl, 4-aryl, and 4-alkyn-
yl piperidines (Scheme 1).[15] Palladium and nickel catalysis
rules the field but some examples of iron- and cobalt-catalyzed
cross-couplings involving 4-halogeno piperidines have
emerged as an attractive alternative due to the cheapness and
low toxicity of the metal complexes.[16,17]
Myriads of pharmaceuticals and bioactive alkaloids incorporate
substituted piperidines.[1] In particular, 4-aryl and 3-aryl piperi-
dines are present in numerous drugs exhibiting a broad spec-
trum of biological activities (Figure 1). Paroxetine is an antide-
pressant[2] and naratriptan is used in the treatment of migraine
headaches.[3] Preclamol is an antipsychotic drug[4] and MK-4827
inhibits poly(adenosine diphosphate ribose) polymerase, an
enzyme responsible for DNA repair that plays a role in several
cancers.[5]
Figure 1. Bioactive 4-aryl and 3-aryl piperidines.
Scheme 1. Metal-catalyzed cross-couplings involving 4-halogeno piperidines.
The potent biological activities of substituted piperidines
aroused the interest of organic chemists and important efforts
In stark contrast to the functionalization of 4-halogeno pi-
peridines, very few examples of metal-catalyzed cross-cou-
plings on 3-halogeno piperidines have been reported in the lit-
erature.[18] 3-Aryl piperidines are generally formed by construc-
tion of the ring or by reduction of the corresponding pyri-
dines.[19] In 2013, Baudoin and co-workers described a b-selec-
tive arylation of N-(tert-butoxycarbonyl)piperidines by using
a lithiation followed by a transmetallation with zinc and a sub-
sequent Pd-catalyzed Negishi cross-coupling in the presence of
an appropriate phosphine ligand (Scheme 2, Eq. (1)).[20] Mo-
[a] L. Gonnard, Dr. A. GuØrinot, Prof. J. Cossy
Laboratoire de Chimie Organique
Institute of Chemistry, Biology and Innovation (CBI)-UMR 8231
ESPCI ParisTech, CNRS, PSL Research University
10, rue Vauquelin 75231 Paris Cedex 05 (France)
E-mail: amandine.guerinot@espci.fr
janine.cossy@espci.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501543.
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lander et al. developed a nickel-catalyzed reductive cross-cou-
pling between O- and N-heterocyclic bromides or tosylates
and (hetero)aryl bromides.[15c,h] A 3-aryl piperidine was ob-
tained from N-Boc-3-bromopiperidine with this method, albeit
in a moderate 50% yield (Scheme 2, Eq. (2)).
and phenylmagnesium bromide was examined. In the absence
of any catalytic system, no reaction occurred (Table 1, entry 1).
An iron catalyst was first tested but, when FeCl2 was associated
with TMEDA, the cross-coupling product 2a was formed along
with the elimination product 3a and its isomer 4 in a ratio of
57/28/15 (Table 1, entry 2). The use of (R,R)-tetramethylcyclo-
hexanediamine (TMCD) instead of TMEDA suppressed the elim-
ination side-products but, in this case, the dehalogenated
product 5 was formed and the expected aryl piperidine was
isolated in a moderate yield of 60% (Table 1, entry 3). To ad-
dress these issues, we decided to switch to cobalt catalysis
and Co(acetylacetonate)3 (5 mol%), in association with TMEDA
(6 mol%), was tested.[22] Pleasingly, even if an incomplete con-
version of 1a was obtained (79%), the side-products 3a–5
were not detected (Table 1, entry 4). A switch to TMCD slightly
improved the reactivity (Table 1, entry 5) and, finally, the best
result was obtained with CoCl2 (5 mol%) and TMCD (6 mol%;
Table 1, entry 6).[23] Under these conditions, the iodopiperidine
1a was fully converted into the cross-coupling product 2a,
which was isolated with a good yield of 81%.
Scheme 2. 3-Arylation of piperidines. Boc=tert-butoxycarbonyl; TMEDA=te-
tramethylethylenediamine.
In the course of our studies toward the development of sus-
tainable synthetic methods to access pharmaceutically relevant
scaffolds, we recently developed an iron- and cobalt-catalyzed
arylation of saturated N-heterocycles by using Grignard re-
agents.[21] Notably, a large variety of 4-(hetero)aryl piperidines
were prepared through a cobalt-catalyzed cross-coupling. Fur-
ther studies allowed us to extend the method to the prepara-
tion of 4-alkenyl and 4-allyl piperidines. Remarkably, 3-aryl pi-
peridines were synthesized by using a cobalt-catalyzed cross-
coupling with Grignard reagents, which constitutes, to the
best of our knowledge, the first example of cross-coupling in-
volving a 3-halogeno piperidine and an organometallic re-
agent. Herein, a full account of our work on the cobalt-cata-
lyzed functionalization of halogeno piperidines is disclosed
(Scheme 3).
Table 1. Optimization of the catalytic system.
Entry [M] (loading L[a] (loading Conv.[b] 2a/3/4/5[c] Yield of 2a
[mol%])
[mol%])
[%]
[%][d]
1
2
3
4
5
6
–
–
0
–
–
FeCl2 (10)
FeCl2 (10)
Co(acac)3 (5) TMEDA (6)
Co(acac)3 (5) TMCD (6)
TMEDA (10) 100
TMCD (10)
57:28:15:0 n.d.
100
79
87
87:0:0:13
79:0:0:0
87:0:0:0
100:0:0:0
60
n.d.
n.d.
81
CoCl2 (5)
TMCD (6)
100
4-Bromopiperidine 1a’ could also be used as the coupling
partner under the optimized conditions but, due to its lower
reactivity, an increased amount of Grignard reagent was re-
quired to reach full conversion (2 equiv versus 1.2 equiv)
(Scheme 4).[24]
Scheme 3. Functionalization of 4- and 3-halogeno piperidines. Bn=benzyl;
PG=protecting group; Ts=toluene-4-sulfonyl.
Scheme 4. Cross-coupling of 4-bromopiperidine 1a’.
Recently, the scope of the reaction with the optimized con-
ditions was reported and the N-protecting-group tolerance
was first examined.[21] As mentioned before, the reaction was
compatible with an N-carbamate. An iodosulfonamide was suc-
Results and Discussion
To determine the appropriate catalytic system, the metal-cata-
lyzed cross-coupling between the N-Boc-4-iodopiperidine (1a)
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cessfully involved in the cross-coupling with phenylmagnesium
bromide to deliver the aryl piperidine 2b, albeit with a lower
yield than with the N-carbamate (69% versus 81%)
(Scheme 5). A similar result was obtained in the presence of an
N-benzyl protecting group (2c, 66%).[25]
C4 position (Table 2, entry 3) and, interestingly, the coupling
was not sensitive to steric hindrance because o-tolylmagnesi-
um bromide was successfully coupled to the 4-iodopiperidine
in 88% yield (Table 2, entry 4). Electron-poor Grignard reagents
bearing a p-fluoro or a p-trifluoro groups were involved in the
cross-coupling to provide the desired products in good yields
(76 and 96%, respectively) (Table 2, entries 5 and 6).[26] Pleas-
ingly, even the Grignard reagent prepared from O-Boc-p-bro-
mophenol could be coupled to the 4-iodopiperidine in a satis-
fying yield (Table 2, entry 7). One limitation was encountered:
if a p-cyano group was present on the Grignard reagent, the
reaction was sluggish and a poor conversion of the starting
material (30%) was observed (Table 2, entry 8). This result
might be due to a coordination of the nitrile group to the
cobalt center that could poison the metal catalyst. In contrast,
the use of a heteroaryl Grignard reagent, such as 3-pyridylmag-
nesium bromide, was tolerated under the optimized condi-
tions. In this case, a decrease in the temperature to À108C
was beneficial and the coupling product was isolated in an ex-
cellent 96% yield (Table 2, entry 9). It is worthy of note that
the presence of the basic nitrogen atom does not interfere
with the metal catalyst.
Scheme 5. Compatibility of various N-protecting groups.
The N-Boc-4-iodopiperidine (1a) was selected for the evalua-
tion of the reactivity of a large variety of aryl magnesium bro-
mides. We had already noticed that the electronic nature of
the substituent on the aryl group of the Grignard reagent did
not seem to play a significant role in the outcome of the reac-
tion.[21] Indeed, electron-rich aromatic Grignard reagents such
as p-tolyl- and m-OMe-phenylmagnesium bromide were suita-
ble coupling partners and allowed the formation of the corre-
sponding 4-aryl piperidines 2d and 2e in excellent yields (81
and 85%, respectively) (Table 2, entries 1 and 2). A p-dimethy-
lamino aryl group was also introduced on the piperidine at the
Encouraged by these positive results, we then turned our at-
tention to the coupling between 4-iodopiperidines and alkenyl
Grignard reagents. With vinylmagnesium bromide, no reaction
occurred and the starting material 2a was fully recovered
(Table 3, entry 1). If the N-Boc-4-iodopiperidine (1a) was treat-
ed with isopropenylmagnesium bromide, the expected prod-
uct 2m was delivered with a moderate 55% yield (Table 3,
entry 2). A similar result was obtained when prop-1-en-1-yl-
magnesium bromide (E/Z=1/1.5) was used and 2n was isolat-
ed with no significant change in the E/Z ratio compared to the
E/Z ratio of the Grignard reagent.[29] The use of 2-methyl-1-pro-
penylmagnesium bromide led to the formation of the cross-
coupling product 2o along with the elimination product 3a in
Table 2. Variation of the aryl Grignard reagent.
Entry
1
ArMgBr[a]
2 (yield [%])
2d (81)
Table 3. Cross-coupling with alkenyl Grignard reagents.
2
2e (85)[21]
2 f (90)[21]
3[b]
4
2g (88)
Entry
PG
RMgBr[a]
T [8C]
2/3[b]
–
2 (yield [%])
–
5
2h (76)[21]
2i (96)[21]
1
2
Boc
Boc
0 to RT
0 to RT
6[b]
7[b]
8[b]
9[b]
100:0
2m (55)
3[c]
4
Boc
Boc
Boc
Ts
0 to RT
0 to RT
À10
100:0
2n (55)[d]
2o (52)
2o (70)
2p (72)
2j (74)[21]
78:22
100:0
100:0
1
2k (n.d.)[21]
2l (62) (96[c])[21]
5
6
À10
[a] Two equivalents were used. [b] Determined by H NMR analysis. [c] E/Z
ratio of the Grignard reagent=1:1.5. [d] The E/Z ratio was estimated to
be 1:1.25.
[a] 1.2–2 equiv; see the Supporting Information for details. [b] ArMgBr·LiCl
prepared by Mg insertion in the presence of LiCl.[27,28] [c] At À108C.
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a 78/22 ratio, which resulted in a moderate yield of 2o (52%;
Table 3, entry 3). Pleasingly, a decrease in the temperature to
À108C suppressed the undesired elimination process and al-
lowed a significant improvement of the yield of 2o (70%; Ta-
ble 3,entry 4). The N-carbamate could be changed for an N-sul-
fonamide with no influence on the yield of the cross-coupling
(Table 3, entry 5).
To further extend the scope of the cross-coupling, the intro-
duction of an allyl motif on the piperidine ring was investigat-
ed. However, if the 4-iodopiperidine 1a was treated with allyl
magnesium bromide in the presence of CoCl2 and TMCD,
a low conversion of 1a into 2q (23%) was observed and some
unidentified impurities were formed (Table 4, entry 1). An in-
crease in the catalytic loading improved the conversion (50%)
but, once again, 2q was obtained together with some impuri-
ties (Table 4, entry 2). Inspired by the work of Oshima and co-
workers, we switched to another catalytic system composed of
CoCl2 (10 mol%) and 1,3-bis(diphenylphosphino)propane
(12 mol%).[30] Under these conditions, 2q was the unique prod-
uct of the reaction, even if it was isolated in a low 36% yield
(Table 4, entry 3). A decrease in the temperature to À108C was
the key to reach a satisfying yield of 58% and a similar result
was obtained at À788C (Table 4, entries 4 and 5).[31] Gratifying-
ly, a switch to a sulfonamide allowed the yield to be improved
significantly and 2r was isolated in 89% yield (Table 4, entry 6).
Scheme 6. Synthesis of N-Boc-3-iodopiperidine (8). DIB=(diacetoxyiodo)ben-
zene.
the reactions at À108C to reach high yields in the coupling
products and excellent yields, of up to 94%, were obtained for
the formation of the desired compounds. A wide range of aryl
Grignard reagents were successfully coupled to the 3-iodopi-
peridine, irrespective of the electronic nature of the substitu-
ents on the aryl group (Scheme 7). The tolerance of some func-
tional groups, such as a Boc-protected phenol, under the reac-
tion conditions offers the opportunity for further transforma-
tions. If a Grignard reagent possessing a pyridyl ring was in-
volved, a moderate yield of 47% of 9h was obtained in the
presence of 6 mol% of TMCD. An increase in the catalytic load-
ing of TMCD to 50 mol% allowed the yield to be improved to
57%.
Table 4. Allylation of 4-iodopiperidines 1a and1b.
Entry
PG
T [8C]
CoCl2 loading
[mol%]
L[a] (loading
[mol%])
2 (yield [%])
1
2
3
4
5
6
Boc
Boc
Boc
Boc
Boc
Ts
0 to RT
0 to RT
0 to RT
À10
5
10
10
10
10
10
TMCD (6)
TMCD (12)
dppp (12)
dppp (12)
dppp (12)
dppp (12)
2q (23)[a]
2q (50)[a]
2q (36)
2q (58)
2q (61)
2r (89)[b]
À78
À10
Scheme 7. Cross-coupling involving 3-iodopiperidine 8. [a] Grignard pre-
pared as ArMgBr·LiCl.[29] [b] Using 50 mol% of TMCD.
[a] dppp: 1,3-bis(diphenylphosphino)propane. [b] Conversion of 1a into
2q was estimated by H NMR spectroscopy; some unidentified impurities
1
were observed. [c] A trace of an unidentified impurity was observed.
The coupling method was successfully applied to a short
synthesis of (Æ)-preclamol (Scheme 8).[33] The N-Boc-3-iodopi-
peridine (8) was first coupled with 3-methoxyphenylmagnesi-
um bromide to give 9i (88%). The propyl substituent on the
nitrogen atom was then introduced by treatment with tri-
fluoroacetic acid followed by a reductive amination with
propanal. Finally, the cleavage of the methoxy ether in the
presence of HBr delivered (Æ)-preclamol (32% overall yield).
This sequence illustrates the great potential of our coupling
method in the synthesis of pharmaceutically relevant mole-
cules.
Intrigued by the scarcity of reports on metal-catalyzed cross-
couplings involving 3-halogeno piperidines, we then focused
on the reactivity of N-Boc-3-iodopiperidine in the cross-cou-
pling. The 3-iodopiperidine 8 could not be accessed from the
corresponding alcohol 6 and a radical decarboxylation was ap-
plied to 7 to overcome this difficulty (Scheme 6). In the pres-
ence of iodine and (diacetoxyiodo)benzene under irradiation, 8
was isolated in a moderate yield of 58%.[32]
With the desired substrate in hand, various aryl Grignard re-
agents were tested under the previous optimized conditions
[CoCl2 (5 mol%), TMCD (6 mol%)]. It was essential to perform
The mechanism of the cobalt-catalyzed cross-coupling has
not been fully elucidated yet; however, the formation of radical
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Scheme 10. Cross-couplings involving radical clocks 12a and 12b.
Scheme 8. Synthesis of (Æ)-preclamol. TFA=trifluoroacetic acid.
the first SET. The 5-exo-trig cyclization is approximately 1000
times faster than the 6-exo-trig cyclization. As a consequence,
in the case of 12a, the cyclization is fast enough to occur
before the cross-coupling (Scheme 11, Pathway A), whereas the
cross-coupling is faster than the cyclization step for 12b
(Scheme 11, Pathway B). In both pathways, a final reductive
elimination provided the product and a subsequent transme-
tallation afforded the active catalyst.
intermediates has been demonstrated on several occasions.[34]
According to literature reports, it can be proposed that, after
the reduction of CoCl2 into an active Co(0) catalyst by the
Grignard reagent, a first single-electron transfer (SET) occurs to
release a radical intermediate. A second SET completes the
formal oxidative addition of the cobalt atom into the CÀI
bond. Finally, a reductive elimination furnishes the coupled
product and a transmetallation with PhMgBr releases the
active catalyst (Scheme 9).
Conclusion
In summary, an efficient, chemoselective, cheap, and conven-
ient cobalt-catalyzed cross-coupling between iodopiperidines
and Grignard reagents was developed. The reaction is general
because 4-iodo- as well as 3-iodopiperidines were functional-
ized with a wide range of Grignard reagents, including aryl, al-
kenyl, and allyl Grignard reagents. The reactions generally pro-
ceed with high yields and are compatible with several func-
tionalized groups, such as carbamates, ethers, and pyridine;
the reaction thus offers a large modularity. To the best of our
knowledge, this constitutes the first example of metal-cata-
lyzed cross-coupling between a 3-halogeno piperidine and an
organometallic partner. The method could be of high synthetic
value to prepare biologically active compounds incorporating
Scheme 9. Hypothetical mechanism for the Co-catalyzed cross-
coupling. SET: single-electron transfer.
To support the hypothesis of radical-intermediate
formation, the two radical clocks 12a and 12b were
prepared[35] and involved in Co-catalyzed cross-cou-
pling with phenylmagnesium bromide (Scheme 10).
When 12a was treated with phenylmagnesium bro-
mide in the presence of the optimized catalytic
system, the bicyclic product 13a, which results from
a 5-exo-trig cyclization prior to the cross-coupling,
was formed exclusively. By contrast, the use of 12b,
which bears an additional carbon atom on the ether
pendant chain, only led to the disubstituted piperi-
dine 13b.
The apparently opposite results obtained with radi-
cal clocks 12a and 12b might be explained by kinet-
ic considerations relative to the step subsequent to Scheme 11. Hypothetical mechanism with radical clocks 12a and 12b.
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piperidine scaffolds, as was demonstrated through the short
synthesis of (Æ)-preclamol with a cross-coupling as the key
step. With consideration of the various pharmaceutical proper-
ties of numerous piperidine-containing molecules, this cross-
coupling could become a powerful tool in drug discovery.
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Experimental Section
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General procedure for the cobalt-catalyzed cross-coupling
CoCl2 (5 mol%) and TMCD (6 mol%) were added to a solution of
the halogeno piperidine (1 equiv). The Grignard reagent (1.2–
2 equiv) was then added dropwise (no need for a syringe pump) at
the appropriate temperature and the resulting mixture was stirred
for 3 h at the appropriate temperature. The reaction was quenched
by addition of a saturated aqueous solution of NH4Cl and the
aqueous phase was extracted with Et2O. The combined organic
phases were dried over MgSO4 and filtered, then the solvent was
removed under vacuum. Flash chromatography afforded the ex-
pected cross-coupling product.
Keywords: catalysis · cobalt · cross-coupling · piperidines ·
synthetic methods
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Full Paper
[25] When the N-Ts-iodopiperidine and the N-Bn-iodopiperidine were used,
two equivalents of Grignard reagent were required. In the case of the
N-Bn-iodopiperidine, TMCD was used at a loading of 50 mol%.
[26] A cross-coupling between bromide derivative 1a’ and the 4-trifluoro-
methylphenylmagnesium bromide reagent (2 equiv) was carried out
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1H NMR spectra of the crude mixture), which confirmed that iodide de-
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with the cross-coupling reaction.
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1H NMR spectrum and an estimation is given. Unfortunately, we were
not able to identify the major isomer; see the NMR spectrum in the
Supporting Information for details.
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Received: April 21, 2015
Published online on July 14, 2015
Chem. Eur. J. 2015, 21, 12797 – 12803
www.chemeurj.org
12803
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim