Additive effects in the palladium-catalyzed carboiodination of chiral N-allyl carboxamides

Article abstract of DOI:10.1002/anie.201404007

The use of Pd catalysis as a means to synthesize organic halides has recently received increased attention. Among the reported methods is the Pd-catalyzed carboiodination, which uses extremely bulky ligands to facilitate carbon-halogen reductive eliminati

Full text of DOI:10.1002/anie.201404007

Angewandte
Chemie
DOI: 10.1002/anie.201404007
Carboiodination
Additive Effects in the Palladium-Catalyzed Carboiodination of Chiral
N-Allyl Carboxamides**
David A. Petrone, Hyung Yoon, Harald Weinstabl, and Mark Lautens*
Abstract: The use of Pd catalysis as a means to synthesize
organic halides has recently received increased attention.
Among the reported methods is the Pd-catalyzed carboiodi-
nation, which uses extremely bulky ligands to facilitate carbon–
halogen reductive elimination from PdII as the key catalytic
step. When approaching substrates exhibiting low stereoselec-
tivity, catalyst troubleshooting becomes difficult as there are
few ligands known to promote the key reductive elimination.
Herein, we present our finding that tertiary amines act as
weakly coordinating ligands which significantly enhance
diastereoselectivity in the Pd/QPhos-catalyzed carboiodina-
tion of chiral N-allyl carboxamides. This methodology allows
efficient access to enantioenriched and densely functionalized
dihydroisoquinolinones, and has been applied toward the
asymmetric formal synthesis of (+)-corynoline.
W
e have been investigating the synthetic potential of
reversible oxidative addition[1] in catalytic processes since
our first report in 2010.[2a] Our group subsequently developed
an olefin carboiodination process[3] by reacting an aryl iodide
containing a tethered alkene in the presence of sterically
hindered ligands and a palladium catalyst (Scheme 1a).[2b]
Tong et al. found similar reactivity with alkenyl iodides
containing tethered alkenes using palladium and a large
excess of a bidentate ligand.[2c] We have broadened the scope
of the carboiodination process by demonstrating that aryl
bromides could serve as precursors in the presence of added
iodide,[2d] and investigated the selective carboiodination of
polyhalogenated starting materials.[2e] Diastereoselective pro-
cesses were also probed by studying substrates with pre-
existing stereocenters. All of these studies employ QPhos or
Scheme 1. Development of Pd0-catalyzed alkene carboiodination.
SM=starting material; L=QPhos.
PtBu3 as ligands. A computational study undertaken with
Houk found that ArI oxidative addition occurs from a four-
coordinate ArPdIII species A which contains a single phos-
phine ligand and a bound olefin. Alkene insertion ensues to
form T-shaped tricoordinate species B, which undergoes
turnover-limiting reductive elimination to form the desired
alkyl iodide (Scheme 1b). The use of less bulky phosphines
leads to tetracoordinate Pd species, which fail to undergo
reductive elimination.[4] In substrates which give lower
selectivity, a dilemma arises when seeking to improve the
diastereoselectivity of carbopalladation, since there is cur-
rently a limited number of suitable bulky phosphines that
trigger the necessary reductive elimination. The ligands found
to promote high selectivity during alkene insertion (A to B)
were found to be significantly different than those needed to
go from B to the final product. Herein, we report a solution to
this dilemma by using weakly binding amine additives[5] in the
diastereoselective synthesis of enantioenriched dihydroqui-
nolinones[5] from chiral N-allyl carboxamides. The optimal
amine (1,2,2,6,6-pentamethylpiperidine, PMP) has the correct
balance of enhancing diastereoselectivity and chemoselectiv-
ity while only minimally reducing the reaction rate (Sche-
me 1c). This highly stereoselective transformation was
required for our asymmetric formal synthesis of (+)-coryno-
line 3,[7–10] a member of the phenanthridine alkaloids.
[*] D. A. Petrone, H. Yoon, Dr. H. Weinstabl, Prof. Dr. M. Lautens
Department of Chemistry, University of Toronto
80 St. George St. Toronto, Ontario (Canada)
E-mail: mlautens@chem.utoronto.ca
Homepage: http://www.chem.utoronto.ca/staff/ML/index.php
[**] We thank the Natural Sciences and Engineering Research Council of
Canada (NSERC), the University of Toronto, and Alphora Inc. for
financial support. M.L. thanks the Canada Council for the Arts for
a Killam Fellowship. D.A.P. thanks NSERC for a postgraduate
scholarship (CGS-D). H.W. thanks the Austrian Science Fund (FWF)
(J3250-N19) for an Erwin Schrçdinger postdoctoral fellowship. The
authors wish to acknowledge CFI project number 19119 for funding
the CSICOMPNMR Facility. Dr. Darcy Burns (Chemistry Depart-
ment, U of T) is sincerely thanked for his intuitive assistance with
NMR. Dr. Alan Lough (Chemistry Department, U of T) is thanked for
single-crystal X-ray structural analysis. We thank Johnson Matthey
for kind gifts of [Pd(QPhos)2]. Theo Bruun (U of T) is thanked for
assistance in preparing starting materials for the racemic assays.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404007.
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Our study commenced by preparing enantioenriched N-
allyl carboxamide 1a (> 99:1)[10] by a 5-step route employing
Ellmanꢀs auxilliary in order to test the subsequent carboiodi-
nation. When 1a was subjected to the previously developed
conditions of [Pd(PtBu3)2] (5 mol%) and NEt3 (1 equiv)[12] in
PhMe (0.05m) at 1108C,[2e] 2 was obtained in 65% yield with
85:15 d.r. (2a:2a’) and no erosion of e.r. Two by-products in 4
(2%) and 5 (5%) were observed which likely form by
a reduction of the PdII species resulting from alkene
insertion,[13] or a C H functionalization of the aromatic ring
À
oriented cis to this species,[14] respectively. In the absence of
amine base the yield and diastereoselectivity of 2a decreased
to 16% and 72:28, respectively, when using this catalyst
[Eq. (1)]. After screening various reaction parameters, the
optimal conditions were found to be [Pd(QPhos)2] (5 mol%)
and PMP (2 equiv) in PhMe (0.1m), at 1008C for 22 h.[15]
Under these conditions, 2a was isolated in 88% yield with
> 95:5 d.r., whereas in the absence of PMP, 2a was afforded in
95% yield with 83:17 d.r. [Eq. (2)]. The positive influence of
Scheme 2. In situ reaction monitoring for the intramolecular carbo-
iodination of 1a. a) Reaction conditions: Pd(QPhos)2 (0.05 equiv),
[1a]0 =0.1m, [D8]PhMe, 368 K, 600 MHz. b) Reaction conditions: Pd-
(QPhos)2 (0.05 equiv), PMP (2 equiv), [1a]0 =0.1m, [PMP]=0.2m,
[D8]PhMe, 368 K, 600 MHz.
amine base addition on the selectivity became clear and was
general across a series of tertiary amines, however, PMP
provided superior yields and selectivities.
mine the diastereoselectivity.[19] Therefore, it appears that the
added amine is interacting with the catalyst in this step.
However, in order to have all three substrate-derived ligands
(aryl, halide, and alkene) as well as both, QPhos and PMP,
bound during this step, a pentacoordinate PdII intermediate
would need to exist,[20] and olefin insertion reactions of
pentacoordinate PdII species are energetically unfavorable.[21]
Overman reported that a pentacoordinate PdII intermediate
undergoes associative ionization to form a cationic tetracoor-
dinate PdII-BINAP species in polar solvents like DMA during
the asymmetric Heck reaction.[22] However, our use of
a nonpolar solvent (PhMe) casts a level of doubt on a similar
cationic process occurring here. Mikami et al. reported that
either four- or five-coordinate species can undergo carbopal-
ladation during PdII-catalyzed cyclization of 1,6-enyes, when
a polar (DMSO) or nonpolar solvent (PhH) is used,
respectively.[23] Two options are: 1) an associative mechanism
involving olefin-assisted ligand dissociation of C, thereby
creating a neutral four-coordinate species D which undergoes
carbopalladation (Scheme 3, route a), or 2) a neutral five-
coordinate complex containing both, QPhos and PMP, ligands
One possible explanation for the change in d.r. is the
selective decomposition under the reaction conditions, but
this proved to not be the case. Alternatively, the bulky and
basic tertiary amine PMP[16] may alter the geometry of the
active catalyst by weak coordination, thus making the
carbopalladation more selective. We believed that a deeper
understanding of these results could be gained by in situ
NMR reaction monitoring (Scheme 2).[15,17] Therein, we
found that the reaction had reached full conversion after
35 min in the absence of PMP (Scheme 2a), whereas ca. 60%
conversion had been reached after the same time frame in the
presence of PMP (Scheme 2b). The possibility of selective
decomposition was contradicted by observing the consistent
production of both diastereomers with no observable dimin-
ution of yield. Conversely, these experiments support the
notion of amine coordination, as its presence attenuates the
overall reaction rate, while imparting nearly a fivefold
increase in selectivity.
Based on earlier studies,[18] the facial selectivity of olefin
coordination, and subsequent carbopalladation will deter-
directly undergoes olefin carbopalladation to form E
(Scheme 3, route b). Both routes ultimately lead to a tricoor-
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This methodology was used to ach-
ieve the asymmetric formal synthesis of
(+)-corynoline 3 (Scheme 5). Hexacycle
3 has exhibited diverse pharmacological
effects including inhibition of cell adhe-
sion[8a] and acetylcholinesterase,[8b] as
well as fungi- and cytotoxicity,[8c] yet
only a limited number of total syntheses
of this molecule have been reported.[9,10]
We achieved the diastereoselective car-
boiodination of 1n on a 5 gram scale
under slightly modified conditions,[15] to
afford 2n in 84% yield in 91:9 d.r.
Cyanide displacement of the hindered
neopentyl iodide afforded nitrile 8 in
67% yield, which was not susceptible to
Scheme 3. Possible fates of the proposed pentacoordinate ArPdIIX-olefin intermediate C.
dinate neopentyl PdII complex F which undergoes reductive
elimination to form product.
hydrolysis under acidic or basic conditions. Therefore, a two-
step reduction/oxidation sequence was employed to afford
The effect of added amine on the d.r. was explored for
a variety of substrates and was found to provide a straightfor-
ward route to dihydroisoquinolinones (Table 1). In all cases,
enantioenriched carboxamides (1a–o) were cyclized to the
corresponding products (2a–o) with no erosion of e.r.
Furthermore, either starting material enantiomer is accessible
with nearly complete enantioenrichment. For instance, ent-1a
was prepared and reacted to give ent-2a in 90% yield with
> 95:5 d.r. Electron-rich aryl iodides (1b–c, 1g) participated
under the standard reaction conditions to provide the desired
dihydroisoquinolinones (2b–c, 2g) in good yields (82 to 88%)
and selectivities (93:7 to 94:6 d.r.). Electron-deficient
aryl iodides 1d and 1e underwent cyclization to the corre-
sponding products 2d and 2e with identical levels of
selectivity (97:3 d.r.) in 54% and 76% yields, respectively.
The former required a 7.5 mol% [Pd] to avoid a sluggish and
low yielding reaction. When the N-protecting group on
nitrogen was converted from Me to Bn (1h–j), the highest
selectivities were observed (> 98:2) with comparable product
yields (87–95%) in substrates possessing an allylic aromatic
group (2h–j). Substitution on the noniodinated aromatic ring
appeared to have no serious deleterious effects on yield, and
1k and 1l were efficiently cyclized to the desired products (2k
and 2l) in 76% and 82% yield with 93:7 and 94:6 d.r.,
respectively.
Table 1: Reaction scope.[a–d]
PMB ether 1m was efficiently cyclized to the correspond-
ing orthogonally protected product 2m in 91% yield with
80:20 d.r. Ether 2m could be deprotected using DDQ to
afford alcohol 6, which underwent smooth cyclization to
pyrano-fused tricycle 7 (Scheme 4). When 1 f containing an N-
Bz group was subjected to the reaction conditions using
7.5 mol% [Pd], the corresponding product 2 f was obtained in
61% yield after 48 h, albeit with a decreased diastereoselec-
tivity of 65:35 d.r. Finally, the robustness of this reaction was
highlighted by highly electron-rich substrates 1n and 1o
undergoing cyclization to the corresponding products 2n and
2o in 84% and 91% yield with 92:8 and 87:13 d.r.,
respectively, when 7.5 mol% [Pd] was used. It should be
noted that products arising from b-hydrogen elimination were
isolated exclusively when starting materials containing mono-
substituted olefins were employed.[15]
[a] 0.2 mmol scale. [b] All yields shown are yields of the combined
isolated diastereomers. [c] D.r. values determined by 1H NMR analysis of
the crude reaction mixture. [d] E.r. values determined by HPLC using
a chiral stationary phase. [e] 7.5 mol% [Pd(QPhos)2], PMP (3.5 equiv).
[f] The reaction was run for 48 h. [g] Both diastereomers were found to be
present in >99:1 e.r.
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Experimental Section
A dry 2 dram vial was charged with 1b (81.0 mg, 0.2 mmol, 1 equiv)
and [Pd(QPhos)2] (15.3 mg, 0.01 mmol, 5 mol%), and purged with
argon. The contents of the vial were taken up in PhMe (2 mL), and
PMP (72.4 mL, 0.4 mmol, 2 equiv) was added to the mixture. The
reaction vial was fitted with a Teflon lined screw cap, sealed with
Teflon tape, and placed into a preheated oil bath (1008C). After 22 h
the reaction was cooled, filtered through a short pad of silica gel
eluting with EtOAc, and concentrated. The d.r. was determined by
1H NMR analysis of the crude reaction mixture, which was sub-
sequently purified by silica gel flash column chromatography using
hexanes/EtOAc (3:1 v/v) as the mobile phase to give 2b
Scheme 4. Synthesis of fused pyran 6 from 2l. DDQ: 2,3-dichloro-5,6-
dicyano-1,4-benzochinone; TBAI: tetrabutylammoniom iodide.
as a white solid (71.6 mg, 0.177 mmol, 88%).
Received: April 4, 2014
Published online: && &&, &&&&
Keywords: carboiodination · heterocycles ·
.
palladium · phosphine ligands
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Communications
Carboiodination
D. A. Petrone, H. Yoon, H. Weinstabl,
M. Lautens*
&&&& — &&&&
Additive Effects in the Palladium-
Catalyzed Carboiodination of Chiral N-
Allyl Carboxamides
A-mean combination: A general and
efficient synthesis of chiral dihydroiso-
quinolinones by a highly diastereoselec-
tive Pd0-catalyzed carboiodination is
reported. As an additive, the bulky tertiary
amine base PMP (1,2,2,6,6-pentamethyl-
piperidine) is presumed to act as a weakly
coordinating ligand, leading to a signifi-
cant and general increase in diastereose-
lectivity. The utility of the method was
applied to the asymmetric formal syn-
thesis of (+)-corynoline.
6
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