Organocatalytic Stereoselective Addition of Aldehydes to Acylquinolinium Ions

Article abstract of DOI:10.1002/ejoc.201600284

A direct and simple activation of quinolines, without isolating unstable intermediates, or using isolated N,O-acetals in the presence of Lewis or Br?nsted acids, is described. The procedure is quite straightforward and allows the addition in a stereoselective manner of different aldehydes to various differently substituted quinolines. The desired products were obtained in 28–76 % yields, with dr values up to 83:17 in favor of the syn isomer, and up to 99 % ee. Studies towards the use of acetaldehyde were also performed with different catalysts and the addition was promoted affording the desired product in 62 % yield with 46 % ee. Finally, deprotection and chemical transformations of the enantioenriched adducts were performed.

Full text of DOI:10.1002/ejoc.201600284

DOI: 10.1002/ejoc.201600284
Full Paper
Aldehyde Addiction!
Organocatalytic Stereoselective Addition of Aldehydes to
Acylquinolinium Ions
Luca Mengozzi,[a] Andrea Gualandi*[a] and Pier Giorgio Cozzi*[a]
Dedicated to Professor Achille Umani-Ronchi on the occasion of his 80th birthday
Abstract: A direct and simple activation of quinolines, without the syn isomer, and up to 99 % ee. Studies towards the use of
isolating unstable intermediates, or using isolated N,O-acetals
in the presence of Lewis or Brønsted acids, is described. The
procedure is quite straightforward and allows the addition in a
stereoselective manner of different aldehydes to various differ-
ently substituted quinolines. The desired products were ob-
tained in 28–76 % yields, with dr values up to 83:17 in favor of
acetaldehyde were also performed with different catalysts and
the addition was promoted affording the desired product in
62 % yield with 46 % ee. Finally, deprotection and chemical
transformations of the enantioenriched adducts were per-
formed.
Introduction
cally important nitrogen-containing compounds.[4] Conse-
quently, these molecules constitute an important class of
heterocycles, as the structural motif is also found in a wide
range of natural products and biologically active substances.
Despite their importance, stereoselective catalytic approaches
towards their preparation have found only limited success.[5] As
quinolines are electron poor heterocycles, the most effective
strategy for activation of the heterocyclic ring towards the at-
tack of suitable nucleophiles involves nitrogen acylation with
The quinoline is a common motif present in several families of
natural alkaloids.[1] Additionally, the related tetrahydroquinoline
alkaloids[2] constitute another very important class of natural
compounds that have been identified in many plants and vege-
tables and that often exhibit interesting biological activities
(Figure 1).[3]
Enantioenriched α-substituted tetrahydroquinolines have
also found important applications as synthetic intermediates
and commonly used units en route to numerous pharmacologi-
Figure 1. Natural and biologically active products containing quinoline and tetrahydroquinoline moieties.
suitable reagents.[6] The reaction produces the corresponding
[a] Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum, Università
di Bologna,
acylquinolinium derivatives,[7] weak electrophiles positioned at
–10/–12 of the Mayr scale,[8] that undergo reactions with vari-
ous nucleophiles. Although diastereoselective addition of nu-
cleophiles to chiral quinolinium derivatives have been re-
ported,[9] successful early examples of activation and use of cat-
alytic conditions were described by Shibasaki.[10] Specifically,
Address Via Selmi 2, 40126 Bologna, Italy
E-mail: andrea.gualandi10@unibo.it
piergiorgio.cozzi@unibo.it
https://www.unibo.it/sitoweb/piergiorgio.cozzi
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600284.
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the Shibasaki work detailed the first example of a Reissert-type other hand, enamine activation modes can be used to activate
addition of trimethylsilyl cyanide to quinolines promoting the aldehydes and ketones towards a variety of electrophiles.[21]
reaction with specifically designed bifunctional BINOL-derived
ligands. Few other examples of metal-promoted addition of nu-
cleophiles to quinolines have been reported.[11] Another quite
interesting approach to enantioenriched tetrahydroquinolines
employed hydrogenation promoted by metal complexes.[12] It
is also worth mentioning the excellent results reported by
Aponick[13] in the alkynylation of activated quinolines promoted
by phosphine ligands.
Although catalytic enantioselective addition of aldehydes to
carbonyls and imines was widely investigated in the past dec-
ade,[22] other electrophiles, such as alkyl halides and alkenes,
were seldom used.[23] On the contrary, the stereoselective alkyl-
ation of aldehydes has been extensively investigated through
the generation of stable cationic intermediates (carbenium or
oxocarbenium) in SN1-type alkylations.[24] This approach be-
came a well-established methodology in organocatalysis.[25] In
With the advent of organocatalysis,[14] catalytic complemen- this context, the organocatalytic addition of aldehydes to N-
tary strategies for the production of enantioenriched dihydro acyliminiums was developed by Jørgensen, who described an
and tetrahydroquinolines were tested with various organocata- enantioselective intramolecular reaction of aldehydes and iso-
lytic activation modes.[15] Takemoto, using non-covalent inter- quinoliniums. We reported an intermolecular version of the re-
actions, described an asymmetric Petasis[16] reaction of acti- action,[26] and used this chemistry for a general, enantioselect-
vated quinolines.[17] It is also worth mentioning that inexpen- ive and straightforward approach to 13-alkyl tetrahydroproto-
sive tartaric acid was employed by Schaus and co-workers in berberine alkaloids.[27] It is also important to add that the gen-
the Petasis asymmetric addition of vinylboronic acids to quin- eration of isoquinolinium salts by oxidation of N-aryltetra-
olinium ions.[18] Efficient organocatalyzed asymmetric transfer hydroisoquinolines and the enantioselective, oxidative cross-de-
hydrogenation of quinolines was described by Rueping, using hydrogenative coupling of aldehydes[28] and ketones[29] have
an asymmetric counterion-directed catalysis (ACDC) ap- been reported. Regarding quinolines, the SN1 organocatalytic
proach.[19] Finally, Mancheño reported the alkylation of quino- alkylation of quinoline N,O-acetals,[30] through generation of
linium ions with silyl enol ethers in the presence of catalysts the acyliminium species with Lewis or Brønsted acids,[31] was
able to surround the quinolinium as counterion.[20] All C-nu- recently described in the same period by three different re-
cleophiles used in the addition to activated quinolines require search groups (Scheme 1).[32] However, this appealing and inter-
separate preparation and thus, extra synthetic steps. On the esting methodology for accessing alkaloids[32b] through
Scheme 1. Alkylation of N,O-quinoline acetals promoted by synergistic acid- and organo-catalysis, as well as by direct alkylation of in situ activated quinolines.
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organocatalytic alkylation uses acetals, such as 2-ethoxy-1- yields. In addition, it has been reported that the Jørgensen cata-
ethoxycarbonyl-1,2-dihydroquinoline, that need to be obtained lyst can be quickly desilylated in unfavorable reaction condi-
from quinolines with an extra synthetic step. In this paper, we tions.[33]
report our full study of the direct and simple addition of differ-
ent aldehydes to various substituted commercially available or
simply prepared quinolines without any extra steps leading to
the reactive intermediate. In addition, we have evaluated the
use of different organocatalysts and the possibility of using ac-
etaldehyde in this chemistry. Moderate results in terms of yields
and stereoselectivities were obtained.
The alkylation of aldehydes with quinolines activated in situ
using benzyl chloroformate was optimized by screening differ-
ent solvents and temperatures using four equiv. of propionalde-
hyde and 10 mol-% of the Jørgensen catalyst. The optimal sol-
vent was toluene, whereas the application of other solvents (see
Table S1 in Supporting Information for further details) rendered
inferior results. The methodology described here is substantially
different from previous reports because there is no need to pre-
synthesize quinoline N,O-acetals and, thus, there is no need for
a Brønsted or Lewis acid co-catalyst. GC–MS was used to evalu-
ate the crude reaction mixtures after 16 h. The reaction prod-
ucts were isolated as the corresponding alcohols, after reduc-
tion with a slight excess of NaBH4 and dilution with MeOH.
Diastereomeric ratios and enantiomeric excesses were deter-
mined by chiral HPLC on the crude alcohols. Although the 2
position of the quinoline represents the activated electrophilic
carbon, small amounts of 4-substituted products 7 (6–18 %)
were always observed. These byproducts were always separated
from the desired major syn product after chromatographic puri-
fication. Increasing the amount of base led to a slight reduction
in conversion although, in its absence, reactions proceeded to
a much lower extent. One equiv. of acylating agent allowed the
efficient activation of quinoline avoiding the catalyst deactiva-
tion. It is also worth noting that, contrary to the case with iso-
quinolines, the slow addition of activating agent by syringe
pump is not mandatory in this case.[24] Other acylating agents
were tested instead of benzyl chloroformate; the use of ethyl
chloroformate afforded similar results in terms of stereoselectiv-
ity but led to reduced product yields (product 10 see Support-
ing Information). The use of TrocCl as a potential activating
agent failed to afford product.
Results and Discussion
On the basis of our previous work focused on aldehyde alkyl-
ations with isoquinolinium ions,[26] we started the current work
by investigating the possible use of our established procedure
in the addition of aldehydes to quinolines. Quinoline 4a was
activated by addition of CbzCl at 0 °C in anhydrous tert-butyl-
methyl ether and after 30 min, propionaldehyde 5a, the sec-
ondary amine Jørgensen catalyst ent-2a (10 mol-%) and NaH-
CO3 (as a base) were added to the mixture. To our delight, this
simple procedure afforded the desired product in good conver-
sion (78 %), with good enantioselectivity (86 % ee syn, 82 % ee
anti) and with moderate diastereoselectivity (syn/anti = 2.8:1,
see Table S1 in Supporting Information) (Scheme 2).
Although products containing an aldehydic group are less
stable, they can be isolated by quenching the reaction with
MeOH (to consume unreacted CbzCl), and subsequent evapora-
tion of reaction solvent under reduced pressure, followed by
direct purification by silica gel column chromatography. In the
case of propanal, the aldehydic product was indeed isolated
with slightly reduced yields (about 70 %) compared to the re-
ductive work-up. However, it was not possible to obtain analyti-
cally pure product by chromatographic purification, as it was
contaminated with the secondary amine catalyst. Moreover the
major syn diastereoisomer could not be separated from the mi-
nor anti isomer or from the product obtained by alkylation in
C-4 position. In light of such limitations, along with the recog-
nized higher stabilities offered by alcohol products, we chose
to isolate all products following a reductive work-up.
Scheme 2. Model reaction for the addition of propanal to quinoline, in the
presence of CbzCl as an activating agent.
A control experiment performed in air and using wet tert-
butylmethyl ether afforded no product. Quinolinium ions are
sensitive electrophiles and an excess of water decomposes the
activated quinoline species. As was stated in the introduction,
three reports by Lu, Pineschi and Rueping have described the
asymmetric alkylation of quinoline N,O-acetals with aldehydes
using catalysts 1, 2a, and 3 via a synergistic enamine-acid catal-
ysis system in the presence of Lewis[32a,32c] or Brønsted ac-
ids.[32b] In all cases, products were obtained by using the pre-
formed N,O-acetals, generated by the reaction of quinoline de-
rivatives with acylating agents in the presence of ethanol. As in
With the optimized conditions in hand we then explored the
scope of the methodology using different aldehyde and quinol-
ine reaction partners (Table 1).
Enantioselectivities were optimal for linear aliphatic alde-
the employment of N,O-acetals, activation by Lewis or Brønsted hydes and hydrocinnamaldehyde, whereas when the α position
acids is mandatory, different organocatalysts can suffer from of the aldehyde incorporated a bulky group, such as phenyl
decomposition. In fact, when a Lewis acid was used, the Mac- or isopropyl, ee values decreased to approximately 80 %. The
Millan imidazolidinone-based catalysts enabled improved diastereoselectivities observed with the variety of aldehydes in-
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Table 1. Scope of the functionalization of quinolines with different aldehydes
promoted by the Jørgensen catalyst.
Table 2. Addition of propanal to various substituted quinolines.
Entry[a]
FG
Prod. syn/anti:7[b] ee syn[c] ee anti[c] Yield syn[d]
Entry[a]
R
Prod. syn/anti:7[b] ee syn[c]
ee anti[c] Yield syn[d]
[%]
[%]
[%]
[%]
[%]
[%]
1
2
6-Br
6-
OMe
5-Br
6-allyl
6-Ph
6ba
6ca
61:28:11
74:15:11
94
92
28
1
2
3
4
5
6
Me
n-C6H13
Ph
PhCH2
(CH3)2CH
H
6aa
6ab 70:16:14
6ac 58:26:16
6ad 54:23:23
63:21:16
94
93
82
99
81
4
93
95
34
96
77
53
58
54
96
90
57
3
4
5
6da
6ea
6fa
46:39:15
64:20:16
50:32:18
91
90
92
89
91
82
44[e]
49
43
41[f]
6ae
6af
63:37:0
39
[e]
100[e]:0
–
76[e]
[a] All reactions were carried out using 0.2 mmol of quinoline, CbzCl and
NaHCO3, 0.8 mmol of aldehyde and 0.02 mmol of the cat. ent-2a for 16 h at
0 °C. [b] Determined by 1H-NMR on the crude reaction mixture; 7 is present
as a mixture of diastereoisomers. [c] Enantiomeric excesses were measured
by chiral HPLC analysis after chromatographic purification. [d] Yield of iso-
lated syn-6ba–fa after chromatographic purification. [e] Inseparable mixture
of syn-6da/anti-6da/7da. [f] Inseparable mixture of syn-6fa/7fa.
[a] All reactions were carried using 0.2 mmol of quinoline, CbzCl and NaHCO3,
0.8 mmol of aldehyde and 0.02 mmol of the cat. ent-2a for 16 h at 0 °C.
[b] Determined by 1H-NMR on the crude reaction mixture; 7 is present as a
mixture of diastereoisomers. [c] Enantiomeric excesses were measured by
chiral HPLC after chromatographic purifications. [d] Yield of isolated syn-6aa–
af after chromatographic purification. [e] For 6af no diastereoisomers were
formed.
phile and this may explain the failure of this reaction. Finally,
we evaluated the reactivity of 2-methylquinoline to see if in-
creasing steric hindrance at position 2 might aid in directing
aldehyde attachment to the quinolone C-4. However, this effort
also failed to afford any desired adduct. For all the quinolines
or aldehydes tested [except for isovaleraldehyde (Table 2, Entry
5)], small amounts of the C-4 addition products were observed
(5–16 % yield). In most cases, these undesired products could
vestigated proved to be only moderate. Acetaldehyde gave sim-
ilar results in terms of yield (76 %). However, and more impor-
tantly, the reaction with acetaldehyde afforded almost no enan-
tioselectivity (4 % ee); this is likely a reflection of the moderate
to low diastereoselectivity combined with the absence of an α-
substituent leading to a lack of facial selectivity for the putative
enamine intermediate.
Quinoline substitution patterns strongly influence reaction be efficiently eliminated by flash column chromatography or by
outcomes using the detailed reaction conditions. Substituents preparative TLC on silica after reduction to the corresponding
at positions 5 and 6 of the quinoline ring were well tolerated, alcohols. In some cases, the anti product was obtained as a
and in these cases (Table 2, Entries 1–5) we were able to obtain component of a mixture containing undesired products 7. How-
the desired products with good ee values and moderate dia- ever, major syn diastereoisomers could always be separated
stereoselectivities. The isolated yields were satisfactory when from the minor anti diastereoisomers, (with the exception of
neutral or electron-donating groups were present on the quin- 6da), and isolated as pure compounds. In the cases of 6ac and
oline ring. However, when bromine was inserted, a decrease in 6ad, the minor products could not be separated from the alco-
reaction yield was observed. The presence of strong electron- hols derived from reduction of excess of aldehyde starting ma-
withdrawing groups, such as the nitro group on the isoquino- terials. Notably, products 6 are very stable compounds that can
line ring, strongly inhibited the reaction. Steric hindrance con- be conserved at –20 °C in sealed vials under air for 1 year with-
siderations imposed by quinoline substituents were also found out any degradation. Conversely, products 7 are quite unstable.
to influence reactivity. In fact, the presence of a methyl group For instance, isolated 7ab decomposed in a matter of just a few
at the 8 position dramatically inhibits the reaction, according to weeks.
previous reports;[20] this is likely the result of impaired acylation
The reaction between acetaldehyde and quinoline affords
needed to form the corresponding quinolinium ion.
corresponding product 6af in good yield, but with low stereo-
The use of 4-hydroxyquinoline failed to give rise to any de- selection. Because this adduct can be a valuable starting mate-
sired product. Instead, the hydroxyl group reacted with the rial for the synthesis of the Galipea alkaloids,[3] we decided to
acylating agent under the reaction conditions. 4-Methoxyquin- investigate more deeply this transformation using different cat-
oline, obtained by alkylation of the 4-hydroxyl moiety, was alysts and conditions. It is also worth mentioning that the strat-
found to be less soluble in toluene. However, even the addition egies published with N,O-acetal quinoline derivatives proceed
of co-solvents such as CH2Cl2 and employing a mixture of in a maximum 25 % ee with respect to acetaldehyde addi-
CH2Cl2/toluene (1:1), failed to afford the desired product. Nota- tion.[32] Catalysts 2c–f[34] were prepared using straightforward
bly, 4-methoxyquinoline can behave as an activated nucleo- reactions.[35] All the catalysts were investigated in different sol-
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vents, and the salient results obtained are reported in Table 3.
It is likely that the presence of enhanced steric hindrance
Interestingly, commercially available catalyst 2b[36] was found attributable to the trans substituent influences the face of the
to be active (37–39 % ee), although low yields of desired prod- quinolinium ion that approaches the enamine. However, sol-
uct were noted when the reaction was carried out in CH3CN or vents and entropic effects[38] cannot be neglected considering
DMF; no reaction was observed when using toluene as solvent. that the enantiomeric excess of isolated product was quite low.
Recently Pihko[39] reported the use of a 5-trans-aryl-substi-
tuted prolinol catalyst in Mukayama–Michael reactions. These
effective new catalysts gave better results by exploiting second-
ary interactions, and we are planning to investigate further sim-
ilar interesting opportunities with additional work.
The use of a bulkier silyl substituent (catalyst 2c) led to an
added increase to 46 % ee while at the same time enabling a
good yield. The use of catalyst 2d, bearing phenyl groups in-
stead of the bis-trifluoromethylated aryl moieties, led to a slight
decrease in ee. To achieve a better result we sought to impose
a higher degree of control over the electrophile's approach to
the enamine.
The relative and absolute configurations of the obtained
1
products were assigned by comparing the H-NMR traces and
the specific rotations with the corresponding products already
reported in the literature.[32b] The reported characteristic 1H-
NMR signals of syn-6aa and anti-6aa were compared with our
products and the syn-relative configuration was easily assigned
to the major product and the anti-relative configuration to the
minor product. The assigned relative configurations were fur-
ther confirmed by comparing the elution orders of 6aa with
those reported by Pineschi (see Supporting Information for de-
tails). The absolute configuration of product 6ac was deter-
mined by isolating the pure syn diastereoisomer and comparing
its specific rotation with the one previously reported in the liter-
ature.[32b,40] The (S,S) absolute configuration was then assigned
by analogy to all syn-6aa–fa products.
Table 3. Various organocatalysts employed to promote the addition of acet-
aldehyde to quinoline, in the presence of CbzCl.
Having verified the scope and limitations of the methodol-
ogy, we investigated possible derivatizations of model substrate
6aa. Standard hydrogenation conditions were tested in order
to remove the Cbz group and reduce the 3,4-double bond.
When syn-6aa was dissolved in methanol and reacted under an
atmosphere of H2 in the presence of 10 % wt Pd/C, tetrahydro-
quinoline product 8aa was obtained in good yield, but as a
2.9:1 mixture of syn/anti diastereoisomers (Scheme 3).
Entry[a]
Cat.
Solvent
ee [%][b]
Conversion[c] Yield [%][c]
1
1
2
3
4
5
6
7
ent-2a
2b
2b
2b
2c
2d
2e
2f
toluene
toluene
DMF
CH3CN
toluene
toluene
toluene
toluene
4 (R)
–
89
–
76
37 (S)
39 (S)
46 (S)
40 (S)
10 (R)
22 (S)
19
23
74
32
48
56
The relative configuration of the tetrahydroquinoline dia-
stereoisomers, was confirmed by subjecting the anti diastereo-
isomer to the same hydrogenation conditions. In this case, a
less significant epimerization was observed and product 8aa
was obtained with a reversed diastereomeric ratio syn/anti of
1:4. From these reactions it was evident that cleavage of the
Cbz group leads to partial epimerization of both syn-6aa and
anti-6aa; in the case of syn-6aa this appears to happen to
greater extent than is the case for other substrates. As the final
diastereoisomeric ratio is different starting from syn-6aa or anti-
6aa, it is reasonable to assume that the deprotection-hydrogen-
ation reaction occurs faster than the epimerization process
which cannot reach its thermodynamic equilibrium. It is impor-
tant to note that when we subjected to the same hydrogen-
ation conditions, products syn-10 and anti-10, having the ethyl
carbamate instead of Cbz, no epimerization was observed.
Moreover, the corresponding products of these reactions were
obtained as single diasteroisomers, in agreement with earlier
Rueping findings (see Supporting Information).[32c]
62
[a] All reactions were carried on 0.2 mmol of quinoline, CbzCl and NaHCO3,
0.8 mmol of acetaldehyde and 0.02 mmol of the cat. ent-2a, 2b–f for 16 h at
0 °C. [b] Enantiomeric excesses were measured by chiral HPLC analysis of the
crude reaction mixture, after reduction. [c] Conversions were determined by
GC–MS analysis before reduction. [d] Yield of isolated products after chromat-
ographic purification.
We hypothesized that the presence of a bulkier group on
the less hindered face of the catalyst, would reduce the number
of possible approaches for the electrophile in the reaction with
the enamine thereby increasing enantioselectivity. With this in
mind, novel catalyst 2e, derived from trans-4-hydroxyproline,
was prepared (see Supporting Information for synthetic details).
The trans substituent had a strong, but detrimental, effect on
the reaction outcome and the product was obtained with only
10 % ee. In addition, the use of (S)-2e having the bulky trans-
oriented substituent at the 4 position of the pyrrolidine ring,
Several other conditions were tested, but we were unable to
led to the enantiomeric product, compared to the products ob- avoid partial epimerization. In addition, whereas the Wilkinson
tained with all other investigated (S)-prolinol catalysts. Notably, catalyst left the starting material completely untouched, other
previously described constrained catalyst 2f[37] was found to be conditions reported by Mancheño,[20] for hydrogenation of N-
unsuitable for the desired transformation.
Troc dihydroquinolines, gave a 1.5:1 mixture of re-aromatized
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whereas desired product 13 was present as mixture of dias-
tereoisomers (Scheme 5).
Scheme 5. Re-aromatization of syn-6aa with reductive and hydrolytic condi-
tions.
Re-aromatization can be envisioned to involve LiAlH4-medi-
ated deprotonation of the 2-allylic proton followed by loss of
the Cbz group or by hydrolysis of the benzyl carbamate by
adventitious water followed by decaboxylation of the resulting
quinoline-1(2H)-carboxylic acid. In fact, when 6aa was treated
in EtOH with concentrated solution of KOH, according to Rue-
ping report,[32c] the re-aromatized product was isolated in 83 %
yield and in 88 % ee. This strategy enables ready access to enan-
tioenriched quinolines bearing a chiral substituent at the 2 po-
sition. Although deprotection and reduction chemistries are
possible with these adducts, successive purifications are neces-
sary to separate the resultant diastereoisomeric mixtures.
Scheme 3. Hydrogenation conditions for cleavage of Cbz and COOEt groups
from N-protected substrates.
quinoline 12 and desired deprotected product 8aa as a mixture
of diastereoisomers (Scheme 4).
Conclusions
In conclusion, we have reported the first direct organocatalytic
enantioselective alkylation of aldehydes with quinolines acti-
vated with benzyl chloroformate. The reaction uses a commer-
cially available prolinol catalyst, and proceeds without the aid
of an acidic co-catalyst. The reaction gives good results with all
the tested aldehydes and with 5- or 6-substituted quinolines,
affording the desired 2-alkylated products in moderate to good
yields. The reaction also proceeds with good regioselectivity; 4-
alkylation products are present in minor amounts relative to
the desired C-2 addiction products. The synthesis of modified
Jørgensen catalysts allowed us to obtain a 46 % ee for the alkyl-
ation of acetaldehyde with quinoline; thus far, this constitutes
the optimal result for this coupling.
The products generated in this fashion can be efficiently re-
aromatized to the corresponding 2-alkylquinolines having a
stereocenter at the position adjacent to the aromatic ring. De-
tailed investigations into deprotection and hydrogenation of
the N-Cbz products en route to 2-alkyl tetrahydroquinoline
products revealed an unexpected epimerization process. Efforts
to apply this methodology to the synthesis of alkaloids and
natural products will be the subject of future studies in our
laboratory.
Scheme 4. Different reductive conditions for deprotection and full hydrogen-
ation of the isolated enantioenriched adducts.
Finally, selective reduction of the double bond, leaving the
Cbz group in place, as we have demonstrated in the case of
isoquinoline adducts,[26] was tested. Isolated syn-6aa was
treated with Et3SiH in TFA/DCM at room temperature, but no
conversion was observed. Instead, the recovered starting mate-
rial was a 1:1 syn/anti mixture. The epimerization likely proceeds
through a shift of the double bond and re-protonation under
the acidic conditions.
Treatment of syn-6aa with LiAlH4 at 0 °C with the intention of
converting the Cbz group to the corresponding methyl group,
a structural motif recurring in most of the tetrahydroquinoline
alkaloids, unfortunately afforded a complex mixture of prod-
ucts. The major characterized product was consistent with loss
Experimental Section
General Procedure for the Alkylation of Aldehydes with Quin-
of the Cbz group and re-aromatization of the quinoline ring, olines: In
a
flame-dried two-necked round-bottomed flask
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[9]
a) A. I. Meyers, D. G. Wettlaufer, J. Am. Chem. Soc. 1984, 106, 1135–1136;
b) F. Rezgui, P. Mangeney, A. Alexakis, Tetrahedron Lett. 1999, 40, 6241–
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12 mg) and aldehyde 5a–f (0.8 mmol) were added and the mixture
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The “Fondazione del Monte di Bologna e Ravenna”, Bologna,
the University of Bologna (Farb project, SLaMM, fellowship to
A. G.), and the European Commission with the project TEC 7P7-
Molarnet, are acknowledged for financial support of this re-
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Keywords: Organocatalysis · Enantioselectivity · Aldehydes ·
Alkaloids
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may represent the lower limit of electrophilicity.
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Received: March 10, 2016
Published Online: ■
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Aldehyde Addiction!
L. Mengozzi, A. Gualandi,*
P. G. Cozzi* ........................................... 1–9
Organocatalytic Stereoselective Ad-
dition of Aldehydes to Acylquinolin-
ium Ions
A variety of aldehydes are added in a quinoline activation, and requires no
straightforward and organocatalytic Lewis acidic metals. The reaction is
manner to activated quinolines. The characterized by good yields, moder-
procedure is simple, employs commer- ate diastereoselectivity, and excellent
cially available organocatalyst, does ee values.
not require an additional step for
DOI: 10.1002/ejoc.201600284
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim