Enantioselective β-Alkylation of Aldehydes through an Organocatalyzed C-C Bond-Scission Reaction

Article abstract of DOI:10.1055/s-0035-1561397

A novel organocatalyzed C-C bond-scission reaction of saturated aldehydes containing a suitable leaving group at the β-position was used for the in situ formation of iminium intermediates, which were then captured by nucleophiles to achieve a direct enantioselective β-alkylation of aldehydes. Within short reaction times, the corresponding β-alkylated aldehyde products were obtained in high yields (48-87%) and with excellent enantioselectivities (84-98%).

Full text of DOI:10.1055/s-0035-1561397

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
H. Huang et al.
Letter
Synlett
Enantioselective β-Alkylation of Aldehydes through an Organo-
catalyzed C–C Bond-Scission Reaction
Huicai Huang
Santhi Abbaraju
John C.-G. Zhao*
Department of Chemistry, University of Texas at San Antonio,
One UTSA Circle, San Antonio, TX 78249-0698, USA
cong.zhao@utsa.edu
Received: 26.12.2015
Accepted after revision: 22.01.2016
Published online: 01.03.2016
Hayashi,4b the enamine intermediate formed by the reac-
tion of the aldehyde and the amine catalyst is oxidized in
situ by a suitable oxidant, such as 2-iodoxybenzoic acid
(IBX),4a,c DDQ,4b or O2 in the presence of a metal catalyst,4d
to generate the iminium intermediate 1 (Scheme 1). The re-
action of 1 with an appropriate nucleophile then yields the
β-alkylated aldehyde.4 In the second approach, developed
by MacMillan and co-workers,5 the enamine intermediate
is converted into a β-enaminyl radical intermediate 2 under
photoredox conditions (Scheme 1). The reaction of radical 2
with a suitable radical or electrophile permits direct β-al-
kylation of the aldehyde.5 This latter approach can also be
used for the direct β-alkylation of saturated ketones.5
DOI: 10.1055/s-0035-1561397; Art ID: st-2015-r0999-l
Abstract A novel organocatalyzed C–C bond-scission reaction of satu-
rated aldehydes containing a suitable leaving group at the β-position
was used for the in situ formation of iminium intermediates, which
were then captured by nucleophiles to achieve a direct enantioselective
β-alkylation of aldehydes. Within short reaction times, the correspond-
ing β-alkylated aldehyde products were obtained in high yields (48–
87%) and with excellent enantioselectivities (84–98%).
Key words bond scission, alkylation, organocatalysis, aldehydes,
enantioselectivity
The past fifteen years have witnessed an exponential
growth in organocatalysis in the wake of the seminal work
of MacMillan1 and List 2 and their respective co-workers on
organocatalytic reactions involving enamine or iminium in-
termediates, and many novel organocatalytic reactions have
been reported.3 Recently, there has been considerable inter-
est in developing organocatalytic enantioselective methods
for the direct β-alkylation of saturated aldehydes and ke-
tones.4–6 Nonetheless, whereas organocatalytic enantiose-
lective α-alkylation of aldehydes can be readily achieved
through the reaction of an electrophile with the enamine
intermediate,3b,7 the direct organocatalytic β-alkylation of
saturated aldehydes is more challenging, which currently
can only be achieved through the iminium intermediate,4
through the singly occupied molecular orbital mechanism,8
or through catalysis by an N-heterocyclic carbene (NHC).9
Currently, only three organocatalytic methods are
known (Scheme 1), two involving amine catalysis4,5 and one
involving NHC catalysis.6 For amine catalysis, in the first ap-
proach, reported almost simultaneously by Wang4a and by
N
[O]
R
CHO
N
N
1
H
Wang and Hayashi's approach
R
N
R
hν
photoredox
catalyst
R
2
Reported methods
MacMillan's approach
O
N
CHO
O
N
H
1
MeO
4-MeOC6H4O
R
MeO
R
Our proposed method
Scheme 1 Reported and proposed methods for β-alkylation of satu-
rated aldehydes by amine catalysis
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
H. Huang et al.
Letter
Synlett
Our group recently attempted a tandem Michael/Mi-
chael reaction of aldehyde 3a (R = H) and [(E)-2-nitrovi-
nyl]benzene by using the amine catalyst 4a. As shown in
Scheme 2, we did not obtain the desired product 5. Instead,
4-methoxyphenol (6) was obtained in high yield. Because
4-methoxycyclohexa-2,5-dien-1-one is a very good leaving
group (as 4-methoxyphenoxide; Scheme 1, bottom equa-
tion), we speculated that this reaction operates through an
amine-catalyzed β-scission of the C–C bond of the enamine
intermediate (Scheme 1, bottom equation).10 Indeed, when
substrate 3b (R = Ph) was treated with amine 4a, the ex-
pected trans-cinnamaldehyde 7b (R = Ph) was obtained in a
high yield along with 6. To our knowledge, such an amine-
catalyzed C–C bond scission is unprecedented in the litera-
ture.10 Most importantly, because the same iminium inter-
mediate 1 (Scheme 1, bottom equation) as that generated
in Wang’s and Hayashi’s reactions should be formed in this
C–C bond-scission reaction, we surmised that this reaction
might provide a new route for direct β-alkylation of alde-
hydes. Here, we wish to report a highly enantioselective β-
alkylation of aldehydes by this approach.
a good yield (87%) and a high ee (96%) when lithium hy-
droxide monohydrate was used as the base (entry 6). Be-
cause the elimination reaction occurs under neutral condi-
tions (Scheme 2), whereas the Michael addition does not
occur without a base (Table 1, entry 1), our reaction must
operate through the proposed tandem elimination/Michael
addition sequence shown in Scheme 1. The reaction is also
much faster than reported β-alkylation methods.4 Reducing
the amount of this base to 50 mol% or 20 mol% led to much
Table 1 Optimization of the Reaction Conditionsa
O
EtO2C
Ph
CO2Et
CHO
4, base
+
EtO2C
CO2Et
solvent, r.t.
MeO
Ph
CHO
3b
8a
9a
Ph
Ph
Ph
Ph
N
H
N
N
H
Ph
OTES
Ph
OTBDMS
H
OTMS
4a
Entry Catalyst Base
4b
4c
O
Solvent
Time (h) Yieldb (%) eec (%)
NO2
1
2
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4a
4a
4a
4a
4a
4a
4a
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
2
2
2
2
2
2
2
3
2
2
2
3
3
3
3
2
2
4
0
81
80
72
32
87
76
61
81
81
68
43
67
48
69
82
84
42
–
Ph
MeO
NaOAc
89
65
55
52
96
94
46
90
81
80
48
80
54
22
94
95
97
O
N
H
Ph
OTMS
Ph
3
LiOAc
CHO
4a
NO2
+
4
KOAc
5
Ph
OH
5
Et3N
MeO
R
CHO
6
LiOH·H2O
LiOH·H2Od
LiOH·H2Oe
LiOH·H2Of
LiOH·H2O
LiOH·H2O
LiOH·H2O
LiOH·H2O
LiOH·H2O
LiOH·H2O
LiOH·H2O
LiOH·H2O
LiOH·H2O
CHO
+
R
3
7
7
3a, 7a: R = H
3b, 7b: R = Ph
8
OMe
6
9
Scheme 2 Organocatalyzed C–C bond-scission reaction
10
11
12
13
14
15
16
17
18g
Aldehyde 3b and diethyl malonate (8a)11 were used as
model substrates, and amine 4a was used as the catalyst in
the initial optimization studies (Table 1). When the reaction
was carried out at room temperature in CH2Cl2 without any
additive, none of the desired product 9a was formed (Table
1, entry 1). Instead, compounds 6 and 7b were obtained ex-
clusively. These results suggested that formation of the
iminium intermediate 1 was so fast that it could not be
trapped by the low concentration of the nucleophilic spe-
cies present under the neutral conditions. We therefore
added various bases in an attempt to increase the concen-
tration of the nucleophile and, to our pleasure, we succeed-
ed in obtaining compound 9a. As shown in Table 1, when
NaOAc, LiOAc, KOAc, or Et3N was used as the additive, the
reaction was complete in just two hours, giving the desired
product 9a in good to excellent yield (entries 2–5). Never-
theless, the ee values of 9a were unsatisfactory with these
bases (entries 2–5). However, aldehyde 9a was obtained in
EtOAc
MeCN
CHCl3
DCE
CH2Cl2
a Unless otherwise noted, all reactions were carried out with aldehyde 3b
(0.10 mmol), diethyl malonate (8a, 0.30 mmol), catalyst 4 (0.010 mmol,
10 mol%), and the base (0.10 mmol, 100 mol%) in the specified solvent
(0.4 mL) at r.t.
b Yield of the isolated product 9a after column chromatography.
c Determined by HPLC analysis using a chiral column. The stereochemistry
was assigned by comparing the measured optical rotation with that report-
ed in the literature.
d LiOH·H2O (0.050 mmol, 50 mol%) was used.
e LiOH·H2O (0.020 mmol, 20 mol%) was used.
f LiOH·H2O (0.20 mmol, 200 mol%) was used.
g The reaction was carried out at 0 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
H. Huang et al.
Letter
Synlett
poorer results (entries 7 and 8). On the other hand, the ad-
dition of an excess of the base (200 mol%) also led to a low-
er product ee value (entry 9). Besides 4a, the similar but
bulkier catalysts 4b and 4c also catalyzed this reaction, but
they were less effective than 4a (entries 10 and 11). Thus,
4a was identified as the best catalyst. Among some com-
mon organic solvents, nonchlorinated solvents (entries 12–
15) were significantly inferior to chlorinated solvents such
as CH2Cl2 (entry 6), CHCl3 (entry 16), or DCE (entry 17) in
terms of their product yields and ee values. Among these
three chlorinated solvents, a slightly higher product yield
and ee value were achieved in CH2Cl2 (entry 6). An attempt
to conduct the reaction at 0 °C led to a slightly improved ee
value of 9a (97% ee), but the reaction was slower and the
yield was markedly reduced (entry 18).
had almost no influence on the enantioselectivity of the re-
action (Table 2, entries 1–6), but the yield generally de-
creased with increasing size of this group (entries 1–6). The
best results were obtained with ethyl malonate (8a, entry
1). Next, we screened various β-substituted aldehydes 3
with ethyl malonate (8a). For the β-aryl-substituted alde-
hydes (entries 7–14), the electronic nature of the substitu-
ent (entries 7–12) and its location on the phenyl ring (en-
tries 13–14) had a minimal influence on the product yield
and ee value. Furthermore, besides β-aryl-substituted alde-
hydes, good product ee values were also obtained with β-
alkyl-substituted aldehydes (entries 15–16), although
slightly lower yields were obtained with these substrates.
Besides malonates, nitromethane or cyclohexane-1,2-
dione can also be used as a pronucleophile in this reaction
(Scheme 3). Under the optimized conditions, the reaction of
nitromethane gave the expected Michael product 10 in 81%
yield and 98% ee (Scheme 3, top equation), whereas that of
cyclohexane-1,2-dione gave the known product 1112 in 72%
yield, 99:1 dr, and 97% ee (Scheme 3, bottom equation).
The scope of this reaction was then studied (Table 2).
First, with aldehyde 3b, the effect of the ester alkyl group of
the malonate was evaluated. We found that the alkyl group
Table 2 Substrate Scope Studya
NO2
O
4a, NaOAc
3b
+
MeNO2
R2O2C
R1
CO2R2
CHO
CHO
CH2Cl2, r.t., 3 h
4a, LiOH•H2O
Ph
R2O2C
CO2R2
+
CH2Cl2, r.t.
10 (81%, 98% ee)
8
MeO
R1
CHO
O
O
O
4a, LiOH•H2O
OH
3
9
3b
+
CH2Cl2, r.t., 3 h
Entry
R1
R2
Time (h) Product Yieldb (%) eec (%)
CHO
11 (72%, 99:1 dr, 97% ee)
Ph
1
2
Ph
Et
2
2
3
3
4
3
2
2
2
2
3
3
2
3
3
3
9a
9b
9c
9d
9e
9f
87
81
78
70
58
75
78
79
76
82
78
82
79
73
62
48
96
95
95
97
94
94
95
98
91
95
98
96
94
97
94
84
Ph
Ph
Ph
Ph
Ph
Me
Pr
Scheme 3 Reaction of 3b with other pronucleophiles
3
4
i-Pr
t-Bu
Bn
Et
In summary, we have discovered a novel, amine-cata-
lyzed, C–C bond-scission reaction of aldehydes13 containing
a suitable leaving group at the β-position that proceeds via
an enamine intermediate. This reaction provides a fast and
highly stereoselective method for the β-alkylation of satu-
rated aldehydes through a tandem elimination/Michael ad-
dition process. We also demonstrated that β-(1-methoxy-4-
oxocyclohexa-2,5-dien-1-yl)aldehydes can potentially be
used as masked enals in organic reactions.14
5
6
7
4-FC6H4
4-ClC6H4
4-BrC6H4
4-F3CC6H4
4-Tol
9g
9h
9i
8
Et
9
Et
10
11
12
13
14
15
16
Et
9j
Et
9k
9l
4-MeOC6H4
3-ClC6H4
2-Tol
Et
Et
9m
9n
9o
9p
Acknowledgment
Et
We are grateful for financial support from the Welch Foundation (AX-
1593).
Pr
Me
Me
Me
a All reactions were carried out with aldehyde 3 (0.10 mmol), malonate 8
(0.30 mmol), catalyst 4a (0.010 mmol, 10 mol%), and LiOH·H2O (0.10
mmol) in CH2Cl2 (0.4 mL) at r.t.
Supporting Information
b Yield of isolated product 9 after column chromatography.
c Determined by HPLC analysis using a chiral column. The stereochemistry
was assigned by comparing the measured optical rotations with those re-
ported in the literature.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561397.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
H. Huang et al.
Letter
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References and Notes
(10) Previously, β-scission of C–C bond of enamines has only been
observed in their mass spectra via their radical cations, see:
(a) Jakobsen, H. J.; Lawesson, S.-O.; Marshall, J. T. B.; Schroll, G.;
Williams, D. H. J. Chem. Soc. B 1966, 940. For an example of
amine-catalyzed oxidative α-scission of aldehydes, see:
(b) Tiwari, B.; Zhang, J.; Chi, Y. R. Angew. Chem. Int. Ed. 2012, 51,
1911.
(11) For an example of Michael addition of malonates to trans-cin-
namaldehydes catalyzed by similar catalysts, see: Brandau, S.;
Landa, A.; Franzen, J.; Marigo, M.; Jorgensen, K. A. Angew. Chem.
Int. Ed. 2006, 45, 4305.
(1) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243.
(2) List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc. 2000, 122,
2395.
(3) For reviews, see: (a) Berkessel, A.; Groeger, H. Asymmetric
Organocatalysis: From Biomimetic Concepts to Applications in
Asymmetric
Synthesis;
Wiley-VCH:
Weinheim,
2005.
(b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471. (c) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem.
Rev. 2007, 107, 5416. (d) Enantioselective Organocatalysis: Reac-
tions and Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH:
Weinheim, 2007.
(12) The product was previously obtained through an amine-cata-
lyzed tandem Michael/aldol reaction, see: Rueping, M.; Kuenkel,
A.; Tato, F.; Bats, J. W. Angew. Chem. Int. Ed. 2009, 48, 3699.
(13) β-Alkylation Reaction; General Procedure
(4) (a) Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.;
Wang, W. Nat. Commun. 2011, 2, 211; doi: 10.1038/ncom-
ms1214. (b) Hayashi, Y.; Itoh, T.; Ishikawa, H. Angew. Chem. Int.
Ed. 2011, 50, 3920. (c) Zeng, X.; Ni, Q.; Raabe, G.; Enders, D.
Angew. Chem. Int. Ed. 2013, 52, 2977. (d) Zhao, Y.-L.; Wang, Y.;
Hu, X.-Q.; Xu, P.-F. Chem. Commun. 2013, 7555.
(5) (a) Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W.
C. Science 2013, 339, 1593. (b) Terrett, J. A.; Clift, M. D.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 6858.
(c) Petronijević, F. R.; Nappi, M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2013, 135, 18323.
(6) Mo, J.; Shen, L.; Chi, Y. R. Angew. Chem. Int. Ed. 2013, 52, 8588.
(7) For selected reviews, see: (a) Notz, W.; Tanaka, F.; Barbas, C. F.
III. Acc. Chem. Res. 2004, 37, 580. (b) List, B. Acc. Chem. Res. 2004,
37, 548. (c) Córdova, A. Acc. Chem. Res. 2004, 37, 102. (d) Barbas,
C. F. III. Angew. Chem. Int. Ed. 2008, 47, 42. (e) Moyano, A.; Rios,
R. Chem. Rev. 2011, 111, 4703. (f) Silvi, M.; Arceo, E.; Jurberg, I.
D.; Cassani, C.; Melchiorre, P. J. Am. Chem. Soc. 2015, 137, 6120.
(8) Beeson, T. D.; Mastracchio, A.; Hong, J.; Ashton, K.; MacMillan,
D. W. C. Science 2007, 316, 582.
A mixture of the appropriate malonate ester 8 (0.30 mmol, 3.0
equiv) and LiOH·H2O (4.2 mg, 0.10 mmol, 1.0 equiv) in CH2Cl2
(0.4 mL) was stirred at r.t. for 5 min. Catalyst 4a (3.2 mg, 0.01
mmol, 10 mol%) and aldehyde 3 (0.1 mmol, 1.0 equiv) were
then added, and the mixture was stirred at r.t. until the reaction
was complete. The mixture was directly transferred onto a silica
gel column and purified by column chromatography (hexane–
EtOAc) to give the pure product 9.
Diethyl [(1R)-3-Oxo-1-phenylpropyl]malonate (9a)
24
Colorless oil; yield: 25.3 mg (87%); [α]D –38.1 (c 1.0, CHCl3;
1
96% ee). H NMR (500 MHz, CDCl3): δ = 9.60 (s, 1 H), 7.30–7.20
(m, 5 H), 4.21 (q, J = 7.0 Hz, 2 H), 4.03–3.99 (m, 1 H), 3.95 (q,
J = 7.0 Hz, 2 H), 3.72 (d, J = 10 Hz, 1 H), 2.96–2.85 (m, 2 H), 1.26
(t, J = 7.0 Hz, 3 H), 1.00 (t, J = 7.0 Hz, 3 H). 13C NMR (125 MHz,
CDCl3): δ = 200.0, 168.0, 167.4, 139.8, 128.7, 128.1, 127.5, 61.8,
61.4, 57.5, 47.4, 39.5, 14.0, 13.7. The enantiomeric excess of 9a
was determined by chiral-stationary-phase HPLC analysis using
a
ChiralPak AD-H column (80:20 hexanes–i-PrOH at 0.5
mL/min; λ = 220 nm), major enantiomer: tR = 17.9 min; minor
enantiomer: tR = 22.3 min.
(9) (a) Zhao, X.; Ruhl, K. E.; Rovis, T. Angew. Chem. Int. Ed. 2012, 51,
12330. (b) Mo, J.; Yang, R.; Chen, X.; Tiwari, B.; Chi, Y. R. Org.
Lett. 2013, 15, 50.
(14) We thank one of the referees for pointing out this important
aspect.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D