Chiral primary amine catalyzed enantioselective protonation via an enamine intermediate

Article abstract of DOI:10.1002/anie.201105477

Enamine protonation: A chiral diamine catalyzes an asymmetric Friedel-Crafts reaction through catalytic enantioselective protonation of an enamine. This process can be applied to a range of α-substituted acroleins and indoles with high yields of products and high enantioselectivity (up to 94 % ee). An Oi-H/π interaction between H₂O and the indole ring was found to play an important role in the transition state (see scheme).

Full text of DOI:10.1002/anie.201105477

DOI: 10.1002/anie.201105477
Asymmetric Catalysis
Chiral Primary Amine Catalyzed Enantioselective Protonation via an
Enamine Intermediate**
Niankai Fu, Long Zhang, Jiuyuan Li, Sanzhong Luo,* and Jin-Pei Cheng
Enantioselective protonation is one of the most straightfor-
ward approaches for building a-chiral carbonyl compounds in
nature and in synthetic chemistry.[1] The majority of methods
rely on protonation of a prochiral enolate, which is either
preformed[2] or generated in situ, in the presence of a chiral
Lewis acid,[3] transitional metal,[4] or organocatalyst[5]
(Scheme 1). Once regarded as complementary to the enolate
the tremendous challenges associated with this transforma-
tion. Manipulating a proton is a nontrivial task, as frequently
encountered in the enolate-based processes.[1b,2] The problem
may be further exacerbated with enamines, since enamine
formation inherently involves multiple proton transfers.[7b]
Furthermore, unlike its enolate counterpart that is normally
employed as a well-defined E/Z isomer, catalytic enamine
intermediates are highly dynamic, with variable E/Z geome-
try.[7b] Finally, the tendency of the chiral product to undergo
racemization is of serious concern in enamine catalysis.
Indeed, enamine formation has been successfully utilized as
the key racemization step in several dynamic kinetic reso-
lutions.[9] Considering the potential pitfalls, we were surprised
to find that enantioselective protonation through enamine
catalysis with a vicinal primary–tertiary diamine/toluenesul-
fonic acid (TfOH) catalyst is feasible, and that high enantio-
selectivity can be achieved under carefully tuned conditions.
In this study, we chose to explore Friedel–Crafts reactions
of a-substituted acroleins with indoles through an iminium–
enamine-catalyzed process (Scheme 1).[10] In previous studies
of iminium-based, asymmetric Friedel–Crafts reactions with
a,b-unsaturated enals or enones,[10,11] the stereoselectivity was
ꢀ
generated in the C C bond-forming step at the b position. In
contrast, an asymmetric Friedel–Crafts reaction of an a-
ꢀ
substituted acrolein, which involves tandem C C bond
Scheme 1. Tandem Friedel–Crafts and enantioseletive protonation via
an enamine intermediate.
formation and enantioselective protonation of the enamine
intermediate at the a position (Scheme 1, II), has not been
reported to date.[12] Asymmetric Friedel–Crafts reactions of
a-substituted, a,b-unsaturated enals with indoles have been
attempted.[13] These reactions achieve good enantioselectivity
but rather poor diastereoselectivity,[13b] which clearly indi-
cates the lack of stereocontrol in the protonation step and
further attests to the difficulties in enantioselective protona-
tion of enamines.
chemistry, enamine-based processes[6] are now prominent
catalytic strategies that facilitate a range of chiral trans-
formations which are beyond the reach of typical enolate
approaches.[7] Despite the prevalence of enamine-based
methods in the field of asymmetric organocatalysis,[8] enan-
tioselective protonation through enamine catalysis has
remained an elusive goal. This is understandable, considering
Previously, we established that chiral primary–tertiary
diamines are effective catalysts for activation of ketones and
aldehydes as enamines,[14] and this approach has recently been
applied to the activation of a-substituted acroleins as iminium
ions.[14e,f] On extending our catalytic system to the hitherto
unexplored Friedel–Crafts reaction of a-substituted acroleins,
we were pleased to observe significant enantioselectivity in
this tandem Friedel–Crafts and protonation sequence. After
extensive screening of different diamine catalysts (see the
Supporting Information for the screening results), we even-
tually identified diamine 1/TfOH (Table 1) as the optimum
catalyst system. The reaction of indole 2a with acrolein 3a
catalyzed by 1/TfOH in dichloromethane at room temper-
ature afforded a 61% yield of product 4a, with a promising
79% ee (Table 1, entry 1). Optimization of the reaction
parameters revealed that the reaction was more efficient
[*] N. Fu,[+] L. Zhang,[+] J. Li, Prof. S. Luo, Prof. J.-P. Cheng
Beijing National Laboratory for Molecular Sciences (BNLMS)
CAS Key of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
E-mail: luosz@iccas.ac.cn
[+] These authors contributed equally to this work.
[**] We thank the Natural Science Foundation of China (20972163), the
National Science Fund for Distinguished Young Scholars
(21025208), and the National Basic Research Program of China
(2011CB808600) for financial support. We also thank Prof. M. X.
Wang from Tsinghua University for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105477.
Angew. Chem. Int. Ed. 2011, 50, 11451 –11455
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11451

Communications
Table 1: Selected results of screening and optimization.[a]
Table 2: Survey of different a-substituted acroleins in the primary amine
catalyzed Friedel–Crafts reaction.[a]
Entry
Product
Yield [%][d]
ee [%][d]
Entry
Solvent
Additive
Yield [%][b]
ee [%][c]
1[b]
2[b]
3
R = PhCH2- (4a)
74 (76)
75 (78)
72
75
72 (78)
80
40
64
70 (68)
56
80
93 (94)
90 (90)
88
87
92 (91)
89
83
89
82 (88)
86
83
1
2
3
4
5
6
7
8
CH2Cl2
DMF[d]
MTBE[e]
brine
toluene
PhCl
PhCl
PhCl
PhCl
PhCl
none
none
none
none
none
none
(R)-BINOL
BHT[f] (1 equiv)
H2O (5 equiv)
brine (5 equiv)
brine (50 equiv)
61
43
40
34
76
76
57
61
76
72
74
79
7
R = 1-NaphthCH2- (4b)
R = 2-MeOPhCH2- (4c)
R = 2,4-(MeO)2PhCH2- (4d)
R = 4-ClPhCH2- (4e)
R = 2-FPhCH2- (4 f)
R = Me (4g)
R = Ph(CH2)3- (4h)
R = n-C6H13- (4i)
R = n-C7H15- (4j)
74
85
85
87
82
84
88
91
93
4
5[c]
6[c]
7[b,c,e]
8
9
9
10
11
10
11
12
R = cyclohexyl- (4k)
R = 1-oct-2-enyl- (4l)
PhCl
52
75
[a] General conditions: 2 (0.100 mmol), 3 (0.200 mmol), 1 (10 mol%),
and TfOH (12 mol%) in solvent (0.2 mL) at room temperature, 5 h.
[b] Yield of isolated product. [c] Determined by HPLC analysis. [d] DMF:
dimethylformamide. [e] MTBE: methyl tert-butyl ether. [f] BHT: 2,6-di-
tert-butyl-4-methylphenol.
[a] General conditions: 2 (0.100 mmol), 3 (0.200 mmol), 1/TfOH (10/
12 mol%) in PhCl (0.2 mL), and brine or saturated NaCl/D2O (9 mL) at
room temperature for 5–14 h. [b] With brine (100 mL). [c] Isolated as
alcohol after in situ reduction with NaBH4. [d] Data in parenthesis refer
to yields obtained in the presence of D2O (X=D). [e] In the presence of
11 mol% TfOH. Completed conversion of starting material and
decomposition of product 4g were observed.
with chlorobenzene as the solvent (Table 1, entry 6 versus
entries 1–5). Furthermore, external proton donors, such as
alcohols or phenols, that are typically employed to protonate
enolates were not preferred in this reaction (Table 1, entries 7
and 8). Instead, the addition of water, and particularly brine,
was found to increase the enantioselectivity. An ee value of
93% was obtained under heterogeneous conditions, in the
presence of 50 equivalents of brine (entry 11).
still proceeded smoothly to furnish high yields of the desired
products 5c and 5d (Table 3, entries 5 and 6). An example of a
3-substituted indole, 3-methylindole, was also examined in the
reaction with catalyst 1/TfOH. In this case, the reaction was
much slower and we were unable to isolate the desired
product from the compex reaction mixture. Additionally, we
determined that a-deuterated products (> 80% deuteration)
could be readily obtained with similar enantioselectivity as
the a-protonated products, when the reactions were con-
ducted in the presence of saturated NaCl/D2O (Table 2,
entries 1, 2, 5, and 9; Table 3, entries 2, 3, 5, 7, and 8).
Mechanistic studies were conducted on the sequence of
iminium–enamine formation to elucidate this intriguing
protonation process. No deracemization was observed when
racemic 4a was treated with 1/TfOH. This result suggests that
the enantioselectivity is generated directly from the tandem
iminium–enamine sequence and is not the consequence of
dynamic kinetic resolution.[9] In addition, racemization of the
reaction products through enamine formation was found to be
negligible when the isolated, optically pure products were
subjected to the optimized reaction conditions (see the
Supporting Information for details). A series of labeling
experiments [Eqs. (1) and (2) and see also the examples in
Tables 2 and 3] were also carried out. In the presence of
saturated NaCl/D2O, deuterated products (> 80% deutera-
tion) were generally obtained. On the other hand, the use of
deuterated indole D-2 led to only 20% a-deuteration in
anhydrous chlorobenzene, or nearly no deuteration in the
presence of H2O [Eq. (2)]. Taken together, these results
suggest that water, either generated in situ on formation of
the iminium ion or added to the reaction, might serve as the
With the new process and optimized conditions in hand,
the scope of the catalytic system was examined. An array of a-
substituted acroleins were tested in the reaction, resulting in
good yields of products 4a–l and high enantioselectivity
(Table 2).[15,16] 2-Benzyl-substituted acroleins were identified
as one class of preferred substrates, and benzyl groups bearing
either electron-rich (Table 2, entries 2–4) or electron-defi-
cient (Table 2, entries 5 and 6) substituents were also good
substrates. Additionally, acroleins bearing other a-alkyl
groups, including linear primary alkanes (Table 2, entries 7–
10), secondary alkanes, such as cyclohexyl (Table 2, entry 11),
and allyl-type groups (Table 2, entry 12) were all suitable
substrates, and afforded the corresponding products in high
yields and with high enantioselectivity. Acroleins with a-
heteroatom substituents, such as benzyloxyl and tert-butyl
carbamate, were not compatible with the enamine catalysis
and no product formation was observed (data not shown).
The scope of the reaction with respect to indole substi-
tution was also investigated (Table 3). A series of indoles with
different substituents at the C5- (Table 3, entries 1, 2 and 9),
C2- (Table 3, entries 3 and 4), and N-positions (Table 3,
entries 7 and 8) were tested in the reaction with catalyst 1/
TfOH. The desired products 5a–i were obtained in high yields
and with high enantioselectivity. The use of 2-unsubstituted
indoles led to some loss of enantioselectivity, but the reactions
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Angew. Chem. Int. Ed. 2011, 50, 11451 –11455

From the absolute configuration of product 5i (deter-
mined by X-ray crystallography; see the Supporting Informa-
tion for details), we propose the transition states shown in
Figure 1 to account for the stereoinduction. Accordingly,
stereospecific, H2O-bridged protonation of the dominant E-
proton donor, and that water-mediated proton transfer is
likely preferred in the current reaction.[17] The large primary
kinetic isotope effect of kH O=kD O ¼1.54 for added water is
Figure 1. Calculated intermediates and transition structures for water-
bridged proton transfer (only enamine a1 and TS-a1 shown).
2
2
clearly consistent with this hypothesis [Eq. (1)].
Table 3: Survey of different indoles.[a]
enamine a1, which is generated from the preferred s-
trans-iminium III in situ, leads to the enantioselec-
tivity observed.
DFT calculations were undertaken to study the
proposed mode of stereocontrol. The reaction
between 2-methylindole and methacraldehyde was
chosen for our study. The theoretical calculations
were carried out with B3LYP/6-311 ++ G(2df,2p)//
B3LYP6-31 + G(d) in Gaussian 03 programs.
Indeed, S-trans-iminium III was found to be the
most stable iminium conformer by 3.0 kcalmolꢀ1
(Figure 1). The iminium III is stabilized by a strong
hydrogen bond between the vicinal amino groups. A
similar proton-fixed iminium conformer has also
been proposed for other primary amine catalysts.[12a]
Subsequent addition of an indole to iminium III
would lead preferentially to E-enamine intermedi-
ates with varied conformations. Accordingly, we
have located four E-enamine conformers a1–a4 and
successfully reached the corresponding transition
states for H2O-bridged proton-transfer processes
(Table 4, TS-a1–a4; structures are shown in
Scheme S3 in the Supporting Information). The
activation barrier was calculated to be 13.7 kcal
molꢀ1, which indicates that the water-bridged process
is quite facile. The calculated enantioselectivity
based on the four transition states was 76% ee in
favor of the S product (Table 4), which is in good
agreement with the experimental result (83% ee). In
addition, the most favored transition state TS-a1 was
Entry Product
Entry Product
1[b]
2
3
5
4[b]
6
7
9
8
ꢀ
stabilized by an O H/p interaction between the
water molecule and the indole ring.[18] This inter-
[a] General conditions: 2a (0.100 mmol), 3 (0.200 mmol), 1/TfOH (10/12 mol%) in
PhCl (0.2 mL), and brine or saturated NaCl/D2O (100 mL), at room temperature for
4–20 h. [b] With brine (9 mL). Bn=benyzl
action was absent in the other three transition states
(see Scheme S3 in the Supporting Information).
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Communications
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Table 4: DFT-predicted enantiomeric excess for the reaction of 2-
methylindole and methacrylaldehyde in chlorobenzene.
Transition
state[a]
Erel
Ratio at
258C [%]
Product
Calcd ee [%]
[kcalmolꢀ1 [b]
]
TS-a1
TS-a2
TS-a3
TS-a4
0
82.2
5.6
6.2
S
S
R
R
1.59
1.53
1.54
76
(exptl 83)[c]
6.0
[a] Calculated at the B3LYP/6-311+ +G(2df,2p)//B3LYP/6-31+G(d)
level; the structures of E-enamine a2-a4 and TS-a2-a4 are listed in
Scheme S3 in the Supporting Information. [b] Enthalpy in chlorobenzene
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ꢀ
Although unprecedented in asymmetric catalysis, such an O
H/p interaction is prevalent in biological systems involving
tryptophan residues, and account for the favorable confor-
mation and catalysis.[19] With its propensity for participating in
ꢀ
O H/p interactions, the indole moiety in the current system
seems to be critical for stereocontrol, since similar reactions
with pyrrole, 3-methoxybenezenethiol, or benzotriazole give
low chiral induction.[20]
In conclusion, we have successfully developed the first
enantioselective protonation via a catalytic enamine inter-
mediate. This process is made possible through chiral primary
amine catalyzed Friedel–Crafts reactions of a-substituted
acroleins. Critical to the success of the reaction was the
identification of a vicinal primary–tertiary diamine/Brønsted
acid catalyst and the finding that water, particularly brine, is
the inherently preferred proton donor. Theoretical studies
indicated that the water-bridged proton transfer is indeed a
ꢀ
favorable pathway and an unprecedented O H/p interaction
was found to contribute significantly to the stereocontrol of
the reaction. The current enantioselective protonation pro-
tocol, which accommodates a range of acroleins and indoles,
represents the first such catalytic protonation processes that
produces chiral aldehydes, and also has significant potential
for generating chiral indole derivatives.
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Revised: August 22, 2011
Published online: October 10, 2011
Keywords: aldehydes · asymmetric catalysis · enamines ·
.
Friedel–Crafts · protonation
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[15] Minor side products were observed by TLC and NMR spectro-
scopic analysis of the crude reaction mixtures. However, we were
unable to characterize these products because of their instability
during isolation and purification.
[16] A larger scale (3 mmol) reaction has been conducted to afford
4a (0.59 g) in 71% yield and 90% ee in 4 h.
[17] A possible intramolecular proton transfer cannot be excluded,
since the deuterated indole D-2 was found to undergo rapid H/D
exchange under the optimized reaction conditions with a rate
comparable to or even faster than that of the Friedel–Crafts
reaction. Further theoretical studies are necessary to examine
this issue. We thank the referee for bringing our attention to this
point.
b
4
ꢀ
[18] In TS-a1, the shortest O H –C distance is 2.33 ꢁ. Atoms in
Molecules (AIM) analysis at the bond critical point suggested a
weak interaction between Hb and C4 where the electron denstity
(1b) is 0.0137 au and the Laplacian values (D21b) is 0.0431 au.
ꢀ
These values indicate that an O H/p interaction is present.
[19] Tryptophan is known to be one of the most potent and prevalent
ꢀ
p acceptors in O H (H2O)/p interactions, see T. Steiner, G.
Koellner, J. Mol. Biol. 2001, 305, 535 – 557.
[20] N-Methylpyrrole: ꢀ10 8C, 16 h, 87% yield, 40% ee; 3-methox-
ylbenzenethiol (thio-addition product), ꢀ10 8C, 16 h, 90% yield,
3% ee; benzotriazole, 12 h, 65%, 7% ee. Ethyl malonate has
also been examined, but showed no product formation was
observed.
Angew. Chem. Int. Ed. 2011, 50, 11451 –11455
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11455