Direct asymmetric Mannich reaction of phthalides: Facile access to chiral substituted isoquinolines and isoquinolinones

Article abstract of DOI:10.1039/c2cc31439h

The first Mannich reaction employing phthalides using a quinidine-based multifunctional catalyst has been developed. The reported method led to the synthesis of 3,3-disubstituted phthalide derivatives in excellent yields, with good diastereo- and enantioselectivities. Convenient synthesis of chiral isoquinolinones and isoquinolines has also been demonstrated.

Full text of DOI:10.1039/c2cc31439h

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COMMUNICATION
Direct asymmetric Mannich reaction of phthalides: facile access to chiral
substituted isoquinolines and isoquinolinoneswz
Jie Luo,a Haifei Wang,b Fangrui Zhong,a Jacek Kwiatkowski,a Li-Wen Xuc and Yixin Lu*a
Received 27th February 2012, Accepted 15th March 2012
DOI: 10.1039/c2cc31439h
The first Mannich reaction employing phthalides using a quinidine-
based multifunctional catalyst has been developed. The reported
method led to the synthesis of 3,3-disubstituted phthalide derivatives
in excellent yields, with good diastereo- and enantioselectivities.
Convenient synthesis of chiral isoquinolinones and isoquinolines has
also been demonstrated.
catalytic asymmetric synthesis of optically enriched substituted
isoquinolinones and isoquinolines remains elusive. An efficient
method to access these biologically and synthetically significant
molecules is certainly of enormous importance.
To derive optically enriched isoquinolinones, we reasoned that
chiral 3,3-disubstituted phthalides could serve as a convenient
precursor. It is noteworthy that 3,3-disubstituted phthalides5 are
also molecules of biological significance (Scheme 1), and thus
methods for their asymmetric preparation are highly desired. As
shown in Scheme 1, 3,3-disubstituted phthalides with a b-amino
group are anticipated to undergo intramolecular cyclization
smoothly to afford isoquinolinones, and we envisioned that such
phthalide structures may be prepared via a direct Mannich
reaction between activated phthalides and imines. Up to the
present time, utilization of phthalide derivatives in direct Mannich
reaction is unknown. We envisioned that installation of an
activating group at the 3-position of phthalides may render them
enhanced reactivities suitable for the direct Mannich reaction. It
should be noted that such reactions of phthalides are versatile and
powerful in constructing molecules of biological significance; in
addition to the substituted phthalide products bearing a quaternary
stereogenic center,6 optically enriched isoquinolinones and
isoquinolines are also readily attainable.
Substituted isoquinolines and isoquinolinones are useful building
blocks in organic synthesis due to their structural importance,
chemical stability and relative accessibility. Furthermore, such
structures display a broad spectrum of biological properties, and
they are widely present in many bioactive molecules and natural
products (Scheme 1).1 In spite of broad interest in chemical
preparation of isoquinolines and isoquinolinones,2 synthetic
methods to access chiral derivatives of these molecules are very
limited. One common approach was to utilize a tandem 1,2-
addition–cyclization sequence to construct the isoquinoline or
isoquinolinone core, and a stoichiometric amount of a chiral imine
was typically employed in such an approach.3 Another strategy, in
which optically pure amino acids were used as starting materials,
has found limited applications.4 To the best of our knowledge,
Organic catalysts containing a tertiary amine group and a
Brønsted acid moiety seem to be appropriate for both substrate
activations and stereochemical control in the projected Mannich
reaction. Therefore, a number of bifunctional and trifunctional
catalysts were prepared and screened for the Mannich reaction of
phthalide derivative 1 with imine 2 (Table 1). L-Tryptophan-derived
Trp-16k was able to promote the reaction, however, the stereo-
selectivity was poor (entry 1). Quinidine-derived sulfonamide
QD-16j was ineffective (entry 2), and Cinchona alkaloid-based
tertiary amine–thioureas QD-2 and Q1 also had low catalytic
activities (entries 3 and 4). Trifunctional catalysts6f with amino
acid residue incorporated were next examined. Combination of
quinine with L-valine and L-isoleucine did not yield effective
catalysts (entries 5 and 6). On the other hand, when D-valine was
incorporated into the catalyst structure (QD-5), a marked
increase in enantioselectivity was observed (entry 7), suggesting
the importance of chirality matching between amino acids and
Cinchona alkaloids. We were prompted to explore more
extensively the different combinations of these two privileged
chiral scaffolds. Insertion of L-tert-leucine into cinchonine or
quinine yielded a promising catalyst, whereas a quinine-based
Scheme 1 Selected examples of biologically important isoquinolines,
isoquinolinones, phthalides and the projected Mannich reaction.
a Department of Chemistry & Medicinal Chemistry Program,
Life Sciences Institute, National University of Singapore,
3 Science Drive 3, Singapore 117543, Singapore.
E-mail: chmlyx@nus.edu.sg
b Hunan University of Technology, Hunan, P.R. China
c Key Laboratory of Organosilicon Chemistry and Material
Technology of Ministry of Education, Hangzhou Normal University,
Hangzhou 310012, P. R. China. E-mail: liwenxu@hznu.edu.cn
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘‘Organocatalysis’’ web themed issue.
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc31439h
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4707–4709 4707

Table 1 Catalyst screening for asymmetric Mannich reaction of 1
and 2a
Table 2 Reaction scopea
Entry
1
R2
3
Yieldb/%
drc
eed/%
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1d
1d
1d
1d
1d
1d
1e
1a
1a
4-MeC6H4
4-OMeC6H4
4-OMeC6H4
3-MeC6H4
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
90
92
81
86
86
83
81
80
76
80
85
84
93
79
71
86
92
80
93
79
90
81
88
82
80
88 : 12
88 : 12
91 : 9
86 : 14
91 : 9
92 : 8
88 : 12
83 : 17
89 : 11
91 : 9
85 : 15
88 : 12
92 : 8
82 : 18
67 : 33
73 : 27
86 : 14
87 : 13
84 : 16
88 : 12
85 : 15
83 : 17
87 : 13
70 : 30
63 : 37
95
91
92
93
95
91
92
91
97
92
93
91
85
85
80
83
91
86
93
87
91
82
83
62
55
3e,f
4
5
6e,f
7
Ph
4-BrC6H4
3-BrC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
2-FC6H4
3,4-OMeC6H3
4-CF3C6H4
2-Furanyl
3-Furanyl
Ph
3-MeC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-CF3C6H4
Ph
8
9
10e,f
11
12
13f
14
15f
16
17
18
19
20e,f
21
22
23
24e,f
25e,f
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
3y
Entry
1
R2
Catalyst
Yieldb/%
drc
eed/%
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Cbz
Bz
Trp-1
QD-1
QD-2
Q-1
QD-3
QD-4
QD-5
C-1
Q-2
Q-2
Q-2
Q-2
Q-2
Q-3
Q-4
Q-5
Q-6
Q-2
89
o50
78 : 22
—
39
—
27
40
ꢀ5
ꢀ11
62
82
83
80
—
92
29
89
71
91
92
79 : 21
77 : 23
77 : 23
74 : 26
69 : 31
61 : 39
63 : 37
55 : 45
—
87 : 13
77 : 23
86 : 14
89 : 11
85 : 15
88 : 12
88 : 12
86
87
90
88
85
91
i-Bu
n-Bu
a
Reactions were carried out using 1 (0.05 mmol), 2 (0.06 mmol), Q-2
b
(0.005 mmol) in toluene (0.5 mL) at room temperature. Yield of the
9
isolated product. Determined by 1H NMR analysis of the crude
c
10
11
12
13
14
15
16
17
18e,f
d
products. Determined by HPLC analysis on a chiral stationary
o50
e
phase. N-Tosylimine was used. With 5 mol% catalyst.
f
93
96
Cbz
Cbz
Cbz
Cbz
Cbz
92
90
88
88
and very good enantioselectivities were observed for a wide range
of aryl imines, regardless of the electronic nature and the substitu-
tion pattern of the aromatic ring (entries 1–16). In addition, the
aromatic portion of phthalides could also be varied (entries 17–23).
N-Tosylimines worked equally well, and comparable results were
obtained. Alkyl imines could be employed with less satisfactory
results (entries 24–25).
79
70
95
90
a
Reactions were carried out using 1 (0.05 mmol), 2 (0.06 mmol), the
catalyst (0.005 mmol) in toluene (0.1 mL) at room temperature. b Yield of
the isolated product. c Determined by 1H NMR analysis of the crude
d
products. Determined by HPLC analysis on a chiral stationary phase.
e
f
With 1 mol% catalyst. The reaction was performed in 0.5 mL solvent.
To demonstrate the value of our method in scaleable synthesis,
we performed gram-scale synthesis of 3,3-disubstituted phthalides.
The Mannich reaction between phthalide 1a and Cbz imine 2c
proceeded smoothly in the presence of Q-2, affording gram-scale
Mannich product 3a in 91% yield, with 87 : 13 dr and 93% ee
(Scheme 2). The Mannich products are valuable molecules due to
the importance of 3,3-disubstituted phthalide substructures in
natural products and medicinal chemistry.5 Furthermore, such
structures are versatile synthetic intermediates, and in particular,
are valuable precursors to biologically important isoquinolinones
and isoquinolines. As illustrated in Scheme 2, the tert-butyl ester in
3a was selectively reduced to yield 4, and the subsequent removal
of the Cbz group and basic treatment resulted in smooth lactam
formation to afford chiral isoquinolinone 5, a potential antiviral
agent against RNA viruses.7 Further reduction with LiAlH4 gave
isoquinoline 6, which represents another interesting structural
motif in bioactive compounds.8
catalyst gave slightly better results (entries 8 and 9). We next
focused on tuning the two reaction partners to further improve the
stereoselectivities. Variation of the phthalide ester moiety led to no
improvement (entries 10 and 11). The utilization of N-Cbz imine
greatly enhanced the reaction, and good diastereoselectivity and
excellent enantioselectivity were attainable (entry 12). Further-
more, we tested a number of quinine-based trifunctional catalysts
with different amino acid residues, and Q-2 still stood out to be the
best catalyst (entries 14–17). To make the method more practical
and economical, catalyst loading was further decreased. Under the
optimized reaction conditions and in the presence of only 1 mol%
Q-2, the desired products were obtained in 90% yield and with
88 : 12 dr and 95% ee (entry 18).
We next studied the scope of this direct Mannich reaction
(Table 2). With 1 mol% Q-2, consistently high diastereoselectivities
c
4708 Chem. Commun., 2012, 48, 4707–4709
This journal is The Royal Society of Chemistry 2012

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Scheme 2 Gram-scale direct Mannich reaction and preparation of
isoquinolinones and isoquinolines.
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The C–H bond at position 3 of the phthalide 1 is highly
activated since it is a benzylic proton and is a-substituted with
an oxygen and a carbonyl group, thus the C-3 proton is very
acidic. From a mechanistic viewpoint, there are two possible
pathways for this Mannich reaction: a vinylogous reaction9
and a simple Lewis base activation.10 The exact mechanism of
the reaction has not been elucidated at this early stage, and we
are carrying out further studies to understand the mechanism
underlying this interesting transformation.
In conclusion, we have employed phthalide derivatives as
donors in the direct asymmetric Mannich-type reaction for the
first time; medicinally important and synthetically useful 3,3-
disubstituted phthalides were prepared in excellent yields and
with good diastereoselectivities and enantioselectivities in
the presence of a quinine–tert-leucine trifunctional catalyst.
The Mannich products were readily converted to chiral
isoquinolinones and isoquinolines, both are synthetically and
biologically significant molecular structures. Biological evaluations
of the molecules prepared are underway, and we are also presently
focusing on the extension of phthalides as donors in other asym-
metric reactions.
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This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4707–4709 4709