Sequential combination of Michael and acetalization reactions: Direct catalytic asymmetric synthesis of functionalized 4-nitromethyl-chromans as drug intermediates

Article abstract of DOI:10.1039/c0ob00189a

Functionalized chiral 4-nitromethyl-chromans as drug intermediates were achieved for the first time through sequential combination of Michael and acetalization reactions on 2-(2-nitro-vinyl)-phenols with acetone and alcohols in the presence of a catalytic

Full text of DOI:10.1039/c0ob00189a

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Sequential combination of Michael and acetalization reactions: direct
catalytic asymmetric synthesis of functionalized 4-nitromethyl-chromans as
drug intermediates†
Dhevalapally B. Ramachary* and Rajasekar Sakthidevi
Received 30th May 2010, Accepted 8th July 2010
DOI: 10.1039/c0ob00189a
Functionalized chiral 4-nitromethyl-chromans as drug inter-
mediates were achieved for the first time through sequential
combination of Michael and acetalization reactions on 2-(2-
nitro-vinyl)-phenols with acetone and alcohols in the presence
of a catalytic amount of 9-amino-9-deoxyepiquinine and
Ph2CHCO2H followed by p-TSA.
a metal-free and novel technology for the asymmetric syn-
thesis of substituted 2-hydroxy-2-methyl-4-nitromethyl-chromans
5/6 and 2-alkoxy-2-methyl-4-nitromethyl-chromans 8/9 using
organocatalytic SMA reactions from easily available 2-(2-nitro-
vinyl)-phenols 2, ketones 1, amines/amino acid 3 and alcohols 7
(eqn (2)). In this communication, we report the existence of a fast
dynamic equilibrium between the pair of pseudo-diastereomeric
hemiketals of 2-hydroxy-2-methyl-4-nitromethyl-chromans 5/6
and 4-(2-hydroxy-phenyl)-5-nitro-pentan-2-one 4 under normal
conditions.5
During our investigation of new reactive species for the
development of MCC processes,6 we decided to explore the
potential ability of the 2-(2-nitro-vinyl)-phenols 2 to partici-
pate in an amine-catalyzed SMA reaction with acetone 1. We
expected that the reaction of 2-(2-nitro-vinyl)-phenol 2a with
in situ generated enamine from acetone 1 would lead to 4-
(2-hydroxy-phenyl)-5-nitro-pentan-2-one 4a. However, Michael
adduct 4a was not only detected; instead product 4a showed the
existence of a fast dynamic equilibrium with both cis-2-hydroxy-2-
methyl-4-nitromethyl-chroman 5a and trans-2-hydroxy-2-methyl-
4-nitromethyl-chroman 6a under the standard reaction condi-
tions. This unexpected result represents a novel methodology for
the preparation of 2-hydroxy-2-methyl-4-nitromethyl-chromans
5/6 and a new reactivity for amines or amino acid catalysts.
Herein, we report our findings regarding these new sequential
reactions.
Functionalized chromans display broad spectrum of biological
activities andare widelyused as drugintermediates and ingredients
in pharmaceuticals (see eqn (1)).1 As such, the development of
new and more general catalytic asymmetric methods for their
preparation is of significant interest.2 Interestingly, to the best of
our knowledge there is no report on the direct catalytic asymmetric
method for the synthesis of functionalized 2-hydroxy-2-methyl-4-
nitromethyl-chromans, which can serve as good intermediates for
the functionalized chromans as demonstrated in this communi-
cation. Herein, first time we reported the metal-free approach to
the asymmetric synthesis of functionalized 2-hydroxy-2-methyl-4-
nitromethyl-chromans via “sequential Michael and acetalization
(SMA) reactions”.3
(1)
We initiated our studies of the SMA reactions by screening
a number of organocatalysts for the Michael reaction of 2-(2-
nitro-vinyl)-phenol 2a with 14 equiv. of acetone 1 and some
important results are shown in Table 1. Interestingly, reaction
of 2a with 14 equiv. of acetone 1 in DMSO under 20 mol% of
L-proline 3a-catalysis furnished a 1 : 1 : 1 ratio of Michael↔cis-
lactol↔trans-lactol products 4a/5a/6a in 92% yield with only
£7% ee (see eqn (2) and Table 1, entry 1). Rapid equilibrium
between Michael 4a and lactols 5a/6a in solution was confirmed
by NMR analysis and also finally confirmed by acetalization
with methanol. For the clear understanding of the fast dynamic
equilibrium between 4a and 5a/6a, and also for clear HPLC
separation, we transformed the crude product 4a/5a/6a into
two easily separable SMA products cis-8aa and trans-9aa in
a 1 : 1 ratio with 92% yield via p-TSA-catalyzed acetalization
Recently Barbas and co-workers discovered the novel technol-
ogy of amine or amino acid-catalyzed intermolecular Michael
reactions of ketones/aldehydes with a variety of active olefins
to provide a general route to a variety of Michael adducts in good
yields with high enantioselectivity.4 The advent of this enamine
based Michael technology triggered a burst of activity in the
synthesis of a huge chiral pool of Michael adducts through bio-
mimetic enamine chemistry.4
However, the amine-catalyzed Michael reaction of ketones 1
with 2-(2-nitro-vinyl)-phenols 2 was not known and the resulting
products 4–6 have a wide range of uses in pharmaceutical chem-
istry (see eqn (1) and (2)). Furthermore, there is no methodology
available to prepare achiral compounds 4–6. We have reporting
◦
reaction in MeOH 7a at 25 C for 2 h (see Table 1). In a further
optimization, reaction of 1 and 2a in DMSO under catalysis by
20 mol% of L-Thr(OtBu)–OH 3b followed by p-TSA-catalysis in
MeOH furnished a 1 : 1 ratio of products 8aa and 9aa in only
<30% yield (Table 1, entry 2). Reaction of 1 with 2a in DMSO
under catalysis by 20 mol% of L-2-methoxymethyl-pyrrolidine
3c/PhCO2H followed by p-TSA-catalysis in MeOH furnished a
School of Chemistry, University of Hyderabad, Hyderabad, 500 046, India.
E-mail: ramsc@uohyd.ernet.in; Fax: +91-40-23012460
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data (1H NMR, 13C NMR and HRMS) for
all new compounds. CCDC reference numbers 777137 for (+)-8ba, 765267
for (-)-8ga and 765268 for (-)-9ha. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0ob00189a
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(2)
Table 1 Reaction optimization for the SMA reaction of 1, 2a and 7a
Products yield (%)a
ee(%)b
Entry
Catalyst 3 (20 mol%)
Solvent 0.25 M)
Time/h
8aa
9aa
8aa
9aa
1
2
L-Proline 3a
DMSO
DMSO
DMSO
DMSO
DCM
DMSO
DMSO
DMSO
C6H5CH3
C6H5CH3
DCM
5
48
1
46
<15
47
45
47
—
<15
40
35
42
46
<15
47
45
48
—
<15
40
35
43
-7
-7
L-Thr(OtBu)-OH 3b
3c/PhCO2H
ND
-18
-22
-25
—
ND
-16
-22
-21
—
3
4c
5
3d/D-CSA
2
3d/Ph2CHCO2H
L-DPPOTMS 3e/D-CSA
L-Pyrrolidin-2-ylmethyl-thiourea 3f
3g/AcOH
24
96
24
24
24
24
72
72
6d
7e
8
-30
<5
18
60
84
-30
<5
18
58
82
9
3h
10
11
12f
3h/PhCO2H
3h/Ph2CHCO2H
3h/Ph2CHCO2H
47
40
42
42
DCM
82
82
a Yield refers to the column-purified product. b Ee determined by CSP HPLC analysis. c Similar results obtained without co-catalyst. d (S)-a,a-
Diphenylprolinol trimethylsilyl ether (L-DPPOTMS). e (S)-1-(3,5-Bis-trifluoromethyl-phenyl)-3-pyrrolidin-2-ylmethyl-thiourea. f Reactions were carried
out with each 10 mol% of 3h and Ph2CHCO2H.
1 : 1 ratio of products 8aa and 9aa in 94% yield with increased
(18%) ee (Table 1, entry 3). The same reaction under catalysis by
20 mol% of L-diamine 3d/Ph2CHCO2H in DCM for 24 h followed
by p-TSA-catalysis in MeOH furnished a 1 : 1 ratio of products
8aa/9aa in 95% yield with increased (25%/21%) ee (Table 1, entry
5). Interestingly, there is no product formation under catalysis by
(S)-a,a-diphenylprolinol trimethylsilyl ether (L-DPPOTMS)/D-
CSA in DMSO as shown in Table 1, entry 6. Results are not
fruitful with even bifunctional catalyst (R,R)-1,2-diphenyl-
ethane-1,2-diamine 3g/AcOH and L-(3,5-bis-trifluoromethyl-
phenyl)-3-pyrrolidin-2-ylmethyl-thiourea 3f (Table 1, entries
7–8).
SMA Reaction of 1, 2a and 7a is a catalyst and solvent depen-
dent reaction. After unsuccessful results with chiral pyrrolidines
3a–g as catalyst [many of the results with lower ee’s are not shown
in Table 1], we were interested in further screening alkaloid based
primary amines like 9-amino-9-deoxyepiquinine 3h as catalysts
for the SMA reaction (see Table 1).7 Interestingly, reaction of 2a
with 14 equiv. of 1 under catalysis by 20 mol% of 3h in toluene
for 24 h followed by p-TSA-catalysis in methanol furnished a 1 : 1
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Table 2 Synthesis of chiral SMA products 8 and 9a
ROH
Products
Ratiob
Product yield (%)c
Ee (%)d
Entry
1
2-(2-Nitro-vinyl)-phenols 2
7a/7b
8/9
(8/9)
8
9
8
9
2a
2b
7a
7a
8aa/9aa
8ba/9ba
1 : 1
42
72
42
82
82
2
99 : 1
< 1
98
—
3
4
5
6
2c
2d
2e
2f
7a
7a
7a
7a
8ca/9ca
8da/9da
8ea/9ea
8fa/9fa
1 : 1
1 : 1
1 : 1
1 : 1
43
40
41
41
43
40
41
41
82
69
87
88
76
70
86
91
7
2g
7a
8ga/9ga
1 : 1
38
38
79
79
8
2h
2i
2j
7a
7a
7a
8ha/9ha
8ia/9ia
8ja/9ja
1 : 1
1 : 1
1 : 1
33
37
38
38
37
38
79
80
83
79
80
82
9
10
11
2k
2k
7a
7a
8ka/9ka
1 : 1
1 : 1
44
37
44
37
92
89
89
89
12e
8ka–d5/9ka–d5
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Table 2 (Contd.)
ROH
Products
Ratiob
Product yield (%)c
Ee (%)d
Entry
13
2-(2-Nitro-vinyl)-phenols 2
7a/7b
8/9
(8/9)
8
9
8
9
2a
2e
7b
7b
8ab/9ab
8eb/9eb
1 : 1
1 : 1
44
40
44
80
80
14
40
88
82
a Reactions were carried out in DCM (0.25 M) with 14 equiv. of 1 relative to 2a–k (0.5 mmol) in the presence of 10 mol% of catalyst 3h/Ph2CHCO2H and
the reaction mixture was stirred at 25 ◦C for 72 h. After aqueous workup, the crude product was treated with p-TSA (20 mol%) in solvent ROH 7 (0.2 M),
and the reaction mixture was stirred at 25 ◦C for 2 h. b Ratio is based on NMR analysis. c Yield refers to the column-purified product. d Ee determined by
CSP HPLC analysis (see SI). e CD3COCD3 1-d6 (14 equiv.) was used.
ratio of products 8aa and 9aa in 70% yield each with 18% ee; but
the same reaction under catalysis by PhCO2H salt of 9-amino-9-
deoxyepiquinine 3h furnished the SMA products (+)-8aa in 42%
yield with 60% ee and (-)-9aa in 43% yield with 58% ee as shown
in Table 1, entries 9–10. After this interesting result, we screened
a number of acids as co-catalysts with 3h for the high asymmetric
induction in SMA reaction of 1, 2a and 7a in different solvents
at 25 ◦C for 72 h (Table S1, see Supporting Information†). After
thorough investigation, we envisioned the optimized conditions
to be 25 ◦C in DCM under catalysis by 10 mol% of Ph2CHCO2H
salt of 9-amino-9-deoxyepiquinine 3h followed by p-TSA-catalysis
in methanol to furnish a 1 : 1 ratio of highly substituted SMA
products (+)-8aa in 40% yield with 82% ee and (-)-9aa in 42%
yield with 82% ee (Table 1, entry 12). We also tested number of
other primary amines like 9-amino-9-deoxyepicinchonidine 3i, 9-
amino-9-deoxyepiquinidine 3j, 9-amino-9-deoxyepihydroquinine
3k and 9-amino-9-deoxyepihydroquinidine 3l as catalysts for the
SMA reaction of 1 with 2a in DCM solvent but results are no better
compared to 3h-catalysis (Table S1, see Supporting Information†).
With the optimized reaction conditions in hand, the scope of
the amine-catalyzed asymmetric SMA reactions was investigated.8
A series of substituted 2-(2-nitro-vinyl)-phenols 2a–k were re-
acted with 14 equiv. of acetone 1 catalyzed by 10 mol% of
3h/Ph2CHCO2H at 25 ◦C in DCM for 72 h followed by acetaliza-
tion on crude products 4/5/6 with alcohols 7a–b under p-TSA-
catalysis at 25 ◦C for 2 h (Table 2). The chiral products 8aa–eb
and 9aa–eb were obtained in a 1 : 1 ratio with excellent yields
and ee’s. Electronic factors had little influence: neutral, electron-
withdrawing and electron-donating substituted 2-(2-nitro-vinyl)-
phenols 2a–k generated the expected products 8aa–eb and 9aa–eb
in excellent yields and ee’s (see Table 2). Fascinatingly, reaction
of 1-(2-nitro-vinyl)-naphthalen-2-ol 2b with acetone 1 under
3h/Ph2CHCO2H-catalysis furnished the cis-chroman (+)-5b as
the major product in 80% yield with 98% ee, which on further
acetalization with methanol also furnished the cis-chroman (+)-
8ba as the major product with 98% ee (Table 2, entry 2). The high
stereoselectivity in the synthesis of cis-chromans (+)-5b/(+)-8ba
can be explained using A(1,3)-strain as highlighted by Johnson and
Hoffman in their reviews.9 Maybe due to A(1,3)-strain, the relatively
larger nitromethyl group in 5b/8ba existed in the axial position
in the cyclohexane conformation, which prevented another large
group from approaching on the same side to minimize 1,3-
syn-diaxial repulsions. Without showing much influence from
kinetic factors, deuterated products (+)-8ka–d5 and (-)-9ka–d5
were furnished in 37% yield with 89% ee as shown in Table 2,
entry 12. The structure and stereochemistry of SMA products
8aa–eb/9aa–eb were confirmed by NMR analysis and also finally
confirmed by X-ray structure analysis on (+)-8ba, (-)-8ga and (-)-
9ha as shown in Figures S1 to S3 (see Supporting Information†).
After successful demonstration of the 3h/Ph2CHCO2H-
catalyzed asymmetric SMA reactions of 1 with 2, we decided to
explore the utilization of d-hydroxyketone↔lactol isomerization
in the synthesis of functionalized chiral molecules via acid/base-
catalysis in a sequential manner as shown in eqn (3). Reaction
of pure d-hydroxyketone↔lactol products (+)-4a/5a/6a with 20
mol% of p-TSA in toluene at 110 ◦C for 0.75 h furnished the
selectively cyclized 2-methyl-4-nitromethyl-4H-chromene product
(-)-10a in 86% yield with 81% ee as shown in eqn (3). Treatment
of reaction intermediate (+)-4a/5a/6a with MOM–Cl (a) under
DIPEA-catalysis in DCM at 0 ◦C→25 ◦C for 3.5 h furnished
the selectively protected 4-(2-methoxymethoxy-phenyl)-5-nitro-
pentan-2-one (-)-11aa in 90% yield with 82% ee as shown in eqn
(3). In a similar manner, treatment of (+)-4a/5a/6a with MeI (b)
under NaH in THF at 0 ◦C→25 ◦C for 5 h furnished the selectively
protected 4-(2-methoxy-phenyl)-5-nitro-pentan-2-one (+)-11ab in
65% yield with 80% ee as shown in eqn (3).
With synthetic and pharmaceutical applications in mind, we
further extended the application of acid-catalyzed lactonization
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(3)
◦
methodology to pure isolated d-hydroxyketone↔lactol product
(+)-4a/5a/6a under various conditions as shown in eqn (3).
Interestingly, reaction of (+) - 4a/5a/6a with 6 equiv. of
methylenetriphenylphosphorane in benzene (0.1 M) at 25 C for
3 h furnished the olefin phenol (-)-12a in 95% yield with 82%
ee. Treatment of (-)-12a with 1.2 equiv. of iodine in DCM at
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◦
0 C for 0.25 h furnished the selectively cyclized 2,2-dimethyl-4-
found in many natural products and designed products which
exhibit a wide range of biological activities.2a
nitromethyl-chroman product (-)-13a in 94% yield with 81% ee
as shown in eqn (3). Hydrogenation of (-)-13a with 10% Pd/C
in methanol at 25 ◦C for 5 h furnished the primary amine, which
on protection with Boc2O in DCM at 25 ◦C for 2 h furnished
protected amine (-)-14a in 80% yield with 81% ee. In a similar
ma◦nner, hydrogenation of (-)-9aa with 10% Pd/C in methanol at
25 C for 5 h furnished the◦primary amine, which on protection
with Boc2O in DCM at 25 C for 2 h furnished protected amine
(-)-15aa in 91% yield with 81% ee. But interestingly, we did
not observe hydrogenation reaction of the cis-isomer (+)-8aa
under similar conditions as shown in eqn (3), possibly due to
steric hindrance. Cascade hydrogenation–reductive amination
of (+)-11ab with H2 under Pd-catalysis followed by protection
with p-TsCl under amine-catalysis furnished the stereoselectively
substituted pyrrolidine-sulfonamide (+)-17ab in 64% overall yield
with 80% ee and 70% de as shown in eqn (4). These reactions are
ideal examples for the trapping of both forms of SMA products
4/5/6 from fast dynamic equilibrium as shown in eqn (3) and
eqn (4).
Molecule (-)-14a and analogue (-)-15aa are important com-
pounds as they have potent anti-ischemic properties, and as
anti-hypertensives, spasmolytics for blood vessels and potassium
channel blockers (A–D, see eqn (1)), which emphasizes the value of
this SMA approach to the pharmaceuticals.1 Also functionalized
pyrrolidine-sulfonamide (+)-17ab and their analogues are useful
drugs as modulators of serotonin 5HT6 receptors and dopamine
D3 receptors for the treatment of CNS disorders.1g In addition,
the disubstituted-2H-1-benzopyran structural unit (14 and 15) is
Even though further studies are needed to firmly elucidate
the mechanism of these asymmetric SMA reactions through
3h/Ph2CHCO2H-catalysis, the reaction likely proceeds via an
enamine mechanism (see eqn (5)). In the case of the addition of ace-
tone to 2-(2-nitro-vinyl)-phenols 2 via diamine-catalysis (Table 1,
entries 4–5), we can rationalize the observed stereochemistries
through a favoured transition state where the 2-(2-nitro-vinyl)-
phenol 2 approaches the enamine from the less hindered Re face
as shown in TS-1. In the case of 3h/Ph2CHCO2H-catalysis, the
observed opposite selectivity may be explained by model TS-2, in
which there are favourable electrostatic interactions between the
partially positive nitrogen of the quinine and the partially negative
nitro group, and also between the partially positive phenolic OH
and the partially negative quinine OMe in the transition state (eqn
(5)). The observed stereochemistries of the products 4 could be
explained by approach of the nitro olefin from the less hindered Si
face to the enamine as shown in TS-2.
In summary, first time we have developed the 9-amino-9-
deoxyepiquinine 3h/Ph2CHCO2H-catalyzed asymmetric SMA
reaction of acetone with 2-(2-nitro-vinyl)-phenols under ambient
conditions. The sequential asymmetric reaction proceeds in good
yields with high selectivity using 3h/Ph2CHCO2H as the catalyst.
Furthermore, we have demonstrated the application of chiral d-
hydroxyketone↔lactol products 4/5/6 in the synthesis of highly
functionalized chroman and pyrrolidine molecules. Further work
is in progress to utilize chiral 2-hydroxy-2-methyl-4-nitromethyl-
chromans as intermediates for the bio-active molecule synthesis.
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4264 | Org. Biomol. Chem., 2010, 8, 4259–4265
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4 For selected recent papers on enamine-based Michael reaction of
carbonyl compounds with b-nitrostyrenes, see: (a) K. Sakthivel, W.
Notz, T. Bui and C. F. Barbas III, J. Am. Chem. Soc., 2001, 123, 5260–
5267; (b) J. M. Betancort, K. Sakthivel, R. Thayumanavan and C. F.
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Pojarliev and H. J. Martin, Org. Lett., 2001, 3, 2423–2425; (e) N. Mase,
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6, 2527–2530; (f) J. M. Betancort, K. Sakthivel, R. Thayumanavan, F.
Tanaka and C. F. Barbas III, Synthesis, 2004, 1509–1521; (g) A. J. A.
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Hu¨ttl, C. Grondal and G. Raabe, Nature, 2006, 441, 861–863; (j) P.
Garc´ıa-Garc´ıa, A. Lade´peˆche, R. Halder and B. List, Angew. Chem.,
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5 For the fast dynamic equilibrium between lactol and d-hydroxyketone,
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Int. Ed., 2003, 42, 4955–4957; (b) D. B. Ramachary and R. Sakthidevi,
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Acknowledgements
This work was made possible by a grant from the Department
of Science and Technology (DST), New Delhi [Grant No.:
DST/SR/S1/OC-65/2008]. RS thanks the Council of Scientific
and Industrial Research (CSIR), New Delhi for her research fel-
lowship. We thank Prof. M. V. Rajasekharan and Dr P. Raghavaiah
for their help in X-ray structural analysis.
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7 For selected recent papers on 9-amino-9-deoxyepiquinine 3h-catalyzed
asymmetric reactions, see: (a) C. M. Reisinger, X. Wang and B. List,
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8 For organocatalytic synthesis of substituted 2-(2-nitro-vinyl)-phenols
2a–k and racemic products 8aa–eb and 9aa–eb in good yields, see Tables
S2–S3 in Supporting Information.
3 For recent papers on sequential Michael and lactonization reactions, see:
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Chem., Int. Ed., 2009, 48, 8923–8926; (b) M. Rueping, E. Merino and
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T. N. Snaddon, C. Wirtz, R. Mynott, R. Goddard and A. Fu¨rstner,
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9 For excellent reviews on A(1,3)-strain, see: (a) F. Johnson, Chem. Rev.,
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