Silylcyanation of aldehydes, ketones, and imines catalyzed by a 6,6'-bis-sulfonamide derivative of 7,7'-dihydroxy-8,8'-biquinolyl (azaBINOL)

Article abstract of DOI:10.1002/ejoc.201200333

6,6'-Bis(methylaminosulfonyl)-7,7'-dihydroxy-8,8'-biquinolyl (3) catalyzes (5-10 mol-%) the addition of trimethylsilyl cyanide to aldehydes (aryl, alkyl, and α,β-unsaturated; 42-92 % yields), ketones (aryl alkyl, dialkyl; 22-82 % yields), and N-benzylaldimines (14-78 % yields) in toluene (0 °C or room temp.) to give the expected cyanohydrin and Strecker adducts following desilylation. Among a series of closely related compounds lacking any one of their defining structural features, bis-sulfonamide 3 and its N,N'-dimethyl derivative are exceptional in catalyzing the silylcyanation of benzaldehyde in the absence of all other additives. Hammett analysis of the competitive silylcyanation of para-substituted benzaldehydes catalyzed by 3 showed a linear free-energy relationship (R² = 0.928) with a modest positive reaction constant (ρ = +1.52). X-ray diffraction analysis of (±)-3 indicated a cisoid biaryl conformation and the existence of an intramolecular hydrogen bond between C7'-OH and C7-O. Resolution of (±)-3 was achieved by HPLC separation of its tetravalerate derivative on a chiral stationary phase. The absolute configurations of the optical isomers of 3 were assigned by correlation of the ECD spectra with those of related biquinolyls of known configuration. The silylcyanation of aldehydes catalyzed by (-)-(aR)-3 leads to cyanohydrins with a preference for the (S)-configured product with an ee of <10 %. The organocatalytic action of 3 is ascribed to hydrogen bonding and Bronsted acid catalysis effects that are dependent on its acidifying sulfonamide groups, general base capability, and interannular proximity effects made possible by the biaryl structure. Copyright

Full text of DOI:10.1002/ejoc.201200333

Job/Unit: O20333
/KAP1
Date: 08-05-12 09:59:34
Pages: 13
FULL PAPER
DOI: 10.1002/ejoc.201200333
Silylcyanation of Aldehydes, Ketones, and Imines Catalyzed by a 6,6Ј-Bis-
sulfonamide Derivative of 7,7Ј-Dihydroxy-8,8Ј-biquinolyl (azaBINOL)
Selena Milicevic Sephton,[a] Chao Wang,[a] Lev N. Zakharov,[a] and Paul R. Blakemore*[a]
Keywords: Organocatalysis / Biaryls / Nitrogen heterocycles / Cyanohydrins / Strecker reaction
6,6Ј-Bis(methylaminosulfonyl)-7,7Ј-dihydroxy-8,8Ј-biquin-
olyl (3) catalyzes (5–10 mol-%) the addition of trimethylsilyl
cyanide to aldehydes (aryl, alkyl, and α,β-unsaturated; 42–
92% yields), ketones (aryl alkyl, dialkyl; 22–82% yields), and
N-benzylaldimines (14–78% yields) in toluene (0 °C or room
temp.) to give the expected cyanohydrin and Strecker ad-
ducts following desilylation. Among a series of closely re-
lated compounds lacking any one of their defining structural
features, bis-sulfonamide 3 and its N,NЈ-dimethyl derivative
biaryl conformation and the existence of an intramolecular
hydrogen bond between C7Ј–OH and C7–O. Resolution of
(Ϯ)-3 was achieved by HPLC separation of its tetravalerate
derivative on a chiral stationary phase. The absolute configu-
rations of the optical isomers of 3 were assigned by corre-
lation of the ECD spectra with those of related biquinolyls of
known configuration. The silylcyanation of aldehydes cata-
lyzed by (–)-(aR)-3 leads to cyanohydrins with a preference
for the (S)-configured product with an ee of Ͻ10%. The or-
are exceptional in catalyzing the silylcyanation of benzalde- ganocatalytic action of 3 is ascribed to hydrogen bonding and
hyde in the absence of all other additives. Hammett analysis
of the competitive silylcyanation of para-substituted benzal-
dehydes catalyzed by 3 showed a linear free-energy relation-
ship (R2 = 0.928) with a modest positive reaction constant (ρ
= +1.52). X-ray diffraction analysis of (Ϯ)-3 indicated a cisoid
Brønsted acid catalysis effects that are dependent on its acid-
ifying sulfonamide groups, general base capability, and in-
terannular proximity effects made possible by the biaryl
structure.
N,NЈ-dioxide derivatives which have been employed as chi-
ral Lewis base promoters.[8] Related N,NЈ-dioxides of 2,2Ј-
biquinolyls and 1,1Ј-biisoquinolyls have been similarly
used.[9] Other axially chiral aromatic heterocycles that have
found utility in catalysis include non-C2-symmetric atropi-
someric mixed carba/azacyclic biaryl systems such as the
P,N ligand QUINAP[10] and an axially chiral DMAP ana-
logue introduced by Spivey et al.[11] It is evident that the
exploration of a greater array of heterocyclic biaryl types
could lead to the discovery of significant new metal ligand
families and the identification of new viable modes for or-
ganocatalysis.
In the search for a readily manipulated axially chiral het-
erocyclic biaryl template with a wide range of potential ap-
plications and yet topologically distinct from well-studied
2,2Ј-bipyridyl systems, 7,7Ј-disubstituted 8,8Ј-biquinolyls
(e.g., 1–5) were targeted (Figure 1).[12] In earlier work we
developed synthetic approaches to 7,7Ј-dioxygenated 8,8Ј-
biquinolyls,[12a,12c,12e] introduced methods to resolve these
compounds into their enantiomeric atropisomers,[12b,12c]
and determined many of the physical properties of such
“azaBINOL” molecules,[13] including enantiomerization ki-
netics,[12b,12c] chiroptical behavior,[12b,12c] and the depen-
dence of basicity on conformation.[12d] Polyfunctionalized
azaBINOLs provide a platform for the interrogation of in-
herently chiral interannular proximity effects that may form
the basis of significant new catalysis modes. In this regard,
Introduction
Given the enormous structural diversity of aromatic het-
erocycles, their capacity to directly catalyze certain chemical
transformations, and the ease with which many such ring
systems can be synthetically modified, placement of hetero-
cycles within chiral scaffolds can provide fertile ground for
the discovery of new and potentially enantioselective pro-
cesses. Configurationally stable, axially chiral, heteroarom-
atic biaryl molecules offer ample opportunities for such de-
velopments[1,2] and yet few reactions utilizing this class of
compounds have emerged.[3] In contrast, the proliferation
of methods based on functionally limited carbacyclic biaryl
systems, particularly 1,1Ј-bi-2-naphthol (BINOL) deriva-
tives,[4,5] continues apace.[6] 2,2Ј-Bipyridyls are the best
studied group of heterocyclic biaryl molecules,[7] however,
the interannular axes of these versatile metal ligands are
configurationally labile unless at least one of the pyridyl N
atoms is quaternized, for instance, as an N-alkylpyridinium
salt or an N-oxide. Examples of atropos 2,2Ј-bipyridyls used
in enantioselective synthesis are therefore largely limited to
[a] Department of Chemistry, Oregon State University,
153 Gilbert Hall, Corvallis, OR 97331-4003, USA
Fax: +1-541-737-2062
E-mail: paul.blakemore@science.oregonstate.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200333.
Eur. J. Org. Chem. 0000, 0–0
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S. M. Sephton, C. Wang, L. N. Zakharov, P. R. Blakemore
FULL PAPER
azaBINOLs with a ligating substructure at C6 and C6Ј biphilic (bifunctional) catalysis[19] have seen silylcyanation
(e.g., 3–5) were of initial interest as likely precursors to reactions effected by discrete chiral metal complexes that
novel dinuclear metal complexes possessing pairs of biaryl contain both Lewis acid (LA) and Lewis base (LB) sites.[20]
quadrants flanked by filled (N atom lone pair) and vacant Such complexes (e.g., 7 and 8)[14] offer simultaneous acti-
(metal) orbitals. The topology of notional complexes of this vation of the carbonyl electrophile and cyanosilane nucleo-
nature (e.g., 6) contrasts with that of known ambiphilic cat- phile (typically TMSCN) through the corresponding inter-
alysts derived from the modified BINOLs 7 and 8[14] and actions with the LA and LB functionalities.[21] Given that
we wished to explore what benefits their unique attributes carbonyl silylcyanation provides a platform for the study of
could offer a suitable comparative benchmark process, in new ambiphilic catalysts, we elected to focus on this process
this case, the silylcyanation of carbonyl derivatives. Herein, initially to evaluate the metal complexes derived from che-
we report our findings and the unexpected discovery that lating azaBINOLs 3–5 (e.g., 6). However, it became appar-
the bis-sulfonamide “ligand” 3 is itself an effective catalyst ent that compound 3 was capable of directly catalyzing silyl-
for the synthesis of cyanohydrin TMS ethers from alde- cyanation by a novel organocatalytic mechanism and this
hydes (and related adducts from ketones and imines), but became the major focus of the work now detailed.
that similar compounds lacking any one of its defining
structural features are not. Despite the fact that the organ-
ocatalytic action identified depended critically on the chiral
axis of 3, the specific mechanism controlling silylcyanation
Silylcyanation of Aldehydes, Ketones, and Imines
was found to be only barely enantioselective in the reactions
examined.
At the outset, to establish the catalytic activity of put-
ative ambiphilic biquinolyl–metal complexes, the silylcyan-
ation of benzaldehyde in the presence of racemic aza-
BINOLs 1–5 (prepared as before)[12a,12c,12e] and various
metal and other additives was investigated (Table 1). Nájera
and co-workers previously identified that silylcyanation cat-
alyzed by BINOLAM-AlCl (8)[14d] was optimal when con-
ducted in the presence of Ph3PO and 4 Å molecular sieves
(MS). The phosphane oxide ostensibly prevents oligomer-
ization of the catalyst by binding to Al while enabling the
metal center to adopt a more reactive bipyramidal penta-
valent coordination sphere during the reaction.[22] The role
played by zeolites is less clear and their beneficial action
was attributed to the possibility of molecular sieves actually
contributing a trace of water to the reaction.[23] We began
by adopting the protocol of Nájera and co-workers[14d] and
incubated the biaryl diols of interest with Ph3PO, molecular
sieves (4 Å), and Me2AlCl in toluene (1 h, 30 °C) to form
uncharacterized Al complexes before cooling (to –20 °C)
and the addition of benzaldehyde and TMSCN (entries 1–
7). Conversion to mandelonitrile (10) was dependent on the
exact provenance of the zeolite additive used, making early
experiments difficult to reproduce.[24] Nonetheless, azaBI-
NOL derivatives with a ligating substructure at C6 and C6Ј
gave consistently superior results (cf. entries 5–7 with 3 and
4). AzaBINOL diamine 5, strictly analogous to Nájera’s BI-
NOLAM ligand system performed best under these condi-
Figure 1. AzaBINOL derivatives 1–5, notional dinuclear ambi-
philic metal complex 6 derived from bis-sulfonamide 3, and the
known 1,1Ј-bi-2-naphthol (BINOL)-derived ambiphilic Al com-
plexes 7 and 8.
Results and Discussion
Cyanohydrins are synthetically useful[15] and intense ef- tions (entry 7). TiIV complexes generated from biaryl diols
forts have been directed at the development of efficient and Ti(OiPr)4 in the presence of molecular sieves (4 Å), a
enantioselective methods to target these carbinols and their protocol also demonstrated previously for the silylcyanation
derivatives by cyanide addition to carbonyl derivatives.[16]
A
with modified BINOLs,[14b,14d] were next evaluated (en-
majority of the approaches to stereocontrolled cyanohydrin tries 8–11). Again, the nature of the metal complexes
synthesis rely on metal catalysis,[17] although promoters formed was not established. However, the conversion of 9
based on small organic molecules are being increasingly into 10 was best effected in the presence of bis-sulfonamide
used for their synthesis.[18] The silylcyanation of carbonyls 3 rather than the other ligands.[25]
offers a convenient access to cyanohydrins (by hydrolysis of
At this stage we sought to better define the expectation
the resulting silyl ethers) and this process invites numerous of “blank” reactions conducted in the absence of Lewis
modes for catalysis because cyanosilanes are intrinsically acidic metal additives and discovered a modest promotion
poor nucleophiles that cannot add across a C=O bond of the reaction by using molecular sieves (4 Å) alone (cf.
without activation. Significant recent developments in am- entries 12 and 16). The efficacy improved a little by the
2
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Catalyzed Silylcyanation of Aldehydes, Ketones, and Imines
Table 1. Synthesis of mandelonitrile (10) by silylcyanation of benz-
aldehyde (9) with TMSCN in the presence of biaryl promoters.
Table 2. Silylcyanation of carbonyl compounds and imines cata-
lyzed by bis-sulfonamide (Ϯ)-3.
Entry
R
RЈ
X
Yield[a] [%]
Ref.[b]
[14d]
[14d]
[44a]
[44b]
[44b]
[18d]
[44c]
[14d]
[14d]
[14d]
Entry Ligand/Promoter[a]
Additives
Conditions Conv.[b] [%]
1
2
3
4
5
6
7
8
9
10
Ph
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
O
O
O
O
88
75
86
76
92
92
42
90
89
86
4-MeOC6H4
4-NO2C6H4
3-ClC6H4
2,6-Cl2C6H3
1-naphthyl
3-pyridyl
(E)-PhCH=CH
PhCH2CH2
c-C6H11
1
2
3
4
5
6
7
none
–20 °C, 4 h 28
–20 °C, 4 h 15
–20 °C, 4 h 15
–20 °C, 4 h 13
–20 °C, 4 h 82
–20 °C, 4 h 71
–20 °C, 4 h 92
BINOL (X = CH)
1
Ȇ
Me2AlCl,
Ph3PO,
MS (4 Å)[c]
ȇ
2 (R2 = tBu)
3 (R1 = SO2NHMe)
4 (R1 = CONEt2)
5 (R1 = CH2NEt2)
8
none
Ȇ
0 °C, 1 h
0 °C, 1 h
28
9
9
10
11
BINOL (X = CH)
1
Ti(OiPr)4,
[44d]
[44b]
11
12
13[c]
14[c]
15[c]
Ph
n-C6H13
Me
Me
O
O
22
82
MS (4 Å)[d] 0 °C, 1 h
44
Ն98
3 (R1 = SO2NHMe)
ȇ
0 °C, 1 h
[26a]
[26c]
[26c]
Ph
3-ClC6H4
3-pyridyl
H
H
H
NBn
NBn
NBn
72
78
14
12
13
14
15
none
Ȇ
MS (4 Å)
0 °C, 1.1 h
0 °C, 1.1 h
0 °C, 1.1 h
0 °C, 1.1 h
19
25
33
Ն98
BINOL (X = CH)
1
3 (R1 = SO2NHMe)
ȇ
[a] Isolated yield after SiO2 chromatography. [b] All products 12
exhibited spectroscopic data (IR and NMR) in agreement with
those previously reported. [c] Silylcyanation reactions of imines
performed for 9 h at room temp.
16
17
18
19
none
Ȇ
none
0 °C, 1.25 h
0 °C, 1.25 h
0 °C, 1.25 h
0
0
0
BINOL (X = CH)
1
3 (R1 = SO2NHMe)
ȇ
0 °C, 1.25 h Ն98
[a] Unless otherwise indicated, X = N, R1 = R2 = H, BINOL =
1,1Ј-bi-2-naphthol. [b] The conversion of 9 into 10 was determined
by 1H NMR spectroscopy. [c] Me2AlCl (10 mol-%), Ph3PO
(40 mol-%). [d] Ti(OiPr)4 (10 mol-%).
Mechanistic Studies
Five varied analogues of bis-sulfonamide 3 presenting
unique functional group deletions and/or masking were tar-
geted to identify which structural features were implicated
in the organocatalysis (Scheme 1). In the first series of ana-
combined action of molecular sieves (4 Å) and either logues (13–15), the hydrogen-bond-donating OH and NH
BINOL or azaBINOL (1), but a dramatic increase in con- groups were systematically masked. Bis-carbamate 13 con-
version was noted when bis-sulfonamide 3 was used instead taining free sulfonamide NH but capped OH is the immedi-
(entries 13–15). Further simplification of the reaction mani- ate synthetic precursor to bis-sulfonamide 3 and was pre-
fold indicated that biquinolyl 3 was unique among the com- pared as described previously.[12a] Tertiary sulfonamide 14
pounds initially evaluated in catalyzing the reaction in the containing free OH but capped NH was prepared in an
absence of all other additives (entries 16–19). Structure analogous fashion to secondary sulfonamide 3 by substitut-
probing control experiments later revealed just how critical ing Me2NH for MeNH2 during aminolysis of a bis-sulfonyl
the juxtaposition of functional groups within 3 is for effec- chloride intermediate. Straightforward base-mediated tetra-
tive catalysis of this simple reaction (see below).
methylation of bis-sulfonamide 3 with MeI led to the tar-
Intrigued by the fact that we had uncovered a novel geted analogue 15 lacking all protic/hydrogen-bond donor
metal-free silylcyanation process, the scope of the reaction sites.
was then assessed by gauging the ability of bis-sulfonamide
In the second series of analogues (16 and 17), changes
3 to catalyze cyanide transfer to a range of other carbonyl of a more fundamental nature were envisioned. A 1,1Ј-bi-
compounds and imines (Table 2). Cyanohydrins 12 (X = O) naphthyl-based carbacyclic analogue of 3 (16) was prepared
were obtained in good-to-excellent yields from all but one from the known bis-MOM ether of BINOL (18)[28] by using
of the aromatic aldehydes examined (entries 1–7). Similar the double-directed ortho-metalation strategy of Snieckus
results were also found with α,β-unsaturated and enolizable and co-workers[29] (Scheme 2). Thus, 3,3Ј-dilithiation of 18
aliphatic aldehydes (entries 8–10). The reactions of ketones with nBuLi followed by electrophilic sulfenation with
were less consistent (entries 11 and 12), but it was notable BnSSBn led to a bis-sulfide that was oxidized to the corre-
that simple N-benzylaldimines yielded Strecker adducts 12 sponding bis-sulfonyl chloride. Aminolysis and MOM ether
(X = NBn) under the same conditions (entries 13 and removal then gave the desired 3,3Ј-bis-sulfonamidyl BINOL
15).[26] In all of the reactions examined, sulfonamide cata- derivative 16. A monoquinoline analogue of 3 (17) was pre-
lyst 3 could be recovered chemically unaltered from the pared along similar lines to the bis-sulfonamide itself by
acidic aqueous phase following hydrolytic workup.[27]
omitting oxidative aryllithium dimerization following halo-
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S. M. Sephton, C. Wang, L. N. Zakharov, P. R. Blakemore
FULL PAPER
reactivity.[30] Significantly, an X-ray crystallographic analy-
sis of bis-sulfonamide 3 revealed an intramolecular hydro-
gen bond between neighboring polyfunctionalized quinol-
ine rings (see below). The impact of such an interannular
proximity effect will extend beyond influencing the solid-
state structure of 3 and may distinguish its chemical behav-
ior from that of monoquinoline 17 during the silylcyanation
reaction. Given the catalytic activity of analogue 14 (a terti-
ary bis-sulfonamide), it is evident that free sulfonamide NH
groups are not essential elements for catalysis. However, sul-
fonamidyl substituents of some kind are important because
azaBINOL (1) itself is not an organocatalyst for silylcyan-
Scheme 1. Bis-sulfonamide 3 and five structurally varied analogues ation. In addition to providing further sites for potentially
13–17.
significant dipolar interactions, the requirement for sulfon-
amides is undoubtedly associated with the effect that these
gen-dance rearrangement from the known 8-iodoquinolyl
carbamate 19.[12a] Thus, the net transposition of the corre-
sponding hydrogen and iodine atoms at C6 and C8 in 19
by treatment with LDA followed by proton quenching gave
6-iodoquinoline 20 that evolved to 17 in good overall yield
in a three-step sequence of Pd0-catalyzed thioether forma-
tion, oxidative sulfonamide generation, and saponification.
strongly electron-withdrawing functional groups will have
on modulating the acid–base properties of azaBINOLs
(raising phenol acidity and lowering quinoline basicity).
To shed further light on the nature of the catalytic effect
elicited by bis-sulfonamide 3, a kinetic study was conducted
to establish the relative rates for the silylcyanation of benz-
aldehyde compared with some para-substituted derivatives
(Figure 2). Hammett analysis[31] of the resulting data by
using appropriate literature σp values[32] for the substituents
revealed a good linear free-energy relationship (R2 = 0.928)
with a reaction constant of ρ = +1.52. The modestly posi-
tive ρ value observed is consistent with a reaction that bene-
fits from a catalyst with bifunctional character but with a
rate-determining step dominated by a requirement for elec-
trophilic activation of the aldehyde.[33]
Scheme 2. Synthesis of binaphthyl and monoquinoline analogues
of bis-sulfonamide 3.
With the five sulfonamidyl analogues of 3 in hand, each
was evaluated as a potential organocatalyst for the silylcy-
anation of benzaldehyde according to the protocol pre-
viously developed (cf. Table 2, i.e., 10 mol-% catalyst,
3.0 equiv. TMSCN, 1.0 equiv. PhCHO, PhMe, 1.25 h, 0 °C,
then, aq. HCl). Remarkably, with the notable exception of
14, which gave full conversion, none of the new compounds
tested promoted the addition reaction to any appreciable
extent. Sulfonamides lacking free phenolic OH groups (13
Figure 2. Hammett analysis of the competitive silylcyanation of 4-
substituted benzaldehydes as compared with benzaldehyde. kR/kH
is equal to the ratio of 21-R/21-H and was determined by integra-
1
and 15) or without embedded quinoline moieties (16) failed tion of the H NMR spectrum of the crude product mixture.
to catalyze the reaction at all whereas the monoquinoline
congener of 3 (17) elicited only a 2% conversion of benzal-
dehyde to mandelonitrile. The fact that 17 is almost devoid
of catalytic activity despite possessing all three distinct
X-ray Diffraction Analysis of 3
types of functional groups found in 3 is striking and sug-
Determination of the solid-state structure of racemic bis-
gests that the spatial relationship between these moieties, as sulfonamide 3 revealed tautomerism and conformational is-
defined by the intervening biquinolyl motif, is critical for sues that could influence its chemical reactivity. Single crys-
4
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Catalyzed Silylcyanation of Aldehydes, Ketones, and Imines
tals of (Ϯ)-3 suitable for X-ray diffraction analysis were ob- true intrinsic configurational differences).[34] The more
tained by recrystallization from ethanol to produce a solv- cisoid form of 3 has a formal (R,aR,S)* relative configura-
ate of composition (Ϯ)-3·0.5EtOH. Two symmetrically in- tion and displays an interannular hydrogen bond between
dependent molecules of 3 were identified within the unit C7Ј–OH and C7–O (Figure 3, A). Conversely, the less cisoid
cell of the racemate and each showed numerous interesting form of 3 has a formal (S,aR,S)* relative configuration and
structural features (Figure 3). In contrast to other uncon- lacks any semblance of the interannular hydrogen bond
strained azaBINOLs previously studied by X-ray diffrac- found in its unit cell partner (Figure 3, B). In this case, it
tion analysis,[12a–c] both forms of bis-sulfonamide 3 were can also be seen that both sulfonamide methyl groups are
found to be cisoid rather than transoid in their biaryl con- directed inwards towards the biaryl quadrant flanked by C7
formational preference. Also hitherto unknown for azaBI- and C7Ј (i.e., NW quadrant in the right-hand side-view of
NOLs, in each case here the two hydroxyquinoline units 3 in Figure 3, B) whereas for the more cisoid molecule one
defining the biquinolyl are distinct tautomers, one phenolic methyl group is directed inwards and the other outwards in
and the other of quinolone (vinylogous amide) type. Al- the same quadrant (Figure 3, A).
though similar in these two regards, a closer examination
of the data revealed some significant differences between
Resolution of (؎)-3 and Evaluation of Enantioselectivity
the independent forms of 3. In addition to exhibiting dif-
ferent biquinolyl ring-plane dihedral angles, by virtue of the
presence of pyramidalized sulfonamide nitrogen atoms,
each molecule is seen to be a distinct diastereoisomer (pre-
sumably an artifact of crystal-packing forces rather than
Enantioenriched samples of 3 were obtained by prepara-
tive HPLC separation of the enantiomorphic atropisomers
of its tetravalerate derivative 22 by using a standard chiral
stationary phase (Scheme 3). Saponification of the resulting
enantioenriched pervalerates gave scalemic material in up
to 99% ee.[35] However, in common with other azaBINOL
derivatives with free OH groups,[12b,12c] it was noted that 3
possesses limited configurational stability. For example, a
15% drop in optical activity was noted for a solution of
(–)-(aR)-3 after around 1 d at 28–32 °C (0.2 mm in MeOH).
In contrast, a sample of (+)-(aS)-3 (82% ee) stored at 5 °C
in the solid state for 16 d was then later converted into (+)-
(aS)-22 with 80% ee (by HPLC analysis). The absolute con-
figurations of the optical isomers of 3, as (–)-(aR) and (+)-
(aS),[36] were assigned on the basis of a comparison of the
electronic circular dichroism (ECD) spectra with those pre-
viously recorded for scalemic samples of 1 and 2 of known
configuration (Figure 4).[37] Thus, biquinolyl (–)-(aR)-3 ex-
hibited the same negative exciton chirality phase in its long-
1
axes polarized Bb Platt transition band (λmax = 240 nm)[38]
as that previously observed for both (+)-(aR)-1 and (+)-
(aR)-2.[12b,12c]
Figure 3. A: Two mutually orthogonal views of the ORTEP dia-
gram for the more cisoid symmetrically independent form of bis-
sulfonamide 3 present in the unit cell of (Ϯ)-3·0.5EtOH with rela-
tive stereochemical descriptors. The angle between the least-squares
fitted quinoline ring planes is 54.21(5)°. Parameters associated with
the indicated interannular hydrogen bond, C7Ј–OH···O–C7, are:
d(OЈ–H)
=
0.94(4) Å, d(H···O)
= 1.62(4) Å, d(O···OЈ) =
2.526(3) Å, Є(OЈ–H···O) = 162(4)°. Angle sums for bonds sur-
rounding sulfonamide nitrogen atoms are 336° for C6–SO2NHMe
and 352° for C6Ј–SO2NHMe. B: Two mutually orthogonal views
of the ORTEP diagram for the less cisoid symmetrically indepen-
dent form of bis-sulfonamide 3 present in the unit cell of (Ϯ)-
3·0.5EtOH with relative stereochemical descriptors. The angle be-
tween least-squares fitted quinoline ring planes is 72.33(4)°. Angle
sums for bonds surrounding sulfonamide nitrogen atoms are C6–
SO2NHMe = 338° and C6Ј–SO2NHMe = 343°. Ellipsoids are plot-
ted at the 30% probability level for non-hydrogen atoms and all
hydrogen atoms bonded to carbon atoms have been omitted for
clarity.
Scheme 3. Chromatographic resolution of bis-sulfonamide
through its tetravalerate derivative 22.
3
With access to scalemic samples of 3 secured, the
enantioselectivity in the silylcyanation of a limited number
of aldehydes was examined but found to be uniformly low
(cf. Table 2, entries 1–3, 8, and 9, ee Ͻ 10%).[39] Recovery of
the catalyst 3 from the acidic aqueous phase of the reaction
mixture after workup and subsequent assay for ee (by
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S. M. Sephton, C. Wang, L. N. Zakharov, P. R. Blakemore
FULL PAPER
uct 24 and return 3 to the catalytic cycle. Considering the
low level of enantioselectivity observed, advance of a rigor-
ous stereocontrol model is moot. Nonetheless, given the
openness of the biaryl quadrant occupied by the aldehyde
in the proposed assembly, there is little reason to expect a
significant energetic bias between the presentation of either
a Re (illustrated) or Si face of the carbonyl component
towards the core of a given enantiomer of the TMS-
biquinolyl·HCN adduct 23 [(aR) isomer is shown].
Figure 4. Comparison of the electronic circular dichroism (ECD)
spectra of bis-sulfonamides (–)-3 and (+)-3 with biquinolyls (+)-
(aR)-1 and (+)-(aR)-2 of known configuration.[12b,12c] Collection
parameters (including cell pathlength): 1: 2.4 mm, H2O, 50% ee,
0.01 cm); 2: 1.9 mm, MeOH, 40% ee, 0.01 cm; (–)-3: 0.19 mm,
MeOH, 90% ee, 0.1 cm; (+)-3: 0.19 mm, MeOH, 82% ee, 0.1 cm.
All curves are corrected to 100% ee.
derivatization to 22 followed by HPLC analysis) revealed a
negligible loss in the enantiomeric purity of the sulfon-
amide. It was also established that the cyanohydrin prod-
ucts maintained configurational integrity during the hydro-
lytic workup. Thus, the origin of the low ee was associated
with ineffectual stereoinduction during the enantiodeterm-
ining step of the silylcyanation. Correlation of the chiral
HPLC chromatograms of mandelonitrile (10) obtained in
this manner with literature reports[14d] revealed that sulfon-
amide catalyst (–)-(aR)-3 favored the formation of the (S)-
configured cyanohydrin product.
Scheme 4. Mechanistic proposal for the silylcyanation of aldehydes
as catalyzed by bis-sulfonamide 3.
Conclusions
The study of azaBINOL derivatives equipped with a
metal-ligating substructure at C6 and C6Ј (e.g., 3–5) was
motivated by a desire to develop ambiphilic catalysts based
on frustrated Lewis acid/Lewis base pairs. During the
course of this work, which remains an active area of investi-
gation, bis-sulfonamide 3 was discovered to directly catalyze
the addition of TMSCN to aldehydes, ketones, and imines.
The organocatalysis was dependent on multivalent expres-
Mechanistic Conjecture
From the results of the structure versus catalytic activity sion of basic and hydrogen-bond-donating functional
relationship study, it is evident that bis-sulfonamide 3 acts groups juxtaposed across a chiral biaryl axis. Although in
through a combination of hydrogen bond and Brønsted this case the effect did not give rise to a synthetically useful
acid catalysis effects[40] possibly aided by a cooperative ge- level of enantioselectivity, the findings further strengthen
neral base capability. Apropos to these findings, Fuerst and the view that the catalytic efficiency of functional group
Jacobsen discovered that a small peptide-like thiourea mo- clusters within small molecule activators is determined by a
lecule failed to catalyze the silylcyanation of ketones unless delicate balance of factors and that subtle structural varia-
equipped with a free basic amine within its substructure tions can profoundly affect reactivity. A parallel can be
and also if no means of generating HCN in situ from drawn with the interactions found within the ternary com-
TMSCN were available.[18b] Thus, it is speculated that the plex of the substrate, co-factor, and enzyme in the vicinity
mode of action of 3 involves the initial silylation of a phenol of a proteinogenic active site, albeit, in its role as a simple
group by TMSCN, then transfer of the resulting biquinolyl “chemzyme”,[42] the superstructure of 3 evidently does a
associated HCN to the aldehyde, itself activated by hydro- poor job in orienting the reacting partners for effective
gen-bond donation from either an NH or OH moiety.[41] stereoinduction. Systematic variations in the structure of 3
Breakage of the Si–C bond of TMSCN in the first stage of are reasonably expected to improve its ability to function as
this sequence would be facilitated by the heightened acidity a general platform for enantioselective hydrogen bond and
of bis-sulfonamide 3 resulting from its unique vinylogous Brønsted acid catalysis in a broad array of different reaction
sulfamic acid character.
types.
Ternary complex 23 represents a plausible scenario for
Finally, this work validates the proposition that investi-
cyanide anion delivery that is consistent with the fact that gations of heteroaromatic biaryl molecules can lead to the
most of the analogues of 3, including monoquinoline 17, discovery of new and useful modes of reactivity. The 8,8Ј-
failed to catalyze the same process (Scheme 4). Following biquinolyl scaffold, suitably constrained by 7,7Ј-disubstitu-
cyanide addition, recapture of the phenolic TMS group by tion to confer the attribute of atropisomerism, is an ideal
the incipient alkoxide would lead to the silylcyanated prod- vehicle for such endeavors in many respects, for example, it
6
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Catalyzed Silylcyanation of Aldehydes, Ketones, and Imines
of the integrals for PhCH(CN)OH (δ = 5.53 ppm) and PhCHO (δ
= 10.00 ppm).
can be readily decorated with additional substituents at any
position desired,[12e] the quinoline units have the capacity
to act as general bases or ligating sites and may engage in
nucleophilic catalysis, and the fundamental physical proper-
ties of the entire system can be fine-tuned by substituent
and media effects. Accordingly, further applications of aza-
BINOL-derived molecules in organocatalysis, metal-medi-
ated synthesis, and materials chemistry are anticipated.
Silylcyanation with Ligand/Promoter, Ti(OiPr)4, and MS (4 Å): See
Table 1, entries 8–11. A flame-dried 10 mL round-bottomed flask
was charged with the indicated ligand (50 μmol, 10 mol-%) and
purged with Ar. Anhydrous PhMe (2.0 mL) was then added fol-
lowed by dried molecular sieves (4 Å) (12 beads, ca. 90 mg, dried
as above). Neat Ti(OiPr)4 (15 μL, d = 0.97, 14.6 mg, 50 μmol,
10 mol-%) was added dropwise and the resulting mixture was
stirred at 30 °C (bath temp.) for 1 h. After this time, the preformed
Ti complex was cooled to 0 °C and treated simultaneously with
neat PhCHO (51 μL, d = 1.045, 53.3 mg, 500 μmol) and TMSCN
(200 μL, d = 0.744, 149 mg, 1.50 mmol, 3.0 equiv.). The reaction
mixture was stirred for 1 h at 0 °C and then quenched by the ad-
dition of EtOAc (4 mL) and aq. HCl (4.0 mL, 2.0 m) and then
stirred for 1.25 h at room temp. Subsequent workup and analysis
were then conducted as described above for Table 1, entries 1–7.
Experimental Section
General: All reactions requiring anhydrous conditions were con-
ducted in flame-dried glass apparatus under Ar. THF and PhMe
were obtained from a solvent purification system (SPS) employing
activated Al2O3 drying columns.[43] Chromatographic separations
were performed on silica gel 60 (35–75 μm) and reactions followed
by TLC analysis using silica gel 60 plates (2–25 μm) with fluores-
cent indicator (254 nm) and visualized with UV or phosphomolybd-
ic acid. All commercially available reagents were used as received
unless otherwise noted. Melting points were determined in open
capillary tubes with a melting-point apparatus. IR spectra were re-
corded in Fourier transform mode using KBr disks for solids
whereas oils were supported between NaCl plates (“neat”). 1H and
13C NMR spectra were recorded at the field strength specified and
in the indicated deuteriated solvents in standard 5 mm diameter
tubes. Chemical shifts are quoted in ppm relative to residual solvent
signals: CDCl3: δH (CHCl3) = 7.26 ppm, δC = 77.2 ppm; (CD3)2SO
δH (CD3SOCHD2) = 2.50 ppm, δC = 39.5 ppm. The numbers in
parentheses following carbon atom chemical shifts refer to the
number of attached hydrogen atoms, as revealed by the DEPT spec-
tral editing technique. Low- (MS) and high-resolution (HRMS)
mass spectra were recorded by using either electron impact (EI),
chemical ionization (CI), or electrospray (ES) ionization tech-
niques. Ion mass/charge (m/z) ratios are reported as atomic mass
units. Electronic circular dichroism (ECD) spectra were collected
at 1 nm per step scan with an integration time of 1–2 s over the
range 200–400 nm.
Silylcyanation with Ligand/Promoter and MS (4 Å): See Table 1,
entries 12–15. A flame-dried 10 mL round-bottomed flask was
charged with the indicated ligand (25 μmol, 10 mol-%) and purged
with Ar. Anhydrous PhMe (1.0 mL) was then added followed by
dried molecular sieves (4 Å) (6 beads, ca. 45 mg, dried as above).
The mixture was cooled to 0 °C, treated simultaneously with neat
PhCHO (25 μL, d = 1.045, 26 mg, 250 μmol) and TMSCN (100 μL,
d = 0.744, 74.4 mg, 750 μmol, 3.0 equiv.), and stirred for 1.1 h.
Quenching, workup, and analysis were performed as indicated
above for Table 1, entries 1–7.
Silylcyanation with Only Ligand/Promoter: See Table 1, entries 16–
19. As indicated above without addition of molecular sieves (4 Å).
A detailed protocol for the use of bis-sulfonamide 3 as catalyst
follows in the description of reaction conditions associated with
Table 2.
Silylcyanation of Aldehydes and Ketones Catalyzed by Bis-sulfon-
amide 3: See Table 2, entries 1–12. As a representative procedure
(entry 1), a flame-dried 10 mL round-bottomed flask was charged
with bis-sulfonamide 3 (6.0 mg, 12.5 μmol, 10 mol-%) and purged
with Ar. Anhydrous PhMe (0.5 mL) was then added and the re-
sulting orange suspension stirred for 5 min at room temp. and then
cooled to 0 °C. Neat PhCHO (12.5 μL, d = 1.045, 13 mg, 123 μmol)
and TMSCN (50 μL, d = 0.744, 37 mg, 375 μmol, 3.0 equiv.) were
added simultaneously and the mixture was stirred for 1.25 h at
0 °C. After this time, EtOAc (1 mL) and aq. HCl (1.0 mL, 2.0 m)
were added and stirring was continued for 1.5 h at room temp. The
mixture was then filtered through a short pad of Celite, which was
washed with EtOAc (5 mL) and H2O (5 mL). The combined filtrate
and washings were separated and the organic phase dried (Na2SO4)
and concentrated in vacuo. The residue was purified by column
chromatography (SiO2, eluting with 10–20% EtOAc in hexanes) to
afford mandelonitrile (14.5 mg, 109 μmol, 88%) as a colorless oil.
Silylcyanation with Ligand/Promoter, Me2AlCl, Ph3PO, and MS (4
Å): See Table 1, entries 1–7. Based on the protocol of Nájera and
coworkers,[14d] a flame-dried 10 mL round-bottomed flask was
charged with the indicated ligand (25 μmol, 10 mol-%) and freshly
recrystallized Ph3PO (28 mg, 100 μmol, 40 mol-%) and purged with
Ar. Anhydrous PhMe (1.0 mL) was then added followed by dried
molecular sieves (4 Å) (6 beads, ca. 45 mg, supplied by J. T. Baker
and oven-dried for 24 h at 220 °C before use). A solution of Me2-
AlCl (25 μL, 1.0 m in hexanes, 25 μmol, 10 mol-%) was added drop-
wise and the resulting mixture was stirred at 30 °C (bath temp.) for
1 h. After this time, the preformed Al complex was cooled to
–20 °C and treated simultaneously with neat PhCHO (25 μL, d =
1.045, 26 mg, 250 μmol) and TMSCN (100 μL, d = 0.744, 74.4 mg,
750 μmol, 3.0 equiv.). The reaction mixture was stirred for 4 h at
–20 °C and then quenched by the addition of EtOAc (2 mL) and
aq. HCl (2.0 mL, 2.0 m) and then stirred for 1.25 h at room temp.
The biphasic mixture was filtered through a short pad of Celite,
which was washed with EtOAc (4 mL) and H2O (4 mL). The fil-
trate and combined washings were separated and the organic phase
dried (Na2SO4). The organic phase was concentrated on a rotary
evaporator (with a water bath set at 30 °C) to remove the majority
of the solvent with care taken not to distil out any unreacted
1
The spectral data (IR, H and 13C NMR) for all the cyanohydrins
prepared in this manner were in agreement with those previously
reported.[14d,18d,44]
Silylcyanation of N-Benzylaldimines: See Table 2, Entries 13–15. As
a representative procedure (entry 13), a flame-dried 10 mL round-
bottomed flask was charged with bis-sulfonamide 3 (6.0 mg,
12.5 μmol, 10 mol-%) and purged with Ar. Anhydrous PhMe
(0.5 mL) was added and the resulting orange suspension stirred for
5 min at room temp. and then cooled to 0 °C. PhCHNBn (24.5 mg,
125 μmol) and TMSCN (50 μL, d = 0.744, 37 mg, 375 μmol,
PhCHO. The 1H NMR spectral signature (300 MHz, CDCl3) of 3.0 equiv.) were added simultaneously and the mixture stirred for
the residue was consistent with a mixture of benzaldehyde (9) and
mandelonitrile (10) and conversion was determined by comparison
9 h at room temp. After this time, EtOAc (1 mL) and 2.0 m aq. HCl
(1.0 mL) were added and stirring was continued for 2 h at room
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S. M. Sephton, C. Wang, L. N. Zakharov, P. R. Blakemore
IR (CH Cl ): ν = 3344, 2924, 1614, 1459, 1329, 1151, 965, 909,
FULL PAPER
temp. The pH of the aq. layer was adjusted to 7.0 by addition of
15% aq. NaOH and, after further dilution with EtOAc (5 mL), the
layers were shaken and separated. The organic phase was dried
(Na2SO4) and concentrated in vacuo. The resulting residue was
purified by column chromatography (SiO2, eluting with 5–10%
˜
2
2
731, 706 cm–1. 1H NMR (700 MHz, CDCl3): δ = 8.78 (dd, J = 4.1,
1.7 Hz, 2 H), 8.37 (s, 2 H), 8.25 (dd, J = 8.3, 1.5 Hz, 2 H), 7.34
(dd, J = 8.3, 4.1 Hz, 2 H), 2.86 (s, 12 H) ppm. 13C NMR (175 MHz,
CDCl3, all signals ϫ2): δ = 153.5 (1), 152.0 (0), 150.1 (0), 137.7
EtOAc in hexanes) to afford PhCH(CN)NHBn (20 mg, 90.5 μmol, (1), 131.1 (1), 122.5 (0), 122.3 (0), 120.8 (0), 120.3 (1), 38.1 (2 C,
1
72%) as a colorless oil. The spectral data (IR, H and 13C NMR)
for all the Strecker adducts prepared in this manner agreed with
those previously reported.[26]
3) ppm. MS (CI+): m/z = 503 [M + H]+. HRMS (CI+): calcd. for
C22H23 N4O6S2 503.1059; found 503.1049.
6,6Ј-Bis(dimethylaminosulfonyl)-7,7Ј-dimethoxy-8,8Ј-biquinolyl (15):
A stirred solution of bis-sulfonamide 3 (10 mg, 21.1 μmol) in anhy-
drous DMF (0.50 mL) at room temp. under Ar was treated with
NaH (6.0 mg, 60 wt.-% disp. in oil, 0.150 mmol). After 15 min, the
suspension was treated with neat MeI (9.0 μL, d = 2.28, 20.5 mg,
145 μmol) and the resulting yellow solution was stirred for a further
18 h at room temp. The mixture was then partitioned between H2O
(10 mL) and EtOAc (10 mL) and the pH of the aq. phase adjusted
to 7.0 by addition of 2.0 m aq. HCl. The layers were shaken and
separated and the aq. phase extracted with EtOAc (2ϫ10 mL). The
combined organic phases were then washed with H2O (10 mL) and
brine (5 mL), dried (Na2SO4), and concentrated in vacuo. The
crude residue was purified by column chromatography (SiO2, elut-
ing with EtOAc) to afford the desired methylated compound 15
7,7Ј-Bis(diethylaminocarbonyloxy)-6,6Ј-bis(dimethylaminosulfon-
yl)-8,8Ј-biquinolyl (25). En Route to 14: A steady stream of Cl2
gas (generated by the dropwise addition of concd. aq. HCl to
KMnO4) was bubbled through a biphasic mixture of 6,6Ј-bis-
(benzylthio)-7,7Ј-(diethylaminocarbonyloxy)-8,8Ј-biquinolyl (247 mg,
0.338 mmol, prepared as described in ref.[12a]) in CH2Cl2/AcOH/
H2O (4:2:1 mL, resp.) at 0 °C for 5 min. The reaction mixture
turned a bright-yellow color and excess dissolved Cl2 was dissipated
by sparging with Ar gas for 5 min. The resulting bis-sulfonyl chlor-
ide was then treated with excess 40 wt.-% aq. Me2NH until the pH
of the aqueous phase was 9–10 (caution!), warmed to room temp.,
and stirred for 3 h to allow for complete conversion to the bis-
sulfonamide. The mixture was treated with CH2Cl2 (50 mL) and
H2O (50 mL) and the aqueous phase neutralized by addition of 6 m
aq. HCl. The layers were shaken and separated and the aqueous
phase was extracted with CH2Cl2 (2ϫ100 mL). The combined or-
ganic phases were washed with brine (50 mL), dried (Na2SO4), and
concentrated in vacuo. The crude residue was purified by column
chromatography (SiO2, eluting with 4% MeOH in CH2Cl2) to af-
ford the title compound (25; 156 mg, 0.223 mmol, 66%) as a color-
(8.0 mg, 15.1 μmol, 71%) as a colorless solid. IR (KBr): ν = 2924,
˜
1606, 1478, 1340, 1152, 971, 788, 746 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.78 (dd, J = 4.2, 1.8 Hz, 2 H), 8.66 (s, 2 H), 8.31 (dd,
J = 8.3, 1.8 Hz, 2 H), 7.42 (dd, J = 8.3, 4.2 Hz, 2 H), 3.42 (s, 6 H),
2.87 (s, 12 H) ppm. 13C NMR (100 MHz, CDCl3, all signals ϫ2):
δ = 155.6 (0), 153.0 (1), 150.5 (0), 137.5 (1), 133.6 (1), 131.8 (0),
128.9 (0), 124.5 (0), 121.5 (1), 62.0 (3), 38.0 (3) ppm. MS (CI+):
m/z = 531 [M + H]+. HRMS (CI+): calcd. for C24H27 N4O6S2
531.1372; found 531.1363.
less solid; m.p. 270 °C (dec.). IR (CDCl ): ν = 2965, 1725, 1607,
˜
3
1344, 1162, 1067, 964, 794, 739 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 8.83 (d, J = 2.8 Hz, 2 H), 8.67 (s, 2 H), 8.26 (d, J = 8.0 Hz, 2
H), 7.42 (dd, J = 8.0, 4.0 Hz, 2 H), 3.67 (dq, J = 14.4, 7.1 Hz, 2
H), 3.02–2.90 (m, 4 H), 2.85 (s, 12 H), 2.54 (dq, J = 13.7, 6.9 Hz,
2 H), 1.22 (t, J = 6.9 Hz, 6 H), 0.26 (t, J = 6.7 Hz, 6 H) ppm. 13C
NMR (100 MHz, CDCl3, all signals ϫ2): δ = 152.9 (1), 152.0 (0),
149.8 (0), 146.3 (0), 136.7 (1), 133.7 (1), 131.4 (0), 129.2 (0), 125.2
(0), 121.9 (1), 42.4 (2), 41.9 (2), 36.9 (2 C, 3), 13.8 (3), 12.3 (3) ppm.
MS (ES+): m/z = 723 [M + Na]+, 701 [M + H]+. HRMS (ES+):
calcd. for C32H40 N6NaO8S2 723.2247; found 723.2238.
2,2Ј-Bis(methoxymethyloxy)-3,3Ј-bis(methylaminosulfonyl)-1,1Ј-bi-
naphthyl (26). En Route to 16: See Scheme 2, steps (a) and (b). A
stirred solution of 18 (214 mg, 0.572 mmol)[28] in anhydrous Et2O
(10 mL) at room temp. under Ar was treated with nBuLi (1.12 mL,
1.53 m in hexanes, 1.71 mmol) added dropwise over 2 min. The re-
sulting brown suspension was stirred for 3 h at room temp. and
then cooled to 0 °C and treated over 6 min with a solution of
freshly prepared BnSSBn (491 mg, 2.00 mmol)[45] in anhydrous
Et2O (10 mL). The resulting yellow mixture was warmed to room
temp. and stirred for a further 5 h during which time it became an
homogeneous solution. After this time, satd. aq. NH4Cl (10 mL)
was added and the layers shaken and separated. The aqueous phase
was extracted with CH2Cl2 (3ϫ10 mL) and the combined organic
layers were dried (Na2SO4) and concentrated in vacuo to afford
236 mg of 2,2Ј-bis(methoxymethyloxy)-3,3Ј-bis(benzylthio)-1,1Ј-bi-
naphthyl. A portion of the crude dithioether (176 mg, 75% of total,
Յ0.284 mmol) was dissolved in CH2Cl2/AcOH/H2O (8:4:2 mL,
respectively) and the biphasic mixture cooled to 0 °C. A steady
stream of Cl2 gas (generated by dropwise addition of concd. aq.
6,6Ј-Bis(dimethylaminosulfonyl)-7,7Ј-dihydroxy-8,8Ј-biquinolyl (14): HCl to KMnO4) was bubbled through the solution for 2 min caus-
A suspension of finely powdered NaOH (200 mg, 5.00 mmol) in
DMSO (0.70 mL) was stirred for 30 s at 108 °C (bath temp.) and
then treated with MeOH (0.05 mL) followed by bis-carbamate 25
(4.0 mg, 5.7 μmol). The resulting yellow solution was stirred at
108 °C for 24 h and then allowed to cool to room temp. and H2O
(1 mL) was added. The pH of the aqueous phase was adjusted to
7.0 by careful addition of 1.5 m aq. HCl and the mixture was ex-
tracted with EtOAc (3ϫ5 mL). The combined organic extracts
were washed with H2O (3ϫ5 mL) and brine (5 mL), then dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
ing the mixture to first turn brown and then to bright yellow. Ex-
cess dissolved Cl2 was dissipated by sparging the reaction mixture
with Ar gas for 15 min and the solution of bis-sulfonyl chloride
was then treated with excess aq. MeNH2 (60 mL, 40 wt.-%) and
warmed to room temp. (caution! vigorous reaction). Following a
period of 6 h at room temp., CH2Cl2 (50 mL) was added and the
layers separated. The pH of the aqueous layer was carefully ad-
justed to 7 (by addition of 6 m aq. HCl) and then it was extracted
with CH2Cl2 (2ϫ50 mL). The combined organic phases were dried
(Na2SO4) and concentrated in vacuo. The resulting crude residue
column chromatography (SiO2, 1–3% MeOH in CH2Cl2) to afford was purified by column chromatography (SiO2, eluting with 20–
the desired diphenol 14 (1.0 mg, 2.0 μmol, 35%) as a yellow solid. 100% EtOAc in hexanes) to afford the title bis-sulfonamide 26
8
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Catalyzed Silylcyanation of Aldehydes, Ketones, and Imines
(63 mg, 0.112 mmol, 26% from 18) as a colorless solid; m.p. 182–
3.59 (q, J = 7.1 Hz, 2 H), 3.45 (q, J = 7.1 Hz, 2 H), 1.37 (t, J =
184 °C (TBME). IR (KBr): ν = 3319, 3074, 2976, 2894, 1625, 1587, 7.1 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz,
˜
1500, 1337, 1174, 912, 749 cm–1. 1H NMR (400 MHz, CDCl3): δ = CDCl3): δ = 153.0 (0), 151.5 (0), 151.5 (1), 148.6 (0), 138.5 (1),
8.71 (s, 2 H), 8.06 (d, J = 8.1 Hz, 2 H), 7.58 (tm, J = 7.2 Hz, 2 H),
7.47 (tm, J = 7.5 Hz, 2 H), 7.20 (d, J = 8.5 Hz, 2 H), 5.30 (q, J =
134.7 (1), 127.6 (0), 122.1 (1), 121.3 (1), 91.7 (0), 42.6 (2), 42.3 (2),
14.5 (3), 13.5 (3) ppm. MS (ES+): m/z = 371 [M + H]+. HRMS
5.2 Hz, 2 H), 4.79 (d, J = 5.2 Hz, 2 H), 4.51 (d, J = 5.2 Hz, 2 H), (ES+): calcd. for C14H16127IN2O2 371.0257; found 371.0242.
2.82 (s, 6 H), 2.70 (d, J = 5.3 Hz, 6 H) ppm. 13C NMR (100 MHz,
O-[6-(Benzylthio)quinol-7-yl] N,N-Diethylcarbamate (27). En Route
CDCl3, all signals ϫ2): δ = 149.7 (0), 136.0 (0), 133.3 (1), 131.5
to 17: See Scheme 2, step (a). A stirred solution of iodide 20 (1.20 g,
(0), 129.9 (1), 129.8 (1), 129.5 (0), 127.0 (1), 126.8 (0), 125.9 (1),
3.24 mmol) in NMP (10 mL) at room temp. under Ar was treated
100.8 (2), 57.1 (2), 29.8 (3) ppm. MS (ES+): m/z = 583 [M +
with Et3N (1.80 mL, d = 0.726, 1.31 g, 13.0 mmol) followed by tris-
(dibenzylideneacetone)dipalladium (89 mg, 97.4 μmol) and then
1,1Ј-bis(diphenylphosphanyl)ferrocene (dppf; 215 mg, 388 μmol).
Na]+. HRMS (ES+): calcd. for C26H28 N2O8S2Na 583.1185; found
583.1165.
The resulting mixture was sparged with Ar for 25 min before BnSH
(1.50 mL, d = 1.06, 1.59 g, 12.8 mmol) was added and then the
vessel was heated at 84 °C (bath temperature) for 14 h. After this
time, the mixture was allowed to cool to room temp. and then parti-
tioned between H2O (100 mL) and EtOAc (100 mL). The layers
were separated and the aqueous phase extracted with EtOAc
(2ϫ100 mL). The combined organic phases were washed with H2O
(2ϫ100 mL), dried (Na2SO4), and concentrated in vacuo. The
crude residue was purified by column chromatography (SiO2, elut-
3,3Ј-Bis(methylaminosulfonyl)-1,1Ј-bi-2-naphthol
(16):
See
ing with EtOAc) to afford the title thioether 27 (1.15 g, 3.14 mmol,
Scheme 2. A stirred solution of the MOM diether 26 (34 mg,
0.061 mmol) in MeOH (4 mL) was treated with concd. aq. HCl
(5 drops, 12 m) and the resulting yellow mixture was heated at a
gentle reflux for 85 min. After this time, the mixture was allowed
to cool to room temp. and concentrated in vacuo to give an
amorphous solid which was triturated with Et2O to afford pure diol
16 as a colorless solid (11 mg). The triturate residue was purified by
column chromatography (SiO2, eluting with 40% EtOAc in hex-
anes) to afford an additional 12 mg of diol 16 (total yield 23 mg,
97%) as a yellow solid; m.p. 110–112 °C (THF, yellow prisms). IR
(KBr): ν = 2973, 1718, 1417, 1273, 1159 cm–1. 1H NMR (300 MHz,
˜
CDCl3): δ = 8.85 (dd, J = 4.2, 1.5 Hz, 1 H), 7.98 (d, J = 8.1 Hz, 1
H), 7.87 (s, 1 H), 7.59 (s, 1 H), 7.39–7.26 (m, 6 H), 4.21 (s, 2 H),
3.55 (q, J = 7.0 Hz, 2 H), 3.45 (q, J = 7.1 Hz, 2 H), 1.35 (t, J =
7.0 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 153.5 (0), 150.5 (1), 147.6 (0), 136.59 (0), 134.9 (1),
131.7 (0), 129.2 (2 C, 1), 128.7 (2 C, 1), 127.8 (1), 127.6 (1), 126.6
(0), 121.7 (1), 121.1 (1), 42.6 (2), 42.3 (2), 38.1 (2), 14.5 (3), 13.5
(3) ppm (one quat. carbon signal obscured). MS (CI+): m/z = 367
[M + H]+. HRMS (CI+): calcd. for C21H23N2O2S 367.14803; found
367.14762.
0.049 mmol, 80%); m.p. Ͼ260 °C (dec., MeOH). IR (KBr): ν =
˜
3357, 1620, 1593, 1326, 1299, 1124, 847, 749 cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 9.43 (s, 2 H), 8.54 (s, 2 H), 8.12 (dd,
J = 7.0, 1.9 Hz, 2 H), 7.41–7.35 (m, 4 H), 7.02 (q, J = 4.9 Hz, 2
H), 6.87 (dd, J = 7.4, 1.6 Hz, 2 H), 2.56 (d, J = 4.7 Hz, 6 H) ppm.
13C NMR (100 MHz, [D6]DMSO, all signals ϫ2): δ = 150.1 (0),
136.0 (0), 131.8 (1), 129.6 (1), 128.9 (1), 127.5 (0), 126.9 (0), 124.0
(1), 123.7 (1), 115.7 (0), 28.8 (3) ppm. MS (EI+): m/z = 472 [M]·+.
HRMS (EI+): calcd. for C22H20N2O6S2 472.07629; found
472.07535.
O-[6-(Methylaminosulfonyl)quinol-7-yl] N,N-Diethylcarbamate (28).
En Route to 17: See Scheme 2, step (b). A steady stream of Cl2 gas
(generated by dropwise addition of concd. aq. HCl to KMnO4)
was bubbled through a biphasic mixture of thioether 27 (924 mg,
2.52 mmol) in CH2Cl2/AcOH/H2O (16:8:4 mL, respectively) at 0 °C
for 7 min. The color of the mixture turned to yellow-green and
excess dissolved Cl2 was dissipated by sparging the reaction mixture
with Ar gas for 5 min. The sulfonyl chloride thus produced was
O-(6-Iodoquinol-7-yl) N,N-Diethylcarbamate (20): See Scheme 2. A
stirred solution of iPr2NH (1.15 mL, d = 0.722, 830 mg, 8.22 mmol)
in anhydrous THF (20 mL) at –20 °C under Ar was treated with
nBuLi (5.00 mL, 1.48 m in hexanes, 7.40 mmol). The resulting solu-
tion of LDA was stirred for 20 min, further cooled to –78 °C, and
then O-(8-iodoquinol-7-yl) N,N-diethylcarbamate (19; 2.30 g,
6.21 mmol)[12a] in anhydrous THF (25 mL) was added over 5 min then treated with a large excess of aq. MeNH2 (50 mL, 40 wt.-%),
down the side-wall of the cold flask. The resulting dark-brown mix-
ture was stirred for 10 min at –78 °C and then satd. aq. NH4Cl
(40 mL) was added and the mixture warmed to room temp. The
biphasic system was further diluted with EtOAc (100 mL) and H2O
(60 mL) and the layers shaken and separated. The aqueous phase
was extracted with EtOAc (2ϫ100 mL) and the combined organic
phases dried (Na2SO4) and concentrated in vacuo. The residue was
purified by column chromatography (SiO2, eluting with 80%
EtOAc in hexanes) to afford, in order of elution, recovered starting
material 19 (969 mg, 2.62 mmol, 42%) and the desired halogen-
dance rearrangement product 20 (1.27 g, 3.43 mmol, 55%) as a col-
warmed to room temp., and stirred for 4 h. The mixture of crude
sulfonamide was diluted with H2O (100 mL) and the pH of the
aqueous phase adjusted to 7 by careful addition of aq. HCl (4.0 m).
Further CH2Cl2 (100 mL) was then added and the layers shaken
and separated. The aqueous phase was extracted with CH2Cl2
(3ϫ100 mL) and the combined organic extracts were washed with
brine (2ϫ100 mL), dried (Na2SO4), and concentrated in vacuo.
The crude residue was purified by column chromatography (SiO2,
eluting with 50% EtOAc in hexanes) to afford the title sulfonamide
28 (622 mg, 1.84 mmol, 73%) as a colorless oil. IR (neat): ν = 3303,
˜
2973, 2932, 1729, 1619, 1413, 1160 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.45 (s, 1 H), 8.27
(ddm, J = 8.4, 1.6 Hz, 1 H), 7.90 (s, 1 H), 7.49 (dd, J = 8.3, 4.3 Hz,
1 H), 5.41 (q, J = 5.2 Hz, 1 H), 3.54 (q, J = 7.1 Hz, 2 H), 3.41 (q,
J = 7.1 Hz, 2 H), 2.66 (d, J = 5.3 Hz, 3 H), 1.33 (t, J = 7.1 Hz, 3
orless solid; m.p. 73–75 °C (THF). IR (KBr): ν = 2930, 1615, 1477,
˜
1314, 1282, 1206, 1161, 952, 881, 754 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.91 (dd, J = 4.3, 1.7 Hz, 1 H), 8.34 (s, 1 H), 8.04 (dd,
J = 8.4, 1.7 Hz, 1 H), 7.89 (s, 1 H), 7.37 (dd, J = 8.3, 4.3 Hz, 1 H),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20333
/KAP1
Date: 08-05-12 09:59:34
Pages: 13
S. M. Sephton, C. Wang, L. N. Zakharov, P. R. Blakemore
FULL PAPER
H), 1.23 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
and the aqueous phase was extracted with CH2Cl2 (2ϫ3 mL). The
δ = 154.2 (0), 153.6 (1), 150.2 (0), 147.8 (0), 137.1 (1), 132.1 (1), combined organic phases were dried (Na2SO4) and concentrated in
130.5 (0), 125.2 (0), 124.1 (1), 122.2 (1), 42.8 (2), 42.6 (2), 30.1 (3),
14.1 (3), 13.4 (3) ppm. MS (CI+): m/z = 338 [M + H]+, 307, 265.
HRMS (CI+): calcd. for C15H20N3O4S 338.11745; found
338.11769.
vacuo. The residue was purified by column chromatography (SiO2,
eluting with 20–100% EtOAc in hexanes) to afford the title com-
pound as a colorless solid (33 mg, 40.7 μmol, 92%); m.p. 170–
171 °C (EtOAc). IR (KBr): ν = 2962, 1778, 1707, 1361, 1161,
˜
1086 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.81 (dd, J = 4.1,
1.6 Hz, 2 H), 8.76 (s, 2 H), 8.34 (dd, J = 8.3, 1.5 Hz, 2 H), 7.48
(dd, J = 8.3, 4.2 Hz, 2 H), 3.36 (s, 6 H), 2.70–2.55 (m, 4 H), 2.17
(ddd, J = 15.2, 8.2, 6.5 Hz, 2 H), 1.99 (ddd, J = 15.4, 8.1, 7.0 Hz,
2 H), 1.60–1.52 (m, 4 H), 1.36–1.24 (m, 4 H), 1.07–1.00 (m, 4 H),
0.92–0.77 (m, 4 H), 0.86 (t, J = 7.3 Hz, 6 H), 0.64 (t, J = 7.2 Hz,
6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.3 (0), 170.1 (0),
153.8 (1), 149.6 (0), 145.4 (0), 137.3 (1), 134.1 (1), 131.4 (0), 129.1
(0), 125.4 (0), 122.6 (1), 36.5 (2), 33.6 (2), 33.4 (3), 26.7 (2), 26.2
(2), 22.3 (2), 21.8 (2), 14.0 (2), 13.7 (2) ppm. MS (ES+): m/z = 811
[M + H]+. HRMS (ES+): calcd. for C40H51N4O10S2 811.3047;
found 811.3061.
7-Hydroxy-6-(methylaminosulfonyl)quinoline (17): See Scheme 2. A
stirred solution of carbamate 28 (438 mg, 1.30 mmol) in methanolic
KOH (10 wt.-%, 20 mL) was heated at a gentle reflux for 16 h. The
mixture was then allowed to cool and concentrated in vacuo. The
resulting yellow residue was dissolved in H2O (20 mL) and the pH
adjusted to 7 by careful addition of aq. HCl (4.0 m). The neutral
aqueous phase was then extracted with EtOAc (5ϫ40 mL) and
the combined organic extracts dried (Na2SO4) and concentrated in
vacuo to afford the pure hydroxysulfonamide 17 (243 mg,
1.02 mmol, 79%) as a yellow solid; m.p. 251–253 °C (dec., MeOH,
HPLC Resolution of (؎)-22: The racemate of tetrapentanoyl ad-
duct 22 was resolved by using an Agilent 1100 series HPLC system
interfaced with a Daicel Industries Chiralcel® OD semipreparative
column (250 mm ϫ10 mm) with a chiral stationary phase of cellu-
yellow prisms). IR (KBr): ν = 3311 (sharp), 1621, 1456, 1310, 1151,
˜
1071 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 11.25 (s, 1 H), lose tris(3,5-dimethylphenylcarbamate) on 10 μm SiO2. Multiple
8.86 (dd, J = 4.2, 1.7 Hz, 1 H), 8.45 (dd, J = 8.3, 1.4 Hz, 1 H), 8.42
(s, 1 H), 7.44 (s, 1 H), 7.39 (dd, J = 8.2, 4.2 Hz, 1 H), 7.09 (s, 1 H),
2.45 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 154.7
(0), 153.0 (1), 150.6 (0), 137.2 (1), 131.4 (1), 127.9 (0), 121.1 (0),
chromatographic runs were performed; for each run, 60 μL of a
92.5 mgmL–1 solution of the racemate in MeCN/EtOH (1:1) was
injected onto the above column (5.6 mg per run). Isocratic elution
using a solvent blend of 10% iPrOH in hexanes and a flow rate of
119.7 (1), 112.0 (1), 28.8 (3) ppm. MS (CI+): m/z = 239 [M + H]+. 5.0 mLmin–1 was performed with UV detection at 210 nm. The
HRMS (CI+): calcd. for C10H11N2 O3S 239.04905; found
239.04808.
faster eluting enantiomer, (–)-(aR)-22, was collected from 22–
46 min and the slower eluting isomer, (+)-(aS)-22, was collected
from 47–85 min. Baseline separation was typically achieved by this
protocol and both enantiomorphic atropisomers were routinely ob-
tained with Ͼ96% ee. An enantiopure sample of (–)-(aR)-22 exhib-
ited [α]2D3 = –24.3 (c = 1.75, CHCl3). Enantiomeric purity for
batches of scalemic 22 obtained by the above method was deter-
mined by analytical HPLC analysis using a smaller OD column
(250 mmϫ4.6 mm I.D.), eluting with 10% iPrOH in hexanes at
1.5 mLmin–1 and monitored by UV at 210 nm. Resolved peaks ap-
peared at the following retention times: tret. [(–)-(aR)-22] =
22.9 min, tret. [(+)-(aS)-22] = 42.8 min.
X-ray Crystallographic Analysis of (؎)-3·0.5EtOH: Crystals of bis-
sulfonamide (Ϯ)-3 suitable for X-ray diffraction analysis were ob-
tained by recrystallization from EtOH. Diffraction intensities were
collected at 100 K with a Bruker Apex diffractometer by using Mo-
Kα radiation (λ = 0.710 73 Å). Space groups were determined based
on intensity statistics. Absorption corrections were made by using
SADABS.[46] Structures were solved by direct methods using stan-
dard Fourier techniques and refined on F2 using full-matrix least-
squares procedures. Non-hydrogen atoms were refined with aniso-
tropic thermal parameters except for the carbon and oxygen atoms
in the disordered solvent EtOH molecule, which were refined with
isotropic thermal parameters. Hydrogen atoms were found on the
Fourier map and refined with isotropic thermal parameters except
those in the disordered solvent EtOH molecule, which were refined
in calculated positions in a rigid group model. The solvent EtOH
molecule is disordered over two positions (in a ratio of 3:2) corre-
sponding to two possible hydrogen bonds between the main and
solvent molecules. The hydrogen atom in the OH group of the dis-
ordered solvent molecule (EtOH) was not found and was not taken
into consideration. All calculations were performed by using the
Bruker SHELXTL software package.[47]
(–)-(aR)-6,6Ј-Bis(methylaminosulfonyl)-7,7Ј-dihydroxy-8,8Ј-biquin-
olyl (3): See Scheme 3. Tetravalerate (–)-(aR)-22 (35 mg, 43.2 μmol,
Ն99% ee) was treated with methanolic KOH (8.0 mL, 10 wt.-%)
and stirred at room temp. for 2 h. After this time, the resulting
bright-yellow solution was concentrated in vacuo. The residue was
dissolved in aq. HCl (3.0 mL, 6 m) and the valeric acid byproduct
was removed by washing with EtOAc (3ϫ5 mL). The pH of the
aqueous phase, which at this stage contained the water-soluble cat-
ionic form of the protonated biquinolyl (3·2H+), was then adjusted
first to 13 by the addition of aq. NaOH (15 wt.-%) and then
brought back carefully to 7 by subsequent addition of aq. HCl
(6 m). The now pH-neutral aqueous phase was extracted with
EtOAc (8ϫ8 mL) and the combined organic extracts concentrated
in vacuo. The residue was triturated with MeOH (1–2 mL) to afford
the desired catalytically active bis-sulfonamide (–)-(aR)-3 (17 mg,
35.8 μmol, 83%) as a yellow solid. [α]2D3 = –163 (c = 0.10, MeOH).
Dextrorotatory material (+)-(aS)-3 was similarly obtained from
scalemic samples of (+)-(aS)-22 and gave [α]2D3 = +170 (c = 0.36,
MeOH). Other characterization data for bis-sulfonamide 3 were
identical to those previously reported for the racemate.[12a]
CCDC-871198 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Tetravalerate 22: See Scheme 3. A solution of bis-sulfonamide (Ϯ)-
3 (21 mg, 44.3 μmol)[12a] in aq. NaOH (0.90 mL, 1.5 m) at room
temp. was treated with nBu4NBr (6 mg, 18.6 μmol) in CH2Cl2
(0.90 mL) and then pentanoyl chloride (53 μL, d = 1.02, 54.1 mg,
451 μmol) was added dropwise. The biphasic reaction mixture was
vigorously stirred for 1.1 h at room temp. and then partitioned be-
tween H2O (3 mL) and CH2Cl2 (3 mL). The layers were separated
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all compounds.
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20333
/KAP1
Date: 08-05-12 09:59:34
Pages: 13
Catalyzed Silylcyanation of Aldehydes, Ketones, and Imines
Organic Synthesis, Wiley, Chichester, 2009; DOI: 10.1002/
047084289X.rn00939.
Acknowledgments
[14]
a) Y. Hamashima, D. Sawada, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 1999, 121, 2641–2642; b) Y. Hamashima, D. Sa-
wada, H. Nogami, M. Kanai, M. Shibasaki, Tetrahedron 2001,
57, 805–814; c) J. Casas, C. Nájera, J. M. Sansano, J. M. Saá,
Org. Lett. 2002, 4, 2589–2592; d) J. Casas, C. Nájera, J. M.
Sansano, J. M. Saá, Tetrahedron 2004, 60, 10487–10496.
R. J. H. Gregory, Chem. Rev. 1999, 99, 3649–3682.
Prof. Karl Scheidt (Northwestern University) is thanked for helpful
discussions and Drs. Walter A. Baase and Brandon Green (Univer-
sity of Oregon) are acknowledged for technical assistance in ob-
taining ECD spectra from scalemic samples of bis-sulfonamide 3.
Financial support by the National Science Foundation (grant num-
bers CHE-0722319; CHE-0906409, partial support) is gratefully ac-
knowledged. The Murdock Charitable Trust (2005265) is thanked
for support of the OSU NMR spectroscopy facility.
[15]
[16]
For reviews, see: a) J.-M. Brunel, I. P. Holmes, Angew. Chem.
2004, 116, 2810; Angew. Chem. Int. Ed. 2004, 43, 2752–2778;
b) F.-X. Chen, X. Feng, Curr. Org. Synth. 2006, 3, 77–97; c) A.
Baeza, J. M. Sansano, J. M. Saá, C. Nájera, Pure Appl. Chem.
2007, 79, 213–221; d) M. North, Synlett 1993, 807–820.
For selected recent work, see: a) D. H. Ryu, E. J. Corey, J. Am.
Chem. Soc. 2005, 127, 5384–5387; b) S. Lundgren, E.
Wingstrand, C. Moberg, Adv. Synth. Catal. 2007, 349, 364–
372; c) N. H. Khan, S. Agrawal, R. I. Kureshy, S. H. R. Abdi,
K. J. Prathap, R. V. Jasra, Eur. J. Org. Chem. 2008, 4511–4515;
d) J. Takaki, H. Egami, K. Matsumoto, B. Saito, T. Katsuki,
Chem. Lett. 2008, 37, 502–503; e) Y. N. Belokon, W. Clegg,
R. W. Harrington, V. I. Maleev, M. North, M. Omedes Pujol,
D. L. Usanov, C. Young, Chem. Eur. J. 2009, 15, 2148–2165.
a) S.-K. Tian, L. Deng, J. Am. Chem. Soc. 2001, 123, 6195–
6196; b) D. E. Fuerst, E. N. Jacobsen, J. Am. Chem. Soc. 2005,
127, 8964–8965; c) X. Liu, B. Qin, X. Zhou, B. He, X. Feng,
J. Am. Chem. Soc. 2005, 127, 12224–12225; d) Y. Suzuki, M. D.
Abu-Baker, K. Muramatsu, M. Sato, Tetrahedron 2006, 62,
4227–4231; e) T. Kano, K. Sasaki, T. Konishi, H. Mii, K. Ma-
ruoka, Tetrahedron Lett. 2006, 47, 4615–4618; f) R. Chinchilla,
C. Nájera, F. J. Ortega, Tetrahedron: Asymmetry 2008, 19, 265–
268.
[1] G. Chelucci, R. P. Thummel, Chem. Rev. 2002, 102, 3129–3170.
[2] For work highlighting the diversity in heterocyclic biaryls, see:
a) S. K. Dey, D. A. Lightner, J. Org. Chem. 2007, 72, 9395–
9397; b) M. S. Mudadu, R. P. Thummel, J. Org. Chem. 2006,
71, 7611–7617; c) D. Garciá-Cuadrado, A. M. Cuadro, J. Alva-
rez-Builla, U. Sancho, O. Castaño, J. J. Vaquero, Org. Lett.
2006, 8, 5955–5958.
[3] For selected recent examples, see: a) T. Seki, S. Tanaka, M.
Kitamura, Org. Lett. 2012, 14, 608–611; b) A. Bouet, B. Heller,
C. Papamicaël, G. Dupas, S. Oudeyer, F. Marsais, V. Levacher,
Org. Biomol. Chem. 2007, 5, 1397–1404; c) M. P. A. Lyle, N. D.
Draper, P. D. Wilson, Org. Biomol. Chem. 2006, 4, 877–885; d)
P. Aschwanden, C. R. J. Stephenson, E. M. Carreira, Org. Lett.
2006, 8, 2437–2440.
[4] For reviews of 1,1Ј-bi-2-naphthol (BINOL) chemistry and a
general discourse on 1,1Ј-binaphthyls, see: a) J. M. Brunel,
Chem. Rev. 2005, 105, 857–897; b) Y. Chen, S. Yekta, A. K.
Yudin, Chem. Rev. 2003, 103, 3155–3211; c) L. Pu, Chem. Rev.
1998, 98, 2405–2494.
[5] For reviews of 2,2Ј-bis(diphenylphosphanyl)-1,1Ј-binaphthyl
(BINAP), see: a) M. Berthod, G. Mignani, G. Woodward, M.
Lemaire, Chem. Rev. 2005, 105, 1801–1836; b) R. Noyori, H.
Takaya, Acc. Chem. Res. 1990, 23, 345–350.
[6] For selected recent highlights, see: a) Z. Zhang, P. Jain, J. C.
Antilla, Angew. Chem. Int. Ed. 2011, 50, 10961–10964; b) S.
Shirakawa, K. Liu, K. Maruoka, J. Am. Chem. Soc. 2012, 134,
916–919; c) I. Coric, S. Vellalath, B. List, J. Am. Chem. Soc.
2010, 132, 8536–8537; d) G. Hou, W. Li, M. Ma, X. Zhang,
X. Zhang, J. Am. Chem. Soc. 2010, 132, 12844–12846; e) M.
Turlington, Y. Du, S. G. Ostrum, V. Santosh, K. Wren, T. Lin,
M. Sabat, L. Pu, J. Am. Chem. Soc. 2011, 133, 11780–11794;
f) S. Yu, L. Pu, J. Am. Chem. Soc. 2010, 132, 17698–17700.
[7] N. C. Fletcher, J. Chem. Soc., Perkin Trans. 1 2002, 1831–1842.
[8] S. E. Denmark, Y. Fan, M. D. Eastgate, J. Org. Chem. 2005,
70, 5235–5248.
[9] M. Nakajima, M. Saito, M. Shiro, S.-i. Hashimoto, J. Am.
Chem. Soc. 1998, 120, 6419–6420.
[10] C. W. Lim, O. Tissot, A. Mattison, M. W. Hooper, J. M.
Brown, A. R. Cowley, D. I. Hulmes, A. J. Blacker, Org. Process
Res. Dev. 2003, 7, 379–384.
[17]
[18]
[19]
[20]
For reviews, see: a) P. Li, H. Yamamoto, Top. Organomet.
Chem. 2011, 37, 161–183; b) M. Kanai, N. Kato, E. Ichikawa,
M. Shibasaki, Synlett 2005, 1491–1508; c) J.-A. Ma, D. Cah-
ard, Angew. Chem. 2004, 116, 4666; Angew. Chem. Int. Ed.
2004, 43, 4566–4583; d) G. J. Rowlands, Tetrahedron 2001, 57,
1865–1882.
For examples based on AlIII or TiIV, see ref.[14] and: a) Y. Ham-
ashima, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2000, 122,
7412–7413; b) J.-M. Brunel, O. Legrand, G. Buono, Tetrahe-
dron: Asymmetry 1999, 10, 1979–1984; c) G. J. Rowlands, Syn-
lett 2003, 236–240; d) B. Zeng, X. Zhou, X. Liu, X. Feng, Tet-
rahedron 2007, 63, 5129–5136.
[21]
[22]
H. Gröger, Chem. Eur. J. 2001, 40, 5246–5251.
For insightful commentary on the role that Lewis base associa-
tion can have on enhancing the Lewis acidity of metal centers
by valence shell expansion, see: S. E. Denmark, G. L. Beutner,
Angew. Chem. 2008, 120, 1584; Angew. Chem. Int. Ed. 2008,
47, 1560–1638.
[14d]
[23]
[24]
See ref.
For discussion on the beneficial effects that trace
additives, including H2O and phosphane oxides, can have on
catalysis, see: a) S. Ribe, P. Wipf, Chem. Commun. 2001, 299–
307; b) M. Vogl, H. Gröger, M. Shibasaki, Angew. Chem. 1999,
111, 1672; Angew. Chem. Int. Ed. 1999, 38, 1570–1577.
A significant variation in yield was found when using molecu-
lar sieves (4 Å) obtained from different manufacturers and also
when zeolites were dried according to slightly different proto-
cols. The loading of molecular sieves (4 Å) also had a dramatic
effect on conversion efficiency.
[11] A. C. Spivey, S. Arseniyadis, T. Fekner, A. Maddaford, D.
Leese, Tetrahedron 2006, 62, 295–301.
[12] a) P. R. Blakemore, C. Kilner, S. D. Milicevic, J. Org. Chem.
2005, 70, 373–376; b) P. R. Blakemore, C. Kilner, S. D. Mil-
icevic, J. Org. Chem. 2006, 71, 8212–8218; c) P. R. Blakemore,
S. D. Milicevic, L. N. Zakharov, J. Org. Chem. 2007, 72, 9368–
9371; d) P. R. Blakemore, S. D. Milicevic, H. Perera, A. Shva-
rev, L. N. Zakharov, Synthesis 2008, 2271–2277; e) C. Wang,
D. M. Flanigan, L. N. Zakharov, P. R. Blakemore, Org. Lett.
2011, 13, 4024–4027; for the synthesis of tetrahydroquinoline
analogues of azaBINOL, see: f) J. Xiao, T.-P. Loh, Org. Lett.
2009, 11, 2876–2879.
[13] The parent member of this group, 7,7Ј-dihydroxy-8,8Ј-biquin-
olyl (azaBINOL, 1) is a diaza-analogue of 1,1Ј-bi-2-naphthol
(BINOL) in which two peri CH units have been formally re-
placed by nitrogen atoms, see: P. R. Blakemore, S. D. Milicevic,
7,7Ј-Dihydroxy-8,8Ј-biquinolyl, in: Encyclopedia of Reagents for
The use of TiIV–sulfonamide complexes for the silylcyanation
of aldehydes has previously been examined, see: J.-S. You, H.-
M. Gau, M. C. K. Choi, Chem. Commun. 2000, 1963–1964.
For selected examples of the silylcyanation of imines, see: a)
N. H. Khan, S. Saravanan, R. I. Kureshy, S. H. R. Abdi, H. C.
Bajaj, Tetrahedron: Asymmetry 2010, 21, 2076–2080; b) A. M.
Seayad, B. Ramalingam, K. Yoshinaga, T. Nagata, C. L. L.
Chai, Org. Lett. 2010, 12, 264–267; c) J. Jarusiewicz, Y. Choe,
K. S. Yoo, C. P. Park, K. W. Jung, J. Org. Chem. 2009, 74,
2873–2876; d) I. V. P. Raj, G. Suryavanshi, A. Sudalai, Tetrahe-
[25]
[26]
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S. M. Sephton, C. Wang, L. N. Zakharov, P. R. Blakemore
FULL PAPER
dron Lett. 2007, 48, 7211–7214; e) M. Chavarot, J. J. Byrne,
P. Y. Chavant, Y. Vallée, Tetrahedron: Asymmetry 2001, 12,
1147–1150.
Cyanide anion addition to C2 and/or C2Ј of the biquinolyl
nucleus is therefore discounted. For Reissert-type reactions of
quinolines in the presence of a bifunctional catalyst, TMSCN,
and acyl halides, see: M. Takamura, K. Funabashi, M. Kanai,
M. Shibasaki, J. Am. Chem. Soc. 2000, 122, 6327–6328.
a) S. Matsunagam, J. Das, J. Roels, E. M. Vogl, N. Yamamoto,
T. Lida, K. Yamaguchi, M. Shibasaki, J. Am. Chem. Soc. 2000,
122, 2252–2260; b) M. Shi, C.-J. Wang, Tetrahedron: Asym-
metry 2002, 13, 2161–2166.
1997; c) N. Berova, K. Nakanishi, in: Circular Dichroism: Prin-
ciples and Applications (Eds.: N. Berova, K. Nakanishi, R. W.
Woody), Wiley-VCH, New York, 2000.
[39] Higher enantioselectivities in the silylcyanation of benzalde-
hyde (16% ee at 0 °C; 20% ee at –20 °C) were observed by
using an aged sample of TMSCN, but these results could not
be reproduced with fresh batches of purer TMSCN. Attempts
to duplicate the aging effect, which included doping pure
TMSCN with traces of acids, were unsuccessful.
[40] For reviews of hydrogen bond and Brønsted acid catalysis, see:
a) C. H. Cheon, H. Yamamoto, Chem. Commun. 2011, 47,
3043–3056; b) P. H.-Y. Cheong, C. Y. Legault, J. M. Um, N.
Celebi-Olcum, K. N. Houk, Chem. Rev. 2011, 111, 5042–5137;
c) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–
5743; d) T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal.
2006, 348, 999–1010; for selected recent work, see: e) J. Saadi,
M. Akakura, H. Yamamoto, J. Am. Chem. Soc. 2011, 133,
14248–14251; f) G. K. Ingle, M. G. Mormino, L. Wojitas, J. C.
Antilla, Org. Lett. 2011, 13, 4822–4825; g) Y. Qian, G. Ma, A.
Lv, H.-L. Zhu, J. Zhao, V. H. Rawal, Chem. Commun. 2010,
46, 3004–3006; h) A. A. Rodriguez, H. Yoo, J. W. Ziller, K. J.
Shea, Tetrahedron Lett. 2009, 50, 6830–6833.
[27]
[28]
[29]
[30]
P. J. Cox, W. Wang, V. Snieckus, Tetrahedron Lett. 1992, 33,
2253–2256.
Bis-sulfonamide 3 contains twice as many functional groups as
its “monomeric” congener 17 and it could therefore derive a
reactivity advantage in any equal loading comparison experi-
ment due to a higher effective molarity of the activating moie-
ties. Ruling out this possibility, it was found that the silylcyan-
ation of PhCHO by using just 5 mol-% of 3 under otherwise
identical reaction conditions still resulted in Ն95% conversion.
As noted above, 10 mol-% of 17 gave only 2% conversion.
[41] Jacobsen’s detailed mechanistic studies of tertiary amino-thio-
urea catalysis and Houk’s more recent theoretical treatments
of the Inoue cyclic peptide [cyclo-(l-His-l-Phe)] catalyzed ad-
dition of HCN to aldehydes lend credence to this kind of mech-
anistic hypothesis, see: a) S. J. Zuend, E. N. Jacobsen, J. Am.
Chem. Soc. 2007, 129, 15872–15883; b) F. Schnoenebeck, K. N.
Houk, J. Org. Chem. 2009, 74, 1464–1472; c) J.-I. Oku, S. In-
oue, J. Chem. Soc., Chem. Commun. 1981, 229–230.
[42] For reviews concerning the concept of artificial molecules as
enzyme mimics (“chemzymes”), see: a) J. Bjerre, C. Rousseau,
L. Marinescu, M. Bols, Appl. Microbiol. Biotechnol. 2008, 81,
1–11; b) R. Breslow (Ed.), Artificial Enzymes, 1st ed., Wiley-
VCH, New York, 2005; for selected recent work with leading
references, see: c) Y. Li, S. J. Miller, J. Org. Chem. 2011, 76,
9785–9791; d) G. Hu, A. K. Gupta, R. H. Huang, M. Mukh-
erjee, W. D. Wulff, J. Am. Chem. Soc. 2010, 132, 14669–13675;
e) J. Xiao, F.-X. Xu, Y.-P. Lu, T.-P. Loh, Org. Lett. 2010, 12,
1220–1223; f) R. Skouta, S. Wei, R. Breslow, J. Am. Chem. Soc.
2009, 131, 15604–15605.
[31]
[32]
a) L. P. Hammett, Chem. Rev. 1935, 17, 125–136; b) L. P. Ham-
mett, J. Am. Chem. Soc. 1937, 59, 96–103; c) A. Williams, Free
Energy Relationships in Organic and Bio-organic Chemistry, The
Royal Society of Chemistry, Cambridge, 2003.
C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165–195.
[33] North et al. found ρ = +2.37 (R2 = 0.943) in their Hammett
analysis of the silylcyanation of benzaldehydes as catalyzed by
a strongly Lewis acidic TiIV–salen complex. Use of a less Lewis
acidic VV-based salen complex that was potentially capable of
synergistic Lewis base activation gave ρ = +1.57 (R2 = 0.851),
see: M. North, M. Omedes-Pujol, C. Williamson, Chem. Eur.
J. 2010, 16, 11367–11375.
[34] The barrier to pyramidal inversion at sulfonamide nitrogen
atoms is calculated to be less than 1 kcalmol–1, see: P. V. Bhara-
tam, Amita, A. Gupta, D. Kaur, Tetrahedron 2002, 58, 1759–
1764.
[35] Immediate re-conversion of a scalemic sample of 3 back into
22 (for the purpose of indirect ee determination by HPLC
analysis) revealed that transformation cycles 22Ǟ3Ǟ22 occur
without measurable loss in ee.
[43] A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen,
Organometallics 1996, 15, 1518–1520.
[36] Defined for polarimeter readings in MeOH: (–)-(aR)-3 [α]2D3
=
[44] a) Y. Belokon, F. Massimilano, N. Ikonnikov, M. Moscalenko,
M. North, C. Orizu, V. Tararov, M. Tasinazzo, J. Chem. Soc.
Perkin Trans. 1 1997, 1293–1295; b) S. Nanda, Y. Kato, Y. As-
ano, Tetrahedron 2005, 61, 10908–10916; c) B. E. Kane,
M. K. O. Grant, E. E. El-Fakahany, D. M. Ferguson, Bioorg.
Med. Chem. 2008, 16, 1376–1392; d) A. Aramini, M. R. Sab-
lone, G. Bianchini, A. Amore, M. Fani, P. Perrone, A. Dolce,
M. Allegretti, Tetrahedron 2009, 65, 2015–2021.
[45] R. Leino, J. E. Lönnqvist, Tetrahedron Lett. 2004, 45, 8489–
8491.
[46] G. M. Sheldrick, SADABS, University of Göttingen, Germany,
1995.
–163 (c = 0.10, MeOH); (+)-(aS)-3 [α]2D3 = +170 (c = 0.36,
MeOH).
[37] As a caveat, it is noted that the X-ray crystallographic analysis
of (Ϯ)-3 (Figure 3) revealed that this biaryl does not share the
same solid-state transoid conformational preference common
to both (Ϯ)-1 and (Ϯ)-2 [from the XRD data the interannular
dihedral angles are 104.5° for 1 (ref.[12a]) and 123.5° for 2
(ref.[12c])]. If the solution conformational properties of 3 differ
significantly to those of 1 and 2 (unlikely in MeOH), then a
simple comparison of the exciton chirality phase is not suf-
ficient to assign the absolute configuration with confidence, see
ref.[38]
[47] Bruker, SHELXTL, version 6.10, Bruker AXS Inc., Madison,
Wisconsin, USA, 2000.
[38] a) S. F. Mason, R. H. Seal, D. R. Roberts, Tetrahedron 1974,
30, 1671–1682; b) A. Rodger, B. Nordén, Circular Dichroism
and Linear Dichroism, Oxford University Press, New York,
Received: March 16, 2012
Published Online: ᭿
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Catalyzed Silylcyanation of Aldehydes, Ketones, and Imines
Organocatalysis
6,6Ј-Bis(methylaminosulfonyl)-7,7Ј-dihy-
droxy-8,8Ј-biquinolyl catalyzes the ad-
dition of trimethylsilyl cyanide to alde-
hydes, ketones, and N-benzylaldimines to
give the expected cyanohydrin and Strecker
adducts following desilylation. Related
compounds lacking any one of the defining
structural features of the biquinolyl failed
to promote the same reaction in the ab-
sence of additives.
S. M. Sephton, C. Wang, L. N. Zakharov,
P. R. Blakemore* ............................. 1–13
Silylcyanation of Aldehydes, Ketones, and
Imines Catalyzed by a 6,6Ј-Bis-sulfonamide
Derivative of 7,7Ј-Dihydroxy-8,8Ј-biquin-
olyl (azaBINOL)
Keywords: Organocatalysis / Biaryls / Ni-
trogen heterocycles
Strecker reaction
/
Cyanohydrins
/
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