Three-component reaction discovery enabled by mass spectrometry of self-assembled monolayers

Article abstract of DOI:10.1038/nchem.1212

Multicomponent reactions are employed extensively in many areas of organic chemistry. Despite significant progress, the discovery of such enabling transformations remains challenging. Here, we present the development of a parallel, label-free reaction-discovery platform that can be used in the identification of new multicomponent transformations. Our approach is based on parallel mass spectrometric screening of interfacial chemical reactions on arrays of self-assembled monolayers. This strategy enabled the identification of a simple organic phosphine that can catalyse a previously unknown condensation of siloxyalkynes, aldehydes and amines to produce 3-hydroxyamides with high efficiency and diastereoselectivity. The reaction was further optimized using solution-phase methods.

Full text of DOI:10.1038/nchem.1212

ARTICLES
PUBLISHED ONLINE: 4 DECEMBER 2011 | DOI: 10.1038/NCHEM.1212
Three-component reaction discovery enabled by
mass spectrometry of self-assembled monolayers
Timothy J. Montavon†, Jing Li†, Jaime R. Cabrera-Pardo, Milan Mrksich and Sergey A. Kozmin
*
*
Multicomponent reactions are employed extensively in many areas of organic chemistry. Despite significant progress, the
discovery of such enabling transformations remains challenging. Here, we present the development of a parallel, label-free
reaction-discovery platform that can be used in the identification of new multicomponent transformations. Our approach is
based on parallel mass spectrometric screening of interfacial chemical reactions on arrays of self-assembled monolayers.
This strategy enabled the identification of a simple organic phosphine that can catalyse a previously unknown
condensation of siloxyalkynes, aldehydes and amines to produce 3-hydroxyamides with high efficiency and
diastereoselectivity. The reaction was further optimized using solution-phase methods.
he integration of innovative reaction-screening formats with monolayers are compatible with many organic and organometallic
analytical techniques to identify products rapidly can enable reactions31,32 and showed that the SAMDI method can rapidly
T
the discovery of an arsenal of new catalytic, synthetically detect all interfacial reactions that result in a mass change. This
useful processes. Despite significant progress in developing parallel approach provides a unique opportunity for the label-free discovery
reaction-screening platforms1–19 the rapid discovery of transform- of new catalytic processes.
ations that produce products with unanticipated structures
remains highly challenging. To enable the identification of such Results and discussion
reactions, analysis of the outcome of each individual experiment SAMDI reaction screen. Multicomponent condensations enable a
must be quick, precise and structurally unbiased. Existing rapid increase in structural complexity and molecular diversity by
approaches that tackle this problem require either the conjugation creating new products from more than two reactants in a single
of reactants to information-coding deoxyribonucleic acid operation. Such reactions are employed extensively to generate
strands20–22 or the use of liquid chromatography–mass spectrometry chemical libraries33, assemble bioactive natural products34 and
(LCMS) or gas chromatography–mass spectrometry (GCMS) invent organocatalytic transformations35. Despite significant
methods23–25. Herein we describe the development of an efficient progress, the discovery of new multicomponent transformations
reaction-discovery strategy that entails the screening of interfacial remains challenging. As part of our ongoing investigation of the
chemical transformations on self-assembled monolayers (SAMs) basic reactivity of siloxyalkynes, we decided to take advantage of
of alkanethiolates on gold using matrix-assisted laser desorption/ the unique chemical profile of this class of organosilanes to
ionization and time-of flight mass spectrometry (MALDI-TOF-MS). develop new multicomponent reactions. Previously, siloxyalkynes
This general approach, which previously we termed SAMDI26 were found to participate in a series of catalytic carbon–carbon
enabled the initial identification of a new three-component reaction and carbon–heteroatom bond-forming reactions36–41. Depending
of amines, aldehydes and siloxyalkynes, which was optimized on the mode of activation, such electron-rich alkynes undergo
subsequently using solution-phase methods. This effort validated reactions with either nucleophiles36–39 or electrophiles40,41. Thus,
our structurally unbiased discovery strategy and uncovered a we anticipated that a single catalyst could promote a three-
unique mode of catalytic activation of electron-rich alkynes using component condensation of a siloxyalkyne with two other
simple organic phosphines.
reaction partners of opposite electronic properties, for example a
Our general screening approach starts with a glass slide that is carbonyl-based electrophile and an amine-containing nucleophile.
patterned with an array of gold islands, each of which is modified Although various reaction products are expected from such a
with a monolayer that presents the substrate of interest. Unique three-component combination, we wondered whether the SAMDI
combinations of reagents are applied to each of the islands to method could identify efficiently the formation of new products
create an array of reactions, which are allowed to proceed for a speci- and enable substantial variation of possible reactants, catalysts,
fied amount of time. The reactions are stopped by rinsing the array additives and solvents en route to such discovery.
and are then analysed rapidly by mass spectrometry to identify
We created screening arrays by first treating glass substrates with
those combinations of reactants and reagents that give products in a dilute solution of (tridecafluoro-1,1,2,2-tetrahydrooctyl)-1-tri-
high yield. These ‘hits’ are identified easily and then can be investi- chlorosilane and then masking the substrate with a stencil to
gated in more detail. This technique is highly sensitive (the amount deposit titanium (10 nm) followed by gold (100 nm) in a pattern
of monolayer-linked substrate is on the order of picomoles per of islands. The fluorinated surface that surrounded the islands
square millimetre) and because mass spectrometry is used it does served to confine wetting by a wide range of organic solvents and
not require work-up procedures to separate the products from the therefore kept the droplets on each monolayer in place and separate
reaction mixture. Previously, we employed this method to a range from each other. This platform is compatible with most non-fluori-
of biochemical applications27–30. Furthermore, we found that the nated solvents. Next, monolayers were prepared by treating the gold
Chicago Tri-Institutional Center for Chemical Methods and Library Development, Department of Chemistry, University of Chicago, Chicago, Illinois 60637,
USA, †These authors contributed equally to this work. e-mail: mmrksich@uchicago.edu; skozmin@uchicago.edu
*
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45

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1212
ARTICLES
a
OTIPS
OMe
OH
O
O
O
OMe
N
H
H
H
N
O
O
Me
O
Me
Me
HN
HN
OH
H2N
Me
3
1
2
THF, 20 °C
O
O
O
HBTU, NMM
DMA, 20 °C
O
O
O
O
Me Me
O
Me Me
O
Me Me
O
Me Me
O
Me Me
O
Me Me
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
9
O
O
O
9
O
O
O
O
O
O
9
O
O
O
O
O
9
Catalyst array
9
9
9
9
9
9
9
9
9
S
9
9
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Gold
Glass
Gold
Glass
Gold
Glass
c
d
C41H85NO10S2Na+
C
49H89NO12S2Na+
970.2
C45H74N2O10SNa+
b
857.4
838.1
1205.6
C63H110N2O14S2Na+
820
1040
1260
820
1040
m/z
1260
820
1040
1260
m/z
m/z
Figure 1 | Discovery of a new three-component reaction by SAMDI. a, The reaction screen was set up by first immobilizing aldehyde 1 to the monolayer,
followed by exposure of the resulting monolayer to 2 and 3 in the presence of various possible catalysts. b, SAMDI spectrum of the amine-terminated
monolayer. c, SAMDI spectrum of an aldehyde-functionalized monolayer synthesized via amide coupling. d, SAMDI spectrum of a new three-component
product formed in one of the interfacial reactions.
islands with an ethanolic solution of an amine-terminated alkane- after all the reagents had been added. The reactions were allowed
thiol that contained multiple ethylene glycol spacers and a similar to proceed for 30 minutes at room temperature, and then the mono-
methyl ether-terminated alkanethiol with a tris(ethylene glycol) layer array was rinsed with acetone, THF and ethanol. After drying,
spacer (Fig. 1a). The latter served as an inert background to the array was treated with 2,5-dihydroxybenzoic acid and each spot
control the density of reactive amine-containing functional groups was analysed by MALDI-TOF-MS. The majority of conditions
on the monolayer surface. Figure 1b shows a mass spectrum of screened revealed that no reaction occurred with the immobilized
the monolayer formed initially and reveals a peak at m/z 838.1 aldehyde (Supplementary Fig. S1). For example, a mass spectrum
that corresponds to the sodium adduct of a mixed disulfide of the reaction that contained only siloxyalkyne 2 and amine 3 in
derived from the amine-containing and methyl ether- THF showed a single peak at m/z 970.2 (Fig. 1c), which corresponds
terminated alkanethiolate.
to the starting aldehyde. Although most of the conditions screened
We introduced the aldehyde functionality by treating the amino- yielded no detectable or unidentified products, the mass spectrum
terminated monolayer with 4-formylbenzoic acid (1), O-benzotria- from a reaction spot that contained Pd(PPh3)4 revealed the for-
zole-N,N,N′,N′-tetramethyluranium hexafluorophosphate (HBTU) mation of new peaks at m/z 857.4 and 1205.6 (Fig. 1d), consistent
and N-methylmorpholine (NMM). The monolayer was rinsed, with the sodium adduct of an alkanethiolate terminated in a
dried and analysed by SAMDI to reveal a new peak at m/z 970.2 product derived from 1, 2 and 3, with loss of the triisopropylsilyl
(Fig. 1c), which corresponds to the sodium adduct of a mixed (TIPS) group as well as the sodium adduct of a mixed
disulfide composed of a methyl ether-terminated alkanethiolate disulfide produced from this three-component product and the
and another alkanethiolate that contains the newly installed alde- background methyl ether-terminated alkanethiolate. SAMDI
hyde. This method of immobilizing substrates could be applied to simultaneously provided data on the presence of both the reactants
introduce other functional groups of interest (for example, and potential products, so this analytical technique can be used to
alkynes and alkenes) onto monolayers and avoids the need to syn- assess qualitatively the conversion achieved in an interfacial
thesize functionalized alkanethiols prior to the assembly of reaction. In the mass spectrum from this reaction spot (Fig. 1d),
the monolayer.
no peaks derived from the unreacted aldehyde could be detected,
To perform the reactions we applied a solution of 1-siloxy-1- which indicates that this reaction proceeded efficiently on
hexyne (2) and 4-methoxy-N-methyl aniline (3) in tetrahydrofuran the monolayer.
(THF, Fig. 1a) to each aldehyde-terminated monolayer spot
followed by the addition of a potential catalyst in THF with a Solution-phase optimization. We began a detailed investigation of
10:5:1 molar ratio of 2:3:catalyst. We evaluated several common this novel transformation by performing the reaction in solution
Lewis acids, Brønsted acids and transition-metal complexes under the conditions initially found in the primary SAMDI
(Supplementary Fig. S1). The screening array was assembled reaction screen. The first evaluation of several aldehydes revealed
under a nitrogen atmosphere to prevent degradation of air- and that 4-(trifluoromethyl)benzaldehyde (4) displayed the highest
moisture-sensitive reagents, after which it was transferred to a reactivity. We found that subjecting 4 to siloxyalkyne 2 and
glass chamber saturated with THF to prevent solvent evaporation aniline 3 in the presence of Pd(PPh3)4 (20 mol%) and MeOH
46
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1212
ARTICLES
Table 1 | Effect of catalysts, additives and solvents on the solution-phase reaction.
OTIPS
MeO
MeO
O
OH
O
OH
O
MeO
N
N
H
NH
Me
Me
Me
CF3
CF3
CF3
3
2
5
6
4
Me
Me
Me
Entry
Catalyst (mol%)
Additive (equiv.)
Solvent, temperature (8C)
Conversion (%)
d.r.
1
Pd(PPh3)4 (5)
Pd(OAc)2 (5)
Pd(PCy3)2 (5)
Pd(PPh3)4 (5)
Ph3P (20)
MeOH (5)
MeOH (5)
MeOH (5)
MeOH (5)
MeOH (5)
MeOH (2.5)
MeOH (2.5)
BnOH (2)
THF, 20
56
,2
35
65
50
60
75
89
96
85:15
2
3
4
5
6
7
8
9
Toluene, 20
Toluene, 20
Toluene, 60
Toluene, 60
Toluene, 60
Toluene, 60
Toluene, 60
Toluene, 60
85:15
85:15
88:12
91:9
91:9
91:9
(4-MeC6H4)3P (10)
(4-MeOC6H4)3P (10)
(4-MeOC6H4)3P (20)
(4-MeOC6H4)3P (20)
4-FC6H4CH2OH (2)
91:9
The experiments were performed by treating a solution (0.5 ml) of 3 (0.25 mmol), 2 (0.37 mmol) and 4 (0.50 mmol) with the specified catalysts and additives listed above. After 24 hours, an aliquot of the
reaction was concentrated in vacuo, dissolved in CDCl3 (0.50 ml) and analysed by 1H NMR spectroscopy. For each run, conversion and diastereoselectivity were calculated based on the consumption
of 4-methoxy-N-methylaniline (3) and the formation of products
5
and 6. Diastereomeric ratios (d.r.) were determined by 500 MHz 1H NMR analysis of the crude reaction mixtures prior to
chromatographic purification.
(5 equiv.) in THF at 20 8C produced an 85:15 mixture of the two which indicates that a combination of a phosphine with an appro-
diastereomeric products 5 and 6 with 56% conversion, as priate alcohol additive was responsible uniquely for a successful
monitored by 1H NMR spectroscopy (Table 1, entry 1). We product formation and catalytic turnover. This finding is very sig-
determined the structure of the major anti-product 5 using NMR nificant because prior to this study simple organic phosphines
and mass spectrometry, and subsequent X-ray crystallographic were not known to catalyse any reactions of siloxyalkynes.
analysis. Also, we found that the presence of methanol in the
reaction mixture was critical to the reaction. Although a proton Reaction scope study. Next, we examined a series of aromatic
source was not introduced specifically during the initial reaction aldehydes that could participate in a phosphine-catalysed three-
screening on SAMs, we believe that adventitious moisture could component condensation with alkyne 2 and amine 3. The major
have served this role in the interfacial reaction.
product 5 of the parent reaction with 4-(trifluoromethyl)-
Previously Pd complexes had not been found to promote any benzaldehyde (4) was isolated in 87% yield (Table 2, entry 1),
reactions of siloxyalkynes and the role of this metal in the three- fully consistent with the high degree of conversion observed in
component reaction was not evident, so we examined other Pd- previous NMR spectroscopic studies. Under the same reaction
containing compounds. Interestingly, although Pd(OAc)2 gave conditions, other electron-deficient benzaldehydes afforded the
none of the previously observed products (Table 1, entry 2), a Pd expected products with good yields and high diastereoselectivity
complex that contained another phosphine ligand produced the (Table 2, entries 2–7). Both ortho- and meta-aromatic substitutions
same outcome as Pd(PPh3)4, albeit with a lower efficiency of the aldehyde were well tolerated. Interestingly, the reaction of a
(Table 1, entry 3). Raising the temperature of the reaction to ketone-containing aldehyde (Table 2, entry 2) proceeded with
60 8C resulted in an increase of reaction efficiency (Table 1, entry 4). complete chemoselectivity, with only the aldehyde being reactive
As only phosphine-containing complexes had proved effective under the conditions of the three-component reaction. Also,
thus far, we decided to perform the same reaction in the presence heteroaromatic and halogen-containing aldehydes reacted
of only PPh3 and MeOH, with the complete exclusion of Pd. efficiently (Table 2, entries 8 and 9), but unsaturated and aliphatic
Under such conditions, the same three-component product was aldehydes gave lower yields, presumably because of other
obtained with similar efficiency and diastereoselectivity to those of reactions promoted by secondary amines, including enolization
Pd(PPh3)4 (Table 1, entry 5), which strongly suggests that the of aliphatic aldehydes and conjugate additions to
presence of a transition metal was not required for this reaction. unsaturated aldehydes.
PPh3 was not included in the primary SAMDI reaction screen,
Also, we examined the scope of the reaction with regard to silox-
so the effect of this compound (which is typically used as a yalkyne substitution. The use of 1-siloxy-1-propyne resulted in the
transition-metal ligand) as the sole reaction promoter was not desired product in high yield with slightly diminished diastereos-
evaluated at an earlier stage.
electivity (Table 2, entry 12). The presence of aromatic groups in
To increase the efficiency of the solution-phase three-component the siloxyalkyne structure was tolerated well (Table 2, entry 13).
condensation of 2, 3 and 4, next we evaluated a variety of phos- Furthermore, introduction of bulky substituents, such as cyclohexyl
phines, other nucleophilic reagents and a range of proton sources. or cyclopropyl groups, in direct proximity to the alkyne moiety did
Selected results of our extensive studies are summarized in not seem to impact the efficiency or the diaseteroselectivity of the
Table 1 (entries 6–9). We found that electron-rich triarylphosphines reaction (Table 2, entries 14 and 15). Such results suggest that a
were the most reactive in promoting the desired transformation, wide range of siloxyalkyne substitution would be well tolerated in
with tris(4-methoxyphenyl)phosphine being the best catalyst with the three-component reaction.
methanol as the additive (Table 1, entry 7). Throughout the optim-
The final aspect of the scope study entailed the evaluation of a
ization studies, replacing methanol with benzyl and 4-fluorobenzyl series of amines. Secondary anilines proved to be the most suitable
alcohols improved the diastereoselectivity of this process further (to substrates for this reaction. This observation is not surprising
91:9) and also increased the reaction efficiency (Table 1, entries 8 because most of the initial optimization work was performed
and 9). During these studies, we established that one equivalent employing aromatic amines, which displayed the most promising
of the alcohol is required for the quantitative transfer of the TIPS reactivity profile. For instance, N-methylaniline, N-methyl-4-bro-
group. With complete exclusion of a phosphine or its substitution moaniline and N-methyl-3-methoxyaniline produced the corre-
by phosphine oxides no three-component reaction was observed, sponding three-component reaction products 21–23 in 61–74%
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1212
ARTICLES
Table 2 | Scope of the three-component condensation of aldehydes, siloxyalkynes and amines.
OTIPS
O
OH
(4-MeOC6H4)3P (20 mol%)
O
R1
H
R1
R4
N
+
N
+
H
R4
4-FC6H4CH2OH (2 equiv.)
Toluene, 60 °C
R2
R2
R3
R3
Entry
Major product
Yield (%)
d.r.
Entry
Major product
Yield (%)
d.r.
MeO
MeO
MeO
1
87
91:9
12
75
85:15
O
OH
O
OH
N
N
Me
Me Me
CF3
CF3
5
17
Me
MeO
O
OH
O
OH
2
87
88:12
13
72
91:9
N
N
Me
O
Me
CF3
7
18
Me
Me
MeO
MeO
MeO
O
OH
O
OH
OH
3
4
5
6
7
73
63
74
68
66
88:12
91:9
14
15
16
17
18
80
87
76
74
61
91:9
91:9
91:9
95:5
91:9
N
N
Me
Me
CN
CF3
19
8
Me
MeO
O
OH
O
CF3
N
N
Me
Me
CF3
9
20
Me
MeO
O
OH
O
OH CF3
93:7
91:9
N
N
Me
Me
CF3
10
21
Me
OH
Me
MeO
Br
O
OH
O
N
N
Me
Me
CF3
11
22
Me
Me
MeO
OMe
O
OH
84:16
O
OH
N
Me
N
NO2
Me
CF3
12
Me
OH
23
Me
OH
MeO
O
O
8
59
63
58
44
88:12
90:10
91:9
19
20
21
78
57
52
30
88:12
89:11
N
N
N
N
Me
O
Me
CF3
13
24
Me
Me
MeO
O
OH
O
OH
9
N
Me
CF3
Cl
14
Me
25
Me
MeO
O
OH
O
OH
10
11
80:20
63:37
N
Me
Me
Me
CF3
15
Me
26
Me
MeO
Me
O
OH
O
OH
84:16
22
Me
Me
N
N
Me
Me
CF3
OMe
Me
16
27
Me
All reactions were carried out according to the general procedure described in the Methods section. The yields refer to those isolated for the major diastereomeric product
of each three-component reaction after chromatographic purification. Diastereomeric ratios were determined by 500 MHz 1H NMR analysis of the crude reaction mixtures
prior to chromatographic purification.
48
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1212
ARTICLES
R3Si
a
O
C
O
PR3 (catalyst)
OTIPS
N
30
H
H
R1
R1
R2OH
R2OSiR3
R3
N
O
(4-MeOC6H4)3P (20 mol%)
4-FC6H4CH2OH (2 equiv.)
Toluene, 60 °C
R4
O
N
H
H
N
R5
28
31, 95%
b
c
O
R3
H
O
O
OH
R5
Me
NH2
H
32
OTIPS
R3
R1
HN
N
R4
O
R4
R5
R1
(4-MeOC6H4)3P (20 mol%)
4-FC6H4CH2OH (2 equiv.)
Toluene, 60 °C
H
33, 96%
Figure 2 | Proposed mechanism of the phosphine-catalysed three-
component reaction of siloxyalkynes with amines and aldehydes. The
mechanism involves the initial desilylation of the siloxyalkyne, which is
promoted by phosphine and alcohol, followed by reaction of the resulting
ketene with amine and aldehyde to generate the observed three-component
product. The stereochemistry of the final product can be rationalized based
on the chair-like transition state shown.
Me
28
Me
Me
OH
Me
Me
OTIPS
O
34
Me
O
Me
Me
Me
(4-MeOC6H4)3P (20 mol%)
Toluene, 60 °C
isolated yields (Table 2, entries 16–18). Other N-substituted anilines
participated readily in this reaction (Table 2, entries 19–21). Not
surprisingly, increasing the steric bulk of the N-alkyl substituent
resulted in lower yields of the desired product, as well as a dimin-
ished diastereoselectivity. Although primary anilines did not
afford any three-component products under the same reaction con-
ditions, N,N-dialkylamines displayed a variable pattern of reactivity
and diastereoselectivity. For instance, the three-component reaction
using diisopropylamine afforded the desired major anti-diastereo-
meric product in a decreased isolated yield as a result of a dimin-
ished level of diastereoselection (Table 2, entry 22).
28
35, 85%
O
O
d
i.
O
O
OTIPS
36
EtO
OEt
EtO
OEt
O
(4-MeOC6H4)3P (20 mol%)
Toluene, 60 °C
ii. HF (5%) in MeCN
37, 75%
29
With the reaction scope established, next we demonstrated the
utility of this three-component transformation for the rapid syn-
thesis of a representative small-molecule library of hydroxyamides,
which was generated from three siloxyalkynes, three aldehydes
and four amines (Supplementary Fig. S2). The library was produced
and purified by mass-triggered preparative LCMS to deliver success-
fully 36 requisite compounds on a 20–66 mg scale in high chemical
purity (see Supplementary Information).
Figure 3 | Other representative phosphine-catalysed reactions of
siloxyalkynes. a–d, Such reactions include amidations of siloxyalkynes with
aliphatic (a) and aromatic (b) amines, esterification of a siloxyalkyne with
highly hindered phenols (c) and condensation of a siloxyalkyne with diethyl
malonate (d).
the same conditions to afford amide 33 (Fig. 3b). Furthermore,
Formation of the observed three-component products can be treatment of siloxyalkyne 28 with the hindered phenol 34 yielded
rationalized tentatively based on the mechanism depicted in the corresponding ester 35 in high yield (Fig. 3c). Two
Fig. 2. Reaction of a siloxyalkyne with phosphine and alcohol is equivalents of the alcohol were required in this experiment, as
expected to produce a ketene. This step is supported by our deuter- one equivalent was converted into the corresponding TIPS ether.
ium-incorporation studies using a deuterated alcohol (R2–OD), Finally, we examined whether phosphine catalysis enabled
which demonstrated exclusive incorporation of deuterium at the C-acylation of malonates with siloxyalkynes. Treatment of
a-position of the carbonyl group in the final three-component malonate 36 with alkyne 29 in the presence of tris(4-
product. During the course of the reaction the silyl group is trans- methoxyphenyl)phosphine (20 mol%) followed by desilylation
ferred solely to the corresponding silyl ether (R2–OSiR3), as with HF afforded the C-acylated product 37 (Fig. 3d). The above
shown in Fig. 2. Subsequent addition of the secondary amine to a phosphine-catalysed reactions of siloxyalkynes with several classes
ketene, followed by an aldol reaction with an aldehyde, would gen- of commonly used nucleophiles offer unique and exceedingly
erate the observed hydroxyamide product. The closed transition mild reaction conditions for such transformations and further
state shown in Fig. 2 could explain the predominant formation of expand the newly identified concept of nucleophilic activation of
the major anti-diastereomer. The proposed mechanism is supported this class of organosilicon compounds.
further by a range of other experiments, including the preliminary
kinetic analysis of this process.
Conclusions
The work described herein establishes that SAMDI-based screening
Other phosphine-catalysed reactions of siloxyalkynes. We also can be used to identify novel multicomponent reactions. This
identified several other phosphine-catalysed transformations of method does not require labels to identify specific products, is
siloxyalkynes that are fully consistent with the possible generation well suited to the discovery of transformations that give products
of ketenes under the reaction conditions. For example, treatment with structures not predicted easily from prior knowledge of sub-
of siloxyalkyne 28 with amine 30 in the presence of tris(4- strate reactivity and is adaptable to multiparameter reaction screen-
methoxyphenyl)phosphine (20 mol%) and 4-fluorobenzylalcohol ing. This effective reaction-screening strategy enabled the discovery
(2 equiv.) at 20 8C afforded the corresponding amide 31 in 95% of the first three-component reaction of siloxyalkynes with alde-
yield (Fig. 3a). The primary aniline 32 was also employed under hydes and amines and uncovered a conceptually novel mode of
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1212
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Methods
Preparation of monolayers and SAMDI reaction screen. Glass slides (50 ×
35 mm) were placed in a dilute solution of (tridecafluoro-1,1,2,2-tetrahydrooctyl)-1-
trichlorosilane (1 vol% in anhydrous toluene) for ten minutes to create a fluorinated
glass surface. The resulting slides were rinsed with acetone, sonicated in ethanol
twice for 20 minutes and heated to 80 8C for two hours. The glass platform was
masked with a stencil (made from aluminium) that contained evenly spaced holes
with a diameter of 2.5 mm and centre-to-centre distance of 4 mm. Titanium
(10 nm) and then gold (100 nm) were evaporated onto the masked glass substrate
using an electron-beam evaporator (Thermionics VE-100) at a rate of 0.2 Å s21 for
titanium and 0.4 Å s21 for gold, and at a pressure of less than 5 × 1027 Torr, to
generate the array of gold-coated islands. Then, the modified glass plate was
immersed for 12 hours in an ethanolic solution (1.5 ml) that contained the
background methyl ether-terminated alkanethiol and aminofunctionalized
alkanethiol (for structures, see Fig. 1b) in a 3:2 ratio (total concentration
0.2 mmol l21). Next, the monolayer was treated with 2,5-dihydroxybenzoic acid
(1 ml of a 10 mg m l21 solution in acetonitrile), allowed to air dry and analysed on a
4800 MALDI-TOF/TOF Biospectrometry mass spectrometer (Applied Biosystems,
Framingham, MA) equipped with a 355 nm neodymium-doped yttrium aluminium
garnet laser and using a positive-ion reflector mode. Aldehyde 1 was immobilized by
immersing the amine-functionalized monolayer in a solution that contained
4-formylbenzoic acid (100 mmol l21), HBTU (100 mmol l21) and NMM
(200 mmol l21) in N,N,-dimethylacetamide (DMA). The reaction was allowed to
proceed for 30 minutes at 20 8C. This process was repeated and the slides were rinsed
with acetone, dried under a stream of nitrogen and analysed by MALDI-TOF-MS, as
described above. Then the array was placed in a glove bag filled with nitrogen and
each reaction spot was treated with 3 ml of a solution of alkyne 2 (0.67 mol l21) and
amine 3 (0.33 mol l21). After addition of all the reagents, 1 ml of a solution of a
potential catalyst (0.2 mol l21) in THF was applied to each spot. The array was
transferred to a glass chamber saturated with THF and the reactions were allowed to
proceed for 30 minutes at 20 8C. Next, monolayers were rinsed with acetone, THF
and ethanol, and dried under a stream of nitrogen. Each reaction spot was treated
with 2,5-dihydroxybenzoic acid (1 ml per spot of a 10 mg l21 solution in
acetonitrile) and analysed by mass spectrometry, as described above.
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General procedure for the three-component condensation of siloxyalkynes,
aldehydes and amines. All solution-phase reactions were performed under an
atmosphere of argon in flame-dried (10 × 75 mm) test tubes equipped with stir bars
and sealed with rubber septa. A solution of tris(4-methoxyphenyl)phosphine
(35.2 mg, 0.1 mmol, 20 mol%), amine (0.5 mmol) and siloxyalkyne (0.75 mmol) in
toluene (1.0 ml) was treated with aldehyde (1.00 mmol) and 4-fluorobenzyl alcohol
(0.109 ml, 2.00 mmol). The resulting solution was heated to 60 8C for 48 hours. The
reaction mixture was cooled to room temperature, diluted with CH2Cl2 (1.0 ml),
concentrated by rotary evaporation and subjected to purification by flash
chromatography to afford the resulting three-component products shown in Table 2.
24. Goodell, J. R. et al. Development of an automated microfluidic reaction platform
for multidimensional screening: reaction discovery employing
bicyclo[3.2.1]octanoid scaffolds. J. Org. Chem. 74, 6169–6180 (2009).
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throughput discovery of catalytic reactions. Science 333, 1423–1427 (2011).
26. Min, D-H., Yeo, W-S. & Mrksich, M. A method for connecting solution phase
enzyme activity assays with immobilized format analysis by mass spectrometry.
Anal. Chem. 76, 3923–3929 (2004).
27. Min, D-H., Tang, W-J. & Mrksich, M. Chemical screening by mass spectrometry
to identify inhibitors of anthrax lethal factor. Nature Biotechnol. 22,
717–720 (2004).
Received 26 July 2011; accepted 28 October 2011;
published online 4 December 2011
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networks and peptide arrays for multi-enzyme assays. J. Am. Chem. Soc. 127,
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31. Su, J. & Mrksich, M. Using MALDI-TOF mass spectrometry to characterize
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4867–4870 (2003).
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1212
ARTICLES
39. Sun, J. & Kozmin, S. A. Silver-catalyzed hydroamination of siloxy alkynes.
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Author contributions
T.J.M. and J.L. contributed equally to the work. J.L. performed and analysed all interfacial
reactions on monolayers. T.J.M. carried out most of the solution-based studies. J.R.C-P.
assisted with scope studies. M.M. and S.A.K. equally provided project management.
The manuscript was written by T.J.M., J.L., S.A.K. and M.M.
40. Sweis, R., Schramm, M. P. & Kozmin, S. A. Silver-catalyzed [2þ2] cycloadditions
of siloxyalkynes. J. Am. Chem. Soc. 126, 7442–7443 (2004).
41. Sun, J., Keller, V. A., Meyer, S. T. & Kozmin, S. A. Silver-catalyzed
aldehyde olefination using siloxy alkynes. Adv. Synth. Catal. 352,
839–842 (2010).
Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://www.
nature.com/reprints. Correspondence and requests for materials should be addressed to M.M.
and S.A.K.
Acknowledgements
This work was funded by the National Institutes of Health (P50 GM086145) and the
Chicago Biomedical Consortium with support from the Searle Funds at the Chicago
Community Trust. We thank Ian Steele for the X-ray crystallographic analysis of 5.
NATURE CHEMISTRY | VOL 4 | JANUARY 2012 | www.nature.com/naturechemistry
51
© 2011 Macmillan Publishers Limited. All rights reserved.