Rapid assessment of protecting-group stability by using a robustness screen

Article abstract of DOI:10.1002/chem.201304508

An experimentally simple method has been developed to rapidly establish the stability of widely utilized silyl, acetal, and carbamate protecting groups to a given set of reaction conditions. Assessment of up to twelve protecting groups in a single experiment has been demonstrated. Evaluation of this protocol in two unrelated synthetic transformations suggests that this method can be used to select appropriate protecting groups in the design of synthetic routes.

Full text of DOI:10.1002/chem.201304508

DOI: 10.1002/chem.201304508
Full Paper
&
Screening Methods
Rapid Assessment of Protecting-Group Stability by Using
a Robustness Screen
Karl D. Collins,* Andreas Rꢀhling, Fabian Lied, and Frank Glorius*[a]
Dedicated to the late Professor Chris A. Brookes.
Abstract: An experimentally simple method has been devel-
oped to rapidly establish the stability of widely utilized silyl,
acetal, and carbamate protecting groups to a given set of re-
action conditions. Assessment of up to twelve protecting
groups in a single experiment has been demonstrated. Eval-
uation of this protocol in two unrelated synthetic transfor-
mations suggests that this method can be used to select ap-
propriate protecting groups in the design of synthetic
routes.
Introduction
We demonstrate a high correlation between results in which
the stability of PGs were evaluated discretely, and results ob-
tained when all PGs from a given class (up to twelve PGs) were
evaluated in a single experiment. This protocol represents a sys-
tematic empirical method for determining the stability of PGs
to a given set of reaction conditions, and provides quantitative
data. Finally, PG-containing substrates were employed in the
pyrazole synthesis and, crucially, in an unrelated reaction, to
both evaluate the conclusions drawn from the screen and
demonstrate the potential applications to real synthetic
problems.
Protecting group (PG) chemistry is a fundamental part of the
synthesis of organic molecules. By judicious selection of a PG,
or PGs (often orthogonal with regard to cleavage), the prepara-
tion of molecules that otherwise would have remained elusive
has been achieved.[1] The selection of an appropriate PG is criti-
cal and requires knowledge of both the PG, and the reaction
conditions it will be exposed to. In this regard, protecting-
group chemistry books by Greene and Wuts,[1b] and
Kocienski,[1c] have proved to be indispensable. Despite the
great value of established texts on PGs, owing to the high rate
with which new synthetic methodologies are reported, these
texts often provide little information with regard to contempo-
rary synthetic methods. Consequently, rapid methods to deter-
mine the stability of PGs to a given set of reaction conditions
would be highly beneficial, and would directly facilitate the
application of the methodology to real synthetic
problems.
Experimentally our approach is very simple. The Cu(OAc)2-
mediated reaction of enaminoester 1 with benzonitrile 2 to
give pyrazole 3 (Scheme 1) was conducted in the presence of
Following the recent disclosure of a “robustness screen”[2]
for the rapid assessment of functional group and structural
motif tolerance for a given reaction, we have further devel-
oped this method for application in the assessment of PG sta-
bility. By using the recently reported Cu(OAc)2-mediated prepa-
ration of pyrazoles as a model reaction,[3] herein we report
a simple and rapid method for the evaluation of the stability
of several common PGs to the reaction conditions. We have
evaluated the stability of a range of silyl PGs for alcohols, ace-
tals for carbonyl groups, and amide/carbamate PGs for amines.
Scheme 1. The Cu(OAc)2-mediated synthesis of pyrazoles.
one molar equivalent of an additive bearing a protected func-
tional group. Analysis of the reaction mixture to determine the
yield of 3, and the amount of additive remaining after the pre-
determined reaction time, was then undertaken. This proce-
dure enables an evaluation of both the stability of the PG to
the reaction conditions, and the impact of the PG on product
formation. By using batch reaction preparation and parallel
synthesis techniques, large numbers of PGs can be rapidly
evaluated. We utilized either gas chromatography (GC) or
high-pressure liquid chromatography (HPLC) to analyze the re-
action, allowing for a high-throughput process. Single-point
batch calibration techniques for the calibration of the GC and
HPLC, as previously described and evaluated, minimize the
[a] Dr. K. D. Collins, A. Rꢀhling, F. Lied, Prof. Dr. F. Glorius
Westfꢁlische Wilhelms-Universitꢁt Mꢀnster, Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢀnster (Germany)
E-mail: collinsk@uni-muenster.de
glorius@uni-muenster.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304508.
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screen preparation time.[2a,b] It should be noted that there is
a cumulative error in the experimental process and in the sim-
plified calibration technique, which is reflected in the yields of
the additive and reaction product. The yields quoted are as
measured, and consequently are occasionally>100%; we esti-
mate the error at approximately Æ3%.[2b]
tal error, and demonstrates the consistency of the data ob-
tained. Each PG was evaluated twice, though the reported
data is for a single run to enable simple communication of the
results. The data from any individual run and the average of all
runs is highly comparable and the complete data set is provid-
ed in the Supporting Information. We have categorized the
3
stability of the PGs as high (ꢀ80%, ), medium (50–79%, –),
and low (<50%, ꢂ).
Results and Discussion
Table 1 indicates that the TES PG does not display significant
stability as a PG for primary, secondary, tertiary, or aromatic al-
cohols under the reaction conditions. This is in stark contrast
to the TIPS PG, which demonstrates excellent stability in all ex-
amples reported. The TBS PG displays high stability when used
to protect secondary and tertiary alcohols. Owing to the poor
solubility of the TBS- and TIPS-protected tertiary alcohols in
DMF, inconsistent results were obtained, and as such we con-
clude that these groups are not suitable for evaluation in polar
solvents by this method.[4]
We began our investigation by assessing the stability of twelve
silyl-protected alcohols. Triethylsilyl (TES)-, tert-butyldimetylsilyl
(TBS)-, and triisopropylsilyl (TIPS)-protected primary, secondary,
tertiary, and aromatic alcohols were evaluated. These PGs are
commonly employed in organic synthesis and span the spec-
trum of acid stability, a traditional method of cleavage.[1a–c] Fol-
lowing the synthesis of compounds 4–7 (Figure 1), single-point
batch calibration of the additives by using GC chromatography
was undertaken, and the screen performed.
As the primary function of all PGs is to remain unaffected by
the reaction conditions, we propose that only those demon-
The results, given in Table 1, show the amount of protected
alcohol remaining after the reaction, and the yield of the prod-
uct. A control reaction containing no protected alcohol was
performed in parallel with each set of experiments, and the
yield for the relevant control experiment is given in parenthe-
ses. The control reaction facilitates identification of experimen-
3
strating high stability (ꢀ80%, ) would be suitable for applica-
tion in real synthetic problems; with this consideration in mind
it can be readily identified from Table 1 which silyl PGs would
be suitable for which alcohols, should this reaction be applied
to complex molecules containing such motifs. It should be
noted that, as with all model evaluations and predictions of
the stability of a PG to a given set of reaction conditions, the
local-steric, electronic, and conformational environments of
complex molecules cannot be evaluated.
We subsequently investigated the stability of a number of
benzaldehyde 8 and 4-heptanone 9 derived acetals (Figure 2).
Acyclic, cyclic, and thio-acetals were prepared and evaluated in
Figure 1. Silyl-protected alcohols prepared for evaluation. R=a: SiEt3, b: Si-
Me2tBu, c: SiiPr3.
Table 1. Assessment of the stability of silyl protecting groups to the stan-
dard reaction conditions.
Entry
Protected
alcohol
Protected alcohol
remaining [%][a]
Yield 3 [%][a,b]
1
2
3
4
5
6
7
8
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
51
50
91
48
80
94
66
nd
nd
38
71
95
–
–
3
70 (71)
70 (71)
68 (71)
71 (71)
68 (71)
70 (71)
64 (71)
Figure 2. Acetals and ketals prepared for evaluation.
ꢂ
3
an identical manner to the silyl PGs for alcohols. The results
are given in Table 2. The dimethoxy- and dithiane-derived ace-
tals of benzaldehyde (8a and 8e) and 4-heptanone (9a and
9e) proved to be unstable to the reaction conditions. The re-
duced yield of 3 in these experiments suggests that either the
unprotected functionality (aldehyde or ketone), or by-products
of the (thio)acetal cleavage, inhibit the reaction. The cyclic ace-
tals evaluated show high stability as PGs for benzaldehyde,
and ketone analogues 9b and 9d demonstrate high stability,
though overall the ketal PGs are comparatively less stable.
We have also investigated the stability of common amide-
type PGs. Using 1-phenylethylamine as a model amine, acetate
(Ac) 10a, carboxybenzyl (Cbz) 10b, tert-butoxycarbonyl (Boc)
3
–
9
10
11
12
ꢂ
–
75 (71)
75 (71)
68 (71)
3
General conditions: 1 (0.200 mmol), 2 (3 equiv), 4 (1 equiv), Cu(OAc)2 (1.5
equiv), DMF (0.2 mL), 1108C, 24 h. [a] Yields determined by GC analysis of
the crude reaction product by using mesitylene as an internal standard.
[b] Yields in parenthesis are those of the relevant control reaction con-
taining no protected functionality (performed in parallel with the given
reaction). Symbols are employed to facilitate rapid evaluation of the data:
3
ꢀ80%, – 50–79% and ꢂ <50%. nd=not determined.
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Table 2. Assessment of the stability of acetal and ketal protecting groups
Table 3. Assessment of the stability of amine protecting groups to the
to the standard reaction conditions.
standard reaction conditions.
Yield 3 [%][a,b]
Entry
Acetal/ketal
Acetal/ketal
remaining [%][a]
Yield 3 [%][a,b]
Entry
Protected amine
Protected amine
remaining [%][a]
3
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
22
92
103
83
42
0
88
69
81
0
ꢂ
3
46 (67)
59 (67)
63 (67)
66 (67)
37 (67)
66 (67)
68 (67)
70 (67)
69 (67)
24 (67)
1
2
3
4
5
10a
10b
10c
10d
10e
90
99
101
0
68 (68)
65 (66)
67 (68)
53 (66)
65 (66)
3
3
3
3
ꢂ
3
ꢂ
ꢂ
3
100
General conditions: 1 (0.200 mmol), 2 (3 equiv), 10 (1 equiv), Cu(OAc)2
(1.5 equiv), DMF (0.2 mL), 1108C, 24 h. [a] Yields determined by HPLC
analysis of the crude reaction product by using 1,3,5-triisopropylbenzene
as an internal standard. [b] Yields in parenthesis are those of the relevant
control reaction containing no protected functionality (performed in par-
allel with the given reaction). Symbols are employed to facilitate rapid
–
3
10
ꢂ
General conditions: 1 (0.200 mmol), 2 (3 equiv), 8 or 9 (1 equiv), Cu(OAc)2
(1.5 equiv), DMF (0.2 mL), 1108C, 24 h. [a] Yields determined by GC analy-
sis of the crude reaction product by using mesitylene as an internal stan-
dard. [b] Yields in parenthesis are those of the relevant control reaction
containing no protected functionality (performed in parallel with the
given reaction). Symbols are employed to facilitate rapid evaluation of
3
evaluation of the data: ꢀ80%, – 50–79% and ꢂ <50%.
the additives remaining was undertaken. The results are given
in Table 4, and are an average of two parallel experiments.
Comparison of the absolute values for the additive remain-
ing at the end of the reaction for the one-pot experiment and
the results obtained in the screen demonstrates, in some in-
stances, significant deviation. However, inspection of the data
as a whole provides valuable information that can be used to
determine PGs that would be suitable for a given transforma-
tion. PGs that prove susceptible to cleavage in the initial study,
for example 5a and 7a, typically demonstrate poorer stability
in the one-pot experiments and, in contrast, those that display
3
the data: ꢀ80%, – 50–79% and ꢂ <50%.
10c, 9-fluorenylmethyloxycarbonyl (Fmoc) 10d, and tosyl 10e
derivatives were prepared (Figure 3). In this instance, we found
that GC analysis was unsuitable owing to the fragmentation of
Table 4. One-pot reaction for silyl protecting groups.
Figure 3. Protected amines prepared for evaluation (Bn=benzyl).
substrates during analysis; HPLC was employed as an alterna-
tive. Reactions were undertaken as previously described and
the results are given in Table 3. The screen demonstrated that
the amine protecting groups all showed excellent stability to
the reaction conditions with the exception of 10d.
Protected alcohol
Protected alcohol remaining [%][a]
Original results
One-pot results[b]
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
51
50
91
48
80
94
66
nd
nd
38
71
95
–
–
3
45
74
ꢂ
–
3
3
3
3
104
<10[c]
94
117[d]
72
96
105
21
Following the discrete determination of the stabilities of the
PGs, we looked to further streamline this methodology. We
subsequently investigated the feasibility of determining the
stability of all PGs within a given set in a single experiment. To
do this we repeated the standard reaction on a larger scale
and introduced all PGs from a given group into the reaction
mixture. For the twelve silyl-protected alcohols, the standard
reaction was conducted on a 1.20 mmol scale, in the presence
of 0.100 mmol of each protected alcohol. By using a total of
one molar equivalent of protected alcohol (12ꢂ0.100 mmol),
the stoichiometry of the “one-pot reaction” is identical to that
of the individual experiments and, therefore, we proposed
would provide comparable results. Following the reaction, the
standard analysis to determine the yield of the reaction and
ꢂ
3
3
–
–
3
3
ꢂ
–
ꢂ
–
73
104
3
3
Conditions:
1 (1.20 mmol), 2 (3 equiv), 4a–7c (0.100 mmol each),
Cu(OAc)2 (1.5 equiv), DMF (1.2 mL), 1108C, 24 h. [a] Yields determined by
GC analysis of the crude reaction product by using mesitylene as an inter-
nal standard. [b] Yields are an average of two parallel experiments. [c] Es-
timated owing to overlap with by-product. [d] Overlap with by-product
observed. nd=not determined. Symbols are employed to facilitate rapid
3
evaluation of the data: ꢀ80%, – 50–79% and ꢂ <50%.
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high stability, for example 4c and 5b, typically demonstrate
greater stability in the one-pot reaction. This result can be ex-
plained by considering the relative rates of cleavage of each
PG; even if a group is susceptible to cleavage, more labile
groups are likely to be cleaved first. Despite variation in the
absolute values, it is notable that all PGs classified as highly
stable in the one-pot reaction are also highly stable in the indi-
vidual evaluation.
Table 6. One-pot reaction for amine protecting groups.
Protected amine
Protected amine remaining [%][a]
Original results
One-pot results[b]
10a
10b
10c
10d
10e
90
99
101
0
111[c]
97
3
3
This suggests a highly stable group, as determined by the
one-pot reaction, is likely to be a suitable PG for a “real” sub-
strate. In contrast to the initial screen, in these experiments,
substrates 6b and 6c were found to give consistent results,
presumably owing to the substrates being completely soluble
in a comparatively larger volume of solvent. One-pot reactions
were subsequently undertaken for both the acetal PGs
(Table 5) and the amine PGs (Table 6).
3
3
3
3
87
ꢂ
3
0
ꢂ
3
100
109[c]
Conditions:
1
(0.500 mmol), 2 (3 equiv), 10a–e (0.100 mmol each),
Cu(OAc)2 (1.5 equiv), DMF (1.2 mL), 1108C, 24 h. [a] Yields determined by
HPLC analysis of the crude reaction product by using 1,3,5-triisopropyl-
benzene as an internal standard. [b] Yields are an average of two parallel
experiments. [c] Overlap of by-products from the decomposition of 10d
is presumed to account for the high yields. Symbols are employed to fa-
3
cilitate rapid evaluation of the data: ꢀ80%, – 50–79% and ꢀ <50%.
Table 5. One-pot reaction for acetal protecting groups.
Protected alcohol
Acetal/ketal remaining [%][a]
Original results
One-pot results[b]
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
22
92
103
83
42
0
88
69
81
0
ꢂ
3
3
3
2
90
105
90
0
ꢂ
3
3
3
Figure 4. Substrates containing the relevant protecting groups for evalua-
tion of the PG robustness screen.
Following the screen, we sought to validate the data gener-
ated in an empirical manner. We prepared four aromatic ni-
triles containing PGs 11b–11e (Figure 4). These substrates and
the parent alcohol 11 were then employed in the pyrazole
synthesis.
ꢂ
ꢂ
ꢂ
ꢂ
0
3
3
99
45
89
0
–
3
–
3
ꢂ
ꢂ
As the results from the screen were determined for a single
equivalent of PG, one equivalent of 11 a–e was utilized in each
experiment, rather than three equivalents as reported in the
original report.[3] Although this would likely lead to a decrease
in the yield of the reaction, it would provide a true evaluation
of the data obtained in the screen. Furthermore, the protected
functionality is within the limiting reagent, typically representa-
tive of real synthetic problems.[1a–c] We were delighted to find
that these experiments gave highly comparable results to
those predicted by the screen (Scheme 2). When nitrile 11 b
was employed, TES-containing pyrazole 12b was obtained in
25% yield, alongside 20% of deprotected pyrazole 12a. These
values correspond to a PG stability of 53%, comparable to the
51% (discrete) or 45% (one pot) predicted by the screen.[5] In
contrast, TIPS-containing substrate 11 c gave pyrazole 12c in
47% yield, with no 12a detected. The comparable overall yield
of these reactions suggests the stability of the TIPS group to
be approximately 100%, comparable to the 91% (discrete) or
104% (one pot) predicted by the screen. Furthermore, 11 d
and 11 e gave yields of 67 and 62%, respectively, confirming
that these PGs are suitable for use in this pyrazole synthesis, as
predicted by the screen.
Conditions: 1 (1.00 mmol), 2 (3 equiv), 8a–e and 9a–e (0.100 mmol
each), Cu(OAc)2 (1.5 equiv), DMF (1.2 mL), 1108C, 24 h. [a] Yields deter-
mined by GC analysis of the crude reaction product by using mesitylene
as an internal standard. [b] Yields are an average of two parallel experi-
3
ments. Symbols are employed to facilitate rapid evaluation of the data:
ꢀ80%, – 50–79% and ꢂ <50%.
The general behavior of the acetal PGs, for both ketones
and aldehyde, in the one-pot experiment, parallels that ob-
served for the silyl PGs. The least-stable PGs, as demonstrated
by the individual experiments, showed much less stability in
the one-pot experiments (e.g. 8a and 8e), and those with high
stability (e.g. 8d and 9b) typically proved a little more stable.
Importantly though, as for the protected alcohols, those
groups that displayed high stability in the one-pot experiment
also displayed high stability in the individual experiments and
thus could be regarded as useful PGs. For the amine PGs, the
results for the one-pot experiments were again highly compa-
rable with those obtained when the PGs were evaluated indi-
vidually. In summary, the conclusions parallel those from the
discrete evaluation of the PGs, suggesting that this technique
is an appropriate method for the rapid determination of suita-
ble PGs.
Finally, we envisioned that this screen could be utilized to
directly determine a suitable PG for a given substrate, under
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Scheme 4. Arylation of substrates containing protecting groups.
ing materials remaining in either experiment (Scheme 4). In an
identical approach, we evaluated the suitability of an acetate
and Boc PG for amines by using a one-pot reaction.[7] The
screen demonstrated that the acetate PG was highly stable to
the reaction conditions, and that the Boc group was complete-
ly labile. We subsequently synthesized 17a and 17b, and em-
ployed them as substrates to evaluate the results of the
screen. Pleasingly, the results of these reactions directly corre-
late to those predicted by the one-pot evaluation.
Scheme 2. Evaluation of the PG robustness screen by reaction of PG-con-
taining arylnitriles. Yields were determined by NMR spectroscopy, with
CH2Br2 as an internal standard. [a] Yield of isolated product.
The Boc group proved completely labile, whilst the acetate
PG group enabled the reaction to proceed in an excellent
overall yield of 91%. In contrast to the almost exclusive mono-
arylation typically observed in the original report,[2h] we ob-
served significant double arylation with this substrate. This is
presumably due to the ability of the protecting group to act
as a directing group, facilitating a second arylation.[6j–m]
a particular set of reaction conditions. We proposed that un-
dertaking a single one-pot experiment to evaluate relevant
PGs would enable the selection of an appropriate PG without
the need to prepare several substrates. This would be of par-
ticular use for contemporary methodologies of which little in-
formation is available. To investigate the feasibility of this ap-
proach and to challenge our developed methodology, we
sought to apply this screen to an unrelated synthetic reaction.
We selected the recently reported C-3 arylation of thiophenes
with aryliodonium salts using Pd/C as the catalyst
(Scheme 3).[2h,6]
Conclusion
We have developed a rapid, yet extensive screen, for the evalu-
ation of the stability of PGs to reaction conditions. We have
shown that a single experiment is sufficient to evaluate numer-
ous PGs, and determine suitable PGs for a given reaction. Eval-
uation of the screen by preparation and reaction of PG-con-
taining substrates was undertaken, with the results correlating
very well with those obtained in the screen. Finally, this meth-
odology was applied to an unrelated reaction, demonstrating
a direct application of this methodology and providing signifi-
cant additional validation of this method. We envisage the ap-
plication of this technique for the selection of PGs in real syn-
thetic problems, and therefore believe this protocol is of signif-
icant value to the synthetic community. An extension of this
method for the evaluation of other PGs, and applications in
determining the relative rates of PG cleavage, can be readily
envisaged.
Scheme 3. Pd/C-mediated arylation of thiophenes with aryliodonium salts.
We investigated which PGs would be suitable for the protec-
tion of the primary alcohol and amine of thiophenes 13 and
16, respectively. Compound 16 has previously been shown to
be unreactive under the standard reaction conditions, and we
proposed that this screen would enable the rapid determina-
tion of a suitable PG, enabling reaction of this previously inert
functionalized heterocycle. To determine a suitable silyl PG for
13, we undertook a one-pot evaluation of the silyl-protected
primary alcohols 4a–c by using the standard reaction, as de-
picted in Scheme 3.
Experimental Section
Procedure for individual evaluation of silylated alcohols:
Pyrazole synthesis
Unfortunately, all three silyl PGs proved completely labile
under the reaction conditions and, therefore, would not be
suitable for this reaction. To validate this we prepared sub-
strates 14a and 14b and subjected them to the reaction con-
ditions. In complete agreement with the screen, arylated prod-
ucts 15a and 15b were not detected, nor were there any start-
A solution of 1 (573 mg, 15ꢂ0.200 mmol, one equivalent) in DMF
(3.0 mL) was prepared and distributed to thirteen flame-dried reac-
tion vessels by using a 250 mL microsyringe (230 mL per reaction,
ꢁ0.200 mmol). Sequentially, one silylated alcohol (0.200 mmol, one
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[1] a) H. Kunz, H. Waldmann, Protecting Groups in Comprehensive Organic
Synthesis Vol. 6, (Ed.: B. M. Trost), Pergamon Press, Oxford, 1991,
pp. 631–701; b) P. J. Kocienski, Protecting Groups, 3rd ed., Georg Thieme
Verlag, New York, 2005; c) T. W. Greene, P. G. M. Wuts, Protective Groups
In Organic Synthesis, 3rd ed., John Wiley & Sons, New York, 1991; For
a relevant comment on protecting-group-free syntheses, see: d) R. W.
Hoffmann, Synthesis 2006, 3531; e) I. S. Young, P. S. Baran, Nat. Chem.
2009, 1, 193; f) E. Roulland, Angew. Chem. 2011, 123, 1260; Angew. Chem.
Int. Ed. 2011, 50, 1226.
equivalent), benzonitrile 2 (62 mL, 0.600 mmol, three equivalents),
and Cu(OAc)2 (54 mg, 0.300 mmol, 1.5 equivalents) were added to
each reaction vessel. Reaction vessels were sealed and heated at
110 8C for 24 h. After cooling, mesitylene (28 mL, 0.200 mmol, one
equivalent) was added to each reaction, and the reaction analyzed
by GC chromatography (GC method 1, see the Supporting Informa-
tion). The ratios of the reaction product 3 and the protected alco-
hol relative to the standard were determined and the yields of
each calculated.
[2] a) K. D. Collins, F. Glorius, Nat. Chem. 2013, 5, 597; b) K. D. Collins, F. Glo-
rius, Tetrahedron 2013, 69, 7817; c) I. Churcher, Nat. Chem. 2013, 5, 554;
For first applications, see: d) N. Kuhl, N. Schrçder, F. Glorius, Org. Lett.
2013, 15, 3860; e) H. Wang, B. Beiring, D.-G. Yu, K. D. Collins, F. Glorius,
Angew. Chem. 2013, 125, 12657; Angew. Chem. Int. Ed. 2013, 52, 12430;
f) H. G. Lee, P. J. Milner, S. L. Buchwald, Org. Lett. 2013, 15, 5602; g) S. C.
Cullen, S. Shekhar, N. K. Nere, J. Org. Chem. 2013, 78, 12194; h) D.-T. D.
Tang, K. D. Collins, J. B. Ernst, F. Glorius, Angew. Chem. Int. Ed. 2014, DOI:
10.1002/anie.201309305; For related studies, see: i) D. W. Stephan, S.
Greenberg, T. W. Graham, P. Chase, J. J. Hastie, S. J. Geier, J. M. Farrell,
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Pohl, M. Suri, F. Glorius, D. Schrçder, Organometallics 2013, 32, 807–816.
[4] Phase separation of the additive and solvent can be observed.
[5] Total yield=47%; [yield 12b (25%)/total yield (47%)] ꢂ 100=PG stability
(53%).
[6] For related transformations, see: a) D.-T. D. Tang, K. D. Collins, F. Glorius,
J. Am. Chem. Soc. 2013, 135, 7450; b) K. Ueda, S. Yanagisawa, J. Yamagu-
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Procedure for one-pot evaluation of silylated alcohols: Pyra-
zole synthesis
Sequentially, 0.100 mmol of each silylated alcohol 4–7 (12ꢂ
0.100 mmol=1.20 mmol, one equivalent in total), benzonitrile 2
(372 mL, 3.60 mmol, three equivalents), and Cu(OAc)2 (324 mg,
1.80 mmol, 1.5 equivalents), in this order, were added to
1 (229 mg, 12ꢂ0.100 mmol, one equivalent) in DMF (1.2 mL). The
reaction vessel was then sealed and heated at 1108C for 24 h. After
cooling, mesitylene (168 mL, 1.20 mmol, one equivalent) was added
and the reaction analyzed by GC chromatography (method 1). The
ratios of the reaction product, 3, and the protected alcohol, relative
to the standard were determined and the yields of each calculated.
Procedure for one-pot evaluation of silylated alcohols: Thio-
phene arylation
Diphenyliodonium tetrafluoroborate (155 mg, 0.420 mmol, 1.4
equivalents) was added to a solution of 2-butylthiophene (44 mL,
0.300 mmol, one equivalent), Pd/C (5 wt% Pd/C, 32 mg,
0.015 mmol, 5 mol%), and silylated alcohols 4a, 4b, and 4c
(0.100 mmol each, one equivalent in total) in EtOH (1.5 mL) and
the reaction heated at 608C for 22 h. After cooling, mesitylene
(28 mL, 0.200 mmol, two equivalents) was added to the reaction
mixture and the reaction analyzed by GC chromatography
(method 1).
Protocols for the acetals and protected amines are identical, with
the exception that the protected amines are analyzed by using
HPLC and employing triisopropylbenzene as an internal standard.
Acknowledgements
Generous financial support from the Deutsche Forschungsge-
meinschaft (DFG, Leibniz award) is gratefully acknowledged.
We greatly thank Karin Gottschalk for experimental support.
[7] The stability of the Cbz PG was also assessed simultaneously, though
overlap of 10b and reaction by-product in the HPLC trace prevented de-
termination of its stability. HPLC method optimization would address
this issue.
Keywords: arylation
·
heterocycles
·
high-throughput
Received: November 18, 2013
screening · protecting groups · robustness screen
Published online on February 19, 2014
Chem. Eur. J. 2014, 20, 3800 – 3805
www.chemeurj.org
3805
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim