Enantiospecific Brook Rearrangement of Tertiary Benzylic α-Hydroxysilanes

Article abstract of DOI:10.1002/ejoc.201701469

The Brook rearrangement of simple, chiral tertiary benzylic α-hydroxysilanes is presented. The rearrangement followed by proton trapping is enantiospecific and proceeds with inversion of the configuration at the carbon center. Importantly, the [1,2]-Brook

Full text of DOI:10.1002/ejoc.201701469

DOI: 10.1002/ejoc.201701469
Communication
Brook Rearrangement
Enantiospecific Brook Rearrangement of Tertiary Benzylic α-
Hydroxysilanes
Juan F. Collados,[a][‡] Pablo Ortiz,[a][‡] Juana M. Pérez,[a] Yiyin Xia,[b] Mark A. J. Koenis,[b]
Wybren J. Buma,[b] Valentin P. Nicu,[b,c] and Syuzanna R. Harutyunyan*[a]
Abstract: The Brook rearrangement of simple, chiral tertiary the [1,2]-Brook rearrangement can be followed by trapping of
benzylic α-hydroxysilanes is presented. The rearrangement fol- methyl or allyl electrophiles even in the protic environment,
lowed by proton trapping is enantiospecific and proceeds with although with minimal retention of chirality.
inversion of the configuration at the carbon center. Importantly,
Introduction
reported examples of the rearrangement of secondary benzylic
α-hydroxysilanes including the stereochemistry of the process.
Brook et al. used a chiral silicon whereas Mosher et al. used
chiral deuterated α-hydroxysilanes, but both reported that the
rearrangement proceeded with inversion of configuration at the
carbon center (Scheme 2a).[5b] Shortly after, West et al. showed
that the reverse rearrangement, the migration of silicon from
oxygen to carbon, is also stereospecific and proceeds with in-
version of configuration.[7] Stereospecific Brook rearrangement
was also reported for tertiary α-hydroxysilanes with aliphatic six
member cyclic structures.[8] In these examples the stereospeci-
ficity of the rearrangement was rationalized by kinetic equato-
rial protonation of the anionic intermediate owing to the cyclic
structure of the corresponding α-hydroxysilanes.
Since its discovery, the [1,2]-Brook rearrangement, defined as
the reversible transformation from α-silyl oxyanions to α-silyl-
oxy carbanions (Scheme 1),[1] has attracted considerable atten-
tion, both regarding the mechanism and its implementation in
organic synthesis.[2] Recently, Marek et al. and our group inde-
pendently reported the stereoselective [1,2]-Brook rearrange-
ment-trapping sequence of allylic hydroxysilanes.[3] The pres-
ence of either an allyl or alkenyl group in the hydroxysilane is
a common feature in enantiospecific variants of the [1,2]-Brook
rearrangement because of the enhanced configurational stabil-
ity of the carbanion after migration of the metal to the beta
carbon.[3,4] Another interesting reaction sequence involving
stereoselective Brook rearrangement/acylation sequence was
reported by Johnson et al.[5] Conversely, α-hydroxysilanes lack-
ing configuration stabilizing groups have been less explored in
the [1,2]-Brook rearrangement.
Scheme 1. General [1,2]-Brook rearrangement.
Following the initial discovery of the Brook rearrangement
both Brook and co-workers[6a] and Mosher and co-workers[6b]
Scheme 2. a) [1,2]-Brook rearrangement of deuterated secondary benzylic
α-hydroxysilanes reported by Mosher.[6b] b) Enantiospecific [1,2]-Brook rear-
rangement of tertiary benzylic α-hydroxysilanes.
[a] Stratingh Institute for Chemistry, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
E-mail: s.harutyunyan@rug.nl
http://sr-harutyunyan.com/
[b] Van′t Hoff Institute for Molecular Sciences, University of Amsterdam,
Science Park 904, 1090 GD Amsterdam, The Netherlands
[c] Faculty of Agricultural Sciences, Food Industry and Environmental
Protection,
Lucian Blaga University of Sibiu, Ioan Ratiu Street, 550012 Sibiu, Romania
[‡] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701469.
Recently we developed catalytic asymmetric addition of Gri-
gnard reagents to acylsilanes, which for the first time allows
access to enantioenriched chiral tertiary benzylic α-hydroxysil-
anes.[9] Here we report our findings on Brook rearrangements
of these tertiary benzylic α-hydroxysilanes and the stereochem-
istry of the process (Scheme 2b).
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Results and Discussion
the equilibrium is determined by the relative stabilities of the
charged species, namely the alkoxide and the carbanion
(Scheme 1).[2a]
We started investigating the reaction of benzyl α-hydroxysilane
1a[9] (90 % ee) with a variety of metal bases that could trigger
the Brook rearrangement. A mixture of 1a and the correspond-
ing base (1 equiv.) was stirred overnight in THF at room temper-
ature and then quenched and analyzed by 1H NMR spectro-
scopy. Et2Zn, which initiated the Brook rearrangement for allylic
hydroxysilanes[3] did not work for the benzylic counterpart and
deprotonation with MeMgBr did not trigger the rearrangement
either. In both cases, forcing of the reaction conditions by a
light warm up resulted in decomposition products. In contrast,
in the presence of a lithium base (LiOtBu), Brook rearrangement
did take place and the corresponding product 2a was obtained
with full conversion. Alcohol 3a was then cleanly obtained after
desilylation with TBAF (Table 1, entry 1) with an ee of 40 %.
Subsequently we studied the influence of the different reaction
parameters on the stereospecificity of the process (Table 1). The
first experiment had been carried out with one equivalent of
LiOtBu. However, since it is known that even catalytic amounts
of a base can trigger the Brook rearrangement,[1,2a] we tried to
reduce the amount of LiOtBu. With 0.5 equivalents of base the
outcome was the same as with 1 equiv. but, interestingly, from
that point on, decreasing the amount of base resulted in an
increase of the ee of the product. With 20 % of LiOtBu the enan-
tioselectivity rose to 75 % and with 5 % of base the product
was obtained with nearly full transfer of chirality (entries 2–4).
Only with 1 % of LiOtBu no Brook rearrangement took place
(entry 5).
We then studied the effect of the temperature on the reac-
tion. No reaction took place at –78 °C, but adding the base at
–78 °C and letting it slowly warm up to room temperature
yielded the product in 88 % ee (entry 6). The Brook rearrange-
ment was also observed at –50 °C, yielding the product in
slightly lower ee (73 %), and at 0 °C, giving results that approach
those at room temperature (entry 8). These results clearly indi-
cate that there is no particular dependence of the enantio-
selectivity of the process on the temperature, but that, as ex-
pected, longer reaction times are required to reach full conver-
sion at low temperature (3 h at room temp. vs. overnight at
–50 °C). Finally we examined the role of the metal base under
catalytic conditions (entries 9–13). In line with the initial experi-
ments described above, no Brook rearrangement took place us-
ing MeMgBr or Et2Zn as a base, while Me3Al also did not trigger
the rearrangement. Interestingly, with KOtBu full conversion to
2a was observed and lithium naphthoxide triggered the Brook
rearrangement too. From these results it can be concluded that
only alkali metals trigger the Brook rearrangement. This is fur-
ther supported by the observation that NaH can start the proc-
ess as well (not shown in the Table). Alkoxides formed from
alkali metals are expected to be less stable than those derived
from Mg, Zn or Al, which could be the reason for the rearrange-
ment taking place.
With the aim of studying the electronic effects in the carbon
and the influence of the silicon center in the stereospecificity
of the rearrangement we conducted further experiments. First
we synthesized several structural analogues of the standard
hydroxysilane 1a and subjected them to the Brook rearrange-
ment (Table 2). Products 2b–e were obtained after overnight
reactions. The enantioselectivities of the deprotected products
3b–e were slightly lower than the original values for the start-
ing silylated alcohols 1b–e. Both substrates 1b and 1c, with
electron withdrawing and donating groups, respectively, had
the same loss of 12 percentage points of ee (entries 2–3). This
Table 1. Conditions screening for the enantiospecific Brook rearrangement.[a]
Entry
Metal base (equiv.) Temp. [°C]
Conv. [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
LiOtBu (100 %)
LiOtBu (50 %)
LiOtBu (20 %)
LiOtBu (5 %)
LiOtBu (1 %)
LiOtBu (5 %)
LiOtBu (5 %)
LiOtBu (5 %)
MeMgBr (5 %)
Et2Zn (5 %)
r.t.
r.t.
r.t.
r.t.
r.t.
–78 to r.t.
–50
0
r.t.
r.t.
r.t.
r.t.
100
100
100
100
0
100
100
100
0
0
0
100
80
40
40
75
88
–
88
73
80
–
–
–
80
84
Table 2. Influence of the substrate substituents on the Brook rearrange-
ment.[a]
9
10
11
12
13
Me3Al (5 %)
KOtBu (5 %)
Li napthoxide (5 %) r.t.
Entry
Substrate, ee [%]
R
Si moiety
Product, ee [%][b]
1
2
3
1a, 90
1b, 85
1c, 92
1c, 92
1d, 24
1e, 75
H
F
tBu
tBu
OMe
H
SiPh2Me
SiPh2Me
SiPh2Me
SiPh2Me
SiPh2Me
SiPhMe2
3a, 80–88
3b, 73
3c, 81
[a] Reaction conditions: 0.1 mmol of 1a, 1 mL of THF and base. Stirred for 3–
24 h. Deprotected using TBAF (tetrabutyl ammonium fluoride). [b] Deter-
mined by 1H NMR spectroscopy. [c] Enantiomeric excess was determined by
chiral HPLC.
4[c]
5
3c, 85
3d, 24[d]
3a, 60
6
[a] Reaction conditions: 0.1 mmol of 1, 1 mL of THF, 5 mol-% of LiOtBu.
Stirred for 3 h to 24 h depending on the substrate. The intermediate silyl
ether was deprotected using TBAF (tetrabutyl ammonium fluoride). [b] Enan-
tiomeric excess was determined by chiral HPLC. [c] The reaction was stopped
and analyzed after 20 % conversion. [d] 80 % yield in Brook rearrangement
after overnight reaction.
This behavior can be rationalized on the basis of different
equilibria controlling the reactions under catalytic or stoichio-
metric conditions. It is known that with catalytic amounts of
base the equilibrium depends on the relative stabilities of the
neutral hydroxysilane and silyl ether, while with excess of base
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indicates that electronics play a minimal role in the transfer of
chirality during the rearrangement step. This is corroborated by
entry 5, where methoxy, a very strong electron donating group,
was used and the same enantioselectivity was obtained after
the rearrangement.
Similarly, the substitution at the silicon atom does not seem
to affect the stereochemical outcome of the Brook rearrange-
ment either, as the loss of chirality with compound 1e corre-
sponds to 15 % ee, comparable to the other results (entry 6).
To investigate if the ee changes as the reaction progresses, an
experiment using substrate 1c was carried out, quenching the
reaction after 5 h, with a 20 % of conversion to the product 2c.
An increased enantioselectivity of 85 % observed in this case
(compared to 81 % ee at full conversion, entry 3) might be re-
lated to the amount of base with respect to substrate. At con-
versions higher than 75 % the amount of base with respect to
the remaining substrate resembles the same situation as in en-
tries 1–4 in Table 1, where the increased amount of base causes
a decrease in enantioselectivity. Therefore it is likely that the
last 20 % of the substrate is converted into the product with
lower enantioselectivity, thus leading to an overall decrease in
enantioselectivity at full conversion.
Original [1,2] Brook rearrangement of secondary benzylic α-
hydroxysilanes has been reported to proceed with inversion of
configuration.[6b] In order to see if this holds true for the tertiary
counterparts we determined the absolute configuration of the
starting material 1a and that of the product 3a. The latter was
determined to be S by comparison with the reported optical
rotation.[10] Vibrational Circular Dichroism (VCD) was used for
determining the absolute configuration of the starting material
1a (for further details see Supporting Information).[11] We meas-
ured the VCD spectra of both hydroxysilane 1a and ent-1a (Fig-
ure 1) and found that the first fitted well with the calculated
spectra for the S enantiomer (Figure 2). We thus conclude that
the Brook rearrangement of tertiary benzylic α-hydroxysilanes
proceeds with inversion of configuration.
Figure 2. Experimental and calculated IR and VCD spectra of compound 1a.
We tested several electrophiles, including acyl chlorides, al-
dehydes, alkyl halides and Michael acceptors, but only methyl
iodide and allyl bromide led to the corresponding trapping
products 4, which were racemic (Scheme 3). Variable amounts
of protonated product 3a were also obtained in these reactions,
due to the competition with protonation. When the presence
of protons in the media was avoided by using nBuLi instead
of LiOtBu, full conversion to the trapping products 4a–b was
achieved, but the product was again racemic. This can be ra-
tionalized on the basis that carbanions without any stabilizing
substituents will racemize very fast. Consequently, we thought
of configurationally stabilizing the carbanion using an external
Lewis base that can coordinate both with silicon and lithium
atoms. DMF, HMPA and TMEDA were tried for this purpose but
unfortunately the ee did not surpass 8 % (Scheme 3).
Scheme 3. Brook rearrangement/trapping of carbon electrophiles tandem at-
tempts.
Most reports on [1,2]-Brook rearrangement do not propose
a mechanism to explain the stereochemical outcome. For sec-
ondary benzylic α-hydroxysilanes we distinguish three possible
scenarios:[6b] 1) fast protonation of the carbanion before flip-
ping takes place; 2) transfer of the proton from the solvated
base to the carbon in the pentacoordinate intermediate; 3)
transfer of the proton from the base coordinated to the oxygen
to the carbon in the pentacoordinate intermediate.
Our results seem to suggest the third scenario. We therefore
propose a mechanism in which LiOtBu deprotonates the hy-
droxysilane 1a, followed by the attack of oxygen to the silicon
and formation of the pentacoordinate intermediate. We believe
that at this stage the proton is trapped directly from the penta-
coordinate silicon intermediate, as it is in the vicinity thanks to
Figure 1. Measured VCD spectra of compounds 1a and ent-1a.
The Brook rearrangement, followed by trapping of carbon the coordination of the tBuOH to the lithium (Scheme 4). Sup-
electrophiles, is a powerful strategy for C–C bond formation.[2] port for the intramolecular mechanism was gained when the
However, as mentioned in the introduction, the stereoselective deprotonation/Brook rearrangement was carried out with nBuLi
variants require allyl systems, configurationally stable allenyl and the reaction was warmed up before adding the proton
species, or the presence of a coordinating group such as source. In this case the corresponding protonated product was
carbamoyl to configurationally stabilize the carbanion.
formed, but completely racemic. The proposed concerted
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Communication
mechanism would explain the enantiospecificity of the reaction of Education, Culture and Science (Gravity program 024.001.035
in the case of trapping of protons and the loss of it for external to S. R. H.) is acknowledged. J. M. P. thanks to the European
electrophiles. In the latter case the pentacoordinate silicon in- Commission for an Intra-European Marie Curie fellowship (grant
termediate would evolve to the chiral carbanion which would 746011 - ChirPyr). This research received further support from
quickly racemize and thus the product of the trapping would NWO in the framework of the Fund New Chemical Innovations
lose the enantioenrichment (Scheme 4).[6b]
(NWO Project Nr. 731.014.209).
Keywords: Synthetic methods · Rearrangement ·
Hydroxysilanes · Enantiospecific · Chirality
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Wuest, Chem. Commun. 2008, 5883–5895; c) G. Eppe, D. Didier, I. Marek,
Chem. Rev. 2015, 115, 9175–9206.
[3] a) M. Leibeling, K. A. Shurrush, V. Werner, L. Perrin, I. Marek, Angew. Chem.
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dos, P. Ortiz, S. R. Harutyunyan, Eur. J. Org. Chem. 2016, 2016, 3065–3069.
[4] a) M. Sasaki, Y. Kondo, M. Kawahata, K. Yamaguchi, K. Takeda, Angew.
Chem. Int. Ed. 2011, 50, 6375–6378; Angew. Chem. 2011, 123, 6499; b) P.
Smirnov, J. Mathew, A. Nijs, E. Katan, M. Karni, C. Bolm, Y. Apeloig, I.
Marek, Angew. Chem. Int. Ed. 2013, 52, 13717–13721; Angew. Chem.
2013, 125, 13962.
Scheme 4. Proposed mechanism for the stereospecific protonation of tertiary
benzylic α-hydroxysilane 1a.
Conclusions
[5] a) D. A. Nicewicz, C. M. Yates, J. S. Johnson, Angew. Chem. Int. Ed. 2004,
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3081.
In summary, we have explored the Brook rearrangement of sim-
ple, chiral tertiary benzylic α-hydroxysilanes. We have demon-
strated that the rearrangement followed by proton trapping is
enantiospecific and proceeds with inversion of the configura-
tion at the carbon center analogously to their secondary coun-
terparts. Moreover, we have found that a catalytic amount of
base is not only sufficient, but beneficial for the enantiospecific-
ity of the process. Importantly, the [1,2]-Brook rearrangement
can be followed by trapping of methyl or allyl electrophiles
even in a protic environment, however, in all cases with minimal
retention of chirality.
[10] M. Bandini, A. Bottoni, P. G. Cozzi, G. P. Miscione, M. Monari, R. Pierciac-
cante, A. Umani-Ronchi, Eur. J. Org. Chem. 2006, 4596–4608.
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699–723.
Acknowledgments
Financial support from The Netherlands Organization for Scien-
tific Research (NWO-Vidi and ECHO to S. R. H.) and the Ministry
Received: October 20, 2017
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Communication
Brook Rearrangement
J. F. Collados, P. Ortiz, J. M. Pérez,
Y. Xia, M. A. J. Koenis, W. J. Buma,
V. P. Nicu, S. R. Harutyunyan* ........ 1–5
Enantiospecific Brook Rearrange-
ment of Tertiary Benzylic α-
Hydroxysilanes
Chiral tertiary benzylic α-hydroxysil- enantiospecific and proceeds with in-
anes, upon treatment with LiOtBu, un- version of the configuration.
dergo Brook rearrangement, which is
DOI: 10.1002/ejoc.201701469
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