Strategic Trimethylsilyldiazomethane Insertion into pinB-SR Followed by Selective Alkylations

Article abstract of DOI:10.1021/acs.orglett.6b01840

The insertion of the diazo derivative Me₃SiCHN₂ into pinB-SR σ bonds (R = Ph, Tol, Bn) allows a direct synthesis of multisubstituted H-C(SR)(Bpin)(SiMe₃) compounds. Consecutive base-assisted transformations of HC(S)(B) (Si

Full text of DOI:10.1021/acs.orglett.6b01840

Letter
pubs.acs.org/OrgLett
Strategic Trimethylsilyldiazomethane Insertion into pinB−SR
Followed by Selective Alkylations
Marc G. Civit,† Jordi Royes,† Christopher M. Vogels,‡ Stephen A. Westcott,*,‡ Ana B. Cuenca,*,†
and Elena Fernandez*,†
́
†Department Química Física i Inorgan
̀
ica University Rovira i Virgili, C/Marcel·lí Domingo s/n, Tarragona 43007, Spain
‡Department of Chemistry and Biochemistry, Mount Allison University, Sackville, New Brunswick E4L 1G8, Canada
S
* Supporting Information
ABSTRACT: The insertion of the diazo derivative
Me3SiCHN2 into pinB−SR σ bonds (R = Ph, Tol, Bn) allows
a direct synthesis of multisubstituted H−C(SR)(Bpin)(SiMe3)
compounds. Consecutive base-assisted transformations of
HC(S)(B) (Si) systems lead to deborylative alkylations,
Sommelet−Hauser rearrangements, and deprotoalkylations.
̈
Intramolecular cyclizations can be selectively performed either
via desilylative or deborylative manifolds by fine-tuning the
base employed.
Scheme 1. Strategic Trimethylsilyldiazomethane Insertion
into pinB-SR, Followed by Selective Alkylation Methods
Carried out in This Work
mong the transformations based on the insertion of diazo
1
Aderivatives into a σ bond of interelement species, the use of
boron-containing reagents affords a valuable synthetic strategy
toward the preparation of unprecedented organoboranes. In
particular, the B−H, B−Cl, and B−C species have become
suitable reagents for metal-catalyzed or uncatalyzed α,α-
substitution of diazo compounds.2,3 Amid the diazo compound
derivatives, trimethylsilyldiazomethane (Me3SiCHN2) appears
also as a convenient reagent, since upon insertion, the α-SiMe3
functional unit is introduced.4−6 The insertion of diazo
compounds into B−B bonds has been successfully developed
through Pt-catalyzed reactions, opening a new strategy toward
1,1-diboration protocols.7
The in situ generation of nonstabilized diazo compounds by
thermal decomposition of N-tosylhydrazone salts has become an
alternative method to promote the metal-free insertion of
diazoalkanes into H−Bpin (Bpin = pinacolboryl), Me2PhSi−
Bpin, and pinB−Bpin.8 In the last year, our group developed the
insertions of nonstabilized diazo compound into the σ B−B bond
of the nonsymmetric diboron reagent pinB−Bdan (Bdan = 1,8-
naphthalenediaminoboryl).9
With all these precedents in mind, we became interested in
developing a method for the insertion of the diazo compound
Me3SiCHN2 into B−S bonds to promote a direct synthesis of
main group, multisubstituted sp3 carbons (Si, B, S). We envisage
that these compounds could help to increase structurally diverse
molecules of synthetic potential since subsequent base-mediated
catalyzed dehydrogenative borylation of PhSH with 1 equiv of the
borane H−Bpin, at room temperature).10 Through initial
experiments, it was found that an excess of the diazo compound
(diazo/borane = 2/1) was beneficial for the reaction completion.
The insertion reaction proved amenable to gram scale just by
stirring a mixture of 2 M hexane solution of the Me3SiCHN2 and
the borane at 50 °C for 6 h. Under these conditions, 94% of 2a can
beisolated(Scheme2). Followingthesamemethod, theinsertion
of Me3SiCHN2 was extended to TolS−Bpin (1b) and BnS−Bpin
(1c). Thesereactionsgaverisetosimilarhighisolatedyieldsofthe
corresponding 2b and 2c, although 70 °C and 16 h were required
(Scheme 2).
functionalizations via deborylative alkylation, Sommelet−Hauser
̈
The mechanism of the insertion of the diazo reagent into the
interelement B−S σ bond, might be understood as an initial
interaction of the nucleophilic diazo carbon to the electron
rearrangement, and deprotoalkylation can be developed.
Selective intramolecular deborylative or desilylative cyclizations
are also reported here (Scheme 1).
To verify experimentally the above hypothesis, we started the
study by exploring the insertion of the commercially available
Me3SiCHN2 into PhS−Bpin (1a) (which was prepared by Rh-
Received: June 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01840
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Letter
Scheme 2. Optimized Reaction Conditions for the Metal-Free
Insertion of Me3SiCHN2 into PhS−Bpin, TolS−Bpin, and
BnS−Bpin
Table 1. Substrate Scope of Deborylative Alkylation of
Derivatives 2 via SN2 Pathway
a
deficient boron of the Bpin moiety, followed by the 1,2-migration
of the adjacent SR moiety to yield the α,α-substitued product and
the concomitant release of dinitrogen (Scheme 3). A similar
Scheme 3. Suggested Mechanism for the Insertion of
Me3SiCHN2 into RS−Bpin
mechanism was already postulated by DFT calculations using
pinB−Bpin or pinB−Bdan and CH3CHN2 as the model
diazoalkane, suggesting a concerted, yet asynchronous mecha-
nism.9
The Lewis acidity of the Bpin moiety in the RS−Bpin reagents
seems to be responsible for the insertion reaction but also it might
induce a deborylative alkylation sequence from products 2a−c. If
successful, this two-step sequence would constitute an
unprecedented protocol for the synthesis of α-silyl sulfides.
With the aim of carrying out the first attempt toward the
deborylative alkylation, we selected product 2a as the substrate
and nC14H29Br as the alkylating reagent. The presence of a base
such as NaOtBu was required to promote the alkoxide-induced
deborylation, as described for the generation of α-boryl
carbanions from geminal (bis)boronates.11,12 The reaction
conditions entail the mixing of 1 equiv of nC14H29Br with an
excess of 2a (1.3 equiv) in THF. An excess of 2a versus the alkyl
halide was used to discard any plausible decomposition along the
reaction. Within 3 h, at room temperature, the α-silyl sulfide 3a
was observed in 84% yield (Table 1, entry 1). Longer reaction
times did not provide any higher conversions. Very similar
behavior was observed when 2b reacted with nC14H29Br to isolate
3b in 68% yield (Table 1, entry 2).
Next, we conducted the deborylative alkylation of 2a with 1-
bromobutane. In this case, a 69% yield of the α-silyl sulfide
product was isolated (Table 1, entry 3). When we explored the
alkylation reaction of 2b with nC4H9X (X = I, Br, Cl) we observed
that 1-iodo- and 1-bromobutane reacted faster (64% and 83%,
respectively), while the corresponding chloro derivative was only
converted into the desired product in 19%. Hence, compound 2b
reacted with nC4H9I to give the higher conversion on 4b, 80%
isolated yield (Table 1, entry 4). The superior leaving group
ability of a Br in the presence of chloro- or fluoroalkanes was
exploited in the deborylative alkylation using Br(CH2)4F and
Br(CH2)4Cl. In both cases, the formation of a new C−C bond
a
Reaction conditions: R−X (0.077 mmol), HC(Bpin)(SiMe3)(SR)
b
(1.3 equiv), NaOtBu (4 equiv), THF (0.5 mL), at rt for 3 h. Yields
were determined by H NMR analysis of the crude reaction mixture
with 1,4-dinitrobenzene or naphthalene as an internal standard, which
was added after the reaction.
1
took place selectively at the C−Br site, leaving the C−F and the
C−Cl bonds intact (Table 1, entries 5−8). However, SN2-type
alkylation of the more activated cinnamyl chloride was easily
performed to form 7a and 7b (Table 1, entries 9 and 10). In this
case, the SN2reaction of less reactive C−Clis encouraged because
the double bond stabilization in the transition state. In agreement
with the last result, the deborylative alkylation of other reactive
allylic systems was carried out to form α-silyl sulfides 8a and 8b in
relatively high conversions (Table 1, entries 11 and 12). Similar
values were observed for the deborylative alkylation of benzyl
bromide, providing compounds 9a and 9b, up to 75% and 79%
isolated yield, respectively (Table 1, entries 13 and 14). The
compatibility of other functional groups with respect to the base-
mediated deborylative alkylation was demonstrated with
substrates containing double and triple bonds. In these cases,
the corresponding products 10a,b and 11a,b were nicely formed
without any effect to the unsaturated bonds (Table 1, entries 15−
18). Even more notable is the example where the substrate
featuring an epoxide ring resulted in an alkylated product where
theepoxidefunctionalgroupremainedunaltered(Table1,entries
19 and 20). We also conducted deborylative alkylation with
secondary alkyl halides, and remarkably, we were able to isolate
B
DOI: 10.1021/acs.orglett.6b01840
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Letter
the corresponding geminal thiosilane products 13a (R = Ph) and
13b (R = Tol) in acceptable yields (Table 1, entries 21 and 22).
The use of more sterically hindered secondary alkyl electrophiles,
suchas iBu-I, can alsobe used. Interestingly, compound 14a could
also be isolated from the reaction media, demonstrating the
generality of the substrate scope, even for the most challenging
electronic and steric secondary alkyl halides (Table 1, entry 23).
The reaction of 2c with nC14H29Br as electrophile and NaOtBu
as base, proved to be more sluggish, affording mainly a
constitutional isomer of the expected α-silyl sulfide. The new
compoundwasidentifiedasA(Scheme4)anditsformationcould
Table 2. Substrate Scope of Deprotonation−Alkylation of
a
Derivatives 2 via SN2 Pathway
Scheme 4. Deborylative Alkylation of 2c with NaOtBu and
NaOMe; Desilylation of 2a−c with TBAF (% NMR Yields, [%
Isolated Yields])
be explained as a result of a Sommelet−Hauser rearrangement,
̈
(an intramolecular [2,3]-sigmatropic rearrangement of a
sulfonium salt to ortho-substituted benzyl sulfides by means of
the treatment with a strong base).13 This product was formed
along with relative percentages of the expected alkylation sulfide
(20%) and the protodeborylated product (11%, B); however, the
similar polarity of the last two species hampered the proper
isolation from the reaction mixture. The product A is most likely
arising from substrate 2c and not by the intermediacy of
protodeborylated species B,14 since a blank experiment from B
carried out under the same reaction conditions, did not lead to
product A. Unfortunately, all attempts to maximize the
production of A have been unsuccessful.
Interestingly, the nature of the base demonstrated to be of
crucial importance in these reactions, since only protodeborated
compound B was principally formed (88% NMR yield and 60%
isolated yield) when the reaction was performed with NaOMe
instead of NaOtBu. Notably, when we exposed the substrate 2c to
a fluoride base (TBAF) and nC14H29Br as the model alkylating
reagent, within 1.5 h at room temperature, the desilylated product
C was the only product observed (85% NMR yield), neither
alkylation15 or rearrangement were detected (Scheme 4). The
same reaction outcome was observed in the absence of the
electrophilenC14H29Br, andtheyieldwasthesame. Suchbehavior
seems to indicate a higher ability of the fluoride base to induce the
selective functionalization of the Me3Si group in the presence of
the Bpin moiety.16 This reactivity was extended to the
multisubstituted systems 2a and 2b to produce Ca and Cb in
high isolated yields (Scheme 4, right).
a
Reaction conditions: 2 (0.2 mmol, 1 equiv), R−X (0.24 mmol, 1.2
b
equiv), LTMP (0.21 mmol, 1.05 equiv), THF, t = 2 h. Yields were
determined by 1H NMR with 1,4-dinitrobenzene or naphthalene as an
c
internal standard. R-X (0.1 mmol, 1 equiv), 2a (0.2 mmol, 2 equiv),
d
NaOtBu (0.3 mmol, 3 equiv), toluene, 50 °C, t = 24 h. 2b (0.15
mmol, 1 equiv), R−X (0.19 mmol, 1.3 equiv), LTMP (0.18 mmol, 1.2
e
equiv), THF, t = 3 h. 2b (0.3 mmol, 1 equiv), R−X (0.52 mmol, 1.75
equiv), LTMP (0.35 mmol, 1.2 equiv), THF, t = 6 h.
place in the presence of an alkoxy base, in place of the commonly
employed strong alkyl or amide lithium bases.17 However, only
when we used lithium 2,2,6,6-tetramethylpiperazide (LTMP),18
compound 15a was formed in up to 70% isolated yield (Table 2,
entry 2). The reaction of cinnamyl chloride and 2b also provided
the product 15b in 73% isolated yield (Table 2, entry 3). We
extended the use of 2b for further SN2 deprotoalkylations. The
reaction proved feasible with a series of substrates featuring allylic
and benzylic systems, albeit in moderate yields (Table 2, entries
4−6). The alkylation is also compatible with the presence of a
monosubstituted terminal double bond (Table 2, entry 7).
Noteworthy is the use of more hindered secondary alkyl halides.
In this case, the alkylation took place in anon-negligible 43% yield
(Table 2, entry 9). With these encouraging results, we turned our
attention to the use of dibromo and diiodo alkyl derivatives.11 To
prevent the incorporation of 2 equiv of the reagent 2, a higher
excess (1.75 equiv) of the electrophile was employed. The
reaction proved to be quite efficient with those challenging
Next, we turned our attention to the SN2 alkylations that
involve α-boron and α-silyl-stabilized carbanions generated
through deprotonation of the alkyl boronate esters 2.
Interestingly, the reaction between cinnamyl chloride and 2a (2
equiv) in the presence of NaOtBu (3 equiv) in toluene at 50 °C
produced exclusively compound 15a that was isolated in 42%
(Table2, entry1). Asfarasweareaware, thisisthefirstexampleof
this type of α-boryl deprotonation/alkylation reactions taking
C
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Letter
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(14) See the Supporting Information for details.
(15) Strictly anhydrous conditions were applied. This result indicates
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b01840.
■
S
Experimental procedures and spectral data for insertion of
Me3SiCHN2 into pinB-SR, deborylative alkylation, selec-
tive protodesilylation, deprotonation/alkylation, debory-
lative cyclization, and desilylative cyclization (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(18) Endo, K.; Hirokami, M.; Shibata, T. J. Org. Chem. 2010, 75, 3469.
(19) Knochel, P. J. Am. Chem. Soc. 1990, 112, 7431.
*E-mail: swestcott@mta.ca.
*E-mail: anabelen.cuenca@urv.cat.
*E-mail: mariaelena.fernandez@urv.cat.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The present research was supported by the Spanish Ministerio de
Economia y Competitividad (MINECO) through Project No.
CTQ2013-43395P (EF) and by NSERC (SAW).
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