Formal carbon insertion of n-tosylhydrazone into B-B and B-Si bonds: Gem-diborylation and gem-silylborylation of sp3 carbon

Article abstract of DOI:10.1021/ol403338s

A convenient method is developed to synthesize 1,1-diboronates from the corresponding N-tosylhydrazones. This method is also applicable to synthesize 1-silyl-1-boron compounds. Meanwhile, derivatization and consecutive Pd-catalyzed cross-coupling reaction

Full text of DOI:10.1021/ol403338s

Letter
pubs.acs.org/OrgLett
Formal Carbon Insertion of N-Tosylhydrazone into B−B and B−Si
Bonds: gem-Diborylation and gem-Silylborylation of sp3 Carbon
Huan Li, Xianghang Shangguan, Zhikun Zhang, Shan Huang, Yan Zhang, and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
S
* Supporting Information
ABSTRACT: A convenient method is developed to synthe-
size 1,1-diboronates from the corresponding N-tosylhydra-
zones. This method is also applicable to synthesize 1-silyl-1-
boron compounds. Meanwhile, derivatization and consecutive
Pd-catalyzed cross-coupling reactions with 1,1-boronates were
explored, demonstrating the synthetic potential of 1,1-
diboronates.
imetalated organic compounds have attracted consid-
erable attention due to their unique reactivities.1 In
synthesize 1,1-diboronates (Scheme 1a).6 Cu(I)-Catalyzed
enantioselective hydroboration of alkenylboron compounds
D
particular, 1,1-diborylalkanes are highly valuable synthetic
building blocks because multiple transformations, including
C−C bond formations through Suzuki−Miyaura couplings, are
possible from these diboryl reagents. Compared to the widely
used Suzuki−Miyaura couplings with vinyl- and arylboron
reagents, the coupling reactions with alkylboron compounds
are less common, since these reactions suffered some difficulties
such as protodeboronation, slow transmetalation, and β-H
elimination.2 Interestingly, 1,1-diboron compounds are quite
reactive in Pd-catalyzed cross-coupling reactions with various
electrophiles.3 In 2011, Shibata and co-workers reported a
novel coupling reaction of 1,1-diborylalkanes with aryl
bromides.3a An interesting feature of this coupling is that the
reaction is highly chemoselective, with only one boronate
moiety participating in the cross-coupling and the remaining
boronate moiety keeps intact. Hall and co-workers in the same
year reported coupling reactions of chiral 1,1-diboron
compounds with aryl and vinyl bromides.3b
In contrast to monoboronate alkanes, the Pd-catalyzed cross-
coupling of 1,1-diborylalkanes occurs efficiently under mild
conditions, indicating that the adjacent boron atom in 1,1-
diborylalkanes can facilitate the coupling reaction. Furthermore,
the diverse reactivity of C−B bonds provides various
transformations with 1,1-diboron compounds. For example,
under suitable conditions consecutive cross-coupling of the 1,1-
diboron compound with two different aryl bromides can be
achieved, constituting a unique method to generate two C−C
bonds on a carbon center.3b,e 1,1-Diborylalkanes have also been
used in the lithiation/nucleophilic addition reaction to ketones
for the synthesis of alkenyl boronates, which can be further
converted to tetrasubstituted olefins through Suzuki−Miyaura
cross-couplings.4
Scheme 1. Synthesis of 1,1-Diboronates
has also been achieved (Scheme 1b).3b,f Besides, Srebnik and
co-workers reported that Pt(0)-catalyzed diborylation of diazo
compounds with B2pin2 afforded 1,1-diborylalkanes (Scheme
1c).7 However, these methods still suffer from drawbacks such
as limited substrate scope and the requirement of expensive
transition-metal catalysts. Herein, we communicate a practical
method for the synthesis of 1,1-diborylalkanes through the
reaction of N-tosylhydrazones with B2pin2 under transition-
metal-free conditions (Scheme 1d). The reaction can also be
extended to the synthesis of 1-boryl-1-silylalkanes. Besides, we
explored the sequential coupling reactions with 1,1-dibor-
ylalkanes.
N-Tosylhydrazones can be easily prepared from the
corresponding ketones or aldehydes. They have been known
to generate diazoalkanes upon treatment with base (Bamford−
Stevens reaction),8 and more recently they have been
Although 1,1-diborylalkanes have shown promising reac-
tivities, the methods to access this type of unique dimetalated
organic compounds are still limited.1a,5 Rh(I)-catalyzed
diborylation of alkynes represents an efficient method to
Received: November 19, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403338s | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
extensively explored in transition-metal-catalyzed cross-cou-
pling reactions.9 We have previously reported a metal-free
monoborylation reaction of N-tosylhydrazones with B2pin2.10
In the mechanistic study, we found that 1,1-diboronates could
be effectively formed by thermal reaction of N-tosylhydrazone
sodium salt with B2pin2. In addition, 1,1-diboronate was found
stable in the absence of base or a proton source. Encouraged by
these initial results, we further improved the preparative
procedure by using sodium hydride (NaH, 60%, dispersed in
mineral oil) as the base to generate tosylhydrazone sodium salt
in situ. The advantage of NaH as the base in this reaction is that
the proton removed from N-tosylhydrazone vanishes from the
reaction system with the release of H2, thus avoiding
protodeboronation of the 1,1-diboronate product. Since the
reaction is sensitive to the quantity of base, the loading of NaH
has been optimized (Scheme 2). It was found that optimal
results could be obtained with 1.2 equiv of NaH.
Scheme 3. Reactions of Tosylhydrazones with B2pin2
a
Scheme 2. Reaction Optimization
a
a
Reaction conditions: N-tosylhydrazone (1 mmol), NaH (1.2 mmol),
B2pin2 (1.2 mmol), toluene (10 mL). The products were isolated by
silica gel column chromatography. bThe yields described in
Reaction conditions: N-tosylhydrazone (1 mmol), NaH (x mmol),
B2pin2 (1.2 mmol), toluene (10 mL). Product was isolated by silica gel
chromatography.
c
parentheses refer to the reactions carried out in 10 mmol scale. The
d
reaction was carried out at 90 °C. Dioxane was used as the solvent.
eDioxane was used as the solvent, and 10 mol % of BTMAC was
added.
A series of N-tosylhydrazones were then applied to the
optimized reaction conditions (Scheme 3). For the N-
tosylhydrazones derived from aldehydes, when the R group is
a bulky substituent such as iPr (2c), the yield is also good.
However, if the R group is a very bulky group such as tBu (2d),
the yield is diminished. The reaction conditions tolerate N-
tosylhydrazones bearing halogen, vinyl, and amido substituents
(2b, 2h, 2g, 2i, 2j). The N-tosylhydrazones derived from aryl
and alkenyl aldehydes were also reactive, but the isolated yield
was low due to severe side reactions and instability of the
products. For the N-tosylhydrazones derived from ketones, the
reactivity was relatively low due to the steric hindrance and
poor solubility. Therefore, a polar solvent such as dioxane and
phase transfer catalyst BTMAC (benzyltrimethyl-ammoniun
chloride) were applied to enhance the solubility and the
conversion of the tosylhydrazone salt to the coressponding
diazo compound;11 however, the yields were moderate in these
cases (2k−r). For 2n, a slightly improved yield was obtained
because of its good solubility. However, for the N-
tosylhydrazones derived from linear ketones, the yield was
quite low.
To demonstrate the practical applicability, in several cases we
have carried out the reactions in gram scales (2a, c−f, j, n). As
shown in Scheme 3, the isolated yields were also satisfactory.
Furthermore, for the synthesis of 1,1-diboronate 2a, we have
considered isolating the product by recrystallization. The initial
trial of purifying the product by recrystallization failed because
of cocrystallization of the 1,1-diboronate products with the
remaining B2pin2. This problem can be solved by simply
inverting the molar ratio of N-tosylhydrazone to B2pin2 and in
this way the 1,1-diboronate 2a could be obtained in good yield
by recrystallization from hexane (eq 1).
The 1,1-diboronates are quite stable under various reaction
conditions, which benefit further functionalization of these
compounds. For example, the 1,1-diboronate bearing nitro
group (2s) could be reduced to the corresponding amine (2t)
in moderate yield (Scheme 4a). Likewise, the 1,1-diboronate
bearing ester group (2u) could be reduced to the
corresponding alcohol (2v) using DIBAL-H as the reductant.
Upon Dess-Martin oxidation, a 1,1-diboronate bearing
aldehyde moiety (2w) could be obtained (Scheme 4b). Both
an aryl amine and aldehyde are useful building blocks in organic
synthesis.
Interestingly, under the same reaction conditions but with a
silylborane reagent as the substrate, 1-silyl-1-boryl compounds
could also be obtained in moderate to high yields with good
functional group compatibility (Scheme 5).12,13 In this case, the
silyl group migrated instead of the boron group.10b However, as
shown by the diminished yields of 3e and 3f, the reaction was
affected by steric hindrance.
A possible reaction mechanism is shown in Scheme 6. First,
from N-tosylhydrazone the diazo compound A is generated in
situ. The nucleophilic diazo carbon then reacts with the
electron-deficient boron of the B2pin2 or Me2PhSiBpin to form
a tetracoordinated boron complex B. Subsequently, release of
B
dx.doi.org/10.1021/ol403338s | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conditions). The two-step coupling afforded diarylmethane
Scheme 4. Derivatization of 1,1-Diboronates
derivatives in moderately high yields (Scheme 7).
Scheme 7. Stepwise Coupling Reactions of 1,1-Diboronate
a
2a with Aryl Bromides and Aryl Iodides
a
The reaction was carried out in 0.2 mmol scale. The crude product of
b
the first step was extracted with Et2O before the second step. The
a
reaction time for the second step was prolonged to 48 h.
Scheme 5. Reaction of Tosylhydrazones with Silylborane
Furthermore, we applied diboronates 2r in the allylboration
reactions with aldehyde (eq 2).15 To our delight, the desired
product 6 could be obtained with good yield upon heating the
reactants in toluene. The vinyl boronate moiety formed in this
transformaton may be further functionalized via cross-coupling
reactions or undergo other functional group transformations.
In conclusion, we have developed a new method to
synthesize 1,1-diboronate and 1-silyl-1-boryl compounds. This
method has the following features: (1) the starting material N-
tosylhydrazones can be easily synthesized from the correspond-
ing carbonyl compounds; (2) the reaction can be easily
operated and scaled up and shows wide substrate scope; (3) the
reaction is under transition-metal-free conditions. With these
features, we expect this reaction will become a general method
for the synthesis of 1,1-diboronates. Furthermore, some
transformations of the 1,1-diboronates, including stepwise Pd-
catalyzed cross-coupling reactions, have been explored,
demonstrating the unique reactivity features of 1,1-diboronates.
Further explorations of the reactions with 1,1-diboronates are
underway in our laboratory, and the results will be reported in
due course.
a
Reaction conditions: tosylhydrazone (0.5 mmol), NaH (0.6 mmol),
B2pin2 (0.6 mmol), toluene (5 mL). The products were isolated by
silica gel column chromatography.
Scheme 6. Possible Reaction Mechanism
dinitrogen occurs with the simultaneous 1,2-shift of the Bpin or
SiPhMe2 from boron to carbon to afford the formal B−B or B−
Si insertion product, respectively.
In order to demonstrate the potential of synthetic
applications of 1,1-diboronates, we next carried out inves-
tigations on the transition-metal-catalyzed coupling reactions of
1,1-diboronates. Based on the previous reports by Shibata3a and
Crudden,14 we first explored the stepwise coupling of 1,1-
diboron compounds with two aryl halides. By using Shibata’s
reaction conditions, the 1,1-dibron compound 2a was coupled
with aryl bromides to afford benzyl boronates with Pd(PtBu3)2
as the catalyst. Upon completion of the reaction, the solvent
was removed and the residue was extracted with diethyl ether
several times. The combined ethereal extracts were concen-
trated, and the crude products 4a−c were submitted to the next
coupling with aryl iodides and catalytic Pd2dba3 (Crudden’s
ASSOCIATED CONTENT
* Supporting Information
■
S
Experiment details, spectral data, and 1H and 13C NMR spectra
for products. These materials are available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wangjb@pku.edu.cn.
C
dx.doi.org/10.1021/ol403338s | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the 973 Program
(2012CB821600) and NSFC (Grants 21272010, 21172005
and 21332002).
REFERENCES
■
(1) For selected reviews on dimetalated compounds: (a) Shimizu,
M.; Hiyama, T. Proc. Jpn. Acad., Ser. B 2008, 84, 75. (b) Matsubara, S.
In Handbook of Functionalized Organometallics; Knochel, P., Ed.;
Wiley-VCH: Weinheim, 2005; Vol. 2, p 347. (c) Foubelo, F.; Yus, M.
Curr. Org. Chem. 2005, 9, 459. (d) Langer, P.; Freiberg, W. Chem. Rev.
2004, 104, 4125. (e) Xi, Z. Eur. J. Org. Chem. 2004, 2773. (f) Normant,
J. F. Acc. Chem. Res. 2001, 34, 640. (g) Matsubara, S.; Oshima, K.;
Utimoto, K. J. Organomet. Chem. 2001, 617−618, 39. (h) Marek, I.
Chem. Rev. 2000, 100, 2887.
(2) For reviews, see: (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem.
Rev. 2011, 111, 1417. (b) Doucet, H. Eur. J. Org. Chem. 2008, 12,
2013. (c) Crudden, C. M.; Edwards, D. Eur. J. Org. Chem. 2003, 4695.
(3) (a) Endo, K.; Ohkubo, T.; Hirokami, M.; Shibata, T. J. Am. Chem.
Soc. 2010, 132, 11033. (b) Lee, J. C. H.; McDonald, R.; Hall, D. G.
Nat. Chem. 2011, 3, 894. (c) Endo, K.; Ohkubo, T.; Shibata, T. Org.
Lett. 2011, 13, 3368. (d) Endo, K.; Ohkubo, T.; Ishioka, T.; Shibata, T.
J. Org. Chem. 2012, 77, 4826. (e) Endo, K.; Ishioka, T.; Ohkubo, T.;
Shibata, T. J. Org. Chem. 2012, 77, 7223. (f) Feng, X.; Jeon, H.; Yun, J.
Angew. Chem., Int. Ed. 2013, 52, 3989.
(4) Endo, K.; Hirokami, M.; Shibata, T. J. Org. Chem. 2010, 75, 3469.
(5) For reviews, see: (a) Dembitsky, V. M.; Abu Ali, H.; Srebnik, M.
Appl. Organomet. Chem. 2003, 17, 327. (b) Takaya, J.; Iwasawa, N.
ACS Catal. 2012, 2, 1993.
(6) Endo, K.; Hirokami, M.; Shibata, T. Synlett 2009, 1331.
(7) Abu Ali, H.; Goldberg, I.; Srebnik, M. Organometallics 2001, 20,
3962. (b) Abu Ali, H.; Goldberg, I.; Kaufmann, D.; Burmeister, C.;
Srebnik, M. Organometallics 2002, 21, 1870. (c) Abu Ali, H.; Berkovitz,
R.; Reich, R.; Srebnik, M. Arch. Pharm. Pharm. Med. Chem. 2004, 337,
183.
(8) Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735.
(9) (a) Barluenga, J.; Valdes, C. Angew. Chem., Int. Ed. 2011, 50,
́
7486. (b) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012, 41, 560. (c) Xiao,
Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236.
(10) (a) Li, H.; Wang, L.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed.
2012, 51, 2943. (b) For a related review, see: (b) Li, H.; Zhang, Y.;
Wang, J. Synthesis 2013, 45, 3090.
(11) See Supporting Information for details.
(12) The reaction of ethyldiazoacetate with silylborane was
previously reported. However, only protodeboronated product was
obtained. See: Buynak, J. D.; Geng, B. Organometallics 1995, 14, 3112.
(13) For the reactions of carbenoids with silylboranes leading to 1-
silyl-1-boron compounds, see: (a) Shimizu, M.; Kurahashi, T.;
Kitagawa, H.; Shimono, K.; Hiyama, T. J. Organomet. Chem. 2003,
686, 286. (b) Shimizu, M.; Kurahashi, T.; Kitagawa, H.; Hiyama, T.
Org. Lett. 2003, 5, 225.
(14) Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M. J.
Am. Chem. Soc. 2009, 131, 5024.
(15) For reviews on allylboration with allylboron compounds, see:
(a) Pilarski, L. T.; Szabo,
(b) Hall, D. G. Synlett 2007, 1644.
́
K. J. Angew. Chem., Int. Ed. 2003, 42, 4732.
D
dx.doi.org/10.1021/ol403338s | Org. Lett. XXXX, XXX, XXX−XXX