Transition-metal-free synthesis of 1,1-diboronate esters with a fully substituted benzylic center via diborylation of lithiated carbamates

Article abstract of DOI:10.1039/c7ob00654c

A transition-metal-free lithiation-borylation method has been developed to access a variety of 1,1-diboronate esters with a fully substituted benzylic center from readily available secondary benzylic N,N-diisopropyl carbamates. The method is applicable to scale-up synthesis of 1,1-diboron compounds. Furthermore, the current method is also applicable to synthesizing optically active 1,1-silylboronate esters.

Full text of DOI:10.1039/c7ob00654c

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: H. Zhao, M. Tong,
H. Wang and S. Xu, Org. Biomol. Chem., 2017, DOI: 10.1039/C7OB00654C.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 5
View Article Online
DOI: 10.1039/C7OB00654C
Journal Name
COMMUNICATION
Transition-metal-Free Synthesis of 1,1-Diboronate Esters with a
Fully Substituted Benzylic Center via Diborylation of Lithiated
Carbamates
Received 00th January 20xx,
Accepted 00th January 20xx
Haonan Zhao,a,b Min Tong,b Haijun Wang,*,a Senmiao Xu*,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: A transition-metal-free lithiation-borylation method has of deprotonated diborylmethane2d,4a,6a and insertions of in-situ
been developed to access a variety of 1,1-diboronate esters with a generated diazo compounds into B-B bonds of B2Pin2.16
fully substituted benzylic center from readily available secondary
Previous work
: synthesis of 1,1-diboronate esters
benzylic N,N-diisopropyl carbamates. The method is applicable to
scale-up synthesis of 1,1-diboron compounds. Furthermore, The
current method is also applicable to synthesizing optically active
1,1-silylboronate esters.
a) diborylation of terminal alkynes (Shibata, Yun, and Huang):
Rh(I) or [Co]
Bpin
Bpin
R
R
HBpin or B2Pin2
b) boron addition to the vinyl boron derivatives (Hall, Yun):
Cu(I)/ligand
1,1-Dimetallic organic compounds are valuable building blocks
to streamline synthesis of molecules with structural diversity.1
Particularly, 1,1-diboronate esters have gained great interest
recently as they have advantages of unique stability,
operational simplicity, and non-toxicity over other 1,1-
dimetallic organic reagents.2 1,1-diboronate esters can be
served as nucleophilic partners in a variety of chemo-selective
C-C bond forming reactions.3-6 Besides, 1,1-diboron
compounds can also be used in boron-Wittig reaction to form
multisubstituted olefins7 and employed as unconventional
borylation reagents.8
Bdan
Bdan
R
R
B2Pin2 or HBpin
Bpin
R = aryl or α,β-unsaturated carbonyl
Bdan = 1,8-naphthalenediaminatoboryl
c) diborylation of benzylic C-H bonds (Hartwig, Chirik):
Bpin
Ir(I) or [Co], B2pin2
Bpin
R
R
d) Insertion of diazo compounds into B-B bonds of B2pin2
(Srebnik, Kingsbury, and Wang):
R
R
Bpin
Bpin
Pt(0), B2Pin2
N2
R'
R'
Although recent years have witnessed that 1,1-
diboronate esters have engaged in promising application in
organic synthesis, the methods to construct this kind of
compounds are still limited. Most of current methods rely on
transition-metal catalysis, including Rh(I),9 Cu(I),10 or Co11-
catalyzed diboration of terminal alkynes, Cu(I)-catalyzed
asymmetric boron addition to vinylboron derivatives,3b,12
platinum catalyzed insertion of diazo compounds into B-B
bonds of Bis(pinacolato)diboron (B2pin2),13 and Ir(I)14 or Co15-
catalyzed diborylation of benzylic C-H bonds. Besides,
transition-metal-free protocols have also been developed to
synthesize 1,1-diboronate esters, examples including alkylation
R
NaH, B2pin2
R
Bpin
Bpin
N
R'
NHTs
R'
e) Alkylation of deprotonated diborylmethane (Matteson, Morken, and Fu)
R' B(OR)2
B(OR)2
B(OR)2
B(OR)2
This work:
LiTMP, R'X
synthesis of 1,1-diboronate esters with a fully substituted benzylic
center via Lithiation-borylation method.
O
via:
Bpin
Bpin
O
O
N(iPr)2
O
sec-BuLi
B2Pin2
Ar
O
R
N(iPr)2
B
Ar
R
R
O
Ar
H
pinB
R = alkyl, allyl, aryl
Scheme 1 Synthesis of 1,1-diboronate esters.
However, methods to synthesize 1,1-diboronate esters
with a fully substituted benzylic center are sporadic and
limited to insertion of diazo compounds to B-B bonds of
B2Pin2,13,16 which require high reaction temperature and have
scope limitations. The operational mechanism of transition-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 5
View Article Online
DOI: 10.1039/C7OB00654C
COMMUNICATION
Journal Name
the base candidates for the deprotonation of 1a. As show in
table 1, neither commercialized nor freshly prepared lithium
diisopropylamide (LDA) worked for the reaction in Et2O or
cyclopentyl methyl ether (CpOMe) (table 1, entries 1-3),
although LDA has been known to generate lithiated
carbamates efficiently towards synthesis of tertiary
boronates.23 Then we moved to stronger base lithium
tetramethylpiperidide (LiTMP) that has also been used to form
lithiated carbamates.19p However, the corresponding product
1,1-diboron 2a was obtained in less than 50% GC yields (table 1,
entries 4-6). The reaction could not complete even with 2.0
equiv of LiTMP. To facilitate the reaction, we turned to sec-BuLi.
To our great delight, treatment of carbamate 1a with 1.5 equiv
of sec-BuLi in Et2O at –78 ˚C for 30 min followed by addition of
1.5 equiv of B2pin2 resulted in complete conversion (table 1,
entry 7), affording corresponding 1,1-diboronate ester 2a in 94%
GC yield and 92% isolated yield. The reaction was quite
sensitive to the loading amount of sec-BuLi, it was found that
the reaction could not complete when less than 1.5 equiv of sec-
BuLi was used.24
metal-free diboration of diazo compounds consists of two
steps: addition of nucleophilic diazo carbon to one of the
borons in B2Pin2 to form
a boron “ate” complex and
subsequent 1,2-metallate shift of the Bpin group from the
tetrahedral boron to the adjacent carbon by expulsion of the
dinitrogen molecule.16 Therefore, a carbon anion tethered
with a proper leaving group could also be feasible to access
1,1-diboron. Pioneered by Matteson,17 reaction of 1-halo-1-
lithioalkanes with organoboron compounds has emerged as
the powerful chain-extension method in which halogen is
served as the leaving group along with 1,2-metalate shift.18
Recently, Aggarwal and co-workers developed numerous
elegant lithiation-borylation methods of secondary alcohol
derived carbamates to access a variety of transformations with
key step of 1,2-metallate shift of boron “ate” complexes.19 To
the best of our knowledge, the central atoms of migrating
groups are limited to carbon,19 hydrogen,20 and silicon21
exclusively. In addition, successful synthesis of 1,1-
diborylalkenes through reaction of 1-halo-1-lithioalkenes with
B2Pin2 demonstrates that 1,2-metalate shift of Bpin group is
feasible under lithiated conditions.22 Cognizant of these results,
we envisioned that the 1,1-diboronate esters could be
accessible from carbamates via lithiation-borylation procedure
if boryl is served as the migrating group. We herein disclose a
general method for the synthesis of the 1,1-diboronate esters
with a fully substituted benzylic center through lithiation-
borylation of secondary benzylic alcohol derived N,N-
diisopropyl carbamates with B2Pin2 under transition-metal-free
conditions. We also demonstrate the current method is
applicable to synthesize optically active 1,1-silylboronate
esters.
Table 2 Substrate scope of synthesis of 1,1-diboronate esters
by lithiation-borylation methoda
Table 1 Optimization of lithiation-borylation reaction
conditions for the synthesis of 1,1-diboronate ester 2aa
The N,N-diisopropyl carbamates 1 can be easily prepared from
the reaction of corresponding secondary benzylic alcohols with
diisopropylcarbamoyl chloride.19j They have been known to
generate carbon anions upon treatment with strong bases. Our
study commenced with diboration of the 1-phenylethanol
derived carbamate 1a. Initial investigation was concentrated on
With optimized reaction conditions in hand, a series of
secondary benzylic carbamates were then surveyed as shown
in table 2. For the substituted 1-phenylethanol derived
carbamates, the reaction underwent smoothly to give the
corresponding 1,1-diboronate esters in moderate to excellent
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 5
View Article Online
DOI: 10.1039/C7OB00654C
Journal Name
COMMUNICATION
protodeboronation of 2i in the presence of NaOMe afforded
benzylboronate ester
in 75% yield (scheme 4, eq. 1).27
Furthermore, 2a can undergo deborylative allylic alkylation to
yields (table 2, 2a-e). When the substituents in phenyl rings
are electron-withdrawing groups, the isolated yields are
inferior (table 2, 2d and 2e) due to their being more prone to
protodeboronation.25 Reactions of carbamates with benzylic
position of 1-naphthyl and 2-naphthyl moieties also occurred,
albeit with diminished yields (table 2, 2f and 2g). The similar
4
furnish tertiary boronate ester
5 in 89% yield (scheme 4, eq.
2).13c Finally, treatment of 2a with MeLi followed by the
addition of acetophenone furnished the tetra-substituted
olefins 6 in 42% yield (Z/E = 2: 1) (scheme 4, eq. 3).
tendency was also found in carbamates with R in
1 of
extended or branched alkyl substituents that gave the
corresponding 1,1-diboronate esters in moderate yields (table
2, 2h-l). Interestingly, the unprecedented 1,1-diboronate ester
2m bearing the m-tolyl group in benzylic position could also
be obtained in 37% yield although it was found to undergo
deprotoboronation readily. Unfortunately, reaction of primary
benzylic carbamate 1n under standard conditions resulted in
the mixture of inseparable diborylated and mono-borylated
products.
Conclusions
We have developed a lithiation-borylation method to
access 1,1-diboronate esters with a fully substituted benzylic
center from secondary benzylic N,N-diisopropyl carbamates.
The reaction could proceed smoothly with sec-BuLi as the base,
affording a series of 1,1-diboron compounds in moderate to
excellent yields. The readily available starting materials and
transition-metal-free process allow the scale-up synthesis of
1,1-diboronate esters. We also demonstrate the current
method is applicable to synthesizing optically active 1,1-
silylboronate esters with a fully substituted benzylic center.
Further application of the 1,1-dibronates are underway in our
laboratory, and the results will be reported in due course.
The current method is also applicable to synthesizing chiral
1,1-silylboronate esters with a fully substituted benzylic center
in one step. As shown in Scheme 2, reaction of the
enantioriched carbamate (S)-1a (96% ee) under standard
conditions afforded the optically active 1,1-silylboronate ester
3
in 95% isolated yield with 92% ee.26
Acknowledgement
This work was funded by the National Natural Science
Foundation of China (21573262) and Natural Science
Foundation of Jiangsu Province (BK20161259).
Scheme 2 Synthesis of enantioriched 1,1-silylboronate ester 3.
To demonstrate the practical utility, the reaction of model
substrate in gram scales was performed. As shown in Scheme
3, the 1,1-diboronate ester 2a was isolated in 88% yield when
the reaction was carried out in 1.25-gram scale under standard
conditions.
References
1 (a) I. Marek, J.-F. Normant, Chem. Rev., 1996, 96, 3241-3268;
(b) A. Hirai, M. Nakamura, E. Nakamura, J. Am. Chem. Soc.,
1999, 121, 8665-8666; (c) J. F. Normant, Acc. Chem. Res., 2001
34, 640-644.
,
2 (a) M. W. Rathke, R. Kow, J. Am. Chem. Soc., 1972, 94, 6854-
6856; (b) D. S. Matteson, R. J. Moody, P. K. Jesthi, J. Am. Chem.
Soc., 1975, 97, 5608-5609; (c) D. S. Matteson, Moody, R. J. J.
Am. Chem. Soc., 1977, 99, 3196-3197; (d) D. S. Matteson, R. J.
Moody, Organometallics, 1982, 1, 20-28; (e) G. E. Herberich, A.
Fischer, Organometallics, 1996, 15, 58-67.
Scheme 3 Gram-scale synthesis of 1,1-diboron 2a
We are interested in synthetic utility of the 1-substituted-
3 For Pd-catalyzed C-C bond forming reactions, see: (a) K. Endo,
T. Ohkubo, M. Hirokami, T. Shibata, J. Am. Chem. Soc., 2010,
1,1-benzyldiboronate esters 2 obtained from the new reaction,
132, 11033-10135; (b) J. C. H. Lee, R. McDonald, D. G. Hall, Nat.
Chem., 2011, 3, 894-899; (c) C. Sun, B. Potter, J. P. Morken, J.
Am. Chem. Soc., 2014, 136, 6534-6537; (d) B. Potter, A. A.
Szymaniak, E. K. Edelstein, J. P. Morken, J. Am. Chem. Soc.,
2014, 136, 17918-17921; (e) H. Li, Z. Zhang, X. Shangguan, S.
Huang, J. Chen, Y. Zhang, J. Wang, Angew. Chem., Int. Ed.,
2014, 53, 11921-11925; (f) J. C. H. Lee, H.-Y. Sun, D. G. Hall, J.
Org. Chem., 2015, 80, 7134-7143; (g) S. Xu, X. Shangguan, H. Li,
Y. Zhang, J. Wang, J. Org. Chem., 2015, 80, 7779-7784.
4 For Cu-catalyzed C-C bond forming reactions, see: (a) Z.-Q.
Zhang, C.-T. Yang, L.-J. Liang, B. Xiao, X. Lu, J.-H. Liu, Y.-Y. Sun, T.
B. Marder, Y. Fu, Org. Lett., 2014, 16, 6342-6345; (b) M. V.
Joannou, B. S. Moyer, S. J. Meek, J. Am. Chem. Soc., 2015, 137,
6176-6179; (c) Y. Shi, A. H. Hoveyda, Angew. Chem., Int. Ed.,
2016, 55, 3455-3458; (d) J. Park, Y. Lee, J. Kim, S. H. Cho, Org.
Scheme 4 Transformations of 1,1-diboron 2a and 2i
.
and Scheme 4 illustrates that 2 is capable in engaging in
subsequent C-H and C-C bonds forming reactions. For example,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 5
View Article Online
DOI: 10.1039/C7OB00654C
COMMUNICATION
Journal Name
137, 4398-4403; (o) S. Roesner, D. J. Blair, V. K. Aggarwal, Chem.
Sci., 2015, 6, 3718-3723; (p) D. J. Blair, S. Zhong, M. J. Hesse, N.
Zabaleta, E. L. Myers,V. K. Aggarwal, Chem. Commun., 2016, 52,
5289-5292; (q) Y. Wang, A. Noble, E. L. Myers, V. K. Aggarwal,
Angew. Chem., Int. Ed., 2016, 55, 4270-4274.
20 S. Roesner, C. A. Brown, M. Mohiti, A. P. Pulis, R. Rasappan,
D. J. Blair, S. Essafi, D. Leonori, V. K. Aggarwal, Chem. Commun.,
2014, 50, 4053-4055.
21 V. K. Aggarwal, M. Binanzer, M. C. de Ceglie, M. Gallanti, B.
W. Glasspoole, S. J. F. Kendrick, R. P. Sonawane, A. Vázquez-
Romero, M. P. Webster, Org. Lett., 2011, 13, 1490-1493.
22 T. Hata, H. Kitagawa, H. Masai, T. Kurahashi, M. Shimizu, T.
Hiyama, T. Angew. Chem., Int. Ed., 2001, 40, 790-792.
23 K. R. Fandrick, N. D. Patel, J. A. Mulder, J. Gao, M. Konrad, E.
Archer, F. G. Buono, A. Duran, R. Schmid, J. Daeubler, D. R.
Fandrick, S. Ma, N. Grinberg, H. Lee, C. A. Busacca, J. J. Song, N. K.
Yee, C. H. Senanayake, Org. Lett., 2014, 16, 4360-4363.
24 The conversion of reaction was 67% when 1.2 equiv of sec-
BuLi was used under otherwise identical reaction conditions.
25 Significant mono-borylated product was observed by GC-MS
analysis after work-up.
Lett., 2016, 18, 1210-1213; (e) J. Kim, S. Park, J. Park, S. H. Cho,
Angew. Chem., Int. Ed., 2016, 55, 1498-1501; (f) A. Ebrahim-
Alkhalil, Z.-Q. Zhang, T.-J. Gong, W. Su, X.-Y. Lu, B. Xiao, Y. Fu,
Chem. Commun., 2016, 52, 4891-4893; (g) Z.-Q. Zhang, B.
Zhang, X. Lu, J.-H. Liu, X.-Y. Lu, B. Xiao, Y. Fu, Org. Lett., 2016
,
18, 952-955; (h) S. A. Murray, J. C. Green, S. B. Tailor, S. J.
Meek, Angew. Chem., Int. Ed., 2016, 55, 9065-9069.
5 For other transition-metal-catalyzed C-C bond forming
reactions, see: (a) M. V. Joannou, B. S. Moyer, M. J. Goldfogel,
S. J. Meek, Angew. Chem., Int. Ed., 2015, 54, 14141-14145; (b)
M. Zhan, R.-Z. Li, Z.-D. Mou, C.-G. Cao, J. Liu, Y.-W. Chen, D. Niu,
ACS Catalysis, 2016, 6, 3381-3386.
6 For transition-metal free reactions, see: (a) K. Hong, X. Liu, J.
P. Morken, J. Am. Chem. Soc., 2014, 136, 10581-10584; (b) W.
Jo, J. Kim, S. Choi, S. H. Cho, Angew. Chem., Int. Ed., 2016, 55,
9690-9694.
7 (a) K. Endo, M. Hirokami, T. Shibata, J. Org. Chem., 2010, 75,
3469-3472; (b) J. R. Coombs, L. Zhang, J. P. Morken, Org. Lett.,
2015, 17, 1708-1711; (c) K. Endo, A. Sakamoto, T. Ohkubo, T.
Shibata, Chem. Lett., 2011, 40, 1440-1442.
26 The ee value was determined by HPLC analysis of the alcohol
obtained by oxidation of 3 with NaBO3•4H2O.
27 H. Li, L. Wang, Y. Zhang, J. Wang, Angew. Chem., Int. Ed.,
2012, 51, 2943-2946.
8 Y. Lee, S.-y. Baek, J. Park, S.-T. Kim, S. Tussupbayev, J. Kim,
M.-H. Baik, S. H. Cho, J. Am. Chem. Soc., 2017, 139, 976-984.
9. K. Endo, M. Hirokami, T. Shibata, Synlett, 2009, 1331-1335.
10 S. Lee, D. Li, J. Yun, Chem. - Asian J., 2014, 9, 2440-2443.
11 Z. Zuo, Z. Huang, Org. Chem. Frontiers, 2016, 3, 434-438.
12 X. Feng, H. Jeon, J. Yun, Angew. Chem., Int. Ed., 2013, 52,
3989-3992.
13 (a) H. Abu Ali, I. Goldberg, M. Srebnik, Organometallics,
2001, 20, 3962-3965; (b) H. A. Ali, I. Goldberg, D. Kaufmann, C.
Burmeister, M. Srebnik, M. Organometallics, 2002, 21, 1870-
1876; (c) A. J. Wommack, J. S. Kingsbury, Tetrahedron Lett.,
2014, 55, 3163-3166.
14 S. H. Cho, J. F. Hartwig, Chem. Sci., 2014, 5, 694-698.
15 W. N. Palmer, J. V. Obligacion, I. Pappas, P. J. Chirik, J. Am.
Chem. Soc., 2016, 138, 766-769.
16 H. Li, X. Shangguan, Z. Zhang, S. Huang, Y. Zhang, J. Wang,
Org. Lett., 2014, 16, 448-451.
17 D. S. Matteson, R. W. H. Mah, J. Am. Chem. Soc., 1963, 85,
2599-2603.
18 (a) Matteson, D. S. Chem. Rev., 1989, 89, 1535-1551; (b) P. R.
Blakemore, S. P. Marsden, H. W. Vater, Org. Lett., 2008, 8, 773-
776
19 Selected examples, see: (a) J. L. Stymiest, V. Bagutski, R. M.
French, V. K. Aggarwal, Nature, 2008, 456, 778-782; (b) G.
Dutheuil, M. P. Webster, P. A. Worthington, V. K. Aggarwal,
Angew. Chem., Int. Ed., 2009, 48, 6317-6319; (c) M. Althaus, A.
Mahmood, J. R. Suarez, S. P. Thomas, V. K. Aggarwal, J. Am.
Chem. Soc., 2010, 132, 4025-4028; (d) M. Binanzer, G. Y. Fang, V.
K. Aggarwal, Angew. Chem., Int. Ed., 2010, 49, 4264-4268; (e) V.
Bagutski, R. M. French, V. K. Aggarwal, Angew. Chem., Int. Ed.,
2010, 49, 5142-5145; (f) R. P. Sonawane, V. Jheengut, C.
Rabalakos, R. Larouche-Gauthier, H. K. Scott, V. K. Aggarwal,
Angew. Chem., Int. Ed., 2011, 50, 3760-3763; (g) S. Roesner, J.
M. Casatejada, T. G. Elford, R. P. Sonawane, V. K. Aggarwal, Org.
Lett., 2011, 13, 5740-5743; (h) A. P. Pulis, V. K. Aggarwal, J. Am.
Chem. Soc., 2012, 134, 7570-7574; (i) B. M. Partridge, L.
Chausset-Boissarie, M. Burns, A. P. Pulis, V. K. Aggarwal, Angew.
Chem., Int. Ed., 2012, 51, 11795-11799; (j) C. G. Watson, V. K.
Aggarwal, Org. Lett., 2013, 15, 1346-1349; (k) D. J. Blair, C. J.
Fletcher, K. M. P. Wheelhouse, V. K. Aggarwal, Angew. Chem.,
Int. Ed., 2014, 53, 5552-5555; (l) R. Rasappan, V. K. Aggarwal,
Nat. Chem., 2014, 6, 810-814; (m) C. G. Watson, A. Balanta, T. G.
Elford, S. Essafi, J. N. Harvey, V. K. Aggarwal, J. Am. Chem. Soc.,
2014, 136, 17370-17373; (n) S. Balieu, G. E. Hallett, M. Burns, T.
Bootwicha, J. Studley, V. K. Aggarwal, J. Am. Chem. Soc., 2015
,
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00654C
Diborylation of lithiated carbamtes is reported for the first time to
synthesize 1,1-diboronate esters with a fully substituted benzylic center.