Rhodium-Catalyzed B-H Bond Insertion Reactions of Unstabilized Diazo Compounds Generated in Situ from Tosylhydrazones

Article abstract of DOI:10.1021/jacs.8b05946

Although transition-metal-catalyzed B-H bond insertion of carbenes into stable borane adducts has emerged as a promising method for organoborane synthesis, all the diazo compounds used to date as carbene precursors have had an electron-withdrawing group to stabilize them. Herein, we report a protocol for rhodium-catalyzed B-H bond insertion reactions of unstabilized diazo compounds generated in situ from tosylhydrazones. In addition, by using chiral dirhodium catalysts, we also achieved an asymmetric version of the reaction with good to excellent enantioselectivities (up to 98:2 e.r.). This is the first enantioselective heteroatom-hydrogen bond insertion reaction to use unstabilized diazo compounds as carbene precursors. The protocol exhibited good functional group tolerance and could be carried out on a gram scale. It also enabled one-pot transformation of a carbonyl group to a boryl group enantioselectively. The B-H bond insertion products could be easily transformed into chiral alcohols and other widely used organoboron reagents with enantiomeric fidelity.

Full text of DOI:10.1021/jacs.8b05946

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Communication
Rhodium-Catalyzed B–H Bond Insertion Reactions of Unstabilized
Diazo Compounds Generated in situ from Tosylhydrazones
Yue Pang, Qiao He, Zi-Qi Li, Ji-Min Yang, Jin-Han Yu, Shou-Fei Zhu, and Qi-Lin Zhou
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05946 • Publication Date (Web): 13 Aug 2018
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Rhodium-Catalyzed B–H Bond Insertion Reactions of Unstabilized Di-
azo Compounds Generated in situ from Tosylhydrazones
Yue Pang,† Qiao He,† Zi-Qi Li,† Ji-Min Yang,† Jin-Han Yu,† Shou-Fei Zhu,*,† Qi-Lin Zhou†,‡
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†State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
Supporting Information Placeholder
insertion reaction that uses unstabilized diazo compounds as
carbene precursors.5 Unlike the known catalytic methods for
constructing C–B bonds,1 our method directly connects car-
bonyl groups to boryl groups, avoids the regioselectivity prob-
lem often encountered in olefin hydroboration, and can be
performed enantioselectively.
ABSTRACT: Although transition-metal-catalyzed B–H bond
insertion of carbenes into stable borane adducts has emerged
as a promising method for organoborane synthesis, all the
diazo compounds used to date as carbene precursors have
had an electron-withdrawing group to stabilize them. Herein,
we report a protocol for rhodium-catalyzed B–H bond inser-
tion reactions of unstabilized diazo compounds generated in
situ from tosylhydrazones. In addition, by using chiral dirho-
dium catalysts, we also achieved an asymmetric version of the
reaction with good to excellent enantioselectivities (up to 98:2
e.r.). This is the first enantioselective heteroatom–hydrogen
bond insertion reaction to use unstabilized diazo compounds
as carbene precursors. The protocol exhibited good functional
group tolerance and could be carried out on a gram scale. It
also enabled one-pot transformation of a carbonyl group to a
boryl group enantioselectively. The B–H bond insertion prod-
ucts could be easily transformed into chiral alcohols and other
widely used organoboron reagents with enantiomeric fidelity.
Scheme 1. Transition-Metal-Catalyzed B–H Bond Inser-
tion Reactions
Because organoboron compounds have a wide variety of ap-
plications, the development of efficient methods for their syn-
thesis has drawn considerable attention from synthetic chem-
ists.1 Recently, transition-metal-catalyzed B–H bond insertion
reactions of carbenes with stable borane adducts, first devel-
oped by Curran’s group2 and independently by our group,3
emerged as a promising method for organoborane synthesis.4
Various diazo compounds have been used as carbene precur-
sors, and enantioselective transformations have been
achieved (Scheme 1a). However, all the diazo compounds
used to date have contained an electron-withdrawing group
that is directly connected to the diazo carbon and that stabi-
lizes the diazo compound by increasing the number of reso-
nance forms.4a The need for an electron-withdrawing group
greatly limits the diversity of the B–H bond insertion prod-
ucts, as well as their synthetic applications. Herein, we report
a protocol for rhodium-catalyzed B–H bond insertion reac-
tions of unstabilized diazo compounds generated in situ from
tosylhydrazones (Scheme 1b). In addition, by using chiral
dirhodium catalysts we also achieved an asymmetric version
of the reaction with good to excellent enantioselectivities (up
to 98:2 enantiomeric ratio, e.r.). To the best of our knowledge,
this is the first enantioselective heteroatom–hydrogen bond
Our study began with the reaction of tosylhydrazone 1a and
readily accessible trimethylamine-borane adduct 2a (2 equiv)
in 1,2-dichloroethane (DCE) at 55 °C (Table 1). Although un-
stabilized diazo compounds can be easily generated in situ
from tosylhydrazones by means of the Bamford–Stevens pro-
cess in the presence of base at high temperature (generally
over 80 °C),6 this method is problematic for B–H bond inser-
tion reactions because borane adducts are generally thermally
labile. To solve this problem, we used a large amount of base
(LitOBu, 6.0 equiv) to facilitate in situ generation of the diazo
compounds at a relatively low temperature (55 °C). First, we
evaluated various transition-metal catalysts that have been
used in other carbene-transfer reactions (entries 1–10).5c To
our delight, we found that in the presence of a copper, palladi-
um, or rhodium complex, the reaction smoothly afforded de-
sired B–H bond insertion product (1-(naphthalen-2-
yl)ethyl)borane (3aa) in moderate to good yield (entries 1–3
and 6–10). CuI, Rh2(TPA)4, and Rh2(piv)4 gave yields over
70%, with Rh2(piv)4 giving the highest yield (92%, entry 10).7
The amount of Rh2(piv)4 could be reduced to as low as 1 mol
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e
f
% without substantially compromising the yield (entries 10–
12). Fortunately, Rh2(piv)4 could be easily recovered in 83%
by means of flash chromatography after the reaction and
could be reused without any loss in activity (see Table S2 for
details). Evaluation of various solvents showed that chloro-
benzene was also suitable, whereas coordinating and protic
solvents were deleterious (entries 13–15). In addition to tri-
methylamine-borane adduct 2a, borane adducts stabilized by
different Lewis bases, such as N-methylpyrrolidine (2b),
tributylphosphine (2c), pyridine and pyridine derivatives
(2d–2f), and an N-heterocyclic carbene (2g), also underwent
B–H bond insertion reactions smoothly and afforded the de-
sired products in good to excellent yields (entries 16–21).
Used C6H5Cl as solvent. Used 1,4-dioxane as solvent. Used
MeOH as solvent
1
2
3
4
5
6
7
8
Next, we investigated B–H bond insertion reactions of aryl
methyl tosylhydrazones with borane adducts 2a or 2f under
the optimal reaction conditions (Table 2). The reactions gave
the desired B–H bond insertion products in satisfactory yields
(generally around 80%). A variety of functional groups, in-
cluding methoxy (1b, 1e; entries 2 and 5), halogen (1c, 1h,
1n–1p; entries 3, 8, and 14–16), ester (1i; entry 9), nitrile (1j;
entry 10), nitro (1k; entry 11), and trifluoromethyl (1l; entry
12) were tolerated. Phenyl-substituted compounds with an
electron-withdrawing group on the phenyl ring (entries 8–12)
gave higher yields than compounds with an electron-donating
group (entries 2 and 5). The catalytic system was sensitive to
the steric bulk of the substrates; specifically, compound 1q,
which has an ortho-methyl group, gave a dramatically lower
yield (entry 17). Tosylhydrazone 1t, which contains a coordi-
nating quinoline moiety, afforded desired B–H bond insertion
product 3tf in 75% yield when the borane adduct 2f was used
(entry 20). Dialkyl tosylhydrazones were unreactive under the
standard reaction conditions.
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Table 1. Transition-Metal-Catalyzed B–H Bond Inser-
tion of Tosylhydrazone 1a with Borane Adducts 2: Op-
timization of the Reaction Conditions. a
Table 2. Rhodium-Catalyzed B–H Bond Insertion of
Aryl Methyl Substituted Tosylhydrazones. a
yield (%)
89
Ar/1
2
3
entry
1
yield
2-naphtyl/1a
2a
3aa
time conv.
(h)
entry cat. (mol %)
2
(%)c
26
(%)b
80
55
84
2a
2a
3ba
3ca
2
3
Cu(MeCN)4PF6 (10)
2a
2a
2a
4
1
/1b
/1c
74
CuI (10)
4
99
2
45
CuBr2 (10)
4
89
3
80
60
70
80
85
86
83
86
92
84
80
88
90
22
Ph/1d
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3da
3ea
3fa
4
trace
trace
43
FeCl2 (10)
2a 23
2a 23
80
4
4-MeOC6H4/1e
4-MeC6H4/1f
4-PhC6H4/1g
4-IC6H4/1h
5
AuCl (10)
trace
60
5
6
Pd(dba)2 (10)
[Rh(cod) Cl]2 (10)
Rh2(TFA)4 (5)
Rh2(TPA)4 (5)
Rh2(piv)4 (5)
Rh2(piv)4 (2)
Rh2(piv)4 (1)
Rh2(piv)4 (2)
Rh2(piv)4 (2)
Rh2(piv)4 (2)
Rh2(piv)4 (2)
Rh2(piv)4 (2)
Rh2(piv)4 (2)
Rh2(piv)4 (2)
Rh2(piv)4 (2)
Rh2(piv)4 (2)
2a
2a
2a
2a
2a
2a
2a
2a
4
2
6
4
4
4
5
7
6
3ga
3ha
3ia
7
24
35
7
8
10
20
8
4-(CO2Me)C6H4/1i
4-CNC6H4/1j
4-NO2C6H4/1k
4-CF3C6H4/1l
3-MeC6H4/1m
3-FC6H4/1n
9
79
100
100
100
95
9
3ja
10
11
12
13
14
15
16
17
92
10
11
12
13d
14e
15f
16
17
18
19
20
21
3ka
3la
89
80
3ma
3na
3oa
3pa
3qa
79
100
trace
0
33
2a 12
2a
2b 11
2c
2d 11
3-ClC6H4/1o
3-BrC6H4/1p
2-MeC6H4/1q
trace
93
4
100
100
100
100
100
100
66
4
75
79
60
75
2a
2a
2f
3ra
3sa
3tf
18
19
20
/1r
/1s
/1t
91
2e
2f
4
4
81
65
2g 11
aReaction conditions: 1a/2/LiOtBu = 0.2:0.4:1.2 (mmol), in
3 mL of DCE, 4 h. cod = 1,5-cyclooctadiene. dba = dibenzyli-
deneacetone. TFA = trifluoroacetate. TPA = triphenylacetate.
aReaction conditions: Rh2(piv)4/1/2a or 2f/LiOtBu
0.004:0.2:0.4:1.2 (mmol), in 3 mL of DCE at 55 ℃, 4 h.
=
piv = pivalate. b Based on the recovery of 1a. Isolated yield. d
c
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We next evaluated B–H bond insertion reactions of tosylhy-
a Reaction conditions: [Rh]/1a/2/LiOtBu = 0.004:0.2:0.4:1.2
(mmol), in 3 mL of DCE at 55 ℃, 4 h. Isolated yield. Deter-
mined by HPLC.
b
c
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drazones 4 derived from various other carbonyl compounds
as carbene precursors (Table 3). Tosylhydrazones derived
from aromatic aldehydes (4a and 4l; entries 1 and 12), aryl
alkyl ketones with linear or branched R groups
(4b, 4c, and 4j; entries 2, 3, and 10), and diaryl ketones (4e–
4i; entries 5–9) were all suitable carbene precursors for B–H
bond insertion reactions with borane adduct 2a or 2f.7,8 Reac-
tion of an aryl alkyl ketone with a sterically hindered R group
(4d) was achieved with CuI as a catalyst (entry 4). Moreover,
the tosylhydrazone derived from cyclic ketone 4k reacted
smoothly with 2a to afford the desired product 5ka in good
yield (entry 11). It is worth mentioning that the carbene
transfer reactions with α-alkyl diazo compounds easily un-
dergo β-hydride elimination,9 but give B–H bond insertion
products with satisfactory yields in this study.
Table 3. Rhodium-Catalyzed B–H Bond Insertion of
Other Tosylhydrazones with Borane Adduct 2a or 2f. a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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59
60
yield (%)b
Ar/R
4
2
5
entry
1
Table 5. Enantioselective Rhodium-Catalyzed B–H
Bond Insertion Reactions: Substrate Scope. a
75
75
70
71
94
85
88
93
87
72
Ph/H
4a
4b
4c
4d
4e
4f
2a 5aa
2a 5ba
2a 5ca
2a 5da
2a 5ea
2a 5fa
2a 5ga
2a 5ha
2a 5ia
Ph/Et
Ph/ nBu
2
3
4c
Ph/cyclopropyl
Ph/Ph
5
Ph/4-MeOC6H4
Ph/2-ClC6H4
Ph/2-naphtyl
Ph/C6F5
6
yield
e.r.c
4g
4h
4i
7
Ar/R (1 or 4)
Condition A
2
3
entry
(%)b
8
9
4-ClC6H4/Bn
4j
2f
5jf
10
96:4
95:5
2-naphtyl/Me (1a)
2f 3af
2f 3bf
78
49
1
2
75
60
4k
4l
2a 5ka
2a 5la
11
12
/Me (1b)
/Me (1c)
91:9
95:5
93:7
ferrocenyl/H
2f 3cf
2f 3rf
2f 3tf
82
65
74
3
4
5
aReaction conditions: Rh2(piv)4/4/2a or 2f /LiOtBu
=
0.004:0.2:0.4:1.2 (mmol), in 3 mL of DCE at 55 ℃, 4 h. b Isolat-
/Me (1r)
ed yield. c Used 10 mol % CuI as catalyst.
/Me (1t)
Ph/Et (4b)
Ph/nBu (4c)
Table 4. Enantioselective Rhodium-Catalyzed B–H Bond
Insertion of Tosylhydrazone 1a and Borane Adducts 2:
Optimization of the Reaction Conditions. a
88:12
88:12
2e 5be
2e 5ce
63
63
6
7
Condition B
93:7
93:7
92:8
92:8
91:9
92:8
Ph/Me (1d)
2a 3da 70
8
4-MeOC6H4/Me (1e)
4-MeC6H4/Me (1f)
3-MeC6H4/Me (1m)
3-FC6H4/Me (1n)
3-ClC6H4/Me (1o)
2a 3ea
2a 3fa
50
62
9
10
11
12
13
2a 3ma 68
2a 3na 76
2a 3oa
70
98:2
2a 3sa
50
14
/Me (1s)
entry [Rh]
2
3
yield (%)b e.r.c
51:49
1
2
3
4
5
6
7
8
Rh2[5(S)-MEPY]4
2a 3aa
5
95:5
2a 5ka
72
15
Rh2[(S)-DOSP]4
Rh2[(R)-BTPCP]4
Rh2[(S)-PTTL]4
Rh2[(S)-TCPTTL]4
Rh2[(S)-TBPTTL]4
Rh2[(S)-NTTL]4
Rh2[(R)-BTPCP]4
2a 3aa 36
2a 3aa 91
2a 3aa 71
2a 3aa 96
2a 3aa 94
2a 3aa 94
2f 3af 78
54:46
56:44
80:20
89:11
88:12
73:27
96:4
(4k)
aCondition A: Rh2[(R)-BTPCP]4/1 or 4/2f or 2e/LiOtBu =
0.004:0.2:0.4:1.2 (mmol), in 3 mL of DCE at 55 ℃, 4 h. Condi-
tion
B:
Rh2[(S)-TBPTTL]4/1
or
4/2a/LiOtBu
=
0.004:0.2:0.4:1.2 (mmol), in 3 mL of DCE at 55 ℃, 4 h. b Isolat-
ed yield. c Determined by HPLC.
We then investigated the asymmetric version of the B–H
bond insertion reaction (Table 4). First, several commercially
available chiral dirhodium catalysts were tested in the reac-
tion of tosylhydrazone 1a and borane adduct 2a (entries 1–7).
Although Rh2[5(S)-MEPY]4,10 Rh2[(S)-DOSP]4,11 and Rh2[(R)-
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n
BTPCP]4 gave very poor enantioselectivities, dirhodium
toluene/DMSO (5:1, v/v), reflux, 12 h. (d) Bu3P, toluene, 85
complexes modified with α-imido acids (Rh2[(S)-PTTL]4,13
Rh2[(S)-TCPTTL]4, Rh2[(S)-TBPTTL]4 and Rh2[(S)-NTTL]4
oC, 7 h.
1
14
15
)
2
3
4
5
6
7
8
9
The B–H bond insertion reaction of tosylhydrazone 1a and
borane adduct 2e could be performed on a gram scale with
satisfactory yield and e.r. by using 0.5 mol % Rh2[(R)-BTPCP]4
as the catalyst (Scheme 2, eq 1). The B–H bond insertion
product, (R)-(+)-3ae, was readily crystallized, and its optical
purity could be enhanced to 99:1 e.r. by means of recrystalli-
zation. The Rh2[(R)-BTPCP]4 catalyst could be recovered by
flash chromatography (80% yield, see Table S3 for details)
and reused without substantial loss of catalytic activity. More-
over, we successfully converted ketone 6 into the correspond-
ing organoborane in one pot by means of a condensation and
B–H bond insertion sequence with high overall yield and re-
tained e.r. (Scheme 2, eq 2).
gave good enantioselectivities (73:27–89:11 e.r.; entries 4–7).
A careful investigation of other chiral dirhodium catalysts and
orthogonal test of borane adducts and catalysts (see Table S1
for details) showed that the combination of Rh2[(R)-BTPCP]4
and 3,5-diisopropylpyridine-borane adduct (2f) gave the
highest enantioselectivity (96:4 e.r.; Table 4, entry 7).
Under the optimal reaction conditions, asymmetric B–H
bond insertion reactions with various tosylhydrazones were
then performed (Table 5). The enantioselectivity of the reac-
tion was highly sensitive to the combination of catalysts and
substrates, so we developed two different catalytic systems.
The combination of Rh2[(R)-BTPCP]4 and pyridine-borane
adduct 2f or 2e (condition A) exhibited good enantioselectivi-
ty for tosylhydrazones with shapes similar to that of 1-
(naphthalen-2-yl)ethan-1-ones (1a–1c, 1r, and 1t; entries 1–
5) and with tosylhydrazones of aryl alkyl ketones (R = Et or
nBu, 4b and 4c, entries 6 and 7). In contrast, the combination
of Rh2[(S)-TBPTTL]4 and trimethylamine-borane adduct (2a,
condition B) gave better enantioselectivity for the tosylhydra-
zones of acetophenone and its derivatives (1d–1f, 1m–1o, and
1s; entries 8–14) or cyclic ketone 4k (entry 15). Notably, the
highest e.r. (98:2) was obtained in the reaction of tosylhydra-
zone 1s and borane adduct 2a under condition B (entry 14).
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Organoboranes obtained from the B–H bond insertion reac-
tion were relatively stable during subsequent transformations
and during storage. However, they could also undergo diverse
transformations under mild conditions (Scheme 3). For in-
stance, (R)-(+)-3ae was easily converted to corresponding
alcohol (R)-(+)-7 by oxidation (Scheme 3a), and to widely
used boron reagents (R)-(+)-8 (Scheme 3b) and (R)-(+)-9
(Scheme 3c) by condensation with pinacol and MIDA. Moreo-
ver, (R)-(+)-3ae could be directly transformed to (R)-(+)-3ab
by means of a Lewis base exchange reaction under heating
(Scheme 3d). In all cases, the stereochemistry was retained
and the yield was high. The results shown in Schemes 2 and 3
clearly demonstrate the high potential utility of this protocol.
Scheme 2. Gram-scale and One-pot Preparation of 3ae
Scheme 4. Proposed Mechanism
Scheme 3. Transformations of (R)-(+)-3ae
Scheme 5. Control Experiments
Reaction conditions: (a) H2O2, MeOH, 80 °C, 2 h. (b) pinacol,
toluene, reflux, 2 h. (c) N-methyl imidodiacetic acid (MIDA),
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Qi, W.-Y.; Xu, B.; Xu, M.-H. J. Am. Chem. Soc. 2015, 137, 5268. (c) Cheng,
We proposed a mechanism of the rhodium-catalyzed B–H
bond insertion reaction by analogy with the other rhodium-
catalyzed carbene transfer reactions (Scheme 4).7 The reac-
tion starts with the generation of diazo compound I from a
tosylhydrazone through Bamford-Stevens process.6 Rhodium
catalyst then coordinates with the electron-rich diazo con-
nected carbon (step a, II), extrudes nitrogen gas, and gener-
ates highly active rhodium carbene III (step b). The rhodium
carbene III finally inserts into a B–H bond of the borane ad-
duct to give the insertion product (step c). A deuterium label-
ing experiment (Scheme 5a) showed that all the deuterium
atoms located either at boron or at α-carbon of the insertion
product 3ae-d3, while a kinetic isotopic effect experiment
(Scheme 5b) exhibited a minor kH/kD (1.5:1). These experi-
ments indicate a concerted and fast B–H bond insertion pro-
cess (TS).3 The studies towards detailed mechanism under-
standing of the enantioselectivity are undergoing in our la-
boratory.
Q.-Q.; Xu, H.; Zhu, S.-F.; Zhou, Q.-L. Acta Chim. Sinica 2015, 73, 326. (d)
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In summary, we have described a protocol for rhodium-
catalyzed B–H bond insertion reactions of borane adducts and
unstabilized diazo compounds generated in situ from tosylhy-
drazones at low temperature. This protocol constitutes a new
method for preparation of organoboranes starting from readi-
ly available aldehydes or ketones in reasonable yields and
with high enantioselectivity and good functional group toler-
ance. Investigation of the mechanism and additional synthetic
applications of this reaction is underway in our laboratory.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, spectral data, and computational
study results. The Supporting Information is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*sfzhu@nankai.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
(9) For a review on the use of alkyl substituted diazo compounds in
rhodium-catalyzed intermolecular reactions that proceed with pref-
erence over β-hydride elimination, see: (a) DeAngelis, A.; Panish, R.;
Fox, J. M. Acc. Chem. Res. 2016, 49, 115. For selected examples, see: (b)
Taber, D. F.; Joshi, P. V. J. Org. Chem. 2004, 69, 4276. (c) Panne, P.; Fox,
J. M. J. Am. Chem. Soc. 2007, 129, 22. (d) DeAngelis, A.; Taylor, M. T.;
Fox, J. M. J. Am. Chem. Soc. 2009, 131, 1101. (e) DeAngelis, A.;
Dmitrenko, O.; Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2009, 131,
7230. (f) Goto, T.; Takeda, K.; Shimada, N.; Nambu, H.; Anada, M.; Shi-
ro, M.; Ando, K.; Hashimoto, S. Angew. Chem., Int. Ed. 2011, 50, 6803.
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sen, S. H.; Ghosh, R., J. Am. Chem. Soc. 1993, 115, 9968.
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(13) (a) Watanabe, N.; Ogawa, T.; Ohtake, Y.; Ikegami, S.; Hashimoto,
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Eur. J. 2016, 22, 3447.
(14) Lindsay, V. N. G.; Lin, W.; Charette, A. B. J. Am. Chem. Soc. 2009,
131, 16383.
We thank the National Natural Science Foundation of China
(21625204, 21790332, 21532003), the “111” project
(B06005) of the Ministry of Education of China, the National
Program for Special Support of Eminent Professionals, and the
Fundamental Research Funds for the Central Universities for
financial support.
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