Investigation of the Deprotonative Generation and Borylation of Diamine-Ligated α-Lithiated Carbamates and Benzoates by in Situ IR spectroscopy

Article abstract of DOI:10.1021/jacs.8b06871

Diamine-mediated α-deprotonation of O-alkyl carbamates or benzoates with alkyllithium reagents, trapping of the carbanion with organoboron compounds, and 1,2-metalate rearrangement of the resulting boronate complex are the primary steps by which organoboron compounds can be stereoselectively homologated. Although the final step can be easily monitored by ¹¹B NMR spectroscopy, the first two steps, which are typically carried out at cryogenic temperatures, are less well understood owing to the requirement for specialized analytical techniques. Investigation of these steps by in situ IR spectroscopy has provided invaluable data for optimizing the homologation reactions of organoboron compounds. Although the deprotonation of benzoates in noncoordinating solvents is faster than that in ethereal solvents, the deprotonation of carbamates shows the opposite trend, a difference that has its origin in the propensity of carbamates to form inactive parasitic complexes with the diamine-ligated alkyllithium reagent. Borylation of bulky diamine-ligated lithiated species in toluene is extremely slow, owing to the requirement for initial complexation of the oxygen atoms of the diol ligand on boron with the lithium ion prior to boron-lithium exchange. However, ethereal solvent, or very small amounts of THF, facilitate precomplexation through initial displacement of the bulky diamines coordinated to the lithium ion. Comparison of the carbonyl stretching frequencies of boronates derived from pinacol boronic esters with those derived from trialkylboranes suggests that the displaced lithium ion is residing on the pinacol oxygen atoms and the benzoate/carbamate carbonyl group, respectively, explaining, at least in part, the faster 1,2-metalate rearrangements of boronates derived from the trialkylboranes.

Full text of DOI:10.1021/jacs.8b06871

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Article
Investigation of the Deprotonative Generation and Borylation of Diamine-
Ligated #-Lithiated Carbamates and Benzoates by in situ IR spectroscopy
Rory C. Mykura, Simon Veth, Ana Varela, Lydia Dewis,
Joshua J. Farndon, Eddie L. Myers, and Varinder K. Aggarwal
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b06871 • Publication Date (Web): 27 Sep 2018
Downloaded from http://pubs.acs.org on September 27, 2018
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Investigation of the Deprotonative Generation and Borylation of
Diamine-Ligated α-Lithiated Carbamates and Benzoates by in situ IR
spectroscopy
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Rory C. Mykura,∫‡ Simon Veth,∫‡ Ana Varela,∫‡ Lydia Dewis,∫ Joshua J. Farndon,∫ Eddie L. Myers,†*
Varinder K. Aggarwal.∫*
∫School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK.
†School of Chemistry, NUI Galway, Galway, Ireland.
KEYWORDS. Homologation, boronic esters, lithiation, borylation, IR monitoring.
ABSTRACT Diamine-mediated α-deprotonation of O-alkyl carbamates or benzoates with alkyllithium reagents, trapping of
the carbanion with organoboron compounds, and 1,2-metallate rearrangement of the resulting boronate complex are the
primary steps by which organoboron compounds can be stereoselectively homologated. Although the final step can be easi-
ly monitored by 11B NMR spectroscopy, the first two steps, which are typically carried out at cryogenic temperatures, are
less well understood owing to the requirement for specialized analytical techniques. Investigation of these steps by in-situ
IR spectroscopy has provided invaluable data for optimizing the homologation reactions of organoboron compounds. Alt-
hough the deprotonation of benzoates in non-coordinating solvents is faster than that in ethereal solvents, the deprotona-
tion of carbamates shows the opposite trend, a difference that has its origin in the propensity of carbamates to form inactive
parasitic complexes with the diamine-ligated alkyllithium reagent. Borylation of bulky diamine-ligated lithiated species in
toluene is extremely slow, owing to the requirement for initial complexation of the oxygen atoms of the diol ligand on boron
with the lithium ion prior to boron–lithium exchange. However, ethereal solvent, or very small amounts of THF, facilitate
precomplexation through initial displacement of the bulky diamines coordinated to the lithium ion. Comparing the carbonyl
stretching frequencies of boronates derived from pinacol boronic esters with those derived from trialkylboranes, suggests
that the displaced lithium ion is residing on the pinacol oxygen atoms and the benzoate/carbamate carbonyl group, respec-
tively, explaining, at least in part, the faster 1,2-metallate rearrangements of boronates derived from the trialkylboranes.
cant optimization of reaction conditions, such as reaction
time, solvent, temperature, and whether to use carbamates
1. Introduction
The stereoselective homologation of boronic esters with
lithium carbenoids derived from Hoppe-type carbamates1
and Beak-type triisopropylbenzoates2 has emerged as a
powerful carbon–carbon bond-forming transformation.3
The process involves three main steps (Scheme 1): Step
1—the sparteine-mediated enantioselective deprotonation
(lithiation) of a primary carbamate or benzoate with s-
BuLi in an ethereal solvent (typically, Et2O, TBME, or
CPME) at low temperature (−78 °C); Step 2—the boron–
lithium exchange (borylation) of the resulting sparteine-
ligated lithium carbenoid through the addition of a boronic
ester, a step that is also carried out at low temperature
owing to the level of chemical and configurational stability
of the carbenoid;4 Step 3—1,2-metallate rearrangement of
the resulting boronate, a process that typically takes place
above −20 °C for benzoates and at more elevated tempera-
tures (40 °C) for carbamates.5 The process can be repeated
multiple times with the same or a different carbenoid rea-
gent, allowing carbon chains to be grown one carbon at a
time with complete control over substituent identity and
configuration.3a-c The bringing together of new partners
(the carbenoid precursor and the boronic ester), especially
those presenting steric hindrance, often demands signifi-
or benzoates.6 The last step of the process is easily moni-
tored by 11B NMR spectroscopy as the process operates at
ambient temperatures and the 4-coordinate boronate and
3-coordinate boronic ester resonate at very distinct re-
gions (~6 ppm and ~30 ppm, respectively). This facility
has allowed novel insight that has led to the routine use of
magnesium salts and solvent-switches (Et2O to CHCl3) to
promote this step when slow migrating groups are en-
countered.6b However, monitoring and troubleshooting the
first two steps is more challenging owing to the processes
being carried out at cryogenic temperatures and the added
complication that the boron–lithium exchange can be re-
versible at temperature regimes where the 1,2-metallate
rearrangement occurs.6e,7 However, indirect probing of
these processes through deuterium quenching and the
addition of other electrophiles (allyl bromide) at judicious
points in the process has proven useful.7 With the aim of
gaining more insight into the lithiation and borylation
steps, we decided to investigate the process through in-
situ IR spectroscopy.8 The variation of solvent, diamine,
temperature, as well as the organic group on the organo-
boron and the carbenoid precursor has revealed
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surprising trends and interesting effects that shed light on published on the amine-free n-BuLi deprotonation of ben-
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the elementary events that characterize each step.
zylic carbamates and benzoates in THF/hexane solvent
mixtures. Garcia-Rio and co-workers have shown that ben-
zylic carbamates undergo deprotonation much more rap-
idly than the corresponding benzoates;10 this result points
towards the involvement of a prelithiation complex, the
formation of such an intermediate being both more facile
for the carbamate owing to the higher basicity of the car-
bonyl oxygen atom and rate determining when the depro-
tonation event is relatively facile, such as, for example,
Scheme 1. Stereoselective homologation of boronic
esters.
9
deprotonation at
a benzylic position. Upon near-to-
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complete formation of the α-lithiated carbamate and ben-
zoate, the addition of a 1.0 M solution of phenethyl boronic
acid pinacol ester in Et2O leads to rapid conversion of the
lithiated species into the corresponding boronate, indicat-
ed by the rapid drop in intensity of the bands at 1616 and
1633 cm−1 with concomitant appearance and increase in
intensity of bands at 1642 and 1667 cm−1, respectively. For
the α-lithiated carbamate, the conversion into boronate
was almost complete by the time the last drop of boronic
ester solution was added (<15 sec); for the α-lithiated ben-
zoate boronate formation was complete in just under 2
minutes. Warming to 35 °C and room temperature for the
reaction mixtures of carbamate and benzoate, respectively,
allows for 1,2-metallate rearrangement, giving the one-
carbon homologated boronic ester. Upon oxidative workup
(aq. NaOH/aq. H2O2), the corresponding alcohol was iso-
lated in 98:2 and 95:5 e.r., values that are fully consistent
with the levels of enantioselectivity that are normally im-
posed by sparteine on the deprotonation of carbamates1
and benzoates,2 respectively.
2. Results and Discussion
2.1 Initial comparison of carbamates and benzoates
Solutions of ethyl carbamate 1a and ethyl benzoate 2a in
Et2O (0.3 M) at −78 °C show a strong νC=O band at ~1697
and 1730 cm–1, the lower value for the carbamate being
consistent with significant contribution from the imidate
resonance form, thus engendering a more basic oxygen
atom (Figure 1). Treatment of these solutions with (+)-
sparteine (1.2 equiv) followed by s-BuLi (1.2 equiv, 1.3 M in
cyclohexane) leads to the disappearance of the above sig-
nals with appearance of new signals at lower wave-
numbers, ~1616 and 1633 cm–1, which are consistent with
the dipole-stabilized α-lithiated carbamate 3a and benzo-
ate 4a, respectively, the lithium ion being bound to the
bidentate diamine, the carbenoid carbon atom and the
oxygen atom of the carbonyl group. For the carbamate, an
intermediate signal, ~ 20 cm–1 lower than that of the sub-
strate (1678 cm–1), quickly appears and then disappears;
this signal presumably represents one or a collection of
complexes in which a lithium ion binds to the carbonyl
oxygen atom of the carbamate.8 The stoichiometry of this
complex and whether the complexes are intermediates on
the pathway to lithiated species (prelithiation complexes)
or mostly the products of a parasitic equilibrium was un-
clear. Monitoring of the benzoate did not show any evi-
dence of a similar complex. The benzoate 2a undergoes
much more rapid lithiation compared to the carbamate 1a.
We find it convenient to report the rate of deprotonation
as approximate half-lives (t1/2)– the amount of time it takes
for half of what will be the full amount of the α-lithiated
species to be formed; the alternative method, reporting the
amount of time it takes for half of the substrate to be con-
sumed, is more challenging owing to the confounding ef-
fects of the initially formed complexes and changes in con-
centration during the addition of the organolithium rea-
gent. Note: The use of the term half-life here does not apply
any certainty on the molecularity (or pseudomolecularity)
of the transformation. Ethyl benzoate 2a undergoes depro-
2.2 Effect of steric hindrance at the β position
We investigated the effect of steric hindrance on both the
rate of deprotonation and the subsequent borylation by
sequentially adding a methyl group to the β carbon atom of
the ethyl carbamate and benzoate derivatives (Table 1).
The t1/2 for the sparteine-mediated deprotonation of the
ethyl, propyl and isobutyl carbamate (1a–c) was 30 (as
given above), 33 and 81 minutes, respectively; neopentyl
carbamate 1d did not undergo deprotonation at an appre-
ciable rate at −78 °C. The corresponding values for the
benzoates (2a–d) were 8, 16, 31, and 94 minutes, respec-
tively, the neopentyl substrate undergoing very slow but
steady deprotonation at −78 °C. The similar rate for the
deprotonation of the ethyl and propyl carbamate (entries 1
and 3, respectively) contrasting with a doubling in half-life
in going from the ethyl to the propyl benzoate suggests
both the absence of an inductive effect of increased substi-
tution on the acidity of the pertinent methylene group, and
also perhaps the greater proximity of the benzoate’s
triisopropylphenyl group—lying orthogonal to the carbon-
yl group—to the β carbon atom, compared to that of the
carbamate’s diisopropylamino group. The switching-on of
sensitivity of deprotonation of the carbamate to steric hin-
drance upon moving to the isobutyl substrate (entry 5)
might reflect its inability to avoid a conformation that im-
parts significant steric hindrance near the β carbon atom
and the sparteine-ligated organolithium reagent during
deprotonation. The subsequent borylation appears to be
much more sensitive
tonation ca. four times faster than the carbamate 1a (t1/2
=
8 min and 30 min, respectively), despite the similar pKa
values.9 However, this trend contrasts with results recently
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Figure 1. 2D and 3D plots of absorbance versus time for species involved in the lithiation and borylation of ethyl carbamate (A)
and ethyl benzoate (B). TP = 2,4,6-triisopropylphenyl.
d
sis of the alcohol product by using a chiral stationary phase.
No reaction.
Table 1: Effect of steric hindrance at the β positiona
(+)ꢀsp.
Li
t1/2 Li
O
B
t1/2
B
O
to steric hindrance. Although borylation of the carbamate
was rapid across the series (<15 sec, <15 sec, 3 min; the
neopentyl substrate was not lithiated at −78 °C), the rate of
borylation of the lithiated benzoate dropped steeply with
each addition of a methyl group (2, 8, 35, 296 min). That
borylation of an organolithium could be so slow at −78 °C
was a surprise, thus giving us cause to reassess our stand-
ard protocols for borylation. Additionally, we also investi-
gated the isobutyl derivative of another popular type of
s-BuLi
(+)ꢀsparteine
(+)ꢀsp.
R
Li—
O
O
O
O
Ph
B
Ph
5a
H
O
X
R
O
X
O
Et2O, _78 °C
Et2O, _78 °C
R
O
X
1a
d
−
3a
d
−
6a d
−
(X = NiPr2)
(X = NiPr2)
(X = NiPr2)
2a−d (X = TP)
4a−d (X = TP)
7a−d (X = TP)
R/X/Substrate t1/2 Li
(min)
t1/2
B
Yield
e.r.c
(min) (%)b
<15 s 44
1
2
3
4
5
6
7
Me/NiPr2/1a
Me/TP/2a
Et/NiPr2/1b
Et/TP/2b
30
8
98:2
95:5
98:2
97:3
98:2
97:3
98:2
carbamate
– the Cby group (2,2,4,4-tetramethyl-1,3-
2
45
oxazolidin-3-yl), which gives slightly higher e.r. than the
standard carbamate.11 Interestingly, it undergoes deproto-
nation approximately 2-fold slower than the diisopropyl
carbamate (t1/2: 145 versus 81 minutes; entry 7). Although,
the N,O-acetal moiety of the Cby group would be expected
to acidify the pertinent methylene, while engendering a
less basic carbonyl group, it seems that the rate of depro-
tonation is more strongly impacted by the geminal pairs of
methyl groups, which, owing to the ring structure, are
locked pointing toward the carbonyl group, thus being
more sterically imposing than those of the more flexible
isopropyl groups in the Cb substrate. The Cby substrate
also exhibited a prelithiation complex.
33
16
81
31
145
<15 s 60
8
77
67
66
28
iPr/NiPr2/1c
iPr/TP/2c
3
35
3
iPr/
d
8
tBu/NiPr2/1d
tBu/TP/2d
-
-
-
-
9
94
296
21
99:1
a
Conditions: 1/2 (0.66 mmol), (+)-sparteine (0.79 mmol), s-
in cyclohexane), Et2O, −78 °C; then
BuLi (0.79 mmol, 1.3
M
phenethyl boronic ester (0.79 mmol), Et2O, −78 °C; warming
to RT (X=TP) or 40 °C (X=NiPr2); NaOH/H2O2, THF/H2O.
Yield of alcohol as isolated by column chromatography follow-
ing oxidation of the homologated boronic ester, structures of
which are located in the SI. c Determined through HPLC analy-
2.3 Effect of a proximal aromatic group
b
For methodology development in this area, our group
normally uses the phenylpropyl carbamate and benzoate
as model substrates because lithiation appears to be facile.
Indeed, the carbamate and benzoate derivative of this sub-
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strate (1e and 2e) undergoes much more rapid deprotona- butylmethylether (TBME) is sometimes used when using
very lipophilic substrates3c and cyclopentylmethyl ether
(CPME) engenders higher yields when lithiating secondary
alkyl benzoates.13 Notably, the use of tetrahydrofuran
(THF) in sparteine-mediated enantioselective deprotona-
tion leads to products of low e.e. values, presumably due to
non-diamine ligated alkyllithium monomers and higher
aggregates that are competent at deprotonation;14 interest-
ingly, the use of THF/TMEDA for the stereospecific depro-
tonation of secondary alkyl benzoates leads to poor yields
compared to Et2O and TBME, indicating other deleterious
attributes.13 Toluene is another common solvent for the
deprotonation of carbamates and benzoates,14b but has not
been adequately explored for lithiation/borylation se-
quences. Using the n-propyl benzoate as a test substrate,
the relative rates of sparteine-mediated lithiation were
determined in Et2O, TBME, and toluene, the t1/2 values be-
ing 16, 26 and 9 minutes, respectively (Table 3, entries 4–
6). The corresponding values for the n-propyl carbamate
were 33, 43 and 66 minutes, respectively (Table 3, entries
1–3). That toluene is a very good solvent for lithiating ben-
zoates and a very poor solvent for lithiating carbamates
was also apparent with the ethyl (see Supporting Infor-
mation) and the isobutyl carbamates/benzoates (Table 3,
entries 7–11). The solvent trends are difficult to rationalize
with a high level of confidence. Presumably, a high rate of
lithiation will be promoted by a suitably high concentra-
tion of both monomeric sparteine-ligated s-BuLi and sub-
strate so that they can come together to form a complex
that is competent for subsequent intracomplex proton
transfer. The concentration of both species will be dictated
by the stability of other non-productive complexes. Previ-
ous work with iPrLi has shown that a major species in
ethereal solvents is the heterosolvated dimer of the al-
kyllithium (Figure 2, 9: the sparteine ligating one lithium
ion and up to two solvent molecules ligating the other lith-
ium ion).15 This species will presumably need to fragment
to monomeric forms (Figure 2, 12) to al-
1
2
3
4
5
6
7
8
tion than the corresponding n-propyl parent derivative
(Cb: t1/2 5 min versus 33 min; TIB: t1/2 1 min versus 16
min). This
Table 2: Effect of a proximal aromatic groupa
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12
13
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15
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Entry Z/X/Substrate
t1/2 Li t1/2
(min) (min)
B
Yield
(%)b
1
2
3
H/NiPr2/1e
5
1
2
<15 s 58
H/TP/2e
4
5
67
58
77
4-OMe/TP/2f
3,5-(CF3)2/TP/2g
4
<15 s 12
a
Conditions: 1/2 (0.66 mmol), (+)-sparteine (0.79 mmol),
s-BuLi (0.79 mmol, 1.3 M in cyclohexane), Et2O, −78 °C;
then phenethyl boronic ester 5a (0.79 mmol), Et2O, −78 °C;
b
warming to 40 °C/RT; NaOH/H2O2, THF/H2O. Yield of
alcohol as isolated by column chromatography following
oxidation of the homologated boronic ester.
rate enhancement could be due to a through-bond induc-
tive withdrawal of electron density or due to a through-
space effect, such as a cation–π interaction between the
aromatic ring and a lithium ion.12 Beak and co-workers
observed that N-Boc-4-phenyl-piperidines underwent
much more rapid lithiation at the 2 position compared to
the unsubstituted piperidines;13 this result would suggest
that the rate enhancement is due to an inductive effect, as
the equatorially positioned phenyl group would not be
able to assist in a through-space interaction. We decided to
investigate the phenylpropyl benzoate (2e), together with
the 4-methoxy and 3,5-bis(trifluoromethyl) substituted
derivatives (2f, 2g) (Table 2). The 4-methoxyphenyl deriv-
ative underwent deprotonation at a slightly lower rate
than the phenyl derivative (t1/2 2 min versus 1 min) while
the 3,5-bis(trifluoromethyl)phenyl derivative underwent
deprotonation at a noticeably higher rate, conversion be-
ing complete by the time the solution of s-BuLi was added
(t1/2 < 15 sec). The rate of borylation dropped in the order
phenyl (t1/2 3 min) > 4-methoxyphenyl (t1/2 5 min) > 3,5-
bis(trifluoromethyl)phenyl (t1/2 12 min). These results
suggest that increased inductive withdrawal leads to faster
lithiation and slower borylation, as one would expect.
However, the lithiated n-propyl benzoate, 2b, undergoes
borylation with a t1/2 value of 8 min, placing it in the mid-
dle of the above series, and not at the beginning, suggest-
ing that the pendent phenyl group promotes borylation
through a through-space effect (see Section 2.4 for further
discussion). The treatment of a 1:1 mixture of sparteine-
ligated lithiated n-propyl benzoate and phenylpropyl ben-
zoate with phenethyl boronic ester gave a 1:1.9 ratio of
homologated boronic esters, respectively, thus being con-
sistent with the above half-lives.
Table 3: Effect of solventa
Entry R/X/Substrate
Solvent
t1/2 Li t1/2
B
(min) (min)
1
Et/NiPr2/1b
Et/NiPr2/1b
Et/NiPr2/1b
Et/TP/2b
Et2O
33
43
66
16
26
9
<15 s
<15 s
42
2
TBME
Toluene
Et2O
3
4
8
5
Et/TP/2b
TBME
Toluene
Et2O
13
6
Et/TP/2b
501
3.5
>50
35
7
iPr/NiPr2/1c
iPr/NiPr2/1c
iPr/TP/2c
iPr/TP/2c
145
195
31
52
8
Toluene
Et2O
2.4 Effect of solvent
9
Diamine-promoted lithiation reactions for subsequent
10
TBME
45
borylation are primarily conducted in Et2O;3g t-
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N.R.b
(see Table 4). The borylation of carbamates was also slow-
er in toluene solvent (ethyl carbamate: t1/2 ether <15 s, t1/2
toluene 42 min), but still relatively fast compared to the
benzoates (ethyl benzoate: t1/2 ether 8 min, t1/2 toluene 501
min). That there was a solvent effect at all was surprising
and gave us cause to consider the finer details of boryla-
tion. In an earlier comparison of the stereospecificity of the
borylation of secondary benzylic carbamates with boronic
11
iPr/TP/2c
Toluene
15
1
2
3
4
5
6
7
a
Conditions: 1/2 (0.66 mmol), (+)-sparteine (0.79 mmol),
s-BuLi (0.79 mmol, 1.3 in cyclohexane), Solvent, −78 °C; then
phenethyl boronic ester (0.79 mmol), Solvent, −78 °C; warm-
ing to RT (X=TP) or 40 °C (X=NiPr2); NaOH/H2O2, THF/H2O.
The rate of borylation was extremely low.
M
b
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2: Alkyllithium/sparteine/substrate equilibria
low for productive complexation. The use of poorly coor-
dinating toluene as a solvent will promote the formation of
homosolvated dimer 11 (both lithium ions ligated by a
bidentate diamine),16 which, in the case of sparteine, will
be relatively labile, thus promoting a relatively high con-
centration of monomeric sparteine-ligated s-BuLi 12. For
the triisopropylbenzoate, complexation with the 3-
coordinate monomer (to give 13) will lead directly to lithi-
ation; this hypothesis is supported by the higher rate of
lithiation of benzoates in toluene compared to reactions in
Et2O. However, the lithiation of carbamates shows the op-
posite trend: the reactions are slower in toluene. This dif-
ferent solvent trend could be explained by carbamates
being more likely to form stable unproductive heterosolv-
ated dimers (e.g. 10: sparteine ligating one lithium and one
or two molecules of carbamate bound to the other lithium
ion), owing to their smaller size and more electron-rich
carbonyl oxygen atom, thus engendering a low concentra-
tion of both monomeric sparteine-ligated alkyllithium and
carbamate. This hypothesis is supported by the high con-
centrations of lithium-complexed carbamates in toluene
(their presence being indicated by the rapid appearance of
an IR band of lower frequency relative to free carbamate
upon addition of the organolithium reagent), which, in line
with data to be presented below, appear to be parasitic
intermediates for lithiation. Explaining the lower rate of
lithiation in TBME, compared to the reaction in Et2O, re-
quires much more speculation but might be a consequence
of the dynamics centering around the heterosolvated di-
mer (akin to 9), including how many solvent molecules
(one or two) bind to one of the lithium ions and how this
coordination number effects the rate of fragmentation to
monomeric form.
Figure 3: Solvent-mediated boron–lithium exchange
esters and boranes, the retentive boron–lithium exchange
for boronic esters versus an invertive exchange for trialkyl
boranes strongly suggested that one of the oxygen atoms
of the diol ligand on boronic esters coordinate to the lithi-
um ion of the lithiated carbonyl compound prior to boron–
lithium exchange.17
This precomplexation could happen through initial disso-
ciation of the carbonyl oxygen atom of the carba-
mate/benzoate, giving a 3-coordinate lithium ion (the lig-
ands being bidentate sparteine and the α carbon atom of
the carbonyl substrate) that has an empty site for coordi-
nation for the boronic ester (Figure 3; 14→15→16→17).
Dissociation of the carbonyl oxygen atom from the lithium
ion should also lead to a more reactive carbon–lithium
bond and a more flexible intermediate for boron–lithium
exchange. The solvent effect unveiled here suggests that
dissociation of the sparteine ligand, either fully or partially
(monodentate diamine) and replacement with smaller
solvent molecules may be required for either coordination
of the boronic ester, subsequent boron–lithium exchange
or both, with both steric as well as electronic effects being
at play (Figure 3; 14→18→19/20→21 →17). Such a mech-
anism may be operating in parallel to one where sparteine
remains coordinated in a bidentate fashion to the lithium
ion, a pathway that may be more efficient in the case of
carbamates. Because we had identified toluene as a good
solvent for the lithiation of benzoates, we tested the use of
additives for promoting borylation in the hope of identify-
ing a viable toluene-based process for the lithiation–
borylation of benzoates. Addition of 0.6 equivalents (based
on substrate) of THF to a toluene solution of sparteine-
The effect of solvent on the rate of borylation was both
striking and surprising (Table 3). Although the borylation
of lithiated carbamates was always faster than the corre-
sponding benzoates in all solvents, thus in line with the
results above (Section 2.1), the use of toluene solvent en-
gendered extremely low rates of borylation for benzoates;
even the relatively unhindered ethyl substrate underwent
borylation with a half-life of approximately 165 minutes
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ligated lithiated propyl benzoate and phenethyl boronic remained high (~95:5 e.r.). Indeed, our research group
1
2
3
4
5
6
7
8
ester led to a marked increase in the rate of borylation
(Figure 4). The addition of the boronic ester as a solution
in THF (1 M) led to very rapid borylation (t1/2 = 2 minutes;
Table 4). Moreover, the enantioselectivity of the process
remained high (~95:5 e.r.). The effect of adding the bo-
ronic ester as a solution in THF had a similarly dramatic
effect on the rate of borylation of the lithiated isobutyl
benzoate (essentially undetectable borylation versus a t1/2
of 11 minutes). As documented
observed a similar and highly enabling enhancement in
rate for the α-lithiation of a benzoate intermediate in the
total synthesis of (−)-stemaphylline.6c Similarly, the re-
search group of O’Brien have observed rate enhancements
in the lithiation of N-Boc piperidines8b and pyrrolidines,19
thus providing further evidence to support the continued
investigation of sparteine surrogate (and the development
of routes to the (−)-sparteine surrogate),20 despite the im-
provement in the availability of (+)-sparteine.21 Interest-
ingly, the use of the sparteine surrogate leads to faster
lithiation compared to that mediated by TMEDA (t1/2 of 15
versus 42 minutes). This comparison
9
Table 4: Effect of THF on the rate of borylationa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
R
Solvent
A
t1/2 Li t1/2
B
t1/2 B
(min) (min) (min)b
0.4
1
2
3
4
a
Me/2a
Et/2b
Toluene
Toluene
Toluene
Et2O
7
<15 s 165
0.35
Addition of
Addition of
9
2
501
N.R.c
296
sec-BuLi
boronic ester
0.3
iPr/2c
tBu/2d
15
78
11
15
Addition of
THF
0.25
0.2
0.15
0.1
Conditions: 2 (0.66 mmol), (+)-sparteine (0.79 mmol), s-
in cyclohexane), Solvent, −78 °C; then
BuLi (0.79 mmol, 1.3
M
phenethyl boronic ester (0.79 mmol, Solvent, −78 °C; warming
to RT; NaOH/H2O2, THF/H2O. The rate of borylation when
boronic ester 5a was added as a solution in solvent A. The
rate of borylation was extremely low.
b
0.05
c
0
00:00:00
01:00:00
02:00:00
03:00:00
04:00:00
05:00:00
06:00:00
07:00:00
Time (hh:mm:ss)
above, the borylation of the very sterically hindered neo-
pentyl benzoate in Et2O solvent was very slow (t1/2 of ~296
minutes). When phenethyl boronic ester was added as a
solution in THF, borylation was much more rapid (t1/2 of 15
minutes), indicating that the addition of boronic esters as
solutions in THF should form part of most lithiation–
borylation protocols. In accordance with the above analy-
sis on the solvent effect on borylation, THF efficiently dis-
places sparteine as a ligand on lithium, leading to faster
borylation. This result also sheds light on the intriguing
promotion of borylation in the presence of a pendent elec-
tron-rich aromatic ring (Section 2.3). It seems reasonable
that the pendant phenyl group can displace the sparteine
ligand and act as a weak intramolecular ligand on lithium,
thus providing a more accessible environment for the bo-
ronic ester.12
Boronate complex at 1664 cmꢀ1
Preꢀlithiated species at 1712 cmꢀ1
Lithiated species at 1633 cmꢀ1
TIB ester at 1723 cmꢀ1
Figure 4: 2D plot of absorbance versus time for the lithia-
tion and borylation of propyl benzoate in toluene solvent,
with the addition of THF to promote borylation.
contrasts with that observed by O’Brien where N-Boc pyr-
rolidine is lithiated fastest by using TMEDA. 8b,19 A similar
trend was observed for the lithiation of isobutyl benzoate,
the t1/2 values for sparteine, TMEDA and sparteine surro-
gate being 31, 17, and 3 minutes, respectively. The surro-
gate’s reduced steric hindrance (compared to sparteine)
and increased rigidity (compared to TMEDA) probably
contributes to its effectiveness. Furthermore, the more
basic nitrogen atoms within the sparteine scaffold com-
pared to those of TMEDA (three bonds versus two bonds
between the electronegative nitrogen atoms) probably
enhance the basicity of s-BuLi.22 As mentioned above, spar-
teine forms a heterodimer with iPrLi (a model for s-BuLi)
in diethyl ether, with sparteine complexed to one lithium
ion and solvent molecules on the other lithium ion;15
O’Brien has shown that the smaller size of the surrogate
engenders the homodimer (a diamine ligand on both lithi-
um ions) being the major species in diethyl ether (see Fig-
ure 2).23 Therefore, the kinetics and thermodynamics of
the pre-equilibria involving substrate are also likely to be
important. That two different types of substrates
(O’Brien’s N-Boc piperidines/pyrrolidines8b,19 and the n-
alkyl carbamates/benzoates) show different trends in di-
amine-mediated deprotonation gives credence to the im-
portance of these equilibria. Owing to the contrasteric re-
sult of the comparison between TMEDA and sparteine sur-
2.5 Effect of diamine
The reactions described above involved the use of sparte-
ine as the diamine promoter. Owing to the interesting ef-
fect of solvent on the rate of lithiation and borylation, we
were keen to investigate and compare other diamine lig-
ands. We were particularly interested in the use of the
sparteine surrogate (Table 5), a less-sterically hindered
derivative of sparteine; this diamine was initially prepared
and investigated by the O’Brien laboratory as a surrogate
for (+)-sparteine, which at the time was extremely scarce
and expensive.18 Relative to sparteine, the use of the (+)-
sparteine surrogate in the deprotonation of isobutyl car-
bamate led to an approximate 5-fold increase in the rate
relative to that with sparteine (t1/2 of 15 versus 81
minutes). Moreover, the enantioselectivity of the process
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Journal of the American Chemical Society
rogate, we decided to prepare and investigate N,N’- mediated deprotonations α to the the nitrogen atom of
1
2
3
4
5
6
7
8
dimethylbispidine, the least sterically hindered diamine
for the sparteine scaffold (Table 5).24 As expected, it was
the most effective diamine for lithiation of isobutyl benzo-
ate 2c (t1/2 of 3 versus 1 minutes for the sparteine surro-
gate and N,N’-dimethylbispidine, respectively). For both
lithiated benzoates and carbamates, the TMEDA ligand
leads to the highest rates of borylation (Table 5). Interest-
ingly, the sparteine surrogate leads to the lowest rates of
borylation. The effectiveness of TMEDA is consistent with
its relatively small size and high flexibility— boron–
lithium exchange might be sufficiently facile without ex-
change of TMEDA for solvent, and if not, exchange should
be very rapid. Initially surprised by the low rate of boryla-
tion with
carbamates in THF followed by electrophilic trapping leads
to almost exclusive formation of the racemate, that medi-
ated by the sparteine surrogate leads to product with high
ee values; only the sparteine surrogate can out-compete
THF for the generation of active alkyllithium aggre-
gates/monomers.23 O’Brien also observed that sparteine-
surrogate-ligated α-lithiated piperazines could not be dis-
placed by TMEDA, unlike the corresponding sparteine-
ligated species.25 Borylation of N,N’-dimethylbispidine-
ligated lithiated benzoates in Et2O was faster than that of
sparteine and sparteine surrogate, the t1/2 values being 15
(8 min in TBME), 35 (45 min in TBME), and 111 (TBME)
minutes, respectively. Presumably, boron–lithium ex-
change is relatively facile with the less-sterically hindered
N,N’-dimethylbispidine ligand still bound to the lithium
ion. Therefore, this result further reinforces the notion that
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5: Effect of diaminea
borylation occurs through two mechanisms
– direct
borylation of the tricoordinate diamine-ligated lithium ion
(the carbonyl group being in a dissociated state and the
carbon–oxygen single bond being anti to the carbon–
lithium bond) and borylation of the solvent-displaced de-
rivative, the latter being important with bulky yet labile
diamine ligands. Interestingly, the borylation of N,N’-
dimethylbispidine-ligated lithiated species in TBME is fast-
er than that in Et2O (8 versus 15 minutes); sparteine-
ligated species show the opposite trend. The need to dis-
place the diamine ligand is no longer great for the boryla-
tion of the sterically accessible N,N’-dimethylbispidine-
ligated lithiated species, so that instead the less-donating
TBME solvent, which previously was poor at displacing the
diamine from the diamine-ligated lithiated species, leads to
the empty p orbital of the boron atom being more available
for engagement in boron–lithium exchange.
Entry R/X/Substrate Diamine
t1/2 Li t1/2
(min) (min)
B
1
iPr/NiPr2/1c
iPr/NiPr2/1c
iPr/NiPr2/1c
iPr/TP/2c
iPr/TP/2c
iPr/TP/2c
iPr/TP/2c
iPr/TP/2c
iPr/TP/2c
iPr/TP/2c
tBu/TP/2d
tBu/TP/2d
(+)-sp
(+)-sps
TMEDA
(+)-sp
(+)-sps
TMEDA
DMBS
81
15
42
31
3
3
2
5
3
<15 s
4
35
2.6 Effect of the organoboron partner
b
5
-
Considering the evidence supporting initial coordination of
the boronic ester to the lithium ion of the α-lithiated spe-
cies prior to boron–lithium exchange, we decided to inves-
tigate the use of trialkylborane electrophiles. Trialkyl-
boranes are more Lewis acidic than boronic esters but do
not contain Lewis basic sites that can coordinate to the
lithium ion. We investigated the borylation of benzoates
rather than carbamates because the former borylate at a
much lower rate, thus allowing differences to be more easi-
ly observed. Upon treatment of a sparteine-ligated α-
lithiated 3-phenylpropylbenzoate (1636 cm−1) with tribu-
tylborane (1M in Et2O) at −78 °C, we observed the appear-
ance of a new signal at slightly lower wavenumber (1630
cm−1). At a lower rate, we observed disappearance of the
new signal at 1630 cm−1 and appearance of a new broader
signal at lower wavenumber (1592 cm−1), which corre-
sponds to the lithiated benzoate anion (TPCO2Li), the by-
product of 1,2-metallate rearrangement. The intermediate
species indicating at 1630 cm−1 is believed to be the
tetraalkylboronate; the very low wavenumber of the car-
bonyl group compared to that of boronates derived from
boronic esters (~1665 cm−1) suggests that the lithium ion
is coordinating to the carbonyl oxygen atom (in pinacol
boronates, the lithium ion presumably coordinates to one
of the oxygen atoms of the pinacol
6
17
1
<15 s
15
7
8c
9c
10c
11
12
DMBS
1
8
(+)-sp
(+)-sps
(+)-sp
(+)-sps
52
2
45
111
78
5
150 (15)d
–e (–)d,e
a Conditions: 1/2 (0.66 mmol), diamine (0.79 mmol), s-BuLi
(0.79 mmol, 1.3 in cyclohexane), Et2O, −78 °C; then
M
phenethyl boronic ester (0.79 mmol), Et2O, −78 °C; warming
to RT (X=TP) or 40 °C (X=NiPr2); NaOH/H2O2, THF/H2O. b Pre-
cipitation of lithiated benzoate confounded measurement of
the rate of borylation, which was very slow; see results of
c
reaction carried out in TBME (entries 3) The lithiation–
borylation process was carried out in TBME solvent. d Boronic
e
ester added as a solution in THF. The rate of borylation was
undetectably low.
sparteine surrogate, we tested the use of THF as a sub-
stoichiometric additive and as a vehicle for the introduc-
tion of the boronic ester. The low rate of borylation was
unperturbed, suggesting that the sparteine surrogate can-
not be displaced by THF solvent. This hypothesis is sup-
ported by the work of O’Brien: whereas sparteine-
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Li
B
t1/2
t1/2
exchange. In line with the above results, the
s-BuLi
(+)ꢀsparteine
(+)ꢀsp.
O
Li—
O
B
1
2
B(Bu)3
O
B
A
H
O
TP
O
TP
O
O
L .
n Li
TBME, _78 °C
TBME, _78 °C
Ph
O
(1.2 equiv) 5a
B
O
TP
3
4
5
6
(+)ꢀsp.
O
Li—
O
B
Ph
+
H
O
Bu3B (1.2 equiv)
H
O
TP
O
Et2O, _78 °C
O
TP
O
TP
4c
(in TBME)
L .
n Li
1. Warm to RT
7
2. H2O2/NaOH, THF/H2O
8
9
Ph
H
H
OH
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2: 1
O
B
(1.2 equiv)
B
O
O
O
L .
n Li
L .
n Li
22
23
O
O
(+)ꢀsp.
Li—
O
O
B
O
O
O
B
B
(1.2 equiv)
H
H
O
TP
O
O
Et2O, _78 °C
O
TP
O
TP
4c
(in Et2O)
Figure 5: 3D in situ IR spectroscopy trace of the lithiation of
isobutyl TIB ester and trapping with tributylborane, showing
1,2-migration at –78 °C.
Warm to
RT, 16 h
Bpin
O
O
ligand). That the 1,2-metallate rearrangement of
tetraalkyl-boronates already occurs at −78 °C (the corre-
sponding pinacol boronates requires temperatures of at
least −20 °C)3c might be partially due to the positioning of
the lithium ion. The alcohol product isolated after oxida-
tion of the homologated organoboron showed that the lev-
el and sense of enantioenrichment was similar to the reac-
tion with the boronic ester, thus confirming that the trial-
kylborane also undergoes stereoretentive boron–lithium
exchange. To compare the rates of borylation of boranes
and pinacol boronic esters, we used the lithiated isobutyl
benzoate as a substrate owing to its low rate of borylation
relative to the rate of addition of boronic ester to the lithi-
ated species, as per our normal protocol. The borylation of
this substrate with tributylborane exhibited features that
were similar to that of the borylation of the phenylpropyl
benzoate, although the IR band of the carbonyl group asso-
ciated with the boronate and lithiated species were now
coincident (see Figure 5). Rapid addition of a 1:1 mixture
of tributylborane (1.2 equiv) and phenethyl boronic ester
(1.2 equiv) in Et2O (1 M) to a TBME solution of sparteine-
ligated lithiated isobutyl benzoate 4c, allowing the result-
ing solution to evolve for 4 h at −78 °C followed by warm-
ing to room temperature and subsequent oxidative
workup gave a 2:1 mixture of alcohols derived from ho-
mologation of the boronic ester and the trialkylborane,
respectively (Scheme 2). This result shows that despite
boronic esters being less Lewis acidic than trialkylboranes,
they exhibit similar rates of boron–lithium exchange owing
to the ability of the oxygen atoms of the diol ligand to co-
ordinate to the lithium ion. Borate esters, B(OR)3, which
are less Lewis acidic than boronic esters, were investigated
to determine whether the presence of an additional Lewis
basic oxygen site would lead to more rapid lithium–boron
B
OTIB
1:1.4
Scheme 2: A: Comparison of the rate of borylation of boronic
esters and trialkylboranes. Ratio derived after isolation.
B: Comparison of the rate of borylation of boronic esters and
borate esters. Ratio derived by crude 1H NMR.
addition of a 1:1 mixture of isopropoxy borate ester 22
(t B = 36 min) and the isosteric isobutyl boronic acid pi-
½
nacol ester 23 (t B > 50 min) in Et2O to the sparteine-
½
ligated lithiated isobutyl benzoate 4c ultimately led to a
1:1.4 ratio of products, in favour of the borate ester de-
rived product. These results provide reinforcing evidence
in support of the importance of lithium–oxygen coordina-
tion prior to lithium–boron exchange.
Table 6: Effect of temperaturea
(+)ꢀsp. Li
t1/2 Li
O
B
O
t1/2
B
O
(+)ꢀsp.
Li—
B
s-BuLi
Ph
O
O
Ph
O
(+)ꢀsparteine
5a
H
O
O
TP
O
TP
Et2O, T
Et2O, T
2h
O
TP
4h
7h
Entry T (°C)
t1/2 Li t1/2
(min)
B
Yield e.r.c
(%)b
(min)
1
2
3
−65
−78
−95
2
1
69
78
68
92:8
4
12
363
93:7
95:5
18
a
Conditions: 2h (0.66 mmol), (+)-sp (0.79 mmol), s-BuLi
(0.79 mmol, 1.3 in cyclohexane), Et2O, T; then phenethyl
M
boronic ester (0.79 mmol), Et2O, T; warming to RT;
NaOH/H2O2, THF/H2O. b Yield of alcohol as isolated by column
chromatography following oxidation of the homologated bo-
ronic ester. c Determined through HPLC analysis of the alcohol
product by using a chiral stationary phase
2.7 Effect of temperature
We decided to investigate the effect of temperature on
lithiation and borylation (Table 6). Because we were par-
ticularly interested to ascertain whether the enantioselec-
tivity of the process could be increased by lowering the
temperature of lithiation, we chose 3-butenyl benzoate 2h
as
a substrate, which undergoes sparteine-mediated
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Journal of the American Chemical Society
deprotonation and borylation at −78 °C to give product ditions. Underlining the diverging behavior of carbamates
1
2
3
4
5
6
7
8
with relatively moderate e.r. levels (93:7). Dropping the
temperature to −95 °C led to slight increase in enantiose-
lectivity (e.r. 95:05); conducting the reaction at the higher
temperature of −65 °C led to a slight decrease in enantiose-
lectivity. Overall, the rate of lithiation doubles for every 10
°C increase in temperature. The rate of borylation was
much more sensitive to temperature, with t1/2 values of ~1,
12, and 363 minutes at −65, −78, and −95 °C.
and benzoates, ethyl benzoate, which does not form ob-
servable prelithiation complexes, underwent smooth lithi-
ation under these pseudo first order conditions.
3. Summary and Conclusions
We have investigated the deprotonative generation and
borylation of diamine-ligated lithiated benzoates and car-
bamates by using in-situ IR analysis. The results give rise
to the following conclusions, which will be valuable for the
troubleshooting and further development of homologation
reactions of organoboron compounds by using lithiated
carbamates and benzoates:
2.8 Effect of Concentration
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We investigated the effect of reaction mixture concentra-
tion on the rate of lithiation, whilst maintaining the rela-
tive stoichiometry of reactants at 1:1. Although for ethyl
benzoate, the approximate rate of lithiation increased pro-
portionally with reaction mixture concentration in accord-
ance with a reaction that was almost second order—a
log/log plot of rate versus concentration fitted a straight
line of slope 1.82 (R2 = 0.987)—that for ethyl carbamate
suggested a fractional reaction order between 1 and 2
(slope = 1.22, R2 = 0.996). We also investigated the lithia-
tion of carbamates and benzoates under pseudo first order
conditions because Beak and co-workers had studied the
sparteine-mediated α-lithiation of N-aryl Boc carbamates
of allyl amines under these conditions.25 To a large excess
of s-BuLi/sparteine (28 equiv, 0.69 M) in Et2O/cyclohexane
(~1:1) at −78 °C was added ethyl carbamate. Interestingly,
the carbamate did not
(1) The diamine/s-BuLi-mediated deprotonation of benzo-
ates is approximately 2–3 times more rapid than that of
the corresponding carbamates. This difference appears to
be due to the involvement of parasitic complexes involving
the organolithium reagent, the diamine, and the carba-
mate. IR signals of the carbonyl group in such complexes
are observed at slightly lower wavenumbers than those of
uncomplexed carbamate. That the use of very high concen-
trations of sparteine/s-BuLi relative to carbamate gives
rise to quantitative formation of such IR-observable com-
plexes and no observable deprotonation at −78 °C, strongly
supports this hypothesis. The less-basic carbonyl group
and more sterically hindered nature of benzoates preclude
or keep the concentration of such complexes at very low
levels.
(2) Increased steric hindrance at the β carbon atom of car-
bamates and benzoates leads to slower lithiation and
borylation, the significant buttressing ability of the triiso-
propylphenyl group of benzoates engendering them more
sensitive to the change.
K1
N
N
K1 very small for X = TP
K1 large for X = NiPr2
N
N
O
Li
Li
Li
Li
+
R
O
X
sꢀBu
sꢀBu
sꢀBu
OEt2
sꢀBu
L
O
Et2O
inactive
complex
R
O
X
(3) The borylation of diamine-ligated lithiated carbamates
is considerably more rapid than that of the corresponding
benzoates. This difference appears to be steric in origin.
K2
K2 K3 (small)
K3
(4) The replacement of ethereal solvents with the poorly
coordinating solvent, toluene, leads to faster lithiation of
benzoates but slower lithiation of carbamates. The latter
effect appears to be due to the increased concentration of
parasitic complexes of carbamates in toluene, whereas the
former effect is presumably due to a higher concentration
of the monomeric diamine-ligated organolithium in tolu-
ene.
K4
k5
O
N
N
N
N
R
N
N
+
R
O
X
Li
Li
O
Li
O
sꢀBu
sꢀBu
O
X
R
O
X
active complex
Figure 6: Parasitic equilibria in lithiation reactions
undergo lithiation under these conditions; instead, the IR
signal of the carbonyl group of the carbamate was shifted
to a frequency that has been attributed above to a prelithi-
ation complex. This result is further evidence to support
the parasitic nature of these “prelithiation complexes” ob-
served in lithiation reactions of the type of carbamates
studied herein. We believe that all the carbamate substrate
is quickly sequestered through ligand exchange with the
sparteine/solvent-ligated heterodimer of s-BuLi, which is
present in a large excess under Beak’s pseudo first order
conditions, thus leading to very low concentrations of both
free carbamate and 3-coordinate sparteine-ligated s-BuLi,
which we believe need to come together to form an active
complex (Figure 6). This hypothesis is consistent with the
low rate of lithiation of carbamates in toluene solvent and
the apparent fractional overall reaction order just above 1,
as measured for reactions under normal preparative con-
(5) For both carbamates and benzoates, the borylation of
the sparteine-ligated lithiated species is promoted by co-
ordinating solvents (Et2O) or additives (THF); borylation
in toluene solvent in the absence of additives can be unde-
tectably slow. The replacement of the diamine ligand for
solvent molecules on the lithium ion allows easy access for
the boronic ester to coordinate to the lithium ion through
an oxygen atom of the diol ligand, an interaction that ap-
pears to precede boron–lithium exchange. This effect ap-
pears to be crucial for the borylation involving sterically
hindered substrates or diamine ligands. For small or flexi-
ble diamine ligands (TMEDA and N,N’-dimethylbispidine),
the primary mechanism of boron–lithium exchange might
involve dissociation of the carbonyl group from the lithium
ion rather than diamine–solvent exchange. However, the
rate of borylation of sparteine-surrogate-ligated lithiated
species cannot be increased through the addition of coor-
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Chemical Synthesis Centre for Doctoral Training, funded by
dinating additives owing to its strong binding to the lithi-
um ion.
1
2
3
4
5
6
7
8
the EPSRC (EP/L015366/1), AstraZeneca, and the University
of Bristol for Ph.D. studentships. We thank the referees for
insightful comments, which have led to important additions to
this manuscript.
(6) The rate of diamine/s-BuLi-promoted lithiation of ben-
zoates and carbamates increases in the series N,N’-
dimethylbispidine > sparteine surrogate > TMEDA > spar-
teine. The nature of the diamine (steric hindrance, basicity,
and flexibility) presumably affects both the equilibria in-
volving active and parasitic complexes and the rate con-
stant for the deprotonation event. The rate of borylation
ABBREVIATIONS
REFERENCES
(1) (a) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
2282. (b) Hoppe, D.; Marr, F.; Brüggemann, M. Organolithiums in
increases in the contrasteric series TMEDA
> N,N’-
9
dimethylbispidine > sparteine > sparteine surrogate, sug-
gesting the parallel operation of at least two mechanisms:
one where boron–lithium exchange is preceded by ex-
change of the diamine ligand on the lithium ion for sol-
vent/additive molecules and the other where the exchange
is preceded by dissociation of the carbonyl group from the
lithium ion (the diamine ligand remaining on the lithium
ion). The promotion of borylation through the displace-
ment of diamine ligands also appears to be the origin of the
unusually rapid borylation of substrates containing pen-
dant aryl groups, which can intramolecularly displace the
diamine ligand through a cation–π interaction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Enantioselective Synthesis; Hodgson, D. M., Ed.; Springer: Heidel-
berg, 2003; pp 61−137. (c) Beckmann, E.; Desai, V.; Hoppe, D.
Synlett 2004, 2275. (d) Beckmann, E.; Hoppe, D. Synthesis 2005,
2005, 217.
(2) (a) Beak, P.; McKinnie, B. G. J. Am. Chem. Soc. 1977, 99, 5213.
(b) Beak, P.; Baillargeon, M.; Carter, L. G. J. Org. Chem. 1978, 43,
4255. (c) Beak, P.; Carter, L. G. J. Org. Chem. 1981, 46, 2363.
(3) (a) Wu, J.; Lorenzo, P.; Zhong, S.; Ali, M.; Butts, C. P.; Myers, E.
L.; Aggarwal, V. K. Nature, 2017, 547, 436. (b) Burns, M.; Essafi, S.;
Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C.
P.; Harvey, J. N.; Aggarwal, V. K. Nature 2014, 513, 183. (c) Rasap-
pan, R.; Aggarwal, V. K. Nat. Chem. 2014, 6, 810. (d) Larouche
Gauthier, R.; Fletcher, C. J.; Couto, I.; Aggarwal, V. K. Chem. Com-
mun. 2011, 47, 12592. (e) Dutheuil, G.; Webster, M. P.; Worthing-
ton, P. A.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2009, 48, 6317. (f)
Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew.
Chem., Int. Ed. 2007, 46, 7491. For a review, see: (g) Leonori, D.;
Aggarwal, V. K. Acc. Chem. Res. 2014, 47, 3174.
(4) (a) Kapeller, D. C.; Hammerschmidt, F. J. Org. Chem. 2009, 74,
2380. (b) Derwing, C.; Frank, H.; Hoppe, D. Eur. J. Org. Chem. 1999,
3519. (c) Carstens, A.; Hoppe, D. Tetrahedron 1994, 50, 6097. (d)
Hoppe, D.; Carstens, A.; Krämer, T. Angew. Chem., Int. Ed. Engl.
1990 29, 1424.
(5) Aggarwal, V. K.; Fang, G. Y.; Ginesta, X.; Howells, D. M.; Zaja, M.
Pure Appl. Chem., 2006, 78, 215.
(6) (a) Millán, A.; Grigol Martínez, P. D.; Aggarwal, V. K. Chem. Eur.
J. 2018, 24, 730. (b) Varela, A.; Garve, L. K. B.; Leonori, D.; Ag-
garwal, V. K. Angew. Chem., Int. Ed. 2017, 56, 2127. (c) Noble, A.;
Roesner, S.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2016, 55,
15920. (d) Blair, D. J.; Zhong, S.; Hesse, M. J.; Zabaleta, N.; Myers, E.
L.; Aggarwal, V. K. Chem. Commun., 2016, 52, 5289. (e) Roesner,
S.; Blair, D. J.; Aggarwal, V. K. Chem. Sci., 2015, 6, 3718-3723.
(7) (a) Bagutski, V.; French, R. M.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2010, 49, 5142. (b) Blair, D. J.; Fletcher, C. J.; Wheelhouse,
K. M. P.; Aggarwal, V. K.; Angew. Chem. Int. Ed. 2014, 53, 5552.
(8) For other in-situ IR investigations on the lithiation and boryla-
tion of carbamates, see: (a) Fandrick, K. R.; Patel, N. D.; Mulder, J.
A.; Gao, J.; Konrad, M.; Archer, E.; Buono, F. G.; Duran, A.; Schmid,
R.; Daeubler, J.; Fandrick, D. R.; Ma, S.; Grinberg, N.; Lee, H.; Busac-
ca, C. A.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2014, 16,
4360. (b) Jason, A.; Mulder, J. A.; Gao, J.; Fandrick, K. R.; Zeng, Z.;
Desrosiers, J.-N.; Patel, N. D.; Li, Z.; Rodriguez, S.; Lorenz, J. C.;
Wang, J.; Ma, S.; Fandrick, D. R.; Grinberg, N.; Lee, H.; Bosanac, T.;
Takahashi, H.; Chen, Z.; Bartolozzi, A.; Nemoto, P.; Busacca, C. A.;
Song, J. J.; Yee, N. K.; Mahaney, P. E.; Senanayake, C. H. Org. Process
Res. Dev. 2017, 21, 1427.
(7) Although trialkylboranes are more Lewis acidic than
boronic esters, these families of organoboron compounds
undergo boron–lithium exchange at very similar rates. The
poorer Lewis acidity of boronic esters appears to be miti-
gated by their ability to form a complex with the organo-
lithium, through interaction of an oxygen atom of the diol
ligand with the lithium ion, prior to boron–lithium ex-
change. The unusually low carbonyl stretching frequency
of boronate complexes derived from α-lithiated benzoates
and trialkylboranes, compared to that of complexes de-
rived from boronic esters, suggests that the lithium ion
resides on the carbonyl oxygen atom; for complexes de-
rived from boronic esters, the lithium ion is believed to
reside on the oxygen atom of the diol ligand. The ability of
boronates derived from trialkylboranes to undergo 1,2-
metallate rearrangement even at temperatures as low as
−78 °C is believed to be in part due to the positioning of the
lithium ion.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.xxxxxxx.
Reaction set up, experimental procedures, full in situ
IR data and traces (PDF).
AUTHOR INFORMATION
Corresponding Author
* eddie.myers@nuigalway.ie
* V.Aggarwal@bristol.ac.uk.
(8) For previous observations of similar “pre-lithiated” species,
see, for example: (a) Al-Aseer, M.; Beak, P.; Hay, D.; Kempf, D. J.;
Mills, S.; Smith, S. G.; J. Am. Chem. Soc. 1983, 105, 2080. (b) Stead,
D.; Carbone, G.; O’Brien, P.; Campos, K. R.; Coldham, I.; Sanderson,
A.; J. Am. Chem. Soc. 2010, 132, 7260.
(9) Grañ a, P.; Paleo, M. R.; Sardina, F. J. J. Am. Chem. Soc. 2002,
124, 12511.
(10) Fernández-Nieto, F.; Paleo, M. R.; Colunga, R.; Raposo, M. L.;
Garcia-Rio, L.; Sardina, F. J. Org. Lett. 2016, 18, 5520.
(11) (a) Hintze, F.; Hoppe, D. Synthesis 1992, 1216. (b) Royal, T.;
Baumgartner, Y; Baudoin, O.; Org. Lett. 2017, 19, 166.
Author Contributions
‡ R. Mykura, S. Veth, and A. Varela contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the EPSRC (EP/I038071/1) and University of Bris-
tol for financial support. R.C.M, L.D., and J.J.F. thank the Bristol
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(12) Monje, P.; Paleo, M. R.; Garcia-Rio, L.; Sardina, F. J. J. Org.
Chem. 2008, 73, 7394.
(13) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
(13) Pulis, A. P.; Blair, D. J.; Torres, E.; Aggarwal, V. K. J. Am. Chem.
Soc., 2013, 135, 16054.
(14) (a) Hoppe, I.; Marsch, M.; Harms, K.; Boche, G.; Hoppe, D.
Angew. Chem. Int. 1995, 34, 2158. (b) Wu, S.; Lee, S.; Beak, P. J. Am.
Chem. Soc. 1996, 118, 715.
(15) Gallagher, D. J.; Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1992,
114, 5872.
(19) McGrath, M. J.; Bilke, J. L.; O’Brien, P. Chem. Commun. 2006,
2607.
(20) Firth, J. D.; Canipa, S. J.; Ferris, L.; O’Brien, P. Angew. Chem.
Int. Ed. 2018, 57, 223.
(21) Ritter, S. K. Chem. Eng. News. 2017, 95, 18.
(22) Bryantsev, V. S.; Diallo, M. S.; Goddard, W. A. J. Phys. Chem. A
2007, 111, 4422.
(23) Carbone, G.; O’Brien, P.; Hilmersson, G. J. Am. Chem. Soc.
2010, 132, 15445.
(24) See Supporting Information for preparation.
(25) Firth, J. D.; O’Brien, P.; Ferris, L. J. Am. Chem. Soc. 2016, 138,
651.
1
2
3
4
5
6
7
8
(16) Rutherford, J. L.; Hoffmann, D.; Collum, D. B. J. Am. Chem. Soc.
2002, 124, 264.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(17) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
Nature, 2008, 456, 778-782.
(18) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am.
Chem. Soc. 2002, 124, 11870.
(25) Pippel, D. J.; Weisenburger, G. A.; Faibish, N. C.; Beak, P. J. Am.
Chem. Soc. 2001, 123, 4919.
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