N-Heterocyclic Carbene Boryl Iodides Catalyze Insertion Reactions of N-Heterocyclic Carbene Boranes and Diazoesters

Article abstract of DOI:10.1021/acs.orglett.7b01777

Boron-hydrogen bond insertion reactions of N-heterocyclic carbene (NHC) boranes and diazoesters can be catalyzed by NHC-boryl iodides and produce stable α-NHC-boryl esters. The conditions of the reaction resemble the previous rhodium-catalyzed transformations (only the catalyst is different); however, the mechanisms of the two reactions are probably very different. The new boryl iodide catalyzed method is adept at producing α-substituted-α-NHC-boryl esters, and this has led to a family of NHC-boryl esters with amino acid and amino-acid-like side chains.

Full text of DOI:10.1021/acs.orglett.7b01777

Letter
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene Boryl Iodides Catalyze Insertion Reactions of
N‑Heterocyclic Carbene Boranes and Diazoesters
Thomas H. Allen, Takuji Kawamoto, Sean Gardner, Steven J. Geib, and Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: Boron−hydrogen bond insertion reactions of N-
heterocyclic carbene (NHC) boranes and diazoesters can be
catalyzed by NHC-boryl iodides and produce stable α-NHC-boryl
esters. The conditions of the reaction resemble the previous
rhodium-catalyzed transformations (only the catalyst is different);
however, the mechanisms of the two reactions are probably very
different. The new boryl iodide catalyzed method is adept at producing α-substituted-α-NHC-boryl esters, and this has led to a
family of NHC-boryl esters with amino acid and amino-acid-like side chains.
arious Rh and Cu salts catalyze the B−H bond insertion
reactions of ligated boranes 1 with α-diazo carbonyl
In the absence of metal catalysts, diazoesters can function as
nucleophiles on carbon.5 Ethyl diazoacetate, for example, is a
weak neutral nucleophile with an N value of 4.91 on the Mayr
scale.6 Trivalent boranes typically react with diazoesters by
addition and 1,2-shift,5c,7 a pathway not open to ligated
(tetravalent) boranes. However, electrophilic borenium ions or
their functional equivalents sometimes express borane-like
reactivity.8 Thus, we wondered whether there was a pathway to
boron−hydrogen bond insertion of diazo compounds involving
boryl electrophiles as catalysts rather than transition metals.
We initially studied reactions of 1,3-dimethylimidazol-2-
ylidene borane 4 with ethyl diazoacetate 5a (Scheme 1). These
V
compounds 2 (esters, ketones, amides).1 The products of these
reactionsarestableligatedα-borylcarbonylcompounds3(Figure
1a).2 The borane ligands (L) in these reactions must be tightly
Scheme 1. Typical Preparative Reaction with Diiodine As
a
Activator
Figure 1. Metal-catalyzed reactions of ligated boranes with diazo-
carbonyl compounds.
a
boundamines, pyridines, phosphines, or N-heterocyclic
carbenesso that reactive boranes are not released during the
reaction or purification. Transient metal carbenes are presumed
to be catalytic intermediates, as evidenced by asymmetric
induction with chiral ligands.2,3 These B−H insertion reactions
are faster than typical CH insertions, and the ligated boranes are
thought to donate a hydride to the metal carbene.1a,3 Carbenes
generated in other ways also react with ligated boranes.3
No reaction occurs without an activator.
two compounds do not react over 1 day in dichloromethane at rt.
However, a rapid transformation occurs when substoichiometric
amounts of electrophiles or strong acids are added to NHC-
borane4priortotheadditionofthediazoester. Scoutingreactions
were followed by 11B NMR spectroscopy with results shown in
Table S1 of the Supporting Information. Substoichiometric
amounts of bromine, iodine, triflic acid, and triflimide all
produced substantial amounts of insertion product 5a, while
weaker acids such as camphor sulfonic acid did not.
In the NHC-borane series, treatment of dimethylimidazol-2-
4
ylidene borane 4 and assorted diazoacetates 5 with 1% Rh2(esp)2
provides stable α-NHC-boryl esters 6 in varying yields (Figure
1b).1 The yields tend to be good (60−75%) for unsubstituted
diazoesters and for diazoesters substituted with aryl groups or
electron-withdrawing groups. However, alkyl-substituted diazo-
esters provide the corresponding α-NHC-boryl esters in low
yields (<30%).
Received: June 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01777
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
For preparative reactions, we selected iodine as an activator
because it is convenient to handle and reacts quickly and
quantitatively with various NHC-boranes to make NHC-boryl
iodides.9 NHC-borane 4 (1 mmol) was dissolved in dichloro-
methane (1 mL), and then diiodine (10 mol %) was added. The
iodine color dissipated quickly accompanied by bubbling,
presumably due the formation of hydrogen gas. After 5 min, the
neat diazo compound 5a (1.2 equiv) was added. Vigorous
bubbling ensued, this time due to formation of nitrogen gas. After
1 h, an 11B NMR spectrum of the reaction mixture showed that
starting NHC-borane 4 was absent. Present were monoinsertion
product 6a (t, −28.2 ppm) and the corresponding double
insertion product NHC-BH(CH2CO2Et)2 (d, −20.3 ppm) in a
ratio of about 80/20. Solvent evaporation and flash chromatog-
raphy of the residue provided stable α-boryl ester 6a in 53% yield.
Table 1 summarizes preparative reactions of 5a with other
NHC-boranes under the conditions described in Scheme 1. The
showed that small amounts (roughly 10%) of double insertion
products were formed. These are rather polar and were typically
not isolated. The exception was entry 4, the reaction of
tetramethylimidazol-2-ylidene borane 13. In this case, the ratio
of monoinsertion product 14 to the corresponding double
insertion product was 66/34 according to the 11B NMR spectrum
of thecrude product. Thus, thelower yieldinentry4is dueat least
in part to over-reaction of the product 14.
Table 2 summarizes the results of a survey of reactions of
various diazoesters 5b−5k with readily available NHC-borane 4.
Table 2. Isolated Yields in Preparative Reactions of NHC-
a
Borane 4 with Substituted Diazoacetates
Table 1. Isolated Yields in Preparative Reactions of NHC-
a
Boranes with Ethyl Diazoacetate
a
Conditions: 1 mmol of NHC-borane, 10% I2, 1.2 equiv of 5a, 1 mL of
dichloromethane, 1 h at rt.
stable α-boryl ester products were isolated by concentration and
direct flash chromatography. Reaction of 1,3-diisopropyl-
imidazol-2-ylidene borane 7 provided 8 in 57% yield (entry 1).
Differentially substituted imidazolium boranes 9 (N-Me, N-iPr)
and 11 (N-Me, N-Bu) provided products 10 and 12 in 50% and
58% yield, respectively (entries 2, 3). 1,3,4,5-Tetramethyl-
imidazol-2-ylidene borane 13 gave α-boryl ester 14 in 37% yield
(entry 4), while the corresponding benzimidazole analog 15 gave
16in63% yield(entry5). Incontrasttothesesuccesses, areaction
with the hindered 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-
ylidene borane did not give the corresponding insertion product.
Most of the products in Table 1 are new compounds, though
benzimidazole NHC-boryl ester 16 has been made by the
rhodium-catalyzed reaction in about the same isolated yield.1a In
these reactions, the formation of both the boryl iodide and the
boryl ester can be conveniently followed by 11B NMR
spectroscopy, if desired. Spectra of most reaction mixtures
a
Conditions: 1 mmol of 4, 10% I2, 1.2 equiv of 5, 1 mL of
b
c
dichloromethane, 1 h at rt. 25% conversion of 4. 18 h reaction time.
d
61% conversion of 4.
B
DOI: 10.1021/acs.orglett.7b01777
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Organic Letters
Letter
The diazo esters were chosen to feature natural or common
unnatural amino acid side chains, and they were prepared by
literature methods.1b,10 These are also the types of diazo
compounds that gave low yields in the rhodium-catalyzed
reactions.1a The reaction products 6b−6k are unusual boron
analogs of amino esters, with the NHC-boryl group replacing the
amine. The standard conditions were used (1 mmol NHC-
borane, 10% I2, 1.2 equiv of diazo ester 5, 1 mL of
dichloromethane, 1 h at rt) unless otherwise noted. Yields are
reported after concentration and flash chromatography.
Reactions of 4 with 2-diazopropanoates with methyl (5b) and
benzyl (5c) esters provided the corresponding NHC-boryl
alanine esters 6b and 6c in 68% and 43% yields (entries 1 and 2).
Reaction with methyl 2-diazo-3-methylbutanoate 5d gave the
boryl valine analog 6d in only 20% yield (entry 3). However,
reactions of diazoesters 5e and 5f with phenylalanine and
methionine side chains gave 6e and 6f in 71% and 52% yields
(entries 4 and 5). The reaction with 5f was slow and was allowed
to progress for 18 h before purification.
2,6-dichlorophenyl ester 6k on a chiral HPLC column. These
enantiomers proved stable to long-term storage.
Figure 3 shows a plausible mechanism for this reaction that is
based on analogies between borane (BH3) and NHC-borenium
Diazoesters with natural (unprotected) tyrosine and trypto-
phan side chains did not provide insertion products in reactions
with4;however, thecorresponding methylatedanalogs5gand5h
providedprotectedtyrosineandtryptophanNHC-boryl esters 6g
and 6h in 58% and 46% yields (entries 6 and 7). Finally, 2-phenyl-
diazoacetates with ethyl (5i), 2,6-dimethylphenyl (5j) and 2,6-
dichlorophenyl (5k) esters provided the corresponding NHC-
boryl phenylglycines 6i, 6j, and 6k in 64%, 54%, and 26% yields,
respectively.
Figure 3. A plausible catalytic cycle.
+
ions (NHC−BH2 ), both of which are reactive Lewis acids. It is
unlikely that free borenium ions are involved in this reaction, but
NHC-boranes bearing excellent leaving groups (NHC−BH2X)
exhibit borenium-like reactivity.11
The probable catalyst, NHC−BH2I 18, is formed rapidly and
quantitatively by the reaction of NHC−BH3 17 with I2 (Figure
3a).9a,12 As mentioned above, this reaction can be verified by 11B
NMR spectroscopy if desired. One among several possible
catalytic cycles13 is shown in Figure 3b. Here C-borylation of
diazoester 5 with 18 provides an α-NHC-boryl diazonium iodide
19. By analogy to borane chemistry,6 this can undergo a 1,2-
hydride shift from B to C with loss of nitrogen. Collapse of the
iodide onto the forming borenium ion provides inserted boryl
iodide 20. This can then exchange iodide for hydride with starting
NHC-borane 17 to provide the observed α-boryl ester 6 with
return of the catalyst 18. The hydride/iodide exchange reaction
has precedent in 1,2-hydroboration reactions of NHC-boranes,
which are also catalyzed NHC-boryl iodides and related
molecules.9b,11c,14
The progress of these reactions was followed by 11B NMR
spectroscopy as usual, and in many cases the conversion of 4 was
high (90−100%). Exceptions were the lower yielding reactions in
entries 3 and 10. These were not plagued by side-product
formation. Instead, they seemed to stop with substantial amounts
of NHC-borane 4 remaining (75% and 39%, respectively).
Unlike the crystalline NHC-borane starting materials, many α-
NHC-boryl esters in Tables 1 and 2 were clear, free-flowing
liquids. Exceptions included benzimidazole derivative 16,
tryptophan analog 6h, and the two aryl esters 6j and 6k with
the phenylglycine motif. Crystals of the tryptophan analog 6h
were grown by vapor phase diffusion. The X-ray crystal structure
was solved, and the resulting ORTEP diagram is shown in Figure
2.
The viability of the turnover step was probed by independent
generationofaniodidelike20fromoneoftheα-NHC-borylester
products (Scheme 2). Pure boryl ester 6a in DCM was treated
Scheme2. DemonstrationThattheProposedTurnoverStepIs
Competent
Figure 2. ORTEP (left) and standard (right) structures of 6h.
This is the first crystal structure of an NHC-boryl ester, and it
confirms the assignment of constitution that was made by NMR
methods (specifically, the compounds are α-NHC-boryl esters,
not isomeric enol boranes). The molecule adopts an extended
conformation from the tryptophan ring on the left through to the
NHC-ring on the right. This leaves the bond from the chain to the
ester (CH−CO2Me) as gauche to both the CH2−tryptophan
bond on one side and the BH2−NHC bond on the other side.
The chiral α-boryl esters in Table 2 are of course racemates.
However, we expected that the individual enantiomers would
resist racemization. To show this, we resolved the enantiomers of
with 0.5 equiv of iodine. As expected, rapid bubbling occurred
(H2) and the 11B NMR spectrum showed disappearance of 6a
with formation of boryl iodide 20a. Next we added excess NHC-
borane 4 (10 equiv) to mimic the catalytic conditions. The 11
B
NMRspectrumafter1hshowedcompleteconversionof20aback
to 6a. Accordingly, the proposed turnover step is competent
under the reaction conditions.15
C
DOI: 10.1021/acs.orglett.7b01777
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, we have discovered that formal B−H insertion
reactions of NHC-boranes with diazoesters can be effected by
additionofsmallamountsofdiiodine. Thediiodineisaprecatalyst
that reacts rapidly with the NHC-borane to produce an NHC-
boryliodidecatalyst.9 Thereactionsareeasytoconduct andoccur
rapidly at room temperature. There is no extractive workup, and
the mixture is simply concentrated prior to flash chromatography.
Overall, this B−H insertion reaction resembles the previous
Rh-catalyzed transformations,1a and even the reaction conditions
are very similar (only the catalyst is different). However, the
mechanisms of these two reactions are, generally, opposites of
each other. In the Rh-catalyzed reactions, the key catalytic species
(a rhodium carbene) comes from the diazo ester and reacts
directly with the NHC-borane. In this new transformation, the
key catalytic species (NHC−BH2I)comes from theNHC-borane
and reacts directly with the diazoester. In the Rh-catalyzed
transformation, the NHC-borane serves as a hydride donor in the
leading step with a rhodium carbene serving as an electrophile.
Then C−B bond formation follows. In the new transformation,
C−B bond formation is leading and involves reaction of the boryl
iodide as an electrophile with the diazoester as a nucleophile.
Then hydride transfer follows. In short, similarities in reaction
components and conditions belie major differences.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: curran@pitt.edu.
ORCID
Dennis P. Curran: 0000-0001-9644-7728
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Science Foundation for funding.
■
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+
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S
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b01777.
Crystal structure (CIF)
Experimental details; characterization data; spectra (PDF)
D
DOI: 10.1021/acs.orglett.7b01777
Org. Lett. XXXX, XXX, XXX−XXX