Mechanistic variations in ionic hydrogenation of unsaturated phosphine and amine boranes

Article abstract of DOI:10.1021/ol2031203

Internal hydride transfer occurs when tethered carbocations are generated from unsaturated phosphine or phosphinite boranes. 3-Methylenecyclohexyl-derived boranes 12 or 18 react with MsOH to give ionic hydrogenation products with high syn-selectivity. With unsaturated amine boranes, initial hydrogen evolution gives BH₂(OMs) complexes, but IH occurs using excess MsOH in a slower second stage. A diastereoselective reaction occurs from 26b using camphorsulfonic acid (first stage) and MsOH (second stage), affording 33 (68% ee) after hydrolysis.

Full text of DOI:10.1021/ol2031203

ORGANIC
LETTERS
2012
Vol. 14, No. 3
688–691
Mechanistic Variations in Ionic
Hydrogenation of Unsaturated Phosphine
and Amine Boranes
Timothy S. De Vries, Supriyo Majumder, Angela M. Sandelin, Guoqiang Wang, and
Edwin Vedejs*
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States
edved@umich.edu
Received November 22, 2011
ABSTRACT
Internal hydride transfer occurs when tethered carbocations are generated from unsaturated phosphine or phosphinite boranes.
3-Methylenecyclohexyl-derived boranes 12 or 18 react with MsOH to give ionic hydrogenation products with high syn-selectivity. With
unsaturated amine boranes, initial hydrogen evolution gives BH2(OMs) complexes, but IH occurs using excess MsOH in a slower second stage. A
diastereoselective reaction occurs from 26b using camphorsulfonic acid (first stage) and MsOH (second stage), affording 33 (68% ee) after hydrolysis.
An earlier publication from our laboratory reportedthat
internal hydroboration occurs when the butenylphosphine
borane 1 is activated with TfOH (1.1 equiv), resulting in
alcohols 2 and 3 (3:1 ratio) after standard oxidative work-
up (Scheme 1).1 However, the same procedure applied to
the methyl-substituted analogue 4 affords 5 as the major
product (56%) due to competing ionic hydrogenation
(IH).2 The expected alcohol 6 is a minor product in this
case (22%). Evidently, formation of the intermediate 7 as
required for internal hydroboration is faster starting from 1,
while protonation of the disubstituted alkene 4 is faster
compared to the formation of 8. The result is a modest
advantage for the IH pathway.1
detected prior to oxidative workup, tentatively assigned
structure 10 from the downfield shift of the BꢀH signal
Scheme 1. Ionic Hydrogenation of Phosphine 1
We have revisited the activation of 4 to gain mechanistic
insight and to learn whether modified conditions would
favor the ionic hydrogenation pathway with Lewis base
borane complexes. Weaker acids were examined in an
attempt to minimize hydrogen evolution and hydrobora-
tion, but 4 was unreactive with CF3CO2H after 1 h at rt.
The more acidic methanesulfonic acid (MsOH) did initi-
ate the ionic hydrogenation, although the reaction was
slow using stoichiometric MsOH. On the other hand, with
3 equiv of acid the alkene was consumed within 10 min at rt
according to a 1H NMR assay. A major intermediate was
(2H, centered at δ 3.3 ppm, compared to δ 1.0 ppm for
the BꢀH signal of 4) and a singlet integrating for 3H at
δ 2.84 ppm (H3CꢀSO3B). A minor phosphonium salt
(1) Shapland, P.; Vedejs, E. J. Org. Chem. 2004, 69, 4094.
(2) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633.
r
10.1021/ol2031203
Published on Web 01/17/2012
2012 American Chemical Society

byproduct corresponding to PꢀB bond protonolysis was
also indicated by the presence of a small doublet of triplets
at δ 7.8 ppm (1JPH = 508 Hz, 3JHH = 6.2 Hz) in the 1H
NMR spectrum. Oxidative workup of the reaction mix-
ture gave 5 in an improved 78% yield along with 12% of 6.
However, these results do not require that alkene hydro-
genation necessarily involves an intramolecular hydride
transfer as implied from 9 to 10.
and 15-trans). Isomer 15-trans reacted faster in the SN2
displacement with inversion to give 17, and 14a was
obtained as a single diastereomer after oxidation.
Intramolecular hydride transfer was also observed in a
related phosphinite borane 18, available from 3-methylene
cyclohexanol via conversion to the phosphinite with
ClPPh2/NEt3 and subsequent treatment with THF•BH3.
The reaction of 18 with MsOH followed by oxidative
workup gave 19 as the major diastereomer (19:20, 5:1 at
rt; 19:1 at ꢀ10 °C), but several inseparable byproducts
including 21 (according to 1H NMR and mass m/z data)
were also formed. The major product 19 could not be
purified unless activation was performed with TfOH
(1 equiv) at ꢀ78 °C. This variation gave the same 19:1 ratio
of 19:20, but fewer byproducts were formed and 19 could
be purified in 43% yield after repeated chromatography.
The minor isomer 20 could not be isolated, but the struc-
ture was established by independent synthesis of both 19
and 20 from 15-trans and 15-cis, respectively.
The phosphinite example of Scheme 2 suggested other
applications for oxygen-directed, diastereoselective ionic
hydrogenation. Accordingly, several acyclic phosphinite
boranes 22 were studied (Scheme 3) and good conversion
to saturated products 23 was generally observed using the
standard MsOH activation procedures, as evidenced by
the formation of 24 after oxidative workup. However,
diastereoselectivity was modest at best and could not be
significantly improved at lower temperatures or (in the
case of 24b) at 10-fold greater dilution to minimize inter-
molecular hydride transfer. Furthermore, the initial pro-
ducts included not only the “activated” and easily cleaved
mesyloxyborane complexes 23 expected from internal
hydride transfer but also the analogous borane complexes
25. In contrast to 23, the borane adducts 25 are stable,
isolable, and quite resistant to oxidative cleavage using the
conventional NaOH/H2O2 recipe. The origins of 25 were
not probed experimentally, but disproportionation by
hydride/mesylate exchange would explain the outcome.
Minor products of competing hydroboration were also
detected in some cases.
A cylic phosphine borane environment was designed to
confirm that IH occurs via intramolecular hydride trans-
fer. Thus, phosphine borane 12 was prepared by Wittig
methylenation of the known cyclohexanone 11.3 Subject-
ing 12 to the MsOH activation conditions (0.1 M in 12)
followed by oxidative workup resulted in isolation of 14b
as the sole reduction product; no trace of 14a was observed
1
by H NMR assay (>99:1 dr). This remarkable stereo-
selectivity did not erode until the concentration of 12 was
increased from ca. 0.1 to 1.0 M. The latter experiment gave
a 7:1 ratio of 14b:14a, suggesting minor competition by an
intermolecular hydride transfer to the intermediate cation
13eq. However, the major product was the same isomer
14b, corresponding to an internal hydride transfer via the
less stable cation conformer 13ax.
To confirm the assigned stereochemistry, the minor
diastereomer 14a was prepared independently from the
Scheme 2. Directed Intramolecular Ionic Hydrogenation
Having demonstrated a simple one-stage activation
pathway for internal IH in the phosphorus examples, we
Scheme 3. Acyclic Phosphinite Boranes
reaction of LiPPh2 with a 2.6:1 cis/trans mixture of tosy-
lates 16 (from the commercial mixture of alcohols 15-cis
turned to the investigation of unsaturated amine boranes.
Although IH was eventually observed, it became clear that
(3) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K.
J. Am. Chem. Soc. 1990, 112, 5244.
Org. Lett., Vol. 14, No. 3, 2012
689

the amine boranes follow a more complex pathway upon
MsOH activation. In contrast to phosphine borane 4, the
amine borane 26a reacted with stoichiometric MsOH to
release hydrogen without undergoing IH.4 An organic
product was also formed, identified as the unsatu-
rated mesyloxyborane complex 27a from NMR and
MS data (52% recovered after flash chromatography,
partial decomposition). Further reaction of27a withexcess
MsOH or treatment of 26a with 3 equiv of MsOH was
necessary to effect ionic hydrogenation of the alkene,
affording an isolable bis-mesyloxyborane complex 29a
(44%). This is the product expected from internal hydride
transfer at the stage of carbocation 28, assisted (or
followed) by bonding of the mesyloxy anion at boron.
Similar treatment of 26b with 3 equiv of MsOH gave 29b
(70%).5 The higher yield probably reflects easier protona-
tion of the styrene 27b compared to 27a due to greater
stabilization of the cationic intermediate 28b. Evidently,
the electron-withdrawing B-mesyloxy group of 27 formed
in the first stage of MsOH activation attenuates hydridic
reactivity and allows competing protonation of the alkene
with subsequent IH via 28 in the second stage.
procedure from 26b, the intermediate complex resulting
from IH did not survive the aqueous workup. This is
consistent with a single stage IH pathway via carbocation
31, followed by hydride transfer to give the hydrolytically
labile 32(Z = OTf or OAc). No evidence for the formation
of a stable (TfO)2BH complex analogous to the bis-mesyloxy
complex 29b was found using the Lewis acid activation
method. These observations are consistent with a one-
stage activation mechanism from 30, but NMR spectro-
scopy assay prior to NaOH workup indicated a more
complex situation, implicating unknown disproportiona-
tion events as well as the one-stage IH process.6,7
According to the two-stage IH mechanism of Scheme 4
for amine borane activation, it should be possible to use
a different sulfonic acid in each stage. This feature has
interesting consequences using a chiral acid such as
camphorsulfonic acid (CSA) in the first stage because the
expected nonracemic intermediate 35 (Scheme 5) may
function as a chiral hydride donor in a second stage
initiated by subsequent addition of excess MsOH. To test
this premise, 26b was treated with (þ)-CSA (1 equiv)
followed by MsOH (2 equiv). Ionic hydrogenation did
take place according to 1H NMR assay (ca. 75% conver-
sion of the alkene). Hovever, the initial products could not
be separated and proved difficult to identify or assay,
presumably because several diastereomers of 36 are possi-
ble given the presence of stereogenic boron as well as
carbon. To simplify the assay, the mixture of products
was cleaved using HCl in refluxing MeOH to afford the
chiral amine 33. Determination of 68% ee for 33 by HPLC
on a chiral support confirmed that the intramolecular
hydride transfer step had occurred with surprisingly high
(84:16) diastereofacial selectivity.
Scheme 4. Ionic Hydrogenation of Amine Boranes
Scheme 5. Ionic Hydrogenation of 18b Using CSA/MsOH
In view of the unproductive evolution of hydrogen
starting from 26 and MsOH, an alternative approach
for generation of the key carbocationic intermediate was
evaluated starting from the tertiary acetate 30. Treatment
of 30 with boron trifluoride etherate in dichloromethane
resulted in conversion to saturated products within 1 h at
rt, and workup with aqueous NaOH afforded the free
amine 33 (83%). In contrast to the MsOH activation
(4) Et3N BH3 reacts with CF3CO2H at rt in DCM to give H2, with
>50% conversion in 45 min, and is more hydridic than Bu3P BH3
3
3
(<2% conversion under the same conditions). For systematic compar-
isons, see: Funke, M.-A.; Mayr, H. Chem.;Eur. J. 1997, 3, 1214.
(5) Complex 21b survives treatment with LiAlH4, Bu4NF, and
methanolic KHF2 at rt (16 h). Cleavage to the parent amine occurs in
refluxing MeOH/HCl (43% after 16 h) or by reaction with 8 equiv of
DMAP in refluxing MeOH or with neat pyrrolidine at reflux.
Although the above result supported initial incorpora-
tion of a chiral CSA subunit by bonding at boron as
690
Org. Lett., Vol. 14, No. 3, 2012

suggested for 35, some of the observations were not
consistent with the expected mechanism. The vigorous
hydrogen evolution that was seen upon addition of MsOH
to simple amine boranes was not observed in the first stage
(CSA addition to 26b) or in the second stage (MsOH
addition). Furthermore, the structure of 36 (R*SO3 =
camphorsulfonyloxy) presumed by analogy to the mecha-
nism of Scheme 4 could not be reconciled with the presence
of a proton signal at δ 4.11 ppm, a 13C signal at δ 76.4 ppm,
and the absence of a carbonyl stretch in the IR spectrum in
the crude product. However, the NMR spectrum did
support the presence of a modified camphor subunit as
well as the methanesulfonyloxy fragment, and could be
understood assuming initial reduction of the camphor
carbonyl group to the corresponding hydroxyl, a con-
clusion that was also supported by an OꢀH stretch at
3496 cmꢀ1 in the IR spectrum. Overall, this evidence
supports modified structures for 35 and 36 with R*SO3 =
dihydro-camphorsulfonyloxy. However, the product mix-
ture of diastereomers and residual unsaturated amine
boranes could not be separated. Fortunately, convincing
indirect support for structure 36 was obtained from the
related reaction of CSA with trimethylamine borane (37).
In this case, the resulting trimethylamine complex 38 was
characterized by X-ray crystallography, and NMR com-
parisons with crude 36 revealed the expected similarities
for characteristic chemical shifts.
In view of the corrected structure of 36 and the absence
of substantial hydrogen evolution in either the CSA or
MsOH steps, a distinct amine borane activation mechan-
ism is involved using CSA. In the first stage, one hydride of
the substrate 26b reduces the carbonyl group of CSA (34)
to afford 35 (R*SO3 = dihydro-camphorsulfonyloxy), a
process that is probably assisted by intramolecular car-
bonyl protonation by the sulfonic acid. In the second stage,
MsOH protonates the alkene, followed by internal hydride
migration to convert 35 into 36. This modification of the
two-stage pathway resembles the simpler mechanism using
excess MsOH in that both mechanisms lead from 26a to a
stable bis-sulfonyloxyborane complex. However, the initial
hydride abstraction steps are different and involve different
electrophiles in the first stage.
To summarize, internal IH via a one-stage mechanism
has been demonstrated for unsaturated phosphine or
phosphinite boranes. The decisive event involves carboca-
tion generation by protonation of the double bond with
MsOH, followed by rapid internal hydride transfer. For
analogous unsaturated amine boranes, a two-stage path-
way for IH is favored using sulfonic acids for activation
because hydrogen evolution is faster than in the phos-
phorus series. The resulting unsaturated amine-MsOBH2
complex participates in a relatively slow second stage IH
via carbocation generation and hydride transfer.
A different activation pathway for the first stage is
favored using CSA (34) in place of MsOH. Instead of
initiating hydrogen evolution, CSA abstracts hydride via
internal acid-catalyzed carbonyl reduction. Addition of
MsOH then triggers IH in the second stage to afford
saturated products. An alternative one-stage internal IH
is also possible with amine boranes via Lewis acid induced
carbocation generation from tertiary acetoxyalkylamine
boranes. Lewis acid activation affords the free amine
product after basic workup because the initially formed
28 is easily hydrolyzed, in contrast to MsOH activation
where the corresponding products are the hydrolytically
robust (MsO)2BH complexes 29.
We could find a single priorstudy where internal hydride
transfer from an amine borane has been proposed (acid-
induced reduction of indoles by a tethered amine borane).8
Judging from the simple aqueous workup, this reaction
involves a one-stage activation pathway, probably because
the increased basicity of the indole double bond favors
direct protonation over hydrogen evolution. Internal ionic
hydrogenation has also been encountered in a study invol-
ving tethered alkoxysilane substrates where the presence of a
single SiH bond ensures the one-stage IH mechanism.9
Further studies are warranted to explore applications of
the diverse mechanistic pathways for ionic hydrogenation.
Acknowledgment. This work was supported by the
National Institute of General Medicine (GM067146). The
authors also thank Dr. J. W. Kampf for solving the crystal
structure of 25 and Dr. V. Cwynar for the NOESY study
(Dept. of Chemistry, University of Michigan).
(6) For prior reports of one stage IH with amine boranes, see: Berger,
J. G. Synthesis 1974, 508. Maryanoff, B. E.; McComsey, D. F. M. J. Org.
Chem. 1978, 43, 2733.
(7) Lewis acid catalyzed IH was also observed from i to ii (82%, 2.4:1
dr (major product shown, based on NOESY data), and similar results
were observed using TMSOTf (MeCN solution). MsOH-induced IH
from the exocyclic alkene corresponding to i gave a complex mixture
Supporting Information Available. Experimental pro-
cedures and characterization data (PDF). Crystal data
for 25 (CIF). This material is available free of charge via
the Internet at at http://pubs.acs.org.
including unsaturated products formed by
migration.
a competing olefin
(8) Berger, J. G.; Teller, S. R.; Adams, C. D.; Guggenberger, L. J.
Tetrahedron Lett. 1975, 1807.
(9) McCombie, S. W.; Ortiz, C.; Cox, B.; Ganguly, A. K. Synlett.
1993, 541. These authors described the internal ionic hydrogenation
process using the abbreviation IIH.
Org. Lett., Vol. 14, No. 3, 2012
691