Hydrophosphination of Bicyclo[1.1.0]butane-1-carbonitriles

Article abstract of DOI:10.1021/acs.orglett.6b02051

Hydrophosphination of bicyclo[1.1.0]butyl nitriles with phosphine boranes and phosphites provided novel cyclobutyl-P derivatives. The reaction generally favors the syn-diastereomer, and the nitrile can be reduced and converted to other functional groups, thus enabling the preparation of bidentate ligands that access new conformational space by virtue of their attachment to the torsionally malleable but sterically restrictive cyclobutane scaffold. The enantioselective hydrogenation of dehydrophenylalanine using a bidentate phosphine-phosphite ligand illustrates the synthetic utility of the newly prepared scaffold.

Full text of DOI:10.1021/acs.orglett.6b02051

Letter
pubs.acs.org/OrgLett
Hydrophosphination of Bicyclo[1.1.0]butane-1-carbonitriles
†
,‡
,‡
,†
John A. Milligan, Carl A. Busacca,* Chris H. Senanayake,* and Peter Wipf*
†
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
‡
Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United
States
*
S Supporting Information
ABSTRACT: Hydrophosphination of bicyclo[1.1.0]butyl ni-
triles with phosphine boranes and phosphites provided novel
cyclobutyl-P derivatives. The reaction generally favors the syn-
diastereomer, and the nitrile can be reduced and converted to
other functional groups, thus enabling the preparation of
bidentate ligands that access new conformational space by virtue of their attachment to the torsionally malleable but sterically
restrictive cyclobutane scaffold. The enantioselective hydrogenation of dehydrophenylalanine using a bidentate phosphine−
phosphite ligand illustrates the synthetic utility of the newly prepared scaffold.
icyclo[1.1.0]butanes are highly strained (ca. 65 kcal/mol)
yet bench-stable, synthetically versatile carbocycles.
Scheme 1. Overview of Hydrophosphinations
1
,2
B
Bicyclobutanes with heteroatom-containing tethers, for exam-
ple, can be utilized in thermal, radical, or transition-metal-
mediated conversions to form structurally unique products and
1
,3
generally useful functionalized building blocks.
The central bond in bicyclo[1.1.0]butanes has significant π-
bond character, and homo- or heterolysis of this bond releases
3
most of the ring strain in the carbocyle. Thus, bicyclo[1.1.0]-
butanes are “spring loaded” toward a variety of transformations,
4
5
including protonations, halogenations, and photochemical
6
processes, across the central bond to afford 1,3-functionalized
cyclobutanes. Nucleophilic 1,3-additions of carbon and nitro-
gen nucleophiles generally require electron-withdrawing
activators, as shown in the recent elegant studies by Fox
2
,7,8
(
esters), Baran (sulfones), and co-workers.
In contrast, the
addition of a P-nucleophile to a bicyclobutane is, to the best of
9
our knowledge, still unprecedented.
As part of our ongoing studies to utilize phosphine boranes
as convenient, air-stable reagents for hydrophosphination
1
0
reactions, we were interested in extending this process
toward bicyclo[1.1.0]butanes to generate novel cyclobutyl
phosphines. Previous work has shown that secondary
phosphine borane anions effectively hydrophosphinate alkynes
process. Nitriles such as 3-methylbicyclo[1.1.0]butane-1-
carbonitrile 1, obtained in two steps from commercial
4b,13
10
methylenecyclobutane-3-carbonitrile,
reacted efficiently at
and carbodiimides, and we are now extending this protocol to
strained carbocycles (Scheme 1). The product of such an
addition to a bicyclo[1.1.0]butane would be a cyclobutyl
phosphine with a quaternary carbon α to the phosphorus
substituent. Phosphines of this type could be of potential use in
ambient temperature to give a separable 1.7:1 mixture of
cyclobutanes syn-2 and anti-2 in a combined yield of 76%
(
Scheme 2). The major syn-isomer was reduced with DIBAL-H
to give aldehyde 3, which was further reduced to alcohol 4 in an
overall yield of 52%.
11,12
transition-metal catalysis.
The hydrophosphination of nitriles could be extended to a
variety of aliphatic and aromatic phosphine boranes (Scheme
In a preliminary screen to determine the reactivity of
bicyclobutanes and other strained carbocycles to the phosphine
borane anion (see the Supporting Information), it became
apparent that bicyclobutanes lacking an electron-withdrawing
group were unreactive or showed low conversions. These
results suggested that the addition reaction was not solely
driven by relief of ring strain but resembled a Michael addition
3
). The overall yield is moderate to high and increases for
sterically hindered phosphines (6), suggesting some loss of less
Received: July 13, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02051
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Organic Letters
Letter
Scheme 2. Hydrophosphination of 3-
Methylbicyclo[1.1.0]butane-1-carbonitrile 1 and
Transformation to Phosphine Borane Alcohol 4
Scheme 3. Hydrophosphination of Nitrile 1 with Various
Phosphine Boranes
sterically shielded phosphine boranes during workup con-
ditions. Substitutions on the aryl phosphine portion, including
electron-donating groups, are well tolerated (2, 8, and 9).
Mixed alkyl/aryl phosphines can be prepared (7, 10) as well as
chiral phosphines (11). In almost all cases, syn- and anti-
isomers (which were readily separated using chromatography
on SiO ) were obtained in about a 2:1 ratio, regardless of the
2
nature of the phosphine borane. Interestingly, this isomer ratio
is regenerated when either isolated diastereomer is resubjected
to the reaction conditions (NaH, DMAc); i.e., the hydro-
phosphination is under thermodynamic control. Accordingly,
the minor anti-isomer can readily be converted to the more
stable syn-isomer. The relative configuration was assigned by
NMR (the syn-isomers exhibit a distinct NOE between the
4
methyl C−H’s and the methine C−H as well as a small J
CP
coupling of the nitrile carbon in most cases).
Substitutions on the bicyclo[1.1.0]butane are also well
tolerated in this reaction. 3-Phenylbicyclo[1.1.0]butane-1-
carbonitrile 13 was prepared from dibromocyclopropane 12
by dilithiation and subsequent trapping with dimethyl
14
malononitrile (Scheme 4). It should be noted that this is
the first example of a synthesis of a bicyclobutane nitrile by
transnitrilation. Bicyclobutane 13 underwent a smooth hydro-
phosphination with aromatic or aliphatic phosphine boranes to
give cyclobutanes 14 and 15 in 60−70% yield. In contrast to
methyl-substituted 1, phenyl-substituted 13 provided a slight
preference for the anti-isomer 14. The origin of this reversal of
selectivity is not obvious. Interestingly, the sterically hindered
2
,2-dimethylbicyclo[1.1.0]butane-1-carbonitrile 16 (which lacks
substitution at the bridgehead position) provided only the syn-
isomers 17 and 18, albeit in low yields of 27−34% (Scheme 5).
For mechanistic reasons, the conversion of 1 to 5 was also
performed in the presence of a galvinoxyl (0.15 equiv) radical
trap and in the dark, leading to comparable yields, ratios, and
reaction times, and thus, a radical pathway could be excluded.
The addition of P-nucleophiles other than phosphine
boranes to bicyclobutane nitriles was also investigated (Scheme
6
). Initial attempts to accomplish the addition of an H-
phosphonate in the same manner as phosphine boranes was
unsuccessful. However, in accord with observations of
Montchamp and co-workers, DBU was found to be an
effective base, and dibenzyl phosphite (which is slightly more
acidic than the more common diethyl phosphite) led to an
efficient conversion. Under these conditions, the cyclobutyl
phosphonates 19 and 20 were obtained in yields of 59% and
Bidentate phosphine−phosphites and phosphine−phosphor-
amides have frequently been utilized in catalysis, particularly in
15
16
asymmetric hydrogenations and hydroformylations. In order
to assess the potential of cyclobutyl phosphines as a new ligand
class in asymmetric catalysis, alcohol 4 was deprotected with
DABCO and subsequently treated with a BINOL-derived
chlorophosphite to afford bidentate phosphine−phosphite 21
(Scheme 7). In the presence of 3 mol % of 21, 1 mol % of
6
2%, respectively, as inseparable mixtures of syn/anti-stereo-
17
isomers.
cationic rhodium complex Rh(NBD)BF4, and hydrogen gas
B
DOI: 10.1021/acs.orglett.6b02051
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Organic Letters
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Scheme 4. Preparation and Hydrophosphination of 3-
Phenylbicyclo[1.1.0]butane-1-carbonitrile 13
In summary, the first hydrophosphinations of bicyclo[1.1.0]-
butane-1-carbonitriles have been achieved with secondary
phosphine borane anions. In a similar fashion, H-phosphonates
can be added across the central bond of this strained
carbocycle. Most cyclobutylphosphine borane products are
obtained as a readily separable mixture of syn- and anti-
diastereomers that can be re-equilibrated for higher con-
versions. Alkyl and aryl substitutions on bicyclobutane and
phosphine are readily tolerated, and the nitrile moiety in the
cyclobutane product can be converted to aldehydes and
alcohols, which enables the synthesis of chiral bidentate
phosphine−phosphite ligands. The utility of this new scaffold
has been demonstrated in the enantioselective hydrogenation
of a dehydrophenylalanine derivative. Future extensions of this
work include exploring applications of these phosphine
derivatives in transition-metal catalysis and developing related
nucleophilic ring openings of bicyclobutanes.
ASSOCIATED CONTENT
Supporting Information
■
Scheme 5. Hydrophosphination of 2,2-
Dimethylbicyclo[1.1.0]butane-1-carbonitrile 16
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02051.
Experimental procedures, NMR spectra for new
compounds, and a differential scanning calorimetry plot
for 1 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*
*
*
Scheme 6. Addition of H-Phosphonates to
Bicyclo[1.1.0]butanes 1 and 16
E-mail: carl.busacca@boehringer-ingelheim.com.
E-mail: chris.senanayake@boehringer-ingelheim.com.
E-mail: pwipf@pitt.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Bhaskar Godugu (University of Pittsburgh) for
HRMS analyses. Max Sarvestani (Boehringer-Ingelheim) is
acknowledged for conducting a calorimetry analysis on 1. Dr.
Jon Reeves (Boehringer-Ingelheim) is acknowledged for helpful
discussions.
Scheme 7. Preparation of Bidentate Phosphine Ligand 21
and Asymmetric Hydrogenation of Dehydrophenylalanine
2
2
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Org. Lett. XXXX, XXX, XXX−XXX