The acid promoted Petasis reaction of organotrifluoroborates with imines and enamines

Article abstract of DOI:10.1039/c7cc04397j

The acid promoted addition of organotrifluoroborate salts to imine and enamine electrophiles is reported. Use of the pre-activated trifluoroboronate complex bypasses the need for α-hetero substitution on the electrophile component, greatly expanding the scope of the Petasis borono-Mannich reaction. A variety of vinyl, aromatic and heteroaromatic trifluoroborate salts undergo addition with good efficiency under mild reaction conditions. The reaction is amenable for use with a variety of carbamate protected imine and enamine electrophiles, achieving for the first time the effective coupling with aliphatic aldehydes.

Full text of DOI:10.1039/c7cc04397j

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The Acid Promoted Petasis Reaction of Organotrifluoroborates
with Imines and Enamines
Received 00th January 20xx,
Accepted 00th January 20xx
Diane E. Carrera. †*
The acid promoted addition of organotrifluoroborate salts to imine and enamine electrophiles is reported. Use of the pre-
activated trifluoroboronate complex bypasses the need for α-hetero substitution on the electrophile component, greatly
expanding the scope of the Petasis borono-Mannich reaction. A variety of vinyl, aromatic and heteroaromatic
trifluoroborate salts undergo addition with good efficiency under mild reaction conditions. The reaction is amenable for
use with a variety of carbamate protected imine and enamine electrophiles, achieving for the first time the effective
coupling with aliphatic aldehydes.
DOI: 10.1039/x0xx00000x
www.rsc.org/
1, TS-1). This requirement has effectively limited the aldehyde
salicylaldehyde11 and heteroaromatic species12. We postulated
that starting from a pre-activated boron species, namely an
Introduction
Following the initial literature report by Petasis1, the borono-
Mannich reaction has found widespread use in the chemical
community as a useful three component coupling reaction,
generating highly functionalized amine product from simple
aldehyde, amine and boronic acid precursors (eq 1).2
Subsequent to this first report, much work has been devoted
to expanding the scope of this transformation, with recent
organotrifluoroborate salt, would eliminate this requirement
for intramolecular activation by rendering the transformation
intermolecular in nature, thereby expanding the scope and
utility of this transformation (Eq. 2, TS-2). Herein we report
the successful realization of this strategy with the addition of a
variety of organotrifluoroborate salts to imine and enamine
electrophiles.
reports
of
metal
catalyzed3,4
,
“traceless”5
and
Earlier reports of the organocatalytic Friedel-Crafts alkylation
of α,β-unsaturated aldehydes with aryl trifluoroborate salts13
effectively demonstrated the utility of these species as mild,
easily handled coupling partners. While previous work14-16 has
enantioselective6-8 variants highlighting the prominence it has
achieved as a synthetic tool. However, a common limitation of
this process is the need for a pendant heteroatom on the
iminium intermediate, which is required to facilitate
intramolecular addition of the resulting boronate species (Eq.
shown that trifluoroborate salts undergo
π-nucleophilic
addition reactions through the proposed intermediacy of their
dihalogenated equivalents under Lewis acid catalysis, this
mode of activation faces the same limitation as more
traditional Petasis systems in that pre-association with the
electrophile is required before addition occurs. We wondered
if the electrophile was instead subjected to Brønsted acid
activation and the trifluoroborate salt was allowed to remain
as the boronate species, one could overcome this limitation
and obtain reactivity with non-α-heteroatom functionalized
electrophiles.
Results and discussion
Towards this end, the reaction of potassium trans-
styryltrifluoroborate, camphorsulfonic acid (CSA) and a variety
of differentially protected benzaldehyde imines was evaluated
(Table 1). It was found that only the carbamate protected
imine gave desired product (entry 4, 12% yield) so this
substrate was chosen for further optimization. Solvent polarity
was found to play a key role in the observed levels of reactivity
with highly polar solvents such as acetonitrile giving the
component of this transformation to glyoxylate9, -hydroxy10,
α
a.Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544,
United States. E-mail: carrera.diane@gene.com
† Current Address: Small Molecule Process Chemistry, Genentech, Inc., 1 DNA
Way, South San Francisco, CA 94080.
Electronic Supplementary
DOI: 10.1039/x0xx00000x
Information
(ESI)
available:
See
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Table 1 Evaluation of Parameters for Trifluoroborate Addition
Table 2 Scope of Vinyl and Aryl Trifluoroborate Salt Nucleophiles
aConversion determined by GLC analysis relative to an internal standard.
greatest levels of conversion over shorter reaction times (entry
7, 40% yield). This result can be directly attributed to solubility
effects as homogenous solutions of potassium trifluoroborate
salt are only obtained in solvents with high dielectric
constants. It was observed during the course of these
reactions that a significant amount of hydrodeboration was
occurring in the acidic reaction media and it was postulated
that this was leading to the low observed yields. Switching aPerformed with dichloroacetic acid bPerformed at –20 ˚C.
from the highly acidic CSA (pKa = –2.17) to trifluoroacetic acid
Table 3 Reaction Scope with Aryl Imines and Aliphatic Enamines
(TFA, pKa = –0.25) seems to support this hypothesis as
significantly less hydrodeboration was observed and resulted
in a corresponding increase in yield (entry 9, 86% yield, 4 h).
Interestingly, no deprotection products were observed despite
the use of strong acids.
While trans-styryl boronic acid derivatives are known to be
particularly reactive in Petasis systems, we were pleased to
find that
a diverse range of trifluoroborate salts also
participate in this reaction (Table 2). The less electron-rich cis
and trans methyl vinyl organotrifluoroborates both undergo
intermolecular addition in this system (entries 2–3, 63–68%
yield) with retention of olefin geometry. Electron rich
heterocycles such as furan, N-Boc-pyrrole and 4-
methylthiophene also undergo addition with good levels of
reactivity (entries 5–7, 73–82% yield) with the use of cryogenic
conditions serving to retard the rate of competing
hydrodeboration of the trifluoroborate starting material.
Similarly, in the case of electron-rich aromatics such as 4-
methoxyphenyl trifluoroborate, dichloroacetic acid is used in
place of TFA to limit this competing hydrodeboration pathway
(entry 8, 79% yield).
Having shown that benzaldehyde derived imines react well
with a variety of organotrifluoroborate nucleophiles, we next
turned our attention to the goal of exploring the applicability
of this methodology to diverse electrophile frameworks. In
addition to the parent benzaldehyde imine, both the electron-
rich 4-methoxy and electron-poor 4-trifluoromethyl
substituted imines undergo reaction with good levels of
efficiency (Table 2, entries 1–2, 78-83% yield) while
substitution at the meta position is also well tolerated (entry 3,
95% yield). In addition to substituted phenyl systems,
heteroaromatic imines also undergo net styrene addition with
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with good levels of reactivity (Table 2, entries 4–5, 65–99% electrophiles are susceptible to such radical fragmentation
yield).
pathways17 and organotrifluorborates have been shown
After demonstrating the success of this protocol with susceptible to single-electron oxidation events to generate
aromatic electrophiles, we next turned our attention towards benzylic radicals18. In order to determine which reaction
applying this methodology to aliphatic systems with the aim of mechanism is in effect, a Hammett study probing the role of
accomplishing our goal of expanding the scope of this imine electronics on the rate of addition was undertaken
transformation to encompass a wide range electrophiles. To (Figure 2).
our satisfaction, it was found that easily prepared alkyl
For this study a number of variously substituted imines were
enamines also undergo reaction with styryl trifluoroborate, synthesized and the initial rate of their reaction with benzyl
through their imine tautomer, upon exposure to trifluoroacetic trifluoroborate at 0 ˚C was measured. If this reaction is
acid in excellent yields and relatively short reaction times proceeding through a two-electron mechanism, one would
(Table 3, entries 6–10, 89–98% yield). It should also be noted expect to see correlation with two electron Hammett
that both the tert-butyl (Boc) and benzyl (Cbz) carbamate N- constants. Conversely, if it proceeds through a one-electron
protecting groups can be used, with both furnishing the mechanism, then better correlation should be seen with the
desired addition products with high levels of reactivity (entries single-electron Hammett constant
6–7). The use of such alkyl enamines represents a particularly
σ•.
Figure 2. Hammett Study of Potassium Benzyl Trifluoroborate
Addition
valuable transformation, as this opens up an entirely new class
of previously non-reactive substrates to Petasis
functionalization.
In order to demonstrate of the intermolecular nature of the
organotrifluoroborate addition, it was shown that a fully
substituted cyclic enamine
1 can also undergo styryl addition
under standard reaction conditions (Eq 3). This result supports
that an alternative pathway, coordination to the imine
nitrogen and subsequent intramolecular nucleophile delivery,
is not taking place as the cyclic substrate has no open
coordination site.
Much to our surprise, initial results revealed that though
unable to participate in a π-nucleophilic addition mechanism,
potassium benzyl trifluoroborate also undergoes addition,
albeit in moderate yield (Eq 4). Due to the inability of this
substrate to participate in a Friedel-Crafts type mechanism,
this intriguing result raises the possibility of alternative
mechanisms for trifluoroborate addition including anionic,
rearrangement and radical addition pathways. In the anionic
mechanism, polarization of the boron-carbon bond would lead
to a localization of negative charge on the benzylic carbon,
which could behave as
a carbanionic nucleophile. An
alternative mechanism, reminiscent of the classical Petasis
mechanism, is that of intramolecular rearrangement of the
benzylic group following coordination to the imine nitrogen.
There is also the possibility of a one-electron radical addition
mechanism, as it has been shown that a similar class of imine
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4
5
6
For nickel catalyzed Petasis-like reactions see: A. G. Doyle, T.
J. A. Graham, J. D. Shields, J. D. Chem. Sci 2011, , 980.
R. J. Thomson, D. A. Mundal, K. E. Lutz. J. Am. Chem. Soc.
2012, 134, 5782.
Y. Takemoto, Y. Yamaoka, H. Miyabe, J. Am. Chem. Soc. 2007,
129, 6686.
As seen in Figure 2, better correlation is obtained with σ,
indicating that this addition proceeds through a two-electron
2
pathway. This suggests that either the anionic or
rearrangement pathways are in effect for the addition of
benzyltrifluoroborate.
7
8
S. E. Schaus, S. J. Lou, J. Am. Chem. Soc. 2008, 130, 6922.
W-C. Yuan, W-Y. Han, Z-J. Wu, X-M Zhang, Org. Lett. 2012,
14, 976.
For the use of glyoxylates see: N. A. Petasis, I. A. Zavialov, J.
Am. Chem. Soc. 1997, 119, 445; N. A. Petasis, Z. D. Patel,
Tetrahedron Lett. 2000, 41, 9607; M. Scobie, T. Koolmeister,
M. Soedergren, Tetrahedron Lett. 2002, 43, 5969; S. R.
Piettre, H. Jourdan, G. Gouhier, L. V. Hijfte, ; P. Angibaud, P.
In an attempt to render this transformation enantioselective,
the reaction of trans-styryltrifluoroborate with a number of
electrophiles containing chiral auxiliaries was examined (Figure
3). While the chiral carbamate protected substrates in
equation 5 were able to undergo trifluoroborate addition with
moderate levels of reactivity, no diastereomeric preference
was observed.19
9
Tetrahedron Lett. 2005, 46
Southwood, M. C. Curry, M. C. Tetrahedron 2006, 62, 236.
10 For the use of -hydroxy aldehydes see: N. A. Petasis, I. A.
, 8027; C. A. Hutton, T. J.
Figure 3 Chiral Auxiliary Approach to Asymmetric Induction
α
Zavialov, J. Am. Chem. Soc. 1998, 120, 11798.
11 For the use of salicylaldehydes see: N. A. Petasis, S. Boral,
Tetrahedron Lett. 2001, 42, 539; M. G. Finn, Q. Wang, Q. Org.
Lett. 2000, 2, 4063.
12 For heterocyclic aldehydes, see: T. K. Hansen, N. Schlienger,
M. R. Bryce, Tetrahedron Lett. 2000, 41, 1303.
13 S. Lee, D. W. C. MacMillan J. Am. Chem. Soc. 2007, 129
15438.
,
14 Lewis acid catalyzed organotrifluoroborate additions: S.
Raeppel, J-P. Tremblay-Morin, Tetrahedron Lett. 2004, 45,
3471.
15 Organotrifluoroborate additions with ionic liquids: G. W.
Kabalka, B. Venkataiah, G. Dong, Tetrahedron. Lett. 2004, 45
729.
,
16 Lewis acid catalyzed allylation and crotylation: R. A. Batey, S-
W. Li, Chem. Comm. 2004, 1382.
17 K. L. Tan, E. N. Jacobsen, Angew. Chem. Int. Ed. 2007, 46
1315.
,
18 G. A. Molander, V. Colombel, V. A. Braz, Org. Lett. 2011, 13
,
Conclusions
1852; P. S. Baran, J. W. Lockner, D. D. Dixon, R. Risgaard, Org.
Lett. 2011, 13, 5628; G. A. Molander, J. C. Tellis, D. N. Primer,
Science 2014, 345, 433.
In conclusion, we have demonstrated the first use of
organotrifluoroborate salts as nucleophiles in the Petasis
borono-Mannich reaction. Furthermore, through the use of
these commercially available, air and moisture stable boronate
salts we have been able to greatly expand the scope of
electrophiles used in this synthetically valuable and versatile
transformation.
19 The chiral sulfinimines (2a-b) used extensively by Ellman
proved unreactive to the standard reaction conditions. In all
cases the unreacted sulfinimine starting material was
recovered unchanged, even at temperatures up to 60 ˚C.
Acknowledgements
The author would like to thank Prof. David W.C. MacMillan
(Princeton University) for help preparing this manuscript and
providing intellectual guidance and financial support for this
work. The author also thanks Drs. Haiming Zhang and Francis
Gosselin (Genentech, Inc.) for proofreading the manuscript.
References
1
2
N. A. Petasis, I. Akritopoulou, Tetrahedron Lett 1993, 34, 583.
N. R. Candeias, F. Montalbano, P. M. S. D. Cal, P. M. P. Gois,
Chem. Rev. 2010, 110, 6169.
3
For copper catalyzed Petasis-like reactions see: B. A.
Arndtsen, M. S. T. Morin, Y. Lu, D. A. Black, J. Org. Chem.
2012, 77, 2013; E. Bergin, R. Frauenlob, R., C. Garcia, G. A.
Bradshaw, H. M. Burke, J. Org. Chem. 2012, 77, 4445.
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