A General Method for Imine Formation Using B(OCH2CF3)3

Article abstract of DOI:10.1021/acs.orglett.5b00949

Tris(2,2,2-trifluoroethyl)borate [B(OCH₂CF₃)₃] was found to be a mild and general reagent for the formation of a variety of imines by condensation of amides or amines with carbonyl compounds. N-Sulfinyl, N-toluenesulfonyl,

Full text of DOI:10.1021/acs.orglett.5b00949

Letter
pubs.acs.org/OrgLett
A General Method for Imine Formation Using B(OCH2CF3)3
Jonathan T. Reeves,* Michael D. Visco,† Maurice A. Marsini, Nelu Grinberg, Carl A. Busacca,
Anita E. Mattson,† and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/P.O. Box 368, Ridgefield, Connecticut
06877-0368, United States
S
* Supporting Information
ABSTRACT: Tris(2,2,2-trifluoroethyl)borate [B(OCH2-
CF3)3] was found to be a mild and general reagent for the
formation of a variety of imines by condensation of amides or
amines with carbonyl compounds. N-Sulfinyl, N-toluenesul-
fonyl, N-(dimethylamino)sulfamoyl, N-diphenylphosphinoyl,
N-(α-methylbenzyl), and N-(4-methoxyphenyl) aldimines are
all accessible using this reagent at room temperature. The
reactions are operationally simple, and the products are
obtained without special workup or isolation procedures.
he imine or azomethine functional group is exceptionally
neous; (3) be amenable to aldehydes of diverse electronic and
1
Tuseful in organic synthesis. Chiral N-sulfinyl imines in steric properties; and (4) use benign and commercially available
materials. Herein we report that tris(2,2,2-trifluoroethyl)borate
is an effective reagent for promoting the condensation of 1 with
aldehydes and even ketones, and also for the preparation of
several other valuable types of aldimines.
particular have emerged in the past two decades as practical and
selective auxiliaries.2 N-tert-Butanesulfinyl imines, developed by
Ellman and co-workers, are the most versatile and well-explored
class of N-sulfinyl imines.2b,c Ellman and co-workers reported
the first asymmetric synthesis of tert-butanesulfinamide 1 and
its condensation with aldehydes and ketones to give N-sulfinyl
imines.3 The initial conditions developed for the condensation
employed either MgSO4 or CuSO4.3a−c Ellman and co-workers
later reported the use of Ti(OEt)4 for the condensation of
ketones with 1 and showed this reagent was also effective for
the condensation of all types of aldehydes.3b−d Importantly,
Ti(OEt)4 enabled conversion of aldehydes not amenable to the
MgSO4 or CuSO4 conditions. The Ti(OEt)4 procedure has the
drawback of requiring the removal of insoluble TiO2 waste
during the workup, however. The filtration of TiO2 is often
extremely slow and can become prohibitive on large scale.4,5
Numerous other reagents have been developed for condensa-
tion of 1 with aldehydes, such as Cs2CO3,6 NaOH or KOt-Bu,7
Yb(OTf)3,8 and KHSO4.9 Recently, Ruano and Cid reported a
general protocol for imine formation using catalytic pyrrolidine
and 4 Å MS in CH2Cl2 at 60 °C.10 As part of our continuing
work on nucleophilic additions to N-sulfinyl imines, we
required a scalable procedure for preparation of a variety of
N-sulfinyl imines. We employed Ellman’s Ti(OEt)4 procedure
for a wide variety of N-sulfinyl aldimines and ketimines with
excellent results, but the postreaction filtration and disposal of
large amounts of TiO2 waste often proved tedious, especially
for large scale reactions. The use of Ti(OEt)4 also necessitated
extensive reactor cleaning protocols to ensure complete
removal of Ti residue. The heterogeneous nature of many of
the alternative reagents was not desirable, as these systems
could lead to etching of reactor walls. We thus searched for an
alternative reagent system which would ideally (1) require no
filtration of insoluble materials postreaction; (2) be homoge-
In previous work on making N-acetyl enamides, we found
that trialkyl borates were effective reagents to promote the
condensation of ammonia with ketones, being surpassed in
performance only by titanium alkoxides.5 Borates have the
advantage of giving aqueous soluble boric acid as a byproduct
upon hydrolysis and, consequently, help avoid the workup
issues encountered with titanium alkoxides. A screen of various
trialkyl borates as promotors for N-sulfinyl imine formation was
therefore initiated. 4-Bromobenzaldehyde was reacted with (S)-
tert-butanesulfinamide 1 (1.2 equiv) and trialkyl borate (3
equiv) (Table 1). In most cases the trialkyl borate was
employed as both the condensation reagent and the solvent.
The reactions employing trialkyl borates (entries 1−5) at
ambient temperature (22 °C) proceeded slowly but cleanly to
give 48−94% conversion to 2a after 72 h. Among these
reagents, triisopropyl borate (entry 3) gave the highest
conversion of 94%. The use of triphenyl borate (entry 6)
resulted in a significant increase in rate, giving full conversion to
2a after 8 h. An even more dramatic acceleration occurred
when tris(2,2,2-trifluoroethyl)borate [B(OCH2CF3)3] was used
(entry 7), as full conversion was achieved in only 1 h. When the
amount of B(OCH2CF3)3 was reduced to 1 equiv and THF was
used as solvent (entry 8), full conversion was reached after 4 h.
The use of a substoichiometric amount of B(OCH2CF3)3 (0.5
equiv) was possible, but resulted in an increased reaction time
(entry 9). Sheppard and co-workers have pioneered the use of
B(OCH2CF3)3 as a highly effective reagent for amide bond
Received: April 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00949
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Organic Letters
Letter
a
Table 1. Reagent Screening Results
Scheme 1. Scope of N-Sulfinyl Aldimine Formation
a
entry
borate
time (h)
conversion (%)
1
B(OMe)3
B(OEt)3
72
72
72
72
72
8
71
85
2
3
B(Oi-Pr)3
B(Ot-Bu)3
94
4
48
5
i-PrOB(pin)
67
b
6
B(OPh)3
100
100
100
97
7
B(OCH2CF3)3
1
c
8
B(OCH2CF3)3 (1 equiv)
4
c
9
B(OCH2CF3)3 (0.5 equiv)
Si(OEt)4
16
72
72
10
11
28
Si(OCH2CF3)4
91
a
Conversion of 4-bromobenzaldehyde to 2a as measured by HPLC
b
analysis. CH2Cl2 was employed as solvent since B(OPh)3 is a solid.
c
THF was used as solvent.
formation.11 While the use of tetraethyl orthosilicate (entry 10)
gave a low conversion of 28% after 72 h, the trifluoroethyl
variant Si(OCH2CF3)4 gave a 91% conversion after the same
reaction time (entry 11).12
The scope of N-sulfinyl aldimine formation using B-
(OCH2CF3)3 was next explored (Scheme 1). In addition to
1, the condensation was also effective for 4-p-tolylsulfinamide
and 2,4,6-triisopropylphenylsulfinamide, providing the corre-
sponding imines 2b and 2c in high yields. The reaction was
amenable to both electron-poor (products 2a−c, 3, and 5) and
electron-rich aromatic aldehydes (products 4 and 7). Aldehydes
bearing one (product 6) or two (product 7) ortho substituents
were converted smoothly to N-sulfinyl imines. It is noteworthy
that the previously reported synthesis of the 2,4,6-trimethoxy-
phenyl sulfinimine 7 required the use of Ti(OEt)4 in THF at
reflux.13 Heterocyclic (product 8) and α,β-unsaturated
(product 9) substrates could be employed. Finally, the
B(OCH2CF3)3 mediated condensation was also effective for
alkyl aldehydes, as aldehydes with two, one, or zero α-protons
reacted to give N-sulfinyl imines 10−13 in good yields. Notably
the hindered trimethylacetaldehyde derived imine 13, which
previously was accessible only through the use of Ti(OEt)4, was
formed without difficulty. The reactions were conveniently
worked up by addition of saturated aqueous NaHCO3 solution
and EtOAc. This resulted in two clear phases; no insoluble
materials required filtration. Importantly, no epimerization of
the sulfur stereocenter was observed, since 1 of >99.5% ee gave
2a of >99.5% ee.14
a
Reaction conditions: 2.0 mmol of aldehyde, 2.4 mmol of 1, 2.0 mmol
b
of B(OCH2CF3)3, 2 mL of THF, rt, 2−6 h. Isolated yields. (S)-4-
Methylphenylsulfinamide used instead of 1. (R)-2,4,6-Triiso-
propylphenylsulfinamide used instead of 1.
c
a
Scheme 2. Scope of N-Sulfinyl Ketimine Formation
Given the facility of the reaction with a broad spectrum of
aldehydes, we explored the extension to ketones. After some
optimization, it was found that the condensation with ketones
could be effected using 1.5 equiv of sulfinamide 1 and 3 equiv
of B(OCH2CF3)3 in THF at 55 °C for 48 h (Scheme 2). Under
these conditions, acetophenone and 4-methoxyacetophenone
gave ketimines 14 and 15 in modest yields. Aldol-derived
byproducts were observed by LC-MS analysis of these reaction
mixtures and constituted the main detractors to product yield.
The use of dialkyl ketones proceeded more cleanly, as isopropyl
methyl ketone and pinacolone reacted to give ketimines 16 and
17 in 71% and 79% yields, respectively. The more electron-rich
a
Isolated yields.
dialkyl ketones may be less prone to enolization and aldol side
reactions than the aryl alkyl ketones. It is noteworthy that N-
sulfinyl ketimines have previously required Ti(OEt)4 for their
preparation.3b−d
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DOI: 10.1021/acs.orglett.5b00949
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Organic Letters
Letter
We next extended the reaction to the preparation of N-
toluenesulfonyl aldimines (Scheme 3). This type of imine has
Scheme 4. Scope of N-Dimethylsulfamoyl Aldimine
Formation
a
Scheme 3. Scope of N-Toluenesulfonyl Aldimine
a
Formation
a
Isolated yields.
The B(OCH2CF3)3 mediated imine formation was also
applicable to N-(diphenylphosphinoyl)imines (Scheme 5). As
Scheme 5. Scope of N-Diphenylphosphinoyl Aldimine
a
Formation
a
Isolated yields.
found utility in several catalytic asymmetric additions15 and has
been prepared either by the acid catalyzed condensation of
aldehydes and p-toluenesulfonamide in refluxing toluene with
azeotropic removal of water16 or by the action of TiCl4/Et3N.17
The pyrrolidine catalyzed method of Ruano and Cid is also
effective for the preparation of N-toluenesulfonyl aldimines.10
The reaction conditions developed for N-sulfinyl aldimine
formation using B(OCH2CF3)3 were directly applicable to N-
toluenesulfonyl aldimine formation, with the exception of the
reaction time, which was increased to 18 h. A variety of aryl
aldehydes underwent the condensation, including electron-poor
and -rich substrates, giving products 18−23 in high isolated
yields. As observed for the reaction with tert-butanesulfinamide
1 to give 7, condensation of the sterically hindered and
electron-rich 2,4,6-trimethoxybenzaldehyde with p-toluene-
sulfonamide proceeded smoothly to give imine 22 in 90%
yield. The reaction of cinnamaldehyde gave α,β-unsaturated
imine 24 in 85% yield. The sterically hindered trimethyl-
acetaldehyde derived alkyl imine 25 was accessible in good
yield as well (81%).
N-Dimethylsulfamoyl aldimines were first prepared by van
Leusen and co-workers in 1997.18 Their synthesis was
accomplished by refluxing a mixture of aldehyde and N-
(dimethylsulfamoyl)amide in toluene with azeotropic removal
of water. After nucleophilic addition to the imine, the N-
dimethylsulfamoyl group may be cleaved under either acidic19
or basic20 reaction conditions. Application of the B-
(OCH2CF3)3 mediated imine formation conditions to the
condensation with N-(dimethylsulfamoyl)amide was effective
and provided a mild avenue to the corresponding imines
(Scheme 4). As with the N-toluenesulfonyl imines, a reaction
time of 18 h was employed to ensure complete conversion.
Both electron-rich and -poor aryl aldehydes provided the
corresponding imines 26−29 in high yields. The heterocyclic
substrate 2-thienyl carbaldehyde furnished N-dimethylsulfamo-
yl imine 30 in good yield. Cinnamaldehyde and trimethyl-
acetaldehyde also reacted smoothly to give imines 31 and 32.
a
Isolated yields.
with N-toluenesulfonyl imines, this class of imines has found
significant utility for a variety of catalytic asymmetric addition
reactions.21 The diphenylphosphinoyl group often confers high
crystallinity to products and can be cleaved under mildly acidic
conditions.22 The traditional methods for making N-(diphenyl-
phosphinoyl)imines require either TiCl4/Et3N mediated
condensation of diphenylphosphinamide with aldehydes,17 the
reaction of oximes with Ph2PCl,23 or the Kresze reaction of
aldehydes with diphenyl-N-sulfinylphosphoramidate.24 Alter-
natively, the sulfinate adduct of the phosphinoyl imine may be
prepared and the imine released in situ with a base.22 Ruono
and Cid’s recently reported pyrrolidine catalyzed imine
formation was demonstrated for N-(diphenylphosphinoyl)-
imine formation for three aryl aldehydes.10 To achieve the
condensation using B(OCH2CF3)3, it was necessary to increase
the stoichiometry of diphenylphosphinamide and B-
(OCH2CF3)3 to 2 and 3 equiv, respectively. It was also found
that the use of CHCl3 as solvent was critical, as it was the only
solvent which solubilized Ph2P(O)NH2. Under these con-
ditions, the condensation occurred at rt within 24 h for
electronically diverse aryl aldehydes (33−36) as well as for a
heterocyclic (37) and an α,β-unsaturated (38) substrate.
Finally, we briefly examined the utility of the B(OCH2CF3)3
procedure for the formation of N-alkyl and N-aryl imines.
C
DOI: 10.1021/acs.orglett.5b00949
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Organic Letters
Letter
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a
Scheme 6. Scope of N-Alkyl or N-Aryl Aldimine Formation
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a
Isolated yields.
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The products 39 and 40 were isolated in excellent yields. The
condensation was also amenable to N-aryl imines, as the
reaction of p-anisidine with 4-bromobenzaldehyde furnished
imine 41 in 92% yield.
In summary, B(OCH2CF3)3 was shown to be an effective
and general reagent for the formation of a variety of
synthetically useful imines via condensation of amides or
amines with aldehydes. The reactions proceed at room
temperature. Upon aqueous workup, the reagent B-
(OCH2CF3)3 is hydrolyzed to give aqueous-soluble boric
acid, and no filtration of insoluble reagents or byproducts is
required. The formation of N-sulfinyl ketimines was also
possible at elevated temperature and represents the first
alternative to Ti(OEt)4 for preparation of this type of ketimine.
Notably, B(OCH2CF3)3 is commercially available and may also
be prepared on large scale in one step from boric anhydride and
trifluoroethanol as described by Sheppard and co-workers.11b
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analytical data (1H and 13C
NMR). This material is available free of charge via the Internet
at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jonathan.reeves@boehringer-ingelheim.com.
Present Address
†Department of Chemistry and Biochemistry, Ohio State
University, Columbus, OH 43210.
(25) Nugent, T. C.; Marinova, S. M. Synthesis 2013, 153.
Notes
The authors declare no competing financial interest.
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D
DOI: 10.1021/acs.orglett.5b00949
Org. Lett. XXXX, XXX, XXX−XXX