Hydrogen-free alkene reduction in continuous flow

Article abstract of DOI:10.1021/ol400051n

The first continuous hydrogenation that requires neither H₂ nor metal catalysis generates diimide by a novel reagent combination. The simple flow reactor employed minimizes residence time by enabling safe operation at elevated temperature.

Full text of DOI:10.1021/ol400051n

ORGANIC
LETTERS
2013
Vol. 15, No. 3
710–713
Hydrogen-Free Alkene Reduction in
Continuous Flow
Andrew S. Kleinke and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States
tfj@mit.edu
Received January 8, 2013
ABSTRACT
The first continuous hydrogenation that requires neither H2 nor metal catalysis generates diimide by a novel reagent combination. The simple flow
reactor employed minimizes residence time by enabling safe operation at elevated temperature.
Herein we report the first continuous method for H2-free
hydrogenation1 via diimide (diazene, HNdNH 1)2 gener-
ated from the new reagent combination of N,O-bistrifluoro-
Scheme 1. Novel Method of Diimide Generation
acetylhydroxylamine 2 and hydroxylamine (Scheme 1).
This transformation proceeds with significantly reduced
reaction times relative to batch reductions, enjoys a wide
substrate scope with excellent functional group compat-
ibility, and features a user-friendly flow reactor easily con-
structed from commercial components.
While diimide reductions in batch mode provide a degree
of complementarity to transition metal mediated hydro-
genation, they are not without their own set of limita-
tions.3 Among these are prolonged reaction times, incon-
sistencies in reproducibility, and large excesses of reagents.
We hypothesized that continuous flow, in contrast, would
provide a platform for improvement of diimide reduc-
tions due to enhanced mixing and the ability to heat reac-
tion mixtures effectively. Additionally, continuous flow
conditions are particularly attractive for the development of
reactions that involve highly reactive intermediates or
harsh conditions, as exposure to the elevated tempera-
tures is limited to small quantities of material at any given
(1) Pioneering flow hydrogenation protocols and instrumentation have
ꢀ
been developed. Homogeneous: (a) Newton, S.; Ley, S. V.; Arce, E. C.;
Grainger, D. M. Adv. Synth. Catal. 2012, 354, 1805. (b) Mercadante, M. A.;
Kelly, C. B.; Lee, C. X.; Leadbeater, N. E. Org. Process Res. Dev. 2012, 16,
1064. Heterogeneous: (c) Kirschning, A.; Solodenko, W.; Mennecke, K.
Chem.;Eur. J. 2006, 12, 5972. (d) Irfan, M.; Glasnov, T. N.; Kappe, C. O.
ChemSusChem 2011, 4, 300.
(2) (a) Pasto, D. J.; Taylor, R. T. Org. React. 1991, 40, 91. (b) Miller,
C. E. J. Chem. Educ. 1965, 42, 254. (c) Corey, E. J.; Mock, W. L.; Pasto,
D. J. Tetrahedron Lett. 1961, 11, 347.
(4) For example, handling azides: (a) Palde, P. B.; Jamison, T. F.
Angew. Chem., Int. Ed. 2011, 50, 3525. (b) Gutmann, B.; Roduit, J.-P.;
Roberge, D.; Kappe, C. O. Angew. Chem. 2010, 122, 7255. Angew.
Chem., Int. Ed. 2010, 49, 7101. Diazos: (c) Martin, L. J.; Marzinzik,
A. L.; Ley, S. V.; Baxendale, I. R. Org. Lett. 2011, 13, 320. Diazo-methane:
(d) Struempel, M.; Ondruschka, B.; Daute, R.; Stark, A. Green Chem. 2008,
10, 41. Aromatic nitration: (e) Kulkami, A. A.; Kalyani, V. S.; Joshi, R. A.;
Joshi, R. R. Org. Process Res. Dev. 2009, 13, 999.
(3) For an excellent discussion, see: Smit, C.; Fraaije, M. W.; Minnaard,
A. J. J. Org. Chem. 2008, 73, 9482.
r
10.1021/ol400051n
Published on Web 01/22/2013
2013 American Chemical Society

time.4 Thus, safety concerns regarding pressure build-up
from nitrogen gas generation at elevated temperatures
would be mitigated by this approach.
With an initial set of reaction parameters in hand, we
commenced our studies in a continuous flow reactor
(Figure 1). The small-footprint setup (60 cm  60 cm)
conveniently fits inside a standard fume hood and consists
of (a) the reagent solutions, (b) two syringe pumps, (c) a
T-shaped mixer (i.d. = 500 μm), (d) a perfluoroalkoxy
(PFA) tubing reactor (i.d. = 750 or 1,000 μm), (e) a back
pressure regulator (bpr, 40 or 100 psi), and (f) the sample
collection flask.11 Elevated temperatures are conveniently
(and safely) achieved with a standard oil bath, and hydrox-
ylamine solutions are prepared directly from commercially
available 50% aqueous solutions. For ease of setup we
typically execute this reaction employing a two-pump
setup with a T-mixer,14 necessitating that the substrate be
premixed with either hydroxylamine or 2. (Both are
equally effective; vide infra.)
During the course of the reaction, nitrogen gas is gen-
erated and a gasÀliquid segmented flow is observed. This
byproduct formation necessitates employing the back-
pressure regulator to not only mitigate unsafe pressure
buildup but also maintain a uniform flow rate throughout
the system. Ultimately, the gas generation may in fact be
advantageous to the overall efficinecy of the reaction
through increased mixing efficiency as a result of the
segmented flow.15
Of the reported conditions for diimide generation, we
considered several, including acid-promoted decarboxyla-
tion of potassium diazodicarboxylate5 and treatment of
sulfonylhydrazines with base.6 Ultimately, inconsistent re-
sults, largely due to low solubility and heterogeneity,
prompted us to design a new reagent combination. Inspired
by diimide formation via elimination of water from
hydrazine oxide 4 (Scheme 1, step C),7 we reasoned that
electrophilic amination of hydroxylamine would provide
a safe, metal-free, alternative to classical hydrazine
oxidation.8 Namely, with an appropriatereagent, selective
O-functionalization (e.g., trifluoroacetylation, Scheme 1,
step A) of hydroxylamine would generate an electrophilic
nitrogen source in the form of an O-trifluoroacetylhy-
droxylamine (3).9 Amination of a second equivalent of
hydroxylamine by 3 (step B) would then form 4.
Paramount to the success ofthis approach was discovery
of a reagent selective for O-functionalization of hy-
droxylamine. Jencks assayed the N- versus O-selectivity
of various acyl electrophiles, finding nearly exclusive
O-acylation with N,O-diacetylhydroxylamine.10 We thus
evaluated a collection of related derivatives for alkene
reduction and identified N,O-bistrifluoroacetylhydroxyla-
mine (2) as the most efficient.11 Originally developed for
conversion of aldehydes to nitriles,12 2 is a stable, commer-
cially available reagent.13 Preliminary studies revealed
1.5 equiv of 2 in 1,4-dioxane with 5 equiv of hydroxylamine
to be sufficient for further reaction development. Of parti-
cular note is the importance of solvent in this reaction; high
solubility of hydroxylamine is necessary, and therefore,
hydrogen bond acceptors were found to be the most
effective solvents.
Hydrogenation of cyclooctene was used for comparison
of conditions (Table 1). The reaction was found to be
sensitive to both residence time (tR) and temperature
(entries 1À4). The optimal conditions were determined to
be heating at 100 °C with a tR of 20 min (entry 5).
Table 1. Continuous Flow Temperature and tR Optimization
entry
temp (°C)
tR (min)
yield (%)a
1
2
3
4
5
80
80
90
90
100
20
30
20
10
20
72
86
92
69
98
a GC yield.
(8) For classical hydrazine oxidation methods, see: (a) Aylward, F.;
Sawistowska, M. Chem. Ind. 1962, 484. (b) Lamani, M.; Ravikumara,
G. S.; Prabhu, K. R. Adv. Synth. Catal. 2012, 354, 1437. For recent use
of flavins for hydrazine oxidation, see: (c) Imada, Y.; Iida, H.; Naota, T.
J. Am. Chem. Soc. 2005, 127, 14544. (d) Smit, C.; Fraaije, M. W.;
Minnaard, A. J. J. Org. Chem. 2008, 73, 9482. (e) Imada, Y.; Kitagawa,
T.; Ohno, T.; Iida, H.; Naota, T. Org. Lett. 2010, 12, 32. (f) Imada, Y.;
Iida, H.; Kitagawa, T.; Naota, T. Chem.;Eur. J. 2011, 17, 5908. (g)
Marsh, B. J.; Heath, E. L.; Carbery, D. R. Chem. Commun. 2011, 47, 280.
(h) Teichert, J. F.; den Hartog, T.; Hanstein, M.; Smit, C.; ter Horst, B.;
Hernandez-Olmos, V.; Feringa, B. L.; Minnaard, A. J. ACS Catal. 2011,
1, 309.
Figure 1. Reaction setup: (a) reagent solutions; (b) syringe
pumps; (c) T-shaped mixer (i.d. = 500 μm); (d) PFA tubing
reactor (i.d. = 760 or 1,000 μm); (e) bpr (40 or 100 psi); (f)
sample collection flask.
(5) Hamersma, J. W.; Snyder, E. I. J. Org. Chem. 1965, 30, 3985.
(6) (a) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2002, 4, 1771. (b)
Marsh, B. J.; Carbery, D. R. J. Org. Chem. 2009, 74, 3186.
€
(7) Durckheimer, W. Liebigs Ann. Chem. 1969, 721, 240.
(9) Wade, P. A.; Amin, N. V. Synth. Commun. 1982, 12, 287.
Org. Lett., Vol. 15, No. 3, 2013
711

group (entry 1) and polymerizable styrenes (entry 4), are
tolerated. The benzoyl (entry 2), benzyl (entries 3 and 9),
and silicon-containing TBDPS (entry 7) protecting groups
are stable under the reaction conditions. This method is
suitable for the hydrogenation of 1,1-disubstituted alkenes
(entry 7) and 1,2-disubstituted alkenes (entries 5, 6, and 8),
although these substrates do require heating at 140 °C to
achieve complete conversion. Doubling the stoichiometry
of 2 and hydroxylamine employed enabled the reduction of
terminal alkynes (entry 9). Internal alkynes suffered from
incomplete conversion and product mixtures. Further sub-
strate limitations include aldehydes, as condensation with
hydroxylamine and/or 2 is a competing process.
Table 2. Substrate Scope
For substrates that may react with hydroxylamine in the
stocksolution, the substrate waspremixed with2 (Table3).
This setup enabled the selective reduction of the alkene of
m-nitrostryene (entry 1). Additionally, alkenes of R,β-
unsaturated esters and amides (entries 2 and 3, respec-
tively) were efficiently reduced with no observed formation
of the corresponding hydroxamic acids. It should be noted
that in nearly all cases the products were of high purity
(>95%) upon simple aqueous workup and generally did
not require additional purification.
Table 3. Functional Group Compatibility
a Isolated yield. b GC yield. c NH2OH, 10 equiv; 2, 3.0 equiv.
We found these conditions to be suitable for the hydro-
genation of a variety ofalkenes inthe presence of a range of
functional groups. The saturated products were generally
afforded in good to excellent yield (Table 2). Although an
equivalent of TFA is formed in the reaction (see Scheme 1),
acid-sensitive functional groups, including the Boc protecting
a Isolated yield.
(10) Jencks, W. P. J. Am. Chem. Soc. 1958, 80, 4581. (b) Jencks, W. P.
J. Am. Chem. Soc. 1958, 80, 4585.
(11) Please see Supporting Information for details.
(12) Pomeroy, J. H.; Craig, C. A. J. Am. Chem. Soc. 1959, 81, 6340.
(13) 2 is readily, and cheaply, prepared on multigram scale as out-
lined in ref 12.
(14) A three-pump setup employing a cross mixer could also be
employed; for simplicity we preferred the two-pump setup described.
Another feature of this reaction is that it is readily
modified for site-specific deuterium incorporation. Em-
ploying hydroxylamine-d3 (90% deuterium) and 2 in the
€
(15) (a) Gunther, A.; Jhunjhunwala, M.; Thalmann, M.; Schmidt,
€
A.; Schmidt, M. A.; Jensen, K. A.; Bawendi, M. G. Angew. Chem., Int.
Ed. 2005, 44, 5447.
M. A.; Jensen, K. F. Langmuir 2005, 21, 1547. (b) Yen, B. K.; Gunther,
(16) (a) Corey, E. J.; Pasto, D. J.; Mock, W. L. J. Am. Chem. Soc.
1961, 83, 2957. (b) Berson, J. A.; Poonian, M. S. J. Am. Chem. Soc. 1966,
88, 170.
712
Org. Lett., Vol. 15, No. 3, 2013

reduction of tert-butylstyrene 11 (Scheme 2) afforded 29 in
92% yield with 90% deuterium incorporation (as deter-
mined by 1H NMR). This method is complementary to pre-
vious reports of diimide mediate deuterium incorporation.16
no specialized equipment and is safely operated at elevated
temperatures. A range of substrates are reduced using a
20-min residence time, and products are generally isolated with
high purity upon simple aqueous workup. Finally, employing
hydroxylamine-d3 enables deuterium incorporation and,
by extension, incorporation of the radioactive isotope
tritium.
Scheme 2. D2-Incorporation
Acknowledgment. We thank Novartis for its generous
financial support of the Novartis-MIT Center for Contin-
uous Manufacturing (CCM). Dr. Jennifer Kozak, Dr.
Yuan Zhang, and Dr. James Mousseau (MIT) are ac-
knowledged for helpful and stimulating discussions. Eric
Standley and Li Li (MIT) are thanked for HRMS data.
Supporting Information Available. Experimental pro-
cedures, experimental setups, analytical characterization
data, and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed the first H2-free con-
tinuous flow hydrogenation protocol. This reaction pro-
ceeds via diimide generated from the reaction of hydroxyl-
amine with N,O-bistrifluoroacetylhydroxylamine 2 and
without added transition metal. The flow setup requires
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
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